CN1168720A - 对化学分析和合成进行微流体处理的装置和方法 - Google Patents
对化学分析和合成进行微流体处理的装置和方法 Download PDFInfo
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- CN1168720A CN1168720A CN95195417A CN95195417A CN1168720A CN 1168720 A CN1168720 A CN 1168720A CN 95195417 A CN95195417 A CN 95195417A CN 95195417 A CN95195417 A CN 95195417A CN 1168720 A CN1168720 A CN 1168720A
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Abstract
一种微芯片实验室系统(10)和方法,提供对各种应用的流体处理,包括适合微芯片化学分离的试样注入。微芯片用标准光刻工艺和化学湿法蚀刻工艺制作,基片和盖板用直接粘结工艺连接。毛细管电泳和电色谱法在基片中形成的通道(26、28、30、32、34、36、38)中进行。由电动力把被分析物经交叉处(40)泵入使被分析物加载到通道的四通交叉处,随后由电势转换,迫使被分析物堵塞物进入分离通道(34)。
Description
本发明是根据美国能源部与Martin Marietta Energy Systems,Inc.签订的DE-AC05-840R21400号合同,在美国政府支持下完成,政府对本发明具有一定权利。
发明领域
本发明一般涉及用于化学分析、化学传感和合成的微型仪器,尤其是,涉及在经过微切削加工的通道中对流体进行电学控制处理。这些处理可用于各种应用场合,包括毛细管电泳、液相层析、流体注入分析和化学反应及合成的电学控制处理。
发明背景
实验室分析是很麻烦的过程,要获得化学和生物化学信息需要昂贵的设备、专门的实验室和训练有素的人员。因此,只有在获得化学信息会有用的情况下才进行实验室试验。在研究和临床环境中,大量的试验是用粗糙的人工方式来进行,其特点是劳动成本高、试剂消耗大、反复时间长,相对来说不精确和重复性差。这些技术,例如电泳,已广泛用于生物和医学实验中,但三十年来没有太大的变化。
典型的实验室操作过程包括试样制备、化学/生物化学转化、样品分馏、信号检测和数据处理。为完成这些任务,液体通常按容积精度进行测量和配伍,混合在一起,并在一种或多种不同物理或化学环境中完成转化或分馏。在研究、诊断或开发中,这些操作在宏观尺度下进行,使用一次几微升到几升范围的流体量。连续进行各个操作,通常对过程中不同阶段用不同的专门设备和仪器。其结果是,这种包括多个实验室处理步骤的操作常常是复杂、困难和昂贵的。
很多人已经作了许多尝试,试图通过建立整体化的实验系统来解决这些问题。常规的机器人装置已用来进行移液、试样处理、溶液混合以及某些分馏和检测操作。但是,这些装置非常复杂,非常昂贵,并且其操作需要大量的训练,以致其用途仅局限于相当少数的研究和开发项目。较为成功的则有自动化临床诊断系统,能够迅速而价廉地完成少量任务,例如对糖血水平、电解质和气体进行临床化学试验。不幸的是,由于复杂、体积大和成本高,这些设备仅限于在少数诊断场合使用。
发展具有广泛的实验室用途的整体化系统的希望已趋向这一目标,即系统应小型化。在二十世纪八十年代,对生物传感器的概念作了相当大的探索研究和开发,希望其会满足需要。这些装置使用选择性的化学系统或生物分子,并与新的检测方法,例如电化学检测法和光学检测法结合,以把化学信号转换成电信号,再可由计算机或其它信号处理装置作出解释。不幸,生物传感器的商业化令人失望。在1993年少于20种商业化产品,在美国的营业额统计少于一亿美元。大多数观察家同意,这种失败主要是技术上的,而不是对市场潜力的错误估计。事实上,在许多场合,例如对新药的批量筛选、可以高度比拟的遗传研究和试验、可以在成本上最大限度地减少试剂消耗及浪费的微量化学分析,以及临床或医生诊所的诊断等,都将从整体化的小型实验系统中获益匪浅。
在九十年代早期,人们开始讨论传统技术微型化的可能性。Andreas Manz是首先在科学出版物中发表这一概念的人之一,称其为“微型化的综合分析系统”,或“μ-TAS”。他预言有可能使处理化学或生物化学样品必需的各个单元集合成单一的微型形式,由此得到自动的实验。从那以后,出现了微型元件,特别是分子分离方法和微型阀。曾试图使这些系统完整地集合成整体化的系统,但并未获得成功,这主要是因为业已证明:在极其狭窄的通道中精确地处理微量流体是一个技术难题。
另一容易受到微型化影响的领域是毛细管电泳。毛细管电泳是种常用的技术,用于分离溶液中带电的分子粒子。该技术在微小的毛细管中进行,以减少因热对流引起的带宽效应,从而改进分辨率。小管意味着容积很小的材料,其数量级为毫微升,必须加以处理,以把试样注入到毛细分离管中。
目前的注入技术包括电迁移和虹吸,使试样从一个容器到另一连续的分离管中。这两种技术再现性较差,电迁移还会引起电泳淌度偏差。对这两种取样技术来说,分析毛细管的输入端必须从一缓冲容器转移到保存该试样的容器。这样,就涉及了机械动作。对虹吸注入,试样容器在一段固定时间内高出保持毛细管出口端的缓冲容器。
通过在毛细管上加上一合适的极化电势,并保持一段时间来进行电迁移注入,同时毛细管的入口保持在同一容器内。这会引起取样偏差,因为不成比例的大量较大电泳淌度的粒子迁移到管子中。对这两种技术而言,在注入阶段后毛细管从试样容器中移走,重新放入入口缓冲容器。
所以仍然需要有提高电泳分辨率和改进注入稳定性的方法和装置。
发明综述
本发明提出了微芯片实验室系统和方法,可以在电子控制下在一微芯片上进行复杂的生物化学和化学分析。微芯片实验室系统包括一材料处理装置,其通过微芯片上一互连的集成通道系统输送材料。通过控制集成通道中产生的电场来对材料的移动精确地导向。这种材料移动的精确控制保证了进行所需的生物化学或化学过程所需的精确混合、分离和反应。
本发明的微芯片实验室系统以精确而可再现的方式分析和(或)合成化学材料。该系统包括一主体,其有着集成的通道,连接多个储存该系统所进行的化学分析或合成中所用的化学材料的容器。一方面,至少五个容器同时有受控的电势,这样来自至少一个容器的材料通过通道输送到至少一个其余容器。材料通过通道的输送实现了暴露于一种或多种选定的化学或物理环境,由此合成或分析该化学材料。
微芯片实验室系统最好包括连接三个或多个容器的集成通道的一个或多个交叉处。这种实验室系统控制容器中哪一种材料经过交叉处输送的方式控制通道中产生的电场。在一个实施例中,微芯片实验室系统作为一种混合器或稀释器通过在交叉处产生小于要混合的材料的两个容器中的每个容器的电势,在交叉处混合材料。或者,该实验室系统可作为一种分配器,经交叉处电动力学地注入精确的、受控数量的材料。
通过对至少五个容器中的每个容器同时施加电势,微芯片实验室系统则可作为用于进行完全的化学分析或合成的完整的系统。这五个或更多个容器可这样安排,使得可以对要分析的样品(被分析物)进行电动力学分离,其后,该试样与来自试剂容器的试剂混合。或者,可首先进行被分析物和溶剂的化学反应,然后由反应生成的材料进行电动力学分离。这样,采用五个或多个容器实现了集成实验室系统,实际上可进行任何化学分析或合成。
在本发明的另一方面,微芯片实验室系统包括一由互连至少六个容器而形成的双交叉。第一交叉可用于把一段尺寸精确的被分析物的堵塞物注入到一通向废弃物容器的分离通道。在第二交叉处的电势可选为对被分析物的堵塞物的大小进行附加控制。此外,电势可这样控制,即从第五和第六容器经第二交叉处向第一交叉处和向第四容器输送材料,在此之前选定数量的材料从第一交叉处经第二交叉处送往第四容器。这种控制可用于把被分析物的堵塞物进一步推向分离通道,同时使第二被分析物的堵塞物经第一交叉处注入。
另一方面,微芯片实验室系统作为微芯片流通控制系统,控制材料经连接至少四个容器的集成通道形成的交叉处的流动。微芯片流通控制系统同时对至少三个容器施加控制电势,这样,从第一容器经该交叉处送到第二容器的材料容积,仅借助从第三容器经过交叉处的材料运动来进行选择性控制。最好是,经过第三容器的材料,选择性控制从第一容器输送的材料,然后再送往第二容器。这样,微芯片流通控制系统作为一个阀或一扇门,有选择地控制经交叉处输送的材料容积。微芯片流通控制系统也能构成一分配器,其防止第一材料经交叉处移到第二容器,在此之前选定量的第一材料已通过该交叉处。或者,微芯片流通控制系统也可作为一种稀释器,同时把第一和第二材料从交叉处送往第二容器,使交叉处的第一和第二材料混合。
本发明的其它目的、优点和特点将结合附图对最佳实施例作下述详细叙述而变得显而易见。
附图简述
图1是本发明的一个最佳实施例的示意图;
图2是一通道的放大的纵向剖视图;
图3是一按照本发明第二最佳实施例的微芯片的俯视图;
图4是图3中交叉区域的放大视图;
图5是一段被分析物的堵塞物经过图30实施例中交叉处的CCD图象;
图6是按照本发明的微芯片的第三个最佳实施例的微芯片实验室系统的示意性俯视图;
图7是“若丹明B的样品加载方式”的CCD图象(阴影区);
图8(a)是在被分析物注入前图6微芯片的交叉区的示意图;
图8(b)是在样品以挤压方式加载后图8(a)所示同一区域的CCD荧光图;
图8(c)是在样品以漂浮方式加载后图8(a)所示同一区域的显微照片;
图9表示注入的容积对挤压和漂浮注入的时间的积分荧光信号;
图10是按照本发明第四最佳实施例的微芯片的示意性俯视图;
图11是图10交叉区的放大图;
图12是按照本发明第五最佳实施例的微芯片实验室系统的示意性俯视图;
图13(a)是图12微芯片实验室系统交叉区的CCD摄象图;
图13(b)是在以挤压方式加载样品后图13(a)所示同一区域的CCD荧光图;
图13(c)-13(e)是在切换到运行方式后图13(a)所示同一区域的CCD荧光图,依次分别表示被分析物的堵塞物离开通道交叉处1秒、2秒和3秒时的情景;
图14表示二丹酰-赖氨酸注入2秒时的两个注入轮廓形状,γ=0.97和9.7;
图15是在离开若丹明B(较少阻滞)和硫代若丹明(较多阻滞)的注入点在(a)3.3cm、(b)9.9cm和(c)16.5cm处得到的电泳图;
图16是由图15的电泳图产生的一组效率数据曲线图,表示基板数量随若丹明B(带+的小方块)和硫代若丹明(带+的小方块)通道长度的变化,以及硫代若丹明(带点的小方块)对每一被分析物的最佳线性符合(实线)。
图17(a)是有着1.5kV/cm的分离场强和0.9mm的分离长度的若丹明B和荧光生的电泳图;
图17(b)是有着1.5kV/cm的分离场强和1.6mm的分离长度的若丹明B和荧光生的电泳图;
图17(c)是有着1.5kV/cm的分离场强和11.1mm的分离长度的若丹明B和荧光生的电泳图;
图18是每单位时间基板数量变化的图,其作为在分离长度为1.6mm(圆圈)和11.1mm(方块)的若丹明B的电场强度函数,以及分离长度为1.6mm(菱形)和11.1mm(三角形)的荧光生的电场强度函数;
图19表示用图12的系统由电色谱法分析的香豆素的色谱图;
图20表示用图12的系统由微电动力毛细管色谱分析得到的香豆素的色谱图;
图21(a)和21(b)表示用图12的系统的三个金属离子的分离;
图22是按照图3实施例的微芯片的示意性俯视图,额外带有试剂容器和反应通道;
图23是图20的实施例的示意图,表示外加电压;
图24表示用图22的实施例产生的两个电泳示意图;
图25是按照本发明第六个最佳实施例的微芯片实验室系统的示意图;
图26是表示由图25的系统对精氨酸和甘氨酸注入量的再现性;
图27表示用图25的系统的三种电泳分离的重叠;
图28表示用图25的系统的注入量对反应时间的曲线图;
图29表示用图25的系统产生的限制段的电泳图;
图30是按照本发明第七最佳实施例的微芯片实验室系统的示意图;
图31是图21的装置的示意图,表示依次施加电压以影响所希望的流体操作;以及
图32是表示为影响图23的流体操作所加的不同电压的图。
发明的详细内容
用于分析或合成化学物的整体化微实验室系统要求有一种精确的方法来处理流体和流体所载的材料,并使流体处于选定的化学或物理环境下,以产生所希望的转化或分离。使被分析物集中,产生化学转变,在合理的时标、分子检测性质、扩散时间和制造方法等方面,在微观规模的、小型集成微实验室系统上产生装置,并提供直径的数量级为1微米到100微米的通道。在这方面,电动力学泵已被证明是多用途的和有效的,可在微观形成的实验室系统中输送材料。
本发明利用电动力学泵抽作用,不仅在分离,而且在实施其它重要的试样处理步骤,例如化学转变或试样分隔,以完成液体处理方面,是必不可少的工具。通过同时控制由微观芯片结构中各通道连接的一组管口处的电压,有可能高精度地测量和分配流体、混合试剂、诱导反应成份,将各成份引导到物理或生物化学区,促使各成份由检测系统处理。通过把这些能力集合到单一的芯片上,有可能产生完整的、微型的、整体化的自动实验室系统,以分析或合成化学物。
这种整体化的微实验室系统可由几个元件组成,这些元件可包括液体分配系统,液体混合系统,分子分隔系统,检测器等。例如,正如这里讨论的,可以组成一较完整的系统,以鉴别DNA分子中限制性核酸内切酶的地点。这种微制作的单一器件的特点是,单个系统包含多种功能,这些功能传统上是由技术员通过使用吸移管管理器、恒温器、凝胶电泳系统以及数据获得系统来完成的。在这一系统中,DNA与酶混合,混合物被培养,一定量的反应混合物被分配到一分离通道中。在用荧光标出DNA的同时,进行电泳。
图1所示是一微芯片实验室系统10的例子,其用于进行完整的化学分析或合成。实验室系统10包括六个容器12、14、16、18、20和22,由通道系统24彼此连接到基板或基片(图1中未画出),下面将详述。每一容器12-22与通道系统24的相应通道26、28、30、32、34、36和38形成流体连通。从第一容器12延伸的第一通道26在第一交叉处连接到从第二容器14延伸的第二通道28。类似地,第三容器16伸出的第三通道在第二交叉处40连接到第四通道32。第一交叉处38由一反应室或通道42连接到第二交叉处40。从第五容器20来的第五通道34也连接到第二交叉处40,这样第二交叉处40是一四通交叉处,连接通道30、32、34和42。第五通道34也在第三交叉处44与第六容器的第六通道36交叉。
储存在容器中的材料最好是电动力学地通过通道系统24输送,以进行所希望的分析或合成。为提供这种电动力输送,该实验室系统10包括一电压控制器46,能施加可选择的电压电平,包括基准电压。这种电压控制器可用多个电压分配器和多个继电器来实现,以得到可选择的电压电平。电压控制器由电压线V1-V6连接到位于六个容器12-22的每个容器上的电极上,以把所需的电压加到容器内的材料上。最好是,电压控制器也包括传感器通道S1、S2和S3,其分别连接到第一、第二和第三交叉处38、40、42,以感受出现在这些交叉处的电压。
在微小型化的平面液相分离装置上采用电动输送,如上所述,是用于样品处理的一种变通途径和液相色谱法的泵吸机构。本发明也在于用电渗流动使各种流体的受控的可再现方式混合。当合适的流体处于由相应的合适材料制成的管子中,管子表面的官能团能离子化。在管子材料最终形成羟基的情形下,质子会离开表面并进入某种水成溶剂。此时,表面带净负电荷,溶剂则有多余的正电荷,大多数处于充电的表面两层。在管子中施加电场,溶液中多余的阳离子会被吸引到阴极,即负极。这些正电荷经过管子的运动会随身带动溶剂。稳定状态速度由式1给出。
式中V是溶剂速度,ε是流体的介电常数,ζ是表面的ζ电势,E是电场强度,π是溶剂精度。由式1,显然流体流速或流率可通过电场强度加以控制。这样,电渗可用作可编程的泵吸机构。
图1所示实验室微芯片系统可用于执行各种类型的实验室分析或合成,例如DNA排序或分析、电色谱法、微胞电动毛细管色谱法(MECC)、无机离子分析以及梯度液体洗脱色谱法,如下详述。第五通道34通常用于电泳或电色谱分离,在某些例子中可称之为分离通道或分离柱。反应室42可用来混合储存在第一和第二容器12、14中的任何两种化学物。例如,来自第一容器12的DNA可与来自第二容器14的酶在第一交叉处38混合,混合物可在反应室42中加以诱导,诱导后的混合物然后经第二交叉处40送到分离柱34进行分离。第六容器22可用于储存荧光标记,其在第三交叉处44与分离柱34中分离的材料混合。合适的检测器(D)可随后用来分析第三交叉处44与第五容器20之间这些被标记的材料。通过在第一交叉处38和反应室42安排预分离柱反应,以及在第三交叉处44安排后分离柱反应,实验室系统10可用于实施许多标准的实验室技术,而这些实验室技术通常要在传统的实验室中用人工方法实施。此外,实验室系统10的部件可用于建立更复杂的系统,以解决更复杂的实验过程。
实验室微芯片系统10包括一基片或基板(图1中未画出),其约为两英寸乘一英寸的单片式载片(Corning,Inc.#2947)。尽管玻璃是较好的材料,其它类似的材料也可以采用,例如,熔融硅、晶体石英、熔融石英、塑料以及硅(若表面被处理成足以改变其电阻率)。最好是,使用一种非导体材料,例如玻璃或熔融石英,以允许施加较高的电场,这样便可经微芯片中的通道达到电动输送材料的目的。半导体材料,例如硅也可以使用,但所施加的电场通常要保持最小(采用当前的提供绝缘层的技术,约小于每厘米300伏),其也许不能提供足够的电动力移动。
通道图形24在基片平面表面上形成,采用标准的光刻工艺,随后用化学湿法蚀刻制成。通道图形可用正光阻材料(Shipley 1811)和电子束写入铬掩膜(Instituteof Advanced Manufacturing Sciences,Inc.)转移到基片上。这一图形可用HF/NH4F溶液化学蚀刻。
在形成通道图形后,盖板可用直接粘合法粘合到基片上,由此基片和盖板表面首先在稀释的NH4OH/H2O2溶液中水解,然后粘连在一起。该组件随后在500℃下退火,以保证盖板对基片的适当粘合。
在盖板粘合后,容器用环氧或其它合适方法粘结固定到基片上,盖板的各部分夹在其间。容器可以是圆筒形,相对的轴线端开口。典型地,通过在每一容器中放置铂丝电极来达到电接触。电极连到电压控制器46,其对选定的电极施加所需的电势,其方法在下面详述。
图2表示第一通道的横截面,并与每一其它集成通道的横截面相同。当采用非晶体材料(如玻璃)作为基片时,并当通道是用化学湿法蚀刻时,则会出现各向同性蚀刻,即玻璃在所有方向均匀蚀刻,形成的通道几何形状为梯形。梯形截面是由在光阻材料边缘用的化学蚀刻工艺进行“下方蚀刻”所造成的。在一个实施例中,图示实施例的通道截面尺寸为深5.2μm,顶部宽57μm和底部宽45μm。在另一实施例中,通道深度“d”为10μm、上部宽度“w1”为90μm、下部宽度“w2”为70μm。
本发明的一个重要方面是材料通过通道系统24的受控电动力输送。这种受控的电动力输送可用于将来自一个容器的选定数量的材料经通道结构24的一个或多个交叉处分配,或者,如上所述,来自两个容器的选定数量的材料可被输送到一交叉处,在该处材料可按所需的浓度混合。闸门分配器
图3所示是一实验室部件10A,其可用来实施经通道结构24A输送材料的一种最佳方案。图3中每一标号后的A表示其相应于图1中不带A的同一标号所指出的模拟部件。为简化起见,图3中未画出控制材料经通道系统24A输送的电压控制器的电极和连接。
图3所示微芯片实验室系统10A控制从第一容器12经交叉处40A向第四容器20A输送的材料量,输送是由电动力打开和关闭从第一通道26A对交叉处40A的连接来进行的。这样,实验室微芯片系统10A基本上起着受控电动力阀的作用。这种电动力阀可用作分配器,以分配选定数量的单一材料,或作为混合器,在交叉处40A混合选定数量的多种材料。通常,电渗析用来输送“流体材料”,电泳用来输送离子而不输送离子周围的流体材料。这样,如这里所采用的,“材料”一词从广义上说是指任何形式的材料,包括流体和离子。
实验室系统10A提供了一种流体经分离通道34A的无定向连续流动,这一注入或分配方法仅需从一个(或两个)容器改变或去掉电压,并允许第四容器20A保持基准电势。这也使得可以用单极性电源来进行注入和分离。
图4表示交叉处40A的放大图。箭头指出在交叉处40A的流动状的时间次序。实线箭头表示最初的流型。各容器的电压被调整,以得到所描述的流型。初始流型以足够的速率从第二容器16A带来第二种材料。这样,从容器12A输送到交叉处40A的第一种材料被推向第三容器18A。通常,电势分布是这样的,最高的电势在第二容器16A,略低的电势在第一容器12A,更低的电势在第三容器18A。第四容器20A则被接地。在这些条件下,朝第四容器20A的流动仅为来自第二容器16A的第二种材料。
为从第一容器12A经交叉处40A分配材料,在第二容器16A的电势可转换到小于第一容器12A的值,或容器16A和/或18A的电势可即刻浮动,以提供图4中短虚线所示的流动。在这些条件下,最初的流动将是从第一容器12A下到分离通道废弃物容器20A。从第二和第三容器16A、18A的流动将是很小的,可在任一方向。这种状况保持得足够长,以便把所需数量的材料从第一容器12A经交叉处40A输送到分离通道34A。在所需的材料有足够时间经过交叉处40A后,电压分布重新转换到原先值,以防止额外的材料从第一容器12A经交叉处40A流向分离通道34A。
这种“闸门分配器”的一个用途是从第一容器12A注入一受控的、大小可变的被分析物的堵塞物到分离通道34A,用于电泳或色谱分离。在这种系统中,第一容器12A储存被分析物,第二容器16A储存离子缓冲剂,第三容器18A是第一废弃物容器,第四容器20A是第二废弃物容器。为从第一容器12A注入一微小的、大小可变的被分析物的堵塞物,缓冲剂和第一废弃物容器16A、18A的电势仅仅提升一小段时间(≈100ms),以允许被分析物向下迁移到分离柱34A。为关闭注入的堵塞物,缓冲容器16A和第一废弃物容器18A的电势被重新加上。或者,阀的顺序可由使容器16A和18A升至交叉处40A的电势来加以安排,随后又回到其原先电势。该方法的不足在于注入的堵塞物的成份有电泳移动偏差,这样较快的迁移化合物比较慢的迁移化合物优先进入分离段34A。
图5中,可借助CCD图象看到图3实施例中一被分析物的堵塞物经过交叉处的顺序图。被分析物从实验室系统10A中泵出,其为若丹明B(阴影区)。注入截面或交叉处的CCD图象的取向与图3相同。第一图(A),表示被分析物被泵出,在注入之前经注入交叉处朝第一废弃物容器18A被泵去。第二图(B),表示被分析物被注入分离柱34A。第三图(C),表示在被注入的堵塞物被完整地引入分离柱34A后被分析物从注入交叉处移开。缓冲剂和第一容器16A、18A的电势浮动100ms,同时试样移入分离柱34A。在(c)图象的时刻,关闭的闸门方式重新恢复,阻止被分析物进一步从交叉处40A移入分离柱34A,并且,一长142μm的清洁的被注入的堵塞物被引入到分离柱中。 如下所述,闸门注入器对总的板高度来说仅占一小部分。被注入的堵塞物的长度(体积)是注入时间和隔离柱中的电场强度的函数。被注入的堵塞物的形状由于分解的缓冲流的方向性而略有倾斜。但是,对于给定的注入期限,由对峰值区域积分所定的注入量,其再现性对一系列10个重复的注入来说为1%RSD。
电泳实验用图3的微芯片实验室系统10A进行,用按照本发明的方法进行。芯片动态情况用被分析物荧光分析。一种电荷耦合器件(CCD)摄象机用于监视芯片的指定区域,一光电倍增管(PMT)用于跟踪单点事件。CCD摄象机(Princeton Instruments,Inc.TE/CCD-512TKM)安装在一立体显微镜(Nikon SMZ-U)上,该实验室系统10A采用一氩离子激光器(514.5nm,Coherent Innova 90),工作在3W,波束扩大到一直径约为2cm的圆形点。备有选样光学系统的PMT安装在微芯片下,光轴垂直于微芯片表面。激光器工作于约20mW,波束以45度角从微芯片表面投射到微芯片上,并平行于分离通道。激光束和PMT观察轴分开达135度角。逐点检测方法采用一氦氖激光器(543nm,PMS Electro-optics LHGP-0051),带有一静电计(Keithley 617),以监视PMT(Coriel 77340)的响应。电压控制器46(Spellman CZE1000R)用于电泳,在对地为0和4.4kV之间工作。
对图3和4所述的这类闸门注入器如传统的电渗注入那样表示电泳移动性斜线。然而,这一方案在电压转换要求和构造方面非常简单,并提供了经分离通道的连续的单向流动。此外,闸门注入器提供了一种用阀门调节进入分离通道34A的变量流体的方法,这一方式由所加的电势精确控制。
闸门分配器10A的另一应用是以一种受控方式稀释或混合所需数量的材料。为实施这种混合方案,以把来自第一和第二容器12A、16A的材料混合,第一和第二通道26A、30A中的电势要求被保持得比在混合时高于交叉处40A的电势。这种电势会引起来自第一和第二容器12A和16A的材料同时经过交叉处40A并由此混合两种材料。加到第一和第二容器12A、16A的电势可按需调整,以获得每一材料的选定浓度。在分配每一材料的所需数量后,在第二容器16A的电势可以被增大到足以防止第一容器12A的材料进一步经交叉处40A向第三容器30A输送。被分析物注入器
图6所示是一按照本发明的微芯片被分析物注入器10B。通道区24B有四个离开的通道26B、30B、32B和34B,它们经微切削加工而构造到一基片49上,如前所述。每一通道有一伴随的容器,安装在每一通道部分的端点,所有四个通道一端在一四通交叉处40B处交叉。每一段的相反端具有刚伸出安装在基片49上盖板49′周缘的末端。图6所示被分析物注入器10B实质上与门分配器10A相同,只是所加的电势使从容器16B经交叉处40B注入被分析物,以在分离通道34B中分离。被分析物注入器10B可工作在“加载”方式或“运行”方式。容器16B被送入被分析物,容器12B具有缓冲区。容器18B作为被分析物的废弃物容器,容器20B作为废弃物容器。
在“加载”方式,至少可能有两种方式引入被分析物。在第一种方式,称为“浮动”加载中,电势加到被分析物容器16B,容器18B为接地。同时,容器12B和20B浮动,这表示其既不连接到电源,也不接地。
第二种加载方式为“收缩”加载模式,其中电势同时加到容器12B、16B和20B,容器18接地,以控制注入堵塞物的形状,如下加以详述。如这里所用的,同时控制几个容器的电势意味着电极在化学上同样重要的时间期限内连接到一个工作电源。浮动一容器意味着从电源断开容器的电极,这样就不控制该容器的电势。
在“运行”方式,电势加到缓冲容器12B,容器20B接地,容器16B和18B电势改为容器12B的大约一半。在运行方式中,加到缓冲容器12B的较高电势使交叉处40B的被分析物体移向分离柱34B中的废弃物容器20B。
用若丹明B和琉代若丹明101(Exciton Chemical Co.,Inc.)作为被分析物,在60μM CCD图象和6μm点检测时进行诊断实验。四硼酸钠缓冲剂(50mM,pH9.2)在实验中处于可变相位。注入空间限制得很小的容积(≈100pL),并且纵向范围很小(≈100μm),在进行这类分析时注入是有益的。
被分析物加载到注入截面,作为前沿电泳,一旦最慢的被试物成份的前沿经过注入截面或交叉处40B,被分析物就准备好被分析。在图7中,CCD图象(其区域由虚线方框表示)显示被分析物54(阴影区)和缓冲剂(白色区)经过注入交叉处40B的流动形状。
通过收缩被分析物的流动,被分析物的堵塞物的容积随时间而稳定。堵塞物的略微不对称性是由于当1.0kV施加到缓冲剂、被分析物和废弃物的容器上时,在缓冲通道26B(470v/cm)和分离通道34B(100v/cm)中呈现不同的电场强度而造成的,而被分析物容器是接地的。但是,不同的电场强度并不影响注入的被分析物的堵塞物的稳定性。理想情况下,当被分析物的堵塞物被注入到分离通道34B中时,仅在注入截面或交叉处40B中的被分析物会迁移到分离通道中。
在注入截面中注入堵塞物的容积约是120pL,堵塞物长度为130μm。在被分析物通道30B和被分析物的废弃物通道32B中,一部分被分析物54进入分离通道34B。随着转换到分离(运行)方式以后,注入堵塞物的容积约为250pL,堵塞物长度为208μm。这些尺寸是根据一系列在刚转换到分离方式时得到的CCD图象来估计的。
将被分析物引入到分离通道34B,试验两种加载方式。被分析物处于被分析物容器16B中,并在两种注入方式中,按容器18B方向“输送”,其为一废弃物容器。两类注入的CCD图象如图8(a)-8(c)所示。图8(a)示意地表示交叉处40B以及通道的端部。
图8(b)的CCD图象是在收缩模式下加载,恰好是在转换到运行方式之前。在收缩模式中,被分析物(黑背景上的白色部分)从容器16B由电动力泵出,并电渗透到容器18B(从左到右),同时缓冲剂从缓冲剂容器12B(顶部)和废弃物容器20B(底部)向容器18B(右面)移动。加到容器12B、16B、18B和20B上的电压分别为电源输出的90%、90%、0和100%,分别对应于相应通道的电场强度为400、270、650和20v/cm。尽管加到废弃容器20B的电压大于加到被分析物容器18B上的电压,分离通道34B与被分析物通道30B相比的额外长度带来了额外的电阻,这样从被分析物缓冲区16B到交叉处的流动成为主流。结果,在注入截面或交叉处40B的被分析物有一梯形形状,在通道32B中由此材料输送形状受到空间限制。
图8(c)表示一浮动方式加载。被分析物从容器16B至18B泵出,正如收缩注入那样,但无电势加到容器12B和20B。由于不控制通道部分26B和34B中的可变相位(缓冲剂)的流动,被分析物可自由膨胀,经对流和扩散流动进入这些通道,由此产生延伸的注入堵塞物。
当收缩注入和浮动注入相比时,收缩注入在三方面表现出优越性:注入容积的暂时稳定,注入容积以及长度的精确性。当要分析两种或以上有着显著不同的移动性的被分析物时,具有暂时稳定的注入确保了同样体积的快和慢被分析物被引入到分离柱或通道34B。注入容积的高度再现性有利于定量分析。较小的堵塞物长度导致更高分离效率,结果,导致对给定仪器的更大元件容量和更高速度的分离。
为确定每一模式的临时稳定性,一系列CCD荧光图象以1.5秒间隔进行收集,从被分析物恰好到达注入交叉处40B之前开始。注入的被分析物的数量估计由对交叉处40B和通道26B和34B的荧光图积分来确定。该荧光图与时间的关系在图9中画出。
对应收缩注入,注入容积在几秒钟内稳定,稳定性为1%相对标准偏差(RSD),其可与照明激光的稳定性相比。对于浮动注入,要注入到分离通道34B的被分析物的数量,随时间增加,这是因为被分析物进入通道26B和34B的分散流动。对30秒的注入,注入堵塞物的容积为ca90pL,对收缩注入而言是稳定的。对比浮动注入情况下为ca300pL,并随时连续增加。
通过在离交叉处40B的0.9cm点处监视分离通道,由按照进入分离通道34B的带轮廓面积积分来测试收缩注入方式的再现性。对6次持续时间为40秒钟的注入,收缩注入的再现性为0.7%RSD。这种测量的不稳定性大多来源于光学测量系统。收缩注入有较高的再现性,这是因为注入容积的暂时稳定性。采用电子控制的电压转换,可期望改善两种方式的RSD。
注入堵塞物的宽度,以及最根本的,被分析物的分辨率很大程度上取决于被分析物的流动形状和注入截面或交叉处40B处的尺寸大小。对此分离柱,通道的顶部宽度为90μm,但宽10μm的通道是适宜的,其使收缩注入的注入堵塞物的容积从90pL减少到1pL。
有些情况,并不希望逆转分离通道中的流动,正如上面对“收缩”和“浮动”注入方式所述。这种情形的例子可以是在先前的堵塞物完全被洗出前的新试样的堵塞物的注入,或是使用后分离柱反应器,此时试剂被连续地注入到分离柱的末端。在后一情形下,通常不希望有试剂回流到分离通道。不同的被分析物注入器
图10表示不同的被分析物注入系统10C,它分别具有6个不同的端口或通道26C、30C、32C、34C、56和58,它们分别连接到6个不同的容器12C、16C、18C、20C、60和62。每一部件标号后的字母C表示被指出的部件类似图1中相应数字的部件。微芯片实验室系统10C类似于前述实验室系统10、10A和10B,即具有注入截面或交叉处40C。在图10实施例中,还具有第二交叉处64和两个附加容器60和62,以克服在分离通道中逆向流动的问题。
如前实施例,被分析物注入器系统10C可用于进行由电泳或色谱法的被分析物分离,或将材料扩散到某些其它处理部件中。在实验室系统10C中,容器12C容纳有分离缓冲剂,容器16C容有被分析物,容器18C和20C为废弃物容器。交叉处40C最好是以收缩方式工作,如图6实施例所示。下方的交叉处64与容器60和62流体连通,用于提供额外的流动,这样可将连续的缓冲剂流向下引导到废弃物容器20C,以及当需要时,向上引导到注入交叉处40C。容器60和附带的通道56不是必需的,尽管其因缩小了当堵塞物通过下面的交叉处64时的带宽而改善了性能。在许多例子中,从容器60来的流体会与从容器62来的流体相对称。
图11是两交叉处40C和64的放大图。不同类型的箭头表示在注入被分析物的堵塞物到分离通道时的给定时刻的流动方向。实线箭头表示初始流动形状,此时被分析物被电动力泵入到上方交叉处40C,并被来自容器12C、60和62流向同一交叉处的材料所“收缩”。离开注入交叉处40C的流动被带到被分析物的废弃物容器18C。被分析物也从容器16C流到被分析物的废弃物容器18C。在这些条件下,来自容器60(以及容器62)的流动也从分离通道34C下行到废弃物容器20C。这种流动形式由同时控制所有六个容器的电势而建立。
通过转换到短虚线箭头所示流动外形,被分析物的堵塞物经交叉处40C注入到分离通道34C。缓冲剂从容器12C向下流到注入交叉处40C,并流向容器16C、18C和20C。这一流动外形也促使被分析物的堵塞物推向废弃物容器20C,进入分离通道34C,正如前所述。这一流动外形被保持足够长的时间,以去掉经过下面的交叉处64的被分析物的堵塞物。从容器60和62来的缓冲剂流应如短箭头所指那样小,并进入分离通道34C,以使变形最小。
上下交叉处40C和64之间的距离应尽可能小,以使两流动状态转换时堵塞物的变形的临界计时为最小。用于感受电势的电极也可以置于下方的交叉处及在通道56和58中,以帮助调整电势,用于合适的流量控制。下方的交叉处64的精确的流量控制对防止不希望有的流带变宽会是必要的。
在试样堵塞物通过下面的交叉点后,电势转换回复到初始状态,以给出如长虚线箭头所示原先的流动外形。这一流动形状将允许缓冲剂流入分离通道34C,同时下一被分析物的堵塞物被输送到上方交叉处40C的堵塞物形成区。这一注入方法可允许迅速接续各个注入,对迁移缓慢的试样来说是非常重要的,或是花长时间在上方交叉处40C获得一均匀的试样,例如对于缠结的聚合物溶液就是如此。采用收缩注入也保持了通过分离通道的单向流动,如后分离柱反应所要求的那样,见下面关于图22的讨论。蛇形通道
本发明的另一实施例是如图12所示的被分析物改型注入系统10D。实验室系统10D如图12所示,实际上相同于图6所示实验室系统10B,例外的是分离通道34D在一蛇形通道之后。分离通道34D的蛇形通道可大大增加分离通道的长度,而不明显增大采用蛇形通道的基片49D的面积。增加分离通道34D的长度,就增加了实验室系统10D区别被分析物成份的能力。在一特别推荐的例子中,通道从容器16D延伸到容器18D的封闭长度(其由盖板49D覆盖)为19mm,而通道部分26D的长度为6.4mm,通道34D为171mm。通道34D其作为分离柱,每一转弯处的回转半径为0.16mm。
为用被分析物改型注入系统10D进行分离,被分析物首先用上述加载方法之一加载到注入交叉处40D。在被分析物加载到微芯片实验室系统10的交叉处40D之后,电压被手动地从加载方式转换到运行(分离)工作方式。图13(a)-13(e)表示若丹明B(较少阻滞)和硫代若丹明(较多阻滞)的分离,采用下列条件:Einj=400v/cm,Erun=150v/cm,缓冲剂=50mM四硼酸钠,pH9.2。CCD图象以1秒间隔表示分离过程。图13(a)表示成象一段芯片的成象示意图,图13(b)-13(e)表示呈现出分离。
图13(b)也表示收缩注入,容器12D、16D和20D所加的电压相等,储存器18D是接地的。图13(c)-13(e)表示转换到运行方式后试样堵塞物分别以1、2和3秒钟离开交叉处的情形。在图13(c)中,注入的堵塞物迁移时转弯90°。因堵塞物的内侧部分行程少于外侧部分而可见流动带的变形。图13(d)中,被分析物已分成分开的流动带,变形为平行四边形。图13(e)中,流动带完全分离并成为更接近于矩形,即平行四边形的瓦解,这是由径向分布引起的额外效率损失所造成的。
当开关从加载方式转换到运行方式,希望从被分析物流的注入堵塞物有一干脆的停顿,以避免拖泥带水。这由把流动相或缓冲剂从通道26D泵入通道30D、32D和34D来实现,同时保持交叉处40D的电势低于容器12D的电势,并高于容器16D、18D和20D的电势。
在这里的代表性实施例中,交叉处40D在运行方式中保持为容器12D电势的66%。这提供了足够被分析物从注入交叉处40D回流到通道30D和32D,而不显著减小分离通道34D中的电场强度。不同的通道设计会允许加到容器12D的更大部分的电势加到分离通道34D上,由此提高了效率。
图13(c)-13(e)所示的三路流动表示通道30D和32D(分别在左和右)中的被分析物进一步随时间离开交叉处。三路流动使注入得到良好的限制和可再现性,使渗入分离通道34D的被分析物为最少。检测器
在大多数应用中,对于这些用于化学分析或合成的集成微系统,有必要对出现在通道中的材料在一个或多个位置上确定其定量,类似于传统的实验室测量过程。用于定量分析的技术典型地包括(但并非局限于)吸光度、折射率变化,荧光辐射,化学发光,各种形式的喇曼光谱学,电导定量测定,电化学安培电流测定,声波传播测量。
吸光度测量常用于传统的实验室分析系统,这是因为普遍存在电磁波谱的部分UV现象。吸光度通常由测量入射光功率在通过要定量的已知长度材料时的衰减来确定。其他用激光技术的可能途径包括光声成象技术和光热成象技术。这些测量可用于这里讨论的微芯片技术,同时具有在微型器件上集成光波导的优点。采用固态光源例如LED和具有或没有变频元件的二极管激光器对减少系统尺寸会很有吸引力。在一块芯片上集成固态光源和检测器的技术目前看来尚未成功,但有朝一日会令人感兴趣的。
折射率检测器也常被用于化学分析系统中的流动定量分析,因这种现象普遍存在,但通常不如光学吸收那样敏感。应用激光检测折射率在某些情形下可提供足够的灵敏度,并有简单的优点。荧光辐射(或荧光检测)是非常灵敏的检测技术,常用于生物物质的分析。这一检测手段更适合于微型化学分析和合成装置,这是因为该技术灵敏度高以及可操作和分析小的容积(微微升范围是合适的)。例如,浓度为1nM的被分析物的100pL试样容积只有60,000个被分析物分子要处理和检测。在文献中有几种方法可用荧光检测法检测溶液中单个分子。激光源常用作超灵敏检测的激发源,但传统的光源,例如稀有气体放电灯和发光二极管(LED),也可使用。荧光发射可由光电倍增管、光二极管或其它光传感器检测。阵列检测器,例如电荷耦合器件(CCD)检测器,可用来对被分析物进行空间分布成象。
喇曼光谱学可作为微芯片器件的一种检测方法,其优点是可获得分子振动信息,但缺点是不太灵敏。灵敏度已借助表面增强喇曼光谱学(SERS)效应而得到提高,但仅处在研究水平上。电或化学的检测手段也有特别的优点,可用在微芯片器件上,因为易于集成到一微型结构上,以及能得到潜力很大的高灵敏度。电学定量分析的最一般方法是电导定量测定,即测量离子试样的导电性。离子化的被分析物的出现能相应地增加流体的导电性,并允许定量分析。安培电流测量意味着测量在一给定电势下因电极分子减少或氧化经过电极的电流的测量。控制电极的电势可有某些选择,但是很小。安培电流测量不如导电性测量那样普遍,因为不是所有分子都能在普通溶剂能用的有限电势内被减少或氧化。1nM范围内的灵敏度已在小容积(10nL)中表现出。该技术的其它优点是(经电流)测得的电子数量等于分子出现的数量。这些检测方法中任意一种所需的电极可包括在一微观制作的器件上,经光刻制作布线图案和金属沉积工艺而形成。电极也可以用于引发一化学发光检测过程,即通过一氧化还原工艺产生激发态分子,其将能量传递给被分析物分子,随后发出光子,被检测到。
声测量也能用于材料的定量分析,但目前尚未被广泛使用。一种主要用于气相检测的方法是表面声波(SAW)的衰减或相移。传播SAW的基片表面的材料吸收会影响到传播特性,并允许浓度确定。SAW器件的表面选择性吸收也常被采用。类似的技术在这里所述的装置中是会有用的。
这里所述的微芯片实验室系统的组合能力使其可用于检测各个过程,包括添加一种或多种试剂。衍生反应常用于生物化学测定。例如,氨基酸、缩氨酸和蛋白质常被标以丹酰试剂或o-苯二醛,以产生荧光分子,其易于被检测到。或者,可加入某种可作为标记分子和试剂的酶,包括基片,从而可作为一种酶放大检测方法,即酶能产生一种可检测的产物。还有许多例子已用于传统实验室过程的手段来增强检测,如吸光度或荧光性。可由集成混合方法得到好处的第三种检测法的例子是化学荧光检测。在这些类型的检测方案中,试剂和催化剂与适当的靶子分子混合,以产生受激态的分子,该分子能发出可检测的光子。被分析物堆集
为提高微芯片实验室系统16D的灵敏度,在分离前可进行被分析物的预浓缩。用浓缩提高灵敏度是一有用的工具,尤其是当分析环境试样和生物物质时。这两者都是微芯片技术追求的目标。被分析物堆集结合到电泳分析中是一很方便的技术。为使用被分析物堆集,被分析物在一导电性低于分离缓冲剂的缓冲剂中置备。导电性的差别使得被分析物中离子堆集在被分析物堵塞物的始端部分,由此形成浓缩的被分析物堵塞物,其易于被检测。更复杂的预浓缩技术包括两个和三个缓冲剂系统,即瞬时等速电泳预浓缩。显然有关的溶液数量越大,注入技术就越难实施。预浓缩步骤很适合于在微芯片上实行。电渗驱使的流动使分离和试样缓冲剂可不用阀或泵控制。通道间的小的死容积连接易于实施,使得流体的处理具有高精度、高速度和再现性。
再次参看图12,被分析物的预浓缩在分离通道34D顶部进行,采用改进的闸门注入,以使被分析物堆集。首先,用电渗流动把被分析物堵塞物引进到分离通道34D上。然后,被分析物堵塞物后面跟着来自缓冲剂容器16D的更多分离缓冲剂。此时,被分析物堆集在被分析物与分离缓冲剂的边界处,丹酰化的氨基酸被用作被分析物,其为堆集在被分析物缓冲剂堵塞物后边界的阴离子。被分析物堆集的应用结合堆集对分离效率和检测极限的影响一起加以叙述。
为用微芯片实验室系统10D进行闸门注入,被分析物储存在顶部容器12D中,缓冲剂储存在左容器16D中。用于被分析物堆集的闸门注入在离子强度小于运行中的缓冲剂的被分析物上进行。缓冲剂由从缓冲剂容器16D到被分析物废弃物和废弃物容器18D、20D的电渗来进行输送。这一缓冲剂流可防止被分析物流入分离通道34D。在一代表性的实施例中,缓冲剂、被分析物、被分析物废弃物和废弃物容器的相对电势为1、0.9、0.7和0。当1kV加到微芯片上时,缓冲剂、被分析物、被分析物废弃物和分离通道在分离时的电场强度分别为120、130、180和120V/cm。
为把被分析物注入到分离通道34D上,缓冲剂容器16D的电势浮动(断开高压开关)一段时间(0.1至10秒),被分析物迁移到分离通道。当1kV加到微芯片上时,缓冲剂、试样、试样废弃物和分离通道在注入时的电场强度分别为0、240、120和110V/cm。为断开被分析物堵塞物,重新施加缓冲剂容器16D处的电势(闭合高压开关)。被分析物堵塞物的容积是注入时间、电场强度和电泳迁移率的函数。
分离缓冲剂和被分析物成份可以是相当不同的,而随着闸门注入被分析物和缓冲剂流两者的整体性可交替地维持在分离通道34D中,以进行堆集操作。被分析物堆集取决于分离缓冲剂对被分析物的相对导电性γ。例如,对5mM分离缓冲剂和0.516mM试样(0.016mM丹酰赖氨酸和0.5mM试样缓冲剂),γ等于9.7。图14所示为用γ等于0.97和9.7注入2秒的两注入形状。γ=0.97(分离和样本缓冲剂都为5mM)的注入形状显示没有堆集,第二种γ=9.7时的形状显示出相对峰值高度比γ=0.97的注入有3.5的中等程度增强。丹酰赖氨酸是一种阴离子,这样就堆集在试样缓冲剂堵塞物的后边界。除了增加被分析物的浓度外,也限制了堵塞物空间伸展程度。γ=9.7的注入形状宽度在半高度处为0.41s,而γ=0.97的注入形状在半高度处宽度为1.88s。注入期间分离通道34D中的电场强度(注入电场强度)是分离期间分离通道中电场强度(分离电场强度)的95%。这些形状在施加分离电场强度时测量。对于注入时间为2s,γ=0.97来说,预期注入堵塞物的宽度为1.9s。
对由堆集引起的浓度提高作了评价,评价时参照了分离缓冲剂和被分析物的几个试样堵塞物的长度和相对导电性。由于堆集的浓度提高,也增大了相对导电性γ。表1中,对g从0.97到970列出了浓度提高。尽管这种提高在γ=970为最大,分离效率却受损失,因为电渗压力源于相对导电性太大的浓缩边界。因此必须在堆集浓度提高和分离效率之间作出折衷,结果发现γ=10是最佳的。对于用γ=97和970的堆集的注入,丹酰赖氨酸和丹酰异亮氨酸由于效率损失而不能被溶解。而且,因为微芯片上的注入过程是由计算机控制的,不是实际地从管形瓶到管形瓶,堆集注入的再现性对6个重复的被分析物的峰值区是2.1%rsd(百分相对标准偏差)。比较而言,非堆集的6个重复的被分析物的峰值区的闸门注入为1.4%,收缩注入6个被分析物的峰值区为0.75%rsd。这些很好地对应于大型商用自动毛细管电泳仪器的报告值。但是,微芯片上的注入在容积上约小100倍,即微芯片上的100pL,对应于商用仪器上的10nL。
表1:堆集增大随相对导电性γ的改变
γ 浓度增大
0.97 1
9.7 6.5
97 11.5
970 13.8
不同导电性的缓冲剂流可精确地结合在微芯片上。这里描述的是一简单堆集方法,尽管详尽的堆集方案可用制造具有额外缓冲剂容器的微芯片来实现。此外,引导和清洁电解质缓冲剂可被挑选一增强试样堆集,最好是,使检测极限低于这里所示。也应注意对无机(元素)阳离子期望有更大的(浓度)提高,这是因为结合了电场强度放大的被分析物的注入以及被分析物与缓冲剂离子迁移率的更好的匹配。
不管是否使用试样堆集,图12的微芯片实验室系统10D可用于得到由若丹明B和硫代若丹明组成的被分析物的电泳分离。图15是若丹明B(较少滞留)和硫代若丹明(较多滞留)的注入点离开(a)3.3cm、(b)9.9cm和(c)16.5cm的电泳图。这些用下列条件得到:注入类型为压缩的,Einj=500V/cm,Esept=170V/cm,缓冲剂=50mM四硼酸钠,pH=9.2。为得到传统方法中的电泳图,在分离通道34D轴线下方不同位置使用了氦氖激光(绿线)单点检测。
分离系统实用性的一个重要衡量是每单位时间产生的板数,由下式给出:
N/t=L/(Ht)
式中N是理论的板数,t是分离时间,L是分离柱长度,H是等同于理论板数的高度,板高度H可写为
H=A+B/u
式中A是注入堵塞物长度和检测器通道长度的和,B等于2Dm,这里Dm是缓冲剂中被分析物的扩散系数,u是被分析物的线速度。
结合上述两式,并代入u=μE,这里μ是被分析物的有效电泳迁移率,E是电场强度,则每单位时间的板数可表示为电场强度的函数:
N/t=(μE)2/(AμE+B)
在低电场强度下,轴向扩散是流带分散的主要形式,AμE项相对于B是很小的,结果,每秒钟的板数随电场强度的平方增加。
当电场强度增大时,板高度达到一恒定值,每单位时间的板数随电场强度B线性地增加,因为B相对于AμE是很小的。这样,使A尽可能小是有利的,这是压缩注入法的一个优点。
在10个均匀间隔的位置上监视若丹明B和硫代若丹明的电泳分离效率,每个位置构成一单独的实验。在离注入点16.5cm处,若丹明B和硫代若丹明的效率分别是38100和29000板。这样大小的效率对许多分离应用而言是足够的。数据的线性度则提供了关于通道沿其长度所体现出来的均匀性和质量的信息。若通道中有一缺陷,即出现大的凹坑的话,则会导致效率的急剧下降,但并未检测到。效率数据在图16中画出(图16的条件与图15相同)。
用图6的微芯片被分析物注入器10B进行类似的分离实验。由于正直场强分离通道34B,被分析物注入器10B比采用图12所示另一被分析物注入器10D的蛇形分离通道34D可有更快的分离。此外,采用的电场强度比较高(对缓冲剂和分离通道26B、34B来说分别为470V/cm和100V/cm),这进一步提高了分离速度。
本发明的平面式微芯片实验室系统10B的一个特别优点是,采用激光诱发的荧光,检测点可位于沿分离柱的任一处。在离开注入交叉处40B的分离长度为0.9mm、1.6mm和11.1mm处检测电泳图。在电场强度0.06至1.5kV/cm范围内,使用1.6mm和11.1mm分离长度,而且在这一范围内,分离具有基线分解能力。在电场强度为1.5kV/cm时,被分析物若丹明B和荧光生对0.9mm分离长度来说,溶解少于150ms,如图17(a)所示;对1.6mm分离长度来说,溶解少于260ms,如图17(b)所示;以及对11.1mm分离长度来说,溶解少于1.6秒,如图17(c)所示。
由于通道的梯形几何形状,当电势从试样加载方式转换到分离方式时,上方转角难以精确地清除试样堵塞物。这样,注入堵塞物就略微有些拖泥带水,这种效应也许可以解释在分离的峰值中所观察到的拖尾现象。
图18中,对电场强度画出了1.6mm和11.1mm分离长度每秒的板数。每秒钟的板数很快成为电场强度的线性函数,因为板的高度到达一恒定值。图18中的符号代表对在1.6mm和11.1mm分离长度的两个被分析物收集的实验数据。图线是用预定的方程计算,系数则由实验确定。对于在11.1mm分离长度处的若丹明B,实验数据和计算数字之间略有偏差,这主要是由于实验误差。电色谱法
电泳用于一般分析的一个问题是其不能分离不带电粒子。特定试样中所有中性粒子的电泳迁移率为零。因此,迁移时间也为零。图12所示微芯片被分析物注入器10D也能被用于采用电色谱法来分离非离子被分析物。为进行这种电色谱法,对分离通道34D表面进行准备,用化学粘结将一反相涂层粘结到分离通道壁上,在此之前盖板粘结到基片上,以封闭通道。分离通道用1M氢氧化钠处理,随后用水冲洗。分离通道在125℃下干燥24小时,同时充以表压约为50kPa的氦。25%(w/w)的氯二甲基八癸基硅烷(ODS,Aldrich)在甲苯中加载到分离通道,同时氦保持约90kPa的过压。ODS甲苯混合物在125℃整个18小时反应期间连续泵入通道段中。用甲苯冲洗通道,随后是用乙腈,以去掉未反应的ODS。实验室系统10D被用来对由香豆素440(c440)、香豆素450(c450)和香豆素460(c460,Exciton Chemical Co.,Inc.)组成的被分析物进行电色谱法,对分离的直接荧光测量,在10μm进行,对空隙时间的间接荧光测量,在1μm进行。带25%(v/v)乙腈的四硼酸钠缓冲剂(10mM,pH9.2)为缓冲剂。
被分析物注入器10D在收缩的被分析物加载方式下工作,分离(运行)方式如上面对图6中所述。被分析物加载到注入截面,经由前色谱从被分析物容器16D移动到被分析物废弃物容器18D,一旦最慢的被分析物前端通过注入交叉点40D,试样即准备好被分析。为转换到分离方式,所加的电势重新调整,例如用手动开关。当转换所加的电势时,分离的主流通路是从缓冲容器12D到废弃物容器20D。为注入小的被分析物堵塞物到分离通道34D和为防止过量的被分析物流入分离通道,被分析物和被分析物废弃物容器16D、18D保持在加到缓冲剂容器12D的电压的57%。这一加载和注入试样的方法是不依赖于时间、无偏差和可再现的。
图19中,香豆素的色谱表示为线速度0.65mm/s。对c440来说,11700块板被观察到,这相当于120块板/秒。最滞迟的成份,即c460,其效率几乎比c440小一个数量级,为1290块板。色谱图中波动背影是由于来自玻璃基片的背影荧光,表明激光的功率不稳定,但是,这不妨碍分离或检测的质量。这些结果与传统的实验室高性能LC(HPLC)技术相比,就板数而言,是相当好的,并在速度上,超过HPLC十个数量级。停滞快于理论预测,随之效率下降。这种效应可能是由单层的静止或动态效应所造成的,而动态效应则是由高分离速度所引起的。微胞电动力毛细管色谱法
在上面对图19讨论的电色谱法实验中,试样成份由其与涂在通道壁上的固定相部分相互作用而分离。分离中性被分析物的另一方法是微胞电动力毛细管色谱法(MECC)。MECC是一种电泳工作方式,其中表面活性剂例如十二烷硫酸钠(SDS)加到缓冲剂中,其浓度足以形成缓冲剂中的微胞。在一典型的安排中,微胞向阴极移动比周围的缓冲剂溶液要慢得多。微胞和周围缓冲剂溶液之间的溶质部分提供了类似于液体色谱中的分离机制。
图12的微基片实验室10D,用于在由中性染料香豆素440(C440)、香豆素450(C450)和香豆素460(C460 Exciton Chemical Co.,Inc)组成的被分析物上进行。各染料的个别储备溶液在甲醛中准备,然后在使用前稀释到分析缓冲剂中。各染料的浓度大约为50μm,除非另行指出。MECC缓冲剂由10mM硼酸钠(pH9.1)、50mMSDS和10%(V/V)甲醛组成。甲醛有助于加溶水成缓冲剂系统中的香豆素染料,也影响某些染料进入微胞。用香豆素染料时必须十分小心,因为这些染料的化学、物理和毒物学性质尚未彻底研究过。
微芯片实验室系统10D工作在前述“收缩注入”方式。施加到容器上的电压设定为加载方式或“运行”(分离)方式。在加载方式,被分析物容器16D中溶液的前色谱由电动力泵出,经交叉处进入被分析物废弃物容器18D。施加到缓冲剂和废弃物容器上的电压也使两侧的少许流动进入交叉处,然后进入被分析物废弃物容器18D。芯片停留在这一方式直至被分析物的最慢的移动成份经过多叉处40D。此时,交叉处的被分析物堵塞物代表被分析物溶液,无电动力偏差。
通过把芯片转换到“运行”方式,改变施加到容器上的电压,这样缓冲剂从缓冲剂容器12D经交叉处40D流入分离通道34D,再流向废弃物容器20D。处于交叉处40D的被分析物的堵塞物被送入分离通道34D。按比例较小的电压被施加到被分析物和被分析物废弃物容器16D、18D上,以使缓冲剂中的微弱流从缓冲剂容器12D进入这些通道。这些流动确保试样堵塞物干净地从被分析物流中“清除”出去,没有过量的被分析物在分析时漏到分离通道中。
C440、C450和C460的混合物的MECC分析结果如图20所示。对每一染料的个别分析算出了峰值。第一峰值C440的迁移时间稳定性,随着甲醛浓度变化,是一个明显的指示标志,它表明这一染料很大程度上并不分为微胞。所以,它被认为是微胞迁移时间to的标志。最后峰值C460被认为是微胞迁移时间tm的标志。用图27中这些数据的to和tm值,算出的洗脱范围to/tm=0.4。对类似的缓冲剂系统来说,这十分符合to/tm=0.4的文献值,并支持了我们的假设。这些结果与在毛细管中进行的传统MECC相比相当好,也表现出上述电色谱实验的某些优点,即效率保持为停留比率。这一分离中性粒子的方法的进一步优点是无需修改壁表面,以及在实验中连续刷新固定相。无机离子分析
图6的实验室系统10B或图12的实验室系统10D,可进行的另一实验室分析是无机离子分析。用图6的实验室系统10B,对与8-羟基喹啉-5-磺酸(HQS)化合的金属离子进行无机离子分析,由电泳分离和用UV激光诱发的荧光检测。HQS已被广泛用作配位体,用于金属离子的光确定。水成介质中HQS的光学性质和溶解性最近已被用于检测由离子色谱和毛细管电泳分离的金属离子。因为未络合的HQS不发荧光,过量的配位体加到缓冲剂中,以保持在分离时的络合平衡,不引起大的背景信号等。这对分离效率和试样检测能力都有利。用于实验的化合物为硫化锌、硝酸镉和硝酸铝。缓冲剂为磷酸钠(60mM,pH6.9),带8-羟基喹啉-5-磺酸(除图5外所有实验中为20mM,Sigma化学公司)。至少50mM磷酸钠缓钠缓冲剂需要用来溶解到20mMHQS。所用的基片49B为熔融石英,其比玻璃基片更透明。
浮动或收缩的被分析物加载,对照图6,如前所述,用于把被分析物输送到注入叉处40B。对浮动试样的加载,注入的堵塞物没有电泳偏差,但试样容积是试样加载时间的函数。因为试样加载时间是与所用的电场强度成反比,所以对高注入电场强度来说,所用的注入时间比低注入电场强度要短。例如,对注入电场强度为630V/cm(图3a)来说,注入时间为12s,而对注入电场强度520V/cm(图3b)来说,注入时间为14.5s。收缩和浮动试样加载都可采用,可以有和没有电渗流动抑制。
图21(a)和21(b)表示三种金属离子与8-羟基喹啉-5-磺酸络合的三种金属离子的分离。所有三种络合物都带净的负电荷。电渗流动由于聚丙烯酰胺被共价键合到通道壁上而下降到最低程度,对地的负电荷在试样加载和分离期间被用来处理络合物。在图21(a)和21(b)中,分离通道电场强度分别为870和720V/cm,分离长度为16.5mm。注入堵塞物的容积为120pL,其分别对应于图4a中的相对Zn、Cd和Al注入而言的16、7和19fmol。在图4b中,0.48、0.23和0.59fmol的Zn、Cd和Al分别注入到分离柱。注入数量的平均再现性为1.6%rsd(百分相对标准偏差),按峰值面积测量(6个重复的分析)。用于激发络合物的激光稳定性约为1%rsd。检测极限在一能执行有用的分析的范围内。后分离通道反应器
图22表示一种微芯片实验室系统10E。五个端口图形的通道置于基片49E上,具有一滑盖49E,如前述实施例中。微芯片实验室系统10E的实施例用标准光刻、湿法化学蚀刻和粘结工艺制作。光掩膜的制作是溅射铬(50nm)在玻璃滑片上,并用CAD/CAM激光烧蚀系统(Resonetics,Inc.)烧蚀到铬薄膜内。然后采用正抗光蚀剂把通道图案转移到基片上。在稀释的Hf/Nh4f浴中,在基片上蚀刻出通道。为形成分离通道34E,用直接粘结技术把盖板粘结到蚀刻后的通道的基片上。表面在稀释的NH4OH/H2O2溶液中水解,在除去离子的、过滤过的H2中漂洗,接合并在500℃下退火。圆柱形玻璃容器附着到基片上,用RTV硅氧烷(GE制造)来实现。铂电极提供从电压控制器46E(Spellman CZE1000R)到容器中溶液的电接触。
通道26E是一从第一容器12E到交叉处40E的长度为2.7mm的实施例,同时通道30E为7.0mm,第三通道32E为6.7mm。分离通道34E改为长度仅7.0mm,因为加上了试剂容器22E,其有一试剂通道36E,在混合三通44E处连接到分离通道34E。这样,分离通道34E的长度从交叉处40E测量到混合三通44E。从混合三通44E延伸到废弃容器20E的通道是反应柱或通道,在图示实施例中该通道长度为10.8mm。试剂通道36E的长度为11.6mm。
在一代表性的实施例中,图22的实施例用于分离被分析物,通过荧光监视微芯片上的分离,用氩离子激光(351.1nm、50mW、Coherent Innova 90)进行激励。荧光信号用一光电倍增管(PMT,Oriel 77340)收集,以对点检测,一电荷耦合器件(CCD,Princeton Intruments,Inc.TE/CCD-512TKM)用于对微芯片90的区域成象。用于测试装置的成份是若丹明B(Exciton Chemical Co.,Inc.)精氨酸、甘氨酸、苏氨酸和邻苯二甲二醛(Sigma Chemical Co.)。四硼酸钠缓冲剂(20mM,pH9.2)与2%(v/v)甲醛和0.5%(v/v)β-巯基乙醇在所有试验中为缓冲剂。氨基酸、OPA和若丹明B溶液的浓度分别为2mM、3.7mM和50μm。几种运行条件被采用。
图23的示意图表示当1kV施加到整个系统时的一个例子。按此电压安排,分离通道34E(Esep)和反应通道36E(Erea)分别为200和425V/cm。这使得在混合三通44E处1份分离流出物与1.125份试剂混合。象这样的带或不带后柱反应的被分析物引入系统允许对多个分析有快速的循环时间。
图24中(A)和(B)的电泳图表示两对氨基酸的分离。电压配置与图23相同,除了所加的总电压为4kV,其对应于分离柱中800V/cm的电场强度Esep和反应柱中电场强度1700V/cm(Erea)。对相应于估计注入堵塞物长度为384、245和225μm的精氨酸、甘氨酸和苏氨酸的注入时间为100ms。对应于200、130和120fmol注入的精氨酸、甘氨酸和苏氨酸注入容积分别为102、65和60pL。检测点在混合三通处下游6.5mm,其对分离和反应给出13.5mm的总柱长度。
氨基酸与OPA的反应速率适当快,但对这些实验的时标来说并不足够快。观察到了流带变形的增加,因为衍生化合物的迁移率与纯氨基酸不同。直至反应完成,未反应和反应的氨基酸的区域将以不同的速度移动,引起被分析物区的变宽。如图24所表明,甘氨酸在衍生和未衍生氨基酸之间的电泳迁移率中有最大的不连续。为保证过量的流带变宽不是保留时间的函数,也测试了苏氨酸。苏氨酸的保留时间比甘氨酸略长,但变宽不如甘氨酸那样宽。
为测试在分离柱和反应柱的微芯片效率,荧光激光染料若丹明B被用作探针。从半高度的峰宽算出的效率测量,用点检测法进行,在离注入截面距离6mm和8mm处进行,或离混合三通上游1mm和下游1mm。这提供了两股流动混合的影响信息。
试剂柱和分离柱中的电场强度大约相同,反应柱中的电场强度为分离柱的两倍。这一电压配置允许衍生试剂与分离柱溢出的约1∶1容积比。随着电场强度增加,混合三通的湍流程度增加。在6mm的分离距离(混合三通下游1mm),板高度与被分析物的线速度成反比。在8mm的分离距离(离混合三通1mm上游),板高度数据从140V/cm降到240V/cm,再降到1400V/cm)。这一表现是异常的,表示当两个相等容积集中在一处时的流带变宽现象。混合三通的形状并未被优化,使这一流带变形为最小。在上述分离电场强度为840V/cm下,系统变得稳定,板高度再次随着线速度的增加而下降。对Esep=1400V/cm,板高度8mm和分离长度6mm的比率为1.22,其对分离效率来说,并不是不能接受的效率损失。
通过不断地把甘氨酸泵入分离通道与OPA在混合三通中混合来测试OPA与氨基酸反应产生的荧光信号强度。随着产物从混合三通往下流移动,OPA/氨基酸反应的荧光信号用CCD收集。再一次,OPA和甘氨酸流的相对容积比仍为1.125。OPA典型的与氨基酸半反应时间为4s。当反应柱中的电场强度Erea为240、480、960和1920V/cm时,被分析物分子在观察窗口中的平均停留时间分别为4.68、2.34、1.17和0.58s。荧光的相对强度在数量上对应于这一4秒的半反应时间。随着电场强度在反应通道中增强,荧光强度的斜度和最大值进一步向下游偏移,因为甘氨酸和OPA在高电场强度下从混合三通离开得更快。理想情况下,从产物中观察到的荧光有一阶梯响应函数,按照分离通道溢出和衍生试剂的混合。但是,反应的动力学和扩散占主流的混合的有限速率阻止了其出现。
使用后分离通道反应器进行的分离,采用闸门注入方式,以保持被分析物、缓冲剂和试剂流隔离,如对照图3所述。对后分离通道反应,微芯片在连续的被分析物加载/分离模式下工作,由此被分析物连续地从被分析物容器12E经注入交叉处40E向被分析物废弃物容器18E泵出。缓冲剂连续地从缓冲剂容器16E向被分析物废弃物和废弃物容器18E、20E泵出,以使被分析物流偏折及防止被分析物迁移到分离通道。为注入小量等分的被分析物,缓冲剂和被分析物废弃物容器16E、18E简单地浮动一小段时间(≈100ms),以允许被分析物迁移到分离通道,作为被分析物注入堵塞物。为断开注入堵塞物,重新加上缓冲剂和被分析物废弃容器16E、18E的电势。
使用微切削加工的后柱反应器,能改进后分离通道反应,可作为一种被分析物工具,使额外通道体积为最小,尤其是分离和试剂通道34E、36E。这一微芯片设计(图22)做成使分离通道34E(7mm)和试剂通道36E(10.8mm)有适当限制的长度,其比本例更有效。更长的分离通道可以做在类似尺寸的微芯片上,采用蛇形通道,以进行更困难的分离,如前对图12所讨论那样。为降低后混合三通流带变形,分离通道34E和反应通道56之间的通道尺寸可被减小,这样分离通道34E的电场强度就大,即窄通道,以及反应通道56中的电场强度就小,即宽通道。
对毛细管分离系统,小的检测量能限制可用于得到信息的检测方法数量。荧光检测仍然是用于毛细管电泳的最灵敏的检测技术之一。当把荧光检测结合到一没有中性荧光被分析物的系统中时,被分析物的衍生一定会出现在分离前后,当荧光“标签”持续较短或分离被预分离衍生隐藏时,后柱添加衍生试剂成为可选择的方法。一类后分离反应器已被表现为毛细管电泳。但是,用极少的容积连接物来构成后分离反应器,以使流带变形最小,一直是困难的。本发明采取制作一微芯片器件的方法来进行电泳分离,在单一器件上具有集成的后分离反应通道56,这使得在各个通道功能之间可有极低的容积交换。预分离通道反应系统
与图22所示后分离通道反应器设计不同,图25所示微芯片实验室系统包括一预分离通道反应器。图25所示预分离通道反应器设计类似于图1中的,只是第一和第二通道26F、28F与反应室42F形成一“球门柱”设计,而不是图1的“Y”设计。反应室42F设计成宽于分离通道34F,以使反应室中电场强度较低,这样试剂停留时间较长。反应室的半深度为96μm宽,以及6.2μm深。分离通道34F在半深度处为31μm宽,以及6.2μm深。
微芯片实验室系统10F被用于进行在线预分离通道反应,并与反应产物的电泳分析相结合。这里,反应器连续工作,少量的等分试样用对图3讨论的闸门分配器周期性地引入到分离通道34F。微芯片的工作由三个部分组成:氨基酸与OPA的衍生,将试样注入分离段,以及反应器流出成份的分离/检测。实验所用成份为粒氨酸(0.48mM)、甘氨酸(0.58mM),以及OPA(5.1mM,Sigma Chemical Co.)。在所有容器中的缓冲剂为20mM四硼酸,带2%(v/v)甲醛和0.5%(v/v)2-巯羟基乙醇。2-巯集乙醇加到缓冲剂中,作为对衍生反应的还原剂。
为进行反应,容器12F、14F、16F、18F和20F同时分别加上0.5HV、0.5HV、HV、0.25HV和接地的控制电压。这一配置允许在反应室42F有最低的电势降(当1.0kV加到微芯片时为25V/cm),在分离通道34F有最大的电势降(当1.0kV加到微芯片时为300V/cm),而在采用闸门注入方式时无明显的产物溢出到分离通道中。用于建立加到每一容器的电势的电压分配器的总电阻为100MΩ,具有10MΩ分量。来自第一容器12F的被分析物和来自第二容器14F的试剂被通过电渗泵入反应室42F,容积比为1∶1.06。所以,来自被分析物和试剂容器12F、14F的溶液被按约为2的因子稀释。缓冲剂同时通过电渗由缓冲剂容器16F朝被分析物废弃物和废弃物容器18F、20F泵出。这一缓冲剂阻止新形成的产物流入分离通道34F。
最好是,一种如图所述的闸门注入方法用来把溶液从反应室42F注入到分离通道34F。缓冲剂容器16F的电势简短地浮动一段时间(0.1至1.0s),试样迁移到分离通道34F中。为断开注入堵塞物,重新施加缓冲剂容器16F的电势。注入堵塞物的长度是注入时间和电场强度两者的函数。按照这施加的电势安排,氨基酸与OPA的反应连续地产生有待分析的新鲜产物。
许多毛细管电泳实验的明显缺点是注入的再现性差。这里,因为微芯片注入过程是由计算机控制,且注入过程包括打开一高压开关,所以注入可精确地定时控制。图26表示精氨酸和甘氨酸在注入电场强度为0.6和1.2kV/cm和注入时间从0.1至1.0s时注入数量(峰值积分面积的百分相对标准偏差,%rsd)的再现性。对于注入时间大于03s,百分相对标准偏差小于1.8%。这与商用自动化毛细管电泳仪器的报告值是可比的。但是,微芯片上的注入容积约小100倍,即在微芯片上为100pL,而在商用仪器上为10nL。这部分波动是由于激光的稳定性,其约为0.6%,对于注入时间大于0.3s,误差似乎与注入的化合物和注入电场强度无关。
图27表示精氨酸和甘氨酸在与OPA微芯片上前柱偏差后三个电泳分离的重叠,分离电场强度为1.8kV/cm和分离长度为10mm。分离场强为分离期间分离通道34F中的电场强度。反应室42F中的电场强度为150V/cm。被分析物的反应时间与其迁移率相关,即对精氨酸反应时间为4.1s,对甘氨酸反应时间为8.9s。精氨酸和甘氨酸的注入堵塞物的容积分别为150和71pL,其对应于注入到分离通道34F上的35和20fmol氨基酸。闸门注入允许进行快速按序注入。在这特定情况下,可每4s进行一次分析。观察到的化合物电泳迁移率是由线性符合随分离电场强度变化的线速度变化来确定的。精氨酸和甘氨酸的斜率分别为29.1和13.3mm2/(kV-as)。由速度的线性对电场强度数据表明,未观察到焦耳加热现象。在分离电场强度从0.2到2.0kV/cm中,线性符合产物相关系数对精氨酸为0.999,对甘氨酸为0.996。
随着更大的电势施加到微芯片实验室系统10F,反应室42F和分离通道34F中的电场强度增大。这导致反应室中反应物更短的停留时间和更快的产物分析时间。通过改变施加到微芯片上的电势,可研究反应动力。图28画出了随反应时间产生的产物数量的变化。该结果是对检测器观察窗中停留时间的蜂值积分面积的校正以及对产物的光漂白作用的校正。图28中精氨酸和甘氨酸的数据偏差主要是由于注入量的不同,即对于氨基酸的不同电泳迁移率。十倍的过量OPA用于得到假一级反应条件。符合数据的曲线斜率对应于衍生反应的速率。精氨酸的斜率为0.13s-1,对甘氨酸为0.11s-1,分别对应于5.1和6.2s的半反应时间。这些半反应时间可与丙氨酸以前报道的4s相比。我们未发现以前对精氨酸或甘氨酸的报道数据。
这些结果表明进行化学过程的集成微制作系统的电势功率。图28中出现的数据可在计算机控制下在五个约5分钟的时间内产生,假定其数量级为100nL的试剂。这些结果在化学反应的自动化、速度和容积方面是无先例的。DNA分析
为表现一有用的生物分析过程,限制溶解和电泳分类实验在图29所示集成生物化学反应器/电泳微芯片系统10G上进行。微芯片实验室系统10G与图25的实验室系统相同,只是实验室系统10G的分离通道34G在蛇形管通道之后。质粒pBR322的序列和酶HinfI的识别序列是已知的。在溶解后,用分离通道34G中筛选媒介中的电泳分离溶解产物来进行片段分布的确定。对这些实验,用羟乙基纤维素作为筛选媒介。在分离通道34G下游一固定点,用带嵌入染料噻唑橘色二聚物(TOTO-1)作为荧光团的芯片上激光感应荧光来探查迁移的片段。
图29所示反应室42G和分离通道34G分别为1和67mm长,半深度处宽度为60μm,深度为12μm。此外,通道壁涂以聚丙烯酰胺,使电渗流动和吸收最小。用单点检测激光感应荧光检测产生电泳。氩离子激光(10mW)用一透镜(100mm焦距)聚焦在芯片上一点,用一21倍物镜(N.A.=0.42)收集荧光信号,随后是空间过滤(0.6mm直经针孔)和光谱过滤(560nm带通,40nm带宽),并用一光电倍增管(PMT)测量。数据采集和电压转换装置用计算机控制。反应缓冲剂为10mM三乙酸盐,10mM乙酸镁和50mM乙酸钾。反应缓冲剂置于图29所示的DNA、酶和废弃物1容器12G、14G、18G中。分离缓冲剂为9mM三硼酸盐,带0.2mMEDTA和1%(w/v)羟乙基纤维素。分离缓冲剂置于缓冲剂和废弃物2容器16F、20F中。质粒pBR322和酶HinfI的浓度分别为125ng/μl和4单位/μl。溶解和分离在室温(20℃)下进行。
通过施加适当的电势,DNA和酶通过电泳从其相应的容器12G、14G加载到反应室42G。在DNA(12G)、酶(14G)、缓冲剂(16G)、废弃物1(18G)和废弃物2(20G)容器的相对电势分别为10%、10%、0、30%和100%。由于DNA与酶之间的电泳迁移率差别,需要足够长的加载期间,以得到平衡。而且,由于反应室42G的体积小,为0.7nL,则出现迅速的扩散混合。电渗流动由于线性聚丙烯酰胺的共价定位而为极小。这样,仅有阴离子随着所加的电势分布从DNA和酶容器12G、14G迁移到反应室42G。带有一定阳离子的酶溶解所需的反应缓冲剂,即Mg2,也置于废弃物1容器18G中。这使得阳离子可在反应室加载期间扩散到与DNA和酶逆流的反应室。因DNA经过反应室的时间较短,通过在加载反应室42G后除去所有电势来静态地进行溶解。
在溶解期结束之后,通过浮动接缓冲剂和废弃物1容器16F、18F的电压,产物迁移到分离通道34F,以作分析。注入有一迁移率偏差,此时较小的片段被注入,有利于较大的片段。在这些实验中,75基对(bp)片段的注入堵塞物长度被估计为0.34mm,而对1632-bp的片段仅为0.22mm。这些堵塞物长度分别相当于反应室容积的34%和22%。反应室42F的全部含量不能在当前分离条件下分析,因为注入堵塞物长度对板高度的作用会被湮没。
在溶解和注入到分离通道34F后,用1.0%(w/v)的羟乙基纤维素作为筛选介质,溶解片段。图30表示质粒pBR322在为时2分钟被酶HinfI溶解后,限制片段的电泳图。为使双股DNA在溶解后的探询前能有效地在途中着色,插入染料TOTO-1(1μm)只投于废弃物2容器20G中,并逆流迁移到DNA。如预期的那样,流带相对强度随片段大小增加,因为更多的插入点是在较大的片段中。未溶解的220/221和507/511-bp片段因流带重叠而有比相邻的单片段更大的强度。五个复制分析的迁移时间的再现性和注入容积分别为0.55和3.1%相对标准偏差(%rsd)。
进行质粒DNA限制片段分析的微芯片实验室系统10G的展示表明了自动的和小型的更高级生物化学过程的可能性。这一实验代表了当今展示的最先进的集成微芯片化学分析装置。该装置使试剂与被分析物结合,培育被分析物/试剂混合物、标示产物,以及在计算机控制下完整地分析产物,同时此典型的小型实验室过程少消耗10,000倍的材料。
总的来说,本发明可被用于混合不同端口或容器中的不同流体。这可用于流体色谱分离实验,随之进行后柱标示反应,其中给定容积的不同的化学溶液被泵入主要分离通道,其它试剂或溶液可在不同时刻注入或泵入到液流中,以精确和已知的浓度混合。为执行这一过程,有必要精确地控制和利用各个通道中的溶液。前/后分离反应器系统
图31表示与图1所示相同的六端口微芯片实验室系统10,其利用了这一新的混合方法的优点,不同端口的具体特点反映了溶剂容器。这一实验室系统可用于液体色谱分离实验,随之进行后柱标示反应。在这种实验中,容器12和14会含有用于液体色谱溶剂编程型分离的溶剂,即水和乙腈。
通道34连接到废弃物容器20和连接被分析物和溶剂容器12和14的两个通道26和28,其为主要分离通道,即进行液体色谱实验的通道。交叉通道30、32连接缓冲剂和被分析物废弃物容器16和18,被用于进行如上所述注入到液体色谱或分离通道34。最后,容器22及其连接到分离通道34的通道36被用于加入试剂,其按比例加入,以使分离通道中分离的粒子可被检测。
为执行这一过程,有必要精确地控制和利用各个通道中的溶液。上述实验从容器12和40中取得极小容积的溶液(≈100),并精确地注入到分离通道34中。对这些不同方案,给定容积的溶液需要从一个通道转移到另一个通道。例如,液体色谱的溶剂编程或后柱标示反应的试剂添加,均要求溶液流以精确和已知的浓度混合。
各种溶液按已知比例的混合可按本发明进行,其方法是控制最终控制如式1指出的电渗流动的电势。按照式1,需要知道电场强度,以确定溶剂的直线速度。通常,在这些类型的流体利用中,已知的电势或电压施加到给定的容器上,电场强度可以所施加的电压和通道的特性来计算。此外,通道中流体的电阻或电导也必须知道。
通道的电阻由式2给出,式中R是电阻,k是电阻率,L是通道长度,A是横截面积。流体通常由电导来表征,其为式3所示电阻的倒数。式3中,K是电导,p是导电 率,A是横截面积,L是如上长度。
用欧姆定律和式2、式3,可将给定通道中的电场强度写为该通道两端电压降除以其长度,其等于经过通道i的电流Ii乘以该通道的电阻率由式4的横截面积所除。
这样,若通道由尺寸大小和电学方式来表征,则通道上的电压降或经过通道的电流可用于确定通过该通道的速度或流通率,如式5所示。还注意到流体流动依赖于表面的ζ电势,因此也依赖于流体和表面的化学组成。
Vi∝Ii∝流动 (5)
显然,导电率K或电阻率p,将取决于溶液的特性,在各个通道中是不同的。其在各个通道中是不同的。在许多CE应用中,缓冲剂的特性会对流体的电学特性起主要作用,这样电抗是不变的。在液相色谱情形下,进行溶剂编程,若不使用缓冲剂,则两个流动相的电学特性会相当不同。在溶剂编程运行期间,混合物的摩尔百分数发生变化,混合物的导电率会以非线性方式变化,但会单调地从一种纯溶剂的导电率变化到另一种导电率。随摩尔百分数的电抗实际变化,除了各个离子的导电率外,还取决于溶剂的离解常数。
如上所述,图31中所示装置可用于进行逐级洗出液相色谱,带有后柱标示,以便于检测。图31(a)、31(b)和31(c)表示为进行包含上述液相色谱实验任务的流体流动要求。图中箭头表示通道中流动的方向和相关大小。在图31(a)中,从被分析物容器16来的被分析物加载到分离交叉处40。为执行收缩注入,有必要将来自被分析物容器16的试样经过交叉处输送到被分析物废弃物容器18。此外,为限制被分析物容积,从分离通道34和溶剂容器12、14来的材料必须流向交叉处40。从第一容器12来的流动比第二容器14来的大得多,因为这些是用于逐级给出实验的初始条件。在逐级洗出实验开始时,希望防止试剂容器22中的试剂进入分离通道34。为避免这种试剂流动,要求有少量的缓冲剂从废弃物容器20直接流向试剂通道36,这一流动应尽可能接近零。在一代表性的被分析物出现在注入交叉处40后,可进行分离。
图31(b)中,表示运行(分离)方式,溶剂从容器12和14经交叉处40流到分离通道34。此外,溶剂流向容器4和5,以进行被分析物进入分离通道34的洁净注入。从试剂容器22来的适当的试剂流动也引向分离通道。如图31(b)所示的初始条件为有着大摩尔百分数的溶剂1和小摩尔百分数的溶剂2。施加到溶剂容器12、14的电压是作为时间的函数而变化的,这样溶剂1和2的比例从溶剂1占主要部分变化到多数为溶剂2,如图31(c)所示。后者在所加电压的单调变化影响着逐级洗出液体的色谱实验。当隔离成份通过试剂加入通道36时,在这种试剂与隔离的材料之间可发生合适的反应,以形成可检测的质粒。
图32表示在假想的逐级洗出实验中施加到各种容器上的电压如何变化。图中示出的电压仅表示相对大小,而不是绝对电压。在加载方式的工作中,静电压加到各个容器上中。除试剂容器22外,所有容器的溶剂流向被分析物废弃物容器18。这样,被分析物容器18为最低电势,所有其它容器为较高电势。在试剂容器处的电势应比废弃物容器10足够低,以提供向试剂容器的微小流动。在第二溶剂容器14处的电压足够大,以提供朝着注入交叉处40的净流动,但流动应为小幅度的。
在变化到图31(b)所示运行(开始)方式时,电势重新调节到如图32所示。现在的流动是溶剂从溶剂容器12和14到分离通道34,流向废弃物容器20。还有一小股溶剂从注入交叉处40流向被分析物和被分析物废弃物容器16和18,以及一股合适的试剂从试剂容器22流入分离通道34。废弃物容器20现在需要处于最低电势,第一溶剂容器12处于最大电势。所有其他电势调节到提供如图31(b)所示流体流向和大小。而且,如图32所示,施加到溶剂容器12和14的电压单调地变化,从溶剂1的大摩尔百分数变化到溶剂2的小摩尔百分数。
在溶剂编程运行结束时,该装置随时准备转回到注入条件,以加载另一试样。如图32所示,电压变化仅为示意,用以表示为实现图31(a)-(c)所示的各种流体流动,须采取什么措施。在实际的实验中,不同电压的相对幅度会有很大不同。
尽管已选用了较好的实施例来说明本发明,应理解技术人员可作出各种变化和修改,而不离开权利要求书中所限定的范围。
Claims (25)
1.一种用于分析和合成化学材料的微芯片实验室系统,包括:
一主体,具有连接多个容器的集成通道,其中至少五个容器同时有与其有关的受控电势,这样从至少一个容器来的材料经通道输送到至少一个其它容器,以暴露于一种或多种选定的化学或物理环境中,由此分析或合成化学材料。
2.如权利要求1的系统,其特征在于,被输送的材料为流体。
3.如权利要求1的系统,进一步包括,
连接至少三个容器的第一通道交叉处,以及
用于将来自两个容器的材料在第一交叉处混合的混合装置
4.如权利要求3的系统,其特征在于,混合装置包括用于产生在第一交叉处的电势的装置,该电势小于待混合的材料来源的两个容器中每个容器的电势。
5.如权利要求1的系统,进一步包括:
连接第一、第二、第三和第四容器的第一交叉处,以及
通过从第三容器经第一交叉处输送第二种材料来控制从第一容器经第一交叉处输送到第二容器的第一种材料的容积的控制装置。
6.如权利要求5的系统,其特征在于,控制装置包括用于将第二种材料经第一交叉处向第二和第四容器输送的装置。
7.如权利要求5的系统,其特征在于,控制装置包括分配装置,用于将第二种材料经第一交叉处输送,其方式是在选定容积的第一种材料经过第一交叉处朝第二容器去之后,防止第一种材料经第一交叉处移向第二容器。
8.如权利要求5的系统,其特征在于,控制装置包括稀释装置,用于以将第一种和第二种材料同时从第一交叉处输送到第二容器的方式,在第一交叉处混合第一和第二种材料。
9.如权利要求1的系统,其特征在于,集成通道包括一连接第一和第二容器的第一通道,连接第三和第四容器的第二通道,其形成与第一通道的第一交叉处,以及一第三通道,其在第一交叉处和第四容器之间的位置连接第五容器与第二通道。
10.如权利要求9的系统,进一步包括:
混合装置,用于将来自第五容器的材料与从第一交叉处向第四容器输送的材料混合。
11.如权利要求9的系统,其特征在于,第三通道衡跨第二通道形成一第二交叉处,该系统进一步包括:
12.如权利要求11的系统,进一步包括:
输送装置,将第五和第六容器的材料同时送入第二交叉处。
13.如权利要求12的系统,其特征在于,输送装置将第五和第六容器的材料在选定容积的材料从第一交叉处经第二交叉处送往第四容器后经第二交叉处送往第一交叉处和第四交叉处。
14.一种微芯片流控制系统,包括:
一主体,具有连接至少四个容器的集成通道,通道形成一第一交叉处,其中,至少三个容器同时有与其有关的受控电势,这样从第一容器经第一交叉处送到第二容器的材料容积,仅由从第三容器经第一交叉处向另一容器的材料移动有选择地控制。
15.如权利要求14的系统,其特征在于,被输送的材料为流体。
16.如权利要求14的系统,进一步包括:
控制装置,将第二种材料从第三容器经第一交叉处朝第二容器输送。
17.如权利要求16的系统,其特征在于,控制装置包括分配装置,用于经第一交叉处输送第二种材料,其方式可在选定容积的第一种材料通过第一交叉处朝第二容器去后,防止第一种材料经第一交叉处移向第二容器。
18.如权利要求16的系统,其特征在于,控制装置包括稀释装置,用于在第一交叉处混合第一和第二种材料,其方式是将第一和第二种材料同时从第一交叉处朝第二容器输送。
19.如权利要求14的系统,其特征在于,集成通道包括连接第一和第二容器的第一通道,连接第三与第四容器的第二通道,其方式是与第一通道形成第一交叉处,以及一第三通道,其在第一交叉处与第四容器之间连接第五容器与第二通道。
20.如权利要求19的系统,进一步包括:
混合装置,用于将第五容器来的材料与从第一交叉处向第四容器输送的材料混合。
21.如权利要求19的系统,其特征在于,第三通道在第二交叉处横跨第二通道,该系统进一步包括:
第六容器,由第三通道连接到第二交叉处。
22.如权利要求21的系统,进一步包括:
用于将材料从第五和第六容器同时输送到第二交叉处的装置。
23.如权利要求21的系统,进一步包括:
在选定数量的材料从第一交叉处从第二交叉处向第四容器输送后将第五和第六容器经第二交叉处向第一交叉处和第四容器输送的装置。
24.一种微流控制系统,包括:
一主体,具有连接至少四个容器的集成通道,其中四个容器的第一和第二容器分别含有第一和第二种材料,一连接第一容器和第三容器的通道与连接第二和第四容器的通道形成交叉,以及
一电压控制器,
在第一容器和第三容器之间施加一电势差,其方式是从第一容器经交叉处向第三容器输送选定的、可变数量的第一种材料,以及
在选定时间期限后,对所有四个容器同时施加电势,其方式是从第二容器经交叉处向第三容器输送第二种材料,由此阻止第一种材料经交叉处向第三容器移动。
25.一种控制材料经至少有着四个容器的交叉通道系统的流动的方法,其中四个容器的第一容器含有第一种材料,交叉通道系统有连接容器的集成通道,这些通道形成一交叉处,该方法包括:
在四个容器的第一容器和第三容器之间施加一电位差,其方式是将选定的、可变容积的第一种材料从第一容器经交叉处向第三容器输送,以及,
在一选定时间期限后,对所有四个容器的每个容器同时施加一电势,其方式是阻止第一种材料经交叉处朝第三容器移动。
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US08/283,769 US6001229A (en) | 1994-08-01 | 1994-08-01 | Apparatus and method for performing microfluidic manipulations for chemical analysis |
US08/283,769 | 1994-08-01 |
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CN1168720A true CN1168720A (zh) | 1997-12-24 |
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2002
- 2002-10-01 US US10/262,533 patent/US20030150733A1/en not_active Abandoned
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2003
- 2003-04-30 US US10/426,366 patent/US20030205469A1/en not_active Abandoned
- 2003-04-30 US US10/426,818 patent/US20030226753A1/en not_active Abandoned
- 2003-04-30 US US10/426,370 patent/US20030226755A1/en not_active Abandoned
- 2003-04-30 US US10/426,371 patent/US20030205470A1/en not_active Abandoned
- 2003-05-09 US US10/435,185 patent/US20040137445A1/en not_active Abandoned
- 2003-05-09 US US10/434,874 patent/US20040007464A1/en not_active Abandoned
- 2003-05-09 US US10/434,918 patent/US20040009517A1/en not_active Abandoned
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