Transcript A CMOS Imager for DNA Detection Samir Parikh MASc Thesis Defense

A CMOS Imager for DNA
Detection
Samir Parikh
MASc Thesis Defense
Dept. of Electrical and Computer Engineering
University of Toronto
24th January, 2007
Outline
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Introduction
Motivation and Objectives
Design Details
Experimental Results
Conclusion
Future Work
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Introduction: DNA Microarrays
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DNA microarrays used to detect DNA sequence concentration
Chemical
Processing
DNA
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ssDNA Fragments
DNA is split into its two constituent strands
One strand is broken into fragments
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Introduction: Using DNA Microarrays
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Within a spot multiple identical ssDNA probes are attached
Each spot is tailored to match with a particular target ssDNA sequence
target ssDNA is created from Messenger RNA extracted from a cell
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Introduction: DNA Detection
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Solution containing target ssDNA+fluorescing dye molecule is
introduced to the slide
Spots on the DNA microarray pair/unpair depending on the
nucleotide sequence of the probe and target ssDNA
DNA microarray is washed to remove unpaired target ssDNA
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Introduction: DNA Detection
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Solution containing target ssDNA+fluorescing dye molecule is
introduced to the slide
Spots on the DNA microarray pair/unpair depending on the
nucleotide sequence of the probe and target ssDNA
DNA microarray is washed to remove unpaired target ssDNA
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Introduction: Basic Microarray Scanner
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Fluorescing dye molecule absorbs energy at λ1nm and emits
energy at λ2nm
Light detectors are discussed in the next slide
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Introduction: Existing Light Detectors
Commonly used detectors in microarray scanners are:
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Photomultiplier Tube (PMT) - accurate
Charge-Coupled Device (CCD) - fast
Detector Disadvantages
 Bulky
 Expensive
PMT
 PCB-level integration
 10μm resolution → Long scan time
 Needs to be cooled
CCD
 Monolithic integration is costly
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Motivation and Objectives
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Determine the feasibility of using standard
CMOS technology for light detection and
quantification
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Integrated
Smaller
Cheaper
Validate the design without the use of cooling
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Reduce cost related to cooling
Reduce power consumption due to cooling equip.
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Design Details: Microarray Scanner
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Signal from entire spot captured at once
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Design Details: Microarray Scanner
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Signal from entire spot captured at once
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Design Details: Microarray Scanner
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Signal from entire spot captured at once
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Design Details: Microarray Scanner
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Signal from entire spot captured at once
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Design Details: Microarray Scanner
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Signal from entire spot captured at once
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Design Details: Active Pixel Sensor (APS)
photons
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5-transistor circuit with pseudo-differential output
Pinned photodiode performs the photon-to-electron conversion
Circuits has two phases: reset and integration
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Design Details: ΔΣ Modulator
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2nd Order Discrete-Time ΔΣ
Can be combined with a decimation
filter for a complete ADC
Boser-Wooley Architecture
Delaying Integrators with 1bit feedback
Folded-Cascode Op-amp used
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Design Details: Fabricated Chip
TSMC 1P6M
0.18µm CMOS
Core
690×490 μm2
Area
Die
1.2×1.4 mm2
Area
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Experimental Results: APS
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Photodetector Type
P+/n-well/Psubstrate
Sensitivity to low light
< 2.6 х 10-2 lux
SNR @ 2.6 х 10-2 lux
16.6dB
Dark-signal@(room temp.)
10mV/sec
Source-Follower non-linearity
0.12%
Photodetector Size
150µm х 150µm
Pixel Size
162.5µm х 154µm
Fill Rate
90%
Dark signal limits the integration time for the APS
Low light sensitivity sets the min # of photons detectable
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Experimental Results: ΔΣ Modulator
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Simulation includes flicker and thermal noise
Close matching between simulation and measured
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Experimental Results: ΔΣ Modulator
Discrete-Time 2nd Order Single-bit ΔΣ
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Power Consumption
26.4 mW
Peak SNDR
75.9 dB
Effective Number of Bits
12 bits
Dynamic Range
74.63 dB
SFDR
85.5 dB
Sampling Rate
3.6 MHz
Nyquist Sampling Rate
14.2 kHz
Commercial microarray scanners have 12 to 16-bits accuracy
Sampling rate sets an upper limit on the maximum light level
Sampling rate not critical, minimum light level is more important
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Experimental Results:
Microarray Scanner Setup
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Experimental Results:
Microarray Scanner Setup
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Experimental Results:
Microarray Scanner Setup
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Experimental Results:
Microarray Scanner Setup
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Experimental Results:
Scanner Characterization Slide
Decreasing dye density
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Slide contains spots with dilution series
Each spot contains fluorescing dye molecules with fixed density
Spot density (fluorophores/um2) decreases at a fixed rate
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Experimental Results:
Microarray Scanner
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Experimental Results:
Commercial Microarray Scanner
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Discussion: Microarray Scanner
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Portability Potential
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Detection Limit
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Microarray scanner: Smaller, integrated detector w/o cooling
Agilent scanner: PMT
Microarray scanner: 4590 fluorophores/um2
Agilent scanner: 4 fluorophores/um2
Resolution and Scan time
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Microarray scanner: Larger pixel→Entire spot imaged at once
Agilent scanner: 10μm resolution→takes longer to image a spot
Microarray scanner: Multiple pixels → short scan time
Agilent scanner: Single element → long scan time (8 min/slide)
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Discussion: APS
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Dark signal of APS not the limiting factor
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Background of the slide = 1.5 ADU/sample
Dark signal of the APS = 0.08 ADU/sample
Integration time of the APS is limited by the slide background
Improve the sensitivity of the APS beyond 2.6х10-2 lux
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Increase its conversion gain
Reduce its read noise and reset noise
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Discussion: Optical and Mechanical
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Improve optical coupling between
APS ↔ fluorescing spots
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Use a focusing/collimating element
Compensate for slide tilt
Reduce laser noise and drift from 3% to 0.1%
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Improved power supply
Better laser control/feedback
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Conclusion
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Standard CMOS technology shows potential
to be an alternative to existing PMT/CCD
detectors used in microarray scanners
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The detection limit of a microarray scanner is
determined by:
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Mechanical and Optical Non-idealities
Detector Non-idealities
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Future Work
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Improve the conversion gain of the APS
Reduce the read noise, and reset noise of the
APS
Improve the accuracy of the ADC
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Thank You
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