CN1735383A - 电外科发生器 - Google Patents

电外科发生器 Download PDF

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CN1735383A
CN1735383A CN200380108510.0A CN200380108510A CN1735383A CN 1735383 A CN1735383 A CN 1735383A CN 200380108510 A CN200380108510 A CN 200380108510A CN 1735383 A CN1735383 A CN 1735383A
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考林·查尔斯·欧文·吉奥博
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
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    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00636—Sensing and controlling the application of energy
    • A61B2018/00696—Controlled or regulated parameters
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00636—Sensing and controlling the application of energy
    • A61B2018/00696—Controlled or regulated parameters
    • A61B2018/00702—Power or energy
    • A61B2018/00708—Power or energy switching the power on or off
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
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    • A—HUMAN NECESSITIES
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    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
    • A61B18/1206—Generators therefor
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Abstract

一种用于向用于切割或汽化组织的电外科器械提供RF功率的电外科发生器，其中该发生器包括RF输出级(42)，该RF输出级具有：射频功率桥(Q1，Q2，Q3，Q4)，一对输出线(74)和串联谐振输出网络(48)，其中输出级(42)在输出线处的输出阻抗小于200/欧姆，其中P是以瓦为单位的发生器最大连续射频输出功率。该发生器提供改进的切割或汽化性能。通过保护电路响应诸如输出线上的短路而进行的快速操作来放置输出级的过载。在优选实施例中，通过从大储存电容器(60)向功率电桥提供能量，输出级能够在至少1kW的峰值保持输出脉冲。通过控制响应储存电容电压的每脉冲最大能量，随着负载条件的变化动态第产生脉冲。

Description

电外科发生器
技术领域
本发明涉及一种用于向电外科器械提供射频(RF)功率的电外科发生器(electrosurgical generator)，并且主要涉及一种具有串联谐振输出网络的发生器。
背景技术
按照惯例，电外科发生器利用包括电压源的配置，该其中该电压源通过一个限定了50至500欧姆之间的匹配输出阻抗的耦合电容器耦合到电外科器械。这种配置产生了在匹配阻抗处具有最大功率值的功率对负载阻抗特性，并且在峰值的每一侧功率都逐渐下降。实际上，当实施电外科手术时，负载阻抗可以在很宽范围内变化，导致了不可预测的临床效果。
为解决该问题，已知一种能够提供宽范围阻抗匹配的RF输出级。这具有快速负载阻抗变化可能产生大输出电压偏移的缺点。一种替换方法是，响应反馈信号来控制向RF输出级的直流(DC)供电，以使得传送的功率实际上是连续的。这可以通过调节电源DC电压、或者通过维持供给的DC功率恒定来实现。这些技术导致了实际上在某一阻抗范围内平坦的功率对负载阻抗特性，但是一个局限是，当开始切割或汽化(与组织切割相反)组织时，难以控制能量传送。为了利用射频功率来切割或汽化组织，需要使由组织或周围液体带来的初始低阻抗负载变为较高阻抗，以便激起电弧。传送太多能量可能造成手术部位附近的烧伤、过多烟雾或器械故障。传送太少能量造成大的延迟，并且可能造成有害的组织凝结。
还已知利用电外科发生器以很高电压向双极性电外科器械提供脉冲电外科功率，例如当切除被浸入诸如盐水的导电液体中的手术部位的组织时，该高电压为大约1千伏峰到峰电压。器械可以具有：有源电极，该有源电极位于要与要治疗的组织邻近或接触的器械最末端；以及返回电极，该返回电极被设置为从有源电极返回、并具有用于和导电液体进行电连接的液体接触面。为实现组织切除，使有源电极周围的导电液体汽化，以造成在电极上放电弧。当器械经历低负载阻抗时，用于在变化的负载阻抗情况下实现组织切割或汽化的高压尤其需要发生器。实际上，如上所述，在这种情况下难以可靠地开始放电弧而没有有害效果。已经采取措施，通过减小电极尺寸以及通过例如涂敷氧化层以使电极表面变粗糙，来增加有源电极处的功率密度，并因此提高开始放电弧的可靠性。后一种技术具有以下效果：捕获不规则表面中的蒸汽，作为增加功率密度的手段。
已经发现，这种器械在高压下的操作易于造成有源电极的腐蚀。腐蚀速率随供电电压增加而增加，并且也通过减小电极尺寸以及提供变粗糙的表面而加剧，如刚才所述。
己公开的欧洲专利申请No.EP1053720A1披露了一种用于产生高电外科电压的发生器。
发明内容
根据本发明第一方面，一种用于向电外科器械提供RF功率的电外科发生器，包括RF输出级，该RF输出级具有：至少一个RF功率器件；用于向电外科器械传送RF功率的至少一对输出线；以及耦合在RF功率器件和所述一对输出线之间的串联谐振输出网络，其中输出级在输出线处的输出阻抗小于
Figure A20038010851000061
欧姆，在此P是以瓦为单位的发生器最大连续RF输出功率。当发生器被配置成用于湿区域(wetfield)外科，例如供被浸入诸如盐水的导电液体中的器械的一个或多个电极使用时，最大连续功率优选地大约为300W至400W。因此，如果最大输出功率是400W，则输出阻抗小于10欧姆。干区域(dryfield)电外科，即正常地不浸没电极的电外科，需要较少的RF输出功率。在该情况下，可以这样配置发生器，以致最大连续RF输出功率大约为16W，在该情况下输出阻抗小于50欧姆。在这两种情况下，在利用用于切割或汽化组织的输出电压进行操作、即在至少300V峰值的电压下进行操作的时候，获得这些数字。输出阻抗优选地小于
Figure A20038010851000071
欧姆，这在以上功率输出处产生5欧姆至25欧姆的最大输出阻抗值。
将要理解，当发生器的RF输出是脉冲的时候，即当RF能量以脉冲串形式、一般作为RF正弦波被提供给负载时，最大连续功率是在几个这样的脉冲串内测量的平均功率。
根据本发明的另一方面，一种用于向用于切割或汽化组织的电外科器械提供RF功率的电外科发生器，包括RF输出级，该RF输出级具有：至少一个RF功率器件；用于向电外科器械传送RF功率的至少一对输出线；以及耦合在RF功率器件和所述一对输出线之间的串联谐振输出网络，这样配置输出网络，以致输出线的输出电流的最大上升速率小于每微秒
Figure A20038010851000072
安培，P的定义如上。
因此，对于用于湿区域电外科的400W典型最大连续RF功率，一般，在输出线在发生器最大功率设定下发生短路时的输出电流幅度的最大上升速率小于5A/μs。在用于干区域电外科的P典型值为16W的情况下，输出电流幅度的上升速率小于1A/μs。
在根据本发明的优选发生器中具有保护电路，该保护电路响应实质上指示例如由输出线短路造成的输出电流过载的预定电状态，以便中断供给串联谐振输出网络的RF功率。该保护电路足够快地响应短路，以致在与被传送RF功率的仅仅20个周期相对应的时期内切断向输出网络的RF功率供给。该保护电路优选地可以快得多地操作，以便在3个周期甚至1个周期内中断功率传送。串联谐振输出网络的作用是，在故障状态下，例如当输出线上出现极低阻抗或短路时，延迟电流的增大。本申请人已经发现，只在几个RF周期之后，从开路到短路的阻抗转变就导致了RF功率器件的有效短路。通过安排保护电路进行快速响应，能够在这发生以前禁止输出级。一般地，保护电路足够快地响应输出线短路的发生，以便在由于短路而使通过射频功率器件的电流上升到额定最大电流之前，禁止射频功率器件。
具有较低输出阻抗的RF输出级的使用意谓，RF电压输出实质上直接与施加于输出级的DC供电电压相关(具体地说，与输出级所包含的一个或多个RF功率器件相关)。在本发明的优选实施例中，每个RF功率器件都以开关方式操作，结果方波输出被施加于串联谐振输出网络。输出线的可变均方根(RMS)电压与供电电压成正比。从而，最大峰到峰输出电压由DC供电电压确定，并且结果在该实施例中不需要到控制输出电压的动态反馈。
保护电路优选地能够在上述预定电状态开始之后的一个半RF周期内禁止输出级。优选地，预定电状态指示输出级中超过预定电平的瞬时电流，并且保护电路的响应速度是这样的，以致在瞬时电流超过预定电平的相同RF周期内检测到瞬时电流突破预定电平。可以通过这样的电流感测电路来执行这种检测，该电流感测电路包括：串联耦合一个或多个RF功率器件和串联谐振输出网络之间、并且典型地为变流器的拾取装置(pick-up arrangement)；以及具有耦合到拾取装置(例如耦合到变压器的次级绕组)的第一输入和耦合到参考电平源的第二输入的比较器。参考电平源可以是基本上没有滤波的瞬时电流的电压表示，以便促使比较器输出的状态在阈值首先被超过的相同二分之一RF周期内、或者在随后的二分之一RF周期内发生变化，这取决于是否在比较器前面应用了全波整流。对于湿区域电外科，预定瞬时输出电平优选地为至少5A，并且典型地为15A。比较器的输出耦合到禁止电路，以便当响应通过拾取装置感测的超过参考源所设置的预定电平的瞬时电流、而使比较器输出的状态改变时，禁止一个或多个功率器件。保护电路的电流断开方式不限于阻抗。
一般，只需要使功率传送中断短时间。因此，保护电路包括单稳态级，并且可以响应预定状态的检测、使功率器件禁用由单稳态级的时间常数确定的有限时期，该时间常数典型地小于发生器工作频率的20个周期。
优选地，发生器具有耦合到一个或多个功率器件的RF源，该RF源包括定义发生器工作频率的振荡器。串联谐振输出网络被调谐到该工作频率。一般，这样配置RF源，以致工作频率基本上是恒定的(例如在任何给定的治疗周期期间)。
这样设置优选的发生器，以致对于给定用户设置，RMS RF输出电压基本上在 欧姆至1000欧姆的负载阻抗范围内，其中P的定义如上。因而，例如在RF能量的每个脉冲串期间的RMS RF输出电压常数被维持在最大值的20％以内。作为输出网络的串联谐振配置的结果，可以部分地实现这一点。
为维持低阻抗下的恒定峰值输出电压，根据本发明的特殊优选特征，输出级的RF电源包括电荷存储元件，该电荷存储元件优选地为超过1mF的电容器，输出器件受脉冲调制电路的脉冲调制(pulsing)，以致这些输出器件以脉冲串的形式提供RF能量，并且响应耦合到该电容器的电压感测电路的输出来控制脉冲串的定时、尤其是每个脉冲串的终止。输出级的DC供电电压优选地为100V或更大。为避免供电电压的大幅度衰减，电压感测电路和脉冲调制电路被设置成，当感测的电压降到预定电平以下时终止RF能量的单个脉冲，典型地这样设置该预定电平，以致当电压下降5％至20％之间的预定百分值时脉冲终止发生，该预定百分值典型地与输出线传送的、降到各个脉冲起始电压值以下25V至100V之间的值的峰值RF电压相对应。对于湿区域电外科，每个脉冲期间传送的RF能量典型地为60焦耳，对于干区域电外科，每个脉冲期间传送的RF能量典型地为2焦耳。峰值功率典型地达到至少1kW，优选地为4kW。
优选湿区域发生器的极高峰值功率性能(超过1kW)允许在组织切割或汽化周期开始时发生的阻抗转变非常快地完成，因为只有超过放电弧所需电压的电压才被传送。这大大减小了某些现有技术发生器的延迟和有害凝结效果。基本上恒定的电压传送导致切割或汽化以一致速率发生，而与组织类型或接合(engagement)的变化无关。
根据本发明的又一方面，提供一种用于向电外科器械提供RF功率的电外科发生器，其中发生器包括RF输出级，该RF输出级具有至少一个RF功率器件、用于向电外科器械传送RF功率的至少一对输出线、以及耦合在RF功率器件和所述输出线之间的串联谐振输出网络，该发生器进一步包括响应输出线短路的保护电路，其中输出级的输出阻抗小于
Figure A20038010851000092
欧姆，在此P是以瓦为单位的发生器最大运续RF输出功率，以及其中保护电路足够快地响应所述短路，以便在由于短路而使通过功率器件的电流上升到额定最大电流之前禁止功率器件。可以在与少于3个RF周期相对应的时期内，响应输出线短路的发生，来禁止所述或每个功率器件。
本发明的另一方面提供一种用于向用于在湿区域电外科中切割或汽化组织的电外科器械提供RF功率的电外科发生器，其中该发生器包括RF输出级，该RF输出级具有：至少一个RF功率器件；用于向电外科器械传送RF功率的至少一对输出线；以及耦合在RF功率器件和所述一对输出线之间的串联谐振输出网络，以及其中输出级输出线的输出阻抗小于10欧姆。
本发明的又一方面提供一种用于向用于在干区域电外科中切割或汽化组织的电外科器械提供RF功率的电外科发生器，其中该发生器包括RF输出级，该RF输出级具有：至少一个RF功率器件；用于向电外科器械传送RF功率的至少一对输出线；以及耦合在RF功率器件和所述一对输出线之间的串联谐振输出网络，以及其中输出级输出线的输出阻抗小于50欧姆。
根据本发明的又一方面，一种用于向用于切割或汽化组织的电外科器械提供RF功率的发生器包括RF输出级，该RF输出级具有：至少一个RF功率器件；用于向电外科器械传送RF功率的至少一对输出线；以及耦合在RF功率器件和所述一对输出线之间的串联谐振输出网络，其中该发生器被配置成能够在
Figure A20038010851000101
欧姆至1000欧姆的负载阻抗范围内维持至少300V的峰值输出电压，在此P是以瓦为单位的额定输出功率。在国际电工技术委员会标准IEC 60601-2-2中定义了该额定输出功率。
根据本发明的又一方面，提供一种用于向用于切割或汽化组织的电外科器械提供RF功率的电外科发生器，其中该发生器包括RF输出级，该RF输出级具有：至少一个RF功率器件；用于向电外科器械传送RF功率的至少一对输出线；以及耦合在RF功率器件和所述一对输出线之间的串联谐振输出网络，其中该发生器进一步包括耦合到RF输出级的电源级，该电源级具有能够存储以焦耳为单位的发生器最大连续功率P(以瓦为单位)的3％至30％的储能电容器。
在本发明的另一方面，每脉冲的能量传送(以焦耳为单位)在最大连续RF输出功率(以瓦为单位)的1％至10％之间。
本发明也包括一种用于向用于切割或汽化组织的电外科器械提供RF功率的电外科发生器，其中该发生器包括RF输出级，该RF输出级具有：至少一个RF功率器件；用于向电外科器械传送RF功率的至少一对输出线；以及耦合在RF功率器件和所述一对输出线之间的串联谐振输出网络，以及其中该发生器进一步包括耦合到输出级的脉冲调制电路，该脉冲调制电路用于以这样一种方式对被传送的RF功率进行脉冲调制，以致当在脉冲期间的峰值输出电压被维持在大于300V的值的时候输出线上存在的负载阻抗减小时，输出线上产生的电压波峰因数增大。对于湿区域电外科，输出级的输出阻抗优选地小于10欧姆，并且在 欧姆至1000欧姆(典型地从10欧姆到1000欧姆)的负载阻抗范围内波峰因数按至少2∶1的比值变化。对于干区域电外科，输出阻抗小于50欧姆，并且在
Figure A20038010851000112
欧姆至50千欧(典型地从50欧姆到50千欧)的负载阻抗范围内波峰因数按至少2∶1的比值变化。
“波峰因数”表示峰值电压与RMS电压之比。在脉冲输出波形的情况下，在多个脉冲内进行测量。
根据本发明的第十方面，一种电外科发生器，包括RF能量源、有源输出端、返回输出端、位于RF能量源和有源输出端之间的隔直流电容器、以及用于RF能量源的脉冲调制电路，其中RF能量源和脉冲调制电路被设置成在输出端产生脉冲RF输出信号，该输出信号具有至少1A的峰值电流、至少300V的同时峰值电压、5Hz至2kHz之间的调制速率、以及100μs至5ms之间的脉冲长度。在本发明的优选实施例中，信号具有至少3A的峰值电流。
利用这种发生器，即使在较低负载阻抗的情况下，也有可能开始放电弧。一旦形成电弧，负载阻抗就倾向于上升，结果可以利用连续RF输出波形维持放电弧。有源电极处的增加功率密度可用于汽化，同时减小电极腐蚀。
脉冲长度优选地在0.5ms至5ms之间，脉冲占空系数典型地在1％至20％之间，并且优选地在2％至20％之间。
根据本发明的优选发生器具有谐振输出网络，并且可以操作以便例如至少在治疗周期的初期产生至少1千瓦、并且典型地至少为3千瓦或4千瓦的峰值功率。通过在发生器中提供用于将输出电压限于大约900V至1100V峰到峰的值的装置，可以实现电极腐蚀性能的改善。
在优选的发生器中，RF能量源和脉冲调制电路被设置成，在初期在输出端产生具有至少1A的峰值电流、至少300V的同时峰值电压、5Hz至2kHz之间的调制速率、以及100μs至5ms之间的脉冲长度的脉冲RF输出信号，并且在后期在输出端产生恒定功率RF输出信号。
不同的使发生器结束上述操作初期、并开始所谓的后期的方法是可行的。这样设置一个发生器实施例，以致在初期开始之后的预定时间间隔、从初期到后期的转换自动发生。在替换实施例中，发生器具有用于在发生器使用过程中监测有源输出端和返回输出端之间的负载阻抗的装置，并且被设置成，当输出阻抗的大小增大预定因数、典型地为5至20并且优选地为10，或者当输出阻抗大小超过预定阈值时，促使转换到后期。
优选的发生器使用涉及上述电荷存储元件的第三转换技术。在该情况下，RF能量源包括RF输出级，并且发生器具有包括用于向输出级提供功率的、诸如大电容器的电荷存储元件的电源。当治疗周期包括初期和后期，如上所述，则电容器用于至少在初期提供功率。和电容存储元件相关联的是用于感测通过电荷存储元件提供给输出级的电压的电压感测电路，这样安排发生器，以致响应电压感测电路所感测的供电电压达到预定电压阈值、而结束治疗或开始后期。的确，有可能利用相同电压感测电路来控制单个脉冲的长度和定时。在该情况下，电压感测电路形成上述脉冲调制电路的一部分，并且响应供电电压达到上述电压阈值而至少确定由输出级在初期产生的脉冲的开始定时。有可能将输出级所产生的脉冲的前沿和后沿都设置成，通过分别降到相应电压阈值以下和超过相应阈值以上的供电电压，来确定该脉冲前沿和后沿。
电荷存储电容器优选地为至少1000μF，并且有利地具有超过5焦耳的容量。
如上所述，优选发生器具有调谐的输出。的确，具有谐振输出网络的发生器获得了良好结果，发生器负载曲线(即被传送的功率对负载阻抗的曲线)在50欧姆以下的负载阻抗处具有峰值。通过将输出网络形成为包括电感器和电容器的串联组合的串联谐振网络，来帮助将峰值功率电平传送到低负载阻抗中，从该电容器得到输出网络的输出。可以通过耦合电容器以及任选的升压变压器，从串联组合的电感器和电容器之间的节点，将输出取出到发生器的所有输出端。虽然有可能改为从电感器得到输出，但是从电容器得到输出具有减小开关瞬态的优点。作为进一步替换例，发生器可以使其输出端连接到谐振输出网络，以致实际上当负载连接到端子时，它作为阻抗与形成谐振组合的电感器和电容器串联，例如串联在电感器和电容器之间。
谐振输出网络典型地在50欧姆至500欧姆的范围内在输出端提供源阻抗。
相当重要的是，因为由于耦合电容器、使输出网络的谐振频率可以随负载阻抗而变，因此RF源可以包括可变频率RF振荡器，当连接到匹配负载阻抗、即连接到等于其源阻抗的负载阻抗时，输出频率有利地被限制在输出网络谐振频率以下的最大值。
可以将发生器和双极性电外科器械结合起来形成电外科系统，该电外科器械至少具有耦合到发生器有源输出端的有源电极、以及耦合到发生器返回输出端的返回电极。本发明特别应用于以下电外科系统：该电外科系统中，双极性电外科器械具有被形成为导电的、优选地为U形环的有源电极。这种环常常用于切除组织样本，但是在实现盐水汽化和放电弧方面，对发生器提出了特殊要求。
根据本发明第十一方面，一种电外科系统，包括：具有RF能量源的发生器；以及耦合到发生器、并具有带有至少一对电极的电极组件的双极性电外科器械，其中发生器适于在初期将RF功率作为脉冲调制RF信号传送给电极组件，在和这对电极一起使用时，该脉冲调制RF信号具有至少1A的峰值电流、至少300V的同时峰值电压、5Hz至2kHz之间的调制速率、以及100μs至5ms之间的脉冲长度。
再次，该电外科系统可以适于在初期将RF能量作为脉冲调制RF信号传送给电极组件，在和这对电极一起使用时，该脉冲调制RF信号具有至少1A的峰值电流、至少300V的同时峰值电压、5Hz至2kHz之间的调制速率、以及100μs至5ms之间的脉冲长度，并且该电外科系统可以适于在后期将RF能量作为连续功率RF信号传送给电极组件。峰值电流优选地为至少3A。
附图说明
现在将参考附图举例描述本发明，其中：
图1所示为包括根据本发明的发生器和双极性电外科器械的电外科系统的总体图；
图2A和2B分别是形成图1所示的双极性器械一部分的环电极组件的透视图和侧视图；
图3所示为发生器主要部件的框图；
图4是形成发生器一部分的RF输出级的简化电路图；
图5是图1发生器的说明性负载曲线；
图6是RF输出级的更详细电路图；
图7是根据本发明的替换电外科发生器的框图；
图8是替换发生器的谐振输出网络的电路图；以及
图9是图7发生器的负载曲线。
具体实施方式
参考图1，发生器10具有输出插座10S，该输出插座10S用于通过接线绳14向内窥镜附件12形式的电外科器械提供射频(RF)输出。可以从器械12通过绳14中的控制连接执行发生器的启动，或者可以借助于如图所示通过脚踏开关接线绳18独立连接到发生器10背面的脚踏开关单元16，来执行发生器的启动。在所示的实施例中，脚踏开关单元16具有两个分别用于选择发生器的凝结模式和切割模式的脚踏开关16A和16B。发生器前面板具有分别用于设置在显示器24中指示的凝结和切割功率电平的按钮20和22。按钮26被提供作为用于在凝结和切割模式之间进行选择的交替装置。器械12包括具有双电极结构、并意欲在盐水区域中使用的可拆开环电极组件28。
器械12包括具有双电极结构、并意欲在盐水区域中使用的可拆开环电极组件28。图2A和2B是电极组件28的末端放大视图。在其最末端，组件28具有从一对电极组件臂32下垂的U形环电极30，这对电极组件臂32并排地被安装在要咬到内窥镜上的夹子34中。环电极30是有源电极。每一个臂32都被形成为同轴电缆，在所有情况下该同轴电缆的暴露导电外罩都形成返回电极36。在被浸入盐水场中的操作中，环电极30典型地用于切割组织样本，在环电极12A和返回电极36的液体接触面之间形成的电外科电压促进环电极30周围的盐水液体的汽化，并且由此形成通过蒸汽包封的放电弧。
环电极30包括具有氧化涂层的合成钼铼导线，该合成钼铼导线用于促进电极/液体界面中的阻抗增加，并因此增加电极表面的功率密度。
环的宽度典型地在2.5mm至4mm的范围内，并且导线的直径典型地在0.20至0.35mm的范围内。
在开始汽化和形成电弧方面，该环电极组件提出了对发生器的特殊要求。
通过减小导线直径以及形成氧化层来改进该电极组件的放电弧(“点火”)启动的努力易于增加腐蚀速率或导致环在机械上易坏。
应该注意，根据本发明的发生器不限于和环电极组件一起使用，也不限于在湿区域外科中使用。
现在将参考图3更详细地描述发生器。发生器具有振荡器40形式的RF源，该振荡器40可以连接到RF输出级42。输出级42包括形成功率金属氧化物半导体场效应晶体管(MOSFET)与驱动电路44一部分的MOSFET功率桥(power birdge)、电流感测元件46和谐振输出网络48。振荡器40被配置成在基本上恒定的RF频率操作，并且输出网络48被调谐到那个频率。一般地说，耦合到一个或多个RF功率器件的RF源限定发生器的工作频率，并且输出网络(如下所述，该输出网络是串联谐振的)被调谐到该工作频率。在本发明的该实施例中，工作频率基本上是恒定的。
通过电源干线(supply rail)58、从DC电源50向RF输出级42供电，或者更具体地说，向功率MOSFET供电。4.7mF储存电容器60连接在电源干线58和地之间。电源干线58上的电压由电压感测电路62感测，该电压感测电路62控制串联在RF振荡器40和功率MOSFET与驱动电路44中的驱动器件之间的第一传输门64。
输出级42中的电流感测元件46是串联变流器，该变流器的次级绕组耦合到比较器66的第一输入，该比较器66在其另一输入接收来自参考输入68的参考信号。比较器的输出控制单稳态元件70，单稳态元件70又控制与振荡器40和功率MOSFET与驱动电路44中的驱动器之间的路径中的门电路64串联耦合的第二传输门72。输出网络48向输出终端74提供RF功率，输出终端74实际上是一对输出线，如下所述。就RF能量被突发地供给受操作为脉冲调制电路一部分的电压感测电路62与门电路64组合的控制的输出线74来说，发生器的操作正常是脉冲的。当启动发生器时，至少在与输出线74交叉耦合的负载阻抗较低的时候，由于储存电容器60的放电，使得电源干线58上的电压倾向于下降。当电源干线58上的DC供电电压下降到预设值时，电压感测电路62的输出改变状态，并且传输门64被驱动到其开路状态，由此禁止功率MOSFET与驱动电路44。然后，当电源干线电压达到较高的第二预设值时，储存电容器60再充电，并且电压感测电路62使门电路64重新连接振荡器40。这样，有可能控制在每个脉冲中传送的能量数量。
电流感测元件46、比较器66、单稳态元件70和第二传输门72一起充当保护电路，以使电路44中的MOSFET功率器件免于例如由输出线74的短路造成的过量电消耗。输出网络48中的能量存储延迟了输出线74的短路到功率MOSFET与驱动电路44中的功率器件的传送。
电流感测元件46和比较器66检测的电路状态是，在电路44中的功率MOSFET和输出网络48之间流动的电流上升到能够指示输出线74的短路的电平。当电流达到如比较器66所检测的预设电流电平时，比较器输出改变状态，并且单稳态元件70使第二传输门72变成开路，由此禁止功率MOSFET与驱动器级44。单稳时间常数典型地被设置为0.5秒或更少，这允许产生报警信号来警告用户。然而，由于串联谐振电路中的能量存储，有可能保护单稳时间常数大约为400kHz工作频率下的20个RF周期的RF功率器件。
在图4的简化电路图中，原则上显示了输出级42的配置。参考图4，图3所示的功率MOSFET与驱动器级44具有包括第一对推挽场效应晶体管(FET)功率器件Q1、Q2和第二对推挽FET功率器件Q3、Q4的功率MOSFET桥，每一对都具有各自的输出节点，当这两对被驱动成具有180°相位差时，每一对各自的输出节点在串联谐振输出网络48的输入产生具有振荡器40(图2)的频率的方波。每一对功率MOSFET Q1、Q2及Q3、Q4都耦合在电源干线58和地之间。因此，因为当被驱动为“通”时，每一个MOSFET都是虚短路，所以施加于输出网络48的电压实际上在地和电源干线电压之间摆动。图3所示的储存电容器60当然与各对功率MOSFET并联，如图4所示。
输出网络是串联谐振的，因为电感器L1和谐振电容器C1分别串联耦合在第一对功率MOSFET和第二对功率MOSFET的输出节点76、78。在该实施例中，负载电阻器RL串联在电感器L1和电容器C1之间，该负载电阻器RL实际上由耦合在输出线74和跨越电外科器械电极组件的组织和/或液体之间的电外科器械构成。如上所说明的，由电感器L1和电容器C1形成的串联谐振调谐电路充当能量存储器件，如果负载电阻器RL下降到极低值，则该能量存储器件使功率MOSFET桥Q1至Q4的节点之间的电流增大延迟。该谐振配置的另一特征在于，只不过当然是有条件的，一旦网络48的谐振频率和振荡器级40(图3)的工作频率的谐振频率相同，它在一个频率下是低阻抗，这意谓被传送的输出信号几乎只由功率MOSFET所产生的波形基本分量组成。
以上参考图4描述的输出配置赋予发生器的特性之一是，在RF能量的每一脉冲串或脉冲期间、它具有近似恒定的电压负载曲线，如图5中显示的功率对负载阻抗负载曲线所示。该特性尤其适于组织切割或汽化，因为它提供了在低阻抗下所需的高功率、而没有电压过冲。通过功率MOSFET到电源干线和地的直接耦合，以及通过储存电容器60，来提供所需的低输出阻抗和高电流，即使升压变压器耦合在串联谐振元件L1、C1和输出线74之间。有可能利用该配置将发生器输出线74的输出阻抗保持为2欧姆或更小。对于故障状态下的峰值电流传送，这意味着需要诸如以上提到的保护电路。
图6中更详细地显示了RF输出级42。如图6所示，电流感测元件46是变流器，该变流器串联耦合在功率MOSFET桥的输出节点76、78之一和串联谐振输出网络的元件L1、C1之一之间，在该情况下串联耦合在节点76和电感器L1之间。在该优选的发生器中，电源干线58上的正常DC供电电压大约为120V。为激起电弧以便执行组织切割或汽化，可能需要超过380V的峰值电压。因此，为绝缘起见，RF输出网络48包括升压绝缘变压器TR1，以便将峰值输出电压提升到500V峰值区。变压器TR1的初级绕组具有与之并联，以便产生被调谐到工作频率的并联谐振电路的调谐电容器C2，从而充当并联陷波器。这改善了被供给输出线74的功率信号中的谐拨排斥，尤其是当输出阻抗高时，由此产生的益处是RFI(RF干扰)的减少。
通过变压器TR1次级绕组和输出线74之一之间的耦合电容器C3，来提供隔直流。
输出网络48的实际谐振频率是几个元件的结果，这些是(1)由集总的电感器L1和调谐电容器C1代表的主调谐元件，(2)变压器漏电感和交叉耦合电容，(3)隔直流电容C3，以及(4)输出线74和电外科器械自己之间的连接电缆(未显示)的电感和电容性负载。故障状态下电流增大的延迟归因于该调谐配置中的能级。在谐振情况下，该配置具有可以由串联电阻表示的有限损耗，虽然该串联电阻很小。然而，动态地，谐振输出网络中的能级不可能立即变化。在工作频率下的几个RF周期之后，从开路到短路的阻抗转变只给开关级带来短路。图3所示的比较器66能够在从输出线74开始的转变的1至1.5个周期内检测这种阻抗变化。上述的迅速响应，以及允许功率MOSFET与驱动电路44在损坏发生以前被断开，具有以下效果：在短路器件传送的能量数量非常小。
再次参考图3，并且尤其参考电压感测和输出级脉冲调制电路62、64，可以利用以上参考图5和图6描述的输出级来实现的极高峰值功率具有以下好处：在向低阻抗传送功率的期间，在发生器启动的时刻之后，储存电容器60的电压逐渐减小。电容器值被选择为大得足以确保，能够在RF能量的一个脉冲串中产生在组织切割或汽化周期开始时发生的从低到高负载阻抗转变。典型地，在初始猝发期间传送的能量数量在干燥环境下大约为1焦耳，并且在潮湿环境下在10至20焦耳之间。RF脉冲或猝发中的实际能量受电压感测电路62中设置的一个或多个阈值控制，具体地说，受脉冲启动和脉冲终止之间的供电电压差控制。因为输出级具有极低输出阻抗，因此该电压差显现为输出处传送的RF电压的变化。从而，使电容器60足够大(在该实施例中为4.7mF)，以致于电压变化只代表输出处绝对电压的较小比例。因而，如果传送的输出电压是峰值电压为500V的正弦波，则这样选择电源干线58上的供电电压、电容器60的大小以及变压器TR1升压比，以致于在RF脉冲串期间输出压降不超过100V峰值(20％)。在该优选的实施例中，输出压降大约为50V峰值或10％。
阻止向输出提供较低电压的作用之一是，在组织切割或汽化期间，不允许电压降到不希望的凝结效果发生的电平。
根据本发明的优选发生器允许这样改变馈给储存电容器60的DC能量，使得能够改变切割电压存在于输出处的时期。实际上，由于发生器的低输出阻抗，该时期与存储的能量成正比。
根据感测的储存电容器电压阈值来控制RF能量脉冲串或脉冲的控制方法允许使用极低占空系数，由此允许在低平均功率下执行组织切割或汽化。的确，有可能利用低于5瓦的平均功率(在几个电容器充电和放电周期内平均)进行操作。因此，该发生器在低功率以及高功率应用中都有用。
现在将参考图7来描述供以上参考图1所述的系统中使用的替换发生器。该发生器具有包括电压控制振荡器(VCO)40A的可变频率RF源。在该例子中，VCO馈给1比2分频电路级40B，1比2分频电路级40B又馈给功率驱动器级44A，功率驱动器级44A驱动功率桥44B形式的RF输出级。功率桥44B馈给谐振输出网络80，谐振输出网络80在输出端74传送发生器输出信号。实际上，功率驱动器级44A和功率桥44B可以具有和以上参考图3描述的发生器的功率MOSFET与驱动电路44相同的配置。功率桥44B从DC电源50的电源干线58接收其DC供电，但是驱动器级44A具有较低供电电压。对于功率桥44B，典型的供电电压为最大180V，对于驱动器级44A，典型的供电电压最大为16.5V。
为将VCO 40A和1比2分频电路级40B组合的频率变成输出网络80的谐振频率，将RF源的上述部件耦合在锁相环路中，该锁相环路包括耦合在功率桥44B和输出网络80之间，以便感测输出网络的输入引线中的电流相位的相位感测元件82。该电流相位信号被施加于相位比较器84的一个输入，并且相位比较器84的另一输入接收代表经由延迟级86从1比2分频电路级40B的输出得到的VCO 40A输出的信号，当RF信号通过功率驱动器和功率桥时，延迟级86补偿RF信号的延迟。
如在最先描述的发生器中，从附于储存电容器60上的DC电源干线58向RF输出级44B供电，这允许输出级44B在短的时期内汲取大电流，即大大高于连接到DC电源干线58的电源(未显示)的额定电流的电流。从而，电源干线58上的电压将在大电流汲取期间下降。这种电压变化被耦合到电源干线58的电压感测级62所感测。电压感测电路62具有耦合到线88中的第一传输门64的控制输出，线88将VCO 40A的分频输出耦合到功率驱动器44A的输入。
如前所述，这样配置电压感测级62和门电路64，以致于当电源干线58上的电压(供给功率桥44B的电压)下降到预定电压阈值以下时，门电路64被操作，以中断VCO 40A和功率驱动器44A之间的信号路径。当电源干线电压再次上升时，门电路64恢复到其导通状态。当电压上升到上述阈值或第二阈值电压以上时，这可以发生。
在信号线88中和电压操作门64串联的第二传输门72具有连接到0.5秒单稳态元件70的输出的控制输入，单稳态元件70受包括输出网络80输入引线之一中的电流感测元件46和比较器66的电流感测电路系统触发。当功率桥输出电流超过预定阈值时，这些元件起作用，以使到功率桥驱动器44A的信号线88中断0.5秒。
参考图8，谐振输出网络80包括线内电感器(in-line inductance)L和槽路电容器C1的串联组合。经由第一耦合电容器C2从槽路电容器C1(去掉开关噪声)获得输出。该第一耦合电容器C2经由升压比为1∶2的升压匹配变压器T耦合到输出(由端子74表示)。变压器T的次级绕组经由第二耦合电容器C3耦合到输出端。在该实施例中，L大约为0.47μH，槽路电容器大约为10nF，并且两个耦合电容器C2和C3合作(它们之一经由变压器T)形成大约为23nF的耦合电容。
将要理解，当输出端74开路时，输出网络的谐振频率由L和C1的串联组合确定。当输出端74短路时，谐振频率由L和由C1、C2、C3、T代表的网络的串联组合确定。在给定值的情况下，短路谐振频率大约为开路谐振频率的0.55倍。
串联调谐输出级的特征之一是，峰值功率传送固有地在极低和极高阻抗下发生。参考图9，谐振时的串联调谐网络负载曲线(即传送的功率对负载阻抗)由虚线A指示。在端子74(图7和图8)的负载阻抗为大约200欧姆时，网络80具有最小功率传送，这可以被认为是“匹配条件”。将要注意，具有负斜率的曲线A部分紧跟在曲线长主要部分近似为双曲线的路径之后，这意谓曲线这部分的形状类似于图9的曲线图上的恒压线。
本申请人已认识到，当应用于电外科发生器的输出级时，对于某一负载阻抗范围内的给定恒压极限，这种特性允许使输出功率达到最大值。已经发现，当输出电压上升到大约900V至1100V峰到峰阈值以上时，在导电液体中操作的电外科器械的有源电极的腐蚀显著增加。通过安排输出网络48的负载曲线，以便在大约1000V峰到峰(340Vrms)处跟随近似恒压曲线，被传送到变化负载阻抗中的功率可以接近于那个电压理论上可达到的最大值。
实际上，在对所谓的“水下(underwater)”电外科有重大意义的负载阻抗范围内，可以使发生器起恒压电源的作用。这可以利用比图2A和2B所示的电极组件在潮湿环境下所代表的负载阻抗高得多的匹配输出阻抗来实现，对于4mm环、该负载阻抗大约为25欧姆。这转换成340Vrms下大约4.5kW的最大功率。
图9中的曲线B显示了利用图7和图8所示配置获得的实际负载曲线。由于利用电流感测级电路46、比较器66、单稳态元件70和传输门72(图7)强加了限流，在低阻抗处该负载曲线偏离了串联调谐曲线A。在该实施例中，限流被设置为大约13安培的电流。在向曲线A负斜率部分的较低部分，实际负载曲线B也偏离固有串联调谐负载曲线A，使得当负载阻抗上升时，传送的功率遵照连续负斜率，由此再次模仿恒压电源。由于极值功率到极高阻抗中的传送是不希望的，这后一种偏离是故意的。该偏离的原因是，如上所述和RF频率输出的高频极限强加耦合的输出网络80的谐振频率移动了，如以下将要描述的。相位比较器84对如相位感测电路82所感测的输出网络80的输入处的电流相位和1比2分频电路40B的延迟型式输出进行比较，1比2分频电路40B又由VCO 40A馈给。因此，VCO的相位和频率变化、以维持从属于上述频率上限的输出网络80输入的恒定相位。因而，在没有其它影响的情况下，当负载阻抗变化时，输出网络80被保持为谐振状态。
假定锁相环路的自由运行频率被设置成是其最大工作频率，则锁相环路的锁定特性是这样的，以致它能够在对应于最小负载阻抗的最小频率处转到锁定状态，以便在输出脉冲的早期部分足够快地达到谐振，但是不至于快得使在电流超过预定电流阈值的时候，限流电路(感测电路46、66、单稳态元件70和传输门72)未能跳闸。
现在，如果将输出载波频率限于匹配负载谐振状态的频率以下的值，则当负载阻抗增加并且谐振频率相应地上升时，传送的功率将减少。实际上，包含VCO 40A(图7)的锁相环路的自由运行输出频率被设置成是该最大频率。这确保输出网络总是代表比负载阻抗高的源阻抗，如果发生短路，该较高源阻抗将提供过电压保护。
总之，为获得最佳谐振频率，将激励振荡器(VCO)相位锁定到谐振输出网络。定义VCO的范围提供了负载曲线定义，因为当输出网络谐振频率上升到VCO 40A的分频输出最大频率以上时，传送的输出功率降到理论最大值以下。换句话说，通过阻止VCO产生谐振所需的较高频率，来防止高负载阻抗下的匹配。因而，在高负载阻抗下，根据频率来控制最大输出电压。
从图9可以看到，在与潮湿或部分潮湿的电极相对应的负载阻抗范围内，传送的输出功率超过1kW。一旦汽化和放电弧被启动，阻抗就上升，并且传送的功率就下降。为将平均输出功率维持在200W或更小，当负载阻抗低时，输出信号是脉冲的。将要理解，在峰值功率超过4kW的情况下，脉冲占空系数需要下降到大约5％或更低的级别。脉冲重复率应该在5Hz至2kHz之间，并且优选地为至少10Hz。考虑到在电极表面启动汽化所花的时间，来选择这些数字。这意谓，为了进入需要最大功率的低阻抗状态，脉冲具有大约4或5ms的最大长度。典型地，脉冲长度大约为1至2ms。当不是必需的时候，优选地将发生器的RF输出级配置为对来源于分开振荡器的信号输出进行放大、而不是具有自振荡输出级的放大器，以便能够在上述脉冲长度内实现全峰值功率。(在该实施例中，为实现高效率，输出级44B是被配置为功率开关桥的放大器。)如果VCO不能在与输出网络80的谐振相对应的频率下操作，如可能在每个脉冲开始时发生的，则阻止和这种不匹配关联的过大输出电流，因为串联调谐输出网络只在谐振时才是低阻抗的。
可以以多种方式来执行输出信号的脉冲发生，包括利用预定脉冲长度和脉冲重复率的简单脉冲调制。在上述替换发生器的操作模式下，只有在从治疗开始的初期期间，输出才是脉冲的，此后，即一般在汽化和放电弧已实现并且负载阻抗处于上界的时候，输出信号是连续波(CW)信号。初期的持续时间可以是固定的，或者可以通过监测负载阻抗并在阻抗超过预定值的时候终止初期来确定初期的持续时间。在该实施例中，初期持续时间和脉冲长度及频率可以响应通过电源干线58上的电源干线电压测量的传送能量，动态地变化。如以上所说明的，仅仅通过允许输出级44B从电荷储存器汲取电流来获得高瞬时功率电平，在此该电荷储存器为诸如47mF电容器60的大电容器。当从电容器60中汲取电荷时，电源干线电压下降。在脉冲之间，电源干线电压再次上升。因此，根据供电电压电平和电压感测电路62中设置的一个或多个阈值之间的关系，利用门电路64交替地允许和阻止RF信号沿信号线88向功率驱动器44A的传递，发生器的输出可以是脉冲的，以便当在预定平均功率极限内操作时获得最大峰值传送功率。通过以下方式来实现功耗和DC供电电压的这种平衡：这样设置电压阈值，使得当电源干线电压足以达到最大汽化电压(例如340V rms)时、RF输出级被启动，以及当达到较低阈值时，RF输出级被切断。较低阈值定义了对于给定平均功率电平的每脉冲最大能量和重复率。当电极已经“点火”时，换句话说，当汽化和放电弧已经开始时，以上提到的初期终止，以致负载阻抗上升，并且电源干线电压保持在一个或多个开关阈值以上。这样，有可能在低到20欧姆的阻抗下实现电极周围导电液体的汽化，而没有不可接受的电极表面腐蚀。

Claims (17)

1、一种用于向用于切割或汽化组织的电外科器械提供射频(RF)功率的电外科发生器，其中该发生器包括射频输出级，该射频输出级具有：
至少一个射频功率器件，
至少一对输出线，用于向电外科器械传送射频功率，以及
串联谐振输出网络，该串联谐振输出网络耦合在射频功率器件和所述一对输出线之间，以及
其中输出级在输出线处的输出阻抗小于200/
Figure A2003801085100002C1
欧姆，在此P是以瓦为单位的发生器最大连续射频输出功率。
2、根据权利要求1所述的发生器，进一步包括保护电路，响应实质上指示输出电流过载的预定电状态，以便中断供给输出网络的射频功率。
3、根据权利要求2所述的发生器，进一步包括响应输出线短路的发生的保护电路，以及其中，串联谐振输出网络是这样的，以致在短路发生时输出线的输出电流的上升速率小于每微秒(
Figure A2003801085100002C2
)/4安培。
4、根据权利要求2所述的发生器，进一步包括响应输出线短路的发生的保护电路，以及其中，保护电路足够快地响应所述短路，以便在由于短路而使通过射频功率器件的电流上升到额定最大电流之前，禁止射频功率器件。
5、根据权利要求4所述的发生器，其中，响应输出线短路的发生而禁止功率器件，该禁止是在与少于被传送射频功率的3个射频周期相对应的时期内发生的。
6、根据权利要求2至5中任一权利要求所述的发生器，其中，预定电状态指示输出级中超过预定电平的瞬时电流，以及保护电路的响应速度是这样的，以致在瞬时电流超过所述电平的射频周期内检测到所述状态。
7、根据以上任一权利要求所述的发生器，包括：
电源级，该电源级耦合到射频输出级，该电源包括用于向一个或多个功率器件提供功率的电荷存储元件，以及被安排成感测通过电荷存储元件提供给射频输出级的电压的电压感测电路；以及
脉冲调制电路，该脉冲调制电路耦合到电压感测电路，并用于对所述或每个功率器件进行脉冲调制，设置电压感测电路和脉冲调制电路，以致响应感测的电压来控制脉冲定时。
8、根据权利要求7所述的发生器，其中，电压感测电路和脉冲调制电路被设置成，当感测的电压降到预定电平以下时，终止通过一个或多个射频功率器件传送的射频能量的单个脉冲。
9、根据权利要求8所述的发生器，其中，设置预定电平，以致当电压下降5％至20％之间的预定百分值时，脉冲终止发生。
10、根据权利要求7或8所述的发生器，其中，设置预定电平，以致当在输出线上传送的峰值射频电压下降到各个脉冲的起始电压值以下25V至100V之间的值时，脉冲终止发生。
11、根据权利要求7至10中任一权利要求所述的发生器，其中，电源和脉冲调制电路被设置成在输出端产生脉冲射频输出信号，该输出信号具有至少1A的峰值电流、至少300V的同时峰值电压、5Hz至2kHz之间的调制速率、以及100μs至5ms之间的脉冲长度。
12、根据权利要求11所述的发生器，其中，脉冲长度在0.5ms至5ms之间。
13、根据权利要求11或12所述的发生器，其中，脉冲占空系数在1％至20％之间。
14、根据权利要求11至13中任一权利要求所述的发生器，其中，电源和脉冲调制电路被设置成在输出端产生脉冲射频输出信号，该输出信号在整个脉冲长度内都具有至少300V的峰值电压。
15、根据权利要求11至14中任一权利要求所述的发生器，其中，电源和脉冲调制电路被设置成在初期在输出端产生具有至少1A的峰值电流、至少300V的同时峰值电压、5Hz至2kHz之间的调制速率、以及100μs至5ms之间的脉冲长度的脉冲射频输出信号，并且在后期在输出端产生恒定功率射频输出信号。
16、根据以上任一权利要求所述的电外科发生器，其中，发生器用于在湿区域电外科中向用于切割或汽化组织的电外科器械提供射频功率，以及输出级在输出线的输出阻抗小于10欧姆。
17、根据权利要求1至15中任一权利要求所述的电外科发生器，其中，发生器用于在干区域电外科中向用于切割或汽化组织的电外科器械提供射频功率，以及输出级在输出线的输出阻抗小于50欧姆。
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EP1581128B1 (en) 2007-05-30
CN1323649C (zh) 2007-07-04
ATE363236T1 (de) 2007-06-15
AU2003290301A1 (en) 2004-08-10
CA2512904C (en) 2011-06-14
ES2286487T3 (es) 2007-12-01
DE60314184T2 (de) 2008-01-24
WO2004062516A1 (en) 2004-07-29
JP2006512959A (ja) 2006-04-20
US7717910B2 (en) 2010-05-18
US20040138654A1 (en) 2004-07-15
EP1581128A1 (en) 2005-10-05
US7211081B2 (en) 2007-05-01
DE60314184D1 (de) 2007-07-12
EP1782741A2 (en) 2007-05-09
EP1782741A3 (en) 2008-11-05
US20070173808A1 (en) 2007-07-26
CA2512904A1 (en) 2004-07-29
JP4463113B2 (ja) 2010-05-12

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