Therapeutic Approaches for Volumetric Muscle Loss Injury: A Systematic Review and Meta-Analysis.

Our goal was to understand the impact of regenerative therapies on the functional capacity of skeletal muscle following volumetric muscle loss (VML) injury. An extensive database search (e.g., PubMed, Cochrane Library, and ClinicalTrials.gov) was conducted up through January 2019 to evaluate the following: "In humans or animals with VML injury, is treatment better than no treatment at recovering functional capacity?" Study eligibility criteria required studies to have both an untreated and at least one treated VML injury group. From 2312 study reports, 44 studies met the inclusion criteria. Quantitative functional capacity data (absolute and/or normalized strength) or proportional measures (histological analysis quantifying viable muscle tissue, mitochondrial function, and/or exhaustive treadmill running) were extracted for use. While both human and animal studies were included in the searches, only animal studies met the eligibility criteria. Using a random-effects model, Hedges' g was used as the effect size (ES) and calculated such that a positive ES indicated treatment efficacy. The overall ES was 0.75 (95% confidence interval: 0.53-0.96; p < 0.0000001), indicating that the treatments, on average, resulted in a significant improvement in functional capacity. From network meta-analyses, it was determined that an acellular biomaterial combined with stem and/or progenitor cells had the greatest treatment effectiveness. The findings indicate that various treatments in animal models of VML improve the functional capacity of muscle compared to leaving the injury untreated; however, the ∼16% beneficial effect is small. Our results suggest that current regenerative therapy paradigms require further maturation to achieve clinically meaningful improvements in the functional capacity of the muscle. Impact Statement Our most salient findings are that (1) various treatment approaches used in animal models of volumetric muscle loss (VML) injury improve functional capacity compared to leaving the injury untreated and (2) an acellular biomaterial in combination with cellular components was the most effective treatment to improve functional capacity following VML injury to date. The nature of our findings has substantial implications for regenerative medicine, biomedical engineering, and rehabilitative techniques currently being evaluated and developed for VML injury repair, and are pivotal to the progression of the regenerative medicine effort aimed at restoring maximal function to traumatized and disabled limbs.