Development and Characterization of Photocrosslinkable Hyaluronic Acid Hydrogels for Cartilage Regeneration

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Doctor of Philosophy (PhD)
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cartilage tissue engineering
hyaluronic acid
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Damage to cartilage from general wear, disease, or injury can lead to joint pain and tissue degeneration. With its limited ability for self-repair, cartilage has become a target for tissue engineering (TE). As current treatments have yet to provide long-term functional cartilage repair, this dissertation introduces the development and use of photopolymerizable hyaluronic acid (HA) based hydrogels for TE to optimize cellular interactions and neocartilage formation. By altering hydrogel design parameters (e.g., molecular weight and macromer concentration), a wide range of hydrogel properties were obtained. These hydrogels all preserved the rounded morphology of chondrocytes, but cell viability and neocartilage formation were dependent on hydrogel design, where increased crosslinking resulted in cell death and increased macromer molecular weight yielded inhomogeneities in cell and ECM distribution within the hydrogel. These variables also influenced the formed neocartilage properties. The ability of HA hydrogels to promote neocartilage formation was also dependent on cell source and culture. The expansion of chondrocytes in 2D in vitro affected neocartilage formation in HA hydrogels after the second passage, as construct properties further decreased with continued passage. Chondrocytes from different tissue sources also behaved variably in the hydrogels; auricular chondrocytes excelled in static culture and subcutaneous culture over articular chondrocytes, while articular chondrocytes were stimulated in a mechanically loaded environment. As the use of chondrocytes for cartilage TE is limited clinically, we turned to mesenchymal stem cells (MSCs). In vitro culture of MSC-laden HA hydrogels demonstrated that these HA hydrogels not only supported, but enhanced chondrogenesis when compared to relatively inert hydrogels, potentially due to receptor interactions with HA. However, in these hydrogels, ECM was localized to pericellular regions. To accelerate the diffusion and distribution of ECM proteins, hydrolytically degradable HA macromers were synthesized to create a dynamic environment. When degradation complemented ECM deposition, ECM distribution and ultimately the functional maturation of the construct were improved. While this dissertation focused on material development to improve cartilage regeneration, growth factor delivery optimization and successful implementation of these hydrogels in cartilage defect models remain, towards our goal of a successful long-term repair solution to cartilage damage.

Jason A. Burdick
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