Erythropoietin Functionalized Hierarchical Scaffolds Enable Immunomodulated and Vascularized Bone Repair in Periodontal Defect

The regeneration of periodontal bone is hindered by unresolved inflammation, insufficient angiogenesis, and compromised osteogenesis, conditions that are rarely addressed simultaneously by existing scaffold designs. Conventional hydrogel-based constructs often lack the mechanical robustness required for maxillofacial defects, while many synthetic scaffolds fail to replicate the multiscale pore organization essential for functional regeneration. Here, we present a dual-fabrication strategy for constructing hierarchically porous scaffolds via digital light processing (DLP)-based 3D printing of a porogen-containing resin. This hybrid approach achieves well-defined macropores for load-bearing stability and vascular infiltration, together with interconnected hierarchical micro-nanoporous that promote nutrient transport and cell-matrix interactions. To endow the scaffold with biological functionality, it was modified with polydopamine (PDA) for efficient immobilization and sustained release of erythropoietin (EPO). The resulting scaffolds (DMPS-PDA-EPO) simultaneously regulated inflammation by promoting M2 macrophage polarization, enhanced angiogenesis through endothelial migration and tube formation, and stimulated osteogenic differentiation of human periodontal ligament stem cells under pro-inflammatory conditions. In vivo implantation in rat periodontal defect models resulted in markedly enhanced bone regeneration, with bone volume fraction and bone mineral density increasing by 161.9% and 167%, respectively, at 8 weeks compared with controls. By integrating structural precision, mechanical robustness, and immuno-angiogenic bioactivity, this EPO-functionalized hierarchical scaffold represents a clinically translatable strategy for the treatment of complex periodontal defects.