? Articular cartilage lines the surfaces of joints and functions to transmit the forces associated with joint loading. Limited by its poor healing capacity, there exists a growing demand for cell-based strategies for repair. Given the mechanical role of the native tissue, the successful replacement of articular cartilage using engineered constructs will require grown tissue possessing functional mechanical properties. In this study, we propose the combination of chondrocytes or mesenchymal stem cells (which can undergo chondrogenic differentiation) in a hydrogel environment (agarose and self-assembling peptide hydrogels), and focus on the development of compressive and tensile properties of these constructs. Tensile properties in mature cartilage are anisotropic, particularly in the superficial zone, and emerge during adolescence as maturation occurs with joint loading. Borrowing from this developmental concept, we suggest a novel bioreactor system designed to recapitulate the sliding contact that occurs between two contacting articular cartilage layers. Using this bioreactor, chondrocyte biosynthesis and chondrogenic differentiation of MSCs will be valuated as a function of pre-incubation period and duration and intermittency of sliding. It is hypothesized that the patterns of gene expression and differentiation will be dictated by the relation of the position in the gel to the applied contact, with enhancements occurring beneath and along the line of contact, particularly in the superficial layer. Subsequent long-term studies will utilize these optimized loading protocols to direct the increase the compressive and tensile (in the direction of sliding) mechanical properties of MSC- and chondrocyte-laden hydrogel constructs. Furthermore, it is hypothesized that these constructs will exhibit enhanced collagen content as well as a parallel collagen fiber orientation in the direction of sliding contact. This application examines the ability of chondrocyte- and MSC-laden hydrogels to achieve cartilage-like tensile properties, and to instill anisotropy in these constructs via culture in a novel sliding contact bioreactor system. These studies will provide insight into the mechanisms of cartilage differentiation and maturation. If realized, the specific aims of this proposal will further our efforts to produce clinically relevant chondrocyteand MSC-laden functional cartilage replacements that exhibit the complex material properties and anisotropies that define the native tissue and are necessary for its mature function. ? ? ?
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