CN1409110A - Two-dimensional optic coder produced by micro processing and use - Google Patents
Two-dimensional optic coder produced by micro processing and use Download PDFInfo
- Publication number
- CN1409110A CN1409110A CN 02105337 CN02105337A CN1409110A CN 1409110 A CN1409110 A CN 1409110A CN 02105337 CN02105337 CN 02105337 CN 02105337 A CN02105337 A CN 02105337A CN 1409110 A CN1409110 A CN 1409110A
- Authority
- CN
- China
- Prior art keywords
- dimensional
- coding
- scrambler
- reaction
- coder
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000012545 processing Methods 0.000 title description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 116
- 238000000034 method Methods 0.000 claims abstract description 78
- 239000000463 material Substances 0.000 claims abstract description 77
- 230000003287 optical effect Effects 0.000 claims abstract description 77
- 150000001875 compounds Chemical class 0.000 claims abstract description 62
- 239000000126 substance Substances 0.000 claims description 99
- 230000008569 process Effects 0.000 claims description 39
- 238000000018 DNA microarray Methods 0.000 claims description 27
- 230000005291 magnetic effect Effects 0.000 claims description 21
- 238000005520 cutting process Methods 0.000 claims description 19
- 238000001514 detection method Methods 0.000 claims description 14
- 230000000694 effects Effects 0.000 claims description 12
- 229910052710 silicon Inorganic materials 0.000 claims description 12
- 239000010703 silicon Substances 0.000 claims description 12
- 229910052751 metal Inorganic materials 0.000 claims description 10
- 239000002184 metal Substances 0.000 claims description 10
- 238000003672 processing method Methods 0.000 claims description 10
- 108091026890 Coding region Proteins 0.000 claims description 9
- 238000007385 chemical modification Methods 0.000 claims description 8
- 239000007795 chemical reaction product Substances 0.000 claims description 5
- 239000004033 plastic Substances 0.000 claims description 5
- 229920003023 plastic Polymers 0.000 claims description 5
- 239000011521 glass Substances 0.000 claims description 4
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- 108090000623 proteins and genes Proteins 0.000 claims description 4
- 102000004169 proteins and genes Human genes 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 102000004190 Enzymes Human genes 0.000 claims description 3
- 108090000790 Enzymes Proteins 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 239000000696 magnetic material Substances 0.000 claims description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 claims description 2
- 108020004414 DNA Proteins 0.000 claims description 2
- 229910052581 Si3N4 Inorganic materials 0.000 claims description 2
- 241000700605 Viruses Species 0.000 claims description 2
- 239000000427 antigen Substances 0.000 claims description 2
- 108091007433 antigens Proteins 0.000 claims description 2
- 102000036639 antigens Human genes 0.000 claims description 2
- 229940088597 hormone Drugs 0.000 claims description 2
- 239000005556 hormone Substances 0.000 claims description 2
- 150000002632 lipids Chemical class 0.000 claims description 2
- 238000006116 polymerization reaction Methods 0.000 claims description 2
- HQVNEWCFYHHQES-UHFFFAOYSA-N silicon nitride Chemical compound N12[Si]34N5[Si]62N3[Si]51N64 HQVNEWCFYHHQES-UHFFFAOYSA-N 0.000 claims description 2
- 230000031700 light absorption Effects 0.000 claims 1
- 238000012216 screening Methods 0.000 abstract description 8
- 239000000758 substrate Substances 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 239000010410 layer Substances 0.000 description 100
- 230000003228 microsomal effect Effects 0.000 description 24
- 239000000523 sample Substances 0.000 description 15
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 14
- 238000005516 engineering process Methods 0.000 description 13
- 239000002346 layers by function Substances 0.000 description 12
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 11
- 238000002474 experimental method Methods 0.000 description 10
- 229910001093 Zr alloy Inorganic materials 0.000 description 9
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 8
- 230000003647 oxidation Effects 0.000 description 8
- 238000007254 oxidation reaction Methods 0.000 description 8
- JUTRBLIIVLVGES-UHFFFAOYSA-N cobalt tantalum Chemical compound [Co].[Ta] JUTRBLIIVLVGES-UHFFFAOYSA-N 0.000 description 7
- 230000004907 flux Effects 0.000 description 7
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 7
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 6
- 238000000151 deposition Methods 0.000 description 6
- 230000008021 deposition Effects 0.000 description 6
- 238000001259 photo etching Methods 0.000 description 6
- 238000005842 biochemical reaction Methods 0.000 description 5
- 238000013461 design Methods 0.000 description 5
- 238000005530 etching Methods 0.000 description 5
- 101710134784 Agnoprotein Proteins 0.000 description 4
- 101710124584 Probable DNA-binding protein Proteins 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 229910052759 nickel Inorganic materials 0.000 description 4
- 241001597008 Nomeidae Species 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000005137 deposition process Methods 0.000 description 3
- 239000007850 fluorescent dye Substances 0.000 description 3
- 238000001215 fluorescent labelling Methods 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- 102000004856 Lectins Human genes 0.000 description 2
- 108090001090 Lectins Proteins 0.000 description 2
- 108091092724 Noncoding DNA Proteins 0.000 description 2
- 239000004677 Nylon Substances 0.000 description 2
- 229910000831 Steel Inorganic materials 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000004411 aluminium Substances 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- -1 as monox Substances 0.000 description 2
- 238000003705 background correction Methods 0.000 description 2
- 238000003486 chemical etching Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 238000001917 fluorescence detection Methods 0.000 description 2
- 238000001948 isotopic labelling Methods 0.000 description 2
- 239000002523 lectin Substances 0.000 description 2
- 238000003754 machining Methods 0.000 description 2
- 238000013507 mapping Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000002493 microarray Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000003068 molecular probe Substances 0.000 description 2
- 229920001778 nylon Polymers 0.000 description 2
- 238000000059 patterning Methods 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229910052814 silicon oxide Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000010959 steel Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- CXCHEKCRJQRVNG-UHFFFAOYSA-N 2,2,2-trifluoroethanesulfonyl chloride Chemical compound FC(F)(F)CS(Cl)(=O)=O CXCHEKCRJQRVNG-UHFFFAOYSA-N 0.000 description 1
- 239000012103 Alexa Fluor 488 Substances 0.000 description 1
- 239000012110 Alexa Fluor 594 Substances 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 244000265913 Crataegus laevigata Species 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 238000000636 Northern blotting Methods 0.000 description 1
- 108020004711 Nucleic Acid Probes Proteins 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 238000002105 Southern blotting Methods 0.000 description 1
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 1
- 229910000071 diazene Inorganic materials 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N dihydromaleimide Natural products O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 238000001312 dry etching Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 239000002902 ferrimagnetic material Substances 0.000 description 1
- 230000005294 ferromagnetic effect Effects 0.000 description 1
- 238000002795 fluorescence method Methods 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 239000002853 nucleic acid probe Substances 0.000 description 1
- 229920002120 photoresistant polymer Polymers 0.000 description 1
- 239000013047 polymeric layer Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000002310 reflectometry Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000004065 semiconductor Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- BPSIOYPQMFLKFR-UHFFFAOYSA-N trimethoxy-[3-(oxiran-2-ylmethoxy)propyl]silane Chemical compound CO[Si](OC)(OC)CCCOCC1CO1 BPSIOYPQMFLKFR-UHFFFAOYSA-N 0.000 description 1
Images
Landscapes
- Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
- Physical Or Chemical Processes And Apparatus (AREA)
Abstract
An optical coder with two dimensions is manufactured with a proper substrate material which has two dimentional optical coding processed by the microprocessing method on it. The optical coder with two dimensions can be used as a carrier to be applied to large-scale compound synthesis for control of the synthetic reaction process and also can be used for making the biological chip and screening of compound high-flux. It is simple in structure, is flexible and has large capacity in coding, can be widely used in the fields of chemistry, pharmacy and biology for unit identification in chemial reaction or for the automatic control.
Description
The present invention relates to chemistry, pharmacy and biological field, concrete content is design and makes two-dimensional optic coder, utilize this scrambler as carrier, according on the scrambler with coding carry respective substance thereon, or carry out corresponding biochemical reaction thereon, as long as the coding that reads during detection on the scrambler is known the substance classes of carrying or carried out which biochemical reaction on it, just can determine the classification of reaction product by confirming the biochemical reaction kind that is taken place.
In the modern pharmaceutical industry, an important source of medicine is to obtain by the compound that screens synthetic.(combinatorial chemistry is to utilize the macromolecule carrier analog of synchronously synthetic guide's thing and a kind of chemical method of derivant fast along with the appearance of combinatorial chemistry technique, it develops into series connection and synchronously synthetic thousands of and even tens thousand of the combination of compounds synthesis modes of parallel way derivant individuation synthesis mode in the past, this according to the quick synthetic compound of parent compound structure colony, the foreseeable again method of its range of structures can be set up huge chemical derivative storehouse very soon, make that the chemical modification process of lead compound is accelerated greatly), the researchist can synthesize according to synthetic thousands of analogs of guide's thing or derivant, therefrom filters out real effectively drug molecule then.It is exactly to synthesize these compounds that but the researchist also faces a problem how fast parallelly, how to instruct and monitors the synthetic process of compound to guarantee to obtain correct product.
For example American I RORI company utilizes radio frequency (radiofrequency, RF) technology is carried out the sign and the control of the synthetic process of compound.At first, the researchist makes microreactor, and the surface of microreactor is the solid phase supporting body of functionalization, and all compounds are synthetic will be finished on this supporting body.The inside of microreactor is the identification code of a uniqueness, is used to indicate this microreactor, and the sign between every kind of microreactor is different.This identification code is to be taken place and the receiving circuit realization by radio frequency, the getting up with glass capsulation of entire circuit.When carrying out compound synthetic, determine to use the kind of microreactor according to the kind of required synthetic compound, as synthesizing n kind compound, just need the n kind to have the microreactor of different identification symbol.Like this can be according to pre-set program, need to determine the synthetic reaction kind of carrying out according to identification codes different in the microreactor on microreactor (identification code is to export by radio frequency at every turn, the frequency that different identification code is corresponding different after being received by outside receiving trap is transported to microreactor and carries out synthetic reaction in the corresponding reactor).Like this, after all synthetic reactions finish, with microreactor not of the same race separately, read the identification code in the microreactor respectively, just can know on microreactor, to have carried out which synthetic reaction by this identification code, and the precedence of these synthetic reactions how, also can infer the kind of reaction product on this microreactor thus.Reaction product is on the surface of microreactor, can it be taken off by the method for chemical cleavage, and encapsulation is got up.The largest benefit of this method is when synthetic different compounds, if they need carry out identical reaction in a certain step, can carry out simultaneously in same reactor so, and needn't separately carry out, and this process can robotization.But this radio frequency takes place and receiving circuit apparatus structure more complicated, and cost is also higher, and in addition, the radio-frequency unit launching electromagnetic wave needs external energy, as add power-supply unit in radio-frequency unit, as battery, so use certain timeliness restriction is arranged.Currently need carry out large-scale chemical reaction, wherein, be even more important for the identification and the control of each unit that participates in reaction at chemistry, pharmacy and biological field.In addition, in the drug screening process, the compound number in the combination of compounds storehouse to be screened is thousands of, how to realize that high-throughout screening is very crucial.There is carrying out that a technology that is called LabMAP (Multi-Analyte Profiling assay) can the success high flux screening to compound in the Luminex company of the U.S..The said firm utilizes own advantage at the chemiluminescence technical elements, and in microballon surface parcel one deck particular chemicals, this material can produce the fluorescence of different colours under the laser excitation of characteristic frequency.Luminex can make 100 kinds of such fluorescence microballon bodies.Like this, on variety classes microballon body, connect different biological substances or chemical substance.Simultaneously the question response target molecule is marked, carry out chemical reaction.After the reaction, the sorting unit by robotization one by one with such microballon body.At first, detect the mark of target molecule, promptly judge target molecule whether and biological substance or chemical substance on this microballon body that is detecting reaction has taken place.If signal is arranged, be that reaction has taken place for biological substance or chemical substance on target molecule and this microballon body of detecting, again with the chemical substance of the laser excitation microballon surface of characteristic frequency parcel, by detecting the color that this chemical substance inspires fluorescence, can learn the kind of biological substance on the microballon body or chemical substance.Like this, in primary first-order equation, can detect 100 kinds of reaction types simultaneously, realize high-throughout purpose.
The initial design thought of two-dimensional optic coder of the present invention is to derive from a kind of above-mentioned radio frequency microreactor and fluorescence microballon body can realized of searching to carry out the replacement device of identification function; then we find that again such two-dimensional optic coder is synthetic except extensive compound; beyond the compound high flux screening, can also be used to make other fields such as biochip.
One of purpose of the present invention be to provide a kind of simple in structure, cost is low, operating period limit for length, the scrambler flexibly of encoding, and can be widely used in chemistry, pharmacy and biological field, is used for identification or control automatically to each unit that participates in chemical reaction.
Two of purpose of the present invention is to provide a kind of carrier that is applied to the synthetic reaction of extensive compound or is used for mark substance, and this carrier structure is simple, and cost is low, the operating period limit for length.
Three of purpose of the present invention is to provide a kind of synthetic control method of reacting of extensive compound that two-dimensional optic coder is realized of using, and the cost of this control method is lower
Four of purpose of the present invention is to provide a kind of biochip of two-dimensional optic coder making and material detection method of utilizing this biochip to realize utilized, this biochip can detect the kind of each biological substance wherein or chemical substance easily, the user can determine needed probe combinations as required, easy to use, this biochip and the material detection method that is realized thereof are particularly useful for the high flux screening to reaction artifact material or chemical substance.
Technical scheme of the present invention is as follows:
Two-dimensional optic coder described in the present invention adopts suitable base material to make, and processes various types of two-dimensional optical code by micro-processing method on base material.
The base material of making two-dimensional optic coder can be silicon, monox, silicon nitride, glass, plastics or chemical polymerization thing, magnetic material, carbon, metal or their combination.The coding pattern of the two-dimensional optical code in the two-dimensional optic coder comprises poroid coding, bar coding, digital pattern, monogram, symbol pattern etc., generally can adopt wherein any or combination.The implementation of two-dimensional optical code pattern is included in and carves deep mixed pattern on the base material, holes on base material, is represented different codings, is used different material coding regions to be arranged in certain pattern or their combination by the position grouping in hole.Wherein employed making coding region can be the material different to absorptivity with the different material that is arranged in certain pattern, adopts a branch of rayed code area like this, can form specific pattern according to the absorbed situation mapping of light; Also can adopt the different material of reflectivity, adopt a branch of rayed code area like this, can form specific pattern according to the difference mapping of the intensity of light reflection; Also can adopt different material of refractive index or the like.The size of two-dimensional optic coder can be from 0.01 micron to several centimetres, can be processed into various shape according to actual needs, and the coding on two-dimensional optic coder can only be in certain part of scrambler, does not influence the function of scrambler other parts.Because each two-dimensional optic coder all has the specific coding that can represent itself, and this is encoded to the physical property mark, so two-dimensional optic coder has purposes widely.
Two-dimensional optic coder structure and processing technology are all fairly simple, and cost is low, if use micro fabrication large-scale production, its cost can be quite cheap, and two-dimensional optic coder once to make the back durable in use, the detection of optical encoding also realizes easily; On the other hand, in theory, the combination of optical encoding can have infinite multiple, the dirigibility height of coding, and code capacity is big, therefore is particularly suitable for the high flux screening of extensive compound reaction and biological substance or chemical substance.
A kind of carrier that is applied to the synthetic reaction of compound of the present invention, has the surface that is used for synthetic compound, this carrier is provided with the two-dimensional optical code that processes with micro-processing method, this two-dimensional optical code is represented the synthetic reaction of a series of compounds that this carrier need carry out, and can be used for determining the classification of reaction product.
Because the present invention adopts two-dimensional optic coder as carrier, so this carrier structure is simple, cost is low, the operating period limit for length.
In a preferred embodiment, described carrier adopts segment shape, processes corresponding two-dimensional optical code on the planar section of this carrier, and its land portions is used for synthetic compound.This carrier can swim on the solution, to realize the control of chemical reaction, for example apace carrier is carried out sorting to determine its next step synthetic reaction that will carry out according to its coding by the code reader identification back that its top is set; This carrier also can be suspended in the solution, by being arranged on its code reader identification back on every side to realize the control of chemical reaction.The surface of the not coding region of described carrier has the chemical modification layer, but and be connected with cutting arm, but should be connected between the compound and this carrier that is synthesized by cutting arm.But but but but described cutting arm adopts light cutting arm, enzyme cutting arm, temperature cutting arm, but and guarantee that follow-up chemosynthesis reaction all is to connect on this cutting arm.
A kind of carrier that is used for mark substance of the present invention has the surface that is used for bound substances, and this carrier is provided with the two-dimensional optical code that processes with micro-processing method, and this two-dimensional optical code is used for determining the kind of material entrained on this carrier.
This carrier structure is simple, and cost is low, the operating period limit for length.
In a preferred embodiment, described carrier adopts segment shape, processes corresponding two-dimensional optical code on the planar section of this carrier, and its land portions is used for bound substances.
The above-mentioned compound that is used for synthesizes the carrier that reacts or be used for mark substance, its shape also can adopt any one shape of right cylinder, cone, square, rectangular parallelepiped, prism, pyramid, truncated cone-shaped etc. or their combination, processing corresponding two-dimensional optical code on selected zone on the carrier of these shapes, and other zone is used for synthetic compound or be used for bound substances.
The present invention has disclosed the control method of the synthetic reaction of a kind of extensive compound; in the method;,, control this scrambler and enter corresponding reaction tank and carry out the synthetic reaction of compound as carrier with this two-dimensional optic coder according to the coding of this two-dimensional optic coder.
The control method of the synthetic reaction of described extensive compound in preferred scheme, may further comprise the steps:
(1) represent the corresponding product of the synthetic reaction that need carry out and reaction back with two-dimensional optical code, a plurality of two-dimensional optic coders that have the uniqueness coding respectively mixed, to its not coding region carry out surface chemical modification;
(2) allow each optical encoder sorting unit of the coding by can discerning this scrambler according to this, and should be transported in which reaction tank by this scrambler of coding decision of scrambler;
(3) each scrambler enters corresponding reaction tank and carries out the synthetic reaction of compound;
(4) after synthetic reaction finishes each time, all each scrambler is mixed once more, according to the coding on the scrambler, carry out sorting once more by sorting unit, can carry out new sorting by the coding of the next one on the recognition coding device, each scrambler enters new, corresponding reaction tank, carries out the synthetic reaction of new compound, up to finishing all synthetic reactions.
Wherein said sorting unit is provided with one and only is suitable for the passage aisle that a scrambler passes through at every turn, by this passage, near the code reader that is used for encoding on the recognition coding device that is arranged on passage reads the coding of this optical encoder to the optical encoder that exists in solution under certain external force effect.
Above-mentioned put on two-dimensional optic coder or its be with that power comprises the acting force that electrostatic force, magnetic field force, dielectric row ripple, magnetic field row ripple or sound field row ripple are produced outside the material, promptly adopt the acting force of the method generation of dielectric row ripple, magnetic field row ripple, sound field row ripple, this acting force puts on two-dimensional optic coder or the material of being with on it, so that reaction system only is suitable for the passage aisle that a scrambler passes through by this at every turn, carry out sorting.
Above-mentioned put on two-dimensional optic coder or be with outside the material power also to comprise on it and use the acting force that electroosmotic pump, mechanical pump or electric liquid-moving pump (electrohydrodynamic pump) is produced, this acting force puts on the solution of reaction system, so that solution is carrying two-dimensional optic coder and the material on it only is suitable for the passage aisle that a scrambler passes through by this at every turn, carry out sorting.
After the identification of sorting unit to the coding of scrambler, scrambler will be transported in each reaction tank of described passage back, coded signal by the scrambler that reads, corresponding reaction tank can be connected with passage, allow the corresponding codes device enter in the corresponding reaction tank, carry out next step synthetic reaction.
In the control method of the synthetic reaction of extensive compound of the present invention,, reduced cost, and had good identification function simultaneously, alternative radio frequency microreactor or fluorescence microballon body owing to adopt two-dimensional optic coder as carrier.
The present invention has further disclosed a kind of biochip, this biochip comprises a plurality of two-dimensional optic coders that process with micro-processing method, this optical encoder links to each other with biological substance or chemical substance, and the two-dimensional optical code that each optical encoder had is represented the biological substance of this scrambler place connection or the kind of chemical substance.Non-coding region at two-dimensional optic coder is modified with the functional layer that is used for fixing biological substance or chemical substance.
In the application of this biochip, above-mentioned biological substance comprises DNA, RNA, peptide, protein, antigen, antibody, sugar, lipid, cell factor, hormone or their compound, cell, virus.The more common a kind of form of biological substance or chemical substance is exactly the probe molecule on the biochip.
The notion of biochip stems from computer chip, the biochip of narrow sense is a micro-array chip, the base unit of its analysis be at certain size substrate (as silicon chip, glass, plastics and nylon membrane etc.) but the orderly a series of identification molecules that are fixed in the addressing of certain position arranged with dot matrix way in surface, each such molecule can be considered as the probe of a sensor.Carry out association reaction under certain conditions, the result utilizes fluorescence method, chemoluminescence method or isotope method to show, again with optical device records such as scanners, analyzes by special computer software at last.The biochip of broad sense is meant the slim device of miniature solid that can carry out fast parallel processing and analysis to biomolecule.So existing any biochemical reaction microization and rapid device are summed up and be biochip.As pcr chip, capillary array electrophoresis chip etc.The above-mentioned biochip of the present invention belongs to a kind of biochip of broad sense just.This biochip can detect the biological substance that each two-dimensional optic coder wherein fixes or the kind of chemical substance easily, the user can determine needed probe combinations as required, easy to use, this biochip is owing to adopt two-dimensional optical code, makes it be particularly useful for high flux screening to big quantitative response artifact material or chemical substance.
The present invention has also disclosed a kind of material detection method of utilizing above-mentioned biochip to realize, and this method may further comprise the steps:
(1) the material body is done special marking;
(2) with its biological substance fixed of coded representation of two-dimensional optic coder or the kind of chemical substance, a plurality of two-dimensional optic coders and the material body that will have different biological substances or chemical substance carry out chemical reaction;
(3) after reaction is finished, optical encoder is cleaned through strict degree;
(4) allow these optical encoders successively by a special marking pick-up unit, detection has the optical encoder of mark, and reads the coding of optical encoder, correspondingly can determine the kind or the quantity of material body.
Above-mentioned special marking can adopt fluorescence labeling, isotope labeling or the like.
In above-mentioned material detection method, owing to adopt the carrier of two-dimensional optical code, can determine the kind or the quantity of material body easily, and be applicable to high flux screening reaction artifact material or chemical substance as biological substance or chemical substance.
The present invention's two-dimensional optic coder can be widely used in chemistry, pharmacy and biological field.
Further specify the present invention below in conjunction with drawings and Examples.
Fig. 1 is to use the present invention's two-dimensional optic coder to carry out the synthetic process synoptic diagram of compound;
Fig. 2 is three kinds of coding patterns that two-dimensional optic coder adopted of the present invention;
Fig. 3 is the example of another kind of two-dimensional optic coder, and (A) microdevice shown in is disc and is distributed with the hole 6 of usefulness of encoding, but also has processed the border note 5 that location/centering is used; (B) be an instantiation-miniature disc of two-dimensional optic coder provided by the present invention, this miniature disc has two-dimentional bar coding, and it represents the numeral of this coding down.
Shown in Figure 4 is the technological process that is used to process a class two-dimensional optical encoding device (or encoding microsomal) provided by the present invention.The first step is the preparation of substrate; Second step was a deposition of sacrificial layer; The 3rd step was the deposition ground floor; The 4th step was the deposition second layer; The 5th step was the photoetching second layer; The 6th step was the 3rd layer of a deposition; The 7th step was photoetching ground floor and the 3rd layer; The 8th step was an etching sacrificial layer.
Fig. 5 is applied to the synoptic diagram that one of the synthetic carrier that reacts of compound embodiment is in the sorting state in actual applications;
Fig. 6 is the synoptic diagram that the two-dimensional optic coder of the present invention's biochip carries out the embodiment of material detection.
Shown in Figure 7 is that miniature disc is distributed on the microslide.
Shown in Figure 8 is that miniature disc forms chain type and arranges under the influence of effect Weak magentic-field (being produced by a C shape magnet steel) in the plane.
Shown in Figure 9 is a plurality of miniature discs one perpendicular to the effect of the high-intensity magnetic field on plane under and erect (magnetic field is produced by the neodium magnet of a plate-like) in the plane.
Shown in Figure 10 is two miniature discs.
Shown in Figure 11 is under the effect in magnetic field to the positioning action of miniature disc.
Shown in Figure 12 is the covalent bond result of experiment.
Shown in Figure 13 is a biological test result of experiment.
The further result of a biological test experiment that shown in Figure 14 is, this measuring the fluorescence signal of different types of miniature disc in the same experiment.
Because every kind of two-dimensional optic coder all has the optical encoding that can represent its uniqueness, so it is the same to be similar to the radio-frequency technique that American I RORI recited above company adopts, two-dimensional optic coder also can be applicable to the synthetic of compound.Exemplify a two-dimensional optic coder and be applied to the synthetic embodiment of extensive compound; be that above-mentioned use two-dimensional optic coder carries out the synthetic process synoptic diagram of compound as shown in Figure 1; need synthetic three kinds of compounds; the building-up process of every kind of compound is: compound W1 (a-b-c); compound W2 (a-c-c); compound W3 (b-a-c), compound W4 (c-b-a).Here a, b, c represent the synthetic reaction that need carry out and react the corresponding product in back.Get three kinds of two-dimensional optic coders, scrambler M1 is encoded to 123, and scrambler M2 is encoded to 133, and scrambler M3 is encoded to 213.At first set coding 1 and represent synthetic reaction a, coding 2 is represented synthetic reaction b, and the like, coding 3 is represented synthetic reaction c.These three kinds of scramblers are blended in the same container, to its not coding region carry out surface chemical modification, but connect a last cutting arm earlier, but should cutting arm can be that light can cut, enzyme can cut, temperature can be cut or the like, but and guarantee that the subsequent chemistry synthetic reaction all was to connect on this cutting arm.Then allow scrambler successively by sorting unit, on this sorting unit decoding device is housed, can read the coding on the scrambler, and should be transported in which reaction tank by this scrambler of coding decision.As three kinds of above-mentioned scramblers, during for the first time by sorting unit, demoder only reads first coding on the scrambler and carries out sorting thus, and scrambler M1, M2 will enter reaction tank a and carry out synthetic reaction a, and scrambler M3 enters reaction tank b and carries out synthetic reaction b.After reaction finishes, three scramblers are mixed once more, carry out sorting through sorting unit once more, can carry out new sorting by second coding on the decoding and coding device, scrambler M3 enters reaction tank a and carries out synthetic reaction a, scrambler M1 will enter reaction tank b and carry out synthetic reaction b, and scrambler M2 enters reaction tank c and carries out synthetic reaction c.By parity of reasoning, and reaction each time all mixes all scramblers the coding sorting again of relevant position on according to scrambler, back after finishing, and carries out new synthetic reaction.After waiting all reactions all to finish, be located on the surface of scrambler in requisition for synthetic compound, various scramblers are encapsulated preservation respectively, just can know corresponding compounds kind and structure by the coding that reads on the scrambler during use, but owing to link together by a cutting arm between compound and the scrambler, so but can obtain corresponding compounds easily by the cutting cutting arm.
Each comprises 3 lowercases (a, b, rectangle frame c) is a two-dimensional optic coder, the reaction code of lowercase wherein for carrying out according to its coding, the capitalization in the dark circles (A, B, C) code of the actual reaction of finishing of expression among Fig. 1.
Fig. 2 is three kinds of optical encoding modes for example, wherein, (A) is poroid coding example, microdevice shown in it is rectangular, the hole of coding is arranged on the center line of this device, (B) is the coding example of symbols such as numeral, letter, (C) is bar code shape coding example.
Fig. 3 is the example of another kind of two-dimensional optic coder, and (A) microdevice shown in is disc and is distributed with the hole 6 of usefulness of encoding, but also has processed the mark 5 that location/centering is used; (B) be an instantiation-miniature disc of two-dimensional optic coder provided by the present invention, this miniature disc has two-dimentional bar coding, and it represents the numeral of this coding down.This miniature disc diameter is 80 microns, 70 microns of the external oxidation silicon layer of 0.5 micron thickness and diameters, the nickel middle layer of 0.5 micron thickness.Bright zone is a nickel on the coding pattern, and dark zone is a monox.From this miniature disc of top irradiation, enlargement factor 220 *.
Fig. 4 has shown the processing technology of processing a class two-dimensional optical encoding.Coding described herein has three layers, sees it is respectively top layer from orientation shown in Figure 13, and bottom and/or middle layer have coded message on the middle layer.Be used to surround the bottom in middle layer and quilting material can be modified and combine with suitable molecule.The process example that just is used to process encoding microsomal in the technology shown in Fig. 4 and technology described below.Those professional persons at little manufacture field can adopt different technology to process with geometric configuration according to the material of encoding microsomal.
As shown in Figure 4, the technology of demonstration is from preparing solid substrate.Substrate must clean up in advance and make it to be suitable for little processing.The silicon chip that for example is used for semiconductor machining just can be used as substrate.Then in the substrate that cleans up, deposit or the coating sacrifice layer.As hereinafter described, in the final step of processing, sacrifice layer will be passed through such as dissolving, and method places to go such as etching are fallen.Sacrifice layer can be metal such as copper, Si
3N
4, or other material.When selecting suitable material, must guarantee when sacrifice layer is carried out selective removal can not exert an influence to the material that is used to make encoding microsomal itself as sacrifice layer.Sacrifice layer can have different thickness, as 1 micron.The method that is used to deposit this class sacrifice layer comprises sputter, evaporation or other deposition process.The selection of various deposition processs is based on the material of a plurality of factors such as sacrifice layer, working ability of thickness and little machining experiment chamber or the like.
After forming sacrifice layer, the bottom of encoding microsomal, promptly the ground floor shown in the step 3 among Fig. 4 is deposited on the sacrifice layer.This layer can be made as monox aluminium oxide, plastics, polymkeric substance etc. by multiple material.Suit, the material of bottom is can be adorned, and molecule (s) of interest can be combined on the surface of bottom like this.Can adopt diverse ways to process this one deck.For example, sputter or evaporation can be used for processing silicon oxide layer.Bottom can depend on the particular design of encoding microsomal by different thickness.This one deck can be thinned to as long as several nanometers are perhaps thick in several microns or several millimeter.For example our encoding microsomal of processing has 50 nanometers, and 0.1 micron, 0.3 micron, the silica bottom layer of 0.5 micron or 1 micron thickness.
After encoding microsomal forms bottom, i.e. ground floor shown in the step 3 among Fig. 4, the middle layer, promptly the second layer shown in the step 4 among Fig. 4 is formed or is deposited on the bottom.This one deck has a plurality of different purposes.It can be used to carry coded message, as shown in Figure 4.For example, metal level (as aluminium) can be used as the middle layer, can process various coding characteristic structures such as line, point, square, numeral etc. by photoetching technique on this metal level.This middle layer also may be made up of suitable material, and whole like this encoding microsomal just has suitable physical property.For example, this one deck may be magnetic, and is ferromagnetic, or the ferrimagnetic material composition, and encoding microsomal just has magnetic characteristic like this.For example, nickel metal or cobalt-tantalum-zircaloy (CoTaZr) or other magnetic material can be used.This class layer can be made of different depositions or formation method, depends on such as the material that can deposit, and the thickness of layer, factors such as adoptable method are not limited to evaporation, methods such as sputter.This one deck can depend on the particular design and the requirement of encoding microsomal by different thickness.This one deck can be thinned to as long as several nanometers are perhaps thick in several microns or several millimeter.For example our encoding microsomal of processing has 0.02 micron, and 0.05 micron, 0.1 micron, 0.3 micron, 0.5 micron, the different materials such as the aluminium of 1 micron or 3 micron thickness, nickel, the middle layer of cobalt-tantalum-zircaloy etc.After forming the middle layer by different deposition processs, the middle layer also needs to be processed into required coding characteristic structure or forms the required geometric scheme of determining (second layer shown in step 5 among Fig. 4).Coding characteristic structure each independent particulate that is used to encode.Feature structure can be including, but not limited to, numeral, letter, symbol, line, square, 1 dimension bar coding, 2 dimension bar codings etc.There is multiple business-like coding pattern to use, described two-dimensional encoded as " Automatic I.D.News " lining in October nineteen ninety-five.Utilize mask and photoetching technique can process the pattern in middle layer.The pattern that this class obtains based on photoetching technique can be processed by several different methods.Those can Select and Apply different suitable technology according to the physical dimension of the material in middle layer and required pattern the professional person of little manufacture field and process the required geometric scheme/character shape of must encoding in middle layer.For example, we can obtain required pattern by the photoresist layer that first photoetching is coated on the metal level, then metal level are carried out chemical etching and obtain corresponding pattern.
After the patterning of middle layer (being the second layer shown in the step 5 among Fig. 4), top layer (being the 3rd layer shown in the step 6 among Fig. 4) is processed or be deposited on the middle layer.This one deck can be made by multiple different material, as monox, and aluminium oxide, plastics, polymkeric substance etc.In some example, top layer is the same with the material of bottom, but this is not essential yet.Top layer can have the material/composition different with bottom.Suit, the material of top layer is can be adorned, and molecule (s) of interest can be combined on the surface of top layer like this.Can adopt diverse ways to process this one deck.For example, sputter or evaporation can be used for processing silicon oxide layer.Top layer can depend on the particular design of encoding microsomal by different thickness.This one deck can be thinned to as long as several nanometers are perhaps thick in several microns or several millimeter.For example our encoding microsomal of processing has 50 nanometers, and 0.1 micron, 0.3 micron, 0.5 micron, 1 micron, the monox top layer of 1.5 microns or 1.9 micron thickness.For designed and the optics codified particulate of selecting have as shown in figure 13 similar layer structure, when deposited top layer, must carefully guarantee that top layer has covered all middle layers, if when particularly intermediate layer material is the non-inert material of metal or other.But this is the not requirement of a strictness always also.In some application of determining,, top layer do not have any problem in some reaction solution owing to having covering to cause some intermediate layer materials to be exposed to yet.In this class example, there is no need to require top layer must cover the middle layer fully.
After with suitable deposition top layer, can further process the single encoded particulate that does not link mutually to produce to top layer and bottom.If bottom (being the ground floor shown in the step 3 among Fig. 4) and top layer (being the 3rd layer shown in the step 6 among Fig. 4) are same materials, can carry out simultaneously the processing and the processing of top layer and bottom, but this neither be essential.Bottom and top layer can be divided into two steps to be processed respectively and handles, if when particularly the used material of top layer and bottom is different.For example, we determine the top layer and the bottom of encoding microsomal with monox processing.For these particulates, we can be with chemical etching or dry etching method processing simultaneously or patterned top layer and bottom.
After top layer and bottom patterning, encoding microsomal processes but still is bonded on the sacrifice layer.Therefore, the final step of processing comprises the encoding microsomal that removal or etching sacrificial layer process with release.For example, the etching solution of Que Dinging (as acid) can be used for the etching sacrificial metal layer and discharge encoding microsomal.
In the foregoing description, we have showed the exemplary process technology that is used to process a class encoding microsomal.Must be pointed out that encoding microsomal can have the structure different with encoding microsomal shown in Figure 4.For example, the encoding microsomal shown in Fig. 4 has three-decker, but in fact encoding microsomal can be one deck, and is two-layer, four layers or more multi-layered.And, can adopt very different processing technologys and means to process this class encoding microsomal.For example, people such as the Hagedorn job operation of processing the little engine of dielectric in being used to of delivering on the Journal of Electrostatics (volume 33,159-195,1994) just can directly or after modification be used to process the optical encoding particulate shown in the present invention.
In said method, how to carry out the two-dimensional optic coder sorting apace to determine that its next step synthetic reaction that will carry out is very crucial.In a preferred embodiment of the invention, as shown in Figure 5, the two-dimensional optic coder of employing be a segment shape scrambler 1 as carrier, the corresponding optical encoding of processing on the planar section of scrambler, and land portions is used for synthetic compound; The density of this scrambler 1 is suitable, makes scrambler can swim on the solution, and like this, the plane of encoder strip coding will be all the time up.When the scrambler that mixes need carry out sorting, one passage aisle 2 is arranged on the sorting unit, the size of this passage only is suitable for passing through a scrambler at every turn, the scrambler that exists in solution will pass through this passage fast, be useful on apparatus for encoding 3 on the recognition coding device above the passage, through after the identification of code reader, scrambler will be transported in each reaction tank of passage back, the passage back can be a device that is similar to the distribution gatherer, the signal that provides by code reader can be connected corresponding reaction tank with passage, allow the corresponding codes device enter and carry out next step synthetic reaction in the corresponding reaction tank.
In the preferred embodiments of the present invention 2, also as shown in Figure 5, the two-dimentional segment shape optical encoder 1 of employing process corresponding optical encoding on the planar section of scrambler, and land portions is used for synthetic compound as carrier.The density of this scrambler is suitable, makes scrambler to be suspended in the solution.When the scrambler that mixes need carry out sorting, one passage aisle 2 is arranged on the sorting unit, the size of this passage only is suitable for passing through a scrambler at every turn, the scrambler that exists in solution will pass through this passage fast, around passage, be useful on apparatus for encoding 3 on the recognition coding device, through after the identification of code reader, scrambler will be transported in each reaction tank of passage back, the passage back can be a device that is similar to the distribution gatherer, the signal that provides by code reader can be connected corresponding reaction tank with passage, allow the corresponding codes device enter and carry out next step synthetic reaction in the corresponding reaction tank.
In above-mentioned two preferred embodiments as shown in Figure 5, described carrier also can adopt other shape, as cone, right cylinder, square, rectangular parallelepiped, prism, pyramid or Rotary-table etc.When described carrier passes through the passage aisle 2 of sorting unit, can use the method for electrostatic force, magnetic field force, dielectric row ripple, magnetic field row ripple, sound field row ripple, by to two-dimensional optic coder or on it apply the effect of power with material, so that reaction system only is suitable for the passage aisle that a scrambler passes through by this at every turn, carry out sorting; Also can use the method for electroosmotic pump, mechanical pump or electric liquid-moving pump (electrohydrodynamic pump), apply the effect of power by solution to reaction system, make solution carry two-dimensional optic coder and the material on it only is suitable for the passage aisle that a scrambler passes through by this at every turn, carry out sorting.
Two-dimensional optic coder of the present invention also can be used to make various biochips, as DNA chip, protein chip, polysaccharide chip or the like.
Traditional micro-array chip is that the biomolecule of some (being biological substance or chemical substance) is fixed on certain substrate surface, the target molecule in the free solution of mark, and mark mode is generally fluorescence, isotope or the like.If biological substance or chemical substance and target molecule can carry out corresponding biochemical reaction, then biological substance or chemical substance with regard to because and target molecule in conjunction with and be with and gone up mark.Here, biological substance or chemical substance are the core that detects all the time.The mark that whether has target molecule by detection of biological material or chemical substance, can determine the whether combination of biological substance or chemical substance and target molecule, promptly the mark to biological substance or chemical substance is to realize by the chemical reaction of biological substance or chemical substance and target molecule; In addition, the position on chip according to biological substance or chemical substance, can determine the kind of biological substance or chemical substance, promptly biological substance or chemical substance have been carried out position mark, this mark be and biological substance or chemical substance and target molecule between chemical reaction irrelevant, be a kind of physical markings.Extend, except position mark, can also utilize the two-dimensional optic coder among the present invention to carry out the physical markings mode of biological substance or chemical substance.
When utilizing two-dimensional optic coder to make biochip, at first, need preparation to have the scrambler 1 of different coding, modify functional layer at the non-coding region of scrambler, this functional layer is the immobilization that is used for biological substance or chemical substance.For example, functional layer can be following thin layer (but being not limited thereto): the material layer of unimolecular layer, rete, glue-line, porous or atresia.Functional layer also can be to be grown in the lip-deep one deck subsidiary layer of scrambler (obtaining by micro-processing method).In addition, functional layer also can form by directly the scrambler surface molecular being carried out chemical modification.Under the perfect condition, except biological substance or chemical substance to be fixed, functional layer not with other molecule generation non-specific binding, and with the specific bond of biological substance of waiting to fix or chemical substance be efficiently.Specifically, functional layer can be the combination of hydrophilic unimolecular layer or hydrophobic unimolecular layer, hydrophilic or hydrophobic film, hydrophilic or organophilic gel layer, polymeric layer, porous or pore-free material and/or these materials.Unimolecular layer membrane is meant unimolecular layer (as the Langmuir-Blodgett film).Be the fixed nucleic acid probe, can use at Southern blot and used bond material such as nitrocellulose or the nylon of Northern blot.Albumen and polypeptide can come in conjunction with (for example hydrophobic) by various physics or chemical means.For example, in conjunction with albumen or polypeptide, specific acceptor such as antibody or lectin can be added on the functional layer.Reach reaction and the analysis that on scrambler, will carry out according to target molecule, different molecules can be added on the functional layer.These are called functional group for the molecule that immobilization of biological substances or chemical substance are added on the functional layer.Functional group can be (but being not limited to) acetaldehyde, diimine carbon, succinimide ester, antibody, acceptor and lectin.These functional groups also comprise by the scrambler surface being carried out chemical radicals or the molecular locus that chemical modification forms.
To make protein chip is example, each is used to make the functional layer of the proteopexy of probe in a kind of optical encoder, then the coding that is had on this optical encoder is just represented this kind probe albumen, just can know the probe albumen kind that has on this scrambler by the coding that reads on the optical encoder like this.When utilizing these scramblers to experimentize, at first the agnoprotein in the sample solution is done fluorescence labeling, the multiple optical encoder that will have different probe albumen then joins and carries out compatible reaction in the sample solution.After finishing, reaction cleans through strict degree again, allow these optical encoders successively by a pick-up unit then, as shown in Figure 6, be similar to the sorting unit shown in top Fig. 5, by a microchannel 2, microchannel 2 sizes allow that just in time an optical encoder 1 passes through, can use the method for electrostatic force, magnetic field force, dielectric row ripple, magnetic field row ripple, sound field row ripple, by to two-dimensional optic coder or on it apply the effect of power with material, so that reaction system only is suitable for the passage aisle that a scrambler passes through by this at every turn, carry out sorting; Also can use the method for electroosmotic pump, mechanical pump or electric liquid-moving pump (electrohydrodynamic pump), apply the effect of power by solution to reaction system, make solution carry two-dimensional optic coder and the material on it only is suitable for the passage aisle that a scrambler passes through by this at every turn, carry out sorting.There are corresponding two windows up and down at the same position place of passage, and a fluorescence detection device 4 is arranged under window below the passage, and a code reader is arranged on the top window.When optical encoder passes through this passage 2 successively, if compatible reaction has taken place in probe albumen of fixing on this optical encoder 1 and the agnoprotein in the sample, owing to have fluorophor on the agnoprotein, when so this optical encoder passes through detection window, the code reader 3 that fluorescence detection device 4 will detect fluorescence signal and trigger the top reads the coding on the optical encoder, can determine probe albumen kind fixing on this optical encoder 1 according to the coding that reads, correspondingly also can know the kind of agnoprotein in the sample solution.
The advantage of this biochip is that the user can be about to various probe proteopexies certainly and form the various optical encoders that have probe albumen and preserve respectively on the two-dimensional optic coder that processes, determine required probe combinations according to the actual needs of each experiment then, easy to use.
Be the kind or the quantity of detection material, mark in addition on the target molecule in material to be detected, as fluorescence labeling, isotope labeling or the like.Carry out chemical reaction.After the reaction, make two-dimensional optic coder pass through pick-up unit one by one.This pick-up unit also is provided with the detecting device that can detect mark on the target molecule except the optical encoding that can discern two-dimensional optic coder.Can detect simultaneously each kind by the two-dimensional optical code of detecting device with and on probe whether with target molecule reaction has taken place.
Compare with the LabMAP technology of Luminex company, the biggest advantage of two-dimensional optic coder of the present invention is, can reach the flux that many higher than the LabMAP technology.Because the restriction of chemiluminescent substance itself and pick-up unit, the kind that can differentiate fluorescence microballon body of Luminex company only has 100 kinds now, and the kind of two-dimensional optic coder obviously is far above 100 kinds, and in theory, the combination of optical encoding can have infinite multiple.In addition, fluorescence microballon body is by wrapping up one deck chemiluminescent substance in common microballon surface, and along with use, the firm degree of the luminescence efficiency of fluorescence, bag quilt all should be taken into account.And two-dimensional optic coder is made by micro-processing method, relatively firm and durable.
Fig. 7-14 has described the use of microdevice-miniature disc.
Fig. 7 is that disc is distributed on the microslide randomly.It is 80 microns that miniature disc has diameter, 70 microns of the external oxidation silicon layer of 1 micron thickness and diameters, the cobalt-tantalum of 0.3 micron thickness-zircaloy middle layer.Enlargement factor 44 *.
Fig. 8 is (this magnetic field is produced by a C shape magnet steel) under the effect of a Weak magentic-field in the plane, and miniature disc forms chain and arranges.It is 80 microns that miniature disc has diameter, 70 microns of the external oxidation silicon layer of 1 micron thickness and diameters, the cobalt-tantalum of 0.3 micron thickness-zircaloy middle layer.(A) enlargement factor 44 *, (B) enlargement factor 88 *.
Fig. 9 is that a plurality of miniature discs are erected on the plane under an effect perpendicular to the high-intensity magnetic field on plane (this magnetic field is produced by the plate-like neodium magnet).It is 80 microns that miniature disc has diameter, 70 microns of the external oxidation silicon layer of 1.9 micron thickness and diameters, the cobalt-tantalum of 0.1 micron thickness-zircaloy middle layer.Enlargement factor 44 *.
Figure 10 shows two miniature discs.(A) be that miniature disc is erected on the plane under an effect perpendicular to the high-intensity magnetic field on plane (this magnetic field is produced by the plate-like neodium magnet) in.(B) show the state remove miniature disc behind the magnetic field.It is 80 microns that miniature disc has diameter, 70 microns of the external oxidation silicon layer of 1 micron thickness and diameters, the cobalt-tantalum of 0.3 micron thickness-zircaloy middle layer.Enlargement factor 88 *.
Figure 11 is presented at the magnetic operation positioning states of miniature disc down.It is 80 microns that miniature disc has diameter, 70 microns of the external oxidation silicon layer of 1 micron thickness and diameters, the cobalt-tantalum of 0.3 micron thickness-zircaloy middle layer.Enlargement factor 88 *.
Figure 12 shows the covalent bond experimental result.After miniature disc was handled with 3-glycidoxypropyltrimethoxy silane, the epoxide that obtains produced the glycol surface after with acid hydrolysis.The miniature disc that glycol is modified is again with 2,2, and 2-Trifluoroethanesulfonyl chloride (tresyl chloride) acts on.(C) show miniature disc and the fluorophore (Biocytin-Alexafluor594 that activates; Molecular probe company) covalently bound result.(D) be control experiment, used is that the glycol that does not have to activate is modified miniature disc.(A) shown image under white light, (B) be fluorescence signal.After carrying out background correction, the fluorescence signal that the fluorescence signal on the miniature disc of activation is modified on the miniature disc than the glycol that does not have to activate is strong more than 100 times.It is 80 microns that miniature disc has diameter, 70 microns of the external oxidation silicon layer of 1 micron thickness and diameters, the cobalt-tantalum of 0.3 micron thickness-zircaloy middle layer.Enlargement factor 88 *.
Figure 13 has shown a biological detection experiment.The miniature disc of tresyl-activated and mouse IgG covalent bond (C).Then, miniature disc and fluorescently-labeled anti-mouse antibody (Alexafluor488 sheep anti-mouse igg, molecular probe company) co-incubation.(D) shown that the control experiment use does not have the glycol of activation to modify miniature disc.(A) shown image under white light, (B) be fluorescence signal.After carrying out background correction, the fluorescence signal that the fluorescence signal on the miniature disc that joins with mouse IgG covalency is modified on the miniature disc than the glycol that does not have to activate is strong more than 100 times.It is 80 microns that miniature disc has diameter, 70 microns of the external oxidation silicon layer of 1 micron thickness and diameters, the cobalt-tantalum of 0.3 micron thickness-zircaloy middle layer.Enlargement factor 88 *.
Figure 14 shows the fluorescence signal that detects the miniature disc of two classes in the same experiment simultaneously.(A) be image under the white light; (B) be fluorescence signal.In each figure, the miniature disc that has covalently bound mouse IgG is positioned at the left side of figure, and the miniature disc that glycol is modified is positioned at the right side of figure, enlargement factor 88 *.
Below in conjunction with the preferred embodiments two-dimensional optic coder according to the present invention and application thereof are described.The parameter that those skilled in the art are appreciated that above to be mentioned such as quantity, size etc. all are exemplary and should not be considered as limitation of the present invention.Scope of the present invention has the accompanying Claim book to limit.
Claims (23)
1, a kind of two-dimensional optic coder, this scrambler adopt suitable base material to make, and have the two-dimensional optical code that processes with micro-processing method on this base material.
2, two-dimensional optic coder according to claim 1 is characterized in that described base material comprises silicon, monox, silicon nitride, glass, plastics, chemical polymerization thing, magnetic material, carbon, metal or their combination.
3, two-dimensional optic coder according to claim 1, it is shaped as any one shape in square, rectangular parallelepiped, right cylinder, cone, prism, pyramid, Rotary-table, the spheroid or their combination.
4, two-dimensional optic coder according to claim 3, its thickness are 0.01 micron to 100 microns.
5, two-dimensional optic coder according to claim 3, its area in order to the face of making two-dimensional optical code is 10 square microns to 10,000 square micron.
6, two-dimensional optic coder according to claim 1 is characterized in that the coding pattern of described two-dimensional optical code comprises poroid coding, bar coding, digital pattern, monogram, symbol pattern or their combination.
7, two-dimensional optical code pattern according to claim 6, the implementation that it is characterized in that described two-dimensional optical code pattern are included in the different material coding region of the pattern, boring, the use that carve different depth on the base material to be arranged in certain pattern or their combination.
8, the making coding region of use according to claim 7 comprises to the different material of the absorption of light, to the different material of reflection of light rate, to different material of the refractive index of light or their combination with the different material that is arranged in certain pattern.
9, a kind of carrier that is applied to the synthetic reaction of compound, has the surface that is used for synthetic compound, it is characterized in that this carrier is provided with the two-dimensional optical code that processes with micro-processing method, this two-dimensional optical code is represented the synthetic reaction of a series of compounds that this carrier need carry out, and can be used for determining the classification of reaction product.
10, carrier according to claim 9 is characterized in that described carrier adopts segment shape, processes corresponding two-dimensional optical code on the planar section of this carrier, and its land portions is used for synthetic compound.
11, a kind of carrier that is used for mark substance, has the surface that is used for bound substances, it is characterized in that this carrier is provided with the two-dimensional optical code that processes with micro-processing method, this two-dimensional optical code is used for determining the kind of material entrained on this carrier.
12, carrier according to claim 11 is characterized in that described carrier adopts segment shape, processes corresponding two-dimensional optical code on the planar section of this carrier, and its land portions can be used for bound substances.
13, carrier according to claim 9 is characterized in that the surface of the not coding region of described carrier has the chemical modification layer, but and is connected with cutting arm.
14, carrier according to claim 13, but it is characterized in that but but but described cutting arm adopts light cutting arm, enzyme cutting arm, temperature cutting arm, but and guarantee that follow-up chemosynthesis reaction all is to connect on this cutting arm.
15, a kind of extensive compound that utilizes the described two-dimensional optic coder of claim 1 to be implemented synthesizes the control method of reaction; in the method; with this two-dimensional optic coder as carrier; according to the coding of this two-dimensional optic coder, control this scrambler and enter corresponding reaction tank and carry out the synthetic reaction of compound.
16, control method according to claim 15, this method may further comprise the steps:
(1) represent the corresponding product of the synthetic reaction that need carry out and reaction back with two-dimensional optical code, a plurality of two-dimensional optic coders that have the uniqueness coding respectively mixed, to its not coding region carry out surface chemical modification;
(2) allow each optical encoder sorting unit of the coding by can discerning this scrambler according to this, and should be transported in which reaction tank by this scrambler of coding decision of scrambler;
(3) each scrambler enters corresponding reaction tank and carries out the synthetic reaction of compound;
(4) after synthetic reaction finishes each time, all each scrambler is mixed once more, according to the coding on the scrambler, carry out sorting once more by sorting unit, carry out new sorting by the coding of the next one on the recognition coding device, each scrambler enters new, corresponding reaction tank, carries out the synthetic reaction of new compound, up to finishing all synthetic reactions.
17, control method according to claim 16, it is characterized in that described sorting unit is provided with one and only is suitable for the passage aisle that an optical encoder passes through at every turn, the optical encoder that exists in solution by this passage, is arranged on the coding that near the code reader that is used for encoding on the recognition coding device of this passage reads this optical encoder under certain external force effect.
18, control method according to claim 17, it is characterized in that described put on optical encoder or on it be with on the material outside power comprise the acting force that electrostatic force, magnetic field force, dielectric row ripple, magnetic field row ripple or sound field row ripple are produced, this acting force puts on two-dimensional optic coder or the material of being with on it, so that reaction system only is suitable for the passage aisle that a scrambler passes through by this at every turn, carry out sorting.
19. control method according to claim 17, it is characterized in that described put on the optical encoder outside power comprise and use the acting force that electroosmotic pump, mechanical pump or electric liquid-moving pump (electrohydrodynamic pump) is produced, this acting force puts on the solution of reaction system, so that solution is carrying two-dimensional optic coder and the material on it only is suitable for the passage aisle that a scrambler passes through by this at every turn, carry out sorting.
20, according to claim 16 or 17 described control methods, it is characterized in that through after the identification of sorting unit to the coding of scrambler, scrambler will be transported in each reaction tank of described passage back, coded signal by the scrambler that reads, corresponding reaction tank can be connected with passage, allow the corresponding codes device enter in the corresponding reaction tank, carry out next step synthetic reaction.
21, a kind of biochip, it is characterized in that, this biochip comprises a plurality of two-dimensional optic coders that process with micro-processing method, this optical encoder links to each other with biological substance or chemical substance, and the two-dimensional optical code that each optical encoder had is represented the biological substance of this scrambler place connection or the kind of chemical substance.
22, biochip according to claim 21 is characterized in that described biological substance comprises DNA, RNA, peptide, protein, antigen, antibody, sugar, lipid, cell factor, hormone or their compound, cell, virus.
23, a kind of material detection method of utilizing the described biochip of claim 21 to realize is characterized in that may further comprise the steps:
(1) the material body is done special marking;
(2) with its biological substance fixed of coded representation of two-dimensional optic coder or the kind of chemical substance, a plurality of two-dimensional optic coders and the material body that will have different biological substances or chemical substance carry out chemical reaction;
(3) after reaction is finished, optical encoder is cleaned through strict degree;
(4) allow these optical encoders successively by a special marking pick-up unit, detection has the optical encoder of mark, and reads the coding of optical encoder, correspondingly can determine the kind or the quantity of material body.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021053375A CN100409010C (en) | 2001-02-23 | 2002-02-25 | Two-dimensional optic coder produced by micro processing and use |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN01104318 | 2001-02-28 | ||
| CN01104318.0 | 2001-02-28 | ||
| CNB021053375A CN100409010C (en) | 2001-02-23 | 2002-02-25 | Two-dimensional optic coder produced by micro processing and use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1409110A true CN1409110A (en) | 2003-04-09 |
| CN100409010C CN100409010C (en) | 2008-08-06 |
Family
ID=25740275
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB021053375A Expired - Fee Related CN100409010C (en) | 2001-02-23 | 2002-02-25 | Two-dimensional optic coder produced by micro processing and use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100409010C (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102322878A (en) * | 2011-05-28 | 2012-01-18 | 安徽大学 | Preparation method for high-accuracy encoder and high-accuracy angle sensor |
| CN105716637A (en) * | 2016-03-10 | 2016-06-29 | 华中科技大学 | Optical encoder |
| CN107298426A (en) * | 2016-04-14 | 2017-10-27 | 中国科学院苏州纳米技术与纳米仿生研究所 | Magnetic microchip, its preparation method and application with encoding of graphs |
| CN109073632A (en) * | 2016-02-23 | 2018-12-21 | 诺尔有限公司 | The kit of antibody is provided, stores the patch of antibody and immune diagnostic method and device using it |
| US11360005B2 (en) | 2016-02-23 | 2022-06-14 | Noul Co., Ltd. | Contact-type patch, staining method using the same, and manufacturing method thereof |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102009043597A1 (en) * | 2009-09-25 | 2011-04-07 | Siemens Aktiengesellschaft | Method for producing a marked object |
| CN111307809B (en) * | 2020-02-24 | 2021-01-12 | 浙江大学 | Small pipeline gas-liquid two-phase flow phase distribution optical detection system and method |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57163815A (en) * | 1981-04-01 | 1982-10-08 | Ricoh Co Ltd | Photoencoder |
| JPH039216A (en) * | 1989-06-05 | 1991-01-17 | Nec Corp | Photoencoder circuit |
| JP3009216B2 (en) * | 1990-11-30 | 2000-02-14 | 豊田工機株式会社 | Automatic grinding wheel correction device for numerically controlled grinding machines |
| CN1185492C (en) * | 1999-03-15 | 2005-01-19 | 清华大学 | Single-point gating type micro-electromagnetic unit array chip, electromagnetic biochip and application |
| CN1167939C (en) * | 1999-03-24 | 2004-09-22 | 明基电通股份有限公司 | Rotary optical coding device |
-
2002
- 2002-02-25 CN CNB021053375A patent/CN100409010C/en not_active Expired - Fee Related
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102322878A (en) * | 2011-05-28 | 2012-01-18 | 安徽大学 | Preparation method for high-accuracy encoder and high-accuracy angle sensor |
| CN102322878B (en) * | 2011-05-28 | 2013-07-17 | 安徽大学 | Preparation method for high-accuracy encoder and high-accuracy angle sensor |
| US11366043B2 (en) | 2016-02-23 | 2022-06-21 | Noul Co., Ltd. | Contact-type patch, staining method using the same, and manufacturing method thereof |
| CN109073632A (en) * | 2016-02-23 | 2018-12-21 | 诺尔有限公司 | The kit of antibody is provided, stores the patch of antibody and immune diagnostic method and device using it |
| US11041842B2 (en) | 2016-02-23 | 2021-06-22 | Noul Co., Ltd. | Culturing patch, culturing method, culture test method, culture test device, drug test method, and drug test device |
| US11208685B2 (en) | 2016-02-23 | 2021-12-28 | Noul Co., Ltd. | Diagnostic method and device performing the same |
| US11360005B2 (en) | 2016-02-23 | 2022-06-14 | Noul Co., Ltd. | Contact-type patch, staining method using the same, and manufacturing method thereof |
| US11385144B2 (en) | 2016-02-23 | 2022-07-12 | Noul Co., Ltd. | Antibody-providing kit, antibody-containing patch, method and device for immunoassay using the same |
| US11740162B2 (en) | 2016-02-23 | 2023-08-29 | Noul Co., Ltd. | Contact-type patch, staining method using the same, and manufacturing method thereof |
| US11808677B2 (en) | 2016-02-23 | 2023-11-07 | Noul Co., Ltd. | Polymerase chain reaction patch, method and device for diagnosis using the same |
| US11898947B2 (en) | 2016-02-23 | 2024-02-13 | Noul Co., Ltd. | Diagnostic method and device performing the same |
| CN105716637A (en) * | 2016-03-10 | 2016-06-29 | 华中科技大学 | Optical encoder |
| CN107298426A (en) * | 2016-04-14 | 2017-10-27 | 中国科学院苏州纳米技术与纳米仿生研究所 | Magnetic microchip, its preparation method and application with encoding of graphs |
| CN107298426B (en) * | 2016-04-14 | 2019-07-05 | 中国科学院苏州纳米技术与纳米仿生研究所 | Magnetic microchip, preparation method and application with encoding of graphs |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100409010C (en) | 2008-08-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101529227B (en) | A microarray system and a process for producing microarrays | |
| Finkel et al. | Peer reviewed: barcoding the microworld | |
| US6908737B2 (en) | Systems and methods of conducting multiplexed experiments | |
| CN1192745A (en) | Chemical, Biochemical and biological processing in thin films | |
| CN102246037B (en) | Biocompatible and photocurable polymers | |
| CN107694649B (en) | Microarray based on coding chip, preparation method and application thereof | |
| US20030036096A1 (en) | Chemical-library composition and method | |
| CN1285917A (en) | Method comprising capture molecule fixed on disc surface | |
| WO1999060170A1 (en) | Linear arrays of immobilized compounds and methods of using same | |
| WO1999024822A1 (en) | Rapid screening assay methods and devices | |
| CN102083575A (en) | Patterned microcodes | |
| CN1288446C (en) | Substrate for bioassay, bioassay apparatus, and reading apparatus | |
| CN1710104A (en) | Array biochip based on microspheric carrier and its coding-decoding method | |
| CN100409010C (en) | Two-dimensional optic coder produced by micro processing and use | |
| CN103645308B (en) | Two-dimensional coding method of micro-carrier | |
| US20010049101A1 (en) | Micro-label biological assay system | |
| JP4125244B2 (en) | Apparatus comprising locally oxidized porous silicon and method for producing the same | |
| WO2011150675A1 (en) | Biochip comprising multiple microchannels | |
| KR20090081758A (en) | Particle using for biomolecule detection or analysis, Composition having the same and Manufacturing method thereof | |
| CN100347545C (en) | Method of preoceeding qualitative and/or quantitative analysis against target substance in sample and its detecting device | |
| JP2007171144A (en) | Microarray having cover | |
| CN1182255C (en) | Flowing Biochip and its usage | |
| CN1458525A (en) | Integrated capillary biological chip and its producing method | |
| WO2001062699A1 (en) | Micro-label biological assay system | |
| CN2575676Y (en) | Vehicles & boats satellite positioning radio monitor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20080806 Termination date: 20200225 |