Evaluation of Functional Outcomes Following Modification of a Tissue Engineered Muscle Repair Technology for the Treatment of Volumetric Muscle Loss

Skeletal muscle has an incredible capacity for repair following injuries where muscle architecture (basal lamina and ECM) and cellular components (satellite cells) remain intact. However, the removal of muscle beyond what the body has the endogenous regenerative ability to repair is the definition of volumetric muscle loss injuries (VML). These injuries lead to permanent cosmetic and functional deficits for which there are no adequate surgical or rehabilitative interventions. Tissue engineered therapies show great promise as treatments for VML, as they provide scaffolding and cues to fill the defect area where no tissue remains post-injury. The Christ lab at UVA has had success in the development of the tissue engineered muscle repair (TEMR) construct, which is created by seeding muscle progenitor cells (MPCs) onto a porcine derived bladder acellular matrix (BAM) and preconditioned in a novel cyclic stretch bioreactor. We have successfully treated progressively larger and clinically relevant VML injuries in the sheet-like rat latissimus dorsi (LD) muscle, and coupled these results with in silico modeling to describe the mechanisms of injury and repair. In the rat tibialis anterior (TA), a cylindrical muscle in the anterior hindlimb, we have observed a dichotomy of responses to TEMR treatment, with a 61% functional improvement in 46% of TEMR-treated animals at 12 weeks post-injury. This dissertation builds directly from what was previously observed in that we modulated the TEMR construct to enhance its endogenous regenerative capacity and fit various injury models that are more clinically relevant. In addressing the proposed driving variables behind the dichotomy in the TA, we observed a decrease in the variability of responses following TEMR treatment with 67% of TEMR-treated animals exhibiting 69% recovery at 24 weeks, indicating a durable response to treatment. In 25% of TEMR-treated animals, near perfect functional recovery was observed. In the LD, we changed the TEMR manufacturing process to apply the construct to treat a large injury in which 22% of the muscle was removed. Finally, we coupled a stem cell enhanced TEMR with physical rehabilitation in order to more accurately recapitulate the native muscle cellular milieu. These findings underscore the importance of understanding the mechanisms of regeneration following tissue engineered treatment in order to drive therapeutic improvements and increase treatment efficacy.