A multifunctional pearl powder-incorporated scaffold for bone regeneration: Simultaneous enhancement of osteogenesis, immune modulation, and angiogenesis.

Bone defect regeneration requires precise spatiotemporal orchestration of inflammatory response, blood vessel formation, and bone formation processes. A major unresolved issue is the fabrication of biomaterial scaffolds that can synergistically combine immunomodulation with angiogenic-osteogenic coupling to hierarchically regulate this regenerative cascade. This study developed a novel biomimetic composite scaffold that structurally and compositionally replicates natural bone by integrating methacrylic anhydride modified gelatin (GelMA) with pearl powder (PP) and dimethyloxalylglycine (DMOG) to enhance bone repair. Fabricated through controlled gradient cooling, ice-templating, and ultraviolet-photocrosslinking techniques, the scaffold exhibited a well-defined interconnected large porous structure with average pore sizes larger than 90 μm. The scaffold demonstrated optimal physicochemical properties, including high porosity (62.2%-81.5%), favorable swelling characteristic (476.4%-737.4%), exceptional mechanical performance, and sustained structural stability (180-day PBS immersion). In vitro assessments revealed the scaffold's superior cell adhesion capacity and significant enhancement of stem cell osteogenic differentiation, attributable to thecombined effects of PP and DMOG. Remarkably, the scaffold effectively modulated macrophage polarization, redirecting lipopolysaccharides (LPS)-activated macrophages toward the pro-regenerative M2 phenotype via suppression of tumor necrosis factor (TNF), mitogen-activated protein kinase (MAPK), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways. Furthermore, it substantially promoted endothelial cell migration and robust capillary network formation in tube formation assay. In a rat femoral condyle defect model, the scaffold demonstrated tri-modal therapeutic efficacy: accelerated bone regeneration, significant immune modulation, and enhanced angiogenesis. These multifunctional properties position this engineered scaffold as a clinically translatable solution for bone tissue regeneration.