CN103813829B - 具有可定位于螺旋引导件中的神经调制元件的神经调制系统 - Google Patents
具有可定位于螺旋引导件中的神经调制元件的神经调制系统 Download PDFInfo
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- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B2018/00571—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for achieving a particular surgical effect
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Abstract
一种用于神经调制的系统包括:第一细长元件(14),其具有远端和近端,并且具有螺旋引导件(26),螺旋引导件具有近端和远端。该系统还包括第二细长元件(12),其具有远端和近端并且具有靠近远端的神经调制元件(22)。护套(16)围绕第一细长元件和第二细长元件二者而安置。
Description
相关申请的交叉引用
根据35U.S.C.§119,本申请要求保护在2011年7月22日提交的美国临时申请序列号No.61/510,900的优先权,其全文以引用的方式合并到本文中。
技术领域
本发明涉及用来通过血管壁进行神经调制的方法和设备。这样的调制可以包括消融神经组织或者其它破坏性调制技术。
背景技术
某些治疗需要暂时或永久中断或改变选定神经功能。一种示例治疗为肾神经消融,其有时用来治疗与充血性心衰竭有关的病症。肾脏对于充血性心衰竭产生交感响应/共鸣(sympatheticresponse),其增加了水和/或钠的不当的潴留。对于延伸到肾脏的神经中的某些进行的消融减小或排除了这种交感功能,这提供相关联的不当症状的相对应减轻。
许多神经(和诸如脑组织的神经组织),包括肾神经,沿着血管壁或者靠近血管延伸并且因此可以通过血管壁进入血管内。因此,希望提供用于血管内神经调制的系统和方法。
发明内容
邻近血管定位的神经常常沿着血管的一部段的长度延伸。神经难以使用诸如放射线照相术等标准成像技术来成像。因此,希望在血管壁上的不同径向部位处施加消融或其它神经调制程序来实现围绕血管壁的整个圆周的消融。也希望在不同的纵向部位处施加该程序以避免沿着单个周向部段弱化或以其它方式影响血管壁。因此实施例包括螺旋引导件,其提供电极或其它治疗元件的简单并且同时径向和纵向移动。这种螺旋引导件可以例如为螺旋凹槽、轨或螺纹。螺旋引导件可延伸至少一个完整的周向旋转并且在某些实施例中两个或更多个周向旋转。在向近端牵拉电极时,其被迫遵循螺旋引导件以更改(容易地并且可预测地)其纵向和径向位置。
某些实施例可包括以下三个元件,这三个元件可相对于彼此移动:中心轴杆,其合并螺旋引导件;细长电极承载元件;以及,护套。在示例使用方法的总结中,细长电极承载元件和中心轴杆位于护套中,电极(附连到承载元件的远端)安置于轴杆的远端处或附近。该系统移动到身体血管中所希望的部位并且收回护套,允许电极和/或承载元件在径向扩展使得电极能接触血管壁。承载元件可以相对于轴杆向近端牵拉并且电极被间歇地或持续地启动。在牵拉承载元件时,电极在纵向和径向移动以提供所希望的模式。电力可通过承载元件或在某些情况下通过轴杆供应到电极。一旦完成治疗,轴杆和承载元件可以被抽回到护套内并且系统可从身体抽回。
某些实施例包括定心元件,诸如可扩展的撑架、腿、笼状物或螺旋元件或者可膨胀的气球,其在该程序期间保持轴杆在血管内居中。可通过抽回护套或供应膨胀流体来适当地部署定心元件并且可以通过抽回到护套内或者排空膨胀管腔来使定心元件收拢。定心元件中的某些被描绘为两个或三个成组,但设想到并可使用其它数量的定心元件(例如,撑架或腿)诸如4、5、6个或更多个。
在某些实施例中,可通过中心轴杆供应电力。中心轴杆可以具备多个接触贴片,可通过多个接触贴片向在中心轴杆和承载元件的特定预定相对位置处供应电力。以此方式,在承载元件相对于中心轴杆向近端牵拉时,电极可以在预定部位处自动地启动。
如本文所用的术语电极当然指适用于射频消融或调制程序的电极,但其不应认为受此限制。应了解在使用“电极”的情况下,也意图指适用于激光、超声、微波、电阻加热或低温程序的其它元件。另外,电极涵盖单路径电极和包括返回路径的电极。此外,本文所描述的方法和设备可易于适用于其它治疗元件,诸如冲洗、药物递送、抽吸或动脉粥样硬化切除术(atherectomy)元件并且也设想到结合这样的其它元件使用。术语调制指消融和可以更改受影响的神经功能的其它技术。
上文某些示例实施例的总结预期并不描述本发明的每个公开的实施例或者每个实施方式。
附图说明
可以结合附图,考虑下文各种实施例的详细描述更全面地理解本发明,
图1为示出就位的肾神经调制系统的示意图。
图2示出肾神经调制系统的远端。
图3a至图3d示出了就位的图2的肾神经消融系统的远端,其中电极处于各个位置。
图4a和图4b为可用于例如图2的实施例以及其它实施例的各种中心轴杆的截面图。
图4c为肾神经调制系统的中心轴杆的截面图。
图4d为肾神经调制系统的中心轴杆的截面图。
图5a和图5b为可例如用于图2的实施例的中心轴杆的远端部分的视图。
图5c为肾神经调制系统的中心轴杆的远端部分的视图。
图5d为肾神经调制系统的中心轴杆的远端部分的视图。
图6为可使用图5c所示的轴杆的肾神经调制系统的截面图。
图7为可使用图5c所示的轴杆的肾神经调制系统的截面图。
图8a为具有定心元件的肾神经调制系统的远端部分的视图。
图8b为具有定心元件的肾神经调制系统的远端部分的视图。
图8c为具有定心元件的肾神经调制系统的远端部分的视图。
图8d为具有定心元件的肾神经调制系统的远端部分的视图。
图9a为具有定心元件的肾神经调制系统的远端部分的视图。
图9b为图9a的肾神经调制系统的截面图。
图10为具有诸如图4c所示的多凹槽轴杆的肾神经调制系统的远端部分的视图。
图11a示出肾神经调制系统的远端部分的视图。
图11b示出肾神经调制系统的远端部分的视图。
图12为符合图11a或图11b的肾神经调制系统的截面图。
图13为肾神经调制系统的中心轴杆的远端视图。
图14为使用图13的中心轴杆的肾神经调制系统的远端视图。
图15a示出肾神经调制系统的远端部分的视图。
图15b为图15a的肾神经调制系统的部件的远端部分的视图。
尽管本发明能够做出各种修改和具有替代形式,将在附图中以举例说明的方式示出并且将详细地描述本发明的细节。但应当指出的是,预期并不将发明方面限制为所描述的特定实施例。相反,预期涵盖属于本发明的精神和范围内的所有修改、等效和替代物。
具体实施方式
对于以下定义的术语,除非在权利要求或本说明书中的其它地方给出不同的定义,将采用这些定义。
所有数值在本文中由术语“约(大约)”修饰,无论是否明确地指示。术语“约(大约)”大体上指本领域技术人员将认为等效于所叙述的值(即,具有形同的功能或结果)的数值范围。在许多情形下,术语“约(大约)”可以指示为包括四舍五入到最接近的有效数字的数值。
以端点叙述数值范围包括在该范围内的所有数字(例如,1至5包括1、1.5、2、2.75、3、3.80、4和5)。
尽管公开与各种部件、特点和/或规范有关的某些合适尺寸、范围和/或值,受益于本公开的本领域技术人员将了解到所希望的尺寸、范围和/或值可偏离明确地公开的那些。
如在本申请和所附权利要求中所用的单数形式“一”、“该”和“所述”包括复数参考,除非内容明确地指示为其它情况。如在本说明书和所附权利要求中所用的术语“或”通常以其包括“和/或”的意义来采用,除非内容清楚地指示为其它情况。
将参考附图来阅读下文的详细描述,在不同附图中,相似的元件以相同的附图标记来标注。详细描述和未必按照比例绘制的附图描绘了说明性实施例并且预期并不限制本发明的范围。所描绘的说明性实施例预期只是示例性的。任何说明性实施例的选定特点可以合并到额外实施例内,除非清楚地陈述为相反情况。
作为总体介绍和方位,图1为示出了就位的肾神经调制系统的示意图。系统10包括可围绕中心轴杆14并且在护套16内可滑动地安置的细长电极承载元件12,其细节将在下面的附图中更好地看到。细长电极承载元件12连接到控制和电力元件18,控制和电力元件18供应必需的电能以在电极承载远端12的远端处或附近启动一个或多个电极。返回电极贴片20可以供应到腿上,或患者身体上的另一常规部位处以完成电路。
控制和电力元件18可以包括监视元件以监视参数,诸如功率、温度、电压、脉冲大小和/或形状和其它合适参数以及用来执行所希望的程序的合适控件。
图2示出肾神经调制系统的示例实施例的远端。细长电极承载元件12围绕中心轴杆14并且在护套16内安置。元件12、14和16可相对于彼此移动。细长电极承载元件12包括附连到导体24上的电极22,并且导体24和电极的基座部32安置于中心轴杆14的凹槽26中。当导体相对于中心轴杆14被向近端牵拉时,电极22同样向近端转移并且也绕中心轴杆沿着凹槽26旋转。
凹槽26为螺旋引导件,其可具有显著地大于螺距的导程使得螺旋引导件的相邻的圈(coil)彼此间隔开。在某些情况下,导程可以是螺距的两倍、三倍、四倍或更多倍。凹槽的螺距可以近似与电极的宽度相同或者在某些情况下比电极的宽度更宽。
图3A至图3D示出了在电极向近端移动时电极的此旋转和径向移动。在图3A中,电极22被预先加载于轴杆14的远端处。在由导体24向近端牵拉电极22时,其围绕轴杆14旋转并且其远端接触在不同纵向部位处的血管壁28的不同径向部位,跟踪沿着血管壁的螺旋接触路径。电极22可以在沿着这个接触路径的3个、4个、5个、6个、7个、8个或更多个部位处选择性地启动,或者可持续地并且间歇地启动而同时跟踪此路径。
此外,图3A至图3D示出了就位的肾神经模制系统的远端。这样的系统可前移到血管内的所希望的部位,其中细长电极承载元件12和中心轴杆14在护套16内。设想到电极22为弹性构件,其在递送期间可以在护套16内压缩以在收回护套16时扩展。
图4A和图4B示出了中心轴杆14和凹槽26的示例截面形状。凹槽26可以具有相对较窄的口部30并且随着其加深而加宽以便固持所述电极22的基座部32。图4C为中心轴杆14的示例截面形状,其示出了可以在轴杆中包括两个或更多个凹槽的系统的实施例。图4D为下文所描述的特定实施例的轴杆14的示例截面形状,其中,凹槽26仅充当引导件并且并未被成形为主动地固持所述电极22的基座部32。
可以使用与图4D的凹槽类似的凹槽26的一个这样的实施例为在图11A中示出在下文描述的实施例。可以使用凹槽诸如图4D的凹槽的另一实施例包括细长电极承载元件,其中导体24具有盘绕形状使得其能本身固持在凹槽内而无需如上文所描述那样使用基座部。电极可以是这样的导体的直远端部段,其当从护套释放时扩展到其部署位置和形状。当然,在任何实施例中的任何导体24可以被偏压到盘绕形状。
图5A示出了可以用于图2的实施例的轴杆14的远端部分。在此轴杆中,凹槽26可以包括螺旋远端部分34和直近端部分36。导体24将当然沿循通过远端部分34的螺旋路径并且然后沿着直近端部分36并且在直近端部分36内延伸。
图5B示出了可以用于图2的实施例的另一轴杆14的远端部分。这个轴杆14在具有第一较大的外径的远端部段38中包括凹槽26。此远端部段38从具有第二更小外径的较窄近端部段40延伸。部段40的外径可延伸到凹槽26的底部或者可更小。对于轴杆14的此实施例,导体24(未图示)的近端部分可以为带或线(如先前所示)或者可为圆柱形并且中空的并且围绕近端部段40安置。
图5C示出了替代轴杆14的远端部分,其中,螺旋引导元件为轨42,而不是先前示出的凹槽26。图6为上面安置了电极22的图5C的轴杆14的示意截面图。电极22附连到套环44,套环44具有对应于轨42的缺口46。这样的电极22可以附连到带状导体24(如先前所讨论的那样)或者可以是导体护套48的远端部分(如图7所示)。在这样的导体护套48中,缺口46沿着护套的长度延伸,或者在其它实施例中,护套沿着其长度的更大部分的内径可以大于轨42的外径向范围并且缺口部具有相对较小的范围。
图5D示出了替代轴杆14的远端部分,其中,轴杆围绕中心轴线43是螺旋的。在此轴杆中凹槽26朝向中心轴线43。此处,该通道比沿着直轴杆伸展的通道更直。诸如图11A的环形电极70的电极可以用于这样的轴杆。
图8A示出了包括远端定心元件50的实施例的远端部分。定心元件50为弹性弹簧元件,弹性弹簧元件可易于在护套16内压缩并且当收回护套16时扩展以接触血管壁从而保持轴杆14在系统操作期间居中定位。定心元件50具有防止损伤远端并且可包括衬垫或其它这样的元件。定心元件50可以具有如图所示的弯曲形状,并且远端可以是自由的或者可以联结在一起。替代地,定心元件可以是直的或者可具有向内弯曲的远端。
图8B示出了包括远端定心元件50和近端定心元件52的实施例的远端部分。定心元件52同样为可弹性压缩的构件,当收回护套16时(未图示)其以类似于定心元件50的方式向外膨胀。定心元件52被图示为具有自由远端,但也可具有往回弯曲以联结到轴杆14的远端。
图8C示出了包括螺旋远端定心元件54和近端定心元件56的实施例的远端部分。这些元件可以在护套16内压缩并且在收回护套16时扩展到它们的图示形状。在定心元件54与56之间为圆柱形轴杆部58,圆柱形轴杆部58具有如先前所讨论的凹槽26。具有基座部32的电极22可滑动地安置于凹槽26中并且连接到导体24(未图示)。
图8D示出了其中定心元件60和62为可膨胀的构件的实施例的远端部分。可膨胀的构件60在轴杆14的远端,其在此实施例中将包括膨胀管腔。可膨胀构件62被示出安置于薄片16上,其也将包括膨胀管腔。膨胀构件60和62中的任一个或二者可以具有不规则或非圆形的扩展形状以允许持续地灌注血液或者可以包括灌注管腔(未图示)。例如,可膨胀构件60和62中每一个可以包括两个或更多个圆形突出部。可膨胀构件60和62可以被配置成闭合介于中间的空间或者接近使之闭合,并且可以在两个气球之间注射冷却流体诸如盐水。
图9A示出了其中定心元件64安置在轴杆14的外表面上在不同纵向部位处的实施例的远端部分。类似于定心元件50,存在弹性弹簧构件,其在收回薄片16时扩展。由于电极22在操作期间在凹槽26内螺旋地移动,定心元件64在该过程中并不干扰电极。图9B为示出了定心元件64的径向位置的截面图,定心元件64基本上围绕轴杆14的圆周均匀地安置。
设想到在某些实施例中,定心元件50、52、54、56、60、62和64大小使得当定心元件部署或扩展时,元件或元件的组合完全延伸到血管壁。在这样的实施例中,定心元件具有与(多个)电极的径向范围近似相等的径向范围。在其它实施例中,定心元件可略微更小使得定心元件本身的组合并不横跨血管。替代地,定心元件的大小使得(多个)电极和(多个)定心元件的组合横跨血管。这样的实施例可以允许更自由的灌注和(多个)电极移动。
图10示出了在轴杆14中包括第一凹槽26和第二平行螺旋凹槽66的实施例的远端部分。在第一凹槽26中设有第一电极22并且在第二凹槽66中设有相对应的第二电极68(并未示出导体24)。
图11A示出了具有带三个定心元件72的环形电极70的实施例的远端部分。定心元件72中的一个、两个或更多个也可充当电极。如上文所述,定心元件72为弹性弹簧构件,当护套16收回时,其扩展。接触贴片74安置于中心轴杆14上。示出了两个,但设想到2个、3个、4个、5个、6个或更多个可以包括于轴杆上。电力可以穿过轴杆运送。在环形电极被向近端顺着轴杆牵拉时,其与接触贴片74接触并且因此在预定间隔自动启动(多个)电极。
图11B示出了其中定心元件72(其中的一个或更多个为电极)安置于圆筒76的远端部分上的实施例的远端部分。此实施例可包括如上文所描述的接触贴片。这样的接触贴片可以安置于沿着轴杆在圆筒76下的任何位置。
图12为示出环形电极70(或圆筒76)和置于其上的定心元件72的截面图。键78与轴杆的凹槽26接合并且可用来与接触垫片74进行电接触。应意识到关于此图,具有轨42的图5C的轴杆14可易于用于图11A和图11B的这些实施例的变型。
图13示出了其中电极82承载于中心轴杆80上的实施例的远端。中心轴杆80结合图14的中空圆筒84使用。圆筒84包括螺旋槽86,电极安置穿过于螺旋槽86中。在向近端牵拉轴杆80时,电极82向近端并且在径向沿循螺旋槽86。
图15A示出了其中电极22承载于中心轴杆14上的实施例的远端。旋钮88与护套90的螺旋凹槽92(在图15B中示出)形成接口连接以使得中心轴杆14旋转。定心元件诸如上文所描述的定心元件74可以附连到护套90上。作为旋钮88的替代,螺旋轨可安置于轴杆14上以与螺旋凹槽92形成接口连接。
诸如不透辐射的环或其它元件等成像元件可以放置于上文所述部件中的任何部件上以辅助可视化。这样的元件通常包括金属,诸如金或铂,如本领域中已知的那样。也可以包括一种冲洗管腔或者护套可以流体地附连到冲洗供应源。冲洗可以用来可视化、冷却或其它治疗目的。
在某些实施例中,细长电极承载元件12或轴杆80的可抓握的近端部分可以包括衬套或转动接头以在向近端牵拉细长电极承载元件12时允许细长电极承载元件12自由旋转。使用者可以在衬套上或在转动接头的近端抓握细长电极承载元件12并且因此当电极22在径向旋转时避免细长电极承载元件12的任何可能的扭结或其它弯曲。
定心元件被示出在这些实施例中的某些实施例上,但应了解定心元件可以适当地合并到这些实施例中的任何实施例内。例如,远端定心元件50、远端定心元件54或者远端气球60可易于附连到图2、图7、图9A、图10、图11A、图11B的实施例中的轴杆上或者图5A、图5B和图5C的轴杆的远端上或者图14的实施例的轴杆80或圆筒84上。
同样,关于图11A的实施例描述了接触贴片74,但接触贴片74可以合并到其它实施例的任何实施例内。例如,接触贴片可以合并到上文关于图2、图5A、图5B,、图5C、图6、图7、图8A、图8B、图8C、图8D、图9A、图9B,、图10、图11B、图12、图13和图14中描述的实施例中,
合适材料为本领域中已知的聚合物和金属。护套可以具有多于一个层,包括润滑内层和外层并且可以包括加强元件,诸如线圈或编织物。其它元件可以由具有合适涂层的导电材料制成以避免不希望的导电或者可以由其中嵌入导电元件的非导电材料诸如聚合物制成。
在使用中,引导丝和引导导管可以用来根据需要或优选地放置该系统,如在血管内技术中常规地那样。一旦就位后,护套向远端抽回以部署(多个)电极和任何定心元件。然后通过相对于轴杆14或圆筒84向近端牵拉细长电极承载元件12或轴杆80的近端部分来相对于轴杆向近端抽回(多个)电极。在这种相对近端移动期间,根据需要启动(多个)电极。在一示例启动模式中,在螺旋路径的不连续的区段上启动电极。随后,将元件抽回到护套内并且然后从身体抽回该系统。
在另一示例使用中,当抽回护套预定距离时,其与细长电极承载构件的一部分接合以固定在护套与细长电极承载元件之间的相对纵向运动。随后护套向近端抽回然后也使电极向近端移动。可选地,在护套/承载构件组合进一步抽回预定距离之后,轴杆然后与承载构件接合以固定在这两个元件之间的相对纵向移动。在此点,护套手动地或自动地脱离然后在纵向固定的承载构件/轴杆,承载构件/轴杆然后可以抽回到护套内以从身体收回该系统。可需要对近端部分或在某些情况下对元件的另外远端部分做出特定修改以使用所描述的方法。
上述方法可以结合实施例中的任何实施例使用,但是可特别有利地用于关于图11A所描述的包括接触贴片的实施例。这种使用方法进一步简化了医生的动作。
另外,为了可视化目的的冲洗、冷却或其它疗法可用于上述方法中的任何方法。
本领域技术人员将认识到本发明可以体现为除了本文中描述和设想的具体实施例之外的多种形式。因此,在不偏离如所附权利要求所限定的本法的范围和精神的情况下,可以做出形式和细节的偏离。
Claims (12)
1.一种用于神经调制的系统,包括:
第一细长元件,其具有远端和近端,沿所述第一细长元件延伸的凹槽形成螺旋引导件,所述螺旋引导件具有近端和远端,所述螺旋引导件围绕所述第一细长元件并沿所述第一细长元件的长度延伸;
第二细长元件,其具有远端和近端,所述第二细长元件包括靠近所述第二细长元件的远端的消融元件,所述第二细长元件可移动地设置在所述凹槽内并沿所述凹槽延伸,使得所述第二细长元件盘绕所述第一细长元件;以及
护套,其围绕所述第一细长元件和第二细长元件安置,
其中所述第一细长元件和所述第二细长元件以及所述护套可相对于彼此移动;并且
其中所述系统适于使得向近端牵拉所述第二细长元件的所述近端通过使所述第二细长元件在所述螺旋引导件内移动造成所述消融元件的同时径向和纵向移位。
2.根据权利要求1所述的系统,其特征在于,所述凹槽的相邻的圈彼此间隔开。
3.根据权利要求2所述的系统,其特征在于,所述凹槽还包括近端直部段。
4.根据权利要求2所述的系统,其特征在于,所述凹槽终止于所述第一细长元件的近端的远侧。
5.根据权利要求2至4中任一项所述的系统,其特征在于,所述凹槽具有口部,并且在所述口部处具有与平行于所述口部的并且在所述凹槽内更深的维度处相比的更窄截面形状。
6.根据权利要求5所述的系统,其特征在于,所述消融元件具有与所述凹槽可滑动地接合的基座部。
7.根据权利要求1所述的系统,其特征在于,所述第一细长元件还包括多个可弹性扩张的定心腿。
8.根据权利要求7所述的系统,其特征在于,所述腿安置于所述第一细长元件的所述远端,或者其中所述腿绕所述螺旋引导件在所述螺旋引导件的近端与远端之间在径向和纵向分布。
9.根据权利要求1所述的系统,其特征在于,所述第二细长元件在所述消融元件的近端处包括环并且包括从所述环向近端延伸并且安置于所述第一细长元件的一侧上的牵拉元件。
10.根据权利要求1所述的系统,其特征在于,所述护套包括绕所述第一细长元件的长度的大部分安置的圆筒。
11.根据权利要求1所述的系统,其特征在于,所述第一细长元件还包括多个沿着所述第一细长元件在纵向安置的多个电接触贴片,使得可在所述第一细长元件和第二细长元件的预定相对位置处启动所述消融元件。
12.根据权利要求11所述的系统,其特征在于,电源操作性地连接到所述第二细长元件并且其中电力可通过所述第二细长元件传送到在所述预定相对位置处的所述消融元件。
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- 2012-07-20 AU AU2012287189A patent/AU2012287189B2/en not_active Ceased
- 2012-07-20 JP JP2014521832A patent/JP6106669B2/ja not_active Expired - Fee Related
- 2012-07-20 US US13/554,459 patent/US9186209B2/en not_active Expired - Fee Related
Patent Citations (3)
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US5259395A (en) * | 1992-01-15 | 1993-11-09 | Siemens Pacesetter, Inc. | Pacemaker lead with extendable retractable lockable fixing helix |
US5935159A (en) * | 1996-12-19 | 1999-08-10 | Medtronic, Inc. | Medical electrical lead |
CN101553165A (zh) * | 2005-05-04 | 2009-10-07 | 波士顿科学神经调制公司 | 用于诸如可植入装置之类的电子装置的改良型电导线 |
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Publication number | Publication date |
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JP2014522702A (ja) | 2014-09-08 |
EP2734264A1 (en) | 2014-05-28 |
AU2012287189A1 (en) | 2014-02-13 |
US9186209B2 (en) | 2015-11-17 |
WO2013016203A1 (en) | 2013-01-31 |
CN103813829A (zh) | 2014-05-21 |
AU2012287189B2 (en) | 2016-10-06 |
US20130165920A1 (en) | 2013-06-27 |
JP6106669B2 (ja) | 2017-04-05 |
EP2734264B1 (en) | 2018-11-21 |
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