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.

Doping bioactive elements into a collagen scaffold based on synchronous self-assembly/mineralization for bone tissue engineering

Pure collagen is biocompatible but lacks inherent osteoinductive,osteoimmunomodulatory and antibacterial activities.To obtain collagen with these characteristics,we developed a novel methodology of doping bioactive elements into collagen through the synchronous self-assembly/mineralization(SSM)of collagen.In the SSM model,amorphous mineral nanoparticles(AMN)(amorphous SrCO3,amorphous Ag3PO4,etc.)stabilized by the polyampholyte,carboxymethyl chitosan(CMC),and collagen molecules were the primary components under acidic conditions.As the pH gradually increased,intrafibrillar mineralization occurred via the self-adaptive interaction between the AMNs and the collagen microfibrils,which were self-assembling;the AMNs wrapped around the microfibrils became situated in the gap zones of collagen and finally transformed into crystals.Srdoped collagen scaffolds(Sr-CS)promoted in vitro cell proliferation and osteogenic differentiation of rat bone marrow mesenchymal stromal cells(rBMSCs)and synergistically improved osteogenesis of rBMSCs by altering the macrophage response.Ag-doped collagen scaffolds(Ag-CS)exhibited in vitro antibacterial effects on S.aureus,as well as cell/tissue compatibility.Moreover,Sr-CS implanted into the calvarial defect of a rat resulted in improved bone regeneration.Therefore,the SSM model is a de novo synthetic strategy for doping bioactive elements into collagen,and can be used to fabricate multifunctional collagen scaffolds to meet the clinical challenges of encouraging osteogenesis,boosting the immune response and fighting severe infection in bone defects.