Periosteum-bone inspired hierarchical scaffold with endogenous piezoelectricity for neuro-vascularized bone regeneration

The development of scaffolds for repairing critical-sized bone defects heavily relies on establishing a neuro-vascularized network for proper penetration of nerves and blood vessels. Despite significant advancements in using artificial bone-like scaffolds infused with various agents, challenges remain. Natural bone tissue consists of a porous bone matrix surrounded by a neuro-vascularized periosteum, with unique piezoelectric properties essential for bone growth. Drawing inspiration from this assembly, we developed a periosteum-bone-mimicking bilayer scaffold with piezoelectric properties for regeneration of critical-sized bone defects. The periosteum-like layer of this scaffold features a double network hydrogel composed of chelated alginate, gelatin methacrylate, and sintered whitlockite nanoparticles, emulating the viscoelastic and piezoelectric properties of the natural periosteum. The bone-like layer is composed of a porous structure of chitosan and bioactive hydroxyapatite created through a biomineralization process. Unlike conventional bone-like scaffolds, this bioinspired bilayer scaffold significantly enhances osteogenesis, angiogenesis, and neurogenesis combined with low-intensity pulsed ultrasound-assisted piezoelectric stimulation. Such a scheme enhances neuro-vascularized bone regeneration in vivo . The results suggest that the bilayer scaffold could serve as an effective self-powered electrical stimulator to expedite bone regeneration under dynamic physical stimulation. Inadequate neuro-vascularization presents a significant hurdle in treating critical-sized bone defects. The periosteum, acknowledged for its distinct piezoelectric nature and abundant neuro-vascular networks, is integral to osteogenesis. Inspired by natural bone tissue, we introduce a novel bone implant emulating periosteum-bone architecture and integrating unique piezoelectric properties. This innovative strategy targets neuro-vascularized bone regeneration. • A novel bone scaffold is prepared by emulating periosteum-bone features. • The viscoelastic and piezoelectricity of the periosteum-bone interface are well emulated. • Bone-like layer is of 3D porous structure and in-situ biomineralized hydroxyapatite. • Boosting osteogenesis by piezoelectricity and Mg 2+ of the periosteum-mimicking hydrogel. • The bioinspired scaffold enhanced neuro-vascularized bone regeneration.