CN102448611A - 控制片上实验室系统中流体流的设备和方法及设备的制造方法 - Google Patents
控制片上实验室系统中流体流的设备和方法及设备的制造方法 Download PDFInfo
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Abstract
本发明涉及一种控制片上实验室系统中流体流的设备。它具有阀阵列,这些阀布设成n列Sn和m行Zm,以及分别设计用于控制相关流动通道(4)内的流体流。所述阵列包括至少两个阀,其中每一列Sn最多有一个阀,而每一行Zm有在0与n个之间的阀。设置一个用于操纵阀的操纵装置(13)。所述阀通过压力操纵。为了制造所述设备,流动通道(4)按照阀的布局设置。
Description
技术领域
本发明涉及一种控制片上实验室系统(Lab-on-a-Chip-Systeme)中流体流的设备,包括一个阀的阵列。阀排成n列Sn和m行Zm,其中n和m是整数。它们分别设计用于控制相关流动通道内的流体流。此外,所述设备具有一个用于阀的操纵装置。例如由EP0180064B1已知一种具有上述特征的设备。此外本发明还涉及一种控制这种片上实验室系统中流体流的方法以及设备的制造方法。
背景技术
在生物传感技术中使用片上实验室系统,以便能实施平行的生化分析。在例如由塑料卡片组成的基体上,集成微流体装置和包括传感器阵列的芯片。传感器阵列例如由电化学传感器组成,它们在芯片上排成行和列。这些传感器用分子镀层,要检测的物质特异性地与它们结合。这种特异性的结合,电化学地通过电流和/或电压的变化检测。由此可以在要化验的溶液例如血液或尿液内,检测生化物质,例如抗体、肽或DNA。
测得的电化学信号可以通过在芯片上的集成电路直接处理,或它们可以通过外部评估设备从芯片读出。为化验所需要的化学药物可以从外部评估设备供给基体,或它们例如以干试剂的形式已经处于基体上。在化验时,溶液,亦即液体,供给基体并在基体上经微通道导入反应室。有传感器阵列的芯片处于反应室内。为了检测所需要的反应,可以在微通道和/或反应室内进行。
在为了检测所需要的复杂生化反应时,必须控制溶液的液流。因此可能需要,在微通道的一个区域中,在预定的时间内堵塞住液体,由此存放在此区域内的例如干试剂被溶解和发生化学反应。只有在完成化学反应后,液体才在微通道内继续流动。此外还可能需要,在反应室内检测生化物质时液体密封地关闭反应室。为此目的,在基体中采用阀。它们设置在基体内某些选择的位置,例如在反应室的进口和出口中。
由EP0180064B1已知由阀组成的阀阵列,这些阀设计用于关闭微通道。微通道布置在第一基体中,该第一基体在微通道侧用薄膜覆盖。薄膜夹层式地设在第一基体与第二基体之间。在第二基体内设冲头状装置,它可借助弹簧通过微通道口上的薄膜压入第一基体内。在这种情况下微通道被薄膜封闭。所介绍的阀相应于流动通道的位置排列在基体上。它们逐个和彼此独立地控制。
对于复杂的分析过程,不得不需要多个化学过程彼此独立地同时在芯片卡上实施。为此一个阵列的多个阀必须由芯片卡上的阀同时操纵。在例如在EP0180064B1中介绍的按照现有技术的系统,彼此独立地逐个控制阀,这非常麻烦和导致高昂的成本。
发明内容
因此本发明要解决的技术问题是,提供一种包括阀的阵列的设备,其中阀可以通过简单而便宜的结构同时控制。此外本发明要解决的技术问题是提供一种方法,它无需复杂的电子器件和阀的单个电控装置,允许按一种固定的程序同时进行阀的控制。本发明还有要解决的技术问题是,提供一种阀阵列的制造方法,此方法缘于阀的布局。
所提出的有关用于控制片上实验室系统中流体流的设备方面的技术问题,通过权利要求1的特征得以解决,有关用于控制这种设备的方法的技术问题,通过权利要求8的特征得以解决,以及有关这种设备制造方法的技术问题,通过权利要求13的特征得以解决。
按本发明用于控制片上实验室系统中流体流的设备有利的扩展设计,设备控制方法和设备制造方法有利的扩展设计,可以由各自对应的从属权利要求得出。在这里,独立权利要求的特征可以与从属权利要求的特征组合,以及从属权利要求的特征可以互相组合。
按本发明用于控制片上实验室系统中流体流的设备具有阀的阵列,阀布设成n列Sn和m行Zm。在这里n和m是整数。所述阵列包括至少两个阀,其中每一列Sn没有阀或最多有一个阀,而每一行Zm有在0与n个之间的阀。这些阀分别设计用于控制相关流动通道内的流体流。此外,设备还具有阀的操纵装置。
在阵列中阀的这种特殊布局使控制能简单地实施。仅一个阀处于每一列中。但通过在行中任意多个阀,可以实现任何必要的阀布局,因为行数和列数可以自由选择。可以根据要控制的化学过程的要求,并因而根据在分析或检验时射流的要求以及过程的时间进程,尤其在不同地点同时发生的过程的时间进程的要求,设计阀的阵列。流动通道和反应室相应于阀阵列的设计来配置。阀按阵列形式的布局,使得有可能采取简单的措施,特别方便和能适应于许多过程或可再现地制造所述设备。
用于控制阀的装置可以有一块基本上平的板,它有从平面突起的隆凸,隆凸排成n′列Sn′和m′行Zm′。在这里相邻列Sn′的距离与阀的对应配设的相邻列Sn的距离相同。
用于控制阀的装置使得有可能按固定的程序同时机械地控制所有的阀。它的排成n′列Sn′和m′行Zm′的结构,使之与阀的阵列相协调。
通过基本上平的板可沿第一方向相对于阀阵列运动地安装,其中第一方向平行于阀阵列的列Sn延伸,可以通过运动基本上平的板来控制阀。在这里,从板的平面突起的隆凸可以按这样的方式布设成n′列Sn′和m′行Zm′,亦即当基本上平的板沿第一方向相对于阀的阵列运动时,按规定的程序控制各个阀的关闭或打开。
因为在阵列的每一列Sn中只设一个阀,所以在基本上平的板内的一个隆凸在此板沿该列运动时只控制这一个阀。根据隆凸的距离和数量,这一个阀可以打开和关闭。在一行中多个隆凸导致同时操纵布置在一行中的阀。因此阀和隆凸的这种布局决定了阀据此控制的程序。当阵列中的阀按规定布置时,程序可以通过隆凸的布局确定。
阀的阵列可以布置在芯片卡内,其中芯片卡可包括用塑料在信用卡模具内制成的扁平的基体,在基体的前侧上敷设薄膜,尤其胶粘薄膜。在基体内在前侧的表面上可以设置设计为凹槽的流动通道以及阀,阀含有弹性体物质,它至少部分与各自对应配设的流动通道相邻地布置。由此得到一种阀阵列的所要制造的特别简单和低成本的结构。芯片卡尤其在生物传感器技术中是常用的,并因而可以在标准设备中使用。这同样使成本降低,因为不必开发全新设计的分析设备。
在这里塑料基体可由聚碳酸酯或聚丙烯组成。弹性体物质可以是一种热塑性弹性体,尤其是橡胶或由聚丙烯和乙二醇-丙烯-聚二烯M级弹性体组成的混合物。这些材料加工方便和便宜。而且它们在遭遇大多数在生物传感器技术中使用的化学药品时是惰性的。此外这些材料与要分析的物质不反应或仅小量反应。采用这些材料一般不会发生使化验有误的物质或分子交叉(Faltung)改变或其他反应。
芯片卡可夹层式地装在阀的操纵装置内。在芯片卡后侧针对每个阀,在装置的板内分别安装一个操纵各阀的冲头,其中冲头通过至少一个在装置的板与冲头之间的弹簧预紧为,使冲头与阀之间基本上不存在压力。由此免除阀操纵装置中机械上比较复杂并因而成本较高的部分。因此在一次性使用后抛弃的装置中的芯片卡,可以使用便宜的材料和无需复杂的生产过程。
芯片卡在阀操纵装置中夹层式地设置,导致一种可靠的位置固定的支承,由此不会发生芯片卡相对装置滑动。因此随时保证冲头能可靠地操纵对应配设的阀。从而确保可靠的工作方式。
按本发明控制上述设备的方法包括,阀分别通过在各自的阀上用压力加载来操纵,压力尤其通过至少一个冲头施加。没有用压力加载时阀打开,以及流体流入对应配设的流动通道内,以及在对阀施加压力时阀关闭,以及阻断在对应配设流动通道内的流体流。
这种方法特别简单以及能有效地控制流体流。在这里重要的是,保证气体和/或液体密封地关闭阀。通过借助压力启动,可以实现阀和启动机构简单的结构。即使频繁打开和关闭,仍能得到一种没有材料疲劳的可靠的工作方式。
阀的打开和关闭可以按预定的程序,通过基本上平的板平行于列Sn地相对于阀阵列运动实现。
这里不需要电编程或复杂的调节和控制回路。在频繁实施始终相同的分析程序时,这导致简单、可靠以及低成本的结构和方法。阀的控制可以通过运动基本上平的板仅仅机械地完成。正是与涉及的液体和化验室环境相关联,这使得化验有更高的可靠性,因为与复杂的电子控制设备相比故障率低。
由阀控制装置的m′行Zm′与阀阵列的m行Zm之差可以得出过程步骤数,在过程步骤中操纵至少一个阀。
首先可以实施一种控制阀的过程,为此基本上平的板相对于阀阵列以固定的速度运动,在这里,一个过程步骤的持续时间,当所有行Zm彼此间距相同时,通过行Zm′彼此的间距确定,或一个过程步骤的持续时间,当所有行Zm′彼此间距相同时,通过行Zm彼此的间距确定。
以恒定的速度简单地和用比用加速的速度低的化费可靠地推动基本上平的板。用恒定的速度,驱动成本低而可靠。通过行的间距确定过程步骤的持续时间,导致检验有高的可重现性和可靠性。
但此外也可以实施一种控制阀的过程,为此基本上平的板相对于阀的阵列用一个速度运动,这一速度总是与一个过程步骤的持续时间相匹配,其中行Zm彼此和行Zm′彼此设置为间距相同。
行彼此的间距相同简化了设备的结构和制造。不过在加速运动的情况下为驱动基本上平的板所需的费用较高。
一种制造上述设备的方法包括,根据阵列的阀的布局,在设备中流动通道设置成n列Sn和m行Zm。这使得可以根据阀设计设备。然后基于要昂贵地生产的阀,布置或设计流动通道和反应室。因此阀的阵列可以用始终相同的阵列形式,简单而便宜地通过模具的重复使用生产,此时仅需确定,在阵列的什么位置安置或不安置阀。在这种情况下要便宜和简单地制造流动通道和反应室,取决于阀和要实施的反应和期望的射流。因此,可获得的设计和生产成本方面的优点类似于半导体电子设备。在那里构件根据电路的任务和生产技术布置在芯片上,以及布线按照构件的位置设计和实施。因此构件通过布线互相电连接,从而得到期望的电路。
与设备控制的方法和与设备制造的方法相关联的优点,与前面涉及控制片上实验室系统中流体流的设备已说明的优点相似。
附图说明
下面借助附图详细说明本发明优选的实施形式和按从属权利要求特征给出的优选的扩展设计,但不也并不局限于此。
附图中:
图1示意性地表示出阀的结构剖面图;以及
图2以俯视图以及沿剖切线A-A′的剖面图和沿剖切线B-B′的剖面图表示出按本发明的控制片上实验室系统中流体流的设备,包括阀的控制装置。
具体实施方式
为了更好理解流体流控制设备,在图1中举例表示一个阀。此阀由塑料基体1和弹性体物质2构成。基体1意味着是一个支座或基底,以及可以有芯片卡的形式,其中,在埋入的芯片上排列一个电化学传感器阵列,用于检测生化物质。为了简化起见,在这里不应详细阐述芯片卡的设计。也可以是没有芯片卡的实施形式,例如在光学分析装置中。
在基体1内设计第一凹槽4。第一凹槽4朝基体1前侧10方向开口。它具有通道的形状以及用作流动通道4′。液体或气体可以流过流动通道4′。与第一凹槽4直接相邻地,设计有与流动通道邻接的第二凹槽3。它与第一凹槽4在第一凹槽4的部分区9内有一个公共边界面。如图1所示,第二凹槽3设计为从前侧10直通基体1后侧11。它完全用弹性体物质2充填。
在基体1前侧10上,平面状施加胶粘薄膜5。胶粘薄膜5的胶粘层6保证薄膜5良好地粘附在基体1上以及弹性体物质2上。薄膜5通过其与基体1和弹性体物质2连接的胶粘层6,相对于外部环境空气密封或气体密封和/或液体密封地密封流动通道4′。
为了能在生化设备中使用按本发明的阀,与液体或气体接触的材料必须要适合于要化验的物质。在生化化验时使用的液体,例如是血液、尿液、水、酒精或其他溶剂。应例如通过生化设备分析或检测的物质,例如是蛋白质、DNA或抗体。通过所使用的材料不允许影响或改变它们。
可能使用于基体1的材料是硬聚合物,为了便于制造的原因它们应能采用压注技术加工。这种材料应是塑性的,亦即它应难以变形甚至不能变形。这些材料例如通过聚碳酸酯或聚丙烯提供。在预浇注模内,芯片卡基体1与其第一凹槽4和第二凹槽3一起,在一道工序中通过压注技术制造。在第二道工序中,在第二凹槽内通过压注技术加入弹性体物质2。作为可能用作弹性体物质2的材料,热塑性弹性体是特别适合的。例如一种特别良好地适用的热塑性弹性体,是一种由聚丙烯和乙二醇-丙烯-聚二烯M级弹性体组成的混合物,已知它的商标名为Santoprene。
有传感器阵列的芯片可以从后侧11置入基体1内,它可以通过读出装置7从后侧接触和读出。基体1的设置流动通道4′和反应室的前侧,可以借助胶粘薄膜完全无菌覆盖。由此得到气体和液体密封的流动通道4′。一种可能用于薄膜的材料是聚乙烯。但也可以使用其他薄膜材料。
图2用俯视图、沿剖切线A-A′和沿剖切线B-B′的剖面图,表示按本发明控制片上实验室系统中流体流的设备,包括阀的控制装置。基底或基体1与阀一起夹层式地固定在读出装置7内。读出装置7的一些部分压靠到基体1的前侧10和后侧11上。由此将基体1不能运动地装在读出装置7中。若基体1设计为具有电芯片的芯片卡形式,则读出装置7可以读出并处理传感器阵列的信号。为了控制在基体1第一凹槽4中的流动过程和化学反应,可以通过读出装置7来操纵阀。
如图2中B-B′剖面所示,在基底或基体1内设置两个阀,它们作为举例说明阀的工作方式。冲头8可将阀置于打开(右阀Ⅰ)状态或关闭(左阀Ⅱ)状态。第一凹槽4或流动通道4′可以通过操纵阀来液体密封和/或气体密封地关闭。装在读出装置7中并由它控制的冲头8,将压力从后侧11施加到弹性体物质2上。这通过冲头8朝弹性体物质2方向的运动实现。通过冲头8施加到弹性体物质2上的压力促使弹性体变形。因为弹性体只能朝第一凹槽4的方向延展,所以它被压入第一凹槽4中。这一过程一直进行到第一凹槽4沿第一凹槽4的横截面完全充填弹性体为止。这又促使阀关闭。
若相对于弹性体物质2移开冲头8,则作用到弹性体物质2上的压力减小直至接近零,因此弹性体恢复到其原始形状。弹性体从第一凹槽收回,并因而释放第一凹槽。阀重新打开。
为了同时操纵这些阀,将冲头8固定在读出装置固定板7a上。固定板7a处于塑料基体1的后侧11。冲头8通过没有表示的弹簧预紧在打开的阀上,使冲头8在此状态没有压力施加在阀上。具有隆凸12的平板可运动地安装在读出装置固定板7a后面。固定板7a后面是指固定板7a的那个与基体1所处的不同侧。若运动平板12的隆凸直接处于后面,亦即与冲头8接触,则冲头8朝相关阀的弹性体物质2的方向加压并将阀关闭。若运动平板12并没有隆凸处于冲头8后面,则冲头被弹簧朝运动平板12的方向加压或预紧,以及没有压力施加在弹性体2上。配属于冲头8的阀打开。
带隆凸12的运动平板与读出装置7结合,特别是读出装置的固定板7a与冲头8结合,得到阀的操纵或控制装置13。带隆凸12的运动平板与读出装置的固定板7a以及冲头8,出于稳定性的原因通常用金属制成,例如钢。但是也可以使用其他固体材料,如硬塑料。弹簧一般用弹簧钢制造。
按预定的程序同时操纵或不操纵由阀组成的阵列中的所有阀,通过阀的操纵装置13和尤其通过基本上平的板12进行。在带隆凸的运动平板12相对于读出装置的固定板7a并因而相对于带阀的塑料基体1运动时,相应于隆凸在板12上的布局来操纵阀,通过运动将隆凸移到阀下面。若将板12没有隆凸的区域移到阀下面,则阀保持打开。若通过运动将处于阀下面的隆凸从该阀的下面移开,以及板12的一个区域取代它移到阀下面,则阀被打开。
通过阀布设成成行Zn和列Sm以及隆凸布设成行Zn′和列Sm′,其中隆凸的列距与阀阵列的列距相等,以及通过板12沿与列平行的方向运动,所有的阀按固定的程序同时被操纵。因为在每列Sm内只设一个阀,所以一个隆凸一次仅操纵一个阀。在阀按规定固定布设时,程序通过隆凸的布局确定。一个程序步骤通过Zn′=Zn确定列。当板12运动一行的距离时,按照隆凸的布局在下一行中实施下一个程序步骤。若阀在两个程序步骤之间应保持关闭,则隆凸必须沿一列Sn′连续设计在两行之间。
在板12均匀运动时,在板12相对板7a的进给速度规定为恒定时,一个程序步骤的持续时间,在阀的行Zn间距固定地规定时,通过隆凸行Zn′的距离确定。但也可以与之不同,在隆凸行Zn′的间距已预定时,根据一个程序步骤期望的持续时间,改变进给速度。
如图2的俯视图所表示的那样,阀只布设在阀阵列的规定点上。每列Sm只有一个阀。根据要实施的化学反应和期望的微射流,在一行Zn内设置相应多的阀。为了简化起见在这里没有示出流动通道和反应室,它们按照阀的布局设计为在塑料基体1前侧10内的凹槽。因此复杂的化学或生化反应可以用上述方法方便地控制。通过控制阀来控制流体流的程序,由隆凸在板12上的布局确定。为了简单起见,阀在图2中以彼此相同的间距在基体1内布设行Sn和行Zm。通过板12的运动同时控制,亦即操纵或不操纵所有的阀。
同样可以实施在图中没有表示的其他实施形式,例如在塑料基底或基体1内阀彼此按不同间距地布设成列Sn和行Zm。通过板12控制冲头8,也可以借助板12中的凹穴而不是隆凸实现。此时一个凹穴与打开阀相对应。也可以设想,为了没有任何压力施加在阀上,冲头8不预紧,而是在预紧的状态下压在基体1上或根本不预紧。此时负压可以通过板12参与冲头8的运动。
Claims (13)
1.一种控制片上实验室系统中流体流的设备,包括阀的阵列,阀布设成n列Sn和m行Zm,以及分别设计用于控制相关流动通道(4)内的流体流,其中n和m是整数,以及包括用于操纵阀的操纵装置(13),其特征为:所述阵列包括至少两个阀,其中每一列Sn没有阀或最多有一个阀,而每一行Zm有在0与n个之间的阀。
2.按照权利要求1所述的设备,其特征为,用于操纵阀的操纵装置(13)具有基本上平的板(12),它有从平面突起的隆凸,隆凸布设成n′列Sn′和m′行Zm′,其中相邻列Sn′的间距与阀的对应的相邻列Sn的间距相同。
3.按照权利要求2所述的设备,其特征为,基本上平的板(12)可沿第一方向相对于阀的阵列运动地安装,其中该第一方向平行于阀阵列的列Sn延伸。
4.按照权利要求3所述的设备,其特征为,从所述板(12)的平面突起的隆凸以这样的方式布设成n′列Sn′和m′行Zm′,即,当基本上平的板(12)沿第一方向相对于阀的阵列运动时,按规定的程序控制各个阀的关闭和打开其他阀。
5.按照前列诸权利要求之一所述的设备,其特征为,阀的阵列布置在芯片卡内,其中芯片卡包括用塑料在信用卡模具内制成的扁平的基体(1),在基体(1)的前侧(10)上敷设薄膜,尤其胶粘薄膜,以及在基体(1)内在前侧(10)的表面上设置设计为凹槽的流动通道(4),以及阀含有弹性体物质(2),它至少部分与各自对应的流动通道(4)相邻地布置。
6.按照权利要求5所述的设备,其特征为,基体(1)由聚碳酸酯或聚丙烯组成,和/或弹性体物质(2)是一种热塑性弹性体,尤其是橡胶或由聚丙烯和乙二醇-丙烯-聚二烯M级弹性体组成的混合物。
7.按照权利要求5或6所述的设备,其特征为,芯片卡夹层式地安装在用于阀的操纵装置(13)内,以及在芯片卡的后侧(11)针对每个阀,在装置的板(7a)内分别安装一个操纵各自阀的冲头(8),其中冲头(8)通过至少一个在装置的板(7a)与冲头(8)之间的弹簧预紧为,使冲头(8)与阀之间基本上不存在压力。
8.一种用于控制按照权利要求2至7之一所述设备的方法,其特征为:阀分别通过在各自的阀上用压力加载来操纵,压力尤其通过至少一个冲头(8)施加,以及没有用压力加载时阀打开,并且流体流入相关的流动通道(4)内,以及在对阀施加压力时阀关闭,并且阻断在相关流动通道(4)内的流体流。
9.按照权利要求8所述的方法,其特征为:阀的打开和关闭按预定的程序,通过基本上平的板(12)平行于所述列Sn地相对于阀阵列运动来实现。
10.按照权利要求9所述的方法,其特征为,由基本上平的板(12)的m′行Zm′与阀阵列的m行Zm之差得出过程的步骤数,在所述过程步骤中操纵至少一个阀。
11.按照权利要求10所述的方法,其特征为,基本上平的板(12)相对于阀的阵列以固定的速度运动,在这里,一个过程步骤的持续时间,当所有行Zm彼此间距相同时,通过所述行Zm′彼此的间距确定,或一个过程步骤的持续时间,当所有行Zm′彼此间距相同时,通过行Zm彼此的间距确定。
12.按照权利要求10所述的方法,其特征为,基本上平的板(12)相对于阀的阵列以一种速度运动,这一速度总是与一个过程步骤的持续时间相匹配,其中行Zm彼此和行Zm′彼此设置为间距相同。
13.一种制造按照权利要求1至7之一所述设备的方法,其特征为,根据阵列中阀的布局,将流动通道(4)设置成n列Sn和m行Zm。
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DE102009023430.6 | 2009-05-29 | ||
PCT/EP2010/055817 WO2010136298A1 (de) | 2009-05-29 | 2010-04-29 | Vorrichtung und verfahren zum steuern von fluidströmen in lab-on-a-chip-systemen sowie verfahren zum herstellen der vorrichtung |
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