Date of Award

5-2014

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Bioengineering

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

Clinical translation of cardiovascular tissue engineering (CVTE) is rapidly shifting from concept to application, granting a myriad of opportunities for the treatment of cardiovascular disorder (CVD). There remains, however, a critical hurdle to overcome: the application of tissue engineering to a comprised patient - more specifically, a patient with diabetes mellitus (DM). The alarming prevalence of DM is of great concern due to its duel threat as both a risk factor for CVD and a predictor of biomedical device failure. Elevated levels of inflammation and impaired wound healing are hallmarks of DM contributing to cardiomyopathy, atherosclerosis, and valve disease. The primary focus of my research was two-fold: 1) to evaluate diabetes-related complications to scaffolds and stem cells used for cardiovascular tissue engineering; and 2) to attenuate these complications by addition of a non-toxic matrix-binding polyphenolic antioxidant, pentagalloyl glucose (PGG). Two types of extracellular matrix (ECM) scaffolds were investigated in this study: collagen-based and elastin based. In vivo biocompatibility studies revealed that the diabetic environment invoked detrimental alterations to the matrix scaffolds including crosslinking, advanced glycation end product (AGE) accumulation, and elevated inflammation. However, these complications could be mitigated by scaffold pre- treatment with PGG. By virtue of its antioxidant properties, PGG halted diabetes-related stiffening, AGE accumulation, inflammation, and calcification. The effect of seeded autologous adipose stem cells (ASCs) were also investigated in vivo. We observed immunomodulatory capabilities of ASCs to the implanted constructs by reducing the pro-inflammatory response, shifting the polarization of macrophages towards constructive remodeling, and preventing inflammation-driven calcification. The combination of ASCs with PGG formed a truly diabetic-resistant construct capable of combating glycoxidation, crosslinking, destructive inflammation, and calcification. The overall goal of this research was to establish the framework of clinical translation of tissue engineering. Tissue engineering is often heralded as a patient- tailored approach for disease treatment; however, our translational efforts are useless if we cannot address the comorbidities associated with the patient. This research takes a step towards the development of a deliverable and robust tissue engineered construct for use in treatment of cardiovascular disease.

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