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Chemical Current-Conveyor: a New Approach in Biochemical Computation

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Chemical Current-Conveyor: a New Approach in Biochemical Computation Chemical Current-Conveyor: a new approach in biochemical computation by Panavy Pookaiyaudom A thesis submitted for the Doctor of Philosophy of Imperial College London and the Diploma of Imperial College London Department of Electrical and Electronic Engineering, Imperial College London 18 March 2011 Dedicated to my wonderful parents, Prof. Sitthichai and Pornpan Pookaiyaudom and, the Kingdom of Thailand Abstract Biochemical sensors that are low cost, small in size and compatible with integrated circuit technology play an essential part in the drive towards personalised healthcare and the research described in this thesis is concerned with this area of medical instrumentation. A new biochemical measurement system able to sense key properties of biochemical fluids is presented. This new integrated circuit biochemical sensor, called the Chemical Current- Conveyor, uses the ion sensitive field effect transistor as the input sensor combined with the current-conveyor, an analog building-block, to produce a range of measurement systems. The concept of the Chemical Current-Conveyor is presented together with the design and subsequent fabrication of a demonstrator integrated circuit built on conventional 0.35µm CMOS silicon technology. The silicon area of the Chemical Current-Conveyor is (92µm x 172µm) for the N-channel version and (99µm x 165µm) for the P-channel version. Power consumption for the N-channel version is 30µW and 43µW for the P-channel version with a full load of 1MΩ. The maximum sensitivity achieved for pH measurement was 46mV per pH. The potential of the Chemical Current Conveyor as a versatile biochemical integrated circuit, able to produce output information in an appropriate form for direct clinical use has been confirmed by applications including measurement of (i) pH, (ii) buffer index ( ), (iii) urea, (iv) creatinine and (v) urea:creatinine ratio. In all five cases the device has been demonstrated successfully, confirming the validity of the original aim of this research project, namely to produce a versatile and flexible analog circuit for many biochemical measurement applications. Finally, the thesis closes with discussion of another potential application area for the Chemical Current Conveyor and the main contributions can be summarised by the design and development of the first: ISFET based current-conveyor biochemical sensor, called „Chemical Current Conveyor, CCCII+‟ has been designed and developed. It is a general purpose biochemical analog building-block for several biochemical measurements. Real-time buffer capacity measurement system, based on the CCCII+, which exploits the imbedded analog computation capability of the CCCII+. ii Real-time enzyme based CCCII+ namely, Creatinine-CCCII+ and Urea-CCCII+ for real-time monitoring system of renal system. The system can provide outputs of 3 important parameters of the renal system, namely (i) urea concentration, (ii) creatinine concentration, and (ii) urea to creatinine ratio. iii Acknowledgements First and foremost, I would like to express my deepest gratitude to my supervisor, Professor Chris Toumazou, for his suggestion, motivation and guidance not only throughout my PhD but also since 2003, when we met in Bangkok. Without his support, belief, vision and encouragement, I would not be here today. It is such an honour to be his student and to be able to work a long side his team at the Centre for Bio-Inspired Technology, CBIT. I would also like to give a very special thank to my co-supervisor, Professor John Lidgey and his family (Jill Lidgey), for their continual friendship, support, and motivation since I have started my study in the UK. I am fortunate to have his feedbacks, countless discussions, helps and advices not only throughout my PhD but also toward life in the UK. I will be forever grateful. I thank my colleagues and friends in „the CBIT, Imperial College, London‟, „MMRC, Mahanakorn University of Technology, Thailand‟ and „Electronics and Communications group, Oxford Brookes University‟ for their outstanding supports, useful information and discussions during the course of my PhD: Dr. Timothy Constandinou, Dr. Pantelakis Georgiou, Dr. Amir Eftekhar, Dr. Themis Prodromakis, Wai Pan Chan, Yan Lui, Surachoke Thanapitak, Parinya Seelanan, Tassanai Parittotokkaporn, Orada Chumphukam, Dr. Apisak Worapishet, Dr. Ittipat Roopkom and Dr. Khaled Hayatleh. A special mention must also go to Thanaporn Kongprapunt who always there when I needed. I thank her for her understanding, support and love through all my darkest and gloomy time during this long journey. I would also like to give special thanks to Maria Khaleeq from the department of physics at Imperial College for doing the encapsulation and wire-bonding of the chip and, Dr. Themis Prodromakis from CBIT for taking the micro photographs of my chip. Last but not least, I would also like to thank Wiesia Hsissen for her kindness and warmth while looking after me during my PhD. And most of all, I thank my wonderful parents, Prof. Sitthichai Pookaiyaudom and Pornpan Pookaiyaudom, for all their love and support, for their understanding and iv sacrifices they have made, they are the best parents any son could ask for and I am grateful for that. Lastly, I dedicated this thesis to my family (Dad, Mum, King and Kaew). v Contents List of figures ix List of tables xiv List of companies xv List of publications xvi Chapter 1: Introduction 1 1.1 Motivation and achievements 1 1.2 Overview and structure of the thesis 3 1.3 References 5 Chapter 2: Using Ion Sensitive Field Effect Transistors (ISFETs) in Biochemical Instrumentation 7 2.1 Introduction 7 2.2 Operation of the ISFET 9 2.2.1 ISFETs in an unmodified CMOS process 20 2.3 Reference Electrode 24 2.4 Drift, hysteresis and lifetime in ISFETs 28 2.5 Temperature sensitivity in ISFETs 30 2.6 Trapped charges in CMOS ISFETs 32 2.7 Noise in CMOS ISFETs 35 2.8 ISFET interfacing techniques 37 2.9 Summary of Chapter 2 50 2.10 References 50 Chapter 3: Current-Conveyor: The Current Mode Approach 57 3.1 Introduction 57 3.2 Background 58 3.3 Current-Conveyor implementation 62 3.4 Current-Conveyor (CCII) applications 65 3.4.1 Voltage and current readout amplifiers using the CCII 66 3.4.2 Analog computation using the CCII 69 3.4.3 Impedance conversion using the CCII 70 3.4.4 Filters 73 3.4.5 The relationship between the ideal transistor and current-conveyor 76 3.4.6 The relationship between the current-conveyor and the current-feedback operational amplifier (CFOA) 79 3.5 Summary of Chapter 3 81 vi 3.6 References 81 Chapter 4: Chemical Current-Conveyor for Biochemical Computation 83 4.1 Introduction 83 4.2 Concept of the CCCII+: Topology and analysis 84 4.3 Design and implementation of Chemical Current-Conveyor 86 4.3.1 The basic initial design of the Chemical Current-Conveyor 88 4.3.2 Full implementation of the Chemical Current-Conveyor 96 4.4 Simulation results 99 4.5 Design fabrication 108 4.5.1 Matching of transistors, common-centroid layout and dummy transistors 109 4.5.2 Full layout of N-channel and P-channel ISFET CCCII+ Devices 113 4.5.3 Electrostatic discharge (ESD) protection 115 4.6 Measured results 117 4.6.1 Wire bonding the CCCII+ chips 118 4.6.2 Test board preparation 120 4.6.3 Measured results on N-channel ISFET CCCII+ in comparison with fixed and ISFET readout circuit 123 4.6.4 Measured results on P-channel ISFET CCCII+ 129 4.7 Applications of Chemical Current-Conveyor for biochemical computation 131 4.7.1 Basic readout: Voltage-mode and current-mode amplifiers built with the Chemical Current-Conveyor 132 4.7.2 Analog biochemical computation 138 4.7.3 Current-feedback Chemical Current-Conveyor 142 4.7.4 „Super‟ ISFET 148 4.8 Summary of Chapter 4 149 4.9 References 149 Chapter 5: Real-Time Buffer Capacity and Buffer Index Measurement using Chemical Current-Conveyor (CCCII+) 152 5.1 Introduction 152 5.2 Buffer the fundamental acid/base concepts 153 5.2.1 Acid/base buffer operation 154 5.2.2 Buffer index/capacity and pH 156 5.2.3 Buffer capability of blood 157 5.3 Chemical Current-Conveyor for buffer index/capacity measurement 160 5.4 Operation of the Chemical Current-Conveyor for buffer index/capacity measurement 165 5.5 Measured results and discussion 167 5.6 Measurement of ISFET response time 170 vii 5.6.1 Circuit operation and description 171 5.6.2 Result and discussion 173 5.7 Summary of Chapter 5 175 5.8 Reference 175 Chapter 6: Real-Time Measurement of Urea, Creatinine and Urea to Creatinine Ratio using Enzyme Based Chemical Current-Conveyor (CCCII+) 177 6.1 Introduction 177 6.2 Renal disorders 179 6.3 ISFET as a versatile biosensor 180 6.3.1 Procedure of EnFET fabrication 182 6.4 Chemical Current-Conveyor for urea and creatinine measurement 183 6.5 Chemical Current-Conveyor for urea to creatinine ratio measurement 185 6.6 Measured results and discussion 188 6.6.1 Possible anti-logarithm approach at the output 195 6.7 Output to the Nth-power circuit 199 6.8 Summary of Chapter 6 200 6.9 References 201 Chapter 7: Conclusion and Future Work 204 7.1 Conclusion 204 7.2 Future work: Determination and monitoring of cells culture using array CCCII+ platform 207 7.3 References 209 Appendix A: Matching of Transistors, Common-Centroid Layout and Dummy Transistors for CCCII+ 210 Appendix B: The Full Circuit Schematic of the CCCII+ Test and Application Board 215 Appendix C: CCCII+: Voltage Input/Output Transfer and Titration Test 220 viii List of figures Figure 2-1. [1] Comparison of (a) MOSFET and (b) ISFET cross section ......................................... 10 Figure 2-2.
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