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

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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‐1α@MT01) consisting of PLLA/MT01 micro‐sol electrospun nanofibers as intima and PLLA/PEG/SDF‐1α electrospun nanofibers as adventitia are fabricated through micro‐sol electrospinning and manual multi‐layer stacking technologies. In vitro releasing profiles show that PLLA@SDF‐1α@MT01 represents the rapid release of stromal cell‐derived SDF‐1α (SDF‐1α) 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‐1α@MT01 manifests good biocompatibility both in vitro and in vivo. Furthermore, PLLA@SDF‐1α@MT01 can promote bone marrow mesenchymal stem cells (BMSCs) migration by amplifying the SDF‐1α/CXCR4 axis and stimulating BMSCs osteo‐differentiation via activating the MAPK pathway in vitro. PLLA@SDF‐1α@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‐1α@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.

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