CN107376037A - 复合肝素生物抗凝涂层液及制备方法与应用 - Google Patents
复合肝素生物抗凝涂层液及制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种复合肝素生物抗凝涂层液及制备方法与应用，该复合肝素生物抗凝涂层液具有抗组织增生、抗炎性反应等功能，对于人造血管、血管支架、血管补片等植入器械在人体内减少血栓形成，降低术后并发症，提高产品的使用寿命至关重要。
Description
技术领域
本发明涉及一种复合肝素生物抗凝涂层液及制备方法与应用，属于生物医用材料技术领域。
背景技术
随着人们生活水平的提高，动脉粥样硬化，血管栓塞以及动脉瘤等心血管疾病对人类的健康造成了极大的威胁。因上述疾病等原因导致人体自身血管无法正常供血时，则需采用人工血管进行外科更换手术。人体内血管口径由2mm至30mm不等，在这其中，小口径(直径<6mm)极易发生内膜增生以及血栓形成，进而导致小口径血管远期通畅率低。目前，医院手术中使用的人造血管材料多为ePTFE，PU等材料，但这些材料本身不具备良好的抗凝血性能，需在材料表面进行抗凝血涂层。
现有常用的抗凝血涂层有肝素涂层，其涂层方法各异，不同的方法所制备的肝素涂层材料性能也有所差异。
发明内容
本发明的目的在于提供一种复合肝素生物抗凝涂层液及制备方法与应用。
为实现上述目的，本发明所提供的复合肝素生物抗凝涂层液中包含有交联状态的联氨基姜黄素-肝素。
本发明的复合肝素生物抗凝涂层液中起效的部分为交联状态的联氨基姜黄素-肝素。所述联氨基姜黄素通过其上的氨基与肝素交联。
本发明还提供了一种上述复合肝素生物抗凝涂层液的制备方法，步骤如下：
将联氨基姜黄素溶解于乙醇溶液中，配置成姜黄素醇溶液，向姜黄素醇溶液中加入MES缓冲液，再加入肝素，然后再加入EDC和NHS交联剂，搅拌1～2h，使联氨基姜黄素中的氨基与肝素充分反应，将反应完成的溶液放入透析袋透析24～72h，透析完成后，得到复合肝素生物抗凝涂层液。
上述方案中，所述联氨基姜黄素和肝素的添加重量比为1～10:40。该比例是联安姜黄素和肝素的较佳反应比值，本发明中的有效成分为交联状态的联氨基姜黄素-肝素，所以只要能够生成它的联氨基姜黄素和肝素任意配比添加量都是可以使用的。
需要说明的是，上述涂层液在单独作为涂层液使用时效果并不理想，它需要和生物活性蛋白联用发挥功效。如胶原蛋白、丝素蛋白、粘连蛋白。在研究过程中，发明人发现在一定的配比下，联氨基姜黄素-肝素和丝素蛋白联用有较好的效果。
因此，本发明还提供了一种联氨基姜黄素-肝素及丝素蛋白的生物抗凝涂层液，所述生物抗凝涂层液中包含有交联状态的联氨基姜黄素-肝素，还包括丝素蛋白；所述生物抗凝涂层液中所述联氨基姜黄素-肝素在的浓度为0.5～5％wt，所述丝素蛋白的浓度为5～15％wt，且联氨基姜黄素-肝素与丝素蛋白的浓度比值为1:1～10。
本发明利用姜黄素具有的抗组织增生、抗炎症反应等特性，将它和肝素结合在一起，以克服植入性医疗器械(如人造血管)在植入人体之后易发生的问题(如凝血作用会导致血小板聚集引起血栓导致血管再次狭窄，而组织过度增生和炎性反应也会引起排异反应而导致血管狭窄，最终使人造血管等植入器械的生物相容性变差而植入失败)。
本发明的有益效果：现代药理研究表明姜黄素类成分具有抗凝血、抗组织增生、抗炎性反应等多种药理作用，本发明将姜黄素与肝素两者连用不仅可以增强肝素涂层的抗凝血功能，还能起到单纯用肝素或蛋白等涂层所无法达到的抗组织增生、抗炎性反应等功能，对于人造血管、血管支架、血管补片等植入器械在人体内减少血栓形成，降低术后并发症，提高产品的使用寿命至关重要。
具体实施方式
以下结合具体实施例对本发明作进一步的详细描述。
需要说明的是，下述例子中使用的人造血管(ePTFE)在涂层之前均经过前处理，以提高其对涂层的结合力，使生物涂层能够稳定且有效的发挥抗凝血等功能。
人造血管(ePTFE)基材，前处理过程如下：
第一层
将ePTFE人造血管浸没于异丙醇(IPA)5～10mins，然后用镊子取出再浸泡于4％聚乙烯亚胺(PEI)和IPA混合液(体积比PEI:IPA＝1:1)15～30mins后，取出浸泡的人造血管，用去离子水浸泡冲洗人造血管。待冲洗完后，将人造血管放置于0.05％戊二醛溶液中15～20mins进行交联，待反应完成后将人造血管再次浸泡在0.5％PEI溶液中15～30mins，用去离子水对构造后的人造血管进行浸泡冲洗。冲洗完成后，将人造血管浸泡在氰基硼氢化钠溶液中反应15～30mins，反应完成后用去离子水浸泡冲洗。
第二层
将上述处理后的人造血管浸泡于0.05％戊二醛溶液中进行交联，待反应完成后将人造血管再次浸泡在0.5％PEI溶液中反应，用去离子水对构造后的人造血管进行浸泡冲洗。冲洗完成后，将人造血管浸泡在氰基硼氢化钠溶液中反应反应完成后用去离子水浸泡冲洗。
第三层
将0.15g硫酸葡聚糖和100gNaCl溶解于1L去离子水中，将上述第二层处理后的人造血管浸泡于混合液中，在60℃反应1～2h，待反应完成后，用去离子水对人造血管反复冲洗。制备中间电荷层。
第四层
将第三层处理后的人造血管浸泡于0.3％PEI溶液中0.5～1h，用50g/L的氯化钠溶液对人造血管浸泡冲洗，再用去离子水浸泡冲洗，得到人造血管(ePTFE)基材。
实施例1联氨基姜黄素-肝素
一种复合肝素生物抗凝涂层液，涂层液中包含有交联状态的联氨基姜黄素-肝素。
该复合肝素生物抗凝涂层液的制备方法，步骤如下：
将联氨基姜黄素溶解于乙醇溶液中，配置成浓度为5mg/mL的姜黄素醇溶液，向姜黄素醇溶液中加入MES缓冲液使姜黄素浓度降低为2.5mg/mL，向300mL姜黄素溶液中加入10g肝素后，再加入4g EDC和4g NHS，搅拌1～2h，使联氨基姜黄素中的氨基与肝素充分反应，将反应完成的溶液放入透析袋透析24～72h，透析完成后，得到复合肝素生物抗凝涂层液。可以对该涂层液进行冷冻干燥制得复合肝素生物抗凝涂层冻干粉，长期保存。
实施例2联氨基姜黄素-肝素与丝素蛋白涂层
联氨基姜黄素-肝素与丝素蛋白混合的生物抗凝涂层人造血管制备方法，步骤如下：
1)将实施例1制得的冻干粉溶于丝素蛋白大分子溶液，得到的混合涂层溶液中联氨基姜黄素-肝素浓度为1％wt，丝素蛋白浓度为10％wt，为联氨基姜黄素-肝素及丝素蛋白的生物抗凝涂层液。
2)将人造血管(ePTFE)基材浸没在步骤1)的生物抗凝涂层液中10～30mins，随后取出置于通风处，待干燥完全后，浸泡在30～75％甲醇溶液中2～4h，浸泡完成后放置于通风处干燥。
3)重复步骤2)两次，给人造血管(ePTFE)涂第二、三层涂层。
其中，步骤1)的丝素蛋白制备方法：将20～30g生丝放入10～12L含有Na2CO3(2.12g/L)溶液中沸水煮20～30mins，随后用去离子水反复冲洗煮好后的脱胶丝以去除残余丝胶。将洗净后的蚕丝蛋白纤维平铺于通风处干燥。称取15～25g干燥蚕丝纤维溶于60℃100～150mL的LiBr溶液中(9.3M)，待溶解完成后，用透析袋对蚕丝蛋白溶液进行偷袭36～72h，透析完成后对溶液进行离心去除杂质，得到丝素蛋白大分子溶液。
实施例3联氨基姜黄素-肝素与丝素蛋白涂层
本实施例和实施例2基本相同，区别在于，联氨基姜黄素-肝素及丝素蛋白的生物抗凝涂层液中联氨基姜黄素-肝素浓度为0.7％wt，丝素蛋白浓度为5.6％wt。
实施例4联氨基姜黄素-肝素与丝素蛋白涂层
本实施例和实施例2基本相同，区别在于，联氨基姜黄素-肝素及丝素蛋白的生物抗凝涂层液中联氨基姜黄素-肝素浓度为5％wt，丝素蛋白浓度为15％wt。
实施例5肝素/聚-L-赖氨酸涂层
肝素/聚-L-赖氨酸涂层人造血管，其制备方法步骤如下：
1)肝素大分子制备
将0.176g聚-L-赖氨酸溶解于300mL MES缓冲液中，再向其中加入4g磺酸-NHS和4g盐酸EDC，待上述混合液在室温中反应1h后，加入10g肝素钠粉末反应4h，反应完成后，用透析袋透析混合液24～36h。透析完成后，向透析液中加入10mg亚硝酸钠和2mL乙酸，在0℃反应2h，反应完成后，继续对溶液进行透析24h，透析完成后，对溶液进行冷冻、干燥得到肝素/聚-L-赖氨酸冻干粉。
2)涂层制备
取肝素/聚-L-赖氨酸冻干粉0.9g溶解于200mL去离子水，制得肝素大分子溶液，将三中处理后的人造血管浸泡于前述制得的肝素大分子溶液中于60℃反应10～20min后，再加入572uL 2.5％氰基硼氢化钠继续反应2～3h。所有反应完成后，用去离子水和硼酸盐缓冲液将人造血管冲洗干净，冷冻干燥处理即可。
实施例6肝素与丝素蛋白涂层
丝素蛋白肝素涂层人造血管，制备方法步骤如下：
1)肝素大分子制备(同实施例5)，丝素蛋白大分子溶液制备(同实施例2)
2)丝素蛋白与肝素涂层
丝素蛋白大分子溶液与肝素/聚-L-赖氨酸共混，得到的混合液中的丝素蛋白浓度为10％溶液，肝素/聚-L-赖氨酸浓度为4％。
3)涂层制备
第一层：取人造血管(ePTFE)基材浸没于上述混合液中10～30mins，随后取出置于通风处，待干燥完全后，浸泡在30～75％甲醇溶液中2～4h，浸泡完成后放置于通风处干燥。
第二/三层：重复第一层操作。
实施例7粘连蛋白与肝素涂层
粘连蛋白肝素涂层人造血管制备方法，步骤如下：
将粘连蛋白与肝素/聚-L-赖氨酸溶液共混，混合液中粘连蛋白浓度为10～30％wt，肝素/聚-L-赖氨酸浓度为0.5～5％wt，37℃反应1～2h，随后加入摩尔比为1M:2M:2M的EDC/NHS/MES交联剂，肝素/PLL与交联剂体积比为1:2～15。将人造血管(ePTFE)基材浸没在混合液中于37℃反应1～5h。
待上述反应完成后，取100～1000uL浓度为200ng/mL的SDF-1α浸润基底材料，该反应在4℃中反应12～24h，待反应完成后，用磷酸盐缓冲液浸泡冲洗15～30mins，再用去离子水浸泡冲洗30mins，干燥即可。
实施例8胶原蛋白涂层
胶原蛋白涂层人造血管制备方法，步骤如下：
用冰醋酸将胶原蛋白配置成浓度为10～30％wt，向200mL胶原蛋白混合液中加入肝素冻干粉，使肝素浓度为0.5～5％wt，待充分溶解后，将人造血管(ePTFE)基材浸润在混合液中，充分浸润后，并对其进行冷冻干燥24～48h。待冷冻干燥完成后，采用紫外线照射对胶原蛋白进行交联。如此反复浸润、冻干三次即可得表面胶原蛋白涂层聚合物材料。
实施例9聚多巴胺涂层
聚多巴胺涂层人造血管制备方法，步骤如下：
将人造血管(ePTFE)基材浸入浓度为8mg/mL多巴胺溶液中室温反应12h后，至于去离子水中超声清洗，然后后再次浸入多巴胺溶液中反应，如此反应4次后，将人造血管置于100℃中热处理1h。处理完成后用去离子水清洗人造血管，常温下干燥即可。
实验例1细胞毒性检测
以浸提液法检测涂层人造血管细胞毒性，具体实验步骤如下：
1)取对照例及实施例2～9中制备的涂层人造血管或涂层材料按照0.2g/mL用含胎牛血清的高糖细胞培养液浸提24～72h。
2)取正常生长对数期细胞(NIH/3T3)，消化吹打，用培养液配置成1×105个/mL浓度的细胞悬液，接种于96孔板，每孔100μL。放置于二氧化碳恒温培养箱24h后，弃去原培养液。
3)每组分别加入DMEM完全培养液(空白组)，聚乙烯浸提液(阴性对照)，含5％DMSO培养液(阳性对照)，人造血管样品浸提液(样品组)。继续培养24h后弃去孔内液体。
4)MTT反应，每孔中加入10uL 5mg/mL的MTT溶液，在培养箱内继续培养孵育4h。
5)每孔加入100μL的Formanzan溶解液，在细胞培养箱内继续孵育，直至普通光学显微镜下Formanzan全部溶解。
6)将96孔板放置于酶标仪上测量570nm处的吸光度值。
依据各组细胞浓度计算细胞相对增殖度(RGD)：
表1细胞相对增殖度分级表
| 分级 | 相对增殖度(％) |
| 0 | ≥100 |
| 1 | 75～99 |
| 2 | 50～74 |
| 3 | 25～49 |
| 4 | 1～24 |
| 5 | 0 |
实验结果：
表2各组细胞毒性检测结果
实验例2：凝血时间实验
1)部分凝血活酶时间(APTT)实验：取实施例2～9中制备的涂层人造血管，向其中加入100～200μL贫血小板血浆在37℃水浴0.5h。待加热完成后，加入100～200μL部分凝血活酶试剂液100μL和氯化钙溶液，混合均匀后，利用自动凝血仪检测APTT。
2)凝血酶原时间(PT)实验：向人造血管样品中加入100～200μL贫血小板血浆并在37℃水浴0.5h。待加热完成后，向其中加入PT试剂，用自动凝血仪检测PT。
3)凝血酶时间(TT)实验：向人造血管样品中加入100～200μL贫血小板血浆并在37℃水浴0.5h。待加热完成后，向其中加入TT试剂，用自动凝血仪检测TT。
表3人造血管或材料在涂层前后凝血实验结果
如表3所示，如表3所示，未涂层的人造血管凝血时间与正常血浆凝血时间相近，经姜黄素-肝素丝素蛋白共混溶液涂层过的人造血管凝血时间(实施例2～4)相比未涂层人造血管有显著提高，且相比于其他不同涂层的基材人造血管的APTT时间延长了约3～16s，PT时间延长了约4～7s，TT时间延长了约5～8s。以上试验表明经姜黄素-肝素涂层的人造血管涂层比其他未涂层的人造血管具有更明显的抗凝血性能，同时对于其他采用肝素及大分子蛋白涂层的人造血管在抗凝血性能上也有提升，表明姜黄素与肝素连用起到了增强抗凝血的作用，涂层效果更好。
本发明实施例中均以ePTFE人造血管为基材，实际上其他材料如PU、PE、涤纶、聚乳酸、聚硅酮、聚羟基乙酸、硅橡胶等，也可以采用本发明中的涂层液进行涂覆，只需要处理好基材，使生物涂层能够稳定结合，同样能获得较好的凝血效果。
Claims (6)
1.一种复合肝素生物抗凝涂层液，其特征在于：所述涂层液中包含有交联状态的联氨基姜黄素-肝素。
2.根据权利要求1所述的复合肝素生物抗凝涂层液，其特征在于：所述联氨基姜黄素通过其上的氨基与肝素交联。
3.一种权利要求1所述复合肝素生物抗凝涂层液的制备方法，其特征在于，步骤如下：
将联氨基姜黄素溶解于乙醇溶液中，配置成姜黄素醇溶液，向姜黄素醇溶液中加入MES缓冲液，再加入肝素，然后再加入EDC和NHS交联剂，搅拌1～2h，使联氨基姜黄素中的氨基与肝素充分反应，将反应完成的溶液放入透析袋透析24～72h，透析完成后，得到复合肝素生物抗凝涂层液。
4.一种权利要求3所述复合肝素生物抗凝涂层液的制备方法，其特征在于：所述联氨基姜黄素和肝素的添加重量比为1～10:40。
5.一种联氨基姜黄素-肝素及丝素蛋白的生物抗凝涂层液，其特征在于：所述生物抗凝涂层液中包含有交联状态的联氨基姜黄素-肝素，还包括丝素蛋白；所述生物抗凝涂层液中所述联氨基姜黄素-肝素在的浓度为0.5～5％wt，所述丝素蛋白的浓度为5～15％wt，且联氨基姜黄素-肝素与丝素蛋白的浓度比值为1:1～10。
6.根据权利要求5所述联氨基姜黄素-肝素及丝素蛋白的肝素生物抗凝涂层液，其特征在于：所述联氨基姜黄素通过其上的氨基与肝素交联。
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