CN115337471B - 一种用于体外膜肺氧合系统的血液相容性涂层及其制备方法和应用 - Google Patents
一种用于体外膜肺氧合系统的血液相容性涂层及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种用于体外膜肺氧合系统(ECMO)的血液相容性涂层及其制备方法和应用。该制备方法包括对基底材料进行等离子体浸没离子注入表面处理,使基底材料的表面富含氨基;最后在交联剂的作用下将肝素结合到基底材料表面。等离子体浸没离子注入的表面处理方式加强了涂层的稳定性,结合肝素之后的基底材料具有良好的血液相容性。该方法流程简单,使用试剂安全,适合于工业化生产,具有良好的应用前景。
Description
技术领域
本发明涉及医疗器械表面改性领域,具体涉及一种用于体外膜肺氧合系统的血液相容性涂层及其制备方法和应用。
背景技术
体外肺膜氧合系统(ECMO)作为一种体外生命支持设备,自1972年首次用于临床以来,一直是一种治疗严重心肺功能障碍患者的有效手段。ECMO在治疗中用于替代患者的肺部功能,为患者提供长期持续的体外呼吸和循环,为患者延长治疗时间。ECMO主要由代替心脏功能的血泵和代替肺部功能的氧合器构成。氧合器的气体交换膜为中空纤维膜,内部通过气体,表面通过血液。由于氧合器中需要将血液与中空纤维膜充分接触以达到气体交换目的,在此过程中ECMO的组件如外壳和管路等易引发蛋白质沉积、血栓形成、溶血等问题,因此需要对ECMO的组件材料进行一些处理以达到足够高的生物相容性尤其是血液相容性。
提升材料表面的血液相容性的方法有很多,主要分为两种,表面改性和表面生物化。前者通过物理或化学手段将具有生物活性的物质接枝到材料表面,改善表面的亲水性、生物相容性等,常见的如肝素、白蛋白等;后者则通过在材料上构建生物化表面,以达到提升血液相容性的目的,常见的如使用磷酰胆碱构建类细胞膜结构等。
但是现有的方法存在一些问题,如传统的肝素涂层方法是通过材料表面的疏水性吸附一些带有反应基团或正电荷的基底聚合物,然后通过离子键和或共价结合的方式固定肝素。但是通过吸附的方法构建的基底结合能力较差,长时间的冲刷会导致涂层脱落,导致抗凝和抗血栓性能急剧下降,同时脱落的肝素进入血液会导致出血、血小板减少等不良反应;并且传统的湿法化学方法还可能引入具有细胞毒性的试剂或基团,造成更为严重的不良反应。目前报道的磷酰胆碱涂层的方法是将两亲性的磷酰胆碱聚合物溶于有机溶剂中,通过有机溶剂的挥发形成涂层。但是在挥发过程中会导致有机溶剂进入中空纤维膜内部形成亲水性涂层,增加血液经孔隙渗漏进内部的风险。因此寻求一种流程简单,全程无毒性物质参与的涂层方法就显得迫在眉睫,且具有重大的应用意义。
发明内容
本发明的目的是提供一种用于体外膜肺氧合系统(ECMO)的血液相容性涂层及其制备方法和应用,该方法中采用等离子体浸没离子注入的表面处理方式加强了涂层的稳定性,结合肝素之后的材料具有良好的血液相容性。该方法流程简单,使用试剂安全,适合于工业化生产,具有良好的应用前景。
为了达到上述目的,本发明提供了一种用于体外膜肺氧合系统的血液相容性涂层的制备方法,该方法包含以下步骤:
步骤一:通过等离子体浸没离子注入的方法处理基底材料,使基底材料的表面富含氨基;
步骤二:将处理后的材料在交联剂的作用下与生物活性分子溶液进行共价结合;
步骤三:将步骤二所得的基底材料用去离子水冲洗干净,
其中,上述的基底材料为体外膜肺氧合系统的外壳、循环管路以及转接口;上述生物活性分子为具有血液相容性的肝素或白蛋白。
优选地,上述制备方法中的等离子体浸没离子注入方法,其气体环境为氮气、氧气中的任意一种。
优选地,上述制备方法中的等离子体浸没离子注入方法,其浸没处理的条件为:本底真空度为2*10-3KPa,气体引入流量为60sccm,样品盘负压为1.0kV,注入脉宽为50μs,注入脉冲频率为1000Hz,产生气体等离子体所使用的射频功率为300W,处理时间为1h。
优选地,上述制备方法中的交联剂为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺和N-羟基丁二酰亚胺。
优选地,上述制备方法中的生物活性分子溶液的使用浓度为0.2~2mg/mL,处理时间为12~18h。
优选地,上述制备方法中的生物活性分子:EDC:NHS的摩尔比为1:0.4:0.24。
本发明还提供了一种由上述制备方法制备得到的具有血液相容性涂层的材料。
本发明提供的上述制备方法可被应用于医疗器械表面改性领域中,尤其可用于ECMO中基底材料的处理,使其具备良好的血液相容性。
本发明的一种用于体外膜肺氧合系统(ECMO)的血液相容性涂层及其制备方法,解决了现有技术中ECMO中材料的血液相容性差的问题,为临床应用提供了有利的参考,并具有以下优点:
等离子体浸没离子注入技术对于形状较复杂的外壳等离子体浸没离子注入技术比普通的等离子体效果更好,可以使本身没有可结合基团的聚合物表面具有可反应的基团,且与化学方法相比步骤简单,且过程中没有使用有毒性的试剂。
等离子体浸没离子注入技术形成的等离子体可贴合材料表面,形状较为复杂的表面也可均匀地处理。
等离子体浸没离子注入处理过程中的气体使用没有特殊要求,且不同的气体可以产生不同的效果,更有利于接枝不同的生物活性分子。
所用的试剂均无毒性,且整个过程简便易操作,有利于工业化生产。
附图说明
图1为本发明中基底材料经等离子体浸没离子注入处理后结合肝素涂层染色的结果图。
图2为本发明中涂层稳定性检验的结果。
具体实施方式
下面将对本发明实施例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。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
说明:本发明中用到的试剂如无特殊说明,均为常规试剂;所用到的方法如无特殊说明的,均为常规方法。
实施例1
将氧合器的循环管路和转接口用酒精清洗干净,随后放入PIII处理机中,抽真空至2*10-3kPa,然后设置条件:气体流速为60sccm通入氮气,所加负偏压为1.0kV,注入脉宽为50μs,注入脉冲频率为1000Hz,射频功率为300W,处理1h。
然后按2mg/mL浓度的肝素溶于MES缓冲溶液(50mM/L、9.76mg/mL)制成溶液,将外壳和管路浸泡在肝素溶液中18h,然后配置EDC/NHS溶液(EDC:50mM、9.585mg/mL;NHS:25mM、2.875mg/mL)固定肝素2h,随后将循环管路和转接口清洗干净。
实施例2
将氧合器的循环管路和转接口用酒精清洗干净,随后放入PIII处理机中,抽真空至2*10-3kPa,然后设置条件:气体流速为60sccm通入氧气,所加负偏压为1.0kV,注入脉宽为50μs,注入脉冲频率为1000Hz,射频功率为300W,处理1h。
将处理好的材料放入体积比为20%(v/v)的APTES水溶液中,80℃反应2h后取出冲洗干净。然后按2mg/mL浓度的肝素溶于MES缓冲溶液(50mM/L、9.76mg/mL)制成溶液,将外壳和管路浸泡在肝素溶液中18h,然后配置EDC/NHS溶液(EDC:50mM、9.585mg/mL;NHS:25mM、2.875mg/mL)固定肝素2h,随后将循环管路和转接口清洗干净。
实验例1
将实例1中的循环管路和转接口置于浓度为0.187mg/mL的甲苯胺蓝溶液中浸泡12h后取出,去离子水冲洗未附着的染料,有涂层和无涂层的组件染色对比结果如图1所示,其中图中的A为循环管路处理及染色结果,图中的B为转接口处理及染色结果。随后在50%的乙酸溶液中浸泡10min,使用紫外分光光度计在633nm测量上清液的光密度。
标准曲线使用0.01mM(0.00374mg/mL)的甲苯胺蓝O(TBO)在50%乙酸溶液的系列稀释产生的校准曲线来计算,定量检测表面肝素结合量;将管路和转接口连接好后以200mL/min的流量通入PBS溶液,循环3天后重新定量检测表面肝素结合量,检测结果如图2所示,其中图2中的“管”和“转接口”为做好涂层后的肝素定量结果,“3day”为循环三天后重新测定涂层肝素量的结果,表明经过处理后的管和转接口,其上的血液相容性涂层具备良好的保存效果,应用性也更强。
尽管本发明的内容已经通过上述优选实施例作了详细介绍,但应当认识到上述的描述不应被认为是对本发明的限制。在本领域技术人员阅读了上述内容后,对于本发明的多种修改和替代都将是显而易见的。因此,本发明的保护范围应由所附的权利要求来限定。
Claims (4)
1.一种用于体外膜肺氧合系统的血液相容性涂层的制备方法,其特征在于,该方法包含以下步骤:
步骤一:通过等离子体浸没离子注入的方法处理基底材料,使基底材料的表面富含氨基;所述的基底材料为体外膜肺氧合系统的外壳、循环管路、转接口中任意一种或两种以上;其中,所述等离子体浸没离子注入的方法,其处理的条件为:本底真空度为2*10-3KPa,气体引入流量为60sccm,样品盘负压为1.0kV,注入脉宽为50μs,注入脉冲频率为1000Hz,产生气体等离子体所使用的射频功率为300W,处理时间为1h;
步骤二:将处理后的材料在交联剂的作用下与生物活性分子溶液进行共价结合;所述生物活性分子为具有血液相容性的肝素或白蛋白;其中,所述生物活性分子溶液的使用浓度为0.2~2mg/mL,处理时间为12~18h;所述生物活性分子:EDC:NHS的摩尔比为1:0.4:0.24;
步骤三:将步骤二所得的基底材料用去离子水冲洗干净。
2.根据权利要求1所述的用于体外膜肺氧合系统的血液相容性涂层的制备方法,其特征在于,所述的等离子体浸没离子注入方法,其气体环境为氮气、氧气中的任意一种。
3.根据权利要求1所述的用于体外膜肺氧合系统的血液相容性涂层的制备方法,其特征在于,所述的交联剂为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺和N-羟基丁二酰亚胺。
4.根据权利要求1~3中任意一项所述的制备方法制备得到的具有血液相容性涂层的材料。
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