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Amino Acid-Based Poly(Ester Urea)S for Soft-Tissue Repair Applications

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Amino Acid-Based Poly(Ester Urea)S for Soft-Tissue Repair Applications © 2019 Nathan Zachary Dreger ALL RIGHTS RESERVED Amino Acid-Based Poly(ester urea)s for Soft-tissue Repair Applications A Dissertation Presented to The Graduate Faculty of The University of Akron In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy Nathan Z. Dreger February 2019 AMINO ACID-BASED POLY(ESTER UREA)S FOR SOFT-TISSUE REPAIR APPLICATIONS Nathan Zachary Dreger Dissertation Approved: Accepted: _______________________________ ______________________________ Advisor Department Chair Dr. Matthew L. Becker Dr. Tianbo Liu _______________________________ ______________________________ Committee Member Dean of College Dr. Li Jia Dr. Ali Dhinojwala _______________________________ ______________________________ Committee Member Dean of the Graduate School Dr. Chrys Wesdemiotis Dr. Chand Midha _______________________________ ______________________________ Committee Member Date Dr. Darrell Reneker _______________________________ Committee Member Dr. Rebecca Willits ii ABSTRACT Preclinical Assessment of L-Valine-Based Poly(ester urea)s for Soft-Tissue Applications. New degradable polymer materials are required to aid in the treatment of soft-tissue injuries. Designing materials with mechanical properties similar to that of the tissue at the implant site is often overlooked. To more fully meet the needs required for an implantable biomaterial, a series of amino acid-based linear and branched poly(ester urea)s (PEU)s with varied diol chain length spacers were synthesized that were found to have mechanical properties similar to clinically employed polymer materials used in the treatment of hernia-repair. Concomitantly, these materials were designed and found to be degradable in vivo in to relatively benign byproducts readily excreted indicated by a limited inflammatory response through a comprehensive histological assessment. Amino Acid-based Poly(ester urea) Copolymer Films for Hernia-Repair Applications. The use of synthetic degradable materials is needed to help bridge the gap between currently utilized materials to aid in the treatment of hernia-repair. Readily available clinical materials include but are not limited to non-resorbable synthetic materials (i.e. polypropylene) which are mechanically robust however are permanent, and biologically derived tissues (i.e. small intestine submucosa extracellular matrix (SIS-ECM)) which provoke a limited inflammatory response yet are precluded by failure at low iii strain. To improve upon current options, a series of amino acid-based poly(ester urea) (PEU) copolymers comprised of L-valine and L-phenylalanine were synthesized and fabricated in to solvent cast stand-alone films or as composite films with SIS-ECM. Cell spreading, proliferation, viability, and an improved inflammatory response was observed in a rat hernia model for all PEU derivatives. Additionally, improved mechanical integrity of SIS-ECM was observed when combined as a composite film with PEUs. Surface-functionalized Poly(ester urea)s as Adhesion Barriers in Hernia-Repair. Regardless of material selected to aid in the treatment of hernia-repair, there is a significant risk of adhesion of the implant to the peritoneal space. This complication can lead to a fusion between the abdominal wall and other organs which often times requires further corrective surgery. A surface functionalized anti-adhesion poly(ester urea) (PEU)s with varied amounts of a scalable zwitterion thiol attached via thiol-ene chemistry was found to have limited cytotoxicity while also preventing adhesion of fibrinogen in vitro. Furthermore, a reduction of adhesion was observed for surface functionalized materials when compared to unfunctionalized controls in an intraabdominal rat adhesion model. DEDICATION This body of work is dedicated in three parts. First to my wife, Jessica. You have always supported my endeavors with patience and love. This work would not have come to fruition without you. Second, to my parents, Eric and Theresa Dreger. You have created and fostered an environment of “life-long learning” that has undoubtedly facilitated where I have gone in life. For this I am eternally grateful. Finally, to my brother Kyle. My relationship with you has helped me become a better thinker and, more importantly, a better person. Throughout this process, it has helped me keep perspective. v ACKNOWLEDGEMENTS This body of work could not have been completed without the contribution of many individuals. First and foremost, I want to thank my advisor, Dr. Matthew L. Becker. You have fostered an environment where the team is more important than the individual and where the best idea has to win. This enables students of all ages, backgrounds, and skill levels to help and contribute; this has driven me to contribute more and more. Al Davis said it best, “Just win baby, win.” I also want to thank my committee members Dr. Li Jia, Dr. Rebecca Willits, Dr. Chrys Wesdemiotis, and Dr. Darrell Reneker for challenging me to be a better student in the classroom and a better researcher in the laboratory. To all Becker group members, thank you for constantly creating a fun and collaborative work environment. On the road towards this degree, it has made all the difference. Finally, I want to thank my family for the constant support. The completion of this body of work is as much theirs as it is mine. vi TABLE OF CONTENTS LIST OF TABLES .................................................................................................................... xi LIST OF FIGURES ................................................................................................................. xii CHAPTER ............................................................................................................................ 1 II. INTRODUCTION .............................................................................................................. 1 1.1. Material design for diverse applications .............................................................. 1 1.2. The role of polymers in the evolution of hernia-repair ..................................... 18 II. MATERIALS AND INSTRUMENTATION .......................................................................... 27 2.1. Materials ............................................................................................................ 27 2.2. Instrumentation ................................................................................................. 27 III. PRECLINICAL IN VITRO AND INVIVO ASSESSMENT OF LINEAR AND BRANCHED L-VALINE- BASED POLY(ESTER UREA)S FOR SOFT TISSUE APPLICATIONS ......................................... 30 3.1. Abstract .............................................................................................................. 30 3.2. Introduction........................................................................................................ 31 3.3. Experimental ...................................................................................................... 34 3.3.1. Materials ..................................................................................................... 34 3.3.2. Characterization .......................................................................................... 34 3.3.3. Synthesis of Poly(ester urea) monomers ..................................................... 35 3.3.4. Synthesis of Poly(ester urea) polymers ....................................................... 38 3.3.5. Mechanical Property Measurements .......................................................... 41 3.3.6. In Vivo Implant Degradation ....................................................................... 42 3.3.7. Host-Implant Interaction ............................................................................. 43 3.4. Results ................................................................................................................ 43 vii 3.4.1. Synthesis...................................................................................................... 43 3.4.2. Physical Properties ...................................................................................... 45 3.4.3. In Vivo Degradation .................................................................................... 47 3.4.4. Mechanical Properties ................................................................................ 51 3.4.5. Histology ..................................................................................................... 55 3.5. Conclusion .......................................................................................................... 60 3.6. Acknowledgement ............................................................................................. 60 IV. AMINO ACID-BASED POLY(ESTER UREA) COPOLYMER FILMS FOR HERNIA-REPAIR APPLICATIONS ................................................................................................................... 62 4.1. Abstract .............................................................................................................. 62 4.2. Introduction........................................................................................................ 63 4.3. Experimental ...................................................................................................... 66 4.3.1. Materials ..................................................................................................... 66 4.3.2. Characterization .........................................................................................
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