A salidroside-crosslinked multi-responsive injectable hydrogel to alleviate tissue stress microenvironment and promote muscle injury repair

The persistent imbalance of the wound microenvironment after volumetric muscle loss (VML) critically impedes endogenous repair. Therefore, establishing a favorable cellular milieu following skeletal muscle injury is essential for effective regeneration. Herein, we developed a microenvironment-responsive injectable hydrogel, with alginate as the primary component, crosslinked with salidroside through aminophenylboronic acid, which provides mechanical support with stiffness relevant to skeletal muscle repair and promotes muscle regeneration. The hydrogel exhibits excellent porosity, injectability, responsiveness, and biodegradability. In vitro experiments demonstrated its capacity to efficiently scavenge excessive reactive oxygen species, mitigate oxidative stress, and facilitate macrophage repolarization toward the M2 phenotype, thereby attenuating inflammation. It markedly promotes myoblast proliferation and differentiation, as well as endothelial cell growth, migration, and tube formation. In a rat tibialis anterior defect model, the hydrogel reshaped the local microenvironment by exerting anti-inflammatory and antioxidant effects, thereby facilitating angiogenesis and improved myofiber regeneration with a more orderly histological arrangement. Collectively, this work presents a promising therapeutic strategy to restore the stress microenvironment of skeletal muscle injuries, thereby promoting muscle tissue regeneration and functional recovery.