Date of Award

Spring 5-17-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Wei Tan

Second Advisor

Peter Hamlington

Third Advisor

Kurt Stenmark

Fourth Advisor

Virginia Ferguson

Fifth Advisor

Antonella Motta

Abstract

Cardiovascular disease (CVD) is the most common cause of death in the United States of America, accounting for 24% of all deaths each year,(Anderson et al., 2003) and is projected to rise above 20% globally by 2030.(Mathers and Loncar, 2006) Options for CVD treatment do exist, but are limited by availability of healthy replant tissue from the patient or long term effectiveness and failure rates of both autologous tissue grafts and artificial implants. Grafting failure may often be attributed to the poor mimicry of the site-specific, healthy arterial tissue. While much TEVG research focuses on endothelialization of the graft lumen through chemical signaling, mechanotransduction plays a large role in forming and maintaining a healthy endothelial cell (EC) monolayer. Arteries and grafts interact with hemodynamics to determine flow pulsatility and create healthy, or pathological, mechanical signaling environments. Though arterial tissue is known to be viscoelastic,(Armentano et al., 2006; Bergel, 1961; Bia et al., 2006) the importance of this in developing healthy blood flow is undetermined. Therefore, a gap in the knowledge occurs in the importance of arterial mechanics affecting graft outcomes. To address this we attempt to examine specific shortcomings: 1) Determine whether pathological flow is capable of maintaining EC monolayer in a low arterial compliance model, 2) Establish methods of catering protein hydrogel frequency-dependent properties towards establishing biodegradable materials intended for TEVG, 3) Determine benefits of viscous wall damping in improving hemodynamics towards improved cell response.

This proposal centers on improving cell response to pathological hemodynamics through catered viscoelastic material response at the arterial wall. To address this, we hypothesize that maintaining healthy EC monolayer is predicated on hemodynamic mechanotransduction, which results from both graft compliance and viscous damping of the material. To validate this hypothesis, we examine healthy and pathological hemodynamic effects on EC monoculture, and systematically determine the role of viscoelastic material response in maintaining healthy hemodynamics.

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