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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