Montreal – Canada - International Cartilage Repair Society

2012
Montreal – Canada
May 12 – 15, 2012
10 th World Congress of the International Cartilage Repair Society
Main Programme & Extended Abstracts
www.cartilage.org
P l a t i n u m S p o n s o r s :
Please join us for the
Sponsored Symposium
“The Evolution of Autologous Chondrocyte
Implantation and Cartilage Repair”
Description: In this cartilage repair symposium, participants
will learn about the genesis of autologous chondrocyte
implantation, the importance of the chondrocyte and how
the standards of clinical evidence, global regulation and
manufacturing have evolved in this dynamic and exciting field
Date: Monday, May 14th
Time: 13:00 - 14:00
Location: Grand Salon
For more information please visit us at booth #6.

Chondro-Gide ® is not available in all markets. Availability is subject to
the regulatory or medical practices that govern individual markets.
www.geistlich-surgery.com
Chondro-Gide ®
enhanced marrow
stimulation – also for ankle and hip?
AMIC ® – A promising approach in cartilage regeneration
ICRS 2012, Montreal
Satellite Symposium
Sunday, 13 May 2012 – 13:00 until 14:00
Chairman: Markus Walther, Munich, Germany
Blood clot biology after marrow stimulation
Caroline Hoemann, Canada
AMIC ® Talus – Surgical technique and first clinical results
Markus Walther, Germany
AMIC ® Hip – Surgical approach and 5-year clinical outcome
Andrea Fontana, Italy
Meet the Expert
Geistlich Surgery, booth Nr. 8
Sunday, 13 May, 10:45–11:15 AMIC ® Talus, Markus Walther
Sunday, 13 May, 15:15–15:45 AMIC ® Talus, Martin Wiewiorski
Monday, 14 May, 10:45–11:15 AMIC ® Hip, Andrea Fontana
Monday, 14 May, 15:15–15:45 AMIC ® Knee Arthroscopic,
Thomasz Piontek
Geistlich Pharma AG
Business Unit Surgery
Bahnhofstrasse 40
CH–6110 Wolhusen

10 th World Congress of the
International Cartilage Repair Society
ICRS 2012
May 12 – 15, 2012
Montreal / Quebec, Canada
“Advancing science & education in cartilage repair worldwide!”
Main Programme & Extended Abstracts
Editorial Office:
Cartilage Executive Office GmbH – Wetzikon – Switzerland
www.cartilage.org
Copyright: International Cartilage Repair Society – ICRS 2012
Cover acknowledgment:
Images kindly provided by Tourism Montreal Programme Price: ! 15.00
ICRS does not accept responsibility for errors or misprints

Knee Repair Solutions
Save the menicus.
Preserve the cartilage.
Lunchtime Symposium at ICRS 2012
Sunday, 13 May, 2012
13:00 – 14:00
Grand Salon
Smith & Nephew, Inc.
Andover, MA 01810
USA
From Simple to Complex Meniscal Injury –
How and When to Resect, Repair and Replace
Faculty:
Tim Spalding, MD, UK
• Anatomy of Meniscus
• When to Repair/Resect
• How I Repair
• My Experiences
• Case Studies
T +1 978 749 1000
www.smith-nephew.com
Visit us at
booth #4
Peter Verdonk, MD, Belgium
• Repairs using Allograft, Scaffolds
• When to Repair
• How I Repair
• My Experiences
• Case Studies
Trademark of Smith & Nephew. Registered US Patent
and Trademark Office. ©2012 Smith & Nephew. All
rights reserved. Printed in USA. 03/12 2909 Rev. A

Zimmer Biologics
innovative solutions for joint preservation
We invite you to join us at the ICRS Zimmer Symposium:
“Innovative Solutions for Joint Preservation
with DeNovo ® NT Natural Tissue Graft and
Chondrofix ® Osteochondral Allograft”
Speakers:
David Caborn, M.D.
Jack Farr, M.D.
Eric Giza, M.D.
Norman Marcus, M.D.
Date: May 14, 2012
Time: 1:00 - 2:00pm EST
Location: Marquette
Visit us at www.zimmer.com or
Call us at 1-800-348-2759
©2012 Zimmer, Inc. All Rights Reserved

“ChondroCelect: When evidence
makes a difference”
TiGenix NV
Researchpark Haasrode 1724
Romeinse straat 12 bus 2, 3001 Leuven
Belgium
Phone +32 (0) 16 39 60 66
Fax +32 (0) 16 39 79 70
info@tigenix.com
www.tigenix.com
Prof Fredrik Almqvist, University of Ghent, Belgium
Visit us
at booth
# 1
ChondroCelect ® is a medicinal product EU/1/09/563/001
For more information on ChondroCelect please read the prescribing information at booth # 1.
TiGenix Satellite Symposium
at ICRS 2012
Monday, 14 May at 13:00
Meeting Room Jolliet

Healthcare
knowledge action care
BST-CarGel ® :
A Novel Bioscaffold for
Enhanced Tissue Regeneration
in Cartilage Repair Procedures
Satellite Lunch Symposium
Sunday, May 13 2012,
from 1:00 pm – 2:00 pm
Presentations
• Underlying Principles of Enhancing
Bone Marrow Stimulation with BST-CarGel ®
• MRI-based Imaging Biomarkers for Cartilage
• Final Outcomes from the BST-CarGel ®
Randomized Clinical Trial
Faculty
Co-chairs:
• Pierre Ranger, MD
• Matthias Steinwachs, MD
Speakers:
• Timothy Mosher, MD
• Matthew Shive, PhD
• William Stanish, MD
Booth #7 : Piramal Bio-Orthopaedics
Visit our booth and discover BST-CarGel ® .
You will have the chance to
meet the Investigators
and learn how
you could be involved in an international
Center of Excellence training program.
Piramal Bio-Orthopaedics
Bringing international innovations to the world.

Cartilage Repair - “A Merging of Basic
Research and Clinical Applications”
ICRS is a unique forum for international collaboration in cartilaginous
tissue research by bringing together clinicians, clinical researchers
and basic scientists, engaged or interested in the field of cartilage biology,
imaging, cartilaginous tissue engineering and translational clinical approaches to
treatment of cartilage pathologies. The link between laboratory work and the daily
treatments of patients in a clinical setting is extremely important to the Society.
The Society envisages the scientific research and the exchange of knowledge among
physicians, scientists & patients of the industry in the field of cartilage repair. To serve
its purpose, the society organizes international congresses and events, publishes
journals and provides a universal internet discussion-platform. Furthermore the
society provides an outstanding scientific database, financially supports research
projects and pays for scholarships / fellowships which are available for members only.
Join ICRS Now!
Benefits for ICRS Members
• 2 Issues of the ICRS Newsletter
• 4 Issues of the new official ICRS Journal
Cartilage, published by SAGE
• 4 issues of the Musculoskeletal Report (US &
Europe reports)
• Highly reduced registration fees for to all ICRS
educational events
• Eligibility for ICRS Scholarships
• Eligibility for ICRS Travelling Fellowships
The Annual Membership Fees are:
Ordinary Members: € 135.00
Junior Members: € 70.00
Corporate Members: € 2300.00
• Reduced price of the ICRS database software
SOCRATES
• Access to the “Member Only” section of the
ICRS Website (incl. Membership Database and
access to the Cartilage Knowledge Database,
Electronic Posters, Abstracts and selected
Symposia presentations)
• Free advertising of your cartilage meeting
/ course in the ICRS Newsletter and online
event calendar
Join ICRS online at
www.cartilage.org
office@cartilage.org
HJ10010102_1108045

Programme Overview
Saturday, May 12
09:00 – 18:00
Registration
13:00 – 14:00 Plenary Session 1.0
Sports Injury: ICRS – FIFA Page 56
Room: Grand Salon
14:15 – 15:15 14:15 – 15:15 14:15 – 15:15
Session 2.1 Session 2.2 Session 2.3
Growth Nerve Femoropatellar
Factors Dependence Joint
Page 56 Page 56 Page 57
Room: Grand Salon Room: Marquette Room: Jolliet
15:15 – 15:45
Coffee Break/Industry Exhibition
15:45 – 16:45 15:45 – 16:45 15:45 – 16:45
Session 3.1 Session 3.2 Session 3.3
Opportunities Medication Meniscus
of Bioprinting and Cartilage
Page 57 Page 57 Page 58
Room: Jolliet Room: Marquette Room: St. François
17:00 – 17:45 Plenary Session 4.0
Opening Ceremony & Awards Session Page 58
Room: Grand Salon
17:45 – 18:45 Plenary Session 5.0
Honorary Lectures Page 58
Room: Grand Salon
19:00 – 20:30
Welcome Reception
Exhibition Hall
Sunday, May 13
07:30 – 08:15 07:30 – 08:15
Workshop 6.1 Workshop 6.2
Imaging of Meet the Experts
Cartilage Defects (Basic Scientists)
Page 59 Page 59
Room: Jolliet Room: Marquette
08:30 – 09:30 Plenary Session 7.0
Clinical Studies using Cartilage Fragements Page 59
Room: Grand Salon
09:45 – 10:45 09:45 – 10:45 09:45 – 10:45
Session 8.1 Session 8.2 Session 8.3
Cartilage Culture Intervertebral
Repair, Foot Techniques Disc
and Ankle
Page 59 Page 59 Page 60
Room: Marquette Room: Grand Salon Room: St. François
10:45 – 11:15
Coffee Break/Industry Exhibition
11:15 – 12:45 Free Paper Sessions
9.1 ISAKOS Symposium Page 60
Room: Grand Salon
9.2 Chondrocytes 1 Page 60
Room: Marquette
9.3 Biomaterials & Scaffolds 1 Page 61
Room: St. François
9.4 Other Musculoskeletal Tissues Page 62
Room: Jolliet
13:00 – 14:00 Industry Symposia
10.1 Geistlich Page 63
Room: Marquette
10.2 Smith & Nephew Page 63
Room: Grand Salon
10.3 Piramal Page 63
Room: Jolliet
10.4 Anika Page 64
Room: St. François
14:15 – 15:45 Free Paper Sessions
11.1 Animal Models Page 64
Room: Grand Salon
11.2 Chondrocytes 2 Page 65
Room: St. François
11.3 Biomaterials & Scaffolds 2 Page 66
Room: Marquette
11.4 Imaging Page 67
Room: Jolliet
15:45 – 17:00
General Assembly (For Members only)
15:45 – 18:00
Poster Viewing Cocktail
Rooms: Duluth/Richelieu
18:45 – 23:30 (Meeting point 06:30 Fairmont lobby)
Canadian Sugar Shack & Maple Forest Party
Room: Jolliet
7

Programme Overview
Monday, May 14
07:30 – 08:15 07:30 – 08:15
Workshop 13.1 Workshop 13.2
Rehabilitation after Meet the Experts
Cartilage Repair (Clinicians)
Page 68 Page 68
Room: Jolliet Room: Marquette
08:30 – 09:30 Plenary Session 14.0
Cell Free Approaches for Cartilage Repair Page 68
Room: Grand Salon
09:45 – 10:45 09:45 – 10:45 09:45 – 10:45
Session 15.1 Session 15.2 Session 15.3
Platelet Rich Development of Subchondral
Plasma and Joint new Biomaterials Bone & Cartilage
Tissue Repair & Scaffolds Repair
Page 68 Page 69 Page 69
Room: Grand Salon Room: Marquette Room: St. François
10:45 – 11:15
Coffee Break/Industry Exhibition
11:15 – 12:45 Free Paper Sessions
16.1 Osteoarthritis 1 Page 69
Room: St. François
16.2 Cartilage/Cell Transplantation Page 70
Room: Marquette
16.3 Microfracture/Bone Marrow Page 71
Room: Jolliet
16.4 Stem Cells 1 Page 72
Room: Grand Salon
13:00 – 14:00 Industry Symposia
17.1 Sanofi Page 73
Room: Grand Salon
17.2 Zimmer Page 73
Room: Marquette
17.3 Tigenix Page 73
Room: Jolliet
17.4 BioTissue Page 74
Room: St. François
14:15 – 17:15 Plenary Session 18.0
Stem Cells for Cartilage Repair Page 74
Room: Grand Salon
15:30 – 16:30 15:30 – 16:30 15:30 – 16:30
Session 19.1 Session 19.2 Session 19.3
Imaging YSOS Biomakers
Technologies Symposium
Tissue Repair
Page 74 Page 75 Page 75
Room: Marquette Room: Jolliet Room: Grand Salon
16:30 – 17:30
Poster Viewing/Coffee Break Page 82–99
Rooms: Duluth/Richelieu
17:30 – 18:30 17:30 – 18:30 17:30 – 18:30
Session 21.1 Session 21.2 Session 21.3
Joint Lubrication Rehabilitation Stryker Clinical
& Cartilage Health Scientist Progr.
Page 75 Page 76 Page 76
Room: Grand Salon Room: Marquette Room: Jolliet
Tuesday, May 15
08:30 – 09:30 Plenary Session 22.0
Biomechanics & Stability of Cartilage Repair Page 77
Room: Grand Salon
09:30 – 10:00 Plenary Session 23.0
Strategic Outlines ICRS Page 77
Room: Grand Salon
10:00 – 10:30
Coffee Break/Industry Exhibition
10:30 – 11:30 10:30 – 11:30 10:30 – 11:30
Session 24.1 Session 24.2 Session 24.3
Cartilage Animal Distraction
Repair in Models Arthroplasty
the Hip Joint
Page 77 Page 77 Page 78
Room: Marquette Room: Grand Salon Room: Jolliet
11:30 – 13:00 Free Paper Sessions
25.1 Osteoarthritis 2 Page 78
Room: St. François
25.2 Cartilage / Cell Transplantation Page 79
Room: Marquette
25.3 Rehabilitation Page 80
Room: Jolliet
25.4 Stem Cells 2 Page 81
Room: Grand Salon
13:00 – End of Meeting
8

Programme
at a glance
Please Fold out this
Page...
The ICRS would like to acknowledge the
following companies for their generous
support to the 10 th ICRS World Congress
in Montreal – Canada.
P l a t i n u m S p o n s o r s :
S i l v e r S p o n s o r :
9

10
I am pleased to extend my warmest greetings to everyone taking
part in the 10th World Congress of the International Cartilage Repair Society‐
ICRS 2012.
This convention offers a wonderful opportunity for scientists and
surgeons from more than 70 countries to gather with their peers to advance their
knowledge in cartilage biology and tissue engineering and to bring new hope and
treatments to patients affected by cartilage damage. I am certain that delegates
will make the most
I am
of
pleased
the scientific
to extend
presentations
my warmest
and
greetings
discussions
to everyone
taking
taking
place
part
here
in
in
the
Montréal,
10th World
as well
Congress
as the many
of the
informal
International
networking
Cartilage
opportunities
Repair Society‐
ICRS
provided
2012.
by the conference hosts.
This
I would
convention
like to commend
offers a wonderful
the organizers
opportunity
for their
for
efforts
scientists
to promote
and
surgeons
scientific
from
excellence
more than
in the
70
field
countries
through
to
research,
gather with
collaboration,
their peers
and
to advance
education.
their
knowledge in cartilage biology and tissue engineering and to bring new hope and
treatments to patients
On behalf
affected
of the
by
Government
cartilage damage.
of Canada,
I am
I
certain
wish you
that
all
delegates
an
will
informative
make the
and
most
productive
of the scientific
meeting.
presentations and discussions taking place
here in Montréal, as well as the many informal networking opportunities
provided by the conference hosts.
I would like to commend the organizers for their efforts to promote
scientific excellence in the field through research, collaboration, and education.
On behalf of the Government of Canada, I wish you all an
informative and productive meeting. The Rt. Hon. Stephen Harper, P.C., M.P.
OTTAWA
2012
OTTAWA
2012
The Rt. Hon. Stephen Harper, P.C., M.P.
10

Mot du premier ministre
Je suis heureux de souhaiter la bienvenue
à Montréal à tous celles et ceux que réunit
le World Congress of the International
Cartilage Repair Society.
Voilà pour chacun de vous une occasion
choisie de rencontrer des collègues des
quatre coins du monde et d’échanger avec
eux sur les dernières connaissances qui
marquent le développement de votre
spécialité médicale. En ce sens, je salue
votre participation à ce grand rendez-vous
qui contribue directement à l’amélioration
continue des soins et de la santé publique.
Félicitations aux organisateurs de ce
congrès dont on célèbre cette année la
10 e édition, et bravo aux gens de
l’International Cartilage Repair Society qui
soutiennent sans relâche l’avancement de
la science et de la recherche.
Bon congrès à tous,
A Word from the Premier
Welcome to Montréal for the World
Congress of the International Cartilage
Repair Society.
What an ideal opportunity to meet
colleagues from around the world and
discuss the latest developments in your
medical specialty. I salute you for
attending this major gathering that
contributes directly to the continuous
improvement of healthcare and public
health.
Congratulations to the organizers of this
10th edition of the congress and bravo to
the International Cartilage Repair Society
that tirelessly supports the advancement
of science and research.
Best wishes to all for a constructive
congress.
Jean Charest
11

Submit your manuscript
Editor-in-Chief:
Roy D. Altman, M.D.
http://cart.sagepub.com
Pick up
your free
copy at
the SAGE
booth!
Cartilage publishes articles related to the musculoskeletal system with particular attention to
cartilage repair, development, function, degeneration, transplantation and rehabilitation. The
journal is a forum for the exchange of ideas for the many types of researchers and clinicians
involved in cartilage biology and repair. A primary objective of Cartilage is to foster the crossfertilization
of the fi ndings between clinical and basic sciences throughout the various disciplines
involved in cartilage repair.
The journal publishes full length original manuscripts on all types of cartilage including articular,
nasal, auricular, tracheal/bronchial and intervertebral disc fi brocartilage. Manuscripts on clinical
and laboratory research are welcome. Review articles, editorials and letters are also encouraged.
Cartilage is a forum for the exchange of knowledge among clinicians, scientists, patients and
researchers.
Instructions to authors and directions for submissions will be available at http://cart.sagepub.com.
Manuscripts can be submitted at http://mc.manuscriptcentral.com/cart.
The International Cartilage Repair Society (ICRS) is dedicated to promotion, encouragement and
distribution of fundamental and applied research of cartilage in order to permit a better knowledge
of function and dysfunction of articular cartilage and its repair (www.cartilage.org).
Cartilage is published by SAGE on behalf of the ICRS.

Dear ICRS Members, Colleagues and Friends
The 2012 ICRS Programme Committee is committed in
providing our membership, friends and industry partners,
new and exciting developments in clinical and preclinical
applications to the repair and regeneration of cartilage
and related musculoskeletal injuries. Our overall
goal for this meeting was to broaden the scope of presentations
provided at our world congress and to promote
better interdisciplinary education and understanding
between the clinical and pre-clinical scientists.
From the clinical perspective the programme will present
new surgical procedures used for cartilage repair, including
the use of new biomaterials and bioengineering
technologies. Moreover, the programme presents the
best available evidence for routinely accepted procedures,
as well. The Programme Committee has also introduced
some new sessions including the femoropatellar
joint, medication & cartilage, follow up assessment of
clinical cases, platelet rich plasma, joint tissue repair –
facts – the hope, hype and reality as well as another session
on cell free approaches for cartilage repair.
From the basic science (pre-clinical) perspective important
research areas of biomarkers, proteomics and
genomics as well as new imaging technologies will be
approached. New sessions of interest include nerve de-
In Strategic collaboration with:
pendence on cartilage development, the use of bioprinting
in cartilage regeneration, evaluation of cellular therapies
from chondrocytes to stem cells as well as genetic
influences on cartilage repair. In addition, there will be
a dedicated special session on the intervertebral disc
(brought back by popular demand!) and also a special
session on subchondral bone and its relevance with repair
and osteoarthritis.
We hope you enjoy both, the quality of the presented
science and the great opportunity for networking and social
interactions with participants from all over the world.
Sign-up for the “Fun Run for Healthy Joints” or for the
exciting “Canadian Sugar Shack & Maple Forest Party”,
both events hold on Sunday, May 13.
Sincerely,
Jos Malda and Wayne McIlwraith
Scientific Programme Chairmen 2012
Michael Buschmann and Patrick Lavigne
Congress Co-Chairmen 2012
13
Michael Buschmann
Patrick Lavigne
Wayne McIlwraith
Jos Malda

14
Past World Congresses, Presidents and Award Winners
Past World Congresses
1997 – 1st World Congress
Freiburg, Switzerland; Roland Jakob
1998 – 2nd World Congress
Boston, USA; Alan Grodzinsky
2000 – 3th World Congress
Gothenburg, Sweden; Lars Peterson
2002 – 4th World Congress
Toronto, Canada; Shawn O’Driscoll
2004 – 5th World Congress
Gent, Belgium; Rene Verdonk
2006 – 6th World Congress
San Diego, USA; Bert Mandelbaum, Bill Bugbee
2007 – 7th World Congress
Warsaw, Poland; Jaroslaw Deszczynski,
Jacek Kruczynski, Konrad Slynarski
2009 – 8th World Congress
Miami, USA; Jack Farr, Tom Minas
2010 – 9th World Congress
Sitges / Barcelona, Spain; Ramon Cugat, Pedro Guillen
Past Presidents
1997 Roland Jacob, Switzerland
1998 Roland Jacob, Switzerland
1999 Alan Grodzinsky, USA
2000 Lars Peterson, Sweden
2001 Lars Peterson, Sweden
2002 Shawn O’Driscoll, USA
2003 Shawn O’Driscoll, USA
2004 Ernst Hunziker, Switzerland
2005 Ernst Hunziker, Switzerland
2006 Mats Brittberg, Sweden
2007 Mats Brittberg, Sweden
2008 Bert Mandelbaum, USA
2009 Lisa Fortier, USA
2010 Lisa Fortier, USA
2011 Daniël Saris, NL
2012 Daniël Saris, NL (current)
Honorary Fellows
2007 Alan Grodzinski, USA
2007 Roland Jakob, Switzerland
2007 Lars Peterson, Sweden
2009 Mats Brittberg, Sweden
2012 Tom Minas, USA
2012 Stefan Nehrer, Austria
Award Winners
Genzyme – ICRS Award for Excellence in
Cartilage Research
2004 Ronald Dorotka et al, Austria
2006 Mark Randolph et al, United Kingdom
2007 Gerjo Van Osch et al, The Netherlands
2009 Avner Yayon et al, Israel
2010 Attila Aszody et al, Germany
Genzyme – ICRS Lifetime Award
2004 Lars Peterson, Sweden
2006 Allan Gross, Canada
2007 Arnold Caplan, USA
2009 Richard Steadman, USA
2010 Mats Brittberg, Sweden
Best Rated Abstracts
2007 K. Nakagawa et al, Japan
2007 C. Moser et al, Germany
2009 J.F. Harrington et al, USA
2010 S. D’Arcy et al, Ireland
2012 G. Van Den Akker, NL

Table of Contents
Programme at a Glance (Fold-out) 8–9
Welcome messages 10–13
Past Meetings, Presidents & Award Winners 14
ICRS Society- and Meeting Committees 16
General Information 17–22
Hotel, Travel & Social Event Information 23–26
Invited Faculty Members 27–45
Exhibitor's Guide, Exhibition Plan & Sponsor List 46–54
Scientific Programme / Agenda 56–81
Poster Sessions 82–99
Extended Abstracts 102–181
“Advancing science & education in cartilage repair worldwide!”
15

16
ICRS Society- and Meeting Committees
ICRS Executive Board
President:
Daniël Saris, Utrecht, The Netherlands
Past-President:
Lisa Fortier, Ithaca, USA
Vice-President:
Anthony Hollander, Bristol, UK
Secretary General:
Norimasa Nakamura, Osaka, JP
Treasurer:
Susan Chubinskaya, Chicago, USA
ICRS General Board
Altman Roy, Los Angeles, USA
Buschmann Michael, Montreal, CA
Chubinskaya Susan, Harrison, USA
Erggelet Christopher, Zurich, CH
Fortier Lisa, Ithaca, USA
Hollander Anthony, Bristol, UK
Kon Elizaveta, Bolgna, Italy
Malda Jos, Utrecht, NL
Marlovits Stefan, Vienna, AT
McIlwraith Wayne, Fort Collins, USA
Minas Tom, Chestnut Hill, USA
Nakamura Norimasa, Suita, Japan
Nehrer Stefan, Krems, AT
Peterson Lars, Västra Frölunda, SE
Daniël Saris, Utrecht, NL
Van Osch Gerjo, Rotterdam, NL
Kennneth Zaslav, Richmond, USA
Invited Faculty Members
Please find the “who is who” of our distinguished invited
faculty members on pages 27 to 45.
(Only invited faculty members, who have sent us their
biosketch and portrait pictures by March 20, could be
included in this book and therefore it does not represent
an exhaustive listing.)
Scientific Programme Committee
Co-Chairmen:
Malda Jos, Utrecht, NL
McIlwraith Wayne, Fort Collins, USA
Members:
Caterson Bruce, Cardiff, Wales UK
Erggelet Chris, Zurich, CH
Kafienah Wael, Bristol, UK
Jurvelin Jukka, Kuopio, FI
Richardson James, Oswestry, UK
Ferretti Mario, São Paulo, BR
Educational Committee
Co-Chairmen:
Stefan Nehrer, Krems, Austria
Tom Minas, Chstnut Hill, USA
Members:
Alberto Gobbi, Milano, Italy
Görtz Simon, La Jolla, USA
Nesic Dobrila, Bern, CH
Polacek Martin, Tromso, NO
Slynarsky Konrad, Warsaw, PL
Tratttnig Siegfried, Vienna, AT
Local Organising Committee
Congress Co-Chairmen:
Buschmann Michael, Montreal, CA
Lavigne Patrick, Montreal, CA
Members:
Gross Alan, Toronto, CA
Hoemann Caroline, Montreal, CA
Hurtig Mark, Guelph, CA
Kandel Rita, Toronto, CA
Mc Cormack Robert, Vancouver, CA
Morelli Moreno, Montreal, CA
Poole Robin, Montreal, CA
Stanish William, CA

General Information
Venue
Fairmont – The Queen Elizabeth Hotel
900 Rene-Levesque West
Montréal (Québec) H3B 4A5
Phone: +1 514 861-3511
Fax: +1 514 954-2256
www.fairmont.com/queenelizabeth
queenelizabeth.hotel@fairmont.com
Organizing Office
Cartilage Executive Office GmbH
Mr. Stephan Seiler
Spitalstrasse 190, House 3
8623 Wetzikon, Switzerland
Phone +41 44 503 73 70
Fax +41 44 503 73 72
office@cartilage.org
Congress Dates
Start: Saturday, May 12 at 13.00
End: Tuesday, May 15 at 13.00
Language
The official language of the congress is English.
No simultaneous translation will be provided.
Congress Registration
Pre-Registration
Until April 30, only internet online registrations are accepted
at www.cartilage.org. After that date, only onsite
registration at the Hotel Fairmont congress registration
desk will be possible.
On-Site Registration
The registration desks are located in the mezzanine of
the Fairmont conference centre.
Congress Registration Fees
Early, until February 29
ICRS Members $ 390.00
Non-Members $ 550.00
Industry Representatives $ 650.00
Junior-Members/Residents/Nurses* $ 290.00*
Acc. Persons** $ 90.00**
Late, March 1 to April 10
ICRS Members $ 490.00
Non-Members $ 650.00
Industry Representatives $ 750.00
Junior-Members/Residents/Nurses* $ 390.00*
Acc. Persons** $ 100.00**
On-Site, as from April 11
ICRS Members $ 550.00
Non-Members $ 690.00
Industry Representatives $ 850.00
Junior-Members/Residents/Nurses* $ 450.00*
Acc. Persons** $ 110.00**
* to be accompanied by a certificate signed by the head
of department, if not a Junior Member of ICRS
** accompanying persons do not have access to attend
scientific sessions but can visit the industry exhibition
and are cordially invited to attend the Welcome
Reception, Coffee Breaks and the Opening & Closing
ceremonies
Attention: ICRS-Members who are not in good standing
with their membership dues 2011/2012 will automatically
be charged with the non-member fee by the registration
system.
Payment – Registration Fees
Registration fees must be paid to ICRS within 10 days after
the date of registration or latest until the end of the
registration period of the respective fee type. Payments
can be made as follows:
By Bank remittance to
Berner Kantonalbank (BEKB)
CH-3001 Bern, Switzerland
Clearing-No: 790
BIC/SWIFT Code: KBBECH22
Konto-Nr.: 16 246244671
IBAN: CH97 0079 0016 2462 4467 1
By Credit Card
VISA, Euro/Mastercard and American Express
Cash (onsite)
CAD$, US$ & Euros are accepted
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18
General Information
Regular Registration Fee includes
- Access to all Scientific Sessions
(except Workshops)
- Access to the Technical Industry Exhibition
- Access to the Scientific Poster Exhibition
(Wine & Cheese)
- Welcome Reception
- Coffee Breaks
- Congress Bag with Main Programme
- Personal Badge and Certificate of Attendance
On-site Registration Desk Opening Hours
The secretarial office and the registration desk will be
open as follows:
Friday May 12 16.00 – 18.30
Saturday May 12 10.00 – 18.30
Sunday May 13 07.30 – 18.30
Monday May 14 07.30 – 18.30
Tuesday May 15 07.30 – 18.30
On-site Check-in Procedures
Delegates must personally check-in at the appropriate
registration desk at the main entrance with a valid ID. An
express lane for check-in of pre-registered and prepaid
delegates will be available.
Participants, who are not yet in possession of their badges
when leaving their home country, are requested to
bring the confirmation letter or a copy of the invoice with
them. This will facilitate an efficient congress check-in.
Cancellations of Congress Registrations &
Name Changes
Written notification is required for all registration cancellations
and name changes. Cancellation of registration
should be sent to the ICRS Congress Office in Zurich.
Name changes will be charged with € 100.00 each.
Refunds for registration cancellations
are as follows
80% for cancellations before February 20
50% for cancellations from February 21 to April 20
No refund can be made thereafter
In case of cancellation due to the rejection of abstracts
or refuse of entry visa to Canada, the full amount of the
registration fee will be refunded.
Cancellation of the Congress
by the Organizer
In case of cancellation of the congress by the organizer,
congress fees will be refunded in case of cancellation
due to other reasons than war, war-like events, acts of
terrorism or epidemics, in which case only a proportional
part would be refundable.
Badges
After successful registration and payment of your registration,
your personal congress badge and further information
will be sent to the address (in Europe only),
indicated on the online registration form (registrations
received/paid by March 30). All participants, registered
after march 30, should pick-up their badges at the registration
desk. The personalized badge is not transferrable
and it is your admission card to the congress.
Badge Replacement: Please do not forget or lose your
badge. In case of loss, a replacement badge will only be
provided against an administrative charge of $ 50.00.
Security Checks
For organizational and security reasons, badges have to
be worn all the time at the congress venue. A lanyard will
be given to you with the congress bag. ID-checks may occur
at any time.
Final Programme
Participants will find a copy of the “Final Programme &
Abstract book” in the congress bags. The bags will be
handed out upon congress check-in. The congress abstracts
will be available well in advance of the congress
in a searchable database on our website as well as in pdf
format. New this year will be that congress abstracts and
the programme of interest can be downloaded to your
iPhones and/or to other mobile devices.
Additional copies may be purchased at the rate of
€ 15.00 per book, at the registration desk.

General Information
Speaker’s Ready Room / AV Centre
The Speaker Ready Room is located on Congress Level 1
at Room Saint Charles. All presentations must be in English
and must be provided on CD-ROM or USB-Memory
Stick to be placed on the central server on-site. It is mandatory
that the data carriers are delivered to the Speaker
Ready Room at least 3 hours prior to the respective session.
The computers in the server room are equipped with
Microsoft Windows 7 and Microsoft Office 2010. If you
use Macintosh, please convert your Keypoint presentation
or your PowerPoint Presentation for MAC into Power-
Point for PC Windows format. In case of using QuickTime
movies into you presentation, please take care to convert
the movies into a standard video codec like MPEG
2. If you have any doubt, please contact the AV Centre 4
hours before your presentation. Our technicians will have
enough time to verify and adapt your presentation if needed.
If you use Macintosh, please convert your Keypoint
presentation or your PowerPoint Presentation for MAC
into PowerPoint for PC Windows format. In case of using
QuickTime movies into you presentation please take care
to convert the movies into a standard video codec like
MPEG 2. If you have any doubt, please contact the AV
Centre 4 hours before your presentation. Our technicians
will have enough time to verify and adapt your presentation
if needed.
It will not be possible to use your own laptop or your memory
stick for your presentation in the session rooms.
If a presenter has included videos into the PPT presentations,
she/he should make sure that the movies run
on the most commonly used video software with Windows
compatible codec. Example: MPEG 2.
The material remains the property of the speakers and
will only be re-used by ICRS with the speaker’s permission.
Without this formal permission, your data will be
definitely deleted after the congress.
Opening hours Speaker’s Ready Room / AV Centre:
Friday May 11 16.00 – 18.30
Saturday May 12 08.00 – 18.30
Sunday May 13 07.00 – 18.30
Monday May 14 07.00 – 18.30
Tuesday May 15 07.00 – 14.00
Podium Presentations / Free Papers
Speaking Time: 7 Minutes
Discussion Time: 3 Minutes
It is absolutely necessary that all podium presenters respect
the given speaking time in order not to delay the
entire congress schedule. Session Moderators are instructed
to interrupt a presentation in case of exceeding
the speaking time of 7 Minutes.
Traditional Wall Poster Sessions
Sunday May 13 from 16.00 – 18.00 (Wine & Cheese)
Monday May 14 from 16.30 – 17.30 (Coffee Break)
In addition to the electronic poster exhibit, the authors where
asked to produce traditional paper posters by reserving
in advance a poster wall with ICRS. All congress participants
are strongly encouraged to join both poster sessions.
To facilitate discussions and networking, all wall poster
presenters are required to stay near their poster boards
during both poster sessions. Authors should encourage
a lively discussion with interested participants. The
presenters should introduce themselves as poster presenters
and be well prepared to answer questions and
initiate discussions.
The wall posters are located in rooms Duluth/ Mackenzie
& Richelieu/Peribonca/Bersimis at congress level 1 and
the electronic posters stations are located in Room Saint
Maurice. The abstracts of the posters can be found on
our website www.cartilage.org and in the electronic poster
viewing system onsite.
Electronic Poster Exhibition (EPOS)
(partly sponsored by Geistlich Surgery)
16 Workstations will be available for viewing about 250
electronic scientific exhibits.
The system offers great flexibility and provides enhanced
opportunities for communication. The ability to use moving
images, to link to related websites, to search quickly
the whole of the scientific exhibition for specific topics
in minute detail, to e-mail entire exhibits to one’s-self or
to a colleague and to access the exhibit from any internet-linked
computer in the world are amongst its many
advantages besides the post congress availability of the
presentations during many years.
Users have also the possibility to informally score/rate
the electronic posters by clicking on the “stars” in the system,
besides to bookmark important ones.
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20
General Information
Our onsite staff will be happy to introduce you to the
system and assist you during these hours.
E-Poster Certificates:
2 Awards “Magna cum Laude”
2 Awards “Cum Laude”
2 Awards “Certificate of Merit”
Publication – Supplement Journal “Cartilage”
Congress abstracts are citable and will be published
electronically in the congress supplement of our official
Journal “Cartilage”, published by Sage ISSN 1947-6043.
We furthermore encourage all authors to submit their
full manuscripts to our peer reviewed journal “Cartilage”
which publishes full length original manuscripts on
all types of cartilage including articular, nasal, auricular,
tracheal/bronchial, and intervertebral disc fibrocartilage.
Manuscripts on clinical and laboratory research are
welcome. Instructions to authors for submissions are
available at http://cart.sagepub.com
General Assembly / Business Meeting
(for members only)
Sunday, May 13, 2012, 15.45 – 17.00 - Room Jolliet
All ICRS members are kindly invited to attend our General
Assembly. Retired Members and Corporate Members
have no right to vote, but are most welcome to attend the
Business Meeting.
CME – Credits (22.25 Hours)
The ICRS 2012 – 10th World Congress of the International
Cartilage Repair Society is an Accredited Group Learning
Activity (Section 1) as defined by the Maintenance of Certification
programme of The Royal College of Physicians
and Surgeons of Canada, and approved by The Canadian
Orthopaedic Association. The ICRS 2012 is designated
for a maximum of 22.25 hours of Section 1 Credits. Live
educational activities, occurring in Canada, recognized
by the Royal College of Physicians and Surgeons of Canada
as Accredited Group Learning Activities (Section 1)
are deemed by the European Union of Medical Specialists
(EUMS) eligible for ECMEC credits but are they not
recognized by the American Medical Association AMA towards
the Physician’s Recognition Award (PRA).
Certificate of Attendance / CME Credits
To obtain your confirmation of attendance and your CME
Credits, you may choose one of two options
Print your certificate onsite at the Congress
Please use one of the dedicated workstations next to the
ICRS Registration Desk to print out your certificate. After
having identified yourself by means of your badge number
and your last name, the personalized certificate of
attendance will be printed automatically.
Print your certificate at your home
Upon your return from Canada, please visit www.cartilage.org.
After having identified yourself online by means
of your badge number and last name you can print-out at
home your personalized certificate of attendance.
Time Zone
Standard time zone daylight saving: UTC/GMT -4 hours.
Time zone abbreviation: EDT – Eastern Daylight Time
Language
The official congress language is English. No simultaneous
translation will be provided. French is Québec’s official
language but English is widely spoken in Montréal.
The city has more than 80 cultural groups and over 20%
of the population speaks three languages.
Climate
Spring climate in Montreal can be particularly pleasant,
with temperatures beginning to rise. Late May is a
popular time to visit the city, when temperatures averaging
around 18°C / 64°F but occasional snow flurries in
spring are not unknown.
Clothing
Warm & casual wear is recommended. Some Montreal
establishments (nightclubs and bars) have a 'no jeans,
no running shoes policy,' and certain dining rooms
require men to wear jackets to dinner.
Credit Cards / Cash Machines
All major credit cards are widely accepted. Bank cash machines
can be found everywhere and debit cards are also
widely used. If you are using a foreign card at a bank machine,
your money will be disbursed in Canadian funds.

General Information
Currency
The currency in Canada is the Canadian Dollar $ CAD.
1 € Euro ~ 1.30 $ CAD (Date of printing, March 2012)
Tipping
Tips or service charges are not usually added to a bill in
Canada. In general, a tip of up to 15% of the sub-total (before
taxes) is given. This applies to waiters, waitresses,
barbers and hairdressers, taxi drivers, etc. At hotels, airports
and railway stations, bellhops, doormen, porters,
etc. are generally paid $1 – $2 per item of luggage
Health Care
Vaccinations are not required for entry into Canada but
an individual travel- and health- insurance is highly recommended
because health insurance plans often do
not extend full coverage for medical services received
outside the country of residence.
Entry Formality / Visa
We strongly recommend that all participants needing a
visa to attend the Congress in Canada to start the application
process as soon as possible. We also advise contacting
the local Canadian Consulate before beginning
the process to obtain and follow all instructions. Most
consulates and embassies have web sites that can be
accessed through www.cic.gc.ca.
Currently, exempt from VISA requirement for tourist or
business travel to Canada include: citizens of Andorra,
Antigua and Barbuda, Australia, Austria, Bahamas,
Barbados, Belgium, Botswana, Brunei, Croatia, Cyprus,
Denmark, Estonia, Finland, France, Germany, Greece,
Hungary, Iceland, Ireland, Israel (National Passport holders
only), Italy, Japan, Korea (Republic of), Latvia (Republic
of), Lithuania, Liechtenstein, Luxembourg, Malta,
Monaco, Namibia, Netherlands, New Zealand, Norway,
Papua New Guinea, Poland, Portugal, St. Kitts and Nevis,
St. Lucia, St. Vincent, San Marino, Singapore, Slovakia,
Solomon Islands, Spain, Swaziland, Sweden, Slovenia,
Switzerland, United States, and Western Samoa. This information
may change without further notice.
Disclaimer
ICRS and the congress organizer cannot accept any liability
for the acts of any suppliers to this meeting nor the safety
of any attendee while in transit to or from this event.
All participants are strongly advised to carry proper travel
and health insurance as the ICRS cannot accept liability
for any accidents or injuries that may occur. The information
in this programme is subject to change without prior
notice. For updated information please visit frequently
our congress online programme on our website.
Cancellation of the Congress by the Organizer
Congress fees will be reimbursed if the congress is cancelled
for other reasons than war, warlike events, and acts
of terrorism or sickness epidemics. In the latter circumstances
only a proportion of the congress fee would be
refundable.
Technical Industry Exhibition
A technical industry exhibition with will take place at
the Fairmont convention centre. It will be open every
day throughout the meeting and exhibitors will present
a wide range of orthopaedic- and cartilage repair related
products. Participants are encouraged to take advantage
of this unique opportunity to be updated with the most
recent advances and latest news from our industry partners.
Interested companies may contact the ICRS Executive
Office for further exhibit- and sponsoring information.
Intermissions
During intermissions, coffee, tea and refreshments will
be served in the exhibition area as a courtesy from the
ICRS.
Services for Persons with Disabilities
Please inform the ICRS office or indicate on the accommodation
online booking form any special requirements
you may have to allow us to best serve you. The Fairmont
has international-standard facilities for the physically
challenged, including access ramps, elevators and toilets
for people with special needs.
Security / Badges
The safety of all congress attendees is of utmost importance
to our society. ICRS and the Fairmont have taken
security precautions to ensure the maximum possible
safety for all participants. Identity check controls may occur
at any time by the security staff. Congress badges are
personalized, not transferable and guarantee individual
access to different section of the event. For organizational
and security reasons, badges have to be worn all the
time at the congress venue.
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22
General Information
Electricity, Weights and Measures
• Electricity: 110 volts 60 hz (US Sockets)
• Weights: Kilo/Gramm system
• Measures: Metric system
Water
Canadian tap water is among the cleanest in the world
and is safe to drink.
Internet/WLAN
As a special courtesy, ICRS will provide free WLAN Hot
Spots and a public Internet corner to all attendees and
exhibitors.
Meals, Snacks & Refreshments
A Restaurant & Bar near the Hotel Lobby will be at
your disposal during the opening hours. Delegates
may purchase light meals, snacks, sandwiches, salads,
sweets and soft drinks against payment. No lunch or
lunch boxes will be provided by the ICRS. However, most
Industry Satellite Symposia organizers will offer exclusive
lunch boxes during their symposia at lunch time.
During morning intermissions, coffee, tea and refreshments
are served in the exhibition area. The coffee
breaks are offered by ICRS to all delegates and company
representatives.
Mobile Phones
Please turn off or put your mobile phone to the “silentmodus”
during all scientific sessions.
Photos/Recording
Taking pictures, video- or audio- recording during presentations
is not allowed.
Security
The safety of all congress attendees is of the utmost
importance to the ICRS meeting. The conference centre
and ICRS have taken security precautions to ensure the
maximum possible safety for all the participants. Identity
check controls may occur at any time.
Smoking
The ICRS World Congress is a non-smoking congress.
Smoking is not permitted at the conference centre except
in designated smoking areas outside of the building.
Opening Ceremony, ICRS Awards
Saturday May 12, 2012, 17.00 – 17.45
Room: Grand Salon
Awards
The following offical ICRS honors will be awarded:
• ICRS – Genzyme Lifetime Award
• ICRS – Genzyme Award for Excellence in Cartilage
Research (US$ 5000.00)
• 6 Electronic Poster Awards
• Best Rated Abstract

Hotel and Travel Information/Official Flight Carrier
Fairmont – The Queen Elizabeth Hotel
(Official Hotel & Congress Venue)
At the centre of Montréal's vibrant cultural and commercial
district sits the city's grandest and most gracious hotel
Fairmont - The Queen Elizabeth with 1037 comfortable
rooms and suites.
Located above the train station (Via Rail & AMTRAK) and
connected to the extensive underground city of thousands
of boutiques, restaurants and cafés, and within
walking distance of sports and cultural attractions, this
Montreal hotel reflects the city’s distinct elegance and
charm. The Fairmont comprises a skillfully integrated
Health Club featuring state-of-the-art equipment and an
indoor pool, as well as three distinctive restaurants to experience
Montréal's gastronomy at its best.
Special Courtesy
As a special courtesy, the hotel offers complimentary
health club access and free high speed internet access
in the hotel rooms. Children under 18 years, sharing the
room with their parents are free of charge. Each additional
adult beyond double room occupancy is charged
with only CAD$ 40.00.
Room Rates
(Breakfast & approx. 18% Taxes not included)
Fairmont Room: CAD$ 189.00 (Sgl/Dbl)
Moderate Room*: CAD$ 165.00 (Sgl/Dbl)*
Junior Suite: CAD$ 289.00 (Sgl/Dbl)
Fairmont Gold**: CAD$ 309.00**
* Moderate rooms available to students/residents
& physiotherapists only
** Business Club Floor, rate includes breakfast
Reservation Department
Fairmont – The Queen Elizabeth Hotel
c/o Ms. Mattea Savino
Phone: +1 514 861 3511, Extension: 2463
Email: mattea.savino@fairmont.com
Toll Free
U.S. & Canada: 1 (800) 257-7544
International: 800 441 1414
Travel and Transportation
The Montréal-Pierre Elliott Trudeau International Airport
(YUL) is only a 20 Minutes Taxi-drive away from the Hotel
Fairmont (14 Miles or 22 KM).
• Taxi: There is a flat rate of around CAD$ 40.00 to downtown
hotels. Arrangements for a private limousine transfer
can be made with through your hotel concierge upon
request.
• 747 Express Bus: Featuring nine stops in each direction,
the 747 service is provided 24 hours a day, 365 days a year
transportation between downtown Montréal (this bus stops
right in front of the Fairmont) and Montréal-Pierre Elliott
Trudeau International Airport. For more information visit
the STM website: www.stm.info/english/info/a-747.htm
Official Airline Network – Code AC04S12
SAVE UP TO 20% ON TRAVEL WITH THE STAR ALLIANCE
NETWORK
The Star Alliance member airlines are pleased to be
appointed as the Official Airline Network for ICRS 2012
Montreal, Canada.
To obtain the Star Alliance Conventions Plus discounts
and for booking office information please visit www.staralliance.com/conventionsplus
and:Choose “For delegates”
– Under “Delegates login” enter the conventions code
AC04S12. Choose one of the participating airlines listed
or call the respective reservation contact listed and quote
the conventions code AC04S12 when booking the ticket.
Registered participants plus one accompanying person
travelling to the event can qualify for a discount of up to
20%, depending on fare and class of travel booked.
The participating airlines for this event are: Adria Airways,
Aegean Airlines, Air Canada, Air China, ANA, Asiana
Airlines, Austrian Airlines, Blue1, bmi, Brussels Airlines,
Continental Airlines, Croatia Airlines, EgyptAir, LOT
Polish Airlines, Lufthansa, Scandinavian Airlines, Singapore
Airlines, South African Airways, Spanair, SWISS
International Air Lines, TAM Airlines, TAP Portugal, THAI,
Turkish Airlines, United, US Airways
Discounts are offered on most published business and
economy class fares, excluding website/internet fares,
senior and youth fares, group fares and Round the World
fares. Please note: For travel from Japan and New Zealand
special fares or discounts are offered by the participating
airlines on their own network.
23

As the official airline network for ICRS 2012, we’d like to
thank you for choosing the Star Alliance network and hope
that all goes really well for you here today.
Whilst you concentrate on the day’s events, we hope you’ll
consider us the next time you need to attend a conference.
With over 21,000 flights a day to 1,185 airports across 189 countries,
our 26 member airlines will extend a wide choice of flights to any
future conference you’re planning to attend. And no matter which
of those airlines’ frequent flyer programmes you belong to, you
can earn and redeem miles across all of them.
So the next time you want to concentrate all your energies
on your conference, we hope you’ll decide to leave the travel
arrangements to us.
www.staralliance.com
Information correct as at 02/2012

Social Events
Saturday, May 12
Welcome Reception
from 19.00 – 20.30
All participants, industry representatives and accompanying
persons are invited to join the opening ceremony
and welcome cocktail at the Fairmont exhibition area.
This reception is offered to you by the ICRS.
After the cocktail, participants have free time for their
own leisure to discover Montreal and enjoy one of the
many nice restaurants / bars that Montreal offers to you.
Sunday, May 13
2 nd ICRS Fun Run for Healthy Joints
from 06.15 – 07.00 AM
ICRS and the Fairmont understand that maintaining a
fitness routine while traveling is difficult. Congress participants
wanting to get off the treadmill and take their
workout outside can join the complimentary ICRS Fun
Run led by members of the ICRS & Fairmont management
teams. Runners meet at 6:00 A.M. in the Lobby for
a four-mile jog through Old Montreal, the Latin Quarter,
on Mount-Royal or along the Lachine Canal returning by
7:00 A.M.
Sunday, May 13
Canadian Sugar Shack & Maple Forest Party
from 19.30 – 23.00
We transport you back in time and provide you with a
momentary glimpse of life as it was hundreds of years
ago for Québec and Canadian pioneers. You will enjoy
Québec folkloric traditions in an authentic “Sugar
Shack” setting in a maple wood farm, known as a place
where Québec heritage is respected and relived through
fun and traditional activities. Discover Quebec folklore
and enjoy its traditional sugaring-off party in true family
style. Dine and let you be immersed in a magical and
unforgettable atmosphere together with your colleagues
from all around the world. Here, you can look forward to
delicious specialties, regional beverages and enjoy typical
music and cultural show acts.
Price per person:
Individual Participants: € 85.00
Industry Representatives: € 110.00
(incl. transport, dinner, drinks & entertainment)
Monday, May 14
Free evening for participants’ individual programmes
and for industry related events. The Hotel Concierge will
be pleased to recommend and book a table for you at one
of your favourite restaurants in town.
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Points of interest
Local Attractions, Sightseeing and things to do in Montreal….
The following attractions are only a small selection of
points of interest in Montreal and do not constitute a
recommendation by the ICRS. More information and
reservation for tours are available through the hotel concierge.
Botanical Garden and Insectarium
Montreal‘s Botanical Garden is the second largest botanical
garden in the world, next to the one in London,
England. It features species from all over the world:
plants, fountains, thematic greenhouses, butterflies. The
Insectarium is a section of the Botanical Gardens featuring
the butterfly pavilion, as well as a collection of 25,000
insects on display. The attraction is located 10 minutes
away from the Fairmont.
Bell Centre
The Bell Centre opened on March 16, 1996, and is the
home to the National Hockey League‘s Montreal Canadiens.
It is a five minute walk from the hotel Fairmont
The Queen Elizabeth. Hockey tickets can be purchased
directly through our concierge. Le Centre Bell also offers
guided tours.
Six Flag La Ronde Amusement Park
Six Flags La Ronde Amusement Park features 35 different
rides, something for every member of the family. The
park is located on Ile-Ste Hélène, about a 15 minute drive
from the Fairmont. It is also accessible via subway. It is
open from mid-May to September. For more information,
please call 1 800 797-4537 or 514 872-4537.
Montreal Casino
The Montreal Casino is one of the largest casinos in the
world! It captures all the excitement, all the drama, all
the international allure of the world class city that is its
home: Montréal. Likewise, the Casino spares no effort
to ensure you the thrill of a lifetime and unforgettable
memories.
Mount Royal
Mount Royal is a small mountain and park overlooking
the city, which offers great views from several scenic
points. Prominent in St. Joseph‘s Oratory, with its copper
dome surpassed in size only by St. Peter‘s in Rome.
Those who enjoy strolling in nature will appreciate Mount
Royal‘s many paths. Bird watching is possible at the bird
sanctuary. It is also the home of the University of Montreal,
the second largest French-language University in
the world.
Old Montreal
Discover the city‘s oldest district with its wealth of history
and architecture unique in North America, a variety of
museums, boutiques, art galleries and restaurants. Other
Montreal sightseeing opportunities and attractions in the
old port will please the whole family: IMAX (3-D movies
on a giant screen), bateau mouche cruises, and the site of
several summer and winter festivals. There‘s also the SOS
Labyrinth (Mayaventura) which is great for kids, cycling and
rollerblading. As well, don‘t miss the Lachine Canal with
its 8.7 miles (14 km) of recreational paths. Old Montreal is
located about five minutes from the Fairmont.
Olympic Stadium
Across the street from the Botanical Garden, the Olympic
Stadium is located about 15 minutes away from the Fairmont
and is easily accessible by subway. Visit the Montréal
Tower Observatory, located in the highest inclined
tower in the world, with its 175 metre elevation and
45-degree angle. Also on-site is the Biodôme, an oasis
in the heart of the city. The Montréal Biodôme recreates
some of the most beautiful ecosystems of the Americas.
A must-see!

Invited Faculty 2012 in alphabetical order (not complete)
Amendola Annunziato (Ned), Prof., MD
Orthopaedics and Rehabilitation,
University Iowa, USA
Annunziato (Ned) Amendola, MD, Professor
of orthopaedics and rehabilitation at the University of Iowa is
the director of the University of Iowa Sports Medicine program
and Head team physician. He currently holds the Kim and John
Callaghan Endowed Chair in sports medicine. He is internationally
recognized in sport related and reconstructive surgery
of the knee and ankle. His clinical research interests focus on
improving the understanding, prevention, treatment, and rehabilitation
of sports and activity-related injuries. His basic research
interests include articular cartilage biology and healing,
effects of unloading and joint resurfacing. Dr Amendola earned
his medical degree and completed his orthopaedic residency
at the University of Western Ontario in London, Ontario. Prior
to joining the University of Iowa in 2001, he was an associate
Professor and chief of orthopaedic surgery at the University of
Western Ontario University Hospital. Dr Amendola is a Diplomate
of the American Board of Orthopaedic Surgery, Fellow of
the Royal College of Surgeons of Canada, and Diplomate of the
Canadian Academy of Sports Medicine. He is an active member
of many orthopaedic and sports medicine organizations,
including Director on the American Academy of Orthopaedic
Surgeons, American Board of Orthopaedic Surgery, and Board
of Directors of American Orthopaedic Society for Sports Medicine
and ISAKOS. He is a past president of Canadian Academy of
Sports Medicine (1997).
Apprich Sebastian, MD
Medical University of Vienna, High Field MR -
Centre, Vienna, Austria
Sebastian Apprich is a member of the High Field
MR-Centre of Excellence (under the direction of Univ. Prof. Dr.
Siegfried Trattnig) at the Department of Radiology at the Medical
University of Vienna since 2008 and has a special interest in
the development and implementation of new MR techniques in
clinical orthopaedic research. He received his MD at the Medical
University of Innsbruck in 2010. As an undergraduate he already
demonstrated his growing interest in orthopaedic imaging research
and investigated the potential of new isotropic MR - sequence
for the detection of cartilage defects and meniscal tears
for his doctoral thesis. He spent one year as a postdoctoral fellow
at the Department of Orthopaedic Surgery at the Inselspital
Bern (Switzerland; under the direction of Univ. Prof. Dr. Klaus
Siebenrock), concentrating on new MR imaging modalities for
early detection of cartilage defects in femoroacetabular impingement
patients. In 2011, Sebastian Apprich returned to Vienna
to the High Field MR-Centre of Excellence where he is in charge
of the planning and execution of a number of musculoskeletal
imaging studies. After several years of research, he has begun
specialized clinical training in orthopaedics. Sebastian Apprich’s
research has been focused on imaging cartilage and its repair,
with main focus on biochemical quantitative MRI techniques.
Although he is still young, a number of author- and co-authorships
in top journals attest to his specialist knowledge in MRI.
Barry Frank, Prof., MD, PhD
National Centre for Biomedical Engineering
Science (NCBES),National University of Ireland,
Galway, Ireland
Frank Barry is Professor of Cellular Therapy at the National University
of Ireland Galway, Director of the University’s National
Centre for Biomedical Engineering Science (NCBES) and a principle
investigator at the Regenerative Medicine Institute (REME-
DI). Here he directs a large group of researchers who focus on
the development of new repair strategies in stem cell therapy
and gene therapy in orthopaedics. Previously he was Director of
Arthritis Research at Osiris Therapeutics in Baltimore, MD and a
Research Fellow at Shriners hospital for Children, Tampa, FL. He
has contributed to the fields of tissue engineering and regenerative
medicine by developing innovative and successful cellular
therapies for the treatment of acute joint injury and arthritic disease.
This has included the generation of a large body of new
data in ground-breaking preclinical studies, and has lead to the
first phase of clinical testing of mesenchymal stem cells in clinical
trials for joint injury. In a career that has spanned both industry
and academic research; he has been a driver in the development
of cellular therapy as a biological repair strategy. It is his
belief that the application of new technologies in regenerative
medicine, including cellular therapy, gene therapy, growth factor
augmentation, implantable scaffolds and nonmaterial, will have
a profound impact in Orthopaedics.
Beier Frank, Prof., PhD
Department of Physiology & Pharmacology,
University of Western Ontario, USA
Frank Beier received his PhD in Biology at the
University of Erlangen-Nürnberg, Germany, in 1995. He is now
a Professor in the Department of Physiology & Pharmacology
at The University of Western Ontario. Dr. Beier is the current director
of the Collaborative Graduate Program in Developmental
Biology at The University of Western Ontario. He holds a Tier II
Canada Research Chair in Musculoskeletal Health, received a
Dean's Award of Excellence for Graduate Student Teaching in
2008 and a Faculty Scholar Award in 2009. He was the 2010
Scientist of the Year at the Children's Health Research Institute.
Dr. Beier’s lab works on the signalling pathways and molecular
mechanisms that regulate the biology of cartilage cells (chondrocytes)
and other skeletal cells, both during development and
in osteoarthritis. In this research, the Beier lab uses a combination
of gene expression profiling, in-depth studies of identified
genes in genetically altered mice and surgical models in mice
and rats. Beier’s studies are currently funded by CIHR and NIH.
Currently he is a member of CIHR and NIH peer review committees,
of the Faculty of 1000 and the Editorial Board of PLoS One.
27

28
Invited Faculty 2012 in alphabetical order (not complete)
Bonassar Lawrence, Ass. Prof., PhD
Cornell University. Biomedical Engineering,
Ithaca, New York, USA
Brittberg Mats, Ass. Prof., MD, PhD
Orthopaedic Department, Cartilage Research
Unit, Göteborg University, Sweden
Mats Brittberg is a member of the Cartilage Research
Unit, Department of Orthopaedics, at
University of Gothenburg and orthopaedic surgeon at Kungsbacka
Hospital, Sweden. He received his MD in 1978 and completed
a specialization in orthopaedics in 1985. In 1992 he passed the
Swedish Orthopaedic Board Exam (S.O.B.E.) and earned a PhD
in 1996. In 2002, he became Associate Professor of orthopaedics
at University of Gothenburg and now also Gothenburg university
lecturer. Mats Brittberg’s research has been focused on
cartilage regeneration with autologous chondrocytes. Today the
main interest is the European Connective Tissue Engineering
centre (ECTEC) which is a collaboration between the Sahlgrenska
Academy at University of Gothenburg and Chalmers Technical
University. The research focus on musculoskeletal tissue engineering
and pain mechanisms in joint injuries and osteoarthritis.
Mats Brittberg has also had research collaboration with Virginia
Tech in USA on biotribology in cartilage as well as research
collaborations with other centres in Europe and North America.
Mats Brittberg has been on the board of TESi (Tissue engineering
Society International) and has been chairing the Cartilage
Committee of ESSKA 2006-08. Since the start 1997, he has been
working with ICRS, as a secretary, Vice-president and President
(2006-2008) and finally Past-President (2008-2009). He is now
associate editor for the Sage journal ¨CARTILAGE¨ and associate
editor with ESSKA journal and in the editorial board of Osteoarthritis
and Cartilage. In September, 2010, Mats Brittberg
received the ICRS Genzyme Lifetime Achievement Award in cartilage
research. Mats Brittberg is also clinical representative in
the program committee of ORS for the meeting in 2013.
Buckwalter Joseph, Prof., MD
Orthopaedics and Rehabilitation,
University of Iowa, USA
Dr. Joseph A. Buckwalter is Professor and chairman
of Orthopaedics and Rehabilitation and Arthur Steindler
Chair of Orthopaedics at the University of Iowa. His clinical practice
and research interests include osteoarthritis, joint injuries
and primary tumours of the skeleton and musculoskeletal soft
tissues. He has served as chairman of the American Academy
of Orthopaedic Surgeons Council on Research and president of
the Orthopaedic Research Society, the American Board of Orthopaedic
Surgery, and the American Orthopaedic Association.
His research awards include the Kappa Delta Award, the Cabaud
Award for Research in Sports Medicine, the American Orthopaedic
Association Award for Distinguished Achievement in Ortho-
paedic Research, the Orthopaedic Research Society and American
Orthopaedic Association Alfred Shands Award for Research,
and the Orthopaedic Research Society-Orthopaedic Research
and Education Foundation Distinguished Investigator Award. He
is the Senior Editor of the Journal of Orthopaedic Research. He is
a member of the Royal College of Surgeons of Edinburgh and the
Institute of Medicine, National Academies of Sciences, and is
the author of more than 500 scholarly publications. His current
research involves study of the pathogenesis of post-traumatic
osteoarthritis and methods of preventing osteoarthritis following
joint injuries.
Bugbee William, Prof., MD
University of California, Department of
Orthopaedics La Jolla, San Diego, USA
Bill Bugbee is attending physician at Scripps
Clinic, La Jolla and Professor, department of Orthopaedics,
university of California, San Diego. His clinical interests are in
arthritis surgery of the hip, knee and ankle, joint replacement,
osteochondral allograft transplantation and cartilage restoration.
Research interests include biologic response to implants,
innovation in knee replacement technique and design, Osteochondral
transplantation, cartilage tissue engineering and biologic
joint repair.
Buschmann Michael, Prof., PhD
Director Biomedical Science and Technology
Research Group (FRSQ), École Polytechnique
de Montreal, Canada
Michael Buschmann received a B. Engineering Physics from the
University of Saskatchewan in 1984, and a Ph.D. in Medical Engineering
and Medical Physics from the Division of Health Sciences
and Technology at the Massachusetts Institute of Technology
and Harvard University in 1992. His postdoctoral training in
cartilage microscopy and histology was then completed at the
University of Bern in Switzerland in 1994. Since 1994, Dr. Buschmann
has established a multidisciplinary research program at
École Polytechnique (http://www.polymtl.ca/tissue/) that focuses
on the use of biomaterials to repair joint tissues, gene
therapy and diagnostic technologies to assess the function of
articular cartilage. Work that has been translated to industry as
medical devices include a biomaterial that stimulates cartilage
repair (BST-CarGel) and an arthroscopic instrument that maps
articular cartilage function (Arthro-BST). Dr. Buschmann is Director
of the FRSQ Group in Biomedical Science and Technology
and has received the Innovator Prize from the Quebec Association
for Industrial Research (ADRIQ), the Melville Medal from
the American Society of Mechanical Engineers (ASME), and an
Award of Merit of the Canadian Arthritis Network of Centres of
Excellence.

Invited Faculty 2012 in alphabetical order (not complete)
Caborn David, MD
Jewish Hospital, Louisville, Kentucky, USA
Caterson Bruce, Prof., PhD
Cardiff School of Biosciences, connective tissue
biology lab, Wales, UK
Bruce Caterson, Prof., of Biochemistry
in the Connective Tissue Biology Group within
the School of Biosciences, Cardiff University,
Wales, U.K.
Over the past 27 years Professor Bruce Caterson’s research has
focussed on the production, development and use of monoclonal antibody
(mAb) technologies for studies of connective tissue proteoglycan
metabolism in health and disease. These studies have focussed
on matrix proteoglycan metabolism in musculoskeletal tissues with
a particular emphasis on studies involving molecular mechanism underlying
the pathogenesis of degenerative joint diseases; i.e. osteoarthritis
and rheumatoid arthritis. Our lab has now developed and
characterised numerous mAbs that recognise both carbohydrate and
protein epitopes and neoepitopes that are present on proteoglycans
in all connective tissues throughout the body. Many of these mAbs
are now commercially available to researchers worldwide.
He has degrees from Monash University, Clayton, Victoria, Australia,
(B.Sc. and Ph.D. in Biochemistry, 1971 & 1976, respectively).
From 1975–1995 he spent 20 years in academia in the USA;
1975–82, Postdoc – Assistant Professor, UAB, AL; 1982–89, Associate
Professor – Professor, West Virginia University; 1989–95,
Professor & Endowed Chair in Orthopaedic Research, University
of North Carolina at Chapel Hill, NC. In 1995 he moved to Cardiff
University into an Established Chair and from 1998 - 2003 was
Head of Connective Tissue Biology in the School of Biosciences.
He is currently Associate Director of Musculoskeletal Research in
the School of Medicine.
In the past, he has served on several USA national research committees
(N.I.H. Pathobiochemistry; Arthritis Foundation & Orthopaedic
Research and Education Fund), been a member of Editorial
Boards (J. Biol. Chem., Archives of Biochemistry and Biophysics,
and Osteoarthritis & Cartilage). He was also the past-President
(1993) and Board of Directors member of the USA-based Orthopaedic
Research Society (1988–1996). In the UK, he has served
on the Wellcome Trust Cell & Molecular Grant Review Panel, been
President of the Society for Back Research and was past-Chairman
of the British Society for Matrix Biology and past-President of the
British Orthopaedic Research Society.
His primary research interests have centred around using monoclonal
antibody technologies to study matrix proteoglycan
structure, function and metabolism in health and disease with
particular emphasis on musculoskeletal tissues. Recent research
has focussed on the glycobiology of chondroitin/dermatan sulphate
glycosaminoglycans in the stem/progenitor cell niche. In
the past 37 years he has published a total of 170 full papers and
27 chapters and reviews. In 1986 he was awarded the Benedum
Distinguished Scholar Award in Biosciences and Medicine from
West Virginia University, in 1998 the Kappa Delta Elizabeth Win-
ston Lanier Award for Outstanding Orthopaedic Research from
the American Academy of Orthopaedic Surgeons and Orthopaedic
Research Society and recently, in 2011 the Fell-Muir Award
from the British Society for Matrix Biology.
Chubinskaya Susan, Prof., PhD
Rush University Medical Center, Chicago, USA
Susan Chubinskaya, PhD, The Ciba-Geigy, Professor
of Biochemistry; has a primary appointment as Professor of Biochemistry
with secondary appointments as Professor of Internal
Medicine (Section of Rheumatology) and Orthopaedic Surgery at
Rush University Medical Center. She is also a member of Cartilage
Restoration Research Core at Rush. Susan was born in Kiev, Ukraine
and received her Ph.D. in 1990 from the Department of Metastasis,
Institute of Oncology, Ukrainian Academy of Sciences, Kiev, Ukraine.
In 1992 she immigrated with her family to the United States.
From 1993 to 1996 she was a postdoctoral fellow at the Department
of Biochemistry at Rush. In 1996 she joined the faculty at Rush Medical
College. She is an internationally recognized expert in the
field of growth factors/bone morphogenetic proteins in cartilage
repair and regeneration. She is a Recipient of William J. Stickel Gold
award, Am. Pod. Med. Assn., 1997, Eugene T. Nordby MD Research
Award, Internat. Intradiscal Therapy Soc., 2005, Ciba-Geigy Endowed
Chair award, Rush University Medical Center, 2007–; grantee
Research grant, NIH/NIA, 1998–99, NIH/NIAMS, 2002-2006, 2009.
Her research is continuously sponsored by Pharmaceutical and Biotech
Companies (Proctor & Gamble, Stryker Biotech, Glaxo Welcome,
Hoechst Pharmaceutical, Regentis, Arthrex, Zimmer, etc).
She is a member of the OARSI Communication Committee, ORS
program committee, and ICRS Executive Board/Treasurer. Susan
published 5 book chapters, 56 peer-reviewed articles, and more
than 130 peer-reviewed abstracts. Susan’s research focuses on the
biology of cartilage and intervertebral disc homeostasis in physiological
and pathophysiological processes. More specifically, her
laboratory studies the mechanisms of interaction between growth
factors, pro-inflammatory cytokines and neuromediators in articular
cartilage and intervertebral disc; the mechanisms responsible
for cartilage degeneration in aging, trauma, and osteoarthritis, molecular
mechanisms of tissue engineering, and the development of
diagnostic and prognostic biomarkers in arthritis.
Cole Brian, Prof., MD, MBA
Chairman Department of Surgery, Rush Oak
Park Hospital, Rush University Medical Center, USA
Brian Cole is a Professor in the Department of
Orthopaedics with a conjoint appointment in the Department
of Anatomy and Cell Biology at Rush University Medical Center
in Chicago, Illinois. He is the Section Head of the Cartilage Research
Program at Rush University Medical Center and the Cartilage
Restoration Center at Rush, a multidisciplinary program
specializing in the restoration of articular cartilage and meniscal
deficiency. He also serves as the head of the Orthopaedic
Master's Program and trains residents and fellows in sports medicine.
Most recently, he received appointment as the Chair of
Surgery at Rush Oak Park Hospital. Dr. Cole received his MD and
29

30
Invited Faculty 2012 in alphabetical order (not complete)
MBA from the University of Chicago in 1990, completed his residency
at The Hospital for Special Surgery in New York in 1996,
and his Sports Medicine Fellowship at the University of Pittsburgh
in 1997. He specializes in arthroscopic shoulder, elbow
and knee surgery. He is the principal investigator for numerous
FDA clinical trials and regularly performs basic science research.
He has authored and edited several hundred peer-reviewed publications,
including highly recognized orthopaedic textbooks
on arthroscopy, sports medicine and cartilage transplantation.
Dr. Cole is the team physician for the Chicago Bulls NBA Basketball
team, co-team physician for the Chicago White Sox Major
League Baseball team and DePaul University in Chicago.
Dahlberg Leif, Prof., MD, PhD
Head of Joint and Soft Tissue Unit, Department
of Orthopaedics, Skåne University Hospital,
Lund University, Sweden
Leif Dahlberg is Professor and Head of Joint and Soft Tissue Unit,
Department of Orthopaedics, Skåne University Hospital, Lund
University, Sweden. He received his MD at Karolinska Institutet,
Stockholm in 1983. In 1994 he earned a PhD in Lund. In 1998
he became Associate Professor at Lund University and in 1999
Staff Surgeon. University Lecturer in 1999 and Professor of Orthopaedics
in 2008 at Lund University. The research group as
follows: Leif Dahlberg is main supervisor to seven PhD-students
and co-supervisor to three PhD-students. The group includes
three post-docs, research coordinator, secretary, university administrator,
statistician and clinical research nurse/study coordinator.
Dahlberg has research collaborators at Lund University,
the Medical Radiation Physics and the Medical Radiology Unit at
Skåne University Hospital in Malmö. He has also collaboration
with the Sahlgrenska Academy at University of Gothenburg and
the Swedish University of Agricultural Sciences in Uppsala. His
international collaborators are in Canada, USA, Japan, South Africa
and Finland. Dahlberg’s research focuses on joint health and
disease in order to optimize non-operative treatment of joint disease.
Research includes cartilage molecular studies, MRI and
clinical interventions, specifically using human models of OA development
in post-injured patients. Dahlberg is Director of the
National Quality Registry, BOA (Better management of patients
with Osteoarthritis), Expert consultant of the National Board of
Health and Welfare (SoS) and Expert consultant of the Swedish
Association of Local Authorities and Regions (SKL). Dahlberg
has published more than 100 scientific articles, is cited more
than 2700 times and has an h-index of 27.
Daisuke Sakai, Ass. Prof.
Department of Orthopaedic Surgery,
Tokai University School of Medicine, Isehara,
Kanagawa, Japan
His clinical interest is in management of various spinal diseases,
including complex spinal deformity and scoliosis. He also has
particular interest in application of functional rehabilitation for
spinal problems. Dr. Sakai's current researches focus on maintenance
of homeostasis and intrinsic stem cell system of the
intervertebral disc cells and stem cell therapy, investigation of
master transcription gene network of the intervertebral disc cell
lineage, specifically the role of TGF-beta/Wnt/Notch signalling.
Dr. Sakai has given over 110 presentations, invited lectures and
seminars, in universities, professional societies, international
conferences (invited lecturer of 2004 and 2010 Gordon Research
Conference in musculoskeletal biology and bioengineering and
cartilage biology and pathology), and government organizations
around the world. He actively participated in grant review for
NIH, NSERC, SNF, RGC (Hong Kong) and other funding agencies,
and serves as an editorial board member for Journal of Orthopaedic
Science, reviewer for Arthritis &Rheumatism, Arthritis Research
& Therapy, Journal of Orthopaedic Research and Spine.
He also serves as committee member of the international affairs
committee of the Japanese Orthopaedic Association.
De Bari Cosimo, Prof., MD, PhD
Translational Medicine at the University
of Aberdeen, UK
Cosimo graduated in Medicine (maxima cum
laude) from the University of Bari (Italy), where he also underwent
specialist training in Rheumatology. He then moved to Belgium,
where he obtained his PhD from the Catholic University
of Leuven and was recipient of the Rotary Young Investigator
Award 2003 from the Royal Belgian Society for Rheumatology.
In 2003 Cosimo moved to the UK in the Department of Rheumatology
at King's College London. In May 2005 he was awarded a
Clinician Scientist Fellowship from the Medical Research Council
and in December 2005 he was appointed Clinical Senior Lecturer
& Consultant Rheumatologist. Since September 2007 Cosimo is
Professor of Translational Medicine at the University of Aberdeen,
where he heads the Regenerative Medicine Group in the
Musculoskeletal Research Programme. Cosimo has expertise in
translational stem cell research for musculoskeletal repair, regenerative
medicine and tissue engineering. His current research
interests focus on the development of novel stem cell-based
therapies for the musculoskeletal system, mainly articular cartilage
and bone; they also include the study of the resident joint
stem cells and their niches in health and diseases such as osteoarthritis
and rheumatoid arthritis. Cosimo is a member of the
Research & Training Committee of the Osteoarthritis Research
Society International (OARSI) and of the editorial board of several
journals including Regenerative Medicine and Arthritis &
Rheumatism. He serves on the Scientific Advisory Panel of Action
Medical Research and on the Fellowships Implementation
Committee of Arthritis Research UK.
Dhollander Aad, MD PT
Ghent University Hospital
Aad Dhollander studied physiotherapy (PT,
2002) and afterwards medicine (MD, 2009) at
the Ghent University. In 2009, he began his residency in Orthopaedic
Surgery and Traumatology at the Ghent University Hospital
(Head of the Department: Prof. Dr. Jan Victor). His clinical and
research interests focus on traumatology, knee- and hip-surgery.
Currently, he is doing his PhD with Professor Dr. G. Verbruggen
involving basic research focusing on metabolic characteristics

Invited Faculty 2012 in alphabetical order (not complete)
of different connective tissue cell types and clinical research
focusing on the outcome of several cartilage repair strategies.
Aad Dhollander is a member of various scientific societies, such
as the ICRS since 2010, the Young Scientist and Orthopaedic
Surgeons (YSOS), the Belgian Society for Orthopaedic Surgery
and Traumatology (BVOT), Belgian Knee and Hip Society (BKS-
BHS), Osteoarthritis Research Society International (OARSI),
and vice-president of the Belgian Orthopaedics and Traumatology
Residents Association (BOTRA). Together with Prof. Dr. Peter
Verdonk, he hosted the ICRS travelling fellowship 2011 visiting
Ghent.
Farr Jack, MD
Cartilage Restoration Center of Indiana,
Greenwood, USA
Dr. Farr received his undergraduate degree in
Biological Engineering from Rose Hulman Institute of Technology
in Terre Haute, Indiana in 1975, where he also was awarded
an honorary doctorate of Biological Engineering. He earned his
medical degree from Indiana University in 1979. He completed
his Orthopaedic Surgery residency at Indiana University Medical
Center in 1986. Over the past 20 years, Dr. Farr has continued to
focus his practice in sports medicine and knee restoration. His
numerous appointments and affiliations include a voluntary clinical
Professorship in Orthopaedic Surgery at Indiana University
Medical Center (Honorary Doctorate Biological Engineering) and
a board position with the Cartilage Research Foundation (Board
Certified Orthopaedic Surgeon). As a leader in US cartilage restoration
advances, Dr. Farr participates in several ongoing articular
and meniscal cartilage clinical trials. He also designed and
received a patent for a Meniscal Allograft Transplant System. For
patients with knee changes too far advanced for restoration, Dr.
Farr worked as a design surgeon for a new partial knee replacement
system. Dr. Farr is actively affiliated with the Indiana Orthopaedic
Hospital. He also has courtesy affiliations with other
Indianapolis area hospitals. He is a member of the American
Academy of Orthopaedic Surgeons, the American Orthopaedic
Society of Sports Medicine, the International Cartilage Repair
Society and numerous other professional organizations.
Ferkel Richard, MD
Southern California Orthopaedic Institute,
Van Nuys, CA, USA
Richard Ferkel grew up in Illinois and attended
UCLA where he played football for two years. Subsequently,
he graduated from Northwestern University Medical School
in Chicago and accomplished his orthopedic training at UCLA.
He completed fellowship training in Sports Medicine and Reconstructive
Knee and Shoulder Surgery at the Southern California
Orthopedic Institute, and had additional training in foot
and ankle surgery at that time. He is currently the Director of
the Sports Medicine Fellowship Program at Southern California
Orthopedic Institute. Dr. Ferkel has published numerous articles
regarding the shoulder, knee, foot and ankle, and sports medicine.
He co-edited the book, “Prosthetic Ligament Reconstruction
of the Knee,” and authored the text book “Arthroscopic Surgery
of the Foot and Ankle.” He lectures extensively all over the
world. In addition, he has invented numerous surgical devices
and performed live surgery throughout Europe. He has received
numerous awards and was selected to be in the book entitled
“The Best Doctors in America.“ Dr. Ferkel is a Clinical Instructor
of Orthopedic Surgery at UCLA, and was Chief of Arthroscopic
Surgery at Wadsworth Veterans Hospital for fifteen years. He is a
member of Arthroscopy Association of North America, American
Orthopaedic Society for Sports Medicine, International Society
for Arthroscopy, Knee Surgery, and Orthopedic Sports Medicine,
and the American Orthopaedic Foot and Ankle Society. He is a
Qualified Medical Examiner (Q.M.E.) for the State of California
Industrial Medical Council, Department of Industrial Relations.
Dr. Ferkel started the Athletic Training Program at Southern California
Orthopedic Institute. In addition, he has been the Team
Physician for Crespi, Oaks Christian, and Harvard-Westlake High
Schools, and Los Angeles Valley College for many years. He has
worked with the U.S. Olympic teams, U.S. Soccer Team, Special
Olympics, and is a consultant to the NFL, MLB, and NBA.
Flannery Carl, PhD
Pfyzer – Bio Therapeutics Division,
Cambridge, USA
Carl Flannery received a PhD in Medical Sciences
from the University of South Florida in 1995. He has conducted
research and studies on cartilage and joint pathobiology
and therapeutics at Rhode Island Hospital, the Shriners Hospital
in Tampa, Cardiff University, and at Wyeth Research and Pfizer in
Cambridge, Massachusetts.
Fortier Lisa, Ass Prof., DVM, PhD
Cornell University, Ithaca, NY, USA
Lisa Fortier is an Associate Professor of Surgery
at Cornell University in Ithaca, NY. She received
her DVM from Colorado State University and completed her
PhD and surgical residency training at Cornell University. She
is boarded with the American College of Veterinary Surgeons
and is an active equine orthopaedic surgeon at Cornell. Her laboratory
studies the intracellular pathways involved in the pathogenesis
of osteoarthritis, with particular emphasis on posttraumatic
osteoarthritis. In addition, Lisa’s research program
investigates the clinical application of stem cells and biologics
such as PRP for cartilage repair and tendonosis. She has received
the Jaques Lemans Award from the International Cartilage
Repair Society, the New Investigator Research Award from the
Orthopaedic Research Society, and the Pfizer Research Award
for Research Excellence from Cornell University. Lisa is the Vice
President of the International Veterinary Regenerative Medicine
Society and the immediate Past President of the International
Cartilage Repair Society.
31

32
Invited Faculty 2012 in alphabetical order (not complete)
Frisbie David, DVM, PhD Assoc Prof
Equine Surgery CSU’s Orthopaedic Research
Center, Fort Collins, USA
David Frisbie earned an undergraduate biochemistry
degree at the University of Wisconsin as well as a Doctor
of Veterinary medicine. He completed a Surgical Internship at
Cornell University and began his research in joint disease. Dr.
Frisbie went to Colorado State University, where he completed
a Surgical Residency in Large Animal Surgery and a Masters Degree
in Joint Pathobiology. He then began his work on a novel
way to treat joint disease using gene therapy. Dr. Frisbie is an
Associate Professor of Equine Surgery CSU’s Orthopaedic Research
Center. He is a partner in Equine Sports Medicine, LLC,
specializing in orthopaedics and sports medicine. Diplomate of
the American College of Veterinary Surgeons and a Diplomate of
the American College of Veterinary Sports Medicine and Rehabilitation.
Dr. Frisbie specializes in orthopaedic research, equine
lameness, orthopaedic surgery and gene therapy.
Fu Freddie, Prof., MD
Department of Orthopaedic Surgery,
University of Pittsburgh,
School of Medicine, Pittsburgh, USA
Freddie H. Fu is the David Silver Professor and Chairman of the
Department of Orthopaedic Surgery, University of Pittsburgh
School of Medicine. Dr. Fu specializes in Sports Medicine and
holds secondary appointments as Professor of Physical Therapy,
Health & Physical Activity, and Mechanical Engineering and
serves as the Head Team Physician for the University of Pittsburgh
Athletic Department. Dr. Fu graduated summa cum laude
from Dartmouth College in 1974 and received his BMS in 1975
from Dartmouth Medical School. He earned his medical degree
in 1977 from the University of Pittsburgh and completed his residency
training at Pitt in 1982. Dr. Fu’s major research interest lies
in clinical outcomes as well as bioengineering of sports-related
problems. His research efforts have led to over 200 professional
awards and honours, 960 national and international presentations,
and editorship of 29 major orthopaedic textbooks. Dr. Fu
is also the author or co-author of 450 peer-reviewed articles and
116 book chapters on the management of sports injuries. In July
2008 he assumed the Presidency of the American Orthopaedic
Society for Sports Medicine and, in April 2009, was named President
of the International Society of Arthroscopy, Knee Surgery
and Orthopaedic Sports Medicine
Gawlitta Debby, PhD
Orthopaedics, University Medical Center
Utrecht, NL
Her research is part of the strategic impulse of
the UMC Utrecht directed at improvement of current techniques
in regenerative medicine. The special focus she has within the
strategic impulse is on the orthopaedic applications, involving
tissue engineering of cartilage and bone using adult human
stem cells. Other topics within this project are the design of a bioreactor
system for stimulating optimal tissue development and
angiogenesis. Her Key side activities include the supervision of
undergraduate students.
EDUCATION AND CAREER HISTORY: Post-doc (2007 - now),
Dept. Orthopaedics, UMC Utrecht, Dept. Biomedical Engineering,
MaTe, Eindhoven University of Technology, PhD in Biomedical
Engineering, (2007) 'Compression-induced factors influencing
the damage of engineered skeletal muscle.’, Eindhoven
University of Technology , MSc in Biomedical Engineering (2002)
Eindhoven University of Technology
Gersoff Wayne, MD
Advanced Orthopedics and Sports Medicine
Specialists, Denver, USA
Wayne Gersoff is an orthopedic surgeon specializing
in sports medicine and cartilage restoration in Denver,
Colorado. After completing his residency in Orthopedic Surgery
at Yale University in 1986, he went on to complete a fellowship
in Sports Medicine at the University of Wisconsin in 1987. From
1987 – 1994, he was an Assistant Professor at the University of
Colorado Health Sciences Center where he also served as Director
of Sport Medicine and Head Team Physician for the University
of Colorado. Upon leaving the university for private practice,
Dr. Gersoff has maintained his active involvement in sports
medicine and cartilage restoration of the knee. He continues to
serve as team physician for professional, collegiate, and high
school athletes. His expertise in articular cartilage restoration
and meniscal transplant has allowed him to lecture and write on
these areas. He is on the general board of the ICRS and is president
of the Major League Soccer physicians’ group.
Getgood Alan, Ass Prof., MD
University Hospital Coventry and Warwickshire
NHS Trust, Coventry, UK
Alan is Associate Professor of Trauma and Orthopaedic
Surgery at the University of Warwick, UK. His clinical
interests include sports injuries of the knee and shoulder, and
the treatment of young arthritics, with a particular focus on osteotomy,
articular cartilage repair and meniscal reconstruction.
His research includes both a clinical and basic science focus,
with an emphasis towards combination biological products,
which can potentially enhance tissue regeneration. Following
graduating from the University of Edinburgh in 2000, Alan moved
to Cambridge to complete his orthopaedic training. In 2009
he completed his Doctor of Medicine thesis entitled ‘Articular
Cartilage Tissue Engineering’ from the University of Cambridge.
A one-year fellowship in orthopaedic sports medicine followed
at both the Fowler Kennedy Sport Medicine Clinic (London,
Ontario, Canada) and Banff Sport Medicine (Alberta, Canada),
where he was involved in the medical care for Alpine Canada
ski team. On returning to the UK, he then completed a further
knee reconstruction fellowship in Coventry. In September this
year he will return to the Fowler Kennedy Clinic to take up a faculty
position at the University of Western Ontario and continue
his clinical and research interests. When away from work Alan
enjoys skiing, climbing and running marathons, destroying his
own knees.

Invited Faculty 2012 in alphabetical order (not complete)
Giza Eric, Ass Prof., MD
Foot and Ankle Service at UC Davis Department
of Orthopaedics in Sacramento, CA, USA
Eric Giza is an Associate Professor and Chief of
the Foot and Ankle Service at UC Davis Department of Orthopaedics
in Sacramento, CA. Dr. Giza did his undergraduate work at
Haverford College in Philadelphia and received his MD degree
from Temple University, also in Philadelphia. He completed his
residency at Harvard University in Boston. Following residency,
he completed a Foot and Ankle Surgical Fellowship at the Foot
and Ankle Clinic in Sydney, Australia and a Sports Medicine Fellowship
at the Santa Monica Orthopaedic Group. Being a former
collegiate soccer player, Dr. Giza maintains his interest in sports
by caring for athletes on both Professional and amateur soccer
teams. He plays an active role on the Major League Soccer medical
staff and currently serves as an assistant team physician for
the US Soccer Federation.
Gomoll Andreas, Ass Prof., MD
Brigham and Women’s Hospital
Boston, USA
Born and raised in Germany, Dr. Gomoll attended
Ludwig-Maximilians-Medical School in Munich prior to
spending 2 years at Brigham and Women’s Hospital as a research
fellow. He then completed his residency training at the
Harvard Combined Orthopaedic Residency Program in Boston,
MA, and a Sports Medicine Fellowship at Rush University in Chicago,
IL. After his return to Boston, he joined Dr. Tom Minas at
the Cartilage Repair Center at Brigham and Women’s Hospital,
where he specializes in biologic knee reconstruction, such as
cartilage repair, meniscal transplantation and osteotomy. Dr.
Gomoll has an academic appointment as Assistant Professor
of Orthopaedic Surgery at Harvard Medical School. His main research
interests are clinical outcome studies of existing, as well
as the investigation of new cartilage repair procedures.
Goodrich Laurie, DVM, PhD Assoc Prof.
Equine Surgery, Colorado State University, USA
Laurie completed her DVM in 1991, an internship
in equine surgery in 1992 and surgical residency
in 1996. She became board certified in surgery thereafter.
She was a faculty surgeon at Cornell College of Veterinary Medicine
from 1996 through 2001 and then went on to complete a
PhD in cellular and molecular therapy related to cartilage repair.
She became an assistant Professor in equine surgery at Colorado
State University as well as a member of the research team at
the Equine Orthopedic Research Center at CSU. Her research is
NIH funded and her areas of focus include gene therapy for cartilage
and bone repair, and regenerative therapies as they relate
to musculoskeletal healing in the equine model. She is now an
associate Professor in the department of clinical sciences and
divides her time between being a surgeon in the equine hospital
at CSU and a translational scientist at the Orthopedic Research
Center. She is a member of the ICRS, the Orthopedic Research
Society and the American Society of Gene and Cell Therapy.
Grande Daniel, Ass Prof., PhD
Feinstein Institute for Medical Research
Manhasset, NY, USA
Daniel Grande is associate investigator and
director of orthopaedic research at the Feinstein Institute for
Medical research. He is also associate Professor at the newly
accredited Hofstra School of Medicine. He completed his PhD
at New York University and his post-doctoral fellowship ion biomechanics
at the Hospital for Special Surgery. He has worked
extensively in the area of regenerative medicine and tissue engineering.
His early work developed the first use of cell based
therapy for cartilage repair, currently known as autologus chondrocyte
transplantation. He has served on committees with the
Orthopaedic Research Society as spine topic chair and the basic
science committee. Dr, Grande is significantly involved in mentoring
and teaching of orthopaedic residents for his department.
He has been a reviewer for a number of journals including: Journal
of Orthopaedic Research, Clinical Orthopaedics, Osteoarthritis
and Cartilage, American Journal of Sports Medicine, Nature
Reviews Rheumatology and Applied Biomaterials. He has
been awarded eight patents and helped found two companies in
the orthopaedic surgery field of use. He has served as a member
of several companies’ scientific advisory boards. He completed
a five year rotation with OREF to assist in grant reviews. He also
regularly serves on NIH study sections for RO1, R21, and SBIR/
STTR grants specific to musculoskeletal applications.
Hambly Karen, MS, PhD
Senior Lecturer/PhD Research Student,
Centre for Sports Studies -University of Kent, UK
Karen Hambly qualified as a physiotherapist in
1998 from the University of Southampton having already completed
a degree in sports science. Prior to moving into academia
Karen worked as the sports medicine coordinator for both
British Cycling and UK Sport and has worked with Olympic and
Paralympic teams and elite athletes in several sports. Karen's
research interests are cantered around rehabilitation for articular
cartilage repair and in 2011 she completed her PhD on the patient
perspective of outcome measures after articular cartilage
repair of the knee. Karen has published and presented at internationally
and is an editorial reviewer for eleven peer-reviewed
journals. Karen is currently the Co-Chair of the ICRS Sports Injury
and Rehabilitation workgroup.
Hoemann Caroline, Ass. Prof., PhD
Dept. Chemical Engineering,
École Polytechnique Montreal, Canada
Caroline. Hoemann (PhD, MIT, 1992) is an associate
Professor of Chemical Engineering and Biomedical Engineering,
an FRSQ National Research fellow, and has over 45
publications and 6 patents. She has been a member of the ICRS
since 2002, was lead author on the ICRS recommendation paper,
“International Cartilage Repair Society (ICRS) recommended
guidelines for histological endpoints for cartilage repair studies
in animal models and clinical trials Cartilage 2011, 2:153-172”
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34
Invited Faculty 2012 in alphabetical order (not complete)
and serves on the editorial board of Cartilage, and The Open Orthopaedics
Journal. She spent 5 years as Director of Cartilage
Repair, in a Montreal-based biomedical device company, where
she co-invented and co-developed a novel medical device for
articular cartilage repair, BST-CarGel ® that recently completed
an 80-patient randomized controlled clinical trial. Her current
research program has created bioengineered blood clots, developed
new methods for staining and analyzing human cartilage
repair biopsies, and has made advances in understanding the
role of therapeutic inflammation and subchondral bone remodelling
in cartilage repair responses. Her translational research
program aims to understand the mechanisms of cartilage repair,
in order to bring new treatment options to patients with arthritis
Hollander Anthony, Prof., PhD
School of Medical Sciences University Walk
Clifton Bristol, UK
Anthony Hollander is the Arthritis Research UK
Professor of Rheumatology and Tissue Engineering at the University
of Bristol and Head of The School of Cellular and Molecular
Medicine. He has many years experience in cartilage biology
and his research is particularly focused on osteoarthritis.
He also has a more general expertise in the wider fields of stem
cells and tissue engineering. In 2010 the “Times” newspaper
ranking of Britain’s 100 most important scientists included him
at 39th on the list. Professor Anthony Hollander has been working
in the field of cartilage biology and arthritis research for two
decades. Three of those years were spent at the internationally
recognised cartilage laboratory at McGill University in Montreal.
More recently he has focused on tissue engineering and stem
cell biology for cartilage repair. Professor Hollander has received
funding in excess of £5 million of peer-reviewed funding over the
past 10 years from The UK government, medical charities, the
EU framework programmes and from biotechnology companies.
He has been the named inventor on several patents. He is cofounder
and Scientific Director of a University of Bristol spin-out
company, Azellon Cell Therapeutics. His work includes a study
on the regulation of stem cell differentiation for cartilage repair
and has pioneered the development of new assays and methodological
approaches for the measurement of repair tissue quality
in very small biopsies of cartilage from patients with knee
injuries. In 2008, Professor Hollander and a team of scientists
and surgeons successfully created and then transplanted the
first tissue-engineered trachea (windpipe), using a patient's own
stem cells. The bioengineered trachea immediately provided the
patient with a normally functioning airway, thereby saving her
life. Professor is Hollander vice president/president-elect of The
International Cartilage Repair Society. He is Associate Editor of a
leading journal, Osteoarthritis and Cartilage. He is an editorial
board member for several other journals.
Hunziker Ernst, Prof., MD
ITI Research Institute, University of Bern,
Switzerland
After completing his training as a medical doctor,
Ernst B. Hunziker launched on a research career in the field
of growth-plate cartilage, which focused on its development,
structure and physiological activity. After his appointment as
Director of the M.E.Müller-Institute of Biomechanics (University
of Bern), his research activities were geared more towards articular
cartilage: its structure, microbiomechanics and repair.
Later, as Director of the ITI Research Institute of Dental and Skeletal
Biology, his interest in the engineering (repair) of articular
cartilage continued. However, he also became involved in the
field of Implantology. Now, as Director of the Center of Regenerative
Medicine for Skeletal Tissues (University of Bern), Ernst
Hunziker`s research activities continue in the same directions.
He was ICRS President from 2004 – 2006.
Hurtig Mark, Prof., DVM
Canadian Arthritis Network, Clinic Studies,
University of Guelph, Canada
Mark Hurtig is the director of the Strategic Research
Resource Laboratory for the Canadian Arthritis Network
at the University of Guelph in Canada. He received a DVM at Guelph
in 1978, an MVSc from the University of Saskatchewan in
1983, and completed American College of Veterinary Surgeon
Diplomate status in 1989. While working 15 years as a staff surgeon
for the Ontario Veterinary College at the University of Guelph
he developed a career interest in joint injuries and sports
medicine that has led to collaborations in cell & molecular biology,
biomechanics, engineering, biochemistry, and biophysics.
He has been an ICRS member since 1998 and served as an ICRS
board member, chairing the animal models subcommittee during
2005–2008. His working group on risk factors that predict
osteoarthritis after knee injury includes faculty and clinicianscientists
from hospitals across Canada with collaborations in
many other countries. His laboratory encourages graduate students
from many other disciplines who wish to focus their career
on articular injuries and tissue repair.
Hutmacher Dietmar, Prof.
Professor and Chair of Regenerative Medicine
at the Institute of Health and Biomedical
Innovation of QUT, Kelvin Grove, AUS
Dietmar W Hutmacher is the Professor and Chair of Regenerative
Medicine at the Institute of Health and Biomedical Innovation of
QUT, where he leads the Regenerative Medicine Group, a multidisciplinary
team of researchers including engineers, cell biologists,
polymer chemists, clinicians, and veterinary surgeons.
Professor Hutmacher is a multidisciplinary biomedical engineer,
an educator, an inventor, and a creator of new intellectual property
opportunities. As a reflection of his pioneering ethos, his
recent research efforts have resulted in traditional scientific/
academic outputs as well as pivotal commercialisation outco-

Invited Faculty 2012 in alphabetical order (not complete)
mes. He is one of very few academics in the field of biomaterials/tissue
engineering who have taken a research programme
from the holistic concept through to clinical application. Professor
Hutmacher’s pre-eminent international standing and impact
on the field are illustrated by his publication record (more than
200 journal articles, edited 3 books, 35 book chapters and some
350 conference papers) and citation record (more than 6200 citations,
h-index of 39). Three of his papers in Materials Science
have received citations in the top 1% for the field, and he is also
ranked by Thomas Reuters 45th world-wide in citations per paper
(54 per paper) in Materials Science over the past decade.
Over the past 10 years in academia he has been lead CI, Co-CI
or collaborator in grants totalling more than AUD$ 35 million.
During the most recent 4 years in Australia, he has been an investigator
on external grants totalling in excess of AUD$ 8 million.
These grants have included ARC Discovery, ARC Linkage, ARC
LIEF NHMRC Projects, NIH, and Prostate Cancer Foundation of
Australia awards. He holds Adjunct Professorships at prestigious
universities e.g. in the USA (Georgia Institute of Technology).
His team is endeavouring to meet the challenge to provide
new bone to replace or restore the function of traumatised bone
or bone lost as a consequence of age or disease. Bone tissue
engineering concepts developed by his group promise to deliver
specifiable replacement tissues and the prospect of efficacious
alternative therapies for orthopaedic applications such as nonunion
fractures, healing of critical-sized segmental defects and
regeneration. Another key project for Professor Hutmacher’s
group has been to develop an animal model for bone repair research.
His group has established and fully characterised a critical-sized
tibial defect model in sheep tibiae to evaluate different
tissue engineering-based treatment concepts. Finally, Professor
Hutmacher’s group is using their expertise in biomaterials & tissue
engineering to tackle a different problem: development of
3D cancer models in the lab from scratch. In comparison to the
2D models currently used, the complex 3D culture model being
developed by Professor Hutmacher’s group is much closer to the
in vivo conditions which will allow researchers testing for example,
drug efficacy, to achieve much more realistic results.
Jakob Roland, Prof., MD
Professor Emeritus of University of Berne
Former Chairman of Orthopaedic Surgery of
Kantonsspital, Fribourg (1995–2007), Founding
President of ICRS 1997-98, Past President of Swiss Orthopaedic
Society (1994-96), ISAKOS (1999–2001), AO Switzerland (2002-
2009), Passed Activity as Member in Editorial Boards of Scientific
Journals: Journal of Bone and Joint Surgery, British Volume,
Journal of Knee Surgery, Sports Traumatology and Arthroscopy,
KSSTA (Board of Trustees), La chirurgia degli organi di movimento,
Author and Co-author of 200 scientific articles and 4 text
books: “The Knee and the Crucial Ligaments”, R.P. Jakob and
H.U. Stäubli, Springer, 1991, “Planning and Reduction Technique
in Fracture Surgery”, J. Mast, R.P. Jakob, R. Ganz, Springer, 1989,
“European Instructional Course Lectures”, R.P. Jakob, P. Fulford,
F. Horan, The British Editorial Society of Bone and Joint Surgery,
1999, Osteotomies around the Knee, Ph. Lobenhoffer, R. Heer-
warden, A. Staubli, R.P. Jakob (Thieme, AO Publication, 2008),
Honours: Corresponding member Austrian AO-Chapter (2000),
Godfather Herodicus Society USA, 2000, Surgeon in Chief pro
temp. The Hospital For Special Surgery New York, 2002, Honorary
Member of ANA (American Society of Arthroscopy, 2004), Honorary
Member of ISAKOS (International Society of Arthroscopy,
Knee Surgery and Orthopaedic Sports Medicine), 2007, Honorary
Fellow of ICRS (International Cartilage Repair Society), 2007,
Honorary Member of Swiss Society of Accident Surgery and Insurance
Medicine, 2008, Honorary Member of Swiss Orthopaedic
Society, 2009
Johnstone Brian, Prof., PhD
Oregon Health & Science University
Portland, USA
Brian Johnstone did his predoctoral research at
the Kennedy Institute of Rheumatology, London, England and
postdoctoral work at West Virginia University and the University
of North Carolina at Chapel Hill, USA. His work on intervertebral
disc biology was acknowledged with two Volvo prizes for spine
research. He moved to Case Western Reserve University in 1993
and developed the in vitro system for the chondrogenic induction
of adult stem cells. In 2004, he became Director of Research
in the Department of Orthopaedics at Oregon Health and Science
University, Portland, Oregon where he continues his work
on adult stem cells in skeletal tissue repair and regeneration.
He is a scientific editor for the open access journal eCells and
Materials, and was the President of the Orthopaedic Research
Society for 2011–2012.
Jurvelin Jukka, MSc, PhD
Dept of medical physics, University of Kuopio,
Finland
Jukka Jurvelin graduated from the Department
of Physics, University of Kuopio 1981. He completed a specialization
in hospital physics in 1991 and received Ph.D degree in
1993. He was a post doc researcher 1993–1995 in Mueller Institute
for Biomechanics, Bern, Switzerland. He worked 1995–2003
as Physicist and 2004–2008 as Chief Physicist, Department of
Clinical Physiology and Nuclear Medicine, Kuopio University
Hospital and as Vice-Dean, Faculty of Natural and Environmental
Sciences, University of Kuopio, Finland. During 2008-9 he was
the Vice-Rector for research in University of Kuopio. Currently he
is a Professor of Medical Physics at the Department of Applied
Physics, University of Eastern Finland. Jukka Jurvelin is the head
of the Biophysics of Bone and Cartilage (BBC) research group
(www.luotain.uku.fi). Jukka Jurvelin acts in the editorial board of
Sage journal CARTILAGE. The current research interests include
development of quantitative biomechanical, ultrasound, MRI
and x-ray methods for sensitive diagnostics of osteoporosis and
osteoarthrosis, and monitoring of cartilage repair.
35

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Invited Faculty 2012 in alphabetical order (not complete)
Kandel Rita, MD
Mount Sinai Hospital
Toronto, Canada
Rita Kandel is a clinician-scientist and Chief of
Pathology and Laboratory Medicine at Mt. Sinai Hospital, Toronto,
Canada. She is a Professor in the Department of Laboratory
Medicine and Pathobiology, cross-appointed to the Dept
of Surgery and a member of the Institute of Biomaterials and
Biomedical Engineering at the University of Toronto. She is the
Director of the Bioengineering of Skeletal Tissues Team, which
consists of a multidisciplinary group of investigators, including
engineers, biologists, stem cell biologists, and clinicians whose
work focuses on regenerative medicine. Her research interest is
in the bioengineering of tissues for articular cartilage repair and
intervertebral disc replacement. She is a long standing member
of the ORS. She is currently an Associate Editor of Cartilage and
a member of the Editorial Board of Osteoarthritis and Cartilage.
She has published over 170 papers.
Kisiday John, Assoc Prof., PhD
Colorado State University
Fort Collins, USA
John Kisiday is a member in the Equine Orthopaedic
Research Center (EORC) and the Department of Clinical
Sciences at Colorado State University. He received his Ph.D. in
Bioengineering from the Massachusetts Institute of Technology
in 2003, and joined the faculty at Colorado State University in
2005. His research activities have included the characterization
of novel scaffolds for cartilage tissue engineering, the effects
of dynamic compression on chondrocyte biosynthesis and mesenchymal
stem cell differentiation, and techniques for inducing
mesenchymal stem cell chondrogenesis geared towards clinical
translation. He has worked closely with EORC faculty investigating
the use of autologous mesenchymal stem cells in clinical
cases of equine tendonitis and joint disease. He has served as
an organizer for the tissue engineering topic for the annual meeting
of the Orthopaedic Research Society since 2010.
Klein Travis, PhD
Cartilage Regeneration Laboratory (CRL),
the Institute of Health and Biomedical
Innovation, Queensland University of
Technology, Brisbane, Australia
Travis Klein heads the Cartilage Regeneration Laboratory (CRL)
at the Institute of Health and Biomedical Innovation, Queensland
University of Technology, in Brisbane, Australia. Travis
received his PhD in Bioengineering from the University of California,
San Diego in 2005. He is now a Future Fellow of the
Australian Research Council. The ultimate goal of the CRL is
to help develop long-term regenerative therapies for treating
cartilage defects, including osteoarthritis. To help understand
chondrogenesis and joint pathologies, the group is developing:
model systems using human cells (chondrocytes and progenitor
cells); functionalised biomaterials; biofabrication technologies;
and mechanical stimulation techniques. In addition, the CRL
works towards advancing imaging technologies for monitoring
changes in native and tissue-engineered cartilage. One special
area of interest has been in understanding the cellular and extracellular
matrix differences between different depth zones,
and recapitulating these in vitro.
Kon Elizaveta, MD
Department of Orthopaedic Surgery and
Biomechanics Laboratory of Rizzoli
Orthopaedic Institute, Italy
Elizaveta Kon was born in Moscow. Degree in Medicine in 1994 and
specialization in “Orthopaedics and Traumatology” at the University
of Bologna 1999. Since 1993 carry out surgical, clinical, and research
activities at the Rizzoli Orthopaedic Institute in Bologna, Italy. Staff
member of the III Clinic Orthopaedic and Traumatology and Biomechanics
Laboratory (leaded by Prof. Maurilio Marcacci), orthopaedic
surgeon and researcher focusing on clinical and basic research in
the musculoskeletal tissue engineering. Assistant Professor of Motor
Sciences Faculty of the University of Bologna, held the course
of “Bioengineering applying to the locomotor apparatus pathology”
(2000-2005). Since 2010 Director of Nano-Biotechnology Laboratory
and carry on personally numerous research projects and clinical trials
regarding biotechnology applications in orthopaedics (from preclinical
studies to clinical trials). Principal investigator of numerous
research projects funded by the Italian Government and European
Community. President of Cartilage Committee of European Society
of Sports Traumatology Knee Surgery and Arthroscopy (ESSKA).
Chair of the ICRS Fellowship Scholarships and Grants Committee
and member of the ICRS General Board. Co- founder and past president
of Young Surgeons and Orthopaedic Surgeons (YSOS) club of
International Cartilage Repair Society (ICRS). President of the Cartilage
Committee and Board Member of the Italian Society of Knee,
Arthroscopy Sport Cartilage and Orthopaedic Technologies (SIGA-
SCOT). Elizaveta Kon has authored over 80 peer-reviewed scientific
articles and over 20 chapters in text books in orthopaedic surgery.
She has presented at over 200 society meetings all over Europe, Asia
and North America. Awards: ICRS Travelling Fellowship in 2004 and
ESSKA – AOSSM travelling fellowship in 2009. She is a member of
the Editorial Board of the BMC Musculoskeletal Disorders Journal
and European Journal of Sports Traumatology, reviewer for many
Orthopaedic journals including American Journal of Sports Medicine
(golden reviewer), Cartilage, Journal of Arthroscopy, Clinical Orthopaedics
and Related Research, Knee Surgery Sports Traumatology
Arthroscopy Journal, Journal of Tissue Engineering, Biomaterials etc.
Lafeber Floris P.J.G., Prof., PhD
University Medical Centre Utrecht
Netherlands
Professor of Experimental Rheumatology Floris
Lafeber is manager of research of the department of Rheumatology
& Clinical Immunology, at the University Medical Centre Utrecht,
Utrecht the Netherlands. In 1984 he obtained his degree as
Master of Science in Biology and received 4 years later in 1988 his
Ph.D. at the Faculty of Science of the University of Nijmegen, the
Netherlands. In Utrecht he started a new research group at the department
of Rheumatology, originally in the field of cartilage dege-

Invited Faculty 2012 in alphabetical order (not complete)
neration and regeneration, extended with research in immunology
and treatment strategies in rheumatic diseases in general. In 1999
he was installed as full Professor. Floris Lafeber has more than 200
peer reviewed publication half of them in the field of osteoarthritis.
He is member of ICRS, ORS, and OARSI. In addition to organization,
initiation, and facilitation of research in his department,
there is a personal interest in osteoarthritis, more specifically in a
unique treatment of severe osteoarthritis (joint distraction) which
has been developed over the past years, in a unique and internationally
accepted animal model of osteoarthritis (the canine Groove
model) that has been developed and validated, and more recently
in imaging and biochemical markers of joint tissue damage. Topics
which have received great international interest from scientists
and companies (involved in treatment of osteoarthritis).
Lavigne Patrick, MD, PhD
University of Montreal
Montreal, Canada
Dr Patrick Lavigne received a degree in Biochemistry
from University of Sherbrooke in 1995.
He then completed his medical degree in 1999 and orthopedic
residency training in 2005 at University of Montreal. During is
orthopedic training, Dr Lavigne earned a PhD degree in Biomedical
Sciences. He next completed an Arthroscopy and Sports
Medicine fellowship in Australia under the supervision of Mr Ian
Henderson and Mr David Wood. Since 2006, Dr Lavigne is an
Associate Professor of orthopedics at University of Montreal. He
specializes in shoulder, knee and ankle surgery with an emphasis
on osteoarthritis treatment in young patients. Dr Lavigne has
both basic science and clinical expertise in cartilage repair and
osteoarthritis research. He is a funded clinician-scientist from
the FRSQ and is actively involved in the development of diagnostic
tools for early stage OA detection and dynamic diagnostic
instruments for knee pathology. He is currently supervising the
clinical introduction of cartilage cell therapy in Quebec.
Little Chris, Ass Prof., PhD, BVSc (DVM equivalent)
Royal North Shore Hospital, St. Leonards,
Australia
Christopher Little is director of the Raymond
Purves Bone and Joint Research Labs at the Kolling Institute
of Medical Research at Royal North Shore Hospital, Australia.
Chris is a qualified Veterinarian with specialist surgery training
and ACVS certification. He was awarded a PhD degree from the
University of Sydney in 1996 for his studies of cartilage degradation
in a sheep model of osteoarthritis (OA). Following a 5-year
postdoctoral position at Cardiff University (UK), he was awarded
an Arthritis Foundation of Australia Fellowship at the University
of Melbourne. In 2004 he moved to his current position in
the University of Sydney Faculty of Medicine. Chris’s research
interests centre on the biochemical and molecular mechanisms
of joint pathology in OA, and tendon and intervertebral disc degeneration.
Chris has extensive experience in developing and
using small and large animal models of bone and joint disease.
He has authored/co-authored 95 scientific papers and 7 book
chapters. Dr Little is an Associate Editor of Osteoarthritis and
Cartilage, served on the OARSI histopathology initiative panel to
establish standardised methods for evaluation of animal models
of OA. He received the 2010 Barry Preston Award from the Matrix
Biology Society of Australia and New Zealand, presented to an
outstanding leader in the field.
Lohmander Stefan, Prof., MD, PhD
Lund University, Sweden
Stefan Lohmander, is Professor of Orthopaedic
Surgery at Lund University, Sweden. He serves
on the editorial board of several international journals, and is
the editor-in-chief of ‘Osteoarthritis and Cartilage’. He has published
more than 250 scientific papers, having received more
than 9000 citations with an H-factor of 54.
Stefan Lohmander is a past president of the Osteoarthritis Research
Society International, OARSI. In 1994 he received the
OARSI Award for Clinical Osteoarthritis Research, in 2004 the
Orthopaedic Research Society USA (ORS) Arthur Steindler Award
for significant international contributions to the understanding of
musculoskeletal disease and injury. In 2006 he received the Marshall
Schiff Lecture Award from the American College of Rheumatology
(ACR): “A special lectureship established to address the
interface between rheumatology and orthopaedics in the area of
musculoskeletal medicine”, and in 2007 the Bone and Joint Decade
2000-2010 Award for Research in Osteoarthritis.
He is the PI of the multidisciplinary Lund University Osteoarthritis
Research Group, focusing on basic and clinical aspects of
osteoarthritis:
• Risk factors and disease mechanisms of OA on gene, molecule
and patient level
• Monitoring OA Outcome by Biomarkers, Imaging and Patient-
reported Outcomes
• Evidence-based treatment of OA – Examining Old and New
Interventions for OA in Clinical Trials
Lu Helen, Ass Prof
Columbia University, Biomedical Engineering,
New York, NY, USA
Maden Malcolm, Prof., MD, PhD
Department of Biology at the University of
Florida in Gainesville, Florida, USA
Malcolm Maden is a member of the Department
of Biology at the University of Florida in Gainesville, Florida, USA
and a Joint Professor in the Department of Molecular Geentics
and Microbiology. He received his PhD in Genetics from the University
of Birmingham in 1975 on the subject of Urodele limb
regeneration. He did a post-doctoral fellowship at the University
of Sussex and then was a scientist at the National Institute for
37

38
Invited Faculty 2012 in alphabetical order (not complete)
Medical Research, London for 11 years where his studies centred
on the role of retinoic acid in development and regeneration of
several different vertebrate systems including limb regeneration,
the developing hindbrain and the developing limb. In 1998
he moved to King’s College London to teach Anatomy and continue
his research on retinoic acid where this work became more
translational and concerned the potential roles for retinoic acid
in the treatment of neurological and pulmonary diseases. In
2008 he moved to the University of Florida and returned to study
the regeneration of various systems in Urodeles and mammals.
His work is currently centred on the role of retinoic acid in limb
regeneration, regeneration of the limb and nervous system in
Urodeles, evolutionary aspects of regeneration in Vertebrates,
the relationship between development and regeneration and
possibilities for the induction of regeneration or its appearance
in mammals. He has published over 170 scientific papers on these
subjects, is an associate editor of the International Journal of
Developmental Biology and a member of Faculty of 1000.
Madry Henning, Prof., MD
Zentrum für Experimentelle Orthopaedie,
Saarland University, Homburg, Germany
Henning Madry studied Medicine at the Charité
Medical School in Berlin, Germany, supported by the German
Merit Foundation from 1990 – 96. Electives at the Universities of
Southampton, Jerusalem, Geneva, Nice and the Baylor College
of Medicine, Houston, USA. M.D. thesis “summa cum laude” at
the Max-Delbrück-Center for Molecular Medicine, Berlin. Resident
at the Department of Trauma and Reconstructive Surgery,
Virchow Hospital, Charité, Berlin. 1996 – 98. Postdoctoral Fellow
(supported by the German Academy of Scientists Leopoldina)
from 1998 – 2000 at the Massachusetts General Hospital, Harvard
Medical School, Boston and at the Massachusetts Institute
of Technology, Cambridge, USA. In 2000, he founded the
Laboratory for Experimental Orthopaedics at the Department of
Orthopaedic Surgery, Saarland University, Homburg, Germany.
In 2004 board-certified in Orthopaedic Surgery and cumulative
“Habilitation” on the subject: “Therapeutic Gene Transfer in
Chondrocytes”. Since 10/06 Attending Clinician. From 2008 –
2010 Chairman of the Articular Cartilage Committee of ESSKA,
since 2010 Vice-Secretary General of ESSKA. He has received international
and national awards, among which the Heine-Award
of the DGOOC, the AO Research Fund Prize and the New Investigator
Recognition Award of the Orthopaedic Research Society.
He currently holds the Endowed Chair of Experimental Orthopaedics
and Osteoarthritis Research at the Saarland University. His
basic scientific interests are the subchondral bone in articular
cartilage repair, regeneration of cartilage defects using genebased
approaches and osteoarthritis. His clinical interests are
reconstructive therapies for articular cartilage defects.
Malda Jos, Ass Prof., MSc, PhD
Orthopaedics, University Medical Center
Utrecht, NL
Jos Malda is an Assistant Professor at the Department
of Orthopaedics at the University Medical Center Utrecht
(The Netherlands) and an adjunct Associate Professor at
the Queensland University of Technology (QUT, Brisbane, Australia).
He received his MSc degree in Bioprocess Engineering
from Wageningen University in 1999 and completed his PhD on
Cartilage Tissue Engineering in 2003 (University of Twente). He
subsequently accepted a research fellowship at the Institute of
Health and Biomedical Innovation, (QUT, Brisbane, Australia),
where he still holds an adjunct position. In 2007, he was awarded
a prestigious Veni Grant by STW/NWO for the engineering
of articular cartilage with biomimetic zones using bioprinting
technologies. Since 2010, he is an Assistant Professor at the
Department of Orthopaedics and his research has a particular
focus on implants for regeneration of osteochondral defects.
He has published over 55 peer-reviewed publications and book
chapters and has been actively involved in the organisation of
international conferences in the field of regenerative medicine.
He is currently a board member of the ICRS and has been a
member of the ICRS Programme Committee since 2008. In 2012
he co-chairs this committee for the conference in Montreal 2012
with Prof. Wayne McIlwraith.
Mandelbaum Bert, MD
Santa Monica Orthopedic & Sports Medicine
Group, California, USA
Bert Mandelbaum is a medical graduate of
Washington University Medical School in St. Louis in 1980,
which completed his residency in Orthopaedic Surgery at The
Johns Hopkins Hospital and fellowship in Sports Medicine from
UCLA. He served on the faculty at UCLA from 1986–89 and subsequently
joined the Santa Monica Orthopaedic and Sports
Medicine Group. He presently practices there and serves as the
Director of the Sports Medicine Fellowship Program and the Research
and Education Foundation and Medical Director for the
FIFA Medical Center of Excellence in Santa Monica. He is also
the Director of Research for Major League Baseball (MLB). Academically,
he is well published including multiple journal articles
(85) and five books. He has received five national awards
for Excellence in Research in the Field of Sports Medicine. Since
1995 he has been on the editorial board of the American Journal
of Sports Medicine and associate editor for Current Concept Reviews.
He also served 1999–2001 as executive board member for
the American Orthopaedic Society for Sports Medicine. Presently,
he is Past President of the International Cartilage Repair Society.
He has also has been awarded a NIH Grant on Prevention
of ACL Injuries in Children and Adolescents in collaboration with
Chris Powers PhD of USC. He was honoured in a distinguished
fashion in 2009 with an Honorary Doctorate of Humane Letters (
DHL) from the State University of New York. As a team physician
Dr. Mandelbaum has worked with UCLA Athletics (1985–1989)
and Pepperdine University (1990–present, LA Galaxy and Chivas
USA MLS teams. He was the Chief Medical Officer for Women’s

Invited Faculty 2012 in alphabetical order (not complete)
World Cup Soccer 1999 and 2003, US Soccer Men’s National
Teams Physician since 1991, and the assistant Medical Director
for Major League Soccer since 1996, and served as USA Team
Physician for Soccer World Cups ’94 in the USA, ’98 in France,
2002 in Japan and Korea ,Germany in 2006 and South Africa in
2010. He serves on the USA Gymnastics Sports Medicine Advisory
Board. In 2002 he was appointed to FIFA Medical Assessment
and Research Committee (F-MARC). In 2007 he was appointed to
FIFA’s Sports Medicine Committee. He also served on the Sports
Medical Committee and Olympic Medical Officer for the Sydney
2000 , Athens 2004 and Beijing 2008.
Mao Jeremy, DDS, PhD
Columbia University College of Dental Medicine,
New York, NY, USA,
Mardones Rodrigo, MD
Clinica Las Condes, Santiago, Chile
Associate Professor Rodrigo Mardones is the
director of the Hip and Knee reconstructive surgery
fellowship program, Department of Orthopedics Surgery
Clinica Las Condes. Auxiliar Profesor of Orthopedics at Universidad
de Chile. The Director of the Tissue Engineering Laboratory
in Orthopedics Stem Cells based Therapy, at Clínica Las Condes.
President of, the Chilean Hip Society and Congress President of
the Chilean Sport Medical Society (SOCHMEDEP).
He received his MD at the University of Chile in 1998, with maximal
honors, and completed a specialization in orthopedics
at Pontificia Universidad Católica de Chile in 2002 and a twoyears
fellowship program at Mayo Clinic, Rochester Minesotta,
in 2004. In tissue engineering on Cartilage Repair under the directions
of Dr Shawn Odriscoll and then Clinical Fellow in Adult
Reconstructive Surgery Lower Extremities. Rodrigo Mardones’
research has been focused on hip reconstructive surgery (arthroscopy
and arthroplasty) and cartilage repair with main focus
on cartilage regeneration with differentiated expanded autologous
mesenchymal stem cells. Today the main interest has been
focused in his resently started Tissue Engineering Laboratory at
Clínica Las Condes, the first center in Chile focused on human
stem cell expansion for cell tehrapies in different clinical uses.
He has over 50 per review articles and book chapters and has
been presented numerous podium and guest speaker’s talks on
Hip surgery and Cartilage repair
Rodrigo Mardones has been member of the general board of
ICRS and until this year member of the memebership and bylaws
committee. He is actually board member of the ISHA (International
Society of Hip Arthroscopy). Member of numerous scientific
societies including ISHA, AANA, SLARD, ISAKOS, ICRS, SCHOT,
Sochmedep. Part of the editorial board of Cartiage and reviewer
of different journals including CORR, AJSM and Arthroscopy.
Mauck Robert, Ass Prof, PhD
Orthopaedic Surgery and Bioengineering at the
University of Pennsylvania, Philadelphia, USA
Robert Mauck is an Associate Professor of Orthopaedic
Surgery and Bioengineering at the University of Pennsylvania.
Dr. Mauck’s group focuses on the engineering of musculoskeletal
tissues, with a particular interest in restoring articular
cartilage, the knee meniscus, and the intervertebral disc. They use
rigorous mechanical and molecular analyses to characterize native
tissue structure and function, and employ this information to enhance
the functional properties of engineered constructs through
focused technology development. This work employs stem cells,
custom mechanobiologic culture conditions, and novel cell scaffolding
technologies. Dr. Mauck is an active member of a number of
national and international societies, including the ICRS. He serves
on the editorial board of Tissue Engineering and the Journal of the
Mechanical Behavior of Biomedical Materials, and has published
> 80 manuscripts, > 200 abstracts, multiple book chapters,
and co-edited a book on Biomaterials for Tissue Engineering. Dr.
Mauck is currently chair of the Regenerative Medicine Review Panel
for the Veteran’s Administration, and reviews regularly for the
NIH. Dr. Mauck was recently awarded the ISSLS Prize in Biomechanics
(2008), the YC Fung Young Investigator Award from the ASME
(2009), and was selected as a ‘Rising Star’ at the BMES-SPRBM
Conference on Cellular and Molecular Bioengineering (2011).
McIlwraith Wayne, Prof., DVM, PhD
Colorado State University, Fort Collins, USA
Wayne McIlwraith is a University Distinguished Professor,
Barbara Cox Anthony University Endowed
Chair in Orthopaedics, and Director of the Orthopaedic Research
Center (ORC) at Colorado State University (CSU). He also directs the
Musculoskeletal Research Program which is a CSU Program of Research
and Scholarly Excellence. He is an equine orthopaedic surgeon
as well as a researcher and has received numerous awards for
his contributions to orthopaedic surgery and joint research. Professor
McIlwraith received his veterinary degree in 1971 from Massey
University, New Zealand and after two and a half years in private
veterinary practice in New Zealand he did and internship at the University
of Guelph, Canada and his surgical residency and MS and PhD
degrees at Purdue University in the USA. He has been at CSU since
1979. He is the co-author of five textbooks, over 400 textbook chapters
and refereed publications, and has given 600 presentations and
workshops. He is a Diplomate of the American College of Veterinary
Surgeons (ACVS) and, The European College of Veterinary Surgeons
(ECVS) and, the American College of Veterinary Sports Medicine and
Rehabilitation (ACVSMR), as well as, a Fellow of the Royal College
of Veterinary Surgeons. His research focuses included osteoarthritis
therapy (including gene therapy and stem cell therapies), articular
cartilage repair and early diagnosis in osteoarthritis and pre-fracture
disease using imaging and fluid biomarkers. He is a Past President
of the American College of Veterinary Surgeons, the American Association
of Equine Practitioners and the Veterinary Orthopaedic Society
as well as an Associate Member of the American Academy of
Orthopaedic Surgeons. He is Fellow and current Board Member of
the ICRS. In 2012, he Co-Chairs the Programme Committee for the
conference in Montreal with Ass. Prof. Jos Malda.
39

40
Invited Faculty 2012 in alphabetical order (not complete)
Melchels Ferry, MSc, PhD
University Medical Centre Utrecht
Utrecht, Netherlands
Ferry Melchels is a young scientist doing basic
research into biomaterials for tissue engineering and drug delivery.
He received his MSc in chemical engineering and PhD in
biomaterials from the University of Twente (The Netherlands) in
2010. Then he moved on to a post-doc position in Professor Dietmar
W. Hutmacher’s Regenerative Medicine group at the Institute
of Health and Biomedical Innovation, Queensland University
of Technology (Brisbane, Australia). Currently he is a Marie
Curie fellow between University Medical Center Utrecht (NL) and
QUT, under supervision of Dr. Jos Malda and Prof. Dietmar Hutmacher.
His principal research interests lie in the development
of polymeric biomedical materials for additive manufacturing
techniques. During his PhD project he developed biodegradable
materials for preparing sophisticated scaffolds for tissue engineering
using stereolithography, and studied the effect of scaffold
architecture on mechanical properties, and on cell seeding
and culturing. His current topic is additive manufacturing including
biology by printing cell-laden hydrogel tissue engineering
constructs, with a particular focus on developing new hydrogel
systems for cartilage regeneration.
Minas Tom, MD
Brigham and Women’s Hospital and Director of
the Cartilage Repair Center, Boston, USA
Tom Minas is an Attending Orthopedic Surgeon
at the Brigham and Women’s Hospital and Director of the Cartilage
Repair Center. He is a national and international leader in
his work on cartilage repair and his expertise with autologous
chondrocyte implantation (ACI). He also performs arthroscopic
surgery of the knee and hip, joint preserving osteotomies, unicompartmental
knee replacements, patellofemoral joint replacements,
as well as total joint arthroplasty of the knee and hip. Dr.
Minas completed two fellowships: in pelvis & acetabulum, trauma
and joint reconstruction, at the Sunnybrook Medical Centre,
Toronto, Canada, in total joint arthroplasty in the Department
Orthopedic Surgery at the Brigham and Women’s Hospital, Boston,
MA, Dr. Minas has a strong focus on joint preservation in
the young adult, by primarily developing and assessing cartilage
repair and osteotomy techniques. He has performed two of the
only ACI’s in the hip joint in the United States and he has also
performed over 400 ACI’s. He has also designed an interpositional
device (Conformis) and patellofemoral joint prosthesis to
help osteoarthritic patients avoid a total knee replacement.
Mithoefer Kai, MD
Sports Medicine and Cartilage Restoration at
Harvard Vanguard Medical Associates in
Boston, USA
Kai Mithoefer is currently the Director of Sports Medicine and
Cartilage Restoration at Harvard Vanguard Medical Associates in
Boston and clinical faculty member at Harvard Medical School.
He received his medical degree from Heinrich-Heine University in
Düsseldorf Germany in 1991. He obtained his residency training
in Orthopedic Surgery at Harvard Medical School and completed
a fellowship in Shoulder and Sports Medicine at the Hospital for
Special Surgery in New York. Dr. Mithoefer is board certified in
Orthopedic Surgery and Sports Medicine in both the USA and
Germany. He has been a member of the ICRS since 2003 and is
currently serving as the co-chair of the ICRS Rehabilitation and
Sports Committee. His research interest is in the clinical application
and evaluation of novel tissue engineering techniques for
articular cartilage repair with a special focus on their use in the
high-demand athletic population. Kai Mithoefer has served as
an active member of the Scientific Program Committee for the
2010 ICRS Meeting in Sitges/Barcelona. He is a member of the
editorial board of the journal “Cartilage” and has co-edited the
2012 FIFA/ICRS Supplement on Articular Cartilage Injury in the
Football (Soccer) Player as well as the 2011 ICRS Newsletter on
Cartilage Rehabilitation.
Nehrer Stefan, Prof., MD, PhD
Department for Orthopaedic Surgery at the
hospital in Krems, Austria
Stefan Nehrer is an orthopaedic surgeon at
Department for Orthopaedic Surgery at the hospital in Krems,
Professor for Tissue Engineering at Center for Regenerative
Medicine and since 2011 he is also Dean of Faculty Health and
Medicine at Danube University Krems. He studied at the Medical
University Vienna where he obtained his MD in 1984 and his
PhD in 1999. From 1995 to 1996 he was at the Harvard Medical
School in Boston, USA, at Prof. Myron Spector where he started
his scientific work in cell-based therapies in cartilage regeneration.
From 2000 to 2006 he was head of orthopaedic research
at the Medical University Vienna and leading surgeon in sports
medicine and paediatric orthopaedic. In 2007 he was appointed
Professor for Tissue Engineering at Danube University Krems.
Over the years he has continued his research on experimental
and clinical applications of chondrocyte transplantation and
formed a group for tissue engineering research. Furthermore,
his interests focused on mesenchymal cell differentiation and
design/implementation of tissue culture bioreactors for automated
and controlled manufacturing of cartilage, bone and osteochondral
grafts, based on autologous cells and 3D porous
scaffolds. He has published more than 52 peer reviewed and
81 other articles in national and international journals and 14
book chapters. Prof. Nehrer has presented at many national and
international meetings and he is member of 10 national and international
societies.

Invited Faculty 2012 in alphabetical order (not complete)
Neyret Philippe, Prof.
Department of Orthopaedic and Traumatological
Surgery at the Croix Rousse Hospital
Lyon, France
Philippe Neyret is an orthopaedic surgeon and the head of department
of Orthopaedic and Traumatological Surgery at the
Croix Rousse hospital, Lyon, France. As a Professor, he is responsible
for three academic formations at the University of Lyon,
France. Philippe Neyret received his initial training with Albert
TRILLAT and being a former pupil of Henri DEJOUR, it was quite
natural that in 1988 he devoted his activity on knee surgery. Philippe
Neyret was nominated Professor at the University of Lyon
in 1994, and he is head of the department at the Centre Livet
since 1996. His main activity is clinical. Philippe Neyret treats
an equal number of sports lesions and degenerative pathologies
of the knee. The many publications, books, CD-Roms reflect
this clinical research activity. For his work on the results after
meniscectomy, Philippe Neyret received the “John Joyce Award”
by International Arthroscopy in 1989. In 1995 Philippe Neyret
participated in the ESSKA-AOSSM “Traveling Fellowship”. His
participation during the “7th, 9th journées lyonnaises de chirurgie
du genou” dedicated to the degenerative knee and the “15th
Journées” dedicated to the total knee arthroplasty shows his
great interest for the degenerative pathology of the knee. Philippe
Neyret is member of several medical societies and he is an
active participant in the SOFCOT, ESSKA 2000, EFORT as member
at large and ISAKOS as Second Vice President. He is also
Second Vice Chair of the “ACL Study Group”, and member of the
board of the “Patello Femoral Foundation”. In 1999 he was involved
in the development of the subjective IDC form and more
recently under the leadership of Anderson in the development of
the meniscal documentation form. In 2000, Philippe Neyret was
co-organizer of the Journées Lyonnaises de Chirurgie du Genou
held in Porto Allègre, Brasil, in 2004, in Fortaleza (Brasil) and in
2007 Florianapolis. In 2002-2004, 2008 and 2010, together with
Dr Chambat, Philippe Neyret organised the “Journées de Chirurgie
du genou” devoted to the athlete’’ knee or/and prosthesis
knee. In 2004, 2006 and 2008, Philippe Neyret was part of the
scientific committee of the European course of Knee Arthroplasty
in Val d’Isère.
Nixon Alan, Prof., BVSc, MS
Department of Clinical Sciences,
Cornell University
Ithaca, USA
Alan Nixon is Professor of Orthopedic Surgery and Director
of The Comparative Orthopaedics Laboratory and the JD&ML
Wheat Orthopaedic Sports Medicine Laboratory at Cornell University.
He has an adjunct appointment as Professor at Colorado
State University Graduate Field. He obtained his veterinary
degree from the University of Sydney in 1978 and completed a
surgical residency and research degree at Colorado State University
in 1983. After five years in the Department of Surgical
Sciences at the University of Florida, Dr. Nixon moved to New
York in 1988 where he is currently a Professor in the Department
of Clinical Sciences, and served as Chief of Surgery from 1998 to
2002. Dr Nixon has authored over 290 papers and book chapters,
and has written 2 texts on equine orthopedics. Dr Nixon’s
clinical and teaching at Cornell University focus on musculoskeletal
injury and repair, with a specific interest in regenerative
medicine. Research and translational clinical application over
the past 2 decades have included: Joint pathobiology and cartilage
repair with cell grafting, growth factor recombinant protein
and gene-enhanced chondrocyte and stem cell transplantation
techniques, Stem cell propagation, characterization, and application
in musculoskeletal diseases, including bone marrow and
adipose derived stem cells for repair of tendinitis, Clinical application
of growth factor recombinant proteins and gene therapy
for improved joint, tendon, and bone repair, Genetic characterization
of OCD in animals and man using microarray gene chip expression
studies, Arthroscopic approaches and techniques for
enhanced repair in the stifle, shoulder, elbow, and hip in horses.
Dr Nixon’s laboratory group has engaged in over 80 funded research
projects and 8 contracts with industry engaged in musculoskeletal
research, with total budget expenditures of over $17
million. He currently has a 5-year National Institutes of Health
R01 award with total costs of 1.8 million dollars. Dr Nixon has
lectured on his research findings in the US and abroad on over
110 occasions. He serves as a consultant to industry and to the
FDA panel on Cell and Gene Therapy.
Pacifici Maurizio, Prof.
Division of Orthopaedic Surgery,
Children’s Hospital of Philadelphia, USA
Pacifici received his doctorate degree from the
University of Rome and postdoctoral training under the auspices
of a European Molecular Biology Fellowship. He joined the faculty
at the University of Pennsylvania where he rose to the rank of
Professor. He subsequently moved to Jefferson University Medical
School where he served as Director of Research in Orthopaedics.
About two years ago, he and his team were recruited by
the Children’s Hospital of Philadelphia. Dr. Pacifici’s biomedical
research work focuses on mechanisms controlling skeletal development
and growth in fetal and postnatal life. Emphasis is on
the identification of molecular regulators acting at the nuclear
levels that direct commitment, determination and differentiation
of progenitor skeletal cells. The overall goal is to target
those regulators using gene-, cell- and drug-based therapies to
treat skeletal pathologies including congenital skeletal malformations
or growth defects and acquired conditions such as Heterotopic
Ossification. Emphasis is also on signalling diffusible
factors that normally act within developing skeletal elements
to coordinate growth and morphogenesis. When these factors
act abnormally and affect adjacent non-skeletal tissues due to
failure of signalling or restraining mechanisms, they can trigger
pathologies, including benign tumours such as those seen Hereditary
Multiple Exostoses. Experimental therapies are being
tested to restore normal signalling mechanisms and block or
reverse these and related pathologies. Dr. Pacifici’s biomedical
research work has been continuously funded by the NIH for over
25 years.
41

42
Invited Faculty 2012 in alphabetical order (not complete)
Philippon Marc J., MD
The Steadman Clinic
Vail, USA
Marc J. Philippon is a partner at The Steadman
Clinic and is one of the world's leading orthopaedic hip surgeons.
Dr. Philippon joined The Steadman Clinic in 2005 after
a successful time period at the University of Pittsburgh Medical
Center where he served as Director of sports related hip disorders
and was also Director of the UPMC Golf Medicine Program.
Previously, he was chief of orthopaedic surgery at Holy Cross
Hospital in Fort Lauderdale, Florida. Dr. Philippon is internationally
known for performing joint preservation techniques utilizing
arthroscopic hip surgery to treat painful joint injury in highlevel
athletes who constantly use powerful hip rotation, such as
golfers, NFL players and NHL players, making themselves prone
to acute and chronic injuries of the hip joint. He has published
numerous scientific articles in sports medicine and orthopaedic
journals and is a frequently invited presenter at international
sports medicine and orthopaedic meetings. Dr. Philippon earned
his medical degree with an academic scholarship from Mc-
Master University Medical School in Hamilton, Ontario, Canada
in 1990, and completed an orthopaedic surgery residency at the
University of Miami, Jackson Memorial Hospital in 1995. Dr. Philippon
is a consultant to NHL, NFL, NBA, and MLB Professional
teams and has treated numerous PGA golfers. He is also a consultant
to the NHL Players Association. Some of the Professional
athletes he has treated include golfers Greg Norman and Peter
Jacobsen, hockey player Mario Lemieux, Professional football
player Priest Holmes, and baseball player Alex Rodriquez. Dr.
Philippon is an Active Member with the American Orthopaedic
Society for Sports Medicine and the Arthroscopy Association of
North America. He is also a Fellow with the American Academy
of Orthopedic Surgeons and a Master Instructor with the Arthroscopy
Association of North America, Masters Experience Hip
Course, and a Member of the Herodicus Society. Dr. Philippon
enjoys spending time with his family and participating in sports
such as skiing, tennis, swimming and cycling.
Poole A. Robin, Prof. Emeritus, BSc
McGill University, Lancaster
Ontario, Canada
Robin Poole received his BSc degree 1961 and his
PhD degree in 1969 from Reading University, U.K. Following early
research in microbiology (in industry), on membrane fusion and
tissue invasion in cancer, he was invited in 1970 to join a research
group at the Strangeways Research Laboratory in Cambridge, England
working on cartilage degradation in arthritis. In 1977 he moved
to Montreal to the Shriners Hospital and McGill University to create
and become director of a new research laboratory (The Joint Diseases
Laboratory) working on arthritis. He became a full Professor
at McGill in 1981.Here he established an international research
group working on skeletal development and cartilage degradation
in arthritis. This was funded by the Medical Research Council of Canada/
Canadian Institutes of Health research, Shriner’s Hospitals,
industry and National Institutes of Health, USA (NIH). The successes
of his research on the pathobiology of inflammatory and degenerative
joint disease, focussing on cartilage degradation in health and
disease, has led to numerous awards. These include the Kappa Delta
Award of the American Academy of Orthopaedic Surgeons/Orthopaedic
Research Society; the Howard and Martha Holley Research
Prize in Rheumatology and the award of Master, the latter two from
the American College of Rheumatology; the Carol Nachman International
Research Prize in Rheumatology; Honorary Doctor of Science
degree, Reading University, England; Lifetime Achievement Award
of the Osteoarthritis Research Society International; President, 6th
World Congress of Inflammation Research Associations; President,
Canadian Orthopaedic Research Society and Professor Emeritus
at McGill University on his retirement from the laboratory at the
Shriner’s Hospital in December, 2005. He also worked in an advisory
capacity with the Food and Drugs administration (FDA), USA. He has
personally trained over 40 graduate students and fellows from clinical
and basic research backgrounds and assisted many others. He
continues to mentor a number of trainees and young investigators
in his “retirement”. His research has resulted in 238 peer reviewed
papers and 93 invited reviews/book chapters. His work on molecular
markers of cartilage matrix metabolism and joint damage and
repair in arthritis has led to their commercialization and use in research
and drug development in academia and industry. He wrote
the white paper on biomarkers for the NIH Osteoarthritis Initiative
in 2000 and recently was involved in the preparation for the FDA of
a guidance document on biomarker usage in clinical trials for osteoarthritis.
He was a co-founder and later Scientific Director of the
Canadian Arthritis Network, a National Centre of Excellence composed
of almost 200 principal investigators. This was founded in 1998
to promote collaborative research activities and research training in
the arthritis field within Canada and internationally and the translation
of new knowledge to improve the care of patients with arthritis.
He maintains his numerous scientific and research interests being
involved in research collaborations, mentoring, reviewing, lecturing
and editorial and scientific advisory boards, including Osteoarthritis
Research Society International. He continues to act as a consultant
to biotech and pharmaceutical companies.
Quinn Thomas, Ass Prof., PhD,
McGill University, Lancaster
Ontario, Canada
Thomas M. Quinn obtained a BSc in Engineering
Physics from Queen’s University at Kingston, Canada and a PhD in
Mechanical and Medical Engineering from the Harvard-MIT Division
of Health Sciences and Technology, USA in 1996. After a twoyear
postdoctoral fellowship at the Müller Institute for Biomechanics
in Bern, he established the Cartilage Biomechanics Group
at EPFL in Lausanne, Switzerland. He joined the Department of
Chemical Engineering at McGill University, Canada in 2007, where
he is currently Associate Professor and Canada Research Chair in
Soft Tissue Biophysics. His research aims to clarify and use cell
responses to soft tissue deformation, and has emphasized the
electromechanics of cartilage matrix, cell responses to cartilage
injury, transport of fluids and solutes through soft tissues, and
development of technologies for cell culture on extendable substrates
for improved tissue engineering.

Invited Faculty 2012 in alphabetical order (not complete)
Richardson James, Prof., MD
Institute of Orthopaedics, Robert Jones &
Agnes Hunt Orthopaedic Hospital, Oswestry,
Shropshire, UK
James Richardson is an orthopaedic surgeon who has studied
cells in culture for over 20 years. The development of ACI in Gothenburg
led to him leading a team at Oswestry in developing a
GMP laboratory within the British National Health Service. Eurocell
and MyJoint have been EU funded research projects. He
has treated over 400 patients with ACI and combines a range of
reconstructive techniques in the hip, knee and ankle.
Rodeo Scott, Prof., MD
Orthopaedic Surgery, Weill Medical College of
Cornell University, USA
Scott Rodeo is a clinician-scientist at Hospital
for Special Surgery, with appointments in the Department of Orthopaedic
Surgery (Sports Medicine and Shoulder Service) and
the Research Department (Laboratory for Soft Tissue Research).
He is Professor of Orthopaedic Surgery at Weill Cornell Medical
College and Co-Chief of the Sports Medicine and Shoulder
Service at Hospital for Special Surgery. He specializes in sports
medicine injuries of the knee, shoulder, ankle, and elbow. He
also performs arthritis surgery of the knee and shoulder, including
joint replacement surgery. His research focuses on the basic
biology of tendon and ligament healing, meniscal allograft
transplantation, and rotator cuff repair. He has been Associate
Team Physician of the New York Giants football team since 2000.
In 2004 and 2008, he served as Team Physician for USA Olympic
Swimming, a position he will return to in London for the 2012
games. Dr. Rodeo also holds a Board position at Asphalt Green,
a community-based athletic organization in Manhattan, where
he helps to promote injury prevention and healthy living through
exercise and health education information to its members.
Sah Robert, Prof., MD
Bioengineering, University of California,
San Diego, USA
Robert L. Sah is Professor of the Department of
Bioengineering, Adjunct Professor of the Department of Orthopaedic
Surgery, and co-director of the Center for Musculoskeletal
Research at UCSD. He received the B.S. and M.S. in Electrical
Engineering and the Sc.D. in Medical Engineering from M.I.T.,
and the M.D. from Harvard. He joined UCSD Bioengineering in
1992 and was promoted to Professor in 2001. Dr. Sah has contributed
to the Tissue Engineering and Regenerative Medicine
International Society as a North America council member, to
the International Cartilage Repair Society as a member of the
Executive Board, to a number of journals including Arthritis and
Rheumatism, Cartilage, Journal of Orthopaedic Research, Osteoarthritis
and Cartilage, and Tissue Engineering in editorial
roles. His research interests are the biomechanics, mechanobiology,
and tissue engineering of articular cartilage, synovial fluid,
and synovial joints with the ultimate goal of improving the treatment,
diagnosis, and prevention of osteoarthritis. He is recipient
of the Van C. Mow medal, a fellow of the American Institute for
Medical and Biological Engineering, and a Professor of the Howard
Hughes Medical Institute.
Sanchez Luis J., MD, DPM
Podiatric Medicine & Surgery of the Foot & Ankle
He received his MD from the CETEC School of
Medicine, Santo Domingo, Dominican Republic
in 1983. He worked from 1991–1996 at the Orlando Foot &
Ankle Clinic, Inc, then 1996–2000 at Accent Foot, Ankle, & Leg
Clinic and from 2000–2009 at the Orlando Foot & Ankle Clinic.
Dr. Sanchez held teaching positions from 1983–2008 in Puerto
Rico, Dominican Republic, Mexico as well as in Tallahassee, FL,
USA mainly multiple lectures related to the field of Foot & Ankle,
Leg medicine and surgery.,
Sandell Linda, Prof., PhD
Washington University School of Medicine,
Washington, USA
Linda Sandell is the Mildred B. Simon Professor
and Director of Research in the Department of Orthopaedic Surgery
and Director of the Center for Musculoskeletal Biology and
Medicine at Washington University in St. Louis. She has been a
leader in the field of orthopaedic research, pioneering the use of
molecular biologic techniques, protein biochemistry, large screening
technologies, microscopy and computational biology to
study cell responses to cartilage cell injury and the regulation of
gene expression in connective tissues. Dr. Sandell received her
bachelor’s and master’s degrees from Denver University, her Ph.D.
in biochemistry at Northwestern University, and did postdoctoral
work in molecular biology at the University of Chicago. Dr. Sandell
was a faculty member at Rush Medical College in Chicago
from 1982 to 1987, and at the University of Washington in Seattle
from 1987 to 1997 when she moved to Washington University. Dr.
Sandell has authored more than 200 publications, in addition
to three books and seven patents. She has provided extensive
leadership in the orthopaedic research field, particularly in the
Orthopaedic Research Society, as President in 2000, and as a
founder of the Women’s Leadership Forum. Over the past several
years, has chaired three Gordon Conferences and numerous
other conferences including co-founding the Cartilage Gordon
Conference. She has been President of the Orthopaedic Research
Society (2000), the Histochemical Society (2005-2007) and the
Society for Matrix Biology (2006-2008). In 2010, she received the
Women’s Leadership Award from the Orthopaedic Research Society
and is currently director of the OARSI OA Biomarkers Global
43

44
Invited Faculty 2012 in alphabetical order (not complete)
Initiative and President of the Osteoarthritis Research Society International
(2010- 2013). Dr. Sandell has been awarded the Kappa
Delta Award for Basic Science Research by the American Association
for Orthopaedic Surgeons, and has served on the Advisory
Council of the National Institute for Arthritis, Musculoskeletal and
Skin Diseases. She is Deputy Editor for the Journal of Orthopaedic
Research, Associate Editor for the Journal of Histochemistry and
Cytochemistry, and is a member of the editorial boards for many
other journals including Arthritis Research and Care, the Journal
of Biological Chemistry, and Osteoarthritis and Cartilage.
Saris Daniël, Prof., MD, PhD
Orthopaedic Department, University Medical
Center Utrecht, NL
Graduated University of Amsterdam Medical
School in 1992. During orthopaedic residency he did a fellowship
at the Mayo Clinic in Rochester MN USA under Prof. Shawn
O’Driscoll of the Cartilage and Connective Tissue Research Laboratory
and Prof. Kai-Nan An of the orthopaedic biomechanics
laboratory. His PhD thesis completed in 2002 at the University
of Utrecht was titled “Joint Homeostasis in Tissue Engineering
for Cartilage Repair”. It first introduced the now generally accepted
concept of joint homeostasis. In 2000 Daniël joined as
staff member in the department of Orthopaedics at the UMC Utrecht.
In March of 2010 Dr Saris was appointed as Professor of
Reconstructive Medicine at the University of Twente. Prof. Dr Saris
is co director of the Biological Joint Reconstruction research
program and head of the orthopaedic residency program at the
University of Utrecht. He describes his goal and driving force as
a wish to satisfy natural curiosity into optimizing the regenerative
biological capacity of the musculoskeletal system, improve
treatment and understanding of knee afflictions and to help in
building an international network for ICRS with high potential
and productive group dynamics.
Schmidt Tannin, Ass Prof., PhD
Centre for Bioengineering Research and
Education, University of Calgary, Calgary, Canada
Tannin Schmidt is also an Associate Director of
the Biomedical Engineering Graduate Program. He received his
B.A.Sc. in Engineering Science from the University of Toronto in
2000, then his MS and PhD in Bioengineering from the University
of California San Diego in 2002 and 2006, respectively. He
then completed a post doctoral fellowship in the Department
of Biochemistry at Rush University Medical Center, Chicago.
His bioengineering research interests lie within cartilage biomechanics,
biotribology, and biochemistry. Long term cartilage
research interests include mechanistic based, multidisciplinary
study of articular cartilage boundary lubrication through clinical,
biochemical and engineering collaborations. Relevant areas
include the study of normal, injured, and diseased cartilage and
synovial fluid, where composition, structure, and interactions of
mechanically relevant biomolecules, such as proteoglycan 4 (lubricin)
and hyaluronan, can be altered, as well as other tissues
in the joint affected by injury and disease.
Shive Matthew, BSc, MSc, PhD
Piramal Healthcare,
Laval, Montreal, CA
Matthew Shive is currently a consultant specializing
in research and development of orthopaedic medical devices.
Dr Shive received his B.S. from the Johns Hopkins University, and
his M.Sc. and Ph.D. from Case Western Reserve University, all in Biomedical
Engineering with a focus on Biomaterials. His scientific expertise
relates to the interactions between implanted biomaterials
and biological systems supported by over 100 publications, scientific
articles and conference proceedings in the fields of biomaterials,
tissue and cartilage repair. From 2000–2009, Dr Shive oversaw
product development as Chief Scientific Officer at BioSyntech Canada
Inc, a medical device company in Montreal that developed and
manufactured regenerative products for tissue repair. Notably, Dr.
Shive designed and implemented the clinical development program
for BST-CarGel, a device for cartilage repair, that was the subject of
a multicenter, randomized clinical trial in Canada, Spain and Korea
completed in Feb 2010 and which will now support commercialization
applications. The Company's assets were recently acquired
(June 2010) by Indian pharmaceutical giant, Piramal Healthcare. Dr.
Shive’s current efforts as a primary consultant to Piramal Healthcare
work towards completion of previous product development, clinical
and regulatory activities. He is responsible for analysis and interpretation
of efficacy data resulting from multicenter BST-CarGel clinical
trial and subsequent reporting and publications.
Spalding Tim, Ass Prof.
University of Warwick Leamington, UK
Tim Spalding is a specialist knee surgeon at
University Hospitals Coventry and Warwickshire
NHS Trust and Honorary Associate Professor at the University
of Warwick. His specialist interest in reconstructive knee surgery
includes meniscal transplantation, articular cartilage repair,
ligament reconstruction including multi-ligament injuries, and
osteotomy. Training took place in Oxford and at Royal Hospital
Haslar, prior to a specialist arthroscopy and knee surgery fellowship
in Toronto in 1994–1995. He qualified in 1982 from Charing
Cross Hospital, London and spent the first part of his medical
career with the Royal Marines and the Royal Navy. He joined Coventry
in 2000 after 5 years as a Consultant in the armed forces.
He has a busy sports knee surgery practise, runs a knee fellowship
program and continues to be very active in teaching and
research, pioneering several new techniques. His hobbies are
his family and his competitive sailing.

Invited Faculty 2012 in alphabetical order (not complete)
Steinwachs Matthias, Prof. h.c. PD MD
Schulthess Klinik
Zurich, Switzerland
Consultant Orthopaedics, Traumatology & Sports
Medicine, Head of the Center of Orthobiologics & Cartilage Repair,
Schulthess Klinik, Zürich, (FIFA Medical Centre of Excellence, Swiss
Olympic Base, Member of ISOC). Study of Medicine, University of
Heidelberg & Göttingen, 1990 Research study at the Dept. of Pharmacology
and Toxicology, University of Göttingen, 1/1991–3/1992
Ass. Doctor Dept. of Trauma Surgery, Bernward-Hospital Hildesheim,
1992 Dissertation MD/PhD University of Göttingen, 1997
Specialist education, Dept. for Orthopaedic Surgery, University
of Freiburg, 1995 Training by Prof. L. Peterson, GMC Gothenburg,
Sweden, 1997 Specialist exam for Orthopaedic Surgery, University
of Freiburg, 1997–2007 Specialist for Cartilage Repair and Tissue
Engineering, Knee Surgery, Dept. of Orthopaedic and Trauma
Surgery, University Hospital Freiburg, 1998–2007 Member of the
Steering Committee Valley Tissue Engineering Centre University
Freiburg, 1998–2007 Head of the Cartilage Research Group, Valley
TEC Freiburg, 12/2004 “Privatdozent” (Habilitation), Venia legendi
for Orthopaedic Surgery, University Freiburg, 2003–2007 Head of
the first Cartilage Transplantation Unit, Dept. of Orthopaedic and
Trauma Surgery, University Hospital Freiburg, 2003- Expert of
“Bundesausschuss Krankenhaus (G-BA), Methodenbewertung
ACT”, 2005-Member of the Expert board BMBF Project „Regenerative
Medizin, 2006 Professional Development for Sports Medicine,
2006 Honorary Professor Inst. of Sports medicine, Peking University
2007, 2008 Specialist for Orthopaedic & Traumatology 2008
Member of Expert board EMEA, London and Paul Erlich-Inst. (PEI,
Langen), Congress President AGA 2012, Zürich. ICRS Board Member
2004–2008, Chair of the outcome committee of the ICRS 2008.).
Van Osch Gerjo, Prof., PhD
Erasmus MC, University Medical Center
Rotterdam, Netherlands
Gerjo van Osch (1967) studied medical biology at
the University of Utrecht (MSc 1990) and received her PhD in 1994
at the University of Nijmegen on animal models for osteoarthritis.
Since then she became involved in cartilage tissue engineering and
especially the use of different cell types and growth factors. She is
currently appointed as associate Professor at the Erasmus MC, University
Medical Center in Rotterdam the Netherlands where she is
leading a research group of approx. 12 people that is part of the departments
of Orthopaedics and Otorhinolaryngology. Her research
focuses on cellular aspects of connective tissue degeneration and
regeneration. (www.erasmusmc.nl/orthopaedie/research/labor/
CTCRgroup). Gerjo van Osch has been working in the field of cartilage
since 1990. She is co-author on over 100 international peer-reviewed
publications. She has been active in various committees of the
International Cartilage Repair Society (ICRS). She served as council
member of the European chapter of the TERMIS and chaired the
TERMIS-EU meeting in Rotterdam in 2006. Presently she is board
member of ICRS and European Science Foundation network on Regenerative
Medicine (REMEDIC). She is associate editor of Cartilage
and editorial board member of Tissue Engineering and Journal of
Tissue Engineering and Regenerative medicine.
Van Roermund Peter, MD
University Medical Center Utrecht, Netherlands
Peter van Roermund was born on 30 April 1949 in Kockengen,
The Netherlands. His Professional experience:
1985 – today staff member, department of orthopaedics ,UMC Utrecht.
2001–2003: President Dutch Orthopaedic Society, 2005-present: President
Bone and Joint Decade the Netherlands. Reports and documents written:
Thesis in 1994: Tibial lengthening by distraction epiphysiolysis. Clinical
and experimental studies. University of Utrecht, Award 2002: The Kenneth
A.Johnson Memorial Award and Lecturer AOFAS winter meeting Dallas USA:
joint distraction as treatment of OA ankle joints.
Walsh David, Prof.
Arthritis Research UK Pain Centre
University of Nottingham, UK
David Walsh is a clinical academic at the University of
Nottingham Medical School and Director of the Arthritis Research UK Pain
Centre. The Centre undertakes a translational programme of research exploring
the mechanisms by which changes within the joint and in the nervous
system interact with psychosocial factors to result in the pain of arthritis in
order to develop new treatments and to enhance the effectiveness of current
therapies. His preclinical research has focused on structural changes
that contribute to joint pain, in particular angiogenesis, nerve growth and
inflammation in the synovium and subchondral bone. This research benefits
from a repository of joint tissues donated by > 2500 people with arthritis
and > 400 post mortem cases, complemented by a range of preclinical inflammatory
and osteoarthritis models. He is also co-Chief Investigator of
the Early Rheumatoid Arthritis Network (ERAN), a registry for patients with
Early RA recruiting from centres across the UK and Eire. Professor Walsh is
Consultant Rheumatologist at Sherwood Forest Hospitals NHS Foundation
Trust, where he developed an Early Rheumatoid Arthritis service and is Clinical
Director of the Back Pain Unit, providing multidisciplinary Pain Management
Programmes for people with chronic low back pain.
Welsch Goetz, Ass Prof.
University of Erlangen, Department of Trauma
Surgery, Erlangen, Germany
Goetz H. Welsch is a German board certified orthopaedic
and trauma surgeon with the speciality of knee surgery and sports medicine.
Furthermore he is team physician of a Professional German soccer
team. His clinical and scientific focus is since more than 10 years regenerative
cartilage therapy including different techniques of cartilage repair procedures.
Besides this, Dr. Welsch is a well known musculoskeletal imaging
expert in close collaboration with the Medical University of Vienna, Austria.
He has been involved in several studies mainly concerning advanced
MR imaging technologies in cartilage repair. In this field he has published
many studies about the MOCART score and recently the 3D MOCART score.
Furthermore he works very intensely in biochemical cartilage imaging techniques
like T2 mapping, dGEMRIC, T1rho and Diffusion Weighted Imaging.
Especially within the field of quantitative T2 mapping, Dr. Welsch published
many studies and is one of the most active researchers world-wide.
Dr. Welsch is member of different orthopaedic and radiological societies,
authored more than 60 peer-reviewed papers and about 20 book chapters,
is an active reviewer for more than 15 journals and in the advisory board of
Archives of Orthopaedic and Trauma Surgery (AOTS).
45

46
Industry Exhibition & Sponsoring
Technical Exhibit Opening Hours
Saturday 12.00 – 20.00 hrs.*
Sunday 09.00 – 18.00 hrs.
Monday 09.00 – 18.00 hrs.
Tuesday 09.00 – noon.
Sufficient time during intermissions is reserved for visiting
the booths of leading manufacturers which present
the latest achievements and give competent information.
For detailed information on the exhibiting companies,
please consult the exhibit guide on the following pages.
ICRS 2012 and the ICRS Society express their gratitude
to all collaborators and volunteers for this meeting.
Particularly the participation of the following companies
is much appreciated and gratefully acknowledged:
Exhibitors (Alphabetical Order)
Company Booth Nr.
Anika Therapeutics Inc. 15
Arthrex, Inc. 13
ArthroCare 19
Bacterin 14
Biomomentum Inc 18
BioPoly 20
BioTissue AG 26
Croma-Pharma GesmbH 5
DePuy Mitek 23
DJO Global 2
Fin-Ceramica Faenza S.p.A 11
Geistlich Pharma AG 8
Harvest Technologies 14A
Histogenics 25
Knee Creations, LLC 22
Moximed, Inc. 10
Piramal Healthcare Ltd. 7
REGEN Lab 17
Regentis Biomaterials LTD 16
SAGE Publications 9
Sanofi Genzyme Biosurgery 6
SBM Inc. Science & Bio Materials 12
Smith & Nephew Inc. 4
Tigenix 1
Zimmer Inc. 3
Donors and Sponsors
Platinum Sponsors
Geistlich Surgery, Wolhusen, CH
Sanofi Biosurgery, Cambridge, USA
Zimmer Inc., Austin, USA
Piramal Healthcare Ltd., Montreal, Canada
Smith & Nephew Inc., Andover, USA
Silver Sponsor
Tigenix, Leuven, BE
Other Sponsors
Anika Therapeutics, Inc., Bedford, USA
DJO International, Guildford, UK
Exhibitors (Numerical Order)
Company Booth Nr.
Tigenix 1
DJO Global 2
Zimmer Inc. 3
Smith & Nephew Inc. 4
Croma-Pharma GesmbH 5
Sanofi Genzyme Biosurgery 6
Piramal Healthcare Ltd. 7
Geistlich Pharma AG 8
SAGE Publications 9
Moximed, Inc. 10
Fin-Ceramica Faenza S.p.A 11
SBM Inc. Science & Bio Materials 12
Arthrex, Inc. 13
Bacterin 14
Harvest Technologies 14A
Anika Therapeutics Inc. 15
Regentis Biomaterials LTD 16
REGEN Lab 17
Biomomentum Inc 18
ArthroCare 19
BioPoly 20
Knee Creations, LLC 22
DePuy Mitek 23
Histogenics 25
BioTissue AG 26

Situation Plan
47

48
Exhibitor’s Guide (a – z)
Anika Therapeutics Inc. Booth Nr. 15
32 Wiggins Avenue
Bedford, MA 01730, USA
Phone +1 781 457 9000
jointhealth@anikatherapeutics.com
www.anikatherapeutics.com
Anika Therapeutics is a pioneer in developing therapeutic
products for tissue protection, healing and repair. These
products are based on hyaluronic acid (HA), a naturally
occurring polymer found throughout the body. With the
recent acquisition of Fidia Advanced Biopolymers, S.r.l.,
Anika has expanded its range of orthopedic HA products
from pain relief to cartilage repair and regeneration.
Hyalograft ® C autograft is the first bio-engineered cartilage
for minimally invasive surgical procedures. More than
5,000 patients have been treated to date with Hyalograft
C autograft. Hyalofast is a HA matrix for arthroscopic
use in single step cartilage repair procedures. It is highly
conformable and can be used without fixation in most
cases.
Anika’s portfolio of viscosupplements includes MONO-
VISC, ORTHOVISC ® and ORTHOVISC ® mini. MONOVISC
is formulated specifically for treatment with a singleinjection.
FDA approved ORTHOVISC is a three injection
regimen, and ORTHOVISC mini is designed to treat small
joints.
To learn more about Anika’s cartilage regeneration products,
please visit us at Booth 15.
Arthrex Inc. Booth Nr. 13
1370 Creekside Blvd.
Naples, FL 34108
www.arthrex.com
Please stop by booth #13 for a hands-on demonstration
using our new iBalance HTO & UKA Systems, BioMatrix
Cartilage Repair Device and ArthroFlex Systems, just to
name a few.
ArthroCare Corporation Booth Nr. 21
Sports Medicine
Austin, TX 78735, USA
www.arthrocare.com
Bacterin International Holdings Inc. Booth Nr. 14
732 Cruiser Lane
Belgrade, MT 59714
Phone: 406.388.0480
Fax: 406.388.0915
mkoch@bacterin.com
www.bacterin.com
Bacterin develops innovative biologics designed for specific
surgical procedures. Proprietary scaffolds, such as
OsteoSponge ® and OsteoSelect ® DBM Putty, provide superior
handling characteristics and osteoinductive properties
for optimal surgical outcomes.
Biomomentum Inc. Booth Nr. 18
970 Michelin, Suite 200
Laval, Quebec, H7L 5C1, Canada
Tel: (450) 667-2299
info@biomomentum.com
www.biomomentum.com
Biomomentum specializes in providing solutions for the
biomechanical evaluation of biomaterials and cartilage.
The Arthro-BST is a hand-held medical device used in
conjunction with arthroscopic procedures for the nondestructive
measurement of compression-induced streaming
potentials of articular cartilage. The instrument
measures streaming potentials generated during gentle
compression of the articular cartilage and calculates a
quantitative parameter reflecting its electromechanical
properties. Scientific literature has indicated that streaming
potentials are not only a function of the stiffness
of cartilage, but also of its composition, structure, and
thickness. In addition to its clinical applications, the Arthro-BST
offers a vast array of research opportunities
in the field of cartilage repair.
The company also commercializes the Mach-1, a modular,
multiple-axis mechanical tester capable of performing
compression, tension, shear, and torsion tests for
the precise characterization and mechanical stimulation
of cartilage and other soft tissue or materials. Biomomentum
also offers biomechanical testing services using
its unique instrumentation.

Exhibitor’s Guide (a – z)
BioPoly, LLC Booth Nr. 20
a Schwartz Biomedical Company
3201 Stellhorn Rd.
Fort Wayne, Indiana 46815, USA
Phone: 260-399-1694
Fax: 260-492-0452
info@BioPolyortho.com
www.BioPolyortho.com
BioPoly, LLC is committed to advancing materials and
device designs to address orthopaedic problems. The
BioPoly ® RS Knee System is the leading product in the
company’s pipeline. This product is a family of femoral
condyle partial resurfacing devices uniquely designed
to restore the knee’s articulating surfaces. Made from a
patented microcomposite of Hyaluronic Acid and UHM-
WPE, the BioPoly ® RS Knee implant provides a smooth,
hydrophilic and lubricous surface to interface favorably
with native joint tissues while at the same time supporting
anatomical loads. Stop by our booth to learn more
about this new technology and other applications under
development.
BioTissue AG Booth Nr. 26
Seefeldstrasse 279 A
CH-8008 Zurich, Switzerland
Phone: +41 43 222 4004
customerservice@biotissue.ch
www.biotissue.ch
For almost 15 years BioTissue has been the pioneer par
excellence in the field of cartilage regeneration treatments.
BioTissue combines state of the art applied science
with the growing demands of orthopaedic treatment
methods. This is made possible by the BioTissue´s
experienced and visional R&D team, a hi-tech GMP Lab
and by the continuous scientific exchange with clinicians.
This year´s booth is dedicated to chondrotissue ® , the
cell-free implant for joint cartilage repair.
• chondrotissue ® is used in a one-step procedure in
combination with microfracturing.
• chondrotissue ® ´s capacity to form highly advanced
hyaline-like cartilage tissue has been proven in ex-
tensive preclinical and clinical studies, confirmed by
detailed histological stainings.
• chondrotissue ® has unique shape and mechanical sta-
bility, allowing a stable subchondral fixation with nails
and anchors.
Croma-Pharma GmbH Booth Nr. 5
Stockerauerstr. 181
2100 Korneuburg, Austria
Phone: +43/2262/684 68-0
Fax +43/2262/ 68468-4
www.croma.at
Contact person: Mr. Arthur Fleischmann
Croma-Pharma, an internationally operating pharmaceutical
company headquartered in Austria, is a leading
manufacturer of sterilized ready-to-use syringes of viscoelastic
hyaluronic acid for intra-articular use. Full dedication
to and achievement of highest quality is guaranteed.
DePuy Mitek Booth Nr. 23
a Johnson & Johnson Company
325 Paramount Drive
Raynham, MA 02767, USA
www.depuymitek.com
DePuy Mitek, Inc., a Johnson & Johnson company, is the
leading developer and manufacturer of innovative surgical
sports medicine and soft tissue repair devices. The
company offers a vast array of surgical solutions to assist
in addressing the challenges of soft tissue repair.
Through the on-going process of improving upon and
creating new, technologically advanced materials, instruments
and techniques, DePuy Mitek looks for continued
growth in developing the means to advance procedural
solutions in the field of sports medicine.
DJO Global Inc. Booth Nr. 2
1430 Decision St
Vista, CA 92081, USA
Phone: 760.734.3125
Fax: 760.734.3595
www.djoglobal.com
DJO is a leading global developer, manufacturer and
distributor of high-quality medical devices that provide
solutions for musculoskeletal health, vascular health
and pain management. The Company’s products address
the continuum of patient care from injury prevention to
rehabilitation after surgery, injury or from degenerative
disease.
Our products are used by orthopedic specialists, spine
surgeons, primary care physicians, pain management
49

50
Exhibitor’s Guide (a – z)
specialists, physical therapists, podiatrists, chiropractors,
athletic trainers and other healthcare professionals.
In addition, many of the Company’s medical devices and
related accessories are used by athletes and patients for
injury prevention and at-home physical therapy treatment.
The Company’s product lines include rigid and soft orthopedic
bracing, hot and cold therapy, bone growth stimulators,
vascular systems, electrical stimulators used for
pain management and physical therapy products. The
Company’s surgical division offers a comprehensive suite
of reconstructive joint products for the hip, knee and
shoulder. DJO’s products are marketed under the brands
Aircast ® , DonJoy ® , ProCare ® , CMF, Empi ® , Saunders ® ,
Chattanooga Group, DJO Surgical, Cefar ® - Compex ®
and Ormed ® . For additional information on the Company,
please visit www.DJOglobal.com.
FIN-CERAMICA Faenza S.p.A Booth Nr. 11
Via Granarolo 177/3
48018 Faenza (RA) ITALY
www.finceramica.com
ddonati@finceramica.it
www.finceramica.it
Finceramica develops and produces propietary bone and
cartilage substitutes, including custom-made solutions
for particular clinical needs. Research activity focuses on
innovative bioceramic materials, ceramic-polymer composites
and a new generation of biologial joint replacements
and knee resurfacings.
Geistlich Pharma AG Booth Nr. 8
Business Unit Surgery
Bahnhofstrasse 40
6110 Wolhusen, Switzerland
Phone: +41 41 492 55 55
Fax: +41 41 492 56 39
surgery@geistlich.com
www.geistlich-surgery.com
Geistlich Surgery develops premier global solutions for
the formation of bone and cartilage in the rapidly advancing
field of regenerative medicine.
Chondro-Gide ® is the leading natural collagen matrix in
cartilage regeneration. This standardised, easy to handle
matrix can be used to treat cartilage defects using the
innovative AMIC ® technique or using ACI.
AMIC ® is a single-step, cost efficient and effective procedure
for treating traumatic cartilage defects. Chondro-
Gide ® provides a suitable cell carrier and positively influences
chondrogenic differentiation of mesenchymal
stem cells to form a mostly hyaline-like cartilaginous
repair tissue.
Orthoss ® is a natural bone graft substitute. Its inorganic
bone matrix has a macro- and microporous structure similar
to human spongeous bone. It is structurally integrated
into the surrounding bone and incorporated into the
natural remodelling process. As a result of the excellent
biofunctionality, Orthoss ® is an ideal bone graft substitute
which can be used alone or during composite bone
grafting using autologous bone or bone marrow aspirate
when treating large defects. This includes the repair of
defects following trauma, reconstruction in orthopaedics
and in spinal surgery. Over 25 years of clinical experience
show a high degree of safety and efficacy.
Harvest Technologies Corp. Booth Nr. 14a
40 Grissom Road, Suite 100
Plymouth, MA 02360, USA
Phone: 508-732-7500
Toll Free (U.S.): +1-877-842-7837
Fax: 508-732-0400
info@harvesttech.com
www.harvesttech.com
Developing Technologies for Accelerating Healing, NaturallyÒ,
Harvest manufactures the SmartPRePÒ BMACÒ
(Bone Marrow Aspirate Concentrate) System for Concentrating
Autologous Adult Stem Cells and the SmartPReP
APC+Ò System for Concentrating Platelets.
Harvest’s BMACÒ System is the first technology that rapidly
concentrates clinically significant amounts of stem
and precursor cells from a small aspirate of autologous
bone marrow at patient point-of-care. As little as 30-60ml
of bone marrow aspirate can be concentrated at point of
care in just 15 minutes. The SmartPReP BMAC2 series
efficiently concentrates and recovers regenerative cells
while retaining their cellular viability and proliferative
potential. With minimal processing time, concentrated
autologous adult stem cells are now available to the clinician
at patient point-of-care.
Harvest’s APC+Ò System for concentrating platelets
starts with only 20ml of patient blood and produces
a platelet concentrate enriched with multiple growth

Exhibitor’s Guide (a – z)
factors and white blood cells, at 4X or greater above
baseline--the clinical requirement needed to accelerate
wound healing.
The SmartPReP BMAC and APC+ Systems make concentrated
autologous adult stem cells and concentrated platelets
available to the clinician as needed, with minimal
processing time, at patient point-of-care.
Histogenics Corp. Booth Nr. 25
830 Winter Street
Waltham, MA 02451, USA
www.histogenics.com
Histogenics is a leading regenerative medicine company
that combines cell therapy and tissue engineering technologies
to develop highly innovative products for tissue
repair and regeneration. The company’s flagship products
focus on the treatment of active patients suffering
from articular cartilage derived pain and immobility.
Histogenics has developed technology and products
to reverse or prevent cartilage damage, regenerating
healthy hyaline cartilage tissue. NeoCart ® , autologous
engineered neocartilage grown outside the body using
the patient’s own cells, has been developed for regeneration
of full thickness cartilage lesions. The VeriCart
single-step cartilage matrix is a cell-free matrix designed
to be used in conjunction with marrow-stimulating procedures,
or alternatively, reconstituted with the patient’s
bone marrow, thereby initiating the repair process. The
goal: solutions upstream to Osteoarthritis that restore
patients to an active lifestyle that can last all life long.
Knee Creations Booth Nr. 22
West Chester, PA, USA
customerservice@kneecreations.com
www.kneecreations.com
Knee Creations develops innovative bone-based technologies,
procedures, and instrumentation. Knee Creations
pioneered the Subchondroplasty (SCP ® ) procedure, a
minimally invasive treatment of defects associated with
bone marrow edema. Bone marrow edema is a known,
painful element of osteoarthritis (OA), a disease which affects
one in two Americans. SCP ® effectively targets bone
defects that are not addressed by current arthroscopic
and conservative care treatments.
Moximed ® Inc. Booth Nr. 10
26460 Corporate Ave, Suite 100
Hayward, CA 94545 USA
Phone: +1 510 887 3300
Fax: +1 510 887 3499
www.moximed.com
info@moximed.com
Moximed ® , Inc. is dedicated to improving the standard of
care for patients with osteoarthritis (OA) and is initially
focused on developing joint sparing solutions for patients
with knee OA.
The KineSpring ® System is an implantable load absorber
designed to relieve pain and improve function in patients
suffering from medial knee OA and who might be
too young, too active, or otherwise disinclined for HTO
or UKA. The concept of joint unloading is a proven treatment:
orthotics, braces, and HTO can relieve OA pain,
and recent studies indicate that reducing joint load can
potentially delay OA progression or regenerate damaged
cartilage.
The KineSpring System consists of an implantable, extracapsular
load absorber and femoral and tibial base components.
The device is implanted in a standard orthopaedic
procedure that does not require any bone, ligament,
or cartilage removal. The extra-capsular positioning and
structure preserving technique creates an essentially reversible
procedure.
The KineSpring System has been evaluated by leading
surgeons in multiple, international clinical studies over
the past four years. It has been granted CE Mark and is
currently available for sale in select centers in Europe
and Australia.
To learn more about Moximed and the KineSpring System,
please visit us at Stand 10.
51

52
Exhibitor’s Guide (a – z)
Piramal Healthcare Ltd Booth Nr. 7
475 Boulevard Armand Frappier
Laval, Canada
www.piramal.com
Piramal Healthcare Ltd, a Piramal Group company, is a
globally integrated healthcare company with a diverse
product portfolio spanning several therapeutic areas,
and a growing commitment in Bio-Orthopedics. Piramal
Healthcare Ltd is one of the largest custom healthcare
manufacturing companies with a footprint across North
America, Europe and Asia.
Since 2005, Piramal Healthcare has devoted itself to
bio-orthopedic research through strategic investments
in Canadian innovations such as BST-CarGel ® , a novel bioscaffold
for advanced cartilage regeneration which was
shown clinically to result in consistently higher quality
cartilage repair while at the same time being economically
viable within challenging reimbursement healthcare
systems. Being introduced to the European and Canadian
orthopedic communities in 2012, BST-CarGel ® offers a
new standard in cartilage regeneration.
At Piramal Healthcare, our core values of Knowledge, Action
and Care propel us to improve the quality of lives by
democratizing healthcare. We aim to attain leadership in
market share and innovation by:
• Partnering with the medical fraternity
• Building strong capabilities to deliver product and process
innovations
• Attracting and developing the best in class talent
Piramal Healthcare, a proud Platinum sponsor of ICRS 2012
Regen Lab Booth Nr. 17
En Budron B2
CH - 1052 Le Mont-sur-Lausanne
Switzerland
Phone: +41 (0)21 864 01 11
Fax +41 (0)21 864 01 10
www.regenlab.com
Regen Lab is recognized as the leading provider of patented
technologies to produce Autologous Platelet Rich
Plasma (A-PRP) and other cell concentrates. The technology
is processing the patient´s own blood, fat or bone
marrow to use the concentrated cells for indications in
various medical disciplines such as sports medicine,
wound healing and aesthetics. Regen Lab is an independent
biotech company from Lausanne (Switzerland)
that has been established in 2003 and is marketing its
products worldwide. Its Medical Devices for the close
circuit preparation of Autologous Platelet Rich Plasma
are known under the RegenACR ® and RegenKit ® brand
names.
Regentis Biomaterials Ltd. Booth Nr. 16
2 Ha'Ilan Street, Northern Industrial Zone
P.O.Box 260, Or-Akiva 30600, Israel
Livnat@regentis.co.il
www.regentis.co.il
Regentis Biomaterials is a tissue repair company developing
innovative biodegradable hydrogels for local repair
of soft and hard tissue. Our platform technology is
a family of hydrogels called Gelrin. These gels can be
injected or applied to a specific local site and offer beneficial
properties for the local repair of damaged tissue
such as cartilage and bone.
The Gelrin technology offers off-the-shelf products
that are designed to be suitable for both open surgery
and minimally invasive procedures. An ideal solution for
physicians and their patients, the products are easy to
implant and have been shown to stimulate the regeneration
of healthy cartilage and bone tissue.
Regentis’ first orthopedic product is GelrinC, a biodegradable
hydrogel for articular cartilage regeneration, providing
a controlled environment for gradual tissue repair
and formation of hyaline-like cartilage. GelrinC is comprised
of polyethylene glycol diacrylate (PEG-DA) and
denatured fibrinogen, a natural substrate for tissue regeneration.
These materials form a matrix for tissue repair
– combining the stability and versatility of a synthetic
material with the bio-functionality of a natural material.
CAUTION: GelrinC is an investigational product, not
available in Europe and in the US

Exhibitor’s Guide (a – z)
SAGE Booth Nr. 9
2455 Teller Road
Thousand Oaks, CA 91320, USA
lisa.lamont@sagepub.com
www.sagepub.com
SAGE is a leading international publisher of journals,
books, and electronic media for academic, educational,
and professional markets. Since 1965, SAGE has helped
educate a global community spanning a wide range of
subject areas including business, humanities, social sciences,
and science, technology, and medicine. Visit us at
www.sagepub.com.
Sanofi Biosurgery Booth Nr. 6
55 Cambridge Parkway
Cambridge, MA 02142, USA
www.genzyme.com
Sanofi Biosurgery is a global strategic business unit of
Sanofi. It develops and markets innovative, biologically
based products for osteoarthritis relief, adhesion prevention,
cartilage repair, and severe burn treatment.
Sanofi Biosurgery’s products include: Synvisc ® , Synvisc-
One (hylan G-F 20), Carticel ® (autologous cultured
chondrocytes), MACI ® (Matrix-induced Autologous Chondrocyte
Implantation), Seprafilm ® and Epicel ® (cultured
epidermal autografts). Sanofi Biosurgery is committed
to transforming disease management through innovative
medical interventions.
About Sanofi
Sanofi, a global and diversified healthcare leader, discovers,
develops and distributes therapeutic solutions
focused on patients’ needs. Sanofi has core strengths in
the field of healthcare with seven growth platforms: diabetes
solutions, human vaccines, innovative drugs, consumer
healthcare, emerging markets, animal health and
the new Genzyme. Sanofi is listed in Paris (EURONEXT:
SAN) and in New York (NYSE: SNY).
SBM Inc. Booth Nr. 12
19 Hancock St
Winchester, MA, USA
gboue@s-b-m.us
www.s-b-m.us
Since 1991, SBM innovates in the field of orthopaedic biosurgery
by working closely with renowned surgeons to
design and manufacture unique solutions based on bioresorbable
materials, e.g. Bone void fillers, ACL composite
fixations. In 1996, SBM has been the first company to
manufacture a resorbable and load-bearing implant for
Opening Wedge High Tibial Osteotomies.
Today, SBM is perfecting its HTO system with a very
unique locking dual-compression plate that promotes
faster Bone healing, causes less post-operative pain and
leads to quicker return to function.
Smith & Nephew Booth Nr. 4
150 Minuteman Road
Andover, MA 01810, USA
www.smith-nephew.com
Smith & Nephew is a global medical technology business
with global leadership positions in Orthopaedic
Reconstruction, Advanced Wound Management, Sports
Medicine, Trauma and Clinical Therapies. The Company
has distribution channels, purchasing agents and buying
entities in over 90 countries worldwide. Annual sales in
2010 were nearly $4.0 billion.
Smith & Nephew is dedicated to helping improve people's
lives. The Company prides itself on the strength of its relationships
with its surgeons and professional healthcare
customers, with whom its name is synonymous with
high standards of performance, innovation and trust.
In established markets such as the United States, Canada,
Europe, Japan, Australia and New Zealand we operate
Advanced Surgical Devices and Advanced Would
Management.
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Exhibitor’s Guide (a – z)
Our Advanced Surgical Devices Division consists of:
- Orthopaedic Reconstruction in the form of hip/knee/
shoulder implants
- Trauma products that help heal broken bones and cor-
rect deformities
- Biologics Clinical Therapies including next generati-
on tissue repair treatments and therapies that provide
everything from bone growth stimulation to relief from
back pain
- Sports Medicine instruments used to access, visualize,
resect and repair injuries through minimally invasive
surgery (arthroscopy)
Our Advanced Wound Management Division develops
innovative dressings and systems that provide faster healing
and infection protection for patients with chronic,
hard-to-heal wounds. Our Emerging Markets Organization
focuses on Brazil, Russia, India and China. Our International
Organization focuses on all the other countries
and regions, such as South Africa, the Middle East, South
East Asia and Central and Latin America
Across the Group as a whole, we benefit from being a
truly global company, with approximately 45% of our revenue
being in the US, 30% in Europe and 25% in rest
of world.
TiGenix NV Booth Nr. 1
Researchpark Haasrode 1724
Romeinse straat 12 bus 2
3001 Leuven, Belgium
Phone: +32 (0) 16 39 60 60
Fax: +32 (0) 16 39 79 70
info@tigenix.com
www.tigenix.com
TiGenix NV (NYSE Euronext: TIG) is a leading European
cell therapy company with two marketed products and a
strong clinical stage pipeline of adult stem cell programs.
The company’s lead product, ChondroCelect ® , for cartilage
repair in the knee, is the first and only approved cellbased
product in Europe, and is currently being launched
in different European countries.
TiGenix’s stem cell programs are based on a validated
platform of allogeneic expanded adipose-derived stem
cells (eASCs) targeting autoimmune and inflammatory
diseases.
Built on solid pre-clinical and CMC packages, they are
being developed in close consultation with the European
Medicines Agency. The company is slated to start a
Phase III clinical trial in complex perianal fistulas in patients
with Crohn’s disease, is conducting a Phase IIa trial
in rheumatoid arthritis, and in early 2012 will initiate a
Phase I trial to investigate the potential of intra-lymphatic
administration of eASCs for autoimmune disorders.
TiGenix is based out of Leuven (Belgium), and has operations
in Madrid (Spain), Cambridge (UK) and Sittard-
Geleen (the Netherlands). For more information please
visit www.tigenix.com.
Zimmer Inc. Booth Nr. 3
9301 Amberglen Blvd
Austin, Tx 78729, USA
www.zimmer.com
Founded in 1927 and headquartered in Warsaw, Indiana,
Zimmer designs, develops, manufactures and markets
orthopaedic reconstructive, spinal and trauma devices,
dental implants, and related surgical products. Zimmer
has operations in more than 25 countries around the
world and sells products in more than 100 countries.
Zimmer's 2011 sales were approximately $4.5 billion. The
Company is supported by the efforts of more than 8,500
employees worldwide. For more information about Zimmer,
visit www.zimmer.com

10 th World Congress of the
International Cartilage Repair Society
ICRS 2012
May 12 – 15, 2012
Agenda
Scientific Programme
“Advancing science & education in cartilage repair worldwide!”
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Programme: Saturday, May 12, 2012
ICRS Editorial Board Meeting Room: Chaudiere
07:30 – 08:30
ICRS Executive Board Meeting Room: Chaudiere
09:00 – 10:30
ICRS General Board Meeting Room: Chaudiere
10:30 – 12:00
Session 1.0 Plenary
Sports Injury: ICRS - FIFA Session
13:00 – 14:00 Room: Grand Salon
Moderators: Bert Mandelbaum (US), Stefano Della Villa (IT)
1.1 Articular Cartilage Mechanisms, Management and Outcome
B. Mandelbaum, Santa Monica/US
1.2 Basic science mechanisms & animal models of articular cartilage injury
M.B. Hurtig, Guelph/CA
1.3 Cartilage problems in the athlete: The scope of the problem
K. Mithoefer, Chestnut Hill/US
1.4 Injury repair options in the athlete - Special concerns
B. Mandelbaum, Santa Monica/US
Session 2.1 Special
Growth Factors, Morphogens & Cytokines
14:15 – 15:15 Room: Grand Salon
Moderators: Gerjo Van Osch (NL), Maurizio Pacifici (US)
2.1.1 Growth factors pathways as regulators of chondrogenesis
F. Beier, London/CA
2.1.2 Signaling proteins and transcription factors in joint development and degeneration
M. Pacifici, M. Iwamoto, Philadelphia/US
2.1.3 Growth factors in cartilage homeostasis in vitro / in vivo
S. Chubinskaya, Chicago/US
Session 2.2 Special
Nerve Dependence on Cartilage Development, Repair and Joint Pain
14:15 – 15:15 Room: Marquette
Moderators: Mats Brittberg (SE), Norimasa Nakamura (JP)
2.2.1 Nerve dependence and cartilage development during Urodele limb regeneration and its
relevance to mammals.
M. Maden, Gainesville/US

Programme: Saturday, May 12, 2012
2.2.2 Neurogenic factors in the etiopathogenesis of osteoarthritis
D. Walsh, Nottingham/UK
2.2.3 Cartilage lesions; which lesions are painful and what is the cause of pain ?
M. Brittberg, Kungsbacka/SE
Session 2.3 Special
Femoropatellar Joint
14:15 – 15:15 Room: Jolliet
Moderators: Christoph Erggelet (CH), Tim Spalding (UK)
2.3.1 Cartilage defects in the femoropatellar joint
B.J. Cole, Chicago/US
2.3.2 Clinical decisions for cartilage repair in the femoropatellar joint
T. Spalding, Coventry/UK
2.3.3 Surgical treatment and results
T. Minas, Chestnut Hill/US
Coffee Break/Industry Exhibition
15:15 – 15:45 Room: Exhibition Hall
Session 3.1 Special
Opportunities of Bioprinting in Cartilage Regeneration
15:45 – 16:45 Room: Jolliet
Moderators: Jos Malda (NL), Lawrence Bonassar (US)
3.1.1 Basic concepts and potential application of tissue/organ printing
D. Hutmacher, Brisbane/AU
3.1.2 Potential of natural and synthetic biomaterials for bioprinting
F.P.W. Melchels 1, 2 , W.J.A. Dhert 2 , D. Hutmacher 1 , J. Malda 1, 2 , 1 Kelvin Grove/AU, 2 Utrecht/NL
3.1.3 Bioprinting for osteochondral repair
L. Bonassar, Ithaca/US
Session 3.2 Special
Medication and Cartilage
15:45 – 16:45 Room: Marquette
Moderators: John Tarlton (UK), Wayne McIlwraith (US)
3.2.1 Effect of medications on articular cartilage health and repair
W. McIlwraith, Fort Collins/US
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Programme: Saturday, May 12, 2012
3.2.2 In vitro models for development and screening of cartilage repair strategies
G.J.V.M. Van Osch, Rotterdam/
3.2.3 Nutraceuticals & Osteoarthritis: Do omega-3 fatty acids, glucosamine & chondroitin sulphates
have chondro-protective actions?
B. Caterson, Cardiff/UK
Session 3.3 Special
Meniscus
15:45 – 16:45 Room: St. François
Moderators: Peter Verdonk (BE), Andreas Gomoll (US)
3.3.1 Can meniscus reconstruction prevent or even cure OA?
W. Gersoff, Denver/US
3.3.2 Clinical options for meniscus reconstruction and regeneration
R. Jakob, Fribourg/CH
3.3.3 How critical is the meniscus to the pathology of OA?
P. Lavigne, Montreal/CA
Session 4.0 Plenary
Opening Ceremony & Award Session
17:00 – 17:45 Room: Grand Salon
Session 5.0 Plenary
Honorary Lectures
17:45 – 18:45 Room: Grand Salon
5.1 Advances in understanding of post-traumatic osteoarthritis – Implications for treatment of joint injuries
J. Buckwalter, Iowa City/US
5.2 Cartilage Repair: Where are we now? Where are we going?
D. Grande, Manhasset/US
Welcome Reception Exhibition Hall
19:00 – 20:30

Programme: Sunday, May 13, 2012
Session 6.1 Instructional Course - Imaging of Cartilage Defects
07:30 – 08:15 Room: Jolliet
Moderators: Goetz Welsch (DE), Sebastian Apprich (AT)
Session 6.2 Meet the Experts (Basic Scientists)
07:30 – 08:15 Room: Marquette
Moderators: Sally Roberts (UK), Bruce Caterson (UK)
Session 7.0 Plenary
Clinical Studies using Cartilage Fragments
08:30 – 09:30 Room: Grand Salon
Moderators: Anthony Hollander (UK), Allan Gross (CA)
7.1 The use of autologous cartilage fragments – clinical studies
J. Farr, Greenwood/US
7.2 The use of allogenic cartilage fragments – clinical studies
D. Caborn, Louisville/US
Session 8.1 Special
Cartilage Repair in the Foot and Ankle Joint
09:45 – 10:45 Room: Marquette
Moderators: James Richardson (UK), Roland Jakob (CH)
8.1.1 Treatment of Osteochondral Lesions of the Talus
E. Giza, Sacramento/US
8.1.2 Clinical options for cartilage reconstruction in the ankle.
R. Ferkel, Van Nuys/US
8.1.3 Dermal graft application in Hallux Limitus / Rigidus for salvage of the 1st metatarsophallangeal joint
L.J. Sanchez, Orlando/US
Session 8.2 Special
Culture Techniques for Controlling Cell Differentiation
09:45 – 10:45 Room: Grand Salon
Moderators: Jan Schageman (US), Tim Welting (NL)
8.2.1 In vitro culture of chondrocytes - what are the limitations?
B. Johnstone, Portland/US
8.2.2 Expansion of chondrocyte populations on high extension culture surfaces for improved
retention of phenotype
T.M. Quinn 1 , B. Hinz 2 , M. Matmati 1 , D.H. Rosenzweig 1 , 1 Montreal/CA, 2 Toronto/CA
8.2.3 2D and 3D cultures of chondrocytes
T.J. Klein, Kelvin Grove/AU
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Programme: Sunday, May 13, 2012
Session 8.3 Special
Intervertebral Disc
09:45 – 10:45 Room: St. François
Moderators: Rita Kandel (CA), Susan Chubinskaya (US)
8.3.1 Intervertebral Disc Tissue Engineering: Is it ready for weight bearing?
R. Kandel, Toronto/CA
8.3.2 Current clinical treatment strategies and future concepts
S. Daisuke, Kanagawa, Isehara/JP
8.3.3 Materials for intervertebral disc tissue engineering
R. Mauck, M.B. Fisher, D.M. Elliott, Philadelphia/US
Coffee Break / Industry Exhibition
10:45 – 11:15 Room: Exhibition Hall
Session 9.1 Special
ICRS – ISAKOS Symposium "Joint Preservation"
11:15 – 12:45 Room: Grand Salon
Moderators: Norimasa Nakamura (JP), Rocky Tuan (US)
9.1.1 Cartilage repair to prevent osteoarthritis. – Fact or fiction?
T.S. De Windt, D.B.F. Saris, Utrecht/NL
9.1.2 What is the key pathway to prevent post-traumatic arthritis for future molecule-based therapy?
S. Chubinskaya, Chicago/US
9.1.3 ACL reconstruction and osteoarthritis: Evidence from long-term follow-up and potential solutions
R.A. Magnussen 1 , V. Duthon, E. Servien 2 , P. Neyret 2 , 1 Columbus/US, 2 Lyon Cedex 04/FR
9.1.4 Anatomic ACL Reconstruction – Current concept and future perspective
F.H. Fu, Pittsburgh/US
Session 9.2 Free Papers
Chondrocytes 1
11:15 – 12:45 Room: Marquette
Moderators: Stefan Marlovits (AT), William Bugbee (US)
9.2.1 Overview & Introduction
A. Nixon, Ithaca/US
9.2.2 Redifferentiation of Human Articular Chondrocytes in 2D versus 3D culture
M.M.J. Caron, P. Emans, M.M.E. Coolsen, L. Voss, D.A.M. Surtel, L.W. Van Rhijn,
T.J.M. Welting, Maastricht/NL
9.2.3 Effect of TGF – on Sox9 Function and Chondrocyte Phenotype
J. Perez 1 , H. Seo 2 , R. Serra 1 , 1 Birmingham/US, 2 Vancouver/CA

Programme: Sunday, May 13, 2012
9.2.4 Development of an intracellular flow cytometry assay of S100 for quantitative assessment of
chondrogenic potency
J. Diaz Romero, A. Quintin, D. Nesic, Bern/CH
9.2.5 An Unique Metabolic Profile of Human Acetabular Labrum Cells.
A.A.M. Dhollander 1 , S. Lambrecht 2 , P.C. Verdonk 1 , E.A. Audenaert 1 , K.F. Almqvist 1 , C. Pattyn 1 ,
R. Verdonk 1 , D. Elewaut 2 , G. Verbruggen 2 , 1 Ghent/BE, 2 Gent/BE
9.2.6 Advances in the Development of Engineered Ear
M.A. Randolph, A. Tseng, I. Pomerantseva, E. Bassett, J. Vacanti, C.A. Sundback, Boston/US
9.2.7 Monitoring COMP Expression during Articular Chondrocyte Compression
D. Amanatullah 1 , J. Lu 1 , J. Yik 1 , J. Hecht 2 , K. Posey 2 , P. Di Cesare 1 , D. Haudenschild 1 ,
1 Sacramento/US, 2 Houston/US
9.2.8 OA-chondrons outperform OA-chondrocytes in late-stage OA: relevance for biological therapy?
M. Rothdiener 1 , Q. Wang 1 , T. Uynuk-Ool 1 , T. Felka 1 , B.G. Ochs 1 , C. Bahrs 1 , U. Stoeckle 1 ,
A.J. Grodzinsky 2 , W.K. Aicher 1 , B. Rolauffs 1 , 1 Tuebingen/DE, 2 Cambridge/US
Session 9.3 Free Papers
Biomaterials & Scaffolds 1
11:15 – 12:45 Room: St. François
Moderators: Tim Woodfield (NZ), Jeremy Mao (US)
9.3.1 Overview & Introduction
J. Mao, New York/US
9.3.2 Low oxygen tension increases the tensile properties of engineered articular cartilage through
enzyme mediated collagen cross-linking.
E.A. Makris, K. Athanasiou, Davis/US
9.3.3 Hypoxia Promotes Phenotype Preservation of Human Chondrocytes Embedded within
Collagen Matrices
J. Sernik, R. Croutze, C.C. Secretan, L. Laouar, N.M. Jomha, A.B. Adesida, Edmonton/CA
9.3.4 Mesenchymal Stem Cells Show Improved Cartilage Formation on Extracellular Cartilage
Matrix-derived Scaffolds for Cartilage Defect Repair
K.E.M. Benders 1 , W. Boot 1 , P.R. Van Weeren 1 , D.B.F. Saris 1 , 2 , W.J.A. Dhert 1 , J. Malda 1 , 1 Utrecht/NL,
2 Enschede/NL
9.3.5 Natural polymer blends processed using ionic liquids can initiate chondrogenic differentiation
of mesenchymal stem cells
N. Singh 1 , S.S. Rahatekar 1 , K.K. Koziol 2 , A.J. Patil 1 , T.H.S. Ng 1 , S. Mann 1 , A.P. Hollander 1 ,
W. Kafienah 1 , 1 Bristol/UK, 2 Cambridge/UK
9.3.6 Chitosan modulates the ability of U937 macrophage-like cells to secrete chemokines and
attract human bone marrow-derived mesenchymal stem cells
D. Fong, M.B. Ariganello, S. Bolduc Beaudoin, C.D. Hoemann, Montreal/CA
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Programme: Sunday, May 13, 2012
9.3.7 Use of SDF and sphingosine impregnated scaffolds in addressing isolated cartilaginous defects
of the knee: can we stimulate hyaline cartilage regeneration?
N. Chinitz 1 , A. Catanzano 1 , P. Razzano 2 , N.V. Shah 2 , Z. Klapholz 2 , N.A. Sgaglione 2 , D. Grande 2 ,
1 New Hyde Park/US, 2 Manhasset/US
9.3.8 Scaffold and cell combination influence chondrogenesis in 3D coculture of chondrocytes with
mononuclear fraction cells
J.E.J. Bekkers, A.I. Tsuchida, A. Kolk, W.J.A. Dhert, D.B.F. Saris, L.B. Creemers, Utrecht/NL
9.3.9 A Self-Setting Hydrogel Mechanically reinforced with a marine polysaccharide as a Scaffold for
Cartilage Tissue Engineering
E. Rederstorff, C. Vinatier, S. Sourice, M. Masson, S. Colliec-Jouault, B.H. Fellah, P. Weiss,
J. Guicheux, Nantes/FR
Session 9.4 Free Papers
Other Musculoskeletal Tissues
11:15 – 12:45 Room: Jolliet
Moderators: Stefan Nehrer (AT), Sally Roberts (UK)
9.4.1 Decreased hypertrophic differentiation accompanies enhanced matrix formation in cocultures
of outer meniscus cells with bone marrow mesenchymal stromal cells
D. Saliken, A. Sierra-Mulet, N.M. Jomha, A. Adesida, Edmonton/CA
9.4.2 The effect of arthroscopic partial medial meniscectomy on tibiofemoral stability
S. Arno, S. Hadley, K.A. Campbell, C. Bell, M. Hall, L. Beltran, M.P. Recht, O. Sherman, P. Walker,
New York/US
9.4.3 Microarray analysis of human meniscus cell dedifferentiation
S.P. Grogan, S.F. Duffy, C. Pauli, S. Das, M.K. Lotz, D.D. D'Lima, La Jolla/US
9.4.4 Clinical and Immunoassay evaluation in meniscal allograft transplant at eighteen months follow up.
F. Cruz 1 , M. Acuña 1 , 2 , F.E. Villalobos Córdova 1 , C. Ibarra 1 , A. Almazan 1 , F. Pérez 1 , L. Sierra 1 ,
A. Izaguirre 1 , 1 Mexico City/MX, 2 Mexico/MX
9.4.5 MRI mid-term outcome after partial meniscus substitution using the collagen meniscal implant (CMI)
M.T. Hirschmann 1 , M.P. Arnold 1 , R. Berbig 2 , U. Luethi 3 , 1 Bruderholz/CH, 2 Zuerich/CH, 3 Zürich/CH
9.4.6 Comparison between arthroscopic meniscal allograft transplantation and polyurethane scaffold
implantation: Clinical outcome, reinterventions and implant intergrity after a minimum followup
period of 2 years. A prospective clinical trial.
P.C. Verdonk, K. Moens, L. Willemot, T. Tampere, K.F. Almqvist, R. Verdonk, Gent/BE
9.4.7 Quantitative MRI of degenerated lumbar caprine discs correlates with biomechanical and
histological changes.
C.P.L. Paul 1 , G.J. Strijkers 2 , M. De Graaf 1 , A. Bisschop 1 , A.J. Veen Van Der 1 , T.H. Smit 1 ,
M.N. Helder 1 , B.J. Royen Van 1 , M.G. Mullender 1 , 1 Amsterdam/NL, 2 Eindhoven/NL
9.4.8 Cell models for the human intervertebral disc: nucleus pulposus and annulus fibrosis
G. Van Den Akker, T.J.M. Welting, D.A.M. Surtel, A. Cremers, J.-W. Voncken, L. Van Rhijn,
Maastricht/NL
9.4.9 Anterior Cruciate Ligament and Cartilage injury of the knee: A descriptive study
K.K.V. Acharya, V. Pandey, Manipal/IN

Programme: Sunday, May 13, 2012
Session 10.1 Industry Symposium
Geistlich – Chondro-Gide® enhanced marrow stimulation – also for Ankle and Hip?
13:00 – 14:00 Room: Marquette
Moderator: Markus Walther (DE)
10.1.1 Blood clot biology after marrow stimulation
C.D. Hoemann, Montreal/CA
10.1.2 AMIC Talus – Surgical technique and first clinical results
M. Walther, Munich/DE
10.1.3 AMIC Hip – Surgical approach and 5-year clinical outcome
A. Fontana, Monza/IT
Session 10.2 Industry Symposium
Smith & Nephew – From Simple to Complex Meniscal Injury - How and When to Resect,
Repair and Replace
13:00 – 14:00 Room: Grand Salon
Moderators: Peter Verdonk (BE), Tim Spalding (UK)
10.2.1 How and When to Resect, Repair and Replace I
T. Spalding, Coventry/UK
10.2.2 How and When to Resect, Repair and Replace II
P.C. Verdonk, Gent/BE
Session 10.3 Industry Symposium
Piramal – BST-CarGel ® : A novel bioscaffold for enhanced tissue regeneration in cartilage
repair procedures
13:00 – 14:00 Room: Jolliet
Moderators: Matthias Steinwachs (DE), Pierre Ranger (CA)
10.3.1 Underlying Principles of Enhancing Bone Marrow Stimulation with BST-CarGel ®
M.S. Shive, Laval/CA
10.3.2 MRI-based Imaging Biomarkers for Cartilage
T. Mosher, Hershey/US
10.3.3 Final Outcomes from the BST-CarGel ® Randomized Clinical Trial
W.D. Stanish, Halifax/CA
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Programme: Sunday, May 13, 2012
Session 10.4 Industry Symposium
Anika – Cartilage regeneration with Hyalograft ® C autograft: Long term clinical results
and future perspectives
13:00 – 14:00 Room: St. François
Moderator: Mats Brittberg (SE)
10.4.1 Second Generation ACI 2012: An update on methodology and clinical results using Hyalograft C
autograft transarthroscopically
M. Brittberg, Kungsbacka/SE
10.4.2 Experience with Hyalograft C autograft in the arthroscopic treatment of cartilage lesions;
Long term results in athletes
E. Kon, Bologna/IT
10.4.3 Successful patient management with Hyalograft C autograft.
S. Nehrer, Krems/AT
Session 11.1 Free Paper
Animal Models
14:15 – 15:45 Room: Grand Salon
Moderators: David Frisbie (US), Ernst Hunziker (CH)
11.1.1 Overview & Introduction
E. Hunziker, Bern/CH
11.1.2 Versatility of cartilage limits flexibility in composition
J. Malda, J.C. De Grauw, K.E.M. Benders, M. Kik, L.B. Creemers, W.J.A. Dhert, P.R. Van Weeren,
Utrecht/NL
11.1.3 Disruption of SIRT1 in chondrocytes causes accelerated development of osteoarthritis induced
by joint instability in the mouse
T. Matsuzaki, T. Matsushita, S. Kubo, T. Matsumoto, K. Takayama, H. Sasaki, M. Kurosaka,
R. Kuroda, Kobe/JP
11.1.4 In vivo effect of bone-specific EphB4 overexpression in mice on subchondral bone and cartilage
during osteoarthritis
G. Valverde-Franco 1 , M. Kapoor 1 , D. Hum 1 , K. Matsuo 2 , B. Lussier 3 , J.-P. Pelletier 1 ,
J. Martel-Pelletier 1 , 1 Montreal/CA, 2 Tokyo/JP, 3 Saint-Hyacinthe/CA
11.1.5 Four-day continuous blood exposure leads to prolonged joint damage in a canine in vivo model,
whereas intermittent blood exposure does not
M.E.R. Van Meegeren, G. Roosendaal, K. Van Veghel, N.W.D. Jansen, S.C. Mastbergen,
F.P.J.G. Lafeber, Utrecht/NL
11.1.6 Repair of Critical-Sized Defects with Engineered Constructs Generated Without Cell Expansion
J. Brenner, Y. Tse, J. Pang, A. Winterborn, D. Bardana, S. Pang, S. Waldman, Kingston/CA
11.1.7 Evidence for a role of the Wnt signalling pathway in osteochondral repair
F. Henson, J. Power, A. Getgood, N. Rushton, Cambridge/UK

Programme: Sunday, May 13, 2012
11.1.8 Distribution of laminin in early osteochondral repair in a goat model
C.B. Foldager 1,2 , T. Cheriyan 2 , H.-P. Hsu 2 , M. Lind 1 , M. Spector 2 , 1 Aarhus/DK, 2 Boston/US
11.1.9 The In Vivo Performance of Osteochondral Allografts in the Goat is Diminished with Extended
Storage and Decreased Cartilage Cellularity
A.L. Pallante 1 , S. Görtz 2 , A.C. Chen1, S.T. Ball 2 , D. Amiel 1 , K. Masuda 1 , R.L. Sah 1 , W.D. Bugbee 1 ,
1 La Jolla/US, 2 San Diego/US
Session 11.2 Free Paper
Chondrocytes 2
14:15 – 15:45 Room: St. François
Moderators: Laurie Goodrich (US), Pieter Emans (NL)
11.2.1 Human platelet lysate successfully promotes proliferation and subsequent chondrogenic
differentiation of adipose-derived stem cells: a comparison to articular chondrocytes
F. Hildner 1, 2 , M.J. Eder 1 , J. Aberl 1 , H. Redl 2 , C. Gabriel 1, 2 , M. Van Griensven 2 ,
A. Peterbauer-Scherb 1,2 , 1 Linz/AT, 2 Vienna/AT
11.2.2 Platelet Rich-Plasma Improves The Formation of Tissue Engineered Cartilage
M. Petrera 1 , J.A. Decroos 1 , J. Iu 1 , M.B.Hurtig 2 , R. Kandel 1 , J.Theodoropoulos 1 , 1 Toronto/CA, 2 Guelph/CA
11.2.3 Activation of NF-KB/p65 Initiates Chondrogenic Differentiation of progenitor cells
M.M.J. Caron, P. Emans, D.A.M. Surtel, A. Cremers, J.-W. Voncken, T.J.M. Welting, L.W. Van Rhijn,
Maastricht/NL
11.2.4 Modulation of NF-KB-dependent production of PGE2, IL-8, and MCP-1 in transfected chondrocytes
S.L. Ownby, K.E. Walker, M.W. Grzanna, A.C. Mrozinski, L.F. Heinecke, A.Y. Au, C.G. Frondoza,
Edgewood/US
11.2.5 Egr-1 mediates the suppressive effect of IL-1 on PPARg expression in human OA chondrocytes
S.S. Nebbaki, F. El Mansouri, N. Zayed, M. Benderdour, J. Martel-Pelletier, J.-P. Pelletier,
H. Fahmi, Montreal/CA
11.2.6 Development of chondrocytes resistant to IL-1beta and TNF-alpha through integrating
transposon based RNA interference improve autologous chondrocyte implantation
A.J. Nixon 1 , M. Scimeca 1 , K. Ortved 1 , J. Rossi 2 , 1 Ithaca/US, 2 Duarte/US
11.2.7 Human Articular Chondrocytes Induce IL-2 Non-responsiveness to Allogeneic Lymphocytes
S. Abe, H. Nochi, T. Ruike, T. Matsuno, Asahikawa/JP
11.2.8 Spatial and Temporal Distribution of MAP Kinase Activity in Mechanically Injured Cartilage Explants
D.H. Rosenzweig, M. Djap, T.M. Quinn, Montreal/CA
11.2.9 Molecular Hydrogen Scavenges Hydroxyl Radicals and Protects Human Chondrocytes In Vitro
K. O'Shaughnessey, A. Matuska, J. Woodell-May, Warsaw/US
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Programme: Sunday, May 13, 2012
Session 11.3 Free Paper
Biomaterials & Scaffolds 2
14:15 – 15:45 Room: Marquette
Moderators: Kenneth Zaslav (US), Marcel Karperien (NL)
11.3.1 Novel Scaffold-Based BST-CarGel ® Treatment Results in Superior Cartilage Repair in a
Randomized Controlled Trial Compared to Microfracture. Better Structural Repair at 12 Months
in Terms of Repair Tissue Quantity and Quality
W.D. Stanish 1 , R. McCormack 2 , F. Forriol Campos 3 , N. Mohtadi 4 , S. Pelet 5 , J. Desnoyers 6 ,
A. Restrepo 7 , M.S. Shive 7 , 1 Halifax/CA, 2 Vancouver/CA, 3 Madrid/ES, 4 Calgary/CA, 5 Quebec
City/CA, 6 Greenfield Park/CA, 7 Laval/CA
11.3.2 Comparison of safety and efficacy using synthetic scaffolds for treatment of medial and lateral
painful irreparable partial meniscal defects; 24 months follow-up
P.C. Verdonk 1 , R. Verdonk 2 , P. Beaufils 3 , J. Bellemans 4 , P. Colombet 5 , R. Cugat 6 , P. Djian 7 ,
H. Laprell 8 , P. Neyret 9 , H. Paessler 10 , R. Siebold 10 , 1 Gent/BE, 2 Ghent/BE, 3 Versailles/FR,
4 Leuven/BE, 5 Bordeaux/FR, 6 Barcelona/ES, 7 Paris/FR, 8 Kiel/DE, 9 Lyon/FR, 10 Heidelberg/DE
11.3.3 A Nano-Composite Multilayered Biomaterial (MaioRegen) for the Treatment of Osteochondritis
Dissecans in the Knee
A.A.M. Dhollander 1 , K.F. Almqvist 2 , R. Verdonk 2 , G. Verbruggen 1 , P.C. Verdonk 3 , 1 Ghent/BE,
2 Gent/BE, 3 Gent-Zwijnaarde/BE
11.3.4 Synergistic Action of Fibroblast Growth Factor-2 and Transforming Growth Factor-beta1
Enhances Human Neocartilage Formation in Bioprinted 3D Hydrogels
X. Cui, M.K. Lotz, D.D. D'Lima, La Jolla/US
11.3.5 Overall cytokine production correlates with cartilage matrix formation of expanded but not
primary chondrocytes: a comparison of four biomaterials
A.I. Tsuchida 1 , J.E.J. Bekkers 1 , M. Beekhuizen 1 , L. Vonk 1 , D.B.F. Saris 1, 2 , W.J.A. Dhert 1 ,
L.B. Creemers 1 , 1 Utrecht/NL, 2 Enschede/NL
11.3.6 Anti-inflammatory and anabolic effects of a new alginate-chitosan hydrogel beads on human
chondrocytes
F. Oprenyeszk 1 , C. Sanchez 1 , J.-E. Dubuc 2 , V. Maquet 3 , Y. Henrotin 1 , 1 Liege/BE, 2 Brussels/BE,
3 Herstal/BE
11.3.7 Effect of Irradiation on the Strength and Lubricity of PVA-PAA Hydrogels for Cartilage Repair
D. Ling, H. Bodugoz Senturk, H.L. Kluk, O.K. Muratoglu, Boston/US
11.3.8 Development of a novel collagen-glycosaminoglycan scaffold for cartilage repair applications:
Compositional, micro-structural and mechanical optimisation
A. Matsiko, T.J. Levingstone, F.J. O'Brien, J.P. Gleeson, Dublin/IE
11.3.9 Hydrogel-Nanofiber Scaffold System for Integrative Osteochondral Repair
N.T. Khanarian, R.A. Burga, N.M. Haney, E. Strauss, H. Lu, New York/US

Programme: Sunday, May 13, 2012
Session 11.4 Free Paper
Imaging
14:15 – 15:45 Room: Jolliet
Moderators: Sebastian Apprich (AT), Jukka Jurvelin (FI)
11.4.1 Overview & Introduction
J.S. Jurvelin, Kuopio/FI
11.4.2 Delayed Gadolinium Enhanced MRI of Cartilage (dGEMRIC) demonstrates how cartilage
regeneration influences other knee compartments
J.E.J. Bekkers 1 , W. Bartels 1 , L.B. Creemers 1 , R. Benink 2 , A.I. Tsuchida 1 , K.L. Vincken 1 ,
W.J.A. Dhert 1 , D.B.F. Saris 1 , 1 Utrecht/NL, 2 Den Helder/NL
11.4.3 Biochemical MRI of Transplanted Osteochondral Allograft (OCA) cartilage with delayed
Gadolinium-Enhanced MRI of Cartilage (dGEMRIC) and zonal T2 mapping at 1 and 2 years.
D.S. Brown, M.G. Durkan, U. Szumowski, D.C. Crawford, Portland/US
11.4.4 Standardized quantitative 3D MRI can detect superior cartilage repair in clinical trials and is
correlated with collagen architecture in biopsies assessed by polarized light microscopy
M.S. Shive 1 , W.D. Stanish 2 , R. McCormack 3 , F. Forriol Campos 4 , N. Mohtadi 5 , S. Pelet 6 ,
J. Desnoyers 7 , J. Tamez-Pena 8 , S.M. Totterman 9 , A. Changoor 10 , A. Yaroshinsky 11 , S. Trattnig 12 ,
A. Restrepo 1 , 1 Laval/CA, 2 Halifax/CA, 3 Vancouver/CA, 4 Madrid/ES, 5 Calgary/CA,
6 Quebec City/CA, 7 Greenfield Park/CA, 8 Monterrey/MX, 9 Rochester/US, 10 Montreal/CA,
11 San Andreas/US, 12 Vienna/AT
11.4.5 In-vivo evaluation of biomechanical properties after cartilage repair in the patellofemoral joint
by means of quantitative T2-mapping
M. Pachowksi 1 , 2 , S. Trattnig 2 , B. Wondrasch 2 , S. Apprich 2 , S. Marlovits 2 , G.H. Welsch 1 , 2 ,
1 Erlangen/DE, 2 Vienna/AT
11.4.6 Cartilage Defects And Joint Problems In Morbidly Obese Children And Adolescents
H.K. Widhalm, A. Neuhold, G.H. Welsch, G. Vekszler, S. Arbes, M. Hamboeck, S. Aldrian,
S. Hajdu, S. Marlovits, K. Widhalm, Vienna/AT
11.4.7 Does the mechanical alignment correlate with the tracer uptake pattern and intensity in
SPECT/CT? A retrospective series on 104 knees
M.T. Hirschmann, M.P. Arnold, N.F. Friederich, H. Rasch, Bruderholz/CH
11.4.8 Quantitative Detection of Cartilage and Bone Tissue Quality via Spectral MARS-CT Imaging
T. Woodfield, A.P.H. Butler, A. Siegert, G.J. Hooper, Christchurch/NZ
11.4.9 Early Cartilage Injury Quantified and Characterized with Multiphoton Microscopy Imaging
K. Novakofski, R. Williams, L.A. Fortier, L. Bonassar, Ithaca/US
Session 12.0 ICRS General Assembly (For Members Only)
15:45 – 17:00 Room: Jolliet
Moderators: Daniël Saris (NL), Anthony Hollander (UK)
Session 12.1 Poster Viewing Cocktail
15:45 – 18:00 Room: Duluth/Richelieu
Canadian Sugar Shack & Maple Forest Party
18:30: Meeting point Fairmont hotel lobby
18:45: Bus departure
23:00: Return
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Programme: Monday, May 14, 2012
Session 13.1 Instructional Course 13.1
Rehabilitation after Cartilage Repair
07:30 – 08:15 Room: Jolliet
Instructors: Kai Mithoefer (US), Matthias Steinwachs (DE), Stefano Della Villa (IT)
13.1.1 The Evolution of Cartilage Repair Rehabilitation
K. Mithoefer, Cambridge/US
13.1.2 Current Practice of Cartilage Rehabilitation
M. Steinwachs, Zürich/CH
13.1.3 On-Field Rehabilitation and Return to Sport
S. Della Villa, Bologna/IT
Session 13.2 Meet the Experts (for Clinicians)
07:30 – 08:15 Room: Marquette
Moderators: Brian Cole (US), Christoph Erggelet (CH)
Session 14.0 Plenary
Cell Free Approaches for Cartilage Repair
08:30 – 09:30 Room: Grand Salon
Moderators: Daniël Saris (NL), Jos Malda (NL)
14.1 Homing of MSC as response to Growth factor
J. Mao, New York/US
14.2 The current prospects for gene therapy as a non-cellular therapy
L. Goodrich 1 , W. McIlwraith 1 , J. Samulski 2 , 1 Fort Collins/US, 2 Chapel Hill/US
Session 15.1 Special
Platelet Rich Plasma and Joint Tissue Repair
09:45 – 10:45 Room: Grand Salon
Moderators: Maurilio Marcacci (IT), Elizaveta Kon (IT)
15.1.1 Platelet rich plasma: Overview of current knowledge: hope, hype and reality.
L.A. Fortier 1 , T. McCarrell 1 , B.J. Cole 2 , S. Boswell 1 , L.V. Schnabel 1 , 1Ithaca/US, 2 Chicago/US
15.1.2 Platelet rich plasma and joint tissue repair
E. Kon, G. Filardo, B. Di Matteo, A. Di Martino, M. Marcacci, Bologna/IT
15.1.3 Clinical experiences with Platelet-Rich Plasma
S. Rodeo, New York/US

Programme: Monday, May 14, 2012
Session 15.2 Special
Development of new Biomaterials & Scaffolds
09:45 – 10:45 Room: Marquette
Moderators: Michael Buschmann (CA), Dietmar Hutmacher (AU)
15.2.1 Biomaterials and the osteochondral interface
H. Lu N.T. Khanarian E. Hunziker E. Strauss,
15.2.2 Hydrogels in cartilage repair
J.D. Kisiday, D.D. Frisbie, L. Goodrich, W. McIlwraith, Fort Collins/US
15.2.3 Clinical application of scaffolds for cartilage repair
S. Nehrer, Krems/AT
Session 15.3 Special
Subchondral Bone & Cartilage Repair
09:45 – 10:45 Room: St. François
Moderators: Henning Madry (DE), Mario Ferretti (BR)
15.3.1 Importance of subchondral bone in cartilage repair
H. Madry, Homburg/DE
15.3.2 Digital imaging of subchondral bone density
F.P.J.G. Lafeber, M. Kinds, F. Intema, S.C. Mastbergen, Utrecht/NL
15.3.3 Fresh Osteochondral Allografting in the Knee
W.D. Bugbee, La Jolla/US
Coffee Break/Industry Exhibition
10:45 AM – 11:15 AM Room: Exhibition Hall
Session 16.1 Free Paper
Osteoarthritis 1
11:15 – 12:45 Room: St. François
Moderators: Linda Sandell (US), Anthony Hollander (UK)
16.1.1 Overview & Introduction
A.P. Hollander, Bristol/UK
16.1.2 Biochemical characterization of osteoarthritis and osteochondritis dissecans in the ankle
H. Schmal, R. Henkelmann, I.H. Pilz, A.T. Mehlhorn, N.P. Südkamp, P. Niemeyer, Freiburg/DE
16.1.3 Osteoarthritis of lower extremities in former skiers
M.I. Iosifidis, I. Melas, E. Iliopoulos, K. Apostolidis, A. Kyriakidis, Thessaloniki/GR
16.1.4 Genetic correlation between articular cartilage regeneration and ear-wound healing:
implications in osteoarthritis
M.F. Rai, S. Hashimoto, J. Fitzgerald, E. Heber-Katz, J.M. Cheverud, L.J. Sandell, St. Louis/US
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16.1.5 A Promising Triad in the Biological Prevention of Experimental Post-Traumatic Osteoarthritis
R. Olewinski, A.A. Hakimiyan, L. Rappoport, C. Pacione, M.A. Wimmer, S. Chubinskaya,
Chicago/US
16.1.6 Leptin and adiponectin are differentially regulated in cartilage from patients with osteoarthritis
P.-J. Francin, C. Guillaume, P. Gegout-Pottie, P. Netter, D. Mainard, N. Presle, Vandoeuvre Les
Nancy Cedex/FR
16.1.7 Inflammatory factors released by osteoarthritic chondrocytes and synoviocytes are downmodulated
by adipose stromal cells
C. Manferdini 1 , A. Piacentini 1 , E. Gabusi 1 , J.A. Peyrafitte 2 , P. Bourin 2 , C. Jorgensen 3 ,
M. Maumus 3 , D. Noël 3 , A. Facchini 1 , G. Lisignoli 1 , 1 Bologna/IT, 2 Toulouse/FR, 3 Montpellier/FR
16.1.8 MicroRNA-125b Regulates the Expression of Aggrecanase-1 (ADAMTS4) in Human Osteoarthritic
Chondrocytes
T. Matsukawa, T. Sakai, H. Hiraiwa, T. Hamada, T. Omachi, M. Nakashima, S. Ishizuka, T. Oda, A.
Takamatsu, S. Yamashita, N. Ishiguro, Nagoya/JP
16.1.9 Human articular cartilage metabolism as modulated by collagen hydrolysates
S. Schadow, J. Kordelle, G. Lochnit, J. Steinmeyer, Giessen/DE
Session 16.2 Free Paper
Cartilage / Cell Transplantation (Pre-clinical)
11:15 – 12:45 Room: Marquette
Moderators: Alberto Gobbi (IT), Daniel Grande (US)
16.2.1 Overview & Introduction
D. Grande, Manhasset/US
16.2.2 An osteochondral culture model to study mechanisms involved in articular cartilage repair
M.L. De Vries - Van Melle 1 , E. Mandl 1,2 , N. Kops 1 , W. Koevoet 1 , J. Verhaar 1 , G.J.V.M. Van Osch 1 ,
1 Rotterdam/NL, 2 Dordrecht/NL
16.2.3 Simulated autologous chondrocyte transplantation within arthritic surroundings
J.D. Erggelet 1, 2 , G.M. Salzmann 1 , P. Niemeyer 1 , G. Pattappa 2 , S. Grad 2 , M. Alini 2 , 1 Freiburg/DE,
2 Davos Platz/CH
16.2.4 Hypoxic expansion of MSCs improves chondrogenicity and cell yield – implications for the
optimal use of MSCs in cartilage tissue engineering
N. Georgi, C. Van Blitterswijk, M. Karperien, Enchede/NL
16.2.5 The effects of an in vitro low oxygen tension preconditioning of MSC on their in vivo
chondrogenic potential: application for cartilage tissue engineering
S. Portron, C. Merceron, O. Gauthier, J. Lesoeur, S. Sourice, M. Masson, B.H. Fellah, O. Geffroy,
E. Lallemand, P. Weiss, J. Guicheux, C. Vinatier, Nantes/FR
16.2.6 Chromosomal stability of human chondrocytes in the process of scaffold-assisted cartilage
tissue engineering.
M. Endres 1 , M. Trimborn 1 , C. Bommer 1 , J.-P. Krüger 1 , U. Freymann 1 , L. Morawietz 2 , P.C. Kreuz 3 ,
C. Kaps 1 , 1 Berlin/DE, 2 Stuttgart/DE, 3 Rostock/DE

Programme: Monday, May 14, 2012
16.2.7 A Novel Approach For Preserving The Chondrogenic Phenotype Of Expanded Primary And Bone
Marrow-Derived Chondrocytes: Implications For Cell-Based Cartilage Repair
C.M. Simonaro, S. Sachot, E.H. Schuchman, New York/US
16.2.8 Mechanical Stimulation Enhances Integration in an in vitro model of Cartilage Repair
J. Theodoropoulos, J.A. Decroos, M. Petrera, S. Park, R. Kandel, Toronto/CA
16.2.9 CAIS: European Multicenter Results of a Single Stage Procedure for cell-based Cartilage Repair:
36-month follow up
M. Brittberg 1 , S. Nehrer 2 , A.B. Imhoff 3 , T. Spalding 4 , C.S. Winalski 5 , J. Bothos 6 , B.A. Byers 7 ,
K.F. Almqvist 8 , 1 Kungsbacka/SE, 2 Krems/AT, 3 Munich/DE, 4 West Midlands/UK, 5 Cleveland/
US, 6 Somerville/US, 7 Raynham/US, 8 Gent/BE
Session 16.3 Free Paper
Microfracture / Bone Marrow Stimulation
11:15 – 12:45 Room: Jolliet
Moderators: William Rodkey (US), Marc Philippon (US)
16.3.1 Overview & Introduction
M. Philippon, Vail/US
16.3.2 Stereological analysis of subchondral angiogenesis in bone marrow stimulated cartilage repair
C. Mathieu 1 , G. Chen 1 , A. Chevrier 1 , V. Lascau-Coman 1 , C. Marchand 1 , J. Sun 2 , G.-É. Rivard 1 ,
C.D. Hoemann 1 , 1 Montreal/CA, 2 Laval/CA
16.3.3 4-Hole microfracture (MFX) with platelet rich plasma (PRP) soaked synovial sponges
A.B. Anderson 1 , J.J. Rodrigo 2 , J. Desjardins 3 , M.C. Ware 3 , D. Wyland 1 , M. Suri 4 , G.W. Bennett 1 ,
P.H. Wessinger 1 , P.C. Siffri 1 , R.J. Hawkins 1 , 1 Greenville/US, 2 Waco/US, 3 Clemson/US, 4 Harahan/US
16.3.4 Bone marrow stimulation induces greater chondrogenesis in trochlear versus condylar cartilage
defects in skeletally mature rabbits
H. Chen 1 , A. Chevrier 1 , C.D. Hoemann 1 , J. Sun 2 , V. Lascau-Coman 1 , M.D. Buschmann 1 ,
1 Montreal/CA, 2 Laval/CA
16.3.5 Microfracture Treatment In Athletes With Knee Grade IV Chondral Lesion – A 10 Year Follow Up.
A. Gobbi, A. Kumar, G. Karnatzikos, Milan/IT
16.3.6 Does a meta-analysis reveal differences in the clinical outcome achieved by microfracture and
autologous condrocyte implantation?
L.L. Negrin, V. Vecsei, Vienna/AT
16.3.7 Microfracture or AMIC for arthroscopic repair of acetabular cartilage defects in
femoroacetabular impingement.
A. Fontana, Milano/IT
16.3.8 Incidence, grading and clinical significance of subchondral bone changes after microfracture of
chondral defects in the knee
K. Mithoefer, V. Venugopal, Cambridge/US
16.3.9 The reaction of subchondral bone to ex vivo microfracture using awls with distinct shape and
symptomatic human OA knee condyles with and without prior steroid therapy
C.D. Hoemann 1 , Y. Gosselin 1 , P. Cazelais 1 , J. Sun 2 , H. Chen 1 , V. Lascau-Coman 1 , M.B. Hurtig 3 ,
A. Carli 1 , W.D. Stanish 4 , 1 Montreal/CA, 2 Laval/CA, 3 Guelph/CA, 4 Halifax/CA
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Session 16.4 Free Paper
Stem Cells 1
11:15 – 12:45 Room: Grand Salon
Moderators: Lisa Fortier (US), Barry Oakes (AU)
16.4.1 Overview & Introduction
W. Kafienah, Bristol/UK
16.4.2 Direct generation of mature chondrocytes from human induced pluripotent stem cells
A. Owaidah 1 , S.C. Dickinson 1 , H. Jia 1 , L. Carpenter 2 , S.M. Watt 2 , A.P. Hollander 1 , W. Kafienah 1 ,
1 Bristol/UK, 2 Oxford/UK
16.4.3 Comparison of gene-specific DNA methylation patterns in equine induced pluripotent stem cell
lines with cells derived from equine adult and fetal tissues
C. Hackett 1 , L. Greve 2 , K.D. Novakofski 1 , L.A. Fortier 1 , 114853/US, 2 Copenhagen/DK
16.4.4 Multiscale Approach to Stem Cell-based Chondrogenesis for Cartilage Repair
C.-L. Chou, A.L. Rivera, A. Caplan, V.M. Goldberg, J.F. Welter, H. Baskaran, Cleveland, Oh/US
16.4.5 Mesenchymal stem cells exert paracrine effects on osteoarthritic cartilage and synovium
G. Van Buul 1 , E. Villafuertes 1, 2 , J. Waarsing 1 , P.K. Bos 1 , N. Kops 1 , R. Narcisi 1 , J. Verhaar 1 ,
H. Weinans 1, 3 , M. Bernsen 1 , G.J.V.M. Van Osch 4 , 1 Rotterdam/NL, 2 Madrid/ES, 3 Delft/NL, 4 Rotterdam/
16.4.6 Hypoxia Delays Hypertrophy In Human Multipotent Stromal Cells
D. Gawlitta, M.H.P. Van Rijen, E. Schrijver, J. Alblas, W.J.A. Dhert, Utrecht/NL
16.4.7 Liposome-mediated transfection of microRNA-145 into mesenchymal stem cells and articular
chondrocytes induce unwanted upregulation of immune genes
T.A. Karlsen, T. Küntziger, J.E. Brinchmann, Oslo/NO
16.4.8 Structured 3D Co-culture of Mesenchymal Stem Cells with Fibrochondrocytes Promotes
Meniscal Phenotype without Hypertrophy
X. Cui, M.K. Lotz, D.D. D'Lima, La Jolla/US
16.4.9 Implantation of Allogenic Synovial Stem Cells Promotes Meniscal Regeneration in a Rabbit
Meniscal Defect Model
M. Horie 1 , M.D. Driscoll 2 , H..W. Sampson 2 , I. Sekiya 1 , C. Caroom 2 , D. Prockop 2 , D. Thomas 2 ,
1 Tokyo/JP, 2 Temple/US

Programme: Monday, May 14, 2012
Session 17.1 Industry Symposium
Sanofi Biosurgery – The Evolution of Autologous Chondrocyte Implantation and Cartilage Repair
13:00 – 14:00 Room: Grand Salon
Moderators: Sven Kili (US)
17.1.1 The Genesis of ACI and the Significance of the Chondrocyte in Cartilage Repair
L. Peterson, Västra Frölunda/SE
17.1.2 Evolving Standards in Clinical Research
M. Brittberg, Kungsbacka/SE
17.1.3 Evolving Standards in the Manufacturing of Cell – Based Therapies
S.J. Duguay, Cambridge/US
Session 17.2 Industry Symposium
Zimmer Inc. – Innovative Solutions for Joint Preservation with DeNovo ® NT Natural Tissue
Graft and Chondrofix ® Osteochondral Allograft
13:00 – 14:00 Room: Marquette
17.2.1 Strategies for Articular Cartilage Restoration
D. Caborn, Louisville/US
17.2.2 Clinical Applications of Cartilage Repair
J. Farr, Greenwood/US
17.2.3 Cartilage Technologies for Talus OCD
E. Giza, Sacramento/US
17.2.4 New Concepts in Cartilage Repair
N. Marcus, Springfield/US
Session 17.3 Industry Symposium
Tigenix – ChondroCelect: When evidence makes a difference
13:00 – 13:30 Room: Jolliet
Moderators: Karl Almqvist (BE)
17.3.1 ChondroCelect – When evidence makes a difference
K.F. Almqvist, Gent/BE
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Session 17.4 Industry Symposium
BioTissue – BioTissue’s stable implants for cartilage repair: up to 10 years clinical data,
biomechanics and histologies
13:00 – 14:00 Room: St. François
17.4.1 Clinical application of BioTissue products for cartilage regeneration: A decade of experience
J. Holz, Hamburg/DE
17.4.2 Pin fixation of BioSeed ® -C and chondrotissue ® – Biomechanical properties and pitfalls of this
arthroscopic procedure
M. Herbort, Muenster/DE
17.4.3 Knee articular cartilage resurfacing using synthetic scaffolds and fresh chondral autografts
J. Fernandes, Montreal/CA
17.4.4 Four – year results after polymer-based ACI with BioSeed ® -C for the treatment of chondral
defects in the knee.
P.C. Kreuz, Rostock/DE
Session 18.0 Plenary
Stem Cells for Cartilage Repair
14:15 – 15:15 Room: Grand Salon
Moderators: Anthony Hollander (UK)
18.1 Stem Cell Therapy for Joint Repair
F. Barry, Galway/IE
18.2 Stem cell - based therapeutic approaches to joint surface repair
C. De Bari, Aberdeen/UK
Session 19.1 Special
Imaging Technologies for MS Tissue Repair
15:30 – 16:30 Room: Marquette
Moderators: Jukka Jurvelin (FI), Carl Winalski (US)
19.1.1 Basics on ultrastructural-multiparametric MR techniques
S. Apprich 1 , G.H. Welsch 1, 2 , S. Zbyn 1 , B. Schmitt 1 , S. Trattnig 1 , 1 Vienna/AT, 2 Erlangen/DE
19.1.2 Clinical application of ultrastructural-multiparametric MR techniques in patients after repair surgery
G.H. Welsch 1, 2 , 1 Erlangen/DE, 2 Vienna/AT
19.1.3 Quantitative X-ray and ultrasound methodology for cartilage repair
J.S. Jurvelin 1 , T. Viren 1 , H. Kokkonen 1 , J. Liukkonen 1 , K. Kulmala 1 , A. Joukainen 1 , I. Kiviranta 2 ,
J. Salo 1 , H. Kröger 1 , J. Töyräs 1 , 1 Kuopio/FI, 2 Helsinki/FI

Programme: Monday, May 14, 2012
Session 19.2 Special
YSOS Symposium “One-Stage Procedures for Cartilage Repair”
15:30 – 16:30 Room: Jolliet
Moderators: Simon Görtz (US), Joris Bekkers (NL)
19.2.1 Current Treatment Paradigm for Single-Stage Cartilage Repair
A.H. Gomoll, Boston/US
19.2.2 Emerging technologies
A.A.M. Dhollander 1 , K.F. Almqvist 2 , P.C. Verdonk 2 , R. Verdonk 2 , G. Verbruggen 2 , J. Victor 2 ,
1 Gent/BE, 2 Ghent/BE
19.2.3 Concomitant procedures
A. Getgood, Coventry/UK
Session 19.3 Special
Biomarkers
15:30 – 16:30 Room: Grand Salon
Moderators: Bruce Caterson (UK), Anthony Poole (CA)
19.3.1 Biomarkers for diagnosis, screening and monitoring of treatment in cartilage repair and
osteoarthritis
S. Lohmander, Lund/SE
19.3.2 Emerging molecular biomarker technologies and the way forward
A.R. Poole, Montreal/CA
19.3.3 Genetic influence on cartilage repair
L.J. Sandell, St. Louis/US
Session 20.0 Poster Viewing / Coffee Break
16:30 – 17:30 Room: Duluth/Richelieu
Session 21.1 Special
Joint Lubrication & Cartilage Health
17:30 – 18:30 Room: Grand Salon
Moderators: Robert Sah (US), Carl Flannery (US)
21.1.1 Role of lubrication and joint homeostasis: Cartilage Boundary Lubricating Ability of Full-Length
Recombinant Human PRG4 – Alone and In Combination with Hyaluronan
S. Abubacker 1 , N. Masala 1 , S. Morrison 1 , G.D. Jay 2 , T.A. Schmidt 1 , 1 Calgary/CA, 2 Providence/US
21.1.2 Opportunities and challenges for joint lubrication therapies
R.L. Sah, M.M. Temple-Wong, La Jolla/US
21.1.3 New frontiers in joint lubrication therapy
C.R. Flannery, Acton/US
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Programme: Monday, May 14, 2012
Session 21.2 Special
Rehabilitation
17:30 – 18:30 Room: Marquette
Moderators: Kai Mithoefer (US), Moreno Morelli (CA)
21.2.1 Rehabilitation after cartilage repair
M. Steinwachs, Zürich/CH
21.2.2 Return to sports after articular cartilage repair
K. Mithoefer, Chestnut Hill/US
21.2.3 Challenges in Standardizing Rehabilitation in Cartilage Repair RCTs
M.S. Shive, Montreal/CA
Session 21.3 Special
ICRS / Stryker Clinical Scientist Programme
17:30 – 18:30 Room: Jolliet
Moderators: Lisa Fortier (US), Lars Peterson (SE)
21.3.1 The Evolution of Osteochondral Storage and Preservation Techniques
A.L. Pallante, La Jolla/US
21.3.2 The Immunology of Osteochondral Grafting
W.D. Bugbee, La Jolla/US
President's Dinner (Upon invitation only)
19:15: Meeting point Fairmont lobby
19:30 – 23:00: Dinner

Programme: Tuesday, May 15, 2012
Session 22.0 Plenary
Biomechanics & Stability of Cartilage Repair
08:30 – 09:30 Room: Grand Salon
Moderators: Tom Minas (US), Wayne Gersoff (US)
22.1 Contribution of other tissues to cartilage degeneration
C.B. Little, St. Leonards, Nsw/AU
22.2 Cartilage repair; what does it mean and how to assess cartilage repair outcome?
L.E. Dahlberg, Malmö/SE
Session 23.0 Plenary
Strategic Outlines ICRS
09:30 – 10:00 Room: Grand Salon
Moderators: Anthony Hollander (UK), Daniël Saris (NL)
23.1 Where are we now?
D.B.F. Saris, Utrecht/NL
23.2 Where do we want to go?
A.P. Hollander, Bristol/UK
Coffee Break/Industry Exhibition
10:00 – 10:15 Room: Exhibition Hall
Session 24.1 Special
Cartilage Repair in the Hip Joint
10:30 – 11:30 Room: Marquette
Moderators: Christoph Erggelet (CH), Marc Philippon (US)
24.1.1 Change of thinking in treating cartilage defects in the hip
M. Philippon, Vail/US
24.1.2 ACI in the hip joint
J.B. Richardson, Oswestry/UK
24.1.3 Cartilage repair in the hip joint
R.M. Mardones, Santiago/CL
Session 24.2 Special
Animal Models for Cartilage Tissue Regeneration
10:30 – 11:30 Room: Grand Salon
Moderators: Wayne McIlwraith (US), Ernst Hunziker (CH)
24.2.1 ICRS consensus on animal models
M.B. Hurtig, Guelph/CA
24.2.2 Rabbit cartilage repair models: a review
C.D. Hoemann, Montreal/CA
24.2.3 Equine models: a review
D.D. Frisbie, W. McIlwraith, Fort Collins/US
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Programme: Tuesday, May 15, 2012
Session 24.3 Special
Distraction Arthroplasty
10:30 – 11:30 Room: Jolliet
Moderators: Simon C Mastbergen (NL), Annunziato Amendola (US)
24.3.1 Does unloading of joint surfaces affect cartilage healing in patients with end-stage ankle
osteoarthritis; an overview of the literature
A.N. Amendola 1 , M. Nguyen 1 , C. Saltzman 2 , 1 Iowa City/US, 2 Salt Lake City, Ut/US
24.3.2 Cartilage and subchondral bone repair by joint distraction in clinical and experimental models
of joint degeneration
P.M. Van Roermund, Utrecht/NL
24.3.3 Panel Discussion
S.C. Mastbergen, Utrecht/NL
Session 25.1 Free Paper
Osteoarthritis 2
11:30 – 13:00 Room: St. François
Moderators: Elizaveta Kon (IT), Anthony Poole (CA)
25.1.1 PRP injections versus viscosupplementation for early knee osteoarthritis: a randomized
double-blind study
G. Filardo, E. Kon, A. Di Martino, S. Patella, B. Di Matteo, F. Perdisa, M.L. Merli, M. Marcacci,
Bologna/IT
25.1.2 Structural Tissue Repair and Prolonged Clinical Improvement by Joint Distraction in Treatment of
End-stage Knee Osteoarthritis; Two Years Follow-up
K. Wiegant 1 , F. Intema 1 , P.M. Van Roermund 1 , A.C.A. Marijnissen 1 , S. Cotofana 2 , F. Eckstein 2 ,
S.C. Mastbergen 1 , F.P.J.G. Lafeber 1 , 1 Utrecht/NL, 2 Salzburg/AT
25.1.3 Early stages of knee OA alter type 2b fibers of the vastus lateralis muscle and decrease
eccentric knee extensor torque
P.R. Serrão 1 , K. Gramani-Say 1 , F.A. Vasilceac 1 , G.C. Lessi 1 , R. Reiff 2 , A.C. Mattiello-Sverzut 3 ,
S.M. Mattielo 1 , 1 São Carlos/BR, 2 Sao Carlos/BR, 3 Ribeirao Preto/BR
25.1.4 Relationship between serum hyaluronan level and progression of knee osteoarthritis –
A two-year longitudinal study in a Japanese general population –
E. Sasaki, Y. Ishibashi, E. Tsuda, Y. Yamamoto, R. Inoue, I. Takahashi, M. Matsuzaka, T. Umeda,
S. Nakaji, S. Toh, Hirosaki/JP
25.1.5 Relationship between cartilage wear and meniscal contact in medial osteoarthritis of the knee
S. Arno, P. Walker, C. Bell, S. Krasnokutsky, J. Samuels, S. Abramson, R. Regatte, M.P. Recht,
New York/US
25.1.6 Specific absence of PPAR-gamma in mouse cartilage results in early cartilage developmental
defects and spontaneous osteoarthritis
F. Vasheghani Farahani 1 , R. Monemjou 1 , H. Fahmi 1 , G. Perez 1 , M. Blati 1 , N. Taniguchi 2 , M.K.
Lotz 2 , R. St-Arnaud 1 , J.-P. Pelletier 1 , J. Martel-Pelletier 1 , F. Beier 3 , M. Kapoor 1 , 1 Montreal/CA,
2 La Jolla/US, 3 London/CA

Programme: Tuesday, May 15, 2012
25.1.7 Inhibition of Interleukin-1 Prevents Post-Traumatic Arthritis Following Articular Fracture in the
Mouse Knee
D.S. Mangiapani, E.M. Zeitler, B.D. Furman, J.L. Huebner, V.B. Kraus, F. Guilak, S.A. Olson,
Durham, Nc/US
25.1.8 In Vivo Localization, Persistence, and External Control of Adeno-Associated Virus (AAV)-
Mediated Transgene Expression in Injured Knees
H.H. Lee 1 , M. O'Malley 1 , N.A. Friel 1 , K.A. Payne 1 , X. Xiao 2 , C. Chu 1 , 1 Pittsburgh/US, 2 Chapel Hill/US
25.1.9 The relationship between HTRA1 and type VI collagen in a single impact load model of cartilage
damage
P. Hernandez, A. Getgood, N. Rushton, F. Henson, Cambridge/UK
Session 25.2 Free Paper
Cartilage / Cell Transplantation (Clinical)
11:30 AM – 13:00 Room: Marquette
Moderators: Barry Oakes (AU), Patrick Lavigne (CA)
25.2.1 Overview & Introduction
A. Gobbi, Milano/IT
25.2.2 Evidence of Response Shift in Patient Reported Outcomes (PROs) following Autologous
Chondrocyte Implantation (ACI)
J.S. Howard 1 , C.G. Mattacola 1 , D.R. Mullineaux 2 , R.A. English 1 , C. Lattermann 1 , 1 Lexington/US,
2 Lincoln/UK
25.2.3 Repair of focal cartilage defects with polymer-based autologous chondrocyte grafts: clinical,
functional and biomechanical results 48 months after transplantation
P.C. Kreuz 1 , S. Müller 2 , U. Freymann 3 , C. Erggelet 2 , P. Niemeyer 2 , C. Kaps 3 , A. Hirschmüller 2 ,
1 Rostock/DE, 2 Freiburg/DE, 3 Berlin/DE
25.2.4 Autologous Chondrocyte Implantation and Anteromedialization of Isolated Patella Articular
Cartilage Lesions: 5 to 12 Year Follow-up
R.M. Arnold 1 , S.D. Gillogly 2 , 1 Omaha/US, 2 Atlanta/US
25.2.5 Incidence of Osteophyte regrowth in Patients treated with autologous chondrocyte
implantation and previous bone marrow stimulating techniques: a radiographic study.
A. Von Keudell, S. Sodha, K. Small, T. Minas, A.H. Gomoll, Boston/US
25.2.6 Clinical and radiologic long-term outcome following first genereation autologous chondrocyte
implantation for cartilage defects across the knee joint
G.M. Salzmann 1 , S. Porichis 1 , N. Ghanem 1 , M. Uhl 1 , M. Steinwachs 2 , N.P. Südkamp 1 ,
P. Niemeyer 1 , 1 Freiburg/DE, 2 Zürich/CH
25.2.7 In vivo evaluation of four surgical variants for autologous chondrocyte implantation
M. Maréchal 1 , H. Vanhauwermeiren 2 , J. Neys 1 , T. Van De Putte 1 , 1 Leuven/BE, 2 Diest/BE
25.2.8 Novel surgical treatment for cartilage reconstruction in the foot and ankle
H. Thermann, F. Süzer, Heidelberg/DE
25.2.9 Second Generation ACI: Mid-term Results and Prognostic Factors
G. Filardo, E. Kon, A. Di Martino, S. Patella, F. Perdisa, B. Di Matteo, F. Vannini, M. Marcacci,
Bologna/IT
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Programme: Tuesday, May 15, 2012
Session 25.3 Free Paper
Rehabilitation
11:30 – 13:00 Room: Jolliet
Moderators: Jack Farr (US), Mario Ferretti (BR)
25.3.1 Overview & Introduction
K. Hambly, Chatham/UK
25.3.2 Weekly Changes in Serum Cartilage Oligomeric Matrix Protein (sCOMP) Levels for Soccer
Athletes Over a 10 Week Spring Soccer Season
J.M. Hoch, J.L. Mateer, C.G. Mattacola, C. Lattermann, Lexington/US
25.3.3 Polarized Light Microscopy and ICRS Histological Assessments as Validated Methodologies for
the Analysis of Tissue Quality in Cartilage Repair Randomized Controlled Trials
S. Méthot 1 , W.D. Stanish 2 , R. McCormack 3 , F. Forriol Campos 4 , N. Mohtadi 5 , S. Pelet 6 ,
J. Desnoyers 7 , A. Changoor 8 , N. Tran-Khanh 8 , S. Roberts 9 , M.S. Shive 1 , A. Restrepo 1 ,
1 Laval/CA, 2 Halifax/CA, 3 Vancouver/CA, 4 Madrid/ES, 5 Calgary/CA, 6 Quebec City/CA, 7 Greenfield
Park/CA, 8 Montreal/CA, 9 Shropshire/UK
25.3.4 Nd:YAG laser therapy for the treatment of human chondral defects.
B. Grigolo 1 , A. Zati 1 , G. Desando 1 , C. Cavallo 1 , D. Fortuna 2 , A. Facchini 1 , S. Giannini 1 , R.E.
Buda 1 , 1 Bologna/IT, 2 Calenzano (Florence)/IT
25.3.5 Recovery of isokinetic knee strength following matrix-induced autologous chondrocyte
implantation (MACI)
K. Hambly, J. Ebert, D.G. Lloyd, T.R. Ackland, D.J. Wood, Perth/AU
25.3.6 Long term survival of autologous chondrocyte implantation - predictive factors of the
survivorship.
T. Paatela 1 , A.I. Vasara 1 , H. Nurmi 2 , I. Kiviranta 1, 3 , 1 Hus/FI, 2 Jyväskylä/FI, 3 Helsinki/FI
25.3.7 Cost-Effectiveness Analysis of Autologous Chondrocyte Implantation: A Comparison of
Periosteal Patch Versus Type I/III Collagen Patch
E. Samuelson 1 , D.E. Brown 2 , 1 Ralston/US, 2 Omaha/US
25.3.8 MR imaging results of particulated juvenile cartilage allograft for repair of chondral lesions in
the knee
J. Farr 1 , B.J. Cole 2 , S.K. Tabet 3 , G. Gold 4 , S. Vasanawala 4 , P. Reischling 5 , 1 Indianapolis/US,
2 Chicago/US, 3 Albuquerque/US, 4 Stanford/US, 5 Austin/US
25.3.9 Systematic Review and Meta-Analysis of Patient Reported Outcome Instruments Following
Autologous Chondrocyte Implantation
J.S. Howard, C. Lattermann, J.M. Hoch, C.G. Mattacola, J.M. Medina McKeon, Lexington/US

Programme: Tuesday, May 15, 2012
Session 25.4 Free Paper
Stem Cells 2
11:30 – 13:00 Room: Grand Salon
Moderators: Charles Archer (UK), Wael Kafienah (UK)
25.4.1 Lysophoshatidic acid inhibits chondrogenic differentiation of human mesenchymal cells
F. Petrigliano, D. McAllister, J.S. Adams, D. Evseenko, Los Angeles/US
25.4.2 Equine mesenchymal stem cells lose their angiogenic properties when differentiated toward
chondrogenic and osteogenic lineages.
J.J. Bara 1 , E. Humphrey 1 , H. McCarthy 2 , W.E.B. Johnson 3 , S. Roberts 1 , 1 Oswestry/UK, 2 Cardiff/
UK, 3 Birmingham/UK
25.4.3 MicroRNA profiles during chondrocyte dedifferentiation and chondrogeneic differentiation of
bone marrow derived MSC
T.A. Karlsen, R.B. Jakobsen, J.H. Stendal, J.E. Brinchmann, Oslo/NO
25.4.4 Comparison between progenitor cells from infrapatellar fat pad and subcutaneous adipose
tissue: selecting a specific cell type for knee chondral applications
S. Lopa, A. Colombini, L.J. Turner, L. De Girolamo, V. Sansone, M. Moretti, Milan/IT
25.4.5 Genetic background affects induced pluripotent stem (iPS) cell generation
L.V. Schnabel, C.M. Abratte, J.C. Schimenti, L.A. Fortier, Ithaca/US
25.4.6 The importance of cell-cell interactions during in vitro differentiation of human
chondroprogenitor cells
K. Schrobback 1 , S. Stroebel 1 , B.S. Schon 1 , D. Hutmacher 2 , T.J. Klein 2 , T. Woodfield 1 ,
1 Christchurch/NZ, 2 Brisbane/AU
25.4.7 Sox Transcription Factors and TGF-Beta Gene Transduction Drives Pre-Transplant
Chondrogenesis in Adult Bone-Marrow Derived Stromal Cells
A.J. Nixon, J. Lui, A.E. Watts, Ithaca/US
25.4.8 Genome-wide mapping of epigenetic changes during in vitro 3D chondrogenic differentiation of
human bone marrow-derived mesenchymal stem cells
S.R. Herlofsen 1 , J.C. Bryne 1 , T. Høiby 1 , L. Meza-Zepeda 1 , P. Collas 1 , T.S. Mikkelsen 2 ,
J.E. Brinchmann 1 , 1 Oslo/NO, 2 Cambridge Massachusetts/US
25.4.9 Development of scaffold-free tissue-engineered construct (TEC) with chondrogenic
differentiation capacity using rabbit embryonic stem cell-derived mesenchymal stem cells
Y. Moriguchi 1 , K. Shimomura 1 , T. Teramura 2 , W. Ando 3 , M. Sakaue 1 , H. Hasegawa 1 , N. Sugita 1 ,
A. Myoui 1 , H. Yoshikawa 1 , N. Nakamura 1, 4 , 1Suita/JP, 2 Osaka Sayama/JP, 3 Hyogo/JP, 4 Osaka/JP
ICRS General Board Meeting (New GB 2012/2013)
13:30 – 14:30 Room: Chaudiere
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Poster Sessions (Electronic & Traditional)
Sunday, May 13, 2012 from 16:45 – 18:00 Rooms: Duluth/Richelieu
Monday, May 14, 2012, from 16:30 – 17:30 Rooms: Duluth/Richelieu
Poster presenters are required to stay near their poster boards during both poster sessions. Authors should encourage
discussions with interested participants. The poster presenters should introduce themselves and be prepared
to answer questions and initiate discussions.
Allografts
P1 The role of surgical insertion and pro-inflammatory cytokines in graft survival and metabolism
S. Gitelis, R. Olewinski, S. Kirk, A.A. Hakimiyan, L. Rappoport, C. Pacione, B.J. Cole, M.A. Wimmer,
S. Chubinskaya, Chicago/US
P2 Chondrofix ® Osteochondral Allograft has Reduced Immunogenicity and Inflammatory Stimulation
Z. Zhao, G. Ofek, T. Jiang, D.M. Squillace, R. Garrett, J. Gao, Austin/US
P3 Outcome of Failed Osteochondral Allografts Treated with Revision Osteochondral Allografting
M.T. Horton 1 , P.A. Pulido 1 , J.C. McCauley 2 , W.D. Bugbee 2 , 1 La Jolla, Ca/US, 2 La Jolla/US
P4 Long Term Follow-Up of Fresh Osteochondral Allografting of the Femoral Condyle
Y.D. Levy 1 , S. Görtz 1 , P.A. Pulido 2 , J.C. McCauley 2 , W.D. Bugbee 2 , 1 San Diego/US, 2 La Jolla/US
P5 Functional evaluation of patients treated with bipolar fresh osteochondral allograft transplantation
for post-traumatic ankle arthritis
L. Berti, F. Vannini, M. Cavallo, G. Lullini, D. Luciani, A. Ruffilli, S. Giannini, Bologna/IT
P6 Mid-term Results of the Treatment of Cartilage Defects in the Knee using Alginate Beads containing
Human Mature Allogenic Chondrocytes
A.A.M. Dhollander 1 , P.C. Verdonk 2 , S. Lambrecht 1 , R. Verdonk 2 , D. Elewaut 1 , G. Verbruggen 1 ,
K.F. Almqvist 1 , 1 Gent/BE, 2 Gent-Zwijnaarde/BE
P7 Effect of Allogenic Serum Addition to UW Solution for Prolonged Cold Preservation of Osteochondral Allografts
K. Onuma 1 , K. Urabe 1 , K. Naruse 1 , K. Uchida 1 , K. Sukegawa 1 , T. Kenmoku 1 , R. Higashiyama 1 , M. Takaso 1 ,
M. Itoman 2 , 1 Sagamihara/JP, 2 Kitakyushu/JP
P8 Subchondral bone cysts increase buckling and stress formation along the cartilage-bone interface of
osteochondral allografts
G. Ofek, T. Jiang, Z. Zhao, D.M. Squillace, R. Garrett, J. Gao, Austin/US
P9 Bipolar Fresh Osteochondral Allografting of the Tibiotalar Joint
G. Khanna 1 , M.E. Brage 2 , M. Cavallo 3 , J.C. McCauley 4 , S. Görtz 5 , W.D. Bugbee 4 , 1 Baldwin Park, Ca/US,
2 Seattle, Wa/US, 3 Bologna/IT, 4 La Jolla/US, 5 San Diego/US
P10 Bipolar Fresh Total Osteochondral Allograft: Why, Where, When
S. Giannini, R. Buda, M. Cavallo, A. Ruffilli, S. Neri, F. Vannini, Bologna/IT
P11 Bone formation and osteointegration of the bone portion of Chondrofix ® Osteochondral Allografts: an
experimental study in rabbits
J. Gao, Z. Zhao, G. Ofek, D.M. Squillace, T. Jiang, R. Garrett, Austin/US
P12 Chondrofix ® Osteochondral Allograft Does Not Affect Chondrocyte Viability in an In Vitro Tissue Culture Model
T. Jiang, G. Ofek, Z. Zhao, D.M. Squillace, R. Garrett, J. Gao, Austin/US

Poster Sessions (Electronic & Traditional)
P13 Hyaluronic acid (HA) Enhances Human Chondrocyte Viability in Cold-Stored Allografts
A. Pearsall, A. Mates, K. Reed, G.L. Wilson, V. Grishko, Mobile/US
P14 Mitochondrial Oxidative Stress Enhances MMP Activity in OA Chondrocytes
A. Pearsall, K. Reed, G. Wilson, V. Grishko, Mobile/US
P15 Treatment of knee defects with fresh-frozen massive osteochondral allografts
A. Safi, R. Hart, Znojmo/CZ
Animal Models
P16 A simplified method to determine joint loading as a surrogate marker of pain/disability in a canine mo
del of osteoarthritis, validated using force plate analyses as a gold standard.
K. Wiegant, H.A.W. Hazewinkel, A. Doornenbal, A.D. Barten-Van Rijbroek, S.C. Mastbergen,
F.P.J.G. Lafeber, Utrecht/NL
P18 Intra Articular Therapy of Chondroitin Sulphate with Hydrogel Scaffold in Porcine Cartilage Defect Model
K. Kannan 1 , R. Xiafei 1 , J.H.P. Hui 1 , E.H. Lee 1 , Z. Yang 1 , J. Gao 2 , H. Afizah 1 , G. Call 1 , J.Q. Yao 2 , T. Jiang 2 ,
1 Singapore/SG, 2 Austin/US
P19 Histomorphometric analysis of subchondral bone repair in a large animal osteochondral defect model
J. Power, A. Getgood, N. Rushton, F. Henson, Cambridge/UK
P20 Developed an animal model for intervertebral disc degeneration and regeneration
C.-C. Niu 1 , L.-J. Yuan 1 , S.-S. Lin 1 , W.-J. Chen 2 , 1 Kweishan/TW, 2 Taoyuan/TW
P21 Efficacy of common surgical compounds in the prevention of chondrocyte death in a bovine knee model
A. Von Keudell, H. Syed, J. Canseco, A.H. Gomoll, Boston/US
P22 A tissue engineering strategy for replacing the meniscus in a sheep model of OA.
A. Izaguirre 1 , R. Gomez-Garcia 1 , G. Gonzalez 1 , H. Lecona 1 , H. Garcia-Campillo 1 , A. Ortiz 1 , I. Quiñones-
Uriostegui 1 , L. Solis-Arrieta 1 , C. Velasquillo 2 , C. Pineda 1 , C. Ibarra 1 , 1 Mexico City/MX, 2 México/MX
P23 A novel nano-structured porous polycaprolactone scaffold improves hyaline cartilage repair in a rabbit
model compared to a collagen type I/III scaffold: in vitro and in vivo studies
B.B. Christensen 1 , O.M. Hansen 2 , C.B. Foldager 1 , A. Krstiansen 2 , D.Q.S. Le 2 , J.V. Nygaard 2 ,
A.H. Nielsen 3 , C. Bünger 1 , M. Lind 2 , 1 Aarhus/DK, 2 Aarhus C/DK, 3 Silkeborg/DK
P24 The strong influence of the strength exercise on the cartilage constituents in animal model of osteoarthritis.
S.M. Mattielo, F.A. Vasilceac, M.C. Souza, São Carlos/BR
P25 Intra-articular blood coagulation aggravates joint damage after a bleed in a canine in vivo model
M.E.R. Van Meegeren, G. Roosendaal, A.D. Barten-Van Rijbroek, R.E.G. Schutgens, S.C. Mastbergen,
F.P.J.G. Lafeber, Utrecht/NL
P26 The use of novel aragonite-hyluronate biphasic implant in chondral and osteochondral regeneration
E. Kon 1 , D. Robinson 2 , Y. Chorev 3 , J. Shani 4 , K.R. Zaslav 5 , J.A. Eisman 6 , A.S. Levy 7 , G. Filardo 1 ,
N. Altschuler 8 , 1 Bologna/IT, 2 Petah Tikwa/IL, 3 Netanya/IL, 4 Beit Berl/IL, 5 Richmond/US, 6 Sydney/
AU, 7 Morristown/US, 8 Ariel/IL
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Poster Sessions (Electronic & Traditional)
P27 Novel poly(L/D)lactide scaffold for cartilage repair: a pilot study in a porcine chondral lesion model
V. Muhonen 1 , E. Järvinen 1 , T. Paatela 1 , A.I. Vasara 1 , A. Meller 1 , V. Ellä 2 , M. Kellomäki 2 , I. Kiviranta 1 ,
1 Helsinki/FI, 2 Tampere/FI
Biomarkers
P29 Hitting the Marker for Autologous Chondrocyte Implantation – is there a Role for Proteomics?
K. Wright, H. Fuller, E. Humphrey, J.B. Richardson, P. Jones, A. Kerr, S. Roberts, 7ag/UK
P30 A Quantitative Method for Evaluating Cartilage Defect Repair: Intra- and Inter- Reader Reproducibility
J. Tamez-Pena 1, 2 , S. Trattnig 3 , S.M. Totterman 1 , P. Szomolanyi 3 , M.S. Shive 4 , M.D. Buschmann 5 ,
A. Restrepo 4 , 1 Rochester/US, 2 Monterrey/MX, 3 Vienna/AT, 4 Laval/CA, 5 Montreal/CA
P31 Markers of Success for Autologous Chondrocyte Implantation
K. Wright, J.B. Richardson, P. Jones, H. Evans, A. Kerr, S. Roberts, 7ag/UK
P32 Prohibitin a novel osteoarthritis biomarker for early detection and staging of OA patients
A. Moreau 1 , C. Picard 1 , M. Taheri 2 , J.-F. Lavoie 1 , P. Lavigne 1 , 1 Montreal/CA, 2 Montréal/CA
P33 The Collagen Type II Degradation Biomarker CTX-II In Athletes From Different Modalities
P. Baches Jorge, G. Runco, A. Duarte, M. Vaz De Lima, P. Kertzman, A. Simões, N. Severino, São Paulo/BR
P34 Inflammatory Cytokine Composition and Metabolic Profile of Post-Traumatic Ankle Joint Arthritis
S. Adams, Jr. 1 , E. Kensicki 1 , L. Jones 2 , A. Haile 2 , S.D. Miller 2 , G. Guyton 2 , L. Schon 2 , 1 Durham/US, 2 Baltimore/US
Biomaterials and Scaffolds
P35 Temporal assessment of lysyl oxidase on tissue engineered articular cartilage.
E.A. Makris, D.J. Responte, K. Athanasiou, Davis/US
P36 Direct Human Cartilage Repair Using 3D Bioprinting Technology
X. Cui, K. Breitenkamp, M.G. Finn, M.K. Lotz, D.D. D'Lima, La Jolla/US
P37 Innovative approach for osteochondral defect using magnetic scaffold
A. Russo 1 , S. Panseri 1 , T. Shelyakova 1 , M. Sandri 2 , C. Dionigi 1 , A. Strazzari 1 , A. Ortolani 1 , A. Tampieri 2 ,
V. Dediu 1 , M. Marcacci 1 , 1 Bologna/IT, 2 Faenza/IT
P38 Articular Cartilage Regeneration: Is there a role for a PVA PCL semi-IPN scaffold? Comparing a novel
monophasic vs a novel biphasic scaffold vs cultured chondrocytes without scaffolds.
V. Dutt 1 , B. Balakumar 1 , R. Karthikeyan 1 , N.M. Walter 1 , S. Chilbule 1 , V. Madhuri 1 , P. Nair 2 , 1 Vellore/
IN, 2 Trivandrum/IN
P39 Alternative macrophage activation and neutrophil chemotaxis induced in vivo by chitosan/blood im
plants correlate with mast cell recruitment
C.-H. Lafantaisie-Favreau 1 , D. Rusu 2 , P.E. Poubelle 2 , J. Sun 3 , C.D. Hoemann 1 , 1 Montreal/CA, 2 Quebec/
CA, 3 Laval/CA
P40 Arthroscopic meniscal scaffold implantation: early clinical results at 20 months of follow-up
C. Zorzi, V. Condello, V. Madonna, F. Cortese, R. Giovarruscio, Negrar Vr/IT
P41 Improvement and optimization of mechanical properties hyaluronic acid derivatives based hydrogels
L. Wolfová, M. Pravda, M. Nemcová, M. Foglarová, V. Velebny, Dolní Dobrouc/CZ

Poster Sessions (Electronic & Traditional)
P42 Bio-functional and bio-mimetic injectable hydrogels for cartilage repair
L. Moreira Teixeira, J. Feijen, C. Van Blitterswijk, P. Dijkstra, M. Karperien, Enschede/NL
P43 Employment of hydrogels and Nanomagnetics to direct the Formation of Organized Engineered Tissues
in Cartilage Defects.
S.P. Grogan 1 , C. Pauli 1 , H. Hoenecke 1 , C.W. Colwell 1 , M.K. Lotz 1 , C.B. Chung 2 , S. Jin 1 , D.D. D'Lima 1 ,
1 La Jolla/US, 2 San Diego/US
P44 How to treat Osteocondritis Dissecans of the Knee: surgical techniques and new trends
E. Kon, F. Vannini, R. Buda, G. Filardo, M. Marcacci, S. Giannini, Bologna/IT
P45 Nanostructured biomimetic scaffold for the treatment of osteochondral defects: pilot clinical study at 4
years follow-up
S. Patella, E. Kon, A. Di Martino, G. Filardo, F. Perdisa, B. Di Matteo, S. Zaffagnini, M. Marcacci, Bologna/IT
P46 Does 3D micro-tissue assembly eliminate the need for cell-material interactions and improve engineered
cartilage quality?
B.S. Schon, T. Woodfield, Christchurch/NZ
P47 Biocompatibility evaluation of Chitosan-Gelatin hydrogels with embedded PLGA particles as a useful tool
for in vitro culture human chondrocytes
Z.Y. Garcia Carvajal 1 , V. Martinez 2 , D. Garciadiego-Cazeres 3 , F.E. Villalobos Jr 2 , F.S. Arévalo 4 , E.F. Israel 4 ,
M.A.C. Martinez 4 , C. Velasquillo 3 , A. Izaguirre 2 , R. Gomez 3 , F. Pérez 2 , G. Luna-Barcenas 5 ,
R.A.M. Sanchez 5 , L. Solis-Arrieta 2 , C. Ibarra 1 , 1 Del. Tlalpan, Df/MX, 2 Mexico City/MX, 3 México/MX,
4 Mexico, Df/MX, 5 Queretaro/MX
P48 Multilayered Engineered Constructs for Cartilage Engineering
C. Millan 1 , R. Mhanna 1 , K. Maniura 2 , Y. Yang 3 , T. Groth 3 , M. Zenobi-Wong 1 , 1 Zürich/CH, 2 St Gallen/CH,
3 Halle/DE
P49 Controlled Release of rhTGF-ß3 from Extracellular Matrix Membrane
S.S. Yang 1 , M.S. Kim 1 , Y.J. Kim 1 , B.H. Choi 2 , S.R. Park 2 , B.-H. Min 1 , 1 Suwon/KR, 2 Incheon/KR
P50 Characterization of Radiation Induced Chitosan Films with Acrylic and Silane Monomers: Fabrication of
Resorbable Composites for Biomedical Application
K. Dey, R.A. Khan, Dhaka/BD
P51 Fabrication and Evaluation of Tissue Engineered Femoral Head Implants for Resurfacing of Osteoarthritic
Joints
F. Pfeiffer 1 , S.P. Franklin 1 , B.S. Bal 2 , J.L. Cook 2 , 1 Boonville/US, 2 Columbia/US
P52 The benefits of a composite design for a Novel Polycarbonate-Urethane Meniscal Implant
J.J. Elsner 1 , G. Zur 1 , E. Hershman 2 , R. Arbel 3 , A. Shterling 1 , F. Guilak 4 , E. Linder-Ganz 1 , 1 Netanya/IL,
2 New York/US, 3 Tel Aviv/IL, 4 Durham/US
P53 Cartilage Tissue Engineering with Human Young Chondrocyte and Porcine Cartilage ECM powder Scaffold
H.J. Oh 1 , L.H. Jin 1 , Y.J. Kim 1 , J.-H. Cho 1 , B.H. Choi 2 , B.-H. Min 1 , 1 Suwon/KR, 2 Incheon/KR
P54 Characterization of eggshell (membrane) derived biomaterials as potential scaffolds for cartilage tissue
engineering
M. Khanmohammadi, A. Baradar Khoshfetrat, S. Eskandarnezhad, S. Ebrahimi, Tabriz/IR
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P55 Feasibility study of collagen type I/III membrane fixation in a human cadaver model of the distal
radioulnar joint.
E.A. Van Amerongen, N. Kaoui, J.E.J. Bekkers, A.H. Schuurman, L.B. Creemers, Utrecht/NL
P56 Regeneration of Osteochondral Defects with Novel Multi-Layer Collagen-Based Scaffolds
T.J. Levingstone, E. Thompson, A. Schepens, F.J. O'Brien, J.P. Gleeson, Dublin/IE
P57 Cartilage Tissue Engineering with Human Young Chondrocyte and Porcine Cartilage ECM Powder Scaffold
H.J. Oh 1 , L.H. Jin 1 , 2 , Y.J. Kim 2 , B.H. Choi 3 , J.-H. Cho 2 , B.-H. Min 1, 4 , 1 Suwon/KP, 2 Suwon/KR, 3 Incheon/
KR, 4 Suwon/KI
P58 A Pilot Study of the Use of an Osteochondral Scaffold Plug for Cartilage Repair in the Knee and How to
Deal with Early Clinical Failures?
A.A.M. Dhollander 1 , K. Liekens 1 , K.F. Almqvist 2 , R. Verdonk 2 , S. Lambrecht 2 , D. Elewaut 2 ,
G. Verbruggen 2 , P.C. Verdonk 3 , 1 Ghent/BE, 2 Gent/BE, 3 Gent-Zwijnaarde/BE
P59 Biological reconstruction in high grade osteonecrosis of the femoral head: results to a minimum of 2
years of follow-up.
D. Dallari, N. Del Piccolo, N. Rani, R. Fantasia, C. Carubbi, C. Stagni, Bologna/IT
P60 Osteochondral scaffold implant in complex cases management
A. Di Martino, E. Kon, G. Filardo, S. Patella, B. Di Matteo, F. Perdisa, M. Marcacci, Bologna/IT
P61 Chitosan-Polyvinyl alcohol based scaffold for human auricular neocartilage.
C. Velasquillo 1 , E. Abarca 2 , E. Ruvalcaba 1 , Z. Garcia 1 , V. Martinez 3 , L. Solis-Arrieta 1 , M. Perez 1 , C. Ibarra 3 ,
G. Luna-Barcenas 1 , 1 Mexico/MX, 214389/MX, 3 México/MX
P62 Implantation of a thin double-network gel sheet can induce spontaneous articular cartilage regeneration
in vivo in a large osteochondral defect
N. Kitamura 1 , H. Matsuda 1 , T. Kurokawa 1 , K. Arakaki 2 , J.P. Gong 1 , F. Kanaya 2 , K. Yasuda 1 , 1 Sapporo/JP, 2 Naha/JP
P63 A Novel Treatment for Osteonecrotic Femoral Head – An Animal Study
C.-J. Liao 1 , C.-C. Jiang 2 , H. Chiang 2 , W.-H. Chang 1 , 1 Hsinchu/TW, 2 Taipei/TW
P64 Reconstruction of Osteochondral Lesions of the Talus with Autologous Spongiosa Graft and Autologous
Matrix Induced Chondrogenesis (AMIC)
M. Wiewiorski, M. Miska, V. Valderrabano, Basel/CH
P65 New biodegradable and biocompatible synthetic scaffold for meniscal regeneration: prospective
evaluation at 2 years follow-up
S. Patella, A. Di Martino, E. Kon, G. Filardo, G.M. Marcheggiani Muccioli, F. Iacono, S. Zaffagnini,
M. Marcacci, Bologna/IT
P66 One step cartilage repair by PVA-H hydrogel implants in the knee: long term results
F.V. Sciarretta, Rome/IT
P68 Biological Reconstruction in Osteo-Chondral Lesion of Talus
D. Dallari, N. Rani, N. Del Piccolo, M. Filanti, G. Sabbioni, C. Stagni, Bologna/IT
P69 Treatment of osteochondritis dissecans of the knee with the nanostructured biomimetic scaffold
combined with platelet-rich plasma gel
W. Widuchowski, P. Lukasik, W. Wawrzynek, R. Kokot, B. Koczy, J. Widuchowski, Piekary Slaskie/PL

Poster Sessions (Electronic & Traditional)
P70 Articulating cartilage versus pHEMA hydrogel. A tribological and histological "in vitro" study
J.L. Sague, B. Andreatta, R. Egli, Y. Loosli, R. Luginbühl, Bettlach/CH
Biomechanics
P71 Frictional response of cartilage after prolonged walking and recovery – an in-vitro study
S. Taylor, J. Ingram, E. Ingham, J. Fisher, S. Williams, Leeds/UK
P72 Arthroscopic fixation of matrix associated Autologous Chondrocyte Implantation - Joint compression
forces following biodegradable pin fixation
M. Herbort 1 , S. Zelle 1 , M. Raschke 1 , W. Petersen 2 , T. Zantop 3 , 1 Muenster/DE, 2 Berlin/DE, 3 Straubing/DE
P73 Hypoxia as a possible method of promoting collagen crosslinking in native articular cartilage
E.A. Makris, K. Athanasiou, Davis/US
P74 Flow-perfusion suppresses hypertrophic differentiation of novel MSC-based cartilage constructs
D. Gawlitta, J. Malda, W.J.A. Dhert, Utrecht/NL
P75 Stress relaxation due to pore formation in cartilage under mechanical load and laser heating
A. Shnirelman 1 , E. Sobol 2 , A. Omelchenko 2 , 1 Montreal/CA, 2 Troitsk/RU
P76 In-vitro stability testing of a non-fixed meniscal implant: the effect of surgical technique and knee condition
J.J. Elsner 1 , T.F. Bonner 2 , A. Greene 1 , R.R. Gupta 2, R.S. Butler 2, E. Linder-Ganz 1 , E. Hershman3, R.W. Colbrunn2 , 1Netanya/IL, 2Cleveland/US, 3New York/US
P77 Aetiology of experimentally induced osteoarthritis of the knee; biomechanical or biochemical factors?
K. Wiegant, M. Beekhuizen, S.C. Mastbergen, A.D. Barten-Van Rijbroek, D.B.F. Saris, L.B. Creemers,
F.P.J.G. Lafeber, Utrecht/NL
P78 Characterisation of the Regional Osteochondral Properties of Quadruped Tibio-Femoral Joints
S.W.D. McLure, P. Conaghan, J. Fisher, S. Williams, Leeds/UK
Cartilage
P79 One-stage cartilage defect treatment combining chondrons and mesenchymal stromal cells; in vitro and
in vivo results
J.E.J. Bekkers, L. Vonk, W.J.A. Dhert, L.B. Creemers, D.B.F. Saris, Utrecht/NL
P80 Influence of cryopreservation, cultivation time and patient’s age on the gene expression in cartilage transplants
C. Albrecht, B. Tichy, S. Hosiner, L. Zak, S. Aldrian, S. Nürnberger, S. Marlovits, Vienna/AT
P81 Ex-vivo gene therapy-induced cartilage regeneration: comparison of different subpopulations of primary
muscle-derived cells
H. Li, M. Poddar, A. Usas, J. Huard, Pittsburgh/US
P82 ACI in the management of Bilateral knee chondral defects
A. Von Keudell, M. Berninger, T. Bryant, T. Minas, Boston/US
P83 S100 - a biomarker for human articular chondrocyte potency
C. Czücs, J. Diaz-Romero, A. Quintin, D. Nesic, Bern/CH
P84 Expression of Collagen I in macroscopically healthy cartilage. Useful for tissue engineering?
C. Velasquillo, A. Lopez-Reyes, I. Alba-Sanchez, C. Ortega-Sanchez, M. Santamaria-Olmedo,
V. Martinez-Lopez, L. Tamay De Dios, A. Izaguirre, C. Ibarra, Mexico/MX
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P85 An Autologous Cartilage Tissue Implant (ACTI) NeoCart® for Treatment Grade III Chondral Injury to the
Femur. Intermediate Term Results from Initial FDA Trials.
D.C. Crawford 1 , T.M. Deberardino 2 , C.T. Moorman 3 , D. Taylor 3 , B. Nelson 4 , J. Chesnutt 1 , C.B. Ma 5 ,
R.J. Williams, Iii 6 , 1 Portland/US, 2 Farmington/US, 3 Durham/US, 4 Minneapolis/US, 5 San Francisco/
US, 6 New York/US
P86 Treatment of osteochondritis dissecans of the knee with arthroscopic Bone Marrow-Derived Cells
transplantation (“one step” technique): Results and T2 mapping evaluation
R. Buda, F. Vannini, M. Battaglia, M. Cavallo, G. Pagliazzi, A. Ruffilli, S. Giannini, Bologna/IT
P87 Autologous chondrocyte Implantation (ACI) with a bilayer collagen membrane and bone graft in the
knee: 2-8 year follow-up study
S. Vijayan, W. Bartlett, G. Bentley, R. Carrington, J. Skinner, R. Pollock, M. Alorjani, T. Briggs, Stanmore/UK
P88 Two-year follow up from arthroscopic implantation of matrix-seeded autologous chondrocytes at the knee
J.C. Ibarra, F.E. Villalobos Córdova, A. Izaguirre, V. Guevara, C. Velasquillo, S. Cortes, D. Chavez, F. Pérez,
V. Martinez, L.G. Ibarra, Mexico City/MX
P89 In vitro preculture enhances the in vivo cartilage forming capacity of constructs generated by combining
human bone marrow stromal cells with a low fraction of human articular chondrocytes in collagen scaffold
M.-A. Sabatino 1 , R. Santoro 2 , S. Gueven 2 , D. Wendt 2 , I. Martin 2 , M. Moretti 1 , A. Barbero 2 , 1 Miland/IT, 2 Basel/CH
P90 Comparison between articular chondrocytes from osteoarthritis knees and mesenchymal stem cells from
young healthy donors in an alginate scaffold model of in vitro chondrogenesis
A.M. Fernandes, S.R. Herlofsen, T.A. Karlsen, A.M. Küchler, J.E. Brinchmann, Oslo/NO
P91 Matrix assisted chondrocyte implantation (MACI ® ) improves healing of full thickness cartilage defects in
an equine model
A.J. Nixon 1 , H. Sparks 1 , W. Linnenkohl 1 , L. Begum 1 , J. Hart 1 , N. Moran 2 , G. Matthews 2 , 1 Ithaca/US, 2 Farmingham/US
P92 Autologous Chondrocyte Implantation Augments the Production of Clusterin in Repair Cartilage
H. McCarthy 1 , J. Malda 2 , J.B. Richardson 1 , S. Roberts 1 , 1 Oswestry/UK, 2 Utrecht/NL
P93 One Step Repair In Talar Osteochondral Lesions: 4 Years Results And T2-mapping Capability In
Outcome Prediction
F. Vannini, R. Buda, M. Battaglia, M. Cavallo, L. Ramponi, A. Ruffilli, A. Timoncini, S. Giannini, Bologna/IT
P94 Arthroscopic matrix-induced autologous chondrocyte implantation: 24 month clinical and radiological outcomes
J. Ebert, K. Hambly, M. Fallon, D.J. Wood, G. Janes, Perth/AU
P95 Five-year clinical and radiological outcome following matrix-induced autologous chondrocyte
implantation (MACI) in the patellofemoral joint
J. Ebert, K. Hambly, D. Meyerkort, M. Fallon, T.R. Ackland, M.H. Zheng, D.J. Wood, Perth/AU
P96 Using Partial Enzyme Digestion to Facilitate the Fusion of Cartilage Interface
C.-J. Liao 1 , C.-C. Jiang 2 , H. Chiang 2 , W.-H. Chang 1 , W.-J. Liao 1 , 1 Hsinchu/TW, 2 Taipei/TW
P97 Getting closer to hyaline repair - Xenograft chondrocytes
G. Maor, G. Nierenberg, Haifa/IL

Poster Sessions (Electronic & Traditional)
P98 Behaviour of adult human articular chondrocytes during in vivo culture in semipermeable cell chambers.
M. Polacek 1 , T. Annala 2 , I. Martinez 1 , 1 Tromsø/NO, 2 Tampere/FI
P99 Biologic Arthroplasty In Patello-Femoral Cartilage Lesions
A. Gobbi, A. Kumar, G. Karnatzikos, Milan/IT
P100 CARTIPATCH ® phase III clinical trial: Comparison of autologous chondrocytes implantation versus
Mosaicplasty, 1 year follow-up
P. Neyret 1 , J.-F. Potel 2 , H. Robert 3 , C. Bussiere 4 , E. Servien 1 , F. Dubrana 5 , 1 Lyon/FR, 2 Toulouse/
FR, 3 Mayenne/FR, 4 Dracy Le Fort/FR, 5 Brest/FR
P101 Articular cartilage repair with magnetically labeled mesenchymal stem cells and external magnetic device
G. Kamei, N. Adachi, M. Deie, T. Kobayashi, H. Shibuya, S. Ohkawa, K. Takazawa, W. Kongcharoensombat,
M. Ochi, Hiroshima/JP
P102 Evaluation of a mesenchymal stem cell seeded PEOT/PBT scaffold in an osteochondral defect in vivo.
K.M. Salih Mohamed 1 , V. Barron 1 , A. Manian 1 , A. Nandakumar 2 , L. Moroni 2 , P. Habibovic 2 , F. Shannon 1 ,
M. Murphy 1 , F. Barry 1, 1 Galway/IE, 2 Twente/NL
P103 Autologous nasal chondrocytes and a cellulose-based self-setting hydrogel for the repair of articular
cartilage in horses
C. Vinatier, E. Lallemand, O. Geoffroy, C. Merceron, O. Gauthier, B.H. Fellah, S. Portron, M. Masson,
J. Lesoeur, P. Weiss, J. Guicheux, Nantes/FR
P104 Cartilage of different mammalian species demonstrate variable tissue thickness, cell density,
proteoglycan content and cartilage specific genes
T. Zaman, N.B. Kamisan, S. Naveen, R.E. Ahmad, Kuala Lumpur/MY
P105 Effect of intra-articular Hyaluronic acid, mesenchymal stem cells and microfracture in the treatment of
cartilage defects – In vivo study
T. Zaman, P.N. Shilpa, P. Wagner, N. Huiyin, K. Puvanan, Kuala Lumpur/MY
P106 Chondrogenic differentiation of bone marrow-derived MSCs with the high affine GDF-5 variant (R57A) in vitro
F. Gilbert 1 , M. Kunz 1 , J. Nickel 2 , M. Rudert 1 , A.F. Steinert 1 , 1 Wuerzburg/DE, 2 Würzburg/DE
P107 Instant CEMTROCELL ® , a new approach based on autologous chondrocyte implantation for the
treatment of cartilage lesions.
P. Guillen-Garcia 1 , E. Rodriguez Iñigo 1, 2 , M. Guillen-Vicente 1 , I. Guillen-Vicente 1 , E. Santos 1 ,
R. Caballero-Santos 1 , 2, J.M. Lopez-Alcorocho 1, 2 , 128045/ES, 2 Madrid/ES
P108 One-Year Clinical and Radiological Results of a Prospective, Investigator-Initiated Trial Examining a
Novel, Purely Autologous 3-Dimensional Autologous Chondrocyte Transplantation Product in the Knee
S. Fickert 1 , P. Gerwien 1 , B. Helmert 1 , T. Schattenberg 1 , S. Weckbach 2 , M. Kaszkin-Bettag 1 , L. Lehmann 1 ,
1 Mannheim/DE, 2 Munich/DE
P109 Mechanical loading reduces chondrocyte death after impact injury in porcine model
L. Vernon 1 , D. Wilensky 2 , D. Ajibade 2 , L.D. Kaplan 1, 2, C.-Y.C. Huang 1 , 1 Coral Gables/US, 2 Miami/US
P110 Feasibility of an arthroscopic 3-dimensional, purely autologous chondrocyte transplantion for the
treatment for full thickness chondral lesions in the hip caused by femoroacetabular impingement
S. Fickert, S. Thier, Mannheim/DE
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P111 Biological resurfacing techniques, fully arthroscopically performed, for degenerative multifocal chondral
defects, at the knee. Mid term results
S. Alevrogiannis, G. Skarpas, Athens/GR
P112 Coefficient of Friction of Poly(vinyl alcohol) Hydrogels Against Swine Articular Cartilage
H. Bodugoz Senturk, D. Ling, S. Nanda, H.L. Kluk, G. Braithwaite, O.K. Muratoglu, Boston/US
P113 Protection of chondrocyte phenotype by heat inactivation of serum in monolayer expansion cultures.
M. Matmati, T.F. Ng, T.M. Quinn, Montreal/CA
P114 Evaluation of the clinical results and MRI of a novel II generation autologous chondrocytes implant, for
cartilage repair in Knees and Ankles.
R. Arbel, Tel Aviv/IL
P115 Nonclinical Efficacy Tests of Pellet-Type Autologous Chondrocytes for Regeneration of Articular Cartilage
J.-Y. Lee 1 , J. Lee 1 , B.C. Chae 1 , Y. Son 2 , 1 Seoul/KR, 2 Yongin/KR
P116 Ten year follow up of matrix associated autologous chondrocyte transplantation in the knee
M. Brix 1 , C. Chiari 1 , S. Nehrer 2 , R. Windhager 1 , S. Domayer 1 , 1 Vienna/AT, 2 Krems/AT
Chondrocytes
P117 Enhanced cartilage repair in defects implanted with autologous chondrocytes transduced with AAV5-
IGF-I in the equine model
K. Ortved, L. Begum, M. Scimeca, A.J. Nixon, Ithaca/US
P118 Differential Effects of Cyclooxygenase-1 and -2 specific NSAIDs on Chondrogenic Differentiation
M.M.J. Caron, P. Emans, D.A.M. Surtel, A. Cremers, D. Ophelders, K. Sanen, L.W. Van Rhijn, T.J.M. Welting,
Maastricht/NL
P119 c-Maf Regulates ADAMTS-12 Expression in Human Chondrocytes
E. Hong, J. Yik, D. Amanatullah, P. Di Cesare, D.R. Haudenschild, Sacramento/US
P120 Inhibition of Cyclooxygenase-2 Impacts Chondrocyte Hypertrophy
M.M.J. Caron, P. Emans, M.P.F. Janssen, K. Sanen, M.M.E. Coolsen, L. Voss, D.A.M. Surtel, A. Cremers,
J.-W. Voncken, T.J.M. Welting, L.W. Van Rhijn, Maastricht/NL
P121 BMP-2 and BMP-7: Differential Regulation of Chondrogenic Differentiation
M.M.J. Caron, T.J.M. Welting, M.M.E. Coolsen, D.A.M. Surtel, A. Cremers, L.W. Van Rhijn, P. Emans,
Maastricht/NL
P122 Extendable Surfaces for Dynamic Culture of Chondrocytes: Surface Functionalization with a
Decellularized Cartilage ECM Extract to Enhance Chondrogenic Phenotype.
D.H. Rosenzweig, S. Solar-Cafaggi, T.M. Quinn, Montreal/CA
P123 Spatial and Temporal Apoptotic Activity in Mechanically Injured Cartilage Explants
D.H. Rosenzweig, T.M. Quinn, Montreal/CA
P124 Differential Responses of Normal and OA Human Chondrocytes to Local Anesthetics: Role of Oxidative Stress
A. Pearsall, A. Mates, G. Wilson, V. Grishko, Mobile/US
P125 Long-term patient satisfaction and clinical outcome of autologous chondrocyte implantation in the knee joint
M.N. Dugard, J.C. Parker, E. Robinson, J.H. Kuiper, S. Roberts, J.B. Richardson, Oswestry/UK

Poster Sessions (Electronic & Traditional)
P126 Hyaluronic acid decreases proliferation time and improves redifferentation of isolated chondrocytes
K. Wijnands 1 , E.J.P. Jansen 2 , T.J.M. Welting 1 , D.A.M. Surtel 1 , L.W. Van Rhijn 1 , P. Emans 1 , 1 Maastricht/
NL, 2 Maastricht And Sittard/NL
P127 Inhibition of Catabolic Responses in Rat Chondrocytes via Delivery of Interleukin-1 Receptor Antagonist
Protein (IRAP) Using Adeno-Associated Virus (AAV)
H.H. Lee 1 , X. Xiao 2 , C. Chu 1 , 1 Pittsburgh/US, 2 Chapel Hill/US
P128 Enhanced Tissue Regeneration Potential of Juvenile Articular Cartilage
H. Liu, Z. Zhao, R. Clarke, J. Gao, R. Garrett, Austin/US
P130 Expression of PPARa, b, and g in the Hartley guinea pig model of primary osteoarthritis
F.E. El Mansouri, S.S. Nebbaki, N. Zayed, M. Benderdour, J. Martel-Pelletier, J.-P. Pelletier, H. Fahmi, Montreal/CA
P131 Influence of Growth Factors for Chondrogenic Re-differentiation under Normoxic and Hypoxic
Culture Conditions
A. Jonitz, K. Lochner, D. Hansmann, T. Tischer, R. Bader, Rostock/DE
P132 10- years experience in Autologous Disc Chondrocyte Tranplantation (ADCT) A critical clinical review
of 115 cases
C. Hohaus 1 , H.J. Meisel 1 , T. Ganey 2 , U. Mansmann 3 , 1 Halle/DE, 2 Atlanta/US, 3 Muenchen/DE
P133 Global gene array comparison between successful and failed outcome after autologous chondrocyte
implantation
J. Stenberg 1 , T.S.S. De Windt 2 , J. Van Der Lee 1 , M. Brittberg 3 , D.B.F. Saris 2 , A. Lindahl 1 , 1 Gothenburg/SE,
2 Utrecht/NL, 3 Kungsbacka/SE
P134 The Use of Talus Osteochondral Defect Cartilage for Chondrocyte Harvesting: Results of 151
Consecutive Patients
C. Kreulen 1, 2 , E. Giza 2 , J. Kim 2 , M. Sullivan 1 , 1 Sydney/AU, 2 Sacramento/US
P135 Effect of SOX9 and IGF-I overexpression over some extracellular matrix components in cultivated human
articular chondrocytes.
M. Simental, J. Lara, A. Soto, E. Álvarez, J. Sepúlveda, H.G. Martínez, Monterrey/MX
Clinical Outcome
P138 Chondropenia Severity Score: An Arthroscopic Stratification tool of Structural Cartilage Changes in the
Knee as Correlated to Patient Reported Outcomes.
S.L. Pro 1 , B.W. Blatz 2 , T.R. McAdams 3 , B. Mandelbaum 2 , 1 Tigard/US, 2 Santa Monica/US, 3 Palo Alto/US
P139 Single V/S Double Bundle ACL Reconstruction: Functional Outcome At 3 Years In Athletes
A. Gobbi, A. Kumar, G. Karnatzikos, Milan/IT
P140 AMIC or ACI for arthroscopic repair of delaminated acetabular cartilage in femoroacetabular impingement.
A. Fontana, Milano/IT
P141 Arthroscopic treatment of ankle anterior bony impingement: the long term clinical outcome
F. Vannini, R. Buda, A. Parma, G. Pagliazzi, M. Cavallo, A. Ruffilli, S. Giannini, Bologna/IT
P142 A Phase I/II study of a tissue engineered cartilage implant derived from allogeneic juvenile chondrocytes:
3 year results
B.J. Cole 1 , J. Farr 2 , K. Bonner 3 , G. Gold 4 , H.D. Adkisson 5 , P. Reischling 6 , 1 Chicago/US, 2 Greenwood/
US, 3 Virginia Beach/US, 4 Stanford/US, 5 St. Louis/US, 6 Austin/US
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P143 Strategies for Patient Profiling in Articular Cartilage Repair of the Knee: A Prospective Cohort of Patients
Treated by One Experienced Cartilage Surgeon
T.S.S. De Windt 1 , S. Concaro 2 , A. Lindahl 3 , D.B.F. Saris 1 , M. Brittberg 4 , 1 Utrecht/NL, 2 Kungälv/SE,
3 Göteborg/SE, 4 Kungsbacka/SE
Extracellular Matrix
P145 Evaluation of the type II collagen expression in the extracellular matrix of chondrocyte by atomic force
microscopy
C.-H. Hsieh, C.-H. Liu, S. Lin, J.-J. Tsai-Wu, H. Chiang, S. Chen, C.-C. Jiang, Taipei/TW
P146 Effects of Different Three-dimensional Conditions on Chondrocyte and MSC Capacity to Regenerate
Cartilaginous Tissue
S.P. Grogan, X. Chen, S. Sovani, T. Olee, M.K. Lotz, D.D. D'Lima, La Jolla/US
Growth Factors and Cytokines
P147 The effect of retroviral-mediated overexpression of BMP-2 on hMSCs during monolayer proliferation
A. Neumann 1 , M. Alini 1 , M. Anton 2 , C. Archer 3 , M. Stoddart 1 , 1 Davos Platz/CH, 2 Muenchen/DE, 3 Cardiff/UK
P149 Intermittent but not continuous exposure to recombinant human fibroblast growth factor-18 (rhFGF18)
promotes chondrocyte anabolism and phenotype in 3D culture.
A. Gigout, S. Lindemann, H. Guehring, Darmstadt/DE
P150 TGFß during expansion phase negatively affects the chondrogenic redifferentiation of human chondrocytes
R. Narcisi 1, 2 , L. Signorile 1 , P. Giannoni 2 , G.J.V.M. Van Osch 1 , 1 Rotterdam/NL, 2 Genova/IT
P151 The Role of IL-6 in Osteoarthritis and Cartilage Regeneration
A.I. Tsuchida 1 , M. Beekhuizen 1 , A.G.J. Bot 1 , B. Geurts 1 , J.E.J. Bekkers 1 , W.J.A. Dhert 1 , L.B. Creemers 1 ,
D.B.F. Saris 1, 2, 1 Utrecht/NL, 2 Enschede/NL
P152 Repair of Rabbit Osteochondral Defects by an Acellular Technique Using an Ultrapurified Alginate Gel
Containing Stromal Cell-Derived Factor-1
A. Sukegawa, N. Iwasaki, Y. Kasahara, T. Onodera, T. Igarashi, A. Minami, Sapporo/JP
P153 A short time window to profit from IL-4 plus IL-10 addition to protect cartilage from blood-induced
damage in vitro
M.E.R. Van Meegeren, G. Roosendaal, J.A.G. Van Roon, S.C. Mastbergen, F.P.J.G. Lafeber, Utrecht/NL
P154 Direct BMP-2 Gene Delivery to Osteochondral Defects using Coagulated Bone Marrow Aspirate - Potent
Cartilage Regeneation with the Risk of Osteophyte Formation in a Rabbit Model
J. Sieker 1 , M. Kunz 2 , M. Weissenberger 2 , F. Gilbert 2 , C.H. Evans 3 , M. Rudert 2 , A.F. Steinert 2 , 1 Würzburg/DE,
2 Wuerzburg/DE, 3 Boston/US
P156 CXCL8 in osteoarthritis, symptomatic cartilage defects and cartilage regeneration
A.I. Tsuchida 1 , D.B.F. Saris 1, 2 , B. Geurts 1 , A.H.M. Kragten 1 , M. Beekhuizen 1 , J.E.J. Bekkers 1 , W.J.A.
Dhert 1 , L.B. Creemers 1 , 1 Utrecht/NL, 2 Enschede/NL
Histology
P157 The Effect of Recombinant Human Fibroblast Growth Factor-18 on Articular Cartilage Following Single
Impact Load
L. Barr, A. Getgood, N. Rushton, F.M. Henson, Cambridge/UK

Poster Sessions (Electronic & Traditional)
P158 A Stereological Method for the Quantitative Evaluation of Cartilage Repair Tissue
C.B. Foldager 1, 2 , J.R. Nyengaard 1 , M. Lind 1 , M. Spector 2 , 1 Aarhus/DK, 2 Boston/US
P159 Healing of cartilage lesions in sheep after microfracturing technique and transcutaneous application of
non-steroidal anti-inflammatory or chondroprotective medication - histological evaluation
M. Sidler, N. Fouche, I. Meth, B. Von Rechenberg, P. Kronen, Zurich/CH
Imaging
P160 Comparison of Three Methods to Quantify Repair Cartilage Collagen Orientation
K. Ross 1 , H.G. Potter 2 , R. Williams 1 , L.V. Schnabel 1 , G. Bradica 3 , E. Castiglione 3 , S.L. Pownder 1, 2 ,
P.W. Satchell 1 , L.A. Fortier 1 , 1 Ithaca/US, 2 New York/US, 3 Exton/US
P161 High resolution diagnosis of cartilage and meniscus damage with a novel extremity-CBCT.
J. Salo, H. Kokkonen, H. Kröger, J.S. Jurvelin, J. Töyräs, Kuopio/FI
P162 Cartilage assessment after mosaicplasty with delayed gadolinium-enhanced MRI of the cartilage (dGEMRIC)
M. Kobayashi, T. Shirai, S. Nakamura, R. Arai, K. Nishitani, T. Satake, H. Kuroki, Y. Nakagawa,
T. Nakamura, Kyoto/JP
P163 Normative Articular Cartilage T2 Values in Clinically Relevant Subregions of the Knee
E. Lucas, R. Surowiec, J..E. Giphart, E. Fitzcharles, B. Petre, C. Ho, Vail/US
P164 Compositional Observation of Cartilage Repair Tissue by Magnetic Resonance Imaging – a Clinically
Oriented Approach
G.H. Welsch 1, 2 , S. Apprich 2 , D. Stelzeneder 2 , M. Blanke 1 , S. Marlovits 2 , S. Trattnig 2 , 1 Erlangen/
DE, 2 Vienna/AT
P166 Cartilage Repair of the Ankle: First Results of T2 mapping at 7.0 Tesla after Microfracture and Matrix
associated autologous Cartilage Transplantation
S. Apprich, M. Brix, M. Sokolowski, R. Windhager, S. Trattnig, S. Domayer, Vienna/AT
P167 Can x-ray morphometric parameters for the hip be assessed on magnetic resonance imaging?
A. Hingsammer, D. Stelzeneder, Y.-J. Kim, Boston/US
P168 Development of central osteophytes in native cartilage: an observational MR imaging study
F.A. Sakamoto, C.S. Winalski, E. Schneider, J.P. Schils, Cleveland/US
P169 Application of micro-CT for non-destructive quality control in engineered cartilage
L.H. Jin 1 , Y.J. Kim 1 , B.H. Choi 2 , H.J. Oh 1 , T.Z. Li 1 , B.-H. Min 1 , 1 Suwon/KR, 2 Incheon/KR
P170 Utilizing Cartilage T2 Relaxation Time in Clinical Trials
J. Riek, Rochester/US
Intervertebral Disc
P171 Intervertebral disc regeneration after implantation of a cell-free bioresorbable implant in an ovine disc
degeneration model.
M. Endres, U. Freymann, A. Abbushi, M.L. Zenclussen, P. Casalis, C. Woiciechowsky, C. Kaps, Berlin/DE
P172 Viscoelastic moduli of the nucleus pulposus decrease with mild degeneration in a goat lumbar
intervertebral disc model
S.E.L. Detiger, R.J.W. Hoogendoorn, A.J. Van Der Veen, B.J. Van Royen, M.N. Helder, G.H. Koenderink,
T.H. Smit, Amsterdam/NL
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Poster Sessions (Electronic & Traditional)
P173 An immunohistochemical investigation of progenitor cell markers in the human intervertebral disc.
S. Turner, C. Morgan, J. Trivedi, S. Roberts, Oswestry/UK
P174 The Microscopic Pictures of Degenerative Intervertebral Disc with Histochemical Methods
C.-M. Shih 1 , K.-C. Liu 2 , J.-T. Chien 2 , S.-F. Lai 2 , T.-Y. Tsai 2 , 1 Taichung City/TW, 2 Chiayi County/TW
Meniscus
P175 Marrow Stimulation Improves Healing following Avascular Zone Meniscal Injury in a Rabbit Model
M.D. Driscoll 1 , B.N. Robin 1 , M. Horie 2 , H..W. Sampson 1 , Z. Hubert 1 , B. Tharakan 1 , R.E. Reeve1,
W.P. Hamilton 1 , 1 Temple/US, 2 Tokyo/JP
P176 Differentiation of mesenchymal stem cells by soluble factors mediated by direct co-culture of meniscus
cells and mesenchymal stem cells
M. Sommerfeldt, L. Laouar, A. Sierra, N. Jomha, A.B. Adesida, Edmonton/CA
P177 A Novel Polycarbonate-Urethane Meniscal Implant: A Functional Evaluation of Sizing
J.J. Elsner 1 , V. Condello 2 , E. Hershman 3 , R. Arbel 4 , A. Shterling 1 , C. Zorzi 5 , F. Guilak 6 , E. Linder-Ganz 1 ,
1 Netanya/IL, 2 Negrar, Verona/IT, 3 New York/US, 4 Tel Aviv/IL, 5 Negrar – Verona/IT, 6 Durham/US
P178 Poly-urethane scaffold for the treatment of medial and lateral partial meniscus defects: A single center
experience with focus on scaffold integrity.
P.C. Verdonk, L. Willemot, P. Beekman, R. Verdonk, Gent/BE
P179 Transplantation of Achilles tendon treated with BMP-7 promoted meniscus regeneration in a rat massive
meniscus defect model.
N. Ozeki 1 , 2 , I. Sekiya 1 , T. Saito 2 , T. Muneta 1 , 1 Tokyo/JP, 2 Yokohama/JP
P180 Co-culture of meniscus cells and bone marrow mesenchymal stromal cells on a collagen scaffold for
inner meniscus reconstruction
A. Adesida, S. Lim, N.-F. Matthies, A. Sierra-Mulet, N.M. Jomha, Edmonton/CA
P181 All-arthroscopic technique of biological meniscal tear therapy with collagen membrane- early results
T. Piontek 1 , K. Ciemniewska-Gorzela 1 , J. Naczk 1 , M. Slomczykowski 2 , R. Jakob 3 , 1 Poznan/PL, 2 Scholles/
UK, 3 Tafers/CH
P182 Oxygen tension is a determinant of cultured human meniscus cells matrix-forming phenotype
A. Adesida, A. Sierra-Mulet, N.M. Jomha, Edmonton/CA
P183 Comparison of the displacement pre- and post-surgery of 24 polyurethane meniscal implants; is there a
difference in displacement and is there any correlation with the thickness of the residual meniscal rim?
P.C. Verdonk 1 , T. De Coninck 1 , W.C.J. Huysse 1 , R. Verdonk 2 , 1 Gent/BE, 2 Ghent/BE
P184 Tissue Engineered Whole Menisci Generated from High Density Type I Collagen Gels
J. Puetzer, L. Bonassar, Ithaca/US
P185 A pilot study of the use of a polycarbonate-urethane implant (NUsurface) for the treatment of
postmeniscectomy medial knee pain.
P.C. Verdonk 1 , A.A.M. Dhollander 2 , R. Verdonk 2 , 1 Gent-Zwijnaarde/BE, 2 Ghent/BE
P186 Biological reconstruction of the failing knee: experience of meniscus allograft transplantation with
osteotomy, ligament reconstruction and articular cartilage repair.
A. Getgood, S. Spencer, J. Bird, P. Thompson, T. Spalding, Coventry/UK

Poster Sessions (Electronic & Traditional)
P187 Degradation of articular cartilage after partial meniscectomy – is there a need for meniscal transplantation?
S. Quirbach 1 , M. Eichinger 1 , S. Apprich 2 , R. Rosenberger 1 , 1 Innsbruck/AT, 2 Vienna/AT
P188 Too old for regenerative treatment? Too young for joint replacement? Clinical indication for a novel
meniscus implant
C. Zorzi 1 , V. Condello 2 , P.C. Verdonk 3 , R. Arbel 4 , S. Israeli 5 , Y. Beer 6 , N. Blumberg 4 , N. Shabshin 4 ,
J.J. Elsner 7 , E. Nocco 7 , E. Linder-Ganz 7 , G. Agar 6 , N. Rozen 5 , R. Verdonk 8 , E. Hershman9, 1 Verona/IT,
2 Negrar, Verona/IT, 3 Gent-Zwijnaarde/BE, 4 Tel Aviv/IL, 5 Afula/IL, 6 Zeriffin/IL, 7 Netanya/IL, 8 Gent/
BE, 9 New York/US
Microfracture
P189 Bone marrow stimulation produces superior cartilage repair in trochlea versus medial femoral condyle in
a rabbit model
H. Chen 1 , A. Chevrier 1 , C.D. Hoemann 1 , J. Sun 2 , G. Picard 1 , M.D. Buschmann 1 , 1 Montreal/CA, 2 Laval/CA
P190 Autologous matrix-induced chondrogenesis (AMIC) combined with platelet-rich plasma gel compared to
AMIC enhanced by concentrated bone marrow for the treatment of severe patellar cartilage defects in
the knee.
W. Widuchowski, P. Lukasik, W. Wawrzynek, R. Kokot, J. Widuchowski, Piekary Slaskie/PL
P192 Surgical Treatment of Chondral Defects of Knee Using Microdrilling and Atelocollagen Gel as One Stage
Arthroscopic Procedure
A.A. Shetty 1 , S.-J. Kim 2 , D. Stelzeneder 1 , P. Bilagi 1 , 1 Kent/UK, 2 Uijeongbu City/KR
P193 T2* Mapping After Arthroscopic Treatment of Cartilage Defects of the Knee using Microdrilling and an
Atelocollagen Gel as a One Stage Procedure
P. Bilagi 1 , D. Stelzeneder 1 , S.-J. Kim 2 , A.A. Shetty 1 , 1 Kent/UK, 2 Uijeongbu City/KR
P194 Microfracture in the Treatment of Osteochondral Defects of the Talus: Clinical results at an average
follow-up of 9 years with T2-Mapping at 3 Tesla
C. Becher 1 , D. Zuehlke 1 , C. Plaas 1 , M. Ewig 1 , C. Stukenborg-Colsman 1 , H. Thermann 2 , 1 Hannover/DE,
2 Heidelberg/DE
P195 All arthroscopic AMIC cartilage reconstruction in the knee – 1 year results
T. Piontek, K. Ciemniewska-Gorzela, A. Szulc, J. Naczk, Poznan/PL
P197 The AMIC technique in the cartilage lesions of the knee: 97 cases
A. Siclari 1 , E. Boux 1 , C. Gentili 2 , C. Kaps 3 , U. Freymann 3 , 1 Biella/IT, 2 Genova/IT, 3 Berlin/DE
Osteoarthritis
P198 Blocking oncostatin M in synovial fluid of osteoarthritic patients increases matrix turnover.
M. Beekhuizen 1 , A.G.J. Bot 1 , D.B.F. Saris 1 , 2 , W.J.A. Dhert 1 , G.J.V.M. Van Osch 3 , L.B. Creemers 1 , 1 Utrecht/NL,
2 Enschede/NL, 3 Rotterdam/NL
P199 Comprehensive Arthroscopic Management (CAM) Survivorship: Alternative to Arthroplasty in Active
Patients with Advanced Shoulder Osteoarthritis
P.J. Millett, M. Horan, A. Pennock, D. Rios, Vail, Co/US
P200 Does Kellgren-Lawrence Grade Correlate with Arthroscopic Findings in the Knee?
K.K. Briggs, L. Matheny, J..R. Steadman, W.G. Rodkey, Vail/US
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Poster Sessions (Electronic & Traditional)
P201 Superficial chondrocytes from osteoarthritis patients have reduced matrix metalloproteinase expression
and increased matrix synthesis following dynamic compression
J.E. Jeon, K. Schrobback, D. Hutmacher, T.J. Klein, Kelvin Grove/AU
P202 Quantitative CT and MRI changes in arthritic and prearthritic hips
A.D. Speirs, A. Cárdenas-Blanco, K. Rakhra, M. Schweitzer, P. Beaule, Ottawa/CA
P203 Hyaluronan Derivative Hydrogel treatment for Preserving Cartilage Integrity in Rabbit Model of
Osteoarthritis (ACLT)
A. Schiavinato 1 , M. Ganster 2 , P. Mainil-Varlet 3 , 1 Abano Terme (pd)/IT, 2 Bern/CH, 3 Marly/CH
P204 >Topographical Distribution of Glycosaminoglycans in Developmental Dysplasia of the Hip as Measured
by Delayed Gadolinium-Enhanced MRI of Cartilage (dGEMRIC)
A. Hingsammer, J. Chan, L.A. Kalish, Y.-J. Kim, Boston/US
P205 Pattern of cartilage erosion in end-stage osteoarthritis of the knee
O.R. Kwon, S.K. Kwon, Seoul/KP
P206 Intra-articular lubricin injection as a means of preventing early articular surface damage
N. Galley 1 , M. Rivera-Bermudez 2 , T. Blanchet 2 , C.R. Flannery 2 , L. Bonassar 1 , 1Ithaca/US, 2 Cambridge/US
P207 Prostaglandin E2 upregulation by cyclic compressive loading on 3-D tissue of human synovial fibroblasts
via COX-2 and IL-1 receptor signal pathway
K. Shimomura, K. Kita, T. Kanamoto, N. Nakamura, S. Miyamoto, T. Mae, T. Matsuo, H. Yoshikawa,
K. Nakata, Osaka/JP
P208 The effects of Hyaluronic Acid and Allogenic Bone Marrow derived-Mesenchymal stem cells in delaying
osteoarthritic progression of the knee: A preliminary study
T. Zaman, A. Suhaeb, S. Naveen, Kuala Lumpur/MY
P209 Comparison of Factors Associated with Early Osteoarthritis vs. Moderate to Severe Osteoarthritis of the Knee
K.K. Briggs, L. Matheny, J..R. Steadman, W.G. Rodkey, Vail/US
P210 Pattern of cartilage erosion in end-stage osteoarthritis of the knee; its association with the condition of
anterior cruciate ligament and medial meniscus posterior horn
O.R. Kwon, S.K. Kwon, Seoul/KP
P211 Sequentially Programmed Magnetic Fields (SPMF) therapy as an effective treatment for osteoarthritis:
follow up of phase II study.
V.G. Vasishta, Bangalore/IN
P212 Inhibition of Inflammatory Response in Human, Camel, Dog, and Cat Chondrocyte Microcarrier Spinner
Cultures by NSAIDs and the Combination of Avocado Soybean Unsaponifiables, Glucosamine and
Chondroitin Sulfate
M.W. Grzanna, L.F. Heinecke, A.Y. Au, S.L. Ownby, A.C. Mrozinski, C.G. Frondoza, Edgewood/US
P213 The effect of hyaluronic acid on the outcome of a total hip arthroplasty
S. Colen 1 , L. Maeckelbergh 2 , M. Mulier 2 , 1 Maastricht/NL, 2 Leuven/BE
P214 Validation of Novel Indentation Device for Measuring Indentation Forces of Cartilage in Osteoarthritic Knees
C. Bell, H. Khan, S. Arno, P. Walker, P. Desai, New York/US

Poster Sessions (Electronic & Traditional)
P215 Chitosan-hyaluronate hybrid is superior to hyaluronate or saline in delaying osteoarthrtis in a rat model
D. Robinson 1 , Z. Nevo 2 , S. Patchornik 1 , N. Ben Shalom 1 , 1 PetahTikwa/IL, 2 Tel Aviv/IL
P216 Hemicap- and Unicap – miniprosthesis and Hemicap patellofemoral (PF) - and PF-xl ( Wave ) – miniprosthesis.
J.O. Laursen, Sønderborg/DK
P217 The Load Absorbing KineSpring System as an Early Surgical Option for Patients with Knee Osteoarthritis
R. Williams 1 , N.J. London 2 , K.F. Almqvist 3 , R. Verdonk 3 , T. Wilton 4 , J.B. Richardson 5 , C.S. Waller 6 ,
D.A. Hayes 7 , 1 Cardiff/UK, 2 Harrogate/UK, 3 Gent/BE, 4 Derby/UK, 5 Oswestry/UK, 6 Sydney/AU, 7 Brisbane/AU
Osteochondral Grafts
P218 Autologous Osteochondral Transplantation of the Talus Partially Restores Contact Mechanics of the Ankle Joint
A. Fansa, C.D. Murawski, C.W. Imhauser, J.T. Nguyen, J.G. Kennedy, New York/US
P219 Vitrification of intact human articular cartilage
N.M. Jomha, J.A.W. Elliott, G.K. Law, B. Maghdoori, J.F. Forbes, A.B. Adesida, A. Abazari, L. Laouar, X.
Zhou, L.E. McGann, Edmonton/CA
P220 Functional and T2-Mapping MRI Results of Autologous Osteochondral Transplantation of the Talus in 72 Patients
C.D. Murawski, J.G. Kennedy, New York/US
P221 Osteochondral repair using a novel biphasic implant made of scaffold-free tissue engineered construct
derived from synovial mesenchymal stem cells and hydroxyapatite-based artificial bone
K. Shimomura 1 , Y. Moriguchi 1 , W. Ando 2 , R. Nansai 3 , T. Susa 3 , K. Imade 3 , S. Mochizuki 3 , H. Fujie 3 , K.
Kita 1 , T. Mae 1 , K. Nakata 1 , K. Shino 1 , H. Yoshikawa 1 , N. Nakamura 1 , 1 Osaka/JP, 2 Hyogo/JP, 3 Tokyo/JP
P222 Viral Inactivation of Human Osteochondral Grafts with Methylene Blue and Light
D.M. Squillace, Z. Zhao, G. Ofek, T. Jiang, R. Garrett, J. Gao, Austin/US
P223 Second-Look Arthroscopic and Clinical Evaluation of Osteochondral Autograft Transplantation in Patients
with Early Osteoarthritis Aged 45 or More
H.-S. Seo, S.C. Lee, Seoul/KR
P224 Mosaicpalsty (osteochondral autografting) in osteochondral lesions of the knee: a prospective study
T.Y. Emre, M. Uzun, B. Seyhan, H.T. Cift, Ankara/TR
P225 Open mosaicplasty in osteochondral lesions of the talus : A prospective study
T.Y. Emre, M. Uzun, B. Seyhan, H.T. Cift, Ankara/TR
P226 Cryoprotective agent efflux from intact articular cartilage
H. Yu, K. Al-Abbasi, X. Zhou, A. Abazari, J.A.W. Elliott, L.E. McGann, N.M. Jomha, Edmonton/CA
P227 Polyvinyl alcohol-polyacrylic acid (PVA-PAA) hydrogels for osteochondral defect repair
D.A. Bichara, H. Bodugoz-Senturk, C.R. Bragdon, D. Ling, O.K. Muratoglu, Boston/US
Others
P229 Prevalence of Chondral Defects of the Hip in Professional Hockey Players vs. Non-Contact Professional Athletes
M. Philippon, M.M. Herzog, K.K. Briggs, Vail/US
P230 Intra- and Inter-rater Reliability of Arthroscopic Measurements of Cartilage Defects
D. Flanigan 1 , R.H. Brophy 2 , J. Carey 3 , J. Mitchell 1 , W. Graham 1 , D. Hamilton 4 , R. Siston 1 , H. Nagaraja 1 ,
C. Lattermann 4 , 1 Columbus/US, 2 Chesterfield/US, 3 Philadelphia/US, 4 Lexington/US
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Poster Sessions (Electronic & Traditional)
P231 The gene-expression profiles of immature bovine articular cartlage are joint-specific and differentially
influenced by BMP-2
N. Shintani, F. Bourquin, E. Hunziker, Bern/CH
P232 Partial Anterior Cruciate Ligament Tears: Anatomic Reconstruction Versus Non Anatomic Augmentation Surgery
R. Buda, F. Vannini, A. Ruffilli, M. Cavallo, A. Parma, L. Ramponi, S. Giannini, Bologna/IT
P233 A Moderate-Intensity Static Magnetic Field Enhances Repair of Cartilage Damage in Rabbits
F. Mojtahed Jaberi 1 , S. Keshtgar 2 , A. Tavakoli 1 , E. Pishva 1 , B. Gramizadeh 3 , N. Tanideh 3 , M. Mojtahed Jaberi 4 ,
3 Shiraz/IR, 4 Montreal/CA
P234 Using diffuse reflectance spectroscopy for optical detection of cartilage degeneration arthroscopically
M. Junker 1 , N. Trutiak 2 , J..Q. Brown 1 , J. Von Windheim 1 , N. Ramanujam 1 , M.B. Hurtig 2 , 1 Durham/US, 2 Guelph/CA
P236 Single Versus Double Strand Anterior Cruciate Ligament Reconstruction With Hamstrings: A 12 years
follow-up Study
R. Buda, A. Ruffilli, F. Vannini, A. Parma, L. Ramponi, G. Pagliazzi, S. Giannini, Bologna/IT
P237 Treatment of osteochondral injuries of the ankle: Our Experience
F. Cortese 1 , V. Iacono 1 , A. Russo 2 , G. Piovan 3 , C. Zorzi 1 , 1 Verona/IT, 2 Napoli/IT, 3 Trieste/IT
P238 All-arthroscopic labral reconstruction in the hip by use of collagen graft - operative technique and early results
T. Piontek, K. Ciemniewska-Gorzela, A. Szulc, J. Naczk, Poznan/PL
P239 Gene expression profiles of the regenerated cartilage tissue induced by implantation of a novel double-network
hydrogel : comparisons with the immature articular cartilage
R. Imabuchi 1 , Y. Ohmiya 1 , H.J. Kwon 1 , S. Onodera 1 , N. Kitamura 1 , T. Kurokawa 2 , J.P. Gong 2 , K. Yasuda 1 ,
1 Sappro/JP, 2 Sapporo/JP
Platelet Rich Plasma
P241 The Anti-inflammatory and Matrix Restorative Mechanisms of Platelet Rich Plasma in Osteoarthritis.
E. Sundman 1 , B.J. Cole 2 , V. Karas 2 , C. Della Valle 2 , L.A. Fortier 1 , 1 Ithaca/US, 2 Chicago/US
P243 In vivo and in vitro effects of PRP in chondrogenic differentiation
A. Siclari 1 , E. Boux 1 , C. Gentili 2 , C. Kaps 3 , J.P. Krueger 3 , 1 Biella/IT, 2 Genova/IT, 3 Berlin/DE
P244 Effect of platelet gel on healing response after anterior cruciate ligament reconstruction
J. Naranda, M. Vogrin, Maribor/SI
P246 Platelet rich plasma enhanced collagen II production in Transwell cultured mesenchymal stem cells
A. Kabiri, M. Mardani, E. Esfandiary, B. Hashemibeni, A. Esmaeili, A. Pourazar, 8174673548/IR
Rehabilitation
P247 Five year outcomes of a randomized comparison of traditional and accelerated approaches to post-operative
rehabilitation following matrix-induced autologous chondrocyte implantation (MACI)
J. Ebert, K. Hambly, M. Fallon, T.R. Ackland, M.H. Zheng, D.J. Wood, Perth/AU
P248 A web-based clinical decision support system for individualising rehabilitation after articular cartilage
repair of the knee.
K. Hambly, Chatham/UK
P249 Physiotherapeutic treatment after AMIC knee all arthroscopic reconstruction of cartilage procedure –
cases study
A. Prusinska, T. Piontek, K. Ciemniewska-Gorzela, J. Naczk, M. Grygorowicz, W. Dudzinski, Poznan/PL
P250 Flexibility disorder of lower extremity muscles affects the location of pain in the patellofemoral pain
syndrome (PFPS) patients.
N. Reke, A. Madaj, T. Piontek, K. Ciemniewska-Gorzela, A. Pyda, M. Grygorowicz, W. Dudzinski, Poznan/PL
P253 Relationship Between Leg Strength and Patient Report Outcomes in Autologous Chondrocyte
Implantation (ACI) Patients C.G. Mattacola, J.S. Howard, C. Lattermann, Lexington/US

Poster Sessions (Electronic & Traditional)
Stem Cells
P254 A checkerboard analysis of the effect of commonly used growth factors on in vitro chondrogenesis using
a custom-made probeset and the Nanostring nCounter platform
R.B. Jakobsen 1 , T.S. Mikkelsen 2 , A.M. Küchler 1 , J.E. Brinchmann 1 , 1 Oslo/NO, 2 Cambridge Massachusetts/US
P256 Pharmacological modulation of human mesenchymal stem cells chondrogenesis by a chemically
over-sulphated polysaccharide of marine origin: potential application to cartilage regenerative medicine.
C. Merceron, S. Portron, C. Vignes-Colombeix, E. Rederstorff, M. Masson, J. Lesoeur, S. Sourice,
C. Sinquin, S. Colliec-Jouault, P. Weiss, C. Vinatier, J. Guicheux, Nantes/FR
P257 Low oxygen tension prevents the terminal hypertrophic differentiation of chondrogenic cells
S. Portron, C. Merceron, O. Gauthier, M. Masson, J. Lesoeur, S. Sourice, P. Weiss, J. Guicheux, C. Vinatier,
Nantes/FR
P258 Demonstration of the Chondrogenic Capacity of Mesenchymal Stem Cells Derived from Human Foetal
Bone Marrow
K. Brady 1 , S.C. Dickinson 1 , W. Kafienah 1 , P.V. Guillot 2 , J. Polak 2 , A.P. Hollander 1 , 1 Bristol/UK, 2 London/UK
P261 Intra-individual comparison of the chondrogenic differentiaton capacity of ASCs and MSCs in type I
collagen-hydrogel
A. Nedopil 1 , R. Hallinger 1 , T. Schuster 2 , M. Rudert 1 , U. Nöth 1 , L. Rackwitz 1 , 1 Wuerzburg/DE, 2 Munich/DE
P262 Isolation and characterisation of mesenchymal stem cells from different regions of the human umbilical cord
C. Mennan, A. Bhattacharjee, K. Wright, S. Roberts, J.B. Richardson, Oswestry/UK
P264 Multilineage differentiation potential of the cells derived from degenerative torn human rotator cuff
I. Nagura, T. Kokubu, Y. Mifune, R. Sakata, H. Nishimoto, T. Muto, M. Kurosaka, Kobe/JP
P265 Chondrogenesis by Bone Marrow-Derived Stem Cells Grown in Chondrocyte Conditioned Media for
Possible Auricular Reconstruction
X. Zhao 1 , N.S. Hwang 2 , D.A. Bichara 1 , I. Pomerantseva 1 , C.A. Sundback 1 , J. Vacanti 1 , D.G. Anderson 2 ,
M.A. Randolph 1 , 1 Boston/US, 2 Cambridge/US
P267 Adult adipose mesenchymal stem cell implantation for one step knee chondral defects repair
F.V. Sciarretta, C. Ascani, Rome/IT
P268 Infrapatellar Fat Pad-Derived Mesenchymal Stem Cell Therapy for Knee Osteoarthritis
Y.J. Choi, Y.G. Koh, Y.-C. Kim, Y.-S. Park, 137-820/KR
P270 Effect of intraarticular injection of stem cells on joint pain and structural changes associated with
monoiodoacetate injection in rats
L. Song 1 , A. Bendele 2 , S. Coyle 1 , R. Zhang 1 , T. Davisson 1 , 1 Mahwah/US, 2 Boulder, Co/US
P271 Combined effect of mechanical load and BMP-2 overexpression on the chondrogenesis of human bone
marrow derived stem cells
A. Neumann 1 , C. Archer 2 , M. Alini 1 , M. Stoddart 1 , 1 Davos Platz/CH, 2 Cardiff/UK
P272 Tet-regulated, lentivirally mediated BMP2 expression in rabbit mesenchymal stem cells for treatment of
osteochondral defects
S. Vogt 1 , D. Wuebbenhorst 1 , G. Wexel 1 , B. Gansbacher 1 , A.B. Imhoff 2 , M. Anton 1 , 1 Muenchen/DE, 2 Munich/DE
P273 Manipulating the rate of biosynthesis and patterns of distributions of GAG macromolecules in murine
chondrocyte cultures, by employing para-nitrophenyl ß-D-xyloside
Z. Nevo, T. Weinstein, Z. Evron, M. Aviv, D. Robinson, Tel Aviv/IL
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Notes

Extended Abstracts & Index
1. Abstract Book
The abstracts of all Free Papers and posters can be found in a searchable
database as well as in a pdf-format for your print-out or download
on our website www.cartilage.org
(ICRS 2012 – Final Programme & Abstracts)
2. Online Itinerary Planner
Create and export your personal ICRS 2012 congress programme and
abstracts to your own calendar on your computer or mobile device.
The ICRS online itinerary planner is an interactive tool for
ICRS conference attendees to plan their individual meetings and
activities during the ICRS 2012 conference.
Various search options and filters empower the user to find the
presentations and sessions of his interest. Filters can be easily applied to
narrow the search results to only specific days, rooms, key words, topics,
authors. After browsing the program, all sessions or only individual
presentations of interest can be added to a personal itinerary. The individualized
PDF document and the information downloaded to the calendar can
include abstracts or any available media.

102
Extended Abstracts
1.1
Articular Cartilage Mechanisms, Management and Outcome
B. Mandelbaum
Santa Monica/United States of America
Introduction: The game of Football as it is called worldwide is the
played by more than 300 million people globally. It is the most
popular sport in the world and participation in this dynamic sport
continues to grow. We will from this point forward refer to the
Football athlete as a Football (Soccer) Player for the importance
of convention. The inherent nature of the game is played at the
extremes of intense performance and at times is a high-impact
contact sport associated with significant acute and chronic joint
contact forces with potential detrimental effects to the joint surface.
Articular cartilage injury is observed with increasing frequency in
football players and is commensurate with the competitive level.
Due to the limited spontaneous regeneration of articular cartilage
injuries often lead to significant symptoms under the continued
high demands of football ultimately resulting in the decrease in
performance or the inability to play. The FIFA Medical Assessment
and Research Center (F-MARC) and International Cartilage Repair
Society (ICRS) recognize the enormous impact of articular cartilage
injury for the football (Soccer) player. This session amplifiies the
relationship between FIFA and ICRS in an effort to help advance
the science and the understanding of articular cartilage injury and
degeneration in the football (soccer) player as well as the options
for its treatment and prevention The approach to the athlete always
uses the “Spectrumåof Care” Paradigm . Prevention, Performance
optimization, Injury care, rehabilitation and restoration and return
to sport, prevention of re-injury and osteoarthritis and keeping
the aging athlete healthy through exercise, These are the hallmark
principles that illuminate the importance of these collaborative
relationships.
Content: During this session we will demonstrate how evidence based
medicine (EBM) and innovation drives clinical decision making and
practice and vice versa. The Scientific Evidence Base for Cartilage
Injury and Repair in the Athlete in Football (Soccer) players frequently
injure the Anterior Cruciate Ligament (ACL) and menisci. These injuries
and the inherent risk of the game create an overall prevalence of knee
articular cartilage lesions of 36% to 38%. The resultant for athletes
with articular cartilage lesions is often challenging because of the
high demands placed on the normal, repaired and regenerated tissue
by the game over time. These cartilage defects in athletes can be
treated with microfracture, osteochondral auto or allogeniec tissues
and autologous chondrocyte implantation. There is increasing and
robust scientific evidence for cartilage repair in athletes, with more
extensive information available for microfracture and autologous
chondrocyte implantation than for osteochondral grafting. The
ultimate challenge is the quality of the repair tissue; Repaired and or
regenerated cartilage must closely must resemble and function like
hyaline cartilage may be the most significant factor for the return to
sport. So what do we do for the specific athlete with a spectrum of
cartilage deficits? How do we select the best specific option and at
what timing? We will present the best available evidence for cartilage
surgery and treatment selection, evaluate specific patient profiles
for professional and recreational athletes, and propose a treatment
algorithm for the treatment of focal cartilage lesions in football
(soccer) players. Once the intervention is completed attention to
detail of post operative protocols, rehabilitation, restoration of
function, return to sport participation and competition and prevention
of future injury and or progression towards osteoarthritis is essential.
This necessitates a multidisciplinary approach to rehabilitation,
especially in the transition from therapy to performance, training
and playing in games. Return to football is always a “significant
challenge” as presented by Drs. Mithoefer and Della Villa. . It should
be recognized that not all players will return to football after articular
cartilage repair. Factors that must be considered are return rate, time
to return and durability after return. The .average return rate to sport
after Articluar Cartilage repair is 79% without a significant difference
in return rate or postoperative level of play between cartilage
repair techniques. The range of time to return varied between 7
to 17 months, with the longest time is for autologous chondrocyte
transplantation (ACI).These parameters and expectations by the
patient, athlete and coach must considered in all clinical decisions.
Advanced sport-specific and a multidisciplinary phasic rehabilitation
were able to reduce recovery time. The durability of results was best
after ACI, with up to 96% continued sport participation after more
than 3 years. There are several factors that determine favorable
and successful return to football (soccer). These include player age
(younger), time between injury symptoms and treatment (less time),
competitive level of participation, (higher) defect size (smaller),
and repair tissue morphology (hyaline or hyaline like). Sports and
exercise participation after cartilage repair can and will facilitate
joint restoration, functional recovery and fitness levels. Although the
spectrum of care approaches listed above are hopeful, the probability
of developing Osteoarthritis in soccer players is 5 – 12 times more
frequent than in the general population. It is also highest for the most
elite athletes. It is also responsible for retirement in about a third of
professional players and diagnosed 4-5 years earlier. This process is
a spectrum of degeneration and loss of volume or chondropenia that
ultimately leads to frank osteoarthritis The etiology is multifactorial
and involves the demands of the game, biochemical, biomechanical,
inflammatory, nutritional and aging factors. As a result, athletes,
particularly those with a history of knee injury, have an earlier onset
and higher prevalence of osteoarthritis that would be expected based
on their age. In essence these are “old knees in young people”. It
remains a major cause of disability from the sport of football (soccer).
This is our call for concern! Therefore the ultimate goal for FIFA and
the ICRS is a prevention paradigm. Prevention of the injury, whether
acute or overuse, prevention of chondropenia and osteoarthritis and
the progression over time. .Injury prevention has been a major focus
of FIFA and F-MARC through development of the PEP Program (Prevent
Injury and Enhance Performance program) and then the evolution to
the FIFA 11+ program. The PEP program was designed to reduce ACL
injuries and several studies including a level I randomized control
trial have documented significant reductions when this program
is successfully utilized as a warm up. The evolution to the FIFA 11+
program now includes focus on not only knee, but also muscle,
groin and ankle injury. Significant reductions in severe, overuse and
knee injuries have been demonstrated in controlled trials Therefore
injury reduction is not only possible, it can and should be a reality
and part of any football program. These programs are time efficient,
easy to do, and are free of expense! The natural course progression
is that articular cartilage defects are to become osteoarthritis over
time. The next step in the FIFA/ ICRS initiative is how to prevent this
progression? Although recent treatments for damage to articular
cartilage have been successful in alleviating symptoms, more durable
and complete, long-term articular surface restoration remains the
unattained. This hopeful and futuristic approach looks an at both
new ways to prevent damage to articular surfaces as well as new
techniques to recreate biomechanically sound and biochemically
true articular surfaces once an athlete injures this surface. This
“holy grail “objective should be to produce hyaline cartilage with
a well-integrated and flexible subchondral base and the normal
zonal variability. Newer surgical techniques, some already in clinical
study, and others on the horizon offer opportunities to improve the
surgical restoration of the hyaline matrix often disrupted in athletic
injury. These include new scaffolds, single-stage cell techniques,
engineered allogeneic tissues, the use of mesenchymal stem cells,
and gene therapies. The last step of the prevention paradigm is to
prevent the progression of Osteoarthitis severity over time. There are
a number of non-operative interventions have shown early promise in
mitigating cartilage symptoms and in preclinical studies have shown
evidence for the potential disease modification, chondrofacilitation
and chondroprotection. These include the use of glucosamine,
chondroitin, and other neutraceuticals, viscosupplementation with
hyaluronic acid, platelet-rich plasma, and pulsed electromagnetic
fields In conclusion, the approach to the athlete always uses the
“Spectrum of Care” systematic paradigm. Prevention, Performance,
Injury care, rehabilitation and restoration and return to sport,
prevention of re-injury and osteoarthritis and keeping the aging
athlete healthy through exercise. The main objective of the FIFA and
the ICRS collaboration is the identify the scope of these problems;
develop multidisciplinary solutions with the major goal of prevention
for now and the future. It was Einstein that said, “It is the intelligent
that can solve problems but the genius will prevent them.” It is with
this spirit that we thank FIFA and its President Mr.Sepp Blatter, the
ICRS and its president Professor Daniel Saris and all the authors
for their timely and impactful contributions all of which making the
game of football… a better game! Play on!
References:
1. Peterson L, Junge A, Chomiak J, Graf-Baumann T, Dvorak J. Incidence
of football injuries and complaints in different age groups and skilllevel
groups. Am J Sports Med. 2000;28(5 Suppl):S51-7
2. Levy AS, Lohnes J, Sculley S, et al: Chondral delamination of the knee
in soccer players. Am J Sports Med 1996; 24:634-39.
3. Dvorak J.Br J Sports Med. 2011 Jun;45:673-6.
4. Steinwachs, Engebretsen, Brophy, Cartilage 2012, FIFA/ICRS
Supplement

5. McAdams T, Mithoefer K, Scopp J, Mandelbaum B. Articular cartilage
injury in athletes. Cartilage, 2010;1, 3:165-179.
6. Roos H, Dahlberg L, Hoerrner LA, Lark MW, Thonar EJ, Shinmei M,
Lindqvist U, Lohmander LS. Osteoarthritis Cartilage. 1995 Mar;3(1):7-
14.
7. Mithoefer and Steadman, Cartilage 2012, FIFA/ICRS Supplement
8. Panics et al, Cartilage 2012, FIFA/ICRS Supplement
9. Mithoefer, Peterson, Minas, Mandelbaum, Cartilage 2012, FIFA/ICRS
Supplement
10. Mithöfer K, Peterson L, Mandelbaum B, Minas T. Articular cartilage
repair in soccer players with autologous chondrocyte transplantation:
functional outcome and return to competition. Am J Sports Med.
2005;33:1639-46.
11. Gortz et al, Cartilage 2012, FIFA/ICRS Supplement
12. Robertson CM, Williams R. Return to sport after fresh osteochondral
allograft transplantation. Annula Meeting of the American Orthopedic
Society for Sports Medicine (AOSSM), Providence, Rhode Island, July
17, 2010.
13. Bekkers, de Windt, Brittberg. Cartilage repair in football athletes:
What evidence leads to which treatment. Cartilage 2012 , FIFA/ICRS
Supplement
14. Hambly, Silvers, Steinwachs. Rehabilitation and Injury Prevention
of Cartilage Injury in the Football Athlete, Cartilage 2012, FIFA/ICRS
Supplement
15. Mithoefer, Della Villa , Cartilage 2012, FIFA/ICRS Supplement
16. Della Villa S, Kon E, Filardo G, Ricci M, Vincentelli F, Delcogliano
M, Marcacci M. Does intensive rehabilitation permit early return to
sport without compromising the clinical outcome after arthroscopic
autologous chondrocyte implantation in highly competitive athletes.
Am J Sports Med. 2010 ;38(1):68-77.
17. Kreuz PC, Steinwachs M, Erggelet C, Lahm A, Krause S, Ossendorf
C, et al. Importance of sports in cartilage regeneration after autologous
chondrocyte implantation. Am J Sports Med 2007; 35: 1261-68.
18. Lee and Chu, Cartilage 2012, FIFA/ICRS Supplement
19. Drawer S, Fuller CW: Propensity for osteoarthritis and lower limb
joint pain in retired professional soccer players. Br J Sports Med 2001;
35:402-408.
20. Kujala UM, Kettunen J, Paananen H, Aalto T, Battie MC, Impivaara
O, Videman T, Sarna S. Knee Osteoarthritis in former runners, soccer
players, weight lifters, and shooters. Arth Rheum 1995; 38:539-546.
21. Kirkendall and Garrett. Cartilage 2012, FIFA/ICRS Supplement
22. Mandelbaum BR, Silvers HJ, Watanabe DS, Knarr JF, Thomas SD,
Griffin LY, Kirkendall DT, Garrett W Jr. Effectiveness of a neuromuscular
and proprioceptive training program in preventing anterior cruciate
ligament injuries in female athletes: 2-year follow-up. Am J Sports Med.
2005 Jul;33(7):1003-10.
23. Soligard T, Nilstad A, Steffen K, Myklebust G, Holme I, Dvorak J,
Bahr R, Andersen TE. Comprehensive warm-up programme to prevent
injuries in young female footballers: cluster randomised controlled
trial. Br J Sports Med. 2010 Sep;44(11):787-93
24. Zaslav et al. Cartilage 2012, FIFA/ICRS Supplement
Extended Abstracts 103
1.2
Basic science mechanisms & animal models of articular cartilage
injury
M.B. Hurtig
Guelph/Canada
Introduction: Osteoarthritis and osteochondral injury are possibly
the most pressing medical issues of our time as population dynamics,
psychosocial factors, and increasing life expectancy drive aging adults
to maintain their activity level in the hope of optimizing their BMI,
muscle tone, neuromuscular coordination, mental acuity and mental
health. The current generation of children faces a less optimistic
forecast because inactivity, diabetes and obesity contribute to multisystem
metabolic disorders that are only partially understood. These
children will miss the window of opportunity for conditioning their
developing tissues during an active childhood (Helminen, 2000),
and their less optimized neuromuscular conditioning and larger BMI
may make them more susceptible to osteoarticular disease. Our
attempts to control the incidence of joint injury and OA by modifying
contributing factors in young people have only met with partial
success; Knee injury prevention by neuromuscular conditioning in
young female athletes may be the notable exception. Unlike mice,
we have not identified genotypes among our population who display
down-regulated inflammation and osteochondral repair after injury,
though virtually all surgeons seem to believe that tissue quality and
response to injury (surgical or otherwise) is a major determinant of
postoperative success. In deference to our heterogeneous society, it
seems that our scientific community should focus on the complexities
of contributing factors in joint injury and repair. The reductionist
approach we have needed in past was necessary to provide a proof
of principle in genetically similar laboratory and other animals.
Now that OA can be cured in mice and rats, and chondral defects
repaired in rabbits, sheep, goats, pigs and horses; however noble
these targets may have been, what are our next challenges? Clearly,
notwithstanding the financial and regulatory barriers facing us, our
scientific mandate must be to understand more complex model
systems that have better predictive value for our patients.
Content: Acute versus chronic chondral injuries
As outlined in the ICRS consensus report on animal models (Hurtig
2011), delayed repair of chronic chondral defects is a logical target.
No patient arrives at the operating room within minutes of a chondral
injury so it is no surprise that surgically induced defects treated at
time=0 have much predictive value in development of new therapies.
Cartilage resurfacing might need to be combined with therapies that
address the dysregulation of matrix metabolism because many of
our patients have long-standing synovitis, cartilage thinning and
other evidence of a catabolic synovial environment environment.
The anti-catabolic effects of antibodies against chemokines such at
TNFα needed to be investigated better, and other targets developed.
The anabolic effect of growth factors has been exploited in tissue
engineering and to some extent in the selection of chondrocytes
expressing genes that would support anabolism. One technical issue
is cost, delivery and avoiding adverse systemic effects. A significant
regulatory barrier exists for combination therapies that might include
some combination of drugs, biologics, scaffolds or cells so a strong
case for efficacy and safety needs to be constructed.
Cartilage repair in suboptimal biomechanical, metabolic and other
conditions
The rapidly growing literature around diagnosis and management
of FAI (femoro-acetabular impingement) is possibly the best
example of how controversial clinical practices can develop before
evidence based medicine is available. Reshaping the femoral
neck, trimming the acetabular rim, repairing and reattaching the
acetabular labrum all have uncertain long term outcomes, and
the evidence that these change the progression of OA is lacking.
It seems unlikely that the geometrical and shape changes in this
joint can be completely addressed with surgery since both femoral
and acetabular components can have changes in their orientation
that would require invasive osteotomies and internal fixation. The
evolution of hip arthroscopy is gaining considerable momentum and
this will create a need for biologic hip resurfacing that can withstand
some incongruity. It is interesting to note that a canine model of OA
induced by reduced acetabular coverage was described by Inerot
et al (1991) but few investigators have risen to this challenge. The
considerable incidence of canine hip dysplasia, a polygenetic
trait in large breed dogs, could provide a proving ground for new
technologies in the face of naturally occurring disease with variable
expression. National and international case canine surgical registries
would be invaluable.

104
Extended Abstracts
Intercurrent disease and complex model systems
Diabetes, other metabolic syndromes as well as environmental toxins
share a common pathway in creating dysvascular tissues that response
poorly to injury and interventions. There is clear clinical evidence that
bone regeneration and cell-mediated cartilage repair are both affected
by smoking. Diabetes and other peripheral vasculopathies have not
been modeled in conjunction with animal models of cartilage repair, so
little is known about how to promote vascularity, for what duration and
during which phase of the repair.
Logistics of delivery to the synovial environment
Delivery of ancillary treatments for cartilage repair and prevention of
chondral injury after injury
The contraction of the pharmaceutical industry’s interest in OA is partly
due to the need for patients to be exposed to a drug or therapy for a
very long period-perhaps 10 or more years. This triggers safety concerns
and the probability of registering a drug without long, expensive and
possibly inconclusive results seems remote. To date, intra-articular
therapies have been limited to long acting corticosteroids and (shortacting)
hyaluronates but the development of sustained release intraarticular
formulation of existing parental therapies seems logical. This
could include growth factors, apoptosis inhibitors, surfactants, antiinflammatory
drugs and other small molecules. Anderson et al (2011)
describes the range of known therapies that could no doubt be expanded
upon. The evolution of microspheres, encapsulated proteins, and other
vehicles in sustained release formulations is well described in the tissue
engineering literature and has potential to solve some of the problems
inherent in managing patients with large, chronic chondral defects.
References:
Selected References
1. Functional adaptation of articular cartilage from birth to maturity under
the influence of loading: a biomechanical analysis. Brommer H., Brama
P. A., Laasanen M. S., Helminen H. J., van Weeren P. R. and Jurvelin J. S.
Equine Vet J 37(2):148-54 (2005)
2. Early exercise advances the maturation of glycosaminoglycans and
collagen in the extracellular matrix of articular cartilage in the horse.
van Weeren P. R., Firth E. C., Brommer B., Hyttinen M. M., Helminen A.
E., Rogers C. W., Degroot J. and Brama P. A. Equine Vet J 40(2):128-35
(2008).
3. Regular joint loading in youth assists in the establishment and
strengthening of the collagen network of articular cartilage and
contributes to the prevention of osteoarthrosis later in life: a hypothesis.
Helminen H. J., Hyttinen M. M., Lammi M. J., Arokoski J. P., Lapveteläinen
T., Jurvelin J., Kiviranta I. and Tammi M. I. J Bone Miner Metab 18(5):245-
57 (2000).
4. Anterior cruciate ligament injuries: etiology and prevention.. Brophy
RH, Silvers HJ, Mandelbaum BR. Sports Med Arthrosc. 2010 Mar;18(1):2-
11. Review.
5. The association between knee joint biomechanics and neuromuscular
control and moderate knee osteoarthritis radiographic and pain severity.
Astephen Wilson JL, Deluzio KJ, Dunbar MJ, Caldwell GE, Hubley-Kozey
CL. Osteoarthritis Cartilage. 2011 Feb;19(2):186-93.
6. Proteoglycan alterations during developing experimental osteoarthritis
in a novel hip joint model. Inerot S., Heinegård D., Olsson S. E., Telhag
H. and Audell L. Degenerative hip joint disease was induced in dogs by
extra-articular surgery that created a condition that mimics hip dysplasia.
J Orthop Res 9(5):658-73 (1991).
7. Response shift in self-reported functional scores after knee
microfracture for full thickness cartilage lesions. Balain B., Ennis O.,
Kanes G., Singhal R., Roberts S. N., Rees D. and Kuiper J. H. Osteoarthritis
and Cartilage 17(8):1009-13 (2009)
8. Does smoking influence outcome after autologous chondrocyte
implantation?: A case-controlled study. Jaiswal P. K., Macmull S., Bentley
G., Carrington R. W., Skinner J. A. and Briggs T. W. J Bone Joint Surg Br
91(12):1575-8 (2009)
9. Regenerative treatment with platelet-rich plasma combined with
a bovine-derived xenograft in smokers and non-smokers: 12-month
clinical and radiographic results. Yilmaz S., Cakar G., Ipci S. D., Kuru B.
and Yildirim, B. Journal of clinical periodontology 37(1):80-7 (2010)
10. May smokers and overweight patients be treated with a medial openwedge
HTO? Risk factors for non-union. Meidinger G., Imhoff A. B., Paul
J., Kirchhoff C., Sauerschnig M. and Hinterwimmer S. Knee Surg Sports
Traumatol Arthrosc 19(3):333-9 (2011).
11. Cartilage regeneration by gene therapy. Gelse K., von der Mark K. and
Schneider H. Curr Gene Ther 3(4):305-17 (2003).
12. Anticytokine therapy for osteoarthritis. Goldring M. B. Expert Opin
Biol Ther 1(5):817-29 (2001).
13. Beneficial effects of intra-articular caspase inhibition therapy
following osteochondral injury
Dang A. C., Warren A. P. and Kim H. T. Osteoarthritis and Cartilage
14(6):526-32 (2006).
14. Weekly intra-articular injections of bone morphogenetic protein-7
inhibits osteoarthritis progression. Hayashi M., Muneta T., Ju Y. J.,
Mochizuki T. and Sekiya I. Arthritis Res Ther 10(5):R118 (2008).
15. Efficacy of intra-articular injection of celecoxib in a rabbit model of
osteoarthritis. Jiang D., Zou J., Huang L., Shi Q., Zhu X., Wang G. and Yang
H. Int J Mol Sci 11(10):4106-13 (2010).
16 .Repeated Platelet Concentrate Injections Enhance Reparative
Response of Microfractures in the Treatment of Chondral Defects of the
Knee: An Experimental Study in an Animal Model. Milano G., Deriu L.,
Sanna Passino E., Masala G., Manunta A., Postacchini R., Saccomanno
M. F. and Fabbriciani C. Arthroscopy (2012).
Acknowledgments:
The Canadian Arthritis Network and Canadian Institutes of Health
Research contributed research funding.
1.3
Cartilage problems in the athlete: The scope of the problem
K. Mithoefer
Cambridge/United States of America
Introduction: Injuries of the articular cartilage surfaces of the knee
are observed with increasing frequency in athletes. Particularly
participation in pivoting sports such as football, basketball, and
soccer has been associated with a rising number of sports-related
articular cartilage injuries with higher injury rates at the competitive
and professional level. Injuries of the articular cartilage surface of the
knee in the athlete can often occur in association with other acute
injuries such as ligament or meniscal injuries, traumatic patellar
dislocations, and osteochondral injuries and have been described
in up to 50% of athletes undergoing anterior cruciate ligament
reconstruction. Besides acute traumatic injury, articular cartilage
injury can develop in the high-impact athletic population from
chronic pathologic joint loading patterns such as joint instability
or axis deviation. While intact articular cartilage adjusts to the
increasing weightbearing activity in athletes by increasing cartilage
volume and thickness in a linear dose-response relationship, recent
studies indicate that this dose-response curve reaches a threshold
and that activity beyond this threshold can result in maladaptation
and injury of articular cartilage. High-impact joint loading above this
threshold has been shown to decrease cartilage protoglycan content
and to increase levels of degradative enzymes and chondrocyte
apoptosis. Over time the integrity of the functional weight bearing
unit is lost and a chondropenic response is initiated that can include
loss of articular cartilage volume and stiffness, elevation of contact
pressures, and development or progression of articular cartilage
defects.
Content: The limited spontaneous repair following acute or chronic
articular cartilage injury is well documented. Recent reports
demonstrated that hyaline cartilage defects in athletes resulted in
significant pain and swelling and were associated with marked lifestyle
changes and limitation of athletic activity. Some long-term data
in athletes with isolated severe chondral or osteochondral damage
in the weightbearing condyles showed a 75% initial return to sport
initially, but a significant decline of athletic activity was observed over
time with development of radiographic evidence of osteoarthritis in
the 45-60% of athletes 14-34 years after the injury. These results are
supported by the up to 12 fold increased risk of knee osteoarthritis in

high-impact athletes established by the National Institute of Health
(NIH) and other independent studies. Untreated articular cartilage
defects have been shown to result in significantly worse long-term
joint function. The high demands on the joint surfaces in athletes
make treatment of articular cartilage injuries and restoration of
the injured joint surfaces critically important to facilitate continued
athletic participation and to maintain a physically active lifestyle.
The documented detrimental effect of high-impact articular loading
in the athletic population requires cartilage surface restoration that
can effectively withstand the significant mechanical joint stresses
generated during high-impact, pivoting sports. Besides reducing
pain, increasing mobility and improving knee function, the ability to
return the athlete to sport and to continue to perform at the pre-injury
athletic level presents one of the most important parameters for a
successful outcome from articular cartilage repair in this challenging
population. Treatment of articular cartilage injuries in the athletic
population has traditionally presented a significant therapeutic
challenge. However, development of new surgical techniques has
created considerable clinical and scientific enthusiasm for articular
cartilage repair. Based on the source of the cartilage repair tissue,
these new surgical techniques can generally be categorized into
three groups: marrow stimulation based techniques, osteochondral
transplantation techniques, and cell-based repair techniques.
Several studies have evaluated the microfracture technique
specifically in the athletic population. These studies included
recreational and professional athletes with follow-up ranging
from 2-6 years. Activity scores and knee function scores increased
significantly after microfracture in these athletes. Athletes were
able to successfully return to high-impact, pivoting sports including
football, soccer, alpine skiing, basketball, rugby, and tennis. Return
to sports was reported at an average of 6.5-10 months. However,
there was marked variability in the ability to return to sport after
microfracture. The ability to return to athletics at the preoperative
level also varied significantly. Return to professional and competitive
level sports was much better than to recreational athletics. A
recent study showed that while return to sports participation after
microfracture can be achieved rapidly, performance and playing time
will increase gradually to full participation. Return to high-impact
sports after microfracture has been found to be higher in younger
athletes with small lesion size, shorter preoperative symptoms, and
without prior surgical intervention. A decline of initial improvement
of postoperative sports participation was observed in some studies
after microfracture in athletes and occurred between 24-37 months,
however, activity levels and functional scores were still better than
at baseline. Osteochondral mosaicplasty has also been specifically
evaluated in athletes. Up to 95% good or excellent results with
improved functional scores and MRI rating have been reported.
Return to full athletic activity was reported in 61-93% of athletes at an
average of 6.5 months. Longer preoperative symptoms and increased
athlete age resulted in delayed return to sport after mosaicplasty.
Preoperative radiographic or clinical evidence of joint degeneration
predicted a return to sport at a lower level or even retirement from
competitive sports following mosaicplasty. Prospective randomized
comparison of mosaicplasty and microfracture in athletes reported
significantly better results with mosaicplasty at an average of 36
months. While studies have evaluated autologous osteochondral
transfer in athletes, no specific information has been reported on this
technique using allograft in this population. Autologous chondrocyte
transplantation has recently been evaluated in the demanding
athletic population. Good to excellent results were demonstrated in
72-96% with significant improvement of activity score. Best results
were obtained with single cartilage lesions of the medial femoral
condyle. Return to high impact-athletics was higher in younger,
competitive athletes, with short preoperative intervals while return in
recreational athletes was less predictable. The time to return to sport
was shorter in competitive level athletes. Athletes often returned
to the same skill level and a high portion of returning athletes
maintained their ability to perform 52 months after chondrocyte
implantation. Return to athletics was better with fewer prior surgeries
but return to sports was successful also with autologous cartilage
transplantation as a salvage procedure. Combined pathology
such as malalignment, ligamentous instability, or meniscal injury
and deficiency is frequently encountered by the surgeon treating
articular cartilage defects in the athletic knee. Surgically addressing
these concomitant pathologies is critical for an effective and durable
articular cartilage repair. Recent data demonstrated that isolated or
combined adjuvant procedures have no significant negative effect
on the ability to return to athletics after microfracture, mosaicplasty,
or autologous chondrocyte transplantation. In conclusion, articular
cartilage repair in athletes is aimed at returning the athlete to the
pre-injury level of athletic participation without increased risk for
long-term arthritic degeneration. Several surgical techniques have
been shown to improve function and athletic activity after articular
cartilage repair in this population but the rate of improvement and
Extended Abstracts 105
ability to return to athletic activity is dependent on several factors.
The choice of repair technique should be tailored to individual
patient and lesion characteristics using an established treatment
algorithm. Long-term studies in this population will determine the
efficacy of articular cartilage repair to reverse chondropenia and to
prevent development of secondary arthritic degeneration.
References:
1. Della Villa S, Kon E, Filardo G, Ricci M, Vincentelli F, Delcogliano
M, Marcacci M. Does intensive rehabilitation permit early return to
sport without compromising the clinical outcome after arthroscopic
autologous chondrocyte transplantation in highly competitive
athletes? Am J Sports Med. 2010 Jan;38(1):68-77
1. Drawer S, Fuller CW: Propensity for osteoarthritis and lower limb
joint pain in retired professional soccer players. Br J Sports Med
2001; 35:402-408.
2. Flanigan DC, Harris JD, Trin TQ, Siston R, Brophy RH. Prevalence
of chondral defects in athlete’s knees. A systematic review. Med Sci
Sports Exerc 2010.
3. Gudas R, Kelesinskas RJ, Kimtys V, Stankevicius E, Toliusis
V, Benotavicius G, Smailys A: A prospective randomized clinical
study of mosaic osteochondral autologous transplantation versus
microfracture for the treatment of osteochondral defects in the knee
joint in young athletes. Arthroscopy 2005; 21:1066-75.
4. Kujala UM, Kettunen J, Paananen H, Aalto T, Battie MC, Impivaara
O, et al. Knee Osteoarthritis in former runners, soccer players, weight
lifters, and shooters. Arth Rheum 1995; 38:539-546.
5. Levy AS, Lohnes J, Sculley S, LeCroy M, Garrett W. Chondral
delamination of the knee in soccer players. Am J Sports Med 1996;
24:634-39.
6. Maletius W, Messner K: The long-term prognosis for severe
damage to the weightbearing cartilage in the knee: A 14-year clinical
and radiographic follow-up in 28 young athletes. Acta Orthop Scand
1996; 165-168.
7. Mithoefer K, Gill TJ, Cole BJ, Williams RJ, Mandelbaum BR. Clinical
outcome and return to competition after microfracture in the
athlete’s knee: An evidenc-based syetematic review. Cartilage 2010;
1:113-20.
8. Mithoefer K, Hambly K, Della Villa S, Silvers H, Mandelbaum
BR. Return to sports participation after articular cartilage repair in
the knee: scientific evidence. Am J Sports Med 2009; 37 Suppl 1:
167S-76S.
9. Mithöfer K, Minas T, Peterson L, Yeon H, Micheli LJ: Functional
outcome of articular cartilage repair in adolescent athletes. Am J
Sports Med 2005; 33:1147-1153.
10. Mithöfer K, Peterson L, Mandelbaum BR, Minas T: Articular
cartilage repair in soccer players with autologous chondrocyte
transplantation: Functional outcome and return to competition. Am J
Sports Med 2005; 33(11):1639-46.
11. Mithoefer K, Williams RJ, Warren RF, Wickiewicz TL, Marx
RG. High-impact athletics after knee articular cartilage repair: A
prospective evaluation of the microfracture technique. Am J Sports
Med. 2006;34:1413-8.
12. Piasecki DD, Spindler KP, Warren TA, Andrish JT, Parker RD:
Intraarticular injuries associated with anterior cruciate ligament tear:
findings at ligament reconstruction in high school and recreational
athletes. Am J Sports Med 2003; 31:601-5.
13. Walzcac BE, McCulloch PC, Kang RW, Zelazny A, Tedeschi F,
Cole BJ. Abnormal findings on knee magnetic resonance imaging in
asymptomatic NBA players. J Knee Surg 2008; 21:27-33.

106
Extended Abstracts
2.1.1
Growth factors pathways as regulators of chondrogenesis
F. Beier
London/Canada
Introduction: Growth factors and their downstream sign align
pathways are essential regulators of chondrogenesis during
development and thus prime candidates for applications in tissue
engineering of cartilage. We will discuss general issues associated
with these topics and present some of our recent findings.
Content: The mechanisms regulating chondrogenesis during
skeletal development are highly relevant both to our understanding
of developmental diseases such as chondrodysplasias and to
approaches towards tissue engineering of cartilage, for example to
repair cartilage defects in osteoarthritis and other joint diseases.
Growth factors are endogenous regulators of this process in vivo
and a logical choice for use in tissue engineering, due to their
relative ease of application and their extracellular mode of action
(e.g. they can be added to the culture medium and don’t require
cellular uptake). For example, bone morphogenetic proteins (BMPs)
and other members of the transforming growth factor beta families
generally act as promoters of chondrogenic differentiation (Bobick
et al., 2009; Seo and Na, 2011). In contrast, Wnt proteins that signal
through the canonical beta-catenin pathway promote osteogenic over
chondrogenic differentiation of mesenchymal precursor cells. While
these two families of growth factors received the bulk of attention in
recent years, numerous other factors including hedgehog proteins,
members of the fibroblast, insulin-like and epidermal growth factor
(FGF, IGF and EGF) families and C-type natriuretic peptide have all
been implicated in modulation of chondrogenesis in vivo and/or in
vitro (Bobick et al., 2009; Seo and Na, 2011; Weiss et al., 2010; Woods
et al., 2007a). Importantly, the specific effects of these growth factors
are dependent on their concentration and their spatial and temporal
patterns of action. Moreover, all these factors do not act in isolation,
but cross-regulate each other and converge on key cellular signaling
pathways and transcription factors. The cellular response therefore
presents the integration of all the different, often contradictory
signals the cells receive from the various growth factors. Further
complexity is added by additional, non-growth factor signals that
act on the cells, such as cell-matrix and cell-cell interactions and
other signaling molecules including retinoic acid, nitric oxide and
prostaglandins. Chondrogenesis is a multistep process that includes
the steps of: 1) precursor cell condensation; 2) cellular commitment
and subsequent differentiation to the chondrogenic fate; 3) secretion
of a cartilage-specific extracellular matrix composed of collagen II and
aggrecan (among other proteins and non-protein matrix components
such as hyaluronic acid); 4) chondrocyte proliferation and, in the
case of growth plate chondrocytes, 5) further differentiation towards
hypertrophy followed by 6) apoptosis and replacement of cartilage
by bone tissue(Bobick et al., 2009). All these steps are regulated
by distinct (but overlapping) signals and mechanisms. In tissue
engineering approaches, the signals that can be utilized depend
on the desired application. For example, if one aims to generate
articular cartilage for applications in degenerative joint disease, it is
essential to promote early chondrocyte differentiation and possibly
proliferation, but at the same time prevent differentiation further
along the growth plate chondrocyte track towards hypertrophy.
This makes BMPs unlikely candidates for such approaches as they
ultimately cause hypertrophy and replacement of cartilage by
bone. In contrast, for other applications (for example the repair of
developmental defects, growth plate injuries or bone fractures),
differentiation along the entire growth plate pathway might be
desirable, which will then require a different approach. Thus, design
and optimization of growth factor treatments for a particular tissue
engineering strategy is complex and has to consider combination of
different factors, timing and concentration of each individual factor.
Thorough analyses of growth factor regulation of chondrogenesis
during development can certainly be used to guide such designs.
However, in addition to the complexities of growth factor effects
on cells discussed above, other regulatory processes complicate
analyses of these activities in vivo. These posttranslational
mechanisms include the presence of extracellular antagonists and
decoy receptors for many growth factors, sequestration of growth
factors in the matrix, and proteolytic activation as well as inactivation
of these factors. Thus, simple analyses of growth factor expression
during development give, at best, an approximation of the potential
function of these growth factors during chondrogenesis. Thorough
and detailed functional analyses, such as through sophisticated
conditional gene targeting in mice, is required to uncover how
growth factors act together to control chondrogenesis. One
potential drawback to the wide use of growth factors in cartilage
tissue engineering is the high cost of recombinant growth factors.
A potential strategy to overcome this limitation is the use of more
economic small molecule modulators (inhibitors or activators) of
the respective receptors or of downstream signaling molecules. The
later also have the advantage that most major signaling molecules
mediate cellular responses to many different growth factors. One
group of signaling molecules that have been implicated in the
control of chondrogenesis are the mitogen-activated protein (MAP)
kinases (Bobick and Kulyk, 2008; Stanton et al., 2003). These
proteins occupy a central role in the cell’s signaling network and are
activated by many growth factors involved in chondrogenesis, such
as TGFbeta family members, FGFs, EGFs etc. Of the major Map kinase
subfamilies, ERK1/2 generally suppress, while p38 proteins promote
chondrogenesis. MAP kinases exert their biological effects by
controlling the activities of transcription factors and other proteins,
but the specific downstream mediators responsible for the activities
of ERK1/2 and p38 during chondrogenesis are not well understood.
Another important group of signaling molecules that have been
implicated in the control of chondrogenesis are small molecular
switches of the Rho GTPase family (Woods et al., 2007a). Similar to
MAP kinases, their activities are modulated by many different growth
factors as well as by signals from cell-matrix and cell-cell interactions
(through integrins, cadherins etc). Our work, and subsequently that
of others, has shown that the classical member of the family, RhoA,
suppresses chondrogenesis, in part through repression of Sox9, the
chondrogenic ‘master’ transcription factor (Woods and Beier, 2006;
Woods et al., 2005, 2007a). In contrast, two other Rho GTPases, Rac1
and Cdc42, promote chondrogenesis (Woods et al., 2007b). A similar
antagonism between RhoA and Rac1/Cdc42 applies to later stages
of chondrocyte maturation, e.g. hypertrophy and apoptosis (Wang
and Beier, 2005; Wang et al., 2004), at least in vitro. Many additional
signaling pathways with important roles in chondrogenesis have been
described. One pathway of particular interest is presented by glycogen
synthase kinase 3 (GSK-3) which acts as a ‘brake’ on many of the
discussed pathways (Kaidanovich-Beilin and Woodgett, 2011). The
two GSK-3 proteins, GSK-3alpha and GSK-3beta, are best known for
inducing the degradation of beta-catenin, the central component of the
canonical Wnt pathway. However, these proteins are also involved in
most of the other pathways controlling chondrogenesis. Manipulation
of their activity thus has the potential to modulate the cell response
to many of these factors and to drive the cells towards the desired
chondrocyte phenotype. In closing, both the controlled application of
growth factors and the manipulation of downstream pathways have
the potential to further improve chondrogenesis for tissue engineering
approaches. However, a better understanding of the endogenous role
of these pathways in developmental chondrogenesis is likely required
to optimize tissue engineering approaches so that chondrocytes of the
desired phenotype and characteristics can be obtained.
References:
Bobick, B.E., Chen, F.H., Le, A.M., and Tuan, R.S. (2009). Regulation
of the chondrogenic phenotype in culture. Birth Defects Res C Embryo
Today 87, 351-371.
Bobick, B.E., and Kulyk, W.M. (2008). Regulation of cartilage formation
and maturation by mitogen-activated protein kinase signaling. Birth
Defects Res C Embryo Today 84, 131-154.
Kaidanovich-Beilin, O., and Woodgett, J.R. (2011). GSK-3: Functional
Insights from Cell Biology and Animal Models. Front Mol Neurosci 4,
40. Seo, S., and Na, K. (2011).
Mesenchymal stem cell-based tissue engineering for chondrogenesis.
J Biomed Biotechnol 2011, 806891. Stanton, L.A., Underhill, T.M., and
Beier, F. (2003). MAP kinases in chondrocyte differentiation. Dev Biol
263, 165-175.
Wang, G., and Beier, F. (2005). Rac1/Cdc42 and RhoA GTPases
antagonistically regulate chondrocyte proliferation, hypertrophy, and
apoptosis. J Bone Miner Res 20, 1022-1031.
Wang, G., Woods, A., Sabari, S., Pagnotta, L., Stanton, L.A., and Beier,
F. (2004). RhoA/ROCK signaling suppresses hypertrophic chondrocyte
differentiation. J Biol Chem 279, 13205-13214.
Weiss, S., Hennig, T., Bock, R., Steck, E., and Richter, W. (2010).
Impact of growth factors and PTHrP on early and late chondrogenic
differentiation of human mesenchymal stem cells. J Cell Physiol 223,
84-93.
Woods, A., and Beier, F. (2006). RhoA/ROCK signaling regulates
chondrogenesis in a context-dependent manner. J Biol Chem 281,
13134-13140.

Woods, A., Wang, G., and Beier, F. (2005). RhoA/ROCK signaling regulates
Sox9 expression and actin organization during chondrogenesis. J Biol
Chem 280, 11626-11634.
Woods, A., Wang, G., and Beier, F. (2007a). Regulation of chondrocyte
differentiation by the actin cytoskeleton and adhesive interactions. J
Cell Physiol 213, 1-8. Woods, A., Wang, G., Dupuis, H., Shao, Z., and
Beier, F. (2007b). Rac1 signaling stimulates N-cadherin expression,
mesenchymal condensation, and chondrogenesis. J Biol Chem 282,
23500-23508.
Acknowledgments:
F.B. acknowledges funding from the Canadian Institutes of Health
Research and the Canada Research Chair Program.
2.1.2
Signaling proteins and transcription factors in joint development
and degeneration
M. Pacifici, M. Iwamoto
Philadelphia/United States of America
Introduction: During limb skeletogenesis, chondrocytes located at the
epiphyseal ends of long bone anlagen develop into permanent articular
chondrocytes that sustain joint function though life (1). Instead,
the chondrocytes constituting the shaft are transient cells, become
organized in growth plates, undergo maturation and hypertrophy, and
are replaced by bone via endochondral ossification (2). The essential
nature of this developmental bifurcation in chondrocytes is widely
appreciated, but its regulation remains poorly understood, particularly
at the molecular level.
We previously showed that the transcription factor Erg is specifically
expressed in developing limb synovial joints during mouse and chick
embryogenesis. Erg belongs to the ets family of transcription factors.
The current 29 members regulate a variety of developmental processes
and when mutated, can cause severe pathologies (3-4). They share the
highly conserved 85-amino
acid ets domain that binds to the core DNA core motif 5’-GGA(A/T)-3’
and displays a winged helix-turn-helix
organization with three α-helices and four β-sheets (5). Based on
the structure of other domains and in particular the Pointed/SAM
domain (6), the proteins are distinguished into ets sub-families. This
is of significant relevance because the SAM domains mediate proteinprotein
interactions and regulate interactions of Ets members with other
SAM- and non-SAM containing nuclear proteins, thus exerting a major
influence on function and bioactivity (7). Ets protein-protein interactions
are also modulated by phosphorylation and conformational changes.
Based on their similar SAM domain, Erg, Fli-1 and Fev constitute one
such ets sub-family.
We found that Erg is expressed in the mesenchymal interzone together
with the signaling proteins Gdf5 and Wnt9a at very early stages of
joint formation and is then expressed in articular chondrocytes (8-9).
To study function, we over-expressed Erg in mice under the control
of cartilage-specific Col2a1 regulatory sequences and found that the
entire skeleton of the transgenic mice had remained cartilaginous and
failed to undergo endochondral ossification (9). This led us to conclude
that Erg may be important to establish and maintain the permanent
phenotype of articular chondrocytes. To test this possibility directly, we
have now created floxed Erg mice and examined the consequences of
conditional Erg deletion on short and long term formation and function
of articular cartilage.
Content: To test the possible roles of Erg in joint formation, we first
created floxed Erg mice by targeting an essential protein-encoding
exon. The floxed Erg mice were then mated with mice that express Cre
recombinase under the control of Gdf5 regulatory sequences. We had
previously used the Gdf5-Cre mice to conditionally delete genes in early
developing joints, including Ext1 (10). We had used them also to carry
out genetic track-and-trace experiments after mating with RosaR26R
mice to identify the origin of joint progenitor cells; we showed for the
first time that the joint tissues are for the most produced by interzone
mesenchymal cells only (11). The compound Gdf5-Cre/Erg-mutant
mice were born at mendelian ratios but unexpectedly, did not exhibit
overt joint defects when young. To account for absence of a major joint
developmental phenotype, we asked whether the ets subfamily member
Extended Abstracts 107
Fli-1 was co-expressed and in fact it was, and may have compensated
for Erg absence. To test possible postnatal roles of Erg, we subjected
2 month-old Erg-deficient mice to knee’s medial collateral ligament
(MCL) transection to induce experimental osteoarthritis (OA) (12).
Strikingly, the Erg-deficient mice developed serious OA-like defects
far sooner than operated wild type companions. Indeed, we observed
similar severe OA-like defects in aging un-operated 7-11 month-old
Erg-deficient mice, while control littermates displayed mild defects. To
gain insights into how Erg maintains long-term articular chondrocyte
function, we focused on parathyroid hormone-related protein (PTHrP)
which is also expressed in developing joints, stabilizes the chondrocyte
phenotype (13) and prevents chondrocyte hypertrophy when overexpressed
in cartilage (just as transgenic Erg over-expression does).
We found that Erg (as well as Fli-1) stimulates PTHrP expression and
the PTHrP gene promoter contains several conserved ets binding sites
needed for responsiveness.These and other data lead us to conclude
that Erg regulates the development and long-term stabilization and
function of articular chondrocytes and does so in cooperation with
transcription factor subfamily member Fli-1 and with the signaling
protein PTHrP.
References:
1. Pacifici M, Koyama E, Iwamoto M 2005 Mechanisms of synovial joint
and articular cartilage formation: recent advances, but many lingering
mysteries. Birth Defects Research, Pt. C 75:237-248.
2. Kronenberg HM 2003 Developmental regulation of the growth plate.
Nature 423:332-336.
3. Sharrocks AD 2001 The ets-domain transcription factor family. Nature
Reviews Mol. Cell Biol. 2:827-837.
4. Gutierrez-Hartmann A, Duval DL, Bradford AP 2007 ETS transcription
factors in endocrine systems. Trends Endocrinol. Metab. 18:150-158.
5. Karim FD, Urness LD, Thummel CS, Klemsz MJ, McKercher SR, Celada
A, Van Beveren C, Maki C, Gunther RA, Nye JA, Graves BJ 1990 The ETSdomain:
a purine-rich core DNA sequence. Genes Dev. 4:1451-1453.
6. Qiao F, Bowie JU 2005 The many faces of SAM. Science STKE
286:re7
7. Papoutsopolou S, Janknecht R 2000 Phosphorylation of ETS
transcription factor ER81 in complex with its coactivators CREB-binding
protein and p300. Mol. Cell. Biol. 20:7300-7310.
8. Iwamoto M, Higuchi Y, Koyama E, Enomoto-Iwamoto M, Yeh H,
Abrams WR, Rosenbloom J, Pacifici M 2000 Transcription factor ERG
variants abone development. J. Cell Biol. 150:27-39.
9. Iwamoto M, Tamamura Y, Koyama E, Komori T, Takeshita N, Williams
JA, Nakamura T, Enomoto-Iwamoto M, Pacifici M 2007 Transcription
factor ERG and joint and articular cartilage formation during mouse
limb and spine skeletogenesis. Dev. Biol. 305:40-51.
10. Mundy C, Yasuda T, Yamaguchi Y, Iwamoto, M. Enomoto-Iwamoto
M, Koyama E, Pacifici M 2011 Synovial joint formation require slocal
Ext1 expression and heprana sulfate production in developing mouse
limbs and spine. Dev. Biol. 351:70-81.
11. Koyama E, Shibukawa Y, Nagayama M, Sugito H, Young B, Yuasa T,
Okabe T, Ochiai T, Kamiya N, Rountree RB, Kingsley DM, Iwamoto M,
Enomoto-Iwamoto M, Pacifici M 2008 A distinct cohort of progenitor
cells participates in synovial jskeletogenesis. Dev. Biol. 316:62-73.
12. Kamekura S, Hoshi K, Shimoaka T, Chung U-I, Chikuda H, Yamada
T, Uchida M, Ogata N, Seichi A, Nakamua K, Kawaguchi H 2005
Osteoarthritis development ininduced by knee joint instability.
Osteoarthr. Cart. 13:632-641.
13. Macica CM, Liang G, Nasiri A, Broadus AE 2011 Genetic evidence of
the regulatory role of parathyroid hormone-related protein in articular
chondrocyte maintenance in an experimental mouse model. Arthr.
Rheum. 63 3333-3343.
Acknowledgments:
We thank our colleagues for essential contributions to this research.
We also thank Dr. D. Kingsley for providing the Gdf5-Cre mouse line.
The research work was supported by NIH RO1 grants AR046000 and
AR062908.

108
Extended Abstracts
2.1.3
Growth factors in cartilage homeostasis in vitro / in vivo
S. Chubinskaya
Chicago/United States of America
Introduction: Cartilage repair and regeneration is a major obstacle in
orthopedics. The importance is enormous since osteoarthritis (OA) is
a primary cause of disability among the adult population in the United
States. OA is a disease of the joint, in which a process of attempted,
but gradually failing, repair of damaged cartilage extracellular
matrix occurs due to imbalance between synthesis and breakdown
of matrix components. Currently, the only treatments available for
cartilage damage are surgical interventions, such as microfracture,
articular chondrocyte transplantation, autografting, allografting,
debridement, lavage, and joint replacement at the end-stage
disease. Innovations in bioengineering include the use of juvenile
cartilage, isolated chondrocytes, stem cells together with scaffolds
and various polymeric matrices, but those are still in development.
To the best of our knowledge none of the existing approaches could
regenerate normal adult hyaline cartilage that is able to perform
required functions, sustain the load and integrate with the host
tissue. Importantly, newly repaired tissue due to its imperfect
structural organization may also be more susceptible to re-injury.
From a therapeutic potential, there is no drug on the market that
can halt the destruction of the joint seen in OA, though the progress
has been made in disease-modifying OA drugs aimed to target
several molecular pathways involved in the pathophysiology of OA.
These include bisphosphonates, tetracyclines, metalloproteinase
inhibitors, diacerein and cytokine antagonists, OA targeted gene
therapy, and growth factors. In this presentation we will review the
current knowledge on the use of growth factors for cartilage repair
and their overall role in cartilage homeostasis.
Content: Growth factors appear to be the most promising agents to
stimulate anabolic responses and repair of articular cartilage. The
most known are the members of the Transforming Growth Factor
(TGF)-β superfamily including the Bone Morphogenetic Proteins
(BMPs), Insulin-Like Growth Factor-1 (IGF-1), Fibroblast Growth
Factors (FGF), especially FGF-2 and FGF-18, Epidermal Growth Factor,
Vascular-Endothelial Growth Factors (VEGFs), and other. TGF-β
is widely used in various animal models of OA and in stem cells
research as the growth factor that drives chondrogenesis. In articular
chondrocytes TGF-β has been shown to induce both catabolic and
anabolic responses and its utilization for cartilage repair remains
to be questionable due to its ability to stimulate tissue fibrosis and
formation of osteophytes. IGF-1 is another anabolic factor, which
chondroprotective activity was primarily demonstrated in various
animal models of OA. In humans, however, the responsiveness to
IGF-1 is significantly reduced with ageing, which limits its application
for human cartilage repair. FGFs are important regulators of cartilage
development and homeostasis. FGF-2 can stimulate cartilage repair
responses, but its potent mitogenic effects may lead to chondrocyte
cluster formation and poor extracellular matrix due to a relatively
low level of type II collagen. FGF-2 has been also shown to induce
pro-catabolic and pro-inflammatory responses. In a rabbit ACL
transection model, however, sustained release formulations of
FGF-2 reduced OA severity. Another member of the same family,
FGF-18, has been shown to induce anabolic effects in chondrocytes
and chondroprogenitor cells, and to stimulate cell proliferation
and type II collagen production. In a rat meniscal tear model of OA,
intra-articular FGF-18 injections induced a remarkable formation of
new cartilage and reduced the severity of the experimental lesions.
Thus far, only two anabolic factors, FGF-18 and BMP-7, are being
tested in clinical studies in patients with established OA. FGF-18
was investigated in a randomized, double-blind, placebo controlled
multicenter studies in patients with primary knee OA, scheduled for
total knee replacement. No local or systemic concerns were reported
for single or multiple injections of FGF-18 and positive biological
activity was documented on joint histology (cartilage damage/OA
severity) and biomechanical properties (cartilage stiffness). However,
no difference with placebo treatment was found in joint space
narrowing and cartilage thickness. The members of the BMP family
of proteins are important stimuli of mesenchymal cell differentiation
and extracellular matrix formation. Few of them, BMP-2 and BMP-7,
appear to be extremely potent in cartilage and bone repair. The most
studied BMP for human and animal cartilage repair is BMP-7, also
known as osteogenic protein-1 (OP-1). The results suggest that BMP-
7 may be the best candidate thus far as a disease-modifying drug
for OA and post-traumatic OA (PTOA). Unlike TGF-β and other BMPs,
BMP-7 up-regulates chondrocyte metabolism and protein synthesis
without creating uncontrolled cell proliferation and formation of
osteophytes. BMP-7 prevents chondrocyte catabolism induced by
IL-1 or fragments of matrix components. It has synergistic anabolic
effects with other growth factors such as IGF-1, which in addition to
its anabolic effect acts as a cell survival agent. Importantly, BMP-
7 restores the responsiveness of human chondrocytes to IGF-1 lost
with ageing through the regulation of IGF-1 and its signaling pathway.
In our most recent studies on BMP-7 in acute ex vivo cartilage
trauma model BMP-7 stimulated PG synthesis and preserved matrix
integrity. The treatment with BMP-7 also significantly promoted cell
survival in the impacted region and prevented the expansion of cell
death and matrix degeneration into the adjacent, but not impacted
regions. Furthermore, BMP-7 has been used in various PTOA animal
models in dogs, sheep, goats and rabbits. In all these PTOA models
(ACL transaction, osteochondral defect, and impaction), BMP-7
regenerated articular cartilage, increased repair tissue formation
and improved integrative repair between new cartilage and the
surrounding articular surface. Critically, in a study with sheep
impaction model a window of opportunity for the treatment with
BMP-7 has been identified. It was found that therapeutic application
of BMP-7 was the most effective in arresting progression of cartilage
degeneration if administered twice with a weekly interval either
immediately after trauma or delayed by three weeks. If delayed by
three month, the treatment was ineffective. These important results
suggest that the development and progression of PTOA could
be arrested and maybe even prevented if the right treatment is
administered at the right time. In addition, strong pro-anabolic and
anti-catabolic properties of BMP-7 have been demonstrated in gene
array studies with human chondrocytes and in disc degeneration
animal models, where BMP-7 was also effective as an anti-pain
treatment. Phase I clinical study produced very encouraging results
by showing tolerability to the treatment, absence of toxic response,
and a greater symptomatic improvement in patients that received a
single injection of BMP-7. At this stage of our cumulative knowledge,
BMP-7 appears to be one of the best candidate therapeutic agents
for cartilage repair since it affects multiple catabolic and anabolic
pathways.
References:
Anderson, DD; Chubinskaya, S; Guilak, F; Martin, JA; Oegema, TR;
Olson, SA and Buckwalter, JA. (2011). Post-traumatic osteoarthritis:
improved understanding and opportunities for early intervention.
J Orthop Res, 29(6):802-9. Chubinskaya, S; Hurtig, M and Rueger,
DC. (2007). OP-1/BMP-7 in cartilage repair. Int Orthop, 31(6):773-81.
Chubinskaya, S; Otten, L; Soeder, S; Borgia, JA; Aigner, T; Rueger, DC
and Loeser, RF. (2011). Regulation of chondrocyte gene expression
by osteogenic protein-1. Arthritis Res Ther, 13(2):R55. Ellman,
MB; An, HS; Muddasani, P and Im, HJ. (2008). Biological impact
of the fibroblast growth factor family on articular cartilage and
intervertebral disc homeostasis. Gene, 420(1):82-9. Ellsworth, JL;
Berry, J; Bukowski, T; Claus, J; Feldhaus, A; Holderman, S; Holdren,
MS; Lum, KD; Moore, EE; Raymond, F; Ren, H; Shea, P; Sprecher,
C; Storey, H; Thompson, DL; Waggie, K; Yao, L; Fernandes, RJ; Eyre,
DR and Hughes, SD. (2002). Fibroblast growth factor-18 is a trophic
factor for mature chondrocytes and their progenitors. Osteoarthritis
Cartilage, 10(4):308-20. Fortier, LA; Mohammed, HO; Lust, G and
Nixon, AJ. (2002). Insulin-like growth factor-I enhances cell-based
repair of articular cartilage. J Bone Joint Surg Br, 84(2):276-88. Lotz,
MK and Kraus, VB. (2010). New developments in osteoarthritis.
Posttraumatic osteoarthritis: pathogenesis and pharmacological
treatment options. Arthritis Res Ther, 12(3):211. Dahlberg LE,
Flechsenhar K, Gouteux S, Jurvelin JS. A randomized, double-blind,
placebo controlled, multicenter center study of rhFGF-18 administered
intra-articularly using single or multiple ascending doses in patients
with primary knee osteoarthritis, scheduled for knee replacement.
OARSI, San Diego, 2011.
Acknowledgments:
This work was supported by the NIH/NIAMS grants, Stryker Biotech
research support, National Football League Charities, Ciba-Geigy
Endowed Chair and Department of Biochemistry, Rush University
Medical Center. The authors would like to acknowledge Dr. Arkady
Margulis for tissue procurement and Dr. Lev Rappoport and Mrs.
Arnavaz Hakimiyan for their technical assistance. The authors also
would like to acknowledge the Gift of Hope Organ & Tissue Donor
Network and donor’s families.

2.2.1
Nerve dependence and cartilage development during Urodele
limb regeneration and its relevance to mammals.
M. Maden
Gainesville/United States of America
Content: When the Urodele limb is amputated anywhere along its
length it can replace a perfect copy of itself in a remarkably rapid
time. Following amputation and wound healing the internal tissues
- muscle, cartilage/bone, dermis - dedifferentiate to liberate a
population of apparently pluripotent cells, called the blastema, which
proliferate and redifferentiate into the missing structures. Although
initial studies suggested that these blastemal cells were pluripotent,
for example, if the cartilage is removed from the stump, new cartilage
nevertheless regenerates distal to the amputation plane, recent
studies have revealed far less interchange between tissue types.
We have shown, using transgenically labeled cells grafted into the
regenerating limb, that there is a considerable degree of lineage
preservation especially with regard to the muscle. Cartilage can,
however, be regenerated from the dermal fibroblasts of the stump
and these experiments will be described. The dermal fibroblast
seems to be the ‘stem cell’ of the regenerating limb and in addition
to being able to undergo this fate change to generate cartilage, has
considerable organizing properties in terms of patterning.
Proliferation of the blastemal cells in the regenerate has long been
known to be a nerve dependent phenomenon. In 1823 it was revealed
that severing of the nerves supplying the newt limb prevented
regeneration and ideas on the role that nerves played were generated
in the 1950’s in a careful series of experiments showing that the
effect was quantitative and depended on the number of nerve fibres
remaining at the amputation plane. Most recently the identity of the
factor that the nerves provide has been found to be newt Anterior
Gradient protein which is secreted by the Schwann cells of the distal
nerve sheath and then by the gland cells in the wound epidermis
covering the amputated limb. Our recent studies on the neural
control of regeneration and the role of retinoic acid have led us to
show that the maintenance of the differentiated cartilage phenotype
is retinoic acid dependent since the application of an antagonist to
retinoic acid signaling to the fully formed axolotl limb causes the
cartilage to regress and the limb to shrink. We will describe our
investigations into this aspect of cartilage maintenance.
Our regeneration studies also encompass mammals and in particular
the regeneration of ear tissue following circular punches. It is known
that rabbits can fully regenerate after such damage, but we have
found a species of mouse that also perform this surprising feat and
can thus regenerate cartilage. We consider this regenerative property
to be due to be the formation of a blastema which shows striking
similarities to the Urodele limb blastema and these experiments will
also be described.
2.2.2
Neurogenic factors in the etiopathogenesis of osteoarthritis
D. Walsh
Notthingham/United Kingdom
Introduction: Osteoarthritis (OA) typically presents with pain, and
yet how changes in the joint lead to pain in OA remains incompletely
understood. Furthermore, the nervous system influences normal
joint function, and may contribute to OA pathogenesis.
Content: OA is often considered a disease of articular cartilage, but
this tissue, as with the inner 2 thirds of the meniscus, contains no
nerves in the normal joint in which it cannot therefore be a direct
source of pain. Synovitis and subchondral bone marrow lesions
have been associated with pain in imaging studies, although it
remains unclear whether these lesions are themselves painful, or
surrogate biomarkers of other pathology within the joint. Peripheral
sensitization of nerves within the joint contributes to OA pain.
Sensitization may be induced by inflammatory mediators (e.g. kinins,
prostaglandins), or growth factors (e.g. nerve growth factor, NGF),
produced both in OA synovium and subchondral bone. Clinical trials
have confirmed the relative importance of such factors in OA pain.
Subchondral nerves are normally protected from mechanical and
chemical stimuli by force dissipation in the articular cartilage and
subchondral bone plate, and by the relatively impermeable tidemark
at the osteochondral junction. Exposure of subchondral nerves,
Extended Abstracts 109
due to abnormal biomechanical properties and permeabilisation
of the osteochondral junction may further contribute to OA pain.
In OA, sensory nerves invade through vascularised channels that
extend from subchondral bone into articular cartilage and chondroosteophytes.
Similarly nerves grow towards the meniscal tip during
the meniscal degeneration that accompanies knee OA. Sensory
innervation of previously non-innervated structures in the joint
may also contribute to pain in OA, even if subjected only to normal
mechanical stresses. Mechanisms of sensitization, joint damage
and nerve growth are closely inter-related. Synovitis contributes
to both joint damage and peripheral sensitization. Treatments that
help maintain integrity of the osteochondral junction reduce pain
in OA. Sensory nerve growth follows blood vessel growth, both in
time and in space, and nerve growth is integrated with angiogenesis.
Nerve growth and angiogenic factors are each upregulated in OA,
and recent preclinical studies and clinical trials have demonstrated
the potential that blocking NGF or angiogenesis may reduce OA
pain. Much mechanistic understanding of OA derives from animal
models, although existing models may have limitations in predicting
responses to new treatments in man. OA is a heterogeneous disease,
and no single model can mimic all aspects or stages of OA. Models,
however, are helping to define the mechanisms, timecourse and
interplay between peripheral and central sensitization, cartilage
damage, osteochondral and subchondral pathology, osteophyte
formation and nerve growth. Angiogenic and nerve growth factors
overlap in their functions. NGF can stimulate angiogenesis.
Neuropilin-1 on endothelial cells is a co-receptor for vascular
endothelial growth factor (VEGF), and on sensory nerves binds the
nerve guidance factors; semaphorins. Semaphorins inhibit both
angiogenesis and sensory axonal growth. Angiogenesis facitiltates
inflammation and is a prerequisite for endochondral ossification
characteristic of osteophytes and at the osteochondral junction in
OA. Factors that regulate nerve growth may also directly influence
cartilage function in OA. NGF, its receptors and neuropilin-1
are expressed in OA cartilage, and semaphorin-3A and -3F by
hypertrophic chondrocytes. Furthermore, nerve-derived factors may
additionally moderate chondrocyte function. Nerve-derived factors
also regulate inflammation and vascular function in the synovium.
The neuropeptides substance P and calcitonin gene-related peptide
(CGRP) are released by peripheral terminals of sensory nerves within
the joint, where they bind specific receptors on adjacent blood vessels
and increase permeability and vasodilation respectively. These
vasoactive neuropeptides can also initiate angiogenesis, and new
blood vessel growth is emerging as one of the factors that determines
persistence rather than resolution of synovitis. Neuropeptides may
also regulate chondrocyte function, although whether this signifies
neurogenic influences or autocrine or paracrine pathways from nonneuronal
peptide sources remains unclear. Neurovascular factors
are important in maintaining tissue phenotype. Angiogenesis into
joint cartilage is associated with its ossification. Similarly, sensory
innervation may be a beneficial facilitator of repair in some tissues
(e.g. skin and bone), but may contribute to heterotypia in repairing
cartilage defects. Inhibition of blood vessel and nerve growth may
be important to ensure symptomatic benefit from tissue engineering
approaches to cartilage repair. As well as having direct effects within
the joint, neurogenic factors make important contributions to joint
function through proprioceptive and neuromuscular pathways.
Alterations in central processing of afferent signals in OA lead to
altered body image and proprioceptive feedback. These contribute
to symptoms, distress and disability, but also, potentially lead the
joint to be subject to abnormal biomechanical stress. Furthermore,
joint pain leads to muscle inhibition, both through moderation of
spinal reflexes, and through changes in neurotrophic support to
the musculature. Muscle weakness further contributes to disability,
and exacerbates biomechanical stresses and consequential damage
and pain. Neurogenic influences on the OA joint may be both
beneficial and harmful. Nodal OA developing after neuronal damage
may spare the affected joints, although it is unclear whether this
effect is purely biomechanical due to reduced usage, or represents
important neurogenic contributions to OA evolution. Conversely,
sensory neuropathy may be associated with a severe destructive but
hypertrophic arthropathy (named after Charcot), which may share
some pathological features with OA. Analgesic-associated joint
damage, however, may be more likely attributable to `off target’
effects of specific agents, rather than exacerbation of OA pathology
by sensory inhibition. Accelerated joint damage associated with
corticosteroids, non-steroidal anti-inflammatory agents, and, most
recently anti-NGF treatments is unlikely to be explained by a common
analgesic mechanism. The precise contributions of neurogenic
factors to OA etiopathogenesis remain to be completely elucidated.
What is clearer is that nerves within the joint critically determine the
symptoms of OA. Failure of total hip replacement to satisfactorily
relieve OA pain in up to 15% of patients may point to important
contributions of peri-articular structures and abnormal central pain

110
Extended Abstracts
processing. However, undoubted benefits for the large majority
indicate pivotal roles for the articular surface and subchondral
bone, at least in late disease. Disease modification must be directed
at structural changes that are relevant to patients’ symptoms,
particularly pain. Better understanding the symptomatic relevance
of changes within the joint, and the interactions between nerves and
their surrounding tissues, should lead to important advances in OA
therapy in the near future.
References:
Mapp PI, Walsh DA. Angiogenesis in osteoarthritis: Mechanisms of
disease and potential therapeutic targets. Nat. Rev. Rheumatol. (In
press).
Suri S, Walsh DA. Osteochondral alterations in osteoarthritis. Bone
(In press) DOI: 10.1016/j.bone.2011.10.010
Ashraf, S, Wibberley, H, Mapp, PI, Hill, R, Wilson, D, Walsh, DA.
Increased vascular penetration and nerve growth in the meniscus:
a potential source of pain in osteoarthritis. Ann. Rheum. Dis. 2011,
70, 523-529.
Walsh DA, McWilliams DF, Turley MJ, Dixon M, Fransès RE, Mapp PI,
Wilson D. Angiogenesis and nerve growth factor at the osteochondral
junction in rheumatoid arthritis and osteoarthritis Rheumatology
2010, 49, 1852-61.
Acknowledgments:
I am grateful to the members of the Arthritis Research UK Pain Centre,
and to patients and public who contribute to our research.
2.2.3
Cartilage lesions; which lesions are painful and what is the cause
of pain ?
M. Brittberg
Kungsbacka/Sweden
Introduction: There exist today a large number of techniques to treat
and repair articular cartilage defects. However, there is no consensus
of which defects that are needed to be treated and no information
about which defects are causing the pain situation for the patients.
When one detect a large cartilage defect in a joint surface and there
are no other pathological findings, one may easily assume that
this defect is the cause of the patient’s joint disability. The defect
is repaired and in some patients the pain situation disappears
but in some patients the pain remains even though arthroscopy
examinations and MRI shows a nice repair. Pain development in a
joint with isolated cartilage lesions is maybe different compared
to pain in an organ disease like osteoarthritis. However, the pain
mechanisms could partly use the same channels of information, the
nerves and neural peptides.
Content: A system to detect and show where the pain is and where
it emanate from is crucial Elevated stress in the subchondral bone
has been discussed as being a pain cause (Draper et al, 2011). To
measure such stress is difficult. As part of pain studies, intraosseous
pressure has been measured. Björkström et al. could note an increased
pressure in a patella with chondromalcia and in patella OA versus a low
pressure in a control normal patella (Björkström et al, 1980). Elevated
subchondral stresses also induce an increased metabolic activity
(Draper et al, 2011). Such an activity could be identified by scintigraphic
examination. A MRI could show subchondral oedema which also could
be due to such an increased metabolic activity. In chronic medial knee
pain, increased tracer uptake in bone scintigraphy is more sensitive
for medial knee pain than bone marrow oedema pattern on MRI (Buck
et al. 2009). However, to use different sequences could help us better
differentiate between the potential painful and not pain full lesions
if pain could be related to a local subchondral oedema. Hayashi
et al.(2011) studied semi quantitative assessment of subchondral
bone marrow oedema-like lesions and subchondral cysts using
intermediate-weighted (IW) fat-suppressed (fs) spin echo and Dual
Echo Steady State (DESS) sequences on 3 T MRI. They showed that
in a direct comparison an IW fs sequence depicted more subchondral
bone marrow oedema-like lesions and better demonstrated the extent
of their maximum size. A DESS sequence helped in the differentiation
of subchondral bone marrow oedema-like lesions and subchondral
cysts.Subchondral cysts may be involved in pain due to intra-cystic
pain. The authors suggested that the IW fs sequence should be used
for determination of lesion extent whenever the size of subchondral
bone marrow oedema-like lesions is the focus of attention. Single
photon emission computed tomography (SPECT) could be used to
assess the physiology and homeostasis of subchondral bone adjacent
to untreated and treated articular cartilage defects(Vellala et al, 2007,
Hirschmann et al, 2011). Draper et al.(2012)found that painful knees
exhibited increased tracer uptake when using PET/CT compared to
the pain-free knees of four subjects with unilateral pain (P = 0.0006).
They also also found a correlation between increasing tracer uptake
and increasing pain intensity Possible sources of pain in patients
with OA include the synovial membrane, joint capsule, periarticular
ligaments,periosteum, and subchondral bone (Grubb et al, 2004). The
subchondral bone related causes of pain include periostitis associated
with osteophyte formation, subchondral micro fractures, bone angina
due to decreased blood flow and elevated intraosseous pressure,
and bone marrow lesions detected on magnetic resonance imaging
(MRI). Such sources of pain could possibly also be part of the pain
in isolated cartilage lesions. The synovial lining could also produce
pain by a pain irritation of sensory nerve endings within the synovium
from osteophytes and synovial inflammation caused by to the release
of prostaglandins, leukotrienes, and cytokines. (Wong et al, 1993,
Dirmeyer et al, 2008) The subchondral bone involvement is possibly
much more important in the success of cartilage repair techniques and
such bone involvement could be part of the development of OA and the
following pain situation. Bone cells are under the influence of different
systemic and local auto/paracrine factors. One such regulatory factor
that can play both a sensory/ afferent and a regulatory/efferent role
consists of neuropeptide-containing nerves. In particular, the calcitonin
gene-related peptide (CGRP) (Brain et al. 1985, Kruger et al, 1999),
substance P (Bjurholm et al, 1988, Halliday et al, 1993) and vasoactive
intestinal peptide (VIP)(Rahmann et al. 1992) have been suggested to
be involved in such regulatory loopes. Of interest to know is also the
fact that chondrocytes have receptors for substance P (Millward-Sadler
et al. 2004). In 1969, Greenwald and Hayes found that a pathway for
dye from the medullary cavity to the articular cartilage in the human
femoral head does exist. In 1994 Milz and Putz demonstrated also the
existence of several channels between the subchondral region and
the uncalcified cartilage into the cartilage. Early subchondral changes
include redistribution of blood supply with marrow hypertension and
bone marrow oedema. The chock absorption properties of articular
cartilage depend on the combined unit of the cartilage layer and the
subchondral bone layer giving the articular cartilage its visco elastic
properties. Disturbances of the unit in isolated lesions as well as
in widespread OA may elicit disturbances in the subchondral bone
signalling system with a subsequent pain development. Highly
vascularized areas in the human body are present in regions of high
functional activity with high needs for nutrition. The subchondral bone
in OA is such a region and it is connected with the basal layers of the
cartilage via vascular channels. When the fine homeostatic balance is
disturbed, secretions of neuropeptides in the subchondral region may
occur and could be transported via the channels to the cartilage and
subsequently direct influence receptors on the chondrocytes (Suri et
al, 2007). A large number of dorsal root ganglion cells are small and
medium sized, and sometimes called “type B” ganglion (BG) These
neurons generally emit unmyelinated and thinly myelinated axons most
commonly associated with nociception, and a substantial proportion of
these neurons express one, or generally several neuropeptides Sensory
nerve fibres (NFs) contain two major neuropeptides, substance P (SP)
and calcitonin gene-related peptide (CGRP).(Edoff et al, 2000, 2001,
2003). The distribution of axons displaying immunoreactivity (IR) for
the peptide, substance (SP), has been examined in numerous tissues
primarily by using immunofluorescence methods (Bjurholm et al,
1988).CGRP immunoreactivity (CGRP-IR) is the most prevalent of BG
neuropeptide markers, with neurons containing several other peptides
constituting subsets of these CGRP-IR BG neurons (Buma at el. 1992).
Not enough is known of the biological effects of CGRP, although it is
the most potent vasodilator among endogenous peptides and CGRPIR
nerve fibres are also associated with vascular edema. Vascularisation
and the associated innervation of articular cartilage may contribute to
tibiofemoral pain in OA as sympathetic and sensory nerves have been
found to be present within vascular channels in the articular cartilage, in
both mild and severe OA. Perivascular and free nerve fibres, and nerve
trunks have bee observed within the subchondral bone marrow and
within the marrow cavities of osteophytes. Such nerve ingrowth and
neuropeptide influence via the channels as well as the direct contact
seen in osteochondral defects may induce localized pain from the
lesions. Future research on cartilage repair has to be focused also on
the subchondral bone metabolic activity. The vascularity involvement
is of great interest with subsequent neural ingrowth with possible
effect on pain appearance (Neugebauer et al. 1995).

References:
1.Bjurholm, A, A. Kreicbergs, E. Brodin, and M. Schultzberg (1988)
Substance P and CGRP-immunoreactive nerves in bone. Peptides 165-
171.
2.Brain, S.D., and T.J. Williams (1985) Inflammatory oedema induced
by synergism between calcitonin gene-related (CGRP) and mediators of
increased vascular permeability. Br. J. Pharmacol. 855-860.
3.Brain, S.D.,T.J. Williams, J.R. Tippins, H.R. Morris, andI. Maclntyre(1985)
Calcitonin gene-related peptide is a potent vasodilator. Nature 313.54-
56.
4.Buck FM, Hoffmann A, Hofer B, Pfirrmann CW, Allgayer B. Chronic
medial knee pain without history of prior trauma: correlation of pain
at rest and during exercise using bone scintigraphy and MR imaging.
Skeletal Radiol. 2009 Apr;38(4):339-47. Epub 2008 Dec
5. Björkström S, Goldie IF, Wetterqvist H. Intramedullary pressure of the
patella in Chondromalacia.Arch Orthop Trauma Surg. 1980;97(2):81-5.
6. Buma P, Verschuren C, Versleyen D, Van der Kraan P, Oestreicher
AB. Calcitonin gene-related peptide, substance P and GAP-43/B-50
immunoreactivity in the normal and arthrotic knee joint of the mouse.
Histochemistry. 1992 Dec;98(5):327-39.
7. Lower density of synovial nerve fibres positive for calcitonin generelated
peptide relative to substance P in rheumatoid arthritis but not in
osteoarthritis. Rheumatology (Oxford). 2008 Jan;47(1):36-40
8.Draper CE, Fredericson M, Gold GE, Besier TF, Delp SL, Beaupre GS,
Quon A. Patients with patellofemoral pain exhibit elevated bone metabolic
activity at the patellofemoral joint.J Orthop Res. 2012 Feb;30(2):209-13.
doi: 10.1002/jor.21523. Epub 2011 Aug 2
9. Neuropeptide content and physiological properties of rat cartilageprojecting
sensory neurones co-cultured with perichondrial cells.
Neurosci Lett. 2001 Nov 27;315(3):141-4
10. Retrograde tracing and neuropeptide immunohistochemistry
of sensory neurones projecting to the cartilaginous distal femoral
epiphysis of young rats.Cell Tissue Res. 2000 Feb;299(2):193-200.
11.Neuropeptide effects on rat chondrocytes and perichondrial cells
in vitro.Neuropeptides. 2003 Oct;37(5):316
12. A pathway for nutrients from the medullary cavity to the articular
cartilage of the human femoral head. J Bone Joint Surg Br. 1969
Nov;51(4):747-53
13. Activation of sensory neurons in the arthritic joint. Novartis Found
Symp. 2004;260:28-36; discussion 36-48, 100-4, 277-9.
14. Hayashi D, Guermazi A, Kwoh CK, Hannon MJ, Moore C, Jakicic JM,
Green SM, Roemer FW. Semiquantitative assessment of subchondral
bone marrow edema-like lesions and subchondral cysts of the
knee at 3T MRI: a comparison between intermediate-weighted fatsuppressed
spin echo and Dual Echo Steady State sequences. BMC
Musculoskelet Disord. 2011 Sep 9;12:198.
15. The substance P fragment SP-(7-11) increases prostaglandin E2,
intracellular Ca2+ and collagenase production in bovine articular
chondrocytes.Biochem J. 1993 May 15;292 (Pt 1):57-62
16.Hirschmann MT, Davda K, Rasch H, Arnold MP, Friederich NF.
Clinical value of combined single photon emission computerized
tomography and conventional computer tomography (SPECT/CT)
in sports medicine. Sports Med Arthrosc. 2011 Jun;19(2):174-81.
Review.
17.Integrin-dependent signal cascades in chondrocyte
mechanotransduction. Ann Biomed Eng. 2004 Mar;32(3):435-46.
Review
18. Peripheral patterns of calcitonin-gene-related peptide general
somatic sensory innervation: cutaneous and deep terminations.J
Comp Neurol. 1989 Feb 8;280(2):291-302.
19. Involvement of substance P and neurokinin-1 receptors in the
hyperexcitability of dorsal horn neurons during development of acute
arthritis in rat‘s knee joint. J Neurophysiol. 1995 Apr;73(4):1574-83
20. The regulation of connective tissue metabolism by vasoactive
intestinal polypeptide. Regul Pept. 1992 Jan 23;37(2):111-21
Extended Abstracts 111
21. Neurovascular invasion at the osteochondral junction and in
osteophytes in osteoarthritis. Ann Rheum Dis. 2007 Nov;66(11):1423-
8. Epub 2007 Apr 19.
22.Tiderius CJ, Svensson J, Leander P, Ola T, Dahlberg L. dGEMRIC
(delayed gadolinium-enhanced MRI of cartilage) indicates adaptive
capacity of human knee cartilage. Magn Reson Med. 2004
Feb;51(2):286-90.
23.Vellala RP, Mabjures S, Ryan PJ. Single photon emission computed
tomography scanning in the diagnosis of knee pathology. J Orthop
Syrg (HongKong) 2004; 12: 87-90 24. Neural mechanisms of joint
pain. Ann Acad Med Singapore. 1993 Jul;22(4):646-50. Review
2.3.1
Cartilage defects in the femoropatellar joint
B.J. Cole
Chicago/United States of America
Introduction: Chondral defects in the patellofemoral joint have
varied etiologies. For example, the chondrosis may be genetically
related, as with focal or diffuse degeneration secondary to trauma
(direct impact or a result of patellofemoral instability) or secondary
to repetitive microtrauma (e.g., excessive loads such as in jumping
sports), or related to the cumulative microtrauma of biomechanical
abnormalities (e.g., chronic patellar subluxation). High-grade
(grades III and IV) focal chondral defects are reported to occur
between 11% and 20% in patients undergoing knee arthroscopy.
Of these defects, 11–23% involved the patella and 6–15% were
trochlear. Not all of these lesions were symptomatic. In fact, some
patients are asymptomatic even at very high functional levels.
Kaplan et al. performed MRIs on asymptomatic NBA basketball
players and found articular cartilage lesions in 47% of these
players, with 50% of these lesions classified as high grade (III or IV).
The patella was affected in 35%, and the trochlea in 25% of these
players who were asymptomatic. Similarly, Walczak et al. found
abnormal cartilage signal on MRI in 57% of asymptomatic NBA
players with a 7% incidence of focal defects. Just as with other PF
problems, symptoms and pathology have incomplete correlations.
It is not entirely clear why some patients with PF chondral lesions
present with pain while others can perform at a high level. Ficat
and Hungeford proposed that the elevated intraosseous pressures
seen in the face of an articular cartilage lesion could be the source
of pain and today with MRI, it is not uncommon to see areas of
bone overload associated with chondral lesions as evidenced by
“bone bruises.” As noted, the articular cartilage is aneural, so pain
other than bone may emanate from the soft tissues, including the
joint capsule, ligaments, tendons, and synovium. In addition to
mechanical factors, pain may be initiated in part by irritation from
chondral debris, which activates an inflammatory and nociceptive
response. As the true pain generator is often not well defined, it is
crucial to thoroughly evaluate all potential sources of discomfort
before attributing symptoms to a chondral defect.
Content: Options for restoring articular cartilage are limited by the
ability to replicate the complex three-dimensional anatomy of the
PF joint. The decision of which cartilage restoration procedure to
pursue depends on the size of the lesion, the level of demand the
patient places on his/her knees, and whether a previous attempt
at cartilage restoration has failed. In general, microfracture is the
first-line therapy for low-demand patients and for smaller lesions.
Though short-term results of microfracture of trochlear and patellar
lesions have been acceptable, these results have deteriorate at
midterm and long-term follow-up. The mechanical properties of the
fibrocartilage created by microfracture may be poorly suited to the
PF joint because of the high shear stresses. Caution in interpreting
the literature describing the outcomes of microfracture is warranted.
Because microfracture is relatively easy to perform and is often the
first-line treatment for a symptomatic cartilage defect, comorbidities
such as malalignment are often neglected at this early decisionmaking
stage. If all the principles of comorbidity correction are
adhered to, however, it is entirely possible that microfracture could
perform more optimally in this patient population. Osteochondral
allograft transplantation has also been used in the PF joint, although
previous attempts have been limited to diffuse lesions as a salvage
procedure. The complex topology of the PF joint and the requirement
for high congruence have limited past attempts. Overall, results of
osteochondral allograft transplantation have not been as successful
for lesions on PF joint surfaces as they have been for lesions on

112
Extended Abstracts
the femoral condyles, but in some clinical scenarios osteochondral
allograft transplantation remains an early treatment option. ACI is
preferred for high-demand patients, patients with large lesions, and
for those who have undergone a failed previous cartilage restoration
attempt. ACI has been extensively studied, with the largest and most
well-conducted trials of any cartilage restoration procedure used in
the PF joint, and has the additional benefit of “self-conforming” to the
topography of the joint. Contraindications to ACI in the PF joint include
inflammatory arthritis, loss of subchondral bone, disease within the
tibiofemoral joint, and a high likelihood of patient noncompliance with
postoperative rehabilitation and restrictions. The potential benefits
of ACI must be juxtaposed against the disadvantages, which include
a high revision rate for débridement (33% for trochlear lesions). A
bipolar lesion such as a “kissing lesion” is a relative contraindication
to cartilage restoration and would likely benefit from PF arthroplasty.
Notably, the complication rate for ACI, including the need for
reoperation, has dramatically decreased as a result of the off-label
usage of a synthetic collagen I/III membrane as an alternative to
periosteum. AMZ is the most commonly used realignment procedure
in the treatment of PF cartilage defects. The patients who are most
likely to benefit from AMZ are those with (1) symptomatic lesions,
(2) patellar maltracking, and (3) lesions that can be unloaded onto
healthy cartilage through tibial tubercle osteotomy. Numerous
authors have recommended AMZ, either alone or in association
with a cartilage restoration procedure, if these three conditions
are met. Prior to osteotomy, surgeons should document patellar
maltracking via abnormal TT-TG values whenever possible, as well as
healthy medial trochlear cartilage and, if possible, central trochlear
and patellar cartilage as well. Symptoms must also be attributed to
maltracking, otherwise the interventions upon the resulting articular
cartilage lesions will fail to improve the patient’s outcome. In addition,
while AMZ may work well for patients with articular cartilage defects
and early-stage degeneration, advanced osteoarthritis may signal
that this procedure is less likely to succeed, primarily because of the
lack of healthy cartilage onto which the diseased cartilage can be
unloaded. These patients may be better served by PF arthroplasty or
total knee arthroplasty, depending on the condition of the tibiofemoral
cartilage. The AMZ procedure itself can be customized to unload the
diseased cartilage by changing the slope of the osteotomy to provide
more anteriorization in patients with central or proximal lesions, or
more medialization in patients with lateral lesions. If chondral lesions
are proximal and medial, AMZ alone is contraindicated, and may
worsen symptoms because the forces would be transferred to this
area. Benefits of AMZ must be weighed against the additional risks
of infection, symptomatic hardware, wound complications, nonunion
(especially in obese patients, diabetic patients, and smokers), tibial
fracture, compartment syndrome, and deep vein thrombosis. Removal
of hardware may be required in up to 50% of patients. Several series
have reported tibial fractures with AMZ, recommending extended
weight-bearing limitations.
References:
Aroen A, Loken S, Heir S, et al. Articular cartilage lesions in 993
consecutive knee arthroscopies. Am J Sports Med. 2004;32:211-215.
Curl WW, Krome J, Gordon ES, et al. Cartilage injuries: a review of 31,516
knee arthroscopies. Arthroscopy. 1997;13:456-460. Hjelle K, Solheim E,
Strand T, et al. Articular cartilage defects in 1,000 knee arthroscopies.
Arthroscopy. 2002;18:730-734
Kaplan LD, Schurhoff MR, Selesnick H, et al. Magnetic resonance
imaging of the knee in asymptomatic professional basketball players.
Arthroscopy. 2005;21:557-561.
Walczak BE, McCulloch PC, Kang RW, et al. Abnormal finding on
magnetic resonance imaging in asymptomatic NBA players. J Knee Surg.
2008;21:27-33.
Nomura E, Inoue M, Kurimura M: Chondral and osteochondral injuries
associated with acute patellar dislocation. Arthroscopy 2003;19(7):717-
721.
Gallo RA, Feeley BT: Cartilage defects of the femoral trochlea. Knee Surg
Sports Traumatol Arthrosc 2009;17(11):1316-1325.
Pascual-Garrido C, Slabaugh MA, L’Heureux DR, Friel NA, Cole BJ:
Recommendations and treatment outcomes for patellofemoral articular
cartilage defects with autologous chondrocyte implantation: Prospective
evaluation at average 4-year follow-up. Am J Sports Med 2009;37(suppl
1):33S-41S.
Kreuz PC, Steinwachs MR, Erggelet C, et al: Results after microfracture
of full-thickness chondral defects in different compartments in the knee.
Osteoarthritis Cartilage2006;14(11):1119-1125.
Jamali AA, Emmerson BC, Chung C, Convery FR, Bugbee WD: Fresh
osteochondral allografts: Results in the patellofemoral joint. Clin Orthop
Relat Res 2005;437:176-185.
Farr J: Autologous chondrocyte implantation improves patellofemoral
cartilage treatment outcomes. Clin Orthop Relat Res 2007;463:187-194.
Mandelbaum B, Browne JE, Fu F, et al: Treatment outcomes of autologous
chondrocyte implantation for full-thickness articular cartilage defects of
the trochlea. Am J Sports Med2007;35(6):915-921.
Acknowledgments:
Geoffrey S. Van Thiel, MD/MBA Andrew Lee, MS
3.1.1
Basic concepts and potential application of tissue/organ printing
D. Hutmacher
Brisbane/Australia
Introduction: The fundamental concept underlying tissue
engineering is to combine a scaffold or matrix, with living cells,
and/or biologically active molecules to form a tissue engineering
construct (TEC) to promote the repair and/or regeneration of
tissues. The scaffold (a cellular solid support structure comprising
an interconnected pore network) or matrix (often a hydrogel in which
cells can be encapsulated) is expected to perform various functions,
including the support of cell colonization, migration, growth and
differentiation. Further, for their design physicochemical properties,
morphology and degradation kinetics need to be considered. External
size and shape of the construct are of importance, particularly if
it is customized for an individual patient [1]. Besides the physical
properties of a scaffold or matrix material (e.g. stiffness, strength,
surface chemistry, degradation kinetics), the micro-architecture of
the constructs is of great importance for the tissue formation process
[2]. In recent years, a number of automated fabrication methods have
been employed to create scaffolds with well-defined architectures [3,
4]. These have been classified as rapid prototyping (RP) technologies,
solid freeform fabrication (SFF) techniques, or according to the latest
ASTM standards, additive manufacturing (AM) techniques [5]. With
AM techniques, scaffolds with precise geometries can be prepared
[6], using computer-aided design combined with medical imaging
techniques to make anatomically shaped implants [7]. Together with
the development of biomaterials suitable for these techniques, the
automated fabrication of scaffolds with tunable, reproducible and
mathematically predictable physical properties has become a fastdeveloping
research area.
Content: The last few years have seen an upturn in economic activity
and successful application of newly developed tissue engineering
products, which for the largest part has resulted from identification
of products that are translatable from bench to bedside with
available technology and under existing regulatory guidelines [8].
Cell-free scaffolds have shown clinical success, e.g. for bone (Fig. 1),
osteochondral tissue repair, cartilage and skin [9]. Also, strategies to
create new vasculature - a critical aspect of tissue engineering - are
being developed by making use of the body’s self-healing capacity
[10].
Nevertheless, cell-based therapeutics have largely failed from both
a clinical and financial perspective [12, 13]. The developed tissue
engineering products were not necessarily inferior to previous
alternatives, but the efficacy and efficiency were not sufficient
to justify the associated increases in costs [14,15]. Manual cell
seeding and culturing of pre-fabricated scaffolds is time-consuming,
user-dependent, semi-efficient and, therefore, economically
and logistically not feasible to achieve clinical application at an
economical scale [16, 17]. Particular shortcomings of the current
tissue engineering paradigm involving cell seeding of pre-fabricated
scaffolds are the inabilities to: a)mimic the cellular organization
of natural tissues b) upscale to (economically feasible) clinical
application and c) address the issue of vascularization.
The use of additive tissue manufacturing addresses these points
by the incorporation of cells into a computer-controlled fabrication
process, thus creating living cell/material constructs rather than

cell-free scaffolds. The fundamental premise of computer-controlled
tissue fabrication is that tissue formation can be directed by the
spatial placement of cells themselves (and their extracellular matrix),
rather than by the spatial architecture of a solid support structure
alone. Although still at an early stage of concept development and
proof-of-principle experiments, it appears that endeavors following
this approach are the most promising to deliver clinical solutions
on the longer term where cell-free approaches cannot. Automated
tissue assembly opens up a route to scalable and reproducible mass
production of tissue precursors. Furthermore, implementing good
manufacturing practices (GMP), quality control and legislation are
facilitated by the use of automated processes.
Additive manufacturing will enable the production of cell-containing
constructs in a computer-controlled manner, thereby bypassing
costly and poorly controlled manual cell seeding. Although big
steps have been taken since the origins early in the past decade,
the technology is still in its infancy. It is now critical to address
key issues in biomaterials development (matching degradation
to cellular production and providing adequate mechanical
properties, while achieving rheological properties required for the
manufacturing process), construct design (including vascularization
of the construct), and system integration (inclusion of multiple cells,
materials and manufacturing processes in a sterile and controlled
environment). It is also important to pursue the development and
commercialization of constructs in a manner that is acceptable to
regulatory agencies, such as the Food and Drug Administration,
where they will more than likely be classed as “combination
products”, to efficiently translate research outcomes to clinical
benefits. With the joint effort of researchers combining chemistry,
mechanical engineering, information technology and cell biology,
AM techniques can evolve into a technology platform that allows
users to create tissue-engineered constructs with economics of
scale in the years to come.
References:
1. Langer R, Vacanti JP. Tissue Engineering. Science 1993;260:920-6.
2. Malda J, Woodfield TBF, van der Vloodt F, Wilson C, Martens DE,
Tramper J, et al. The effect of PEGT/PBT scaffold architecture on the
composition of tissue engineered cartilage. Biomaterials 2005;26:63-
72.
Acknowledgments:
Australian Research Council (ARC) for funding.
3.1.2
Potential of natural and synthetic biomaterials for bioprinting
F.P.W. Melchels 1 , W.J.A. Dhert 1 , D. Hutmacher 2 , J. Malda 1
1 Utrecht/Netherlands, 2 Brisbane/Australia
Introduction: Additive manufacturing techniques offer the potential
to fabricate well-defined structures, combining computer-aided
design and/or medical imaging with computer-controlled fabrication
techniques to make anatomically shaped implants. The level of control
offered by these computer-controlled technologies to design and
fabricate tissues will accelerate our understanding of the governing
factors of tissue formation and function [1]. Moreover, it will provide
a valuable tool to study the effect of anatomy on graft performance.
Bioprinting refers to the use of additive manufacturing techniques
(particularly computer-controlled extrusion or dispensing) with
incorporation of biology in the form of peptides, growth factors or
even living cells. A major bottleneck in the development of bioprinting
techniques is the limited availability of suitable biomaterials, which
will be discussed in this paper.
Content: Despite the promising results that have come out of tissue
engineering research in the past 2 decades, the numbers of tissue
engineering products and patients treated are still very low in light of
the volume of funding in this research area. Obviously the complexity
of engineering tissues is a main contributor to this fact, as tissue
engineering is a knowledge-intensive area in which a multitude of
expertises, materials and processes will have to be combined
synergistically to come to the end product: a medical treatment.
Traditionally, the preparation of a tissue engineered construct (TEC)
Extended Abstracts 113
involves many manual handlings, such as cell isolation, cell
expansion, scaffold fabrication, cell seeding, cell culturing and
implantation. This way of operation might work well in a research
setting but is hard to translate to a clinical setting for the following
reasons: · the logistics and resources required would be nearimpossible
to realise · the labour-associated costs would be
prohibitive · due to the many manual handlings, reproducible results
are far from guaranteed · good manufacture practice (GMP) standards
would be hard to meet in terms of standardisation and quality control
For these reasons, automation of tissue engineering processes will
be indispensible to raise its practical applicability to the level
required for the clinic [2]. Over the last decade, a general trend can
be seen towards higher levels of automation of several steps in the
process of preparing TECs, generally with improved outcomes. The
development of AM technologies and suitable biomaterials has
created the ability to fabricate scaffolds with well-defined internal
pore architectures based on medical imaging computer-aided design
(CAD) [3]. Compared to scaffolds prepared by conventional
techniques such as porogen leaching and gas foaming, AM-fabricated
scaffolds exhibit improved mechanical properties, improved pore
accessibility and (hence) better cell seeding and nutrient transport.
Furthermore, the automation of the cell seeding and culturing phase
using bioreactors has improved tissue uniformity [4]. Still, the current
tissue engineering paradigm involving cell seeding of pre-fabricated
scaffolds has some inherent shortcomings. For example, the complex
anisotropic cellular organisation found in native tissues can not be
mimicked. Furthermore, the very important issue of vascularisation
(for most tissues other than cartilage at least) is insufficiently
addressed. In bioprinting, the scaffold fabrication and cell seeding
stages are combined and fully automated by concurrent deposition
of cells and biomaterials [1]. This allows for the highly automated
preparation of TECs in a scalable and reproducible manner, with
designed construct architecture and computer-controlled placement
of cells. Since cells require a moist environment, hydrogels are the
most suited class of biomaterials to contain the cells in the bioprinting
process. Hydrogels are networks of water-soluble polymers that are
crosslinked through either physical (reversible) or chemical
(irreversible) crosslinks. As a result, these highly hydrated
environments (typically containing 75-99 % water) allow for diffusion
of nutrients and metabolites, whilst immobilising the cells [5]. To be
used in conjunction with cells in tissue engineering applications,
hydrogels have to meet be non-toxic and allow cells in the gel to
perform all their natural functions, which may include attachment,
proliferation, (re)differentiation and production of ECM components.
Finally, degradability of the hydrogel is desired to allow for cell
motility and tissue remodelling. To this end, soft, loosely crosslinked
gels with low polymer concentrations are often the most appropriate.
Printing of well-defined structures poses completely different -if not
opposite- requirements on hydrogel properties. The viscosity needs
to be sufficiently high to enable drawing of thin filaments of material
and to prevent cells from settling in the precursor suspension.
Subsequently, a relatively quick gelation is instrumental to retain
the shape of the fabricated structure. A last requirement is adequate
mechanical properties to preserve shape during culture, and/or to
withstand loads after implantation. The mentioned properties are
optimal at high polymer concentrations and high crosslink densities,
which are conditions that are counter-productive for cell survival and
functioning. Therefore, one of the largest challenges is to establish
the ‘bioprinting window’, i.e. to find the conditions which allow for
printing as well as cell encapsulation [6]. Moreover, smart ways will
have to be found to increase viscosity, shape retainment and
mechanical properties, without necessarily increasing polymer
concentration or crosslink density. For this, one has to make use of
rheological phenomena such as yield stres and shear-thinning, and
to design superstrong hydrogels with particular network topologies
[7]. Hydrogels can be of either natural or synthetic origin. Naturally
derived gels are generally good cell support materials, but intrinsically
suffer from batch-to-batch variation, limited tunability and the
possibility of disease transfer. Synthetic hydrogels do not bear these
disadvantages, but often lack biofunctionality. Naturally derived
hydrogels that have been employed for bioprinting include proteins,
polysaccharides and glycosaminoglycans. Collagen is a protein
derived from animal skin or bones that forms a good cell substrate
as it presents binding peptide motifs and allows for cell-mediated
tissue remodelling through enzymatic degradation. It has been used
quite successfully for bioprinting endothelial cells [8]. Due to the low
concentration (0.3 %) and low crosslink density, large structures
could not be built; however the cells were motile and could proliferate
fast (30 % increase in 24 hrs), making collagen a good candidate for
cell delivery in bioprinting. Gelatine is denatured collagen bearing
similar properties but with increased water solubility and lower
antigenic risk than collagen due to its denatured state. It has been
printed at 20 % into large structures, laden with hepatocytes that
remained viable for as long as 3 months after aldehyde crosslinking

114
Extended Abstracts
[9]. Agarose and alginate are polysaccharides extracted from the cell
walls of algae and have both been used for cell immobilisation and
bioprinting. Bioprinting of warm agarose solutions is feasible (at 5
%), although the gelation is relatively slow which causes some
broadening and sagging of the printed filaments [10]. Alginate forms
a gel when divalent cations (usually Ca2+) are mixed in, by
electrostatic crosslinking. Therefore, sodium alginate solutions can
be dispensed into a bath of CaCl2 solution resulting in the formation
of gel strands [11]. Alternatively, the sodium alginate and CaCl2
solution can be pre-mixed and printed within the time frame of
gelation [12]. Dextran is another polysaccharide that has been
applied in bioprinting. It has no intrinsic gelation property, so it can
be modified with methacrylate groups to allow photo-initiated
crosslinking to retain the printed shape. Furthermore, to obtain an
appropriate viscosity for printing it has been mixed with more viscous
components such as hyaluronan [13]. Hyaluronan (synonymous for
hyaluronic acid or HA) is a glycosaminoglycan which has a relatively
high occurrence in articular cartilage, and therefore seems a good
candidate for chondrocyte encapsulation and bioprinting. Besides
as a mixture with dextran, HA has been printed in conjunction with
gelatine (both components methacrylate-functionalised for UVinitiated
crosslinking) [14] and with star-shaped PEG-tetraacrylate
[15]. In neither case evidence was given of high-resolution printed
structures, however the cells (hepatoma cells, intestine epithelial
cells and fibroblasts) did proliferate when encapsulated in the gels,
indicating the suitability of HA as an environment for tissue
development. Compared to the examples of bioprinting of naturally
derived hydrogels above, far less examples of bioprinting of synthetic
hydrogels exist. The mostly used polymer is sold under the brand
name Lutrol F127 and is used in the pharmaceutical industry. It is an
amphiphilic block copolymer consisting of two hydrophilic PEG
blocks and one slightly hydrophobic poly(propylene oxide) (PPO)
block. In water it is fluid at low temperatures and gels at around 30
°C as the PPO blocks collapse and form physical crosslinks. Its
rheological properties allow printing of up to 10 layers of well-defined
gel strands [8, 11]. Initial cell viability after printing is good, but when
incubated in medium at 37 °C the physical hydrogel slowly dissolves
and most of the cells die within 3 days. Modification with alaninemethacrylate
endgroups to allow for photo-initiated crosslinking
enables at least 3 weeks culture with retainment of shape and
reasonable cell viability (60 % 3 days post-printing, unchanged over
up to 3 weeks) [16]. Except for this gel, currently only one other
polymer has been reported specifically designed for bioprinting [17].
It is also a PEG-based polymer with hydrophobic blocks that induce
thermal gelation (hydroxypropylmethacrylamide-lactate in this case)
and has methacrylate end-groups for photo-initiated crosslinking as
well. Short-term viability of encapsulated cells was demonstrated,
but longer-term cultures with assessment of differentiation and
production of ECM components will have to prove the suitability of
these gels for bioprinting of viable TECs. In summary, over the past
few years researchers have made a start in identifying hydrogels that
may be suitable for bioprinting. Computer-designed hydrogel
structures with encapsulated cells have been prepared with
reasonable accuracy. Over the next decade we can expect the
development of biomaterials specifically engineered for bioprinting,
and a considerable increase in the quality of printed constructs.
Furthermore, the functionality of printed cell-laden constructs in
terms of tissue development and regeneration capacity will have to
be critically assessed.
References:
1. Melchels, F.P.W., et al., Progress in Polymer Science, 2012.
doi:10.1016/j.progpolymsci.2011.11.007.
2. Archer, R. and D.J. Williams, Nature Biotechnology, 2005. 23: p.
1353-1355.
3. Peltola, S.M., et al., Annals of Medicine, 2008. 40: p. 268-280.
4. Martin, I., D. Wendt, and M. Heberer, Trends in Biotechnology,
2004. 22: p. 80-86.
5. Nicodemus, G.D. and S.J. Bryant, Tissue Engineering Part
B-Reviews, 2008. 14: p. 149-165.
6. Khalil, S. and W. Sun, Journal of Biomechanical Engineering-
Transactions of the Asme, 2009. 131.
7. Johnson, J.A., et al., Progress in Polymer Science, 2010. 35: p. 332-
337.
8. Smith, C.M., et al., Tissue Engineering, 2004. 10: p. 1566-1576.
9. Wang, X.H., et al., Tissue Engineering, 2006. 12: p. 83-90.
10. Fedorovich, N.E., et al., Tissue Engineering Part A, 2008. 14: p.
127-133.
11. Fedorovich, N.E., et al., Tissue Engineering, 2007. 13: p. 1905-
1925.
12. Cohen, D.L., et al., Tissue Engineering, 2006. 12: p. 1325-1335.
13. Pescosolido, L., et al., Biomacromolecules, 2011. 12: p. 1831-
1838.
14. Skardal, A., et al., Tissue Engineering Part A, 2010. 16: p. 2675-
2685.
15. Skardal, A., J. Zhang, and G.D. Prestwich, Biomaterials, 2010. 31:
p. 6173-81.
16. Fedorovich, N.E., et al., Biomacromolecules, 2009. 10: p. 1689-
1696.
17. Censi, R., et al., Advanced Functional Materials, 2011. 21: p. 1833-
1842.
Acknowledgments:
For funding we thank the European Union (Marie Curie International
Outgoing Fellowship)
3.2.2
In vitro models for development and screening of cartilage repair
strategies
G.J.V.M. Van Osch
Rotterdam/Netherlands
Introduction: Traumatic cartilage defects can be treated with
autologous chondrocyte implantation or microfracture. The results
of these treatments are encouraging but are not equally good for all
patients, do not always last for years and the repair tissue does not
completely resemble the original. So there is room for improvement
of these treatments. For generalized cartilage degeneration,
osteoarthritis, there is no treatment available that can stop, slow or
cure the disease. NSAIDs, cox-2 inhibitors, glucosamine and stem
cells, amongst other treatment options, continue to raise interest
and are under investigation.
Content: In early stages of development of a cartilage repair strategy,
treatments are evaluated with in-vitro models as well as animal
models. In-vitro models are being applied frequently especially in
OA research. There is a broad range of culture models of isolated
chondrocytes or cartilage explants, of animal or human origin. The
fast developments in the field of cartilage tissue engineering is
expected to reveal new models, but these are not yet frequently used
as test models for new treatments. The choice for a certain culture
model usually depends on robustness, costs and experience with
the models. But in spite of the availability of these well characterised
chondrocyte and cartilage culture systems one has to realize that
in the joint cartilage in not the only tissue present. Continuous
interactions exist between the different joint tissues, largely based
on secreted factors. For a good representation of the situation in the
joint, these interactions should be taken into account. This requires
more complex model systems with multiple tissues. The last years
the involvement of subchondral bone in cartilage degeneration and
regeneration became more obvious. Subchondral bone contains
many growth factors that will be released upon damage. Furthermore
the development of a model including cartilage and subchondral
bone allows studying repair strategies of chondral defects as well
as osteochondral defects (de Vries-van Melle et al 2011). Although
it is accepted for long time that synovial inflammation influences
cartilage metabolism in rheumatoid arthritis, its role in cartilage
repair and osteoarthritis was largely neglected till recently. The
effect of synovium of patients with osteoarthritis on cartilage
formation by mesenchymal stem cells was recently demonstrated
(Heldens et al, 2011). We recently demonstrated that cartilage and
synovium secrete different cytokines and that the combination of
cartilage and synovium in culture better represents the situation
in a joint (Beekhuizen et al 2011). With this model we were able to
show that triamcinolone, that is for years being discussed for its

negative effects on cartilage metabolism, has a protective effect
on cartilage in the presence of osteoarthritic synovium. Finally,
joints contain a large amount of intra-articular adipose tissue. More
recently the contribution of intra-articular adipose tissue received
attention (Clockaerts et al 2010). Next to adipocytes, this intraarticular
fat tissue contains immune cells and stem cells. We have
recently shown that the immune cell composition is influenced by
joint pathology (Klein-Wieringa et al 2011; Bastiaansen-Jenniskens
et al 2011). Due to this altered cellular composition, the adipose
tissue secretes different factors into the synovial fluid. These
secreted factors do influence cartilage and synovium metabolism
(Bastiaansen-Jenniskens et al 2011). These in-vitro models that
contain multiple tissues better represent the conditions in a joint
in-vivo. These are, however still models, thus simplifying the real
situation. It is for example not clear if and how the relatively large
cutting edges, which are created during preparation of the tissues,
influence the responses. Whole organ cultures are being used, albeit
infrequently; These used to involve developing embryonic bones of
rodents, but also patellae of small animals (Schalkwijk et al 1985)
and even sesamoid bones of cows (Korver et al 1989) can be cultured.
Furthermore, long-term culturing will definitely have an effect on cell
metabolism, but these effects are not completely clear. Finally, joint
loading is an important condition that is only sometimes taken into
account (Grad et al 2006) since it is difficult to apply physiological
loading regimes in large series. Although animal models will remain
an important tool in development of medications, each of the invitro
models can be useful as first screening for a newly developed
cartilage repair strategy, to investigate mechanisms of action or to
find ways for further improvement of therapy. The use of in-vitro
models can reduce costs and number of animals used and offers the
opportunity to use a fully human system.
References:
Bastiaansen-Jenniskens YM, Clockaerts S, Feijt C, Zuurmond AM,
Stojanovic-Susulic V, Bridts C, de Clerck L, Degroot J, Verhaar JA,
Kloppenburg M, van Osch GJ. Infrapatellar fat pad of patients with
end-stage osteoarthritis inhibits catabolic mediators in cartilage.
Ann Rheum Dis. 2011 Oct 13. [Epub ahead of print]
Beekhuizen M, Bastiaansen-Jenniskens YM, Koevoet W, Saris DB,
Dhert WJ, Creemers LB, van Osch GJ. Osteoarthritic synovial tissue
inhibition of proteoglycan production in human osteoarthritic
knee cartilage: establishment and characterization of a long-term
cartilage-synovium coculture. Arthritis Rheum. 2011 Jul;63(7):1918-
27.
Clockaerts S, Bastiaansen-Jenniskens YM, Runhaar J, Van Osch GJ,
Van Offel JF, Verhaar JA, De Clerck LS, Somville J. The infrapatellar fat
pad should be considered as an active osteoarthritic joint tissue: a
narrative review. Osteoarthritis Cartilage. 2010 Jul;18(7):876-82.
De Vries-van Melle ML, Mandl EW, Kops N, Koevoet WJ, Verhaar JA,
van Osch GJ. An Osteochondral Culture Model to Study Mechanisms
Involved in Articular Cartilage Repair. Tissue Eng Part C Methods.
2011 Oct 18. [Epub ahead of print]
Grad S, Gogolewski S, Alini M, Wimmer MA. Effects of simple and
complex motion patterns on gene expression of chondrocytes
seeded in 3D scaffolds. Tissue Eng. 2006 Nov;12(11):3171-9.
Heldens GT, Blaney Davidson EN, Vitters EL, Schreurs BW, Piek
E, van den Berg WB, van der Kraan PM. Catabolic Factors and
Osteoarthritis-Conditioned Medium Inhibit Chondrogenesis of
Human Mesenchymal Stem Cells. Tissue Eng Part A. 2011 Oct 17.
[Epub ahead of print]
Klein-Wieringa IR, Kloppenburg M, Bastiaansen-Jenniskens YM,
Yusuf E, Kwekkeboom JC, El-Bannoudi H, Nelissen RG, Zuurmond
A, Stojanovic-Susulic V, Van Osch GJ, Toes RE, Ioan-Facsinay A.
The infrapatellar fat pad of patients with osteoarthritis has an
inflammatory phenotype. Ann Rheum Dis. 2011 May;70(5):851-7.
Korver GH, van de Stadt RJ, van Kampen GP, Kiljan E, van der Korst
JK. Bovine sesamoid bones: a culture system for anatomically intact
articular cartilage. In Vitro Cell Dev Biol. 1989 Dec;25(12):1099-106.
Schalkwijk J, van den Berg WB, van de Putte LB, Joosten LA. Hydrogen
peroxide suppresses the proteoglycan synthesis of intact articular
cartilage. J Rheumatol. 1985 Apr;12(2):205-10.
Acknowledgments:
Extended Abstracts 115
The research was financially supported by the Dutch Arthritis
Association, Top Institute Pharma, BioMedical Materials Program,
GAMBA (FP7)
3.3.1
Can meniscus reconstruction prevent or even cure OA?
W. Gersoff
Denver/United States of America
Introduction: see content
Content: Can Meniscus Reconstruction Prevent or Even Cure OA? The
development of knee OA is a multifactorial process. Some factors
are presently not controllable (genetics), while others are potentially
controllable (weight and activity), and others are potentially
modifiable(injury to the knee). In evaluating whether mensical
allograft transplantation can modify the development of osteoarthritis
of the knee several important factors must be considered: the role
of the meniscus; the effects of menisectomy on knee function and
biomechanics; and, the success of meniscal allograft transplantation
as a procedure to restore meniscal function. The meniscus functions
as the key component of the shock absorbency and force distribution
system of the knee joint. In this capacity it acts to decrease the
compressive and loading forces transmitted to the articular cartilage
and subchondral bone therefore protecting them from excessive
loads. The meniscus has an important biomechanical role in the knee
joint contributing to joint stability. The development of osteoarthritis
in the knee joint after menisectomy has been recognized as early
as 1949 in Fairbank’s original work. Subsequent studies have
also demonstrated the high potential for the development of
osteoarthritis in the post-menisectomy knee. As arthroscopy has
developed further studies have shown the varying roles of partial
menisectomy and total meniscetomy in the development of knee
osteoarthritis and therefore the need to maintain as much meniscus
tissue as possible. Improved techniques of meniscal repair have
facilitated the preservation of the meniscus as well.The concept
of functional menisectomy has also been developed to delineate
the importance of regions of the meniscus in regard to increasing
risk of the development of osteoarthritis.The posterior horn areas
of both the medial and lateral meniscus have been shown to bear
the majority of load in the knee. The loss of the posterior horn
will result in a functional menisectomy although there may still be
over 50% of the meniscus tissue remaining.In general the loss of
greater then 50% of the meniscal tissue is considered detrimental
regardless of anatomical area. Meniscal allograft transplantation
was first performed by Milachowski in 1986. Since that time there
has been significant advancements in both surgical techniques and
tissue preservation. During this time there has also been continued
confirmation of the importance of the intact functioning meniscus.
While the first meniscus allograft transplantation procedures
were done as open procedures with formal arthrotomy and often
collateral ligament release , the technique has now evolved to a
minimally invasive procedure performed arthroscopically assisted..
Instrumentation has been developed that allows for consistent
placement of the allograft tissue based on the known landmarks of
the anterior and posterior horn attachments of the meniscus.The
techniques involve either the use of a bone bridge, double bone plugs,
or all soft tissue. The bone bridge techniques either incorporate a
slot or trough. Regardless of the technique performed, meticulous
detail must be used to maintain the anatomical positioning of the
meniscus. Meniscal repair fixation devices have also been developed
that allows for all inside fixation of the majority of the meniscal
segments. Some of these devices however are not well designed
for the attachment of meniscus to synovium but rather meniscus
to meniscus. Advances have also been made in tissue processing,
preservation, sizing and availability. Early issues associated with
tissue shrinkage and friability secondary to excessive radiation and
freezing techniques have been eliminated. Meniscal allograft tissue
is considered to be immunologically privileged. Therefore the risk of
tissue rejection is minimal, although a subclinical immune response
may occur.The post-operative rehabilitation has also improved as a
better understanding of the science of the meniscal allograft healing
has taken place. The patient will undergo minimal immobilization
and start earlier weight bearing. The importance of knee ligament
stability, femoral tibial alignment, and articular cartilage integrity
in association with meniscal pathology has also been given greater
consideration. Procedures to address any of these deficiencies are
commonly combined with meniscal allograft transplantation.The
patient receiving a meniscal allograft transplantation in 2012 is most

116
Extended Abstracts
likely receiving an overall improved surgical procedure with higher
success rates and better long-term outcomes than 26 years ago.
With these developments in consideration is it possible to critically
look at the results of meniscal allograft transplantation? A recent
meta-analysis published by ElAttar et al reviewed publications
in the English speaking literature over the past 26 years. This
would therefore include publications before,during and after the
previously described developments. This publication fouty-four
trials representing 1136 grafts and 1068 patients. Of these 678
were medial and 458 were lateral with a mean age of 34,8 years.
The authors concluded that meniscal allograft transplantation
was a safe and reliable procedure with a consistent satisfactory
outcome. However,does symptom improvement directly correlate
with the prevention of osteoarthritis ? This is a extremely challenging
question and there are no studies that could document this for an
isolated meniscal allograft transplantation. Indeed, this study could
be extremely difficult to design and implement as it would have to
be designed to take in multiple factors that could contribute to the
development of knee osteoarthritis. The study would also require
a long period of follow-up to truly determine the prevention or
development of knee ostaoarthritis. The post- menisecetomy knee
has a 14-fold increase in the development of osteoarthritis as
documented by radiograph. This is secondary to increased loading
in the affected compartment of the knee and altered biomechanics
of the knee. Mensical allograft transplantation has been shown
to decrease these compressive forces in animal studies. Meniscal
allograft transplantation has also been shown to be be a safe,reliable
and effective operation in the clinical setting. Therefore, based on
the information available in 2012 it is reasonable to assume that
mensical allograft transplantation at the very least functions to
alter the course of degeneration in the knee that would otherwise
be destined for the development of osteoarthritis. This ultimately
may not prevent osteoarthritis development but may prolong its
development. The future development of improved techniques
and tissue healing enhancement factors will certainly continue
to improve the outcomes of the procedure. The development of
synthetic meniscal replacement devices for either partial or total
menisectomies will continue to revolutionize the ability to preserve
mensical integrity and function in the knee.
Can Meniscus Reconstruction Prevent or Even Cure OA? The
development of knee OA is a multifactorial process. Some factors
are presently not controllable (genetics), while others are potentially
controllable (weight and activity), and others are potentially
modifiable(injury to the knee). In evaluating whether mensical
allograft transplantation can modify the development of osteoarthritis
of the knee several important factors must be considered: the role
of the meniscus; the effects of menisectomy on knee function and
biomechanics; and, the success of meniscal allograft transplantation
as a procedure to restore meniscal function. The meniscus functions
as the key component of the shock absorbency and force distribution
system of the knee joint. In this capacity it acts to decrease the
compressive and loading forces transmitted to the articular cartilage
and subchondral bone therefore protecting them from excessive
loads. The meniscus has an important biomechanical role in the knee
joint contributing to joint stability. The development of osteoarthritis
in the knee joint after menisectomy has been recognized as early
as 1949 in Fairbank’s original work. Subsequent studies have also
demonstrated the high potential for the development of osteoarthritis
in the post-menisectomy knee. As arthroscopy has developed further
studies have shown the varying roles of partial menisectomy and total
meniscetomy in the development of knee osteoarthritis and therefore
the need to maintain as much meniscus tissue as possible. Improved
techniques of meniscal repair have facilitated the preservation
of the meniscus as well.The concept of functional menisectomy
has also been developed to delineate the importance of regions
of the meniscus in regard to increasing risk of the development
of osteoarthritis.The posterior horn areas of both the medial and
lateral meniscus have been shown to bear the majority of load in
the knee. The loss of the posterior horn will result in a functional
menisectomy although there may still be over 50% of the meniscus
tissue remaining.In general the loss of greater then 50% of the
meniscal tissue is considered detrimental regardless of anatomical
area. Meniscal allograft transplantation was first performed by
Milachowski in 1986. Since that time there has been significant
advancements in both surgical techniques and tissue preservation.
During this time there has also been continued confirmation of
the importance of the intact functioning meniscus. While the first
meniscus allograft transplantation procedures were done as open
procedures with formal arthrotomy and often collateral ligament
release , the technique has now evolved to a minimally invasive
procedure performed arthroscopically assisted.. Instrumentation has
been developed that allows for consistent placement of the allograft
tissue based on the known landmarks of the anterior and posterior
horn attachments of the meniscus.The techniques involve either the
use of a bone bridge, double bone plugs, or all soft tissue. The bone
bridge techniques either incorporate a slot or trough. Regardless of
the technique performed, meticulous detail must be used to maintain
the anatomical positioning of the meniscus. Meniscal repair fixation
devices have also been developed that allows for all inside fixation
of the majority of the meniscal segments. Some of these devices
however are not well designed for the attachment of meniscus to
synovium but rather meniscus to meniscus. Advances have also been
made in tissue processing, preservation, sizing and availability. Early
issues associated with tissue shrinkage and friability secondary to
excessive radiation and freezing techniques have been eliminated.
Meniscal allograft tissue is considered to be immunologically
privileged. Therefore the risk of tissue rejection is minimal, although
a subclinical immune response may occur.The post-operative
rehabilitation has also improved as a better understanding of the
science of the meniscal allograft healing has taken place. The patient
will undergo minimal immobilization and start earlier weight bearing.
The importance of knee ligament stability, femoral tibial alignment,
and articular cartilage integrity in association with meniscal
pathology has also been given greater consideration. Procedures
to address any of these deficiencies are commonly combined with
meniscal allograft transplantation.The patient receiving a meniscal
allograft transplantation in 2012 is most likely receiving an overall
improved surgical procedure with higher success rates and better
long-term outcomes than 26 years ago. With these developments in
consideration is it possible to critically look at the results of meniscal
allograft transplantation? A recent meta-analysis published by ElAttar
et al reviewed publications in the English speaking literature over the
past 26 years. This would therefore include publications before,during
and after the previously described developments. This publication
fouty-four trials representing 1136 grafts and 1068 patients. Of these
678 were medial and 458 were lateral with a mean age of 34,8 years.
The authors concluded that meniscal allograft transplantation was a
safe and reliable procedure with a consistent satisfactory outcome.
However,does symptom improvement directly correlate with the
prevention of osteoarthritis ? This is a extremely challenging question
and there are no studies that could document this for an isolated
meniscal allograft transplantation.This study could be extremely
difficult to design and implement as it would have to be designed
to take in multiple factors that could contribute to the development
of knee osteoarthritis. The study would also require a long period of
follow-up to truly determine the prevention or development of knee
ostaoarthritis. The post- menisecetomy knee has a 14-fold increase
in the development of osteoarthritis as documented by radiograph.
This is secondary to increased loading in the affected compartment
of the knee and altered biomechanics of the knee. Mensical allograft
transplantation has been shown to decrease these compressive forces
in animal studies. Meniscal allograft transplantation has also been
shown to be be a safe,reliable and effective operation in the clinical
setting. Based on the information available in 2012 it is reasonable
to assume that mensical allograft transplantation at the very least
functions to alter the course of degeneration in the knee that would
otherwise be destined for the development of osteoarthritis. The
development of synthetic meniscal replacement devices for either
partial or total menisectomies will continue to revolutionize the
ability to preserve mensical integrity and function in the knee.
References:
1. Milachowski KA, Weismeier K, Wirth CJ (1989) Homologous
meniscus transplantation,experimental and clincical results. Int
Orthop 13:1-11
2. ElAttar M, Dhollander A, Verdonk R, Almquist KF, Verdonk P
(2011) Twenty-six years of meniscal allograft transplantation: is it
still experimental? A meta-analysis of 44 trials. Knee Surg Sports
Traumatol Arthrosc 19:147-157.
3. Roos H, Lauren M, Adalberth T, Roos EM, Jonsson K, Lohmander
LS (1998) Knee osteoarthritis after menisectomy: prevalence of
radiographic changes after twenty-one years, compared with
matched controls. Arthritis Rheum 41:697-693.
4. von Lewinski G, Milachowski KA, Weismeier K, Kohn D, Wirth
CJ (2007) Twenty year results of combined meniscal allograft
transplantation, anterior cruciate ligament reconstruction and
advancement of the medial collateral ligament. Knee Surg Sports
Traumatol Arthrosc 15:1072-1082.
3.2.3
Nutraceuticals & Osteoarthritis: Do omega-3 fatty acids,
glucosamine & chondroitin sulphates have chondro-protective
actions?

B. Caterson
Cardiff/United Kingdom
Introduction: See content.
Content: Nutraceuticals such as omega-3 fatty acids, glucosamine
and chondroitin sulphates (either separately or in combination) are
widely used by people suffering a wide variety of musculoskeletal
tissue diseases such as osteoarthritis (OA) that has arisen from
a multiplicity of potential causes (e.g. genetic predispositions,
obesity, sports injuries, trauma and ageing). The efficacy of using
nutraceuticals to alleviate pain and OA disease progression has been
claimed for many years without there being unequivocal biological,
biochemical and/or medical evidence explaining their beneficial
mechanisms of action. In this presentation I will review some of the
recent research both supporting and refuting their claims of chondroprotection
in the pathogenesis of OA. The beneficial actions of dietary
cod liver oil (enriched in Omega-3 fatty acids) on alleviating arthritis
were first described in the English scientific literature in the early
1700’s. In more recent years (i.e. late 1980’s – present) there have
now been numerous publications providing evidence for some of the
potential targets underlying the mechanism(s) of action of omega-3
fatty acid dietary supplementation. In general, these ‘recent’ basic
biomedical science studies have suggested that omega-3 fatty acid
metabolism acts by reducing the levels of prostaglandin-mediated
inflammation as well as down-regulating the degradative actions of
aggrecanases (ADAMTS-4 & -5) and other matrix metalloproteinases
that destroy the articular cartilage that leads to joint space
narrowing in later stage OA. A variety of clinical trials and metaanalyses
of these trials have been conducted over the past 30 – 40
years; however, none of these have provided indisputable medical
data and evidence supporting the claims of chondro-protection and/
or slowing disease progression. The clinical trial results have been
hampered by the heterogeneous causes and nature of human OA
and the meta-analyses of the trial results have been influenced by
both the heterogeneous nature of human OA and the quality of
some of the papers selected to generate the meta-analysis data.
However, a recent study my Knott et al [Osteoarthritis & Cartilage
(2011) 19: 1150 – 1157] using a homogenous (natural genetic
predisposition) model of knee OA have published results definitively
demonstrating the beneficial effects of omega-3 fatty acid dietary
supplementation on both cartilage and bone metabolism. The effects
of dietary supplementation with Glucosamine on the pathogenesis of
osteoarthritis were initially published in the late 1970s & early 1980s
with increasing research occurring in the 1990s and early 21st century.
Similar to the studies performed on the beneficial effects on omega-3
fatty acids there have been a number of in vitro biochemical studies
showing the beneficial effects of glucosamine on decreasing the
expression and activity of cartilage matrix degrading enzymes (e.g.
the aggrecanases); however, large concentrations of glucosamine
were needed to produce these beneficial effects in vitro and these
results thus explaining the large doses (> 1 gram per day) needed
for treatment of human OA sufferers. In some recent studies from
our laboratory [McGuigan et al (2008) J. Med. Chem. 51: 5807 – 5812]
we have chemically modified glucosamine to make it more lipophilic;
this biochemical change allowing significantly lower doses of this
‘modified-glucosamine to enter the cell (where it is converted back
to intracellular glucosamine) this delivery process thereby reducing
the expression and activity of the aggrecanases that are responsible
for cartilage degradation in OA. Recent studies from the van Osch
lab [Rozendaal RM et al (2009) Osteoarthritis & Cartilage 17: 427
– 432] have demonstrated the beneficial effects of glucosamine
dietary supplementation, these effects occurring in both anabolic
and catabolic aspects of synovial joint tissue metabolism. Similarly
to the omega-3 fatty acid studies, the potential chondro-protective
effects of dietary glucosamine supplementation have been tested
in many clinical trials and subsequent meta-analyses. However,
unequivocal conclusions have not been possible because of the
heterogeneous nature of human OA as well as quality of some of
the published papers selected for the meta-analyses. The beneficial
effects in healthy living with dietary supplementation with different
sources of chondroitin sulphates go way back in time and history
(e.g. Asian shark fin soup). However, unlike omega-3 fatty acids and
glucosamine, there have been very few definitive in vitro or in vivo
basic science studies performed that can directly elucidate the effects
(if any) chondroitin sulphates have on cartilage metabolism and/or
it benefits in the treatment of OA. One of the biggest complications
with understanding the effects of dietary supplementation with
‘chondroitin sulphate’ is that there are numerous different structural
types and sources of chondroitin sulphate and its epimerised partner
dermatan sulphate; e.g. a penta-saccharide unit of a chondroitin/
dermatan sulphate (CS/DS) glycosaminoglycan (GAG) chain has a
possible 1008 different combinatorial structures [Caterson B (2012)
Int. J. Exp. Path. 93: 1 – 10]. Many of these very specific and different
Extended Abstracts 117
sulphation motifs in CS/DS GAG oligosaccharides are specifically
expressed in “stem/progenitor cell niches” of most tissues in
many animal species [i.e. chicken – humans; Caterson 2012]. These
oligosaccharide motifs are involved in binding growth factors,
morphogens and chemokines and in tissue and organ development
the establishment of morphogen & chemokine gradients. At present,
we believe that any beneficial effects of dietary chondroitin sulphate
ingestion may be due to systemic effects on many different tissues
depending on where tissue injury and subsequent regeneration and
repair is needed. Many human OA patient clinical trials have also
attempted to determine the efficacy of chondroitin sulphates alone
or in combination with other popular nutraceuticals. However, these
trials and subsequent meta-analyses have had the same problems
as those for omega-3 fatty acids and glucosamine described above.
In summary, in my opinion, there is some reasonable to very good
evidence to support the use of nutraceutical supplements to slow
down the progression of OA in humans [for recent Review see:
Jerosch J (2011) Int. J. Rheumatol. 2011:969012. E-pub 2011 Aug 2].
However, in the future, researchers may probably benefit from using
homogeneous models of OA to better decipher the biochemical and
physiological mechanisms underpinning the onset of osteoarthritis
in the heterogeneous human population. In addition, I believe that it
would be worthwhile for researchers involved in tissue engineering/
regeneration technologies to consider the potential benefits of
post-operatively adding nutraceutical supplementation to their
procedures investigating their potential benefits in expediting the
outcomes of autologous cartilage implantation/transplantation
technologies.
3.3.2
Clinical options for meniscus reconstruction and regeneration
R. Jakob
Fribourg/Switzerland
Introduction: Thoughts regarding reconstruction, restoration and
regeneration of meniscal volume, size and function after traumatic
disruption of meniscal tissue
Basically, after diagnosing a meniscal tear, fresh or old, you may
decide to:
1- Leave it alone
2- Remove it, partially or totally
3- Suture it (+/- unloading osteotomy in case of compartmental
overload!)
4- Replace it totally by allogenous tissue or partially by artificial
material
In the following we shall concentrate on the means to maintain
meniscal tissue after traumatic lesions.
Content: Meniscal tissue is made of fibrocartilage which is similar
in vulnerability as hyaline articular cartilage. Malalignment,
associated cartilage injuries and ligament instability are definite co-
morbidities. Clinical and radiographic and patient-related outcome
data has established a direct relation of loss of meniscal tissue to
impairment of all these parameters mentioned (Englund et al; Lee et
al). Baratz et al showed an increase in contact pressures of 75% and
an overall increase of 235% in peak-contact pressures after subtotal
meniscectomy.
Consensus exists that in younger patients chances for reconstruction
and healing of meniscal tears are higher than in older patients.
However, ageing and degeneration of the meniscus starts already
at 35 years. Therefore, following a similar principle as in a major
fresh unipolar articular surface lesion or in chronic bipolar
unicompartmental damage you may, in case of definite overload,
decide for an unloading OT. This may as well be indicated in a
difficult meniscal reconstruction which, in our opinion and as has
been observed in the past in the clinical case, is easier than with
marked overload of the treated compartment.

118
Extended Abstracts
Meniscal suture techniques are divided in “inside-out”, “outsidein”
or “all-inside” techniques. While it is so far unsure if the three
methods offer all the same mechanical stability it seems obvious
that the speed of the procedure (surgical time) is in favor of the
all-inside technique but its disadvantage is the higher price. 500 US
$ for two sutures using the modern devices versus 30 US $ using
a couple of “outside-in” sutures! Nerve entrapments or vascular
injuries are the risk and disadvantage of the “outside-in” and
“inside-out” technique. But also the “all-inside” techniques are
not without hazard. Anchors may displace or damage vessels and
nerves if too deeply inserted. Shorter surgical time may weigh a lot
but without any doubt the elegant surgeon may do a solid refixation
using the “outside-in” technique in 25 minutes for 10% of the cost
of a few of the modern anchor systems. As long as the tear site is
more peripherally and not too posteriorly located this may be valid.
Some critical tears are very posteriorly located starting right at the
posterior root so that only an “all-inside” technique using one of the
modern anchor or suture systems is capable, without too high a risk
for neurovascular structures, to lead to a mechanically successful
and solid fixation. Indication for suture is critical and it may need a
sound ethical judgment since meniscal suture associated with an
ACL tear will most likely not be “extra” reimbursed in case the ACL
is reconstructed. To escape this dilemma and submit the patient to
a staged procedure with two surgeries within 6 weeks should not be
the first choice but it is sometimes unavoidable but it carries more
and obvious risks with infection or thromboembolic complications.
We fear that this paramedical conflict of today’s hospital practice
may unfortunately lead the surgeon, who stays under pressure of
the administration and keen hospital directors, to remove a torn
meniscus or leave it unfixed, the latter of the two still being better
because of the inherent chance of a spontaneous healing “despite
the surgeon”. The financial pressure in today’s hospital policy is
high and the remuneration systems are not rendering easy the fate
of the poor meniscus.
Although it is well known that the future of a torn and sutured
meniscus to successfully heal is higher with a stable knee one is
nevertheless allowed to question the relevance of which structure
to be salvaged at every cost or price? Is it the meniscus or the ACL?
The answer comes readily when we ask the question which absent or
poorly functioning structure is more “arthrogenic” (OA producing), a
torn or absent meniscus or an absent ACL? This question, although
justified, may remain open. Among others, three main factors play
hereby a role: The type of meniscal tear, medial or lateral (the lateral
being more rapidly followed by articular damage), concomitant
cartilage surface lesions, morphotype and others, maybe not yet
discovered and described, and the type and intensity of activity of
a given patient.
A few situations merit mentioning. Not only the reconstruction
of meniscal “volume” but the restoration of its function with
maintained circumferential fiber tension must remain the target
and the two cannot be separated from each other. This is easily
understandable with the situation of a posterior root avulsion
or a complete posterior horn radial tear (Seung Beom Han et
al.). Both do basically not decrease volume but allow the entire
meniscus consequently to displace in the periphery and lose a lot
of its function. In other words, mere existence and maintenance or
recreation of meniscal volume is not enough, if it is not invited or
allowed to function in the right location and position! As soon as we
observe peripheral subluxation there must be doubt about having
reached the original purpose and goal of ”shape and function”
which cannot be separated. Correct diagnosis and interpretation
of posterior horn avulsion and adequate, if needed transosseous
refixation is therefore mandatory to give such a meniscus a chance
for anatomic healing and maintenance of function.
Lee et al showed that the periphery of the meniscus is more
important for the overall pressure distribution in the compartment
than the central portion which may indicate that patients after
partial meniscectomy still have a nearly normal pressure distribution
in the joint. An isolated partial meniscectomy therefore may not
pose a significant short-term risk for a cartilage repair procedure.
However, long-term data exists linking partial meniscectomies to
the development of OA over a 15-year time span. This data are even
more compelling in conjunction with ligamentous instability.
Special attention needs to be given to white on white tears which
make up to about 30% of all tears (own estimation) and which still get
sacrificed too loosely and frequently by the average arthroscopist in
a 20 minute, well paid procedure. With the justification that healing
is impossible such a tear too easily serves as the learning path for
the second year orthopaedic resident. And that often marks the start
of a “knee history”. We think that this attitude needs to be revised.
Our own experience over the last 10 years has taught us that the
potential for healing of such tears is real as long as a few principles
are followed.
1. Suture alone of avascular tears may suffice although the success
rate may not be as high as in red-red or red-white tears (Noyes and
Westin).
2. Wrapping the meniscus in a fascial sleeve as demonstrated by
Henning already in 1991 may be successful and although technically
difficult and time-intensive be rewarding with 70% of healing.
Despite these promising results that technique has not really be
followed.
3. Since 2003 we wrap avascular meniscus tears in a Collagen Matrix
which can act as an internal bioreactor attracting cells of the synovial
fluid and the blood, preferably from intra-osseous source richer in
MSC’s (Jacobi and Jakob; Juelke at al). In animal experiments other
authors have shown the superior effect for healing when autologous
cells were embedded in the suture gap with an impregnated matrix
(Pabbruwe et al; Peretti et al).
In summary, future will allow us to focus more attention on the
maintenance of meniscal tissue and value it higher than in the
past so as to save menisci by reversing today’s tendency where
most efforts are focused on the reconstruction of the ACL. We
would welcome when in future torn ACL’s would be allowed to heal
naturally, maybe by adding some cells and growth factors and when
on the other hand careful surgical assistance would be offered to
avascular meniscus tears. It is time to change the thinking in this
regard!
Picture 1
Avascular Meniscus tear site is covered with collagen I/III Matrix
(Geistlich Biomaterials). The insertion and fixation can be done using
any of the classical fixation methods.
Picture 2
Invasion of meniscal synoviocytes and MSCs of synovial fluid and
bone onto matrix that attracts them like a sponge and into rupture
gap.

References:
Baratz ME, Rehak DC, Fu FH, Rudert MJ. Peripheral tear of the
meniscus. The effect of open versus arthroscopic repair on
intraarticular contact stresses in the human knee. Am J Sports Med
1988;16(1):1–6
Baratz ME, Fu FH, Mengato R. Meniscal tears: the effect of
meniscectomy and of repair on intraarticular contact areas and
stress in the human knee. A preliminary report. Am J Sports Med
1986;14(4):270–275
Englund M, Guermazi A, Lohmander LS. The meniscus in knee
osteoarthritis. Rheum Dis Clin North Am 2009;35(3):579-590
Henning CE, Yearout KM, Vequist SW, et al (1991). Use of the fascia
sheath coverage and exogenous fibrin clot in the treatment of
complex meniscal tears. Am J Sports Med 19:626-631
Jacobi M, Jakob RP (2010)Meniscal repair: enhancement of healing
process. In: The meniscus (R.V. Philippe Beaufils, ed), Springer
Verlag, Berlin Heidelberg, pp 129-135.
Jülke H, Jakob RP, Brehm W, Mainil-Varlet P, Schäfer B, Nesic D.
Meniscus repair in a goat model: an Autologous Chondrocyte
Implantation (ACI)-like approach for tears in the avascular zone (In
preparation)
Lee SJ, Aadalen KJ, Malaviya P, et al. Tibiofemoral contact mechanics
after serial medial meniscectomies in the human cadaveric knee. Am
J Sports Med 2006;34(8):1334–1344
Noyes F, Barber, Westin, BW. Arthroscopic repair of meniscus tears
extending into the avascular zone with or without anterior cruciate
reconstruction in patients 4 years of age or older. The Journal of
Arthroscopy and Related Surgery. Vol 16, Issue 8, November 2000,
pages 822-829
Noyes F, Barber-Westin SD. Arthroscopic Repair of Meniscal Tears
Extending into the Avascular Zone in Patients Younger Than Twenty
Years of Age. Presented at the interim meeting of the AOSSM, San
Francisco, California, March 2001. Am J Sports Med July 2002 vol. 30
no. 4 589-600
Noyes F, Barber, Westin, BW. Repair of Complex and Avascular
Meniscal Tears and Meniscal Transplantation. The Journal of Bone &
Joint Surgery. 2010; 92:1012-1029
Peretti GM, Caruso EM, Randolph MA, et al (2001) Meniscal repair
using engineered tissue. J Orthop Res 19:278-285
Peretti GM, Gill TJ, Xu JW, et al (2004) Cell-based therapy for meniscal
repair: a large animal study. Am J Sports Med 32:146-158
Pabbruwe MB, Esfandiari E, Kafienah W, Tarlton JF, Hollander AP
(2009). Induction of cartilage integration by a chondrocyte/collagenscaffold
implant. Biomaterials 30(26):4277-86
Pabbruwe MB, Kafienah W, Tarlton JF, Mistry S, Fox DJ, Hollander AP
(2010). Repair of meniscal cartilage white zone tears using a stem
cell/collagen-scaffold implant. Biomaterials 31(9):2583-91
Seung Beom Han et al. Unfavorable Results of Partial Meniscectomy
for Complete Posterior Medial Meniscus Root Tear With Early
Osteoarthritis: A 5- to 8-Year Follow-Up Study. The Journal of
Arthroscopic and Related Surgery, Vol 26, No 10 (October), 2010: pp
1326-1332
Extended Abstracts 119
3.3.3
How critical is the meniscus to the pathology of OA?
P. Lavigne
Montreal/Canada
Introduction: In 1897, Bland and Sutton described the meniscus as
“a functionless remains of a leg muscle”. It was not until 1936, that a
specific role for the meniscus proposed using a canine model. In his
classic study, King showed for the first time a chondroprotective role
for the meniscus. He suggested that “The amount of degeneration
appears to be roughly proportional to the size of the segment
removed”. King further suggested that the amount of meniscus
removed during surgery should be minimized.This was the first of
many studies associating meniscus pathology and later development
of osteoarthritis, which is the topic of this review.
Content: Fairbanks, in 1948, described roentgenographic changes
of osteoarthritis following meniscectomy (1). He concluded that
meniscectomy was not totally innocuous because it interferes at
least temporarily with joint biomechanics. Many years later, basic
science studies combined with clinical observations have identified
several meniscal functions, such as load distribution, shock
absorption, lubrication, assistance in articular cartilage nutrition and
maintenance of joint stability. Despite these evidences, open total
meniscectomy remained the standard of care for meniscal tears untill
the mid 1970s. With the advent of arthroscopy and the mounting
literature regarding menisci function, partial meniscectomy began
to be discussed in the late 1970s. Today, arthroscopic meniscal
surgery is one of the most commonly performed orthopaedic
procedures. The annual incidence of meniscal tears is 60 to 70 per
100 000 general population, with a peak incidence between 21 and
30 years of age in male and 11 and 20 years in female. An estimated
850 000 meniscal procedures are performed in the United States
yearly. In the 1980s, Baratz et al showed decrease in joint contact
surface areas and increase in peak contact pressures (up to 235%)
when total meniscectomy was performed (2). Clinical observations
of increased susceptibility to osteoarthritis following meniscectomy
later supported biomechanical studies. In 1998, Roos et al reported
that total meniscectomy resulted in a relative risk of 14 of developing
knee osteoarthritis 21 years later (3). Many studies also reported
radiographic signs of knee osteoarthritis in about 50% of patients
10 to 20 years after meniscectomy and the extent of meniscal
resection is now believe to relate to the degree of radiographic
osteoarthritis (4,5). A better understanding of meniscus structure,
intrinsic meniscal healing capacity and function in the last 20 years
has led to a “repair/replace” instead of a “remove” approach.
This change in clinical practice led to the introduction of meniscal
repair techniques and meniscus allograft transplantation in hopes
of preventing degenerative joint disease resulting from partial or
subtotal meniscectomy. While some studies have shown fewer
radiologic signs of osteoarthritis with meniscal repair, others have
failed to report a substantial protection of degenerative changes
progression following meniscus repair (6,7).
Recently, Paxton et al systematically reviewed the literature
comparing meniscal repair and partial meniscectomy (8). They were
able to compare 6 studies with a minimum follow up of 10 years that
reported either radiographic or MRI progression of osteoarthritis
following meniscus repair or partial meniscectomy. They found
that 78% of patients undergoing meniscus repair showed no
radiographic signs of osteoarthritis compared to 64% in the partial
meniscectomy patients at a minimum of ten years. Further, Fairbank
grade 0 or 1 changes were found in 97% of patients after meniscus
repair compared to 87% in the partial meniscectomy patients. These
results are in accordance with the study of Stein et al, published in
2010 (9). In a cohort study including 42 medial meniscus repairs
compared to 39 medial meniscectomy, Stein reported that 80%
of patients in the repair group showed no radiographic signs of
osteoarthritis compared to 40% in the meniscectomy group at an
average follow up of 8.8 years. Although recent reports suggest an
apparent chondroprotective effect following meniscal repair, there is
an evident need for a prospective study that would take into account
various variables such as age, type of tear, mechanical alignment,
history of previous trauma and surgery to name a few. Similarly,
very little evidences currently exist in the literature supporting the
chondroprotective effect of meniscus allograft transplantation (10).
Verdonk et al have reported the outcome of 47 meniscus allograft
transplantations at a minimum follow up of 10 years (11). Looking at
osteoarthritis progression, 48% of knees showed signs of joint space
narrowing and MRI analysis showed no progression of cartilage
degeneration in 35% of operated knees. In a recent study, Marcacci
et al studied 32 meniscal allograft transplantations at a minimum
follow up of 3 years (12). They reported a chondroprotective effect on

120
Extended Abstracts
knee joint cartilage using the Yulish score both on the femoral and
tibial surfaces. It will be interesting to see if the reported protective
effect on cartilage degradation is maintained at a longer follow up.
While articular cartilage degeneration following meniscectomy is
well described, there is a relative paucity of literature on the potential
chondroprotective effect following meniscal repair or meniscal
allograft transplantation. It remains difficult to date, to determine
to what extent these surgical techniques protect articular cartilage
against osteoarthritis development. There is a need for longer
clinical studies assessing the protective role of meniscus preserving
surgery in the development of knee osteoarthritis.
References:
1. Fairbank TJ. Knee joint changes after meniscectomy. J Bone Joint
Surg Br 1948; 30B:664-670.
2. Baratz ME, Fu FH, Mengato R. Meniscal tears: the effect of
meniscectomy and of repair on intraarticular contact areas and
stress in the human knee. A preliminary report. Am J Sports Med
1986; 14(4):270-275.
3. Roos H, Laurén M, Adalberth T, Roos EM, Jonsson K, Lohmander LS.
Knee osteoarthritis after meniscectomy: prevalence of radiographic
changes after twenty-one years, compared with matched controls.
Arthritis Rheum 1998; 41(4):687-693.
4. Lohmander LS, Englund PM, Dahl LL, Roos EM. The long-term
consequence of anterior cruciate ligament and meniscus injuries:
osteoarthritis. Am J Sports Med 2007; 35(10):1756-1769.
5. Englund M, Lohmander LS. Risk factors for symptomatic knee
osteoarthritis fifteen to twenty-two years after meniscectomy.
Arthritis Rheum 2004; 50(9):2811-2819
6. Sommerlath KG. Results of meniscal repair and partial
meniscectomy in stable knees. Int Orthop 1991; 15(4):347-350.
7. Shelbourne KD, Carr DR. Meniscal repair compared with
meniscectomy for bucket-handle medial meniscal tears in anterior
cruciate ligament-reconstructed knees. Am J Sports Med 2003;
31(5):718-723. 8- Paxton ES, Stock MV, Brophy RH. Meniscal repair
versus partial meniscectomy: a systematic review comparing
reoperation rates and clinical outcomes. Arthroscopy. 2011
Sep;27(9):1275-1288.
9. Stein T, Mehling AP, Welsch F, von Eisenhart-Rothe R, Jäger A. Longterm
outcome after arthroscopic meniscal repair versus arthroscopic
partial meniscectomy for traumatic meniscal tears. Am J Sports Med
2010;38(8):1542-1548.
10. McDermott I. Meniscal tears, repairs and replacement:
their relevance to osteoarthritis of the knee. Br J Sports Med
2011;45(4):292-297.
11. Verdonk PC, Verstraete KL, Almqvist KF, De Cuyper K, Veys EM,
Verbruggen G, Verdonk R. Meniscal allograft transplantation: longterm
clinical results with radiological and magnetic resonance
imaging correlations. Knee Surg Sports Traumatol Arthrosc
2006;14(8):694-706.
12. Marcacci M, Zaffagnini S, Marcheggiani Muccioli GM, Grassi A,
Bonanzinga T, Nitri M, Bondi A, Molinari M, Rimondi E. Meniscal
Allograft Transplantation Without Bone Plugs: A 3-Year Minimum
Follow-up Study. Am J Sports Med 2012;40(2):395-403.
Acknowledgments:
The author wishes to thank the Fonds de Recherche en Santé du
Québec (FRSQ) and University of Montreal - Department of Surgery
for their support.
5.10
Advances in understanding of post-traumatic osteoarthritis –
Implications for treatment of joint injuries
J. Buckwalter
Iowa City/United States of America
Introduction: Advances in Understanding of Post-Traumatic
Osteoarthritis Implications for Treatment of Joint Injuries University of
Iowa Department of Orthopaedics Joseph Buckwalter Excessive joint
loadings, either single (acute contact stress) or repetitive (cumulative
contact stress), cause progressive joint degeneration and subsequent
development of the clinical syndrome of osteoarthritis (OA). Joint
injuries causing acute excessive contact stress are common and often
affect young adults: each year one in people between the ages of -
seeks medical attention for treatment of joint injury, and more than
% of all lower limb OA is caused by joint trauma. Despite advances
in surgical treatment and rehabilitation of injured joints, the risk
of OA following joint fractures has not decreased in the last years.
Cumulative excessive articular surface contact stress that leads to OA
results from joint dysplasia, incongruity and instability, but also may
cause OA in patients without known joint abnormalities. Advances in
understanding of the thresholds for mechanical damage to articular
cartilage, and of the biologic mediators that cause progressive loss
of articular cartilage due to excessive mechanical stress, will lead to
better treatments of joint injuries and improved strategies for restoring
damaged joint surfaces. Recent in vitro investigations show that
reactive oxygen species (ROS) released from mitochondria following
excessive articular cartilage loading can cause chondrocyte death
and matrix degradation. Preventing the release of ROS or inhibiting
their effects preserves chondrocytes and their matrix. Fibronectin
fragments released from articular cartilage subjected to excessive
loads also stimulate matrix degradation; inhibition of the molecular
pathways initiated by these fragments prevents this effect. Distraction
and motion of osteoarthritic articular surfaces in humans can promote
joint remodeling, decrease pain and improve joint function in patients
with end-stage post-traumatic OA This result, combined with the
observation that chondroprogenitor cells are active in osteoarthritic
joints, suggests that altered loading creates an environment that
promotes beneficial joint remodeling. Taken together, these recent
advances in understanding of how mechanical forces cause loss of
articular cartilage, including identification of mechanically induced
mediators of cartilage loss, and of how changing joint loading can
promote joint remodeling provide the basis for new biologic and
mechanical approaches to the prevention and treatment of OA.
Content: Advances in Understanding of Post-Traumatic Osteoarthritis
Implications for Treatment of Joint Injuries University of Iowa
Department of Orthopaedics Joseph Buckwalter Excessive joint
loadings, either single (acute contact stress) or repetitive (cumulative
contact stress), cause progressive joint degeneration and subsequent
development of the clinical syndrome of osteoarthritis (OA). Joint
injuries causing acute excessive contact stress are common and often
affect young adults: each year one in people between the ages of -
seeks medical attention for treatment of joint injury, and more than
% of all lower limb OA is caused by joint trauma. Despite advances
in surgical treatment and rehabilitation of injured joints, the risk of
OA following joint fractures has not decreased in the last years.
Cumulative excessive articular surface contact stress that leads to OA
results from joint dysplasia, incongruity and instability, but also may
cause OA in patients without known joint abnormalities. Advances in
understanding of the thresholds for mechanical damage to articular
cartilage, and of the biologic mediators that cause progressive loss
of articular cartilage due to excessive mechanical stress, will lead to
better treatments of joint injuries and improved strategies for restoring
damaged joint surfaces. Recent in vitro investigations show that
reactive oxygen species (ROS) released from mitochondria following
excessive articular cartilage loading can cause chondrocyte death
and matrix degradation. Preventing the release of ROS or inhibiting
their effects preserves chondrocytes and their matrix. Fibronectin
fragments released from articular cartilage subjected to excessive
loads also stimulate matrix degradation; inhibition of the molecular
pathways initiated by these fragments prevents this effect. Distraction
and motion of osteoarthritic articular surfaces in humans can promote
joint remodeling, decrease pain and improve joint function in patients
with end-stage post-traumatic OA This result, combined with the
observation that chondroprogenitor cells are active in osteoarthritic
joints, suggests that altered loading creates an environment that
promotes beneficial joint remodeling. Taken together, these recent
advances in understanding of how mechanical forces cause loss of
articular cartilage, including identification of mechanically induced
mediators of cartilage loss, and of how changing joint loading can
promote joint remodeling provide the basis for new biologic and
mechanical approaches to the prevention and treatment of OA.

References:
Adkisson HDt, Martin JA, Amendola RL, Milliman C, Mauch KA, Katwal
AB, Seyedin M, Amendola A, Streeter PR, Buckwalter JA. 2010. The
potential of human allogeneic juvenile chondrocytes for restoraion
of articular cartilage. Am J Sports Med 38:1324-1333.
Anderson DD, Chubinskaya S, Guilak F, Martin JA, Oegema TR, Olson
SA, Buckwalter JA. 2011. Post-traumatic osteoarthritis: Improved
understanding and opportunities for early intervention. J Orthop Res
29:802-809.
Anderson DD, Iyer KS, Segal NA, Lynch JA, Brown TD. 2010.
Implementation of discrete element analysis for subject-specific,
population-wide investigations of habitual contact stress exposure.
J Appl Biomech 26:215-223.
Anderson DD, Van Hofwegen C, Marsh JL, Brown TD. 2011. Is
elevated contact stress predictive of post-traumatic osteoarthritis
for imprecisely reduced tibial plafond fractures? J Orthop Res 29:33-
39.
Beecher BR, Martin JA, Pedersen DR, Heiner AD, Buckwalter JA. 2007.
Antioxidants block cyclic loading induced chondrocyte death. Iowa
Orthop J 27:1-8.
Bonasia DE, Martin JA, Marmotti A, Amendola RL, Buckwalter JA,
Rossi R, Blonna D, Adkisson HD, Amendola A. 2011) Cocultures of
adult and juvenile chondrocytes compared with adult and juvenile
chondral fragments: in vitro matrix production. Amer J Sports Med:
Electronic Publication. Brown TD, Johnston JC, Saltzman CL, Marsh
JL, Buckwalter JA. 2006. Posttraumatic osteoarthritis: a first estimate
of incidence, prevalence, and burden of disease. J Orthop Trauma
20:739-744.
Buckwalter JA. 1992. Mechanical Injuries of Articular Cartilage. In:
Finerman, G. editor, Biology and Biomechanics of the Traumatized
Synovial Joint. Park Ridge IL: American Academy of Orthopaedic
Surgeons, pp. 83-96.
Buckwalter JA, Brown TD. 2004. Joint injury, repair and remodeling:
Roles in post-traumatic osteoarthritis. Clin Ortho Rel Res 423:7-
16. Buckwalter JA, Martin JA, Brown TD. 2006. Perspectives on
chondrocyte mechanobiology and osteoarthritis. Biorheology
43:603-609.
Cross JD, Wenke JC, Buckwalter JA, Ficke JR, Johnson AE. Post-
Traumatic Osteoarthritis Caused by Battlefield Injuries is the Primary
Source of Disability in Warriors. J American Academy of Orthopaedic
Surgeons (submitted)
Ding L, Heying E, Nicholson N, Stroud NJ, Homandberg GA, Buckwalter
JA, Guo D, Martin JA. 2010. Mechanical impact induces cartilage
degradation via mitogen activated protein kinases. Osteoarthritis
Cartilage 18:1509-1517.
Goodwin W, McCabe D, Sauter E, Reese E, Walter M, Buckwalter JA,
Martin JA. 2010. Rotenone prevents impact-induced chondrocyte
death. J Orthop Res 28:1057-1063. Heiner AD, Martin JA, McKinley
TO, Goetz JE, Thedens DR, Brown TD (in press) Frequency Content
of Cartilage Impact Force Signal Reflects Acute Histologic Structural
Damage. Cartilage.
Intema F, Thomas TP, Anderson DD, Elkins JM, Brown TD, Amendola
A, Lafeber FP, Saltzman CL. 2011. Subchondral bone remodeling is
related to clinical improvement after joint distraction in the treatment
of ankle osteoarthritis. Osteoarthritis Cartilage.
Koelling S, Kruegel J, Irmer M, Path JR, Sadowski B, Miro X, Miosge
N. 2009. Migratory chondrogenic progenitor cells from repair tissue
during the later stages of human osteoarthritis. Cell Stem Cell 4:324-
335.
Martin JA, Brown T, Heiner A, Buckwalter JA. 2004. Post-traumatic
osteoarthritis: the role of accelerated chondrocyte senescence.
Biorheology 41:479-491.
Martin JA, Klingelhutz AJ, Moussavi-Harmi F, Buckwalter JA. 2004.
Effects of oxidative damage and telomerase activity on human
articular cartilage chondrocyte senscence. J Gerontology: Biol
Sciences 59:B324-36.
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of stress induced chondrocyte damage. Bioreheology 43:517-521.
Extended Abstracts 121
Martin JA, McCabe D, Walter M, Buckwalter JA, McKinley TO.
2009. N-acetylcysteine inhibits post-impact chondrocyte death in
osteochondral explants. J Bone Joint Surg Am 91:1890-1897.
Maxian TA, Brown TD, Weinstein SL. 1995. Chronic stress tolerance
levels for human articular cartilage: two nonuniform contact models
applied to long-term follow-up of CDH. J Biomech 28:159-166.
McKinley TO, Rudert MJ, Koos DC, Brown TD. 2004. Incongruity
versus instability in the etiology of posttraumatic arthritis. Clin
Orthop Relat Res:44-51.
McKinley TO, Tochigi Y, Rudert MJ, Brown TD. 2008. The effect of
incongruity and instability on contact stress directional gradients in
human cadaveric ankles. Osteoarthritis Cartilage 16:1363-1369.
McKinley TO, Tochigi Y, Rudert MJ, Brown TD. 2008. Instabilityassociated
changes in contact stress and contact stress rates near a
step-off incongruity. J Bone Joint Surg Am 90:375-383.
Ramakrishnan P, Hecht BA, Pedersen DR, Lavery MR, Maynard
J, Buckwalter JA, Martin JA. 2010. Oxidant conditioning protects
cartilage from mechanically induced damage. J Orthop Res 28:914-
920.
Segal NA, Anderson DD, Iyer KS, Baker J, Torner JC, Lynch JA, Felson
DT, Lewis CE, Brown TD. 2009. Baseline articular contact stress levels
predict incident symptomatic knee osteoarthritis development in the
MOST cohort. J Orthop Res 27:1562-1568.
Seol D,. McCabe DJ, Choe H, Zheng H, Jang K, Walter M, Yu Y, Lehman
A, Ramakrishnan PS, Buckwalter JA, Martin JA. Chondrogenic
Progenitor Cell Responses to Cartilage Injury. Osteoarthritis Cartilage
(submitted) Thomas TP, Anderson DD, Mosqueda TV, Van Hofwegen
CJ, S. L. Hillis SL, Marsh JL T. D. Brown TD. 2010. Objective CT-based
metrics of articular fracture severity to assess risk for posttraumatic
osteoarthritis. J Orthop Trauma 24(12): 764-769.
Tochigi Y, Buckwalter JA, Martin JA, Hillis SL, Zhang P, Vaseenon
T, Lehman AD, Brown TD. 2011. Distribution and progression of
chondrocyte damage in a whole-organ model of human ankle intraarticular
fracture. J Bone Joint Surg Am 93:533-539.
Tochigi Y, Vaseenon T, Heiner AD, Fredericks DC, Martin JA, Rudert
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Acknowledgments:
The work described in this presentation, the abstract and the
references was supported by the National Insitutes of Health -
National Institute of Arthritis, Musculskeletal and Skin Diseases and
the Veterans Adminstration.

122
Extended Abstracts
5.20
Cartilage Repair: Where are we now? Where are we going?
D. Grande
Manhasset/United States of America
Introduction: The Clinical Problem of Cartilage Damage
Lesions in articular cartilage can cause considerable musculoskeletal
morbidity, with significant economic and social implications.
Osteoarthritis (OA) has a significant impact on human health, particularly
in the active military and veteran’s population who are at higher risk for
cartilage trauma over the course of active duty. Although cartilage has
a relatively simple structure compared to other tissues, cartilaginous
injuries can be extremely unforgiving. The limited blood supply in
cartilage is thought to be responsible for the inadequate repair post
injury. A substantial fraction (~12%) of the overall burden of OA arises
secondary to joint trauma, where the risk of post-traumatic OA (PTOA)
ranges from 20% to 50% [1, 2]. Currently, 9% of the U.S. population
aged 30 and older has OA of the hip or knee, costing an estimated $28.6
billion dollars with >400,000 primary knee replacements currently
being performed each year in the U.S. alone [3].
Content: History of a Cell Based Strategy for Cartilage Repair: Autologous
Chondrocyte Transplantation
In the early 1980’s the concept of healing cartilage with predominantly
hyaline tissue was largely considered a myth. Popular procedures at the
time included Pirdie drilling and abrasion arthroplasty which resulted
in largely fibrocartilage to fibrous tissue. It was at that time I first met
Lars Peterson,MD who was on a sports medicine sabbatical while I was
a graduate student at the Hospital for Joint Diseases in New York City.
While conducting a journal club on the subject of articular cartilage he
posed this question to me: What if it was possible to properly repair
articular cartilage? This clearly piqued my interest and we began a
collaboration to try and develop a new method for achieving this goal.
The motivation for pursuing this project were patients who had sustained
cartilage injury but were still deemed to young for total joint arthroplasty
which resulted in pain and disability for young active individuals. The
concept of a cell based strategy was explored and determined to be
a viable option. After several experiments we concluded that articular
chondrocytes exhibited several intrinsic properties of the tissue we
hoped to repair: They already synthesized type II collagen and aggrecan.
At that time the alternate cell source was mesenchymal stem cells
pioneered by Arnold Caplan at Case-Western Reserve University. These
were the early 1980’s and the term tissue engineering was not yet used
to define this new branch of science. The clinical strategy developed
around the need to first obtain a biopsy of cartilage which would then
be used to isolate free chondrocytes and expanded in culture. Based on
earlier work by Benya and Shaffer, we hypothesized that chondrocyte
phenotype was plastic a limited culture time and could be reestablished
by return to a 3-D environment. Optimizing cell delivery and a technique
for maintaining the chondrocytes within a defect was problematic as
suitable biomaterial membranes were scarce at that time. The decision
to use periosteum was based on its anatomical proximity to the surgical
site as well as its historical use in many orthopaedic applications such
interpositional arthroplasty. The first results of rabbit experiments were
decidedly superior then expectations and our team realized that a new
chapter in orthopaedic research had been opened. The first reports of
the technique were presented at the annual meeting of the Orthopaedic
Research Society in 1985 and were promptly met with skepticism as
the promising results were in conflict with over two hundred years of
dogma. This was followed up by two seminal publications, one in the
journal of orthopaedic research in 1989 received significant attention. In
spite of initial skepticism, Lars Peterson remained undeterred and was
confident in our preclinical studies he then conducted the first human
clinical trials using the exact same protocols.
Other Cartilage Repair Strategies Developed During this Era: 1980-1990
The use of immature, neonatal chondrocytes for cartilage repair was
based on the higher metabolic rates of these cells compared to those
of adult. These were shown to be capable of excellent repair in an avian
model by Nevo and Itay [4]. Although not developed further at that time
the use of young cartilage has recently been adapted by Zimmer as their
product DeNovo-NT.
The archetypes of plug type scaffolds for arthroscopic delivery were
fabricated of carbon fiber by Dunlop Corp. in Birmingham, UK, and
investigated in clinical trials by McMinn. Coutts and Amiel [5] studied
cartilage repair using the bioabsorbable scaffold material poly-L-lactic
acid [PLLA] with the addition of perichondrial derived chondrocytes.
Their descendants include the True-Fit plug along with other similar
plugs like the Chondromimetic product.
The prototype for a tissue engineered strategy was developed by [6]
using vicryl suture [polylactic glycolide; PLGA] formed into a rudimentary
nonwoven scaffold and seeded with chondrocytes. They demonstrated
that chondrocytes could generate cartilage tissue de novo as the scaffold
degraded leaving only the cells and their synthesized extracellular
matrix. The field of tissue engineering has seen a prolific amount of
activity with respect to cell types explored [Stem cells; marrow, muscle,
adipose, synovial, embryonic, IPS] and scaffold fabrication.
Current State of the Articular Cartilage Repair
While the etiology of joint degeneration leading to PTOA occur at the
molecular, cellular and tissue level, current treatments for PTOA are
primarily surgical [7,8,9]. Several procedures, such as microfracture
(MFX), osteochondral autograft transfer system, mosaicplasty,
autologous chondrocyte implantation (ACI), and matrix-induced
autologous chondrocyte implantation (MACI) [10-13] have been devised
to relieve pain, restore function, and delay or halt the progression of focal
cartilaginous defects. Each of these methods has its own characteristic
advantages and limitations [14-17]. MFX involves the piercing of the
subchondral bone to allow marrow and its host stem cells to colonize
the wound bed, promoting cartilage formation that is more fibrous than
hyaline in quality. Osteochondral allografting involves the transfer of
bone-cartilage units from ‘healthy’ regions to damaged regions and
rapidly restores load-bearing capacity and cartilage structure; however
limitations arise due to donor site morbidity, lack of healthy donor tissue,
and insufficient integration. ACI (injection of chondrocytes in suspension
under a periosteal flap) has shown promise in small defects in non- and
low-load bearing sites, however it employs adult human chondrocytes
from OA cartilage, which possess a limited capacity to form a hyaline
rich tissue. In MACI, a scaffold cut to the shape and size of the defect is
seeded with autologous chondrocytes and secured in the defect using
a fibrin glue [18]. New techniques involving tissue engineering use cells
in combination with scaffolds to regenerate a cartilage plug in vitro, for
implantation into the joint (e.g. [19,20]. However, these approaches
generally provide a biological replacement of cartilaginous plugs, as an
alternative to chondral autografts, ACI or MACI.
The Need for Early Intervention in Cartilage Repair
The early phase of inflammation post joint trauma triggers a cascade
of catabolic changes in cartilage, synovial tissue and underlying bone.
While acute inflammation can be part of the normal healing process,
chronic inflammation in PTOA is associated with a positive feedback
cycle that augments the destructive and degenerative pathways
mediated by matrix degrading enzymes, primarily MMPs. The use of
an MMP inhibitor as an early intervention shortly after the incidence of
injury is attractive because it may be deployed outside of a surgical unit,
where oral administration may be preferred. By specifically inhibiting
MMPs, we are targeting the pathophysiologic enzymes responsible
for ECM breakdown, without inhibiting the other mediators of normal
inflammatory responses, associated with physiological healing. MMP
inhibition can reduce or potentially delay the onset of PTOA, thus
decreasing the need for massively invasive procedure such as total joint
replacement. Moreover, MMP interventions early in the acute posttraumatic
period can significantly improve the therapeutic outcomes
of treatments administered later during surgical repair, by reducing
the severity of the disease. MMP inhibition is also expected to reduce
the production of fibrous cartilage (inferior quality ‘scar like’ tissue) in
favor of improved production of hyaline (type II collagen rich) cartilage
with mechanical properties significantly improved over existing repair
techniques. The production of a natural hyaline cartilage can also
improve the integration of the repair tissue with surrounding tissue and
underlying bone.
Successful Large Defect Resurfacing
While chondrocytes have been instrumental in repair of focal cartilage
defects, it is unlikely that they will be available in sufficient quantity for
clinical applications involving large whole condylar defects. The success
of MFX is dependent on the premise that MSCs are recruited to the
repair site. However, the presence of multiple populations of cells in the
marrow limits the specific contribution of MSCs, normally represented
in less than 0.1% of all marrow cells. The use of the homing agent SDF-
1 offers a specific augmentation of MFX, resulting in an environment
enriched with MSCs. The biomechanical importance of a properly
functioning articular surface presents a unique challenge when treating
articular cartilage pathology. The use of mechanically stable scaffolds
coated with SDF-1 provides a large porous substrate for the enriched
MSCs to attach and form cartilage, de novo.

In Situ Tissue Engineering as the New Paradigm for Rapid Clinical
Translation
MFX is successful in regeneration of small cartilage defects, but has a
wide variance in the quality of the cartilage fill. Cartilage repair quality
is thought to be directly proportional to the recruitment of MSCs to the
wound site. In-vitro studies by our group have shown that SDF-1 can
affect the recruitment of MSCs by acting as a homing molecule, and can
also affect their growth and differentiation. Moreover, we examined
the efficacy of SDF-1 for cartilage repair in vivo. Defects were repaired
with either scaffold only (PLLA or collagen sponge), scaffold coated
with SDF-1 (50 ng/ml), or left empty. The quality of repair was analyzed
histologically after 4 weeks with safranin-O/fast green staining and
quantified with the O’Driscoll score. The quality of repair in the empty
defect was poor, with fibrillation at articular surface, and degenerative
changes in surrounding tissue. The SDF-1 coated scaffolds had
congruent and smooth cartilage surfaces that were well integrated with
the surrounding cartilage. Quantitatively, the scaffold only group had
modest improvement in cartilaginous filling compared to empty defect.
However, the SDF-1 coated scaffold had significantly improved quality
of cartilage repair with GAG rich cartilage ECM. Interestingly, we saw no
major differences in repair quality between PLLA and collagen scaffold
treated groups. These findings on small defects support the hypothesis
that SDF-1 promotes significant improvement in cartilaginous repair.
We theorize that this is mechanistically due to increased recruitment
of MSCs into the injury site. For large defect repairs, a clinical strategy
would be to administer allogenic MSCs to increase the number of
reparative cells available for contiguous repair across the defect
Summary: Effective and comprehensive treatment of all phases of
injury is essential in order to address the initial structural joint injury
and as well the inflammatory and destructive processes that follow
and can result in more diffuse joint pathology. Acute, subacute and
chronic surgical resurfacing of larger or multifocal symptomatic hyaline
tissue traumatic defects as well as associated osteochondral defects
is essential. Although current marrow stimulation (microfracture) and
autogenous osteochondral transplantation techniques have been
available, these methods have had less effective application in treating
larger sizes defects (> 2 centimeter 2). Use of volume stable scaffolds
coated to chemotactically enhance mesenchymal stem cell recruitment
to the repair construct is an attractive option. The concurrent use
of biochemical catabolic inhibitors that can reduce degradative
inflammatory mechanisms that can biologically expedite recovery and
improve the quality of structural repair is a promising strategy as there
are few surgical techniques that result in superior and durable clinical
outcomes in young active patients.
References:
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124
Extended Abstracts
7.1
The use of autologous cartilage fragments - clinical studies
J. Farr
Indianapolis/United States of America
Introduction: Current surgical treatment options for symptomatic
cartilage lesions include debridement/lavage, marrow stimulation
with or without augmentation, osteochondral autograft implantation,
stored osteochondral allograft implantation, and autologous
chondrocyte implantation first and subsequent generations.7-12
There are two new approaches that use minced/particulated
cartilage to treat chondral defects. One investigational technique
uses autograft cartilage (Cartilage Autograft Implantation System
[CAIS]; DePuy Mitek Rayham MA USA) and the other uses juvenile
allograft cartilage (DeNovo NT; Zimmer Warsaw IN USA).3,13 This
report will focus on CAIS (originally reported at the Warsaw ICRS) as
Dr. Caborn will report on DeNovo NT.
Content: Even a few years ago, the concept that cartilage could be
implanted and heal without underlying bone would be considered ill
conceived by most cartilage surgeons. While using minced articular
cartilage to repair a chondral defect is relatively new in US journals,
Albrecht, a German scientist, reported the technique in 1983.19 He
demonstrated that in the rabbit cartilage autograft cut into small
pieces without bone led to cartilage defect healing noting, however,
the subchondral plate was breached. United States based scientists
Francois Binette and Ed Lu noted (as others in the field of investigating
chondrocytes had) that during preparation to enzymatically free the
chondroctyes, after mincing and before enzymatic digestion of the
extracellular matrix, some chondrcytes appeared outside of the
matrix and new matrix formation appeared adjacent to the minced
cartilage fragments. Binette, Lu and their associates began a series
of experiments to further investigate these findings first with in vitro
experiments and then in the mouse, goat, and finally horse preclinical
models.20,21. In essence, these studies showed that chondrocytes in
the cartilage fragments could “escape” from the dense extra-cellular
matrix, migrate, multiply, and form new hyaline-like cartilage tissue
matrix that would integrate with the surrounding host tissue. This new
tissue demonstrated both basilar and marginal integration. Unlike
cultured chondrocytes that assume a spindle shape morphology
during ex vivo culture, the chondrocytes from the minced cartilage
retained the standard chondrocyte spheroid shape.21 In aggregate
these studies demonstrated that autograft cartilage defect repair
was possible when autograft cartilage was mechanically minced into
cubes of 1-2 mm and then implanted into the defect.19,21
This preclinical data was compelling enough for the FDA to approve
a safety pilot study of what the sponsor referred to as CAIS (Cartilage
Autograft Implantation System).3 The clinical outcomes are now
published at 2 years and an extension follow up study is complete
to 4 years post-op with publication to follow. A parallel pilot study
has been completed in Europe. In the US, the FDA has approved a
pivotal study of the technique, which began recruiting patients in
2010 and will enroll over 300 patients for a randomized prospective
comparison of CAIS to MFX (that is, CAIS is not available for general
use but limited to clinical study patients).
INDICATIONS/CONTRAINDICATIONS
CAIS is being investigated for treatment of symptomatic articular
cartilage defects of the knee in patients from age 18-55. Arthroscopic
evaluation should confirm one or two ICRS grade 3a to 4a chondral
lesions of the femoral condyles or trochlea that after debridement
measure from 1 cm2 to 10 cm2. As is standard for cartilage restoration
in general, the meniscal tissue should be functional, the knee stable
and limb alignment neutral. Potential contraindications to CAIS
include bipolar lesions, significant underlying subchondral bony
edema, or subchondral bone defect > 6mm subchondral bone loss.
SURGICAL TECHNIQUE
In the pilot study, standard arthroscopy confirmed CAIS inclusion/
exclusion criteria, and hyaline cartilage similar to the amount harvested
for ACI (roughly 200 mg) was then harvested arthroscopically from a
low load-bearing surface using a proprietary device (DePuy Mitek)
that minced the cartilage into 1- to 2-mm pieces. The device then
uniformly dispersed the minced cartilage onto a biodegradable
scaffold that is comprised of an absorbable co-polymer foam of
35% polycaprolactone [PCL] and 65% polyglycolic acid [PGA] and
reinforced with a polydioxanone [PDO mesh] [DePuy Mitek]). The
minced cartilage was then glued to the scaffold using a commercially
available fibrin sealant (Tisseel, Baxter, Illinois). A mini-arthrotomy
was performed, and the defect was identified and prepared similar to
the technique utilized for ACI. A template was cut to match the lesion
and guided cutting the minced cartilage/scaffold construct. The sized
CAIS scaffold implant was transferred to the defect with the cartilage
fragments facing the subchondral bone and affixed with 2 or more
biodegradable polyglycolic acid (PGA)/polydioxanone (PDO) staple
anchors (DePuy Mitek.
Rehabilitation Protocol
The rehabilitation program for the pilot study purposely mimicked
the Steadman microfracture rehabilitation program. This program
begins with protection of the cartilage repair process and then
progresses toward controlled loading, increased range of motion,
and progressive muscle strengthening.3 Rehabilitation is specific
for the patellofemoral and tibiofemoral compartment. Standard limb
strengthening then follows with functional progression to activity.
Results
The FDA approved the pilot study in the United States to assess the
safety of CAIS and to test whether CAIS improves quality of life by
using standardized outcomes assessment tools. In the study, 29
patients were randomized with the intent to treat with either MFX
or CAIS. Patients were followed at pre-determined time points for 2
years using several standardized outcomes assessment tools (SF-36,
International Knee Documentation Committee [IKDC], Knee injury and
Osteoarthritis Outcome Score [KOOS]). Magnetic resonance imaging
was performed at baseline, 3 weeks, and 6, 12, and 24 months.
Lesion size and International Cartilage Repair Society (ICRS) grade
were similar in both groups. General outcome measures (e.g. physical
component score of the SF-36) indicated an overall improvement in
both groups, and no differences in the number of adverse effects
were noted in comparisons between the CAIS and MFX groups. The
IKDC score of the CAIS group was significantly higher compared with
the MFX group at both 12 and 24 months. Select subdomains (4/5) in
the KOOS instrument were significantly different at 12 and 18 months,
and all subdomains (Symptoms and Stiffness, Pain, Activities of Daily
Living, Sports and Recreation, Knee-related Quality of Life) were
significantly increased at 24 months in CAIS versus MFX.
Qualitative analysis of the imaging data did not note differences
between the 2 groups in fill of the graft bed, tissue integration, or
presence of subchondral cysts. Patients treated with MFX had a
significantly higher incidence of intralesional osteophyte formation
(54% and 70% of total number of lesions treated) at 6 and 12 months
when compared with CAIS (8% and 25% of total number of lesions
treated). To be reported in 2012, the results at 3 years in Europe and
4 years in the US demonstrate durability compared to the 2 year
outcomes.
DISCUSSION
In short term clinical studies, CAIS appears to be safe and feasible, with
improvements in subjective patient scores, and with MRI evidence of
good defect fill.2,3,26 There are several potential advantages to this
technique. CAIS does not require the violation of the subchondral
bone, as is necessary for marrow stimulation procedures that may
compromise subsequent revision surgeries as reported by Minas.27
Obviously, CAIS does not create an osteochondral defect for treatment
of a cartilage only lesion as is necessary for osteochondral auto and
allograft transplantation. CAIS and DeNovo NT utilize a strategy of
cartilage-cartilage healing in the defect bed. This may help to avoid
problems of bony healing as seen in failed osteochondral allograft
procedures, including lack of bone incorporation, necrosis, and
avascular necrosis like collapse. As CAIS is single stage procedureit
avoids the cost of cell culturing and the need for a second surgery
for implantation. A disadvantage specific to CAIS is the potential for
donor site morbidity at cell harvest; however, this risk is minimal and
is, in theory, similar to the risk involved in ACI harvest.
CONCLUSION
CAIS appears to be a promising new treatment option for patients
with symptomatic focal chondral defects in the knee. Further studies
including formal reporting of the 4 year follow up of US patients, the
3 year follow up of the European patients and the ongoing US pivotal
study will improve evidence based recommendations.
Financial Disclosure:
Farr is a consultant for Depuy Mitek and is a principle investigator for
the CAIS pivotal study

References:
1. Chondral Defect Repair with Particulated Juvenile Cartilage
Allograft. Updated 2010;Available from: http://www.zimmer.
com/web/enUS/pdf/DeNovo_Chondral_Defect_Repair_White_
Paper_05_2010.pdf
2. Farr J, Yao JQ. Chondral defect repair with particulated juvenile
cartilage allograft. Cartilage 2011;epub ahead of print.
3. Cole BJ, Farr J, Winalski CS, Hosea T. Outcomes after a single-stage
procedure for cell-based cartilage repair: a prospective clinical safety
trial with 2-year follow-up. Am J Sports Med 2011;39:1170-1179
4. Hjelle K, Solheim E, Strand T, Muri R, Brittberg M. Articular cartilage
defects in 1,000 knee arthroscopies. Arthroscopy 2002;18:730-734
5. Maletius W, Messner K. The effect of partial meniscectomy on the
long-term prognosis of knees with localized, severe chondral damage.
A twelve- to fifteen-year follow up. Am J Sports Med 1996;24:258-
262
6. Saris DBF, Vanlauwe J, Victor J, Almqvist KF. Treatment of
symptomatic cartilage defects of the knee: characterized chondrocyte
implantation results in better clinical outcome at 36 months in
a randomized trial compared to microfracture. Am J Sports Med
2009;37 Suppl 1:10S-19S
7. Brittberg M, Lindahl A, Nilsson A, Ohlsson C. Treatment of
deep cartilage defects in the knee with autologous chondrocyte
transplantation. N Engl J Med 1994;331:889-895
8. Zaslav K, Cole B, Brewster R, DeBerardino T. A prospective study
of autologous chondrocyte implantation in patients with failed prior
treatment for articular cartilage defect of the knee: results of the
Study of the Treatment of Articular Repair (STAR) clinical trial. Am J
Sports Med 2009;37:42-55
9. Gross AE, Shasha N, Aubin P. Long-term followup of the use of
fresh osteochondral allografts for posttraumatic knee defects. Clin
Orthop Relat Res 2005;435:79-87
10. Hangody L, Kish G, Kárpáti Z, Szerb I, Udvarhelyi I. Arthroscopic
autogenous osteochondral mosaicplasty for the treatment of femoral
condylar articular defects. A preliminary report. Knee Surg Sports
Traumatol Arthrosc 1997;5:262-267
11. Moseley JB, O’Malley K, Petersen NJ, Menke TJ. A controlled trial
of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med
2002;347:81-88
12. Steadman JR, Rodkey WG, Singleton SB, Briggs KK. Microfracture
technique for full-thickness chondral defects: technique and clinical
results. Operative techniques in orthopaedics 1997;7:300-304
13. Farr J. DeNovo NT natural graft tissue. Poster presented at: 8th
World Congress of the International Cartilage Repair Society; 2009;
Miami, FL
14. Asik M, Ciftci F, Sen C, Erdil M, Atalar A. The microfracture technique
for the treatment of full-thickness articular cartilage lesions of the
knee: midterm results. Arthroscopy 2008;24:1214-1220
15. Cole BJ, Pascual-Garrido C, Grumet RC. Surgical management
of articular cartilage defects in the knee. J Bone Joint Surg Am
2009;91:1778-1790
16. Saris DBF, Vanlauwe J, Victor J, Haspl M. Characterized chondrocyte
implantation results in better structural repair when treating
symptomatic cartilage defects of the knee in a randomized controlled
trial versus microfracture. Am J Sports Med 2008;36:235-246
17. Knutsen G, Drogset JO, Engebretsen L, Grøntvedt T. A
randomized trial comparing autologous chondrocyte implantation
with microfracture. Findings at five years. J Bone Joint Surg Am
2007;89:2105-2112
18. Knutsen G, Engebretsen L, Ludvigsen TC, Drogset JO. Autologous
chondrocyte implantation compared with microfracture in the knee. A
randomized trial. J Bone Joint Surg Am 2004;86-A:455-464
19. Albrecht F, Roessner A, Zimmermann E. Closure of osteochondral
lesions using chondral fragments and fibrin adhesive. Arch Orthop
Trauma Surg 1983;101:213-217
Extended Abstracts 125
20. Frisbie DD, Lu Y, Kawcak CE, DiCarlo EF. In vivo evaluation of
autologous cartilage fragment-loaded scaffolds implanted into
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implantation. Am J Sports Med 2009;37 Suppl 1:71S-80S
21. Lu Y, Dhanaraj S, Wang Z, Bradley DM. Minced cartilage without
cell culture serves as an effective intraoperative cell source for
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22. Cheung HS, Cottrell WH, Stephenson K, Nimni ME. In vitro collagen
biosynthesis in healing and normal rabbit articular cartilage. J Bone
Joint Surg Am 1978;60:1076-1081
23. Adkisson HD, Martin JA, Amendola RL, Milliman C. The potential
of human allogeneic juvenile chondrocytes for restoration of articular
cartilage. Am J Sports Med 2010;38:1324-1333
24. Stockwell RA. The interrelationship of cell density and cartilage
thickness in mammalian articular cartilage. J Anat 1971;109:411-421
25. Namba RS, Meuli M, Sullivan KM, Le AX, Adzick NS. Spontaneous
repair of superficial defects in articular cartilage in a fetal lamb
model. J Bone Joint Surg Am 1998;80:4-10
26. Bonner KF, Daner W, Yao JQ. 2-year postoperative evaluation of
a patient with a symptomatic full-thickness patellar cartilage defect
repaired with particulated juvenile cartilage tissue. J Knee Surg
2010;23:109-114
27. Minas T, Gomoll AH, Rosenberger R, Royce RO, Bryant T.
Increased failure rate of autologous chondrocyte implantation after
previous treatment with marrow stimulation techniques. Am J Sports
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collagen membrane decreases reoperation rates for symptomatic
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29. Gibson T, Brian Davis W, Curran R. The long-term survival of
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at 2 years. Am J Sports Med 2009;37:1334-1343
8.1.1
Treatment of Osteochondral Lesions of the Talus
E. Giza
Davis/United States of America
Introduction: Epidemiology of Talus Injury Ankle sprains are common
injuries with a daily incidence of one per 10,000 people per day.
There are 23,000 ankle injuries each day in the USA with basketball,
soccer, and volleyball having the highest incidence per hour of play.
Both acute injury and chronic lateral ligament insufficiency can lead
to talar osteochondral lesions.
Content: Talus Anatomy The talus articulates with the tibia, fibula,
calcaneus, and navicular and of its surface 60% is covered in cartilage.
It serves as a link to transmit load to the foot and experiences up to
six times body weight with each step. It affords pronation-supination
and dorsiflexion-plantarflexion through multiple facets, a unique
bony architecture and multiple ligament attachments. The talus
has no tendonous attachments. The chondrocytes have a limited
capacity for intrinsic repair due to encasement in matrix proteins and
limited vascularity. Full thickness injuries below the subchondral
bone allow recruitment of marrow elements but injuries greater than
two to four millimeters have a poor potential to heal with normal
appearing cartilage. A chondrocyte’s biosynthetic machinery is
impaired with senescence and further hampers healing of defects
regardless of technique. Evaluation of talus injury Symptoms Patients
usually present with persistent pain after an ankle sprain. Time to
presentation may be prolonged. Pain is typically localized to the
side of the lesion and may be accompanied by intermittent swelling,

126
Extended Abstracts
stiffness, and weakness. Mechanical symptoms such as locking and
catching are variable. High level athletes can usually tolerate the pain
and may present after numerous injury events. A complete history
pertaining to both medial and lateral ankle instability is paramount
as findings on exam can be subtle. Alignment of the hindfoot should
be noted as pes cavus deformity can contribute to inversion injuries.
Stability should be tested with both anterior drawer testing and
bilateral prone inversion challenge testing of the ankle and subtalar
joints. Surgical Treatment For talus OCD, consistency in reporting
of outcomes are inconsistent, and may studies have small sample
sizes. Acute restoration is performed on the rare lesion with a bony
defined fragment that is technically repairable. True osteochondritis
dissecans lesions are possible candidates but overall relatively
rare. Delamination must not be present and the best candidates are
young athletes with good healing potential who are able to comply
with weight bearing restrictions. Techniques include open reduction
and internal fixation with recessed transchondral screws, retrograde
internal fixation and biodegradable fixation devices. Arthroscopy,
Curettage and Microfracture/Drilling The initial surgical treatment for
most lesions involves arthroscopy with curettage and microfracture.
Arthroscopy is indicated for unstable lesions and those that have
failed conservative treatment with stable lesions. Best results are
seen in patients with small lesions (
1.5 cm², age less than 50 years old and failure of either non-operative
treatment or an index cartilage surgery. Kissing talo-tibial lesions
and axial defects or deformity are contraindications. Autografts are
harvested as full thickness cartilage with subchondral bone. Multiple
small sized cylindrical plugs of varying small diameters (2-4 mm) are
harvested to implant and cover a larger area in the mosaicplasty
technique. The intervening spaces are filled with newly generated
fibrocartilage but hyaline transplanted cartilage populates the bulk
remainder. Advantages for the OATS or mosiacplasty technique
include the use of autograft tissue with robust fixation and a single
stage procedure that can be performed open or arthroscopically.
Surgical exposure of the posterior talar dome, large defect size, and
matching cartilage shape, curvature and depth of resection are all
technically demanding skills that need to be practiced on a cadaver
specimen with appropriate preoperative planning. Both techniques
necessitate an orthogonal approach to the articular surface. Bulk
fresh osteochondral allografts are replacement options for multifocal
and large defects (>1cm2) particularly in the setting of avascular
necrosis. Indications include subchondral and extensive disease,
possibly necessitating a bipolar graft and salvage procedures
for failed autografting restoration attempts. Patients seeking to
minimize the donor site morbidity of autograft procedures can be
considered. Both fresh frozen and fresh osteochondral allografts are
available however cryopreservation results in a loss of chondrocyte
viability. Autologuous Chondrocyte Implantation (ACI) Autologuous
Chondrocyte Implantation (ACI) uses cultured chondrocytes with a
periosteal patch. Harvesting is first accomplished from either the
knee or ankle and can include the damaged area of chondral tissue.
The biopsy typically yields 2-3 million cells and these cells can
be stored for greater than one year. Once the decision is made to
transplant the cells are cultured for 6-8 weeks and results in at least
12 million cells available for implantation. The process of growing the
cells increases the number of viable cells for implantation by at least
ten fold. The ability to culture large numbers of cells for implantation
is critical for the success of the procedure. Matrix-Based Chondrocyte
Implantation Matrix-Based Chondrocyte Implantation (MACI) is
similar to ACI. Cells are first harvested from the ankle or knee. Next,
chondrocyte cells are enzymatically separated from the matrix and
cultured to produce 15-20 million cells. Instead of injecting the
cultured chondrocytes under periosteam, the cells are imbedded
in a type I/III collagen membrane bilayer. Similar to ACI, the MACI
technique allows the surgeon to increase by at least ten fold the cells
available for implantation into the defect. A second stage operation is
used to implant the membrane over the talar defect. The advantages
of MACI include that it is technically easier than ACI and no tibial/
malleloar osteotomy is needed. Two operations are required and
the cells can be stored for greater than one year after initial harvest.
Summary Osteochondral defects of the talus continue to be a
challenging entity. The role of ankle instability as both an acute and
chronic etiology is evident. Early attempts at stimulating healing,
whether by curettage and/or drilling and microfracture have been
shown to be equivalent. Patients with failed first line treatments are
candidates for cartilage replacement surgeries such as OATS, ACI
and MACI. Larger, non-healing lesions are potential candidates for
bulk osteochondral allografts. Development of precise indications,
optimal rehabilitation, all-arthroscopic techniques, and advanced
biomaterials to accelerate healing are current topics of ongoing
investigation.
8.1.2
Clinical options for cartilage reconstruction in the ankle.
R. Ferkel
Van Nuys/United States of America
Introduction: In 1743, Hunter stated that “From Hippocrates down to
the present age, we shall find that an ulcerated cartilage is universally
allowed to be very troublesome disease; that amidst of a cure with
more difficulty than a carious bone; and that, when destroyed it is
never recovered B. PRIMARY PROBLEM 1. Fibrocartilage repair not
been shown to withstand mechanical wear over time 2. Fibrocartilage
might degenerate and lesion progress into osteoarthritis
Content: I. Treatment Alternatives A. Osteochondral autograft plugs
(OATS) 1. “Robs Peter to pay Paul” 2. Question of long term problems
with femoral plug holes; subsequent pain 3. Size limitations for autograft
transplantation 4. Advantage of single setting procedure 5. Scranton et
al. (2005): 50 patients, significant improvement; 90% good/excellent.
Karlsson scores increased 24 to 83 B. Osteochondral allografts 1. Chu
(1999): 55 knees, average follow-up 75 months 2. Overall success 76%
3. Gross (2001): 9 patients; 6 patients remain in situ, mean survival 11
years. 3 cases required fusion 4. Bugbee et al. (2010): 12 ankles a. Mean
follow-up 38 months b. Average previous surgery 1.8 c. Graft survival
83% d. Mean OMAS improved 28 to 71 5. Kelikian et al. (2011): allografts
on 38 patients a. Mean follow-up 38 months b. Graft survival 89% c.
AOFAS score from 52 to 79 II. Autologous Chondrocyte Implantation A.
Definition – implantation of in vitro cultured autologous chondrocytes
using periosteal tissue or membrane cover after expansion of isolated
chondrocytes B. ACI – Generations 1. Generation 1 – Carticel suspended
under periosteal flap or membrane 2. Generation 2 – Carticel inserted
under tissue patch or onto carrier scaffold 3. Generation 3 – Carrier-free,
immature cartilage tissue III. Indications A. Indications 1. Age 15 to 55
2. Focal defect > 1 cm2 3. Unipolar (only talus affected) 4. Contained
5. Edge loading 6. Failed previous surgery 7. Large lesions, extensive
subchondral cystic changes B. Relative 1. Multifocal unipolar lesions 2.
Uncontained lesions IV. Contraindications A. Relative 1. Kissing (bipolar)
lesions 2. No previous surgery 3. Early degenerative changes B. Absolute
1. Osteoarthritis 2. Uncorrected malalignment 3. Uncorrected instability
V. Surgical Procedure A. Biopsy procedure – Step 1 1. Chondral biopsy
200-300 mg 2. Biopsy done in intercondylar notch of knee or ankle
arthroscopically B. Surgical Technique – Step 2 1. Medial or lateral
malleolar osteotomy performed under fluoroscopy 2. Defect preparation
- vertically incise and remove defect and all damaged cartilage from
subchondral bone 3. Harvest periosteum from medial distal tibia,
measure appropriately 4. Biogide a. Absorbable porcine bilayer
collagen I/III membrane has been used in knee and ankle ACI in place of
periosteum b. Has a rough and smooth layer c. Made by same company
as Chondro-gide and very similar 5. Apply fibrin glue circumferentially
along periosteum-cartilage margin or at suture lines 6. Cell implantation
a. Insert soft catheter tip through opening of periosteum and inject
cells, then close defect and put additional fibrin glue over it VI. Surgical
Technique with “Sandwich Procedure” A. Done for large cystic lesions
>6 mm deep B. Osteochondral lesion is excised and cyst curetted out
C. Bone graft obtained from proximal or distal tibia, depending on size
of cyst. Place 2 layers of periosteum or BioGide VII. Postoperative Care
A. Early phase, day 1 to week 8 B. Transition phase, 8-12 weeks C. Mid
Phase, 3-5 months D. Final phase, 6-12 months E. Time line for activities
1. Low impact activities 4-6 months 2. Repetitive impact activities 6-8
months 3. High level activities 10-12 months VIII. Results of ACI – First
Generation (ACI-P) A. Whittaker et al. (2005): 10 patients 1. Mean followup
23 months 2. Mazur score increased 23 points 3. Increased donor site
morbidity 4. “Second looks” done on 9 patients; showed filled defects,
stable cartilage 5. Biopsies showed mostly fibrocartilage with some
hyaline cartilage B. Baums et al. (2006): 12 patients 1. Mean follow-up
63 months 2. Hannover score increased from 40 to 86 points 3. AOFAS
increased 45 points 4. Patients involved in competitive sports able to
return to full activity level C. Ferkel (2011): 32 patients 1. First 11 patients
have been reviewed and published in AJSM 2. Current: Follow-up 29 of

32 (91%) 3. Average age: 34 (18-54) 4. Average follow-up: 70 months
(24-129) 5. 9 “sandwich” procedures done, with bone grafting of large
cystic underlying defect and use of two periosteal grafts back to back
6. 2nd look arthroscopy 90% of patients (26/29) 7. Results: Excellent:
8; Good: 15; Fair: 5; Poor: 1 8. Entire paper presented at AAOS 2011 X.
Second Generation ACI A. Variety of scaffolds being used in Europe,
implanted through small arthrotomy or arthroscopically. 1. Used as patch
and cells inserted underneath 2. Cells seeded onto scaffold membrane
B. Collagen-covered autologous chondrocyte implantation (CACI or
ACI-C) 1. Absorbable porcine bilayer collagen I/III membrane 2. Chondro-
Gide membrane with one compact and one porous surface 3. Gooding
found no difference in results between periosteum and membrane cover
in knees with CACI C. Hyalograft C 1. Benzyl ester of Hyaluronic acid 2.
Bioabsorbs in 3 months 3. Marcacci et al.: 175 patients with grafts in knee,
46 month mean follow-up. Results: 93% improvement at ICRS 2006 4.
Giannini et al. (2008) – 46 patients in ankle a. Mean age 32; follow-up
3 years b. Preop 57; postop 90 mean AOFAS score c. Biopsies collagen
type II D. Membrane/matrix autologous chondrocyte implantation (MACI)
1. Highly purified type I/III collagen membrane 2. Guillen and Abelow
presented first 50 cases (42 knees; 8 ankles) 3. 8 ankles (ages 22-46)
4. Large full thickness cartilage lesions of talus (2-6 cm) 5. 5/6 good/
excellent results with follow-up 4 months-2 1/2 years 6. Giza et al.: MACI
on 10 patients; AOFAS 61 to 73 XI. Third generation ACI A. Use carrierfree,
immature cartilage tissue B. Lack of carrier scaffold C. Avoids carrier
integration, degradation and biocompatibility complications D. Jubel et
al. used alginate matrix to produce cell-rich chondrocyte disc in MFC of 48
sheep E. Chondral defects treated with De Novo cartilage transplantation
showed qualitatively better micro and macroscopic regeneration than
those with periosteal flaps alone 1. Fair and Yao reported early good
results in knee 2. Adams et al. reported particulated juvenile articular
cartilage transplant for OLT with early good results XII. Summary A.
Zengerink et al. has nicely summarized when to use which treatment for
OLT B. Is there a critical defect size for poor outcome? 1. Choi et al (2009)
found initial defect size is important prognostic factor for OLT and can
serve as a basis for preop surgical decisions 2. OLT defect of 150 mm2
or greater as calculated from MRI has a high correlation of having a poor
clinical outcome
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assisted autologous osteochondral transplantation for osteochondral
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Ferkel RD: Arthroscopic Surgery: The Foot and Ankle. Philadelphia;
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Extended Abstracts 127
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128
Extended Abstracts
8.1.3
Dermal graft application in Hallux Limitus / Rigidus for salvage
of the 1st metatarsophallangeal joint
L.J. Sanchez
Orlando/United States of America
Introduction: Hallux Limitus / Hallux Rigidus presents as a
gradual “deformity” of the foot Greater toe metatarsophallangeal
joint. Its presentation includes a partial luxation of the first
metatarsophallangeal joint, where the Hallux proximal phallanx
base presents a plantar attitude or luxation in reference to the
first metatarsal head. This foot pathology has been well described
in a pletora of medical writtings in literature. It was first described
as “Hammerzehenplattfuss” or “Hallux-hammertoe-flatfoot”, by
Nicoladoni, in 1881. And it has been given other names as well,
but it was Cotteril who denomiated it as “Hallux Rigidus”, in 1887.
Later, the term of “Hallux Limitus” was given in 1937, by Hiss, as
to describe the limited capasity of the hallux toe to dorsiflex on the
first metatarsophallangeal joint. Part of the definition includes the
inability of the hallux to dorsiflex on the first metatarsal head past
60 degrees, as an initial presentation. Coughlin and Shumas, (1999)
provided a radigraphical classification of this pathology. Up to
date, this classification is most used to describe the Hallux Limitus
/ Rigidus pathology . This classification starts with a Grade”0”,
as the first metatarsophallageal joint looses 20% of dorsiflexion
capasity, and is able to dorsiflex 40-60 degrees, and the X-Rays
on this joint are normal, and there is no pain. The classification
goes up to Grade “4” , where there is a “stiff joint” or ankylosis of
the metatarsophallangeal joint, with “loose body fragments” or
“OCD’s”. Hallux limitus / rigidus presents multi factorial causes
and ethiologic factors. Its ethiology is divide in Traumatic vs Nontraumatic
causes. A description of the non-traumatic ethiologic
causes will be mentioned as part of this article. Even thou
“arthrodesis of the first metatarsophalangeal joint” has become the
“gold standard” in the surgical approach to Coughlin stage 3 and
4 of hallux Limitus/Rigidus, there are other operative options that
offers a less agressive approach with better initial outcomes and
provides the patient with less post operative complications. This
article presents 22 cases of Hallux Limitus/ Rigidus patients foot
pathology treated with a combination of a first metatarsal distal
decompression osteotomy, a cheilectomy of the joint in question,
a mechanism to perform a full surgical release of the contracted /
fibrotic tissue surrounding the joint and the plantar sesamoids, and
the use a dermal allogenic scaffold graft to cover the first metatarsal
head and mantain the glidding mechanism after surgical correction.
These surgical interventions have been performaed in a two years
period , between January of 2009, and January 2011. A postoperative
“Modified Hallux-Metatarsophalangeal joint and Interphallangeal
Joint Scale” have not been yet finished , and thus , not provided
at the time this article / presentation is realised. age on patients
ranged from 34 to 70 years of age, with mean average age of 54
years of age. A postoperative patient pain / function / satisfaction
results is provided as a preliminary information for which all 22
patients responded to “possibly have the same surgery if the other
foot was involved with the same pathology”. All patients were able
to initiate full protected walking in a surgical shoe, within a period
of three weeks of the surgery. There has been no surgical revitions,
and minor complications of wound closure slight necrosis was seen
in two patients, which resolved promptly upon diligent in office
wound care. One patient had a moderate cellulitis / skin infection
that resolvedas well upon diligent local care and antibiotic therapy.
In all , (when compared to the gold standard “ joint arthrodesis”),
this surgical procedure provides the patient with Hallux Limitus /
Rigidus: a prompt recovery time, a reduced post surgical sequelae
of possible complications, a functional ability to use normal shoe
wear with orthoses, minimal bone loss in metatarsal or phallangeal
components of the affected joint, and no excessive internal fixation
hardware that may need to be removed.
Content: The use of a”Dermal Acellular Scafold” as a joint spacer
in the surgical treatment of Hallux Limitus / Rigidus has been
documented in literature by several authors. It has been classify as
an “Interpossitional Implant” and it has similar results to the use of
“Autogenous first metatarsal capsular/periosteum interpositional
grafting technique”, described in literature as well. All 22 patients
in this preliminary study received Dermal acellular cadaveric scafold
grafts from two different medical companies in the US: Wright
Medical , “Graft Jacket” non fenestrated grafts, and Stryker US ,
MMI non fenestrated acellular dermal grafts. All patients surgically
intervened had a “Coughlin Hallux Limitus/rigidus staging” 2 to 4
with respect to their first metatarsal arthritic disease progress. All
22 patients were surgically treated equally, with minimal alterations
in the surgical technique described. Steps in the surgical technique:
1. A longitudinal incision approach is done dorsal and medial to the
Extensor Hallucis Longus, measuring 6 cm in lenght. The incision
is carried down to the 1st metatarsal periosteum and crossing the
fist metatarsophallangeal joint into the base of the Halux proximal
phallanx. The ful thickness of the periosteum and capsule is elevated
surrounding the first metatarsal shaft, the metatarsal head , and the
base of the proximal hallux phallanx. 2. A “full cheilectomy” procedure
is performed around the joint, metatarsal head is completely
denuded of any abnormal osseous growth, including osteophytes
and deseased cartilagenous tissue surrounding the joint margins
and any fibrotic tisuue is as well removed. 3. A modified transverse
“V” osteotomy, (Austin or Chevron modified osteotomy), is produced
to the metatarsal head and distal metatarsal shaft. The osteotomy
addresses the “bunion deformity”, reducing the intermetatarsal
angulation between the first and second metatarsals, as well as
plantar-flexes the distal metatarsal head fragment, in order to
decompresss the diseased arthritic joint, and adrresses the issue of
a “first metatarsal elevatus” commonly seen in this pathology. This
osteotomy is rigidly fixated with 2.0 cortical screws. In some cases
whereas the bony tissue seemed soft / osteoporotic, a combination
of Kishner wires and 2.0 cortical screws were utilised for proper
fixation. 4. The deseased cartilage comprissing the metatarsal head
and the base of the hallux proximal phallanx, was repetitively drilled
with a .045” Kishner wire, so as to to create future vascular channels
between the subchondral vascular bed and the internal aspect of the
joint, where the “Acellular dermal graft” is to be applied. Copious
irrigation of the surgical area with normal physiological saline
solution is performed. 4. A Wright Medical “Graft Jacket” or a Stryker
MMI Dermal Acellular Graft measuring 4cm x6cm long was cut or
fashioned into a “ Cross fashion”. The 4 legs of this graft “Cross”
were applied around the first metatarsal head, and tightly fixated to
the first metatarsal head , proximal to the plantar head condyles or
surgical neck), with 2-0 vicryl suture material, in a “tie wrap” fashion.
The central aspect of the graft is well compressed against the internal
metatarsal head cartilagenous area. At no time grafting material was
left floating free in the joint. And no grafting material was applied to
the Hallux proximal phallanx. After affixing the dermal acellular graft,
the first metatarsophallangeal joint is re-articulated and the joint
dorsal extension and plantarflexion range of motion is examined,
making sure there is at least 70-80 degrees of dorsal extension of the
proximal phallanx upon the first metatarsal head. Also, making sure
there is available at least 30 degrees of plantarflexion of this joint. 5.
Closure of tissues is realised in layers. The periosteum and capsular
tissue is closed with 3-0 vicryl suture material. The superficial fascia
underlying the skin is closed with 4-0 vicryl suture material. The skin
is closed with 5-0 prolene suture material in a “horizontal matress”
stitching technique. 6. The closed surgical wound is infiltrated with
0.5% Marcaine plain local anesthetic, for post operative analgesia.
References:
1. Nicoladoni C. Uber zehenkontrakturen. Wien Klin Wochenschr
51:1418, 1881.
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3. Hiss JM: Hallux Valgus: Its cause and simplified treatment. Am J.
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6. Durrant MN, Siepert KK: Role of soft tissue structures as an
etiology of hallux limitus. JAPMA 83: 173, 1993.
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forefoot. Orthop Clin North Am 4:165, 1973.
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perspective. Clin Podiatr Med Surg 13: 449, 1996.
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classification for hallux limitus. J Foot Ankle Surg 32: 397, 1993.
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classification of hallux limitus and hallux rigidus, Lower Extremity
1:55,1994.
11. Mahan KT: „Joint Preservations Techniques in Hallux Limitus/
Rigidus Repair,“ in Musculoskeletal Deformities of the Lower
Extremities, ed by LM Oloff, p529, WB Saunders, Philadelphia,
1994.

12. Keogh P, Nagaria J, Stephens M: Cheilectomy for hallux rigidus. Ir
J Med Sci 161:681, 1992.
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J Bone Joint Surg Am 80: 1795, 1998.
15. Hamilton WG, O‘Malley MJ, Thompson FM, ET AL: Capsular
interposition arthroplasty for severe hallux rigidus. Foot Ankle Int
18: 68, 1997.
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functional capacity. J Foot Surg 21: 292, 1982.
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clinical, radiographic, and intra-operative features of hallux limitus
and hallux rigidus: short-term follow up and analysis. Paper presented
at the American College of Foot and Ankle Surgeons Annual Meeting
and Scientific Seminar, February 8, 2001, New Orleans.
19. Poussa M, Rubak J, Ritsila V: Differentiation of the
osteochondrogenic cells of the periosteum in chondrotrophic
environment. Acta Orthop Scand 52: 235, 1981.
20. O‘ Driscoll SW, Salter RB: The induction of neochondrogenesis
in free intra-articular periosteal autografts under the influence of
continous passive motion: an experimental investigation in the
rabbit. J Bone Joint Surg AM 66: 1248, 1984.
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in human cartilage repair tissue in autologous chondrocyte
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23. Hanft JR, Merrill T, Marcinko DE, ET AL: First metatarsophallangeal
joint replacement. J Foot ankle Surg 35: 78, 1996.
24. Haddad SL: the use of osteotomies in the treatment of hallux
limitus and rigidus. Foot ankle Clin 5: 629, 2000.
25. Feltham GT, Hanks SE, Markus RE: age -based outcomes of
cheilectomy for the treatment of hallux rigidus. Foot ankle Int 22:
192,2001.
26. Heller WA, Brage ME: the effects of cheilectomy on dorsiflexion
of the first metatarsophallangeal joint. Foot Ankle Int 18: 803,1997.
27. Grady JF, Axe TM: The modified Valenti procedure for the
treatment of hallux limitus, a long term follow-up and analysis. J Foot
Ankle Surg 38:123, 1999.
28. Ganley JV, Lynch FR, Darrigan RD: Keller bunionectomy with
fascia and tendon graft. JAPMA 76: 602, 1986.
29. Lau JTC, Daniels TR: Outcomes following cheilectomy and
interpositional arthroplasty in hallux rigidus. Foot Ankle Int 22:462,
2001.
30. Gusman DN, Messmer TE: Newell decompression procedure for
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31. Toolan BC, Wright-Quinones VJ, Cunningham BJ, ET AL: an
evaluation of the use of retrospectively adquired pre-operative
AOFAS clinical rating scores to asses surgical outcome after elective
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32. Roukis TS, Landsman AS, Et AL: Distally based capsule-periosteum
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tcnique, and short-term follow-up. JAPMA , Sept / Oct 2003, Vol 93,
No 5.
Acknowledgments:
Provided at lecture time due to writting space limitations.
Extended Abstracts 129
8.2.2
Expansion of chondrocyte populations on high extension culture
surfaces for improved retention of phenotype
T.M. Quinn 1 , B. Hinz 2 , M. Matmati 1 , D.H. Rosenzweig 1
1 Montreal/Canada, 2 Toronto/Canada
Introduction: Cell-based cartilage therapies such as autologous
chondrocyte implantation require isolation of chondrocytes
from a healthy tissue biopsy, population expansion in vitro and
implantation in a defect [1, 2]. During population expansion,
moderate chondrocyte densities must be maintained for
efficient cell growth [3]. However, contact inhibition can lead to
loss of phenotype and reduced proliferation [3, 4]. This limited
desirable range of cell densities means that in standard culture,
repeated passaging and reseeding of chondrocytes is required.
Passaging is associated with rapid changes in the chondrocyte
phenotype [5, 6]. This dedifferentiation decreases the capacity for
implanted chondrocytes to regenerate functional neocartilage and
necessitates additional protocols for redifferentiation toward the
desired phenotype. Improved understanding and control of factors
promoting dedifferentiation may therefore lead to significant
improvements in cell-based cartilage repair. To inhibit chondrocyte
dedifferentiation during population expansion, we have developed
a technique that facilitates more continuous growth of cells while
limiting contact inhibition and reducing the necessity for passaging
[7, 8]. Cells are grown at relatively high density on a continuously
expanding elastic dish which provides increasing culture surface
area as their population grows. This “continuous expansion” culture
technique has been used previously to expand human mesenchymal
stem cell populations more efficiently than by standard methods
while maintaining pluripotent stem cell phenotype and inhibiting
undesired fibrotic phenotypes [7, 8]. We hypothesized that
continuous expansion culture could also be beneficial for primary
chondrocytes.
Content: Materials and Methods
Knee joints from freshly slaughtered skeletally mature cows were
obtained from a local slaughterhouse. Articular cartilage was cut
from the femoropatellar groove with a scalpel, and chondrocytes
were isolated according to established methods [9].
Chondrocytes were cultured on several different surfaces. These
included (1) high-extension silicone rubber (HESR) dishes which were
continuously expanded, (2) standard polystyrene culture dishes, and
(3) polystyrene culture dishes coated with approximately 1 mm of
silicone rubber. All silicone rubber culture surfaces were chemically
modified to coat them with covalently bound collagen type I to
promote cell adhesion as previously described [7, 8].
To initiate cultures, 10,000 chondrocytes per cm2 were seeded and
subcultured in chondrocyte growth medium. Continuous expansion
(CE) cultures were performed on high extension silicone rubber (HESR)
dishes expanded from 12 cm2 to 76.8 cm2 over 10 days following a
3-day initial attachment period. Surface expansion was performed
using a motorized iris-like device. This 13-day period was defined
as one generation, which corresponded to three conventional 1:2
passages in standard (SD) culture on polystyrene. The final surface
area in CE culture equaled the total surface area of the third passage
in SD culture (8 wells at 9.6 cm2 each). Confluence at each passage
in SD culture was ~80% and 0.25% Trypsin-EDTA solution was used.
For experiments to control for silicone surface chemistry, standard
cultures were performed on polystyrene dishes coated with silicone
functionalized rubber (“static silicone” or SS cultures).
At the end of each generation in CE, SD or SS culture, cells were
trypsinized and counted. For a subsequent generation, 105 cells
were then reseeded. 106 cells resulting from each generation were
used for redifferentiation experiments (pellet cultures), and the
remaining cells (1-2x106) were used for analyses of gene and protein
expression. Cells were lysed in 1 mL of TRIzol reagent and RNA was
isolated for quantitative real-time PCR analysis. PCR primers for
collagen type II, aggrecan, COMP, Sox9, collagen type I, and GAPDH
were generated exactly as described elsewhere [10]. Western blot
analysis was also performed for alpha smooth muscle actin and
α-tubulin.
At the end of each generation, ~2×106 cells were centrifuged at
500×g for 10 minutes in 1.5 mL microfuge tubes, and pellet cultures
for assessment of de novo cartilage synthesis capacity were initiated
as previously described [7, 11, 12]. TGFβ was intentionally excluded
from redifferentiation medium in order to emphasize effects of CE
versus SD culture without the concern of overwhelming growth

130
Extended Abstracts
factor stimulation. Pellets were incubated in centrifuge tubes for six
days until they became firm and then transferred to a six-well plate
(which helped maintain viability) and incubated for an additional
six days to observe chondrocyte outgrowth. Medium was changed
every two days. Pellets were then fixed with 4% paraformaldehyde
and prepared for cryosectioning.
For histological analysis, pellet cultures were fixed in 4%
paraformaldehyde and embedded in tissue freezing medium. Frozen
sections 10 μm thick were stained with Alcian Blue for proteoglycan
and counterstained with Nuclear Fast Red. For immunofluorescence,
sections were incubated with antibodies against phospho-histone
H3, cleaved Caspase 3 and collagen type II, and visualized on an
inverted fluorescence microscope.
Results
Chondrocyte attachment on both static silicone (SS) and standard
polystyrene (SD) typically occurred by 3 days after seeding, at
which point experiments began (Day 0). Cell morphology appeared
similar for the two culture conditions during passaging. RNA-level
expression of the cartilage-specific genes collagen type II, aggrecan,
and cartilage oligomeric matrix protein (COMP) declined with each
passage number for both culture conditions while collagen type I
expression increased.
Chondrocytes in continuous expansion (CE) culture had a more
rounded and less spindle-like morphology than in SD culture. At the
end of generation G1, real-time quantitative PCR revealed significantly
higher expression of the cartilage-specific genes collagen type II,
aggrecan and COMP in CE versus SD culture. These trends remained
consistent through generations G2 and G3. In contrast, the fibrotic
marker collagen type I was significantly downregulated in CE versus
SD culture. Cell lysates from CE and SD cultures were subjected to
SDS-PAGE and Western blot probing for the fibrotic marker α-SMA.
SD culture lysates revealed a steady induction of α-SMA through the
three generations which was inhibited in the CE culture lysates for
generations G1 and G2. At the end of each generation, cell counting
revealed fewer total chondrocytes in CE culture compared to SD
culture.
Pellets derived from SD cultures strongly adhered to the culture
dish during the final 6 days of the 12-day pellet culture. In contrast,
pellets derived from CE cultures only weakly adhered. Moreover,
chondrocyte migration from adhered pellets was clearly evident for
all three generations of SD culture but only for generation G3 of CE
culture. CE pellets contained more sulphated glycosaminoglycans
compared to SD pellets, as evident by Alcian blue staining. After
generation G1, both CE and SD pellets stained strongly for collagen
type II immunofluorescence. However, after generations G2 and
G3, collagen type II immunofluorescence was only detectable in CE
pellet cultures.
Discussion
Cell morphology, cartilage-specific gene expression, fibrotic
gene expression, and cell numbers all indicated that continuous
expansion (CE) culture preserves the chondrocyte phenotype during
population expansion. Standard (SD) culture chondrocytes exhibited
a spindle-like morphology characteristic of a more fibroblastlike
phenotype compared to the more rounded chondrocyte-like
appearance evident in CE culture. RNA-level expression of collagen
type II, aggrecan and COMP were consistently upregulated in CE
versus SD culture while RNA-level expression of collagen type I and
protein-level expression of α-SMA were downregulated, indicative of
less dedifferentiation. Consistent with improved preservation of the
chondrocyte phenotype and associated reduced proliferation rates,
fewer chondrocytes were obtained from CE culture at the end of
each generation. Nevertheless, ample numbers of chondrocytes can
still be generated in CE culture for clinical application in cell-based
therapies.
Chondrocytes from CE culture were superior to those from SD
culture with respect to their ability to redifferentiate toward a mature
chondrocyte phenotype. Pellets from SD culture readily attached to
culture surfaces and exhibited dramatic outgrowth of chondrocytes,
indicating they had transitioned to a more fibroblastic cell type.
In contrast, pellets from CE culture were better able to generate
neotissue with more nonadhesive, cartilage-like characteristics.
Both SD and CE pellets initially were able to produce GAG and
collagen type II, however only CE pellets maintained this production
through three generations.
The only differences between CE and static silicone (SS) cultures
were the application of mechanical surface expansion in CE culture,
compensated by more frequent enzymatic passaging in SS culture. In
two generations, SS cultures were passaged five times compared to
once in CE cultures, and CE cultures exhibited significantly superior
retention of chondrogenic phenotype versus SS cultures, and also
superior redifferentiation capacity for production of cartilage-like
neotissue. The mechanical expansion aspect of CE culture and its
reduction of the need for passaging therefore appears to specifically
contribute to enhancement of the phenotype of chondrocytes
cultured for cell-based therapies.
A factor by which CE culture inhibits dedifferentiation may be
associated with reduced passaging and limited exposure to
degradative enzymes. Considering that passaging involves repeated
nonspecific degradation of cell surface proteins and receptors and
the frequent need for wholesale re-establishment of cell-surface
attachments, this is perhaps not surprising. Minimization of the
need for passaging also has important practical advantages: more
easily automated methods reduce the need for human intervention
and handling of cells. These features likely decrease the risk of error
and bacterial contamination over long-term cultures.
Physical factors contributing to chondrocyte phenotype preservation
in CE culture may also include mechanical signalling. Dynamic strain
or compression can have positive effects on the phenotype of
cultured chondrocytes [13, 14], particularly regarding proteoglycan
synthesis [15, 16]. In contrast to situations involving oscillatory
dynamic strain, CE culture chondrocytes experience very slow
but very high amplitude (over 600%) stretch applied steadily and
monotonically over the course of several days. Further studies of
the mechanotransduction pathways active during slow, continuous
strain may therefore yield insights into how CE culture preserves
chondrogenic phenotype compared to conventional passaging.
In addition, opportunities remain for optimization of CE culture by
superimposed dynamic stimulation of cells during growth.
The cell signalling mechanisms involved in more advanced
chondrocyte dedifferentiation downstream of increased enzymemediated
passaging remain unclear, but several candidate
mechanisms have been identified. Interleukin-1 (IL-1) production
increases with chondrocyte passaging [5], and IL-1 signalling is
directly involved in chondrocyte dedifferentiation [17]. Other studies
have indicated that passaged and dedifferentiated chondrocytes
display degradation of the receptor of hyaluronic acid, CD44 [18].
Disruption of CD44 signalling in chondrocytes results in receptor
cleavage, decreased expression of chondrogenic genes, and
decreased production of sulphated-GAG [19]. IL-1 activity and CD44
expression may therefore participate in the mechanisms by which CE
culture improves maintenance of cartilage phenotype.
Continuous expansion culture represents a significant departure
from standard methods used for chondrocyte expansion. Given the
economic and therapeutic importance of the final product, these
fundamental changes to decades-old methods of cell culture may
nevertheless be warranted.
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1. Batty L et al. ANZ J Surg 2011;81:18-25.
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19. Takahashi N et al. Arthritis Rheum 2010;62:1338-48.
Acknowledgments:
Supported by the Collaborative Health Research Program (CIHR/
NSERC) grant #1004005 to TMQ and BH, and Natural Sciences and
Engineering Research Council (NSERC) Discovery Grant #342320-07
to TMQ, a Canada Research Chair in Soft Tissue Biophysics to TMQ,
and the Canadian Institutes of Health Research grant #210820 to BH.
We also thank Ghazaleh Khayat and Sidharth Chaudhry for technical
assistance.
8.2.3
2D and 3D cultures of chondrocytes
T.J. Klein
Brisbane/Australia
Introduction: Chondrocytes normally reside in relatively low density in
a dense network of extracellular matrix. The resident chondrocytes are
responsible for growth, maturation, and remodelling of the articular
cartilage to ensure its function in a mechanically challenging environment.
Chondrocytes have a long lifespan and proliferation is normally not
appreciable. Further, this thick tissue is not vascularised or innervated.
As a consequence of these factors, cartilage does not regenerate when
damaged, leading eventually to large-scale degeneration, in osteoarthritis.
As osteoarthritis is one of the major causes of disability and loss of quality
of life, understanding how the chondrocytes work, and whether they can
be coaxed to form a more robust repair tissue has been and continues to
be a major research interest.
To probe the behaviour of chondrocytes in detail, a number of in vitro
model systems have been developed. Pioneering work in chondrocyte
culture was carried out by Holtzer, et al., in a series of publications starting
in 1960 [1]. In these studies, chondrocytes were enzymatically removed
from their matrix and plated onto two-dimensional surfaces or on fibrin
clots as a differentiation model. Through these works, it became apparent
that chondrocytes lose their differentiation status (de-differentiate) in 2D
culture, and also their differentiation capacity after such culture. Further
studies showed that once chondrocytes reach a high enough density,
they can re-differentiation, marked by an increase in glycosaminoglycan
accumulation and synthesis rates [2]. In a seminal paper by Benya and
Shaffer, it was shown that 2D-cultured chondrocytes can revert back to
the original phenotype when embedded in a 3D (agarose) matrix [3]. This
has led to many advances in understanding of chondrocyte biology and
also in the development of biomaterials for chondrocyte culture. One key
aspect of the 3D culture system is the accumulation of extracellular matrix.
This has led to the development of tissue engineering-based therapies
for treatment of patients with cartilage defects [4 5], which is the ultimate
utilitarian goal for chondrocyte research.
It has become apparent through decades of research that the natural
microenvironment, or niche, is critical for maintaining the native phenotype
of cells, including stem cells and differentiated cells such as chondrocytes.
Thus, recapitulating this niche in vitro is an important aim [6]. The
chondrocyte niche includes a low oxygen tension, a range of physical
stresses, growth factors, enzymes and cytokines, and a surrounding of
extracellular matrix. Considering the complexity of the niche, it is unlikely
that cell biologists, material scientists, tissue engineers, etc., will able to
incorporate all of these factors. Therefore, simplified model systems that
take into account the critical parts of the niche have been developed. This
paper will review some of the current 2D and 3D chondrocyte culture
systems.
Content: 2-dimensional Cultures:
2-dimensional (monolayer) cultures are the simplest, and most pervasive
throughout the cell culture community. They provide excellent opportunities
Extended Abstracts 131
for imaging, controlling oxygen and other culture media conditions,
and harvesting cells for biochemical analyses. They also allow for major
expansion of cell numbers, which can be needed for clinical use and also
for experimental studies. However, there are some severe limitations, most
notably in the dedifferentiation of chondrocytes during their expansion [7].
This phenomenon has been repeatedly documented on a gene and protein
basis. Thus, studies involving 2D cultured chondrocytes must always keep
in mind that the cells are no longer behaving as they would in the cartilage,
and therefore the conclusions drawn by changing experimental conditions
may not be valid in vivo.
There are options for controlling the niche within a 2D system. In one
instance, the material properties of the surface can be varied by either
using another material or functionalizing the base material with synthetic
or biological ligands. This has been shown to have some positive effects
through changing the binding mechanisms [8]. Another option is to
change the mechanical properties of the cell substrate. It is clear from
work with MSCs, especially, that the stiffness of the substrate can affect
the cell differentiation status [9]. A third option is to vary the cell seeding
density. High density (e.g. >= 100,000 cells/cm^2) limits proliferation
and results in a more chondrocyte-like cell. The microenvironment can
also be modified by inclusion of additional cell types, which could include
mesenchymal stem cells, or cells from a specific zone of cartilage [10].
Despite advances in functionalisation of 2D surfaces, they are inherently
limited by their 2D nature. Irrespective of surface treatments, only part of
the cell will be in contact with the functionalized surface, leaving the rest in
an unnatural state that does not favor a round chondrocyte shape.
3-dimensional Cultures:
3-dimensional cultures offer the most options for developing an appropriate
chondrocyte niche, and are needed for advancing cartilage repair methods.
The simplest and oldest method is the micromass pellet, where a large
number of chondrocytes are centrifuged and allowed to interact and form
a small neo-tissue. This method has proven useful for determining the
chondrogenic potential of different cell types, as well as the influence of
different media additives on cartilage formation. Taken one step further,
cells can be seeded onto microporous membranes to form tissue disks or
other shapes[11], which could be potentially useful in vivo. This has been
shown to be useful in generating tissues with depth-dependent properties
that are functionally important in the natural cartilage [12 13]. One asset of
this method is that there is no exogenous biomaterial, so degradation and
other common issues with scaffold-based approaches are avoided.
The most versatile and rapid approach is the use of hydrogels. Hydrogels
have been used to encapsulate cells for several decades [2 3 14], and
more and more hydrogels incorporating different functionalities continue
to emerge. Interestingly, still many of the best results in terms of matrix
accumulation come from the use of simple polysaccharide gels (e.g.
alginate), in comparison to more complex degradable synthetic gels
[15]; it remains to be seen why this is. Alginate-agarose [4] and collagen
gels are already in clinical use [5], and fibrin gel is commonly used as a
sealant in clinical application, where it likely plays a larger role than a
simple glue. Synthetic hydrogels, or those combining synthetic and
natural components have great potential for both understanding the best
conditions for chondrogenesis, but also the application in large clinical
defects. Over the past several years, photo-sensitive hydrogels have been
introduced as a simple, reproducible, and fast way to generate 3D neotissues
and apply them in a minimally invasive manner [16]. Incorporation
of extracellular matrix components [17 18], and/or selectively releasable
adhesion motifs appears to be useful for improving the cartilage formation
in these photocrosslinkable gels [19]. There currently is a large toolbox
of techniques we can use to customize our hydrogel niche. Additive
manufacturing techniques can further be used for fabrication of specific
sizes and shapes to fit defects or interaction between specific cell types in
defined geometries and biomaterials [20].
What is the best model?
As models become sophisticated, we must constantly question the value
of the current and newly developed models. What is the benefit of each
model? How will the new model advance our understanding of chondrocyte
biology, cartilage formation, and/or cartilage repair? There can be different
best models for different research questions, and our ever-increasing
knowledge of cells, materials, and their interactions will facilitate model
improvement. Finally, we must keep in mind the clinical aim to ensure that
these models are translatable to the clinic.
References:
1. Holtzer H, Abbott J, Lash J, Holtzer S. The Loss of Phenotypic Traits by
Differentiated Cells in Vitro, I. Dedifferentiation of Cartilage Cells. Proc

132
Natl Acad Sci U S A 1960;46(12):1533-42.
Extended Abstracts
2. Abbott J, Holtzer H. The loss of phenotypic traits by differentiated
cells.
3. The reversible behavior of chondrocytes in primary cultures. J Cell
Biol 1966;28(3):473-87. 3. Benya PD, Shaffer JD. Dedifferentiated
chondrocytes reexpress the differentiated collagen phenotype when
cultured in agarose gels. Cell 1982;30(1):215-24.
4. Selmi TA, Verdonk P, Chambat P, Dubrana F, Potel JF, Barnouin L, et
al. Autologous chondrocyte implantation in a novel alginate-agarose
hydrogel: outcome at two years. J Bone Joint Surg Br 2008;90(5):597-
604.
5. Schneider U, Rackwitz L, Andereya S, Siebenlist S, Fensky F, Reichert J,
et al. A prospective multicenter study on the outcome of type I collagen
hydrogel-based autologous chondrocyte implantation (CaReS) for
the repair of articular cartilage defects in the knee. Am J Sports Med
2011;39(12):2558-65.
6. Lutolf MP, Gilbert PM, Blau HM. Designing materials to direct stem-cell
fate. Nature 2009;462(7272):433-41.
7. Darling EM, Athanasiou KA. Rapid phenotypic changes in passaged
articular chondrocyte subpopulations. J Orthop Res 2005;23(2):425-32.
8. Mahmood TA, Miot S, Frank O, Martin I, Riesle J, Langer R, et al.
Modulation of chondrocyte phenotype for tissue engineering by
designing the biologic-polymer carrier interface. Biomacromolecules
2006;7(11):3012-8.
9. Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem
cell lineage specification. Cell 2006;126(4):677-89.
10. Blewis ME, Schumacher BL, Klein TJ, Schmidt TA, Voegtline MS, Sah
RL. Microenvironment regulation of PRG4 phenotype of chondrocytes. J
Orthop Res 2007;25(5):685-95.
11. Han E, Bae WC, Hsieh-Bonassera ND, Wong VW, Schumacher BL,
Gortz S, et al. Shaped, stratified, scaffold-free grafts for articular cartilage
defects. Clin Orthop Relat Res 2008;466(8):1912-20.
12. Sun Y, Kandel R. Deep zone articular chondrocytes in vitro express
genes that show specific changes with mineralization. J Bone Miner Res
1999;14(11):1916-25.
13. Klein TJ, Schumacher BL, Schmidt TA, Li KW, Voegtline MS, Masuda K,
et al. Tissue engineering of stratified articular cartilage from chondrocyte
subpopulations. Osteoarthritis Cartilage 2003;11(8):595-602.
14. Guo JF, Jourdian GW, MacCallum DK. Culture and growth characteristics
of chondrocytes encapsulated in alginate beads. Connect Tissue Res
1989;19(2-4):277-97.
15. Klein TJ, Rizzi SC, Schrobback K, Reichert JC, Jeon JE, Crawford RW,
et al. Long-term effects of hydrogel properties on human chondrocyte
behavior. Soft Matter 2010;6:5175-5183.
16. Elisseeff J, Anseth K, Sims D, McIntosh W, Randolph M, Langer R.
Transdermal photopolymerization for minimally invasive implantation.
Proc Natl Acad Sci U S A 1999;96(6):3104-7.
17. Bryant SJ, Arthur JA, Anseth KS. Incorporation of tissue-specific
molecules alters chondrocyte metabolism and gene expression in
photocrosslinked hydrogels. Acta Biomater 2005;1(2):243-52.
18. Salinas CN, Anseth KS. Decorin moieties tethered into PEG networks
induce chondrogenesis of human mesenchymal stem cells. J Biomed
Mater Res A 2009;90(2):456-64.
19. Kloxin AM, Kasko AM, Salinas CN, Anseth KS. Photodegradable
hydrogels for dynamic tuning of physical and chemical properties.
Science 2009;324(5923):59-63.
20. Melchels FPW, Domingos MAN, Klein TJ, Malda J, Bartolo PJ,
Hutmacher DW. Additive manufacturing of tissues and organs. Progress
in Polymer Science 2011;Accepted 18/11/2011.
Acknowledgments:
I would like to acknowledge the Australian Research Council for funding,
and members of the Cartilage Regeneration Laboratory for their hard
work and support.
8.3.1
Intervertebral Disc Tissue Engineering: Is it ready for weight
bearing?
R. Kandel
Toronto/Canada
Introduction: Degeneration of the intervertebral disc, which is
composed of the annulus fibrosus (AF), nucleus pulposus (NP),
and cartilage endplates, causes loss of disc function and can be
associated with low back pain (1,2). Approximately 1 in 50 individuals
become disabled by intervertebral disc degeneration; the annual
total costs, which in 2004 in the United States alone, was estimated
at over $100 billion. There is a growing consensus that the surgical
treatments used currently for disc degeneration are not effective
and cannot be further optimized; thus there is great interest in
developing a biological therapy to treat the chronic pain that arises
from disc degeneration (1,3).
Content: Biological repair or replacement results in tissue that
can remodel and respond to load, an outcome not achievable by
current surgical therapies. Many different approaches to disc repair
are being investigated. However a recent study raised concern
about intradiscal injections and their potential to contribute to
disc degeneration so a particular interest has developed in the use
of regenerative medicine to generate an intervertebral disc that
structurally and functionally resembles the in vivo disc (4). To date,
we have advanced significantly towards accomplishing this goal.
Studies have described the formation of the nucleus pulposus tissue.
However we do not yet know whether we require the presence of
both nucleus pulposus cells and notochordal cells in this tissue or
whether generating tissue by just nucleus pulposus cells alone will
be sufficient to form tissue of appropriate quality to withstand weight
bearing over the long term. Investigation into the role of notochordal
cells in nucleus tissue is a subject of intense investigation currently
and much attention is directed towards trying to develop methods
to obtain pure populations of these cells. In contrast engineering
the annulus fibrosus has been more problematic given its complex
structure. The annulus fibrosus surrounds the nucleus pulposus
and has a cross-ply laminate structure consisting of between 10-
25 lamellae, each composed of collagen fibres oriented parallel to
each other and about 65o from the vertical, so every second lamella
has the same orientation. Various approaches have been utilized to
generate annulus fibrosus tissue ranging from the use of allograft
tissue to in vitro generated annulus fibrosus tissue. (5,6). Annulus
fibrosus cells are very responsive to their microenvironment. Our
recent studies have shown that how a scaffold is pre-treated, such as
coating it with fibronectin versus collagen or the amount of tension
the cells experience can affect annulus cell and collagen alignment
and thus tissue formation. Clearly creating annulus fibrosus tissue
will require more study. An additional issue to be considered is
ensuring that all the necessary components of the disc are replaced.
It likely will not be sufficient to replace only the annulus fibrosus
and nucleus pulposus as studies have shown that an intact cartilage
endplate may be necessary for maintenance of the nucleus pulposus
tissue. Co-culture of in vitro-formed nucleus pulposus tissue with in
vitro-formed cartilage resulted in increased aggrecan and collagen
gene expression compared with that in NP tissue grown alone. In
addition there was reduced expression of degradative enzymes,
MMP-3, MMP-13, and ADAMTS-5. Expression of genes for tumor
necrosis factor α (TNFα) and TACE in nucleus pulposus cells was
higher when grown in the absence of cartilage and corresponded
with increased TNFα protein levels. This suggests that chondrocytes
may secrete a factor(s) that inhibits TNFα production and positively
enhances tissue maintenance. Loss of the cartilage endplate could
be a potential mechanism explaining how changes in this tissue
may contribute to the development of NP degenerative changes and
suggesting that part of the disc replacement strategy must include
repairing the cartilage endplate. Identifying a cell source to generate
the different disc tissues is also another issue. Use of autogenous
cells may be a problematic as studies in nucleus pulposus tissue
engineering demonstrate that although nucleus pulposus tissue can
be formed by the nucleus cells obtained from older animals (cows),
they formed less tissue compared to cells obtained from younger
animals (younger than adolescents). Interestingly the older cells had
lower constitutive gene expression of collagen type II and aggrecan
whereas collagen type I and link protein levels were similar to those
of the younger cells. Metalloprotease (MMP) 13 gene and protein
expression increased with age. There was no change in the levels of
gene expression of MMP 2 and TIMP 1, 2, or 3 with age. Thus cells
obtained from nucleus pulposus tissue harvested from younger or
mature animals showed both genotypic and phenotypic differences
in vitro. Although these changes may be circumvented by gene
therapy the use of other sources of cells, such as stem cells, are

eing explored. Until we have markers that are definitively specific
to the cells of the different disc tissues it will not be possible to use
stem cells. Finally the method to implant the biological replacement
will have to be developed. The surgical approach will have to be
optimized and then it will be necessary to ensure that the implanted
disc will integrate to bone in the presence of weight bearing. Clearly
although a biological disc replacement is not yet available we appear
to be making great progress, and in some ways moving faster than
that of cartilage tissue engineering. Furthermore our attempts to
create a disc have provided insights as to the biology of the disc
and some of the requirements that may be critical to successful
generation of an intervertebral disc. In the interim to ensure rapid
translation into clinical practice once a biological disc replacement
has been developed we should also be turning our attention to
determining who would be a candidate for such a treatment, what
is the optimal rehabilitation regimen, and how to define a successful
outcome for those receiving a disc replacement.
References:
1) Raj PP. Pain Pract. 2008; 8(1):18- 24.
2) Cheung K et al. The Spine J. 2010;10, 958-60.
3) Kandel et al. Eur Spine J Suppl 2008; 4:480-91.
4) Carragee EJ, Don AS, Hurwitz EL, Cuellar JM, Carrino JA, Herzog R.
Spine (Phila Pa 1976). 2009;34:2338-45.
5) Bowles RD et al. PNAS 2011;108:13106-11
6) Luk KD and Ruan RK. Eur Spine J. 2008 Suppl 4:504-10.
Acknowledgments:
This work was supported by a grant from CIHR # MOP 114991.
8.3.2
Current clinical treatment strategies and future concepts
S. Daisuke
Kanagawa/Japan
Introduction: The intervertebral disc (IVD) functions as an essential
load absorber between all vertebrae by allowing bending, flexion, and
torsion of the spine. IVD degeneration is a cell-mediated response to
progressive structural failure and causes instability of the vertebral
motion segments that are responsible for neural compressive
manifestations and low back pain. Prolonged segmental instability
eventually leads to deformity of the spine and many clinical
problems. Current clinical concept, their limitations, and progress of
future treatment investigations will be presented.
Content: Treatment usually begins with non-operative modalities,
such as physical therapy or methods for core strengthening;
symptomatic medical treatment with non-steroidal anti-inflammatory
medications is a further common method to reduce pain. Surgical
methods are considered if conservative therapy fails. Although only
a small percentage of patients with disc disorders finally will undergo
surgery, spinal surgery has been one of the fastest growing
disciplines in the musculoskeletal field in recent years. Nevertheless,
current treatment options are still a matter of controversial
discussion. The standard surgical intervention has been spinal
arthrodesis with the aim to immobilize the spinal segment, preferably
by bony fusion. The aim is to cease mechanical cues and inflammatory
processes causing pain and disability. However, compared to
conservative treatment only small benefits could be achieved, as
assessed in several clinical studies. In addition, the occurrence of
adjacent segment disease should not be underestimated. With the
goal to better preserve the biomechanics of the spine, total disc
replacement has been introduced and has become part of surgical
routine in recent years. Since this technology has not been able to
demonstrate any significant advantage to the standard spinal
arthrodesis and in contrast has faced considerable complication
rates, it has been critically debated. Other newer technologies
include nucleus pulposus replacement or dynamic stabilization
methods. Long-term clinical outcomes that may disclose any
potential benefit of these new methods are not yet available;
however the long-term success rates of all these procedures are
Extended Abstracts 133
estimated to be generally similar. Although in the main satisfying
results can be achieved, all these treatment methods attempt to
reduce pain but cannot repair the degenerated disc. In particular,
they hardly can restore normal spine biomechanics and prevent
degeneration of adjacent tissues. Therefore new treatments are
under development with the aim to restore disc height and
biomechanical function. The objective of such new regenerative
strategies is to generate healthy disc tissue or functional
replacements that decelerate or reverse painful degeneration
processes. A number of biological approaches such as molecular,
gene, and cell based therapies have been investigated and have
shown promising results in both in vitro and in vivo studies. Recently,
cell transplantation based on the supplementation of matrixproducing
cells in an attempt to correct the decrease of matrix
components, primarily proteoglycan and collagen, a major factor in
disc degeneration has been under clinical trial. The concept goes
back to 1996, when Mochida et al. demonstrated the importance of
preserving NP elements for preventing the acceleration of disc
degeneration following discectomy. This clinical study opened a new
area of research into replacement of the cells lost by pathological
manifestations or surgical intervention, potentially retarding the
progression of disc degeneration. To test this hypothesis, an animal
model study, performed by Nishimura and Mochida, demonstrated
that reinsertion of autologous fresh or cryopreserved NP cells slowed
degeneration in the rat IVD. Numerous subsequent studies have
reported the efficacy of cell transplantation therapy using various
animal models and donor cell types. The author’s lab has studied the
potential of MSCs as an alternative cell source. They transplanted
autologous MSCs tagged with the gene for green fluorescent protein
(GFP) in rabbit disc degeneration model created by nucleus
aspiration, and followed the GFP-labelled cells for a period of 48
weeks, tracking the effects using MRI and radiography. They also
used immunohistochemistry for chondroitin sulphate, keratin
sulphate, collagen types I, II, and IV, HIF-1alpha and beta, HIF-2alpha
and beta, glucose transporters GLUT-1 and GLUT-3, and MMP-2, and
applied RT-PCR to assess expression of the genes for aggrecan,
versican, collagen types I and II, IL-1b, IL-6, TNF-alpha, MMP-9, and
MMP-13. MRI and radiographic results confirmed the regenerative
effects of the procedure. GFP-positive cells were detected in the
nucleus throughout the time course at proportions rising from 21% ±
6% at 2 weeks to 55% ± 8% at 48 weeks, which demonstrated the
survival and proliferation of MSCs. Immunohistochemistry showed
positive staining for all proteoglycan epitopes and type II collagen in
some of the GFP-positive cells. MSCs produced HIF-1alpha, MMP-2,
and GLUT-3 with phenotypic activity comparable to NP cells. The RT-
PCR demonstrated significant restoration of aggrecan, versican, and
type II collagen gene expression, and significant suppression of TNFalpha
and IL-1b expression in the transplantation group. Thus, MSCs
transplanted into degenerating discs in vivo can survive, proliferate,
and differentiate into cells expressing the phenotype of NP cells with
suppression of inflammatory genes. In order to achieve a maximal
effect in stem cell therapy for IVD disease, knowledge on cells,
extracellular matrix and the microenvironment of the native disc
must be extensively studied. Fully committed adult cells are cells
that actively function as main cell population eventually going into
apoptosis. Other than committed adult cells are the tissue specific
somatic progenitor/stem cells which are an undifferentiated cells
found among differentiated cells in tissue or organ that can renew
itself. Stem cells are distributed around the body in various other
‘niches’. Evidence of existence of the small stem cell population has
not been well studied in the IVD. In order to identify the somatic stem
cell population that reside in the IVD, “stem cell markers” were
immunohistochemically analyzed in rat, beagle and human IVDs.
The immunohistochemical analysis in rat IVD specimens revealed
that most of these classical stem cell markers may not be useful in
identifying endogenous stem cells in the disc. Especially, positivity
of the hall mark markers CD90, CD105 and CD 166 was 85, 92 and 98
percent (n=5). This was far different from the standard characteristics
of stem cells which reside in small population with inactive cell
viability at rest and after initiation, shows high self-renewal and
proliferative ability with multi-potent differentiation. Regarding
other markers, no significant expression (0-10percent) was detected
for CD56, CD120a CD124 MHC class I, etc. in the rat disc, which may
remain these markers as potential candidates. To note, negative
expression in some of these markers may be a result of non-cross
reactivity of the antibody to the rat. Result of human disc specimens
showed that CD56, 90 105,166 was expressed in some young disc
cells in sparse areas, such as NP cells forming clusters but in old
aged disc where cells are isolated in single cells, merely none of
these markers were positive in most discs. To overcome the lack of
stem cell population indicated by the results, identification of
progenitor cells by marker analysis was continued through FACS
analysis. By plotting the positivity of these markers through serial
culture periods, we are able to detect cell markers which correlate

134
Extended Abstracts
with cell proliferation. As mentioned, stem/progenitor cell
populations show little or decreased cell number at primary culture
and give rise to rapid proliferation several weeks after, meaning
potential for high self-renewal. We also found that by culturing
beagle NP cells in gels, several different colonies can be induced.
These included sphere shaped colony and few adherent colonies.
Number of adherent colonies increased with time with no change
with culture period. On the other hand, change in number of sphere
colonies formed showed correlation with proliferation curve pattern
of progenitor cells. These findings provide useful information on the
progenitor cell population in the IVD. Collectively, new techniques
based on rigorous animal studies and clinical trials are on the way to
be brought into future treatment of the intervertebral disc
degeneration. Uncovering of cells and their microenvironment is
needed to be investigated in parallel for obtaining maximal efficacy
and safety.
References:
1. Alini M, Sakai D, Eglin D, et al. Cells and Biomaterials for
Intervertebral Disc Rgeneration. Synthesis Lectures on Tissue
Engineering. Morgan and Claypool Publishers. 2010; 1-104. 2. Sakai
D. Stem cell regeneration of the intervertebral disk. Orthop Clin
North Am. 2011;42(4):555-62.
Acknowledgments:
This work was supported in part by a Grant-in-Aid for Scientific
Research and a Grant of The Science Frontier Program from the
Ministry of Education, Culture, Sports, Science and Technology of
Japan and a grant from AO Spine International.
8.3.3
Materials for intervertebral disc tissue engineering
R. Mauck, M.B. Fisher, D.M. Elliott
Philadelphia/United States of America
Introduction: Intervertebral disc (IVD) degeneration is linked to
multiple causal factors, including age and genetics, mechanical
fatigue, injury through trauma, continued exposure to vibrational
loading, and mechanical overload. Disc degeneration progresses
over time and impacts a large percentage of the world population.
Low back pain in the U.S. is widespread in the general population,
and limits activity in more than 50% of the population over the age
of 55 [1]. Lumbar disc degeneration has been strongly implicated
as a causative factor in low back pain [2], and neither conservative
treatments (stretching and exercise) nor surgical options (discectomy,
fusion, and arthroplasty) restore disc structure or mechanical
function. Indeed, fusion permanently locks adjacent vertebral bodies
in place, while disc arthroplasty is relatively new to clinical practice
and will likely suffer from the same problems as traditional implant
materials – wear and the need for eventual replacement. As such,
biomaterial and biologic interventions to regenerate a degenerate
IVD would have a distinct competitive advantage over current clinical
procedures, while also potentially reducing painful conditions and
delaying or preventing the need for spinal fusion or replacement.
This talk will focus on the critical structure-function relationships of
the native disc, with a particular focus on the annulus fibrosus, and
highlight emerging biomaterials and cell-based methods designed
to foster regeneration and/or produce functional analogues for the
repair and/or replacement of this unique load-bearing structure.
Content: The IVD is composed of the nucleus pulposus (NP), a
hydrated, gelatinous structure, and the annulus fibrosus (AF), a
multi-lamellar fibrocartilage that surrounds the NP between the
vertebral bodies. The NP is structurally and mechanically isotropic
and contains a network of type II collagen interspersed with
proteoglycans, resulting in high water content within the tissue.
Conversely, the fibrocartilaginous AF has a high degree of structural
organization over multiple length scales: aligned bundles of collagen
fibers reside within each lamella and the direction of alignment
alternates from one lamella to the next by 30° above and below the
transverse plane [3, 4]. The resulting angle-ply laminate possesses
pronounced mechanical anisotropy and nonlinearity, allowing the AF
to support tension, shear, compression, and torsion [5]. The NP and
AF regions work in concert; when the disc is compressed, hydrostatic
pressure in the NP increases, resulting in stresses along the
circumferential direction of the AF, which are in turn resisted by the
organized lamellar AF structure. Injury or degeneration to either
portion of this composite can compromise overall disc mechanical
function, and as such, methods have been devised to address failure
in either or both components. While disc degeneration can originate
in multiple locations, tears within the AF region are especially
pernicious as they can propagate to the NP region, eventually
resulting in complete tears involving leakage of the NP (disc
herniation). Along with herniation, there is often a loss of annulus
tissue [6, 7]. In fact, annular tears are seen in more than half of the
patients in early adulthood and are found in the majority of the
elderly [8]. Yet, the most common surgical treatment for disc
herniation, e.g. microdiscectomy, does nothing to repair the AF,
which has a limited intrinsic healing potential [9]. As such,
reherniation rates following these procedures can range from 5-15%
[10-13], compromising long term disc health. Given the prevalence of
low back pain associated with damage or degeneration of all or part
of the IVD, a host of products and devices have been developed, with
some reaching the commercial market. These include products that
restore pressurization in the NP region or mechanically augment the
torn AF (i.e., suture, meshes, and reinforcing barriers) [7, 14]. While
such approaches have shown promise in cadaveric studies, those
focused on the AF do not recapitulate the structure or function of the
native tissue, and thus, abnormal loading and continued degeneration
may occur. Furthermore, the majority of these devices are inert,
preventing integration with the native disc. Given these limitations
in current commercial devices and clinical methods, a number of
tissue engineering and regenerative medicine approaches have
been pursued (for review, see [5]). These approaches have focused
on the AF, the NP, or a combination of the two. In most cases, the
disc is separated into an NP region containing chondrocyte-like cells
and an AF region containing fibroblast-like cells. These cellular subpopulations
have been seeded in a variety of tissue engineering
scaffolds or hydrogels to evaluate their ability to reconstitute the
histological structure and composition of native tissue [15-19].
Scaffolds have included alginate and agarose hydrogels, collagen
gels, collagen/glycosaminoglycan gels, collagen/hyaluronic acid
scaffolds and collagen sponges, to name but a few [20-25]. These
and other studies have established that disc cells can be maintained
in three dimensional culture, that they produce plentiful ECM with
time, and that certain mechanical, biological, and structural cues
may foster construct maturation (i.e., a hydrogel for the NP and a
porous/fibrous scaffold for the AF). More recently, multi-potential
mesenchymal stem cells (MSCs) have been employed in a number of
these scaffolding systems, with evidence of disc-like matrix formation
in these 3D biomaterial contexts [26]. While these studies highlight
the potential to generate disc-like neo-tissue by combining cells and
scaffolds, for many years, little consideration was given to the
mechanical properties and function of these engineered materials
within a load bearing environment. The mechanical requirements for
an engineered disc construct will depend largely on its intended
location and use. An AF ‘patch’ would be expected to integrate across
an AF fissure, resist further NP herniation, and transfer tensile forces
with disc compression. An NP construct would be expected to fill the
central region of the disc and pressurize and engage the AF with
loading. A total biologic disc replacement would be expected to carry
out both of these critical functions, while also integrating seamlessly
with the surrounding vertebral bodies. Depending on application,
these materials or constructs might be required to match native
tissue at the time of implantation (if early remobilization is expected)
or could conceivably mature in place to match these properties (if a
period of protection from loading were possible). In either format or
application, these engineered materials would eventually be
expected to withstand dynamic mechanical loading (at multiple body
weights) in multiple directions, consistent with the complex and
demanding loading environment of the disc with normal activities.
While these requirements may seem insurmountable, the last
decade has borne witness to marked progress in the area of disc
tissue engineering. For example, in seminal work in the field,
Bonassar and colleagues created a composite disc by encapsulating
NP cells in an alginate hydrogel surrounded by an AF cell-seeded
random fibrous scaffold of polylactic acid reinforced polyglycolic
acid [27, 28]. After 16 weeks of subcutaneous implantation,
biochemical content of these disc-like constructs approached native
levels, and, importantly, compressive mechanical properties
increased with time [27]. More recently, using a collagen-gel annular
region along with an alginate NP region, both seeded with disc cells,
this same group reported on the long term (>6 month) maintenance
of disc height, reproduction of native tissue properties, and
physiologic remodeling and integration of an engineered construct
in a rat tail disc replacement model [29]. These promising studies
highlight the potential for the engineering of a mechanically viable
NP, AF, or whole disc structure. As an alternative to implantation of
an immature construct (with in vivo maturation), new materials can
be used to direct the formation of an organized tissue matching

native disc structure and function. For example, using aligned
nanofibrous scaffolds as a starting template, we demonstrated that
a single annulus layer, with physiologic fiber organization, could be
produced [30]. When these oriented nanofibrous constructs were
seeded with AF cells [31], constructs increased in tensile modulus
with time and the orientation of collagen coincided with the scaffold
fiber direction. Extending this work to consider the multi-lamellar
hierarchy of the native AF, we next assembled MSC-seeded angle-ply
bi-lamellar structures with a fiber orientations of ±30° in each layer
[32]. By 10 weeks, angle-ply bi-layers reached a modulus very close
to the modulus of the native AF (~18 MPa). When sections across
two fiber planes were viewed using polarized light microscopy, a
multi-scale collagen architecture mirroring the cross-ply organization
of the native AF was observed: two layers of aligned, opposing
collagen. Such studies provided insight into the fundamental
reinforcing effect of alternating directions in angle ply laminates,
and may serve as a promising tissue engineering template for AF
repair. Further, these angle-ply laminate structures can be formed
into disc-like angle-ply structure (DAPS) that replicate the multiscale
architecture of the intervertebral disc, inclusive of a laminate
AF region and a gelatinous NP region [33]. In vitro culture of such
constructs showed that the mechanical characteristics of the disc
under compression and torsion were qualitatively similar to native
tissue, although lesser in magnitude, and increased with time in
culture. Cells seeded into both AF and NP regions adopted
morphologies that mirror those seen in native tissue, with rounded
cells in the NP and more elongated cells in the AF regions. In the AF
region, the collagenous matrix deposited followed the angle-ply
configuration of the scaffold. While considerable advances have
been made in disc tissue engineering, most notably the transplant of
a mechanically functional disc-like analogue in vivo in a rodent
model, there remain a number of hurdles to overcome before biologic
disc replacement becomes a clinical reality. Advances in disc
replacement in a small animal model will need to be evaluated in
larger species, where diffusional and mechanical demands will be
greater. Engineering for an inflamed environment, likely present in
degenerating discs, will further complicate this transition, and novel
materials that can address this scenario may be required. Despite
these limitations, lessons learned in the pursuit of a full biologic disc
replacement will likely provide nearer term solutions for instances of
NP degeneration or AF fracture. Along with these applications, new
and minimally surgical approaches will need to be developed to ease
clinical application. These advances will provide early stage
treatment options that may slow disc degeneration, until such time
as biologic substitutes become a clinical reality. Despite the
remaining hurdles, progress in disc tissue engineering has been
rapid and is already making an impact. These advances will continue
to accelerate and will one day provide a paradigm shift in the
treatment of disc degeneration, providing long term and functional
solutions for what is today an intractable, debilitating, and
widespread condition.
References:
1. Katz, R.T., Impairment and disability rating in low back pain. Clin
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2. Albert, H.B., et al., Modic changes, possible causes and relation to
low back pain. Med Hypotheses, 2008. 70(2): p. 361-8.
3. Cassidy, J.J., A. Hiltner, and E. Baer, Hierarchical structure of the
intervertebral disc. Connect Tissue Res, 1989. 23(1): p. 75-88.
4. Marchand, F. and A.M. Ahmed, Investigation of the laminate
structure of lumbar disc anulus fibrosus. Spine (Phila Pa 1976), 1990.
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criteria for intervertebral disc tissue engineering. J Biomech, 2010.
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6. Ahlgren, B.D., et al., Effect of anular repair on the healing strength
of the intervertebral disc: a sheep model. Spine (Phila Pa 1976),
2000. 25(17): p. 2165-70.
7. Heuer, F., et al., Biomechanical evaluation of conventional
anulus fibrosus closure methods required for nucleus replacement.
Laboratory investigation. J Neurosurg Spine, 2008. 9(3): p. 307-13.
8. Videman, T. and M. Nurminen, The occurrence of anular tears and
their relation to lifetime back pain history: a cadaveric study using
barium sulfate discography. Spine (Phila Pa 1976), 2004. 29(23): p.
2668-76.
Extended Abstracts 135
9. Fazzalari, N.L., et al., Mechanical and pathologic consequences of
induced concentric anular tears in an ovine model. Spine (Phila Pa
1976), 2001. 26(23): p. 2575-81.
10. Veresciagina, K., B. Spakauskas, and K.V. Ambrozaitis, Clinical
outcomes of patients with lumbar disc herniation, selected for onelevel
open-discectomy and microdiscectomy. Eur Spine J, 2010.
19(9): p. 1450-8.
11. Yeung, A.T. and P.M. Tsou, Posterolateral endoscopic excision
for lumbar disc herniation: Surgical technique, outcome, and
complications in 307 consecutive cases. Spine (Phila Pa 1976), 2002.
27(7): p. 722-31.
12. Thome, C., et al., Outcome after lumbar sequestrectomy compared
with microdiscectomy: a prospective randomized study. J Neurosurg
Spine, 2005. 2(3): p. 271-8.
13. Fakouri, B., et al., Lumbar microdiscectomy versus
sequesterectomy/free fragmentectomy: a long-term (>2 y)
retrospective study of the clinical outcome. J Spinal Disord Tech,
2011. 24(1): p. 6-10.
14. Bron, J.L., et al., Repair, regenerative and supportive therapies
of the annulus fibrosus: achievements and challenges. Eur Spine J,
2009. 18(3): p. 301-13.
15. Chiba, K., et al., Metabolism of the extracellular matrix formed by
intervertebral disc cells cultured in alginate. Spine (Phila Pa 1976),
1997. 22(24): p. 2885-93.
16. Gruber, H.E., et al., Three-dimensional culture of human disc cells
within agarose or a collagen sponge: assessment of proteoglycan
production. Biomaterials, 2006. 27(3): p. 371-6.
17. Gruber, H.E., et al., Cell shape and gene expression in human
intervertebral disc cells: in vitro tissue engineering studies. Biotech
Histochem, 2003. 78(2): p. 109-17.
18. Wang, J.Y., et al., Intervertebral disc cells exhibit differences in
gene expression in alginate and monolayer culture. Spine (Phila Pa
1976), 2001. 26(16): p. 1747-51; discussion 1752.
19. Baer, A.E., et al., Collagen gene expression and mechanical
properties of intervertebral disc cell-alginate cultures. J Orthop Res,
2001. 19(1): p. 2-10.
20. Sato, M., et al., An atelocollagen honeycomb-shaped scaffold
with a membrane seal (ACHMS-scaffold) for the culture of annulus
fibrosus cells from an intervertebral disc. J Biomed Mater Res A,
2003. 64(2): p. 248-56.
21. Rong, Y., et al., Proteoglycans synthesized by canine intervertebral
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of adult canine annulus fibrosus cells in collagen-glycosaminoglycan
scaffolds. J Biomed Mater Res A, 2004. 71(2): p. 233-41.
23. Alini, M., et al., The potential and limitations of a cell-seeded
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matrix. Spine (Phila Pa 1976), 2003. 28(5): p. 446-54; discussion
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fiber scaffold for annulus fibrosus cells. J Biomed Mater Res A, 2007.
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2006. 27(3): p. 362-70.

136
Extended Abstracts
28. Mizuno, H., et al., Tissue-engineered composites of anulus
fibrosus and nucleus pulposus for intervertebral disc replacement.
Spine (Phila Pa 1976), 2004. 29(12): p. 1290-7; discussion 1297-8.
29. Bowles, R.D., et al., Tissue-engineered intervertebral discs
produce new matrix, maintain disc height, and restore biomechanical
function to the rodent spine. Proc Natl Acad Sci U S A, 2011. 108(32):
p. 13106-11.
30. Nerurkar, N.L., D.M. Elliott, and R.L. Mauck, Mechanics of
oriented electrospun nanofibrous scaffolds for annulus fibrosus
tissue engineering. J Orthop Res, 2007. 25(8): p. 1018-28.
31. Nerurkar, N.L., R.L. Mauck, and D.M. Elliott, ISSLS prize winner:
Integrating theoretical and experimental methods for functional
tissue engineering of the annulus fibrosus. Spine, 2008. 33(25): p.
2691-701. 32. Nerurkar, N.L., et al., Nanofibrous biologic laminates
replicate the form and function of the annulus fibrosus. Nat Mater,
2009. 8(12): p. 986-92. 33. Nerurkar, N.L., et al., Engineered disc-like
angle-ply structures for intervertebral disc replacement. Spine (Phila
Pa 1976), 2011. 35(8): p. 867-73.
Acknowledgments:
This work was supported by the National Institutes of Health, the
Department of Veterans’ Affairs, the US Department of Defense, and
the Penn Center for Musculoskeletal Disorders.
9.1.1
Cartilage repair to prevent osteoarthritis. -Fact or fiction?-
T.S. De Windt, D.B.F. Saris
Utrecht/Netherlands
Introduction: We should remain modest and realistic in our
perception of outcomes and discussion with patients of cell based
treatment for osteoarthritis (OA) and end stage cartilage damage.
As best we know the challenge still remains to show prevention of
OA after cell therapy as well as the successful implementation of cell
therapy in the treatment of OA. However many important steps have
been made and some relevant boundaries and advances have been
described. Time to reflect and take score since, OA is a common
condition affecting many adults through pain and decreased joint
function which has a significant impact on quality of life.1 The
general increase in activity level of the past decades and the high
demands in terms of diagnostic and treatment modalities for fast
return to the pre-injury level create one of the biggest challenges
in our field. As such, early OA is increasingly being recognized in
younger active patients, raising the bar. Early OA is considered
more difficult to diagnose than ‘obvious full blown’ OA as signs
and symptoms may still be limited, often becoming manifest after
higher strains such as sport activities.2 In contrast, the diagnosis in
OA is easily made based on the history, physical examination and
radiologic investigation in patients older than 50. In early OA, the
articular cartilage shows fibrillation and vertical fissures that extend
into the mid-zone of the cartilage. The articular surface becomes
discontinuous and there is progressive increase in subchondral bone
plate and subarticular spongiosa.3 Other structures such as the
menisci and ligaments are frequently affected simultaneously, thus
disturbing the joint homeostasis. 4, 5 As early OA generally presents
in younger more active patients with high demands, traditional
treatment strategies for OA such as, anti-inflammatory drugs and
physical therapy will provide temporary relief while endoprosthetic
joint replacement limits function and is prone to future revision
surgery.6 As such, articular cartilage repair is hoped to hold promise
in the treatment of (early) OA patients, providing symptom relief and
potentially delaying or altering osteoarthritic changes and the need
for joint replacement.
Content: Cartilage repair procedures for (early OA) Marrow
stimulation Microfracture, is a surgically fast and cost-effective bone
marrow stimulating procedure indicated in cartilage lesions up to 2
cm2 or sometimes even 4 cm2 which provides clinical improvement
for at least two to five years.7, 8 Bae et al. evaluated 44 patients
with an average lesion size of 3.9 cm2 (range 1-6 cm2, Outerbridge
grade IV) with moderate osteoarthritic changes who underwent
microfracture.9 After a mean of 2.3 years, significant improvement
in pain and daily living was seen. In addition, using second-look
arthroscopy, defect filling was determined which was confirmed with
histologic evaluation and collagen type II staining. Miller et al.10
and Steadman et al.11 evaluated microfracture for degenerative
lesions and high impact athletics, respectively with satisfying
clinical outcome and return to high impact sports for more than
five seasons. However, these studies were not aimed specifically at
(early) OA. Brittberg et al. used drilling and subsequent carbon fiber
scaffold implantation for treatment of early osteoarthritic defects in
two separate cohorts with a short-term success rate of over 80% in
terms of pain and clinical outcome.12, 13 Autologous chondrocyte
implantation Autologous chondrocyte implantation (ACI) has found
its place in our treatment algorithm for larger lesions 4 cm2, or on
special indication between 2-4 cm2, demonstrating efficacy for over
ten years follow- op.14 We know that the disturbed joint homeostasis
in early osteoarthritis creates extra difficulty in local cellular
regeneration.6 However, increasing interest in cartilage repair for
(early) osteoarthritis has shown promising results. Indeed In vitro
studies have demonstrated good proliferation and re-differentiation
potential of osteoarthritic chondrocytes, with capability to produce
cartilage specific proteins.15, 16 Furthermore, Kuroda et al.
demonstrated effective cartilage repair after ACI in anterior cruciate
ligament transacted rats.17 Minas et al. reported on a large cohort
consisting of 153 patients (mean age 38 years) with early OA treated
with ACI and followed for up to 11 years. At final follow-up eight
percent of joints were considered failures while 50-75% experienced
significant improvement. At five years, 92 % of patients were
functioning well, delaying the need for joint replacement.18 Filardo
et al. also demonstrated significant improvement after second
generation ACI in patients with degenerative lesions.19 However, it
must be stated that compared to the general population, a higher
failure rate (18.5% at 6 years) was found. Several other studies
have reported improvement in clinical outcome and MRI determined
defect filling after ACI in degenerative and focal osteoarthritis.20,
21 As of yet, no clinical data is available for cell-based therapy in
generalized (early) OA. Osteochondral autologous and allograft
transfer Although limited clinical data is available, osteochondral
autograft transfer (OAT) has been implemented by Hangody et al. in
82 professional athletes with signs of OA. In this 17 year prospective
study, similar success rates were found to that of less athletic patients,
although high motivation resulted in better subjective evaluation.22
In addition, Jakob et al. found good results in ten patients with
patellofemoral OA treated with OAT.23 However concomitant
procedures for patellofemoral maltracking may be an important
confounder. Könst et al. used autologous bone grafting combined
with gel-type ACI (GACI) to treat 9 patients with severe osteochondral
defects. At one year follow-up, statistically significant improvement
was demonstrated in eight patients with only one patient needing
conversion to total knee arhtroplasty. (TKA)24 Osteochondral
allograft tranfer has susccesfully been applied in patients (mean
age 24.3, range 16-44) with steroid-induced osteonecrosis with 90%
graft survival at six years.25 At their last follow-up, TKA was avoided
in 27 out of 28 knees. In contrast, Beaver et al. found a higher failure
rate for post-traumatic osteoarticular bipolar lesions treated with
fresh allografts.26 Furthermore, primary OA has been reported to
reduce clinical outcome after allograft transfer.27 Discussion: fact
from fiction As cartilage repair procedures for treatment of (early)
OA is still a challenge, careful treatment selection is warranted,
specifically in more advanced OA and younger patients. Concomitant
injuries to the whole joint and surroundings are important to treat
as these disturb the joint homeostasis. For instance, anterior
cruciate ligament tears are known to be a risk factor for OA.28-32
Furthermore, correction of malalignment in unicompartemental OA
through osteotomy has proven to reduce pain and improve knee
function.33 Numerous studies have demonstrated the importance of
early treatment in cartilage repair, as reduced clinical outcome was
correlated with defect age ie longer time since symptom onset.7,
35-38 It remains unclear however, if cartilage repair can prevent
OA from developing and the long-term effect on OA has yet to be
determined. Current evidence does suggest however, that TKA can
be delayed with cartilage repair, but there are others means to do
this as well or better. Furthermore, the short-term results (up to five
years) in patients with early osteoarthritic defects are promising.39
New (surgical) strategies may provide symptom relief in active
patients with more severe OA as well. This is an extra challenging
population in which randomized controlled trials have shown that
arthroscopic debridement has no advantage over optimal physical
and medical care.40, 41 However, optimizing tissue regeneration
with functioning cartilage and use of mesenchymal stem cell therapy
are promising strategies which could be implemented for (early) OA.
Conclusion We should remain modest and realistic in our perception
of outcomes and discussion with patients of cell based treatment
for osteoarthritis (OA) and end stage cartilage damage. At best the
challenge still remains to show prevention of OA after cell therapy
as well as the successful implementation of cell therapy in the
treatment of OA. However many important steps have been made
and some relevant boundaries and advances have been described.

Promising results of cartilage repair in early OA encourage us to
continue aiming at long-term effectiveness of preventive and curative
treatment modalities for OA. While not yet a fact; cartilage repair is
a feasible new treatment for (early) OA demonstrating preliminary
short-term effectiveness.
References:
1. Woolf AD, Pfleger B. Burden of major musculoskeletal conditions.
Bull World Health Organ 2003; 81(9):646-656.
2. Luyten FP, Denti M, Filardo G, Kon E, Engebretsen L. Definition and
classification of early osteoarthritis of the knee. Knee Surg Sports
Traumatol Arthrosc 2012; 20(3):401-406.
3. Madry H, Luyten FP, Facchini A. Biological aspects of early
osteoarthritis. Knee Surg Sports Traumatol Arthrosc 2012; 20(3):407-
422.
4. Madry H, Luyten FP, Facchini A. Biological aspects of early
osteoarthritis. Knee Surg Sports Traumatol Arthrosc 2012; 20(3):407-
422.
5. Saris DB, Dhert WJ, Verbout AJ. Joint homeostasis. The discrepancy
between old and fresh defects in cartilage repair. J Bone Joint Surg Br
2003; 85(7):1067-1076.
6. Gomoll AH, Filardo G, de GL et al. Surgical treatment for early
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7. Vanlauwe J, Saris DB, Victor J, Almqvist KF, Bellemans J, Luyten FP.
Five-year outcome of characterized chondrocyte implantation versus
microfracture for symptomatic cartilage defects of the knee: early
treatment matters. Am J Sports Med 2011; 39(12):2566-2574.
8. Mithoefer K, McAdams T, Williams RJ, Kreuz PC, Mandelbaum BR.
Clinical efficacy of the microfracture technique for articular cartilage
repair in the knee: an evidence-based systematic analysis. Am J
Sports Med 2009; 37(10):2053-2063.
9. Bae DK, Yoon KH, Song SJ. Cartilage healing after microfracture in
osteoarthritic knees. Arthroscopy 2006; 22(4):367-374.
10. Miller BS, Steadman JR, Briggs KK, Rodrigo JJ, Rodkey WG. Patient
satisfaction and outcome after microfracture of the degenerative
knee. J Knee Surg 2004; 17(1):13-17.
11. Steadman JR, Ramappa AJ, Maxwell RB, Briggs KK. An arthroscopic
treatment regimen for osteoarthritis of the knee. Arthroscopy 2007;
23(9):948-955.
12. de Windt TS, Concaro S, Lindahl A, Saris DB, Brittberg M.
Strategies for patient profiling in articular cartilage repair of the
knee: a prospective cohort of patients treated by one experienced
cartilage surgeon. Knee Surg Sports Traumatol Arthrosc 2012.
13. Brittberg M, Faxen E, Peterson L. Carbon fiber scaffolds in the
treatment of early knee osteoarthritis. A prospective 4-year followup
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14. Peterson L, Vasiliadis HS, Brittberg M, Lindahl A. Autologous
chondrocyte implantation: a long-term follow-up. Am J Sports Med
2010; 38(6):1117-1124.
15. Tallheden T, Bengtsson C, Brantsing C et al. Proliferation and
differentiation potential of chondrocytes from osteoarthritic patients.
Arthritis Res Ther 2005; 7(3):R560-R568.
16. Jiang YZ, Zhang SF, Qi YY, Wang LL, Ouyang HW. Cell transplantation
for articular cartilage defects: principles of past, present, and future
practice. Cell Transplant 2011; 20(5):593-607.
17. Kuroda T, Matsumoto T, Mifune Y et al. Therapeutic strategy
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18. Minas T, Gomoll AH, Solhpour S, Rosenberger R, Probst C, Bryant
T. Autologous chondrocyte implantation for joint preservation
in patients with early osteoarthritis. Clin Orthop Relat Res 2010;
468(1):147-157.
19. Filardo G, Kon E, Di MA et al. Second-generation arthroscopic
Extended Abstracts 137
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degenerative cartilage lesions. Knee Surg Sports Traumatol Arthrosc
2011.
20. Kreuz PC, Muller S, Ossendorf C, Kaps C, Erggelet C. Treatment of
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11(2):R33.
21. Ossendorf C, Kaps C, Kreuz PC, Burmester GR, Sittinger M,
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22. Hangody L, Dobos J, Balo E, Panics G, Hangody LR, Berkes I.
Clinical experiences with autologous osteochondral mosaicplasty in
an athletic population: a 17-year prospective multicenter study. Am J
Sports Med 2010; 38(6):1125-1133.
23. Jakob RP, Franz T, Gautier E, Mainil-Varlet P. Autologous
osteochondral grafting in the knee: indication, results, and
reflections. Clin Orthop Relat Res 2002;(401):170-184.
24. Konst YE, Benink RJ, Veldstra R, van der Krieke TJ, Helder MN,
van Royen BJ. Treatment of severe osteochondral defects of the knee
by combined autologous bone grafting and autologous chondrocyte
implantation using fibrin gel. Knee Surg Sports Traumatol Arthrosc
2012.
25. Gortz S, De Young AJ, Bugbee WD. Fresh osteochondral
allografting for steroid-associated osteonecrosis of the femoral
condyles. Clin Orthop Relat Res 2010; 468(5):1269-1278.
26. Beaver RJ, Schemitsch EH, Gross AE. Disassembly of a one-piece
metal-backed acetabular component. A case report. J Bone Joint
Surg Br 1991; 73(6):908-910.
27. Gomoll AH, Filardo G, Almqvist FK et al. Surgical treatment for
early osteoarthritis. Part II: allografts and concurrent procedures.
Knee Surg Sports Traumatol Arthrosc 2012; 20(3):468-486.
28. Daniel DM, Stone ML, Dobson BE, Fithian DC, Rossman DJ,
Kaufman KR. Fate of the ACL-injured patient. A prospective outcome
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31. Von PA, Roos EM, Roos H. High prevalence of osteoarthritis 14
years after an anterior cruciate ligament tear in male soccer players:
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Dis 2004; 63(3):269-273.
32. Stein V, Li L, Lo G et al. Pattern of joint damage in persons with
knee osteoarthritis and concomitant ACL tears. Rheumatol Int 2011.
33. Brouwer RW, van-Raaij TM, Bierma-Zeinstra-Sita MA, Verhagen
AP, Jakma-Tijs TSC, Verhaar-Jan AN. Osteotomy for treating knee
osteoarthritis. Cochrane Database of Systematic Reviews 2007.
34. Bauer S, Khan RJ, Ebert JR et al. Knee joint preservation with
combined neutralising High Tibial Osteotomy (HTO) and Matrixinduced
Autologous Chondrocyte Implantation (MACI) in younger
patients with medial knee osteoarthritis: A case series with
prospective clinical and MRI follow-up over 5years. Knee 2011.
35. de Windt TS, Bekkers JE, Creemers LB, Dhert WJ, Saris DB. Patient
profiling in cartilage regeneration: prognostic factors determining
success of treatment for cartilage defects. Am J Sports Med 2009;
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36. Krishnan SP, Skinner JA, Bartlett W et al. Who is the ideal
candidate for autologous chondrocyte implantation? J Bone Joint
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37. Mithoefer K, Williams RJ, III, Warren RF, Wickiewicz TL, Marx
RG. High-impact athletics after knee articular cartilage repair: a
prospective evaluation of the microfracture technique. Am J Sports
Med 2006; 34(9):1413-1418.

138
Extended Abstracts
38. Saris DB, Vanlauwe J, Victor J et al. Treatment of symptomatic
cartilage defects of the knee: characterized chondrocyte implantation
results in better clinical outcome at 36 months in a randomized
trial compared to microfracture. Am J Sports Med 2009; 37 Suppl
1:10S-19S.
39. Luyten FP, Vanlauwe J. Tissue engineering approaches for
osteoarthritis. Bone 2011.
40. Kirkley A, Birmingham TB, Litchfield RB et al. A randomized trial
of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med
2008; 359(11):1097-1107.
41. Moseley JB, O‘Malley K, Petersen NJ et al. A controlled trial of
arthroscopic surgery for osteoarthritis of the knee. N Engl J Med
2002; 347(2):81-88.
42. Kaul G, Cucchiarini M, Remberger K, Kohn D, Madry H. Failed
cartilage repair for early osteoarthritis defects: a biochemical,
histological and immunohistochemical analysis of the repair tissue
after treatment with marrow-stimulation techniques. Knee Surg
Sports Traumatol Arthrosc 2012.
9.1.2
What is the key pathway to prevent post-traumatic arthritis for
future molecule-based therapy?
S. Chubinskaya
Chicago/United States of America
Introduction: Joint injuries are becoming increasingly common, with
young adults between the ages of 18-44 seeking medical attention
for joint sprains, dislocation, fractures, anterior cruciate ligament and
meniscal tears, and others. The cascade of events that follow these
joint injuries have been shown to increase the risk (20-50%) of posttraumatic
osteoarthritis (PTOA). Understanding biological responses
that predispose the onset of PTOA will help in determining treatment
strategies in order to delay and/or prevent the progression of the
disease.
Content: Recent research on the events that follow joint trauma
have shown chondrocyte death/apoptosis, inflammation (elevation
of caspases, selected pro-inflammatory cytokines, matrix fragments,
nitric oxide, reactive oxygen species, etc.) and matrix damage
(activation of aggrecanases and matrix metalloproteinases that
lead to the cleavage of cartilage matrix constituents) to be early
phase responses to injury. Together they lead to the development
of OA-like focal cartilage lesions characterized by the loss of matrix
molecules, surface fibrillation, and fissures that if untreated have
a tendency to expand and progress to fully-blown disease. One of
the unanswered PTOA questions is when and which therapies that
have been developed as disease-modifying OA drugs are indicated
for patients with post-traumatic OA and whether a different set of
treatments and molecular targets has to be considered. Through
basic and clinical research an impressive progress has been made
towards elucidation of pathogenesis of PTOA and understanding
the mechanisms that govern immediate cellular responses to
injury. However, this still requires further validation in a large
cohort of patients with various types of joint injuries. The ideal
therapy to arrest and prevent the development and progression
of PTOA must be multi-varied and include anabolic effects on
chondrocyte metabolism characterized by elevated intrinsic repair,
while protecting integrity of cell membrane and inhibiting catabolic
pathways that lead to chondrocyte death and matrix loss. The
following are the key mechanisms that should constitute the basis
for the design of intervention therapies: 1) Chondroprotection; 2)
Anti-inflammatory; 3) Matrix protection; and 4) Pro-anabolic, stimuli
of cartilage remodeling and regeneration. Chondroprotective factors
prevent the damage of chondrocyte membrane, inhibit apoptosis, or
antagonize pathways that lead to cell death. Among those available
for clinical or experimental use are P188 surfactant, various specific
and broad inhibitors of caspases, anti-oxidants (inhibitors of nitric
oxide synthase, rotenone, N-acetylcysteine) and other. As antiinflammatory,
anti-tumor necrosis factor and interleukin-1 receptor
antagonist received the most attention due to their availability for
clinical use in rheumatoid arthritis or in various experimental animal
models of OA or PTOA. To protect cartilage matrix integrity various
inhibitors of aggrecanases and matrix metalloproteinases have been
considered. One of the very important directions in the development
of pharmacological interventions in PTOA is the ability to stimulate
production of new cartilage extracellular matrix. The best candidates
are growth factors including members of the Transforming Growth
Factor (TGF)-β superfamily, bone morphogenetic proteins (BMP),
Fibroblast Growth Factors, and Insulin like Growth Factor (IGF)-
1. The most studied and the most promising for cartilage repair
is osteogenic protein-1 or BMP-7 (OP-1/BMP-7). At this stage of
our cumulative knowledge, BMP-7 appears to be one of the best
candidate therapeutic agents for cartilage treatment after injury,
since it affects both catabolic and anabolic responses. We believe that
the most beneficial agents for the treatment of PTOA are those that
target multiple pathways and mechanisms. A number of molecular
targets have been identified and many of the existing therapeutic
agents have been already tested in vitro and in vivo. However, the
biggest remaining challenge is the translation of this knowledge into
the clinic and the development of appropriate effective therapy/
therapies administered within the window of opportunity. Currently,
the most suitable route for administering such therapy appears to
be intra-articular injections that allow accumulation of critical doses
of the drug within the damaged area and also reduce the risk of
systemic side effects. To monitor the efficacy of the PTOA therapy,
an appropriate set of bio- and imaging markers is needed that could
predict and correlate with the progression of the disease, since it
takes years and decades for the disease to develop.
References:
1. Anderson, DD; Chubinskaya, S; Guilak, F; Martin, JA; Oegema, TR;
Olson, SA and Buckwalter, JA. (2011). Post-traumatic osteoarthritis:
improved understanding and opportunities for early intervention. J
Orthop Res, 29(6):802-9.
2. Bajaj, S; Shoemaker, T; Hakimiyan, AA; Rappoport, L; Pascual-
Garrido, C; Oegema, TR; Wimmer, MA and Chubinskaya, S. (2010).
Protective effect of P188 in the model of acute trauma to human ankle
cartilage: the mechanism of action. J Orthop Trauma, 24(9):571-6.
3. Buckwalter, JA and Brown, TD. (2004). Joint injury, repair, and
remodeling: roles in posttraumatic osteoarthritis. Clin Orthop Relat
Res, 423):7-16.
4. Chubinskaya, S; Hurtig, M and Rueger, DC. (2007). OP-1/BMP-7 in
cartilage repair. Int Orthop, 31(6):773-81.
5. Chubinskaya, S; Otten, L; Soeder, S; Borgia, JA; Aigner, T; Rueger,
DC and Loeser, RF.(2011). Regulation of chondrocyte gene expression
by osteogenic protein-1. Arthritis Res Ther, 13(2):R55.
6. Ellsworth, JL; Berry, J; Bukowski, T; Claus, J; Feldhaus, A;
Holderman, S; Holdren, MS; Lum, KD; Moore, EE; Raymond, F; Ren,
H; Shea, P; Sprecher, C; Storey, H; Thompson, DL; Waggie, K; Yao,
L; Fernandes, RJ; Eyre, DR and Hughes, SD. (2002). Fibroblast Post-
Traumatic Osteoarthritis: Biologic Approaches to Treatment growth
factor-18 is a trophic factor for mature chondrocytes and their
progenitors. Osteoarthritis Cartilage, 10(4):308-20.
7. Elsaid, KA; Machan, JT; Waller, K; Fleming, BC and Jay, GD.
(2009). The impact of anterior cruciate ligament injury on lubricin
metabolism and the effect of inhibiting tumor necrosis factor
alpha on chondroprotection in an animal model. Arthritis Rheum,
60(10):2997-3006.
8. Lotz, MK and Kraus, VB. (2010). New developments in osteoarthritis.
Posttraumatic osteoarthritis: pathogenesis and pharmacological
treatment options. Arthritis Res Ther, 12(3):211.
Acknowledgments:
This work was supported by the National Football League Charities,
Ciba-Geigy Endowed Chair and Department of Biochemistry, Rush
University Medical Center. The author would like to acknowledge
Drs. Markus A. Wimmer, Theodore R Oegema, and Jeffrey A. Borgia
for their important contributions to this work. The authors would
like to acknowledge Dr. Arkady Margulis for tissue procurement and
Dr. Lev Rappoport and Mrs. Arnavaz Hakimiyan for their technical
assistance. The author also would like to acknowledge the Gift of
Hope Organ & Tissue Donor Network and donor’s families.

9.1.3
ACL reconstruction and osteoarthritis: Evidence from long-term
follow-up and potential solutions
R.A. Magnussen 1 , V. Duthon 2 , E. Servien 3 , P. Neyret 3
1 Columbus/United States of America, 2 Geneva/Switzerland, 3 Lyon/
France
Introduction: Injury to the anterior cruciate ligament frequently
results in symptomatic knee instability that significantly limits
knee function. Modern surgical and rehabilitation techniques are
frequently able to restore knee stability and allow return to high
function; however, a major long-term concern remains the high risk
of subsequent development of arthritis in this young, active patient
population. The goal of this presentation is to explore several
questions, the answers to which are key to our understanding and
eventually to the prevention of this frequent source of morbidity.
These questions include:
- What is the natural history of ACL deficiency?
- How important is the status of the meniscus at the time of
reconstruction?
- Does ACL reconstruction prevent the development of osteoarthritis
in the long term?
- Can we predict which patients will develop osteoarthritis?
- What can be done???
Content: What is the natural history of ACL deficiency?
Review of the literature reveals osteoarthritis rates of about 40%
following fifteen years of ACL deficiency. Longer-term follow-up
demonstrates these rates to increase to near 90% by 25 to 35 years,
with up to 50% of patients undergoing TKA in some series. Meniscal
status does not appear to be the major predictor of outcome in
this population. Meniscal loss likely contributes to more rapid
development of osteoarthritis in this patient population.
How important is the status of the meniscus at the time of
reconstruction?
Meniscus status appears to be a much strong predictor of subsequent
development of osteoarthritis in cases of ACL reconstruction.
Review of the literature reveals numerous comparative studies
with 4 to 12 year follow-up comparing rates of osteoarthritis in ACLreconstructed
patients who underwent partial meniscectomy with
normal menisci versus those with normal menisci. These studies
demonstrate 2- to 10-fold increased risk of osteoarthritis following
partial meniscectomy.
Our series of patients who underwent ACL reconstruction in Lyon
between 1978 and 1983 that have been followed for a mean of 24.5
years demonstrate similar findings. Patients were twice as likely to
develop IKDC grade C or D osteoarthritis if they underwent partial
meniscectomy at the time of ACL reconstruction. Articular cartilage
lesions noted at the time of ACL reconstruction also appear to be
significant predictors of future development of osteoarthritis. In this
same series, the presence of medial compartment cartilage defects
at reconstruction was associated with a 5-times increased risk of
osteoarthritis at final follow-up.
Does ACL reconstruction prevent the development of osteoarthritis
in the long term?
Unfortunately, long-term comparative studies evaluating osteoarthritis
rates in similar ACL-injured populations treated with or without ACL
reconstruction are rare. One can compare case series of patients
treated with and without surgery to estimate expected rates of
osteoarthritis. In patients with normal menisci at the time of surgery,
rates of osteoarthritis appear to be higher 25 to 35 years later in patients
that did not undergo ACL reconstruction (40 to 90%) relative to those
who did undergo reconstruction (35%). Similar results are found in
patients with abnormal menisci at the time of reconstruction, with nonreconstructed
patients exhibiting higher rates of osteoarthritis (90%)
than those who underwent ACL reconstruction (40 to 50%). One must
remember that such comparisons are subject to numerous sources of
bias and represent low-level evidence.
Several comparative studies evaluating these same questions 11 to
19 years after ACL injury has recently been published. The results are
variable with osteoarthritis rates between 28 and 65% in all groups.
No clear change in osteoarthritis rates with ACL reconstruction is
consistently evident.
Extended Abstracts 139
Can we predict which patients will develop osteoarthritis?
Following ACL reconstruction, it would be ideal to be able to predict
which patients are at highest risk for subsequent osteoarthritis
development and then intervene in some way to minimize this risk.
As above, undergoing partial meniscectomy at the time of surgery
does appear to increase this risk. Further, our data from Lyon indicate
that patients with no evidence of degenerative change on plain films
11 years after surgery are at very low risk to develop osteoarthritis
over the next 15 years. Similarly, if early evidence of degenerative
change is visible on radiographs 11 years following surgery, the risk
of significant progression of osteoarthritis over the next 15 years is
quite high.
What can be done???
Strategies to reduce osteoarthritis risk begin at the time of the initial
ACL reconstruction. Meniscal repair and preservation has been
shown in several series to reduce subsequent risk of osteoarthritis.
Meniscus tissue can also potentially be maximized by operating
earlier on ACL-deficient knees and preventing the occurrence of
some meniscal tears that can develop with persistent instability.
Similarly, when evidence of early degenerative change is seen,
one can consider intervention at the time through either activity
modification (limiting high-impact activities) or altering joint loading
forces through high tibial osteotomy. There is also great potential
exhibited by many new techniques that may aid in meniscal
preservation, cartilage restoration, and joint protection. Further
research and longer follow-up are necessary to accurately evaluate
the potential of such techniques.
References:
Pernin J, Verdonk P, Aïtsiselmi T, Marsin P, Neyret P, Long-term
Follow-up of 24.5 years After Intra-Articular AnteriorCruciate
Ligament Reconstruction With Lateral Extra articular Augmentation,
Am J Sports Med 2012, June 38(6) 1094-102
Rotterud J, Risberg MA, Engelretsen L, Aroen A, Patients with focal
full-thickness cartilage lesions benefit less from ACL reconstruction
at 2-5 years follow-up Knee Surg Sports Traumatol Arthrosc; DOI
10.1007/S00167-011-1739-y; E. Ruh 2011 Nov 8
Hjermundrud V, Bune T, Risberg M, Engelretsen L, Aroen A; Full
Thickness cartilage lesion do not offer knee function in patients with
ACL injury; Knee Surg Sports Traumatol Arthrosc 2010, March 18
(3)298-303; DOI 10.1007/S00167.009-0894-x
Widuschowski W, Widuschowski J, Koczy B, Szyluk K; Untreated
asymptomatic deep cartilage lesions associated with anterior
cruciate ligament injury : results at 10 and 15 years follow-up; Am J
Sports Med 2009, Apr ; 37(4) 688-92 Epub 2009 Feb 3;
Bonin N, Aïtsiselmi T, Donell St, Dejour H, Neyret P; Anterior cruciate
reconstruction combined with valgus upper tibial osteotomy : 12
years follow-up; The Knee 2004, 11(6) : 431-37
Neyret P, Walch G, Dejour H; Rev Chir Orthop 1998; Intra-nural
medical menisectomy by the Trillat technique Long Term follow-up
of 258 operations; French J. Orthop Sur 1988, 4, 520-34
Acknowledgments:
- TBF (cartipatch)
- Smith and Nephew
- Tornier

140
Extended Abstracts
9.1.4
Anatomic ACL Reconstruction -Current concept and future
perspective
F.H. Fu
Pittsburgh/United States of America
Introduction: Rationale for Anatomic DBACL Reconstruction
- Anatomy is the basis of orthopedic surgery. The goals of anatomic
ACL reconstruction are to restore 60-80% of the native ACL anatomy,
and to maintain a long term knee health.
- Traditional ACL-R has been successful in returning patients to sports
activities. However, radiographic evidence of degenerative changes has
been observed in up to 90% of patients at mid-term follow-up study after
traditional SBACL reconstruction.1-2
- Critical review of the literature from the last ten years reveals that
between 10% and 30% of patients complain of pain and residual
instability following traditional SB (SB) ACL reconstruction.3 Metaanalysis
showed that no more than 60% of the patients will make a full
recovery after their ACL reconstruction.4
- The PL bundle, which is not traditionally reconstructed, plays a significant
role in rotatory stability in the knee. Numerous clinical and basic science
studies have demonstrated that: 1) traditional SBACL reconstruction
does not adequately restore normal knee kinematics, particularly tibial
rotation5, and 2) anatomic DB (DB) reconstruction more closely restores
normal knee kinematics when compared to SB reconstruction.6
- Recent biodynamic research has shown evidence that anatomic DB
ACL-R restores knee kinematics during daily activities back to normal
and might help prevent the early onset of knee osteoarthritis.7
- A recently performed RCT, with 85% follow-up at 3-5 years, showed
clinical superiority for anatomic placement of the graft and small but
significant differences between anatomic DB and SB ACL-R.8
Content: The principle of anatomic ACL DB reconstruction
- Reproducing the two bundle anatomy of ACL
- The ACL is composed of two functional bundles, the anteromedial (AM)
bundle and the posterolateral (PL) bundle.9
- Reproducing the insertion sites of ACL
- The insertion sites of the AM and PL bundle should be identified and
marked for anatomic tunnel placement. The femoral insertion sites of
the AM and PL bundle are oriented vertically with the knee in extension
and become horizontal in 90º of knee flexion (surgical position for ACL
reconstruction surgery). In extension the two bundles are parallel and in
flexion they become crossed.9
- Reproducing the tension pattern of ACL
- The AM bundle has its highest tension at 45o of knee flexion, and was
taut throughout the range of motion. The PL bundle has its highest
tension at full extension, and becomes lax as the knee flexes. The AM
and PL graft should be fixed at these angles of knee flexion to closely
reproduce the native tension pattern.10
- Individualized surgery
- The insertion sites of each bundle should be identified and marked, and
the size of the insertion sites should be measured to tailor the surgery
for each individual. The concept of anatomic ACL reconstruction can be
applied to all ACL surgeries (SB, DB, revision, one-bundle augmentation).
The decision of whether to perform a single or DB ACL reconstruction
should be dictated by the unique anatomy of the patient.11
Pitfalls in Traditional ACL reconstruction
- Femoral insertion sites orientation changes with knee flexion: The
femoral AM and PL insertion sites are horizonally oriented when the
knee is close to 90 degrees of flexion, while they are vertically oriented
in knee extension. The important concept is often neglected in ACL
reconstruction.
- The use of clock face reference: The knee is a 3 dimensional structure.
The clock concept is easy to use. However, it is inaccurate in describing
the location of femoral tunnel placement and lead to non-anatomic
tunnel position.
- Inability to observe the femoral insertion site well by using the
anteromedial portal: The anteromedial portal provides a superior
view of the lateral wall of the notch and the femoral insertion site of
ACL than the anterolateral portal, which is sufficient in observing the
tibial insertion site.
- Graft impingement: It is a concept created by us because of nonanatomic
tunnel placement. The native ACL does NOT impinge with
notch and PCL. As long as the tunnels were placed in an anatomic
fashion, there will be no impingement. However, if the tunnel is
placed non-anatomically, impingement may occur.
- Mismatch tunnels: With fear of impingement, we traditionally mismatch
our tunnel placement by placing the tibial tunnel more posteriorly
(close to the PL insertion site), and placing the femoral tunnel at the
native AM or high AM position.11-13 Non-anatomic ACL reconstruction
leads to inferior biomechanical properties and biological healing due
to non-physiological biomechanical stress to the graft.
- DB ACL-R does not necessarily mean anatomic reconstruction, if the
native anatomy was not followed as a guideline for placement of the
tunnels.
Anatomic DB ACL Reconstruction
- Pre-operatively, the ACL insertion site and ACL length can be measured
on the sagittal MRI. The ACL inclination angle can also be measured.
- The MRI can also be used to measure the size of the certain autografts.
Both the patellar tendon and the quadriceps tendon size can be
measured on the sagittal MRI sequence. The quadriceps tendon is
often much larger than the patellar tendon and can offer more autograft
substance.
- Anatomic DB ACL-R is an “Insertion Site Surgery”. We utilize three
portals: Lateral Portal (LP), Medial Portal (MP), and Accessory Medial
Portal (AMP).
- We routinely place the arthroscope in the MP and work through
the AMP. In doing so, visualization of the femoral insertion of the
ACL is greatly enhanced and the need for notchplasty is virtually
eliminated.14
- The anatomic insertion sites of each native ACL bundle are marked on
the femur and tibia with a thermal device, with care taken to preserve
the border of the bundles for later reference. This is a critical step in
identifying the correct placement of the tunnels, and is performed
prior to resection of any residual ACL tissue. In addition, the length
and width of the AM and PL bundle insertion site are measured as
references to decide tunnel diameters. The surgery is individualized for
each patient.
- A “lateral bifurcate ridge” is often seen on the femoral insertion
between the AM and PL bundles, where as a “lateral intercondylar
ridge” is often seen on the upper limit of both the AM and PL bundles.
These are useful surgical landmarks in addition to the native insertion
fibers.15-16
- Notchplasty destroys the femoral anatomy of the ACL and is
unnecessary if medial and accessory medial portals are used.
- The tibial and femoral tunnels are placed at their native insertion site,
which were previously marked by thermal device.
- The PL femoral tunnel is always drilled through the anteromedial
portal. The primary advantage of drilling trans-tibially for the AM
femoral tunnel is the creation of a longer tunnel which diverges from
the PL femoral tunnel, and we routinely attempt this approach first
before using the accessory medial portal. However, sometimes it can’t
reach the anatomic insertion site. In that case, the tunnel will be drill
through the anteromedial portal.
- The PL graft is then passed first, followed by the AM graft. Femoral
fixation is typically performed with an EndoButton.
- Post-operatively, the MRI can be used to compare the pre- and postop
insertion site size to measure how much of the insertion site is
restored. To assess proper tunnel and graft placement the pre- and
post-operative inclination angle and tunnel angle can be compared on
MRI and AP radiographs respectively.17 Additionally 3D CT scan can be
used to evaluate tunnel position.
Anatomic SB ACL Reconstruction

- Except for an one bundle augmentation (performed when only one of
the two native bundles are torn), there are a few other scenarios where
we prefer to perform SB surgery (30%):18
- Small native ACL insertion site (< 14mm)
- Open growth plates
- Severe arthritic changes
- Multiple knee ligament injuries
- Severe bone bruising
- Narrow or shallow intercondylar notch
- SB surgery is performed with attention to soft tissue and bony
landmarks, while identifying rupture pattern and native ACL insertion
sites (similar to DB ACL surgery). Then, the tibial tunnel is placed at
midway between the native insertion sites of the AM bundle and PL
bundles.
- The distance from anterior margin of ACL footprint to center of tibial
tunnel should be measured, and the femoral tunnel should be placed
at the same distance from the posterior margin (knee in 90º flexion) of
the femoral ACL footprint.
One Bundle Augmentation
- In some cases only the AM or the PL bundle is torn, then the intact
bundle is saved and “augmented” with a SB reconstruction – either the
AM or PL, whichever one is torn.
Clinical Outcomes
- Clinical improvements have been demonstrated in recent prospective
and randomized level I and level II studies. These studies have shown
superior outcomes for anatomic DB reconstruction rather than
conventional SB reconstruction.8,19
- While preliminary results are encouraging, additional work is needed
to critically evaluate the outcomes of DB ACL reconstruction in terms
of joint kinematics, degenerative joint changes, and patient-reported
outcomes. Better (true objective) methods for rotational laxity
measurement, intermediate and long-term outcomes are needed in
the future.
- A meta-analysis by Lubowitz et al. summarized the results of pivot
shift consistent with the convention of IKDC. The normal and nearly
abnormal data were pooled together for pivot shift and therefore,
SB and DB achieved 94.6% and 97.5% of good pivot shift results
respectively with no difference between the two groups. This is how we
reported clinical outcome for many years. However, if we want to review
the data more critically by only comparing the “normal” category, DB
provided significantly better results (83.1% DB vs. 67.9% SB).20,21
- Complications such as graft failure, hardware failure, and infections
are also seen with DB ACL reconstruction. The double tunnels in femur
and tibia may increase the difficulty in revising failed grafts.
To fully assess the outcome of ACL reconstruction, we need to improve
our outcome measures. Outcome measures should be objective,
accurate, precise and reliable. Examples are in vivo kinematics with
dynamic stereo x-ray, high resolution/ 3D MRI and 3D CT scan. Only
then we can improve our surgical technique and protect the long-term
knee health of our patients.
Conclusion
- The goals of anatomic ACL reconstruction are to restore 60-80% of
the native ACL anatomy, and to maintain a long term knee health.
- The DB anatomy, insertion sites, and tension pattern need to be
reproduced to restore native ACL anatomy and knee kinematics.
- Surgery should be individualized to the patient.
- Better restoration of ACL anatomy leads to better restoration of the
knee joint function.
- Anatomic DBACL Reconstruction is a principle that can be applied to
SB, one-bundle augmentation and revision ACL surgeries
- We need improved, more objective outcomes measures, including
biology, kinematics and imaging.
Extended Abstracts 141
References:
1) Fithian DC, Paxton EW, Stone ML, Luetzow WF, Csintalan RP,
Phelan D, Daniel DM. Prospective trial of a treatment algorithm for
the management of the anterior cruciate ligament-injured knee. Am
J Sports Med 2005;33-3:335-46.
2) Keays SL, Newcombe PA, Bullock-Saxton JE, Bullock MI, Keays AC.
Factors involved in the development of osteoarthritis after anterior
cruciate ligament surgery. Am J Sports Med 2010;38-3:455-63.
3) Yunes M, Richmond JC, Engels EA, Pinczewski LA. Patellar versus
hamstring tendons in anterior cruciate ligament reconstruction: A
meta-analysis. Arthroscopy 2001;17-3:248-57.
4) Biau DJ, Tournoux C, Katsahian S, Schranz P, Nizard R. ACL
reconstruction: a meta-analysis of functional scores. Clin Orthop
Relat Res 2007;458:180-7.
5) Tashman S, Collon D, Anderson K, Kolowich P, Anderst W.
Abnormal rotational knee motion during running after anterior
cruciate ligament reconstruction. Am J Sports Med 2004;32-4:975-
83.
6) Yagi M, Kuroda R, Nagamune K, Yoshiya S, Kurosaka M. Doublebundle
ACL reconstruction can improve rotational stability. Clinical
Orthopaedics and Related Research 2007-454:100-7.
7) Kopf, S; Moloney, G; Freismuth, K; Fu, FH; Tashman, S. Anatomic
DB Anterior Cruciate Ligament Reconstruction Restores Normal
Dynamic In Vivo Knee Kinematics. Presented as podium presentation
during the Orthopaedic Research Society Meeting in San Francisco,
February, 2012.
8) Hussein M, van Eck CF, Cretnik A, Dinevski D, Fu FH. Prospective
randomized clinical evaluation of conventional single-bundle,
anatomic single-bundle, and anatomic DBanterior cruciate ligament
reconstruction: 281 cases with 3- to 5-year follow-up. 2011 November
15. [Epub ahead of print]
9) Chhabra A, Starman JS, Ferretti M, Vidal AF, Zantop T, Fu FH.
Anatomic, radiographic, biomechanical, and kinematic evaluation of
the anterior cruciate ligament and its two functional bundles. J Bone
Joint Surg Am 2006;88 Suppl 4:2-10.
10) Gabriel MT, Wong EK, Woo SL, Yagi M, Debski RE. Distribution of
in situ forces in the anterior cruciate ligament in response to rotatory
loads. J Orthop Res 2004;22-1:85-9.
11) van Eck CF, Schreiber VM, Liu TT, Fu FH. The anatomic approach
to primary, revision and augmentation anterior cruciate ligament
reconstruction. Knee Surg Sports Traumatol Arthrosc 2010;DOI
10.1007/s00167-010-1191-4
12) Kopf S, Forsythe B, Wong AK, Tashman S, Anderst W, Irrgang JJ,
Fu FH. Nonanatomic tunnel position in traditional transtibial singlebundle
anterior cruciate ligament reconstruction evaluated by threedimensional
computed tomography. J Bone Joint Surg Am 2010;92-
6:1427-31.
13) Forsythe B, Kopf S, Wong AK, Martins CA, Anderst W, Tashman S,
Fu FH. The location of femoral and tibial tunnels in anatomic doublebundle
anterior cruciate ligament reconstruction analyzed by threedimensional
computed tomography models. J Bone Joint Surg Am
2010;92-6:1418-26.
14) Cohen SB, Fu FH. Three-portal technique for anterior cruciate
ligament reconstruction: use of a central medial portal. Arthroscopy
2007;23-3:325 e1-5.
15) van Eck CF, Morse KR, Lesniak BP, Kropf EJ, Tranovich MJ, van
Dijk CN, Fu FH. Does the lateral intercondylar ridge disappear in ACL
deficient patients? Knee Surg Sports Traumatol Arthrosc 2010;DOI
10.1007/s00167-009-1038-z.
16) Fu FH, Jordan SS. The lateral intercondylar ridge--a key to
anatomic anterior cruciate ligament reconstruction. J Bone Joint
Surg Am 2007;89-10:2103-4.
17) Illingworth KD, Hensler D, Working ZM, Macalena JA, Tashman
S, Fu FH. A simple evaluation of anterior cruciate ligament femoral
tunnel position: the inclination angle and femoral tunnel angle. Am J
Sports Med. 2011 Dec;39(12):2611-8. Epub 2011 Sep 9.

142
Extended Abstracts
18) van Eck CF, Lesniak BP, Schreiber VM, Fu FH. Anatomic Single-
and Double-Bundle Anterior Cruciate Ligament Reconstruction
Flowchart. Arthroscopy 2010;26-2:258-68
19) Kondo E, Yasuda K, Azuma H, Tanabe Y, Yagi T. Prospective
clinical comparisons of anatomic double-bundle versus singlebundle
anterior cruciate ligament reconstruction procedures in 328
consecutive patients. American Journal of Sports Medicine.36(9)()
(pp 1675-1687), 2008.Date of Publication: Sep 2008. 2008-9:1675-
87.
20) Meredick RB, Vance KJ, Appleby D, Lubowitz JH. Outcome of
single-bundle versus double-bundle reconstruction of the anterior
cruciate ligament: a meta-analysis. Am J Sports Med 2008;36-
7:1414-21.
21) Irrgang JJ, Bost JE, Fu FH. Re: Outcome of single-bundle versus
double-bundle reconstruction of the anterior cruciate ligament: a
meta-analysis. Am J Sports Med 2009;37-2:421-2; author reply 2.
Acknowledgments:
University of Pittsburgh Medical Center Department of Orthopaedic
Surgery
14.2
The current prospects for gene therapy as a non-cellular therapy
L. Goodrich 1 , W. Mcilwraith 1 , J. Samulski 2
1 Fort Collins/United States of America, 2 Chapel Hill/United States
of America
Introduction: The following is an overview of what will be presented
in the presentation of “the current prospects for gene therapy as a
non-cellular therapy.
Content: Gene therapy for joint disease has been in existence for 2
decades. Its applications have included therapy for osteoarthritis,
cartilage repair, rheumatoid arthritis and other, less common joint
abnormalities. There is a large body of evidence in both animal studies
and clinical trials that suggest the therapy is safe and effective[1-4]. So
where are we now and what does the future hold for gene therapy? Will
it be a clinical reality and if so when? This presentation will give a brief
overview of gene therapy, a background on what has been done and
where it is going as a clinical modality to treat joint disease. Intra-articular
gene therapy is typically administered by one of two approaches, 1)
direct or otherwise known as in-vivo or 2) indirect or otherwise known
as ex-vivo[3]. Direct gene therapy is most often administered into the
joint by intra-articular injection and indirect is commonly performed by
delivering cells that have been genetically modified to the joint. Many
different types of cells have been utilized for ex-vivo gene therapy
including synoviocytes, chondrocytes, mesenchymal stem cells, or
antigen presenting cells. For this presentation, gene therapy as a noncellular
therapy will be discussed and therefore, ex-vivo approaches
will not be covered. The concept of direct in-vivo injection of gene
therapy vectors is straightforward. Therapeutic complementary DNA
(cDNA), is placed into a vector backbone (usually derived from a virus)
and the gene therapeutic vector is then injected into the joint. The
injection of these vector particles usually results in transduction of the
tissues within the joint to result in production of the desired therapeutic
protein intra-articularly. Tissues within the joint that are targets most
commonly include synovium, ligaments, cartilage and perhaps joint
capsule[5]. For many gene therapeutic vectors, chondrocytes within
the cartilage are not efficiently transduced due to the dense matrix
components of cartilage although one viral vector, adenoassociated
viral vector (AAV) appears to perhaps overcome that barrier. The
overarching goal for the gene therapeutic approach is to get long-term
protein production in the diseased joint to both reduce inflammation
and enhance catabolism to result in a reduction or a reversal of
disease progression. Many different transgenes have been used intraarticularly
to treat joint disease, the most common including interleukin
receptor antagonist protein (IL-1ra), insulin-like growth factor-I (IGF-I),
transforming growth factor beta (TGF-ß), and human tumor necrosis
factor receptor-immunoglobulin Fc (TNFR:Fc). Viral gene therapy has
been most commonly utilized due the fact that nonviral gene delivery
has not been efficacious in animal models[6]. Viral vectors that have
been successfully utilized in-vivo in animal models include adenovirus,
AAV, retrovirus, herpes simplex virus (HSV) and lentivirus[1, 7, 8]. As
one would expect, all viral vectors have advantages and disadvantages.
Adenovirus and HSV initiate inflammation and cytotoxicity within the
joint and, most importantly, do not result in long-term expression of
transgenes. Retroviruses require host-cell division and therefore are
generally only utilized for ex-vivo transfer since cell division is low in the
intra-articular environment[9]. Lentivirus, also considered a retrovirus
but a nononcoretrovirus, can stably transduce joint tissues but also
inserts the cDNA into the cellular genome which has been associated
with disease from insertional mutagenesis[10]. While lentivirus can
result in long-term expression, the complexity of their biology and
safety concerns have lessened the enthusiasm for their use. Much
excitement has been generated for use of AAV vectors in intra-articular
gene therapy in the last decade. The viral vector appears to safely and
efficiently transduce joint tissues and while it does not incorporate
into the cellular genome, it stays episomally and results in long-term
production of protein[1, 4, 11]. Advances in the biology of AAV have
also made the vector more efficient as in its wild type state it exists
as a single stranded DNA virus that counts on the cellular machinery
to produce protein. Advances in self-complementary AAV viral vectors
(scAAV) have overcome this barrier and resulted in much more efficient
intra-articular vectors[12, 13]. To date, there have been six clinical trials
of in-vivo gene therapy, 4 of which are published[1]. Two clinical trials
have been performed using retrovirus to deliver IL-1ra[9, 14], two
clinical trials have been performed using AAV to deliver TNFR-Fc[4,
11], one has used plasmid HSV-tk (unpublished) and one using NFkB
oligonucleotide (unpublished). While initial results of clinical trials
have shown promise, the field has been troubled by FDA mandates
of gene therapy trials to be either terminated or put on hold due to
complications of patients in trials until they have been successfully
proven to be gene therapy related or not. In one trial in which a subject
died that was injected into the circulation of the liver proved to be a
large barrier to getting gene therapy back on track[15]. Another trial in
which a subject died after a high dose intra-articular injection of AAV
again put progress on hold until the death was concluded to be non
treatment related[16]. Further clinical trials both in humans and animals
are on the forefront of advancement of gene therapy. Most likely the
few clinical trials published along with the large body of pre-clinical
data that exist on the utility of gene therapy for nonfatal diseases such
as osteoarthritis, cartilage degeneration and rheumatoid arthritis will
prove that this therapy will most likely conquer most concerns related
to safety and efficacy. Since no highly effective drugs exist for the
treatment of OA and over 40 million people suffer from this disease, an
efficacious treatment would be a welcomed clinical entity. Currently,
gene therapy is experiencing resurgence, especially in the field of
arthritis. Many animal models reveal efficacy and enthusiasm exists
for continued testing to treat both humans and animals that suffer
from cartilage damage and osteoarthritis[7, 8, 12, 17, 18]. The field will
continue to experience significant hurdles such as the need to prove
safety and efficacy, as well as adequate funding. This will most likely
slow progress but the current data indicate great promise and most
certainly gene therapy will overcome significant hurdles and achieve
success in the face of various challenges.
References:
1. Evans CH, Ghivizzani SC, Robbins PD (2011). Getting arthritis gene
therapy into the clinic. Nat Rev Rheumatol 7: 244-249.
2. Gelse K, von der Mark K, Schneider H (2003). Cartilage regeneration
by gene therapy. Current gene therapy 3: 305-317.
3. Robbins PD, Evans CH, Chernajovsky Y (2003). Gene therapy for
arthritis. Gene Ther 10: 902-911.
4. Mease PJ, et al. (2010). Safety, tolerability, and clinical outcomes
after intraarticular injection of a recombinant adeno-associated vector
containing a tumor necrosis factor antagonist gene: results of a phase
1/2 Study. The Journal of rheumatology 37: 692-703.
5. Gouze E, Gouze JN, Palmer GD, Pilapil C, Evans CH, Ghivizzani SC
(2007). Transgene persistence and cell turnover in the diarthrodial
joint: implications for gene therapy of chronic joint diseases. Mol Ther
15: 1114-1120.
6. Ghivizzani SC, et al. (2008). Perspectives on the use of gene therapy
for chronic joint diseases. Current gene therapy 8: 273-286.
7. Goodrich LR, Brower-Toland BD, Warnick L, Robbins PD, Evans CH,
Nixon AJ (2006). Direct adenovirus-mediated IGF-I gene transduction
of synovium induces persisting synovial fluid IGF-I ligand elevations.
Gene Ther 13: 1253-1262.
8. Nixon AJ, et al. (2007). Gene therapy in musculoskeletal repair. Ann
N Y Acad Sci 1117: 310-327.

9. Evans CH, et al. (2005). Gene transfer to human joints: progress
toward a gene therapy of arthritis. Proceedings of the National Academy
of Sciences of the United States of America 102: 8698-8703.
10. Kohn DB, Sadelain M, Glorioso JC (2003). Occurrence of leukaemia
following gene therapy of X-linked SCID. Nat Rev Cancer 3: 477-488.
11. Mease PJ, et al. (2010). Efficacy and safety of retreatment in patients
with rheumatoid arthritis with previous inadequate response to tumor
necrosis factor inhibitors: results from the SUNRISE trial. The Journal of
rheumatology 37: 917-927.
12. Kay JD, et al. (2009). Intra-articular gene delivery and expression
of interleukin-1Ra mediated by self-complementary adeno-associated
virus. The journal of gene medicine 11: 605-614.
13. Ishihara A, Bartlett JS, Bertone AL (2012). Inflammation and
immune response of intra-articular serotype 2 adeno-associated virus
or adenovirus vectors in a large animal model. Arthritis 2012: 735472.
14. Wehling P, et al. (2009). Clinical responses to gene therapy in joints
of two subjects with rheumatoid arthritis. Human gene therapy 20: 97-
101.
15. Raper SE, et al. (2003). Fatal systemic inflammatory response
syndrome in a ornithine transcarbamylase deficient patient following
adenoviral gene transfer. Molecular genetics and metabolism 80: 148-
158.
16. Frank KM, et al. (2009). Investigation of the cause of death in a
gene-therapy trial. The New England journal of medicine 361: 161-169.
17. Morisset S, Frisbie DD, Robbins PD, Nixon AJ, McIlwraith CW (2007).
IL-1ra/IGF-1 gene therapy modulates repair of microfractured chondral
defects. Clin Orthop Relat Res 462: 221-228.
18. Frisbie DD, Ghivizzani SC, Robbins PD, Evans CH, McIlwraith CW
(2002). Treatment of experimental equine osteoarthritis by in vivo
delivery of the equine interleukin-1 receptor antagonist gene. Gene
Ther 9: 12-20.
Acknowledgments:
K08AR054903-01A2 and Grayson Jockey Club Foundation
15.1.1
Platelet rich plasma: Overview of current knowledge: hope, hype
and reality.
L.A. Fortier 1 , T. Mccarrell 2 , B.J. Cole 2 , S. Boswell 1 , L.V. Schnabel 1
1 Ithaca/United States of America, 2 Chicago/United States of
America
Introduction: Platelet concentrates such as platelet-rich plasma
(PRP) have gained popularity in sports medicine and orthopedics to
promote accelerated physiological healing and return to function.
The concept that PRP can improve joint or tendon disease is based on
the physiologic role of platelets and their contained growth factors
in wound healing. However, PRP is comprised of all substances in
blood and components in this milieu have bioactive functions that
positively and negatively affect musculoskeletal tissue regeneration
and healing. Mixed reports of success have been reported after
use of PRP in sports medicine, but with the field in its infancy,
there are sufficiently positive outcome data to continue use of and
investigations into PRP.
Content: In sports medicine there are numerous clinical objectives
motivating the use of PRP including promotion of tissue regeneration
in both bony and soft tissues, prevention and treatment of infection,
and restoration of function. Reviews on the basic science and clinical
indications of PRP are common. Originally, PRP was considered as a
method to deliver platelets and therefore growth factors. This lead to
the common thought that more is better, leading to a race amongst
manufacturers to develop systems that would increase platelet
concentrations to a greater level compared to their competitors.
However, concerns were raised about the increase in leukocytes
in some preparations leading to the concept that PRP is a milieu
of all blood components and not simply a means of growth factor
delivery. Ex vivo studies indicated that concentrations of leukocytes
in PRP were directly correlated to loss of normal tendon matrix
Extended Abstracts 143
and an increase in inflammatory molecules. It is unclear what the
clinical ramifications of increased leukocytes are in clinical patients
because the majority of studies do not report leukocyte or platelet
concentration in PRP being administered to the patient. This raises
another significant concern because PRP is not always generated
from a patient’s blood. There are numerous factors that affect a
patient’s platelet count including nutrition, hydration, smoking, and
natural diurnal variation. This makes it important that at a minimum,
PRP be tested for platelet counts when performing clinical studies so
that outcome can be related to the PRP product delivered. Ideally,
leukocyte counts in the PRP product are determined as well.
The hype over PRP in North America began in early 2009 when two
famous athletes received PRP injections and successfully returned
to professional athletics earlier than anticipated if they were treated
with conventional therapy. PRP was being used and reported on
in small case series prior to this time, but this is when the real
media blitz began, and PRP became of interest to a broad range of
physicians and patients. There are few level 1 studies and several
level 2 or 3 studies that have mixed results regarding the efficacy of
PRP for treatment of musculoskeletal ailments including joint pain,
patellar tendonitis, Achilles tendonosis, and epicondylitis. Clinical
observation and opinion suggests that pain relief and restoration
of function occur more rapidly than expected for some orthopedic
problems with the use of PRP. This has led to investigations of antinociceptive
and anti-inflammatory properties of PRP in our laboratory
and others. Our data indicates that in patients with osteoarthritis,
PRP does decrease the production of pro-inflammatory markers of
pain such as tumor necrosis factor which supports the concept that
PRP functions to decrease pain and inflammation. A by-product of
decreasing inflammation would be joint preservation, but there is
no clinical data to suggest that PRP increases production of cartilage
extracellular matrix proteins such as aggrecan or type II collagen.
In summary, PRP is a useful regenerative therapy to address many
musculoskeletal injuries. It is important to understand that PRP is
more than just platelets and that it contains many bioactive factors that
act in anabolic, catabolic, pro-inflammatory, and anti-inflammatory
pathways. The precise combination and concentration of platelets,
leukocytes, and other plasma components best for musculoskeletal
healing is not presently known, and clinicians should be aware that the
effects of PRP are not solely based on platelet concentration. Finally,
it is imperative for those involved in clinical study design to take into
consideration diurnal variation in platelet count and to understand that
some patients in some instances will simply fail to generate PRP. This
information is important for assessment of clinical outcome.
References:
1. Rodeo SA, Delos D, Weber A, et al. What’s new in orthopaedic
research. J Bone Joint Surg Am 2010;92:2491-501.
2. Schnabel LV, Mohammed HO, Miller BJ, et al. Platelet rich plasma
(PRP) enhances anabolic gene expression patterns in flexor digitorum
superficialis tendons. J Orthop Res 2007;25:230-40.
3. Paoloni J, De Vos RJ, Hamilton B, Murrell GA, Orchard J. Plateletrich
plasma treatment for ligament and tendon injuries. Clin J Sport
Med 2011;21:37-45.
4. Peerbooms JC, Sluimer J, Bruijn DJ, Gosens T. Positive effect of an
autologous platelet concentrate in lateral epicondylitis in a doubleblind
randomized controlled trial: platelet-rich plasma versus
corticosteroid injection with a 1-year follow-up. Am J Sports Med
2010;38:255-62.
5. Lopez-Vidriero E, Goulding KA, Simon DA, Sanchez M, Johnson DH.
The use of platelet-rich plasma in arthroscopy and sports medicine:
optimizing the healing environment. Arthroscopy 2010;26:269-78.
6. McCarrel T, Fortier L. Temporal growth factor release from plateletrich
plasma, trehalose lyophilized platelets, and bone marrow
aspirate and their effect on tendon and ligament gene expression. J
Orthop Res 2009;27:1033-42.
7. Dohan Ehrenfest DM, Bielecki T, Corso MD, Inchingolo F,
Sammartino G. Shedding light in the controversial terminology
for platelet-rich products: Platelet-rich plasma (PRP), platelet-rich
fibrin (PRF), platelet-leukocyte gel (PLG), preparation rich in growth
factors (PRGF), classification and commercialism. J Biomed Mater
Res A 2010;.
8. Senzel L, Gnatenko DV, Bahou WF. The platelet proteome. Curr
Opin Hematol 2009;16:329-33.
9. Foster TE, Puskas BL, Mandelbaum BR, Gerhardt MB, Rodeo SA.
Platelet-rich plasma: from basic science to clinical applications. Am J
Sports Med 2009;37:2259-72.

144
Extended Abstracts
15.1.2
Platelet rich plasma and joint tissue repair
E. Kon, G. Filardo, B. Di Matteo, A. Di Martino, M. Marcacci
Bologna/Italy
Introduction: Definition and biological rational Orthopaedic and
rheumatologic physicians must everyday face the complex issue of
cartilage pathology, whose prevalence (1,2,3) is rapidly increasing due
to the massive involvement in sport activity by the entire population,
from the youngs to the middle-aged and even elder individuals, all
moved by the awareness of the importance of physical activity as
a preventive medical approach. Despite the positive aspects of
this widespread life-style, new medical problems have emerged: in
particular, cartilage lesions are becoming one of the most important
challenge for both basic researchers and clinicians. In fact, although
being able to sustain huge mechanical stresses, cartilage has limited
healing potential due to several reasons: first of all, the relative
isolation from systemic regulation caused by the lack of nerves and
vessels when compared to other tissues. Furthermore, its complex
histological structure, consisting of chondrocytes surrounded by
matrix made of a specialized framework of collagen, aggrecans
and fluid, determines an intrinsic vulnerability that, starting from
small and focal lesions, can evolve in an accelerated degenerative
process whose final stage is osteoarthritis (OA), a chronic condition
difficult to treat by conservative means and often requiring a surgical
approach such as arthroplasty. Several treatment, both conservative
and surgical, could address cartilage pathology (4,5,6) and the
therapeutic decision has to be taken according to the specific
case and the eventual presence of other comorbidities (meniscal
status, axial alignment, etc..). Besides traditional pharmacological
approaches (paracetamol, NSAIDs, opioids), physiotherapy and
recognized injective treatments (i.e.,viscosupplementation or
corticosteroids), some new trends have emerged in the last years,
opening a large and sometimes controversial research topic: the
application of blood-derivatives for joint degenerative pathology.
Recently, a blood-derived product, platelet-rich plasma (PRP), has
gained increasing attention as a promising procedure to stimulate
cartilage repair. PRP is an autologous concentrate of plateletderived
growth factors (GFs) and other molecules, obtained directly
from the peripheral venous blood of the patient. GFs are a group
of polypeptides playing a fundamental role in the regulation of
growth and development of several tissues, including cartilage. The
biological rational of PRP is that platelets contain storage pools of GFs
including: platelet-derived growth factor (PDGF); transforming growth
factor (TGF-β); platelet-derived epidermal growth factor (PDEGF);
vascular endothelial growth factor (VEGF); insulin-like growth factor
1 (IGF-1); fibroblastic growth factor (FGF); and epidermal growth
factor (EGF) (7, 8). Besides GFs, alpha granules are also a source of
cytokines, chemokines and many other mediators (1) all involved
in complex biological mechanisms stimulating chemotaxis, cell
proliferation and maturation, modulating inflammatory molecules
and attracting leukocytes (1). Platelets also store dense granules,
rich of ADP, ATP, calcium ions, histamine, serotonin and dopamine,
which play a complex role in tissue modulation and regeneration
(9). Finally, platelets contain lisosomal granules which can secrete
acid hydrolases, cathepsin D and E, elastases and lysozyme
(10,11), and most likely other not yet well characterized molecules,
the role of which in tissue healing should not be underestimated.
Several in vitro and in vivo animal studies showed the potential
beneficial effect of PRP in promoting cellular anabolism and tissue
regeneration (12, 13). This fascinating regenerative approach has led
to some urging controversies among the scientific community. First
of all, the lack of universal definition: in general, PRP is regarded as
a blood derivative generated by differential centrifugation of whole
blood, with a higher concentration of platelets compared to basal
level, commonly about 400% of the peripheral blood count (14,15).
However, in the literature PRP concentrations have been reported to
range widely, from 4 to 8 times than those found in whole blood (18),
and good results have been reported also with lower concentrations
(16,17). Furthermore, several different procedures have been
described to obtain PRP, thus implying the existence of qualitative
and quantitative differences among substances used in various preclinical
and clinical studies. In particular, the presence of leukocytes
in the final product has been considered a crucial point, due to their
potential negative pro-inflammatory effect. Further differences lie
in the storage modalities and the activation methods, thus adding
other variables to consider when comparing clinical results reported
in literature (18).
Content: Clinical application Besides the application in cartilage
degenerative pathology, platelet derived growth factors have been
applied in a large number of clinical conditions both as a mere
conservative treatment or as a “biological augmentation” during
surgical procedures. The range of pathologies treated with PRP
comprehends a remarkable variety of tendinopathies (19, 20, 21),
muscle lesions and even anterior cruciate ligament (ACL)
reconstruction (14). For what concerns cartilage pathology, PRP
application has been investigated in several studies. Also in this
case conservative and surgical approaches have been attempted.
With respect to the surgical approach the first paper, a case report,
was published in 2003 by Sanchez et al. (22) concerning a 12 years
old football player with a large (> 2 cm2) articular cartilage avulsion
in the knee and treated arthroscopically with re-attachment of the
chondral fragment and platelet concentrate injection at the fragment
center and all around the interface with the healthy surrounding
tissue. Clinical results were excellent with full functional recovery
and resumption of the sport practice after 18 weeks. The patient
returned to the same pre-injury level just a few weeks later. Another
surgical application of PRP was explored by Dhollander et al. (23)
who treated 5 osteochondral defects of the patella with a combined
collagen I/III scaffold membrane implant on the prepared lesion site
and PRP injection underneath. Clinical results at 24 months of followup
were satisfying and even MRI evaluation showed good quality of
the repair tissue, but a clear role of the platelet concentrate couldn’t
be demonstrated. A further study of Siclari et al. (24) proved the
efficacy of a polyglycolic acid/hyaluronan scaffold immersed in PRP
for treating full-thickness chondral defects of the knee: 52 patients
were treated arthroscopically and evaluated at 1 year follow-up
obtaining a significant clinical improvement. Five biopsies were also
performed revealing an homogeneous, well integrated repair tissue.
Giannini et al. (25) applied an innovative technique in treating focal
osteochondral talar lesions, using an autologous preparation
consisting of bone marrow concentrate and PRP applied on a
hyaluronan scaffold or mixed with collagen powder. They treated 48
patients through an arthroscopic single-step procedure and reported
their results at 24 months of follow-up: clinical score registered a
sensible increase with most of the patients coming back to sport
activity. In light of these studies, PRP seems an effective biological
enhancer for acellular scaffolds used in treating chondral defects.
Another study (26), however, pointed out that, at least in the animal
model, PRP could even decrease the regenerative potential of an
osteochondral biomimetic scaffold. PRP intra-articular injective
treatment has been the subject of nine studies to date, mostly
focusing on knee application. In 2008 Sanchez et al. published a
retrospective observational study on 60 patients (27) comparing
platelet concentrate and HA. Patients from both groups underwent
three injections one week apart and were evaluated basally and at 5
weeks of follow up. Results were encouraging, with a better pain
control in PRP group, even though the short follow-up is an important
limitation. In 2010 Sampson et al. published a study (28) on 14
patients with primary or secondary OA of the knee and previous
unsuccessful treatments. The patients received 3 PRP injections one
month apart and were evaluated at basal level and up to one year of
follow-up. A statistically significant clinical improvement was
documented , with a reduction of the pain both at rest and during
physical activity. In 2010 Wang-Saegusa et al. (29) reported their
results after treating 261 patients, affected by uni- or bilateral knee
OA, with three injections of platelet concentrate two weeks apart.
Prospective evaluation up to 6 months was performed and also in
this case statistical analysis revealed significant results with increase
in all the scores applied. Kon et al. published in 2009 a prospective
study (30) on 91 patients (for a total of 115 knees) treated with three
injections of PRP (one every three weeks). Inclusion criteria were:
clinical history of knee pain or articular swelling lasting more than 4
months, radiographic or MRI signs of OA or cartilage degenerative
lesions. Patients underwent clinical evaluation at basal level and at
2, 6, and 12 months of follow-up. Eighty percent of the patients
treated expressed satisfaction for the treatment received. Clinical
outcome registered a statistically relevant improvement in all the
variables considered just after 2 months from the end of the
treatment. These results were later confirmed at 6 months of followup,
whereas a tendency of worsening was reported from 6 to 12
months of follow-up. Despite the decrease reported after one year,
the clinical scores at that time were still higher than the basal level.
Some influencing factors were detected: in particular it was observed
that young male patients are the best responding group, especially
in case of simple chondropathy without signs of OA. A later study by
the same authors (31) evaluating the patients at 24 months of followup
confirmed this trend with a further decrease in the clinical
outcome thus concluding that intra-articular therapy with plateletderived
GFs is time dependent with an average duration of 9 months
and better and long lasting results in younger patients with lower
level of joint degeneration. In another multi-center study carried on
by Kon et al. (32), the clinical effectiveness of PRP was compared to
low molecular weight HA (LWHA) and high molecular weight HA
(HWHA). Three homogeneous groups of patients were respectively
treated with 3 weekly injections of PRP, LWHA, or HWHA. The results

evidenced a better performance for PRP group at 6 months of followup.
In particular, subgroups analysis (chondropathy vs early vs
severe OA) revealed again that, in the chondropathy group, PRP
gave markedly higher results than HA at 6 months of follow-up,
whereas in the early OA group the gap in favor of PRP is reduced and
in the severe OA subgroup no difference in clinical outcome was
observed between treatments. Furthermore, patients under 50 years
old have greater chance to benefit from this biological approach
with GFs supplementation. Finally, a comparative study between
PRP with or without leukocytes used to treat 144 patients affected
by knee cartilage pathology has recently been published by Filardo
et al. showing comparable positive clinical effects with both
treatments, with PRP-leukocyte group suffering from more swelling
and pain reaction after the injections (33). Injective application of
PRP has been tested also in case of hip osteoarthritis and
osteochondral lesions of the talus. A pilot study led by Battaglia et
al. (34) reported the results of PRP ultra-sound guided injective
treatment in 20 patients affected by hip OA. At short term evaluation,
clinical outcome was positive but a gradual worsening occurred up
to one year of follow-up. Lastly, a prospective study of Mei-Dan et al.
(35) compared the efficacy of HA and PRP in 30 patients (15 per
group) affected by talar osteochondral lesions and evaluated up to
28 weeks of follow-up. Results were statistically significant and PRP
proved to be more effective in controlling pain and re-establishing
function. Conclusions Many studies have been published on PRP
application for joint tissues repair and there is evidence about the
safety of this method either through injections or during surgical
procedures. The majority of these studies reveals interesting
preliminary results for cartilage degenerative pathology and also for
tendinopathies, but too many are still the questions to clarify,
concerning the real biological potential, the indications, and the
application methods. Many aspects have still to be understood also
in terms of basic science. A “miracle aura” has arisen in the last
years toward PRP application but the literature is still controversial
and further high quality, randomised control trials are needed to
endorse this therapy as a real valid option among joint regenerative
procedures.
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Extended Abstracts 145
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fibrin matrices. Am J Sports Med. 2007 Feb;35(2):245-51.
18. Tschon M, Fini M, Giardino R, Filardo G, Dallari D, Torricelli P,
Martini L, Giavaresi G, Kon E, Maltarello MC, Nicolini A, Carpi A. Lights
and shadows concerning platelet products for musculoskeletal
regeneration. Front Biosci 2011 Jan 1;3:96107.Review
19. Kon E, Filardo G, Delcogliano M, Presti ML, Russo A, Bondi A,
Di Martino A, Cenacchi A, Fornasari PM, Marcacci M. Platelet-rich
plasma: new clinical application: a pilot study for treatment of
jumper’s knee. Injury. 2009 Jun;40(6):598-603. Epub 2009 Apr 19.
20. Filardo G, Kon E, Della Villa S, Vincentelli F, Fornasari PM, Marcacci
M. Use of platelet-rich plasma for the treatment of refractory jumper’s
knee. Int Orthop. 2010 Aug; 34(6):909-15. Epub 2009 Jul 31.
21. Filardo G, Presti ML, Kon E, Marcacci M. Nonoperative biological
treatment approach for partial Achilles tendon lesion. Orthopedics.
2010 Feb;33(2):120-3. doi: 10.3928/01477447-20100104-31.
22. Sánchez M, Azofra J, Anitua E, Andía I, Padilla S, Santisteban J,
Mujika I. Plasma rich in growth fac tors to treat an articular cartilage
avulsion: a case report. Med Sci Sports Exerc. 2003 Oct;35(10):1648-
52.
23. Dhollander AA, De Neve F, Almqvist KF, Verdonk R, Lambrecht
S, Elewaut D, Verbruggen G, Verdonk PC Autologous matrix-induced
chondrogenesis combined with platelet-rich plasma gel: technical
description and a five pilot patients report. Knee Surg Sports
Traumatol Arthrosc. 2011 Apr;19(4):536-42. Epub 2010 Dec 11.
24. Siclari A, Mascaro G, Gentili C, Cancedda R, Boux E.A Cell-free
Scaffold-based Cartilage Repair Provides Improved Function Hyalinelike
Repair at One year. Clin Orthop Relat Res. 2012 Mar;470(3):910-
9. Epub 2011 Oct 1.
25. Clin Orthop Relat Res. 2009 Dec;467(12):3307-20. Epub 2009
May 16.One-step bone marrow-derived cell transplantation in talar
osteochondral lesions.Giannini S, Buda R, Vannini F, Cavallo M,
Grigolo B.
26. Kon E, Filardo G, Delcogliano M, Fini M, Salamanna F, Giavaresi G,
Martin I, Marcacci M. Platelet autologous growth factors decrease the
osteochondral regeneration capability of a collagen-hydroxyapatite
scaffold in a sheep model. BMC Musculoskelet Disord. 2010 Sep
27;11:220.
27. Sánchez M, Anitua E, Azofra J, Aguirre JJ, Andia I . Intra-articular
injection of an autolo gous preparation rich in growth factors for
the treatment of knee OA: a retrospective cohort study. Clin Exp
Rheumatol. 2008 Sep-Oct;26(5):910-3.
28. Sampson S, Reed M, Silvers H, Meng M, Mandelbaum B. Injection
of platelet-rich plasma in patients with primary and secondary
knee osteoarthritis: a pilot study. Am J Phys Med Rehabil. 2010
Dec;89(12):961-9.

146
Extended Abstracts
29. Wang-Saegusa A, Cugat R, Ares O, Seijas R, Cuscó X, Garcia-
Balletbó M. Infiltration of plasma rich in growth factors for
osteoarthritis of the knee short-term effects on function and quality
of life. Arch Orthop Trauma Surg. 2011 Mar;131(3):311-7. Epub 2010
Aug 17.
30. Kon E, Buda R, Filardo G, Di Martino A, Timoncini A, Cenacchi
A, Fornasari PM, Giannini S, Marcacci M. Platelet-rich plasma: intraarticular
knee injections produced favorable results on degenerative
cartilage lesions. Knee Surg Sports Traumatol Arthrosc. 2010
Apr;18(4):472-9. Epub 2009 Oct 17.
31. Filardo G, Kon E, Buda R, Timoncini A, Di Martino A, Cenacchi
A, Fornasari PM, Giannini S, Marcacci M. Platelet-rich plasma intraarticular
knee injections for the treatment of degenerative cartilage
lesions and osteoarthritis. Knee Surg Sports Traumatol Arthrosc.
2011 Apr;19(4):528-35. Epub 2010 Aug 26.
32. Kon E, Mandelbaum B, Buda R, Filardo G, Delcogliano M, Timoncini
A, Fornasari PM, Giannini S, Marcacci M. Platelet-Rich Plasma Intra-
Articular Injection Versus HyaluronicAcid Viscosupplementation
as Treatments for Cartilage Pathology: From Early Degeneration to
Osteoarthritis. Arthroscopy. 2011 Aug 8. (Epub ahead of print)
33. Filardo G, Kon E, Pereira Ruiz MT, Vaccaro F, Guitaldi R, Di
Martino A, Cenacchi A, Fornasari PM, Marcacci M.Platelet-rich
plasma intra-articular injections for cartilage degeneration and
osteoarthritis: single- versus double-spinning approach. Knee Surg
Sports Traumatol Arthrosc. 2011 Dec 28. (Epub ahead of print)
34.Battaglia M, Guaraldi F, Vannini F, Buscio T, Buda R, Galletti S,
Giannini S. Platelet-rich plasma (PRP) intra-articular ultrasoundguided
injections as a possible treatment for hip osteoarthritis: a
pilot study. Clin Exp Rheumatol. 2011 Jul-Aug;29(4):754.
35. Mei-Dan O, Carmont MR, Laver L, Mann G, Maffulli N, Nyska
MPlatelet-Rich Plasma or Hyaluronate in the Management of
Osteochondral Lesions of the Talus. Am J Sports Med. 2012 Jan 17.
(Epub ahead of print)
Acknowledgments:
We would like to thank Letizia Merli, MD; Francesco Perdisa, MD;
Luca Andriolo, MD; Silvio Patella, MD; Federica Balboni, MS; Giulio
Altadonna, MS; Angela Montaperto, JD, all from Rizzoli Orthopaedic
Institute, Bologna, Italy.
15.1.3
Clinical experiences with Platelet-Rich Plasma
S. Rodeo
New York/United States of America
Introduction: 10th World Congress of the International Cartilage
Repair Society Clinical Experience with Platelet Rich Plasma Scott
A. Rodeo, MD Co-Chief, Sports Medicine and Shoulder Service
Professor, Orthopaedic Surgery, Weill Medical College of Cornell
University Attending Orthopaedic Surgeon, The Hospital for Special
Surgery Associate Team Physician, New York Giants Football
This talk will review recent clinical data on the use of PRP for tissues
in and around the synovial joint, including hyaline cartilage, ligament,
tendon, and meniscus. Cytokines are known to have important and
fundamental roles in connective tissue biology Cytokines affect: -
cell proliferation - matrix synthesis - angiogenesis - chemotaxis
Connective tissue healing requires a complex timing and sequence
of cytokine expression à thus, single factor therapy has distinct
limitations The rationale and attraction of PRP is the ability to deliver
numerous cytokines in physiologically-relevant proportions Despite
vast basic science and laboratory data demonstrating a positive
effect of various PRP formulations on basic cell biology, this has not
translated into a consistently positive clinical effect. A fundamental
limitation in studying PRP is the fact that there is tremendous
variability in various commercially-available PRP formulations.
There are variations in: • Platelet recovery • Inclusion of WBCs •
Platelet activation (thrombin, Ca+) • Kinetics of cytokine release
from PRP/PRFM • Preservation/function of the platelets and WBCs
• Ratio between fibrinogen and thrombin concentration • Formation
of a fibrin matrix (fibrin polymerization) • Microstructure of the final
fibrin network (ability to trap cytokines and other bioactive factors)
There is also variability with an individual:
• Platelet counts vary markedly between patients
• Platelet counts vary day to day within an individual
• Growth factor content per platelet
• Other proteins/factors in the plasma
• Another important limitation in the use of PRP:
Exogenous growth factor therapy often only improves the structural
properties of tissues by inducing more (scar) tissue formation, while
NOT improving the material properties
A large body of data shows that cytokines can increase production of
matrix proteins BUT a critical deficiency is that tissue microstructure
is not reformed Thus, it appears that growth factors (PRP) still do
not provide the proper cellular and molecular signals to drive
regenerative healing I hypothesize that both pluripotent cells AND
appropriate signals (cytokines) are needed to reconstitute tissue
composition and structure Summary of major points for each
different tissue type: Articular cartilage/osteoarthritis A number
of studies have demonstrated clinical improvement in symptoms
following PRP injections in the knee. There is very little data available
for joints other than the knee. Most studies report better results in
younger patients with lesser degrees of degeneration.
The clinical effect typically wears off after 6-12 months. There is very
little (virtually zero) data that has demonstrated a positive structural
effect (actual regeneration of cartilage tissue). Very few studies that
have compared to intra-articular steroid or hyaluronic acid. Kon et
al (Arthroscopy 2011) reported PRP superior to hyaluronic acid in
younger patients and with earlier grade of OA.
PRP releasate may inhibit the adverse effects of IL-1β and other
negative factors in the inflammatory environment.
Further studies required in this area: 1. Further define best way to
isolate and concentrate IL-1 receptor antagonist (IL-1Ra). 2. Define
the role (positive or negative) of white blood cells when treating
cartilage lesions. 3. Arthritis is very heterogeneous condition: the
effect of a specific PRP formulation may differ significantly based
on the underlying biologic/inflammatory milieu. Patellar Tendon:
There is very little data available on the effect of PRP for patellar
tendonopathy There is some positive data for lateral epicondylitis,
suggesting that PRP may be effective for extra-articular tendons
(such as patellar tendon). One study reports positive results and
demonstrates potential for improvement in MRI appearance of
degenerative patellar tendon (Filardo et al, Int Orthop 2010)
Meniscus:
There is very little data available on the effect of PRP on meniscus
healing. Placement of an exogenous fibrin clot has been used in
conjunction with meniscus repair, and thus the concept of using PRP
during meniscus repair makes sense. Ishida et al showed a positive
effect in both in vitro and in vivo studies (rabbit model). However,
there is very little clinical data available at this time.
ACL:
A number of studies have examined the effect of PRP applied to an
ACL graft and/or the graft-bone interface in the bone tunnel. MRI
has been used to examine signal in the graft, as a reflection of graft
maturation and remodeling. Some studies have shown a positive
effect on graft remodeling. Further studies are required to better
define the potential for PRP to affect either graft-bone healing and
remodeling/maturation of the intra-articular portion of the graft.
Furthermore, the relationship between morphologic changes in the
graft and graft function/knee stability is still unclear.
Content: 10th World Congress of the International Cartilage Repair
Society Clinical Experience with Platelet Rich Plasma Scott A. Rodeo,
MD Co-Chief, Sports Medicine and Shoulder Service Professor,
Orthopaedic Surgery, Weill Medical College of Cornell University
Attending Orthopaedic Surgeon, The Hospital for Special Surgery
Associate Team Physician, New York Giants Football
This talk will review recent clinical data on the use of PRP for tissues

in and around the synovial joint, including hyaline cartilage, ligament,
tendon, and meniscus. Cytokines are known to have important and
fundamental roles in connective tissue biology Cytokines affect:
- cell proliferation - matrix synthesis - angiogenesis - chemotaxis
Connective tissue healing requires a complex timing and sequence
of cytokine expression à thus, single factor therapy has distinct
limitations The rationale and attraction of PRP is the ability to deliver
numerous cytokines in physiologically-relevant proportions Despite
vast basic science and laboratory data demonstrating a positive
effect of various PRP formulations on basic cell biology, this has not
translated into a consistently positive clinical effect. A fundamental
limitation in studying PRP is the fact that there is tremendous
variability in various commercially-available PRP formulations.
There are variations in: • Platelet recovery • Inclusion of WBCs •
Platelet activation (thrombin, Ca+) • Kinetics of cytokine release
from PRP/PRFM • Preservation/function of the platelets and WBCs
• Ratio between fibrinogen and thrombin concentration • Formation
of a fibrin matrix (fibrin polymerization) • Microstructure of the final
fibrin network (ability to trap cytokines and other bioactive factors)
There is also variability with an individual:
• Platelet counts vary markedly between patients
• Platelet counts vary day to day within an individual
• Growth factor content per platelet
• Other proteins/factors in the plasma
Another important limitation in the use of PRP:
Exogenous growth factor therapy often only improves the structural
properties of tissues by inducing more (scar) tissue formation, while
NOT improving the material properties
A large body of data shows that cytokines can increase production of
matrix proteins BUT a critical deficiency is that tissue microstructure
is not reformed Thus, it appears that growth factors (PRP) still do
not provide the proper cellular and molecular signals to drive
regenerative healing I hypothesize that both pluripotent cells AND
appropriate signals (cytokines) are needed to reconstitute tissue
composition and structure Summary of major points for each
different tissue type: Articular cartilage/osteoarthritis A number
of studies have demonstrated clinical improvement in symptoms
following PRP injections in the knee. There is very little data available
for joints other than the knee. Most studies report better results in
younger patients with lesser degrees of degeneration. The clinical
effect typically wears off after 6-12 months.
There is very little (virtually zero) data that has demonstrated a
positive structural effect (actual regeneration of cartilage tissue).
Very few studies that have compared to intra-articular steroid or
hyaluronic acid. Kon et al (Arthroscopy 2011) reported PRP superior
to hyaluronic acid in younger patients and with earlier grade of OA.
PRP releasate may inhibit the adverse effects of IL-1β and other
negative factors in the inflammatory environment. Further studies
required in this area: 1. Further define best way to isolate and
concentrate IL-1 receptor antagonist (IL-1Ra). 2. Define the role
(positive or negative) of white blood cells when treating cartilage
lesions. 3. Arthritis is very heterogeneous condition: the effect of
a specific PRP formulation may differ significantly based on the
underlying biologic/inflammatory milieu. Patellar Tendon:
There is very little data available on the effect of PRP for patellar
tendonopathy There is some positive data for lateral epicondylitis,
suggesting that PRP may be effective for extra-articular tendons
(such as patellar tendon). One study reports positive results and
demonstrates potential for improvement in MRI appearance of
degenerative patellar tendon (Filardo et al, Int Orthop 2010)
Meniscus:
There is very little data available on the effect of PRP on meniscus
healing. Placement of an exogenous fibrin clot has been used in
conjunction with meniscus repair, and thus the concept of using PRP
during meniscus repair makes sense. Ishida et al showed a positive
effect in both in vitro and in vivo studies (rabbit model). However,
there is very little clinical data available at this time.
ACL:
A number of studies have examined the effect of PRP applied to an
ACL graft and/or the graft-bone interface in the bone tunnel. MRI
has been used to examine signal in the graft, as a reflection of graft
Extended Abstracts 147
maturation and remodeling. Some studies have shown a positive
effect on graft remodeling. Further studies are required to better
define the potential for PRP to affect either graft-bone healing and
remodeling/maturation of the intra-articular portion of the graft.
Furthermore, the relationship between morphologic changes in the
graft and graft function/knee stability is still unclear.
15.2.2
Hydrogels in cartilage repair
J.D. Kisiday, D.D. Frisbie, L. Goodrich, W. Mcilwraith
Fort Collins/United States of America
Introduction: Hydrogels are a class of polymer materials consisting
of a hydrophilic network that is capable of absorbing water up to
hundreds of times the dry weight of the polymer. The high water
content of hydrogels is a favorable environment for cells as the
polymer network readily allows for diffusion of oxygen, nutrients,
and waste products. As a result, many biocompatible synthetic and
natural polymers that assemble into hydrogels have been explored
as scaffolds for cartilage tissue engineering (1).
Content: Enthusiasm for hydrogels for cartilage repair has been
generated from a long history of the use of hydrogels to study
chondrocyte biology. For example, agarose, a polysaccharide
derived from algae, has been used for nearly 40 years to create
three dimensional suspension cultures that holds chondrocytes
in a round morphology as they exist in cartilage. Chondrocytes
encapsulated in agarose have been use to study a variety of cellular
behaviors, including redifferentiation following dedifferentation to
a fibroblastic phenotype that occurs during monolayer expansion
(2), the response to physical forces (3), and the influence of growth
factors and pro-inflammatory cytokines. In addition, in recent
years agarose has been shown to support chondrogenesis of
various types of progenitor cells in the presence of a chondrogenic
cytokine (4-6) and/or resulting from mechanical loading (7). In both
chondrocyte and progenitor cell studies, the encapsulated cells
have secreted a robust cartilaginous neo-tissue that is retained
within the hydrogel, which lends support to the potential of
hydrogels to host repair in cartilage defects. Given these findings,
the exploration of novel scaffolds for tissue engineering are often
initiated in vitro by designing experiments that are based on
multiweek cultures and cartilaginous extracellular matrix synthesis
as used to study chondrocyte biology. In our lab, we continue to use
agarose hydrogels as control cultures for the development of novel
scaffolds or for characterizing chondrogenic priming technologies for
progenitor cells. Hydrogels lend themselves to ongoing optimization
for cartilage repair by the potential to introduce modifications to the
polymer network. For example, researchers have explored whether
the incorporation of biomolecules enhances cartilaginous neotissue
synthesis. One such approach has been to incorporate the cell
adhesion RGD peptide sequence, which has been added to alginate
(8) and polyethylene glycol (PEG) (9) hydrogels as it is known that
cells do not attach to these polymer networks. Another approach
involved chemically crosslinking chondroitin sulfate moieties to
PEG hydrogel to stimulate bone marrow-derived mesenchymal
stem cell chondrogenesis (10). A second modification is to provide a
concentrated, local supply of growth factors attached to the polymer
network, which can influence cell behaviors after implantation. This
approach may prove to be particularly important for progenitor
cell therapies as the majority of cartilage repair animal studies
have implanted undifferentiated cells, with the expectation that
the joint environment stimulates chondrogenesis and subsequent
accumulation of repair tissue. One method for incorporating growth
factors into hydrogels is to tether growth factors to the hydrogel
network (11). Or, the polymer network of certain hydrogels have been
found to adsorb growth factors when they are added to the solution
of monomers prior to assembly (11, 12). Given the importance of
inducing progenitor cell chondrogenesis, many of these studies have
focused on the tethering or adsorption of the chondrogenic cytokine
transforming growth factor beta. Modifications of the hydrogel
network may also be used to better control degradation in an effort
to achieve the ideal tissue engineering goal of coordinating neotissue
accumulation with resorption of the scaffold. For example,
matrix metalloproteinase cleavage sites have been engineered into
PEG hydrogels (13) to increase the rate of degradation in the joint,
allowing for the maturation of a continuous repair tissue over time
that may otherwise be impeded by undegraded scaffold. These
examples illustrate the potential to tune hydrogels to meet the needs
of a cartilage tissue engineering scaffold. Hydrogels have also been

148
Extended Abstracts
used to prepare cells for implantation, with the most established
method being the alginate-recovered chondrocyte technique (14).
In this method, chondrocytes are encapsulated in alginate and
cultured in vitro to allow for the accumulation of extracellular matrix.
The alginate network is readily dissociate without harming the
encapsulated cells, resulting in a population of chondrocytes that
are surrounded by a cell-associated neo-cartilage which may be
used for treating cartilage defects within a scaffold or as a scaffoldfree
implant. In our lab, we have investigated the use of selfassembling
peptide hydrogel as a temporary in vitro environment
for chondrogenic priming of bone marrow mesenchymal stem cells.
Similar to the motivation for tethering or adsorbing growth factors,
this work is intended to induce chondrogenesis so that successful
cartilage repair is not entirely dependent on chondrogenic cues
from the joint environment. Our preliminary data has demonstrated
that this technique results in an individual cell suspension of
chondrogenic mesenchymal stem cells that may be seeded into
hydrogels using conventional techniques. From a clinical perspective,
a favorable aspect of many hydrogels is the potential to cast a cellseeded
hydrogel directly into a defect, obviating the need for ex vivo
handling or a fixation strategy. This may be achieved when cells
may be resuspended in a solution of unassembled polymers prior
to gelation and subjected to a crosslinking step without causing
harm to the cells. All of the hydrogels discussed in this abstract
meet these requirements for injectability, with crosslinking achieved
through innocuous processes such as changes in temperature,
pH, or exposure to ions or light. The ease of application of such
hydrogels can be illustrated with fibrin hydrogels, which have
been used as scaffolds or sealants in human clinics for many years
(15). Fibrin hydrogels may be cast using an arthroscopic approach
in which cells suspended in fibrinogen solution are mixed with
thrombin during injection (16). We have used this technique in our
research center to deliver cells to cartilage defects. While the ease
of administration is favorable for clinical translation, most hydrogels
share a property that is common among tissue engineering scaffolds
in that the mechanical stiffness of the hydrogel is much lower than
those of articular cartilage; therefore, hydrogels are typically unable
to support normal joint loading immediately after implantation.
This limitation must be considered for restrictions on joint loading
until functional neo-cartilage is synthesized and assembled by
the implanted cells over time. However, the ability of hydrogels to
support the chondrocyte phenotype, potential for optimization, and
ease of application merit the ongoing investigation of hydrogels for
cartilage repair.
References:
1. Spiller KL, Maher SA, Lowman AM. Hydrogels for the repair of
articular cartilage defects. Tissue Eng Part B Rev. 2011;17(4):281-99
2. Benya PD, Shaffer JD. Dedifferentiated chondrocytes reexpress
the differentiated collagen phenotype when cultured in agarose
gels. Cell. 1982;30(1):215-24.
3. Grodzinsky AJ, Levenston ME, Jin M, Frank EH. Cartilage tissue
remodeling in response to mechanical forces. Annu Rev Biomed Eng.
2000;2:691-713.
4. Huang CY, Reuben PM, D’Ippolito G, Schiller PC, Cheung HS.
Chondrogenesis of human bone marrow-derived mesenchymal
stem cells in agarose culture. Anat Rec A Discov Mol Cell Evol Biol.
2004;278(1):428-36.
5. Kisiday JD, Kopesky PW, Evans CH, Grodzinsky AJ, McIlwraith CW,
Frisbie DD. Evaluation of adult equine bone marrow- and adiposederived
progenitor cell chondrogenesis in hydrogel cultures. J Orthop
Res. 2008;26(3):322-31.
6. Mauck RL, Yuan X, Tuan RS. Chondrogenic differentiation and
functional maturation of bovine mesenchymal stem cells in longterm
agarose culture. Osteoarthritis Cartilage. 2006;14(2):179-89.
7. Kisiday JD, Frisbie DD, McIlwraith CW, Grodzinsky AJ. Dynamic
compression stimulates proteoglycan synthesis by mesenchymal
stem cells in the absence of chondrogenic cytokines. Tissue Eng Part
A. 2009;15(10):2817-24.
8. Genes NG, Rowley JA, Mooney DJ, Bonassar LJ. Effect of substrate
mechanics on chondrocyte adhesion to modified alginate surfaces.
Arch Biochem Biophys. 2004;422(2):161-7.
9. Salinas CN, Anseth KS. The influence of the RGD peptide motif
and its contextual presentation in PEG gels on human mesenchymal
stem cell viability. J Tissue Eng Regen Med. 2008;2(5):296-304.
10. Varghese S, Hwang NS, Canver AC, Theprungsirikul P, Lin DW,
Elisseeff J. Chondroitin sulfate based niches for chondrogenic
differentiation of mesenchymal stem cells. Matrix Biol. 2008;27(1):12-
21.
11. Miller RE, Kopesky PW, Grodzinsky AJ. Growth factor delivery
through self-assembling peptide scaffolds. Clin Orthop Relat Res.
2011;469(10):2716-24.
12. Shah RN, Shah NA, Del Rosario Lim MM, Hsieh C, Nuber G, Stupp
SI. Supramolecular design of self-assembling nanofibers for cartilage
regeneration. Proc Natl Acad Sci U S A. 2010;107(8):3293-8.
13. Park Y, Lutolf MP, Hubbell JA, Hunziker EB, Wong M. Bovine
primary chondrocyte culture in synthetic matrix metalloproteinasesensitive
poly(ethylene glycol)-based hydrogels as a scaffold for
cartilage repair. Tissue Eng. 2004;10(3-4):515-22.
14. Masuda K, Sah RL, Hejna MJ, Thonar EJ. A novel two-step method
for the formation of tissue-engineered cartilage by mature bovine
chondrocytes: the alginate-recovered-chondrocyte (ARC) method. J
Orthop Res. 2003;21(1):139-48.
15. Ahmed TA, Dare EV, Hincke M. Fibrin: a versatile scaffold for tissue
engineering applications. Tissue Eng Part B Rev. 2008;14(2):199-
215.
16. Wilke MM, Nydam DV, Nixon AJ. Enhanced early chondrogenesis
in articular defects following arthroscopic mesenchymal stem cell
implantation in an equine model. J Orthop Res. 2007;25(7):913-25.
15.2.3
Clinical application of scaffolds for cartilage repair
S. Nehrer
Krems/Austria
Introduction: Cell based therapies in cartilage repair Autologous
Chondrocyte Transplantation with the periosteal flap has changed
the paradigm of the treatment of cartilage defects from repair to
regeneration. This has been demonstrated in randomized trials proving
the concept of regenerating tissue in a cell based therapy approach.
However, the limitations of the periosteal flap concerning size and
thickness and surgical demands with suturing and the variability of the
biological reaction including hypertrophy, as well as the uncontrolled
celltransplatation in a cell suspension has supported the introduction
of biomaterials. The first attempt was to replace the periosteal flap
by membranes which were sutured or glued to the defect combined
with the cellsuspension injected or seeded onto the membrane during
the surgery before implantation. Concerns about the phenotype of
the cultured cells led to the use biomaterial assisted technologies in
sponges or gels to maintain the chondrocyte function of the cells and
allow a more controlled dispersion of the chondrocytes throughout the
defect. The matrix characteristics concerning biochemical composition,
biophysical appearance in gel, foams or sponges, degradation
dynamics and products, toxicity, immunological reactions and general
biocompatibility are important parameters of biomaterial development.
The cell-biomaterial interaction in a biological environment is lastly the
decisive process of successful cartilage regeneration.
Content: Clinical application of scaffolds for cartilage repair Stefan
Nehrer, Florian Halbwirth Center for Regenerative Medicine Danube
University Krems Biomaterials in clinical use Various materials have
been tested in in-vitro laboratory studies and in-vivo animal
experiment to evaluate the best material for human use. Most of the
materials are able to support the chondrocyte phenotype, allow
proliferation and cell migration and facilitate production of cartilage
specific substances. Animal models show in most cases that cell
loaded constructs show superior results than unloaded matrices.
Based on this results clinical studies were employed to prove
feasibility and safety of these technologies. Most of the reported
results are based on case studies only few randomized controlled
trials were performed. There is still discussion about the appropriate
control group in the study design, since microfracture is performed
arthroscopically and basically a different approach, only very few
studies compare matrix techniques with other cell transplantation
methods, however the benchmark is still autologous chondrocyte
transplantation with the periosteum patch. Collagen membrane The
collagen membrane was the first biomaterial used in clinical studies.

Based on positive results in animal studies, confirming the biological
concept of matrix assisted cell technology a bilayer Type 1/3 collagen
membrane was sutured instead of the periosteal flap to the defect
site and the cell suspension is injected underneath. This method still
requires suturing of the membrane and low control of the seeding
process of the cellsuspension. The clinical results of five years followup
are comparable to the periosteum technique. In biopsy studies
hyaline-like tissue have been found. The preseeding of the membrane
was the next development, allowing a more controlled distribution of
the cultured cells and also allows glueing of the graft to the defect. In
this technique the chondrocytes are seeded in a fibrin glue
suspension, however the impact of fibringlue on chondrocytes is still
controversial and experimental and studies on the stability of such
fixation show minor mechanical properties. Hyaluronan In a next step
a preseeded hyaluronan based scaffold has been introduced in the
indication of a chronic cartilage defect. The material consists of a non
woven mesh of hyaluronan fibers which are modified by esterification
by benzylesters to improve the biocompatibility of the material. Since
the hyaluronan is a natural constituent of cartilage and the material
desolves into hyaluronan and is a promising candidate for chondrocyte
transplantation. The in-vitro studies revealed the Hyaff 11 mesh as an
appropriate scaffold for chondrocytes regarding the chondrocytic
phenotype, however the animal studies on the material are sparse
and no conclusive controlled data available. However, the clinical
performance of the material in three- and five-years follow-up studies
document successful performance in over 80 % across the study
population. Stageing the data according to age and severity of the
cartilage defect, patients under the age of 35 and single circumscribed
defects do a lot better with success rates over 90 %. The precultured
hyaluronan matrix shows good attachment of the chondrocytes and
also allows an arthroscopic implantation. The preformed shaping of
the defect and the rough surface of the graft allows fixation without
glueing and pressfit technique and reduces joint morbitiy due to the
arthroscopic approach. PLA/PGA membranes Similar arthroscopic
techniques are performed with precultured matrices consisting of
PLA/PGA meshes, which are secured with technically demanding
intraosseous suture-knot technique or lately with easier pin fixation.
The cell seeded construct shows comparable results to ACT in
midterm follow-up in cohort studies and the stable, mechanically
resistant graft allows also treating circumscribed osteoarthritic
lesions with satisfying outcomes. Recent techniques using minced
cartilage pieces glued to the membrane have been developed,
assuming that outgrowth of chondrocytes from the minced tissue
provide adequate chondrogenic stimulation to facilitate cartilage
regeneration. The minced tissue is harvested with a newly developed
shaver system which allows automized seeding on the artificial
membrane. The 2 years clinical follow up shows better results
compared to microfracture. Collagen Gel The 3D-culture system in
gels allows the chondrocytes to maintain the chondrocytic phenotype,
especially when unpassaged cells are used. The distribution of the
cells resembles more the sparsely dispersion of cells like in natural
cartilage and a high bioactivity of the cell is achieved. The soft
collagen gel needs a well debrided defect with stable walls to allow a
press fit stabilisation which is supported by fibrin glue. The graft
shows a complete fill of the defect and a perfect bonding to the
adjacent cartilage. Clinical results of case controlled studies and
multicenter data show comparable results to ACT and better
performance with regards to effusion and surgery time. Fibrin Fibrin
as a biomaterial was used in liquid form in a glue-cell suspension or
lately also in a spongelike matrix. The fibrin technique allows a
homologous approach to the cell transplantation and the support of
FGF growth factor stimulates cell proliferation and differentiation to
shorten the necessary culture period. First clinical case series show
promising results of the material. The spongelike appearance serves
as a more stable construct than liquid glues. Other combinations of
gels and membranes are available to combine 3D environment with a
biomechanical stable fixation technique. Clinical performance The
clinical results of scaffold techniques are comparable to the
midtermresults of ACT, hence longterm results are not yet available.
Especially circumscribed lesions on the condyle in the younger
patients are doing well in all the studies. However, most studies are
case series and only few are controlled trials including controls. The
advantage of the use of biomaterials is the shorter surgery time, the
easier handling and fixation, the secure and biological appropriate
environment for the chondrocytes during the transplantation process,
the smaller incision including arthroscopic techniques and the more
predictable biological regeneration process avoiding overgrowth like
hypertrophy of the periosteum graft. The safety reports reveal only
minor adverse events most of the time and from the ethic standpoint
no bridges are burned for further treatment options including
revisions, mosaicplasty or redos of cell transplantation. The use of
biomaterials without cultured cells is of course the logistical and
legistical easier process and serves economical interest of companies
and healthcare stake holders. Most of the matrices were developed
Extended Abstracts 149
for the cell based therapies and are now serving as scaffolds for the
bloodclot techniques like microfracture. Some early midtermresults
show increased healing response but –like microfracture alone-
inadequate tissue formation and thinning of the surface layer by
intracartilagenous bone formation. However clinical and experimental
studies are on the way and will help to develop the optimal biomaterial
based cartilage repair procedure. Up to now the evidence in
experimental studies is low to suggest successful use of cell-free
constructs and most animal experiments show advantages of the cell
augmented techniques, however the addition of growth hormones,
chondrocyte nutrients or application nanotechnology aspects in
biomimetic materials may allow such technique. First applications of
biomimetic matrices using hydroyapatite and collagen in a gradient
concentration from the osseus to the cartilaginous layer have shown
good results. However, cell based therapies without biomaterials like
chondrospheres or stemcells may be a relevant alternative to
biomaterials and make the difference at last.
References:
1) Bartlett W, Skinner JA, Gooding CR, Canington RW, Flanagan AM,
Briggs TW, Bentley G (2005) Autologous chondrocyte implantation
versus matrix-induced autologous chondrocyte implantation for
osteochondral defects of the knee: a prospective, randomised study.
J Bone Joint Surg Br 87:640-645
2) Behrens P, Bitter T, Kurz B, Russlies M (2006) Matrix-associated
autologous chondrocyte transplantation/implantation (MACT/
MACI)-5-year follow-up. Knee 13: 194-202
3) Bentley G, Biant LC, Carrington RWT, Akmal M, Goldberg A,
Williams AM, Skinner JA, Pringle J (2003) A prospective, randomized
comparison of autologous chondrocyte implantation versus
mosaicplasty for ostechondral defects of the knee. J Bone Joint Surg
Br 85:223-230
4) Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson
L (1994) Treatment of deep cartilage defects in the knee with
autologous chondrocyte transplantation. N Eng J Med 331:889-895
5) Erggelet C, Sittinger M, Lahm A (2003) The arthroscopic
implantation of autologous chondrocytes for the treatment of fullthickness
cartilage defects of the knee joint. Arthroscopy 19:108-110
6) Gobbi A, Kon E, Berruto M, Francisco R, Filardo G, Marcacci M
(2006) Patellofemoral full-thickness chondral defects treated with
Hyalograft-C: a clinical, arthroscopic, and histologic review. Am J
Sports Med 34:1763-1773
7) Gooding CR, Bartlett W, Bentley G, Skinner JA, Carrington R,
Flanagan A (2006) A prospective, randomised study comparing
two techniques of autologous chondrocyte implantation for
osteochondral defects in the knee: Periosteum covered versus type
I/III collagen covered. Knee 13:203-210
8) Jakobsen RB, Engebretsen L, Slauterbeck JR (2005) An analysis
of the quality of cartilage repair studies. J Bone Joint Surg Am
87:2232-2239 9) Knutsen G, Engebretsen L, Ludvigsen TC, Drogset
JO, Grontvedt T, Solheim E, Strand T, Roberts S, Isaksen V, Johansen
O (2004) Autologous chondrocyte implantation compared with
microfracture in the knee. A randomized trial. J Bone Joint Surg Am
86:455-464
10) Knutsen G, Drogset JO, Engebretsen L, Grontvedt T, Isaksen V,
Ludvigsen TC, Roberts S, Solheim E, Strand T, Johansen O (2007)
A randomized trial of autologous chondrocyte implantation with
microfracture. Findings at five years. J Bone Joint Surg Am 89:2105-
2112
11) Marcacci M. Kon E, Zaffagnini S, Filardo G, Delcogliano M, Neri
MP, Iacono F, Hollander AP (2007) Arthroscopic second generation
autologous chondrocyte implantation. Knee Surg Sports Traumatol
Arthrosc 16:610-619
12) Nehrer S, Dorotka R, Domayer S, Stelzeneder D, Kotz R. Am J
Sports Med. 2009 Nov;37 Suppl 1:81S-87S. Epub 2009 Oct 27.
13) Nehrer S, Chiari C, Domayer S, Barkay H, Yayon A. Clin Orthop
Relat Res. 2008 Aug;466(8):1849-55. Epub 2008 Jun 5.
14) Nehrer S, Domayer S, Dorotka R, Schatz K, Bindreiter U, Kotz . R
(2006) Three-year clinical outcome after chondrocyte transplantation
using a hyaluronan matrix for cartilage repair. Eur J Radiol 57:3-8

150
Extended Abstracts
15) Ossendorf C, Kaps C, Kreuz PC, Burmester GR, Sittinger M,
Erggelet C (2007) Treatment of posttraumatic and focal osteoarthritic
cartilage defects of the knee with autologous polymer-based threedimensional
chondrocyte grafts: 2-year clinical results. Arthritis Res
Ther 9:R41
16) Steinwachs M, Kreuz PC (2007) Autologous chondrocyte
implantation in chondral defects of the knee with a type I/III collagen
membrane: a prospective study with a 3-year follow-up. Arthroscopy
23:381-387
17) Zheng MH, Willers C, Kirilak L, Yates P, Xu J, Wood D, Shimmin A
(2007) Matrix-induced autologous chondrocyte implantation (MACI):
biological and histological assessment. Tissue Eng 13:737-746
15.3.1
Importance of subchondral bone in cartilage repair
H. Madry
Homburg/Germany
Introduction: The subchondral bone lies immediately below the
calcified zone of the articular cartilage, separated from it by the
cement line. It consists of two mineralized layers, the subchondral
bone plate and the subarticular spongiosa. The subchondral bone
plate is composed of dense cancellous bone. Adjacent to the
articular cartilage, this bone consists of relatively thick plates which
join together to enclose relatively narrow intervening spaces. In the
deeper regions of the subchondral bone, these spaces are gradually
enlarged and become elongated in a direction parallel to the
diaphysis, forming the subarticular spongiosa. Its trabeculae arise
from the subchondral bone plate. The subchondral bone is subjected
to a range of static and dynamic forces, such as shear, tension,
compression. These mechanical loads are mainly absorbed by the
extracellular matrix of the articular cartilage and are transmitted
to the subchondral bone. The subchondral bone and the articular
cartilage form the osteochondral unit.
Content: Marrow stimulation techniques for articular cartilage
repair, resulting in a surgically-created communication between
a symptomatic cartilage defect and the bone marrow, affect the
subchondral bone. Recent data from experimental studies in small
and large animal models and clinical investigations suggest significant
alterations of the subchondral bone microarchitecture following
marrow stimulation. Initially, early bone resorption is followed by
bone remodeling as in fracture healing. Caroline Hoehmann and
Michael Buschman have shown in the rabbit model that microfracture
leads to bone compaction as indicated by significantly higher bone
density and trabecular thickness, compared to drilling. The depth
of drilling also plays a role - deep drilling leading to a larger volume
of bone remodelling than shallow drilling. We have recently shown
in a sheep model that drilling induces significant alterations of
nearly all microarchitectural parameters of the subchondral bone
plate and the subarticular spongiosa after 6 months. These include,
but are not limited, the bone volume (BV/TV), bone surface /
volume ratio, trabecular thickness, separation, and pattern factor
and bone mineral density. Particularly of interest, these observed
microarchitectural changes were similar to the structural patterns
observed in osteoporosis and osteoarthritis such as a decrease in
BV/TV, bone mineral density, and trabecular thickness vis-à-vis an
increase in trabecular separation. In addition, the appearance of
subchondral bone cysts, the formation of intralesional osteophytes,
and the upward migration of the subchondral bone plate are key
features that have been described both in small and large animal
models and in patients. Subchondral bone cyst formation may
result from penetration of the subchondral bone combined with
immediate full weight bearing. A recent long-term investigation of
ovine subchondral bone microarchitecture found subchondral bone
cysts in 62% of cartilage defects that were treated by drilling and
intralesional osteophytes in 26% of cases.
An intralesional osteophyte is defined as new bone formation
apical to the cement line, projected into the articular cartilage.
Upward migration of the entire subchondral bone plate into the
cartilaginous repair tissue has been also observed in several animal
studies. Such new bone formation may be a factor playing a role
in the degeneration of cartilaginous repair tissue over time. In
addition, also the subchondral plate surrounding treated defects is
affected. The subchondral plate has been shown to thicken following
subchondral drilling, suggesting that marrow stimulation may also
induce long-term changes in the subchondral bone adjacent to the
treated defects.
Clinical results after marrow stimulation of small symptomatic
articular cartilage defects are promising, especially within the first 2
years after surgery. In agreement with the data generated in animal
models, however, clinical evidence suggests that marrow stimulation
may induce similar alterations in the subchondral bone plate such
as upward migration, intralesional osteophytes or subchondral bone
cysts, which may play a role in the degeneration of the repair tissue
over time. Also, autologous chondrocyte implantation (ACI) has been
reported to have a three-fold higher failure rate when applied to
articular cartilage defects previously treated with marrow stimulation
techniques compared with previously untreated defects.
In general, the lower resolution of imaging techniques applicable
in clinical investigations compared with experimental tools such
as high-resolution micro CT makes the differentiation between a
laminar upward migration of the entire subchondral bone plate
and a localized formation of intralesional osteophytes difficult.
Although MRI is a valuable tool for to monitor cartilage repair,
depiction of subchondral bone microarchitecture is still not possible
in patients. Cartilage defects treated by microfracture developed
more subchondral bone reaction after 3 years compared with the
baseline using MRI. Such changes of the subchondral bone plate
may predispose for the degeneration of the repair tissue in a pattern
similar to osteoarthritis, when the thickened and stiff subchondral
bone plate increases friction and shear forces. A bone marrow edema
is a frequent but non-specific signal pattern that can be related
to ischemia (i.e. osteonecrosis, bone marrow edema syndrome),
mechanical (bone bruise, microfracture) or reactive (osteoarthritis,
postoperative bone marrow edema) causes. Often, the presence
of such a bone marrow edema is a first sign of a corresponding
chondral lesion.
Taken together, alterations of the subchondral bone are associated
with the clinical use of marrow stimulation techniques for articular
cartilage repair. These changes have been confirmed in various
small and large animal models of different types of cartilage defects.
The emerging experimental and clinical data suggest that a possible
deterioration of the subchondral bone plate and subarticular
spongiosa underlying the cartilage defect might be an additional,
previously underestimated factor that significantly influences the
long-term outcome of articular cartilage repair following marrow
stimulation and possibly other reconstructive surgical techniques.
More data are therefore needed to better understand the clinical
relevance of subchondral cysts as they are often unrelated to the
symptoms of the patients. Clinical evidence confirms that marrow
stimulation induces upward migration of the subchondral bone plate
and formation of bone marrow edemas, intralesional osteophytes or
bone cysts in approximately 25% of patients, possibly playing a role
in the degeneration and failure of the repair tissue. Future studies
will also have to focus on the containment of these subchondral bone
alterations, e.g. by optimizing surgical techniques or postoperative
regimes. Also, highly resolving imaging techniques need to be
developed and clinically tested to gain more insights into the clinical
mechanisms of subchondral bone changes.
A deeper comprehension of the subchondral bone alterations
associated with cartilage repair will translate into further improved
techniques to preserve and restore the entire osteochondral unit.
References:
H. Madry, C.N. van Dijk and M. Mueller-Gerbl, The basic science of
the subchondral bone, Knee Surg. Sports Traumatol. Arthrosc. 18
(2010), 419-433.
P.C. Kreuz, M.R. Steinwachs, C. Erggelet, S.J. Krause, G. Konrad,
M. Uhl and N. Sudkamp, Results after microfracture of fullthickness
chondral defects in different compartments in the knee,
Osteoarthritis Cartilage 14 (2006), 1119-1125.
K. Mithoefer, R.J. Williams, 3rd, R.F. Warren, H.G. Potter, C.R. Spock,
E.C. Jones, T.L. Wickiewicz and R.G. Marx, The microfracture technique
for the treatment of articular cartilage lesions in the knee. A prospective
cohort study, J. Bone Joint Surg. Am. 87 (2005), 1911-1920.
H. Chen, J. Sun, C.D. Hoemann, V. Lascau-Coman, W. Ouyang, M.D.
McKee, M.S. Shive and M.D. Buschmann, Drilling and microfracture
lead to different bone structure and necrosis during bone-marrow
stimulation for cartilage repair, J. Orthop. Res. 27 (2009), 1432-
1438.

H. Chen, A. Chevrier, C.D. Hoemann, J. Sun, W. Ouyang and
M.D. Buschmann, Characterization of subchondral bone repair
for marrow-stimulated chondral defects and its relationship to
articular cartilage resurfacing, Am. J. Sports Med. 39 (2011), 1731-
1740.
P. Orth, L. Goebel, U. Wolfram, M.F. Ong, S. Gräber, D. Kohn,
M. Cucchiarini, A. Ignatius, D. Pape and H. Madry, Effect of
subchondral drilling on the microarchitecture of subchondral
bone: analysis in a large animal model at 6 months, Am. J. Sports
Med. (2012) PMID:22223716. in press.
D. Lajeunesse, G. Hilal, J.P. Pelletier and J. Martel-Pelletier,
Subchondral bone morphological and biochemical alterations in
osteoarthritis, Osteoarthritis Cartilage 7 (1999), 321-322.
T. Minas, A.H. Gomoll, R. Rosenberger, R.O. Royce and T. Bryant,
Increased failure rate of autologous chondrocyte implantation
after previous treatment with marrow stimulation techniques, Am.
J. Sports Med. 37 (2009), 902-908.
D.D. Frisbie, S. Morisset, C.P. Ho, W.G. Rodkey, J.R. Steadman and
C.W. McIlwraith, Effects of calcified cartilage on healing of chondral
defects treated with microfracture in horses, Am. J. Sports Med. 34
(2006), 1824-1831.
D.B. Saris, J. Vanlauwe, J. Victor, K.F. Almqvist, R. Verdonk, J.
Bellemans and F.P. Luyten, Treatment of symptomatic cartilage
defects of the knee: characterized chondrocyte implantation
results in better clinical outcome at 36 months in a randomized
trial compared to microfracture, Am. J. Sports Med. 37 Suppl 1
(2009), 10S-19S.
Acknowledgments:
Supported in part by AGA and GOTS.
15.3.2
Digital imaging of subchondral bone density
F.P.J.G. Lafeber, M. Kinds, F. Intema, S.C. Mastbergen
Utrecht/Netherlands
Introduction: Subchondral bone changes in osteoarthritis: Osteoarthritis
(OA) is a degenerative joint disease characterized by cartilage destruction
and changes in subchondral bone. Joints most affected are hip, knees,
and spine, but every joint can be affected including ankle joints.
Subchondral bone changes are a distinctive feature in OA development,
and they include sclerosis, cyst formation, bone attrition, bone marrow
lesions, and osteophytes. Subchondral bone changes alter the joint‘s
mechanical as well as biochemical environment and have a direct and
indirect influence on the overlaying articular cartilage. Consequently,
subchondral bone has been identified as an attractive target for
treatment in OA, and should be monitored in detail. (1)
Content: Subchondral bone remodelling is related to clinical
improvement after clinical effective treatment of OA.(2) Joint distraction
as a treatment of OA has been shown to provide pain relief and
functional improvement through mechanisms that are not well
understood. It was demonstrated that subchondral bone remodelling
is associated with clinical improvement in OA patients treated with
joint distraction. In twenty-six patients with advanced post-traumatic
ankle OA, treated with joint distraction for 3 months using an Ilizarov
frame, bone density (BD) change were analysed by computed
tomography (CT) scans. Longitudinal, manually segmented CT
datasets for a given patient were brought into a common spatial
alignment. Changes in BD (Hounsfield Units; relative to baseline) were
calculated at the weight-bearing region, extending subchondral to a
depth of 8 mm. Clinical outcome was assessed using the ankle OA
scale. Baseline scans demonstrated subchondral sclerosis with local
cysts. At 1 and 2 years of follow-up, an overall decrease in BD (-23%
and -21%, respectively) was observed. Interestingly, BD in originally
low-density (cystic) areas increased. Joint distraction resulted in a
decrease in pain (from 60 to35, scale of 100) and functional deficit
(from 67 to 36). Improvements in clinical outcomes were best
correlated with disappearance of low-density (cystic) areas (R=0.69).
From this study it is concluded that treatment of advanced posttraumatic
ankle OA with joint distraction results in BD normalization
that is associated with clinical improvement. While overall BD
decreased, BD in cystic lesions actually increased (normalization of
Extended Abstracts 151
BD) and a correlation was found between clinical improvement and
the resolution of subchondral bone cysts. Feasibility of bone density
evaluation using plain digital radiography.(3) Clearly, (a change in)
subchondral BD is an important feature of OA. For measurement of BD
several methods have been reported on, including dual energy digital
radiography (DEDR), (quantitative) computed tomography (QCT; as
described above), radiographic absorptiometry, but most importantly
dual energy X-ray absorptiometry (DEXA) which is the most validated
and commonly used method. However, for evaluation of structural
changes due to OA, in general practice, plain radiographs are
commonly acquired. If the quantitative evaluation of clinically relevant
BD changes on these radiographs is proved feasible, it obviates the
need to acquire additional methods. In general practice subchondral
BD changes are commonly subjectively assessed. Although the use of
film-screen radiography has been described in the evaluation of BD,
this technique has been almost completely replaced by digital
radiography. The accuracy of digital radiography in BD measurement
has received no attention, however. One important feature of digital
radiography is that image post-processing (PP) is incorporated in the
scan protocol. This PP generally includes adjustment of contrast
curves and application of non-linear image filters to optimize image
quality parameters such as contrast and noise. PP aims at improving
diagnostic readability, rather than allowing quantitative analyses to
assess BD changes for longitudinal evaluation. Furthermore, the
acquisition settings including tube voltage (in kilovolt: kV), exposure
(in milli ampere seconds: mAs), and filtration can vary between
technologists, exam rooms, and institutes, which may influence crosssectional
or longitudinal BD evaluation. To enable quantification of
BD, independently of PP and acquisition settings, the inclusion of an
aluminium (step) wedge in the radiographic field-of-view has been
suggested.(4) In this way the grey values of the bone can be expressed
in mm aluminium equivalents (mm Al). The feasibility of BD evaluation
using digital radiography was evaluated. A bone density standard
(BDS) of hydroxyapatite (HA) mimicked a BD range of 1.0 - 5.75 g/cm2.
Digital radiographs were acquired with variation in acquisition
settings, and with clinical and minimal PP. An aluminium step wedge
served as an internal reference to express the grey values of the BDS
in mm aluminium equivalents (mm Al). The relation between actual BD
and BD normalized to the reference wedge was evaluated with linear
regression analyses for radiographs with variations in PP and
acquisition settings. Precision of BD measurement of the BDS was
evaluated for application in clinical practice. The correlation between
actual BD and BD normalized to the reference was improved by
changing PP from clinical (R2 = 0.96) to minimal (R2 = 0.98). Higher
tube voltage [kilovolt (kV)] improved the correlation further. Even for
clinical PP, average standard deviation (SD) was 0.97 mmAl, much
smaller than the change of 2.51 mm Al clinically observed in early OA,
which implies the feasibility of BD measurements on digital radiographs
It was demonstrate that BD measurement on plain digital radiographs
is feasible. However, since variations in digital radiography settings at
acquisition influence the outcome, BD measurements should be
interpreted with caution. In clinical practice variations in acquisition
settings within institutes and specifically between institutes (in
multicenter trials) have been found to vary in a relevant range.
Furthermore, differences in performance between different brands
and types of digital radiography acquisition systems will exist. Digital
radiographs without a reference need to be evaluated with caution
since in optimization of images, PP algorithm plays an important role.
For example, during longitudinal evaluation of a knee joint, the clinical
PP algorithm might yield radiographs with a similar appearance while
BD actually changed based on disease (e.g. OA). On the other hand,
radiographs might appear different as a result of variations in PP
settings (or different radiography systems) within and between centres
rather than as a result of BD changes. Although in clinical practice
variations in digital radiography and PP settings will occur that
influence BD measurement, the addition of a reference enables an
adequate assessment of the grey values. A limitation of the use of a
BDS might be that it is in general a simplified representation of tissue
composition of a human knee without anatomical resemblance.
However, the mean subchondral BD values determined with DEXA at
the medial tibia were 2.21 g/cm2 for a healthy human knee joint, with
a linear correlation with BD values on digital radiographs (R2 = 0.91),
and1.70 g/cm2 for a cadaver knee joint, which shows that the BDS
represented a clinically relevant range. The BDS experiments indicated
that the precision of BD measurement could be increased by using
minimal PP rather than clinical PP and by applying relatively high kV.
The relation between actual BD and BD normalized to the reference is
weak when low tube voltage (44 kV) is used especially at larger BD
values, which might be due to relatively more absorption of the beam
by the knee joint. Although the application of higher kV improves
linearity of the relation between actual and normalized BD, patient
exposure needs to be taken into account. Improved accuracy without
additional patient exposure can be reached by using higher kV in
combination with lower mAs. Applying minimal PP to improve accuracy

152
Extended Abstracts
is not easily applicable in regular clinical practice since clinical PP is
required to provide optimal diagnostic image quality, and in general
cannot easily be bypassed in clinical practice. Overall, the BDS
experiments and the comparison to clinical data indicate that BD
measurement using digital radiography is feasible in a clinically
relevant range. Variations in acquisition and PP settings within and
between clinics can have profound effect on BD evaluation and should
therefore be considered with caution. As compared to the default
clinical protocol, the accuracy of BD measurements can be improved
by applying only minimal image PP and a relatively high kV. Provided
properly performed, plain digital radiography may yield, in addition to
OA characteristics, reliable data on BD which reduces the need for
additional imaging techniques.
References:
1) Bijlsma JWJ, Berenbaum F, and Lafeber FPJG. Osteoarthritis: an
update with relevance for clinical practice. Lancet. 2011; 377:2115-26.
2) Intema F, Thomas TP, Anderson DD, Elkins JM, Brown TD, Amendola
A, Lafeber FPJG, and Saltzman CL. Subchondral bone remodeling is
related to clinical improvement after joint distraction in the treatment
of ankle osteoarthritis. Osteoarthritis and Cartilage 2011; 19: 668-675.
3) Kinds MB, Bartels LW, Marijnissen ACA, Vincken K, Viergever MA,
Lafeber FPJG, andDeJong HWAM. Feasibility of bone density evaluation
using plain digital radiography. Osteoarthritis and Cartilage 2011; 19:
1343-1348.
4) Marijnissen AC, Vincken KL, Vos PA, Saris DB, Viergever MA, Bijlsma
JW, Bartels LW, Lafeber FP. Knee Images Digital Analysis (KIDA): a
novel method to quantify individual radiographic features of knee
osteoarthritis in detail. Osteoarthritis Cartilage. 2008;16:234-43.
Acknowledgments:
-Orthopaedics & Rehabilitation, The University of Iowa, Iowa City, IA,
USA
-Image Sciences Institute, University Medical Centre (UMC), Utrecht,
The Netherlands
15.3.3
Fresh Osteochondral Allografting in the Knee
W.D. Bugbee
La Jolla/United States of America
Introduction: The concept of treating articular cartilage diseases with
bone and cartilage substitution in the knee has now a history of more
than a century, since the first joint transplantation described by Lexer
in 1908.1,2 Animal and clinical studies concerning transplantation
and immunology were carried out in the sixties, demonstrating that
transplanted fresh cadaver cartilage is viable.3-5 In the seventies Gross
and colleagues began reporting on their experience with osteochondral
allograft for post traumatic and periarticular tumor reconstruction.6,7
In the eighties Meyers and Convery firstly applied this technique to
specific chondral and osteochondral diseases such as chondromalacia,
osteoarthritis and osteonecrosis,8 developing the shell-shaped graft.
Later in the nineties that Garrett first reported on the use of allograft
plugs for the treatment of osteochondritis dissecans of the knee.9 In
the last twenty years a large number of basic scientific and clinical
studies have been performed by a number of investigators. These
studies and the increasing availability of fresh allografts, have led to
an increasing popularity of fresh allografts and the inclusion of this
procedure as part of the “cartilage repair paradigm” for the treatment
of chondral or osteochondral lesions in the knee.10,11,12
Content: ALLOGRAFT RECOVERY, PROCESSING AND STORAGE
Historically, in North America, fresh osteochondral allograft procedures
were performed at university based centers that had associated
tissue banks which independently established recovery, processing
and release protocols. Fresh osteochondral allografts (OCA) were
typically stored in lactated Ringer’s solution and transplanted fresh
within one week after donor death. Under this model approximately
100 allografts per year were implanted in North America in the
eighties and nineties. Beginning around 1998, commercially supplied
allografts became available in the United States through a number
of tissue banks that established new protocols under the oversight
of the Food and Drug Administration (FDA). Commercial distribution
of grafts required a prolonged storage interval (10-45 days) to allow
for completion of recovery and testing protocols. This resulted in an
increase in the number of allografting procedures performed in the US
to approximately 2000 per year.
Allograft tissue recovery is performed within 12-24 hours of donor
death.13 Suitable donors are generally between 15 and 35 years old with
macroscopically healthy articular cartilage. Since the transplantation
procedure is based on cartilage substitution, a process that maintains
allograft cartilage tissue health during storage is mandatory. Many
studies have been carried out to identify the ideal storage media and
to evaluate the effects of hypothermic storage on chondrocytes and
extracellular matrix.14-19
Osteochondral allografts can be stored frozen, cryopreserved or fresh.
Each of these options affects chondrocyte viability, immunogenicity,
and length of time to transplantation. Frozen grafts showed a
chondrocyte survivorship of less than 5%, because of the freezing
process at -80°C.20 As chondrocytes are responsible for maintenance
of the extracellular matrix, studies have shown that the matrix in these
frozen allografts tends to deteriorate over time. 21,22 Along with
the decreased chondrocyte viability, fresh-frozen allografts showed
decreased immunogenicity.23
With cryopreservation it is possible to maintain chondrocyte viability
during this freezing process by adding glycerol and dimethyl sulfoxide
(DMSO) to the tissue. Theoretically, the addition of these chemicals
prevents ice formation within cells. Multiple studies have reported
variable results, with chondrocyte survival ranging from 20% to
70%.24-27 Unfortunately, viable cells were found only at the surface
of the articular cartilage layer.28 Fresh allografts proved to have the
highest rates of chondrocyte viability of the three different methods
of storage.19,25,29,30 Fresh grafts are usually placed in tissue culture
medium at 4°C (or potentially 37°C). Chondrocyte viability is significantly
affected by length of storage, with little effect from storage times less
than one week.31,32 The time of storage before implantation is a key
point. Studies have shown a time-dependent decreased chondrocyte
viability and degradation of biomechanical properties of fresh grafts
stored for greater than 14 days.33-35 Currently the trend of the
tissue banks is to hold transplants for a minimum of 14 days, to allow
completion of microbiologic and serologic testing prior to release.36
More recently a new off-the-shelf alternative to classic OCA has
been developed and released in the US market: The Chondrofix®
Osteochondral Allograft (Zimmer, Inc. 1800 West Center Street
Warsaw, IN, USA). This product is an osteochondral allograft
consisting of decellularized hyaline cartilage and cancellous bone,
recovered by an accredited tissue bank, processed to be sterile and
viral-inactivated, hydrated, precut, and ready for implantation. The
relative advantages include an off the shelf availability, sterility and
ease of use while potential limits are availability in sizes only up
to 15mm and the absence of viable cells within the graft. Currently
no published peer reviewed data is available, however preliminary
experience suggests a place for this product in the pool of newer
alternatives for chondral and osteochondral repair or replacement.
INDICATION FOR ALLOGRAFTS
The structural features and multi shaping possibilities makes
osteochondral allografts suitable for the treatment of a wide spectrum
of diseases, which can be grouped into two main paradigms (Table
1). The first treatment paradigm includes complex reconstruction
procedures, such as post traumatic deformity and degenerative
lesions associated with intra-articular fracture malunion, most
commonly of the tibial plateau,40,41 and unicompartmental
arthrosis or multifocal chondrosis including patellofemoral
degeneration.42-44 This group also includes massive type 3 or 4
osteochondritis dissecans (OCD),9,10 osteonecrosis,45 as well as
other diseases primarily affecting the subchondral bone. The second
treatment paradigm is formed by conditions primarily affecting
articular cartilage. These include large chondral defects treated
primarily with an allografts or defect that have been previously
treated by another cartilage repair technique such as microfracture,
OATS or Autologous Chondrocyte Implantation that have failed or
that have developed compromise of the subchondral bone.
Although the knee is the most common joint for osteochondral
allografting, experience in other joints has been reported. Several
case series have been reported in the ankle joint. Good results
have been shown with the use of allografts in the treatment of large
osteochondral lesions of the talus.46-50 Mixed results have been
demonstrated for Bipolar shell grafting for ankle osteoarthritis.

51,52 Experience with allografts has also been described in the
hip or in the shoulder, as treatment of femoral or humeral head
osteonecrosis or for osteochondral lesions associated with shoulder
instability. 53-55
RESULTS
Clinical results of fresh osteochondral allografts in the knee joint
have shown encouraging long-term results, with overall success
rates from 50% to 95%.10,30,32,41,45,58. The most commonly
treated lesion location is the femoral condyle. Table 2 outlines the
major studies reporting outcomes of osteochondral allografting of
isolated lesions of the femoral condyle.
In post traumatic reconstruction of the tibial plateau, Shasha et al. in
2003 41 reported the long term outcome of sixty-five patients treated
with fresh tibial osteochondral allografts. At a mean of twelve years,
forty-four patients had an intact graft, while twenty-one had had
conversion to a total knee arthroplasty at an average of ten years.
The reported survival rate was 95% at five years, 80% at ten years
and 65% at fifteen years.
The “San Diego experience” with osteochondral allografting in
the knee extends almost thrity years. In 1983, an institutional
review board (IRB) approved osteochondral allografting program
was established for the evaluation and treatment of complex or
advanced articular cartilage disease. This comprehensive program
was comprised of scientific and clinical components, including
retrieval studies. Over the last 30 years, we have collected outcomes
data on all patients unergoing fresh osteochondral allografting with
the purpose of better defining the indications and understanding
clinical outcome. Since 1983, 515 patients have undergone 576
knee allografting procedures. Of those, 328 patients (354 knees)
currently have minimum 2-year follow-up and 187 patients (222
knees) do not have 2-year follow-up data (59 patients are less than
2 years from surgery). The following results includes only the 354
knees with minimum 2-year follow-up. The mean follow-up was 86
months (range 24–309 months). Patient characteristics and details
regarding the allograft are presented in table 3 . Objective clinical
outcome showed improvements in both pain and function on all
measures utilized (table 4). Subjectively, 96% of patients reported
satisfaction (73% extremely satisfied), 93% reported less pain, and
94% reported better function as a result of the allograft procedure.
Almost all patients (92%) stated they would have the surgery again
under similar circumstances.
Seventy-two knees (20%) underwent a reoperation that included
removal or revision of the allograft and were defined as clinical
failures. The 72 failures included 41 total knee arthroplasties, 23
revision allografts, 4 partial knee arthroplasties, 2 patellectomies,
and 2 knee fusions. The mean time to failure was 40 months (range,
3–165 months). Survivorship was 82% at 5 years, 72% at 10 years,
and 70% at 25 years. The best outcome, by diagnosis, was seen in
the patients with osteochondral dissecans (12% failures). Of the
osteochondral dissecans non-failures, the mean modified D’Aubigne
and Postel score 64 improved from 12.9 to 16.7, the mean IKDC 65
pain score improved from 5.2 to 2.2, the mean IKDC function score
improved from 3.9 to 8.1, and the mean KS-F score 66 improved from
76 to 92 (all p

154
Extended Abstracts
Annotation: Table 4 Results of objective outcome measures
*paired t-test
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Acknowledgments:
Shiley Center for Orthopaedic Research and Education
Extended Abstracts 155
18.1
Stem Cell Therapy for Joint Repair
F. Barry
Galway/Ireland
Introduction: Adult mesenchymal stem cells (MSCs) isolated
from bone marrow and a variety of connective tissues have been
extensively tested in the treatment of bone and caetilage repair and
in osteoarthritis (OA). In addition, fully allogeneic transplantation
of human MSCs is tolerated in the immunocompetent host and
allogeneic therapy has been effective in the treatment of graftversus-host
disease. However, there are many aspects of the
biology of MSCs that are poorly described and a more exhaustive
characterization is necessary to exploit these cells fully in the context
of tissue repair. Adequate translation of MSC therapy will only be
successful if the following are addressed: (1) development of new
cell-specific markers, (2) deciphering the therapeutic mechanism
of action and unravelling the paracine signals that contribute to
tissue repair, (3) understanding clonal heterogeneity in cultured
populations, (4) ensuring that batch variability is controlled and (5)
understanding the nature of host immunomodulation by transplanted
MSCs and allogencity. Further studies are also necessary to gaoin
a comprehensive understanding of how MSCs may contribute to
cartilage repair and how they may impede the progression of OA.
This review will address aspects of the characterization of MSCs and
the development of new markers and will also discuss their use in
cartilage repair models.
Content: Characterization of MSCs While the preclinical and clinical
testing of hMSCs has advanced rapidly over the last few years,
the development of efficient and standardised methods for their
isolation and characterization has not. Most attempts to isolate
these cells depend on adherent culture systems with a significant
risk of preparing heterogeneous or poorly characterized populations.
There is evidence that hMSCs isolated by current methods are not
homogenous and in fact consist of mixtures of progenitors and
other cells. The uncertain nature of primary isolates of hMSCs, the
possibility of culture-induced heterogeneity and the lack of highly
specific markers raise issues of regulatory compliance that may
impede clinical testing. There is a risk that emerging clinical data
will be compromised by this lack of standardization and that current
methods of cell isolation may not result in the most therapeutically
effective cells. The lack of MSC-specific markers has also made it
difficult to construct meaningful hierarchical models of multilineage
differentiation and to probe the in vivo antecedents of cultured
cells. Presently there are several antibodies that are routinely used
to characterize MSCs from human bone marrow by flow cytometry
and other methods and some have been adopted as release tests
for clinical grade cells. These include CD105, CD73, CD90, STRO-1
and CD271. None of these represents a canonical marker of MSCs
and therefore the homogeneity, reproducibility and consistency
of isolated populations is not assured. MSC reagents have been
generated using a variety of methods including monoclonal antibody
technology, by screening a naive human antibody phage display
library or by preparing aptamers. Despite these efforts specific and
unambiguous markers have not been forthcoming. To overcome
potential immune tolerance and to generate a new antibody
discovery platform for hMSCs we prepared an avian immune phage
display library. We hypothesized that the phylogenetic distance
would greatly increase the probability of generating high affinity
recombinant antibodies to MSC surface proteins and overcome
the difficulties associated with conserved mammalian sequences.
The use of the avian immunoglobulin system for generation of
recombinant antibodies to human proteins has been demonstrated
previously. In this study we immunized chickens with early passage
hMSCs and generated an antibody phage display library from the
spleen and marrow. After stringent screening of the library and the
removal of antibodies reactive with peripheral blood mononuclear
cells we randomly isolated four recombinant single-chain antibody
fragments (scFvs) termed TMSC1, 2, 3 and 4. We found that these
bound to a population of cells in human bone marrow that were
CD45low, lineage negative and which were enriched in early passage
directly plated hMSCs. One of the scFvs, TMSC3 was particularly
useful in the direct isolation of MSCs from human marrow. TMSC3+
cells isolated using magnetic cell separations (MACS) were
fibroblastic, proliferative and exhibited trilineage differentiation.
MSCs in Cartilage Repair There are several factors which influence
the selection of cells for cartilage repair therapy. These include
ease of isolation, differentiation potential, evidence of engraftment
and tissue repair and the absence of a host immune response.
Chondrocytes represent one type of repair cells that are cultured
ex vivo and then delivered to the cartilage surface, but it is not
clear that these are the best choice. Stem cells with chondrogenic

156
Extended Abstracts
potential may represent a more effective and more readily available
cellular therapeutic for this purpose. Several tissue-engineering
approaches have been used for cartilage repair, for example the
fixation of implanted chondrocytes beneath a sutured flap of ectopic
tissue or a collagen membrane. Other approaches have centered
on the use of cells loaded on a scaffold and delivered to a lesion
site. These methods are applicable to the repair of focal defects
of defined dimensions but not to the treatment of complex lesions
that cover a large surface area of the joint that may be associated
with severe and progressive inflammatory conditions such as
OA. It is attractive to hypothesize that MSCs could have a role in
cartilage protection by direct resurfacing of the articular cartilage.
However, it seems more likely, based on low levels of engraftment,
that transplanted MSCs are effective mediators of repair by virtue
of their capacity to deliver to the host a cascade of cytoprotective,
antiaptoptotic, immunomodukatory or proangiogenic factors.
Based in this principle, the capacity of MSCs to enhance tissue
restoration in the complex degenerate environment of the OA joint
may be high. The MSC Niche There is little clarity surrounding the
niche, or tissue-specific microenvironment, in which MSCs reside.
Despite this, they can be easily isolated and differentiated in vitro
into chondrocytes which synthesize an abundant extracellular
matrix rich in type II collagen, aggrecan and other cartilage-specific
components. Despite the lack of understanding of these cells and
their natural history, it is clear that they have therapeutic potential
in a broad variety of clinical applications. At this point we have
an incomplete understanding of the regulation of differentiation,
commitment and plasticity of the MSC population isolated from
marrow. What is clear is that their proliferative activity in vitro is
high and that, when exposed to TGF-beta, they have a chondrogenic
capacity that far exceeds that of primary chondrocytes in culture.
It is also clear that MSCs are fully tolerated in an allogeneic setting
when delivered to an immunocompetent host. This creates new
opportunities for the therapeutic use of these cells without the need
for a tissue biopsy. There are other properties of MSCs that make
them attractive candidates in cartilage repair: (1) they have an ability
to resist hypoxic stress and remain active after transplantation when
host cells are compromised, (2) they may deliver a series of repair
cytokines and chemokines to the transplantation site which stimulate
a repair response in host cells and (3) they may have the capacity to
migrate in a targeted fashion to injured tissues. Despite this, cellbased
cartilage repair remains a challenging objective. Most efforts
to date have relied on the local delivery of undifferentiated cells
to the cartilage surface, often in association with a biocompatible
scaffold. It is useful now to consider newer approaches, including
the application of cells which are predifferentiated to match the
tissue target, and to devise new approaches that will ensure optimal
engraftment and retention at the site of injury. In the case of articular
cartilage engraftment and retention of delivered cells is difficult to
achieve.
18.2
Stem cell - based therapeutic approaches to joint surface repair
C. De Bari
Aberdeen/United Kingdom
Introduction: Arthritis, with osteoarthritis (OA) accounting for most
of this burden, is a leading cause of disability in the western world
and its total costs have been estimated over $65 billion annually in
United States. Post-traumatic OA represents 13% of knee OA and
73% of ankle OA. Symptomatic chronic full-thickness defects of
the knee joint surface require surgical treatment for both symptom
relief and to prevent possible evolution towards OA. In a simplistic
way, the evolution towards secondary OA may result from a failure
of reparative processes to counteract the tissue damage induced
by injuring factors. Hence, joint surface repair represents an
important therapeutic goal. Regenerative medicine has opened up
the unprecedented opportunity to promote repair through tissue
regeneration (1). The current prototype of cell-based biological
repair of the joint surface was first described in 1994 by Brittberg
and colleagues (2), who reported treatment of symptomatic defects
of the joint surface in humans by implantation of autologous,
culture-expanded articular chondrocytes underneath a periosteal
flap. Chondrocytes were obtained with a cartilage biopsy from a
healthy and minor-load bearing area of the same joint surface.
This study showed symptomatic relief in 14 out of 16 patients with
lesions of the femoral condyle at 2 years follow up (2). Currently,
ACI represents gold standard of cell therapy for cartilage repair
with up to 20 years’ follow-up showing ACI being an effective and
durable solution for the treatment of large full-thickness cartilage
lesions of the knee joint (3). Articular chondrocytes, however, are
difficult to expand because of their limited proliferative capacity
and rapid de-differentiation in vitro, resulting in the loss of their
capacity to form cartilage when transplanted in vivo (4). The use of
mesenchymal stem cells (MSCs) as chondrocyte substitutes in an
ACI-equivalent procedure is intensely pursued because MSCs are
easily accessible, easy to isolate and to expand in culture, and they
have ability to form cartilage and bone. In addition, MSCs appear to
be immune privileged under specific conditions. Altogether, these
properties would allow upscaling and generation of large batches of
quality controlled MSC preparations ready for allogeneic use, thus
circumventing the limitations and patient-to-patient variability of
autologous cell protocols. Preclinical and clinical studies are needed
to compare MSCs with articular chondrocytes to see whether
implantation of MSCs will result in a cartilage tissue that is as
durable as the one following implantation of articular chondrocytes.
Importantly, the use of MSCs would extend the application of cellbased
technologies to non-localised chronic lesions in OA patients,
as reported (5).
Content: Originally isolated from bone marrow, MSCs are now
known to be obtainable virtually from any connective tissue of
the adult human body (6). We previously reported the isolation
and characterization of MSCs from the adult human synovium and
periosteum, and provided evidence of their multipotency at the
single cell level using a series of in vitro and in vivo assays (7-12).
There is evidence to indicate that human MSCs from different tissues
possess distinctive biological properties (13-14) and the issue
remains as to whether MSCs would be capable of forming stable
hyaline-like cartilage as opposed to the transient cartilage template
that is replaced with bone during the process of endochondral
ossification. The propensity of bone marrow MSCs to form a
cartilage tissue with a high frequency of chondrocyte hypertrophy
(15) could explain the excessive advancement of the bone front
due to endochondral ossification and leading to a thinner articular
cartilage as observed in experimental animals (16). The variability in
the biological properties of MSC populations is likely to affect the
outcome of clinical applications; hence, the need to standardize
MSC bioprocessing to obtain MSC preparations with consistent and
reproducible biological potency, quality-controlled for therapeutic
applications with specific clinical indications (1). At the same
time, the availability of different MSCs with distinct differentiation
properties is also desirable because it allows a broader choice in the
optimisation of different tissue repair protocols. For example, MSCs
with a preferential osteogenic differentiation would be desirable
for preparation of biological bone substitutes while for articular
cartilage repair the ideal MSCs should be able to form hyaline-like
cartilage that is resistant to endochondral ossification. The use of
MSCs, in suspension or in combination with biomaterials, requires
assessment of potency for quality control in order to ensure clinical
effectiveness at least in structural outcome. The availability of
large batches of “off-the-shelf” quality-controlled cell populations
will enhance consistency of treatments while abating costs; it will
also eliminate the need for two operations and enable large scale

production. This however poses obvious risks of rejection. There
is evidence that MSCs can be poorly immunogenic in vivo under
specific conditions (17). However, the differentiation into a mature
phenotype of the implanted stem cells is likely to result in the loss
of the immunological privilege with consequent rejection. MSCs
could also be implanted immediately after their purification. A
huge effort in the field is directed towards developing therapeutic
protocols employing freshly purified cells in a one-stop procedure.
Minimally manipulated cellular preparations are still required to
undergo identity characterization and potency assessment, but they
are expected to greatly simplify autologous procedures, deliverable
to patients in one single intervention, and the regulatory paths. In
addition to the use of ex vivo manipulated MSCs, another approach
to the repair of the joint surface could be the activation of intrinsic
regenerative mechanisms by using medications that target the
stem cells naturally present in their own environments and related
reparative signalling pathways. In this respect, several jointassociated
tissues such as synovial membrane and fluid, fat pad,
periosteum, bone marrow, and even the articular cartilage itself,
have been reported to contain cells that, after isolation and culture
expansion, display properties of MSCs. However, it remains to be
seen whether “professional” MSCs exist in vivo in their own tissue/
organ environments or are a clinically relevant artefact due to ex vivo
manipulations. Recently, by combining a double nucleoside labelling
scheme with a clinically relevant mouse model of joint surface injury
(18), we provided data on the identification and characterization
of endogenous resident MSC niches in the knee joint synovium in
vivo (19). We are currently investigating endogenous MSCs in joint
tissues, their role in the mechanisms underlying articular cartilage
maintenance and healing and, more generally, how signals in the
niches are coupled to functional events and related outcomes in joint
homeostasis, remodelling and repair. Bone marrow transplantation
in haematology best illustrates the success of a cell therapy that
has evolved with the increasing understanding of cell phenotypes,
functions, and niches. Classical ACI has already evolved into
second and third generation ACI. In a near future, novel strategies
for biological joint resurfacing will be developed in parallel to
refinements of ACI-based protocols. It is anticipated that the type
of intervention will be dependent on clinical indication and factors
such as size and depth of the lesion, status of the surrounding
cartilage and other joint tissues. Interventions will not be mutually
exclusive and will be likely to span from ACI (with chondrocytes or
stem cells) to pharmacological targeting, by using drugs, of the joint
stem cell niches in order to regenerate joint tissues. Ultimately, such
interventions will have to address two main issues: symptom relief
and durable repair for effective prevention of OA.
References:
1. Roberts S, Genever P, McCaskie A, De Bari C. Prospects of stem
cell therapy in osteoarthritis. Regen Med. 2011; 6 (3): 351-66. 2.
Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson
L. Treatment of deep cartilage defects in the knee with autologous
chondrocyte transplantation. N Engl J Med. 1994; 331 (14): 889-95
3. Peterson L, Vasiliadis HS, Brittberg M, Lindahl A. Autologous
chondrocyte implantation: a long-term follow-up. Am J Sports Med.
2010; 38 (6): 1117-24. 4. Dell’Accio F, De Bari C, Luyten FP. Molecular
markers predictive of the capacity of expanded human articular
chondrocytes to form stable cartilage in vivo. Arthritis Rheum.
2001; 44 (7): 1608-19. 5. Wakitani S, Imoto K, Yamamoto T, Saito
M, Murata N, Yoneda M. Human autologous culture expanded bone
marrow mesenchymal cell transplantation for repair of cartilage
defects in osteoarthritic knees. Osteoarthritis Cartilage 2002; 10
(3): 199-206. 6. Augello A, Kurth TB, De Bari C: Mesenchymal stem
cells: a perspective from in vitro cultures to in vivo migration and
niches. Eur Cell Mater. 2010; 20: 121-33. 7. De Bari C, Dell’Accio F,
Tylzanowski P, Luyten FP. Multipotent mesenchymal stem cells from
adult human synovial membrane. Arthritis Rheum. 2001; 44 (8):
1928-42. 8. De Bari C, Dell’Accio F, Luyten FP: Human periosteumderived
cells maintain phenotypic stability and chondrogenic
potential throughout expansion regardless of donor age. Arthritis
Rheum. 2001; 44 (1): 85-95. 9. De Bari C, Dell’Accio F, Vandenabeele
F, Vermeesch JR, Raymackers JM, Luyten FP. Skeletal muscle repair
by adult human mesenchymal stem cells from synovial membrane.
J Cell Biol. 2003; 160 (6): 909-18. 10. De Bari C, Dell’Accio F, Luyten
FP. Failure of in vitro-differentiated mesenchymal stem cells from
the synovial membrane to form ectopic stable cartilage in vivo.
Arthritis Rheum. 2004; 50 (1): 142-50. 11. De Bari C, Dell’Accio F,
Vanlauwe J, Eyckmans J, Khan I, Archer CW, Jones E, McGonagle D,
Pitzalis C, Luyten FP: Mesenchymal multipotency of adult human
periosteal cells demonstrated by single cell lineage analysis.
Arthritis Rheum. 2006; 54 (4): 1209-21. 12. Karystinou A, Dell’Accio
F, Kurth TB, Wackerhage H, Khan IM, Archer CW, Jones EA, Mitsiadis
Extended Abstracts 157
TA, De Bari C: Progenitor cell subsets revealed by clonal analysis of
human synovial membrane mesenchymal stem cells. Rheumatology
(Oxford). 2009; 48 (9): 1057-64. 13. Sakaguchi Y, Sekiya I, Yagishita
K, Muneta T. Comparison of human stem cells derived from various
mesenchymal tissues: superiority of synovium as a cell source.
Arthritis Rheum. 2005; 52 (8): 2521-9. 14. De Bari C, Dell’Accio F,
Karystinou A, Guillot PV, Fisk NM, Khan IM, Archer CW, Jones EA,
McGonagle D, Mitsiadis TA, Donaldson AN, Luyten FP, Pitzalis C.
A biomarker-based mathematical model to predict bone forming
potency of human synovial and periosteal mesenchymal stem
cells. Arthritis Rheum. 2008; 58 (1): 240-50. 15. Scotti C, Tonnarelli
B, Papadimitropoulos A, Scherberich A, Schaeren S, Schauerte
A, Lopez-Rios J, Zeller R, Barbero A, Martin I. Recapitulation of
endochondral bone formation using human adult mesenchymal stem
cells as a paradigm for developmental engineering. Proc Natl Acad
Sci U S A. 2010; 107 (16): 7251-6. 16. Qiu YS, Shahgaldi BF, Revell WJ,
Heatley FW. Observations of subchondral plate advancement during
osteochondral repair: a histomorphometric and mechanical study
in the rabbit femoral condyle. Osteoarthritis Cartilage 2003; 11 (11):
810-20. 17. MacDonald G, Augello A, De Bari C: Role of mesenchymal
stem cells in reestablishing immunologic tolerance in autoimmune
rheumatic diseases. Arthritis Rheum. 2011; 63 (9): 2547-57. 18.
Eltawil NM, De Bari C, Achan P, Pitzalis C, Dell’Accio F: A novel in vivo
murine model of cartilage regeneration. Age and strain-dependent
outcome after joint surface injury. Osteoarthritis Cartilage. 2009; 17
(6): 695-704. 19. Kurth TB, Dell’Accio F, Crouch V, Augello A, Sharpe
PT, De Bari C. Functional mesenchymal stem cell niches in adult
mouse knee joint synovium in vivo. Arthritis Rheum. 2011; 63 (5):
1289-300.
Acknowledgments:
The author is grateful to support to his research from Arthritis
Research UK.
19.1.1
Basics on ultrastructural-multiparametric MR techniques
S. Apprich 1 , G.H. Welsch 1 , S. Zbyn 1 , B. Schmitt 1 , S. Trattnig 2
1 Vienna/Austria, 2 Wien/Austria
Introduction: Osteoarthritis (OA) changes in hyaline articular
cartilage are characterized by important changes in the biochemical
composition of cartilage. The macromolecular network of cartilage
consists mainly of collagen and proteoglycans. Normally, the
highly organized collagen network serves as the tissue’s structural
framework and is the principal source of tensile and shears strength.
Glucosaminoglycans (GAGs) are repeating disaccharides with
carboxyl and sulfate groups attached to the larger aggrecan molecule
(proteoglycan) that is part of the extracellular matrix network of
cartilage. GAG molecules possess considerable net negative charge
and confer compressive strength to the cartilage. Loss of GAGs and
increased water content represent the earliest stage of cartilage
degeneration, while the collagenous component of the extracellular
matrix still remains intact. Several MR imaging techniques are
available that enable detection of biochemical changes that precede
the morphologic degeneration in cartilage. All of these techniques
attempt to selectively demonstrate the GAG components and/or the
collagen fiber network of the extracellular matrix and are usually
summarized as “compositional imaging” of cartilage.
Content: Delayed Gadolinium enhanced MRI of Cartilage (dGEMRIC)
The dGEMRIC and sodium (23 Na) MR imaging techniques are based
on similar principles, with positive sodium ions being attracted by
the negatively fixed charged density of the GAG side chains. These
electrostatic forces are responsible for a direct relationship between
the local sodium concentration and fixed charged density with a
strong correlation between fixed charged density and GAG content
(1,2). dGEMRIC is based on the fact that GAGs contain negatively
charged side chains, which lead to an inverse distribution of
negatively charged contrast agent molecules (eg, gadolinium) with
respect to GAG concentration (3,4). Drawbacks of this technique
are the need to use a double dose of a gadolinium-based contrast
agent (0.2 mmol per kilogram of body weight) and the requirement
for a delay between intravenous administration of the agent and
the start of the MR examination (usually 60–90 minutes) to allow
complete penetration of the contrast agent into the cartilage. Varus
malalignment is associated with a lower dGEMRIC index on the medial
side, while the opposite trend is evident in valgus malalignment
(5). Correlations between dGEMRIC index and pain, as measured

158
Extended Abstracts
by the Western Ontario and McMaster Universities Arthritis Index,
were evident in patients with hip dysplasia (5). dGEMRIC studies
have demonstrated that moderate exercise can improve knee
cartilage GAG (estimated by T1 in the presence of gadopentetate
dimeglumine) in patients at high risk for OA (6). In patients with an
injury to the anterior cruciate ligament, lower GAG concentrations
were found in the medial compartment of the femoral and tibial
articular cartilage of the injured knee when compared with the
contralateral (uninjured) knee (7). In patients with femoroacetabular
impingement, correlations were observed between dGEMRIC index,
pain, and alpha angle, suggesting that hips with more femoral
deformity may show signs of early OA (8).
T1rho mapping T1 rho is a time constant that characterizes magnetic
relaxation of spins under the influence of a radiofrequency field
parallel to the spin magnetization. The resultant contrast is sensitive
to the low-frequency interactions between water molecules and their
local macromolecular environment, such as GAG and collagen, which
are the main constituents of the extracellular matrix in cartilage. In
early studies, changes in T1 rho were found in proteoglycan-depleted
cartilage plugs, but, on the other hand, other investigators (9-13)
reported that T1 rho did not correspond to a modified dGEMRIC
technique or to the proteoglycan distribution seen at histologic
examination, which suggests that several factors contribute to
variations in T1 rho . Recently, rapid 3D in vivo T1 rho mapping
techniques of knee cartilage at high field strength (3 T) have been
developed and applied in patients with OA (14,15). Other in vivo
studies (15) have shown increased cartilage T1 rho values in patients
with OA compared with those values in control subjects, which
suggests the potential of T1 rho imaging for noninvasive evaluation
of diseased cartilage. In cartilage overlying traumatic bone marrow
lesions, the average T1 rho values were significantly higher than
those in surrounding cartilage, demonstrating that macromolecular
changes in cartilage may be related to traumatic bone marrow damage
(12). Sodium imaging Previous research (1, 16, 17) has already shown
that 23 Na MR imaging has a potential advantage over conventional
proton MR imaging for the investigation of biochemical markers in
cartilage during the early stages of OA. Although 23 Na MR imaging
has high specificity and does not require any exogenous contrast
agent, it does require special hardware (multinuclear) capabilities,
specialized RF coils (transmit-receive sodium coils), and, likely, 3D
very short echo time sequences. These challenges currently limit the
use of 23 Na MR imaging in the clinical and research settings. T2 and
T2* mapping T2 mapping has been used to describe the composition
of hyaline articular cartilage in the knee joint on the basis of collagen
structure and hydration (18). In addition to the transverse relaxation
time (T2) of articular cartilage, T2* relaxation measures have recently
been investigated (2) for depiction of the collagen matrix. In healthy
articular cartilage, an increase in T2 values from deep to superficial
cartilage layers can be observed; this is based on the anisotropy of
collagen fibers running perpendicular to cortical bone in the deep
layer of cartilage and parallel to the surface in the superficial layer
(19). Therefore, zonal evaluation of articular cartilage is important
in T2 analyses. Analyses of T2 relaxation times in the knee have
been performed previously, usually at 1.5 T or, more recently, 3.0
T, demonstrating the ability to depict abnormalities before there
is evident morphologic change. In vivo MR imaging studies (20)
have demonstrated that cartilage T2 values are related to age.
Cartilage T2 values seem to be associated with the severity of OA,
and there are variations between tibial and femoral cartilage T2 (21).
A significant correlation between cartilage T2 and the severity and
grade of cartilage and meniscus lesions has been demonstrated.
Subjects with high activity levels had significantly higher prevalence
and grade of abnormalities and higher T2 values than did subjects
with low activity levels (22). Chemical Exchange Saturation Transfer
(gagCEST) Chemical exchange saturation transfer (CEST) (23)imaging
has recently been presented as a technique with the potential
to measure PG content in cartilage. This technique exploits the
biochemical properties of GAG, i.e., the chemical exchange of labile
protons with bulk water (gagCEST). It was shown that labile –NH
(δ=3.2 ppm offset from the water resonance) and –OH (δ=0.9 to 1.9
ppm) protons of GAG can be used as CEST agents through selective
saturation of their resonance signals (23). This selectivity is also the
fundamental difference between gagCEST and T1 rho relaxation, with
the latter being caused by a sum of non-distinguishable exchange
effects. Recent studies aimed mostly at general optimization of
gagCEST imaging technique, but also the feasibility of gagCEST
imaging in patients was demonstrated at 7 Tesla (24). In the latter
study, a strong correlation was found between gagCEST results and
sodium imaging, which is a sensitive and highly specific method to
determine cartilage GAG content at 7 Tesla.
References:
1 . Shapiro EM , Borthakur A , Gougoutas A , Reddy R . 23Na MRI
accurately measures fi xed charge density in articular cartilage.
Magn Reson Med 2002 ; 47 (2): 284 – 291 .
2 . Welsch GH , Mamisch TC , Hughes T , et al . In vivo biochemical 7.0
Tesla magnetic resonance: preliminary results of dGEMRIC, zonal
T2, and T2* mapping of articular cartilage . Invest Radiol 2008 ; 43
(9): 619 – 626
3 . Bashir A , Gray ML , Burstein D . Gd-DTPA2-as a measure of
cartilage degradation .Magn Reson Med 1996 ; 36 (5): 665 – 673 .
4 . Bashir A , Gray ML , Boutin RD , Burstein D . Glycosaminoglycan
in articular cartilage: in vivo assessment with delayed Gd(DTPA)
(2-)-enhanced MR imaging . Radiology 1997 ; 205 (2): 551 – 558 .
5 . Kim YJ , Jaramillo D , Millis MB , Gray ML , Burstein D . Assessment
of early osteoarthritis in hip dysplasia with delayed gadoliniumenhanced
magnetic resonance imaging of cartilage . J Bone Joint
Surg Am 2003 ; 85-A (10): 1987 – 1992 .
6 . Roos EM , Dahlberg L . Positive effects of moderate exercise
on glycosaminoglycan content in knee cartilage: a four-month,
randomized, controlled trial in patients at risk of osteoarthritis .
Arthritis Rheum 2005 ; 52 (11): 3507 – 3514 .
7 . Fleming BC , Oksendahl HL , Mehan WA , et al . Delayed gadoliniumenhanced
MR imaging of cartilage (dGEMRIC) following ACL injury .
Osteoarthritis Cartilage 2010 ; 18 (5): 662 – 667 .
8 . Jessel RH , Zilkens C , Tiderius C , Dudda M , Mamisch TC , Kim
YJ . Assessment of osteoarthritis in hips with femoroacetabular
impingement using delayed gadolinium enhanced MRI of cartilage
. J Magn Reson Imaging 2009 ; 30 (5): 1110 – 1115 ..
9 . Duvvuri U , Reddy R , Patel SD , Kaufman JH , Kneeland JB , Leigh
JS . T1rho-relaxation in articular cartilage: effects of enzymatic
degradation . Magn Reson Med 1997 ; 38 (6): 863 – 867 .
10 . Akella SV , Regatte RR , Gougoutas AJ , et al .Proteoglycaninduced
changes in T1rhorelaxation of articular cartilage at 4T .
Magn Reson Med 2001 ; 46 (3): 419 – 423 .
11 . Menezes NM , Gray ML , Hartke JR , Burstein D . T2 and T1rho
MRI in articular cartilage systems . Magn Reson Med 2004 ; 51 (3):
503 – 509 .
12 . Regatte RR , Akella SV , Wheaton AJ , et al . 3D-T1rho-relaxation
mapping of articular cartilage: in vivo assessment of early
degenerative changes in symptomatic osteoarthritic subjects . Acad
Radiol 2004 ; 11 (7): 741 – 749 .
13 . Mlynárik V , Szomolányi P , Toffanin R , Vittur F , Trattnig S
.Transverse relaxation mechanisms in articular cartilage . J Magn
Reson 2004 ; 169 (2): 300 – 307 .
14 . Li X , Han ET , Busse RF , Majumdar S .In vivo T(1rho) mapping
in cartilage using 3D magnetization-prepared angle-modulated
partitioned k-space spoiled gradient echo snapshots (3D MAPSS) .
Magn Reson Med 2008 ; 59 (2): 298 – 307 .
15 . Li X , Benjamin Ma C , Link TM , et al . In vivo T(1rho) and T(2)
mapping of articular cartilage in osteoarthritis of the knee using 3 T
MRI . Osteoarthritis Cartilage 2007 ; 15 (7): 789 – 797 .
16 . Shapiro EM , Borthakur A , Dandora R , Kriss A , Leigh JS , Reddy
R . Sodium visibility and quantitation in intact bovine articular
cartilage using high fi eld (23)Na MRI and MRS . J Magn Reson 2000
; 142 (1): 24 – 31 .
17 . Borthakur A , Shapiro EM , Beers J , Kudchodkar S , Kneeland JB
, Reddy R . Sensitivity of MRI to proteoglycan depletion in cartilage:
comparison of sodium and proton MRI . Osteoarthritis Cartilage
2000 ; 8 (4): 288 – 293 .
18 . Mosher TJ , Dardzinski BJ . Cartilage MRI T2 relaxation time
mapping: overview and applications . Semin Musculoskelet Radiol
2004 ; 8 (4): 355 – 368 .
19 . Mosher TJ , Smith HE , Collins C , et al .Change in knee cartilage
T2 at MR imaging after running: a feasibility study . Radiology 2005
; 234 (1): 245 – 249 . 20 . Mosher TJ , Dardzinski BJ , Smith MB .
Human articular cartilage: influence of aging and early symptomatic

degeneration on the spatial variation of T2—preliminary findings at
3 T . Radiology 2000 ; 214 (1): 259 – 266 .
21 . Dunn TC , Lu Y , Jin H , Ries MD , Majumdar S . T2 relaxation
time of cartilage at MR imaging: comparison with severity of knee
osteoarthritis . Radiology 2004 ; 232 (2): 592 – 598 .
22 . Stehling C , Liebl H , Krug R , et al . Patellar cartilage: T2 values
and morphologic abnormalities at 3.0-T MR imaging in relation to
physical activity in asymptomatic subjects from the osteoarthritis
initiative . Radiology 2010 ; 254 (2): 509 – 520 . concentration in vivo
by chemical exchange-dependent saturation transfer (gagCEST).
Proc Natl Acad Sci 2008;105(7):2266-2270.
23. Schmitt B, Zbyn S, Stelzeneder D, Jellus V, Paul D, Lauer L,
Bachert P, Trattnig S. Cartilage Quality Assessment by Using
Glycosaminoglycan Chemical Exchange Saturation Transfer and
23Na MR Imaging at 7 T. Radiology 2011;260(1):257-264.
19.1.2
Clinical application of ultrastructural-multiparametric MR
techniques in patients after repair surgery
G.H. Welsch
Vienna/Austria
Introduction: Articular cartilage lesions are a common pathology of
the knee joint and many patients could benefit from cartilage repair.
Such surgical treatment options may offer the possibility for patients
with cartilage defects to avoid the development of osteoarthritis
or delay its progression. Different sophisticated cartilage repair
techniques, including arthroscopic or open surgical approaches, as
well as marrow-stimulation techniques, osteochondral grafting, and
chondrocyte implantation/transplantation, require knowledgeable
and high quality follow-up. Although clinical findings are the primary
criteria, a more objective outcome measure would possibly have the
ability to provide predictive values. Advanced magnetic resonance
imaging (MRI) is able to depict the morphological and biochemical
condition of the cartilage repair tissue and the surrounding
structures [1-4]. Within the ICRS a consensus paper on the recent
possibilities and advances in imaging of cartilage repair tissue has
been published in the journal cartilage [5]. An ideal MRI protocol
for articular cartilage and cartilage repair should provide accurate
assessment of cartilage thickness and volume, reveal information
about signal changes within cartilage, and demonstrate clear
delineation of the cartilage surface, the cartilage and bone interface,
as well as the subchondral bone and also provide information about
the biochemical composition of articular cartilage and cartilage repair
tissue. To evaluate such MRI protocols, cartilage repair procedures,
such as arthroscopic or open surgical approaches as well as marrowstimulation
techniques, osteochondral grafting, and chondrocyte
implantation/transplantation could be used. The uniqueness of
cartilage repair in the use of advanced morphological and especially
biochemical MR methodologies is bases in the fact that these
procedures include defined areas of repair cartilage in addition to an
often-intact surrounding cartilage in mostly young patients. Thus,
modified and healthy cartilage can be compared within one subject.
Nevertheless, the aim of an ideal MRI protocol must be its ease of
implementation in scientific studies as well as day-to-day clinical
routine. The combination of high-resolution morphological MR
evaluation with biochemical assessment in a clinically applicable
scan time needs to exploit high-field MRI (1.5T, 3.0T) together with
advanced imaging techniques and sophisticated coil technology.
Aim of this manuscript is to demonstrate advanced MRI techniques
to depict the morphological and especially the biochemical
constitution of cartilage repair tissue as a multiparametric approach
in the follow-up of cartilage repair procedures.
Content: Morphological MRI The morphological shape of the repair
tissue, the degree of repair filling (1), the integration of the cartilage
repair tissue to the border zone (2), the structure of the surface (3),
the structure of the whole repair tissue (4), the signal intensity (5),
the constitution of the subchondral lamina (6), the the constitution
of the subchondral bone (7), possible adhesions (8), and possible
effusion (9) can be combined in the nine variables of the magnetic
resonance observation of cartilage repair tissue (MOCART) scoring
system [6] which is claimed to allow subtle and suitable assessment
of the articular cartilage repair tissue. The MR assessment of the
MOCART score is based on standard MR sequences, also
recommended by the International Cartilage Repair Society (ICRS)
Extended Abstracts 159
[7]. Depending on the locality of the area of cartilage repair, the MR
evaluation of the cartilage repair tissue is performed on sagittal,
axial or coronal two-dimensional (2D) planes using high spatial
resolution together with a slice thickness of 2-4 mm. Following the
current standard procedure, the recommended MR sequences by
the ICRS and the recommended sequences for the MOCART scoring
visualize the area of cartilage repair and the adjacent cartilage as
well as the surrounding structures in 2D. In contrast, new isovoxel
sequences have the potential for high-resolution isotropic imaging
with a voxel size down to 0.4mm3, and can be reformatted in every
plane without any loss of spatial resolution. Hence the cartilage
repair tissue can be visualized three-dimensionally (3D) in every
plane, its subsequent classification and grading by an MR-based
scoring system benefits and a new 3D-MOCART [8]. This new MOCART
score can be achieved by standard 2D MR sequences as well as by
modern isotropic MR sequences. Besides the possibility of a
depiction of the repair tissue in more than one plane, other benefits
of this new MOCART score are the better and more precise description
of the repair tissue itself however also of the underlying subchondral
bone plate. Hence e.g. the cartilage hypertrophy can be scored in
more detail. Within the subchondral bone, osteophytes (as very
often present after marrow stimulating techniques) are included in
the score. Furthermore other changes within the subchondral bone
and the bone marrow are better included into this score scheme.
This results in now 11 variables and a better scoring algorithm. This
helps especially in longitudinal evaluations of a specific patient over
time. dGERMIC and other glycosamnioglycan specific techniques Of
the major macromolecules, glycosamnioglycans (GAG), are important
to the cartilage tissue’s biochemical and biomechanical function.
GAG are the main source of fixed charge density (FCD) in cartilage,
often decreased in reparative cartilage after cartilage repair [9].
Intravenously administered gadolinium diethylenetriamine
pentaacetate anion, (Gd-DTPA2-) penetrates the cartilage through
both the articular surface and the subchondral bone. The contrast
equilibrates in inverse relation to the FCD, which is, in turn, directly
related to the GAG concentration; therefore, T1, which is determined
by the Gd-DTPA2- concentration, becomes a specific measure of
tissue GAG concentration, suggesting that T1 mapping enhanced by
delayed administration of Gd-DTPA2- (T1 dGEMRIC) has the potential
for monitoring GAG content of cartilage in vivo [10; 11]. Besides
standard inversion recovery (IR) evaluation, a new approach for fast
T1 mapping has shown promising results and is increasing the
clinical applicability of the dGEMRIC technique [12]. Since GAG
content is responsible for cartilage function, particularly its tensile
strength, the monitoring of the development of GAG content in
cartilage repair tissues may provide information about the quality of
the repair tissue. A recent study by our group showed dGEMRIC to
be able to differentiate between different cartilage repair tissues
with higher delta DR1 values, and thus, lower GAG content for
cartilage repair tissue after MFX compared to MACT [13]. As the
mapping of the GAG concentration is desirable in the follow-up of
cartilage repair procedures and the presented dGEMRIC technique
has the limitation of contrast agent administration and a time delay
before post-contrast MRI, a recently described technique for the
assessment of GAG concentration in vivo by chemical exchangedependent
saturation transfer (CEST) may have potential in future
applications on articular cartilage [14]. At high fields and ultra-high
fields, sodium MR imaging might become a gold-standard in future
approaches. Sodium MRI has been validated as direct and
quantitative method of computing FCD and, hence, proteoglycan
content. Achieving high enough signal-to-noise ratio, the sensitivity
of sodium MRI is high enough for detecting small changes in
proteoglycan content. T2 and other collagen specific techniques
Changes in water and collagen content and tissue anisotropy are
most frequently analyzed using the transverse relaxation time (T2)
of cartilage [15]. The collagen fiber orientation, its three-dimensional
organization and curvature can be reliably visualized by cartilage T2
mapping, however influencing its appearance at 55° (with respect to
the main magnetic field (B0)) resulting in the magic angle [16; 17]. In
healthy articular cartilage, an increase in T2 values from deep to
superficial cartilage layers can be observed based on the anisotropy
of collagen fibers running perpendicular to cortical bone in the deep
layer of cartilage [18]. Histologically validated animal studies have
shown this zonal increase in T2 values as a marker of hyaline or
hyaline-like cartilage structure after cartilage repair procedures
within the knee [19; 20]. To visualize this zonal variation is essential
for cartilage T2 mapping and high enough spatial resolution has to
be provided. In cartilage repair tissue, full-thickness T2 values, as
zonal evaluation have been shown able to visualize cartilage repair
maturation [21; 22]. Another study by our group further showed the
ability of zonal T2 evaluation to differentiate cartilage repair tissue
after MFX and MACT [23]. In a clinical approach, the differentiation of
two matrices after MACT was possible based on T2 mapping showing
the dependency of the ultra-structure of the repair tissue based on

160
Extended Abstracts
the initial matrix it was build from / seeded on [24]. Hence the
specific collagen structure of the repair tissue can be depicted and
quantified by T2 relaxation time mapping. In addition to standard 2D
multi-echo spin-echo T2 relaxation, T2*- weighted 3D gradient-echo
articular cartilage imaging has shown reliable results in the
evaluation of chondromalacia of the knee [25]. In recent studies, T2*
mapping, with its potentially short scan times, was correlated to
standard T2, and showed information comparable to that obtained
for articular cartilage in the knee, but with overall lower T2* values
(ms) [26]. Furthermore, also for T2*, a clear zonal variation between
deep and superficial cartilage layers can be shown. Another
advanced approach to combine morphological and biochemical T2
cartilage imaging is based on a Double-Echo-Steady-State (DESS)
sequence, which generates two signal echoes that are characterized
by a different contrast behavior where the underlying T2 can be
calculated. Further emerging biochemical MR techniques that are
gaining more and more importance are, besides others, diffusion
weighted imaging (DWI), magnetization transfer contrast (MTC) or
T1rho. The cartilage composition or component visualized by these
methodologies is not yet clearly validated. However initial studies
are showing very promising results and additional information
besides dGERMIC and T2 can be gained also in patients after cartilage
repair. Concluding, a combination of morphological and biochemical
MRI might provides the chance to gain a precise follow-up of the
knee joint and may offer a predictive value for the future development
and performance of the cartilage repair tissue and the joint. Ongoing
approaches in MRI of joint after cartilage repair surgery try to
furthermore include the state of the whole joint as assessed e.g. by
the Whole-Organ Magnetic Resonance Imaging Score (WORMS) in
relation to the area of cartilage repair. This is of outmost importance
as the status of the whole joint predicts the follow-up of the repaired
joint possibly even more as the repair tissue itself.
References:
1 Potter HG, et. al. Clin Sports Med, 28:77-94. ^
2 Trattnig S, et. al. Eur Radiol, 19:1582-1594.
3 Welsch GH, et. al. Semin Musculoskelet Radiol, 12:196-211. doi:
10.1055/s-0028-1083104
4 Welsch GH, et. al. J Magn Reson Imaging, 33:180-188.
5 Trattnig S, et. al. Cartilage, 2:5-26.
6 Marlovits S, et. al. Eur J Radiol, 52:310-319.
7 Brittberg M, et. al. J Bone Joint Surg Am, 85-A Suppl 2:58-69.
8 Welsch GH, et. al. Invest Radiol, 44:603-612.
9 Watanabe A, et. al. Radiology, 239:201-208.
10 Tiderius CJ, et. al. Magnet Reson Med, 49:488-492.
11 Williams A, et. al. Am J Roentgenol, 182:167-172.
12 Trattnig S, et. al. J Magn Reson Imaging, 26:974-982.
13 Trattnig S, et. al.Eur Radiol.
14 Ling W, et. al. Proceedings of the National Academy of Sciences of
the United States of America, 105:2266-2270.
15 Mosher TJ, et. al.Semin Musculoskelet Radiol, 8:355-368.
16 Goodwin DW, et. al. Acad Radiol, 5:790-798.
17 Goodwin DW, et. al. AJR Am J Roentgenol, 174:405-409.
18 Smith HE, et. al. J Magn Reson Imaging, 14:50-55.
19 Watrin-Pinzano A, et. al.Magn Reson Mater Phy, 17:219-228.
20 White LM, et. al. Radiology, 241:407-414.
21 Trattnig S, et. al. Invest Radiol, 42:442-448. 22 Welsch GH, et. al.
J Orthop Res, 27:957-963.
23 Welsch GH, et. al. Radiology, 247:154-161.
24 Welsch GH, et. al. Am J Sports Med, 38:934-942.
25 Murphy BJ (et. al.Skeletal Radiol, 30:305-311.
26 Welsch GH, et. al.Eur Radiol. 2010
Acknowledgments:
The authors achnowledge funding of the Austrian National Founds
(OENB, FWF) and the German Research Foundation (DFG)
19.1.3
Quantitative X-ray and ultrasound methodology for cartilage
repair
J.S. Jurvelin 1 , T. Viren 1 , H. Kokkonen 1 , J. Liukkonen 1 , K. Kulmala 1 , A.
Joukainen 1 , I. Kiviranta 2 , J. Salo 1 , H. Kröger 1 , J. Töyräs 1
1 Kuopio/Finland, 2 Helsinki/Finland
Introduction: Improved possibilities for cartilage reconstruction
require accurate diagnostic tools both to evaluate the results,
and to find out the right patients early enough to take advantage
of these treatment methods.At present, quantitative MRI methods
provide noninvasive means to follow the outcome of cartilage
repair. Unfortunately, due to limited availability and high costs,
MRI investigations may not always be readily at disposal. Further,
limited resolution of MRI impair its applicability for initial cartilage
diagnostics. Traditional diagnostic techniques of osteoarthritis (OA),
including clinical examination and plain X-ray imaging can only detect
late and major tissue changes. Using arthroscopic inspection and
probe palpation, cartilage injury is possible to evaluate and grade,
but the reliability of this classification is poor, especially in the early
cartilage changes (Spahn et al. 2011). Due to immature diagnostics,
many cartilage defects are only seen incidentally during arthroscopy.
This can be seen as one reason to delayed increase in the number
of cartilage repair with modern techniques. Novel noninvasive or
minimally invasive methods are needed to successfully develop new
cartilage repair approaches. Especially, sensitive and quantitative
methods should be in use to evaluate the extent and severity of the
original injury and to follow the healing process. In the past, several
methodologies, based on mechanical (Lyyra et al. 1995), acoustic
(Laasanen et al. 2003), electric (Quenneville et al. 2004) and optical
(Han et al. 2003) techniques have been proposed for evaluation
purposes. However, none of those has propagated to extensive
clinical use.
Content: Based on long-term basic science research two novel
quantitative techniques, relying on use of contrast agent enhanced
computed tomography (CECT) (Palmer et al. 2006, Silvast et al.
2009, Aula et al. 2009), or high frequency ultrasound (Viren et
al. 2009, Huang et al. 2009) are under development for cartilage
diagnostics. Both techniques have been systematically developed
for cartilage repair assesment in in vitro and in situ studies with
animal models and are now in the stage of in vivo testing in humans.
Contrast enhanced computed tomography (CECT) Analogously to
delayed gadolinium enhanced MRI of cartilage (dGEMRIC), CECT
has been introduced for quantitative imaging of articular cartilage
proteoglycan (PG) content (Palmer et al. 2006). In this method
anionic contrast agent is assumed to distribute into cartilage
inversely proportionally to spatial distribution of fixed charge
density (FCD). It has also been shown that in degenerated, or in
acutely injured, cartilage significantly higher contrast agent intake
locates in injured tissue than in intact cartilage (Kokkonen et al.
2011). CECT technique enables simultaneous quantitative analysis
of the properties of articular cartilage and subchondral bone (Aula
et al. 2009). Subtle subchondral changes have been shown to be
important in OA diagnostics. An additional advantage is higher
resolution with the use of isotrophic voxels (conical beam CT),
allowing free reconstruction of curved joint facet surfaces. Our
earlier study showed that CECT combined with finite element (FE)
analysis could be used to determine solute diffusion coefficients
which appeared to depend on the composition and structure of the
cartilage (Kulmala et al. 2010). Therefore, instead of investigating
the equilibrium distribution of the contrast agent, the nonequilibrium
diffusion properties of cartilage monitored with CECT
may be assessed to evaluate articular cartilage of clinical patients
in vivo (Kokkonen et al. 2011). Further, the optimal time points and
other practical issues regarding the in vivo imaging were evaluated.
Contrast agent concentration maximum in the cartilage was
achieved at 30 to 60 minutes after the injection and the CT-contrast
agent concentration in the knee joint was still adequate at two
hours after the injection. Normalized contrast agent concentration
was higher in the OA knee than in the healthy knee. Thus, CECT
showed potential for clinical evaluation of cartilage integrity. The
first in vivo CECT of human knees have been conducted using intraarticular
injection, however, premises to use intravenous injection
for introduction of the contrast agent are under investigations. The
challenge is to obtain contrast agent concentrations in cartilage
high enough for quantitation with CECT (Bansal et al. 2012).. Miniinvasive
ultrasound arthroscopy Ultrasound imaging application,
based on FDA approved ultrasound catheters (Viren et al. 2009,
Kaleva et al. 2011), enables imaging of cartilage surfaces during
arthroscopy. Catheters are thin, and they give a detailed structure of
cartilage with high resolution (~40 μm) Further, several quantitative
ultrasound backscatter parameters, such as integrated reflection

coefficient (IRC), apparent integrated backscatter (AIB) and
ultrasound roughness index (URI), sensitive to integrity of cartilage
and subchondral bone, can be calculated. Articular surfaces of
bones from horse intercarpal joints, featuring both intact tissue
and spontaneously healed chondral or osteochondral defects, were
imaged ex vivo with an arthroscopic ultrasound device. It was possible
to detect lesion sites and adjacent intact tissue based on IRC, AIB
and URI. The ultrasound backscattering from the inner structures of
the cartilage matched well with the histological findings, reflecting
abnormal intrinsic collagen architecture within repaired cartilage.
Surface roughness and the integrity of the intact and repaired rabbit
cartilage could also be quantitatively evaluated with the minimally
invasive ultrasound technique. Furthermore, qualitative information
about integration of the repair tissue, integrity of the surface of
repair tissue and the internal structure could be extracted from the
ultrasound images. In the clinical setting, the diagnostic potential
of high frequency ultrasound is two-fold. It can be used during
arthroscopy as an additional method to see the detailed structure of
cartilage, or it can be seen as a possible diagnostic tool to map the
condition of cartilage on the outpatient visits. We have already used
it successfully during arthroscopy in diagnostics of the earliest signs
of OA, severity of acute cartilage injuries and the outcome of surgical
repair of the injuries. The technique has revealed the high diagnostic
potential, and it will be integrated more closely with the arthroscopic
instrumentation. Further, consistent quantitative measurements set
need for the perpendicularity of the ultrasound pulse incidence as
well as for accurate localization of measurements. These issues
need to be further investigated and technically solved. Additionally,
the optimal frequency or frequency range remains to be determined,
as it determines the iamge resolution and penetration of the
ultrasound into the tissue. Correction of the effects of overlying
cartilage in bone measurements should also be further investigated.
As the thin ultrasound probe can be inserted into joint through a
small needle, the use of the technique without arthroscopic control
is investigated.
References:
Aula AS et al.: Simultaneous computed tomography of articular
cartilage and subchondral bone. Osteoarthritis Cartilage 17:1583-8,
2009
Bansal PN et al.: Cationic contrast agents improve quantification of
glycosaminoglycan (GAG) content by contrast enhanced CT imaging
of cartilage. J Orthop Res Dec 23 [Epub ahead of print]
Han CW at al.: Analysis of rabbit articular cartilage repair after
chondrocyte implantation using optical coherence tomography.
Osteoarthritis Cartilage 11: 111-21, 2003;
Huang YP, Zheng YP. Intravascular Ultrasound (IVUS): A Potential
Arthroscopic Tool for Quantitative Assessment of Articular Cartilage.
Open Biomed Eng J 26:13-20, 2009
Kaleva E et al.: Arthroscopic ultrasound assessment of articular
cartilage in human knee joint: A potential diagnostic method.
Cartilage 2: 246-53, 2011
Kokkonen HT et al.: Contrast enhanced computed tomography of
human knee cartilage in vivo. Baltic bone and cartilage, Malmö,
2011
Kulmala KA et al.: Diffusion coefficients of articular cartilage for
different CT and MRI contrast agents. Med Eng Phys. 32: 878-82,
2010
Laasanen MS et al.: Mechano-acoustic diagnosis of cartilage
degeneration and repair. J Bone Joint Surg Am. 2003;85-A Suppl
2:78-84.
Lyyra T et al.: Indentation instrument for the measurement of
cartilage stiffness under arthroscopic control. Med Eng Phys. 1995;
17(5):395-9.
Palmer AW et al.: Analysis of cartilage matrix fixed charge density
and three-dimensional morphology via contrast-enhanced
microcomputed tomography. Proc Natl Acad Sci U S A. 103: 19255-
60, 2006
Quenneville E et al.: Fabrication and characterization of nonplanar
microelectrode array circuits for use in arthroscopic diagnosis of
cartilage diseases. IEEE Trans Biomed Eng. 2004; 51(12):2164-73.
Extended Abstracts 161
Silvast TS et al.: Diffusion and near-equilibrium distribution of MRI
and CT contrast agents in articular cartilage. Phys Med Biol 54:
6823-36, 2009
Spahn G et al. Reliability in arthroscopic grading of cartilage lesions:
results of a prospective blinded study for evaluation of inter-observer
reliability. Arch Orthop Trauma Surg. 131: 377-81, 2011
Virén T et al.: Minimally invasive ultrasound method for intraarticular
diagnostics of cartilage degeneration. Ultrasound Med Biol
35:1546-5, 2009
Acknowledgments:
Financial support from the Academy of Finland, Sigrid Jusélius
Foundation, Sakari Sohlberg Foundation, Kuopio University Hospital
(EVO 5041715) and University of Eastern Finland (strategic spearhead
funding) is acknowledged.
19.2.1
Current Treatment Paradigm for Single-Stage Cartilage Repair
A.H. Gomoll
Boston/United States of America
Introduction: Cartilage repair remains in evolution. Single stage
technologies appear attractive to reduce cost and patient morbidity
alike. This presentation will review several of these technologies that
are currently either on the market or in later stage clinical trials.
Content: Single stage procedures can be divided in cell-free
implants, mainly scaffolds, and cell-based implants, which are
further sub-divided according to whether auto- and allograft tissue
is being utilized. From a US perspective, there are currently no
cell-free implants available on the market. Several devices are in
current late-stage trials that are based on multi-phasic collagen
plugs for osteochondral repair. Autograft cell-based technologies
are attractive, and one device (CAIS, Mitek, Raynham, USA) is
currently undergoing phase III evaluation. Autologous cartilage is
harvested with a special shaving device, morcellized and secured
onto a resorbable polymer mesh with fibrin glue, which in turn is
stapled into the defect. Allograft cartilage has traditionally been
used in fresh osteochondral allograft transplantation. However,
the limited time span between graft harvest and implantation
complicates availability and scheduling. Therefore, a new preserved
osteochondral allograft (Chondrofix, Zimmer, Warsaw, USA) has
entered the market last year. During processing, cells and lipids
are being removed from the tissue, allowing shelf-storage at room
temperature. For defects limited to the articular surface with intact
subchondral bone, a cartilage-only allograft product (DeNovo NT,
Zimmer, Warsaw, USA) has become available in the US, which
utilizes morcellized juvenile (ave. donor age 3 years) cartilage,
which is secured into the defect with fibrin glue. Both CAIS and
DeNovo NT rely on chondrocyte migration out of the cartilage tissue
with subsequent matrix production to fill the defect. Pre-clinical
models have been encouraging, but clinical evidence so far has been
limited. Lastly, an allogenic cell-based implant (DeNovo ET, Zimmer,
Warsaw, USA) is in late stage clinical trial in the US, using allogenic
chondrocytes that are grown in a matrix-free process to form a disklike
implant.

162
Extended Abstracts
19.2.2
Emerging technologies
A.A.M. Dhollander 1 , K.F. Almqvist 1 , P.C. Verdonk 2 , R. Verdonk 1 , G.
Verbruggen 3 , J. Victor 1
1 Gent/Belgium, 2 Gent-zwijnaarde/Belgium, 3 Ghent/Belgium
Introduction: In the synovial joints, tissues such as cartilage,
meniscus/acetabular labrum, subchondral bone and the musclecapsule-ligament
complex constitute a functional unit, which is
called the synovial joint organ. Chondrocytes in articular cartilage
use mechanical signals in conjunction with other environmental and
genetic factors to regulate their metabolic activity. This results in
an alteration of the structure and composition of the extracellular
matrix (ECM) to meet physical demands of the body. Articular
cartilage serves to absorb mechanical shocks and to distribute joint
loads more evenly across the underlying bone structures. Articular
cartilage lesions are found during the course of degenerative joint
disease, or as a result of articular trauma. In normal circumstances,
ECM homeostasis is maintained by an equilibrium between anabolic
and catabolic pathways. The most relevant growth factors and
cytokines known to be involved in cartilage metabolism are produced
by the chondrocytes themselves. Excessive mechanical load due to
obesity, malalignment, occupation, … can lead to structural changes
in joints and finally to joint degeneration. The first detectable
event is a loss of PGs, followed by the disruption of the collagen
network. The initially smal focal degenerative lesions may gradually
increase in depth and length. Chondocytes react to these changes
by increasing their metabolic activity. However, catabolic processes
predominate over the anabolic ones.
Content: Surgical treatment for articular cartilage injury is of major
interest to orthopaedic surgeons because most lesions of articular
cartilage do not heal spontaneously and may predispose the
joint to the subsequent development of secondary osteoarthritis.
Various techniques have been used to treat this injury with variable
success rates. The ultimate aim of treatment is the restoration of
normal knee function by regenerating hyaline cartilage in the defect
and complete integration of the regenerated cartilage with the
surrounding cartilage and underlying bone. Currently, three major
trends can be observed among one-stage cartilage repair strategies:
one trend based on bone marrow stimulating techniques, one based
on acellular scaffolds and finally, cellular based techniques. Several
marrow-stimulating procedures directed at the recruitment of bone
marrow cells have been widely used to treat local cartilage defects.
In these type of procedures, mesenchymal stem cells (MSCs)
migrate in the fibrin network of the blood clot. However, the fibrin
clot is not mechanically stable to withstand the tangential forces. An
implanted exogenous scaffold may improve the mechanical stability
of the fibrin clot and its specific molecular composition may provide
a proper stimulus for chondrogenic differentiation and cartilage
regeneration. In this presentation we will discuss the combination
of microfracture with a collagen type I/III scaffold (Autologous
Matrix Induced Chondrogenesis, AMIC) (1) and platelet-rich plasma
(PRP, AMIC plus) (2) and with a cell-free matrix chondrotissue (3),
which consists of an absorbable non-woven polyglycolic acid textile
treated with hyaluronic acid. Then two acellular scaffold designs will
be discussed. The use of these bioabsorbable scaffolds for repair
of chondral and osteochondral defects has recently been explored
in laboratory and preclinical investigations. Such matrix scaffolds,
implanted alone or in combination with cells, allow immediate
filling of the defect and support local migration of chondrogenic
and osteogenic cells that synthesize new ground substance. First,
we will give an update about the TruFit plug (Smith & Nephew,
Andover, MA) (4). This osteochondral scaffold plug is an acellular
synthetic polymer scaffold that is inserted into the osteochondral
bone to provide a stable scaffold that in theory could encourage
the regeneration of a full thickness of articular cartilage to repair
chondral defects. Secondly, we will discuss the MaioRegen
scaffold. This is an osteochondral nanostructured biomimetic
scaffold (FinCeramica Faenza SpA, Faenza, Italy). It has a porous,
3-dimensional composite, trilayered structure, to reproduce the
cartilaginous layer, the tide mark, and the subchondral bone (5).
In the last part of the lecture, we will highlight one-stage cellularbased
approaches. It is now over 20 years since the first patient was
operated on with autologous chondrocyte implantation (ACI). This
two-stage technique has gained wide scientific and clinical support
for use in the repair of focal articular lesions. However, during in
vitro propagation of the chondrocytes, dedifferentiation of the cells
can occur, and afterward these fibroblast-like chondrocytes show
different biosynthetic properties than the original cartilage cells in
the knee joint. To avoid the issue of dedifferentiation during in vitro
propagation of chondrocytes, instantaneously delivered allogenic
chondrocytes could be used. In this part of the lecture, we will
discuss the use of a biodegradable, alginate-based biocompatible
scaffold containing human allogenic chondrocytes for the treatment
of cartilage lesions in the knee (6). Finally, we will talk about a new
one-stage cellular based approach combining chondrocytes with
mesenchymal stem cells seeded on a polymer-based scaffold.
References:
· Benthien J.P., Behrens P. Autologous matrix-induced chondrogenesis
(AMIC) combining microfracturing and a colla- gen I/III matrix for
articular cartilage resurfacing. Cartilage. 2010; 1:65-68.
· Dhollander A.A.M., De Neve F., Almqvist K.F., Verdonk R., Lambrecht
S., Elewaut D., Verbruggen G., Verdonk P.C.M.: Autologous Matrix
Induced Chondrogenesis (AMIC) combined with Platelet Rich Plasma
Gel (PRP). Technical description and a five pilot patients report. Knee
Surg. Sports Traumatol. Arthrosc., 2011, 19, 536-542.
· Dhollander A.A.M., Verdonk P.C.M., Lambrecht S., Almqvist
K.F., Elewaut D., Verbruggen G., Verdonk R.: The combination of
microfracture and a cell-free polymer-based implant immersed with
autologous serum for cartilage defect coverage. Knee Surg. Sports
Traumatol. Arthrosc. 2011, Nov 9 [epub ahead of print].
· Dhollander A.A.M., Liekens K., Almqvist K.F., Verdonk R., Lambrecht
S., Elewaut D., Verbruggen G., Verdonk P.C.M.: A Pilot Study of the
Use of an Osteochondral Scaffold Plug for Cartilage Repair in the
Knee and How to Deal with Early Clinical Failures. Arthroscopy, 2011,
Oct 18 [epub ahead of print].
· Kon E., Delcogliano M., Filardo G., Busacca M., Di Martino A.,
Marcacci M.: Novel nano-composite multilayered biomaterial for
osteochondral regeneration: a pilot clinical trials. Am J Sports Med.,
2011, 39, 1180-1190.
· Dhollander A.A.M., Verdonk P.C.M., Lambrecht S., Verdonk R.,
Elewaut D., Verbruggen G., Almqvist K.F.: Mid-term Results of the
Treatment of Cartilage Defects in the Knee using Alginate Beads
containing Human Mature Allogenic Chondrocytes. Am. J. Sports
Med., 2011, Sep 29 [epub ahead of print].
Acknowledgments:
The authors like to thank Dr. W. Huysse and Prof. Dr. K. Verstraete
from the department of Radiology, Ghent University Hospital,
Belgium for their support concerning the use of MRI facilities.
19.2.3
Concomitant procedures
A. Getgood
Cambridge/United Kingdom
Introduction: The cause of full thickness articular cartilage injury is
multifactorial. Traumatic injury is often associated with meniscus
and ligament damage, whilst early degeneration has been shown
to be associated with lower limb mal-alignment. The combination
of altered kinematics and reduced biological function can lead to
progressive articular cartilage damage and ultimately osteoarthritis.
When faced with a patient with a symptomatic articular cartilage
injury, the philosophy of addressing the biomechanical function of
the joint first, prior to performing articular cartilage restoration is
followed. A number of articular cartilage repair technologies have
been developed which aim to restore the mechanical and biological
function of the articulating surface. However, for these to be
successful, the root cause of the problem should be identified and
addressed. This presentation will outline the different concomitant
procedures available and will describe the experience of using them
in combination with articular cartilage restoration.
Content: Patient assessment A full history and examination is
performed, during which the personality of both the patient and the
cartilage defect is ascertained. The patients’ occupation and activity
level is important, as may preclude certain procedures. Associated
medical conditions are of significance, as the complication rate
associated with osteotomy has been shown to be greater in diabetics
and smokers. A clear understanding of patients’ symptoms is
important. Does pain predominate, or is instability the major issue.
Is there evidence of mechanical symptoms? Physical examination

will include assessment of gait, looking for evidence of dynamic
laxity, assessment of alignment, core stability, quadriceps tone
and function and evidence of synovitis or effusion. It is important
to try to ascertain which compartment is predominantly affected,
to see if this correlates with the imaging. A thorough exam of the
ligaments, looking for evidence of laxity, as well as the tracking
and control of the patella is made. Plain radiographs including AP/
lateral and 30 degree flexed weight bearing PA views are routinely
ordered. If there is evidence of patellofemoral involvement, a skyline
view is requested. Standardised weight bearing long leg alignment
views are also requested. Further imaging will include MRI scan
with articular cartilage specific sequences, and if any history of
bony trauma, a CT scan. A period of rehabilitation is recommended,
which may help alleviate symptoms, but also optimise the
patients condition pre-operatively. This is particularly important in
patellofemoral conditions. Surgical decision making: A full profile of
the patient and the associated articular cartilage lesion can now be
made once all of the imaging is available. If non-operative measures
have failed, the decision to perform articular cartilage restoration
with or without concomitant procedures is made. The philosophy
is to correct the biomechanical environment of the knee prior to
performing any biological procedures. The goal is to restore normal
alignment, ligamentous stability and structure and function of the
meniscus. A combination of re-alignment osteotomy, ligament
reconstruction, meniscus reconstruction/allograft transplantation
can be performed along with cartilage repair, however, depending
on how many procedures are required to be performed, a staged
reconstruction may be more appropriate in some circumstances. Realignment
osteotomy: Long leg alignment radiographs are used to
ascertain the mechanical axis of the lower limbs. Measurement of
the distal femoral and proximal tibial articular angles are also made
to work out where the deformity is, thereby allowing the deformity
correction to be addressed on the appropriate side of the joint[1].
In a knee with an articular cartilage lesion, the preference is to
unload the joint out of the affected compartment, thereby providing
a favourable environment for the repair procedure to mature. On
the tibial side the opening wedge technique is preferred on medial
and lateral sides for varus and valgus deformities respectively. If
performing a lateral opening wedge varus osteotomy, care must be
taken not to create joint line obliquity of greater than 10 degrees.
On the femoral side, the valgus deformity is most common, in which
a medial closing wedge technique is preferred. In patellofemoral
cases, anteromedialisaton of the tibial tubercle can be utilised to
both offload the joint surface, but also improve patella tracking,
particularly if the tibial tubercle-trochlea groove (TT-TG) distance
is greater than 20mm[2]. Ligament reconstruction: Ligamentous
instability is addressed with a mixture of reconstructive techniques.
Anatomic anterior cruciate ligament reconstruction is performed with
the use of either hamstring or patella tendon autograft. Collateral
ligament instability may be addressed with either autograft,
allograft of occasionally synthetic ligaments. If multiple ligament
reconstruction is to be performed, a combination of grafts may often
be utilised. A combination of ligament reconstruction and osteotomy
can be used to address combined coronal and sagittal plane laxity. In
the presence of patella instability, a medial patellofemoral ligament
reconstruction may be indicated. Meniscus reconstruction: The
primary goal of meniscus surgery is to preserve tissue, particularly
on the lateral side. Meniscus repair should therefore be performed
when possible. Biological adjuncts, such as platelet rich plasma,
fibrin clots and microfracture of the intercondylar notch can be used
to try and augment the healing process. In the event of segmental
failure, scaffolds are used to re-build the meniscus and restore
structure and function[3]. The pre-requisite for meniscal scaffolds,
is an intact peripheral rim and posterior and anterior horn. Meniscus
allograft transplantation: In the event of meniscus rim or anterior/
posterior horn loss, arthroscopic meniscus allograft transplantation
is performed. Deep frozen allografts are implanted into the knee
and held with sutures, attached to the posterior and anterior horns,
delivered through bone tunnels and tied over a bony bridge on the
anteromedial tibia. The periphery is then sutured to the capsule via
a combination of inside-out and all-inside suture devices. Saving the
failing knee: Patients presenting with ICRS grade IV degenerative
change in one or more compartment, associated with meniscus loss,
were treated with meniscus allograft transplantation in combination
with one or more of osteotomy, ligament reconstruction and articular
cartilage repair. Outcome data was collected pre-operatively then
annually including IKDC, Lysholm, Tegner and KOOS scores. MRI and/
or second look arthroscopy was also performed at one year post op.
Results: Of the 58 meniscus allograft transplants performed in our
institution, 26 patients had grade IV ICRS degenerative change and
had combination ‘salvage surgery’. The mean age at surgery was 37
years (19–49). 19 have minimum 12 month follow up with 17 (89%)
of those rated as good or excellent at latest follow-up. MRI showed
normal appearances of the graft in 17, with minimal graft extrusion.
Extended Abstracts 163
Second look arthroscopy was performed in 9 showing encouraging
recovery of the chondral surface. Eight showed good peripheral
integration of the graft, with only 1 failure requiring removal (15
months). One patient has been converted to arthroplasty at 4 years.
Three required arthroscopic arthrolysis for adhesions. Conclusions:
Salvage of the failing knee can be successful if a number of
procedures are combined to firstly address biomechanical deficits,
followed by biological reconstruction. It remains unclear as to which
of these procedures have the greatest impact on patient symptom
relief and cessation of disease progression.
References:
1. Brinkman JM, Lobenhoffer P, Agneskirchner JD, et al. Osteotomies
around the knee: patient selection, stability of fixation and bone
healing in high tibial osteotomies. J Bone Joint Surg Br 2008;90
1548-57
2. Caton JH, Dejour D. Tibial tubercle osteotomy in patello-femoral
instability and in patellar height abnormality. Int Orthop 2010; 34
305-9
3. Efe T, Getgood A, Schofer MD, et al. The safety and short-term
efficacy of a novel polyurethane meniscal scaffold for the treatment
of segmental medial meniscus deficiency. Knee Surg Sports
Traumatol Arthrosc 2011;
Acknowledgments:
This work was not supported by any external funding source.
19.3.1
Can biomarkers be used as outcome measures in cartilage repair
and osteoarthritis?
S. Lohmander
Lund/Sweden
Introduction: The monitoring of cartilage regeneration and
osteoarthritis in natural history or intervention studies carries with
it the need for outcome measures. Without appropriate outcome
measures, results cannot be documented or validated. We should
consider patient-reported outcomes on symptoms, function and
quality of life as the gold standard, the clinical endpoint. Other
outcomes may include functional tests, imaging techniques to
monitor structure and quality of joint tissues, and molecular
biomarkers to reflect the turnover, structure and state of joint tissues.
Studies on cartilage repair and osteoarthritis with currently available
outcome measures require long observation times and trials, and
there is therefore a great need for new measures that could predict
the long-term clinical outcome after a shorter observation time.
Considerable efforts are therefore being invested in the development
of biomarkers that reflect normal and pathological processes in the
joint. Biomarkers developed for osteoarthritis will likely find use
also in studies of cartilage repair and regeneration.
Content: For osteoarthritis biomarkers, a terminology named
BIPEDS was proposed, which classifies these biomarkers into five
categories corresponding to their proposed use: Burden of disease,
Investigational, Prognostic, Efficacy of Intervention, Diagnostic and
Safety. Biomarkers that are likely to have the earliest beneficial
impact on clinical trials fall into two categories. The first are those
markers that would allow us to select for trials subjects that are
most likely to respond or progress (prognostic markers) within
a reasonable time for a clinical study, which for an osteoarthritis
study could be one to two years. The second category of biomarkers
includes those that provide early feedback for preclinical decisionmaking
and for trial organizers that an intervention has the desired
effect on the primary molecular target (efficacy markers). Both types
of biomarkers are highly desirable in chronic conditions where
conventional clinical outcomes may take years to present. These
two categories of biomarkers could reduce the burden and risk of
clinical trials by delivering essential early information, speeding up
the product development cycle and making osteoarthritis a more
manageable target for developing new drugs. Many biomarkers are
being tested in relation to their utility for studies on osteoarthritis,
and exist in various states of validation. The term validation here
refers to the evidence for a marker in support of its use as a surrogate
endpoint, and includes verification of analytical performance

164
Extended Abstracts
characteristics and correlation of the biomarker with a specific
biological process. Naturally, validation of a biomarker against a
gold standard endpoint depends critically also on the performance
and specificity of that gold standard endpoint. A second useful
classification system divides biomarkers into four categories
according to their current level of qualification. Exploration level
biomarkers are research and development tools with in vitro and/
or preclinical evidence but without consistent information linking
the biomarker to clinical outcomes in humans. Demonstration
level biomarkers are associated with clinical outcomes in humans
but have not been reproducibly demonstrated in clinical studies.
Characterization level biomarkers are reproducibly linked to clinical
outcomes in more than one prospective clinical study in humans.
Surrogacy level biomarkers can substitute for a clinical endpoint,
corresponding to ‘‘surrogate end point’’ as mentioned above, and
require agreement with regulatory authorities as an FDA registrable
endpoint. The table below lists a selection of commercially available
osteoarthritis-related biomarkers and an approximation with
regard to their level of qualification. However, that qualification is
as always dependent on a specific context, limiting generalizability
in the early development phase. There are at this time no qualified
biomarkers that can be considered as surrogate clinical endpoints in
OA. It should further be noted that the majority of currently studied
biomarkers, including those exemplified below, lack a detailed
verification of the tissue source and molecular structures that
generate the signal in the assay, severely limiting our ability to draw
conclusions from results generated by the assays. The development
and validation of biomarkers with utility for osteoarthritis will require
the combination of reproducible and specific biomarker assays with
large prospective, controlled clinical trials. To demonstrate utility
of e.g. efficacy biomarkers, these trials will need to show structural
joint protection and/or clinically relevant efficacy.
References:
Bauer DC et al. Classification of osteoarthritis biomarkers: a
proposed approach. Osteoarthritis Cartilage 2006;14:723-7.
Felson DT, Lohmander LS. Whither Osteoarthritis Biomarkers?
Osteoarthritis Cartilage 2009;17:419-22.
Kraus VB, Burnett B, Coindreau J, Cottrell S, Eyre D, Gendreau M,
Gardiner J, Garnero P, Hardin J, Henrotin Y, Heinegard D, Ko A,
Lohmander LS, Matthews G, Menetski J, Moskowitz R, Persiani S,
Poole R, Rousseau JC, Todman M. Application of Biomarkers in the
Development of Drugs Intended for the Treatment of Osteoarthritis.
OARSI FDA Osteoarthritis Biomarkers Working Group: FDA initiative
for the coordination of a critical appraisal related to the design of
clinical development programs for drugs, biological products &
medical devices for the treatment/prevention of OA. Osteoarthritis
Cartilage 2011;19:515-42.
van Spil W, DeGroot J, Lems W, Oostveen J, Lafeber F. Serum and
urinary biochemical markers for knee and hip osteoarthritis:
a systematic review applying the consensus BIPED criteria.
Osteoarthritis Cartilage 2010;18:605-12.
Wagner J A, Williams S A, Webster C J. Biomarkers and surrogate end
points for fit-for-purpose development and regulatory evaluation of
new drugs. Clin Pharmacol Ther 2007;81:104-7.
19.3.2
Emerging molecular biomarker technologies and the way forward
A.R. Poole
Quebecr/Canada
Introduction: Molecular or biochemical biomarkers of cartilage
metabolism offer the potential to detect and monitor cartilage damage
in arthritis, the progression of this damage and the effectiveness of
therapy designed to arrest cartilage damage and/or stimulate its
repair. In addition these biomarkers can be used to examine the
metabolism of cartilage in healthy individuals that may predispose
them to joint damage and who may exhibit different capacities for
joint repair. In this presentation we will look at the turnover of type
II collagen, the dominant component of the extracellular matrix of
cartilage, without which cartilage cannot exist.
Content: The most important requirements for the development of
successful skeletal biomarker technology are the ability to accurately
identify the source of the biomarker; the molecular event(s) that
generates it; what the biomarker assay measures in terms of the
molecular fragment and where best to measure this biomarker-in
synovial fluid, serum or urine since different results can be obtained
with each of these body fluids. In this presentation we look at the
development of technology to detect the synthesis and degradation
of type II collagen in cartilage. The focus on cartilage degradation is
on the cleavage of type II collagen by collagenases which is a key
event in health and disease and is increased in articular cartilage in
osteoarthritis (OA; Dejica et al, 2008) and rheumatoid arthritis (RA).
The first immunoassay that was developed (Col2-3/4Clong or C2C)
produced a competitive ELISA inhibition assay that measured the
primary cleavage neoepitope generated by collagenases (Poole et al,
2004). Thereby, any collagen II fragments containing this neoepitope
would be detected. To detect collagen II synthesis a competitive
ELISA immunoassay (CPII) was also developed, in this case to detect
the c-propeptide of collagen II that is removed extracellularly as
newly synthesized collagen is secreted (Nelson et al, 1998). These
assays, used in combination and singly, have proved of value in
ascertaining the amount of collagen II cleavage and synthesis in
normal individuals and in patients with OA and rheumatoid arthritis
(RA). Much of what is measured appears to relate to the cleavage
of newly synthesized type II collagen in the pericellular domain
around chondrocytes.These assays used in combination can detect
differences between individuals with early pre- and radiographic
knee osteoarthritis (OA) and those without knee OA (Cibere et al,
2010).They reveal differences between those with knee OA who
exhibit progression and those who do not (Cahue et al, 2007). They
indicate early responses to disease-modifying therapy in patients
with RA (Mullan et al, 2007). Surprisingly, in healthy active military
trainees exposed to identical training programs these assays also
revealed differences in those who subsequently succumbed to
cruciate ligament rupture and those who did not (Svoboda et al,
2012). Clearly differences in cartilage metabolism reflected by the
differences in these cartilage biomarkers revealed differences in
cartilage metabolism that put people either at risk for joint injury
or not at risk.The reasons for this are currently under investigation.
But what it signifies is that cartilage metabolism can vary between
individuals of the same age and these differences may also identify
people at risk for OA and whose disease is progressing. Such
detectable differences in cartilage metabolism may also identify
those who may respond differently to therapies designed to
stimulate cartilage repair. All these studies focussed on cartilage
metabolism measured systemically in serum peripheral blood. What
we then discovered was that the cleavage assay, that also worked
in urine, produced different results to what were seen in serum. The
increase in cleavage of type II collagen seen in OA cartilage and in
urine was not detectable in serum in patients with OA. It was then
discovered that urine contained a dominant 45mer peptide of type
II collagen that contained the C2C cleavage neoepitope and which
was increased in OA (Nemerovskiy et al, 2007).This appeared to
be reflect more the pathology of cartilage collagen cleavage rather
than its turnover in health and disease .The cleavage 45mer peptide
seemed to be masked in serum by the cleavage products generated
by physiology.By developing a new sandwich assay (C2C HUSA)
that is designed to detect this 45mer fragment in type II collagen it
is now possible to use this new urine assay to better discriminate
between cartilage turnover in those without knee OA and those
with pre-radiographic and more advanced damage to articular
cartilage in radiographic OA (Ha et al, 2012). These advances point
to the great importance of looking at specific molecular events in
biomarker development in detail. Otherwise a biomarker assay can
be developed that measure something other than what you think
it measures, as has been the case on some occasions. As we have
seen, skeletal biomarkers have the potential to detect and monitor
cartilage synthesis and degradation. A balance between synthesis
and degradation is viewed as essential in maintaining healthy
cartilage.Changes in this balance can be measured using currently
available biomarker assays. In studies of cartilage repair one
would expect that synthesis would be favoured over degradation,
determined from assay ratios.From what has been discussed above
it would be important to use these assays in studies of cartilage
repair using both serum for synthesis and degradation as well as
urine for degradation.

References:
Cahue, S et al. Osteoarthritis Cartilage 15:819-23,2007; Cibere, J et
al. Arthritis Rheum 60: 1372-80, 2009; Dejica, VM et al. Am J Pathol
173: 161-69, 2008; Ha,N et al. In preparation;
Mullan, RH et al. Arthritis Rheum 56: 2919-28, 2007; Nelson,F et al. J
Clin Invest 102: 2115-25, 1998; Nemirovskiy, OV et al. Anal Biochem
361: 93-101, 2007; Poole AR et al. J Immunological Meth 294: 145-
53,2004.
Acknowledgments:
These studies were funded by Canadian Institutes of Health;
NIAMS,National Institutes of Health; Canadian Arthritis Network;
IBEX Technologies Inc.
19.3.3
Genetic influence on cartilage repair
L.J. Sandell
St. Louis/United States of America
Introduction: Emerging evidence suggests that genetic components
contribute significantly to cartilage degeneration in osteoarthritis
pathophysiology but little evidence is available on genetics of
cartilage regeneration. Therefore, we investigated cartilage
regeneration in genetic murine models using common inbred strains
and a set of recombinant inbred lines generated from LG/J (healer
of ear-wounds) and SM/J (non-healer) inbred strains. Using the two
healing extreme recombinant inbred lines, we tested the relationship
between the ability to regenerate cartilage and the susceptibility to
osteoarthritis (OA).
Content: To investigate cartilage regeneration, we created an acute
full-thickness cartilage injury through microsurgery in the trochlear
groove of 265 mice by the method of Fitzgerald and colleagues (1).
Knee joints were sagittally sectioned and stained with toluidine
blue to evaluate regeneration. The ear-wound phenotype was also
established. For ear-wound, a bilateral 2-mm through-and-through
puncture was made and healing outcomes measured after 30-days.
Broad-sense heritability and genetic correlations were calculated
for both phenotypes. Time-course studies from recombinant inbred
lines show no significant regeneration until 16-weeks post-surgery;
at that time, the strains can be segregated into three categories:
good, intermediate and poor healers. Broad-sense heritability
showed that both cartilage regeneration and ear-wound closure are
significantly heritable traits. The genetic correlations between the two
healing phenotypes were found to be extremely high. We concluded
that articular cartilage regeneration is heritable, the phenotypic
differences between the lines are due to genetic differences and a
strong genetic correlation between the two phenotypes (cartilage
regeneration and ear-wound healing) exists indicating that they
plausibly share a common genetic basis (2). We are currently studying
gene expression differences in cartilage and bone in several of the
recombinant inbred strains of mice already used for phenotyping by
employing novel technology of QuantiGene Plex assay. This beadbased
assay utilizes RNA from tissue lysates prepared from formalinfixed
paraffin embedded sections. We are quantifying genes related
to tissue healing, osteoarthritis, DNA repair, cell cycle control and
other relevant pathways to determine differences among strains. We
have also examined the susceptibility to osteoarthritis of our genetic
mouse lines. We compared strain-dependent development of posttraumatic
osteoarthritis and its association with tissue regeneration
in two recombinant inbred lines LGXSM-6 and LGXSM-33 generated
from LG/J and SM/J intercross. Our findings above indicated that
LGXSM-6 can regenerate both articular cartilage and ear-hole punch
while LGXSM-33 cannot. In this study, osteoarthritis was induced
in over 70 mice through the transection of the medial meniscotibial
ligament and cartilage and bone changes were evaluated by the
method of Glasson (3). Cartilage damage showed that LGXSM-33
developed a significantly higher grade of osteoarthritis than LGXSM-6.
Bone analysis showed that LGXSM-33 had substantial subchondral
bone and trabecular bone thickening post-surgery, while LGXSM-6
showed bone loss over time. We also confirmed that LGXSM-6 can
heal ear tissues significantly better than LGXSM-33. Thus, we found
that osteoarthritis is negatively correlated with the degree of tissue
regeneration (4).
Extended Abstracts 165
References:
1. Fitzgerald J, Rich C, Burkhardt D, Allen J, Herzka AS, Little CB.
Evidence for articular cartilage regeneration in MRL/MpJ mice.
Osteoarthritis Cartilage. 2008;16(11):1319-26.
2. Rai MF, Hashimoto S, Johnson EE, Janiszak K, Fitzgerald J, Heber-
Katz E, Cheverud JM, Sandell LJ. Heritability of Articular Cartilage
Regeneration and its Association with Ear-Wound Healing. Arthritis
Rheumatism In Press. doi: 10.1002/art.34396. PMID: 22275233.
2012
3. Glasson SS. In vivo osteoarthritis target validation utilizing
genetically-modified mice. Curr Drug Targets 2007;8:367-76.
4. Hashimoto S, Rai MF, Janiszak K, Cheverud JM, Sandell LJ.
Cartilage and Bone Changes during Development of Post-Traumatic
Osteoarthritis in Selected LGXSM Recombinant Inbred Mice.
Osteoarthritis Cartilage In Press. doi:10.1016/j.joca.2012.01.022.
2012
Acknowledgments:
The project was supported by an ARRA Grand Opportunity Grant,
Award Number RC2 AR058978; the micro-CT and histological
analysis were supported by the Musculoskeletal Research Center,
Grant Award Number P30 AR057235, from the National Institute of
Arthritis, Musculoskeletal and Skin Diseases.
21.1.1
Role of lubrication and joint homeostasis: Cartilage Boundary
Lubricating Ability of Full-Length Recombinant Human PRG4 -
Alone and In Combination with Hyaluronan
S. Abubacker 1 , N. Masala 1 , S. Morrison 1 , G.D. Jay 2 , T.A. Schmidt 1
1 Calgary/Canada, 2 Providence/United States of America
Introduction: The proteoglycan 4 (PRG4) gene [1] encodes for mucinlike
O-linked glycosylated proteins with several names, including
lubricin [2] and superficial zone protein [3]. PRG4 proteins, herein
referred to as PRG4, are synthesized and secreted by various cells
within the joint, including synoviocytes [4] and articular chondrocytes
in the superficial zone of cartilage [3]. As such, PRG4 is present in
synovial fluid (SF) and at the surfaces of tissues within the joint,
including articular cartilage [5]. Mutations in the PRG4 gene cause an
autosomal recessive disorder in humans, camptodactylyarthropathycoxa
vara-pericarditis (CACP), which results in juvenile-onset,
noninflammatory, precocious joint failure [6]. PRG4-null mice show
early signs of wear and higher friction than normal mouse joints -
suggesting that friction is coupled with wear at the cartilage surface
in vivo [7]. Therefore, normal expression of PRG4 is necessary for
normal joint health. PRG4 has multiple biophysical properties [8,
9], including the boundary lubrication of cartilage [10] (hence the
classic name lubricin [11]), that contribute to the overall maintenance
and integrity of the joint. Boundary lubrication is an operative and
essential mechanism of articular cartilage lubrication in synovial
joints, where surface-to-surface contact occurs and surface bound
molecules provide lubrication. This mode of lubrication is thought
to be important for the protection and maintenance of articular
cartilage, since the apposing cartilage surfaces within the joint
make contact over ~10% of the total area - where most of the
friction may occur [12]. PRG4 has demonstrated in vitro boundary
lubricating ability, in a dose-dependent manner, at a physiologically
relevant cartilage-cartilage interface [10]. PRG4 has also been shown
to act synergistically with hyaluronan (HA), through an unknown
mechanism, to further reduce friction to levels near that of SF [10, 13].
PRG4-deficient human SF lacks normal in vitro boundary lubricating
ability [7], which suggests PRG4 is an important boundary lubricant
that contributes to the low-friction articulation of cartilage surfaces
in vivo. Moreover, the destructive joint phenotype associated with
the lack of PRG4 in vivo [6, 7], clearly demonstrates the importance of
both boundary lubrication and PRG4 for joint health. Recent studies
suggest that a decrease of PRG4 concentration in SF following a knee
injury, and the associated decreased boundary lubricating ability of
SF, contributes to ensuing cartilage surface damage. In patients with
acute knee injuries or progressive chronic inflammatory arthritis,
cartilage damage has been associated with decreased boundary
lubricating ability of SF [14]. This association was also observed in an
animal model following anterior cruciate ligament (ACL) transection,
as well as decreased levels of PRG4 in SF [15]. Decreased PRG4

166
Extended Abstracts
concentrations have been reported in SF of patients soon after
an ACL injury [16], which is associated with an increased risk of
subsequent progressive degeneration leading to osteoarthritis
(OA) [17]. More recent studies collectively suggest that restoring
normal boundary lubrication with PRG4 in situations where it is lost
or diminished, could contribute to the maintenance of cartilage in
vivo. Indeed, the diminished in vitro cartilage boundary lubricating
ability of human OA SF deficient in PRG4, could be restored with
PRG4 supplementation [18]. Furthermore, local administration of
PRG4 [19], as well as both a truncated version [20] and more recently
a full-length [21] recombinant human PRG4 (rh-PRG4), has been
demonstrated to be therapeutically effective in preventing cartilage
degeneration in a rat model of OA. Previous supporting studies
demonstrated the ability of truncated and full-length rh-PRG4 to
both bind to an articular surface [22] and reduce friction at a glasscartilage
interface [23]. While PRG4’s molecular interactions with the
articular surface, and with other lubricant molecules in SF, remains
to be fully elucidated, local administration of rh-PRG4 appears to
be a promising biotherapeutic intervention to potentially halt or
slow the progression of OA. Recent advances in protein expression
technology [24] has enabled the abundant expression of full-length
rh-PRG4, which could be used for such therapeutic applications. The
objectives of this study were to 1) biochemically characterize fulllength
rh-PRG4, and 2) assess the cartilage boundary lubricating
properties of rh-PRG4, both alone and in combination with HA.
Content: METHODS: (rh-)PRG4 Preparation. rhPRG4. rh-PRG4 was
enriched from media conditioned by Chinese hamster ovary cells,
transfected with the rh-PRG4 gene, by concentration and filtration
in a 100kDa MW cut-off filter. Total concentration was determined
by bicinchoninic acid assay, and then determined for rh-PRG4
based on purity of the preparation as assessed by SDS-PAGE
protein stain (see below). PRG4. PRG4 was purified from culture
medium conditioned by mature bovine cartilage explants from the
superficial zone using anion exchange chromatography, essentially
as described previously [10]. Biochemical Characterization. Samples
were analyzed by SDS-PAGE followed by protein staining or western
blotting, as described previously [13, 25]. Briefly, non-reduced (NR)
and reduced (R) samples, with and without additional enzymatic
treatment with neuraminidase and O-glycanase (Prozyme) to remove
O-linked glycosylations, were electrophoresed on 3-8% Tris Acetate
gels (Invitrogen). Gels were then stained for protein (SimplyBlue
Stain, Invitrogen) or electroblotted to a 0.2 μm polyvinylidene
fluoride membrane. Membranes were blocked, probed with a variety
of anti-PRG4 Ab (pAb LPN and J108N [26], mAb 5C11 [26] and 9G3
[19]) or lectins (peanut agglutinin: PNA, wheat germ agglutinin:
WGA) and developed with an ECL chemiluminescent substrate
and visualized with a Bio Imaging System. Cartilage Lubricating
Ability. Lubricating ability of rh-PRG4 was tested with a cartilageon-cartilage
friction test in the boundary lubrication regime using
normal bovine osteochondral cores, as described previously [27].
Briefly, after incubation in the test lubricant overnight, samples
were compressed, allowed to stress relax, then subjected to relative
rotation at an effective velocity of 0.3mm/s (to ensure a boundary
mode of lubrication) with prespin durations, Tps, of 1200-1.2s. Static,
μstatic,Neq, and kinetic, , friction coefficients
were calculated [27]. Two sets of tests were performed to determine
the boundary lubricating ability of the rh-PRG4, compared to native
PRG4, at a physiological concentration of 450 μg/ml, both alone or
in combination with 1.5MDa HA at a physiological concentration
[28] of 3.33 mg/ml. Phosphate buffered saline (PBS) and bovine SF
served as negative and positive controls, respectively. Test 1: PBS,
rh-PRG4, PRG4, then SF. Test 2: PBS, rh-PRG4, rh-PRG4+HA, then
SF. RESULTS: Biochemical Characterization. rh-PRG4 demonstrated
similar immunoreactivity to PRG4. Western blotting indicated
immunoreactive rh-PRG4 bands had a similar apparent molecular
weight (MW) to those in PRG4. High MW species were observed in NR
samples probed with pAb LPN and mAb 5C11 & 9G3, and lectins PNA
and WGA. Upon reduction, a single high MW species was observed
with pAb J108, mAb 5C11 and lectin PNA. Upon removal of the terminal
sialic acid with neuraminidase in R samples, a reduction in MW of a
J108N immunoreactive species was observed. A further reduction in
MW was observed upon subsequent removal of the O-glycosylations
via O-glycanase. Cartilage Lubricating Ability. rh-PRG4 effectively
lowered friction at the cartilage-cartilage biointerface, both alone
and in combination with HA. Lubricants and Tps modulated friction.
μstatic,Neq increased with increasing Tps, whereas
varied only slightly; both varied with test lubricant. Test 1: Both
μstatic,Neq and were highest in PBS and lowest in
SF, with values of PRG4 and rh-PRG4 being intermediate and similar
to each other. Test 2: Both μstatic,Neq and were
again highest in PBS and lowest in SF, and was again intermediate in
rh-PRG4. With subsequent addition of HA, values of μstatic,Neq and
in rhPRG4+HA were further lowered, approaching
that of SF. DISCUSSION: This study demonstrates that full-length
rh-PRG4 can be expressed with structural properties and cartilage
boundary lubricating function similar to that of native PRG4. Western
blot data suggests the rh-PRG4 has the appropriate higher order
structure, with intermolecular disulfide bonds [26], as well as the
expected O-linked glycosylations (α(2,3)NeuAc- β(1,3)Gal-GalNAc),
although further detailed characterization [29] is required. rh-PRG4
also demonstrated equivalent cartilage boundary lubricating ability
to PRG4, both alone and in combination with HA, suggesting rh-
PRG4 is able to both bind/interact with the native articular surface
as well as HA to reduce friction during cartilage-cartilage articulation.
Industrial scale-up of rh-PRG4 expression and purification, will
facilitate future pre-clinical animal model work, and ultimately
clinical trials, to further evaluate the effectiveness of rh-PRG4 as a
biotherapeutic treatment to prevent or slow the progression of OA.
Additionally, rh-PRG4 may be a useful biotherapeutic treatment at
other biointerfaces where lubrication is needed, such as the ocular
surface where PRG4 has been recently discovered and shown to
provide lubricating function [30], either alone or in combination with
existing HA-containing products.
References:
1. S. Ikegawa et al. Cytogenet Cell Genet 90, 291 (2000).
2. D. A. Swann et al. J Biol Chem 256, 5921 (1981).
3. B. L. Schumacher et al. Arch Biochem Biophys 311, 144 (1994).
4. G. D. Jay et al. J Orthop Res 19, 677 (2001).
5. G. D. Jay. Curr Opin Orthop 15, 355 (2004). 6. J. Marcelino et al. Nat
Genet 23, 319 (1999).
7. G. D. Jay et al. Arthritis Rheum 56, 3662 (2007).
8. D. K. Rhee et al. J Clin Invest 115, 622 (2005).
9. G. D. Jay et al. Proc Natl Acad Sci U S A 104, 6194 (2007).
10. T. A. Schmidt et al. Arthritis Rheum 56, 882 (2007).
11. D. A. Swann et al. J Biol Chem 247, 8069 (1972).
12. K. C. Morrell et al. Proc Natl Acad Sci U S A 102, 14819 (2005).
13. J. J. Kwiecinski et al. Osteoarthritis Cartilage 19, 1356 (2011).
14. K. A. Elsaid et al. Arthritis Rheum 52, 1746 (2005).
15. E. Teeple et al. J Orthop Res 26, 231 (2008).
16. K. A. Elsaid et al. Arthritis Rheum 58, 1707 (2008).
17. A. C. Gelber et al. Ann Intern Med 133, 321 (2000).
18. T. E. Hill et al. Trans Orthop Res Soc 57, 34 (2011).
19. E. Teeple et al. Am J Sports Med 39, 164 (2011).
20. C. R. Flannery et al. Arthritis Rheum 60, 840 (2009).
21. G. D. Jay et al. Arthritis Rheum 62, 2382 (2010).
22. A. R. Jones et al. J Orthop Res 25, 283 (2007).
23. J. P. Gleghorn et al. J Orthop Res 27, 771 (2009).
24. P. A. Girod et al. Nature methods 4, 747 (2007).
25. M. C. Alvarez et al. Trans Orthop Res Soc 56, 850 (2010).
26. T. A. Schmidt et al. Biochim Biophys Acta 1790, 375 (2009).
27. T. A. Schmidt et al. Osteoarthritis Cartilage 15, 35 (2007).
28. J. R. Watterson et al. J Am Acad Orthop Surg 8, 277 (2000).
29. R. P. Estrella et al. Biochem J 429, 359 (2010). 30. S. Morrison et
al. Eye Contact Lens 38, 27 (2011).
Acknowledgments:
Alberta Innovates – Health Solutions, Canadian Arthritis Network,
Lubris, Natural Sciences and Engineering Research Council of
Canada.

21.1.3
New frontiers in joint lubrication therapy
C.R. Flannery
Cambridge/United States of America
Introduction: Recent advances in our understanding of the
(mechano)biological attributes of key molecular regulators
of cartilage lubrication have led to escalating progress in the
development of therapeutic strategies designed to enhance joint
function in pathological and repair environments. The results from a
number of encouraging preclinical studies, and discussion of some
translational elements applicable to aiding risk mitigation on the
path to the clinic, are presented herein.
Content: Articular joints are highly dependent on effective lubrication
mechanisms to prevent the wear and degeneration of articular
cartilage. Natural lubricants in synovial fluid include hyaluronan
(HA), a viscous, high molecular weight glycosaminoglycan, and
lubricin (also referred to as Proteoglycan 4/PRG4 or Superficial Zone
Protein/SZP), a mucinous glycoprotein which confers specialized
protection at cartilage surfaces (1). In addition to its rheological
properties, recent data indicates that HA, like lubricin, appears to
play an important role in boundary-mode lubrication, helping to
guard cartilage surfaces from wear under conditions of high contact
load and slow sliding speeds (2, 3). The biomolecular composition
of cartilage itself is also critical for reducing friction and shear at
the tissue surface. Thus, high concentrations of water-adsorbing
proteoglycan (aggrecan) molecules entrapped within the cartilage
collagen meshwork allow for interstitial pressurization and fluid
exudation during joint loading cycles (4), thereby facilitating
the generation of a surface hydration layer which contributes to
joint lubrication. Several detrimental processes can contribute
to lubrication deficiencies during joint pathology. For example,
following traumatic injury, a significant decrease in the concentration
of HA in the synovial fluid can occur, as well as alterations in
lubricin expression levels and cartilage surface properties (5-8). In
addition, proteolytic fragmentation of aggrecan by aggrecanases
(ADAMTS proteases) is acutely elevated post-injury, resulting in
significant proteoglycan loss from the articular cartilage (9). Various
therapeutic strategies can therefore be pursued to help restore joint
lubrication and diminish disease progression. Intraarticular (IA)
viscosupplementation with HA has been used in the clinic now for
several decades, and improvements in patient pain and function
outcome measures are well documented (10). More recently, IA
treatment with lubricin has been tested in preclinical animal models,
and found to be effective in providing both chondroprotection
(prevention of cartilage structural damage) and evidence of pain
relief (11, 12). Likewise, chondroprotective effects are observed for
aggrecanase (ADAMTS5) knockout mice (13), and oral administration
of an aggrecanase inhibitor is efficacious in preventing cartilage
aggrecan catabolism in a rat model of post-traumatic osteoarthritis
(14). While attractive for their mode of local delivery, intraarticular
treatment procedures are not without challenges. The clearance
rate of macromolecules from synovial fluid is quite rapid, indicating
that strategies to improve joint residence time could substantially
improve therapeutic effects. Interestingly, lubricin, which possesses
a targeted affinity for cartilage surface binding (15), appears to
display a tri-phasic distribution profile following IA administration.
While there is a rapid early decline in the levels of radiolabelled
recombinant lubricin (LUB:1) from rat knees, detectable counts
remain in the joint for at least 28 days, and can be observed at both
intact and damaged cartilage surfaces by micro-autoradiography (16).
Additional and complimentary strategies may therefore be envisioned
in the further development of joint lubrication therapies, including
treatments designed to enhance lubricant biosynthesis. In the case
of lubricin, biochemical stimuli such as TGF-beta and related family
members can increase its expression (17, 18). Microencapsulation of
therapeutic agents/lubricants into polymeric delivery particles may
thus be employable to enable extended release and delivery within
the joint. Interestingly, it is also worth noting that the levels of both
lubricin and hyaluronan are enhanced by biomechanical forces such
as surface motion, which may thereby contribute to the beneficial
effects of continuous passive motion applied during post-operative
patient rehabilitation (19, 20). Clearly, efficient lubrication will also
be important for the success of cartilage repair and cartilage tissue
engineering procedures. In this regard, the presence of lubricin has
been detected in biopsies of repair tissue from patients treated
with autologous chondrocyte implantation (21). Of the 43 samples
analyzed, most were immunopositive for lubricin, with a high
percentage demonstrating its presence in the surface layer. Protocols
for enhancing lubricin localization at the articular surface, such as
described above, may therefore serve to further improve repair
tissue performance and hence clinical outcomes. In another recent
Extended Abstracts 167
study, chondrocyte differentiation under hypoxic conditions was
found to increase lubricin expression by superficial (but not middle/
deep) zone cells, highlighting the rationale for composing stratified/
zonally-organized cartilaginous constructs (22). Furthermore, the
ability to demonstrate a functional/biophysical correlation (i.e.
improved lubrication) with enhanced lubricant expression, as has
been shown for growth factor-stimulated cartilage explants and
chondrocyte-seeded scaffolds subjected to sliding motion (23, 24),
serves to provide an additional measure of confidence for translation
into the clinic.
References:
1. Hui AY, McCarty WJ, Masuda K, Firestein GS, Sah RL. A systems
biology approach to synovial joint lubrication in health, injury, and
disease. WIREs Syst Biol Med. 2012;4:15-37.
2. Schmidt TA, Gastelum NS, Nguyen QT, Schumacher BL, Sah RL.
Boundary lubrication of articular cartilage: role of synovial fluid
constituents. Arthritis Rheum. 2007;56:882-91.
3. Greene GW, Banquy X, Lee DW, Lowrey DD, Yu J, Israelachvili JN.
Adaptive mechanically controlled lubrication mechanism found in
articular joints. Proc Natl Acad Sci USA. 2011;108:5255-9.
4. Ateshian GA. The role of interstitial fluid pressurization in articular
cartilage lubrication. J Biomech. 2009;42:1163-76.
5. Elsaid KA, Fleming BC, Oksendahl HL, Machan JT, Fadale PD,
Hulstyn MJ, Shalvoy R, Jay GD. Decreased lubricin concentrations and
markers of joint inflammation in the synovial fluid of patients with
anterior cruciate ligament injury. Arthritis Rheum. 2008;58:1707-15.
6. Jones AR, Chen S, Chai DH, Stevens AL, Gleghorn JP, Bonassar
LJ, Grodzinsky AJ, Flannery CR. Modulation of lubricin biosynthesis
and tissue surface properties following cartilage mechanical injury.
Arthritis Rheum. 2009;60:133-42.
7. Wong BL, Chris Kim SH, Antonacci JM, McIlwraith CW, Sah RL.
Cartilage shear dynamics during tibio-femoral articulation: effect
of acute joint injury and tribosupplementation on synovial fluid
lubrication. Osteoarthritis Cartilage. 2010;18:464-71.
8. Catterall JB, Stabler TV, Flannery CR, Kraus VB. Changes in serum
and synovial fluid biomarkers after acute injury (NCT00332254).
Arthritis Res Ther. 2010;12:R229.
9. Larsson S, Lohmander LS, Struglics A. Synovial fluid level of
aggrecan ARGS fragments is a more sensitive marker of joint disease
than glycosaminoglycan or aggrecan levels: a cross-sectional study.
Arthritis Res Ther. 2009;11:R92.
10. Iannitti T, Lodi D, Palmieri B. Intra-articular injections for the
treatment of osteoarthritis. Focus on the clinical use of hyaluronic
acid. Drugs R D. 2011;11:13-27.
11. Flannery CR, Zollner R, Corcoran C, Jones AR, Root A, Rivera-
Bermudez MA, Blanchet T, Gleghorn JP, Bonassar LJ, Bendele AM,
Morris EA, Glasson SS. Prevention of cartilage degeneration in a rat
model of osteoarthritis by intraarticular treatment with recombinant
lubricin. Arthritis Rheum. 2009;60:840-7.
12. Jay GD, Elsaid KA, Kelly KA, Anderson SC, Zhang L, Teeple E,
Waller K, Fleming BC. Prevention of cartilage degeneration and gait
asymmetry by lubricin tribosupplementation in the rat following ACL
transaction. Arthritis Rheum. 2011;Published online Nov 29.
13. Glasson SS, Askew R, Sheppard B, Carito B, Blanchet T, Ma HL,
Flannery CR, Peluso D, Kanki K, Yang Z, Majumdar MK, Morris EA.
Deletion of active ADAMTS5 prevents cartilage degradation in a
murine model of osteoarthritis. Nature. 2005;434:644-8.
14. Chockalingam PS, Sun W, Rivera-Bermudez MA, Zeng W, Dufield
DR, Larsson S, Lohmander LS, Flannery CR, Glasson SS, Georgiadis
KE, Morris EA. Elevated aggrecanase activity in a rat model of
joint injury is attenuated by an aggrecanase specific inhibitor.
Osteoarthritis Cartilage. 2011;19:315-23. 15. Jones AR, Gleghorn JP,
Hughes CE, Fitz LJ, Zollner R, Wainwright SD, Caterson B, Morris EA,
Bonassar LJ, Flannery CR. Binding and localization of recombinant
lubricin to articular cartilage surfaces. J Orthop Res. 2007;25:283-
92.
16. Vugmeyster Y, Wang Q, Xu X, Harrold J, Daugusta D, Li J,

168
Extended Abstracts
Zollner R, Flannery CR, Rivera-Bermudez MA. Disposition of human
recombinant lubricin in naïve rats and in a rat model of post-traumatic
arthritis after intra-articular or intravenous administration. AAPS J.
2012:Published online Jan 7.
17. Jones AR, Flannery CR. Bioregulation of lubricin expression by
growth factors and cytokines. Eur Cell Mater. 2007;13:40-5.
18. Niikura T, Reddi AH. Differential regulation of lubricin/superficial
zone protein by transforming growth factor beta/bone morphogenetic
protein family superfamily members in articular chondrocytes and
synoviocytes. Arthritis Rheum. 2007;56:2312-21.
19. Grad S, Lee CR, Gorna K, Gogolewski S, Wimmer MA, Alini M.
Surface motion upregulates superficial zone protein and hyaluronan
production in chondrocyte-seeded three-dimensional scaffolds.
Tissue Eng. 2005;11:249-56.
20. Nugent-Derfus GE, Takara T, O‘neill JK, Cahill SB, Görtz S, Pong T,
Inoue H, Aneloski NM, Wang WW, Vega KI, Klein TJ, Hsieh-Bonassera
ND, Bae WC, Burke JD, Bugbee WD, Sah RL. Continuous passive
motion applied to whole joints stimulates chondrocyte biosynthesis
of PRG4. Osteoarthritis Cartilage. 2007;15:566-74.
21. Roberts S, Menage J, Flannery CR, Richardson JB. Lubricin: its
presence in repair cartilage following treatment with autologous
chondrocyte implantation. Cartilage. 2010;1:298-305.
22. Schrobback K, Malda J, Crawford RW, Upton Z, Leavesley DI, Klein
TJ. Effects of oxygen on zonal marker expression in human articular
chondrocytes. Tissue Eng Part A. 2012;Published online Jan 4.
23. Gleghorn JP, Jones AR, Flannery CR, Bonassar LJ. Alteration of
articular cartilage frictional properties by transforming growth
factor beta, interleukin-1beta, and oncostatin M. Arthritis Rheum.
2009;60:440-9.
24. Grad S, Loparic M, Peter R, Stolz M, Aebi U, Alini M. Sliding
motion modulates stiffness and friction coefficient at the surface of
tissue engineered cartilage. Osteoarthritis Cartilage. 2012;Published
online Jan 10.
Acknowledgments:
The valued contributions and insights provided by colleagues and
collaborators are gratefully acknowledged.
21.2.1
Rehabilitation after cartilage repair
M. Steinwachs
Freiburg/Germany
Introduction: The native joint cartilage is not able to structurally
repair traumatic or repetitive overload injuries to the articular
cartilage.A higher-grade cartilage injury leads to a shift in the balance
towards cartilage degradation. This results in greater deformation
of the cartilage under the enormous impact forces of sports and
thereby mechanical structural damage of the ECM.
Content: The treatment of specific cartilage defects can be
distinguished between tissue transplants and cell-based regenerative
techniques (7). The tissue transplantation techniques include the
autologous osteochondral transplantation system (OATS) or tissue
engineered cartilage tissue. Studies have identified three stages in
cartilage regeneration (9):
Phase I (Proliferative Phase 0-12 weeks): After cell attachment a
non specific, soft repair tissue is formed. Phase II (Transition Phase
3-6 month): A specific integration into the local environment and
the improvement of the structural quality of the repair cartilage
can be observed. Up to phase II, there generation steps are similar
in both, the ACI as well as in the bone marrow based technique.
Phase III (Remodelling and Maturation Phase 6-24month): The final
adaptation of the cartilage is made to the biomechanical needs of
the various joint compartments (1). This process includes a period of
up to 2 years, as seen in MRI studies. The ACI proved to be superior
in the quality of the regenerate tissue achieved compared to marrow
stimulation techniques resulting in a longer maturation process up
to 2 years (2,4,5, 6,7
The primary objective for rehabilitation following cartilage repair
procedures is the provision of an optimal environment and protection
for overloading of the chondral repair tissue. Return to sport after
Ccrtilage repair range from 8-24 month(1,7). The range in timescale
for return to the preeinjury level of activities reflects the histological
differences in the repair tissue across the cartilage repair procedures
and the speed of the final maturation process after surgery (7).
The precise timelines for the rehabilitation after cartilage repair will
be dependent on a number of patient specific and lesion specific
factors. These factors have been previously identified in differnt
publications like leasion size, defect location etc.
The tradditional rehabilitation program include in the phase I
nonweight bearing
for the first two weeks followed by partial weight bearing (5-10
KG) for the next four weeks. After the sixth postoperativ week the
progression to full weight bearing is necessary (2,5,6,9) There is still
a controversial discussion in literature about the use of continuous
passive motion (CPM). Although the results of partial retrospective,
partial prospective,sometimes randomized or double blinded studies
are incontradiction, there can only be found a trend to better results.
New clinical studies for evidence based guidelines in the handling of
continous passive motion after knee surgery are necessary (8).
Due to the very complex biological and cell biological processes
in general and specific tissue healing, to secure good results, a
standardised rehabilitation depending on the methods, the defect
location and the associated injuries is important.
References:
1) Della Villa S, Kon E, Filardo G, Ricci M, Vincentelli F, Delcogliano
M, et al. Does intensive rehabilitation permit early return to sport
without compromising the clinical outcome after arthroscopic
autologous chondrocyte implantation in highly competitive athletes?
Am J Sports Med. 2010;38(1):68-77.
2) Hambly K, Bobic V, Wondrasch B, Van Assche D, Marlovits
S. Autologous chondrocyte implantation postoperative care
and rehabilitation: science and practice. Am J Sports Med.
2006;34(6):1020-1038
3) Hurst JM, Steadman JR, O’Brien L, Rodkey WG, Briggs KK.
Rehabilitation following microfracture for chondral injury in the
knee. Clin Sports Med. 2010;29(2):257-265, viii.
4) Kreuz PC, Steinwachs M, Erggelet C, Lahm A, Krause S, Ossendorf C,
et al. Importance of sports in cartilage regeneration after autologous
chondrocyte implantation: a prospective study with a 3-year followup.
Am J Sports Med. 2007;35(8):1261-1268.
5) Van Assche D, Caspel DV, Staes F, Saris DB, Bellemans J, Vanlauwe
J, et al. Implementing one standardized rehabilitation protocol
following autologous chondrocyte implantation or microfracture
in the knee results in comparable physical therapy management.
Physio Ther Prac. 2011;27(2):125-136.
6) Steinwachs MR, Kreuz PC, Guhlke-Steinwachs U, Niemeyer P.
Current treatment for cartilage damage in the patellofemoral joint
Orthopade. 2008 Sep;37(9):841-7.
7) Hambly K, Silvers H, Steinwachs M. Rehabilitation after articular
cartilage repair of the knee in the football player. Cartilage 2012
8) Kirschner P. CPM – continuous passive motion in the treatment of
injured or operated
knee-joints: a metaanaylis of current literature Unfallchirurg
2004107:328–340
9) Minas T, Chui R. Autologous Chondrocyte implantation. Am J Knee
Surg 2000; 41-50

21.2.2
Return to sports after articular cartilage repair
K. Mithoefer
Cambridge/United States of America
Introduction: Articular cartilage injury in athletes is frequently
observed and often associated with significant acute or chronic
limitation of the ability to participate in athletic activities. For the
symptomatic, injured athlete, the ability to return to competitive
sports participation presents one of the most important measures
of functional outcome and treatment success. Information on the
ability to return to sport is therefore of critical relevance in this
active population.
Content: The ability to return to sport provides a categorical but
nonspecific outcome measure after treatment of an athletic injury.
Return to sports participation alone does not provide any discrete
variables of the athletic function and performance. Due to the
complexity of the process of returning to sports participation a
detailed analysis of the return to athletic activity is recommended.
Post-recovery sports activity should be categorized based on the
competitive level of the sports activity and compared to the preinjury
level of play. In addition, objective performance parameters
should be recorded to assess athletic functional outcome. The
presence of any residual symptoms during sports participation
should be noted. Besides the ability to return to sport, continued
sports participation over time and risk for re-injury present important
measures of long-term functional outcome. Independent of physical
and performance parameters, psychological and social aspects of
the athlete may affect return to sport and need to be included in
a thorough functional evaluation of the athlete’s return or failure
to return to sport. Health care providers treating injured athletes
are frequently required to make decisions regarding the timing of
exercise progression, the resumption of functional activities and
return to competitive play. The decision when the athlete can safely
return to sport after recovering from a performance-limiting injury
often presents a particular challenge to the athlete’s physician,
physical therapist, and athletic trainer. Quickly and safely returning
the athlete to sport can be achieved by adopting an outcomesbased
approach to treatment progression, in which the athlete must
reach specific benchmarks before advancing activity levels. This
strategy allows for quantification of an athlete’s functional ability,
comparison with pre-injury performance status and verification that
an appropriate level of rehabilitation has been achieved. Based on
the method of data collection, functional outcome measures utilized
in the process of returning the athlete to sport can be divided into
subjective (patient-reported) and objective (clinician-reported)
measures. Subjective measures typically include questionnaires
and patient-based outcome scores. Objective measures include
clinical examination, radiological studies, and testing of the athlete’s
function and performance. Subjective and objective outcome
parameters provide complementary information and are best used
in combination to provide the most comprehensive assessment of
the athlete’s functional ability. The criteria for return to sport may
vary depending on the injury location, type of sport, and athlete’s
performance level. In summary, return to sports after injury in
the athletic population presents a critical but complex issue that
requires a systematic and individualized approach to assure the
safe return of the athlete to competition at pre-injury performance
level and successful continued participation without re-injury. The
rate of return to sport after articular cartilage repair in the athletic
population is comparable between currently available surgical
repair techniques but differences exist in the ability to continue
active sports participation over time.
References:
1. Della Villa S, Kon E, Filardo G, Ricci M, Vincentelli F, Delcogliano
M, Marcacci M. Does intensive rehabilitation permit early return to
sport without compromising the clinical outcome after arthroscopic
autologous chondrocyte transplantation in highly competitive
athletes? Am J Sports Med. 2010 Jan;38(1):68-77.
2. Gudas R, Kelesinskas RJ, Kimtys V, Stankevicius E, Toliusis
V, Benotavicius G, Smailys A: A prospective randomized clinical
study of mosaic osteochondral autologous transplantation versus
microfracture for the treatment of osteochondral defects in the knee
joint in young athletes. Arthroscopy 2005; 21:1066-75.
3. Irrgang JJ, Pezzullo, D. Rehabilitation following surgical procedures
to address articular cartilage lesions in the knee. J Orthop Sports
Phys Ther. 1998;28:232-240.
Extended Abstracts 169
4. Kreuz PC, Steinwachs M, Erggelet C, Lahm A, Krause S, Ossendorf C,
et al. Importance of sports in cartilage regeneration after autologous
chondrocyte implantation. Am J Sports Med 2007; 35: 1261-68.
5. Maletius W, Messner K: The long-term prognosis for severe
damage to the weightbearing cartilage in the knee: A 14-year clinical
and radiographic follow-up in 28 young athletes. Acta Orthop Scand
1996; 165-168.
6. Mithoefer K, Gill TJ, Cole BJ, Williams RJ, Mandelbaum BR. Clinical
outcome and return to competition after microfracture in the athlete’s
knee: An evidenc-based syetematic review. Cartilage 2010; 1:113-20.
7. Mithoefer K, Hambly K, Della Villa S, Silvers H, Mandelbaum
BR. Return to sports participation after articular cartilage repair in
the knee: scientific evidence. Am J Sports Med 2009; 37 Suppl 1:
167S-76S.
8. Mithöfer K, Minas T, Peterson L, Yeon H, Micheli LJ: Functional
outcome of articular cartilage repair in adolescent athletes. Am J
Sports Med 2005; 33:1147-1153.
9. Mithöfer K, Peterson L, Mandelbaum BR, Minas T: Articular
cartilage repair in soccer players with autologous chondrocyte
transplantation: Functional outcome and return to competition. Am J
Sports Med 2005; 33(11):1639-46.
10. Mithoefer K, Williams RJ, Warren RF, Wickiewicz TL, Marx
RG. High-impact athletics after knee articular cartilage repair: A
prospective evaluation of the microfracture technique. Am J Sports
Med. 2006;34:1413-8.
11. Reinold MM, Wilk KE, Macrina LC, Dugas JR, Cain EL. Current
concepts in the rehabilitation following articular cartilage repair
procedures in the knee. J Orthop Sports Phys Ther. 2006;36:774-
794.
12. Roberston CM, Williams RJ, Warren RF, Rodeo SA, Wickiewicz TL.
Return to sports after fresh osteochondral allograft transplantation
in the knee. Abstract 8970 presented at the 2010 annual meeting
of the American Orthopedic Society of Sports Medicine (AOSSM),
Providence, RI, USA, July 17, 2010.
13. Van Assche D, Van Caspel D, Vanlauwe J, Bellemans J, Saris
DB, Luyten FP, Staes F. Physical activity levels after characterized
chondrocyte implantation versus microfracture in the knee and the
relationship to objective functional outcome with 2-year follow-up
Am J Sports Med. 2009 Nov;37 Suppl 1:42S-49S.
14. Wondrasch B, Zak L, Welsch GH, Marlovits S. Effect of accelerated
weightbearing after matrix-associated autologous chondrocyte
implantation on the femoral condyle on radiographic and clinical
outcome after 2 years: A prospective, randomized controlled pilot
study. Am J Sports Med. 2009;37:88S-96S.
21.2.3
Challenges in Standardizing Rehabilitation in Cartilage Repair
RCTs
M.S. Shive
Quebec/Canada
Introduction: Current orthopaedic efforts towards improving
evidence-based treatment algorithms in cartilage repair should
also recognize post-treatment rehabilitation as a critical covariate
in the analysis and understanding of outcome success. However,
the standardization and control of patient rehabilitation offers
unique challenges, particularly in multicenter studies of large or
varied geographic scale and even more so for those intended to
meet regulatory requirements and conducted under Good Clinical
Practice (GCP). Currently, there is little scientific evidence comparing
rehabilitation protocols following different cartilage repair therapies.
This, compounded with ‘custom’ programs developed by orthopaedic
surgeons with little or no scientific basis, or programs established
by therapists themselves, leaves those trying to design new studies
with little scientific support. However, some clinical evidence has
begun to surface focused on rehabilitation. Clinical, radiological
and biomechanical outcomes following only MACI cartilage repair
treatment were studied in patients randomized to 2 different
rehabilitation approaches, with either conservative or accelerated
weight bearing, bringing some new insight into weight bearing to

170
Extended Abstracts
those using MACI.[1] And perhaps the only published randomized
clinical trial (RCT) which controlled and studied rehabilitation and
subsequent outcomes was reported by Van Assche et al [2], who
compared functional outcomes under standardized rehabilitation
protocols for microfracture versus ACI. Further awareness has been
raised by broader discussions as found recently in the International
Cartilage Repair Newsletter [3] dedicated to the topic, and
highlighting the fact that rehabilitation is a true adjunct to cartilage
repair. And to standardize and study rehabilitation in cartilage repair
RCTs, multiple challenges must be overcome.
Content: Specific Challenges to Overcome: 1) Rehabilitation
Protocol. The design of new cartilage repair studies should carefully
weigh the choice of rehabilitation protocols, their implementation
and the type of data that will be collected. Study protocols should
dictate the selection of the appropriate therapeutic modalities
and post-operative timeframe, such as the period of restricted
weightbearing, or the use (or non-use) of continuous passive
motion (CPM). Furthermore, clinical trials which compare cartilage
repair therapies that differ in their repair mechanisms- as with an
osteochondral graft device compared to arthroscopic microfracture-
might call for different protocols altogether. 2) Studied parameters
and relationship to outcomes. Special consideration should be made
as to the role that rehabilitation plays within a study protocol and
its relationship to study endpoints. Choosing specific rehabilitation
parameters and the extent of data collection can represent an
excellent, albeit challenging, opportunity to understand how a
rehabilitation protocol influences repair outcomes. Even obvious
variables like patient compliance, the progression of range of
motion and weightbearing and physical knee characteristics
could be informative, as well as more complex data obtained from
functional tests of gait or proprioception. The extent of the data and
the method of collection should be established with the therapists
prior to treatment. Use of electronic data capture facilitates this
collection and permits real-time tracking of both therapists and
the progression of patients. 3) Standardization of rehabilitation.
The selection and training of study therapists is an essential step
in successfully implementing a standardized rehabilitation program.
International studies offer the challenge of multi-lingual protocols
and datasets and may need to employ therapists with differing
educational backgrounds but who have appropriate experience.
Training of therapists should not be left to documentation as direct
contact permits Q&A and explanation of subtleties, if any. Frequent
communication regarding patients is helpful, especially with regards
to study treatment, lesion size and location or other unique study
components. Furthermore, the logistics and financial management,
if needed, of such a relationship with the clinic or hospital providing
the rehabilitation services, needs to be established well in advance
of patient treatment. 4) Patient compliance. Patients should be well
informed regarding the importance of protocol compliance (eg.
attending sessions, weightbearing requirements) to both the health
of their knee as well as the clinical study. Encouragement should
not only come from the clinical site and the investigator, but also
from the participating therapists. The objective of an unbiased
study rehabilitation program should try to avoid the situation where
compliance becomes a function of the efficacy of treatment, or of the
willingness or ability to pay. 5) Regulatory unknowns. Regulatory
agencies are expecting to see standardized rehabilitation data
(duration, type, frequency of weight bearing, methods etc) conducted
under GCPs in approval submissions. However, recent FDA Guidance
for Industry [4] on cartilage repair clinical trials is not clear regarding
the expected correlation of rehabilitation parameters to treatment
outcomes and the extent of statistical analysis, if any, which must
be carried out. There is, nonetheless a stated concern that the
inability to standardize and track rehabilitation may introduce
bias and as such, any potential influence on outcomes should be
examined. Furthermore, supporting documentation and rationales
are expected. This important issue needs to be clarified at an agency
level- particularly if poor rehabilitation compliance or progression
is viewed as a study protocol deviation with direct consequences
on final endpoint statistical analyses. As the cartilage repair field
advances with new therapies, more randomized controlled trials
will be needed to improve evidence based treatment algorithms. It
is critical that the appropriate energy and resources are allocated
to implement well thought-out and standardized rehabilitation
programs, not only to normalize cartilage repair outcome data, but
also to focus much needed attention on the specific rehabilitation
modalities currently used but for which there is little scientific
evidence. Consequently, cartilage repair patients will benefit from
rehabilitation protocols with valid scientific basis.
References:
[1] Ebert JR, Robertson WB, Lloyd DG, Zheng MH, Wood DJ, Ackland
T. Traditional vs accelerated approaches to post-operative
rehabilitation following matrix-induced autologous chondrocyte
implantation (MACI): comparison of clinical, biomechanical and
radiographic outcomes. Osteoarthritis & Cartilage. 16(10):1131-40,
2008
[2] Van Assche D, Staes F, Van Caspel D, Vanlauwe J, Bellemans J,
Saris DB, Luyten FP. Autologous chondrocyte implantation versus
microfracture for knee cartilage injury: a prospective randomized
trial, with 2-year follow-up. Knee Surg Sports Traumatol Arthrosc;
18(4):486-95, 2010
[3] “Special Focus: Rehabilitation. Global Concepts for Successful
Joint Restoration”. International Cartilage Repair Society Newsletter,
Winter Issue 14, 2011
[4] US FDA Guidance for Industry: Preparation of IDEs and INDs for
Products Intended to Repair or Replace Knee Cartilage, December
2011
Acknowledgments:
The author would like to acknowledge the BST-CarGel (Piramal
Healthcare, formerly BioSyntech) clinical development team which
included over 60 dedicated physiotherapists who participated in the
BST-CarGel multicenter RCT
22.1
Contribution of other tissues to cartilage degeneration
C.B. Little
St Leonards/Australia
Introduction: The maintenance of any tissue is a balance between
anabolism and catabolism, both of which are inevitably occurring
simultaneously as part of normal homeostasis. In musculoskeletal
tissues such as cartilage and bone where the extracellular matrix
makes up such a large proportion of the tissue volume and is key
to the mechanical properties, this balance is particularly important.
In diseases such as osteoarthritis (OA) despite evidence for
increased biosynthesis of cartilage matrix components at least
early in the disease, the catabolic processes predominate and
matrix breakdown and cartilage loss occurs. It is clear that just as
the capacity to synthesize cartilage matrix and (re)generate and
repair cartilage resides with the resident cells (chondrocytes), so
much of the catabolism of cartilage in disease occurs as the result
of secretion matrix degrading enzymes by the same cells. Targeting
chondrocyte anabolic and catabolic mechanisms has therefore been
a major focus of OA and cartilage repair research.
Content: Despite the central role of chondrocytes in maintenance
and turnover of cartilage, it is becoming increasingly evident
that diseases of the joint such as OA, do not represent disorders
solely of cartilage, but rather they are maladies of the entire “joint
organ”. In OA, pathological change is seen in synovium, joint
capsule, subchondral bone (SCB), and where present intra-articular
ligaments and menisci, as well as cartilage. There is the opportunity
for extensive cross-talk between all of these joint tissues by both
soluble mediators and biomechanical signaling pathways. As a
result of this potential joint tissue interaction, different “scientific
schools” have evolved, each with its favorite tissue(s) placed at the
center of the joint pathology cascade and subsequently as the focus
of anti-catabolic therapeutics. The cartilage-centric view of the joint,
posits that the primary pathological change is in cartilage and this
leads to secondary pathology in other joint tissues. Thus, cartilage
damage can incite a cascade of events including altered loading on
the subjacent subchondral bone inducing its remodeling, release
of cartilage degradation products/fragments inciting inflammation
in the synovium, the synovitis-associated effusion decreasing joint
lubrication and biomechanical stability, and together with secretion
of growth factors from synovial macrophages initiating osteophyte
development. The validity of this model is supported by in vivo
studies where partial thickness scarification of the load-bearing
femoral condyle cartilage in dogs leads to progressive subchondral
bone remodeling, osteophytosis and synovitis changes similar to
that seen with transection of the anterior cruciate ligament (1-3).

It is of course obvious, that the entry point into the above outlined
vicious cycle of joint degeneration could be in any of the involved
tissues. Indeed in vivo models of OA and its characteristic cartilage
degradation have been described where the primary initiating event
is in the ligament or meniscus, synovium, or subchondral bone
(reviewed in (4-6)). What these various models demonstrate is the
strong interrelationship between all joint tissues, and highlight
that to focus on one tissue in isolation and without reference to
its neighbors/partners is fraught with risk. Longitudinal studies of
human knee joints using sensitive MRI imaging techniques, have
demonstrated significant association between pathology in the
various joint tissues. Importantly, there are significantly increased
risk/odds of incident and/or rapid progressive cartilage erosion
(in knees without or with pre-existing OA, respectively) with the
presence of subchondral bone lesions, degenerative meniscal
change and synovitis with joint effusion (7-10). These studies suggest
that changes in these other joint tissues are not just secondary
to cartilage degradation, but may be important in initiating and
driving the chondral change. Whether the mechanisms behind the
influence of these other joint tissues on cartilage degradation are
mechanical, soluble signaling molecules (cytokines, growth factors),
direct contribution to degradative enzyme burden in the joint or a
combination remains to be determined. We have undertaken various
in vitro and in vivo studies to address these questions.
We have studied the relationship between cartilage and bone
changes in a surgical model of post-traumatic (pt)OA using wild
type (WT) and genetically-modified (GM) mice. Cartilage erosion,
subchondral bone sclerosis and osteophyte size were scored in
serial histological sections of knee joints from over 400 age matched
male WT mice 2-16 weeks after surgical destabilization of the medial
meniscus (DMM). Not surprisingly there is a significant temporal
progression of cartilage and bone pathology after meniscal injury.
There is a significant correlation between cartilage damage and
both subchondral bone sclerosis and osteophyte size at all times,
but particularly in early and progressive phases of joint disease.
Ordinal logistic regression analysis demonstrates that the odds of
worse cartilage damage are significantly greater when increased
SC bone density (2.6 x) or osteophytes (3.7 x) are present, either
separately or together and when corrected for (i.e. independent
of) time post surgery and differences within strains of mice. This
association supports the hypothesis of a causal relationship
between subchondral bone sclerosis and osteophytosis and
cartilage degradation. However, in none of the 12 different GM mice
strains examined were the same associations maintained, and none
of the GMs has a significant effect (better or worse) on all three of
the pathology outcomes. While pathology in bone and cartilage are
associated in ptOA, the data from GM mice indicates this parallel
pathology and not causally linked, and disease in one tissue can be
modulated independent of the other. This has important implications
for OA therapy, and on the potential effects on any cartilage repair
strategy.
In the knee joint the meniscus plays a significant mechanical role in
dissipating and transferring loads, as well as contributing to joint
stability. Disruption of the ability of the meniscus to appropriately
undertake these mechanical functions (through excision, transection
or severing its attachment to the tibia) results in all species examined
(including humans), all the hallmark pathologies of OA including
progressive cartilage destruction. While excision of the meniscus
likely has its major impact through altering joint mechanics, injury
to or degenerative change in the meniscus may also contribute to
cartilage breakdown directly through release of catabolic enzymes.
There is a distinct zonal difference in the catabolic events that occur
in the meniscus, the inner cartilaginous zone having significant
ADAMTS-driven proteolysis while in the outer fibrous zone MMP
activity predominates (11). The expression ADAMTS4, ADAMTS5,
MMP13 was significantly higher in meniscus than cartilage from
the same joint in response to IL-1 and TNF stimulation. The outer
meniscus secreted active MMP-2 and MMP-13 ± cytokine stimulation.
The meniscus is thus a significant source of key enzymes involved
in cartilage breakdown, and may have a major impact on both
progressive cartilage breakdown in OA, and the success of cartilage
repair strategies.
The synovium is a potential source of degradative enzymes and
catabolic cytokines. Whether inflammation (synovitis) in OA is a
secondary event to cartilage degradation or may play a primary
role in initiation and progression of cartilage breakdown is unclear.
Long-term treatment with NSAIDs and corticosteroids do not have
a disease modifying effect in human OA. GM mice with deletion of
prostaglandin E synthase, Cox1 or Cox2 do not show any diminution
of ptOA cartilage degradation (12, 13). Clinical trials of IL-1 or TNF
blocking strategies in established human OA have not shown
Extended Abstracts 171
significant benefit, however, IL-1beta deficient mice do have reduced
cartilage loss in ptOA (14), and treatment with IL-1ra abrogates
cartilage damage in animal models of ptOA (15). It may be that there
is a window of opportunity to target inflammation after joint injury to
protect against long term OA and cartilage damage. However there
is very limited information on the changes in joint inflammation that
occur in OA, and it may be that the principal inflammatory cytokine
or cell type, and thus treatment target changes with time. We have
evaluated the cellular and expression changes in the synovium that
occur with time after joint injury and between OA-inducing (DMM
surgery) versus non-inducing (sham) trauma. Increased IL-1 and TNF
expression occur rapidly in both DMM and sham but return t baseline
by 7-14 days. In contrast there were distinct temporal patterns of
activated macrophage, CD4 and CD8 lymphocyte accumulation in the
synovium and importantly significant differences between sham and
DMM surgeries. Importantly this was a local event as no systemic
changes were observed. This exciting data suggests that cellular
inflammatory/immune events occur early in OA and may drive the
disease process and progression. Current studies are targeting
different cell populations in the joint at distinct times after injury to
determine whether this may be a viable treatment to prevent the
onset and halt the progression of OA.
References:
1. Frost-Christensen LN, Mastbergen SC, Vianen ME, Hartog
A, DeGroot J, Voorhout G, et al. Degeneration, inflammation,
regeneration, and pain/disability in dogs following destabilization
or articular cartilage grooving of the stifle joint. Osteoarthritis
Cartilage. 2008;16(11):1327-35.
2. Marijnissen AC, van Roermund PM, Verzijl N, Tekoppele JM, Bijlsma
JW, Lafeber FP. Steady progression of osteoarthritic features in the
canine groove model. Osteoarthritis Cartilage. 2002;10(4):282-9.
3. Sniekers YH, Intema F, Lafeber FP, van Osch GJ, van Leeuwen JP,
Weinans H, et al. A role for subchondral bone changes in the process
of osteoarthritis; a micro-CT study of two canine models. BMC
Musculoskelet Disord. 2008;9:20.
4. Little C, Smith M. Animal models of osteoarthritis. Current
Rheumatology Reviews 2008;4:175-82.
5. Little CB, Fosang AJ. Is cartilage matrix breakdown an appropriate
therapeutic target in osteoarthritis--insights from studies of aggrecan
and collagen proteolysis? Curr Drug Targets. 2010;11(5):561-75.
6. Smith M, Little C. Experimental Models of Osteoarthritis. In:
Moskowitz R, Altman R, Hochberg M, Buckwalter J, Goldberg V,
editors. Osteoarthitis: Diagnosis and Medical/Surgical Management.
Philadelphia: Lipincott Williams & Wilkins; 2007. p. 107-25. .
7. Felson DT. Developments in the clinical understanding of
osteoarthritis. Arthritis Res Ther. 2009;11(1):203.
8. Hill CL, Hunter DJ, Niu J, Clancy M, Guermazi A, Genant H, et al.
Synovitis detected on magnetic resonance imaging and its relation
to pain and cartilage loss in knee osteoarthritis. Ann Rheum Dis.
2007;66(12):1599-603.
9. Hunter DJ, Zhang YQ, Niu JB, Tu X, Amin S, Clancy M, et al. The
association of meniscal pathologic changes with cartilage loss in
symptomatic knee osteoarthritis. Arthritis Rheum. 2006;54(3):795-
801.
10. Roemer FW, Zhang Y, Niu J, Lynch JA, Crema MD, Marra MD, et
al. Tibiofemoral joint osteoarthritis: risk factors for MR-depicted fast
cartilage loss over a 30-month period in the multicenter osteoarthritis
study. Radiology. 2009;252(3):772-80.
11. Fuller ES, Smith MM, Little CB, Melrose J. Zonal differences in
meniscus matrix turnover and cytokine response. Osteoarthritis
Cartilage. 2012;20(1):49-59.
12. Glasson S, Blanchet T, Ma H, Hopkins B, Diane P, Carito B, et al.
Evaluation of twelve knock-out mice following surgical induction of
osteoarthritis. Trans Orth Res Soc. 2006;31:216.
13. Yamakawa K, Kamekura S, Kawamura N, Saegusa M, Kamei
D, Murakami M, et al. Association of microsomal prostaglandin E
synthase 1 deficiency with impaired fracture healing, but not with
bone loss or osteoarthritis, in mouse models of skeletal disorders.
Arthritis Rheum. 2008;58(1):172-83.
14. Glasson SS. In vivo osteoarthritis target validation utilizing
genetically-modified mice. Curr Drug Targets. 2007;8(2):367-76.
15. Calich AL, Domiciano DS, Fuller R. Osteoarthritis: can anti-cytokine
therapy play a role in treatment? Clin Rheumatol. 2010;29(5):451-5.

172
Acknowledgments:
Extended Abstracts
Portions of the work presented were funded by grants received from
the National Health and Medical Research Council of Australia, the
Hillcrest Foundation through Perpetual Philanthropies, Arthritis
Australia, Pfizer Inc, and Sydney Medical School Foundation.
22.2
Cartilage repair; what does it mean and how to assess cartilage
repair outcome?
L.E. Dahlberg
Malmö/Sweden
Introduction: Often, cartilage repair is considered restoring
macroscopic defects. Defects may originate as a result of an acute
injury or because of osteoarthritis (OA). However, defects may also be
considered as molecular loss in an intact matrix. Where there may be
a rationale to restore defects after an acute injury by e.g., stimulating
matrix production by means of cartilage cell transplantation, there is no
convincing evidence for restoring cartilage loss in OA joints to improve
symptoms or decrease further OA deterioration. In OA it seems more
rationale to use the repair capacity of cartilage chondrocytes within
the matrix to support the restoration of degraded and lost matrix
molecules before macroscopic loss occur. This abstract, as well as my
talk, will therefore focus on the latter form of cartilage repair.
Content: In OA, it is generally agreed that as joint space narrowing and
osteophytes are identified by radiography, cartilage matrix changes
involved in the pathogenesis of OA have occurred for a long time. The
fact that OA joint symptoms commonly come about in patients without
radiographic OA changes supports this and suggests that in the interest
of the patient, the OA diagnosis should be based on symptoms rather
than x-ray findings (1). Pain mechanisms in OA are not well understood,
but clearly the cartilage matrix molecular status in symptomatic patients
without radiographic changes needs further attention. Risk for knee
OA is associated with meniscectomy, obesity, muscle weakness and
major injury whereas hip OA is commonly associated with congenital
and developmental defects such as acetabular dysplasia and possibly
obesity (2, 3). Patients with inreased OA risk may serve as OA models.
The cartilage matrix consists of two main macromolecules, type II
collagen and the large, aggregating proteoglycan, aggrecan. With its
highly negatively charged glycosaminoglycans (GAG), aggrecan can
bind up to 50 times its weight in water resulting in a swelling pressure
that is normally constrained by the tensile strength of the collagen
fibrillar network (4). This interaction is the key mechanism behind the
visco-elastic properties of articular cartilage that provides joints with
the necessary resistance to mechanical loading (5).
The hallmark of OA, cartilage loss, suggests a metabolic imbalance with
less repair and increased enzymatic degradation and loss of matrix
molecules in the pathogenesis. In a cartilage of low quality, depleted
of aggrecan and other matrix molecules, more stress is transmitted to
the collagen fiber-network. That may eventually result in fatigue, fiber
damage and cartilage oedema which will further dilute the matrix and
impair the biomechanical properties.
Clearly, we need methods that identify in vivo molecular joint cartilage
alterations related to early OA pathogenesis in order to enable the
development of treatments with the ability to slow down matrix
degradation and stimulate molecular repair. Similarly, matrix repair
in acutely injured subjects by means of transplantation needs to be
monitored at the molecular level and not only via macroscopic grading
systems. In this respect MRI is a valuable tool. In the last decade
several different techniques have emerged that enable the monitoring
of molecular cartilage quality; dGEMRIC, gagCEST, T1rho, sodium-MRI,
different T1 and T2 parameters (6, 7, 8, 9, 10). dGEMRIC, gagCEST,
T1rho and sodium-MRI are considered GAG-related whereas T1 and T2
measurements are less specific and influenced by water and collagen
content and other variables. gagCEST and sodium-MRI are still at an
experimental level whereas there are considerable clinical experience
with dGEMRIC although the technique still needs further validation.
Recent in vivo and in vitro dGEMRIC studies have increased our
understanding of cartilage biology, specifically matrix changes related
to joint biomechanics in health and disease, as load, over-load,
exercise and x-ligament and meniscus injuries. dGEMRIC estimates
cartilage GAG content using a negatively charged contrast agent that,
after intravenous injection, distributes into the cartilage inversely to
cartilage negative charge (6).
More and more, we understand the cartilage contrast-distribution in
dGEMRIC which has helped us to interpret the MRI signal in different
clinical cohorts. In vivo, there is no equilibrium between surrounding
fluid contrast concentration and that in the cartilage but a continued
wash-in and wash-out of the contrast medium which is in contrast to
the in vitro experimental situation. In in vitro examinations, variables
determining contrast diffusion as well as relationship between
Gadolinium concentration and T1Gd, usually regarded as the dGEMRIC
index, can be determined. Recent studies examining depth-wise
contrast concentration in vivo and in vitro show the importance of
having a strict protocol regarding the timing of MRI examinations after
contrast-injection and also that the cartilage thickness needs to be
included in the protocol (11). Determining cartilage GAG by dGEMRIC
and in the synovial fluid by a colorimetric assay, may give information
on the relationship between metabolic and structural changes (12).
A cross-sectional dGEMRIC study showed that the index was higher in
athletes than in sedentary people which suggest an adaptive capacity
of human knee cartilage (13). An exercise study in healthy subjects
showed improved cartilage quality after running (14). To examine the
influence of exercise to the cartilage in meniscetcomized subjects,
a randomized trial showed that a 4 month exercise intervention
significantly increased the dGEMRIC index (15). Interestingly, exercise
is also a core treatment of OA patients and meniscectomy is a risk factor
for OA. However, at the same time OA is often considered a “wear and
tear” disease which may seem contradictory to treatment guidelines.
In acutely injured cruciate ligament subjects, dGEMRIC index generally
decreases (12) indicating a generalized cartilage matrix impairment
with GAG loss. After meniscectomy, known to increase OA risk,
dGEMRIC index is low in the meniscectomized compartment (16).
Accordingly, a study of cruciate ligament injuried patients shows
that compartments that had suffered a meniscus injury had a lower
dGEMRIC index compared to those without meniscus injury (17). In
patients with early cartilage disease, the dGEMRIC index is lower in
diseased than in normal appearing cartilage (18, 19). At follow-up,
patients having a low dGEMRIC index at baseline had increased risk
of developing radiographic OA 6 years later (20). In patients with hip
dysplasia, another group at OA risk, the dGEMRIC index was lower than
in asymptomatic subjects, despite the absence of radiographic OA
changes. Surgical treatment of dysplasia (periacetabular osteotomy)
is associated with a poor outcome if the patient had a low preoperative
dGEMRIC index (21).
Other known risk factors for OA are obesity and muscle weakness. To
identify possible correlates between molecular GAG changes and joint
disease, these risk factors have been related to the dGEMRIC index. A
lower quadriceps muscle strength and worse muscular performance
is associated with inferior cartilage quality (dGEMRIC index) (16).
Recently, Anandacoomarasamy et al. in an obese cohort study (22),
where only one third of had clinical OA, subjects were scheduled for
gastric banding or exercise and diet programs. Results show weight
loss to be associated with improved dGEMRIC index and cartilage
quantity medially in the knee.
These studies provide evidence that structural changes related to
GAG is involved in the OA process and that such alterations may be
identified with dGEMRIC. Furthermore, they support the content that
cartilage is a dynamic tissue and that molecular loss that may be
related to OA can be repaired by intrinsic mechanisms. However to
enable this, monitoring techniques that identifies cartilage events at
the molecular level need to be utilized.
References:
1 Ericsson YB, Roos EM, Dahlberg L. Muscle strength, functional
performance and self-reported outcome four years after arthroscopic
partial meniscectomy in middle-aged patients. Arthritis Care Res.
2006;55:946-952.
2 Felson DT, Lawrence RC, Dieppe PA, et al. Osteoarthritis: new insights.
Part 1: the disease and its risk factors. Ann Intern Med. 2000;133:635-
46.
3 Jacobsen S, Sonne-Holm S. Hip dysplasia: a significant risk factor
for the development of hip osteoarthritis. A cross-sectional survey.
Rheumatology (Oxford). 2005;44:211-8.
4 Venn M, Maroudas A. Chemical composition and swelling of normal
and osteoarthrotic femoral head cartilage. I. Chemical composition.
Ann Rheum Dis. 1977;36:121-9.
5 Mow VC, Lai M. Biorheology of swelling tissue. Biorheology.
1990;27:110-9.

6 Dahlberg LE, Lammentausta, Tiderius CJ, Nieminen MT. In Vivo
Monitoring of Joint Cartilage – Lessons to Be Learned by Delayed
Gadolinium Contrast-enhanced Magnetic Resonance Imaging of
Cartilage. European Musculoskeletal review. In press
7 Wheaton AJ, Casey FL, Gougoutas AJ, Dodge GR, Borthakur A, Lonner
JH, et al. Correlation of T1rho with fixed charge density in cartilage.
J.Magn.Reson.Imaging. 2004; 20:519-25.
8 Wheaton AJ, Borthakur A, Shapiro EM, Regatte RR, Akella SV, Kneeland
JB, et al. Proteoglycan loss in human knee cartilage: quantitation with
sodium MR imaging--feasibility study. Radiology. 2004; 231:900-5.
9 Burstein D, Velyvis J, Scott KT, Stock KW, Kim YJ, Jaramillo D, Boutin
RD, Gray ML. Protocol issues for delayed Gd(DTPA)(2-)-enhanced MRI
(dGEMRIC) for clinical evaluation of articular cartilage. Magn Reson
Med. 2001;45:36-41.
10 Tiderius CJ, Olsson LE, de Verdier H, Leander P, Ekberg O, Dahlberg L.
Gd-DTPA2)-enhanced MRI of femoral knee cartilage: a dose-response
study in healthy volunteers. Magn Reson Med. 2001;46:1067-71.
11 Hawezi Z, Tiderius CJ, Svensson J, Dahlberg LE, Lammentausta E.
Temporal dynamics of Gd-enhanced T1 relaxation time in deep and
superficial femoral articular cartilage. 17th Annual Scientific Meeting,
International Society for Magnetic Resonance in Medicine 16:3963,
2009. Honolulu, Hawaii.
12 Tiderius CJ, Olsson LE, Nyquist F, Dahlberg L. Cartilage
glycosaminoglycan loss in the acute phase after an anterior cruciate
ligament injury: delayed gadolinium-enhanced magnetic resonance
imaging of cartilage and synovial fluid analysis. Arthritis Rheum.
2005;52:120-7.
13 Tiderius CJ, Svensson J, Leander P, Ola T, Dahlberg L. dGEMRIC
(delayed gadolinium-enhanced MRI of cartilage) indicates adaptive
capacity of human knee cartilage. Magn Reson Med. 2004;51:286-90.
14 Van Ginckel A, Baelde N, Almqvist KF, Roosen P, McNair P, Witvrouw
E. Functional adaptation of knee cartilage in asymptomatic female
novice runners compared to sedentary controls. A longitudinal analysis
using delayed Gadolinium Enhanced Magnetic Resonance Imaging of
Cartilage (dGEMRIC). Osteoarthritis Cartilage. 2010 Dec;18(12):1564-9.
15 Roos EM, Dahlberg L. Positive effects of moderate exercise
on glycosaminoglycan content in knee cartilage: a four-month,
randomized, controlled trial in patients at risk of osteoarthritis. Arthritis
Rheum. 2005;52:3507-14.
16 Ericsson YB, Tjörnstrand J, Tiderius CJ, Dahlberg LE. Relationship
between cartilage glycosaminoglycan content (assessed with dGEMRIC)
and OA risk factors in meniscectomized patients. Osteoarthritis
Cartilage. 2009;17:565-70.
17 Neuman P, Tjörnstrand J, Svensson J, Ragnarsson C, Roos H, Englund
M, Tiderius CJ, Dahlberg LE. Longitudinal assessment of femoral knee
cartilage quality using contrast enhanced MRI (dGEMRIC) in patients
with anterior cruciate ligament injury--comparison with asymptomatic
volunteers. Osteoarthritis Cartilage. 2011 Aug;19(8):977-83.
18 Tiderius CJ, Olsson LE, Leander P, Ekberg O, Dahlberg L. Delayed
gadolinium-enhanced MRI of cartilage (dGEMRIC) in early knee
osteoarthritis. Magn Reson Med. 2003;49:488-92.
19 Tiderius CJ, Jessel R, Kim YJ, Burstein D. Hip dGEMRIC in asymptomatic
volunteers and patients with early osteoarthritis: the influence of
timing after contrast injection. Magn Reson Med. 2007;57:803-5.
20 Owman H, Tiderius CJ, Neuman P, Nyquist F, Dahlberg LE. Association
between findings on delayed gadolinium-enhanced magnetic
resonance imaging of cartilage and future knee osteoarthritis. Arthritis
Rheum. 2008;58:1727-30.
21 Kim YJ, Jaramillo D, Millis MB, Gray ML, Burstein D. Assessment
of early osteoarthritis in hip dysplasia with delayed gadoliniumenhanced
magnetic resonance imaging of cartilage. J Bone Joint Surg
Am. 2003;85-A:1987-92.
22 Anandacoomarasamy A, Leibman S, Smith G, Caterson I, Giuffre B,
Fransen M, Sambrook PN, March L.Weight loss in obese people has
structure-modifying effects on medial but not on lateral knee articular
cartilage. Ann Rheum Dis. 2012 Jan;71(1):26-32.
Extended Abstracts 173
Acknowledgments:
Supported by grants from the Swedish Research Council, King Gustaf
V’s 80-year Fund, Swedish National Center for Research in Sports, The
Herman Järnhardt Foundation, The Alfred Österlund Foundation and
The Skåne University Hospital Funds.
24.1.1
Change of thinking in treating cartilage defects in the hip
M. Philippon
Vail/United States of America
Introduction: Chondral Injuries occur in conjunction with many hip
disorders, both traumatic and atraumatic. These injuries can be acute,
chronic or degenerative and partial or full thickness defects.
Content: Recently, literature showed that chondral defects with
identified in 79% of hip arthroscopies.(Arthroscopy Journal. 2008)
There is also a strong association between chondral defects and
femoroacetabular impingement. Full-thickness of acetabular cartilage
occurred with an average alpha angle of 60 degrees while hips with no
delamination had an average alpha angle of 51 degrees. The average
alpha angles was also associated with chondral defect size. Treatment
Currently chondral defects of the hip are most commonly treated
by debridement or microfracture. Microfracture is well-established
treatment for fill thickness chondral lesions in the knee. Perforations
in the subchondral bone bring marrow elements into the chondral
defect that are capable of differentiating into fibrocartilaginous tissue.
Advances in the field of hip arthroscopy make it possible to use this
technique for treatment of chondral injuries of the hip. Indication for
the use of microfracture include focal and contained lesions, 2-4 cm in
size, full thickness loss of articular cartilage in weight-bearing areas,
and unstable chondral flaps overlying intact subchondral bone. Contra-
Indications include partial thickness defects and patient unwillingness
to comply with rigorous rehabilitation protocol. Proper technique
and rehabilitation are critical to the success of this procedure. New
techniques have been reported recently in the literature. Fibrin glue
has been used to treat delaminated acetabular articular cartilage.
More research is needed to determine the survivorship of this repair
over time. A recent study also reported on the use of autologous
chondrocyte transplantation compared to debridement. This study
showed that ACT have improved outcomes compared to debridement
in large chondral lesions. Chondral Grafts are also being reported in the
literature for large chondral defects. These grafts include mosiacplasty
and biological plugs. Currently our practice is to use these grafts when
bone loss is present on the femoral head. We then microfracture in
between plugs and fill the donor hole with a biological plug.
References:
Crawford K, Philippon MJ, et al. Microfracture of the hip in athletes.
Clin Sports Med. 2006 ;25:327-35
Field RE, Rajakulendran K,et al. Arthroscopic grafting of chondral defects
and subchondral cysts of the acetabulum. Hip Int. 2011;21:479-86
Fontana A, Bistolfi A, et al. Arthroscopic Treatment of Hip Chondral
Defects: Autologous Chondrocyte Transplantation Versus Simple
Debridement-A Pilot Study. Arthroscopy. 2011 Dec 3.
Johnston TL, Schenker ML, et al. Relationship between offset angle alpha
and hip chondral injury in femoroacetabular impingement. Arthroscopy.
2008;24:669-75.
Philippon MJ, Briggs, KK, et al. Outcomes Following Hip Arthroscopy
for femoroacetabular Impingement with Associated Chondrolabral
Dysfunction Minimum 2 year Follow-up. JBJS Br. 2009;91:16-23.
Philippon MJ, Kuppersmith DA, et al. Arthroscopic findings following
traumatic hip dislocation in 14 professional athletes. Arthroscopy.
2009;25:169-74.
Philippon MJ, Schenker ML, et al. Can microfracture produce repair tissue
in acetabular chondral defects? Arthroscopy. 2008;24:46-50.
Philippon MJ, Schenker ML, et al. Revision Hip Arthroscopy. Am J Sports
Med.2007;35:1918-1921.
Stafford GH, Bunn JR, et al.Arthroscopic repair of delaminated acetabular
articular cartilage using fibrin adhesive. Results at one to three years.
Hip Int. 2011;21:744-50.

174
24.1.2
ACI in the hip joint
J.B. Richardson
Oswestry/United Kingdom
Extended Abstracts
Introduction: Autologous chondrocyte implantation (ACI) has been
used most commonly as a treatment for cartilage defects in the
knee and there are few studies of its use in other joints. Can ACI
work in the hip? We have used hip arthroscopy for over 15 years and
identified a significant proportion of patients with chondral defects
but relatively normal radiology. Increasing use of hip arthroscopy
will identify more patients with localised chondral defects of both
the femoral head and the acetabulum. Can these problems be
treated by autologous chondrocyte implantation?
Content: Assessing chondral defects in the hip requires assessment
of loss of function, accurate mapping of size and location of defects,
and identification of predisposinbg factors. These three dimensions
are useful for evaluation of any joint with a chondral defect. We
consider the development of arthritis to be a process of loss of
function of the joint as an organ. Thus there is not one particular
point at which a joint becomes ‘arthritic’, but a gradual process that
develops over time. Some of this process is pre-clinical and thus
joint narrowing or osteophyte formation often develops prior to
symptoms. These pre-clinical features can be assessed by imaging,
but may not lead to treatment. We propose chondral defects to be part
of this process, and also are not always symptomatic. Indeed many
heal with repair tissue, as is seen in a full thickness ACI harvest site.
This new tissue we propose to call novocartilage. It is characterised
by being well attached to underlying bone, to have type 2 collagen
and variable proteoglycan content but has no ingrowth of vessels or
nerves. This is a true repair tissue which may remodell to articular
cartilage. It may have differing amounts of hyaline characteristics
as assessed by polarised light microscopy. We believe this tissue is
an end in itself as is callus healing a fracture en route to remodelled
bone. Renovocartilage may be sufficient for purpose to slsoow joint
function as callus can be sufficient for purpose, although it consists
of woven bone. The scientist may seek regeneration of the original
tissue, but the clinician may be satisfied with a functioning repair
tissue. The process of organ failure that is seen as a chondral defect
of the knee may be quantified by a self-assessed score of function for
the knee that has been weighted and validated as an interval score
(Smith et al., 2009). In the hip we advocate a modified Harris Hip
score which has allowed evaluation of 5000 BHR hip resurfacings
(Khan et al, 2009). Mapping by a geometric projection allows the
arthoscopic site to be correlated with the MRI findings (Gokhale et al,
2008). Why develop biological repair for the hip? Function following
hip resurfacing or hip replacement can be excellent. This sets a high
standard for a biological therapy. However the high function leads
to wear and eventual failure of most devices. Metal-polythene hip
replacements have had an excellent outcome in the older patient,
but relatively high failure rates of around 12% by 10 years in the
under-50 year-olds. Higher rates of failure in osteoarthritis leave
only 50% surviving by 20 years. A patient having hip replacement
for osteoarthritis at the age of 30 is likely to have several revisions
over the next 50 years, and each revision is marked by loss of bone.
Metal-on-metal bearings were re-introduced as a solution for hip
resurfacing and here for most designs have been very successful
in the young active male patients. We have identified femoral head
size less than 46mm and female gender as pre-operative factors
that identify earlier failure of the implant. Stemmed metal-metal hip
designs may suffer from high local levels of metal debris as the trunion
is an additional source of metal debris. New ceramic designs and
cross-linked polythene containing vitamin E may provide improved
solutions for the future, but all synthetic implants carry a risk of
infection that is difficult to eradicate. There is therefore an argument
for developing biological reconstructions that maintain bone stock
and avoid the problems of synthetic bearing surfaces. The cost
that can be supported can be considered not just the cost of a joint
replacement but the cost of a difficult revision post-phoned in later
life. This life-time perspective is similar for the hip, ankle and knee. A
surgeon’s perspective may focus on the duration of survival for each
implant, but the patient generally seeks high levels of function. This
supports a routine self-assessed measure of function of the affected
joint at every clinic with ‘hot-audit’ providing a chart for each patient
in the clinic. Renovo-cartilage: an end in itself? 1. Pain relief which
should be prolonged to 10 years 2. Improved function measured on
a self-assessment scale validated for chondral defects (Sith et al.,
2009) 3. Absence of secondary changes : a) osteophyte formation,
b) bone marrow oedema. 4. Preferably evidence of: a) Good
attachment to underlying bone b) Lateral integration c) Sufficient
thickness d) Low surface friction e) Resistance to fluid movement
In the hip the development of different patterns of cartilage loss is
not well documented. The femoral head and the acetabulum appear
to have separate patterns, and are usefully considered separately.
Cysts are a difficult problem to successfully bone-graft in the
hip, presumably because of the very high pressures that develop
under load compared to other joints. Bone loss can be addressed
in the femoral head by mosaicplasty combined with ACI. Avascular
necrosis of the femoral head has been treated by mesenchymal
stem cell insertion in France, and in Tromsoe, Norway by ACI alone.
Our preferred technique has been the use of a plug of autologous
bone from the greater trochanter, either 15mm or 20mm in diameter.
This plug is shaped to fit the normal contour of the femoral head
and then ACI performed over the top. We have treated several
patients with femoral head chondral or osteochondral defects of six
cm square average area. In all cases surgical dislocation of the hip
was necessary for surgery. We have observed some excellent results
(Akimau, 2006) but in our experience patients with cyst formation
do not respond as well. Initially we used the ipsilateral knee as a
source of cartilage for culture but in later cases used the hip. The
normal knee will have symptoms for several months following
biopsy, but this does not hinder the rehabilitation of the hip. These
hips have been treated between 2 and 10 years ago. Five patients
have progressed to hip replacement relatively quickly. We believe
this is partly due to the high levels of pain-free function that hip
replacement can offer the younger patient. All these patients had
cyst formation pre-operatively and we therefore caution against
undertaking ACI in the presence of cyst formation. We do not believe
it is technically feasible to perform sutured ACI in the acetabulum
by open surgery. The acetabulum is however ideally treated by
arthroscopic ACI. Fontana et al reported in 2011 to have good results
with arthroscopic matrix induced autologous in 15 patients. In their
study 15 patients with an average 2cm acetabular defect had an
improvement of over 40 points in the Harris Hip score with a 6 year
follow-up. A similar group of patients treated with debridement had
no significant improvement in symptoms. This group were strongly
of the opinion that a non-sutured matrix would not stay in place on a
defect of the femoral head. In conclusion it would appear that ACI is
a possible option for femoral chondral and osteochondral defects by
open procedure, and arthroscopic ACI a good option for acetabular
defects.
References:
AKIMAU, P, BHOSALE, A, HARRISON, P.E. ROBERTS, S, MCCALL,
I.W., JB RICHARDSON, J.B. ASHTON B.A. Autologous chondrocyte
implantation with bone grafting for osteochondral defect due to
posttraumatic osteonecrosis of the hip. Acta Orthopaedica. 2006;
77 (2): 333-336.
GOKHALE S, KHAN M, KUIPER JH, RICHARDSON JB, DAVIES JP An
arthroscopic hip documentation form Arthroscopy. 2008; 24 (7):
839 – 842.
KHAN M, EDWARDS D, RICHARDSON JB Birmingham Hip Arthroplasty:
Five to Eight Years Prospective Multicentre Centre Results Journal of
Arthroplasty. 2009; 24(7): 1044 – 1050. H J SMITH, JB RICHARDSON,
A TENNANT Modification and validation of the Lysholm Knee Scale
to assess articular cartilage damage. Osteoarthritis and Cartilage.
2009; 17:53-58.
Fontana, A., Bistolfi, Crova, M., Rosso, F., Massazza, G. Arthroscopic
Treatment of Hip Chondral Defects: Autologous Chondrocyte
Transplantation Versus Simple Debridement—A Pilot Study
Acknowledgments:
With many thanks to Brian Ashton, Paul Harrison, Sally Roberts, Jan
Herman Kuiper, Iain McCall and all in the Oscell team ()

24.1.3
Cartilage repair in the hip joint
R.M. Mardones
Santiago/Chile
Introduction: Chondral lesions of the hip represent a diagnostic
challenge and can be an elusive source of pain. Treatment may
present difficulties due to localization and spherical form of the joint
and is most commonly limited to excision, debridement, thermal
chondroplasty and microfractures.
Content: Femoroacetabular impingement is frequently associated
with chondral damage. The abnormal contact between femoral
neck and acetabular rim results in labral detachment and chondral
damage. In the hip the types of chondral lesions differs from other
joints; the cam type femoroacetabular impingement is frequently
associated with chondrolabral junction damage with the subsequent
cartilage detachment. Delamination is a characteristic chondral
lesion of the hip (wave sign), in which the cartilage detaches from
the subchondral bone leading to a “bag lesion” and chondral
flaps. Outerbridge is the most used chondral lesion classification
system although delamination was not originally described it could
be considered as a type III. Konan et al recently described a new
classification system for hip chondral lesions, including the wave
sign, delamination and chondrolabral lesions considering extension
and location.
The frequency of chondral lesions in hip arthroscopy for
femoroacetabular impingement is high, up to 67.3% of the patients,
as described by Nepple et al. Risk factors for the presence of a
chondral lesion are: male, tonnis 1 or 2 and an alpha angle over
50º.
The arthroscopic treatment of chondral lesions of the hip is limited to
excision (rim trimming and femoral neck osteoplasty), debridement,
chondroplasty and microfractures. Rim trimming and femoral neck
osteoplasty can lead to excise the chondral lesion if located in the
overcoverage area. When the chondral damage extends beyond
resection area the treatment of choice will be chosen according to
Outerbridge or Konan classifications, as follows:
- Type I or II with thermal chondroplasty
- Delamination with fibrin glue or microfractures
- Type III or IV (full thickness chondral lesion) with microfractures
Thermal chondroplasty has shown to be a safe technique for closed
chondral lesions leading to morphological changes with better
structural characteristics than mechanical debridement.
Delamination represents a treatment challenge among chondral
lesions. Excising such an area of chondral instability seems an
unnecessary surgical manoeuvre, particularly if the articular cartilage
itself may contain a significant number of viable chondrocytes. The
main objective is the reattachment of the cartilage to the underlying
subchondral bone. This could be achieved with transchondral
microfractures, forming an adherent retrolabral clot or with the use of
an adhesive such as fibrin glue. Tzaveas and Villar report on a series
of 19 patients treated with fibrin adhesive showing improvement in
pain and function at 6 months and one year after surgery.
The indications for microfracture of the hip are similar to the knee
and include focal and contained lesions, tipically less than 2 to 4 cm2
in size, (Outerbridge III or IV) including delamination. Microfracture
is a marrow-stimulating procedure that brings undifferentiated
stem cells from a subchondral perforation into the chondral defect.
A clot formed in the microfractured area provides an environment
for both pluripotent marrow cells and mesenchymal stem cells to
differentiate into stable fibrocartilaginous tissue. Several studies
had shown good midterm results with this technique; however we
know that this fibrocartilaginous tissue does not have the required
mechanical properties and eventually will fail, leading to advanced
chondral damage and osteoarthritis.
Animal and clinical studies have demonstrated that the use of a
Platelet Rich Plasma clot or bone marrow mesenchymal stem cells
over the microfractured area could lead to a better quality hyalinelike
fibrocartilage with better mechanical properties.
Gadolinium enhanced arthrography MRI is limited in its ability
to reliably show the presence and extent of these lesions. More
recently, however, delayed gadolinium enhanced MRI of cartilage
(dgemric) has shown to be useful to delineate chondral damage
Extended Abstracts 175
within the hip.
Our surgical technique is described below. In our clinical practice the
treatment of choice for hip condral lesions is the use of a Platelet Rich
Pplasma clot and bone marrow concentrate over the microfractured
area with excellent results shown by delayed gadolinium enhanced
MRI cartilage (dGEMRIC).
Surgical Technique: After rim trimming and labrum refixation;
cartilage assessment is made. If chondral lesion exists, we proceed to
harvest autologous bone marrow stem cells, which are centrifugated
obtaining 2 to 4 cc of autologous bone marrow – mesenchymal stem
cells concentrate (average 14 millions of nucleated cells/cc3). At
the same time, 50 cc of peripheral blood is taken and centrifugated
twice, in order to obtain 4 cc of PRP (6 to 9x), ready to be activated
with autologous thrombin. Treatment of chondral lesion is made
as described by Steadman in the knee, with debridement of all
remaining unstable cartilage, followed for the removal of the calcified
plate. After preparation of the bed, multiple holes in the exposed
subchondral bone plate are made, leaving about 3 to 4 mm between
each. Once microfracture is complete, traction is release and we
focus on the femoral osteoplasty, obtaining free range of motion
with no abnormal contact between acetabular rim and femoral neckhead
junction. At the end of the procedure, traction is reinstalled
and we proceed to the final part of the procedure. After activation of
Platelet Rich Plasma and clot formation, a slotted cannula is inserted
via the anterior portal. Platelet Rich Plasma clot is inserted through
the cannula and positioned over the microfractured area. A 21-gauge
trocar is then inserted passing through previously located clot and
autologous bone marrow – mesenchymal stem cells concentrate is
instilled under PRP clot. Traction is then released and the procedure
is finished.
Rehabilitation protocol: Passive motion device is maintained for 8
hours. Two crutches with partial weight bearing are indicated for 6
to 8 weeks. Progressive physical activities are allowed.
Preliminary Results: At the time, 13 patients with chondral lesion
of the hip had been treated with microfractures and autologous
bone marrow – mesenchymal stem cells concentrate transplanted
on a Platelet Rich Plasma clot. All patients symptoms improved over
the follow-up period of 8 months (4 to 12 months). Average Hip
Outcome, Vail Hip and Modified Harris Hip scores for all patients
showed significant improvement at 3 and 6 months. Dgemric of 4
patients at 6 months postoperatively revealed complete defect fill
and complete surface congruity with native cartilage.
Conclusions: Surgical technique of a novel treatment for chondral
lesions of the hip is presented. Autologous bone marrow –
mesenchymal stem cells concentrate transplanted on a Platelet Rich
Plasma clot may be an effective approach to promote the repair
of articular cartilage defects of the hip. Further study is currently
underway to identify medium and long-term effects in cartilage
repair and outcomes.
References:
1. Yen YM, Kocher MS. Chondral lesions of the hip: microfracture and
chondroplasty. Sports Med Arthrosc. 2010 Jun;18(2):83-9.
2. Nepple JJ, Carlisle JC, Nunley RM, Clohisy JC. Clinical and
radiographic predictors of intra-articular hip disease in arthroscopy.
Am J Sports Med. 2011 Feb;39(2):296-303.
3. Konan S, Rayan F, Meermans G, Witt J, Haddad FS. Validation of
the classification system for acetabular chondral lesions identified
at arthroscopy in patients with femoroacetabular impingement. J
Bone Joint Surg Br. 2011 Mar;93(3):332-6.
4. Kaplan LD, Chu CR, Bradley JP, Fu FH, Studer RK. Recovery of
chondrocyte metabolic activity after thermal exposure. Am J Sports
Med. 2003 May-Jun;31(3):392-8.
5. Johnston TL, Schenker ML, Briggs KK, Philippon MJ.
Relationship between offset angle alpha and hip chondral injury in
femoroacetabular impingement. Arthroscopy. 2008 Jun;24(6):669-
75.
6. Philippon MJ, Schenker ML, Briggs KK, Maxwell RB. Can
microfracture produce repair tissue in acetabular chondral defects?
Arthroscopy. 2008 Jan;24(1):46-50.

176 174
24.1.2
Extended Abstracts
7. Tzaveas AP, Villar RN. Arthroscopic repair of acetabular chondral
delamination with fibrin adhesive. Hip Int. 2010 Jan-Mar;20(1):115-9.
ACI in the hip joint
J.B. 8. Lotto Richardson ML, Wright EJ, Appleby D, Zelicof SB, Lemos MJ, Lubowitz
Oswestry/United JH. Ex vivo comparison Kingdom of mechanical versus thermal chondroplasty:
assessment of tissue effect at the surgical endpoint. Arthroscopy.
Introduction: 2008 Apr;24(4):410-5. Autologous chondrocyte implantation (ACI) has been
used most commonly as a treatment for cartilage defects in the
knee 9. Edwards and there RB, are Lu few Y, Cole studies BJ, of Muir its use P, Markel in other MD. joints. Comparison Can ACI
work of radiofrequency in the hip? We have treatment used hip and arthroscopy mechanical for over debridement 15 years and of
identified fibrillated cartilage a significant in an proportion equine model. of patients Vet Comp with Orthop chondral Traumatol. defects
but 2008;21(1):41-8.
relatively normal radiology. Increasing use of hip arthroscopy
will identify more patients with localised chondral defects of both
the 10. Voss femoral JR, Lu head Y, Edwards and the RB, acetabulum. Bogdanske Can JJ, these Markel problems MD. Effects be
treated of thermal by autologous energy on chondrocyte implantation?
viability. Am J Vet Res. 2006
Oct;67(10):1708-12.
Content: Assessing chondral defects in the hip requires assessment
of 11. loss McIlwraith of function, CW, accurate Frisbie DD, mapping Rodkey of WG, size and Kisiday location JD, Werpy of defects, NM,
and Kawcak identification CE, Steadman of predisposinbg JR. Evaluation factors. of intra-articular These three mesenchymal
dimensions
are stem useful cells to for augment evaluation healing of any of joint microfractured with a chondral defect. defects. We
consider Arthroscopy. the 2011 development Nov;27(11):1552-61. of arthritis to be a process of loss of
function of the joint as an organ. Thus there is not one particular
point 12. Frisbie at which DD, a Oxford joint becomes JT, Southwood ‘arthritic’, L, but Trotter a gradual GW, process Rodkey that WG,
develops Steadman over JR, Goodnight time. Some JL, of McIlwraith this process CW. Early is pre-clinical events in and cartilage thus
joint repair narrowing after subchondral or osteophyte bone microfracture. formation often Clin develops Orthop Relat prior Res. to
symptoms. 2003 Feb;(407):215-27.
These pre-clinical features can be assessed by imaging,
but may not lead to treatment. We propose chondral defects to be part
of 13. this Steadman process, JR, and Rodkey also are WG, not Rodrigo always symptomatic. JJ. Microfracture: Indeed surgical many
heal technique with repair and rehabilitation tissue, as is seen to treat in a full chondral thickness defects. ACI harvest Clin Orthop site.
This Relat new Res. tissue 2001 Oct;(391 we propose Suppl):S362-9.
to call novocartilage. It is characterised
by being well attached to underlying bone, to have type 2 collagen
and 14. Steadman variable proteoglycan JR, Rodkey WG, content Briggs but KK. has Microfracture no ingrowth of to vessels treat full- or
nerves. thickness This chondral is a true defects: repair tissue surgical which technique, may remodell rehabilitation, to articular and
cartilage. outcomes. It J Knee may have Surg. differing 2002;15(3):170-6. amounts of hyaline characteristics
as assessed by polarised light microscopy. We believe this tissue is
an 15. end Milano in itself G, Sanna as is callus Passino healing E, Deriu a fracture L, Careddu en route G, to Manunta remodelled L,
bone. Manunta Renovocartilage A, Saccomanno may MF, be Fabbriciani sufficient for C. The purpose effect to of slsoow platelet joint rich
function plasma combined as callus can with be microfractures sufficient for purpose, on the treatment although of it chondral consists
of defects: woven an bone. experimental The scientist study may in seek a sheep regeneration model. of Osteoarthritis
the original
tissue, Cartilage. but 2010 the Jul;18(7):971-80.
clinician may be satisfied with a functioning repair
tissue. The process of organ failure that is seen as a chondral defect
of 16. the Gobbi knee A, may Karnatzikos be quantified G, Scotti by a C, self-assessed Mahajan V, Mazzucco score of L, function Grigolo for B.
the One-Step knee that Cartilage has been Repair weighted with Bone and Marrow validated Aspirate as an interval Concentrated score
(Smith Cells and et Collagen al., 2009). Matrix In the in hip Full-Thickness we advocate Knee a modified Cartilage Harris Lesions: Hip
score Results which at 2-years has allowed follow-up. evaluation Cartilage, of July 5000 2011;2(3):286-299
BHR hip resurfacings
(Khan et al, 2009). Mapping by a geometric projection allows the
arthoscopic 17. De Girolamo site L, to Bertolini be correlated G, Cervellin with the M, MRI Sozzi findings G, Volpi (Gokhale P. Treatment et al,
2008). of chondral Why develop defects biological of the knee repair with for the one hip? step Function matrix-assisted following
hip technique resurfacing enhanced or hip by replacement autologous can concentrated be excellent. bone This marrow: sets a high in
standard vitro characterisation for a biological of mesenchymal therapy. However stem cells the high from function iliac crest leads and
to subchondral wear and eventual bone. Injury. failure 2010 of Nov;41(11):1172-7.
most devices. Metal-polythene hip
replacements have had an excellent outcome in the older patient,
but 18. Haleem relatively A, high El Singergy failure rates A, Sabry of around D, Atta 12% H, Rashed by 10 years L, Chu in C, the El
under-50 Shewy M, year-olds. Azzam A, Higher Abdel rates Aziz of M. failure The Clinical in osteoarthritis Use of Human leave
only Culture–Expanded 50% surviving Autologous by 20 years. Bone A patient Marrow having Mesenchymal hip replacement Stem
for Cells osteoarthritis Transplanted at on the Platelet-Rich age of 30 is Fibrin likely to Glue have in the several Treatment revisions of
over Articular the next Cartilage 50 years, Defects: and each A Pilot revision Study is and marked Preliminary by loss of Results. bone.
Metal-on-metal Cartilage 2010;1(4):253-261.
bearings were re-introduced as a solution for hip
resurfacing and here for most designs have been very successful
in Acknowledgments:
the young active male patients. We have identified femoral head
size less than 46mm and female gender as pre-operative factors
that Catalina identify Larrain earlier M.D. failure of the implant. Stemmed metal-metal hip
designs may suffer from high local levels of metal debris as the trunion
is Alexander an additional Tomic source M.D. of metal debris. New ceramic designs and
cross-linked polythene containing vitamin E may provide improved
solutions Matías Salineros for the M.D. future, but all synthetic implants carry a risk of
infection that is difficult to eradicate. There is therefore an argument
for developing biological reconstructions that maintain bone stock
and avoid the problems of synthetic bearing surfaces. The cost
that can be supported can be considered not just the cost of a joint
replacement but the cost of a difficult revision post-phoned in later
life. This life-time perspective is similar for the hip, ankle and knee. A
surgeon’s perspective may focus on the duration of survival for each
implant, but the patient generally seeks high levels of function. This
supports a routine self-assessed measure of function of the affected
joint at every clinic with ‘hot-audit’ providing a chart for each patient
in the clinic. Renovo-cartilage: an end in itself? 1. Pain relief which
should be prolonged to 10 years 2. Improved function measured on
a self-assessment scale validated for chondral defects (Sith et al.,
2009) 3. Absence of secondary changes : a) osteophyte formation,
b) bone marrow oedema. 4. Preferably evidence of: a) Good
attachment to underlying bone b) Lateral integration c) Sufficient
thickness d) Low surface friction e) Resistance to fluid movement
In the hip the development of different patterns of cartilage loss is
24.2.1
not well documented. The femoral head and the acetabulum appear
to have separate patterns, and are usefully considered separately.
Cysts ICRS consensus are a difficult on animal problem models to successfully bone-graft in the
hip, M.B. presumably Hurtig because of the very high pressures that develop
under Guelph/Canada load compared to other joints. Bone loss can be addressed
in the femoral head by mosaicplasty combined with ACI. Avascular
necrosis Introduction: of the The femoral ICRS white head paper has been on recommendations treated by mesenchymal for use of
stem animal cell models insertion in cartilage in France, repair and in included Tromsoe, a Norway diverse group by ACI with alone. a
Our broad preferred knowledge technique of model has systems been the used use in their of a locale; plug of In autologous Japan and
bone most from of Europe the greater it is not trochanter, possible either to use 15mm dogs, or in 20mm the southwestern
in diameter.
This USA, plug central is shaped and South to fit the America normal healthy contour goats of the and femoral sheep head are
and readily then available, ACI performed while horses over the are easily top. We available have treated in some several parts
patients of the USA with and femoral Europe. head Using chondral an or iterative osteochondral consensus defects building of six
cm approach square agreement average area. was In achieved all cases about surgical the relative dislocation strengths of the and hip
was weaknesses necessary of for the surgery. model systems. We have observed some excellent results
(Akimau, 2006) but in our experience patients with cyst formation
do Also, not we respond found that as well. events Initially in the we orthopaedic used the ipsilateral industry was knee driving as a
source changes of in cartilage the research for culture environment. but in later Regulatory cases agency used the guidelines hip. The
normal are a moving knee target will have as higher symptoms standards for for several repair and months replacement following of
biopsy, articular but surfaces this does are imposed. not hinder Part the of rehabilitation this is due to of the the early hip. failure These
hips of prostheses have been which treated has between triggered 2 and government-led 10 years ago. investigations
Five patients
have and class progressed action to suits hip replacement in several countries. relatively quickly. Amalgamation We believe and
this restructuring is partly of due large to the pharmaceutical high levels and of pain-free biotechnology function companies that hip
replacement in the last few can years offer constitutes the younger a contraction patient. All of these the Research patients had and
cyst Development formation industry, pre-operatively triggering and concerns we therefore that there caution are against fewer
undertaking entities capable ACI in of the making presence the of multi-million cyst formation. dollar We investment do not believe to
it bring is technically a new product feasible to market. to perform Reduced sutured risk taking ACI in and the emphasis acetabulum on
by small open changes surgery. to existing The acetabulum products seems is however to be favored ideally strategies. treated by
arthroscopic ACI. Fontana et al reported in 2011 to have good results
with Content: arthroscopic Our mandate matrix was induced to establish autologous a consensus in 15 patients. for In animal their
study models 15 studies patients and with promote an average more logical 2cm acetabular research methods. defect had To do an
improvement this we initiated of over a review 40 points of models in the and Harris strategic Hip score steps with that a 6 led year to
follow-up. successful A registration similar group of new of patients therapies. treated Though with the debridement success of these had
no models significant was unassailable, improvement failures in symptoms. were equally This group instructive were because strongly
of they the demonstrated opinion that a non-sutured the need for matrix easily would overlooked not stay components
in place on a
defect of a successful of the femoral project head. including: In conclusion adequate it would integrative appear that repair, ACI is
a reliable possible fixation, option for accurate femoral clinically-relevant chondral and osteochondral imaging and defects interim by
open assessments procedure, in long and term arthroscopic studies ACI including a good arthroscopic option for acetabular biopsies,
defects. etc.. It was our hope that logical recommendations might stop the
wastefulness that has been pervasive in the cartilage R&D culture.
A good example of this is the still-widespread use of immature rabbits
References:
for cartilage repair experiments, which due to their brisk intrinsic
AKIMAU,
repair response
P, BHOSALE,
have little
A,
predictive
HARRISON,
value
P.E.
for
ROBERTS,
patients. Investors
S, MCCALL,
and
I.W.,
others
JB
outside
RICHARDSON,
our industry
J.B. ASHTON
could be easily
B.A. Autologous
misled by such
chondrocyte
studies.
implantation
Though many
with
examples
bone grafting
exist, Wakitani
for osteochondral
et al in 1994
defect
and Grande
due to
posttraumatic
et al (1995) demonstrated
osteonecrosis
that
of the
adherent
hip. Acta
cells
Orthopaedica.
from bone marrow
2006;
77
in collagen
(2): 333-336.
1 gel or polyglycolic acid could restore large defects
in the rabbit by 24 weeks. Recently, Chang (2011) demonstrated
GOKHALE
that empty
S,
PLGA
KHAN
scaffolds
M, KUIPER
with
JH,
continuous
RICHARDSON
passive
JB, DAVIES
motion
JP
were
An
arthroscopic
equally successful.
hip documentation
If near perfect
form
repair
Arthroscopy.
in rabbit cartilage
2008; 24
can
(7):
be
839
driven
– 842.
by number of conditions, rather than completely condemn
the use of laboratory animals, we adopted guidelines for maturity
KHAN that were M, EDWARDS not based D, on RICHARDSON chronological JB Birmingham age or skeletal Hip development.
Arthroplasty:
Five A fully to Eight mature Years “cartilage Prospective organ” Multicentre should contain: Centre zonal Results distribution Journal of
Arthroplasty. of chondrocytes, 2009; a 24(7): continuous 1044 – tidemark 1050. H J with SMITH, a calcified JB RICHARDSON, cartilage
A layer, TENNANT and regional Modification specialization and validation of biochemical of the Lysholm and biomechanical
Knee Scale
to properties. assess articular In the rabbit, cartilage Wei damage. and Messners Osteoarthritis (1995, 1997) and Cartilage. excellent
2009; work demonstrated 17:53-58. age-related repair in rabbits is substantially
different than larger species until rabbits are 8 months old. Thus,
Fontana, since most A., workers Bistolfi, are Crova, unable M., Rosso, or unwilling F., Massazza, to obtain G. rabbits Arthroscopic of this
Treatment age, the utility of of Hip this Chondral model system Defects: is limited Autologous to use as Chondrocyte
a screening
Transplantation tool in preliminary Versus studies. Simple Our Debridement—A society should encourage Pilot Study our peers,
reviewers and editors to combine preliminary studies in rabbits or
laboratory animals with a large animal study for publication.
Acknowledgments:
Due to the concern about durability and maturation of the repair
With tissue many or neocartilage, thanks to Brian long Ashton, term studies Paul Harrison, of a year Sally or more Roberts, in two Jan
Herman species are Kuiper, recommended. Iain McCall and Though all in Good the Oscell Laboratory team ()
Practices are
not absolutely required, most regulatory authorities require near-
GLP conditions with a gap analysis for cartilage repair studies. The
cost of such studies is substantial and time consuming, since larger
species require specialized care and housing conditions. Adequate
statistical power will require groups of 10 or more per variable
with equivalent controls. Bilateral treatments are not allowed in
many jurisdictions but have the advantage of controlling for interanimal
variability in repair response. Unilateral models provide
more opportunity for controlled weight bearing and assessment of
lameness. The consensus document reviews the evidence-based
medicine around use of the larger species since the mini-pig, sheep,
goat and horse have all contributed to new product registrations. The
thick cartilage of the horse, suitability for arthroscopic procedures
including interim biopsies, growing availability of biomarkers and
reagents and similarity to the cartilage volume of the human knee

have made this an attractive model for those who have specialized
facilities, trained personnel and approval from animal use
committees. Despite the relatively thin cartilage of the sheep and
goat, which makes fixation of scaffolds and retention of implanted
cells or tissue more difficult, experience and expertise can overcome
these obstacles. The incidence of subchondral cysts and persistent
remodeling after deep subchondral bone drilling or microfracture in
the sheep, goat and horse remains enigmatic and can interfere with
assessment of cartilage repair (Orth et al 2012). Unfortunately none
of the larger species can simulate the extremely thin subchondral
bone plate and low trabecular volume of the metaphysis in the
human knee.
The consensus document also contains comprehensive
recommendations for outcome measures. Though histology at
the time of sacrifice remains the gold standard of cartilage repair
studies, functional imaging at interim time points and biopsies to
allow biochemical, immunohistology and mechanical testing can
play important roles in long term studies.
The cost of bringing new cartilage repair products to market is
daunting and in our present world economy demands efficiencies.
The consensus document represents our current understanding
and should guide us away from wasteful inconclusive studies and
towards progress and regulatory approvals.
References:
Hurtig M, et al. Pre-clinical studies for cartilage repair:
Recommendations from the international cartilage repair society.
Cartilage 2011 2: 137-153.
Wakitani S, et al. Mesenchymal cell-based repair of large, fullthickness
defects of articular; cartilage. J Bone Joint Surg Am. 1994
Apr;76(4):579-92.
Grande DA, et al. Repair of articular cartilage defects using
mesenchymal stem cells. Tissue Eng. 1995;1(4):345-53.
Wei XC, et al. Maturation-dependent durability of spontaneous
cartilage repair in rabbit knee joint. J Biomed Mater Res. 1999;46:539-
548.
Wei XC, et al. Maturation-dependent repair of untreated
osteochondral defects in the rabbit knee joint. J Biomed Mater Res.
1997;34:63-72.
Orth P, et al. Effect of subchondral drilling on the microarchitecture
of subchondral bone: Analysis in a Large Animal Model at 6 Months.
Am J Sports Med.2012 Jan 5.
Acknowledgments:
Michael D. Buschmann, Lisa A. Fortier, Caroline D. Hoemann, Ernst B.
Hunziker, Jukka S. Jurvelin, Pierre Mainil-Varlet, C. Wayne McIlwraith,
Robert L. Sah, Robert A. Whiteside.
Extended Abstracts 177
24.2.2
Rabbit cartilage repair models: a review
C.D. Hoemann
Montreal/Canada
Introduction: The rabbit has both promising and limiting features as an
orthopedic model for cartilage repair. Rabbit articular cartilage is ~10x
thinner than human, and osteochondral defects repair quite rapidly,
~3 to 5-fold faster than large animals and humans. The fast repair
rate accelerates hypothesis testing and formulation screening, which
is economical, but potentially raises other challenges in scale-up to
large animals. Adolescent rabbits (3-6 months old) have a high rate of
spontaneous osteochondral repair. Acute defects in otherwise healthy
rabbits (and all other species) do not mimic the clinical condition where
cartilage lesions have variable cartilage degradation, subchondral bone
changes, chronicity, and concomitant factors (ACL/meniscal tear, knee
mal-alignment), in patients with variable health (BMI, age, smoking,
medications, prior trauma, osteoporosis, activity level) and mental
status (compliance, rehab). Yet since the 1970’s, significant progress has
been made in cartilage repair therapies through data generated in rabbit
models. This paper looks into the historical use of rabbit preclinical
models.
Content: Methods A literature review was carried out on rabbit cartilage
repair studies, with particular attention to models that supported the
use of new clinical treatments. Experiments dating from the 1970’s were
compared for rabbit age, number, method of surgical defect creation
and defect site, treatment used, timepoints analyzed, methodologies
used for quantitative outcome measures. Evolving methodologies
over the past 50 years were noted. Results In the 1970’s, rabbits were
a testing ground for analyzing surgical procedures already being used
in the clinic including drilling, shaving, and abrasion. Studies in rabbits
confirmed that partial thickness lesions fail to heal spontaneously,
that debridement alone is insufficient to stimulate cartilage repair,
and that subchondral drilling elicits a repair tissue that grew out of the
bone marrow, “resurfaced” the lesion and contained variable levels
of glycosaminoglycan 2-4. In 1975 it was first reported that a sutured
patch of ear-derived perichondrium with the cambium layer facing out
produced a cartilage-like tissue 4 to 8 weeks post-surgery in a rabbit
cartilage defect 5. In the early 1980’s biochemical assays showed that
bone marrow-derived tissue outgrowth is initially 60% collagen type
I and 40% collagen type II 6. Researchers began to experiment with
periosteal grafts, post-operative joint immobilization and continuous
passive motion (CPM) 7, 8. Some of these early rabbit studies
employed N=50 to hundreds of rabbits, sometimes with up to 20%
of operated rabbits having a serious adverse event (death, infection,
condylar fracture, patellar dislocation)6-8. In the late 80’s, the first
patient was treated with in vitro passaged autologous chondrocytes
injected below a periosteal graft (ACI) 9, and the first rabbit study
using autologous chondrocytes and a periosteal patch to treat patellar
defects was also published, with a 6-week endpoint 10. In the 1990’s
many studies were still using immature rabbits to analyze the effect
of periosteal grafts, ACI, bone marrow-derived mesenchymal stem
cells, fibrin glue, and various biomaterial and synthetic carriers11-14.
However, in osteochondral defects with no further treatment, a hyalinelike
tissue could be consistently elicited in 3-month old rabbits, and
much less frequently, in 8-month-old rabbits, up to 48 weeks postoperative
15. A time series of marrow-derived repair (3 mm diameter,
3 mm deep drill holes) showed that very good tissues developed at 4
to 8 weeks that subsequently degenerated at 1 year post-surgery16.
Occasional outliers with excellent repair at 1 year were also seen to
arise from drilling and no further treatment16. These observations are
very important because it suggests that if enough adolescent rabbits
are included in a study, with defects that penetrate the subchondral
bone, at least one excellent repair is likely to be observed, especially
if a biological treatment is ineffective or the implant is not retained.
The first quantitative histology scoring methods were developed in the
late 1980’s and 90’s and are still used today 8, 17. Early timepoints
to verify residency of delivered cells or tissues were still lacking. By
the 2000’s skeletal maturity began to be recognized as an important
feature for extrapolating to the human condition. Rabbit periosteum
was found to thin out and have a dramatic loss of stem cell precursors
with aging 18. In a rabbit model with free caged activity, the periosteal
patch was retained in most defects for 4 days but rarely after 7
days19. Many more scaffolds were being tested, as well as cytokines
and different cell sources 20-22. One-shot growth factor delivery
previously optimized in vitro with cultured cells was giving negative
results in vivo in some rabbit models23. Experiments with mini-pumps
to deliver recombinant human FGF2 to the synovial cavity in adolescent
rabbits showed promising early repair that was quite heterogeneous
24. Data began to hint at pragmatics involved in developing biologics
with rabbit preclinical models, where xenogenic formulations were
being tested with unknown cross-reactivity. Other scaffolds began

178 174
24.1.2
Extended Abstracts
to be used in the clinic (HYAFF, collagen matrices ChondroGuide and
MACI, PLGA acellular plugs, alginate, BST-CarGel, carbon fiber pads),
without ACI in the or hip with joint cells (ACI, characterized chondrocyte implantation or
CCI, J.B. Richardson
bone marrow-derived mesenchymal cells) and biologics (plateletrich
Oswestry/United plasma, PRP). Kingdom All of these treatments used rabbit models as their
testing ground10, 12-14, 20, 22, 25-28. In 2007, the FDA recognized
the Introduction: lack of regulation Autologous and emitted chondrocyte draft implantation guidelines that (ACI) are has now been final
for used preclinical most commonly models leading as a treatment to new cartilage for cartilage repair defects products, in and the
indicated knee and that there rabbits are few were studies useful of for its formulation use in other screening joints. Can 29, ACI 30.
Rabbit work in studies the hip? started We have using used micro-computed hip arthroscopy tomography for over 15 to years analyze and
subchondral identified a significant bone below proportion repairing rabbit of patients cartilage-bone with chondral defects defects 31-33
Since but relatively 2010, it normal was shown radiology. that augmented Increasing microfracture use of hip arthroscopy treatments
that will identify displace more chondrogenic patients foci with close localised to the chondral subchondral defects bone of plate both
give the femoral a better head hyaline and quality the acetabulum. of cartilage repair Can these tissue problems at later time be
points treated 34. by autologous Osteoclasts chondrocyte were implicated implantation? in marrow-derived cartilage
repair 35, and reasonable models of microfracture were attained in
mature Content: rabbits36. Assessing Geriatric chondral rabbits defects (24-months in the hip requires old) were assessment shown to
have of loss a of further function, dampened accurate response mapping to of marrow size and stimulation location of compared defects,
to and adult identification rabbits (12-months of predisposinbg old)35 factors. confirming These the three importance dimensions of
this are useful age dependence. for evaluation New of approaches any joint with to a stimulate chondral subchondral
defect. We
repair consider using the biologics, development different of arthritis cell types, to be and a new process solid of scaffolds loss of
and function carriers of the have joint been as tried. an organ. In response Thus there to the is FDA not guidelines, one particular the
ICRS point mandated at which a working joint becomes groups ‘arthritic’, to write recommendation but a gradual process papers that for
preclinical develops over models time. and Some histological of this outcome process measures is pre-clinical 37, 38. and These thus
recently joint narrowing published or guidelines osteophyte re-affirmed formation the often importance develops of prior skeletal to
maturity symptoms. in These preclinical pre-clinical models, features although can some be assessed teams are by still imaging, using
immature but may not rabbits. lead to Immature treatment. rabbits We propose could be chondral still potentially defects to useful be part in
some of this types process, of studies and also looking are not at acute always implant symptomatic. residency. Indeed Conclusions many
Rabbit heal with models repair are tissue, useful as for is seen proof-of-concept in a full thickness data and ACI as harvest a stepping site.
stone This new to large tissue animal we propose pivotal studies. to call novocartilage. The overlying recurrent It is characterised outcome
of by rabbit being studies well attached is the heterogeneous to underlying repair bone, response. to have type There 2 is collagen still no
clear and variable explanation proteoglycan for animal-to-animal content but variation. has no ingrowth Bilateral of models vessels with or
head-to-head nerves. This is comparison a true repair of treatment tissue which versus may control remodell defect to articular can use
fewer cartilage. animal It may numbers have due differing to higher amounts power of hyaline multivariate characteristics and paired
statistics. as assessed The by high polarised rate of light spontaneous microscopy. repair We in believe adolescent this tissue animals is
is an not end reproduced in itself as is in callus mature healing or geriatric a fracture rabbits. en Therefore, route to remodelled skeletally
mature bone. Renovocartilage animals (i.e., ≥7 may months be sufficient old) should for purpose be used to to slsoow screen joint the
efficacy function of as formulations callus can be whose sufficient indication for purpose, for use although is in adult it consists human
patients. of woven Standardized bone. The scientist surgical may defects seek and regeneration outcome measures of the original could
help tissue, facilitate but the objective clinician comparison may be satisfied between with studies a functioning and accelerate repair
progress tissue. The in the process field. of organ failure that is seen as a chondral defect
of the knee may be quantified by a self-assessed score of function for
the knee that has been weighted and validated as an interval score
References:
(Smith et al., 2009). In the hip we advocate a modified Harris Hip
score which has allowed evaluation of 5000 BHR hip resurfacings
1. (Khan Masoud et al, I, Shapiro 2009). F, Mapping Kent R, Moses by a geometric A. (1986) J. projection Orthop. Res. allows 4(2):221- the
231. arthoscopic site to be correlated with the MRI findings (Gokhale et al,
2008). Why develop biological repair for the hip? Function following
2. hip Mankin, resurfacing H. J. (1974) or hip N. replacement Engl. J. Med. 291:1285-1292
can be excellent. This sets a high
standard for a biological therapy. However the high function leads
3. to Meachim, wear and G., eventual and Roberts, failure C. (1971) of most J Anat devices. 109:317-327 Metal-polythene hip
replacements have had an excellent outcome in the older patient,
4. but Mitchell, relatively N., and high Shepard, failure N. rates (1976) of J. around Bone Joint 12% Surg. by - 10 Am. years 58:230-233 in the
5.Engkvist, under-50 year-olds. O., Johansson, Higher S. H., rates Ohlsen, of L., failure and Skoog, in osteoarthritis T. (1975) Scand. leave J.
Plast. only 50% Reconstr. surviving Surg. 9:203-206 by 20 years. A patient having hip replacement
for osteoarthritis at the age of 30 is likely to have several revisions
6. over Furukawa, the next T., 50 Eyre, years, D. and R., Koide, each S., revision and Glimcher, is marked M. by J. (1980) loss of J. bone. Bone
Joint Metal-on-metal Surg.- Am. 62:79-89 bearings were re-introduced as a solution for hip
resurfacing and here for most designs have been very successful
7. in Amiel, the young D., Coutts, active R. male D., Abel, patients. M., Stewart, We have W., Harwood, identified F., femoral and Akeson, head
W. size H. less (1985) than J. Bone 46mm Joint and Surg.- female Am. 67:911-920 gender as pre-operative factors
that identify earlier failure of the implant. Stemmed metal-metal hip
8. designs O’Driscoll, may S. suffer W., Keeley, from high F. W., local and levels Salter, of R. metal B. (1988) debris J. Bone as the Joint trunion Surg.-
Am. is an 70:595-606 additional source of metal debris. New ceramic designs and
cross-linked polythene containing vitamin E may provide improved
9. solutions Brittberg, for M., the Lindahl, future, A., but Nilsson, all synthetic A., Ohlsson, implants C., Isaksson, carry a O., risk and of
Peterson, infection that L. (1994) is difficult N. Engl. to J. eradicate. Med. 331:889-895 There is therefore an argument
for developing biological reconstructions that maintain bone stock
10. and Grande, avoid D. the A., problems Pitman, M. of I., synthetic Peterson, bearing L., Menche, surfaces. D., and The Klein, cost M.
(1989) that can J. Orthop. be supported Res. 7:208-218 can be considered not just the cost of a joint
replacement but the cost of a difficult revision post-phoned in later
11. life. Moran, This life-time M. E., Kim, perspective H. K. W., and is Salter, similar R. for B. (1992) the hip, J. Bone ankle Joint and Surg.-Br. knee. A
7:659-667 surgeon’s perspective may focus on the duration of survival for each
implant, but the patient generally seeks high levels of function. This
12. supports Wakitani, a routine S., Goto, self-assessed T., Pineda, S. J., measure Young, R. of G., function Mansour, of the J. M., affected Caplan,
A. joint I., and at every Goldberg, clinic V. with M. (1994) ‘hot-audit’ J. Bone providing Joint Surg.- a chart Am. 76A:579-592
for each patient
in the clinic. Renovo-cartilage: an end in itself? 1. Pain relief which
13. should Brittberg, be prolonged M., Nilsson, to 10 A., years Lindahl, 2. Improved A., Ohlsson, function C., and measured Peterson, on L.
(1996) a self-assessment Clin. Orthop. & scale Rel. Res., validated 326:270-283 for chondral defects (Sith et al.,
2009) 3. Absence of secondary changes : a) osteophyte formation,
14. b) Freed, bone L. marrow E., Marquis, oedema. J. C., Nohria, 4. Preferably A., Emmanual, evidence J., Mikos, of: A. a) G., Good and
Langer, attachment R. (1993) to underlying J. Biomed. Mater. bone Res. b) Lateral 27:11-23 integration c) Sufficient
thickness d) Low surface friction e) Resistance to fluid movement
15. In the Wei, hip X. C., the and development Messner, K. (1999) of different J. Biomed. patterns Mater. of Res. cartilage 46:539-548 loss is
not 16. Shapiro, well documented. F., Koide, S., The and femoral Glimcher, head M. J. (1993) and the J. Bone acetabulum Joint Surg. appear - Am.
to 75A:532-553 have separate patterns, and are usefully considered separately.
Cysts are a difficult problem to successfully bone-graft in the
hip, 17. Pineda, presumably S., Pollack, because A., Stevenson, of the very S., high Goldberg, pressures V., and that Caplan, develop A.
under (1992) Acta load Anatomica compared 143:335-340 to other joints. Bone loss can be addressed
in the femoral head by mosaicplasty combined with ACI. Avascular
necrosis 18. O’Driscoll, of the S. W. femoral M., Saris, head D. B. has F., Ito, been Y., and treated Fitzimmons, by mesenchymal
J. S. (2001) J.
stem Orthop. cell Res. insertion 19:95-103 in France, and in Tromsoe, Norway by ACI alone.
Our preferred technique has been the use of a plug of autologous
bone 19. Aroen, from A., the Heir, greater S., Loken, trochanter, S., Reinholt, either F. 15mm P., and or Engebretsen, 20mm in diameter. L. (2005)
This Acta Orthopaedica plug is shaped 76:220-224 to fit the normal contour of the femoral head
and then ACI performed over the top. We have treated several
patients 20. Grigolo, with B., femoral Roseti, L., head Fiorini, chondral M., Fini, or M., osteochondral Giavaresi, G., Nicoli defects Aldini, of six N.,
cm Giardino, square R., average and Facchini, area. A. In (2001) all cases Biomaterials surgical 22:2417-2424
dislocation of the hip
was necessary for surgery. We have observed some excellent results
(Akimau, 21. Hoemann, 2006) C. D., but Sun, in our J., Legare, experience A., McKee, patients M. D., with and cyst Buschmann, formation M.
do D. (2005) not respond Osteoarthritis as well. Cartilage Initially 13:318-329 we used the ipsilateral knee as a
source of cartilage for culture but in later cases used the hip. The
normal 22. Hoemann, knee C. will D., have Sun, J., symptoms McKee, M. for D., Chevrier, several A., months Rossomacha, following E.,
biopsy, Rivard, G. but E., this Hurtig, does M., not and hinder Buschmann, the rehabilitation M. D. (2007) of the Osteoarthritis hip. These
hips Cartilage have 15:78-89 been treated between 2 and 10 years ago. Five patients
have progressed to hip replacement relatively quickly. We believe
this 23. Holland, is partly T. A., due Bodde, to the E. W. high H., Cuijpers, levels of V. pain-free M. J. I., Baggett, function L. S., that Tabata, hip
replacement Y., Mikos, A. G., can and offer Jansen, the younger J. A. (2007) patient. Osteoarthritis All these Cartilage patients 15:187- had
cyst 197 formation pre-operatively and we therefore caution against
undertaking ACI in the presence of cyst formation. We do not believe
it
24.
is
Yamamoto,
technically
T.,
feasible
Wakitani,
to
S.,
perform
Imoto, K.,
sutured
Hattori,
ACI
T., Nakaya,
in the acetabulum
H., Saito, M.,
by
and
open
Yonenobu,
surgery.
K. (2004)
The
Osteoarthritis
acetabulum
Cartilage
is however
12:636-641
ideally treated by
arthroscopic ACI. Fontana et al reported in 2011 to have good results
with
25. Solchaga,
arthroscopic
L. A., Temenoff,
matrix induced
J. S., Gao,
autologous
J. Z., Mikos,
in
A.
15
G.,
patients.
Caplan, A.
In
I.,
their
and
study
Goldberg,
15
V.
patients
M. (2005)
with
Osteoarthritis
an average
Cartilage
2cm acetabular
13:297-309
defect had an
improvement
26. Fragonas, E.,
of over
Valente,
40 points
M., Pozzi-Mucelli,
in the Harris
M.,
Hip
Toffanin,
score with
R., Rizzo,
a 6 year
R.,
follow-up.
Silvestri, F.,
A
and
similar
Vittur,
group
F. (2000)
of patients
Biomaterials
treated
21:795-801
with debridement had
no significant improvement in symptoms. This group were strongly
of 27. the Willers, opinion C., that Chen, a non-sutured J., Wood, D., matrix and would Zheng, not M. stay H. (2005) in place Tissue on a
defect Engineering of the 11:1065-1076 femoral head. In conclusion it would appear that ACI is
a possible option for femoral chondral and osteochondral defects by
open 28. Marchand, procedure, C., Chen, and arthroscopic G., Tran-Khan, ACI N., a Sun, good J., option Chen, H., for Buschmann, acetabular
defects. M. D., and Hoemann, C. D. Tissue Engineering, Pt A (in press)
29. FDA, U. S. A. (2007) Guidance for Industry: Preparation of IDEs and
References:
INDs for Products Intended to Repair or Replace Knee Cartilage. Draft
Guidance (ed., CBER, U.S. Department of Health and Human Services),
AKIMAU, Rockville, MD P, BHOSALE, A, HARRISON, P.E. ROBERTS, S, MCCALL,
I.W., JB RICHARDSON, J.B. ASHTON B.A. Autologous chondrocyte
implantation 30. FDA, U. S. A. with (2011) bone Guidance grafting for Industry: for osteochondral Preparation of defect IDEs and due INDs to
posttraumatic for Products Intended osteonecrosis to Repair or of Replace the hip. Knee Acta Cartilage. Orthopaedica. (ed., CBER, 2006; U.S.
77 Department (2): 333-336. of Health and Human Services), Rockville, MD
GOKHALE 31. Maehara, S, H., KHAN Sotome, M, KUIPER S., Yoshii, JH, T., RICHARDSON Torigoe, I., Kawasaki, JB, DAVIES Y., Sugata, JP An
arthroscopic Y., Yuasa, M., Hirano, hip documentation M., Mochizuki, form N., Kikuchi, Arthroscopy. M., Shinomiya, 2008; 24 K., and (7):
839 Okawa, – 842. A. (2010) J. Orthop. Res. 28:677-686
KHAN 32. Chen, M, EDWARDS H. M., Sun, D, J., RICHARDSON Hoemann, C. JB D., Birmingham Lascau-Coman, Hip Arthroplasty:
V., Wei, O. Y.,
Five McKee, to Eight M. D., Years Shive, Prospective M. S., and Buschmann, Multicentre M. Centre D. (2009) Results J. Orthop. Journal Res. of
Arthroplasty. 27:1432-1438 2009; 24(7): 1044 – 1050. H J SMITH, JB RICHARDSON,
A TENNANT Modification and validation of the Lysholm Knee Scale
to 33. assess Marchand, articular C., Chen, cartilage H. M., damage. Buschmann, Osteoarthritis M. D., and Hoemann, and Cartilage. C. D.
2009; (2011) Tissue 17:53-58. Engineering Part C-Methods 17:475-484
Fontana, 34. Chevrier, A., Bistolfi, A., Hoemann, Crova, C. M., D., Rosso, Sun, J., F., and Massazza, Buschmann, G. Arthroscopic
M. D. (2011)
Treatment Osteoarthritis of Cartilage Hip Chondral 19:136-144 Defects: Autologous Chondrocyte
Transplantation Versus Simple Debridement—A Pilot Study
35. Chen, G., Sun, J., Lascau-Coman, V., Chevrier, A., Marchand, C., and
Hoemann, C. D. (2011) Cartilage 2:173-185
Acknowledgments:
36. Chen, H., Hoemann, C. D., Sun, J., Chevrier, A., McKee, M. D., Shive, M.
With S., Hurtig, many M., thanks and Buschmann, to Brian Ashton, M. D. (2011) Paul J. Harrison, Orthop. Res. Sally 29:1178-1184 Roberts, Jan
Herman Kuiper, Iain McCall and all in the Oscell team ()
37. Hoemann, C. D., Kandel, R., Roberts, S., Saris, D. B. F., Creemers, L.,
Mainil-Varlet, P., Methot, S., Hollander, A. P., and Buschmann, M. D. (2011)
Cartilage 2:153-172
38. Hurtig, M. B., Buschmann, M. D., Fortier, L. A., Hoemann, C. D.,
Hunziker, E. B., Jurvelin, J. S., Mainil-Varlet, P., McIlwraith, C. W., Sah, R. L.,
and Whiteside, R. A. (2011) Cartilage 2:137-152
Acknowledgments:
Salary support is acknowledged from the Fonds de la Recherche sur la
Santé du Quebec. I’d like to thank Julie Tremblay for helping retrieve
articles and Michael Buschmann for critical reading of the paper.

24.2.3
Equine models: a review
D.D. Frisbie, W. Mcilwraith
Fort Collins/United States of America
Introduction: Articular cartilage injuries of the knee and ankle are
common and a number of different methods have been developed
in an attempt to improve their repair. There are two clinical aims of
cartilage repair the first, restoration of joint function and the second,
prevention or at least delay of the onset of osteoarthritis. These goals
can potentially be achieved through replacement of damaged or lost
articular cartilage with tissue capable of functioning under normal
physiological environments for an extended period. Further, it may not
require the return or restoration of the original tissue, a goal that has
eluded researchers and clinicians.1
Content: The ability to screen novel procedures for human clinical use
is done by preclinical studies using animal models. While a multitude
of models exists, this abstract will focus on the horse as a model
describing current techniques as well as the horses advantages and
disadvantages. The majority of equine cartilage resurfacing models
have been focused on the equine knee or “stifle” as it is commonly
called. The anatomy is similar to the human with the exception of
three patellar ligaments instead of one. Comparative studies have
demonstrated that the horse has articular cartilage of similar thickness
to that in the human knee, in fact much closer than other species
commonly used in preclinical trials.2 Further, this joint in the horse
is commonly clinically affected with cartilage lesions allowing equine
clinicians experience with not only research but clinical outcomes
as well; these experiences can aid in the interpretation of preclinical
data. This clinical disease in the horse also provides similar diagnostic,
surgical and follow-up methods as those utilized in many human
preclinical and clinical trails. Other species used in preclinical trials
do not have a similar clinically recognized cartilage disease process.
Defect models in the femoropatellar, femorotibial, and tibiotalar joints
have been developed. Work in defining the critical sized defect in the
stifle has also been advantageous to the use of the horse. A minimum
9mm diameter defect has been determined to be a critical size in
the equine stifle.3 Many studies have used a 15mm diameter defect,
which represent a clinically relevant size in the human knee. The ability
to differentially determine the calcified cartilage and subchondral
bone plate have allowed further refinement of defect creation both
through open and arthroscopic methods. The thickness of the articular
cartilage also allows the reliable suturing of membranes or constructs
to cartilage surrounding the defect. The size of the equine joint allows
multiple defects to be placed in the same joint increasing the defect
numbers without additional animals being needed. As mentioned
previously defects can be created and treated either using an
arthrotomy or arthroscopically. This can be an advantage in replicating
the final human application. A distinct disadvantage of the horse is
the ability to provide compression bandaging of the stifle area as is
often done in human patients. In addition, another disadvantage is the
lack of a non-weight bearing period post-operatively. The latter issue
can be over come based on defect location. More specifically, defects
in the more distal region of the joint surface will only be loaded in
more intense exercise which can be controlled based on housing and
exercise protocols. For example a defect can be non-weight bearing for
the most part if a distal location is chosen and the horse is confined in
a stall or small area. The defect can then be reliably loaded by using a
high-speed treadmill to control the exercise speed and duration. The
number of horses can be kept to a minimum in many cases by using the
horse as its own control as well as evaluating the outcomes at various
time points (i.e., second look arthroscopies or biopsy). Performing a
repair procedure in one limb can do this and using the opposite limb
as a control or having two defects in the same joint allowing for the
investigator to use statistical evaluations that account for inter-patient
variability therefore, fewer animals are required to achieve sufficient
power. The extensive number of outcome parameters that can be
utilized is a significant strength of using the equine model. Because
of the relatively large size of defects that can be made in the horse,
more outcome parameters can be measured on each repair response
than is possible in other animal models. Potential assessments include
clinical examination for lameness and synovial effusion as well as
response to flexion; pretreatment and post-treatment radiographs;
MRI; synovial fluid and serum biomarkers; routine synovial fluid
analysis; sequential arthroscopies; optical coherence tomography;
gross postmortem examination; histopathological, histochemical,
and immunohistological analyses; biochemical analysis for type II
collagen/type I collagen as well as aggrecan and glycosaminoglycan
content; real-time quantitative PCR evaluation for mRNA expression
in the tissue; and biomechanical evaluation. Several studies in which
biopsies were taken of repair tissue at 4 or 6 months have indicated no
detrimental long-term implications for the repair tissue from biopsies.
Extended Abstracts 179
There is no perfect model for objectively evaluating the repair in
human articular cartilage defects. However, the need for preclinical
studies using animal models in evaluating a new technique for repair
is important and mandated by licensing bodies. The authors believe
that there has been a positive evolution of model selection from it
being based on cost and convenience to more critically evaluating how
well an animal model simulates the human situation. It is recognized
that some laboratories are content with small animal models and
that these models will continue to be used. On the other hand, it
needs to be recognized that complete removal of calcified cartilage
with retention of a subchondral bone plate is important to model the
human clinical scenario, and this is not possible in some smaller animal
models. The horse is a large animal and requires special animal care
capabilities as well as expertise. However, because of the ability to do
follow-up arthroscopic evaluations, the increased amount of tissue
for evaluation, and the fewer number of animals to have sufficient
statistical power, the costs are necessarily disparate from studies
with smaller laboratory animals. It is also important to recognize the
need for long-term studies because of experience with failure between
8 and 12 months, both in quality of the tissue as well as integration.
It should also be remembered that one should strive for the closest
approximation between preclinical research results in a given model
and its extrapolation to the human situation and that the horse itself is
also an end-goal animal for potential therapeutic cartilage repair.
References:
1. McIlwraith CW, Fortier LA, Frisbie DD, Nixon AJ. Equine models of articular
cartilage repair. Cartilage 2011;2:317-326.
2. Frisbie DD, Cross MW, McIlwraith CW. A comparative study of articular
cartilage thickness in the stifle of animal species used in human pre-clinical
studies compared to articular cartilage thickness in the human knee. Vet
Comp Orthop Traumatol 2006;19:142-6.
3. Hurtig MB, Fretz PB, Doige CE, Schnurr DL. Effects of lesions size and
location on equine articular cartilage repair. Can J Vet Res. 1988;52:137-46.
24.3.1
Does unloading of joint surfaces affect cartilage healing in
patients with end-stage ankle osteoarthritis; an overview of the
literature
A.N. Amendola 1 , M. Nguyen 1 , C. Saltzman 2
1 Iowa City/United States of America, 2 Salt Lake City, Ut/United
States of America
Introduction: End stage osteoarthritis (OA) is a debilitating disease
which causes pain, stiffness and hinders mobility in all joints. In
contrast to hip and knee osteoarthritis which is of primary origin
in middle aged and elderly individuals, ankle osteoarthritis is
usually occurs secondary to trauma, affecting mainly in a younger
population (1). Post traumatic ankle osteoarthritis is the most
common form of ankle OA, progressive and usually leads surgical
methods of management (2-5). However, research related to
optimizing treatment of ankle osteoarthritis remains limited. Ankle
fusion and total ankle replacement have been the mainstays of
treatment for end stage osteoarthritis of the ankle, but both of these
options have significant limitations (6-12). Recently, joint distraction
has emerged as a promising treatment for ankle osteoarthritis.
Unlike fusion or replacement surgery, distraction does not “burn
any bridges” and patients who fail ankle distraction can still later be
eligible for arthrodesis or total ankle arthroplasty. Studies utilizing
thin wire and small pin external fixators including retrospective
and prospective studies from the Netherlands and recently, the
United States have demonstrated significant short term follow-up
improvements for patients following joint distraction surgery. Long
term follow-up outcomes, however are largely unknown (13-18).
Adjunctive measures such as early range of motion to improve ankle
distraction efficacy, are also under investigation.
Content: Overview of the Literature: Osteoarthritis and Distraction
The use of distraction to treat painful arthritis of the ankle was first
introduced by Judet and Judet in 1978 (20). Sixteen patients with painful
ankle arthritis had hinged ankle distraction (4-8 mm of distraction with
motion for 6-12 weeks). At a mean follow up of 16 months, thirteen
were retrospectively reported to have improved symptoms, and eight
had restoration of unlimited walking ability. A subsequent study of
patients with hip arthrosis showed that articulated distraction of the
hip yielded good results in 42 of 59 (71%) patients who were younger
than 45 years but poor results in patients older than 45 years and

180
Extended Abstracts
in patients with inflammatory arthritis (19). The treatment of ankle
OA with distraction, using thin wire external fixators, has been
reported in both retrospective and prospective clinical series from
the Netherlands (13-19). Van Valburg et al. documented that ankle
distraction resulted in intermittently fluctuating joint hydrostatic
pressures, (17) and that similar fluctuations in vitro resulted in
increased proteoglycan synthesis in osteoarthritic cartilage (16-17). A
study of ankle distraction in 11 patients with post-traumatic arthritis
showed that all patients had less pain at follow-up of 20 months (13).
Persistent ankle swelling and crepitus has been noted after removal
of the external fixator, but average function improved after 1 year after
surgery. In a more recent prospective study of 57 patients followed
for an average of 2.8 years after ankle distraction, significant clinical
improvement was noted in three fourths of the patients, improvement
increased over time, and joint distraction had significantly better
results than ankle joint debridement alone (22). A subsequent review
by the same researchers at minimum 7 years of follow-up evaluation
after ankle distraction for osteoarthritis showed that 16 of 22 (73%)
patients had significant improvement of all clinical parameters and
6 (27%) patients had failed treatment (18). Following these early
papers others have published on the outcome of distraction. Tellisi
et al. completed a retrospective review of 25 patients, in which they
found improvement of AOFAS score and SF-36 at 30 month f/u and
satisfactory results in 91% of the patients (24). Others have reported
on their clinical experience as well (22,23,26) in limited numbers with
similar outcomes. Distraction and joint Changes There is also effort
of characterizing changes following ankle distraction using imaging.
Lamm et al. conducted a preliminary MRI study to characterize joint
changes following distraction (26). In more in-depth studies, Intema
et al. reported on the subchondral bone changes using CT in 26
patients treated with distraction with and without motion. While
overall density decreased, density in cystic lesions actually increased
(normalization of bone density). In addition, a correlation was found
between clinical improvement and the resolution of subchondral
bone cysts (25). In a subsequent study (27) on knee distraction,
at one year demonstrated increase in joint space, MRI increase in
cartilage thickness, increased synthesis of collagen type 2, improved
function and decreased pain. This was reported recently at the AAOS
2012 at 2 year follow up. Joint Motion and Distraction Joint motion has
been accepted as an essential adjunctive component in the biological
restoration of articular cartilage from injury. This has largely followed
from previous clinical and experimental studies that confirmed the
deleterious effects of prolonged immobilization on musculoskeletal
tissues, including cartilage. The only study assessing the effect of
motion with distraction in a clinical study is currently accepted for
publication (28). A prospective RCT was carried out comparing
motion with distraction versus distraction alone for a 3 month
period. Thirty-six patients were followed for a minimum of 2 years.
Results demonstrated significant improvement in pain and function
in both groups, but greater improvement in the motion group (28).
Distraction and Cartilage Regeneration In terms of regenerating
cartilage in clinical patients with ankle OA, very little direct published
information is available. In a rabbit model with articular injury,
some direct evidence exists for cartilage healing with the effect of
distraction. Kajiwara et al. demonstrated in a rabbit model that with
a combination of subchondral drilling, joint motion and distraction by
an articulated external fixator, repair of a fresh osteochondral defect
in the weight bearing area occurred. Although distraction for 4 weeks
was not a long enough period to repair the defect, distraction for 8
and 12 weeks resulted in a good outcome (29). Nishino et al. applied
joint distraction and motion to rabbit model articular defect, and with
graduated loading improved regeneration of cartilage (30).
References:
1. Saltzman CL, Kamp J, Cook TA. The leather ankle lacer. Iowa Orthop
J. 1995; 15: 204-8.
2. Pagenstert GI, Hinterman B, Barg A, Leuman A, Valderrabano V.
Realignment surgery as alternative treatment of varus and valgus ankle
osteoarthritis. Clin Orthop Relat Res. 2007; 462:156-68.
3. Takakura Y, Tanaka Y, Kumai T, Tamai S. Low tibial osteotomy for
osteoarthritis of the ankle. Results of a new operation in 18 patients. J
Bone Joint Surg Br. 1995; 77(1): 50-4.
4. Tanaka Y, Takakura Y, Hayashi K. Taniguchi A, Kumai T, Sugimoto K.
Low tibial osteotomy for varus-type osteoarthritis of the ankle. J Bone
Joint Surg Br. 2006; 88(7): 909-13.
5. Baltzer AW, Arnold JP. Bone-cartilage transplantation from the
ipsilateral knee for chondral lesions of the talus. Arthroscopy. 2005;
21(2):159-66.
6. Glazebrook MA, Arsenault K, Dunbar M. Evidence-based classification
of complications in total ankle arthroplasty. Foot Ankle Int. 2009;
30(10):945-9.
7. Haddad SL, Coetzee JC, Estok R, Fahrbach K, Banel D, Nalysnyk L.
Intermediate and long-term outcomes of total ankle arthroplasty and
ankle arthrodesis. A systematic review of the literature. J Bone Joint
Surg Am. 2007; 89(9):1899-905.
8. Saltzman CL, Amendola A, Anderson R, Coetzee JC, Gall RJ, Haddad
SL, Herbst S, Lian G, Sanders RW, Scioli M, Younger AS. Surgeon
training and complications in total ankle arthroplasty. Foot Ankle Int.
2003; 24(6):514-8.
9. Coester LM, Saltzman CL, Leupold J, Pontarelli W.. Long-term results
following ankle arthrodesis for post-traumatic arthritis. J Bone Joint
Surg Am. 2001; 83-A(2):219-28.
10. Lee KB, Cho SG, Hur CL, Yoon TR. Perioperative complications of
HINTEGRA total ankle replacement: Our initial 50 cases. Foot Ankle Int.
2008; 29(10):978-84.
11. Spirt AA, Assal M, Hansen Jr. ST. Complications and failure after total
ankle arthroplasty. J Bone Joint Surg Am. 2004; 86-A(6):1172-8.
12. Morrey BF, Wiedeman, Jr GP. Complications and long-term results
of ankle arthrodeses following trauma. J Bone Joint Surg Am. 1980;
62(5):777-84.
13. van Valburg AA, vanRoermund PM, Lammens J, VanMelkebeek J,
Verbout AJ, Lafeber EP, Bijlsma JW. Can Ilizarov joint distraction delay
the need for an arthrodesis of the ankle? A preliminary report. J Bone
Joint Surg Br. 1995; 77(5):720-5.
14. van Roermund PM, Lafeber FP. Joint distraction as treatment for
ankle osteoarthritis. Instr Course Lect. 1999; 48:249-54.
15. Marijnissen AC, Vincken KL, Viergever MA, vanRoy HL, VanRoermund
PMLefeber FP, Bijlsma JW. Ankle images digital analysis (AIDA): Digital
measurement of joint space width and subchondral sclerosis on
standard radiographs. Osteoarthritis Cartilage. 2001; 9(3):264-72.
16. Marijinssen AC. Osteoarthritis and joint distraction: Models,
mechanisms and long-term effects. PhD Thesis, Rheumatology
and Cinical Immunology, University Medical Center, Utrecht, The
Netherlands, 2001.
17. van Valburg AA, van Roy HL, Lafeber FP, Bijlsma JW. Beneficial
effects of intermittent fluid pressure of low physiological magnitude
on cartilage and inflammation in osteoarthritis. An in vitro study. J
Rheumatol. 1998; 25(3):515-20.
18. Ploegmakers JJ, vanRoemund RP, van Melkebeek J, Lammens J,
Bijlsma JW, Lafeber FP, Marijnissen AC. Prolonged clinical benefit from
joint distraction in the treatment of ankle osteoarthritis. Osteoarthritis
Cartilage. 2005; 13(7):582-8.
19. Aldegheri, R.; Trivella, G.; and Saleh, M.: Articulated distraction
of the hip. Conservative surgery for arthritis in young patients. Clin
Orthop. 1994; 301:94-101.
20. Judet R, Judet T. The use of a hinge distraction apparatus after
arthrolysis and arthroplasty (author’s transl). Rev Chir Orthop
Reparatrice Appar Mot. 1978; 64(5):353-65.
21. Marijnissen AC, Van Roermund PM, Van Melkebeek J, et al. Clinical
benefit of joint distraction in the treatment of severe osteoarthritis
of the ankle: Proof of concept in an open prospective study and in a
randomized controlled study. Arthritis Rheum. 2002; 46:2893-2902.
22. Paley D, Lamm BM. Ankle joint distraction. Foot Ankle Clin. 2005;
10(4):685-98, ix.
23. Paley D, et al. Distraction arthroplasty of the ankle--how far can you
stretch the indications? Foot Ankle Clin. 2008; 13(3):471-84, ix.
24. Tellisi N, et al. Joint preservation of the osteoarthritic ankle using
distraction arthroplasty. Foot Ankle Int. 2009; 30(4):318-25.
25. Intema F, et al. Subchondral bone remodeling is related to
clinical improvement after joint distraction in the treatment of ankle
osteoarthritis. Osteoarthritis Cartilage. 2011; 19(6):668-75.
26. Lamm BM, Gourdine-Shaw M. MRI evaluation of ankle distraction:
A preliminary report. Clin Podiatr Med Surg. 2009; 26(2):185-91.
27. Intema F, et al. Tissue structure modification in knee osteoarthritis
by use of joint distraction: An open 1-year pilot study. Ann Rheum Dis.
2011; 70(8):1441-6.
28. Saltzman CL, et al. Prospective randomized controlled trial of motion
vs. distraction in the treatment of ankle OA. Accepted for Publication, J
Bone Joint Surg Am. 2012 (in Print).
29. Kajiwara R, Ishida O, Kawasaki K, Adachi N, Yasunaga Y, Ochi M.
Effective repair of a fresh osteochondral defect in the rabbit knee joint
by articulated joint distraction following subchondral drilling. J Orthop
Res. 2005; 23:909-915.
30. Nishino T, Ishii T, Chang F, Yanai T, Watanabe A, Ogawa T, Mishima
H, Nakai K, Ochiai N. Effect of gradual weight-bearing on regenerated
articular cartilage after joint distraction and motion in a rabbit model. J
Orthop Res. 2010; 28(5):600-6.

24.3.2
Cartilage and subchondral bone repair by joint distraction in
clinical and experimental models of joint degeneration
P.M. Van Roermund
Utrecht/Netherlands
Introduction: Osteoarthritis is a progressive disabling joint disease and is
accompanied by stiffness, crepitus and swelling of the joint. Characteristic
changes in the structure of the joint are damage in the articular cartilage,
changes in the subchondral bone structure, osteophyte formation, and
synovial inflammation. Untill now, the multi factorial etiology and pathophysiology
of such changes in OA are still unclear making osteoarthritis
to a disease that still cannot be cured. Traditional options of treatment
involve joint arthroplasty or arthrodesis meaning that patients will not
only loose the pain but also their joint. Especially in young patients,
long term effects following arthroplasty and arthrodesis may have
deleterious effects such are the need for repeated revision surgery and the
development of osteoarthritis in adjacent joints. Joint distraction is based
on the assumption that mechanical unloading of the damaged articular
surfaces in combination with intermittent intra-articular fluid pressures ma
y stimulate cartilage- and subchondral bone repair. Therefore, distraction,
or arthrodiastasis of an OA ankle joint or knee joint has being used as a
joint salvage procedure for the patient in whom fusion or joint replacement
is not appropriate.
Content: Van Valburg et al reported 1the first results of OA ankle joint
distraction using a distraction period of three months. Acceptance of this
technique is increasing 2-6. Although the mechanism of action remains
unknown, clinical studies, although limited, have resulted in significant
patient benefit in the short-term and long-term treatment of arthritis in
the ankle joint. 2-7 . Encouraging short term effects have been reported
also following distraction of severely painful OA knee joints in relatively
young patients8. Studying the possible mechanisms of joint distraction
requires structural parameters representing the changes in the cartilage
and peri -articular bone. Radiographs during joint loading and measuring
the distance between the two cartilage-bone interfaces still serve as the
gold standard to demonstrate indirectly (diminishing) cartilage thickness.
An increase in joint space width has been found in a number of patients
following distraction of an OA ankle joint 9 or an OA knee joints 8 Radiographs
demonstrate also structural changes in surface geometry and subchondral
sclerosis before, during and following joint distraction of OA ankle 10 and
knee joints. 8 A decrease in peri-articular bone density have been found in
high density areas following OA ankle joint distraction 9 using standardized
radiographs in the AIDA (Ankle Images Digital Analysis) method. Similar
findings have been reported after OA knee joint distraction using the KIDA
(knee Images Digital Analysis) method .8 In addition, serial standardized
CT measurements of OA ankle joints s after distraction showed an increase
in density in cystic regions near the joint which strongly correlated with
clinical improvement in pain and disability. 8 MRI is able to quantify cartilage
and to show changes in its morphology, volume and even composition. 18
Following a two months OA knee joint distraction period, MRI revealed a
significant increase in cartilage thickness and a decrease of denuded bone
areas8. Biomarker levels showed a trend towards increased collagen type
II synthesis and a decreased breakdown. 8Further studies are needed
to evaluate the exact value of MRI measurements. Unfortunately, actual
repair of articular cartilage remains difficult to study in humans. Several
models of inducing OA in canine or rabbit knee joints with subsequent
distraction have been developed in literature such are by ACL transsection
11, or in combination with total meniscectomy,12 papain injection13, , or
by making osteochondral defect in the femur 14or tibia15, or by damaging
the weigth bearing cartilage of both femoral condyles: the groove model.
16. The characteristics of the experimentally induced canine knee joint OA
in ACLT/ medial meniscectomy - and Groove model reflect greatly those
of human OA making these models suitable for studying human OA.12
An 8 weeks joint distraction of an OA knee joint in beagles induced by
ACLT resulted in a normalization of the proteoglycan (PG) turn over of
the articular cartilage directly after treatment. However, histology did not
show cartilage repair11. The study was repeated using the groove model.
A significant less loss of PG content and collagen damage was found in the
distracted OA canine knee joints compared to the not treated OA group. In
addition, both the macroscopic and histological grade of cartilage damage
was found to be less in the distraction group. 17 Further research and
analysis will be necessary to understand he patho-physiologcal changes
which may occur in OA joints during and following joint distraction.
References:
1) van Valburg AA, van Roermund PM, Lammens J, van Melkebeek J, Verbout
AJ, Lafeber EP, Bijlsma JW. Can Ilizarov joint distraction delay the need for
an arthrodesis of the ankle? A preliminary report. J Bone Joint Surg Br. 1995
Sep;77(5):720-5.
Extended Abstracts 181
2) Kluesner AJ, Wukich DK. Ankle arthrodiastasis. Clin Podiatr Med Surg.
2009 Apr;26(2):227-44.
3) Lamm BM, Gourdine-Shaw M. MRI evaluation of ankle distraction: a
preliminary report
Clin Podiatr Med Surg. 2009 Apr;26(2):185-91.
4) Tellisi N, Fragomen AT, Kleinman D, O’Malley MJ, Rozbruch SR. Joint
preservation of the osteoarthritic ankle using distraction arthroplasty.
Foot Ankle Int. 2009 Apr;30(4):318-25. Erratum in: Foot Ankle Int. 2009
Jun;30(6):vi
5)Paley D, Lamm BM, Purohit RM, Specht SC
Distraction arthroplasty of the ankle--how far can you stretch the indications?
Foot Ankle Clin. 2008 Sep;13(3):471-84, ix.
6) Morse KR, Flemister AS, Baumhauer JF, DiGiovanni BF Distraction
arthroplasty. Foot Ankle Clin. 2007 Mar;12(1):29-39
7) Chiodo CP, McGarvey W. Joint distraction for the treatment of ankle
osteoarthritis.Foot Ankle Clin. 2004 Sep;9(3):541-53, ix. Review
8) Intema F, Van Roermund PM, Marijnissen AC, Cotofana S, Eckstein F,
Castelein RM, Bijlsma JW, Mastbergen SC, Lafeber FP Tissue structure
modification in knee osteoarthritis by use of joint distraction: an open 1-year
pilot study. Ann Rheum Dis. 2011 Aug;70(8):1441-6. Epub 2011 May 12.
9) Marijnissen AC, Vincken KL, Viergever MA, van Roy HL, Van Roermund
PM, Lafeber FP, Bijlsma JW. Ankle images digital analysis (AIDA): digital
measurement of joint space width and subchondral sclerosis on standard
radiographs.Osteoarthritis Cartilage. 2001 Apr;9(3):264-72
10) Intema F, Thomas TP, Anderson DD, Elkins JM, Brown TD, Amendola A,
Lafeber FP, Saltzman CL Subchondral bone remodeling is related to clinical
improvement after joint distraction in the treatment of ankle osteoarthritis
Osteoarthritis Cartilage. 2011 Jun;19(6):668-75. Epub 2011 Feb 13.
11) van Valburg AA, van Roermund PM, Marijnissen AC, Wenting MJ, Verbout
AJ, Lafeber FP, Bijlsma JW. Joint distraction in treatment of osteoarthritis
(II): effects on cartilage in a canine model. Osteoarthritis Cartilage. 2000
Jan;8(1):1-8
12) Intema F, Hazewinkel HA, Gouwens D, Bijlsma JW, Weinans H, Lafeber
FP, Mastbergen SC.In early OA, thinning of the subchondral plate is directly
related to cartilage damage: results from a canine ACLT-meniscectomy
model.Osteoarthritis Cartilage. 2010 May;18(5):691-8. Epub 2010 Feb 6
13) Karadam B, Karatosun V, Murat N, Ozkal S, Gunal No beneficial effects
of joint distraction on early microscopical changes in osteoarthrotic knees. A
study in rabbits.Acta Orthop. 2005 Feb; 76(1):95-8
14) Kajiwara R, Ishida O, Kawasaki K, Adachi N, Yasunaga Y, Ochi M Effective
repair of a fresh osteochondral defect in the rabbit knee joint by articulated
joint distraction following subchondral drilling. J Orthop Res. 2005 Jul;
23(4):909-15.
15) Yanai T, Ishii T, Chang F, Ochiai N. Repair of large full-thickness articular
cartilage defects in the rabbit: the effects of joint distraction and autologous
bone-marrow-derived mesenchymal cell transplantation. J Bone Joint Surg
Br. 2005 May;87(5):721-9
16) Mastbergen SC, Marijnissen AC, Vianen ME, van Roermund PM, Bijlsma
JW, Lafeber FP The canine ‚groove‘ model of osteoarthritis is more than
simply the expression of surgically applied damage. Osteoarthritis Cartilage.
2006 Jan;14(1):39-46. Epub 2005 Sep 26.
17) Intema F, DeGroot J, Elshof B, Vianen ME, Yocum S, Zuurmond
A, Mastbergen SC, Lafeber FP The canine bilateral groove model of
osteoarthritis. J Orthop Res. 2008 Nov;26(11):1471-7.
18) Lamm BM, Gourdine-Shaw M. MRI evaluation of ankle distraction: a
preliminary report.Clin Podiatr Med Surg. 2009 Apr;26(2):185-91
Acknowledgments:
• Prof. F Lafeber
• Dr. ACA Marijnissen
• Dr. F Intema
• Dr. A van Valburg
• Dr.SC Mastbergen

182
This author index lists the names of all
authors and co-authors of the all congress
abstracts (Podium Presentations, Poster
Presentations & submitted Extended
Abstracts by the invited faculty). The
numbers in the index refer to the final
programme number and the letter “P”
before the final programme number refers
to the poster section.
A
Abarca, E.: P61
Abazari, A.: P219, P226
Abbushi, A.: P171
Abe, S.: 11.2.7
Aberl, J.: 11.2.1
Abramson, S.: 25.1.5
Abratte, C. M.: 25.4.5
Abubacker, S.: 21.1.1
Acharya, K.: 9.4.9
Ackland, T. R.: 25.3.5, P95, P247
Acuña, M.: 9.4.4
Adachi, N.: P101
Adams, Jr., S.: P34, 25.4.1
Adesida, A. B.: 9.3.3, 9.4.1, P176,
P180, P182, P219
Adkisson, H. D.: P142
Afizah, H.: P18
Agar, G.: P188
Ahmad, R.: P104
Aicher, W. K.: 9.2.8
Ajibade, D.: P109
Al-abbasi, K.: P226
Alba-sanchez, I.: P84
Alblas, J.: 16.4.6
Albrecht, C.: P80
Aldrian, S.: 11.4.6, P80
Alevrogiannis, S.: P111
Alini, M.: 16.2.3, P147, P271
Almazan, A.: 9.4.4
Almqvist, K. F.: 9.2.5, 9.4.6,
11.3.3, 16.2.9,
19.2.2, P6, P58,
P217
Alorjani, M.: P87
Altschuler, N.: P26
Álvarez, E.: P135
Amanatullah, D.: 9.2.7, P119
Amendola, A. N.: 24.3.1
Amiel, D.: 11.1.9
Anderson, A. B.: 16.3.3
Anderson, D. G.: P265
Ando, W.: 25.4.9, P221
Andreatta, B.: P70
Annala, T.: P98
Anton, M.: P147, P272
Apostolidis, K.: 16.1.3
Apprich, S.: 11.4.5, 19.1.1,
P164, P166, P187
Arévalo, F. S.: P47
Arai, R.: P162
Arakaki, K.: P62
Arbel, R.: P52, P114, P177,
P188
Arbes, S.: 11.4.6
Archer, C.: P147, P271
Ariganello, M. B.: 9.3.6
Arno, S.: 9.4.2, 25.1.5, P214
Arnold, M. P.: 9.4.5, 11.4.7
Arnold, R. M.: 25.2.4
Ascani, C.: P267
Athanasiou, K.: 9.3.2, P35, P73
Au, A. Y.: 11.2.4, P212
Audenaert, E. A.: 9.2.5
Aviv, M.: P273
B
Bünger, C.: P23
Baches Jorge, P.: P33
Bader, R.: P131
Authors‘ Index
Bahrs, C.: 9.2.8
Bait, C.: P263
Bal, B.: P51
Balakumar, B.: P38
Ball, S. T.: 11.1.9
Bara, J. J.: 25.4.2
Baradar Khoshfetrat, A.: P54
Barbero, A.: P89
Bardana, D.: 11.1.6
Barr, L.: P157
Barron, V.: P102
Barry, F.: 18.1, P102
Bartels, W.: 11.4.2
Barten-van Rijbroek, A. D.: P16, P25, P77
Bartlett, W.: P87
Baskaran, H.: 16.4.4
Bassett, E.: 9.2.6
Battaglia, M.: P86, P93
Beaufils, P.: 11.3.2
Beaule, P.: P202
Becher, C.: P194
Beekhuizen, M.: 11.3.5, P77, P151,
P156, P198
Beekman, P.: P178
Beer, Y.: P188
Begum, L.: P91, P117
Beier, F.: 2.1.1, 25.1.6
Bekkers, J. E.: 9.3.8, 11.3.5, 11.4.2,
P55, P79, P151, P156
Bell, C.: 9.4.2, 25.1.5, P214
Bellemans, J.: 11.3.2
Beltran, L.: 9.4.2
Ben Shalom, N.: P215
Bendele, A.: P270
Benderdour, M.: 11.2.5, P130
Benders, K. E.: 9.3.4, 11.1.2
Benink, R.: 11.4.2
Bennett, G. W.: 16.3.3
Bentley, G.: P87
Berbig, R.: 9.4.5
Berninger, M.: P82
Bernsen, M.: 16.4.5
Berti, L.: P5
Bhattacharjee, A.: P262
Bichara, D. A.: P227, P265
Bilagi, P.: P192, P193
Bird, J.: P186
Bisschop, A.: 9.4.7
Blanchet, T.: P206
Blanke, M.: P164
Blati, M.: 25.1.6
Blatz, B. W.: P138
Blumberg, N.: P188
Bodugoz Senturk, H.: 11.3.7, P112, P227
Bolduc Beaudoin, S.: 9.3.6
Bommer, C.: 16.2.6
Bonassar, L.: 3.1.3, 11.4.9, P184,
P206
Bonner, K.: P142
Bonner, T. F.: P76
Boot, W.: 9.3.4
Bos, P.: 16.4.5
Boswell, S.: 15.1.1
Bot, A. G.: P151, P198
Bothos, J.: 16.2.9
Bourin, P.: 16.1.7
Bourquin, F.: P231
Boux, E.: P197, P243
Bradica, G.: P160
Brady, K.: P258
Bragdon, C. R.: P227
Brage, M. E.: P9
Braithwaite, G.: P112
Breitenkamp, K.: P36
Brenner, J.: 11.1.6
Briggs, K. K.: P200, P209, P229
Briggs, T.: P87
Brinchmann, J. E.: 16.4.7, 25.4.3,
25.4.8, P90, P254
Brittberg, M.: 2.2.3, 16.2.9, P133,
P143
Brix, M.: P116, P166
Brophy, R. H.: P230
Brown, D. S.: 11.4.3, 25.3.7
Brown, J.: P234
Bryant, T.: P82
Bryne, J. C.: 25.4.8
Buckwalter, J.: 5.10
Buda, R. E.: 25.3.4, P10, P44,
P86, P93, P141, P232,
P236
Bugbee, W. D.: 11.1.9, 15.3.3, 21.3.2,
P3, P4, P9
Burga, R. A.: 11.3.9
Buschmann, M. D.: 16.3.4, P30, P189
Bussiere, C.: P100
Butler, A. P.: 11.4.8
Butler, R. S.: P76
Byers, B. A.: 16.2.9
C
Cárdenas-blanco, A.: P202
Caballero-Santos, R.: P107
Caborn, D.: 7.2
Call, G.: P18
Campbell, K. A.: 9.4.2
Canseco, J.: P21
Caplan, A.: 16.4.4
Carey, J.: P230
Carli, A.: 16.3.9
Caron, M. M.: 9.2.2, 11.2.3, P118,
P120, P121
Caroom, C.: 16.4.9
Carpenter, L.: 16.4.2
Carrington, R.: P87
Carubbi, C.: P59
Casalis, P.: P171
Castiglione, E.: P160
Catanzano, A.: 9.3.7
Caterson, B.: 3.2.3
Cavallo, C.: 25.3.4
Cavallo, M.: P5, P9, P10, P86,
P93, P141, P232
Cazelais, P.: 16.3.9
Cervellin, M.: P263
Chae, B. C.: P115
Chan, J.: P204
Chang, W.: P63, P96
Changoor, A.: 11.4.4, 25.3.3
Chavez, D.: P88
Chen, A. C.: 11.1.9
Chen, G.: 16.3.2
Chen, H.: 16.3.4, 16.3.9, P189
Chen, W.: P20
Chen, X.: P146
Chen, S.: P145
Cheriyan, T.: 11.1.8
Chesnutt, J.: P85
Cheverud, J. M.: 16.1.4
Chevrier, A.: 16.3.2, 16.3.4, P189
Chiang, H.: P63, P96, P145
Chiari, C.: P116
Chien, J.: P174
Chilbule, S.: P38
Chinitz, N.: 9.3.7
Cho, J.: P53, P57
Choi, B.: P49, P53, P57, P169
Choi, Y.: P268
Chorev, Y.: P26
Chou, C.: 16.4.4
Christensen, B. B.: P23
Chu, C.: 25.1.8, P127
Chubinskaya, S.: 2.1.3, 9.1.2, 16.1.5, P1
Chung, C. B.: P43
Ciemniewska-Gorzela, K.: P181, P195,
P238, P249, P250
Cift, H. T.: P224, P225
Clarke, R.: P128
Colbrunn, R. W.: P76
Cole, B. J.: 2.3.1, 15.1.1, 25.3.8,
P1, P142, P241
Colen, S.: P213
Collas, P.: 25.4.8
Colliec-jouault, S.: 9.3.9, P256
Colombet, P.: 11.3.2
Colombini, A.: 25.4.4

Colwell, Lambrecht, C. W.: S.: 9.2.5, P43 P6, P58
Conaghan, Laouar, L.: P.: 9.3.3, P78 P176, P219
Concaro, Laprell, H.: S.: P143 11.3.2
Condello, Lara, J.: V.: P40, P135 P177, P188
Cook, Lascau-coman, J. L.: V.: P51 16.3.2, 16.3.4, 16.3.9
Coolsen, Lattermann, M. M.: C.: 9.2.2, 25.2.2, P120, 25.3.2, P121
Cortes, S.: P88 25.3.9, P230, P253
Cortese, Laursen, F.: J.: P40, P216 P237
Cotofana, Lavigne, P.: S.: 25.1.2 3.3.3, P32
Coyle, Lavoie, S.: J.: P270 P32
Crawford, Law, G. K.: D. C.: P219 11.4.3, P85
Creemers, Le, D. Q.: L.: P23 9.3.8, 11.1.2, 11.3.5,
Lecona, H.: 11.4.2, P22 P55, P77, P79,
Lee, E. H.: P151, P18 P156, P198
Cremers, Lee, H. H.: A.: 25.1.8, 9.4.8, 11.2.3, P127 P118,
Lee, J.: P120, P115, P115 P121
Croutze, Lee, S.: R.: P223 9.3.3
Cruz, Lehmann, F.: L.: 9.4.4 P108
Cugat, Lesoeur, R.: J.: 11.3.2 16.2.5, P103, P256,
Cui, X.: 11.3.4, P257 16.4.8, P36
Czücs, Lessi, G. C.: C.: P83 25.1.3
Levingstone, T. J.: 11.3.8, P56
Levy, d A. S.:
Levy, Y.:
P26
P4
D’lima, Liao, C.: D. D.: P63, 9.4.3, P96 11.3.4, 16.4.8,
Liao, W.: P36, P96 P43, P146
Dahlberg, Liekens, K.: L. E.: P58 22.2
Daisuke, Li, H.: S.: P81 8.3.2
Dallari, Li, T.: D.: P59, P169 P68
Das, Lim, S.: 9.4.3 P180
Davisson, Lin, S.: T.: P20, P270 P145
De Lind, Bari, M.: C.: 11.1.8, 18.2 P23, P158
De Lindahl, Coninck, A.: T.: P183 P133, P143
De Lindemann, Girolamo, S.: L.: P149 25.4.4, P263
De Linder-Ganz, Graaf, M.: E.: 9.4.7 P52, P76, P177, P188
De Ling, Grauw, D.: J. C.: 11.3.7, 11.1.2 P112, P227
De Linnenkohl, Vries - Van W.: Melle, M. P91 L.: 16.2.2, P259
De Lisignoli, Windt, G.: T. S.: 9.1.1, 16.1.7 P133, P143
Deberardino, Little, C. B.: T. M.: P85 22.1
Decroos, Liu, C.: J. A.: P145 11.2.2, 16.2.8
Dediu, Liu, H.: V.: P37 P128
Deie, Liu, K.: M.: P101 P174
Del Liukkonen, Piccolo, J.: N.: 19.1.3 P59, P68
Della Lloyd, Valle, D. G.: C.: P241 25.3.5
Desai, Lochner, P.: K.: P214 P131
Desando, Lochnit, G.: G.: 25.3.4 16.1.9
Desjardins, Lohmander, J.: S.: 16.3.3 19.3.1, 19.3.1
Desnoyers, London, N. J.: 11.3.1, P217 11.4.4, 25.3.3
Detiger, Loosli, Y.: S. E.: P70 P172
Dey, Lopa, K.: S.: P50 25.4.4
Dhert, Lopez-Alcorocho, W.: J.: 3.1.2, P107 9.3.4, 9.3.8,
Lopez-Reyes, A.: 11.1.2, P84 11.3.5, 11.4.2,
Lotz, M. K.: 16.4.6, 9.4.3, 11.3.4, P74, P79, 16.4.8,
P151, 25.1.6, P156, P36, P198 P43,
Dhollander, A. A.: P146 9.2.5, 11.3.3, 19.2.2,
Lu, H.: P6, 11.3.9, P58, 15.2.1 P185
Di Lu, Cesare, J.: P.: 9.2.7 9.2.7, P119
Di Lucas, Martino, E.: A.: 15.1.2, P163 25.1.1, 25.2.9,
Luciani, D.: P45, P5 P60, P65
Di Luethi, Matteo, U.: B.: 9.4.5 15.1.2, 25.1.1, 25.2.9,
Luginbühl, R.: P45, P70 P60
Diaz Lui, J.: Romero, J.: 9.2.4, 25.4.7P83
Dickinson, Łukasik, P.: S. C.: 16.4.2, P69, P190 P258
Dijkstra, Lullini, G.: P.: P5 P42
Dionigi, Luna-Barcenas, C.: G.: P37 P47, P61
Djap, Lussier, M.: B.: 11.2.8 11.1.4
Djian, P.: 11.3.2
Domayer, m S.:
Doornenbal, A.:
Driscoll, Méthot, S.: M. D.:
Duarte, Müller, S.: A.:
Dubrana, Ma, C. B.: F.:
Dubuc, Madaj, A.: J.:
Dudzinski, Maden, M.: W.:
Duffy, Madhuri, S. F.: V.:
Dugard, Madonna, M. V.: N.:
Durkan, Madry, H.: M. G.:
Duthon, Mae, T.: V.:
Dutt, Maeckelbergh, V.: L.:
Maghdoori, B.:
P116, P166
P16
25.3.3 16.4.9, P175
25.2.3 P33
P85 P100
11.3.6 P250
P249, 2.2.1 P250
9.4.3 P38
P40 P125
15.3.1 11.4.3
P207, 9.1.3 P221
P38 P213
P219
Magnussen, R. A.: 9.1.3
Mainard, D.: 16.1.6
Mainil-Varlet, P.: P203
Authors‘ Index 183 185
Makris, e E. A.: 9.3.2, P35, P73
Malda, J.: 3.1.2, 9.3.4, 11.1.2,
Ebert, J.: P74, 25.3.5, P92 P94, P95,
Mandelbaum, B.: P247 1.1, 1.4, P138
Mandl, Ebrahimi, E.: S.: 16.2.2 P54
Manferdini, Eckstein, F.: C.: 16.1.7 25.1.2
Mangiapani, Eder, M.: D. S.: 25.1.7 11.2.1
Manian, Egli, R.: A.: P70 P102
Maniura, Eichinger, K.: M.: P48 P187
Mann, Eisman, S.: J. A.: 9.3.5 P26
Mansmann, El Mansouri, U.: F.: P132 11.2.5, P130
Mao, Elewaut, J.: D.: 9.2.5, 9.3.1, 14.1 P6, P58
Maor, Ellä, V.: G.: P97 P27
Maquet, Elliott, D. V.: M.: 11.3.6 8.3.3
Maréchal, Elliott, J. A.: M.: 25.2.7 P219, P226
Marcacci, Elsner, J. J.: M.: 15.1.2, P52, P76, 25.1.1, P177, 25.2.9, P188
Emans, P.: P37, 9.2.2, P44, 11.2.3, P45, P118, P60,
P65 P120, P121, P126
Marchand, Emre, T.: C.: 16.3.2 P224, P225
Marcheggiani Endres, M.: Muccioli, 16.2.6, G. M.: P171 P65
Mardani, English, R. M.: A.: P246 25.2.2
Mardones, Erggelet, C.: R. M.: 24.1.3 25.2.3
Marijnissen, Erggelet, J. D.: A.: 16.2.3 25.1.2
Marlovits, Esfandiary, S.: E.: P246 11.4.5, 11.4.6, P80,
Eskandarnezhad, S.: P54 P164
Martínez, Esmaeili, A.: H. G.: P135 P246
Martel-pelletier, Evans, C. H.: J.: 11.1.4, P154 11.2.5, 25.1.6,
Evans, H.: P130 P31
Martin, Evron, Z.: I.: P89 P273
Martinez-Lopez, Evseenko, D.: V.: P84 25.4.1
Martinez, Ewig, M.: I.: P98 P194
Martinez, M. C.: P47
Martinez, f V.: P47, P61, P88
Masala, N.: 21.1.1
Masson, Facchini, M.: A.: 9.3.9, 16.1.7, 16.2.5, 25.3.4 P103,
Fahmi, H.: P256, 11.2.5, P257 25.1.6, P130
Mastbergen, Fallon, M.: S.: 11.1.5, P94, P95, 15.3.2, P247 24.3.3,
Fansa, A.: 25.1.2, P218, P242 P16, P25, P77,
Fantasia, R.: P59 P153
Masuda, Farr, J.: K.: 11.1.9 7.1, 25.3.8, P142
Mateer, Feijen, J.: J. L.: 25.3.2 P42
Mates, Felka, T.: A.: P13, 9.2.8 P124
Matheny, Fellah, B.: L.: P200, 9.3.9, 16.2.5, P209 P103
Mathieu, Ferkel, R.: C.: 16.3.2 8.1.2
Matmati, Fernandes, M.: A. M.: P90 8.2.2, P113
Matsiko, Fernandes, A.: J.: 11.3.8 17.4.3
Matsuda, Fickert, S.: H.: P62 P108, P110
Matsukawa, Filanti, M.: T.: 16.1.8 P68
Matsumoto, Filardo, G.: T.: 11.1.3 15.1.2, 25.1.1, 25.2.9,
Matsuno, T.: P26, 11.2.7 P44, P45, P60,
Matsuo, K.: 11.1.4 P65
Matsuo, Finn, M.: T.: P207 P36
Matsushita, Fisher, J.: T.: 11.1.3 P71, P78
Matsuzaka, Fisher, M. B.: M.: 25.1.4 8.3.3
Matsuzaki, Fitzcharles, T.: E.: 11.1.3 P163
Mattacola, Fitzgerald, J.: C. G.: 25.2.2, 16.1.4 25.3.2,
Flanigan, D.: 25.3.9, P230 P253
Matthews, Flannery, C. G.: R.: P91 21.1.3, P206
Matthies, Foglarová, N.: M.: P180 P41
Mattiello-Sverzut, Foldager, C. B.: A. C.: 11.1.8, 25.1.3 P23, P158
Mattielo, Fong, D.: S. M.: 25.1.3, 9.3.6 P24
Matuska, Fontana, A.: 11.2.9 16.3.7, P140
Mauck, Forbes, R.: J. F.: 8.3.3 P219
Maumus, Forriol Campos, M.: F.: 16.1.7 11.3.1, 11.4.4, 25.3.3
Mcadams, Fortier, L. A.: T. R.: 11.4.9, P138 15.1.1, 16.4.3,
Mcallister, D.: 25.4.1 25.4.5, P160, P241
Mccarrell, Fortuna, D.: T.: 25.3.4 15.1.1
Mccarthy, Fouche, N.: H.: 25.4.2, P159 P92
Mccauley, Francin, P.: J. C.: P3, 16.1.6 P4, P9
Mccormack, Franklin, S. P.: R.: 11.3.1, P51 11.4.4, 25.3.3
Mcgann, Freymann, L. U.: E.: 16.2.6, P219, P226 25.2.3, P171,
Mcilwraith, W.: P197 3.2.1, 14.2, 15.2.2,
Friederich, N. F.: 24.2.3 11.4.7
Mclure, Friel, N. S. A.: W.: 25.1.8 P78
Medina Frisbie, D. Mckeon, D.: J. M.: 25.3.9 15.2.2, 24.2.3
Mehlhorn, Frondoza, C. A. G.: T.: 11.2.4, 16.1.2 P212
Meisel, Fu, F. H.: H. J.: 9.1.4 P132
Melas, Fujie, H.: I.: 16.1.3 P221
Melchels, Fuller, H.: F. P.: 3.1.2 P29
Meller, Furman, A.: B. D.: P27 25.1.7
Mennan, C.: P262
Merceron, C.: 16.2.5, P103, P256,
P257
Merli, M.: 25.1.1
Meth, g I.: P159
Meyerkort, D.: P95
Meza-Zepeda, Görtz, S.: L.: 25.4.8 11.1.9, P4, P9
Mhanna, Gabriel, C.: R.: P48 11.2.1
Mifune, Gabusi, E.: Y.: P264 16.1.7
Mikkelsen, Galley, N.: T. S.: 25.4.8, P206 P254
Millan, Ganey, C.: T.: P48 P132
Miller, Gansbacher, S. D.: B.: P34 P272
Millett, Ganster, P. M.: J.: P199 P203
Min, Gao, B.: J.: P49, P2, P8, P53, P11, P57, P12, P169 P18,
Minami, A.: P152 P128, P222
Minas, Garcia-Campillo, T.: H.: P22 2.3.3, 25.2.5, P82
Miska, Garcia Carvajal, M.: Z. Y.: P47 P64
Mitchell, Garcia, Z.: J.: P230 P61
Mithoefer, Garciadiego-Cazeres, K.: D.: 1.3, 13.1.1, P47 16.3.8,
Garrett, R.: 21.2.2 P2, P8, P11, P12,
Miyamoto, S.: P207 P128, P222
Mochizuki, Gauthier, O.: S.: P221 16.2.5, P103, P257
Moens, Gawlitta, K.: D.: 9.4.6 16.4.6, P74
Mohtadi, Geffroy, O.: N.: 11.3.1, 16.2.5 11.4.4, 25.3.3
Mojtahed Gegout-Pottie, Jaberi, P.: F.: P233 16.1.6
Mojtahed Gentili, C.: Jaberi, M.: P233 P197, P243
Monemjou, Geoffroy, O.: R.: 25.1.6 P103
Moorman, Georgi, N.: C. T.: P85 16.2.4
Moran, Gersoff, N.: W.: P91 3.3.1
Morawietz, Gerwien, P.: L.: 16.2.6 P108
Moreau, Getgood, A.: P32 11.1.7, 19.2.3, 25.1.9,
Moreira Teixeira, L.: P42 P19, P157, P186
Moretti, Geurts, B.: M.: 25.4.4, P151, P156 P89
Morgan, Ghanem, C.: N.: P173 25.2.6
Moriguchi, Giannini, S.: Y.: 25.4.9, 25.3.4, P221 P5, P10, P44,
Moroni, L.: P102 P86, P93, P141, P232,
Morrison, S.: 21.1.1 P236
Mrozinski, Giannoni, P.: A. C.: 11.2.4, P150 P212
Muhonen, Gigout, A.: V.: P27 P149
Mulier, Gilbert, M.: F.: P213 P106, P154
Mullender, Gillogly, S. D.: M.: 9.4.7 25.2.4
Mullineaux, Giovarruscio, D. R.: 25.2.2 P40
Muneta, Giphart, J.: T.: P179 P163
Muratoglu, Gitelis, S.: O. K.: 11.3.7, P1 P112, P227
Murawski, Giza, E.: C. D.: P218, 8.1.1, P134 P220, P242
Murphy, Gleeson, M.: J. P.: P102 11.3.8, P56
Muto, Gobbi, T.: A.: P264 16.3.5, 25.2.1, P99,
Myoui, A.: 25.4.9 P139, P269
Gold, G.: 25.3.8, P142
Goldberg, n V. M.:
Gomez-Garcia, R.:
16.4.4
P22
Němcová, Gomez, R.: M.:
Nöth, Gomoll, U.: A. H.:
Nürnberger, Gong, J. P.: S.:
Naczk, Gonzalez, J.: G.:
Goodrich, L.:
Nagaraja, Gosselin, Y.: H.:
Nagura, Grad, S.: I.:
Nair, Graham, P.: W.:
Nakagawa, Gramani-Say, Y.: K.:
Nakaji, Gramizadeh, S.: B.:
Nakamura, Grande, D.: N.:
Nakamura, Greene, A.: S.:
Nakamura, Greve, L.: T.:
Nakashima, Grigolo, B.: M.:
Nakata, Grishko, K.: V.:
Nanda, Grodzinsky, S.: A. J.:
Nandakumar, Grogan, S. P.: A.:
Nansai, Groth, T.: R.:
Naranda, Grygorowicz, J.: M.:
Narcisi, Grzanna, R.: M. W.:
Naruse, Guehring, K.: H.:
Naveen, Guevara, S.: V.:
Nebbaki, Gueven, S.: S.:
Nedopil, Guicheux, A.: J.:
Negrin, L. L.:
Nehrer, Guilak, F.: S.:
Nelson, Guillaume, B.: C.:
Neri, Guillen-Garcia, S.: P.:
Nesic, Guillen-Vicente, D.: I.:
Netter, Guillen-Vicente, P.: M.:
Neuhold, Guillot, P. A.: V.:
Neumann, Gupta, R. R.: A.:
Nevo, Guyton, Z.: G.:
P41 P47
P261 19.2.1, 25.2.5, P21
P80 P62, P239
P22 P181, P195, P238,
14.2, P249 15.2.2
P230 16.3.9
P264 16.2.3
P38 P230
P162 25.1.3
P233 25.1.4
25.4.9, 5.20, 9.3.7, P207, 16.2.1 P221
P162 P76
P162 16.4.3
16.1.8 25.3.4
P13, P207, P14, P221 P124
9.2.8 P112
P102 9.4.3, P43, P146
P221 P48
P249, P244 P250
16.4.5, 11.2.4, P212 P150
P7 P149
P104, P88 P208
11.2.5, P89 P130
P261 9.3.9, 16.2.5, P103,
16.3.6 P256, P257
15.2.3, 25.1.7, 16.2.9, P52, P177 P116
P85 16.1.6
P107 P10
P107 9.2.4, P83
P107 16.1.6
11.4.6 P258
P147, P76 P271
P215, P34 P273
Neyret, P.: 9.1.3, 11.3.2, P100
Neys, J.: 25.2.7
Ng, T. H.: 9.3.5, P113

184
H
Høiby, T.: 25.4.8
Habibovic, P.: P102
Hackett, C.: 16.4.3
Hadley, S.: 9.4.2
Haile, A.: P34
Hajdu, S.: 11.4.6
Hakimiyan, A. A.: 16.1.5, P1
Hall, M.: 9.4.2
Hallinger, R.: P261
Hamada, T.: 16.1.8
Hambly, K.: 25.3.1, 25.3.5, P94,
P95, P247, P248
Hamboeck, M.: 11.4.6
Hamilton, D.: P230
Hamilton, W. P.: P175
Haney, N. M.: 11.3.9
Hansen, O. M.: P23
Hansmann, D.: P131
Hart, J.: P91
Hart, R.: P15
Hasegawa, H.: 25.4.9
Hashemibeni, B.: P246
Hashimoto, S.: 16.1.4
Haudenschild, D.: 9.2.7, P119
Hawkins, R. J.: 16.3.3
Hayes, D. A.: P217
Hazewinkel, H. A.: P16
Heber-katz, E.: 16.1.4
Hecht, J.: 9.2.7
Heinecke, L. F.: 11.2.4, P212
Helder, M. N.: 9.4.7, P172
Helmert, B.: P108
Henkelmann, R.: 16.1.2
Henrotin, Y.: 11.3.6
Henson, F.: 11.1.7, 25.1.9, P19,
P157
Herbort, M.: 17.4.2, P72
Herlofsen, S. R.: 25.4.8, P90
Hernandez, P.: 25.1.9
Hershman, E.: P52, P76, P177, P188
Herzog, M. M.: P229
Higashiyama, R.: P7
Hildner, F.: 11.2.1
Hingsammer, A.: P167, P204
Hinz, B.: 8.2.2
Hiraiwa, H.: 16.1.8
Hirschmüller, A.: 25.2.3
Hirschmann, M. T.: 9.4.5, 11.4.7
Ho, C.: P163
Hoch, J. M.: 25.3.2, 25.3.9
Hoemann, C. D.: 9.3.6, 16.3.2, 16.3.4,
16.3.9, 24.2.2, P39,
P189
Hoenecke, H.: P43
Hohaus, C.: P132
Hollander, A. P.: 9.3.5, 16.1.1, 16.4.2,
23.2, P258
Holz, J.: 17.4.1
Hong, E.: P119
Hoogendoorn, R. J.: P172
Hooper, G. J.: 11.4.8
Horan, M.: P199
Horie, M.: 16.4.9, P175
Horton, M. T.: P3
Hosiner, S.: P80
Howard, J. S.: 25.2.2, 25.3.9, P253
Hsieh, C.: P145
Hsu, H.: 11.1.8
Huang, C. C.: P109
Huard, J.: P81
Hubert, Z.: P175
Huebner, J. L.: 25.1.7
Hui, J. H.: P18
Huiyin, N.: P105
Hum, D.: 11.1.4
Humphrey, E.: 25.4.2, P29
Hunziker, E.: 11.1.1, 15.2.1, P231
Hurtig, M. B.: 1.2, 11.2.2, 16.3.9,
24.2.1, P234
Hutmacher, D.: 3.1.1, 3.1.2, 25.4.6,
P201
Huysse, W. C.: P183
Authors‘ Index
Hwang, N. S.: P265
I
Iacono, F.: P65
Iacono, V.: P237
Ibarra, C.: 9.4.4, P22, P47, P61,
P84
Ibarra, J. C.: P88
Ibarra, L.: P88
Igarashi, T.: P152
Iliopoulos, E.: 16.1.3
Imabuchi, R.: P239
Imade, K.: P221
Imhauser, C. W.: P218
Imhoff, A. B.: 16.2.9, P272
Ingham, E.: P71
Ingram, J.: P71
Inoue, R.: 25.1.4
Intema, F.: 15.3.2, 25.1.2
Iosifidis, M. I.: 16.1.3
Ishibashi, Y.: 25.1.4
Ishiguro, N.: 16.1.8
Ishizuka, S.: 16.1.8
Israel, E. F.: P47
Israeli, S.: P188
Itoman, M.: P7
Iu, J.: 11.2.2
Iwamoto, M.: 2.1.2
Iwasaki, N.: P152
Izaguirre, A.: 9.4.4, P22, P47, P84,
P88
j
Järvinen, E.: P27
Jakob, R.: 3.3.2, P181
Jakobsen, R.: 25.4.3, P254
Janes, G.: P94
Jansen, E. J.: P126
Jansen, N. W.: 11.1.5
Janssen, M. P.: P120
Jay, G. D.: 21.1.1
Jeon, J. E.: P201
Jia, H.: 16.4.2
Jiang, C.: P63, P96, P145
Jiang, T.: P2, P8, P11, P12, P18,
P222
Jin, L.: P53, P57, P169
Jin, S.: P43
Johnson, W. E.: 25.4.2
Johnstone, B.: 8.2.1
Jomha, N. M.: 9.3.3, 9.4.1, P176,
P180, P182, P219,
P226
Jones, L.: P34
Jones, P.: P29, P31
Jonitz, A.: P131
Jorgensen, C.: 16.1.7
Joukainen, A.: 19.1.3
Junker, M.: P234
Jurvelin, J. S.: 11.4.1, 19.1.3, P161
k
Küchler, A. M.: P90, P254
Küntziger, T.: 16.4.7
Kabiri, A.: P246
Kafienah, W.: 9.3.5, 16.4.1, 16.4.2,
P258
Kalish, L.: P204
Kamei, G.: P101
Kamisan, N.: P104
Kanamoto, T.: P207
Kanaya, F.: P62
Kandel, R.: 8.3.1, 11.2.2, 16.2.8
Kannan, K.: P18
Kaoui, N.: P55
Kaplan, L. D.: P109
Kapoor, M.: 11.1.4, 25.1.6
Kaps, C.: 16.2.6, 25.2.3, P171,
P197, P243
Karas, V.: P241
Karlsen, T.: 16.4.7, 25.4.3, P90
Karnatzikos, G.: 16.3.5, P99, P139,
P269
Karperien, M.: 16.2.4, P42
Karthikeyan, R.: P38
Kasahara, Y.: P152
Kaszkin-bettag, M.: P108
Kellomäki, M.: P27
Kenmoku, T.: P7
Kennedy, J. G.: P218, P220, P242
Kensicki, E.: P34
Kerr, A.: P29, P31
Kertzman, P.: P33
Keshtgar, S.: P233
Khan, H.: P214
Khan, R. A.: P50
Khanarian, N. T.: 11.3.9, 15.2.1
Khanmohammadi, M.: P54
Khanna, G.: P9
Kik, M.: 11.1.2
Kim, J.: P134
Kim, M.: P49
Kim, S.: P192, P193
Kim, Y.: P49, P53, P57, P167,
P169, P204, P268
Kinds, M.: 15.3.2
Kirk, S.: P1
Kisiday, J. D.: 15.2.2
Kita, K.: P207, P221
Kitamura, N.: P62, P239
Kiviranta, I.: 19.1.3, 25.3.6, P27
Klapholz, Z.: 9.3.7
Klein, T. J.: 8.2.3, 25.4.6, P201
Kluk, H. L.: 11.3.7, P112
Kobayashi, M.: P162
Kobayashi, T.: P101
Koczy, B.: P69
Koenderink, G. H.: P172
Koevoet, W.: 16.2.2, P259
Koh, Y.: P268
Kokkonen, H.: 19.1.3, P161
Kokot, R.: P69, P190
Kokubu, T.: P264
Kolk, A.: 9.3.8
Kon, E.: 10.4.2, 15.1.2, 25.1.1,
25.2.9, P26, P44,
P45, P60, P65
Kongcharoensombat, W.: P101
Kops, N.: 16.2.2, 16.4.5, P259
Kordelle, J.: 16.1.9
Koziol, K. K.: 9.3.5
Kröger, H.: 19.1.3, P161
Krüger, J.: 16.2.6
Kragten, A. H.: P156
Krasnokutsky, S.: 25.1.5
Kraus, V. B.: 25.1.7
Kreulen, C.: P134
Kreuz, P.: 16.2.6, 17.4.4, 25.2.3
Kronen, P.: P159
Krstiansen, A.: P23
Krueger, J.: P243
Kubo, S.: 11.1.3
Kuiper, J.: P125
Kulmala, K.: 19.1.3
Kumar, A.: 16.3.5, P99, P139,
P269
Kunz, M.: P106, P154
Kuroda, R.: 11.1.3
Kurokawa, T.: P62, P239
Kuroki, H.: P162
Kurosaka, M.: 11.1.3, P264
Kwon, H.: P239
Kwon, O.: P205, P210
Kwon, S.: P205, P210
Kyriakidis, A.: 16.1.3
Lafantaisie-favreau, C.: P39
l
Lafeber, F.: 11.1.5, 15.3.2, 25.1.2,
P16, P25, P77, P153
Lai, S.: P174
Lallemand, E.: 16.2.5, P103

Lambrecht, S.: 9.2.5, P6, P58
Laouar, L.: 9.3.3, P176, P219
Laprell, H.: 11.3.2
Lara, J.: P135
Lascau-coman, V.: 16.3.2, 16.3.4, 16.3.9
Lattermann, C.: 25.2.2, 25.3.2,
25.3.9, P230, P253
Laursen, J.: P216
Lavigne, P.: 3.3.3, P32
Lavoie, J.: P32
Law, G. K.: P219
Le, D. Q.: P23
Lecona, H.: P22
Lee, E. H.: P18
Lee, H. H.: 25.1.8, P127
Lee, J.: P115, P115
Lee, S.: P223
Lehmann, L.: P108
Lesoeur, J.: 16.2.5, P103, P256,
P257
Lessi, G. C.: 25.1.3
Levingstone, T. J.: 11.3.8, P56
Levy, A. S.: P26
Levy, Y.: P4
Liao, C.: P63, P96
Liao, W.: P96
Liekens, K.: P58
Li, H.: P81
Li, T.: P169
Lim, S.: P180
Lin, S.: P20, P145
Lind, M.: 11.1.8, P23, P158
Lindahl, A.: P133, P143
Lindemann, S.: P149
Linder-Ganz, E.: P52, P76, P177, P188
Ling, D.: 11.3.7, P112, P227
Linnenkohl, W.: P91
Lisignoli, G.: 16.1.7
Little, C. B.: 22.1
Liu, C.: P145
Liu, H.: P128
Liu, K.: P174
Liukkonen, J.: 19.1.3
Lloyd, D. G.: 25.3.5
Lochner, K.: P131
Lochnit, G.: 16.1.9
Lohmander, S.: 19.3.1, 19.3.1
London, N. J.: P217
Loosli, Y.: P70
Lopa, S.: 25.4.4
Lopez-Alcorocho, J.: P107
Lopez-Reyes, A.: P84
Lotz, M. K.: 9.4.3, 11.3.4, 16.4.8,
25.1.6, P36, P43,
P146
Lu, H.: 11.3.9, 15.2.1
Lu, J.: 9.2.7
Lucas, E.: P163
Luciani, D.: P5
Luethi, U.: 9.4.5
Luginbühl, R.: P70
Lui, J.: 25.4.7
Łukasik, P.: P69, P190
Lullini, G.: P5
Luna-Barcenas, G.: P47, P61
Lussier, B.: 11.1.4
m
Méthot, S.: 25.3.3
Müller, S.: 25.2.3
Ma, C. B.: P85
Madaj, A.: P250
Maden, M.: 2.2.1
Madhuri, V.: P38
Madonna, V.: P40
Madry, H.: 15.3.1
Mae, T.: P207, P221
Maeckelbergh, L.: P213
Maghdoori, B.: P219
Magnussen, R. A.: 9.1.3
Mainard, D.: 16.1.6
Mainil-Varlet, P.: P203
Authors‘ Index 185
Makris, E. A.: 9.3.2, P35, P73
Malda, J.: 3.1.2, 9.3.4, 11.1.2,
P74, P92
Mandelbaum, B.: 1.1, 1.4, P138
Mandl, E.: 16.2.2
Manferdini, C.: 16.1.7
Mangiapani, D. S.: 25.1.7
Manian, A.: P102
Maniura, K.: P48
Mann, S.: 9.3.5
Mansmann, U.: P132
Mao, J.: 9.3.1, 14.1
Maor, G.: P97
Maquet, V.: 11.3.6
Maréchal, M.: 25.2.7
Marcacci, M.: 15.1.2, 25.1.1, 25.2.9,
P37, P44, P45, P60,
P65
Marchand, C.: 16.3.2
Marcheggiani Muccioli, G. M.: P65
Mardani, M.: P246
Mardones, R. M.: 24.1.3
Marijnissen, A.: 25.1.2
Marlovits, S.: 11.4.5, 11.4.6, P80,
P164
Martínez, H. G.: P135
Martel-pelletier, J.: 11.1.4, 11.2.5, 25.1.6,
P130
Martin, I.: P89
Martinez-Lopez, V.: P84
Martinez, I.: P98
Martinez, M. C.: P47
Martinez, V.: P47, P61, P88
Masala, N.: 21.1.1
Masson, M.: 9.3.9, 16.2.5, P103,
P256, P257
Mastbergen, S.: 11.1.5, 15.3.2, 24.3.3,
25.1.2, P16, P25, P77,
P153
Masuda, K.: 11.1.9
Mateer, J. L.: 25.3.2
Mates, A.: P13, P124
Matheny, L.: P200, P209
Mathieu, C.: 16.3.2
Matmati, M.: 8.2.2, P113
Matsiko, A.: 11.3.8
Matsuda, H.: P62
Matsukawa, T.: 16.1.8
Matsumoto, T.: 11.1.3
Matsuno, T.: 11.2.7
Matsuo, K.: 11.1.4
Matsuo, T.: P207
Matsushita, T.: 11.1.3
Matsuzaka, M.: 25.1.4
Matsuzaki, T.: 11.1.3
Mattacola, C. G.: 25.2.2, 25.3.2,
25.3.9, P253
Matthews, G.: P91
Matthies, N.: P180
Mattiello-Sverzut, A. C.: 25.1.3
Mattielo, S. M.: 25.1.3, P24
Matuska, A.: 11.2.9
Mauck, R.: 8.3.3
Maumus, M.: 16.1.7
Mcadams, T. R.: P138
Mcallister, D.: 25.4.1
Mccarrell, T.: 15.1.1
Mccarthy, H.: 25.4.2, P92
Mccauley, J. C.: P3, P4, P9
Mccormack, R.: 11.3.1, 11.4.4, 25.3.3
Mcgann, L. E.: P219, P226
Mcilwraith, W.: 3.2.1, 14.2, 15.2.2,
24.2.3
Mclure, S. W.: P78
Medina Mckeon, J. M.: 25.3.9
Mehlhorn, A. T.: 16.1.2
Meisel, H. J.: P132
Melas, I.: 16.1.3
Melchels, F. P.: 3.1.2
Meller, A.: P27
Mennan, C.: P262
Merceron, C.: 16.2.5, P103, P256,
P257
Merli, M.: 25.1.1
Meth, I.: P159
Meyerkort, D.: P95
Meza-Zepeda, L.: 25.4.8
Mhanna, R.: P48
Mifune, Y.: P264
Mikkelsen, T. S.: 25.4.8, P254
Millan, C.: P48
Miller, S. D.: P34
Millett, P. J.: P199
Min, B.: P49, P53, P57, P169
Minami, A.: P152
Minas, T.: 2.3.3, 25.2.5, P82
Miska, M.: P64
Mitchell, J.: P230
Mithoefer, K.: 1.3, 13.1.1, 16.3.8,
21.2.2
Miyamoto, S.: P207
Mochizuki, S.: P221
Moens, K.: 9.4.6
Mohtadi, N.: 11.3.1, 11.4.4, 25.3.3
Mojtahed Jaberi, F.: P233
Mojtahed Jaberi, M.: P233
Monemjou, R.: 25.1.6
Moorman, C. T.: P85
Moran, N.: P91
Morawietz, L.: 16.2.6
Moreau, A.: P32
Moreira Teixeira, L.: P42
Moretti, M.: 25.4.4, P89
Morgan, C.: P173
Moriguchi, Y.: 25.4.9, P221
Moroni, L.: P102
Morrison, S.: 21.1.1
Mrozinski, A. C.: 11.2.4, P212
Muhonen, V.: P27
Mulier, M.: P213
Mullender, M.: 9.4.7
Mullineaux, D. R.: 25.2.2
Muneta, T.: P179
Muratoglu, O. K.: 11.3.7, P112, P227
Murawski, C. D.: P218, P220, P242
Murphy, M.: P102
Muto, T.: P264
Myoui, A.: 25.4.9
n
Němcová, M.: P41
Nöth, U.: P261
Nürnberger, S.: P80
Naczk, J.: P181, P195, P238,
P249
Nagaraja, H.: P230
Nagura, I.: P264
Nair, P.: P38
Nakagawa, Y.: P162
Nakaji, S.: 25.1.4
Nakamura, N.: 25.4.9, P207, P221
Nakamura, S.: P162
Nakamura, T.: P162
Nakashima, M.: 16.1.8
Nakata, K.: P207, P221
Nanda, S.: P112
Nandakumar, A.: P102
Nansai, R.: P221
Naranda, J.: P244
Narcisi, R.: 16.4.5, P150
Naruse, K.: P7
Naveen, S.: P104, P208
Nebbaki, S.: 11.2.5, P130
Nedopil, A.: P261
Negrin, L. L.: 16.3.6
Nehrer, S.: 15.2.3, 16.2.9, P116
Nelson, B.: P85
Neri, S.: P10
Nesic, D.: 9.2.4, P83
Netter, P.: 16.1.6
Neuhold, A.: 11.4.6
Neumann, A.: P147, P271
Nevo, Z.: P215, P273
Neyret, P.: 9.1.3, 11.3.2, P100
Neys, J.: 25.2.7
Ng, T. H.: 9.3.5, P113

186
Nguyen, J. T.: P218
Nguyen, M.: 24.3.1
Nickel, J.: P106
Nielsen, A. H.: P23
Niemeyer, P.: 16.1.2, 16.2.3, 25.2.3,
25.2.6
Nierenberg, G.: P97
Nishimoto, H.: P264
Nishitani, K.: P162
Niu, C.: P20
Nixon, A. J.: 9.2.1, 11.2.6, 25.4.7,
P91, P117
Noël, D.: 16.1.7
Nocco, E.: P188
Nochi, H.: 11.2.7
Novakofski, K.: 11.4.9, 16.4.3
Nurmi, H.: 25.3.6
Nyengaard, J. R.: P158
Nygaard, J. V.: P23
o
O’brien, F. J.: 11.3.8, P56
O’malley, M.: 25.1.8
O’shaughnessey, K.: 11.2.9
Ochi, M.: P101
Ochs, B. G.: 9.2.8
Oda, T.: 16.1.8
Ofek, G.: P2, P8, P11, P12,
P222
Oh, H.: P53, P57, P169
Ohkawa, S.: P101
Ohmiya, Y.: P239
Olee, T.: P146
Olewinski, R.: 16.1.5, P1
Olson, S. A.: 25.1.7
Omachi, T.: 16.1.8
Omelchenko, A.: P75
Onodera, S.: P239
Onodera, T.: P152
Onuma, K.: P7
Ophelders, D.: P118
Oprenyeszk, F.: 11.3.6
Ortega-sanchez, C.: P84
Ortiz, A.: P22
Ortolani, A.: P37
Ortved, K.: 11.2.6, P117
Owaidah, A.: 16.4.2
Ownby, S. L.: 11.2.4, P212
Ozeki, N.: P179
p
Pérez, F.: 9.4.4, P47, P88
Paatela, T.: 25.3.6, P27
Pachowksi, M.: 11.4.5
Pacifici, M.: 2.1.2
Pacione, C.: 16.1.5, P1
Paessler, H.: 11.3.2
Pagliazzi, G.: P86, P141, P236
Pallante, A. L.: 11.1.9, 21.3.1
Pandey, V.: 9.4.9
Pang, J.: 11.1.6
Pang, S.: 11.1.6
Panseri, S.: P37
Park, S.: 16.2.8, P49
Park, Y.: P268
Parker, J. C.: P125
Parma, A.: P141, P232, P236
Patchornik, S.: P215
Patella, S.: 25.1.1, 25.2.9, P45,
P60, P65
Patil, A. J.: 9.3.5
Pattappa, G.: 16.2.3
Pattyn, C.: 9.2.5
Paul, C.: 9.4.7
Pauli, C.: 9.4.3, P43
Payne, K. A.: 25.1.8
Pearsall, A.: P13, P14, P124
Pelet, S.: 11.3.1, 11.4.4, 25.3.3
Pelletier, J.: 11.1.4, 11.2.5, 25.1.6,
P130
Pennock, A.: P199
Authors‘ Index
Perdisa, F.: 25.1.1, 25.2.9, P45,
P60
Perez, G.: 25.1.6
Perez, J.: 9.2.3
Perez, M.: P61
Peterbauer-Scherb, A.: 11.2.1
Petersen, W.: P72
Petre, B.: P163
Petrera, M.: 11.2.2, 16.2.8
Petrigliano, F.: 25.4.1
Peyrafitte, J.: 16.1.7
Pfeiffer, F.: P51
Philippon, M.: 16.3.1, 24.1.1, P229
Piacentini, A.: 16.1.7
Picard, C.: P32
Picard, G.: P189
Pilz, I. H.: 16.1.2
Pineda, C.: P22
Piontek, T.: P181, P195, P238,
P249, P250
Piovan, G.: P237
Pishva, E.: P233
Plaas, C.: P194
Poddar, M.: P81
Polacek, M.: P98
Polak, J.: P258
Pollock, R.: P87
Pomerantseva, I.: 9.2.6, P265
Poole, A. R.: 19.3.2
Porichis, S.: 25.2.6
Portron, S.: 16.2.5, P103, P256,
P257
Posey, K.: 9.2.7
Potel, J.: P100
Potter, H. G.: P160
Poubelle, P. E.: P39
Pourazar, A.: P246
Power, J.: 11.1.7
Pownder, S. L.: P160
Pravda, M.: P41
Presle, N.: 16.1.6
Pro, S. L.: P138
Prockop, D.: 16.4.9
Prusinska, A.: P249
Puetzer, J.: P184
Pulido, P. A.: P3, P4
Puvanan, K.: P105
Pyda, A.: P250
q
Quaglia, A.: P263
Quiñones-Uriostegui, I.: P22
Quinn, T. M.: 8.2.2, 11.2.8, P113,
P122, P123
Quintin, A.: 9.2.4, P83
Quirbach, S.: P187
r
Rackwitz, L.: P261
Rahatekar, S. S.: 9.3.5
Rai, M.: 16.1.4
Rakhra, K.: P202
Ramanujam, N.: P234
Ramponi, L.: P93, P232, P236
Randolph, M. A.: 9.2.6, P265
Rani, N.: P59, P68
Rappoport, L.: 16.1.5, P1
Rasch, H.: 11.4.7
Raschke, M.: P72
Razzano, P.: 9.3.7
Recht, M. P.: 9.4.2, 25.1.5
Rederstorff, E.: 9.3.9, P256
Redl, H.: 11.2.1
Reed, K.: P13, P14
Reeve, R. E.: P175
Regatte, R.: 25.1.5
Reiff, R.: 25.1.3
Reischling, P.: 25.3.8, P142
Reke, N.: P250
Responte, D. J.: P35
Restrepo, A.: 11.3.1, 11.4.4, 25.3.3,
P30
Richardson, J. B.: 24.1.2, P29, P31, P92,
P125, P217, P262
Riek, J.: P170
Rios, D.: P199
Rivard, G.: 16.3.2
Rivera-Bermudez, M.: P206
Rivera, A. L.: 16.4.4
Robert, H.: P100
Roberts, S.: 25.3.3, 25.4.2, P29,
P31, P92, P125, P173,
P262
Robin, B. N.: P175
Robinson, D.: P26, P215, P273
Robinson, E.: P125
Rodeo, S.: 15.1.3
Rodkey, W. G.: P200, P209
Rodrigo, J. J.: 16.3.3
Rodriguez Iñigo, E.: P107
Rolauffs, B.: 9.2.8
Roosendaal, G.: 11.1.5, P25, P153
Rosenberger, R.: P187
Rosenzweig, D. H.: 8.2.2, 11.2.8, P122,
P123
Ross, K.: P160
Rossi, J.: 11.2.6
Rothdiener, M.: 9.2.8
Royen Van, B.: 9.4.7
Rozen, N.: P188
Rudert, M.: P106, P154, P261
Ruffilli, A.: P5, P10, P86, P93,
P141, P232, P236
Ruike, T.: 11.2.7
Runco, G.: P33
Rushton, N.: 11.1.7, 25.1.9, P19,
P157
Russo, A.: P37, P237
Rusu, D.: P39
Ruvalcaba, E.: P61
s
Słomczykowski, M.: P181
Südkamp, N. P.: 16.1.2, 25.2.6
Süzer, F.: 25.2.8
Sabatino, M.: P89
Sabbioni, G.: P68
Sachot, S.: 16.2.7
Safi, A.: P15
Sague, J. L.: P70
Sah, R. L.: 11.1.9, 21.1.2
Saito, T.: P179
Sakai, T.: 16.1.8
Sakamoto, F. A.: P168
Sakata, R.: P264
Sakaue, M.: 25.4.9
Salih Mohamed, K.: P102
Saliken, D.: 9.4.1
Salo, J.: 19.1.3, P161
Saltzman, C.: 24.3.1
Salzmann, G. M.: 16.2.3, 25.2.6
Sampson, H.: 16.4.9, P175
Samuels, J.: 25.1.5
Samuelson, E.: 25.3.7
Samulski, J.: 14.2
Sanchez, C.: 11.3.6
Sanchez, L. J.: 8.1.3
Sanchez, R. M.: P47
Sandell, L. J.: 16.1.4, 19.3.3
Sandri, M.: P37
Sanen, K.: P118, P120
Sansone, V.: 25.4.4
Santamaria-Olmedo, M.: P84
Santoro, R.: P89
Santos, E.: P107
Saris, D. B.: 9.1.1, 9.3.4, 9.3.8,
11.3.5, 11.4.2, P77,
P79, P133, P143,
P151, P156, P198
Sasaki, E.: 25.1.4
Sasaki, H.: 11.1.3
Satake, T.: P162
Satchell, P. W.: P160

Schadow, S.: 16.1.9
Schattenberg, T.: P108
Schepens, A.: P56
Schiavinato, A.: P203
Schils, J. P.: P168
Schimenti, J. C.: 25.4.5
Schmal, H.: 16.1.2
Schmidt, T. A.: 21.1.1
Schmitt, B.: 19.1.1
Schnabel, L. V.: 15.1.1, 25.4.5, P160
Schneider, E.: P168
Schoenhuber, H.: P263
Schon, B. S.: 25.4.6, P46
Schon, L.: P34
Schrijver, E.: 16.4.6
Schrobback, K.: 25.4.6, P201
Schuchman, E. H.: 16.2.7
Schuster, T.: P261
Schutgens, R. E.: P25
Schuurman, A. H.: P55
Schweitzer, M.: P202
Sciarretta, F.: P66, P267
Scimeca, M.: 11.2.6, P117
Secretan, C. C.: 9.3.3
Sekiya, I.: 16.4.9, P179
Seo, H.: 9.2.3, P223
Sepúlveda, J.: P135
Sernik, J.: 9.3.3
Serrão, P. R.: 25.1.3
Serra, R.: 9.2.3
Servien, E.: 9.1.3, P100
Severino, N.: P33
Seyhan, B.: P224, P225
Sgaglione, N. A.: 9.3.7
Shabshin, N.: P188
Shah, N. V.: 9.3.7
Shani, J.: P26
Shannon, F.: P102
Shelyakova, T.: P37
Sherman, O.: 9.4.2
Shetty, A. A.: P192, P193
Shibuya, H.: P101
Shih, C.: P174
Shilpa, P.: P105
Shimomura, K.: 25.4.9, P207, P221
Shino, K.: P221
Shintani, N.: P231
Shirai, T.: P162
Shive, M. S.: 11.3.1, 11.4.4, 21.2.3,
25.3.3, P30
Shnirelman, A.: P75
Shterling, A.: P52, P177
Siclari, A.: P197, P243
Sidler, M.: P159
Siebold, R.: 11.3.2
Siegert, A.: 11.4.8
Sieker, J.: P154
Sierra-mulet, A.: 9.4.1, P180, P182
Sierra, A.: P176
Sierra, L.: 9.4.4
Siffri, P. C.: 16.3.3
Signorile, L.: P150, P150
Simões, A.: P33
Simental, M.: P135
Simonaro, C. M.: 16.2.7
Singh, N.: 9.3.5
Sinquin, C.: P256
Siston, R.: P230
Skarpas, G.: P111
Skinner, J.: P87
Small, K.: 25.2.5
Smit, T. H.: 9.4.7, P172
Smyth, N.: P242
Sobol, E.: P75
Sodha, S.: 25.2.5
Sokolowski, M.: P166
Solar-Cafaggi, S.: P122
Solis-Arrieta, L.: P22, P47, P61
Sommerfeldt, M.: P176
Son, Y.: P115
Song, L.: P270
Soto, A.: P135
Sourice, S.: 9.3.9, 16.2.5, P256,
P257
Authors‘ Index 187
Souza, M. C.: P24
Sovani, S.: P146
Spalding, T.: 2.3.2, 16.2.9, P186
Sparks, H.: P91
Spector, M.: 11.1.8, P158
Speirs, A. D.: P202
Spencer, S.: P186
Squillace, D. M.: P2, P8, P11, P12,
P222
St-Arnaud, R.: 25.1.6
Stagni, C.: P59, P68
Stanish, W. D.: 11.3.1, 11.4.4, 16.3.9,
25.3.3
Steadman, J.: P200, P209
Steinert, A. F.: P106, P154
Steinmeyer, J.: 16.1.9
Steinwachs, M.: 13.1.2, 21.2.1, 25.2.6
Stelzeneder, D.: P164, P167, P192,
P193
Stenberg, J.: P133
Stendal, J. H.: 25.4.3
Stoddart, M.: P147, P271
Stoeckle, U.: 9.2.8
Strauss, E.: 11.3.9, 15.2.1
Strazzari, A.: P37
Strijkers, G.: 9.4.7
Stroebel, S.: 25.4.6
Stukenborg-Colsman, C.: P194
Sugita, N.: 25.4.9
Suhaeb, A.: P208
Sukegawa, A.: P152
Sukegawa, K.: P7
Sullivan, M.: P134
Sun, J.: 16.3.2, 16.3.4, 16.3.9,
P39, P189
Sundback, C. A.: 9.2.6, P265
Sundman, E.: P241
Suri, M.: 16.3.3
Surowiec, R.: P163
Surtel, D. A.: 9.2.2, 9.4.8, 11.2.3,
P118, P120, P121,
P126
Susa, T.: P221
Syed, H.: P21
Szomolanyi, P.: P30
Szulc, A.: P195, P238
Szumowski, U.: 11.4.3
t
Töyräs, J.: 19.1.3, P161
Tabet, S. K.: 25.3.8
Taheri, M.: P32
Takahashi, I.: 25.1.4
Takamatsu, A.: 16.1.8
Takaso, M.: P7
Takayama, K.: 11.1.3
Takazawa, K.: P101
Tamay De Dios, L.: P84
Tamez-pena, J.: 11.4.4, P30
Tampere, T.: 9.4.6
Tampieri, A.: P37
Tanideh, N.: P233
Taniguchi, N.: 25.1.6
Tavakoli, A.: P233
Taylor, D.: P85
Taylor, S.: P71
Temple-Wong, M. M.: 21.1.2
Teramura, T.: 25.4.9
Tharakan, B.: P175
Theodoropoulos, J.: 11.2.2, 16.2.8
Thermann, H.: 25.2.8, P194
Thier, S.: P110
Thomas, D.: 16.4.9
Thompson, E.: P56
Thompson, P.: P186
Tichy, B.: P80
Timoncini, A.: P93
Tischer, T.: P131
Toh, S.: 25.1.4
Totterman, S. M.: 11.4.4, P30
Tran-Khanh, N.: 25.3.3
Trattnig, S.: 11.4.4, 11.4.5, 19.1.1,
P30, P164, P166
Trimborn, M.: 16.2.6
Trivedi, J.: P173
Trutiak, N.: P234
Tsai-Wu, J.: P145
Tsai, T.: P174
Tse, Y.: 11.1.6
Tseng, A.: 9.2.6
Tsuchida, A. I.: 9.3.8, 11.3.5, 11.4.2,
P151, P156
Tsuda, E.: 25.1.4
Turner, L. J.: 25.4.4
Turner, S.: P173
u
Uchida, K.: P7
Uhl, M.: 25.2.6
Umeda, T.: 25.1.4
Urabe, K.: P7
Usas, A.: P81
Uynuk-ool, T.: 9.2.8
Uzun, M.: P224, P225
v
Vacanti, J.: 9.2.6, P265
Valderrabano, V.: P64
Valverde-Franco, G.: 11.1.4
Van Amerongen, E. A.: P55
Van Blitterswijk, C.: 16.2.4, P42
Van Buul, G.: 16.4.5
Van De Putte, T.: 25.2.7
Van Den Akker, G.: 9.4.8
Van Der Kraan, P.: P259
Van Der Lee, J.: P133
Van Der Veen, A. J.: P172
Van Griensven, M.: 11.2.1
Van Meegeren, M. E.: 11.1.5, P25, P153
Van Osch, G. J.: 3.2.2, 16.2.2, 16.4.5,
P150, P198, P259
Van Rhijn, L. W.: 9.2.2, 9.4.8, 11.2.3,
P118, P120, P121,
P126
Van Rijen, M. H.: 16.4.6
Van Roermund, P. M.: 24.3.2, 25.1.2
Van Roon, J. A.: P153
Van Royen, B. J.: P172
Van Veghel, K.: 11.1.5
Van Weeren, P.: 9.3.4, 11.1.2
Vanhauwermeiren, H.: 25.2.7
Vannini, F.: 25.2.9, P5, P10, P44,
P86, P93, P141, P232,
P236
Vasanawala, S.: 25.3.8
Vasara, A. I.: 25.3.6, P27
Vasheghani Farahani, F.: 25.1.6
Vasilceac, F. A.: 25.1.3, P24
Vasishta, V. G.: P211
Vaz De Lima, M.: P33
Vecsei, V.: 16.3.6
Veen Van Der, A.: 9.4.7
Vekszler, G.: 11.4.6
Velasquillo, C.: P22, P47, P61, P84,
P88
Velebný, V.: P41
Venugopal, V.: 16.3.8
Verbruggen, G.: 9.2.5, 11.3.3, 19.2.2,
P6, P58
Verdonk, P. C.: 9.2.5, 9.4.6, 11.3.2,
11.3.3, 19.2.2, P6,
P58, P178, P183,
P185, P188
Verdonk, R.: 9.2.5, 9.4.6, 11.3.2,
11.3.3, 19.2.2, P6,
P58, P178, P183,
P185, P188, P217
Verhaar, J.: 16.2.2, 16.4.5, P259
Vernon, L.: P109
Victor, J.: 19.2.2
Vignes-Colombeix, C.: P256
Vijayan, S.: P87
Villafuertes, E.: 16.4.5

188
Villalobos Córdova, F.: 9.4.4, P88
Villalobos Jr, F. E.: P47
Vinatier, C.: 9.3.9, 16.2.5, P103,
P256, P257
Vincken, K. L.: 11.4.2
Viren, T.: 19.1.3
Vogrin, M.: P244
Vogt, S.: P272
Volpi, P.: P263
Von Keudell, A.: 25.2.5, P21, P82
Von Rechenberg, B.: P159
Von Windheim, J.: P234
Voncken, J.: 9.4.8, 11.2.3, P120
Vonk, L.: 11.3.5, P79
Voss, L.: 9.2.2, P120
w
Waarsing, J.: 16.4.5
Wagner, P.: P105
Waldman, S.: 11.1.6
Walker, K. E.: 11.2.4
Walker, P.: 9.4.2, 25.1.5, P214
Waller, C. S.: P217
Walsh, D.: 2.2.2
Walter, N. M.: P38
Wang, Q.: 9.2.8
Ware, M. C.: 16.3.3
Watt, S. M.: 16.4.2
Watts, A. E.: 25.4.7
Wawrzynek, W.: P69, P190
Weckbach, S.: P108
Weinans, H.: 16.4.5
Weinstein, T.: P273
Weiss, P.: 9.3.9, 16.2.5, P103,
P256, P257
Weissenberger, M.: P154
Welsch, G. H.: 11.4.5, 11.4.6, 19.1.1,
19.1.2, P164
Welter, J. F.: 16.4.4
Welting, T. J.: 9.2.2, 9.4.8, 11.2.3,
P118, P120, P121,
P126
Wendt, D.: P89
Wessinger, P. H.: 16.3.3
Wexel, G.: P272
Widhalm, H. K.: 11.4.6
Widhalm, K.: 11.4.6
Widuchowski, J.: P69, P190
Widuchowski, W.: P69, P190
Wiegant, K.: 25.1.2, P16, P77
Wiewiorski, M.: P64
Wijnands, K.: P126
Wilensky, D.: P109
Willemot, L.: 9.4.6, P178
Williams, I, R. J.: P85
Williams, R.: 11.4.9, P160, P217
Williams, S.: P71, P78
Wilson, G.: P13, P14, P124
Wilton, T.: P217
Wimmer, M. A.: 16.1.5, P1
Winalski, C. S.: 16.2.9, P168
Windhager, R.: P116, P166
Winterborn, A.: 11.1.6
Woiciechowsky, C.: P171
Wolfová, L.: P41
Wondrasch, B.: 11.4.5
Wood, D. J.: 25.3.5, P94, P95,
P247
Woodell-May, J.: 11.2.9
Woodfield, T.: 11.4.8, 25.4.6, P46
Wright, K.: P29, P31, P262
Wuebbenhorst, D.: P272
Wyland, D.: 16.3.3
x
Xiafei, R.: P18
Xiao, X.: 25.1.8, P127
Authors‘ Index
y
Yamamoto, Y.: 25.1.4
Yamashita, S.: 16.1.8
Yang, S.: P49
Yang, Y.: P48
Yang, Z.: P18
Yao, J. Q.: P18
Yaroshinsky, A.: 11.4.4
Yasuda, K.: P62, P239
Yik, J.: 9.2.7, P119
Yoshikawa, H.: 25.4.9, P207, P221
Yu, H.: P226
Yuan, L.: P20
z
Zaffagnini, S.: P45, P65
Zak, L.: P80
Zaman, T.: P104, P105, P208
Zantop, T.: P72
Zaslav, K. R.: P26
Zati, A.: 25.3.4
Zayed, N.: 11.2.5, P130
Zbyn, S.: 19.1.1
Zeitler, E. M.: 25.1.7
Zelle, S.: P72
Zenclussen, M. L.: P171
Zenobi-Wong, M.: P48
Zhang, R.: P270
Zhao, X.: P265
Zhao, Z.: P2, P8, P11, P12,
P128, P222
Zheng, M. H.: P95, P247
Zhou, X.: P219, P226
Zorzi, C.: P40, P177, P188,
P237
Zuehlke, D.: P194
Zur, G.: P52

Authors‘ Index 189

190
Notes

Please join join us us for for the
Sponsored Symposium
“The Evolution of Autologous Chondrocyte
“The Evolution of Autologous Chondrocyte
Implantation and Cartilage Repair”
Implantation and Cartilage Repair”
Description: In this cartilage repair symposium, participants
Description: In this cartilage repair symposium, participants
will learn about the genesis of autologous chondrocyte
will learn about the genesis of autologous chondrocyte
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implantation, the importance of the chondrocyte and how
the standards of clinical evidence, global regulation and
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manufacturing have evolved in this dynamic and exciting field
Date: Monday, May 14th
Date: Monday, May 14th
Time: 13:00 - 14:00
Time: 13:00 - 14:00
Location: Grand Salon
Location: Grand Salon
For more information please visit us at booth #6.
For more information please visit us at booth #6.