Doctor of Philosophy, The Ohio State University, 2022, Biomedical Sciences

Regenerative medicine has the potential to revolutionize the field of surgical medicine. More specifically, tissue-engineered vascular grafts (TEVGs) offer a promising solution to current challenges associated with the use of synthetic conduits in cardiac diseases. Since its first use in humans back in 1999 numerous advances have been made describing the remodeling, performance, and outcomes of TEVGs; however, the barriers to its widespread adoption remain largely the same. First, there remains a tendency for the lumen of TEVGs to narrow due to excessive tissue formation. Second, an issue broadly implicated within the field of cardiothoracic surgery, is the development of adhesions following repeat operations thus hindering access and function. This dissertation seeks to overcome both issues through the application of novel therapeutic agents. The findings reported further advance mechanistic knowledge of the regenerative process that may one day improve outcomes of associated with tissue engineering.

Committee: Christopher Breuer (Advisor); Philip Binkley (Committee Member); Jeffrey Parvin (Committee Member) Subjects: Biology; Biomedical Engineering; Biomedical Research; Cellular Biology; Medicine

Doctor of Philosophy, The Ohio State University, 2021, Biomedical Sciences

Tissue engineered scaffolds and regenerative medicine-based therapeutics hold great potential for a growing patient population in need of alternative tissue replacements. The initial work of this dissertation is on efforts to improve the translational capability of tissue engineered vascular grafts (TEVGs) to the clinic. A challenge in translating our group's TEVGs, as well as is seen with other tissue engineered scaffolds, is balancing the host response where an appropriate amount of healthy neotissue is created and remodeled overtime replacing the biodegradable scaffold and avoiding complications such as graft thrombosis and stenosis. Approaches to optimize tissue engineered scaffolds for use in patients often focuses on material alterations, cell seeding, bioreactor growth, or drug/small molecule co-administration. Seeding our TEVGs with bone-marrow derived nucleated cells has proven to be an effective approach to minimize graft occlusion and alter neotissue development; however, the exact mechanism underlying this remains unclear. The initial focus of this dissertation sought to elucidate what effect interleukin-10, an anti-inflammatory cytokine, had on graft patency and neotissue development from cells seeded onto TEVGs, from the host TEVG recipient, and from a recombinant protein drug delivery. This work demonstrated interleukin-10 from the host was critical in maintaining TEVG patency. Another promising approach optimizing a thrombosis and stenosis resistant TEVG has been our group's investigations into a novel wound healing modulator known as the lysosomal trafficking (LYST) protein. The protein, encoded by the LYST gene, is poorly understood with much of existing information coming from observations into disease states and cellular dysfunction that occurs in presence of a LYST gene mutation. A notable cellular finding is the perniculear clustering of enlarged lysosomes in mutant LYST cells due to defects in lysosomal fusion/fission. We serendipitously (open full item for complete abstract)

Committee: Christopher Breuer (Advisor); Ginny Bumgardner (Committee Member); Ryan Roberts (Committee Member); David Dean (Committee Member) Subjects: Biomedical Engineering; Cellular Biology; Experiments; Histology; Immunology; Medicine