Cellulose-engineered janus periosteum with compartmentalized angiogenic and osteo-immunomodulatory abilities for bone regeneration

Bone regeneration is clinically challenging because vascularization, osteo-induction, and immune modulation are difficult to synchronize. Inspired by the native periosteum's bilayer architecture and multifunctional roles, we developed a wood-engineered Janus periosteum (EW-P-D@HACA-T) that integrates deferoxamine (DFO)-functionalized elastic wood (EW-P-D) with a bio-adhesive catechol-modified hyaluronic acid/tricalcium phosphate hydrogel (HACA-T). This construct mimics the anisotropic structure and compartmentalized functions of natural periosteum, providing dual support for angiogenesis and osteo-immunomodulation. EW-P-D maintains mechanical integrity and guides cell orientation, while sustained release activates the HIF-1α/VEGF pathway to enhance endothelial maturation and bone formation. Concurrently, the HACA-T composite hydrogel promotes osteogenic differentiation and polarizes macrophages toward an M2 phenotype, creating a pro-regenerative immune microenvironment. Furthermore, transcriptomic profiling revealed coordinated activation of p53, TGF-β, and ECM remodeling pathways, highlighting the scaffold's capacity to orchestrate tissue regeneration at the molecular level. In vivo evaluation using a rat skull defect model confirmed superior bone bridging, collagen deposition, neovascularization, and systemic biosafety. This study presents a structurally and functionally integrated wood-engineered periosteum substitute, demonstrating a paradigm shift toward engineered solutions that synchronize mechanical, angiogenic, and immunomodulatory cues for bone defect repair.