Scientific Report 2003-2004 - Cleveland Clinic Lerner Research ...

The Department of Biomedical EngineeringBone Biology, Skeletal Reconstruction,Aging and OsteoporosisCONNECTIVETISSUEBIOLOGYOur laboratory is focused on advancingunderstanding the field of boneformation and repair. This has particularrelevance to age-associated skeletal changes suchas osteoporosis. Our work includes developmentof more effective, less invasive methods fortreatment of fractures and deformities of theskeleton through advanced clinical procedures.This increasingly draws us into work directed atunderstanding early events in osteoblasticdifferentiation. We integrate and draw ondisciplines of cell and molecular biology, growthfactor expression and action, cell matrixinteraction, image processing, and biomechanics.Osteoblastic Stem CellsNormal bone marrow is populated byundifferentiated stem cells, which are recruitedthroughout life in the processes of bone growth,repair, and remodeling. These cells are critical tobone formation. One aspect of our work focuseson understanding changes which occur in theserare cells during normal aging and additionalchanges which result from hormonal changes atmenopause, medications (e.g., corticosteroids)habits (e.g. smoking) and from selected diseases(e.g. Diabetes and Sickle Cell Anemia).We have also devised innovative andminimally invasive methods for harvest and rapidcollection of bone stem cells, which will facilitatethe use of these cells for bone tissue engineeringand other therapeutic applications.Bone RegenerationRegeneration of new bone segments andlimb lengthening can be accomplished using thebiologic process known as distraction osteogenesis.Distraction osteogenesis involves theestablish of a vascular healing fracture callus andthen stretching the callus using controlledmechanical distraction. This distraction results ina prolonged proliferation of osteoblasticprogenitors in the callus (the growth phase ofbone formation) generating new bone tissue inthe area where the bone is pulled apart. We arecurrently developing fully implantable devicesthat use the process of distraction osteogenesis toregenerate bone segments and lengthen limbswithout cumbersome and painful frames.Development and Testing of EffectiveMaterials for Bone GraftingCurrently, most clinical bone graftprocedures involve the harvest of bone from onesite and transplantation to another. This subjectspatients to additional surgery, blood loss, andpain. A number of synthetic materials (includingcalcium phosphate ceramics, purified collagenpreparations, and some polymers) have been usedsuccessfully to heal small bone defects in animals.Similarly, several growth factors appear to have asignificant positive effect on bone healing.However, the formulation of an optimal compositeof available materials (matrix, proteins, and cells)for clinical use requires evaluation of thesecomposites in a model that is appropriate in bothsize and anatomy to model the clinical setting. Manymaterials work well in small defects in rodent bones,but fail in larger animals.Since one-half of all bone grafting materialsis used for spinal fusions, our laboratory hasdeveloped a segmental canine posterior spinalfusion model that allows efficient and sensitiveevaluation of composite graft materials for spinalfusion. This model has documented the failure ofsome composite materials that were underconsideration for clinical application. Wehave also shown that a polymeric materialdelivering a recombinant human bonemorphogenetic protein (rhBMP-2) inmicrogram quantities results in fusionproperties equal to autogenous cancellousbone.We are currently a clinical test sitein a prospective FDA-approvedmulticenter trial of osteogenic protein-1(BMP-7) for treatment of tibial nonunion.The development of safe andeffective synthetic bone graft materialswill have a dramatic impact in reducingthe morbidity of bone grafting proceduresin the near future.THE MUSCHLERLABORATORYThe Muschler LaboratoryYoichi Matsukura, M.D., Ph.D.Chizu Nakamoto, Ph.D.Cynthia Boehm, B.S.George F. Muschler, M.D.Muschler GF, Kotschi H: Bone Transport and Lengthening System. U.S. Patent#5,429,638. Issued July 4, 1995.Hyodo A, Kotschi H, Kambic H, Muschler G. Bone transport using intramedullaryfixation and a single flexible traction cable. Clin Orthop 325:256-268, 1996.Muschler GF, Boehm C, Easley K: Aspiration to obtain osteoblastic progenitorscells from human bone marrow: The influence of aspiration volume. J Bone JointSurg 79A: 1699-1709, 1997.Majors A, Boehm C, Nitto H, Midura R, Muschler G: Characterization of humanbone marrow stromal cells with respect to osteoblastic differentiation. J OrthopRes 15:546-457, 1997.Muschler GF: Method of preparing a composite bone graft. U.S. Patent #5,824,084issued: Oct. 20, 1998.Muschler GF, Lane JM. Principles of Bone Fusion. In: Principles and Techniques ofSpinal Surgery. Rothman and Simeone eds. (New York, W.B. Saunders, Co.,1999).Muschler GF, Boehm CA, Nitto H: Age and gender related changes in the numberand prevalence of osteoblastic progenitors in human bone marrow (submitted).41