CN104263631A - Microarray system - Google Patents
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- CN104263631A CN104263631A CN201410430953.1A CN201410430953A CN104263631A CN 104263631 A CN104263631 A CN 104263631A CN 201410430953 A CN201410430953 A CN 201410430953A CN 104263631 A CN104263631 A CN 104263631A
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- B01L2300/0654—Lenses; Optical fibres
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- B01L2300/069—Absorbents; Gels to retain a fluid
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- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
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- B01L7/52—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples
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Abstract
The invention discloses a microarray system. The microarray system comprises microarrays formed on a flat substrate and incubation chambers formed around the microarrays. Each incubation chamber comprises a plurality of internal surfaces including a bottom surface and a top surface, the microarrays are formed on the bottom surface, and the top surface is roughly parallel to the bottom surface and faces the bottom surface. At least one surface of the plurality of internal surfaces is hydrophilic.
Description
Technical field
The art is microarray system, particularly has the microarray system of the camera incubata connected with check valve and/or waste liquid chamber.
Background
Microarray provides the very large possibility of the complex analyses implementing sample by carrying out Multiple detection reaction simultaneously.Usually, the microarray of the multiple spot of reactant molecule is formed in the planar substrates of such as glass microscope slide, normally two-dimensional grid pattern.Then, liquid sample and reagent are applied to slide glass to contact multiple spot simultaneously.Multiple reactions steps can be carried out with the binding molecule in microarray, comprise and combine reactants molecule is exposed to described liquid sample and reagent, and washing step.Can the progress of the reaction of each point in monitoring micro-array or result, object characterizes to be fixed on the one or more material on slide glass or the one or more materials in liquid sample.
Microarray analysis needs the incubation period from several minutes to a few hours usually.Time length of incubation period is depended on and detects and determined by many factors, the type of such as reactant, degree of mixing, sample volume, target copy number and array density.In incubation period, the target molecule in liquid sample must with micro probe array close contact.Hatch and normally carry out in camera incubata.Camera incubata normally by forming pad and being formed around microarray.Pad cover plate covers to form closed room.Cover plate can be made up of the transparent material of such as glass, thus allows the optical challenge of hatching rear microarray.
If cover plate does not have admission port and relief outlet, liquid sample and other reagent need to add camera incubata to before top cover plate being placed in pad.If reaction mixture is filled into the edge of pad, reaction mixture may spill from the side of pad, jeopardizes pad/lid and seals and the risk increasing contaminate environment.The cover plate with the hole for filling and discharging overcomes this two problems.But filling camera incubata by the hole on cover plate has risk bubble or air pocket being introduced camera incubata usually.In addition, the surface tension of liquid sample or reaction mixture also may stop liquid sample or reaction mixture to fill camera incubata completely.The room that is full of of part can cause false negative, if air pocket covers array point and stop the contact between array point and liquid sample or reaction mixture.
General introduction
Disclose microarray system.Described microarray system comprises formation microarray on a planar base and the camera incubata be formed in around described microarray.Described camera incubata has the multiple interior surface comprising lower surface and top surface, and described microarray is formed in described lower surface, and described top surface is also parallel to described lower surface usually towards described lower surface.At least one in multiple interior surface is water-wetted surface.
Also disclose and there is following microarray system: form microarray on a planar base, be formed in camera incubata around described microarray, for by liquid sample sample introduction to the dome valve in described camera incubata and the passage linking described check valve and described camera incubata.
Accompanying drawing describes
Detailed description can relate to the following drawings, and wherein similar numeral refers to similar element, and wherein:
Fig. 1 is the embodiment schematic diagram of the camera incubata of microarray system.
Fig. 2 holds the schematic diagram penetrating the dome valve of rifle head in upholder.
Fig. 3 is the schematic diagram of the embodiment of the microarray system with waste liquid chamber.
Fig. 4 is the schematic diagram of another embodiment of the microarray system with waste liquid chamber.
Fig. 5 is the schematic diagram of the embodiment of the microarray system integrated.
Fig. 6 is the schematic diagram of the embodiment size of display microarray system.
Fig. 7 is that display enters 4 microarray camera incubata assemblies (illustration A) of waste liquid chamber and the picture combination of results of hybridization (illustration B) for evaluating wicking (wicking).
Fig. 8 is the embodiment (illustration A) of the microarray system that display is integrated and combines from the picture of the results of hybridization (illustration B) of this microarray system.
Fig. 9 is the picture combination of the schematic diagram (illustration A) of the embodiment of display microarray system, array of figure (illustration B) and results of hybridization (illustration C).
Describe in detail
This specification sheets is read intentionally by reference to the accompanying drawings, and described accompanying drawing should be considered as the part of entire written description of the present invention.Figure need not proportionally, and clear and simple and clear in order to be beneficial to, some feature of the present invention may in ratio be exaggeration or how many in schematic form.In this manual, relative term such as " front ", " back side ", " on ", D score, " top " and " bottom " and derivative words thereof should be interpreted as referring to according to direction described at that time or under discussion direction as illustrated in the drawing.These relative terms are for convenience of description and are not that intention requires specific direction usually.About connecting (attachments), connect the term of (coupling) and analogue such as " (connected) of link " and " (attached) of connection " and refer to wherein by intermediate structure (intervening structures), structure is each other by the relation of directly or indirectly fixing or connect, and it is moveable or to be rigidly connected or both relation, unless separately done expression especially.
As used herein, term " microarray " refers to the oldered array for the point existed with object ligand binding.Microarray is made up of at least two points.Described object part includes but not limited to, nucleic acid, albumen, peptide, polysaccharide, antibody, antigen, virus and bacterium.
As used herein, term " water-wetted surface " refers to surface, and formation 60 ° or less contact angle can be dripped with the pure water be still on this surface in described surface.As used herein, term " hydrophobic surface " refers to surface, and the contact angle being formed and be greater than 60 ° can be dripped with the pure water be still on this surface in described surface.Contact angle goniometer can be used to measure contact angle.
As used herein, term " camera incubata " refers to the enclosed space around microarray.Described camera incubata is when being full of liquid sample, and allow described microarray to be immersed in described liquid sample, the target molecule in described like this liquid sample can keep close contact with micro probe array.
Described herein is the microarray system with camera incubata, and described camera incubata has water-wetted surface.The use of water-wetted surface allows being full of completely of camera incubata, and described water-wetted surface is when liquid enters room and liquid comes into contact.
As described above, the surface tension of liquid sample or reaction mixture stops liquid sample or reaction mixture to be full of the little space of the camera incubata of such as microarray system completely usually.Surface tension is the result attracted between the fluid molecule by power between differing molecular.In most of liquid, each molecule is close to fluid molecule at all directions equally tractive, which results in and makes a concerted effort to be zero.On the surface of liquid, molecule by the darker inside tractive of other molecules of liquid internal, and is not attracted by the molecule in contiguous medium (such as vacuum, air or another liquid) strongly.Therefore, all be positioned at surface molecule be subject to inside van der Waals' force, this van der Waals' force can only by liquid to compression opposing balance.This inside tractive tend to reduce surface area, and in this respect fluid surface similar in appearance to stretch elastic force film.Therefore, liquid by self extrusion together, until it has the possible Minimum Surface Area in local.Net result is that liquid may keep the shape of approximate sphere and can not be full of corner in little space, the particularly right-angle corner in little space.Liquid compression is become cylindrical by typical small―gap suture usually that be separated with microarray surface by coverture.
For microarray system, fill the liquid of camera incubata most likely based on the liquid of water, such as hybridization buffer or lavation buffer solution.By can overcome the surface tension of the liquid based on water by the interior surface of water wetted material coating camera incubata at least partially.
Fig. 1 shows the embodiment of camera incubata.In this embodiment, camera incubata 10 is formed at microarray 20 around, and microarray 20 is made up of the multiple array points 22 being printed on or being formed on the top surface 32 of planar substrates 30.Surface 32 also form the lower surface of camera incubata 10.The top cover plate 40 of room 10 covers.Camera incubata 10 can be and the arbitrary size of the size match of planar substrates 30 or shape, and planar substrates 30 is glass or plastic slide normally.
In this embodiment, camera incubata 10 is tops by pad 34 being placed in planar substrates 30 and covers pad 34 with cover plate 40 and formed.In another embodiment, camera incubata 10 is by following formation: in planar substrates 30, create cave (pocket) or sunk area (such as by casting or etching), print microarray 20 in the bottom of cave or sunk area, and cover cave or sunk area with cover plate 40.In another embodiment, cave or sunk area are formed on cover plate 40, then on direct top cover plate 40 being directly placed in planar substrates 30.
Camera incubata 10 is formed at around microarray 20 usually, so that the hybridization reduced in camera incubata 10 or any other liquid volume required for reaction.In one embodiment, camera incubata has about 0.1-10cm
2, preferably about 0.5-5cm
2trace, and about 0.05-5mm, the preferably height of about 0.1-1mm.In one embodiment, the cubic capacity of camera incubata is in the scope of 1-250 μ l.
According to its shape, camera incubata 10 can have several interior surface, comprise lower surface, top surface and one or more side surface, microarray 20 is formed in described lower surface, and described top surface downwardly described lower surface is also parallel to described lower surface usually.In order to ensure the object of the uniform filling of camera incubata 10, not all interior surface all needs to be hydrophilic.In one embodiment, only the top surface of camera incubata 10 is hydrophilic.In another embodiment, only the lower surface of camera incubata 10 is hydrophilic.In another embodiment, top and lower surface are all hydrophilic.In yet another embodiment, all internal surfaces of camera incubata is all hydrophilic.
Water-wetted surface is the surface attracting water.The molecule that also can form hydrogen bond of water-wetted surface usually containing charge polarization.In one embodiment, planar substrates 30 or cover plate 40 are manufactured by water wetted material, and therefore provide hydrophilic lower surface or hydrophilic topsheet surface respectively.In another embodiment, the top surface of camera incubata 10 or the insoluble water wetted material of lower surface are coated with.The example of water wetted material includes but not limited to, hydrophilic polymer, the sorbitan ester of such as poly-(N-vinyl lactam), poly-(vinylpyrrolidone), poly-(ethylene oxide), poly-(propylene oxide), polyacrylamide, cellulosic, methylcellulose gum, polyanhydride, polyacrylic acid, polyvinyl alcohol, polyvinyl ether, alkylphenol ethoxylate, Pluronic polyols monoesters, the polyoxyethylene ester of oleic acid, the polyoxyethylene sorbitan esters of oleic acid and lipid acid, inorganic hydrophilic material, such as inorganic oxide, gold, zeolite and class bore carbon, and tensio-active agent, such as Triton X-100, tween (Tween), sodium laurylsulfonate (SDS), ammonium lauryl sulfate, alkyl-sulphate, SODIUM LAURYL ETHER SULPHATE (SLES), alkylbenzene sulfonate, soap, soap, CETRIMIDE POWDER (CTAB) is also referred to as hexadecyl trimethyl ammonium bromide, alkyltrimethylammonium salt, Cetylpyridinium chloride yl pyrimidines (CPC), polyethoxye tallow amine (POEA), benzalkonium chloride (BAC), Solamin (BZT), empgen BB, oxidation domiphen, AMONYL 380LC, coconut both sexes glycinate (coco ampho glycinate) alkyl gathers (ethylene oxide), poly-(ethylene oxide) and gather the multipolymer (commercial be called poloxamer (Poloxamers or Poloxamines)) of (propylene oxide), alkyl polyglucosides, fatty alcohol, coco amine MEA, coco amine DEA, coco amine TEA.Tensio-active agent can mix using as hydrophilic coating with the reactive polymeric thing of such as polyurethane(s) and epoxy resin.In another embodiment, the top surface of camera incubata 10 or lower surface is made to become hydrophilic by atmospheric plasma processes.
Alternatively, the lower surface of camera incubata or top surface can use the obtainable hydrophilic band of business or plastic film covering.The example of hydrophilic band includes but not limited to, Adhesives Research (AR) is with 90128, AR band 90469, AR band 90368, AR band 90119, AR band 92276 and AR are with 90741 (Adhesives Research, Inc., Glen Rock, PA).The example of hydrophilic film includes but not limited to, from (Film Specialties Inc., Hillsborough, NJ)
with
film, and Lexan HPFAF (GE Plastics, Pittsfield, MA).Other water-wetted surfaces can obtain from Surmodics, Inc. (Eden Prairie, MN), Biocoat Inc. (Horsham, PA), Advanced Surface Technology (Billerica, MA) and Hydromer, Inc. (Branchburg, NJ).
In one embodiment, hydrophilic band or film have enough transparencys to allow the optical challenge from the microarray at camera incubata top.In another embodiment, by creating water-wetted surface with the top surface of hydrophilic coating coating camera incubata.In another embodiment, water-wetted surface is created by substituting cover plate 40 with hydrophilic band or hydrophilic film simply.
In yet another embodiment, water-wetted surface is the hydrophilic matrix with dipping (impregnated) chemical, described chemical lysing cell film, makes protein denaturation and capture nucleic acid.This hydrophilic matrix can exercise two functions, purification of samples and equably sample is wicked into camera incubata.In one embodiment, hydrophilic matrix is
(Whatman, Florham Park, NJ).Biological sample is applied to
and the cell contained in sample is cleaved on this paper.Wash this paper to remove any non-DNA material (DNA still keeps being entangled in paper).Then eluted dna is used for follow-up microarray analysis.Alternatively, microarray can be used for detect by the DNA that combines of original position amplification, and there is no elution step.
apparent surface's (i.e. top surface of camera incubata) of array can be used as.Alternatively, microarray can be printed on FTA
and the transparency cover slide on camera incubata top can allow the visual of microarray.In another embodiment, PCR reagent can be introduced into camera incubata for
the amplification of upper nucleic acid samples.In this embodiment, amplification can be carried out in camera incubata 10 inside.
Microarray 20 can be the microarray of any type, includes but not limited to, Oligonucleotide microarray and arrays of immobilized protein.In one embodiment, use printing gelation point method (printing gel spots method) to form microarray 20, print gelation point method and be described in such as United States Patent (USP) the 5th, 741, No. 700, the 5th, 770, No. 721, the 5th, 981, No. 734, the 6th, 656, No. 725 and U.S. Patent application the 10/068th, No. 474, the 11/425th, No. 667 and the 60/793rd, No. 176, above all this by reference entirety be incorporated to.
In another embodiment, microarray system is also containing the check valve for liquid (such as sample, hybridization buffer or lavation buffer solution) being introduced camera incubata 10.Sample is introduced camera incubata 10 to prevent the pollution of the environment by check valve, and environmental pollution is the important consideration in some application, and described application examples is as the detection of biological war agent.Described check valve can be vacuum breaker or the dome valve of the entrance being placed in camera incubata 10.The dome valve of different size business can obtain (such as from Minivalve International, Yellow Springs, OH).In embodiment in fig. 2, dome valve 50 is containing two assemblies: dome-shaped valve body 52 and upper sealing (back seal) 54.On this, sealing has the hole (not shown) allowing intromittent organ 56 to penetrate sealing 54.Intromittent organ 56 can be any liquid delivery devices with the sharp tips penetrating sealing 54.In this embodiment, intromittent organ 56 is rifle heads.In another embodiment, intromittent organ 56 is entry needles.
Dome valve 50 allows easily entering of intromittent organ 56 and meets the tip of intromittent organ 56 when tip enters dome valve 50 by upper sealing 54.After intromittent organ 56 exits, the spontaneous closedown of opening in upper sealing 54 spills camera incubata 10 to prevent sample from dome valve 50.Therefore, dome valve 50 as in can piercing through every and vacuum breaker.Dome valve can be arranged on microarray assembly by underwork 58.In one embodiment, dome valve is attached to camera incubata 10 (Fig. 3) by entrance 11 and admission passage 14.
In yet another embodiment, microarray system also comprises waste liquid chamber.Such as Aurora Photonics Port Array 5000
tMa lot of optical reader of microarray reader, when reading dry image, provide the signal to noise ratio of improvement.Therefore, waste liquid chamber is incorporated to microarray system, thus before microarray is inserted microarray reader from camera incubata remove liquid be favourable.Existing composition graphs 3, camera incubata 10 is attached to the waste liquid chamber 60 be formed on same microarray slide.
Waste liquid chamber 60 can be any shape, and usually has the volume being greater than camera incubata 10 volume.In one embodiment, waste liquid chamber is formed in gasket strip, and then described gasket strip is connected to substrate 30 (see Fig. 1), and microarray 20 is printed in described substrate 30.In yet another embodiment, substrate 30 has excision place (cut-out) over the top surface.Described excision place has the size and position that match with the size of the waste liquid chamber 60 in pad 34 and position, and such waste liquid chamber 60, once be formed between substrate 30 and pad 34, can have the degree of depth being greater than camera incubata 10 degree of depth.In another embodiment, substrate 30 is made up of plastic material, and such excision place can easily be made in substrate 30.In yet another embodiment, camera incubata 10 and waste liquid chamber 60 are all formed in substrate 30, and do not use pad 34.But waste liquid chamber 60 can have the degree of depth being greater than camera incubata 10 degree of depth.
In one embodiment, waste liquid chamber 60 containing absorption agent 62, described absorption agent 62 once with the liquid comes into contact in camera incubata 10, from camera incubata 10 wicking liquid, therefore allow microarray 20 to read in the dry state.
Absorption agent 62 can be any material that can retain relatively large quantity of fluid.In one embodiment, absorption agent 62 is made up of the aggregate of fiber.In another embodiment, absorption agent 62 is non-woven bonding and produce in (through-air bonding) technique of ventilating.The composition fiber of non-woven can be native cellulose fibre or the regenerated cellulose fibre of hydrophilic synthon, pulp etc.Fiber with tensio-active agent or hydrophilic oil coating or can infiltrate to improve liquid-absorbent.Be not limited to ventilation adhesion technique, can produce in any other technique for non-woven herein, such as spunbond process, air-laid process, water thorn (spun-lacing) technique etc.In one embodiment, absorption agent 62 is the cellulose papers (C048) from Millipore (Billerica, MA).
Composition graphs 3 again, waste liquid chamber 60 is linked by passage 12 and camera incubata 10.Passage 12 serves as dual purpose.When filling liquid, passage 12 provides the liquid between camera incubata 10 and waste liquid chamber 60 to pass through approach.When filling air, camera incubata 10 is isolated from waste liquid chamber 60 by passage 12, and prevents the too early wicking of the absorption agent 62 in waste liquid chamber 60.
By forcing the liquid inlet channel 12 of camera incubata 10 inside and contact between absorption agent 62 in the liquid set up in passage 12 and waste liquid chamber 60, remove the liquid of camera incubata 10 inside.Can by camera incubata 10 liquid apply pressure with by liquid slide aperture 12 or by apply in the outlet 64 of waste liquid chamber 60 suction so that liquid extraction channel 12 is set up described contact.The pressure of pressure (being such as with transfer pipet or syringe) generation to liquid in camera incubata 10 can be applied by means of dome valve 50.If camera incubata 10 only covers with hydrophilic band or hydrophilic film, can by pressing the hydrophilic band or the pressure of film generation to liquid in camera incubata 10 that form camera incubata 10 top surface simply.Alternatively, by making absorption agent 62 towards passage 12 forward until absorption agent 62 touches the liquid in passage 12, the contact between liquid and absorption agent 62 in passage 12 can be set up.
Once set up contact, the liquid in camera incubata 10 by passage 12 by the absorption agent 62 wicked in waste liquid chamber 60.The flow velocity of liquid is by the size of passage 12, and the wicking rate of the surface tension of liquid and viscosity and absorption agent 62 determined.In addition, when absorption agent becomes more saturated, flow velocity declines.Also can coutroi velocity by the placement of absorption agent 62 in waste liquid chamber 60.The absorption agent placed close to the outlet of passage 12 causes the flow velocity higher than the absorption agent of farther placement.Therefore, the angle cutting absorption agent 62 causes lower flow velocity, this is because the distance increased between the outlet of passage 12 and absorption agent 62.
If bubble is introduced into camera incubata 10, bubble may be present in passage 12 liquid-flow also partially or even wholly blocked in passage 12.Bubble also may stop the core sucting action of absorption agent 62, if bubble is positioned at the interface of liquid and absorption agent 62 just.This problem can be overcome by the channels designs shown in Fig. 4.In this embodiment, passage 12 comprises 3 parts: inlet part 15, funnel-form linking portion 16 and exit portion 17.Exit portion 17 has the diameter being less than inlet part 15 diameter.Less diameter causes compared with the pressure in inlet part 15, capillary pressure stronger in exit portion 17.Pressure gap causes liquid to the movement of exit portion 17.In operation, the liquid in exit portion 17 is pushed out exit portion 17, and walks around the air pocket being positioned at liquid and absorption agent 62 interface.Funnel-form linking portion 16 provides the overflow area of the capillary too early wicking prevented due to passage.In another embodiment, exit portion 17 is further divided into two sub sections, the second section of larger-diameter first part (horizontal component corresponding to part in Fig. 4 17) and small diameter (vertical component of part 17 corresponding to entering waste liquid chamber 60).
If the hybridization in camera incubata 10 or amplification procedure relate to heating steps, the denaturing step of such as, in polymerase chain reaction (PCR) thermal cycling, liquid in camera incubata 10 may be pushed out passage 12 and due in camera incubata 10 increase pressure, make the contact too early with absorption agent 62.In these cases, air can be stayed (when camera incubata 10 is filled) in passage 12 wittingly, with the wicking preventing absorption agent 62 too early.Alternatively, hydrophobic retainer can be placed in passage 12 with the wicking preventing absorption agent 62 too early.In one embodiment, hydrophobic retainer comprises the channel part with hydrophobic interior surface.In one embodiment, by forming hydrophobic surface with hydrophobic material coating or surface, process natural lane, described hydrophobic material such as
silicone or silicomethane.In another embodiment, the interior surface of passage 12 is with water wetted material coating, and hydrophobic retainer comprises the part of passage 12, and this part has the uncoated surface exposing native hydrophobic plastic material.
In another embodiment, camera incubata 10 and many waste liquid chamber 62 link to guarantee that wicking occurs with suitable interval.
What also describe herein is the microarray system integrated, and it has the hydrophilic camera incubata for uniform filling, in order to avoid the check valve of sample contamination and the waste liquid chamber for removing liquid from camera incubata.Existing composition graphs 5, the embodiment of the microarray system 100 of integration is comprised and is printed on or is formed in microarray 20 in substrate 30, is formed in hydrophilic camera incubata 10 around microarray 20, by passage (not shown) and the dome valve 50 of camera incubata 10 fluid communication and the waste liquid chamber 60 that linked by passage 12 and camera incubata 10.Absorption agent 62 is incorporated in waste liquid chamber 60, and waste liquid chamber 60 is discharged in air by relief outlet 64.Transparent hydrophilic coverture 70 defines the top surface of camera incubata 10 and waste liquid chamber 60.In one embodiment, relief outlet 64 is produced by holing on the coverture of waste liquid chamber 60 simply.
Are films by an advantage of hydrophilic band or plastic film covering camera incubata 10 and waste liquid chamber 60 or are with and can be out of shape under stress.Therefore, be possible by applying modest pressure mixing liquid in camera incubata 10 to waste liquid chamber, described applying pressure can cause the slight deformation of camera incubata 10 and therefore cause the motion of liquid in camera incubata 10.
Embodiment
Embodiment 1. covers camera incubata with hydrophilic band and causes being full of completely of room
The geometric construction of the embodiment of Fig. 6 display microarray slide glass.Circle is filling access 11, and square is microarray camera incubata 10, and rectangle waste liquid chamber 60.Width is that the passage 14 of 0.5mm links filling access 11 and microarray camera incubata 10,2.0mm passage 12 links microarray camera incubata 10 and waste liquid chamber 60, and the 1.0mm passage 64 from waste liquid chamber 60 to outside is as relief outlet.Microarray camera incubata 10 has the size of 10mm × 10mm.Laser shearing thickness is the inside gasket strip of 0.25mm (can obtain from 3M, parts number 9087), to form the pad with above-mentioned geometric construction.This pad is placed in hydrophobic surface with the contact angle similar to the slide glass printing process for gelation point.The top of pad seals with hydrophilic band (AR 90128) to provide water-wetted surface.30 μ l water uniform filling rooms, and do not leave bubble or air pocket.30 μ l hybridization buffers (3M guanidinium isothiocyanate, 150mM HEPES pH7.5 and 15mM EDTA) yet filled chamber equably, does not have bubble.With the similar test of hydrophobic strip (AR 8192) due to filling heterogeneous, in microarray chamber, leave air pocket.
This experiment shows, the water-wetted surface of room overcomes the surface tension of liquid and allows room, comprises the filling completely of square edge.This result is beyond thought, because when liquid filling room, right-angle corner is bottled up air pocket usually.
The evaluation of the wicking efficiency of embodiment 2. waste liquid chamber
Fig. 7 A shows 4 test microarray slide, each hydrophilic camera incubata with the waste liquid chamber be attached to containing absorption agent.Waste liquid chamber is discharged in air.Forming chamber the top supporting slide glass by pad (the double-sided belt laser provided from Grace Biolab is sheared) being placed in microarray.By covering camera incubata space with hydrophilic band (AR 90469), produce the water-wetted surface in camera incubata.Absorption agent comes from Millipore (C048).95 μ l contain sample from the amplified production of Yersinia pestis (Yersinia pestis), hybridization mark, BSA and hybridization buffer 95 DEG C of sex change 5 minutes introduces camera incubata by entrance.Then, entrance band (AR90697) sealing.React and hatch 1 hour with 50 DEG C in the MJ research PTC-200 DNA engine thermal cycler of the slide glass tower with connection.Microarray slide to be shifted out from tower and in room temperature 150 μ L water washings.When water is added in camera incubata by entrance, the liquid in camera incubata is pushed into waste liquid chamber by the passage linking camera incubata and waste liquid chamber.Once set up the contact between the liquid in camera incubata and the absorption agent in waste liquid chamber, absorption agent can by liquid (comprising wash volumes) from camera incubata wicking out.Then, microarray slide heats 20 minutes with finish-drying camera incubata at 95 DEG C.Microarray is at Aurora Photonics Port Array 5000
tMupper imaging, not to any operation of device.Image is obtained by the hydrophilic band covering camera incubata.
After Fig. 7 B shows hybridization, washing and drying step, the image of embodiment microarray.Product point is shown as black dull point.Control point comprises Cy3 point and hybridization mark.Each array is the repetition of 4 secondary arrays, therefore 4 groups of Yp product points.Uniform hybridization is achieved in all test slide.
The microarray system of embodiment 3. containing dome valve, hydrophilic camera incubata and waste liquid chamber
Fig. 8 A shows the embodiment of microarray system integrated, the microarray system of described integration have cover with hydrophilic band camera incubata, there is the waste liquid chamber of the absorption agent of merging and be attached to the dome valve of camera incubata.The sample be made up of hybridization pre-mixture (master mix) and Yersinia pestis product of 95 μ l 95 DEG C of sex change 5 minutes, and is introduced into camera incubata with Rainin P200 μ L pipettor by dome valve.Sample flows into microarray chamber equably, and does not leave bubble or air pocket.Camera incubata is studied with 50 DEG C of heating 60 minutes on PTC-200DNA engine thermal cycler, without any the change of flow cytometric device at the MJ of the slide glass tower with connection.Microarray slide is shifted out from slide glass tower and uses 150 μ L water washings.When water is introduced into camera incubata, the hybridization mixture in camera incubata is pushed into waste liquid chamber, and Millipore C048 absorption agent from camera incubata by the wicking of whole volume out.Then, microarray slide heats 20 minutes with finish-drying camera incubata at 95 DEG C.Microarray is at Aurora Photonics Port Array 5000
tMupper imaging, not to any operation of device.Image is obtained by the hydrophilic band covering camera incubata.
After Fig. 8 B shows hybridization, washing and drying step, the image of exemplary microarray.Product point is shown as black dull point.Control point comprises Cy3 point and hybridization mark.Each array is the repetition of 4 secondary arrays, therefore 4 groups of Yp product points.As shown in Figure 8 B, in all secondary arrays, uniform hybridization is achieved.
Embodiment 4. contains the microarray system of hydrophilic camera incubata and waste liquid chamber
Fig. 9 A display has another embodiment of the microarray system of hydrophilic room 10 and waste liquid chamber 60.Two rooms are linked by passage 12, and passage 12 has inlet part 15, funnel-form linking portion 16, major diameter exit portion 17
1with minor diameter exit portion 17
2.Liquid sample is added to camera incubata 10 by entrance 11 and passage 14.
Microarray system shown in Fig. 9 A uses the pad sheared from double-sided belt (Grace Biolabs) laser to build on a glass slide.Waste liquid chamber 60 contains filter paper absorption agent (CF4, Millipore) and is discharged into air.The microarray assembly obtained is covered with Lexan HPFAF (0.007 "/175 μm) anti-fog belt (GE Plastics).20 μ l containing the sample from the amplified production of micrococcus scarlatinae (Streptococcus pyrogenase), hybridization mark (corresponding contrast), BSA and hybridization buffer 95 DEG C of sex change 5 minutes, and be introduced into camera incubata 10 with Rainin P200 μ L pipettor by entrance 11.With band sealed entry 11 and whole slide glass allow to study in PTC-200DNA engine thermal cycler at the MJ with the slide glass tower connected to hatch 30 minutes with 55 DEG C.Slide glass to be shifted out from tower and in room temperature 150 μ L water washings.Array is at Aurora Photonics Port Array 5000
tMimaging on microarray reader (2 second open-assembly time).Fig. 9 B shows results of hybridization.Fig. 9 C is the chip figure of the layout of array of display point.As shown in fig. 9b, strong positive result is obtained from Hybridization Controls and suis specific probe.
Embodiment 5. 1 step protein microarray system
The gel drops element containing capture antibody is used to build the protein microarray system of a step, integration, one in such as, embodiment shown in Fig. 5 and Fig. 9.Described capture antibody is the antibody be combined with biological war agent (BWAs) group-specific.Each gelation point contains the antibody be combined with particular B WA.By two of the colloid gold label anti-positions be placed on close to access road.The BWAs of two identical group of anti-identifications.When liquid sample is loaded in camera incubata by access road, two of colloid gold label resists when sample enters camera incubata and sample mix.In hatching, object BWAs to catch by the antibody in array gelation point and the two anti-BWAs with being captured are combined.After incubation period, wash away unconjugated two and resist.Two anti-with gelation point on the BWAs that catches tie to be incorporated in microarray and produce positive signal.
As used herein, term " antibody " is for the widest possible meaning and can includes but not limited to the antibody of antibody, recombinant antibodies, genetic modification, chimeric antibody, Mono-specific antibodies, bi-specific antibody, multi-specificity antibody, double antibody, chimeric antibody, humanized antibody, people's antibody, heteroantibody, monoclonal antibody, polyclonal antibody, camelised antibodies, removes immune antibody, antiidiotypic antibody and/or antibody fragment.Term " antibody " can also include but not limited to such as with the antibody of Types Below: IgA, IgD, IgE, IgG and/or IgM, and/or hypotype IgG1, IgG2, IgG3, IgG4, IgA1 and/or IgA2.Term " antibody " can also include but not limited to antibody fragment, such as at least part of complete antibody, such as antigen-binding variable regions.The example of antibody fragment comprise Fv, Fab, Fab ', F (ab '), F (ab ')
2, Fv fragment, double antibody, linear antibodies, single-chain antibody molecules, other antigen-binding subsequences of multi-specificity antibody and/or antibody.Other information are found in United States Patent (USP) the 5th, 641, No. 870, United States Patent (USP) the 4th, 816, No. 567, WO93/11161, Holliger et al., Diabodies:small bivalent and bispecific antibody fragments (double antibody: little divalence and bispecific antibody fragment), PNAS, 90:6444-6448 (1993), Zapata et al., Engineering linear F (ab ') 2 fragments for efficient production in Escherichia coli and enhanced antiproliferative activity (is the antiproliferative activity effectively produced in intestinal bacteria and strengthen and the linear F of through engineering approaches (ab ')
2fragment), Protein Eng.8 (10): 1057-1062 (1995), are incorporated to herein by reference.
Embodiment 6. liang step protein microarray system
The gel drops element containing antibody is used to build the protein microarray system of two steps, integration, one in such as, embodiment shown in Fig. 5 and Fig. 9.Each gelation point contains the antibody be combined with specificity target.Sample is introduced into camera incubata and in room, hatches regular time section.Add lavation buffer solution to remove in conjunction with sample.Lavation buffer solution is wicked into waste liquid chamber, thus removes all liquid from camera incubata.In a subsequent step, one or more two anti-added to camera incubata and hatch regular time section.After incubation period, wash away unconjugated two and resist.What the target of catching on gelation point was combined two resists produce positive signal in microarray.
In this embodiment, bubble is left in the passage linking camera incubata and waste liquid chamber, to be separated with waste liquid by the liquid in camera incubata and to prevent too early wicking.When other wash volumes is added to camera incubata, unconjugated antibody is pushed out camera incubata and is wicked into waste liquid chamber.Many waste liquid chamber guarantee that wicking occurs with suitable interval.
Term used herein and description are only carried out setting forth instead of be intended to be expressed as restriction in the illustrated manner.One skilled in the art will recognize that, as in following claims in the spirit and scope of the present invention that define and equivalent thereof, many changes are possible, and wherein all terms are interpreted as its widest possible meaning, unless otherwise mentioned.
Claims (12)
1. microarray system, it comprises:
Form microarray on a planar base; With
Be formed in the camera incubata around described microarray;
Waste liquid chamber; And
Link the passage of described waste liquid chamber and described camera incubata;
Wherein said camera incubata comprises multiple interior surface, described interior surface comprises lower surface and top surface, described microarray is formed in described lower surface, and described top surface is towards described microarray, and at least one in wherein said multiple interior surface is water-wetted surface.
2. microarray system as claimed in claim 1, the degree of depth of wherein said waste liquid chamber is greater than the degree of depth of described camera incubata.
3. microarray system as claimed in claim 1, also comprises the check valve for being loaded to by liquid sample in described camera incubata.
4. microarray system as claimed in claim 3, wherein said check valve is dome valve.
5. microarray system as claimed in claim 3, wherein said check valve is vacuum breaker.
6. microarray system as claimed in claim 1, wherein said passage comprises the channel part with hydrophobic interior surface.
7. microarray system as claimed in claim 6, wherein by forming described hydrophobic interior surface with hydrophobic material coating or surface, process natural lane.
8. microarray system as claimed in claim 7, wherein said hydrophobic material is Teflon, silicone or silicomethane.
9. microarray system as claimed in claim 1, wherein said passage comprises the inlet part close to described camera incubata, the exit portion close to described waste liquid chamber and links the funnel-form linking portion of described camera incubata and described waste liquid chamber, and the cross-sectional area of wherein said inlet part is greater than the cross-sectional area of described exit portion.
10. microarray system as claimed in claim 9, wherein said inlet part and described exit portion are all vertical with described linking portion.
11. microarray systems as claimed in claim 9, wherein said exit portion is longer than described inlet part.
12. microarray systems as claimed in claim 9, wherein said exit portion comprises in a zigzag.
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| WO2020192742A1 (en) * | 2019-03-27 | 2020-10-01 | 深圳市尚维高科有限公司 | Self-driven microfluidic chip and method for using same |
| CN112442101A (en) * | 2019-09-05 | 2021-03-05 | 华为技术有限公司 | Method and apparatus for synthesizing oligonucleotide |
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2008
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2020192742A1 (en) * | 2019-03-27 | 2020-10-01 | 深圳市尚维高科有限公司 | Self-driven microfluidic chip and method for using same |
| CN112442101A (en) * | 2019-09-05 | 2021-03-05 | 华为技术有限公司 | Method and apparatus for synthesizing oligonucleotide |
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