CN116370723A - 一种在金属密网支架表面构建磷酰胆碱涂层的方法 - Google Patents
一种在金属密网支架表面构建磷酰胆碱涂层的方法 Download PDFInfo
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Abstract
本发明属于生物医用材料领域,公开了一种在金属密网支架表面构建磷酰胆碱涂层的方法,包括:在金属密网支架的表面首先形成一层多巴胺涂层;然后将表面具有多巴胺涂层的金属密网支架置于聚烯丙胺溶液中,反应后在金属密网支架表面形成一层富氨基涂层;之后再将表面带有富氨基涂层的金属密网支架置于磷酰胆碱溶液中,反应后干燥以在金属密网支架表面形成磷酰胆碱涂层。该制备方法由于聚多巴胺的通用粘附能力,适用于多种惰性材料表面;而由于磷酰胆碱的存在,可以进一步提高金属密网支架在植入期间的抗凝血能力并抑制平滑肌细胞的生长。
Description
技术领域
本发明涉及一种在金属密网支架表面构建磷酰胆碱涂层的方法,具体涉及一种具有抗凝功能的涂层及其制备方法,属于生物医用材料领域。
背景技术
颅内动脉瘤是指颅内动脉的血管壁因先天发育不全或发生脑颅损伤而出现异常的膨出。有研究发现中国成年人颅内动脉瘤的患病率高达7%,此外随着检查方法的进步以及人类寿命的延长,颅内动脉瘤的患病率有进一步增高的趋势。目前颅内动脉瘤的治疗方式主要有开颅夹闭术和血管内介入治疗。近年来,随着介入材料以及技术方法的不断进步,血管内介入治疗成为颅内动脉瘤的首选治疗方法。目前血管内介入治疗使用的辅助装置主要是密网支架,它在治疗巨大动脉瘤时存在着较大的优势,它主要是通过细小密集的网孔以及较大的金属覆盖率来减少动脉瘤囊内的血流动力学作用并来诱导动脉瘤内的血流停滞以及随后的血栓形成,同时又可以保证正常的母血管和分支血管血流不受影响。但是另一方面由于密网支架的网孔较为密集以及其植入后异常的血流流体力学条件也使得它加剧了血管内血栓栓塞的风险。因此找到一种可靠的能够有效减少密网支架血栓栓塞问题的方法可以进一步扩大其应用范围。
减少血栓形成的常见解决方案是将抗血小板药物引入血液中以维持全身抗凝,但抗血小板药物的使用会产生出血等风险。随着新技术的发展,最新的解决方案是对血管内介入支架进行表面改性。表面改性可以在保持基底材料的原有结构和性能不变的前提下,针对性地修饰材料表面,从而提高材料表面某些方面的性能。磷酰胆碱是一种高度亲水的两性离子头基,存在于红细胞双分子层细胞膜外表面,可以结合水分子来形成水合层,不会激活内源性凝血途径,可以用其提高材料表面的血液相容性。王晓丽发表了《医用不锈钢的细胞膜仿生表面修饰》的文章,说明可以利用先羟基化后硅烷化进而利用迈克尔加成反应接枝磷酰胆碱分子进行细胞膜仿生修饰,从而提高材料表面的抗凝血性能。然而该方法在偶联生物大分子MPC时,反应条件较为苛刻,需要强碱性环境,因此在一定程度上限制了其应用。故在简单条件下制备具有MPC的涂层来解决密网支架血管内血栓栓塞的问题具有重要意义。
发明内容
本发明的目的是在反应条件比较温和安全的情况下提供一种在金属密网支架表面构建磷酰胆碱涂层的方法,该涂层针对颅内动脉瘤支架,会降低该支架植入后所引起的血管内血栓栓塞的风险。
本发明的技术方案:
一种在金属密网支架表面构建磷酰胆碱涂层的方法,首先在支架表面接枝一层多巴胺涂层;然后在碱性条件下将聚烯丙胺通过席夫碱反应和迈克尔加成方式接枝在多巴胺涂层表面,构建出富氨基涂层;最后利用迈克尔加成反应将2-甲基丙烯酰氧乙基磷酰胆碱共价固定于富氨基涂层表面即得到抗凝涂层。
具体步骤如下:
(1)表面预处理:将金属密网支架依次用丙酮、去离子水、乙醇超声洗涤多次,吹干,得到处理过的金属密网支架备用;
(2)制备富氨基涂层:将处理过的金属密网支架放置于多巴胺的碱性溶液中反应,反应结束后用去离子水超声清洗样品并干燥,得到改性的金属密网支架;再将改性的金属密网支架置于聚烯丙胺的碱性溶液中反应,反应结束后去离子水超声清洗并干燥,得到富氨基化的金属密网支架;
(3)制备磷酰胆碱涂层:将富氨基化的金属密网支架放入2-甲基丙烯酰氧乙基磷酰胆碱溶液中进行反应,再将其用乙醇超声清洗并干燥,得到接枝磷酰胆碱的金属密网支架。
步骤(1)中,所述预处理中超声的时间为10min~2h。
步骤(2)中,所述多巴胺的碱性溶液以及聚烯丙胺的碱性溶液中含有三羟甲基氨基甲烷缓冲液。
步骤(2)中,所述多巴胺的碱性溶液以及聚烯丙胺的碱性溶液的pH为8~10。
步骤(2)中,所述两次反应的温度均为10~50℃,两次反应的时间均为12~48h。
步骤(2)中,所述多巴胺的碱性溶液浓度为0.1mg/mL~2mg/mL。
步骤(2)中,所述聚烯丙胺的碱性浓度为5mg/mL~20mg/ml。
步骤(2)中,所述干燥温度为10~150℃。
步骤(3)中,所述2-甲基丙烯酰氧乙基磷酰胆碱的浓度为1mg/mL~20mg/mL,溶剂为乙醇。
步骤(3)中,所述溶液中反应温度为10~50℃,反应时间为12~48h,所述干燥温度为30~80℃。
本发明将2-甲基丙烯酰氧乙基磷酰胆碱分子接枝在富氨基化多巴胺涂层表面,利用MPC的超亲水性和生物相容性,提高了材料表面的抗凝血性能和细胞相容性。
与现有技术相比,本发明的有益效果:
本发明采用了先接枝多巴胺,再利用聚烯丙胺进行富氨基化,最后接枝2-甲基丙烯酰氧乙基磷酰胆碱的方法在金属密网支架表面构建磷酰胆碱涂层。该方法操作较为简便,所用原材料均对人体无害,具有良好的生物相容性,反应条件温和且容易实现,有望作为人体植入材料的表面涂层大规模应用。另外由于聚多巴胺优异的通用粘附能力,该方法适用于多种惰性材料表面,可以进一步扩大该涂层的应用范围。
附图说明
图1为XPS测试中得到的表面接枝磷酰胆碱涂层的基底材料的XPS测试的磷谱图;
图2为XPS测试中得到的表面接枝磷酰胆碱涂层的基底材料的XPS测试的氮谱图;
图3为表面接枝磷酰胆碱涂层的基底材料的亲疏水性评判图;
图4为血小板粘附在空白基底材料上的扫描电镜图像;
图5为血小板粘附在表面接枝磷酰胆碱涂层的基底材料上的扫描电镜图像;
图6为在不同基底材料的表面培养平滑肌细胞的增殖检测图。
具体实施方式
下面将结合本发明的实施例及说明书附图,对本发明具体实施方式中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例,不能将它们理解为对本发明保护范围的限定。
实施例1
本实施例提供一种在金属密网支架表面构建磷酰胆碱涂层的方法,其制备方法包括:
(1)表面预处理
依次用丙酮、去离子水、乙醇将基底材料进行洗涤,超声清洗3次,每次超声处理30min,去除表面残留杂质,干燥后得到处理过的基底材料备用。
(2)制备富氨基涂层
将清洗过的基底材料置于pH为8的反应溶液中反应24h,该反应溶液含有多巴胺,多巴胺的浓度为1mg/mL,反应后在40℃进行干燥,干燥后在基底材料的表面形成具有多巴胺薄膜层;将表面具有多巴胺薄膜层的基底材料置于聚烯丙胺溶液中,聚烯丙胺溶液的pH为8,浓度为10mg/mL,在30℃温度下反应12h,反应后在40℃进行干燥以在基底材料表面形成富氨基涂层。
(3)制备磷酰胆碱涂层
将表面具有富氨基涂层的基底材料置于浓度为1%的2-甲基丙烯酰氧乙基磷酰胆碱溶液中,在30℃温度下反应24h,反应后在40℃下进行干燥以在基底材料表面形成磷酰胆碱涂层,从而得到支架涂层。
使用X射线光电子能谱对实施例1制得的表面接枝磷酰胆碱涂层的基底材料进行元素组成以及化学价态进行分析,该测试的激发光源为单色化Al Ka源。
表面接枝磷酰胆碱涂层的基底材料的XPS测试磷谱图如图1所示。在图中可以看出,接枝磷酰胆碱涂层的基底材料中出现了较为明显的磷元素特征峰。表面接枝磷酰胆碱涂层的基底材料的XPS测试氮谱图如图2所示。在N1s的高分辨拟合图中可以看出,该支架涂层材料表面含有-NR3 +、芳香族N、脂肪族N-N和N-H2、-N+(CH3)3等多种特征基团。
使用水接触角测量仪测量表面接枝磷酰胆碱涂层的基底材料的水接触角,将2μL去离子水滴在待测样品表面,并选取水滴接触涂层240ms的图片通过拟合分析法测量接触角大小。
表面接枝磷酰胆碱涂层的基底材料的水接触角测试结果如图3所示。可以看出,接枝磷酰胆碱涂层的基底材料表面表现出良好的亲水性。
将用到的实验器材用生理盐水超声清洗30min,并用酒精对板材进行消毒;加入生理盐水直至浸没板材,润湿板材后用胶头滴管移除生理盐水;在润湿后的空白基底材料以及表面接枝磷酰胆碱涂层的基底材料上加入5mL新鲜的PRP,并在转速120rmp,37℃的摇床中培育120min;用生理盐水清洗板材,用2.5%戊二醛溶液对板材固定12h后用50%-100%的酒精进行梯度脱水;室温下干燥24h后用扫描电镜对样品表面血小板粘附形貌进行表征。
图4为血小板粘附在空白基底材料上的扫描电镜图像。从图中可以看出,从图中可以看出,在空白板材基底材料上粘附的血小板较多,并出现了树枝状以及粘附形态的血小板。
图5为血小板粘附在表面接枝磷酰胆碱涂层的基底材料上的扫描电镜图像。相较于图4而言,在接枝磷酰胆碱涂层的基底材料上的血小板数量较少并且呈现圆形,表明该涂层具有较好的抗凝血性能。
将平滑肌细胞接种在空白基材、富氨基化基材以及表面接枝磷酰胆碱基材的表面,在培养箱分别培养1、3、5天后,加入细胞计数试剂继续在培养箱培养3h,然后利用酶标仪检测培养液在450nm波长下的吸光度。
图6是平滑肌细胞在空白基材、富氨基化基材以及表面接枝磷酰胆碱基材的表面上培养1、3、5天的检测结果。由图中可知,在三种不同形貌表面的细胞数量均随着时间延长而增加,这证明了涂层表面均没有细胞毒性。此外可以看出接枝磷酰胆碱涂层的基底材料上细胞数量较其他板材上细胞数量较少,表明磷酰胆碱可能会稍微抑制平滑肌细胞的生长,可能有助于减轻支架内再狭窄。
实施例2
本实施例提供一种在金属密网支架表面构建磷酰胆碱涂层的方法,其制备方法包括:
(1)表面预处理
依次用丙酮、去离子水、乙醇将基底材料进行洗涤,超声清洗3次,每次超声处理1h,去除表面残留杂质,干燥后得到处理过的基底材料备用。
(2)制备富氨基涂层
将清洗过的基底材料置于pH为8.5的反应溶液中反应24h,该反应溶液含有多巴胺,多巴胺的浓度为1.5mg/mL,反应后在60℃进行干燥,干燥后在基底材料的表面形成具有多巴胺薄膜层;将表面具有多巴胺薄膜层的基底材料置于聚烯丙胺溶液中,聚烯丙胺溶液的pH为8.5,浓度为5mg/mL,在40℃温度下反应24h,反应后在60℃进行干燥以在基底材料表面形成富氨基涂层。
(3)制备磷酰胆碱涂层
将表面具有富氨基涂层的基底材料置于浓度为2%的2-甲基丙烯酰氧乙基磷酰胆碱溶液中,在40℃温度下反应24h,反应后在60℃下进行干燥以在基底材料表面形成磷酰胆碱涂层,从而得到支架涂层。
XPS测试表明了磷酰胆碱涂层的成功制备;血小板粘附实验表明磷酰胆碱涂层具有优异的抗凝血性能。
Claims (6)
1.一种在金属密网支架表面构建磷酰胆碱涂层的方法,其特征在于,首先在支架表面接枝一层多巴胺涂层;然后在碱性条件下将聚烯丙胺通过席夫碱反应和迈克尔加成方式接枝在多巴胺涂层表面,构建出富氨基涂层;最后利用迈克尔加成反应将2-甲基丙烯酰氧乙基磷酰胆碱共价固定于富氨基涂层表面即得到抗凝涂层;
具体步骤如下:
(1)表面预处理:将金属密网支架依次用丙酮、去离子水、乙醇超声洗涤多次,吹干,得到处理过的金属密网支架;
(2)制备富氨基涂层:将处理过的金属密网支架放置于多巴胺的碱性溶液中反应,反应结束后用去离子水超声清洗样品并干燥,得到改性的金属密网支架;再将改性的金属密网支架置于聚烯丙胺的碱性溶液中反应,反应结束后去离子水超声清洗并干燥,得到富氨基化的金属密网支架;
(3)制备磷酰胆碱涂层:将富氨基化的金属密网支架放入2-甲基丙烯酰氧乙基磷酰胆碱溶液中进行反应,再将其用乙醇超声清洗并干燥,得到接枝磷酰胆碱的金属密网支架。
2.根据权利要求1在金属密网支架表面构建磷酰胆碱涂层的方法,其特征在于,步骤(1)中,预处理中超声的时间为10min~2h。
3.根据权利要求1在金属密网支架表面构建磷酰胆碱涂层的方法,其特征在于,
步骤(2)中,多巴胺的碱性溶液以及聚烯丙胺的碱性溶液中含有三羟甲基氨基甲烷缓冲液;
多巴胺的碱性溶液以及聚烯丙胺的碱性溶液的pH为8~10;
多巴胺的碱性溶液浓度为0.1mg/mL~2mg/mL;
聚烯丙胺的碱性浓度为5mg/mL~20mg/ml。
4.根据权利要求1在金属密网支架表面构建磷酰胆碱涂层的方法,其特征在于,
步骤(2)中,两次反应的温度均为10~50℃,两次反应的时间均为12~48h;
两次干燥温度为10~150℃。
5.根据权利要求1在金属密网支架表面构建磷酰胆碱涂层的方法,其特征在于,
步骤(3)中,2-甲基丙烯酰氧乙基磷酰胆碱的浓度为1mg/mL~20mg/mL,溶剂为乙醇。
6.根据权利要求1在金属密网支架表面构建磷酰胆碱涂层的方法,其特征在于,
步骤(3)中,反应温度为10~50℃,反应时间为12~48h;干燥温度为30~80℃。
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