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, University of Akron, 2019, Biomedical Engineering

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is an elusive disease that presents as exposed necrotic bone following tooth extraction. It occurs in patients undergoing bisphosphonate therapy for metastasizing cancers and osteoporosis. Experts believe the condition is caused by a defect in bone remodeling, the process by which osteoclasts resorb bone and osteoblasts form new bone, within the oral cavity. Its complexity requires a multicellular model to address the net effects of two key risk factors: tooth extraction (overload) and inflammation associated with bacterial infection. In this work, a system comprised of a deformable polymeric chip and mechanical loading device is used to expose bisphosphonate-treated osteocytes, the mechanosensing bone cells, to overload. Osteocyte viability is evaluated as a function of load, and soluble activity is assessed. Effects of these factors on bone resorption by osteoclasts and bone formation by osteoblasts are quantified. Osteoclast activity is also quantified in the presence of inflammatory agents, lipopolysaccharide and interferon gamma. Results support a role for osteocyte mechanotransduction in suppressing osteoblast bone formation within a BRONJ environment. They also suggest inflammation may inhibit resorption of necrotic bone by osteoclasts. These findings provide insights into BRONJ that may contribute to its elucidation. This dissertation also lays the foundation for a biomimetic lab-on-a-chip platform for the study of bone turnover and remodeling-related disease. Fabrication techniques are developed, and osteocyte, osteoclast and osteoblast characterizations are performed on relevant substrates within microfluidic devices. Culture conditions, including seeding densities, feeding requirements and time points for analyses are determined. This work will enable the development of a controlled multicellular lab-on-a-chip capable of quantifying the aggregate response of bone cells to disease cofactors.

Committee: Marnie Saunders PhD (Advisor); Hossein Tavana PhD (Committee Member); Ge Zhang PhD (Committee Member); Jiang Zhe PhD (Committee Member); Sailaja Paruchuri PhD (Committee Member) Subjects: Biomedical Engineering