Ibuprofen‐Grafted Gelatin Hydrogel Modulates Inflammatory Response and Promotes Muscle Regeneration

ABSTRACT Volumetric muscle loss (VML) presents a significant clinical challenge, exacerbated by the chronic inflammation and oxidative stress that impair muscle regeneration. To address this, we developed an injectable hydrogel for muscle repair by enzymatically crosslinking gelatin covalently grafted with ibuprofen (Gel‐IBU) using microbial transglutaminase (mTG). Ibuprofen was covalently grafted to gelatin via carbodiimide chemistry to obtain the Gel‐IBU conjugate, which was then prepared into an injectable hydrogel by mTG crosslinking. Solubilized Gel‐IBU showed good injectability and underwent sol–gel transition in the presence of mTG within 5 min at 37°C to form a hydrogel. The resulting hydrogel exhibited good adhesiveness to muscle tissue, facilitated by liquid penetration and mTG‐mediated crosslinking with tissue proteins. Sustained release of IBU endowed the hydrogel with potent inflammation‐modulating capacity, promoting macrophage polarization toward the anti‐inflammatory M2 phenotype, suppressing pro‐inflammatory cytokines, and reducing reactive oxygen species (ROS) and nitric oxide (NO) oxidative products. In a murine VML model, the Gel‐IBU hydrogel effectively attenuated local inflammation and enhanced tissue regeneration, demonstrating significant promise for clinical muscle regeneration.