Tendon–bone insertion (TBI) injuries, such as anterior cruciate ligament injury and rotator cuff injury, are the most common soft tissue injuries. In most situations, surgical tendon/ligament reconstruction is necessary for treating such injuries. However, a significant number of cases failed because healing of the enthesis occurs through scar tissue formation rather than the regeneration of transitional tissue. In recent years, the therapeutic potential of mesenchymal stem cells (MSCs) has been well documented in animal and clinical studies, such as chronic paraplegia, non-ischemic heart failure, and osteoarthritis of the knee. MSCs are multipotent stem cells, which have self-renewability and the ability to differentiate into a wide variety of cells such as chondrocytes, osteoblasts, and adipocytes. Numerous studies have suggested that MSCs could promote angiogenesis and cell proliferation, reduce inflammation, and produce a large number of bioactive molecules involved in the repair. These effects are likely mediated by the paracrine mechanisms of MSCs, particularly through the release of exosomes. Exosomes, nano-sized extracellular vesicles (EVs) with a lipid bilayer and a membrane structure, are naturally released by various cell types. They play an essential role in intercellular communication by transferring bioactive lipids, proteins, and nucleic acids, such as mRNAs and miRNAs, between cells to influence the physiological and pathological processes of recipient cells. Exosomes have been shown to facilitate tissue repair and regeneration. Herein, we discuss the prospective applications of MSC-derived exosomes in TBI injuries. We also review the roles of MSC–EVs and the underlying mechanisms of their effects on promoting tendon–bone healing. At last, we discuss the present challenges and future research directions. Graphical Abstract

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Background: Anterior cruciate ligament (ACL) injuries and bone tunnel enlargement (BTE) after ACL reconstruction (ACLR) remain frequent issues. Bone dust (BD) produced by tunnel preparation with osteogenic ability and reverse drilling (RD), an easy compaction technique, make it accessible to enhance tendon-bone healing in the clinic. Hypothesis: RD and BD synergistically promote tendon-bone healing by improving peritunnel bone and preventing BTE in femurs. Study Design: Controlled laboratory study. Methods: In total, 96 New Zealand White rabbits underwent ACLR. The semitendinosus tendon was freed before medial parapatellar arthrotomy. After the native ACL was transected, bone tunnels were prepared through the footprint of the native ACL. All animals were randomly assigned to 1 of 4 groups according to different tunnel preparation methods: group 1 (irrigation after extraction drilling [ED]; control group), group 2 (irrigation after RD), group 3 (no irrigation after ED), and group 4 (no irrigation after RD). BD was harvested by irrigating tunnels and was characterized by morphology and size. The specimens underwent microarchitectural, histological, and biomechanical evaluations at 4, 8, and 12 weeks postoperatively. Results: Micro–computed tomography demonstrated more peritunnel bone and less BTE in the femurs of group 4 compared with the other groups. Histologically, BD possessed osteogenic activity in bone tunnels postoperatively. Meanwhile, group 4 regenerated a higher amount of the tendon-bone interface and more peritunnel bone than group 1. Biomechanically, group 4 showed higher failure loads and stiffness than group 1. However, peritunnel bone loss, active osteoclasts, and significant BTE were found in the femurs of group 1 and group 3 at 12 weeks postoperatively, while no strong correlation was found between BTE and inflammatory cytokines. Scanning electron microscopy and particle size analysis suggested that BD produced by ED and RD had no difference in size. Conclusion: Tendon-bone healing was facilitated by the synergistic effect of RD and BD in femurs. Clinical Relevance: This study provides a more accessible and effective surgical strategy to promote tendon-bone healing after ACLR by increasing peritunnel bone and preventing BTE in femurs.

ObjectiveTo investigate whether preoperative lateral anterior tibial subluxation (LATS) measured from magnetic resonance imaging (MRI) can influence tibial insertion and postoperative sagittal alignment after anterior cruciate ligament reconstructions (ACLRs).Methods84 patients who underwent single-bundle ACLRs were retrospectively investigated. Among them, 39 patients (LATS of <6 mm) 23 patients (LATS of ≥6 mm and <10 mm) and 22 patients (excessive LATS of ≥10 mm) were defined as group 1, 2 and 3, respectively. LATS, the position of graft insertion into tibia as ratio of anterior-posterior width (AP ratio) and the sagittal graft angle (SGA) were postoperatively assessed from MRI at 2-year follow-up. Following linear regression analyses were employed.ResultsThe group 3 exhibited the largest preoperative LATS and remained the most postoperative LATS. Moreover, the group 3 possessed the most posteriorly located tunnel insertion with the largest AP ratio and the most vertical graft orientation. Of all included patients, a moderate correlation was demonstrated between pre- and postoperative LATS (r = 0.635). A low correlation was observed between preoperative LATS and AP ratio (r = 0.300) and a moderate correlation was displayed between AP ratio and SGA (r = 0.656).ConclusionFor ACL injuries with excessive LATS (≥10 mm), most posteriorly located tibial insertion was found out, and worse sagittal alignment containing high residual LATS was associated with more vertical graft orientation following ACLRs.