Lumbrokinase-loaded GelMA hydrogels with inflammatory regulatory capacity promote vascularized bone regeneration in critical-sized cranial defects

The management of critical-sized bone defects resulting from trauma and resective surgeries still poses significant clinical challenges. Factors contributing to inadequate bone regeneration in critical-sized defects are complex and multifaceted, including vascular injury and inflammation. Inspired by earthworms' remarkable regenerative abilities, we incorporated lumbrokinase (LK), an extract from earthworms, into injectable gelatin methacryloyl (GelMA) hydrogels to achieve controlled release of LK, thereby enhancing vascularized bone regeneration in critical-sized defects. While LK has been clinically utilized as an antithrombotic agent for decades in treating cerebrovascular and cardiovascular diseases, this study reveals its novel anti-inflammatory properties and dual capacity to promote both osteogenesis and angiogenesis. The LK-loaded GelMA hydrogel demonstrated favorable biocompatibility, good injectability and viscoelastic properties, tunable degradation kinetics, and optimal swelling characteristics. Comprehensive <i>in vitro</i> and <i>in vivo</i> evaluations confirmed the hydrogel's efficient LK loading and sustained release profile. The combined effects of enhanced osteogenesis, angiogenesis, and immunomodulation significantly improved critical-sized bone defect regeneration, demonstrating substantial potential of the LK-loaded GelMA hydrogel for clinical translation in the reconstruction of critical-sized bone defects.