CN101541354B - 含聚磷氮烯的生物人工心瓣膜 - Google Patents
含聚磷氮烯的生物人工心瓣膜 Download PDFInfo
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- CN101541354B CN101541354B CN2007800432709A CN200780043270A CN101541354B CN 101541354 B CN101541354 B CN 101541354B CN 2007800432709 A CN2007800432709 A CN 2007800432709A CN 200780043270 A CN200780043270 A CN 200780043270A CN 101541354 B CN101541354 B CN 101541354B
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- heart valve
- phosphorus nitrence
- phosphorus
- nitrence
- gathers
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Abstract
本公开涵盖具有聚磷氮烯聚合物例如聚[二(三氟乙氧基)磷氮烯]的生物人工心瓣膜，其显示改善的抗血栓形成、生物相容性和血相容性特性。还描述了具有聚磷氮烯聚合物的生物人工心瓣膜的生产方法。
Description
对相关申请的交叉引用
本申请要求2006年10月10日提交的U.S.临时专利申请No.60/828,840的权益，将其全部通过引用并入本文。
发明领域
本发明涉及生物人工植入物例如具有抗血栓形成、生物相容性和血相容性特性的生物人工心瓣膜。
发明背景
通过两侧压力差异引起开启和关闭从而保持血液的单向流动，心瓣膜在循环功能中发挥关键作用。然而，天然心瓣膜可能因为各种病理原因例如狭窄和关闭不全变得机能不良。狭窄的心瓣膜由于瓣组织僵硬而不能完全打开，从而心脏需要做更多的功来迫使血液通过瓣膜。关闭不全的瓣膜通过使血液返流回来源室引起无效的血液循环。
在许多患者中，可用人工心瓣膜代替病态心瓣膜。人工瓣膜可宽泛地分成两种主要类型：机械的和生物人工的。机械瓣膜完全由合成材料构成并且耐久性优异。传统机械心瓣膜可以带来良好的流动工作特性并且可能比生物人工瓣膜更耐久，但机械瓣膜也有许多缺点。机械心瓣膜需要长期或者甚至终生的抗凝血疗法从而降低血栓形成和栓塞的风险。这种方案实际上使得使用机械心瓣膜的患者几近成为血友病患者。使用机械心瓣膜的患者还需要严格的饮食和/或活动限制，并且机械心瓣膜还可以发出讨厌的瓣膜“咔嗒”声。
生物人工或生物学瓣包括任何含生物组织的瓣膜，并且它们可以宽泛地分成两种主要类型：“移植型”，其中基本上整个瓣膜都是从另外的个体移植而来；和“组织型”，其全部或部分用天然组织部分例如瓣叶来构成。对移植型，实际的心瓣膜取自死亡人体(自体移植或同种异体移植)或者宰杀的猪或其它动物(异种移植)。可将取得的瓣膜保存和/或灭菌，例如，同种移植物通常冷藏保存而异种移植物通常交联在一般的戊二醛溶液中。
组织型生物人工心瓣膜包含具有各种并入量的生物材料的组件。生物学组织通常取自牛的(牛)、马的(马)、猪的(猪)或其它哺乳动物来源的心瓣膜或心包膜。例如，这些瓣膜中的一些包括源自天然材料(通常为猪)的小叶并且还包括天然支撑结构或主动脉壁的环。在其他瓣膜中，修剪源自天然材料(一般为牛心包)的小叶并将其粘附至合成的、近环形的结构或者模拟天然主动脉壁功能的环。在其他瓣膜中，小叶和环形支撑环都由生物聚合物例如胶原和/或弹性蛋白形成。包括某些生物组织或生物聚合物的全部这些瓣膜在本文中都称作生物人工瓣膜，还包括称作“支架的”瓣膜的这种组件，其包括支架和生物瓣膜部分。
生物人工心瓣膜通常不如机械瓣膜耐久，但它们能够降低与机械瓣膜有关的某些风险，比如降低血块形成、可能的血栓形成和栓塞的风险和/或减少对长期抗凝血疗法的需要。因此，对组织型瓣膜来说与需要抗凝血剂有关的问题通常是短期的并且它们很少突然失效。此外，生物人工心瓣膜设计上更接近天然瓣膜，具有更佳的血液动力学并且不引起对血细胞的损伤。然而，生物学心瓣膜并非不具风险。由于戊二醛固定术、机械应力和磷酸钙在表面的沉积，生物学心瓣膜对变性和/或钙化敏感。由于生物学心瓣膜的变性，这种瓣膜通常工作约10到15年，常常需要额外的手术来替换或修理瓣膜。
所以，需要改善生物或生物人工心瓣膜从而具有良好抗血栓形成、生物相容性和血相容性特性。这种生物人工心瓣膜应该对变性和/或钙化更不敏感，并显著地改善所述植入物的总寿命。发明概要
本发明提供包含生物组织和式(I)所示的聚磷氮烯的生物人工心瓣膜：
n是2到∞；并且R1到R6各自独立地选自烷基，氨基烷基，卤代烷基，硫代烷基，硫代芳基，烷氧基，卤代烷氧基，芳氧基，卤代芳氧基，烷基硫醇酸根(alkylthiolate)，芳基硫醇酸根(arylthiolate)，烷基磺酰基，烷基氨基，二烷基氨基，包含选自氮、氧、硫、磷或其组合的一个或多个杂原子的杂环烷基，或者包含选自氮、氧、硫、磷或其组合的一个或多个杂原子的杂芳基。
本发明还提供生产人工生物心瓣膜的方法，包含提供生物组织并将该生物组织与如本文所示的式(I)聚磷氮烯接触。例如，可通过简单地将生物人工心瓣膜的表面与聚磷氮烯接触，将式(I)聚磷氮烯应用至生物人工心瓣膜的表面，其中所述聚磷氮烯可以是任何形式并且通常在溶液中，含或不含其它组分例如表面活性剂或固定剂。
本发明还提供生物人工心瓣膜的生产方法，包含：组合聚[二(三氟乙氧基)磷氮烯]聚合物、固定剂、表面活性剂和可溶解聚[二(三氟乙氧基)磷氮烯]的有机溶剂从而形成溶液；并且将该溶液应用(接触)至生物人工移植物。该聚磷氮烯的三氟乙氧基部分是2，2，2-三氟乙氧基，即OCH2CF3。
本发明还提供处理生物人工心瓣膜的方法，包含将瓣膜中的组织与前文公开的式(I)代表的聚磷氮烯接触。本发明还提供生物人工移植物，包含：生物组织；和应用至所述生物组织的聚磷氮烯例如聚[二(三氟乙氧基)-磷氮烯]聚合物。
本发明还提供包含生物组织和前文公开的式(I)聚磷氮烯的生物人工移植物，其中通过涂覆组织和浸入组织中的至少一种将所述聚磷氮烯掺入植入物。
本发明进一步提供改善生物人工心瓣膜的抗血栓形成、生物相容性、或血相容性特性的方法，包含将所述生物人工心瓣膜与本文提供的式(I)聚磷氮烯接触，其中将所述聚磷氮烯涂覆、扩散、浸渍、接枝或其任意组合至所述生物人工心瓣膜之内或之上。
在另一方面，本发明提供包含哺乳动物心瓣膜和聚[二(三氟乙氧基)磷氮烯]的生物人工心瓣膜。本发明还提供生物人工心瓣膜的制造方法，包含：提供哺乳动物心瓣膜；和将所述哺乳动物心瓣膜与聚[二(三氟乙氧基)-磷氮烯]接触；其中将所述聚[二(三氟乙氧基)磷氮烯]涂覆、扩散、浸渍、接枝或其任意组合至所述哺乳动物心瓣膜之内或之上。
附图说明
图1是猪的移植型(异种移植)心瓣膜的透视图，可如本文公开来处理。
图2是人的移植型(同种移植)心瓣膜的透视图，可如本文公开来处理。
图3举例说明示例性的组织型心瓣膜，表示为打开(A)和闭合(B)形式，可如本文公开来处理。
图4举例说明组织型心瓣膜的另一个实例，表示为打开(A)和闭合(B)形式，可如本文公开来处理。
图5举例说明组织型心瓣膜的又一个实例，可如本文公开来处理，其中所述组织小叶粘附于适于移植的合成环形部分。
发明详述
本发明涉及生物人工心瓣膜移植物，其包括包含磷氮烯基聚合物即聚磷氮烯的生物人工心瓣膜。此外，本发明提供生产包含聚磷氮烯的生物人工心瓣膜的方法。用于本文中，涉及心瓣膜时，措辞“处理”看作比术语如“涂覆”更宽泛。经处理的心瓣膜是以任意方式与聚磷氮烯接触的心瓣膜，无论聚磷氮烯与心瓣膜在接触时以何种具体机理相互作用，只要某些聚磷氮烯保持在所述经处理的心瓣膜之内或之上。例如，在经处理的心瓣膜中，除了如“涂覆”中仅在表面上聚集或成层，所述聚磷氮烯还可以扩散入或者被浸渍入或接枝至生物组织，尽管不要求任何特定的相互作用模式或机理。所以，如本文所用，“处理”包括涂覆、扩散、浸渍、接枝等，及其任意组合，还有聚磷氮烯与生物组织相互作用的任意其它方式。
发现当用来涂覆各种非生物材料时，特定的磷氮烯基聚合物聚[二(三氟乙氧基)磷氮烯]具有良好的生物相容性和抗血栓形成特性。参见德国专利No.DE 196 13 048。还参见，例如，美国专利申请公开Nos.2003/0157142 A1和2005/0136093 A1，将其全部通过引用并入本文。本公开涉及磷氮烯基聚合物特别是聚[二(三氟乙氧基)磷氮烯]的用途，用来处理用于生物人工心瓣膜的生物材料。
本发明的生物人工心瓣膜包括并入生物组织的任何瓣膜，包括所述“移植型”，其中基本上全部瓣膜都移植自另一个体；和所述“组织型”，其用天然组织部分例如瓣膜小叶构成。例如，在这方面，生物人工心瓣膜可以由哺乳动物心瓣膜、哺乳动物心包、哺乳动物血管移植物、其它哺乳动物器官等构成。例如，哺乳动物器官包括人的、牛的或猪的心脏。所以，所述生物人工心瓣膜通常包含生物心瓣膜或者改装为心瓣膜的生物组织。
在本发明的某些优选实施方式中，将式(I)代表的优选聚磷氮烯用来处理生物人工心瓣膜，而在某些方面用来涂覆生物人工心瓣膜。
n是2到∞；并且R1到R6是各自独立的变量并且各自独立地选自烷基，氨基烷基，卤代烷基，硫代烷基，硫代芳基，烷氧基，卤代烷氧基，芳氧基，卤代芳氧基，烷基硫醇酸根，芳基硫醇酸根，烷基磺酰基，烷基氨基，二烷基氨基，包含选自氮、氧、硫、磷或其组合的一个或多个杂原子的杂环烷基，或者包含选自氮、氧、硫、磷或其组合的一个或多个杂原子的杂芳基，或者适于计划用途的其它类似基团。指出式(I)中的n可以高达∞意在确定n值，从而包含可以具有至多约75百万道尔顿的平均分子量的聚磷氮烯聚合物。例如，在一方面，n可以是至少约100到约100,000。在另一方面，指出式(I)中的n可以是∞意在确定n值是约4,000到约50,000，更优选地n是约7,000到约40,000，最优先地n是约13,000到约30,000。
在另一方面，指出式(I)中的n可以高达∞意在确定n值，从而包含其中分子量是至少约70,000g/mol的聚磷氮烯聚合物。在另一方面，可以选择n以使平均分子量为至少约1,000,000g/mol。进一步地，可以选择n以使平均分子量为至少约1,000,000g/mol。在还另一方面，平均分子量的有用范围是约7×106g/mol到约25×106g/mol。
悬垂侧基R1到R6是各自独立的变量从而可以是相同或不同的。进一步地，R1到R6可以是经取代的或未经取代的。在一方面，例如，基团R1到R6中至少一个可以是未经取代的烷氧基例如乙氧基(OCH2CH3)或正丙氧基(OCH2CH2CH3)。在另一方面，例如，取代基或基团R1到R6中至少一个是被至少一个氟原子取代的烷氧基部分。此外，当R1到R6是烷氧基时，可以用氟原子完全取代氢原子，从而所述烷氧基是全氟化的。有用的氟取代烷氧基基团R1到R6的实例包括，但不限于OCF3、OCH2CF3、OCH2CF2CF3、OCH(CF3)2、OCCH3(CF3)2、OCH2CF2CF2CF3、OCH2(CF2)3CF3、OCH2(CF2)4CF3、OCH2(CF2)5CF3、OCH2(CF2)6CF3、OCH2(CF2)7CF3、OCH2CF2CHF2、OCH2CF2CF2CHF2、OCH2(CF2)3CHF2、OCH2(CF2)4CHF2、OCH2(CF2)5CHF2、OCH2(CF2)6CHF2、OCH2(CF2)7CHF2等。基团R1和R6还可以是卤代烷氧基，其可以包括经氟-、氯-、溴-和/或碘代-取代的烷氧基。
在另一方面，式(I)的R1到R6可以独立地选自烷基，或者包含烷基的其它取代基例如烷氧基、烷基磺酰基、氨基烷基、卤代烷基、烷硫基等。在这方面，任何烷基可以是，例如，具有1到约20个碳原子的直链或支链烷基，所述烷基还可以是被进一步取代的，例如被至少一个卤素原子例如氟原子或者其它官能基团例如上述对R1到R6基团说明的那些取代。指明烷基基团诸如丙基或丁基时，意在包含所述具体烷基基团的任意异构体。
烷氧基的实例包括，但不限于，甲氧基、乙氧基、丙氧基和丁氧基，其也可进一步被至少一个氟原子取代，优选2，2，2-三氟乙氧基。
烷基磺酰基的实例包括，但不限于，甲基磺酰基、乙基磺酰基、丙基磺酰基和丁基磺酰基。
二烷基氨基的实例包括，但不限于，二甲基-、二乙基-、二丙基-和二丁基氨基。
示例性芳氧基基团包括，例如，具有一个或多个芳族环系的化合物，所述化合物具有至少一个氧原子、非氧原子和/或具有烷氧基取代基的环，芳基基团可以是经取代的，例如被至少一个前文定义的烷基或烷氧基所取代。芳氧基基团的实例包括，但不限于，苯氧基和萘氧基及其衍生物，包括例如经取代的苯氧基和萘氧基。
所述杂环烷基基团可以是，例如，包含3到10个原子的环系，其中至少一个环原子是氮、氧、硫、磷或这些杂原子的任意组合。所述杂环烷基基团可以是经取代的，例如，被如前文所定义的至少一个烷基或烷氧基取代基所取代。杂环烷基基团的实例包括，但不限于，哌啶基、哌嗪基、吡咯烷基和吗啉基及其经取代的类似物。
所述杂芳基基团可以是，例如具有一个或多个芳族环系的化合物，其中至少一个环原子是氮、氧、硫、磷或这些杂原子的任意组合。所述杂芳基基团可以是经取代的，例如被前文定义的至少一个烷基或烷氧基取代基所取代。杂芳基基团的实例包括，但不限于，咪唑基、噻吩、呋喃、噁唑基、吡咯基、吡啶基、吡啶醇基(pyridinolyl)、异喹啉基和喹啉基及其衍生物。
在本发明另一方面，将所述生物人工心瓣膜用聚[二(三氟乙氧基)磷氮烯]来处理和可选地涂覆。
在本发明的又一方面，生物人工移植物包括生物组织和应用至所述生物组织的聚磷氮烯例如聚[二(三氟乙氧基)磷氮烯]聚合物。所述生物组织可以包括心瓣膜、心包、血管移植物、旁通管或身体器官，特别是哺乳动物心瓣膜、哺乳动物心包、哺乳动物血管移植物或哺乳动物器官。实例包括人的、牛的或猪的心瓣膜；人的、牛的或猪的心包；人的、牛的或猪的血管移植物；或者人的、牛的或猪的器官。
用聚磷氮烯以任何方式处理本发明的生物人工心瓣膜，所述方式使得所述聚磷氮烯与所述生物材料接触并以某种方式相互作用从而将某些聚磷氮烯保持在经处理的心瓣膜之内或之上。在一方面，所述生物材料的处理方法通常包括如下步骤：组合聚磷氮烯聚合物、固定剂、表面活性剂和所述聚磷氮烯聚合物在其中至少部分溶解从而形成溶液的溶剂，将所述溶液应用至所述生物人工移植物。许多有机溶剂，包括极性有机溶剂适于所述聚磷氮烯溶液的制备。在一方面，显示在水中的一定溶解度或与水的混合度的溶剂是适宜的，例如，丙酮、四氢呋喃等。对于喷雾应用，挥发醚溶剂例如二甲基醚是适宜的。
例如，适宜的溶剂包括，但不限于，乙酸乙酯、乙酸丙酯、乙酸丁酯、乙酸戊酯、乙酸己酯、乙酸庚酯、乙酸辛酯、丙酮、甲基乙基酮、甲基丙基酮、甲基异丁基酮、四氢呋喃、环己酮、二甘醇二甲醚、叔丁基甲基醚、二甲基醚、六氟苯、四甲基脲、四甲基胍、二甲基乙酰胺等，及其任意组合。另外，可以使用这些溶剂的混合物，或可以加入其它溶剂或非溶剂例如乙烷、丙烷、丁烷、戊烷、己烷、庚烷、甲苯、苯、二甲苯、均三甲苯、二乙基醚、水等来补充任一溶剂。在又一个方面，在特定的温度和压力参数下形成适宜溶剂例如二氧化碳或二甲基醚中的聚磷氮烯超临界溶液，并用来处理目标基底。另外，可以向所述聚磷氮烯溶液中加入其它成分，其实例包括，但不限于，调节溶解度的共溶剂、表面活性剂、分散剂、乳化剂、填充剂、稳定剂、染料、色素、湿润剂、均化剂、分层剂、粘合剂等，及其任意组合。用来与生物人工移植物中的生物组织接触的聚磷氮烯溶液通常包含至少一种通式(I)化合物，在溶剂中的浓度是约0.1％到约99％。
可通过任意方法或以任意方式将聚磷氮烯应用至所述生物人工移植物。如本文所用，术语“应用”是指以任何方式“接触”，并且使用时并不涉及任何通过其聚合物可与它所应用至的心瓣膜相互作用的具体机理或反应。因此，可以通过本文说明的任何处理和/或涂覆来应用所述聚磷氮烯。本发明的优选聚磷氮烯聚合物是聚[二(三氟乙氧基)磷氮烯]。用所述聚磷氮烯来处理生物组织的时间和温度在本发明中不是关键，但可以进行调节从而适应所需应用的具体需要。
例如，聚磷氮烯和生物材料间的接触时间可以是约1秒到数天。在这方面，例如，接触时间可以是约20秒到约3天，从约1分钟到约1天，从约3分钟到约6小时，或者从约5分钟到约3小时。处理步骤的温度也不是关键，只要该温度适合所述生物组织。例如，生物人工移植物可以通过浸入聚磷氮烯溶液中来接触，随即取出，然后空气干燥从而蒸发溶剂。在此情况下，与溶液的接触时间主要取决于溶剂的挥发性。在另一方面，所述生物人工移植物可以通过浸入聚磷氮烯溶液中来接触，并在所述溶液中保持一段时间，随后取出并干燥。在此情况下，与溶液的接触时间取决于所述移植物在所述溶液中保持的时间以及溶剂的挥发性。因此，可以通过任何方法将所述聚磷氮烯应用至所述生物人工移植物。
通常，选择对所选具体接触时间足够高的温度，从而所述聚磷氮烯可以充分与所述生物材料相互作用从而保持在所述经处理的心脏之内或之上，但是不能高到不利地影响所述生物材料。例如，在此方面，接触温度可以是约4℃到约50℃、约10℃到约40℃或约15℃到约37℃。通常所述接触时间取决于溶剂的蒸发速率。在一方面，优选接触温度是大致室温，即约18℃到约24℃。在另一方面，约3到约5分钟的接触时间和大致室温的温度也很合适。如果应冷却移植物，可使用低至约3℃到约4℃的接触温度。在这方面，约4℃到约37℃的接触温度是适宜的。
固定剂的实例可以包括各种功能有机溶剂，其实例包括，但不限于，醛、胺、多胺、氨基硅烷等。醛的实例包括，但不限于，甲醛、戊二醛、乙醛、丙醛、2-甲基丙醛、丁醛、异丁醛、2-甲基丁醛、2-乙基丁醛、戊醛、2-甲基戊醛、1，6-己二醛、己醛、2-乙基己醛、庚醛、辛醛、壬醛、癸醛、十一醛、十二醛，或其任意组合。固定剂的组合包括可用醛的组合。不受理论限制地，认为醛固定剂的作用方法是醛的失水共缩聚反应，或者胺和醛缩合形成酰胺，例如聚(乙烯亚胺)和醛的组合可以形成交联的稳定界面。
氨基硅烷固定剂的实例，包括，但不限于，(3-氨基丙基)三乙氧基硅烷、(3-氨基丙基)三甲氧基硅烷、N-(2-氨基乙基)-3-氨基丙基三甲氧基硅烷、二[(3-三甲氧基硅烷基)丙基]乙二胺、(3-三甲氧基硅烷基丙基)二亚乙基三胺等。此外，脲基封端硅烷和缩水甘油基封端硅烷可以充当适宜的固定剂。脲基封端硅烷的实例包括，但不限于，γ-脲基丙基三甲氧基硅烷和γ-脲基乙基三甲氧基硅烷。缩水甘油基封端硅烷的实例，包括，但不限于，3-(缩水甘油氧基丙基)三乙氧基硅烷、3-(缩水甘油氧基丙基)三甲氧基硅烷和3-(缩水甘油氧基丙基)二甲基乙氧基硅烷和3-(缩水甘油氧基丙基)-甲基二甲氧基硅烷。
在又一个方面，所述可溶解聚磷氮烯的有机溶剂可以是醛并充当固定剂。在另一方面，可以在特别适宜的溶剂中进行聚磷氮烯的溶解，所述溶剂例如二甲氧基甲烷(单甘醇二甲醚)或原甲酸三甲酯，其可在酸性条件下水解从而原位形成甲醛，由此固定目标组织，并且在将聚磷氮烯沉淀在组织上的同时各自浸渍组织。
表面活性剂可以是阴离子、阳离子或两性离子的，只要所述表面活性剂与整个组合物相容。例如，有用的表面活性剂包括，但不限于，聚山梨醇酯、泊洛沙姆、甘油、聚乙烯亚胺、壳聚糖、聚烯丙胺、聚乙烯吡咯烷酮、PVP、DEAE葡聚糖等，及其任意组合。
此外，所述聚磷氮烯可以与或者可替代地不与下述物质组合使用：单体、寡聚或聚合的粘合促进剂，连接层，表面活性剂，分散剂，填充剂，稳定剂，或者旨在改善所述聚磷氮烯和所述生物人工移植物相互接触时它们之间的界面相容性和/或稳定性的任何其它试剂。这种界面相容性和/或稳定性有助于实现所需的生物医学和机械弹性性能。
在又一个方面，通过预先形成聚磷氮烯膜并随后将所述膜应用至所述生物人工移植物或者用所述生物人工移植物来接触所述聚磷氮烯，可以用所述聚磷氮烯来涂覆所述生物人工移植物。可以用本文所描述的粘合促进剂来应用所述膜，或者可替代地通过应用也与聚磷氮烯结合的组织粘合剂，或者简单地将所述膜溶剂焊接至所述基底，其中所述溶剂将基底表面改性从而所述膜与所述基底良好地结合。形成聚磷氮烯膜的实例提供于U.S.Patent No.7,265,199，通过引用将其全部引入本文。不受理论限制，认为两种成分间可以形成半互穿网络。然而，本发明涵盖生物人工移植物和聚磷氮烯的任意组合，包括预先形成的应用至生物人工移植物的聚磷氮烯膜，而无论所述聚磷氮烯与生物人工移植物以何种机理相互作用。
一旦所述聚磷氮烯和所述生物组织相接触，无需任何其它方法即可蒸发所述溶剂和剩余的挥发物。在这方面，例如，以受控方式优化地设定基底上的溶剂蒸气浓度，以及压力和温度。干燥步骤的压力和温度也不是关键，只要该压力和温度适于该生物组织。
在又一方面，本发明涉及处理生物人工心瓣膜的方法，包括将所述心瓣膜组织与本文所提供的由式(I)代表的聚磷氮烯相接触的步骤。这方面可进一步包括用所述聚磷氮烯来涂覆所述组织和/或用所述聚磷氮烯来浸渍所述组织，所述浸渍是指部分或完全填充入或者穿透或穿入。因此，本公开还提供改善生物人工心瓣膜的抗血栓形成、生物相容性或血相容性特性的方法，包含将所述生物人工心瓣膜与上述式(I)的聚磷氮烯接触，其中将所述聚磷氮烯涂覆、扩散、浸渍、接枝或其任意组合至所述生物人工心瓣膜的之内或之上。
本发明可用于任何组织型生物人工心瓣膜，其包含具有各种量、甚至少量生物材料的组件。例如，某些这种瓣膜仅包括源自天然材料例如猪或牛或其他哺乳动物来源的小叶，还有合成的环形结构或支撑所述瓣膜的支架。在其它瓣膜中，所述小叶和所述环形支撑环都由生物聚合物例如胶原和/或弹性蛋白构成。全部这些瓣膜，包括所述生物聚合物瓣膜和包含支架和生物瓣膜部分的所谓支架瓣膜，都可用于本发明。此外，对可以使用的具体生物组织并无限制，尽管组织通常取自牛、马或猪的心瓣膜或心包膜。因此，可用于上述心瓣膜组织的生物组织的实例可以包括哺乳动物心包、哺乳动物心瓣膜、哺乳动物血管移植物或哺乳动物器官例如心脏。
应用至人和其他动物的组织型生物假体的装置的实例见于美国专利Nos 3,656,185和4,106,129。目前生产并且上市的组织型瓣膜的两种实例是Mitroflow International，Inc.，11220 VoyagerWay，Unit 1，Richmond，B.C.，Canada V6X 351的MITROFLOWTMHeartValve，和Sorin Biomedical，S.P.A.，13040 Saluggia(VC)，Italy的Bovine Pericardial Valve。
在本发明的另一个优选实施方式中，生物人工移植物包括生物组织和应用至所述生物组织的聚[二(三氟乙氧基)磷氮烯]聚合物。所述生物组织可以包括前文描述的任意生物组织，包括心瓣膜、血管移植物、旁通管或其它身体器官。
根据上述任意实施方式涂覆的生物人工心瓣膜可以具有约1nm到约100μm的涂层厚度。在这方面，所述生物人工心瓣膜可以具有约1nm到约10μm或者约1nm到约1μm的涂层厚度。
处理和/或涂覆技术方法可以包括但不限于喷雾涂覆、浸渍涂覆、电子自旋(electrospinning)、表面互穿网络、相分离、沉淀等。因此，处理和/或涂覆可以通过将生物人工心瓣膜与聚磷氮烯接触的任何方法来实现。
本发明优点可以包括改善的生物相容性(例如，降低的血小板粘附和蛋白结合以及无血栓形成)、细菌抵抗力、抗再狭窄、血相容性、减少生物心瓣膜组织的钙化、增加组织耐久性和对异体移植的有害免疫反应的减少。
在另一方面，本发明提供减少哺乳动物心瓣膜组织钙化的方法，以及将抗钙化特性赋予哺乳动物心瓣膜的方法，包含将所述哺乳动物心瓣膜与聚磷氮烯接触。在这方面，所述聚磷氮烯可以是聚[二(三氟乙氧基)磷氮烯]、本文公开的任何其他聚磷氮烯或本文公开的聚磷氮烯的任意组合。此外，所述聚磷氮烯可以涂覆、扩散、浸渍、接枝或其任意组合至所述哺乳动物心瓣膜的之内或之上。
在附图中举例说明本发明的实施方式和方面的实例。例如，图1和2是可用于本发明中的两种移植型心瓣膜的透视图。图1是可如本文公开来处理的猪移植型(异体移植)心瓣膜5的透视图，图中还有天然小叶10和支撑性的环形部分15。类似地，人移植型(自体移植)心瓣膜20在图2中画作透视图，其中示出天然小叶25和支撑环形部分30。
图3显示示例性的组织型心瓣膜35，表示为打开和闭合形式。图3A中，打开的管状瓣膜和支撑环形部分40具有柔性结合部或折缝45、50、55、60、65和70。图3B是闭合状态的图3A所描述瓣膜的透视图，显示支撑环形部分40和柔性结合部或折缝45、50、55、60、65和70，对应图3A中的打开形式。
图4代表本发明的另一个实施方式。在图4A中，管状瓣膜75是打开状态并且具有柔性的结合部或折缝80、85和扩展部分90。图4B显示闭合状态的图4A实施方式，描述柔性结合部80和85具有足够的支持从而保持它们的相对位置并具有足够的柔性来闭合，从而在扩展部分90可以进行紧密结合，由此切断血流。
图5举例说明组织型心瓣膜100的又一个实例，其中组织小叶附于适于移植的合成环形部分。在图5中，所述生物人工心瓣膜包含生物组织105，具有尖瓣110和包壳115，形如主动脉窦，附于更具刚性的环形框架120，所述环形框架120具有封套125用于附着。
本领域技术人员应理解，可对上述实施方式进行改变而不偏离其宽泛的创造概念。所以应理解，本发明并不限于所公开的具体实施方式，而是意在包含在本发明主旨和范围内的变化，如权利要求书所定义。
具体实施方式
实施例1
从人或其他哺乳动物取出心瓣膜并在处理前在脱水试剂/溶剂中冲洗。然后通过与固定剂例如胺、多胺、氨基硅烷等接触来预处理经冲洗的心瓣膜。然后将经预处理的心瓣膜浸入聚[二(三氟乙氧基)磷氮烯]聚合物在丙酮或THF溶剂中的溶液，此后将经处理的瓣膜放干。在此涂覆步骤后，再次使经处理的心瓣膜吸水并在培养液或盐水溶液中保存，进一步调整、灭菌、保存并按照用作生物人工移植物的任何移植型心瓣膜的用途来使用。
实施例2
按照美国专利申请公开No.2003/0157142，来制备具有约10×106g/mol到约2×107g/mol的平均分子量的聚[二(三氟乙氧基)磷氮烯]聚合物。将包含约0.1％到约99％浓度的聚磷氮烯的聚[二(三氟乙氧基)磷氮烯]溶液配制于溶剂例如甲基乙基酮中，与固定剂例如甲醛或戊二醛以及表面活性剂一起。所述表面活性剂可选自聚山梨醇酯或泊洛沙姆、聚乙烯亚胺或聚烯丙基胺等，如本文所公开。可替代地，甲醛或戊二醛可充当溶剂和固定剂，从而不需要另外的溶剂，如本文所述。还可替代地，所述溶剂或所述固定剂还可充当表面活性剂，从而不需要另外的表面活性剂。
将猪移植型心瓣膜浸入所述聚[二(三氟乙氧基)磷氮烯]溶液并在所述溶液中保持约5分钟到20分钟，从溶液中取出，在室温(大约23℃)和大气压下空气干燥，从而基本上除去所述聚[二(三氟乙氧基)磷氮烯]溶液的挥发性成分。然后对所述瓣膜进行调整、灭菌、保存并按照用作生物人工移植物的任何猪移植型心瓣膜的用途来使用。
实施例3
将包含约250mL/150g二甲基醚的可加压容器例如气阀瓶、压力罐或高压釜用固体CO2/乙醇冷却浴(或可替代的液N2浴)从外部冷却，直到温度达到它的沸点以下(-23℃)但在它的熔点温度(-138.5℃)以上，容器用黄铜壳、微型气体调节器封闭。使用合适的安全保护措施(保护屏/盾、通风)，在内部压力与大气压相等后通过缓慢地打开阀门，打开气体调节器，取下调节器。将聚[二(三氟乙氧基)磷氮烯]聚合物的固体样品，1.25g，(0.5％w/v)快速加入上述容器内的内含物中，再次密封所述可加压容器。然后在室温下将所述聚磷氮烯样品溶于二甲基醚中，持续24小时，使用水平振荡器来搅动可加压瓶中的内含物。
从供体动物取得猪心瓣膜并用本领域技术人员已知的方式或者或本文所公开的方法来用戊二醛/甲醛进行固定。然后视需要将所述移植物用其它表面活性剂和/或粘合促进剂来处理，如前文所述。
使用可加压容器阀，用准备好的聚[二(三氟乙氧基)磷氮烯]喷雾容器从各个面来涂覆所述心瓣膜样品。用Wilhelmy天平或椭圆计测量接触角来监测涂覆进程。对手术和实用方法，该进程也显见于赋予所述移植物的疏水特性。
实施例4
按照实施例1-3中的任一个，制备聚[二(三氟乙氧基)磷氮烯]聚合物并应用至人移植型(同种移植)心瓣膜，比如图2中图解的心瓣膜。一旦完成对生物人工心瓣膜的处理，所述瓣膜随后可按照用作生物人工移植物的任何人移植型心瓣膜的用途来使用。
实施例5
按照实施例1-3中的任一个，制备聚[二(三氟乙氧基)磷氮烯]并应用至组织型心瓣膜，比如图3或4中图解的那些，或者如图5示出了包含组织小叶和合成环形部分和框架的心瓣膜。一旦完成对生物人工心瓣膜的处理，所述瓣膜随后可按照用作生物人工移植物的任何此具体类型的移植型心瓣膜的用途来使用。
Claims (24)
1.包含生物组织和式(I)所示的聚磷氮烯的生物人工心瓣膜：
n是100到100,000；并且
R1到R6各自独立地选自烷基，氨基烷基，卤代烷基，硫代烷基，硫代芳基，烷氧基，卤代烷氧基，芳氧基，卤代芳氧基，烷基硫羟酸根，芳基硫羟酸根，烷基磺酰基，烷基氨基，包含选自氮、氧、硫、磷或其组合的一个或多个杂原子的杂环烷基，或者包含选自氮、氧、硫、磷或其组合的一个或多个杂原子的杂芳基。
2.权利要求1的生物人工心瓣膜，其中R1到R6中至少一个是被至少一个氟原子取代的烷氧基。
3.权利要求1的生物人工心瓣膜，其中所述聚磷氮烯是聚[二(三氟乙氧基)磷氮烯]。
4.权利要求1的生物人工心瓣膜，其中将所述聚磷氮烯涂覆、扩散、浸渍、接枝或其任意组合至所述生物组织之内或之上。
5.权利要求1的生物人工心瓣膜，其中将所述聚磷氮烯以1nm到100μm的厚度涂覆至所述生物组织之上。
6.权利要求1的生物人工心瓣膜，其中所述聚磷氮烯具有10百万到13百万道尔顿的平均分子量。
7.权利要求1的生物人工心瓣膜，其中所述生物组织包含哺乳动物心瓣膜、哺乳动物心包或哺乳动物血管移植物中的至少一种。
8.生产生物人工心瓣膜的方法，包含
提供生物组织；和
将所述生物组织与式(I)的聚磷氮烯接触：
其中
n是100到100,000；并且
R1到R6各自独立地选自烷基，氨基烷基，卤代烷基，硫代烷基，硫代芳基，烷氧基，卤代烷氧基，芳氧基，卤代芳氧基，烷基硫羟酸根，芳基硫羟酸根，烷基磺酰基，烷基氨基，包含选自氮、氧、硫、磷或其组合的一个或多个杂原子的杂环烷基，或者包含选自氮、氧、硫、磷或其组合的一个或多个杂原子的杂芳基。
9.权利要求8的方法，其中将所述聚磷氮烯涂覆、扩散、浸渍、接枝或其任意组合至所述生物组织之内或之上。
10.权利要求8的方法，其中R1到R6中的至少一个是被至少一个氟原子取代的烷氧基。
11.权利要求8的方法，其中所述聚磷氮烯是聚[二(三氟乙氧基)磷氮烯]。
12.权利要求8的方法，其中所述生物组织包含哺乳动物心瓣膜、哺乳动物心包或哺乳动物血管移植物中的至少一种。
13.权利要求8的方法，进一步包含
组合所述聚磷氮烯、固定剂、表面活性剂和可溶解聚磷氮烯的有机溶剂从而形成聚磷氮烯溶液，之后将所述生物组织与所述聚磷氮烯溶液接触。
14.权利要求13的方法，其中所述聚磷氮烯是聚[二(三氟乙氧基)磷氮烯]。
15.权利要求13的方法，其中所述固定剂选自甲醛、戊二醛或其组合。
16.权利要求13的方法，其中所述表面活性剂选自聚山梨醇酯、泊洛沙姆、甘油、聚乙烯亚胺、壳聚糖、聚烯丙胺、聚乙烯吡咯烷酮、DEAE葡聚糖或其组合。
17.改善生物人工心瓣膜的抗血栓形成、生物相容性或血相容性特性的方法，包含：
将所述生物人工心瓣膜与式(I)聚磷氮烯接触：
其中
n是100到100,000；并且
R1到R6各自独立地选自烷基，氨基烷基，卤代烷基，硫代烷基，硫代芳基，烷氧基，卤代烷氧基，芳氧基，卤代芳氧基，烷基硫羟酸根，芳基硫羟酸根，烷基磺酰基，烷基氨基，包含选自氮、氧、硫、磷或其组合的一个或多个杂原子的杂环烷基，或者包含选自氮、氧、硫、磷或其组合的一个或多个杂原子的杂芳基；
其中将所述聚磷氮烯涂覆、扩散、浸渍、接枝或其任意组合，至生物人工心瓣膜之内或之上。
18.权利要求17的方法，其中将所述聚磷氮烯以1nm到100μm的厚度涂覆至所述生物人工心瓣膜之上。
19.权利要求17的方法，其中R1到R6中至少一个是被至少一个氟原子取代的烷氧基。
20.权利要求17的方法，其中所述聚磷氮烯是聚[二(三氟乙氧基)磷氮烯]。
21.权利要求17的方法，其中所述聚磷氮烯具有10百万到13百万道尔顿的分子量。
22.权利要求17的方法，进一步包含
组合所述聚磷氮烯、固定剂、表面活性剂和可溶解聚磷氮烯的有机溶剂从而形成聚磷氮烯溶液，之后将所述生物人工心瓣膜与所述聚磷氮烯溶液接触；
其中所述聚磷氮烯是聚[二(三氟乙氧基)磷氮烯]；
所述固定剂选自甲醛、戊二醛或其组合；和
所述表面活性剂选自聚山梨醇酯、泊洛沙姆、甘油或其组合。
23.包含哺乳动物心瓣膜和聚[二(三氟乙氧基)磷氮烯]的生物人工心瓣膜。
24.生物人工心瓣膜的制造方法，包含
提供哺乳动物心瓣膜；和
将所述哺乳动物心瓣膜与聚[二(三氟乙氧基)-磷氮烯]接触；
其中将所述聚[二(三氟乙氧基)磷氮烯]涂覆、扩散、浸渍、接枝或其任意组合至所述哺乳动物心瓣膜之内或之上。
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| DE10010074B4 (de) | 2000-02-28 | 2005-04-14 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | Vorrichtung zur Befestigung und Verankerung von Herzklappenprothesen |
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2007
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1385142A (zh) * | 2001-12-21 | 2002-12-18 | 中国科学院上海微系统与信息技术研究所 | 改善人工心脏瓣叶材料血液相容性和使用安全性的方法 |
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| US20080086205A1 (en) | 2008-04-10 |
| BRPI0717738A2 (pt) | 2018-09-11 |
| AU2007307715A1 (en) | 2008-04-17 |
| WO2008045949A2 (en) | 2008-04-17 |
| AU2007307715B2 (en) | 2012-08-30 |
| US7922764B2 (en) | 2011-04-12 |
| ATE537853T1 (de) | 2012-01-15 |
| JP2010505597A (ja) | 2010-02-25 |
| CA2690539A1 (en) | 2008-04-17 |
| AU2007307715A8 (en) | 2009-05-28 |
| HK1137669A1 (en) | 2010-08-06 |
| WO2008045949A3 (en) | 2009-06-04 |
| CN101541354A (zh) | 2009-09-23 |
| KR101083471B1 (ko) | 2011-11-16 |
| IL198148A0 (en) | 2009-12-24 |
| EP2089071B1 (en) | 2011-12-21 |
| CA2690539C (en) | 2014-10-07 |
| ES2378905T3 (es) | 2012-04-19 |
| PT2089071E (pt) | 2012-03-09 |
| KR20090086980A (ko) | 2009-08-14 |
| EP2089071A2 (en) | 2009-08-19 |
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