CN1329729C - 微流体系统 - Google Patents
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Abstract
管道(140)被分成多个部分(142,144)。每个管道部分(142,144)的侧壁上有极性相反的面电荷。两个管道部分(142,144)通过诸如玻璃料或凝胶层等盐桥(133)以物理方式相连。盐桥(133)分离管道(140)中来自离子化流体储库(135)的流体。分别在A部和B部沿管道(140)产生电渗力和电泳力。另外,在储库(135)中布置第三电极(137)。
Description
相关申请的交叉文献
本申请是申请日为1996年12月6日的美国专利申请第08/760,446号的部分续展申请,而美国专利申请第08/760,446号是申请日为1996年6月28日的美国专利申请第08/671,986号的部分续展申请,为了所有的目的,这些申请的全部内容通过引用包括在此。
发明背景
人们对制造和运用微流体(microfluidic)系统来获得化学和生化信息的兴趣日益增大。目前,用通常与半导体电子工业相关的技术(诸如光刻法、湿式化学蚀刻等)来制造这些微流体系统。术语“微流体”是指这样的系统或装置,它们所具有的管道和小室一般在微米或亚微米标度上构造,例如,至少有一个截面尺寸在大约0.1μm到大约500μm的范围内。早期,Manz等人在1990年
Trends in Anal. Chem.10(5)第144-149页以及1993年
Avd.in Chromatog 33第1-66页中,讨论了用平面芯片技术制造微流体系统的方法,叙述了在硅和玻璃基片中构造这种流体装置,尤其是微毛细管装置。
微流体系统有多种应用。例如,国际专利申请WO 96/04547(公布于1996年2月15日)将微流体系统用于毛细管电泳、液体层析、注流分析(flow injectionanalysis)以及化学反应和合成等。1996年6月28日提交的美国专利申请第08/671,987号公开了微流体系统在快速分析大量化合物方面的广泛应用,分析其对各种化学系统,特别是生化系统的影响,该专利申请的内容通过引用包括在此。术语“生化系统”一般是指一种化学相互作用,其中涉及一般在活的生物体里发现的分子。这类相互作用包括在活体系统里发生的分解代谢和合成代谢反应的全部范围,包括酶反应、结合反应、信号反应和其它反应。特别感兴趣的生化系统例如包括受体-配体相互作用、酶-酶解物相互作用、细胞信号途径、供生物药效筛选所涉及的模型屏障系统(如细胞或膜部分)的传送反应和其它各种一般系统。
已描述了在这些微流体系统或装置中传输和导向流体(例如,样品、分析物、缓冲剂和试剂)的多种方法。一种方法是用微构造装置中的微型机械泵和阀使流体在该装置中流动。参见,已公开的英国专利申请第2248 891号(10/18/90),已公开的欧洲专利申请第568 902号(5/2/92),美国专利第5,271,724号(8/21/91)和5,277,556号(7/3/91)。还可以参见,Miyazaki等人获得的美国专利第5,171,132号(12/21/90)。另一种方法是依靠声学流的作用,用声能使流体样品在装置中流动。参见,由Northrup和White等人发明的已公开PCT申请第94/05414号。一种直接的方法是施加外压,使流体在装置中流动。参见,由Wilding等人获得的美国专利第5,304,487号。
再一种方法是运用电场使流体物料流过微流体系统的管道。例如,参见由Kovacs发明的已公开欧洲专利申请第376611号(12/30/88),Harrision等人在1992年
Anal.Chem.64第1926-1932页上发表的文章,Manz等人在1992年J.Chromatog.593第253-258页上发表的文章,以及由Soane获得的美国专利第5,126,022号。电动力具有直接控制、快速响应以及简单的优点。然而,仍存在一些缺点。
为了获得最大的效率,希望将试验物料尽可能靠在一起传输。但是,传输物料时不能与其它传输物料混杂。另外,物料在微流体系统的某一位置处于某一状态,在其移动到微流体系统的另一位置后,物料应保持相同的状态。需要时,这些条件允许控制对化合物物料的测试、分析和反应。
在用电动力移动物料的微流体系统中,试验物料区中带电分子和离子,以及用于分隔这些试验物料区的区域中的带电分子和离子受到不同的电场作用,从而影响流体的流动。
但是,当施加这些电场时,试验物料内带不同电荷的物质将呈现不同的电泳移动,即带正电荷的的移动速度与带负电荷的物质品种不同。过去,在受电场作用的样品内分离不同物质品种不被看成是一问题,而且事实上还将其看成是毛细管电泳现象的所需结果。但是,当希望进行简单的流体传输时,这些不同的移动会在试验物料中引起不希望有的改变或“电泳偏离”。
如没有避免混杂的考虑和措施,微流体系统只好大距离地分离试验物料,或者更糟的是,一次将一种物料移过系统。在任何一种情况下,这都会大大地降低微流体系统的效率。另外,如果传输中不能保持被传输物料的状态,那么就会失去要求不改变物料而达到某一位置的许多应用。
本发明解决或基本上解决了这些电动传输问题。利用本发明,微流体系统能够有效地移动物料,并且在被传输物料中没有不希望有的变化。本发明提供了一种高通过量的微流体系统,该系统可以定向、快速和直接控制材料移过微流体系统的管道,在诸如化学、生化、生物技术、分子生物学领域以及许多其它领域中具有广泛的应用。
发明内容
依照本发明的一个方面,提供了一种微流体系统。该系统包括:基片,所述基片中布置了至少一个第一管道和至少一个第二管道,所述第二管道与所述第一管道相交,并且所述第一管道比所述第二管道深,所述第一管道之宽度对深度的纵横比大于5;和电渗流导向系统。
在本发明的微流体系统中,所述至少一个第一管道的深度至少可以是所述第二管道的2倍、5倍或10倍。
依照本发明的另一方面,提供了用于上述的本发明微流体系统的微流体装置。该装置包括基片,所述基片中至少布置了第一和第二交叉的流体管道,所述第一管道的宽度对深度的纵横比大于5,并且所述第一和第二管道具有不同的深度。
在本发明的微流体装置中,所述第一管道的深度可以为所述第二管道深度的2-10倍。
依照本发明的又一方面,提供了一种微流体系统。该系统包括:第一基片;至少第一和第二管道,它们布置在所述第一基片中,所述第一和第二管道在第一交会处进行流体连通,所述第一管道的深度至少是所述第二管道的两倍,并且所述第一管道的宽度对深度的纵横比大于5;和用于移动物料以便使所述物料通过所述第一和第二管道的系统。用于移动物料的系统包括:至少第一、第二和第三电极,所述第一和第二电极在所述第一交会处的两侧与所述第一管道电接触,所述第三电极与所述第二管道电接触;和电源,用于为所述第一、第二和第三电极提供电压,以便沿所述第一和第二管道中至少一个管道的长度,有选择地产生一电压梯度。
在本发明的微流体系统中,所述第一管道的深度至少可以是所述第二管道深度的5倍或10倍。
在本发明的微流体系统中,所述第一基片具有至少一个平表面,所述第一和第二管道被制作在所述第一基片的所述至少一个平表面中;并且所述微流体系统还可以包括至少一个第二基片,所述至少一个第二基片覆盖所述第一基片的所述至少一个平表面。所述至少一个第二基片具有入口。
本发明提供了一种微流体系统,该系统通过电渗作用,使试验物料在微流体系统中以流体团(也称为“试验物料区”)的形式沿管道从第一点移动到第二点。高离子浓度的第一分隔区与每个试验物料区的至少一侧接触,而低离子浓度的第二分隔区与包含试验物料的试验物料区以及第一或高离子浓度分隔区布置在一起,致使在第一和第二点之间总是至少有一低离子浓度区,从而确保两点间的大部分压降和所得的电场施加在低离子浓度区的两端。
本发明还提供了一种电吸移管,该电吸移管与利用电渗力移动试验物料的微流体系统兼容。电吸移管具有一带管道的毛细管。电极沿毛细管的外侧长度固定,并且终止于位于毛细管末端的电极环。通过控制该电极以及目标储库中电极上的电压,在电动作用下,将物料导入管道,这里当把毛细管放入物料源中时,所述目标储库与管道流体连接。为了便于导入微流体系统,可以在管道中形成一个由试验物料区、高离子浓度缓冲分隔区以及低离子浓度缓冲分隔区组成的队列。
当电动作用使试验物料沿微流体系统的管道传输时,本发明还能对电泳偏离进行补偿。在一实施例中,微流体系统中两点间的管道具有两个部分,这两个部分的侧壁带有相反的面电荷。两部分之间放有一电极。将两点上的电压设置成基本上相等,而在这两部分之间的中间电极上设置不同的电压,由此,两部分中的电泳力沿相反的方法,而电渗力沿同一方向。当试验物料从一点传输到另一点时,电泳力得到补偿,同时电渗力将流体物料移过管道。
在另一实施例中,在微流体系统多个管道的交会处形成一小室。小室的侧壁与相交管道的侧壁相连。当试验物料区在交会处从一根管道转向另一根管道时,小室的侧壁使试验物料区漏入第二管道中。第二管道的宽度使得扩散作用可以混合当试验物料区沿第一管道传输时区域中受电泳偏离的任何试验物料。
在又一实施例中,本发明提供了一种微流体系统,以及使用该系统的方法,所述方法可以控制流体流在至少具有两根相交管道的微流体装置内传输。系统包括一基片,基片中至少安置了两根相交的管道。在该情况下,一根管道比另一根管道深。系统还包括一电渗流定向系统。当流体流至少包含两个离子浓度不同的流体区时,该系统特别有用。
本发明还提供了一种使用本发明电吸移管的采样系统。采样系统包括样品基片,基片上固定有多个不同的样品。还包括平移系统,用于相对所述样品基片移动电吸移管。
如上所述的发明可以有多种不同的用途,用途本身也有具有创造性。举例如下:
在带管道之基片的一种用途中,至少把第一试验物料沿管道从至少第一位置传输到第二位置,并且至少使用一个低离子浓度的区域,所述低离子浓度区因所加电压沿管道传输。
在上述发明的一种用途中,一个区域的离子浓度基本上低于试验物料的离子浓度。
在上述发明的一种用途中,传输由高离子浓度分隔区分开多种试验物料。
把一种带管道的基片用于补偿电泳偏离的方法,其中沿所述管道至少传输第一试验物料,管道被分成第一和第二部分,在该方法中,管道的侧壁带相反的电荷,致使第一试验物料因在第一部分中传输而受到的电泳偏离基本上可以用因在第二部分中传输而受到的电泳偏离来补偿。
在上述发明的一种用途中,第一电位于一部分的远端,第二电极位于各部分之间的交会处,而第三电极位于第二部分的远端。
在上述发明的一种用途中,基片是一微流体系统。
在上述发明的一种用途中,基片是一电吸移管。
在上述发明的一种用途中,电吸移管具有一主管道,用于传输试验物料;以及至少另一个管道,它与主管道流体连接,从主管道获得沿主管道传输的另一种物料。
在上述发明的一种用途中,另一种物料被拖入主管道,在多种分离的试验物料的每种物料之间成为一缓冲剂区。
一种把微流体系统用于优化流动条件的方法,其中微流体系统至少具有相交的第一和第二流体管道,管道具有不同的深度。
在上述发明的一种用途中,一根管道的深度是另一根管道的2至1 0倍。
一种把微流体系统用于电泳补偿的方法,微流体系统具有第一管道和与第一管道相交的第二管道,管道之间交会处的形状使得沿第一管道朝第二管道传输的流体在交会处混合,从而削除流体中的电泳偏离。
附图概述
图1是微流体系统一实施例的示意图;
图2A示出了依照本发明一实施例,在图1微流体系统的管道中传输的一种由流体区组成的结构;图2B是一比例图,示出了依照本发明在微流体系统的管道中传输的另一种由不同流体区组成的结构;
图3A示出了另一种具有高离子浓度分隔区的结构,该结构是在微流体系统的管道内传输试验物料区之前,图3B示出了一种具有高离子浓度分隔区的结构,该结构是在微流体系统的管道中传输试验物料区之后;
图4A示出了依照本发明一电吸移管实施例的示意图;图4B是依照本发明另一电吸移管的示意图;
图5是一示意图,示出了本发明微流体系统中的管道,该管道的多个部分具有带相反电荷的侧壁;
图6A-6D示出了本发明微流体系统中,漏斗侧壁在管道交会处的混合作用。
图7A示出了将样品流体三次注入充满低盐缓冲剂中的结果,其中样品流体由两种带相反电荷的化学物质组成。图7B示出了三次样品注射的结果,其中样品处于高盐缓冲剂中,将高盐缓冲流体注射在样品区的任何一端,起保护带的作用,并且样品/保护带在充满低盐缓冲剂的毛细管中运动。图7C示出了类似于图7B的三次样品注射的结果,不同之处在于降低了样品/高盐分隔区(保护带)之间的低盐分隔区的大小,允许部分分辨样品内的物质,但不允许样品单元影响后续或先前的样品。
图8是一示意图,示出了利用固定(例如,干燥)在基片或基体上的样品与采样系统一起使用的电吸移管。
图9A是荧光性对时间的曲线图,示出了依照本发明被周期性注入并移过电吸移管的样品流体的移动情况,其中样品流体由测试化学物质组成。图9B是另一曲线图,示出了不同参数下样品流体与化学物质一起移过与电吸移管相连的微流体系统的情况。图9C是一曲线图,示出了样品流体和化学物质移过一电吸移管的情况,其中电吸移管由经气蚀的基片制成。
图10是一曲线图,示出了再次示出了依照本发明,样品流体中的某一化学物质的移动情况,其中样品流体被周期性地注入电吸移管。在该实验中,物质是小分子化合物。
本发明的详细描述
I.
微流体系统的一般结构
图1例示了依照本发明的微流体系统100。如图所示,总体设备100被组装在平面基片102上。合适的基片材料根据它们与所述设备进行特定操作的条件的匹配性来选择。这类条件包括pH、温度、离子浓度和施加电场的极端值。另外,基片材料也可根据它们对由设备进行分析或合成的关键组分的惰性来选择。
有用的基片材料包括,例如玻璃、石英和硅,以及聚合基片(如塑料)。若是导体或半导体基片,通常需要在基片上包含一绝缘层。如下所述,当设备中包含电气元件(如电气流体导向系统和传感器之类),或者用电渗力使材料在系统周围移动时,这点尤为重要。对于聚合基片,基片材料可以是刚性、半刚性或非刚性,不透明、半透明或全透明,这根据它们的用处而定。例如,包括光学或肉眼检测元件的设备通常用(至少部分用)透明的材料制成,以允许(或至少有利于)检测。另一种方法是,对于这类检测元件,在设备中包含由玻璃或石英制成的透明窗。另外,聚合材料可为直链或支链(linear or branched backbone),并且可以交联或非交联。特别优选的聚合物材料例子包括,如聚二甲基硅氧烷(PDMS)、聚氨酯、聚氯乙烯(PVC)、聚苯乙烯、聚砜、聚碳酸酯等。
图1所示的装置包括一系列管道110、112、114和116,它们被制于基片的表面内。如在定义“微流体”时所讨论的,这些管道一般具有非常小的截面尺寸,最好在大约0.1微米至100微米的范围内。在下述的特殊应用中,尽管尺寸可能有偏差,但深度大约为10微米且宽度大约为60微米的管道可以有效地工作。
可以用本领域公知的任何数目的微制造技术将这些管道和其它微尺度元件制备到基片102的表面内。例如,运用半导体制造工业中公知的方法,可把石版印刷技术应用于制造玻璃、石英或硅基片。光刻掩模、等离子蚀刻或湿式蚀刻,以及其它半导体处理技术限定了基片表面中和表面上的微尺度元件。另一方面,可以使用诸如激光钻孔、微研磨等微机械方法。类似地,对于聚合基片,也可使用公知的制造技术。这些技术包括注模技术或冲压模塑方法,以及聚合物微铸造技术,其中前者通过滚动冲压生产出大张的微尺度基片,由此生产大量基片,而后者将基片聚合在微制模具内。
除了基片102之外,微流体系统还包括包括一附加的平面元件(未示出),平面元件覆盖在开有管道的基片102上,密闭和液封各种管道,从而形成导管。可以用各种手段将平面覆盖元件与基片相连,所述手段例如包括热粘结、使用粘合剂,或者在玻璃基片或半刚性和非刚性的聚合基片的情况下,在两个部件之间进行自然粘合。平面覆盖元件可另外带有入口和/或储库,用以引入特定筛选所需的各种液体组分。
图1所示的装置还包括储库104、106和108,它们分别被放置成与管道114、116和110和114的末端流体相连。如图所示,采样管道112用来将多种不同的试验物料(subject material)引入装置。这样,管道112与大量分离的试验物料源流体连接,所述试验物料被个别引入采样管道112,然后进入另一管道110。如图所示,利用电泳,可用管道110来分析试验物料。应该注意,术语“试验物料”仅仅是指诸如化学化合物或生物化合物的有关材料。试验化合物可以包括各种不同的化合物,包括化学化合物、化学化合物的混合物,如多糖类、小的有机或无机分子,生物大分子,如肽、蛋白质、核酸,或从生物物料如细菌、植物、真菌,或者动物细胞或组织中制备的提取物,天然形成或合成的组合物。
系统100通过电动力使诸材料通过管道110、112、114和116,其中电动力由一电压控制器提供,该电压控制器能够同时将可选择的电压电平施加到每个储库(包括,地)上。利用多个分压器和多个继电器可以获得可选择的电压电平,实现所述电压控制器的功能。另一种方法是,使用多个独立的电压源。电压控制器通过电极与每个储库电气连接,所述电极被定位或制作在多个储库的每一个内。例如,参见已公开的国际专利申请WO 96/04547(Ramsey),为了所有的目的,该申请的全部内容通过引用包括在此。
II.
电动传输
A.
一般情况
作用在系统100之管道内的流体物料上的电动力可以分为电渗力和电泳力。本发明系统中使用的流体控制系统使用电渗力在位于基片102之表面上的各种管道和反应室内移动、引导和混合流体。概括地说,当把合适的流体放入表面上带有官能团的管道或者其它流体导管时,这些基团会离子化。例如,当管道表面包含羟基官能团时,质子可以脱离管道表面并进入流体。在这种情况下,表面带有负的净电荷,而流体带有过量的质子或正电荷,尤其在管道表面与流体之间的界面附近。
通过沿管道长度施加电场,阳离子向负电极流动。带正电的物质在流体中移动拖着溶剂与其一同移动。流体的稳态移动速度一般由下式给出:
其中,v是溶剂速度,ε是流体的介电常数,ξ是表面的ξ电势,E是电场强度,而η是溶剂的粘度。因此,从该式可知,溶剂速度直接与ξ电位和所加电场成正比。
除了电渗力之外,还存在电泳力,当带电分子通过系统100的管道时,电泳力会影响带电分子。试验物料在系统100中从一点传输到另一点时,通常希望试验物料的组合物在传输中不受影响,即试验物料在传输中不被电泳区分。
依照本发明,试验物料作为流体团(下文称“试验物料区”)在管道中来回移动,流体团具有较高的离子浓度,可使作用在这些特殊区域内的试验物料上的电泳力最小。为了尽量减小电泳力在试验物料区内的影响,可在流体团的每一侧安排流体分隔区(“第一分隔区”)。这些第一分隔区具有较高的离子浓度,可以使这些区域内的电场最小,如以下说明的,这使得试验物料基本上不受传输(在流体系统中从一个地点传输到另一地点)的影响。试验物料通过系统100的代表性管道110、112、114和116在具有某种离子浓度的区域以及离子浓度不同于那些运载试验物料之区域的其它区域中传输。
图2A示出了一具体的结构,该图表示,试验物料区200沿微流体系统100的一条管道从点A传输到点B。在试验物料区200的每一侧,具有由高离子浓度流体构成的第一分隔区201。另外,由低离子浓度流体构成的第二分隔区202周期性地分离由试验物料区200和第一分隔区201形成的结构。由于第二分隔区202的离子浓度较低,所以点A与点B之间的大部分压降都加在这些第二分隔区202上。将第二或低浓度分隔区202间置在试验物料区200和第一分隔区202组成的结构之间,致使当以电渗方式通过管道抽运试验物料区200和第一分隔区201时,在点A和点B之间至少存在一个第二或低离子浓度分隔区202。这保证了大部分压降都加在第二分隔区202上,而不是加在试验物料区200和第一分隔区201上。换句话说,点A和点B之间的电场集中在第二分隔区202,而试验物料区200和第一分隔区201受较小电场(和较小电泳力)的作用。因此,根据试验物料区200、第一分隔区201和第二或低离子浓度分隔区201内的相对离子浓度,可以制备由这些试验物料区200以及第一和第二分隔区201和202组成的结构。
例如,图2B示出了一种结构,该结构将第二或低离子浓度分隔区202规则地间隔在第一分隔区202/试验物料区200/第一分隔区201的每一组合之间。这种结构保证了在点A和点B之间至少存在了个第二或低离子浓度分隔区202。另外,附图画出了试验物料区200、第一或高浓度分隔区201以及第二或低浓度分隔区202的一个可能组合的相对长度。在图2B的示例中,试验物料区200在高离子浓度150mM的NaCl中含有试验物料。试验物料区200在管道中的长度为1mm。两个第一分隔区201具有离子浓度为150mM的NaCl。每个第一分隔区201的长度均为1mm。第二分隔区202为2mm长,并且具有离子浓度为5mM的硼酸盐缓冲剂。设计这种特殊的配置可以在试验物料区200和缓冲区201中保持快速电泳的化合物,同时化合物传过微流体系统的管道。例如,利用这些方法,可用72秒以上的时间使一个含有例如苯甲酸的试验物料区流过微流体系统,而不受到过度的电泳偏离。
一般地说,可以确定流体流过微流体系统之管道的速度vEoF,并且通过测量可以确定一个试验物料分子将通过管道的总长度1T。因此,试验物料分子通过总长度的渡越时间tTr为:
tTr=lT/vEoF
为了在位于试验物料区200后的第一分隔区201内包含试验物料分子x,第一分隔区201的长度1q应该大于试验物料分子x在第一分隔区201中的电泳速度vqx乘以渡越时间:
1q>(vqx)(tTr)
由于电泳速度正比于第一分隔区201中的电场,所以本发明可以控制vqx,以便通过微流体系统的管道,传输试验物料。
在图2A和2B的结构中,第一或高离子浓度分隔区201帮助把试验物料的位置保持在其试验物料区200的附近。无论试验物料的电荷极性如何,位于试验物料区200任何一侧的第一分隔区201保证脱离试验物料区200的任何试验物料仅受到一较小电场的作用,因为第一分隔区201具有相对较高的离子浓度。如果已知试验物料的极性,那么也就知道了电泳力对试验物料分子的作用方向。
图3A例示的情况是,所有试验物料区200中试验物料的电荷使得电泳力对试验物料分子的作用方向与电渗流的方向相同。因此,第一分隔区201沿流动方向推进试验物料区200。试验物料区200后面不存在第一分隔区201,因为电泳力在该方向上保持试验物料不脱离试验物料区200。通过取消一半第一分隔区201,每条管道长度可以运送更多的包含其试验物料的试验物料区200。这提高了微流体系统的传输效率。相对于试验物料区200和第一或高离子浓度分隔区201,如此安排第二或低离子浓度分隔区202,使得对第二分隔区202加较大的电场,而试验物料区200和第一分隔区201中的电场(和电泳力)保持较小。
在图3B中,第一分隔区201沿电渗流的方向跟在试验物料区200的后面。在该例中,所有试验物料区200中试验物料的电荷使得作用在试验物料分子上的电泳力与电渗流的方向相反。因此,试验物料可以脱离其试验物料区的边界,在效果上,落在其试验物料区200的后面。紧跟在试验物料区200后面的第一分隔区201保持试验物料不会离其试验物料区200太远。同样,相对于试验物料区200和第一或高离子浓度分隔区201,如此安排第二或低离子浓度分隔区202,使得较大的电场加在第二分隔区202上,而试验物料区200和第一分隔区201中的电场保持较小。
选择各种高低离子浓度的溶液,为第一和第二分隔区201和202制备具有所需电导率的溶液。赋予溶液导电率的特定离子可以从无机盐(诸如NaCl、KI、CaCl2、FeF3、(NH4)2SO4等)、有机盐(诸如苯甲酸吡啶翁盐,月桂酸苯甲烃铵),或者混合的无机盐/有机盐(诸如苯甲酸钠,脱氧硫酸钠,盐酸苄基胺)中获得。这些离子的选择还要与微流体系统中进行的化学反应、分离等兼容。除了水性溶剂之外,水性/有机溶剂的混合物(诸如DMSO浓度较低的水)可用来帮助增溶试验物料分子。例如,有机溶剂的混合物(诸如CHCl3:MeOH)还可用于加速分析磷酯酶活性。
一般,当使用水性溶剂时,用无机离子调节溶液的电导率。当使用低极性溶剂时,一般使用有机离子或混合的无机/有机离子。当两种不混合的溶剂同时存在(例如,水与癸烷之类的烃),致使电流必须从一种溶剂流入另一种溶剂时,可以通过无极溶剂用离子载体(例如,表霉素,无活菌素,各种冠醚等)及其适当的离子传导电流。
B.
对基于压力的流水进行电动控制
在本文所述的电动流系统中,由于管道中存在差动流体(例如,在特定系统中,具有不同的电动迁移率),所以在系统中,沿管道长度存在多个不同的压力。例如,这些电动流系统一般在一给定的管道中使用一系列由低离子浓度流体和高离子浓度流体形成的区域(例如第一和第二分隔区,和试验物料的试验物料区),以影响电渗流,同时防止在容纳试验物料区的试验物料内出现电泳偏离。当管道内的低离子浓度区趋向于在其长度上施加在大部分电压时,它们将把流体推过管道。相反,管道内的高离子浓度区在其长度上提供相当小的压降,从而由于粘性拖带减慢流体流动。
作为这些推拖效应的结果,一般会沿充满流体的管道的长度产生压力变化。最大压力一般在低离子浓度区的前沿(例如,第二分隔区),而最小压力一般在这些低离子浓度流体区的后沿。
尽管在直道系统,这些压差几乎不相关,但它们的作用会减弱对流体方向的控制以及对使用相交管道结构的微流体装置的操纵,即先前通过引用包含的,美国专利申请第08/671,987号所述描述的系统。例如,在把第二管道构造成与包含不同离子浓度之流体区的第一管道相交的情况下,当这些不同的流体区移过交会处时,上述压力波动会使流体流入和流出相交的第二管道。这种波动流可能会明显地干扰流体在电渗作用驱动下从第二管道定量流出,以及/或者扰乱管道内不同的流体区。
通过减小相交管道(例如第二管道)相对第一或主管道的深度,可以基本上消除流体流动中的波动。特别是,对于一给定的电压梯度,对于纵横比(宽度∶深度)大于10的管道,在电渗流推进方向上,流速一般按管道深度的倒数而变化。对于计算中一些较小的无关紧要的误差,这一通用比对于较小的纵横比(例如,纵横比>5)仍然保持正确。相反,相同管道中压力引起的流动将按管道深度倒数的三次幂来变化。因此,因同时存在离子浓度不同的流体区而在管道中增大的压力将按管道深度倒数的平方来变化。
由此,通过相对于第一或主管道的深度将相交第二管道的深度减小因子X,可以明显地减小由压力引起的流动,即减小因子X3,同时仅略微减小由电渗引起的流动,即减小因子X。例如,当相对第一管道将第二管道的深度减小一个数量级时,那么由压力引起的流动减小1000倍,而由电渗引起的流动将仅减小10倍。因此,在某些方面,本发明提供了如本文中作一般描述的微流体装置,例如这些装置中至少安置了第一和第二相交管道,但第一管道比第二管道深。一般情况下,可以改变管道的深度,为所需应用获得优化的流动条件。这样,根据应用,第一管道的深度可以大于第二管道深度的大约二倍、大于第二管道深度的大约5倍,甚至大于第二管道深度的大约10倍。
除了在减小压力效应时使用不同的管道深度外,还可用变化的管道深度使同一装置中不同管道内有流体作差动流动,例如混合来自不同源的不同比例的流体等。
III.
电吸移管
如上所述,通过微流体系统100,可以在试验物料区200中或附近有效地传输任何试验物料。当试验物料通过系统管道传输时,利用第一和第二分隔区201和202可以将试验物料限制在一区域中。为了有效地将试验物料导入微流体系统中,本发明还提供了一种电吸移管,该电吸移管可以在试验物料区200与第一和第二分隔区201和202的同一序列组合流中,将试验物料导入微流体系统。
A.
结构和操作
如图4A所示,电吸移管250由一中空毛细管251构成。毛细管251具有一管道254,该管道的尺寸与微流体系统100的管道的尺寸相同,并且与其流体接连。如图4A所示,管道254是一圆柱体,其截面直径在1-100微米的范围内,直径最好大约为30微米。电极252沿毛细管251的外壁而行,并终止一环状电极253,其中环状电极253围绕在毛细管251的末端。为了将试验物料区200中的试验物料以及缓冲区201和202吸入电吸移管的管道254,相对于与管道254流体连接的目标储库(未示出),对电极252施加电压。目标储库位于微流体系统中,从而按序列将试验物料区200和缓冲区201和202从电吸移管传输到系统100中。
从程序上讲,将电吸移管250的毛细管道末端放入试验物料源。相对于目标储库中的电极,对电极252施加一电压。环状电极253与试验物料源接触放置,对电源电气偏压,从而在试验物料源和目标储库之间产生一压降。结果,试验物料源和目标储库变成微流体系统中的点A和点B,即如图2A所示。电动作用将试验物料导入毛细管道254,产生一试验物料区200。然后,截断电极252上的电压,并放毛细管道放入高离子浓度的缓冲物料源。再次相对目标储库电极,对电极252施加一电压,致使通过电动作用将第一分隔区201导入毛细管道254内,紧接在试验物料区200之后。如果之后希望在电吸移管管道254内获得第二或低离子浓度分隔区202,那么毛细管道254的末端插入低离子浓度缓冲物料源中,并对电极252施加一电压。然后,将电吸移管250移动到另一个试验源,在管道254中产生另一个试验物料区200。
通过重复上述步骤,在电动作用下,将由第一和第二分隔区201和202分隔开的具有不同试验物料的多个试验物料区200导入毛细管道254中,从而导入微流体系100中。
注意,如果试验物料源和(低离子浓度和高离子浓度的)缓冲物料源具有其自己的电极,那么就不需要电极252。目标储库和源电极之间的电压对电吸移管起作用。另一种方法可使电极252与毛细管251成固定关系,但相互分离,以便当毛细管251的末端接收储库时,电极252也接触储库。操作过程与针对图4A的电吸移管的描述相同。
图4B示出了图4A中电吸移管250的一种变化。在该变化中,不要求将电吸移管270在试验物料源和缓冲物料源之间转移,从而在吸移管内产生第一和第二分隔区201和202。电吸移管270具有本体271和三个毛细管道264、275和276。主管道274的工作方式与上述电吸移管250的相同。但是,两个辅助毛细管道275和276的一端与缓冲源储库(未示出)流体连接,而管道275和276的另一端与主管道274流体连接。一个储库(即与辅助管道275相连的储库)含有高离子浓度的缓冲物料,而另一储库(即与管道276相连的储库)含有低离子浓度的缓冲物料。
所有储库都与电极连接,用于在操作电吸移管270时对这些储库电气偏压。电吸移管270还可以沿其本体271的壁具有电极272,该电极终止于位于主管道274末端的环状电极273。通过对电极272(和环状电极273)施加电压从而沿管道274、275和276产生压降,不仅可以把试验物料从试验物料源拖入主管道274,而且还可以把高离子浓度和低离子浓度的缓冲物料从辅助管道275和276拖入主管道274。
为利用电极272操作电吸移管270,将主毛细管道274的末端放入试验物料源280。相对于目标储库中的电极,对电极272施加一电压,从而在试验物料源280和目标储库之间产生一压降。电动作用将试验物料拖入毛细管道274。然后,将毛细管道末端移离试验物料源280,并在连接管道274的目标储库和连接管道275的储库之间产生一压降。在管道274中形成第一或高离子浓度分隔区201。当从辅助管道275拖入缓冲物料时,毛细管的作用禁止将空气导入管道274中。如果之后希望在主管道274中获得第二或低离子浓度分隔区202,那么对目标储库中的电极以及低离子浓度缓冲物料储库中的电极施加一电压。电动作用将第二分隔区202从第二辅助管道276导入毛细管道274。然后,可以将电吸移管270移到另一个试验物料源,以便在管道274中产生另一个试验物料源200。
通过重复上述步骤,在电动作用下,将由第一和第二分隔区201和202分隔开的具有不同试验物料的多个试验物料区200导入毛细管道274中,从而导入微流体系100中。
如果不希望使试验物料源经受来自环状电极273的氧化/还原反应,那么可以不用电极272操作电吸移管。由于在高离子浓度的溶液中,电渗流较慢,所以从连接管道274的储库到连接管道275的储库施加电势(-至+)将在管道274和275的交会点形成真空。该真空将来自试验物料源的采样拖入管道274。当用这种方式操作时,管道275和276中的溶液会在某种程度上冲淡试验物料。通过减小管道276和275相对于管道274的尺寸,可以减缓这种冲淡。
为了把第一和第二分隔区201和202导入毛细管道274,如上所述操作电吸移管270。将毛细管道末端移离试验物料源280,并在管道274的目标储库和连接所选管道275或276的储库之间产生一压降。
尽管根据两个辅助管道和一个主管道的情况作了一般描述,但应该理解,不可以提供另外的辅助管道,将其它流体、缓冲剂、稀释液和试剂等导入主管道。
如上所述,对于微流体装置(例如,芯片)内的相交管道,因不同吸移管管道内差动流体所产生的压差还会影响对吸移管管道内流体流动的控制。因此,如上所述,为了优化对流体的控制,还可以提供各种吸移管管道,使其彼此具有不同的管道深度。
B.
电吸移管的制造方法
电吸移管可以由一中空的毛细管制成,如图4A所述的那样。但是,对于更复杂的结构,电吸移管最好由与上述微管道系统相同的基片材料制成。用对于微流体系统之微管道的相同方式在基片上制作电吸移管管道(和储库),并且如上所述用平面覆盖元件覆盖带管道的基片。然后,对基片和覆盖元件的边界成形,按要求为吸移管形成合适的水平尺寸,特别在其末端。可以使用诸如蚀刻、气蚀(用粒子和受迫气体冲击表面)以及磨削等技术。然后,按要求在基片表面和可能的覆盖物上形成电极。另一种方法是,在把基片和覆盖元件固定在一起之前,对基片和覆盖元件的边界整形。这种制造方法特别适于多管道的电吸移管,例如刚刚就图4B所描述的以及以下将对图8描述的。
IV.
采样系统
如上所述,上述方法、系统和设备一般将在各种学科中寻找到广泛的应用。例如,如上所述,这些方法和系统特别适于药物发现应用中高通过量的化学筛选,参见1996年6月28日提交的、共同待批的美国专利申请第08/671,987号,该专利申请在前面已通过引用包括在此。
A.
样品基体
一般,就液体样品的采样数目(例如,来自多井板multi-well plate),对本发明的吸移和流体传输系统进行描述。但是,在许多情况下,需要采样的基于流体的样品的数目和种类会产生许多样品处理问题。例如,在化学筛选和药物发现应用中,筛选用的化合物库的数目可以成千上万。因此,这类库要求数量极大的样品板,即使在自动机械系统的帮助下,这也会在样品存储、处理和识别上产生各种困难。另外,在某些情况下,当以液态保存时,特殊的样品化合物会劣化、复杂化,或者具有相当短活性的半活体。当在筛选之前以液态长时间存储样品时,有可能导致不可信的结果。
因此,本发明以固定格式提供需采样的化合物,从而获得可以解决这些问题的采样系统。“固定格式(immobilized format)”是指通过结合到固定基体(即,多孔基体、带电基体、疏水或亲水基体)内,在固定位置上提供样品材料,其中固定基体将样品保留在固定位置上。另一种方式是,这类固定样品在给定的样品基体上包含被定位和干燥的样品。在较佳情况下,以干燥形式在样品基体上提供要筛选的化合物。一般,这种样品基体将包括任何数量的材料,用于材料的定位或固定,例如包括诸如纤维素、硝化纤维、PVDF、尼龙、聚砜等。一般,最好用柔性的样品基体,这可使固定有大量不同化合物的样品基体折叠或卷起,有利于存储和处理。
一般,可以用任何已知的方法对样品基体施加样品。例如,用允许对大量化合物定位的自动机械吸液系统将样品库定位在样品基体的薄片上。另一种方法是,处理样品基体,为样品定位提供预定的区域,例如,锯齿状的井,或者由疏水屏障围绕的亲水区,或者由亲水屏障围绕的疏水区(例如,样品原始处于疏水溶液中),这样将在干燥处理过程中保持被定位的材料。于是,这种处理允许使用更先进的样品施加方法,诸如在美国专利第5,474,796号中描述的,用压电泵和喷嘴系统将液体样品射到表面上。但是,一般地说,’796专利中描述的方法是关于在表示上施加液体样品,以便随后与其它液体样品反应。但是,这些方法很容易被修改成,在基片上提供干燥的定位样品。
类似地,可以使用其它的固定或定位方法。例如,当样品稳定于液态时,样品基体可以包括多孔层,凝胶或其它聚合物材料,它们保持液体样品,不允许过度扩散和蒸发,但允许按需要至少提取一部分样品材料。为了把样品拖入吸移管,吸移管将使一部分样品脱离基体,例如通过溶解基体、离子交换、稀释样品等方法。
B.
再增溶吸移管
如上所述,本发明的采样及液体传输方法和系统容易适用于筛选、分析或处理以这些样品格式固定的样品。例如,当在样品基体上以干燥形式提供样品材料时,可以把电吸移管系统施加到基体的表面。然后,如上所述,例如通过倒转施加在吸移管上的电场极性,或者通过从低离子浓度缓冲剂储库到高离子浓度缓冲剂储库施加一电位,来操作电吸移管,以排出小体积的液体,增溶先前位于基体表面上的干燥样品(溶解保留的基体,或从固定支持物中洗出样品)。一旦使样品再增溶,就按其通常的正向方式操作吸移管,如前所述将增溶的样品拖入吸移管管道中。
图8示出了对于实现该功能很有用的电吸移管的一个实施例,以及它的工作情况。概括地说,吸移管(如图所示)800的顶端802一般与分析系统(例如,微流体芯片)相连,以使对吸移管804、806和808独立施加电压。一般,管道804和808分别与包含低离子浓度流体和高离子浓度流体的缓冲剂储库流体连接。在操作过程中,吸移管810的尖端与样品基体812的表面接触,该表面上有一固定(例如,干燥的)样品814。从低离子浓度缓冲剂管道804到高离子浓度缓冲剂管道施加一电压,以便迫使缓冲剂排出吸移管的尖端,从而接触并溶解样品。如图所示,为了将排出的溶液保持在吸移管尖部和基体表面之间,吸移管816可以包括一凹陷区或“样品杯”818。在某些情况下,例如当筛选有机样品时,为了保证溶解样品,可以在低离子浓度缓冲剂中包含一种合适浓度的可接收的溶剂,例如DMSO。然后,从高离子浓度缓冲剂管道到样品管道806施加一电压,以便按样品栓的形式将样品拖入吸移管中。一旦完全将样品从样品杯提取到吸移管中,由于空气进入样品管道将产生较大的表面张力,从而停止吸入样品,并且高离子浓度的缓冲剂溶液将开始流入样品管道,在样品之后形成第一分隔区822。然后,通过从低离子浓度缓冲剂管道804到样品管道806施加电压,可以将低离子浓度缓冲溶液注入样品管道,即成为第二分隔区824。在表述基体上下一个样品位置之前或期间,通过在高离子浓度缓冲剂管道和样品管道之间施加电压,可以将第一或高离子浓度分隔区822导入样品管道。如前所述,用这种方式可以表述具有成千或上万种需筛选的不同化合物的一个或多个样品基体卷、片或板,允许在合适的设备或系统中对它们进行序列筛选。
V.
消除电泳偏离
如上所述,用电动力将试验物料传过微流体系统100。如果在溶液中使试验物料带电,那么它不仅会受到电渗力,而且会受到电泳力。因此,试验物料在沿微流体系统的管道从一点移动到另一点的过程中,可能会受到电泳的作用。因此,起点处试验物料的混合物以及带不同电荷的物质在试验物料区200中的位置可能不同于终点处的混合物或位置。另外,在终点处,试验物料甚至可能不在试验物料区200内,尽管处于第一分隔区201内。
因此,本发明的另一方面是,当把试验物料传过微流体系统100时,补偿电泳偏离。图5示出了一种补偿电泳偏离的方法。在上述微流体系统中,沿长度将每根管道110、112、114和116看作一整体结构。在图5中,例示的管道140被分成两个部分142和144。每个管道部分142和144的侧壁具有极性相反的面电荷。盐桥133(诸如玻璃料或凝胶层。)以物理方式将两个管道部分142和144连接在一起。尽管盐桥133将管道140中的流体与储库135中的离子流体(离子流体被盐桥133部分限定)分离,但盐桥133允许离子穿过。因此,储库135以电气方式而不是以流体方式与管道140联系。
为了在点A和点B之间沿管道140产生电渗力和电泳力,分别在占A和点B处安装电极132和134。另外,将第三电极137布置在位于两个部分142和144交汇处的储库135中。使电极132和134保持相同的电压,而电极137处于另一电压。在图5所示的例子中,两个电极132和134处于负电压,而电极137以及两部分142和144的交汇点处于零电压,即地电压。因此,在部分142和144中产生压降,并使两部分中的电场指向相反的方向。具体地说,电场指向彼此背离。因此,在管道部分142中,作用在特定带电分子上的电泳力沿一个方向,而在管道部分144中,电泳力沿另一方向。当通过两部分142和144后,可以补偿试验物料的任何电泳偏离。
但是,两部分142和144中的电渗力仍然沿同一方向。例如,如图5所示,假设管道部分142的侧壁具有正的面电荷,它们吸引溶液中的负离子,而管道部分1 44的侧壁具有负的面电荷,它们吸引溶液中的正离子,那么两部分142和144中的电渗力是向附图右方的。因此在电渗力的作用下,试验物料从点A传输到点B。但是电泳力在部分142中沿一个方向,而在另一部分144中沿相反的方向。
为了形成侧壁带正或负面电荷的管道,用带有面电荷的绝缘薄膜(诸如聚合物)涂覆管道的一个或两个部分。例如,在微流体系统100中,基片102和管道可以由玻璃制成。用带有相反面电荷的聚合物(例如聚赖氨酸)涂覆每根管道的一部分,或者用包含氨基官能团的硅烷化剂(例如,氨基丙基三氯三烷)对每根管道的一部分进行化学改良。另外,两个管道部分的面电荷密度和体积应该大约相同,以便补偿电泳偏离。
代替用固体的平面基片制备管道,还可以用两根毛细管制备管道,其中用盐桥将两根毛细管对接在一起,盐桥将离子流体储库与毛细管中的流体分离。还在离子流体储库中放置一个电极。一个毛细管具有负的面电荷,而另一毛细管具有正的面电荷。所行的毛细管管道如上所述工作。
图6A-6D示出了本发明的另一实施例,在该实施例中,补偿了当试验物料从点A移动到点B时,因电泳偏离引起的对试验物料的影响。在该实施例中,在点B(如图1所示在两管道之间的相交处)混合试验物料。
图6A-6D示出了小室160,它位于管道150、252、154和156的交会处。小室160具有四个侧壁162、164、166和168。侧壁162与管道152的一个侧壁以及管道150的一个侧壁相连;侧壁164与管道154的一个侧壁以及管道152的另一侧壁相连,侧壁166与管道156的一个侧壁以及管道154的另一侧壁相连,以及侧壁168与管道156的相对侧壁以及管道150的相对侧壁相连。假设材料通过管道152向管道156流动,如果材料转向管道150,那么侧壁162和168形成一漏斗。
侧壁162和168的尺寸可以容纳沿管道152传输的试验物料栓200的长度。侧壁162和168将栓200漏入管道150的宽度中。管道150的宽度致使试验物料在管道150的宽度上发生扩散,即发生混合,并消除了试验物料区200沿管道162传输时产生的试验物料的任何电泳偏离。例如,如果管道150为50微米宽,那么对于扩散常数为1×10-5cm2/sec的分子,横跨管道的扩散大约在一秒钟内发生。
在图6A中,阳离子试验物料的栓200沿管道152向管道156移动。当栓200到达小室160时,试验物料已受电泳作用,从而物料更集中于试验物料区200的前端。图6B示出了这一情况。然后,终止沿管道152和156施加的压降,并沿管道154和150产生一压降,以便将试验物料区200拖入管道150。小室160的侧壁162和168使试验物料区200与其经电泳偏离的试验物料一起漏下。图6C示出了这一情况。通过扩散,在试验物料沿管道150传输任何明显的距离之前,试验物料在管道150的宽度上展开;混合试验物料区200中的试验物料,并准备在微流体系统100中进行下一步操作。
除了可以用来校正单一样品内的电泳偏离,应该理解,图6所示的结构可用于在这些微流体装置中混合流体单元,例如两种不同的试验物料,缓冲剂,反应剂等。
举例
例1-按电吸移管的类型格式,迫使带不同电的物质同移
为了证明用来消除或减小电泳偏离的诸方法的有效性,在毛细管管道中,通过电动作用抽运两种带相反电荷的物质,并使其在单个样品栓中同移。用Beckman毛细管电泳系统模拟毛细管管道中的电泳力。
概括地说,在本实验中使用一种样品,它在低离子浓度(或“低盐”)(5mM硼酸盐)或高离子浓度(“高盐”)(500mM硼酸盐)的缓冲剂中包含苄基胺和苯甲酸。苯甲酸大约是苄基胺浓度的2倍。所有的注射时间持续0.17分钟。注射电压8或30kV决定了注射栓的长度。低盐和高盐缓冲剂如上所述。
在第一实验中,将在低盐缓冲剂中连续三次注射的样品导入充满低盐缓冲剂的毛细管中。注射在8kV的电压下进行,并在30kV的电压下通过低盐注射使它们分离。图7A示出了这些注射产生的数据。这些数据表示,第一和第二注射的苄基酸峰(识别为低峰,因其浓度较低)先于第一注射的苯甲酸峰(高峰)。另外,第三注射的苄基胺峰几乎于第一苯甲酸峰重合。因此,该实验显示了电泳偏离的作用,其中样品峰没有不按其进入管道的次序离开毛细管管道。由图可以清楚地看出,这种分离实质上会影响单一样品的特性,或更糟地是,还会央及先前或后续导入的样品。
在第二实验中,毛细管充满低盐缓冲剂。在8kV电压下,通过第一次导入/注入高盐缓冲剂将样品注射到毛细管中(第一分隔区1)。接着,在8kV电压下注射高盐缓冲剂中的样品,然后在8kV电压下第二次注射高盐缓冲剂(第一分隔区2)。用这一方式注射三种样品,并在30kV电压下通过注射低盐缓冲剂使其分离。如图7B所示,样品中所含的两种化合物被迫在同一样品栓中一同移动通过毛细管管道,并且每次注射由单个峰表示。这证明了样品是对齐的,与电泳移动无关。
通过相对于样品大小,减小样品间低盐分隔栓的大小,可以部分分辨每次样品注射的各成份。当在电动抽运期间希望对样品进行某些分离,但不影响前后注入的样品时,这是非常有用的。这可以通过在8kV而非30kV电压下注射低盐分隔栓来获得。图7C示出了该例的数据。
例2-试验物料通过电吸移管迁移到微流体系统基片中
图9A-9C示出了如上所述通过电吸移管将试验物料(即样品)导入微流体系统的实验测试结果。样品是PH值为7.4的磷酸盐缓冲盐溶液中含若丹明B。高离子浓度(“高盐”)缓冲剂也由PH值为7.4的磷酸盐缓冲盐溶液形成。低离子浓度(“低盐”)缓冲剂由PH值为8.6的5mM硼酸钠溶液形成。
在测试中,周期性地将含有荧光若丹明B注入电吸移管的毛细管管道中,其中电吸移管与微流体系统的基片相连。如前所述,还将高盐和低盐缓冲剂注射到试验物料区之间。图9A是若丹明B荧光强度对时间的曲线图,其中若丹明B的荧光强度是在毛细管道与基片管道的连接处附近,沿毛细管道的某一点上测得的。(顺便提一下,应该看出图9A-9V和图10曲线图中荧光强度轴上的数字表示相对参考值,不是绝对值。)注射周期为7秒,将试验物料区移过吸移管的电场为1000伏/厘米。用光电二极管监测来自毛细管道的光的综合时间被设置为10毫秒。由图9A可见,很容易证明光强峰以7秒的间隔出现,这与荧光若丹明B的注射周期匹配。
在另一实验中,将相同的缓冲剂与若丹明B样品一起使用。监测占在与电吸移管相连的基片管道中。注射周期设为13.1秒,包含若丹明B的源储库与基片中的目标储库之间的电压设为-3000伏。监测光电二极管的综合时间为400毫秒。如图9B所示,荧光强度峰接近于若丹明B的注射周期。
图9C示出了第三实验的测试结果。在该实验中,电吸移管由基片制成,并通过气蚀成形。监测点沿基片(和平面覆盖物)中形成的毛细管道。这里,样品材料是pH值为7.4的PBS缓冲剂中包含100μM若丹明B。高盐缓冲剂溶液仍是pH值为7.4的PBS,而低盐缓冲剂溶液仍是pH值为8.6的5mM硼酸钠。同样,周期性的荧光强度峰与若丹明B注入电吸移管的周期一致。
图10示出了依照本发明将另一种试验物料周期性地注入电吸移管的结果。在该实验中,样品是100μM的小分子化合物,pH值为7.4的磷酸盐缓冲盐溶液中含1%的DMSO。高盐缓冲剂仍是pH值为7.4的磷酸盐缓冲盐溶液,而低盐缓冲剂仍是pH值为8.6的5mM硼酸钠。将试验物料区移过电吸移管的所加电压为-4000伏,而用光电二极管监测来自毛细管道的光的综合时间设为400毫秒。如前所述,将样品周期性地注入电吸移管中。同上述结果一样,图10表明,对于小分子化合物,电吸移管以匀均的时间间隔移动样品。
尽管为了清楚和理解的目的,已详细描述了上述发明,但本领域的技术人员通过阅读该公开内容,显然可以不脱离本发明实质范围,在形式和细节上进行各种变化。例如,可以按各种组合使用上述所有技术。为了所有目的,本申请中引用的所有公开物和专利文献均通过引能包括在此,其引用程度与单独表示每个公开物或专利文献的一样。
Claims (11)
1.一种微流体系统,其特征在于,包括:
基片,所述基片中布置了至少一个第一管道和至少一个第二管道,所述第二管道与所述第一管道相交,并且所述第一管道比所述第二管道深,所述第一管道之宽度对深度的纵横比大于5;和
电渗流导向系统。
2.如权利要求1所述的微流体系统,其特征在于,所述至少一个第一管道的深度至少是所述第二管道的两倍。
3.如权利要求1所述的微流体系统,其特征在于,所述至少一个第一管道的深度至少是所述第二管道的5倍。
4.如权利要求1所述的微流体系统,其特征在于,所述至少一个第一管道的深度至少是所述第二管道的10倍。
5.一种用于如权利要求1所述的微流体系统的微流体装置,其特征在于,包括基片,所述基片中至少布置了第一和第二交叉的流体管道,所述第一管道比所述第二管道深,所述第一管道的宽度对深度的纵横比大于5。
6.如权利要求5所述的微流体装置,其特征在于,所述第一管道的深度为所述第二管道深度的2-10倍。
7.一种微流体系统,其特征在于,包括:
第一基片;
至少第一和第二管道,它们布置在所述第一基片中,所述第一和第二管道在第一交会处进行流体连通,所述第一管道的深度至少是所述第二管道的两倍,并且所述第一管道的宽度对深度的纵横比大于5;和
用于移动物料以便使所述物料通过所述第一和第二管道的系统,该系统包括:
至少第一、第二和第三电极,所述第一和第二电极在所述第一交会处的两侧与所述第一管道电接触,所述第三电极与所述第二管道电接触;和电源,用于为所述第一、第二和第三电极提供电压,以便沿所述第一和第二管道中至少一个管道的长度,有选择地产生一电压梯度。
8.如权利要求7所述的微流体系统,其特征在于,所述第一管道的深度至少是所述第二管道深度的5倍。
9.如权利要求7所述的微流体系统,其特征在于,所述第一管道的深度至少是所述第二管道深度的10倍。
10.如权利要求7所述的微流体系统,其特征在于,
所述第一基片具有至少一个平表面,所述第一和第二管道被制作在所述第一基片的所述至少一个平表面中;并且
所述微流体系统还包括至少一个第二基片,所述至少一个第二基片覆盖所述第一基片的所述至少一个平表面。
11.如权利要求10所述的微流体系统,其特征在于,所述至少一个第二基片具有入口。
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US08/760,446 US5880071A (en) | 1996-06-28 | 1996-12-06 | Electropipettor and compensation means for electrophoretic bias |
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WO (1) | WO1998000705A1 (zh) |
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DE69732935D1 (de) | 2005-05-12 |
US20020017464A1 (en) | 2002-02-14 |
US5958203A (en) | 1999-09-28 |
NZ333345A (en) | 2000-09-29 |
JP2003075407A (ja) | 2003-03-12 |
AU3501297A (en) | 1998-01-21 |
US6547942B1 (en) | 2003-04-15 |
EP0909385A1 (en) | 1999-04-21 |
JP3795823B2 (ja) | 2006-07-12 |
US7001496B2 (en) | 2006-02-21 |
US5972187A (en) | 1999-10-26 |
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