CN102811681A - 调节片状生物假体组织的方法 - Google Patents
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Abstract
用于调节生物假体材料的方法应用牛围心膜。指向膜纤维表面并相对于其移动的激光器将膜厚度减小至特定的均匀厚度并使表面变光滑。选择激光器的波长、功率和脉冲频率,其将使纤维表面变光滑以及将表面烧蚀成合适的厚度。可选地,皮刀被用于从膜的纤维表面去除材料层。也可以应用压缩来变薄。在交联以使膜稳定下进行逐步压缩被用来避免通过非弹性压缩而损坏膜。相反地,通过另外的交联,膜在弹性压缩状态下被连接。前述若干变薄技术可以一起应用,以获得非常薄的膜。最终变薄的膜然后可以通过加帽钙化成核位置和硼氢化物还原而被处理。可以形成具有一个以上均匀厚度区域诸如较厚的外周缝合区域的小叶。
Description
相关申请
本申请根据35U.S.C.§119(e)要求2010年3月23日提交的美国临时申请序列号61/316,801和2010年9月10日提交的美国临时申请序列号61/381,858的优先权。
发明领域
本发明的领域是调节用于植入物中的生物假体组织,更具体而言,是使片状生物假体组织变光滑和变薄以用于人工心脏瓣膜的方法。
发明背景
医疗技术早就能够通过心脏直视手术置换受损或患病的心脏瓣膜。这种瓣膜包括机械装置以及利用来自人(同种移植组织)和动物(异种移植组织)的生物材料的那些。本领域中已知的两种主要类型的人工心脏瓣膜是机械瓣膜和生物假体瓣膜。生物假体瓣膜可以由完整的、多小叶猪(porcine,pig)心脏瓣膜形成,或通过塑型来自牛围心组织或其它材料的多个单独柔韧小叶并组合小叶以形成瓣膜而形成。与机械瓣膜不同,生物假体瓣膜的一个优势是接收瓣膜的患者通常并不需要用抗凝血剂长期治疗。
心包膜是围绕脊椎动物心脏的囊,其含有润滑液,而牛(母牛)心包膜通常用于制造人工心脏瓣膜的单独的小叶。首先从动物中得到牛心包膜,然后,将其以化学方法固定,以与组织中的胶原蛋白和弹性蛋白分子交联并提高组织耐力,然后将其切成小叶。
在Simionescu等,Mapping of Glutaraldehyde-Treated Bovine Pericardium andTissue Selection For Bio-prosthetic Heart Valves,Journal of Bio-Medical MaterialsResearch,Vol.27,697-704,John Wiley &Sons,Inc.,1993中提供了关于固定的牛心包膜的各种物理性能的精辟论述。Simionescu等认识到围心组织,甚至相同围心囊的物理性能的不时的显著变化。
围心囊由两种不同的组织成分组成。内脏层或浆液层是最接近于心脏的、非常薄的半透明组织,其不用于构建人工心脏瓣膜小叶。心包膜的内层是锥形的,其围绕心脏和大血管的根部。体壁围心膜是具有多层以脂肪组织覆盖的***的较厚的膜。当被获得时,外面的脂肪/脂肪组织被去除(例如,剥离)。剩下的多层纤维组织主要含有胶原蛋白纤维,其具有一般的纤维外表面和光滑内表面。剩下的膜被用于制造人工心脏瓣膜的小叶。
在用于制备心脏瓣膜小叶的围心组织的典型商业方法中的一些步骤示例在图1中。首先,新鲜的围心囊20获自正规的屠宰场。然后,沿着预定的解剖学标记——如22所示——切开囊20。然后,囊在24被弄平,并通常去除多余的脂肪和其它杂质。在修整明显无用的区域之后,组织的窗口(window)26被固定——通常通过浸入到醛中以与组织交联,然后被隔离约2周。通常,可以从一个牛围心囊获得在一个面上的两个窗口——4到6英寸。去除组织窗口26的粗糙边缘,并且,对组织进行生物拣选(bio-sorted),以产生组织切片(section)28。生物拣选的过程涉及在视觉上检查窗口26的无用区域,并从中修整切片28。随后,切片28进一步被清洁,如30所示。
然后,将切片28平放在平台32上,以利用接触式指示仪(contact indicator)34进行厚度测量。通过围绕平台32随机移动切片28同时指示仪34的轴36在各个点上下运动来测量厚度。每一个点的厚度显示在38处,并***作者记录。通过厚度将测量的切片28拣选后,如在40处所示,从切片中冲切小叶42,其中,较薄小叶42通常用于较小的瓣膜,而较厚小叶用于较大的瓣膜。当然,该方法相对费时,并且,最终小叶的质量取决于若干步骤中技术员的技能。此外,从每一个囊获得的小叶数目是不一致的,其受手工选择过程的一些无效的影响。该费时的手工方法的一个解决方案提供在Ekholm等的美国专利号6,378,221中,其中,三轴可程序化控制器相对于厚度测量头(measurement head)操作围心片,以从地形上在类似厚度区中将片定位,用于稍后使用。然而,即使用先进的方法,牛心包膜的易变性也会导致可用于心脏瓣膜小叶的片的极其低的产率,平均为每囊小于2片。
典型地,获得的牛围心组织厚度范围为250微米上至700微米,尽管大部分材料厚度在300-700微米之间。
利用柔韧小叶的瓣膜,如由牛围心组织制成的那些,在后期更重要,因为这些瓣膜可以通过除心脏直视手术以外的方法被植入。瓣膜利用连接柔韧(例如,围心的)小叶的、可径向扩张的支架构建。移植方法包括以明显的量径向压缩瓣膜,以减小其直径或递送剖面(delivery profile),将瓣膜***到递送工具,如导管或插管,并将递送工具推动到心脏中的正确的解剖学位置。适当布置之后,瓣膜通过径向扩张而在天然瓣膜环内展开——或者通过自扩张支架结构或者利用扩张气囊。导管中折叠的瓣膜可以通过脉管***诸如通过股动脉或更直接地,通过胸中的肋间切口被引入。在不需要心脏直视手术,并且可能在手术过程中不需要停止心脏的情况下可以完成该程序。
经皮心脏瓣膜递送的一个实例是Cribier and Edwards Lifesciences of Irvine,CA的美国专利号6,908,481,其显示具有可扩张框架的瓣膜假器官,该框架上安装可折叠瓣膜性结构。另外的可压缩/可扩张心脏瓣膜显示在美国专利公布号2010/0036484中,其也来自Edwards Lifesciences。这种方法和装置的进一步的实例公开在美国专利号7,621,948和美国专利公布号2006/0259136中,并且,这种瓣膜的其它构造的数目随着技术前景的成长而激增。这些参考文献中每一篇的公开内容均通过引用被并入本文。
这些新的装置要求较薄的组件,该组件能够使瓣膜向下卷曲成可以通过递送工具的尺寸。一个限制性要素是生物假体组织的厚度。如所述的,围心层范围为250-700微米,但仅一小部分获得的心包膜接近于低端,而低端对于可压缩/可扩张瓣膜是最有用的。
美国专利号7,141,064提议压缩牛心包膜,使其厚度减小约50%,以用于心脏瓣膜小叶中。压缩也可以使组织表面平滑,以减小厚度不均匀性。
尽管对各种生物假体组织,尤其是用于心脏瓣膜小叶的各种生物假体组织有很多研究,但仍需要较薄的和更一致厚度的组织来用于制造较小递送剖面的生物假体。
发明内容
本发明涉及用于心植入的生物假体材料的制备。选择具有纤维表面和光滑表面的牛围心膜。这种制备方法可以提高围心膜的心瓣膜小叶的产率,并且可以消除血栓形成剂,如悬垂纤维(dangling fiber)。
根据一个方面,制备生物假体组织膜材料的方法包括:首先选择具有纤维面和光滑面的组织膜(例如,牛围心膜)。然后,从选择的膜的纤维面去除材料,以减小膜厚度并使纤维面光滑。材料可以通过用机械装置诸如皮刀或振动切片机(vibratome)剪切去除。可选地,材料可以通过用激光烧蚀被去除。
在刚才所述的方法中,选择的膜可以通过压缩选择的组织膜和在压缩下同时使膜材料交联而被调节。此外,该方法可以包括通过加帽钙化成核位置和/或通过硼氢化物还原来处理厚度减小的膜。根据一个方面,该方法还包括在去除步骤之前至少部分固定选择的膜。
根据本文所述的另一方法,生物假体组织膜材料如下被制备:首先,选择具有纤维面和光滑面的组织膜,通过压缩并在压缩下同时交联膜来调节选择的组织膜,然后从选择的组织膜的纤维面去除被调节的材料,以减小膜厚度和使纤维面变光滑。组织膜可以是围心膜,如牛或马的。该方法可以包括通过加帽和/或通过硼氢化物还原来处理厚度减小的膜。根据一个方面,去除步骤通过用机械装置诸如皮刀或振动切片机剪切来完成。或者,去除步骤通过用用激光烧蚀被调节的材料来完成。
根据再一个方面,制备生物假体组织膜材料的方法包括:首先,选择具有纤维面和光滑面的组织膜。膜材料至少部分交联,然后被灌注具有链长度的第二交联材料,以允许度过大的原纤维间结构域。随后,组织膜至少部分被压缩。组织膜可以是牛围心膜。该方法也可以包括在至少部分交联膜之前轻微压缩选择的膜。该方法可以包括通过加帽和/或通过硼氢化物还原来处理厚度减小的膜。根据一个方面,从轻微压缩的组织膜的纤维面去除材料。
本申请的另一个方面是心脏瓣膜,其包括多个小叶,每个小叶均由片状组织形成,所述片状组织拥有具有均匀的第一厚度的第一区域和具有均匀的第二厚度的第二区域,所述第二厚度大于所述第一厚度。优选每一个小叶均具有与自由边缘相对的尖边缘,并且第二区域以总体均匀宽度的带沿尖边缘延伸。第二区域也可以以总体均匀宽度的带沿每个小叶的自由边缘延伸。此外,第二区域可以以总体均匀宽度的带从自由边缘的中心到尖边缘径向延伸。期望地,第一和第二区域之间厚度的过渡是逐渐的。在一个实施方式中,心脏瓣膜包括支撑框架,以缝合线小叶的外周边缘与其连接,并且第二区域沿小叶边缘延伸,缝合线经过该小叶边缘。
在本发明的第一单独方面,皮刀被用于膜的纤维表面并相对于其移动,以使表面光滑和/或将膜厚度减小到特定的均匀厚度,例如不大于250微米。皮刀受隔离物(spacer)限制,以控制去除修剪的材料后剩余的膜厚度。
在本发明的第二单独方面,去除膜的纤维表面,以使表面光滑和/或将膜厚度减小到特定的均匀厚度。膜首先经受轻微压缩和交联,以使纤维表面光滑和改进材料用于烧蚀。
在本发明的第三单独方面,激光器被指向膜的纤维表面并相对于其移动来烧蚀表面,以使表面光滑和/或将膜厚度减小到特定的均匀厚度。选择激光器的波长、功率和脉冲频率,其将使纤维表面变光滑以及将表面烧蚀成合适的厚度。膜可以首先经受轻微压缩和交联,以使纤维表面光滑和改进材料用于烧蚀。
在本发明的第四单独方面,选择的牛围心膜首先至少部分被交联,然后被灌注具有链长度的第二交联材料,以允许跨过大的原纤维间结构域。然后,压缩膜,其随后通过加帽和硼氢化物还原被处理。
在本发明的第五单独方面,任何前述方法均可组合使用以产生更大的优势。
对本发明的性质和优势的进一步理解在下面描述和权利要求书中阐明——尤其在结合附图考虑时,在所述附图中相同的部件具有相同的参考编号。
附图简介
现将阐释本发明,并且其它优势和特征将通过参考所附示意图而呈现,其中:
图1图解用于在从组织形成小叶之前制备和测量牛围心组织厚度的现有技术步骤的顺序;
图2是可用根据本申请的被调节的组织制造的人工心脏瓣膜的代表性实施方式的透视图;
图3是可用于图2人工瓣膜的支撑框架的透视图;
图4是图2所示瓣膜的小叶的平面图;
图5是与加强外缘(skirt)连接以形成小叶组件的瓣膜小叶结构的底部透视图;
图6A描述在气囊式递送导管上卷曲的示例性人工心脏瓣膜的侧视图;
图6B显示安装在气囊式递送导管上并处于其扩张状态的图6A的人工瓣膜;
图7是用激光烧蚀对围心膜进行组织调节的顺序的示意图;
图8是瓣膜小叶的平面图,其显示由邻近小叶底部边缘的厚度均匀的组织形成的加强区域;
图9是瓣膜小叶的边缘视图,其显示加强区域;
图10是人工心脏瓣膜小叶的平面图,所述人工心脏瓣膜小叶在缝合线穿透以与结构支架连接的区域具有增厚的外周边缘;
图10A和10B是经过图10小叶的径向中线的截面图,其显示两个不同厚度的剖面;
图11是人工心脏瓣膜小叶的平面图,所述人工心脏瓣膜小叶在缝合线穿透以与结构支架连接的区域具有增厚的外周边缘以及增厚的自由边缘,以减小在该位置延长的风险;
图11A和11B是经过图11小叶的径向中线的截面图,其显示两个不同厚度的剖面;
图12是人工心脏瓣膜小叶的平面图,所述人工心脏瓣膜小叶在缝合线穿透以与结构支架连接的区域具有增厚的外周边缘以及在刺激阿朗希乌斯小结的自由边缘中具有增厚的三点区域;
图12A和12B是经过图12小叶的径向中线的截面图,其显示两个不同厚度的剖面;
图13图解可选小叶的平面图,所述可选小叶具有增厚的外周边缘区域、沿自由边缘的增厚带以及从自由边缘延伸到尖边缘的多个增厚径向带;
图14A和14B是利用轮廓形成模型的示例性小叶削割方法的示意图;
图15A是切割组织的皮刀的示意图,而图15B图解围心组织的一般切片上的结果;
图16是压缩的示意侧视图,其中,附近的隔离物为了清楚而被去除。
优选实施方式的详细描述
在主要实施方式中,描述用于人工心脏瓣膜,尤其是可扩张心脏瓣膜的小叶的制备。小叶期望地结合在可扩张人工心脏瓣膜中,该可扩张人工心脏瓣膜最初卷曲(或者甚至卷起)成小的递送剖面或直径以经过导管或其它递送***,然后在植入位点,典型地为瓣膜环处扩张。心脏瓣膜包括结构支架体,其中结合多个柔韧小叶。多种材料适于支架体,尽管某些镍-钛合金(即,镍钛诺)由于它们的超弹性和生物相容性而被优选。还应该注意,特定的支架体构造并不被认为是限制性的,而且,各种结构细节可以被修改。
尽管形成较薄的人工心脏瓣膜小叶有助于减小可扩张瓣膜的递送尺寸,但如本文所述地形成较薄小叶以及调节小叶被认为对于常规心脏瓣膜也是有优势的。例如,使围心组织的粗糙表面变光滑被认为通过减少松散纤维和伴随的血栓形成而提高小叶的耐用性。
耐用性超过10年的心脏瓣膜的牛围心小叶厚度范围为0.014-0.023英寸(~350-580微米),其中较小的瓣膜利用较薄小叶而较大的瓣膜具有较厚小叶。当前的经皮瓣膜可以使用厚度小至0.004-0.005英寸(~100-130微米)的猪围心组织。尽管天然产生的猪组织与天然产生的围心组织相比稍薄,但利用围心小叶存在某些优势。
多种组织可用于小叶,尽管在心脏瓣膜小叶的主要应用中优选使用的组织是牛体壁围心膜。虽然牛围心组织的厚度和强度被认为对于更持久的瓣膜是期望的,但可以使用其它生物假体组织诸如猪、马和其它哺乳动物——包括人的心包膜。此外,可以使用来自其它解剖学源的组织,如硬膜、腹膜(peritoneum)、隔膜或其它。像心包膜一样具有适当的耐用性和弹性的任何组织膜都是候选的组织,尽管本领域的技术人员将理解,某些材料可以更适于任意一种具体应用。通常,包含纤维胶原蛋白,尤其被分类为I型或III型胶原蛋白,和弹性纤维或弹性蛋白的组织可以适合用于制备心脏瓣膜小叶。可以使用的胶原蛋白的其它可能类型是混合的天然胶原蛋白溶液或电纺(electrospun)胶原蛋白弹性蛋白织物。同样地,可以使用某些所谓的工程化组织,它们通过使胶原蛋白组织在典型的网框架或台架(scaffold)上生长而合成。这些源被统称为“组织膜”,并且均可以受益于本文所述的原理,尽管某些类似的牛心包膜特别适于调节根据本申请的心脏瓣膜小叶。
如上所述,围心囊由两个或更多个不同的层组成,所述层的一面相对光滑,而相对的表面包括以脂肪组织覆盖的***,其中一些在被获得时剥离,其因此是纤维性的。本文所述的方法对于使纤维面变光滑以形成厚度一致并且光滑的膜是特别有用的。在一些情况中,纤维脂肪组织面的厚度也可以被减小,以产生均匀的薄膜,优选在300微米以下,以用于可折叠/可扩张瓣膜。
参考图2,显示示例性单片(one-piece)人工心脏瓣膜50可以利用具有均匀厚度的牛膜。将一定程度详细地描述瓣膜50,以说明本文所述小叶制造方法的某些益处,但对于瓣膜结构的更多细节可以在2009年6月8日提交的美国专利公布号2010/0036484中找到,其名称为“LOW PROFILE TRANSCATHETER HEARTVALVE”,并被转让给Edwards Lifesciences,其公开内容通过引用被并入本文。可选地,可以利用薄围心膜的另一微创瓣膜在2004年5月11日发行的美国专利号6,733,525中找到,其名称为“ROLLED MINIMALLY INVASIVE HEART VALVESAND METHODS OF USE”,其公开内容通过引用被明确地并入本文。
图解实施方式中的瓣膜50一般包括结构框架或支架52、由框架支撑的柔韧小叶结构54和固定到小叶结构外表面的柔韧外缘56。图解的瓣膜50可以植入到天然主动脉瓣膜的环中,但也可适于植入到心脏的其它天然瓣膜中或身体的各种其它管或孔中。瓣膜50具有“较低”或流入端60和“上部”或流出端62。血液向上自由流动经过瓣膜50,但柔韧小叶结构54关闭以防止向下逆流。柔韧小叶结构54因此提供柔韧的流动性封闭表面(occluding surface),使血液能够单向流动。
瓣膜50和框架52被配置成可径向折叠成折叠的或卷曲的状态,以在递送导管上引入到身体,并且可径向扩张到扩张的状态,以将瓣膜植入到身体中期望的位置(例如,天然主动脉瓣膜)。框架52可以由塑性-可扩张(plastically-expandable)材料制成,所述材料允许瓣膜卷曲成较小剖面,以利用扩张装置如气囊式导管的气囊递送和扩张瓣膜。示例性塑性-可扩张材料包括、但不限于不锈钢、镍基合金(例如,镍-钴-铬合金)、聚合物或其组合。可选地,瓣膜50可以是其中框架由自扩张(self-expanding)材料如镍钛诺(Nitinol)制成的所谓自扩张瓣膜。自扩张瓣膜可以卷曲并用限制装置(restraining device)如覆盖瓣膜的护套(sheath)保持处于折叠状态。当瓣膜被安置在目标部位或其附近时,可以移除限制装置,以允许瓣膜自扩张成其扩张的功能尺寸。
也参考图3(为了说明,其仅显示框架),框架52是一般的管状、支架样结构,其具有多个成角度间隔的、垂直延伸的支柱(strut)或接合连接杆(post)64。读者将注意到,图3中的杆64与图2所显示的稍微有些修改,差异很小。杆64通过若干排外周延伸的支柱66相互连接。居于接合连接杆64中间的较薄的垂直(轴向)杆68与邻近的横排的支柱66连接并在其之间延伸。每一排的支柱期望地如所示地以在框架外周方向延伸的“之”字形或大致锯齿形图案排列。相同排中邻近的支柱如所示地彼此相互连接,以在延伸时形成角度,期望地在约90和110度之间。这在扩张时使框架52的径向强度最优化,而仍允许框架52均匀地卷曲,然后以下面描述的方式扩张。
小叶结构54期望地包括三个单独连接的小叶70,诸如图4所示,其可以被排列成三尖瓣排列折叠(皱缩,collapse),如在图2和5中最佳显示的。每一个小叶70均具有与大致直的上部自由边缘74相对的弯曲较低尖边缘72和在自由边缘74和较低边缘72之间延伸的两个接合活叶(flap)76。弯曲的尖边缘72在小叶结构54中形成单一的扇形区域(scallop)。当被固定到两个其它小叶70以形成小叶结构54时,小叶的弯曲尖边缘72共同形成小叶结构的扇形较低边缘(如在图5中最佳显示的)。如在图4中进一步显示的,两个加强条78可以被固定到邻近于活叶76的每一个小叶70(例如,利用缝合线)。然后,活叶可以在条78上折叠并利用缝合线固定在折叠的位置中。如果期望,每一个条78均可被放置在保护套管(sleeve)(例如,PET套管)中,然后被固定到小叶。
小叶70在其邻近面相互连接以形成小叶结构的接合处80(见图2小叶集合在一起的边缘)。小叶结构54可以利用各种技术和机构被固定到框架52。例如,如在图2中最佳显示的,小叶结构的接合处80期望地与支撑杆64排成一行并利用缝合线通过孔82(图3)固定到其上。小叶与杆64的连接点可以通过条(bar)78(图4)来加强,所述条78期望地由相对硬的材料(与小叶相比)如不锈钢制成。
如所述的,小叶结构54的较低边缘期望地具有波浪形的、弯曲扇形。在图2的外缘56的外部上可见的缝合线84追随(track)小叶结构54的扇形。通过以这种扇形几何形状形成小叶,小叶上的应力被减小,这反过来提高瓣膜的耐用性。此外,借助于扇形,在每个小叶腹部(每个小叶的中心区域)的折痕(fold)和褶(ripple)——其可以引起在这些区域的早期钙化——可以被消除或至少被最小化。扇形几何形状也减少用于形成小叶结构的组织材料的量,从而允许在瓣膜流入端的较小的,甚至更卷曲的剖面。
再次参考图2和5,外缘56可以,例如由聚对苯二甲酸乙二酯(PET)带状物形成。小叶结构54通过薄的PET加强带88(或套管)与外缘连接,图5,这使得能够进行固定缝合并保护小叶结构的围心组织免于破裂。小叶结构54被夹在外缘56和加强带88之间。缝合线84——将加强带和小叶结构54缝合到外缘56——可以是任意合适的缝合线,其期望地追随小叶结构54底部边缘的弯曲部分,如在图2的外缘56的外部上所见的。外缘56和小叶结构54组件在框架52内并通过一连串“之”字形图案的缝合线86固定到水平支柱66,如图2所示。
为了组装,将心脏瓣膜小叶70从膜诸如牛心包膜切割下来,并根据本文所述的原理将其变薄、调节或以其它方式进行塑型。在上述可扩张瓣膜50中,小叶70连接在管状支架框架52中,并且,三对邻近的自由边缘74在相对于彼此等角定向的结合线处的瓣膜中间集合。自由边缘74向内鼓起(billow),以沿着结合线集合。然后,组装的瓣膜在植入前储存在无菌液体中,通常为戊二醛,一段时间。
图6A显示在气囊式递送导管90的气囊92上卷曲的人工心脏瓣膜50。如本文所说明的,应用于小叶材料的生物假体组织的变薄有助于使组装的瓣膜和气囊式导管的外直径D小至6mm。扩张的人工心脏瓣膜尺寸通常在20mm上至约30mm之间的任何地方。
图6B显示人工瓣膜100的可选实施方式,其包括框架102和安装到框架内的小叶结构104(例如,利用如上所显示和描述的缝合线)。显示瓣膜100在扩张气囊92已经膨胀后处于其扩张状态。扩张的瓣膜100的尺寸根据患者而变化,通常在22和40mm之间。
移植方法包括以明显量径向压缩瓣膜50,以减小其直径或递送剖面,将瓣膜***到递送工具诸如导管或插管,和将递送工具推进到心脏中正确的解剖学位置。当被适当布置之后,瓣膜50通过用扩张气囊92在天然瓣膜环内径向扩张而展开。导管中折叠的瓣膜50可以通过脉管***诸如通过股动脉被引入,或更直接地,通过胸中的肋间切口被引入。瓣膜尽可能地小是重要的。大的瓣膜需要大直径的导管,其难以推动经过,例如股动脉。为了使收缩的心脏瓣膜更小,制造者将用于制造小叶70的组织变薄。优选地,调节包括减小组织厚度,但也可以包括使组织变光滑以产生薄的、厚度不变的膜,从该膜切割下小叶。或者,小叶可以首先被形成然后被变薄。存在一些使组织变薄的方法,包括利用下面说明的激光烧蚀。
应该再次注意,本文所述变薄的围心膜可以用于各种类型的心脏瓣膜,包括常规外科手术瓣膜。该方法也可用于仅仅使组织表面变光滑或“修缮”组织表面,以消除血栓形成剂诸如悬垂纤维,而没有任何可以看得出的变薄。这种变光滑的组织——仍然相对厚——可用于常规外科手术心脏瓣膜中。可以利用根据本发明的组织的常规心脏瓣膜的一个具体实例是围心生物假体的 系列(line),可从Edwards Lifesciences获得。瓣膜的基本结构见于美国专利号5,928,281,其公开内容通过引用被明确地并入本文。
期望地,用于经导管心脏瓣膜小叶的围心层范围在250-500微米,并且优选更接近于250微米。不幸地是,仅少数获得的心包膜接近于250微米的厚度。大部分材料为300-700微米。结果,每个围心囊仅产生约1-2个适于THV的小叶。然而,用于构建心脏瓣膜的围心组织由具有相似成分的多个组织层组成,并且,大部分胶原蛋白纤维在层之间平行。这种独特的结构使其能够使用各种手段,例如激光器、剃刀来去除一些组织。期望被去除的组织来自纤维面,脂肪组织之前从该纤维面被去除。这产生更明确的、更薄的围心膜,其具有更适合的低剖面。
随着激光技术的到来,角膜组织的烧蚀变得普通。准分子激光器(excimer laser)已被用于这样的程序。参考美国专利号4,840,175。具有在皮秒和飞秒范围内具有非常短的脉冲长度的锁模激光器的最近的机件(work)也被认为减少加热。激光也被用于切割组织,用于烧蚀心肌以治疗心律不齐和用于牙科应用。关于激光用于人组织去除的用途的两个其它公开内容在Holha的美国专利号7,022,119和Stoltz等的美国专利号7,367,969中。这些激光参考文献通过引用被并入本文。利用激光辅助原位屈光性角膜移植方法的激光烧蚀也被提出减小牛心包膜的厚度以产生用于各种用途的膜组织,所述用途包括美国专利公布号2007/0254005中的心脏瓣膜,其公开内容通过引用被并入本文。
图7示意性显示烧蚀制备中的生物假体组织以制造植入物组件诸如心脏瓣膜小叶的事件的顺序。为了制备用于心植入的围心材料,大量外部脂肪/脂肪组织被去除的牛围心膜的膜110被选择,其厚度为250微米或更厚(通常在300-700微米的范围内)。显示在下面的胶原蛋白层112——组成体内围心囊的内表面——仍然附着有一些外部脂肪/脂肪组织114。
组织烧蚀可以通过,例如膜110以平面形式暴露完成,如由图7的流程图所说明的。在平面构造中,膜110被固定或保持在合适的平面中。激光器116指向膜110的上部纤维表面114,其中被调整用于烧蚀的焦点在胶原蛋白层112的顶部或邻近。可选地,尽管未显示,膜110可被布置在旋转心轴上,以便邻近的激光可以去除组织。考虑用于产生相对组织/激光器移动的其它物理构造。激光器116和表面114之间的相对移动然后导致烧蚀膜110的材料。根据膜组织对激光束的透明度,需要不止一个通路来实现期望的均匀厚度。
发现在烧蚀心包膜以产生心脏瓣膜小叶中有用的激光器规格包括:双轴扫描透镜;2×束扩张;1550nm波长;对目标的31.5μJ脉冲能量;1.6W平均功率;50Hz重复频率;650fs脉冲宽度(ref);30μm激光斑大小;椭圆偏振;112mm焦距;400mm/s粗磨速度(在网状线图案(cross hatch pattern)中20μm填充间距);和800mm/s细磨速度(在网状线图案中20μm填充间距)。
已经开发了用于高精度引导激光和烧蚀组织的大量技术。角膜烧蚀已经被广泛实施近20年。利用准分子激光器的该技术已经变得普通。再次参考美国专利号4,840,175,其公开内容通过引用被并入本文。具有减少加热在皮秒和飞秒范围内具有非常短的脉冲长度的锁模激光器的最近的机件已经被研究。
用于这种不针对患者的精确机件的碾磨机器也是可以获得的。应用具有上述规格激光器作为对于方便地处理心包膜有用的操作工具的碾磨机器具有2-轴扫描激光头、组织固定器(tissue holder)以帮助将机件载入到机器、X-Y台(table)以增加激光器的工作面积和自动组织固定器载入机构。上述机构可以用于选择性地烧蚀安装的心包膜,以产生具有不同厚度的式样,如下所论述。
碾磨机器根据限定切口式样和粗糙度的输入数据自动进行操作。典型地,这种机器被排列,以根据被切割的表面的具体高度控制切口深度。通过这种排列,所得表面将反映预切割的轮廓。为了避免这样的结果,可以使用固定的参考物(reference)而不是被切割的表面的高度。以这种方式,机件上的完整式样将位于具有每个完整切口的平面中。然后,多个切口被用于实现期望的膜厚度。
为了保持围心膜小叶的适当寿命并实现足够紧密的包装,以通过股动脉被***到位,需要特定组织厚度的小叶。例如,发现250微米的均匀厚度特别有用,尽管在250-500微米之间的均匀厚度可能是合适的。选择激光器116、120的波长、功率和脉冲频率,其将使纤维表面变光滑,以消除血栓形成剂以及将表面烧蚀成合适的厚度。各种波长均可适应于该方法而不产生过量的热,同时也是有效的。如果使用超短脉冲激光,相信激光波长并不明显地改变结果。已经利用1550nm波长制备小叶样品。
该制备方法可以增加来自围心膜的心瓣膜小叶的产量。事实上,利用本文公开的方法,预期从每个围心囊至少可以获得5个心脏瓣膜小叶。
如果在干组织上进行,心包膜的激光烧蚀被理解为是有优势的。这可以通过首先用戊二醛或等同物用基于丙三醇的处理固定样本110并在激光烧蚀前干燥组织来完成。这种基于丙三醇的干燥方法公开在Tian等的2008年5月1日公开的美国专利公开号2008/0102,439中,其公开内容通过引用被并入本文。
除了产生单一的均匀厚度之外,本文所述的方法也可以用于选择性地使组织变薄,以获得具有均匀但不同厚度的区域。一个特别有用的实例显示在图8中,该图显示心脏瓣膜小叶130,其具有外周区域132,比小叶的剩余区域134厚。尤其地,小叶的较低弯曲或尖边缘可被增厚,以便稍后固定到上述外缘56。增厚的区域132期望地包括大致均匀宽度的带。这类似于如上所述地固定加强带88,并且两种技术均可用于甚至更大的加强。可以以相同方式制备三个这样的小叶130,然后,在其接合边缘以三尖瓣排列将其彼此连接,以形成小叶结构,如图2和5的54处所示。小叶上的加强区域132共同限定带或套管,其沿着小叶结构54的内表面的较低边缘部分延伸。
图9图解具有应力减缓剖面的小叶130的边视图(edge view),该小叶具有加强区域132,从如坡136处可见的厚度缓慢过渡到小叶130的较薄的主要部分134。加强区域132被图解稍微粗糙,以模拟显微镜组织不均匀性,尽管利用本文所述的某些技术可以使相同的表面更光滑。加强区域132可以限定最大小叶厚度Tmax,在约300-700微米之间,而较薄的主要区域134期望地具有最小小叶厚度Tmin,在约200-500微米之间,并且可能更薄。更具体而言,对于小至17或19mm的较小心脏瓣膜,考虑最小厚度Tmin在150-250微米之间的小叶组织,而较大瓣膜,如26mm瓣膜可以具有上至350微米的组织。一个考虑的实施方式是数量级仅为100微米的超薄组织。最大小叶厚度Tmax期望地高达小叶较薄部分厚度的两倍。在具体实例中,19mm的较小瓣膜可以具有这样的小叶,其Tmin在150-250微米之间,同时最大小叶厚度Tmax在加强的区域高达300-500微米。
图10-12图解来自本文所述的选择性变薄方法的围心组织人工心脏瓣膜小叶中的可选厚度剖面。每个小叶均以平面图显示,其具有弓形尖边缘140、与尖边缘相对的大致直的自由边缘142和在自由边缘任一端的一对相对定向的突出物(tab)144。每个突出物144均包括渐尖侧面146,其过渡到自由边缘142。每个小叶中的中心部分148形成流动性封闭表面,其将振荡进和出流动流,以可选地打开和关闭瓣膜。该形状仅是示例性的,并且其它小叶形状是已知的。图10-12中显示的每个小叶均具有相同的形状,因此将针对形状特征使用相同的元件编号。
图10图解小叶150,其在缝合线穿透以与结构支架连接(未显示)的区域具有增厚的外周边缘区域152。更具体而言,增厚的外周边缘区域152围绕整个尖边缘140延伸并上达突出物144的至少一部分。如所述的,这些是其中缝合线被用于连接小叶到支撑支架的区域。外周边缘区域152的厚度可以上至700微米,优选在300-700微米之间。同时,形成中心区部分148,其具有相对小的厚度,从而有助于被压缩的薄膜的较小的递送剖面。例如,中心部分148的250微米的均匀厚度被认为对于减小可折叠/可扩张瓣膜的卷曲剖面特别有用,尽管均匀厚度在250-500微米之间可能是合适的。
图10A和10B是经过图10小叶径向中线(垂直的)的截面图,其显示两种不同厚度的剖面。在图10A中,较厚的外周边缘区域152在相对陡的阶(step)154过渡到较薄的中心部分148。相反地,图10B图解后边缘区域152和较薄的中心部分148之间的缓坡156。显示坡156是线性的,尽管其它轮廓诸如弯曲或逐阶的可以被使用。相信更缓的坡156提供更期望的应力分布和在小叶上的流动。可能通过调整激光功率应用而提供逐渐的过渡。实现缓坡的另一方式是使用削割技术结合形成模型,如通过参考图14A和14B在下面描述的。
图11是人工心脏瓣膜小叶158的平面图,其具有如图10所示的增厚的外周边缘区域152以及沿着自由边缘142的增厚的带160。人工心脏瓣膜有时由于其中小叶集合或接合在一起的小叶自由边缘延长而破坏,这最终会导致瓣膜脱垂。提供沿着整个自由边缘142的增厚的带160减小延长的风险,因为自由边缘经历的应力与其厚度成比例。图11A和11B再次显示图11小叶的两个不同厚度的剖面,其中,增厚的外周边缘区域152和增厚的带160可以在阶162(图11A)或缓坡164(图11B)处过渡到较薄的中心区域148。
最后,图12再次图解心脏瓣膜小叶166,其在用于连接结构心脏瓣膜支架的区域具有增厚的外周边缘152。另外,小叶166在模拟阿朗希乌斯小结的自由边缘142的中间具有增厚的三点区域168。为了清楚,在心脏瓣膜小叶中所谓的三点是小叶在流动口中心与其它小叶集合在一起(接合)的点。因为三个小叶向中间弯曲,在三点处其间的空隙可能足以引起回流。在天然小叶中,自由边缘的中心有时具有增厚的区域,被称为阿朗希乌斯小结,其往往填充三点处的空隙。当使用均匀厚度的围心组织用于小叶时,仅可以通过具有需要额外小叶材料的长的接合表面来避免渗漏。然而,这样不利地影响将瓣膜压缩成低剖面的能力,并且,有时导致小叶在关闭时变形,这会导致早期的钙化。通过在每个小叶中产生增厚的三点区域168,可以模拟阿朗希乌斯小结。示例性三点区域168作为自由边缘142中心的小三角形被显示,尽管形状可以是弯曲的,如半圆形或其它形状。此外,三点区域168可以沿着自由边缘142与增厚的带162组合,如在图11中可见。事实上,本文所述的任何各种增厚的区域均可以为了期望的效果而与其它区域组合。
图12A和12B显示小叶166的两种不同厚度的剖面。图12A显示较薄的中心部分148和增厚的外周边缘152和增厚的三点区域168之间的陡阶,而图12B显示在相同位置的缓慢过渡。
图13图解本申请的可选小叶170,其可以帮助减小小叶下垂,这被发现是某些人工心脏瓣膜失败的原因。对小叶延长的抵抗与沿着径向应力线的小叶厚度直接成比例。因此,除了增厚的外周边缘区域152和沿着自由边缘142的增厚的带160之外,小叶170还包括多个增厚的径向带172、174,其大约从自由边缘142的中心延伸到弓形尖边缘140。在这种意义上“径向线”被绘制,如同尖边缘140为以自由边缘142的中间为中心的圆形的边缘,尽管应该理解,尖边缘140可以不被单一的弧限定,并且可以不在自由边缘142的中心。典型地,然而,人工小叶围绕径向中线是对称的,因此,一个优选的排列包括沿着中线(垂直的)的增厚的径向带172和在垂直带172任一面的对称的增厚的径向带174。在图解的实施方式中,有三个带:中线带172和与中线带大约成30°角的两个径向带174。还应该注意,如所图解的,围绕小叶的各个增厚的带具有大约相同的宽度,尽管不必须是这种情况。例如,尖边缘带160和径向带172、174可以基本上比缝合线必需经过的边缘区域152更薄。
如上所述,轮廓形成模型可用于在本文所述的小叶中产生逐渐的厚度变化。图14A和14B是利用这种模型的示例性小叶削割方法的示意图。在图14A中,形成模型176包括小叶支撑表面,其具有比另一侧边(side)180低的一个侧边178。碾磨工具,如激光器182在小叶184的上部表面上经过,并且可以被控制,以针对预定的参考平面去除材料。以这种方式,小叶的左边缘保持较厚,而更多的材料从右面被去除,以在该位置产生较薄的小叶区域。在图14B中,第二形成模型186包括小叶支撑表面,其具有比中间部分189低的外周侧边188。再次,当激光器182在小叶184的上部表面上经过时,其被控制,以去除材料使其低至参考平面,更多的材料将从小叶的中心区域被去除。当然,考虑形成模型的许多不同的形状,图解在图14A和14B中的那些仅是示例性的。
所得均匀的膜优选被处理以使其大致惰性(inert)、安全地用于人移植。处理通常包括将膜浸入化学溶液诸如戊二醛达预定的时间段,以去掉微生物实体的组织或“病菌”。示例性隔离期约为14天。可选地或另外,完成的膜可以利用加帽钙化成核位置和硼氢化物还原而被处理,以减轻稍后的体内钙化。
例如,一种考虑的调节组织的顺序包括:首先,使组织(例如,牛心包膜)与戊二醛缓冲溶液交联。接下来,可以利用,如在1999年8月3日发行的Carpentier的美国专利号5,931,969——其公开内容通过引用被明确并入本文——中公开的方法将组织加热处理。随后,可以利用本申请中公开的任何方法减小组织厚度。最后,较薄组织可以用加帽和/或还原剂处理,以减轻稍后的体内钙化,这也可以包括用丙三醇/乙醇溶液处理。对于人工心脏瓣膜小叶,组织然后形成小叶、连接到围绕的心脏瓣膜支撑框架或其它这样的组件、并用诸如环氧乙烷灭菌。将组织研碎、捣碎、切片、激光烧蚀、拉伸(drawn down)或挤压以减小其厚度之后,钙化成核位置(例如,醛和席夫碱类)可以被暴露,这产生钙化的倾向。用加帽剂(例如,乙醇胺)还原剂(例如,硼氢化钠)和胶原蛋白防腐剂(例如,丙三醇)处理使成核位置加帽并保持胶原蛋白完整性。这允许组织像它厚度减小以前一样耐用。此外,该方法也将允许组织被储存在非液体(即,戊二醛)环境中。换言之,该方法尤其适于组织的干燥储存。
如上所述,膜可以至少部分交联或“固定”。交联胶原蛋白基质在移植前提供稳定性,以延迟退化。此外,固定方法通常通过阻碍供体组织的表面和内部的反应性分子而进行操作,从而使其基本上无抗原性并适于移植。固定生物假体组织通常包括使组织与交联剂——正常地为溶液——接触。用于生物假体组织诸如牛心包膜的示例性固定溶液包括戊二醛、甲醛、其它醛、EDC、聚乙二醇等。存在固定组织的其它方式,包括加热、照射等。固定步骤可以在膜以另外方式被制备后帮助保持心包膜处于特定的三维形式——如果采用的话。
应该理解,尽管交联组织导致比较容易处理工件,但变薄也可以在交联之前发生。同样地,大块组织片可以在固定前或后被首先变薄,或者小叶可以首先从大块膜切割下来,然后在固定前或后变薄
除了上述激光组织去除之外,用于剪切组织的各种机械装置诸如剃刀或刨削装置还可以用于去除一些组织。例如,具有刨削剃刀或刀片在其上平移的平压板(platen)的装置可以代替图7的线性激光器构造。也考虑用于产生相对组织/剃刀移动的其它物理构造,如例如利用车床样剃刀来使组织的外表面变光滑。这些装置的每一种均可以利用光学表面测量组件被自动控制或被计算机控制,以控制切口的深度。研磨组织去除(例如,砂磨或锉)也可以证明是合适的,尽管工具的砂砾应该相对细微。
用于使围心组织片变薄的特别吸引人的机械***的工具是皮刀。皮刀在外科手术中被用于从供体区域获得皮肤薄片,以用于皮肤移植,尤其用于3级烧伤或损伤。这些装置始于二十世纪三十年代,它们是悉知的外科手术工具。皮刀已被手动,气动或电动操作。用于移植的皮肤厚度的均匀性对于心脏瓣膜小叶需要的程度并不重要。
图15A和15B图解皮刀192,其从围心组织的普通切片削割粗糙层。不是从膜获得用作心脏瓣膜小叶的材料薄片,而是通过皮刀192去除的材料190被丢弃以利于剩下的围心膜194。为了达到可靠的片厚度,应用隔离物196,皮刀192在其上移动。从膜194削割的表面材料190是心包膜的纤维面。膜被放置在橡胶背板198上并被夹住。背板在膜的任一侧面具有隔离物196,其充当轨道以在皮刀192穿过膜194时支撑皮刀192。皮刀192也可以被控制,以限制切割成期望式样,以便可以产生具有不同高度的区域。有利地,利用机械装置产生均匀厚度并不在围心膜中产生热或化学作用。应该理解,如本文中所使用的,术语“皮刀”是指皮刀、振动切片机或任何其它功能类似于用于剪切组织的常规皮刀的机械切割或碾磨装置。
为了克服激光烧蚀所得的表面以另一方式反映预切割轮廓,可以应用对围心膜的第一压缩。足以使表面不规则变平并实现更均匀的厚度的压缩可以在激光烧蚀之前进行。以这种方式使表面不规则变平有助于确保激光烧蚀步骤导致更均匀地去除表面。相反地,不进行压缩,激光器操作可以遵循不规则表面的轮廓并在其表面上去除相同量的材料,产生不规则的终端产物。确保规则起始表面以产生光滑表面的方式被烧蚀的一种其它方法是利用指示激光器相对于固定的、均匀的表面水平去除材料的参考程来序控制激光碾磨仪器,这与遵循被碾磨的表面轮廓相反。
典型的围心组织以约78%的水处于平衡;而且,水可以从组织中挤出。为实现纤维表面变平和更均匀的厚度的过度压缩会使胶原蛋白聚合物骨架伸长并破坏,消除胶原蛋白“卷曲”结构并破坏组织固有的生物弹性。然而,不超出屈服点允许固有的生物弹性随着时间推移而回弹。在弹性压缩下部分或完全固定围心膜可以保持压缩期间激光烧蚀的有利作用。甚至用适度的较小的压缩,一些结合物(bonds)也会被破坏,产生一些自由醛、胺和酸性基团。通过以这种温和压缩状态固定围心膜,结合物被产生以保持这种状态。可选地,围心膜趋于不立即充分回弹。压缩后立即进行激光烧蚀可以减轻弹性再扩张。
可选地,可以应用首先调节表面不规则性然后压缩组织膜的顺序。例如,围心组织纤维面上的较大表面不规则可以利用激光器、碾磨机或皮刀变光滑,然后,利用本文所述的各种方法压缩组织。优选地,压缩组织同时至少部分固定组织,以帮助防止回弹。该顺序可以产生更多的机械均匀组织结构。
如上所述,温和压缩同时在压缩状态下固定围心膜可以使心包膜的纤维表面变光滑并使厚度更均匀。这种压缩和固定可以在使组织变薄之前或之后进行。在变薄之后,利用加帽和硼氢化物还原的稳定步骤可以减轻稍后的体内钙化。
在烧蚀或加工方法存在或不存在的情况下,甚至更大的压缩也是可能的。如果使用激光烧蚀或加工方法,组织在压缩后被固定的程度不怎么重要,因为使用物理修正而不是进一步压缩。如果最初被充分固定,则温和压缩、进一步的压缩趋于是完全弹性的,除非组织被损坏。以温和压缩进行部分固定然后以更大的压缩进行进一步固定的方法可用于获得较薄的最终膜,其具有明显的拉伸强度。
上面考虑初始温和压缩和固定步骤。该方法也可以在没有初始温和压缩而是初始至少部分固定组织的情况下进行。再次,可以使用戊二醛或其它固定剂或方法。这种首先固定的顺序稳定组织的生物力学并保护胶原蛋白的天然“卷曲”结构。灌注具有足够链长度的第二固定材料以允许跨过大的原纤维间结构域,这然后可以产生稳定的膜。可以使用具有足够链长度的二-或多胺材料。跨过大的原纤维间结构域的其它交联材料同时包括线性和分支的聚氮丙啶、聚乙烯醇和各种聚醚胺(Jeffamine)聚合物。可选地,组织可以用,例如亚氯酸钠氧化,以将新形成的醛转化成羧酸。这些然后可以利用EDC化学术与上述胺偶合。压缩可以发生在方法开始时,或发生在灌注第二固定材料后,或者两者均发生。激光烧蚀或加工可以在压缩步骤之后和/或在第一固定步骤之后被突然***,以使变得光滑或进一步变薄。在第一固定步骤之后,这些组织可以被加帽并还原,或者可选地,压缩和交联的组织片可以在形成过程之后通过加帽和硼氢化物还原被稳定。进一步处理可以包括干燥和灭菌。这样的处理描述在2009年6月25日公开的、Dove等的美国专利公开号2009/0164005中,其公开内容通过引用被明确地并入本文。
任一或所有压缩步骤中使用的设备图解在图16中。多孔陶瓷压力板200、202被用于给组织204提供刚性压缩。透析膜206、208被***到板200、202和组织204之间。陶瓷压力板200、202允许各种化学处理物(treatment)自由循环到组织204中。一次性透析膜206、208被用于防止陶瓷压力板200、202堵塞、以防止在生产期间的溶液流动。在组织204任一侧的、多孔陶瓷压力板200、202之间的隔离物210限制压缩。
本文描述的变薄和调节方法的另一应用是在围心片(patch)领域中,所述围心片由牛或马心包膜制成。围心片产品可以用作组织修复的结构材料,如主动脉导管、心包膜、血管等,其在患有先天性心血管疾病的儿科患者中非常普遍。一种这样的商业牛围心片可以从Edwards Lifesciences获得,其尺寸为4×6英寸(10×15cm),尽管马片可以更小(3×4英寸)。围心片产品通常用与心脏瓣膜小叶类似的方法处理(对于马片可以稍微不同)。有一个问题,即围心片对于某些这种应用可能太厚,所以使得片均匀地更薄会明显提供其适应性。同样地,在片之间以及在任何给定片内的不同位置中常常存在实质上厚度的变化。最终产品的期望的均匀厚度范围可以为150到500微米,这取决于片产品的尺寸。上述的选择性变薄也可以有利于片,其中一个边缘或整个外周被更厚地形成以帮助保持锚定缝合。
因此,公开了制备用于心植入的围心材料的改进方法。虽然本发明的实施方式和应用已经被显示和描述,但对于本领域技术人员来说显而易见的是,在不背离本文的发明原则的情况下,许多更多的修饰是可能的,并且,应该理解,已被使用的用语是描述性而不是限制性的用语。因此,可以在所附权利要求书的范围内进行变化而不背离本发明的真实范围。
Claims (20)
1.制备生物假体组织膜材料的方法,包括:
选择具有纤维面和光滑面的组织膜;和
从所述选择的膜的所述纤维面去除材料,以减小所选择区域但不是所有区域中的膜厚度并使所述纤维面变光滑。
2.权利要求1所述的方法,其中所述组织膜是牛围心膜。
3.权利要求1所述的方法,其中所述去除步骤通过用机械装置剪切来完成。
4.权利要求1所述的方法,其中所述去除步骤通过用激光器烧蚀来完成。
5.权利要求1所述的方法,还包括
通过压缩所述选择的组织膜和在压缩下同时交联所述膜材料来调节所述选择的膜。
6.权利要求1所述的方法,还包括通过加帽来处理厚度减小的所述膜。
7.权利要求1所述的方法,还包括通过硼氢化物还原来处理厚度减小的所述膜。
8.权利要求1所述的方法,还包括在所述去除步骤之前至少部分固定所述选择的膜。
9.制备生物假体组织膜材料的方法,包括:
选择具有纤维面和光滑面的组织膜;
通过压缩并在压缩下同时交联所述膜来调节所述选择的组织膜;和
从所述选择的组织膜的纤维面去除被调节的材料,以减小所选择区域但不是所有区域中的膜厚度并使所述纤维面光滑。
10.权利要求9所述的方法,其中所述组织膜是牛围心膜。
11.权利要求9所述的方法,还包括通过加帽来处理厚度减小的所述膜。
12.权利要求9所述的方法,还包括通过硼氢化物还原来处理厚度减小的所述膜。
13.权利要求9所述的方法,其中所述去除步骤通过用机械装置剪切来完成。
14.权利要求9所述的方法,其中所述去除步骤通过用激光烧蚀被调节的材料来完成。
15.心脏瓣膜,包括多个小叶,每个小叶均由片状组织制成,所述片状组织拥有具有均匀的第一厚度的第一区域和具有均匀的第二厚度的第二区域,所述第二厚度大于所述第一厚度。
16.权利要求15所述的心脏瓣膜,其中每个小叶具有与自由边缘相对的尖边缘,并且所述第二区域以总体均匀宽度的带沿所述尖边缘延伸。
17.权利要求15所述的心脏瓣膜,其中每个小叶具有与自由边缘相对的尖边缘,并且所述第二区域也以总体均匀宽度的带沿所述自由边缘延伸。
18.权利要求15所述的心脏瓣膜,其中每个小叶具有与自由边缘相对的尖边缘,并且所述第二区域以总体均匀宽度的带从所述自由边缘的中心到所述尖边缘径向延伸。
19.权利要求15所述的心脏瓣膜,其中第一和第二区域的厚度之间的过渡是逐渐的。
20.权利要求15所述的心脏瓣膜,还包括支撑框架,所述小叶的外周边缘以缝合线与其连接,并且其中所述第二区域沿所述小叶边缘延伸,所述缝合线经过所述小叶边缘。
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