Date of Award

8-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Bioengineering

Committee Chair/Advisor

Dr. Agneta Simionescu

Committee Member

Dr. Dan Simionescu

Committee Member

Dr. Martine LaBerge

Committee Member

Dr. Christopher Wright

Committee Member

Dr. John Bruch

Abstract

Diabetes Mellitus, a major risk factor for cardiovascular disease, currently affects 463 million people, or 9.3% of the world’s population – with numbers estimated to reach 578 million people by 2030. Hyperglycemia, dyslipidemia, oxidative stress, and inflammation, major manifestations of diabetes, together, significantly increase the risk of vascular tissue damage. Vascular damage is primarily caused by the interaction of cells and extracellular matrix (ECM) components with the elevated levels of glucose and lipids circulating through the blood and in the ECM. ECM proteins, such as elastin and collagen, are subject to glycation and crosslinking via advanced glycation end products (AGE) and reactive oxygen species, which can result in vascular stiffening and calcification.

Current treatments include the use of vascular stents. However, stenting cannot be used as a long-term solution as plaque can continue to form resulting in restenosis of the vessel. Bypass grafting can be used in peripheral artery applications and, most commonly, in coronary artery applications. However, few diabetic patients have autologous vessels that are healthy enough to use for this procedure. There is a critical need for a biocompatible solution, with regenerative potential, to replace atherosclerotic prone vessels.

To serve this need, we aimed to better understand vascular pathologies in diabetes and utilize this knowledge to develop tissue engineered blood vessels (TEBVs) resistant to diabetic complications. To reach this goal, we first analyzed carotid arteries from diabetic minipigs, focusing on oxidative stress, AGE formation, ECM degradation, mechanical properties, calcification, and inflammatory cell infiltration (Aim 1). We then compared three decellularization methods and tested host responses by subdermal implantation in diabetic rats (Aim 2). Finally, we treated decellularized arterial scaffolds with penta-galloyl-glucose (PGG), an antioxidant that protects scaffolds from oxidation and degradation, seeded them with allogeneic vascular cells, and implanted them end-to-end as vascular grafts in the abdominal aorta of diabetic rats (Aim 3).

Results show that elastic arteries are prone to fibrous thickening and calcification in addition to damage microvasculature, while muscular arteries underwent glycation and endothelial dysfunction (Aim 1). A detergent based decellularization method was optimized to develop TEBVs that did not calcify when used exposed to hyperglycemic environments (Aim 2). PGG treatment of TEBVs prevented diabetes-related complications when used as vascular grafts. Overall, these studies have strengthened our knowledge of the vascular pathologies in diabetes and have offered avenues for the development of diabetes-resistant vascular grafts.

Available for download on Thursday, August 31, 2023

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