THE GLIA-NEURONAL RESPONSE TO CORTICAL ELECTRODES: INTERACTIONS WITH SUBSTRATE STIFFNESS AND ELECTROPHYSIOLOGY by JAMES PATRICK HARRIS Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation Adviser: Dr. Dustin J. Tyler Department of Biomedical Engineering CASE WESTERN RESERVE UNIVERSITY January, 2012 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of James Patrick Harris candidate for the Doctor of Philosophy degree *. (signed) Dustin J. Tyler (chair of the committee) Jeffrey R. Capadona Robert H. Miller Dawn Taylor Christoph Weder (date) August 26, 2011 *We also certify that written approval has been obtained for any proprietary material contained therein. To Mom and Dad, the people that make me the proudest. Table of Contents List of Tables ............................................................................................................................vii List of Figures..........................................................................................................................viii Acknowledgements ..................................................................................................................xii Abstract....................................................................................................................................xvi CHAPTER 1. SPECIFIC AIMS...................................................................................... 1 Aim 1 ........................................................................................................................................... 2 Aim 2 ........................................................................................................................................... 3 Aim 3 ........................................................................................................................................... 3 Outline......................................................................................................................................... 4 CHAPTER 2. INTRODUCTION.................................................................................... 5 2.1. Statement of Problem ......................................................................................................... 5 2.2. Importance of Problem ...................................................................................................... 6 2.3. Review.................................................................................................................................. 7 2.3.1. Brain Recording Technologies...................................................................................... 7 2.3.1.1. Electrical Versus Other Recording Paradigms ..................................................................... 7 2.3.1.2. Electrical Electrode Recording Types .................................................................................. 9 2.3.1.3. Information Transfer Rates of Electrodes and Other Assistive Technologies .................. 12 2.3.1.4. Intracortical Electrode Technologies.................................................................................. 14 2.3.1.5. Importance of Intracortical Electrode Recording Site Size................................................ 15 2.3.1.6. Types and Characteristics of Intracortical Electrode Recordings ...................................... 16 2.3.1.7. Performance and Limitations of Intracortical Electrodes................................................... 17 2.3.2. Trauma from Microelectrode Insertion ....................................................................... 19 2.3.3. Tissue Response .......................................................................................................... 21 2.3.3.1. Acute Phase of Injury ......................................................................................................... 22 2.3.3.2. Chronic Phase of Injury...................................................................................................... 22 2.3.3.2.1. Chronically Activated Inflammatory Cells (Macrophages/Microglia)....................... 22 2.3.3.2.2. Blood Brain Barrier (BBB)......................................................................................... 25 2.3.3.2.3. Astrocytes ................................................................................................................... 27 2.3.3.2.4. Chemokines and Cytokines ........................................................................................ 29 2.3.3.2.5. Other Cell Types and Factors Associated in Response .............................................. 29 2.3.3.2.6. Summary of Chronic Response .................................................................................. 30 2.3.3.3. Mechanical effects.............................................................................................................. 31 2.3.3.3.1. Micro Mechanical Effects on Cells ............................................................................ 31 2.3.3.3.2. Macro Mechanical Effects on Tissue ......................................................................... 32 2.3.3.3.3. Pathways for Mechanical Effects on Cells ................................................................. 34 2.3.3.3.4. Mechanical Effects on Device and Packaging............................................................ 35 2.3.3.4. Intracortical Electrode Recording Longevity ..................................................................... 36 2.4. Summary............................................................................................................................ 41 CHAPTER 3. IN VIVO DEPLOYMENT OF MECHANICALLY ADAPTIVE NANOCOMPOSITES FOR INTRACORTICAL MICROELECTRODES*........... 42 3.1 Abstract............................................................................................................................... 42 3.2. Introduction....................................................................................................................... 43 3.3. Materials and Methods..................................................................................................... 47 iv 3.3.1. Device Fabrication....................................................................................................... 47 3.3.2. Surgical Procedures..................................................................................................... 49 3.3.3. Mechanical Test Procedures........................................................................................ 50 3.3.3.1. Microtensile Testing Setup................................................................................................. 50 3.3.3.2. Moisture and Temperature Maintenance............................................................................ 51 3.3.3.3. Dimensional Changes Due to Swelling.............................................................................. 52 3.3.4. Insertion Force Measurements .................................................................................... 52 3.3.5. Buckling Load Calculations ........................................................................................ 53 3.3.6. Buckle Testing............................................................................................................. 53 3.3.7. Histology ..................................................................................................................... 54 3.4. Results................................................................................................................................ 55 3.4.1. Microprobe Insertion into Rat Cortex ......................................................................... 55 3.4.2. Dry NC Modulus Measurements................................................................................. 57 3.4.3. In vivo Mechanical Switching..................................................................................... 58 3.4.4. Examination of Ex Vivo Modulus Testing Moisture .................................................. 59 3.4.5. Buckling and Insertion of Neat and NC Polymers ...................................................... 61 3.4.6. Implanted NC Microprobe Histology.......................................................................... 65 3.5. Discussion .......................................................................................................................... 67 3.6. Conclusions........................................................................................................................ 74 3.7. Acknowledgements ........................................................................................................... 75 CHAPTER 4. Mechanically adaptive intracortical implants improve the proximity of neuronal cell bodies* .................................................................................................. 76 4.1 Abstract............................................................................................................................... 76 4.2. Introduction....................................................................................................................... 77 4.3. Materials and Methods..................................................................................................... 80 4.3.1. Implant Fabrication and Imaging ................................................................................ 80 4.3.2.