A 0.18mm CMOS 10-6 lux Bioluminescence Detection System-on-Chip

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Ralph Morrison
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1 MP 12.3 A 0.18mm CMOS 10-6 lux Bioluminescence Detection System-on-Chip H. Eltoukhy, K. Salama, A. El Gamal, M. Ronaghi, R. Davis Stanford University

2 Bio-sensor Applications Gene Expression Immunoassay DNA Sequencing Medical diagnostics Biohazard detection and Biodefense Pharmaceutical and drug discovery

3 Photoemissive Assay Methods Fluorescence: Widely used, but Need excitation source Need interference filters Photobleaching Difficult to integrate Excitation Light 650nm Fluorescent tag 670nm Luminescence Lower background High sensitivity Long emission time Suited for lab-on-chip Luminescence Probe 562nm

4 Pyrosequencing Real time DNA sequencing through synthesis (Ronaghi 96) Polymerase Nucleotide PPi PPi ATP-Sulfurylase ATP Luciferase 562nm DNA sequence C G - T CC GG A G C T A G C T Nucleotide added Light intensity

5 Current Detection Systems Use cooled CCD/PMT-based systems: Bulky Slow Need large amounts of reagents High loss in optical path Need a computer for processing Need inexpensive, hand-held detection systems for point of care/on site applications

6 Application Characteristics Small array size ( spots) Large spots ( 150µmx150µm) Long integration times (1s to 3min) Challenge: Detect below 10-6 lux over room temperature Off-the-shelf CCD&CMOS sensors are not suited Small pixels: High leakage, low sensitivity Off-chip ADC and processing CCDs: Slow, destructive reads

7 Luminescence Detection System Transparent slide with immobilized luminescent reporters/probes Optical detection and analysis CMOS chip Joint work with Stanford Genome Technology Center and Stanford Nano-Fabrication Group

8 Outline Chip block diagram Circuit schematics and measurements Measured performance: Optical characteristics ADC characteristics Achieving low light detection Conclusion

Chip Characteristics 8x16 Pixel Array 128 channel ADC DSP SIMD Array Ramp 0.18µm CMOS (CIS) process 5mm x 5mm (492K transistors) 8 x 16 pixel array (230µm sq.

9 Chip Characteristics 8x16 Pixel Array 128 channel ADC DSP SIMD Array Ramp 0.18µm CMOS (CIS) process 5mm x 5mm (492K transistors) 8 x 16 pixel array (230µm sq.) P+/N/Psub photodiode Pseudo-differential pixel Per-pixel 2-step 13-bit ADC Integrated ramp generator Per-column DSP 320 Mbits/s readout rate Static power: 26mW

10 Chip Block Diagram Reset Pixel Pixel 2 Pixel Pixel Pixel Array Ramp Generator Shift/Load 2 ADC ADC ADC ADC 128 channel 13-bit ADC Output Control x20 SR ALU 64x20 SRAM 20 8x20 SR ALU 64x20 SRAM DSP SIMD Array

11 Pseudo-Differential Pixel 1.8V BIAS VREF VSET Reset M2 M1 Out Measured Dark signal (mv/sec) VSET (V)

12 13-bit 2-step ADC Step 1 V in 1x 9 Bit ADC Bit DAC + - Step x 9 Bit ADC bits

13 ADC Implementation Positive Ramp From Pixel _ + + _ + + Negative Ramp 4-bit DAC 4 Column DSP Register Counter

14 Differential Ramp Circuit 3.3v Low Offset Reset RAMP High Offset Measured Ramp (V) Reset Ramp Negative Ramp Positive Ramp Time (µs)

15 Differential Amplifier 3.3v INP INM CM OUTM OUTP

16 Measured VGA Noise PSD PSD (V 2 /Hz) /f Frequency (Hz)

17 Differential Difference Comparator 3.3v OUTP OUTM 1.8v Column DSP Register

18 Measured Optical Characteristics Array Size Pixel size Photodetector Voltage Range Dark Signal 560nm Sensitivity Follower non-linearity Dynamic Range 8x16 pixels 230µmx230µm P+/N/Psub 150µmx150µm V 2.6 mv/s V/lux.sec < 0.1% 61 db

19 2-Step Full ADC Measured DN VSET (V)

20 Measured ADC Characteristics Architecture Resolution Area Conversion Rate INL DNL FOM=Power/(2 b+1 BW) 128 channel 2-step 13-bit 7mm 2 7.1Msample/sec 0.033% 50µV (0.5LSB) 1.2pJ b : Effective number of bits

21 Achieving Low Light Detection Direct optical coupling (Eggers 94) Detector and luminescent assay matching Low noise design High ADC resolution Background subtraction Averaging for read noise reduction Correlated Multiple Sampling (Fowler 91)

22 System Operation Ramp Reset 0 1 N Ramp 16X Gain Accumulate/ Store Pixel Output B 1 B 2 B 3 B 4 S 1S2 S 4 S 3 Background Signal+Background S= (S 3 -S 2 )-(S 4 -S 1 )-(B 3 -B 2 )+(B 4 -B 1 ) Correlated Multiple Sampling

23 Comparing Sampling Techniques Experiment: Frames = 50 T int = 80sec N = 16 T i = 25µs S 1i S 2i S 3i S 4i Technique S= (S 3 -S 4 ) S= (S 3 -S 2 ) Offset Reset 1/f Read 2X 2X Loss dB -6.94dB S= (S 3 -S 2 )-(S 4 -S 1 ) S= (S 3 -S 2 ) S= (S 3 -S 2 )-(S 4 -S 1 ) 4X 2X/N 4X/N -9.42dB -2.05dB -1.12dB

24 System Detection Limit bit w/o averaging 13-bit 128 averaged digitizations Shot Noise Limit SNR(dB) X10-7 lux Photon flux (lux)

25 Measured Pyrosequencing Reaction fmol ATP T int = 25 sec DN Time(sec)

26 Conclusion There is need for hand-held luminescence detection systems Described a 0.18µm detection SoC: 8x16 pseudo-differential pixel array Per-pixel 13-bit 2-step ADC Per-column SIMD DSP Detects 10-6 lux over 30sec integration time: Direct optical coupling and array customization High ADC resolution and averaging Correlated multiple sampling

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