Date of Award

Spring 1-1-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Stephanie J. Bryant

Second Advisor

Karin A. Payne

Third Advisor

Robert R. McLeod

Fourth Advisor

Virginia L. Ferguson

Fifth Advisor

Andrew P. Goodwin

Abstract

Cartilage defects, whether caused by injury or disease, often lead to further degeneration and ultimately osteoarthritis. Current treatments such as autologous chondrocyte implantation (ACI) and microfracture have shown limited success at repairing and regenerating cartilage tissue, thus an alternative treatment is necessary. Cartilage tissue engineering using scaffolds as a vehicle to deliver cells, biochemical cues, and soluble factors presents a promising strategy to regenerate cartilage tissue. Photopolymerizable poly(ethylene glycol) (PEG) hydrogels that can be modified with different biochemical moieties, degradable and nondegradable peptides, and therapeutic agents are an attractive platform to design and develop scaffolds that can be tailored to enhance cartilage regeneration. Mesenchymal stem cells (MSCs) are a promising cell source for cartilage tissue engineering as they can chondrogenically differentiate. However, MSCs readily undergo hypertrophy in vitro, which can ultimately lead to endochondral ossification and bone formation during chondrogenesis. The interaction between MSCs and their surrounding environment plays a vital role in their differentiation. This begs the question as to whether the unique environment of cartilage is important for MSC chondrogenesis.

The goal of this thesis was to develop a PEG-based hydrogel that enhances chondrogenic differentiation of MSCs encapsulated within. Initial work focused on recapitulating the native cartilage environment within a PEG hydrogel. The incorporation of ECM analogs found in native cartilage tissue in combination with mechanical loading enhanced non-hypertrophic chondrogenesis. These physiochemical cues inhibited hypertrophy via Smad signaling. Scaffold degradation is necessary for macroscopic tissue elaboration, therefore, an enzymatically degradable peptide sequence was incorporated into the PEG hydrogel and allowed for cellular mediated degradation while enhancing cartilaginous matrix deposition. This degradable cartilage mimetic hydrogel was evaluated in vivo and the hydrogel alone showed successful results at repairing the chondral defects. Growth factors were tethered into the cartilage mimetic hydrogel and further enhanced the chondrogenesis of MSCs. Additionally, to maintain the health of the cartilage surrounding the defect, a hybrid hydrogel that incorporated a 3D printed structural support was developed. This thesis demonstrated that an enzymatically degradable cartilage mimetic hydrogel environment has the potential to promote tissue regeneration and chondral defect repair.

Comments

Sixth advisor: Jeffrey W. Stansbury.

Available for download on Friday, December 21, 2018

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