Engineered muscle drives bone repair and functional healing after composite musculoskeletal injury.

Abstract

Composite lower extremity injuries, characterized by open bone fractures with soft tissue damage, frequently result in delayed or failed fracture union, chronic pain and long-term disability. Standard clinical care overlooks the muscle as a critical driver of composite tissue healing, and current regenerative approaches fail to fully restore physical function. This study explores a muscle-driven approach to promote coordinated regeneration across both muscle and bone tissue. An engineered muscle (EM) composed of cell-laden nanofibrillar patterned scaffolds, was transplanted into the injured muscle in a mouse model of composite injury. EM constructs of either primary myoblasts or differentiated myotubes significantly improved healing outcomes and functional recovery compared to untreated controls. Myoblast-EM treatment led to accelerated tibial union, increased early bone mineral density, and faster restoration of symmetrical limb loading, along with enhanced single muscle fiber contractile power and velocity. Myotube-EM treatment yielded complimentary gains, including increased muscle cross-sectional area and whole-muscle force production. Importantly, all EM-treated animals exhibited higher survival rates and reduced limb morbidity. Notably, the superior functional outcomes observed with Myoblast EMs may be attributed to greater engraftment and in vivo differentiation of transplanted myogenic cells into mature myofibers. These findings introduce a paradigm-shifting regenerative strategy in which targeted muscle therapy drives systemic musculoskeletal repair, challenging conventional compartmentalized treatment models.