CN108348658B - 使用外科附属物和药剂诱导组织粘连 - Google Patents
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Abstract
本发明提供了使用外科附属物和药剂的组织粘连。一般来讲,可植入附属物可以具有可释放地保持在其中的一种或多种药剂,所述一种或多种药剂被配置成能够诱导组织粘连。所述附属物可被构造成能够使用外科缝合器结合外科钉施加到肺组织。可以通过将附属物递送至肺组织来协助胸膜固定术。
Description
技术领域
本公开整体涉及使用外科附属物和药剂诱导组织粘连。
背景技术
外科缝合器用于外科手术中,以闭合在特定手术中所涉及的组织、血管、导管、分流管、或者其他对象或身体部分中的开口。这些开口可为天然存在的,诸如血管或类似于胃的内部器官中的通路,或者它们可为在外科手术期间由外科医生形成的,诸如通过穿刺组织或血管以形成旁路或吻合部,或通过在缝合手术期间切割组织。
大多数缝合器具有柄部,该柄部具有细长轴,该细长轴具有形成于其端部上的一对可动的相对的钳口,以用于在钳口之间保持钉并且使钉成形。钉通常容纳在钉仓中,该钉仓可容纳多排钉并且通常设置在两个钳口中的一者中以用于将钉射出到手术位点。在使用期间,钳口被定位成使得待缝合的对象被设置在钳口之间,以及在钳口闭合并且装置致动时使钉射出并成形。一些缝合器包括刀,该刀被构造成能够在钉仓中的钉排之间行进,以纵向地切割并且/或者打开钉排之间的已缝合组织。
尽管外科缝合器已经过多年改善,但它们自身仍存在多个问题。一个常见问题是当钉穿透组织或其中设置钉的其他对象时可因钉形成孔而产生渗漏。血液、空气、胃肠液、和其他流体可通过由钉形成的开口而渗出,甚至是在钉完全成形之后。经处理的组织也可因由缝合引起的创伤而发炎。此外,可结合类似于缝合的手术来植入的钉、以及其他对象和材料通常缺乏它们所植入的组织的一些特征。例如,钉以及其他对象和材料可缺乏它们所植入的组织的天然柔韧性。本领域的技术人员应当认识到,通常期望组织在钉设置其中后保持其尽可能多的天然特征。
在一些情况下,生物材料已结合组织缝合来使用。然而,生物材料的使用呈现出多个附加的问题。例如,可能在钉射出之前和射出期间难以保持生物材料相对于钉的钳口的位置。还可能在完成缝合后难以将生物材料保持在手术部位的期望位置处。此外,可能难以将生物材料制造成期望的形状和厚度。常用的塑料和模塑制造技术通常不利于制造与外科缝合器结合使用的薄生物层。许多生物材料的脆弱性质也使得它们难以用于外科缝合器,因为它们缺乏结构支撑。
因此,仍需要改善的装置和方法,以用于缝合组织、血管、导管、分流管或者其他对象或身体部分,使得渗漏和发炎最小化同时仍基本上保持治疗区域的自然特征。还存在对包括生物制剂的改进的可植入材料的需要。
发明内容
一般来讲,提供了使用外科附属物和药剂诱导组织粘连。
在一个方面,提供了一种与外科缝合器一起使用的钉仓组件,该钉仓组件在一个具体实施中包括仓体、生物相容性附属材料和有效量的至少一种药剂。该仓体包括多个钉腔。每个钉腔具有设置在其中的外科钉。生物相容性附属材料可释放地保持在仓体上并且被配置成能够通过仓体中的钉的部署来形成至少一条部署的钉线而递送到肺组织。有效量的至少一种药剂设置在附属材料内并且可从附属材料释放。至少一种药剂有效地诱导与至少一条部署的钉线相邻的组织粘连。
钉仓组件可以多种方式变化。例如,附属材料可被配置成能够以逐渐释放的方式从其中释放至少一种药剂。又如,附属材料可被配置成能够从其释放至少一种药剂作为单次释放剂量。又例如,附属材料可以包括被配置成能够经历从固态到液态的相变的载体,并且至少一种药剂可被配置成能够在载体处于液态而非固态时从附属材料释放。又如,至少一种药剂可以包括生长因子。再例如,至少一种药剂可以包括白介素(IL)β、组织生长因子β(TGF-B)和富血小板血浆中的至少一种。
在另一方面,提供了一种使用钉仓组件的方法,在一个具体实施中,该方法包括将仓体附接到外科缝合器,将缝合器定位在与肺组织相邻的目标位置处,并且在缝合器位于目标位置的情况下,致动缝合器以从仓体部署钉并使其进入肺组织,从而将附属材料递送到肺组织。
该方法可以任意种方式变化。例如,至少一种药剂有效地诱导具有递送的该附属材料的肺组织的胸膜表面之间的组织粘连。
另一方面,提供了一种用于外科器械的端部执行器,在一个具体实施中,该端部执行器包括第一钳口、第二钳口、生物相容性附属材料和有效量的至少一种药剂。第一钳口具有与其可移除地附接的仓体。仓体在其面向组织的表面上具有多个钉腔,该多个钉腔被构造成能够将钉安置在其中。第二钳口具有砧座,该砧座具有形成在其面向组织的表面上的多个钉成形腔。该第一钳口和第二钳口中的至少一者能够相对于另一者移动。生物相容性附属材料可释放地保持在第一钳口的面向组织的表面和第二钳口的面向组织的表面中的至少一者上,并且被配置成能够通过仓体中的钉的部署以形成至少一条部署的钉线而递送到组织。有效量的至少一种药剂设置在附属材料内并且可从附属材料释放。至少一种药剂有效地诱导与至少一条部署的钉线相邻的组织粘连。
端部执行器可以任意种方式变化。例如,附属材料可被配置成能够以逐渐释放的方式从其中释放至少一种药剂。又如,附属材料可被配置成能够从其释放至少一种药剂作为单次释放剂量。又例如,附属材料可以包括被配置成能够经历从固态到液态的相变的载体,并且该至少一种药剂可被配置成能够在载体处于液态而非固态时从附属材料释放。又如,至少一种药剂可以包括生长因子。再例如,至少一种药剂可以包括ILβ、TGF-B和富血小板血浆中的至少一种。
在另一方面,提供了一种使用端部执行器的方法,在一个具体实施中,该方法包括将外科缝合器定位在患者体内邻近肺组织的目标位置处。缝合器在其远侧端部处具有端部执行器。该方法还包括,在缝合器定位在目标位置处时,致动缝合器以从仓体部署钉并使其进入组织,从而将附属材料递送到肺组织。
该方法可具有任何数量的变型。例如,至少一种药剂有效地诱导具有递送的该附属材料的肺组织的胸膜表面之间的组织粘连。
附图说明
通过以下结合附图所作的详细描述,将更充分地理解本发明,在附图中:
图1是外科缝合器的一个实施方案的透视图;
图2是图1的外科缝合器的远侧部分的分解图;
图3是图1的外科缝合器的击发杆的透视图,击发杆在其远侧端部处具有电子束;
图4是外科缝合器的另一个实施方案的透视图;
图5是外科缝合器的又一个实施方案的透视图;
图6是在药剂释放之前使用不同释放机制封装有不同类型的药剂的附属材料的实施方案的图形表示;
图7是图6的附属材料的图形表示,示出了第一药剂的释放;
图8是图6的附属材料的图形表示,示出了第二药剂的释放;
图9是在药剂释放之前使用不同释放机制封装具有不同类型的药剂的附属材料的实施方案的另一图形表示;
图10是图9的附属材料的图形表示,示出了第一包衣的吸收导致的药剂释放;
图11是图9的附属材料的图形表示,示出了第二包衣的吸收导致的药剂释放;
图12是包括具有不同降解速率的可吸收聚合物的顶层和底层的附属材料的图示;
图13是图12的附属材料的图形表示,示出了部分降解的顶层;
图14是图12的附属材料的图形表示,示出了顶层已降解后部分降解的底层;
图15是被配置成能够响应于至少一种环境条件而释放至少一种药剂的附属材料的图形表示;
图16是图15的附属材料的图形表示,示出了响应于至少一种环境条件而从附属材料部分释放至少一种药剂;
图17是图15的附属材料的另一图形表示,示出了响应于至少一种环境条件而从附属材料基本上完全释放至少一种药剂;
图18是被配置成能够通过改变其构象而释放至少一种药剂的附属材料的图形表示;
图19是图18的附属材料的图形表示,示出了其构象发生变化并且至少一种药剂部分释放的附属材料;
图20是包括与其中设置有至少一种药剂的容器相关联的多种纤维的附属材料的图形表示;
图21是图20的附属材料的图形表示,示出了在应变作用下从附属材料释放至少一种药剂;
图22是被配置成能够响应于施加到附属材料上的应变而释放至少一种药剂的附属材料的图形表示;
图23是图22的附属材料的图形表示,示出了响应于施加到附属材料上的应变而释放至少一种药剂;
图24是具有封装在其中的至少一种药剂的容器的图形表示;
图25是图24的容器的图形表示,示出了响应于施加到容器上的应变而释放至少一种药剂;
图26是被配置成能够当附属材料改变其构象时释放至少一种药剂的附属材料的图形表示;
图27是图26的附属材料的图形表示,示出了响应于附属材料的构象变化而释放至少一种药剂;
图28是被配置成能够当附属材料改变其构象时释放至少一种药剂的附属材料的另一图形表示;
图29是图28的附属材料的图形表示,示出了响应于附属材料的构象变化而释放至少一种药剂;
图30是具有被配置成能够以非均匀方式释放封装在其中的至少一种药剂的容器的附属材料的图形表示;
图31是被配置成能够以非均匀方式释放封装在其不同层中的多种药剂的容器的图形表示;
图32是具有被配置成能够以非均匀方式释放至少一种药剂的不同部分的附属材料的图形表示;
图33是具有被配置成能够以非均匀方式释放至少一种药剂的不同部分的附属材料的另一图形表示;
图34是图33的附属材料的侧视图的图形表示;
图35是具有被配置成能够以非均匀方式释放至少一种药剂的不同部分的附属材料的侧视图的图形表示;
图36是具有被配置成能够以非均匀方式释放至少一种药剂的不同部分的附属材料的侧视图的另一图形表示;
图37是具有被配置成能够以不同速率释放至少一种药剂的不同同心区域的附属材料的图形表示;
图38是具有被配置成能够以不同速率释放至少一种药剂的不同径向区域的附属材料的图形表示;
图39是具有被配置成能够以不同速率释放至少一种药剂的不同同心区域的附属材料的另一图形表示;
图40是在不同的药剂剂量下随时间推移伤口愈合的实施方案的图形表示;
图41是图40的伤口愈合中止血阶段的图形表示;
图42是图40的伤口愈合中炎症阶段的一部分的图形表示;
图43是图40的伤口愈合中炎症阶段的另一部分的图形表示;
图44是图40的伤口愈合中增生阶段的图形表示;
图45是其中包含至少一种药剂的多层附属物的示例的局部横截面侧视图,所述药剂被配置成能够诱导组织粘连;
图46是利用钉固定到肺组织的图45的附属物的局部横截面侧视图;
图47是具有包含附属物的钉线的切除肺的示意图;并且
图48是图47的肺和附属物的放大示意图。
具体实施方式
现在将描述某些示例性实施方案,以从整体上理解本文所公开的装置和方法的结构、功能、制造和用途原理。这些实施方案的一个或多个示例已在附图中示出。本领域的技术人员将会理解,本文具体描述并在附图中示出的装置和方法是非限制性的示例性实施方案,本公开的范围仅由权利要求书限定。结合一个示例性实施方案进行图解说明或描述的特征部可与其他实施方案的特征部进行组合。此类修改和变型旨在包括在本发明的范围之内。
此外,在本公开中,各实施方案中名称相同的部件通常具有相似的特征部,因而在一个具体实施方案中,不一定完整地详细说明每个名称相同的部件的每个特征。另外,就使用线性或圆形尺寸来描述本发明所公开的系统、装置和方法而言,此类尺寸并非旨在限制可结合此类系统、装置和方法使用的形状的类型。本领域的技术人员将认识到,可容易地针对任何几何形状确定此类线性和圆形尺寸的等效尺寸。系统和装置及其部件的大小和形状可至少取决于系统和装置将用于其中的受治疗者的解剖结构、系统和装置将与其一起使用的部件的大小和形状、以及系统和装置将用于其中的方法和手术。
应当理解,本文相对于抓握器械柄部的使用者诸如临床医生来使用术语“近侧”和“远侧”。诸如“前”和“后”的其他空间术语分别类似地对应于远侧和近侧。还应当理解,为便利和清楚起见,本文结图示使用空间用语诸如“竖直”和“水平”。然而,外科器械在许多取向和位置上使用,并且这些空间术语并非限制性和绝对的。
提供了用于执行外科手术的各种示例性装置和方法。在一些实施方案中,该装置和方法设置用于开放式外科手术,并且在其他实施方案中,该装置和方法设置用于腹腔镜式、内窥镜式和其他微创外科手术。这些装置可由人类用户直接击发或在机器人或类似操纵工具的直接控制下远程击发。然而,本领域的技术人员将理解,本文所公开的各种方法和装置可用于许多外科手术和应用中。本领域的技术人员将进一步理解,本文所公开的各种器械可以任何方式插入到身体中,诸如通过自然孔口、通过在组织中形成的切口或穿孔、或通过进入装置(诸如套管针插管)。例如,该器械的工作部分或端部执行器部分可直接插入到患者的身体中或者可通过进入装置插入,该进入装置具有外科器械的端部执行器和细长轴可推进穿过的工作通道。
可能需要结合外科器械使用一种或多种生物材料和/或合成材料(在本文中统称为“附属物”)来帮助改善外科手术。虽然各种不同的外科端部执行器可受益于附属物的使用,但在一些示例性实施方案中,端部执行器可以是外科缝合器。当结合外科缝合器使用时,该一种或多种附属物可设置在缝合器的钳口之间和/或其上、结合到设置在钳口中的钉仓中或以其他方式邻近钉放置。当部署钉时,该一种或多种附属物可与钉一起保持在治疗部位,继而提供许多益处。例如,该一种或多种附属物可增强治疗部位处的组织,防止在治疗部位处被钉撕开或扯裂。如果组织患病、从另一种治疗诸如照射治疗、药剂治疗诸如化学疗法或其他组织性质改变状况愈合,则可能需要组织增强以防止钉撕开组织。在一些情况下,该一种或多种附属物可使钉穿孔部位中和周围的组织运动(例如,肺膨胀、胃肠道扩张等)最小化,这种组织运动可因缝合之后发生的组织变形而发生。本领域的技术人员将认识到,钉穿孔部位可用作应力集中部,并且当其周围的组织处于张力下时,由钉形成的孔的大小将增大。限制这些穿孔部位周围的组织运动可以使孔在张力下可增大至的大小最小化。在一些情况下,该一种或多种附属物可被配置成能够芯吸或吸收进一步促进愈合的有益流体,例如密封剂、血液、粘着剂,并且在一些情况下,该一种或多种附属物被配置成能够降解以形成进一步促进愈合的凝胶,例如密封剂。在一些情况下,该一种或多种附属物可用于帮助密封在钉被植入组织、血管和各种其他对象或身体部分中时由钉形成的孔。该一种或多种附属物也可通过与该一种或多种附属物相关联的任何纤维或股线的间隔、定位和/或取向来影响组织生长。
该一种或多种附属物也可在其上和/或其中具有一种或多种药剂。该一种或多种药剂可根据该一种或多种药剂对周围组织的期望效果而变化。作为非限制性示例,可提供该一种或多种药剂来影响止血、炎症、巨噬细胞和/或成纤维细胞。同样取决于对组织的期望效果,可以任意组合对一种或多种药剂进行混合或组合,或者可单独提供一种药剂。该一种或多种药剂可以各种不同的方式从该一种或多种附属物中洗脱出来。作为非限制性示例,该一种或多种附属物上的包衣可变化以在不同时间点被吸收,从而在不同时间点释放该一种或多种药剂;该一种或多种附属物可变化以允许该一种或多种药剂以不同速率扩散穿过该一种或多种附属物;该一种或多种附属物可在分子量和/或物理特性上有所不同,从而使得该一种或多种药剂在不同时间点释放;等等。
外科缝合器械
各种外科器械可与本文所公开的一种或多种附属物和/或一种或多种药剂结合使用。“附属物”在本文中也被称为“附属材料”。外科器械可包括外科缝合器。可使用各种外科缝合器,例如线性外科缝合器和圆形缝合器。通常,线性缝合器可被构造成能够产生纵向钉线并且可包括细长钳口,该细长钳口具有与其联接的容纳纵向钉排的仓。细长钳口可包括能够沿保持在钳口内的组织在钉排之间产生切口的刀或其他切割元件。通常,圆形缝合器可被构造成能够形成环形钉线,并且可包括具有容纳环形钉排的仓的圆形钳口。圆形钳口可包括刀或其他切割元件,该刀或其他切割元件能够在钉排内形成切口以限定穿过保持在钳口内的组织的开口。在各种不同的外科手术中,缝合器可用于各种组织的各种不同外科手术,例如胸外科手术或胃手术。
图1示出了适合与一种或多钟附属物和/或一种或多种药剂一起使用的线性外科缝合器10的一个示例。缝合器10通常包括柄部组件12、从柄部组件12的远侧端部12d朝远侧延伸的轴14,以及位于轴14的远侧端部14d处的端部执行器30。端部执行器30具有相对的下钳口和上钳口32、34,但其他类型的端部执行器可与轴14、柄部组件12、以及与其相关联的部件一起使用。下钳口32具有被构造成能够支撑钉仓40的钉通道56,并且上钳口34具有面向下钳口32并被构造成能够作为砧座操作以帮助部署钉仓40的钉的砧座表面33(钉在图1和图2中被遮挡)。该相对的下钳口和上钳口32、34中的至少一者能够相对于下钳口和上钳口32、34中的另一者运动以夹紧设置在其间的组织和/或其他对象。在一些具体实施中,该相对的下钳口和上钳口32、34中的至少一者可以是固定的或以其他方式不可动的。在一些具体实施中,该相对的下钳口和上钳口32、34两者可以是可动的。击发系统的部件可被构造成能够穿过端部执行器30的至少一部分以将钉射出到被夹紧的组织中。在各种具体实施中,刀片36或其他切割元件可与击发系统相关联以在缝合手术期间切割组织。
端部执行器30的操作可开始于使用者(例如,临床医生、外科医生等)在柄部组件12处的输入。柄部组件12可具有被设计用来操纵和操作与其相关联的端部执行器30的许多不同的构型。在所示示例中,柄部组件12具有手枪抓握型外壳18,该手枪抓握型外壳具有设置在其中的各种机械和/或电子部件以操作器械10的各种特征结构。例如,柄部组件12可包括与其远侧端部12d相邻安装的旋钮26,该旋钮可有利于轴14和/或端部执行器30围绕轴14的纵向轴线L相对于柄部组件12的旋转。柄部组件12还可包括作为由夹紧触发器22致动的夹紧系统的一部分的夹紧部件和作为由击发触发器24致动的击发系统的一部分的击发部件。夹紧触发器22和击发触发器24可例如由扭力弹簧偏压到相对于固定柄部20的打开位置。夹紧触发器22朝向固定柄部20的运动可致动夹紧系统,如下文所述,其可使钳口32、34朝向彼此塌缩并由此将组织夹紧在它们之间。击发触发器24的运动可致动击发系统,如下所述,其可使钉从其所设置于其中的钉仓40射出和/或使刀片36推进以切断捕获在钳口32、34之间的组织。本领域的技术人员将认识到,可使用用于击发系统的各种构型(机械、液压、气动、机电、机器人或其他)的部件来射出钉和/或切割组织。
如图2所示,所示具体实施的端部执行器30具有用作仓组件或携载件的下钳口32和用作砧座的相对的上钳口34。在其中具有多个钉的钉仓40支撑在钉托盘37中,该钉托盘继而支撑在下钳口32的仓通道内。上钳口34具有多个钉成形凹坑(未示出),该钉成形凹坑中的每一个钉成形凹坑定位在来自容纳在钉仓40内的多个钉的对应钉的上方。尽管在所示具体实施中,上钳口34仅在其与轴14的接合的远侧具有近侧枢转端部34p,该近侧枢转端部可枢转地接纳在钉通道56的近侧端部56p内,但上钳口34可以各种方式连接到下钳口32。当上钳口34向下枢转时,上钳口34使砧座表面33运动并且使形成在其上的钉成形凹坑朝向相对的钉仓40运动。
可使用各种夹紧部件来实现钳口32、34的打开和闭合以选择性地将组织夹紧在它们之间。如图所示,上钳口34的枢转端部34p在其与钉通道56的枢转附接部的远侧包括闭合特征结构34c。因此,响应于夹紧触发器22,闭合管46选择性地在该闭合管朝近侧纵向运动期间赋予上钳口34打开动作并且在闭合管朝远侧纵向运动期间赋予上钳口34闭合动作,该闭合管的远侧端部包括接合闭合特征结构34c的马蹄形孔46a。如上所述,在各种具体实施中,端部执行器30的打开和闭合可通过下钳口32相对于上钳口34的相对动作、上钳口34相对于下钳口32的相对动作或通过钳口32、34两者相对于彼此的动作来实现。
所示具体实施的击发部件包括如图3所示的在其远侧端部上具有电子束38的击发杆35。击发杆35包含在轴14内,例如,在轴14的纵向击发杆槽14s中,并且由来自柄部12的击发动作引导。击发触发器24的致动可影响电子束38穿过端部执行器30的至少一部分的远侧动作,以借此引起容纳在钉仓40内的钉的击发。如图所示,从电子束38的远侧端部突出的引导件39可接合如图2所示的楔形滑动件47,这继而可将钉驱动器48向上推动穿过形成在钉仓40中的钉腔41。钉驱动器48的向上运动对仓40内的多个钉中的每一个钉施加向上的力,从而将钉向上推动抵靠上钳口34的砧座表面33并产生成形钉。
除了使得钉击发以外,电子束38还被配置成能够有利于钳口32、34的闭合,上钳口34相对于钉仓40的隔开,和/或捕获在钳口32、34之间的组织的切断。具体地讲,一对顶销和一对底销可接合上钳口和下钳口32、34中的一者或两者,以在击发杆35推进穿过端部执行器30时将钳口32、34朝向彼此压缩。同时,在顶销和底销之间延伸的刀36被构造成能够切断被捕获在钳口32、34之间的组织。
在使用时,外科缝合器10可设置在插管或口中并设置在手术部位处。待切割和缝合的组织可放置在外科缝合器10的钳口32、34之间。缝合器10的特征结构可由使用者根据需要来操纵以实现钳口32、34在手术部位处以及组织相对于钳口32、34的期望位置。在已实现适当定位之后,可将夹紧触发器22朝向固定柄部20拉动以致动夹紧系统。触发器22可使夹紧系统的部件工作,使得闭合管46朝远侧推进穿过轴14的至少一部分以引起钳口32、34中的至少一者朝另一者塌缩以夹紧设置在它们之间的组织。然后,可将触发器24朝固定柄部20拉动以使击发系统的部件工作,使得击发杆35和/或电子束38朝远侧推进穿过端部执行器30的至少一部分以实现钉的击发并任选地切断捕获在钳口32、34之间的组织。
线性外科缝合器50形式的外科器械的另一个示例如图4所示。缝合器50通常可与图1的缝合器10类似地构造和使用。类似于图1的外科器械10,外科器械50包括柄部组件52以及轴54,该轴从柄部组件朝远侧延伸并在轴的远侧端部上具有用于治疗组织的端部执行器60。端部执行器60的上钳口和下钳口64、62被构造成能够将组织捕获在它们之间,通过从设置在下钳口62中的仓66击发钉来缝合组织并且/或者在组织中产生切口。在该具体实施中,轴54的近侧端部上的附接部分67被构造成能够允许轴54和端部执行器60可移除地附接到柄部组件52。具体地讲,附接部分67的配合特征结构68可与柄部组件52的互补配合特征结构71配合。配合特征结构68、71可被构造成能够经由例如卡扣式联接、卡口式联接等联接在一起,但可使用任何数量的互补配合特征结构和任何类型的联接来将轴54可移除地联接到柄部组件52。虽然所示具体实施的整个轴54被构造成能够从柄部组件52拆下,但在一些具体实施中,附接部分67被构造成能够允许轴54的仅远侧部分拆下。轴54和/或端部执行器60的可拆卸联接可允许针对特定手术选择性地附接期望的端部执行器60,和/或针对多个不同的手术再利用柄部组件52。
柄部组件52可具有位于其上的用于操纵和操作端部执行器60的一个或多个特征结构。作为非限制性示例,安装在柄部组件52的远侧端部上的旋钮72可有利于轴54和/或端部执行器60相对于柄部组件52的旋转。柄部组件52可包括作为由可动触发器74致动的夹紧系统的一部分的夹紧部件和作为也可由触发器74致动的击发系统的一部分的击发部件。因此,在一些具体实施中,触发器74朝固定柄部70运动穿过第一动作范围可致动夹紧部件,使得相对的钳口62、64彼此靠近以达到闭合位置。在一些具体实施中,相对的钳口62、24中的仅一者可运动到钳口62、64的闭合位置。触发器74朝固定柄部70进一步运动穿过第二动作范围可致动击发部件,使得钉从钉仓66中射出和/或使刀或其他切割元件(未示出)的推进切断捕获在钳口62、64之间的组织。
圆形外科缝合器80形式的外科器械的一个示例如图5所示。缝合器80通常可与图1和图4的线性缝合器10、50类似地构造和使用,但其中一些特征结构适应其作为圆形缝合器的功能。类似于外科器械10、50,外科器械80包括柄部组件82以及轴84,该轴从柄部组件朝远侧延伸并且在该轴的远侧端部上具有用于治疗组织的端部执行器90。端部执行器90可包括仓组件92和砧座94,该仓组件和砧座各自具有其形状基本上为圆形的组织接触表面。仓组件92和砧座94可经由从砧座94延伸到缝合器80的柄部组件82的轴98联接在一起,并且操纵柄部组件82上的致动器85可回缩和推进轴98以使砧座94相对于仓组件92运动。砧座94和仓组件92可执行各种功能,并且可被构造成能够将组织捕获在它们之间、通过从仓组件92的仓96击发钉来缝合组织,并且/或者可在组织中产生切口。一般来讲,仓组件92可容纳包含钉的仓,并且可将钉部署抵靠砧座94以形成圆形钉图案,例如钉围绕管状主体器官的周边。
在一个具体实施中,轴98可由第一部分和第二部分(未示出)形成,该第一部分和第二部分被构造成能够以可释放方式联接在一起以允许砧座94与仓组件92分离,这可允许将砧座94和仓组件92定位在患者的身体中的更大灵活性。例如,轴的第一部分可设置在仓组件92内并朝远侧延伸到仓组件92之外,终止于远侧配合特征结构中。轴84的第二部分可设置在砧座94内并朝近侧延伸到仓组件92之外,终止于近侧配合特征结构中。在使用时,该近侧配合特征结构和远侧配合特征结构可联接在一起以允许砧座94和仓组件92相对于彼此运动。
缝合器80的柄部组件82可具有设置在其上的可控制缝合器运动的各种致动器。例如,柄部组件82可具有设置在其上以便于经由旋转来定位端部执行器90的旋钮86,和/或用于端部执行器90的致动的触发器85。触发器85朝固定柄部87运动穿过第一动作范围可致动夹紧系统的部件以接近钳口,即,使砧座94朝仓组件92运动。触发器85朝固定柄部87运动穿过第二动作范围可致动击发系统的部件以使从钉仓组件92部署钉并且/或者使刀推进以切断被捕获在仓组件92与砧座94之间的组织。
外科缝合器械10、50和80的所示示例仅提供了可与本文提供的公开内容结合使用的许多不同构型和相关使用方法的几个示例。虽然所示示例均被构造成能够用于微创手术,但应当理解,被构造成能够用于开放式外科手术的器械,例如,2007年2月28日提交的名称为“Surgical Stapling Devices That Produce Formed Staples Having DifferentLengths”的美国专利8,317,070中所述的开放式线性缝合器,可与本文提供的公开内容结合使用。在以下专利中提供了所示示例的更多细节以及外科缝合器的附加示例、其部件以及它们的相关使用方法。2013年2月8日提交的名称为“Layer Comprising DeployableAttachment Members”的美国专利公布2013/0256377,2010年9月30日提交的名称为“Selectively Orientable Implantable Fastener Cartridge”的美国专利8,393,514,2007年2月28日提交的名称为“Surgical Stapling Devices That Produce FormedStaples Having Different Lengths”美国专利8,317,070,2005年6月21日提交的名称为“Surgical Instrument Incorporating EAP Blocking Lockout Mechanism”的美国专利7,143,925,2013年11月8日提交的名称为“Sealing Materials For Use In SurgicalStapling”的美国专利公布2015/0134077,和2013年11月8日提交的名称为“SealingMaterials for Use in Surgical Procedures”,2013年11月8日提交的名称为“HybridAdjunct Materials for Use in Surgical Stapling”的美国专利公布2015/0134076,和2013年11月8日提交的名称为“Positively Charged Implantable Materials and Methodof Forming the Same”的美国专利公布2015/0133996,2013年11月8日提交的名称为“Tissue Ingrowth Materials and Method of Using the Same”的美国专利公布2015/0129634,2013年11月8日提交的名称为“Hybrid Adjunct Materials for Use inSurgical Stapling”美国专利公布2015/0133995,2014年3月26日提交的名称为“SurgicalInstrument Comprising Sensor System”的美国专利申请14/226,142,和2014年6月10日提交的名称为“Adjunct Materials and Methods of Using Same in Surgical Methodsfor Tissue Sealing”的美国专利申请14/300,954,所有专利全文借此以引用方式并入本文中。
可植入附属物
如上文所指出的那样,提供了用于与外科缝合器械结合使用的各种可植入附属物。该附属物可具有多种构型并且可由多种材料形成。通常,附属物可由膜、泡沫、注塑热塑性塑料、真空热成型材料、纤维结构及其混合物中的一者或多者形成。该附属物还可包括一种或多种生物衍生材料和一种或多种药物。这些材料中的每一者在下文中有更详细地讨论。
附属物可由泡沫形成,诸如闭孔泡沫、开孔泡沫或海绵。可如何制造此类附属物的示例是来自动物衍生的胶原(诸如猪肌腱),其可随后被加工并冻干成泡沫结构。各种泡沫附属物的示例在先前提到的2010年9月30日提交的名称为“Selectively OrientableImplantable Fastener Cartridge”的美国专利8,393,514中有进一步描述。
附属物也可由下文讨论的任何合适的材料或其组合形成的膜形成。该膜可包括一个或多个层,每个层可具有不同的降解速率。此外,膜可具有形成在其中的各种区域,例如,能够可释放地保持一种或多种不同形式的药剂的贮存器。可使用一个或多个不同的包衣来密封其中设置有至少一种药剂的贮存器,该包衣可包括可吸收或不可吸收的聚合物。该膜可以各种方式形成,例如,其可以是挤出模塑膜或压缩模塑膜。
附属物也可由注塑热塑性材料或真空热成型材料形成。各种模制附属物的示例在2013年2月8日提交的名称为“Fastener Cartridge Comprising A Releasably AttachedTissue Thickness Compensator”的美国专利公布2013/0221065中有进一步的描述,该专利全文以引用方式并入本文。附属物也可以是基于纤维的格,其可以是织造物、针织物或非织造物,诸如熔喷、针刺或热构建的松散织造物。附属物可具有可由相同类型的格或不同类型的格形成的多个区域,这些格可以多种不同的方式一起形成附属物。例如,纤维可织造、编织、针织或以其他方式相互连接以便形成规则或不规则的结构。纤维可相互连接,使得所得的附属物相对松散。或者,附属物可包括紧密互连的纤维。附属物可以是片材、管材、螺旋或任何其他可包括柔性部分和/或更刚性的增强部分的结构的形式。附属物可被构造成能够使得其某些区域可具有更致密的纤维,而其他区域具有较低密度的纤维。基于附属物的预期应用,纤维密度可沿附属物的一个或多个维度在不同方向上变化。
附属物也可以是混合构建物,诸如层压复合物或熔融互锁纤维。各种混合构建附属物的示例在以下专利中有进一步描述:2013年2月8日提交的名称为“Adhesive FilmLaminate”的美国专利公布2013/0146643,以及2007年9月12日提交的名称为“MinimallyInvasive Medical Implant And Insertion Device And Method For Using the Same”的美国专利7,601,118,其全文以引用方式并入本文中。
材料
根据所述技术的附属物可由各种材料形成。这些材料可用于各种实施方案中以用于不同目的。这些材料可根据待递送至组织的期望治疗来选择以便便于组织的向内生长。下文描述的材料可用于以任何期望的组合形成附属物。
这些材料可包括可生物吸收的聚合物和生物相容性聚合物,包括均聚物和共聚物。均聚物和共聚物的非限制性示例包括对二氧杂环己酮(PDO或PDS)、聚羟基乙酸(PGA)、乳酸-羟基乙酸共聚物(PLGA)、聚己酸内酯(PCL)、亚丙基碳酸酯(TMC)和聚乳酸(PLA)、聚(羟基乙酸-共-乳酸)(PLA/PGA)(例如,用于Vicryl、Vicryl Rapide、PolySorb和Biofix的PLA/PGA材料)、聚氨酯(诸如Elastane、Biospan、Tecoflex、Bionate和Pellethane纤维)、聚原酸酯、聚酐(例如,Gliadel和Biodel聚合物)、聚含氧酸酯、聚酯酰胺和基于酪氨酸的聚酯酰胺。共聚物还可包括聚(乳酸-共-聚己酸内酯)(PLA/PCL)、聚(L-乳酸-共-聚己酸内酯)(PLLA/PCL)、聚(羟基乙酸-共-亚丙基碳酸酯)(PGA/TMC)(例如,Maxon)、聚(羟基乙酸-共-己内酯)(PCL/PGA)(例如,Monocryl和Capgly)、PDS/PGA/TMC(例如,Biosyn)、PDS/PLA、PGA/PCL/TMC/PLA(例如,Caprosyn)和LPLA/DLPLA(例如,Optima)。
附属物还可包括活性剂,诸如活性细胞培养物(例如,切块的自体组织、用于干细胞疗法的试剂(例如,Biosutures和Cellerix SL)、止血剂和组织愈合剂)。止血剂的非限制性示例可包括纤维素(诸如氧化再生纤维素(ORC)(例如,Surgicel和Interceed))、血纤蛋白/凝血酶(例如,Thrombin-JMI、TachoSil、Tiseel、Floseal、Evicel、TachoComb、Vivostat和Everest)、自体血小板血浆、明胶(例如,Gelfilm和Gelfoam)、透明质酸(诸如微纤维(例如,纱线和纺织品))或基于透明质酸的其他结构或基于透明质酸的水凝胶。止血剂还可包括聚合物密封剂,诸如例如牛血清白蛋白和戊二醛、人血清白蛋白和聚乙烯交联剂以及乙二醇和亚丙基碳酸酯。聚合物密封剂可包括由Focal Inc.开发的FocalSeal外科密封剂。
本文所述的附属物能够可释放地保持至少一种可选自大量不同药剂的药剂。药剂包括但不限于包含在附属物内或与附属物相关的具有期望功能的药物或其他剂。药剂包括但不限于例如抗微生物剂(诸如抗菌剂和抗生素)、抗真菌剂、抗病毒剂、抗炎剂、生长因子、止痛药、麻醉剂、组织基质退化抑制剂、抗癌剂、止血剂和引发生物反应的其他剂。
抗微生物剂的非限制性示例包括离子银、氨基糖苷、链霉素、多肽、杆菌肽、三氯生、四环素类、多西环素、米诺环素、地美环素、四环素、氧四环素、氯霉素、硝基呋喃类、呋喃唑酮、呋喃妥因、β-内酰胺、青霉素、阿莫西林、阿莫西林+克拉维酸、阿洛西林、氟氯西林、替卡西林、哌拉西林+他唑巴坦、特治星、Biopiper TZ、Zosyn、碳青霉烯类、亚胺培南、美罗培南、厄他培南、多尼培南、比阿培南、帕尼培南/倍他米隆、喹诺酮、环丙沙星、依诺沙星、加替沙星、吉米沙星、左氧氟沙星、洛美沙星、莫西沙星、萘啶酸、诺氟沙星、磺胺类、磺胺米隆、磺胺醋酰、磺胺嘧啶、磺胺嘧啶银、磺胺二甲嘧啶、磺胺甲二唑、磺胺甲恶唑、柳氮磺吡啶、磺胺异恶唑、复方新诺明、百浪多息、袢霉素、格尔德霉素、除莠霉素、非达霉素、糖肽、替考拉宁、万古霉素、特拉万霉素、达巴霉素、Oritavancin、林可酰胺类、氯林肯霉素、林可霉素、脂肽、达托霉素、大环内酯类、阿奇霉素、克拉霉素、红霉素、罗红霉素、泰利霉素、螺旋霉素、恶唑烷酮、利奈唑胺、氨基糖苷类、丁胺卡那霉素、庆大霉素、卡那霉素、新霉素、奈替米星、妥布霉素、巴龙霉素、巴龙霉素、头孢菌素、头孢比普、头孢洛扎、头孢克定、氟氧头孢、单内酰环、氨曲南、粘杆菌素和多粘菌素B。
抗真菌剂的非限制性示例包括三氯生、多烯、两性霉素B、杀假丝菌素、非律平、哈霉素、那他霉素、制霉菌素、龟裂杀菌素、唑类、咪唑、三唑、噻唑、烯丙胺、阿莫罗芬、布替萘芬、萘替芬、特比萘芬、棘球白素类、阿尼芬净、卡泊芬净、Micafungin、环吡酮和苯甲酸。
抗病毒剂的非限制性示例包括:未加包衣的抑制剂,诸如例如金刚烷胺、金刚乙胺、普来可那立(Pleconaril);逆转录酶抑制剂,诸如例如阿昔洛韦、拉米夫定、反义药物(Antisense)、福米韦生、吗啉代化合物、核糖酶、利福平;以及杀病毒剂,诸如例如蓝病毒素-N(Cyanovirin-N)、Griffithsin、Scytovirin、α-月桂酰基-L-精氨酸乙基酯(LAE)和离子银。
抗炎剂的非限制性示例包括非甾族抗炎剂(例如,水杨酸盐、阿司匹林、二氟尼柳、丙酸衍生物、布洛芬、萘普生、非诺洛芬和洛索丙芬)、乙酸衍生物(例如,托美丁、舒林酸、双氯芬酸钠)、烯醇酸衍生物(例如,吡罗昔康、美洛昔康、朵昔康和氯诺昔康)、邻氨基苯甲酸衍生物(例如,甲芬那酸、甲氯芬那酸和氟芬那酸)、选择性COX-2抑制剂(例如,塞来考昔(Celebrex)、帕瑞考昔、罗非考昔(Vioxx)、磺酰基苯胺、尼美舒利和克霉素)、免疫选择性抗炎衍生物、皮质类固醇(例如,地塞米松)和iNOS抑制剂。
生长因子的非限制性示例包括为那些刺激细胞生长、愈合、重塑、增殖和分化的细胞信令分子。示例性的生长因子可以是短程的(旁分泌)、远程的(内分泌)或自刺激的(自分泌)。生长因子的其他示例包括生长激素(例如,重组生长因子、Nutropin、Humatrope、Genotropin、Norditropin、Saizen、Omnitrope和生物合成生长因子)、表皮生长因子(EGF)(例如,抑制剂、吉非替尼、厄洛替尼、阿法替尼和西妥昔单抗)、肝素结合EGF样生长因子(例如,表皮调节素、Betacellulin、双调蛋白和Epigen)、转化生长因子α(TGF-a)、神经调节蛋白1-4、成纤维细胞生长因子(FGF)(例如,FGF1-2、FGF2、FGF11-14、FGF18、FGF15/19、FGF21、FGF23、FGF7或角质形成细胞生长因子(KGF)、FGF10或KGF2和苯妥英)、胰岛素样生长因子(IGF)(例如,IGF-1、IGF-2和血小板衍生生长因子(PDGF))、血管内皮生长因子(VEGF)(例如,抑制剂、贝伐单抗、雷珠单抗、VEGF-A、VEGF-B、VEGF-C、VEGF-D和贝卡普勒明)。
生长因子的其他非限制性示例包括细胞因子,诸如粒细胞巨噬细胞集落刺激因子(GM-CSF)(例如,抑制炎症反应的抑制剂,以及已使用重组DNA技术和通过重组酵母来源制造的GM-CSF)、粒细胞集落刺激因子(G-CSF)(例如,非格司亭、雷诺司替和Neupogen)、组织生长因子β(TGF-B)、瘦蛋白和白细胞介素(IL)(例如,IL-1a、IL-1b、康纳单抗、IL-2、阿地白介素、Interking、Denileukin Diftitox、IL-3、IL-6、IL-8、IL-10、IL-11和Oprelvekin)。生长因子的非限制性示例还包括促红细胞生成素(例如,达贝泊汀、Epocept、Dynepo、Epomax、NeoRecormon、Silapo和Retacrit)。
止痛药的非限制性示例包括麻醉剂、阿片类药物、吗啡、可待因、羟考酮、氢可酮、丁丙诺啡、曲马多、非麻醉剂、扑热息痛、对乙酰氨基酚、非甾体抗炎药和氟吡汀。
麻醉剂的非限制性示例包括局部麻醉剂(例如,利多卡因、苯佐卡因和罗哌卡因)和全身麻醉剂。
抑制金属蛋白酶(MMP)和其他蛋白酶作用的组织基质退化抑制剂的非限制性示例包括MMP抑制剂(例如,外源MMP抑制剂、基于异羟肟酸盐的MMP抑制剂、巴马司他(BB-94)、伊洛马司他(GM6001)、马立马司他(BB2516)、硫醇、Periostat(多西环素)、方酸、BB-1101、羟基脲、肼、内源性氨基甲酰磷酸酯、β内酰胺和MMP的组织抑制剂(TIMP))。
抗癌剂的非限制性示例包括单克隆抗体、贝伐单抗(Avastin)、细胞/化学引诱物、烷化剂(例如,双功能的环磷酰胺、氮芥、苯丁酸氮芥、美法仑,单功能的亚硝基脲和替莫唑胺)、蒽环类抗生素(例如,柔红霉素、多柔比星、表柔比星、伊达比星、米托蒽醌和戊柔比星)、细胞骨架干扰剂(例如,紫杉醇和多西他赛)、通过抑制微管功能限制细胞分裂的埃坡霉素剂、阻断细胞分裂或某些细胞功能所需的各种酶的抑制剂、组蛋白脱乙酰酶抑制剂(例如,伏林司他和罗米地辛)、拓扑异构酶I抑制剂(例如,伊立替康和拓扑替康)、拓扑异构酶II抑制剂(例如,依托泊苷、替尼泊苷和Tafluposide)、激酶抑制剂(例如,硼替佐米、埃罗替尼、吉非替尼、伊马替尼、威罗菲尼和Vismodegib)、核苷酸类似物(例如,阿扎胞苷、硫唑嘌呤、卡培他滨、阿糖胞苷、脱氧氟尿苷、氟尿嘧啶、5-FU、Adrucil、Carac、Efudix、Fluoroplex、吉西他滨、羟基脲、巯嘌呤、硫鸟嘌呤)、切割DNA并破坏DNA解旋/缠绕的肽抗生素剂(例如,博来霉素和放线菌素)、使抑制DNA修复和/或合成的DNA交联的铂基抗肿瘤剂(例如,卡铂、顺铂、奥沙利铂和乐沙定)、类维生素A(例如,维甲酸、阿利维A酸和贝沙罗汀)、抑制有丝分裂和微管形成的长春花碱制剂(例如,长春碱、长春新碱、长春地辛、长春瑞滨)、抗肠梗阻剂、促运动剂、免疫抑制剂(例如,他克莫司)、血液方面改性剂(例如,血管扩张剂、伟哥和硝苯地平)、3-羟基-3-甲基-戊二酰-辅酶A(HMG CoA)还原酶抑制剂(例如,阿托伐他汀)和抗血管生成剂。
示例性药剂还包括被动地有助于伤口愈合的剂,例如营养物质、氧气排出剂、氨基酸、胶原合成剂、谷氨酰胺、胰岛素、丁酸盐和葡聚糖。示例性药剂还包括抗粘连剂,其非限制性示例包括透明质酸/羧甲基纤维素(seprafilm)、氧化再生纤维素(Interceed)和4%艾考糊精(Extraneal,Adept)。
药物释放
根据所述技术的附属物可以多种不同的方式与至少一种药剂相关联,以便以期望的方式诸如对组织的向内生长提供期望的作用。该至少一种药剂可被配置成能够以多种空间和时间模式从附属物释放以在治疗部位处触发期望的愈合过程。药剂可被设置在附属物中、与附属物结合、并入附属物种、分散在附属物中或以其他方式与附属物相关联。例如,附属物可具有可释放地保持其中一种或多种不同药剂的一个或多个区域。这些区域可以是具有各种大小和形状并且以各种方式保持药剂的不同贮存器或者附属物内的其他不同或连续的区域。在一些方面,附属物的特定构型允许其可释放地保持其中的一种药剂或多于一种的不同药剂。
无论药剂设置在附属物内的方式如何,可将有效量的至少一种药剂封装在容器内,该容器诸如可以是微胶囊、微珠形式的丸粒或任何其他容器。该容器可由可生物吸收的聚合物形成。
从附属物中靶向递送和释放至少一种药剂可以取决于各种因素的多种方式完成。通常,该至少一种药剂可作为团注剂量从附属材料中释放,使得在将附属材料递送至组织时药剂基本上立即释放。或者,该至少一种药剂可在一定持续时间内从附属物释放,该持续时间可以是几分钟、几小时、几天或更长时间。定时释放的速率和释放的药剂量可取决于各种因素,诸如药剂释放区域的降解速率、用于保持附属物中药剂的一种或多种包衣或其他结构的降解速率、治疗部位的环境条件以及各种其他因素。在一些方面,当附属物具有设置在其中的多于一种药剂时,第一药剂的团注剂量释放可调节在第一药剂释放后开始释放的第二药剂的释放。附属物可包括多种药剂,该多种药剂中的每一种都可以任何合适的方式影响一种或多种其他药剂的释放。
作为团注剂量或定时释放的至少一种药剂的释放可在将附属材料递送至组织后基本上立即发生或开始,或者可延迟预先确定的时间。延迟可取决于附属物或其一个或多个区域的结构和性质。
附属材料可被配置成具有如下结构:其便于分配有效量的携带在附属物内的一种或多种药剂以提供期望的作用。例如,药剂的靶向递送可通过将药剂并入附属物内的以图案形成的区域(例如,贮存器诸如孔或其他结构)中来实现,该图案允许药剂在递送时形成某种空间分布。设置在贮存器内的药剂可并入到不同的容器中。贮存器可包括多于一种类型的不同药剂。该一种或多种药剂可以均匀方式或以不均匀的空间和/或时间方式从附属物洗脱以递送期望的治疗。附属物的结构和药剂从其释放的方式可用于影响或控制组织再生长。此外,可在治疗部位的某些位置促进组织再生,而在治疗部位的其他位置不促进组织再生。
图6至图8示出了具有多个携带不同药剂的孔的生物相容性附属物100,这些药剂被封装在设置在不同位置并使用不同的可吸收包衣的孔内。在将附属物100递送至治疗部位和钉部署之后,包衣可在不同时间被吸收、溶解或以其他方式崩解,以便允许药剂也在不同时间且在不同方向上释放。因此,药剂可以非均匀的方式从附属物100中释放。例如,这些药剂中的一者可在递送和/或钉部署之后立即释放,而其他药剂中的一者或多者可在稍后释放,诸如随着预先确定的释放曲线而释放。这些随后释放药剂的释放可受控制于第一药剂的释放或取决于第一药剂的释放。附属物100的相对的侧可由具有不同吸收速率(或由各种材料形成)的包衣覆盖,使得某些药剂在附属物的一侧释放,而其他药剂在附属物的另一侧释放。这提供了一种向组织递送治疗的更受控制和更有针对性的方式。
在该示例中,附属物100是具有多个多孔区域的层的形式,其中两者以举例的方式示出为孔101、103。如图6所示,多孔区域101、103携带相应的可以是不同药剂的第一药剂和第二药剂102、104。应当理解,附属物100具有多个多孔区域,其可以交替方式或以任何其他图案携带药剂102、104。
如图6所示,附属物100的第一侧100a具有包衣A、C,使得包衣A密封具有第一药剂102的多孔区域101,并且包衣C密封具有第二药剂104的多孔区域103。附属物100的第二相对侧100b被包衣B覆盖。在所示示例中,可选择产生影响药剂释放的阻隔层的包衣A、B、C,使得在钉部署后包衣A首先吸收,在包衣A至少部分被吸收后包衣B吸收,并且包衣C不可吸收。
如图7所示,在递送和/或钉部署之后,首先吸收包衣A以允许第一药剂102在附属物100的第一侧100a从多孔区域101中释放。例如,如果第一侧100a是组织接触表面,则第一药剂102可以是促进治疗部位愈合的药剂。随后,在一定时间段之后,包衣B可被吸收,以便允许第二药剂104在附属物100的第二侧100b从多孔区域103中释放,如图8所示。例如,如果第二侧100b是非组织接触表面,则第二药剂104可以是防止粘连的药剂。还如图8所示,包衣C在第一侧面100a处密封多孔区域103,并且因此防止第二药剂104在附属物100的第一侧100a释放。虽然在该示例中包衣C是不可吸收的,但其可另选地在包衣B已被吸收并且第二药剂104已在第二侧100b释放之后是可吸收的。应当理解,为了使多孔区域暴露并使药剂释放,可使包衣整体或至少部分被吸收。包衣的吸收速率可控制药剂的释放速率。
本领域技术人员将会理解,多于两种的不同药剂能够可释放地并入附属物内的不同多孔区域或其他结构中。可使用可选择的各种包衣将药剂保持在附属物内,以便控制药剂释放的速率和方向。
附属物可包括可释放地保持多个容器(诸如微珠或其他容器)的区域,这些容器具有封装在其中的一种或多种药剂。图9至图11示出了包括封装在多个容器中的至少一种药剂的附属物108,所述容器由相应的区域可释放地保持,所述区域调节容器从附属物的分散性。容器可以是微胶囊、微珠或适当尺寸和形状的任何其他类型的容器。每个容器可具有可吸收的外层,该外层可被降解并因此一旦容器从附属物中释放则释放保持在该容器内的药剂。附属物可用于至少相对于释放时间和释放位置以非均匀方式递送药剂。
如图9所示,附属物108具有多个贮存器或区域,其中的五个被示出为携带相应容器110、112、114、110、112的区域109a、111a、113a、109b、111b。因此,如图9示意性所示,区域109a,、109b携带相同的第一类型容器110,区域111a、111b携带相同的第二类型容器112,并且区域113a携带第三类型容器114。
如图9所示,在附属物108的第一侧108a上,一层包衣B1密封区域111a、113a和区域111b。一层包衣A1设置在整个第一侧108a上并覆盖包衣B1的各层。在附属物108的第二相对侧108b上,一层包衣B1密封区域109a,另一层包衣B1密封区域109b。一层包衣C1密封第二侧108b上的区域113a。类似于第一侧108a,整个第二侧108b被包衣A1覆盖。
在该示例中,包衣A1、B1、C1具有不同的降解或吸收速率,使得在将附属物递送至组织后包衣A1首先开始吸收,包衣B1在包衣A1至少部分地被吸收后吸收,并且包衣C1不可吸收。可选择包衣A1使得其在将附属物递送至组织后基本上立即或在稍后时间吸收。包衣A1可在包衣B1之前被吸收,因为包衣A1被布置在附属物的表面上并因此更易接近处理侧的水和/或其他剂。除此之外或另选地,包衣A1的其他性质可有助于其吸收速率。
由于所用包衣的吸收特性不同,包衣A1吸收,以便在第一侧108a从区域109a、109b释放第一药剂110,并且在第二侧108b从区域111a、111b释放第二药剂112,如图10所示。还如图10所示,包衣B1的各层保持与附属物108相关联。如图11所示,在第一药剂110在第一侧108a释放并且第二药剂112在第二侧108b释放之后,包衣B1被吸收,以便在第一侧108a从第一区域113a释放第三药剂114。以这种方式,不同的药剂可在适当的时间递送至正在处理的组织中的期望位置。应当理解,附属物可具有任何合适图案的区域,这些区域可释放地保持各种药剂以产生期望的愈合过程/曲线。
在一些方面,另选地或除了使用各种包衣之外,附属物可以是具有不同吸收特性的区域的纤维格形式。例如,每个区域可以是具有不同吸收率的纤维格的形式。与纤维格相关的药剂可随着纤维格的崩解而释放。由于形成附属物的可吸收聚合物的不均匀降解,附属物可被配置成使得与其相关的一种或多种药剂可以各种空间和时间模式释放。可将药剂并入具有可溶解包衣的丸粒(例如,硬糖)中,使得当包衣崩解时,药剂可作为团注剂量或作为定时释放剂量分配。
图12至图14示出了具有由具有不同降解速率的可吸收聚合物形成的第一(顶部)层和第二(底部)层118、120的附属物116。例如,第一层118可以是在附属物116递送至组织之后的第一时间段期间吸收的低分子量可吸收聚合物,而第二层120可以是在第一段时间完成后的第二时间段期间吸收的高分子量可吸收聚合物。第一层和第二层118、120可由不同的聚合物形成,或者由经过处理以便形成具有不同降解性质的层或其他结构的相同类型的聚合物形成。
在图12至图14的示例中,第一层118具有存在于其中的第一药剂119,并且第二层120具有存在于其中的第二药剂121。然而,应当理解,第一层和第二层118、120中的每一者可包括多于一种类型的不同药剂。这些药剂可以多种合适的方式保持与第一层和第二层118、120相关联。如图13所示,由于第一层118的吸收,第一药剂119可首先释放,其中第一层118示出为部分崩解,使得含有第一药剂119的丸粒正在释放。如图所示,第一层118从其表面开始吸收,该表面与第一层118的相对于表面较远的移除部分相比更易接近水和其他剂。在第一层118被完全或部分吸收之后,第二层120可从其表面开始崩解以便释放包含第二药剂121的丸粒,如图14所示,其中第二层120示出为部分崩解并且包含第二药剂121的丸粒正在从附属物116中释放。
在一些方面,可释放地保持一种或多种药剂的附属物可被构造成使得附属物的一个或多个区域由于温度、pH、光或其他环境因素的影响而分解以便释放该一种或多种药剂。或者,附属物可在施加在其一个或多个部分上的应变下断开。图15至图17示出了具有保持药剂124的主体123、设置在主体123上的多孔层125、和设置在多孔层125上的可吸收外膜层126的附属物122。药剂124可以是可释放地携带一种或多种药剂的丸粒(例如,固体微胶囊或微珠或其他容器)的形式。
在所示示例中,在其原始构型中,附属物122具有第一宽度X1,如图15所示。在此类构型中,外膜层126限制多孔层125,并且多孔层125中的孔的尺寸不允许药剂124逸出附属物122。然而,当附属物122递送至组织并且外膜层126因此变得暴露于治疗部位处的pH、温度、各种剂和/或其他环境条件时,可吸收外膜层126可开始崩解,如图16中的膜层126中的撕裂或开口127所示。除此之外或另选地,外膜层126可在附属物122上的由钉部署产生的应变或其他机械应变下断开。
无论导致外膜层126崩解或断开的具体因素如何,附属物122都可膨胀或以其他方式改变其构象,使得其宽度从原始宽度X1增加至较大宽度X2。还如图15所示,多孔层125的孔的尺寸增加,从而允许孔的内容物即携带药剂124的丸粒穿过扩大的孔并因此从附属物122释放。
附属物主体123伸展和具有药剂124的丸粒释放的时间段可根据外膜126的吸收速率、附属物主体123的性质、附属物122所递送至的环境的特性和其他因素而变化。在一定时间段之后,外膜层126可崩解,并且附属物122可进一步伸展至具有宽度X3,使得全部或基本上全部的药剂124从主体123释放以递送适当的治疗或实现预期的作用,如图17所示。附属物122可由调节容器的分散性的至少一种可吸收聚合物(例如,明胶、纤维素等)形成。因此,附属物122可用作空间填料,其在治疗部位处产生暂时的密封,然后被溶解以随后被组织替换。
图18和图19示出了可释放地保持不同药剂并被构造成能够以非均匀方式释放药剂的附属物128的另一个示例。附属物128可被构造成能够由于温度、pH、各种剂和/或其他环境因素对附属物128的影响来释放药剂。响应于环境因素,附属物128可改变其一个或多个部分的构象。如图18所示,附属物128可具有多个区域或贮存器,示出了其中的两者,即分别携带第一药剂和第二药剂131、133的第一贮存器和第二贮存器130、132。贮存器130、132可以是管、腔、孔或任何其他结构的形式。第一贮存器130由附属物128的第一侧128a的第一包衣A2和附属物128的第二侧128b的第二包衣B2密封。第二贮存器131由第一侧128a的第二包衣B2和第二侧128的第一包衣A2密封。在该示例中,选择第一包衣和第二包衣A2、B2,使得第一包衣A2及其性质和/或构型可由于温度、pH、活性剂和/或其他因素的影响而改变并因此打开其密封的贮存器。例如,第一包衣A2可膨胀、软化或以其他方式变形。
因此,如图19所示,在将附属物128递送至治疗部位时,第一包衣A2可改变其构型,使得其在附属物128的第一侧128a不再密封贮存器130,并且在附属物128的第二侧128b不再密封贮存器132。结果,第一药剂和第二药剂131、133分别在附属物的第一侧和第二侧128a、128b释放,也如图19所示。第二包衣B2保持就位至少直到全部药剂释放到期望的组织位置中,如此防止药剂释放。
在一些方面,附属物可以是保持药剂的纤维或与一种或多种粘性流体组分相关联的其他结构部件(例如,容器)的形式。该粘性组分可以是干燥形式(例如,呈冻干粉末形式),并且可在部署附属物时再水合。当粘性组分再水合时,其可打开并因此释放药剂。除此之外或另选地,保持药剂的容器可在应变下被破坏,例如由钉或其他手段施加在其上的机械断裂。
图20和图21示出了呈多根纤维形式的附属物140,其中的三者以举例的方式表示为纤维142、144、146。如图所示,纤维142、144、146中的每一者与保持药剂的容器143、145、147中的相应一者相关联。容器143、145、147可保持相同或不同的药剂。在所示示例中,容器143、145、147呈具有不同尺寸的不规则圆形珠的形式,但是它们可以任何其他方式成形并且可具有各种尺寸。容器可作为粉末施加到纤维上,或者它们可粘合、锚定或以其他方式与纤维股线相关联。容器可保持与纤维相关联,或者它们可从纤维释放,从而使用附属物递送期望的治疗。
如图21所示,当向附属物140施加应变时(其由箭头141示意性示出),纤维可变形并且容器可破裂并释放并入其中的药剂。应变的大小可控制药剂释放的速率。例如,如图21所示,容器143破裂并且药剂148正在释放。在一些方面,容器可在不同的时间点破裂,这取决于它们的尺寸和/或其他性质。在该示例中,如图21所示,容器143可首先破裂以释放保持在其中的药剂148,然后较小的容器145然后甚至更小的容器147可破裂从而在不同的时间点释放相应的药剂(未示出)。但是,根据所施加的压力和其他因素,一个或多个容器可能同时破裂。此外,如上所述,容器143、145、147可在不同的时间点吸收,以便在不同的时间点释放相应的药剂。
在一些方面,附属物可具有其纤维的各种表面纹理,并且其可以各种方式释放一种或多种药剂以影响或控制组织的再生长。附属物可通过在其上携带该附属物的钉递送,使得当钉在钉部署下变形时药剂释放。例如,图22示出了具有外层或包衣152的附属物150,该外层或包衣封装被设置在用于递送附属物150的外科装置的钉151上的内层154。然而,在一些方面,附属物150可设置在可折叠成管状或其他形状的纤维格上,而不是设置在钉上。
第一药剂可保持在外包衣152和内层154之间,并且第二药剂可并入内层154中。内层154可以是缠绕在纤维156上的柔性网的形式。当向附属物150施加应变时(例如,当钉151变形时),如图23中的箭头153示意性地示出,外包衣152也可变形和破裂。在外包衣152破裂时,保持在外包衣152和内层154之间的第一药剂可以作为团注剂量释放第一药剂(155)。并入内层154中的第二药剂可在第一药剂释放后或第一药剂释放期间作为定时释放开始释放。第二药剂到组织的释放可通过第一药剂的释放来调节。第二药剂可另选地以团注剂量释放。应当理解,附属物150可包括设置在内层154内的可作为团注剂量释放的一种药剂。
如上所述,设置在附属物内或与附属物相关联的有效量的至少一种药剂可保持在由附属物携带的不同容器内。这些容器可设置在附属物的一个或多个区域内或以其他方式与其相关联。图24和图25示出了呈丸粒或胶囊剂形式的容器158的一个示例,其具有在其中封装至少一种药剂160的外包衣159。在该示例中,容器158具有球形形状并且像一块硬糖。然而,应当理解,容器可具有任何其他形状。此外,在一些示例性具体实施中,外包衣159可封装内部区域,该内部区域包括至少一种其中并入有至少一种药剂的可生物吸收聚合物。容器158可包括具有不同降解速率并且可释放地在其中保持一种或多种药剂的多个层。每层可保持不同的药剂,或者两层或更多层可携带相同的药剂。
如图25中的箭头161示意性地示出,当向容器158施加应变时,外包衣159可破开或破裂,使得其呈至少一种药剂160形式的内容物释放。除此之外或另选地,外包衣159可在容器158暴露于一种或多种环境条件时吸收、溶解或以其他方式崩解,使得至少一种药剂160从容器158释放。
图26和图27示出了呈纤维格形式的附属物162的一个示例,该纤维格具有可诸如受到附属物在治疗部位处经受的水和/或其他剂的作用而改变的某种构象。如图26所示,具有紧密缠绕螺旋形状的附属物162可在其中保持携带药剂164的一个或多个容器。药剂164可通过被附属物的纤维紧实地保持而与附属物162相关联。例如,本领域技术人员将会理解,药剂可包括多层药剂/可吸收聚合物结构,其中最外面的一层包括可与附属物的纤维结合的可吸收聚合物,例如将一种可吸收聚合物结合到另一种可吸收聚合物上。
当在治疗部位处递送附属物162时,其缠绕的纤维可膨胀并且长度增加或拉长,使得纤维之间的距离增加并且附属物162“解开”并释放“被捕获”在附属物162内的药剂164,如图27所示。附属物162的纤维可解开,使得整个附属物162采取不同的构象,如图26和图27的示例那样。然而,在某些方面,附属物的纤维可从附属物的末端或其他表面开始解开或磨损。
图28和图29示出了具有可释放地保持其中的药剂168的附属物166的另一个示例。在该示例中,附属物166呈片状纤维编织网的形式。如图28所示,处于其原始构型的附属物166的紧密纤维允许药剂168保持在其中。当在治疗部位处递送附属物166时,在图28中示意性地示出为滴状物167a、167b的水和/或其他剂可引起纤维膨胀并拉长,使得纤维之间的距离增加,如图29所示。以这种方式,药剂168被释放,也如图29所示。本领域技术人员将会理解,附属物166可由不同类型的纤维形成。纤维可具有任选择以便提供期望的组织再生长的不同的吸收速率、密度、方向、图案、尺寸和其他性质。尽管附属物的一些区域可被构造成能够释放至少一种药剂以便促进组织再生长,但是附属物的一个或多个区域可被构造成能够释放至少一种药剂以便抑制组织再生长。
在其中至少一种药剂设置在由封装药剂的可生物吸收聚合物包衣形成的容器内的方面,药剂可被配置成能够基于各种因素在特定时间从容器中释放。这些因素可包括例如可生物吸收聚合物的降解速率、容器的体积、容器的表面积、容器周围的生理环境中的环境条件以及可生物吸收聚合物对这些条件的反应性、可生物吸收聚合物层的数量、药剂的浓度以及药剂与可生物吸收聚合物之间的缔合类型。
图30示出了可与示意性示出的附属物171相关联的第一容器和第二容器170、172的示例。在该示例中,第一容器和第二容器170、172呈球形珠的形式。然而,可除此之外或另选地使用其他类型的容器,使得附属物171可包括携带不同类型的药剂的一种或多种不同类型的容器。第一容器和第二容器170、172具有可吸收聚合物外包衣A3、B3,其具有不同的降解速率,因此以不同方式控制封装在包衣A3、B3内的第一药剂和第二药剂D1、D2的释放。外包衣A3的降解速率可高于外包衣B3的降解速率。因此,在第二药剂D2从第二容器172释放之前,第一药剂D1从第一容器170释放。例如,第一药剂D1可以是在附属物171递送至治疗部位后的1-2天内释放的致炎剂。第二药剂D2可以是在递送附属物171后3-5天内释放的抗炎剂。以这种方式,药剂D1、D2从第一容器和第二容器170、172的释放可对组织向内生长提供期望效果。
其中封装有至少一种药剂的容器可具有以多种不同方式与其相关联的多种药剂。图31示出了呈具有多个同心层的球体形式的容器174的一个示例,其中每个同心层携带相应的至少一种药剂。在该示例中,如图31所示,容器174从外向内具有四个不同的层E1、E2、E3、E4,其分别具有第一药剂、第二药剂、第三药剂和第四药剂F1、F2、F3、F4。层E1、E2、E3、E4中的每一者可具有不同的降解速率、厚度、密度、对环境条件的反应性以及控制设置在其中的药剂释放的其他性质。例如,最外面的第一层E1可被构造成能够首先降解使得药剂首先释放,而其他层E2、E3、E4可被构造成能够降解使得外层在内层降解之前降解。
随着每层的降解,并入其中的相应药剂被释放。应当理解,可对这些层进行选择使得至少一个内层可在至少一个外层的仅一部分已降解之后开始降解。设置在多层容器174内的药剂F1、F2、F3、F4可以是不同的,或者至少一些药剂可以是相同的。药剂可作为团注剂量或以其他方式释放。例如,设置在第一层E1内的第一药剂F1可在将保持容器174的附属物递送至组织时基本上立即作为团注剂量释放。设置在第二层E2内的第二药剂F2的释放可通过第一药剂F1的释放来调节。
药剂在附属物中的空间分布可根据药剂的类型和对组织向内生长的期望效果而变化。药剂的靶向递送可以多种方式完成。例如,附属物可被构造成能够以不均匀方式释放一种或多种药剂,使得各种药剂可在不同的时间点递送至组织以便于期望的愈合。附属物的不同部分可由不同的材料形成或由经处理以便具有不同吸收速率的相同材料形成。
图32示出了呈层压体形式的附属物176,该层压体包括具有不同降解速率并且并入不同药剂的不均匀部分或层。如图所示,附属物176具有顶层或顶部部分178和底层或底部部分180,这两者具有不同的降解速率。此外,顶部部分和底部部分178、180中的每一者可具有不同的部分,这些部分具有以不同或连续的方式变化的降解速率。降解速率可以多种合适的方式在附属物中变化,这取决于附属物待提供的理想治疗效果。
在图32的示例中,附属物176的顶部部分178具有两个具有不同降解速率的部分178a、178b。底部部分180具有两个具有不同降解速率的部分180a、180b。每个部分可包括不同的药剂,使得当某部分降解时,相应的药剂被洗脱或释放。部分178a、178b、180a、180b中的一个或多个部分内的药剂的降解速率和分布可以不同或连续的方式进一步变化,使得附属物176可提供图32中的曲线图177所示的洗脱曲线。如图所示,围绕其中间部分179居中的附属物176的中心区域182具有一种或多种药剂的在中间部分179达到峰值的增加的洗脱率,而从沿长度L的附属物176的相对侧洗脱出较少量的药剂。该增加的洗脱率可归因于附属物176在中心区域182处的性质和药剂的浓度。
如图32进一步所示,附属物176被构造成能够沿其长度L并沿其宽度W以不同的洗脱曲线释放药剂。例如,药剂可沿宽度W作为团注剂量释放,而沿长度作为时间释放剂量释放。一种或多种药剂的释放可调节至少一种其他药剂的释放。但是,药剂可以任何其他方式释放,这取决于待递送的期望治疗。
图33示出了具有顶层或顶部部分和底层或底部部分186、188的附属物184的另一个示例。类似于图32中的附属物176,附属物184的顶部部分和底部部分186、188中的每一者可具有设置在其中的不同药剂。因此,如图33所示,顶部部分186可在其相应部分具有第一药剂G1和第二药剂G2。如图34所示,底部部分188可在其相应部分具有第三药剂G3和第四药剂G4,其设置方式使得第三药剂G3处于设置在携带第四药剂G4的部分上的部分中。
图35示出了可类似于附属物176(图32)或附属物184(图33)的附属物185的一部分的示例。如图35所示,附属物185可具有其中设置有不同的药剂G5、G6的左右部分185a、185b。图36示出了具有内部部分187a和外部部分187b的附属物187的一部分的另一个示例,该内部部分和外部部分具有设置在其中的不同药剂G7、G8。
在一些方面,至少一种药剂从具有由至少一种可生物吸收聚合物形成的一个或多个不同部分的附属物的洗脱率可取决于该部分在附属物内的位置、该至少一种可生物吸收聚合物的降解速率、该至少一种可生物吸收性聚合物对环境条件的反应性以及附属物的总体构型。
图37示出了呈具有外同心层和内同心层191、192的圆柱体形式的附属物190的一个示例,该外同心层和内同心层可由不同类型的可吸收聚合物形成并且可具有不同的厚度和其他性质。外层和内层191、192可具有设置在其中并可在不同的时间点以不同的速率从相应的层191、192释放的不同药剂B4、A4。在该示例中,由内层192限定的最内腔193可以是空的。药剂A4可被配置成能够在药剂B4释放之前开始释放。应当理解,在一些方面,外层和内层191、192可设置在纤维上。
图38示出了具有由不同类型的可吸收聚合物形成的多个径向部分的管状附属物194的一个示例。如图所示,附属物194具有内腔194a,该内腔具有同心地设置在其周围的径向部分。在所示示例中,这些部分可以交替方式由第一类型和第二类型的聚合物形成,如图38中分别由第一类型和第二类型的聚合物形成的部分195、196所示。由第一聚合物形成的部分195具有设置在其中的药剂A5,由第二聚合物形成的部分197具有设置在其中的药剂B5,并且由第一聚合物和第二聚合物形成的其他部分具有以相同的交替方式设置在其中的药剂A5、B5,如图38所示。类似于之前的示例,药剂A5、B5可在不同的时间点以不同的速率从相应的层释放。例如,药剂A5可被配置成能够在药剂B5释放之前开始释放。
图39示出了类似于附属物190(图37)的管状附属物197的一个示例。如图39所示,附属物197具有外同心层和内同心层198、199,该外同心层和内同心层可由不同类型的可吸收聚合物形成并且可具有不同的厚度和其他性质。外层和内层198、199可具有设置在其中并可在不同的时间点以不同的速率从相应的层198、199释放的不同药剂B6、A6。例如,如图39中的曲线图197a所示,药剂A6可在药剂B6释放之前释放。此外,药剂A6可以比药剂B6更高的剂量释放,也如曲线图197a所示。
在至少一些具体实施中,钉仓可包括施加到该钉仓的润滑剂(例如,硬脂酸钠或其他润滑剂),该润滑剂包括可从其释放的至少一种药剂(例如,LAE、多西环素和/或其他抗微生物剂)。润滑剂可作为喷雾剂施加到钉仓上并且可涂覆钉仓和可释放地设置在其中的钉。包括一种或多种药剂的润滑剂可允许该一种或多种药剂被施加到钉上。以这种方式,如本文所讨论的,该一种或多种药剂可递送至该一种或多种药剂可最能够促进伤口愈合的目标区域(例如,沿着由钉限定的钉线)。包括一种或多种药剂的润滑剂可与包括一种或多种药剂的附属物一起使用,这可促进目标伤口愈合。
伤口愈合
在进行外科手术期间,患者的组织可以多种方式中的任何一种被创伤(例如,切割、撕裂、刺破等)。伤口可以是外科手术的预期方面,诸如在吻合手术中和/或当使用诸如外科缝合器的外科装置切割和紧固组织时。对于所有患者而言,受伤组织通常以大致相同的方式愈合。
传统上认为伤口愈合包括四个阶段:止血、炎症、增生和重塑。止血阶段通常涉及凝血,例如止血。一般来讲,受损的血管收缩以减缓血流,血小板聚集以帮助密封伤口部位,血小板活化血纤蛋白以进一步促进伤口密封,并且在伤口部位形成血块。炎症阶段通常涉及伤口部位的清理。一般来讲,免疫系统通过向防御性免疫细胞诸如中性粒细胞和巨噬细胞发送信号来对伤口部位处可能感染的威胁作出反应。增生阶段通常涉及通过组织生长和血管生成(血管生长)重建组织。一般来讲,成纤维细胞到达伤口部位,然后成纤维细胞沉积胶原蛋白,成纤维细胞释放吸引上皮细胞的生长因子,然后上皮细胞吸引内皮细胞。重塑阶段,也被称为成熟阶段,通常涉及加强伤口部位的结疤组织。通常,胶原纤维排列并交联,并且瘢痕成熟,最终消失。下文将进一步讨论这四个阶段中的每个阶段。
尽管伤口愈合的四个阶段中的每个阶段涉及愈合过程的不同方面,但这些阶段通常彼此重叠。即,最后三个阶段中的每一阶段通常与其前一阶段重叠,例如,炎症阶段与止血阶段重叠,增生阶段与炎症阶段重叠,重塑阶段与增生阶段重叠。阶段之间发生转变的速度通常会影响整体伤口愈合的速度,并因此通常影响患者的恢复时间、引起并发症几率和/或患者的舒适度。类似地,四个独立阶段中的每一阶段的长度通常影响整体伤口愈合的速度和患者的全面恢复。通常,伤口愈合过程越慢,尤其是开始重塑阶段花费的时间越长,伤口将被感染、导致患者不适、成为慢性伤口、引起溃疡和/或发展病理性瘢痕的可能性越大。
止血阶段通常在最初损伤的几分钟内开始,除非存在潜在的凝血障碍,在这种情况下止血可能被延迟。在炎症阶段开始之前(例如,在中性粒细胞到达之前,如下所述),止血阶段通常持续30分钟至60分钟,并且通常在损伤后数小时(例如,损伤后2小时至6小时)结束。导致止血时间较长的止血控制不佳可导致出血增加和组织受损。另外,延长的止血阶段可导致额外的瘢痕形成,从而延迟增生和重塑阶段。
在止血阶段,损伤的血管在伤口部位处被密封。血管响应于损伤(例如,响应于被切割)而收缩,但这种痉挛最终会松弛。血小板分泌血管收缩物质以协助该过程。血小板还形成密封受损血管的稳定凝块。在从伤口部位的受损组织中渗漏的二磷酸腺苷(ADP)的影响下,血小板聚集并粘附在暴露的胶原蛋白上。血小板分泌因子,这些因子通过产生凝血酶而与凝血因子相互作用并刺激内在的凝血级联反应,这继而引起血纤蛋白原形成血纤蛋白。发生凝血级联反应以实现止血,或通过血纤蛋白凝块阻止失血。更具体地讲,血纤蛋白形成网,其将血小板聚集体强化成稳定的止血塞或凝块,从而减少和/或防止出血。该网在炎症和增生阶段充当入侵细胞诸如中性粒细胞、巨噬细胞、成纤维细胞和内皮细胞的支架。另外,血小板分泌各种可溶性因子,诸如趋化因子、细胞因子和血小板衍生生长因子(PDGF)。这种分泌通常引发伤口愈合的炎症阶段,因为可溶性因子吸引吞噬物质(例如,碎片、微生物(诸如细菌)和受损组织)的细胞。
凝血级联发生在炎症阶段开始之前的止血阶段。炎症阶段通常在损伤后一小时内开始并且通常持续2至6天,但可持续更长时间,例如,多至10天。炎症阶段越长,发生额外瘢痕形成的可能性越大,由此延迟增生和重塑阶段。在炎症阶段期间,受伤的组织可显示出各种炎症迹象,诸如红斑、发热、水肿、疼痛和功能障碍。这些迹象可持续大部分或整个炎症阶段。因此,炎症阶段越长,组织受到这些炎症的不利影响的时间越长,这继而可延长患者的不适感和/或延长患者特别容易受感染的时间段。炎症的不利影响可能严重到会导致一些患者死亡。然而,在正常的伤口愈合期间必然发生炎症,并且为了使伤口愈合的最后阶段开始,必须忍受其不利影响。
在炎症阶段,被在止血阶段分泌的可溶性因子吸引的这些细胞吞噬物质。即,包括吞噬细胞、中性粒细胞和巨噬细胞的免疫细胞破坏物质以帮助防止感染。中性粒细胞的到达通常表示炎症阶段的开始。中性粒细胞通常在受伤的一小时内到达伤口部位。中性粒细胞能够吞噬碎片和微生物,并且提供抗感染的第一道防线。他们受到伤口部位处肥大细胞的帮助。血纤蛋白被分解,并且降解产物吸引巨噬细胞。巨噬细胞通常在损伤后1至2天出现。巨噬细胞能够吞噬细菌并提供抗感染的第二道防线。巨噬细胞分泌多种趋化因子和生长因子,诸如成纤维细胞生长因子(FGF)、表皮生长因子(EGF)、转化生长因子β(TGF-β)和白细胞介素-1(IL-1),传统上认为这些因子会指导后续的增生和重塑阶段。换句话讲,巨噬细胞释放血管生成物质以帮助开始增生阶段以刺激毛细血管生长和肉芽发生,从而为重塑阶段做好准备。吸引到伤口部位的淋巴细胞(例如,T淋巴细胞)通常在巨噬细胞出现后出现在伤口部位。
增生阶段通常在损伤后2至5天开始并且通常持续2至21天。在增生阶段,巨噬细胞的分泌物诱导成纤维细胞增生。成纤维细胞进入伤口部位并通过分泌胶原蛋白和纤连蛋白而形成细胞外基质(ECM)。伤口因此利用包括胶原蛋白和ECM的其中形成新的血管网络的新的肉芽组织而“重建”,这个过程传统上称为血管生成。胶原蛋白增加伤口的强度。因此,可越早产生胶原蛋白,例如,成纤维细胞越早进入伤口区域,伤口越早获得加强,并因此不太可能引起诸如感染和患者不适等任何问题。
ECM形成的同时,上皮细胞(例如,角质形成细胞)从伤口边缘迁移以覆盖伤口并在伤口与其环境之间形成屏障。换句话讲,上皮细胞在传统上称为上皮形成的过程中重新形成伤口表面。上皮细胞迁移到肉芽组织之上,但在伤口上的痂下面(如果瘢痕早先形成)。上皮细胞必须溶解凝块、碎片和ECM的部分以正确迁移到伤口之上。为了便于其迁移,上皮细胞分泌纤溶酶原活化物,其活化纤溶酶原,将其转化为纤溶酶以溶解凝块、碎片和ECM的部分。另外,由于细胞只能在活体组织上迁移,因此上皮细胞分泌胶原酶和蛋白酶(诸如基质金属蛋白酶(MMP))以在其迁移路径中溶解ECM的受损部位。在上皮形成的最后阶段,当成纤维细胞分化成肌成纤维细胞以形成保护性外层或角质层时,伤口发生收缩。收缩可持续数日或数周,甚至在伤口完全再上皮化之后仍继续。收缩是与创伤愈合相关的瘢痕形成的主要原因。
重塑阶段通常在胶原蛋白产生和降解水平平衡时开始。换句话讲,通常瘢痕一旦形成并且伤口的拉伸强度开始增加,则重塑开始。重塑阶段通常在损伤后7至21天开始,并且通常持续至少3周并且可持续数月或数年,这取决于诸如伤口尺寸和再损伤等因素。
在重塑阶段,伤口成熟以变得更强,例如,拉伸强度增加。通常,在增生阶段的伤口部位常见的较弱的III型胶原蛋白被较强的I型胶原蛋白替换。这种替换通常涉及重组、交联和排列该临时的胶原纤维。随着重塑的进行,瘢痕消失。
图40示出了随着时间推移伤口愈合的描绘。图40的上部示出了组织强度(拉伸力F)与时间(t)的关系的第一伤口愈合曲线图200。图40的下部示出了药剂剂量与时间(t)的关系的第二伤口愈合曲线图202。第一曲线图和第二曲线图200、202用共享的水平轴绘制,以便于比较第一曲线图和第二曲线图200、202中所示的数据。第一曲线图和第二曲线图200、202中的时间零点(t=0)表示损伤时间,例如产生伤口时。因此,第一曲线图200中的第一组织强度F1表示损伤时伤口处的组织强度。
第一曲线图200包括在典型伤口愈合期间随时间推移的组织强度的第一曲线204,并且包括根据本文提供的至少一些方法、系统和装置的加速伤口愈合期间随时间推移的组织强度的第二曲线206。加速伤口愈合的第二曲线206可使用在第二曲线图202中提供的一种或多种剂量的药剂来实现,如下文进一步讨论的。在图40中相对于第二曲线图202以及因此也相对于第一曲线图200的第二曲线206示出了伤口愈合的不同阶段(止血阶段208、炎症阶段210和增生阶段212)。如下文所讨论的,第一曲线图200中的第一曲线204具有止血、炎症和增生阶段的不同时段。
图40中的时间尺度仅为示例。如上所述,伤口愈合的时段可不同,例如伤口愈合阶段可针对不同伤口和/或不同患者在不同的时间点开始。图40证明,对于同一患者中的相同伤口,如第一曲线204所示,伤口的典型愈合在根据第二曲线图202将一种或多种药剂给药给患者时得到改善,如由第二曲线206所示。换句话讲,无论第一曲线图和第二曲线图200、202的横轴的时间尺度如何,一种或多种药剂的给药可提供比典型伤口愈合更快的伤口愈合,并且相比于典型伤口愈合,可提供最小组织拉伸强度的更短的周期。
如第一曲线204所示,典型的伤口愈合涉及在时间零点具有第一组织强度F1并且随时间推移强度降低至最小组织强度F4的组织,该最小组织强度起始于炎症期间的第四天期间(5>t>4)并持续到第六天的某个时间(7>t>6),然后组织强度开始逐渐提高恢复到第一组织强度F1。如第一曲线204所示,在典型的伤口愈合期间,在增生阶段期间或之后的某个时间点,可重新达到第一组织强度F1。在第一天(2>t>1)期间,响应于炎症(例如,响应于进入炎症阶段),组织的强度开始从第一组织强度F1降低,然后继续朝向其最低水平F4降低和/或保持在该最低水平,直到第六天期间组织的炎症开始消退,例如直到增生阶段开始。因此,在从第一天开始并持续到第六天的相对长的时间段内组织的强度降低并且最容易受到任何数量的炎症的不利影响。
如第二曲线206所示,根据本文提供的方法、系统和装置的至少一些实施方案的加速伤口愈合涉及在时间零点具有第一组织强度F1并且随时间推移强度降低至最小组织强度F3的组织,该最小组织强度起始于炎症阶段210期间的第三天期间(4>t>3)并持续到第四天的某个时间(5>t>4),然后组织强度开始逐渐提高恢复到第一组织强度F1。加速伤口愈合中的最小组织强度F3大于典型的伤口愈合中的最小组织强度F4。因此经历加速伤口愈合的组织从未具有与典型的伤口愈合期间一样低的强度。换句话讲,加速伤口愈合比典型伤口愈合允许更少的组织弱化。在第一天(2>t>1)期间,响应于炎症(例如,响应于进入炎症阶段210),组织的强度从第一组织强度F1开始降低,然后继续朝向其最低处水平F3降低和/或保持该最低处水平,直到第四天期间炎症开始改善,例如直到增生阶段212开始。因此,相比于典型的伤口愈合,组织的强度下降并且最容易受到任何数量的炎症的不利影响的时间更早并且持续时间更短,即从第一天开始并持续到第四天而不是从第一天开始并持续到第六天。换句话讲,加速伤口愈合可提供比典型伤口愈合更短的炎症阶段。组织强度在炎症阶段210之后可能不会增加恢复到其受伤前的组织强度F1,而是可增加到与其接近的水平,如第二曲线206在增生阶段212期间达到新的最大组织强度F2所示。
第二曲线图202示出了可施用于患者以实现由第二曲线206所指示的加速伤口愈合的药剂剂量的示例。药剂的剂量可包括:被配置成能够在止血阶段208促进止血的药剂A的剂量,也如图41所示;被配置成能够在炎症阶段210促进炎症的药剂B、药剂B1、药剂C和药剂C1的剂量,也如图42所示;被配置成能够在炎症阶段210的巨噬细胞期214期间(例如,在巨噬细胞在炎症阶段210中在伤口部位存在并且活跃的时间期间),抑制MMP的药剂D和药剂D1的剂量,也如图43所示;被配置成能够在增生阶段212的成纤维细胞期216期间(例如,在成纤维细胞在增生阶段212中在伤口部位存在并且活跃的时间期间),防止增生阶段212中的炎症的药剂E的剂量,也如图44所示;以及被配置成能够在增生阶段212的成纤维细胞期216期间(例如,在成纤维细胞在增殖阶段212中在伤口部位存在并且活跃的时间期间),促进增生阶段212中的组织生长的药剂F的剂量,也如图44所示。下面进一步讨论药剂A、B、B1、C、C1、D、D1、E、F中的每一种。
在一个示例中,可以在伤口愈合的止血阶段208、炎症阶段210和增生阶段212中的每一个阶段期间将至少一种药剂施用于组织,以全面改善伤口愈合过程,其中施用第二曲线图202中所示的所有药剂,例如,止血阶段208中的药剂A,炎症阶段210中的药剂B、B1、C、C1、D、D1,以及增生阶段212中的药剂E、F。在另一个示例中,可以在伤口愈合的止血阶段208、炎症阶段210和增生阶段212中的每一个阶段期间将至少一种药剂施用于组织,以全面改善伤口愈合过程,其中无需施用第二曲线图202中所示的所有药剂,例如,止血阶段208中的药剂A,炎症阶段210中的药剂B、B1、C、C1、D、D1中的至少一种(并且在又一个示例中,药剂B、B1、C、C1、D、D1中的至少两种),以及增生阶段212中的药剂E、F中的一种或两种。施用的药剂A、B、B1、C、C1、D、D1、E、F的子组可以根据任何一种或多种因素逐个确定,诸如伤口类型、伤口尺寸、外科医生偏好、手术时可用药剂、患者病史等。在又一个示例中,至少一种药剂可在止血阶段208、炎症阶段210和增生阶段212中的仅一个或两个阶段期间施用于组织,以改善伤口愈合过程的选择阶段(在一个阶段中的改善能够改善伤口愈合过程的后续阶段,如上所述),而无需施用第二曲线图202中所示的所有药剂。此外,如第二曲线图202中所示,药剂可以在所选择的一个或两个阶段中施用(例如,止血阶段中的药剂A,炎症阶段210中的药剂B、B1、C、C1、D、D1,增生阶段212中的药剂E、F),或者可以在所选择的一个或两个阶段中选择性地施用(例如,止血阶段208中的药剂A,炎症阶段210中的药剂B、B1、C、C1、D、D1中的至少一种(并且在另一个示例中,药剂B、B1、C、C1、D、D1中的至少两种),以及增生阶段212中的药剂E、F中的一种或两种。其中施用药剂剂量的阶段208、210、212中的一个或两个阶段可以根据任何一种或多种因素逐个确定,诸如伤口类型、伤口尺寸、外科医生偏好、手术时可用药剂、患者病史等。
如本文所讨论的,可例如使用外科缝合器将包括一种或多种可从其释放的药剂的附属材料递送至组织。附属材料的一种或多种药剂可包括施用的药剂A、B、B1、C、C1、D、D1、E、F中的每一种,不管它是药剂A、B、B1、C、C1、D、D1、E、F的全部还是其子组。因此,药剂A、B、B1、C、C1、D、D1、E、F中的施用药剂可在发生损伤的时间(t=0)同时递送到患者。如本文所讨论的,附属材料的药剂可以各种方式从其释放。释放的时间选择可允许药剂在伤口愈合过程中的适当时间施用于组织,也如本文所讨论的。药剂A、B、B1、C、C1、D、D1、E、F(或其所选择的子组)因此可以同时递送到患者,但可在不同的时间并随时间推移释放到患者的组织来达到期望效果。
被配置成能够促进止血的药剂A可具有多种构型。通常,药剂A可包括被配置成能够促进止血的止血剂。因此,药剂A的施用可以帮助止血并且帮助缩短止血阶段208的时长,并且因此帮助炎症阶段210比典型的伤口愈合更早地开始。药剂A的示例包括血纤蛋白和凝血酶。此外,被配置成能够促进止血及其递送的止血剂的示例描述于2011年12月13日提交的名称为“Hemostatic Bioabsorbable Device with Polyethylene Glycol Binder”的美国专利公布2013/0149343、2012年8月22日提交的名称为“Reinforced AbsorbableSynthetic Matrix For Hemostatic Applications”的美国专利8,383,147,以及2010年5月17日提交的名称为“Reinforced Absorbable Multi-Layered Fabric For HemostaticApplications”的美国专利8,329,211中,这些专利据此全文以引用方式并入。
药剂A可以多种方式施用。在一个示例中,药剂A可由容器施用。该容器可包括包围药剂A的可生物吸收的或可溶解的包衣,例如糖衣等。包衣可被配置成能够相对快速地生物吸收/溶解,以便在发生损伤的几分钟内(例如,在t=0的几分钟内)施用于受伤组织。药剂A的止血效果因此可以在炎症阶段210开始之前就开始。如图40和图41所示,药剂A的剂量可随着该药剂在组织/患者体内消散的时间推移而减少。
被配置成能够促进炎症的药剂B、B1、C、C1可各自具有多种构型。通常,药剂B、B1、C、C1可各自包括被配置成能够促进炎症的致炎剂。药剂B、B1、C、C1因此可有助于加速炎症过程,并因此有助于与典型的伤口愈合相比缩短炎症阶段210,有助于与典型的伤口愈合相比更早开始增生阶段212,有助于与在典型的伤口愈合中达到最小强度F4的时间相比组织更快达到其最小强度F3,并且有助于与典型的伤口愈合相比缩短组织处于其最小强度F3的时间段。药剂B、B1、C、C1的示例包括促炎药剂。在一些方面,药剂B、B1、C、C1可各自包括相同的剂。在其他方面,药剂B、B1可各自包括相同的剂,并且药剂C、C1可各自包括彼此相同的剂,但是为与药剂B、B1不同的剂。在其他方面,药剂B、B1、C、C1可各自包括彼此不同的剂。
药剂B、B1、C、C1可各自以多种方式施用。在一个示例中,药剂B可作为容器施用,其中药剂B1是药剂B容器的包衣,并且药剂C可作为另一容器施用,其中药剂C1是药剂C容器的包衣。如图40和图42所示,容器药剂B、C的剂量可大于包衣药剂B1、C1的剂量,因为容器包衣通常包括比它们所包围的容器更少的物质。
在一个示例中,药剂B1可被配置成能够在药剂B之前开始释放,药剂B可被配置成能够在药剂C1之前开始释放,而药剂C1可被配置成能够在药剂C之前开始释放。因此,致炎药剂B、B1、C、C1可被配置成能够交错释放,其中每种药剂在不同时间(例如,在沿着第二曲线图202的时间t轴的不同点)处剂量达到峰值。致炎药剂B、B1、C、C1的不同峰值剂量可允许药剂B、B1、C、C1具有累积致炎剂量,如图40和图42中示为“BC”,比其任一单独剂量更大。换句话讲,可以对单独药剂B、B1、C、C1的峰值剂量进行定时,以使总体致炎剂量“BC”大于单独用其剂量可达到的剂量。也如图40和图42所示,致炎剂量“BC”通常可具有方波的形状。
致炎药剂B、B1、C、C1可被配置成能够在释放在炎症阶段210中有效的其他药剂之前各自开始释放,药剂D、D1被配置成能够抑制MMP。以这种方式,伤口部位处的组织可被允许发炎并在第三天(t=3)之前的短时间内接近其最小拉伸强度F3,此时炎症阶段210的巨噬细胞期214通常会开始并且在此期间可施用药剂D、D1。
被配置成能够抑制MMP的药剂D、D1可各自具有各种构型。通常,药剂D、D1可各自包括被配置成能够抑制MMP的药剂,例如MMP抑制剂。因此,药剂D、D1可有助于在炎症阶段210释放更少的MMP,从而允许更少的ECM在炎症阶段210中被破坏。伤口部位的组织因此可以较少被撕裂,同时仍然允许炎症过程,并因此允许组织具有比典型的伤口愈合过程更高的强度(例如,F3>F4)。药剂D、D1的示例包括抑制MMP和其他蛋白酶的作用的组织基质退化抑制剂。在一个示例中,药剂D、D1各自包括相同的剂,但药剂D、D1在至少一些示例中可以彼此不同。
药剂D、D1可各自以多种方式施用。在一个示例中,药剂D、D1中的每一种可通过容器施用。两个容器中的每一个都可包括包衣,该包衣被配置成能够在伤口愈合过程中的适当时间,例如在释放致炎药剂B、B1、C、C1之后的时间,诸如有时在发生损伤后4至7天(4<t<7),促进药剂D、D1的释放。包衣的示例包括具有90%聚乙交酯(也称为聚乙醇酸(PGA))和10%聚丙交酯(也称为聚乳酸(PCA))的共聚物,诸如VicrylTMRapide。
在一个示例中,药剂D可被配置成能够在药剂D1之前开始释放。因此,MMP抑制药剂D、D1可被配置成能够交错释放,其中每种药剂在不同时间(例如,在沿着第二曲线图202的时间t轴的不同点)处剂量达到峰值。MMP抑制药剂D、D1的不同峰值剂量可允许药剂D、D1具有累积MMP抑制剂量,如图40和图43中示为“DD1”,比其任一单独剂量更大。换句话讲,可以对单独药剂D、D1的峰值剂量进行定时,以使总体MMP抑制剂量“DD1”大于单独用其剂量可达到的剂量。
MMP抑制药剂D、D1可被配置成能够在药剂E、F释放之前各自开始释放。这样,伤口部位处的组织可被允许发炎并且在增生阶段212在第四天的某个时间开始之前经受其最小拉伸强度F3。
被配置成能够防止炎症的药剂E可具有多种构型。通常,药剂E可包括被配置成能够抑制炎症的剂,例如抗炎剂。因此,药剂E可被配置成能够有助于减少伤口部位的炎症,并因此有助于结束炎症阶段210。药剂E的示例包括双氯芬酸。
药剂E可以多种方式施用。在一个示例中,药剂E可作为容器施用。该容器可包括包衣,该包衣被构造成能够在伤口愈合过程中的适当时间,例如在释放MMP抑制药剂D、D1之后的时间,诸如在发生损伤后至少4天(4<t),例如有时在发生损伤后7至10天(7<t<10),促进药剂E的释放。包衣的示例包括共聚物,该共聚物具有90%PGA和10%PCA并且具有高分子量,例如比用于MMP抑制药剂D、D1的包衣更高的分子量以便随后释放。
被配置成能够促进组织生长的药剂F可具有多种构型。通常,药剂F可包括被配置成能够促进组织生长的剂,例如生长因子。药剂F因此可被配置成能够有助于组织在增生阶段212重建。药剂F的示例包括TGF-β。
药剂F可以多种方式施用。在一个示例中,药剂F可作为容器施用。该容器可包括包衣,该包衣被配置成能够在伤口愈合过程中的适当时间,例如在释放抗炎药剂E之后的时间,诸如在发生损伤后至少5天(5<t),例如有时在发生损伤后5至10天(5<t<10),促进药剂F的释放。包衣的示例包括具有65%PGA和35%PCA的共聚物。
具体实施
本文描述了用于诱导组织粘连的各种示例性外科附属物和药剂。一般来讲,可植入附属物可以具有可释放地保持在其中的一种或多种药剂,所述药剂被配置成能够诱导组织粘连。如本文所讨论的,附属物可被构造成能够使用外科缝合器结合外科钉施加到肺组织。
涉及肺组织的外科手术可能导致肺部漏气,诸如沿着在外科手术过程中施加到肺组织的任何钉线。当尝试在诸如肺切除的外科手术过程中使用钉闭合肺组织时,因为肺部需要在术后充气和放气而不会漏气或导致患者疼痛,漏气尤其成问题。外科医生通常更倾向于使患者肺组织中的漏气自行关闭。然而,如果漏气未能自行矫正,或者如果外科医生选择干预而不等待漏气自愈,则外科医生通常将血样注入到患者的胸腔中,该过程称为胸膜固定术。胸膜固定术通常包括通过使肺周围的胸膜表面(例如,胸膜)粘在一起来诱导粘连从而防止流体在胸膜表面之间的空间(例如,胸膜腔)累积。血样在胸腔中的存在扰乱了患者的组织并导致在肺组织与患者胸腔之间形成粘连。粘连旨在阻止和/或防止漏气。然而,漏气可能非常难以检测,使得即使它们存在也不能加以检测,并且因此可能无法知晓胸膜固定术是否必要。为了解决这种不确定性,外科医生通常在外科手术的进行过程中将粘连诱导物质施加到肺表面(这可能导致漏气)或术后通过胸管施加粘连诱导物质。然而,这些术中和术后方法耗费时间,因为它们增加了外科手术的时长(在术中干预的情况下)或需要附加的患者创伤(在术后干预的情况下)。术中和术后方法尤其对于经验较少的外科医生也可能具有挑战性。
设置在附属物内并可从附属物释放的至少一种药剂可被配置成能够诱导组织粘连并且因此有助于防止漏气并且/或者使得术中或术后不需要将血样引入患者胸腔的胸腔固定术。换句话讲,可以通过将附属物递送至肺组织来协助胸膜固定术。能够结合外科钉进行递送的附属物可能比在缝合肺组织的外科手术之后通过胸管缝合肺组织并且/或者施加物质的外科手术过程中手动施加粘连诱导物质的传统的胸膜固定术具有更少的挑战性,至少因为缝合是手术本身的一部分而不是其后的步骤。
除了被配置成能够诱导组织粘连之外,一种或多种药剂还可被配置成能够促进伤口愈合的一个或多个方面,例如,促进止血、促进组织生长等,和/或促进肺功能。因此,一种或多种药剂可被配置成能够诱导组织粘连并且被配置成能够促进受伤的肺的愈合,例如,缝合的肺组织的愈合和/或促进肺功能。被配置成能够促进肺功能的附属物和药剂在与本发明同日提交的标题为“Surgical Adjuncts And Medicants For Promoting LungFunction”的美国专利申请[][代理人案卷号47364-174F01US(END7637USNP)]中有详细描述,该专利申请据此全文以引用方式并入本文。
包括被配置成诱导组织粘连的至少一种药剂的附属物可以以各种方式如本文所讨论的那样进行构造,诸如通过包括基于纤维的格、泡沫和/或膜。
在至少一些具体实施中,附属物可以包括被构造成能够促进从附属物释放至少一种药剂的载体。载体自身可以形成附属物或可以设置在其中,例如,设置在形成附属物的聚合物中。载体可被构造成能够经历从固态到液态的相变,诸如通过被构造成能够由于温度、pH、光和/或其他环境因素的影响而改变状态。被配置成能够经历从固态到液态的相变的载体的一个示例是聚乙二醇(PEG),其被配置成能够响应于温度(例如,室温到体温)而改变状态。当载体处于固态时,至少一种药剂可以由附属物保持以不从其中释放。当载体处于液态时,至少一种药剂可以从附属物释放,例如,通过载体流出附属物或通过附属物自身变成液态。至少一种药剂可以以固态分散在载体内,使得至少一种药剂可以由液态载体携带。例如,至少一种药剂可被封装在分散在载体中的微胶囊、微珠或任何其他容器中,如上所述。微胶囊、微珠或其他容器可被构造成能够粘附到软组织,例如,粘附到胸膜表面,诸如通过在其上涂布粘合剂或其他组织粘合剂。因此,包含在微胶囊、微珠或其他容器中的一种或多种药剂可被配置成能够在微胶囊、微珠或其他容器粘附到软组织的位置诱导组织粘连。一种或多种药剂的洗脱可以在整个初始释放期间经由载体和/或通过吸收微胶囊、微珠或其他容器的包衣而发生。由液态载体携带的至少一种药剂可允许至少一种药剂通过正常肺功能(例如,肺的膨胀和收缩)广泛地分散,因为正常肺功能可以促进液态载体在肺叶、胸壁、膈肌等之间的运动。
如上所述,至少一种药剂由附属物可释放地保持并且可被配置成能够根据多种时间模式中的任一种释放(诸如通过作为团注剂量或定时释放剂量),以及根据多种空间模式中的任一种释放。被配置成能够作为单次剂量(例如,作为团注剂量)从附属物释放的至少一种药物可允许更快地诱导组织粘连。粘连的更快形成可以帮助防止任何泄漏并因此防止与之相关联的问题。被配置成能够作为定时释放剂量随着时间推移从附属物释放的至少一种药剂可允许在更大的区域上形成粘连,因为药剂在先前已形成组织粘连的区域上方流动、渗透或换句话讲行进或穿过所述区域,从而在新的区域中诱导粘连。因此,可以在更大的区域内防止泄漏。所述一种或多种药剂可以以如上所述的多种方式(例如通过涂覆在附属物上,包括在与附属物联接的一个或多个容器中,等等)被附属物可释放地保持。各种不同的药剂可被配置成能够诱导组织粘连。被配置成能够诱导组织粘连的药剂的非限制性示例包括生长因子(例如,ILβ、TGF-B等)和富血小板血浆。
被配置成能够诱导组织粘连的一种或多种药剂的广泛分散可导致患者体内组织粘连的广泛分布。如果在粘连形成之后在患者的胸腔中进行另一种外科手术,粘连的广泛分布可能使得后续的外科手术更难以进行。在至少一些具体实施中,诸如基准标记(例如,射线不可透标记)的标记物可以附接至保持被配置成能够诱导组织粘连的一种或多种药剂的附属物。标记物可被配置成能够永久保持在原位。标记物可帮助在胸部区域中对患者执行后续外科手术的外科医生返回到相同的解剖位置,例如,返回到附属物施加的位置,并因此位于或靠近在后续手术中组织粘连形成的区域。因此,标记物有助于外科手术计划和指导。一个或多个标记物可以附接到附属物并随其递送。
图45示出了具有至少一种可释放地保持在其中并且被构造成能够诱导组织粘连的药剂1608的附属物1660的一个具体实施。一般来讲,附属物1660具有多个层,包括设置在可适形层1606和增强层1602之间的阻挡层1604。可适形层1606可以由被构造成适形于不规则表面并且具有粘性和可流动性的材料形成。如图所示,至少一种药剂1608可以设置在可适形层1606中。因此,包括可适形层1606的附属物1660可以特别适用于递送到自然伸展并且可延伸的肺组织。包括多层的附属物的具体实施在与本发明同一日提交的标题为“Composite Adjunct Materials For Delivering Medicants”的美国专利申请[代理人案卷号47364-163F01US(END7626USNP)]中有详细描述,该专利申请据此全文以引用方式并入。
图46示出了利用钉1620固定到肺组织1610的外表面的附属材料1600。可适形层1606由来自钉1620的压力压缩。为了便于说明,仅示出了一个钉1620。通常将使用多个钉1620来将附属物1600固定到组织1610。如图所示,由于阻挡层1604的存在,至少一种药剂1608没有从可适形层1606中洗脱出来并进入增强层1602。然而,药剂1608远离钉冠1622侧向地洗脱。至少一种药剂1608的侧向洗脱可以帮助至少一种药剂1608在创伤区域附近诱导组织粘连,例如,在钉1620附近,并且类似地,在将附属物1600附接到组织1610的多个钉附近。当缝合肺时,传统上沿着肺的外部边缘渗漏最多。至少一种药剂1608的侧向洗脱可以帮助至少一种药剂1608进入并且/或者渗透到包括肺组织1610的肺的外部边缘上,并由此帮助解决肺边缘处的泄漏,例如,通过包括一种或多种被配置成能够促进密封的止血剂的一种或多种药剂1608。
如上所述,来自附属物1600的至少一种药剂1608的定时释放速率在不同的具体实施中可以不同。例如,可适形层1606可以变化(例如,在由不同材料形成的具体实施之间变化,在具有不同崩解速率的具体实施之间变化等)以允许至少一种药剂1608的可选择的释放速率。例如,可适形层1606可以从快速溶解(允许至少一种药剂1608从附属物1600快速释放)改变到缓慢溶解(允许至少一种药剂1608从附属物1600缓慢释放)。同样如上所述,缓慢定时释放速率对于被配置成能够诱导组织粘连的药剂可能特别有用,与利用团注剂量或以更快的释放速率进行释放所能实现的组织粘连相比,以便在更长的时间段内诱导更多的组织粘连和/或更强的组织粘连。
图47和图48示出了具有至少一种可释放地保持在其中并且被构造成能够诱导组织粘连的药剂2032的附属物2030的另一个具体实施。图47和图48示出了利用多个钉2042将附属物2030附接到肺2040,其中肺2040的一部分被移除,诸如通过切除手术。图47示出了处于松弛状态的肺2040(例如,在正常肺功能期间,肺2040处于放气状态)。图48示出了处于扩张状态的肺2040(例如,在正常肺功能期间,肺2040处于充气状态)。如图48所示,至少一种药剂2032可以从附属物2030释放到胸膜腔2052中和/或其附近,其中如本文所述,至少一种药剂2032可被配置成能够诱导组织粘连。
附属物2030可被构造成能够具有这种结构,该结构有利于分配有效量的一种或多种药剂2032以提供期望的效果,如上文所讨论的那样。如所示具体实施中,期望的效果可以包括将一种或多种药剂2032引导到胸膜腔2052中。例如,一种或多种药剂2032的靶向递送可以通过将一种或多种药剂2032结合到附属物2030内的区域中来实现,该附属物形成于允许在从附属物2030释放时将一种或多种药剂2032空间分配进入胸膜腔2052的模式。
本领域的技术人员将会理解,本发明已应用于常规微创和开放式外科器械中,以及机器人辅助的外科手术中。
本文所公开的装置可被设计成在单次使用后废弃,或者其可被设计成能够使用多次。然而无论是哪种情况,该器械都可在至少使用一次后经过修复再行使用。修复可包括拆卸装置、清洁或更换具体部件以及后续重新组装的其中任意几个步骤的组合。具体地,所述装置可拆卸,而且可以任意组合选择性地更换或移除所述装置的任意数目的特定零件或部件。在清洁和/或替换特定部件后,可对所述装置进行重新组装,以便随后在修复设施处使用或就在外科手术之前由手术团队使用。本领域的技术人员将会理解,修复装置可利用各种技术来进行拆卸、清洁/替换和重新组装。此类技术的使用以及所得的修复装置均在本申请的范围内。
根据上述实施方案,本领域的技术人员将会认识到本发明的另外的特征和优点。因此,本发明不应受到已具体示出和描述内容的限制,除非所附权利要求有所指示。本文引用的所有出版物和参考文献全文明确地以引用方式并入本文中。
Claims (8)
1.一种与外科缝合器一起使用的钉仓组件,包括:
仓体,所述仓体具有多个钉腔,每个钉腔具有设置在其中的外科钉;
生物相容性附属材料,所述生物相容性附属材料可释放地保持在所述仓体上并被配置成能够通过所述仓体中的所述钉的部署来形成至少一条部署的钉线而递送到肺组织,所述附属材料具有可适形层、增强层和设置在所述可适形层和所述增强层之间的阻挡层,所述可适形层被构造为适形于肺组织的不规则表面使得所述可适形层被构造为适形于肺组织的扩张和延伸;和
有效量的至少一种药剂,所述至少一种药剂设置在所述附属材料内并能够从所述可适形层释放,并且所述至少一种药剂有效地诱导与所述至少一条部署的钉线相邻的组织粘连,所述阻挡层阻止所述药剂从所述可适形层进入所述增强层,
其中所述附属材料包括被配置成能够经历从固态到液态的相变的载体,所述至少一种药剂被配置成能够在所述载体处于所述液态而非所述固态时从所述附属材料释放,所述至少一种药剂被封装在分散在所述载体内的微胶囊中,所述微胶囊被构造为通过在所述微胶囊上涂覆粘附组织粘合剂从而使所述微胶囊粘附至软组织。
2.根据权利要求1所述的组件,其中所述附属材料被配置成能够从其释放所述至少一种药剂作为单次释放剂量。
3.根据权利要求1所述的组件,其中所述至少一种药剂包括生长因子。
4.根据权利要求1所述的组件,其中所述至少一种药剂包括以下中的至少一种:白介素(IL)β、组织生长因子β(TGF-B)和富血小板血浆。
5.一种用于外科器械的端部执行器,包括:
第一钳口,所述第一钳口具有与其可移除地附接的仓体,所述仓体在其面向组织的表面上具有多个钉腔,所述钉腔被构造成能够在其中安置钉;
第二钳口,所述第二钳口具有砧座,所述砧座具有形成在其面向组织的表面上的多个钉成形腔,其中所述第一钳口和所述第二钳口中的至少一者能够相对于另一者移动;
生物相容性附属材料,所述生物相容性附属材料可释放地保持在所述第一钳口的所述面向组织的表面和所述第二钳口的所述面向组织的表面中的至少一者上,并被构造成能够通过所述仓体中的所述钉的部署来形成至少一条部署的钉线而递送到肺组织,所述附属材料具有可适形层、增强层和设置在所述可适形层和所述增强层之间的阻挡层,所述可适形层被构造为适形于肺组织的不规则表面使得所述可适形层被构造为适形于肺组织的扩张和延伸;和
有效量的至少一种药剂,所述至少一种药剂设置在所述附属材料内并能够从所述可适形层释放,并且所述至少一种药剂有效地诱导与所述至少一条部署的钉线相邻的组织粘连,所述阻挡层阻止所述药剂从所述可适形层进入所述增强层,
其中所述附属材料包括被配置成能够经历从固态到液态的相变的载体,所述至少一种药剂被配置成能够在所述载体处于所述液态而非所述固态时从所述附属材料释放,所述至少一种药剂被封装在分散在所述载体内的微胶囊中,所述微胶囊被构造为通过在所述微胶囊上涂覆粘附组织粘合剂从而将所述微胶囊粘附至软组织。
6.根据权利要求5所述的端部执行器,其中所述附属材料被配置成能够从其释放所述至少一种药剂作为单次释放剂量。
7.根据权利要求5所述的端部执行器,其中所述至少一种药剂包括生长因子。
8.根据权利要求5所述的端部执行器,其中所述至少一种药剂包括以下中的至少一种:白介素(IL)β、组织生长因子β(TGF-B)和富血小板血浆。
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