Symptomatic knee osteoarthritis is estimated to affect nearly 1 in 5 Americans over the age of 45. Osteoarthritis patients often experience pain caused by damage to articular cartilage in load-bearing joints. Matrix-assisted autologous chondrocyte transplantation (MACT) has emerged as a promising tissue engineering strategy to enhance the ability of chondrocytes to repair cartilage defects. This strategy often employs water-swollen polymer networks, known as hydrogels, as delivery vehicles to support chondrocytes and permit extracellular matrix (ECM) deposition. Hydrogels used for cartilage tissue engineering can be covalently crosslinked to withstand compressive forces experienced in articulating joints. However, traditional covalent crosslinks exhibit elastic responses to mechanical deformation and can limit ECM deposition to pericellular space. One potential strategy to improve regenerative outcomes of MACT is to incorporate viscoelastic properties, making hydrogels more similar to the viscoelastic ECM chondrocytes experience in vivo. However, few covalent hydrogels used for cartilage tissue engineering exhibit viscoelastic properties. Moreover, the effects of viscoelasticity (e.g., stress relaxation, creep compliance) on cartilage tissue engineering remain largely understudied.
Covalent adaptable networks (CANs) represent a rapidly growing class of polymers with reversible covalent crosslinks which potentially offer both robust mechanical support and viscoelastic network reorganization for cartilage tissue engineering. In this thesis, we aim to add to this growing body of research by examining the effects of mechanobiological cues on chondrocytes encapsulated in hydrazone CANs. First, we sought to engineer hydrazone CANs with user-defined control over the viscoelastic properties by leveraging differences in the equilibrium kinetics of alkyl-hydrazone and benzyl-hydrazone crosslinks. Next, viscoelastic stress relaxation timescales of these networks are investigated to modulate ECM deposition by encapsulated chondrocytes. Then viscoelastic creep compliance is examined to temporally direct chondrocyte morphology during mechanical deformation. Finally, mechanobiological interactions between viscoelasticity and dynamic compression on chondrocytes in hydrazone CANs are studied using dynamic compression bioreactors to simulate biomechanical forces experienced within articulating joints. Overall, this work lends insight about how viscoelastic material properties influence chondrocyte behavior in hydrazone CANs with the hope of informing the design of polymer matrices for cartilage tissue engineering to treat osteoarthritis in load-bearing joints.
|Advisor:||Anseth, Kristi S.|
|Commitee:||Bryant, Stephanie J., Ferguson, Virginia L., Stansbury, Jeffry W., Vernery, Franck J.|
|School:||University of Colorado at Boulder|
|Department:||Chemical and Biological Engineering|
|School Location:||United States -- Colorado|
|Source:||DAI-B 82/6(E), Dissertation Abstracts International|
|Subjects:||Chemical engineering, Materials science, Biophysics, Bioengineering, Mechanics, Histology|
|Keywords:||Cartilage tissue engineering, Covalent adaptable networks, Dynamic loading, Hydrazones, Hydrogels, Viscoelasticity, Symptomatic knee osteoarthritis|
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