Articular cartilage is the primary compressive load bearing soft tissue in diarthrodial joints. While the tissue can function remarkably well in a demanding environment over a lifetime of use, focal defects and other trauma can initiate progressive degeneration. Cartilage tissue engineering approaches have been developed with the goal of forming biologic replacement materials with functional mechanical properties [1]. While chondrocytes are a popular cell source for such approaches, and can produce constructs with near-native functional properties [2], mesenchymal stem cells (MSCs) derived from bone marrow have emerged as an attractive alternative cell type. MSCs are multi-potent and easy to expand, and so are available in a nearly unlimited supply, and in an autologous fashion. While MSCs can undergo functional chondrogenesis in a variety of 3D contexts [3], we are particularly interested in the translational capacity of hyaluronic acid (HA). Hydrogels formed from this natural constituent of the cartilage extracellular matrix provide a biologically relevant interface for encapsulated cells and gel properties are readily tunable [4, 5]. Indeed, using a methacrylated (and so photo-crosslinkable) HA macromer, we have optimized gel formation and functional matrix production by MSCs with variations in both macromer (1%, [5]) and MSC (∼60 million cells/mL, [6]) concentration, consistently producing cartilage-like constructs with near native compressive properties. Additionally, we have reported that transient exposure of TGF-β3 (for three weeks) to MSCs in agarose constructs at a high-density induced a stable chondrogenic phenotype, with functional properties at six weeks greater than continual exposure to this pro-chondrogenic factor [7]. Transient exposure presents an interesting paradigm with clinical relevance, in vivo defect filling will require robust maturation of the engineered tissue driven by TGF-β3 delivered from the material itself in a controlled and sustained fashion. The purpose of this study was to determine the minimal TGF-β3 dosage and duration of exposure required to promote the most robust chondrogenesis and functional maturation of MSCs in this HA hydrogel system.

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