New Materials Group, Applied Physics Dpt, IISGS, University of Vigo, Spain.
Biomed Mater. 2018 Feb 2;13(2):025017. doi: 10.1088/1748-605X/aa95f1.
The use of statins in the field of bone regeneration is under current investigation due to the existing demand for non-toxic anabolic agents capable of enhancing bone formation in cases of substantial loss. Simvastatin, a coenzyme currently prescribed in clinics to inhibit cholesterol biosynthesis, has been proven to promote osteogenic differentiation by stimulating bone formation and inhibiting osteoclasts activity. We present the loading of simvastatin in mesoporous TiO thin films toward combining the pro-osteogenic properties of this molecule with the demonstrated bioactivity of titania. TiO thin films processing and characterization were carried out, as well as evaluation of MC3T3-E1 pre-osteoblasts viability when directly incubated with different concentrations of simvastatin, followed by the analysis of osteogenic activity promoted by simvastatin upon loading in the thin films. The accessible porosity of 36% quantified on the 95 ± 5 nm thick mesoporous thin films, together with pore diameters of 5.5 nm, necks between pores of 2.8 nm and interpore distances of 12 ± 2 nm allow the loading of the simvastatin molecule, as confirmed by FTIR spectroscopy. Simvastatin was found to promote MC3T3-E1 pre-osteoblasts viability at concentrations ≤0.01 g l, with a cytotoxicity threshold of 0.05 g l. We additionally found that film loadings with 0.001 g l simvastatin promotes statistically higher MC3T3-E1 pre-osteoblast proliferation whereas a higher concentration of 0.01 g l leads to statistically higher osteogenic activity (ALP synthesis), after 21 days of incubation, as compared to unloaded films. These results demonstrate the potential of simvastatin local administration based on bioactive mesoporous thin films to promote pro-osteogenic properties. By focusing this strategy on the coating of metallic prostheses, the supply of simvastatin to the target tissue can be favored and risks of systemic side effects will be reduced while enhancing the osteointegration of the implants.
由于需要寻找非毒性的促合成代谢药物来增强实质性骨丢失部位的骨形成，他汀类药物在骨再生领域的应用目前正在研究中。辛伐他汀是一种目前在临床上用于抑制胆固醇生物合成的辅酶，已被证明通过刺激骨形成和抑制破骨细胞活性来促进成骨细胞分化。我们将辛伐他汀载入介孔 TiO 薄膜中，旨在将该分子的促成骨特性与已证明的 TiO 生物活性结合起来。我们进行了 TiO 薄膜的处理和特性评估，以及直接用不同浓度的辛伐他汀孵育 MC3T3-E1 前成骨细胞时细胞活力的评估，随后分析了载入薄膜后辛伐他汀促进的成骨活性。95±5nm 厚的介孔薄膜的可及孔隙率为 36%，孔径为 5.5nm，孔之间的颈宽为 2.8nm，孔间距离为 12±2nm，这使得辛伐他汀分子能够载入其中，这一点通过傅里叶变换红外光谱得到了证实。FTIR 光谱证实，辛伐他汀在浓度≤0.01g/L 时可促进 MC3T3-E1 前成骨细胞的活力，其细胞毒性阈值为 0.05g/L。我们还发现，与未载入薄膜相比，载有 0.001g/L 辛伐他汀的薄膜在孵育 21 天后可显著促进 MC3T3-E1 前成骨细胞的增殖，而浓度较高的 0.01g/L 则可显著提高成骨活性（碱性磷酸酶合成）。这些结果表明，基于生物活性介孔薄膜的局部辛伐他汀给药具有促进成骨特性的潜力。通过将该策略集中在金属假体的涂层上，可以促进辛伐他汀向靶组织的供应，同时降低系统副作用的风险，增强植入物的骨整合。
