clinical biosensors: an interfacing challenge and a ... · clinical biosensors: an interfacing...
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Clinical Biosensors: An interfacing Challenge and a Materials Question
Pankaj VadgamaInterdisciplinary Research Centre (IRC) in Biomedical Materials
Queen Mary, University of London
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So how much more chemistry do we really need?
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IRC in Biomedical Materials
Founded 1992EPSRC Core Grant Focus on BiomaterialsCross-disciplinary cultureMaterials, Engineering, Dentistry17 senior staff
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Why biosensors?
Direct transduction(Bio)selectivitySimple, monolithic structuresMiniaturisedElectrical/optoelectronic readoutContinuous monitoringDeskilled usein vivo / ex vivo / in vitroPOCTTissue + blood monitoring
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User advantages
Consumer commodityMedical ‘bypass’CheapReliableNo sample preparationDisposable Clean technology
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The right chemistry ?
Ionic Substitution
Si-HA
Bone ingrowth (3 week timepoint)
HA
1 mm 1 mm
HA Purity
HA + CaO50 µm 50 µm
Pure HA
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Surface modification of biosensors
Modification of materials interfacial properties in contact with biofluids in order to:
• Create a selective barrier• Allow transport of targeted analyte• Reduce fouling and maintain performance• Improve long term biocompatibility
(inflammation/coagulation)
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Organic polymer membranes
• Cellulose acetate
• Poly(Vinyl Chloride)
• Nafion®
Self-assembled monolayers
• Alkyl thiols
• Organosilanes
Materials used
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Polymer membranes for biosensor interfacing
Classification of polymer membranes:
• Polymeric constituents
• Structural anisotropy
• Pore size(Provides aperture control on biosensors)
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Membrane technology
Particles, cells (≥ 50 nm)
MICROFILTRATION
Macromolecules, colloids (≥ 5 nm)
ULTRAFILTRATION
Organics of high M.W. (≥ 0.5 nm)
REVERSE OSMOSIS
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Calibration of lactate enzyme electrode with outer, cast PVC membranes incorporating different
amounts of Triton X-100
90% 45%
27%
18%
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Formation of poly (phenol) on Pt electrode(5mM phenol, pH7.4, 50mV/s)
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Effect of whole blood on (a) bare (b) poly (phenol)
(a)
(b)
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Needle electrode
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Open microflow
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0 80 120 160 200 280 320 360 400
Glucose (mM)
Glucose (mM)
Implantation Time (m)Implantation Time (m)
14
12
10
8
4
2
0
6
24040
G G I G
Continuous in-vivo glucose monitoring using isotonic phosphate buffer (pH 7.4) microflowContinuous in-vivo glucose monitoring using isotonic phosphate buffer (pH 7.4) microflow
Tissue glucoseBlood glucose
G = Glucose infusion I = Insulin infusion
G = Glucose infusion I = Insulin infusion
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y = 0.75x + 0.33r2 = 0.23 n=15
0
2
4
6
8
0 2 4 6
blood lactate (mM)
estim
ated
tiss
ue la
ctat
e (m
M)
y = 0.79x + 0.59r2 = 0.31 n=33
0
1
2
3
4
5
6
0 2 4 6
blood lactate (mM)es
timat
ed ti
ssue
lact
ate
(mM
)
without microflow11 electrodes
with microflow5 electrodes
Blood-tissue lactate correlation
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0
20
40
60
80
100
120
0 0.5 1 1.5 2 2.5 3
1.3mm6.5mm11mm17mm22mm
0
20
40
60
80
100
120
0 0.5 1 1.5 2 2.5 3
1.3mm6.5mm11mm17mm22mm
Flow rate = 300 µl/min
Flow rate = 500 µl/min
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Detection of various glucose concentrations in the indirect stream with 1mg/ml GOx in the direct stream
glucose
Working electrode
GOx
0
0.01
0.02
0.03
0.04
0.05
0.06
0.07
buffer control 0.5 1 5 10 20
Glucose concentration (mM)
Elec
troc
hem
ical
cur
rent
(µA
)
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Organic – aqueous interface for polymer formation
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Smoother entry angle
Absence of over-and backpressure
Thin, continuous membranes
Entry anglefavours attachment
Single Y channel
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Interfacial protein crosslinking20% (w/v) BSA (in buffer solution)
4% (w/v) Terephthaloyl chloride (in xylene)
Flow rates:
1000 µl/min (xylene phase)
300 µl/min (aqueous phase)
Channelwalls
Crosslinkedalbumin
membrane
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Poly(pyrrole)
N
N
H
N
H
N
H H
n
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Two electrode impedance
• TWO ELECTRODE; Symmetrical, Accurate Instrumentation.
• Interdigitated Electrodes (IDE)
• Conducting Polymer as Reference- 20mV AC potential
15 microns
15 microns
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Thin Films Left and Thick Films (Right)
PPy/Cl
PPy/PVS
PPy/X
PPy/Col
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Cell growth on PPy films
Examples of stained SVK14 keratinocytes on various substrates after 5 Days in culture (× 600)
From Growth Assays (AlamarBlue™ confirmed with Total Protein and ATP Quantitation) as well as Staining for Proliferation (PCNA), differentiation (K10) and Hyperproliferation (K16) Markers, Keratinocytes Growth was preferential on PPy substrates (PPy-Dermatan in particular) compared to bare gold
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Sensing cells on gold
0
2500
5000
0 2500 5000
0
500
1000
0 500 1000
A
B
Representative Bode Plots (Left) and Complex Plane Plots (Right)of SVK14 Keratinocytes on Gold digit-Coated PC Coverslips
(A) Controls and (B) 4 × 105 Cells Seeded
Day 0 Day 7Day 1 Day 2 Day 3 Day 4
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Equivalent circuit analysis
S
R
Applied Current I
Intracellular Fluid
Cellular Membrane, CIntercellular Fluid
A
RS
C
R∞ = RS / (R+S)
Rdif = R – R∞Cnew = C × KK = (R+S)2 / R2
B
(A) Schematic of Cells in Tissue and Equivalent Electrical Components, (B) Equivalent Circuit for Tissue Model and Circuit of Equal Frequency Response Showing
Relationship to (C) Cole Equation Parameters on Complex Plane RepresentationAdapted from Waterworth (2000), PhD Thesis, University of Sheffield
0
0.2
0.4
0 0.2 0.4 0.6 0.8 1.0
f = fc
f = DCf = ∞
R∞
C
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Glaucoma Sensor
Retina Implant
Cochlear Implant
Sphincter sensor
Intracranial Pressure Sensor
IMU for Human Body Motion
Functional Electrical Stimulation
Gyro
Accelerometer
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What next?
Multilayer membrane constructsReactive surfacesCharge / functional group controlMembrane miniaturisation for MEMSBiomimetic surfaces
Biomaterials
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Interrogating signalOptical/acoustic/ultrasound/RF/microwave/inductive
Return signal
Sensor/implant combination or Implanted sensor
Signal detection and processing
Signal transmitter
BODY
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Accelerating FactorsImproved technology diffusion
Reset national prioritiesBasic science advances
Economy of scale up
Regulatory BarriersSafety thresholds lower
Multinational bodiesSensational reportEthical changes
Competing technologiesNew therapeutics
Existing biomaterialsMEMS devices
Microfabrication advances
Retarding FactorsMedical conservation
Insufficient cost-benefitSocietal resistance to
technologyApplication complexity
Healthcare needsHigher patient expectationsNew surgical techniques Reduced bed occupancy
Improved diagnosticsOver the counter diagnosticsExploitation of New Biology
CostsDisproportionate increase.
Large work force requirementExtended development time
Expensive QA
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New materials innovations
Obligatory
Comprehensive change inpractice
Genomic smart card
Smart Diagnostics
Chemical & Structural Biomimicry
Targeted drug therapy
Microbial resistance
Neurosensoryprostheses
Adjustable stents and catheters
Self diagnostic materials
Smart surgical tools
Sector Impact
Single specialty
No requirement Preferable
Multiple specialty
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http://www.iom3.org/foresight
The UK Foresight Programme