A matrix metalloproteinase-responsive hydrogel with spatially orchestrated delivery of stem cells and raleukin for enhanced bone regeneration

Stem cell therapy has demonstrated efficacy in treating bone defects. However, a critical challenge remains in effectively anchoring stem cells at the defect site and creating a conducive microenvironment that supports their proliferation and enhances bone regeneration. To address the dynamic microenvironmental changes occurring at different stages of bone defect healing, we designed a matrix metalloproteinase (MMP)-responsive biomimetic multilayer hydrogel system. The intermediate layer contains raleukin to provide targeted anti-inflammatory therapy, while the innermost layer comprises alginate/carboxymethyl cellulose microcapsules encapsulating bone marrow mesenchymal stem cells (BMSCs) to support stem cell retention, viability, and maintenance of stemness. The synergistic interaction between encapsulated BMSCs and raleukin effectively modulates the immune-inflammatory response and promotes angiogenesis, osteoblast proliferation, and differentiation. In vivo evaluation using rat skull defect model additionally demonstrates that the hydrogel system significantly enhances bone regeneration by accelerating bone metabolism and promoting osteoblast differentiation following implantation. Collectively, these findings underscore the therapeutic potential of MMP-responsive hydrogel platforms in advancing bone regeneration and related biomedical applications.