By Arshya Feizi a Thesis Submitted in Conformity with the Requirements For
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A CMOS MULTI-MODAL CONTACT-IMAGING SCANNING MICROSCOPE by Arshya Feizi A thesis submitted in conformity with the requirements for the degree of Master of Applied Science Graduate Department of Electrical and Computer Engineering University of Toronto Copyright c 2014 by Arshya Feizi A CMOS multi-modal contact-Imaging Scanning Microscope Arshya Feizi Master of Applied Science Graduate Department of Electrical and Computer Engineering University of Toronto 2014 Abstract This thesis presents the design, implementation and partial experimental characterization of a multi-modality scanning-contact microscope (SCM) with application in biomedical imaging. Bench-top light microscopes are bulky and expensive and provide only one imaging modality. The SCM’s imaging component is a custom-made CMOS imager in the AMS0.35µm imaging process. Six pixel types are integrated into the imager, which enable the SCM to support six imaging modalities. For sub-pixel resolution imaging, a specialized pixel layout is used which allows the system to support a super-resolution algorithm which takes multiple images with sub-pixel shifts as its input and generates a single high-resolution image. Each pixel type may generate an output voltage or current, depending on whether it is active or passive. A low-power dual-input 2nd order ΔΣ ADC with an SNR of 78dB is implemented to accommodate both current and voltage inputs while preserving noiseshaping characteristics for both inputs. ii Acknowledgements Despite the fact that this work solely bears my name, it would not have been possible without the help of many significant individuals. First, I would like to thank my parents for their unconditional love and emotional support through the ups and downs of this project. I owe additional appreciation to my father, Prof. M. Reza Feyzi, who also provided professional support and insight for this work. I like to thank my dear friend, Saba Rahimi, who helped in making Toronto feel like home; and my peers at University of Toronto, especially Hossein Kassiri, Aynaz Vatankhah, Saeid Rezaei, and Javid Musayev for their presence and friendship during both rain and shine. Finally, I like to thank my supervisors, Prof. Roman Genov and Prof. Glenn Gulak for providing the motivation and academic resources for this work. I would also like to appreciate my course instructors, Prof. Tony Chan Carusone, and Prof. Richard Schreier for teaching me many aspects of advanced circuit design. iii Contents List of Tables vii List of Figures viii List of Acronyms xii 1 Introduction 1 1.1 Domains of Biological Imaging . 1 1.1.1 Body Imaging . 2 1.1.2 Organ/Tissue Imaging . 3 1.1.3 Cell Imaging . 3 1.1.4 Intra-cellular and Molecular Imaging . 4 1.2 Microscopy . 4 1.2.1 Light (Lens-based) Microscopy . 5 Bright-field/Dark-field microscope: . 5 Fluorescence microscope: . 6 Confocal microscope: . 7 Polarization microscopy: . 8 Summary of light microscopy . 10 1.2.2 Contact (Lens-less) Imaging and Microscopy . 10 Sub-pixel resolution Imaging: . 11 Fluorescence Imaging . 13 Polarization Imaging . 14 iv 1.3 Motivation . 14 1.4 Thesis Organization . 16 2 Sub-pixel-Resolution Scanning Contact-Imaging Microscope 17 2.1 Introduction . 17 2.2 Sub-pixel Resolution Imaging . 18 2.2.1 Super resolution algorithm . 18 2.2.2 Super-resolution algorithm hardware . 19 Static sample . 19 Moving sample . 20 2.3 Principle of Line Scanning . 21 2.3.1 Line sensors vs. 2D pixel arrays . 21 2.3.2 Staggered line sensor . 23 2.3.3 Staggering and implementation of the super-resolution algorithm . 24 2.3.4 Folded-staggering and multi-modality imaging . 25 2.4 VLSI Architecture . 26 2.4.1 Multi-modality Pixels . 27 Targeted Modalities . 27 Staggered Pixel Array . 37 Static 2D Imaging Pixel Array . 40 System specifications . 41 2.4.2 Readout Circuit . 41 ADC Bank . 42 Output Multiplexer . 44 2.5 Summary . 45 3 Dual-mode Current/Voltage-input ∆Σ ADC 47 3.1 Introduction . 47 3.2 Readout Architecture . 49 3.3 ADC Design . 51 3.3.1 Background . 51 v 3.3.2 System Level Design . 52 3.4 CMOS Implementation of ADC . 54 3.4.1 Integrators . 54 3.4.2 Opamp design . 57 3.4.3 Quantizer . 58 3.4.4 Complete circuit . 58 3.4.5 Decimation Filter . 59 3.4.6 Clock Generator . 60 4 Experimental Results 63 4.1 ADC characterization . 63 4.1.1 Voltage-input ADC . 63 4.1.2 Current-input ADC . 64 4.1.3 Comparison . 66 4.1.4 Summary of ADC performance . 66 4.2 Microscope Setup . 67 4.2.1 Image Sensor . 67 4.2.2 Sample movement . 69 4.2.3 Back-end and Post Processing . 71 4.3 Experimental Image Sequence . 73 4.3.1 Data Acquisition . 73 4.3.2 Image Reconstruction . 74 ”Zig-zag” outline . 76 Incorrect aspect ratio . 76 5 Conclusions 79 5.1 Thesis Contributions . 79 5.2 Future Work . 80 References 81 vi List of Tables 1.1 Summary of light microscopes . 10 1.2 Table of envisioned specifications . 15 2.1 Summary of pixel types . 42 2.2 Summary of ADC specifications . 44 3.1 Summary of pixel outputs . 49 4.1 Comparative analysis of the ADC . 69 vii List of Figures 1.1 Domains of biological imaging based on sample size . 2 1.2 CT-Scanner [7] . 2 1.3 MRI Machine [7] . 3 1.4 Optics of a bright-field and dark-field microscope . 5 1.5 Image comparison in a bright-field and dark-field microscope . 6 1.6 Optics of a fluorescence microscope . 7 1.7 Optics of a confocal microscope . 8 1.8 Optics of a polarization microscope . 9 1.9 Fundamental of contact imaging [28] . 11 1.10 Opto-fluidic microscope conceptual illustration [37], reused with permission from author . 12 1.11 Utilization of small apertures on pixels to increase resolution . 13 2.1 Illustration of the super resolution algorithm . 19 2.2 (a) Photodiode structure of a static-sample 2D imager (b) Shifting the photodi- ode electronically to acquire sub-pixel shifted images . 20 2.3 Image acquisition and reconstruction in a 2D pixel array . 21 2.4 Image acquisition and reconstruction using a line scanner . 22 2.5 Concept of staggering pixels . 23 2.6 Increase in resolution using the concept of staggering pixels . 24 2.7 Folded staggering of pixels . 24 2.8 Illustration of the folded-staggered formation and rows inserted between adja- cent pixels . 25 viii 2.9 Problem of wasted silicon area between lines . 26 2.10 Combination of folded-staggering and multi-modality imaging, implementable with a super resolution algorithm (three modalities in this illustrative figure) . 26 2.11 Chip architecture . 27 2.12 Chip micrograph, 7.5mm×3.2mm AMS0.35µm imaging process . 28 2.13 3T pixel circuit and layout . 29 2.14 3T pixel timing diagram . 30 2.15 Schematic and layout of the high-resolution imaging pixels . 30 2.16 Timing diagram for the high-resolution pixel . 31 2.17 Layout of the polarization pixels, photodiode area of 25µm2 . 33 2.18 Phase difference in between excitation and emission light in a fluorescent marker 33 2.19 Circuit diagram and layout of staggered array passive pixel . 34 2.20 Structure of the wavelength-sensitive diode.