Healthy Tendon Stem Cell-Derived Exosomes Promote Tendon-To-Bone Healing of Aged Chronic Rotator Cuff Tears by Breaking the Positive-Feedback Cross-Talk between Senescent Tendon Stem Cells and Macrophages through the Modulation of Macrophage Polarization.

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Abstract

[Indexed for MEDLINE] 9. Am J Sports Med. 2026 Jan;54(1):162-173. doi: 10.1177/03635465251395275. Epub 2026 Jan 1. Purified Exosome Product Enhances Tendon-Bone Healing in a Rat Rotator Cuff Repair Model. Zhao G(1)(2)(3), Tsukamoto I(1), Yousefi F(1), Moran SL(1), Behfar A(3), Sanchez-Sotelo J(1), Zhao C(1)(4). Author information: (1)Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA. (2)Department of Orthopedics, The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou, China. (3)Changzhou Medical Center, Nanjing Medical University, Changzhou, China. (4)Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota, USA. BACKGROUND: Tendon-bone healing after rotator cuff injury is, or remains, a clinical challenge. PURPOSE: To examine the role of intraoperative use of purified exosome products (PEPs) in the treatment of rotator cuff injuries and to assess the effect of PEP on supraspinatus tendon-bone healing after rotator cuff repair in a rat model. STUDY DESIGN: Controlled laboratory study. METHODS: This study used 120 Sprague-Dawley rats that underwent an acute supraspinatus tendon transection from the insertion, followed by repair using a single transosseous suture. They were divided into 3 groups: a control group that received only sutures, a TISSEEL group that used a commercially available fibrin sealant patch (TISSEEL) of approximately 0.5 cm2, and a PEP-TISSEEL group that used a similarly sized TISSEEL patch combined with PEP. Autopsies were performed at 1, 3, 6, and 8 weeks after surgery. Analyses were performed using molecular biological, biomechanical, and histological techniques. RESULTS: At 6 weeks, the PEP-TISSEEL group achieved greater failure load (mean, 27.5 ± 5.3 N) than the control (mean, 16.4 ± 4.2 N; P = .012) and TISSEEL (mean, 23.4 ± 5.0 N; P = .041) groups, with superiority persisting at 12 weeks (27.2 ± 6.5 N vs 13.1 ± 2.6 N [P = .002] for the control group and 21.1 ± 5.8 N [P = .037] for the TISSEEL group). DigiGait showed earlier recovery of stride length and paw angle. Histology revealed organized collagen and reduced scarring, while molecular assays demonstrated early inflammatory modulation with subsequent upregulation of collagen type 1 or 3 and TGF-β, supporting accelerated tendon-bone healing. CONCLUSION: Intraoperative application of PEP-TISSEEL enhanced tendon-bone healing in a rat model by improving biomechanical strength, promoting enthesis-specific histological regeneration, and accelerating functional recovery as evidenced by gait analysis. CLINICAL RELEVANCE: The intraoperative application of PEP combined with TISSEEL significantly enhances rotator cuff tendon healing by modulating early inflammation, promoting collagen synthesis, and improving biomechanical properties in a rat model. These findings suggest that PEP-based therapies could offer a promising adjunct in surgical repair, potentially reducing retear rates and improving functional outcomes in patients with rotator cuff injuries. Further clinical studies are warranted to translate these benefits into human applications. DOI: 10.1177/03635465251395275