Background: Fatty infiltration and poor tendon-bone healing in chronic rotator cuff tears (RCTs) are associated with unsatisfactory prognosis. Adipose stem cell–derived exosomes (ASC-Exos), having multiple biological effects, can prevent muscle degeneration in acute RCTs. However, the effects of ASC-Exos on fatty infiltration and tendon-bone healing in chronic RCTs remain unknown. Purpose: To study the effects of ASC-Exos on fatty infiltration and tendon-bone healing in a chronic RCT rabbit model. Study Design: Controlled laboratory study. Methods: At week 0, we randomly allocated 35 rabbits to receive sham surgery (14 rabbits) or establish a bilateral RCT model (21 rabbits, detachment of the supraspinatus tendon). At week 6, a total of 7 rabbits received sham surgery, and 7 rabbits with RCT were sacrificed for fatty infiltration assay. The remaining 14 rabbits with bilateral RCTs were randomly assigned to a saline group (7 rabbits that received local saline injection and rotator cuff repair) or an ASC-Exos group (7 rabbits that received local ASC-Exos injection and rotator cuff repair). At week 18, all rabbits were sacrificed for histological examination and biomechanical testing. Results: At week 18, the ASC-Exos group showed significantly lower fatty infiltration (14.01% ± 2.85%) compared with the saline group (21.79% ± 3.07%) ( P < .001), and no statistical difference compared with the time of repair (10.88% ± 2.64%) ( P = .127). For tendon-bone healing, the ASC-Exos group showed a higher histological score and more newly regenerated fibrocartilage at the repair site than did the saline group. Regarding biomechanical testing, the ASC-Exos group showed significantly higher ultimate load to failure, stiffness, and stress than the saline group. Conclusion: Local injection of ASC-Exos in chronic RCTs at the time of repair could prevent the progress of fatty infiltration, promote tendon-bone healing, and improve biomechanical properties. Clinical Relevance: ASC-Exos injection may be used as a cell-free adjunctive therapy to inhibit fatty infiltration and improve rotator cuff healing in the repair of chronic RCTs.

Background: Fatty infiltration, inflammation, and apoptosis are common degenerative changes in patients with chronic rotator cuff tears that can lead to muscle atrophy and can even result in massive irreparable rotator cuff tears. Some data have demonstrated the proregenerative, anti-inflammatory, and anti-apoptotic properties of stem cell–derived exosomes in some orthopaedic disorders, but their effect on torn rotator cuff muscles has never been investigated. Purpose: To study the effect of exosomes isolated from human adipose-derived stem cells (ASCs-Exos) on muscle degeneration, regeneration, and biomechanical properties in a rat model of a massive rotator cuff tear (MRCT). Study Design: Controlled laboratory study. Methods: A bilateral supraspinatus and infraspinatus tenotomy was performed on rats to create an MRCT model. Forty-two rats were randomly assigned to 3 groups: the sham surgery group, the saline group (lesions treated with a saline injection), and the ASCs-Exos group (lesions treated with an ASCs-Exos injection). Wet muscle weight, fatty infiltration, inflammation, vascularization, regeneration, and biomechanical properties were evaluated at 8 and 16 weeks after surgery. Results: The results revealed that the ASCs-Exos treatment could prevent the atrophy, fatty infiltration, inflammation, and vascularization of muscles in the MRCT model ( P < .001). Additionally, the myofiber regeneration and biomechanical properties of ASCs-Exos-treated rotator cuffs were significantly elevated compared with those in the saline-treated group ( P < .001). Conclusion: This study demonstrates that ASCs-Exos can effectively decrease atrophy and degeneration and improve muscle regeneration and biomechanical properties in torn rotator cuff muscles. Clinical Relevance: ASCs-Exos can be used as a new cell-free approach to prevent the muscle degeneration associated with torn rotator cuffs and may be helpful to repair torn rotator cuffs. Nevertheless, further work needs to be done in a large animal model owing to the inherent regenerative potential possessed by rodents.

Background: Chronic rotator cuff (RC) tendinopathy is one of the most prevalent causes of shoulder pain. Growing evidence suggests that macrophages play a significant role in the proinflammatory response, resolution of inflammation, and tissue healing of tendinopathy. In particular, enhancement of M2 macrophage (M2φ) activity contributes to the accelerated healing of tendinopathy. Therefore, a treatment that enhances M2φ polarization would be useful for patients with this common musculoskeletal disorder. Purpose: To investigate whether adipose stem cell–derived exosomes (ASC-Exos) enhance M2φ polarization and ameliorate chronic RC tendinopathy. Study Design: Controlled laboratory study. Methods: First, we compared the effects of ASC-Exos on polarization of mouse bone marrow–derived macrophages between a classically activated phenotype (M1φ) and an alternatively activated phenotype (M2φ) in vitro. In total, 72 C57BL/6 mice were assigned to normal cage activity (n = 24) or 5 weeks of treadmill overuse (n = 48). The supraspinatus tendon of each treadmill overuse mouse was treated with ASC-Exos (n = 24) or saline (n = 24). Histological and biomechanical outcomes were assessed 4 weeks after treatment. Finally, tissue samples from human patients with RC tendinopathy were obtained to assay the effect of ASC-Exos on the M1φ/M2φ balance in tissue-resident macrophages. Results: ASC-Exos inhibited M1φ polarization and augmented M2φ polarization in vitro and in vivo. Mice in the ASC-Exos group showed less severe pathological changes than those in the saline group, including less cellular infiltration, disorganization of collagen, and ground substance deposition. The modified Bonar score of the ASC-Exos group (mean ± SD, 7.68 ± 1.03) was significantly lower than that of the saline group (9.81 ± 0.96; P < .05). Furthermore, the maximum failure load was significantly higher in the ASC-Exos group than in the saline group (4.23 ± 0.66 N vs 3.86 ± 0.65 N; P < .05), as was stiffness (3.38 ± 0.34 N/m vs 2.68 ± 0.49 N/m; P < .05). Conclusion: ASC-Exos–mediated polarization balance of M1φ/M2φ contributes to the amelioration of chronic RC tendinopathy. Regulation of the M1φ/M2φ balance could be a new target for the treatment of chronic RC tendinopathy. Clinical Relevance: Administration of ASC-Exos is a cell-free approach that may become a novel treatment option for chronic RC tendinopathy and should be explored further.