CN101703813B - 利用内源性no供体构建抗凝血性血管支架材料的方法 - Google Patents
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Abstract
本发明公开了一种利用内源性NO供体构建抗凝血性血管支架材料的方法，包括：依次将有机硒化的聚阳离子高聚物和聚阴离子高聚物通过层层自组装方法交替涂敷在血管支架材料表面，形成多层双分子膜修饰的血管支架材料表面；从而催化体内存在的S-亚硝基谷胱甘肽(GSNO)等内源NO载体，实现NO持续、局部释放；并通过调控层层自组装双分子膜的层数可以有效调控NO的释放速率；进而提高血管支架材料的抗凝血性能。本发明方法，可用于金属血管支架或有机高分子人工血管支架或脱细胞人工血管支架，还可用于与血液接触的其它医疗器械。
Description
所属技术领域：
本发明涉及组织工程血管支架材料表面修饰方法，具体说是利用内源性NO供体构建抗凝血性血管支架材料的方法。
背景技术：
动脉硬化性心脏病及其相应的周围血管性疾病，是目前发病率、死亡率最高的疾病，这种疾病导致动脉管径狭窄并最终使血管堵塞。目前针对这种血管性疾病的终端治疗手段主要包括采用血管支架的血管扩张手术和血管移植。无论是血管支架扩张术还是血管移植都有很高的失败率，主要表现为血栓形成，血管狭窄、阻塞。因此，如何改善血管支架和组织工程血管材料的生物相容性和生物功能，开发出更安全有效的血管支架和血管移植材料，有效延长其通畅时限，是心血管临床医学迫切需要解决的关键问题。
为了在临床减少血栓形成带来的危害，医学上常使用抗凝血剂，然而，长期使用外源抗凝血剂也有副作用，特别是增加了出血的可能性。
内皮细胞是保持血管稳定性的天然调节物。内皮细胞在抗血栓形成、抑制血小板聚集、分泌血管活性因子等方面发挥着重要作用。内皮细胞中具有抗血栓、抗血小板凝聚性质的分子包括一氧化氮(NO)和肝素。其中NO是生物体内的一种信息分子，其从内皮细胞表面的持续释放能够有效地防止血小板在正常血管壁上的粘附和活化，具有显著的抗凝血效果。更重要的是，NO也能抑制平滑肌细胞的增殖，有助于减少伴随球囊血管成形术而发生的再狭窄。
基于此，有实验室研究制备了多种可释放NO的高分子材料。这些研究大多是将NO供体混合进或连接到聚合物上用来制备能释放NO的材料。虽然采用可释放NO的高分子材料是提高人工血管抗凝血性质的新途径，但，由于这类可释放NO的聚合物材料所储存和能够释放NO的量有限，释放速率也太快，从而影响了NO释放的持久性，在很大程度上限制了其在长期植入材料中的应用，这是使用这类材料最大的局限性。
由于在健康血液中已经存在S-亚硝基硫醇等NO供体的前驱体，而体内的谷胱甘肽过氧化酶是含有硒的催化酶，在谷胱甘肽的存在下能够循环催化体内的亚硝基硫醇释放NO。依据这一原理制备模拟含硒的谷胱甘肽过氧化酶的化合物，利用这些内源型的NO供体所制得的聚合物材料可以在聚合物与血液的界面上长期定点地产生出NO，实现NO释放的持久性，因此特别适用于血管支架表面修饰。
发明内容：
为了实现本发明的目的，本发明模拟体内NO产生机制和血管内皮再生微环境，提供一种利用内源性NO供体构建抗凝血性血管支架材料的方法。
本发明的技术方案为：利用内源性NO供体构建抗凝血性血管支架材料的方法，包括：依次将有机硒化的聚阳离子高聚物和聚阴离子高聚物通过层层自组装方法交替涂敷在血管支架材料表面，形成多层双分子膜；通过调控层层自组装双分子膜的层数可以有效调控NO的释放速率。
本发明的血管支架为金属支架或有机高分子人工血管支架或脱细胞血管支架。
本发明的聚阳离子高聚物包括聚赖氨酸PLL、聚乙烯亚胺PEI、壳聚糖中的一种或几种的混合物；聚阴离子高聚物包括海藻酸、透明质酸、聚谷氨酸、聚苹果酸、肝素中的一种或几种的混合物。
本发明形成的多层双分子膜为2-20层；优选10-15层。
本发明层层自组装方法交替涂敷的吸附平衡时间为5-60分钟。
本发明聚阳离子高聚物和聚阴离子高聚物的交替涂敷是在浓度为0.1-5mg/ml的水溶液或PBS(pH7.4)中进行的，每吸附平衡完成后，用蒸馏水洗涤，空气吹干，再进行带相反电荷高聚物的涂敷。
本发明所述的有机高分子人工血管支架材料，其特征在于：包括PCL，PLGA和PHA和PLA中的一种或几种的共纺或混纺多孔支架材料。
本发明所述的方法不仅能用于血管支架材料，还可用于与血液接触的其它医疗器械。
本发明的突出优点在于：1)采用本发明方法构建的血管支架材料，以含Se催化剂修饰材料表面，催化体内存在的S-亚硝基谷胱甘肽(GSNO)等内源NO载体，实现NO持续、局部释放；2)通过调控层层自组装双分子膜的层数可以有效调控NO的释放速率。进而，有效利用NO这一重要的生物信号分子，发挥NO抑制血小板激活、抗血小板黏附和抑制平滑肌细胞增殖的功能；从而提高其抗凝血性能，诱导和促进血管再生，防止血管再狭窄，改善血管功能；3)组装分子的选择范围广，制备方法温和，工艺简单，适用的基体材料种类多，对基体材料体型结构的适应性强。
具体实施例：
实施例1：利用内源性NO供体构建抗凝血性人工血管支架材料的方法，依次包括如下步骤：
①制备固载有机硒的聚乙烯亚胺(SePEI)：
先将二丙酸基二硒化物(SeDPA)用EDC和NHS活化。再将该混合物与PEI(Mw 25kD)在MES缓冲液(pH 6.0)中反应2小时。产物SePEI离心分离。SePEI高聚物中的Se含量用ICP-MS定量。
②L-b-L自组装方法在聚己内酯(PCL)经静电纺丝形成的多孔血管支架材料表面形成多层双分子膜：
先将SePEI和聚谷氨酸(PGA)分别在PBS(pH 7.4)中配成1mg/ml的溶液，将聚二烯丙基二甲基氯化铵(PDDA)溶于生物缓冲剂CHES(2-环己胺基乙磺酸)(pH 9.3)中，配成1mg/ml的溶液。将PCL多孔血管支架材料表面先涂敷(PDDA)和PGA各10分钟，形成预涂层，稳定和扩大基质表面电荷。再交替涂敷SePEI和PGA各10分钟；每吸附平衡完成后，用蒸馏水洗涤，空气吹干，再进行带相反电荷高聚物的涂敷；直到SePEI/PGA L-b-L层数为10层；然后退火，以进一步稳定聚电解质层状结构。
实施例2利用内源NO供体构建抗凝血性金属血管支架材料的方法，依次包括如下步骤：
①制备固载有机硒的聚赖氨酸(SePLL)：
先将二丙酸基二硒化物(SeDPA)用EDC和NHS活化。再将该混合物与聚赖氨酸(PLL)(Mw 25kD)在MES缓冲液(pH 6.0)中反应2小时。产物SePLL离心分离。SePLL高聚物中的Se含量用ICP-MS定量。
②L-b-L自组装方法在金属血管支架材料表面形成多层双分子膜：
先将SePLL和聚海藻酸(ALG，Mw 30kD)分别在PBS(pH 7.4)中配成1mg/ml的溶液，将聚二烯丙基二甲基氯化铵(PDDA)溶于CHES(pH 9.3)中，配成1mg/ml的溶液。将成品金属血管支架材料表面先涂敷PDDA和ALG各10分钟，形成预涂层，稳定和扩大基质表面电荷。再交替涂敷SePLL和ALG各10分钟；直到SeLL/ALGL-b-L层数为15层；然后退火，以进一步稳定聚电解质层状结构。
实施例3利用内源NO供体构建抗凝血性共纺纤维多孔人工血管支架材料的方法
用与实施例2类同的方法在中长链聚羟基脂肪酸酯与聚乳酸共纺纤维(PHAMCL/PLA)多孔人工血管支架材料内表面将有机硒化的聚阳离子高聚物——水溶性壳聚糖(SeCS，Mw30kD)和聚阴离子高聚物——聚苹果酸(PMA，Mw 10kD)通过层层自组装方法交替涂敷，形成水溶性壳聚糖/聚苹果酸(SeCS/PMA)的多层双分子膜；L-b-L层数为12层。
实施例4利用内源NO供体构建抗凝血性人工血管支架材料的方法
用同法在脱细胞人工血管支架材料内表面将有机硒化的聚阳离子高聚物——聚赖氨酸(SePLL)和聚阴离子高聚物——聚谷氨酸酸(PGA)通过层层自组装方法交替涂敷，形成SePLL/PGA的多层双分子膜；L-b-L层数为13层。
实施例5 动静脉回路(AV-Shunt)实验考察抗凝血性
将上述实施例1-4制得的表面修饰后的人工血管支架材料，在新西兰大耳白兔体内的动静脉直通分路串联，并使血液贯通，持续1h，评价血管支架材料的血液相容性。通过扫描电镜(SEM)和体式显微镜观察到，上述四种血管支架材料都没有明显的血栓形成，而没有进行表面修饰的相应裸支架都有明显的凝血现象。从而证明此发明方法具有明显的提高抗凝血效果。
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1.利用内源性NO供体构建抗凝血性血管支架材料的方法，包括：依次将有机硒化的聚阳离子高聚物和聚阴离子高聚物通过层层自组装方法交替涂敷在血管支架材料表面，形成多层双分子膜；通过调控层层自组装双分子膜的层数可以有效调控NO的释放速率；所述聚阳离子高聚物为聚赖氨酸PLL、壳聚糖、聚乙烯亚胺PEI中的一种或几种的混合物；所述聚阴离子高聚物为海藻酸、透明质酸、聚谷氨酸、聚苹果酸、肝素中的一种或几种的混合物；所述聚阳离子高聚物和聚阴离子高聚物的交替涂敷是在浓度为0.1-5mg/ml的水溶液或PBS中进行的，所述PBS的pH值为7.4，每吸附平衡完成后，用蒸馏水洗涤，空气吹干，再进行带相反电荷高聚物的涂敷。
2.根据权利要求1所述的利用内源性NO供体构建抗凝血性血管支架材料的方法，其特征在于：血管支架为金属支架或有机高分子人工血管支架或脱细胞组织工程血管支架。
3.根据权利要求1所述的利用内源性NO供体构建抗凝血性血管支架材料的方法，其特征在于：形成的多层双分子膜为2-20层。
4.根据权利要求1所述的利用内源性NO供体构建抗凝血性血管支架材料的方法，其特征在于：层层自组装方法交替涂敷的吸附平衡时间为5-60分钟。
5.根据权利要求2所述的利用内源性NO供体构建抗凝血性血管支架材料的方法，其特征在于：所述有机高分子人工血管支架材料为聚己内酯PCL、聚丙交酯-乙交酯共聚物PLGA、聚羟基脂肪酸酯PHA或聚乳酸PLA中的一种或几种的共纺或混纺多孔支架材料。
6.根据权利要求1所述的利用内源性NO供体构建抗凝血性血管支架材料的方法，其特征在于：所述的方法不仅能用于血管支架材料，还可用于与血液接触的其它医疗器械。
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| CN102441192B (zh) * | 2011-09-30 | 2014-08-27 | 上海交通大学 | 基因释放型支架及其制备方法 |
| MY177473A (en) * | 2013-01-21 | 2020-09-16 | Kyowa Hakko Bio Co Ltd | Agent for elevating nitric oxide concentration |
| DK2999494T3 (da) * | 2013-05-20 | 2020-09-28 | Univ Yale | Anti-trombogene transplantater |
| CN103330960A (zh) * | 2013-06-26 | 2013-10-02 | 西南交通大学 | 一种具有内皮仿生功能涂层的制备方法 |
| KR101555523B1 (ko) * | 2014-02-28 | 2015-09-25 | 부산대학교 산학협력단 | 산화질소 방출성 상처치료 필름 및 이의 제조방법 |
| CN104208761B (zh) * | 2014-08-12 | 2015-11-25 | 西南交通大学 | 一种具有诱导催化内源性no释放功能的抗凝血材料制备方法 |
| CN104225675B (zh) * | 2014-08-12 | 2016-10-05 | 西南交通大学 | 一种具有一氧化氮(no)催化活性的材料的制备方法 |
| CN104208760B (zh) * | 2014-08-12 | 2016-08-17 | 西南交通大学 | 一种铜离子介导的具有原位催化no释放功能的抗凝血涂层制备方法 |
| CN104673096B (zh) * | 2014-08-12 | 2017-05-17 | 西南交通大学 | 一种具有一氧化氮(no)催化活性的涂层的制备方法 |
| CN104307053B (zh) * | 2014-10-11 | 2015-11-25 | 西南交通大学 | 一种表面具有l-手征性的催化活性多功能生物活性涂层的制备方法 |
| CN106267369B (zh) * | 2016-08-05 | 2019-05-31 | 华中科技大学同济医学院附属协和医院 | 一种人造血管及其制备方法 |
| CN111603616B (zh) * | 2020-06-04 | 2021-04-30 | 青岛大学 | 具有双药负载和分阶缓释功能的纳米纤维血管支架材料及其制备方法 |
| CN115212350B (zh) * | 2021-04-14 | 2024-02-13 | 南京师范大学 | 水凝胶在制备高仿生人造血管材料中的应用 |
| CN116747360B (zh) * | 2023-07-04 | 2024-09-24 | 攀枝花学院 | 镁基血管支架材料表面修饰用涂层材料、修饰方法、及修饰后的镁基血管支架材料和应用 |
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