CN1842368B - 流体物种的电子控制 - Google Patents
流体物种的电子控制 Download PDFInfo
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- CN1842368B CN1842368B CN200480024742.2A CN200480024742A CN1842368B CN 1842368 B CN1842368 B CN 1842368B CN 200480024742 A CN200480024742 A CN 200480024742A CN 1842368 B CN1842368 B CN 1842368B
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Abstract
本发明的多个方面涉及例如在微流体***中控制和操作流体物种。一个方面,本发明涉及用于形成被流体包围的流体液滴的***和方法,例如使用电场、机械改变、添加干涉流体等。在一些情况下,液滴中可以各自具有基本上均匀数量的实体。例如,该液滴的95%或更多可以各自含有特定物种相同数量的实体。另一方面,本发明涉及用于将流体液滴分成两个液滴的***和方法,例如,通过电荷和/或偶极与电场的相互作用进行。根据本发明另一方面,本发明还涉及用于融合液滴的***和方法,例如,通过电荷和/或偶极相互作用。在一些情况下,液滴的融合可以引发或决定反应。在本发明相关方面,还提供用于使液滴内发生流体混合的***和方法。在另一方面,本发明涉及用于分选液滴的***和方法,例如通过使液滴移动到流体***内的确定区域进行分选。实例包括使用电学相互作用(例如,电荷、偶极等)或者力学***(例如,流***移)来分选液滴。在一些情况下,可以以较高速率分选流体液滴,例如,以约10液滴/秒或更高的速率。本发明另一方面提供测定液滴或其组分的能力,例如,使用荧光和/或其它光学技术(例如,显微镜),或者电感技术,例如电介质检测。
Description
相关申请
本申请要求2003年8月27日提交的Link等人的题名为“Electronic Control ofFluidic Species”的美国临时专利申请60/498,091的权益,该申请通过引用并入本文。
技术领域
一般而言,本发明涉及用于控制流体物种的***和方法,具体而言,涉及用于电子控制流体物种的***和方法。
背景技术
操作流体以形成所需形状的流体流、不连续流体流、液滴、颗粒、分散体等,目的是为了输送流体、制备产品、分析等,这是研究较为充分的技术。例如,直径小于100微米的高度单分散的气泡用称为毛细流集中的技术制得。在该技术中,迫使气体从毛细管出来进入液体浴中,该管位于小孔之上,并且外部液体的收缩流通过该孔将气体集中为细的射流,随后由于毛细管不稳定性分为大小大致相等的泡。在相关技术中,可以使用类似装置在空气中形成液体液滴。
题为“Generation of Steady Liquid Microthreads and Micron-SizedMonodisperse Sprays and Gas Streams,”Phys.Rev.Lett.,80:2,January 12,1998(Ganan-Calvo)的文章描述了通过层状加速气流形成微观液体线,产生细喷射。题为“Dynamic Pattern Formation in a Vesicle-Generating Microfluidic Device,”Phys.Rev.Lett.,86:18,April 30,2001(Thorsen等人)的文章描述了通过在两条微流体通道之间的“T”结合处将水引入到流动油中,经过微流体错流从而在连续油相中形成不连续水相。
2000年9月19日公布的美国专利US 6,120,666描述了一种具有流体集中腔室的微型制造装置,该流体集中腔室用于空间限制用于分析流体介质中的微观颗粒的第一和第二样品流体流,例如在生物流体分析中。2000年9月12日公布的美国专利US 6,116,516描述了毛细管微射流的形成,和通过该微射流的分离形成单分散的气溶胶。2001年2月13日公布的美国专利US 6,187,214描述了大小范围为约1-约5微米的雾化颗粒,是由两种不混溶的流体相互作用产生的。2001年6月19日公布的美国专利US 6,248,378描述了使用微射流产生引入到食物中的颗粒,并且当该微射流分离时形成单分散的气溶胶。
微流体***已在多种文章背景中有述,一般是在微型化实验室(例如,临床)分析的文章中。其它应用也有所描述。例如,2001年11月29日公开的Anderson等人的国际专利公开WO 01/89789中描述了多级微流体***,可以用于在表面上提供材料例如生物材料和细胞的图案。其它出版物描述了包括阀、开关和其它组件的微流体***。
随着宏观或微观流体动力学已经取得明显进步,需要改进技术以及这些技术的效果。
发明内容
本发明涉及用于电子控制流体物种的***和方法。在一些情况下,本发明的主题包括相关产品、针对特殊问题的替代方案和/或一种或多种***和/或制品的多种不同用途。
在一个方面,本发明提供一种方法。在一组实施方案中,该方法是一种在微流体***中以受控方式结合至少两个物种的方法。该方法包括以下步骤:提供一串在微流体***中流动的液滴;从该串液滴中选择第一液滴,并从该串液滴中的至少一些其它液滴分离第一液滴(其中,该第一液滴具有小于约100微米的最大横截面尺寸,并含有第一化学、生物或生物化学物种),提供从该串液滴分离的第二液滴(其中,该第二液滴具有小于约100微米的最大横截面尺寸,并含有第二化学、生物或生物化学物种),选择性推动第一液滴和/或第二液滴朝向一个可以发生合并的位置,并允许第一液滴和第二液滴合并为一个组合液滴,并确定涉及至少是第一液滴中第一物种和第二液滴中第二物种的反应。
根据另一组实施方案的方法是一种在微流体***中以受控方式分选液滴的方法。该方法包括以下步骤:提供一串在微流体***中流动的液滴,从该串液滴中选择第一液滴,并从该串液滴的至少一些其它液滴分离第一液滴。在一些情况下,该第一液滴具有小于约100微米的最大横截面尺寸。
在又一组实施方案中,该方法是一种为微流体***中一个或多个液滴赋予电荷的方法。该方法可以包括以下步骤:提供微流体***中的液滴,赋予该液滴偶极矩,当偶极矩存在时,将该液滴分成至少两个子液滴,子液滴中的至少一个带有来自赋予该初始液滴的偶极矩的电荷。
在另一组实施方案中,该方法是一种在微流体***中结合至少两个液滴的方法。该方法包括以下步骤:在微流体***中提供至少两个液滴,将该液滴暴露在电场中,从而在液滴中诱导偶极矩,并且至少部分通过由于诱导偶极矩导致的液滴-液滴吸引将至少两个液滴合并为单个液滴。
根据另一组实施方案,该方法包括以下步骤:在被第二液体流体包围的第一流体上产生至少约10-14C的电荷。根据又一组实施方案,该方法包括以下步骤:在被第二液体流体包围的第一流体上施加至少约10-9N的电场力。
在又一组实施方案中,在含有第一液滴和第二液滴的第一流体中,第一流体被第二液体流体包围,该方法包括:以至少约10或至少约100液滴/s的速率分选第一和第二液滴。在又一组实施方案中,该方法包括以下步骤:提供被第二液体流体包围的第一流体的液滴,其中该液滴具有一定比值的含有第一物种的液滴与不含第一物种的液滴,并且分选该液滴,以将含有第一物种的液滴与不含第一物种的液滴的比值增加至少约2倍。
在另一组实施方案中,在含有第一液滴和第二液滴的第一流体中,其中第一流体被第二液体流体包围,该方法包括:在基本上不改变第二液体流体流速的情况下,对第一和第二液滴进行分选。在又一组实施方案中,该方法包括以下步骤:使用电场将被第二液体流体包围的第一流体液滴分为两个液滴。
在另一方面,本发明是一种制品。在一组实施方案中,该制品包括被第二液体流体包围的、电荷至少约为10-14C的第一流体液滴。在另一组实施方案中,该制品包括含有被第二液体流体包围的第一流体的液滴,其中该液滴的至少约90%各自由相同量的物种实体组成。
在又一方面,本发明是一种装置。根据一组实施方案,该装置包括微流体通道以及构造和布置为在微流体通道内产生至少约1V/微米电场的电场发生器。
在又一方面,本发明涉及一种实施文中描述的一种或多种实施方案的方法。在又一方面,本发明涉及一种使用文中描述的一种或多种实施方案的方法。在又一方面,本发明涉及一种改进文中描述的一种或多种实施方案的方法。
结合附图,从以下详细描述的本发明各种非限定性实施方案中,本发明的其它优点和新特征将变得明显。如果本说明书和通过引用并入的文件包括抵触和/或不一致的内容,则以本说明书为准。如果通过引用并入的两份或更多份申请包括彼此抵触和/或不一致的内容,则以后提交的申请为准。
附图说明
通过实施例并参考附图来描述本发明非限定性的实施方案,附图是示意性的,并非是按比例画出的。这些图中,所示的每个相同或近似相同的组件通常以单一数字表示。为清楚起见,并非每个组件在每个图中都标出,而且当不必说明即可使本领域技术人员理解本发明时,也并不是本发明每个实施方案的每个组件都要表示出来。在这些图中:
图1A和1B表示根据本发明一个实施方案将液滴分开;
图2A和2B表示施加电场之前的根据本发明实施方案的装置;
图3A和3B表示施加电场之后的图2A和2B的装置;
图4A和4B表示施加反向电场之后的图2A和2B的装置;
图5是根据本发明一个实施方案液滴分开的示意图;
图6A和6B是本发明其它实施方案的示意图;
图7A和7B表示根据本发明实施方案形成液滴;
图8A-8F表示根据本发明一个实施方案分选和/或分开液滴;
图9A-9D表示根据本发明另一实施方案分选和/或分开液滴;
图10A-10D表示根据本发明另一实施方案分选流体液滴;
图11A-11C表示根据本发明又一实施方案分选流体液滴;
图12A-12J表示根据本发明一个实施方案具有两个或更多个流体区的液滴中的流体混合;
图13A-13D表示根据本发明某些实施方案在通道中的未带电和带电的液滴;
图14A-14C表示本发明多种实施方案,包含第一流体和第二流体的交变液滴(alternating droplets);和
图15A-15E表示本发明多种实施方案的特征装置实例。
发明内容
一般而言,本发明涉及通常被液体包围(例如,悬浮)的流体物种的控制和操作。本发明的多个方面涉及形成流体液滴、将液滴分成多个液滴、在液滴上产生电荷、在液滴中诱导偶极、使液滴融合或合并、促使在液滴内发生混合、分选和/或分离液滴、和/或检测和/或测定液滴和/或液滴内的成分。还包括控制和操作流体物种的这些和/或其它***和方法的组合,例如,以下公开的***和方法:Link等人的2003年8月27提交的美国临时专利申请60/498,091;Stone等人的2002年6月28日提交的美国临时专利申请60/392,195;Link等人的2002年11月5日提交的美国临时专利申请60/424,042;Kumar等人的1996年4月30日公布的美国专利5,512,131;Whitesides等人的1996年6月26日公开的国际专利WO 96/29629;Kim等人的2002年3月12日公布的美国专利6,355,198;Anderson等人的2001年5月25日提交的国际专利申请PCT/US01/16973,2001年11月29日公开为WO 01/89787;Stone等人的2003年6月30日提交的国际专利申请PCT/US03/20542,2004年1月8日公开为WO2004/002627;Link等人的2004年4月9日提交的国际专利申请PCT/US2004/010903;和Link等人的2003年4月10日提交的美国临时专利申请60/461,954;每一篇都通过引用并入本文。
在本发明的多个方面中,本文公开的流体***可以包括液滴形成***、检测***、控制器、和/或液滴分选和/或分离***,或者这些***的任意组合。可以以任何合适的次序布置这些***和方法,这取决于具体应用,一些情况下,可以使用给定类型的多个***,例如两个或更多个液滴形成***、两个或更多个液滴分离***等。作为布置的实例,可以布置本发明的***,以形成液滴、稀释流体、控制液滴内物种的浓度、分选液滴从而选择那些具有理想的物种或实体浓度的液滴(例如,均含有一分子反应物的液滴)、使单个液滴融合从而使单个液滴中含有的物种之间发生反应、测定一个或多个液滴中的反应和/或反应速率等。根据本发明,可以使用多种其它布置。
液滴的产生/形成
本发明一个方面涉及产生被液体包围的流体液滴的***和方法。很多情况下该流体和该液体基本上是不能混溶的,即,在关心的时间范围内是不能混溶的(例如,通过特定***或装置输送流体液滴所需的时间)。某些情况下,液滴可以各自具有基本上相同的形状或大小,如以下进一步所述。流体也可以含有其它物种,例如某些分子物种(例如,如以下进一步所述)、细胞、颗粒等。
在一组实施方案中,在被液体包围的流体上可以产生电荷,这可以使该流体在液体内被分成单个的液滴。在一些实施方案中,流体和液体可以存在于通道中,例如微流体通道,或者其它狭窄空间中,便于电场(可以是″AC″或交流、″DC″或直流等)施加到流体上,例如,通过限制流体相对于液体的运动。因此,流体在液体内可以以一系列单个带电和/或可电诱导的液滴存在。在一个实施方案中,施加于流体液滴上的电场力可以足够大,以至于使得液滴在液体内运动。在一些情况下,施加于流体液滴上的电场力可以用于引导液滴在液体内进行预期的运动,例如,移向或者在通道或微流体通道内运动(例如,如文中进一步所述)等等。作为一个实例,在图3A的装置5中,使用由电场发生器20产生的电场可以使由流体源10产生的液滴15带电。
使用任何合适的技术可以在液体内的流体中产生电荷,例如,通过将该流体置于电场(可以是AC、DC等)内,和/或导致发生反应,使得该流体带上电荷,例如化学反应、离子反应、光催化反应等。在一个实施方案中,该流体是电导体。文中使用的“导体”是导电率至少约为18兆欧(MOhm或MΩ)水的导电率的材料。包围该流体的液体的导电率可以小于该流体的导电率。例如,相对于该流体,该液体可以是绝缘体,或者至少是“泄漏绝缘体”,即,至少短时间内,该液体可以至少部分电绝缘该流体。本领域普通技术人员能够确定流体的导电率。在一个非限定性实施方案中,该流体基本上是亲水性的,并且包围该流体的该液体基本上是疏水性的。
在一些实施方案中,该流体上(例如一系列流体液滴上)产生的电荷可以是至少约10-22C/微米3。某些情况下,电荷可以是至少约10-21C/微米3,其它情况下,电荷可以是至少约10-20C/微米3、至少约10-19C/微米3、至少约10-18C/微米3、至少约10-17C/微米3、至少约10-16C/微米3、至少约10-15C/微米3、至少约10-14C/微米3、至少约10-13C/微米3、至少约10-12C/微米3、至少约10-11C/微米3、至少约10-10C/微米3,或者至少约10-9C/微米3或者更多。在某些实施方案中,该流体上产生的电荷可以是至少约10-21C/微米2,一些情况下,电荷可以是至少约10-20C/微米2、至少约10-19C/微米2、至少约10-18C/微米2、至少约10-17C/微米2、至少约10-16C/微米2、至少约10-15C/微米2、至少约10-14C/微米2,或者至少约10-13C/微米2或者更多。在其它实施方案中,电荷可以是至少约10-14C/液滴,一些情况下,至少约10-13C/液滴,其它情况下至少约10-12C/液滴,其它情况下至少约10-11C/液滴,其它情况下至少约10-10C/液滴,或者别的情况下至少约10-9C/液滴。
在一些实施方案中,电场是由电场发生器产生的,即,能够产生可以施加于流体的电场的装置或***。该电场发生器可以产生AC场(即,相对于时间周期性改变的场,例如呈正弦状、锯齿状、矩形等)、DC场(即,相对于时间恒定的场)、脉冲场等。可以构造和布置该电场发生器,以在通道或微流体通道内所包含的流体内产生电场。按照一些实施方案,该电场发生器可以与包含通道或微流体通道的流体***组成为整体或者与之分开。文中使用的“组成为整体”是指连接相互组成为整体的各部分组件,使得在没有切削或折断至少一个组件的情况下不能手动地彼此分离各组件。
产生合适电场(可以是AC、DC等)的技术是本领域普通技术人员已知的。例如,在一个实施方案中,通过向一对电极施加电压而产生电场,该电极可以位于流体***上或者嵌入其中(例如,在限定通道或微流体通道的基质中),和/或位于最接近流体的位置,使得至少部分电场与该流体相互作用。该电极可以由任何合适的电极材料或本领域普通技术人员已知的材料制得,该材料包括但不限于银、金、铜、碳、铂、铜、钨、锡、镉、镍、氧化铟锡(“ITO”)等,以及它们的组合。在一些情况下,可以使用透明或基本上透明的电极。在某些实施方案中,可以构造和布置(例如定位)该电场发生器,以产生可施加于该流体的至少约0.01V/微米的电场,一些情况下,至少约0.03V/微米、至少约0.05V/微米、至少约0.08V/微米、至少约0.1V/微米、至少约0.3V/微米、至少约0.5V/微米、至少约0.7V/微米、至少约1V/微米、至少约1.2V/微米、至少约1.4V/微米、至少约1.6V/微米,或者至少约2V/微米。在一些实施方案中,可以使用甚至更高的电场强度,例如,至少约2V/微米、至少约3V/微米、至少约5V/微米、至少约7V/微米,或者至少约10V/微米或者更高。
在一些实施方案中,可以将电场施加于流体液滴上,使得该液滴承受电场力。一些情况下,施加于该流体液滴上的电场力可以是至少约10-16N/微米3。某些情况下,施加于该流体液滴上的电场力可以更大,例如,至少约10-15N/微米3、至少约10-14N/微米3、至少约10-13N/微米3、至少约10-12N/微米3、至少约10-11N/微米3、至少约10-10N/微米3、至少约10-9N/微米3、至少约10-8N/微米3,或者至少约10-7N/微米3或者更大。在其它实施方案中,施加于该流体液滴上的电场力,相对于该流体的表面积,可以是至少约10-15N/微米2,一些情况下,至少约10-14N/微米2、至少约10-13N/微米2、至少约10-12N/微米2、至少约10-11N/微米2、至少约10-10N/微米2、至少约10-9N/微米2、至少约10-8N/微米2、至少约10-7N/微米2,或至少约10-6N/微米2或者更大。在别的实施方案中,施加于该流体液滴上的电场力可以是至少约10-9N、至少约10-8N、至少约10-7N、至少约10-6N、至少约10-5N,或者至少约10-4N或者一些情况下更大。
在本发明一些实施方案中,提供用于至少部分中和流体液滴上存在的电荷的***和方法,例如如上所述具有电荷的流体液滴。例如,为了至少部分中和电荷,可以使该流体液滴通过电场和/或使其靠近电极,例如,使用诸如文中描述的那些技术。当该流体液滴从电场退出时(即,使得电场不再有可以基本上影响该流体液滴的强度),和/或对电场进行其它消除时,该流体液滴可以是电中和的,和/或具有减少的电荷。
在另一组实施方案中,通过以能够导致流体形成单个液滴的方式改变通道尺寸,可以从通道内被液体包围的流体产生流体的液滴。该通道例如可以是相对于流动方向扩张的通道,例如,使得该流体不附着在通道壁上而是形成单个的液滴,或者是相对流动方向变窄的通道,例如,使得该流体被迫合并为单个的液滴。一个实例表示在图7A中,其中,通道510包括被液体505包围的流动流体500(向下流动)。通道510在位置501处变窄,使得流体500形成一系列单个的流体液滴515。在其它实施方案中,还可以使用内部障碍物导致液滴形成的发生。例如可以使用挡板、脊、柱等干扰液流,使得该流体合并为流体液滴。
在一些情况下,可以随着时间而改变通道尺寸(例如机械法或电机械法、气动法等),从而形成单个的流体液滴。例如该通道可以被机械式紧缩(“挤压”)以导致液滴形成,或者可以机械式干扰流体流以导致液滴形成,例如通过使用活动式挡板、转动式叶片等。作为非限定性实例,在图7B中,流体500朝下流过通道510。流体500被液体505所包围。随后,靠近通道510或与之组成为整体的压电装置520会机械式紧缩或“挤压”通道510,使流体500***成单个流体液滴515。
在另一组实施方案中,在含有三种基本上相互不能混溶的流体(即,在关心的时间范围内是不混溶的)的***中可以产生并保持单个的流体液滴,该***中,一种流体是液体载体,第二种流体和第三种流体在该液体载体内交替作为单个的流体液滴。在这样的***中,不必需要表面活性剂以确保第二和第三种流体的流体液滴发生分离。作为实例,参考图14A,在通道700内,第一种流体701和第二种流体702均被承载在液体载体705内。第一种流体701和第二种流体702交替作为一系列交替的、单个的液滴,均在通道700内被液体载体705承载,由于该第一种流体、第二种流体和液体载体都是基本上相互不能混溶的,所以任何两种流体(或者三种流体都)可以接触而不发生液滴合并。这种***实例的显微照片在图14B中表示,说明以单个交替的液滴存在的第一种流体701和第二种流体702均包含在液体载体705内。
涉及三种基本上相互不能混溶的流体的***实例是硅油、矿物油和水溶液(即,水或者含有一种或多种其它物种的水,所述其它物种溶解和/或悬浮于水中,例如,盐溶液、盐水溶液、含有颗粒或细胞的水的悬浮体等)。***的另一个实例是硅油、氟代烃油和水溶液。***的另一个实例是烃类油(例如十六烷)、氟代烃油和水溶液。在这些实例中,任何这些流体都可以被用作液体载体。合适的氟代烃油的非限定性实例包括十八氟十氢萘:
或者1-(1,2,2,3,3,4,4,5,5,6,6-十一氟环己基)乙醇:
这种***的非限定性实例在图14B中表示。该图中,流体网络710包括含有液体载体705以及第一种流体701和第二种流体702的通道。液体载体705通过入口725被引入到流体网络710中,而第一种流体701通过入口721被引入,第二种流体702通过入口722被引入。流体网络710内的通道716含有从入口725引入的液体载体715。起初,第一种流体701被引入液体载体705中,形成其中的流体液滴。接下来,第二种流体702被引入液体705中,形成其中的流体液滴,其与含有第一种流体701的流体液滴交替散布。因此,当达到通道717时,液体载体705含有包含第一种流体701的第一批流体液滴,其与包含第二种流体702的第二批流体液滴交替散布。在所示的实施方案中,通道706任选含有一系列弯曲,其可以允许在每种流体液滴内发生混合,如以下进一步所述。不过,应注意的是,在该实施方案中,由于第一种流体701和第二种流体702是基本上不能混溶的,所以通常不能指望含有第一种流体701的液滴与含有第二种流体702的液滴发生明显的融合和/或混合。
形成被液体包围的流体液滴的其它实例描述在Link等人的2004年4月9日提交的国际专利申请PCT/US2004/010903和Stone等人的2003年6月30日提交的2004年1月8日公开为WO 2004/002627的国际专利申请PCT/US03/20542中,均通过引用并入本文。
在一些实施方案中,流体液滴均有基本上相同的形状和/或大小。例如,可以通过测量液滴的平均直径或其它特征性尺寸而测定形状和/或大小。文中使用的术语“测定”通常是指例如定量或定性地对物种进行分析或测量,和/或检测该物种存在与否。“测定”还可以指例如定量或定性地分析或测量两个或更多物种之间的相互作用,或者检测存在或不存在该相互作用。合适的技术实例包括但不限于:光谱法,例如红外光谱法、吸收光谱法、荧光光谱法、UV/可见光谱法、FTIR(“傅立叶变换红外光谱法”)或者拉曼光谱法;重量分析技术;椭圆光度法;压电测量法;免疫测定;电化学测量法;光学测量法,例如光密度测量法;圆二色性法;光散射测量法,例如准电光散射;旋光测定法;折射法;或者浊度测量法。
多个或一系列液滴的“平均直径”是各液滴平均直径的算术平均值。本领域普通技术人员能够测定多个或一系列液滴的平均直径(或其它特征性尺寸),例如使用激光光散射法、显微观察或者其它已知技术。非球形液滴的液滴直径是该液滴数学上定义的平均直径,对整个表面进行积分。液滴的平均直径(和/或多个或一系列液滴的平均直径)例如可以是小于约1mm、小于约500微米、小于约200微米、小于约100微米、小于约75微米、小于约50微米、小于约25微米、小于约10微米,或者一些情况下小于约5微米。平均直径也可以是至少约1微米、至少约2微米、至少约3微米、至少约5微米、至少约10微米、至少约15微米,或者某些情况下至少约20微米。
在本发明的某些实施方案中,该流体液滴可以含有另外的实体,例如其它化学、生物化学或生物实体(例如,溶解或悬浮在该流体中)、细胞、颗粒、气体、分子等。在一些情况下,该液滴可以均具有基本上相同的形状或大小,如以上讨论的。在某些情况下,本发明提供主要由其中基本上相等数量的物种实体(即,分子、细胞、颗粒等)组成的液滴的制备。例如多个或一系列液滴的约90%、约93%、约95%、约97%、约98%或者约99%或更多可以各自含有相同数量的特定物种的实体。例如,如上所述形成的大量流体液滴例如可以分别含有1种实体、2种实体、3种实体、4种实体、5种实体、7种实体、10种实体、15种实体、20种实体、25种实体、30种实体、40种实体、50种实体、60种实体、70种实体、80种实体、90种实体、100种实体等,其中该实体是分子或大分子、细胞、颗粒等。在一些情况下,该液滴可以各自独立地含有一定范围的实体,例如少于20种实体、少于15种实体、少于10种实体、少于7种实体、少于5种实体,或者一些情况下少于3种实体。在一组实施方案中,在含有流体液滴的液体中,其中一些含有感兴趣的物种并且其中一些不含有感兴趣的物种,该流体液滴可以被筛选或分选得到那些含有这些物种的流体液滴,如以下进一步所述(例如使用荧光或其它技术,如上述那些技术),在一些情况下,该液滴可以被筛选或分选得到那些含有特定数量或范围的感兴趣物种实体的流体液滴,例如,如前所述的那些。因此,在一些情况下,多个或一系列流体液滴中一些含有该物种并且其中一些不含有,这些流体液滴可以以含有该物种的液滴的以下比值进行富集(或贫化),例如至少约2倍、至少约3倍、至少约5倍、至少约10倍、至少约15倍、至少约20倍、至少约50倍、至少约100倍、至少约125倍、至少约150倍、至少约200倍、至少约250倍、至少约500倍、至少约750倍、至少约1000倍、至少约2000倍,或至少约5000倍或者一些情况下更大。在其它情况下,可以以下面的比值进行富集(或贫化):至少约104、至少约105、至少约106、至少约107、至少约108、至少约109、至少约1010、至少约1011、至少约1012、至少约1013、至少约1014、至少约1015或更大。例如,含有特定物种的流体液滴可以从含有多种物种的流体液滴的库中进行选择,其中所述库可以有约105、约106、约107、约108、约109、约1010、约1011、约1012、约1013、约1014、约1015或更多的品种,例如DNA库、RNA库、蛋白质库、组合化学库等。在某些实施方案中,承载物种的液滴可以随后被融合、反应或者被使用或处理等以例如引发或确定反应,如以下进一步所述。
***液滴
在另一方面,本发明涉及用于将流体液滴分成两个或更多个液滴的***和方法。该流体液滴可以被液体所包围,例如,如前所述,并且在一些情况下,该流体和该液体基本上是不能混溶的。通过***最初的流体液滴产生的两个或更多个液滴可以各自有基本上相同的形状和/或大小,或者该两个或更多个液滴可以有不同的形状和/或大小,这取决于***最初的流体液滴所用的条件。在很多情况下,可以以某些方式控制***最初的流体液滴所用的条件,例如手动或自动(例如用处理器,如下所述)。在一些情况下,可以独立地控制多个或系列流体液滴中的各个液滴。例如,一些液滴可以被分成相等部分或不等部分,而其它液滴没有被***。
根据一组实施方案,使用外加电场可以***流体液滴。该电场可以是AC场、DC场等。在该实施方案中,该流体液滴可以具有比周围的液体更大的导电率,在一些情况下,该流体液滴可以被中和性地充电。在一些实施方案中,由最初的流体液滴形成的液滴有大致相等的形状和/或大小。在某些实施方案中,在外加电场中,可以促使电荷从流体液滴内部迁移到表面从而分布在表面上,因而可以取消作用在液滴内部的电场。在一些实施方案中,流体液滴表面上的电荷也可以受到外加电场产生的力的作用,这使得具有相反极性的电荷向相反方向迁移。在一些情况下,电荷迁移可以导致该滴被拉开,成为两个分开的流体液滴。例如可以使用上述技术产生施加到流体液滴的电场,例如通过电场发生器的反应等。
作为非限定性实例,在图1A中,其中没有施加电场,通道230中含有的流体液滴215被周围的液体承载,该液体流向交叉点240,通向通道250和255。在该实例中,周围的液体以相等流速流过通道250和255。因此,在交叉点240处,流体液滴215不具有优选的取向或方向,并由于周围液体流动而以相等概率移入排出通道250和255。相反,在图1B中,当周围的液体以与图1A相同的方式流动时,在1.4V/微米外加电场的影响下,流体液滴215在交叉点240被分成两个液滴,形成新的液滴216和217。液滴216在通道250中向左流动,而液滴217在通道255中向右流动。
在图5中可以看到该过程的示意图,其中,在通道540中被液体535包围的中性流体液滴530受由电极526和527产生的外加电场525的作用。电极526靠近通道542布置,而电极527靠近通道544布置。在电场525的影响下,在流体液滴530内诱导电荷分离,即,使得在液滴的一端诱导为正电荷,而在液滴的另一端诱导为负电荷。然后该液滴可以被分成带负电的液滴545和带正电的液滴546,然后它们可以分别在通道542和544中流动。在一些情况下,所产生的带电液滴上的一种电荷或两种电荷还可以被中和,如前所述。
将流体液滴分成两个液滴的其它实例描述在Link等人2004年4月9日提交的国际专利申请PCT/US2004/010903;Link等人2003年8月27日提交的美国临时专利申请60/498,091;和Stone等人2003年6月30日提交的2004年1月8日公开为WO 2004/002627的国际专利申请PCT/US03/20542中,每篇都通过引用并入本文。
融合液滴
在又一方面中,本发明涉及用于将两个或更多个流体液滴融合或合并为一个液滴的***和方法。例如,在一组实施方案中,当两个或更多个液滴通常例如由于组成、表面张力、液滴大小、存在或不存在表面活性剂等而不能融合或合并的情况下,提供能够导致该两个或更多个液滴(例如由不连续流体流产生的)融合或合并为一个液滴的***和方法。在某些微流体***中,相对于液滴的大小,液滴的表面张力有时也可以阻止发生液滴的融合或合并。
在一个实施方案中,例如使用本文中描述的技术,可以使两个流体液滴带上相反的电荷(即,正电荷和负电荷,不一定具有相同的量),这可以增加该两个液滴的电相互作用,使得液滴由于它们相反的电荷而可以融合或合并。例如可以将电场施加于液滴,可以使液滴通过电容器,化学反应可以使该液滴带电,等等。作为实例,如图13A中示意性所示,使微流体通道653内含有的液体654所承载的未带电液滴651和652彼此接触,但是例如由于它们的大小和/或表面张力,该液滴不能融合或合并。在一些情况下,即使使用表面活性剂来降低液滴的表面张力,该液滴也可能不能融合。不过,如果该流体液滴充以相反电荷(它们可以是等量的,但并不是必须是等量的),则该液滴可以融合或合并。例如,在图13B中,带正电的液滴655和带负电的液滴656通常被彼此相向引导,这样,带相反电荷的液滴的电相互作用导致该液滴融合为融合液滴657。
在另一实施方案中,可以不必使该流体液滴带相反电荷(而且在一些情况下可以不带任何电荷),通过利用在该流体液滴中诱导的导致流体液滴合并的偶极而融合所述流体液滴。在图13C所示的实例中,被通道670中液体665所包围的液滴660和661(其可以各自独立地带电或是中性的)通过通道移动,这样,它们受到外加电场675的作用。电场675可以是AC场、DC场等,并且例如可以使用电极676和677产生,如文中所示。如图13C所示,各流体液滴中诱导的偶极可以由于它们局部相反的电荷导致流体液滴变得相互电吸引,因此使液滴660和661融合从而形成液滴663。在图13D中,液滴660和661
应当注意的是,在不同实施方案中,允许合并的两个或更多个液滴不必要求“迎头的”相遇。只要该液滴最初发生至少部分融合,则任何角度的接触都是足够的。作为实例,在图12H中,液滴73和74各自在基本相同的方向上移动(例如以不同速度),可以相遇并融合。作为另一实例,在图12I中,液滴73和74以一定角度相遇并融合。在图12J中,三个流体液滴73、74和68相遇并融合,形成液滴79。
融合或合并流体液滴的其它实例描述在Link等人2004年4月9日提交的国际专利申请PCT/US2004/010903中,该申请通过引用并入本文。
液滴内的混合
在相关方面,本发明涉及使一种以上的流体在流体液滴内混合的***和方法。例如,在本发明的多个实施方案中,如上所述,可以使两个或更多个流体液滴融合或合并,然后在融合的液滴内,来自两个或更多个最初流体液滴的两个或更多个流体接着可以发生混合。应该注意的是,当两个液滴融合或合并时,液滴内的充分混合不会即刻发生。而是例如图12B所示,合并的液滴起初可以由第一种流体区71(来自第一液滴73)和第二种流体区72(来自第二液滴74)形成。因此,在一些情况下,该流体区可以仍然是分开的区,例如由于流体液滴内的内部″反渐进式(counter-revolutionary)″流动(图12G中以液滴968表示,箭头977表示方向),从而导致非均一的流体液滴75,如图12A中所示。
不过,在其它情况下,可以使流体液滴内的流体区混合、反应或者彼此相互作用,如图7B所示,从而产生混合的或部分混合的流体液滴78。可以通过自然手段进行混合,例如通过扩散(例如通过各区之间的界面),通过各流体彼此反应,通过液滴内的流体流动(即,对流)等等。不过,在一些情况下,通过流体液滴外部的某些***可以提高区71和72的混合。例如,可以使该流体液滴穿过导致该液滴改变它的速度和/或运动方向的一个或多个通道或其它***。方向改变可以改变液滴内的对流方式,导致该流体至少部分混合。作为实例,在图12C中,液滴76可以通过通道内的一个或多个弯曲,从而导致液滴76内的流体至少部分混合,得到液滴79;或者液滴76可以通过通道内的一个或多个障碍物等。作为另一实例,在图12D中,液滴76通过通道内的一个或多个扩张区77,导致液滴76内的流体至少部分混合,得到液滴79。在图12E中,液滴76通过一个或多个紧缩区69,导致液滴76内的流体至少部分混合,得到液滴79。也可以组合使用。例如,在图12F中,液滴76通过弯曲70、扩张区77和紧缩区69,导致液滴内的流体区至少部分混合。作为又一实例,图14B中的通道706含有一系列弯曲,可以使通道706内液滴内的流体发生混合。
在一组实施方案中,可以将流体注入流体液滴中,这可以导致注入的流体与流体液滴内的其它流体发生混合。有时可以将流体微量注入该流体液滴中,例如使用微型针或其它这样的装置。在其它情况下,当流体液滴与流体通道接触时,使用流体通道可以将流体直接注入流体液滴中。例如此时参考图14C,通道750含有包含一系列流体液滴760的载体流体755。液滴761与流体通道752接触。然后流体可以通过流体通道752被引入流体液滴761中,该流体可以与流体液滴761中的流体相同或不同。
液滴中流体混合的其它实例描述在Link等人2004年4月9日提交的国际专利申请PCT/US2004/010903中,该申请通过引用并入本文。
筛选/分选液滴
在又一方面,本发明提供用于筛选或分选液体中流体液滴的***和方法,并且在一些情况下以较高速率进行。例如可以以某种方式检测和/或测定液滴的特征(例如,如下文进一步描述),然后可以将该液滴引导至例如用于分选或筛选目的的装置的特定区域。
在一些实施方案中,可以以某种方式检测和/或测定流体液滴的特征,例如,如文中所述(例如可以测定该流体液滴的荧光),并且,作为响应,可以施加电场或者从该流体液滴除去电场,以将该流体液滴导向特定区域(例如通道)。在一些情况下,使用本发明的某些***和方法可以实现高分选速度。例如,有时可以测定和/或分选至少约10液滴/秒,并且在其它情况下,至少约20液滴/秒、至少约30液滴/秒、至少约100液滴/秒、至少约200液滴/秒、至少约300液滴/秒、至少约500液滴/秒、至少约750液滴/秒、至少约1000液滴/秒、至少约1500液滴/秒、至少约2000液滴/秒、至少约3000液滴/秒、至少约5000液滴/秒、至少约7500液滴/秒、至少约10000液滴/秒、至少约15000液滴/秒、至少约20000液滴/秒、至少约30000液滴/秒、至少约50000液滴/秒、至少约75000液滴/秒、至少约100000液滴/秒、至少约150000液滴/秒、至少约200000液滴/秒、至少约300000液滴/秒、至少约500000液滴/秒、至少约750000液滴/秒、至少约1000000液滴/秒、至少约1500000液滴/秒、至少约2000000或更多液滴/秒,或者以此方式可以测定和/或分选至少约3000000或更多液滴/秒。
在一组实施方案中,可以通过在液滴上产生电荷(例如,如前所述)以及利用外加电场操纵液滴来引导该流体液滴,其中所述外加电场可以是AC场、DC场等。作为实例,参考图2-4,可以按照需要选择性施加和除去电场(或者可以施加不同的电场,例如,如图4A所示的反向电场),以将该流体液滴导向特定区域。在一些实施方案中,可以根据需要选择性施加和除去电场而基本上不改变含有该流体液滴的液体的流动。例如液体可以在基本稳态的基础上(即,含有该流体液滴的液体的平均流速偏移稳态流动或液体流动相对于时间的预期值小于20%或小于15%,在一些情况下,该平均流速可以偏移小于10%或小于5%)或者其它预定基础上流过本发明的流体***(例如流过通道或微通道),并且液体内含有的流体液滴可以例如使用电场被导向不同区,而基本上不改变通过该流体***的液体的流动。作为具体实例,在图2A、3A和4A中,含有流体液滴15的液体从流体源10流出,通过通道30到达交叉点40,并通过通道50和55排出。在图2A中,流体液滴15被引导通过通道50和55,而在图3A中,流体液滴15只被导向通道55,在图4A中,流体液滴15只被导向通道50。
在另一组实施方案中,通过在流体液滴(其最初可以是带电或不带电的)中诱导偶极而分选或操纵流体液滴,并且使用外加电场分选或操纵液滴。电场可以是AC场、DC场等。例如参考图9A,含有流体液滴530和液体535的通道540分成通道542和544。流体液滴530可以具有电荷,或者可以是不带电的。电极526靠近通道542布置,而电极527靠近通道544布置。电极528靠近通道540、542、和544的会合处布置。在图9C和9D中,使用电极526、527和/或528在流体液滴中诱导偶极。在图9C中,使用电极527和528,通过向液滴530施加电场525而在该液滴中诱导偶极。由于电场的强度,该液滴被强烈吸引向右侧,进入通道544。类似地,在图9D中,使用电极526和528,通过向液滴530施加电场525而在该液滴中诱导偶极,导致该液滴被吸引进入通道542。因此,通过施加适当的电场,液滴530可以根据需要被导向通道542或544。
不过,在其它实施方案中,通过改变含有液滴的液体的流动,可以在本发明的流体***内筛选或分选流体液滴。例如在一组实施方案中,通过将包围流体液滴的液体导向进入第一通道、第二通道等,可以引导或分选流体液滴。作为非限制性实例,参考图10A,流体液滴570被通道580中的液体575包围。通道580分成三条通道581、582和583。例如,使用本领域普通技术人员已知的流控装置例如阀、泵、活塞等可以按照希望将液体流575导向进入通道581、582和583任一个。因此,在图10B中,通过将液体575导向流入通道581(以箭头574表示),将流体液滴570导向进入通道581;在图10C中,通过将液体575导向流入通道582(以箭头574表示),将流体液滴570导向进入通道582;并且在图10D中,通过将液体575导向流入通道583(以箭头574表示),将流体液滴570导向进入通道583。
在另一组实施方案中,可以控制流体***内,例如不同通道内或通道不同部分内的压力,从而引导流体液滴的流动。例如可以将液滴导向通道会合处,此处包括对流动进一步导向的多种选择(例如导向限定任选下游流道的通道中的支路或岔流)。可以控制一条或多条任选下游流道内的压力,从而将液滴选择性地导向进入所述通道中的一个,需要对相继的液滴以时间顺序来改变压力,使其达到会合处,这样可以独立地控制每个相继的液滴下游流动的路径。在一种布置中,液体储器的扩张和/或收缩可以用于将流体液滴引导或分选进入通道中,例如通过使含有流体液滴的液体进行定向运动。可以这样布置液体储器,使得当开动时,由开动的储器引起的液体运动导致该液体在优选的方向上流动,在该优选的方向上运载该流体液滴。例如液体储器扩张可以导致液体流向该储器,而液体储器收缩可以导致液体流离开储器。在一些情况下,液体储器的扩张和/或收缩可以与例如文中所述的其它流控装置和方法组合。可以导致液体储器扩张和/或收缩的非限定性装置实例包括活塞和压电组件。在一些情况下,由于相对快速的响应时间,例如对电信号的响应,压电组件可以是特别适用的。
作为非限定性实例,在图11A中,流体液滴600被通道610中的液体605包围。通道610分成通道611、612。与通道611和612流体连接地布置液体储器617和618,其可以是扩张和/或收缩的,例如,通过压电组件615和616、通过活塞(未示出)等进行。在图11B中,液体储器617扩张,而液体储器618收缩。储器扩张/收缩的作用将导致液体净流流向通道611,如箭头603所示。因此,当流体液滴600达到通道之间的会合处时,通过液体605的运动而被导向通道611。图11C中表示相反的情形,其中,液体储器617收缩,而液体储器618扩张。液体净流流向通道612(如箭头603所示),导致流体液滴600移入通道612中。不过应该注意的是,储器617和618不需要两者都被开动,以将流体液滴600导向进入通道611或612。例如在一个实施方案中,通过液体储器617的扩张(储器618没有任何改变)可以将流体液滴600导向通道611,而在另一实施方案中,通过液体储器618的收缩(储器617没有任何改变)可以将流体液滴600导向通道611。在一些情况下,可以使用两个以上的液体储器。
在一些实施方案中,可以将流体液滴分选进入两条以上的通道。图6A和6B表示在流体***内具有用于输送液滴的多个区的本发明实施方案的非限定性实例。其它布置示于图10A-10D中。在图6A中,通过分别使用电极321/322、323/324和325/326来施加电场以控制在交叉点340、341和342处液滴的运动,通道330中的带电液滴315可以按照希望被导向排出通道350、352、354或356中的任意一条。在图6A中,利用类似于以上讨论的原理,使用外加电场300和301将液滴315导入通道354中。类似地,在图6B中,通过分别使用电极421/422、423/424、425/426和427/428来施加电场以控制在交叉点440、441、442和443处液滴的运动,通道430中的带电液滴415可以被导向排出通道450、452、454、456或458中的任意一条。该图中,液滴415被导向通道454;当然,该带电液滴可以按照希望被导向任何其它排出通道。
在另一实例中,如图2A示意性所示,在装置5中,由流体源10产生的流体液滴15由于使用电场发生器20产生的外加电场而带正电,所述电场发生器20含有两个电极22、24。流体液滴15被含有该液滴的液体引导通过通道30,并导向交叉点40。在交叉点40,该流体液滴没有优选的取向或方向,以相等概率移入排出通道50和55(在该实施方案中,液体以基本相等的速率通过排出通道50和55排出)。类似地,由流体源110产生的流体液滴115由于使用电场发生器120产生的外加电场而带负电,所述电场发生器120含有两个电极122和124。通过通道130流向交叉点140后,该流体液滴没有优选的取向或方向,以相等概率移入排出通道150和155,同样该液体以基本相等的速率通过排出通道150和155排出。交叉点140的典型显微照片在图2B中表示。
在图3A的示意图中,1.4V/微米的电场100以朝向图2A的装置5右侧的方向施加在装置5上。通道30中带正电的流体液滴15在到达交叉点40时,由于外加电场100而被导向通道55右侧,而含有液滴的液体以基本相等的速率通过排出通道50和55连续排出。类似地,通道130中带负电的流体液滴115在到达交叉点40时,由于外加电场100而被导向通道150左侧,而液体流体以基本相等的速率通过排出通道150和155连续排出该装置。因此,根据需要,电场100可以用于将流体液滴导向进入特定通道。交叉点140的典型显微照片在图3B中表示。
图4A是图2A中装置5的示意图,也具有1.4V/微米的外加电场100,但方向相反(即,-1.4V/微米)。该图中,通道30中带正电的流体液滴15在到达交叉点40时,由于外加电场100而被导向左侧从而进入通道50,而通道130中带负电的流体液滴115在到达交叉点140时,由于外加电场100而被导向右侧从而进入通道155。含有液滴的液体以基本相等的速率通过排出通道50和55以及150和155排出。交叉点140的典型显微照片在图4B中表示。
在本发明一些实施方案中,例如根据具体应用,流体液滴可以被分选和/或***成两个或更多个分开的液滴。上述技术中的任一种可以用于***和/或分选液滴。作为非限定性实例,通过向装置(或该装置的部分)施加(或除去)第一电场,可以将流体液滴导向第一区或通道;通过向装置(或该装置的部分)施加(或除去)第二电场,可以将液滴导向第二区或通道;通过向装置(或该装置的部分)施加第三电场,可以将液滴导向第三区或通道;等等,其中,各电场在某些方面可以有所区别,例如强度、方向、频率、持续时间等。在一串液滴中,各液滴可以独立地被分选和/或***;例如,一些液滴可以被导向一个位置或另一个位置,而其它液滴可以被分成被导向两个或更多个位置的多个液滴。
作为一个具体实例,在图8A中,通道560中的流体液滴550、周围液体555可以被导向通道556、通道557,或者被以某种方式在通道562和564之间被***。在图8B中,通过将周围液体555导向通道562,流体液滴550可以被导向左侧从而进入通道562;在图8C中,通过将周围的液体555导向通道564,流体液滴550可以被导向右侧从而进入通道564,在图8D中,可以施加电场,同时结合包围流体液滴550的液体555的流动控制,从而导致液滴冲击会合处561,这可使该液滴被分成两个分开的流体液滴565、566。流体液滴565被导向通道562,而流体液滴566被导向通道566。可以实现外加电场的高度控制,从而控制液滴形成;因此,例如在流体液滴550被分成液滴565和566后,液滴565和566可以有基本上相等的大小,或者液滴565和566之一可以更大些,例如分别如图8E和8F所示。
作为另一实例,在图9A中,运载流体液滴530和液体535的通道540分成通道542和544。流体液滴530可以带电,或者可以是不带电的。电极526靠近通道542布置,而电极527靠近通道544布置。电极528靠近通道540、542和544的会合处布置。当流体液滴530到达会合处时,其受到电场作用,和/或被导向通道或其它区,例如通过将周围的液体导向进入该通道中。如图9B所示,通过使用电极526和527而向液滴施加电场525,可以将流体液滴530分成两个分开的液滴565和566。在图9C中,通过使用电极527和528而向液滴施加电场525,可以在液滴530中诱导偶极。由于外加电场的强度,该液滴可以被强烈吸引到右侧,进入通道544。类似地,在图9D中,通过使用电极526和528而向液滴施加电场525,可以在液滴530中诱导偶极,从而导致该液滴被吸引进入通道542。通过控制哪个电极用于诱导作用在液滴530上的电场和/或外加电场的强度,通道540内的一个或多个流体液滴可以被分选和/或分成两个液滴,并且各液滴可以独立地被分选和/或***。
检测液滴;检测液滴的含量
在本发明某些方面,以一定的方式提供传感器使得允许测定流体液滴的一个或多个特征,该传感器以可以检测和/或测定该流体液滴的一个或多个特征、和/或含有该流体液滴(例如包围流体液滴的液体)的部分流体***的特征。对于液滴可测定的并且可用于本发明的特征可以由本领域普通技术人员鉴别。这些特征的非限定性实例包括荧光、光谱(例如可见、红外、紫外等)、放射性、质量、体积、密度、温度、粘度、pH、物质例如生物物质(例如蛋白质、核酸等)的浓度等。
一些情况下该传感器可以连接至处理器,该处理器反过来又可以对该流体液滴进行操作,例如如前所述通过分选液滴、添加电荷或从液滴中除去电荷、使液滴与其它液滴融合、***液滴、使液滴内发生混合等。例如对流体液滴的传感器测量作出响应,处理器可以使该流体液滴***、与第二个流体液滴合并等。
布置一个或多个传感器和/或处理器,使其与流体液滴传感性连通。文中使用的“传感性连通”是指该传感器可以布置在任何位置,使得可以以某种方式检测和/或测定流体***内(例如通道内)和/或含有流体液滴的部分流体***内的流体液滴。例如,传感器可以与流体液滴和/或含有该流体液滴的部分流体***以流体、光学或可见、热、气动、电等方式传感性连通。传感器可以紧邻流体***布置,例如包埋在内或者与通道壁一体化连接,或者与流体***分开布置,但与该流体***物理、电和/或光连通,这样可以检测和/或测定该流体液滴和/或含有该流体液滴的部分流体***(例如,通道或微通道、含有该流体液滴的液体等)。例如,传感器与含有液滴的通道可以没有任何物理连接,但可以布置传感器以便检测从液滴或流体***发出的电磁辐射,例如红外、紫外或可见光。电磁辐射可以由液滴产生、和/或可以来自流体***(或者流体***外部)的其它部分,并且与流体液滴和/或含有该流体液滴的部分流体***相互作用,使得可以显示该流体液滴的一个或多个特征,例如通过吸收、反射、衍射、折射、荧光、磷光、极性转变、相转变、相对时间的改变等等。作为实例,可以将激光导向该流体液滴和/或包围该流体液滴的液体,并且可以测定流体液滴和/或周围液体的荧光。文中使用的“传感性连通”也可以是直接的或非直接的。作为实例,来自流体液滴的光可以被引到传感器,或者在被导向传感器前首先直接通过光纤***、波导管等。
可用于本发明的传感器的非限定性实例包括基于光或电磁的***。例如,该传感器可以是荧光传感器(例如由激光激发)、显微镜***(其可以包括相机或其它记录设备)等等。作为另一实例,该传感器可以是电子传感器,例如可以测定电场或其它电学特征的传感器。例如,该传感器可以检测流体液滴和/或含有该流体液滴的部分流体***的电容、电感等。
文中使用的“处理器”或“微处理器”是可以从一个或多个传感器接收信号、存储信号和/或控制作出一个或多个响应(例如,如上所述)的任何组件或装置,例如通过使用数学公式或者电子或计算电路。该信号可以是由传感器测得的环境参数的任何合适的指示性信号,例如气动信号、电子信号、光学信号、力学信号等。
作为特定的非限定性实例,本发明装置可以含有包括一个或多个细胞的流体液滴。如果存在某些条件,则细胞可以暴露于结合的荧光信号指示器,例如,指示器可以结合第一种细胞类型,但不结合第二种细胞类型,指示器可以结合表达蛋白,指示器可以显示细胞的成活性(即,该细胞是活的还是死的),指示器可以显示细胞生长或分化的状态等,并且基于荧光信号指示器的存在/不存在和/或量值,该细胞可以被引导通过本发明的流体***。例如,荧光信号指示器的测得可以导致该细胞被导向装置的一个区(例如收集室),而不存在荧光信号指示则可以导致该细胞被导向装置的另一区(例如废料室)。因此,在该实例中,基于细胞的一个或多个可测定的或可作为目标的特征,可以筛选和/或分选细胞群,例如,选择活细胞、表达某种蛋白的细胞、某种细胞类型等。
定义
现在提供多个定义,这将有助于理解本发明的多个方面。下文的更多内容将结合这些定义更完全地描述本发明。注意,本发明多个方面涉及被液体包围的流体液滴(例如悬浮的)。根据具体应用,该液滴可以有基本相同的形状和/或大小,或者有不同的形状和/或大小。文中使用的术语“流体”一般是指易于流动并且符合其容器外形的物质,即,液体、气体、粘弹性流体等。一般地,流体是不能承受静剪切应力的材料,当施加剪切应力时,该流体持续且永久性变形。该流体可以具有允许流动的任何合适的粘度。如果存在两种或更多种流体,则通过考虑流体之间的关系,本领域普通技术人员可以独立地从基本上任何流体(液体、气体等)中选择每种流体。该流体可以各自是可混溶的或不能混溶的。例如,可以选择两种流体,使得它们在形成流体流的时间范围内或者在反应或相互作用的时间范围内基本上是不能混溶的。当部分在相当的时期内保持液体时,则该流体应该是基本上不能混溶的。当接触和/或形成后,分散的部分由于聚合等迅速***,则该流体不需要是不能混溶的。利用接触角测量等,本领域普通技术人员可以选择合适的可混溶或不能混溶的流体以实施本发明的技术。
如文中使用的,如果可以仅通过第二实体围绕第一实体引出闭合的平面环,则第一实体被第二实体“包围”。如果可以不论方向(环的取向)而围绕第一实体引出只穿过第二实体的闭合环,则第一实体被“完全包围”。在一个实施方案中,第一实体是细胞,例如,悬浮在介质中的细胞被该介质包围。在另一实施方案中,第一实体是颗粒。在又一实施方案中,第一实体是流体。在一些情况下(例如当在悬浮体、乳液中等)第二实体也可以是流体,例如,亲水性液体可以悬浮在疏水性液体中,疏水性液体可以悬浮在亲水性液体中,气泡可以悬浮在液体中等等。一般地,疏水性液体和亲水性液体彼此之间基本上是不能混溶的,其中,亲水性液体比疏水性液体对水有更大的亲合性。亲水性液体的实例包括但不限于水和含有水的其它水溶液例如细胞或生物介质、盐溶液等以及其它亲水性液体例如乙醇。疏水性液体的实例包括但不限于油例如烃类、硅油、矿物油、氟代烃油、有机溶剂等。合适流体的其它实例前面已经有述。
类似地,文中使用的“液滴”是被第二种流体完全包围的第一种流体的隔离部分。应注意的是,液滴不必是球形的,例如,根据外部环境也可以采用其它形状。在一个实施方案中,液滴具有基本上等于与包含液滴的流体流动垂直的通道最大尺寸的最小横截面尺寸。
如上所述,在一些而非所有的实施方案中,文中描述的***和方法可以包括一个或多个微流体组件,例如一条或多条微流体通道。文中使用的“微流体”是指包括至少一条流体通道的装置、设备或***,所述流体通道横截面尺寸小于1mm,并且长度与最大横截面尺寸的比至少为3∶1。文中使用的“微流体通道”是满足这些标准的通道。通道的“横截面尺寸”是垂直于通道内流体流动方向测得的。因此,本发明的微流体实施方案中一些或所有流体通道的最大横截面尺寸可以小于2mm,并且某些情况下小于1mm。在一组实施方案中,本发明所有含有流体通道的实施方案都是微流体的或具有不大于2mm或1mm的最大横截面尺寸。在某些实施方案中,该流体通道可以部分地由单个组件(例如蚀刻基质或模铸单元)形成。当然,更大的通道、管、腔室、储器等可以用于向本发明的多种组件或***存储流体和/或传送流体。在一组实施方案中,本发明含有通道的最大横截面尺寸的实施方案小于500微米、小于200微米、小于100微米、小于50微米或者小于25微米。
文中使用的“通道”是指制品(基质)上或其中的部件,其至少部分引导流体的流动。该通道可以具有任何横截面形状(圆形、椭圆形、三角形、不规则形、正方形或长方形等),并且可以是覆盖或未覆盖的。在其被完全覆盖的实施方案中,通道的至少一部分可以有完全密闭的横截面,或者整条通道除了其入口和/或出口外,可以是沿着全部长度完全密闭的。通道也可以有至少2∶1的纵横比(长度比平均横截面尺寸),更一般地至少为3∶1、5∶1、10∶1、15∶1、20∶1或更大。敞开的通道通常包括便于控制流体输送的特征,例如,结构性特征(伸长的压痕)和/或物理或化学特征(疏水性对亲水性)或可以在流体上施加力(例如牵制力)的其它特征。通道内的流体可以部分或完全填充该通道。一些情况下,当使用敞开通道时,该流体可以保持在通道内,例如,使用表面张力(即,凹形或凸形弯液面)。
通道可以是任何尺寸,例如,垂直于流体流动的最大尺寸小于约5mm或2mm,或者小于约1mm,或者小于约500微米、小于约200微米、小于约100微米、小于约60微米、小于约50微米、小于约40微米、小于约30微米、小于约25微米、小于约10微米、小于约3微米、小于约1微米、小于约300nm、小于约100nm、小于约30nm或者小于约10nm。在一些情况下,可以这样选择通道尺寸,使得流体可以自由流过制品或基质。也可以选择通道尺寸,例如,允许通道中流体的特定体积或线性流速。当然,通道数量和通道形状可以通过本领域普通技术人员已知的任何方法进行改变。在一些情况下,可以使用一条以上的通道或毛细管。例如,可以使用两条或更多条通道,其中,它们被布置为在彼此内部,布置为彼此邻接,布置为彼此交叉等等。
在一组实施方案中,该流体液滴可以含有细胞或其它实体,例如蛋白质、病毒、大分子、颗粒等。文中使用的“细胞”具有生物学中使用的普通意义。细胞可以是任何细胞或细胞类型。例如,细胞可以是细菌或其它单细胞生物体、植物细胞或动物细胞。如果细胞是单细胞生物体,则该细胞例如可以是原生动物、锥虫、变形虫、酵母细胞、藻类等。如果细胞是动物细胞,则该细胞例如可以是无脊椎动物细胞(例如,果蝇的细胞)、鱼细胞(例如,斑马鱼(zebrafish)细胞)、两栖动物细胞(例如,青蛙细胞)、爬行动物细胞、鸟类细胞或者哺乳动物细胞例如灵长类动物细胞、牛细胞、马细胞、猪细胞、山羊细胞、狗细胞、猫细胞,或者啮齿类动物例如大鼠或小鼠的细胞。如果细胞来自多细胞生物体,则该细胞可以来自该生物体的任何部分。例如,如果细胞来自动物,则该细胞可以是心肌细胞、成纤维细胞、角质形成细胞、肝细胞(heptaocyte)、软骨细胞(chondracyte)、神经细胞、骨细胞、肌细胞、血细胞、内皮细胞、免疫细胞(例如,T-细胞、B-细胞、巨噬细胞、嗜中性粒细胞、嗜碱性粒细胞、肥大细胞、嗜伊红粒细胞)、干细胞等。一些情况下,细胞可以是遗传工程细胞。在某些实施方案中,细胞可以是中国仓鼠卵巢(“CHO”)细胞或3T3细胞。
材料
根据本发明的某些方面,可以使用多种材料和方法来形成本发明***和装置的任何上述组件。在一些情况下,所选择的多种材料可用于多种方法。例如,本发明的多种组件可以由固体材料形成,其中,可以通过显微机械加工、膜沉积工艺例如旋涂和化学气相沉积、激光制造、光刻技术、包括湿法化学或等离子体工艺的蚀刻方法等形成通道。例如参见Scientific American,248:44-55,1983(Angell等人)。在一个实施方案中,流体***的至少一部分是通过蚀刻硅片中的特征图案(feature)而由硅形成的。用于从硅精确而有效地制造本发明的各种流体***和装置的技术是已知的。在另一实施方案中,本发明***和装置的各种组件可以由聚合物形成,例如弹性体聚合物,如聚二甲基硅氧烷(“PDMS”)、聚四氟乙烯(“PTFE”或Teflon)等等。
不同组件可以由不同材料制得。例如,包括底壁和侧壁的基底部分可以由不透明材料例如硅或PDMS制得,顶部可以由透明或至少部分透明的材料例如玻璃或透明的聚合物制得,用来观察和/或控制流体过程。组件可以被涂覆,从而将所期望的化学官能暴露于接触通道内壁的流体中,其中基底支撑材料不具有精确的、所期望的官能。例如可以如前所述制造组件,通道内壁涂有另一种材料。用于制备本发明***和装置各种组件的材料,例如用于涂覆流体通道内壁的材料,可以理想地选自那些不会负面影响流过流体***的流体或者被其负面影响的材料,例如,在将用于装置内的流体存在下是化学惰性的材料。
在一个实施方案中,本发明的多种组件由聚合物材料和/或柔性材料和/或弹性材料制得,并可以方便地由可硬化的流体形成,便于通过模塑(例如复制成型、注射成型、浇铸成型等)而制造。可硬化的流体基本上可以是任何流体,该流体可以被诱导而固化、或者自发固化为能够容纳和/或输送计划用于流体网络并与该流体网络一起使用的流体的固体。在一个实施方案中,可固化的流体含有聚合物液体或液体聚合物前体(即“预聚物”)。合适的聚合物液体可以包括例如热塑性聚合物、热固性聚合物或者加热到其熔点以上的这些聚合物的混合物。作为另一实例,合适的聚合物液体可以包括一种或多种聚合物在合适溶剂中的溶液,当除去溶剂时该溶液形成固体聚合物材料,例如通过蒸发。这样的聚合物材料是本领域普通技术人员所熟知的,其可以从例如熔融态或通过溶剂蒸发而固化。其中有很多是弹性体的多种聚合物材料是合适的,并且也适合用于形成塑模或主模(mold master),适合用于主模之一或两者都由弹性体材料组成的实施方案。这些聚合物实例的非限定性清单包括普通类型的硅氧烷聚合物、环氧聚合物和丙烯酸酯聚合物。环氧聚合物的特征在于存在通常称为环氧基、1,2-环氧化物或环氧乙烷的三元环醚基团。例如,除了基于芳族胺、三嗪和环脂主链的化合物,可以使用双酚A的二环氧甘油醚。另一实例包括众所周知的酚醛清漆聚合物。根据本发明,适合使用的硅氧烷弹性体非限定性实例包括由包括氯硅烷例如甲基氯硅烷、乙基氯硅烷、苯基氯硅烷等的前体形成的那些。
在一组实施方案中优选硅氧烷聚合物,例如硅氧烷弹性体聚二甲基硅氧烷。PDMS聚合物的非限定性实例包括由Dow Chemical Co.,Midland,MI以商标Sylgard出售的那些,特别是Sylgard 182、Sylgard 184和Sylgard 186。包括PDMS的硅氧烷聚合物有几点有利的性质,使本发明微流体结构的制造简单化。例如,这种材料不昂贵、易于得到,并且通过热固化可以从预聚物液体固化。例如,一般可如下固化PDMS:将该预聚物液体暴露在例如约65℃到约75℃温度下,暴露时间例如约为一小时。而且,硅氧烷聚合物例如PDMS可以是弹性的,因此可以用于形成具有较高纵横比、在本发明某些实施方案中必需的非常小的部件。在这点上,柔性的(例如弹性的)塑模或主模是有利的。
从硅氧烷聚合物例如PDMS形成本发明的结构例如微流体结构的一个优点在于这种聚合物被氧化的能力,例如通过暴露于含有氧的等离子体例如空气等离子体中,使得被氧化的结构在其表面上含有化学基团,该基团能够与其它氧化的硅氧烷聚合物表面或者与多种其它聚合物和非聚合物材料氧化的表面进行交联。因此,可以制造组件,然后氧化,并基本上不可逆地密封到其它硅氧烷聚合物表面上,或者密封到与氧化的硅氧烷聚合物表面反应的其它基质的表面上,不需要单独的胶粘剂或其它密封措施。在多数情况下,通过使氧化的硅氧烷表面与其它表面接触,可以简单地完成密封,而不需要施加辅助压力以形成密封。也就是说,预氧化的硅氧烷表面作为合适的配合表面的接触胶粘剂。特别地,除了对自身是可以不可逆密封的,氧化的硅氧烷例如氧化的PDMS还可以不可逆密封除本身外的多种氧化的材料,包括例如玻璃、硅、硅氧化物、石英、硅氮化物、聚乙烯、聚苯乙烯、玻璃化炭黑和环氧聚合物,其以简单方式被氧化为PDMS表面(例如通过暴露于含有氧的等离子体中)。现有技术中,例如题为“Rapid Prototyping of Microfluidic Systems andPolydimethylsiloxane”,Anal.Chem.,70:474-480,1998(Duffy等人)的文章中,描述了可用于本发明的氧化和密封方法以及整体模塑技术,所述文章通过引用并入本文。
从氧化的硅氧烷聚合物形成本发明的微流体结构(或者内部的、接触流体的表面)的另一优点在于,这些表面与典型的弹性体聚合物表面相比是明显更亲水的(其中,亲水性内表面是理想的)。因此,与由典型的、未氧化的弹性体聚合物或者其它疏水性材料组成的结构相比,这样的亲水性通道表面可以因此更易于被水溶液填充并润湿。
在一个实施方案中,底壁由不同于一个或多个侧壁或顶壁或者其它组件的材料形成。例如,底壁的内表面可以含有硅片或微芯片或者其它基质的表面。如上所述,其它组件可以被密封到这种作为替代方案的基质上。当希望将含有硅氧烷聚合物(例如PDMS)的组件密封到不同材料的基质(底壁)上时,该基质可以选自氧化的硅氧烷聚合物可以不可逆地密封上去的材料(例如已被氧化的玻璃、硅、硅氧化物、石英、硅氮化物、聚乙烯、聚苯乙烯、环氧聚合物和玻璃化炭黑表面)。作为替代方案,可以使用其它密封技术,这对本领域普通技术人员是明显的,包括但不限于使用单独的胶粘剂、热结合、溶剂结合、超声波焊接等。
以下实施例用于说明本发明的某些实施方案,但不能例举本发明的全部范围。
实施例1
图15A表示具有以上所述一些特征的流体***的实例。该实例中,流体液滴被引入流体***800(图15A示意性表示。流体***800含有入口区801(标为″a″)、分叉区802(″b″)、含有柱的区803(″c″)和收集区804(″d″)。入口区801产生一系列包含在液体815内的液滴810。液滴的平均直径约20微米。该实施例中液体是水,并且流体液滴含有十六烷,有约3wt%SPAN80(表面活性剂)。液滴串表示在图15B中,其是图15A示意性所示的入口区801的放大图。
在图15C中,一系列分叉(显微照片左侧所示)将流体液滴分入一系列通道。由于没有有目的地将液滴导向任何特定通道,所以液滴随机分布在通道内。然后液滴被载运到含有一系列柱818的区。该区的放大图表示在图15D中。可以看到,由于存在表面活性剂,单个的液滴保持它们各自的身份而不融合。在图15E中,液滴在收集区804被收集。
实施例2
在该实施例中,说明用微流体装置精确操作流体流。该技术使得利用微量反应试剂的高通量反应器得以实现。当这些反应器的规模缩小时,由于表面吸附和扩散的污染作用会限制可以使用的最小量。将反应试剂限制在处于不能混溶的载体流体中的液滴中可以克服这些局限,但要求新的流体处理技术。基于带电的液滴和电场提出了平台技术的实例,这些带电的液滴和电场使得能够进行电寻址液滴的产生、高效的液滴合并、精确的液滴破裂和再带电以及可控制的液滴分选。
在该实施例中,提出了一般性和实用的平台技术,用于在微流体装置中操作和控制单个的液滴。通过结合液滴上的静电电荷和装置上的电场,分别表示了产生、再结合、***和分选液滴的模式,提供了对各微反应器的精确控制,同时保持高纯度并实现了很高的通量。通过结合由于在电场E中使水性流体带电而产生的力,与只依赖粘力克服表面张力的其它方法相比,来它们各个时间的更精确控制来产生更小的液滴;这提供了实用的液滴产生模式,可以产生体积小至毫微微升的微反应器。不同液滴上相反符号电荷的结合允许液滴可控制地并可靠地发生合并,克服了由于表面张力和润滑作用产生的稳定化力;这提供了实用的液滴合并模式,可以精确混合反应物的等分部分。通过结合电场诱导的拉伸力,大的液滴可以可控地被分成用于进一步分析的较小的等分部分,在一些情况下,可以同时使中性液滴再带有电荷,用于进一步处理;这提供了实用的***或充电模式,可以对相同材料进行多次检验。通过结合由电场在带电液滴上产生的力,单个的液滴可以被引导进入选定的通道;这提供了实用的液滴分选模式,允许选择理想的反应产物。这些模式可用于高速操作和控制各液滴,并且可以用作基于液滴的微流体装置的技术。而且,因为所有控制是通过切换电场实现的,没有活动的部件,并且高至106Hz的频率也可以;这推动了很高通量的组合性技术。
使用软光刻法在透明聚合物材料聚二甲基硅氧烷(PDMS)中形成通道图案。玻璃片形成通道顶部。通过在靠近通道的玻璃片表面上形成氧化铟锡(ITO)电极图案来引入电场,并使用氧等离子体将玻片密封到PDMS上。以PDMS制得的装置的优点在于,强烈疏水性确保油载体相润湿它们的表面,并且水滴不接触通道壁的壁,便于生物分子的分离,并消除了由于表面相互作用导致的交叉污染。
使用集流几何(flow-focusing geometry)形成液滴。水流从一条通道通过狭窄的紧缩处而注入;反向传送的油流流体动力地集中该水流,当其通过该紧缩处时减小其尺寸。可以以形成均匀的油包水液滴稳态流的流动方式运行该液滴发生器。通过油和水的相对流速控制水滴的大小;粘力克服表面张力,形成均匀液滴。如果水的流速太高,则较长的流体射流通过孔并***为液滴,进一步向下流;这些液滴的大小不太均匀。如果水的流速太低,则在孔中***的液滴变得不规则,产生宽范围的液滴尺寸。
然后结合电场产生可电寻址的乳化***。为达到该目的,向水流施加高电压,并使油水界面带电。水流起到导体作用,而油是绝缘体;电化学反应使流体界面充电,如同电容器。在急射处,界面上的电荷保留在液滴上。此外,液滴体积Vd,和频率f可以改变至少三个数量级,而不会改变油或水的注入速率。在该实施例中,液滴大小和频率不是无关的;而是它们的乘积由分散相的注入速率决定Qd=fVd。液滴大小随电场强度增加而减小。在低电场强度时,液滴大小由连续相的流速决定。不过,在高电场强度时,液滴大小由电场决定,并随着E而迅速减小。
对于三种不同流速,液滴大小与外加电压的相关性如下。在低外加电压时,电场的作用可以忽略,液滴形成受表面张力和粘性流动之间竞争的驱动。相反,在高电场强度时,在生长的液滴上存在明显的附加力,F=qE,其中q是液滴上的电荷。由于液滴界面起到电容器作用,q正比于外加电压V。这导致与力是V2关系,这说明了液滴大小随所加电场的增加而减小。对于更高的电场,水流的带电界面被带电的液滴所排斥。
在一个实施方案中,油和水流在30微米的孔处会合。在玻璃上的氧化铟锡(ITO)电极上施加的电压V产生电场E,从而为水油界面进行电容性充电。发现,液滴大小在低电场强度时与电荷无关,但在高场时则减小。液滴大小是电压的函数,表示在连续相油的三种不同的流速(Qc=80nL/s、110nL/s和140nL/s)下流动占优势的和场占优势的急射之间的交迭(crossover)。水的注入速率恒定为Qd=20nL/s。
场诱导的液滴形成所产生的电子控制在该实施例中提供额外的益处:允许在形成循环内调整液滴相中断。只在需要液滴的时刻,将场增加到临界的中断场以上即可实现。这提供了一种在特定位置精确地协调各液滴的产生和到达的便利手段。
在某些基于液滴的反应限制性***中的重要组件是混合器,其混合两种或更多种反应试剂以引发化学反应。一个混合器实例利用静电电荷;使各液滴上带有相反符号的电荷,施加电场使得它们合并。作为实例,阐述了一种带有两个独立喷嘴的装置,所述喷嘴产生具有不同组成和相反电荷的液滴。在两流会合处液滴汇集在一起。在形成时,用于给液滴充电的电极还提供电场,以促使液滴流过流线路,发生合并。在没有电场的情况下,两个喷嘴结构的轻微改变导致它们液滴形成的频率和相方面的轻微差别。因此即使注入速率是相同的,液滴的大小也不同。而且,液滴没有在确实相同的时间到达会合点。结果,液滴没有合并。相反,当施加电场时,液滴形成通常是同时发生的,这确保相同大小的液滴对同时到达会合点。而且,液滴带相反电荷,导致它们穿过流线路并彼此接触,从而使其合并。液滴形成的同步性是由电场介导的两个液滴耦合中断引起的;随着两个液滴前沿之间的分离而变化的电场数值发生改变,并且液滴中断的频率是由电场锁定的模式。该实施例中,假定因为表面活性剂层的稳定化作用,要求最小电荷应该导致液滴合并;E场取决于彼此接触而实际合并的液滴的百分数。
在一个实施方案中,通过向两个水流施加电压,可以产生具有相反符号静电电荷的液滴。在另一实施方案中,在不存在电场的情况下,在两个喷嘴处液滴形成的频率和时机可以是无关的,并且各喷嘴以不同频率产生不同大小的液滴;两个喷嘴处的注入速率是相同的。两个流会合后,来自上和下喷嘴的液滴停留在该流的各自半个部分中。由于表面活性剂,没有发生合并,即使在填充通道宽度的大堵塞情况下。而在另一实施方案中,在喷嘴的500微米间隙施以200V的外加电压,从两个喷嘴同时中断的液滴基本上是一致的;对于注入速率不等的水流,甚至体积差别高达2倍,也可以同时形成液滴。当存在表面活性剂、失水山梨糖醇(sorbiton)单油酸酯3%时,彼此相遇并合并的液滴分数在临界场以上线性增加。
使用带相反电荷的液滴和电场以合并和混合反应试剂是极其实用的,来自两流的几乎100%的液滴与来自相反流的它们的对子(partner)合并。不过,它们合并后,所得的液滴基本上不带静电荷。不过,在形成过程中使液滴带电很方便,必要时,在任何实用的基于液滴的微流体***中,可以使用其它方法使混合的液滴重新带电,用于进一步处理。例如可通过下列方法实现:在电场存在下,使用拉伸流以使中性液滴***,该电场使液滴极化从而形成两个带相反电荷的子液滴。在一个实施方案中,中性液滴进入分叉处,并***成带电的子液滴。在一些情况下,在电场中可以观察到带电液滴的不对称伸长。竖直的虚线显示电极的边缘,其中,液滴回复到它们的对称球形。电场还使得可以精确控制液滴***,提供了实用的液滴***模式的基础,使得可以将含有物分成两份或更多份等分部分的相同反应试剂,有利于对相同微反应器的含有物进行多次检验。
在另一实施方案中,中性液滴可以通过在电场存在下使其破裂而重新带电。未带电的液滴(q=0)在电场(ES不等于0)中被极化,前提是ES足够大,在分叉处的拉伸流动中,液滴破裂为两个带相反电荷的子液滴。在电场ES中带电的液滴被拉伸,但接触电极时回复到球形。
可用于微流体液滴反应***构造的另一组件是液滴分选器。必须检查各自的含有物,选定的液滴可以被分选为离散流(discreet stream)。如该实施例所示,在微流体装置中的这种分选可以通过使用机械阀而实现。利用对液滴的静电充电可以提供一种可选方法,该方法可以被精确控制,可以在高频率下进行切换,并且不需要移动部件。基于电荷与外部电场的线性耦合,液滴上的静电电荷使得能够进行逐滴的分选。将载体流体均等地分开的T-会合处分叉也随机地将液滴群相等地分成两个流。不过,施加于分叉处的小电场可以准确地指示该液滴进入哪个通道;场的方向变换会改变液滴分选的方向。可以作用在液滴上的大的力和高的切换频率能够制成快速且实用的分选机,而没有移动部件;因此,处理速率主要受液滴产生速率的限制。
在一个实施方案中,当没有施加电场时(ES=0),带电的液滴交替地进入右和左通道。当电场施加在右侧时,液滴进入分叉的右支路;当电场反向时,它们进入左支路。分叉之后,液滴间的距离减小到以前的一半,说明该油流是均匀分开的。在一些情况下,可以观察到电场中高度带电的液滴的形状发生变形。
微流体装置中静电电荷带给液滴的提高的官能性能够扩大微流体的应用领域。用于操作液滴的技术的工具箱(toolkit)将使得用于输送和使少量分子反应的***能够进行模块集成。高通量筛选、组合化学以及在库中搜索稀有生物官能都可以潜在地得益于在微通道中对液滴进行的静电操作。例如,基于液滴的微流体技术也可以用于开发芯片规模的荧光激活的细胞分选器(FACS),该细胞分选器具有超出荧光的提高的激活官能性,并且在液滴形成和分选步骤之间包括多个基于反应试剂的检验。而且,通过使用直径几微米的毫微微升的液滴,甚至单个生物分子也显示出>>1nM的浓度,足以用于有效的化学活性和单个分子检验。
基于液滴的微流体装置的多种用途是由以下需要所推动的:将分子、细胞或颗粒的不同种群或库封装入微反应器,然后对含有物进行检验,也许通过添加反应试剂进行,最后,在特殊情形的研究中,需要选择性从收集物中除去特定的微反应器。这要求103/秒的处理速率,以在合理时间内通过最小库进行分选,而对于较大的库,105/秒的处理速率是理想的。如文中所述,这些速率是可行的。而且,因为该微流体装置可以使用冲压技术进行制备,例如,如文中所讨论的,因此可以制造平行流动的流或者流体***,进一步提高总的通量。综上所述,液滴和高通量操作的优点在于为广泛使用提供了明显的机会。
虽然文中描述并说明了本发明的几个实施方案,但本领域普通技术人员易于设想多种其它手段和/或结构用于实现该功能和/或获得文中描述的结果和/或一个或多个优点,这样的变化和/或改进都被认为在本发明的范围内。更一般地,本领域技术人员易于理解,文中描述的所有参数、尺寸、材料和构造都是示例性的,并且实际的参数、尺寸、材料和/或构造将取决于具体应用或本发明教导所用于的领域。本领域技术人员仅仅使用常规实验方法即能了解,或者能够弄清楚文中描述的本发明具体实施方案的等价方案。因此,应该理解,上述实施方案仅是通过实施例给出的,并且在所附权利要求及其等价物范围内,可以不象特别描述和权利要求的那样实施本发明。本发明是指文中描述的每个单个特征、***、制品、材料,箱和/或方法。此外,两个或更多个这些特征、***、制品、材料、箱和/或方法的任何组合也包括在本发明范围内,如果这些特征、***、制品、材料、箱和/或方法相互不矛盾的话。
如文中定义和使用的所有定义应该被理解为包括字典的定义、通过参考并入的文献中的定义和/或所定义术语的通常意义。
在说明书和权利要求中使用的不定冠词″a″和″an″,除非明确的相反性指明,应该理解为是指“至少一个”。
在说明书和权利要求中使用的用语“和/或”应该理解为是指这样结合的各元素的“任一或都”,即,各元素有时一起出现,有时独立地出现。用″和/或″列举的多个元素应该以相同的方式理解,即,这样结合元素的″一种或多种″。由″和/或″从句特别指明的元素以外的其它元素可以任选地存在,不论是否涉及特定指明的那些元素。因此,作为非限定性实例,当与开放式措辞例如″含有″结合使用时,在一个实施方案中,提法″A和/或B″可以只指A(任选包括B以外的元素);在另一实施方案中,只指B(任选包括A以外的元素);在又一实施方案中,指A和B(任选包括其它元素)等。
在说明书和权利要求中使用的″或″应该理解为与以上定义的″和/或″有相同意义。例如,当分开列举中的条目时,″或″或者″和/或″应该解释为是包含性的,即,包括元素的数目或清单中的至少一个,但也可以包括一个以上,并且任选地包括其它未列举的条目。只有明确相反性指明的措辞,例如“只有之一”或者“刚好之一”,或者当用于权利要求中时,“由…构成”是指包括元素的数目或清单中的刚好一个元素。通常,当前面有排除性措辞例如“任一”、“之一”、“只有之一”或者“刚好之一”时,文中使用的术语“或”只解释为是指排除性的选择(即“一个或另一个,而不是都”)。“主要由…构成”当用于权利要求中时,应该具有如专利法领域使用的普通意义。
当用于本文说明书和权利要求中时,涉及一个或多个元素的用语“至少一个”应该理解为是指从在元素列举中的一个或多个元素中选出的至少一个元素,但不必包括该元素列举范围内具体列举的至少每一个以及每一个元素,并且不排除元素列举中元素的任何组合。该定义也允许可以任选存在除元素列举范围内具体指出的用语“至少一个”所指元素外的元素,不论是否涉及或不涉及特定指明的那些元素。因此,作为非限定性实例,“A和B中至少一个”(或者,等价的为“A或B中至少一个”或者等价地“A和/或B中至少一个”)在一个实施方案中是指至少一个,任选包括一个以上的A,而B不存在(并且任选包括B以外的元素);在另一实施方案中,是指至少一个,任选包括一个以上的B,而A不存在(并且任选包括A以外的元素);在又一实施方案中,是指至少一个,任选包括一个以上的A,和至少一个,任选包括一个以上的B(并且任选包括其它元素)等。
还应该理解,除非明确的相反性指明,在这里要求保护的、包括一个以上步骤或做法的方法中,方法的步骤或做法的次序不必限于所述方法的步骤或做法的次序。
在权利要求中以及在上述说明书中,所有的过渡性用语例如“包含”“包括”、“带有”、“具有”、“含有”、“涉及”、“容有”、“由…组成”等应理解为是开放的,即,是指包括但不限于。只有过渡性用语“由…构成”和“主要由…构成”应该分别是封闭的或半封闭的过渡性用语,如美国专利局专利审查程序手册、第2111.03节中所提出的。
Claims (7)
1.一种在微流体***中以受控方式结合至少两种物质的方法,该方法包括以下步骤:
提供一串在微流体***中流动的液滴;
从该串液滴中选择第一液滴,并使第一液滴与该串液滴中的至少一些其它液滴分离,其中,该第一液滴具有小于100微米的最大横截面尺寸,并含有第一种化学物质;
提供从该串液滴分离的第二液滴,其中,该第二液滴具有小于100微米的最大横截面尺寸,并含有第二种化学物质;
选择性推动第一液滴和/或第二液滴朝向可以发生合并的位置;
将所述第一液滴和第二液滴暴露在电场中,从而在所述第一液滴和第二液滴中诱导偶极矩,并通过由于诱导的偶极矩引起的液滴-液滴吸引而使所述第一液滴和第二液滴合并为一个组合液滴;和
测定涉及至少是第一液滴中第一物质和第二液滴中第二物质的反应。
2.根据权利要求1的方法,其中所述第一种化学物质是生物物质。
3.根据权利要求1的方法,其中所述第一种化学物质是生物化学物质。
4.根据权利要求1的方法,其中所述第二种化学物质是生物物质。
5.根据权利要求1的方法,其中所述第二种化学物质是生物化学物质。
6.一种在微流体***中结合至少两个液滴的方法,该方法包括:
在微流体***中提供至少两个液滴;
将该至少两个液滴暴露在电场中,从而在液滴中诱导偶极矩;和
至少部分地通过由于诱导的偶极矩引起的液滴-液滴吸引,将至少两个液滴合并为单个液滴。
7.根据权利要求6的方法,该方法包括,在不存在场诱导的偶极矩时液滴不会合并的条件下合并该液滴。
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Families Citing this family (319)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006507921A (ja) | 2002-06-28 | 2006-03-09 | プレジデント・アンド・フェロウズ・オブ・ハーバード・カレッジ | 流体分散のための方法および装置 |
US20060078893A1 (en) * | 2004-10-12 | 2006-04-13 | Medical Research Council | Compartmentalised combinatorial chemistry by microfluidic control |
GB0307403D0 (en) | 2003-03-31 | 2003-05-07 | Medical Res Council | Selection by compartmentalised screening |
GB0307428D0 (en) | 2003-03-31 | 2003-05-07 | Medical Res Council | Compartmentalised combinatorial chemistry |
WO2004091763A2 (en) * | 2003-04-10 | 2004-10-28 | President And Fellows Of Harvard College | Formation and control of fluidic species |
CN104069784B (zh) | 2003-08-27 | 2017-01-11 | 哈佛大学 | 流体物种的电子控制 |
WO2005073410A2 (en) * | 2004-01-28 | 2005-08-11 | 454 Corporation | Nucleic acid amplification with continuous flow emulsion |
US20050221339A1 (en) * | 2004-03-31 | 2005-10-06 | Medical Research Council Harvard University | Compartmentalised screening by microfluidic control |
US9477233B2 (en) * | 2004-07-02 | 2016-10-25 | The University Of Chicago | Microfluidic system with a plurality of sequential T-junctions for performing reactions in microdroplets |
US9566558B2 (en) | 2004-09-09 | 2017-02-14 | Institut Curie | Device for manipulation of packets in micro-containers, in particular in microchannels |
US7968287B2 (en) | 2004-10-08 | 2011-06-28 | Medical Research Council Harvard University | In vitro evolution in microfluidic systems |
US20070054119A1 (en) * | 2005-03-04 | 2007-03-08 | Piotr Garstecki | Systems and methods of forming particles |
JP2008535644A (ja) | 2005-03-04 | 2008-09-04 | プレジデント・アンド・フエローズ・オブ・ハーバード・カレツジ | 多重エマルジョンの形成のための方法および装置 |
US20070141593A1 (en) * | 2005-08-22 | 2007-06-21 | Lee Linda G | Apparatus, system, and method using immiscible-fluid-discrete-volumes |
US7556776B2 (en) | 2005-09-08 | 2009-07-07 | President And Fellows Of Harvard College | Microfluidic manipulation of fluids and reactions |
JP4639391B2 (ja) * | 2005-10-06 | 2011-02-23 | 財団法人生産技術研究奨励会 | 微小液滴の溶合による液滴の形成方法及びその装置 |
EP2363205A3 (en) | 2006-01-11 | 2014-06-04 | Raindance Technologies, Inc. | Microfluidic Devices And Methods Of Use In The Formation And Control Of Nanoreactors |
EP2263787A3 (en) | 2006-01-27 | 2012-02-22 | President and Fellows of Harvard College | Fluidic droplet coalescence |
WO2007094739A1 (en) * | 2006-02-13 | 2007-08-23 | Agency For Science, Technology And Research | Method of processing a biological and/or chemical sample |
US20090181864A1 (en) * | 2006-03-31 | 2009-07-16 | Nam Trung Nguyen | Active control for droplet-based microfluidics |
US9562837B2 (en) | 2006-05-11 | 2017-02-07 | Raindance Technologies, Inc. | Systems for handling microfludic droplets |
EP3335782B1 (en) * | 2006-05-11 | 2020-09-09 | Bio-Rad Laboratories, Inc. | Microfluidic devices |
EP2077912B1 (en) | 2006-08-07 | 2019-03-27 | The President and Fellows of Harvard College | Fluorocarbon emulsion stabilizing surfactants |
WO2008097559A2 (en) | 2007-02-06 | 2008-08-14 | Brandeis University | Manipulation of fluids and reactions in microfluidic systems |
US9029085B2 (en) | 2007-03-07 | 2015-05-12 | President And Fellows Of Harvard College | Assays and other reactions involving droplets |
CN102014871A (zh) | 2007-03-28 | 2011-04-13 | 哈佛大学 | 乳液及其形成技术 |
WO2008127533A1 (en) * | 2007-04-13 | 2008-10-23 | Freeman Energy Corporation | Biomass cultivation system and corresponding method of operation |
US8592221B2 (en) | 2007-04-19 | 2013-11-26 | Brandeis University | Manipulation of fluids, fluid components and reactions in microfluidic systems |
US8691164B2 (en) * | 2007-04-20 | 2014-04-08 | Celula, Inc. | Cell sorting system and methods |
US8465706B2 (en) | 2007-06-20 | 2013-06-18 | Trustees Of Columbia University In The City Of New York | On-demand microfluidic droplet or bubble generation |
WO2008156837A1 (en) * | 2007-06-20 | 2008-12-24 | The Trustees Of Columbia University In The City Of New York | On-demand microfluidic droplet or bubble generation |
US20100255556A1 (en) * | 2007-06-29 | 2010-10-07 | President And Fellows Of Harvard College | Methods and apparatus for manipulation of fluidic species |
GB0712861D0 (en) * | 2007-07-03 | 2007-08-08 | Eastman Kodak Co | Continuous ink jet printing of encapsulated droplets |
GB0712863D0 (en) * | 2007-07-03 | 2007-08-08 | Eastman Kodak Co | Monodisperse droplet generation |
US20090068170A1 (en) * | 2007-07-13 | 2009-03-12 | President And Fellows Of Harvard College | Droplet-based selection |
JP5547071B2 (ja) * | 2007-08-09 | 2014-07-09 | セルラ・インコーポレイテッド | 関連付け多パラメーター単一細胞測定および残留する生物学的材料の回収のための方法および装置 |
US20090263870A1 (en) * | 2007-09-10 | 2009-10-22 | Agency For Science, Technology And Research | System and method for amplifying a nucleic acid molecule |
GB0720202D0 (en) | 2007-10-16 | 2007-11-28 | Cambridge Entpr Ltd | Microfluidic systems |
US9267918B2 (en) | 2007-10-16 | 2016-02-23 | Cambridge Enterprise Limited | Microfluidic systems |
JP5738597B2 (ja) | 2007-12-21 | 2015-06-24 | プレジデント アンド フェローズ オブ ハーバード カレッジ | 核酸の配列決定のためのシステムおよび方法 |
EP2103244B1 (de) * | 2008-03-20 | 2012-06-20 | Hako-Werke GMBH | Bodenreinigungsmaschine mit einer Wasserenthärtungseinrichtung |
US9664619B2 (en) | 2008-04-28 | 2017-05-30 | President And Fellows Of Harvard College | Microfluidic device for storage and well-defined arrangement of droplets |
WO2009149257A1 (en) * | 2008-06-04 | 2009-12-10 | The University Of Chicago | The chemistrode: a plug-based microfluidic device and method for stimulation and sampling with high temporal, spatial, and chemical resolution |
KR20110042050A (ko) * | 2008-06-05 | 2011-04-22 | 프레지던트 앤드 펠로우즈 오브 하바드 칼리지 | 폴리머좀, 콜로이드좀, 리포좀 및 유체 액적과 관련된 다른 종 |
EP2307560A2 (en) * | 2008-06-27 | 2011-04-13 | Massachusetts Institute of Technology | Microfluidic droplets for metabolic engineering and other applications |
EP4047367A1 (en) | 2008-07-18 | 2022-08-24 | Bio-Rad Laboratories, Inc. | Method for detecting target analytes with droplet libraries |
US12038438B2 (en) | 2008-07-18 | 2024-07-16 | Bio-Rad Laboratories, Inc. | Enzyme quantification |
WO2010033200A2 (en) * | 2008-09-19 | 2010-03-25 | President And Fellows Of Harvard College | Creation of libraries of droplets and related species |
CN101718795B (zh) * | 2008-09-22 | 2012-08-29 | 中国科学院大连化学物理研究所 | 基于气动微阀的微流控芯片液滴操控方法 |
US8709762B2 (en) | 2010-03-02 | 2014-04-29 | Bio-Rad Laboratories, Inc. | System for hot-start amplification via a multiple emulsion |
US9156010B2 (en) | 2008-09-23 | 2015-10-13 | Bio-Rad Laboratories, Inc. | Droplet-based assay system |
US11130128B2 (en) | 2008-09-23 | 2021-09-28 | Bio-Rad Laboratories, Inc. | Detection method for a target nucleic acid |
US9492797B2 (en) | 2008-09-23 | 2016-11-15 | Bio-Rad Laboratories, Inc. | System for detection of spaced droplets |
US9399215B2 (en) | 2012-04-13 | 2016-07-26 | Bio-Rad Laboratories, Inc. | Sample holder with a well having a wicking promoter |
US9132394B2 (en) | 2008-09-23 | 2015-09-15 | Bio-Rad Laboratories, Inc. | System for detection of spaced droplets |
US8633015B2 (en) | 2008-09-23 | 2014-01-21 | Bio-Rad Laboratories, Inc. | Flow-based thermocycling system with thermoelectric cooler |
US10512910B2 (en) | 2008-09-23 | 2019-12-24 | Bio-Rad Laboratories, Inc. | Droplet-based analysis method |
US9417190B2 (en) | 2008-09-23 | 2016-08-16 | Bio-Rad Laboratories, Inc. | Calibrations and controls for droplet-based assays |
US9764322B2 (en) | 2008-09-23 | 2017-09-19 | Bio-Rad Laboratories, Inc. | System for generating droplets with pressure monitoring |
US8951939B2 (en) | 2011-07-12 | 2015-02-10 | Bio-Rad Laboratories, Inc. | Digital assays with multiplexed detection of two or more targets in the same optical channel |
EP2373812B1 (en) | 2008-12-19 | 2016-11-09 | President and Fellows of Harvard College | Particle-assisted nucleic acid sequencing |
EP2406003A2 (en) | 2009-03-13 | 2012-01-18 | President and Fellows of Harvard College | Scale-up of flow-focusing microfluidic devices |
WO2010104604A1 (en) | 2009-03-13 | 2010-09-16 | President And Fellows Of Harvard College | Method for the controlled creation of emulsions, including multiple emulsions |
US8528589B2 (en) | 2009-03-23 | 2013-09-10 | Raindance Technologies, Inc. | Manipulation of microfluidic droplets |
US9447461B2 (en) | 2009-03-24 | 2016-09-20 | California Institute Of Technology | Analysis devices, kits, and related methods for digital quantification of nucleic acids and other analytes |
US10196700B2 (en) | 2009-03-24 | 2019-02-05 | University Of Chicago | Multivolume devices, kits and related methods for quantification and detection of nucleic acids and other analytes |
CA2756463C (en) | 2009-03-24 | 2019-01-22 | University Of Chicago | Slip chip device and methods |
US9464319B2 (en) | 2009-03-24 | 2016-10-11 | California Institute Of Technology | Multivolume devices, kits and related methods for quantification of nucleic acids and other analytes |
US8689981B2 (en) | 2009-04-10 | 2014-04-08 | President And Fellows Of Harvard College | Manipulation of particles in channels |
EP2446278B1 (en) | 2009-06-26 | 2021-11-17 | President and Fellows of Harvard College | Fluid injection |
US20110020855A1 (en) * | 2009-07-21 | 2011-01-27 | Masataka Shinoda | Method and apparatus for performing cytometry |
CN102612652B (zh) * | 2009-08-06 | 2016-05-04 | 康奈尔大学 | 用于分子分析的设备和方法 |
US9789451B2 (en) | 2009-08-28 | 2017-10-17 | Georgia Tech Research Corporation | Method and electro-fluidic device to produce emulsions and particle suspensions |
CA3021714C (en) | 2009-09-02 | 2021-03-09 | Bio-Rad Laboratories, Inc. | System for mixing fluids by coalescence of multiple emulsions |
US20120211084A1 (en) | 2009-09-02 | 2012-08-23 | President And Fellows Of Harvard College | Multiple emulsions created using jetting and other techniques |
US10520500B2 (en) | 2009-10-09 | 2019-12-31 | Abdeslam El Harrak | Labelled silica-based nanomaterial with enhanced properties and uses thereof |
JP5791621B2 (ja) * | 2009-10-27 | 2015-10-07 | プレジデント アンド フェローズ オブ ハーバード カレッジ | 液滴生成技術 |
WO2011079176A2 (en) | 2009-12-23 | 2011-06-30 | Raindance Technologies, Inc. | Microfluidic systems and methods for reducing the exchange of molecules between droplets |
US9366632B2 (en) | 2010-02-12 | 2016-06-14 | Raindance Technologies, Inc. | Digital analyte analysis |
US10351905B2 (en) | 2010-02-12 | 2019-07-16 | Bio-Rad Laboratories, Inc. | Digital analyte analysis |
US9399797B2 (en) | 2010-02-12 | 2016-07-26 | Raindance Technologies, Inc. | Digital analyte analysis |
CA2789425C (en) | 2010-02-12 | 2020-04-28 | Raindance Technologies, Inc. | Digital analyte analysis with polymerase error correction |
US8399198B2 (en) | 2010-03-02 | 2013-03-19 | Bio-Rad Laboratories, Inc. | Assays with droplets transformed into capsules |
US8802441B2 (en) * | 2010-03-04 | 2014-08-12 | National University Of Singapore | Method of synthesizing colloidal nanoparticles |
BR112012023441A2 (pt) * | 2010-03-17 | 2016-05-24 | Basf Se | emulsificação por fusão |
EP2550528B1 (en) | 2010-03-25 | 2019-09-11 | Bio-Rad Laboratories, Inc. | Droplet generation for droplet-based assays |
JP2013524169A (ja) | 2010-03-25 | 2013-06-17 | クァンタライフ・インコーポレーテッド | 液滴によるアッセイ用の検出システム |
JP6155419B2 (ja) | 2010-03-25 | 2017-07-05 | バイオ−ラッド・ラボラトリーズ・インコーポレーテッド | 検出用の液滴輸送システム |
WO2012047324A2 (en) | 2010-06-10 | 2012-04-12 | President And Fellows Of Harvard College | Systems and methods for amplification and phage display |
JP2012024313A (ja) * | 2010-07-23 | 2012-02-09 | Nitto Denko Corp | 液滴生成器及び液滴生成方法 |
US9695390B2 (en) | 2010-08-23 | 2017-07-04 | President And Fellows Of Harvard College | Acoustic waves in microfluidics |
EP2622103B2 (en) | 2010-09-30 | 2022-11-16 | Bio-Rad Laboratories, Inc. | Sandwich assays in droplets |
CN102019277B (zh) * | 2010-10-29 | 2013-05-22 | 北京惟馨雨生物科技有限公司 | 一种用于细胞和颗粒分离的分选仪及分选方法 |
CN106268390B (zh) | 2010-11-01 | 2020-01-10 | 伯乐生命医学产品有限公司 | 用于形成乳液的*** |
AU2011338502B2 (en) | 2010-12-07 | 2016-08-11 | Bio-Rad Laboratories, Inc. | Nucleic acid target detection using a detector, a probe and an inhibitor |
EP2654939A2 (en) | 2010-12-21 | 2013-10-30 | President and Fellows of Harvard College | Spray drying techniques |
KR20140063507A (ko) * | 2011-02-07 | 2014-05-27 | 프레지던트 앤드 펠로우즈 오브 하바드 칼리지 | 액적을 분할하기 위한 시스템 및 방법 |
EP2673614B1 (en) | 2011-02-11 | 2018-08-01 | Raindance Technologies, Inc. | Method for forming mixed droplets |
EP3736281A1 (en) | 2011-02-18 | 2020-11-11 | Bio-Rad Laboratories, Inc. | Compositions and methods for molecular labeling |
EP2685266A1 (en) | 2011-03-08 | 2014-01-15 | Japan Science And Technology Agency | Bead sealing method, method for detecting target molecule, array, kit, and target molecule detection device |
US10018627B2 (en) | 2011-03-08 | 2018-07-10 | Japan Science And Technology Agency | Method for sealing substances, method for detecting target molecule, array, kit, and target molecule detection device |
AU2012231098B2 (en) | 2011-03-18 | 2016-09-29 | Bio-Rad Laboratories, Inc. | Multiplexed digital assays with combinatorial use of signals |
EP2691676B1 (en) | 2011-03-30 | 2019-03-27 | Bio-Rad Laboratories, Inc. | Injection of multiple volumes into or out of droplets |
WO2012135327A1 (en) | 2011-03-31 | 2012-10-04 | Gnubio Inc. | Managing variation in spectroscopic intensity measurements through the use of a reference component |
AU2012236748B2 (en) | 2011-03-31 | 2015-11-26 | Bio-Rad Laboratories, Inc. | Scalable spectroscopic detection and measurement |
AU2012249759A1 (en) | 2011-04-25 | 2013-11-07 | Bio-Rad Laboratories, Inc. | Methods and compositions for nucleic acid analysis |
US9238206B2 (en) | 2011-05-23 | 2016-01-19 | President And Fellows Of Harvard College | Control of emulsions, including multiple emulsions |
US8841071B2 (en) | 2011-06-02 | 2014-09-23 | Raindance Technologies, Inc. | Sample multiplexing |
EP3216872B1 (en) | 2011-06-02 | 2020-04-01 | Bio-Rad Laboratories, Inc. | Enzyme quantification |
BR112014000141A2 (pt) | 2011-07-06 | 2017-06-13 | Harvard College | emulsões múltiplas e técnicas para a formação de emulsões múltiplas |
US8658430B2 (en) | 2011-07-20 | 2014-02-25 | Raindance Technologies, Inc. | Manipulating droplet size |
EP2737089B1 (en) | 2011-07-29 | 2017-09-06 | Bio-rad Laboratories, Inc. | Library characterization by digital assay |
BR112014004554A2 (pt) | 2011-08-30 | 2017-04-04 | Basf Se | sistemas e processos para encapsulamento de cápsulas |
CN103958050B (zh) | 2011-09-28 | 2016-09-14 | 哈佛学院院长等 | 用于液滴产生和/或流体操纵的***和方法 |
US10222391B2 (en) | 2011-12-07 | 2019-03-05 | The Johns Hopkins University | System and method for screening a library of samples |
IN2014DN06644A (zh) | 2012-02-08 | 2015-05-22 | Harvard College | |
WO2013120089A1 (en) | 2012-02-10 | 2013-08-15 | Raindance Technologies, Inc. | Molecular diagnostic screening assay |
WO2013126741A1 (en) | 2012-02-24 | 2013-08-29 | Raindance Technologies, Inc. | Labeling and sample preparation for sequencing |
EP3495503A1 (en) | 2012-03-05 | 2019-06-12 | President and Fellows of Harvard College | Systems and methods for epigenetic sequencing |
US10080997B2 (en) * | 2012-03-16 | 2018-09-25 | Versitech Limited | System and method for generation of emulsions with low interfacial tension and measuring frequency vibrations in the system |
US20150177115A1 (en) | 2012-04-06 | 2015-06-25 | Slingshot Biosciences | Hydrogel particles with tunable optical properties |
EP2839260B1 (en) | 2012-04-20 | 2018-07-18 | Talis Biomedical Corporation | Fluidic devices and systems for sample preparation or autonomous analysis |
US9808798B2 (en) | 2012-04-20 | 2017-11-07 | California Institute Of Technology | Fluidic devices for biospecimen preservation |
US9803237B2 (en) | 2012-04-24 | 2017-10-31 | California Institute Of Technology | Slip-induced compartmentalization |
WO2013163246A2 (en) | 2012-04-25 | 2013-10-31 | President And Fellows Of Harvard College | Polymerization reactions within microfluidic devices |
WO2013165748A1 (en) | 2012-04-30 | 2013-11-07 | Raindance Technologies, Inc | Digital analyte analysis |
GB2539836B (en) | 2012-08-13 | 2017-03-29 | Univ California | Methods for detecting target nucleic acids in sample lysate droplets |
US10323279B2 (en) | 2012-08-14 | 2019-06-18 | 10X Genomics, Inc. | Methods and systems for processing polynucleotides |
US9951386B2 (en) | 2014-06-26 | 2018-04-24 | 10X Genomics, Inc. | Methods and systems for processing polynucleotides |
US10221442B2 (en) | 2012-08-14 | 2019-03-05 | 10X Genomics, Inc. | Compositions and methods for sample processing |
US9701998B2 (en) | 2012-12-14 | 2017-07-11 | 10X Genomics, Inc. | Methods and systems for processing polynucleotides |
US10584381B2 (en) | 2012-08-14 | 2020-03-10 | 10X Genomics, Inc. | Methods and systems for processing polynucleotides |
US10273541B2 (en) | 2012-08-14 | 2019-04-30 | 10X Genomics, Inc. | Methods and systems for processing polynucleotides |
US11591637B2 (en) | 2012-08-14 | 2023-02-28 | 10X Genomics, Inc. | Compositions and methods for sample processing |
US10752949B2 (en) | 2012-08-14 | 2020-08-25 | 10X Genomics, Inc. | Methods and systems for processing polynucleotides |
BR112015003354A8 (pt) | 2012-08-14 | 2018-01-16 | 10X Genomics Inc | métodos e composições de microcápsula |
CN104781386B (zh) | 2012-09-12 | 2018-04-06 | 基纽拜奥股份有限公司 | 用于进行试验的集成微流体***、方法和试剂盒 |
EP2897719A2 (en) * | 2012-09-21 | 2015-07-29 | President and Fellows of Harvard College | Systems and methods for spray drying in microfluidic and other systems |
WO2014085801A1 (en) | 2012-11-30 | 2014-06-05 | The Broad Institute, Inc. | Cryo-treatment in a microfluidic device |
WO2014093676A1 (en) | 2012-12-14 | 2014-06-19 | 10X Technologies, Inc. | Methods and systems for processing polynucleotides |
US10533221B2 (en) | 2012-12-14 | 2020-01-14 | 10X Genomics, Inc. | Methods and systems for processing polynucleotides |
CN105074303B (zh) | 2013-01-25 | 2018-04-10 | 基纽拜奥股份有限公司 | 实施液滴膨胀的***和方法 |
KR20230003659A (ko) | 2013-02-08 | 2023-01-06 | 10엑스 제노믹스, 인크. | 폴리뉴클레오티드 바코드 생성 |
WO2014138154A1 (en) | 2013-03-06 | 2014-09-12 | President And Fellows Of Harvard College | Devices and methods for forming relatively monodisperse droplets |
US10119134B2 (en) | 2013-03-15 | 2018-11-06 | Abvitro Llc | Single cell bar-coding for antibody discovery |
WO2014172288A2 (en) | 2013-04-19 | 2014-10-23 | Raindance Technologies, Inc. | Digital analyte analysis |
US9809851B2 (en) | 2013-05-29 | 2017-11-07 | Bio-Rad Laboratories, Inc. | Systems and methods for sequencing in emulsion based microfluidics |
CN105393094B (zh) | 2013-05-29 | 2019-07-23 | 生物辐射实验室股份有限公司 | 低成本光学高速离散测量*** |
WO2014201196A2 (en) | 2013-06-14 | 2014-12-18 | President And Fellows Of Harvard College | Coalescence of droplets |
EP3039119A4 (en) | 2013-08-27 | 2017-04-05 | GnuBIO, Inc. | Microfluidic devices and methods of their use |
US10395758B2 (en) | 2013-08-30 | 2019-08-27 | 10X Genomics, Inc. | Sequencing methods |
CN105636697B (zh) | 2013-09-30 | 2018-06-12 | 基纽拜奥股份有限公司 | 微流体盒装置和使用方法以及组件 |
US11901041B2 (en) | 2013-10-04 | 2024-02-13 | Bio-Rad Laboratories, Inc. | Digital analysis of nucleic acid modification |
US9592198B2 (en) * | 2013-10-28 | 2017-03-14 | University Of Maryland, College Park | Microfluidic liposome synthesis, purification and active drug loading |
EP3062654B1 (en) * | 2013-10-28 | 2018-12-05 | Travel Light Ltd | Axle free wheels and luggage mounting such wheels |
EP3065712A4 (en) | 2013-11-08 | 2017-06-21 | President and Fellows of Harvard College | Microparticles, methods for their preparation and use |
WO2015077717A1 (en) | 2013-11-25 | 2015-05-28 | The Broad Institute Inc. | Compositions and methods for diagnosing, evaluating and treating cancer by means of the dna methylation status |
US10130950B2 (en) | 2013-11-27 | 2018-11-20 | Bio-Rad Laboratories, Inc. | Microfluidic droplet packing |
WO2015085147A1 (en) | 2013-12-05 | 2015-06-11 | The Broad Institute Inc. | Polymorphic gene typing and somatic change detection using sequencing data |
US9944977B2 (en) | 2013-12-12 | 2018-04-17 | Raindance Technologies, Inc. | Distinguishing rare variations in a nucleic acid sequence from a sample |
US9824068B2 (en) | 2013-12-16 | 2017-11-21 | 10X Genomics, Inc. | Methods and apparatus for sorting data |
JP7060324B2 (ja) | 2013-12-20 | 2022-04-26 | ザ・ブロード・インスティテュート・インコーポレイテッド | ネオ抗原ワクチンによる併用療法 |
US11193176B2 (en) | 2013-12-31 | 2021-12-07 | Bio-Rad Laboratories, Inc. | Method for detecting and quantifying latent retroviral RNA species |
EP4219010A1 (en) | 2014-04-10 | 2023-08-02 | 10X Genomics, Inc. | Methods for encapsulating and partitioning reagents |
CN106232217B (zh) * | 2014-04-15 | 2020-08-04 | 安捷伦科技有限公司 | 创建并收获表面结合的乳液 |
WO2015160919A1 (en) | 2014-04-16 | 2015-10-22 | President And Fellows Of Harvard College | Systems and methods for producing droplet emulsions with relatively thin shells |
EP3132072B1 (en) * | 2014-04-17 | 2019-12-04 | President and Fellows of Harvard College | Methods for droplet tagging |
US20150298091A1 (en) | 2014-04-21 | 2015-10-22 | President And Fellows Of Harvard College | Systems and methods for barcoding nucleic acids |
JP6853667B2 (ja) | 2014-04-21 | 2021-03-31 | プレジデント アンド フェローズ オブ ハーバード カレッジ | 核酸をバーコーディングするためのシステムおよび方法 |
US10232373B2 (en) | 2014-06-16 | 2019-03-19 | Bio-Rad Laboratories, Inc. | Size alternating injection into drops to facilitate sorting |
KR20170023979A (ko) | 2014-06-26 | 2017-03-06 | 10엑스 제노믹스, 인크. | 핵산 서열 조립을 위한 프로세스 및 시스템 |
US10258987B2 (en) | 2014-06-26 | 2019-04-16 | President And Fellows Of Harvard College | Fluid infection using acoustic waves |
CN113249435A (zh) | 2014-06-26 | 2021-08-13 | 10X基因组学有限公司 | 分析来自单个细胞或细胞群体的核酸的方法 |
WO2015200717A2 (en) | 2014-06-27 | 2015-12-30 | The Regents Of The University Of California | Pcr-activated sorting (pas) |
CN106573245B (zh) | 2014-06-30 | 2019-06-18 | 生物辐射实验室股份有限公司 | 实现pcr的浮动热接触 |
WO2016006208A1 (ja) | 2014-07-08 | 2016-01-14 | 国立研究開発法人科学技術振興機構 | 物質封入方法及びターゲット分子を検出する方法 |
AU2015318011B2 (en) | 2014-09-15 | 2020-07-23 | Abvitro Llc | High-throughput nucleotide library sequencing |
WO2016065056A1 (en) | 2014-10-22 | 2016-04-28 | The Regents Of The University Of California | High definition microdroplet printer |
KR20170073667A (ko) | 2014-10-29 | 2017-06-28 | 10엑스 제노믹스, 인크. | 표적화 핵산 서열 분석을 위한 방법 및 조성물 |
US9975122B2 (en) | 2014-11-05 | 2018-05-22 | 10X Genomics, Inc. | Instrument systems for integrated sample processing |
US10258986B2 (en) * | 2014-11-12 | 2019-04-16 | University Of New Hampshire | Viscoelastic fluid drop production |
CA2967635C (en) | 2014-11-14 | 2023-06-06 | Athena Diagnostics, Inc. | Methods to detect a silent carrier genotype |
CA2966915A1 (en) | 2014-11-24 | 2016-06-02 | The Procter & Gamble Company | Methods for encapsulation of actives within droplets and other compartments |
EP3234130B1 (en) | 2014-12-19 | 2020-11-25 | The Broad Institute, Inc. | Methods for profiling the t-cell- receptor repertoire |
WO2016100975A1 (en) | 2014-12-19 | 2016-06-23 | Massachsetts Institute Ot Technology | Molecular biomarkers for cancer immunotherapy |
KR102321863B1 (ko) | 2015-01-12 | 2021-11-08 | 10엑스 제노믹스, 인크. | 핵산 시퀀싱 라이브러리의 제조 방법 및 시스템 및 이를 이용하여 제조한 라이브러리 |
AU2016206706B2 (en) | 2015-01-13 | 2021-10-07 | 10X Genomics, Inc. | Systems and methods for visualizing structural variation and phasing information |
WO2016118949A1 (en) | 2015-01-23 | 2016-07-28 | Neofluidics Llc | A microfluidic serial dilution platform based well-plate using an oil-free immiscible phase driven by manual or electronic pipettors |
CA2974306A1 (en) | 2015-02-04 | 2016-08-11 | The Regents Of The University Of California | Sequencing of nucleic acids via barcoding in discrete entities |
SG11201705996PA (en) | 2015-02-09 | 2017-09-28 | 10X Genomics Inc | Systems and methods for determining structural variation and phasing using variant call data |
KR102564360B1 (ko) | 2015-02-09 | 2023-08-04 | 슬링샷 바이오사이언시즈 인코포레이티드 | 튜닝가능한 광 특성을 갖는 하이드로겔 입자 및 이를 사용하기 위한 방법 |
EP4286516A3 (en) | 2015-02-24 | 2024-03-06 | 10X Genomics, Inc. | Partition processing methods and systems |
KR20170119710A (ko) | 2015-02-24 | 2017-10-27 | 10엑스 제노믹스, 인크. | 표적화된 핵산 서열 커버리지 방법 |
CN116064731A (zh) | 2015-03-13 | 2023-05-05 | 哈佛学院院长及董事 | 使用扩增测定细胞 |
CA2983122A1 (en) | 2015-04-17 | 2016-10-20 | President And Fellows Of Harvard College | Barcoding systems and methods for gene sequencing and other applications |
TWI806815B (zh) | 2015-05-20 | 2023-07-01 | 美商博德研究所有限公司 | 共有之gata3相關之腫瘤特異性新抗原 |
US10632479B2 (en) * | 2015-05-22 | 2020-04-28 | The Hong Kong University Of Science And Technology | Droplet generator based on high aspect ratio induced droplet self-breakup |
CN104888675A (zh) * | 2015-06-08 | 2015-09-09 | 南京理工大学 | 集成传热单元和检测单元的微流体反应器 |
WO2016205728A1 (en) | 2015-06-17 | 2016-12-22 | Massachusetts Institute Of Technology | Crispr mediated recording of cellular events |
WO2017034925A1 (en) | 2015-08-25 | 2017-03-02 | Bio-Rad Laboratories, Inc. | Digital immunoassay |
DK3341116T3 (da) | 2015-08-27 | 2022-05-02 | Harvard College | Sorteringsfremgangsmåde under anvendelse af akustiske bølger |
US10647981B1 (en) | 2015-09-08 | 2020-05-12 | Bio-Rad Laboratories, Inc. | Nucleic acid library generation methods and compositions |
MX2018003532A (es) | 2015-09-24 | 2019-04-25 | Abvitro Llc | Conjugados de afinidad-oligonucleotido y usos de los mismos. |
WO2017053903A1 (en) | 2015-09-24 | 2017-03-30 | Abvitro Llc | Single amplicon activated exclusion pcr |
MX2018003534A (es) | 2015-09-25 | 2019-04-25 | Abvitro Llc | Proceso de alto rendimiento para identificacion de blanco de receptor de celula t de secuencias de receptor de celula t apareadas de manera natural. |
CN105170207B (zh) * | 2015-09-29 | 2017-06-16 | 北京工业大学 | 一种基于支路结构的微液滴控制芯片 |
DE102015219023B3 (de) * | 2015-10-01 | 2017-02-23 | Technische Universität München | Vorrichtung zum Analysieren von biologischen Substanzen in einer Testlösung, Herstellungsverfahren und Betriebsverfahren |
US11123297B2 (en) | 2015-10-13 | 2021-09-21 | President And Fellows Of Harvard College | Systems and methods for making and using gel microspheres |
US11092607B2 (en) | 2015-10-28 | 2021-08-17 | The Board Institute, Inc. | Multiplex analysis of single cell constituents |
WO2017075294A1 (en) | 2015-10-28 | 2017-05-04 | The Board Institute Inc. | Assays for massively combinatorial perturbation profiling and cellular circuit reconstruction |
CN105435869B (zh) * | 2015-11-06 | 2017-05-10 | 常州工学院 | 一种微通道内微液滴***的装置及方法 |
US11371094B2 (en) | 2015-11-19 | 2022-06-28 | 10X Genomics, Inc. | Systems and methods for nucleic acid processing using degenerate nucleotides |
CN108291223B (zh) | 2015-11-20 | 2022-06-07 | 生物辐射实验室股份有限公司 | 液滴测序中的稀疏标识空间 |
SG11201804086VA (en) | 2015-12-04 | 2018-06-28 | 10X Genomics Inc | Methods and compositions for nucleic acid analysis |
CN108779491B (zh) | 2016-02-11 | 2021-03-09 | 10X基因组学有限公司 | 用于全基因组序列数据的从头组装的***、方法和介质 |
US10688493B2 (en) * | 2016-03-09 | 2020-06-23 | Texas Tech University System | Integrated microfluidic rectifier for various bioanalytical applications |
CN107233936B (zh) * | 2016-03-28 | 2023-02-17 | 李木 | 液滴向上及向下分选、原滴上浮、注物下沉式微流控芯片 |
CN107233937A (zh) * | 2016-03-28 | 2017-10-10 | 李木 | 液滴水平及向下分选、原滴平走、注物下沉式微流控芯片 |
WO2017180949A1 (en) | 2016-04-15 | 2017-10-19 | President And Fellows Of Harvard College | Systems and methods for the collection of droplets and/or other entities |
WO2017197338A1 (en) | 2016-05-13 | 2017-11-16 | 10X Genomics, Inc. | Microfluidic systems and methods of use |
GB201609437D0 (en) | 2016-05-27 | 2016-07-13 | Sphere Fluidics Ltd | Surfactants |
CN109689887A (zh) | 2016-07-08 | 2019-04-26 | 加州理工学院 | 用于进行低浓度分析物的流动通过捕获的方法和装置 |
WO2018009766A1 (en) | 2016-07-08 | 2018-01-11 | President And Fellows Of Harvard College | Formation of colloids or gels within droplets |
CN110088290A (zh) | 2016-08-10 | 2019-08-02 | 加利福尼亚大学董事会 | 在乳液微滴中结合多重置换扩增和pcr |
AU2017332495A1 (en) | 2016-09-24 | 2019-04-11 | Abvitro Llc | Affinity-oligonucleotide conjugates and uses thereof |
AU2017382905A1 (en) | 2016-12-21 | 2019-07-04 | The Regents Of The University Of California | Single cell genomic sequencing using hydrogel based droplets |
US10550429B2 (en) | 2016-12-22 | 2020-02-04 | 10X Genomics, Inc. | Methods and systems for processing polynucleotides |
US10815525B2 (en) | 2016-12-22 | 2020-10-27 | 10X Genomics, Inc. | Methods and systems for processing polynucleotides |
US10011872B1 (en) | 2016-12-22 | 2018-07-03 | 10X Genomics, Inc. | Methods and systems for processing polynucleotides |
WO2018140391A1 (en) | 2017-01-24 | 2018-08-02 | The Broad Institute, Inc. | Compositions and methods for detecting a mutant variant of a polynucleotide |
EP4029939B1 (en) | 2017-01-30 | 2023-06-28 | 10X Genomics, Inc. | Methods and systems for droplet-based single cell barcoding |
US10995333B2 (en) | 2017-02-06 | 2021-05-04 | 10X Genomics, Inc. | Systems and methods for nucleic acid preparation |
EP3375889B1 (en) | 2017-03-17 | 2019-12-11 | HiFiBiO SAS | Single cell analysis |
MX2019012398A (es) | 2017-04-18 | 2020-09-25 | Broad Inst Inc | Composiciones para detectar secreciones y metodos de uso. |
EP3615220A4 (en) | 2017-04-28 | 2020-12-30 | Neofluidics, LLC | FLUIDIC REACTION WELL DEVICES, AND ASSOCIATED USES |
US11072816B2 (en) | 2017-05-03 | 2021-07-27 | The Broad Institute, Inc. | Single-cell proteomic assay using aptamers |
WO2018213774A1 (en) | 2017-05-19 | 2018-11-22 | 10X Genomics, Inc. | Systems and methods for analyzing datasets |
US10969350B2 (en) | 2017-05-22 | 2021-04-06 | Arizona Board Of Regents On Behalf Of Arizona Stat | Metal electrode based 3D printed device for tuning microfluidic droplet generation frequency and synchronizing phase for serial femtosecond crystallography |
US10844372B2 (en) | 2017-05-26 | 2020-11-24 | 10X Genomics, Inc. | Single cell analysis of transposase accessible chromatin |
CN109526228B (zh) | 2017-05-26 | 2022-11-25 | 10X基因组学有限公司 | 转座酶可接近性染色质的单细胞分析 |
AU2018273999A1 (en) | 2017-05-26 | 2019-12-05 | Abvitro Llc | High-throughput polynucleotide library sequencing and transcriptome analysis |
US20210146365A1 (en) * | 2017-07-24 | 2021-05-20 | New York Genome Center, Inc. | Techniques for high-throughput fluid exchange in droplets |
DE102017213158A1 (de) | 2017-07-31 | 2019-01-31 | Technische Universität München | Sensoranordnung zum Analysieren von Substanzen in einem Stoff und Verfahren zum Betreiben einer solchen Sensoranordnung |
CA3072328A1 (en) | 2017-08-09 | 2019-02-14 | Neofluidics, Llc | Devices and methods for bioassay |
MA50079A (fr) | 2017-09-07 | 2020-07-15 | Juno Therapeutics Inc | Procédés d'identification de caractéristiques cellulaires relatives à des réponses associées à une thérapie cellulaire |
CN107828651B (zh) * | 2017-09-27 | 2021-02-19 | 江汉大学 | 一种用于单细胞微液滴样品制备的微流控芯片 |
US10837047B2 (en) | 2017-10-04 | 2020-11-17 | 10X Genomics, Inc. | Compositions, methods, and systems for bead formation using improved polymers |
US10501739B2 (en) | 2017-10-18 | 2019-12-10 | Mission Bio, Inc. | Method, systems and apparatus for single cell analysis |
WO2019084043A1 (en) | 2017-10-26 | 2019-05-02 | 10X Genomics, Inc. | METHODS AND SYSTEMS FOR NUCLEIC ACID PREPARATION AND CHROMATIN ANALYSIS |
EP3700672B1 (en) | 2017-10-27 | 2022-12-28 | 10X Genomics, Inc. | Methods for sample preparation and analysis |
CN109746061A (zh) * | 2017-11-06 | 2019-05-14 | 北京新羿生物科技有限公司 | 微液滴生成装置 |
WO2019094775A1 (en) | 2017-11-10 | 2019-05-16 | Neofluidics, Llc | Integrated fluidic circuit and device for droplet manipulation and methods thereof |
SG11201913654QA (en) | 2017-11-15 | 2020-01-30 | 10X Genomics Inc | Functionalized gel beads |
US10829815B2 (en) | 2017-11-17 | 2020-11-10 | 10X Genomics, Inc. | Methods and systems for associating physical and genetic properties of biological particles |
WO2019108851A1 (en) | 2017-11-30 | 2019-06-06 | 10X Genomics, Inc. | Systems and methods for nucleic acid preparation and analysis |
US11332736B2 (en) | 2017-12-07 | 2022-05-17 | The Broad Institute, Inc. | Methods and compositions for multiplexing single cell and single nuclei sequencing |
US11173487B2 (en) | 2017-12-19 | 2021-11-16 | Arizona Board Of Regents On Behalf Of Arizona State University | Deterministic ratchet for sub-micrometer bioparticle separation |
SG11202007686VA (en) | 2018-02-12 | 2020-09-29 | 10X Genomics Inc | Methods characterizing multiple analytes from individual cells or cell populations |
US11639928B2 (en) | 2018-02-22 | 2023-05-02 | 10X Genomics, Inc. | Methods and systems for characterizing analytes from individual cells or cell populations |
WO2019169028A1 (en) | 2018-02-28 | 2019-09-06 | 10X Genomics, Inc. | Transcriptome sequencing through random ligation |
US11841371B2 (en) | 2018-03-13 | 2023-12-12 | The Broad Institute, Inc. | Proteomics and spatial patterning using antenna networks |
CN108535239B (zh) * | 2018-03-28 | 2021-05-25 | 上海艾瑞德生物科技有限公司 | 基于微液滴的微流控芯片和检测*** |
CN112262218A (zh) | 2018-04-06 | 2021-01-22 | 10X基因组学有限公司 | 用于单细胞处理中的质量控制的***和方法 |
CN111989158B (zh) * | 2018-04-15 | 2022-08-12 | 奥普图弗卢迪克生物鉴定有限责任公司 | 压差辅助排水*** |
WO2019217758A1 (en) | 2018-05-10 | 2019-11-14 | 10X Genomics, Inc. | Methods and systems for molecular library generation |
US11414701B2 (en) | 2018-05-24 | 2022-08-16 | The Broad Institute, Inc. | Multimodal readouts for quantifying and sequencing nucleic acids in single cells |
US11932899B2 (en) | 2018-06-07 | 2024-03-19 | 10X Genomics, Inc. | Methods and systems for characterizing nucleic acid molecules |
US11703427B2 (en) | 2018-06-25 | 2023-07-18 | 10X Genomics, Inc. | Methods and systems for cell and bead processing |
EP3797279A4 (en) * | 2018-07-11 | 2022-08-03 | The University of Hong Kong | AUTOMATIC MICROFLUIDIC SYSTEM FOR CONTINUOUS AND QUANTITATIVE DROPLET COLLECTION |
US20200032335A1 (en) | 2018-07-27 | 2020-01-30 | 10X Genomics, Inc. | Systems and methods for metabolome analysis |
CN109164073B (zh) * | 2018-08-03 | 2021-12-21 | 大连大学 | 用于水体重金属离子测定的数字微流控芯片***及方法 |
US20220411783A1 (en) | 2018-10-12 | 2022-12-29 | The Broad Institute, Inc. | Method for extracting nuclei or whole cells from formalin-fixed paraffin-embedded tissues |
GB201817321D0 (en) | 2018-10-24 | 2018-12-05 | Nanna Therapeutics Ltd | Microbeads for tagless encoded chemical library screening |
EP3870369A4 (en) | 2018-10-26 | 2022-11-09 | Neofluidics, LLC | FLUID DEVICES HAVING REACTION WELLS AND THROAT CHANNEL AND USES THEREOF |
US11459607B1 (en) | 2018-12-10 | 2022-10-04 | 10X Genomics, Inc. | Systems and methods for processing-nucleic acid molecules from a single cell using sequential co-partitioning and composite barcodes |
WO2020123657A2 (en) | 2018-12-11 | 2020-06-18 | 10X Genomics, Inc. | Methods and devices for detecting and sorting droplets or particles |
WO2020139844A1 (en) | 2018-12-24 | 2020-07-02 | 10X Genomics, Inc. | Devices, systems, and methods for controlling liquid flow |
US11845983B1 (en) | 2019-01-09 | 2023-12-19 | 10X Genomics, Inc. | Methods and systems for multiplexing of droplet based assays |
WO2020168013A1 (en) | 2019-02-12 | 2020-08-20 | 10X Genomics, Inc. | Methods for processing nucleic acid molecules |
US11467153B2 (en) | 2019-02-12 | 2022-10-11 | 10X Genomics, Inc. | Methods for processing nucleic acid molecules |
US11851683B1 (en) | 2019-02-12 | 2023-12-26 | 10X Genomics, Inc. | Methods and systems for selective analysis of cellular samples |
US11655499B1 (en) | 2019-02-25 | 2023-05-23 | 10X Genomics, Inc. | Detection of sequence elements in nucleic acid molecules |
WO2020176449A1 (en) | 2019-02-26 | 2020-09-03 | President And Fellows Of Harvard College | Systems and methods for high throughput selection |
EP3930900A1 (en) | 2019-02-28 | 2022-01-05 | 10X Genomics, Inc. | Devices, systems, and methods for increasing droplet formation efficiency |
EP3938537A1 (en) | 2019-03-11 | 2022-01-19 | 10X Genomics, Inc. | Systems and methods for processing optically tagged beads |
US11624718B2 (en) | 2019-05-14 | 2023-04-11 | Arizona Board Of Regents On Behalf Of Arizona State University | Single piece droplet generation and injection device for serial crystallography |
US11318487B2 (en) | 2019-05-14 | 2022-05-03 | Arizona Board Of Regents On Behalf Of Arizona State University | Co-flow injection for serial crystallography |
AU2020280104A1 (en) | 2019-05-22 | 2022-01-20 | Mission Bio, Inc. | Method and apparatus for simultaneous targeted sequencing of DNA, RNA and protein |
US11667954B2 (en) | 2019-07-01 | 2023-06-06 | Mission Bio, Inc. | Method and apparatus to normalize quantitative readouts in single-cell experiments |
US11701658B2 (en) | 2019-08-09 | 2023-07-18 | President And Fellows Of Harvard College | Systems and methods for microfluidic particle selection, encapsulation, and injection using surface acoustic waves |
US11919002B2 (en) | 2019-08-20 | 2024-03-05 | 10X Genomics, Inc. | Devices and methods for generating and recovering droplets |
CN110449195A (zh) * | 2019-09-05 | 2019-11-15 | 北京工业大学 | 一种提高液滴在不对称通道***均匀度的装置 |
CN110743634B (zh) * | 2019-09-20 | 2021-06-01 | 华南农业大学 | 一种微流控设备 |
CN110643488A (zh) * | 2019-09-27 | 2020-01-03 | 晶准生物医学(深圳)有限公司 | 微流控液滴操纵分割装置及其操纵分割方法 |
US11919000B2 (en) | 2019-10-10 | 2024-03-05 | 1859, Inc. | Methods and systems for microfluidic screening |
CN115004009A (zh) | 2020-01-24 | 2022-09-02 | 弹弓生物科学公司 | 用于细胞样校准颗粒的组合物和方法 |
GB202005615D0 (en) | 2020-04-17 | 2020-06-03 | Sphere Fluidics Ltd | Droplet spacing |
US10953404B1 (en) | 2020-04-24 | 2021-03-23 | Pattern Bioscience, Inc. | Apparatuses for contactless loading and imaging of microfluidic chips and related methods |
US11686730B2 (en) | 2020-04-30 | 2023-06-27 | Quanterix Corporation | Quantitative antibody test |
EP4147049A1 (en) | 2020-05-04 | 2023-03-15 | Slingshot Biosciences, Inc. | Compositions and methods for passive optical barcoding for multiplexed assays |
US11851700B1 (en) | 2020-05-13 | 2023-12-26 | 10X Genomics, Inc. | Methods, kits, and compositions for processing extracellular molecules |
EP3950772A1 (en) | 2020-08-05 | 2022-02-09 | Emulseo SAS | Novel fluorosurfactants and uses thereof in microfluidics |
US20230356226A1 (en) * | 2020-08-31 | 2023-11-09 | Agilent Technologies, Inc. | Microfluidic chip-based droplet processor |
CN116367913A (zh) | 2020-09-02 | 2023-06-30 | 10X基因组学有限公司 | 用于高通量液滴形成的流动聚焦装置、***和方法 |
CN116171200A (zh) | 2020-09-02 | 2023-05-26 | 10X基因组学有限公司 | 用于高通量液滴形成的装置、***和方法 |
US11485632B2 (en) | 2020-10-09 | 2022-11-01 | Arizona Board Of Regents On Behalf Of Arizona State University | Modular 3-D printed devices for sample delivery and method |
WO2022146770A1 (en) | 2020-12-28 | 2022-07-07 | Neofluidics Llc | A microfluidic serial dilution platform based well-plate using an oil-free immiscible phase driven by manual or electronic pipettors and method of operation |
AU2022227563A1 (en) | 2021-02-23 | 2023-08-24 | 10X Genomics, Inc. | Probe-based analysis of nucleic acids and proteins |
EP4297901A1 (en) | 2021-02-24 | 2024-01-03 | 10X Genomics, Inc. | Method for concentrating droplets in an emulsion |
CN113033117B (zh) * | 2021-03-09 | 2024-03-19 | 江苏大学 | 一种运动荷电液滴诱导电场强度及电场力计算方法和*** |
EP4313412A1 (en) | 2021-03-26 | 2024-02-07 | 10X Genomics, Inc. | Devices, methods, and systems for improved droplet recovery |
WO2022232050A1 (en) | 2021-04-26 | 2022-11-03 | The Broad Institute, Inc. | Compositions and methods for characterizing polynucleotide sequence alterations |
WO2023004068A2 (en) | 2021-07-21 | 2023-01-26 | 10X Genomics, Inc. | Methods, devices, and kits for purifying and lysing biological particles |
WO2023099667A1 (en) | 2021-12-01 | 2023-06-08 | Vilnius University | Methods for processing and barcoding nucleic acids |
WO2023168423A1 (en) | 2022-03-04 | 2023-09-07 | 10X Genomics, Inc. | Droplet forming devices and methods having fluoropolymer silane coating agents |
US20240026339A1 (en) | 2022-07-10 | 2024-01-25 | Vilnius University | Composition and the use of cell lysis reagents |
EP4402192A2 (en) | 2022-08-18 | 2024-07-24 | 10X Genomics, Inc. | Droplet forming devices and methods having flourous diol additives |
CN115845685B (zh) * | 2022-12-29 | 2024-05-10 | 大连理工大学 | 一种逆流射流环隙微混合器 |
CN116355725B (zh) * | 2023-03-07 | 2024-04-05 | 广州市艾贝泰生物科技有限公司 | 分配器、分配装置及分配方法 |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4279345A (en) * | 1979-08-03 | 1981-07-21 | Allred John C | High speed particle sorter using a field emission electrode |
EP0718038A2 (de) * | 1991-08-19 | 1996-06-26 | Fraunhofer-Gesellschaft Zur Förderung Der Angewandten Forschung E.V. | Vorrichtung zur Trennung von Gemischten mikroskopisch kleiner, in einer Flüssigkeit oder einem Gel suspendierter dielektrischer Teilchen |
US6149789A (en) * | 1990-10-31 | 2000-11-21 | Fraunhofer Gesellschaft Zur Forderung Der Angewandten Forschung E.V. | Process for manipulating microscopic, dielectric particles and a device therefor |
WO2001094635A2 (en) * | 2000-06-05 | 2001-12-13 | California Institute Of Technology | Integrated active flux microfluidic devices and methods |
US6432630B1 (en) * | 1996-09-04 | 2002-08-13 | Scandinanian Micro Biodevices A/S | Micro-flow system for particle separation and analysis |
CN1378485A (zh) * | 1999-08-12 | 2002-11-06 | Ut-巴特勒有限公司 | 用于可控操纵小体积的微流控装置 |
US20030015425A1 (en) * | 2001-06-20 | 2003-01-23 | Coventor Inc. | Microfluidic system including a virtual wall fluid interface port for interfacing fluids with the microfluidic system |
Family Cites Families (206)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2692800A (en) | 1951-10-08 | 1954-10-26 | Gen Electric | Nozzle flow control |
US3816331A (en) * | 1972-07-05 | 1974-06-11 | Ncr | Continuous encapsulation and device therefor |
US4059552A (en) | 1974-06-21 | 1977-11-22 | The Dow Chemical Company | Cross-linked water-swellable polymer particles |
US3982541A (en) * | 1974-07-29 | 1976-09-28 | Esperance Jr Francis A L | Eye surgical instrument |
SE400841B (sv) | 1976-02-05 | 1978-04-10 | Hertz Carl H | Sett att alstra en vetskestrale samt anordning for genomforande av settet |
JPS52144372A (en) | 1976-05-28 | 1977-12-01 | Agency Of Ind Science & Technol | Equipment for continuous countercurrent contact |
JPS5372016A (en) | 1976-12-08 | 1978-06-27 | Toyo Tire & Rubber Co Ltd | Apparatus for preparation and supply of heavy oil w/o emulsion fuel |
GB2097692B (en) * | 1981-01-10 | 1985-05-22 | Shaw Stewart P D | Combining chemical reagents |
JPS6057907B2 (ja) * | 1981-06-18 | 1985-12-17 | 工業技術院長 | 液体の混合噴霧化方法 |
DE3230289A1 (de) * | 1982-08-14 | 1984-02-16 | Bayer Ag, 5090 Leverkusen | Herstellung von pharmazeutischen oder kosmetischen dispersionen |
US4853336A (en) * | 1982-11-15 | 1989-08-01 | Technicon Instruments Corporation | Single channel continuous flow system |
US4618476A (en) | 1984-02-10 | 1986-10-21 | Eastman Kodak Company | Capillary transport device having speed and meniscus control means |
US4865444A (en) | 1984-04-05 | 1989-09-12 | Mobil Oil Corporation | Apparatus and method for determining luminosity of hydrocarbon fuels |
ATE48477T1 (de) | 1984-09-11 | 1989-12-15 | Partec Ag | Verfahren und vorrichtung zur sortierung von mikroskopischen partikeln. |
GB8604328D0 (en) * | 1986-02-21 | 1986-03-26 | Ici Plc | Producing spray of droplets of liquid |
US4916070A (en) | 1986-04-14 | 1990-04-10 | The General Hospital Corporation | Fibrin-specific antibodies and method of screening for the antibodies |
US5204112A (en) * | 1986-06-16 | 1993-04-20 | The Liposome Company, Inc. | Induction of asymmetry in vesicles |
US5149625A (en) | 1987-08-11 | 1992-09-22 | President And Fellows Of Harvard College | Multiplex analysis of DNA |
US4931225A (en) * | 1987-12-30 | 1990-06-05 | Union Carbide Industrial Gases Technology Corporation | Method and apparatus for dispersing a gas into a liquid |
US5055390A (en) | 1988-04-22 | 1991-10-08 | Massachusetts Institute Of Technology | Process for chemical manipulation of non-aqueous surrounded microdroplets |
US5093602A (en) | 1989-11-17 | 1992-03-03 | Charged Injection Corporation | Methods and apparatus for dispersing a fluent material utilizing an electron beam |
JP3176607B2 (ja) | 1990-02-07 | 2001-06-18 | 群馬大学長 | 均一な液滴の形成方法 |
JPH03292881A (ja) | 1990-04-11 | 1991-12-24 | Yaskawa Electric Corp | マイクロ細胞融合装置 |
SE500071C2 (sv) | 1992-06-25 | 1994-04-11 | Vattenfall Utveckling Ab | Anordning för blandning av två fluider, i synnerhet vätskor med olika temperatur |
DE4308839C2 (de) | 1993-03-19 | 1997-04-30 | Jordanow & Co Gmbh | Vorrichtung zum Mischen von Strömungsmedien |
US5512131A (en) * | 1993-10-04 | 1996-04-30 | President And Fellows Of Harvard College | Formation of microstamped patterns on surfaces and derivative articles |
US5486337A (en) * | 1994-02-18 | 1996-01-23 | General Atomics | Device for electrostatic manipulation of droplets |
BR9502777A (pt) * | 1994-06-13 | 1996-04-23 | Praxair Technology Inc | Equipamento e processo para a atomização de combustível líquido |
US5935331A (en) * | 1994-09-09 | 1999-08-10 | Matsushita Electric Industrial Co., Ltd. | Apparatus and method for forming films |
JP3633650B2 (ja) | 1994-09-09 | 2005-03-30 | 松下電器産業株式会社 | 薄膜形成方法 |
US5762775A (en) * | 1994-09-21 | 1998-06-09 | Lockheed Martin Energy Systems, Inc. | Method for electrically producing dispersions of a nonconductive fluid in a conductive medium |
DE4438232A1 (de) | 1994-10-26 | 1996-05-02 | Guenter Prof Dr Fuhr | Kryokonservierung und Tieftemperaturbearbeitung von biologischen Zellen |
JPH08153669A (ja) | 1994-11-30 | 1996-06-11 | Hitachi Ltd | 薄膜形成方法及び形成装置 |
US5529675A (en) * | 1994-12-16 | 1996-06-25 | Shell Oil Company | Electrostatic coalescer testing apparatus |
WO1996029629A2 (en) | 1995-03-01 | 1996-09-26 | President And Fellows Of Harvard College | Microcontact printing on surfaces and derivative articles |
JP3232525B2 (ja) | 1995-08-22 | 2001-11-26 | 信越化学工業株式会社 | 撥水処理剤 |
US6130098A (en) * | 1995-09-15 | 2000-10-10 | The Regents Of The University Of Michigan | Moving microdroplets |
US5851769A (en) | 1995-09-27 | 1998-12-22 | The Regents Of The University Of California | Quantitative DNA fiber mapping |
JP3759986B2 (ja) * | 1995-12-07 | 2006-03-29 | フロイント産業株式会社 | シームレスカプセルおよびその製造方法 |
US5681600A (en) | 1995-12-18 | 1997-10-28 | Abbott Laboratories | Stabilization of liquid nutritional products and method of making |
US5868322A (en) | 1996-01-31 | 1999-02-09 | Hewlett-Packard Company | Apparatus for forming liquid droplets having a mechanically fixed inner microtube |
US6355198B1 (en) * | 1996-03-15 | 2002-03-12 | President And Fellows Of Harvard College | Method of forming articles including waveguides via capillary micromolding and microtransfer molding |
US5942443A (en) * | 1996-06-28 | 1999-08-24 | Caliper Technologies Corporation | High throughput screening assay systems in microscale fluidic devices |
US6187214B1 (en) | 1996-05-13 | 2001-02-13 | Universidad De Seville | Method and device for production of components for microfabrication |
US6248378B1 (en) * | 1998-12-16 | 2001-06-19 | Universidad De Sevilla | Enhanced food products |
US6116516A (en) | 1996-05-13 | 2000-09-12 | Universidad De Sevilla | Stabilized capillary microjet and devices and methods for producing same |
US6196525B1 (en) * | 1996-05-13 | 2001-03-06 | Universidad De Sevilla | Device and method for fluid aeration via gas forced through a liquid within an orifice of a pressure chamber |
US6405936B1 (en) * | 1996-05-13 | 2002-06-18 | Universidad De Sevilla | Stabilized capillary microjet and devices and methods for producing same |
US6189803B1 (en) * | 1996-05-13 | 2001-02-20 | University Of Seville | Fuel injection nozzle and method of use |
ES2140998B1 (es) * | 1996-05-13 | 2000-10-16 | Univ Sevilla | Procedimiento de atomizacion de liquidos. |
US6299145B1 (en) | 1996-05-13 | 2001-10-09 | Universidad De Sevilla | Device and method for fluid aeration via gas forced through a liquid within an orifice of a pressure chamber |
US6386463B1 (en) * | 1996-05-13 | 2002-05-14 | Universidad De Sevilla | Fuel injection nozzle and method of use |
DE69728269T2 (de) | 1996-06-14 | 2005-03-10 | University Of Washington, Seattle | Absorbtionsverbessertes differentielles extraktionsverfahren |
NL1003442C2 (nl) | 1996-06-27 | 1998-01-07 | Univ Delft Tech | Werkwijze voor het bereiden van een poeder, een met de genoemde werkwijze bereid poeder, een elektrode en een inrichting voor toepassing bij de genoemde werkwijze. |
US6267858B1 (en) | 1996-06-28 | 2001-07-31 | Caliper Technologies Corp. | High throughput screening assay systems in microscale fluidic devices |
US6252129B1 (en) * | 1996-07-23 | 2001-06-26 | Electrosols, Ltd. | Dispensing device and method for forming material |
US6143248A (en) | 1996-08-12 | 2000-11-07 | Gamera Bioscience Corp. | Capillary microvalve |
US6221654B1 (en) * | 1996-09-25 | 2001-04-24 | California Institute Of Technology | Method and apparatus for analysis and sorting of polynucleotides based on size |
US6120666A (en) | 1996-09-26 | 2000-09-19 | Ut-Battelle, Llc | Microfabricated device and method for multiplexed electrokinetic focusing of fluid streams and a transport cytometry method using same |
US5858187A (en) | 1996-09-26 | 1999-01-12 | Lockheed Martin Energy Systems, Inc. | Apparatus and method for performing electrodynamic focusing on a microchip |
JPH10217477A (ja) | 1997-02-07 | 1998-08-18 | Fuji Xerox Co Ltd | インクジェット記録装置 |
EP0981408B1 (en) | 1997-05-16 | 2004-04-21 | Alberta Research Council | Microfluidic system and methods of use |
DE69826697T2 (de) * | 1997-07-07 | 2006-02-16 | Medical Research Council | In vitro selektionsmethode |
US5980936A (en) | 1997-08-07 | 1999-11-09 | Alliance Pharmaceutical Corp. | Multiple emulsions comprising a hydrophobic continuous phase |
US20020001544A1 (en) | 1997-08-28 | 2002-01-03 | Robert Hess | System and method for high throughput processing of droplets |
CA2300203A1 (en) | 1997-09-02 | 1999-03-11 | Caliper Technologies Corporation | Microfluidic system with electrofluidic and electrothermal controls |
US7214298B2 (en) * | 1997-09-23 | 2007-05-08 | California Institute Of Technology | Microfabricated cell sorter |
US6540895B1 (en) * | 1997-09-23 | 2003-04-01 | California Institute Of Technology | Microfabricated cell sorter for chemical and biological materials |
SE512663C2 (sv) | 1997-10-23 | 2000-04-17 | Biogram Ab | Inkapslingsförfarande för aktiv substans i en bionedbrytbar polymer |
US6113078A (en) * | 1998-03-18 | 2000-09-05 | Lytesyde, Llc | Fluid processing method |
JP3081880B2 (ja) * | 1998-03-30 | 2000-08-28 | 農林水産省食品総合研究所長 | マイクロスフィアの連続製造装置 |
AU763433B2 (en) | 1998-05-22 | 2003-07-24 | California Institute Of Technology | Microfabricated cell sorter |
US6003794A (en) * | 1998-08-04 | 1999-12-21 | Progressive Grower Technologies, Inc. | Electrostatic spray module |
US6296020B1 (en) | 1998-10-13 | 2001-10-02 | Biomicro Systems, Inc. | Fluid circuit components based upon passive fluid dynamics |
GB9822185D0 (en) | 1998-10-13 | 1998-12-02 | Zeneca Ltd | Device |
BR9914788A (pt) * | 1998-10-24 | 2001-07-03 | Xaar Technology Ltd | Aparelho de deposição de gotìculas |
US6614598B1 (en) | 1998-11-12 | 2003-09-02 | Institute Of Technology, California | Microlensing particles and applications |
US6450189B1 (en) | 1998-11-13 | 2002-09-17 | Universidad De Sevilla | Method and device for production of components for microfabrication |
WO2000032307A1 (en) | 1998-12-01 | 2000-06-08 | Brown University Research Foundation | Preparation of multiwall polymeric microcapsules from hydrophilic polymers |
AU762100B2 (en) | 1998-12-22 | 2003-06-19 | University Of Tennessee Research Corporation, The | Protective antigen of group A Streptococci (SPA) |
GB9900298D0 (en) * | 1999-01-07 | 1999-02-24 | Medical Res Council | Optical sorting method |
US6565727B1 (en) * | 1999-01-25 | 2003-05-20 | Nanolytics, Inc. | Actuators for microfluidics without moving parts |
US6294063B1 (en) * | 1999-02-12 | 2001-09-25 | Board Of Regents, The University Of Texas System | Method and apparatus for programmable fluidic processing |
US6633031B1 (en) | 1999-03-02 | 2003-10-14 | Advion Biosciences, Inc. | Integrated monolithic microfabricated dispensing nozzle and liquid chromatography-electrospray system and method |
DE19911777A1 (de) | 1999-03-17 | 2000-09-21 | Merck Patent Gmbh | Verfahren zur Herstellung von kosmetischen Formulierungen |
JP2002539289A (ja) | 1999-03-18 | 2002-11-19 | エクソンモービル リサーチ アンド エンジニアリング カンパニー | Fcc原料油を霧化する方法および装置 |
US6506609B1 (en) * | 1999-05-17 | 2003-01-14 | Caliper Technologies Corp. | Focusing of microparticles in microfluidic systems |
US6592821B1 (en) * | 1999-05-17 | 2003-07-15 | Caliper Technologies Corp. | Focusing of microparticles in microfluidic systems |
US20060169800A1 (en) * | 1999-06-11 | 2006-08-03 | Aradigm Corporation | Aerosol created by directed flow of fluids and devices and methods for producing same |
EP1192009B1 (en) | 1999-06-11 | 2013-05-01 | Aradigm Corporation | Method for producing an aerosol |
ATE215673T1 (de) * | 1999-06-28 | 2002-04-15 | California Inst Of Techn | Elastomerische mikropumpen- und mikroventilsysteme |
US6524456B1 (en) * | 1999-08-12 | 2003-02-25 | Ut-Battelle, Llc | Microfluidic devices for the controlled manipulation of small volumes |
US20010050881A1 (en) | 1999-09-20 | 2001-12-13 | Depaoli David W. | Continuous flow, electrohydrodynamic micromixing apparatus and methods |
US6890487B1 (en) * | 1999-09-30 | 2005-05-10 | Science & Technology Corporation ©UNM | Flow cytometry for high throughput screening |
US6361958B1 (en) | 1999-11-12 | 2002-03-26 | Motorola, Inc. | Biochannel assay for hybridization with biomaterial |
DE19961257C2 (de) * | 1999-12-18 | 2002-12-19 | Inst Mikrotechnik Mainz Gmbh | Mikrovermischer |
US6790328B2 (en) * | 2000-01-12 | 2004-09-14 | Ut-Battelle, Llc | Microfluidic device and method for focusing, segmenting, and dispensing of a fluid stream |
AU2001239976A1 (en) | 2000-03-02 | 2001-09-12 | Wind River Systems, Inc. | System and method for common code generation |
US7485454B1 (en) | 2000-03-10 | 2009-02-03 | Bioprocessors Corp. | Microreactor |
AU2001271239A1 (en) | 2000-03-10 | 2001-09-24 | Flow Focusing, Inc. | Methods for producing optical fiber by focusing high viscosity liquid |
DE10015109A1 (de) | 2000-03-28 | 2001-10-04 | Peter Walzel | Verfahren und Vorrichtungen zur Herstellung gleich großer Tropfen |
JP2001340753A (ja) | 2000-03-29 | 2001-12-11 | Sumitomo Chem Co Ltd | 反応方法および反応装置 |
AU2001255458A1 (en) | 2000-04-18 | 2001-10-30 | Waters Investments Limited | Improved electrospray and other lc/ms interfaces |
JP2001301154A (ja) | 2000-04-20 | 2001-10-30 | Dainippon Printing Co Ltd | 電圧印加により表面張力が低下する液体の電界ジェットによる付着方法 |
US20010048637A1 (en) | 2000-05-24 | 2001-12-06 | Weigl Bernhard H. | Microfluidic system and method |
US6686184B1 (en) | 2000-05-25 | 2004-02-03 | President And Fellows Of Harvard College | Patterning of surfaces utilizing microfluidic stamps including three-dimensionally arrayed channel networks |
US6645432B1 (en) | 2000-05-25 | 2003-11-11 | President & Fellows Of Harvard College | Microfluidic systems including three-dimensionally arrayed channel networks |
US6777450B1 (en) * | 2000-05-26 | 2004-08-17 | Color Access, Inc. | Water-thin emulsions with low emulsifier levels |
US20060263888A1 (en) | 2000-06-02 | 2006-11-23 | Honeywell International Inc. | Differential white blood count on a disposable card |
ATE449596T1 (de) | 2000-08-15 | 2009-12-15 | Univ Illinois | Verfahren zur herstellung von mikropartikeln |
US6301055B1 (en) * | 2000-08-16 | 2001-10-09 | California Institute Of Technology | Solid immersion lens structures and methods for producing solid immersion lens structures |
DE10041823C2 (de) | 2000-08-25 | 2002-12-19 | Inst Mikrotechnik Mainz Gmbh | Verfahren und statischer Mikrovermischer zum Mischen mindestens zweier Fluide |
US6610499B1 (en) | 2000-08-31 | 2003-08-26 | The Regents Of The University Of California | Capillary array and related methods |
US6670153B2 (en) | 2000-09-14 | 2003-12-30 | Caliper Technologies Corp. | Microfluidic devices and methods for performing temperature mediated reactions |
AU2001290879A1 (en) * | 2000-09-15 | 2002-03-26 | California Institute Of Technology | Microfabricated crossflow devices and methods |
US6508988B1 (en) * | 2000-10-03 | 2003-01-21 | California Institute Of Technology | Combinatorial synthesis system |
DE10055921A1 (de) | 2000-11-10 | 2002-05-29 | Evotec Ag | Verfahren und Vorrichtung zur Erzeugung von Mikrokonvektionen |
US6778724B2 (en) * | 2000-11-28 | 2004-08-17 | The Regents Of The University Of California | Optical switching and sorting of biological samples and microparticles transported in a micro-fluidic device, including integrated bio-chip devices |
EP1385488A2 (en) | 2000-12-07 | 2004-02-04 | President And Fellows Of Harvard College | Methods and compositions for encapsulating active agents |
US20040096515A1 (en) * | 2001-12-07 | 2004-05-20 | Bausch Andreas R. | Methods and compositions for encapsulating active agents |
US6596239B2 (en) * | 2000-12-12 | 2003-07-22 | Edc Biosystems, Inc. | Acoustically mediated fluid transfer methods and uses thereof |
GB0030708D0 (en) | 2000-12-15 | 2001-01-31 | Imperial College | Single channel proteomics concepts |
ES2180405B1 (es) | 2001-01-31 | 2004-01-16 | Univ Sevilla | Dispositivo y procedimiento para producir chorros liquidos compuestos multicomponentes estacionarios y capsulas multicomponente y/o multicapa de tamaño micro y nanometrico. |
EP1355537A4 (en) | 2001-01-31 | 2010-04-07 | Kraft Foods Global Brands Llc | PRODUCTION OF CAPSULES AND PARTICLES FOR ENHANCING FOOD PRODUCTS |
TW593122B (en) | 2001-02-13 | 2004-06-21 | Qinetiq Ltd | Microchannel device |
US6603118B2 (en) * | 2001-02-14 | 2003-08-05 | Picoliter Inc. | Acoustic sample introduction for mass spectrometric analysis |
US20040134854A1 (en) | 2001-02-23 | 2004-07-15 | Toshiro Higuchi | Small liquid particle handling method, and device therefor |
EP1741482B1 (en) | 2001-02-23 | 2008-10-15 | Japan Science and Technology Agency | Process and apparatus for producing microcapsules |
CA2438856C (en) | 2001-02-23 | 2007-08-07 | Japan Science And Technology Corporation | Process and apparatus for producing emulsion and microcapsules |
US7037417B2 (en) | 2001-03-19 | 2006-05-02 | Ecole Polytechnique Federale De Lausanne | Mechanical control of fluids in micro-analytical devices |
US7192557B2 (en) | 2001-03-28 | 2007-03-20 | Handylab, Inc. | Methods and systems for releasing intracellular material from cells within microfluidic samples of fluids |
US7010391B2 (en) | 2001-03-28 | 2006-03-07 | Handylab, Inc. | Methods and systems for control of microfluidic devices |
DE60220893T2 (de) | 2001-04-03 | 2008-03-06 | Biocept, Inc., San Diego | Verfahren und gelzusammensetzungen zum einkapseln lebender zellen und organischer moleküle |
US6752922B2 (en) * | 2001-04-06 | 2004-06-22 | Fluidigm Corporation | Microfluidic chromatography |
AU2002314820B2 (en) | 2001-05-26 | 2008-01-24 | One Cell Systems, Inc. | Secretion of Molecules by Encapsulated Cells |
GB0114854D0 (en) | 2001-06-18 | 2001-08-08 | Medical Res Council | Selective gene amplification |
WO2003011443A2 (en) | 2001-07-27 | 2003-02-13 | President And Fellows Of Harvard College | Laminar mixing apparatus and methods |
US6555480B2 (en) * | 2001-07-31 | 2003-04-29 | Hewlett-Packard Development Company, L.P. | Substrate with fluidic channel and method of manufacturing |
US6734436B2 (en) * | 2001-08-07 | 2004-05-11 | Sri International | Optical microfluidic devices and methods |
US6520425B1 (en) * | 2001-08-21 | 2003-02-18 | The University Of Akron | Process and apparatus for the production of nanofibers |
KR100438828B1 (ko) | 2001-11-08 | 2004-07-05 | 삼성전자주식회사 | 칩 상의 전기적 미세 검출기 |
GB2383127B (en) * | 2001-12-12 | 2004-10-20 | Proimmune Ltd | Device and method for investigating analytes in liquid suspension or solution |
CA2470533A1 (en) * | 2002-01-14 | 2003-07-24 | Dow Global Technologies Inc. | Drug nanoparticles from template emulsions |
US6737634B2 (en) * | 2002-01-16 | 2004-05-18 | The University Of Chicago | Use of multiple optical vortices for pumping, mixing and sorting |
US7147763B2 (en) * | 2002-04-01 | 2006-12-12 | Palo Alto Research Center Incorporated | Apparatus and method for using electrostatic force to cause fluid movement |
US6976590B2 (en) * | 2002-06-24 | 2005-12-20 | Cytonome, Inc. | Method and apparatus for sorting particles |
US7901939B2 (en) * | 2002-05-09 | 2011-03-08 | University Of Chicago | Method for performing crystallization and reactions in pressure-driven fluid plugs |
AU2003290508A1 (en) | 2002-05-09 | 2004-05-13 | The University Of Chicago | Microfluidic device and method for pressure-driven plug transport and reaction |
US20060199168A1 (en) * | 2002-05-31 | 2006-09-07 | Wills Ivan N | Cell recovery |
JP2006507921A (ja) * | 2002-06-28 | 2006-03-09 | プレジデント・アンド・フェロウズ・オブ・ハーバード・カレッジ | 流体分散のための方法および装置 |
JP4031322B2 (ja) * | 2002-08-26 | 2008-01-09 | 独立行政法人科学技術振興機構 | 液滴操作装置 |
US7329545B2 (en) * | 2002-09-24 | 2008-02-12 | Duke University | Methods for sampling a liquid flow |
US6911132B2 (en) * | 2002-09-24 | 2005-06-28 | Duke University | Apparatus for manipulating droplets by electrowetting-based techniques |
US6941005B2 (en) * | 2002-11-01 | 2005-09-06 | Coulter International Corp. | Monitoring and control of droplet sorting |
GB2395196B (en) * | 2002-11-14 | 2006-12-27 | Univ Cardiff | Microfluidic device and methods for construction and application |
US7595195B2 (en) * | 2003-02-11 | 2009-09-29 | The Regents Of The University Of California | Microfluidic devices for controlled viscous shearing and formation of amphiphilic vesicles |
US7041481B2 (en) | 2003-03-14 | 2006-05-09 | The Regents Of The University Of California | Chemical amplification based on fluid partitioning |
US7045040B2 (en) | 2003-03-20 | 2006-05-16 | Asm Nutool, Inc. | Process and system for eliminating gas bubbles during electrochemical processing |
GB0307403D0 (en) | 2003-03-31 | 2003-05-07 | Medical Res Council | Selection by compartmentalised screening |
US20060078893A1 (en) * | 2004-10-12 | 2006-04-13 | Medical Research Council | Compartmentalised combinatorial chemistry by microfluidic control |
GB0307428D0 (en) | 2003-03-31 | 2003-05-07 | Medical Res Council | Compartmentalised combinatorial chemistry |
WO2004091763A2 (en) * | 2003-04-10 | 2004-10-28 | President And Fellows Of Harvard College | Formation and control of fluidic species |
AU2004239599A1 (en) | 2003-05-16 | 2004-11-25 | Global Technologies (Nz) Ltd | Method and apparatus for mixing sample and reagent in a suspension fluid |
WO2004103565A2 (de) | 2003-05-19 | 2004-12-02 | Hans-Knöll-Institut für Naturstoff-Forschung e.V. | Vorrichtung und verfahren zur strukturierung von flüssigkeiten und zum zudosieren von reaktionsflüssigkeiten zu in separationsmedium eingebetteten flüssigkeitskompartimenten |
JP2005037346A (ja) | 2003-06-25 | 2005-02-10 | Aisin Seiki Co Ltd | マイクロ流体制御システム |
US7115230B2 (en) | 2003-06-26 | 2006-10-03 | Intel Corporation | Hydrodynamic focusing devices |
GB0315438D0 (en) | 2003-07-02 | 2003-08-06 | Univ Manchester | Analysis of mixed cell populations |
US20050032238A1 (en) * | 2003-08-07 | 2005-02-10 | Nanostream, Inc. | Vented microfluidic separation devices and methods |
CN104069784B (zh) | 2003-08-27 | 2017-01-11 | 哈佛大学 | 流体物种的电子控制 |
AU2004269406B2 (en) | 2003-08-28 | 2010-12-16 | Progenity, Inc. | Methods and apparatus for sorting cells using an optical switch in a microfluidic channel network |
US7204431B2 (en) * | 2003-10-31 | 2007-04-17 | Agilent Technologies, Inc. | Electrospray ion source for mass spectroscopy |
US20050103690A1 (en) * | 2003-11-19 | 2005-05-19 | Aisin Seiki Kabushiki Kaisha | Micro liquid control system |
WO2005049787A2 (en) | 2003-11-24 | 2005-06-02 | Yeda Research And Development Co.Ltd. | Compositions and methods for in vitro sorting of molecular and cellular libraries |
US20050221339A1 (en) | 2004-03-31 | 2005-10-06 | Medical Research Council Harvard University | Compartmentalised screening by microfluidic control |
US8696952B2 (en) | 2004-04-23 | 2014-04-15 | Eugenia Kumacheva | Method of producing polymeric particles with selected size, shape, morphology and composition |
US7655470B2 (en) | 2004-10-29 | 2010-02-02 | University Of Chicago | Method for manipulating a plurality of plugs and performing reactions therein in microfluidic systems |
US9477233B2 (en) * | 2004-07-02 | 2016-10-25 | The University Of Chicago | Microfluidic system with a plurality of sequential T-junctions for performing reactions in microdroplets |
EP1796828A1 (en) | 2004-07-02 | 2007-06-20 | VersaMatrix A/S | Spherical radiofrequency-encoded beads |
US7759111B2 (en) * | 2004-08-27 | 2010-07-20 | The Regents Of The University Of California | Cell encapsulation microfluidic device |
US9566558B2 (en) * | 2004-09-09 | 2017-02-14 | Institut Curie | Device for manipulation of packets in micro-containers, in particular in microchannels |
US7968287B2 (en) * | 2004-10-08 | 2011-06-28 | Medical Research Council Harvard University | In vitro evolution in microfluidic systems |
WO2006051552A2 (en) | 2004-11-15 | 2006-05-18 | Yeda Research And Development Co. Ltd. At The Weizmann Institute Of Science | Directed evolution and selection using in vitro compartmentalization |
US20080213593A1 (en) | 2005-01-21 | 2008-09-04 | President And Fellows Of Harvard College | Systems And Methods For Forming Fluidic Droplets Encapsulated In Particles Such As Colloidal Particles |
JP2008535644A (ja) | 2005-03-04 | 2008-09-04 | プレジデント・アンド・フエローズ・オブ・ハーバード・カレツジ | 多重エマルジョンの形成のための方法および装置 |
US20070054119A1 (en) * | 2005-03-04 | 2007-03-08 | Piotr Garstecki | Systems and methods of forming particles |
FR2882939B1 (fr) * | 2005-03-11 | 2007-06-08 | Centre Nat Rech Scient | Dispositif de separation fluidique |
US20070141593A1 (en) * | 2005-08-22 | 2007-06-21 | Lee Linda G | Apparatus, system, and method using immiscible-fluid-discrete-volumes |
US8734003B2 (en) * | 2005-09-15 | 2014-05-27 | Alcatel Lucent | Micro-chemical mixing |
US7704457B2 (en) * | 2005-11-18 | 2010-04-27 | Patton Charles J | Automatic, field portable analyzer using discrete sample aliquots |
EP2363205A3 (en) | 2006-01-11 | 2014-06-04 | Raindance Technologies, Inc. | Microfluidic Devices And Methods Of Use In The Formation And Control Of Nanoreactors |
US7537897B2 (en) | 2006-01-23 | 2009-05-26 | Population Genetics Technologies, Ltd. | Molecular counting |
EP2263787A3 (en) | 2006-01-27 | 2012-02-22 | President and Fellows of Harvard College | Fluidic droplet coalescence |
US20090181864A1 (en) | 2006-03-31 | 2009-07-16 | Nam Trung Nguyen | Active control for droplet-based microfluidics |
US7955764B2 (en) | 2006-04-07 | 2011-06-07 | Micron Technology, Inc. | Methods to make sidewall light shields for color filter array |
EP3335782B1 (en) | 2006-05-11 | 2020-09-09 | Bio-Rad Laboratories, Inc. | Microfluidic devices |
FR2901717A1 (fr) | 2006-05-30 | 2007-12-07 | Centre Nat Rech Scient | Procede de traitement de gouttes dans un circuit microfluidique. |
CN102014871A (zh) * | 2007-03-28 | 2011-04-13 | 哈佛大学 | 乳液及其形成技术 |
WO2008134153A1 (en) | 2007-04-23 | 2008-11-06 | Advanced Liquid Logic, Inc. | Bead-based multiplexed analytical methods and instrumentation |
US20090068170A1 (en) | 2007-07-13 | 2009-03-12 | President And Fellows Of Harvard College | Droplet-based selection |
WO2009149257A1 (en) | 2008-06-04 | 2009-12-10 | The University Of Chicago | The chemistrode: a plug-based microfluidic device and method for stimulation and sampling with high temporal, spatial, and chemical resolution |
EP4047367A1 (en) * | 2008-07-18 | 2022-08-24 | Bio-Rad Laboratories, Inc. | Method for detecting target analytes with droplet libraries |
US9156010B2 (en) | 2008-09-23 | 2015-10-13 | Bio-Rad Laboratories, Inc. | Droplet-based assay system |
JP2010198393A (ja) | 2009-02-26 | 2010-09-09 | Alpine Electronics Inc | 地図表示装置 |
CA2814049C (en) | 2010-10-08 | 2021-07-13 | President And Fellows Of Harvard College | High-throughput single cell barcoding |
EP2673614B1 (en) * | 2011-02-11 | 2018-08-01 | Raindance Technologies, Inc. | Method for forming mixed droplets |
CN109082462B (zh) | 2012-05-21 | 2022-10-28 | 斯克利普斯研究所 | 样品制备方法 |
-
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Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4279345A (en) * | 1979-08-03 | 1981-07-21 | Allred John C | High speed particle sorter using a field emission electrode |
US6149789A (en) * | 1990-10-31 | 2000-11-21 | Fraunhofer Gesellschaft Zur Forderung Der Angewandten Forschung E.V. | Process for manipulating microscopic, dielectric particles and a device therefor |
EP0718038A2 (de) * | 1991-08-19 | 1996-06-26 | Fraunhofer-Gesellschaft Zur Förderung Der Angewandten Forschung E.V. | Vorrichtung zur Trennung von Gemischten mikroskopisch kleiner, in einer Flüssigkeit oder einem Gel suspendierter dielektrischer Teilchen |
US6432630B1 (en) * | 1996-09-04 | 2002-08-13 | Scandinanian Micro Biodevices A/S | Micro-flow system for particle separation and analysis |
CN1378485A (zh) * | 1999-08-12 | 2002-11-06 | Ut-巴特勒有限公司 | 用于可控操纵小体积的微流控装置 |
WO2001094635A2 (en) * | 2000-06-05 | 2001-12-13 | California Institute Of Technology | Integrated active flux microfluidic devices and methods |
US20030015425A1 (en) * | 2001-06-20 | 2003-01-23 | Coventor Inc. | Microfluidic system including a virtual wall fluid interface port for interfacing fluids with the microfluidic system |
Non-Patent Citations (4)
Title |
---|
冯焱颖等.微流体实验技术研究.制造技术与机床 9.2002,(9),27-30. |
冯焱颖等.微流体实验技术研究.制造技术与机床 9.2002,(9),27-30. * |
朱滨等.生物芯片微制造技术.功能材料与器件学报7 4.2001,7(4),435-438. |
朱滨等.生物芯片微制造技术.功能材料与器件学报7 4.2001,7(4),435-438. * |
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JP4630870B2 (ja) | 2011-02-09 |
WO2005021151A1 (en) | 2005-03-10 |
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