Yoda1 Promotes Tendon-to-Bone Healing by Regulating M1/M2 Macrophage Polarization in a Rat Model of Rotator Cuff Repair

Background: Rotator cuff tears lead to bone loss because of reduced mechanical loading at the tendon-bone interface, which results in poor healing after rotator cuff repair (RCR). Whether Yoda1, the specific Piezo1 agonist, can counteract bone loss and promote rotator cuff healing has not yet been explored. Hypothesis: Yoda1 promotes tendon-to-bone healing in a rat model of RCR and regulates M1/M2 macrophage polarization at the tendon-bone interface. Study Design: Controlled laboratory study. Methods: A total of 120 male rats aged 12 weeks, which were randomly divided into 4 groups, were used to establish the RCR model: vehicle-only (control [CON]), low-concentration Yoda1 (LC), moderate-concentration Yoda1 (MC), and high-concentration Yoda1 (HC) intraperitoneal injection. The rats were sacrificed at 4 and 8 weeks. Tendon-to-bone healing at the repair site was evaluated using histological, bone microstructure, and biomechanical analyses. Macrophage polarization was observed through immunofluorescence staining. Results: The LC group showed higher histological scores compared with the CON group at each time point ( P < .001). More organized collagen fibers and greater cartilage regeneration were observed in the intervention groups compared with the CON group, as confirmed by immunohistochemistry for collagen type II. Additionally, the LC group exhibited more new bone formation compared to the CON group at 4 weeks ( P < .001). Biomechanically, all intervention groups exhibited significantly higher failure loads and stiffness than the CON group at 4 and 8 weeks. In immune regulation, the expression of CD86 was significantly decreased, and CD206 expression was significantly increased, in the intervention groups compared to the CON group at 4 weeks. However, there were no significant differences in the expression of CD86 and CD206 among the groups at 8 weeks. Conclusion: Yoda1 improved tendon-to-bone healing in a rat model of RCR. In addition, Yoda1 promoted the infiltration of M2 macrophages at the repair site, which may have facilitated healing at the tendon-bone interface. Clinical Relevance: The present study is an exploratory investigation. Postoperative treatment using Yoda1 could be a potential therapeutic strategy to improve tendon-to-bone healing in patients with rotator cuff tears.