Date of Award

Spring 1-1-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemical & Biochemical Engineering

First Advisor

Stephanie Bryant

Second Advisor

Joel Kaar

Third Advisor

Amy Palmer

Fourth Advisor

Andrew Goodwin

Fifth Advisor

Tim Quinn

Abstract

The field of tissue engineering aims to create replacements for diseased or damaged tissues which restore function and integrate with the host. Poly(ethylene glycol) (PEG) hydrogels are promising materials for the delivery of cells for tissue engineering applications, however, as with all synthetic materials, they elicit a foreign body response (FBR) upon implantation. Generally, the FBR begins with an initial inflammatory response and ends with the encapsulation of the implant in an avascular fibrous capsule. The harsh environment present during the FBR may harm encapsulated cells and impair integration into the host, ultimately reducing the efficacy of tissue engineering therapies. However, a mechanistic understanding of the cell types and signaling pathways present during the FBR is incomplete. Therefore, this dissertation explores the roles of immune regulators in the FBR and characterizes the cellular infiltrate in response to implanted PEG hydrogels – yielding insight into the mechanistic workings of the FBR. Specifically, this dissertation explores the role of signaling through the adaptor protein MyD88 during the FBR, exposing a relationship between inflammation and fibrosis in the response to implanted PEG hydrogels. In addition, this dissertation develops a biomimetic PEG hydrogel as a bone tissue engineering platform, and explores the tissue engineering outcome in the context of the FBR. Specifically, a biomimetic PEG hydrogel formed with crosslinks that are susceptible to matrix metalloproteinases (MMPs) 2 and 9 was characterized. The hydrogels developed herein allow for the encapsulation of mesenchymal stem cells (MSCs), which can locally degrade the material in an MMP dependent fashion. Promisingly, this hydrogel platform facilitates the production of bone-like tissue from encapsulated osteogenically differentiated MSCs when implanted in vivo, in spite of eliciting a FBR, which provides new insights into the relationship between the FBR and the tissue engineering outcome. Future work will explore whether tissue production in this platform can be enhanced when the FBR is reduced by antagonizing the signaling pathways uncovered in this dissertation.

Share

COinS