Date of Award

2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Bioengineering

First Advisor

Jason A. Burdick

Abstract

Guest-host chemistry is an emerging tool in the preparation of biomaterials. Towards the design of hydrogels, guest-host chemistry has been used to impart unique shear-thinning and self-healing properties that allow these materials to be injected through syringes and catheters as a single component, avoiding complications associated with traditional covalent systems. As a treatment for myocardial infarction, injectable guest-host hydrogels may be injected directly into the myocardial wall and have shown therapeutic benefit in a number of strategies, including drug delivery, cell delivery, and tissue bulking. As delivery systems, injectable hydrogels provide controlled release of payloads that attenuate maladaptive remodeling of the left ventricle, by inhibiting expression of proteases, recruiting cells to the region, or otherwise stimulating therapeutic biological processes such as angiogenesis. Guest-host biomaterials must be refined and advanced to overcome challenges associated with delivering therapeutics in these areas, as well as to provide novel materials platforms for investigating therapeutic delivery in the future. This dissertation describes the engineering of two injectable hydrogel platforms that address challenges in the delivery of therapeutics after myocardial infarction. Each of these systems is investigated both in vitro for an understanding of material properties and the parameters that tune them, as well as in vivo, in a number of clinically relevant animal models and therapeutic targets. In the first aim of this thesis, isotropic guest-host hydrogels are designed for the sustained release of a variety of small molecules. Through the control of small molecule binding with cyclodextrin host moieties engineered in the hydrogel, we show that both cyclodextrin content and molecule affinity for cyclodextrin are critical factors that provide tunable release of small molecules from these systems. Furthermore, we demonstrate that this system is broadly applicable to the release of a number of pharmaceutical small molecule payloads. In the second aim of this thesis, isotropic guest-host hydrogels are specifically formulated for the delivery of the small molecule protease inhibitor SD-7300, a therapeutic requiring local delivery after myocardial infarction. Here we demonstrate that the engineered guest-host hydrogels provide sustained release and retain activity of this molecule, which in turn provides improved functional and biological outcomes in a large-animal model of myocardial infarction. In the third aim of this thesis, guest-host chemistry is utilized to assemble microstructured granular hydrogels for the design of multifunctional material platforms. Granular hydrogels are demonstrated to have disease responsivity in myocardial infarction, and functional benefit through the delivery of the chemokine SDF-1α.

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