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
Bio-sensor Applications Gene Expression Immunoassay DNA Sequencing Medical diagnostics Biohazard detection and Biodefense Pharmaceutical and drug discovery
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
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
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
Application Characteristics Small array size (1-1000 spots) Large spots ( 150µmx150µm) Long integration times (1s to 3min) Challenge: Detect below 10-6 lux over 30sec @ 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
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
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.) 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
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 3 12 8 8x20 SR ALU 64x20 SRAM 20 8x20 SR ALU 64x20 SRAM DSP SIMD Array
Pseudo-Differential Pixel 1.8V BIAS VREF VSET Reset M2 M1 Out Measured Dark signal (mv/sec) 8 6 4 2 0.4 0.6 0.8 1 1.2 1.4 VSET (V)
13-bit 2-step ADC Step 1 V in 1x 9 Bit ADC 1010 01001 4 Bit DAC + - Step 2 + 16x 9 Bit ADC 010001011 1010010001011 13 bits
ADC Implementation Positive Ramp From Pixel _ + + _ + + Negative Ramp 4-bit DAC 4 Column DSP Register Counter
Differential Ramp Circuit 3.3v Low Offset Reset RAMP High Offset Measured Ramp (V) Reset Ramp Negative Ramp Positive Ramp Time (µs)
Differential Amplifier 3.3v INP INM CM OUTM OUTP
Measured VGA Noise PSD 10-14 PSD (V 2 /Hz) 10-15 1/f 10 3 10 4 10 5 Frequency (Hz)
Differential Difference Comparator 3.3v OUTP OUTM 1.8v Column DSP Register
Measured Optical Characteristics Array Size Pixel size Photodetector Voltage Range Dark Signal QE @ 560nm Sensitivity Follower non-linearity Dynamic Range 8x16 pixels 230µmx230µm P+/N/Psub 150µmx150µm 0.1-0.9 V 2.6 mv/s 0.4 160 V/lux.sec < 0.1% 61 db
2-Step Full ADC 9000 8000 7000 Measured DN 6000 5000 4000 3000 2000 1000 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 VSET (V)
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
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)
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
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 -15.44dB -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
System Detection Limit 50 40 13-bit w/o averaging 13-bit 128 averaged digitizations Shot Noise Limit SNR(dB) 30 20 10 2.2X10-7 lux 0 10-6 10-5 10-4 Photon flux (lux)
Measured Pyrosequencing Reaction 930 1.3 fmol ATP T int = 25 sec 920 910 900 890 DN 880 870 860 850 840 830 0 100 200 300 400 500 600 700 Time(sec)
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