CN1105914C - 改进了通道几何结构的微型流体装置 - Google Patents
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Abstract
一种微型流体装置,它具有:主分析通道(100);进样通道(102);进样通道(102)与主分析通道(100)形成交叉口(108),样品引入通道(104、106)与进样通道(102)连通且位于交叉口(108)的对侧;与样品引入通道(104、106)连通的第一和第二样品源(110和112);与进样通道(102)连通且位于交叉口(108)两侧的加样/退液通道(114、116);与加样/退液通道(114、116)连通的加样/退液库(118、120)。
Description
技术领域
本发明涉及微型流体系统。
背景技术
人们对用于获取化学和生物化学方面信息的微型流体系统的开发和制造既在其制备,又在其分析能力上越来越感兴趣。在这种流体系统中采用电子工业的技术,例如平板照相、湿化学蚀刻等,更促进了人们在这方面的兴趣。
微型流体系统最早用于化学或生物化学分析是在毛细管电泳(CE)领域。CE系统一般使用熔凝二氧化硅毛细管,而最近使用的是在平面二氧化硅基片上蚀刻出的通道,其中充以适当的分离基质或介质。待分析的样品流体在毛细管或通道的一端注入。给毛细管两端加上电压,使得样品中的物质发生电泳迁移。样品流体中组成元素因各自净电荷或大小的不同造成的电泳迁移率差别使得它们得以分离、鉴定和分析。有关CE法的全面论述,可参见Wiktorowicz的美国专利5,015,350和Petersen等的美国专利5,192,405。
关于使用平面基片制造CE系统也进行了讨论,可参见Mathies等,Proc.Natl.Acad.Sci.(1994)91:11348-11352;Jacobsen等,Anal.Chem.(1994)66:1114-1118,Effenhauser等;Anal.Chem.(1994)66:2949-2953。但是,这类系统通常只有一个样品引入口,例如只有一个引入有待在毛细通道中接受分析的样品的孔。这就需要在每次分析前进行清洗和重新进样。而且,如果需要分析的样品数目较多,各样品中尺寸较大的组分(例如大的核酸片段、蛋白质等)会在进样孔和分离通道内聚集,还/或被毛细管壁吸附,最终影响系统的运行。
所以,有必要提供包括CE系统在内的微型流体系统,它能够更快的分析许多份样品,而所需的费用、空间和时间则最少,甚至有所降低。本发明就满足了这些要求以及其它要求。
发明内容
首先,本发明提供了一种微型流体装置,它包括具有第一表面的平面基片。其内部至少有三条微细通道,第二通道与第一通道相交于第一交叉口,第三与第一通道相交于第二交叉口。其体结构内分布着许多样品库,它们都与第二通道连按。至少有一个第一退液库与第三通道连接。
本发明还提供了一种类似上述的微型流体装置,但是至少一个样品库与第二通道连接,而至少一个样品库与第三通道连接。该装置还包括至少第一和第二退液库,第一退液库与第一通道连接,第二退液库与第二通道连接。
本发明还提供了一种类似上述的微型流体装置,但是包括一个与第一通道连通的预加样组件。该预加样组件具有第一进样通道,与第一通道相交于第一交叉口。该组件还具有第一批多个样品库,它们与第一进样通道连通;还有一个第一加样/退液库,它在第一批多个样品库和第一交叉口之间与第一进样通道连通。
本发明还提供了一种利用上述微型流体装置分析许多份样品的方法。在体结构内分布有许多样品库,都与第二通道连接。至少有第一退液库连接于第三通道。该方法是令样品材料从多个样品库中的第一样品库流经第二通道,流经第一和第二交叉口进入第三通道,流向第一退液库。部分样品材料在第一交叉口注入第一通道,沿第一通道传送,在分析通道内检测。
相关地,本发明提供了一种利用如上所述但是具有多个样品库的微型流体装置分离样品中组分的方法。这样多样品库都连接于第二通道,至少第一退液库连接于第三通道。该方法是令样品从所述多个样品库中的第一个样品库流经第二通道,流经第一和第二交叉口进入第三通道,流向第一退液库。部分样品材料在第一交叉口注入第一通道,沿第一通道传送,从而将样品中的组分分离开来。
本发明还提供了一种微型流体装置分离样品组分的用途,这种装置包括具有内部和外部的体结构,内部分布着至少第一、第二和第三微细通道,第二通道与第一通道相交于第一交叉口,第三通道与第一通道相交于第二交叉口,有多个样品库与第二通道连通,各自含有不同的样品;还有一个退液库连通于第三通道。
本发明还提供了一种微型流体装置,它包括分析通道和进样通道,后者在第一交叉口与分析通道连通。有多个样品源连通于进样通道,这多个样品源中至少各有一个在第一交叉口的两侧与进样通道连通。第一和第二加样/退液通道与进样通道分别相交于第二和第三交叉口。第二和第三交叉口位于第一交叉口的不同侧。
本发明还提供了一种包括一个分析通道的微型流体装置。有一个进样通道在所述分析通道的第一侧,与其相交于第一交叉口。有多个样品库在第一交叉口的第一侧与进样通道连通,并有一个退液通道在分析通道的第二侧,与分析通道相交于第二交叉口。有一个退液库在第一交叉口的第二侧与退液通道连通。
本发明还提供了一种包括一个分析通道的微型流体装置。进样通道与分析通道相交于第一交叉口。该装置还具有一个样品的预加样组件,该组件的体结构内具有多个样品库和一个退液库。每个样品库和该退液库都在第一交叉口的同一侧与进样通道连通。
本发明还提供了一种包括一个分析通道,并在内部具有第一和第二横向通道的微型流体装置。第一横向通道位于分析通道的第一侧,与其相交于第一交叉口。第二横向通道位于分析通道的第二侧,与其相交于第二交叉口。第一样品源与第一横向通道连通,第二样品源与第二横向通道连通。第一退液通道位于第一横向通道第三交叉口,第二退液通道位于第二横向通道第四交叉口。该装置还具有一个导流系统,用来引导来自第一和第二样品源的样品分别通过第一和第二横向通道流入第一和第二退液通道,并使得样品选择性地注入分析通道。
本发明还提供了一种具有一个分析通道,并在内部具有第一和第二横向通道的微型流体装置。第一横向通道位于分析通道的第一侧,与其相交于第一交叉口。第二横向通道位于分析通道的第二侧,与其相交于第二交叉口。有多个样品源与第一横向通道连通。第一退液通道位于内部,并与第一横向通道相交于第三交叉口。内部至少有一个第二退液通道,与第二横向通道相交于第四交叉口。该装置还具有一个导流系统,用来引导来自第一和第二样品源的样品分别通过第一和第二横向通道流入第一和第二退液通道,并使得样品选择性地注入分析通道.
本发明还提供具有一个分析通道和与之连通的进样通道的微型流体装置。而且,有多个样品源与进样通道连通。
本发明还提供了利用具有分析通道的微型流体装置来分析多种不同物质的方法。装置内有一个进样通道,与所述分析通道相交于第一交叉口。有多个样品源与所述进样通道连通。第一样品从所述多个样品源中的第一个样品源经所述进样通道流至第一交叉口。一部分所述第一样品注入所述分析通道。第二样品从所述多个样品源中第二个样品源经所述进样通道流至所述交叉口。一部分所述第二样品注入所述分析通道;在分析通道内分析所述的部分第二样品。
本发明还提供用一种微型流体装置分析多种不同样品的方法,所述装置包括具有第一表面(其上面有分析通道)的平面基片。该装置的所述体结构内还包括与所述分析通道相交于第一交叉口的进样通道,具有至少第一和第二样品库以及一个退液库的样品预加样组件,所述多个样品库和所述退液库都与进样通道连通。样品由所述第一库流至第一交叉口。部分所述第一样品注入所述分析通道。所述部分第一样品在所述分析通道内同时接受分析,此时,第二样品由所述第二样品库进入所述进样通道,然后进入所述退液库。所述第二样品由所述进样通道传送至所述交叉口,然后注入所述分析通道,在其中接受分析。
本发明还提供一种其体结构中具有一个分析通道的微型流体装置。其体结构内还含有多个样品源,通过一个或多个样品通道与分析通道的第一位点连通。许多样品源中第一个样品源与分析通道该位点间的通道距离基本上相等于许多样品源中第二个样品源到分析通道该位点的距离。
本发明还提供了以下微型流体装置,其体结构中具有一个分析通道和第一样品引入通道,该样品引入通道与分析通道相交于第一位点。体结构内还具有第一批的许多样品源,它们都分别通过体第一批各自分开的样品通道与第一样品引入通道连通。许多样品源中第一个样品源至第一位点的通道距离基本上等于许多样品源中第二个样品源至该位点的距离。
本发明还涉及其体结构具有一个分析通道和与之相交连通的一个进样通道的微型流体装置。根据本发明这部分内容,分析通道和进样通道一般不超过50μm宽。许多样品源也与进样通道连通。
相关地,本发明提供了一种制造微型流体装置的方法,所述方法包括在第一基片的第一平面上先制成许多通道。这许多通道一般包括一个分析通道、一个位于其第一侧并与之相交于第一交叉口的进样通道。还包括与进样通道相交并位于第一交叉口第一侧的多个样品通道和位于分析通道第二侧并与之相交于第二交叉口的一个退液通道。在这第一基片的平表面上覆盖上第二平面基片以界定上述许多通道。第二平面基片上有许多穿透的眼,它们包括与分析通道两端连通的两个眼,与退液通道非相交末端连通的退液眼,以及分别与各样品通道非相交末端连通的许多样品眼。
本发明还提供具有一个分析通道和与其相交于第一交叉口的进样通道的微型流体装置。为了提供许多种样品进行分析,它还具有许多与进样通道连通的样品源。
此外,本发明还提供实施本发明方法和装置的成套盒。本发明成套盒可以包括以下物件之一种或多种:(1)所述装置或装置部件;(2)进行所述方法和/或操作所述装置或装置部件的说明书;(3)一种或多种试验物质;(4)装有装置或试验物质的容器;(5)包装材料。
附图说明
图1A-1C示意的是本发明装置使用的通道和储库的几何结构,以及它们在加样注入许多种样品(图1A和图1B),在预加样样品(图C)时的运作。
图2示意的是在本发明微型流体装置中进行毛细管电泳中物质传送各步骤的时间顺序(下方),并与没有预加样特征的CE系统(上方)进行比较。
图3显示为了连续分析许多种样品而改进了通道/样品库几何结构的微型流体装置的一个实施例。
图4显示为了连续分析许多种样品而改进了通道/样品库几何结构的微型流体装置的另一个实施例。
图5显示连续分析许多种样品的微型流体装置内的另一种通道几何结构。
图6是荧光染色核酸片段的滞留时间图,该种核酸片段是注入由采用本发明改进的通道/样品库几何结构的基片构成的CE通道中的。
图7A-7C是一组嵌有荧光染料的PCR片段(图7A)、用HaeIII剪切然后嵌入有荧光染料的Phix174 DNA(图7B)和空白缓冲液(图7C)的荧光温度-时间图,它们被相继注入利用本发明通道/样品库几何结构的微型流体装置的分析通道。
图8A和8B显示的是微型流体装置内进行的核酸分离试验,所述装置的通道宽度分别为30微米(图8A)和70微米(图8B)。
具体实施方式I.
综述
本发明提供改进了通道和储库几何结构的微型流体装置,以及在分析、制备或处理其它以流体为载体的物质时使用这类装置的方法,以期获得更大的处理能力,而对费用、物质和/或空间的需要却更低。
在此,“微型流体装置”通指这样的装置或系统:它具有至少两个相交的通道即流体管道,其中至少一根通道的横截面直径至少在约0.1至500微米之间,约1至约100微米更好。
本发明的微型流体装置具有一个中心结构,其中分布着各种微型流体元件。该装置具有一个外表部分即表面,以及一个界定整个微型流体装置中各种细微通道和/或库的内部。例如,本发明微型流体装置的体结构通常采用平结构(即基本上平的或具有至少一个平表面)的固体或半固体基质。合适的基片可由各种材料或混合材料制成。通常,平面基片是用微型制造领域常用的固体基材制造的,例如玻璃、石英、硅或聚硅烷等二氧化硅基的基材,以及砷化镓等其它已知的基材。如果是以上基片,可以方便地应用例如平板照相、湿化学蚀刻、微型机械加工(即微型钻孔和研磨等)等常用微型制造技术来制造微型流体装置和基片。或者,可以使用聚合基材材料来制造本发明的装置,包括使用聚二甲基硅氧烷(PDMS)、聚甲基丙烯酸甲酯(PMMA)、聚氨基甲酯、聚氯乙烯(PVC)、聚苯乙烯、聚砜、聚碳酸酯、聚甲基戊烯、聚丙烯、聚乙烯、聚偏氟乙烯、ABS(丙烯腈一丁二烯-苯乙烯的共聚物)等。如果用上述聚合材料,可以用注射成形法或压印法来制造具有所述通道和储库几何结构的基片。此时,原模可以用上述材料和方法中任意一种来制造。
装置的通道和储库通常制造在平面基片的一个平面上,例如制成该平面上的沟槽或凹陷区域。一般用相同或相似材料制成的另一个基板覆盖在前述基片上并与之结合,由此界定了装置的通道和/或储库。位于下面的基片的上表面和位于上面的基片的下表面共同界定着装置的内部结构,即装置的通道和储库。
在上述装置内,底板的表面上至少有一根主通道(又称分析通道),样品通过它传送并接受一定的分析。通常,许多样品从他们各自的来源连续地输出,通过进入与主通道相交的横向通道而注入主通道。这一横向通道又称“进样通道”。样品源最好包括在装置内,例如以许多库的形式分布在装置内,并通过例如居中的样品通道与进样通道连通。但是,本发明装置的样品源也可以位于装置外,但是仍然必须如上所述与进样通道连通。
进样通道内的样品流经进样通道和分析通道的交叉口。然后,这两个通道的交叉口内的那部分或那一“段”样品输送进分析通道,在此接受所需的分析。两通道的交叉口,例如主通道和进样通道内的交叉口可以是“T”形即“三路”交叉口,进样通道在此与主通道相交并在主通道内终结,或者反过来。两个通道又可以相交穿过,形成“四路”交叉口。此时,注入样品的体积与交叉口的体积直接有关。如果需要较多的样品,一般可以使进样通道入口侧即样品侧的交叉口和进样通道出口侧即退液侧的交叉口错开,这样,更多的样品可在加样过程中进入分析通道,视两个错开的交叉口之间分析通道的长度而异。
为了方便讨论,一般是通过对样品进行毛细管电泳分析(CE)来说明本发明的装置和系统。所以,对这种操作而言,主通道即分析通道内通常含有筛选基质、缓冲液或介质,用于优化样品中各组分的分离。但是,在阅读此处公开的内容时应该理解的是,此处所述改进了几何结构的微型流体装置也适用于许多非CE用途,可以用于对样品进行多种不同的分析反应,就此可参见国际专利申请WO98/00231,本文将其参考结合于本发明中。
如上所述,本发明装置使用的通道和储库的几何结构降低了生产这类装置的费用,因为可以减少制造装置所需的材料。此外,本发明装置能够以更高的处理能力进行试验,而且改进了这些试验,之所以有这个优点是由于:(1)缩短了样品从装置上的来源输送到分析区即分析通道的路程;(2)任意两种样品从各自来源到达分析区即分析通道的距离相等,这使得输送过程对样品的影响相等;(3)增加了可置于同一装置内的样品的份数;(4)允许一种样品接受分析时,另一种样品则输送到一定区域即预先加样以备后来进行分析;(5)为各样品提供了一个预加样到达的共同位点,因此,各样品的加样注入循环的时间得以标准化;(6)改善了分析通道内各物质区(例如液带或液段)的检测和分辨率。II.
成本的降低
通常,在微型制造领域,需要使用“收缩”原则来优化制造过程。所谓收缩一般是指先在最初的尺度上对装置结构进行优化,然后进行比例缩小到装置的尺寸。收缩为装置的设计和制造提供了两方面的优点。首先,其明显优点是可以减小实际产品的总体尺寸。因为尺寸较小,即产品所占空间较小,就可以继而将该装置装在较小的整体系统中。而且,许多情况下,用微型制造技术制成的装置(包括微处理器、微型流体装置等)可以在较大的基片(例如硅、二氧化硅等)上制成。因此,通过减小各单独装置的尺寸,可以增加在同一基片上生产的装置的数量,由此降低了成本。
而且,增加用同一基片生产的装置的数量还显著减少了因给定基片中的缺陷而损失的装置数量。例如,如果一张基片只能生产4个装置,该基片的一个小的关键性缺陷存在于一个装置内就会造成25%的损耗,即4个装置中的一个装置会具有该缺陷。但是,如果同一基片可生产20个不同装置,则仅5%即20个装置中的一个装置有缺陷。所以,减小装置尺寸本身在成本上的优点是双重的。
就本发明装置而言,要能够分析许多份样品,单个装置的长度和宽度约为5mm至100mm,但是根据要求的分析数目以及反应试剂库的所需体积,可以制备更大或更小的装置。较好的是,装置的长与宽约为5mm至50mm。
通过本发明装置内通道和储库几何结构的优化,可以显著减少单个装置所需的基材。这种对基材需求的减少加上基片数/基片的增加和基材损耗/基片的降低显著降低了成本。虽然这里是用二氧化硅基或硅基基片材料进行说明,但是不难理解的是,本发明在成本和材料方面的节省也适用于更多种类的基材,例如玻璃、聚合材料等。III.
处理能力的提高
如前所述,本发明装置中改进的通道和储库的几何结构还显著改善了对许多份样品进行一定试验的处理能力。具体地说,在各种流通系统中,有相当多的时间只是用于将物质从系统的一个位置运送到另一个位置。在毛细管电泳系统中,物质是以电泳的方式从系统的一个位置运送到另一个位置,即从样品库运送到分析毛细管的,情况尤其如此。如果系统被用于连续分析许多份样品,则该问题更严重。
另一方面,本发明装置和系统中使用的通道和储库的几何结构显著缩短了从装置的样品库到分析部位(即分析通道)的运送时间。改进的几何结构还允许在单位面积基片上容纳更多的样品库。此外,这种改进的几何结构允许进行“预加样”操作,这一操作允许一份样品在分析区即分析通道内分析的同时,另一份样品从其储库传送至邻近分析区即分析通道的位置。以上几种因素结合起来就使装置的处理能力显著提高。
A.
多样品库
本发明内容之一,是本发明装置和系统对于一个给定的分析通道使用多个样品源或样品库,仅靠各样品顺次从其储库注入分析通道(即从第一样品库吸出样品注入分析通道,然后从第二样品库吸出样品注入分析通道)就能在同一装置内连续分析许多份样品。虽然,在这里的一般叙述是就制造在微型流体装置内的样品库而言的,但需要明白的是,样品库也可以在本发明装置以外,但是须保持着与本发明装置上各个位点的连通。
多样品库的使用提供的优点在于能够连续分析许多份样品而无需每次在结束前一次样品分析后手工加样。本发明装置包括至少两个位于同一基片上并与一个给定分析通道连通的隔开的样品库。通常,所述装置包括与一个给定分析通道相通的4个隔开的样品库,更常见的是6个隔开的样品库,以至少8个为佳,至少12个更好,经常是至少16个。每个样品库一般都与进样通道连通,后者又与分析通道相交连通。通常有一个位于进样通道与分析通道交叉口另一侧的加样/退液库与进样通道连通。这就可以通过抽吸样品穿过交叉口导向加样/退液库而进行加样。还可以另加一个位于样品进入同一侧的预加样通道和储库与进样通道连通,以便当前一份样品正通过主通道时可对后一份样品进行加样,加样时这份样品由其储库传送至交叉口同侧的加样/退液库,但不穿过交叉口。
如上所述,在本发明装置的单位基片面积上有着较高的样品库和其它库的密度。具体地说,样品库和缓冲液库一般在装置内,密度约2个库/cm2,超过4个库/cm2更好,有时可能超过8个库/cm2。特别好的是,本发明装置内的各个库间隔均匀。更具体地说,这样的间隔是对现有流体处理系统中间距的补充,例如,与多库片的尺寸是相适的。例如较好的是,储库排列成规则间距的线状方式(为沿一直线)或网状方式。例如,装置的储库以9mm的中心距(适合96库的片)排布成线状或网状,以4.5mm中心距更好(适合384库的片),有时约为2.25mm中心距(适合1636库的片)。
较好的是,多个样品储库在基片上位于分析通道的两侧。这样将样品库集中在样品注入分析通道位点的周围,给定储库和样品注入分析通道位点之间的距离最短,通道长度也就最短。样品库与分析通道之间长度最短,就可以令样品传送到分析通道所需的时间最短。而且还尽可能减小了流体运送过程中会造成的影响,例如组分粘附在装置上,电渗(E/O)或电泳系统中的电效应,(在进入分析通道前是不希望出现这些效应的)例如样品内组分的电泳偏移或分离。
更好的是,样品库在分析通道两边均等分布。这样,在分析通道的两侧各有相互隔开的样品库至少2个,一般至少各3个,至少各4个为佳,至少6个更好,至少8个则还要好。
或者更好的是,各样品源或样品库的位置使得物质从各样品源或样品库到达注入通道(或者是后文将详细说明的样品注入通道)的必经路程基本相等。“基本相等”的意思是任何一个储库的这段通道路程与另一储库的相差不超过25%,低于15%为佳,低于10%更好,低于5%则还要好。最好的是,这些通道路程彼此相差在2%之内。
就到达注入点或预加样点的通道路程而言,令样品库分布等距离具有许多优点。起先,在许多应用中,运行缓冲液、筛选基质、动力涂料等流体加到微型流体装置的通道中是先加在一个储库例如缓冲液库或退液库中,然后,这些流体通过毛细作用、和/或液压或外加的压力传送到装置的通道内。在这类情况下,流体通过管径大致相同的通道,且流速大致相同。所以,如果微型流体装置从注入点的通道路程不同,流体将最先到达位于最短通道末端的储库。如果有施加的压力或液压,这些储库会在流体到达其它储库之前开始充液。结果造成不同样品库中不同的液位,继而造成各样品稀释度的不同,由此影响对各样品进行定量比较的能力。通道的距离相等就可解决这个问题,因为流体以相同的速度和时间到达并充满各个储库。
通道距离相等,除了可解决稀释问题外,还会使各个样品从其储库到注入点的时间即加样时间相等。这有好几个优点。首先,每一样品经过相同时间传送到相同环境,结果传送时间的效应相同。例如,在核酸分析中,嵌入染料常与运行缓冲液在装置的通道内混合,此时该染料就被在这些通道中传送(即从样品源到分析通道的传送过程中)的核酸所吸取。传送时间不同会造成染料被吸取量的不同,结果不同样品的最后信号强度不同。此外,进样时间相同的优点还在于使系统的操作者能够将各种样品进样或预加样所需的时间标准化。具体地说,每份样品进样或预加样需要相同的时间,就极大地改善了微型流体装置的操作。
通过采用其它通道的形状或结构也可以达到使得各样品源与注入点等距的优点,因为此时给定流体(例如样品)去向或来自一样品源的传送时间与其去向或来自另一样品源的传送时间相同。例如,如果样品源不等距,可以通过改变通道宽度来使得去向或来自两个不同样品源的流体传送速度相同。具体地说,靠近注入点或预加样点的样品源可以通过较宽的通道与注入点或预加样点连通,这样,在类似或完全相同的物质传送条件下(例如相同的电场),样品从其源通过该通道流向注入点或预加样点所需的时间与通过较长较细通道连通的样品源所需的时间基本相同。类似的,根据本文的详细说明,这样的通道改变还可以用于均衡流体通过一共同通道引入各自样品源所需的时间,例如在给装置加入缓冲液等时。
“基本相同的时间”是指,对于任意其它样品源或储库而言,样品从其来源流至装置的注入点或预加样点的时间在相同的传送条件下(例如在电动力传送中施加的压力和电场相同)相差不超过25%,不超过15%为佳,不超过10%更好,不超过5%则还要好。最好的是,样品从各自样品源流至注入点或预加样点的时间彼此相差在约2%之内。
除了保证装置内各种样品的传送时间相同之外,一般还要求缩短样品为到达注入点而必须经过的共同通道(例如进样通道)的长度。具体地说,缩短进样通道从其与样品通道交叉口至其与预加样/退液通道交叉口之间的长度,就减少了最后注入的物质的交叉污染的机会。具体地说,在下一份样品实际注入交叉口之前,缩短的进样通道更可能被完全充满。这样,本发明至少包括这样一种情况,样品通道与进样通道的交叉口距进样通道与加样/退液通道的交叉口很近,例如在约5mm之内,4mm之内为佳,约2mm之内更好,通常约1mm之内,这样进样通道在其与样品通道的交叉口和其与注入交叉口或预加样交叉口之间的长度少于约5mm,少于4mm为佳,少于约2mm则更好。
如前所述,样品注入主分析通道的过程通常包括将样品传送穿过进样通道与分析通道的交叉口。所以,较好的是,本发明的装置或系统一般包括加样/退液库和与进样通道连通但位于与分析通道进样侧相对另一侧的通道。给位于分析通道两侧的所需样品库和加样/退液库之间加上电压,就使得物质沿进样通道并穿过进样通道与分析通道的交叉口(又称注入点)进入加样/退液通道和储库。
由于本发明的装置和系统以让各种样品位于分析通道的两侧为佳,所以这类装置通常还包括分析通道两侧的一个加样/退液库和与进样通道连通的相应通道。具体地说,分析通道一侧的预加样室是分析通道另一侧的加样/退液库。这一结构特征可参见图1。
图1A简明地展示了微型流体装置(未示出)内两个通道(例如主分析通道100与进样通道102)的一个交叉口。进样通道还包括第一和第二样品引入通道,分别为104和106,它们与进样通道位于交叉口108两侧的段分别连通,这两个样品引入通道还与第一样品源110和第二样品源112连通,这些样品源例如是位于装置内的样品库。进样通道位于交叉口两侧的段除了与第一和第二样品引入通道连接外还与第一和第二加样/退液通道114和116分别连通,后两者又与第一和第二加样/退液库118和120连通。
图1B显示从第一和第二样品库顺次注入样品。具体地说,图1B中的分图1和II显示的是第一样品(用斜线阴影表示)被传送进入进样通道102,穿过进样通道与主通道100的交叉口,进入第二加样/退液通道116。在电引导系统(例如本发明中一般所述的E/O流即电泳传输系统)中,这个传送过程是通过在第一样品库110和第二加样/退液库120之间加上电压令物质顺电流途径的运动实现的。然后,交叉口的那段样品注入到主通道100中,这是通过在交叉口108两侧的主通道的两个位置(即主通道100两端的缓冲液库和退液库)之间加电压实现的。在此注入过程中,可以去除样品库110和第二加样/退液库120之间的电压,例如,允许这些储库“漂送”。但是,通常,这两个库之间的电压仍是维持的,为了使得恰好是交叉口中的物质流入(例如引入)到主通道中,也是为了避免分析过程中样品可能扩散或渗到交叉口中。
如图1B的分图III和IV所示,将第二样品(用交叉线阴影表示)加入然后注入主通道100中,方法与第一样品相同,所不同的是,在加样过程中,电压加在第二样品库112和第一加样/退液库118之间。
除了可从分析通道两侧注入样品外,与没有这一特征的装置相比,在分析通道的两侧都设置了加样/退液库还允许当一个样品在分析通道内接受分析时,另一样品可以预先加入。
例如,在典型的平面基片式CE装置(其中分离通道和进样通道彼此交叉)中,样品加入分离通道的过程是将样品装在进样通道末端的库内,在进样通道上加上电压,直至样品电泳通过进样通道与分离通道的交叉口。通常,电压是通过设在给定通道末端的库(又称“港口”)内的电极施加的。然后,交叉口内的那段物质沿分离通道进行电泳,这是利用在分析或分离通道长度方向上施加电压实现的。为了避免干扰样品的分析或分离,即避免对电场进行干扰,必须等到分离结束才可加入后继样品。
但是这里所述的通道结构中,当第一样品正在分析通道中接受分析(例如电泳)时,后继样品可以传送到进样通道内靠近甚至毗邻注入点的位置。具体地说,在样品库以及与进样通道连通且与该样品库位于分析通道同一侧的加样/退液库之间施加电压,样品就从相应的样品库通过进样通道一段传送至加样/退液通道/库,此时不通过分析通道。而且,在这个后继样品的预加样进料过程中维持所加的电压,使得预加样点(例如加样/退液通道114和进样通道102的交叉口处)的电压基本上等于注入点108的电压,这个预加样过程的进行就不会影响分析通道内物质的传送,例如,在进样通道和分析通道之间不会产生横向电场。当某一通道的一端施加电压Va,其另一端施加电压Vb时要确定该通道内某个给定居中点的电压值Vi,可采用以下公式:
Vi=Rb+(Va-Vb)/(Ra+Rb)其中Ra是施加Va的点与其电压Vi的居中点之间的电阻,Rb是施加Vb的点与居中点之间的电阻。
在结束分析前一个样品后,只要将已在进样通道内的后一个样品传送通过进样通道和分析通道的交叉口,然后和前次一样,交叉口内的样品段被传送进入分析通道。
图1C显示的通道交叉结构与图1B的相同,但是该结构是用来当前一样品在主通道中接受分析时另一样品预先进样的。具体地说,分图I显示的是图1B第一样品进入后期的情况。在分析第一样品时,通过传送第二样品进入进样通道然后进入第二加样/退液通道,第二样品就送至进样通道内靠近注入点即交叉口108的位置。如分图II所示,第一样品分析(例如电泳分离等)完成后,将第二样品传送通过交叉口108再进入分析通道(分图III)。然后对全部要分析的若干样品重复上述过程。
图2显示,具有后续样品预加样结构的装置,与没有这种结构的装置相比,明显节省了时间。分图A简明地显示使用一般微型流体装置(即在分析通道两侧没有分开的加样/退液库)将多份样品添加注入分析通道所经历的时间过程。具体地说,加入任何给定样品都需要传送样品通过分析通道与进样通道的交叉口,然后将交叉口处的样品传送到分离通道内。在这类一般装置中,当一份给定样品接受分析时,没有其它样品加入,因为那样将会扰乱分析通道内的物流。所以,必须在一份样品完全分析完毕后才能加入后面的样品,结果在进样注入的时间线上,如箭头所示,样品的进样和分析在时间上是不重叠的。
图2的分图B显示了在本发明装置中连续分析各个样品的时间线,该装置中在含有要加入的样品的库的同侧还具有附加的加样/退液库。因此可以允许样品从其库进入进样通道(这又称为预加样),此时不与分析通道内的物流交叉,也不在其它方面影响该物流。因此,当一份样品正沿分析通道传送并接受分析时,后面的样品可以预先加入到进样通道内。如分图B所示,时间上的节省是很明显的,尤其是要分析许多份样品(例如8、10、12、16或更多)时。
为了减少预加入的样品和分析通道之间的死体积,通常要求加样/退液通道与进样通道相交的位点比较靠近进样通道和分析通道的交叉口。在本发明微型流体装置中,这两个交叉口的距离一般小于5mm,小于2mm为佳,小于1mm更好,通常小于0.5mm。
此外,对多样品库的装置来说,一般要求能将各样品预加样在进样通道内相同的位点。这样可以对预加样、加样和注入各样品的时间安排进行标准化和简化。而且,在预加样期间,对该样品可以进行许多其它操作,包括稀释、与底料或其它反应物混合等。因此,加样/退液通道与进样通道的相交的位点在全部的样品库和主通道之间是较好的。这样,较好的是,每个加样/退液通道与进样通道的相交位点是在:(1)进样通道和主通道的交叉口和(2)进样通道与各样品通道的交叉口之间。以下将更详细的说明样品的加样和预加样。
最后,除上述优点以外,设置多样品库且各样品库具有一根单独通道与注入点至少部分地连通,这还至少提供了另一个优点,尤其是用在CE用途中时。典型的CE系统通过同一通路(例如同一样品库或同一通道和路径)引入各样品。这一点经常造成例如核酸大分子或络合物或蛋白质等迁移极慢的物质在该路径内累积,这种累积可能造成分离通道或毛细管的堵塞。
就象本发明这样,为每一份待测样品设置隔开的引入通路,与不同样品通过同一路径引入不同,迁移缓慢的物质通常会滞留在样品源或与共用进样通道连接的那个通道内。这一影响在CE用途中尤其明显,CE在装置的不同通道内含有筛选基质或介质,该基质会强化大尺寸组分的差异迁移率。
在某些实施例中,本发明微型流体装置中还可以有较窄的通道,特别在装置的注入点处。具体地说,缩小至少在注入交叉口的尺寸可以大大减少注入分析通道的样品量,这样,测出的带更窄,而相邻带之间的分辨率更高。
分析通道较窄在利用激光荧光进行检测的系统中尤其有用。具体地说,将注入通道和分析通道的宽度减小至入射到分析通道检测部分上激光斑大小的约1倍至5倍,如前所述,可以提高分析通道内条带的分辨率,而不会显著改变装置的灵敏度。虽然进入分析通道和通过检测器的物质较少,但是检测器能够检测的物质所占的百分比较高。所以,较好的是,使用光斑为10微米的激光时,分析通道的宽度宜为约10至50微米,约20至40微米为佳,约30至35微米更佳。IV.
装置说明
改进了通道和储库几何结构的本发明装置实施例之一见图3所示:装置300是由一块平面基片302制成的,在其表面上制成许多通道。将第二层平面基片覆盖在第一块上形成许多储库,前者上分布了许多孔。然后,第二层基片与第一层基片结合。
如图所示,该装置包括一个主要的分离或分析通道304沿着基片的中部纵向沿伸。它开始于缓冲液库306并与其连通,终止于退液库308和310并通过通道312与它们连通。进样通道314与主通道304相交并连通。如图所示,该装置还具有许多样品库316到346,通过各自的样品通道348至378或通过中间样品通道都与进样通道314连通。另有加样/退液通道380和382,它们与进样通道314连通,分别位于进样通道与主通道304交叉口的两侧,且位于该交叉口及交叉口各侧相应样品通道之间。这两个加样/退液通道都分别终止于加样/退液库384和386。
多个隔开的样品库分布在主通道两侧,这是为了在基片上设置尽可能多的储库,同时样品到达分析通道的必经路程尽可能短。
为了调控和引导装置内物质的电泳移动,有一个电极与各储库306-310、316-346、348和386都有电气连接。同样,虽然本实施例是以装置内物质的电泳传送和引导来说明的,但显然,其它形式的物质传送和引导也是可以的,例如电渗流体传送和引导、压力或气动的流体传送系统、包括使用微型泵或其它位移驱动系统的,同样都能受益于本发明。
运行中,第一样品位于样品库例如316中。在样品库316和退液库386间电压的作用下,样品沿样品通道348传送至进样通道314,穿过进样通道314与主通道304的交叉口。较好的是,在缓冲液库306和退液库308和310间也加上电压,提供一段来自主通道的限制流,对流过交叉口的样品进行“收聚”,避免交叉口内样品的泄漏和扩散。有关节制进样的详情可参见Ramsey等的PCT申请No.WO96/04547,将其参考结合在本发明中。
进样通道314和主通道304交叉口处的样品段例如收聚流段,在缓冲液库306和退液库308及310之间的电压作用下沿主通道304传送,此时储库316和386则让其“漂送”。有时,可以在这些漂送库上施加适当的电压使得进样通道的样品离开交叉口,以避免样品渗进分析通道。
当第一样品沿主通道304传送并接受分析(例如电泳分离)时,第二样品可以预加样在进样通道314内待作分析。在样品库318和加样/退液库384上加一个合适的电压,后继样品就从样品库318进入进样通道314并通过加样/退液通道380后到达加样/退液库384。如前所述,通常维持加在这些储库上的电压使得注入点(通道304与314的交叉口)的电压基本上等于预加样点(通道314与382的交叉口)的电压,为的是在预加样时避免在进样通道和主通道之间产生横向电场,即横向电压梯度。
第一样品沿主分析通道304流动后,在样品库318和加样/退液库386之间施加电压,进样通道314内的预先加入的样品就流过进样通道314与主通道304的交叉口。再在主通道304上施加合适电压使交叉口处的样品段沿主通道传送,此时如前所述尺寸第三样品预加料。对主通道两侧的各样品库都重复上述过程。如图所示,主通道的两则各有一个隔开的“预加样组件”,它包括一组与进样通道连通的样品库和通道。这两个预加样组件各具有与进样通道连通的自己的加样/退液库和通道,通过它们,样品可以从各自储库流入进样通道到达其中靠近其与主通道交叉口的某个位置,此时不会影响主通道内物质的运动。如前所述,为了尽可能减小样品预加样和注入之间的死体积,预加样组件的加样/退液通道(例如加样/退液通道380)与其进样通道(例如314)的相交位置应靠近进样通道与主通道的交叉口。
图4显示了装置的一种类似的通道/储库几何结构,它具有12个分开的样品库,也具有上述预加样结构特征。为了使几何结构更紧凑,在装置的底部,缓冲液库306、退液库310和加样/退液库384及386排成一列。由此形成样品/退液/缓冲液库的网格阵列,这样,这个12个样品的装置所占基片面积仅为图3中的大约一半。虽然这一装置的样品库少于前述的图3装置,但是通过优化通道和储库的几何结构,样品数对于面积的比例显著提高。具体地说,如果图4装置的边长为17.5mm(例如17.5mm×17.5mm),从一张5英寸×5英寸的正方形基片可获得49个装置,即每个基片可进行588份样品的分析。假设图3装置尺寸为22.4mm×37mm,每个基片仅可制得15个装置,仅可进行240份样品的分析。
如前所述,本发明的装置、系统和方法不局限于毛细管电泳,可以广泛应用于采用许多种不同物质传送机制的整个微型流体领域,包括例如电渗运送系统、电泳运送系统,甚至压力驱动系统。但是,如果这类装置、系统和方法应用于毛细管电泳,即用于分离核酸片段之类的样品组分时,一般要求降低装置通道内的电渗流的量,从而优化系统内电荷或大小不同的组分的迁移度差异,继而优化它们的可分离度。
所以,如果本发明的装置和系统应用于毛细管电泳,宜先用动力筛选基质预先处理装置的通道。这类动力筛选基质一般包含带电聚合物,例如线性聚丙烯酰胺,它们能够与毛细管壁结合,由此屏蔽管壁的带电表面,减小电渗流。特别适用的动力筛选基质包括美国专利5,264,101(参考结合于此)中的那些动力筛选基质以及Perkin Elmer Corp的GeneScanTM筛选缓冲液。
图5是采用本发明另一种通道几何结构的装置。如图所示,该装置的通道几何结构与图4的类似。具体地说,如图所示,微型流体装置500由基片502制成,基片上具有主通道504,在其末端是缓冲液库506和退液库508。主通道504分别在左侧和右侧与进样通道512及514的第一末端相交连通。样品通道512的第二末端分别通过样品通道542至550与样品库516至526连通,但进样通道514的第二末端分别通过样品通道552至562与样品库528至538连通。样品预加样/退液通道582及584分别在注入点或交叉口附近与进样通道512及514相交。
该装置的运行与图3和图4装置基本相同。但是,如同所示,装置500的样品通道540至562从各自储库至样品通道与各自进样通道(512或514)相交点的长度基本相等。该装置显示了前文所概括的全部优点。
而且,在图5的另一方面内容中,为了尽可能缩短进样通道的长度来避免预加样期间样品交叉污染的可能性,进样通道512及514与各自样品/预加样通道582及584的交叉口被安排在这些通道与各自样品通道例如540至500及552至562交叉口的附近。较好的是,这些交叉口之间的进样通道长度小于约5mm,小于约2mm为佳。
如上所述,本发明装置可广泛用于化学和生物化学物质的分析。例如,本发明至少有一方面内容提供了这类装置和系统在分离核酸、蛋白质、或其它大分子物质以及电荷差异物质的组分时的用途。本发明装置有时以成套盒的形式提供。本发明成套盒可以包含以下组件之一或多种:(1)前文所述的装置或装置部件,例如前文所述的微型流体装置;(2)进行所述方法和/或操作所述装置或装置部件的说明书;(3)一种或多种试验物质,例如反应试剂、荧光染料、标准物质、筛选基质等;(4)装有装置或试验物质的容器;(5)包装材料。
上述微型流体装置通常装在电气调节器单元内,在装置的每个储库内都设有电极如前所述地进行装置的运作。调节器单元通过与装置内储库接触的电极传递合适的电流,为的是引导物质经过装置的通道流动。调节器传递的电流通常是每个电极适用的,使用者将每个电极的电流时间曲线输入与调节器连接的电脑。然后,电脑指令调节器向不同的电极发送电流令物质在装置的通道中以受控方式运行,例如提供足够的电流进行前述的物质电动传送。
以下将结合实施例更详细的说明本发明。
实施例 实施例1:多样品分析
一可容16份样品的装置,称LabChipTM,其几何结构如图3所示,由直径100mm厚500微米的白冕玻璃基片制成。使用的基片可与市售最常见的平板照相装置配合使用。利用标准平板照相技术在玻璃基片上蚀刻出所示构型的75微米宽、12微米深的通道。在另一片每边长5英寸的玻璃基片上穿孔,孔对应各个通道的末端。将两片基片热结合形成所示的通道和库结构。从这块大的材料上切下22.4mm×37mm大小的装置。
制备筛选缓冲液:称取2.5g GeneScan Polymer(Perkin Elmer Corp.),0.5g基因分析缓冲液(Perkin Elmer Corp.)和2.5ml水,装入20ml的闪烁瓶,该瓶离心30秒。每0.5ml筛选缓冲液添加1μl Syber Green 1 DNA嵌入染料(Molecular ProbeInc.),再在1.5ml的Eppendorf管中离心30秒。含大小从50至1000bp的6个DNA片段的5μl PCR标志物(Promega Corp.)与含Syber Green的15μl缓冲液混合并离心。
在LabChipTM的通道内充以3.5%的GeneScanTM缓冲液(Perkin Elmer Corp.):在缓冲液库内加入55μl筛分缓冲液,用注射筒给该库施加少许压力。该缓冲液含有的聚合物按其大小能阻碍DNA的迁移,而且对通道壁有修饰作用,能减小电渗流。然后在缓冲液库和退液库内添加4μl GeneScanTM缓冲液。
将DNA标准物质,用HinfI(Promega Corp.)剪切的PhiX174,在含有1μM SyberGreen 1 DNA嵌入染料(Molecular Probe Inc.)的3.5%GeneScanTM缓冲液中进行50∶1的稀释,取4μl该溶液加入16个样品库的每个库内。然后,将装置放在Nikon反转显微镜Diaphot 200下,配以PTI型814PMT检测系统,进行荧光闪烁检测。光源是配以40X显微镜物镜的OptiQuip 1200-1500 50W钨/卤灯。用配有合适滤光镜/二色镜的滤光管(Chroma,Brattleboro VT)选择激发波长和发射波长。基片上反应物库的电流和电压由一调压器来调节,该调压器对在微型流体装置的每个单独储库都各有一个可调电极。样品的连续注入遵循以下循环:
步骤1:最初的样品预加样(45秒)
步骤2:加样(5秒)
步骤3:注入(1秒)
步骤4:后抽(2秒)
步骤5:进行分析/下一样品的预加样(85秒)
步骤6:下一样品的加样(5秒)
步骤7:重复步骤3-6
以下表提供了在一个循环内加在各储库上电流的例子。插入一个后抽步骤是为了将样品抽离进样通道和主通道的交叉口,从而避免样品的渗漏。而且,在加样步骤例如步骤2和6,向交叉口施加一收聚,使得样品流不会因对流效应扩散到主通道内。用基于电流的控制系统来调节施加的电压,如用参考结合于此的普通转让的1996年7月3日提交的美国专利申请08/678,436所述。上述各步骤中使用的电流见表1。调节加在主缓冲液库306上的电压,使其能为系统的其余部分提供合适的平衡电流。
表1步骤 样品库 样品电流(μA) 加样/退液室 加样/退液电流(μA) 缓冲液室 退液电流(μA)1 332 -7 386 10 310 -22 332 -7 384 10 310 -23 332 5 384 5 308 -124 334 1 384 1 308 -85 334 -7 386 10 308 -7.56 334 -7 384 10 310 -2
用该方法进行最初分离的结果见图6。显然,利用毛细管电泳的该方法在明显缩短时间的同时得到了较高的分辨率。而且,在分离16份样品的全过程中,没有发生分辨率的降低。实施例2:连续样品交叉污染的检测
为了确定装置内的连续运行是否发生样品的交叉污染,连续试验了两份不同的核酸片段样品和一份纯缓冲液样品,并检测污染结果。
上述16库装置中的每一个库都加入PCR标志物、HAEIII剪切的PhiX174或纯缓冲液。根据各库的相继注人顺序来加样。记录每次运行的荧光数据随时间的变化。
图7A、7B和7C是相继注入PCR标志物、PhiX174/HAEIII和缓冲液空白的图。图7B显示,没有测到表明由前面的PCR标志物试验渗到PhiX174/HAEIII试验中的异常荧光峰。另外,图7C显示,即使在纯缓冲液试验中也未测到来自前面含DNA样品的交叉污染。实施例3:窄通道注入
如实施例1所述制备一微型流体装置,其通道的几何结构如图5所示,所不同的是,装置内所有通道的宽度都减小至30微米,而通道深度仍保持为约12微米。用它来与实施例1中几何结构如图4所示但通道宽度约70微米的微型流体装置比较。两装置内分离通道的长度基本相等。
如前所述,准备两装置时都用筛选缓冲液,且都用来分离购自Promega Corp.,Madison WI的核酸的标准100碱基对序列梯。窄通道和宽通道装置内的分离结果分别见图8A和8B。显然,窄通道装置得到的分辨率(图8A)高于宽通道装置的(图8B)。
本说明书中具体并单独指明了某些出版物或专利申请参考结合于此,但所有出版物和专利申请都也相同程度地参考结合于此。虽然,为了清楚和便于理解,通过叙述和实施例对本发明进行了详细的说明,但显然,在所附的权利要求范围内是可以进行某些改变和修正的。
Claims (47)
1.一种微型流体装置,它包括:
具有内部和外部的体结构;
分布在内部的至少第一、第二和第三微细通道,第二通道与第一通道相交于第一交叉口,第三通道与第一通道相交于第二交叉口;
分布在体结构内的多个样品库,各库均与第二通道连接;
至少一个连接于第三通道的第一退液库;
至少一个连接于第三通道的样品库和至少一个连接于第二通道的第二退液库;
其中的第一退液库在至少一个样品库和第一交叉口之间与第三通道连接;
第一退液库通过第一加样/退液通道连接于第三通道,第一加样/退液通道与第三通道相交于第三交叉口,第三交叉口位于至少一个样品库和第二交叉口之间;
第二退液库通过第二加样/退液通道连接于第二通道,第二加样/退液通道与第二通道相交于第四交叉口,第四交叉口位于多个样品库和第一交叉口之间。
2.根据权利要求1所述的微型流体装置,其中第二和第三通道在第一通道的两侧与第一通道相交。
3.根据权利要求2所述的微型流体装置,其中的第一和第二交叉口位于第一通道上的同一点。
4.根据权利要求3所述的微型流体装置,其中的第二与第三通道共线。
5.根据权利要求1所述的微型流体装置,其中第三和第四交叉口与第二和第一交叉口分别相距不超过5mm。
6.根据权利要求1所述的微型流体装置,其中第三和第四交叉口与第二和第一交叉口分别相距不超过2mm。
7.根据权利要求1所述的微型流体装置,其中的体结构包括:
具有至少第一平表面的第一平面基片;
至少分布在第一平表面上的许多槽,这些槽对应于至少第一、第二和第三通道;
具有第一平表面的第二基片,第二基片的第一平表面与第一基片的第一平表面匹配,覆盖在槽上密封形成第一、第二和第三通道,这些通道构成内部;
分布在第一和第二基片至少其一上的多个孔,这些孔与第一、第二和第三通道连通,界定出多个样品库和至少第一退液库。
8.根据权利要求7所述的微型流体装置,其中第一和第二平面基片中至少其一是二氧化硅型基片。
9.根据权利要求8所述的微型流体装置,其中的二氧化硅型基片选自玻璃、石英和熔凝二氧化硅。
10.根据权利要求8所述的微型流体装置,其中的二氧化硅型基片是玻璃。
11.根据权利要求1所述的微型流体装置,其中第一和第二平面基片中至少其一是聚合材料。
12.根据权利要求11所述的微型流体装置,其中的聚合材料选自聚二甲基硅氧烷、聚甲基丙烯酸甲酯、聚氨基甲酯、聚氯乙烯、聚苯乙烯、聚砜、聚碳酸酯、聚甲基戊烯、聚丙烯、聚乙烯、聚偏氟乙烯和丙烯腈-丁二烯-苯乙烯的共聚物。
13.根据权利要求11所述的微型流体装置,其中的聚合材料是聚甲基丙烯酸甲酯。
14.根据权利要求1所述的微型流体装置,其中的多个样品库至少有2个。
15.根据权利要求1所述的微型流体装置,其中的多个样品库至少有4个。
16.根据权利要求1所述的微型流体装置,其中的多个样品库至少有8个。
17.根据权利要求1所述的微型流体装置,其中的多个样品库至少有12个。
18.根据权利要求1所述的微型流体装置,其中的多个样品库在体结构内是线性排列,并间隔均匀的。
19.根据权利要求18所述的微型流体装置,其中间隔均匀的样品库之间的中心距约9mm。
20.根据权利要求18所述的微型流体装置,其中间隔均匀的样品库之间的中心距约4.5mm。
21.根据权利要求18所述的微型流体装置,其中间隔均匀的样品库之间间的中心距约2.25mm。
22.根据权利要求1所述的微型流体装置,其中多个样品库排列成网格状,而且间隔均匀。
23.根据权利要求22所述的微型流体装置,其中间隔均匀的样品库之间的中心距约9mm。
24.根据权利要求22所述的微型流体装置,其中间隔均匀的样品库之间的中心距约4.5mm。
25.据权利要求22所述的微型流体装置,其中间隔均匀的样品库之间的中心距约2.25mm。
26.根据权利要求1所述的微型流体装置,其中多个样品库中每一个都通过相互隔开的样品通道连接于第二通道,这些样品通道与各样品库分别连通并与第二通道相交。
27.根据权利要求26所述的微型流体装置,其中样品通道连通于多个样品库中的每一个,且与第二通道相交于一共同交叉口。
28.根据权利要求27所述的微型流体装置,其中的共同交叉口距第一交叉口约5mm之内。
29.根据权利要求27所述的微型流体装置,其中的共同交叉口距第一交叉口约2mm之内。
30.根据权利要求27所述的微型流体装置,其中各样品通道长度大致相等。
31.根据权利要求1所述的微型流体装置,其中至少第一通道内包含分离介质。
32.根据权利要求1所述的微型流体装置,其中的分离介质是一种筛选基质。
33.根据权利要求32所述的微型流体装置,其中的筛选基质是聚丙烯酰胺。
34.根据权利要求1所述的微型流体装置,其样品库内还有样品,样品是核酸。
35.根据权利要求1所述的微型流体装置,其中的第一和第二交叉口位于第一通道上的一共同位点。
36.根据权利要求1所述的微型流体装置,其中第一和第二进样通道共线。
37.一种分析多份样品的方法,它包括:
a)提供一种微型流体装置,它包括具有内部和外部的体结构;
分布在内部的至少第一、第二和第三微细通道,第二通道与第一通道相交于第一交叉口,第三通道与第一通道相交于第二交叉口;
分布在体结构内的多个样品库,各库均与第二通道连接;
至少一个连接于第三通道的第一退液库;
至少第四通道,它通过加样/退液通道在第三交叉口将第二退液库与第二通道连接,第三交叉口在第二通道上,介于多样品库和第一交叉口之间;
b)运送样品从所述多样品库中的第一库经过第二通道,经过第一和第二交叉口,进入第三通道,流向第一退液库,其中,运送样品自第一样品库至第一交叉口的步骤包括预先运送样品经过第二通道至第三交叉口,然后进入第四通道,流向第二退液库;
c)将第一交叉口的该部分样品注入第一通道;
d)沿第一通道运送该部分第一样品;和
e)在分析通道内分析该部分第一样品。
38.根据权利要求37所述的方法,还包括对于来自多样品库中每一库的样品重复步骤b)至e)。
39.根据权利要求37所述的方法,其中运送样品自第一样品库至第一交叉口的步骤包括运送第三交叉口处的物质经过第二通道进入第一交叉口。
40.根据权利要求37所述的方法,其中自样品库送出样品的步骤包括利用电动力使样品自样品库向第一交叉口运动。
41.根据权利要求40所述的方法,其中电动力使样品运动的步骤包括在样品库和第一退液库之间施加一电压梯度来使样品流经第一和第二交叉口,进入第三通道,流向第一退液库。
42.根据权利要求40所述的方法,其中:
提供的微型流体装置中,第一和第二交叉口都位于第一通道上的一共同位点;
还包括利用电动力收聚第一和第二交叉口内的第一样品。
43..根据权利要求37所述的方法,其中运送样品经过第一通道的步骤还包括利用电动力运送第二和第三通道内的样品分别离开第一和第二交叉口。
44.根据权利要求37所述的方法,所述的分析包括分离和检测样品中的组分。
45.根据权利要求44所述的方法,其中还包括至少在第一通道内提供分离介质。
46.根据权利要求37所述的方法,其中的样品组分包括核酸。
47.根据权利要求37所述的方法,其中的样品组分包括蛋白质。
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US08/845,754 US5976336A (en) | 1997-04-25 | 1997-04-25 | Microfluidic devices incorporating improved channel geometries |
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Also Published As
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AU7115498A (en) | 1998-11-24 |
EP0988529A4 (en) | 2001-02-07 |
US6068752A (en) | 2000-05-30 |
US6235175B1 (en) | 2001-05-22 |
WO1998049548A1 (en) | 1998-11-05 |
CA2287409A1 (en) | 1998-11-05 |
JP2001523341A (ja) | 2001-11-20 |
AU727083B2 (en) | 2000-11-30 |
KR20010012108A (ko) | 2001-02-15 |
CA2287409C (en) | 2003-06-03 |
CN1253625A (zh) | 2000-05-17 |
JP4171075B2 (ja) | 2008-10-22 |
EP0988529A1 (en) | 2000-03-29 |
US6153073A (en) | 2000-11-28 |
KR100351531B1 (ko) | 2002-09-11 |
EP0988529B1 (en) | 2013-06-12 |
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