CN103705980A - 加帽生物假体组织以减少钙化 - Google Patents

加帽生物假体组织以减少钙化 Download PDF

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CN103705980A
CN103705980A CN201410014350.3A CN201410014350A CN103705980A CN 103705980 A CN103705980 A CN 103705980A CN 201410014350 A CN201410014350 A CN 201410014350A CN 103705980 A CN103705980 A CN 103705980A
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tissue
bioprosthetic tissue
bioprosthetic
calcification
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CN103705980B (zh
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J·S·德芙
D·多布拉
J·A·戴维森
G·A·怀特
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Edwards Lifesciences Corp
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Abstract

对植入物中使用的生物假体组织进行处理或对装配的生物假体心瓣膜进行处理，以减少体内钙化。该方法包括应用钙化缓和剂例如加帽剂或抗氧化剂到组织，以特定地抑制组织中的氧化。同时，该方法可以用于抑制脱水组织中的氧化。加帽剂抑制组织中结合位点的形成，结合位点由于氧化而被暴露或生成并且另外在植入后将吸引钙、磷酸酯、免疫原性因子、或其它钙化前体。在一种方法中，在装配生物假体心瓣膜中的组织小叶用醛加帽剂预处理，然后脱水和灭菌。

Description

加帽生物假体组织以减少钙化
本申请是分案申请，原国际申请的申请日为2008年12月19日、申请号为200880126930.4(PCT/US2008/013879)、发明名称为“加帽生物假体组织以减少钙化”。
相关申请
本专利申请要求在2007年12月21日提交的、美国临时申请号61/016,263的优先权，其整个公开通过引用以此并入。
发明领域
本申请总体涉及用于处理生物假体组织的方法、材料和减少植入后钙化的设备，以及减少植入后钙化的方法，特别是用于心瓣膜中使用的生物假体组织。
发明背景
当出现天然的心瓣膜变窄时——通常被称为狭窄，或当天然的瓣膜渗漏或回流时——例如当小叶钙化时，表明可以进行心瓣膜置换。在一种治疗方案中，天然的瓣膜可以被切除并用生物或机械瓣膜替换。某些医学状况可能要求移植或缝合组织小片(tissue patch)以修补生理畸形。这些包括但不限于疝修补、血管创伤、先天性心脏缺陷修补和重建以及膀胱壁修补。
组织型或“生物假体”瓣膜具有由基底结构支持的柔韧组织小叶，小叶通过彼此对着合紧以确保单向的血流，伸出进入流动流中并起到很像天然的人心瓣膜的那些小叶的作用。在组织型瓣膜中，整个的异种移植瓣膜(例如，猪)或多个异种移植小叶(例如，牛或马心包)典型地提供流体闭合表面(fluid occluding surfaces)。也提出合成的组织小叶。一个或多个柔韧小叶安装在外周支持结构里面，例如，如在可从加利福尼亚州Irvine的Edwards Lifesciences获得的CARPENTIER-EDWARDS猪心瓣膜和PERIMOUNT心包心瓣膜中所看见的。
可植入的生物组织可以由人体组织形成，所述人体组织通过冷冻(即，低温保存)同种移植组织进行保存；或者由动物组织形成，所述动物组织通过化学固定(即，鞣制)异种移植组织进行保存。用作生物假体的生物组织类型包括心脏瓣膜、血管、皮肤、硬脑膜、心包、小肠粘膜下层(“SIS组织”)、韧带和腱。这些生物组织典型地包含充当所述组织的支持构架的结缔组织蛋白(即，胶原和弹性蛋白)。每种生物组织的柔韧性或刚性很大程度上由该组织中存在的胶原和弹性蛋白的相对量和/或其结缔组织构架的物理结构和构造来决定。胶原是大多数组织中存在的最丰富的结缔组织蛋白。每个胶原分子由以卷曲螺旋构造缠绕在一起的三(3)个多肽链形成。
用于化学固定生物组织的技术典型地包括将该生物组织暴露于一种或多种化学固定剂(即，鞣剂)，所述化学固定剂在给定的胶原分子内的多肽链之间形成交联(即，分子内交联)，或者在相邻胶原分子之间形成交联(即，分子间交联)。已经用于交联白纤维组织的化学固定剂的例子包括：甲醛、戊二醛、二醛淀粉、1,6-己二异氰酸酯和某些聚环氧化合物。
与许多生物假体材料植入相关的一个问题是这些材料中的结缔组织蛋白(即，胶原和弹性蛋白)在植入到体内后可以变成钙化的。这种钙化可导致该生物假体发生不期望的硬化或降解。对白纤维组织的这种损伤导致瓣膜故障。
在可用的各种化学固定剂中，戊二醛(也简单地称为“戊二醛(glut)”)自从在1968年由Dr.Alain Carpentier发现它具有抗免疫和抗降解效果以来已经得到了最广泛的应用。参见Carpentier,A.,J.Thorac.Cardiovascular Surgery,58:467-69(1969)。另外，戊二醛是最常见的灭菌剂之一。戊二醛因此被用作许多商业可得的生物假体产品的优选的固定剂和灭菌剂，例如在可从加利福尼亚州Irvine的EdwardsLifesciences获得的生物假体心瓣膜中。戊二醛在组织内产生可以导致体内钙化的潜在的钙结合位点，如残留的醛、酸、希夫碱等等。这些基团可以有助于钙化，除非经过加帽减轻。减轻这种钙化在贮藏期间是特别重要的，特别当组织没有被贮藏在水溶液中时。
已经提出减轻戊二醛固定的生物假体的体内钙化或用其它方法改进戊二醛固定方法的各种技术。包括其中的是在美国专利4,729,139(Nashef)；美国专利4,885,005(Nashef等)；美国专利4,648,881(Carpentier等)；美国专利5,002,566(Carpentier)；EP103947(Pollock等)；美国专利5,476,516(Seufter等)；和美国专利5,215,541(Nashef等)中所描述的方法。美国专利5,862,806(Cheung)中的技术包括在应用有机溶剂中的化学还原剂例如氰基硼氢化钠或硼氢化钠之前，使用有机溶液(即，乙醇，但没有甘油)对戊二醛处理的组织进行脱水。这种方法仅包括加入还原剂而没有任何加帽剂如蛋白质、胺或者氨基酸。在美国专利6,471,723和美国专利4,786,287中公开的钙化减轻技术包括加入各种胺以使戊二醛固定组织中的醛基团解毒。这些化学品不是永久地连接到组织(例如，通过添加还原剂)，并且因此随着时间将扩散出组织，其显著地降低这些处理的钙减轻效果。在美国专利5,476,516中的技术包括加入多羟基化合物(如，甘油)和醇到生物假体组织中单独地作为钙化减轻处理，但是没有提出任何氧化减轻(即，加帽)策略。美国专利6,509,145和美国专利7,078,163提出用于钙化减轻目的的生物假体组织的氧化。美国专利6,630,001和美国专利6,277,555讨论使用甘油保存和冻干组织，但是没有讨论防止氧化的化学方法。美国专利6,352,708包括新鲜的、“非固定的”组织的甘油保存以及用甘油和肝素的处理，但是没有包括防止氧化或用甘油干燥步骤减少钙化的化学处理的组合。
最近，通过在戊二醛中高温固定组织的钙减轻的新技术在美国专利6,561,970(Carpentier等)中描述，其与在美国专利5,931,969(Carpentier等)中的相对组织/流体运动结合。包括调整戊二醛固定溶液的pH的另一种技术在美国专利6,878,168(Carpentier等)中公开。Edwards Lifesciences XenoLogiXTM组织处理消除多至98%的磷脂，力图减少钙结合位点。在也来自于Edwards Lifesciences的Carpentier-Edwards ThermaFixTM高级心瓣膜组织方法中，同时使用热和化学处理以除去不稳定戊二醛分子，因此减少了钙结合位点，相对于只有戊二醛的对照，其导致钙摄入显著减少。
生物假体瓣膜一般贮存在戊二醛或甲醛溶液中，在植入之前，必须漂洗。戊二醛由于其灭菌剂的性而被广泛地用作为贮存溶液，但是已知其有助于钙化。最小化最终产品中的戊二醛含量的策略已经表明减轻体内钙化。研究显示没有戊二醛的贮存溶液与具有戊二醛的贮存溶液相比，减少了体内钙化(Mirzaie等，Ann Thorac Cardiovasc Surg200713:102)。
避免戊二醛作为贮存溶液的一种这样的策略是在甘油/乙醇混合物中使生物假体组织脱水、用环氧丙烷消毒、和包装最终产品为“干的”。这种方法避免了戊二醛作为灭菌剂和贮存溶液的潜在的毒性和钙化作用。已经有多种方法提议使用甘油、醇类和它们的组合物作为戊二醛后处理的方法，使得生成的组织处于干燥”状态，而不是带有过量戊二醛的湿状态。这些方法避免使用含水的液体醛、或液体灭菌剂作为组织和设备的贮存溶液。基于甘油的方法可以用于如下实例中描述的这种贮存。心瓣膜组织在甘油中的贮存由Parker等(Thorax197833:638)描述，但是没有包括任何钙化减轻技术和没有描述任何益处。同样，美国专利6,534,004(Chen等)描述在多元醇如甘油中贮存生物假体组织。然而，这些中没有一个提出减轻组织的潜在氧化。
在其中使组织在乙醇/甘油溶液中脱水的方法中，组织可以通过环氧乙烷、γ照射、或电子束辐射灭菌。环氧乙烷灭菌需要使组织暴露于将在组织中产生氧化损伤的高温和水蒸气(Olde Damink,LH.等.JBiomed Mater Res199529:149)。已知γ照射在胶原底物中生成显著数量的活性氧化种类，其使得胶原纤丝的骨架裂开和破坏（Ohan,MP等.J Biomed Mater Res A200367：1188）。这种损伤将导致组织中的机械和生物化学功能性减少。电子束辐射也将断开胶原骨架和导致组织结构和反应性退化(Grant,RA等.J Cell Sci19707:387)。在灭菌和/或贮存期间来自氧化的损伤将促进瓣膜退化和结构故障。美国专利6,605,667讨论加入各种抗氧化稳定剂到可聚合的粘合剂中，但是没有涉及在贮存期间通过离子辐射或氧化而减轻对生物假体组织的损伤。
虽然这些基于甘油的方法作为在含水的、液体型溶液中贮存的替代方案是有用的，但是它们没有解决这样的事实：处理后官能团(即，醛)可随着时间氧化，并且因此增加钙化的可能性。本发明描述加帽方法，使得氧化和其它变化随贮存时间被显著地减少。现有技术没有解决在贮藏期间脱水的生物假体组织内的变化，所述变化作为体外空气氧化或体内氧化的结果出现。在戊二醛固定的组织中的高醛含量非常易于氧化，其导致钙化和组织故障。因此，本发明教导改进的可植入组织设备的组织处理方法。
本发明解决脱水组织内的某些有害的变化，所述有害的变化可作为来自贮存和处理期间的灭菌、空气暴露的氧化、或来自体内氧化的氧化的结果出现。戊二醛中的生物假体组织的贮存提供一些抗氧化作用并帮助阻止组织中醛官能的氧化，其可能促进增加的钙化。在组织被脱水和在空气中贮存的方法中，组织没有被保护免受氧化，并且将导致来自活性氧化种类的生物化学损伤。生成的氧化生物标志如羧酸可能促进钙结合并且由于钙化而发生生物假体的失败。组织中醛基团的永久加帽(还原胺化)将防止组织的显著氧化并导致该材料的使用寿命更长。本发明包括醛(和其它种类)的化学加帽或组织的其它方式地抑制，以防止脱水组织中的氧化。
本发明也描述加入化学品(例如，抗氧化剂)到脱水溶液(乙醇/甘油)中，以阻止在灭菌(环氧乙烷、γ照射、电子束辐射等)和贮存期间的组织氧化。脱水的生物假体组织在灭菌和贮存期间特别易于氧化。现有技术没有讨论化学阻止这种类型的生物假体材料的这种损伤。
发明概述
本发明的一个目的是提供减轻生物假体植入组织中钙化的方法，包括：a)用加帽剂处理生物假体植入组织，所述加帽剂与所述组织上的官能团反应，和b)用非水溶液使所述加帽的组织脱水。
另一个目的是提供抗钙化组织，包括：a)已经用加帽剂处理的生物假体植入组织，所述加帽剂与所述组织上的官能团反应，和b)用非水溶液脱水。
本发明的性质和益处的进一步理解在以下描述和所附权利要求中说明，特别是当与附图结合考虑时，在所述附图中，相同的部分具有相同的指代数字。
附图简述
图1为显示在数种不同的化学处理后，牛心包组织中的醛和酸含量的图；
图2为将体内组织钙含量与三种不同方式处理的组织的相应酸和醛含量关联起来的图；
图3为图解各种组织处理的酸和醛含量的图；
图4是显示通过加帽、还原和干燥(GLX方法)的钙化减少的图；
图5是显示通过加帽、还原和干燥(GLX方法)的钙化变异性降低的图；
图6是显示在80天的实时贮存期后，通过加帽、还原和干燥(GLX方法)的钙化减少的图；
图7是35天兔肌内研究的箱线图；
图8是35天兔肌内研究、短期贮存期和钙化的箱线图。
优选的实施方式描述
本发明提供改进的生物假体组织处理方法，其通过在脱水步骤之前封闭游离醛基团和/或加入化学剂以防止灭菌期间的氧化损伤，大大降低植入后钙化的可能性。“生物假体组织”包括但不限于在生物假体心瓣膜中通常使用的牛心包和猪组织，以及血管、皮肤、硬脑膜、心包、小肠粘膜下层(“SIS组织”)、组织心瓣膜、韧带和腱。本申请中的“植入物”不仅指包括经导管心瓣膜在内的心瓣膜，而且指血管假体和移植物、组织移植物、骨移植物和眼眶植入物覆盖物(orbital implantwraps)以及其它。
“生物假体心瓣膜”指至少部分地由生物假体组织制成的全装配假体瓣膜。在所谓的“无支架（stentless）”生物假体瓣膜中使用一些完整猪瓣膜，在所谓的“无支架（stentless）”生物假体瓣膜中如果任何合成材料被加入用于支持或固定的目的，其存在是非常少的。“支架式(stented)”生物假体瓣膜典型地具有用于小叶的一些合成(例如，聚合物或金属)支持，其可以是完整的猪异种移植小叶或分开的牛心包小叶。本文考虑的心瓣膜包括手术心瓣膜、切顶心瓣膜(transapical heartvalves)、经骨动脉心瓣膜和其它类型的心瓣膜。
现有技术的组织处理方法针对交联、微生物和在“静态”装置中的组织的其它方面，并且典型地包括使组织浸入在戊二醛、吐温(聚氧乙烯20失水山梨糖醇单油酸酯)、乙醇、甲醛和其它物质中，以减轻植入后的钙化。一些现有技术方法包括加入各种化学品，以便通过使用金属离子(即，Al3+或Fe3+，参见美国专利5,746,775，Levy)或整体封闭剂(bulk blocking agents)(即，2-氨基油酸，参见美国专利4,976,733，Giradot)来降低交联组织的毒性或减轻钙化。但是这些方法中每一个仅应用于最初处理的组织，而不应用于脱水组织或者组织装置以防止氧化损伤。现有技术方法局限于加入化学或生物制剂到临时附着于组织的交联组织，或者它们局限于在没有加入任何“加帽剂”的情况下单独地还原或氧化组织(参见美国专利5,862,806，Cheung)。
与各种现有技术组织处理不同——在现有技术中目标是固定(也就是交联等)组织，本发明描述了另外的方法，藉此，由现有技术固定方法形成的酸和其它潜在结合位点被“加帽”。它也包括“加帽”由固定组织氧化生成的结合位点和潜在的结合位点。用戊二醛、吐温(聚氧乙烯20失水山梨糖醇单油酸酯)、乙醇、甲醛和其它物质进行的组织处理可以提供有用的组织固定。然而，其也将产生能够与钙、磷酸酯、免疫原性因子或其它钙化前体相互作用或吸引钙、磷酸酯、免疫原性因子或其它钙化前体的结合位点。例如，在戊二醛固定组织后，有许多带负电荷的羧酸基团形成，并且这些基团能够吸引钙离子(由于它们的负电荷并且与带正电荷离子的静电相互作用)，导致组织钙化或不利的细胞相互作用。已知羧酸基团像在谷氨酸或γ羧基谷氨酸中的那些基团结合钙原子(Hauschka等PNAS1975，72:3925)。钙结合蛋白例如骨涎蛋白含有富羧酸结构域，目的是吸引和结合钙，导致羟基磷灰石形成(钙化)。在这些蛋白质中的酸基团的总体水平和位置决定蛋白质有效结合钙和形成羟基磷灰石的能力。术语组织的“酸化潜力(acidpotential)”是指在固定组织内通过氧化、脱水、水合、或类似的方法可以最终形成酸基团或“结合位点”的这些化学官能团的水平。
本发明人已经发现这种结合导致生物假体材料中的显著的植入后损伤，特别是用于心瓣膜小叶的组织。例如，在贮存和脱水或“干燥”组织处理期间出现的氧化损伤可产生将结合钙和导致组织障碍的羧酸基团。这种渐进的小叶损伤过程可产生为钙化前体和免疫原性相关通路的新结合位点或潜在结合位点。本发明描述在植入组织基生物假体的组织进入体内之前，加帽这些新形成的结合位点的方法。本发明人也发现暴露于空气氧化的生物假体组织当未浸入戊二醛溶液或在灭菌期间时可能包含更多个促进钙化和炎症的酸基团。在干燥贮存时，脱水组织被灭菌并在没有戊二醛溶液的保护作用下被“干燥”贮存。这种新产品的处理和贮存的方便性由于没有戊二醛贮存溶液而被大大地促进。这种技术可以通过用加帽剂处理此类生物假体组织和/或在脱水阶段加入化学保护剂改进。
本发明内的一个化学目标是酸基团的永久“加帽”，这将显著降低它们吸引钙、磷酸酯、免疫原性因子或其它基团的能力。术语“加帽”指封闭、去除或改变将会对生物假体性能具有不良作用的官能团。例如，加入1-乙基-3-[3-二甲氨基丙基]碳二亚胺盐酸盐(EDC)、N-羟基硫代琥珀酰亚胺(硫代-NHS)和乙醇胺将有效地用非反应性醇基团给酸基团加帽。
除了酸结合位点，用戊二醛或其它含醛物质处理的组织也产生具有许多游离醛基团的组织，所述游离醛基团引起毒性增加、钙化更高和参与免疫原性应答。这些醛基团通过空气氧化、体内血液氧化、巨噬细胞氧化和其它类似氧化路径可以容易地氧化成为羧酸基团。因此，本发明另外的目标包括使为潜在结合位点的醛基团永久加帽，其方式是阻止或减轻它们转化为酸或其它基团的能力并且因此进一步减轻身体内(体内)的钙化潜力。除了酸和醛，还有其它可能的结合位点例如免疫原性和抗原因子，使它们加帽被包括在本发明的范围内。
本发明的加帽方法包括组织的化学还原，当在加帽剂存在时应用于组织时，组织的化学还原将永久地将加帽剂与目标基团连接。例如，加入乙醇胺到组织将加帽醛基团，同时还原剂(例如，硼氢化钠)还原由醛与乙醇胺的胺基团反应产生的任何希夫碱。因此，醛基团最终替换为可有利于组织水合、柔韧性和细胞相互作用的羟基。当然，可以使用其它加帽剂替换乙醇胺以及使用硼氢化钠之外的其它还原剂，并且这些是本领域技术人员已知的，而且它们被包括在本专利的范围内。另一优选的策略是氧化组织醛为酸，然后给酸基团加帽。这可以包括加入1-乙基-3-[3-二甲氨基丙基]碳二亚胺盐酸盐(EDC)、N-羟基硫代琥珀酰亚胺(硫代-NHS)和乙醇胺。这种新的“被加帽”基团将减少对钙、磷酸酯、免疫原性因子或其它类似物质的吸引。
在一个具体实施方式中，本发明提供处理生物假体植入组织以减少体内钙化的方法，包括至少部分地交联生物假体植入组织，然后用醛(或酸)加帽溶液处理所交联的组织以减轻钙化，并且使组织在乙醇/甘油溶液中脱水。甘油溶液可以包括抗氧化剂处理和可以包含水溶性蜡。然后使组织干燥并且随后进行最终灭菌（例如，环氧乙烷、γ照射或电子束辐射)。以下步骤描述在假体心瓣膜的制造中该方法的实施。
醛加帽。在瓣膜泄露和流量观察后，瓣膜在20%乙烷中短暂漂洗以去除粘附到组织的任何过量的戊二醛。这被认为通过保证加帽溶液能够粘结到组织上的醛、而不是溶液中的游离戊二醛而增强加帽工艺。瓣膜然后在室温下摇动下暴露于乙醇胺和硼氢化钠的加帽溶液4小时。从加帽溶液中移走瓣膜，然后在室温用在最终的生物负载(bioburden)还原工艺中使用的相同溶液漂洗几分钟，以去除过量的加帽溶液。
甘油处理。在瓣膜已经通过标准的最终生物负载还原步骤处理之后，它们在75wt%甘油和25wt%乙醇的溶液中进行甘油处理。瓣膜在该溶液中室温浸泡1小时。在该时间期间，在心包组织中存在的大部分水分子被甘油替代。瓣膜从溶液中移走并放置在清洁罩中，以使任何过量溶液从瓣膜中蒸发或滴完。
EO灭菌。脱水瓣膜然后准备包装。它们包装在由硬盒（PETG)与Tyvek盖组成的双层无菌阻隔包装中。包装在洁净室中密封并在100%环氧乙烷中灭菌。
钙化缓和剂优选地包含选自以下的加帽剂：
胺，
氨基酸，
氨基磺酸盐，
亲水性多官能聚合物，
疏水性多官能聚合物，
α-二羰基，
酰肼类，
N,N-二琥珀酰亚胺基碳酸酯，
碳二亚胺，
2-氯-1-甲基碘代吡啶(CMPI)，
抗生素，
细胞募集剂，
血液相容剂，
抗炎剂，
抗增殖剂，
免疫原性抑制剂，
还原剂，和
单环氧烷烃、二环氧烷烃或聚环氧烷烃。
化学抗氧化剂期望选自：
水溶性抗氧化剂如抗坏血酸，
脂溶性抗氧化剂如生育酚，
糖类如果糖、蔗糖或甘露糖，
受阻酚如丁化羟基甲苯(BHT)，
受阻胺光稳定剂(HALS)如对苯胺二胺(p-phenylamine diamine)、三甲基二氢喹啉或烷基化联苯胺，
亚磷酸酯/亚膦酸酯如三苯膦，
和硫代酸酯如硫代肉桂酸酯。
期望以一种以下已选溶液或以下已选溶液的组合来递送钙化缓和剂(加帽剂)和/或化学氧化保护剂：
水溶液例如水缓冲溶液、水、短链醇、甘油或增塑剂，
有机溶剂，及
有机缓冲溶液。
组织在加帽过程之前优选地被完全交联。在一种实施方式中，组织包括在适当装置中安装和处理的预切割的心瓣膜小叶。可选地，组织可以为在适当装置中处理的组织大片(bulk sheets)。
以种类和亚类提供的加帽剂的实例是：
胺，
烷基胺、氨基醇、乙醇胺；
氨基酸，
赖氨酸、羟赖氨酸；
氨基磺酸盐，
牛磺酸、氨基硫酸盐、葡聚糖硫酸盐、软骨素硫酸盐；
亲水性多官能聚合物，
聚乙烯醇、聚乙烯亚胺；
疏水性多官能聚合物，
α-二羰基类，
甲基乙二醛、3-脱氧葡糖醛酮、乙二醛；
酰肼类，
己二酸酰肼，
N,N-二琥珀酰亚胺基碳酸酯；
碳二亚胺类，
1-乙基-3-[3-二甲氨基丙基]碳二亚胺盐酸盐(EDC)、N-环己基-N′-(2-吗啉乙基)碳二亚胺(CMC)、1,3-二环己基碳二亚胺(DCC)；
2-氯-1-甲基碘代吡啶(CMPI)；
抗生素；
细胞募集剂；
血液相容剂，
肝素；
抗炎剂；
抗增殖剂；
免疫抑制剂；
还原剂，
氰基硼氢化钠、硼氢化钠、亚硫酸氢钠+乙酰丙酮、甲酸+甲醛；和
单环氧烷烃、二环氧烷烃或聚环氧烷烃。
优选的加帽剂的作用不仅封闭将吸引钙、磷酸酯、免疫原性因子、或其它类似物质的官能团，而且用优良的生物功能性(Biologicalfunctionality)代替那些基团。术语“生物功能性”定义为组织成分对植入材料的局部生物学的作用。改进的组织处理的生物功能性可以包括组织总电荷(overall charge)的减少、更好的血液相容性、增加的组织水合、更好的细胞相互作用、更好的柔韧性等。例如，用乙醇胺加帽于醛官能将阻止醛基团氧化成为酸并且将其替换为可有益于组织水合、柔韧性和细胞相互作用的羟基。被加帽的组织的期望生物功能性将决定使用的加帽化合物的类型。
加帽策略也旨在阻止可促进不良细胞反应的组织成分的生物功能性。这些目标中的一些包括但不限于α-gal、MHC-1相关蛋白质、HLA抗原等。因此，本发明也涉及加帽于或封闭蛋白质、糖类、脂类和可有助于细胞反应的其它组织成分。例如，α-gal糖可以通过用2-氯-1-甲基碘代吡啶(CMPI)和本领域技术人员所知的中和羟基的其它物质处理进行封闭。另外一个例子包括可以通过用1-乙基-3-[3-二甲氨基丙基]碳二亚胺盐酸盐(EDC)和乙醇胺处理而被加帽或有效中和的MHC-1相关蛋白质。本发明加帽方法中也包括以与细胞和血管残留物(remnants)相关的蛋白质、糖类或脂类作为目标。例如，纤连蛋白可以通过加入甲基乙二醛到组织而被加帽或封闭。已知这种二羰基结合蛋白质内关键的精氨酸官能并且损害这些蛋白质的生物功能性。
本发明的另一方面包括在灭菌后加帽技术的激活。例如，在γ照射灭菌之前，用特定的加帽剂(例如葡萄糖和乙醇胺或牛磺酸)处理组织，在照射后将产生加帽剂的活化。加入到组织的加帽剂将立刻有效地加帽于组织内的目标，但是灭菌(也就是，环氧乙烷、电子束辐射或γ照射)将产生新的结合位点，其随后将被组织内残留的加帽剂加帽。已知胶原的γ照射裂解骨架内的肽键并产生可能对组织有不良作用的新官能团。这些新官能团包括在本文所述的目标或结合位点，并可以通过本文列举的加帽剂加帽或封闭。
免疫原性因子定义为引起或参与刺激免疫原性应答的任何物质。这包括能够诱导免疫型应答的任何化学或生物制剂。例如，组织中留下的血管和细胞膜成分可以引起来自于体内的天然免疫系统的一些类型的免疫原性或抗原应答。本发明包括能够静态或动态地掩蔽、代替、或封闭组织中这些免疫原性元件的加帽剂。例如，完整的瓣膜被固定，随后用非免疫原性或更加血相容的加帽剂例如肝素进行加帽，然后脱水和灭菌。这不同于将肝素添加到固定的组织而没有任何的瓣膜脱水或没有考虑处理后氧化条件的现有技术方法。本发明方法可以用去细胞化（decellularization）方法来补充，以减少免疫或抗原结合位点和潜在的结合位点，并且其也在本发明的范围内。
为了更好地理解为本发明处理技术基础的原理，基于实际试验，提供多个图表(参见附图)。如上提到的，本发明一般包括处理组织，使得钙或磷酸酯结合位点、或可能引发钙化的其它这类位点被封闭。酸结合位点和组织钙化之间的相关性可以被看见(图2，也参见Hauschka等PNAS197572:3925)，并且显示的是酸模板化(acid templating)指引多种种类的矿化。因此，在植入时组织中的游离酸和/或醛的量与这些结合位点的数目相关，并且因此增加了钙化的可能性。组织中存在的游离酸和醛的量可以通过已知的方法测量，例如，标准的分光光度检测。
图1为显示牛心包组织中的游离醛和游离酸含量——通过前述技术测量——的图。应该理解的是，所有在本文提到的实验包括戊二醛固定的牛心包组织。研究的组织都被化学处理，一种只用戊二醛，而其它两种利用已经被Edwards Lifesciences用来制备商业植入用生物假体组织的组织处理。然而，其它交联和组织处理方法可以被使用并且在本发明的范围内。
化学处理后，测量组织的醛和酸含量，并且没有给与组织任何损伤或应力。在图1的图右侧，组织样品只在戊二醛中处理，具体地在0.625%戊二醛溶液中处理14天的时间。总计10个样品被处理并随后被测试。测量显示每毫克干重组织有大约40纳摩尔醛和大约17纳摩尔酸的平均水平。
图1的图中间显示来自于经受处理A的总计10个组织样品测试的结果，处理A商业上被称为XenoLogiXTM组织处理方法，来自于加利福尼亚州Irvine的Edwards Lifesciences。处理A包括首先用戊二醛固定，随后用包括交联剂例如甲醛、表面活性剂例如吐温-80(聚氧乙烯失水山梨糖醇单油酸酯)和变性剂例如乙醇在内的杀菌剂处理两次。经受处理A的组织的醛和酸的含量都小于单独用戊二醛处理的组织的醛和酸的含量，其中醛含量减少了大约25%而酸含量减少大约50%。这种减少归因于酸结合位点的来源的磷脂的进一步还原以及来自醇和醛基团的半缩醛的形成。
图1的左边显示来自于经受处理B的总计10个样品测试的结果，处理B商业上被称为Carpentier-Edwards ThermaFixTM组织处理方法，来自于Edwards Lifesciences。处理B与处理A基本相同，外加在固定后和灭菌前的热处理步骤。受到处理B的组织的醛和酸的含量都小于单独用戊二醛处理的组织的醛和酸的含量，其中醛含量减少了大约33%而酸含量减少大于50%。另外，相对于处理A，处理B减少了10-20%之间的醛和酸含量。
图2为对图1中显示的三种组织处理重复醛/酸含量测量结果的图，并且从单独研究，也添加了来自于皮下植入兔中的相似组织样品的钙摄入的测量。在植入之前，测量组织中的这些酸水平，并且其在体内可能增加。图2显示在植入组织中发现的钙量与来自于三种组织处理的醛/酸的水平相关。即，随着在各种组织样品中游离醛和游离酸的水平降低，植入后吸收的钙量也减少。再次，应当理解的是许多因素有助于钙摄入，但是某些钙和磷酸酯结合位点的可用性以及其它因素是将来钙化的主要指标。图2的图因此表明降低组织中醛/酸的水平将减少组织钙化的倾向。
如以上提到的，现在应当理解的是，组织中醛基团氧化成羧酸基团产生钙化的增加。这种现象的证据在图3的图中提供。具体地，如以上所解释，组织中的酸水平与植入后的钙化倾向直接相关。图3表明在各种组织样品中的酸水平。组织处理的类型是新鲜的未处理的组织、戊二醛-固定的组织、XenoLogiX(XLX)、ThermaFix(TFX)、只用甘油和乙醇处理的ThermaFix组织，以及GLX方法，其包括用戊二醛处理、用乙醇胺加帽同时用硼氢化钠还原、和用甘油和乙醇脱水。
图4和5是兔肌内植入研究的结果，显示GLX方法(在本发明中描述)相对于现有技术(TFX)和相对于简单的甘油处理(GLY-处理的)显著地减少钙化。这些数据也显示GLX方法减少钙化中的变异性。所有的钙化测量通过原子吸收光谱测量并归一化为冻干组织的干重量。
图6和7图解在80天的实时贮存期后，GLX处理的组织相比TFX或单独甘油处理的组织显示显著更少的钙化。GLX方法也降低了80天贮存期后的变异性。所有的钙化测量通过原子吸收光谱测量并归一化为冻干组织的干重量。
基于前述实验结果，本发明人认为施加于生物假体组织的脱水组织的氧化损伤极大促进组织钙化的倾向。具体地，不在戊二醛中贮存的心瓣膜小叶受到显著的氧化损伤。这种有害的组织损伤过程可以产生先前没有检测或识别到的新的结合位点，作为钙和磷离子的潜在附着位点，由此引起钙化。
为了帮助预防这种植入后损伤-钙化过程，本发明涉及通过加帽易于氧化的和增加钙化引发的许多醛来减轻氧化。
优选的实施方式包括但不限于：
1.在包含醛加帽剂的溶液中处理固定的组织瓣膜或组织片。
2.实施方式1，但是其中在加帽过程期间或之后，加入灭菌步骤。
3.实施方式1和2，但是其中处理被摇动。
4.实施方式1、2和3，但是其中加帽剂用于其它结合位点如酸或生物免疫相关的位点。
5.醛加帽溶液可以包含在pH7.4的50mM磷酸盐缓冲液中的胺(10mM乙醇胺)和还原剂(132mM硼氢化钠)。
6.组织或瓣膜然后在甘油溶液中脱水。
7.组织或瓣膜然后用环氧乙烷灭菌。
实施例1-使用乙醇胺和硼氢化钠的戊二醛固定组织的醛加帽。刚好在热处理步骤之后，生物假体组织从0.625%戊二醛中移走，然后在乙醇:盐水（20%/80%)中漂洗2分钟。制备1升包含在50mM磷酸盐缓冲液(pH7.3-7.8)中的10mM乙醇胺(0.06%)和110mM硼氢化钠(0.42%)的加帽溶液。
加帽溶液放置在定轨摇床上，然后组织(小叶或瓣膜)放置在该溶液中，使得它们被完全浸没。组织与溶液的比例是每100ml中3个小叶或每100ml中一个瓣膜。容器被部分地覆盖，但是不完全密封，因为与水化学反应释放的氢气可能使容器爆炸。定轨摇床以80-100rpm在室温运行4小时。然后取出组织并在FET溶液(甲醛、乙醇、吐温-80)中漂洗3分钟。
实施例2-心包瓣膜生物假体组织的甘油脱水过程。心包瓣膜通过用镊子将每个瓣膜保持在瓣膜的缝合环上并将瓣膜放置在甘油/乙醇(75%/25%)混合物中来脱水。含瓣膜的烧杯放置在50-60RPM之间运转的定轨摇床上至少一(1)小时，但是不超过四(4)小时，然后立即处理以去除过量甘油。这通过用镊子将它们保持在瓣膜的缝合环上、从甘油/乙醇混合物中取出瓣膜并且随后将其放置在广口瓶中的吸收毛巾(absorbent towel)上进行。在使其室温干燥至少5分钟后，将广口瓶连接到冻干机和干燥2个小时。瓣膜然后转移至环氧乙烷气体能渗透的包装中并用环氧乙烷灭菌。
实施例3-钙化减轻-小动物模型。为了评估GLX处理和EO灭菌的心包组织的钙化减轻性能，进行两种小动物可行性研究。这些研究表明，1)在减轻组织中钙化发生方面，GLX优于TFX，和2)在减轻钙化方面，实时老化的GLX也优于TFX。在两个研究中，当与TFX瓣膜比较时，GLX瓣膜表明钙化数据中减小的变异性。试验方法和每个结果在下面总结。
实施例3A-兔研究#1。在35天大鼠肌内研究中环氧乙烷灭菌对GLX处理的心包组织的钙化潜力。进行使用六十(60)只兔的研究，以观察对使用100%环氧乙烷灭菌的GLX处理的心包钙化的影响。对照组是ThermaFix(TFX)处理的牛心包，而试验组是GLX处理的心包。使用符号轶和检验(sign-rank test)，发现GLX组织当与TFX比较时，有显著差别(p=0.0004)，并且表明相对于TFX有93%的钙化减少。GLX数据也显示减少的异常值和降低的变异性。对于GLX过程，箱线图显示可观的变异性减小。图7提供数据，其中y-轴测量微克钙/毫克干重量组织。
实施例3B-兔研究#2。在35天大鼠肌内研究中短期贮存期对GLX处理的心包组织的钙化的影响。进行使用另外六十(60)只兔的第二项研究，以观察短期贮存期对GLX处理的心包的钙化的影响。对照组是ThermaFix(TFX)处理的牛心包，而试验组是GLX处理的心包。GLX组织样品被包装在Tyvek袋中，并经100%环氧乙烷灭菌。在25℃和60%湿度下，GLX样品被贮存在受控稳态室中83天的期间。TFX样品没有被老化。在该研究中，GLX处理的组织表现显著降低的钙化水平，与TFX相比73%(p=0.009)，以及减小的异常值和减少的数据变异性。在图8中提供数据，其中y-轴测量微克钙/毫克干重量组织。
虽然发明已经以其优选方式描述，但是应该理解的是已经使用的语言是描述性的言语而不是限制性的。因此，在所附权利要求内可以进行改变，而不偏离本发明的真正范围。

Claims (30)

1.在生物假体组织中减轻钙化的方法，所述方法包括：
至少部分交联所述生物假体组织；
用加帽剂处理所述生物假体组织，其中所述加帽剂同与所述生物假体组织相关的官能团反应；并且
用还原剂处理所述生物假体组织，其中所述还原剂还原所述加帽剂同与所述生物假体组织相关的官能团的反应产生的任何希夫碱。
2.权利要求1所述的方法，其中所述生物假体组织选自牛心包、猪组织、血管、皮肤、硬脑膜、心包、小肠粘膜下层、组织心瓣膜、韧带和腱。
3.权利要求1所述的方法，其中所述至少部分交联所述生物假体组织用戊二醛或其他含醛试剂进行。
4.权利要求1所述的方法，其中所述处理步骤在所述至少部分交联步骤之后进行，并且其中所述官能团与所述至少部分交联生物假体组织相关。
5.权利要求1所述的方法，其中所述官能团与所述生物假体组织的体内毒性、钙化和免疫原性相关。
6.权利要求5所述的方法，其中所述官能团为醛基团和羧酸基团的一个或者二者。
7.权利要求1所述的方法，其中所述加帽剂是选自以下的一个或者多个：胺、烷基胺、氨基醇、乙醇胺、氨基酸、赖氨酸、羟赖氨酸、氨基磺酸盐、牛磺酸、氨基硫酸盐、葡聚糖硫酸盐、软骨素硫酸盐、亲水性多官能聚合物、聚乙烯醇、聚乙烯亚胺、疏水性多官能聚合物、α-二羰基类、甲基乙二醛、3-脱氧葡糖醛酮、乙二醛、酰肼类、己二酸酰肼、肝素、单环氧烷烃、二环氧烷烃和聚环氧烷烃。
8.权利要求1所述的方法，其中所述还原剂选自硼氢化钠、氰基硼氢化钠、乙酰丙酮中的亚硫酸氢钠和甲醛中的甲酸。
9.权利要求1所述的方法，进一步包括使所述至少部分交联的组织脱水或者用甘油溶液处理所述至少部分交联的生物假体组织中的一种。
10.权利要求9所述的方法，进一步包括在脱水或者用甘油溶液处理之后包装所述至少部分交联的生物假体组织。
11.权利要求10所述的方法，进一步包括对所包装的、至少部分交联的生物假体组织进行灭菌。
12.权利要求11所述的方法，其中所述灭菌通过环氧乙烷、γ照射或电子束辐射进行。
13.生物假体心瓣膜，其包括权利要求1-12中的任一项所述的方法处理的生物假体植入组织。
14.在生物组织中减轻钙化的方法，所述方法包括：
用戊二醛或其他含醛试剂至少部分交联所述生物假体组织；和
将所述交联的生物假体组织暴露于加帽剂，所述加帽剂为选自以下的一种或其组合：乙醇胺、羟赖氨酸、牛磺酸、葡聚糖硫酸盐、软骨素硫酸盐、亲水性多官能聚合物、聚乙烯醇、聚乙烯亚胺、疏水性多官能聚合物、α-二羰基类、甲基乙二醛、3-脱氧葡糖醛酮、乙二醛、酰肼类、己二酸酰肼、肝素、单环氧烷烃、二环氧烷烃和聚环氧烷烃。
15.权利要求14所述的方法，其中所述生物假体组织选自牛心包、猪组织、血管、皮肤、硬脑膜、心包、小肠粘膜下层、组织心瓣膜、韧带和腱。
16.权利要求14所述的方法，其中所述暴露步骤在所述至少部分交联步骤之后进行，并且其中所述官能团与所述至少部分交联的生物假体组织相关。
17.权利要求14所述的方法，其中所述加帽剂是乙醇胺。
18.权利要求14所述的方法，其中所述加帽剂是牛磺酸。
19.权利要求14所述的方法，其中所述加帽剂以水溶液、有机溶剂和有机缓冲溶液中的一种或其组合提供。
20.权利要求19所述的方法，其中所述水溶液选自：缓冲溶液、水、短链醇、甘油和增塑剂。
21.权利要求14所述的方法，进一步包括与将所述生物假体组织暴露于所述加帽剂的步骤同时或者在该步骤之后将所述生物假体组织暴露于还原剂。
22.权利要求21所述的方法，其中所述还原剂选自硼氢化钠、氰基硼氢化钠、乙酰丙酮中的亚硫酸氢钠和甲醛中的甲酸。
23.权利要求14所述的方法，进一步包括使所述至少部分交联的生物假体组织脱水或者用甘油溶液处理所述至少部分交联的生物假体组织中的一种。
24.权利要求23所述的方法，进一步包括在脱水或者用甘油溶液处理之后包装所述至少部分交联的生物假体组织。
25.权利要求24所述的方法，进一步包括对所包装的、至少部分交联的生物假体组织进行灭菌。
26.权利要求25所述的方法，其中所述灭菌通过环氧乙烷、γ照射或电子束辐射进行。
27.生物假体心瓣膜，其包括权利要求14-26中的任一项所述的方法处理的所述生物假体植入组织。
28.在生物假体组织中减轻钙化的方法，所述方法包括：
至少部分交联所述生物假体组织；和
用加帽剂溶液处理所述生物假体组织以便同与所述生物假体组织相关的羧酸官能团反应，所述加帽剂溶液包括胺连同N,N-二琥珀酰亚胺基碳酸酯、碳二亚胺、1-乙基-3-[3-二甲氨基丙基]碳二亚胺、N-环己基-N′-(2-吗啉乙基)碳二亚胺、1,3-二环己基碳二亚胺、2-氯-1-甲基碘代吡啶和N-羟基硫代琥珀酰亚胺中的一个或者多个。
29.权利要求28所述的方法，其中所述加帽剂溶液包括乙醇胺、1-乙基-3-[3-二甲氨基丙基]碳二亚胺盐酸盐和N-羟基硫代琥珀酰亚胺。
30.生物假体心瓣膜，其包括根据权利要求28或者29所述的方法处理的所述生物假体植入组织。
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