CN110772313A - 组织切除设备 - Google Patents

组织切除设备 Download PDF

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CN110772313A
CN110772313A CN201910701397.XA CN201910701397A CN110772313A CN 110772313 A CN110772313 A CN 110772313A CN 201910701397 A CN201910701397 A CN 201910701397A CN 110772313 A CN110772313 A CN 110772313A
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electrode
tube
tissue
coil
disposed
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W.科恩
J.梅尔乔
S.阮
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Johnson and Johnson Medical SAS
Ethicon Inc
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Abstract

本发明题为“组织切除设备”。本发明提供了一种组织切除设备，该组织切除设备包括外管，该外管具有设置在远侧端部上的螺旋线圈。该线圈设置有第一电极。中心管具有包括一个或多个表面区段的远侧边缘轮廓。该表面区段中的一个包括第二电极。该中心管可滑动地设置在外管内并且定位成使得该第二电极与该第一电极的至少一部分相对。切割管可滑动地设置在该中心管内并且包括切割边缘。

Description

组织切除设备
相关专利申请的交叉引用
本专利申请要求2018年7月31日提交的申请序列号62/712545的优先权，所述申请全文以引用方式并入本文。
本专利申请要求2018年9月7日提交的申请序列号62/728170的优先权，所述申请全文以引用方式并入本文。
本专利申请要求2018年10月12日提交的申请序列号62/744,797的优先权，所述申请全文以引用方式并入本文。
本专利申请要求2018年10月23日提交的申请序列号62/749302的优先权，所述申请全文以引用方式并入本文。
本专利申请要求2018年11月6日提交的申请序列号62/756234的优先权，所述申请全文以引用方式并入本文。
背景技术
1.技术领域
本发明涉及一种用于组织切除的系统、装置和方法。更具体地，本发明涉及一种用于病变去除的系统、装置和方法。
2.相关领域的讨论
癌症不是一种单一疾病，而是一系列相关的疾病，这些疾病基本上可以从身体的任何部位开始。在所有类型的癌症中，常见的是身体细胞开始不停分裂，从而增殖并潜在地扩散到周围组织中。在正常情况下，细胞根据身体的需要生长和分裂以形成新的细胞，并且当细胞受到损伤或衰老时，它们会死亡，新的细胞代替受损或衰老的细胞；然而，癌症打断了这一过程。患有癌症时，细胞变得异常，应该死亡的细胞不死亡，并且在不需要时形成新的细胞。这些新细胞可以再生或不停增殖，并且可形成被称为肿瘤的生长。
癌症肿瘤是恶性的，这意味着其可扩散或侵入周围的健康组织。此外，癌细胞可以脱落，并通过血液传送到身体的边远部位或到达淋巴系统。与恶性肿瘤不同，良性肿瘤不会扩散或侵入周围组织；然而，它们可变大并造成损害。恶性肿瘤与良性肿瘤二者均可被切除或治疗。恶性肿瘤趋于重新生长，而良性肿瘤可重新生长，但这样的可能性要小得多。
癌症是一种遗传性疾病，因为它是由控制细胞发挥功能的方式(尤其是基因的生长和分裂方式)的基因中的变化引起的。导致癌症的基因变化可能是遗传的，或者可能由于细胞分裂时发生的错误或由于某些环境暴露(例如，工业/商业化学物质和紫外线)造成的DNA损伤，而在个体的生命中出现。可导致癌症的基因变化趋于影响三种类型的基因；即参与正常细胞生长和分裂的原癌基因，还参与控制细胞生长和分裂的肿瘤抑制基因，以及顾名思义参与修复受损DNA的DNA修复基因。
目前已确定超过一百种不同类型的癌症。可根据癌症出现的器官或组织来命名癌症的类型，例如肺癌，或根据形成癌症的细胞类型来命名，例如鳞状细胞癌。不幸的是，癌症在美国和全世界都是造成死亡的主要原因。根据世界卫生组织的数据，未来二十年，每年新发癌症病例的人数将上升至2500万人。
肺癌是当今最常见的癌症之一。根据世界卫生组织的“2014年世界癌症报告”，全世界有1400万人患肺癌，死亡人数达到880万人，成为男性癌症相关死亡的最常见原因，也是女性癌症相关死亡的第二常见原因。肺癌或肺恶性肿瘤是一种恶性肺肿瘤，如果不治疗，可能会转移到邻近的组织和器官中。大多数肺癌是由长期吸烟引起的；然而，大约10％至15％的肺癌病例与烟草无关。这些非烟草病例最常是由遗传因素和暴露于某些环境条件，包括氡气、石棉、二手烟草烟雾、其它形式的空气污染和其它试剂的组合引起的。肺癌以及其它形式的癌症的存活几率取决于早期检测和治疗。
当在肺中检测到病变时，执行活检并送去研究。如果确定病变是癌性的，则可执行二次手术以去除癌症。如果活检未发现癌症，则其可以是正确的，或者活检未检出癌细胞。因此，需要在单个手术中去除整个病变，使得可执行准确的诊断。
发明内容
用于执行本发明的肺部病变去除的系统、装置和方法克服了与现有技术相关的限制。
本发明涉及用于执行肺部病变去除的系统、装置和方法。当在成像测试(例如，X射线或CAT扫描)上发现异常时，通常执行肺针活检。在肺针活检中，使用细针去除肺组织样本以在显微镜下检查，以确定异常细胞的存在。组织诊断在小(<6mm)结节和中间(6-12mm)结节中具有挑战性。通过胸壁(80％)或借助于支气管镜(20％)进行CT引导的外周病变活检仅产生0.001-0.002cm2的诊断组织，因此，癌症(如果存在)为仅成功鉴定了60％的中小结节。尽管支气管镜技术和技术不断发展，但在处理肺部周围的小结节和中间结节时，活检的准确性、特异性和敏感性将始终受到限制。
如果确定病变是癌性的，则可执行二次手术以去除病变，然后进行化疗和/或放射。二次手术很可能涉及肺部手术。这些手术通常通过肋骨之间的切口完成。根据癌症的状态，有许多可能的手术。对于某些类型的肺癌，视频辅助胸腔手术是一种侵入性较小的手术。它通过利用内窥镜方法的小切口执行，并且通常用于对靠近肺部表面的较小损伤执行楔形切除。在楔形切除术中，去除肺叶的一部分。在袖状切除术中，大气道的一部分被去除，从而保持更多的肺功能。
尽管进行了术前图像引导活检和定位，但是一旦被确定为可疑癌症，距离肺部表面2-3cm深的结节难以使用腹腔镜或机器人肺保留技术进行定位和切除。因此，外科医生执行开胸手术或肺叶切除术以切除距离肺部表面2-3cm的肺结节。胸廓切开术是一种开放式手术，其中切除了肺叶的一部分、全肺叶或整个肺。在肺切除术中，去除整个肺。这种手术显然是最具侵略性的。在肺叶切除术中，肺的整个切片或肺叶被去除并且表示比去除整个肺更不具侵略性的方法。所有胸腔镜肺部手术都需要经过培训且经验丰富的胸外科医生，并且手术结果的有利性与手术经验相符。
这些类型的肺部手术中任一个都是大手术，其可能的并发症取决于手术的范围以及患者的整体健康状况。除了与这些手术中任一个相关联的肺功能降低之外，恢复可需要数周至数月。通过胸廓切开术，需要扩张肋骨，从而增加术后疼痛。虽然视频辅助胸腔手术侵入性较小，但仍有相当长的恢复期。此外，一旦手术完成，完全治疗可需要系统化疗和/或放射治疗。
如上所述，细针穿刺活检可无法完全诊断。细针穿刺活检包括在二维成像下在三维空间中引导针。因此，医生可错过病变，或者即使他或她击中正确的目标，通过针去除的病变部分可不包含评估肿瘤侵袭性所必需的癌细胞或细胞。针吸活检去除足够的组织以在载玻片上产生污迹。设计本发明的装置以去除整个病变或其大部分，同时最小化健康肺组织去除的量。这提供了许多优点。首先，可检查整个病变以获得更准确的诊断，而不会混淆抽样误差、细胞堆积损失或总体结构。其次，由于去除了整个病变，因此可不需要如上所述的二次手术。第三，可通过由病变去除产生的腔体引入局部化疗和/或基于能量的肿瘤摘除，诸如放射。
在至少一个实施方案中，本发明包括一种组织切除机构，其包括外管，该外管具有设置在远侧端部上的螺旋线圈，其中线圈包括第一电极。提供中心管，该中心管具有包括一个或多个表面区段的远侧边缘轮廓，表面区段中的至少一个包括第二电极。中心管可滑动地设置在外管内，并且定位成使得第二电极与第一电极的至少一部分相对。切割管包括可滑动地设置在中心管内的切割边缘，并且切割管被构造成前进至少远至线圈区段中的一个。
在另一个实施方案中，本发明包括一种组织切除机构，其包括外管，该外管具有设置在远侧端部上的螺旋线圈，其中线圈包括第一电极。提供中心管，该中心管具有包括一个或多个表面区段的远侧边缘轮廓，表面区段中的至少一个包括第二电极。中心管可滑动地设置在外管内，并且定位成使得第二电极与第一电极的至少一部分相对。第一结扎电极和第二结扎电极设置在中心管中并且暴露于中心管腔。圈套器设置在第一结扎电极和第二结扎电极之间的中心管中。切割管包括可滑动地设置在中心管内的切割边缘，并且切割管被构造成前进至少远至线圈区段中的一个。
在另一个实施方案中，本发明包括一种组织切除机构，其包括外管，该外管具有设置在远侧端部上的螺旋线圈，其中线圈包括第一电极。提供中心管，该中心管具有包括一个或多个表面区段的远侧边缘轮廓，表面区段中的至少一个包括第二电极。中心管可滑动地设置在外管内，并且定位成使得第二电极与第一电极的至少一部分相对。第一结扎电极和第二结扎电极设置在中心管中并且暴露于中心管腔。截肢圈套器设置在中心管中，并且结扎圈套器设置在中心管中。切割管包括可滑动地设置在中心管内的切割边缘，并且切割管被构造成前进至少远至线圈区段中的一个。
附图说明
从以下如附图所示的本发明优选实施方案的更具体的描述，本发明的上述及其它特征和优点将显而易见。
图1示出了根据本发明的实施方案的组织切除装置。
图2示出了图1的组织切除装置的剖视图。
图3示出了根据本发明的实施方案的组织切除装置的剖视图。
图4示出了根据本发明的实施方案的组织切除装置的剖视图。
图5示出了可在根据本发明的实施方案的病变去除方法中采用的示例性锚定件。
图6示出了根据本发明的实施方案的用于病变去除方法的一系列切口刀片。
图7示出了适用于根据本发明的实施方案的病变去除方法的组织扩张器。
具体实施方式
本发明的切除装置包括能够使组织朝向目标病变穿透的基于能量的布置。在图1所示的一个实施方案中，组织切除装置1100包括外管1105，外管1105具有远侧边缘轮廓并且具有内径ID外。线圈1110附接到外管1105，其中线圈匝与外管1105的远侧端部间隔开并与其相对。线圈1110优选地具有略微钝的尖端1115，以最小化其穿透血管的可能性，同时足够锋利以穿透组织诸如胸膜和实质。在一些实施方案中，线圈1110可采取具有恒定或可变节距的螺旋的形式。线圈1110还可具有可变的横截面几何形状。电极1130设置在表面上或嵌入线圈1110内。
在一些实施方案中，如图1所示，线圈1110可包括多个邻接的线圈区段，例如线圈区段1120和1125。线圈区段1120包括具有零节距的螺旋构件，例如，大致平面的开口环结构，其具有内径ID线圈和外径OD线圈。线圈区段1125包括具有恒定或可变节距和恒定或可变横截面几何形状的螺旋结构。在该实施方案中，电极1130可设置在线圈区段1120的表面上或嵌入线圈区段1120中。
提供中心管1200，其具有远侧端部，该远侧端部具有包括一个或多个表面区段的边缘轮廓，并且具有外径OD中心和内径ID中心。如图2所示，电极1205设置在表面区段中的至少一个上或嵌入表面区段中的至少一个内。中心管1200可滑动地设置在外管1105内并且定位成使得电极1205与电极1130的至少一部分相对并重叠。电极1205和电极1130之间的空间称为组织夹持区。根据本发明的一个方面，OD中心>ID线圈并且OD线圈>ID中心。在一些实施方案中，OD中心约等于OD线圈。因此，中心管1200可朝向线圈1110前进通过组织夹持区，使得电极1205邻接电极1130。
切割管1300可滑动地设置在中心管1200内。切割管1300的远侧端部设置有刀刃以便于组织切割。
为了能够进行组织切除，切除装置1100可插入组织中，并且外管1105可朝向目标前进预定距离。线圈区段1125允许装置以类似于软木螺钉的方式穿透组织。当线圈区段1125穿透组织时，其路径中的任何脉管移动到平面线圈区段1120或者被推离线圈1100以用于随后的转动。线圈尖端1115被制成足够钝以最小化它将穿透血管的机会，同时仍然足够锋利以穿透某些组织诸如肺胸膜和实质。然后中心管1200可朝向目标前进预定距离。设置在组织夹持区中的任何脉管将被夹持在电极1130和电极1205之间。然后通过将双极能量施加到电极1130和电极1205可密封脉管。一旦血管被密封，切割管1300就前进以使组织的核心到达外管1105已到达的深度。可重复密封和切割过程以产生期望尺寸的核心。
根据本发明的一个方面，切除装置可进一步被构造成解剖目标病变并密封接近解剖点的组织。为了便于解剖和密封，如图3所示，中心管1200设置有结扎圈套器1230、第一结扎电极1215和第二结扎电极1220、截肢圈套器1225和结扎圈套器1230。如本文所用，词语“圈套器”是指柔性线，例如线丝或线材。中心管1200的内壁表面包括靠近远侧端部设置的上部周向凹槽通路1212和下部周向凹槽通路1214。第一结扎电极1215和第二结扎电极1220设置在中心管1200的内壁上，使得下周向凹槽1214位于它们之间。上凹槽通路1212轴向设置在结扎电极1215和1220上方。
结扎圈套器1230设置在下周向凹槽1214中并且延伸穿过中心管1200并且沿外壁表面轴向延伸到圈套器激活机构(未示出)。截肢圈套器1225设置在上周向凹槽1212中并且延伸穿过中心管1200并沿外壁表面轴向延伸到圈套器激活机构(未示出)。中心管1200的外表面可设置有多个轴向延伸的凹槽通路，其接收截肢圈套器1225、结扎圈套器1230并且与上周向凹槽通路1212和下周向凹槽通路1214连通。另外，用于结扎电极1215和1220的电极引线可经由轴向延伸的凹槽通路延伸到能量源。
在操作中，该实施方案的切除装置可拆卸和密封组织核心。切割管1300可回缩以暴露结扎圈套器1230，其优选地由柔性线(例如，缝合线)制成。结扎圈套器1230可被接合以阻挡组织并将组织拉向第一结扎电极1215和第二结扎电极1220之间的内壁表面。然后将双极能量施加到第一电极1215和第二电极1220以密封(即烧灼)组织。一旦密封，切割管1300可进一步回缩以暴露截肢圈套器1225，然后截肢圈套器1225可被激活，以在组织被密封的点(结扎点)上游切断组织核心。在一些实施方案中，截肢圈套器1225的直径小于结扎圈套器1230的直径。较小的直径有利于组织切片。因此，根据该实施方案的切除装置1100都产生组织核心并使核心与周围组织脱离。
在一个另选的实施方案中，本发明的切除装置设置有在结扎电极之间的单个圈套器，所述结扎电极结扎和切割组织。在该实施方案中，单个圈套器首先将组织拉向结扎电极1215和1220之间的中心管1200的内壁表面。然后将双极能量施加到第一电极1215和第二电极1220以密封(即烧灼)组织。一旦密封，就进一步拉动圈套器以切断组织核心。
在又一个实施方案中，可在不使用电极的情况下执行切割和密封。在该实施方案中，结扎圈套器1230包括在负载下绷紧的一组结1235和1240，例如如图4所示。通过回缩切割管1300以暴露结扎圈套器1210并激活结扎圈套器1230来进行结扎，结扎圈套器1230在结扎结绷紧时套索组织。一旦组织被套索，切割管1300可进一步回缩以暴露截肢圈套器1225，然后截肢圈套器1225可被激活以在组织被套索的点的上游切断组织核心。
本发明还设想了一种用于使用切除装置去除组织病变(例如肺部病变)的方法和系统。该方法通常包括锚固目标病变以去除，在通向目标病变的组织中形成通道，产生包括锚固病变的组织核心，结扎组织核心并密封周围组织，以及从通道去除包括目标病变的组织核心。
通过用于将装置固定到肺部的任何合适的结构来执行锚固。一旦病变被锚固，就可产生通道以便于切除装置1100的插入。通过在肺部区域中制造切口并将组织扩张器和端口插入切口可产生通道。可产生包括锚固病变的组织核心。根据本发明，切除装置1100可插入通道中并用于产生组织核心，以结扎组织核心并密封组织核心并将其与周围组织切断，如上所述。然后可从通道去除组织核心。根据本发明，可在通道中插入腔体端口，以便于通过化学疗法和/或基于能量的肿瘤摘除诸如放射随后治疗目标病变部位。
图5中示出的锚定件适用于执行本文所述的用于去除组织病变的方法。锚定件包括外管1422和内管1424，外管1422具有足够锋利的边缘以刺穿胸腔组织并且肺部而不会引起过度损伤，内管1424设置在外管1422内。由预成型的形状记忆材料(例如，镍钛诺)形成的一个或多个尖齿或指状物1426附接到内管1424的端部。外管1422可回缩地设置在内管1424上方，使得当外管1422回缩时，尖齿1426呈现其预成型形状，如图所示。根据本发明，外管1422在刺穿肺部病变后回缩，从而使尖齿1426与肺部病变接合。其它合适的锚定件可包括线圈和基于抽吸的结构。
图6中示出的切口刀片适用于执行本文所述的用于去除组织病变的方法。一旦锚定件1400被设定，优选地形成小切口或切口以便于胸壁组织扩张器的插入。切口刀片1605用于进行更宽的切割。连续切口刀片1605包括中心孔，该中心孔允许它们沿锚针1405同轴地前进以在胸壁中产生更宽的切口，其中每个连续刀片比前面的刀片更大，从而增加切口的宽度。
图7中示出的组织扩张器适用于执行本文所述的用于去除组织病变的方法。组织扩张器可包括用于在有机组织中形成通道的任何合适的装置。在一个示例性实施方案中，组织扩张器组件包括具有圆形端部1510的单个圆柱形杆或具有圆形端部的圆柱形杆和刚性套管装置1515。连续的组织扩张器沿锚针同轴地前进以在胸壁中形成组织管道或通道，其中每个连续的扩张器比前面的扩张器大，从而增加通道的直径。一旦展开具有刚性套管的最终扩张器，就去除内杆1505，同时将刚性套管留在肋之间的两岸间(intercoastalspace)中以产生通向肺胸膜的直接通道。
能够穿透肺组织并产生包括目标病变的组织核心的任何组织切除装置适用于执行本文所述的用于去除组织病变的方法。上文描述的组织切除装置1100是优选的。
一旦去除组织切除装置1100，肺部中的小通道就会离开目标病变被去除的位置。该通道可用于根据组织诊断的结果引入基于能量的消融装置和/或局部化疗。因此，本发明的方法和系统不仅可用于确保进行有效的活检，而且可在最小的健康肺组织去除的情况下完全去除病变。
虽然所示出和描述的据信是最为实用和优选的实施方案，但显而易见的是对于本领域中的技术人员可以对所描述和所示出的具体设计和方法作出变更，而且在不脱离本发明的实质和范围的情况下可使用这些变更形式。例如，本文描述的用于从肺部去除病变的系统、装置和方法。本领域技术人员应当理解，本文描述的装置和方法可不限于肺部并且可用于在身体的其它区域中进行组织切除和病变去除。本发明并不局限于所述和所示的具体构造，而是应当构造为与可落入所附权利要求书的范围内的全部修改相符。

Claims (20)

1.一种组织切除机构，包括：
外管，所述外管具有设置在远侧端部上的螺旋线圈，所述线圈包括第一电极；
中心管，所述中心管具有包括一个或多个表面区段的远侧边缘轮廓，表面区段中的至少一个包括第二电极，所述中心管可滑动地设置在所述外管内并且定位成使得所述第二电极与所述第一电极的至少一部分相对；
切割管，所述切割管包括可滑动地设置在所述中心管内的切割边缘，所述切割管被构造成前进至少远至所述线圈区段中的一个。
2.根据权利要求1所述的组织切除装置，其中所述线圈包括第一连续线圈区段和第二连续线圈区段，所述第一线圈区段包括所述第一电极。
3.根据权利要求2所述的组织切除装置，其中所述第一线圈区段包括大致平面的开口环。
4.根据权利要求2所述的组织切除装置，其中所述第一线圈区段是螺旋形的并且具有零节距。
5.根据权利要求2所述的组织切除装置，其中所述第二线圈区段是螺旋形的并且具有恒定的节距。
6.根据权利要求5所述的组织切除装置，其中所述第二线圈区段具有可变节距。
7.根据权利要求2所述的组织切除装置，其中所述第一线圈区段是螺旋形的并且具有第一节距，并且所述第二线圈区段是螺旋形的并且具有第二节距，所述第一节距和所述第二节距中的至少一个是可变的。
8.根据权利要求1所述的组织切除装置，其中所述第二线圈区段包括所述钝尖端。
9.根据权利要求1所述的组织切除装置，其中所述第一电极和所述第二电极具有基本上匹配的表面轮廓。
10.根据权利要求2所述的组织切除装置，其中所述第一线圈区段具有内径和外径，并且所述中心管包括内径和外径，其中所述中心管的所述外径大于所述第一线圈区段的所述内径，并且所述第一线圈区段的所述外径大于所述中心管的所述内径。
11.根据权利要求2所述的组织切除装置，其中所述第一线圈区段具有外径，并且所述中心管的外径约等于所述第一线圈的所述外径。
12.一种组织切除机构，包括：
外管，所述外管具有设置在远侧端部上的螺旋线圈，所述线圈包括第一电极；
中心管，所述中心管具有包括一个或多个表面区段的远侧边缘轮廓，表面区段中的至少一个包括第二电极，所述中心管可滑动地设置在所述外管内并且定位成使得所述第二电极与所述第一电极的至少一部分相对；
第一结扎电极和第二结扎电极，所述第一结扎电极和所述第二结扎电极设置在所述中心管中并且暴露于中心管腔；
圈套器，所述圈套器设置在所述第一结扎电极和所述第二结扎电极之间的所述中心管中；和
切割管，所述切割管包括可滑动地设置在所述中心管内的切割边缘，所述切割管被构造成至少前进至所述线圈区段中的一个。
13.根据权利要求12所述的组织切除机构，其中所述中心管包括具有周向凹槽通路的内表面，并且所述圈套器设置在所述周向凹槽通路中。
14.根据权利要求13所述的组织切除机构，其中所述中心管包括外表面，所述外表面具有多个轴向延伸的凹槽通路，所述轴向延伸的凹槽通路中的至少一个与所述周向凹槽通路连通，并且所述圈套器沿所述多个轴向延伸的凹槽通路中的一个从所述周向凹槽通路轴向延伸。
15.一种收集、压缩和密封流体脉管的组织切除机构，包括：
外管，所述外管具有设置在远侧端部上的螺旋线圈，所述线圈包括第一电极；
中心管，所述中心管具有包括一个或多个表面区段的远侧边缘轮廓，表面区段中的至少一个包括第二电极，所述中心管可滑动地设置在所述外管内并且定位成使得所述第二电极与所述第一电极的至少一部分相对；
第一结扎电极和第二结扎电极，所述第一结扎电极和所述第二结扎电极设置在所述中心管中并且暴露于中心管腔；
截肢圈套器，所述截肢圈套器设置在所述中心管中；
结扎圈套器，所述结扎圈套器设置在所述中心管中；和
切割管，所述切割管包括可滑动地设置在所述中心管内的切割边缘，所述切割管被构造成至少前进至所述线圈区段中的一个。
16.根据权利要求15所述的组织切除机构，其中所述结扎圈套器设置在所述第一结扎电极和第二结扎电极之间。
17.根据权利要求15所述的组织切除机构，其中所述结扎圈套器是具有第一直径的柔性线。
18.根据权利要求16所述的组织切除机构，其中所述截肢圈套器设置在所述结扎圈套器的近侧。
19.根据权利要求19所述的组织切除机构，其中所述截肢圈套器包括具有第二直径的柔性线，所述第二直径小于所述第一直径。
20.根据权利要求15所述的组织切除机构，其中所述中心管包括内表面，所述内表面具有第一周向凹槽通路和第二周向凹槽通路，所述结扎圈套器设置在所述第一周向凹槽通路中，并且所述截肢圈套器设置在所述第二周向凹槽通路中。
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BR102019015646A2 (pt) 2020-01-28
PL3603545T3 (pl) 2021-12-06
JP2020018852A (ja) 2020-02-06
US20200038089A1 (en) 2020-02-06
EP3603545A1 (en) 2020-02-05
ES2870804T3 (es) 2021-10-27

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