Mesenchymal stem cells and their application to rotator cuff pathology: A meta-analysis of pre-clinical studies.

Background: Rotator cuff injury (RCI) is a leading cause of morbidity in orthopaedics. Advances in regenerative medicine have led to the novel pleiotropic effects of mesenchymal stromal cells (MSCs) as therapeutic agents for RCI. Objective: Conduct a systematic evaluation of available preclinical studies to quantify the effects of MSCs on RCI. Methods: A literature search was performed in PubMed, Scopus, Cochrane, CINAHL, and Google Scholar. At least two independent investigators screened animal studies assessing the therapeutic effects of MSCs on: (i) biomechanical testing, imaging, and/or range-of-motion (primary outcome), and (ii) histologic analyses of wound healing, gene/protein expression of regenerative factors, and safety/long-term outcomes (secondary outcome). Meta-analysis data is reported as standardized mean difference (SMD) with 95% confidence interval (CI). Results: A total of 858 titles and abstracts were screened; 18 studies (n=576) met inclusion criteria. MSC therapy improved ultimate load failure [SMD -0.43 (95% CI -0.65, -0.22), p<0.0001; 15 studies, 28 comparisons], site stiffness [SMD -0.29 (95% CI -0.55, -0.04), p<0.05; 9 studies, 17 comparisons], bone mineral density [SMD -0.77 (95% CI -1.16, -0.38), p<0.0001; 2 studies, 6 comparisons], and stimulated fibrocartilage formation [SMD of -1.37 (95% CI -1.99, -0.74), p<0.0001; 4 studies, 7 comparisons]. Heterogeneity between studies was high and risk of bias was unclear. Conclusion: Administration of MSCs in preclinical models recapitulating RCI improved aspects of shoulder biomechanics, imaging, and collagen formation. Although these findings are promising, future studies should attempt to limit the risk of bias and focus on optimizing MSCs by standardizing methodologies.