Physiology‐Inspired Multilayer Nanofibrous Membranes Modulating Endogenous Stem Cell Recruitment and Osteo‐Differentiation for Staged Bone Regeneration

Abstract Bone regeneration involves a cascade of sophisticated, multiple‐staged cellular and molecular events, where early‐phase stem cell recruitment mediated by chemokines and late‐phase osteo‐differentiation induced by pro‐osteogenic factors play the crucial roles. Herein, enlightened by a bone physiological and regenerative mechanism, the multilayer nanofibrous membranes (PLLA@SDF‐1 α @MT01) consisting of PLLA/MT01 micro‐sol electrospun nanofibers as intima and PLLA/PEG/SDF‐1 α electrospun nanofibers as adventitia are fabricated through micro‐sol electrospinning and manual multi‐layer stacking technologies. In vitro releasing profiles show that PLLA@SDF‐1 α @MT01 represents the rapid release of stromal cell‐derived SDF‐1 α (SDF‐1 α ) in the outer layers, while with long‐term sustained release of MT01 in the inner layer. Owing to interconnected porosity like the natural bone extracellular matrix and improved hydrophilia, PLLA@SDF‐1 α @MT01 manifests good biocompatibility both in vitro and in vivo. Furthermore, PLLA@SDF‐1 α @MT01 can promote bone marrow mesenchymal stem cells (BMSCs) migration by amplifying the SDF‐1 α /CXCR4 axis and stimulating BMSCs osteo‐differentiation via activating the MAPK pathway in vitro. PLLA@SDF‐1 α @MT01, with a programmed dual‐delivery system, exhibits the synergetic promotion of bone regeneration and vascularization by emulating key characteristics of the staged bone repair in vivo. Overall, PLLA@SDF‐1 α @MT01 that mimics the endogenous cascades of bone regeneration can enrich the physiology‐mimetic staged regenerative strategy and represent a promising tissue‐engineered scaffold for the bone defect.