CN113817200A - 抗凝涂层及其制备方法 - Google Patents
抗凝涂层及其制备方法 Download PDFInfo
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- 239000011248 coating agent Substances 0.000 title claims abstract description 59
- 239000003146 anticoagulant agent Substances 0.000 title claims abstract description 57
- 229940127219 anticoagulant drug Drugs 0.000 title claims abstract description 57
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- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims abstract description 44
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Abstract
本发明公开了一种抗凝涂层及其制备方法,要解决的技术问题是提高抗凝涂层的可持续工作时间,降低成本。本发明采用以下技术方案:一种抗凝涂层,为两层膜构成的膜结构,底层为多巴胺,顶层为肝素,顶层与底层通过共价键结合。本发明的抗凝涂层的制备方法,包括以下步骤:配置多巴胺‑Tris溶液,制作底层,制作肝素溶液,制作顶层。本发明与现有技术相比,抗凝涂层采用多巴胺与肝素,通过共价键结合形成的膜结构,可持续工作时间较长,材料种类较少,制备方法简单,易于操作,成本低。
Description
技术领域
本发明涉及一种手术用涂层及其制备方法,特别是一种抗凝血的涂层及其制备方法。
背景技术
在外科手术和治疗过程中,由于与血液接触的器械会激发宿主防御机制,尤其是血液稳定机制,进而引起凝血甚至栓塞,需要对患者进行全身肝素化,并且还需在外科手术和治疗过程中定时处理,增加了手术的步骤,使外科手术和治疗过程变得复杂。为减少手术步骤,简化其流程,在所使用的医疗器械上涂覆抗凝血涂层,成为了最简单直接的选择。由于抗凝血涂层的存在,可免去对患者的全身肝素化处理和定时注射肝素,同时还可减轻患者的术后炎症反应。
现有技术的抗凝血涂层,主要应用于存放血液的容器类医疗器械和用于血液治疗的相关设备。针对介入类治疗器械,由于血流的物理冲刷作用和与肝素发生反应致其失活,导致抗凝血涂层的可持续工作时间较短。另外,现有技术的抗凝血涂层在制备过程中,所需的辅材种类较多,从而导致流程繁琐、制备具有一定难度、耗时较长、成本较高。
发明内容
本发明的目的是提供一种抗凝涂层及其制备方法,要解决的技术问题是提高抗凝涂层的可持续工作时间,降低成本。
本发明采用以下技术方案:一种抗凝涂层,为两层膜构成的膜结构,底层为多巴胺,顶层为肝素,顶层与底层通过共价键结合。
本发明的多巴胺的厚度为分子级别。
本发明的肝素厚度为分子级别。
本发明的抗凝涂层设置在被涂覆表面,所述被涂覆表面为聚氨酯、聚酰胺、聚醚嵌段聚酰胺或聚乙烯。
一种抗凝涂层的制备方法,包括以下步骤:
一、配置多巴胺-Tris溶液
以0.1~2mol/L浓度的三羟甲基氨基甲烷Tris缓冲液作为溶剂,多巴胺作为溶质,将多巴胺加入到三羟甲基氨基甲烷Tris缓冲液中,使多巴胺在三羟甲基氨基甲烷Tris缓冲液中的浓度为0.5~5mg/ml,完全溶解后,再加入浓度为0.1mol/L的氢氧化钠NaOH水溶液,调节pH值为7,得到多巴胺-Tris溶液;
二、制作底层
在多巴胺-Tris溶液中加入Tris盐,调节多巴胺-Tris溶液的pH值至7.5~9.0,然后将pH值为7.5~9.0的多巴胺-Tris溶液置于温度为20~40℃中,将待涂覆表面浸没于pH值为7.5~9.0的多巴胺-Tris溶液中,在转速为80~120rpm条件下,反应8小时,待涂覆表面自聚合聚多巴胺膜,得到底层;
所述Tris盐为三羟甲基氨基甲烷盐酸盐;
三、制作肝素溶液
以浓度为0.1~1mol/L、pH为7的磷酸盐缓冲液PBS作为溶剂,肝素作为溶质,将肝素加入到磷酸盐缓冲液中,配制成浓度为0.1~20mg/ml的肝素-PBS溶液;
四、制作顶层
向肝素-PBS溶液中加入1mol/L磷酸二氢钾溶液和/或1mol/L磷酸氢二钠溶液,调节肝素-PBS溶液的pH值为5~6,将pH值为5~6的肝素-PBS溶液置于20~40℃中,并将已涂覆多巴胺膜的表面浸没于pH值为5~6的肝素-PBS溶液中,在转速为80~120rpm条件下,反应2小时,肝素共价结合在聚多巴胺膜表面,得到顶层。
本发明的步骤四后用去离子水冲洗顶层的表面,直接置于40℃的烘箱中干燥10分钟后,取出自然降温至室温。
本发明的步骤一在室温下。
本发明的步骤二待涂覆表面自聚合聚多巴胺膜后,用去离子水洗净被涂覆表面。
本发明的步骤二待涂覆表面为聚氨酯、聚酰胺、聚醚嵌段聚酰胺或聚乙烯。
本发明的步骤二将pH值为7.5~9.0的多巴胺-Tris溶液置于温度为20~40℃的恒温摇床中;所述步骤四将pH值为5~6的肝素-PBS溶液置于20~40℃的恒温摇床中。
本发明与现有技术相比,抗凝涂层采用多巴胺与肝素,通过共价键结合形成的膜结构,可持续工作时间较长,材料种类较少,制备方法简单,易于操作,成本低。
具体实施方式
下面结合实施例对本发明作进一步详细说明。本发明的抗凝涂层,结构为两层膜构成的膜结构,底层为多巴胺的自聚合产物:聚多巴胺,在待涂覆表面自形成薄膜,厚度为分子级别,顶层为肝素,厚度为分子级别,顶层与底层通过共价键结合,形成抗凝涂层的膜结构。抗凝涂层使被涂覆表面获得抗凝功能。待涂覆表面涂覆抗凝涂层后为被涂覆表面。
待涂覆表面为聚氨酯、聚酰胺、聚醚嵌段聚酰胺或聚乙烯。
本发明的抗凝涂层为深灰色(多巴胺的自聚合产物的颜色),抗凝涂层由聚多巴胺和肝素组成,可提高被涂覆表面的生物相容性,具有抗凝血功能。由多巴胺和肝素两种物质共同提供生物相容性和抗凝血功能。
本发明的抗凝涂层的制备方法,包括以下步骤:
一、配置多巴胺-Tris溶液
室温(20℃)下,以0.1~2mol/L浓度的三羟甲基氨基甲烷Tris缓冲液作为溶剂,多巴胺作为溶质,配制多巴胺-Tris溶液,将多巴胺加入到三羟甲基氨基甲烷Tris缓冲液中,使多巴胺在三羟甲基氨基甲烷Tris缓冲液中的浓度为0.5~5mg/ml,完全溶解后,采用现有技术的滴定法加入浓度为0.1mol/L的氢氧化钠NaOH水溶液,直至调节溶液的pH值为7,得到多巴胺-Tris溶液。
多巴胺-Tris溶液用于后续步骤制备抗凝涂层底层。
二、制作底层
在多巴胺-Tris溶液中加入Tris盐,调节多巴胺-Tris溶液的pH值至7.5~9.0,然后将pH值为7.5~9.0的多巴胺-Tris溶液置于温度为20~40℃的恒温摇床中,并将待涂覆表面浸没于pH值为7.5~9.0的多巴胺-Tris溶液中,在转速为80~120rpm条件下,反应8小时,反应结束后,待涂覆表面自聚合有聚多巴胺膜,按现有技术用去离子水洗净被涂覆表面,得到聚多巴胺膜,即底层。聚多巴胺膜厚度为分子级别,自主黏附在被涂覆表面,与被浸没的表面形状一致。
Tris盐为三羟甲基氨基甲烷盐酸盐。
待涂覆表面为聚氨酯、聚酰胺、聚醚嵌段聚酰胺或聚乙烯。形状为管状和/或平板状。
聚多巴胺膜作为抗凝涂层底层,由于其本身的黏附性,能黏附在被涂覆表面,同时,具有能与肝素共价结合的官能团,从而保证后续将肝素涂覆在聚多巴胺膜表面。pH值为7.5~9.0,是自聚合反应发生的必要条件,在此范围,自聚合反应才能进行。
三、制作肝素溶液
以浓度为0.1~1mol/L、pH为7的磷酸盐缓冲液PBS作为溶剂,肝素作为溶质,将肝素加入到磷酸盐缓冲液中,配制成浓度为0.1~20mg/ml的肝素-PBS溶液。
四、制作顶层
向肝素-PBS溶液中,采用现有技术的滴定法加入1mol/L磷酸二氢钾溶液和/或1mol/L磷酸氢二钠溶液,磷酸二氢钾和磷酸二氢钠任意取值调节,直至调节肝素-PBS溶液的pH值为5~6,将pH值为5~6的肝素-PBS溶液置于20~40℃的恒温摇床中,并将已涂覆多巴胺膜的表面浸没于pH值为5~6的肝素-PBS溶液中,在转速为80~120rpm条件下,反应2小时,肝素共价结合在聚多巴胺膜表面,得到顶层。顶层厚度为分子级别。
肝素共价结合在聚多巴胺膜表面,与聚多巴胺膜形成抗凝涂层,使被涂覆表面获得抗凝血性能。pH值为5~6,是肝素共价结合在聚多巴胺膜表面的必要条件。
五、清洁干燥
按现有技术用去离子水冲洗顶层的表面,直接置于40℃的烘箱中干燥10分钟后,取出自然降温至室温,得到抗凝涂层。
清洗可以去除表面多余的未反应物质。
本发明的抗凝涂层的被涂覆表面用于需要与血液直接接触的介入类器械的表面,包含超过72小时的长期接触或72小时以内的短期接触。通过抗凝涂层,避免介入类器械在与血液接触的过程中发生凝血现象,甚至引发血栓。
抗凝涂层完成制备后,随介入类器械灭菌包装,有效期2年。
实施例1~6的工艺参数见表1。
测试实施例得到的抗凝涂层的可持续工作时间和稳定性:
将实施例1~6得到的抗凝涂层,进行部分凝血活酶PTT时间测试,测试遵照ASTMF2382-18:对医用循环血液接触性材料进行部分凝血活酶时间(PTT)测试的标准方法,GB/T16886.4-2003《医疗器材的生物学评价-第4部分:与血液的相互作用的试验选择》进行,得到测试结果,凝血时间均超过5分钟。
再将实施例1~6得到的抗凝涂层,室温下,先在pH=7.3的模拟血液环境:PBS溶液中浸泡72小时,进行用上述相同的方法对抗凝涂层的APTT进行测试,得到测试结果,凝血时间均超过5分钟。说明在模拟血液环境下超过72小时之后,被涂覆表面上的抗凝涂层依然具有抗凝血功能。
说明本发明的抗凝涂层可以满足与血液长期接触(超过72小时)的抗凝功能的要求。
本发明的抗凝涂层相比现有技术具有以下优点:
1.性能优异,从实施例可以看出,本发明的抗凝涂层的可持续工作时间、稳定性优于现有技术。
2.简化了制备步骤,现有技术的抗凝血涂层大多需要化学改性,即先通过针对基底的分子链段的镶嵌或接枝,然后再与抗凝血涂层中的有效功能部分肝素结合,使抗凝血涂层稳定。本发明的抗凝涂层采用基底与功能部分肝素直接键合的方式,在保证抗凝涂层的稳定的同时,简化了制备步骤。
3.无需表面预处理,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,从而使抗凝血涂层基底能稳定被涂覆在器械表面。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.成本低,现有技术的抗凝血涂层价格大多比较昂贵,与之相比,本发明的抗凝涂层所需要的材料种类较少,材料成本较低,制备过程简单,易于操作,因此,成本很低,具有极大的市场推广和应用前景。
表1实施例1~6的工艺参数
Claims (10)
1.一种抗凝涂层,其特征在于:所述抗凝涂层为两层膜构成的膜结构,底层为多巴胺,顶层为肝素,顶层与底层通过共价键结合。
2.根据权利要求1所述的抗凝涂层,其特征在于:所述多巴胺的厚度为分子级别。
3.根据权利要求1所述的抗凝涂层,其特征在于:所述肝素厚度为分子级别。
4.根据权利要求1所述的抗凝涂层,其特征在于:所述抗凝涂层设置在被涂覆表面,所述被涂覆表面为聚氨酯、聚酰胺、聚醚嵌段聚酰胺或聚乙烯。
5.一种抗凝涂层的制备方法,包括以下步骤:
一、配置多巴胺-Tris溶液
以0.1~2mol/L浓度的三羟甲基氨基甲烷Tris缓冲液作为溶剂,多巴胺作为溶质,将多巴胺加入到三羟甲基氨基甲烷Tris缓冲液中,使多巴胺在三羟甲基氨基甲烷Tris缓冲液中的浓度为0.5~5mg/ml,完全溶解后,再加入浓度为0.1mol/L的氢氧化钠NaOH水溶液,调节pH值为7,得到多巴胺-Tris溶液;
二、制作底层
在多巴胺-Tris溶液中加入Tris盐,调节多巴胺-Tris溶液的pH值至7.5~9.0,然后将pH值为7.5~9.0的多巴胺-Tris溶液置于温度为20~40℃中,将待涂覆表面浸没于pH值为7.5~9.0的多巴胺-Tris溶液中,在转速为80~120rpm条件下,反应8小时,待涂覆表面自聚合聚多巴胺膜,得到底层;
所述Tris盐为三羟甲基氨基甲烷盐酸盐;
三、制作肝素溶液
以浓度为0.1~1mol/L、pH为7的磷酸盐缓冲液PBS作为溶剂,肝素作为溶质,将肝素加入到磷酸盐缓冲液中,配制成浓度为0.1~20mg/ml的肝素-PBS溶液;
四、制作顶层
向肝素-PBS溶液中加入1mol/L磷酸二氢钾溶液和/或1mol/L磷酸氢二钠溶液,调节肝素-PBS溶液的pH值为5~6,将pH值为5~6的肝素-PBS溶液置于20~40℃中,并将已涂覆多巴胺膜的表面浸没于pH值为5~6的肝素-PBS溶液中,在转速为80~120rpm条件下,反应2小时,肝素共价结合在聚多巴胺膜表面,得到顶层。
6.根据权利要求5所述的抗凝涂层的制备方法,其特征在于,所述步骤四后用去离子水冲洗顶层的表面,直接置于40℃的烘箱中干燥10分钟后,取出自然降温至室温。
7.根据权利要求5所述的抗凝涂层的制备方法,其特征在于,所述步骤一在室温下。
8.根据权利要求5所述的抗凝涂层的制备方法,其特征在于,所述步骤二待涂覆表面自聚合聚多巴胺膜后,用去离子水洗净被涂覆表面。
9.根据权利要求5所述的抗凝涂层的制备方法,其特征在于,所述步骤二待涂覆表面为聚氨酯、聚酰胺、聚醚嵌段聚酰胺或聚乙烯。
10.根据权利要求5所述的抗凝涂层的制备方法,其特征在于,所述步骤二将pH值为7.5~9.0的多巴胺-Tris溶液置于温度为20~40℃的恒温摇床中;所述步骤四将pH值为5~6的肝素-PBS溶液置于20~40℃的恒温摇床中。
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