A CMOS Imager for DNA Detection

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A CMOS Imager for DNA Detection

• Samir Parikh
• MASc Thesis Defense
• Dept. of Electrical and Computer Engineering
• University of Toronto
• 24th January, 2007

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Outline

• Introduction
• Motivation and Objectives
• Design Details
• Experimental Results
• Conclusion
• Future Work

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Introduction DNA Microarrays

• DNA microarrays used to detect DNA sequence
  concentration

Chemical Processing
DNA
ssDNA Fragments

• DNA is split into its two constituent strands
• One strand is broken into fragments

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Introduction Using DNA Microarrays

• 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

• Solution containing target ssDNAfluorescing 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

• Solution containing target ssDNAfluorescing 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

• Fluorescing dye molecule absorbs energy at ?1nm
  and emits energy at ?2nm
• Light detectors are discussed in the next slide

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Introduction Existing Light Detectors

• Commonly used detectors in microarray scanners
  are
• Photomultiplier Tube (PMT) - accurate
• Charge-Coupled Device (CCD) - fast

Detector Disadvantages
PMT Bulky Expensive PCB-level integration 10µm resolution ? Long scan time
CCD Needs to be cooled Monolithic integration is costly
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Motivation and Objectives

• Determine the feasibility of using standard CMOS
  technology for light detection and quantification
• Integrated
• Smaller
• Cheaper
• Validate the design without the use of cooling
• Reduce cost related to cooling
• Reduce power consumption due to cooling equip.

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Design Details Microarray Scanner

• Signal from entire spot captured at once

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Design Details Microarray Scanner

• Signal from entire spot captured at once

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Design Details Microarray Scanner

• Signal from entire spot captured at once

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Design Details Microarray Scanner

• Signal from entire spot captured at once

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Design Details Microarray Scanner

• Signal from entire spot captured at once

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Design Details Active Pixel Sensor (APS)
photons

• 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 ?S Modulator

• 2nd Order Discrete-Time ?S
• 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 TSMC 1P6M 0.18µm CMOS
Core Area 690490 µm2
Die Area 1.21.4 mm2
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Experimental Results APS
Photodetector Type P/n-well/Psubstrate
Sensitivity to low light lt 2.6 ? 10-2 lux
SNR _at_ 2.6 ? 10-2 lux 16.6dB
Dark-signal_at_(room temp.) 10mV/sec
Source-Follower non-linearity 0.12
Photodetector Size 150µm ? 150µm
Pixel Size 162.5µm ? 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 ?S Modulator

• Simulation includes flicker and thermal noise
• Close matching between simulation and measured

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Experimental Results ?S Modulator
Discrete-Time 2nd Order Single-bit ?S Discrete-Time 2nd Order Single-bit ?S
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

• 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

• Portability Potential
• Microarray scanner Smaller, integrated detector
  w/o cooling
• Agilent scanner PMT
• Detection Limit
• Microarray scanner 4590 fluorophores/um2
• Agilent scanner 4 fluorophores/um2
• Resolution and Scan time
• 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

• Dark signal of APS not the limiting factor
• 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
  2.6?10-2 lux
• Increase its conversion gain
• Reduce its read noise and reset noise

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Discussion Optical and Mechanical

• Improve optical coupling between
• APS ? fluorescing spots
• Use a focusing/collimating element
• Compensate for slide tilt
• Reduce laser noise and drift from 3 to 0.1
• Improved power supply
• Better laser control/feedback

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Conclusion

• Standard CMOS technology shows potential to be an
  alternative to existing PMT/CCD detectors used in
  microarray scanners
• The detection limit of a microarray scanner is
  determined by
• Mechanical and Optical Non-idealities
• Detector Non-idealities

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Future Work

• 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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