Bioactive Nanofiber‐Hydrogel Composite Regulates Regenerative Microenvironment for Skeletal Muscle Regeneration after Volumetric Muscle Loss

Abstract Volumetric muscle loss (VML) is a severe form of muscle trauma that exceeds the regenerative capacity of skeletal muscle tissue, leading to substantial functional impairment. The abnormal immune response and excessive reactive oxygen species (ROS) accumulation hinder muscle regeneration following VML. Here, an interfacial cross‐linked hydrogel‐poly(ε‐caprolactone) nanofiber composite, that incorporates both biophysical and biochemical cues to modulate the immune and ROS microenvironment for enhanced VML repair, is engineered. The interfacial cross‐linking is achieved through a Michael addition between catechol and thiol groups. The resultant composite exhibits enhanced mechanical strength without sacrificing porosity. Moreover, it mitigates oxidative stress and promotes macrophage polarization toward a pro‐regenerative phenotype, both in vitro and in a mouse VML model. 4 weeks post‐implantation, mice implanted with the composite show improved grip strength and walking performance, along with increased muscle fiber diameter, enhanced angiogenesis, and more nerve innervation compared to control mice. Collectively, these results suggest that the interfacial cross‐linked nanofiber‐hydrogel composite could serve as a cell‐free and drug‐free strategy for augmenting muscle regeneration by modulating the oxidative stress and immune microenvironment at the VML site.