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

Sarah M. Greising, Benjamin T. Corona, Christopher McGann, Jeremy K. Frankum, Gordon L. Warren

Research output: Contribution to journalReview articlepeer-review

31 Scopus citations


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 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. 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.

Original languageEnglish (US)
Pages (from-to)510-525
Number of pages16
JournalTissue Engineering - Part B: Reviews
Issue number6
StatePublished - Dec 2019

Bibliographical note

Funding Information:
Traditional rehabilitative therapies (i.e., physical therapy) are the mainstay of care for VML injury, but have demonstrated limited benefit toward functional recovery in available clinical reports.3 The high incidence of VML injury among battlefield-wounded soldiers in recent wars prompted a focused regenerative research effort supported by the United States Department of Defense and Veterans Administration.7,21 In response, a broad range of regenerative therapeutic approaches (i.e., treatments) have been developed for the explicit purpose of improving the functional capacity of the injured musculature principally by restoration of contractile tissue.22

Publisher Copyright:
© Copyright 2019, Mary Ann Liebert, Inc., publishers.


  • biomaterial
  • extracellular matrix
  • network meta-analysis
  • orthopedic trauma
  • regenerative medicine
  • satellite cell


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