CN110101912B - 一种含促进内皮化多肽的干燥人工生物心脏瓣膜及其制备方法 - Google Patents
一种含促进内皮化多肽的干燥人工生物心脏瓣膜及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种含促进内皮化多肽的干燥人工生物心脏瓣膜及其制备方法,该方法包括以下步骤:对动物心包膜的氨基和羧基进行交联处理,对动物心包膜进行内皮化处理,水凝胶聚合处理以及脱水干燥处理;其中,内皮化处理过程是采用促进内皮化的多肽对动物心包膜进行处理。通过本发明制备方法,使得制备的干燥生物心脏瓣膜具有良好的浸水展平性能,在较高温度和较高湿度下可以浸水快速展平,进而减少戊二醛等的残留,减少戊二醛等带来的钙化问题及毒性问题,这样能够简化瓣膜系统的术前安装,降低手术的附加风险。本发明在制备过程中还加入了能够促进内皮化的多肽,使得制备得到的生物瓣膜具有促进内皮化的性能。
Description
技术领域
本发明属于医用材料技术领域,具体涉及一种含促进内皮化多肽的干燥人工生物心脏瓣膜及其制备方法。
背景技术
心脏瓣膜疾病是一种常见的瓣膜衰退疾病,在解剖学上表现为血液通路变窄或瓣膜关闭不全。心脏瓣膜疾病的治疗包括开胸瓣膜置换手术以及经皮心脏瓣膜置换手术。开胸手术对病人创伤大、风险高、恢复慢、需体外循环支持,很多患者无法接受。经皮心脏瓣膜置换手术因为对病人创伤小、风险低,成为未来瓣膜手术的主要趋势。
生物心脏瓣膜是指一类用于替换人体病变心脏瓣膜的生物医学材料。生物心脏瓣膜一般由猪心包膜、牛心包膜等通过戊二醛交联制备而成。但现有的生物心脏瓣膜需要浸泡在戊二醛溶液当中保存,导致戊二醛残留、需要术前清洗安装、瓣膜耐久性有限、手术附件风险等问题。另外,现有生物心脏瓣膜基本都是用心包膜制备而成,心包膜自身没有内皮细胞,生物心脏瓣膜很难内皮化,使得生物心脏瓣膜易衰坏、钙化。
发明内容
针对现有技术中的上述不足,本发明提供了一种含促进内皮化多肽的干燥人工生物心脏瓣膜及其制备方法,可有效解决现有的生物心脏瓣膜需要保存在戊二醛溶液当中、无法预先装载于输送系统、需要临时清洗压握组装无法快速吸水展平以及很难内皮化的问题。
为实现上述目的,本发明解决其技术问题所采用的技术方案是:
一种含促进内皮化多肽的干燥人工生物心脏瓣膜,其制备方法包括以下步骤:
对动物心包膜的氨基和羧基进行交联处理,对动物心包膜进行内皮化处理,水凝胶聚合处理以及脱水干燥处理;
其中,对动物心包膜进行内皮化处理过程具体为:将进行交联处理或未经交联处理过的动物心包膜置于含有促进内皮化的多肽的丙烯酸类单体水溶液中进行浸泡;促进内皮化的多肽为REDV、RGD、YIGSR中的至少一种。
上述交联处理、内皮化处理和水凝胶聚合处理的顺序并没有特殊的要求,只要保证水凝胶聚合处理在内皮化处理之后即可,如可以先对动物心包膜进行交联处理,然后再进行内皮化处理,再进行水凝胶聚合处理;也可以先对动物心包膜进行内皮化处理,然后进行水凝胶聚合处理,最后进行交联处理;还可以先对先对动物心包膜进行内皮化处理,然后进行交联处理,再进行水凝胶聚合处理。
进一步地,交联处理过程具体为:将动物心包膜在交联剂一中浸泡,浸泡温度为20-40℃,浸泡时间为1-7天。
进一步地,动物心包膜为猪心包膜或牛心包膜。
进一步地,交联剂一为体积浓度为0.1-2%的戊二醛或碳二亚胺水溶液。
进一步地,丙烯酸类单体水溶液中丙烯酸类单体的体积浓度为10-30%,丙烯酸类单体为聚(乙二醇)甲基丙烯酸酯、2-丙烯酰胺基-2-甲基丙磺酸或2-甲基丙烯酰氧基乙基磷酰胆碱;促进内皮化的多肽在丙烯酸类单体水溶液中的浓度为0.1-10mg/mL。
进一步地,对动物心包膜进行内皮化处理过程中浸泡温度为4-40℃,浸泡时间为1-7天。
进一步地,水凝胶聚合处理过程具体为:将负载有丙烯酸类单体的动物心包膜浸泡在含有交联剂二和引发剂的水溶液中,浸泡温度为20-40℃,浸泡时间为1-7天。
进一步地,丙烯酸酯单体、交联剂二和引发剂的质量比为10-30:0.1-0.3:1-1.5。
进一步地,交联剂二为N,N'-亚甲基双丙烯酰胺、氮二异丁腈或过氧化苯甲酰。
进一步地,引发剂为过硫酸铵和四甲基乙二胺按质量比为1:0.1混合的混合物。
本发明提供的含促进内皮化多肽的干燥人工生物心脏瓣膜及其制备方法,具有以下有益效果:
本发明将动物心包膜采用戊二醛或碳二亚胺进行交联处理,戊二醛或碳二亚胺与动物心包膜中的胶原蛋白之间的交联作用主要是通过与胶原蛋白中的氨基产生缩合反应,生成牢固的交联键;此外,戊二醛或碳二亚胺还可以与胶原蛋白中的羧基作用形成缩醛,生成较牢固的交联键,通过以上二种反应,形成胶原分子的分子内交联与分子间交联,从而增强了机械强度,降低免疫原性。
但通过戊二醛进行交联处理后容易导致异种生物材料钙化,且戊二醛具有细胞细胞毒性,本发明通过将生物心脏瓣膜制成干燥样品,就不需要将其保存在戊二醛溶液中,而是将其预先装载于输送系统输送至需要的地方。
当对心包膜进行负载丙烯酸类单体后,再浸泡于一定浓度的交联剂二和引发剂中后,能够实现丙烯酸类单体水凝胶聚合。交联剂二的用量会影响制备得到的生物瓣膜的吸水性,当交联剂二的使用量较少时,所形成的交联点不足以构建聚合物三维网络空间来吸收水分,而引起凝胶溶胀率变小;当交联剂二的使用量较多时,形成的交联点多,产物形成孔径小的网络,较高的交联密度使凝胶与水分子间的排斥力增大,从而不利于水分子的吸收,这两种情况均为影响最终制得的生物瓣膜的浸水展平性能。本发明通过对凝胶单体、交联剂以及引发剂及其这三种物质的含量进行优化,得到的水凝胶在水中能够快速展平。
因本发明制得的生物心脏瓣膜具有良好的浸水展平性能,在较高温度和较高湿度下可以浸水快速展平后使用。采用本发明制备方法可减少戊二醛等的残留,减少戊二醛等带来的钙化问题及毒性问题,这样能够简化瓣膜系统的术前安装,降低手术的附加风险。
本发明在制备过程中还加入了能够促进内皮化的多肽,使得制备得到的生物瓣膜具有促进内皮化的性能。首先将促进内皮化的多肽先溶于丙烯酸类单体水溶液中是为了实现多肽在单体溶液中的分散,然后才能更好的与动物心包膜接触,当特定浓度的多肽与动物心包膜接触后,能促进心包膜内皮化,同时也不会因局部浓度过大产生副作用。
本发明通过将交联处理、内皮化处理以及水凝胶的形成这三者结合起来制备干燥人工生物心脏瓣膜,可有效解决现有的生物心脏瓣膜需要保存在戊二醛溶液中,无法预先装载于输送系统,使用时需要临时清洗压握组装无法快速吸水展平以及很难内皮化的问题。本发明制得的生物心脏瓣膜具有良好的浸水展平性能,能够促进心包膜内皮化,提高显著提高内皮化细胞的存活率。
具体实施方式
实施例1
一种含促进内皮化多肽的干燥人工生物心脏瓣膜,其制备方法包括以下步骤:
(1)将清洗干净的猪心包膜与1%体积浓度的戊二醛水溶液在室温、pH=7.4条件下交联24h;
(2)将步骤(1)交联后的猪心包膜用去离子水清洗干净,然后置于含有5mg/mL RGD多肽的聚(乙二醇)甲基丙烯酸酯水溶液(100mL)中,在25℃浸泡24h;其中,聚(乙二醇)甲基丙烯酸酯水溶液中聚(乙二醇)甲基丙烯酸酯的体积浓度为10%;
(3)将步骤(2)所得物用去离子水清洗干净后在含有1wt%过硫酸铵和0.1wt%四甲基乙二胺以及0.1wt%N,N'-亚甲基双丙烯酰胺的水溶液(100mL)中浸泡,浸泡温度为25℃,浸泡时间为24h,然后清洗干净,再脱水干燥,制得含促进内皮化多肽的干燥人工生物心脏瓣膜。
实施例2
一种含促进内皮化多肽的干燥人工生物心脏瓣膜,其制备方法包括以下步骤:
(1)将清洗干净的猪心包膜与1%体积浓度的戊二醛水溶液在室温、pH=7.4条件下交联24h;
(2)将步骤(1)交联后的猪心包膜用去离子水清洗干净,然后置于含有1mg/mLYIGSR多肽的聚(乙二醇)甲基丙烯酸酯水溶液(100mL)中,在25℃浸泡24h;其中,聚(乙二醇)甲基丙烯酸酯水溶液中聚(乙二醇)甲基丙烯酸酯的体积浓度为20%;
(3)将步骤(2)所得物用去离子水清洗干净后在含有1wt%过硫酸铵和0.1wt%四甲基乙二胺以及0.1wt%N,N'-亚甲基双丙烯酰胺的水溶液(100mL)中浸泡,浸泡温度为25℃,浸泡时间为24h,然后清洗干净,再脱水干燥,制得含促进内皮化多肽的干燥人工生物心脏瓣膜。
实施例3
一种含促进内皮化多肽的干燥人工生物心脏瓣膜,其制备方法包括以下步骤:
(1)将清洗干净的猪心包膜与0.5%体积浓度的戊二醛水溶液在室温、pH=7.4条件下交联48h;
(2)将步骤(1)交联后的猪心包膜用去离子水清洗干净,然后置于含有1mg/mLREDV多肽的聚(乙二醇)甲基丙烯酸酯水溶液(100mL)中,在25℃浸泡24h;其中,聚(乙二醇)甲基丙烯酸酯水溶液中聚(乙二醇)甲基丙烯酸酯的体积浓度为20%;
(3)将步骤(2)所得物用去离子水清洗干净后在含有1wt%过硫酸铵和0.1wt%四甲基乙二胺以及0.1wt%N,N'-亚甲基双丙烯酰胺的水溶液(100mL)中浸泡,浸泡温度为25℃,浸泡时间为24h,然后清洗干净,再脱水干燥,制得含促进内皮化多肽的干燥人工生物心脏瓣膜。
实施例4
一种含促进内皮化多肽的干燥人工生物心脏瓣膜,其制备方法包括以下步骤:
(1)将清洗干净的猪心包膜浸泡在含有5mg/mL RGD多肽的聚(乙二醇)甲基丙烯酸酯水溶液(100mL)中,浸泡温度为25℃,浸泡时间为24h;其中,聚(乙二醇)甲基丙烯酸酯水溶液中聚(乙二醇)甲基丙烯酸酯的体积浓度为10%;
(2)将步骤(1)所得物用去离子水清洗干净,然后浸泡于含有1wt%过硫酸铵和0.1wt%四甲基乙二胺以及0.1wt%N,N'-亚甲基双丙烯酰胺的水溶液(100mL)中,浸泡温度为25℃,浸泡时间为24h;
(3)将步骤(2)所得物用去离子水清洗干净,然后浸泡于1%体积浓度的戊二醛水溶液中,在室温、pH=7.4条件下交联24h,然后清洗干净,再脱水干燥,制得含促进内皮化多肽的干燥人工生物心脏瓣膜。
实施例5
一种含促进内皮化多肽的干燥人工生物心脏瓣膜,其制备方法包括以下步骤:
(1)将清洗干净的猪心包膜浸泡在含有1mg/mL YIGSR多肽的聚(乙二醇)甲基丙烯酸酯水溶液(100mL)中,浸泡温度为25℃,浸泡时间为24h;其中,聚(乙二醇)甲基丙烯酸酯水溶液中聚(乙二醇)甲基丙烯酸酯的体积浓度为20%;
(2)将步骤(1)所得物用去离子水清洗干净,然后浸泡于含有1wt%过硫酸铵和0.1wt%四甲基乙二胺以及0.1wt%N,N'-亚甲基双丙烯酰胺的水溶液(100mL)中,浸泡温度为25℃,浸泡时间为24h;
(3)将步骤(2)所得物用去离子水清洗干净,然后浸泡于1%体积浓度的戊二醛水溶液中,在室温、pH=7.4条件下交联24h,然后清洗干净,再脱水干燥,制得含促进内皮化多肽的干燥人工生物心脏瓣膜。
实施例6
一种含促进内皮化多肽的干燥人工生物心脏瓣膜,其制备方法包括以下步骤:
(1)将清洗干净的猪心包膜浸泡在含有1mg/mL REDV多肽的聚(乙二醇)甲基丙烯酸酯水溶液(100mL)中,浸泡温度为25℃,浸泡时间为24h;其中,聚(乙二醇)甲基丙烯酸酯水溶液中聚(乙二醇)甲基丙烯酸酯的体积浓度为20%;
(2)将步骤(1)所得物用去离子水清洗干净,然后浸泡于含有1wt%过硫酸铵和0.1wt%四甲基乙二胺以及0.1wt%N,N'-亚甲基双丙烯酰胺的水溶液(100mL)中,浸泡温度为25℃,浸泡时间为24h;
(3)将步骤(2)所得物用去离子水清洗干净,然后浸泡于0.5%体积浓度的戊二醛水溶液中,在室温、pH=7.4条件下交联24h,然后清洗干净,再脱水干燥,制得含促进内皮化多肽的干燥人工生物心脏瓣膜。
实施例7
一种含促进内皮化多肽的干燥人工生物心脏瓣膜,其制备方法包括以下步骤:
(1)将清洗干净的猪心包膜与1%体积浓度的戊二醛水溶液在室温、pH=7.4条件下交联24h;
(2)将步骤(1)交联后的猪心包膜用去离子水清洗干净,然后置于含有5mg/mL RGD多肽的2-甲基丙烯酰氧基乙基磷酰胆碱水溶液(100mL)中,在25℃浸泡24h;其中,2-甲基丙烯酰氧基乙基磷酰胆碱水溶液中2-甲基丙烯酰氧基乙基磷酰胆碱的体积浓度为10%;
(3)将步骤(2)所得物用去离子水清洗干净后在含有1wt%过硫酸铵和0.1wt%四甲基乙二胺以及0.1wt%氮二异丁腈的水溶液(100mL)中浸泡,浸泡温度为25℃,浸泡时间为24h,然后清洗干净,再脱水干燥,制得含促进内皮化多肽的干燥人工生物心脏瓣膜。
实施例8
一种含促进内皮化多肽的干燥人工生物心脏瓣膜,其制备方法包括以下步骤:
(1)将清洗干净的猪心包膜与1%体积浓度的戊二醛水溶液在室温、pH=7.4条件下交联24h;
(2)将步骤(1)交联后的猪心包膜用去离子水清洗干净,然后置于含有5mg/mL RGD多肽的2-丙烯酰胺基-2-甲基丙磺酸水溶液(100mL)中,在25℃浸泡24h;其中,2-丙烯酰胺基-2-甲基丙磺酸水溶液中2-丙烯酰胺基-2-甲基丙磺酸的体积浓度为10%;
(3)将步骤(2)所得物用去离子水清洗干净后在含有1wt%过硫酸铵和0.1wt%四甲基乙二胺以及0.1wt%过氧化苯甲酰的水溶液(100mL)中浸泡,浸泡温度为25℃,浸泡时间为24h,然后清洗干净,再脱水干燥,制得含促进内皮化多肽的干燥人工生物心脏瓣膜。
对实施例1-8制得的生物心脏瓣膜进行如下检测:
1、折压浸水测试
采用5mm内径的塑料管进行模拟折压测试,每组材料用剪刀裁剪面积大小约为3cm*3cm的方形样品,用镊子慢慢将方形样品塞入5mm内径的塑料管,然后在温度为40℃,湿度为60%-80%的恒温恒湿箱中放置72h,之后将材料挤出塑料管并浸泡在PBS缓冲液中,观察并记录材料的展平时间,具体测试数据如下:
样品 | 浸水展平时间(s) |
实施例1 | 68±12 |
实施例2 | 70±3 |
实施例3 | 71±5 |
实施例4 | 70±6 |
实施例5 | 72±7 |
实施例6 | 72±5 |
实施例7 | 73±4 |
实施例8 | 73±8 |
戊二醛对照组 | 无法展平 |
戊二醛对照组为将猪心包膜浸泡于0.625%体积浓度的戊二醛水溶液中,在室温、pH=7.4条件下交联24h,然后脱水干燥。
由上表可知,本发明制得的生物心脏瓣膜浸水后能快速展平,而常规戊二醛处理的对照组生物瓣膜无法展平。
2、内皮细胞实验
(1)实验样品为:猪心包膜薄片(厚度约0.1mm),用24孔板对应打孔器将样品裁成圆片状试样(直径约8mm);24孔板对应不锈钢钢圈。
人脐静脉内皮细胞Human umbilical vein endothelial cells(HUVEC)。
细胞培养液:DMEM培养基+10%胎牛血清(FBS)+1%双抗penicillin-streptomycin。
Trypsin/EDTA用于消化收集细胞。
(2)样品前处理:0.1%过氧乙酸灭菌24h(送过去的样品浸泡于0.1%过氧乙酸),然后加入70%乙醇灭菌至少1h,再采用紫外灯照射灭菌,最后用无菌PBS清洗3次除去残留乙醇。(若要用到不锈钢圈,处理步骤同以上样品处理)。
(3)实验步骤:
①在细胞培养箱当中用培养皿(10cm直径)或培养瓶(25T或75T)培养人脐静脉内皮细胞HUVEC至超过90%覆盖率。
②将圆片状试样放入24孔板,压上不锈钢钢圈,防止材料太轻产生漂浮。
③将培养皿中的内皮细胞用Trypsin/EDTA消化成高浓度细胞悬液备用,并血球计数板计数,确定细胞悬液中的细胞数量,配制成相应低浓度的细胞悬液。
④向24孔板中加入培养基,培养基体积为1mL/孔,然后缓慢加入低浓度细胞悬液(让内皮细胞落在圆片上),最终细胞接种密度为4-6万/孔,滴加完毕,将孔板十字型晃动,使细胞均匀分散。
⑤将24孔板转移到培养箱,孵育1天,采用CCK8试剂盒进行定量检测内皮细胞存活率,结果如下表:
样品 | 内皮细胞存活率(%) |
实施例1 | 75.05±9.93 |
实施例2 | 74.15±2.56 |
实施例3 | 73.58±3.78 |
实施例4 | 73.42±3.65 |
实施例5 | 74.36±5.68 |
实施例6 | 73.51±4.25 |
实施例7 | 72.25±5.17 |
实施例8 | 72.19±5.28 |
戊二醛对照组 | 25.54±5.39 |
由上表可知,本发明制得的生物心脏瓣膜与常规戊二醛处理的对照组生物瓣膜相比,内皮细胞存活率明显提高。
Claims (9)
1.一种含促进内皮化多肽的干燥人工生物心脏瓣膜的制备方法,其特征在于,包括以下步骤:
对动物心包膜依次进行氨基和羧基的交联处理,内皮化处理,水凝胶聚合处理以及脱水干燥处理;或
对动物心包膜依次进行内皮化处理,水凝胶聚合处理,氨基和羧基的交联处理以及脱水干燥处理;或
对动物心包膜依次进行内皮化处理,氨基和羧基的交联处理,水凝胶聚合处理以及脱水干燥处理;
其中,对动物心包膜进行内皮化处理过程具体为:将进行交联处理或未经交联处理过的动物心包膜置于含有促进内皮化的多肽的丙烯酸类单体水溶液中进行浸泡;促进内皮化的多肽为REDV、RGD、YIGSR中的至少一种;
水凝胶聚合处理过程具体为:将负载有丙烯酸类单体的动物心包膜浸泡在含有交联剂二和引发剂的水溶液中,浸泡温度为20-40℃,浸泡时间为1-7天。
2.根据权利要求1所述的含促进内皮化多肽的干燥人工生物心脏瓣膜的制备方法,其特征在于,交联处理过程具体为:将动物心包膜在交联剂一中浸泡,浸泡温度为20-40℃,浸泡时间为1-7天。
3.根据权利要求1或2所述的含促进内皮化多肽的干燥人工生物心脏瓣膜的制备方法,其特征在于,动物心包膜为猪心包膜或牛心包膜。
4.根据权利要求2所述的含促进内皮化多肽的干燥人工生物心脏瓣膜的制备方法,其特征在于,交联剂一为体积浓度为0.1-2%的戊二醛或碳二亚胺水溶液。
5.根据权利要求1所述的含促进内皮化多肽的干燥人工生物心脏瓣膜的制备方法,其特征在于,丙烯酸类单体水溶液中丙烯酸类单体的体积浓度为10-30%,丙烯酸类单体为聚(乙二醇)甲基丙烯酸酯、2-丙烯酰胺基-2-甲基丙磺酸或2-甲基丙烯酰氧基乙基磷酰胆碱;促进内皮化的多肽在丙烯酸类单体水溶液中的浓度为0.1-10μg/mL。
6.根据权利要求1所述的含促进内皮化多肽的干燥人工生物心脏瓣膜的制备方法,其特征在于,对动物心包膜进行内皮化处理过程中浸泡温度为4-40℃,浸泡时间为1-7天。
7.根据权利要求1所述的含促进内皮化多肽的干燥人工生物心脏瓣膜的制备方法,其特征在于,丙烯酸类单体、交联剂二和引发剂的质量比为10-30:0.1-0.3:1-1.5。
8.根据权利要求1或7所述的含促进内皮化多肽的干燥人工生物心脏瓣膜的制备方法,其特征在于,交联剂二为N,N'-亚甲基双丙烯酰胺、氮二异丁腈或过氧化苯甲酰;引发剂为过硫酸铵和四甲基乙二胺按质量比为1:0.1混合的混合物。
9.采用权利要求1-8任一项所述的方法制备得到的含促进内皮化多肽的干燥人工生物心脏瓣膜。
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