Silicone-based Intracortical Implants with Brain-like Stiffness Reduces the Brain Foreign Body Response Edward N. Zhang Department of Biomedical Engineering McGill University, Montreal December 2019 A thesis submitted to McGill University in partial fulfillment of the requirements of the degree Master of Engineering © Edward N. Zhang 2019 Page | 1 Table of Contents 1. Abstracts ........................................................................................................................................4 1.1. English Abstract .......................................................................................................................4 1.2. Résumé Français ......................................................................................................................5 2. Acknowledgements ........................................................................................................................7 3. Contribution of Authors .................................................................................................................9 4. Project Description ....................................................................................................................... 10 4.1. Motivation ............................................................................................................................ 10 4.2. Project Goals ......................................................................................................................... 10 4.3. Declaration of Novelty ........................................................................................................... 11 5. Introduction: Brain Implants ......................................................................................................... 12 5.1. Brain Implant’s in Clinical Practice .......................................................................................... 14 5.1.1. Clinical Significance and Applications of Deep Brain Stimulation Implants ........................................ 14 5.1.2. Clinical Significance and Applications of Intracortical Brain Implants ................................................ 15 5.1.3. Clinical Need for Brain Implants ......................................................................................................... 16 5.2. Brain Implant Challenges in Long-term Reliability and High-Quality Recordings ....................... 18 5.2.1. Brain Implant Designs ........................................................................................................................ 18 5.2.2. Issues in Electrode Functionality and Signal Quality in Chronic Recordings ........................................ 21 5.2.3. Failure Modes of Brain Implants ........................................................................................................ 24 5.3. The Brain Foreign Body Response ........................................................................................... 25 5.3.1. Roles of Reactive Astrocytes in the Brain FBR .................................................................................... 27 5.3.2. Roles of Activated Microglia in the Brain FBR ....................................................................... 29 5.3.3. Glial Scar in the Chronic Brain FBR ..................................................................................................... 30 5.4. Stiffness Mismatch Between Brain Implants and Brain Tissue Exacerbates Brain FBR .......................... 33 5.4.1. Neuron and Glial Response to Stiff and Compliant Substrates ........................................................... 35 5.4.2. Strain Caused by Brain Implants on Brain Tissue ................................................................................ 36 5.4.3. In Vivo Observation of Exacerbated brain FBR due to Young’s Modulus Mismatch ........................... 39 5.5. Current Polymer Materials for Compliant Implant Fabrication and Challenges ......................... 43 5.5.1. Polyimide ........................................................................................................................................... 45 5.5.2. Parylene C .......................................................................................................................................... 47 5.5.3. SU-8 ................................................................................................................................................... 48 5.5.4. Other Polymers .................................................................................................................................. 49 5.6. Current Insertion Methods of Compliant Intracortical Implants and Challenges ....................... 52 5.6.1. Dissolvable Coatings .......................................................................................................................... 52 5.6.2. Insertion Shuttles ............................................................................................................................... 54 5.7 Summary ................................................................................................................................ 55 Page | 2 6. Silicone Implants with Brain-like Stiffness Delivered Using Micro-Molded Dissolvable Sugar Shuttles Reduce the Brain Foreign Body Response ......................................................................................... 56 6.1. Abstract ................................................................................................................................ 56 6.2 Introduction ........................................................................................................................... 57 6.3. Results and Discussion ........................................................................................................... 59 6.3.1 Fabrication of Sacrificial Sugar Molds ................................................................................................. 59 6.3.2. Fabrication of Ecoflex Implants .......................................................................................................... 62 6.3.3. Characterization of Ecoflex and PDMS Young’s Modulus ................................................................... 64 6.3.4. Encasing of Implants in Dissolvable Sugar Shuttles and Implantation into Rats ................................. 67 6.3.5. In Vivo Assessment of Brain Foreign Body Response .......................................................................... 70 6.4. Conclusion ............................................................................................................................. 75 6.5. Experimental Section ............................................................................................................. 77 6.5.1. Ecoflex Implant Fabrication ............................................................................................................... 77 6.5.2. Characterization of Ecoflex and PDMS Young’s Modulus ................................................................... 78 6.5.3. Insertion of Implants .......................................................................................................................... 79 6.5.4. Analysis of Brain Foreign Body Response ........................................................................................... 82 6.6 Supplementary Data ............................................................................................................... 84 6.6.1. SU-8 Mold Fabrication ....................................................................................................................... 84 6.6.2. PDMS Implant Fabrication ................................................................................................................. 87 6.6.3. Silicon Implant Fabrication ................................................................................................................ 89 7. Discussion .................................................................................................................................... 94 7.1 Fabrication of Ecoflex and PDMS Implants ............................................................................... 94 7.1.1 Fabrication of Sacrificial Sugar Molds ................................................................................................. 94 7.1.2 Vacuum Assisted Molding (VAM) of Soft Implants .............................................................................. 96 7.2 VAM of Dissolvable Sugar Shuttles for Delivery of Soft Implants into the Brain ......................... 98 7.3 In Vivo Analysis of the Brain FBR to Ecoflex, PDMS, and Silicon Implants ................................ 102 8. Conclusion ................................................................................................................................. 103 8.1 Future Work ......................................................................................................................... 104 9. References ................................................................................................................................. 106 Page | 3 1. Abstracts 1.1. English Abstract Brain implants have significant implications in treating neurological disorders and diseases and are a key enabler of brain machine interface (BMI) technology. However, brain implants’ widespread adoption in clinical settings is undermined by challenges in obtaining high-quality recordings