CN1125184C - Low density biochip and its making process - Google Patents
Low density biochip and its making process Download PDFInfo
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- CN1125184C CN1125184C CN 00129440 CN00129440A CN1125184C CN 1125184 C CN1125184 C CN 1125184C CN 00129440 CN00129440 CN 00129440 CN 00129440 A CN00129440 A CN 00129440A CN 1125184 C CN1125184 C CN 1125184C
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Abstract
The present invention relates to a low-density biochip and a manufacturing method thereof. The low-density biochip is used for detecting whether antigens or antibodies, medicines or receptors and complementary DNA or RNA exist in samples to be detected or not, and is mainly composed of a carrier substrate and a sample applicator on the carrier substrate, wherein a marker is also arranged on the sample applicator, the sample applicator is in tight contact with the marker, and the sample applicator and the marker are printed on the carrier substrate according to particular programs. The low-density biochip of the present invention has the advantages of simple structure, convenient operation, sensitivity and accuracy.
Description
The invention belongs to biomedical check field, particularly a kind of low-density biochip.The invention still further relates to the making method of this low-density biochip.
The prior biological chip is meant the microarray of the high-density DNA that is coated on the solid phase carrier, antigen, antibody, cell or tissue.Be to utilize the ability that has special mutual identification between biomacromolecule and with their orderly being arranged on the solid phase carrier substrate (film, sheet glass, silicon chip etc.), react simultaneously with the biomolecules of test sample and mark or hybridize, can obtain a large amount of useful bioinformations through automatic reading equipment.
DNA chip in the biochip claims gene chip again, is a kind of highdensity oligonucleotide (dna probe) microarray.It adopts the photoetching technique of former bit pattern synthetic chemistry and microelectronic chip, perhaps utilizes additive method that the dna fragmentation (probe) of a large amount of particular sequences is solidificated on glass or the silicon chip in an orderly manner, thereby constitutes the DNA chip that stores a large amount of life-informations.
Peptide chips in the biochip is that peptide or protein is fixing on specific solid phase carrier matrix, utilize peptide or albumen mass-energy specificity and ligand molecular (as antigen or antibody) bonded principle, with serum or sample liquid generation specific reaction, by corresponding tagged molecule, be used for detecting on a large scale antigen, antibody or protein, polypeptide fragment then.
Peptide chips is called protein chip again, its ultimate principle with gene chip is identical, in conjunction with immune labeled reactant, on a kind of solid phase carrier substrate, with diverse ways directly thereon with the multiple proteins (antigen or antibody) of different sources, make it and the carrier substrate mortise, form proteinic microarray, i.e. protein chip.Antigen or antibody materials major part all are protein, and the combination of antigen-antibody is again specific, can add that on antigen or antibody various marks are to detect corresponding antibody or antigen.Antigen-antibody carries out specific immune response with the protein molecule (antibody or antigen) that has a special marking on protein chip, both in conjunction with after, realize the mutual inspection of antigen-antibody being used to detect corresponding antibody or antigen by detection to marker.The characteristics of this technology are traceization, parallelization, and the detection that can be widely used in antigen-antibody and clinical disease waits each field.
The ultimate principle of utilizing the antigen and antibody specific immune response to detect has following several:
1, sandwich sandwich assay: the antibody in bonded antigen or antibody on the solid phase carrier+sample to be checked or antigen+labelled antigen or antibody, be used for detecting the antibody or the antigen of sample to be checked, it is positive to develop the color, colourless negative.
2, dibit point single stage method: the monoclonal antibody of the another kind of different antigenic determinants of the antigen+mark in bonded monoclonal antibody on the solid phase carrier+sample to be checked, be used for detecting the antigen of sample to be checked, it is positive to develop the color, colourless negative.
3, indirect method: the antibody in bonded antigen on the solid phase carrier+sample to be checked+mark anti-antibody or two anti-antibodys, be used for detecting the antibody of sample to be checked, it is positive to develop the color, colourless negative.
4, prize law: the antibody+specific antigens on the solid phase carrier in the anti-human IgM antibody of bonded+sample to be checked and at the traget antibody of specific antigens, be used for detecting the IgM antibody of sample to be checked, it is positive to develop the color, colourless negative.
Above-mentioned biochip such as gene chip adopt original position mode synthetic and directly point sample to prepare more.The synthetic oligonucleotide that is applicable to of original position, directly point sample is used for large fragment DNA more, also is used for oligonucleotide even mRNA sometimes.Original position is synthesized photolithography, spray printing method and molecular seal method.With in-situ synthesis relatively, the point sample method is simpler, only need samples such as the oligonucleotide that will prepare in advance or cDNA by automatic spot sample device point on the sheet glass of special processing or other material, getting final product.
Synthetic ratio juris of original position spray printing and spray ink Printing are similar, but that chip jet-printing head and print cartridge have is a plurality of, and what adorn in the print cartridge is four kinds of liquid rather than carbon dusts such as base.Jet-printing head can move on the entire chip and according to chip on the sequence needs of different loci oligonucleotide probe with specific base spray printing specific position on chip.The principles of chemistry that this technology adopts are consistent with traditional DNA solid phase synthesis, therefore do not need the chemical reagent of special preparation.The spray printing synthesis method is not owing to need directly to contact with carrier surface, thus very high efficient is arranged, but manufacturing process is also not overripened.
Synthetic point sample method is that synthetic good oligonucleotide probe, cDNA or genomic dna are taken out direct printing or spray printing in chip on oligonucleotide probe from porous plate by the three-dimensional control of specific high speed spotting robot printings/spray printing pin.Syringe needle contacts with chip when directly printing, and when spray printing syringe needle and chip maintenance certain distance.The advantage of impact system is an oligonucleotide probe density height, and shortcoming is that quantitative accuracy and circulation ratio are bad, print needle easily stop up and work-ing life limited.The advantage of spray printing method is quantitatively accurately, favorable reproducibility, long service life.Shortcoming is that the spot of spray printing is big, and oligonucleotide probe density is low.
The covalent attachment method is with synthetic good specific oligonucleotides probe, adopts special covalent chemical technology oligonucleotide probe to be incorporated into the specific region of chip in the microchannel.DNA isolation or RNA and it is carried out fluorescent mark from testing sample, sample flow is crossed chip then, and the fixed oligonucleotide probe is caught phase complementary nucleic acid with it, adopts Gene Logic ' s signal detection system analytical results.This flow type chip is used for the variation of high throughput analysis known, and its characteristics are (1) susceptibility height: because the variation that the formula chip can be monitored rare genetic expression is flow through in the increase on oligonucleotide probe absorption surface; (2) speed is fast: hybridization has been quickened in the microchannel, has reduced each detection required time; (3) price reduces: owing to adopted special covalent chemical technology that oligonucleotide probe is adsorbed in the microchannel, making each flow through the formula chip can use repeatedly repeatedly, thereby its cost is reduced.
Above-mentioned preparation method's complex process needs special expensive equipment usually, is unfavorable for conventional the application.Original position is synthetic higher to the substrate material requirement condition in addition; Directly during point sample owing to adopt complicated technology; regular meeting causes irreversible sex change of generation such as active substance such as DNA or RNA, antigen or antibody, medicine or acceptor, tissue or cell or active loss in the sampling liquid; influence the detection sensitivity and the specificity of biochip, even influenced the stability and the preservation period of biochip.Because the manufacturing process complexity, respective detection means requirement condition is also very high, causes manufacturing and application cost higher, has limited the wide popularization and application of this high-tech technology.
Task of the present invention is: provide a kind of sensitivity and accuracy high and can stablize and deposit and the preparation method is easy, be fit to the low-density biochip device produced in batches.
The invention still further relates to the making method of above-mentioned low-density biochip.
The present invention is achieved in that
A kind of low-density biochip, the existence that is used to detect the antigen of testing sample kind or antibody, medicine or acceptor, complementary DNA or RNA whether, mainly form by carrier substrate and the point sample thing that is solidificated on this carrier substrate, it is characterized in that: also contain marker on the point sample thing on the carrier substrate simultaneously, the two contacts closely; Above-mentioned marker and point sample thing be shaped as point-like or wire, the number of marker and point sample thing is every square centimeter of 10-500, wherein the diameter of point-like marker and point sample thing is the 50-500 micron, the length of wire marker and point sample thing is the 50-500 micron.
Above-mentioned point sample thing is used for catching the determinand of sample to be checked; Marker is the marker of above-mentioned point sample thing, is used for showing the determinand of the sample to be checked of being caught by the point sample thing.
Its making method mainly is that synthetic or the good dissimilar point sample thing of purifying are respectively charged in the different separately print cartridge of ink-jet printer with marker, utilize existing word processor on the computer or other software successively the point sample thing to be printed on the corresponding site on the carrier substrate then, then with on the calf serum sealing carrier substrate not in conjunction with the active group of point sample thing, utilize on the computer existing word processor or other software marker to be printed on the site of corresponding point sample thing successively again with ink-jet printer.
The feature of making method of the present invention is: same delegation on carrier substrate or the same marker that lists are identical with the point sample thing, can carry out as required arbitrarily cutting into different low-density biochip bars by column or row, the low-density biochip bar of these well cuttings can arbitrarily splice again according to actual needs, can be prepared into the low-density biochip device of different purposes or multiple use or various ways in view of the above, to reach the purpose of traceization, the multiple antigen of paralleled detection or antibody and multiple disease.
The present invention is owing to contain marker and point sample thing simultaneously on carrier substrate, only need once add serum or whole blood sample, specific immune response takes place in antibody or antigen in antigen in marker and the point sample thing or antibody and serum to be checked or the whole blood, wash away the material that does not react then, by the color reaction observations of marker.If corresponding antibody or antigen are arranged in serum to be checked or the whole blood, color reaction takes place with regard to energy specificity binding label, the result is positive; If do not have corresponding antibody or antigen in serum to be checked or the whole blood, just can not the specificity binding label, marker is washed to be removed, and just color reaction can not take place, and the result is negative.This device need not add liquid marker again, and easy and simple to handle the result is easy to observe accurately and reliably fast, sensitivity and accuracy height, and can stablize and deposit.Its room temperature stability can be marked percolation process with gold and compare favourably, be applicable to sandwich sandwich assay, dibit point single stage method, indirect method and prize law to be immune labeled method mensuration antigen or antibody, medicine or the acceptor of principle, can also carry out the detection of complementary DNA or RNA, has simple in structure, easy to operate and sensitive, advantage accurately, and preparation technology is simple, and is with low cost.
Accompanying drawing is the vertical extended sectional view of the present invention.
The present invention is described in further detail below in conjunction with accompanying drawing.
In the accompanying drawing, 1 is that marker, 2 is that point sample thing, 3 is carrier substrate.
As shown in drawings, the present invention is a kind of low-density biochip device, mainly is made up of marker 1, point sample thing 2 and carrier substrate 3, and carrier substrate 3 is flexible membranaceous substrate, contain marker 1 and point sample thing 2 on it simultaneously, contact closely between marker 1 and the point sample thing 2.Point sample thing 2 can be multiple parts such as dna probe, cDNA probe, peptide nucleic acid probe, mRNA, antigen, antibody (comprising the monoclonal antibody of different loci, anti-people IgM capture antibody, anti-human IgG antibody or two anti-antibodys), drug receptor, polysaccharide lectin, cell or tissue, is used for catching the determinand of sample to be checked; Marker 1 is the marker of above-mentioned part or acceptor, can be markers such as golden mark, enzyme labelling, fluorescent mark, chemiluminescent labeling, electrochemiluminescence mark and radio-labeling, is used for showing the determinand of the sample to be checked of being caught by point sample thing 2.
Above-mentioned marker 1 and point sample thing mostly 2 are synthetic or purifying is good and adopt trehalose to carry out stabilization treatment.Its making method is: get the dissolved in distilled water that the marker 1 of 1-10mg dry weight or point sample thing 2 and 30-100mg trehalose add 1ml and be stabilization liquid, also can add the trehalose of 30-100mg in the solution 1ml that contains 1-10mg/ml marker 1 or point sample thing 2, the weight ratio of marker or point sample thing and trehalose is 1: 10-30.Be respectively charged in the corresponding print cartridge marker 1 and the point sample thing 2 of aforementioned stable processing standby.
Making method of the present invention mainly comprises: with containing the flexible membranaceous substrate of active group as carrier substrate 3, the membranaceous substrate of this flexibility can be inorganic, organic polymer thin films such as glassine paper, tunica fibrosa, plastic film, it is characterized in that: the film water-fast, that resistance to acids and bases good and the enough general ink-jet printers of energy are printed.
The feature of making method of the present invention is: get synthetic or purifying is good and adopt trehalose to carry out the two or more point sample things 2 of stabilization treatment, be respectively charged in the different separately print cartridges or mix after pack in the same print cartridge, getting the flexible membranaceous carrier substrate 3 that has activated and cut into same size then packs in the carton of ink-jet printer, choosing one or both print cartridges again packs in the printer, last existing word processor or other software of utilizing again on the computer is carried out printing line by line or by row of each carrier substrate 3 according to specific design, successively different point sample things is printed on the carrier substrate 3 with carrier substrate 3 by changing print cartridge, point sample thing 2 and the active group reaction on the carrier substrate 3 are fixed on the carrier substrate 3 in covalently bound mode.The shape of point sample thing 2 can be the shape of any one character in existing word processor or other software on point-like, wire or the computer on the carrier substrate 3.The number of point sample thing 2 is every square centimeter of 10-500 on the carrier substrate 3, and the diameter of spot application thing 2 is the 50-500 micron, and the length of linear spotting thing 2 is the 50-500 micron.
In order to reach the purpose that contains marker 1 and point sample thing 2 on the carrier substrate 3 simultaneously, the above-mentioned carrier substrate 3 that contains different point sample things 2 is put on the calf serum sealing carrier substrate 3 not active group in conjunction with point sample thing 2, the carrier substrate 3 that will seal and have point sample thing 2 is then packed in the carton of ink-jet printer, choosing one or both print cartridges of having packed respective markers thing 1 into again packs in the printer, last existing word processor or other software of utilizing again on the computer is carried out printing line by line or by row of each carrier substrate 3 according to set design, successively different marker 1 is printed on the site of corresponding point sample thing 2 on the carrier substrate 3 with substrate by changing print cartridge.The shape of marker 1 is identical with above-mentioned point sample thing 2 on the carrier substrate 3, can be the shape of any one character in existing word processor or other software on point-like, wire or the computer.The number of marker 1 is every square centimeter of 10-500 on the carrier substrate 3, and the diameter of point-like marker 1 is the 50-500 micron, and the length of wire marker 1 is the 50-500 micron.
DNA chip among the present invention is that gene chip is a kind of special shape of above-mentioned biochip, its key distinction is: marker is the marker of DNA in the testing sample, can be markers such as golden mark, enzyme labelling, fluorescent mark, chemiluminescent labeling, electrochemiluminescence mark and radio-labeling.The process of spray ink Printing testing sample dna marker thing 1 is exactly the process that adds testing sample, point sample thing 2 comprises dna probe, cDNA probe, peptide nucleic acid probe and mRNA effect on testing sample dna marker thing 1 and the carrier substrate 3 afterwards, and the existence that is used for showing the complementary DNA of the sample to be checked of being caught by the point sample thing or RNA whether.
Carrier substrate among the present invention, be with various activating reagent various active groups on the carrier substrate surface bond by chemical reaction, so that with point sample thing covalent attachment, formation has the affinity type carrier substrate of different biologic specificities, be used for fixing and detect various active biomolecule, as protein, polypeptide, enzyme, nucleic acid, antigen, antibody, medicine and acceptor etc.Different carrier substrates can be with different activating reagents the carrier substrate surface active, as the surface is the carrier substrate of carboxyl, with 1-ethyl-3-(3-dimethylamino) carbodiimide hydrochloride (EDC) and N-hydroxy thiosuccinimide (NHS) surface is become active ester, and then with various biomolecules coupling in the point sample thing; So adopt similar known shared method, can become active group to the carrier substrate surface active that contains groups such as hydroxyl, amino, aldehyde radical, diazanyl, sulfydryl respectively, and then carry out different keys and reaction, thereby the bioactive molecules in the point sample thing is fixed on the carrier substrate in covalently bound mode with the point sample thing.
During operation, get the serum to be checked of 1-2ml or whole blood and add in the sample application zone or and invade in serum to be checked or the whole blood the present invention.The present invention is owing to contain marker 1 and point sample thing 2 simultaneously on carrier substrate 3, after adding serum or whole blood sample, 37 ℃ question response 30-60 minute, specific immune response takes place in antibody or antigen in antigen in marker 1 and the point sample thing 2 or antibody and serum to be checked or the whole blood, gets washings then and washs this low-density biochip device, gives a baby a bath on the third day after its birth altogether time, wash away the material that does not react, add developer more subsequently, question response is by the color reaction observations of marker 2.Or with washings washing back sentence read result on scanner or other equipment, the spot colour developing is positive, and spot is colourless negative.If corresponding antibody or antigen are arranged in serum to be checked or the whole blood, color reaction takes place with regard to energy specificity binding label 1, the result is positive; If do not have corresponding antibody or antigen in serum to be checked or the whole blood, just can not specificity binding label 1, marker 1 is washed to be removed, and just color reaction can not take place, and the result is negative.
DNA chip among the present invention is that gene chip is a kind of special shape of above-mentioned biochip, its key distinction is: marker 1 can be markers such as golden mark, enzyme labelling, fluorescent mark, chemiluminescent labeling, electrochemiluminescence mark and radio-labeling for the marker of DNA in the testing sample.The process of spray ink Printing testing sample dna marker thing 1 is exactly the process that adds testing sample, point sample thing 2 comprises dna probe, cDNA probe, peptide nucleic acid probe and mRNA effect on testing sample dna marker thing 1 and the carrier substrate 3 afterwards, be used for showing the sample to be checked of being caught by point sample thing 2 complementary DNA marker 1 existence whether.Its concrete operations are: behind the spray ink Printing testing sample dna marker thing 1,37 ℃ question response 30-60 minute, point sample thing 2 comprises dna probe, cDNA probe, peptide nucleic acid probe and mRNA effect on testing sample dna marker thing 1 and the carrier substrate 3, get washings then and wash this low-density biochip device, give a baby a bath on the third day after its birth altogether time, wash away the material that does not react, add developer more subsequently, question response is by the color reaction observations of marker 1.Or with direct sentence read result on scanner or other equipment after the washings washing, the spot colour developing is positive, and spot is colourless negative.If the existence of complementary DNA or RNA is arranged in serum to be checked or the whole blood, can not be washed with regard to can specificity being combined on the carrier substrate 3 and to remove, color reaction takes place then, the result is positive; If the existence of no complementary DNA or RNA in serum to be checked or the whole blood just can not specificity be combined on the carrier substrate 3 and be washed and removes, color reaction just can not take place, the result is negative.
Claims (11)
1, a kind of low-density biochip, mainly form by carrier substrate that contains active group (3) and the point sample thing (2) that is solidificated on this carrier substrate (3), it is characterized in that: also contain marker (1) simultaneously on point sample thing (2) site on the carrier substrate (3), the two contacts closely; Above-mentioned marker (1) and point sample thing (2) be shaped as point-like or wire, the number of marker (1) and point sample thing (2) is every square centimeter of 10-500, the diameter of point-like marker (1) and point sample thing (2) is the 50-500 micron, and the length of wire marker (1) and point sample thing (2) is the 50-500 micron.
2, low-density biochip according to claim 1 is characterized in that: above-mentioned marker (1) and point sample thing (2) are respectively the mixture that contains the trehalose stabilization.
3, low-density biochip according to claim 1 and 2 is characterized in that: above-mentioned point sample thing (2) can be any or the arbitrary combination in dna probe, cDNA probe, peptide nucleic acid probe, mRNA, antigen, antibody, drug receptor, polysaccharide lectin, the cell or tissue.
4, low-density biochip according to claim 1 and 2 is characterized in that: above-mentioned marker (1) can be any or the arbitrary combination in golden mark, enzyme labelling, fluorescent mark, chemiluminescent labeling, electrochemiluminescence mark and the radio-labeling marker.
5, low-density biochip according to claim 3, it is characterized in that: described point sample thing (2) and the dot matrix of marker (1) on carrier substrate (3) are linear array, contain the different point sample things and the marker linear array of dots of multirow or multiple row on carrier substrate (3).
6, according to claim 3 or 4 described low-density biochips, it is characterized in that: same delegation on carrier substrate (3) or the same marker that lists (1) are identical with point sample thing (2), can carry out as required arbitrarily cutting into different low-density biochip bars by column or row, the low-density biochip bar of these well cuttings can arbitrarily splice again according to actual needs.
7, low-density biochip according to claim 6 is characterized in that: described carrier substrate (3) is flexible membranaceous substrate.
8, low-density biochip according to claim 7 is characterized in that: described carrier substrate (3) can be that glassine paper, tunica fibrosa, plastic film etc. are inorganic, in the organic polymer thin film any.
9, a kind of method of making the described low-density biochip of claim 1, it is characterized in that: will synthesize or dissimilar point sample thing (2) that purifying is good is respectively charged in the different separately print cartridge of ink-jet printer with marker (1), utilize the existing word processor of computer or other software successively point sample thing (2) to be printed on the corresponding site on the carrier substrate (3) then, seal carrier substrate (3) with calf serum then and go up, utilize the existing word processor of computer or other software successively marker (1) to be printed on the site of corresponding point sample thing (2) again with ink-jet printer not in conjunction with the active group of point sample thing (2).
10, method according to claim 9 is characterized in that the making step of above-mentioned marker (1) and point sample thing (2) is: get solid phase labelling thing (1) or point sample thing (2), dissolve with the trehalose adding distil water; Also can in the solution that contains marker (1) or point sample thing (2), add trehalose.
11, method according to claim 10 is characterized in that: solid phase labelling thing (1) or point sample thing (2) are 1 with the weight ratio of trehalose: 10-30.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 00129440 CN1125184C (en) | 2000-12-22 | 2000-12-22 | Low density biochip and its making process |
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| CN 00129440 CN1125184C (en) | 2000-12-22 | 2000-12-22 | Low density biochip and its making process |
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| CN1308131A CN1308131A (en) | 2001-08-15 |
| CN1125184C true CN1125184C (en) | 2003-10-22 |
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| CN 00129440 Expired - Fee Related CN1125184C (en) | 2000-12-22 | 2000-12-22 | Low density biochip and its making process |
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Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101021541B (en) * | 2006-02-15 | 2012-01-25 | 晶宇生物科技实业股份有限公司 | Bio-chip lattice method and device thereof |
| CN102115738B (en) * | 2010-11-29 | 2013-08-14 | 中国科学院化学研究所 | Gold nanoparticle template for promoting cell growth and preparation method thereof |
| CN107462703A (en) * | 2017-09-15 | 2017-12-12 | 如皋福大工程技术研究院有限公司 | A kind of spotting methods |
| CN108181467B (en) * | 2018-02-06 | 2019-03-12 | 长春祈健生物制品有限公司 | A kind of preparation method of the stable antigen slide for the detection of FAMA method |
| CN109116029A (en) * | 2018-07-21 | 2019-01-01 | 福建医科大学 | A method of paper substrate micro-fluidic chip is made based on inkjet printing technology controllability and is detected for glucose quantitation |
| CN109136077A (en) * | 2018-08-20 | 2019-01-04 | 中南大学 | A kind of preparation method of biochip |
| CN113125745B (en) * | 2019-12-31 | 2022-10-28 | 瑞博奥(广州)生物科技股份有限公司 | Cardiac function detection kit |
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