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Stepwise 3D-spatio-temporal magnesium cationic niche: Nanocomposite scaffold mediated microenvironment for modulating intramembranous ossification

ABSTRACT: The fate of cells and subsequent bone regeneration is highly correlated with temporospatial coordination of chemical, biological, or physical cues within a local tissue microenvironment. Deeper understanding of how mammalian cells react to local tissue microenvironment is paramount important when designing next generation of biomaterials for tissue engineering. This study aims to investigate that the regulation of magnesium cationic (Mg2+) tissue microenvironment is able to convince early-stage bone regeneration and its mechanism undergoes intramembranous ossification. It was discovered that moderate Mg2+ content niche (~4.11 mM) led to superior bone regeneration, while Mg2+-free and strong Mg2+ content (~16.44 mM) discouraged cell adhesion, proliferation and osteogenic differentiation, thereby bone formation was rarely found. When magnesium ions diffused into free Mg zone from concentrated zone in late time point, new bone formation on free Mg zone became significant through intramembranous ossification. This study successfully demonstrates that magnesium cationic microenvironment serves as an effective biochemical cue and is able to modulate the process of bony tissue regeneration. The knowledge of how a Mg2+ cationic microenvironment intertwines with cells and subsequent bone formation gained from this study may provide a new insight to develop the next generation of tissue-repairing biomaterials. Graphical abstract Image 1 Highlights • Regulation of Mg2+ concertation in tissue microenvironment can convince early-stage bone regeneration.• Samples without and with strong Mg2+ microenvironments (16.44 mM) suppressed the osteogenic differentiation.• When Mg2+ diffused into free Mg zone from concentrated zone over time, bone formation over free Mg zone becomes significant.• Bone defect repair through intramembranous ossification was promoted by 3D-scaffold-created moderate Mg2+ microenvironment.

SUBMITTER: Shen J

PROVIDER: S-EPMC7492774 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Project description:BackgroundSimvastatin, a drug for lowering serum cholesterol, has been shown to enhance bone regeneration, but few studies have qualitatively and quantitatively tested its effect when used topically in different animal models. This study aims to investigate topical administration of simvastatin as a bone regeneration inducer by testing its effect on bone formation in both long tubular bone and flat bone defect, and the mechanism involved.MethodsTwo animal models were used for testing the effect of simvastatin on entochondrostosis and intramembranous ossification respectively. Simvastatin of different dosages combined with poly lactic acid were implanted in extreme radial defects of 12 adult male New Zealand rabbits. Bone formation was monitored using x-ray and CT-scan and measured using x-ray scales, pixel values and spiral CT-scan for 16 weeks before being subject to histological and immunohistochemistry examination. The result was compared with that of autograft and blank control groups. Simvastatin with thrombin and fibrin sealant were implanted in calvarial defects of three Rhesus monkeys and monitored for 18 weeks. Bone formation was compared between the simvastatin and the blank control group using spiral CT-scan and histological examination.ResultsBoth visual and quantitative measurements by x-ray and spiral CT-scan indicated significant bone formation in radial defects in all simvastatin groups and the autograft group whereas no bone formation was found in control groups. There was no significant difference in bone formation quantity between 100 mg simvastatin and autograft. Histological and immunohistochemistry examination indicated entochondrostosis in association with positive expression of BMP-2 and HIF-1 alpha. Spiral CT-scan and histological examination of calvarial defects of monkeys showed intramembranous ossification after simvastatin implantation. No change was found in the control group.ConclusionsTopical administration of simvastatin induces entochondrostosis and intramembranous ossification by enhancing expression of BMP-2 and HIF-1 alpha. The effect of simvastatin on bone regeneration is comparable to autograft.The translational potential of this articleTopical administration of simvastatin can repair bone defect in both long tubular bones and flat bones of rabbits and monkeys as effectively as autograft. Given that it is cheap, safe and already in clinical use, simvastatin might be considered as a bone regeneration inducer with great potential.

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Stepwise 3D-spatio-temporal magnesium cationic niche: Nanocomposite scaffold mediated microenvironment for modulating intramembranous ossification

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