CN115429936A - 改性生物材料的制备方法及得到的改性生物材料 - Google Patents
改性生物材料的制备方法及得到的改性生物材料 Download PDFInfo
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Abstract
本发明公开了一种制备改性生物材料的方法及得到的改性生物材料，所述方法包括：步骤S1A，在60～80℃下热处理戊二醛溶液直至溶液变成金黄色或棕褐色为止；步骤S2，采用步骤S1A得到的戊二醛溶液对所述生物材料进行交联处理，得到初步改性生物材料。步骤S3，将得到的改性生物材料在环氧氯丙烷溶液中浸泡以进一步去除羧基，得到所述改性生物材料。本发明在交联改性之前对戊二醛溶液进行热处理，可以有效降低生物材料表面残留的羧基含量，减少钙化位点；继续用环氧氯丙烷溶液浸泡处理以进一步去除残留的羧基。本发明的改性方法能够保证组织良好的热皱缩温度、组织湿度和氨基酸含量，还能够保持较好的机械抗张强度，生物材料材料更加透明、柔软、水分更充足。
Description
技术领域
本发明涉及生物医用材料技术领域，进一步涉及一种改性生物材料的制备方法及得到的改性生物材料。
背景技术
心脏瓣膜疾病是一种常见的瓣膜衰退疾病。传统的心脏瓣膜疾病的治疗为开胸瓣膜置换手术。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。随着技术的进步，最近十余年中，瓣膜置换手术的发展趋势已由外科开胸手术向经导管微创介入手术转变。与传统的开胸瓣膜置换手术相比，微创介入心脏瓣膜置换手术具有对病人创伤小、术后恢复快、风险低等优点，已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。基于生物瓣膜材料的特点和优势，当前生物瓣已成为介入式瓣膜的首选方案。
生物瓣膜钙化是因为钙盐在瓣膜上不断沉积结晶，从而使瓣膜变硬最后导致狭窄。目前，现有的介入生物瓣膜一般采用戊二醛交联的生物瓣膜材料，戊二醛交联生物瓣膜在体内的钙化问题已成为造成临床上瓣膜失效非常重要的因素。因此，对现有生物瓣膜材料的进行抗钙化处理能有效延长介入生物瓣膜的使用寿命，对介入生物心脏瓣膜的临床使用以及提高患者的生活质量均具有重要的意义。
发明内容
针对现有技术戊二醛交联处理的生物瓣膜易钙化的技术问题，本发明的目的在于提供一种新的制备改性生物材料的方法。
本发明的制备改性生物材料的方法依次包括如下步骤：
步骤S1A，戊二醛溶液热处理步骤：在60～80℃下热处理戊二醛溶液直至溶液变成金黄色或棕褐色为止；加热戊二醛溶液，可以使交联处理后戊二醛残留液中的游离醛含量下降，相应的，使反应后改性生物材料表面的游离醛含量降低，最终减少了因游离醛基被氧化成羧酸的含量。
步骤S2，交联处理步骤：采用步骤S1A得到的戊二醛溶液在35-50℃对生物材料进行交联处理，得到初步改性生物材料；
步骤S3，浸泡步骤：将步骤S2得到的改性生物材料在环氧氯丙烷溶液中浸泡以去除羧基，。
所述方法还包括：
步骤S1B，在所述交联处理步骤之前的漂洗步骤，所述漂洗步骤采用生理盐水漂洗生物材料，例如漂洗3～5次，并在减负载水溶液中浸泡5～120min，去除表面杂质；优选地所述漂洗步骤采用生理盐水漂洗所述生物材料3次，并在减负载水溶液中浸泡30min，去除生物材料表面的脂肪纤维等杂质。
步骤S1A和步骤S1B不分先后顺序。
较佳地是，在步骤S1A中，在65～75℃下热处理1天～14天，直至溶液变成金黄色或棕褐色，优选在70℃下热处理7天，直至溶液变成金黄色或棕褐色。
较佳地是，步骤S2所述交联处理步骤是指在35-50℃条件下，将所述生物材料浸泡于戊二醛溶液中浸泡1-100h，戊二醛溶液的pH值为5.5-6.5；优选地是在50℃条件下，将所述生物材料浸泡于戊二醛溶液中浸泡24h，戊二醛溶液的pH值为6.0。
较佳地是，步骤S2所述交联处理步骤采用戊二醛溶液对所述生物材料进行交联处理，所述戊二醛溶液的质量分数为0.5～1％，优选的戊二醛溶液的质量分数是0.625％。
较佳地是，所述的生物材料为：心包、瓣膜、脑硬膜、肠粘膜、真皮、韧带、肌腱、巩膜、血管和带瓣管道中的一种或几种。
步骤S3，浸泡步骤：将步骤S2得到的改性生物材料在1～5％环氧氯丙烷溶液中浸泡36～72小时以进一步去除羧基，优选地，将步骤S2得到的改性生物材料在2～4％环氧氯丙烷溶液中浸泡48小时以进一步去除羧基。
所述减负载水溶液中含有3～4g/L磷酸氢二钠、0.4～0.55g/L碳二亚胺、80～120g/L异丙醇、120～220g/L甲醛、150～250g/L乙醇。
本发明的另一目的在于提供一种改性生物材料，本发明的改性生物材料采用本发明所述的方法制备得到。
进一步地说，所述改性生物材料是指具有抗钙化的改性生物材料。
与现有的技术相比，本发明的有益效果：
1、本发明通过在交联改性步骤之前对戊二醛溶液进行热处理，可以有效降低戊二醛溶液处理后生物材料表面残留的醛基含量，并进而减少因醛基氧化而生成的羧基的含量，减少了改性生物材料表面的钙化位点，解决现有介入生物材料的钙化问题。在反应之后再用环氧氯丙烷溶液浸泡处理以进一步去除残留的羧基，以降低钙化位点。
2、本发明在生物材料经戊二醛处理后，接着使用环氧氯丙烷处理初步改性的生物材料，由于环氧氯丙烷的强氧化性，其可以将残余的微量醛基进一步氧化成稳定的结构，进一步降低残留醛基的含量。
3、本发明的改性方法能够保证组织良好的热皱缩温度、同时抗钙化效果得到明显改善。
具体实施方式
以下通过特定的具体实例说明本发明的实施方式，本领域技术人员可由本说明书所揭露的内容轻易地了解本发明的其他优点与功效。本发明还可以通过另外不同的具体实施方式加以实施或应用，本说明书中的各项细节也可以基于不同观点与应用，在没有背离本发明的精神下进行各种修饰或改变。需说明的是，在不冲突的情况下，以下实施例及实施例中的特征可以相互组合。
实施例1～5、对比例2
步骤S1B：选择新鲜的生物材料，将新鲜的生物材料经过生理盐水漂洗N次，然后在减负载溶液中浸泡tS1B时间，去除表面的脂肪纤维等杂质。
步骤S1A：将浓度为C戊二醛的戊二醛于TS1A温度下加热tS1A时间，直至戊二醛溶液变为金黄色或褐色，降至一定pH以下。
步骤S2：然后将新鲜生物材料与戊二醛溶液在TS2温度条件下交联tS2时间。
步骤S3：然后将生物材料置于浓度为C环氧氯丙烷环氧氯丙烷溶液浸泡tS3时间。
对比例1
步骤S1B：选择新鲜的生物材料，将新鲜的生物材料经过生理盐水漂洗N次，然后在减负载溶液中浸泡tS1B时间，去除表面的脂肪纤维等杂质。
步骤S1A：将浓度为C戊二醛的戊二醛于TS1A温度下加热tS1A时间，直至戊二醛溶液变为金黄色或褐色，降至一定pH以下。
步骤S2：然后将新鲜生物材料与戊二醛溶液在TS2温度条件下交联tS2时间。
表1减负载水溶液配方(使用注射水定容至1000mL)
| 氯化钠 | 磷酸氢二钠 | 碳二亚胺 | 异丙醇 | 甲醛 | 乙醇 | |
| 对比例1 | 9g | 6.1g | 0.65g | 60g | 100g | 100g |
| 对比例2 | 9g | 2.2g | 0.36g | 150g | 80g | 300g |
| 实施例1 | 9g | 3.6g | 0.50g | 90g | 150g | 150g |
| 实施例2 | 9g | 3.2g | 0.40g | 110g | 120g | 250g |
| 实施例3 | 9g | 3.5g | 0.52g | 80g | 130g | 200g |
| 实施例4 | 9g | 3.3g | 0.48g | 100g | 180g | 220g |
| 实施例5 | 9g | 3.4g | 0.55g | 120g | 200g | 180g |
表2实施例1～5以及对比实施例1-2的工艺参数
表2(续)实施例1～5以及对比实施例1的工艺参数
效果改性后生物材料的性能测试
实验动物选用6周龄体重200±10g雄性SD大鼠60只，每只动物分别编号并称量体重，并记录第7、30、60天大鼠重量，剔除因饲养环境造成营养不良、体重偏差过大的大鼠。
将改性后的生物材料片切割成10×10mm的方形心包片，分为实施例1、2、3、4、5，对比例1、2共8组，每组各30片。将8组心包片用无菌生理盐水漂洗五次，每次五分钟，待用。
将SD大鼠腹腔注射3％戊巴比妥钠0.1mL麻醉后，剃去术野皮毛，用碘酒和乙醇常规消毒。取其中30只，在每只SD大鼠的背部皮下左侧和右侧分别植入实施例2～5的改性心包各一个，缝合皮肤切口，做平行实验30次。
另取30只，在每只SD大鼠的背部皮下左侧和右侧分别植入对比例1～2、实施例1的改性心包各一个，缝合皮肤切口，做平行实验30次。上述大鼠正常饲养(单笼饲养)，于8周后CO2安乐死小鼠，取出移植物。
钙含量测定：分别剪取适量组织样本,去离子水充分漂洗，烘干(80℃，至少24h)称重，置入25ml三角形烧瓶内，加入5ml混合酸(GR浓硝酸：GR高氯酸＝8:2)，将烧瓶放在电热板上消化(摇混150-180℃)，直至烧瓶内出现白烟，溶液呈现清亮，表示消化完毕，然后将瓶内样品用1％硝酸溶液洗涤并转移至10ml具塞刻度试管内，摇匀备测；将处理好的样品转移至原子吸收光谱仪测定钙含量(以每毫克组织干重计)。
数据统计学处理
实验结果以均值±标准差(x±s)表示，采用方差分析t检验，确定组间差异的显著化
表4植入后生物材料的钙含量(μg Ca/mg生物材料干重)
表4(续)植入后生物材料的钙含量(μg Ca/mg生物材料干重)
由表4可知，相对于对比例2，经过本发明提供的制备方法处理的生物材料，植入生物体内同样的时间后，钙含量比未经改性的心包钙含量低约50％。
效果实施例2热皱缩温度测定
取实施例1以及对比例1～2的改性后心包片，裁剪成6cm×1cm大小，每组10片，以注射水为介质，从室温开始，使用热皱缩温度测定仪(选用SFMIT-PS-83皮革收缩温度测定仪)测定心包片样品的大小，每分钟升高2℃完成测定。取样品收缩率变化最大时的水温为样品的热挛缩温度。
表5热皱缩温度
表5(续)热皱缩温度
热皱缩温度是反应胶原交联度及其热稳定性的重要指标。由表5可知，实施例1～5的热皱缩温度明显高于对比例1～2，实施例1的热皱缩温度最高，因此本发明能够有效提高热皱缩温度，进一步说明，本发明可以显著增加改性生物材料的交联度，能更好的抑制钙化。
本文中所描述的具体实施例仅仅是对本发明精神作举例说明。本发明所属技术领域的技术人员可以对所描述的具体实施例做各种各样的修改或补充或采用类似的方式替代，但并不会偏离本发明的精神或者超越所附权利要求书所定义的范围。
Claims (13)
1.一种改性生物材料的制备方法，其特征在于：
步骤S1A，戊二醛溶液热处理步骤：在60～80℃下热处理戊二醛溶液直至溶液变成金黄色或棕褐色为止；
步骤S2，交联处理步骤：采用步骤S1A得到的戊二醛溶液在35-50℃对生物材料进行交联处理，得到初步改性生物材料；
步骤S3，浸泡步骤：将步骤S2得到的初步改性生物材料在环氧氯丙烷溶液中浸泡以进一步去除羧基，得到所述改性生物材料。
2.根据权利要求1所述的制备方法，其特征在于所述方法还包括：
步骤S1B，在所述交联处理步骤之前的漂洗步骤，所述漂洗步骤采用生理盐水漂洗所述生物材料，并在减负载水溶液中浸泡5～120min，去除表面杂质，优选地所述漂洗步骤采用生理盐水漂洗所述生物材料3次，并在减负载水溶液中浸泡30min，去除表面杂质。
3.根据权利要求1所述的制备方法，其特征在于，在步骤S1A中，在65～75℃下热处理1天～14天，直至溶液变成金黄色或棕褐色，优选在70℃下热处理7天，直至溶液变成金黄色或棕褐色。
4.根据权利要求1所述的制备方法，其特征在于，步骤S2所述交联处理步骤是指在35-60℃条件下，将所述生物材料浸泡于戊二醛溶液中1-100h，戊二醛溶液的pH值为5.5-6.5。
5.根据权利要求4所述的制备方法，其特征在于，步骤S2所述交联处理步骤是指在50℃条件下，将所述生物材料浸泡于戊二醛溶液中浸泡24h，戊二醛溶液的pH值为6.0。
6.根据权利要求1所述的制备方法，其特征在于，步骤S2所述交联处理步骤采用戊二醛溶液对生物材料进行交联处理，所述戊二醛溶液的质量分数为0.5～1％。
7.根据权利要求6所述的制备方法，其特征在于，所述戊二醛溶液的质量分数为0.625％。
8.根据权利要求1所述的制备方法，其特征在于，所述的生物材料为：心包、瓣膜、脑硬膜、肠粘膜、真皮、韧带、肌腱、巩膜、血管和带瓣管道中的一种或几种。
9.根据权利要求1所述的制备方法，其特征在于，所述方法还包括：
步骤S3，浸泡步骤：将步骤S2得到的初步改性生物材料在1～5％环氧氯丙烷溶液中浸泡36～72小时以进一步去除羧基。
10.根据权利要求9所述的制备方法，其特征在于，将步骤S2得到的改性生物材料在2～4％环氧氯丙烷溶液中浸泡48小时以进一步去除羧基。
11.根据权利要求2所述的制备方法，其特征在于，
所述减负载水溶液中含有3～4g/L磷酸氢二钠、0.4～0.55g/L碳二亚胺、80～120g/L异丙醇、120～220g/L甲醛、150～250g/L乙醇。
12.一种改性生物材料，其特征在于：采用权利要求1～9任一项所述的方法制备得到。
13.根据权利要求12所述的改性生物材料，其特征在于，所述改性生物材料是指具有抗钙化的改性生物材料。
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| CN113499479A (zh) * | 2021-07-19 | 2021-10-15 | 科凯(南通)生命科学有限公司 | 改性生物材料的制备方法及得到的改性生物材料 |
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| US20060217804A1 (en) * | 2005-03-25 | 2006-09-28 | Dove Jeffrey S | Treatment of bioprosthetic tissues to mitigate post implantation calcification |
| CN113499479A (zh) * | 2021-07-19 | 2021-10-15 | 科凯(南通)生命科学有限公司 | 改性生物材料的制备方法及得到的改性生物材料 |
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