CN103703365B - 侧向穿流的色谱元件 - Google Patents
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Abstract
本发明涉及一种微流体的色谱元件,其中,所有的组成部分布置在一个平面中,并且移动相侧向地穿流固定相。
Description
技术领域
本发明涉及一种微流体的色谱元件以及其在微流体系统中的应用。
背景技术
在过去的几年里微流体系统已越来越多地在化学、生物化学和医药研究及诊断学中创建起来。在此,尤其是所谓的微全分析系统(μTotalAnalysisSystem,μTAS)提供了如下优点,即能够将单个的工作步骤综合起来、自动化并且同时地减小到一微尺度上。
作为生物化学研究的固定的组成部分,创建了聚合酶链反应(PCR)并且允许核酸扩增,以便使其以可检测的量可接近。在此情况下,在许多流程中需要清洁需扩增的或扩增后的DNA。为此目前提供了不同的产品,例如作为套件或过滤系统。一般来说,这些产品是色谱原理,其中,含有污染物的溶液与所搜寻的核酸经由一固定的固相被传导,其中,所述核酸也被称作移动相,在所述固相上吸收所述核酸。接下来,利用不同的解决方案洗脱较差吸附的杂质。接下来,利用另一个移动相有目的性地洗脱所述核酸。
为此,作为固定相使用二氧化硅纤维、硅胶、氧化铝纤维、氧化铝凝胶或阴离子交换剂。在阴离子交换剂的情况下利用浓盐溶液进行洗脱。因此,主要的石英光纤柱已被洗脱,通过其,借助于离心力使所述移动相运动。
US2008/0277356公开了一种微流体的装置,其按照色谱原理工作。为此,在一过滤器平面上分层地敷设一用于所述移动相的通道结构,从而通过该多层结构产生一横向穿流的过滤器元件。类似的多层的、横向穿流的过滤器结构从US2002/0185431中公开。在根据WO2004/065010的由多个层构成的装置中使用膜过滤器。多个固定相作为单独的段的前后连接例如从EP1916522中公开。
发明内容
因此,本发明的主题是一微流体的色谱元件,具有下列组成部分:
一用于以固定相进行填充的填充开口,
一联接到所述填充开口上的用于容纳所述固定相的空腔,
至少一个用于一移动相的流体入口,
至少一个用于所述移动相的分馏的流体入口,
布置在所述流体入口以及所述流体出口中的用于所述固定相的阻挡结构,
其中,所有的组成部分布置在一个平面中,并且所述移动相横向地穿流所述固定相。
由此将该方法编译到一相应的系统中,该系统可集成到一扁平的微流体的生物芯片中。
在此,作为固定相表示的是如下的相,其与物质混合物的单个物质,也就是说所述移动相发生相互作用。反过来,作为移动相表示的是流体的物质混合物,其穿流所述固定相。
在这一点上,布置在一个平面中表示的是,所述微流体的色谱元件的所有组成部分并排地布置,而不是布置在不同的层中。隶属于此的还有所述移动相的入口和出口以及位于其之间的固定相,所述移动相是侧向地(lateral)而不是横向地(transversal)穿流所述固定相。因此,可以取消在横向穿流的元件中所必需的穿通孔和其它的流体平面。
在所述微流体的色谱元件的一种优选的实施方式中,所述组成部分布置在一结构化元件的平面中。该结构化元件尤其是由一借助于注塑成型、铣削、深冲或热压铸来结构化的塑料成形件。为此考虑不同的聚合物,它们可以热变形或挤压并且相对于不同的固定相和移动相是惰性的。由于该结构化元件也在微流体实验室中用于芯片系统上,该元件当然也可以称作芯片。
在另一种优选的实施方式中,所述微流体的色谱元件的结构化元件具有一平面地放置的、密封地关闭的盖子。其也可以由与所述结构化元件相同的材料制成。可替换的是,所述微流体的色谱元件的一件式构造也是可行的。
此外,所述微流体的色谱元件还具有阻挡结构,所述阻挡结构在一种特殊的实施方式中具有齿、间隙、狭缝、孔洞和/或穿孔,它们的开口小于所述固定相的最小颗粒。正如其名称所暗示的,所述阻挡结构的功能是将所述固定相的颗粒鉴于所述移动相的入口和出口而可靠地阻挡住。因此,根据所述固定相的散装物料的不同,对所述阻挡结构进行匹配。所述阻挡结构位于去往所述固定相的流体入口以及流体出口中。因此,它们可以构造相同地实施或不同地实施,只要所述固定相的颗粒被可靠地阻挡在所述移动相的入口和出口中。不同的颗粒组分适合于所述固定相。具有从20至60μm的颗粒直径,例如Merck公司的硅胶60是优选的。所述阻挡结构相应地具有更小的间距。这样,所述阻挡结构在硅胶60作为固定相的情况下具有大约50μm的间隙。
在一种特殊的实施方式中,所述阻挡结构被微铣削、压铸、注塑成型、从聚合物中借助于激光烧蚀或3D石印、变成多孔的或是多孔的。在此,所述阻挡结构可以由与所述结构化元件相同的材料成形出,或者由一种其它的材料,该材料与所述结构化元件连接。
原则上每一种材料都适合于所述固定相,该材料作为颗粒的散装物料用于色谱分离、清洁和/或识别以及用于离子交换过程是已知的并且可以应用到侧向穿流的微流体系统上。
在一种优选的实施方式中,所述微流体的色谱元件的固定相从无机材料、优选二氧化硅、氧化铝、二氧化钛或沸石中选出,并且以颗粒、粉末、胶体、纤维和/或小球体的形式存在,该小球体具有一与所述空腔的边界相匹配的堆积角(Schüttwinkel)。
在另一种优选的实施方式中,所述微流体的色谱元件的固定相从有机材料,优选生物聚合物、特别优选交联琼脂糖中选出,并且以颗粒、粉末、胶体、纤维和/或小球体的形式存在,该小球体具有一与所述空腔的边界相匹配的堆积角。
在所述微流体的色谱元件的另一种优选的实施方式中,生物化学的组成部分、优选抗体、酶或在噬菌体的表面上呈现的蛋白质的重组库联接到所述固定相上,并且如此地固定化。
所述固定相的堆积角在此可以理解为直至所述固定相的颗粒材料受载的角度,而其不会滑落或崩塌。在此,该堆积角与所述固定相的材料的特定的性质,尤其是种类、内聚力、极性、湿度等等相关。如已经提到,在所述微流体的色谱元件中的空腔的边界与所述固定相的堆积角相匹配。这反过来意味着,在选择所述固定相时,必须考虑所述空腔的尺寸。在通过所述空腔的边界和穿过所述填充开口的横截面所形成的角的辅助下,该角在理想情况下等于所述固定相的堆积角。因此,在一种优选的实施方式中,通过所述空腔的边界和所述填充开口的横截面所形成的角大于或等于所述固定相的堆积角。因此,所填充的空腔是实际上的色谱柱。
在所述微流体的色谱元件的另一种实施方式中,用于所述固定相的填充开口作为相比于所述空腔,也就是说所述实际上的色谱柱更短的通道结构来成形。由此防止了在根据设定的应用中不出现大的不穿流的死体积。在这一点上重要的还有,通过所述柱的边界和所述填充开口的横截面所形成的角不允许比所述固定相的堆积角更扁平,或者说所述空腔的尺寸必须相应地进行匹配。所述开口必须至少在利用所述固定相进行填充时指向上,由此使颗粒能够不受阻地到达所述柱的空腔中。为了利用所述固定相进行填充,将所述色谱元件优选垂直放置或倾斜。可选地,在填充过程期间可以借助于振动或冲击将所述散装物料进行压缩,从而也能够实现具有一堆积角的固定相,其小于在所述空腔的边界和所述填充开口的横截面之间形成的角。利用这些技术可以产生不具有死容积或旁路的特别紧密地包装的柱,这又导致一巨大的成本节约,因为迄今为止成本低廉的颗粒散装物料无法在微流体系统中使用。这样,也可以舍弃昂贵得多的磁性颗粒(磁珠)。
在另一种实施方式中,所述填充开口在填充之后通过粘接、优选利用粘性薄膜、热胶或液体胶;热封,优选利用热冲头;激光焊接或利用机械锁合器具、优选利用旋塞或塞子来锁闭。这样,所述散装物料在所述芯片运输时再也无法运动。
通过所述微流体的色谱元件的简单的集成,使其适合于许多应用。但在此是在压力驱动的或离心力驱动的微流体系统,尤其是在背景技术中所述的微全分析系统中的应用,其中,目的是在于清洁、分离和/或在离子交换过程中的使用。该使用大多在从几个微bar至大约半个bar的超压范围中进行。其它特殊的应用在芯片系统的实验室的研发中给出,例如用于细菌的识别或药敏试验,用于生物化学的分离和/或清洁,或者总体上在医疗保健和诊断产品的研发中。
附图说明
根据本发明的装置的其它优点和有利的设计方案通过附图来图解并且在下面的说明书中阐述。在此要注意的是,所述附图仅具有描述的特征并且不应考虑为以任何一种形式来限制本发明。附图中使用了下列附图标记。
具体实施方式
图1示出了一微流体的色谱元件1的示意性竖直剖面图。在一填充开口2上联接一用于容纳一固定相的空腔3。所述移动相的流体入口4通过一第一阻挡结构6与所述空腔3分界。在所述空腔3上联接一流体出口5,其同样通过一第二阻挡结构6与所述空腔3分界。在此,用于容纳所述移动相和所述固定相的所有组成部分位于一个平面中,该平面仅通过所述阻挡结构6中断。
图2A、B和C示意性示出了所述原理以及三个在所述微流体的色谱元件1的构造上不同的替选方案。经由所述填充开口2将所述空腔3以一散装物料进行填充。所述流体入口4和所述流体出口5通过所述阻挡结构6与所述空腔3分界。通过所述空腔3的边界和穿过所述填充开口2的横截面所围出的角α明确了在填充时所述柱的指向上的边界的定向。在图2A中通过所述柱的壁给出了所述空腔3的边界。在图2B中一方面通过所述柱的壁且另一发明通过所述阻挡结构6定义了所述边界。在图2C中所述阻挡结构6限定了所述空腔3。所述微流体的色谱元件1的构造如此地构成,即所述角α以如下方式与所述固定相的堆积角相匹配,使得所述加α大于或等于所述堆积角。
图3示出了填充一处于一侧的微流体的色谱元件1的示意图、利用一配量装置7,例如一蜗轮蜗杆配量器,将所述固定相经由一漏斗8以及所述填充开口2填入到所述空腔3中。所述阻挡结构6防止了所述固定相到所述移动相的流体入口4和流体出口5中的扩散。通过所述色谱元件1的振动,可以将所述散装物料额外地进行压缩。接下来将所述填充开口2利用一热冲头进行挤压。接下来可以将所述微流体的色谱元件1集成到一微流体系统中。经由所述流体入口4输入所述移动相,其侧向地穿流所述固定相并且随后在分馏中经由所述流体出口6离开所述柱。
图4示出了以所述固定相填充的微流体的色谱元件1,其以一塞子9锁闭或者说封装。在所述填充开口2上联接着以所述固定相填满的空腔3。所述流体入口4和所述流体出口5通过阻挡结构6与所述空腔3分界。用于容纳所述移动相和所述固定相的所有组成部分位于一个平面中,该平面仅通过所述阻挡结构6中断。
Claims (15)
1.微流体的色谱元件(1),具有下列组成部分:
一用于以固定相进行填充的填充开口(2),
一联接到所述填充开口(2)上的用于容纳所述固定相的空腔(3),
至少一个用于一移动相的流体入口(4),
至少一个用于所述移动相的分馏的流体出口(5),
布置在所述流体入口(4)和所述流体出口(5)中的用于所述固定相的阻挡结构(6),
其中,所有的组成部分布置在一个平面中,并且所述移动相侧向地穿流所述固定相,其特征在于,所述固定相从无机材料或有机材料中选出,并且以颗粒、粉末、胶体、纤维和/或小球体的形式存在,其中,所述固定相具有一与所述空腔(3)的边界相匹配的堆积角。
2.按照权利要求1所述的微流体的色谱元件(1),其特征在于,所述组成部分布置在一结构化元件的平面中。
3.按照权利要求2所述的微流体的色谱元件(1),其特征在于,所述结构化元件具有一平面地放置的密封地关闭的盖子。
4.按照权利要求1至3中任一项所述的微流体的色谱元件(1),其特征在于,所述阻挡结构(6)具有齿、间隙、狭缝和/或孔洞,它们的开口小于所述固定相的最小颗粒。
5.按照权利要求1至3中任一项所述的微流体的色谱元件(1),其特征在于,所述阻挡结构(6)是以微铣削、压铸、注塑成型的方式从聚合物中借助于激光烧蚀或3D石印来变成多孔的或是多孔的。
6.按照权利要求1所述的微流体的色谱元件(1),其特征在于,在所述固定相上联接生物化学的组成部分。
7.按照权利要求6所述的微流体的色谱元件(1),其特征在于,所述生物化学的组成部分是抗体、酶或在噬菌体的表面上呈现的蛋白质的重组库。
8.按照权利要求1所述的微流体的色谱元件(1),其特征在于,通过所述空腔(3)的边界和所述填充开口(2)的横截面所形成的角大于或等于所述固定相的堆积角。
9.按照权利要求1至3中任一项所述的微流体的色谱元件(1),其特征在于,所述填充开口(2)作为相比于所述空腔(3)更短的通道结构成形出。
10.按照权利要求1至3中任一项所述的微流体的色谱元件(1),其特征在于,所述填充开口(2)在填充之后通过粘接;热封;激光焊接或利用机械锁合器具来锁闭。
11.按照权利要求10所述的微流体的色谱元件(1),其特征在于,所述粘接利用粘性薄膜、热胶或液体胶完成。
12.按照权利要求10所述的微流体的色谱元件(1),其特征在于,所述热封用热冲头完成。
13.按照权利要求10所述的微流体的色谱元件(1),其特征在于,所述机械锁合器具是塞子(9)。
14.按照权利要求1至13中任一项所述的微流体的色谱元件(1)在一压力运行或离心力运行的微流体系统中的应用,用于清洁、分离,和/或在离析交换过程范畴中使用。
15.按照权利要求14所述的应用,其特征在于,所述微流体系统是一微全分析系统。
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DE102011080527A DE102011080527A1 (de) | 2011-08-05 | 2011-08-05 | Lateral durchströmtes Chromatographieelement |
PCT/EP2012/061402 WO2013020743A1 (de) | 2011-08-05 | 2012-06-15 | Lateral durchströmtes chromatographieelement |
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