Date of Award

Spring 1-1-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Stephanie J. Bryant

Second Advisor

Karin A. Payne

Third Advisor

Amy E. Palmer

Fourth Advisor

Kristi S. Anseth

Fifth Advisor

Joel L. Kaar

Abstract

Osteochondral tissue engineering using multilayer hydrogel scaffolds to recapitulate the native layered structure serves as a promising strategy to repair and regenerate osteochondral defects due to joint trauma, injuries, and long-term diseases. The gold standard of clinical therapies relies on replacing the defect with autologous tissue from a non load-bearing site, yet these techniques often fail due to a lack of mechanical anchoring, donor site morbidity and tissue availability. Multilayered photopolymerizable poly(ethylene glycol) (PEG) hydrogels, with a bony layer that facilitates osteoconductivity and osseointegration present an opportunity to overcome these issues. Ensuring multilayer hydrogels supported bone growth within the native loading environment and encouraged degradation by multiple bone cells are some of the important challenges addressed herein.

The goal of this thesis was to create a multilayer poly(ethylene glycol) (PEG) hydrogel platform, with a bony layer that facilitates cellular mediated degradation to allow for tissue elaboration and osteogenesis of encapsulated cells under physiologically relevant loading regimes. Initial work focused on developing a multilayer PEG hydrogel and characterizing said hydrogel as a function of hydrogel properties and fabrication methods. It was confirmed from multilayer hydrogel studies that a mechanically robust interface forms, but whose thickness can be controlled through the size of monomers and the crosslink density of preceding layers. Nanomechanical analysis confirmed that a gradient in modulus forms across the interface and subsequently leads to a gradual transfer of strain across the interface. Using the multilayer PEG hydrogel, it was demonstrated that a stiff bilayer hydrogel was capable of supporting osteogenesis of human mesenchymal stem cells (hMSCs) under compressive loads. These findings linked MAPK signaling to regulate mineralization in hMSCs under loading and further implicated the role of fluid flow, instead of strain, in fostering osteogenic differentiation of encapsulated cells in bilayer hydrogels. Finally, MMP-sensitive hydrogels were identified to support the osteogenic differentiation of both encapsulated hMSCs, as well as pre-osteocytes. This thesis demonstrated that cell-mediated degradation and loading within multilayer hydrogels can create an osteogenic scaffold to promote tissue regeneration for osteochondral tissue engineering applications.

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