Multifunctional hydrogel promotes rotator cuff healing through anti-inflammation and vascularization

Rotator cuff tears (RCTs) represent a substantial clinical challenge due to their intricate, multi-stage healing process, which encompasses sequential phases of inflammation, proliferation, tissue reconstruction, and remodeling. Disruption of any phase can adversely affect healing and increase the risk of re-tear. To address this issue, we engineered an injectable LA-CMCS-OHA hydrogel by physically blending lactic acid (LA)-a key signaling molecule-into a composite hydrogel system consisting of carboxymethyl chitosan (CMCS) and oxidized hyaluronic acid (OHA). The hydrogel formation was facilitated by a dynamic Schiff base reaction between CMCS and OHA, imparting superior biocompatibility, injectability, and self-healing properties. The LA-CMCS-OHA hydrogel effectively inhibits nuclear factor kappa B (NF-κB) signaling, thereby promoting macrophage polarization toward the anti-inflammatory M2 phenotype and mitigating early inflammatory responses. Additionally, it markedly enhances vascular endothelial growth factor (VEGF) expression, stimulating the proliferation and migration of human umbilical vein endothelial cells (HUVECs) to facilitate neovascularization. These therapeutic effects were comprehensively validated through both in vitro and in vivo studies. Histological and biomechanical assessments using a rat acute RCT model revealed that the LA-CMCS-OHA hydrogel significantly facilitates tendon-bone regeneration. Collectively, these findings highlight the LA-CMCS-OHA hydrogel as a promising therapeutic strategy for RCTs with strong potential for clinical translation.