Regeneration of Osteochondral Defects Using Developmentally Inspired Cartilaginous Templates

There is increased interest in recapitulating aspects of development when designing new tissue engineering strategies. Long bones and their epiphyses are formed through endochondral ossification, a process by which a cartilage template develops in response to genetic and environmental cues to generate a bone organ. The objective of this study was to evaluate the capacity of engineered cartilage templates to regenerate osteochondral (OC) defects created in the femoral condyle of skeletally mature rabbits. To this end, bone marrow-derived mesenchymal stem cells (BMSCs) were encapsulated in RGD (arginine/glycine/aspartic acid)-functionalized, γ-irradiated alginate hydrogel and chondrogenically primed in vitro to engineer cartilage templates tailored for OC defect regeneration. While comparable levels of healing were observed in the bony region of empty and treated groups, the quality of healing was notably different in the chondral region of these defects. Mechanical testing revealed that treatment with engineered cartilage templates promoted the development of a stiffer repair tissue at the articular surface, which correlated with histomorphometric analysis demonstrating the formation of a more hyaline cartilage-like repair tissue. Next, a computational mechanobiological model was used to better understand how local environmental cues were regulating the regenerative process in vivo . This model predicted that higher strains and lower levels of oxygen in the chondral region of the defect were preventing cartilage template progression along the endochondral pathway, with hyaline cartilage or fibrocartilage eventually forming depending on local strain magnitudes. In contrast, higher levels of oxygen and lower magnitudes of strain in the osseous region of the defect facilitated progression of the engineered cartilage template along an endochondral pathway. In conclusion, this study demonstrates that engineered cartilage templates can enhance OC defect regeneration, pointing to the potential for developmentally inspired soft tissue templates, engineered using BMSCs, to regenerate damaged and diseased joints.