CN116036363A - 钛材表面兼备长效抗菌促成骨双功能的缓释药物体系及其制备方法和应用 - Google Patents
钛材表面兼备长效抗菌促成骨双功能的缓释药物体系及其制备方法和应用 Download PDFInfo
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- CN116036363A CN116036363A CN202310033316.XA CN202310033316A CN116036363A CN 116036363 A CN116036363 A CN 116036363A CN 202310033316 A CN202310033316 A CN 202310033316A CN 116036363 A CN116036363 A CN 116036363A
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Abstract
本发明提供了钛材表面兼备长效抗菌促成骨双功能的缓释药物体系及其制备方法和应用，解决现有钛植入物表面释药体系存在释药速度快以及植入后可能出现的感染和松动的技术问题。本发明通过将成骨活性元素锶掺杂入二氧化钛纳米管，利用聚多巴胺辅助沉积抗生素的技术手段，获得了表面兼备长效抗菌促成骨的生物活性钛植入物，克服了现有钛植入物表面生物惰性所导致的植入后感染和松动问题，提高其临床治疗成功率。
Description
技术领域
本发明属于医药生物技术领域，具体涉及一种钛材表面兼备长效抗菌促成骨双功能的缓释药物体系及其制备方法和应用。
背景技术
外来损伤和骨骼疾病都极易造成骨缺损，当骨缺损部位缺口过大时无法通过机体的自生长而愈合，通常需要借助骨植入体。植入体作为临床治疗骨缺损的有效手段，已经有了广泛的应用。但是根据临床调查显示，有超过10％的植入体治疗案例都会以失败告终，而这些失败的案例中，有18％是由于细菌感染导致，有12％是由于松动(由于感染出现炎症，纤维包裹进而出现松动)导致[Mater.Horiz.,2018,5,545--552]。在植入体的手术过程中，尽管严格保持无菌操作，但仍旧可能会被细菌趁虚而入。除此之外，手术会破坏植入部位的免疫系统，使得细菌容易在表面粘附而进一步生长为生物被膜，生物被膜一旦形成极难去除，而且会对后续的用药产生严重的负面影响；并且细菌感染出现的可能性会贯穿整个治疗过程，时间相当长，这就要求植入体表面抗菌性能能够持续一定长的时间以应对整个治疗过程中可能出现的感染现象。植入体在植入体内之后，表面促成骨活性的缺失会导致骨组织长入缓慢，也会使得植入体与骨组织表面长期缺少骨性结合从而导致植入体容易松动甚至脱落。
钛及其合金由于其优良的力学性能和良好的生物相容性使其在硬组织植入体领域被广泛应用。然而钛植入物表面生物惰性，无法应对在植入体内之后可能出现的松动或者感染现象，故而需要对其表面进一步修饰。阳极氧化通过电场力驱动氟离子在钛表面可构建排列整齐的二氧化钛纳米管膜层，并且阳极氧化所构建的纳米管尺寸可控且形貌均一。已有研究表明二氧化钛纳米管在管径小于50nm时能够显著促进成骨细胞和骨髓间充质干细胞的粘附，提高表面促成骨性能。除此之外，纳米管由于其独特的管状结构使得其成为了优良的药物载体，可将具有促成骨功能的药物如骨形成蛋白2、骨生长肽等药物负载进入纳米管中提高其表面促成骨能力，也可将抗菌类药物如抗菌肽、庆大霉素等药物负载进入纳米管中，可使得表面具有显著抗菌性能而改善骨植入体的感染问题。然而，药物在负载进纳米管之后，会快速释放并导致涂层中药物的快速损失从而削弱表面功能，并且药物快速释放会导致局部药物浓度过高从而对机体产生毒性，即直接向纳米管内部装药会释放速度太快，并且导致毒性的同时，会使得表面功能时间太短。
鉴于上述情况，钛植入物表面药物长期缓释载药体系的开发，已成为其能否实际应临床骨整合的关键。
发明内容
本发明的目的在于解决现有钛植入物表面释药体系存在释药速度快以及植入后可能出现的感染和松动的技术问题，而提供了一种钛材表面兼备长效抗菌促成骨双功能的缓释药物体系及其制备方法和应用。
为实现上述目的，本发明所提供的技术解决方案是：
一种钛材表面兼备长效抗菌促成骨双功能的缓释药物体系的制备方法，其特殊之处在于，包括以下步骤：
1)在钛材表面制备二氧化钛纳米管
采用阳极氧化法在钛材表面制备二氧化钛纳米管，并进行退火处理以及超声清洗，得到表面具有二氧化钛纳米管的钛材；其中，二氧化钛纳米管的管径为30～140nm；
2)对二氧化钛纳米管进行锶掺杂
将步骤1)得到的表面具有二氧化钛纳米管的钛材置于高温高压反应釜内胆中，加入氢氧化锶溶液，热处理后取出用稀硝酸超声清洗(清洗掉纳米管上多余的氢氧化锶)，得到表面具有锶掺杂二氧化钛纳米管的钛材；
3)制备缓释药物体系
将步骤2)得到的表面具有锶掺杂二氧化钛纳米管的钛材浸没在pH＝8.0-9.0且含有多巴胺、万古霉素、硫酸庆大霉素的Tris-HCl溶液中，摇床反应，反应完成后清洗、干燥，在钛材表面得到兼备长效抗菌促成骨双功能的缓释药物体系，其中，硫酸庆大霉素具有较好的生物相容性，且广谱抗菌，水溶性良好，同时有苯环结构可以跟多巴胺产生π-π堆积有利于固定抗生素(硫酸庆大霉素、万古霉素与多巴胺上都存在苯环结构)，万古霉素则是弥补硫酸庆大霉素的不足，针对耐药菌感染。
进一步地，步骤1)具体为：
1.1)以纯钛箔为阳极、石墨为阴极，阴阳极之间的距离为4-6cm；电解液采用氟化铵、乙二醇和去离子水混合配制；电解过程采用直流电源，反应电压为40-80V，阳极氧化反应(即对阳极钛箔进行阳极氧化)时间为0.5-2h；
所述电解液中氟化铵、去离子水和乙二醇三者配比为0.5-1∶1-10∶150-300(克∶毫升∶毫升)；
1.2)反应完成后，将反应后的阳极放在磁舟中，并置于管式炉石英管中央以5℃/min的升温速率升温至550℃，保温2h后自然冷却(该工艺条件可以稳定纳米管结构，使其不容易脱落)，取出采用乙醇和去离子水超声清洗，得到表面具有二氧化钛纳米管的钛植入物；
进一步地，步骤2)具体为：
将步骤1)得到的表面具有二氧化钛纳米管的钛植入物置于高温高压反应釜内胆中，加入反应釜内胆体积20％的饱和氢氧化锶溶液，220℃下加热2h后，自然冷却取出，并用稀硝酸超声清洗，得到表面具有锶掺杂二氧化钛纳米管的钛材。
进一步地，步骤3)具体为：
将步骤2)得到的表面具有锶掺杂二氧化钛纳米管的钛材浸没在pH＝8.5且含有多巴胺、万古霉素、硫酸庆大霉素的Tris-HCl溶液中，在摇床中37℃(该温度下有利于沉积)下反应6h，反应完成后，采用去离子水清洗、并干燥，在钛材表面得到兼备长效抗菌促成骨双功能的缓释药物体系；
其中，所述Tris-HCl溶液中Tris、多巴胺、万古霉素和庆大霉素的含量分别为：10mM、0.5mg/ml、2mg/ml和2mg/ml。
进一步地，步骤1.1)中，阴极和阳极之间的距离为5cm，反应电压为60V，反应时间为2h；
氟化铵、去离子水和乙二醇的配比为0.7∶5∶250(克∶毫升∶毫升)。
进一步地，步骤2)中，加热2h；
稀硝酸的摩尔浓度为0.1M，超声清洗30s。
本发明还提供一种采用上述方法制备得到兼备长效抗菌促成骨双功能的缓释药物体系，以及一种钛植入物材料，其特殊之处在于，在钛材表面上按照上述方法制备有兼备长效抗菌促成骨双功能的缓释药物体系。
同时，本发明还提供了上述钛植入物材料在制备骨科植入体和牙种植体中的应用。
本发明的机理：
本发明首先利用阳极氧化在钛表面构建二氧化钛纳米管，提高表面粗糙度，有利于细胞生长，同时，通过水热处理将锶元素掺杂进二氧化钛晶格中进一步提高其表面促成骨性能；多巴胺在碱性溶液中，暴露有氧环境下可发生原位自聚为聚多巴胺并牢固的粘附在各种基材表面，聚多巴胺与抗生素(万古霉素和硫酸庆大霉素)共沉积在纳米管表面赋予其表面优异抗菌性能，聚多巴胺的特殊结构，使得其与上述两种抗生素之间存在着π-π堆积作用，在辅助抗生素沉积在纳米管表面的同时，也能够有效避免其快速释放从而有效延长其表面抗菌性能实现缓释目的，使得该涂层兼备长效抗菌和促成骨双功能。
本发明的优点是：
1.本发明通过将成骨活性元素锶掺杂入二氧化钛纳米管，利用聚多巴胺辅助沉积抗生素的技术手段，获得了表面兼备长效抗菌促成骨的生物活性钛植入物，克服了现有钛植入物表面生物惰性所导致的植入后感染和松动问题，提高其临床治疗成功率。
2.本发明利用阳极氧化构建二氧化钛纳米管作为药物负载的载体，且在一定程度上能够有利于成骨细胞的生长，再将成骨活性元素锶以水热的方式掺杂进入二氧化钛的晶格中进一步提高其表面对成骨细胞的促进作用。同时在二氧化钛纳米管的内壁上将多巴胺和抗生素共沉积赋予表面优良的抗菌性能，聚多巴胺的存在同时有利于抗生素的长期释放，有利于表面抗菌性能的长期性。
3.本发明载药体系的制备方法简单、工艺可控且稳定、所需的材料价格低廉容易得到。
4.采用本发明构建的二氧化钛纳米管，膜层厚度约为12μm，可通过调控工艺控制纳米管的管长和管径以获取所需形貌的二氧化钛纳米管，根据扫面电子显微镜(SEM)形貌可看出纳米管的管径约为30-140nm(主要是90nm)，在锶元素掺杂以及多巴胺与万古霉素共沉积后，其内径缩小至40nm，甚至更小，该管径范围能够显著促进成骨相关细胞的粘附和增殖。同时，结合锶元素的释放，可以进一步提高植入体表面的促成骨效果。
5.本发明采用聚多巴胺将抗生素固定在纳米管的内壁，由于聚多巴胺的强粘附性和稳定性，可以使得抗生素以一种较为稳定的形式存在于纳米管内，避免抗生素的突释现象，在避免由于抗生素局部浓度过高而对机体产生毒性的同时，也延长了抗生素的释放时间，增强了表明抗菌的长效性、持久性。
6.本发明相对于现有技术的优势在于药物长期释放，尤其是锶元素释放可达到接近一个月，更利于骨生长。
附图说明
图1为使用本发明的阳极氧化法在钛表面构建的二氧化钛纳米管阵列的表面和截面的SEM照片。
图2为使用本发明构建锶元素掺杂以及聚多巴胺与万古霉素共沉积后的SEM照片以及表面EDS元素分布。
图3为使用本发明构建兼备长效抗菌促成骨双功能的释药体系表面XPS谱图。
图4为使用本发明所得兼备长效抗菌促成骨双功能的释药体系表面万古霉素释放图。
图5为使用本发明所得兼备长效抗菌促成骨双功能的释药体系表面锶元素释放图。
图6为使用本发明所得兼备长效抗菌促成骨双功能的释药体系表面细菌存活率。
图7为使用本发明构建兼备长效抗菌促成骨双功能的释药体系表面细菌生长形貌SEM照片。
图8为使用本发明构建兼备长效抗菌促成骨双功能的释药体系表面细存活率。
图9为使用本发明构建兼备长效抗菌促成骨双功能的释药体系表面细胞活死染色。
图10为使用本发明构建兼备长效抗菌促成骨双功能的释药体系表面细胞核/骨架染色。
具体实施方式
以下结合附图和具体实施例对本发明的内容作进一步的详细描述：
实施例一
配制阳极氧化电解液：250mL乙二醇、0.7g氟化铵和5mL去离子水，混匀备用。
配制水热锶掺杂溶液：水热反应液为10mL 2mM的氢氧化锶溶液。配制多巴胺与抗生素沉积溶液：配制10mL 10mM的Tris水溶液，并用稀盐酸将pH调至8.5，加入5毫克多巴胺、20毫克的硫酸庆大霉素和20毫克的万古霉素，该溶液需现配现用。
锶元素释放条件：将待测样品(1厘米×1厘米)浸泡在1毫升PBS中，放入37℃恒温培养箱，分别于1d、2d、3d、4d、5d、10d、15d、20d、25d取样，重新加入1毫升PBS后再放回培养箱。所得样品配置用原子吸收光谱火焰法测定溶液中锶元素的含量，计算其累计释放量。
万古霉素释放条件：将待测样品(1厘米×1厘米)浸泡在1毫升PBS中，放入37℃恒温培养箱，分别在2h、4h、6h、8h、10h、12h、24h、36h、48h、3d、5d、7d天取样，所得样品用紫外分光光度计测量其280nm的吸收并计算万古霉素浓度，计算其累计释放量。
样品抗菌性能测试：将制备好的Ti、TNT、TNT-Sr和TNT-Sr-DVG用去离子水冲洗去掉表面未反应上的试剂，室温风干备用。同时，将生长至对数期的金黄色葡萄球菌和耐甲氧西林金黄色葡萄球菌用LB培养基稀释至106个每毫升，取50微升细菌悬液涂布于LB固体培养基，随后将样品(0.5厘米×0.5厘米)放置于细菌涂布后培养板上，倒置于37℃培养箱内12h后取出观察。除此之外，将样品与放置在24孔板中，每个孔中加入1毫升细菌密度为106个每毫升菌液，放置在37℃恒温培养箱中孵育12h。将菌液取出稀释100倍后取50微升，用涂抹棒涂布于LB固体培养板上，放置于37℃恒温培养箱培养12h后取出观察。同时在样品表面接种10微升细菌密度为107个每毫升的菌液，于37℃培养箱中孵育6h后。于每个孔中加入500微升的4％的多聚甲醛溶液在4℃下固定12h。然后依次用20％、40％、60％、80％、90％、95％、99％的乙醇溶液分别进行梯度脱水30分钟。最后将样品风干并用导电胶贴到样品台上，喷金(10毫安，60秒)以进行SEM观察
样品细胞相容性测试：将样品(1厘米×1厘米)放置于24孔板里，紫外灭菌30分钟后用无菌PBS冲洗样品3次。将细胞以10000个/孔的密度接种于材料表面(Ti片组作空白对照)，放入37℃恒温培养箱里培养。1、3、5天后，弃去细胞培养基并用PBS轻柔漂洗3次后，加入300微升alamarBlue染液，37℃孵育4h后，取出培养板转移其中的染液至新的96孔板中放置酶标仪中测试。设置测试参数，530nm激发，590nm发射测得各组的荧光强度值可得出样品表面细胞活力。为了进一步观察细胞在与样品接触后的增殖情况，采用活/死荧光染色实验进行表征。进行测试前，样品放置在24孔板中紫外灭菌30分钟后用无菌PBS清洗三次。将MC3T3-E1细胞以10000个/孔的密度接种于样品表面，放入37℃恒温培养箱里培养。1、3、5天后，弃去细胞培养基并用PBS轻柔漂洗3次后，加入200微升Calcein-AM/PI染液后37℃培养箱中孵育20分钟后，用倒置荧光显微镜观察并拍照，该染色液孵育后，活细胞显示为绿色荧光，死细胞显示为红色荧光。为了进一步观察细胞在样品表面的粘附状态，采用细胞骨架/核染色以及通过SEM观察细胞粘附形态。样品放置在24孔板中紫外灭菌30分钟后用无菌PBS清洗三次。将MC3T3-E1细胞以50000个/孔的密度接种于样品表面，放入37℃恒温培养箱里培养。1天后，弃去细胞培养基并用PBS轻柔漂洗3次后，向每个孔中加入200微升的4％多聚甲醛于4℃下固定1h，随后用PBS清洗三次，再加入500微升0.5％的曲拉通溶液浸泡5分钟，然后用PBS清洗三次后加入200微升稀释100倍的FITC鬼笔环肽染料染色半h。最后把FITC染液吸走，直接加入200微升的DAPI染液，染色五分钟后用倒置荧光显微镜观察。除此之外，将细胞按照上述骨架/核染色的步骤种植在样品表面，分别于第1、3天后，弃去细胞培养基并用PBS轻柔漂洗3次后，加入300微升的4％多聚甲醛于4℃下固定1h，随后依次用20％、40％、60％、80％、90％、95％、99％的乙醇溶液梯度脱水30分钟。最后将样品风干并用导电胶贴到样品台上，喷金(10毫安，60秒)并通过SEM观察。
实施例二：
将纯钛样品固定在电极阳极，阴极使用石墨棒，取电解液250毫升与塑料烧杯中，将阴阳电极插入电解液中，距离为5厘米，接通直流电源设置电压60V。反应时间2h后取出用无水乙醇超声清洗1分钟后，于60℃烘箱烘干备用。
实施例三
将实施例二所得样品，放入管式炉石英管中央，以5℃每分钟的升温速率加热到550℃，保温2h，取出后用乙醇和去离子水超声清洗。
实施例四
将实施例三所得样品，放入50毫升规格高温高压反应釜中，加入10毫升水热锶掺杂溶液，将反应釜拧紧放入鼓风干燥箱中，220℃加热2h后，用0.1M的稀硝酸超声清洗30秒后，于60℃烘箱干燥备用。
实施例五
将步骤四中所得样品，浸入10毫升的多巴胺与抗生素沉积溶液中，在摇床中37℃下反应6h，反应结束后，用离子水冲洗干净后，于60℃烘箱干燥备用。
由于骨植入治疗是一个相当漫长的过程，故而表面功能的长期性对于骨植入体的成功尤为关键。本发明通过阳极氧化构建二氧化钛纳米管，该纳米管不仅能够有效提高植入体表面活性，并且本发明通过水热反应将成骨活性元素锶掺杂进入二氧化钛纳米管的晶格中，长期释放锶元素有利于骨修复，且锶元素掺杂之后。同时较大的管状结构使得其成为了良好的药物载体，使得表面能够负载大量功能性药物，通过多巴胺与药物(万古霉素和硫酸庆大霉素)的π-π共轭效应使得抗生素不会快速释放尽，避免了快速释放导致细胞毒性的同时更有利于其表面功能的长期性。
其中，图1为实施例二在扫描电子显微镜下观察的形貌图片，根据实验结果可看出，样品表面纳米管管径均匀且排列整齐管径约为90nm。
图2为实施例五的样品SEM形貌和表面元素分布，根据表面形貌图片可看出在锶元素掺杂以及抗生素多巴胺共沉积后，样品的内径缩小至约40nm，该管径可以显著促进成骨相关细胞的生长和分化。同时根据EDS元素分布图可观察到表面具有大量的锶元素分布，进一步提高了表面促成骨活性。
图3为各个样品的表面XPS谱图，TNT表面含有Ti和O元素，这是由于阳极氧化生成的TiO2氧化层的缘故。水热法掺锶后可以发现在133eV处出现Sr元素的特征峰。而共沉积后出现N元素的特征峰，这是由于沉积了多巴胺，且C元素含量的显著增加也意味着多巴胺及抗生素在样品表面的成功沉积。
图4为万古霉素释放曲线，根据结果得知样品表面共沉积抗生素后有显著缓慢释放现象，在PBS中浸泡2h仅释放0.05mg/mL。而随着时间的增长，直到8h后释放量达到0.10mg/mL，12h后释放量达到0.12mg/mL。这一段时间抗生素在体内暴释，而后随着时间逐渐增长，抗生素的释放量在缓慢增加，进入所谓的平台期。1天的累计释放量仅有0.13mg/mL，2天的释放量达0.15mg/mL，3天的释放量达0.16mg/mL，5天的释放量达0.17mg/mL，7天后的总释放量有0.18mg/mL。
图5为锶元素释放图们可看出锶元素的长期释放可达24天，且24天是依旧观察出显著的释放行为，有利于表面功能的长期性。
图6为样品抗菌性能，相较于钛片，样品显示出强效杀菌能力，其表面没有细菌能够存活，杀菌率高达100％。
图7为样品表面细菌形貌，纯钛样品表面的S.aureus均能保持其原有细菌状态，呈现球状形态；而实施例五样品表面的细菌有些许变形，甚至于皱缩，呈现出不良的生长状态，进一步印证了样品杀菌性能。
图8为细胞在表面培养1,3,5天后用alamarBlue染液测定样品表面的细胞活性对比，纯钛片作为对照组，样品成骨细胞孵育1天、3天、5天后，均为对细胞产生明显毒性，各个施例表面细胞的存活率均接近100％，也就是说样品具有良好生物相容性，有望作为植入体用于生物体内。
图9为样品表面细胞Live/Dead染色实验结果，从图中可以发现1天、3天、5天后细胞数量一直呈现增加的趋势，这说明材料表面的成骨细胞的增殖没有受到影响。
图10为使用鬼笔环肽染液和DAPI染液分别对成骨细胞的和细胞核进行染色结果，所得到的荧光显微镜图片可以发现纯钛表面的细胞数量最少，而施例五表面细胞数量很多，且都呈现舒展状态，表明样品有利于细胞的黏附。
由此可见，本发明构建的释药体系，在对耐药菌杀伤达到100％的同时还能够保证具有良好的细胞相容性，并能够显著促进前成骨细胞的粘附，综合评价良好。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明公开的技术范围内，可轻易想到各种等效的修改或替换，这些修改或替换都应涵盖在本发明的保护范围之内。
Claims (10)
1.一种钛材表面兼备长效抗菌促成骨双功能的缓释药物体系的制备方法，其特征在于，包括以下步骤：
1)在钛材表面制备二氧化钛纳米管
采用阳极氧化法在钛材表面制备二氧化钛纳米管，并进行退火处理以及超声清洗，得到表面具有二氧化钛纳米管的钛材，其中，二氧化钛纳米管的管径为30～140nm；
2)对二氧化钛纳米管进行锶掺杂
将步骤1)得到的表面具有二氧化钛纳米管的钛材置于高温高压反应釜中，加入氢氧化锶溶液，热处理后取出用稀硝酸超声清洗，得到表面具有锶掺杂二氧化钛纳米管的钛材；
3)制备缓释药物体系
将步骤2)得到的表面具有锶掺杂二氧化钛纳米管的钛材浸没在pH＝8.0-9.0且含有多巴胺、万古霉素、硫酸庆大霉素的Tris-HCl溶液中，置于摇床中反应，反应完成后清洗、干燥，在钛材表面得到兼备长效抗菌促成骨双功能的缓释药物体系。
2.根据权利要求1所述钛材表面兼备长效抗菌促成骨双功能的缓释药物体系的制备方法，其特征在于，步骤1)具体为：
1.1)以纯钛箔为阳极、石墨为阴极，阴阳极之间的距离为4-6厘米；电解液采用氟化铵、乙二醇和水混合配制；电解过程采用直流电源，反应电压为40-80V，阳极氧化反应时间为0.5-2h；
所述电解液中氟化铵、水和乙二醇三者配比为0.5-1∶1-10∶150-300(克∶毫升∶毫升)；
1.2)反应完成后，将阳极置于管式炉石英管中以5℃/min的升温速率升温至550℃，保温2h后自然冷却，取出清洗，得到表面具有二氧化钛纳米管的钛材。
3.根据权利要求1或2所述钛材表面兼备长效抗菌促成骨双功能的缓释药物体系的制备方法，其特征在于，步骤2)具体为：
将步骤1)得到的表面具有二氧化钛纳米管的钛材置于高温高压反应釜内胆中，加入反应釜内胆体积20％的饱和氢氧化锶溶液，220℃下加热1-3h后，自然冷却取出，并用稀硝酸超声清洗，得到表面具有锶掺杂二氧化钛纳米管的钛材。
4.根据权利要求3所述钛材表面兼备长效抗菌促成骨双功能的缓释药物体系的制备方法，其特征在于，步骤3)具体为：
将步骤2)得到的表面具有锶掺杂二氧化钛纳米管的钛材浸没在pH＝8.5且含有多巴胺、万古霉素、硫酸庆大霉素的Tris-HCl溶液中，在摇床中37℃下反应6h，反应完成后，采用去离子水清洗、并干燥，在钛材表面得到兼备长效抗菌促成骨双功能的缓释药物体系；
其中，所述Tris-HCl溶液中Tris、多巴胺、万古霉素和庆大霉素的含量分别为：10mM、0.5mg/ml、2mg/ml和2mg/ml。
5.根据权利要求2所述钛材表面兼备长效抗菌促成骨双功能的缓释药物体系的制备方法，其特征在于：
步骤1.1)中，阴极和阳极之间的距离为5厘米，反应电压为60V，反应时间为2h；
氟化铵、水和乙二醇的配比为0.7∶5∶250(克∶毫升∶毫升)。
6.根据权利要求3所述钛材表面兼备长效抗菌促成骨双功能的缓释药物体系的制备方法，其特征在于:
步骤2)，加热2h；
稀硝酸的摩尔浓度为0.1M，超声清洗30s。
7.一种缓释药物体系，其特征在于：采用权利要求1-6任一所述方法在钛材表面制备得到。
8.一种钛植入物材料，其特征在于：在钛材表面上按照权利要求1-6任一所述方法制备有兼备长效抗菌促成骨双功能的缓释药物体系。
9.权利要求8所述钛植入物材料在制备骨科植入体中的应用。
10.权利要求8所述钛植入物材料在制备牙植入体中的应用。
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| CN117339008A (zh) * | 2023-09-25 | 2024-01-05 | 绵阳市第三人民医院 | 用于治疗感染性骨缺损3d打印pekk负载异制结体系 |
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