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  • CMOS UNIVERSAL REAL-TIME LABEL-FREE DNAANALYSIS SYSTEM-ON-CHIP

    by

    Hamed Mazhab Jafari

    A thesis submitted in conformity with the requirementsfor the degree of Doctorate of Philosophy

    Graduate Department of Electrical and Computer EngineeringUniversity of Toronto

    Copyright c 2013 by Hamed Mazhab Jafari

  • II

    Abstract

    CMOS UNIVERSAL REAL-TIME LABEL-FREE DNA ANALYSIS

    SYSTEM-ON-CHIP

    Hamed Mazhab Jafari

    Doctorate of Philosophy

    Graduate Department of Electrical and Computer Engineering

    University of Toronto

    2013

    Amperometric electrochemical DNA sensors have emerged as a low-cost, high-

    throughput and real-time alternative to the conventional optical sensory methods. This

    thesis presents the design, implementation, and validation of a fully integrated, mixed-

    signal CMOS thermally controlled amperometric electrochemical DNA-sensing system-

    on-chip (SoC).

    The microsystem includes 54 current-to-digital channels, 600 on-chip nanostruc-

    tured DNA sensors and 54 on-chip pH sensors. It reuses key circuits to perform three

    key functions: 1) cyclic voltammetry and pH sensing, 2) impedance spectroscopy, and

    3) temperature regulation.

    Cyclic voltammetry DNA analysis and pH sensing is implemented by utilizing

    the current-to-digital channel and an on-chip programmable waveform generator. The

    current-to-digital channel is multiplexed between a bank of DNA sensors and a pH sen-

    sor. The on-chip programmable waveform generator provides a wide range of user-

    controlled rate, shape, and amplitude parameters of the sensor interrogation wave-

    form, with a maximum scan range of 1.2V and a scan rate ranging from 0.1mV/sec

    to 300V/sec.

    Impedance spectroscopy DNA analysis is implemented by utilizing frequency re-

    sponse analysis (FRA) to extract the impedance components of the biosensor. The most

  • III

    computationally intensive operations, the multiplication and integration, required by

    the FRA algorithm are performed by the in-channel dual-slope multiplying ADC in the

    mixed-signal domain resulting in small integration area and power consumption.

    The on-chip heating and temperature-sensing elements are implemented without

    any post-CMOS processing. Temperature is regulated to within 0.5C using PID feed-

    back control. This enables precise thermal control of on-chip DNA hybridization. The

    two computationally intensive operations, multiplication and subtraction, required by

    the PID algorithm are also efficiently performed by the same in-channel dual-slope mul-

    tiplying ADC in the mixed-signal domain. A digital ultra-wideband transmitter based

    on a delay line architecture provides wireless data communication capabilities.

    The 3mm3mm prototype fabricated in a 0.13m standard CMOS technology has

    been experimentally validated in the context of prostate cancer synthesized DNA marker

    detection. Each recording channel occupies an area of only 0.06mm2 and consumes

    42W of power from a 1.2V supply. The digital ultra-wideband transmitter provides

    wireless data communication capabilities with data rates of up to 50 Mb/s while con-

    suming 400W.

  • IV

    Acknowledgements

    First and foremost I would like to express my sincere thanks and deep appreciation

    to my supervisor, Professor Roman Genov, for his thoughtful and constant guidance

    throughout the course of this thesis, and for giving me the opportunities for the academic

    advancements I have made. His regular encouragement, support and technical insights

    were invaluable to me throughout the course of this work. Further, it enabled me to

    perform to the best of my abilities and he provided me with opportunities and exposure

    that I would otherwise never have had. I am thankful to work with such an outstanding

    researcher and mentor.

    I would like to thank my defense committee: Professor Glen Gulak, Professor David

    Johns, Professor Ng and my external examiner, Professor Mason for their feedback that

    helped improve this thesis. I would also like to thank our collaborators at the McMaster

    University, Professor Leyla Solyemani for assisting us in DNA testing. I would also like

    to thank CMC for fabrication access to to IBM 130nm CMOS, Jaro for CAD support

    and NSERC for providing funding for my project.

    I also thank the following members of Professor Genovs Microelectronics Research

    Laboratory Alireza Nilchi, Ritu Raj Singh, Farzaneh Shahrokhi, Ruslana Shulyzki,

    Derek Ho, Arezu Bagheri, Hossein Kassiri, Nima Soltani, and Arshya Feyzi for their

    support, comments and assistance during the course of this research. I especially thank

    Karim Abdulhalim, who was always helpful to me during the Ph.D program and spe-

    cially during the tape-out.

    Finally, I would like to express my deepest acknowledgements and appreciation to

    my dear friend Morvarid Akhbari, for being a constant and unconditional source of

    support during the writing of this thesis. Thank you for all you have done for me during

    the past year and thank you for all your caring and support specially during the hard

    time. This thesis is dedicated to you.

  • V

    Contents

    List of Tables xi

    List of Figures xiii

    List of Acronyms xxiii

    1 Introduction 1

    1.1 Basics of DNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

    1.1.1 DNA Structure and Chemical Properties . . . . . . . . . . . . . 3

    1.1.2 DNA Concentration . . . . . . . . . . . . . . . . . . . . . . . 4

    1.1.3 DNA Amplification by the Polymerase Chain Reaction (PCR) . 5

    1.2 Conventional Bench-top DNA Analysis Methods . . . . . . . . . . . . 8

    1.2.1 Optical Fluorescent DNA Sensing . . . . . . . . . . . . . . . . 8

    1.2.2 Commercial Optical DNA-Sensing Instruments . . . . . . . . . 10

    1.2.3 pH-based DNA Sensing . . . . . . . . . . . . . . . . . . . . . 11

    1.2.4 Commercial pH-based DNA Sensing Instruments . . . . . . . . 12

    1.3 Existing Integrated Circuits for DNA Sensing . . . . . . . . . . . . . . 14

    1.3.1 CMOS Fluorescent DNA Contact Imaging . . . . . . . . . . . 15

    1.3.2 CMOS Magnetic Field-Based DNA Sensing . . . . . . . . . . . 15

    1.3.3 CMOS Capacitance-Based DNA Sensing . . . . . . . . . . . . 17

    1.4 Amperometric Electrochemical Sensing Principles . . . . . . . . . . . 17

    1.4.1 Three-electrode Sensing Configuration . . . . . . . . . . . . . 19

  • VI

    1.4.2 Electrode-Electrolyte Interface . . . . . . . . . . . . . . . . . . 21

    1.4.3 Reduction-Oxidation Current . . . . . . . . . . . . . . . . . . . 22

    1.4.4 Labeled vs Label-free DNA Sensing . . . . . . . . . . . . . . . 22

    1.4.5 Electrode Material . . . . . . . . . . . . . . . . . . . . . . . . 23

    1.5 Amperometric Electrochemical Sensing Methods . . . . . . . . . . . . 24

    1.5.1 Fast-Scan Cyclic Voltammetry . . . . . . . . . . . . . . . . . . 26

    1.5.2 Amperometric Impedance Spectroscopy . . . . . . . . . . . . . 26

    1.5.3 Temperature Regulation for DNA Analysis . . . . . . . . . . . 27

    1.5.4 Commercial Amperometric Instruments . . . . . . . . . . . . . 28

    1.6 Integrated Circuits for Amperometric DNA Sensing . . . . . . . . . . 28

    1.7 Main Specifications for Amperometric Electrochemical DNA Sensing

    Integrated Circuits Design . . . . . . . . . . . . . . . . . . . . . . . . 30

    1.7.1 Accuracy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

    1.7.2 Dynamic Range . . . . . . . . . . . . . . . . . . . . . . . . . . 32

    1.7.3 Frequency Range . . . . . . . . . . . . . . . . . . . . . . . . . 32

    1.7.4 Non-electrical Design Specification . . . . . . . . . . . . . . . 33

    1.8 Additional Considerations for DNA-sensing Amperometric Integrated

    Circuits Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

    1.8.1 Low-Level Current Acquisition for Amperometry . . . . . . . . 34

    1.8.2 Wireless Data Transmission of DNA Results . . . . . . . . . . 35

    1.8.3 DNA Temperature Regulation . . . . . . . . . . . . . . . . . . 37

    1.8.4 On-chip Computation for DNA Analysis: Analog vs. Digital

    vs. Mixed-Signal VLSI Multiplication . . . . . . . . . . . . . . 38

    1.9 Thesis Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

    1.9.1 Complete DNA Analysis SoC . . . . . . . . . . . . . . . . . . 47

    1.9.2 Cyclic Voltammetry and Sample pH Level Sensing . . . . . . . 48

    1.9.3 Impedance Spectroscopy . . . . . . . . . . . . . . . . . . . . . 48

    1.9.4 Temperature Regulation . . . . . . . . . . . . . . . . . . . . . 49

    1.10 Thesis Outline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

  • VII

    2 Current Acquisition Circuits for Electrochemical Amperometric Biosen-

    sors 51

    2.1 Transimpedance Amplifier (TIA) . . . . . . . . . . . . . . . . . . . . . 52

    2.1.1 Circuit Implementation . . . . . . . . . . . . . . . . . . . . . . 53

    2.1.2 Experimental Results . . . . . . . . . . . . . . . . . . . . . . . 55

    2.2 Current Conveyer (CC) . . . . . . . . . . . . . . . . . . . . . . . . . . 56

    2.2.1 Circuit Implementation . . . . . . . . . . . . . . . . . . . . . . 57

    2.2.2 Channel Noise Analysis . . . . . . . . . . . . . . . . . . . . . 61

    2.2.3 Experimental Results . . . . . . . . . . . . . . . . . . . . . . . 66

    2.3 Comparative Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

    2.4 Chapter Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

    3 Cyclic Voltammet