Regenerative Engineering and Rehabilitation in Musculoskeletal Injury and Ageing

Traumatic musculoskeletal injuries, including volumetric muscle loss (VML) and composite bone-muscle trauma, present significant challenges due to irreparable soft tissue damage, impaired regenerative capacity, and reduced muscle function. In prior work, we demonstrated that engineered muscle made from topographically patterned biomaterials can restore lost spatial cues and are effective modulators of the host healing and inflammatory response following VML in mice. In related work, we also showed that regenerative rehabilitation strategies that combined engineered muscle therapeutics with physical exercise, enhanced skeletal muscle repair and overall healing. Therefore, the aim of our collective work is to restore the structure-function relationship and enhance the regenerative potential of the musculoskeletal niche following lower extremity trauma. Using nanofibrillar collagen scaffolds laden with myogenic cells, engineered muscle (EM) constructs combined with voluntary wheel running, significantly improved muscle regeneration and functional recovery in young mice, with a 1.31-fold increase in muscle mass (p<0.05), 2.45-fold increase in in situ contractile force (p<0.001), and 1.91-fold increase in vascular density (p<0.01), though efficacy diminished in aged populations. While the benefits of regenerative rehabilitation strategies were profound in young populations, the reduced therapeutic response in aged mice highlights the need for a deeper evaluation of aging in rehabilitation engineering. In the setting of composite bone-muscle trauma, EM therapies, significantly enhanced muscle cross-sectional area (p<0.01) and in situ contractile force (p<0.05) compared to animals without EM transplantation. EMs also improved muscle fiber contractile power (p<0.0001) and velocity (p<0.0001); facilitated early bone healing, as evidenced by improved modified Radiological Union Scale for Tibia (mRUST) scores (p<0.05); and enhanced bone mineral density (p<0.01). Treated animals showed higher survival rates, faster recovery of equal limb loading, and reduced limb morbidities compared to untreated controls. These findings establish a foundation for novel regenerative therapies to improve functional outcomes and overall health status in complex musculoskeletal injuries, with broad implications for enhancing restorative care across diverse patient demographics.