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A CMOS Imager for DNA Detection

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  1. A CMOS Imager for DNA Detection Samir Parikh MASc Thesis Defense Dept. of Electrical and Computer Engineering University of Toronto 24th January, 2007

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

  3. 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

  4. 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

  5. Introduction: DNA Detection • 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

  6. Introduction: DNA Detection • 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

  7. Introduction: Basic Microarray Scanner • Fluorescing dye molecule absorbs energy at λ1nm and emits energy at λ2nm • Light detectors are discussed in the next slide

  8. Introduction: Existing Light Detectors • Commonly used detectors in microarray scanners are: • Photomultiplier Tube (PMT) - accurate • Charge-Coupled Device (CCD) - fast

  9. 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.

  10. Design Details: Microarray Scanner • Signal from entire spot captured at once

  11. Design Details: Microarray Scanner • Signal from entire spot captured at once

  12. Design Details: Microarray Scanner • Signal from entire spot captured at once

  13. Design Details: Microarray Scanner • Signal from entire spot captured at once

  14. Design Details: Microarray Scanner • Signal from entire spot captured at once

  15. Design Details: Active Pixel Sensor (APS) • 5-transistor circuit with pseudo-differential output • Pinned photodiode performs the photon-to-electron conversion • Circuits has two phases: reset and integration photons

  16. Design Details: ΔΣ Modulator • 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

  17. Design Details: Fabricated Chip

  18. Experimental Results: APS • Dark signal limits the integration time for the APS • Low light sensitivity sets the min # of photons detectable

  19. Experimental Results: ΔΣ Modulator • Simulation includes flicker and thermal noise • Close matching between simulation and measured

  20. Experimental Results: ΔΣ Modulator • 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

  21. Experimental Results: Microarray Scanner Setup

  22. Experimental Results: Microarray Scanner Setup

  23. Experimental Results: Microarray Scanner Setup

  24. Experimental Results: Microarray Scanner Setup

  25. Experimental Results: Scanner Characterization Slide • Slide contains spots with dilution series • Each spot contains fluorescing dye molecules with fixed density • Spot density (fluorophores/um2) decreases at a fixed rate Decreasing dye density

  26. Experimental Results: Microarray Scanner

  27. Experimental Results: Commercial Microarray Scanner

  28. 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)

  29. 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 2.6х10-2 lux • Increase its conversion gain • Reduce its read noise and reset noise

  30. 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

  31. 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

  32. 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

  33. Thank You