CN110243637A - 用于微流体装置分段装载的毛细屏障 - Google Patents
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Abstract
本发明的各方面针对一种使第一液体和第二液体在一条或多条毛细结构的液体通道内相互作用的方法和装置。该方法和装置可以包括:提供至少一个毛细屏障,该毛细屏障在该毛细结构中利用毛细作用力在液体界面区域设置第一液体的弯液面。另外,提供沿着通道中的一条使第二液体流向液体界面区域的路径。另外,当第一液体的流动被阻截时,通过气体流出口来从液体界面区域释放气压。另外,在毛细屏障于流体界面区域截留第一液体的同时,第一液体和第二液体在液体界面区域内接触。
Description
本申请是申请人于2015年10月16日提交的、申请号为“201480021876.2”的、发明名称为“用于微流体装置分段装载的毛细屏障”的发明专利申请的分案申请。
联邦资助的研究与开发
本发明是按照由国防部高级研究计划署授予的合同HR0011-12-C-0080在政府的支持下完成的。美国政府享有本发明的一定权利。
发明背景
向微流体芯片装载多种液体在许多方面具有挑战性。例如,装载会因为采样口少导致通向微流体芯片的通路受到限制而具有挑战性。另外,通道尺寸可以接近100μm。对于这些实施方式,表面力可能变得重要,因为水性液体除非被外压驱动否则不会进入疏水性通道,且如果通道从多个方向被装载则气泡可能被截留。该微流体芯片的某些应用包括形成位于多种液体之间的液对液界面。在这些情况中,要装载的液体可能不易获得,例如含有稀有细胞或稀缺DNA或RNA样品的液体。因此需要在形成液对液界面时将液体损失降到最低。
本发明的各方面使得在微流体通道内形成液体界面而不损失样品液。关于这些和其它方面,本发明涉及一种使第一液体和第二液体在一一条或多条液体通道内相互作用的装置和方法。这些装置和方法可以包括利用毛细作用力在液体界面区域设置第一液体的弯液面。另外用于第二液体的脱逸路径或通道允许第二液体流向液体界面区域,在该处提供了供液体脱逸的路径。另外,在该脱逸路径中提供用于限制脱逸液体的体积流率的手段。
本发明的某些其它实施方式涉及使第一液体和第二液体在具有液体界面区域的毛细结构中相互作用的装置和方法。这些方法包括提供包括将第一液体引向液体界面区域的第一微流体通道和将第二液体引向液体界面区域的第二微流体通道的毛细结构。该液体界面区域具有毛细屏障以阻截第一液体沿着第一微流体通道在公称流体压力下向液体界面区域的流动。该毛细屏障的上游部分为第一液体提供了弯液面屏障。另外,这些方法包括使第一液体在第一微流体通道内流动直至该毛细屏障已将第一微流体通道中第一液体的流动阻截的状态。当在该毛细屏障已将第一微流体通道内第一液体的流动阻截的状态下,通过气体流出口来从该液体界面区域释放气压。该释放是由于第二液体在第二微流体通道内流向液体界面区域而发生的,且在第二液体在第二微液体通道内流向液体界面区域时发生。
与上述的许多方面相一致,相关装置的实例包括具有用于将第一液体引向液体界面区域的第一微流体通道和用于将第二液体引向该液体界面区域的第二微流体通道的毛细结构。该液体界面区域具有阻截沿着第一微流体通道在公称流体压力下流向液体界面区域的第一液体的毛细屏障。该毛细屏障的上游部分为第一液体提供了弯液面屏障。这种类型的装置还可以包括释放液体界面区域中气压的气体流出口,该气体流出口的构造降低或防止液体的损失。该气体流出口在毛细屏障已将第一微流体通道内的第一液体的流动阻截的状态和在第二微流体通道内的第二液体流向液体界面区域的状态中是有用的。
上述讨论/概述并不旨在描述本发明的每个实施方式或每个实现方式。以下的附图和详细描述也例示了各种实施方式。
附图
通过考虑以下结合附图的详细描述,可以更全面地理解各示例性的实施方式,其中:
图1显示了与本发明的各方面相一致的示例性的毛细结构和状态图;
图2A显示了与本发明的各方面相一致的包括流向液体界面区域的第一液体的示例性的毛细结构,
图2B显示了与本发明的各方面相一致的包括被阻截的第一液体和流向液体界面区域的第二液体的示例性的毛细结构,
图2C显示了与本发明的各方面相一致的毛细结构中的第一液体和第二液体的液对液界面,
图2D显示了与本发明的各方面相一致的毛细结构中的第一液体和第二液体的示例性图像;
图3A显示了与本发明的各方面相一致的第一示例性的毛细屏障,
图3B显示了与本发明的各方面相一致的第二示例性毛细屏障;以及
图4显示了与本发明的各方面相一致的示例性的毛细结构。
本发明适于各种修改和替代形式,其细节通过举例方式显示在附图中,并被详细描述如下。但应当理解,本发明并不仅限于下述的特定实施方式。相反,本发明涵盖了所有落入包括权利要求中所定义的方面在内的本发明范围内的修改、等效物和替代物。另外,本申请中使用的“实例”一词只作为说明,而非限制。
发明描述
相信本发明的各方面可以应用于各种不同类型的涉及通过毛细屏障来形成液对液界面以在界面处将前行液体截停的装置、系统和装置。与本发明的各方面相一致的该毛细屏障利用表面力将液体的弯液面截留或截停在所需且固定的位置。一旦该液体的弯液面在交叉处截停,则不同的液体被装载,且填入第一液体的弯液面。所形成的液对液界面有助于例如用于通过等速电泳(ITP)来高效提取核酸的细胞裂解物的有限注射。然而本发明无需限定于此,通过上下文描述的各个例子的讨论可以理解本发明的各方面。
各示例性的实施方式针对使第一液体和第二液体在具有液体界面区域的毛细结构中相互作用的方法和装置。在该毛细结构中,提供第一微流体通道以将第一液体引向液体界面区域和第二微流体通道以将第二液体引向液体界面区域。该液体界面区域包括毛细屏障,该毛细屏障对沿着第一微流体通道在公称液体压力下流向该液体界面区域的第一液体的流动进行阻截。该毛细屏障的上游部分为第一液体提供了弯液面屏障。第一液体在第一微流体通道内流动直至该毛细屏障阻截了该第一液体的流动的状态。当该毛细屏障已经阻截了第一微流体通道中第一液体的流动时,释放气压。由于第二液体在第二微流体通道中流向该液体界面区域,且在第二液体在该第二微液体通道内流向液体界面区域时,气压通过气体流出端口从液体界面区域释放。在某些实施方式中,在第一液体的流动被阻截后,第二液体流入该第二微流体通道中直到在该第一液体和该第二液体之间形成液对液界面。
本发明的各方面使得在微流体通道内形成液体界面而不损失样品液。这些装置和方法可以包括利用毛细作用力在液体界面区域设置第一液体的弯液面的毛细屏障,同时利用脱逸路径来允许第二液体向该液体界面区域流动。该脱逸路径中提供了用于限制脱逸液体的体积流率的手段,其结构例示于图4和下文的相关讨论中,实例包低容量通道、收缩通道和/或沿途的突变。
在某些其它实施方式中,提供微流体芯片以负载该毛细结构。可以包括例如柱状物形式的突起物,其位于液体界面区域的上游部分或其附近,并位于供第一液体流向液体界面区域的路径的壁上;该突起物配置和排列以通过施加对抗(第二)液体体积流率的作用力来进行限制。该微流体芯片还包括接收指征第一液体和第二液体之间的相互作用的数据的电路。在某些其它实施方式中,与本发明的各方面相一致,在该微流体芯片上提供第一液体引入口以向第一微流体通道供给第一液体,以及在该微流体芯片上提供第二液体引入口以向第二微流体通道供给第二液体。
本发明的某些实施方式中,一条或多条第一微流体通道和第二微流体通道分别包括疏水性表面,以帮助在液体界面区域阻截液流。在某些实施方式中,第一微流体通道和第二微流体通道由聚二甲基硅氧烷(PDMS)构成。另外,在本发明的某些实施方式中,该毛细屏障的上游部分至少有一部分被在该毛细结构中流动的第一液体的横截面积的变化所限定。在这些实施方式中,横截面积的变化足以阻截在液体界面区域内的第一液体流。另外,在这些实施方式中,毛细屏障在第一液体在第一微流体通道中流动时帮助阻截该第一液体。另外,在本发明的其它实施方式中,阻截第一微流体通道中的液流的表面力大约等于阻截该毛细屏障中的液流的表面力。以这种方式,位于该毛细屏障上游部分的该毛细屏障被在该毛细结构中流动的第一液体的横截面积的变化所限定,这在第一液体在第一微流体通道中流动时帮助阻截该第一液体。在本发明的某些实施方式中,第一微流体通道和第二微流体通道的交叉点形成T形交叉(T-junction)。本发明的各实施方式在不使用真空的条件下装载入第一液体和第二液体。
在本发明的某些实施方式中,第一液体和第二液体中的至少一种为包含DNA、RNA、蛋白质和/或细胞的液体。另外,本发明的某些实施方式还包括负载该毛细结构的微流体芯片和接收指征第一液体和第二液体之间相互作用的数据的电路。在各实施方式中,该电路对存在于第一液体或第二液体中的DNA、RNA、蛋白质和/或细胞进行定量的微流体分析和质量控制。另外,在其它实施方式中,微流体芯片上的该电路对存在于第一液体或第二液体中的DNA片段的分离和提取进行制备电泳分析。在其它实施方式中,该电路对第一液体和第二液体中的至少一种中的靶向核酸富集物进行分析。在其它实施方式中,提供该电路以基于聚合酶链反应对第一液体或第二液体的各方面进行遗传分析。如电路的各实施方式和应用所列举,安置于微流体芯片上的该毛细结构可用于许多不同的应用。
该毛细结构可与各种分析和/或处理两种液体之间相互反应的系统和装置相兼容。另外,安置于微流体芯片上且具有对DNA、RNA、蛋白质和/或细胞进行定量分析和质量控制的电路的毛细结构的实施方式与各种装置和系统例如德国凯杰公司(Qiagen)的Qiaxcel全自动DNA/RNA分析系统、美国安捷伦公司(Agilent)的生物分析仪(Bioanalyzer)、美国伯乐(Bio-Rad)的Experion全自动电泳系统、日本岛津(Shimadzu)的MCE-202 MultiNA自动分析平台和美国铂金埃尔默公司(Perkin Elmer)的LabChip GXⅡ自动电泳系统相兼容。另外,安置于微流体芯片上且具有对DNA片段的分离和提取进行制备电泳分析的电路的毛细结构的实施方式与各种装置和系统例如美国Sage Science公司的Pippin Prep核酸制备电泳仪和BluePippen Prep全自动核酸制备电泳系统、和美国铂金埃尔默公司的Labchip XT相兼容。另外,安置于微流体芯片上且具有对靶向核酸富集物进行分析的电路的毛细结构的实施方式与各种装置和系统例如美国富鲁达公司(Fluidigm)的Access Array高通量靶标区段重测序捕获系统相兼容。该毛细结构还可用于微流体热循环仪(例如德国凯杰公司的LabDisk Player)中会发生的试剂和/或样品的装载中。
现在参考附图,图1显示了与本发明的各方面相一致的示例性的毛细结构和状态图。图1显示了包括第一微流体通道105和第二微流体通道115的毛细结构100。提供第一微流体通道105以将第一液体引向液体界面区域110,以及提供第二微流体通道115以将第二液体引向该液体界面区域110。该液体界面区域110包括一个响应在公称流体压力下流向液体界面区域110的第一液体而阻截该第一液体的流动的毛细屏障120。毛细屏障120的上游部分为第一液体提供了弯液面屏障125。第一液体在第一微流体通道内流动直至毛细屏障120阻截了流动的状态。在这种状态下,可以通过液-气流出口130从该液体界面区域110释放气压,同时第二液体在第二微流体通道115内流向液体界面区域110。
如图1中的状态图所示,在第一液体触到弯液面屏障之后,第二微流体通道115被第二液体充满,直到第二液体在弯液面屏障处与第一液体接触。在此阶段,第一和第二液体之间的润湿可能导致液体流经该气体流出口的损失,而该气体流出口被设计成通过阻挡或降低流经允许气体流出的路径的液流(以形成一个相对于(第二)液体的体积流率的反向作用力)来限制该(第二)液体的体积流率。然后,在第一液体和第二液体的界面处进行基于界面的分析。
图2A-2D显示了与本发明的各方面相一致的示例性的毛细结构。图2A显示了包括在微流体通道内流动的第一液体205的毛细结构200。该液流截停在图2B中以虚线表示的屏障210处,图2显示毛细结构200包括被阻截的第一液体205和在毛细结构200的第二通道220中流动的第二液体215。第二液体215继续流动直到在第一液体被阻截的位置(或屏障210)形成液对液界面。该液对液界面在图2C中显示为液体屏障210处的分离。图2A、2B和2C中的每一张图都共通的是具有流出口230(表示涉及图1中的流出口130)。
图2D显示了与本发明的各方面相一致的一种相似结构的毛细结构的示例性图像,其中的第一液体为血液裂解物,而第二液体为电泳缓冲液。另外,该装载有液体的毛细结构是聚二甲基硅氧烷(PDMS)芯片。如图2D的左上角所示,通过在该芯片的右下角处施加真空来从左侧装载血液裂解物。图2D的右上部分显示了截停在屏障上的裂解物。图2D的左下角部分显示从上毛细管装载入的用于ITP的先行电解液(电泳缓冲液)。随即形成了电解质和血液裂解物的清晰界面。图2D的右下角部分显示了裂解物和先行电解质相遇时的快照。在这些液体相遇之后,会产生压力驱动的流动从而破坏该界面。然而,由于与本发明各方面相一致的该芯片的设计,该血液裂解物的容量通过流入一个流出废弃通道来废弃。
图3显示了与本发明的各方面相一致的示例性的毛细屏障。例如,图3A显示了第一示例性毛细屏障。在图3A中,毛细屏障基于前行液体接触线(前行进入一个被一些气体占据的区域)与一种液体毛细管或腔几何形状相遇而形成。毛细作用力阻截了液体的运动,并且即使在液体侧和气体侧之间存在施压差也形成了固定的液体前线。从图3A中可见,液流基于横截面积的变化而被毛细管上游部分的表面力所阻截,该横截面积的变化显示为基于该毛细管的上游部分和该毛细管的下游部分之间的表示角度(φ和Φ)之差。在某些实施方式中,φ和Φ是相等的,而在另一些实施方式中φ和Φ不相等。
图3B显示了与本发明的各方面相一致的第二例液流毛细屏障。图3B显示的毛细屏障是由毛细管中的一系列柱状物所构成的。该结构使得高分辨率制造成为可能,但不能制造全三维结构。例如,倾倒在SU-8掩模上的聚二甲基硅氧烷(PDMS)能够轻易地用于形成具有锋利边缘的柱状物,但这些毛细管受掩模厚度所限。在图3B中所示的实施方式中,该毛细屏障包括一系列沿着毛细管安置的小(例如120μm长的)三角柱。当第一液体沿着毛细管流入该装置时,其被截留于该毛细屏障,从而形成弯液面。此弯液面在第二液体(例如电泳缓冲液)从相连的毛细管(未示出)加入时保持固定,而空气通过一个窄的侧通道(例如,如图1中所示)脱逸。当液体到达该毛细屏障时,第一液体与第二液体接触。图3B中所示的毛细屏障结构是一个斜坡结构。在其它实施方式中,使用多个斜坡结构在毛细通道内形成毛细屏障。
这种斜坡结构可以通过使用热塑成型来实施和制造,其中的3D模具由机械制造。该毛细屏障结构减少了有效通道尺寸,随即让其扩张。液体弯液面是通过穿过扩张物所需的表面积增加而被固定的。
图4显示了与本发明的各方面相一致的示例性的毛细结构。图4中的毛细结构400包括第一微流体通道405和第二微流体通道410。提供第一微流体通道405以将第一液体引向液体界面区域415,提供第二微流体通道410以将第二液体引向液体界面区域415。第一微流体通道405和第二微流体通道410包括各自的屏障结构420和在之后的毛细管中的各自的扩张物(或扩展区域)425。这些屏障结构420和扩展物425帮助形成响应于(在公称流体压力下)流向液体界面区域415的第一液体而阻截第一液体的流动的毛细屏障430。该毛细屏障430的上游部分提供了弯液面屏障,例如,在第一微流体通道405中的扩张物425处。第一液体在第一微流体通道405中流动直至毛细屏障430基于屏障结构420和扩张物425而至少部分地阻截了该第一液体的流动的状态。在该毛细屏障430已经阻截了第一微流体通道405中的第一液体的流动的状态下,通过气体流出口435来从液体界面区域415释放气压,同时第二液体在第二微流体通道410中流向液体界面区域415。屏障结构420和扩张物425排列在第二微流体通道410的附近,以减少液体流经气体流出口435的损失。如图所示,该气体流出口435具有收缩的体积面积(图示的通道尺寸的突变)以提供一种不利于液体损失发生的手段。
本发明的各方面针对利用微流体通道的表面疏水性和/或通道尺寸的突变来形成截停流动的毛细管阀门从而控制液流、而不使用真空的毛细屏障。当前行液体进入扩张至更宽截面的通道区域时,该液-气界面的表面积增加以使液体能够继续前行。此扩张的表面积产生了限制体积流率的作用力(以对抗液体流动的作用力的方式)。如果该表面扩张足够大,则该液体就会停止前行。本发明的各实施方式还形成了基于疏水性表面区域的毛细屏障、和/或其它实现微流体毛细管中的突然扩张和突然收缩的方法,该屏障例如是配置和排列于通道中以施加对抗液体流动的作用力的一个或多个斜面或柱状物。
关于微流体芯片的更具体细节,参考美国专利临时申请61/785255号,本申请要求享受该在先申请的优先权,该申请的申请日为2013年3月14日;此专利文件全部纳入本文以作参考。
基于上述的讨论和例示,本领域的技术人员会容易认识到可以在不严格遵循本文示例和描述的示例性实施方式和应用的条件下对本发明作出各种修改和改变。这些修改没有偏离本发明的真谛和包括所述权利要求在内的范围。
Claims (3)
1.一种使第一液体和第二液体在一条或多条毛细结构的流体通道内相互作用的方法,该方法包括:
提供毛细屏障,该毛细屏障配置和排列以利用毛细作用力在液体界面区域设置第一液体的弯液面;
提供沿着通道中的一条使第二液体流向液体界面区域的路径;
提供可供液体从液体界面区域脱逸的脱逸路径,该脱逸路径包括限制手段,该限制手段连接至气体流出端口、用于限制液体的体积流率;
当第一液体的流动被阻截时,通过脱逸路径和气体流出口来释放气压;以及
在毛细屏障于流体界面区域截留第一液体的同时,第一液体和第二液体在液体界面区域内接触。
2.一种装置,其包括:
毛细结构,该毛细结构包括在液体界面区域附近提供第一液体的第一微流体通道或储液器、以及用于将第二液体引向液体界面区域的第二微流体通道;
毛细屏障,该毛细屏障配置和排列以利用毛细作用力在液体界面区域设置第一液体的弯液面;
气体流出口,该气体流出口配置和排列以在第一液体的流动被阻截时释放气压;以及
可供液体从液体界面区域脱逸的脱逸路径,该脱逸路径包括限制手段,该限制手段连接至气体流出口、用于限制液体的体积流率。
3.一种使第一液体和第二液体在一条或多条液体通道内相互作用的方法,该方法包含:
提供毛细屏障,该毛细屏障配置和排列以利用毛细作用力在液体界面区域设置第一液体的弯液面;
提供沿着通道中的一条使第二液体流向液体界面区域的路径;
提供使脱逸液体从第一和第二液体之间的区域脱逸的脱逸路径;
在脱逸路径内提供用于限制脱逸液体的体积流率的手段;以及
使第一液体和第二液体在液体界面区域内接触。
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AU2018312570B2 (en) * | 2017-08-02 | 2024-01-11 | Purigen Biosystems, Inc. | Systems, devices, and methods for isotachophoresis |
WO2020218234A1 (ja) * | 2019-04-22 | 2020-10-29 | 積水化学工業株式会社 | チップ及び流体の合流方法 |
JP7483892B2 (ja) | 2020-07-29 | 2024-05-15 | 京セラ株式会社 | 流路デバイス |
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CA2906730A1 (en) | 2014-09-25 |
EP2972185A4 (en) | 2017-02-22 |
AU2014236262A1 (en) | 2015-10-15 |
JP2020109413A (ja) | 2020-07-16 |
AU2020239798B2 (en) | 2023-01-05 |
GB2526999B (en) | 2020-02-19 |
AU2020239798A1 (en) | 2020-10-29 |
CN105190280A (zh) | 2015-12-23 |
US20180237767A1 (en) | 2018-08-23 |
US10787660B2 (en) | 2020-09-29 |
US20160160208A1 (en) | 2016-06-09 |
JP2016512886A (ja) | 2016-05-09 |
CN110243637B (zh) | 2022-06-24 |
US11851647B2 (en) | 2023-12-26 |
WO2014153092A1 (en) | 2014-09-25 |
GB2526999A (en) | 2015-12-09 |
EP2972185A1 (en) | 2016-01-20 |
US20210062181A1 (en) | 2021-03-04 |
CN105190280B (zh) | 2019-07-09 |
CA2906730C (en) | 2023-03-21 |
AU2023202077A1 (en) | 2023-05-04 |
AU2018206716A1 (en) | 2018-08-02 |
US20190078077A1 (en) | 2019-03-14 |
US20240182885A1 (en) | 2024-06-06 |
JP6673820B2 (ja) | 2020-03-25 |
GB201517364D0 (en) | 2015-11-18 |
US10233441B2 (en) | 2019-03-19 |
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