Iron‐Dependent Interfacial Regulation Balances Osteogenesis and Iron Homeostasis in Bilayer Hydrogels for Periodontal Bone Regeneration

Periodontal bone defects represent a prevalent complication of oral diseases, for which guided tissue regeneration (GTR) has long been regarded as the therapeutic gold standard. Nevertheless, conventional GTR approaches are technically demanding and frequently yield inconsistent clinical outcomes. In this context, we report the development of a bilayer hydrogel system (PPC/nFeMBG), integrating polyvinyl alcohol (PVA), collagen (Col), and non-magnetic iron-doped mesoporous bioactive glass (nFeMBG), designed to overcome intrinsic limitations of traditional GTR membranes. The bilayer architecture was rationally engineered, with a dense PVA barrier layer effectively restricting soft tissue downgrowth, and a porous PVA/Col/nFeMBG graft layer simultaneously enabling osteogenic stimulation. Notably, moderate Fe doping (PPC/2nFeMBG) enabled suitable interfacial organization within the collagen-nFeMBG network, reinforcing hydrogel mechanical stability and promoting PDGFRA-MAPK axis activation, thereby enhancing osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) while maintaining intracellular iron homeostasis. In contrast, excessive Fe incorporation (PPC/10nFeMBG) induced ferroptosis-associated responses in hPDLSCs and macrophages, ultimately compromising osteogenesis. In vivo evaluation also confirmed that PPC/2nFeMBG significantly promoted new bone formation in periodontal defects. Collectively, these results demonstrate that PPC/2nFeMBG achieves a favorable balance between osteogenesis and iron homeostasis, thereby providing a clinically translatable platform for periodontal bone regeneration.