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DIAGNOSTICS: THE SCIENTIFIC AND<br />
TECHNOLOGY HORIZONS<br />
PROFESSOR C R LOWE FREng<br />
INSTITUTE OF BIOTECHNOLOGY<br />
DEPARTMENT OF CHEMICAL ENGINEERING AND BIOTECHNOLOGY<br />
UNIVERSITY OF CAMBRIDGE
BIOMEDICAL SENSING TECHNOLOGIES<br />
NON-INVASIVE<br />
IMAGING/SPECTROSCOPIC<br />
TECHNIQUES<br />
NON-CONTACT<br />
MINIMALLY-INVASIVE<br />
PERCUTANEOUS<br />
BIOLOGICAL FLUIDS:<br />
SWEAT<br />
TEARS<br />
SALIVA<br />
BREATH<br />
URINE<br />
CONTACT<br />
BIOSENSORS<br />
INVASIVE<br />
BLOOD<br />
CSF<br />
IN-VIVO<br />
IMPLANTED
BIOSENSOR PRINCIPLES<br />
ANALYTE<br />
HOME<br />
(BIO)RECOGNITION SYSTEM<br />
PHYSICIAN’S<br />
OFFICE<br />
TRANSDUCER<br />
CENTRAL LABORATORY<br />
REFERRAL SITE<br />
OPERATING THEATRE<br />
ITU<br />
WORKPLACE<br />
ROADSIDE<br />
FIELD/<br />
FIRST RESPONDERS<br />
INSTRUMENTATION<br />
BATTLEFIELD
(BIO)SENSOR TRANSDUCERS<br />
ELECTRICAL<br />
OPTICAL<br />
ACOUSTIC<br />
THERMAL<br />
MAGNETIC<br />
MICROENGINEERED<br />
POTENTIAL (V)<br />
CURRENT (I)<br />
CONDUCTANCE (Λ)<br />
CAPACITANCE (C)<br />
INDUCTANCE (H)<br />
IMPEDANCE (Z)<br />
FLUORESCENCE<br />
LUMINESCENCE<br />
SPR<br />
RESONANT MIRROR<br />
GRATING COUPLERS<br />
DIFFRACTION GRATINGS<br />
FIBRE OPTIC<br />
QCM<br />
SAW<br />
LOVE/LAMB WAVE
MICROAMPEROMETRIC<br />
BIOSENSORS
MODERN CHALLENGES FOR BIOSENSOR<br />
TECHNOLOGIES<br />
SIMPLE, COST-EFFECTIVE (BIO)SENSORS<br />
FOR ANALYTES IN THE mM-fM RANGE<br />
MULTI-ANALYTE (ARRAY) DEVICES<br />
RAPID, LOW (NO) POWER CONSUMPTION<br />
FULLY INTEGRATED SYSTEMS WITH<br />
SAMPLE PREPARATION, SEPARATION<br />
AND ANALYSIS ON SAME DEVICE<br />
FACILE, COST-EFFECTIVE FABRICATION<br />
E-INTERFACE
MAGNETIC ACOUSTIC RESONATOR SENSOR<br />
(MARS)<br />
LIQUID SAMPLE<br />
PIEZOELECTRIC<br />
QUARTZ DISC<br />
(AT-cut, 0.25mm<br />
thick, 12mm dia)<br />
ACOUSTIC WAVE<br />
RF COIL<br />
N<br />
NdFeB MAGNET<br />
AIR GAP<br />
S
LOCK-IN<br />
AMPLIFIER<br />
MARS EXPERIMENTAL SET-UP<br />
PC/SOFTWARE<br />
SIGNAL<br />
GENERATOR<br />
AM DETECTOR DIODE<br />
MARS DEVICE
hIMMUNOGLOBULIN G BINDING TO MARS<br />
600<br />
500<br />
400<br />
-Δf (Hz)<br />
300<br />
200<br />
100<br />
0<br />
0 25 50 75 100 125 150 175200<br />
[hIgG] (μg/ml)
ACOUSTIC SPECTRA OF PROTEIN MULTILAYERS<br />
Frequency shift (KHz)<br />
50<br />
40<br />
30<br />
20<br />
10<br />
ACOUSTIC SPECTRA<br />
1. IgG 1000 ug/ml<br />
2. Prot A 250 ug/ml<br />
3. IgG 250 ug/ml<br />
4. Prot A 250 ug/ml<br />
5. IgG 250 ug/ml<br />
0<br />
0 100 200 300 400 500 600<br />
Penetration depth (nm)<br />
ACOUSTIC EVANESCENT WAVE<br />
200<br />
150<br />
100<br />
50<br />
0<br />
10 30 50 100 200 500 1000<br />
IgG<br />
Frequency (MHz)<br />
Frequency (MHz)<br />
MASS LOADING<br />
..<br />
ƒ n = n V s / λ = n V s / 2t<br />
Δƒ ∝ mass of the layer<br />
Sauerbrey<br />
t<br />
VISCOELASTIC COUPLING (MOLECULAR<br />
CONFORMATION/ACOUSTIC FINGERPRINT)<br />
. .<br />
Δƒ ∝ (ρη) 1/2<br />
Kanazawa
MULTI-ANALYTE ANALYSIS BY FREQUENCY TAGGING OF<br />
QUARTZ CRYSTAL FRAGMENTS<br />
2<br />
Amplitude (mV)<br />
-2<br />
-6<br />
-10<br />
-14<br />
221.35 221.39 221.43 221.47 221.51<br />
Frequency (MHz)<br />
2<br />
Amplitude (mV)<br />
-2<br />
-6<br />
-10<br />
-14<br />
221.35 221.39 221.43 221.47 221.51<br />
Frequency (MHz)
REMOTE ACOUSTIC MEASUREMENTS<br />
WITH A TOROIDAL ELECTRIC FLUX<br />
GLASS BEAKER<br />
30<br />
20<br />
10<br />
0<br />
-10<br />
QUARTZ DISC<br />
-20<br />
-30<br />
20.1 20.12 20.14 20.16 20.18 20.2<br />
TOROIDAL ANTENNA<br />
(TRANSCEIVER)<br />
f (MHz)
FABRICATION OF HOLOGRAPHIC<br />
SENSORS<br />
LASER<br />
SPATIAL<br />
FILTER<br />
MIRROR<br />
ACHROMAT<br />
GLASS TANK<br />
EMULSION<br />
4°<br />
MIRROR
PRINCIPLE OF HOLOGRAPHIC SENSORS<br />
θ<br />
n<br />
“Smart” Polymer<br />
reflectance (%)<br />
35<br />
30<br />
25<br />
20<br />
15<br />
10<br />
5<br />
l pk<br />
R<br />
pk<br />
ΣR i<br />
0<br />
600 610 620 630 640 650 660<br />
wavelength (nm)<br />
d<br />
λ max<br />
= 2ndcosθ<br />
COLOUR<br />
BRIGHTNESS<br />
IMAGE/<br />
ALPHANUMERIC<br />
MESSAGE<br />
POSITION
DETERMINATION OF WATER CONTENT<br />
OF AVIATION FUEL<br />
No trace of<br />
water in Jet<br />
Fuel<br />
Water<br />
detected in<br />
Jet Fuel
HOLOGRAPHIC<br />
“BREATHALYSER”
Wavelength (nm)<br />
800<br />
750<br />
700<br />
650<br />
600<br />
550<br />
500<br />
pH SENSITIVE HOLOGRAMS<br />
MAA<br />
pH<br />
450<br />
2.5 4.5 6.5 8.5 10.5<br />
pH<br />
3 4 5 6 7 8 9<br />
λ max<br />
(nm)<br />
850<br />
800<br />
750<br />
700<br />
650<br />
600<br />
550<br />
500<br />
450<br />
400<br />
mol%<br />
5<br />
6<br />
4<br />
3<br />
2<br />
1.5<br />
3 4 5 6 7 8 9 10<br />
pH<br />
0<br />
λ max (nm)<br />
800<br />
750<br />
700<br />
650<br />
600<br />
550<br />
500<br />
0 1000 2000 3000 4000 5000 6000 7000 8000 9000 4.0 4.5 5.0 5.5 6.0<br />
time (s)<br />
pH
CATION-SENSITIVE HOLOGRAMS<br />
O<br />
O<br />
O<br />
O<br />
O<br />
50mol% 18C6/HEMA<br />
O<br />
O<br />
O<br />
18C6<br />
Δλ max<br />
(nm)<br />
290<br />
240<br />
190<br />
140<br />
90<br />
40<br />
-10<br />
K + (1.33Å)<br />
Na + (0.97Å)<br />
0 10 20 30 40<br />
[X + ] (mM)<br />
150mM Na + +20mM K +
PENICILLIN-RESPONSIVE HOLOGRAM<br />
200<br />
diffraction wavelength shift (nm)<br />
180<br />
160<br />
140<br />
120<br />
100<br />
80<br />
60<br />
40<br />
20<br />
0<br />
-20<br />
0 2 4 6 8 10 12<br />
diffraction wavelength (nm)<br />
750<br />
700<br />
650<br />
600<br />
550<br />
0<br />
0.1<br />
0.5<br />
1<br />
0 200 400 600 800 1000 1200 1400 1600 1800<br />
time (s)<br />
4<br />
3<br />
2<br />
5<br />
6<br />
7<br />
8<br />
9<br />
10<br />
rate of diffraction wavelength shift (nm / s)<br />
3.5<br />
3.0<br />
2.5<br />
2.0<br />
1.5<br />
1.0<br />
0.5<br />
0.0<br />
-0.5<br />
[penicillin] mM<br />
0 2 4 6 8 10 12<br />
[penicillin G] (mM)
BORONATE-BASED GLUCOSE HOLOGRAM<br />
1<br />
0<br />
Elapsed Time (min)<br />
200 400 600 800 900<br />
Δλmax (nm)<br />
-4<br />
-9<br />
6<br />
HO<br />
11<br />
R1<br />
O R2<br />
- O<br />
B<br />
15.5<br />
19<br />
-14<br />
R<br />
23.5<br />
27 [Glucose]
REAL-TIME HOLOGRAPHIC GLUCOSE<br />
CONTACT LENS BIOSENSOR<br />
KEY ISSUES TO ADDRESS<br />
TOXICITY<br />
TEAR [GLUCOSE] < BLOOD<br />
[GLUCOSE]<br />
pH VARIATION<br />
TIME LAG (~MIN)<br />
SELECTIVITY (LACTATE)<br />
OPTICAL<br />
PHYSICS/DETECTION
TRACKING OF BLOOD GLUCOSE IN<br />
TEAR FLUID IN VIVO<br />
160<br />
740<br />
Blood-Glucose [mg%]<br />
140<br />
120<br />
100<br />
720<br />
700<br />
Wavelength [nm]<br />
80<br />
0 12 16 19 23 26<br />
Time [minutes]<br />
680
L-LACTATE HOLOGRAM<br />
140<br />
730<br />
120<br />
15mol%<br />
710<br />
100<br />
20mol%<br />
Peak Wavelength (nm)<br />
690<br />
670<br />
650<br />
630<br />
Peak Shift (nm)<br />
80<br />
60<br />
40<br />
12mol%<br />
25mol%<br />
10mol%<br />
8mol%<br />
30mol%<br />
610<br />
20<br />
5mol%<br />
40mol%<br />
590<br />
0 5000 10000 15000<br />
20000<br />
0<br />
0 5 10 15<br />
Time (s)<br />
[Lactate] (mM)
“BIOLOGY-ON-A-CHIP” CONCEPT<br />
580nm<br />
2mm<br />
NANOWELL<br />
INPUT<br />
100μm<br />
OUTPUT<br />
HOLOGRAMS<br />
λ max<br />
DETECTORS<br />
A 580
ALCOHOLIC FERMENTATION IN SACCHAROMYCES<br />
CEREVISIAE<br />
30<br />
25<br />
20<br />
Δλ (nm)<br />
15<br />
10<br />
5<br />
0<br />
0 200 400 600 800 1000<br />
Time (min)
SPOILAGE OF WHOLE MILK BY<br />
LACTOBACILLUS CASEI<br />
640<br />
6.5<br />
620<br />
6.3<br />
6.1<br />
600<br />
5.9<br />
λ max<br />
(nm)<br />
580<br />
560<br />
540<br />
λ max (nm)<br />
700<br />
600<br />
500<br />
5.7<br />
5.5<br />
5.3<br />
5.1<br />
pH<br />
520<br />
400<br />
4 5 6 7<br />
pH<br />
4.9<br />
500<br />
4.7<br />
0 2000 4000 6000 8000 10000 12000 14000<br />
Time (s)
30<br />
650<br />
B. SUBTILIS<br />
FERMENTATIO<br />
N<br />
[Glucose] (mM)<br />
25<br />
20<br />
15<br />
10<br />
5<br />
HEXOKINASE<br />
ACCU-CHECK<br />
640<br />
630<br />
620<br />
610<br />
600<br />
590<br />
580<br />
570<br />
Peak Wavelength (nm)<br />
0<br />
560<br />
0 1 2 3 4 5 6 7 8 9 10<br />
Time (h)<br />
10<br />
7.3<br />
7.2<br />
Peak Wavelength (nm)<br />
660<br />
650<br />
640<br />
630<br />
620<br />
610<br />
600<br />
590<br />
580<br />
570<br />
5 10 15 20 25 30<br />
OD 600 nm<br />
1<br />
0.1<br />
7.1<br />
6.9<br />
6.8<br />
6.7<br />
6.6<br />
6.5<br />
0.01<br />
6.4<br />
0 1 2 3 4 5 6 7 8 9 10<br />
7<br />
pH<br />
[Glucose] (mM)<br />
Time (h)
GERMINATION OF Bacillus SPORES:<br />
MONITORED WITH A Ca ++ -SENSITIVE<br />
HOLOGRAM<br />
1.1<br />
0<br />
1.1<br />
1.0<br />
1.0<br />
0.9<br />
Δλ max<br />
(nm)<br />
-1<br />
-2<br />
-3<br />
OD 600nm<br />
0.8<br />
0.7<br />
0.6<br />
0.5<br />
0.4<br />
-5 -4 -3 -2 -1 0<br />
Δλnm<br />
0.9<br />
0.8<br />
0.7<br />
0.6<br />
OD 600nm<br />
-4<br />
0.5<br />
-5<br />
0 5 10 15 20 25 30<br />
Time (min)<br />
0.4
HAND-HELD PATHOGEN DETECTION
APPLICATIONS OF<br />
HOLOGRAPHIC SENSORS<br />
MEDICAL DIAGNOSTICS/DEVICES<br />
INDUSTRIAL<br />
DRUG DISCOVERY<br />
HIGH THROUGHPUT BIOLOGY<br />
FOOD/BEVERAGES<br />
COSMETICS<br />
SECURITY/AUTHENTICITY<br />
BRAND PROTECTION<br />
PACKAGING<br />
TOYS/DECORATIVES<br />
SMART CLOTHES<br />
LIVING ARCHITECTURE
E-MEDICINE<br />
EMERGENCY<br />
ROOM<br />
WEARABLE<br />
PERCUTANEOUS<br />
IMPLANTED<br />
SENSORS<br />
PATIENT<br />
2-WAY VIDEO LINK<br />
FOR IMAGE DATA<br />
CENTRALISED<br />
RECORDS<br />
DATABASE<br />
NETWORK<br />
SWITCHING<br />
FIRST<br />
RESPONDERS<br />
HOME<br />
WORKPLACE<br />
PHYSICIAN’S<br />
OFFICE<br />
BLOOD<br />
CHEMISTRY<br />
PC PERIPHERALS<br />
PRIMARY CARE<br />
PROVIDER
KEY DRIVERS FOR POINT-OF-CARE<br />
DIAGNOSTICS<br />
LIFESTYLE DIAGNOSTICS<br />
WELLBEING MONITORING<br />
PERSONALISED MEDICINE<br />
COST REDUCTION<br />
MINIATURISATION<br />
E-MEDICINE