INVESTIGATION OF MATERIAL AND THERAPEUTIC STRATEGIES TO REDUCE THE INFLAMMATORY RESPONSE TO INTRACORTICAL IMPLANTS by JESSICA KIMBERLY NGUYEN Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Dissertation Advisor: Dr. Jeffrey R. Capadona Department of Biomedical Engineering CASE WESTERN RESERVE UNIVERSITY August 2015 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of Jessica Nguyen, candidate for the degree of Doctor of Philosophy*. Jeffrey R. Capadona Committee Chair Dustin J. Tyler Committee Member Stuart J. Rowan Committee Member Horst von Recum Committee Member Nicholas P. Ziats Committee Member 4/29/2015 Date of Defense *We also certify that written approval has been obtained for any proprietary material contained therein. ii To Mom and Dad, for always believing in me iii Table of Contents List of Tables ...................................................................................................................... x List of Figures .................................................................................................................... xi Acknowledgements ........................................................................................................... xv Abstract ............................................................................................................................... 1 Chapter 1 Specific Aims .................................................................................................. 3 Aim 1: Characterize the neural tissue properties surrounding compliant implants ........ 4 Sub-Aim 1A: Determine the time course of neuroinflammatory events surrounding compliant neural implants ........................................................................................... 5 Sub-Aim 1B: Quantify the strain profiles surrounding acute neural implants of varying compliance .................................................................................................................. 5 Aim 2: Investigate the utility of local antioxidant therapy from compliant implants on improving neuronal health .............................................................................................. 6 Sub-Aim 2A: Characterize the effects of antioxidant-releasing mechanically compliant probes on the neuroinflammatory response ............................................... 7 Sub-Aim 2B: Develop a method to surface conjugate a synthetic antioxidant to neural implants ....................................................................................................................... 7 Chapter 2 Introduction.................................................................................................... 9 2.1 Neural Recordings .................................................................................................. 9 2.1.1 Intracortical Microelectrodes ........................................................................ 10 2.1.1.1 Types of Intracortical Microelectrodes: ................................................. 12 2.1.1.2 Neuronal Recording Signals: Single-Unit Activity (SUA), Multi-Unit Activity (MUA), and Local Field Potentials (LFP) .............................................. 15 2.2 Challenges to Intracortical Microelectrode Use ................................................... 17 2.2.1 Classes of Microelectrode Failure ................................................................... 19 2.2.1.1 Biological Failure Mode ........................................................................ 20 2.2.1.2 Material Failure Mode ........................................................................... 21 2.2.1.3 Mechanical Failure Mode ...................................................................... 22 iv 2.3 The Neuroinflammatory Response ....................................................................... 23 2.3.1 The Acute Inflammatory Phase ..................................................................... 23 2.3.2 The Chronic Inflammatory Phase .................................................................. 25 2.3.2.1 Microglia/Macrophages ......................................................................... 25 2.3.2.2 Astrocytes .............................................................................................. 28 2.3.2.3 Neurodegeneration ................................................................................. 30 2.3.2.4 BBB Permeability .................................................................................. 31 2.3.2.5 Anti-inflammatory Strategies ................................................................. 33 2.4 Strategies to Improve BBB integrity ..................................................................... 35 2.4.1 Effect of Microelectrode Compliance .............................................................. 36 2.4.2 Strategies to Reduce Microelectrode-induced Tissue Strain ........................... 39 2.4.2.1 Polymers ................................................................................................ 39 2.4.2.2 Insertion Shuttles ................................................................................... 42 2.4.2.3 Mechanically-adaptive materials ........................................................... 44 2.4.2.4 Architecture Modifications .................................................................... 46 2.4.2.5 Wireless Systems ................................................................................... 48 2.4.3 Effect of Oxidative Stress .............................................................................. 50 2.4.3.1 Reactive Oxygen Species (ROS) ........................................................... 50 2.4.3.2 Electrode Corrosion ............................................................................... 52 2.4.3.3 Strategies to Reduce Oxidative Stress ................................................... 55 2.5 Summary ............................................................................................................... 56 Chapter 3 Mechanically-Compliant Intracortical Implants Reduce the Neuroinflammatory Response ....................................................................................... 58 3.1 Abstract ................................................................................................................. 58 3.2 Introduction ........................................................................................................... 59 3.2.1 Materials and Methods .................................................................................. 61 v 3.2.2 Intracortical Implants .................................................................................... 61 3.2.3 Strain Field Modeling .................................................................................... 62 3.2.4 Animal Surgery ............................................................................................. 63 3.2.5 Tissue Processing .......................................................................................... 65 3.2.6 Immunohistochemistry .................................................................................. 65 3.2.7 Quantitative Analysis .................................................................................... 67 3.2.8 Statistical Analysis ........................................................................................ 67 3.3 Results ................................................................................................................... 68 3.3.1 Finite Element Analysis of Tissue Strain ...................................................... 69 3.3.2 Neuronal Nuclei ............................................................................................ 70 3.3.3 Glial Cell Markers ......................................................................................... 72 Astrocytes .............................................................................................. 72 Microglia/Macrophages ......................................................................... 74 Blood Brain Barrier Integrity (IgG) ....................................................... 77 3.4 Discussion ............................................................................................................. 79 3.5 Conclusions ........................................................................................................... 90 3.6 Acknowledgements ............................................................................................... 90 Chapter 4 Compliant Intracortical Implants Reduce Strains and Strain Rates in Brain Tissue In Vivo ....................................................................................................... 92 4.1 Abstract ................................................................................................................. 92 4.2 Introduction ........................................................................................................... 93 4.3 Materials and Methods .......................................................................................... 96 4.3.1 Electrode fabrication & characterization ....................................................... 96 4.3.2 Animal surgery and force measurements ...................................................... 97 4.3.3 Force Measurement ....................................................................................... 98 4.3.4 Estimation of stress