Date of Award

Summer 2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Bioengineering

First Advisor

Jason A. Burdick, Ph.D.

Abstract

Left ventricular remodeling following myocardial infarction (MI) often induces congestive heart failure, which has limited treatment options. Advances in tissue engineering and polymer chemistry, however have allowed for the development of alternative treatment strategies. Specifically, the formation of biodegradable polymers into complex scaffolds or injectable materials is being evaluated. The underlying hypothesis for this work is that fibrous scaffolds with controlled properties and structures, as well as injectable hydrogels with tunable properties, can be optimized to attenuate this post-MI remodeling response. To this end, four specific aims have been developed to test this global hypothesis.

First, a collection of biodegradable elastomers based on poly(glycerol sebacate) were synthesized, introducing the reactive acrylate group to capitalize on free radical polymerization. By varying the synthetic components, the structure-property relationships associated with changes in molecular weight and % acrylation were identified. The second Aim focused on processing these materials into fibrous scaffolds via electrospinning. Differences in mechanics and mass loss based on % acrylation were translated to the scaffolds. Cellular infiltration, matrix elaboration, and organization throughout the scaffolds were improved with the inclusion of a sacrificial fiber population and fiber alignment during processing.

The third Aim centered on the development of hyaluronic acid (HA)-based, redox-initiated hydrogels, modified with different amounts of reactive methacrylate groups (MeHA), for injectable applications. An increase in modulus was observed for both increasing % methacrylation, and initiator concentration. The final Aim evaluated the impact of the hydrogel modulus on infarct size, LV geometry, and function upon injection in an ovine model. Only treatment with the higher modulus hydrogel had a statistically smaller infarct size than the control. Furthermore, reductions in LV volumes and improvements in function were observed with this treatment.

The work presented in this thesis represents advancement in the field of biomaterials towards the goal of developing alternative treatments to limit LV remodeling. The use of acellular scaffolds and injectable materials with tunable properties can provide insight into the impact of different treatment paradigms, enabling develop of further therapies and improved patient care.

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