Nanofiber-Based Transforming Growth Factor-β3 Release Induces Fibrochondrogenic Differentiation of Stem Cells.

Fibrocartilage is a tissue that is typically found in regions subject to complex, multi-axial loads and plays a critical role in musculoskeletal function. Mesenchymal stem cell (MSC)-mediated fibrocartilage regeneration may be guided by administration of appropriate chemical and/or physical cues, such as by culturing cells on aligned polymer nanofibers in the presence of the chondrogenic growth factor TGF-β3. However, targeted delivery and maintenance of effective local concentrations remain challenges for implementation of growth factor-based regeneration strategies in clinical settings. Thus, the objective of this study was to develop, characterize, and evaluate the bioactivity of a biomimetic nanofiber scaffold system that can provide localized delivery of TGF-β3. Here, we fabricated TGF-β3-releasing nanofiber meshes that provide sustained growth factor delivery and demonstrated for the first time its potential for guiding synovium-derived stem cell (SDSC)-mediated fibrocartilage interface regeneration. Scaffold-mediated TGF-β3 delivery enhanced cell proliferation and synthesis of relevant fibrocartilaginous matrix in a dose-dependent manner. By developing a system that eliminates the need for exogenous or systemic growth factor administration and demonstrating that fibrochondrogenesis requires a lower growth factor dose compared to chondrogenesis, this study represents a critical step towards developing a clinical solution for regeneration of fibrocartilaginous tissues throughout the musculoskeletal system. STATEMENT OF SIGNIFICANCE: Fibrocartilage is a tissue that plays a critical role throughout the musculoskeletal system. However, due to its limited self-healing capacity, there is a significant unmet clinical need for more effective approaches for fibrocartilage regeneration. We have developed a nanofiber tissue engineering scaffold that provides both the biomimetic physical cues, as well as localized delivery of the chemical factors needed to guide stem cell-mediated fibrocartilage formation. Specifically, methods for fabricating TGF-β3-releasing nanofibers were optimized, and scaffold-mediated TGF-β3 delivery enhanced cell proliferation and synthesis of fibrocartilaginous matrix, demonstrating for the first time the potential for nanofiber-based TGF-β3 delivery to guide stem cell-mediated fibrocartilage regeneration. This nanoscale delivery platform represents an exciting new strategy for regeneration of key fibrocartilage tissues throughout the body.