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DIAGNOSTICS: THE SCIENTIFIC AND
TECHNOLOGY HORIZONS
PROFESSOR C R LOWE FREng
INSTITUTE OF BIOTECHNOLOGY
DEPARTMENT OF CHEMICAL ENGINEERING AND BIOTECHNOLOGY
UNIVERSITY OF CAMBRIDGE

BIOMEDICAL SENSING TECHNOLOGIES
NON-INVASIVE
IMAGING/SPECTROSCOPIC
TECHNIQUES
NON-CONTACT
MINIMALLY-INVASIVE
PERCUTANEOUS
BIOLOGICAL FLUIDS:
SWEAT
TEARS
SALIVA
BREATH
URINE
CONTACT
BIOSENSORS
INVASIVE
BLOOD
CSF
IN-VIVO
IMPLANTED

BIOSENSOR PRINCIPLES
ANALYTE
HOME
(BIO)RECOGNITION SYSTEM
PHYSICIAN’S
OFFICE
TRANSDUCER
CENTRAL LABORATORY
REFERRAL SITE
OPERATING THEATRE
ITU
WORKPLACE
ROADSIDE
FIELD/
FIRST RESPONDERS
INSTRUMENTATION
BATTLEFIELD

(BIO)SENSOR TRANSDUCERS
ELECTRICAL
OPTICAL
ACOUSTIC
THERMAL
MAGNETIC
MICROENGINEERED
POTENTIAL (V)
CURRENT (I)
CONDUCTANCE (Λ)
CAPACITANCE (C)
INDUCTANCE (H)
IMPEDANCE (Z)
FLUORESCENCE
LUMINESCENCE
SPR
RESONANT MIRROR
GRATING COUPLERS
DIFFRACTION GRATINGS
FIBRE OPTIC
QCM
SAW
LOVE/LAMB WAVE

MICROAMPEROMETRIC
BIOSENSORS

MODERN CHALLENGES FOR BIOSENSOR
TECHNOLOGIES
SIMPLE, COST-EFFECTIVE (BIO)SENSORS
FOR ANALYTES IN THE mM-fM RANGE
MULTI-ANALYTE (ARRAY) DEVICES
RAPID, LOW (NO) POWER CONSUMPTION
FULLY INTEGRATED SYSTEMS WITH
SAMPLE PREPARATION, SEPARATION
AND ANALYSIS ON SAME DEVICE
FACILE, COST-EFFECTIVE FABRICATION
E-INTERFACE

MAGNETIC ACOUSTIC RESONATOR SENSOR
(MARS)
LIQUID SAMPLE
PIEZOELECTRIC
QUARTZ DISC
(AT-cut, 0.25mm
thick, 12mm dia)
ACOUSTIC WAVE
RF COIL
N
NdFeB MAGNET
AIR GAP
S

LOCK-IN
AMPLIFIER
MARS EXPERIMENTAL SET-UP
PC/SOFTWARE
SIGNAL
GENERATOR
AM DETECTOR DIODE
MARS DEVICE

hIMMUNOGLOBULIN G BINDING TO MARS
600
500
400
-Δf (Hz)
300
200
100
0
0 25 50 75 100 125 150 175200
[hIgG] (μg/ml)

ACOUSTIC SPECTRA OF PROTEIN MULTILAYERS
Frequency shift (KHz)
50
40
30
20
10
ACOUSTIC SPECTRA
1. IgG 1000 ug/ml
2. Prot A 250 ug/ml
3. IgG 250 ug/ml
4. Prot A 250 ug/ml
5. IgG 250 ug/ml
0
0 100 200 300 400 500 600
Penetration depth (nm)
ACOUSTIC EVANESCENT WAVE
200
150
100
50
0
10 30 50 100 200 500 1000
IgG
Frequency (MHz)
Frequency (MHz)
MASS LOADING
..
ƒ n = n V s / λ = n V s / 2t
Δƒ ∝ mass of the layer
Sauerbrey
t
VISCOELASTIC COUPLING (MOLECULAR
CONFORMATION/ACOUSTIC FINGERPRINT)
. .
Δƒ ∝ (ρη) 1/2
Kanazawa

MULTI-ANALYTE ANALYSIS BY FREQUENCY TAGGING OF
QUARTZ CRYSTAL FRAGMENTS
2
Amplitude (mV)
-2
-6
-10
-14
221.35 221.39 221.43 221.47 221.51
Frequency (MHz)
2
Amplitude (mV)
-2
-6
-10
-14
221.35 221.39 221.43 221.47 221.51
Frequency (MHz)

REMOTE ACOUSTIC MEASUREMENTS
WITH A TOROIDAL ELECTRIC FLUX
GLASS BEAKER
30
20
10
0
-10
QUARTZ DISC
-20
-30
20.1 20.12 20.14 20.16 20.18 20.2
TOROIDAL ANTENNA
(TRANSCEIVER)
f (MHz)

FABRICATION OF HOLOGRAPHIC
SENSORS
LASER
SPATIAL
FILTER
MIRROR
ACHROMAT
GLASS TANK
EMULSION
4°
MIRROR

PRINCIPLE OF HOLOGRAPHIC SENSORS
θ
n
“Smart” Polymer
reflectance (%)
35
30
25
20
15
10
5
l pk
R
pk
ΣR i
0
600 610 620 630 640 650 660
wavelength (nm)
d
λ max
= 2ndcosθ
COLOUR
BRIGHTNESS
IMAGE/
ALPHANUMERIC
MESSAGE
POSITION

DETERMINATION OF WATER CONTENT
OF AVIATION FUEL
No trace of
water in Jet
Fuel
Water
detected in
Jet Fuel

HOLOGRAPHIC
“BREATHALYSER”

Wavelength (nm)
800
750
700
650
600
550
500
pH SENSITIVE HOLOGRAMS
MAA
pH
450
2.5 4.5 6.5 8.5 10.5
pH
3 4 5 6 7 8 9
λ max
(nm)
850
800
750
700
650
600
550
500
450
400
mol%
5
6
4
3
2
1.5
3 4 5 6 7 8 9 10
pH
0
λ max (nm)
800
750
700
650
600
550
500
0 1000 2000 3000 4000 5000 6000 7000 8000 9000 4.0 4.5 5.0 5.5 6.0
time (s)
pH

CATION-SENSITIVE HOLOGRAMS
O
O
O
O
O
50mol% 18C6/HEMA
O
O
O
18C6
Δλ max
(nm)
290
240
190
140
90
40
-10
K + (1.33Å)
Na + (0.97Å)
0 10 20 30 40
[X + ] (mM)
150mM Na + +20mM K +

PENICILLIN-RESPONSIVE HOLOGRAM
200
diffraction wavelength shift (nm)
180
160
140
120
100
80
60
40
20
0
-20
0 2 4 6 8 10 12
diffraction wavelength (nm)
750
700
650
600
550
0
0.1
0.5
1
0 200 400 600 800 1000 1200 1400 1600 1800
time (s)
4
3
2
5
6
7
8
9
10
rate of diffraction wavelength shift (nm / s)
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
-0.5
[penicillin] mM
0 2 4 6 8 10 12
[penicillin G] (mM)

BORONATE-BASED GLUCOSE HOLOGRAM
1
0
Elapsed Time (min)
200 400 600 800 900
Δλmax (nm)
-4
-9
6
HO
11
R1
O R2
- O
B
15.5
19
-14
R
23.5
27 [Glucose]

REAL-TIME HOLOGRAPHIC GLUCOSE
CONTACT LENS BIOSENSOR
KEY ISSUES TO ADDRESS
TOXICITY
TEAR [GLUCOSE] < BLOOD
[GLUCOSE]
pH VARIATION
TIME LAG (~MIN)
SELECTIVITY (LACTATE)
OPTICAL
PHYSICS/DETECTION

TRACKING OF BLOOD GLUCOSE IN
TEAR FLUID IN VIVO
160
740
Blood-Glucose [mg%]
140
120
100
720
700
Wavelength [nm]
80
0 12 16 19 23 26
Time [minutes]
680

L-LACTATE HOLOGRAM
140
730
120
15mol%
710
100
20mol%
Peak Wavelength (nm)
690
670
650
630
Peak Shift (nm)
80
60
40
12mol%
25mol%
10mol%
8mol%
30mol%
610
20
5mol%
40mol%
590
0 5000 10000 15000
20000
0
0 5 10 15
Time (s)
[Lactate] (mM)

“BIOLOGY-ON-A-CHIP” CONCEPT
580nm
2mm
NANOWELL
INPUT
100μm
OUTPUT
HOLOGRAMS
λ max
DETECTORS
A 580

ALCOHOLIC FERMENTATION IN SACCHAROMYCES
CEREVISIAE
30
25
20
Δλ (nm)
15
10
5
0
0 200 400 600 800 1000
Time (min)

SPOILAGE OF WHOLE MILK BY
LACTOBACILLUS CASEI
640
6.5
620
6.3
6.1
600
5.9
λ max
(nm)
580
560
540
λ max (nm)
700
600
500
5.7
5.5
5.3
5.1
pH
520
400
4 5 6 7
pH
4.9
500
4.7
0 2000 4000 6000 8000 10000 12000 14000
Time (s)

30
650
B. SUBTILIS
FERMENTATIO
N
[Glucose] (mM)
25
20
15
10
5
HEXOKINASE
ACCU-CHECK
640
630
620
610
600
590
580
570
Peak Wavelength (nm)
0
560
0 1 2 3 4 5 6 7 8 9 10
Time (h)
10
7.3
7.2
Peak Wavelength (nm)
660
650
640
630
620
610
600
590
580
570
5 10 15 20 25 30
OD 600 nm
1
0.1
7.1
6.9
6.8
6.7
6.6
6.5
0.01
6.4
0 1 2 3 4 5 6 7 8 9 10
7
pH
[Glucose] (mM)
Time (h)

GERMINATION OF Bacillus SPORES:
MONITORED WITH A Ca ++ -SENSITIVE
HOLOGRAM
1.1
0
1.1
1.0
1.0
0.9
Δλ max
(nm)
-1
-2
-3
OD 600nm
0.8
0.7
0.6
0.5
0.4
-5 -4 -3 -2 -1 0
Δλnm
0.9
0.8
0.7
0.6
OD 600nm
-4
0.5
-5
0 5 10 15 20 25 30
Time (min)
0.4

HAND-HELD PATHOGEN DETECTION

APPLICATIONS OF
HOLOGRAPHIC SENSORS
MEDICAL DIAGNOSTICS/DEVICES
INDUSTRIAL
DRUG DISCOVERY
HIGH THROUGHPUT BIOLOGY
FOOD/BEVERAGES
COSMETICS
SECURITY/AUTHENTICITY
BRAND PROTECTION
PACKAGING
TOYS/DECORATIVES
SMART CLOTHES
LIVING ARCHITECTURE

E-MEDICINE
EMERGENCY
ROOM
WEARABLE
PERCUTANEOUS
IMPLANTED
SENSORS
PATIENT
2-WAY VIDEO LINK
FOR IMAGE DATA
CENTRALISED
RECORDS
DATABASE
NETWORK
SWITCHING
FIRST
RESPONDERS
HOME
WORKPLACE
PHYSICIAN’S
OFFICE
BLOOD
CHEMISTRY
PC PERIPHERALS
PRIMARY CARE
PROVIDER

KEY DRIVERS FOR POINT-OF-CARE
DIAGNOSTICS
LIFESTYLE DIAGNOSTICS
WELLBEING MONITORING
PERSONALISED MEDICINE
COST REDUCTION
MINIATURISATION
E-MEDICINE