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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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Publication number
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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CN
China
Prior art keywords
probe
pearl
hole
solid articles
array
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Expired - Fee Related
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CN 00806177
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Chinese (zh)
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CN1347329A (en
Inventor
神原英记
三桥将人
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Hitachi Ltd
Resonac Corp
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Hitachi Chemical Co Ltd
Hitachi Ltd
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Publication of CN1347329A publication Critical patent/CN1347329A/en
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/02—Burettes; Pipettes
    • B01L3/0289—Apparatus for withdrawing or distributing predetermined quantities of fluid
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00457—Dispensing or evacuation of the solid phase support
    • B01J2219/00459—Beads
    • B01J2219/00468—Beads by manipulation of individual beads
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
    • B01L2200/0668—Trapping microscopic beads
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0819—Microarrays; Biochips
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/06—Valves, specific forms thereof
    • B01L2400/0633—Valves, specific forms thereof with moving parts
    • B01L2400/065—Valves, specific forms thereof with moving parts sliding valves
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers 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
    • B01L3/502761—Containers 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N2035/00178—Special arrangements of analysers
    • G01N2035/00237—Handling microquantities of analyte, e.g. microvalves, capillary networks

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dispersion Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)

Abstract

The use of probe arrays in which probes of various biological substances such as DNA are immobilized on the surface of a solid is becoming established as an effective means for high-speed screening. Different kinds of probes, such as DNA, are immobilized on the surface of a multiple number of independently treatable fine particles, such as beads, instead of the surface of a single solid, and the resulting beads are aligned in a capillary or a cell in a designated order. The size of the area where one probe is immobilized is reduced. The bead probe array is characterized in that such small beads are aligned one by one in a designated manner using a sheet with holes, and one or a multiple number of beads are held in the holes and then transferred to a probe array holder such as a capillary.

Description

Use fine granular to produce the method for the probe arrays of biomaterial
Background of invention
Invention field
The present invention relates at detection of peptides, protein and DNA, diagnosis and analysis comprise the probe arrays that uses in the biomaterial of DNA; With the method and apparatus of producing same probe arrays.
Description of related art
For DNA analysis or DNA tests or diagnosis, the separation of the amplification of miniprep dna, the dna fragmentation that is amplified and evaluation and other process are essential.PCR (polymerase chain reaction) is widely used in DNA cloning, thus wherein indivisible DNA can be amplified several orders of magnitude can be detected.On the other hand,, in the middle of other method, used a kind of dna sequencing instrument and fragment analysis instrument, wherein united gel electrophoresis and fluoroscopic examination for separation and the detection of different DNA.Yet, because the quantity of sample or test event increases, the electrophoresis labour intensive in the extreme that becomes.Therefore, a kind of simple method of dna probe of using just attracts much attention, particularly a kind of DNA chip, make a kind of and sample on a kind of solid surface and hybridize thereby wherein many kind of probes are fixed on, after this have only special DNA to be captured on this solid surface and detected probe arrays (Nature Medicine 2,753,1996).
This probe in detecting method also is used to protein or polypeptide or analysis various and their interactional biomaterials, and a kind of peptide chips corresponding to the DNA chip is used now.This separation and detection method that a kind of therein peptide or DNA are fixed on a kind of solid surface and hybridize between this peptide or DNA and a kind of sample, be called as a kind of trace method for a long time, wherein target DNA or similar thing use radio-labeling by a kind of probe that is fixed on the film and detected.Yet a large amount of probes can be fixed on an a kind of pocket (1cm of the solid surface such as glass or siloxanes on the DNA chip 2) on, the DNA chip has only needs sample in a small amount, and can use the advantage of a large amount of different probes simultaneously.The method of producing the DNA chip roughly is divided into two groups.In first group, dna probe is a kind of substrate of synthetic, is by at the little sections (0.05mm of a kind of solid at every turn 2To 0.2mm 2) on a kind of photochemical reaction, use to be same as photomadking technology (Science 251,767, the 1991) synthetic that is used for semi-conductor or similar thing.In second group, for each sections of individual probe, a kind of DNA that is synthesized, the DNA of PCR-amplification, perhaps the DNA that obtains by the clone is fixed on the little sections on a kind of solid surface (Nature Biotech 16,27,1998).The latter has the advantage that peptide chips with needed probe or DNA chip can relatively easily be made, and is the method that many startups company is selected.
Summary of the invention
A kind of probe chip of biomaterial comprises DNA, is used as a kind of testing tool by high expectations.Yet with regard to actual, following condition must satisfy: (A) can make a large amount of different chip in a small amount at low cost, (B) a kind of probe can be fixed equably; (C) data are highly repeatably, and this chip can be used again; And (D) this chip can be heated, thereby removes by the material of non-specific adsorption.Yet problem still exists: for example, (a) probe is inconsistent from a sections to another sections, and it is labour-intensive (b) producing, and (c) the very fine segmentation of immobilization is impossible, and (d) probe is inhomogeneous; Because (i) they are that to be fixed on a kind of solid as drop lip-deep, and (ii) probe is placed simultaneously and fixes.And (d) combination faintly of solid surface and heating in a single day can be removed therewith, because (iii) many probe chips are fixed by absorption or similar effect.
In order to solve the above problems, probe fixing on solid surface can be divided into two or more different steps with the arrangement of these probes, thereby can produce uniform dna probe on this solid surface.Probe can be fixed via heat stable covalent linkage, therefore, can suitably be removed by heating by the material of non-specific adsorption.Arrangement is used as the solid fine granular of stationary probe on it, thereby produces a kind of probe arrays with sections of appropriate size.The fine granular that any probe arrays of wanting can be arranged by exchange and easily producing with these probes.Tweezers can be used to arrange the fine granular of the diameter with about 0.3mm, but this method will be difficult for the particle that has less than the diameter of 0.1mm.Therefore, in one embodiment, the invention provides a kind of method and a kind of device of producing a kind of probe arrays, wherein a kapillary is transported and be arranged in to each fine granular that all is housed inside in the meticulous hole on a kind of lamella, in groove on the one flat plate or the similar thing.In a method of selecting fully, the control fine granular makes it flow to a kind of liquid being transported in the kapillary as individual particles, thereby produces a kind of probe arrays.And in order to improve the repeatability of measurement, for each probe has been arranged a plurality of fine granulars with a plurality of probes, thereby any variation of checkout result is to obtain data highly reliably.
For the purpose of the advantage of the technology formerly of being better than summarizing the present invention and obtained, specific purpose of the present invention and advantage are described hereinbefore.Certainly, be appreciated that any particular not necessarily according to the present invention can obtain all such purpose or advantages.Therefore, for example, those skilled in the art will admit that the present invention can be specialized on the meaning as a kind of advantage of being instructed or advantage set in acquisition or optimization to be implemented in other words here, and other purposes or advantage that not necessarily acquisition here may be instructed or quilt is hinted.
From following detailed description of the preferred embodiments, further aspect of the present invention, feature and advantage will become apparent.
The accompanying drawing summary
With reference to the accompanying drawing that is intended to illustrate rather than limit the preferred embodiments of the invention, these and other features of the present invention will be described now.
Fig. 1 is a kind of theoretical diagram that comprises the probe arrays chip that is arranged on the pearl with probe in the kapillary.
Fig. 2 is a kind of a kind of theoretical diagram that is retained in the detection system of the pearl array with probe in a kapillary or the similar thing of measuring.
Fig. 3 a-3g is a kind of segmentation sectional view of arranging the device of pearl.Fig. 3 a is a theoretical diagram of importing pearl with off-line state into.Fig. 3 b is that one of them pearl is captured on a theoretical diagram in the hole.Fig. 3 c is the just theoretical diagram in kapillary of shift-in or similar thing of one of them pearl.Fig. 3 d-3g illustrates this consecutive steps.
Fig. 4 a and 4b are a kind of theoretical diagram of device of groove-shaped arrangement pearl.Fig. 4 a is a skeleton view.Fig. 4 b is a sectional view.
Fig. 5 a, 5b and 5c are a kind of theoretical diagram of using groove and a kind of transportable valve to produce a kind of method of pearl array.Fig. 5 c is the cross section partial view.
Fig. 6 is a kind of theoretical diagram of system of transhipment probe ball of collar plate shape.
Fig. 7 is a kind of theoretical diagram of pearl array production method of liquid flow pattern.
Fig. 8 is a theoretical diagram of separating a kind of pearl array of a large amount of pearls therein with the mark pearl.
Fig. 9 a and 9b a kind ofly use a kind of lamella with hole to arrange the theoretical diagram of the method for probe ball.
Figure 10 a, 10b and 10c are a kind of theoretical diagram of pearl array container of microtitration template.
Figure 10 a is a general view.Figure 10 b is a sectional view.Figure 10 c is the theoretical diagram of measuring.
Detailed description of the preferred embodiments
The present invention includes several aspects and embodiment.In one aspect, a kind of method of producing a kind of probe arrays comprises the following steps: that (a) selects interested a few types probe; (b) respectively with this a few types probe stationary on the surface of different solid articles; And (c) arrange the solid articles that these have fixed probe, thereby obtain to analyze a kind of probe arrays by its a kind of sample solution according to a kind of specified order.Hereinbefore, probe can be polynucleotide, peptide or protein.In one embodiment, these solid articles are possible be the pearl of fine granular.Further, the arrangement of these solid articles can be that a kind of one dimension is arranged or a kind of two-dimensional arrangements.In another embodiment, this method comprises that also the solid articles with the thing that serves as a mark is placed in this arrangement according to specified interval.These marks can have the size that is different from the solid articles with probe.In one embodiment, each solid articles has a kind of type probes to be fixed thereon, and has prepared the solid articles of a specified quantity for the each type probe.In addition, the arrangement of these solid articles can be carried out in the array of groove and optical unit at a kind of kapillary that is selected from.
In an embodiment of present method, the arrangement of solid articles can followingly be carried out: the solid articles that (i) will fix probe is placed on a kind of lamella of hole, can pass through a solid articles in the described hole, said lamella is placed in the transportable substrate with a straight-through hole of leading to this array inside, and the hole that said transportable substrate is placed on this lamella is the place that do not communicate, the straight-through hole of transportable substrate therewith; (ii) in the hole of this lamella, capture in these solid articles; (iii) from then on lamella is removed remaining solid articles; The hole that (iii) this transportable substrate is moved to this lamella is a place communicating, the straight-through hole of transportable substrate therewith; (iv) this captive solid articles is transported to this array through leading directly to the hole thus; And (v) repeating step (i) is to (iv) being arranged in this array according to specified order until the solid articles of having fixed probe.
In another embodiment of present method, arrangement can followingly be carried out: the solid articles that (i) will fix probe is placed on a kind of lamella with hole, can pass through a solid articles in the described hole, the inside of this array is led in said hole, and said hole is closed with a valve; (ii) in the hole of this lamella, capture in these solid articles; Thereby (iii) open this valve captive solid articles is transported to this array; (iv) repeating step (i) is arranged in kapillary until the solid articles of having fixed probe according to specified order, in groove or the optical unit to (iii).
In another embodiment of present method, arrangement can followingly be carried out: the solid articles of (i) these having been fixed probe is placed in the hole, fixing of single type contained in each hole solid articles of probe, each hole has one can be a hole that solid articles passed through, and said hole is closed; (ii) in each hole in each hole, capture in these solid articles; (iii) after moving these holes, open and close each hole, be transported in a kind of array thereby each is captured solid articles according to a specified order; (iv) move these holes, fixed the solid articles of probe thereby in next array, arrange these; (v) repeating step (i) is to (iv), until using the solid articles of having fixed probe that is arranged in wherein to fill the array of a specified quantity.
In another embodiment of present method, this arrangement can followingly be carried out: the solid articles that (i) will fix probe is placed in the narrow pipe; (ii) move this solid articles one by one along this narrow pipe mobile solution with a kind of, thereby this solid articles is transported in this array, (iii) repeating step (i) and (ii) is arranged in this array according to specified order until the solid articles of having fixed probe.
In addition, in one embodiment, arrangement can followingly be carried out: the solid articles that (i) will fix probe is placed in the joint, each joint has contained fixing of the single type solid articles of probe, each joint has one can be a hole that solid articles passed through, and said hole is closed; (ii) in each hole of each joint, capture in these solid articles; (iii) move these joints according to a specified order after, open and close each hole, thereby captive solid articles is transported in a kind of groove; (iv) repeating step (i) is arranged in this groove according to order up to the solid articles of having fixed probe to (iii); (solid articles of having fixed probe that v) will be arranged is transported in a kind of array, and these solid articles are closely arranged in together in this array.
Hereinbefore, each embodiment can be showed at least a of above-mentioned advantageous effect.
The present invention can be applied to other aspects, comprises a kind of a kind of probe arrays of the sample solution by it and device of a kind of probe arrays of various productions analyzed.
The present invention will be with following embodiment explanation.A kind of probe arrays of the present invention can usually be used DNA, protein, peptide or the explanation of other biological material.Therefore, in following examples, describe with DNA.
In a kind of dna probe array according to the present invention, the solid probe is contained in the kapillary one-dimensionally, perhaps is contained in two-dimensionally in the zonule of an optical unit.For the convenience that illustrates, mainly used kapillary in an embodiment.Though in an embodiment, ball is used as fine granular, and any particle with cube or other shapes can be used.Can use pearl with 1-300 micron diameter; Yet, mainly used pearl in an embodiment with 20 micron diameters.Further, use glass and plastics pearl usually; Yet, also can be used such as the metallic substance of gold.Use the plastics pearl here.
[embodiment 1]
Fig. 1 has illustrated an example according to a kind of probe arrays of the present invention, and wherein numeral 101 is inlets of solution and sample, and 102 is outlets, 103 is kapillaries that hold probe arrays, the 104th, the mark pearl, 105 is the pearls with probe, and 106 is false pearls.Diameter with pearl of the probe that is fixed is 20 microns, and the internal diameter of this kapillary 103 is 25 microns.In this embodiment, arranged about 20 false pearls 106 at two ends, and between them, arranged 999 pearls 105.For 99 mark pearls and 900 probe ball altogether, are black pearls 104 every 10 pearls, and are red pearls that promptly, 900 different types of probes can be used to test simultaneously every 100 pearls.If assembled thick and fast, these pearls can be arranged in the length of 2mm; Yet, in this embodiment, for hybridization and other consideration, these more loosely assemblings of pearls quilt, and be accommodated in the length of 5mm.Keeping length can longer or shorter than above-described scope (for example, in the scope of per 1000 pearl 2-10mm).Yet though long length has increased the amount of needed sample, a too short length causes the problem of processing.And the hybridization of sample may be insufficient.The volume of conversion zone is about 2.3nL.Stopper is placed on two ends, thereby prevents that pearl from flowing out.Sample and washings are introduced and discharging via inlet 101 and outlet 102.Because nearly can be accommodated in a length be in the zone of 20-30mm to 10,000 probes, this probe arrays is closely arranged and is easy to handle is favourable.
Irradiating laser light beam 206 is relatively scanned with the kapillary 202 that holds probe, and uses a kind of fluorescence detection device, for example, as illustrated in fig. 2, has measured the fluorescence that is produced.In Fig. 2, numeral 201 is a kind of pearls with probe, and 202 is kapillaries that hold probe arrays, 203 is flat boards of a traveling probe array, 204 is an irradiation and launching site, and 205 is lens, and 206 is irradiating laser light beams, 207 is spectral filters, 208 is lens, and 209 is LASER Light Source, and 210 is detectors, 211 is that data are handled and the detector controller, and 212 are telltales.The mode of putting a mark pearl by per 10 pearls 201 can be discerned different probes at an easy rate.The mark pearl can be dyed distinct colors, discerning different probes, or selectively, each group that will have 10 pearls of probe is dyed distinct colors.Certainly, in this case, will select color, and make it not have the wavelength that influences fluoroscopic examination.
[embodiment 2]
This embodiment relates to pearl is arranged in a kind of method and a kind of device in the kapillary according to predetermined order.Fig. 3 a-3g illustrates a kind of example of making the device of this pearl array.In these figure, numeral 301 is solution and pearl outlet, 302 is solution inlets, and 303 are one covers flat board, and 304 is the pearls with probe, the 305th, capture pearl, 306 is kapillaries of arranging pearl, and 307 are one supports substrate capillaceous, and 308 is holes of catching pearl, 309 is ozzles of a supply pearl, and 310 are stoppers.For the convenience that illustrates, pearl is arranged in the kapillary in this embodiment; Yet, use for reality, used a plurality of holes and a plurality of kapillary on a kind of lamella.Step 1 (Fig. 3 a): introduce and cover in dull and stereotyped 303, covers dull and stereotyped 303 lamellas 311 that have a band hole in the bottom by the pearl (probe ball #1,304) that will have first kind of probe with a kind of solvent.These pearls are precipitated, and front and back and move left and right solvent, thereby that these are captured in the pearl 305 falls into this hole.Step 2 (Fig. 3 b): remove remaining pearl and wash it via outlet 301 with this solvent 302.The pearl that only falls into this hole is still at this element.Under this situation, this solvent can be blown out with the right angle arrives lamella outside the porthole, thereby removes these pearls near the porthole, and a pearl is retained in this lamella hole, thereby is introduced in the kapillary in step 3.The supported substrate 307 capillaceous in the bottom in this hole is blocked.The kapillary of arranging pearl is fixed on this slide block, but in step 1 and 2, arranges the kapillary 306 of pearl and the hole is not in line so that pearl 305 is retained in the hole.Step 3 (Fig. 3 c): support substrate 307 capillaceous and lamella 311 and moved relative to each other, thereby axle capillaceous and hole are in line.By sucking from the other end or exerting pressure pearl (305) is introduced this kapillary from a side of injection of solution.Under this situation, this slide block relative movement of lamella therewith is the about identical order of magnitude of diameter in hole therewith, and it has successfully been used a piezoelectric element.Step 4 (Fig. 3 d): this supports substrate 307 capillaceous and this lamella 311 is relatively moved, so that this kapillary 306 and this hole 308 of catching pearl of arranging pearl break away from straight line again.Step 5 (Fig. 3 e): the pearl (probe ball #2,320) that will have second kind of probe introduce to cover in dull and stereotyped 303, and in 321 one falls into this hole.Step 6 (Fig. 3 f):, from this element, remove the unnecessary pearl except the pearl in this hole according to the mode same with step 2.Step 7 (Fig. 3 g): this slide block and this lamella are relatively moved, thereby this axle capillaceous is in line in the hole therewith, so that pearl (321) can be introduced in this kapillary.As a result, the pearl (probe ball 2) that has the pearl (probe ball 1) of probe 1 and have a probe 2 is in line in kapillary.By repeating these steps, can produce a kind of pearl array that has the probe of required order.
During measuring, here the kapillary of Shi Yonging can be removed, and as a kind of probe arrays container, perhaps can make individually a kind of with the pearl array to the probe container of its transhipment and be connected to this bottom capillaceous.In this embodiment, used the probe arrays container that in Fig. 4 a and 4b, illustrates.In these figure, numeral 401 is the substrates with the groove that holds a pearl array, 402 is taphole kapillaries, 403 is inlets of a pearl and various solution, 404 is grooves of arranging pearl, 405 is the pearls with probe, and 406 is stoppers, and 407 is the windows on a top.From then on the inlet of the pearl of figure and various solution (403) is injected a kind of sample solution, after fully hybridizing, injects a kind of washing liq from taphole kapillary (402), thereby removes responseless sample partly.After this probe arrays container is assembled to a kind of measuring apparatus, with each pearl of laser beam irradiation and detect emitted fluorescence.Certainly, except laser beam irradiation institute emitted fluorescence, can also detect the emission light that chemical illuminating reagent produces.Can use any can detection to hybridize existence or non-existent detection method.
In this embodiment, only the present invention is described with a kapillary that is fixed on this slide block; Yet, can use many capillaries to produce a large amount of probe arrays simultaneously.Under this situation, nature can be understood, and the quantity in the hole on this lamella must increase with the number of capillaries increase.
[embodiment 3]
This embodiment is in order to illustrate a kind of device, wherein pearl delivery apparatus 504 has the hole (or hole) of preserving various pearls respectively, thereby they are transported on the support base 512 of an arrangement pearl that has groove 507 in the above, or transfer to one and pearl is arranged in a kind of kapillary of probe ball array according to predetermined order.At first, with the solution that contains the different sorts probe ball that is placed in the hole of a microtiter plate, be transported to one by one according to predetermined order in the specified hole (hole) of pearl delivery apparatus, thereby pearl is arranged in the groove that in one flat plate, produces or kapillary in (Fig. 5 a, 5b, 5c).In these figure, numeral 501 is pipette/syringes, 502 is the titer plates with the hole 503 that holds probe ball, the 504th, a kind of pearl delivery apparatus with hole, 505 is holes that hold the probe ball that is delivered to a groove, the 506th, the probe ball that is arranged, 507 is the grooves that various therein probe ball are in line, 508 is probe ball, the 509th, be captured on a probe ball in the hole, 510 is piezoelectric elements, and 511 is transportable valves, and 512 is support base.Pearl is used the hole sucking-off of pipette 501 from titer plate 502, and a transhipment of shift-in hole 505.The hole 520 of capturing pearl is open in the bottom in hole.These one (a plurality of pearls are if provide a plurality of holes) that are injected in the pearl 509 in hole 505 fall into hole 520, and have optically confirmed the existence of the pearl that fallen into.After this, excessive pearl is recovered or by washing with washings pearl is removed from the hole.Can be valve 511 or the similar thing that piezoelectric element 510 driven is placed between the hole 520 and groove 507 or this kapillary of capturing pearl.By moving this valve, a pearl can be transported to groove or kapillary on one side.Actual pearl motion is controlled by a liquid stream.Certainly, can also be by pearl delivery apparatus 504 transhipment pearls, thus groove or this center capillaceous are in line therewith with this hole.In case this pearl is transported fully, this valve is moved back, perhaps change this hole and this relative position capillaceous, thereby this pearl is trapped in this hole.The pearl that uses pipette will have next probe is introduced capture site.Step above repeating, thus a kind of pearl array produced.The probe ball that is arranged 506 that is produced is as using now, perhaps it is transported in another container and keeps this arrangement simultaneously and as a kind of probe arrays.
Can in a system with a plurality of holes, implement above step, thereby save the time that array is produced, perhaps produce a plurality of identical arrays simultaneously.
[embodiment 4]
In embodiment 2, use a kind of pearl delivery apparatus with a hole, once arrange a kind of probe ball.In this embodiment, use and hold the probe ball of a plurality of kinds, thereby improve productivity in a kind of piecewise, a plurality of hole of pearl delivery apparatus.As shown in Figure 6, a plurality of rectangular openings 603 are placed on the disk 601 of rotation.In Fig. 6, numeral 601 is flat boards that hold pearl of sending a kind of collar plate shape of pearl, and 602 is axles of a rotation, the 603rd, and a kind of groove that holds pearl, and 604 are holes that hold pearl.Last described as at embodiment 1, the bottom in each hole and the lamella with hole are installed together.Following part with rotating-disk of these lamellas contacts with a kind of support slide block capillaceous, in order to avoid the pearl that is captured in these holes falls.When rotating-disk is moved, and when these holes and these axles capillaceous were in line, probe ball was by according to transporting into kapillary with the identical mode described in embodiment above.The quantity in these holes is corresponding to these quantity capillaceous.These holes and these kapillaries are settled accordingly; Yet, in case, provide a kind of controlling mechanism, use a kind of and the employed similar location technology of CD-ROMs in its this mechanism in order to prevent rotation to produce distortion, move this according to 602 direction of this disk and have slide block capillaceous.In this embodiment, used a flap with 16cm diameter.Hole 603 (1mm is wide, and 30mm is long) is positioned in the position from the axle 5cm of this disk.The spacing in hole is 2mm, about 150 holes can be placed on this disk radially.Lamella with hole spreads over below these holes, and the spacing in these holes is 2mm.In this embodiment, arrange 10 holes altogether, thereby can in 10 kapillaries, make the probe ball array.Certainly, the quantity capillaceous that once can produce and the quantity of probe arrays can change on request.
Rotating Plates is by two kinds of rotation mode rotations; A kind of high speed rotating pattern and a kind of low speed but highly accurate rotary mode.With a kind of solution pearl is introduced in the hole.By mobile disk and make solution flow out these holes, make these pearls fall into these holes.Next step rotates this disk by the high speed rotating pattern, by centrifugal force and by current excessive pearl is moved into place in the pearl container of the end in these holes.Stop this disk, after this, this disk rotation is set to highly accurate pattern, thereby these kapillaries and probe ball #1 are in line.A valve in this disk bottom is opened, and the flat board contact that support slide block capillaceous is rotated therewith, thereby the hole that will carry probe ball #2 moves to these positions capillaceous.These pearls are transported these kapillaries according to priority, thereby according to specified order production probe ball array.Maybe to be placed on probe ball in these holes by exchanging this disk, and repeat step described above, can arrange a large amount of probe ball and it is contained in the kapillary.By promptly change the color of pearl in this array every 10 pearls, can determine the position of a particular probe in a probe ball array that is produced routinely.
[embodiment 5]
This embodiment relates to and uses a kind of liquid stream that probe ball is arranged into a kind of method and a kind of device in the kapillary according to specified order one by one.Figure 7 shows that the theoretical diagram of this embodiment.In this figure, numeral 701 is a kind of pearl solution holders, the 702nd, and a kind of pearl with probe, the 703rd, a kind of transhipment pipe, 704 is sheath shape flow cells, the 705th, a kind of transfer liquid, 706 is kapillaries that are used to shift, the 707th, and a kind of kapillary that is used for the pearl arrayed; The 708th, a kind of support substrate and 709 is a kind of taphole pipes.Pearl 702 with probe is pumped to and shifts kapillary 707.This end capillaceous is inserted in the liquid stream that forms in sheath shape flow cell 704 with transfer liquid 705, and these pearls are discharged in the feed liquor stream one by one, and its interval substantially constant.But, stablize in order to make to discharge, the capillary portion that these pearls are housed is used ultrasonic wave, thereby form tubercle along axle capillaceous.By control such as conditions such as ultrasonic intensity these pearls are discharged in the feed liquor stream one by one with specified interval.
[embodiment 6]
In the above-described embodiments, a pearl is corresponding to a kind of probe.But,, can use a plurality of pearls for a kind of probe for the homogeneity of checking hybridization or in order to improve detection sensitivity.But do not need all probes to use the pearl of equal number.But,, have the pearl that must insert chromatic pearl or different sizes between the pearl group that different probes serves as a mark if in kapillary, be used to make the number difference of probe array.This embodiment is shown in Fig. 8.In the figure, numeral 801 is the false pearls of a large size, and 802 is probe ball, and 803 is large size mark pearls, and 804 is kapillaries that are used to hold probe, and 805 is sample flow paths.The equipment that is used to produce is same as described above basically, and just the size in hole is than big several times of the size of pearl 802, thereby a plurality of pearls 802 can be sunk in this hole.Step subsequently is same as described above.
Further, if the liquid flow system of use described in embodiment 5 can easily be made the pearl array in the present embodiment.From a spot of pearl of pearl holder sucking-off, and it is injected into this liquid stream with a pipette.Though this number can't confirm, the pearl of being injected sequentially can be put in this kapillary 804.Before the another kind of pearl of injection, inject a coloured pearl of the thing that serves as a mark or the pearl of different big or small (801), thereby can determine the position of individual pearl and the type of probe.
[embodiment 7]
The embodiment of front be a kind of production therein probe ball be arranged on the method for an a kind of probe arrays in the kapillary.As illustrated the same in Fig. 9 a and 9b, this embodiment discloses a kind of method and a kind of device, at first pearl is arranged in the groove that on the one flat plate surface, produces therein, after this it is gathered into a probe arrays or it is transported into kapillary, thereby produce a kind of probe arrays.In Fig. 9 a and 9b, numeral 901 is tool foraminous flat boards, and 902 is holes of a pearl holder.903 is holes that hold pearl, 904 are one has the lamella in hole and is typically connected to dull and stereotyped 901,905 is that a basic array with groove of arranging pearl is produced upholder, 906 is meticulous grooves of arranging probe ball, 907 is the pearls with probe, and 908 is kapillaries of a pearl array.At first, a kind of pearl array that has a plurality of grooves 906 on the one flat plate surface of preparation is produced upholder 905.In each groove, arrange pearl 907 with probe, and they are transported into a kind of kapillary 908 or similar thing, keep their arrangement simultaneously, after this, the pearl that is arranged in a plurality of grooves is introduced in the different kapillaries, and as a kind of probe arrays.A flat board that links together with a kind of lamella with hole (901,904) is placed on the top that the pearl array is produced upholder, and wherein these pearls are captured in these holes, and it is transported in the into above-described groove.As illustrated in fig. 9, this flat board with a kind of lamella has and is orthogonal to the hole (pearl holder 902) that produces the groove on the upholder in the pearl array, and the hole 903 that holds pearl is straight-through holes, and this meticulous groove is opened.This device has a plurality of grooves really, but the pearl with different probe is injected into this dull and stereotyped going up in the different holes, and is accommodated in the different holes.The flat board that uses this and a kind of lamella to link together has the flat board of groove with this, and they closely contact, but can slide over each other.At first, the groove 906 that the hole 903 of this lamella and pearl array are produced upholder is not in line.The pearl that will have probe is fed in the different hole 902 of the flat board on the lamella in the hole with each probe.Pearl is dropped in the hole and is retained in the there, because at this state, the bottom in this hole is closed.When the groove of producing upholder when the hole of this lamella and this pearl array was in line, pearl fell into groove 906 from individual hole one by one.Because different pearl arrays falls into a groove from different positions, various pearl is retained in the groove.In fact these pearls by according to pearl holder 902 in those pearl identical distance be placed on the lamella with hole.In this embodiment, this is 2mm at interval.In this embodiment, 50 pearls are altogether fallen into each groove that this pearl array is produced upholder.Equally, can produce 10 pearl arrays simultaneously in this embodiment, but this number can increase on demand.After falling these pearls, move position and this pearl array of this lamella and produce the groove 906 of upholder, thereby seal these grooves with hole 903, after this these pearls are introduced in this kapillary 908 with a kind of liquid stream.By repeating step described above, the quantity that can arrange different types of probe.
In this embodiment, a probe ball array that one dimension is arranged is disclosed; Yet naturally, these arrays by arranging a plurality of quantity or by these arrays of two-dimensional arrangements can be produced the probe arrays with more kinds of probes.
[embodiment 8]
In this embodiment, a kind of probe ball array upholder comprises that these are by a flat board and the unit that cover glass is formed with one dimension or bivariate distribution hole.At Figure 10 a, among 10b and the 10c, numeral 1001 is pearl array upholders of a microtitration template, and 1002 is spacers, the 1003rd, make a kind of unitary hole of pearl array with a cover glass, 1004 is the pearls with probe, and 1005 is cover glasses, and 1006 is tapholes, 1007 is solution inlets, 1008 is laser beams, and 1009 is lens, and 1010 is detectors.This similar microtiter plate.Suck pearl in a small amount from a titer plate that holds probe ball therein, and they are assigned in the hole (unit) 1003 of flat board 1001.Kind according to probe is assigned to the hole that is arranged in specified location with pearl 1004, thereby produces a kind of pearl array with probe ball of microtitration template.After pearl is assigned with, with optical clear and do not disturb the cover glass 1005 of fluorescence or chemiluminescent measurement to be placed on the top, thereby produce a kind of unit array.The unitary interval of cutting apart microtitration template cell columns battle array between cover glass and wall, less than the size of pearl, so that pearl can not outwards shift out.Reaction soln or similar thing can freely flow through these unit.In order to use, these unit to be put upside down, thereby made this glass side downward.Under this situation, the pearl on glass surface does not rely on these unitary degree of depth and contacts fully with reaction soln, and these probes and target are hybridized.
[invention effect]
As described above, according to the present invention, can produce a large amount of peptides or dna probe array by a simple program.Separate in the process of a kind of solid surface stationary probe and the process of arrangement probe, thereby these two processes can be optimised.As a result, can produce homogeneous and the probe that is fixed that be not easy solid surface removal from then on, after this,, can easily produce a kind of array with probe of required kind by pearl is arranged according to specified order.Equally, a kind of meticulous probe arrays---this is difficult to make by ordinary method---can be by reducing the big small-scale production of these pearls.Can be simply by the needed dna probe of preparation, they are fixed on the surface of pearl, and these probe ball are installed on a kind of production equipment, produce a kind of probe arrays with new constituent, can provide the user desired array like this, any time.By arranging the pearl that carries same probe of a plurality of quantity, can obtain statistical average value analyzing repeatability and quantitative property, and can measure reliably.And this reaction is quick and extremely sensitive, because the reacted surface zone is greater than being retained in the conventional DNA chip on the one flat plate or the surface of similar thing.The size of these pearls can change between 1 micron to 30 microns, thereby, if necessary, can easily produce the high-density probe array.For example,, can in a kapillary, 1,500 probe be arranged on the length of 10-mm,, just can be retained in a 1cm surpassing 1,000,000 probe if perhaps use two-dimentional probe arrays upholder by using 6-micron pearl 2The zone on.
By an extremely simple process, can produce the array that the identical probe of having of a plurality of quantity is arranged, therefore, these arrays also are suitable for producing in batches.
Those technician in this area will be understood that, can do many and various modifications and do not deviate from spirit of the present invention.Therefore, should be expressly understood that various forms of the present invention only is illustrative, rather than is used for limiting the scope of the invention.

Claims (1)

1. a method of producing a kind of probe arrays comprises the steps:
Select polytype interested probe;
With this polytype probe stationary on different solid articles surfaces; With
This solid articles of having fixed probe is arranged by named order, thereby is obtained the probe arrays of a kind of analysis by its sample solution,
Wherein each solid articles have one type probe stationary thereon, and for the probe of each type prepare specified quantity solid articles and
Wherein arrange and carry out as follows: the solid articles that (i) will fix probe is placed in the hole, fixing of single type contained in each hole solid articles of probe, each hole has one can be a hole that solid articles passed through, and said hole is closed; (ii) in each hole in each hole, capture in these solid articles; (iii) move after these holes, open and close each hole, thereby each captive solid articles is transported in the array according to specified order; (iv) move these holes, thereby in next array, arrange the solid articles of having fixed probe; And (v) repeating step (i) is to (iv), up to the array of having filled a specified quantity with the solid articles of wherein having fixed probe.
CN 00806177 1999-04-12 2000-04-11 Method for producing probe arrays for biological materials using fine particles Expired - Fee Related CN1245520C (en)

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Families Citing this family (70)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001004628A (en) * 1999-06-18 2001-01-12 Kanagawa Acad Of Sci & Technol Immune analyzer and immunoassay method
US6432290B1 (en) 1999-11-26 2002-08-13 The Governors Of The University Of Alberta Apparatus and method for trapping bead based reagents within microfluidic analysis systems
US6267884B1 (en) * 2000-01-04 2001-07-31 Waters Investments Limited Capillary columns employing monodispersed particles
US20030153006A1 (en) * 2000-05-22 2003-08-14 Masao Washizu Novel method for forming polymer pattern
JP2002186480A (en) * 2000-12-22 2002-07-02 Hitachi Software Eng Co Ltd Beads
EP1486786B1 (en) 2002-03-15 2008-10-15 Sony Corporation Bio-assay substrate and method
JP3593525B2 (en) 2002-04-19 2004-11-24 株式会社日立製作所 Fine particle array manufacturing method and apparatus
DE60326228D1 (en) * 2002-05-08 2009-04-02 Panasonic Corp BIOMOLECULAR SUBSTRATE AND TEST DEVICE
US20040126875A1 (en) * 2002-09-12 2004-07-01 Putnam Martin A. Assay stick
US7164533B2 (en) * 2003-01-22 2007-01-16 Cyvera Corporation Hybrid random bead/chip based microarray
WO2004024328A1 (en) * 2002-09-12 2004-03-25 Cyvera Corporation Method and apparatus for aligning elongated microbeads in order to interrogate the same
EP1594694A4 (en) 2002-12-30 2010-01-20 Univ California METHODS AND APPARATUS FOR DETECTION AND ANALYSIS OF PATHOGENIC AGENTS
JP4180964B2 (en) 2003-04-18 2008-11-12 日立ソフトウエアエンジニアリング株式会社 Bead array structure, manufacturing method thereof, and bead array method of capillary bead array
JP3711988B2 (en) * 2003-05-12 2005-11-02 株式会社日立製作所 Fine particle array analysis system, fine particle array kit, and chemical analysis method
JP4049713B2 (en) 2003-06-27 2008-02-20 株式会社日立製作所 Bead array chip manufacturing apparatus and manufacturing method
SE0301945D0 (en) * 2003-06-30 2003-06-30 Gyros Ab Confidence determination
JP2005046121A (en) * 2003-07-31 2005-02-24 Japan Science & Technology Agency On-chip bioassay method and kit
AT414047B (en) * 2003-09-16 2006-08-15 Upper Austrian Res Gmbh Arrangement for binding molecules, e.g. useful in fluorescence microscopy studies, comprises individual functional groups or multiple identical functional groups arranged on a solid support at a defined density
JP2005114576A (en) * 2003-10-08 2005-04-28 Hitachi Software Eng Co Ltd Amphipathic molecule-fixed bead, its manufacturing method, and bead-arraying method of capillary bead array
US7799553B2 (en) * 2004-06-01 2010-09-21 The Regents Of The University Of California Microfabricated integrated DNA analysis system
JP4427411B2 (en) * 2004-07-28 2010-03-10 日立ソフトウエアエンジニアリング株式会社 Bead array device and bead array method
JP2006058195A (en) 2004-08-23 2006-03-02 Alps Electric Co Ltd Inspection plate and inspection method using same
JP4279754B2 (en) * 2004-09-13 2009-06-17 アルプス電気株式会社 Plate and inspection method using the plate
EP1794581A2 (en) 2004-09-15 2007-06-13 Microchip Biotechnologies, Inc. Microfluidic devices
JP4263154B2 (en) * 2004-09-30 2009-05-13 日立ソフトウエアエンジニアリング株式会社 Functional fine particle array and method of using the same
US8445265B2 (en) 2004-10-06 2013-05-21 Universal Bio Research Co., Ltd. Reaction vessel and reaction controller
WO2006055736A1 (en) 2004-11-16 2006-05-26 Illumina, Inc. And methods and apparatus for reading coded microbeads
WO2006062236A1 (en) 2004-12-10 2006-06-15 Universal Bio Research Co., Ltd. Chip having biosubstance immobilization region hermetically sealed therein, biosubstance immobilization region treating apparatus and method of treatment
JP4776549B2 (en) * 2004-12-10 2011-09-21 ユニバーサル・バイオ・リサーチ株式会社 Biological material fixed carrier enclosing chip, biological material fixed carrier processing apparatus and processing method therefor
EP1835020A4 (en) 2005-01-07 2011-06-15 Universal Bio Research Co Ltd Carrier enclosing chip, carrier treating apparatus and method of carrier treatment
JP4520359B2 (en) * 2005-05-13 2010-08-04 日立ソフトウエアエンジニアリング株式会社 Particle capturing device, particle arranging method and particle arranging device
JP4655088B2 (en) * 2005-05-20 2011-03-23 日立化成工業株式会社 Analysis method of biochemical substances
JP4520361B2 (en) * 2005-05-25 2010-08-04 日立ソフトウエアエンジニアリング株式会社 Probe bead quality inspection method
CN102830241B (en) 2005-09-05 2015-06-17 环球生物研究株式会社 Various substances holder treating apparatus and method of mentioned treatment
JP4711125B2 (en) * 2005-09-27 2011-06-29 横河電機株式会社 Biochip, biochip reader, and biochip reader method
WO2007057989A1 (en) * 2005-11-16 2007-05-24 Hitachi, Ltd. Method of liquid droplet formation and transport, apparatus therefor and particle manipulating apparatus
KR20080096567A (en) 2006-02-03 2008-10-30 마이크로칩 바이오테크놀로지스, 인크. Microfluidic devices
JP2007248318A (en) * 2006-03-17 2007-09-27 Hokkaido Univ Biosensor array
US7766033B2 (en) 2006-03-22 2010-08-03 The Regents Of The University Of California Multiplexed latching valves for microfluidic devices and processors
JP5531374B2 (en) * 2006-03-23 2014-06-25 日立化成株式会社 Microfluidic device and manufacturing method thereof
US7830575B2 (en) 2006-04-10 2010-11-09 Illumina, Inc. Optical scanner with improved scan time
JP4721958B2 (en) * 2006-06-09 2011-07-13 株式会社日立ソリューションズ Bead chip plate
JP5122091B2 (en) 2006-06-13 2013-01-16 ユニバーサル・バイオ・リサーチ株式会社 Carrier-enclosed deformed container, carrier-enclosed deformed container processing apparatus, and carrier-enclosed deformed container processing method
WO2008034102A2 (en) 2006-09-15 2008-03-20 Haemonetics Corporation Surface mapping by optical manipulation of particles in relation to a functionalized surface
WO2008052138A2 (en) 2006-10-25 2008-05-02 The Regents Of The University Of California Inline-injection microdevice and microfabricated integrated dna analysis system using same
CA2966901C (en) * 2006-11-06 2021-08-17 Clondiag Gmbh Assays using binding members and reporter compounds
WO2009015296A1 (en) 2007-07-24 2009-01-29 The Regents Of The University Of California Microfabricated dropley generator
CN101990516B (en) 2008-01-22 2015-09-09 英特基因有限公司 Multiplex sample preparation system and the use in integrated analysis system thereof
US9040463B2 (en) 2008-12-23 2015-05-26 Mycartis Nv Assay device and method for performing biological assays
EP2384429A1 (en) 2008-12-31 2011-11-09 Integenx Inc. Instrument with microfluidic chip
WO2010141326A1 (en) 2009-06-02 2010-12-09 Integenx Inc. Fluidic devices with diaphragm valves
SG176669A1 (en) 2009-06-05 2012-01-30 Integenx Inc Universal sample preparation system and use in an integrated analysis system
JP2010284101A (en) * 2009-06-11 2010-12-24 Hitachi High-Technologies Corp Reactor vessel, parallel processing apparatus and sequencer
US9523701B2 (en) 2009-07-29 2016-12-20 Dynex Technologies, Inc. Sample plate systems and methods
GB0913258D0 (en) * 2009-07-29 2009-09-02 Dynex Technologies Inc Reagent dispenser
US8584703B2 (en) 2009-12-01 2013-11-19 Integenx Inc. Device with diaphragm valve
US8512538B2 (en) 2010-05-28 2013-08-20 Integenx Inc. Capillary electrophoresis device
WO2012024657A1 (en) 2010-08-20 2012-02-23 IntegenX, Inc. Microfluidic devices with mechanically-sealed diaphragm valves
US9121058B2 (en) 2010-08-20 2015-09-01 Integenx Inc. Linear valve arrays
EP2484447A1 (en) * 2011-02-07 2012-08-08 Biocartis SA Improved encoded microcarriers, assay system using them and method for performing an assay
JP5899908B2 (en) * 2011-12-26 2016-04-06 株式会社Ｊｖｃケンウッド Sample analysis disc
US20150136604A1 (en) 2011-10-21 2015-05-21 Integenx Inc. Sample preparation, processing and analysis systems
US10865440B2 (en) 2011-10-21 2020-12-15 IntegenX, Inc. Sample preparation, processing and analysis systems
JP5354621B2 (en) * 2011-12-27 2013-11-27 一般財団法人生産技術研究奨励会 Microbead array method and array device
JP2013150567A (en) * 2012-01-25 2013-08-08 Hitachi High-Technologies Corp Reaction device for nucleic acid analysis, and nucleic acid analyzing device
JP6195840B2 (en) 2012-10-22 2017-09-13 ユニバーサル・バイオ・リサーチ株式会社 Analysis method and analysis kit for simultaneously detecting or quantifying multiple types of target substances
WO2015073999A1 (en) 2013-11-18 2015-05-21 Integenx Inc. Cartridges and instruments for sample analysis
GB2544198B (en) 2014-05-21 2021-01-13 Integenx Inc Fluidic cartridge with valve mechanism
US10690627B2 (en) 2014-10-22 2020-06-23 IntegenX, Inc. Systems and methods for sample preparation, processing and analysis
WO2018069056A1 (en) 2016-10-12 2018-04-19 Mycartis N.V. Prefilled cartridge

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3563140B2 (en) * 1995-01-19 2004-09-08 株式会社日立製作所 Capillary array electrophoresis device
JP3467995B2 (en) * 1996-11-28 2003-11-17 株式会社日立製作所 Capillary electrophoresis device
JP2001515216A (en) * 1997-08-13 2001-09-18 シーフィード Microstructure for manipulating fluid samples
ATE401415T1 (en) * 1997-12-22 2008-08-15 Hitachi Chemical Co Ltd DIRECT RT-PCR ON MICROTITER PLATES WITH IMMOBILIZED OLIGONUCLEOTIDE

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