CN1245520C - Method for producing probe arrays for biological materials using fine particles - Google Patents

Method for producing probe arrays for biological materials using fine particles Download PDF

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CN1245520C
CN1245520C CN 00806177 CN00806177A CN1245520C CN 1245520 C CN1245520 C CN 1245520C CN 00806177 CN00806177 CN 00806177 CN 00806177 A CN00806177 A CN 00806177A CN 1245520 C CN1245520 C CN 1245520C
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probe
beads
array
hole
bead
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CN1347329A (en
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神原英记
三桥将人
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日立化成工业株式会社
株式会社日立制作所
日立化成研究开发有限公司
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    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/02Burettes; Pipettes
    • B01L3/0289Apparatus for withdrawing or distributing predetermined quantities of fluid
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277Apparatus
    • B01J2219/00457Dispensing or evacuation of the solid phase support
    • B01J2219/00459Beads
    • B01J2219/00468Beads by manipulation of individual beads
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06Fluid handling related problems
    • B01L2200/0647Handling flowable solids, e.g. microscopic beads, cells, particles
    • B01L2200/0668Trapping microscopic beads
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/08Geometry, shape and general structure
    • B01L2300/0809Geometry, shape and general structure rectangular shaped
    • B01L2300/0816Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/08Geometry, shape and general structure
    • B01L2300/0809Geometry, shape and general structure rectangular shaped
    • B01L2300/0819Microarrays; Biochips
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00Moving or stopping fluids
    • B01L2400/04Moving fluids with specific forces or mechanical means
    • B01L2400/0475Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0487Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00Moving or stopping fluids
    • B01L2400/06Valves, specific forms thereof
    • B01L2400/0633Valves, specific forms thereof with moving parts
    • B01L2400/065Valves, specific forms thereof with moving parts sliding valves
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502761Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N2035/00178Special arrangements of analysers
    • G01N2035/00237Handling microquantities of analyte, e.g. microvalves, capillary networks

Abstract

其中诸如DNA的各种生物物质的探针被固定在一种固体的表面上的探针列阵的使用,作为一种有效的高速筛选的工具正在获得公认。 Wherein the various probes of biological substances such as DNA is immobilized on a solid surface of the array probe is used, as an effective tool for high-speed filtering is gaining recognition. 诸如DNA的不同类型探针不是被固定在单个固体的表面上,而是被固定在诸如珠子的大量的可以独立处理的精细颗粒的表面上,并将所产生的珠子按照一个指定的次序排列在一支毛细管或一个单元中。 Different types of probes such as DNA, is not fixed on the surface of a single solid, but is immobilized on the surface of the fine particles can be processed independently, such as a large number of beads, and the resulting beads are arranged in the order of a specified a capillary or a cell. 在一个探针被固定之处区域的大小被减少了。 The size of the region of a probe is immobilized is reduced. 此珠子探针列阵的特征在于使用一种有空穴的片层,这样的小珠子被按照指定的次序一个接一个地排列,并且一个数量或多个数量的珠子被容纳在这些空穴中,并在此后被转运到诸如一支毛细管的一种探针列阵容器。 This bead array probe is characterized in that one sheet of a hole, such beads are arranged one after another in the specified order, and one or more of the number of number of beads are accommodated in these cavities and one probe is thereafter transferred to a container such as a capillary tube array.

Description

使用精细颗粒生产生物材料的探针列阵的方法 Fine particles using a method of producing a biomaterial probe arrays

发明背景发明领域本发明涉及在检测肽、蛋白质和DNA,诊断和分析包括DNA的生物材料中使用的探针列阵;和生产同样的探针列阵的方法和装置。 BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to the detection of peptides, proteins and DNA, including diagnosis and analysis of the DNA probe bio-materials used in array; and a method and apparatus for producing the same probe arrays.

此探针检测方法还被用于蛋白质或多肽或各种与它们相互作用的生物材料的分析,并且一种对应于DNA芯片的肽芯片现在正在被使用。 The probe is also a method for detecting or analyzing a protein or polypeptide and their various interactions of biological materials, and one kind of a peptide corresponding to the DNA chip chips are now being used. 在其中一种肽或DNA被固定在一种固体的表面上并在此肽或DNA与一种样品之间进行杂交的这种分离和检测方法,长久以来被称为一种印迹方法,其中靶DNA或同类的东西通过一种被固定在膜上的探针使用放射性标记而被检测。 In a peptide or DNA which is fixed and this separation and detection of hybridization between the peptide or DNA in a sample with the surface of a solid, has long been known as one kind of imprinting method, wherein the target DNA or something similar by means of a probe is immobilized on the membrane is detected using radiolabeled. 然而,在DNA芯片上大量的探针可以被固定在一种诸如玻璃或硅氧烷的固体的表面的一小块区域(1cm2)上,DNA芯片具有只需要小量的样品,并且可以同时使用大量不同探针的优势。 However, in a large number of probes on a DNA chip may be fixed to one of a small area on the surface of the glass, such as silicone or solid (1cm2), a DNA chip having only a small amount of sample and can be used simultaneously advantages of a large number of different probes. 生产DNA芯片的方法大致被分成两组。 The method for producing a DNA chip is generally divided into two groups. 在第一组中,DNA探针是合成的一种基片,每次是通过在一种固体的小节段(0.05mm2到0.2mm2)上的一种光化学反应,使用相同于用于半导体或同类的东西的光学掩蔽技术(Science 251,767,1991)合成的。 In the first group, the DNA probe is a synthetic substrate, each is in the section by means of a photochemical reaction on a solid section (0.05mm2 to 0.2mm2) using the same or similar to the semiconductor for optical something masking technique (Science 251,767,1991) synthesis. 在第二组中,对于个体探针的每一个节段,一种被合成的DNA,PCR-扩增的DNA,或者通过克隆获得的DNA被固定在一种固体的表面的一个小节段上(Nature Biotech 16,27,1998)。 In the second group, one segment for each individual probe a DNA to be synthesized, a PCR-amplified DNA, DNA obtained by cloning or is immobilized on a solid surface of a section segment ( Nature Biotech 16,27,1998). 后者拥有具有所需要的探针的肽芯片或DNA芯片可以相对容易地制造的优势,并且是许多启动公司选择的方法。 The latter has the advantage of having the desired peptide probe chip or a DNA chip can be relatively easily manufactured, and a method of choice in many startup companies.

发明概述一种生物材料的探针芯片,包括DNA,被高度期望用作一种测试工具。 SUMMARY OF THE INVENTION A biological material chip probes, including DNA, was used as a testing tool highly desirable. 然而,就实际而言,以下条件必须满足:(A)可以低成本地制造小量的大量不同的芯片,(B)一种探针可以被均匀地固定;(C)数据是高度可重复的,并且此芯片是可以再用的;并且(D)此芯片可以被加热,从而去除被非特异性吸附的物质。 However, in practical terms, the following conditions must be met: (A) can be manufactured at low cost in a small number of different chips, (B) A probe can be fixed uniformly; (C) data is highly reproducible , and this chip can be reused; and (D) of this chip may be heated to remove non-specifically adsorbed species. 然而,问题依然存在:例如,(a)探针从一个节段到另一个节段是不一致的,(b)生产是劳动密集的,(c)固定化非常精细的分段是不可能的,以及(d)探针不均匀;因为(i)它们是作为液滴被固定在一种固体的表面上的,并且(ii)探针同时被安置和固定。 However, problems remain: for example, (A) a probe from one segment to another segment is not uniform, (b) production is labor intensive, (c) immobilized very fine segments are possible, uneven and (D) a probe; because (i) they are immobilized on a solid surface of the droplets, and (ii) while the probe is positioned and fixed. 而且,(d)与此固体的表面微弱地结合并且一旦加热即可被移去,因为(iii)许多探针芯片通过吸附或同类的作用被固定。 Further, (d) this solid surface bind weakly and can be removed upon heating, as (iii) a number of probe chip is fixed by adsorption or a similar effect.

为了解决上述的问题,探针在固体表面上的固定和这些探针的排列可以被分成两个或更多不同的步骤,从而能够在此固体表面上生产均匀的DNA探针。 To solve the above problem, the arrangement of these probes, and probes fixed on a solid surface may be divided into two or more distinct steps, it is possible to produce a uniform DNA probe on the solid surface. 探针可以经由对热稳定的共价键被固定,因此,被非特异性吸附的物质可以通过加热被适当地去除。 The probe may be secured via a thermally stable covalent bonds, and therefore, the substance is non-specific adsorption can be suitably removed by heating. 排列被用作在其之上固定探针的固体的精细颗粒,从而生产一种具有适当尺寸的节段的探针列阵。 Which arrangement is used as a probe fixed on the solid fine particles, to produce a probe array having segments of appropriate size. 任何想要的探针列阵可以通过交换被排列的具有这些探针的精细颗粒而容易地生产。 Any desired probe array can be easily produced by exchange with these fine particles are arranged in the probe. 镊子可被用来排列具有大约0.3mm的直径的精细颗粒,但是这个方法对于具有小于0.1mm的直径的颗粒将会是困难的。 Tweezers can be used for fine alignment of the particles have a diameter of approximately 0.3mm, but this method for the particles have a diameter of less than 0.1mm would be difficult. 因此,在一个实施方案中,本发明提供一种方法和一种生产一种探针列阵的装置,其中每一个都被容纳于在一种片层之上的一个精细空穴中的精细颗粒被转运并排列在一支毛细管,一块平板上的一个沟槽或者同类的东西中。 Thus, in one embodiment, the present invention provides a method and an apparatus for producing a probe array, each of which is received in a hole on one kind of fine sheets of fine particles It is transported and arranged in a capillary, a plate or a groove on the kind of thing. 在一个备择的方法中,控制精细颗粒,使其作为个体颗粒流进一种液体以转运到一支毛细管中,从而生产一种探针列阵。 In an alternative method, the control of fine particles, the individual particles so as to transport a liquid flow into a capillary tube to thereby produce a probe array. 而且,为了改进测量的重复性,为每一种探针排列了具有多个探针的多个精细颗粒,从而检查测试结果的任何变化以获得高度可靠的数据。 Further, in order to improve measurement repeatability, are arranged a plurality of fine particles having a plurality of probes for each probe, so that any change in checking the test results to obtain highly reliable data.

为了概述本发明和所获得的优于在先技术的优势起见,本发明的特定目的和优势已经在上文中被描述。 For purposes of summarizing the invention and the advantages superior to the prior art the obtained sake, specific objects and advantages of the present invention have been described above. 当然,要理解,不一定根据本发明的任何特定实施方案可以获得全部这样的目的或优势。 Of course, it is understood that not necessarily all such objects can be obtained in accordance with any particular embodiment or advantages of the embodiment of the present invention. 因此,例如,本领域的技术人员将会承认,本发明可以在获得或优化如同这里所教导的一种优势或优势集合的意义上被具体化或者说被实施,而不一定获得在这里可能被教导或被暗示的其他目的或优势。 Thus, for example, those skilled in the art will recognize, the present invention can be obtained or optimized in the sense as an advantage or advantages as taught herein set are embodied or implemented, there may not necessarily be obtained teach other objects or advantages or implied.

从以下的优选实施方案的详细描述中,本发明的进一步的方面,特征和优势将会变得显而易见。 From the following detailed description of preferred embodiments, further aspects, features and advantages of the present invention will become apparent.

附图简述参照意在说明而不是限制本发明的优选实施方案的附图,本发明的这些和其他特征现在将被描述。 BRIEF DESCRIPTION Referring to the drawings intended to illustrate and not limit the preferred embodiments of the present invention, these and other features of the invention will now be described.

图1是一种包括被排列在一支毛细管中的具有探针的珠子的探针列阵芯片的理论图。 FIG 1 is a theoretical view of a probe array chip having probe beads are arranged in a capillary comprises.

图2是一种测量一种被保留在一支毛细管或同类的东西中的具有探针的珠子列阵的检测系统的理论图。 FIG 2 is a measuring one is retained in a capillary or something similar in theory FIG beads having a probe array of the detection system.

图3a-3g是一种排列珠子的装置的分段剖视图。 FIGS. 3a-3g is a segmented sectional view of a bead arrangement. 图3a是以离线状态传入珠子的理论图。 Figure 3a is offline passed beads graph theory. 图3b是其中一个珠子被俘获在一个空穴中的理论图。 Figure 3b is a bead which is trapped in a cavity theory FIG. 图3c是其中一个珠子正在移进一支毛细管或同类的东西中的理论图。 Figure 3c is a theoretical view of things in which a bead is moved into a capillary or similar in. 图3d-3g说明此连续步骤。 FIGS. 3d-3g illustrate this continuous step.

图4a和4b是一种沟槽型的排列珠子的装置的理论图。 Figures 4a and 4b are arranged in a trench-type device of FIG theory beads. 图4a是透视图。 4a is a perspective view of FIG. 图4b是剖视图。 4b is a cross-sectional view of FIG.

图5a,5b和5c是一种使用沟槽和一种可以移动的阀生产一种珠子列阵的方法的理论图。 Figures 5a, 5b and 5c of grooves and a method for producing a valve that can move the bead array using theoretical FIG. 图5c是横截面局部视图。 Figure 5c is a cross-sectional partial view.

图6是一种圆盘型的转运探针珠子的系统的理论图。 FIG 6 is a theoretical diagram of a system disk-shaped probe beads transport.

图7是一种液流型的珠子列阵生产方法的理论图。 FIG. 7 is a flow diagram of a theoretical type bead array production process.

图8是在其中用标记珠子分隔大量珠子的一种珠子列阵的理论图。 FIG 8 is a theoretical view of the partition large beads mark in one of the beads of the bead array.

图9a和9b是一种使用一种具有空穴的片层排列探针珠子的方法的理论图。 Figures 9a and 9b are arranged in a theory of a method of probe beads having sheet holes used.

图10a,10b和10c是一种微量滴定板型的珠子列阵容器的理论图。 FIG. 10a, 10b and 10c is a microtiter plate bead array container theory FIG.

图10a是全视图。 10a is a full view of FIG. 图10b是剖视图。 10b is a cross-sectional view of FIG. 图10c是测量的理论图。 FIG 10c is a theoretical measurements.

优选实施方案的详细描述本发明包括数个方面和实施方案。 Detailed description of preferred embodiments of the present invention includes a number of aspects and embodiments. 在一个方面,一种生产一种探针列阵的方法包括下列步骤:(a)选择感兴趣的数种类型探针;(b)分别将此数种类型探针固定在不同固体物件的表面上;并且(c)按照一种指定的次序排列这些固定了探针的固体物件,从而获得分析通过它的一种样品溶液的一种探针列阵。 In one aspect, a method for producing a probe array comprising the steps of: (a) Select the number of types of probes of interest; (b) several types of probes, respectively, this is fixed at a different surface of the solid object on; and (c) a way to specify the order of arrangement of these objects is fixed solid probe, thereby obtaining by means of a probe which analyzes a sample solution array. 在上文中,探针可以是多聚核苷酸,肽或蛋白质。 In the above, the probe may be a polynucleotide, peptide or protein. 在一个实施方案中,这些固体物件是可能是精细颗粒的珠子。 In one embodiment, these items are solid fine particles may be beads. 进一步地,这些固体物件的排列可以是一种一维排列或一种二维排列。 Further, the arrangement of these objects may be a solid one-dimensional arrangement or one two-dimensional arrangement. 在另一个实施方案中,此方法还包括将作为标记物的固体物件按照指定的间隔放置在此排列中。 In another embodiment, the method further comprising placing this arrangement as a solid object markers at specified intervals. 这些标记可以具有不同于具有探针的固体物件的尺寸。 These marks may have a different solid object with the probe size. 在一个实施方案中,每一个固体物件有一种类型探针被固定在其上,并且为每一种类型探针制备了一个指定数量的固体物件。 In one embodiment, each solid object has a type which is fixed to the probe, and the probe for each type of a designated number of solid objects prepared. 此外,这些固体物件的排列可以在一种选自毛细管,沟槽和光学单元的列阵中进行。 In addition, these solid objects may be arranged in one selected from the capillary tube, the grooves in the array and the optical unit.

在本方法的一个实施方案中,固体物件的排列可以如下进行:(i)将固定了探针的固体物件放置在一种空穴的片层上,所述空穴中可以通过一个固体物件,所说的片层被放置在一个可以移动的具有一个通向此列阵内部的直通空穴的基底上,所说的可以移动的基底被放置在此片层的空穴与此可以移动的基底的直通空穴不相通的地方;(ii)在此片层的空穴中俘获这些固体物件中的一个;(iii)从此片层去除剩余的固体物件;(iii)将此可以移动的基底移动到此片层的空穴与此可以移动的基底的直通空穴相通的一个地方;(iv)经由此直通空穴将此被俘获的固体物件转运到此列阵;并且(v)重复步骤(i)到(iv)直至固定了探针的固体物件被按照指定的次序排列在此列阵中。 In one embodiment of the method, the arrangement of the solid articles can be carried out as follows: (i) the solid object is fixed probe is placed on the sheet of one hole, the hole may be through a solid object, the said sheet is placed on a substrate having a movable leading to the interior of this through hole array, said movable substrate is placed in a hole in the film layer of the substrate can be moved with this through-holes are not communicating place; (ii) the film trapped in the hole in a layer of such solid objects; (iii) removing the sheet from the remaining solid object; (iii) movement of this movable base hole through this hole with this sheet may be moved to a substrate of the same place; (iv) through this through-hole of this article are trapped solids transport this array; and (v) repeating steps ( i) to (iv) until the retaining solid objects are arranged in this probe array in the order specified.

在本方法的另一个实施方案中,排列可以如下进行:(i)将固定了探针的固体物件放置在一种具有空穴的片层上,所述空穴中可以通过一个固体物件,所说的空穴通向此列阵的内部,所说的空穴被用一个阀关闭;(ii)在此片层的空穴中俘获这些固体物件中的一个;(iii)打开此阀从而将被俘获的固体物件转运到此列阵;和(iv)重复步骤(i)到(iii),直至固定了探针的固体物件被按照指定的次序排列在毛细管,沟槽或光学单元中。 In another embodiment of the method, the arrangement may be as follows: (i) fixing the solid object is placed on a probe sheet having holes, through the hole in a solid object, the this hole to the interior of said array, said holes are closed by a valve; (ii) a capture of these solid objects in the hole in the film layer; (iii) so as to open the valve solid objects trapped transport this array; and (iv) repeating steps (i) to (III), fixed to the solid object until the probes are arranged in a capillary, the optical unit or the groove in the order specified.

在本方法的又一个实施方案中,排列可如下进行:(i)将这些固定了探针的固体物件放置在孔中,每一个孔含有单一类型的固定了探针的固体物件,每一个孔具有一个可以为一个固体物件所通过的空穴,所说的空穴被关闭;(ii)在每一个孔的每一个空穴中俘获这些固体物件中的一个;(iii)在按照一个指定的次序移动这些孔之后打开和关闭每一个空穴,从而将每一个被俘获固体物件转运到一种列阵中;(iv)移动这些孔,从而在下一个列阵中排列这些固定了探针的固体物件;和(v)重复步骤(i)到(iv),直至用排列在其中的固定了探针的固体物件填充一个指定数量的列阵。 In a further embodiment of the method of the present embodiment, the arrangement may be as follows: (i) these probes immobilized solid objects placed in wells, each well containing the immobilized solid objects of a single type of probe, each well having a solid object may be a hole through which said holes are closed; (ii) a capture of these solid objects in each hole in each well; (iii) according to a specified after opening and closing sequence of movement of these holes each hole, so that each of the solid object to be transported into one kind of trapped in the array; (iv) moving the holes to arrange the probes immobilized in the array the next solid objects; and (v) repeating steps (i) to (iv), until a specified number of array are arranged with the probes fixed to solid articles filled therein.

在本方法的再一个实施方案中,此排列可以如下进行:(i)将固定了探针的固体物件放置在一个狭窄的管子中;(ii)用一种沿着此狭窄的管子流动的溶液一个接一个地移动此固体物件,从而将此固体物件转运到此列阵中,和(iii)重复步骤(i)和(ii),直至固定了探针的固体物件被按照指定的次序排列在此列阵中。 In a further embodiment of the method of the present embodiment, the arrangement may be as follows: (i) the solid object is fixed probe placed in a narrow tube; (ii) along with a solution flowing through this narrow tube moving one behind the solid objects, whereby this transport of the solid object in this array, and (iii) repeating steps (i) and (II), until the probe immobilized solid articles are arranged in the specified order. in this array.

此外,在一个实施方案中,排列可以如下进行:(i)将固定了探针的固体物件放置在节中,每一节含有单一类型的固定了探针的固体物件,每一个节具有一个可以为一个固体物件所通过的空穴,所说的空穴被关闭;(ii)在每一个节的每一个空穴中俘获这些固体物件中的一个;(iii)在按照一个指定的次序移动这些节之后打开和关闭每一个空穴,从而将被俘获的固体物件转运到一种沟槽中;(iv)重复步骤(i)到(iii),直到固定了探针的固体物件被按照次序排列在此沟槽中;和(v)将被排列的固定了探针的固体物件转运到一种列阵中,在该列阵中这些固体物件被紧密地排列在一起。 Further, in one embodiment, the arrangement may be as follows: (i) fixing the solid object is placed in the probe section, each section containing a fixed solid objects of a single type of probe, each section having a can a solid object is a hole through which said holes are closed; (ii) a capture object in the solids in each section of each hole; (iii) in the order in which movement of a specified after opening and closing sections of each hole, whereby the solid object to be captured in a trench-transported into; (iv) repeating steps (i) to (III), fixed to the solid object until the probes are arranged in the order in the trench; and (v) to be arranged fixed to the solid object to transport one kind of probe array, these solid articles are arranged closely together in the array.

在上文中,每一个实施方案可以展示上述优势效应之至少一种。 In the above, each of the above-described embodiment may display at least one advantage of the effect.

本发明可以被应用于其他方面,包括一种分析一种通过它的样品溶液的探针列阵,和各种生产一种探针列阵的装置。 The present invention may be applied to other aspects, one probe which comprises an analytical sample solution array, and producing a variety of probe arrays by means.

本发明将用以下实施例说明。 The present invention will be described by the following examples. 本发明的一种探针列阵可以一般地用DNA,蛋白质,肽或其他生物材料说明。 A probe array according to the present invention can be generally used DNA, proteins, peptides or other biological material described. 因此,在以下实施例中用DNA进行说明。 Thus, DNA used in this embodiment will be described below.

在根据本发明的一种DNA探针列阵中,固体探针被一维地容纳在一支毛细管中,或者二维地容纳在一个光学单元的一个小区域中。 A DNA probe array according to the present invention, a solid probe is housed in a capillary-dimensionally or two-dimensionally housed in a small area of ​​an optical unit. 为了说明的方便,在实施例中主要地使用了毛细管。 For convenience of description, in the examples mainly used capillary. 虽然在实施例中,圆珠子被用作精细颗粒,但是任何具有立方形或其他形状的颗粒都可以被使用。 Although in the embodiment, the ball is used as the sub-fine particles, but the particles have a cubic or any other shapes can be used. 可以使用具有1-300微米直径的珠子;然而,在实施例中主要地使用了具有20微米直径的珠子。 The beads may be used having a diameter of 300 microns; however, mainly used beads having a diameter of 20 micrometers in the examples. 进一步地,通常使用玻璃和塑料珠子;然而,诸如金的金属材料也可以被使用。 Further, glass and plastic beads is generally used; however, a metal material such as gold can also be used. 在这里使用塑料珠子。 Here the use of plastic beads.

[实施例1]图1说明了根据本发明的一种探针列阵的一个实例,其中数字101是一个溶液和样品的入口,102是一个出口,103是一支容纳探针列阵的毛细管,104是标记珠子,105是一个具有探针的珠子,而106是假珠子。 [Example 1] FIG. 1 illustrates, according to one example of a probe array according to the present invention, wherein numeral 101 is a solution and the sample inlet, an outlet 102, 103 is a receiving probe array capillary , is a marker beads 104, 105 is a probe having a bead, the bead 106 is false. 具有被固定的探针的珠子的直径是20微米,此毛细管103的内径是25微米。 Beads having a diameter of immobilized probes is 20 m, inner diameter of the capillary tube 103 is 25 microns. 在这个实施例中,在两端排列了大约20个假珠子106,并在它们之间排列了999个珠子105。 In this embodiment, the ends 20 are arranged around false beads 106, the beads 999 and 105 are arranged between them. 对于总共99个标记珠子和900个探针珠子,每隔10个珠子是一个黑色珠子104,并且每隔100个珠子是一个红色珠子,即,900个不同种类的探针可以同时被用于测试。 For a total of 99 labeled probe beads 900 and beads, beads every 10 bead 104 is a black, and every 100 red beads is a bead, i.e., 900 different types of probes may be used to test simultaneously . 如果被密集地装配,这些珠子可以被排列在2mm的长度内;然而,在这个实施例中,出于杂交和其他的考虑,这些珠子被更松散地装配,并被容纳在5mm的长度内。 If densely assembled, the beads may be arranged within the length of 2mm; however, in this embodiment, for hybridization, and other considerations, these beads are more loosely fitted, and is housed in a length of 5mm. 保留长度可以比上文描述的范围更长或更短(例如,在每1000个珠子2-10mm的范围内)。 Retention ratio described above, the length may be longer or shorter range (e.g., in the range of 2-10mm per 1,000 beads). 然而,虽然一个过长的长度增加了所需要的样品的量,但是一个过短的长度引起处理的问题。 However, while a long length increases the amount of sample required, but due to a too short length of the Problem. 而且,样品的杂交可能不充分。 Moreover, the hybrid sample may not be sufficient. 反应区域的体积是大约2.3nL。 Volume of the reaction zone is about 2.3nL. 塞子被放置在两端,从而防止珠子流出。 They are placed at both ends of the stopper, thereby preventing the beads from flowing out. 样品和洗涤液经由入口101和出口102引进和排放。 The introduction of the sample and the washing liquid and the discharge via inlet 102 and outlet 101. 因为多达10,000个探针可以被容纳在一个长度为20-30mm的区域内,该探针列阵紧密排列并且易于处理是有利的。 Since up to 10,000 probes can be accommodated in a length of 20-30mm in the region, the probe array are closely arranged and easy to handle is advantageous.

照射激光光束206和容纳探针的毛细管202被相对地扫描,并且使用一种荧光检测装置,例如,如同图2中所说明的一样,测量了所产生的荧光。 Irradiating a laser beam 206 and receiving probe 202 is relatively scanning the capillary, and the use of a fluorescence detecting apparatus, for example, the same as described in FIG. 2, the resulting fluorescence was measured. 在图2中,数字201是一种具有探针的珠子,202是一支容纳探针列阵的毛细管,203是一块移动探针列阵的平板,204是一个照射及发射点,205是一个透镜,206是一个照射激光光束,207是一个滤光器,208是一个透镜,209是一个激光光源,210是一个检测器,211是一个数据处理和检测器控制器,而212是一个指示器。 In FIG. 2, numeral 201 is a bead having a probe, the probe array 202 is receiving a capillary, moving the probe array 203 is a flat plate, and 204 is a transmission point illumination, 205 is a lens 206 is irradiated with a laser beam, 207 is a filter, 208 is a lens, 209 is a laser light source, a detector 210, 211 is a data processing and detector controller, and 212 is an indicator . 通过每10个珠子201放一个标记珠子的方式可很容易地识别不同的探针。 Put a mark bead 201 can easily recognize a manner different probes every 10 beads. 可将标记珠子染成不同的颜色,以识别不同的探针,或可选择地,将具有探针的10个珠子的每一组染成不同的颜色。 Labeled beads may be dyed different colors to identify different probes, or alternatively, each set having a probe 10 is dyed a different color beads. 当然,在这种情况下,将选择颜色,使其不具有影响荧光检测的波长。 Of course, in this case, the selected color, it does not affect the fluorescence having a wavelength of detection.

[实施例2]这个实施例涉及将珠子被按照预先确定的次序排列在一支毛细管中的一种方法和一种装置。 [Example 2] This embodiment relates to a method and an apparatus for the beads are arranged in a capillary in the order determined in advance embodiment. 图3a-3g说明一种制造此珠子列阵的装置的实例。 FIGS. 3a-3g illustrates an example of an apparatus of this bead array manufacturing. 在这些图中,数字301是一个溶液和珠子出口,302是一个溶液入口,303是一块覆盖平板,304是一个具有探针的珠子,305是俘获珠子,306是一支排列珠子的毛细管,307是一个支撑毛细管的基底,308是一个捕获珠子的空穴,309是一个供应珠子的管嘴,而310是一个塞子。 In these drawings, numeral 301 is a bead solution and an outlet, a solution inlet 302, a cover plate 303, 304 is a probe having beads, capture beads 305, 306 are arranged in a capillary bead 307 the support is a capillary substrate, 308 is a hole trapping beads, a nozzle 309 is supplied bead, and 310 is a plug. 为了说明的方便,在此实施例中珠子被排列在一支毛细管中;然而,为了实际使用,使用了在一种片层之上的多个空穴和多个毛细管。 For convenience of description, in this example embodiment the beads are arranged in a capillary; however, for practical use, a plurality of sheets one over the holes and a plurality of capillaries. 步骤1(图3a):用一种溶剂将具有第一种探针的珠子(探针珠子#1,304)引进覆盖平板303中,覆盖平板303在底部具有一个带空穴的片层311。 Step 1 (FIG. 3a): with a solvent having a first bead probe (probe # 1,304 beads) introduction cover plate 303, the cover plate 303 with a layer 311 having a sheet at the bottom of the hole. 这些珠子被沉淀,并且前后和左右移动溶剂,从而使这些俘获珠子305中的一个落入此空穴中。 The beads were precipitated, and the front-rear and left-right movement of the solvent, so that these beads capture a 305 falls in this cavity. 步骤2(图3b):用此溶剂302经由出口301去除剩余的珠子并洗涤之。 Step 2 (FIG. 3b): Use this solvent to remove the remaining 302 via the outlet 301 and the beads washed it. 只有落入此空穴的珠子仍然在此单元中。 Only beads fall into this hole remains in this cell. 在这个情形下,此溶剂可以被以直角吹出通道口外到达片层,从而去除这些接近通道口的珠子,并将一个珠子保留在此片层空穴中,从而在步骤3中被引进毛细管中。 In this case, the solvent may be at a right angle to reach the outlet passage extraoral sheet, thereby removing the proximity beads passage port, and a sheet beads remain in the cavity so as to be introduced in the capillary tube in step 3. 此空穴的底部被支撑毛细管的基底307封锁。 This is supported by the bottom of the hole 307 to block the capillary substrate. 排列珠子的毛细管被固定到此滑块上,但是在步骤1和2中,排列珠子的毛细管306和空穴不排成一行以致珠子305被保留在空穴中。 Capillary bead alignment is fixed to this slider, but in step 1 and 2, the arrangement of capillary holes 306 and the beads 305 are not aligned so that the beads are retained in the cavities. 步骤3(图3c):支撑毛细管的基底307和片层311被相对彼此地移动,从而将毛细管的轴和空穴排成一行。 Step 3 (FIG. 3c): the supporting substrate 307 and the capillary sheet 311 is moved relative to each other, so that the shaft and the hole of the capillary is arranged in a row. 通过从另一端吸入或者从溶液注射的一方施加压力将珠子(305)引进此毛细管中。 By suction or pressure is applied from the other end of the solution was injected from one of the beads (305) the introduction of this capillary. 在这个情形下,此滑块与此片层的相对运动是与此空穴的直径大约相同的数量级,对其成功地使用了一个压电元件。 In this case, the relative movement of the slider and the film layer is about the same as the diameter of the hole of this magnitude, its successful use of a piezoelectric element. 步骤4(图3d):此支撑毛细管的基底307和此片层311被相对地移动,以致此排列珠子的毛细管306和此捕获珠子的空穴308又脱离一条直线。 Step 4 (FIG. 3d): This capillary substrate support 307 and the film layer 311 are relatively moved, so that the beads are arranged in this hole 306 and the capillary 308 and this capture beads from a straight line. 步骤5(图3e):将具有第二种探针的珠子(探针珠子#2,320)引进覆盖平板303中,并且321中的一个落入此空穴中。 Step 5 (FIG. 3e): beads having a second probe (probe # 2,320 beads) introduction cover plates 303, 321 and a fall in this cavity. 步骤6(图3f):按照与步骤2同样的方式,从此单元中去除除了在此空穴中的珠子以外的多余珠子。 Step 6 (FIG. 3f): According to the same manner as in step 2, excess beads were removed from the beads in addition to the hole in this unit. 步骤7(图3g):此滑块和此片层被相对移动,从而将此毛细管的轴与此空穴排成一行,以致珠子(321)可以被引进此毛细管中。 Step 7 (FIG. 3g): This slider and the sheet is moved relative to this capillary hole aligned with this axis, so that the beads (321) may be introduced in this capillary. 结果,具有探针1的珠子(探针珠子1)和具有探针2的珠子(探针珠子2)在毛细管中被排成一行。 As a result, the probe 1 having a bead (probe beads 1) and having a bead (probe beads 2) the probes 2 are lined up in the capillary. 通过重复这些步骤,可以生产一种带有所需次序的探针的珠子列阵。 By repeating these steps, it is possible to produce a desired order of beads having a probe array.

在测量期间,在这里使用的毛细管可以被取出,并用作一种探针列阵容器,或者可以单独地制造一种将珠子列阵向其转运的探针容器并且将其连接到此毛细管的底部。 During the measurement, the capillary tube may be used herein removed and used as a probe array vessel, or may be separately manufactured A probe bead array containers transported thereto and connecting it to the bottom of the capillary . 在这个实施例中,使用了在图4a和4b中说明的探针列阵容器。 In this embodiment, a probe array of the container illustrated in Figures 4a and 4b. 在这些图中,数字401是一个具有容纳一个珠子列阵的沟槽的基底,402是一个溶液出口毛细管,403是一个珠子及各种溶液的入口,404是一个排列珠子的沟槽,405是一个具有探针的珠子,406是一个塞子,而407是一个上部的窗口。 In these drawings, numeral 401 is a bead array having a receiving groove of the substrate, a solution outlet capillary 402, a bead 403 is an inlet and various solutions, bead 404 is arranged in a trench, 405 beads having a probe, a plug 406, and 407 is a top of the window. 从此图的珠子及各种溶液的入口(403)注射一种样品溶液,在充分杂交之后,从溶液出口毛细管(402)注射一种洗涤液体,从而去除没有反应的样品部份。 FIG beads from the inlet and the various solutions (403) injecting a sample solution, after thorough hybridization, wash the liquid from the solution outlet capillary (402) injecting a, thereby removing the unreacted portion of the sample. 在将此探针列阵容器装配到一种测量装置之后,用一个激光光束照射每一个珠子并检测发射的荧光。 After the vessel is fitted into this array probe A measuring device, a laser beam is detected by each of the beads and fluorescence emission. 当然,除了激光光束照射所发射的荧光,还可以检测化学发光试剂所产生的发射光。 Of course, in addition to the fluorescence emitted laser beam is irradiated, light emission can also detect chemiluminescence generated. 可以使用任何能够检测杂交存在或不存在的检测方法。 It may be capable of detecting any hybridization method for detecting the presence or absence.

在这个实施例中,只用一支固定在此滑块上的毛细管来说明本发明;然而,可同时使用多根毛细管来生产大量探针列阵。 In this embodiment, the present invention will be described only with a capillary tube is fixed to the slider; however, a plurality of capillaries can be used simultaneously to produce large quantities of the probe array. 在这个情形下,自然可理解,此片层上的空穴的数量必须随毛细管数量增加一起增加。 In this case, naturally appreciated, the number of holes on this sheet must be increased together with the increase in the number of capillaries.

[实施例3] [Example 3]

这个实施例为了说明一种装置,其中珠子递送装置504具有分别保存各种珠子的空穴(或孔),从而将它们转运到一个在上面具有沟槽507的排列珠子的支撑基底512上,或转移到一支根据预先确定的次序将珠子排列成一种探针珠子列阵的毛细管中。 To illustrate this embodiment, an apparatus in which the beads were stored delivery device 504 having various bead hole (or holes), so as to transport them to a support base 512 having an upper bead arranged above the trench 507, or the sequence proceeds to a predetermined one probe beads arranged in a capillary bead array. 首先,将被放置在一块微量滴定板的孔中的含有不同种类探针珠子的溶液,按照预先确定的次序一个接一个地转运到珠子递送装置的指定的孔(空穴)中,从而将珠子排列于在一块平板中产生的一个沟槽中或一支毛细管中(图5a,5b,5c)。 Specified hole (hole) First, a hole will be placed in a microtiter plate in a solution containing different types of probes beads, in accordance with a predetermined order one by one to the transport of the beads in the delivery device so that the beads arranged in a groove produced in a plate or in a capillary (FIG. 5a, 5b, 5c). 在这些图中,数字501是一支吸液管/注射管,502是一块具有容纳探针珠子的孔503的滴定板,504是一种具有空穴的珠子递送装置,505是一个容纳被递送到一个沟槽的探针珠子的空穴,506是被排列的探针珠子,507是一个在其中各种探针珠子被排成一行的沟槽,508是一个探针珠子,509是被俘获在一个空穴中的一个探针珠子,510是一个压电元件,511是一个可以移动的阀,而512是一个支撑基底。 In these drawings, numeral 501 is a pipette / injection tube, 502 is a probe having a bore for receiving a bead plates 503, 504 is a hole having a bead delivery device 505 is receiving a delivered a trench hole probe beads, the probe beads 506 are arrayed, and 507 is a bead in which the various probes are arranged in a row in the groove, 508 is a probe bead 509 is captured a probe bead in a cavity, and a piezoelectric element 510, 511 is a movable valve, and 512 is a supporting substrate. 珠子被用吸液管501从滴定板502中的孔吸出,并移进一个转运孔505。 The bead is sucked from the pipette 501 in the microtiter plate wells out of 502 and 505 move into a transport hole. 俘获珠子的空穴520在孔的底部是开放的。 The base capture hole 520 beads of the hole is open. 这些被注射进孔505的珠子509中的一个(多个珠子,如果提供了多个空穴)落入空穴520中,并在光学上确认了所落入的珠子的存在。 These were injected into the bore 505 of a bead 509 (a plurality of beads, a plurality of holes if provided) fall into the hole 520, and confirmed the presence of beads fall optically. 此后,过量的珠子被回收或通过用洗涤液冲洗将珠子从孔中去除。 Thereafter, excess beads were recovered by washing with a washing solution or the beads were removed from the wells. 可为压电元件510所驱动的阀511或同类的东西被放置在俘获珠子的空穴520与沟槽507或此毛细管之间。 The piezoelectric element may be driven by a valve 511 or 510 something similar is placed between the beads trapped holes 520 or the trench 507 this capillary. 通过移动此阀,可以将一个珠子转运到沟槽或毛细管一边。 By moving the valve, it can be transferred to a bead groove or capillary tube side. 实际的珠子运动被一个液流所控制。 The actual movement of the beads is controlled by a flow. 当然,还可以通过珠子递送装置504转运珠子,从而将此空穴与此沟槽或此毛细管的中心排成一行。 Of course, the delivery device 504 may be transported through the beads Beads to this center hole with this groove or this aligned capillaries. 一旦此珠子被完全转运,将此阀移动回去,或者改变此空穴和此毛细管的相对位置,从而将此珠子俘获在此空穴中。 Once the beads were completely transported, this valve is moved back, or changing the relative position of this hole and this capillary, whereby this bead trapped in this cavity. 使用吸液管将具有下一个探针的珠子引进俘获位点。 Use a pipette probe having a bead introduction of the next trap site. 重复上面的步骤,从而生产一种珠子列阵。 Repeat the above steps to produce a bead array. 所产生的被排列的探针珠子506如同现在一样使用,或者将其转运到另一个容器中而同时保持此排列并用作一种探针列阵。 Probe beads are arranged in the generated 506 as now used, or be transferred to another vessel while maintaining this arrangement, and used as a probe array.

可在一个具有多个空穴的系统中实施以上步骤,从而节约列阵生产的时间,或者同时生产多个相同的列阵。 Above may be implemented in a system having a plurality of step holes, thereby saving the production time array, or a plurality of simultaneously produced in the same array.

[实施例4]在实施例2中,使用一种具有一个空穴的珠子递送装置,一次排列一种探针珠子。 [Example 4] In Example 2, using holes having a bead delivery device, once one probe beads are arranged. 在这个实施例中,使用在一种珠子递送装置的多个孔分段地容纳多个种类的探针珠子,从而改善生产率。 In this embodiment, a plurality of holes In one segmented bead delivery device receiving the plurality of types of probes to the beads, thereby improving productivity. 如图6中所示,将多个矩形孔603放置在旋转的圆盘601上。 As shown in FIG. 6, a plurality of rectangular holes 603 placed on the rotating disk 601. 在图6中,数字601是递送珠子的一种圆盘型的容纳珠子的平板,602是一个旋转的轴,603是一种容纳珠子的沟槽,而604是一个容纳珠子的空穴。 In FIG. 6, numeral 601 is a disk-shaped bead delivery of beads receiving plate, a shaft 602 is rotated, the bead 603 is a receiving groove, a hole and a bead 604 is received. 如同在实施例1的最后所描述的一样,每一个孔的底部与一个具有空穴的片层安装在一起。 As specified in the last-described embodiment 1, the bottom of each hole and having a hole in a sheet mounted together. 具有这些片层的旋转圆盘的下面的部分与一种支撑毛细管的滑块有接触,以免被俘获在这些空穴中的珠子落下。 The slider having the following rotary disk portions of these sheets with one contact supporting capillary, to avoid being trapped in these cavities beads fall. 当旋转圆盘被移动,并且,这些空穴与这些毛细管的轴被排成一行时,探针珠子被按照与在上文的实施例中所描述的相同的方式转运进毛细管。 When the rotating disk is moved, and the axes of these holes and are lined capillaries, probe beads are transported into the capillary according to the same manner as in the embodiment described above. 这些空穴的数量对应于这些毛细管的数量。 The number of these holes corresponds to the number of these capillaries. 这些空穴和这些毛细管被对应地安置;然而,为了预防一旦旋转产生扭曲,提供了一种控制机制,其此机制中使用一种与CD-ROMs所使用的相似的定位技术,按照此圆盘的轴602方向移动此具有毛细管的滑块。 These cavities and these capillaries are arranged in correspondence; however, in order to prevent rotation once twisted, there is provided a control mechanism, which in this positioning mechanism using a similar technique is used with CD-ROMs, in accordance with this disc this axial direction with the slider 602 capillaries. 在这个实施例中,使用了一块具有16cm直径的转板。 In this embodiment, the use of a rotating plate having a diameter of 16cm. 孔603(1mm宽,30mm长)被定位在离此圆盘的轴5cm的位置。 Aperture 603 (1mm wide, 30mm long) is positioned at a position away from the axis of this disc 5cm. 孔的间距是2mm,可以将大约150个孔放射状地安置在此圆盘上。 Hole pitch is 2mm, it may be about 150 holes radially arranged on this disc. 具有空穴的片层铺展在这些孔下面,而这些空穴的间距是2mm。 Spreading sheet having a hole in the holes below these holes and the spacing is 2mm. 在这个实施例中,排列了总共10个空穴,从而可以在10个毛细管中制造探针珠子列阵。 In this embodiment, a total of 10 holes are arranged, the probe beads can be manufactured in 10 capillary array. 当然,一次可以生产的毛细管的数量和探针列阵的数量可以按要求改变。 Of course, one can produce a number of capillary number and the probe array can be changed as required.

旋转平板按两种旋转方式旋转;一种高速旋转模式和一种低速但高度精确的旋转模式。 Rotation of the rotary plates rotatably in two; and a high-speed rotation mode in low speed but highly accurate rotation mode. 用一种溶液将珠子引进孔中。 Beads with a solution introduction hole. 通过移动圆盘并使溶液流出这些空穴,使这些珠子落入这些空穴中。 By moving the disc and the solution flow out the hole, so that these beads fall into these cavities. 下一步,通过高速旋转模式旋转此圆盘,通过离心力并通过水流将过量的珠子移动到位于这些孔的末端的珠子容器中。 Next, this high-speed rotation mode of the rotary disk, and the centrifugal force by the excess water beads at the end of the container is moved to the beads of these holes. 停止此圆盘,此后,将此圆盘旋转设定到高度精确的模式,从而将这些毛细管和探针珠子#1排成一行。 This disc, and thereafter, this rotation of the disc is set to a highly precise pattern, whereby the probes and beads these capillaries aligned # 1. 在此圆盘底部的一个活门被打开,并且使支撑毛细管的滑块与此旋转的平板接触,从而将携带探针珠子#2的孔移动到这些毛细管的位置。 A shutter is opened at the bottom of the disk and the slider support with this capillary contact with the rotating plate, so that the beads carrying the probe hole # 2 moves to a position such capillaries. 这些珠子被按顺序地转运进这些毛细管,从而按照指定的次序生产探针珠子列阵。 The beads are sequentially transported into the capillary, thereby producing a probe array of beads in the order specified. 通过交换此圆盘或要被放置在这些孔中的探针珠子,以及重复以上所描述的步骤,可以排列大量的探针珠子并将其容纳在毛细管中。 By this exchange the disc or to be placed in the holes of the probe beads, and repeating the step described above, a large number of probe beads can be arranged and accommodated in the capillary. 通过每隔10个珠子即改变此列阵中珠子的颜色,可以常规地确定一个特定探针在一个所产生的探针珠子列阵中的位置。 I.e., every 10 beads by changing the color of this array of beads, can be routinely determined position of the probe array a bead in a particular probe in the generated.

[实施例5]这个实施例涉及使用一种液流将探针珠子一个接一个地按照指定的次序排列进一支毛细管中的一种方法和一种装置。 A method and a device in a capillary tube [Example 5] This embodiment relates to the use of a flow probe beads arranged one behind into the specified order. 图7所示为这个实施例的理论图。 FIG theory embodiment shown in Fig. 7 for this embodiment. 在这张图中,数字701是一种珠子溶液储存器,702是一种具有探针的珠子,703是一种转运管,704是一个鞘形流动池,705是一种转移液体,706是一个用于转移的毛细管,707是一种用于珠阵列排列的毛细管;708是一种支撑基体,和709是一种溶液出口管。 In this figure, numeral 701 is a bead solution reservoir 702 is a probe having a bead, a feed pipe 703, 704 is a sheath flow cell shape, 705 is a transfer of a liquid, with a 706 the transfer capillary, the capillary for bead 707 is arranged in an array; 708 is a support base, 709 is a solution, and an outlet pipe. 具有探针的珠子702被泵入转移毛细管707。 Beads having a probe 702 is pumped into the capillary 707 transferred. 该毛细管的端部被插入到用转移液体705在鞘形流动池704中形成的液流中,并且这些珠子被一个接一个地释放进液流中,并且其间隔基本上恒定。 An end portion of the capillary tube 705 is inserted into the stream formed by the transfer of liquid form the sheath flow cell 704, and the beads are released one by one into the fluid stream and which is substantially constant interval. 但是,为了使释放稳定,对装有这些珠子的毛细管部分使用超声波,从而沿着毛细管的轴形成结节。 However, in order to release the stability of the capillary portion using ultrasonic waves with the beads, thereby forming nodules along the capillary axis. 通过控制诸如超声波强度等条件使这些珠子一个接一个地以指定的间隔释放进液流中。 By controlling the conditions such as the intensity of ultrasonic waves to make the beads one by one at a specified interval released into the stream.

[实施例6]在上述实施例中,一个珠子相应于一种探针。 [Example 6] In the above embodiment, one probe corresponding to a bead. 但是,为了检查杂交反应的均一性或者为了改善检测灵敏度,对于一种探针可使用多个珠子。 However, in order to check the uniformity of the hybridization reaction or, to improve the detection sensitivity, one probe may be used for a plurality of beads. 但不需要所有的探针使用同等数目的珠子。 But need not all use the same number of probe beads. 但是,如果在毛细管中用于制作探针阵列的数目不同,在具有不同的探针作为标记的珠子组之间必须插入彩色的珠子或者不同大小的珠子。 However, if a different number for making the probe array in the capillary, the beads have different bead sets labeled as a probe between the colored beads must be inserted or different sizes. 该实施例示于图8。 The embodiment illustrated in Figure 8. 在该图中,数字801是一个大尺寸假珠,802是一个探针珠子,803是一个大尺寸标记珠子,804是一个用于容纳探针的毛细管,并且805是一个样品流径。 In the figure, numeral 801 is a large size fake beads, bead 802 is a probe, 803 is a large size marker beads, 804 is a capillary tube for receiving the probe, and 805 is a sample flow path. 用于生产的设备基本上与上述相同,只是孔的大小比珠子802的尺寸大几倍,从而使多个珠子802可陷于该孔中。 The apparatus for producing substantially the same as described above, except that the pore size several times larger than the size of the beads 802, 802 such that the plurality of beads may be trapped in the hole. 随后的步骤与上述相同。 Subsequent steps are the same as described above.

进一步地,如果使用在实施例5中所描述的液体流动系统,可以容易地制造本实施例中的珠子列阵。 Further, if the liquid flow system used in Example 5 described embodiment can be easily manufactured embodiment of the present embodiment in the beads array. 用一个吸液管从一个珠子储存器吸出少量的珠子,并将其注射进此液流。 A pipette with a bead from a small amount of beads reservoir and injected into this stream. 虽然该数目无法证实,可以将所注射的珠子顺序地放进此毛细管804中。 Although this number can not be confirmed, the beads can be injected sequentially into this capillary 804. 在注射另一种珠子之前,注射作为标记物的一个有色珠子或一个不同大小(801)的珠子,从而可以确定个体珠子的位置和探针的类型。 Prior to the injection of another bead, a colored bead as injection marker or a different size (801) beads, which can determine the type and location of the individual beads probe.

[实施例7]前面的实施例是一种生产在其中探针珠子被排列在一支毛细管中的一种探针列阵的方法。 [Example 7] The foregoing embodiment is a method for producing one of the probes in the probe beads are arranged in an array of capillaries. 正如在图9a和9b中所说明的一样,这个实施例公开了一种方法和一种装置,在其中首先将珠子排列于一个在一块平板表面上产生的沟槽中,此后将其聚集成一个探针列阵或者将其转运进一支毛细管,从而生产一种探针列阵。 As in Figures 9a and 9b as explained, this embodiment discloses a method and an apparatus in which the beads are arranged in a first groove in a plate produced on the surface, after which aggregated into one probe array or a capillary tube to transport into, thereby producing a probe array. 在图9a和9b中,数字901是一块具有孔的平板,902是一个珠子储存器的一个孔。 In Figures 9a and 9b, numeral 901 is a flat plate having an aperture, a hole 902 is a bead reservoir. 903是一个容纳珠子的空穴,904是一个具有空穴的片层并且通常连接到平板901,905是一个具有排列珠子的沟槽的基础列阵生产支持物,906是一个排列探针珠子的精细沟槽,907是一个具有探针的珠子,908是一个珠子列阵的毛细管。 Receiving hole 903 is a bead, a hole 904 is a slice and typically is connected to the base plates 901,905 having a groove aligned array production of beads support, the probe 906 is arranged in a bead Narrow trench 907 is a bead having a probe, 908 is a capillary bead array. 首先,制备一种在一块平板表面上具有多个沟槽906的珠子列阵生产支持物905。 First, trenches 906 having a plurality of beads in an array on the surface of the production of the support plate 905. 在每一个沟槽中排列具有探针的珠子907,并将它们转运进一种毛细管908或者同类的东西,同时维持它们的排列,此后,将排列在多个沟槽中的珠子引进不同的毛细管中,并用作一种探针列阵。 Beads having probes are arranged in each of the grooves 907 and 908 are transported into the capillary one kind or something similar, while maintaining their alignment, after which the beads are arranged in a plurality of trenches introduce different capillaries and used as one probe array. 将一块与一种具有空穴(901,904)的片层连接在一起的平板放置在珠子列阵生产支持物的顶部,其中这些珠子被俘获在这些空穴中,并将其转运进上文描述的沟槽中。 The plate with one having a cavity (901, 904) connecting together the sheets placed on top of the bead array production support, wherein the beads are trapped in these cavities, and transport it into the above trenches described. 正如图9中所说明的一样,这个具有一种片层的平板具有正交于在珠子列阵生产支持物上的沟槽的孔(珠子储存器902),并且容纳珠子的空穴903是直通空穴,并对此精细沟槽打开。 As illustrated in Figure 9, this one having one sheet of flat plate having a hole (bead reservoir 902) orthogonal to the array of the grooves produced in the support beads, and the beads 903 are received through holes hole, and this fine grooves opened. 此装置的确具有多个沟槽,但是具有不同探针的珠子被注射进此平板上不同的孔中,并被容纳在不同的空穴中。 This apparatus has a plurality of grooves does, but having beads of different probes are injected into separate wells on this plate, and is housed in a different cavity. 使用此与一种片层连接在一起的平板和此具有沟槽的平板,它们紧密接触,但可以彼此滑动。 Using this plate is connected together with one sheet and this plate has grooves, their close contact, but it can slide on each other. 在开始的时候,此片层的空穴903和珠子列阵生产支持物的沟槽906不排成一行。 In the beginning, the hole 903 and the bead array production of this sheet support groove 906 are not aligned. 将具有探针的珠子供应到在具有每一种探针的空穴的片层之上的平板的不同的孔902中。 Beads having different probe supplied to wells of the plates 902 on each sheet having a hole in the probe. 一个珠子落进一个空穴中并被保留在那里,因为在这个状态,此空穴的底部被关闭。 A bead falls into a cavity and retained there, because in this state, the bottom of this hole is closed. 当此片层的空穴和此珠子列阵生产支持物的沟槽被排成一行时,珠子一个接一个地从个体空穴落入沟槽906中。 When the hole in this layer, and the film production support beads array trenches are lined up one behind the beads fall into the trench hole 906 from an individual. 因为不同的珠子列阵从不同的位置落入一个沟槽中,所以各种珠子被保留在一个沟槽中。 Because different beads fall into a groove in the array from different positions, so that the various beads are retained in a groove. 实际上这些珠子被按照与珠子储存器902内的那些珠子相同的间隔放置在具有空穴的片层上。 In fact the beads are placed on a sheet having holes in the same intervals as those of beads within the bead 902 of the reservoir. 在这个实施例中,此间隔是2mm。 In this embodiment, this spacing is 2mm. 在这个实施例中,将总共50个珠子落入此珠子列阵生产支持物的每一个沟槽中。 Each groove in this embodiment, a total of 50 beads fall within this bead array production of the support. 同样,在这个实施例中可以同时生产10珠子列阵,但是这个数目可以按需要增加。 Also in this embodiment the bead array 10 may be produced simultaneously, but this number may be increased as needed. 在落下这些珠子之后,移动此具有空穴903的片层的位置和此珠子列阵生产支持物的沟槽906,从而密封这些沟槽,此后用一种液流将这些珠子引进此毛细管908中。 After dropping the beads, with this movement and the position of the sheet 903 of this hole bead array production support groove 906 to seal the trenches, after which the beads in a liquid stream introducing this capillary 908 . 通过重复以上描述的步骤,可以排列不同种类的探针的数量。 By repeating the above described steps, the number of probes may be arranged in different species.

在这个实施例中,公开了一个一维排列的探针珠子列阵;然而,自然地,通过安排多个数量的这些列阵或通过二维排列这些列阵,可以生产具有更多种探针的探针列阵。 In this embodiment, there is disclosed a probe beads arranged in a one-dimensional array; however, naturally, by arranging a plurality of such arrays, or by the number of the arrays arranged two-dimensionally, can produce more probes the probe array.

[实施例8]在这个实施例中,一种探针珠子列阵支持物包括这些由一块具有一维或二维分布空穴的平板和一个盖玻片组成的单元。 [Example 8] In this embodiment, one probe array support comprises beads of these plates having a one or two dimensional distribution of the holes and the unit composed of a coverslip. 在图10a,10b和10c中,数字1001是一块微量滴定板型的珠子列阵支持物,1002是一个间隔物,1003是制造一种具有一块盖玻片的珠子列阵单元的一个空穴,1004是一个具有探针的珠子,1005是一块盖玻片,1006是一个溶液出口,1007是一个溶液入口,1008是一个激光光束,1009是一个透镜,而1010是一个检测器。 In FIG. 10a, 10b and 10c, the numeral 1001 is a microtiter plate-type bead support array, a spacer 1002, a hole 1003 is a coverslip producing a beads array unit having, 1004 is a probe having a bead, a cover glass 1005, 1006 is an outlet for the solution, a solution inlet 1007, 1008 is a laser beam, a lens 1009, and 1010 is a detector. 这类似一块微量滴定板。 This is similar to a microtiter plate. 从在其中容纳探针珠子的一块滴定板吸入小量的珠子,并将它们分配到平板1001的空穴(单元)1003中。 From a titer plate in which the receiving suction probe beads small beads, and assign them to a hole plate 1001 (unit) 1003. 根据探针的种类将珠子1004分配到位于指定位置的空穴中,从而生产一种微量滴定板型的具有探针珠子的珠子列阵。 Depending on the type of probe beads 1004 assigned to the specified position in the cavity, the probe beads to produce beads having a microtiter plate array type. 在珠子被分配之后,将光学透明并且不干扰荧光或化学发光的测量的盖玻片1005放置在顶部,从而生产一种单元列阵。 After the beads were allocated, optically clear and does not interfere with the fluorescence or chemiluminescence measured coverslips 1005 is placed on top, thereby producing a cell array. 在盖玻片与壁之间分割微量滴定板型单元列阵的单元的间隔,小于珠子的尺寸,以致珠子不能够向外移出。 Dividing the interval microtiter plate type cell array between the glass and the wall of the unit, it is smaller than the size of the beads so that the beads can not be shifted out. 反应溶液或同类的东西可以自由地流过这些单元。 The reaction solution or something similar may flow freely through these units. 为了使用,将这些单元颠倒,从而使此玻璃侧向下。 For use, these units is reversed, so that the lower side of this glass. 在这个情形下,在玻璃表面上的珠子不依赖于这些单元的深度与反应溶液充分地接触,而这些探针与靶进行杂交。 In this case, the glass beads on the surface does not depend on the depth of the reaction solution sufficient contact with these units, and these probe and the target for hybridization.

[发明效果]如上所描述,根据本发明,通过一个简单的程序可以生产大量的肽或DNA探针列阵。 [Effect of the Invention] As described above, according to the present invention, by a simple procedure can produce large amounts of peptide or DNA probe arrays. 在一种固体的表面固定探针的过程和排列探针的过程是分开的,从而这两个过程都可以被优化。 In the process a solid surface of the fixed probe arrangement and process of the probe are separated, so that the two processes can be optimized. 结果,可以生产均一的并且不容易从此固体表面去除的被固定的探针,此后,通过将珠子按照指定的次序排列,可以容易地生产一种具有所需要种类的探针的列阵。 As a result, uniform and not easily produced from the immobilized probe by removing a solid surface and thereafter, the beads are arranged in the order specified, it can be easily produce a probe array having a desired species. 同样,一种精细的探针列阵——这是难于通过常规方法制造的——可以通过减小这些珠子的大小生产。 Also a fine probe array - which is difficult to fabricate by conventional methods - by reducing the size of the beads produced. 可以简单地通过制备所需要的DNA探针,将它们固定在珠子的表面上,并将这些探针珠子安装到一种生产装置上,生产一种具有新成分的探针列阵,这样,任何时间都可以提供使用者所要求的列阵。 By simply preparing the desired DNA probe, they are fixed on the surface of the beads and the beads to install probes producing device, to produce a probe array having a new composition, so that any time can provide array required by the user. 通过排列多个数量的携带相同探针的珠子,可以获得统计平均值以分析重复性和定量性,并可以进行可靠的测量。 By arranging a plurality of beads carrying the same number of probes, a statistical average can be obtained in quantitative analysis and reproducibility, and can be reliably measured. 而且,此反应是快速而高度敏感的,因为反应的表面区域大于被保留在一块平板上的常规DNA芯片或同类的东西的表面。 Further, this reaction is fast and highly sensitive, since the surface area of ​​the reaction is more than the conventional DNA chip retained or something similar surface on a plate. 这些珠子的大小可以在1微米到30微米之间改变,从而,如果需要的话,可以容易地生产高密度探针列阵。 The size of these beads may vary between 1 to 30 microns, so that, if desired, can easily produce a high density probe array. 例如,通过使用6-微米珠子,可以在一支毛细管中将1,500个探针排列在10-mm的长度上,或者如果使用二维探针列阵支持物,就可以将超过1,000,000个探针保留在一个1cm2的区域上。 For example, by using 6-micron beads, may be arranged on a 10-mm length in 1,500 will be a capillary probe, or if a two-dimensional array probe support, can be retained over 1,000,000 probes in a region of 1cm2.

通过一个极其简单的过程,可以生产多个数量的具有相同的探针排列的列阵,因此,这些列阵也适于批量生产。 By a very simple process, it can produce a plurality of arrays having the same number of probe arrangement, therefore, these arrays are also suitable for mass production.

本领域中的那些技术人员将会理解,可以做许多和各种修饰而不背离本发明的精神。 Those skilled in the art will appreciate that, you can do many and various modifications without departing from the spirit of the invention. 因此,应该清楚地理解,本发明的各种形式仅仅是说明性的,而不是用来限制本发明的范围。 Thus, it should be clearly understood that the forms of the invention are merely illustrative and are not intended to limit the scope of the invention.

Claims (1)

1.一种生产一种探针列阵的方法,包括如下步骤:选择多种类型的感兴趣的探针;将此多种类型的探针固定在不同的固体物件表面上;和将此固定了探针的固体物件按指定的顺序排列,从而获得一种分析通过它的样品溶液的探针列阵,其中每一个固体物件有一种类型的探针固定在其上,并且为每一种类型的探针制备指定数量的固体物件,和其中排列是通过如下步骤进行的:(i)将固定了探针的固体物件放置在孔中,每一个孔含有单一类型的固定了探针的固体物件,每一个孔具有一个可以为一个固体物件所通过的空穴,所说的空穴被关闭;(ii)在每一个孔的每一个空穴中俘获这些固体物件中的一个;(iii)按照指定的次序移动这些孔之后,打开和关闭每一个空穴,从而将每一个被俘获的固体物件转运到一个列阵中;(iv)移动这些孔,从而在下一个列阵中排列 CLAIMS 1. A method of producing a probe array, comprising the steps of: selecting a plurality of types of the probe of interest; this plurality of types of probes are immobilized on different solid object surface; and this fixed solid objects probe arranged in the order specified, so as to obtain an analytical probe by its array of sample solution, wherein each solid object has a type of probe fixed thereto, and for each type probe prepared specified number of solid objects, and wherein the alignment is performed by the following steps: (i) fixing the solid object is placed in the bore of the probe, each well containing the immobilized solid objects of a single type of probe , each well having a solid object may be a hole through which said holes are closed; (ii) a capture of these solid objects in each hole in each well; (iii) in accordance with specified order after the movement of these holes, the opening and closing of each hole, so that each of the captured solid was transported into an array of objects; (iv) moving the holes are arranged so that the next array 定了探针的固体物件;并且(v)重复步骤(i)到(iv),直到用其中固定了探针的固体物件填充了一个指定数量的列阵。 Solid objects set probe; and (v) repeating steps (i) to (iv), until a specified number of filled array of solid objects with which the probe is fixed.
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