based on cmos t - peopleboser/presentations/i... · 2009-09-29 · 1 point-of-care infectious...
TRANSCRIPT
![Page 1: BASED ON CMOS T - Peopleboser/presentations/I... · 2009-09-29 · 1 POINT-OF-CARE INFECTIOUS DISEASE TEST BASED ON CMOS TECHNOLOGY Bernhard E. Boser boser@eecs.berkeley.edu. Berkeley](https://reader036.vdocument.in/reader036/viewer/2022070801/5f02a7ab7e708231d40558fb/html5/thumbnails/1.jpg)
1
POINT-OF-CARE
INFECTIOUS DISEASE TEST
BASED ON CMOS TECHNOLOGY
Bernhard E. [email protected]
Berkeley Sensor & Actuator CenterDept. of Electrical Engineering and Computer SciencesUniversity of California, Berkeley
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2
INFECTIOUS DISEASE - MORTALITY
Source: WHO/wikipedia
ImmunoSensor
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33
HIV PROBLEM
Worldwide 33 million people are infected1 in 4 people who have HIV in the US are unaware and are responsible for up to 75% of new infectionsThe CDC recommends routine testing of everyone between the ages of 13 and 64
ImmunoSensor
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44
DIAGNOSING HIV
1st Appt Venu-puncture
Manage Sample
ELISA*
2nd Appt Counseling
1st Appt Rapid Test Counseling
Current Procedure :
Procedure using Rapid Tests:
ImmunoSensor
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5
INFECTIOUS DISEASE TESTING:CURRENT SOLUTION
Beckman Coulter UniCel DxC 880i400 immunoassay tests per hour
ImmunoSensor
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66
DEVELOPING WORLD
ImmunoSensor
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77
STRIP TESTS
Simple, low cost, rapidLow sensitivity
Control Line
Test Line
Sample
ImmunoSensor
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88
STRIP TEST READOUT
An example of a weakly positive results that is difficult to read
Control Line
Test Line
ImmunoSensor
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9
BASIS FOR INFECTIOUS DISEASE TESTS:ANTIGEN – ANTIBODY INTERACTIONS
Antibody-Antigen Complex
ImmunoSensor
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10
ANTIBODY-ANTIGEN TESTSELISA (ENZYME-LINKED IMMUNOSORBENT ASSAY)
Antibody specific to target analyte (e.g. HIV virus)
ImmunoSensor
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11
ADD ANALYTE(E.G. BLOOD SERUM)
ImmunoSensor
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12
INCUBATE
ImmunoSensor
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13
WASH
Captured target No target
ImmunoSensor
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14
ADD SECONDARY ANTIBODY
Molecular label
ImmunoSensor
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15
INCUBATE
ImmunoSensor
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16
WASH
Label bound to analyte No labels present
ImmunoSensor
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17
ADD SUBSTRATE
ImmunoSensor
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18
QUANTIFY COLOR CHANGE
Substrate activated by label
Color change
No color change
ImmunoSensor
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1919
MICROFLUIDICS/LAB-ON-CHIP
Reproduce laboratory protocols on a disposable cartridgeIntegration of valves, pumps, filters and mixersRequires external support to evaluate assay results
ImmunoSensor
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20
MAGNETIC “ELISA”
1
Hall Sensor
Antibodies coatedon surface of
Hall sensor Array
2
Hall Sensor
Non-specificantigen
Targetantigen
1. Retain antibody-antigen chemistry2. Optical magnetic label3. Hydrodynamic electromagnetic separation4. Electronic detection
Hall Sensor
3
Magnetic
Label
Hall Sensor
4
Magnetic
Separation
Hall Sensor
5
Magnetic
Detection
ImmunoSensor
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2121
IMMUNOSENSOR
Blood from finger stick is placed on filterCartridge is agitated and slotted into reader10-20 minutes later, digital, quantitative results are displayedOffers ELISA sensitivity
ImmunoSensor
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2222
TECHNOLOGY
ImmunoSensor
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2323
OPERATION
Sensor Sensor
ImmunoSensor
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2424
Biotinylated monoclonal antibody
Streptavidin coated 4.5μm magnetic bead
Antigen (Human IgG)
GoldSiO2
Passively adsorbedmonoclonal antibody
MAGNETIC BEADS AS IMMUNO-LABELS
ImmunoSensor
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2525
MAGNETIC BEADS AS IMMUNO-LABELS
ImmunoSensorFlorescu et al., “On-chip magnetic washing of super-paramagnetic beads for integrated assay applications”, Journal of Applied Physics, In Press (2009)
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2626
y (m)
x (m)
Bbead,z (T)Magnetic Bead
Sensor Plane
BBead
BApplied
BBead,z
zr
INTEGRATED MAGNETIC BEAD DETECTION
( ) ( )5
34 r
o beadbeadbead
mrrrmrB
⋅−⋅⋅=
πμ
zBV appliedbb /zmbead χ=
ImmunoSensor
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27
Top View
W=4um
L=6um
Contacts inton-well
Bbead,z
n-well
INTEGRATED MAGNETIC BEAD DETECTION
zbeadHallHH BLWGV ,μ=
zbeade BqvF ,×=
A B dlqFV
B
A
eH ∫=
ImmunoSensor
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2828
INTEGRATED MAGNETIC BEAD DETECTION
Icoil = 10mA
Bapplied= 800uT
Bbead,z= 10uT
SHall= 1.7%/T
HALL SENSOR
COIL
MAGNETICBEAD
CHIP SURFACE
2.8 μm
1.75 μm
1.8 μm
a)
ImmunoSensor
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2929
POST CMOS PROCESSING: EXPOSE SENSORS
Hall Sensor
Micro-coil (Metal 1)
Metal 2
Current Line
Top Metal
ImmunoSensor
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3030
POST CMOS PROCESSING: PROTECT PADS
ImmunoSensor
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3131
POST CMOS PROCESSING: ETCH
ImmunoSensor
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3232
POST CMOS PROCESSING: REMOVE METAL
ImmunoSensor
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3333
POST CMOS PROCESSING: GOLD COATING
ImmunoSensor
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3434
Low NoisePreampG ≈ 7
2 AC Coupled Amplifiers G = 150
12-Bit ADC and DSP
INTEGRATED MAGNETIC BEAD DETECTION
Matching < 5%, before auto-zeroing
Matching < 0.05%, after auto-zeroing
Bn= 300nT/√Hz
ImmunoSensor
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3535
INTEGRATED MAGNETIC BEAD DETECTION
10010 (kHz)
0.1
1
10
(uT)
0.1
1
10(uT)
A single 2.8um magnetic bead was detected with 35dB of SNR for a 1Hz noise bandwidth
No Bead
Bead
ImmunoSensor
Florescu et al., “Fully integrated detection of single magnetic beads in complementary metal-oxide-semiconductor”, Journal of Applied Physics, Volume 103, Issue 4, pp. 046101-046101-3 (2008)
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3636
Hall Sensor
IntegratedCoils
8umBackend Amplifier
INTEGRATED MAGNETIC BEAD DETECTION
ImmunoSensor
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3737
INTEGRATED MAGNETIC BEAD CONCENTRATION
( ) washwash BB ∇⋅=o
beadbeadmag
VF
μχ
3
2
3 bead
washbeadbeadomag x
IrF
πχμ ⋅⋅⋅
=
ImmunoSensor
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3838
INTEGRATED MAGNETIC BEAD CONCENTRATION
t = 30s t = 60s t = 90s t = 120s t = 150st = 0s
Iconcentrate = 2mA
Fmag = 0.2pN from 4um away
60% of beads land in center of trench
ImmunoSensor
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3939
INTEGRATED MAGNETIC BEAD WASHING
ImmunoSensor
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4040
INTEGRATED MAGNETIC BEAD WASHING
Lrbead
Fmag
Au
SiO2
Ftether
Lr
FF beadmagtether 2
=
L = 20nm
rbead = 2.5μm
Amplification = 8
Ftether = 9pN from 18μm away
Iwash = 50mA
ImmunoSensor
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4141
Cth,fluid= 0.17 J/K
Rth1,SiO2= 385 K/W
Rth2,SiO2= 769 K/W
Rth,Si= 0.1 K/W
Pin= 25mW
INTEGRATED MAGNETIC BEAD WASHING
T=Pin(Rth2,SiO2+Rth,Si)
=(Rth2,SiO2 + Rth2,SiO2+Rth,Si)Cth,fluid
( )τ/1 teTT −−=Δ
τ
∆T = 2.7oC after 30 seconds of washing
ImmunoSensor
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4242
0ng/mlBW AW
1ng/mlBW AW
10ng/mlBW AW
INTEGRATED MAGNETIC BEAD WASHING
ImmunoSensor
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4343
INTEGRATED MAGNETIC BEAD WASHING
ImmunoSensor
Florescu et al., “On-chip magnetic washing of super-paramagnetic beads for integrated assay applications”, Journal of Applied Physics, In Press (2009)
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4444
0123456789
Sample 1 Sample 2 Sample 3
Num
ber
of B
eads
Clinical Sample
Dengue Assay Results
On-chip Assay
ELISA
0.5
1
1.5
2
0.5
1
1.5
2
Opt
ical
Den
sity
INTEGRATED MAGNETIC BEAD WASHING
ImmunoSensor
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4545
INTEGRATED ASSAY PLATFORM
ImmunoSensor
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4646
INTEGRATED ASSAY PLATFORM
ImmunoSensor
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MEMBRANE FILTRATION
ImmunoSensor
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35μm
2.5μm
.25mm
• Hydrophilic polymeric membrane – Combination of
PVP/PES– No hemolysis– No non-specific
protein binding• Graduated pore size
– 35μm – 2.5μm– ~250μm thick
MEMBRANE FILTRATION
ImmunoSensor
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Filtration vs. Centrifugation
0
0.5
1
1.5
2
2.5
3
3.5
1/1000 1/4000 1/16000 1/64000
Dilution
ELIS
A O
.D.
ELISA fromcentrifuged wholeblood
ELISA from wholeblood filtrate
FILTRATION VS. CENTRIFUGATION
ImmunoSensor
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0.00
0.50
1.00
1.50
2.00
2.50
3.00
Dengue Positive Serum Dengue Spiked Whole Blood
ELIS
A O
.D.
Filtration Admittance of Dengue Antigen
FILTRATION VS. CENTRIFUGATION
ImmunoSensor
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5151
BEAD ASSAYS ON WHOLE BLOOD FILTRATE
ImmunoSensor
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5252
BEAD ASSAYS ON WHOLE BLOOD FILTRATE
ImmunoSensor
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LIFE SCIENCE PROBLEMS
POC Diagnostics
Developing World Dx
Low Cost Assay Kits
Wireless IntegrationEpidemic Monitoring
POC PCR Multiplexed Assays
Proteomics/GenomicsMars Trip Dx
ImmunoSensor Commercialization plan provided by Silicon BioDevices, Inc.
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ACKNOWLEDGEMENTS
Collaborators:Octavian FlorescuDr. Turgut AyturDr. Mekhail AnwarTomohiro IshikawaJonathan FoleyKevan WangPaul DierMoritz MattmanProf. Robert BeattyProf. Eva HarrisSilicon BioDevices, Inc.
Funding from:Berkeley Sensor & Actuator CenterAcumen foundationTrans-NIH Genes, Environment and Health Initiative grant U54 ES016115-01Pacific Southwest RCE NIH award AI065359
ImmunoSensor