Date of Award

Spring 1-1-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Kristi S. Anseth

Second Advisor

Christopher Bowman

Third Advisor

Stephanie Bryant

Fourth Advisor

Andrew Goodwin

Fifth Advisor

Rui Yi

Abstract

Mammalian cells reside in contact with an extracellular matrix (ECM) with which they are inextricably linked. Native ECMs are instructive, and cells are able to sense the mechanical and chemical landscape through a variety of mechanisms. The ECM is also a dynamic microenvironment: changes in composition and structure occur throughout development and during disease progression and wound healing. Hydrogels, water swollen polymer networks, can be used as synthetic mimics of the ECM. The goal of this thesis is to design hydrogels with dynamic properties and to use these as platforms to study the effect of these properties on cellular behavior and fate decisions. Particular attention is given to photochemical strategies which provide the experimenter with spatial and temporal control over the extent of a reaction. Specifically, a photodegradable hydrogel platform is developed based on cleavage of ortho-nitrobenzyl groups, and the single- and two-photon degradation is characterized. This hydrogel platform is used to guide neurite extension from embryonic stem cell-derived motor neurons and the growth of intestinal organoids. We find that alterations in the hydrogel mechanical properties can be used to instruct the growth and differentiation of an organoid in a defined manner. Furthermore, the resulting tissue constructs establish distinct cellular zones reminiscent of the intestinal epithelium. We then design hydrogels crosslinked with allyl sulfides that are capable of undergoing amplified photodegradation and rapid stress relaxation. This hydrogel is used for the capture and release of human bone marrow-derived mesenchymal stem cells (MSCs) and rapid prototyping of cell-laden hydrogels through selective photodegradation. Finally, we investigate another adaptable chemistry, thioester exchange, as a strategy to reversibly crosslink hydrogels for cell culture. MSCs are able to remodel this network and adopt spread morphologies and migratory behavior. Moreover, cells encapsulated in these dynamic networks are more proliferative than their counterparts in static gels. Collectively, these matrices illustrate how molecular design can be used to impart unique material properties to polymer networks, and how these can be applied to study matricellular interactions.

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