Development of an Acousto-Electric Biochemical Sensor (AEBS) For Monitoring Biological and Chemical Processes A Thesis Submitted to the Faculty of Drexel University by Michel M. A. Francois in partial fulfillment of the requirements for the degree of Doctor of Philosophy June 2008 © Copyright 2008 Michel M. A. François. All Rights Reserved. iii Dedications To my daughters, Michele-Olivia François and Coralie-Michele François. iv Table of Contents LIST OF TABLES ...............................................................................................................x LIST OF ILLUSTRATIONS ............................................................................................ xii ABSTRACT ................................................................................................................... xxvi 1. CHAPTER 1: Introduction – Importance of sensors in our life ...............................1 1.1 Objective ....................................................................................................................2 1.2 Example of a Basic Complex Sensor System ............................................................2 1.3 Present Methods for Identifying and Sensing ............................................................5 1.4 Need for Cost Effective, Fast and Accurate Small Portable System .........................6 1.5 Areas most in Need of Miniature Bio-Sensors ...........................................................7 1.5.1 Medical ..............................................................................................................7 1.5.2 Environmental ...................................................................................................9 1.5.3 Health (Nutrition etc…) ..................................................................................11 1.5.4 Other areas (Manufacturing, Pharmaceutical etc…) .......................................12 1.6 Proposed Approach ..................................................................................................13 2. CHAPTER 2: Background – Detection Methods/fabrication technologies ...........16 2.1 Operational Definition of a Biosensor .....................................................................17 2.2 Biosensor Detection Methods/Fabrication Techniques ............................................19 2.2.1 Optical Transduction .......................................................................................19 2.2.2 Electrochemical Detection ...............................................................................20 v 2.2.3 Thermal Transduction .....................................................................................21 2.2.4 Magnetic Transduction ....................................................................................23 2.2.5 Mechanical Transduction ................................................................................25 2.3 Current Acoustic TSM Sensor Configurations ........................................................28 2.4 Conceptual Description of the Proposed Biosensor Module ...................................34 2.4.1 Transducer Section ..........................................................................................34 2.4.2 Fluidic Section .................................................................................................35 2.4.3 Gas Channel Section ........................................................................................37 2.4.4 Isolated Injection Channel Section ..................................................................38 2.4.5 Electronic Section ............................................................................................38 2.4.6 Packaging Section ...........................................................................................39 2.5 Advantages of the Proposed Acousto-Electric-Biochemical Sensor (AEBS) Device .......................................................................................................................43 2.6 Principles Involved in the Making of the Biochip ...................................................44 2.7 Applications of the Proposed Biosensor ..................................................................45 2.8 Contributions Derived from this Work ....................................................................49 3. CHAPTER 3: Design and Fabrication - Specific AIMS/Biochip Design /Process Development .................................................................................................................53 3.1 Principle of Operation of the Multi-Frequency Thickness Shear Mode (MFTSM) .......................................................................................................55 3.2 Development of the MFTSM Sensor Transducer ....................................................62 3.3 Specific Aim 1: Determination of the Design Criteria for Developing Quartz Biochips ........................................................................................................69 vi 3.3.1 Determination of Optimal Membrane Thickness ............................................69 3.3.2 TSM Transducer and Metal Mask Design Layouts .........................................78 3.3.3 Influence of the Size of Electrode on the TSM Frequency Shift ....................88 3.3.4 Influence of Distance between Electrodes on the TSM Frequency shift ..................................................................................................................92 3.3.5 Specific Aim 1: Summary .............................................................................103 3.4 Specific Aim 2: To Develop an IC-based Fabrication Process ..............................104 3.4.1 Quartz Etch Process .......................................................................................105 • Wet Chemical Etch .....................................................................................105 • Laser Micromachining ................................................................................110 • Ultrasonic Drilling ......................................................................................112 • Plasma Dry Etch .........................................................................................115 • Process Comparison ....................................................................................119 3.4.2 Quartz Etch Processes – Results and Discussion ..........................................120 3.4.3 Quartz Etch Process Comparison ..................................................................125 3.4.4 Quartz Etch Process Final Selection ..............................................................127 3.4.5 Photolithography Process ..............................................................................128 3.4.6 Specific Aim 2: Summary .............................................................................129 3.5 Specific Aim 3: Fabrication of the Biochip ...........................................................130 3.5.1 Process Step Details ......................................................................................131 3.5.2 MFTSM Transducer Final Fabrication Process ............................................143 3.5.3 Substrate Holder Design-1 Layout ................................................................146 vii 3.5.4 Aim 3: Summary ...........................................................................................156 3.6 Specific Aim 4: To Test Biochip Performance with Representative Biological Systems .................................................................................................157 3.6.1 A – Characterization of the Biochip Performance ........................................158 • Experiment I: Sensitivity Analysis .............................................................158 • Experiment II: Effect of Small Electrodes on Mass Sensitivity .................161 • Experiment III: Effect of Clustered Small TSM Electrodes Connected in Parallel on Sensitivity and Dynamic Range .................................................................165 B – Increasing Spatial Resolution .................................................................171 3.6.2 Applications ...................................................................................................182 • Application-1: Glycerin DI Water Concentration .......................................183 • Application-2: Colloidal System (4.5µm Polystyrene Particles) ................186 • Application-3: Antibody Adsorption on the Surface of the Sensor ............188 • Application-4: Biological Detection (E-Coli Detection) ............................191 3.5.4 Aim 4: Summary ...........................................................................................195 4. CHAPTER 4: Summary and Conclusion ................................................................196 5. CHAPRTER 5: Future Work ...................................................................................200 5.1 MFTSM Transducer Design (Future Work) ..........................................................201 5.2 New Quartz Etch Process to Improve Process Throughput (Future Work) .........................................................................................................210 6. CHAPTER 6: Appendices .........................................................................................222 6.1 Appendix-A: Complexity and Size of Laboratory Type Equipment .....................223 viii A.1 Laboratory Systems .........................................................................................223