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Biopolymer-Nanotube Nerve Guidance Conduit Drug Delivery for Peripheral Nerve Regeneration Ohan S

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Biopolymer-Nanotube Nerve Guidance Conduit Drug Delivery for Peripheral Nerve Regeneration Ohan S University of Connecticut OpenCommons@UConn Doctoral Dissertations University of Connecticut Graduate School 3-26-2019 Biopolymer-Nanotube Nerve Guidance Conduit Drug Delivery for Peripheral Nerve Regeneration Ohan S. Manoukian University of Connecticut - Storrs, [email protected] Follow this and additional works at: https://opencommons.uconn.edu/dissertations Recommended Citation Manoukian, Ohan S., "Biopolymer-Nanotube Nerve Guidance Conduit Drug Delivery for Peripheral Nerve Regeneration" (2019). Doctoral Dissertations. 2081. https://opencommons.uconn.edu/dissertations/2081 Biopolymer-Nanotube Nerve Guidance Conduit Drug Delivery for Peripheral Nerve Regeneration Ohan Shant Manoukian, Ph.D. University of Connecticut, 2019 Peripheral nerve injuries account for roughly 3% of all trauma patients with over 900,000 repair procedures annually in the U.S. Of all extremity peripheral nerve injuries, 51% require nerve repair with a transected gap. The current gold-standard autograft repair has several associated shortcomings, while engineered constructs typically offer suboptimal results only suitable for short gaps. In order to achieve enhanced peripheral nerve regeneration and greater functional recovery, we have developed a biodegradable, chitosan-based nerve guidance conduit (NGC) with aligned microchannel porosity and halloysite nanotubes for the sustained release of 4-Aminopyridine (4AP), a small molecule drug that promotes nerve conduction and neurotrophic factor release. In vitro studies characterized the polymer NGC system and confirmed the sustained release of 4AP. Human Schwann cells showed a dose-dependent elevation of critical proteins including nerve growth factor (NGF), myelin protein zero (P0), and brain derived neurotrophic factor (BDNF). When treated with 10 µg/mL 4AP, NGF, P0, and BDNF showed 128.58±0.57%, 310.75±11.92%, and 170.94±4.43% increases over no-drug control groups, respectively. When tested in vivo using a critical- size (15 mm) rat sciatic nerve transection model, the results of functional walking track analysis, morphometric evaluations of myelin development, and histological assessments of various markers confirmed the equivalency of the drug-conduit repair to autograft controls. At 8 weeks post-operative, the sciatic functional index (SFI) of autograft (-44.89±4.73) was not statistically different from drug-conduit (- 45.12±4.45), while myelin thickness (G-ratio) evaluations also showed no statistical difference between autograft (0.61±0.10) and drug-conduit (0.65±0.06). The conduit’s aligned microchannel architecture and sustained release of 4-Aminopyridine may facilitate physical guidance of axons to distal target reinnervation, while increasing nerve conduction, and in turn neurotransmitter and neurotrophic factor release. Overall, our NGC facilitates more efficient and efficacious peripheral nerve regeneration via a drug delivery system that is feasible for clinical application, with potentially transformative implications. Biopolymer-Nanotube Nerve Guidance Conduit Drug Delivery for Peripheral Nerve Regeneration Ohan Shant Manoukian B.S.E., University of Connecticut, 2015 A Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy at the University of Connecticut 2019 Copyright by Ohan Shant Manoukian 2019 ii APPROVAL PAGE Doctor of Philosophy Dissertation Biopolymer-Nanotube Nerve Guidance Conduit Drug Delivery for Peripheral Nerve Regeneration Presented by Ohan Shant Manoukian, B.S.E. Major Advisor ___________________________________________________________________ Sangamesh G. Kumbar, Ph.D. Associate Advisor ___________________________________________________________________ Swetha Rudraiah, Ph.D. Associate Advisor ___________________________________________________________________ Syam Nukavarapu, Ph.D. Associate Advisor ___________________________________________________________________ Ivo Kalajzic, M.D., Ph.D. Associate Advisor ___________________________________________________________________ Kazunori Hoshino, Ph.D. University of Connecticut 2019 iii DEDICATION To my parents, Mourad and Hilda, without whose endless guidance, unconditional love, and unwavering support and encouragement, none of this would be possible. iv ACKNOWLEDGEMENTS This work would not have materialized, and I would not be where I am today, without the guidance and support of many mentors who helped me throughout all phases of my professional and personal life. I would like to, first and foremost, thank my major advisor, Dr. Sangamesh Kumbar, who has been an excellent mentor throughout my years at the University of Connecticut. Dr. Kumbar provided me with invaluable guidance and mentorship, and helped me grow both professionally and personally. Without his support, this work would never have been realized. I would also like to acknowledge and thank my thesis committee members, Dr. Swetha Rudraiah, Dr. Syam Nukavarapu, Dr. Ivo Kalajzic, and Dr. Kazunori Hoshino for their time, technical expertise, and valuable scientific inputs and critiques. Thank you for all the discussions and conversations which undoubtedly helped strengthen this work. I would like to thank the faculty and staff in the Department of Biomedical Engineering for their help throughout my time as a student, in particular Dr. Ki Chon, Dr. David Kaputa, Dr. Patrick Kumavor, Ms. Jennifer Desrosiers, and Ms. Lisa Ephraim, all of whom made my time within the department an enjoyable experience. I would like to thank Dr. Jenna Bartley, from the Department of Immunology at UConn Health, for all of her help and support with the walking track analysis portion of my animal work, as well as her invaluable advice and encouragement, as a mentor and friend. I would also like to extend my gratitude to all members of the lab, past and present, who provided guidance and scientific support, and also made the daily lab life enjoyable. In particular, Dr. Roshan James who helped me every step of the way in my early graduate school career, taught me everything he knew, and helped develop and strengthen my research techniques and scientific skills. Dr. Namdev Shelke, Dr. Aja Aravamudhan, and Dr. Daisy Ramos for teaching me laboratory basics and guiding me with my early work, and in particular Dr. Ramos for all her help and friendship over the years. I would also like to thank Dr. Michael Arul, Sama Abdulmalik, Sara Katebifar, Jonathon Nip, Naseem Sardashti, and Jiana Baker for their help throughout my thesis work and for making my time in the lab memorable. v It would be incomplete to not also acknowledge and thank the National Science Foundation (NSF) Division of Graduate Education, Graduate Research Fellowship Program (GRFP), for awarding me an NSF Graduate Research Fellowship in 2017, without whose financial support this work would not be possible. Being awarded an NSF Graduate Research Fellowship (Grant No. DGE-1747453), for my past and present contributions to science and engineering, was truly a highlight of my graduate school career, as well as a great moment of pride and a humbling honor. I would like to thank all of my friends from all circles who have stood by me and made this time a truly enjoyable and adventurous journey. To my dearest friends from the Armenian community, where I was born and raised, and where lifelong friendships have been forged, your continued respect and support is undoubtedly appreciated. To all of my friends from my amazing times at the University of Connecticut, you have all been an integral part of my professional and personal successes throughout my college years and beyond, and I thank you all for that. Last, but certainly not least, I would like to thank my family for their unwavering support. To my parents, Mourad and Hilda, without whose unconditional love and guidance I would not be where I am today, thank you for teaching me the values of education, hard work, perseverance, integrity, and humility. Your countless sacrifices, and continued support and encouragement, have led me to achieve my wildest dreams and I hope I have, and can continue to, make you both proud. vi TABLE OF CONTENTS APPROVAL PAGE ................................................................................................................................... iii DEDICATION............................................................................................................................................ iv ACKNOWLEDGEMENTS ....................................................................................................................... v CHAPTER 1: PERIPHERAL NERVE INJURY AND REGENERATION ......................................... 1 1.1. INTRODUCTION .................................................................................................................... 1 1.2. BIOLOGY OF PERIPHERAL NERVE INJURY AND REGENERATION .......................... 2 1.3. AUGMENTED PERIPHERAL NERVE REGENERATION .................................................. 9 1.4. EXOGENOUS NEUROTROPHIC GROWTH FACTORS ................................................... 13 1.5. DRUG DELIVERY STRATEGIES AND CELL THERAPIES ............................................ 18 1.6. ANIMAL MODELS AND FUNCTIONAL ASSESSMENTS .............................................. 24 1.7. CLINICAL APPLICATIONS AND COMMERCIALIZED NGCs ....................................... 27 CHAPTER 2: ALIGNED MICROCHANNEL POLYMER-NANOTUBE COMPOSITES FOR PERIPHERAL NERVE REGENERATION: SMALL MOLECULE DRUG DELIVERY .............. 29 2.1. INTRODUCTION .................................................................................................................
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