Optimization of delivery of TGF-beta for improving quality of engineered articular cartilage
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Osteoarthritis (OA) is a painful, debilitating condition that results from the mechanical degeneration of articular cartilage. Cartilage tissue engineering is a promising OA therapy, whereby chondrogenic cells are encapsulation in a hydrogel scaffold and cultivated in vitro in an attempt to create a suitable replacement tissue. Transforming growth factor-beta (TGF-b) is a highly anabolic hormone that has served as one of the most prominent cartilage growth mediators, promoting the development of engineered tissues with native levels of mechanical properties and biochemical contents. In cartilage tissue engineering, TGF-b is conventionally administered supplemented in culture medium with the expectation that it will readily diffuse into tissue constructs. However, recent evidence has brought to light severe limitations with this approach when attempting to generate engineered cartilage of sufficient size to repair clinical OA defects (10-25mm), as mediasupplemented TGF-b exhibits vast transport limitations in constructs, giving rise to undesirable, highly heterogeneous cartilage formation. Consequently, a long-term goal of our research group is to develop novel TGF-b chemical delivery strategies that achieve improved uniformity of its activity in the tissue. Critically, the development of these strategies require a fundamental understanding of the optimal delivery profile (exposure concentration and duration) of TGF-b activity to achieve optimal cartilage tissue growth. Interestingly, while low doses of TGF-b are typically associated with insufficient growth and matrix deposition, supraphysiologic doses are associated with the induction of pathological tissue features, such as fibrosis, chondrocyte hypertrophy and the clustering of chondrocytes in a phenotype that does not resemble healthy articular chondrocytes. Here we perform this characterization by examining the effect of near physiologic doses (0.1- 1ng/mL) and supraphysiologic doses (3-100ng/mL) of TGF-b on constructs growth. Further, we exposed tissue constructs to varying temporal delivery profiles. Results demonstrate that, interestingly, physiologic TGF-b doses (0.1-1 ng/mL) induce the formation of engineered cartilage with native mechanical properties (350-780 kPa) but with improved tissue quality, as marked by more isolated chondrocytes that resemble the phenotype of native cartilage. These results pave the path for the future development of large sized engineered cartilage tissues, whereby, physiologic levels can be delivered uniformly throughout the tissue via biomaterial delivery strategies.