CN108904893B - 一种兼具抗菌和生物相容性的复合涂层及其制备方法和应用 - Google Patents
一种兼具抗菌和生物相容性的复合涂层及其制备方法和应用 Download PDFInfo
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- CN108904893B CN108904893B CN201810818873.1A CN201810818873A CN108904893B CN 108904893 B CN108904893 B CN 108904893B CN 201810818873 A CN201810818873 A CN 201810818873A CN 108904893 B CN108904893 B CN 108904893B
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Abstract
本发明提供了一种兼具抗菌和生物相容性的复合涂层,所述复合涂层包括抗菌涂层和生物相容性涂层,所述抗菌涂层的厚度为2‑1000nm,所述生物相容性涂层的厚度为2‑500nm。通过抗菌涂层和生物相容性涂层复合的方式,延长涂层使用寿命,工艺简单可连续进行大面积快速制备,抗菌效果更佳,使得抗菌元素释放速度适中,生物相容性涂层在所述条件下不影响抗菌元素的释放与抗菌性能的发挥,是植入性医疗器械的理想涂层。
Description
技术领域
本发明属于医疗设备领域,涉及一种兼具抗菌和生物相容性的复合涂层及其制备方法和应用。
背景技术
植入性医疗器械是通过外科手段达到下列目的的器械:全部或者部分***人体或腔道(口)中;为替代上表皮或眼表面用的,并在体内至少存留30天,且只能通过外科或内科手段取出。如:骨钉、骨板、人工器官、心脏支架、人工关节、心脏起搏器等。
植入器械要求一定是无菌的,在包装和植入过程中也是在无菌的环境下进行,尽管在植入过程手术切口闭合前还会直接采用消毒剂或抗菌剂,在手术后也会口服抗菌药物预防感染的发生,但是在临床上仍然有高达2%的感染发生率,一旦发生感染,不仅增加病人的痛苦,还会增加家属的经济负担,紧急情况还可能危及病人生命,且一旦在植入器械表面形成细菌膜,即使使用抗生素也很难将细菌全部消灭,治疗效果并不明显,因此在植入初期就应当避免感染的发生。
局部药物缓释是最有效避免感染的方法,一方面减少药物用量,避免药物对其他组织的药物毒性;另一方面提高药物效率,将特定药物固定在特定部位,可以持续释放,避免持续进药的麻烦及药物暴释的毒副作用;因此药物缓释在医疗器械领域受到广大研发者的关注。钛及其合金是广泛应用的医疗器械,例如常见的钛种植体(如骨、牙齿、关节或其他软组织植入物的部分零件)以及一些有源植入式医疗器械(包括心脏起搏器、心脏复律除颤器、神经刺激仪、脊髓电刺激器、心脏再同步治疗除颤器、心脏再同步治疗起搏器等)。如果能对这部分器械表面进行抗菌处理,使得植入器件在植入后自身能起到抗菌作用,就可以使手术感染概率降低,进而减少治疗成本以及患者痛苦。
目前对钛及其合金表面进行抗菌修饰的方法有以下几种,首先进行表面处理,例如机械法(车削、喷砂、激光直写)、化学处理(酸、碱刻蚀)、热处理、或离子刻蚀使得表面更容易和活性物质结合;然后将处理好的钛及钛合金表面浸泡在含药物的溶液中,使得药物或者含有药物的载体接枝到材料表面。而对有源植入器械来说,其具有结构复杂、形状不规则、组成材料多等特点,对其表面进行抗菌涂层修饰时只能采用温和的表面处理和涂层方法,以免对其重要结构单元和功能的破坏。因此在上述的表面处理方法中,喷砂及机械法等对医疗器械本身造成破坏,不适用于有源植入式医疗器械或不能再进行结构加工的植入器械;酸碱处理尽管可以改善金属表面的活性,但也不适合用于成型的有源植入器械。
现有技术中,在针对医疗器械设备进行抗菌涂层制备时,提供组合物抑制医疗器械设备表面上微生物的生长方法,抗菌剂是能够在一定时间内杀死或者抑制微生物活性的各种制剂,主要分为有机抗菌剂、无机抗菌剂和复合抗菌剂。有机抗菌剂包括天然的和合成的两种,如酰基苯胺类、咪唑类、季铵盐类等,具有杀菌能力强。加工方便和种类多等特点。但有机抗菌剂往往耐热性差、容易分解、不耐洗涤、抗菌性持久性差;此外抗菌剂在溶剂存在的环境下析出,产生耐药性、化学稳定性差和分解产物毒性高等缺陷。如三氯生在光照下容易分解为类似于二噁英的物质,对人体具有潜在的毒性。相比而言无机抗菌剂具有缓释长效性、高耐热性、低耐药性、广谱性、较高的安全性和易加性等优点。无机微纳米抗菌材料对单细胞生物(细菌、真菌)杀伤力较强而对对细胞生物毒性较小。因而成为替代有机抗菌剂的理想选择,已开始在医疗器械、陶瓷洁具、塑料、纺织品及建材等领域广泛使用。
人体骨组织中无机盐的主要成分为羟基磷灰石(HA),主要是Ca、P元素HA等离子喷涂形成的多孔涂层,大大增加种植体和骨接触面积,可以诱导骨组织的形成并达到生物化学性结合,能够改善植入体的表面生物活性。实验证实,HA涂层能激活成骨细胞的增殖和表达。铌(Nb)、锆(Zr)、钽(Ta)具有良好的生物相容性,细胞毒性为零级,与纯钛接近,且更为优秀的耐腐蚀性能和无溶血性。实验证实,Ta对小鼠成骨细胞的粘附、增殖和分化有明显的促进作用,Ta制人工骨小梁、颅骨修复体等已经在临床中获得成功。
传统的抗菌方式材料生产方法,在生产过程中添加具有抗菌作用的金属元素(如Ag、Cu),在通过热处理使材料本身产生抗菌性;但该方式由于抗菌元素的加入改变了金属原有的特性,例如弹性模量等,同时也增加了成本,此外抗菌成分“深埋”于材料内部,使得抗菌效果得不到充分发挥。
离子注入法具有很好的抗菌效果,但是诸如抗菌元素Zn富集在材料表面,能够促进细胞增殖分化,但是对细胞的作用主要表现在材料相互作用的后期,细胞早期与材料之间的相互作用较差,同时其他抗菌元素Cu、Ag、F直接与细胞接触同样也影响细胞的粘附及增殖,同时具有一定的杀菌效果时对细胞也有一定的毒性。
CN102525827A公开了一种通过阳极氧化法在钛材表面生成高度规则有序的二氧化钛纳米管阵列,然后通过旋涂法将银盐溶液添加到二氧化钛纳米管内,高温加热使银盐溶液在纳米管内分解形成银纳米颗粒,最后用季铵盐QAS修饰材料表面,制得了一种同时具有长效抗菌性能和生物相容性的医用钛材,但制备方法复杂,条件要求苛刻,工艺成本高,不利于大面积制备该医用钛材。
CN106310371A公开了一种骨植入用钽铜涂层及其制备方法,该涂层的厚度为0.1-50μm,涂层中铜元素的质量比例为0%<Cu≤10%,采用等离子增强化学气相沉积法,使用氢气将金属钽和铜的卤化物还原为纯金属并沉积在基体表面而获得钽铜涂层,可解决多孔钛合金等基体材料生物相容性的问题,同时具备杀菌功能,但该涂层中铜与细胞直接接触并释放到体内,细胞毒性仍较高,沉积后还需要使用氢气还原,制备工艺复杂,且过多的铜元素在体内沉积,对人体有损伤。
因此针对上述传统方法和抗菌剂的缺陷,提供一种能够快速简单制备出普适性、高性能的抗菌并且不干扰细胞正常增殖,可以提高细胞增殖的涂层具有重要意义和广阔的市场前景。
发明内容
针对现有技术的不足及实际的需求,本发明提供一种兼具抗菌和生物相容性的复合涂层及其制备方法和应用,本发明的复合涂层能快速、简单、大面积制备高效的抗菌涂层,而且不影响细胞正常增殖或者增加细胞粘附和增殖,克服传统制造抗菌材料制备成本高、使用寿命短及其对细胞有一定毒副作用和传统使用的抗菌剂抗菌效果差、运用范围有限的问题。
为达此目的,本发明采用以下技术方案:
第一方面,本发明提供一种兼具抗菌和生物相容性的复合涂层,所述复合涂层包括抗菌涂层和生物相容性涂层,所述抗菌涂层的厚度为2-1000nm,所述生物相容性涂层的厚度为2-500nm。
本发明中,通过抗菌涂层和生物相容性涂层复合的方式,延长涂层使用寿命,工艺简单可连续进行大面积快速制备,表面抗菌元素纳米化,活性强,成分和含量可控,抗菌效果更佳,通过调整抗菌涂层和生物相容性涂层的厚度,使得两个涂层在特定的厚度范围配合下能最大程度发挥作用,再通过涂层组成成分的配合,使得抗菌元素释放速度适中,生物相容性涂层在所述条件下不影响抗菌元素的释放与抗菌性能的发挥,同时促进细胞增殖和分化,是植入性医疗器械的理想涂层。
所述抗菌涂层的厚度为2-1000nm,例如可以是2nm、3nm、4nm、5nm、6nm、7nm、8nm、9nm、10nm、11nm、12nm、13nm、14nm、15nm、18nm、20nm、25nm、30nm、35nm、40nm、42nm、45nm、48nm、50nm、60nm、70nm、80nm、90nm、100nm、150nm、200nm、250nm、300nm、350nm、400nm、450nm、500nm、550nm、600nm、650nm、700nm、750nm、800nm、850nm、900nm、950nm或1000nm,优选为40-100nm。
所述生物相容性涂层的厚度为2-500nm,例如可以是2nm、3nm、4nm、5nm、6nm、7nm、8nm、9nm、10nm、15nm、20nm、25nm、30nm、35nm、40nm、45nm、50nm、55nm、60nm、70nm、80nm、90nm、100nm、150nm、200nm、250nm、300nm、350nm、400nm、450nm或500nm,优选为5-80nm。
优选地,所述复合涂层的层数为2-6层,例如可以是2层、3层、4层、5层或6层,优选为2层。
本发明中,所述抗菌涂层的层数可以是1层或多层,生物相容性涂层可以是1层或多层,抗菌涂层和生物相容性涂层的总层数为2-6层,根据具体植入基体的材质以及形状可自由选择抗菌涂层和生物相容性涂层的层数,达到最佳配合效果,本发明中选择抗菌涂层和生物相容性涂层均为一层的复合涂层。
优选地,所述抗菌涂层包括氧化锌、氧化镁、银、铜、或铜合金中的任一种或至少两种的组合,例如可以是氧化锌和银的组合,氧化镁和铜的组合,银和铜的组合,氧化镁和铜合金的组合,或银和铜合金的组合,优选为铜合金,进一步优选为钽铜合金。
本发明中,发明人发现使用钽铜合金做抗菌涂层相比于其他抗菌材料,更能够降低铜元素在人体中的沉积,铜作为人体微量元素,同时提高生物相容性,延长使用寿命,控制抗菌元素的释放速度,同时不降低抗菌效果。
优选地,所述生物相容性涂层的材料包括钽、铌或羟基磷灰石或磷酸钙盐中的任一种或至少两种的组合,例如可以是钽和铌的组合,钽和羟基磷灰石的组合,铌和磷酸钙盐的组合,或钽、铌和羟基磷灰石的组合,优选为钽。
本发明中,选择钽与钽铜合金层配合,增加抗菌涂层和生物相容性涂层的贴合度,通过复合层的方式使复合涂层在良好生物相容性的前提下,提高抗菌性能,降低因多涂层复合导致的抗菌性能下降。通过钽铜合金抗菌涂层和钽层生物相容性涂层的复合,可有效降低抗菌涂层对细胞的毒副作用,生物相容性显著提升,抗菌涂层不影响生物相容性涂层的稳定性。
第二方面,本发明提供一种如第一方面所述的复合涂层的方法,所述方法包括如下步骤:
(1)在植入基体表面增加抗菌涂层;
(2)在步骤(1)所得植入基体表面再增加生物相容性涂层,得到兼具生物相容性和抗菌性的复合涂层。
优选地,步骤(1)所述植入基体为医用金属,包括不锈钢、钴合金、钛、钛合金、形状记忆合金、贵金属或纯金属中的一种或至少两种的组合,优选为钛和/或钛合金。
优选地,步骤(1)之前还包括预处理,具体包括:清洗植入基体的表面,去除植入基体表面的颗粒物。
优选地,所述清洗为将基体在溶剂中超声20-40min,例如可以是20min、22min、25min、28min、30min、33min、35min、37min或40min,优选为30min。
优选地,所述溶剂包括去离子水、乙醇、丙酮、异丙醇或甲醇。
优选地,所述清洗的具体步骤为:
(1’)将植入在去离子水中超声20-40min;
(2’)将步骤(1’)所得植入基体在乙醇中超声20-40min;
(3’)将步骤(2’)所得植入基体在丙酮中超声20-40min。
优选地,步骤(2)所述增加抗菌层的方式包括热喷涂、电子束蒸镀、原子层沉积、电子束辅助沉积或磁控溅射中的任一种或至少两种的组合,例如可以是热喷涂和电子束蒸镀的组合,原子层沉积和磁控溅射的组合,热喷涂和电子束辅助沉积的组合,或电子束蒸镀和磁控溅射的组合,优选为电子束蒸镀。
优选地,所述电子束蒸镀的真空度为465-940Pa,例如可以是465Pa、470Pa、475Pa、480Pa、485Pa、490Pa、500Pa、510Pa、520Pa、530Pa、540Pa、550Pa、580Pa、600Pa、630Pa、650Pa、660Pa、670Pa、680Pa、690Pa、700Pa、720Pa、750Pa、780Pa、800Pa、830Pa、850Pa、870Pa、900Pa、910Pa、920Pa、930Pa或940Pa,优选为670Pa。
本发明发现,真空度在所述范围内能减少残余气体对电子束的散射,提高镀膜稳定性,同时降低涂层中的杂质,提高涂层的稳定性。
优选地,所述电子束蒸镀的镀膜速率为0.12-0.2nm/min,例如可以是0.12nm/min、0.13nm/min、0.14nm/min、0.15nm/min、0.16nm/min、0.17nm/min、0.18nm/min、0.19nm/min或0.2nm/min。
本发明发现,镀膜速度越快,钽铜合金中的铜沉积的更快,所得抗菌涂层的铜含量越高,影响抗菌涂层与生物相容性涂层的配合,复合涂层的抗菌效果虽然提高了,但生物相容性降低同时稳定性下降。镀膜速率在本发明所述范围内可以获得均匀平整的涂层,镀膜速率过高增加仪器负荷,影响电子束的稳定性;镀膜速率过低增加时间成本,电子束能量低,镀料融化不均匀。通过控制电子束蒸镀的镀膜速率和真空度可以得到表面平整均匀的涂层,同时仪器负荷、时间成本和经济成本降到最低。
优选地,所述方法具体包括如下步骤:
(1)选择钛或钛合金作为植入基体,将植入载体在去离子水中超声20-40min,再在乙醇中超声20-40min,最后在丙酮中中超声20-40min,,采用氮***去除植入基体表面颗粒物;
(2)在步骤(1)所得植入基体表面采用电子束蒸镀的方法蒸镀抗菌层,,电子束蒸镀的真空度为465-940Pa,镀膜速率为0.12-0.2nm/min,抗菌涂层的厚度为2-1000nm;
(3)在步骤(2)所得植入基体表面采用电子束蒸镀的方法再蒸镀一层生物相容性涂层,电子束蒸镀的真空度为465-940Pa,镀膜速率为0.12-0.2nm/min,生物相容性涂层的厚度为2-500nm,得到兼具生物相容性和抗菌性的复合涂层。
第三方面,一种如第一方面所述的兼具抗菌和生物相容性的复合涂层用于制备修饰植入性医疗器械中的用途。
优选地,所述植入性医疗器械包括骨钉、骨板、人工器官、心脏支架、人工关节或心脏起搏器中的任意一种或至少两种的组合。
与现有技术相比,本发明具有如下有益效果:
(1)本发明提供的兼具抗菌和生物相容性的复合涂层,可有效延长涂层使用寿命,表面抗菌元素纳米化,活性强,抗菌效果更佳,通过组合配比抗菌涂层和生物相容性涂层的厚度和组成成分,使得抗菌元素释放速度适中,生物相容性涂层在所述条件下不影响抗菌元素的释放与抗菌性能的发挥,同时促进细胞增殖,是植入性医疗器械的理想涂层;
(2)本发明提供的兼具抗菌和生物相容性的复合涂层,制备成本低,工艺简单可连续进行大面积快速制备,涂层的致密度更好。
附图说明
图1为本发明兼具抗菌和生物相容性的复合涂层的制备方法流程图;
图2A为本发明实施例1中复合涂层的抗菌效果图;2B为本发明实施例1中纯钛基体的抗菌效果图;
图3A为本发明实施例2中复合涂层的抗菌效果图;3B为本发明实施例2中纯钛基体的抗菌效果图;
图4A为本发明实施例3中复合涂层的抗菌效果图;4B为本发明实施例3中纯钛基体的抗菌效果图;
图5A为本发明实施例4中复合涂层的抗菌效果图;5B为本发明实施例4中纯钛基体的抗菌效果图;
图6A为本发明实施例5中复合涂层的抗菌效果图;6B为本发明实施例5中纯钛基体的抗菌效果图;
图7A为本发明实施例6中复合涂层的抗菌效果图;7B为本发明实施例6中纯钛基体的抗菌效果图;
图8A为本发明实施例7中复合涂层的抗菌效果图;8B为本发明实施例7中纯钛基体的抗菌效果图;
图9A为本发明实施例8中复合涂层的抗菌效果图;9B为本发明实施例8中纯钛基体的抗菌效果图;
图10A为本发明实施例9中复合涂层的抗菌效果图;10B为本发明实施例9中纯钛基体的抗菌效果图;
图11为本发明中纯钛表面细菌的电镜扫描图;
图12为本发明实施例1中的复合涂层表面的金黄色葡萄球菌电镜扫描图;
图13为本发明实施例1中的复合涂层表面的大肠杆菌电镜扫描图;
图14为本发明中纯钽层表面的大肠杆菌电镜扫描图。
具体实施方式
为更进一步阐述本发明所采取的技术手段及其效果,以下通过具体实施方式来进一步说明本发明的技术方案,但本发明并非局限在实施例范围内。
实施例1
一种兼具抗菌和生物相容性的复合涂层,其制备方法的流程图如图1所示,具体如下:
(1)将抛光好的钛作为基体,分别在去离子水、乙醇和丙酮中分别超声30min,随后使用氮***将表面清洁干净;
(2)将清洗好的钛片固定到蒸镀盘上,采用电子束蒸镀方式,真空度为670Pa,镀膜速率为0.16nm/min,TaCu5合金作为靶材,在步骤(1)所得钛表面蒸镀40nm TaCu层;
(3)在步骤(2)蒸镀层表面再蒸镀5nm Ta层,基体表面获得生物相容性良好的抗菌涂层,抗大肠杆菌效果见图2A和图2B。
实施例2
一种兼具抗菌和生物相容性的复合涂层,其制备方法如下:
(1)将抛光好的钛合金Ti-6Al-4V作为基体,分别在去离子水、乙醇和丙酮中分别超声30min,随后使用氮***将表面清洁干净;
(2)将清洗好的钛片固定到蒸镀盘上,采用电子束蒸镀方式,真空度为465Pa,镀膜速率为0.2nm/min,TaCu5合金作为靶材,在步骤(1)所得钛表面蒸镀500nm TaCu层;
(3)在步骤(2)蒸镀层表面再蒸镀10nm Ta层,基体表面获得生物相容性良好的抗菌涂层,抗金黄色葡萄球菌效果见图3A和图3B。
实施例3
一种兼具抗菌和生物相容性的复合涂层,其制备方法如下:
(1)将抛光好的钛作为基体,分别在去离子水、乙醇和丙酮中分别超声30min,随后使用氮***将表面清洁干净;
(2)将清洗好的钛片固定到蒸镀盘上,采用电子束蒸镀方式,TaCu5合金作为靶材,真空度为940Pa,镀膜速率为0.12nm/min,在步骤(1)所得钛表面蒸镀100nm TaCu层;
(3)在步骤(2)蒸镀层表面再蒸镀40nm Ta层,基体表面获得生物相容性良好的抗菌涂层,抗金黄色葡萄球菌效果见图4A和图4B。
实施例4
一种兼具抗菌和生物相容性的复合涂层,其制备方法如下:
(1)将抛光好的钛作为基体,分别在去离子水、乙醇和丙酮中分别超声30min,随后使用氮***将表面清洁干净;
(2)将清洗好的钛片固定到蒸镀盘上,采用电子束蒸镀方式在步骤(1)所得钛表面80nm Ta-Ag抗菌涂层,真空度为850Pa,镀膜速率为0.15nm/min,;
(3)在步骤(2)蒸镀层表面再磁控溅射10nm Nb层,基体表面获得生物相容性良好的抗菌涂层,抗大肠杆菌效果见图5A和图5B。
实施例5
一种兼具抗菌和生物相容性的复合涂层,其制备方法如下:
(1)将抛光好的钛作为基体,分别在去离子水、乙醇和丙酮中分别超声30min,随后使用氮***将表面清洁干净;
(2)将清洗好的钛片固定到蒸镀盘上,采用电子束蒸镀方式,真空度为500Pa,镀膜速率为0.18nm/min,在步骤(1)所得钛表面蒸镀10nm MgO层;
(3)在步骤(2)蒸镀层表面再磁控溅射3nm Ta层,基体表面获得生物相容性良好的抗菌涂层,抗大肠杆菌效果见图6A和图6B。
实施例6
一种兼具抗菌和生物相容性的复合涂层,其制备方法如下:
(1)将抛光好的钛作为基体,分别在去离子水、乙醇和丙酮中分别超声20min,随后使用氮***将表面清洁干净;
(2)将清洗好的钛片固定到蒸镀盘上,采用原子层沉积方式,在步骤(1)所得钛表面原子层沉积200nm ZnO层;
(3)在步骤(2)蒸镀层表面再蒸镀200nm Ta层,基体表面获得生物相容性良好的抗菌涂层,抗大肠杆菌效果见图7A和图7B。
实施例7
一种兼具抗菌和生物相容性的复合涂层,其制备方法如下:
(1)将抛光好的钛作为基体,分别在去离子水、乙醇和异丙醇中分别超声30min,随后使用氮***将表面清洁干净;
(2)将清洗好的钛片固定到蒸镀盘上,采用热喷涂方式,在步骤(1)所得钛表面喷涂60nm MgO层;
(3)在步骤(2)蒸镀层表面再电子束蒸镀8nm Ta层,真空度为600Pa,镀膜速率为0.14nm/min,基体表面获得生物相容性良好的抗菌涂层,抗金黄色葡萄球菌效果见图8A和图8B。
实施例8
一种兼具抗菌和生物相容性的复合涂层,其制备方法如下:
(1)将抛光好的钛作为基体,分别在去离子水、甲醇和丙酮中分别超声40min,随后使用氮***将表面清洁干净;
(2)将清洗好的钛片固定到蒸镀盘上,采用热喷涂方式,在步骤(1)所得钛表面喷涂50nm Cu抗菌涂层;
(3)在步骤(2)蒸镀层表面再电子束蒸镀80nm Nb层,真空度为750Pa,镀膜速率为0.13nm/min,基体表面获得生物相容性良好的抗菌涂层,抗金黄色葡萄球菌效果见图9A和图9B。
实施例9
一种兼具抗菌和生物相容性的复合涂层,其制备方法如下:
(1)将抛光好的钛作为基体,分别在去离子水、乙醇和丙酮中分别超声30min,随后使用氮***将表面清洁干净;
(2)将清洗好的钛片固定到蒸镀盘上,采用热喷涂方式,在步骤(1)所得钛表面喷涂1000nm TaCu层;
(3)在步骤(2)蒸镀层表面再电子束辅助沉积500nm HA纳米层,基体表面获得生物相容性良好的抗菌涂层,抗金黄色葡萄球菌效果见图10A和图10B。
实施例10
与实施例1相比,除了电子束蒸镀的真空度为350Pa外,其他条件同实施例1。
本实施例所得复合涂层中检测到残余气体,且涂层中含有杂质,表面不平整。
实施例11
与实施例1相比,除了电子束蒸镀的镀膜速率为0.5nm/min外,其他条件同实施例1。
本实施例得到的复合涂层表面粗糙,仪器负载大,电子束不稳定。
实施例12
与实施例1相比,除了电子束蒸镀的镀膜速率为0.1nm/min外,其他条件同实施例1。
本实施例得到的复合涂层有未融化的镀料,表面不平整,镀膜时间长,电子束能量偏低。
对比例1
与实施例1相比,除了不增加生物相容性涂层外,其他条件同实施例1。
对比例2
与实施例1相比,除了不增加抗菌性涂层外,其他条件同实施例1。
对比例3
与实施例1相比,除了抗菌涂层的厚度为5nm外,其他条件同实施例1。
对比例4
与实施例1相比,除了抗菌涂层的厚度为1200nm外,其他条件同实施例1。
对比例5
与实施例1相比,除了生物相容性涂层的厚度为1nm外,其他条件同实施例1。
对比例6
与实施例1相比,除了生物相容性涂层的厚度为600nm外,其他条件同实施例1。
抗菌性测试
在无菌环境下,将金黄色葡萄球菌(或大肠杆菌)复苏接种于LB琼脂平板上(含10g/L胰蛋白胨、5g/L酵母、10g/L氯化钠、15g/L琼脂),置于37℃培养箱中,将生长状态良好的金黄色葡萄球菌(或大肠杆菌)接种于LB液体培养基中(含10g/L胰蛋白胨、5g/L酵母、10g/L氯化钠),使用细菌浊度仪测定细菌浓度并配制成1×106CFU/mL的菌悬液备用。将400uL菌悬液接种于24孔板中各样品表面,37℃培养1后,将金黄色葡萄球菌(或大肠杆菌)从试件表面洗脱,梯度稀释菌液,取100μL稀释液接种于LB琼脂平板上。37℃培养24h后,采用菌落计数仪对各组细菌数进行计数,通过图中平板细菌数结果计算抗菌率。抗菌率=(对照组菌落数-实验组菌落数)÷对照组菌落数×100%。结果见表1。
稳定性测试
测试实施例1-9与对比例1-6的带涂层的植入基体中抗菌剂稳定释放的时间,结果见表1。
MTT细胞毒性测试
在24孔板中,将成骨细胞以2×104个/孔的初始浓度接种到空白孔及所制备的样品上(每组3个平行样品,即n=3);在培养箱中分别培养1和3天后,吸弃培养液,并用PBS清洗样品1次;每孔中加入900μL新鲜的培养基(不含血清)和100μL 5mg/mLMTT/培养基(不含血清)溶液;将24孔板放回培养箱再培养4h;小心吸弃培养液(尽量不要吸走紫色沉淀),再每孔加入800μL DMSO,然后置24孔板于摇床上轻微振荡15-20min待紫色沉淀完全溶解后,吸取200μL反应液置于96孔板中;在570nm波长下,利用酶标仪检测溶液吸光值。
记录放置培养三天后的OD值,结果见表1。
表1抗菌效果
抗菌率/% | 抗菌剂稳定释放时间/天 | OD值 | |
实施例1 | 80.6 | 33 | 0.45 |
实施例2 | 72.4 | 31 | 0.41 |
实施例3 | 73.7 | 32 | 0.40 |
实施例4 | 75.1 | 15 | 0.33 |
实施例5 | 55.9 | 26 | 0.35 |
实施例6 | 61.2 | 23 | 0.38 |
实施例7 | 65.7 | 25 | 0.42 |
实施例8 | 70.9 | 26 | 0.37 |
实施例9 | 63.8 | 22 | 0.35 |
对比例1 | 99.9 | 5 | 0.15 |
对比例2 | 0 | 0 | 0.46 |
对比例3 | 30.4 | 10 | 0.39 |
对比例4 | 75.6 | 12 | 0.26 |
对比例5 | 80.3 | 9 | 0.29 |
对比例6 | 40.1 | 10 | 0.40 |
由表1可知,比较实施例1与实施例2-9可知,通过配比抗菌涂层和生物相容性涂层的厚度、组成成分及喷涂或蒸镀方式,可有效延长涂层使用寿命,表面抗菌元素纳米化,活性强,抗菌效果更佳,使得抗菌元素释放速度适中,生物相容性涂层在所述条件下不影响抗菌元素的释放与抗菌性能的发挥,同时促进细胞增殖。比较实施例1与实施例10-12可知,在本发明所述电子束蒸镀的参数范围内,可提高复合涂层的平整度,降低仪器的载荷,增加电子束的稳定性,降低制备成本,电子束蒸镀速率和真空度过大或过小均影响所得复合涂层的性能。比较实施例1与对比例1-6可知,抗菌涂层和生物相容性涂层二者缺一不可,相互配合,在本发明所述配比范围内效果最佳,使涂层的抗菌性、稳定性和生物相容性均达到最佳,抗菌率可达80.6%,铜离子稳定持续释放可达33天,稳定性好,抗菌效果显著,MTT细胞毒性测试中OD值达0.45,与不添加抗菌涂层的基体钛的OD值近似,说明本发明所述复合涂层生物相容性极佳,是植入性医疗器械的理想涂层。
本发明中,实施例1作为最优实施例,其抗菌效果图如图2A-B所示,可以看出,在本发明所述厚度范围内,钽铜抗菌涂层的抗菌效果不会受生物相容性涂层的影响,仍可达到80.6%。
扫描电镜观察细菌形态
在实施例1中,采用扫描电镜观察复合涂层表面细菌数量及形态,以纯钛表面做对照组,结果见图11-14。
由图11可以看出,没有抗菌层的纯钛表面细菌繁多,且生长状况良好,形态完好;由图12可知,本发明提供的抗菌和生物相容性复合涂层能有效抑制金黄色葡萄球菌的生长,细菌从涂层表面脱落,且细菌呈椭球状,说明细菌生长状况不佳,抗菌涂层有效抑制金黄色葡萄球菌的增殖;由图13可知,在复合涂层表面的大肠杆菌呈坍塌形貌,细菌的细胞膜已破裂,说明细菌已经死亡,说明本发明提供的复合涂层能有效抗大肠杆菌和金黄色葡萄球菌;由图14可知,钽层生物相容性好,并且不影响涂层抗菌性,比较图2和图14可知,铜离子能有效抑制细菌繁殖,使细菌形态改变,细菌细胞膜破裂。
综上,本发明提供的兼具抗菌和生物相容性的复合涂层通过抗菌涂层和生物相容性涂层复合的方式,延长涂层使用寿命,工艺简单可连续进行大面积快速制备,表面抗菌元素纳米化,活性强,抗菌效果更佳,通过组合配比抗菌涂层和生物相容性涂层的厚度和组成成分,使得抗菌元素释放速度适中,生物相容性涂层在所述条件下不影响抗菌元素的释放与抗菌性能的发挥,同时促进细胞增殖,无细胞毒性,在医疗设备领域具有重要意义和广阔前景。
申请人声明,本发明通过上述实施例来说明本发明的详细方法,但本发明并不局限于上述详细方法,即不意味着本发明必须依赖上述详细方法才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。
Claims (21)
1.一种兼具抗菌和生物相容性的复合涂层,其特征在于,所述复合涂层包括抗菌涂层和生物相容性涂层,所述抗菌涂层为钽铜合金,所述抗菌涂层的厚度为20-500nm,所述生物相容性涂层为钽或铌,所述生物相容性涂层的厚度为2-80nm;
所述复合涂层的制备方法包括如下步骤:
(1)在植入基体表面增加抗菌涂层;
(2)在步骤(1)所得植入基体表面再增加生物相容性涂层,得到兼具生物相容性和抗菌性的复合涂层。
2.根据权利要求1所述的复合涂层,其特征在于,所述复合涂层的层数为2-6层。
3.根据权利要求2所述的复合涂层,其特征在于,所述复合涂层的层数为2层。
4.根据权利要求1所述的复合涂层,其特征在于,所述抗菌涂层的厚度为40-100nm。
5.根据权利要求1所述的复合涂层,其特征在于,所述生物相容性涂层的厚度为5-80nm。
6.一种制备如权利要求1-5任一项所述的复合涂层的方法,其特征在于,所述方法包括如下步骤:
(1)在植入基体表面增加抗菌涂层;
(2)在步骤(1)所得植入基体表面再增加生物相容性涂层,得到兼具生物相容性和抗菌性的复合涂层。
7.根据权利要求6所述的方法,其特征在于,步骤(1)所述植入基体为医用金属,包括不锈钢、钴合金、钛合金、形状记忆合金或纯金属中的一种或至少两种的组合。
8.根据权利要求7所述的方法,其特征在于,所述植入基体为钛和/或钛合金。
9.根据权利要求6所述的方法,其特征在于,步骤(1)之前还包括预处理的步骤。
10.根据权利要求9所述的方法,其特征在于,所述预处理具体包括:清洗植入基体的表面,去除植入基体表面的颗粒物。
11.根据权利要求10所述的方法,其特征在于,所述清洗为将基体在溶剂中超声20-40min。
12.根据权利要求11所述的方法,其特征在于,所述溶剂包括去离子水、乙醇、丙酮、异丙醇或甲醇。
13.根据权利要求10所述的方法,其特征在于,所述清洗的具体步骤为:
(1’)将植入在去离子水中超声20-40min;
(2’)将步骤(1’)所得植入基体在乙醇中超声20-40min;
(3’)将步骤(2’)所得植入基体在丙酮中超声20-40min。
14.根据权利要求6所述的方法,其特征在于,步骤(1)所述增加抗菌层的方式包括热喷涂、电子束蒸镀、原子层沉积、电子束辅助沉积或磁控溅射中的任一种或至少两种的组合。
15.根据权利要求14所述的方法,其特征在于,步骤(1)所述增加抗菌层的方式为电子束蒸镀。
16.根据权利要求15所述的方法,其特征在于,所述电子束蒸镀的真空度为465-940Pa。
17.根据权利要求16所述的方法,其特征在于,所述电子束蒸镀的真空度为670Pa。
18.根据权利要求15所述的方法,其特征在于,所述电子束蒸镀的镀膜速率为0.12-0.2nm/min。
19.根据权利要求6-18任一项所述的方法,其特征在于,所述方法具体包括如下步骤:
(1)选择钛或钛合金作为植入基体,将植入载体在去离子水中超声20-40min,再在乙醇中超声20-40min,最后在丙酮中中超声20-40min,采用氮***去除植入基体表面颗粒物;
(2)在步骤(1)所得植入基体表面采用电子束蒸镀的方法蒸镀抗菌层,电子束蒸镀的真空度为465-940Pa,镀膜速率为0.12-0.2nm/min,抗菌涂层的厚度为20-500nm;
(3)在步骤(2)所得植入基体表面采用电子束蒸镀的方法再蒸镀一层生物相容性涂层,电子束蒸镀的真空度为465-940Pa,镀膜速率为0.12-0.2nm/min,生物相容性涂层的厚度为2-80nm,得到兼具生物相容性和抗菌性的复合涂层。
20.一种如权利要求1-5任一项所述的兼具抗菌和生物相容性的复合涂层用于制备修饰植入性医疗器械中的用途。
21.根据权利要求20所述的用途,其特征在于,所述植入性医疗器械包括骨钉、骨板、人工器官、心脏支架、人工关节或心脏起搏器中的任意一种或至少两种的组合。
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