CN104251875A - 用于控制流控回路中的流体流的方法和流控装置 - Google Patents

用于控制流控回路中的流体流的方法和流控装置 Download PDF

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CN104251875A
CN104251875A CN201410406758.5A CN201410406758A CN104251875A CN 104251875 A CN104251875 A CN 104251875A CN 201410406758 A CN201410406758 A CN 201410406758A CN 104251875 A CN104251875 A CN 104251875A
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fluid
flow control
passage
flow
node
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CN104251875B (zh
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乔纳森·舒尔茨
大卫·马兰
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Life Technologies Inc
Ion Torrent Systems Inc
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Abstract

本发明涉及用于控制流控回路中的流体流的方法和流控装置。提供了被动流控回路，用于引导不同的流体进入共同容积，而没有相互混合或交叉污染。穿过流控回路的连接点、结点和通道的流动方向和速率，由上游阀门的状态(例如打开或关闭)、在回路入口或上游蓄池处的液压差、流动通道阻力等控制。流体从未选择的入口向共同出口或在连接点或结点处的其它入口的自由扩散或渗漏，由选择的入口流体的流动来防止，所述入口流体的一部分扫过未选择的流体的入口，并从废物口离开流控回路，由此建立对抗因渗漏或扩散导致的与出口流的不希望的相互混合的屏障。在用于执行灵敏的多步骤反应、诸如基于pH的DNA测序反应的装置中，本发明是特别有利的。

Description

用于控制流控回路中的流体流的方法和流控装置
本申请是国际申请日为2010年5月27日、国际申请号为PCT/US2010/001547、国家申请号为201080027723.0、发明名称为“用于顺序递送试剂的流控系统”的专利申请的分案申请。
技术领域
本申请涉及用于控制流控回路中的流体流的方法和流控装置。
背景技术
许多用途要求以使不同流体的相互混合或交叉感染最小化的方式调节多个流体流。这样的用途包括多步骤的合成过程或分析过程，所述过程以共同的容积进行，并包括连续试剂递送循环，其中使用来自分开的蓄池的流体，例如Margulies等人,Nature,437:376-380(2005)；Merrifield等人,美国专利3,531,258；Caruthers等人,美国专利5,132,418；Rothberg等人,美国专利公开2009/0127589；等。尽管流控系统可用于选择性地转换多个试剂溶液至共同的室中进行处理，但是它们具有几个缺陷，所述缺陷包括但不限于：存在大的表面积(其可以吸附或保留试剂)、大的物理尺寸(使它难以与小型化的流控组件一起使用，例如参见Rothberg等人(上面引用的))、可接近性低的表面(包括边缘和/或角落，使彻底清除和去除连续的试剂困难或无效)、和使用活动部件(其可以磨损并导致更高的生产和装配成本)，例如Hunkapiller,美国专利4,558,845；Wittmann-Liebold等人,美国专利4,008；736；Farnsworth等人,美国专利5,082,788；Garwood等人,美国专利5,313,984；等。
考虑到上述方面，有利的是，具有克服了现有方案的缺陷的可利用的装置，所述装置用于调节多个流体流至共同的容积中进行复杂的合成过程或分析过程。
发明内容
本发明涉及用于将多个流体递送至共同容积的装置和方法，例如，通向反应室或流动池的通道或导管。本发明还包括这样的装置和方法在多步骤分析过程或合成过程中的应用。在许多实现和用途中例证了本发明，其中的一些总结在下面和在本说明书中。
在一个方面，本发明提供了一种被动流控回路，其用于顺序地引导不同的流体进入共同容积，诸如反应室或流动池，而没有相互混合或交叉污染。本文使用的这样的顺序引导有时称作“多路传送(multiplexing)”多个流体流。穿过流控回路的连接点、结点和通道的流动方向和速率，由上游阀门的状态(例如打开或关闭)、在回路入口或上游蓄池处的液压差、流动通道阻力等控制。流体从未选择的入口向共同出口或在连接点或结点处的其它入口的自由扩散或渗漏，由选择的入口流体的流动来防止，所述入口流体的一部分扫过未选择的流体的入口，并从废物口离开流控回路，由此建立对抗因渗漏或扩散导致的与出口流的不希望的相互混合的屏障。在一个方面，选择的流体入口会提供穿过流控结点的流体层流。
在另一个方面，本发明提供了用于控制多个流体流的流控回路，所述流控回路包括：(a)具有出口和多个流体入口的流控结点；和(b)通过一个或多个各自具有流体阻力的通道与该流控结点流体连通的至少一个废物口，选择所述通道的流体阻力，使得无论何时流体仅流动穿过单个流体入口，以形成在流控结点中的流，这样的流体的一部分穿过出口离开流控结点，且这样的流体的剩余部分穿过所述一个或多个通道离开流控结点，使得从没有流体流的入口(即“未选择的入口”)进入流控结点的任何流体穿过所述一个或多个通道被引导至一个或多个废物口。在一个实施方案中，控制所述多个流体流，以提供流体流穿过流控结点出口的预定顺序。在另一个实施方案中，这样的控制由阀门和施加于流控回路上游的流体流的压差来实现。
在另一个方面，本发明提供了没有活动部件的流控回路，其在无相互混合的情况下顺序引导多个流体进入共同容积。由于该流控回路仅包括结点和多个互联的通道，其中流体运动由位于远处的阀门、泵来控制，它通过常规微流控技术可以容易地小型化，以用于尺寸和质量是关键因素的场合。此外，使用流控回路进行流体转换，而不使用不可透过的屏障，使得该回路可理想地用于需要稳定的参比电势的过程中，诸如电化学过程中。
在另一个方面，本发明提供了一种用于控制流控回路中的流体流的方法，所述流控回路包括分别经由第一通道和第二通道而与结点流体连通的第一流体入口和第二流体入口、与所述结点流体连通的流体出口以及经由所述第一通道和所述第二通道而与所述结点流体连通的至少一个废物口，所述方法包括：使第一流体经由所述第一流体入口流入所述流控回路中，所述第一流体的第一部分流动经过所述第一通道、经过所述结点然后经过所述流体出口，所述第一流体的第二部分流动经过所述第一通道、经过所述结点，经由所述第二通道而穿过所述第二流体入口然后进入所述至少一个废物口，并且所述第一流体的第三部分流动至所述至少一个废物口而没有穿过所述结点。
在另一方面中，提供了一种流控装置，包括：具有流体出口的结点；多个流体入口，所述多个流体入口中的每个流体入口与多个试剂中的各个试剂唯一地关联；至少一个废物口；多个通道，所述多个通道中的每个通道在所述结点与所述至少一个废物口之间提供不同的流体路径，所述多个通道中的每个通道包括至各个入口通道的连接点，所述各个入口通道在所述每个通道与所述多个流体入口中的各个流体入口之间提供流体连通；通过所述流体出口与所述结点流体连通的出口通道；以及与所述出口通道流体连通的洗涤流体入口。
附图说明
图1A是本发明的一个实施方案的图解，其具有在流控结点的相对表面上的入口和出口。
图1B-1D图解了本发明的一个实施方案中的投入、试剂流、和洗涤步骤。
图2图解了本发明的另一个实施方案，其中单个有阻力的通道连接废物口和多个入口。
图3A-3C图解了本发明的另一个实施方案，其中多个入口中的每一个通过平面网络通道连接至中央流控结点和废物口。
图4A-4B图解了另一个具有平面结构的实施方案，所述平面结构可以通过叠堆经由它们的流控结点和废物通道相连的类似单元来重复，由此实现更多的入口流体的调节。
图5图解了本发明的流控回路可以如何为多步骤的电化学过程提供稳定的参比电极。
图6是使用本发明的流控系统的一个示例性装置的示意图。
图7图解了一个在双流动室流动池中提供单独的洗涤控制的实施方案，其提供了在参比电极和流动池的两个室之间的不间断流体通道。
具体实施方式
除非另有说明，本发明的实践可以采用机械工程学、电子学、流体力学和材料科学的常规技术和描述，它们是在本领域的技能范围内。这样的常规技术包括、但不限于：设计和制造流控装置和微流控装置等。通过参照下文的实施例，可以获得合适的技术的具体例证。但是，当然也可以使用其它等效的常规方法。
本发明提供了使用流控回路快速地且清洁地转换不同流体向共同出口的流动的方法和装置。在一个方面，本发明的流控回路与流体蓄池、阀门、压力源、泵、控制系统、和/或相似组件相组合，以形成流控系统，其用于递送具有预定的速率和持续时间的分开的流体流至共同容积，所述共同容积诸如出口、室、流动池等。这样的流控回路特别适用于进行多步骤的化学的、酶的、或电化学的过程的装置中的流控系统，参见例如：Margulies等人,Nature,437:376-380(2005)；Merrifield等人,美国专利3,531,258；Brenner等人,Nature Biotechnology,18:630-634(2000)；Ronaghi等人,Science,281:363-365(1998)；Caruthers等人,美国专利5,132,418；Namsaraev等人,美国专利公开2005/0100939；Rothberg等人,美国专利公开2009/0127589；等。
在一个方面，本发明的流控回路提供了一个连接点，在这里选择的流体流被分成至少2个分支：一个分支被引导至出口，并从那里流至流动池或反应室备用，另一个分支被引导经过未选择的流体入口，并从那里离开出口，流至废物口。在一个实施方案中，如下建立这样的流：平衡流体出口的流体阻力和在流体入口与废物口之间的一个或多个通道的流体阻力。优选地，选择通道、室和结点的流速、流体粘度、组成、和几何形状和大小，使得流控回路内的流体流是层流。关于进行这样的设计选择的指导可以从下述途径容易地得到：常规的流体动力学论文(例如Acheson,Elementary Fluid Dynamics(Clarendon Press,1990))，和免费的或可商业得到的对流控系统建模的软件，所述软件例如来自Dassault Systems(Concord,MA)的SolidWorks、来自FlowMaster USA,Inc.(Glenview,IL)的Flowmaster和OpenFOAM(在环球网www.opencfd.co.uk上可得到用于计算流体动力学的开放源代码)。本发明的流控回路和装置特别适用于中规模和微规模流控系统，例如，这样的流控系统：其具有在几十平方微米至几平方毫米范围内的通道横截面，或具有在几nL/秒至几百μL/秒范围内的流速。由本发明的流控回路控制的流体流的数目可以宽泛地变化。在一个方面，本发明的流控回路控制在2至12个不同流体范围内的多个流，或者在另一个方面，在2至6个不同流体的范围内。
流控回路
在图1A中部分地图解了本发明的一个实施方案的设计和工作。4个流体入口或试剂入口(100、102、104、106)连接至流控结点(108)，与出口(110)流体连通，并在出口(110)相对的表面上。阀门(111)显示为打开，使得流体穿过入口(100)进入流控结点(108)。流体的一部分(124)穿过左边显示的通道流动，一部分(126)穿过右边显示的通道流动，一部分穿过出口(110)离开流控结点。优选地，所述3个流体流是层流，且沿着含有流体入口的表面的流在远远小于来自未选择的入口的物质(扩散流出物(128))扩散至流控结点的相对表面所需的时间的时间段内离开流控结点。以此方式，避免了穿过出口(110)离开的不同入口试剂的相互混合。在一个工作模式中，通过打开与这样的试剂相对应的阀门并关闭所有其它的阀门，选择试剂入口。如在该实施方案中例证的，阀门(111)是打开的，阀门(113、115、和117)是关闭的。在关闭状态，即使在未选择的入口中没有流动，未选择的流体的体积(例如，120)与选择的流体发生自由扩散接触。选择的流体分开的流向出口(110)的层流和经过未选择的入口并流向废物口的层流，会防止不希望的混合。图1B-1D进一步图解了上述实施方案的工作。如在图1A中一样，入口(100、102、104、和106)连接至在出口(110)的相对表面上的流控结点(108)，且通道(130和132)将流控结点(108)连接至废物口(134)。选择通道(130和132)的长度(136)和宽度(138)，以提供流体阻力，使得来自入口的流体流在穿过出口(110)离开该结点的流体和穿过通道(130和132)离开该结点的流体之间平衡。也图解了洗涤流体入口(140)，它连通至出口(110)，并与流控结点(110)流体连通。在一个称作“投入试剂”模式的工作模式中，洗液入口阀门(未显示)是打开的，且试剂入口(104)的阀门(未显示)是打开的。洗涤溶液流入出口(110)中，并流至应用场所，例如含有芯片的流动池(如在Rothberg等人(上面引用的)中所述)，和流至流控结点(108)，在这里它与来自入口(104)的流体相组合，并迫使后者流入废物口(134)。在该图中为下面更完整地描述的具体应用列出了示例性的流速和时间，但是一般而言，这样的流速和时间是取决于特定用途的设计选项。在另一个工作模式(在图1C中称作“流动试剂”模式)中，洗涤溶液流被关闭，从入口(104)进入唯一的流。该流被分成3个分支，2个分支流动穿过通道(130)和(132)，一个分支流动穿过出口(110)。在另一个工作模式(在图1D中称作“洗涤”模式)中，所有流体入口(100、102、104、106)的阀门都是关闭的，洗液入口(140)的阀门是打开的，使得仅洗涤溶液进入流控结点(108)中，穿过入口(100、102、104、106)，并穿过通道(130)和(132)离开。
图2用顶视图和侧视图图解了流控回路的另一个实施方案，其使用环形废物通道和有阻力的通道(分别是206和208)，以容纳比图1A-1D的实施方案更多数量的入口(200)。如上所述，多个入口(200)连接至在与出口(204)所连接的表面的相对表面上的流控结点(202)。来自入口的流体流在流控结点(202)中分开，使得一部分离开出口(204)，剩余部分离开环形通道(208)，选择它的宽度(210)和高度(212)，以提供用于适当地分开入口试剂流的流体阻力。在扫过未选择的入口并穿过有阻力的通道(208)以后，来自选择的入口的流进入废物环通道(206)，并被引导至废物口(214)。
图3A-3C图解了本发明的流控回路的另一个实施方案，其在平面回路结构中容纳5个入口试剂。图3A是含有流控回路(302)的透明主体或壳体(300)的顶视图。外壳(300)可以由多种材料构成，所述多种材料包括金属、玻璃、陶瓷、塑料等。透明的材料包括聚碳酸酯、聚甲基丙烯酸甲酯等。入口(或入孔)(304、306、308、310、和312)通过通道连接至它们各自的连接槽(314)，所述连接槽位于壳体(300)的底侧(显示为与入口同心的双环)，试剂从这里进入流控回路(302)。入口(304、306、308、310、和312)与通道(分别是305、307、309、311、和313)流体连通，所述通道又连接至曲线通道(分别是324、326、328、330、和332)。每个曲线通道由2条腿组成，诸如(336)和(338)，识别为在“T”连接点(335)处的曲线通道(324)，也识别为唯一曲线通道(324)。一条腿是内腿(例如(338))，其将它的各个入口连接至结点(或多用途中央口)(301)，另一条腿是外腿(例如(336))，其将它的各个入口连接至废物通道(或环)(340)。如上所述，可以选择曲线通道的内腿和外腿的横截面面积和长度，以在“T”连接点处和在结点(301)处实现希望的流平衡。穿过通道(344)，废物通道(或管道)(340)与废物口(345)流体连通，所述废物口(345)通过在主体(300)底侧上的连接槽(346)连接至废物蓄池(未显示)。结点(301)通过通道(361)与孔(360)流体连通，所述通道(361)在该实施方案中是在主体(300)的外部，且用虚线来图解。在其它实施方案中，通道(361)可以形成在主体(300)中，使得不需要结点(301)和孔(360)的连接槽。孔(360)通过通道(363)连接至洗涤溶液入口(362)，在这里形成“T”连接点，并连接至连接槽(364)，所述连接槽(364)又提供了通向流动池、反应室等的导管。图3B和3C图解了使用该流控回路来向流动池分配流体的3个模式中的2个。由与每个入口试剂和与洗涤溶液关联的阀门(350)，实现工作模式。在第一个工作模式(选择的试剂阀门是打开的，所有其它试剂阀门被关闭，洗涤溶液阀门被关闭)(图3B)中，选择的试剂被递送至流动池；在第二个工作模式(选择的试剂阀门是打开的，所有其它试剂阀门被关闭，洗涤溶液阀门是打开的)(图3C)中，启动流控回路来递送选择的试剂；在第三个工作模式(所有试剂阀门被关闭，洗涤溶液阀门是打开的)(未显示)中，洗涤流控回路中的所有通道。如上所述，阀门(350)与每个入口关联，所述阀门(350)可以被打开，以允许流体穿过它各自的入口(如关于阀门(352)所示的)进入流控回路(302)，或被关闭，以阻止流体进入回路(302)(如关于除了阀门(352)以外所有阀门所示的)。在每种情况下，当入口的阀门被打开时，其它入口的阀门被关闭(包括洗涤溶液阀门)，如在图3B中关于入口(370)所示，流体穿过通道(354)流至“T”连接点(356)，在这里它被分成2个流，其中的一个被引导至废物通道(340)、然后到达废物口(345)，其中的另一个被引导至结点(301)。从结点(301)，该第二个流再次分成多个流，其中的一个穿过通道(361)离开结点(301)，然后穿过通道(363)并到达流动池，其它流则流至连接结点(301)和其它入口的每个通道，然后流至废物通道(340)和废物口(345)。所述后面的流穿过其它入口，携带从这里扩散或泄漏的任何物质，并引导它至废物口(345)。通过打开选择的试剂的阀门，并同时关闭所有未选择的试剂和洗涤溶液的阀门，可以将一系列不同的试剂引导至流动池。在一个实施方案中，这样的顺序可以通过流控回路的工作模式序列来实现，诸如：洗涤，投入试剂x1，递送试剂x1，洗涤，投入试剂x2，递送试剂x2，洗涤，以此类推。试剂投入工作模式如图3C所示。像在试剂递送模式中一样，除了与选择的试剂相对应的阀门以外，所有试剂入口阀门都被关闭。但是，不同于试剂递送模式，洗涤溶液阀门是打开的，并选择选择的试剂流和洗涤溶液流的相对压力，使得洗涤溶液流动穿过通道(361)并进入结点(301)，然后它在这里穿过连通废物通道(340)的所有通道(除了连通选择的试剂入口的通道以外)离开。
图4A-4B图解了平面流控回路的另一个实施方案，其容纳4个入口试剂，且它的设计可以容纳其它入口试剂，这通过叠堆平面流控回路和连接它们的流控结点来实现。图4A的平面流控回路的拓扑学和工作与图3A相当，但是后者包括额外的入口，且在前者中，如下平衡穿过“T”连接点(由(421)例证)的流：通过选择每个通道(404、406、408、和410)的不同腿(一条腿连接至结点(400)，一条腿连接至废物管道(415))的不同横截面面积，而不是通过选择不同长度和/或曲率的腿。入口(412、414、416和418)通过“T”连接点例如(421)连接至通道(分别是404、406、408、和410)，所述“T”连接点又连接至废物通道或管道(415)和流控结点(400)。出口(402)和废物通道(424、426、428、和430)连接平面流控回路的叠堆，如图4B所示。
图5图解了本发明的流控回路可以如何用于电化学过程中，所述电化学过程需要多个反应物(包括在这样的过程中使用的电解质)，并采用在反应室上游的参比电极。为了稳定的参比电压，希望参比电极接触不超过单个过程试剂。本发明的流控回路提供了穿过反应室的共同入口递送预定顺序的电解质的方法，并同时维持：(i)反应室和参比电极之间的不间断流体连通，和(ii)仅单个电解质(即选择的电解质)接触参比电极。所有其它试剂或电解质(即未选择的电解质)不会接触参比电极。在图4A-4B中描述的平面流控回路(500)通过通道(502)将一系列不同的试剂递送至反应室(510)。如上所述，洗涤溶液流可以穿过通道(504)被引导至“T”连接点(512)，并返回流控回路(500)和反应室(510)。通过把参比电极(506)放在通道(504)中或其附近，可以给反应室(510)提供稳定的参比电压。在一个实施方案中，这样的参比电极可以是形成通道(504)的一段的金属管，如在图5中所示。参比电极(506)电连接至参比电压源(508)。
在本发明的一个方面，这样的装置包括：与电子传感器偶联的反应器，所述电子传感器用于监测反应器中的产物；流控系统，其包括本发明的流控回路，用于顺序地递送多个不同的电解质(包括选择的电解质)至反应器；和与选择的电解质接触的参比电极，其用于给电子传感器提供参比电压，在参比电极不接触任何未选择的电解质的情况下提供所述参比电压。
材料和制造方法
如上所述，通过多种方法和材料，可以制造本发明的流控回路。在选择材料时应当考虑的因素包括：需要的化学惰性程度、工作条件(例如温度等)、要递送的试剂的体积、是否需要参比电压、可制造性等。对于小规模流体递送，微流控制造技术非常适用于制造本发明的流控回路，这样的技术的指导是本领域普通技术人员可容易地得到的，例如Malloy,Plastic Part Design for Injection Molding:An Introduction(HanserGardner Publications,1994)；Herold等人,Editors,Lab-on-a-ChipTechnology(Vol.1):Fabrication and Microfluidics(Caister AcademicPress,2009)；等。对于中规模和更大规模的流体递送，常规的铣削技术可以用于制造可装配进本发明的流控回路中的部件。在一个方面，可以使用塑料诸如聚碳酸酯、聚甲基丙烯酸甲酯等来制造本发明的流控回路。
在电化学过程中的应用
本发明的流控回路可用于将多个试剂递送至一个或多个反应器的电化学过程中，所述一个或多个反应器用需要参比电极的电子传感器来监测。参比电极向多个试剂的暴露，可以将不希望的噪音导入由电子传感器检测的信号中。这会发生在用于实现无标记的DNA测序和具体的基于pH的DNA测序的方法和装置中。无标记的DNA测序(包括基于pH的DNA测序)的概念，已经描述在文献中，包括通过引用并入本文的下述参考文献：Rothberg等人,美国专利公开2009/0026082；Anderson等人,Sensorsand Actuators B Chem.,129:79-86(2008)；Pourmand等人,Proc.Natl.Acad.Sci.,103:6466-6470(2006)；等。简而言之，在基于pH的DNA测序中，通过测量作为聚合酶-催化的延伸反应的天然副产物而产生的氢离子，测定碱基掺入。将DNA模板(其各自具有可操作地结合的引物和聚合酶)装载进反应室(诸如在上面引用的Rothberg等人中公开的微孔)中，然后进行重复的三磷酸脱氧核苷(dNTP)加入和洗涤的循环。这样的模板通常作为克隆群体连接至固体支持物(诸如微粒、珠子等)上，并将这样的克隆群体装载进反应室中。在循环的每个加入步骤中，只有当模板中的下一个碱基是加入的dNTP的补体时，聚合酶才会通过掺入加入的dNTP来延伸引物。如果存在一个互补的碱基，则发生一次掺入，如果存在2个互补的碱基，则发生2次掺入，如果存在3个互补的碱基，则发生3次掺入，以此类推。每次这样的掺入会释放出氢离子，释放氢离子的模板群体一起造成反应室的局部pH的非常轻微的变化，这可以被电子传感器检测到。图6图解了一个采用本发明的流控回路的装置，其用于实现根据Rothberg等人(上面引用的)的基于pH的核酸测序。该装置的每个电子传感器会产生取决于参比电压值的输出信号。该装置的流控回路允许将多个试剂递送至反应室，且它们中不超过一个接触参比电极，由此去除由传感器产生的输出信号的噪音源。在图6中，含有流控回路(602)的壳体(600)通过入口连接至试剂蓄池(604、606、608、610、和612)，连接至废物蓄池(620)，并通过将流控结点(630)连接流动池(634)的入口(638)的通道(632)，连接至流动池(634)。通过多种方法(包括压力、泵诸如注射泵、重力进料等)，可以将试剂从蓄池(604、606、608、610、和612)驱动至流控回路(602)，并受阀门(614)控制进行选择，如上所述。上述内容包括图6的仪器的流控系统。控制系统(618)包括阀门(614)的控制器，其产生用于经由电连接(616)进行打开和关闭的信号。控制系统(618)也包括该系统的其它组件的控制器，诸如通过(622)与其相连的洗涤溶液阀门(624)以及参比电极(628)。控制系统(618)还可以包括流动池(634)的控制和数据获取功能。在一个工作模式中，在控制系统(618)的程序控制下，流控回路(602)将一系列选择的试剂(1、2、3、4、或5)递送至流动池(634)，从而启动和洗涤在二者之间的选择的试剂流流控回路(602)，并洗涤流动池(634)。进入流动池(634)的流体穿过出口(640)离开，并储存在废物容器(636)中。在这样的工作中，在流动池(634)中发生的反应和/或测量具有稳定的参比电压，因为参比电极(628)与流动池(634)之间具有连续的(即不间断的)电解质通道，但是仅与洗涤溶液发生物理接触。
图7图解了可以如何使用流控回路设计概念来制作多个单独的流动室，其中使用单个大流动池和传感器阵列，其中每个流动室的试剂接入被单独地控制，同时仍然维持通向所有流动室中的所有传感器的参比电极的不间断流体通道。图7是流动池(700)的顶视图，所述流动池(700)具有安装在壳体(未显示)上并与所述壳体密封连接的流控接口部件(702)，所述流动池(700)容纳传感器阵列(704)，并界定2个流动室(703)和(705)，每个流动室具有单独的入口(分别是706和708)和单独的对角线相对的出口(分别是710和712)，它们各自经由通道730和735(对于流动室1)以及732和737(对于流动室2)连接至来自流控回路的共同试剂源，并连接至单独的辅助洗液蓄池722(对于流动室1)和724(对于流动室2)。流控接口部件(702)与芯片壳体相连所形成的内壁(714、716、718和720)界定了穿过流动室(703)和(705)的流动通道，并避免了对角区域(750、751、752、和753)接触穿过流动室的试剂。
当阀门(723)打开时，来自辅助洗液蓄池1(722)的洗涤溶液穿过通道(729)，穿过阀门(723)，流至通道(734)，并流至连接点(731)，在这里该流分入通道(735)和通道(741)。与上述的流控回路的设计一样，选择通道(735)和(734)的长度和横截面以及洗涤溶液和试剂的驱动力，使得当阀门(723)打开时(如显示的)，仅洗涤溶液进入流动室1，且来自流控回路的试剂单独地被引导至废物蓄池(744)。当阀门(723)被关闭时，则没有洗涤溶液进入通道(729)，也没有屏障阻碍来自通道(730)的试剂流至通道(735)、流至通道(741)、和流至流动室1。同样地，当阀门(725)打开时，来自辅助洗液蓄池2(724)的洗涤溶液穿过通道(743)，穿过阀门(725)，流至通道(736)，并流至连接点(745)，在这里该流分入通道(737)和通道(747)。如上所述，选择通道(736)和(737)的长度和横截面以及洗涤溶液和试剂的驱动力，使得当阀门(725)打开时，仅洗涤溶液进入流动室2，且来自流控回路的试剂单独地被引导至废物蓄池(744)。当阀门(725)被关闭时(如显示的)，则没有洗涤溶液进入通道(743)，也没有屏障阻碍来自通道(732)的试剂流至通道(737)、流至通道(747)、和流至流动室2。
尽管已经参照几个具体实例实施方案描述了本发明，本领域技术人员会认识到，可以对其做出许多变化，而不脱离本发明的精神和范围。本发明适用于多种传感器实现和其它主题，以及上面讨论的那些。
定义
“微流控装置”是指一个或多个互连的且流体连通的室、孔、和管道的集成系统，并设计成单独地或与装置或仪器协同地实现分析反应或过程，所述装置或仪器会提供支持功能，诸如样品导入、流体和/或试剂驱动装置、温度控制、检测系统、数据收集和/或集成系统等。微流控装置可以另外包括阀门、泵、和在内壁上的专门的功能涂层，例如以防止样品组分或反应物的吸附、促进试剂的电渗移动等。这样的装置通常制造在固体基质中或制造成固体基质，所述固体基质可以是玻璃、塑料、或其它固体聚合材料，且通常具有平面形式，以便于检测和监测样品和试剂运动，特别是通过光学或电化学方法。微流控装置的部件通常具有小于几百平方微米的横截面尺寸，且通道通常具有毛细管尺寸，例如具有约500μm至约0.1μm的最大横截面尺寸。微流控装置通常具有在1μL至几nL(例如10-100nL)范围内的容积容量。微流控装置的制造和工作是本领域众所周知的，如在通过引用并入本文中的下述参考文献中所例证的：Ramsey,美国专利6,001,229、5,858,195、6,010,607、和6,033,546；Soane等人,美国专利5,126,022和6,054,034；Nelson等人,美国专利6,613,525；Maher等人,美国专利6,399,952；Ricco等人,国际专利公开WO02/24322；Bjornson等人,国际专利公开WO99/19717；Wilding等人,美国专利5,587,128、5,498,392；Sia等人,Electrophoresis,24:3563-3576(2003)；Unger等人,Science,288:113-116(2000)；Enzelberger等人,美国专利6,960,437。
本申请通过以下技术方案来实施：
1.一种用于控制多个流体流的流控回路，所述流控回路包括：
具有出口和多个流体入口的流控结点；和
通过一个或多个各自具有流体阻力的通道与所述流控结点流体连通的至少一个废物口，选择所述通道的流体阻力，使得无论何时流体仅流动穿过单个流体入口，以在所述流控结点中形成流，这样的流体的一部分穿过所述出口离开所述流控结点，且这样的流体的剩余部分穿过所述一个或多个通道离开所述流控结点，使得从未选择的入口进入所述流控结点的任何流体穿过所述一个或多个通道被引导至一个或多个废物口。
2.如第1项所述的流控回路，其中所述多个所述流体入口径向地围绕所述出口设置。
3.如第1项所述的流控回路，其中在所述流控结点中形成的所述流是层流。
4.如第3项所述的流控回路，其中所述流控结点具有相对的和垂直的表面。
5.如第4项所述的流控回路，其中所述多个所述入口设置在所述结点的表面上，所述表面与设置所述出口的所述表面垂直。
6.如第4项所述的流控回路，其中所述多个所述入口设置在所述结点的表面上，所述表面与设置所述出口的所述表面相对。
7.如第6项所述的流控回路，其中与所述一个或多个废物口连通的所述通道设置在表面上，所述表面与设置所述出口和所述多个所述流体入口的那些表面垂直。
8.如第1项所述的流控回路，其另外包括废物导管，所述废物导管提供与所述一个或多个废物口和多个所述径向地围绕所述流控结点设置的通道的流体连通，并提供所述流控结点和所述废物导管之间的流体连通，每个所述通道具有单个所述流体入口，并选择具有流体阻力的在所述流体入口的所述结点远端处的所述通道的每个部分，使得无论何时流体仅流动穿过单个流体入口，以在所述流控结点中形成所述层流，这样的流体的一部分穿过所述出口离开所述流控结点，且这样的流体的所述剩余部分穿过所述通道离开所述流控结点，没有流体流至所述废物导管。
9.一种用于顺序地递送多个试剂至共同容积的装置，所述装置包括：
流控回路，所述流控回路包括具有出口和多个流体入口的流控结点；和通过一个或多个各自具有流体阻力的通道与所述流控结点流体连通的至少一个废物口，选择所述通道的流体阻力，使得无论何时试剂仅流动穿过单个试剂入口，以在所述流控结点中形成层流，这样的试剂的一部分穿过所述出口离开所述流控结点，且这样的试剂的剩余部分穿过所述一个或多个通道离开所述流控结点，由此使从没有试剂流的入口进入所述流控结点的任何试剂穿过所述一个或多个通道被引导至一个或多个废物口；
多个试剂阀门，所述试剂阀门各自设置在连接试剂入口和试剂蓄池的导管中；和
控制系统，其用于产生打开或关闭所述多个试剂阀门中的每一个的信号，使得预选择的试剂阀门被打开预选择的持续时间，同时所有其它试剂阀门被关闭，由此递送预定顺序的试剂流穿过所述出口。
10.如第9项所述的装置，所述装置另外包括洗液入口和洗液阀门，所述洗液入口连接至所述出口，使得所述洗液入口穿过所述出口与所述流控结点流体连通，且所述洗液阀门可操作地与所述控制系统相关联，并设置在将所述洗液入口连接至洗涤流体蓄池的导管中，使得无论何时所述控制系统会打开所述洗液阀门并同时关闭所有所述试剂阀门，洗涤溶液流动穿过所述流控结点，穿过所述一个或多个通道，并至所述一个或多个废物口。
11.如第10项所述的装置，所述装置另外包括废物导管，所述废物导管提供与所述一个或多个废物口和多个所述径向地围绕所述流控结点设置的通道的流体连通，并提供所述流控结点和所述废物导管之间的流体连通，每个所述通道具有单个所述流体入口，并选择具有流体阻力的在所述流体入口的所述流体结点远端处的所述通道的每个部分，使得无论何时流体仅流动穿过单个流体入口，以在所述流控结点中形成所述层流，这样的流体的一部分穿过所述出口离开所述流控结点，且这样的流体的所述剩余部分穿过所述通道离开所述流控结点，没有流体流至所述废物导管。
12.一种用于执行多步骤的电化学过程的装置，所述装置包括：
与电子传感器偶联的反应器，所述电子传感器用于监测所述反应器中的产物；
包括流控回路的流控系统，所述流控回路用于将包括选择的电解质在内的多个不同电解质顺序地递送至所述反应器；和
与所述选择的电解质接触的参比电极，所述参比电极用于给所述电子传感器提供参比电压，在所述参比电极不接触未选择的电解质的情况下提供所述参比电压。
13.如第12项所述的装置，其中所述流控回路包括：具有出口和多个流体入口的流控结点，和通过一个或多个各自具有流体阻力的通道与所述流控结点流体连通的至少一个废物口，选择所述通道的流体阻力，使得无论何时电解质仅流动穿过单个流体入口，以在所述流控结点中形成流，这样的电解质的一部分穿过所述出口离开所述流控结点，且这样的电解质的剩余部分穿过所述一个或多个通道离开所述流控结点，使得从未选择的入口进入所述流控结点的任何电解质穿过所述一个或多个通道被引导至一个或多个废物口。
本申请是2010年5月24日提交的美国专利申请序列号12/785,667的继续申请，后者是2009年5月29日提交的美国专利申请序列号12/474,897和12/475,311的部分继续申请，且本申请要求这些申请和2009年12月31日提交的美国临时申请序列号61/291,627的利益。所有前述申请都通过引用整体并入本文。

Claims (18)

1.一种用于控制流控回路中的流体流的方法，所述流控回路包括分别经由第一通道和第二通道而与结点流体连通的第一流体入口和第二流体入口、与所述结点流体连通的流体出口以及经由所述第一通道和所述第二通道而与所述结点流体连通的至少一个废物口，所述方法包括：
使第一流体经由所述第一流体入口流入所述流控回路中，所述第一流体的第一部分流动经过所述第一通道、经过所述结点然后经过所述流体出口，所述第一流体的第二部分流动经过所述第一通道、经过所述结点，经由所述第二通道而穿过所述第二流体入口然后进入所述至少一个废物口，并且所述第一流体的第三部分流动至所述至少一个废物口而没有穿过所述结点。
2.根据权利要求1所述的方法，其中所述第一通道和所述第二通道在所述结点与所述至少一个废物口之间提供不同的流体路径。
3.根据权利要求1所述的方法，其中所述第二部分和第三部分流动经过废物通道到达所述至少一个废物口。
4.根据权利要求1所述的方法，其中使所述第一流体流入所述流控回路包括使所述第一流体流动经过所述流体入口到达入口通道并且流动经过所述入口通道与所述第一通道之间的T连接点。
5.根据权利要求1所述的方法，还包括：
在使第一溶液流入所述流控回路之后，使洗液流入所述流控回路，所述洗液经由与所述流体出口连通的洗液入口进入所述流控回路，所述洗液流动经过所述流体出口并且进入所述结点，流动经过所述第一通道和所述第二通道到达所述至少一个废物口。
6.根据权利要求5所述的方法，还包括：
在使所述洗液流入所述流控回路之后，使第二流体经由所述第二流体入口流入所述流控回路，所述第二流体的第一部分流动经过所述第二通道、经过所述结点然后经过所述流体出口，并且所述第二流体的第二部分流动经过所述第二通道、经过所述结点、经由所述第一通道穿过所述第一流体入口然后进入所述至少一个废物口。
7.根据权利要求6所述的方法，其中所述第二流体的第三部分流动经过所述第二通道到达所述至少一个废物口，而没有穿过所述结点。
8.根据权利要求1所述的方法，还包括：
在使所述第一溶液流入所述流控回路之后，使洗液流入所述流控回路同时继续使所述第一流体流动，所述洗液经由与所述流体出口连通的洗液入口进入所述流控回路，所述洗液流动经过所述流体出口并且进入所述结点、经过所述第一通道和所述第二通道到达所述至少一个废物口，所述第一流体流动经过所述第一通道到达所述至少一个废物口而没有进入所述结点。
9.一种流控装置，包括：
具有流体出口的结点；
多个流体入口，所述多个流体入口中的每个流体入口与多个试剂中的各个试剂唯一地关联；
至少一个废物口；
多个通道，所述多个通道中的每个通道在所述结点与所述至少一个废物口之间提供不同的流体路径，所述多个通道中的每个通道包括至各个入口通道的连接点，所述各个入口通道在所述每个通道与所述多个流体入口中的各个流体入口之间提供流体连通；
通过所述流体出口与所述结点流体连通的出口通道；以及
与所述出口通道流体连通的洗涤流体入口。
10.根据权利要求9所述的流控装置，其中所述多个试剂中的每个试剂存储在各个蓄池中。
11.根据权利要求9所述的流控装置，还包括与所述洗涤流体入口电通信的参比电极。
12.根据权利要求9所述的流控装置，其中所述洗涤流体入口包括与所述出口通道连接的分支管道，所述参比电极布置在所述分支管道中。
13.根据权利要求9所述的流控装置，其中所述出口通道与流动池流体连通。
14.根据权利要求13所述的流控装置，还包括参比电极，所述参比电极具有经过所述出口通道到达所述流动池的连续电解质路径。
15.根据权利要求9所述的流控装置，其中每个不同的流体路径没有不可透过的屏障。
16.根据权利要求9所述的流控装置，其中每个通道包括从所述连接点延伸至所述结点的第一部段和从所述连接点离开所述结点的第二部段。
17.根据权利要求9所述的流控装置，其中所述第二部段连接至与所述废物口流体连通的废物通道。
18.根据权利要求9所述的流控装置，其中所述第二部段具有比所述第一部段更大的流动阻力。
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CN107328949B (zh) * 2017-06-27 2019-05-03 中国科学院长春光学精密机械与物理研究所 一种实现多份液体自发顺序流动的方法及装置

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