Topological Biomimetic Periosteum for Stem Cell-Mediated Vascular Bone Regeneration

Abstract Periosteum plays a pivotal role in bone defect repair. However, the strategies to recapitulate its functions heavily rely on exogenous growth factors or decellularized extracellular matrices, posing significant challenges for clinical application. Inspired by the natural periosteum, a topological biomimetic periosteum (TBP) was fabricated through surface crystallization engineering on electrospun poly(ε-caprolactone) (PCL) fibers. Periodic circular nanolamellae of TBP mimicked the topology of natural collagen. Such hierarchical topographical features significantly enhanced mesenchymal stem cells’ (MSCs) adhesion and spreading while activating the Yes-associated protein (YAP) signaling pathway to promote osteogenic differentiation. Meanwhile, these topographical cues stimulated paracrine signaling in MSCs, increasing the expression of vascular endothelial growth factor (VEGF) secretion and improving subsequent pro-angiogenic effects. In a mouse calvarial defect model, TBP elicited stage-dependent responses during bone healing, promoting endogenous cell recruitment and vascular regeneration at Week 1, followed by enhanced vascularized bone formation at Week 3. By harnessing endogenous cellular mechanisms to achieve balanced osteogenesis and angiogenesis synchronously, our design offers a simple yet physiologically adaptive platform with substantial potential for better bone regeneration.