CN101573084A - 可植入的修复装置 - Google Patents
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Abstract
一种用于修复或加强组织或肌肉壁缺损的可植入假体,其包括第一复合结构,该第一复合结构包括至少一个不可吸收材料层,其中,第一复合结构具有大小和尺寸设置成覆盖组织或肌肉壁缺损的至少一部分的中央部分,并且具有外部周边。该假体还包括第二结构,该第二结构具有外部圆周边缘和被加强的中央区域,加强元件定位在第一和第二结构之间,并且具有外部周边以及比第一和第二结构的刚度大的刚度,并且至少一个拉拽元件连接到第二结构的被加强的中央区域。第二结构与第一结构大体上仅在它们各自的周边处相连接。
Description
技术领域
本发明总体上涉及可植入的假体,更具体地涉及具有用于修复和/或加强诸如疝气的人体结构缺损的特殊应用的可植入假体。
背景技术
已经使用各种形式的可植入假体来修复或加强组织缺损,例如软组织和肌肉壁疝气。例如,众所周知的是使用可植入织物或丝网补片来覆盖开口或缺损。当前面的方法在利用放置补片的“遮蔽”技术(“blind”technique)的腹膜内腹壁疝修补中被使用时,该补片必须被弯折以便通过切口和缺损,并且随后在腹膜内的空间中被释放和展开。然后,补片必须抵靠着腹膜被适当地定位,优选是尽可能平直地定位。通常,补片的面向脏器的侧面具有组织隔层特性,例如隔离层或薄膜。然而,补片通过缺损的中央进入切口的适当定位已经被证明是难以实现的。
近来,已知至少一种可植入假体包括绷带等,所述绷带等被固定到补片的中央位置,并且从补片的面对腹壁的侧面向外通过切口延伸到病人身体的外部。在美国专利No.7,101,381中描述并图示了这种装置。绷带提供了一种装置,一旦补片被插入,则通过该装置拉拽补片以便将补片固定在室壁上,从而封闭缺损。绷带被缝合或以其它方式独立地固定到补片的中央位置,或者如该公开文献的图7中所示以需要固定到补片的两个分离部分的方式构造而成。在补片最终被放置好之后,例如通过缝合将绷带固定到邻近的筋膜或肌肉上,剪掉任何过长的部分。
利用这种装置,由绷带施加在补片中央部分的过大的力可能使补片在中央弯折,从而使补片的中央开始穿过缺损,而补片的径向部分绕中央部分向外翘曲(远离室壁)。因为翘曲或倒转的边缘使无防护的网状材料(无组织隔层的部分)直接暴露于内部脏器,增大了在该网和脏器之间形成不期望的附连的可能性,所以这是非常不期望的。此外,绷带到补片中央部分的固定本身可能损害隔离层。因此,在任一此类装置中,当拉拽绷带来定位补片时,重要的是要确保补片保持位于靠着脏器的均匀平面中。
虽然该类装置可结合有弹性的周向“环”以便在放置之后帮助补片回复到期望的平面构造,但是该环不能显著地防止如上所述的翘曲倾向。此外,所公开的环是由不可吸收的材料构成的,因此会在病人体内永久地遗留下相当数量的材料。如果该环将来破裂,从而导致粗糙的断口边缘损害周围组织,则这可能是特别不利的。
因此,本发明的目的是提供一种用于修复和/或加强软组织或肌肉壁缺损的改进的可植入假体。
发明内容
本发明提供一种用于修复或加强组织或肌肉壁缺损的可植入假体,其包括第一生物相容性结构,该第一生物相容性结构具有大小和形状设置成覆盖组织或肌肉壁缺损的至少一部分的中央部分,并且具有顶侧、底侧和从该中央部分的相反两侧向外横向延伸的第一和第二伸出部分。该假体还包括加强元件和第二生物相容性结构,加强元件定位成邻近于补片部分的顶侧,并且具有顶侧、底侧和外部圆周边缘,该第二生物相容性结构具有顶侧和底侧以及穿过所述第二生物相容性结构的至少一个开口,该至少一个开口基本上设置在中央位置。第一结构的第一和第二伸出部分绕加强元件的外部圆周边缘延伸,然后在加强元件和第二结构之间沿加强元件的顶侧向外延伸到加强元件的中央部分,然后再从该中央部分向外延伸穿过第二结构中的至少一个开口。第一和第二结构还至少绕假体的周向边缘相互固定在一起。
本发明还提供一种用于修复或加强组织或肌肉壁缺损的可植入假体,其包括第一复合结构,该第一复合结构包括至少一个不可吸收材料层,其中,该第一复合结构具有大小和形状设置成覆盖组织或肌肉壁缺损的至少一部分的中央部分,并且具有外部周边。该假体还包括第二结构、加强元件以及至少一个拉拽元件,该第二结构具有被加强的中央区域和外部圆周边缘,该加强元件定位在第一和第二结构之间,并且具有外部周边和比第一和第二结构的刚度大的刚度,所述至少一个拉拽元件联接到第二结构的被加强的中央区域。第二结构与第一结构基本上仅在它们它们各自的周边处相联接。
最后,本发明还提供一种用于修复或加强组织或肌肉壁缺损的可植入假体,其包括基本扁平的、柔性的第一复合结构和基本扁平的、柔性的第二结构,该第一复合结构包括至少一个不可吸收材料层,第一复合结构具有大小和形状设置成覆盖组织或肌肉壁缺损的至少一部分的中央部分,并且具有外部周边,该第二结构具有基本上与第一结构的外部周边类似的外部周边,并且具有被加强的中央区域。该假体还包括三维的加强元件和至少一个拉拽元件,该加强元件定位在第一和第二结构之间并且具有基本上与第一和第二结构的外部周边类似的外部周边,所述至少一个拉拽元件联接到第二结构的中央区域。第一复合结构和第二结构基本上仅绕它们各自的外部周边相互连接在一起。
附图说明
图1是根据本发明的假体的优选实施例的部件的分解图;
图1a示出了部分组装起来的图1中的假体;
图2-5示出了处于组装过程中的不同点处的图1中的假体;
图6示出了完全组装起来的图1中的假体;
图7-8是图1中的假体的加强元件的立体图和侧视图;
图9-13示出了用于植入根据本发明的假体的工序的各个步骤;
图14和14b是图5中的实施例的横剖视图;和
图15和15a是示出了根据本发明的假体的替代性实施例的横剖视图。
具体实施方式
在详细说明本发明之前,应该指出的是,本发明在其应用或使用中并不局限于附图及说明书中所记载的部件的构造和布置的细节。本发明的说明性实施例可以被实施或并入到其他实施例、变型和改型中,并且可以各种方式来实践或执行。例如,虽然本发明被详细地描述为涉及用于修复脐疝的可植入假体,但是应该理解的是,这些装置可以容易地用于修复各种其他软组织或肌肉壁的缺损,包括但不限于套针点穿刺、小型腹疝等。
现在参见图1-8和14a-b,现在将详细描述本发明的假体的优选实施例。假体100是由如图1所示的多个元件形成的复合假体,其包括第一复合结构115、加强元件116(统称为“第一加强结构”)和第二结构140。第一结构115具有中央部分115a和优选的第一和第二伸出部分126、127,该中央部分115a的大小和形状被设置成覆盖组织或肌肉壁缺损的至少一部分,第一和第二伸出部分126、127从该中央部分的相反两侧向外横向延伸。
第一结构进一步包括补片构件102,补片构件102具有顶侧101和底侧103以及大小和形状对应于中央部分115a的补片部分104。在图中示出的实施例中,补片部分104的总体形状大体上为圆形,直径D为大约4.3-6.4cm,其适合于修复典型的脐疝缺损。从补片部分的相反两侧105、106向外横向延伸的是大小和形状大体上对应于第一和第二伸出部分126、127的第一和第二伸出部分107和108。补片构件优选包括不可吸收的网状结构,例如PROLENETM软网,其是由纽约萨默维尔的Ethicon公司制造的不可吸收的聚丙烯编织网,但是也可以使用任何合适的生物相容性材料。
分别邻近于补片部分的顶侧101和底侧103定位的是第一和第二薄膜层109和110,其优选是由例如聚对二氧环己酮(polydioxanone)的可吸收材料构成的。在优选实施例中,第一层109为大约0.0002英寸厚,并且第二层110为大约0.0008英寸厚。邻近于第二薄膜层110的底侧111定位的是第三层112,其也优选是由可吸收材料组成的。该可吸收材料可以是氧化再生纤维素(ORC),其具有例如由Ethicon公司制造和销售的品名为INTERCEDETM的成分。第一、第二和第三层的大小和形状大体上类似于补片部分104的尺寸和形状,并且可以总体上模仿补片构件,如图中针对第一和第二薄膜层所示出的那样。如图1所示地对准这些部件,然后以任何合适的方式将其固定在一起以形成第一结构115,例如通过将该组合件加热到大约130摄氏度的温度并持续大约30秒来进行粘结。当植入时,第三层112提供了生物可吸收层,该生物可吸收层在伤口愈合期间使不可吸收的聚丙烯网与下方的组织和器官表面在物理上分离并保护不可吸收的聚丙烯网不受下方的组织和器官表面的影响,以便最大程度地减小组织附着到聚丙烯网上的可能性。
尽管用于描述结构115的说明性实施例公开了一种复合结构,该复合结构提供了在一侧上具有隔离表面的植入件,该植入件还提供了将要结合到室壁中的第二表面,但是,也可以想象出将两个功能结合到一个结构中的备选的整体层。所述整体结构的一个示例是由特拉华的公司W.L.Gore&Associates生产并且作为GORE DUALMESH出售的。
在形成第一结构115之后,第一和第二伸出部分126、127的端部分别被折叠并缝合或者以其它方式固定就位以形成如图2最佳示出的环状元件120、121。如图2所示,然后将加强元件116(下面将详细描述)邻近第一结构115的顶面113对准,该加强元件优选具有与补片部分104大体相似的大小和形状。如图3所示,第一结构的第一和第二伸出部分126、127围绕加强元件116的周向边缘117并在顶侧面118之上延伸到加强元件的中央部分119。
再次参见图1,假体的优选实施例还包括第二结构140,该第二结构140具有外部周边143和中央区域143a。第二结构进一步包括第二网状层130、邻近于第二网状层130的底侧133和顶侧135定位的第三及第四薄膜层132、134、以及位于中央区域中的独立的加强元件136,该加强元件136优选为薄膜环,其外径小于薄膜层132、134的外径并且定位成邻近于第三薄膜层132的底侧137。第二网状层130优选是由人工合成的、可吸收材料(例如VICRYTM网)制成的,VICRYLTM网是由聚乳酸羟基乙酸(polyglactin)910制备而成并由纽约萨默维尔的Ethicon公司制造和销售的。第三及第四薄膜层和薄膜环优选是由聚对二氧环己酮构成的。这些层如图所示那样对准并且相互结合在一起以形成具有顶侧140a和底侧140b的第二结构140。替代性地,该复合结构可以用整体层来代替,该整体层由不同刚度的区域形成,其中央部分具有明显大于靠近周边的区域的刚度。
如下所述,然后将图3所示的第一加强结构129和第二结构140如图4所示那样对准,从而使第一和第二环120、121如图5所示那样延伸穿过第二结构140中的第一和第二开口142、144,然后,除伸出部分126、127外,第一加强结构129和第二结构140大体上仅围绕它们各自的外部周边粘结(即,通过超声波焊接)、熔接、缝合或以其他方式结合在一起。最后,如图6所示,可以将附加的抓握元件150、151插过第一和第二环120、121,所述抓握元件例如是ETHIBONDTM涤纶缝合线等(也是由Ethicon公司制造的)。
如所指出的那样,薄膜环136被粘结到第二结构140上,但是未被粘结到第一加强结构上。此外,第一和第二伸出部分126、127被连接到第二结构的薄膜环136上,并且除了周向边缘之外未被固定到第一加强结构上。这种构造是有利的,因为能够使施加在第一和第二环120、121上的集中力分布到薄膜环136上,并因此通过第二结构140大体上均匀地分布并最终分布到假体的外部周边146上,该外部周边146是通过加强元件的外圆周环180来加强的。在图14b的剖视图中示出了力的分布,其中P表示施加于环120、121上的拉力,而p表示假体所承受的合力(与示出了其上没有施加拉力的装置的图14a相反)。集中力到植入件的外部周边上的这种大体均匀的分布使本发明在如下能力方面比公知装置具有显著的进步:即避免在绷带的附着点处产生点应力并对植入件造成潜在损害的能力,以及植入并正确地放置假体的能力。
如上所述,利用所描述和图示的优选实施例来实现力的有效的重新分布,但是也可以按其他不同的替代性实施例来实现,只要中央绷带或其他拉拽元件被固定到在中央部位加强的第二结构上,而该第二结构大体上仅围绕其周向边缘连接到第一加强结构上。例如,替代性实施例可以包括如图15所示通过任何合适的方式连接或固定到第二结构140a的环形元件136a上的单个绷带或多个独立绷带120a,或者如图15a所示可以利用附接到相当坚固的中央元件136b上的一个或多个拉拽元件120b、121b或抓握装置。这两个实施例都能够在张紧过程中分散载荷,然而图15a所示的实施例提供了至少能够部分地填满筋膜平面中的缺损的三维中央部分137a。
现在参见图7和8,加强元件116用来加强植入件,并且维持其大体平直的适当方位以覆盖病人体内的缺损。加强元件必须足够柔软以使其能够在通过切口和缺损时被弯折,但是具有足够的弹性以便一旦被适当地定位便恢复为大体平直的构造。当受到径向压力时,所述元件应该部分地或完全地控制应变的方向。另外,加强元件不得抑制组织进入组织支承层中,并且应该提供用于使痊愈的组织到达组织支承层的途径。已经发现本申请中描述和图示的弹性元件特别适合于这些目的,并且其优选的三维构造大大提高了植入件在放置好之后的抗弯折或翘曲的能力。
在放置过程中,所述三维形式提供了控制植入件的应变方向的额外优点。在安装以及接下来将该装置通过缺损插入的过程中,第一和第二环120、121被外科医生拉紧以确保植入件相对于缺损的适当且紧密的配合。在将张力施加到绷带上的过程中,来自用户的作用力从装置的中央均匀地分布到加强层的周边上,从而在加强层中产生径向的压缩载荷。当加强层上的该压缩载荷增大时,加强层中的应变朝向装置的中央并且沿着远离室壁的优选方向。由于加强层的形式或“杯型”的第三维中的应变增大,所以这种受控制的应变方向导致该装置的周边紧密地贴合到室壁上。该装置周边的这种改善的柔顺性防止用户在可能使该装置的侧面暴露于脏器的方向上弯折该装置。尽管具体实施例中记载了半环形,应该指出的是,在安装过程中任何对称的三维形式-例如球形将会提供相同的功能性优点。如图8中的侧视图所示,加强元件优选具有三维的(“三维的”意味着除了平面结构的单一厚度外还具有第三个维度)、有点呈环形的形状,其中加强元件的外圆周环180大体上位于第一水平面中并且内圆周环182大体上位于第二水平面中。辐条状的元件184在外圆周环180和内圆周环182之间延伸,并且在图示的实施例中,中间圆周环186被定位在外圆周环180和内圆周环182之间。加强元件优选是由例如聚对二氧环己酮的可吸收材料制成的,厚度为大约0.015英寸,这使其刚度大于第一和第二结构115、140的刚度。在优选实施例中,其还可包括沿辐条状元件184的各部分沿纵向延伸的一个或多个肋条状元件188。肋条元件进一步加强植入件并为植入件提供稳定性,并且防止由垂直于三维加强层的中央部分的平面的瞬时压缩永久性地逆变为所形成的形状。已经证实,在上述应用中获得挠性、刚性、抗翘曲以及控制应变方向的最佳组合方面,加强元件的三维几何形状和构造是优于二维几何形状的。
图9-13示出了用于植入根据本发明的假体的方法的各个步骤。剖开缺损区域内的皮肤和组织以便为手术部位提供入口。优选的是,如图9所示地露出疝气囊,如图10所示,分开该疝气囊并翻转内容物。如图11所示,折叠补片100,使其含有绷带的侧面位于折叠件的内部,并且露出的ORC织物层112位于折叠件的外部。然后通过切口200将补片100送到手术部位内。这可以按任何合适的方式来实现,包括使用或不使用套管或套针来促使其通过。当补片完全位于腹膜空间内部时,将补片从其折叠构造释放开来,以便其弹性地恢复到最初的、大体上平直的构造。通过轻微地拉动抓握元件150、151来进一步帮助以大体平直的构造抵靠着内部脏器而进行适当地定位(使ORC织物层112面向内部脏器)。在适当的放置之后,如图12所示,将环120、121固定到前部筋膜上,如图13所示地留下被植入的补片。
从前述内容可以明显地看出,虽然已经图示并描述了本发明的特定形式,但是可以在不背离本发明的精神和范围的情况下作出各种改型。因此,本发明旨在不受除所附权利要求之外的任何限制。
Claims (36)
1.一种用于修复或加强组织或肌肉壁缺损的可植入假体,包括:
第一生物相容性结构,其具有中央部分,该中央部分的大小和形状设置成覆盖所述组织或肌肉壁缺损的至少一部分,并且该第一生物相容性结构具有顶侧、底侧以及从所述中央部分的相反两侧向外横向延伸的第一和第二伸出部分;
加强元件,其定位成邻近于补片部分的顶侧,并且具有顶侧、底侧和外部圆周边缘;和
第二生物相容性结构,其具有顶侧和底侧以及穿过所述第二生物相容性结构的至少一个开口,所述至少一个开口基本上设置在中央位置;
其中,所述第一结构的第一和第二伸出部分绕所述加强元件的外部圆周边缘延伸,然后在所述加强元件和所述第二结构之间沿所述加强元件的顶侧向内延伸到所述加强元件的中央部分,然后再从所述中央部分向外延伸穿过所述第二结构中的所述至少一个开口,所述第一和第二结构至少绕所述假体的周向边缘相互固定到一起。
2.如权利要求1所述的假体,其中,所述加强元件具有比所述第一和第二结构的刚度更大的刚度。
3.如权利要求1所述的假体,其中,所述加强元件进一步包括外圆周环和内圆周环以及在所述外圆周环和所述内圆周环之间延伸的多个辐条元件。
4.如权利要求1所述的假体,其中,所述加强元件具有三维形状。
5.如权利要求4所述的假体,其中,所述加强元件进一步包括外圆周环、内圆周环以及在所述外圆周环和所述内圆周环之间延伸的多个辐条元件,并且所述外圆周环基本上位于第一水平面中,而所述内圆周环基本上位于与所述第一水平面间隔开的第二水平面中。
6.如权利要求5所述的假体,还包括从所述多个辐条元件中的至少一个向外延伸的至少一个肋条状元件。
7.如权利要求6所述的假体,其中,所述至少一个肋条状元件的纵向与所述至少一个辐条元件的长度方向对准。
8.如权利要求1所述的假体,其中,所述第一和第二伸出部分的远端被折叠以形成第一和第二环状元件。
9.如权利要求8所述的假体,还包括分别固定到所述第一和第二环状元件的第一和第二抓握构件。
10.如权利要求1所述的假体,其中,所述第一结构进一步包括:
由不可吸收的网构成的补片构件;和
第一和第二可吸收薄膜层,所述第一和第二可吸收薄膜层分别定位成邻近于所述补片构件的顶侧和底侧并且固定到所述补片构件的顶侧和底侧。
11.如权利要求10所述的假体,其中,所述补片构件由聚丙烯构成,并且所述第一和第二薄膜层由聚对二氧环己酮构成。
12.如权利要求10所述的假体,其中,所述第一结构还包括第三层,所述第三层定位成邻近于所述第二薄膜层的底侧并且固定到所述第二薄膜层的底侧。
13.如权利要求12所述的假体,其中,所述第三层由可吸收材料构成。
14.如权利要求13所述的假体,其中,所述第三层由氧化再生纤维素构成。
15.如权利要求1所述的假体,其中,所述第二结构进一步包括外径小于所述第二结构的外径的环形元件,并且所述第一结构的第一和第二伸出部分联接到所述环形元件。
16.如权利要求15所述的假体,其中,所述第二结构还包括网状层以及第三和第四薄膜层,所述第三和第四薄膜层分别定位成邻近于所述网状层的顶侧和底侧并固定到所述网状层的顶侧和底侧。
17.如权利要求16所述的假体,其中,所述第二结构的网状层以及第三和第四薄膜层由可吸收材料构成。
18.如权利要求17所述的假体,其中,所述网状层由聚乳酸羟基乙酸构成,并且所述第三和第四薄膜层由聚对二氧环己酮构成。
19.一种用于修复或加强组织或肌肉壁缺损的可植入假体,包括:
第一复合结构,其包括至少一个不可吸收材料层,所述第一复合结构中央部分,该中央部分的大小和形状设置成覆盖所述组织或肌肉壁缺损的至少一部分,并且该第一复合结构具有外部周边;
第二结构,其具有外部圆周边缘和被加强的中央区域;
加强元件,其定位在所述第一和第二结构之间,并且具有外部周边和比所述第一和第二结构的刚度更大的刚度;和
至少一个拉拽元件,所述至少一个拉拽元件联接到所述第二结构的被加强的中央区域;
其中,基本上仅在所述第一结构和第二结构各自的周边处所述第二结构联接到所述第一结构。
20.如权利要求19所述的假体,该假体具有基本上为圆形的总体形状。
21.如权利要求19所述的假体,其中,所述加强元件具有三维形状。
22.如权利要求21所述的假体,其中,所述加强元件具有位于第一水平面中的外圆周环、和位于与所述第一水平面间隔开的第二水平面中的内圆周环、以及在所述内圆周环与所述外圆周环之间延伸的多个辐条元件。
23.如权利要求19所述的假体,其中,所述第一复合结构进一步包括定位成邻近于所述不可吸收层的顶侧和底侧的第一和第二可吸收薄膜层。
24.如权利要求23所述的假体,其中,所述不可吸收层是网状层。
25.如权利要求24所述的假体,其中,所述第一复合结构还包括定位成邻近于所述第一薄膜层的底侧的可吸收层。
26.如权利要求19所述的假体,其中,所述第二结构的中央区域通过位于其中的环形元件来加强。
27.如权利要求19所述的假体,其中,所述第二复合结构由可吸收材料构成。
28.一种用于修复或加强组织或肌肉壁缺损的可植入假体,包括:
基本扁平的、柔性的第一复合结构,其包括至少一个不可吸收材料层,所述第一复合结构具有中央部分,该中央部分的大小和形状设置成覆盖所述组织或肌肉壁缺损的至少一部分,并且该第一复合结构具有外部周边;
基本扁平的、柔性的第二结构,其具有基本上与所述第一结构的外部周边相似的外部周边,并且具有被加强的中央区域;
三维加强元件,其定位在所述第一和第二结构之间,并且具有基本上与所述第一和第二结构的外部周边相似的外部周边;和
联接到所述第二结构的中央区域的至少一个拉拽元件;
其中,所述第一复合结构和所述第二结构基本上仅绕它们各自的外部周边相互连接在一起。
29.如权利要求28所述的假体,其中,所述加强元件还包括位于第一水平面中的外圆周环、位于第二水平面中的内圆周环以及在所述外圆周环与所述内圆周环之间延伸的多个辐条元件。
30.如权利要求28所述的假体,其中,所述至少一个拉拽元件是直接联接到所述第二结构的被加强的中央区域的独立元件。
31.如权利要求28所述的假体,其中,所述至少一个拉拽元件与所述第一复合结构一体地形成。
32.如权利要求28所述的假体,其中,所述第一叠层结构的不可吸收层是网,并且所述第一结构还包括定位成邻近于所述网的顶侧和底侧的第一和第二可吸收薄膜层。
33.如权利要求32所述的假体,其中,所述网由聚丙烯构成,并且所述第一和第二薄膜层由聚对二氧环己酮构成。
34.如权利要求33所述的假体,其中,所述第二结构进一步地包括网状层以及定位成邻近于所述网状层的顶侧和底侧的第三和第四薄膜层。
35.如权利要求34所述的假体,其中,所述第二结构的网状层及第三和第四薄膜层由可吸收材料构成。
36.如权利要求28所述的假体,其中,所述加强元件由可吸收材料构成。
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- 2007-10-23 WO PCT/US2007/082172 patent/WO2008055028A1/en active Application Filing
- 2007-10-23 KR KR1020097011048A patent/KR101436412B1/ko active IP Right Grant
- 2007-10-23 MX MX2009004781A patent/MX2009004781A/es active IP Right Grant
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- 2007-10-23 JP JP2009535393A patent/JP5280367B2/ja active Active
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US20100312358A1 (en) | 2010-12-09 |
US20130158677A1 (en) | 2013-06-20 |
AU2007313871B2 (en) | 2012-09-06 |
US8591534B2 (en) | 2013-11-26 |
CA2884192C (en) | 2016-11-08 |
WO2008055028A1 (en) | 2008-05-08 |
AU2007313871A1 (en) | 2008-05-08 |
MX2009004781A (es) | 2009-08-25 |
CN101573084B (zh) | 2012-06-27 |
US20080147200A1 (en) | 2008-06-19 |
CA2884192A1 (en) | 2008-05-08 |
US8388633B2 (en) | 2013-03-05 |
US20110178608A1 (en) | 2011-07-21 |
CA2667950A1 (en) | 2008-05-08 |
KR101436412B1 (ko) | 2014-09-02 |
ATE547995T1 (de) | 2012-03-15 |
US7828854B2 (en) | 2010-11-09 |
EP2086464B1 (en) | 2012-03-07 |
EP2086464A1 (en) | 2009-08-12 |
CA2667950C (en) | 2016-02-23 |
US20110172786A1 (en) | 2011-07-14 |
BRPI0718295B8 (pt) | 2021-06-22 |
US9636207B2 (en) | 2017-05-02 |
BRPI0718295B1 (pt) | 2018-07-24 |
KR20090085083A (ko) | 2009-08-06 |
JP5280367B2 (ja) | 2013-09-04 |
JP2010508121A (ja) | 2010-03-18 |
BRPI0718295A2 (pt) | 2013-11-12 |
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