CN110042392A - 一种医用植入体表面兼具优良生物相容性和抗菌性复合涂层的制备方法 - Google Patents

一种医用植入体表面兼具优良生物相容性和抗菌性复合涂层的制备方法 Download PDF

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CN110042392A
CN110042392A CN201910359956.3A CN201910359956A CN110042392A CN 110042392 A CN110042392 A CN 110042392A CN 201910359956 A CN201910359956 A CN 201910359956A CN 110042392 A CN110042392 A CN 110042392A
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medical implant
composite coating
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polylysine
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林昌健
胡洁洁
张艳梅
胡仁
杨云
樊丽丽
段红平
董骧
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Beijing Naton Technology Group Co Ltd
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Xiamen University
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Abstract

一种医用植入体表面兼具优良生物相容性和抗菌性复合涂层的制备方法,涉及医用植入体。将待处理的医用植入体预处理;将预处理后的医用植入体置于混合酸溶液中刻蚀;配制含ε‑聚赖氨酸的钙磷沉积液,在医用植入体表面构筑磷酸八钙与ε‑聚赖氨酸复合涂层,得医用植入体表面兼具优良生物相容性和抗菌性复合涂层。将ε‑聚赖氨酸引入磷酸八钙膜层的构筑过程中,可优化磷酸八钙膜层表面形貌,以利于细胞的生长和黏附,从而在保持磷酸八钙膜层优良的生物活性和生物相容性的基础上,显著提高植入体的抗菌性。对于不同的医用植入体,均可直接在其表面构筑磷酸八钙与ε‑聚赖氨酸复合涂层,从而有效增强植入体表面的生物学性能和抗菌性。

Description

一种医用植入体表面兼具优良生物相容性和抗菌性复合涂层 的制备方法
技术领域
本发明涉及医用植入体,尤其是涉及一种医用植入体表面兼具优良生物相容性和抗菌性复合涂层的制备方法。
背景技术
随着生物技术领域的迅速发展,医用植入体已被广泛地应用于人工关节、骨板骨钉、血管支架以及人体软、硬组织修复体、人工器官等方面。医用种植体不仅需要有良好的力学性能和物理化学性质,还必须有优良的生物活性。磷酸八钙作为人体硬组织的重要组成成分,具有良好的生物活性和生物相容性。而且,磷酸八钙是形成磷灰石的前体,在正常生理环境下可自发转化为磷灰石,与骨组织结合,从而显著提高医用植入体的生物活性。但大量的临床研究发现,植入材料表面的细菌感染是导致种植体松动和种植失败的重要原因之一。曹亚洲等人(曹亚洲,程伟,胡勤刚.钛表面RGD/仿生磷酸钙复合涂层对MC3T3-E1细胞黏附,增殖,分化的影响[J].口腔医学研究,2017,33(7):693-697.)利用两步浸泡法在钛表面构筑了RGD/仿生磷酸钙复合涂层,研究表明该复合涂层具有良好的促进成骨细胞增殖分化的能力,但该涂层缺乏抗菌性。郭誉等人(郭誉,刘咏,谭彦妮,等.放电等离子烧结钛基磷酸三钙陶瓷复合材料的力学性能与生物活性[J].粉末冶金材料科学与工程,2017(04):576-584.)采用放电等离子烧结法可获得抗压强度高、生物活性优良的钛基磷酸三钙复合材料,这种技术升温速度快,生产效率高,但复合涂层并没有抗菌性能,不能抑制细菌的黏附。还有研究(胡燕,彭冰清,赵书云,等.载银羟基磷灰石的制备及抗菌性能[J].北京师范大学学报(自然科学版),2007,43(2):163-165.)结合多种技术在钛基表面制备了载银羟基磷灰石复合涂层,操作过程比较复杂繁琐,成本高,效率低,尽管银的抗菌效果显著,但是银的细胞毒性和生物相容性以及纳米银的杀菌机制仍然还存在很大争议。因此,如何即能保持生物相容性,又同时提高医用植入体的抗菌性能是当前一项重大课题。
ε-聚赖氨酸是一种亲水性的阳离子抗菌肽,通常是由25到35个相同的赖氨酸残基组成,具有抗菌谱广包括酵母菌、真菌、革兰氏阳性和革兰氏阴性细菌,水溶性好、安全性高、热稳定性和自然免疫力强等特点而广泛用于食品和药品领域。此外,ε-聚赖氨酸对正常细胞几乎没有毒性,不仅不影响正常细胞的结构,而且在生理环境中可生物降解为人体必需氨基酸--赖氨酸,对环境没有副作用。ε-聚赖氨酸富含阳离子,与带有阴离子的物质有强的静电作用力并且对生物膜有良好的穿透力,可用于某些药物的载体,因此在医疗和制药方面得到广泛应用。
发明内容
本发明的目的是提供既可保持优异的生物活性和相容性,又可显著提高植入体表面抗菌性,主要应用于人工关节、牙种植体等的一种医用植入体表面兼具优良生物相容性和抗菌性复合涂层的制备方法。
本发明包括以下步骤:
1)将待处理的医用植入体预处理;
在步骤1)中,所述医用植入体包括钛、钛合金、钽合金、不锈钢等;所述预处理是将医用植入体依次浸泡于丙酮、乙醇和去离子水中超声清洗,晾干。
2)将预处理后的医用植入体置于混合酸溶液中刻蚀;
在步骤2)中,所述混合酸溶液可选自HF和HNO3混合酸溶液。
3)配制含ε-聚赖氨酸的钙磷沉积液,在医用植入体表面构筑磷酸八钙与ε-聚赖氨酸复合涂层,得医用植入体表面兼具优良生物相容性和抗菌性复合涂层。
在步骤3)中,所述钙磷沉积液可为Ca(NO3)2和NH4H2PO4混合液;所述磷酸八钙与ε-聚赖氨酸复合涂层采用电化学共沉积法、脉冲电沉积法、自组装沉积法、化学浸泡法中的一种制备;所述电化学共沉积法的制备为:钙磷沉积液按摩尔比含0.05~0.001mol/L Ca(NO3)2和0.05~0.001mol/LNH4H2PO4混合,ε-聚赖氨酸的质量浓度为0~15mg/mL,以待处理基底为工作电极,铂片或石墨棒为对电极,电流密度为0.1~1mA/cm2,水浴锅温度设定为60~80℃,沉积时间为5~10min。
本发明将ε-聚赖氨酸引入磷酸八钙膜层的构筑过程中,可优化磷酸八钙膜层表面形貌,以利于细胞的生长和黏附,从而在保持磷酸八钙膜层优良的生物活性和生物相容性的基础上,显著提高植入体的抗菌性。对于不同的医用植入体,均可直接在其表面构筑磷酸八钙与ε-聚赖氨酸复合涂层,从而有效增强植入体表面的生物学性能和抗菌性。
本发明以钛、钛合金、钽合金、不锈钢等医用植入体为基底,采用电化学共沉积法在待处理基底表面构筑磷酸八钙与ε-聚赖氨酸复合涂层。该复合膜层与纯磷酸八钙膜层相比,显著增强了植入体表面的抗菌性,且不影响原膜层优异的生物活性和生物相容性。该方法可应用于多种医用植入体表面兼具优良生物相容性和抗菌性复合涂层的制备。
本发明以钛、钛合金、钽合金、不锈钢等医用植入体为基底,构筑了磷酸八钙与ε-聚赖氨酸复合涂层,通过选择相应的沉积液配方和反应参数可获得最优的表面形貌,具有如下特征:
在处理后的医用植入体表面通过电化学共沉积法制备的复合涂层表面均匀致密,呈现微孔状,磷酸八钙与ε-聚赖氨酸复合涂层的表面形貌。
本发明通过电化学共沉积法在植入体表面制备磷酸八钙与ε-聚赖氨酸复合涂层,通过细胞增殖实验和抗菌性实验可知,与未添加ε-聚赖氨酸得到的磷酸八钙膜层相比,构筑了磷酸八钙与ε-聚赖氨酸复合膜层的材料表面细胞增殖良好,而且明显提高了医用植入体表面抗菌性能。
本发明可用于所有的钛、钛合金、钽合金、不锈钢等医用植入体的表面改性,如骨钉骨板、牙种植体和人工关节等。本发明也可以应用于医用高分子和医用陶瓷等其他医用植入体的表面多功能化构筑,此时可采用同样的沉积液通过化学浸泡法或表面化学自组装沉积法进行非导体材料的表面构筑。
本发明以钛、钛合金、钽合金、不锈钢等医用植入体为基底,在表面构筑磷酸八钙与ε-聚赖氨酸复合膜层。该膜层与无修饰的磷酸八钙膜层相比,显著增强了植入体表面的抗菌性,且不影响原膜层优异的生物活性和生物相容性,可应用于多种植入体表面的多功能化构筑。除电化学共沉积法外,还可以用其他复合ε-聚赖氨酸的方法如脉冲电沉积法、自组装沉积法、化学浸泡法等。
本发明具有以下突出的技术效果:
1、本发明所构筑的磷酸八钙与ε-聚赖氨酸复合膜层和不添加ε-聚赖氨酸制备的膜层相比,可优化磷酸八钙膜层表面形貌,更适合细胞生长。
2、本发明所构筑的磷酸八钙与ε-聚赖氨酸复合膜层,显著增强了植入体表面的抗菌性,且不影响原膜层优异的生物活性和生物相容性。
3、本发明操作简单、成本低、耗时短、可广泛应用于医用植入体表面改性,可实现批量化生产。
附图说明
图1为本发明实施例1中的电化学共沉积法制备磷酸八钙与ε-聚赖氨酸复合膜层扫描电镜图。
图2为本发明实施例2中的以实施例1中的磷酸八钙与ε-聚赖氨酸复合膜层相同条件下制备的不含ε-聚赖氨酸的磷酸八钙膜层为对比样,用WST-1检测试剂盒测试得到的细胞增殖结果。在图2中,*表示p<0.05(与Ti相比),**表示p<0.05(与OCP相比);a为Ti,b为OCP,c为OCP/εPL10。
图3为本发明实施例3中的以实施例1中的磷酸八钙与ε-聚赖氨酸复合膜层相同条件下制备的不含ε-聚赖氨酸的磷酸八钙膜层为对比样,抗菌性实验的扫描电镜图。
图4为本发明实施例3中的以实施例1中的磷酸八钙与ε-聚赖氨酸复合膜层相同条件下制备的不含ε-聚赖氨酸的磷酸八钙膜层为对比样,抗菌性实验的荧光显微镜图。
具体实施方式
以下实施例将结合附图对本发明作进一步的说明。
实施例1:
电化学共沉积法制备磷酸八钙与ε-聚赖氨酸复合膜层。将纯钛箔剪切为1cm×1cm的大小,依次在丙酮、乙醇和去离子水中超声清洗15min后凉干。配制溶液:HF与HNO3体积比1︰10,预处理后的钛箔浸入混合酸溶液中2min,用去离子水冲洗、晾干。取出后,沉积溶液含10mg/mL的ε-聚赖氨酸、0.014M Ca(NO3)2和0.04M NH4H2PO4,将处理好的钛箔作为阴极,石墨棒为阳极,采用恒电流模式(0.5mA/cm2)在钛箔表面电沉积得到磷酸八钙与ε-聚赖氨酸复合膜层,沉积时间为10min。
图1给出本发明实施例1中的电化学共沉积法制备磷酸八钙与ε-聚赖氨酸复合膜层扫描电镜图。
实施例2:
在纯钛箔表面制备实施例1中的磷酸八钙与ε-聚赖氨酸复合膜层,以相同条件下制备的不含ε-聚赖氨酸的磷酸八钙膜层为对比样用WST-1检测试剂盒进行细胞增殖测试,采用MC3T3-E1细胞,细胞密度2×104/cm2,孵育1天、4天、7天。结果如图2所示,细胞在磷酸八钙与ε-聚赖氨酸复合膜层表面生长黏附良好,具有一定的促进细胞增殖的能力,细胞培养7天时,磷酸八钙与ε-聚赖氨酸复合膜层的细胞增殖速率甚至高于磷酸八钙膜层,表明磷酸八钙与ε-聚赖氨酸复合膜层的生物相容性和生物活性良好。
实施例3:
在纯钛箔表面制备实施例1中的磷酸八钙与ε-聚赖氨酸复合膜层,以相同条件下制备的不含ε-聚赖氨酸的磷酸八钙膜层为对比样利用吖啶橙染色进行抗菌性实验,采用大肠杆菌和金黄色葡萄球菌,培养24h。结果如图3和4所示,由于ε-聚赖氨酸的存在,磷酸八钙与ε-聚赖氨酸复合膜层明显增强了材料表面对大肠杆菌和金黄色葡萄球菌的抑制作用,使得植入体具有强的抗菌性能。
本发明以钛、钛合金、钽合金、不锈钢等医用植入体为基底,在其表面构筑磷酸八钙与ε-聚赖氨酸复合膜层。该复合膜层与磷酸八钙膜层相比,植入体表面既具有很强的广谱抗菌性,同时还拥有良好的生物活性。
本发明提供一种既可保持优异的生物活性和相容性,又可显著提高植入体表面抗菌性,主要应用于人工关节、牙种植体等医用植入体表面兼具优良生物相容性和抗菌性复合涂层的制备方法。将待处理的医用植入体进行预处理,并在混合酸溶液中刻蚀一段时间后,配制含ε-聚赖氨酸的沉积液,在医用植入体表面构筑磷酸八钙与ε-聚赖氨酸复合涂层。由此可显著增强植入体表面的抗菌性。本发明可应用于多种医用植入体表面兼具优良生物相容性和抗菌性复合涂层的制备。具有操作简单、成本低、耗时短、可批量化生产的优点。

Claims (7)

1.一种医用植入体表面兼具优良生物相容性和抗菌性复合涂层的制备方法,其特征在于包括以下步骤:
1)将待处理的医用植入体预处理;
2)将预处理后的医用植入体置于混合酸溶液中刻蚀;
3)配制含ε-聚赖氨酸的钙磷沉积液,在医用植入体表面构筑磷酸八钙与ε-聚赖氨酸复合涂层,得医用植入体表面兼具优良生物相容性和抗菌性复合涂层。
2.如权利要求1所述一种医用植入体表面兼具优良生物相容性和抗菌性复合涂层的制备方法,其特征在于在步骤1)中,所述医用植入体包括钛、钛合金、钽合金、不锈钢。
3.如权利要求1所述一种医用植入体表面兼具优良生物相容性和抗菌性复合涂层的制备方法,其特征在于在步骤1)中,所述预处理是将医用植入体依次浸泡于丙酮、乙醇和去离子水中超声清洗,晾干。
4.如权利要求1所述一种医用植入体表面兼具优良生物相容性和抗菌性复合涂层的制备方法,其特征在于在步骤2)中,所述混合酸溶液选自HF和HNO3混合酸溶液。
5.如权利要求1所述一种医用植入体表面兼具优良生物相容性和抗菌性复合涂层的制备方法,其特征在于在步骤3)中,所述钙磷沉积液为Ca(NO3)2和NH4H2PO4混合液。
6.如权利要求1所述一种医用植入体表面兼具优良生物相容性和抗菌性复合涂层的制备方法,其特征在于在步骤3)中,所述磷酸八钙与ε-聚赖氨酸复合涂层采用电化学共沉积法、脉冲电沉积法、自组装沉积法、化学浸泡法中的一种制备。
7.如权利要求6所述一种医用植入体表面兼具优良生物相容性和抗菌性复合涂层的制备方法,其特征在于所述电化学共沉积法的制备为:钙磷沉积液按摩尔比含0.05~0.001mol/L Ca(NO3)2和0.05~0.001mol/LNH4H2PO4混合,ε-聚赖氨酸的质量浓度为0~15mg/mL,以待处理基底为工作电极,铂片或石墨棒为对电极,电流密度为0.1~1mA/cm2,水浴锅温度设定为60~80℃,沉积时间为5~10min。
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