CN1529170A - Capillary chamber chip, capillary chip and chip element and device - Google Patents
Capillary chamber chip, capillary chip and chip element and device Download PDFInfo
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Abstract
In the invention, parameters of sizes at top face and bottom face as well as interspace and material are selected so as to make reaction medium form capillary phenomenon in the said capillary cavities. Thus, successive reaction and operation can be carried out for the reaction medium so as to obtain the chip of capillary cavity in high performance.
Description
Technical field:
The present invention relates to pick-up unit, the particularly detection chip of the qualitative and/or quantitative test of sample, and the element and the relevant apparatus that constitute detection chip.
Background technology:
Detection chip also is called for short chip in the present invention, is to develop one of the most noticeable pick-up unit at present.At present the most frequently used chip is a biochip, and the most frequently used in the biochip is polypeptide chip and genetic chip.Polypeptide chip is the biochip for preparing on substrate as probe stationary with a plurality of amino acid whose sequential structures (comprising protein).Genetic chip is with sample amplifying nucleic acid to be checked, nucleotide and complementary nucleic acid, nucleotide probe hybridization, forms crossbred, or combines with specific antibody, shows the chip of testing result again with color reaction.The biochip scope that has a wide range of applications comprises gene expression detection, genescreen, drug screening, medical diagnosis on disease treatment, environmental monitoring and fields such as improvement, judicial expertise.
The core of chip is the reactor on it.Chip reactor among the present invention is meant to be fixed with probe in the chip in an orderly manner and to reach other dependency structure that is communicated with it with the place of object generation specific reaction when detecting.The probe of the chip among the present invention comprises that all can be fixed on the material with specific reaction on the solid phase carrier in addressable mode, comprise biological aglucon, for example biotic components such as DNA, polypeptide, protein, cell, tissue.In the present invention, substrate is meant the parts of the solid phase carrier that includes stationary probe in the chip; Probe card is meant the substrate that is fixed with probe.In the present invention, according to the number n of reactor on the chip, chip is defined as single reactor chip (n=1) and multiple reactor chip (n is equal to or greater than 2).
Among the present invention, according to the liquid phase medium that is added in the testing process can be in reactor directed flow, reactor is defined as flow reactor and non-current reactor; With flow reactor and non-current reactor is that the biochip of feature is respectively defined as flow chip and non-current chip.
Among the present invention, in whole testing process, whether open, reactor is defined as open and closed reactor respectively according to reactor probe array top; With this reactor is the chip of feature, is respectively defined as open and closed chip.
The chip reactor has the character of above-mentioned several reactors usually simultaneously.Among the present invention, whole character that these reactors are defined as being had with it are the reactor of common trait, are that the biochip of feature is also similarly defined with this reactor.For example, if above testing process middle probe array, be no obducent open architecture, then the liquid phase medium that is added can be in reactor directed flow, then this reactor is defined as open flow reactor, relevant chip is defined as open mobile chip.Other is analogized in proper order.
The present situation of chip is as follows:
1, non-current chip
Non-current chip comprises closed non-current chip and open non-current chip, and the most widely used at present is open non-current chip.Present open non-current chip comprises open non-current chip of single reactor and the open non-current chip of multiple reactor.An example of the open non-current chip of single reactor is that the chip of other newly-increased structure is made, do not had to activated, point sample based on micro-year microslide.Closed non-current chip seals reactor when reaction, opens the confining bed operation (with reference to " multiple-sample microarray biochip " (Chinese patent notification number 1335501) when liquid feeding and washing.
2, mobile chip
The chip that flows at present is divided three classes: microfluidic circuit chip, capillary chip and the microarray chip that flows.
The microfluidic circuit chip claims micro-fluidic chip again, is meant with microchannel (for example kapillary) to be that network connects the micro-total analysis system that analysis functions such as centralized procurement sample, pre-treatment, liquid conveying such as Micropump, little valve, little reservoir, microelectrode, little detecting element are integrated in one.The microchannel size is generally: width is less than 0.05mm, and the degree of depth is less than 0.025mm.Usually only fixing a kind of aglucon in each reactor of micro-fluid chip, an object in the one-time detection sample.An example of microchannel biochip be Caliper Technologies Inc. company (
Www.caliper.com) the detection biochip.The advantage of microchannel chip be highly sensitive, speed is fast.Its shortcoming is: 1), need etch the microchannel earlier in the production run, and probe on the point, and then carry out the microchannel sealing and make, its complex structure, the suitability for industrialized production difficulty is very big; 2), flow rate of liquid need be with the control of special precision equipment during detection, electro-osmosis device for example, etc.; 3), after reaction is finished,, detect, can not directly use the common chip scanner to read the result for some test example such as fluorescent marker because fixing probe molecule is surperficial within it.
Capillary chip be included on one section wall of capillary channel or one section glass structure of inserting in the kapillary on the fixing chip of aglucon, visible Chinese patent " kapillary biochip device " (Chinese patent notification number 2483395).
Micro-array chip is called biochip or abbreviation chip again many times.What fix in the reactor of micro-array chip is the aglucon array.The closed microarray visible Chinese patent of chip " a kind of include enclosed aglucon plate " (China Patent No. ZL022229310) that flows.The irreversible closed microarray visible Chinese patent of chip " micro chip of integrated microfluidic and microarray aglucon " (Chinese patent notification number 2559986Y) that flows, the reversible closed microarray visible Chinese patent of chip " a kind of include enclosed aglucon plate " (China Patent No. ZL022229310) that flows.
In a word, comprise the closed microarray existing closed chamber of the chip all fixing aglucons on a face only of chip that flow that flow, this is being difficult to meet the demands when high especially to the sensitivity requirement.The distribution of aglucon only limits to array (micro-array chip) in its chamber, also to its growing application sample formation restriction.In addition, when using some signal reader (for example burnt photoscanner of copolymerization), chip need be made reversible closed mobile chip.Particularly, the existing closed chamber chip that flows, the factor of considering when design is aglucon-object reacting dynamics condition and signal observation condition.Liquid phase medium in reactor, moving in the reaction chamber of reactor especially, be by machinery transport, liquid phase medium deadweight, feed liquor structure or/and the combination of one or more of the water wettability of fluid structure realize.For reaction chamber, these all are ectogenic liquid transfer power.Certainly, the end face of reaction chamber, bottom surface and wall be possess hydrophilic property often, is weak yet depend merely on this endogenic liquid transfer power of its water wettability.The result is, present closed micro-array chip at detecting operation, particularly contain in the operation of transfer medium, is inadequate during being distributed with of liquid phase medium in the reaction chamber in its reactor, for example there is gas to have the distribution that hinders liquid phase medium, thereby influences testing result.
Summary of the invention:
The object of the present invention is to provide a kind of simple for production, highly sensitive, reaction medium to be evenly distributed the mobile chip that the reaction medium consumption is little, and the sheet base and aglucon plate and the relevant apparatus that constitute this chip.
Therefore, mobile chip of the present invention is a capillary chamber chip:
Capillary chamber chip of the present invention, be characterised in that: it contains at least one irreversible closed or reversible closed capillary chamber reactor 1 on one side at least, described capillary chamber reactor comprises the capillary chamber 5 that contains end face 2 and bottom surface 3 and chamber wall 4, be fixed on bottom surface in the described capillary chamber or/and the aglucon 6 on the end face and the feed liquor structure 7 and the fluid structure 8 that are communicated with described capillary chamber, the size that comprises end face and bottom surface of capillary chamber wherein, the selection of spacing and material character makes reaction medium to form capillarity in described capillary chamber, described reaction medium comprises aqueous solution or/and organic liquid, and described material character comprises water wettability or/and hydrophobicity.Chip of the present invention, it is a kind of qualitative and/or quantitative microminiaturized testing product, its principle is to be fixed on micro-probe on the surface of solid phase carriers in an orderly manner, make its under testing conditions with sample in target molecule generation idiosyncrasy, and then the micro-aglucon that the result of idiosyncrasy is carried out bag quilt in the recognition reaction device takes place specially with the target molecule in the sample, and the result of reaction can discern in addressable mode.Chip of the present invention includes but not limited to the chip notion (for example " Biochip " in the English, " Microarray ", " Bioarray ") of current trend, and its form is (can be rectangle, garden butterfly, or the like) without limits.Described in the present invention do not take charge of contrary closed or reversible closed capillary chamber reactor be meant respectively in whole testing process for closed or in testing process part steps be that closed part steps is open capillary chamber reactor.Capillary chamber chip of the present invention, be in selection with the difference of present mobile chip and make reaction medium can form capillarity therein, be in its reaction chamber with the difference of present microchannel chip or capillary chip because of reaction chamber size, spacing and material character.Capillary chamber of the present invention is different with the kapillary in the capillary chip, be meant form by the structure between two faces and the two sides and also reaction medium can produce the structure of capillarity therein.
A kind of capillary chamber chip of the present invention is characterised in that: it contains the one or more capillary chamber reactor that is formed or participated in forming by end face element 9 and bottom surface element 10, and at least one includes the sheet base in described end face element and the bottom surface element.Of the present invention base is meant a kind of activation solid phase carrier, and it has the feature on macroscopical plane in order to the fixing surface of aglucon, for example activation slide that is formed by the slide activation or the like.Because the formation of capillary chamber reactor of the present invention needn't be subjected to the restriction of sheet base shape, the sheet base in the chip of the present invention can be various geometric configuratioies such as rectangle, circle.
A kind of capillary chamber chip of the present invention is characterised in that: aglucon wherein, it is the various orderly announcement that comprises array 11, dotted line formula 12, solid line formula 13, empty bar formula 14 and real bar formula 15 on described base.In fact, the use different according to chip can have the different choice that aglucon ordered distribution mode also should be arranged.It is unnecessary being confined to unique array distribution.
A kind of capillary chamber chip of the present invention, be characterised in that: capillary chamber wherein, the maximum lateral width of its end face and bottom surface is 0.5mm-75mm, preferred version 1.5mm-35mm, the spacing of its end face and bottom surface less than 500um, preferred version less than 100um, its end face or/and the static reaction medium contact angle of bottom surface material less than 70 the degree, preferred version less than 50 the degree, more preferably scheme less than 35 the degree.Because the range of choice of area and spacing is big, necessary can be by improving its end face or/and the close medium of bottom surface provides capillarity evenly moistening to guarantee.
On the one hand, a kind of capillary chamber chip of the present invention, be characterised in that: it contains irreversible closed capillary chamber reactor, described sealing be by between end face element and the bottom surface element comprise bonding or/and hot fusion or/and the mode of HF or sodium silicate low-temperature bonding form.
A kind of capillary chamber chip of the present invention is characterised in that: wherein participate in to form the end face componentry of capillary chamber at least or/and the bottom surface componentry is transparent and its thickness less than 1mm, preferred version less than 0.2mm.In the embodiment of the invention, the example of this transparent element is cover glass or the activation cover glass of former high 0.15mm.
A kind of capillary chamber chip of the present invention, be characterised in that: it can directly detect reaction result by the input instrument, and described input instrument comprises the confocal fluorescent scanner.In an embodiment, when end face element cover glass is enough thick (≤0.15mm), chip of the present invention can be directly used in light to be assembled the fluorescent scanning instrument and need not do dismounting and handle, and has or not the resulting result of cover glass to there is no obvious difference.
Another aspect, a kind of capillary chamber chip of the present invention, be characterised in that: it contains reversible closed capillary chamber reactor, end face element wherein is or/and contain the capillary chamber wall and be communicated with or disconnected basic hermetically-sealed construction with described chamber wall in the element of bottom surface, described basic hermetically-sealed construction comprise mechanical seal structure or/and physical chemistry isolating seal structure or/and the adhesive sealing structure.
A kind of capillary chamber chip of the present invention is characterised in that: described chamber wall is or/and mechanical seal structure comprises macromolecule material coating or sheet or the band that contains Shao Er hardness 20-100 degree.
A kind of capillary chamber chip of the present invention is characterised in that: described macromolecular material comprises following one or more macromolecule combination: natural rubber and derivant thereof; Synthetic rubber, as butadiene-acrylonitrile rubber, butyl rubber, fluororubber, silicon rubber, fluorosioloxane rubber etc.; Various organic polymers, as organosilicon polymer, fluoropolymer, polycarbonate, plastics.
A kind of capillary chamber chip of the present invention is characterised in that: described chamber wall or/and physical chemistry isolating seal structure comprise contain static reaction medium contact angle greater than the macromolecular materials of 80 degree or/and the thin reaction medium coating of nano material or thin sheet of reaction medium, band.
A kind of capillary chamber chip of the present invention, be characterised in that: described macromolecular material comprises organosilicon and fluoropolymer.
A kind of capillary chamber chip of the present invention is characterised in that: described nano material comprises and contains following one or more the material of nano-powder: gold, vanadium, lead, silver, iron and oxide powder thereof and monox, titanium dioxide, alumina powder jointed modification are combined with the derivant powder of hydrophobic group.
A kind of capillary chamber chip of the present invention is characterised in that: described chamber wall is or/and the adhesive sealing structure comprises reversible adhesive layer and irreversible adhesive layer, and the capillary chamber forms open chamber by open top side or bottom surface when needed when being irreversible adhesive layer.
On the other hand, a kind of capillary chamber chip of the present invention is characterised in that: wherein said capillary chamber end face is or/and the material of bottom surface is selected from one of following or two or more combination arbitrarily: glass, silicon and silicon compound, metal oxide, metal and polymeric material and they derivant separately or the like.
A kind of capillary chamber chip of the present invention is characterised in that: wherein said aglucon is the material that is selected from one or both and two or more combination in any in following group: aptamer molecule, polypeptide and the strand of antigen, antibody, part, part index enhanced system evolution technology (SELEX) screening or multichain DNA, nucleotide, polynucleotide, sugar, enzyme, co-factor, microbiotic, steroids, virus, cell altogether.
A kind of capillary chamber chip of the present invention is characterised in that: in the capillary chamber wherein fixedly the mask of aglucon array close reaction medium character is arranged and not fixedly the mask of aglucon array thin reaction medium character is arranged.
A kind of capillary chamber chip of the present invention is characterised in that: described capillary chamber reactor feed liquor structure is or/and the fluid structure contains close reaction medium or and suction reaction medium material.
Capillary chip of the present invention is:
Capillary chip of the present invention is characterised in that: the structure that is fixed with aglucon in wherein all reactors all has the capillarity of reaction medium, and wherein has at least one to be above-mentioned capillary chamber reactor.For example, a capillary chamber reactor connects the chip that forms by kapillary and a capillary reactor connection, or the like.
A kind of capillary chip of the present invention, be characterised in that: be fixed with antigen in its at least one reactor, and be fixed with and state the antigen corresponding antibody in another reactor, the microchannel is arranged therebetween or/and be fixed with absorption antigen or/and antibody or/and the structure of antiantibody.In embodiment 3, provided the example of a this capillary chip.
Chip component of the present invention is:
A kind of chip component of the present invention, be characterised in that: its for above-mentioned capillary chamber chip or/and the end face element of capillary chip or/and bottom surface element or described end face element or/and the preparation element of bottom surface element, described preparation element contains the bottom surface of at least one above-mentioned capillary chamber reactor or end face, partly or entirely chamber wall and part or all of enclosed construction at least on the one side.
Device of the present invention is:
A kind of device of the present invention is characterised in that: it forms above-mentioned reversible closed capillary chamber chip with above-mentioned aglucon plate or/and reversible closed capillary chip, and it is an independent device that uses or a part of reaction kit or detecting instrument.
A kind of device of the present invention is characterised in that: it comprises the end face element that adapts with above-mentioned aglucon plate, and described end face element comprises capillary chamber end face, end face feed liquor structure 16, end face fluid structure 17, end face location structure 18 and end face seal element 19.
A kind of device of the present invention is characterised in that: described end face seal element comprises one or more combination of smooth flat, elastic coating and resistance wetting coating.
A kind of device of the present invention is characterised in that: the material of described end face element is selected from one of following or two or more combination arbitrarily: glass, silicon, metal oxide, metal and polymeric material and they derivant separately.
The principal advantages of aglucon plate of the present invention is: this capillary chamber chip-detecting apparatus combines the advantage of various chips described in the background technologies such as closed chamber chip and capillary chip, both had continued operation, had the equally distributed reliability of reaction medium again.Because adopted the capillary chamber design of single application of sample mouth, liquid is full of the whole capillary chamber that exports from entering the mouth to automatically, the phenomenon of aeration testing result can not occur.Since can continuous flow, it is controlled to inject sample size, can improve reaction sensitivity.Detection can also be according to reaction needed control medium use amount, and when particularly needing label, the consumption of label can be controlled at quite low level.Since can two-sided fixedly aglucon, the new way that improves sensitivity is provided.In a word, chip of the present invention, simple for production, highly sensitive, the consumption reaction medium is few, and is easy to operate and shortened detection time.
Accompanying drawing and drawing explanation:
Fig. 1: the closed reactor schematic top plan view on a kind of aglucon plate of the present invention
Fig. 2: the closed reactor a-a cross-sectional schematic on Fig. 1 aglucon plate
Fig. 3: a kind of reversible closed capillary chamber chip end face element elevational schematic view
Fig. 4: aglucon is the form synoptic diagram of ordered distribution at the capillary chamber
Fig. 5: a kind of aglucon is the closed reactor schematic top plan view of disorder distribution in capillary chamber wall, capillary chamber end face, capillary chamber bottom surface
Fig. 6: Fig. 5 closed reactor b-b cross-sectional schematic
Fig. 7: the closed reactor schematic top plan view on a kind of aglucon plate
Fig. 8: the closed reactor c-c cross-sectional schematic on Fig. 7 aglucon plate
Fig. 9: a kind of reversible closed reactor aglucon plate schematic top plan view
Figure 10: a kind of capillary chamber bottom surface and end face be the reversible closed capillary chamber chip schematic top plan view of aglucon fixedly
Figure 11: a kind of capillary chamber bottom surface and end face be the reversible closed capillary chamber chip d-d diagrammatic cross-section of aglucon fixedly
Figure 12: a kind of capillary chamber chip suction box schematic top plan view
Figure 13: a kind of end face is the reversible closed capillary chamber chip double-sided adhesive seal synoptic diagram of aglucon fixedly
Figure 14: a kind of end face is the reversible closed capillary chamber chip synoptic diagram of aglucon fixedly
Figure 15: the closed capillary chamber of a kind of capillary structure chip synoptic diagram
Figure 16: the closed capillary chamber of a kind of capillary structure chip synoptic diagram
Figure 17: be the closed capillary chamber of a kind of capillary structure of Figure 16 chip e-e diagrammatic cross-section
Figure 18: the closed capillary chamber of another kind of capillary structure chip synoptic diagram
Figure 19: the closed capillary chamber of another kind of capillary structure chip synoptic diagram
1, capillary chamber reactor 2, capillary chamber end face 3, capillary chamber bottom surface 4, capillary chamber wall 5, capillary chamber 6, capillary chamber chip aglucon 7, capillary chamber chip feed liquor structure 8, capillary chamber chip fluid structure 9, capillary chamber end face unit 10, capillary chamber bottom surface unit 11, aglucon is array distribution schematic diagram 12, aglucon is dotted line formula distribution schematic diagram 13, aglucon is solid line formula distribution schematic diagram 14, aglucon is empty bar formula distribution schematic diagram 15, aglucon is real bar formula distribution schematic diagram 16, reversible closed capillary chamber chip end face feed liquor structure 17, reversible closed capillary chamber chip end face fluid structure 18, end face location structure 19, end face seal element 20, hermetically-sealed construction 21, absorbent material
Embodiment:
Embodiment 1, a kind of irreversible closed capillary chamber chip
Slide in the present embodiment be respectively micro-year microslide available from U.S. ESCO SCIENTIFIC company (hereinafter to be referred as microslide, size 75 * 25 * 1.0mm) and cover glass (size 60 * 24 * 0.15mm).3 kinds of sheet bases in the present embodiment are by above-mentioned slide preparation: amino microslide, amino cover glass and pitch-dark microslide.The amination method of slide is with reference to " biomolecule mobilization technology and application " such as Jiang Zhonghua, Chemical Industry Press, Beijing, 1998).The preparation of pitch-dark microslide is with reference to " a kind of pick-up unit and detection method of object being carried out qualitative and/or quantitative test " (Chinese patent application number 031174469), used pitch-dark for the wound can spray (HD-036, B-92P, black pearl, Chinese Shanghai opens abundant industry development company).The width of amino cover glass is cut into 12.5.
Aglucon in the present embodiment is respectively HIV antigen and HCV antigen (hepatopathy research institute of Beijing people hospital), and their point sample concentration is all between 1.0-1.5mg/ml.In the present embodiment, also have the silicon oxide particle (diameter 20-40nm, Sigma-alderich company) of debita spissitudo (about 0.08mg/ml) to join in the antigenic solution.
1). the preparation of capillary chamber single face chip
Provide the preparation example of 3 kinds of capillary chamber single face chips in the present embodiment: the bottom surface element contains each a kind (being designated as A1 and A2 respectively) of hydrophilic sheet base (amino microslide) and hydrophobic flakes base (pitch-dark microslide) respectively, and the end face element contains a kind (being designated as A3) of hydrophilic sheet base (amino cover glass).
Contain the preparation of the element of sheet base: on above-mentioned base, the zone that will reserve outside fixedly 6 zones of aglucon (with reference to Figure 16, Figure 17, each regional wide 4mm) with high hydrophobic material (the high hydrophobic coating of organosilicon, Chengdu morning twilight chemical research institute) evenly is coated with full.After treating its dried overnight, above-mentioned aglucon solution is put in the above-mentioned reserved area with the form of 2 * 2 aglucon arrays of 2 points of every kind of aglucon with some model machine (GM 417ARRAYER, GENETIC MICROSYSTEMS company).After at room temperature bag is reacted 3 hours,, standby behind the cleaning-drying through the calf serum sealing.
In A1 and A2, used end face element is that (size 60 * 12.5 * 0.15mm), used bottom surface element is the element that contains the sheet base of above-mentioned preparation to above-mentioned cover glass.In A1 and A2, used end face element is the element that contains the sheet base of above-mentioned preparation, and used bottom surface element is an above-mentioned microslide (size 75 * 25.0 * 1.0mm).The end face element combines with the bottom surface element, adopts gluing method.Used tackifier is binary epoxide resin (versatile adhesive, a Chengdu morning twilight chemical research institute).With tackifier by the operation instructions scumbling on the super-hydrophobic coat of the element that contains the sheet base, again another element is stained with.After gluing the finishing, with the high hydrophobic coating of above-mentioned organosilicon on the element of bottom surface by Figure 16, shown in Figure 17 be coated with out each reactor go into liquid pool and filtrate liquor pool.
Prepared capillary chamber chip, its capillary chamber width is 4mm, and the spacing of end face and bottom surface is less than 0.08mm, and the Static Water contact angle 44 of surface of glass slide is spent, Static Water contact angle 58 degree of pitch-dark coating.
2). the preparation of capillary chamber two-sided chip:
Contain the preparation and present embodiment 1 of the element of sheet base) identical.Used end face element is based on amino cover glass, and used bottom surface element is based on amino microslide.With above-mentioned aglucon solution with above-mentioned point sample machine (GM 417 ARRAYER, GENETIC MICROSYSTEMS company) putting 2 * 2 aglucon square formations on the correspondence position territory of end face element and bottom surface element respectively with identical form, and wrapping and reacted and seal, clean and dry.The formation that combines and go into liquid pool and filtrate liquor pool of used end face element and bottom surface element is same as present embodiment 1).
Prepared capillary chamber chip (note is made A4), its capillary chamber end face and bottom surface are of a size of 4 * 12.5 (wide * height), and the spacing of end face and bottom surface is less than 0.08mm, and the Static Water contact angle 44 of surface of glass slide is spent.
3). the check of capillary chamber chip feature
Use PBS as Detecting medium in the present embodiment.With above-mentioned 1) and 2) in the chip that obtains erect (go into liquid pool below, filtrate liquor pool is up), with 8 pipe application of sample rifles 5ul PBS is injected liquid pool capillary chamber porch, observe the PBS aqueous solution and be full of the capillary chamber and to exporting through this inlet.
4). the use of capillary chamber chip
In the present embodiment, No. 1 sample is a HCV antibody positive serum, No. 2 samples are HIV1+2 antibody positive human serum, No. 3 positive testers of sample (potpourri of HCV antibody and HIV1+2 antibody positive serum tester), No. 4 negative testers of sample (potpourri of HCV antibody and HIV1+2 negative antibody serum tester).All samples all are to determine through using the classical open chip of single reactor to detect in advance under the equivalent responses condition.During experiment, 4 kinds of samples add above-mentioned capillary chamber single face chip (A1, A2 and A3) and capillary chamber two-sided chip (A4) respectively, and every kind of sample adds 2 reaction tanks.Sample is done suitably dilution during application of sample, and the application of sample amount is 3ul.
Add sample loading mode in the present embodiment and have two kinds:
(1). batch application of sample: after liquid-adding cell added sample, because capillary action, sample was full of the whole capillary chamber that exports from entering the mouth to automatically, does not observe bubble during operation.Chip is put into incubator, 37 ℃ of temperature of reaction, 5 minutes reaction time.
(2). continuous application of sample: sample is heated to 37 ℃ during operation, and sample is added liquid-adding cell with flow velocity 1ul/min, because capillary action, sample is full of the whole capillary chamber that exports from entering the mouth to automatically, does not observe bubble.5 minutes application of sample time.
Sample blotted with paper or extracts out with liquid-transfering gun through filtrate liquor pool after reaction was finished.Cleansing solution can add with batch formula or continous way, and the adding total amount is 20ul.
Label is the goat-anti people two anti-(Jackson ImmunoRresearch Laboratories company) of rhodamine mark.For reduce the label consumption as far as possible, present embodiment adds with batch formula, and addition is 3ul, temperature of reaction 37 degree, 5 minutes reaction time.Washing behind the labeled reactant is same as the washing behind the example reaction.Dry back directly uses laser co-focusing to detect result's (GMS of Afymetrix company 418 chip scanners) in micro-year, obtains result such as table 1 after the data processing.
Table 1 chip detection result
| Chip | HCV antibody positive serum | HIV antibody positive serum | Positive control | The negative control thing | ||||
| HCV antibody | HIV antibody | HCV antibody | HIV antibody | HCV antibody | HIV antibody | HCV antibody | HIV antibody | |
| Criticize application of sample | ||||||||
| ????A1* | ????+ | ??- | ??- | ????+ | ????+ | ????+ | ??- | ??- |
| ????A2* | ????+ | ??- | ??- | ????+ | ????+ | ????+ | ??- | ??- |
| ????A3* | ????+ | ??- | ??- | ????+ | ????+ | ????+ | ??- | ??- |
| ????A4* | ????+ | ??- | ??- | ????+ | ????+ | ????+ | ??- | ??- |
| ????A4** | ????+ | ??- | ??- | ????+ | ????+ | ????+ | ??- | ??- |
| Continuous application of sample | ||||||||
| ????A1* | ????+ | ??- | ??- | ????+ | ????+ | ????+ | ??- | ??- |
| ????A2* | ????+ | ??- | ??- | ????+ | ????+ | ????+ | ??- | ??- |
| ????A3* | ????+ | ??- | ??- | ????+ | ????+ | ????+ | ??- | ??- |
| ????A4* | ????+ | ??- | ??- | ????+ | ????+ | ????+ | ??- | ??- |
| ????A4** | ????+ | ??- | ??- | ????+ | ????+ | ????+ | ??- | ??- |
In the table, "+" positive result, "-" is the yin constipation fruit; * be respectively the result of 10 times of dilutions of sample and 20 times of dilutions with * *
2 kinds of sheet bases in the present embodiment (amino microslide and pitch-dark microslide) and 2 kinds of aglucons (HCV antigen and HIV antigen) and embodiment 1 are together.
1). the preparation of bottom surface element:
(1). with the resilient material is the bottom surface element of capillary chamber wall and hermetically-sealed construction: on amino microslide, with resilient material (dried certainly silicone rubber solution, Chengdu morning twilight chemical research institute) will reserve 8 zones of fixing aglucon (with reference to figure 3, Fig. 4, each regional wide 4mm) zone outside evenly is coated with full, and the resilient material bed thickness is less than 0.06mm.After treating its dried overnight, above-mentioned aglucon solution is put in the above-mentioned reserved area with the form of 2 * 2 aglucon arrays of 2 points of every kind of aglucon with some model machine (GM 417 ARRAYER, GENETIC MICROSYSTEMS company).After at room temperature bag is reacted 3 hours,, standby behind the cleaning-drying through the calf serum sealing.Institute obtains bottom surface element note and makes a1.
(2). with high hydrophobic material is the bottom surface element of capillary chamber wall and hermetically-sealed construction: in the present embodiment, among the preparation of bottom surface element and the embodiment 1 1) the element that contains the sheet base preparation with.High hydrophobic material material bed thickness is less than 0.06mm.The bottom surface element based on amino microslide and pitch-dark microslide that is obtained is remembered respectively and is made a2 and a3.
(3). with high hydrophobic material is that capillary chamber wall, resilient material are the bottom surface element of capillary cavity seal: on amino microslide, with high hydrophobic material (the high hydrophobic coating of organosilicon, Chengdu morning twilight chemical research institute) reserving formation boundary line coating on the border of fixedly 8 zones of aglucon (each regional wide 4mm), treat after its drying again with resilient material (dried certainly silicone rubber solution, Chengdu morning twilight chemical research institute) zone outside the hydrophobic border of height evenly is coated with completely, elastic coating is a little more than high hydrophobic coating (bed thickness is less than 0.05mm).Again above-mentioned aglucon solution is wrapped quilt, method for coating is with present embodiment 1) it (1).Institute obtains bottom surface element note and makes a4.
(4). with the adhesive material is the bottom surface element of capillary chamber wall and hermetically-sealed construction: on amino microslide, stick with glue material (teflon single face adhesive sticker, Chengdu morning twilight chemical research institute) will reserve zone evenly bonding (bed thickness is less than 0.2mm) outside fixedly 8 zones of aglucon (reference diagram, each regional wide 4mm).Above-mentioned aglucon solution is wrapped quilt, and method for coating is with present embodiment 1) it (1).Institute obtains bottom surface element note and makes a5.
(5). the bottom surface element of no capillary chamber wall and hermetically-sealed construction: directly above-mentioned aglucon is coated on the amino microslide, method for coating is with present embodiment 1) it (1).Institute obtains bottom surface element note and makes a6.
2). the preparation of end face element:
(1). the end face element of no molding structure: this end face element (Fig. 3) is the reusable corrosion resistant plate that liquid in-out mouth, liquid in-out pipe are arranged of size 100mm * 40mm * 2mm (long * wide * thick).Its face that contacts with the bottom surface element is the plane, no hermetically-sealed construction.Its each corresponding to the turnover liquid zone of each reaction tank on liquid in-out mouth and the bottom surface element.The institute's end face element that obtains note is made b1.
(2). the end face element of molding structure is arranged: this end face element (Fig. 3) is the reusable corrosion resistant plate that liquid in-out mouth, liquid in-out pipe are arranged of size 100mm * 40mm * 2mm (long * wide * thick).Its with face that the bottom surface element contacts on hermetically-sealed construction is arranged.Its hermetically-sealed construction be with bottom surface element reaction tank outside regional corresponding elastomeric layer (dried certainly silicone rubber solution, Chengdu morning twilight chemical research institute) (bed thickness is less than 0.1mm).Its each corresponding to the turnover liquid zone of each reaction tank on liquid in-out mouth and the bottom surface element.The institute's end face element that obtains note is made b2.
3). the check of capillary chamber chip feature
Use PBS as Detecting medium in the present embodiment.With above-mentioned 1) and 2) middle chip end face element that obtains and bottom surface element do sealing binding.Present embodiment uses mechanical jig pressure to form described sealing binding.Various combination according to end face element and bottom surface element forms different chip (seeing Table 2).End face element and bottom surface combination of elements thing are erect (liquid inlet below, liquid outlet up), added PBS respectively and go into the porch to the capillary chamber, open liquid inlet is observed the PBS aqueous solution and is full of the capillary chamber and to outlet through this inlet.
4). the use of capillary chamber chip
In the present embodiment, specimen in use is with embodiment 1.During experiment, 4 kinds of samples add above-mentioned capillary chamber chip (table 2) respectively, and every kind of sample adds 2 reaction tanks.Sample is done suitably dilution during application of sample.
Add sample loading mode in the present embodiment and have two kinds:
(1). batch application of sample: stop after liquid-adding cell adds sample and extremely exports during operation, because capillary action, sample is full of the whole capillary chamber that exports from entering the mouth to automatically, does not observe bubble.Chip is put into incubator, 37 ℃ of temperature of reaction, 5 minutes reaction time.
(2). continuous application of sample: sample is heated to 37 ℃ during operation, and sample is added liquid-adding cell with priority with flow velocity 10ul/min and 1ul/min.5 minutes application of sample time.
Sample blotted with paper or extracts out with machinery through liquid outlet after reaction was finished.Cleansing solution can add with batch formula or continous way, and the adding total amount is 40ul.
Label is the goat-anti people two anti-(Jackson ImmunoRresearch Laboratories company) of rhodamine mark.For reduce the label consumption as far as possible, present embodiment adds with batch formula, and addition is about 5ul, 37 ℃ of temperature of reaction, 5 minutes reaction time.Washing behind the labeled reactant is same as the washing behind the example reaction.Dry back directly uses laser co-focusing to detect result's (GMS of Afymetrix company 418 chip scanners) in micro-year, obtains result such as table 1 after the data processing.
Table 2 chip detection result
| Chip | The end face element | The bottom surface element | HCV antibody positive serum | HIV antibody positive serum | Positive control | The negative control thing | ||||
| HCV antibody | HIV antibody | HCV antibody | HIV antibody | HCV antibody | HIV antibody | HCV antibody | HIV antibody | |||
| ????1 | ??B1 | ??A1 | ??+ | ??- | - | ???+ | ??+ | ??+ | ??- | - |
| ????2 | ??B1 | ??A2 | ??+ | ??- | - | ???+ | ??+ | ??+ | ??- | - |
| ????3 | ??B1 | ??A3 | ??+ | ??- | - | ???+ | ??+ | ??+ | ??- | - |
| ????4 | ??B1 | ??A4 | ??+ | ??- | - | ???+ | ??+ | ??+ | ??- | - |
| ????5 | ??B1 | ??A5 | ??+ | ??- | - | ???+ | ??+ | ??+ | ??- | - |
| ????6 | ??B2 | ??A6 | ??+ | ??- | - | ???+ | ??+ | ??+ | ??- | - |
| ????7 | ??B2 | ??A1 | ??+ | ??- | - | ???+ | ??+ | ??+ | ??- | - |
| ????8 | ??B2 | ??A2 | ??+ | ??- | - | ???+ | ??+ | ??+ | ??- | - |
| ????9 | ??B2 | ??A3 | ??+ | ??- | - | ???+ | ??+ | ??+ | ??- | - |
In the table, "+" positive result, "-" is the yin constipation fruit
Embodiment 3, a kind of capillary chip
2 kinds of sheet bases in the present embodiment (amino microslide and amino cover glass) are same with embodiment 1, and 2 kinds of aglucons are HBS:Ag and HBS:Ad (hepatopathy research institute of Beijing people hospital).
1). the preparation of capillary chip
The fixedly preparation of aglucon element: on above-mentioned base, to reserve the reaction tank of fixing 3 * 3mm of aglucon (long * wide) and the reactive channel of 57 * 0.4mm (long * wide) and the zone outside the microchannel therebetween with high hydrophobic material (the high hydrophobic coating of organosilicon, Chengdu morning twilight chemical research institute) and evenly be coated with full (figure).After treating its dried overnight, above-mentioned HBS:Ag and HBS:Ab solution (1.0-1.5mg/ml) are wrapped respectively by to reaction tank and reactive channel.After at room temperature bag is reacted 4 hours,, standby behind the cleaning-drying through the calf serum sealing.
The used end face element of single face capillary chip is that (size 60 * 12.5 * 0.15mm), used bottom surface element are the (size 75 * 25 * 1.0mm) of the element based on amino microslide of above-mentioned preparation to above-mentioned cover glass.The used end face element of two-sided capillary chip is that (size 60 * 12.5 * 0.15mm), used bottom surface element are the (size 75 * 25 * 1.0mm) of the element based on amino microslide of above-mentioned preparation to above-mentioned element based on amino cover glass.The end face element combines with the bottom surface element, adopt with embodiment 1 1) in gluing method.After gluing the finishing, on the element of bottom surface, go into liquid pool and filtrate liquor pool by what be coated with out reactor shown in the figure with the high hydrophobic coating of above-mentioned organosilicon.Single face capillary chip and two-sided capillary chip are remembered respectively and are made B31 and B32.
Prepared capillary chip, its capillary chamber width is 3mm, and the kapillary width is less than 0.45mm, and the spacing of end face and bottom surface is less than 0.08mm, and the Static Water contact angle 44 of surface of glass slide is spent.
2). the inspection by attributes of capillary chip
Use PBS as Detecting medium in the present embodiment.With above-mentioned 1) in the chip that obtains erect (go into liquid pool below, filtrate liquor pool is up), 5ul PBS is injected place, liquid pool capillary inlet, observe the PBS aqueous solution and be full of kapillary and capillary chamber and overflow from outlet through this inlet.
3). the use of capillary chip
In the present embodiment, No. 1 sample is a HBs antigen positive human serum, and No. 2 samples are HBs antigen negative serum.All samples all are to determine through using the classical open chip of single reactor to detect in advance under the equivalent responses condition.During experiment, 2 kinds of samples add above-mentioned capillary chip (B31 and B32) respectively.
Add sample loading mode in the present embodiment and have two kinds:
(1). batch application of sample: during operation after liquid-adding cell adds sample (the application of sample amount is 3ul) because capillary action, sample be full of automatically whole from inlet, kapillary, capillary chamber to outlet, do not observe bubble.Chip is put into incubator, temperature of reaction 37 degree, 5 minutes reaction time.
(2). continuous application of sample: sample is heated to 37 degree during operation, and sample is added liquid-adding cell with flow velocity 1ul/min, because capillary action, sample is full of the whole capillary chamber that exports from entering the mouth to automatically, does not observe bubble.5 minutes application of sample time.
Sample blotted with paper or extracts out with liquid-transfering gun through filtrate liquor pool after reaction was finished.Cleansing solution can add with batch formula or continous way, and the adding total amount is 20ul.
Label is the HBS:Ab of rhodamine mark.For reduce the label consumption as far as possible, present embodiment adds with batch formula, adds from outlet, and addition is 3ul, temperature of reaction 37 degree, 5 minutes reaction time.Washing behind the labeled reactant is same as the washing behind the example reaction but adds cleansing solution from outlet.Dry back directly uses laser co-focusing to detect result's (GMS of Afymetrix company 418 chip scanners) in micro-year, obtains result such as table 3 after the data processing.
Table 3 chip detection result
| Chip | HBs antigen positive serum | HBs antigen negative serum |
| Criticize application of sample | ||
| ??B31* | ??+ | ??- |
| ??B32* | ??+ | ??- |
| ??B32** | ??+ | ??- |
| Continuous application of sample | ||
| ??B31* | ??+ | ??- |
| ??B32* | ??+ | ??- |
| ??B32** | ??+ | ??- |
In the table, "+" positive result, "-" negative result;
* be respectively the result of 10 times of dilutions of sample and 20 times of dilutions with * *
Embodiment 4, a kind of device
A device of the instrument of present embodiment or detecting instrument is seen Fig. 3, corrosion resistant plate for size 100mm * 40mm * 2mm (long * wide * thick), form the end face element that adapts with the aglucon plate, the end face element comprises capillary chamber end face 4, end face feed liquor structure 16, end face fluid structure 17, end face location structure 18, end face seal element 19.The enterprising liquid outlet of plate passes the place that steel plate reaches another side the interface that links the liquid in-out pipe, and the relevant position with the aglucon array on the corrosion resistant plate is stained with the fluororubber hermetically-sealed construction that thickness is 0.4mm, also includes location structure, fastening structure.The fluororubber hermetically-sealed construction is the fluororubber of reusable not adhesion protein.The reversible packoff of present embodiment mechanical connection part as instrument or detecting instrument on detecting instrument.During use, with being equipped with miniflow pump, constant temperature camera incubata and/or programmable controller to become the closed capillary chamber chip special testing instrument of present embodiment.
Claims (24)
1, capillary chamber chip, be characterised in that: it contains at least one irreversible closed or reversible closed capillary chamber reactor (1) on one side at least, described capillary chamber reactor comprises the capillary chamber (5) that contains end face (2) and bottom surface (3) and chamber wall (4), be fixed on bottom surface in the described capillary chamber or/and the aglucon on the end face (6) and feed liquor structure (7) that is communicated with described capillary chamber and fluid structure (8), the size that comprises end face and bottom surface of capillary chamber wherein, the selection of spacing and material character makes reaction medium to form capillarity in described capillary chamber, described reaction medium comprises aqueous solution or/and organic liquid, and described material character comprises water wettability or/and hydrophobicity.
2, a kind of capillary chamber chip according to claim 1, be characterised in that: it contains the one or more capillary chamber reactor that is formed or participated in forming by end face element (9) and bottom surface element (10), and at least one includes the sheet base in described end face element and the bottom surface element.
3, a kind of capillary chamber chip according to claim 2 is characterised in that: aglucon wherein, it is the ordered distribution that comprises array (11), dotted line formula (12), solid line formula (13), empty bar formula (14) and real bar formula (15) on described base.
4, a kind of capillary chamber chip according to claim 3, be characterised in that: capillary chamber wherein, the maximum lateral width of its end face and bottom surface is 0.5mm-75mm, preferred version 1.5mm-35mm, the spacing of its end face and bottom surface less than 500um, preferred version less than 100um, its end face or/and the static reaction medium contact angle of bottom surface material less than 70 the degree, preferred version less than 50 the degree, more preferably scheme less than 35 the degree.
5, a kind of capillary chamber chip according to claim 4, be characterised in that: it contains irreversible closed capillary chamber reactor, described sealing be by between end face element and the bottom surface element comprise bonding or/and hot fusion or/and the mode of HF or sodium silicate low-temperature bonding form.
6, a kind of capillary chamber chip according to claim 5 is characterised in that: wherein participate in to form the end face componentry of capillary chamber at least or/and the bottom surface componentry is transparent and thickness less than 1mm, preferred version less than 0.2mm.
7, a kind of capillary chamber chip according to claim 6, be characterised in that: it can directly detect reaction result by the confocal fluorescent scanner.
8, a kind of capillary chamber chip according to claim 4, be characterised in that: it contains reversible closed capillary chamber reactor, end face element wherein is or/and contain the capillary chamber wall and be communicated with or disconnected basic hermetically-sealed construction with described chamber wall in the element of bottom surface, described basic hermetically-sealed construction comprise mechanical seal structure or/and physical chemistry isolating seal structure or/and the adhesive sealing structure.
9, a kind of capillary chamber chip according to claim 8 is characterised in that: described chamber wall is or/and mechanical seal structure comprises macromolecule material coating or sheet or the band that contains Shao Er hardness 20-100 degree.
10, a kind of capillary chamber chip according to claim 9 is characterised in that: described macromolecular material comprises and contains following one or more the material of macromolecule combination: natural rubber, nitrile rubber, butyl rubber, fluororubber, silicon rubber, fluorosioloxane rubber, organosilicon polymer, fluoropolymer, plastics.
11, a kind of capillary chamber chip according to claim 8 is characterised in that: described chamber wall or/and physical chemistry isolating seal structure comprise contain static reaction medium contact angle greater than 80 the degree macromolecular materials or/and thin reaction medium coating, sheet or the band of nano material.
12, a kind of capillary chamber chip according to claim 11, be characterised in that: described macromolecular material comprises the material that contains organosilicon or fluoropolymer.
13, a kind of capillary chamber chip according to claim 11 is characterised in that: described nano material comprises and contains the derivant that following one or more the modification of nano-powder is combined with hydrophobic group: gold, vanadium, lead, silver, iron and oxide powder thereof and monox, titanium dioxide, alumina powder jointed.
14, a kind of capillary chamber chip according to claim 8, be characterised in that: described chamber wall is or/and the adhesive sealing structure comprises reversible adhesive layer and irreversible adhesive layer, and the capillary chamber forms open chamber by open top side or bottom surface when needed when being irreversible adhesive layer.
15, according to the described a kind of capillary chamber chip of one of claim 1-14, be characterised in that: wherein said capillary chamber end face is or/and the material of bottom surface is selected from one of following or two or more combination arbitrarily: glass, silicon and silicon compound, metal oxide, metal and polymeric material and they derivant separately.
16, a kind of capillary chamber chip according to claim 15 is characterised in that: wherein said aglucon is the material that is selected from one or both and two or more combination in any in following group: aptamer molecule, polypeptide and the strand of antigen, antibody, part, part index enhanced system evolution technology screening or multichain DNA, nucleotide, polynucleotide, sugar, enzyme, co-factor, microbiotic, steroids, virus, cell altogether.
17, a kind of capillary chamber chip according to claim 15 is characterised in that: in the capillary chamber wherein fixedly the mask of aglucon array close reaction medium character is arranged and not fixedly the mask of aglucon array thin reaction medium character is arranged.
18, a kind of capillary chamber chip according to claim 15 is characterised in that: described capillary chamber reactor feed liquor structure is inhaled reaction medium material or/and kapillary or/and the fluid structure contains close reaction medium.
19, capillary chip is characterised in that: the structure that is fixed with aglucon in wherein all reactors all has the capillarity of reaction medium, and wherein has at least one to be above-mentioned capillary chamber reactor.
20, a kind of capillary chip according to claim 19 is characterised in that: be fixed with antigen in its at least one reactor, and be fixed with in another reactor and described antigen corresponding antibody.
21, a kind of chip component, be characterised in that: its for above-mentioned capillary chamber chip or/and the end face element of capillary chip or/and bottom surface element or described end face element or/and the preparation element of bottom surface element, described preparation element contains the bottom surface of at least one above-mentioned capillary chamber reactor or end face, partly or entirely chamber wall and part or all of enclosed construction at least on the one side.
22, a kind of device is characterised in that: it forms above-mentioned reversible closed capillary chamber chip or/and reversible closed capillary chip with above-mentioned aglucon plate.
23, a kind of device according to claim 22, be characterised in that: it comprises the end face element that adapts with above-mentioned aglucon plate, described end face element comprises capillary chamber end face, end face feed liquor structure 16, end face fluid structure 17, end face location structure 18 and end face hermetically-sealed construction 19, and it is an independent device that uses or a part of reaction kit or detecting instrument.
24, a kind of device according to claim 22 is characterised in that: described end face hermetically-sealed construction comprises one or more combination of smooth flat, elastic coating and resistance wetting coating.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03135958 CN1253585C (en) | 2003-09-30 | 2003-09-30 | Capillary chamber chip, capillary chip and chip element and device |
| PCT/CN2004/000169 WO2004083863A1 (en) | 2003-03-04 | 2004-03-04 | An integrating analysis chip with minimized reactors and its application |
| CN200480000654.9A CN1697976B (en) | 2003-03-04 | 2004-03-04 | High integration analysis chip of minimized height for reactor and application |
| US10/547,681 US20060182655A1 (en) | 2003-03-04 | 2004-03-04 | Integrating analysis chip with minimized reactors and its application |
| JP2006504196A JP2006519384A (en) | 2003-03-04 | 2004-03-04 | Highly integrated analysis chip with extremely small height reactor and its application |
| EP04717012A EP1605264B1 (en) | 2003-03-04 | 2004-03-04 | An integrating analysis chip with minimized reactors and its application |
| PCT/CN2004/001128 WO2005073363A1 (en) | 2003-09-30 | 2004-09-30 | An analysis chip, an apparatus comprising the chip, the chip test kit and the measurement method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03135958 CN1253585C (en) | 2003-09-30 | 2003-09-30 | Capillary chamber chip, capillary chip and chip element and device |
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| Publication Number | Publication Date |
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| CN1529170A true CN1529170A (en) | 2004-09-15 |
| CN1253585C CN1253585C (en) | 2006-04-26 |
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| CN 03135958 Expired - Fee Related CN1253585C (en) | 2003-03-04 | 2003-09-30 | Capillary chamber chip, capillary chip and chip element and device |
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| CN (1) | CN1253585C (en) |
| WO (1) | WO2005073363A1 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1786710B (en) * | 2004-12-06 | 2011-12-14 | 财团法人工业技术研究院 | Microfluid chip for testing analysing body and its method |
| CN102818887A (en) * | 2006-04-25 | 2012-12-12 | 松下电器产业株式会社 | Immunological assay and chip |
| CN110538680A (en) * | 2019-08-19 | 2019-12-06 | 昆山汇先医药技术有限公司 | Micro-fluidic sample processing equipment |
| CN111356528A (en) * | 2017-11-22 | 2020-06-30 | 惠普发展公司，有限责任合伙企业 | Multi-region microfluidic devices |
| US11321454B2 (en) | 2016-01-25 | 2022-05-03 | Hewlett-Packard Development Company, L.P. | Notice of intrusion into firmware |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108982826B (en) * | 2018-09-28 | 2024-03-26 | 广东工业大学 | Test device and test method for detecting embryotoxicity of nano particles by zebra fish |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5491097A (en) * | 1989-06-15 | 1996-02-13 | Biocircuits Corporation | Analyte detection with multilayered bioelectronic conductivity sensors |
| JP3052961B1 (en) * | 1998-11-09 | 2000-06-19 | 株式会社 東海技研工業 | Sexual sensation body stimulator and its storage device |
| CN1117284C (en) * | 1999-10-27 | 2003-08-06 | 陆祖宏 | Microfluid biochip detection-analysis board and its detection method |
| CN1325026A (en) * | 2001-07-10 | 2001-12-05 | 重庆大学 | Piezoelectric biological chip miniflow detector |
| CN1208622C (en) * | 2003-03-04 | 2005-06-29 | 成都夸常科技有限公司 | Biological chip with minimized reactor isolation structure height and its preparation method |
| CN1250969C (en) * | 2003-03-13 | 2006-04-12 | 成都夸常科技有限公司 | Test device and method for making qualitative and/or quantitative analysis to object |
-
2003
- 2003-09-30 CN CN 03135958 patent/CN1253585C/en not_active Expired - Fee Related
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2004
- 2004-09-30 WO PCT/CN2004/001128 patent/WO2005073363A1/en active Application Filing
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1786710B (en) * | 2004-12-06 | 2011-12-14 | 财团法人工业技术研究院 | Microfluid chip for testing analysing body and its method |
| CN102818887A (en) * | 2006-04-25 | 2012-12-12 | 松下电器产业株式会社 | Immunological assay and chip |
| CN102818887B (en) * | 2006-04-25 | 2015-04-01 | 松下电器产业株式会社 | Immunological assay and chip |
| US11321454B2 (en) | 2016-01-25 | 2022-05-03 | Hewlett-Packard Development Company, L.P. | Notice of intrusion into firmware |
| CN111356528A (en) * | 2017-11-22 | 2020-06-30 | 惠普发展公司，有限责任合伙企业 | Multi-region microfluidic devices |
| CN110538680A (en) * | 2019-08-19 | 2019-12-06 | 昆山汇先医药技术有限公司 | Micro-fluidic sample processing equipment |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1253585C (en) | 2006-04-26 |
| WO2005073363A1 (en) | 2005-08-11 |
| WO2005073363A8 (en) | 2005-10-13 |
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