CN101316560A - 使消融过程自动化以使人工干预的需要最小化 - Google Patents
使消融过程自动化以使人工干预的需要最小化 Download PDFInfo
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Abstract
使心脏消融自动化以需要最少的用户干预,由此减少工作人员和患者暴露于X射线的时间,增加患者的通过量,简化消融并使消融更加精密。利用定位器系统(132)和磁性导航器(160)使心脏消融点之间的引导自动化。通过监测系统参数完全自动地执行、中断和检测消融(5630,5670)。消融路径设计自动考虑了患者的特定心脏形态和导管系统的技术规格(S310,S330),并自动向存储器存储最佳消融路径,然后从该最佳消融路径中选择消融点(S340,S350)。
Description
本发明涉及身体组织的消融,更具体而言涉及使该过程的各阶段自动化。
消融是一种例如在去除肿瘤中反复逐点执行的治疗过程,以破坏身体组织选定部分中的这些点或部位。还可以利用消融来防止异常电信号通过心脏——电信号正常地流过心脏以维持心跳,但现有异常信号可能导致异常的心跳节律,即心律不齐。射频(RF)消融是一种具有高成功率,并发症发生率低的消融技术。
对于每种心律不齐而言,都有异常脉搏发生或扩散的解剖区域。如果通过导管消融不可逆地破坏掉该区域,则由于导电性(electrical conduction)被阻断而使心律不齐消失。RF心脏导管消融通过静脉引入导管,以接触心脏内的选定区域。在导管中有消融导管以及用于测量和输送脉冲的导管。导管尖端含有一个或多个电极。例如在从大约300到750kHz的射频处产生交流电流。通常,每次输送大约10到60秒的电流。迅速变化的电场导致电极尖端处的离子快速地交替位置。所得到的摩擦在消融导管尖端处对身体组织进行加热。通过控制电路的电参数,可以将加热保持在一般为65°C左右的水平,这样“烧灼”或消融掉目标组织从而导致该位置的损伤。加热组织的温度随着距尖端的距离而迅速降低。因此,在消融掉一个点之后,如果要消融相邻区域,则引导尖端并移动到下一邻接点。重复该过程,直到消融掉整个区域,或者典型地像治疗心律不齐时一般的情况那样,消融掉整条线或环。由于RF消融与例如直流电(DC)消融相比效率高,因此该过程相对来说痛苦小,患者在整个过程中都是有知觉的。
为了防止在消融中允许有害的导电性穿透的间隙,沿着足以阻断导电性的路径的一段距离密集地逐点消融掉预先设计的消融路径中的特定消融点。可以通过进行电生理学(EP)研究来设计该路径。该EP研究可能涉及通过静脉向心脏中引入导管,将导管导引到特定位置并基于来自导管的读数或样本进行测量。不必在EP阶段进行消融,而是典型地在一旦完全绘制出EP图稍后进行。然后,干预式治疗师通过查看EP图和其他可用信息(例如CT)来决定对哪里进行消融。然而,虽然干预式治疗师通过思考组合了该信息,但它不是由系统的技术方法来叠合或组合以优化和预计结果的。然而,虽然预先设计的路径或许可以在计算机屏幕上看到,但并不被记录用于随后自动执行的消融。
尽管对于良好的干预治疗结果而言精确的消融路径设计和密集的采样路径是至关重要的,但作为受过特殊训练的心脏病学家的电生理学家在消融过程中必需要主要依靠其专业知识。具体而言,在消融的不同阶段几乎没有提供任何质量保证支持。例如,临床医生在事先设计消融路径时未得到基于规则的系统的协助。并未与其他一般可用信息对比检验所设计的路径得到的结果,因此潜在地导致在消融期间要做出匆忙决定或者导致亚最佳的结果。而且也不记录设计的路径。
而且,由于未考虑到所有信息且未考虑到所选路径的所有结果,因此路径设计是不精确的,且所选路径可能不是可行的最佳方案。结果,经常需要对路径进行再次消融,以生成不间断的消融线,这防止通过心脏的信号传播的错误成分通过消融线。同样地,作为未变成期望行为的信号传播的结果,可能需要额外的消融路径以获得充分的结果。在消融期间,临床医生监测诸如温度和功率的参数,在每个点人工控制消融持续的时间,并逐点地人工引导消融导管。由于引导和形成损伤都是人工过程,因此导管消融技术费力费时。
在当今的方法中,平均的消融过程耗时大约2个小时,并且结果的质量严重取决于生理学家的技能。
在涉及X射线时需要降低成像持续的时间,并且需要提高患者的通过量。还需要根据给定边界条件下的最佳解进行更精密的消融。同样地,还需要对消融过程进行简化,尤其是对于经验不多的医师而言。
如下所述,本发明提出连续地执行所有消融步骤,而使直接干预的量尽可能最小。该新颖的消融过程优选地包括:进行设计,以得出路径;在所得出的路径上自动向消融点引导,以到达所述点;基于在消融期间变化的参数自动控制在所到达点处的消融;自动确定所到达点中的消融失败的那些点;自动记录被确定为消融失败的所到达点的位置;以及执行功能性结果控制,所述功能性结果控制自动连续接近从结果控制得到的新消融点。
在本发明的另一方面中,对要进行消融的心脏进行电生理学(EP)图的绘制或进行电生理学研究。分析患者心脏的形态以形成心脏模型。提供要用在消融中的导管系统的技术规格。然后基于所述图并受到所形成的模型和所提供的技术规格约束,无需用户干预且自动地生成最佳的消融路径。无需用户干预且自动地记录所得到的最佳路径。
在另一方面中,选择和存储身体组织中沿预定消融路径的点。对于所存储点中的当前一个,确定该点处的消融是否完成。无需用户干预且自动地进行该确定。在完成时,无需用户干预且自动地引导消融设备,以在身体内从当前点移动到下一点。
在又一个方面中,在对一点处的消融期间监测参数。无需用户干预且自动的确定何时完成对该点的消融。基于所监测的参数,在该点处的消融完成前,无需用户干预且自动地执行要完成的消融直到消融的终止。例如,可以检验在一部位处执行消融的导管是否与进行消融的身体组织失去物理接触,以及在该部位的温度是否降到预定阈值之下。在任一种状况下,都终止该点的消融。还进行自动监测,以检测可能表示对患者危险的任何状况,并在检测到这种状况时立即自动暂停消融。
另外一个方面涉及针对沿消融路径的预定消融点组无需用户干预且自动地执行如下步骤中的每一步:a)引导消融设备接近所述点中的当前一个,以在到达所述当前点时在所述当前点开始消融;B)确定接近是否未成功,如果未成功,则存储当前点的位置;以及c)如果确定接近成功,则确定在当前点的消融是否未成功,如果未成功,则存储该位置。针对路径上的下一点重复步骤a)到c),直到处理完最后的点。
下面借助以下附图阐述本发明的细节,附图中:
图1是根据本发明的需要最少人工干预的示例性集成电生理学(EP)工作站的组成方框图;
图2是对根据本发明的心脏消融过程进行概述的流程图;
图3是根据本发明的心脏消融准备过程范例的流程图;
图4是根据本发明的心脏消融过程的一个实施例的流程图;
图5是根据本发明的示例性消融后结果控制过程的流程图;
图6是阐明根据本发明在消融期间进行的检验的范例的流程图;以及
图7是在根据本发明引导和移动导管的特定实施例中的处理的流程图。
图1以例示性而非限制性示例的方式描述了根据本发明需要最少人工干预的示例性集成电生理学(EP)工作站100。该工作站100具有处理器104,包括存储器106、时钟108、工作站显示器112和图形用户界面(GUI)输入设备116。工作站100还包括心电图单元120、X射线或MR或其他模态单元124、红外照相机128、三维(3D)解剖学导管定位器132和交流电流发生器136。消融导管140具有尖端144,其中并入了用于进行消融的射频(RF)AC电极148、用于监测当前消融点或部位的温度的热电偶或热敏电阻152以及以磁力引导导管140的磁体156。磁性导航器160利用其磁体156引导尖端144。虽然仅示出了消融导管,但应该理解的是,可以并且通常会使用许多导管。测量导管在EP研究期间测量电活动并可以伴有参考导管。可以使用起搏导管来输送和接收脉冲,以人为地对心脏进行起搏并提供测试消融线完整性的可行性,消融线即为了阻断跨越心脏的错误导电性而形成的消融点的线。
虽然在此以RF消融为背景描述了本发明,但取而代之使用其他消融技术也在本发明期望的范围之内,其他消融技术例如是直流电流、激光、超声波、冷冻疗法(cryothermy)、微波和酒精。
图2提供了对根据本发明的新颖消融方法的概述。预先设计消融路径(步骤S210)。在消融期间,向路径上的点引导这一过程是自动的(步骤S220)。基于在消融期间变化的参数自动控制消融(步骤S230)。自动确定一点处的消融的失败(步骤S240)。自动记录每个失败点的位置(步骤S250)。进行功能性输出控制,并自动靠近由该控制产生的新点以进行消融(步骤S260)。可以任选地执行光学输出控制。自动靠近由光学输出控制产生的新点以进行消融(步骤S270)。
图3示出了根据本发明的心脏消融准备过程200的优选实施例,其对应于步骤S210。
最初,可以形成心脏的非患者特异性模型,该模型包含了有关心脏生理学的先验知识。然后基于成像扫描的结果针对患者修正该最初的模型。该模型提供了减少测量数量的优点,更重要的是提供了对可能由即将进行的消融过程产生的电生理学变化的预测。以不同程度对心脏属性建模的不同模型也是可行的。一些范例是基于先验知识和可用的当前输入信息的电生理学模型、电解剖学模型以及包括机械属性的模型。
例如,通过对患者进行计算机断层摄影(CT)扫描获取形态3D数据集,以形成心脏的模型(步骤S310)。为此,可以在3D数据集中对心脏进行分割。可以对CT扫描进行ECG门控以对心脏的不同收缩状态成像,从而可以使心脏的运动成为模型的一部分。在获取数据集时除了使用CT扫描,还可以使用诸如磁共振(MR)成像和X射线体积成像的其他成像模态。
而且,进行EP研究(步骤S320),其涉及在心脏中定位电极以测量和记录电活动。由磁性导航器160通过静脉内将导管140导引到心脏的选定位置,测量和参考电极对电活动进行采样。可以相对于心跳的相位将这些样本绘制在时间坐标上,各个相位地收集信息。由此形成EP图。解剖学导管定位器132仅检测导管尖端144的相对位置,并且将其相应地记录到3D数据集中,以便随后更新在步骤S310中形成的模型。
基于该EP图和心脏模型,在实际消融之前,在路径设计过程中排除掉可能由于患者个体特性而不易接近或无法到达的心脏区域。EP图会示出不传导信号的坏死组织,因此可以从设计的路径中排除掉这些坏死组织。除了这些考虑之外,还需要导管系统规格以引导导管140(步骤S330)。例如,由于导管的形状可能无法进入心脏的某些区域。处理器104基于对模型的预测,无需用户干预且自动地生成最佳消融路径,这又是基于EP图的,并受到心脏模型和导管技术规格的约束(步骤S340)。处理器104可以通过测试一组给定消融路径并确定具有最佳预测结果的路径,而择一地选择最佳的消融路径。在优选实施例中,在EP图给出的边界条件、模型和技术规格已知的情况下,对一小组预定消融路径,例如30条路径进行全面搜索以找到最佳路径。
有利地,无需用户干预且自动地将路径作为点坐标列表或(例如)3D图像记录到存储器106中,用于接下来选择要消融的点(步骤S350)。因此,该新颖的路径设计过程是一种反复的方法,其采用了所有可用的信息并对其进行对比检验,以为电生理学家提供用于每个患者个体和导管系统140的最佳消融路径。
图4提供了根据本发明的示例性心脏消融过程400的细节。从存储器106中检索出先前计算的最佳消融路径。磁性导航器160与解剖学导管定位器132结合用于无需用户干预且自动地将消融导管尖端144引导到当前消融点,从而能够在当前点开始消融,同时自动监测消融的操作参数(步骤S410)。利用患者胸部上的片状电极,来自电极148的电流通过患者的身体返回到发生器136。磁性导航器160利用其磁体156生成磁场以将导管尖端144引导到第一点。由定位器132完成位置测量以检测到达第一点,定位器可以是诸如LocaLisaTM或Real time Position ManagementTM的系统。或者,可以从诸如X射线或荧光检查图像的实时图像数据中提取导管位置。一旦检测到到达,则无需用户干预且自动地将导管电极尖端144激活以开始消融,从而在很小的半径内消融掉身体组织。在完成消融时,因为已经形成了充分的损伤,由处理器104基于其系统参数读数确定停止RF能量的输送。优选不需要用户交互,基于被监测的系统参数以及用于确定当前点处完成情况的一组规则来做出该确定。在一点的消融持续时间通常为10到60秒。可以监测的一个参数为功率输出,通常为20到50瓦。可以通过来自热电偶或热敏电阻152的反馈,将温度保持恒定在例如65℃左右,或者可以允许其变化。阻抗是另一个可以监测的参数。如下文参考图6所述,当在当前点处完成消融(步骤S420),或在当前点的消融失败并中断时,如果还有下一点,则沿消融路径选择下一点(步骤S430、S440)。否则,如果沿该消融路径没有下一点,则将任何失败且早先终止的点作为下一点而再次访问(步骤S440)。对再次访问的替代是由干预式治疗师进行半人工过程以成功消融该失败点,或者是完全人工的过程。当因为每个点都得到成功消融而没有任何要消融的点时,该消融线完成,开始功能性结果控制。作为上述在第一次通过消融线之后进行再次访问的替代,可以立即重新访问失败点。
图5示出了根据本发明的优选消融后结果控制过程500的示例。
功能性结果控制意在覆盖例如如下可能性:在消融过程400中先前形成的疤痕在心脏组织内不够深,无法完全防止错误信号的传播。在功能性结果控制过程500中,在完成消融线时(步骤S430,“否”分支),以执行消融前绘图相同的方式通过导引导管来进行消融后重绘图。对两次绘图进行比较以识别需要消融的新点。对于功能性结果控制而言,还可以利用借助起搏电极进行的起搏,即,跨越消融线从一个电极到另一个电极发送信号来识别新点。以电子方式将新点存储到存储器106中,作为更新后的消融路径(步骤S530)。如果已经识别了新点,使得必需进行进一步消融(步骤S535),则针对这些点再次执行心脏消融过程400。功能性结果控制的自动化包括根据心脏模型使确定将起搏电极放置在哪里的过程自动化。
在随后的光学结果控制过程中,红外照相机128无需用户干预且自动地完成消融线的可见扫描以找到间隙(步骤S540)。在执行扫描期间,遵循在步骤S530中预先存储的消融路径进行。如果找到了间隙(步骤S550),则暂停扫描,并在存储器106中存储一个或多个点位置(步骤S560)。然后在步骤S540继续进行扫描。如果未发现间隙,或者未再发现间隙(步骤S550),则询问是否需要进一步的消融(步骤S570)。如果不需要,则完成了过程500。否则,处理返回到步骤S410进行下一次消融过程,这次致力于填充间隙。
图6示出了根据本发明的消融中断过程600的示例。在步骤S410期间运行该中断过程560,以在出现预定状况时有选择地中断消融。如果被监测的参数超过了设定的安全容限(步骤S610),则自动断开电源(步骤S620)。终止在当前点的消融并存储点位置和当前参数(步骤S630)。作为另一种状况,如果检测到失去接触(步骤S640),则终止当前点的消融并存储参数(步骤S630)。可以利用傅立叶方法通过导管尖端的运动方式检测失去接触。如果将温度维持在预设水平,例如至少50℃,还可以通过所用电流的升高来检测失去接触,这是因为患者的血流充当散热器。如果未将温度保持在设定范围内,则由于热沉效应可以从快速的温度下降立即明显看出失去了接触。另一种状况是容抗的不充分下降(步骤S650),这表明在当前点消融未成功。施加交流电流导致频率升高,这一般会降低容抗。在预定的消融持续时间内阻抗未能下降大约10%可能是由导管尖端144上形成了凝块导致的。最后,如果温度低于50℃(步骤S670),则由于上述“热沉”效应推定为失去接触。如果不存在任何这些状况,且当前点的消融正在进行(步骤S680),则执行返回以重复检验(步骤S610)。
图7示出了根据本发明用于引导导管尖端144的示例性过程700。该过程700与步骤S410并行操作。解剖学导管定位器132通过实时地将位置与预期位置进行比较来监测导管尖端144的当前位置。预期位置是下一个目的地,即消融点的位置,并且可以从存储的3D图像或消融点坐标列表访问该预期位置。因此,定位器132检测导管尖端144的位置(步骤S710),检验其是否与预期位置匹配(步骤S720),并且如果不匹配,则确定操纵到下一点的时间是否已经过期(步骤S730)。如果该时间尚未过期,则从步骤S710开始重复该过程。否则,如果该时间已经过期(步骤S730),则引导到下一点的操作已经超时。存储下一点的位置,即未尝试的目的地位置,以及当前参数,随后的点变成当前目的地(步骤S740)。另一方面,如果对导管尖端的当前位置和预期位置的比较得到的结论是已经到达预期位置,则磁性导航器保持该导管尖端位置,直到消融完成为止(步骤S750)。
尽管以应用于其优选实施例的方式显示、描述并指出了本发明的基本新颖特征,但应当理解的是,本领域的技术人员在不脱离本发明的精神的情况下可以在图示设备的形式和细节上以及它们的操作上做出各种省略、替代以及改变。例如,为了节省时间光学结果过程可以是预先的,因为功能性结果控制可能是足够的了。应当认识到,作为一般性设计选择问题,可以将结合任何公开形式或本发明实施例显示和/或描述的结构和/或元件和/或方法步骤并入到任何其他公开的或描述的或建议的形式或实施例中。
Claims (22)
1、一种计算机实现的消融方法,包括:
选择沿着身体组织中预定消融路径的多个点并存储所选的点(S210);
无需用户干预且自动地确定何时在所述多个点中的当前点处完成由消融设备进行的消融(S420);以及
在所述确定完成时,无需用户干预且自动地将所述设备从所述当前点引导到所述多个点中的下一个(S410)。
2、根据权利要求1所述的方法,其中,所述组织是要进行消融的心脏的组织(S310)。
3、根据权利要求1所述的方法,其中,所述引导步骤在所述身体内移动所述设备(S310)。
4、根据权利要求1所述的方法,还包括:
检测所述设备到达所述下一点;以及
在到达时,无需用户干预且自动地开始所述消融(S410)。
5、根据权利要求1所述的方法,其中,所述消融、确定和引导步骤是反复的,使得在所述引导步骤之后,以所述下一点作为所述当前点再次执行所述消融和确定步骤,随后进行所述引导步骤,直到所述当前点为所选点中的最后一个为止(S430,S440)。
6、根据权利要求1所述的方法,还包括:在检测到预定状况时,无需用户干预且自动地a)中断在所述当前点处的所述消融,b)将所述设备移动所述多个点中的所述下一个,以及c)在所述下一点处执行消融(S630,S670)。
7、一种配置为用于执行根据权利要求1所述的方法的仪器(100)。
8、一种计算机程序产品,其具有计算机可读介质,在所述计算机可读介质中嵌入计算机程序,所述计算机程序包括用于执行权利要求1所述的方法的指令(106)。
9、一种为心脏消融进行准备的方法,所述方法包括:
作出要进行消融的心脏的电生理图(S320);
以下操作中的至少一种:分析所述心脏的形态以形成心脏模型以及提供要用在所述消融中的导管系统的技术规格(S310,S330);
基于所作的图并相应地受所形成的模型和所提供技术规格中的至少一个的约束,无需用户干预且自动地生成消融路径(S340);以及
无需用户干预且自动地记录所形成的路径(S350)。
10、一种计算机实现的消融方法,包括:
在在一点处进行的所述消融期间监测参数(S670);以及
无需用户干预且自动地确定何时完成所述点处的所述消融,这受到基于所监测的参数无需用户干预且自动地在完成前终止所述点处的所述消融的约束(S410)。
11、根据权利要求10所述的方法,还包括:
检测执行所述消融的导管已经失去与身体组织的物理接触(S640)或所述点处的温度已经降到预定阈值之下(S670);以及
如果发生任一种状况则执行所述终止(S630)。
12、根据权利要求11所述的方法,还包括:
检验在预设的消融持续时间内电路遇到的阻抗是否降到预定阈值之下(S650);以及
如果确定该阻抗在所述预设持续时间内未降低所述预定阈值,则终止所述点处的所述消融(S630)。
13、一种计算机实现的消融方法,包括:
无需用户干预且自动地对预定消融点组执行以下步骤a)到d)中的每一个:
a)引导消融设备接近多个点中当前的一个,从而在到达所述当前点时在所述当前点开始进行消融(S410);
b)确定所述接近是否未成功,并且如果未成功,则存储所述当前点的位置(S630);
c)如果确定所述接近成功,则确定在所述当前点处的所述消融是否未成功,并且如果未成功,则存储所述位置(S630);以及
d)对下一点重复步骤a)到c),直到处理了最后一点为止(S430)。
14、根据权利要求13所述的方法,其中,所述确定步骤包括如下操作中的至少一种:检验在所述设备的所检测位置与所述设备的预期位置相匹配之前预定时间段是否已经过期(S730)和将其告知。
15、根据权利要求13所述的方法,还包括:对通过所述方法生成的身体组织中的消融线,并且为了基于一组新点再执行所述方法,无需用户干预且自动地沿着消融路径对可视检查设备进行导航以检测所述线中的间隙,并且将所述间隙中的点位置作为所述新组而存储,所述消融路径存储在存储器中并从其对所述预定消融点组进行采样(S540)。
16、一种配置为用于执行根据权利要求13所述的方法的仪器(100)。
17、一种计算机程序产品,其具有计算机可读介质,在所述计算机可读介质中嵌入计算机程序,所述计算机程序包括用于执行权利要求13所述的方法的指令(106)。
18、一种消融方法,包括:
进行设计,以得出路径(S210);
在所得出的路径上自动向消融点引导,以到达所述点(S220);
基于在所述消融期间变化的参数自动控制在所到达点处的消融(S230);
自动确定所到达点中的所述消融失败的那些点(S240);
自动记录被确定为消融失败的所到达点的位置(S250);以及
执行功能性结果控制,所述功能性结果控制自动地连续接近从所述结果控制得到的新消融点(S260)。
19、根据权利要求18所述的方法,还包括自动进行光学结果控制(S270)。
20、一种消融仪器,包括:
用于在预先设计的路径上自动向消融点引导以到达所述点的装置(160);
用于基于在所述消融期间变化的参数自动控制在所到达点处的消融的装置(104);
用于自动确定所到达点中的所述消融失败的那些点的装置(S240);
用于自动记录被确定为消融失败的所到达点的位置的装置(S250);以及
用于自动地连续接近从功能性结果控制得到的新消融点的装置(S260)。
21、根据权利要求20所述的仪器,其中,所述用于自动接近的装置包括用于比较消融后重绘图和消融前绘图的装置,所述新消融点的得到是从所述比较得出的(S530)。
22、根据权利要求20所述的仪器,还包括光学输出控制,用于沿着包括所述新消融点的路径进行可视化扫描(S540)。
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- 2006-11-15 WO PCT/IB2006/054269 patent/WO2007063443A2/en active Application Filing
- 2006-11-15 US US12/094,615 patent/US20080300588A1/en not_active Abandoned
- 2006-11-15 CN CN2006800449156A patent/CN101316560B/zh not_active Expired - Fee Related
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CN108472076A (zh) * | 2016-01-07 | 2018-08-31 | 伯尔尼大学 | 用于位姿受控的消融的方法和系统 |
CN108472076B (zh) * | 2016-01-07 | 2022-05-31 | 伯尔尼大学 | 用于位姿受控的消融的方法和系统 |
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CN111491581B (zh) * | 2017-11-14 | 2024-02-09 | 波士顿科学医学有限公司 | 消融程序期间使用的计时系统 |
CN108186116A (zh) * | 2018-02-12 | 2018-06-22 | 中南大学湘雅二医院 | 一种手术刀尖热源成像系统及其方法 |
WO2019153983A1 (zh) * | 2018-02-12 | 2019-08-15 | 中南大学 | 一种手术刀尖热源成像系统及其方法 |
CN112790858A (zh) * | 2020-12-31 | 2021-05-14 | 杭州堃博生物科技有限公司 | 消融参数配置方法、装置、系统及计算机可读存储介质 |
CN112790858B (zh) * | 2020-12-31 | 2021-11-09 | 杭州堃博生物科技有限公司 | 消融参数配置方法、装置、系统及计算机可读存储介质 |
Also Published As
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EP1956992A2 (en) | 2008-08-20 |
US20080300588A1 (en) | 2008-12-04 |
WO2007063443A3 (en) | 2007-11-01 |
JP2009517161A (ja) | 2009-04-30 |
CN101316560B (zh) | 2011-01-26 |
JP5227180B2 (ja) | 2013-07-03 |
EP1956992B1 (en) | 2013-03-06 |
WO2007063443A2 (en) | 2007-06-07 |
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