CN1535164A - 外源物质去细胞化的方法用于制备生物假体 - Google Patents

外源物质去细胞化的方法用于制备生物假体 Download PDF

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CN1535164A
CN1535164A CNA018199518A CN01819951A CN1535164A CN 1535164 A CN1535164 A CN 1535164A CN A018199518 A CNA018199518 A CN A018199518A CN 01819951 A CN01819951 A CN 01819951A CN 1535164 A CN1535164 A CN 1535164A
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W·科纳茨
P·德曼
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Abstract

本发明涉及将同种异体和异种的外源物质去细胞化的方法，用于随后制备由假体受体的自体细胞包覆的生物假体，在该方法中将外源物质首先在胆汁酸中，然后在醇中进行化学性处理，并分别在之间和之后的用洗涤步骤处理，并且至少在最后的洗涤步骤中还与作用于组织和细胞上的由流动处理介质产生的力的机械性影响相结合。经处理后，组织完全脱离外源细胞物质和病毒，并表现为极好的用于包覆生物假体受体的细胞的起始产物。

Description

外源物质去细胞化的方法用于制备生物假体
本发明涉及借助生物洗涤剂将同种异体和异种的外源物质去细胞化的方法，用于制备由假体受体的自体细胞包覆的生物假体。
用于制备由受体的自体细胞包覆同种异体和异种的外源物质的生物假体，需要提供一种从外源细胞分离出来的“无细胞”结构，以避免免疫反应和确保新生的自体细胞的生长和繁殖。但是，已知的去细胞化方法和生物洗涤剂的应用不可能从组织基质中解离全部的细胞物质，以致不能排除目前未知病毒的作用，例如在猪组织中含有的病毒。
本发明的任务因此在于，提供将外源物质去细胞化的方法，以保证完全地但是温和地将细胞从外源组织中清除，随后用自体细胞包覆该外源物质。
根据本发明，此任务是由含有权利要求1的特征的方法解决的。
换言之，本发明的基本思路是，从拟用自体细胞重新包覆的同种异体和异种的起始产物中脱去外源细胞，结合胆汁酸处理，醇处理和之间之后进行的洗涤步骤以及在组织基质和要去除的细胞上通过流动介质至少在最后的洗涤步骤中施加机械性影响。
优选使用胆汁酸以去氧胆酸的形式，逐步地-或者在机械性影响下加速地-用酸包覆细胞，以致在胶原和弹性蛋白构成的基质(在下文中称为“胶原基质”)与细胞之间制造隔离层，并从基质中去除细胞。同时，去氧胆酸有溶细胞效应。在随后的洗涤步骤中解离的细胞被冲走，去氧胆酸也被洗涤。在随后的醇处理中，优选乙醇或丙醇，将视情况残存的易溶于醇的去氧胆酸彻底去除。在基质中残留的细胞被视情况残存的去氧胆酸和醇解离，而醇此外有杀细胞作用和抗病毒效应。接下来最后的洗涤步骤优选脉动流，其力量一方面作用于相关的器官部件的壁上，并使基质膨胀，另一方面直接机械性影响于残留细胞，并将其从膨胀的基质中除去。
也可以在本方法其它或所有步骤中，通过相关介质优选脉动的液流与机械性影响相结合。因此上述脉动去氧胆酸流由于介质的移动和膨胀，在细胞和胶原基质之间较快地形成隔离层，并同时通过作用于细胞上的力使细胞更容易解离。
根据从属权利要求和随后的具体实施例的说明揭示了本发明其它特征和有利的设计。
使用提出的方法成功地提供了无细胞的，即无任何细胞物质并因而无病毒的器官部件作为起始产物，例如心脏瓣膜或血管，经各受体的自体细胞包覆用于制备生物假体。
用于处理在流动介质中由外源物质构成的器官部件的装置包括，一个装有相关器官部件的去细胞化室，一个产生介质液流的泵，其先后结合在一个环形管道中。环形管道中有分别用于输入或排出各处理介质的输入阀和排出阀。去细胞化室可以从环形管道中拆卸，以便可以移动去细胞化室和借此移动介质中的器官部件。在容器中，待处理的器官部件通过形如器官部件的适配器在事先加有张力的情形下纵向固定。
借助图示进一步说明本发明的具体实施例。其展示
图1    循环流路中用于心脏瓣膜去细胞化的装置；
图2    连入循环流路的装心脏瓣膜的去细胞化室的截面图；
图3a   根据本发明的方法经去细胞化的主动脉瓣膜壁的显微截面图；
图3b   放大的图3a的主动脉瓣膜壁的中间组织切片。
在此描述的具体实施例是，在屠宰场取出猪的主动脉瓣，去除脂肪，切块测尺寸以及检测病菌(真菌、需氧菌、厌氧菌、支原体)的存在性。中间存储应在最高温度4℃，不超过7天。
将如此准备的心脏瓣膜放入1-2％的去氧胆酸溶液(或者具有类似作用的胆汁酸)中，在其中以37℃存放24小时。去氧胆酸能与脂肪酸形成主宾络合物形式的加合物，以便去氧胆酸可以逐渐全方位贴敷于细胞上，并由此解离细胞与组织基质的粘连。同时，去氧胆酸有杀细胞作用。
随后，经如此处理的心脏瓣膜用系列稀释的磷酸盐缓冲溶液(PBS)以递减的浓度，并在同时心脏瓣膜的移动中，从组织基质中洗去经去氧胆酸处理过的细胞。
在接下来的第三步骤中，心脏瓣膜在室温下用40％的醇处理10分钟，以达到抗病毒效应，并进一步灭绝胶原骨架中残留的细胞。由于醇是一种很好的溶剂，同时还可以洗涤掉可能残留的酸并进一步解离细胞。
用另一套系列稀释的磷酸盐缓冲溶液(PBS)再次洗涤心脏瓣膜，并随即在脉动PBS-介质流中机械处理。通过脉动介质流使在去细胞化室中沿纵向顺流并事先加有张力而固定的心脏瓣膜有节奏地舒张，并同时经受流体的机械冲击。这个步骤也机械分离胶原骨架中的残存细胞，最终去除所有的细胞物质后得到一个无细胞的结构，而且因此不含病毒。经如此处理的无细胞也无所使用的去细胞化介质的心脏瓣膜组织基质-如图2所示-非常适于生物假体受体的自体内皮细胞的重新包覆。这种生物假体移植到人体内没有任何免疫反应或病毒感染的风险。
鉴于拟用于制备生物假体的外源物质的类型和来源，鉴于操作参数，本发明不局限于如上例举说明的处理方案，只要实施基本的实验步骤，即在形成加合物的胆汁酸中的处理，在醇中处理和与用于在组织上产生温和的机械性影响的优选脉动流相结合的之间之后的洗涤，该脉动流流经相关的器官部件。因此也可以不是在最后的步骤中，而是附加地在其它或所有的处理阶段中用流动的介质进行。借此各介质的作用得到机械性支持，较好地全方位地作用于细胞，并且通过脉动流的力作用较易从舒张的胶原基质中解离去除细胞。
图1显示用于心脏瓣膜去细胞化的装置。其包括一个环形管道1，连接了用于容纳并处理心脏瓣膜3的去细胞化室2、膜式泵3和可直接在去细胞化室后开启的平衡室4。膜式泵3经由软管套头5连接到一个驱动设备上(未表示)。膜式泵3的两个连接环形管道1的结合头整合了排出阀6和输入阀7，其功能相应于心脏瓣膜的功能。如果待处理的心脏瓣膜已存在阀瓣，排出阀6可以省略。
装置的核心部分是去细胞化室2，用于借助附加的流动力作用将猪的主动脉瓣8去细胞化。去细胞化室2由如下构成，由Piacryl构造的透明空心柱9，配有置于开放端面中央并密闭固定由聚四氟乙烯构造的垫板10、11，其经由连接管12、13与环形管道1连接，分别具有突入空心柱9的带有放射状环绕排列的固定孔16、17的固定部分14、15，用于在端面边缘的张力下紧绷固定主动脉瓣8。垫板10、11的两个固定部分14、15的外围直径大约相应于主动脉瓣8的直径。在流向中后置的垫板11经连接桥18和第一个密封圈27可与空心柱9的内侧环桥20拉紧，并借助螺纹环21，其阴螺纹与垫板11的阳螺纹契合。垫板10具有套圈22，置于空心柱9的端面，并与其应用螺帽23的阴螺纹与空心柱9的阳螺纹的契合加固。使用第二个密封圈19用于液体防漏的加固。在去细胞化室后接的环形管道1的软管由可弯曲物质(硅树脂)制成，以便保证基于脉动泵作用的流动。
由于上述垫板10、11的构造和排列，可在空心柱9外面将相应的备用的主动脉瓣88缝制到相对而置的垫板10、11的固定部分14、15上。将主动脉瓣8以此形式插入空心柱9。经环形管道1中的输入阀和排出阀24、25或者连接管13、14，首先将去氧胆酸输入去细胞化室2和环形管道1，并随后启动膜式泵3，以使脉动的去氧胆酸流持续地流经或流过主动脉瓣8，并且由于在组织上的机械性影响起到完全解离和去除对于心脏瓣膜受体是异体的细胞的作用。在排出去氧胆酸后输入生理盐水或磷酸盐缓冲液并洗涤直至完全去除去氧胆酸和其它毒性成分。洗涤过程之后是主动脉瓣8在醇中的处理，然后是在磷酸盐缓冲液中的洗涤步骤。
在上述装置中，去细胞化方法的所有处理步骤都在各介质的脉动流下得以实现。其流动方向在此大约相应于生物假体植入状态下的自然流向。使用输入阀和排出阀24、25交换介质，在此也可以输入连续的新鲜洗涤溶液用于洗涤过程并将经使用的洗涤液排离。
也可以选择性地将一个或多个处理步骤拆离环形管道和膜式泵，无细胞化室可视情况驱动或手拧装卸，而不使液流通过，或者也可以如文端所述，在去细胞化室之外实施独立的处理步骤。
                      附图标记说明
1.环形管道
2.去细胞化室
3.血液泵/膜式泵
4.平衡室
5.软管(用于3)
6.排出阀
7.输入阀
8.动脉瓣
9.空心柱
10.第一垫板(在流向的上源)
11.第二垫板(在流向的下源)
12.连接管
13.连接管
14.固定部分
15.固定部分
16.固定孔
17.固定孔
18.11的连接桥
19.密封圈
20.9的环桥
21.螺纹环
22.10得套圈
23.有帽封口螺圈
24.输入和排出阀
25.输入和排出阀
26.膜式阀

Claims (15)

1.本方法借助生物洗涤剂将同种异体和异种的外源物质去细胞化，用于制备由假体受体的自体细胞包覆的生物假体，其特征在于，外源物质首先用胆汁酸处理，用于杀死细胞以及包裹细胞并分离其与组织基质的粘连，然后用醇处理进一步杀死细胞，这两个步骤后都有洗涤程序，其中至少最后的洗涤过程是在介质流中由流动力产生机械性影响施加于组织基质和细胞上进行的。
2.根据权利要求1的方法，其特征在于，介质流是脉动的。
3.根据权利要求1的方法，其特征在于，用于解离细胞的胆汁酸使用的是包裹细胞的去氧胆酸。
4.根据权利要求3的方法，其特征在于，使用1-2％的去氧胆酸。
5.根据权利要求1的方法，其特征在于，用于杀死细胞所用的醇浓度为30-60％。
6.根据权利要求5的方法，其特征在于，使用40％的醇。
7.根据权利要求1的方法，其特征在于，使用磷酸盐缓冲液作为洗涤介质。
8.根据权利要求7的方法，其特征在于，在非流动介质中的洗涤以逐步降低的洗涤介质浓度进行。
9.根据权利要求1-7的方法，其特征在于，在非流动介质中的去氧胆酸处理时间直至24小时，醇处理大约20分钟，洗涤约60分钟。
10.根据权利要求1-7的方法，其特征在于，外源物质在去氧胆酸和/或醇和/或在其间启动的洗涤循环的处理，是在接近于相关器官内自然流动条件的脉动介质流中进行的。
11.根据权利要求1和10方法，其特征在于，流动介质的速率可以变化。
12.根据权利要求1、10和11任意一项的方法，其特征在于，洗涤介质流连续或间断地被更换。
13.根据权利要求11的方法，其特征在于，洗涤剂液流的浓度逐步下降。
14.根据权利要求1、10-13任意一项的方法，其特征在于，待处理的外源物质在各介质流中沿流向在事先加有张力的状态下固定。
15.根据权利要求1和10-14，用于在介质流中处理外源物质的装置，其特征在于，环形管道(1)和用于产生脉动介质流而与其相连的泵(3)和在环形管道(1)中连入的可拆卸的去细胞化室(2)，其中待处理的同种异体或异种的外源物质(8)沿处理介质流的流向，借助于拆卸装入去细胞化室(2)，用连接管(12、13)连接于环形管道(1)的垫板(10、11)具有固定部分(14、15)，沿着流向在事先加有张力的情形下是可固定的。
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