A fps CMOS Ion-Image Sensor with Suppressed Fixed-Pattern-Noise for Accurate High-throughput DNA Sequencing

Transcription

1 A fps CMOS Ion-Image Sensor with Suppressed Fixed-Pattern-Noise for Accurate High-throughput DNA Sequencing Xiwei Huang, Fei Wang, Jing Guo, Mei Yan, Hao Yu*, and Kiat Seng Yeo School of Electrical and Electronic Engineering, Nanyang Technological University, Singapore Symposia on VLSI Technology and Circuits

2 Outline Introduction of DNA sequencing Challenges Our Solution: dual-mode CMOS ion-image sensor Experimental Results Conclusions Slide 1

3 Semiconductor and DNA Sequencing Original AB370 (system) 1 st Gen:454 sequencer (sensing chip) 2 nd Gen: Ion Torrent (sensing & detection chip) Virus ~9700 Bacteria ~4,600,000 Human ~3,200,000,000 Semiconductor technology change biomedical world with lower cost! Slide 2

4 Conventional DNA Sequencing Method Conventional Optical Method High Cost: $1M/test Tagging of bases with fluorescent dye Bulky optical detector Large volume image processing Slide 3

5 2 rd Generation ph (Chemical) DNA sequencing 1. Cut DNA strand into slices & amplify onto microbead 2. Distribute into microwell array above ISFET sensor 3. Sequentially flush ATCG & Measure the corresponding ph variation. Lab-on-chip ph sensing method: Detect H + (or ph) released by DNA polymerase synthesis during sequencing using CMOS ISFET sensor Low Cost: $1000/test Slide 4

6 Challenges for ph (Chemical) DNA Sequencing Local ph response needs to be correlated to the physical location that contains one microbead. ph variation of large-arrayed ISFET sensor exists due to pixel-to-pixel threshold voltage V T mismatch, or fixed pattern noise (FPN). Slide 5

7 Our Solution: Dual-mode CMOS Ion-Image Sensor White Light Source Illumination DNA Slice Microbead H+ H+ H+ Reference Electrode Microwell + - H+ H+ H+ Si 3 N 4 Passivation Layer Ion Sensing GND Contact Image TX Metal Layers Output STI p+ Gate Oixde Gate Poly p+ SF PIN PD n+ n+ n+ STI p-well p-substrate FD n+ STI ISFET based Ion Sensing + CIS based Contact Imaging Slide 6

8 ISFET by Standard CMOS ISFET can be fabricated in standard CMOS image sensor process. The top most Si 3 N 4 passivation layer can be utilized as the ion (ph) sensing membrane. Threshold voltage V T of ISFET device correlates to the solution ph. Traditional ISFET fabricated by special process ISFET fabricated through standard CMOS process Slide 7

9 Dual-mode Pixel Design VAAPIX M1 TX RST M6 FD PD ROW SF M2 M3 PIXOUT VAAPIX M1 TX RST M6 FD PD V REF ROW SF M2 M3 PIXOUT VAAPIX RST V REF M1 ROW M2 SF M3 PIXOUT VLN_CASC VLN_CASC VLN_CASC M4 M4 M4 VLN VLN VLN M5 M5 M5 (a) 4T-CIS Pixel (b) Dual-mode Pixel (c) ISFET Pixel White Light Source Illumination Image Mode: Standard 4T pixel to provide images of Reference Electrode microbeads; DNA Slice PD, Microbead TG and FD form active-pixel-sensor H+ H+ H+ H+ H+ Chemical Mode: SF forms ISFET to provide local ph value H+ Microwell + - Si 3 N 4 Passivation Layer Ion Sensing Slide 8

10 Dual-mode Low FPN CDS Readout VAAPIX TX PD ROW RST TX ISFS ISFR CLAMP SHR SHS RST FD V REF ROW VLN_CASC Φ 1 Φ 2 CB COL Φ ADC VLN SF ISFET Dual-Mode Pixel SHS V CM SHR V SIG V RST ISFR ISFS C SS (1pF) CB C SR (1pF) Column S/H COL CLAMP V CM CLAMP COL (1pF,0.5pF,0.25pF) V INP Φ 1P Φ 1P V INN (a)(b) CDS Readout Timing for ph Mode 64 Rows 64 Rows 64 Columns 64 Columns C FS Global Opamp C FR (1pF,0.5pF,0.25pF) V CM Φ 1 Φ 2 V OUTN Φ 2 Φ 1 Φ 1 V CM V CM 12-bit Pipelined ADC V OUTP V REFN (c) CDS Readout Timing for Image Mode 64 Rows 64 Columns Φ ADC D OUT V REFP Objective: Remove pixelwise V T mismatch Before loading solution: V OUT1 = V OUTP V OUTN = α (C S /C F ) (V RST -V CM +V T ) α: source follower gain After loading solution: V OUT2 = V OUTP -V OUTN = α (C S /C F ) (V REF -V CM +V T -dv) dv: desired voltage signal caused by H + Difference correlated sampling: V OUT1 - V OUT2 = α (C S /C F ) (V RST -V REF +dv) D OUT Column RST Amplifying Sampling Digitalizing (a) Before Loading Solution Column SIG Amplifying Sampling Digitalizing (b) After Loading Solution Column Amplifying Sampling Digitalizing (c) Capture Contact Image V T mismatch removed Slide 9

11 Dual-mode Sensor Implementation Slide 10

12 64x64 Sensor Array Testing Setup Parameters Process Pixel Type Pixel Size Pixel Optical Sensing Area Pixel Chemical Sensing Area Specifications Standard TSMC 0.18μm CIS Dual-Mode (Image and Chemical) 10μm 10μm 20.1μm 2 (FF=18.1% ) 22.3μm 2 (FF=20.1% ) Array Size Die Area ADC ENOB ADC SNDR 2.5mm 5mm 11.4 bits 70.35dB FPN 0.3% Frame Rate Total Power Consumption 1200fps 3.3V Slide 11

13 Dual-mode Local ph Correlation ph scale bar Digital Output (12-bit) Contact Image ph Map Microbead images captured at image mode and ph map generated at chemical mode Local ph values of ph map correlate with the addressed microbeads Uncorrelated ph variation can be filtered out Slide 12

14 Sensitivity of ph Measurement Water used as buffer, and ph changed by adding HCL and NaOH Measured ph sensitivity of 26.3mV/pH at Gain=1 and 103.8mV/pH at Gain=4 of global opamp Slide 13

15 Accuracy of ph Measurement Measured phs of ISFET sensor well match results of commercial ph meter for bacteria (E. Coli) culture solution with glucose at different time intervals Slide 14

16 CDS Readout Noise Reduction With CDS (Mean = 0.09mV) Without CDS (Mean = 0.26mV) Max = 0.71mV Max = 0.46mV Comparison of readout voltage variation obtained by performing spatial FFT to readout voltages with respect to addresses of 64x64 ISFET sensor array with and without CDS Mean and Peak variation-reduction observed at 0.17mV and 0.25mV by CDS readout Slide 15

17 Comparison of State-of-art ISFET Sensors [4] [5] [6] [7] This Work Process 5μm Non- CMOS 0.35μm Modified CMOS 0.35μm Standard CMOS 0.18μm Standard CMOS 0.18μm Standard CMOS Pixel Size 200μm 200μm 12.8μm 12.8μm 10.2μm 10.2μm 20μm 2μm 10μm 10μm Array Size Frame Rate 30fps - 100fps fps Sensitivity 229mV/pH 46mV/pH 20mV/pH 37mV/pH 26.2mV/pH (gain=1) 103.8mV/pH (gain=4) Dual-Mode No No No No Yes Slide 16

18 Conclusions One dual-mode CMOS ISFET sensor is demonstrated in standard CMOS CIS process with state-of-art results small pixel size of 10μm scalable pixel array of fast frame rate of 1200fps sensitivity of 103.8mV/pH (gain=4) Such dual-mode sensor is promising for the next generation high-throughput DNA sequencing and future personalized diagnosis. Slide 17

19 Key References [1] J. M. Rothberg, et al., An integrated semiconductor device enabling nonoptical genome sequencing, Nature, vol. 475, pp , Jul [2] C. Toumazou, et al., Simultaneous DNA amplification and detection using a ph-sensing semiconductor system, Nature Methods, vol. 10, pp , Jun [3] R. R. Singh, et al., A CMOS-Microfluidic Chemiluminescence Contact Imaging Microsystem, J. Solid-State Circuits, vol. 47, pp , Nov [4] T. Hizawa, et. al., Fabrication of a two-dimensional ph image sensor using a charge transfer technique, Sens. Actuat. B Chem., pp , Oct [5] M. J. Milgrew, et al., A 16x16 CMOS proton camera array for direct extracellular imaging of hydrogen-ion activity, ISSCC Dig. Tech. Papers, pp , Feb [6] B. Nemeth, et al., High-resolution real-time ion-camera system using a CMOS-based chemical sensor array for proton imaging, Sens. Actuat. B Chem., Aug [7] W. P. Chan, et al., An integrated ISFETs instrumentation system in standard CMOS technology, J. Solid State Circuits, vol. 45, pp , Sept Slide 18

20 Acknowledgements The authors wish to acknowledge the proof-ofconcept funding support from Singapore National Research Foundation. Also acknowledge the biological samples and experiment help of Prof. Liang Yang from School of Biological Sciences of Nanyang Technological University, Singapore. Slide 19

21 Q & A Thank you! Please send comments to haoyu@ntu.edu.sg Welcome to visit our group website: Slide 20