CN117323473A - 一种亲水抗凝涂层及其制备方法和应用 - Google Patents
一种亲水抗凝涂层及其制备方法和应用 Download PDFInfo
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- CN117323473A CN117323473A CN202311275550.XA CN202311275550A CN117323473A CN 117323473 A CN117323473 A CN 117323473A CN 202311275550 A CN202311275550 A CN 202311275550A CN 117323473 A CN117323473 A CN 117323473A
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- Materials For Medical Uses (AREA)
Abstract
本发明公开了一种亲水抗凝涂层的制备方法:S1、制备底层溶液:取原料PEI、KH560,加入去离子水中,使原料充分反应,得到底层溶液;S2、制备氧化肝素溶液:将氧化剂溶于去离子水中,调节溶液pH值为5.5,然后加入肝素钠,原料充分反应后,旋蒸溶液并冻干,冻干得到的粉末进行纯化,将得到的氧化肝素粉末溶于去离子水中得氧化肝素溶液;S3、涂覆抗凝涂层:让待处理医用材料与底层溶液充分接触,清洗;取氧化肝素溶液,让医用材料与氧化肝素溶液接触1‑3h后,在氧化肝素溶液中加入还原剂,充分接触8‑18h,清洗,干燥,即得到亲水抗凝涂层。本发明的亲水抗凝涂层明显提升了PVC管路的抗凝血性能。
Description
技术领域
本发明涉及医用材料技术领域,具体涉及一种亲水抗凝涂层及其制备方法和应用。
背景技术
在医学领域中,医用高分子材料及医疗器械主要用于诊断和治疗,每天有成千上万的病人使用血液接触类器械,如血液透析循环管路、中心静脉导管、心脏支架、血管移植物、心脏瓣膜等。该类器械直接与血液接触时会发生一系列反应,血浆蛋白首先会瞬间在材料表面吸附形成血浆蛋白,然后血小板会在血浆蛋白表面黏附、聚集,进而使血小板激活、凝血级联及补体激活,最终导致血栓形成。据美国食品药品管理局(FDA)统计,2016年美国此类医疗器械的市场销售额约为90亿美元,但在心脏支架的使用过程中由于血栓形成导致的死亡率高达80%,严重威胁着人类的健康及生命安全。因此,提高血液接触类器械的生物相容性,特别是血液相容性,是解决该问题的关键。
目前,解决该技术问题的现有技术方案有:
1、在治疗中注射抗凝剂来抑制器械表面血栓形成。
2、表面涂层技术,包括在材料表面涂覆或嫁接另一种血液相容性材料,按照其原理大致可分为三类:
A.构建生物材料惰性表面:由于血液中多种组分(如血红蛋白、血小板、部分血浆蛋白质等)在血液环境中呈电负性,血管内壁也呈电负性,静电排斥作用可以阻碍血浆蛋白及血小板等物质的吸附,从而有利于抗凝血。将亲水性阴离子聚合物共价键合在材料表面,提高材料表面亲水性。通过在材料表面构建生物惰性层,可以降低界面自由能,减弱材料表面与血浆蛋白、血细胞的相互作用,从而保持血浆蛋白、血细胞的正常构象和形态,使材料显示出良好的抗凝血性能。目前主要有两种构建方法:①构建聚乙二醇(PEG)或两性离子聚合物等亲水刷或水凝胶,抑制蛋白质、血小板等的吸附。②构建滑移表面,抑制水或血液润湿从而阻碍蛋白质、血小板等在材料/器械表面吸附。
B.材料表面仿生化:模拟生物膜的功能主要有三种技术:用磷酰胆碱、两亲分子或脂质体对材料表面进行修饰;通过在材料表面连接长柔性链或天然磷脂来模拟生物膜的结构和形态;模拟生物膜功能,如运输、催化和分子识别。这些涂层增加了生物材料表面的电荷极性和亲水性,通过吸引水分子降低生物材料的表面能。长链分子侧链的极性基团可使水分子聚集,在材料与血液接触面上形成水分子层,以组织蛋白质和血小板的吸附。这类涂层主要有磷酰胆碱涂层、糖胺多糖涂层等。
C.生物活性涂层:在高分子材料表面引入生物活性物质,如肝素、一氧化氮(NO)、抗凝药物、内皮细胞粘附物、促纤溶酶原吸附物等形成生物活性涂层预防凝血和血栓形成,这些活性物质可以选择性吸附或结合特定的生物大分子与血液相互作用及减少凝血酶的产生。目前最常见的生物活性涂层有:肝素钠盐涂层、抗凝药物涂层和一氧化氮涂层。
但是,目前这些技术的抗凝血处理方式存在以下缺点:1)全身性肝素化可能破坏机体凝血调节能力,导致自发性出血、凝血困难和超敏反应等并发症。并且全身性肝素化,剂量难以把控。低剂量肝素不能达到抗凝血效果,高剂量的抗凝剂又会导致某些副作用,如高剂量肝素会引起血小板减少症(HIT)、出血、肺栓塞及血栓性静脉炎等。2)部分涂层涉及复杂的合成过程,成本高昂,在合成过程中使用一些有毒的试剂,容易导致毒性物质残留。3)现有技术的抗凝血涂层在涂覆肝素之前需要对介入类医疗器械表面进行预处理,如用强碱、等离子体预处理,从而使抗凝血涂层基底能稳定被涂覆在器械表面。但这可能会对表面造成一定的损伤,进一步提升凝血发生的风险。4)传统的肝素改性方法在于针对肝素钠羧基、磺酸基等分子链多位点的修饰改性,容易导致肝素失活,降低了肝素的抗凝血特性。5)目前市面上大多数涂层的涂覆方式是采用浸泡法,会导致涂覆不均匀。
发明内容
本发明的目的之一是针对上述问题,提供一种亲水抗凝涂层的制备方法,包括如下步骤:
S1、制备底层溶液:取原料PEI、KH560,加入去离子水中,PEI的浓度为0.001-0.02g/mL,KH560的浓度为0.01-0.05g/mL,搅拌使原料溶解,调节pH值为8.5,搅拌使原料充分反应,得到底层溶液;
S2、制备氧化肝素溶液:将氧化剂溶于去离子水中,调节溶液pH值为5.5,然后加入肝素钠,溶液中肝素钠的浓度为0.15-0.2g/mL,氧化剂的浓度为0.005-0.05g/mL,室温下避光反应10-24h至原料充分反应后在反应溶液中加入终止剂乙二醇终止反应,然后旋蒸溶液并冻干,冻干得到的粉末采用有机溶剂水溶液进行纯化,得到纯化后的氧化肝素粉末,将得到的氧化肝素粉末溶于去离子水中,得浓度为0.08-1g/mL的氧化肝素溶液;所述氧化剂选自高碘酸钠、过氧化氢、过氧乙酸,所述有机溶剂选自乙醇、丙酮、甲醇;
S3、涂覆抗凝涂层:取步骤S1制备的底层溶液,让待处理医用材料与底层溶液充分接触3-6h,然后用超纯水清洗干净;取步骤S2制备的氧化肝素溶液,让底层溶液处理后的医用材料与氧化肝素溶液充分接触1-3h后,在氧化肝素溶液中加入还原剂,让医用材料继续与氧化肝素溶液充分接触8-18h,反应完成后用超纯水清洗干净,干燥,即在医用材料表面制备得到亲水抗凝涂层;所述还原剂选自硼氢化钠、抗坏血酸、氰基硼氢化钠;还原剂在氧化肝素溶液中的浓度为0.005-0.01g/mL。
优选地,所述步骤S1的反应在25-70℃进行,搅拌反应2-6h;所述步骤S2中室温下避光反应10-24h,步骤2)中氧化肝素溶液的浓度为0.08-0.5g/mL或0.09-0.3g/mL或0.09-0.2g/mL或0.09-0.15g/mL。
优选地,所述步骤S1、S2中采用5-10%氢氧化钠溶液调节pH值。
优选地,步骤S2中终止剂与反应溶液的体积比为1﹕16-24,有机溶剂水溶液与反应溶液的体积比为3-7﹕1;
旋蒸温度为30-70℃,旋蒸时间为3-5h,旋蒸后冻干20-28h,然后将冻干粉加入有机溶剂中沉降出氧化肝素后离心,弃去上清液后进行冷冻干燥处理,即得到纯化后的氧化肝素粉末;
优选有机溶剂为乙醇,优选为浓度为60-85%的乙醇水溶液。
优选地,步骤S3中,底层溶液、氧化肝素溶液在待处理医用材料表面循环流动接触。
优选地,所述医用材料为管路,S3、涂覆抗凝涂层:取步骤S1制备的底层溶液,通入待涂覆管路中,让底层溶液在管路中循环流动3-6h,反应完成后通入超纯水清洗1-3次,然后在管路中通入氧化肝素溶液,氧化肝素溶液循环流通1-3h后加入还原剂继续反应8-18h,反应完成后通入超纯水清洗1-3次,然后将管路在45-55℃下烘干处理3-8h,管路的内表面即涂覆上亲水抗凝涂层。
优选地,所述医用材料的材质选自丙烯腈-丁二烯-苯乙烯共聚物、聚丙烯、聚氯乙烯(PVC)、聚乙烯。
本发明的再一目的是提供上述任一项所述的制备方法制备得到的亲水抗凝涂层。
本发明的最后一目的是提供上述的亲水抗凝涂层在制备血液接触类医疗器械中的应用。
在所述的应用技术方案中,所述血液接触类医疗器械包括血液透析循环管路、中心静脉导管、心脏支架、血管移植物、心脏瓣膜。
本发明的有益效果是:本发明的亲水抗凝涂层为两层膜构成的膜结构,底层为带氨基的硅烷,顶层为带醛基的肝素抗凝层,顶层与底层通过醛胺缩合共价结合。和现有技术相比,本发明的抗凝涂层具有如下优点:
1、全身性肝素化可能破坏机体凝血调节能力,导致自发性出血、凝血困难和超敏反应等并发症。并且全身性肝素化,剂量难以把控。低剂量肝素不能达到抗凝血效果,高剂量的抗凝剂又会导致某些副作用,如高剂量肝素会引起血小板减少症(HIT)、出血、肺栓塞及血栓性静脉炎等。本发明采用肝素涂层的方式,避免全身性肝素化的隐患,并能有效减少肝素的使用量,降低成本。
2、部分涂层涉及复杂的合成过程,成本高昂,在合成过程中使用一些有毒的试剂,容易导致毒性物质残留。本发明所需材料种类少,合成简单,不含任何有毒有害物质,更加安全。
3、现有技术的抗凝血涂层在涂覆肝素之前需要对介入类医疗器械表面进行预处理,如用强碱、等离子体预处理,从而使抗凝血涂层基底能稳定被涂覆在器械表面。但这可能会对表面造成一定的损伤,进一步提升凝血发生的风险。本发明无需表面预处理,本发明的抗凝涂层选用的基底材料自身具有良好的粘附性,无需表面预处理。
4、传统的肝素改性方法在于针对肝素钠羧基、磺酸基等分子链多位点的修饰改性,容易导致肝素失活,降低了肝素的抗凝血特性。本发明通过氧化非还原端端基,使肝素分子带有醛基,并与底层带有反应活性基团的氨基化合物中的氨基的单位点反应,可稳定地将肝素分子固定在各类带涂层基材表面,避免了肝素的羧基活性基团直接与氨基反应从而导致肝素抗凝活性降低的问题,充分保证了改性后接枝肝素的抗凝血性能。
5、目前市面上大多数涂层的涂覆方式是采用浸泡法,会导致涂覆不均匀。通过溶液流动法涂覆,涂覆更均匀。
附图说明
图1为实施例1-3、对比例1-3所得亲水抗凝涂层的水接触角数据。
图2为实施例1所得亲水抗凝涂层涂覆过程中各层的水接触角数据。
图3实施例1所得亲水抗凝涂层材料的细胞毒性测试结果图。
图4实施例1所得亲水抗凝涂层材料的血液相容性结果图。
具体实施方式
下面结合实施例对本发明作进一步说明,但并不因此而限制本发明。
下述实施例中的实验方法,如无特别说明,均为常规方法;所用材料和试剂,如无特殊说明,均为本领域常规材料和试剂,均可商购获得。
主要试剂如下:
3-氨基丙基三甲氧基硅烷(γ-APS):CAS号:13822-56-5;
1,2-双(三乙氧基甲硅烷基)乙烷(BTSE):CAS号:16068-37-4;
聚乙烯亚胺(PEI):CAS号:9002-98-6;
γ-缩水甘油醚丙基三甲氧基硅烷(KH560):CAS号:2530-83-8;
γ-氨丙基三甲氧基硅烷(KH540):CAS号:13822-56-5;
肝素钠(Heparin sodium):CAS号:9041-08-1。
按照本发明方法制备表1的抗凝涂层:
表1
实施例1、制备本发明的亲水抗凝涂层
(1)制备底层溶液:称量1g PEI、1g KH560和50mL去离子水,加入250mL三颈烧瓶中,加入10%的氢氧化钠溶液调节pH至8.5。在65℃水浴条件下搅拌。反应2h,即得KH560/PEI溶液(溶液1)。
KH560中的环氧基团开环后与PEI的氨基基团发生反应,生成带有氨基的硅氧烷。然后,KH560结构中的Si-O-CH3在水溶液中会发生水解,形成硅离子,而医用材料管路PVC中的羟基(-OH)会与硅离子反应,以Si-O键发生键合,使得带氨基的硅氧烷成功粘附在管路表面。
(2)制备抗凝层溶液:取5g高碘酸钠溶于100mL去离子水,用5%的氢氧化钠溶液调整pH至5.5,然后边搅拌边加入20g肝素钠。室温下避光反应10h。反应结束后加5mL乙二醇结束反应。然后在30℃下旋蒸4h,以蒸发水溶液,在30℃下旋蒸后冻干24h。按体积比水﹕无水乙醇=1﹕4的体积比配制500mL乙醇水溶液(即80%的酒精),将冻干后得到的粉末进行纯化:将冻干后得到的粉末加入80%的酒精中沉降出氧化肝素后离心,弃去上清液后进行冷冻干燥处理,即得到纯化后的氧化肝素粉末。将纯化后的氧化肝素粉末溶解于去离子水中配制为浓度为0.1g/mL的氧化肝素涂层溶液(溶液2)。
(3)管壁涂覆:将医用PVC管材进行纯化水超声清洗并风干后,在室温下用蠕动泵带动溶液1在PVC管材内进行循环,反应6h。然后用纯水冲洗PVC管材内部管壁1次后,在室温下用蠕动泵带动溶液2在PVC管材内循环1h,使得试剂中的氨基与醛基反应生成N=C双键;然后将0.5g还原剂硼氢化钠用1ml去离子水溶解成溶液后加入到循环的溶液2中,继续循环反应12h,其中还原剂将N=C双键还原成N-C单键。用纯化水冲洗3次后放入50℃烘箱中交联干燥固定5h,得到抗凝涂层。
实施例2、制备本发明的亲水抗凝涂层
(1)称量0.05g PEI、2.5g KH560和50mL去离子水,加入250mL三颈烧瓶中,加入10%的氢氧化钠溶液,调节pH至8.5。在65℃水浴条件下搅拌。反应2h,即得KH560/PEI溶液(溶液1);
(2)取0.5g过氧化氢溶于100mL去离子水,用5%的氢氧化钠溶液调整pH至5.5,边搅拌边加入15g肝素钠。室温下避光反应10h。反应结束后加5mL乙二醇结束反应。在30℃下旋蒸后冻干。按体积比水﹕乙醇=1﹕4的比例配制500mL溶液,将冻干后得到的粉末进行纯化。弃去液体后,将样品冷冻干燥处理,即得氧化肝素粉末。将氧化肝素粉末溶解于去离子水中配制为浓度为0.1g/mL的氧化肝素涂层溶液(溶液2);
(3)将医用PVC管材进行纯化水超声清洗并风干后,用蠕动泵带动溶液1在PVC管材内进行循环,反应6h。然后用纯水冲洗PVC管材内部管壁1次后,用蠕动泵带动溶液2在PVC管材内循环1h后,加入0.8g硼氢化钠,反应12h。用纯化水冲洗3次后放入50℃烘箱中交联干燥固定5h,得到抗凝涂层。
实施例3、制备本发明的亲水抗凝涂层
(1)称量0.3g PEI、0.5g KH560和50mL去离子水,加入250mL三颈烧瓶中,加入10%的氢氧化钠溶液,调节pH至8.5。在65℃水浴条件下搅拌。反应2h,即得KH560/PEI溶液(溶液1);
(2)取3g过氧乙酸溶于100mL去离子水,用5%的氢氧化钠溶液调整pH至5.5,边搅拌边加入15g肝素钠。室温下避光反应10h。反应结束后加5mL乙二醇结束反应。在30℃下旋蒸后冻干。按体积比水﹕乙醇=1﹕4的比例配制500mL溶液,将冻干后得到的粉末进行纯化。弃去液体后,将样品冷冻干燥处理,即得氧化肝素粉末。将氧化肝素粉末溶解于去离子水中配制为浓度为0.1g/mL的氧化肝素涂层溶液(溶液2);
(3)将医用PVC管材进行纯化水超声清洗并风干后,用蠕动泵带动溶液1在PVC管材内进行循环,反应6h。然后用纯水冲洗PVC管材内部管壁1次后,用蠕动泵带动溶液2在PVC管材内循环1h后,加入1g抗坏血酸,反应12h。用纯化水冲洗3次后放入50℃烘箱中交联干燥固定5h,得到抗凝涂层。
对比例1
(1)称量1gγ-APS溶解于和50mL去离子水,搅拌1h充分水解,γ-APS水解溶液(溶液1);
(2)取5g高碘酸钠溶于100mL去离子水,用5%的氢氧化钠溶液调整pH至5.5,边搅拌边加入20g肝素钠。室温下避光反应10h。反应结束后加5mL乙二醇结束反应。在30℃下旋蒸后冻干。按体积比水﹕乙醇=1﹕4的比例配制500mL溶液,将冻干后得到的粉末进行纯化。弃去液体后,将样品冷冻干燥处理,即得氧化肝素粉末。将氧化肝素粉末溶解于去离子水中配制为浓度为0.1g/mL的氧化肝素涂层溶液(溶液2);
(3)将医用PVC管材进行纯化水超声清洗并风干后,用蠕动泵带动溶液1在PVC管材内进行循环,反应6h。然后用纯水冲洗PVC管材内部管壁1次后,用蠕动泵带动溶液2在PVC管材内循环1h后,加入0.5g氰基硼氢化钠,反应12h。用纯化水冲洗3次后放入50℃烘箱中交联干燥固定5h,得到抗凝涂层。
对比例2
(1)称量1gγ-APS、0.5g BTSE溶解于50mL去离子水,搅拌反应1h,即得γ-APS/BTSE溶液(溶液1);
(2)取5g高碘酸钠溶于100mL去离子水,用5%的氢氧化钠溶液调整pH至5.5,边搅拌边加入20g肝素钠。室温下避光反应10h。反应结束后加5mL乙二醇结束反应。在30℃下旋蒸后冻干。按体积比水﹕乙醇=1﹕4的比例配制500mL溶液,将冻干后得到的粉末进行纯化。弃去液体后,将样品冷冻干燥处理,即得氧化肝素粉末。将氧化肝素粉末溶解于去离子水中配制为浓度为0.1g/mL的氧化肝素涂层溶液(溶液2);
(3)将医用PVC管材进行纯化水超声清洗并风干后,用蠕动泵带动溶液1在PVC管材内进行循环,反应6h。然后用纯水冲洗PVC管材内部管壁1次后,用蠕动泵带动溶液2在PVC管材内循环1h后,加入0.5g氰基硼氢化钠,反应12h。用纯化水冲洗3次后放入50℃烘箱中交联干燥固定5h,得到抗凝涂层。
对比例3
由于KH560结构中不带氨基,不能直接跟肝素结合,因此本对比例中采用与KH560结构相似的KH540制备底层溶液。KH540结构中具有氨基,能够与肝素结合。
(1)称量1g KH540溶解于50mL去离子水中,充分搅拌1h后即得KH540溶液(溶液1);
(2)取5g高碘酸钠溶于100mL去离子水,用5%的氢氧化钠溶液调整pH至5.5,边搅拌边加入20g肝素钠。室温下避光反应10h。反应结束后加5mL乙二醇结束反应。在30℃下旋蒸后冻干。按体积比水﹕乙醇=1﹕4的比例配制500mL溶液,将冻干后得到的粉末进行纯化。弃去液体后,将样品冷冻干燥处理,即得氧化肝素粉末。将氧化肝素粉末溶解于去离子水中配制为浓度为0.1g/mL的氧化肝素涂层溶液(溶液2);
(3)将医用PVC管材进行纯化水超声清洗并风干后,用蠕动泵带动溶液1在PVC管材内进行循环,反应6h。然后用纯水冲洗PVC管材内部管壁1次后,用蠕动泵带动溶液2在PVC管材内循环1h后,加入0.5g抗坏血酸,反应12h。用纯化水冲洗3次后放入50℃烘箱中交联干燥固定5h,得到抗凝涂层。
实施例4性能测试
一、亲水性测试
利用界面张力仪(DSA25)对空白PVC管壁、实施例1-3、对比例1-3所得涂覆了抗凝涂层管壁的亲疏水性能进行分析。将涂有涂层的管路纵向剖开,置于利用界面张力仪(DSA25)进行接触角的测试并记录数据。
测试结果(图1)表明,涂覆实施例1-3所得亲水抗凝涂层后,材料表面接触角减小最多,显著改善了PVC管路的亲水性,而对比例1-3的亲水性改善效果明显不如实施例1-3。
二、涂覆溶液1、溶液2前后管壁的亲疏水性能检测
检测PVC管路管壁在涂覆溶液1、溶液2前后管壁的亲疏水性能,分析溶液1、溶液2对管壁的亲疏水性能影响。
利用界面张力仪(DSA25)对空白PVC管壁、实施例1中步骤(3)中涂覆了溶液1之后的管壁、以及实施例1中步骤(3)操作结束完成溶液2涂覆之后的管壁的亲疏水性能进行分析。
测试结果(图2)表明,相较于空白PVC管壁,涂覆了溶液1之后的管壁,材料表面接触角明显减小,显著改善PVC管路的亲水性;而在涂覆了溶液2之后,材料表面接触角进一步明显减小,进一步显著改善PVC管路的亲水性。
三、细胞毒性实验
使用小鼠成纤维细胞L929细胞测试实施例1-3所得具有亲水抗凝涂层材料的细胞毒性。
制备具有亲水抗凝涂层管路的浸提液:分别将经实施例1-3处理后的管路样品经过灭菌后,按0.2g/mL的浸提比例将管路样品浸泡于含血清的细胞培养液中,浸提容器为无菌、化学惰性的封闭玻璃试管,浸提温度为(37±1)℃,浸提时间为(24±2)h。制备不同浓度(25%、50%、75%、100%)的浸提液。
将生长旺盛的L929细胞按比例用MEM培养基配制浓度为1*105个/mL的细胞悬浮液,然后在96孔板中进行铺板(100μL/孔),待细胞长满孔板后,对照组加入100μL细胞培养液,实验组依次加入100μL不同浓度的浸提液。经过24h培养后,弃掉原有培养液和浸提液,加入含有10%MTT试剂的MEM培养基进行染色,每孔100μL,置于培养箱4h后弃除所有培养液,将DMSO溶液按150μL加入到每个孔中,于室温下避光振荡10min,使紫色结晶充分溶解,用酶标仪在490nm波长下测定各孔OD值,计算各组细胞增殖率:
P%=(实验组OD值/阴性对照组OD值)*100
试验结果显示实施例1-3所得具有亲水抗凝涂层材料的细胞存活率随着浸提液浓度的提高逐渐下降,但存活率均大于75%,表明实施例1-3所得亲水抗凝涂层材料无细胞毒性,图3是示例性的实施例1处理完后的管路的浸提液的细胞毒性实验。
四、溶血性能
用生理盐水填满涂覆了本发明的亲水抗凝涂层的管路,在辐照条件下浸提24h,制备浸提液。将200μL红细胞悬浮液(2%)移动至试管中,添加200μL的浸提液。添加100μLTriton X-100(10%)的组作为阳性对照,添加新鲜生理盐水溶液的组作为阴性对照。样品在37℃下孵育3h。最后,使用RT 6000酶标仪测量上清液在540nm处的吸光度。每个样品的溶血率通过以下公式计算:
溶血率(%)=(样品OD值-阴性对照OD值)/(阳性对照OD值-阴性对照OD值)*100
实验结果显示,实施例1制得的亲水抗凝涂层材料的溶血率为1.8%,具有良好的溶血性能。
五、抗凝血性能
参照中国药典2020版四部1208肝素生物测定法全血凝集时间测定部分对实施例1-3、对比例1-3所得涂覆了抗凝涂层的管路的全血凝集时间进行测定。
具体地,4.5mL的新鲜兔血被收集到含有0.5mL枸橼酸(l09mmol/L)的试管中。以1500r/min的转速离心15min,吸出血浆备用。将APTT检测试剂盒中的激活物加入含有样品块的预温血浆中,并在37℃下孵育5min,再加入预温的CaCl2试剂,用血凝分析仪进行测定,并读取凝固时间。
空白PVC管路与实施例1-3、对比例1-3所得涂覆了抗凝涂层的管路的全血凝集时间分别为:4min、93min、88min、84min、54min、76min、61min。实施例1-3所得亲水抗凝涂层明显提升了PVC管路的抗凝血性能。
Claims (10)
1.一种亲水抗凝涂层的制备方法,其特征在于,包括如下步骤:
S1、制备底层溶液:取原料PEI、KH560,加入去离子水中,PEI的浓度为0.001-0.02g/mL,KH560的浓度为0.01-0.05g/mL,搅拌使原料溶解,调节pH值为7.0-10.0,搅拌使原料充分反应,得到底层溶液;
S2、制备氧化肝素溶液:将氧化剂溶于去离子水中,调节溶液pH值为5.0-6.8,然后加入肝素钠,溶液中肝素钠的浓度为0.15-0.2g/mL,氧化剂的浓度为0.005-0.05g/mL,室温下避光反应10-24h至原料充分反应后在反应溶液中加入终止剂乙二醇终止反应,然后旋蒸溶液并冻干,冻干得到的粉末采用有机溶剂水溶液进行纯化,得到纯化后的氧化肝素粉末,将得到的氧化肝素粉末溶于去离子水中,得浓度为0.08-1g/mL的氧化肝素溶液;所述氧化剂选自高碘酸钠、过氧化氢、过氧乙酸,所述有机溶剂选自乙醇、丙酮、甲醇;
S3、涂覆抗凝涂层:取步骤S1制备的底层溶液,让待处理医用材料与底层溶液充分接触3-6h,然后用超纯水清洗干净;取步骤S2制备的氧化肝素溶液,让底层溶液处理后的医用材料与氧化肝素溶液充分接触1-3h后,在氧化肝素溶液中加入还原剂,让医用材料继续与氧化肝素溶液充分接触8-18h,反应完成后用超纯水清洗干净,干燥,即在医用材料表面制备得到亲水抗凝涂层;所述还原剂选自硼氢化钠、抗坏血酸、氰基硼氢化钠;还原剂在氧化肝素溶液中的浓度为0.005-0.01g/mL。
2.根据权利要求1所述的制备方法,其特征在于:所述步骤S1的反应在25-70℃进行,搅拌反应2-6h;所述步骤S2中室温下避光反应10-24h,步骤2)中氧化肝素溶液的浓度为0.08-0.5g/mL或0.09-0.3g/mL或0.09-0.2g/mL或0.09-0.15g/mL。
3.根据权利要求1所述的制备方法,其特征在于:所述步骤S1、S2中采用5-10%氢氧化钠溶液调节pH值。
4.根据权利要求1所述的制备方法,其特征在于:步骤S2中终止剂与反应溶液的体积比为1﹕16-24,有机溶剂水溶液与反应溶液的体积比为3-7﹕1;
旋蒸温度为30-70℃,旋蒸时间为3-5h,旋蒸后冻干20-28h,然后将冻干粉加入有机溶剂中沉降出氧化肝素后离心,弃去上清液后进行冷冻干燥处理,即得到纯化后的氧化肝素粉末;
优选有机溶剂为乙醇,优选为浓度为60-85%的乙醇水溶液。
5.根据权利要求1所述的制备方法,其特征在于:步骤S3中,底层溶液、氧化肝素溶液在待处理医用材料表面循环流动接触。
6.根据权利要求1所述的制备方法,其特征在于:所述医用材料为管路,S3、涂覆抗凝涂层:取步骤S1制备的底层溶液,通入待涂覆管路中,让底层溶液在管路中循环流动3-6h,反应完成后通入超纯水清洗1-3次,然后在管路中通入氧化肝素溶液,氧化肝素溶液循环流通1-3h后加入还原剂继续反应8-18h,反应完成后通入超纯水清洗1-3次,然后将管路在45-55℃下烘干处理3-8h,管路的内表面即涂覆上亲水抗凝涂层。
7.根据权利要求1或6所述的制备方法,其特征在于:所述医用材料的材质选自丙烯腈-丁二烯-苯乙烯共聚物、聚丙烯、聚氯乙烯、聚乙烯。
8.权利要求1至7任一项所述的制备方法制备得到的亲水抗凝涂层。
9.权利要求8所述的亲水抗凝涂层在制备血液接触类医疗器械中的应用。
10.根据权利要求9所述的应用,其特征在于:所述血液接触类医疗器械包括血液透析循环管路、中心静脉导管、心脏支架、血管移植物、心脏瓣膜。
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