TOWARDS DEVELOPMENT OF AFFINITY POLYMER-BASED ADHESION BARRIERS FOR SURGICAL MESH DEVICES by GREG DANIEL LEARN Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Dissertation Advisor: Horst A. von Recum, PhD Department of Biomedical Engineering CASE WESTERN RESERVE UNIVERSITY May 2021 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of Greg Daniel Learn Candidate for the degree of Doctor of Philosophy *. Committee Chair: Jeffrey Capadona, Ph.D. Committee Member: Horst von Recum, Ph.D. Committee Member: Kathleen Derwin, Ph.D. Committee Member: Guang Zhou, Ph.D. Committee Member: Michael Rosen, M.D. Date of Defense: Monday 14 December 2020 *We also certify that written approval has been obtained for any proprietary material contained therein. 2 This dissertation is dedicated to the memory of Jim Simpson. Though not able to see this, as a scientist, engineer, runner, and family friend I looked up to from a young age, he furthered my inspiration and resolve to pursue and complete my degree. Thank you, Jim. 3 TABLE OF CONTENTS TABLE OF CONTENTS .................................................................................................... 4 LIST OF TABLES ............................................................................................................ 12 LIST OF FIGURES .......................................................................................................... 13 PREFACE ......................................................................................................................... 16 ACKNOWLEDGEMENTS .............................................................................................. 17 LIST OF ABBREVIATIONS ........................................................................................... 20 ABSTRACT ...................................................................................................................... 23 1. CHAPTER 1: PATHOGENESIS AND PREVENTION OF ABDOMINAL ADHESIONS, AND THE ROLE OF SURGICAL MESH BIOMATERIALS ............... 25 1.1. Abstract .............................................................................................................. 25 1.2. Introduction ........................................................................................................ 26 1.2.1. Prevalence of Post-Surgical Adhesions ...................................................... 28 1.2.2. The Relation of Peritoneal Adhesions to Surgical Meshes ......................... 30 1.2.3. Regulatory Environment for Mesh Adhesion Prophylaxis ......................... 32 1.2.4. Purpose ........................................................................................................ 33 1.3. Clinical Significance of Peritoneal Adhesions ................................................... 34 1.3.1. Complications ............................................................................................. 34 1.3.2. Socioeconomic Burden ............................................................................... 37 1.3.3. Insufficient Awareness ................................................................................ 38 1.4. Clinical Treatment of Peritoneal Adhesions ...................................................... 39 1.4.1. Surgical Adhesiolysis.................................................................................. 39 1.4.2. Physiotherapy .............................................................................................. 39 4 1.5. Pathogenesis of Peritoneal Adhesions and Relation to Mesh Biomaterials ....... 40 1.5.1. The Healthy Peritoneum ............................................................................. 40 1.5.2. Adhesion-Free Peritoneal Healing .............................................................. 42 1.5.3. Abnormal Peritoneal Healing and Adhesion Formation ............................. 44 1.5.3.1. Tissue Disturbance .............................................................................. 44 1.5.3.2. Fibrin Deposition ................................................................................. 45 1.5.3.3. Proximity of Surfaces .......................................................................... 45 1.5.3.4. Time for Adhesion Initiation and Maturation ...................................... 46 1.5.3.5. Inflammation ....................................................................................... 47 1.5.3.6. Ischemia and Hypoxia ......................................................................... 48 1.5.4. The Role of Surgical Meshes in Peritoneal Adhesion Formation ............... 48 1.5.4.1. Effects of Material Properties .............................................................. 49 1.5.4.2. Effects of Structural Characteristics .................................................... 52 1.6. Prophylaxis of Peritoneal Adhesions ................................................................. 56 1.6.1. General Preventive Strategies ..................................................................... 56 1.6.1.1. Surgery-Related Factors - Techniques and Instrumentation ............... 56 1.6.1.2. Pharmacologic Strategies .................................................................... 59 1.6.1.3. Barrier Materials - Membranes and Gels ............................................ 63 1.6.2. Mesh-Specific Preventive Strategies .......................................................... 68 1.7. Emerging Opportunities ..................................................................................... 73 1.8. Conclusions and Future Outlook ........................................................................ 78 1.9. Acknowledgments .............................................................................................. 80 5 2. CHAPTER 2: NONTHERMAL PLASMA TREATMENT IMPROVES UNIFORMITY AND ADHERENCE OF CYCLODEXTRIN-BASED COATINGS ON HYDROPHOBIC POLYMER SUBSTRATES ............................................................... 81 2.1. Abstract .............................................................................................................. 81 2.2. Introduction ........................................................................................................ 82 2.3. Materials and Methods ....................................................................................... 86 2.3.1. Materials ..................................................................................................... 86 2.3.2. Plasma Cleaning and Activation of PP Substrate Surfaces ........................ 87 2.3.3. Effects of Plasma Treatment on PP Substrates ........................................... 88 2.3.3.1. Wettability - Contact Angle Goniometry ............................................ 88 2.3.3.2. Surface Chemistry - XPS ..................................................................... 88 2.3.4. pCD Synthesis and Coating onto Surfaces ................................................. 90 2.3.5. Effects of Plasma Treatment on pCD Coatings .......................................... 90 2.3.5.1. Qualitative Uniformity - Direct Visualization ..................................... 90 2.3.5.2. Qualitative Uniformity - SEM ............................................................. 91 2.3.5.3. Semi-Quantitative Uniformity - Direct Visualization ......................... 92 2.3.5.4. Adherence - Lap-Shear Testing ........................................................... 92 2.3.5.5. Interfacial Covalent Bonding - XPS .................................................... 93 2.3.6. Statistical Analysis ...................................................................................... 94 2.4. Results ................................................................................................................ 95 2.4.1. Effects of Plasma on PP Substrate Wettability and Surface Chemistry ..... 95 2.4.2. Effects of Plasma on pCD Coating Uniformity, Adherence, and Interfacial Covalent Bonding ...................................................................................................... 99 6 2.5. Discussion ........................................................................................................ 105 2.6. Acknowledgments ............................................................................................ 108 3. CHAPTER 3: NONTHERMAL PLASMA TREATMENT OF POLYMERS MODULATES BIOLOGICAL FOULING BUT CAN CAUSE MATERIAL EMBRITTLEMENT ....................................................................................................... 109 3.1. Abstract ............................................................................................................ 109 3.2. Introduction ...................................................................................................... 110 3.3. Materials and Methods ..................................................................................... 113 3.3.1. Materials ................................................................................................... 113 3.3.2. Plasma Treatment ...................................................................................... 114 3.3.3. Surface Characterization ........................................................................... 115 3.3.3.1. X-ray Photoelectron Spectroscopy .................................................... 115 3.3.3.2. Fibrinogen Adsorption ....................................................................... 116 3.3.3.3. Bacterial