CN103313735A - 增强植入后生物假体组织耐久性的双交联工艺 - Google Patents

增强植入后生物假体组织耐久性的双交联工艺 Download PDF

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CN103313735A
CN103313735A CN2011800651651A CN201180065165A CN103313735A CN 103313735 A CN103313735 A CN 103313735A CN 2011800651651 A CN2011800651651 A CN 2011800651651A CN 201180065165 A CN201180065165 A CN 201180065165A CN 103313735 A CN103313735 A CN 103313735A
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S·M·卡培提尔
A·F·卡培提尔
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Abstract

生物假体组织及其制造方法，包括在升高的温度下通过用0.1至10wt.%戊二醛处理固定生物假体植入组织，通过用二胺交联剂处理加帽所述固定的组织，和用大约0.6wt.%戊二醛处理所述加帽的组织。

Description

增强植入后生物假体组织耐久性的双交联工艺
技术领域
本发明提供了用于从含胶原组织制造生物假体器械的方法。更具体地，描述了增强植入后生物假体组织耐久性的双交联工艺。
背景技术
在1968年，Alain Carpentier首先提出使用戊二醛(“Glut”)以在植入前处理动物组织，产生了人体中的瓣膜生物假体的首次植入。Carpentier,A.等人，J Thorac Cardiovasc Surg.1969Oct;58(4):467-83。在随后的几年中，该工艺被改进，并且瓣膜被安装在支架(stent)内，产生生物假体的概念。Carpentier,A.Med Instrum.1977;11(2):98-101。
随着经验的增长，许多限制变得明显，包括组织钙化和胶原变性。通过添加表面活性剂和乙醇至戊二醛工艺获得钙缓解。Carpentier A.,Nashef A.等人，Circulation70(3Pt2):1165-68；并在美国专利号4,885,005中集中描述。根据首先由Carpentier S.等人，Ann.Thorac.Surg.Dec.66(6Suppl.)3264-6提出的方法，通过将组织浸入加热的戊二醛溶液获得改进的戊二醛固定，这优选在大约45至55℃的温度下进行10至12天范围的时间段，所述文献在此全文并入。
尽管这些技术已经证明在降低组织钙化和增强组织稳定性中是有效的，但需要进一步的改进，特别是扩大瓣膜生物假体在年轻患者中的使用。
二胺，包括赖氨酸或Jeffamine，已经由其他人提出以交联生物假体组织中的游离的醛基。由Huntsman International销售的Jeffamine
Figure BDA00003520255700011
，首先由Hendricks等人(美国专利号6,166,184和美国专利号7,053,051)使用，以避免用戊二醛处理组织，据说戊二醛增强钙化。这些方法中的缺点是来自邻近的胶原分子的氨基和来自二胺的残余氨基不被交联或进一步修饰。结果，损害了组织稳定性。因此，需要具有增强的植入后耐久性的改进的生物假体组织。
发明内容
本发明教导改进的组织处理工艺，其包括以下的新型组合：1)较高浓度或增加的固定时间的加热的戊二醛溶液，以持久地交联游离的氨基，和2)二胺处理，以持久地交联游离的醛基。
本发明的一个方面为制备生物假体植入组织的方法，包括通过用在0.1至10wt%浓度的戊二醛并且在升高的温度下处理固定生物假体植入组织，通过用二胺交联剂处理加帽所述固定的组织，和用大约0.6wt.%的戊二醛处理所述加帽的组织。该固定步骤在大约50℃和pH5.8下进行2至25天，和加帽步骤优选在还原剂——诸如硼氢化钠——的存在下进行。该二胺交联剂可为Jeffamine、Jeffamine D、赖氨酸、多官能聚合物或有机溶剂，并可投入水或缓冲液中。
在一个实施方式中，二胺交联剂为0.01M至1M浓度的Jeffamine，和加帽处理在4℃和50℃之间的温度、在8和13之间的pH下进行1小时至7天的时间。优选地，浓度为0.1M，并且处理在37℃和pH11.7下进行48小时。
在一个实施方式中，硼氢化钠以0.05%和1%之间的浓度、在4℃和40℃之间的温度下被用作对Jeffamine的添加剂，持续1hr至3天的时间。优选地，浓度为0.25%，并且该处理在37℃下进行24小时。
在该方法的一个实施方式中，在固定步骤期间，戊二醛浓度为0.6至10wt.%，并且该处理在从37至75℃的温度、在pH5.4至6.8下进行1至90天。优选地，戊二醛浓度为5%，并且该处理在52±2.5℃的温度、在pH5.8下进行18天的时间。可选地，热处理在非Glut溶液中实现。
还在另一个实施方式中，固定的组织在表面活性剂溶液中进行处理，由此基本上消除磷脂类。表面活性剂溶液含有甲醛、乙醇和吐温80。
处理的组织可为心脏瓣膜或瓣膜小叶，其来源于动物、安装在支架内并且用作处理的整个瓣膜。它可为处理的和安装为整个瓣膜的天然瓣膜，并且处理的整个瓣膜被保存在0.1%至0.6wt.%浓度的戊二醛溶液中，优选戊二醛保存溶液具有0.6%的浓度。可选地，处理的整个瓣膜可作为脱水瓣膜保存，其中在甘油溶液中实现组织脱水。脱水的瓣膜可在环氧乙烷中进行灭菌。
本发明的另一个方面为由工艺制造的生物假体植入组织，该工艺包括在升高的温度通过用0.1至10wt.%戊二醛处理固定生物假体植入组织；通过用二胺交联剂处理加帽所述固定的组织；和用大约0.6wt.%戊二醛处理所述加帽的组织。
本发明的另一方面为制备生物假体植入组织的方法，其包括：
a)在pH5-6.8、45℃-75℃之间下，用至少0.2wt.%戊二醛处理生物假体植入组织1至90天；
b)通过用二胺交联剂处理加帽所述组织，随后用NaBH4还原席夫碱基，
c)在室温下用大约0.6wt.%戊二醛处理所述加帽的组织，优选至少1个月；
d)在具有甲醛(FET)的醇溶液中用表面活性剂处理组织；和
e)在4℃的0.6%戊二醛中保存组织；
其中实施步骤a)、b)、c)和d)，同时搅拌。
附图简述
利用处理的组织样品的大鼠中的皮下植入进行实验。
图1为显示在室温下、在0.6%Glut中组织的处理前和在4℃下、在0.6%Glut中组织的处理后，在不同Glut浓度下的高温Glut的钙缓解效果的图表。结果显示，与预期相反，50℃下的高浓度Glut比低浓度提供更多的钙缓解，假设随后是低浓度glut处理。
图2为比较暴露于不同胺的Glut处理的组织的钙化的图表：
ALA：丙氨酸；EA：乙醇胺，LYS：赖氨酸，JEFF：Jeffamine。
图3为显示具有不同处理时间的乙醇胺和Jeffamine的钙缓解效果的图表。
图4为显示钙缓解的图表，所述钙缓解通过Jeffamine处理和通过NaBH4的席夫碱基还原反应，并且随后是不同的保存：甘油、Glut、Glut之后是甘油。
图5为显示通过双交联的钙缓解的图表：加热的Glut随后是赖氨酸。
图6为显示非常长期——多达12个月——的双交联工艺的效果的图表，其包括高温Glut、二胺交联和表面活性剂(FET)。
图7为本文描述的示例性双交联工艺的概括。
发明详述
对于天然瓣膜狭窄，并且当天然瓣膜泄漏或回流时，诸如当小叶钙化时，可能需要心脏瓣膜替换。天然瓣膜可被切除并用生物或机械瓣膜假体替换。
生物假体瓣膜具有由被植入血流的基础结构支撑的生物组织小叶。作为实例，安装在支撑结构内的生物小叶用于CARPENTIER-EDWARDS
Figure BDA00003520255700041
猪心脏瓣膜和CARPENTIER-EDWARDSPERIMOUNT
Figure BDA00003520255700043
心包心脏瓣膜，其从加利福尼亚州Irvine的EdwardsLifesciences可得。尽管这些瓣膜已经与在人类中的优异长期功能相关，但它们中的一些已经显示钙化的证据，特别是在年轻患者中。
本发明提供了改进的生物假体组织处理工艺，通过使用交联游离氨基，使用高温、高浓度Glut和通过二胺交联游离醛基的结合，该工艺大大降低了在戊二醛-处理的组织植入后钙化的可能性。
优选的实施方式使用了JEFFAMINE聚醚胺，其为包含连接至聚醚骨架末端的伯氨基的Huntsman产品的扩大的族。该聚醚骨架通常基于环氧丙烷(PO)、环氧乙烷(EO)或混合的PO/EO中的任一个。因此它们被称为“聚醚胺”。JEFFAMINE聚醚胺族包括基于该核心结构的单胺、二胺和三胺。最近，添加仲、受阻、高转化的、和基于聚四亚甲基乙二醇(PTMEG)的聚醚胺已经变得可得。
“生物假体组织”包括但不限于，牛心包和猪组织，其普遍用于生物假体心脏瓣膜、血管、皮肤、硬脑膜、心包、小肠粘膜下层(“SIS组织”)、组织心脏瓣膜、韧带和腱。在一个实施方式中，该组织包括在合适的装置中安装和处理的预切的心脏瓣膜小叶。可选地，该组织可为在合适的装置中处理的组织的块体片(bulk sheet)。
本申请中的“植入物”不仅指心脏瓣膜，包括经导管的心脏瓣膜，还指脉管假体和移植物、组织移植物、骨移植物和眼眶移植包裹物等等。
“生物假体心脏瓣膜”指至少部分由生物假体组织制造的完整组装的假体瓣膜。一些整体的猪瓣膜用于所谓的“无支架”生物假体瓣膜，其中有很少的——如果有的话——合成的材料被添加用于支撑或锚定目的。
“有支架的”生物假体瓣膜通常具有一些种类的用于小叶的合成(例如，聚合物或金属的)支撑物，其可为整个猪瓣膜的小叶或单独的牛心包小叶。本文考虑的心脏瓣膜包括外科心脏瓣膜、切顶轴(transapical)心脏瓣膜、经股心脏瓣膜和其他类型的心脏瓣膜。
本发明的可植入的生物组织可由通过同种移植物组织的冰冻保存(即，深低温保藏)的人类组织形成，或由来自通过化学固定保存的动物的组织(即，生物假体组织)形成。这些组织包含结缔蛋白(即，胶原和弹性蛋白)，其起到支撑框架的作用。
生物组织的化学固定涉及将它们暴露于一种或多种化学固定剂(即，鞣剂)，其形成给出的胶原分子内的多肽链之间的交联(即，分子内交联)，或邻近的胶原分子之间的交联(即，分子间交联)。已经用于交联胶原组织的化学固定剂的例子包括：甲醛、戊二醛、双醛淀粉、六亚甲基二异氰酸酯和某些聚环氧化合物。
关于生物假体材料的尚未解决的问题是结缔组织蛋白、胶原和弹性蛋白可在体内的长期植入后变得钙化，特别是在年轻患者中。钙化产生不期望的生物假体的变硬或退化，其可导致瓣膜失效。
自从发现它的抗免疫和抗变性作用后，戊二醛(或“Glut”)已经成为最广泛使用的固定剂。Carpentier,A.等人，J Thorac Cardiovasc Surg.1969Oct;58(4):467-83。然而，戊二醛处理不防止组织在胶原、弹性蛋白、基质和脂类上的潜在钙结合位点的钙化，这可导致体内钙化。该钙化倾向可通过应用各种化学处理降低，如在以下中所描述的：美国专利号4,729,139(Nashef)；美国专利号4,885,005(Nashef等人)；美国专利号4,648,881(Carpentier等人)；美国专利号5,002,566(Carpentier)；欧洲专利号103947(Pollock等人)，美国专利号5,476,516(Seifter等人)，美国专利号5,215,541(Nashef等人)和美国专利号5,862,806(Cheung)。
美国专利号6,471,723(Ashworth等人)和美国专利号4,786,287(Nashef等人)描述了通过添加多种胺至戊二醛固定的组织中的醛基的钙化缓解。美国专利号5,476,516(Seifter等人)教导了添加多元醇(例如，甘油)和醇至生物假体组织作为钙化缓解处理。美国专利号6,509,145(Torrianni)和美国专利号7,078,163(Torrianni)解决生物假体组织的氧化用于钙化缓解。美国专利号6,630,001(Duran等人)和美国专利号6,277,55(Duran等人)讨论了使用由Zerbini首先提议的甘油保存和组织的冻干法。美国专利号6,352,708(Duran等人)包括新鲜的、“非固定的”组织的甘油保存，和用甘油和肝磷脂的处理。
在美国专利号6,561,970(Carpentier等人)中并且与美国专利号5,931,969(Carpentier等人)中的相对组织/流体移动结合描述了通过在戊二醛中组织的升高温度固定进行钙缓解的方法。包括调节戊二醛固定溶液的pH的技术在美国专利号6,878,168(Carpentier等人)中公开。
本文描述的是处理生物假体植入组织以降低体内钙化的方法，包括：用高温和高浓度戊二醛固定生物假体植入组织，和随后用二胺交联溶液处理固定的组织，以缓解钙化。
利用戊二醛、吐温(聚氧乙烯20失水山梨醇单油酸酯)、乙醇和任选地利用甲醛的组织处理，可提供有用的组织固定。然而，这些化合物也将产生能够与钙相互作用或吸引钙的新的结合位点。用戊二醛处理的组织包含游离的醛基，其引起增加的毒性和更高的钙化。
因此，本文描述的是在植入身体前，加帽这些新形成的结合位点的方法。术语“加帽”指阻断、移除或改变将对生物假体性质具有不利影响的官能团。
不同于现有技术组织工艺，其中单独的目标仅为利用低浓度的戊二醛固定组织，或利用阻断剂加帽组织胺，本方法结合了两种工艺，即，利用二胺交联游离的醛基和利用高浓度二醛交联游离的氨基，而同时优选在还原条件下加帽游离的醛基。
在优选实施方式中，戊二醛固定步骤在利用二胺加帽二醛基之前进行，优选在50℃下利用加热的Glut进行3至25天。Glut固定后是在还原条件(例如，硼氢化钠)下用Jeffamine二胺处理，以便加帽固定的组织中的醛基，和进一步交联组织中的蛋白质，由此增强它的体内稳定性。
本固定/加帽/交联工艺优选包括组织的化学还原，当在聚合二胺存在下应用时，该工艺将永久将交联剂连接至目标醛基。
例如，添加Jeffamine诸如Jeffamine D至组织将同时加帽和交联醛基，同时还原剂(例如，硼氢化钠)将还原由醛基与胺基的反应产生的任何席夫碱基。因此醛基最终被桥连基团或聚合胺部分取代，其可有益于组织水合、柔性和细胞相互作用。
其他二胺加帽/交联剂可代替Jeffamine——诸如赖氨酸或聚合分子——使用。除了硼氢化钠，在水性溶液中可用的还原剂为本领域技术人员已知并且包括在本发明的范围内，其包括硼氢化钾、氰基硼氢化物和其他。
戊二醛处理
戊二醛处理包括3个步骤：首先，在0.6%Glut中，在pH7.4、在室温下固定组织至少1个月，同时搅拌(Glut固定I10，图7)；随后在加热的Glut中，在45-75℃下进一步固定1至90天，同时搅拌(热处理12，图7)；随后在0.6%中，在室温下进一步固定至少1个月(Glut固定II14，图7)。
Jeffamine交联和通过硼氢化钠还原
戊二醛-固定的组织在PBS缓冲液中清洗，以去除任何过量的附着至组织的戊二醛。该组织随后首先暴露于蒸馏水(DW)中的浓度为0.1±0.01M的Jeffamine二胺的加帽/交联溶液，在37℃下搅拌24小时，并且其次在Jeffamine和0.25%硼氢化钠溶液中，在37℃搅拌又24小时(加帽16，图7)。将该组织从溶液中移出并且在几分钟内在室温下，在0.9%NaCl溶液中进行清洗。
表面活性剂处理
将该组织随后在包含甲醛、乙醇和吐温80的表面活性剂溶液中在32℃下处理9小时(表面活性剂18，图7)。在0.9%NaCl溶液中清洗三次后，根据以下工艺，在Glut或甘油中进行保存。
保存
1-在4℃下0.6%Glut中保存。由Glut溶液实现灭菌(保存在Glut20中，图7)
2-保存在甘油中(任选的)。在组织已经通过标准最终生物负载还原步骤进行加工，并随后通过0.6%Glut步骤至少1个月之后，它可经历75wt%甘油和25wt.%乙醇的溶液中的甘油处理。将该组织在室温下浸泡在该溶液中一小时。在该时间期间，存在于心包组织中的大部分水分子被甘油取代。将该组织从溶液移出并且放置在干净的罩中，以使得任何过量的溶液蒸发或从组织中滴完(干燥保存22，图7)。
灭菌
灭菌由环氧乙烷(EO)实现。脱水的组织在由具有Tyvek盖的刚性托盘(PETG)组成的双重无菌阻隔包装(barrier packaging)中进行包装。该包装应在洁净室中进行密封，并可在100%环氧乙烷中进行灭菌。
在固定的和交联的组织——诸如在乙醇/甘油溶液中——被脱水的实施方式中，甘油可包括抗氧化剂并且可包含水溶性蜡。随后允许该组织干燥并且随后经过最终灭菌(例如，环氧乙烷、γ辐照或电子束辐照)。
钙化缓解剂优选包含选自以下的加帽/交联剂：
聚合二胺，诸如Jeffamine D、ED和EDR，
二氨基酸，诸如赖氨酸，
包含至少两个氨基的亲水多官能聚合物，
包含至少两个氨基的疏水多官能聚合物。
还原剂可为硼氢化钠、硼氢化钾、氰基硼氢化物和类似物。
化学抗氧化剂期望选自水溶性抗氧化剂诸如抗坏血酸、脂溶性抗氧化剂诸如生育酚、碳水化合物诸如果糖、蔗糖或甘露醇、受阻酚诸如丁基羟基甲苯(BHT)、受阻胺光稳定剂(HALS)诸如对苯胺二胺、三甲基二氢喹啉或烷基化联苯胺、亚磷酸盐/亚膦酸盐诸如三苯膦，和硫酯诸如硫代肉桂酸盐。
二胺期望被投入以下溶液之一或以下溶液的组合中：
水性溶液，诸如水性缓冲液、水、短链醇、甘油或增塑剂，
有机溶剂，和
有机缓冲液。
二胺交联剂通常如下使用：a)浓度在0.02M至1M，优选0.1M；b)持续1小时至4天的时间，优选48小时；c)在4℃和50℃之间的温度下，优选37℃；和d)pH在8和13之间，优选11.7。
还原剂诸如硼氢化钠通常如下使用：a)浓度在0.05%和1%之间，优选0.25%；b)持续1hr至3天的时间，优选24hr；c)在4℃和40℃之间的温度下，优选37℃。
在高温固定步骤期间，戊二醛浓度通常为0.1至6wt.%，优选0.6wt.%；并在从20至70℃，优选52℃+/-2.5℃的温度下处理1至25天，优选18天；pH在5.4至6.8之间，优选5.8。高温步骤前或后的其他固定步骤通常为在室温下，pH7.4的0.6%Glut。在另一个实施方式中，在类似的条件下加热的Glut可被加热的缓冲液取代。
在优选的实施方式中，固定的组织在表面活性剂溶液中进行处理，以消除磷脂类。例如，表面活性剂溶液可包含甲醛、乙醇和吐温80。
在本发明的一个实施方式中，假体组织为心脏瓣膜或小叶，其来源于动物、安装在支架内并用作处理的整个瓣膜。在另一个实施方式中，该组织为用于形成心脏瓣膜小叶的牛心包组织，其用于生产生物假体心脏瓣膜。
在另一个实施方式中，加工的组织为处理和安装作为整个瓣膜的天然瓣膜。处理的整个瓣膜可保存在浓度从0.1%至2%，优选0.6wt.%的戊二醛溶液中。
在一个实施方式中，处理的整个瓣膜作为脱水瓣膜保存；优选组织脱水在甘油溶液中实现。在优选的实施方式中，脱水瓣膜在环氧乙烷中灭菌。
在用于制备生物假体植入组织的一个实施方式中，戊二醛固定步骤在大约50℃和pH5.8下进行至少7天，和利用二胺交联剂的加帽在还原剂——优选硼氢化钠——的存在下进行。
为了更好地理解本发明的钙化性质，在图中呈现基于多样本的皮下测试的图表。
图1显示了在不同Glut浓度下高温Glut的钙缓解效果。牛心包组织首先在室温下用0.6%Glut进行处理。随后对照组在搅拌下，在50℃用0.6%Glut处理6天。其他两个组在搅拌下，在50℃下用2.4%和5%Glut处理6天。组织被植入大鼠3周。结果显示5%Glut组中的钙缓解优于2.4%和0.6%Glut组(97.40对87.00对72.70μg/mg)，有25%的减少。
图2显示了在植入大鼠6周后用不同的胺处理的心包样品的组织钙化。对照样本仅用戊二醛进行固定。测试样本用戊二醛进行固定，并且随后用丙氨酸(ALA)、乙醇胺(EA)、赖氨酸(LYS)或Jeffamine(JEFF)进行加帽。结果显示交联剂Jeffamine(55.6ug/mg)优于赖氨酸(90.2ug/mg)；赖氨酸也可被用作交联剂，并且两者都优于单胺化合物乙醇胺(135.5ug/ml)和丙氨酸(146.5ug/mg)。
图3显示了与用0.5M乙醇胺处理相同时间、随后皮下植入大鼠6周的戊二醛-固定的组织相比，用0.3M Jeffamine处理24小时或48小时的戊二醛-固定的组织的钙化缓解。结果显示Jeffamine优于乙醇胺。
图4显示了用Jeffamine和硼氢化物处理、随后用戊二醛后处理的戊二醛-固定的组织的钙化抗性。在植入大鼠3个月后，观察到在Jeffamine和NaBH4处理的组织中99.6%的钙减少(144.5对0.6μg/mg)。分析了不同的保存条件：Glut或75%甘油/25%乙醇。
图5显示了在热Glut处理前，由赖氨酸处理16小时的Glut组织的高钙缓解。在植入大鼠5周后，与不含赖氨酸的对照组相比，具有赖氨酸的组显示了99.2%的钙减少。
图6显示了包括加热的Glut、赖氨酸和表面活性剂的处理的钙缓解效果。首先组织在搅拌下，在pH5.8、50℃下暴露于浓缩的(5%)戊二醛溶液6天，随后在室温下暴露于0.6%Glut至少3天。在用蒸馏水(DW)中的0.5M赖氨酸，在37℃下加帽/交联24小时后，用0.6%Glut在pH7.4下处理24hr。在赖氨酸处理前或后，在32℃下进行9hr的表面活性剂处理(FET)。在4℃下在0.6%Glut中进行保存。
图7为显示该发明性工艺的实施方式的流程图。该组织在pH5.8、50℃下被暴露于0.6%戊二醛溶液18天(12)，随后在室温下暴露于0.6%Glut至少2天(11)。在用蒸馏水(DW)中的0.1±0.01M Jeffamine在37℃下加帽/交联24小时后，在37℃下，在具有硼氢化钠的还原条件下进一步暴露于Jeffamine24小时(16)。该步骤(16)之后为在pH7.4下用0.6%Glut处理至少2-3天(17)和随后在32℃下用表面活性剂(FET)处理9hr(18)。在4℃下0.6%Glut中进行保存(20)，或任选地在75%甘油/25%乙醇的溶液中进行保存(22)。
实施例
实施例1：钙化缓解-大鼠模型。
为了评估根据本文描述的方法处理的(“SFX-处理的”)心包组织的钙化缓解性质，进行动物可行性研究。在0.9%NaCl中清洗样本以消除过量的Glut后，18个样本/处理(n=4/大鼠)在12天大的大鼠的背部皮下植入6周(图3)。这些研究证明在缓解组织中钙化发生方面，Jeffamine交联/硼氢化钠处理优于乙醇胺/硼氢化钠，乙醇胺/硼氢化钠优于对照组(仅Glut)(0.1对51.61对103.1μg/mg)。
在大鼠中的所有研究中，SFX-处理的组织论证了当与对照组织相比时钙化数据中降低的可变性。放弃来自兔子肌肉内植入的数据，因为它们与太多变化相关。
实施例2：利用Jeffamine和硼氢化钠，戊二醛-固定的组织的醛交联。
紧接在热处理步骤后将生物假体组织从0.625%戊二醛中移出，并保存在0.6%Glut(pH7.4)中2天。在DW中制备一升交联溶液，其包含333mM Jeffamine(聚(丙二醇)二(2-氨基丙基醚)，平均M230(Aldrichréf.406651)和0.25%硼氢化钠。
加帽溶液被放置在有轨摇床上，随后组织(小叶、心包)以3个小叶每100ml的比率被放置在溶液中。容器不被完全密封，因为与水的化学反应释放的氢气能引起容器爆炸。有轨摇床在37℃下，在60-80rpm之间操作24小时。该组织被移出并保存在0.6%Glut溶液中2-3天，并在32℃下，在FET溶液(甲醛、乙醇、吐温-80)中处理9小时，随后保存在0.6%Glut溶液，直到植入。
实施例3：在高温下利用高浓度二醛的氨基交联
如图6所示，组织首先在50℃下处理6天，随后在37℃下，在0.5M赖氨酸中处理24小时，同时搅拌。FET处理在赖氨酸处理前或后应用。
赖氨酸处理的效果积累至热处理，并且FET进一步改进了结果。当FET在赖氨酸处理后时，FET的位置可优先起作用。
实施例4：保存
已经开发了两种保存工艺：
1-低浓度戊二醛保存：
这对于利用根据本文描述的方法处理的组织制备的瓣膜是优选的保存工艺。假设考虑某些条件，则glut中的保存不增强钙缓解。这些条件为在0.6%Glut中保存至少2个月和在植入前彻底清洗。
2-无戊二醛保存：甘油
避免戊二醛作为保存溶液的可选方案是在甘油/乙醇混合物中使生物假体组织脱水，用环氧乙烷灭菌，和包装最终产品“干燥物”。该工艺据说绕过了戊二醛作为杀菌剂和保存溶液的潜在的毒性和钙化影响。已经提出一些方法以使用甘油、醇和其组合作为glut加工后方法，以便所得组织是“干燥”状态。甘油中心脏瓣膜组织的保存由Parker等人描述(Thorax197833：638)，但不包括任何钙化缓解技术并且没有描述任何优点。同样，美国专利号6,534,004(Chen等人)描述了多羟基醇诸如甘油中生物假体组织的保存。然而，这些方法中的任一个都没有解决缓解组织的潜在氧化。推荐的工艺在Edwards美国专利公布号2009-0164005中进行描述。
尽管本发明已经根据示例性实施方式进行了描述，但将应理解这些实施例是说明性的，并不表示是限制性的。因此，可在所附权利要求内进行更改，而不脱离本发明的真实范围。

Claims (24)

1.制备生物假体植入组织的方法，包括：
a)在升高的温度下通过用0.1至10wt%浓度的戊二醛处理固定生物假体植入组织，
b)通过用二胺交联剂处理加帽所述固定的组织，和
c)用大约0.6wt.%戊二醛处理所述加帽的组织。
2.权利要求1所述的方法，其中所述热处理步骤在大约50℃和pH5.8下进行2至25天。
3.权利要求1所述的方法，其中所述加帽步骤在还原剂的存在下进行。
4.权利要求3所述的方法，其中所述还原剂为硼氢化钠。
5.权利要求1所述的方法，其中所述二胺交联剂选自Jeffamine、Jeffamine D、赖氨酸、多官能聚合物和有机溶剂。
6.权利要求1所述的方法，其中所述二胺交联剂被投入水或缓冲液中。
7.权利要求1所述的方法，其中所述二胺交联剂为以下中的Jeffamine：
a)浓度为0.01M至1M，
b)持续1小时至7天的时间，
c)在4℃和50℃之间的温度，
d)在8和13之间的pH。
8.权利要求7所述的方法，其中a)为0.1M，b)为48hr，c)为37℃，和d)为pH11.7。
9.权利要求4所述的方法，其中所述硼氢化钠用作Jeffamine的添加剂：
a)浓度在0.05%和1%之间，
b)持续1hr至3天的时间，
c)温度在4℃和40℃之间。
10.权利要求9所述的方法，其中a)为0.25%，b)为24h，和c)为37℃。
11.权利要求1所述的方法，其中在所述固定步骤期间，所述戊二醛浓度为0.6至10wt.%，在从37至75℃的温度、pH5.4至6.8下，持续1至90天。
12.权利要求11所述的方法，其中所述戊二醛浓度为5%，在52+2.5℃的温度、pH5.8下，持续18天的时间。
13.权利要求11所述的方法，其中所述处理在非Glut溶液中实现。
14.权利要求1所述的方法，其中所述固定的组织在表面活性剂溶液中进行处理，由此基本上消除磷脂类。
15.权利要求14所述的方法，其中所述表面活性剂溶液包含甲醛、乙醇和吐温80。
16.权利要求1所述的方法，其中所述组织为心脏瓣膜或瓣膜小叶，其来源于动物、安装在支架内并且用作处理的整个瓣膜。
17.权利要求1所述的方法，其中所述加工的组织为处理并且安装为整个瓣膜的天然瓣膜。
18.权利要求17所述的方法，其中所述处理的整个瓣膜被保存在0.1%至0.6wt.%浓度的戊二醛溶液中。
19.权利要求17所述的方法，其中所述处理的整个瓣膜作为脱水的瓣膜被保存。
20.权利要求19所述的方法，其中在甘油溶液中实现组织脱水。
21.权利要求20所述的方法，其中所述脱水的组织在环氧乙烷中进行灭菌。
22.制备生物假体植入组织的方法，包括：
a)在pH5-6.8、45℃-75℃之间下，用至少0.2wt.%戊二醛处理生物假体植入组织1至90天；
b)通过用二胺交联剂处理加帽所述处理的组织，随后用NaBH4还原席夫碱基，
c)在室温下用大约0.6wt.%戊二醛处理所述加帽的组织，优选至少1个月；
d)在具有甲醛的醇溶液(FET)中用表面活性剂处理所述组织；和
e)在4℃的0.6%戊二醛中保存所述组织；
其中实施步骤a)、b)、c)和d)，同时搅拌。
23.权利要求22所述的方法，其中所述固定在50℃的温度下进行18天。
24.生物假体植入组织，由包括以下的工艺制造：
a)在升高的温度下通过用0.1至10wt.%戊二醛处理固定生物假体植入组织，
b)通过用二胺交联剂处理加帽所述固定的组织，和
c)用大约0.6wt.%戊二醛处理所述加帽的组织。
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