| Cartilage, once damaged or diseased, lacks the ability to self-repair. Current therapies fall short of being able to repair the tissue, thus opening the door for tissue engineering strategies. Photopolymerizable hydrogels based on poly(ethylene glycol) (PEG) are promising cell carriers that can be fabricated in situ under mild polymerization conditions. Mechanical stimulation is integral to the development and maintenance of healthy cartilage tissue. However, its role in mediating chondrocyte behavior within PEG hydrogels is largely unknown. This research tests the hypothesis that both the hydrogel environment, dictated by the gel structure, chemistry, and degradation behavior, and the mechanical loading environment will influence chondrocyte behavior, through anabolic and catabolic responses, and impact the developing neo-tissue. Overall, findings from this dissertation illustrate that the hydrogel structure impacts tissue evolution, resulting in neo-tissue deposition that is restricted to the pericellular regions due to the restricted diffusion of the large matrix molecules. This limitation could be overcome by the incorporation of degradable linkages into the crosslinked network. Hydrogel structure did impact the anabolic and catabolic functions of encapsulated chondrocytes but appeared to play less of a role in mediating how chondrocytes respond to mechanical loading. However, chondrocyte response to mechanical loading was dependent on the loading frequency, dynamic strain, duration and timing of the initial load, as well as chondrocyte age. Results from these studies confirmed that both anabolic and catabolic events are initiated as a result of physiological mechanical stimulation, suggesting an important role for catabolic events in neo-tissue development. Interestingly, these responses were mediated by the timing at which loading was applied during tissue development, suggesting that the presence of a pericellular matrix affects how chondrocytes sense biomechanical cues. In addition, mechanical loading was found to enhance matrix loss from the constructs, prompting the design of advanced biomimetic hydrogel environments capable of improving the retention of cell-secreted matrix. While biodegradation is key to forming a macroscopic tissue, degradation kinetics were impacted by loading. Nonetheless, certain loading conditions were identified that enhanced matrix development providing a platform from which to investigate long-term tissue growth. Collectively, these studies enhance our current understanding of mechanical stimulation and hydrogel environment on chondrocyte behavior and tissue development and have identified biomimetic and biodegradable hydrogels for potential use in functional cartilage regeneration. |
