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16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 1 of 26
A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA
SequencingDrew A. Hall, Jonathan S. Daniels, Bibiche Geuskens,
Noureddine Tayebi, Grace M. Credo, David J. Liu, Handong Li, Kai Wu, Xing Su, Madoo Varma, Oguz H. Elibol
16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 2 of 26
Outline
• Background • System Overview• Circuit Architecture • Transducer Integration• Results• Scalability • Summary
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16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 3 of 26
Low Cost Sequencing Drives Applications
Non-clinical industrial monitoring• Environment/Ecology (metagenomics) • Bio-defense; epidemiology• Agriculture/food, beverages
Acceleration of drug development • Disease association • Compound screening • Drug efficacy
Targeted disease management • Prevention, screening • Clinical diagnostics • Treatment, monitoringServices
Datasets
Computation
Algorithms
Silicon
*2020+: $20B+
2008: ~$1B
*http://www.forbes.com/sites/luketimmerman/2015/04/29/qa-with-jay-flatley-ceo-of-illumina-the-genomics-company-pursuing-a-20b-market/
16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 4 of 26
DNA: The Blue Print of Life
20-50 um
Gene 1
Gene 3
Gene 2
Humans: 1012 cells 23 pairs of chromosomes 3B bases20K genes
cell
chromosomeDNA
A pairs with T C pairs with G
16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 5 of 26
DNA Sequencing Process Flow DNA Fragmentation Data Generation Data Processing
Image credits:http://biochem.jacobs-university.de/BDPC/BISMA/manual_unique.php , http://www.454.com/products-solutions/how-it-works/index.asp, http://www.odec.ca/projects/2006/bach6k2/background.htm
Library Preparation
16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 6 of 26
System Overview1- Chemical Signal Generation and Amplification
2- Electrical Signal Amplification and Detection
Standard CMOS
Post Processed
Reaction Fluid(Salt Water)
Transducer
Interconnect
Transistors
16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 7 of 26
DNA Sequencing Flow - Pixel
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Presence of the tag is detected per pixel per base
1- A colony derived from a unique DNA strand is immobilized on each sensor
2- Each modified base is introduced sequentially through the solution (~min)
3- The electrochemical tag is released upon incorporation of the base and detected (after cleaving phosphate) (~sec)
16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 8 of 26
-0.1 0 0.1 0.2 0.3 0.4 0.5 0.6-2
-1
0
1
2x 10-10
Cur
rent
(A)
Potential (V)
Transduction Mechanism
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Physical Model
Redox Cycling Average shuttling time ~
z : gap sizeD: diffusion coefficient of the molecule
>50 fA current per moleculeindependent of lateral dimensions
timeshuttlingmoleculesof#i µlim
Current vs Voltage
ilim
2Dz2
Top Electrode
Bottom Electrode
Nanogap
16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 9 of 26
Transduction Mechanism
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Physical Model Electrical Model
Average shuttling time ~ z2/2D
z : gap sizeD: diffusion coefficient of the molecule timeshuttling
moleculesof#Iµ
Vbot
Vref
Vtop
Vsol
Top Electrode
Bottom Electrode
ICdl
CdlRint
Rint
I
Top Electrode
Bottom Electrode
Nanogap
16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 10 of 26
Discharge Measurement
timeTr
ansd
ucer
Vol
tage
no molecules
with molecules
Current integration window, tint
reset
ΔV
ΔVVox
Vref
Vtop
Vsol
Top Electrode
Bottom Electrode
ICdlRint Vreset
Vbot
Rint Cdl I
Voltage readout of the bottom electrode instead of current
16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 11 of 26
3 transistors per pixel: reset, follower, and row select
Pixel ArchitectureModel with Ideal Elements
Vref
Vtop
Vsol
Top Electrode
Bottom Electrode
ICdlRint Vreset
Vbot
Rint Cdl I
16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 12 of 26
Chip Architecture
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Column parallel readout, cycle through rows
16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 13 of 26
VCO Based ADC
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16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 14 of 26
DNA Sequencing Flow - Pixel
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Presence of the tag is detected per pixel per base
1- A colony derived from a unique DNA strand is immobilized on each sensor
2- Each modified base is introduced sequentially through the solution (~min)
3- The electrochemical tag is released upon incorporation of the base and detected (after cleaving phosphate) (~sec)
16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 15 of 26
Transducer Integration
Cu CappingSacrificial Layer
Top Electrode
Passivation
CopperM8
Bottom Electrode
Interconnect Layers
Post processing on standard CMOS wafer
16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 16 of 26
Transducer Integration
Single Pixel (~1 µm)
Vreset
Reset[0]
RowSel[0]
VccHV
Vreset
Reset[1]
RowSel[1]
VccHV
Vreset
Reset[2]
RowSel[2]
VccHV
Vreset
Reset[3]
RowSel[3]
VccHV
16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 17 of 26
Transducer Integration
~5 mm
30 µm
16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 18 of 26
Transducer Integration
30 µm
4 µm
16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 19 of 26
Transducer Integration
Bottom electrode
Sacrificial layer
Top electrode
Sacrificial layer etched
4 µm1 µm
16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 20 of 26
Measurement System
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Custom board with FPGA connection
Bare chip electrical and fluidic interface
1 inch
Fluid Inlet Chip facing down
16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 21 of 26
Data Collection
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Control Panel Data Display
16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 22 of 26
Measurement Results
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Electrochemical TagResponse and Recovery Sequencing Byproduct Detection
16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 23 of 26
Transducer Scaling
Bottom Electrode
Top Electrode
1M pixel array with 1.5 um pitch devices – Transducer Only
1 µm
16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 24 of 26
Scalability Comparison
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d1~
VolumeArea Signalµ
21~
eCapacitanc1 Signal
dµEndpoint
Detection
Continuous Monitoring
ISFET Nanogap
Frame Rate >10 fps* ~1 fps
Noise Scaling 1/d2 1/d2
Signal Scaling 1/d 1/d2
SNR d 1
* Needed due to fast transient signal
• Relaxed requirements on frame rate
• Lateral dimension independent SNR
16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 25 of 26
• Scalable approach for electronic DNA sequencing on 32 nm process node
• Enabled by co-optimized circuits and transducers
• Demonstration of detection of nucleotide incorporation
• Sensitive and dense bio-sensing platforms can be realized in advanced process nodes
Summary
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SystemTechnology 32 nm CMOSDie size 5 mm x 5 mmNumber of pixels 8,192Number of sensors 224Power consumption 27.9 mWSupply voltage 1.05 V / 1.8 V
PixelArea 1 µm2
Leakage < 10 pASensor
Area 20 µm2
Unit capacitance 1 pF/µm2
Electrode spacing 60 nmSignal/pAP molecule 50 fA
ADCFSR 700 mVConversion time 50 nsResolution 8-bit
16.1: A Nanogap Transducer Array on 32 nm CMOS for Electrochemical DNA Sequencing© 2016 IEEE International Solid-State Circuits Conference 26 of 26
Fabrication:• Steven Cooperman• Michael Lewis• Elizabeth Lee• Intel Fab Staff• SNF Facility StaffCharacterization:• Intel NMLDevice Physics:• Serge Lemay &
Group
Group Members:• Stephane Smith • William Van Trump• Tolga Acikalin• Pradyumna Singh• Ryan Field• Hao Luo• Mark Oldham• Eric Nordman
Acknowledgements
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