Sustained release of magnesium ions mediated by injectable self-healing adhesive hydrogel promotes fibrocartilaginous interface regeneration in the rabbit rotator cuff tear model

The fibrocartilaginous enthesis regeneration after rotator repair is still a major challenge. Although magnesium-based alloy orthopedic implant is effective to promote fibrocartilage formation at the tendon-bone interface in the anterior cruciate ligament reconstruction model, it was limited in the rotator cuff repair for its special anatomical structure. Herein, we developed a multifunctional self-healing magnesium ions-quaternized chitosan/Pluronic® F127 (Mg-QCS/PF) hydrogels to achieve in-situ and customized release of Mg2+, and demonstrated the sustained release of Mg2+ from the hydrogel to significantly promote the rotator cuff repair in the rabbit rotator cuff tear model. The obtained hydrogels showed excellent self-healing and anti-compressive performance. Additionally, the good injectability and adhesive properties of the hydrogels make it easier and stable to deliver Mg2+ at the tendon-bone interface with irregular shapes. The release of Mg2+ from Mg-QCS/PF hydrogels improved the adhesion, proliferation and migration of bone mesenchymal stem cells (BMSCs) and MC3T3 cells in vitro compared with QCS/PF without Mg2+. Furthermore, the composite hydrogels significantly enhanced the fibrocartilaginous interface regeneration in the rabbit rotator cuff tear model in terms of repaired tendon mature scores, fibrocartilage regeneration, collagen remodeling and biomechanical properties. This is the first study to demonstrate the positive effects of Mg2+ for the rotator cuff healing in the rabbit preclinical model, and the results indicate that the acellular injectable self-healing Mg-doped hydrogels are candidates to effectively promote in situ regeneration of rotator cuff.