3D-printed functionalized strontium-silk fibroin-hydroxyapatite scaffolds facilitate bone regeneration via immunomodulatory and sequential angiogenic-osteogenic coupling

The repair of large bone defects remains a significant clinical challenge. The development of bioactive materials for bone tissue engineering offers promising solutions to address these problems. However, the lack of vascularization and the risk of endogenous immune rejection severely hinder the application of implantable biomaterials in bone regeneration. Therefore, in this study, we synthesized a multifunctional 3D-printed biological scaffold (EP@PCL/Sr) for achieving staged vascularized bone regeneration in the immune microenvironment to promote bone defect repair. Firstly, the rough surface morphology of the EP@PCL/Sr scaffolds enhanced cell proliferation and adhesion. Furthermore, epigallocatechin-3-gallate, a surface-coating component, contributed to immune regulation. Finally, strontium-silk fibroin (Sr-SF)-modified hydroxyapatite, embedded within the PCL scaffold, released Sr and Ca ions to improve both angiogenesis and osteogenesis. Both <i>in vivo</i> and <i>ex vivo</i> experimental results demonstrated that EP@PCL/Sr scaffolds exhibited excellent multifunctional properties, including good tissue compatibility, effective scavenging of reactive oxygen species, strong balancing of the immune microenvironment and regulation of macrophage polarization, perfect enhancement of angiogenesis and promotion of osteogenesis for promoting bone regeneration. Furthermore, the underlying mechanism were revealed that EP@PCL/Sr scaffolds promoted osteogenesis of BMSCs by activating the ITGA10/PI3K/AKT pathway. This study presents a comprehensive and innovative strategy for bone regeneration and bone defect repair, providing a new possibility for its clinical application.