CN104524654A - 体外辅助呼吸器 - Google Patents
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Abstract
体外辅助呼吸器被设计成具有环形圆柱状中空纤维膜(纤维束),其以迅速变化的速度进行旋转。流体(例如血液)被导入装置的中心并且径向通过纤维束。在旋转致动器(例如电动机或磁力联轴器)作用下,该纤维束以迅速变化的速度进行旋转。该纤维束的旋转给该流体提供了离心动能,使该装置具有抽送能力,并且可以产生泰勒旋涡以提高物质传递。该纤维束的旋转增加了所述流体与所述中空纤维之间的相对速度,并且提高了所述物质传递。可以改变纤维束的疏松度,以增强气体与血液之间的交换。可选地,旋转芯可以与静止的纤维束连用。
Description
本申请是国际申请日为2006年4月21日、于2007年12月4日进入国家阶段、名称为“体外辅助呼吸器”的中国专利申请200680019791.6的分案申请。
联邦政府资助的研究
相关申请的交叉参考
本申请要求2005年4月21日提交的美国临时申请序列号60/673,885和2005年6月8日提交的美国临时申请序列号60/688,809的优先权,在此通过引用纳入本文。
背景技术
本发明涉及改进的静脉-静脉体外循环充氧器,本文被称为“体外辅助呼吸器(paracorporeal respiratory assist lung)”或“PRAL装置”。PRAL装置被设计成使芯在静止的纤维束中旋转。
据报道,每年有350,000美国人死于肺癌,大部分是由于急性呼吸窘迫综合症(Acute Respiratory Destress Syndrome(ARDS))和慢性阻塞性肺疾病(Chronic Obstructive Pulmonary Disease(COPD))。最常见的治疗方法是机械通风,但是可进一步加重呼吸功能不全并且可能引起严重的副作用,例如气压性损伤(barotrauma)和容量损伤(volutrauma)。据进一步的报道,在手术期间,心-肺机器,其运用充氧器,在全世界每年被使用数十万次。这样的充氧器可被用于治疗COPD和ARDS。然而,用在心-肺机器内的充氧器的一个常见问题是氧气和二氧化碳低效的物质传递(气体交换)。
给血液充氧的膜式充氧器的使用在本领域是已知的。一种传统的膜式充氧器使用了中空纤维束,其被保留在圆柱形的壳内,其中氧是以与血液相同的方向通过所述中空纤维被泵入的。该中空纤维是由微孔膜组成,其对血液不具有渗透性而对气体具有渗透性。当静脉血液 流过该壳并与该中空纤维接触时,发生气体交换。根据扩散定律,氧扩散穿过中空纤维壁,并且使与这些中空纤维接触的静脉血富含氧。这种类型的膜式充氧器的缺点是在中空纤维周围形成血液边界层,这延缓了对没有直接与所述中空纤维接触的血液的充氧。
另一种已知类型的膜式充氧器包括移动充氧器的一个部分,以提供血液流动的增强混合。在这种类型膜式充氧器中,血液流通路径和氧气流通路径被定位在转子和定子之间,并且通过膜与隔片被分隔开来。当转子相对于定子转动时,血流的混合发生,这就导致打破了血液边界层。尽管这样的充氧器使得血液具有一定程度的混合,但是这种混合可能会引起红细胞的破坏。在这样的充氧器的一个实施方式中,含氧气的圆柱形半渗透性的膜在壳内被旋转,使得血液接触且流过该膜,并且氧气通过该旋转膜被转移到该血液中。这种膜式充氧器被报道的一个问题是半渗透膜对氧气和二氧化碳差的渗透性。
还有另一种已知的膜式充氧器包括基本上纵向延伸的复数个中空纤维膜,第一惰性纤维在它们之间间隔开、并且也是基本上纵向延伸。第二惰性纤维一般横向地向所述中空纤维延伸并且一般延伸至其附近,所以含氧气的气体可以穿过所述中空纤维,并且血液可以流过其外部以透过该膜进行气体交换。第二惰性纤维可以形成纬线,并且第一惰性纤维在每两个中空纤维之间被间隔地放上一根,所以该经线是由以摆动方式穿过纬线的中空纤维和第一惰性纤维的交替纤维组成的。该惰性纤维被公开为生物相容性的单丝聚合物,其提供了中空纤维的间隔,甚至产生了血膜。然而,这样的充氧器没有被设计用于体外,其具有相对低的血液流速。
因此,具有增强的气体交换特性的体外充氧器是需要的并且迄今为止是不可得到的,气体交换特性的增强是由于可变速的旋转芯和/或该纤维束疏松度的提高,其具有高的气体交换效率,并且对血液成分的损伤最小。
发明内容
本发明涉及改进的静脉-静脉体外循环充氧器,本文被称为“体外辅助呼吸器(paracorporeal respiratory assist lung)”。该静脉-静脉人工肺 可代替机械通风疗法而被用于慢性阻塞性肺疾病(Chronic Obstructive Pulmonary Disease(COPD))病人,他们的血液中含有高水平的二氧化碳分压(pCO2)。本发明的体外辅助呼吸器提供了积极的混合,使得在血液恒速通过该装置下提高了气体交换。
得知该纤维束的旋转增强了人工肺的气体交换效率,例如二氧化碳(CO2)的传递效率增加了200%(两百个百分点)。已经证实,血液流速在每分钟0.5至1.0升(l/min)的范围内时,CO2的去除可达到每分钟100-120毫升(ml/min)。该旋转纤维束提供血液流过压头低于30毫米汞柱(mmHg)的装置的自抽作用。
然而,已经发现,在体外装置中旋转中芯也提供流过该装置的血液自泵。本发明的体外辅助呼吸器的实施例包括外壳,其具有流体入口、流体出口、气体入口和气体出口。所述PRAL装置包括多个管状气体渗透性纤维膜,其被配置为形成纤维束,所述纤维束被置于所述外壳内,并被连接到所述气体入口和所述气体出口,且与所述气体入口和所述气体出口流体交换,其中第一间隙被配置在所述外壳和所述纤维束之间。所述装置被配置为具有位于所述纤维束内的芯,其中第二间隙被配置为在所述芯和所述纤维束之间。所述装置包括旋转芯的装置,其中所述外壳、纤维束和芯被配置为使得进入所述流体入口的流体穿过所述纤维束并进入所述流体出口。所述PRAL装置可以进一步被配置为在所述第二间隙内产生湍流并在所述第二间隙内产生多个泰勒旋涡。另外,所述纤维束可以被配置为具有疏松度,其允许均匀的流体流过所述纤维束。此外,所述PRAL装置可以被配置为使得所述第一间隙和所述第二间隙被配置为优化流过所述纤维束的流体。
根据本发明,对体外辅助呼吸器改进的另一方面是包括增加了该旋转纤维束的疏松度(porosity)。该增加的疏松度提供更多的流体流过该纤维束,因此增加了该器件整体的物质传递效率。该纤维束额外的疏松度是通过几种可能的途径产生的,包括但不限于,使用隔离物在纤维层之间产生空隙,在该纤维垫子中每隔一个纤维除去一根,以及使用更小直径的纤维。另外,支撑线也可从纤维织物中去除,并且体外辅助呼吸器可以被设计,以致集流管相对更近,以使该纤维束“蓬松(puff out)”。
本发明进一步的方面包括体外辅助呼吸器,其具有以下特征:
●带有经皮套管的体外静脉-静脉体系
●被***到血流的静脉循环中
●在血液到达肺之前,去除CO2并且供应O2
●在血流速度低于每分钟一升下,进行气体交换
●紧密有效的中空纤维组件从外部磨损
本发明所述的体外辅助呼吸器另外的特征包括:
●可变的旋转增强了气体交换
●该纤维束的疏松度可变
●对于维持呼吸来说血流在500-700mL/min
●小的双内腔套管(14-16French(法兰西标度))
●该纤维束的活性表面积小于0.50平方米(m2)
●血流速度在每分钟0.5至1.0升时,CO2的去除为100-120ml/min
●CO2的去除不依赖于天然肺的功能容量
本发明还包括根据以下实施例的体外辅助呼吸器。
条款1.体外辅助呼吸器,其包括:
外壳,其含有流体入口、流体出口、气体入口和气体出口;
多个管式气体渗透性纤维膜,其被配置以形成纤维束,所述纤维束被置于所述外壳内,并且连接到所述气体入口和所述气体出口且与它们发生流体交换,其中第一间隙设计在所述外壳和所述纤维束之间;
芯,其被置于所述纤维束内,其中第二间隙被设计在所述芯和所述纤维束之间;和
使所述芯旋转的工具,其中所述外壳、纤维束和芯被设计,以使进入所述流体入口的流体穿过所述纤维束、并流入所述流体出口。
条款2.根据条款1所述的体外辅助呼吸器,其中所述使该芯旋转的工具在所述第二间隙内产生湍流。
条款3.根据条款1所述的体外辅助呼吸器,其中所述使该纤维束旋转的工具在所述第二间隙内产生多个泰勒旋涡。
条款4.根据条款1所述的体外辅助呼吸器,其中所述纤维束被设计有疏松度,允许均匀的流体流入所述纤维束。
条款5.根据条款1所述的体外辅助呼吸器,其中所述第一间隙和 第二间隙被设计,使得流体通过所述纤维束得到优化。
条款6.根据条款1所述的体外辅助呼吸器,其进一步包括用于改变所述纤维束的旋转速度的工具。
条款7.根据条款1所述的体外辅助呼吸器,其进一步包括使所述纤维束的旋转方向摆动的工具。
条款8.根据条款1所述的体外辅助呼吸器,其进一步包括双腔套管,所述双腔套管被设计以***到病人的静脉循环中,以向所述外壳的流体入口提供血流并且从所述外壳的流体出口接受血流。
条款9.根据条款1所述的体外辅助呼吸器,其中所述芯包括多个管式气体渗透性纤维膜。
条款10.根据条款1所述的体外辅助呼吸器,其进一步包括叶轮,以与流体入口进行流体交换。
条款11.根据条款1所述的体外辅助呼吸器,其中使所述芯旋转的工具包括磁力联轴器。
条款12.体外辅助呼吸器,其包括:
外壳,其含有血液入口、血液出口、气体入口、气体出口以及与所述血液入口进行流体交换的叶轮;
多个管式气体渗透性纤维膜,其被配置以形成纤维束,所述纤维束被置于所述外壳内,并且连接到所述气体入口和所述气体出口且与它们发生流体交换,其中第一间隙设计在所述外壳和所述纤维束之间;
芯,其被置于所述纤维束内,其中第二间隙被设计在所述芯和所述纤维束之间;
使所述芯旋转的工具,其中所述外壳、纤维束和芯被设计,以使进入所述流体入口的流体穿过所述纤维束并流入所述流体出口,并且其中所述使所述芯旋转的工具包括磁力联轴器;和
双腔套管,其被设计以***到病人的静脉循环中,以向所述外壳的血液入口提供血流并且从所述外壳的血液出口接受血流。
从下面的详细描述和附图中,本发明的其它特征和优点将变得明显,其举例阐明了本发明的特征。
附图说明
图1描述了本发明所述的体外辅助呼吸器的在体布置。
图2A-2C描述本发明所述的体外辅助呼吸器一个实施方式的几个视图。
图3A-3D描述本发明所述的体外辅助呼吸器可选实施方式的几个视图。
图4A和4B是本发明所述的体外辅助呼吸器的示意图,其显示了旋转束。
图5A-5P描述本发明所述的体外辅助呼吸器可选实施方式的几个视图。
图6描述本发明所述的体外辅助呼吸器的可选实施方式。
图7描述本发明所述的体外辅助呼吸器的可选实施方式。
图8A-8D描述本发明所述的体外辅助呼吸器可选实施方式的几个视图。
图9显示本发明所述的体外辅助呼吸器可选实施方式的的示意图,其具有磁力驱动机构。
图10A和10B描述本发明所述的体外辅助呼吸器的可选实施方式。
图11是图10所示体外辅助呼吸器的横截面图。
图12A和12B是图11所示体外辅助呼吸器的示意图。
图13显示本发明所述的体外辅助呼吸器可选实施方式的示意图。
图14是本发明所述体系的方框图。
图15显示本发明所述的体外辅助呼吸器可选实施方式的横截面图,其具有磁力驱动机构。
图16A和16B是根据本发明所述的笼式机构,适合于使用所述纤维束。
图17A、17B显示具有间隔的纤维垫示意图,其用于本发明所述的体外辅助呼吸器。
图18是根据本发明的体系所述的一个方框图。
图19是根据本发明的体系所述的一个方框图。
图20是本发明所述的体外辅助呼吸器的一个实施方式所达到的气体交换速率的图示。
图21是本发明所述的体外辅助呼吸器的一个实施方式所达到的气体交换速率的图示。
图22是本发明所述的体外辅助呼吸器的一个实施方式所达到的血流(抽吸能力)的图示。
图23是基于纤维束疏松度的模型预测图示。
图24和25是本发明所述的体外辅助呼吸器中该纤维束可变的疏 松度所达到的二氧化碳去除和血流(抽送能力)的图示。
图26是通过该纤维束的血流模型(FEMLAB)的图示。
具体实施方式
本发明涉及改进的静脉-静脉体外循环充氧器,本文被称为“体外辅助呼吸器(paracorporeal respiratory assist lung)”或“PRAL装置”。本发明所述的体外辅助呼吸器包括旋转圆柱芯,其通过降低血液流过该纤维所引起的边界层现象增加了该装置的气体交换效率。美国专利号5,830,370(Maloney等)、5,900,142(Maloney等)、6,106,776(Borovetz等)、6,217,826(Reeder等)、6,348,175(Borovetz等)、6,723,284(Reeder等)和美国出版号2004/0219,061(Reeder等)通过引用被全部引入本文。
已经研发出本发明所述的体外辅助呼吸器,其适用于正遭受急性肺衰竭和慢性肺疾病急性恶化的病人。该设计概念建立在以前的充氧器的临床成功之上,所述充氧器从病人的股动脉中取出血液,通过商业可利用的膜式充氧器去除二氧化碳(CO2)以及利用天然的动脉-静脉压力梯度将该血液转入该股静脉中。
血液充氧器内气体交换的主要局限性是流体沿着该纤维膜的表面流动所产生的扩散边界层。该流体相对于该纤维的有效运动可有助于减少该边界层。因此,本发明所述的体外辅助呼吸器,在比旋转盘式充氧器低的旋转速度下,可达到给定水平的气体交换。
本发明所述的体外辅助呼吸器包括:外壳,其中安装有纤维环;与轴相连的电动机,其使纤维环旋转;以及封口和轴承,其将流体路径和气体路径分离。该流体(血液/水)流过所述旋转芯内的叶片。随着该流体路经的旋转,流过这些纤维的流体速度和气体交换可以进行调节。随着该装置的纤维环被设计成与旋转中心具有固定的距离,通过均匀使用所有的纤维,实现了流过这些纤维的速度更一致,而不像盘式充氧器,其沿它们的表面产生不同的速度。
与目前的旋转技术相比,本发明所述的体外辅助呼吸器具有截然不同的优点:
―旋转可以是稳定/不稳定的(时间变化增加了物质传递并且抽吸处于中等稳定值);
―环可以被制备成具有一系列疏松度(更高的疏松度引起更高的气体交换,而对泵送没有显著影响);
―该环可以是薄的束,其使得对环绕该束的静止壁具有更大的剪切渗透;
―已经研发出各种技术以改变该纤维束的疏松度;
―抽吸允许静脉-静脉经皮肤的操作。
如图1所示,体外辅助呼吸器(PRAL装置)被配置有电动机驱动28,其放置于病人25的身体外面。该PRAL装置包括血流导管21,其可***到该病人的股静脉27中。可选地,该PRAL血液导管可以通过该病人的颈静脉29被***。该PRAL血液导管21的近端45可以通过病人腿上的切口23或经皮肤的入口被***,以放入到股静脉里。该导管通过该病人的脉管***引入到接近病人心脏的位置,以致该远端45靠近心脏,举例来说在腔静脉里或靠近腔静脉。该PRAL血液导管可以被设计具有双腔,其一边47为血液入口,第二边46为血液出口。将导管远端开槽可能是有利的,这样使得血液出口端46延伸出血液入口开口47的末端之外。
氧气流过该中空纤维,并且流体(例如,水或血液)可通过内部扩散器被引入该纤维束。密封和轴承将气体和流体路径分开,并且允许该纤维束在外部电动机的作用下被旋转。无电刷直流伺服电动机可以控制该中空纤维膜束的运动。体外辅助呼吸器的使用者可以用与控制器相连的计算机设定振荡的频率和振幅。该控制器发出执行输入运动的驱动信号,同时从电动机中接受反馈并且对速度作出调整。
增加的疏松度提供更多流体流过该纤维束,因此增加了该装置整体的物质传递效率。该纤维束额外的疏松度是通过几种可能的途径产生的,包括但不限于,使用取间隔的构件在纤维层之间产生空隙,在该垫中每隔一个纤维除去一根,以及使用更小直径的纤维。另外,支撑线也可从纤维织物中去除,并且体外辅助呼吸器可以被设计,所以集合管相对更近以使该纤维束“蓬松(puff out)”。
在相对低的静脉-静脉血液流速下(500-1000ml/min),本发明所述的体外辅助呼吸器实现了显著的CO2去除(100-120ml/min),而不需要单独的泵。图23-25表明:纤维束疏松度,对体外辅助呼吸器的气体 交换和抽吸性能的影响。制造两种原型的体外辅助呼吸装置,纤维束疏松度为0.43和0.83;但是在其他方面类似,膜表面积分别为0.42平方米(m2)和0.50m2。该装置用水作为测试流体,当在3l/min时,测试流动环路中的气体交换。具有较高束疏松度(higher bundle porosity)的体外辅助呼吸器,在1500rpm下,实现的CO2去除为173ml/min/m2;与之相比,具有较低束疏松度的原型为190ml/min/m2。在牛血液的情况下,具有较高的束疏松度的体外辅助呼吸器,在1500rpm下,在血液流速仅为750ml/min时,达到182ml/min/m2的CO2去除速度。在水中进行一个单独的泵测试,以水作为测试流体,在0.75l/min的流速下,在1500RPM下,具有较高疏松度(higher porosity)的纤维束产生67mmHg;与之相比,具有较低疏松度的纤维束仅为52mmHg。具有增加的疏松度的纤维束是在气体交换目标的十个百分点内(10%),而且抽吸能力与通过小于20Fr的经皮肤套管产生750ml/min的血流相一致。
现在谈到图10A和10B,该PRAL装置的可选实施方式1000可进一步设计有旋转芯机构。该PRAL装置包括外壳体1020,其含有下部1022和上部1024。电动机驱动机构1025被设计在所述下部的里边。气体入口1040也被设计在该壳的下部上。静止的纤维束1050被置于该壳的主体1020内,其被设计以接受旋转塞绳1060(rotating cord1060)。各种密封和紧固器件1062、1064、1066和1068被显示在图10B中。
现在谈到图11,该PARL装置1100也被设计有旋转芯机构和静止纤维束。该装置被设计有外壳1120,其含有下部1122和上部1124,它们被紧固在一起,形成一个部件。该壳的下部包括电动机驱动机构1125,其可操作地被紧固到旋转芯1160上。血液通过血液入口端1130进入,从该部件的上部流到叶片1170上。血液从叶片流经内部间隙1192,穿过静止的纤维束1150,流到外部重复循环间隙1190并流过血液出口端(未显示)。气体通过入口端1140进入纤维束,并且在穿过纤维束流到设计在该PRAL装置上部的出口1145之后排出。该气体入口位于该PRAL壳1120的下部1122上。紧固到该壳的下部之上的稳定部件,包括轴承和密封,被设计以接受旋转驱动机构1125。其它各 种密封和轴承可以被使用,以将气流和血流分开、并且以防止这些流体泄漏。
现在谈到图12A和12B,显示的是关于图10和11所示的PRAL装置的部分剖开的俯视图和仰视图。如图12A所示,血流被导入叶片1170,其具有多个弓形的导流臂1172。血流继续从叶片流到内部间隙1192,内部间隙1192被置于旋转芯1160和静止纤维束1150之间。该血流穿过静止纤维束流到外部再循环间隙1192,并且从血液出口端1135流出。
在该PRAL装置的这种实施方式中,在环状纤维束2650(静止的)和外壳2700之间的外部间隙2690的尺寸,存在优选的大小范围。间隙大小应当正好足够大,以满足血液穿过外部间隙2690直到所设计的装置出口所产生的压降,如此以致不会阻止穿过该环状纤维束2650的径向血流建立起来相对均匀的分布。该间隙大小将视该纤维束的渗透性(疏松度)和厚度而定。
现在谈到图14,显示的是方框图,描述了PRAL装置1400,其配置具有用户界面1420的电子计算机***1410内的控制器,其带有电池组和充电器1430以及交流-直流电源1435。该***可进一步配置有以太网(Ethernet)和其它的外部通讯器件:1425,1427。血液通过入口管线1430进入该PRAL装置,并且通过出口端1435流出进入病人,其具有安全机构,例如流动和气泡检测器。空气入口1440被提供,并且可以连接到壁式氧气供应单元1442或氧气罐1444,以向该装置补充气体。加湿器和/或加热器1475可以被***到空气入口和该PRAL装置1400之间。扫气排气管线1445可以包括:脱水器1446,以及二氧化碳和氧气分析仪1448。其它的阀和通风机构可被包括进来,作为***件。举例来说,真空泵1490可以被***到PRAL装置1400与出口端1495之间,以充当安全机构,如此以致:该***具有负压,使得不会在病人的脉管***中产生气泡。
尽管本发明的特定形式已经被阐述,但是对于本领域技术人员来说,不背离本发明的发明概念可以进行各种改变,也是明显的。论及本发明与膜电极组件和燃料电池的一起使用,仅是举例作为参考,并且所述实施方式在各个方面将仅仅被认为是示例性的、并且不具有限 定性。本发明可以结合有其它特定的形式而具体化,而没有背离它的精神或者实质性特点。因此,除了所附权利要求之外,没有意欲限定本发明。
Claims (6)
1.一种体外辅助呼吸器,其包括:
外壳,其具有上部(1124)和下部(1122),所述外壳(1120)包括位于所述外壳的上部内的血液入口端(1130),位于所述外壳的下部内的血液出口端(1135),气体入口(1140)和气体出口(1145);
多个管式气体渗透性纤维膜,其被配置以形成静止的纤维束(1150),所述纤维束具有长度并被置于所述外壳内,并且被连接到所述气体入口和所述气体出口、且与所述气体入口和所述气体出口流体交换,使得外部重复循环间隙(1190)设计在所述外壳和所述纤维束之间;
旋转圆柱芯(1160)同中心地置于所述纤维束内,所述芯的外部圆柱表面具有的长度使得内部间隙(1192)被配置在所述芯的外部圆柱表面的长度和所述纤维束发生气体交换的长度之间;
流体分配叶轮(1170)位于所述旋转芯内,且与所述血液入口端流体交换,所述流体分配叶轮包含多个导流臂1172,每个导流臂在所述外部圆柱表面与所述内部间隙流体交换时结束;和
旋转所述芯的工具,
其中所述外壳、静止的纤维束和旋转圆柱芯被设计产生湍流,以使以低流速行进进入所述血液入口端的流体行进到所述叶轮,并且所述叶轮将所述流体泵送到所述内部间隙中,其中所述芯的旋转、旋转速度以及所述芯的半径和所述静止的纤维束被设计为产生所述内部间隙内的湍流并最大化泰勒旋涡,引起所述流体基本上沿着所述静止的纤维束的整个长度循环通过所述管式气体渗透性纤维膜进入所述外部重复循环间隙中,所述外部重复循环间隙具有被配置为与所述静止的纤维束、所述内部间隙的厚度以及所述旋转芯的外部圆柱表面匹配的厚度,从而沿着所述静止的纤维束的长度并穿过所述静止的纤维束来回引导所述流体,以在所述流体最终置于所述血液出口端之前,使气体交换最大化。
2.根据权利要求1所述的体外辅助呼吸器,其中所述静止的纤维束被设计有疏松度,其允许均匀的流体流过所述静止的纤维束。
3.根据权利要求1所述的体外辅助呼吸器,其进一步包括用于改变所述旋转圆柱芯的旋转速率的工具。
4.根据权利要求1所述的体外辅助呼吸器,其进一步包括使所述旋转圆柱芯的旋转方向振荡的工具。
5.根据权利要求1所述的体外辅助呼吸器,其进一步包括双腔套管,所述双腔套管被设计以***到病人的静脉循环中,以向所述外壳的血液入口端提供血流、并且从所述外壳的血液出口端接受血流。
6.根据权利要求1所述的体外辅助呼吸器,其中使所述旋转圆柱芯旋转的工具包括磁力联轴器。
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CN107708765A (zh) * | 2015-06-23 | 2018-02-16 | 联邦高等教育***匹兹堡大学 | 体外移动式肺辅助技术装置 |
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US20070020142A1 (en) | 2007-01-25 |
JP4710069B2 (ja) | 2011-06-29 |
EP1888211A1 (en) | 2008-02-20 |
EP2295133A1 (en) | 2011-03-16 |
CA2605259A1 (en) | 2006-11-09 |
AU2006242663A1 (en) | 2006-11-09 |
WO2006118817A1 (en) | 2006-11-09 |
AU2006242663B2 (en) | 2012-01-19 |
CA2605259C (en) | 2015-07-14 |
US20140065016A1 (en) | 2014-03-06 |
US7927544B2 (en) | 2011-04-19 |
EP1888211B1 (en) | 2014-01-08 |
US8647569B1 (en) | 2014-02-11 |
ES2475979T3 (es) | 2014-07-11 |
EP2295133B8 (en) | 2014-07-30 |
CN103381277A (zh) | 2013-11-06 |
ES2442965T3 (es) | 2014-02-14 |
EP2295133B1 (en) | 2014-06-18 |
CN103381277B (zh) | 2015-11-25 |
JP2008536647A (ja) | 2008-09-11 |
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