Abstract
Biomaterials with both excellent osteogenic and angiogenic activities are desirable to repair massive bone defects. In this study, simvastatin with both osteogenic and angiogenic activities was incorporated into the mesoporous hydroxyapatite microspheres (MHMs) synthesized through a microwave-assisted hydrothermal method using fructose 1,6-bisphosphate trisodium salt (FBP) as an organic phosphorous source. The effects of the simvastatin-loaded MHMs (S-MHMs) on the osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs) and angiogenesis in EA.hy926 cells were investigated. The results showed that the S-MHMs not only enhanced the expression of osteogenic markers in rBMSCs but also promoted the migration and tube formation of EA.hy926 cells. Furthermore, the S-MHMs were incorporated into collagen matrix to construct a novel S-MHMs/collagen composite scaffold. With the aid of MHMs, the water-insoluble simvastatin was homogenously incorporated into the hydrophilic collagen matrix and presented a sustained release profile. In vivo experiments showed that the S-MHMs/collagen scaffolds enhanced the bone regeneration and neovascularization simultaneously. These results demonstrated that the water-insoluble simvastatin could be incorporated into the MHMs and maintained its biological activities, more importantly, the S-MHMs/collagen scaffolds fabricated in this study are of immense potential in bone defect repair by enhancing osteogenesis and angiogenesis simultaneously.
Highlights
Statins, inhibitors of the competitive 3-hydroxy-3-methyl coenzyme A (HMG-CoA) reductase, have been widely used to treat hyperlipidemia and hypercholesterolemia
A novel simvastatin-loaded MHMs (S-MHMs)/collagen composite scaffold was constructed by incorporating the S-MHMs into the collagen matrix
With the aid of MHMs, simvastatin was homogenously incorporated into the hydrophilic collagen matrix
Summary
Inhibitors of the competitive 3-hydroxy-3-methyl coenzyme A (HMG-CoA) reductase, have been widely used to treat hyperlipidemia and hypercholesterolemia. Statins have been demonstrated to enhance angiogenesis through up-regulation of gene expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2)[6,9,10] Both VEGF and FGF-2 have been shown to induce BMP-2 expression and stimulate osteoblast differentiation indirectly[11,12]. Similar or superior bone anabolic effects can be expected from lower and sustainable release of statins by a local delivery method. Nanostructured calcium phosphate (CAP) porous microspheres have attracted increasing attention because of their high specific surface area, hierarchical architecture, good biocompatibility and bioactivity[25,26,27]. Nanostructured CAP porous microspheres are promising drug-carriers because of their high specific surface area, excellent biocompatibility and biodegradability. The capacities of the S-MHMs/collagen scaffold to stimulate bone regeneration and neovascularization in vivo were assessed in a rat critical-sized calvarial defect model by micro-computed tomography (micro-CT) measurements and histological assays
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