A biomimetic piezoelectric scaffold with sustained Mg^(2+)release promotes neurogenic and angiogenic differentiation for enhanced bone regeneration

Natural bone is a composite tissue made of organic and inorganic components,showing piezoelectricity.Whitlockite(WH),which is a natural magnesium-containing calcium phosphate,has attracted great attention in bone formation recently due to its unique piezoelectric property after sintering treatment and sustained release of magnesium ion(Mg^(2+)).Herein,a composite scaffold(denoted as PWH scaffold)composed of piezoelectric WH(PWH)and poly(ε-caprolactone)(PCL)was 3D printed to meet the physiological demands for the regeneration of neuro-vascularized bone tissue,namely,providing endogenous electric field at the defect site.The sustained release of Mg^(2+)from the PWH scaffold,displaying multiple biological activities,and thus exhibits a strong synergistic effect with the piezoelectricity on inhibiting osteoclast activation,promoting the neurogenic,angiogenic,and osteogenic differentiation of bone marrow mesenchymal stromal cells(BMSCs)in vitro.In a rat calvarial defect model,this PWH scaffold is remarkably conducive to efficient neo-bone formation with rich neurogenic and angiogenic expressions.Overall,this study presents the first example of biomimetic piezoelectric scaffold with sustained Mg^(2+)release for promoting the regeneration of neuro-vascularized bone tissue in vivo,which offers new insights for regenerative medicine.