Extracellular Vesicles Are Associated With Biological, Mechanical, and Structural Tendon Healing Metrics in Preclinical Models: A Systematic Review and Meta‐Analysis

Tendinopathies comprise half of musculoskeletal injuries, yet medical treatments are lacking. Orthobiologics are novel therapeutics developed to address this gap, with extracellular vesicles (EVs) being a promising prospect. However, we lack a complete understanding of how EVs affect regeneration, both endogenously and as a tool for augmenting tendon healing. Therefore, the purpose of this review was to compile the literature focused on understanding the impact of EV treatment on tendon healing using animal models. We performed a literature search in accordance with PRISMA reporting guidelines. Title, abstract, and full-text screening were performed by two authors. We assessed transparency and risk-of-bias using the ARRIVE, MISEV, and SYRCLE Guidelines, and meta-analyses were performed on overlapping outcome variables. After screening, 46 articles were included. Most studies utilized young male Achilles tendons, with a diversity of EV cell sources, injury types, dosage schemes, and biomaterials. Several ARRIVE (e.g., blinding) and MISEV (e.g., seeding density) recommendations remain poorly reported in this literature, and the risk of bias per SYRCLE guidelines is relatively high. Despite high heterogeneity, EV treatment was associated with improved histological tendon healing scores and increased load to failure, tendon stiffness, and Young's modulus. Further meta-analyses revealed EV treatment was associated with increased type I collagen protein and type III collagen transcript expression, and decreased protein expression of IL-6 and markers of senescence. We recommend that future studies include different ages, sexes, and more systematically protocolized EV delivery scheme. Statement of Clinical Significance: This systematic review identifies gaps in the tendon and EV literature while also unveiling unexplored mechanisms by which EVs may promote tendon healing. This improved understanding and call for rigor in studies enhances the translational potential of EVs as a future treatment for tendon injuries.