CN102499993B - 一种边缘刚性化人工生物瓣膜的制备方法 - Google Patents
一种边缘刚性化人工生物瓣膜的制备方法 Download PDFInfo
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Abstract
本发明涉及医疗器械领域，具体涉及一种边缘刚性化人工生物瓣膜的制备方法，包括先将人工生物瓣膜浸没在预处理的戊二醛溶液中，然后通过还原剂、栲胶将戊二醛预处理过的人工生物瓣膜所形成的游离醛基、羧基、氨基、羟基、羰基基团封闭。本发明方法可使人工生物瓣膜的边缘刚性增强，从而提高了人工生物瓣的长期稳定性和耐久性。
Description
技术领域
本发明涉及医疗器械领域。更具体而言，本发明涉及一种边缘刚性化人工生物瓣(膜)的制备方法。
背景技术
人工生物(心脏)瓣的研制一直是心脏外科领域攻关的主题之一。理想的人工生物瓣的标准是耐久性和生物相容性良好、接近生理瓣膜的血流动力学性能、对血细胞破坏小、易植入、抗感染和无免疫原性等。
微创介入人工生物瓣(膜)包括球囊扩张型生物瓣膜和自扩张型生物瓣膜。
球囊扩张型生物瓣膜是可塑性变形的支架上固定人工生物瓣膜。通过径向压缩支架，使其固定在球囊上，微创介入输送到主动脉瓣后通过给球囊加压的方式使支架扩张固定。这种球囊扩张型生物瓣膜存在的缺点和问题是：在支架压缩和球囊扩张过程中，生物瓣膜的瓣叶组织结构将受到极大地破坏，严重影响了心脏瓣膜植入后的使用寿命。另外心脏瓣膜的支架由球囊直径决定，如果尺寸选择过小，瓣膜有松动或移位的风险，只能进行二次球囊扩张，尺寸选择过大，就会有撕裂主动脉瓣口的风险，导致其他的并发症的发生。这种心脏瓣膜，球囊一旦扩张后就不可重置，在位置放置不当的情况下，会当场危及患者的生命；心脏瓣膜一旦植入，如出现问题，无法回收，只能通过外科手术置换。
自扩张型人工心脏瓣膜是在镍钛自扩张的支架上固定生物瓣膜。将支架放入输送器的导管中，微创介入到达主动脉瓣后将支架释放，通过支架自身的结构使之与主动脉瓣口固定。这种自扩张型生物瓣膜存在的缺点和问题是：支架长度过长，开口设计不理想，容易影响左、右冠脉口的血流动力学，导致心功能失常；心脏瓣膜释放不当，无法重置，会危及患者生命；心脏瓣膜一旦植入，如出现问题，无法回收，只能通过外科手术置换。
目前的人工生物瓣膜还不能够完全达到释放十分自如的目的。人工生物瓣膜在释放过程中，中心血流很容易冲击人工生物瓣膜的边缘使得阻碍下一步的释放过程。并且，从心包材料的钙化现象和老化过程中的损害现象观察到人工生物瓣膜的边缘往往是最容易发生钙化和老化的部位，这也严重影响到了人工生物瓣的使用。如何确保生物瓣膜在使用过程中释放自如，且不容易发生边缘钙化和损坏现象，并使生物瓣膜在结构上更接近正常体内的瓣膜，是研究人工生物瓣过程中所要解决的主要问题。
文献1【Hsing-Wen Sung，Yen Chang，Chi-Tung Chiu，Chiun-NanChen，Huang-Chien Liang.Mechanical properties of a porcine aortic valvefixed with a naturally occurring crosslinking agent.Biomaterials，1999，20：1759-1772】采用京尼平来处理人工生物瓣中的胶原纤维，并和传统的戊二醛方法进行了比较，发现京尼平的防钙化处理的效果优于传统的戊二醛处理法，但是没有对人工生物瓣膜的边缘破损现象进行分析。
文献2【Peter Angele，Jochen Abke，Richard Kujat，HubertFaltermeier，Detlef S chumann，Michael Nerlich，B ernd Kinner，CarstenEnglert，Zbigniew Ruszczak，Robert Mehrl，Rainer Mueller.Influence ofdifferent collagen species on physico-chemical properties of crosslinkedcollagen matrices.Biomaterials，2004，25：2831-2841】采用碳化亚胺来处理人工生物瓣中的胶原纤维，并对其力学性能和溶胀性能进行了研究，但是没有对人工生物瓣膜的整体耐久性进行处理和研究。
中国专利申请No.200680018417.4(美国爱德华兹生命科学公司)公开了对生物假体组织进行处理以缓解植入后钙化。该申请采用热处理过的或者pH调节过的戊二醛溶液预先处理生物假体组织，然后采用封闭剂和还原剂相结合的方法来构建防钙型人工生物瓣。
中国专利申请No.92100096.0(北京阜外医院)公开了异种生物瓣化学改性的方法，其采用羟基铬和戊二醛相结合的方法来构建防钙型人工生物瓣。
发明内容
本发明的目的在于提供一种边缘刚性化人工生物瓣膜的制备方法，以克服现有技术存在的上述缺陷。
本发明方法先将人工生物瓣膜浸没在预处理的戊二醛溶液中，所述人工生物瓣膜在与所述预处理的戊二醛溶液接触之前、之后或者同时可用戊二醛部分固定；然后通过还原剂、栲胶将戊二醛预处理过的人工生物瓣膜所形成的游离醛基、羧基、氨基、羟基、羰基基团封闭。
不受任何现有理论所束缚，本发明人工生物瓣膜边缘刚性化增强的机制推测是：戊二醛使人工生物瓣膜中的胶原蛋白产生化学反应，主要与胶原蛋白中的赖氨酸的ε-氨基产生缩合反应，生成牢固的交联键，同时也可能与羟脯氨酸中的羟基作用形成缩醛，产生牢固的交联键。在上述反应的同时，还能产生烷醇化合。通过以上三种反应，戊二醛使胶原分子的分子内交联和分子间交联，加强结构强度。还原剂，例如，硼氢化钠，可使人工生物瓣在戊二醛溶液处理改性过程中所产生的游离醛基得以还原，减少人工生物瓣表面的醛基数目，提高人工生物瓣的防钙化性能。而栲胶作为一种天然化合物改性剂，主要由单宁、非单宁、简单酚、有机酸等组成。在PBS，Hank’s或D-Hank’s缓冲溶液(组成成分参见下文的表3-5)中，水解单宁中的多元酚羧酸和多元醇将与人工生物瓣膜表面的醛基、羧基、氨基、羟基、羰基等基团以酯键或苷键结合形成复杂化合物。同时，缩合单宁中的黄烷醇聚缩物与酸共热会聚缩成聚合物填鞣在人工生物瓣膜的表面。通过加入亚硫酸盐，可使栲胶的PBS，Hank’s或D-Hank’s缓冲溶液中不溶物含量减少，冷溶性增强，渗透速度和浅化颜色提高，从而得到具有良好界面性能的人工生物瓣。亚硫酸盐包括亚硫酸钾，亚硫酸氢钾，亚硫酸钠，亚硫酸氢钠，亚硫酸锌，亚硫酸铵中的一种或几种，浓度范围0.1～30％。
具体而言，本发明提供一种边缘刚性化人工生物瓣的制备方法，包括下列步骤：
将新鲜人工生物瓣膜材料，经过PBS，Hank’s或D-Hank’s缓冲溶液(pH 7.0～7.8)充分漂洗干净后，选择厚薄均匀和纤维取向一致的人工生物瓣膜切割成1～60cm2大小的膜片放入预处理的戊二醛复方缓冲溶液中固定1～25天，然后用双蒸馏水洗脱人工生物瓣膜，将戊二醛洗脱干净；
将上述戊二醛预处理过的人工生物瓣膜放入含有还原剂的PBS，Hank’s或D-Hank’s缓冲溶液中修饰1～20小时；
将上述还原剂溶液处理过的人工生物瓣膜放入栲胶的PBS，Hank’s或D-Hank’s缓冲溶液中30～60天，取出后经过PBS缓冲溶液充分漂洗和双蒸蒸馏水洗脱干净后放入双蒸蒸馏水中保存。
本发明中，所用的还原剂选自硼氢化钠，氢化铝锂，硼氢化钾，硫代硼氢化钠，三仲丁基硼氢化锂，异丙醇铝，锌粉和镁粉中的一种或几种。
本发明中，所用的戊二醛复方缓冲溶液选自戊二醛/羟乙基哌嗪乙磺酸复方缓冲溶液、戊二醛/无水吗啉乙磺酸复方缓冲溶液、戊二醛/Tris乙磺酸复方缓冲溶液和戊二醛/三羟甲基氨基甲烷复方缓冲溶液中的一种或几种，其中戊二醛浓度为0.1～10％，羟乙基哌嗪乙磺酸浓度为0.1～10％，无水吗啉乙磺酸浓度为0.1～10％，Tris乙磺酸浓度为0.1～10％，三羟甲基氨基甲烷浓度为0.1～10％，戊二醛复方缓冲溶液pH范围为5.0～7.8。
本发明中，所用的栲胶选自杨梅栲胶、荆树栲胶、五倍子栲胶、橡树栲胶、落叶松栲胶、柚柑栲胶、红根栲胶、坚木栲胶、栲树皮栲胶、柯子栲胶、栗木栲胶、椿木栲胶、橡梳栲胶、槟榔浸膏、余柑栲胶、黑荆树栲胶、橡椀栲胶和马占相思栲胶等中的一种或几种。
本发明方法可使人工生物瓣膜的边缘刚性增强，从而提高了人工生物瓣的长期稳定性和耐久性。
附图说明
为了更清楚地描述本发明的技术方案，下面将结合附图作简要介绍。显而易见，这些附图仅是本申请记载的一些具体实施方式。本发明的技术方案包括但不限于这些附图。
图1示出人工生物瓣膜经过实施例1、实施例2和实施例3处理后的醛基、羧基含量。
具体实施方式
为了进一步理解本发明，下面将结合实施例对本发明的优选方案进行描述。这些描述只是举例说明本发明方法的特征和优点，而非限制本发明的保护范围。
实施例1
将人工生物瓣膜在0.625％戊二醛/0.5％羟乙基哌嗪乙磺酸复方缓冲溶液(pH 7.4)中固定3天。
将戊二醛预处理过的人工生物瓣膜放入含有0.5％硼氢化钠的PBS缓冲溶液(pH 6.8)中修饰5小时。
将所述戊二醛预处理过、硼氢化钠的溶液处理过的人工生物瓣膜放入0.5％杨梅栲胶的PBS溶液(pH 6.8)中处理2天。
实施例2
将人工生物瓣膜在0.625％戊二醛/0.5％无水吗啉乙磺酸复方缓冲溶液(pH 7.4)中固定15天。
将戊二醛预处理过的人工生物瓣膜放入含有0.5％硼氢化钠的PBS缓冲溶液(pH 6.8)中修饰10小时。
将所述戊二醛预处理过、硼氢化钠的溶液处理过的人工生物瓣膜放入0.5％荆树栲胶的PBS缓冲溶液(pH 6.8)中处理3天。
实施例3
将人工生物瓣膜在0.625％戊二醛/0.5％三羟甲基氨基甲烷复方缓冲溶液(pH 7.4)中固定20天。
将戊二醛预处理过的人工生物瓣膜放入含有1％硼氢化钠的Hank’s缓冲溶液(pH 6.8)中修饰20小时。
将所述戊二醛预处理过、硼氢化钠的溶液处理过的人工生物瓣膜放入1％坚木栲胶的Hank’s缓冲溶液(pH 6.8)中处理7天。
实施例4
拉伸强度、弯曲强度、残余干重和撕裂点占比的测定方法如下所示：
拉伸测试
测试仪器：Instron 5543型拉伸试验机
测试条件：常温，PBS水浴槽中
测试方法：将人工生物瓣膜裁成5mm×50mm的试条，将试条两端固定在夹具上，设置上下夹具间距离为25mm，固定好后对其进行预加载，预加载条件为：速率为60mN/min，最大数值为1mN，循环3次；预调后按25mm/min的加载速度沿纤维排列方向对样品进行应力加载，进行相应指标的测定，并计算材料的拉伸强度。
弯曲测试
测试仪器：脉冲流体冲击试验机
测试条件：常温，PBS水浴槽中
测试方法：将人工生物瓣膜裁成15mm×60mm的试条，将试条一端固定在夹具上，设置试条的中心距离脉冲流体发射口为50mm，脉冲流体压力为20mmHg，循环3次，进行相应指标的测定，并计算材料的弯曲强度。
残余干重测试
仪器准备：-80℃冰箱，真空冻干机
步骤：将样品置于-80℃冰箱预冻1h后用真空冻干机冻干24h，取出后天平称量，测得干重。
撕裂点测试
测试仪器：大压力流体试验机
测试条件：常温，PBS水浴槽中
测试方法：将人工生物瓣膜缝合在镍钛支架上，将组件固定在夹具上，设置流体压力为300mmHg，循环次数为75次/分钟，总次数为2亿次，结束后进行相应指标的测定，并计算组件中人工生物瓣膜的撕裂点。
测定结果参见表1-2和图1。
表1：人工生物瓣膜经过实施例1、实施例2和实施例3处理后的力学性能比较
表2：实施例1、实施例2和实施例3处理后人工生物瓣膜在300mmHg大压力流体测试35天后的残余干重和撕裂点占比
从图1，表1和表2中可以清楚地看到，采用根据本发明方法制备的人工生物瓣表面的基团分布合理，力学性能优异和大压力流体测试结果良好。
表3：PBS缓冲溶液(g/L)的成分
表4：Hank’s缓冲溶液(g/L)的成分
表5：D-Hank’s缓冲溶液(g/L)的成分
本发明方法能够在化学改性过程中较好地提高人工生物瓣的力学性能和防钙化性能的同时，提高了人工生物瓣的整体耐久性。
本领域技术人员可以理解，以上描述只是示例性的。在不背离发明思想的情况下，本领域技术人员可对本发明作出多种修改和变化，但这些修改和变化将落入本发明的保护范围。
Claims (9)
1.一种边缘刚性化人工生物瓣膜的制备方法，包括先将人工生物瓣膜浸没在预处理的戊二醛复方缓冲溶液中，所述人工生物瓣膜在与所述预处理的戊二醛复方缓冲溶液接触之前、之后或者同时可用戊二醛部分固定；然后通过还原剂和栲胶将戊二醛预处理过的人工生物瓣膜所形成的游离醛基、羧基、氨基、羟基和羰基基团封闭。
2.权利要求1所述的制备方法，其包括下列步骤：
将新鲜人工生物瓣膜材料，经过pH为7.0～7.8的PBS，Hank’s或D-Hank’s缓冲溶液充分漂洗干净后，选择厚薄均匀和纤维取向一致的人工生物瓣膜切割成1～60cm2大小的膜片放入预处理的戊二醛复方缓冲溶液中固定1～25天，然后用双蒸馏水洗脱人工生物瓣膜，将戊二醛洗脱干净；
将上述戊二醛预处理过的人工生物瓣膜放入含有还原剂的PBS，Hank’s或D-Hank’s缓冲溶液中修饰1～20小时；
将上述还原剂溶液处理过的人工生物瓣膜放入栲胶的PBS，Hank’s或D-Hank’s缓冲溶液中2、3或7天，取出后经过PBS溶液充分漂洗和双蒸蒸馏水洗脱干净后放入双蒸蒸馏水中保存。
3.权利要求1或2所述的制备方法，其中所述还原剂选自硼氢化钠，氢化铝锂，硼氢化钾，硫代硼氢化钠，三仲丁基硼氢化锂，异丙醇铝，锌粉和镁粉中的一种或几种。
4.权利要求2所述的制备方法，其中所述戊二醛复方缓冲溶液选自戊二醛/羟乙基哌嗪乙磺酸复方缓冲溶液、戊二醛/无水吗啉乙磺酸复方缓冲溶液、戊二醛/Tris乙磺酸复方缓冲溶液和戊二醛/三羟甲基氨基甲烷复方缓冲溶液中的一种或几种。
5.权利要求4所述的制备方法，其中戊二醛浓度为0.1～10%，羟乙基哌嗪乙磺酸浓度为0.1～10%，无水吗啉乙磺酸浓度为0.1～10%，Tris乙磺酸浓度为0.1～10%，三羟甲基氨基甲烷浓度为0.1～10%，戊二醛复方缓冲溶液pH范围为5.0～7.8。
6.权利要求1或2所述的制备方法，其中所述栲胶选自杨梅栲胶、荆树栲胶、五倍子栲胶、橡树栲胶、落叶松栲胶、柚柑栲胶、红根栲胶、坚木栲胶、栲树皮栲胶、柯子栲胶、栗木栲胶、椿木栲胶、橡梳栲胶、槟榔浸膏、余柑栲胶、黑荆树栲胶、橡椀栲胶和马占相思栲胶中的一种或几种。
7.权利要求2所述的制备方法，其中栲胶的PBS，Hank’s或D-Hank’s缓冲溶液加入亚硫酸盐。
8.权利要求7所述的制备方法，其中亚硫酸盐选自亚硫酸钾，亚硫酸氢钾，亚硫酸钠，亚硫酸氢钠，亚硫酸锌和亚硫酸铵中的一种或几种。
9.权利要求7或8所述的制备方法，其中亚硫酸盐的浓度为0.1～30%。
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|---|---|
| EP2774630A1 (en) | 2014-09-10 |
| AU2011380375B2 (en) | 2015-09-17 |
| BR112014010668A2 (pt) | 2017-12-05 |
| EP2774630A4 (en) | 2015-07-22 |
| EP2774630B1 (en) | 2017-07-05 |
| CN102499993A (zh) | 2012-06-20 |
| IN2014CN03683A (zh) | 2015-09-04 |
| AU2011380375A1 (en) | 2014-05-29 |
| WO2013063842A1 (zh) | 2013-05-10 |
| BR112014010668B1 (pt) | 2019-04-02 |
| ES2639424T3 (es) | 2017-10-26 |
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