Engineering Musculoskeletal Grafts for Multi-Tissue Unit Repair: Lessons From Developmental Biology and Wound Healing

In the musculoskeletal system, bone, tendon, and skeletal muscle integrate and act coordinately as a single multi-tissue unit to facilitate body movement. The development, integration, and maturation of these essential components and their response to injury are vital for conferring efficient locomotion. The highly integrated nature of these components is evident under disease conditions, where rotator cuff tears at the bone-tendon interface have been reported to be associated with distal pathological alterations such as skeletal muscle degeneration and bone loss. To successfully treat musculoskeletal injuries and diseases, it is important to gain deep understanding of the development, integration and maturation of these musculoskeletal tissues along with their interfaces as well as the impact of inflammation on musculoskeletal healing and graft integration. This review highlights the current knowledge of developmental biology and wound healing in the bone-tendon-muscle multi-tissue unit and perspectives of what can be learnt from these biological and pathological processes within the context of musculoskeletal tissue engineering and regenerative medicine. Integrating these knowledge and perspectives can serve as guiding principles to inform the development and engineering of musculoskeletal grafts and other tissue engineering strategies to address challenging musculoskeletal injuries and diseases.