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Biocompatible Electrospun Vehicles to Enhance the Effectiveness of Anti-Fertility Strategies and Their Biomimetic Properties As Blood Vessel Scaffolds

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Biocompatible Electrospun Vehicles to Enhance the Effectiveness of Anti-Fertility Strategies and Their Biomimetic Properties As Blood Vessel Scaffolds Biocompatible Electrospun Vehicles To Enhance the Effectiveness Of Anti-Fertility Strategies And Their Biomimetic Properties As Blood Vessel Scaffolds Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Francisco Javier Chaparro, M.S. Graduate Program in Materials Science and Engineering The Ohio State University 2018 Dissertation Committee: Dr. John J. Lannutti, Adviser Dr. Heather M. Powell Dr. Jianjun Guan Copyright by Francisco Javier Chaparro 2018 ABSTRACT Electrospun fibers have been extensively studied for drug delivery applications. While fibers made through electrospinning can release a desired drug by engineering various properties, drug loading is typically not sufficient to enable long term release. We explored the use of electrospinning to create polycaprolactone (PCL) capsules sintered to full density allowing encapsulation of both a drug and carriers mainly consisting of hydrophobic or hydrophilic oils, ‘HPO’ and ‘HPI’, respectively. The use of HPO demonstrated undetectable water absorption and release of our model drug. In contrast, having HPI as a carrier allowed water uptake into the PCL capsules and was controlled according to the degree of hydrophilicity imparted by these oils. Mechanical properties of as-spun PCL demonstrated to be significantly different from the sintered specimens. PCL samples fully sintered at 100C under vacuum nonetheless demonstrated memory effects as mechanical failure exhibited features of the as-spun microstructure. This memory behavior was lost when samples treated at 150C were analyzed under tensile strength. After 224 days of in vitro and in vivo exposure the microstructure revealed fiber-based yet dense morphology attributed to the memory effects even after sintering at 100C. The use of non-sintered specimens in cylindrical form proved to be effective as a biomimetic scaffold of natural porcine coronary arteries showing similar failure behavior. Although PCL capsules were strong enough to resist compressive force in small animal models, this was not sufficient to study release on large animals. A weak implant can collapse, resulting in an undesired burst release. The incorporation of polyethylene terephthalate (PET) into PCL electrospun fibers in different ratios to then fully densify the capsule through sintering ii was studied. These blended fibers demonstrated to be mechanically stronger than PCL alone at any studied ratio. NMR and acetone exposure to selectively remove PCL demonstrated that we obtained a true blend and not the typical PCL:PET copolymer resulting from high processing temperatures. Water absorption was able to be controlled by the use of HPO and HPI. Zero order release was observed for all PCL:PET ratios when HPI was used as the carrier. The incorporation of a soluble organic salt into PCL:PET at different salt ratios allowed control of pore size and drug delivery. While typical porogen techniques are able to create microscale porosity, the use of soluble organic salt allowed us to obtain nanoscale porosity after leaching. Interestingly, mechanical properties of these PCL:PET:salt blends at a ratio of 80:10:10 and after heat treatment demonstrated to be significantly higher than specimens without the salt. This study provides design guidance for using electrospinning as a forming technique to create, not only for long term drug delivery capsules, but for other applications that require better mechanical or physical properties that can implement the use of PCL:PET, incorporation of soluble salts and proper use of polymeric electrospun blends. iii To my family and friends; especially to those that are not among us anymore. iv ACKNOWLEDGEMENTS First and foremost, I would like to thank Dr. John J. Lannutti. Not only has he provided guidance throughout my graduate school studies and multiple projects, he has made me improve my critical thinking and creativity when obstacles are present. I am really grateful to all collaborations he made possible for my research projects with different departments, not only in Ohio State University, but in other universities like the University of Toledo, Purdue University and The University of New South Wales in Australia. I really appreciate all his help and confidence throughout my days of been a teaching assistant for the Materials Science and Engineering Laboratory 1 and especially the Biomaterials Laboratory. Although my life as a graduate student is coming to an end I am looking forward to keep collaborating with Dr. Lannutti in one way or another. I would like to thank Dr. Heather M. Powell and Dr. Jianjun Guan, not only for been in my candidacy, dissertation overview and defense committee, but for all their guidance throughout my years at The Ohio State University. They also trusted me with the help of teaching the Biomaterials Laboratory for four years, an incredible experience that helped me find better and easier ways to help all students understand different techniques and processes used. I appreciate their willingness to help me at any moment, either with the use of their facilities for my research or with any questions I had throughout my years as a graduate student. I would like to thank Dr. Marco da Silva Coutinho, Dr. Christa R. Moraes and Mahala Eyman for all their help with all drug release experiments. Not only this has helped me broad my knowledge on how in vivo experiments are designed and implemented, but it has also helped me improve my critical thinking on how to design capsules that can benefit our final goal. I v would also like to thank all of them for trusting me on taking care of all the sterilization process and also allow me to get experience with actual implantation of all capsules I created for these in vivo experiments. I am extremely grateful for having amazing lab members throughout my years in Dr. John J. Lannutti’s laboratory. I am extremely thankful for Dr. Carol H. Lee for introducing me to the electrospinning technique and showing me around the city of Columbus when I first moved from Puerto Rico. I am really grateful for Dr. Mark Tyler Nelson, Dr. Ruipeng Xue and Dr. Nishant Tikekar for also helping me with any question I had before they finish with their graduate studies in our laboratory. I am also grateful for having soon to be doctors Kayla F. Presley, Fan Fan and Yi-xiao Liu. I do cherish having Kayla F. Presley as one of my former students in the Biomaterials lab and now as a lab mate. She has provided so great support and company these past four years and I will miss our Friday’s tradition that we started with Dr. Mark Tyler Nelson and supported our research activities. I also appreciate that Fan Fan trusted me as his mentor when he was an undergraduate student and am really grateful that he was able to continue as a PhD student, and even better that he joined us in our laboratory. I sincerely thank all five high school students that worked with me during my years as a graduate student. Their names are Andrew Heermann, Ryan Panzera, Robert A. Aikins, Oladapo Olobatuyi and Daniel Peck. I would also like to thank all fourteen undergraduate students that worked with me and the drug release research project or with the senior design projects. Their names are Monica Oliver, Joshua Enmark, Luke Carpenter, Sarah Fuchs, Cameron Reese, Sarah Carney, Brandon J. Borja, Frank Jin, Michael Posner, Kaden Zachmann, Fan Fan (current PhD student at our laboratory), Ryan M. Arnold, Nayan Mandan and Matthew L. Collachis. I would also thank other undergraduate students that worked in our lab that indirectly helped me one vi way or the other, their names are: Mallory Hutton, Elana Spiegler, Maria Stang, Nicole DiRando and Alex Cochran. I would like to thank the students from the Fontana Corrosion Center (FCC) in our Materials Science and Engineering department for “adopting” me as one of theirs and allow me to get involve in most of their extracurricular activities. Not only this, they allowed me to use different instrumentation that not only helped me with my research studies, but also with the analysis of different samples for the Biomaterials Laboratory. I want to specifically thank Kerrie Holguin, Sara Cantonwine, Angeire Huggins and Dr. Santiago Fajardo for been the ones that were always willing to help me and for their friendship throughout these great years at The Ohio State University. I want to also thank Dr. Yanyi Xu, Dr. Britani N. Blackstone and Hong Niu, and all other students from Dr. Heather M. Powell and Dr. Jianjun Guan research groups for always being willing to help me. I want to also thank the staff of the Materials Science and Engineering department at The Ohio State University, especially to Ken Kushner, Ross Baldwin, Steve Bright and John (Pete) Gosser for always been willing to help, not only for the undergraduate laboratories, but for my own research needs. I also appreciate their trust in lending me instrumentation or different facilities throughout my PhD career. I would love to thank the Puerto Rican Student Association for bringing a little bit of home to every single activity they made. My sincere thanks goes to Nidza Burgos Castellano, Linoshka Santana Barrios, Yairanex Roman Garcia, Zaide Feliciano-Muñiz, Argenys O. Robles Rondón, Michael González Casiano, Liane T. Davila-Medina, Dr. Monica M. Gaudier-Diaz, Gabriel A. Calderon-Ortiz, Carlos E. Berrios, Jennifer Patritti-Cram and Dr. Joselyn Del Pilar and everyone else in this association. I was able to meet great friends that I now consider part of my family. vii I want to acknowledge two friends that started this process with me but are not among us anymore. Thanks Loren Santiago and Angel Candelario for always been there and asking how grad school was treating me.
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