Date of Award

Spring 1-1-2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemical & Biochemical Engineering

First Advisor

Kristi S. Anseth

Second Advisor

Leslie Leinwand

Third Advisor

Christopher Bowman

Fourth Advisor

Stephanie Bryant

Fifth Advisor

Joel Karr

Abstract

Aortic valve stenosis (AS) results in almost 100,000 valve replacement surgeries per year in the United States. These replacements are generally made of synthetic materials that require anticoagulants or decellularized allo/xenografts that tend to quickly calcify in younger patients. Valve replacements containing cells able to grow and repair damaged valve tissue could positively impact patient morbidity. However, matricellular cues associated with healthy tissue deposition by the resident aortic valvular interstitial cells (VICs) are still not well understood. This thesis aims to study the effects and underlying mechanisms of matrix elasticity and biochemical cues (e.g., bound integrins or valvular endothelial cell (VlvEC) paracrine signaling) on VIC activation and tissue deposition. A poly(ethylene glycol) (PEG) hydrogel platform fabricated via a thiolene, photopolymerization mechanism was utilized to precisely control the culture substrate elasticity as well as covalent tethering of integrin binding small peptides in the gel. First, a range of elastic moduli was established and studied in conjunction with varied integrin binding peptides (RGDS, VGVAPG, and P15) in 2D and 3D on VIC activation and de novo tissue secretion. Second, VIC mechanotransduction intracellular signaling pathways were investigated on PEG hydrogels of activating and non-activating moduli. Lastly, the effect and intracellularing signaling mechanisms of VlvEC paracrine signaling on VIC activation and nodule formation were explored. This research furthers the understanding of matricellular cues effect on VIC phenotype and tissue deposition for regenerated aortic valve replacements.

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