CN1422175A - 产生生物聚合物场的过程和设备 - Google Patents

产生生物聚合物场的过程和设备 Download PDF

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CN1422175A
CN1422175A CN01807794A CN01807794A CN1422175A CN 1422175 A CN1422175 A CN 1422175A CN 01807794 A CN01807794 A CN 01807794A CN 01807794 A CN01807794 A CN 01807794A CN 1422175 A CN1422175 A CN 1422175A
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capillaries
biopolymer
valve
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H·艾佩尔
S·马蒂西亚卡
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BASF SE
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Abstract

本发明涉及一种用于在载体基片(4),(14)上产生生物聚合物场(15)的过程和设备,其中待施加的生物聚合物从一个或多个不同的生物聚合物原料取得。可多维运动的毛细管(2)的毛细管尖端(1),用于向基片表面(14)转移极小液量,通过用于填充的一个微型阀(5)以及用于冲洗毛细管(2)的一微型阀(7)被寻址。

Description

产生生物聚合物场的过程和设备
本发明涉及用于产生核酸,蛋白质和/或多糖的生物聚合物场(阵列)的过程和设备,以便在载体或载体材料上排布样品量的这些物质。
为了对生物聚合物-例如核酸,蛋白质和/或多糖-进行高度并行分析,一般是把许多少量样品以液滴形式的排布施加到扁平的载体或载体物质上。对于被采用的样品量所使用的载体是塑料膜,膜片或如显微镜中常用的标本载片。在典型的分析应用中,将数百到数千个分析点施加到载体上。
为了把待分析的范围从几皮升到几纳升极少量样品液体施加到载体或载体材料上,例如采用喷墨打印技术。在喷墨打印技术中,待分析的样品液体要施加的量受到相当大的机械和/或热应力,这可能损坏敏感的生物聚合物。此外,在这一施加技术中,可能常常出现形成不希望有的气泡,这妨碍了液滴精确的定位,以及规则排布的分析场。此外,常常出现由于所施加的液量粘滞性很不同而导致的缺陷。
M.Schena等人在Science 270,1995,pp.467-470中,公开了一种基于自来水笔方法的过程。在从先有技术所知的这种解决办法中,采用了带有成形为针头状的金属针。这些针浸入到待吸移的液体中;一些待施加的液体停留在针头的表面;当针头后来下降时,该液体被转移到待加载的载体或载体材料表面。这一技术的缺陷是受到限制的针头形的液体容纳量,如果在提取液体之后,要对大量的载体表面打点,以形成每一个有相同的图形的待分析的各个阵列。
如果在金属针头上提供槽或开口浸入到样品容器中以便增加待施加的液体容纳量,但它们具有更难于且不便于清洗的缺陷。然而,如果每当金属针头浸入到带有新类型样品的容器中,而以前施加的基片残留物仍然附着在尖端上,则为了避免样品物质的污染清洗是非常重要的,以使得基片上新的样品点不再包含来自先前转移点的物质。
就已指出的先有技术所知道的解决方法缺陷而言,本发明的目的是要使用简单的装置,廉价而可靠地排布待分析的生物聚合物场或阵列。
这一目的是根据本发明在一种过程中实现的,该过程用于在载体基片上产生生物聚合物区域,其中待施加的生物聚合物要从一个或多个样品原料中取得,能够作多维运动的毛细管的毛细管尖端,用于向基片表面转移极少液量,通过用于填充的一种微型阀并通过用于冲洗的另一微型阀被寻址。
具体来说,可以看到这一解决方法的优点在于,根据本发明所提出的该过程,允许以简单的方式使用单个毛细管填充加载多个载物板。为了避免样品污染,对毛细管的两次清洗操作已经证明实际上足以排除样品原料和被转移的样品的交叉污染。另一方面,每当提取样品量原料能够通过两个独立可寻址的微型阀按所需的次数反复清洗毛细管。
在本发明所基于的过程的进一步的实施例中,多个毛细管能够连接到微型阀。这使得能够向基片或基片材料表面并行施加多个极少量液体。
如果在彼此相隔定一距离容器皿采用多个毛细管,则能够通过多载体面的并行处理同时施加大量的待分析的液体样品。
根据本发明所基于的思想更为有利的考虑,能够这样彼此排布多个毛细管,使得它们彼此的间隔对应于生物聚合物质的两个样品量被施加到载体基片表面的间隔。
待分析的极小液体量在基片载体表面上排布得越规则,能够对所施加的液体样品进行越精确的鉴定,并且后继的分析方法能够越容易自动化。
在根据本发明提出的过程的一优选实施例中,一个或多个毛细管能够在X-或Y-方向移动,此外能够在Z-方向进行浸入运动以容纳来自基片容器的液体原料。各毛细管在三个坐标方向可寻址性使得能够最大程度利用分析板上的空间。对于向各载体表面施加待分析的极小液量的一个或多个毛细管的寻址和可移动性,最好采用可在X-方向和Y-方向移动的市售计算机支持的绘图仪。通过借助于个人计算机(PC)市售的绘图仪的寻址,能够实现一个或多个毛细管的廉价的可移动性及可靠的可寻址性。
利用市售的绘图仪能够实现一个或多个毛细管在X-方向和Y-方向的可移动性,除此之外也可替代采用计算机支持的定位工作台。
根据本发明,还提出了用于在载体基片上产生生物聚合物场的设备,其中待施加的生物聚合物能够取自一个或多个不同的样品原料,其中通过用于填充的微型阀并通过用于清洗毛细管的微型阀,在数个方向移动用于向基片表面转移极少液量的毛细管玻璃尖端能够被寻址。在根据本发明提出的用于产生生物聚合物场的设备的另一实施例中,毛细管尖端在其末端被拉成适合于外径范围在10μm到1000μm之间的非常少的液量。在一特别优选的实施例中,毛细管尖端设计为在末端分别适合于外径从50μm到300μm之间的非常少的液量。
一个或多个毛细管的寻址能够借助于计算机支持的绘图仪进行,这种绘图仪产生毛细管分别在X-方向和Y-方向的运动,以及毛细管与容纳在其中的液体原料在Z-方向的的浸入运动,以便向载体或载体材料表面施加极少液量。在根据本发明提出一个实施例中装设在通向毛细管管线系统中的微型阀能够设计为阻塞管路阀。其中能够特别这样装设,使得柔性管管线由固定的阻挡支持,与固定阻挡相对装设柔性的阻挡,借助于这种固定阻挡能够封闭柔性管管线的截面。柔性管线的原来的截面由于管路材料的弹性可自动恢复。
以下参照仅包含一个图的附图更为详细说明本发明。
单个的图示示出用于执行根据本发明提出的过程的设备,其中毛细管与毛细管尖端一同能够在三个方向移动。
单个的附图中的描绘示出毛细管2,它最好由玻璃构成,该毛细管用于容纳待吸移的生物聚合物溶液。它被浸入到样品量容器3,又称为微滴定板井。例如设计为阻塞管路阀的第一微型阀5的通向大气6的开口,使得与大气6等压,于是由于毛细的作用样品量原料13通过毛细管尖端1上升进入毛细管2的内部。
在一优选实施例中,毛细管2由玻璃构成,而毛细管尖端的外径范围是从10μm到1000μm;在根据本发明提出的毛细管的一特别优选的实施例中,毛细管尖端的外径范围是从50μm到300μm。为了提取待施加到载体材料4表面14的生物聚合物溶液,毛细管2的毛细管尖端1浸入到容器3中存在的的溶液中。例如溶液可以位于微滴定板的井3中,这种井能够容纳96或384或甚至1536个体样品。在毛细管尖端1浸入溶液期间,控制气流送入毛细管2的阀7起初保持封闭。反之,由T-形件11处的馈送柔性管19连接到毛细管2的阀5被打开,并这样引起与周围大气6等压。由于出现的毛细力,液体原料13从这时毛细管尖端浸入在其中的微滴定板的井3移动进入毛细管2内部。
然后毛细管尖端1从呈现的溶液移除,接下来在定位在载体4表面14上的X-和Y-方向上移动,然后各待分析的液体样品按生物聚合物图形15施加到该表面上,同时保持彼此精确定义的间隔16。在方向12(Z-方向)降低毛细管尖端1到载体4表面14,第一阀5的设置和第二阀7的设置不变。借助于引起毛细管2在X-方向,Y-方向和Z-方向移动的寻址装置20,仍然是以涉及市售绘图仪的非常简单和廉价的方式,毛细管尖端1能够向上离开载体材料4的表面14,生物聚合物溶液的小点留在载体材料4的表面14上。通过以示例方式所采用的绘图仪适当的寻址20,毛细管2与在其中被提取的液体原料13一同在X-和Y-方向的运动能够根据绘图仪的寻址进行,于是能够对后继的进一步的载体材料4的载体面14以相同的方式提供生物聚合物点。生物聚合物点最好按规则的图形15施加,该生物聚合物图形最好这样区分,使得各个样品点彼此有均匀的间隔16。
在提取新的样品之前,即浸入新的呈现皿3之前,毛细管尖端1必须被彻底清洗,以避免样品污染。为此,毛细管尖端1起初移动到废料皿9上方;连接到大气6的第一阀5这时关闭,并最好是过滤的空气或氮气的气流,经过第二微型阀7通过柔性馈送管线19导入毛细管2的内部。
然后为了彻底的冲洗,毛细管尖端1移动到清洗皿10的上方,这时在关闭第二微型阀7即气阀,并打开第一微型阀5,即外部空气阀之后,毛细管尖端1下降进入到清洗液。由于形成的毛细力的作用,这时清洗液流入毛细管2的内部。毛细管2的毛细管尖端1然后再次移动到废料皿9上方,并通过打开第二微型阀7并关闭通向大气6的第一微型阀5,使清洗液喷出。另外,如果保证在清洗皿10中的清洗液不断被更换,例如借助于连续的泵送,则这也可以进入设置在浸入状态清洗液中进行。为此,清洗皿10能够配置一个用于清洗液的泵回路17,其中最初新鲜未使用过的清洗液能够馈送到清洗皿10,而然后已经使用过的清洗液或沉积的颗粒连续不断地在清洗皿的底部被清除。
清洗液从毛细管2的内部的提取和喷射,能够按所需的频度通过两个微型阀5和7对应的激励进行(这些阀最好设计为阻塞管路阀),直到毛细管内部及其外部已经充分清洁为止,并然后能够继续进行向待加载的载体基片4的上侧14施加生物聚合物阵列。对图1中所示的设备的结构参照示例性实施例更为详细地说明。用于两个微型阻塞管路阀的小支架,夹持在可在X-和Y-方向移动的市售的绘图仪的滑架上(例如ROLAND DXY1150A)。外部直径大约为200μm的尖端1从外径1.0mm,内径0.8mm的玻璃微吸移管2在气体火焰中拉制出,这种毛细管例如是出自Hilgenberg的硼硅酸盐玻璃毛细管。玻璃吸移管2的外径(1mm)以平齐(flush)的方式但要有足够小的间隙适配进入1.5×100注射器的不锈钢套管。这一套管能够以简单的方式作为导向件安装到可在X-和Y-方向移动的市售的绘图仪的弹簧夹上。玻璃微吸移管2在这一导向套管中能够易于在垂直方向移动,且不会被柔性管19下压。另外,这一力可由一小弹簧支撑。
调节毛细管2的导向件,借助通过市售的PC寻址的绘图仪上的命令“提笔”和“落笔”,能够上下运动。通过装设在从阀5,7到柔性管19的馈送管线中的T-形连接器11形成到毛细管2的连接。
已经令人吃惊地发现,除了呈现微滴定板之外,这种结构能够使尽可能多的能够适配在所使用的绘图仪DIN A3工作区上的载体板4,借助于毛细管2内部单次填充以液体原料13被加载。在带有核酸生物聚合物图形15的载体4的生产中,已经发现,以0.5%TWEEN-80溶液进行的两个清洗步骤,通常完全足以排除在实际中有不良作用的样品污染。必须保证,当以清洗液清洗毛细管尖端1里侧浸湿的玻璃毛细管2时,清洗液能够从玻璃毛细管内部再次通过被施加的通过第二微阀7可控制的气流被喷出。通过使玻璃毛细管尖端1浸入到包含清洗液的器皿,保证了毛细管尖端1的外部也与清洗液接触,并这样每次都清除掉先前分析的样品残余。在毛细管2的浸入状态吹出清洗液时,观察到由于在清洗液中气泡的形成,在这一操作期间借助于在毛细管2处上升的气泡,毛细管2的毛细管外侧也被彻底清洗。
与迄今传统的加载结构相比,所提出的结构拥有明显的经济上的优点。一方面,非常精确地购买的市售的毛细管2的可得性与精确地研磨并特别成形的金属针的生产相比起到很大作用,且另一方面,X/Y绘图仪作为自动可寻址定位工作台能够非常廉价地购买到,结合到根据本发明提出的系统中,用于在载体表面生产生物聚合物阵列。
标号列表
1   毛细管尖端
2   毛细管
3   基片容器
4   载体
5   第一微型阀
6   大气
7   第二微型阀
8   气流供给管线
9   废料皿
10  清洗皿
11  T-形连接器
12  毛细管2的Z-方向运动
13  提取样品
14  载体面
15  生物聚合物图形
16  间隔
17.1  清洗液馈送
17.2  清洗液馈出口
18  清洗液水平面
19  柔性馈送管线
20  寻址装置
X-方向
Y-方向
Z-方向(施加方向)

Claims (13)

1.一种用于在载体基片(4)表面(14)上产生生物聚合物场(15)的过程,其中待施加的生物聚合物从一个或多个不同的样品原料(3)取得,其中能够作多维运动的毛细管(2)的毛细管尖端(1),用于向基片表面(14)转移极小液量,通过用于填充的一个微型阀(5)以及用于冲洗毛细管(2)的一微型阀(7)被寻址。
2.权利要求1中所述的过程,其中多个毛细管(2)连接到微型阀(5),(7)。
3.权利要求2中所述的过程,其中多个毛细管(2)彼此并行地被操作。
4.权利要求2中所述的过程,其中多个毛细管(2)排布的彼此间隔对应于呈现板上原料器皿(3)彼此的间隔。
5.权利要求1和/或2中所述的过程,其中一个或多个毛细管(2)能够在X-方向和Y-方向运动,并在Z-方向执行浸入运动(12),以便从样品容器(3)提取液体原料(13)。
6.权利要求1和/或2中所述的过程,其中采用市售的计算机-支持的绘图仪使一个或多个毛细管(2)在X-方向和Y-方向运动。
7.权利要求1和/或2中所述的过程,其中采用计算机-支持的定位工作台使一个或多个毛细管(2)在X-方向或Y-方向运动。
8.一种用于在载体基片(4)表面(14)上产生生物聚合物场(15)的设备,其中待施加的生物聚合物从一个或多个不同的样品原料(3)中取得,其中能够作多维运动带有毛细管尖端(1)的玻璃毛细管(2),用于向基片表面(14)转移极小液量,通过用于填充的第一微型阀(5)并通过用于冲洗毛细管(2)的微型阀(7)被寻址。
9.如权利要求8中所述的设备,其中毛细管尖端(1)已拉制为在提取液体的末端的外径范围是从10μm到1000μm。
10.如权利要求9中所述的设备,其中毛细管尖端(1)在提取液体的末端的外径是从50μm到300μm。
11.如权利要求8中所述的设备,其中通过计算机支持的引起毛细管(2)在X-方向和/或Y-方向运动的X/Y绘图仪,实现一个或多个毛细管(2)的寻址。
12.如权利要求8中所述的设备,其中微型阀(5),(7)为阻塞管路阀的形式。
13.如权利要求12中所述的设备,其中阻塞管路阀(5),(7)设计为围绕柔性馈送管线(19)通向玻璃毛细管(2)的阻挡,这些阻挡之一相对于柔性管线(19)被固定,且它们的另一个相对于固定阻挡可移动,用于使截面变窄以便在柔性管线(19)中实现关闭。
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