A BioLiving Periosteum Evokes Centripetal Regeneration in Challenging Bone Defects

ABSTRACT Large bone defects often exhibit compromised bone healing in the central region. Natural periosteum serves as a bioactive barrier by preventing unwanted fibroblast infiltration and providing regenerative cells. However, a significant gap remains in obtaining desirable central bone healing in large bone defects, and the challenge of achieving a balance between the dense barrier structure and bioactive functionality remains unresolved. Herein, a BioLiving periosteum is engineered to recapitulate key features of native periosteum. The middle mini‐tissue is obtained by the liquid substrate culture (LSC) method, and encapsulated between a fiber‐guiding layer and a recruitment layer, both of which feature topological structures. The LSC method endows endothelial cells (ECs) with an elevated glycolytic activity, facilitating their transition to a type‐H phenotype, which could secrete multiple growth factors (chemical signals) to recruit endogenous cells. Subsequently, the recruited cells are further guided by the radial topological structure (physical signals) to migrate toward the central area. The combination of remote chemical cues and contact physical cues functions in a signaling‐relay manner, effectively promoting bone formation in the central area of the defect. Thus, the BioLiving periosteum triggers centripetal bone regeneration through a physicochemical signaling‐relay mode, representing a promising therapeutic strategy for severe bone defects.