Reconstructing the Periosteal Niche with Regenerated Cellulose Nanofibers for Endogenous Bone Regeneration

Large bone defects remain difficult to treat because current bone substitutes largely restore mechanical integrity without reconstructing the periosteal microenvironment that orchestrates endogenous bone regeneration. Here, we developed a periosteum-inspired composite scaffold by integrating a regenerated cellulose nanofibrous membrane onto a compressed hydroxyapatite scaffold to simultaneously mimic the biological interface and mineralized framework of native bone. A cellulose acetate electrospun membrane was converted into regenerated cellulose through deacetylation while preserving its extracellular matrix-like fibrous architecture, providing a hydrophilic surface favorable for cell-material interactions. The periosteum-mimetic membrane supported cell attachment and increased cellular metabolic activity, demonstrating its ability to establish a regenerative microenvironment at the scaffold surface. In a critical-sized femoral defect model in SD rats, the composite scaffold markedly enhanced bone regeneration compared with the hydroxyapatite scaffold alone, leading to substantially increased newly formed bone area. Histological analysis further revealed elevated expression of the osteogenic transcription factor Osterix, indicating enhanced osteogenic commitment during bone repair. Rather than functioning solely as a structural covering, incorporation of the engineered periosteal membrane provided a cell-supportive interface associated with enhanced bone regeneration. This biomimetic strategy demonstrates that reconstructing periosteal function represents an effective approach for designing next-generation bone grafts with enhanced biological performance and regenerative capacity.