CN1191873C - 冷－湿电极 - Google Patents
冷－湿电极 Download PDFInfo
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Abstract
本发明涉及例如在组织烧蚀过程期间施放射频(RF)能量的装置，包括一电极(1)，其远端(3)与组织穿刺装置相关，其近端(2)可连接至声频能量源；用无毒性(RF)导电液使电极远端(3)致湿的致湿装置；和至少使电极远端冷却的冷却装置。本发明进一步涉及(利用本发明装置)对射频能量施放装置进行冷却和致湿的过程和引导装置。
Description
技术领域
本发明涉及例如在组织消融等过程期间传递射频能量的新颖装置。
背景技术
本发明具体涉及优化射频消融术所用电极的新概念。以下将该概念命名为冷却的湿电极。
尽管外科切除术目前仍然被认为是治疗各类恶性肿瘤的首选方法，但是包括冷冻外科手术、局部注射酒精、微波、空隙激光治疗聚焦超声和射频(RF)组织消融术等各类微创替代疗法相继问世，以便用低创伤性手段消融肿瘤，使手术对于病人来说更安全，费用更低，治疗的适应症更广。
在上述各微创疗法中，射频消融术因其低创伤度，简便易行及高效价廉等优点近年来在实验及临床研究中最为令人注目。
在射频消融术中，射频电磁波由射频发生器产生，经事先插入靶组织中的针状电极的非绝缘尖端施放到靶组织中。以凝固性坏死为形式的组织破坏首先由电极周围组织中的阻抗热所造成，其次由周边被动热传导所造成。
阻抗热与中心电极与周围组织之间距离的平方成比例。因此，显著的阻抗热只发生在与电极直接接触的一圈组织中，此圈以外，由于热的被动传导的结果组织被进一步加热。然而，射频辐射很容易因电极-组织界面的电阻升高而被迫中止，后者是由组织脱水和碳化所致。由于这种非优化的射频能量的传递和消耗，使用已知的经典电极所造成的杀伤区尺寸小于2厘米，很显然这不足以达到肿瘤消融目的。与外科手术切除的原则类似，射频组织毁灭的理想范围应包括整个瘤体和作为安全带的一层瘤周正常组织以避免肿瘤消融不彻底。
为增大射频消融术的杀伤尺寸，已经作了许多已知技术革新。这些改进包括：
1)双极电极；
2)冷却电极和冷却-族化电极；
3)输入高渗盐水的“湿”电极；以及
4)可扩张电极。
根据微创伤性原理，单极电极优于多极电极。
如表1所示，尽管由这些改进电极所产生的杀伤范围已有所增大，但幅度仍然有限，通常直径仍小于4厘米。如果肿瘤大于2厘米，通过一次射频消融术而致肿瘤完全消融的可能性甚微。因此，仍有必要进一步优化这些相关技术及装置。
表1示出射频消融术所用各种已知电极设计产生的杀伤范围。
表1
电极类型 杀伤范围(厘米) 参考文献出处
经典电极 0.8-1.5 1
双极电极 5(为两极间距) 2
冷却电极 1.4-3.6 3
湿电极 4.5+0.75 4
可扩张电极 4.5 5，6
冷却-成族电极 4.7±0.1 7
引用参考文献：
1.Goldberg，S.N.等人(放射学学报
Academic Radiology 1995，2：399-404)
2.Goldberg，S.N.等人(放射学学报
Acad.Radiol.3/929，1996)
3.Lorentzen，T.A.(放射学学报
Acad.Radiol.3：556，1996)
4.Miao Y，等人(外科研究杂志
J.Surg.Res.71：19，1997)
5.Rossi，S.等人(
AJR.Am.J.Roentgenol.，170：1015-1022，1998)
6.Patterson EJ等人(
Ann Surg，227：559-565，1998)
7.Goldberg，S.N.等人(放射学
Radiology 209：371-379，1995)
发明内容
本发明的主要目的在于提供一种取得良好射频消融效果且提供较大杀伤区的新颖装置及其方法。具体而言杀伤区大于5厘米，较佳地大于6厘米。
根据本发明，这是通过将分别的已知特征加以组合而实现的，这种组合导致射频消融取得意想不到的更好效果。这是通过增大靶组织和电极组织界面的导电性以及降低电极远端的温度而实现的。
因此本发明提供一种结合“湿”电极以及冷却电极两者优点的施放射频能量的新颖装置。
本发明提供一种用于在组织消融过程期间传递射频能量的装置，包含：有一远端和一近端的一电极，所述远端为非绝缘的便于组织穿刺的结构，所述近端可与射频能量发生器相连；以及用无毒性射频导电液使电极的远端及其周围组织致湿的致湿装置，其中所述致湿装置包括限定致湿液流动路径的致湿管道。上述递射频能量的装置还包括与电极的非绝缘远端相关联的组织穿刺装置，该组织穿刺装置由内部可抽动轴向针芯形成；以及用于至少冷却电极远端的致冷装置，该致冷装置包括限定致冷液流动路径的冷却管道，其中所述致湿管道在电极的远端处是开口的，而所述冷却管道在电极的远端处是闭合的，所述冷却管道与致湿管道彼此互不相通。
本发明的主要目的是射频消融技术的微创伤性。微创伤性是通过精确穿刺和引导到待治疗组织而实现的。因此，本发明的另一个目的是改善射频电极和更广地包括射频消融中使用的所有仪器的穿刺和引导的效率。穿刺目前是通过电极的尖锐远端进行的。由于电极远端通常有孔，在穿刺时远端处的这些开口就可能会阻塞。然而，应当理解这并非意味着在使用冷-湿电极时一定要加用导引装置。所以，这种电极本身的锐利尖端也可作为穿刺进针的唯一方式。
作为克服这种冷-湿电极缺点的一种方案，本发明提出加用另外的导引器来辅助射频电极等器件的定位穿刺。根据本发明，该导引器基本上由中心为圆柱孔的开口空心管筒形成，其管筒适合在射频消融过程期间被引导器件的临时外壳和轴向位移的尺寸。这里所指器件可以是一根尖端锐利的穿刺针，也可以是射频消融步骤用的射频电极，还可以是一活检针或活检夹，用以获取消融前后组织标本作为明确诊断及疗效评判的依据。
本发明进一步涉及将本发明的传递射频能量的装置用于射频组织消融的过程、向传递射频能量的装置的开口远端及其周围组织提供致湿液和向冷却管道输注冷却液的步骤、以及使用多个温度计监控电极远端周围组织的温度。
应当指出，当被治疗肿瘤巨大时，可以使用若干个冷-湿电极，如2、3、4或更多电极，做成族状电极装置。
以下结合附图具体介绍本发明所涉及装置器件等的结构。
附图说明
图1至7是根据本发明的冷-湿电极的五个实施例的部分剖面截面图和透视图。
图8是使用本发明的冷-湿电极的射频消融系统的示意图。
图9是导引器(图A)、穿刺针(图B)和活检针(图C)的部分剖面透视图。
具体实施方式
图中用细印刷箭头指出循环冷却介质及致湿介质的流动方向，用粗箭头指出电极等器件的移动方向。冷却和致湿介质以液体或溶液为佳，在较佳实施例中，致湿液为盐水，较佳地为高渗(例如0.9％饱和的)盐水，冷却液较佳地为水或诸如0℃盐水的低温介质。
中空直针状电极1包括近端2、远端3和两端间的纵向部分针体4。这种电极1包含若干圆柱壁管5，形成三个同心圆管道，即一个内部管道6和两个外部同心管道7、8。外同心管道7、8在电极1的远端3相互连通形成一个封闭环路9。外同心管道7、8构成冷却液的环流路径，至少使电极1的远端部分3得到充分冷却。
内同心管道6在电极1的远端3处有开口10。该内同心管道6构成致湿液灌注路径并可暂时容纳轴状穿刺内针体(箭头55)及允许尖锐针芯54自前端伸出。在电极插入靶肿瘤11的过程中，尖锐针芯54将开口10封闭以避免阻塞开口10。在消融开始前，一根相同直径的附加活检针可被替换插入以获取瘤组织标本作病理检查和诊断。当电极1穿刺到位后，即可向上抽出尖锐针芯54使致湿液在管道6自由输入(图2)。当电极1插入靶器官12的肿瘤11后，射频能量即可通过电极1的非绝缘远端3输入，与此同时，该远端3被冷却液致冷，该远端3以及与之相接触的组织也同时被输入的致湿液所湿润。电极1的远端3以尖锐形状为佳，这样也同样具备穿刺功能。通过分别调节冷却液和致湿液的浓度、温度等可获得最佳杀伤范围。
电极1通常具有足够坚硬的结构以便能够准确穿刺进入肿瘤。
使用可抽动式轴状针芯54是为了防止致湿液输注管道6的阻塞。一旦电极1在肿瘤11中穿刺到位，针芯54即可抽出。当针芯54抽出后，即可开始射频能量传递，致湿液13与射频能量同时输入。
图3所示的实施例包括两个同心管道27和28，在电极远端30的闭合端29处形成闭合回路。这一闭合回路管道(27，28)限定冷却液的流动管道，如箭头31(向下)和箭头32(向上)所示，与图2的情形相似。在电极远端30，设置一开口的侧向管道33，作为致湿液(以高渗盐水为佳)的输注路径。在远端30处，管道33有多个致湿液13流出开口35，这样致湿液13可在远端30附近充分弥散。箭头36(向下)及箭头35(向外)指出致湿液的流向。
这些针状电极的直径在可能的情况下越小越好，最好小于3毫米。
图4所示电极37的实施例包括三个同心管道：外管道38，电极37的远端42处有多个孔41；两个同心管道27和28，在电极37的远端42处形成一闭合回路29，限定冷却液的循环路径。
图5的电极揭示另一较佳实施例，其中在电极的远端45设置一个输注致湿液13的独立侧向管道44，在电极的远端45形成螺旋行走部分46并开有多个侧孔48以便致湿液流出后更均匀的分布于电极周围的组织中。
在图6的实施例中，冷却液和致湿液流动路径合二为一的电极。这种电极49的优点是结构紧凑而简单。但是在其他实施例中两液分流电极的优点在于可以分别调节两液的流速，因为通常冷却液较致湿液的流量为大。
图7的实施例显示另一种改良的电极结构。它含有一轴向可抽动的针芯状测温装置44(箭头56)。后者包括多个温度传感器50，彼此间相隔一定距离。通常射频辐射能量由电极的远端向周围放射状传播。可伸缩测温器可提供有关射频消融方法效率的客观指标。
应用这些同心管道的优越性不仅在于提供充足而可控的流速，而且具有同时冷却致湿液的协同作用。
很显然，对于一个内行人来说，在不偏离本发明的范畴内，上述任何管道的形状和位置以及导引器，针芯装置和可伸缩温度传感器均可随意组合和变化。例如，中央温度传感器可横向安置以及针芯可以不同方式安置等。
图8描绘了应用本发明的冷-湿电极对靶组织11(如肝脏)进行射频消融术的流程示意图。冷却装置57通常有一冷却液的供应源58，与电极61的近端60处开口59相连，进一步包括一循环装置62，维持冷却液循环流动。
致湿装置通常有一输液泵63，一头与高渗致湿液64相接，另一头与电极61的近端60处开口59相接。电极61的近端60与射频发生器65相连。为了形成电流环路，在受治疗体11下面安置一块接地板66。使用本发明的冷-湿电极后，射频消融杀伤区的直径显著增大到6-10厘米。
实践中可按需使用电极远端设置温控装置来调节和控制射频消融的温度。显然，所有所示的电极内或电极上的管道和元件的结构显然均可调整，结合与互换。
导引装置100基本上由一开口的长管筒101构成，中央设置圆柱孔102，远端103呈钝形开口。圆柱孔102的直径调节为以被导引器100引导的器件恰好密合但又可轴向自如滑动通过为宜。穿刺时宜使用安装在导引装置100内的具备尖锐远端106的穿刺针104。这样导引装置100与穿刺针104作为一个整体一并插入被消融组织。穿刺针的适合大小及尖锐性可保证穿刺顺利进行。一旦穿刺到位，将穿刺针104自导引装置100的圆柱孔102中抽出，同时导引装置100保持原位不动。然后将一射频电极自圆柱孔102插入直至尖端露出导引装置100的远端。当射频消融术结束时将电极自导引装置100中抽出，而后者仍保持原位。
为提供射频消融效果的证据，可将一活检针109自导引装置100的同一圆柱孔中插入被消融组织。活检针109的远端含有一组织获取器108用于采集组织标本供进一步检验。
冷-湿电极的优点及特定特征由以下实验得到验证。
实验的材料和方法：
1.市售牛肝：4块均购于本地屠宰商的牛肝，每块重约10公斤。射频消融前，肝脏的温度从4℃恢复至室温。
2.猪肝：15块猪肝从猪上剖取后立即运至射频消融地点。
3.12只体重各约40至60公斤的家猪，购自本地农场。
所用设备包括射频发生器样品机(RFG-3B，Radionics，美国)。一台冷却泵：Watson-Marlow 31.3(Watson-Marlow Limt，英格兰)；致湿盐水输液泵(Ismatic，瑞士)；本发明的冷-湿电极以及一台1.5T核磁共振扫描仪(Siemens，Erlangen，德国)。
体外实验部分分组如下：
1.A组：传统射频模式(无冷却液及盐水输入)，共22个消融部位。
2.B组：仅仅冷却模式(射频功率50瓦，持续10分钟，冷却液流量40毫升/分)，共27个消融部位。
3.C组：仅仅致湿模式(射频功率50瓦，持续10分钟，5％盐水溶液输注流量1毫升/分)，共20个消融部位。
4.D组：持续冷却-致湿模式(射频功率50瓦，持续10分钟，5％盐水溶液输注流量1毫升/分，冷却流量40毫升/分)，共20个消融部位。
5.E组：断续盐水输注的冷却-致湿模式(射频功率50瓦，持续10分钟，全程循环冷却40毫升/分，但仅前5分钟输入5％盐水毫升/分)，共20个消融部位。
6.F组：断续冷却灌注的冷却-致湿模式(射频功率50瓦，持续10分钟，全程输入5％盐水毫升/分，但仅前5分钟循环冷却40毫升/分)，共13个消融部位。
7.G组：手动控制的射频冷却-致湿模式(射频功率70-90瓦，持续10-30分钟)，共10个消融部位。
猪的体内肝脏实验部分：
在全麻及气管插管人工呼吸条件下，12只猪接受剖腹术。暴露左右肝叶以便直视下作射频消融术。在剖腹手术中，应用新颖的“冷-湿”电极在这12只猪的肝上造成72个射频消融杀伤区，电极结合了内部冷却灌注和高渗盐水孔隙输注。对90W下的两种功率控制模式(A组：仅冷却；B组：仅致湿；C组：冷却-致湿)和手动控制模式(D组：仅冷却；E组：仅致湿；F组：冷却-致湿)比较上述各组的电阻、电流和杀伤区大小。射频消融后立即作T1及T2加权核磁共振扫描，测量杀伤区大小。
表2综合了在牛、猪肝上所作体外实验的结果。在50瓦下射频消融10分钟，冷却-致湿模式(D组)产生最大杀伤区尺寸，比其他模式的尺寸大。仅仅在D组中保证射频能量传递的连续性，以致于如果消融持续时间延长到30分钟而功率设定为70-90瓦，杀伤区尺寸达到接近于10厘米。由于其他组的阻抗在开始消融后或早或晚会突然增大，射频能量的传递几乎终止，杀伤区尺寸不会进一步增大。
表2
组别 杀伤 区盐水输入 冷却 电极温度 功率输出 电阻 电流 杀伤区大小
数
(毫升/分) (毫升/分)(摄氏) (瓦) (欧) (安) (厘米)
A 22 0 0 93.6±3.9 13.7±1.5 ＞900 0.13±0.1 0.86±0.3
B 24 0 40 31.5±4.8 16.1±3.3 81.2±16.5 0.85±0.1 2.43±0.5
C 18 1 0 99.6±0.9 45.2±10.8 99.8±113.4 0.94±0.4 3.80±0.5
D 20 1 40 35.9±6.8 49.5±2.4 55.8±50.7 1.14±0.2 4.90±0.6
E 20 1×5min 40 42.9±4.4 17.8±2.7 725.6±229.3 0.15±0.0 3.89±0.6
F 13 1 40×5min 99.5±0.9 38±12.2 412.5±138.3 0.46±0.4 4.27±0.5
注：
1.A组：传统射频模式(无冷却及盐水液体输入)
2.B组：仅冷却模式(射频功率50瓦，持续10分钟，冷却液流量40毫升/分)。
3.C组：仅致湿模式(射频功率50瓦，持续10分钟，5％盐水液流量1毫升/分)。
4.D组：根据本发明的持续冷却-致湿模式(射频功率50瓦，持续10分钟，5％盐水溶液输注流量1毫升/分，冷却流量40毫升/分)。
5.E组：根据本发明的断续盐水输注的冷却-致湿模式(射频功率50瓦，持续10分钟，全程循环冷却40毫升/分，但仅前5分钟输入5％盐水毫升/分)。
6.F组：根据本发明的断续冷却灌注的冷却-致湿模式(射频功率50瓦，持续10分钟，全程输入5％盐水毫升/分，但仅前5分钟循环冷却40毫升/分)。
体内实验中，所有实验用猪均能承受射频肝脏组织消融术，手术期间及手术后生命体征无明显异常。总体来说，体内实验所得杀伤区较体外实验所得的略小，可能与肝血流的冷却作用有关。体内实验结果如下：伴随较低电阻及较高输出功率，C组(4.8±0.6厘米)和F组(6.5±0.8厘米)的杀伤区尺寸显著大于(P＜0.01)A组(2.4±0.5厘米)、B组(3.1±1.0厘米)、D组(3.3±0.6厘米)及E组(3.5±0.9厘米)。
用冷却电极作射频消融时，电极的内部腔道较佳地灌以冷水或自来水。由于这种冷却作用，电极远端得以维持较低温度，避免周围组织碳化，从而有利于电极-组织界面的导电性，防止电阻上升。但是这种作用仅能维持一定限度，杀伤区将不再继续增大，这是因为：
1)电极本身的大小有一定限度，所以因阻抗热及传道热所造成的消融区域也有一定限度；
2)如果无外加的导电剂，组织本身的导电性是有限的；
3)汽化及组织脱水总会在电极-组织界面处发生，进而造成电阻上升。
致湿电极和冷却电极的技术分别都是已知的，最终都存在一些弊端。
用致湿电极作射频消融时，作为致湿液的一个例子具有高导电性的盐水预先及在施放射频能量的同时经电极不断输入靶组织中。0.9％的生理盐水的导电性较血液的高3-5倍，较组织的导电性高12-15倍。比如本实验所用5％的盐水，其浓度较生理情况增加了5倍以上，自然能使组织的导电性进一步增强。输入被消融组织中的盐水起到一种“液体电极”的作用，将所施放的射频能量自金属电极向四周组织均匀扩散。因此，中央的阻抗热环及周围的被动传导热区域均见增大，从而获得较大的杀伤区。当输注盐水时，电极尖端也受到一定的对流冷却作用。另外，高渗盐水的加入使组织液的沸点升高从而起到延缓汽化的作用。尽管单纯盐水增效的射频消融似乎已较单纯冷却的射频消融作用为好，但仍未优化。电极以及电极-组织界面的温度仍会时常超过组织液沸点。另外，输入到肿瘤中的大量盐水可能会增加组织液的静水压，促使单个肿瘤细胞迁移至邻近及远外部位。
如我们的实验结果所示，本发明所介绍的冷-湿电极同时结合了上述两技术的优点，克服了它们的缺点，优化了射频消融疗法。在本实验温和条件下，杀伤区已达到6厘米以上。这是通过改善靶组织及电极-组织界面的导电性，同时降低电极尖端的温度而实现的。盐水的输注量可较使用单纯致湿电极时有所减少。与使用双电极、族状电极、扩张性电极以及单个电极反复进针等创伤性更大的方法相比，本发明所介绍的技术仅需一根针形电极，仅作一次穿刺动作，却可产生足以导致肿瘤完全消融或根治效果的理想治疗范围。为达同样效果，使用目前现有的装置则必须多次治疗或一次治疗多次穿刺进针，而临床实践常常不允许这样做。很显然，使用本发明的装置只需要一次治疗，一次穿刺，因而更简便易行，更安全有效。
Claims (6)
1.一种用于在组织消融过程期间传递射频能量的装置，包含：
-有一远端(3)和一近端(2)的电极(1)，所述远端为非绝缘的便于组织穿刺的结构，所述近端可与射频能量发生器相连；以及
-用无毒性射频导电液使电极(1)的远端(3)及其周围组织致湿的致湿装置，其中所述致湿装置包括限定致湿液流动路径的致湿管道(6)，
其特征在于，所述传递射频能量的装置还包括组织穿刺装置，该组织穿刺装置由内部可抽动轴向针芯(54)形成，其中，所述电极的尖锐远端允许组织穿刺；以及
用于至少冷却电极(1)远端(3)的致冷装置，该致冷装置包括限定致冷液流动路径的冷却管道(7、8)，其中所述致湿管道(6)在电极(1)的远端处是开口的，而所述冷却管道(7、8)在电极(1)的远端处是闭合的，所述冷却管道(7、8)与致湿管道(6)彼此互不相通。
2.如权利要求1所述的装置，其特征在于：所述致湿管道和所述冷却管道是同心走向。
3.如权利要求1所述的装置，其特征在于：所述的限定致湿液流动路径的致湿管道在电极的远端处呈螺旋状走向并围绕内部的限定冷却液流动路径的冷却管道，所述螺旋致湿管道在所述远端有多个开口。
4.如上述权利要求1所述的装置，其特征在于：电极的远端设置有可伸缩温度控制装置，包括至少两个温度传感器。
5.如权利要求1所述的装置，其特征在于：所述电极为多个，所述多个电极平行排列。
6.如权利要求1所述的装置，其特征在于：所述传递射频能量的装置还包括一个在射频消融过程中用于引导穿刺针、射频消融电极或活检针移动的导引装置，该引导装置由中心为圆柱孔的开口空心针筒形成。
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| CN99812155.XA Pending CN1323234A (zh) | 1998-08-14 | 1999-08-13 | 可扩张式湿电极 |
| CN99812151.7A Expired - Fee Related CN1191873C (zh) | 1998-08-14 | 1999-08-13 | 冷－湿电极 |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99812155.XA Pending CN1323234A (zh) | 1998-08-14 | 1999-08-13 | 可扩张式湿电极 |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US6514251B1 (zh) |
| EP (2) | EP1104328A1 (zh) |
| JP (2) | JP2002522183A (zh) |
| CN (2) | CN1323234A (zh) |
| AT (1) | ATE280617T1 (zh) |
| AU (2) | AU5402899A (zh) |
| DE (1) | DE69921482T2 (zh) |
| ES (1) | ES2228083T3 (zh) |
| WO (2) | WO2000009208A1 (zh) |
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| CA1244889A (en) * | 1983-01-24 | 1988-11-15 | Kureha Chemical Ind Co Ltd | HYPERTHERMIA DEVICE |
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-
1999
- 1999-08-13 WO PCT/BE1999/000106 patent/WO2000009208A1/en active IP Right Grant
- 1999-08-13 CN CN99812155.XA patent/CN1323234A/zh active Pending
- 1999-08-13 EP EP99939867A patent/EP1104328A1/en not_active Withdrawn
- 1999-08-13 WO PCT/BE1999/000107 patent/WO2000009209A1/en not_active Application Discontinuation
- 1999-08-13 JP JP2000564710A patent/JP2002522183A/ja active Pending
- 1999-08-13 DE DE69921482T patent/DE69921482T2/de not_active Expired - Lifetime
- 1999-08-13 AU AU54028/99A patent/AU5402899A/en not_active Abandoned
- 1999-08-13 CN CN99812151.7A patent/CN1191873C/zh not_active Expired - Fee Related
- 1999-08-13 EP EP99939273A patent/EP1104327B1/en not_active Expired - Lifetime
- 1999-08-13 AT AT99939273T patent/ATE280617T1/de not_active IP Right Cessation
- 1999-08-13 JP JP2000564709A patent/JP4138249B2/ja not_active Expired - Fee Related
- 1999-08-13 US US09/762,728 patent/US6514251B1/en not_active Expired - Fee Related
- 1999-08-13 ES ES99939273T patent/ES2228083T3/es not_active Expired - Lifetime
- 1999-08-13 AU AU53655/99A patent/AU5365599A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| US6514251B1 (en) | 2003-02-04 |
| DE69921482T2 (de) | 2005-12-15 |
| CN1323233A (zh) | 2001-11-21 |
| WO2000009208A1 (en) | 2000-02-24 |
| JP2002522182A (ja) | 2002-07-23 |
| JP4138249B2 (ja) | 2008-08-27 |
| ATE280617T1 (de) | 2004-11-15 |
| EP1104328A1 (en) | 2001-06-06 |
| ES2228083T3 (es) | 2005-04-01 |
| JP2002522183A (ja) | 2002-07-23 |
| EP1104327A1 (en) | 2001-06-06 |
| DE69921482D1 (de) | 2004-12-02 |
| CN1323234A (zh) | 2001-11-21 |
| WO2000009209A1 (en) | 2000-02-24 |
| AU5365599A (en) | 2000-03-06 |
| AU5402899A (en) | 2000-03-06 |
| EP1104327B1 (en) | 2004-10-27 |
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