CN1304298A - 单缝合主动脉无伸展生物学组织瓣膜 - Google Patents
单缝合主动脉无伸展生物学组织瓣膜 Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
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- A61F2/24—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body
- A61F2/2412—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body with soft flexible valve members, e.g. tissue valves shaped like natural valves
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/24—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body
- A61F2/2412—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body with soft flexible valve members, e.g. tissue valves shaped like natural valves
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- A61F2220/00—Fixations or connections for prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2220/0025—Connections or couplings between prosthetic parts, e.g. between modular parts; Connecting elements
- A61F2220/0075—Connections or couplings between prosthetic parts, e.g. between modular parts; Connecting elements sutured, ligatured or stitched, retained or tied with a rope, string, thread, wire or cable
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Abstract
一种完全由生物学组织制成的半月形无伸展瓣膜(10)。它具有多片小叶(11A—11C)。这些小叶连接起来形成一个环带,并且由此形成一个单向瓣膜。这些小叶(11A—11C)完全打开使得阻碍最小。一条窄边(12)组织搁置在接合处(22)。在接合处,小叶(11A—11C)连接起来围绕着瓣膜(10)的基底(14A—14C)。瓣膜(10)采用锥形设计,柔韧,易于适应和保护冠状窦的完整性。瓣膜(10)能用单排缝合(46)植入,并能显著减少植入时间。
Description
本发明涉及一种由一段或多段等效生物材料组织制成的无伸展瓣膜生物假体。它使冠状动脉的阻碍最小。这种瓣膜采用单排缝合植入。
已经开发了多种无伸展瓣膜。组织瓣膜典型的用于那些长期抗凝血剂禁忌症患者或者很难坚持接受抗凝血剂治疗的病人。这些无伸展瓣膜采用一种典型的双排缝合术固定方法。一排沿着流入边,一排沿着流出边。它们需要很长的植入时间。
现存技术水平的瓣膜假体存在引入外界组织、物质阻碍和植入损伤的问题。当存在广泛的缝合,比如双排缝合时,植入损伤将会更加突出。
现在市场上的无伸展主动脉瓣膜存在如下问题:体大,可导致冠状口和冠状窦的阻碍,需要双排缝合和长的植入时间。
本发明涉及一种主动脉或肺动脉的无伸展瓣膜,它完全采用交联生物组织制成。这种瓣膜使阻碍最小,并且允许采用单排缝合植入,所需时间少于现存瓣膜的植入时间。作为首选,瓣膜采用单片或多片牛的心包组织制成。采用一种可以提供瓣膜小叶完全接合以防止回流或关闭不全的方式构成多段组织。这种方式还提供瓣膜的完全开放以得到最大的有效孔口面积。瓣膜的外部采用锥形,有助于植入和可靠性。采用锥形使得流出端的直径大于流入端。
这种发明采用的首选形式是三片生物学组织小叶的组合,这些小叶附着在接合区域的相邻小叶上,通过使用组织增强接合处支架和边缘磨带。当使用边缘磨带时,它被缝合到小叶的外部,并提供瓣膜周边或基底的缝合增强。用于制成或组装瓣膜的缝合使用在组织的非关键区域,以此提高瓣膜的耐用性。
通过滑过小叶的对应边缘的临近边缘部分,使附着增强和助于临近小叶接合的关键区域的压力分配,刻制生物学接合处增强支架或垫子以应用在每个接合处。边缘磨带是一种生物组织增强。边缘磨带的某些部分缝合到支架和在小叶接合区域的小叶边缘,另一些部分缝合到小叶基底边缘,以此形成瓣膜的基环。边缘磨带位于小叶的外围,以此使小叶基底端形成的边缘得到增强,并有助于瓣膜在病人环带上的附着。在边缘的双层组织提供用以增强的缝合附着点。这种设计是符合解剖学的,它与人的主动脉和肺动脉瓣膜很相似,并且只需单排缝合植入。低轮廓瓣膜沿流动轴方向短,宽度最小,因此在解剖学上易于操作。
按要求尺寸和形状剪裁的生物学组织或其他兼容生物材料,可以很容易的用来制成瓣膜。瓣膜各部分的组装需要很少的时间,由此减少了制作费用。这种瓣膜容易植入,所需时间少于已经存在的假体植入所需时间。
一旦植入,由于组织小叶的柔韧性,增强支架和小叶开关的结合区域边缘有宽的开口,这样减少了瓣膜上的压力。由于瓣膜部分的衬垫,瓣膜小叶不易破裂。锥形设计以及组织小叶的柔韧性也保证满意的小叶接合,以此减少回流或关闭不全。进而,完全柔韧的瓣膜能用于多数主动脉或肺动脉瓣膜疾患。附着边缘适合所有正常和非正常的植入环带形状。
此发明中使用的牛的生物学主动脉或肺动脉无伸展瓣膜具有解剖学轮廓。缝合套头或边缘是小叶的一部分,并且可能包括增强边缘磨带。它呈现锥形,以便适合多数主动脉和肺动脉的形状,并且避免瓣膜关闭不全。缝合区域易于用针刺入,大约不会超过2mm厚。瓣膜的柔韧性允许它依照病人环带的外形,这样可以保持在两个冠状窦的下面。由于套头或边缘没有覆盖织物,内外直径的比值良好并且优于现存的设计。套头或边缘是小叶的内在部分并且依照病人的环带。
此瓣膜是完全采用生物材料,不包含人造材料,例如聚酯材料覆盖物。瓣膜具有仿自然瓣膜形状的接合轮廓。植入只需单排缝合,并且在缝合时,因为所有组件都在外科大夫的视野之下,小叶可以避免针刺伤。瓣膜套头或边缘可能使用生物磨带或带加以增强,而不是增加套头或边缘的宽度或是影像管口有效区域。有效的降低手术时间。使用的时间是现有的瓣膜植入手术时间的1/3到一半。较低的轮廓给外科大夫提供良好的视野。这能有助于减少植入时间,减少小叶损伤,降低瓣膜未对准和减少孔口闭塞。进而,由于此瓣膜使冠状窦不受到阻塞,伴随冠状窦阻塞而出现的问题得以避免。因此,由于冠状窦和冠状口阻塞引起的情况不可能发生。
就象心脏瓣膜替换一样,可以和瓣膜一起提供一个特殊的托架。
图1是根据本发明制成的一个无伸展主动脉瓣膜的出口端俯视图。
图2是图1示意的瓣膜入口端俯视图。
图3是图1示意的瓣膜的侧视图。
图4是本发明中用来制成瓣膜的等效生物材料小叶的平面布局图。
图5是图4所显示的小叶组装入瓣膜的接合处生物兼容材料支架平面布局图。
图6是用于最终组装瓣膜的扇形生物学边缘的平面展开图。
图7是使用图5中所示增强支架组装的三个小叶的透视图。
图8是图6所示的生物学边缘放置到小叶周围后的更进一步透视图,这刚好是在缝合各组件以制成图1-3所示的瓣膜之前。
图9是安装的瓣膜经分解后的透视示意图。
图10是瓣膜植入后的俯视图。
图1,2和3图解了一个生物等效材料假体的主动脉瓣膜组件10,它是一个瓣膜元件并具有在图1中所示的流出端13。尽管本发明是参考主动脉瓣膜描述的,本发明也能被用于包括肺动脉瓣膜在内的半月形瓣膜。瓣膜组件由三个小叶11A,11B,11C制成。一个扇形的、狭窄的边缘磨带12被缝合在瓣膜组件的基底外围周围,并且沿着小叶的接合区域。
用于小叶、边缘磨带和支架的生物等效材料包括生物学材料或人造聚合体,它们是自然存在的或人工合成的。
此发明中使用的生物组织包含相对完整的组织,以及非分离为许多小室的组织或者改造的组织。这些组织可能从心脏瓣膜,心包组织,硬脑膜,小肠粘膜下层,筋膜,皮肤或其他膜状组织获取。首选的生物学组织是牛心包组织。所选生物学组织具有一定强度和柔韧性。用于小叶,支架和边缘的组织应该避免选择薄的地点。通常,生物学组织是由源自特殊动物种类的,包含胶原质的结构组成,典型的是哺乳动物,比如人,牛,猪,马,海豹,或袋鼠等动物,也包括工程学组织。工程学组织典型地包括种群恢复基质,它能够从以上提及的组织衍生或人工合成。尽管基质不一定需要固定,但是通过防止组织发生酶降解,生物学组织可能被固定以交联组织或者提供机械性的稳定。典型的用来固定材料的物质是戊二醛,但是也可以使用其他固定方法,比如环氧化物,其他双官能醛,或是光氧化。
此发明中,用于假体的合成等效生物材料包括合成聚合物以及生物学聚合物。合成等效生物材料包扩合成聚合物和生物学聚合物。合成聚合物包括聚酰胺(尼龙),聚酯,聚苯乙烯,聚丙烯腈,乙烯基聚合物(比如聚乙烯,聚四氟乙烯,聚丙烯和聚氯乙烯),聚碳酸酯,聚亚安酯,聚二甲基硅氧烷,乙酸纤维素,聚甲基丙烯酸甲酯,甲基丙烯酸,乙酸乙烯基乙烯,多硫化物,以及类似的共聚物。生物学聚合物包括自然形式,比如胶原质,弹性蛋白以及纤维素或者精炼的生物聚合物,比如聚氨基酸或者多聚糖。所有这些材料能够异常地或者以其化合物使用,而且能够模制或浇铸成选择的形式或者能够被编织成网孔以形成基质。
小叶的尺寸将取决于需要修复的瓣膜的尺寸,并能根据要求在制造时加以选择。因为瓣膜组件没有伸展,并且非常柔韧,瓣膜的尺寸能够制成适应较宽范围的孔口尺寸和形状。作为首选,小叶包括牛心包组织。
图4-6以平面布局的形式显示了此发明的首选形式。通常的,总体由11表示的每个小叶的每条边有一个接合安装耳18。使用分离的接合支架22,小叶11A-11C在每个接合处连接在一起,也是首选用牛心包组织制成,如图5所示。每个支架22有一个切口24,它的尺寸能在相邻两个小叶的接合处穿过两倍小叶厚度。切口24允许支架22在两个相邻小叶的边缘上滑动到小叶的接合安装耳18的内部。从接合支架和背对切口24外面的支架22的折皱平面向外放置耳或边缘部分18,如图7所示。当组装三小叶瓣膜时,在接合处使用三个支架22。
以平面布局图显示在图6中的边缘磨带12由上面描述的单片生物等效材料制成,首选材料是牛心包组织,以扇形作为缝合附着。边缘磨带12有三个扇形边缘磨带部分32A-32C,它们通过在扇形凹口之间的接合支架覆盖剖面34A-34C连接起来。在图6的平面布局图中显示了尾扇面32C沿线35处终止。当边缘磨带12加入环带组成瓣膜时,在图的左手侧线35与线36连接。
为了组装瓣膜,表示为11A,11B,11C的三个小叶,连接起来形成一个具有耳部分18的环带,与下一个临近小叶的边缘或耳部分18相连形成两倍厚度的组织。如图所示,在小叶11A的一边,耳部分18A与小叶11B(参看图7)的耳部分18B相邻。一个接合支架22的切口24滑过这些小叶的临近边缘,使耳18A和18B向着外面。
小叶11A反面的耳部分18A与小叶11C的耳部分18C相邻,并且接合支架22穿过两倍厚度的组织。没有附着的相应小叶反面的耳部分18B和18C也放在相邻地方,并且第三个接合支架22穿过最后接合处。每个结合处,由三个小叶连接而成,如图7所示,与支架22一起出现。在它们折叠回支架22边缘部分后,耳18A和18B如图所示。
图8显示了组装的下一步,当放置边缘磨带12以增强支架34A,34B和34C搁置在耳18和支架22的上面。支架位于每个相邻瓣膜小叶之间的接合处。边缘磨带12的扇形部分搁在小叶圆形基底端14A-14C,以便在基底形成组织的另一层或者瓣膜的流入端。在没有增强边缘磨带12时,小叶基底端可以用做缝合套头或缝合边缘。
下一步是将扇形边缘磨带与小叶或支架组件缝合。缝合穿过形成小叶的生物学组织(下面)的相邻部分,尤其是基底部14A-14C和支架22。在图7和8中,可以看出使用支架22和边缘磨带的增强支架34A-34C,小叶的接合形成向外的边缘37。当放置边缘磨带12时,它提供一个环绕的,成型的边缘,还提供了小叶的流出端口或流出边缘42,它们将移向中央,并与其他边缘连接,以便在出口处或流出端连接在一起。较低的小叶圆形基底部分14A-14C环绕流入端扩展,并形成植入套头或基底。在缝合附着点,扇形磨带部分32A,32B和32C,加上基底部分14A-14C的外表面形成双层生物学等效材料。在瓣膜组件中,小叶的所有缝合放置在低压区域,以增加瓣膜的耐用性,比如接合区域51或流出端42。
如图3所示,边缘磨带12的支架34A,34B和34C也与支架22和小叶耳18缝合在一起,采用的缝合方法是将边缘支架34A-34C的边缘交错,并交错接合,以保证没有泄漏。围绕接合支架外围的缝合不仅能绕过边缘,而且能象40处显示的那样,穿过耳18,以确保接合处的密封。如43处所示,边缘支架部分32A-32C也被缝合到弯曲的基底部分14A,14B和14C的边缘。
小叶11A-11C的流出端42通常具有直边缘,它能够在来自瓣膜10流入端的压力下移动和打开,并扩大到三个小叶允许的最大直径。在任何反向流动或反向压力的作用下,小叶将紧紧关闭以避免在流入接合处的回流,如图2中的45处所示。瓣膜直径可适应的变化和持续的紧闭,小叶的相应的流出端折叠在一起。
无伸展瓣膜首选组织(生物材料),具有柔韧性,适合放置在环带中。但是,在此发明的考虑范围内,可以采用合成和生物学聚合物制成全部和部分瓣膜。沿弯曲的小叶基底14A-14C,边缘磨带12提供了束缚增强。小叶可以由单片和三片分离生物等效材料制成(生物学或工程学组织,或是生物或合成聚合物),这些生物等效材料在上面已经作了描述。没有添加人造缝合套头。相同的小叶材料作为缝合套头或边缘,能够在不减少有效的孔口面积条件下,通过边缘支架32A-32C使缝合套头或边缘得以增强。由于不需要织物缝合套环或缝合套头,也不需要伸展,内外直径的比值优于已有的瓣膜。
如图9所示,在必需的病变瓣膜切除和心脏环带完全脱钙后,瓣膜假体的基底将被放置在形成主动脉边缘49的心脏组织的内部。瓣膜组件10被制成锥形。基底的环形直径(在式样上大约4mm)小于流出端直径,它使瓣膜变得狭窄或无意义的关闭不全。瓣膜适用于任何主动脉或肺动脉的病变。由于瓣膜小叶具有多余接合,瓣膜上半部能够伸展。
在图9中,主动脉切开术已经完成,自然瓣膜小叶也已经切除。图9显示了左冠状动脉53B和右冠状动脉53A。如图9所示,依据病人环状组织的质量,可能采用中断缝合。图中还显示了单接合缝合,并且使用单排缝合,可以将瓣膜缝合到病人环带上。沿着生物学边缘12,可以在接合线之间开始单缝合,并且瓣膜10可以容易的缝合。在图9的46处,显示了植入使用的缝合,它示意的说明了先于植入放置的瓣膜10,还显示了心脏主动脉边缘组织50的初始附着。
假体首选完全采用组织制成,无伸展,不需要人造材料缝合环,可以操纵它,使它适合所有半月形瓣膜病变。假体的缝合通常能从其中任一个接合处开始。小叶的基底部分14(包含部分14A和14B)从瓣膜流动轴向外弯曲,并形成缝合边缘基底,这样使得入口尺寸最大,从而增加了直接缝合到的心脏组织上的支架之间的有效的孔口面积,如图9中所示。小叶弯曲的基底端14提供了一个平滑的流动剖面。因为在瓣膜的缝合边缘有双层等效生物材料,瓣膜10的缝合具有可靠性。弯曲小叶,以便给缝合边缘提供一个基底,这将有助于保持一个低轮廓瓣膜。缝合边缘所需的轴向距离和长度将大大减少。在这种瓣膜中,接合处的支架宽度也小于其他组织瓣膜。这些特性将有助于减少植入时间,降低小叶损伤,减少瓣膜失调以及减少孔口闭塞。
在不会碰撞或阻塞环和左冠状窦的条件下,支架34A-34C支撑小叶11A-11C的接合。使用单缝合,形成环带的组织50能直接与支架34A-34C的周边和边缘32A-32C缝合。在单排缝合中,可以采用连续缝合、一系列中断缝合或这二者结合的缝合。在图中所示55处,小叶的每个接合区域,向下扩展到直接附着到心脏组织50的部分圆形基底,可以完全使用这些缝合方法。结点45用于锚定缝合段(参看图10)。
由于瓣膜完全采用有柔韧性的等效生物材料制成,如图2中所示,在流出端的主动脉口有足够的流动直径。其中没有刚性部分,刚性部分会产生工作面外露角或裂口,它们能导致血液淤积,这可能形成血栓。进一步,因为没有缝合套头,在植入组织间能够直接愈合,身体组织和植入组织使得缝合的失败可能性极小。沿着流动轴,瓣膜短,因此在解剖学上容易控制。
如图10示意,环绕动脉53A和53B的冠状窦区域,在植入时,没有瓣膜碰撞。
血液流入瓣膜使小叶11A-11C完全分开,背对主动脉壁,没有锐利边缘,包或者相同的东西。瓣膜的设计确保不会受到冠状窦或孔口的干扰。因为小叶是柔韧的等效生物材料,它们将关闭,几乎没有的泄漏,这样可以防止血液回流。
如图10所示,在55处,使用单排缝合可以得到更好的血液动力学和好的耐用性。单排缝合不会碰撞冠状窦和孔口。瓣膜10具有良好的内外尺寸比例,由此可以得到很好血液动力学效果。
无伸展瓣膜10是完全柔韧的,因此易于植入。瓣膜符合环带和主动脉管腔的形状,不会使病人组织扩张,也不会在缝合附着点施加不适当的压力。在植入后,瓣膜模仿自然瓣膜的动作。
小叶易于接合,由此提供单向的复核瓣膜,并且它们完全打开避免流出的限制,并且只会受到很低的压力。
尽管参考优选实施例已经对本发明作了具体描述,本领域技术人员可在形式和细节上作出变化,这些变化都在本发明的宗旨和范围内。
Claims (14)
1.一种完全由生物组织制成的无伸展瓣膜假体,包含多个边缘连接、环绕流动开口的小叶,并具有接合形成瓣膜的尺寸,以及缝合到围绕流入端的小叶和相邻小叶接合处的边缘磨带。
2.按照权利要求1所述的瓣膜,其特征在于:分离的组织接合支架支持在每个接合处连接的小叶,具有边缘支架部分的边缘磨带沿着接合支架伸展并并另外缝合。
3.按照权利要求1所述的瓣膜,其特征在于:在瓣膜流出端,所述边缘缝合到小叶外侧上的瓣膜的外围。
4.按照权利要求2所述的瓣膜,其特征在于:每个接合支架内有一缝隙,在此缝隙中放置了相邻两个小叶的相配的边缘,边缘支架部分是扩展穿过此缝隙达到接合支架外面的小叶的尾部。
5.按照权利要求1所述的瓣膜,其特征在于:多个瓣膜包含三个形成一个瓣膜的小叶,沿着小叶流入端包含窄边组织的边缘,小叶具有包围着流入端的基底平滑向外弯曲的基底外围。
6.按照权利要求1所述的瓣膜,其特征在于:瓣膜的流出端的直径大于流入端的支架以形成一个锥形。
7.一种无伸展全组织瓣膜假体,在植入支持上是自由的,包含多个三个基本上相同构造的生物组织小叶,所述小叶具有在流出端基本上为直线的流出边缘和弯曲的流入边缘,每个小叶沿着接合处与其他两个小叶连接,接合处从流出端扩展到流出端,从而形成一个内在的流动通路,所述小叶的流出端接合以防止反向流动,小叶的弯曲的流入边缘形成用于附着组织的边缘。
8.按照权利要求7所述的瓣膜假体,其特征在于:一个增强生物组织磨带沿着小叶外面上的小叶的弯曲的流入边缘,以沿边缘形成一个缝合增强。
9.按照权利要求8所述的瓣膜,其特征在于:在每个接合处缝合的分离生物组织磨带,控制相邻小叶以一起形成接合。
10.一种形成用于人类心脏瓣膜的无伸展瓣膜假体的方法,包含以下步骤:从生物组织形成多个小叶;将小叶连接在一起以环绕一个流动通道;在相邻小叶形成的交叉点之间,沿着小叶的入口端,形成从小叶弯曲尾端向外的边缘。
11.按照权利要求10所述的方法,其特征在于:提供搁置在边缘上面的生物组织磨带,它们沿着小叶间的接合点,以及在入口端,沿着边缘和小叶交叉点缝合磨带与小叶。
12.一种修复人类心脏瓣膜的方法包含以下步骤:完全由组织形成一个无伸展瓣膜假体,这个假体具有多个小叶,边缘接合在一起围绕一个流动开口以形成一个瓣膜,并具有至少部分由小叶形成的组织磨带,它们在瓣膜的入口四周,并且包含了穿过小叶接合处的组织层;以及使用单排缝合将瓣膜缝合到病人心脏组织。
13.按照权利要求12所述的方法,其特征在于:无伸展瓣膜在流入方向具有低轮廓,在结合处的宽度较窄的组织层形成支架,并且瓣膜由与心脏口隔开的支架定位,以便没有碰撞心脏口地缝合瓣膜。
14.一种无伸展瓣膜假体,其完全由生物材料制成,包含多个具有连接在一起的边缘的三个小叶,围绕着一个流动开口,具有接合形成瓣膜的尺寸,瓣膜具有三个接合处,在接合处小叶连接在一起,在每个接合处缝合一个组织支架,小叶具有从位于接合处之间的中心轴向外弯曲的基底部分,以形成流入端,基底部分至少形成瓣膜缝合边缘的一部分。
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Also Published As
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ZA200007440B (en) | 2001-06-06 |
US20020077698A1 (en) | 2002-06-20 |
WO2000000107A1 (en) | 2000-01-06 |
CA2335619A1 (en) | 2000-01-06 |
JP2002519098A (ja) | 2002-07-02 |
US6254636B1 (en) | 2001-07-03 |
US6558417B2 (en) | 2003-05-06 |
EP1089675A1 (en) | 2001-04-11 |
BR9911565A (pt) | 2001-09-18 |
AU4709699A (en) | 2000-01-17 |
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