CN111850552B - 一种协同提高镁合金耐蚀性能和生物相容性的多功能表面改性方法 - Google Patents
一种协同提高镁合金耐蚀性能和生物相容性的多功能表面改性方法 Download PDFInfo
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Abstract
本发明公开了一种协同提高镁合金耐蚀性能和生物相容性的多功能表面改性方法,属于生物材料表面改性领域。首先制备壳聚糖功能化氧化石墨烯,并进一步将壳聚糖功能化氧化石墨烯共价固定在自组装表面改性的镁合金表面,然后制备肝素与骨形态发生蛋白2的混合溶液,最后将制备的混合溶液滴加在表面改性的镁合金表面充分装载,干燥清洗后获得具有良好耐蚀性能和生物相容性的镁合金生物材料。采用本发明的方法对镁合金进行表面改性,不仅可以显著提高镁合金的耐生理腐蚀性能,而且可以缓慢释放肝素和骨形态发生蛋白2,从而协同提高材料的抗凝血性能、促内皮生长性能以及成骨性能。
Description
技术领域
本发明属于生物材料表面改性领域,尤其涉及一种协同提高镁合金耐蚀性能和生物相容性的多功能表面改性方法。
背景技术
随着骨科创伤的增加,可生物降解植入物的发展越来越受到人们的关注。镁及其合金被认为是一种理想的骨植入材料,首先,镁合金的密度和力学性能与天然人骨相似,作为骨替代材料可以有效避免应力遮挡效应的发生;其次,镁可在人体内以Mg2+的形式降解,降解产物可排出体外或被人体吸收,因此,作为一种生物可降解金属,它可以避免二次手术取出,减少患者痛苦和再次感染的风险。虽然镁合金对人体无明显毒性,甚至能在一定程度上促进骨组织的愈合,但其在体内的快速降解通常超过人体生理环境所能承受的极限,大量的氢气和镁离子,以及种植体周围迅速上升的pH值,不仅破坏了承载种植体的机械完整性,而且破坏了体内的生理平衡,导致种植体与人体组织界面发生严重的炎症和毒性反应,最终导致植入失败。
众所周知,镁合金的耐蚀性和生物相容性与其表面性质密切相关,因此表面改性已成为提高镁合金耐蚀性和生物相容性的最为有效的方法之一。目前,人们已经采用了大量的表面改性方法来控制镁合金的耐蚀性和生物活性,这些方法通过在表面形成耐腐蚀的转化层或覆盖层,将基质与腐蚀性的周围环境隔离开来,有效地提高了耐腐蚀性,显著减少了快速降解引起的一系列不良生理反应,从而在一定程度上提高了生物相容性。
然而,现有的关于镁合金表面改性的这些方法改善效果有限,在生理环境中的生物活性和耐蚀性仍低于临床要求。且另一方面的研究表明,骨植入物抗凝血不良会导致血小板粘附和活化,导致植入部位血栓和血液流动不良,甚至局部组织坏死,因此,镁合金用于骨植入材料不仅需要控制其在体内的降解行为,而且要具有良好的成骨和抗凝性能以进一步提高生物相容性和耐蚀性。
发明内容
本发明的目的在于一种协同提高镁合金耐蚀性能和生物相容性的多功能表面改性方法,克服现有技术中的缺陷,有效解决背景技术中提出的问题,使得经过改性的镁合金表面可协同提高材料的抗凝血性能和促成骨性能,从而进一步提高镁合金表面的耐蚀性和生物相容性。
为了达到上述目的,本发明采用了以下技术方案:
一种协同提高镁合金耐蚀性能和生物相容性的多功能表面改性方法,具体制备步骤为:
1)制备壳聚糖功能化氧化石墨烯;
2)对镁合金进行自组装表面改性;
3)将步骤1)制备的壳聚糖功能化氧化石墨烯固定在步骤2)的镁合金表面;
4)镁合金表面装载肝素和骨形态发生蛋白2的复合物。
肝素是一种高度硫酸化的糖胺聚糖和线性天然多糖,被广泛应用于生物材料的表面改性,以改善血液相容性,同时,研究也表明肝素具有选择性促进内皮细胞生长的能力,因此,应用于骨材料时可以促进骨组织周围的血管生成,并有效避免血栓的形成。骨形态发生蛋白2(BMP2)能促进成骨细胞的增殖和分化,同时可以与肝素结合。因此本发明通过在经过壳聚糖功能化氧化石墨烯(GOCS)修饰处理的镁合金表面装载肝素和骨形态发生蛋白2(BMP2),可通过肝素和骨形态发生蛋白2(BMP2)的缓慢释放协同提高镁合金的抗凝血性能、促内皮细胞生长性能以及促成骨性能。
本发明的进一步改进方案是,所述步骤1)中,壳聚糖功能化氧化石墨烯的制备方法为:充分混合石墨烯溶液与壳聚糖溶液后加入1-(3-二甲氨基丙基)-3-乙基-碳二亚胺和N-羟基琥珀酰亚胺的混合溶液,搅拌反应6-24小时,最后反复离心水洗获得壳聚糖功能化氧化石墨烯。
本发明的进一步改进方案是,所述石墨烯溶液浓度为0.1-1 mg/ml,所述壳聚糖溶液浓度为1-10mg/ml,加入的所述1-(3-二甲氨基丙基)-3-乙基-碳二亚胺和N-羟基琥珀酰亚胺的混合溶液为1-10mmol/L。
本发明的进一步改进方案是,所述步骤2)中,镁合金自组装表面改性方法为:镁合金浸没于1-10mol/L的氢氧化钠溶液处理6-24小时,接着将处理得到的镁合金浸没于16-膦酰基十六烷酸的溶液中自组装反应6-24小时,最后把浸没过的镁合金取出清洗后120℃处理12小时。
本发明的进一步改进方案是,所述步骤3)中,镁合金表面共价固定壳聚糖功能化氧化石墨烯的方法为:将所述步骤2)获得的镁合金材料浸没到1-10mmol/L的1-(3-二甲氨基丙基)-3-乙基-碳二亚胺和N-羟基琥珀酰亚胺的混合溶液中振荡反应1-4小时,清洗干燥后浸没到1-10mg/ml的壳聚糖功能化氧化石墨烯溶液中继续振荡反应1-4小时,最后清洗干燥后获得表面共价固定了壳聚糖功能化氧化石墨烯的镁合金材料。
本发明的进一步改进方案是,所述步骤4)中,将肝素溶液与骨形态发生蛋白2溶液充分混合,然后滴加到步骤(3)获得的镁合金材料表面,充分吸附装载4-24小时,最后清洗干燥获得表面具有多功能特性的镁合金生物材料。
本发明的进一步改进方案是,所述肝素溶液与所述骨形成发生蛋白2溶液的混合比例为1:1,其中所述肝素溶液浓度采用1-10mg/ml,所述骨形态发生蛋白2溶液的浓度为50-200 ng/ml 。
本发明与现有技术相比,所带来的有益效果有:
(1)肝素是一种高度硫酸化的糖胺聚糖和线性天然多糖,被广泛应用于生物材料的表面改性,以改善血液相容性,同时,研究也表明肝素具有选择性促进内皮细胞生长的能力,因此,应用于骨材料时可以促进骨组织周围的血管生成,并有效避免血栓的形成。骨形态发生蛋白2(BMP2)能促进成骨细胞的增殖和分化,同时可以与肝素结合。因此本发明通过在经过壳聚糖功能化氧化石墨烯(GOCS)修饰处理的镁合金表面装载肝素和骨形态发生蛋白2(BMP2),可通过肝素和骨形态发生蛋白2(BMP2)的缓慢释放协同提高镁合金的抗凝血性能、促内皮细胞生长性能以及促成骨性能。
(2)碱热处理的镁合金表面已经具有一定的耐生理腐蚀性能,通过在镁合金自组装表面改性的基础上共价固定壳聚糖功能化氧化石墨烯(GOCS),不仅可以进一步提高镁合金的耐蚀性能,还能为装载生物活性分子提供良好的平台,并且,GOCS本身也具有良好的生物相容性,可以在一定程度上促进成骨细胞的粘附、增殖和分化。
(3)氧化石墨烯(GO)的芳环结构可以通过非共价相互作用增加对细胞外基质蛋白的吸附,且其表面富含的化学基团可与其它生物活性物质连接,实现多功能改性,而壳聚糖具有生物降解性、良好的生物相容性、抗菌活性等多种生理活性,可进一步提高氧化石墨烯(GO)的生物活性,经过壳聚糖改性后的壳聚糖功能化氧化石墨烯(GOCS)固定在镁合金表面也可以进一步增强镁合金的耐蚀能力。
(4)肝素和骨形态发生蛋白2(BMP2)与表面非共价结合,不影响生物活性分子的生物活性,可以更好地发挥生物分子的生理活性。同时,氧化石墨烯巨大的比面积以及正电荷特性,可以大大增加肝素与骨形态发生蛋白2的装载量,从而可以更加长时间地提高材料的生物相容性。
附图说明
图1为本发明镁合金表面改性方法协同提高材料耐蚀性能和生物相容性的机理示意图
图2为本发明不同表面改性样品的典型扫描电镜照片
图中:(a)Mg;
(b) Mg-OH(NaOH处理的样品);
(c) Mg-16(自组装16-膦酰基十六烷酸的样品);
(d) Mg-GOCS(表面固定壳聚糖功能化氧化石墨烯的样品);
(e) Mg-Hep/BMP2(表面装载肝素和骨形态发生蛋白2的样品)
图3为图2中不同镁合金表面的水接触角测量数据柱状图
图4为肝素和骨形态发生蛋白2的释放行为曲线图
图5为图2五个样品的动电位极化曲线(a)和电化学阻抗谱(b)图
图6为图2五个样品表面典型的血小板粘附电镜照片和相关情况图
图中: (a)五个样品表面典型的血小板粘附电镜照片
(b)五个样品表面典型的血小板粘附数量
(c)五个样品表面典型的血小板激活环磷鸟苷酸的释放浓度
(d)五个样品表面典型的溶血率
图7为本发明成骨细胞相关情况柱状图
图中:(a)成骨细胞培养1天和3天的增殖情况
(b)成骨细胞ALP 的表达情况
(c)成骨细胞OCN的表达情况
(d)矿化行为。
具体实施方式
下面结合附图和具体实施方式,进一步阐明本发明,应理解下述具体实施方式仅用于说明本发明而不用于限制本发明的范围,在阅读了本发明之后,本领域技术人员对发明的各种等价形式的修改均落于本申请所附权利要求所限定的范围。
为使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解,下面结合具体实施方式,进一步阐述本发明。
实施例:
如图1可知,本发明提供一种协同提高镁合金耐蚀性能和生物相容性的多功能表面改性方法,其具体制备步骤为:
1)制备壳聚糖功能化氧化石墨烯;
2)对镁合金进行自组装表面改性;
3)将步骤1)制备的壳聚糖功能化氧化石墨烯固定在步骤2)的镁合金表面;
4)镁合金表面装载肝素和骨形态发生蛋白2的复合物。
氧化石墨烯(GO)具有丰富的羧基,在电解质溶液中具有带负电荷的特性,可以阻止阴离子吸附,因此氧化石墨烯(GO)可用于镁合金的表面改性,以提高镁合金的耐蚀性和生物相容性。同时,氧化石墨烯(GO)的芳环结构可以通过非共价相互作用增加对细胞外基质蛋白的吸附,从而影响细胞的黏附、生长、增殖和分化。此外,氧化石墨烯(GO)表面富含的羟基、羧基、环氧基等化学基团可与其它生物活性物质连接,实现多功能改性。此外,其巨大的比表面积也为负载生物活性分子和药物增强生物活性提供了极好的平台。壳聚糖具有生物降解性、良好的生物相容性、抗菌活性等多种生理活性,因此,壳聚糖可以进一步提高氧化石墨烯(GO)的生物活性。同时,壳聚糖固定在镁合金表面也可以增强镁合金的耐蚀能力。因此,表面固定壳聚糖功能化氧化石墨烯(GOCS)不仅可以提高镁合金表面的耐蚀性和生物相容性,而且为生物活性物质的负载提供了一个很好的平台。
肝素是一种高度硫酸化的糖胺聚糖和线性天然多糖,被广泛应用于生物材料的表面改性,以改善血液相容性,同时,研究也表明肝素具有选择性促进内皮细胞生长的能力,因此,应用于骨材料时可以促进骨组织周围的血管生成。骨形态发生蛋白2(BMP2)能促进成骨细胞的增殖和分化,同时可以与肝素结合。因此本发明通过在经过壳聚糖功能化氧化石墨烯(GOCS)修饰处理的镁合金表面装载肝素和骨形态发生蛋白2(BMP2),可通过肝素和骨形态发生蛋白2(BMP2)的缓慢释放协同提高镁合金的抗凝血性能、促内皮细胞生长性能以及促成骨性能。
所述步骤1)中,壳聚糖功能化氧化石墨烯的制备方法为:
1.1)充分混合0.1-1 mg/ml的石墨烯溶液与1-10mg/ml的壳聚糖溶液;
1.2)加入1-10mmol/L的1-(3-二甲氨基丙基)-3-乙基-碳二亚胺和N-羟基琥珀酰亚胺的混合溶液,搅拌反应6-24小时;
1.3)然后反复离心水洗获得壳聚糖功能化氧化石墨烯。
从图2 的结果看来,经过表面改性后镁合金表面形成了连续完整且致密的改性层,且根据图3可知表面改性后镁合金的亲水性显著增加。
根据图4可知肝素和骨形态发生蛋白2的持续释放超过了14天。
根据图5至图7可以看出,表面改性显著提升了镁合金材料的腐蚀电位,减小了腐蚀电流,并且增加了极化电阻,因此,显著提升了镁合金的耐蚀性能。表面改性的镁合金表面细胞不仅具有良好的增殖行为,而且可以显著促进碱性磷酸酶(ALP)和骨钙素(OCN)的上调表达,促进成骨细胞矿化,表明材料良好的成骨性能。
所述步骤2)中,镁合金自组装表面改性方法为:
2.1)镁合金浸没于1-10mol/L的氢氧化钠溶液处理6-24小时;
2.2)将处理得到的镁合金浸没于16-膦酰基十六烷酸的溶液中自组装反应6-24小时;
2.3)浸没过的镁合金取出清洗后120℃处理12小时。
所述步骤3)中,镁合金表面共价固定壳聚糖功能化氧化石墨烯的方法为:
3.1)将所述步骤2)获得的镁合金材料浸没到1-10mmol/L的1-(3-二甲氨基丙基)-3-乙基-碳二亚胺和N-羟基琥珀酰亚胺的混合溶液中振荡反应1-4小时;
3.2)清洗干燥后浸没到1-10mg/ml的壳聚糖功能化氧化石墨烯溶液中继续振荡反应1-4小时;
3.3)清洗干燥后获得表面共价固定了壳聚糖功能化氧化石墨烯的镁合金材料。
所述步骤4)中,镁合金自组装表面改性方法为:
4.1)将1-10mg/ml的肝素溶液与 50-200 ng/ml 的骨形态发生蛋白2溶液按照1:1的比例充分混合;
4.2)然后滴加到步骤(3)获得镁合金材料表面,充分吸附装载4-24小时;
4.3)最后清洗干燥获得表面具有多功能特性的镁合金生物材料。
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明精神和范围的前提下,本发明还会有各种变化和改进,这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (4)
1.一种协同提高镁合金耐蚀性能和生物相容性的多功能表面改性方法,其特征在于:具体制备步骤为:
1)制备壳聚糖功能化氧化石墨烯;
2)对镁合金进行自组装表面改性;
3)将步骤1)制备的壳聚糖功能化氧化石墨烯固定在步骤2)的镁合金表面;
4)镁合金表面装载肝素和骨形态发生蛋白2的复合物,
所述步骤2)中,镁合金自组装表面改性方法为:镁合金浸没于1-10mol/L的氢氧化钠溶液处理6-24小时,接着将处理得到的镁合金浸没于16-膦酰基十六烷酸的溶液中自组装反应6-24小时,最后把浸没过的镁合金取出清洗后120℃处理12小时,
所述步骤4)中,将肝素溶液与骨形态发生蛋白2溶液充分混合,然后滴加到步骤(3)获得的镁合金材料表面,充分吸附装载4-24小时,最后清洗干燥获得表面具有多功能特性的镁合金生物材料,
所述肝素溶液与所述骨形态发生蛋白2溶液的混合比例为1:1,其中所述肝素溶液浓度为1-10mg/ml,所述骨形态发生蛋白2溶液的浓度为50-200 ng/ml。
2.根据权利要求1所述的一种协同提高镁合金耐蚀性能和生物相容性的多功能表面改性方法,其特征在于:所述步骤1)中,壳聚糖功能化氧化石墨烯的制备方法为:充分混合石墨烯溶液与壳聚糖溶液后加入1-(3-二甲氨基丙基)-3-乙基-碳二亚胺和N-羟基琥珀酰亚胺的混合溶液,搅拌反应6-24小时,最后反复离心水洗获得壳聚糖功能化氧化石墨烯。
3.根据权利要求2所述的一种协同提高镁合金耐蚀性能和生物相容性的多功能表面改性方法,其特征在于:所述石墨烯溶液浓度为0.1-1 mg/ml,所述壳聚糖溶液浓度为1-10mg/ml,加入的所述1-(3-二甲氨基丙基)-3-乙基和N-羟基琥珀酰亚胺的混合溶液为1-10mmol/L。
4.根据权利要求1所述的一种协同提高镁合金耐蚀性能和生物相容性的多功能表面改性方法,其特征在于:所述步骤3)中,镁合金表面共价固定壳聚糖功能化氧化石墨烯的方法为:将所述步骤2)获得的镁合金材料浸没到1-10mmol/L的1-(3-二甲氨基丙基)-3-乙基碳二亚胺和N-羟基琥珀酰亚胺的混合溶液中振荡反应1-4小时,清洗干燥后浸没到1-10mg/ml的壳聚糖功能化氧化石墨烯溶液中继续振荡反应1-4小时,最后清洗干燥后获得表面共价固定了壳聚糖功能化氧化石墨烯的镁合金材料。
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