CN1532548A - Micro device with magnetic shaft and its using method - Google Patents

Abstract

The micro device with magnetized shaft includes substrate material capable of being magnetized and code pattern made on the substrate material and capable of being distinguished optically. The micro device has also one magnetized shaft. The present invention also provides the method and system with the micro device for the separation, detection, analysis and operation of body molecule and the synthesis of compound library, and may be used widely.

Description

The microdevice and the using method thereof that have magnetized axis

Technical field

The present invention relates to a kind of microdevice and using method thereof that has magnetized axis.

Background technology

In present diagnosis and research field, especially need occasion that gene information is obtained and analyzed, high density, high-throughout biology or biochemical analysis have become essential research tool.These analytical approachs often all need be carried out on the medium of solid phase.The example of the common quantitative test of carrying out on solid-phase media comprises by Enzyme Linked Immunoadsorbent Assay (ELISA) method to be measured antigen, or determines the expression of mRNA by the method for hybridization.Though above-mentioned solid-phase media all is to adopt spherical beads body or two kinds of forms of planar array usually, these solid-phase medias can be taked suitable form arbitrarily in fact, and are not limited only to above-mentioned two kinds.

The solid-phase media of planar fashion for example can be with capture molecules based on the slide or the array of chip form, and for example antibody, cDNA or other known capture molecules etc. are fixed on the certain location.The surface of solid-phase media can be by cleaning the material that very easy removal does not have combination.The potpourri adding solid-phase media of analysans is reacted, and analysans can be trapped in the surface of medium, and by general mark, for example fluorescent dye detects.The evaluation of analysans can realize by the positional information of capture molecules on medium of catching this analysans.Because array has smooth surface, for the checkout equipment of pearl body, the easier design of the checkout equipment of array, and cost is also relatively low.One big difficult point of planar array is capture molecules is placed on accurately the ad-hoc location on plane.In order to address this problem, mechanical arm point sample (Schena et al.Quantitativemonitoring of gene expression patterns with a complementary DNA microarray.Science has appearred respectively, 270:467-470 (1995)), photoetching (Fodor et al.Light-directed, spatiallyaddressable parallel chemical synthesis.Science, 251:767-773 (1991)) and ink-jet technology (Blanchard et al.High-density oligonucleotide arrays.BiosensorsBioelectronics, 6/7:687-690 (1996)).But all there is certain limitation in these methods.(surpass 1000 points/cm in order to produce highdensity array ²) need use expensive instrument.In case and array make finish after, can't change arranging of sample, for example with the cDNA that catches in a kind of cDNA replacement array.If change arranging of sample, need make array again, this has just increased cost greatly.Be fixed on molecule on the planar medium with respect to the molecule that freely is distributed in the solution, the efficient of reaction is lower.

Use the surface of molecule can overcome the problems referred to above as solid-phase media.Molecule is usually selected spherical beaded, because they have the geometric shape of homogeneous, also is difficult for taking place mutual effect each other.Use the problem of molecule to be that molecule is difficult to independent identification, because have discrete certain location information the probe of the potpourri of pearl body on array.In order to address this problem, some to have occurred the pearl body has been encoded so that the pearl body is carried out the method for single identification.Some companies, for example Luminex company makes the pearl body can carry out light identification evaluation by the potpourri that mixes different fluorescent dyes in the pearl body.Similar with this method, but some researchers mix the material (for example quantum dot) of other different light identification in the pearl body makes the pearl body can carry out light identification evaluation (Hanet al.Quantum-dot-tagged microbeads for multiplexed optical coding ofbiomolecules.Nature Biotechnology, 19:631-635 (2001)).Quantum dot, the minitype particle of this nanoscale can also be in order to the detection of pearl body.The optical property that quantum dot is special is relevant with size with the composition of quantum dot.Can produce the quantum dot of different size and composition according to concrete needs.Quantum dot can absorbing light, then at once with another frequency emission bright dipping.The most important character of quantum dot is, if the size of suitable change quantum dot, just can be so that quantum dot absorbs or launches the light of characteristic frequency.Genicon scientific ﹠ technical corporation (their resonant light scattering " RLS " particulate has nano level yardstick, and has " resonant light scattering (resonancelight scattering) " character) but also developed micron order and nano level pearl body with light recognition property.But, use above-mentioned any method all to be difficult to produce pearl body more than 1,000 kind with different coding mark.

Also usually use the solid-phase media of pearl bodily form formula in the combinatorial chemistry.In the building-up process of a kind of pearl body/a kind of compound, (be also referred to as and separate and mixed process) (Lam et al.The " one-bead-one-compound " combinatorial library method.Chem.Rev., 97:411-448 (1997)), can produce to contain and surpass 10 ⁸Plant the large-scale compound library of different molecular.The identification of pearl body is to realize by the compound on the pearl body.Have identical compound mark on the pearl body on the same group " tea bag " distinguishing different types of pearl body.Recently, IRORI company " tea bag " mark is extended to little cavity that has electromagnetic wave transmitter or the little cavity that has the optical encoding surface.But the compound library that is to use this technique construction approximately only contains 10,000 kinds of different compounds, and single little cavity approximately occupies the volume of 0.25ml, and this technology is not suitable for the occasion of high flux screening yet.PharmaSeq company also uses the device that has electromagnetic wave transmitter.These size of devices are 250 microns * 250 microns * 100 microns.Method (as the technology of Affymetrix use) by the photochemistry photoetching can directly synthesize bigger compound library in the plane, forms planar array.But this method is owing to be subject to synthetic efficiency (the McGall et al.The efficiency oflight-directed synthesis of DNA arrays on glass substrates.J.Am.Chem.Soc. of multistep in synthetic cost and the photochemistry building-up process greatly, 1 19:5081-5090 (1997)), generally only be applicable to the synthetic of oligonucleotides.Past 30, for many years scientist obtained a large amount of different blocking groups that can be used for the synthetic chemical reagent sensitivity of pearl surface compound, and it is very limited to be used for the kind of the synthetic protection against light sensitivity group of compound.Recently, SmartBeads scientific ﹠ technical corporation has released the particulate product that has bar coding (being of a size of 100 microns * 10 microns * 1 micron) of produced by micro processing, and this particulate can use the identification of decoding of streaming reader.Can make mark easily on the particulate of this produced by micro processing with unlimited multiple coding.How the difficult point of this method is simple analysis, and these have the potpourri of the particulate of coding.Compare with original spherical beaded commonly used, this pearl body that has coding has a plane, just closes overlapping phenomenon than being easier to assemble, and is difficult to disperse.

Nicewarner-Pena etc. have reported Methods for Coding (Nicewarner-Pena et al., Science, 294 (5540): 137-41 (2001)) that a kind of synthetic submicron order striped that is formed by multiple metal constitutes recently.By on base plate, successively using the different metallic ion of electrochemical method deposition, can on base plate, form candy strip.Different stripeds is made up of different metal materials, has different reflectivity, the common optical microscope identification in chamber by experiment of such striped coding.When carrying out the bioanalysis of DNA and protein, usually need the affine analyte that is combined on the pearl body to be detected by the method for fluorescence, the mechanism that above-mentioned this coding is read can't be disturbed the detection of fluorescence.

The system that combines the advantage of planar array and coding microparticle can overcome the limitation of existing method.Illumina company has carried out such trial.They have proposed the method (Ferguson et al.High-density fiber-optic DNA random microspherearray.Anal.Chem., 72:5618-5624 (2000)) of the glass fibre making array of use microballon body and etching.But the use of Illumina company still is subject to the quantity of the different microballon bodies that can obtain based on the method for fluorescence-encoded oligonucleotides microballon body.What BioArraySolutions company used is that LEAPS (Light-controlled Electrokinetic Assembly ofParticles near Surfaces) method forms pearl volume array (WO 97/40385) on the surface.But the method for this LEAPS still runs into the problem of puzzlement great majority based on the technology of pearl body, the limited amount of the kind of the coding that can obtain exactly easily.

Therefore, be badly in need of working out a kind of particulate of produced by micro processing and microdevice of plane discrete array advantage of combining, produce and need of practice to satisfy.

Summary of the invention

The purpose of this invention is to provide a kind of microdevice.

Microdevice provided by the invention comprises: a) magnetizable base material; B) but be produced on the coding pattern of the light identification on the above-mentioned base material; C) magnetized axis.

In a certain practical application, the coded portion of microdevice of the present invention is not realized by platinum, palladium, nickel, cobalt, silver, copper or gold; The composition material of microdevice of the present invention does not comprise platinum, palladium, nickel, cobalt, silver, copper or gold in another practical application.

Described microdevice can use any suitable magnetisable material to make.For example, can use paramagnet, ferromagnetic material or ferrimagnetism material.Described microdevice also can be made by suitable metal material, for example can use the metallic element of transition group: iron, nickel, copper, cobalt, tungsten, tantalum, zirconium or its alloying substance, for example cobalt-tantalum-zircaloy (CoTaZr alloy).In the practical application, what magnetisable material used is metal oxide.

Described microdevice also comprises the substrate that a non-magnetisable material is made.These non-magnetisable materials can be any suitable material such as silicon materials (silicon, silicon dioxide, silicon nitride), plastics, glass, pottery, rubber, polymer, aluminium oxide, aluminium, gold, titanium etc. or their compound.Described magnetizable base material can be connected to substrate in any suitable mode and get on.For example, described magnetizable base material can be the part of described substrate, also can be connected in the described substrate by modes such as deposition, bondings.

Described substrate can be a sandwich construction, for example 3 layers, 4 layers or more multi-layered.For example, described substrate can be a three-decker, and top layer and bottom can use commaterial to make, silicon dioxide (or glass) for example, and the middle layer is made by magnetic material.Certainly, top layer also can use different material with bottom.

The surface of described substrate can be hydrophobic also can be hydrophilic.Described substrate can be made any suitable shape, for example spheroid, square, rectangle, triangle, discoid, cube, parallelepipedon, cone, right cylinder, terrace with edge or Else Rule or irregular shape.Described substrate can be taked any suitable size, and for example the thickness of described substrate can be between 0.1 micron to 500 microns; Preferably thickness is between 1 micron to 200 microns; Best thickness is between 1 micron to 50 microns.For example, described substrate can be a rectangle, and area is between 10 square microns to 1, between 000,000 square micron (taking advantage of 1000 microns for 1000 microns).Described substrate also can be circular, and diameter is between 10 microns to 500 microns.Described substrate also can be a cube structure, and the length of side is between 10 microns to 100 microns.Described substrate can also be a kind of irregular shape, and characteristic dimension is between 1 micron to 500 microns.Described substrate can comprise silicon layer, metal level and polymer layer.Described substrate also can comprise silicon layer and metal level, for example an aluminium lamination.Best, metal level comprises magnetisable material, for example nickel or CoTaZr (Cobalt-Tantalum-Zirconium) alloy.

Any can be as the feature of coding pattern by the character that light is discerned.For example, but the pattern of described light identification can provide by the composition of material itself: the hole of on described base material, getting; On the described base material according to certain mode fixing on and substrate other material with different optical character.But the coded system of the coding pattern of described optical identification can be based on the hole of getting in described substrate itself or the substrate or the figure of fixing, be placed on the material on the base material, quantity, position distribution, optical property, material composition or the combination of aforesaid way.For example, described substrate can be 4 layers of structure, and top layer and bottom can use commaterial to make, silicon dioxide (or glass) for example, and wherein one deck middle layer is made by magnetic material, for example magnetic alloy.But the coding that has light identification in addition on one deck middle layer is as the coding layer.Best, described magnetosphere and coding layer are not overlapped, and be not overlapping fully at least, in order to avoid influence is to the optical detection of the coding on the coding layer.Certainly, described top layer also can use different material with bottom.Described coding can be bar code of numeral, letter, structure plan, one dimension or two dimension or the like.

But described microdevice can only have the coding pattern of a light identification, but but described microdevice also can have the coding pattern of a plurality of light identifications, for example, one group of hole of getting in described substrate or one group are arranged in described suprabasil and described substrate and have the coding that the material of different optical character constitutes.

For the ease of the optical encoding pattern is carried out optical analysis, be preferably with the mark of location usefulness on the described microdevice.For example,, when microdevice keeps flat, be difficult to differentiate the front or the reverse side of microdevice, will cause difficulty to identification like this for discoid microdevice.And just can determine that by telltale mark which face is the front with coding pattern.

But the coding pattern of described light identification can use any suitable fabrication techniques in described substrate.For example, can use micro-processing technology.The micro-processing technology that is suitable for comprises the mask etching technology, for example photoengraving, electron beam lithography and X ray etching (can referring to world patent WO 96/39937 and United States Patent (USP) U.S.Patent Nos.5,651,900,5,893,974 and 5,660,680).Can use microcomputer worker technology directly in substrate, to produce required coding pattern, for example the bar code of numeral, letter, structure plan, one dimension or two dimension.Fig. 8 has provided the example of the coding of some such microdevices.Provided among the figure and made, but the miniature disc that does not also take off from silicon chip.About 400 times of enlargement factor.A is the miniature disc that has rectangle bar magnet and 2D matrix coder; B has rectangle but the miniature disc with bar magnet of sharp-pointed end, and what coding adopted is 3 character codes; C has the rectangle bar magnet but the miniature disc with 3 ends, and coded system is the bar code of 1D; D has rectangle bar magnet and 4 character-coded miniature discs.

If use the material coding pattern that has different optical character with described base material, can use any suitable method that this material is arranged/is fixed in the described substrate.For example, can be by the sputter or the technology of vapour deposition.This material can directly or by certain connector, the connector that for example can cut be arranged or is fixed in the described substrate.Can use micro-processing technology directly in described substrate, to produce required coding pattern, for example the bar code of numeral, letter, structure plan, one dimension or two dimension.This material can be arranged or be fixed in the described substrate by covalently bound or non-covalent ways of connecting.This material can be arranged or be fixed in the described substrate by mode special or non-specific combination.

Any suitable optical markings thing may be used to the present invention.For example, but such optical markings thing can be the coding pattern of the optical identification that is made of metal metal films such as copper, aluminium, gold and platinum, and these coding patterns can be the bar codes of numeral, letter, structure plan, one dimension or two dimension.Particulate (referring to U.S. Patent No. 6,214,560) that but such optical markings thing can be the fluorescent material scattered light to be detected and quantum dot (U.S. Patent No. 6,252,664) etc. are as above-mentioned optical markings thing.

The present invention can use suitable quanta point material.For example, described quantum dot can be cadmium-X (Cd-X) core texture, and wherein X represents selenium (Se), sulphur (S) or tellurium (Te).Described quantum dot can also further wrap up one deck inorganics and carry out passivation, and integument is a Y-Z type structure, and wherein Y represents cadmium or zinc, and Z represents sulphur or selenium.Best, the structure of quantum dot is a cadmium-X (Cd-X) core texture, and wherein X represents selenium (Se), sulphur (S) or tellurium (Te); With a Y-Z type structure, wherein Y represents cadmium or zinc, and Z represents sulphur or selenium; Skin wraps up one deck trialkyl phosphine oxide more in addition, obtains the quantum dot of CdX core/YZ shell mechanism.

The quantum dot of described CdX core/YZ shell mechanism can take suitable method to make the quantum dot of producing have water-soluble.A kind of method is the outer wrappage that replaces the quantum dot of described CdX core/YZ shell mechanism with one deck water-soluble material.For example, can use the sulfydryl carboxylic acid to replace the outer field trialkyl phosphine oxide of quantum dot.Concrete operation just is to use a large amount of sulfydryl carboxylic acids to handle quantum dot.Also can use the CHCl that contains a large amount of sulfydryl carboxylic acids ₃Solution-treated quantum dot (can be referring to Chan and Nie, Science, 281:2016-2018 (1998)).Sulfydryl in the integument molecule can be formed on Cd more stable in the solution (Zn)-S key with quantum dot.Another makes the quantum dot of described CdX core/YZ shell mechanism have water miscible disposal route is quantum dot to be carried out silanization handle (can be referring to Bruchez et al., Science, 281:2013-2015 (1998)).Nano-material surface is carried out silanization can also further carry out chemical modification to the surface of silanization so that material has water-solublely.Generally speaking, the quanta point material of these " water-soluble " still needs to carry out further functionalization so that quantum dot is enough stable under aqueous solution neutralizes the situation that is exposed to illumination and air (oxygen), (can be so that be applied to fluorescence detecting system referring to U.S. Patent No. 6,114,038).Because the photoluminescent property of quanta point material uniqueness (for example, but be not limited only to, high quantum production rate, be difficult for having stability or the like by photobleaching, in the aqueous solution system of complexity), in detection, the water-soluble quantum dot material is very sensitive.Another advantage of quanta point material is, can produce a series of quanta point materials, and they can launch different fluorescence under same excitation light irradiation.

Be applicable to that quantum dot of the present invention can adopt any suitable size.For example, the size of quantum dot can be from 1 nanometer to 100 nanometer.

The microdevice that uses among the present invention can only comprise a kind of quantum dot, also can comprise multiple quantum dot.For example can comprise at least two kinds of quantum dots with different size and different fluorescence.

The microdevice that uses among the present invention can only comprise a kind of optical markings thing, also can comprise multiple optical markings thing.For example can comprise at least two kinds of different optical markings things.

Microdevice of the present invention can include that electricity is led or can be by the dielectric polarization material.These add the electricity electricity or the dielectric properties that lead or that can be changed whole microdevice by the dielectric polarization material of microdevice, thereby influence the interaction between extra electric field and the microdevice, influence the suffered extra electric field induction force of microdevice (for example dielectrophoresis force, row ripple dielectrophoresis force etc.).

In order to realize using described microdevice to separate, handle or the purpose that detects, need appropriately select parameters such as the material of microdevice, composition, structure, sizes.For example, can use described microdevice from potpourri, to separate specific molecule.If use dielectrophoresis force to separate, then described microdevice should have certain dielectric property.If the use magnetic field force separates or handles, should contain magnetisable material in the manufacturing materials in the then described microdevice, for example ferromagnetism or ferrimagnetic material.

Can have on the described microdevice in order to bond in conjunction with the entity molecule of to be separated/manipulation/detection.Best, identification that bond itself can be special and the corresponding entity molecule of combination.In description of the invention, mention in the occasion of bond that bond is represented bond and microdevice compound.For example, if mention the compound that bond and entity molecule form in describing, be meant the compound that the bond that is connected on the microdevice and entity molecule form in fact.

Here, bond can use any suitable material (can be referring to the U.S. Patent application U.S.Patent Application Serial Nos.09/636 in the application process, on August 10th, 104,2000 submitted and 09/679, on October 4th, 024,2000 submitted).Bond can be cell such as animal, plant, fungi or bacterial cell; Organelle such as nucleus, mitochondria, chloroplast, ribosomes, endoplasmic reticulum, golgiosome, lysosome, proteasome, vesica, vacuole or microbody; Virus, particulate or their polymkeric substance or complex.Bond can also be to be fixed on the lip-deep molecule of microdevice.For example, be combined in the lip-deep antibody molecule of microdevice.The microdevice that is combined with antibody molecule can be in order to acquisition target albumen from molecule mixture, also can be in order to acquisition target cell from cell mixture.The surface of described microdevice is fixing Oligo-dT (for example nucleic acid molecules of being made up of 25 T) also.The microdevice that is combined with Oligo-dT can be in order to separating mRNA from molecule mixture.For the capture dna molecule, can also use other bond.Nucleic acid fragment, DNA for example, RNA; Peptide nucleic acid sequence can in order to and target nucleic acid (DNA, RNA) or peptide nucleic acid hybridization.The surface of described microdevice can be connected with or be combined with bonds such as molecule or functional group, like this surface of microdevice just formed one deck can carry out various chemistry/functional layer of biochemical/biological reaction.By various reactions, entity molecule can be combined in the surface of microdevice, thereby by the operation of microdevice being carried out next step the manipulation to entity molecule, separation or detection.The functional layer on microdevice surface makes that also directly carrying out synthetic reaction on the surface of microdevice becomes possibility.Synthesizing like this can be nucleic acid (for example DNA and RNA), also can be synthetic polypeptide or protein.Such functional layer surface comprises, but is not limited only to, and modified the group or the surfaces of their derivant such as carboxyl, amino, hydroxyl, sulfydryl, epoxy radicals, ester group, thiazolinyl, alkynyl, alkyl, aromatic radical, aldehyde radical, ketone group.

The selection of described microdevice with concrete separate, manipulation is relevant with detection mode.For example, when using dielectrophoresis force from potpourri isolation of target molecules the time, the microdevice or the dielectric properties of bond must have bigger difference with other molecule in the potpourri, like this, when bond and target entity molecule in conjunction with the time, entity molecule-bond-microdevice compound just can optionally be handled by dielectrophoresis.For example, when needs separated cancer cell from potpourri, the dielectric properties of cancer cell and normal cell were very approaching, and nearly all cell all has similar dielectric properties, for example all were the negative sense dielectrophoresis.In this case, microdevice or bond should use than the easier polarized material of medium, to be the forward dielectrophoresis.Like this, just can use the forward dielectrophoresis force optionally to handle microdevice-bond-cancer cell compound, and other cell is subjected to the negative sense dielectrophoresis force.

Microdevice can only comprise a kind of bond, also can comprise the occasion of multiple bond to be applicable to that high flux separates, handles and detect.

Because microdevice contains magnetisable material, microdevice, microdevice-entity molecule compound or microdevice-bond-entity molecule compound can rotate under the effect of magnetic field force, move or be handled so.The existence that magnetic field force refers to owing to magnetic field makes the suffered power of entity molecule such as particulate.In general, want to have enough magnetic field forces to come manipulation of particles, particle must have magnetic (for example having paramagnetism or ferromagnetism), or can be magnetized or polarize.We investigate the example of a typical magnetic particle of being made up of the superparamagnetism material, and when this particle was placed to magnetic field B, particle will produce magnetic dipole μ,

$\stackrel{\‾}{\mathrm{\μ}}=V_p({\mathrm{\χ}}_p-{\mathrm{\χ}}_m)\frac{\stackrel{\‾}{B}}{{\mathrm{\μ}}_m},$

$=V_p({\mathrm{\χ}}_p-{\mathrm{\χ}}_m){\stackrel{\‾}{H}}_m$

Wherein, V _pBe the volume of particle, χ _pAnd χ _mBe respectively the coefficient of magnetization of particle and surrounding medium thereof, μ _mThe magnetic that is medium sees through row, H _mIt is magnetic field intensity.Be added in the magnetic field force F on the particle _MagneticCan by moment magnetic dipole and magnetic field gradient obtain ${\stackrel{\‾}{F}}_{\mathrm{magnetic}}=-0.5V_p({\mathrm{\χ}}_p-{\mathrm{\χ}}_m){\stackrel{\mathrm{\ω}}{H}}_m\·\▿{\stackrel{\mathrm{\ρ}}{B}}_m,$

Wherein symbol " " and " " refer to dot product and gradient computing respectively.Clearly whether there is magnetic field force to be added in the coefficient of magnetization that depends on the particulate between particle and its surrounding medium.General particle is to be suspended from (its coefficient of magnetization approaches zero) in the nonmagnetic liquid medium, therefore must utilize magnetic particle (its coefficient of magnetization is much larger than 0).Particle's velocity v when magnetic field force and adhesion reach balance _ParticleCan provide by following formula

$v_{\mathrm{particle}}=\frac{{\stackrel{\‾}{F}}_{\mathrm{magnetic}}}{6{\mathrm{\πr\η}}_m}$

Wherein, r is the radius of particle, η _mMake the viscosity of surrounding medium.Therefore, for obtaining enough big magnetic steering force, must consider following factor: the magnetizability of (1) particle is answered optimization, and (2) magnetic field intensity should maximize, and the magnetic field gradient in (3) magnetic field is answered optimization.

Paramagnetic particles is meant that those externally can generate magnetic dipole under the action of a magnetic field, and after magnetic field removed, it was zero particulate that magnetic dipole can return again.In an application of the invention, can use commercially available paramagnetic particles or magnetic particle.The size of these particulates is generally between submicron order (50 nanometer to 0.5 nanometer) is to tens of microns.These particulates have different structures and composition.A kind of particulate is made by ferrimagnet, and coated outside polymer layer, for example polystyrene layer.Another kind of particulate is to have filled the ferromagnetic nano particulate in the hole of cavernous pearl body (for example polystyrene bead body).The surface of this two based fine particles can be inornate polystyrene, also can be through modifying so that connect various molecules.Also having a kind of particulate, is to mix the ferrimagnetism material uniformly to make in the polymerization procedure of manufacturing process.Like this, contain these paramagnetisms or magnetic particle in the microdevice of the present invention, make microdevice contain the ingredient that can be magnetized.

Described microdevice can use any suitable magnetisable material to make.For example, can use paramagnet, ferromagnetic material, ferrimagnetism material or superparamagnetism material directly to connect or be produced on the microdevice.Microdevice also can be made by suitable metal material, for example can use the metallic element of transition group: iron, nickel, copper, cobalt, tungsten, tantalum, zirconium or its alloying substance, for example cobalt-tantalum-zircaloy (CoTaZr alloy).Can be to use the whole bag of tricks, the method for (as making Fe-Ni alloy) or sputter (as making cobalt-tantalum-zircaloy) of for example electroplating is made magnetisable material.U.S. Patent application " Individually Addressable Micro-ElectromagneticUnit Array Chips in Horizontal Configurations " (Wu et al., application numbers 09/685,410, October 10 2000 date of application) provided the method for the magnetisable material of multiple making (paramagnet and ferromagnetic material etc.) in.

The rotation of magnetic particle, microdevice, microdevice-entity molecule compound or microdevice-bond-entity molecule compound need elder generation magnetic field of generation or handled.Can should be had bigger coefficient of magnetization by the particulate that magnetic field force is handled.In addition, after magnetic field removed, this particulate should not stay remanent magnetism or have a spot of remanent magnetism.Can use little electromagnetic unit to produce above-mentioned required magnetic field.When little electromagnetic unit was applied electric current, this electromagnetic unit can generate magnetic field.Control is applied to electric current on little electromagnetic unit, distribution that just can controlling magnetic field.The structure of little electromagnetic unit and size can design according to required magnetic field.Manipulation to magnetic particle comprises rectilinear motion, focus movement, induced motion etc.The motion of magnetic particle in magnetic field is called as " magnetophoresis ".The theory and the example that are used for the relevant magnetophoresis of cell separation and other purposes can be seen at many documents.As: MagneticMicrospheres in Cell Separation, by Kronick, P.L.in Methods of CellSeparation, Volume 3, edited by N.Catsimpoolas, 1980, pages 115-139; Useof magnetic techniques for the isolation of cells, by Safarik I.And SafarikovaM., in J.of Chromatography, 1999, Volume 722 (B), pages 33-53; A fullyintegrated micromachined magnetic particle separator, by Ahn C.H.et al., in J.of Microelectromechanical systems, 1996, Volume 5, pages 151-157.

Described microdevice can also comprise one and be convenient to microdevice/entity molecule-microdevice compound manipulation or feasible to microdevice/entity molecule-possible unit of microdevice compound manipulation becoming.This unit can be made by conductive material, to be handled by dielectrophoresis force; By the material of high/low acoustic damping character, to be subjected to the manipulation of sound field power; Make by charged materials, to be subjected to the manipulation of electrostatic force.This unit can be cell, organelle, virus, particulate, molecular aggregates thing or their complex.In addition, the U.S. Patent application U.S.PatentApplication Serial No.09/636 in the application, the bond of mentioning in 104 (on August 10th, 2000 submitted) also can be used as above-mentioned unit.Such material can be, but is not limited only to, the material of making by deposition or other technology with specific physical chemical property.Such material can be the metal film of being made by metals such as gold, chromium, titanium or platinum, and they not only can be used as the composition material of microdevice, can also increase the conductivity of microdevice.Such material can also be these megohmite insulants of plastic polymer such as polystyrene, and they not only can be used as the composition material of microdevice, can also reduce the conductivity of microdevice.

Unit in the above-mentioned microdevice, can be so that microdevice/entity molecule-microdevice compound be handled by suitable physical field, or make that using suitable physical field to handle to microdevice/entity molecule-microdevice compound becomes possibility.Such physical field can be referring to the U.S. Patent application U.S.Patent Application Serial No.09/636 in the application process, 104 (on August 10th, 2000 submitted).For example, can be dielectrophoresis force, row ripple dielectrophoresis force, magnetic field force (in the ferromagnetic material or the magnetic field of little electromagnetic unit generation), sound field power (in stationary field or traveling-wave field), electrostatic force (for example in DC electric field), mechanical force (for example liquid shear power), optical radiation power (optical pressure by the light tweezer produces) or the like.

Dielectrophoresis is the motion of polarisable particle (microdevice, microdevice-entity molecule compound or microdevice-bond-entity molecule compound) in non-homogeneous amplitude electric field.When particulate is inserted electric field, if there is certain difference in the dielectric properties of particulate and its surrounding medium, particulate will be polarized.Like this, will induce electric charge at particulate-medium interface.If extra electric field is an AC field heterogeneous, so, electric charge that particulate is induced and extra electric field interact, and the net effort that particulate is subjected to is non-vanishing, thereby particulate is moved to high field or feeble field zone.The suffered net effort of particulate is called dielectrophoresis force, and the motion of particulate is called as dielectrophoresis.The suffered dielectrophoresis force of particulate is by dielectric properties, the dielectric properties of particulate surrounding medium, the frequency of extra electric field, the amplitude distribution decision of particulate itself.

Row ripple dielectrophoresis is similar with above-mentioned dielectrophoresis, the polarization charge that row ripple electric field action has on particulate by the electric field initiation, thereby make particulate (microdevice, microdevice-entity molecule compound or microdevice-bond-entity molecule compound) be subjected to corresponding acting force, make particulate along or move against the direction of transfer of row ripple electric field.The suffered capable ripple dielectrophoresis force of particulate is determined by the dielectric properties of particulate itself, the dielectric properties of particulate surrounding medium, frequency, amplitude and the PHASE DISTRIBUTION of row ripple electric field.The theory of dielectrophoresis and row ripple dielectrophoresis and use the method that dielectrophoresis handles particulate can be referring to below with reference to document: " Non-uniform SpatialDistributions of Both the Magnitude and Phase of AC Electric Fields determineDielectrophoretic Forces " Wang et al.Biochim.Biophys.Acta 1243:185-194 (1995); " Dielectrophoretic Manipulation of Particles " Wang et al.IEEETransaction on Industry Applications 33:660-669 (1997); " Electrokineticbehavior of colloidal particles in traveling electric fields:studies usingyeast cells " Huang et al.J.Phys.D:Appl.Phys.26:1528-1535; " Positioningand manipulation of cells and microparticles using miniaturized electric fieldtraps and traveling waves " Fuhr et al.Sensors and Materials 7:131-146; " Dielectrophoretic manipulation of cells using spiral electrodes " Wang etal.Biophys.J.72:1887-1899 (1997); " Separation of human breast cancercells from blood bv differential dielectric affinity " Becker et al.Proc.Natl.Acad.Sci.92:860-864 (1995).Use dielectrophoresis and row ripple dielectrophoresis to the maneuverability pattern of particulate comprise concentrated, assemble, catch, repulsion, suspension, separate, or make particulate do linearity or other directed motion.Particulate can be hunted down, be enriched in the specific region in the reaction tank.Particulate can be subdivided into each subclass on fine level, also can be transported on certain distance.Being used for the required Electric Field Distribution of special particulate manipulation can design by relevant dielectrophoresis theory and electric field simulation method, and the distribution of electric field is determined by the size and the geometric configuration of electrode in concrete the application.

In the inhomogeneous field, radius is the dielectrophoresis force F that the particulate of r is subjected to _DEPzCan be expressed as:

$F_{\mathrm{DEP\; z}}=2{\mathrm{\&pi;\&epsiv;}}_{\mathrm{<figure-callout\; id="3"\; label="m\; r"\; filenames="A0312082100521.png"\; state="\{\{state\}\}">m</figure-callout>}}{r}^{}{}^3{\mathrm{\&chi;}}_{\mathrm{DEP}}\&dtri;{\mathrm{<figure-callout\; id="2"\; label="E\; rms"\; filenames="A0312082100521.png"\; state="\{\{state\}\}">E</figure-callout>}}_{\mathrm{rms}}^{}\&CenterDot;{\stackrel{\mathrm{\&rho;}}{a}}_z$

E wherein _RmsBe the root-mean-square value of field intensity, symbol is the symbol of expression gradient operation, ε _mIt is the dielectric coefficient of medium.χ _DEPBe the polarization factor of particulate, can be expressed as:

${\mathrm{\&chi;}}_{\mathrm{DEP}}=\mathrm{Re}\left(\frac{{\mathrm{\&epsiv;}}_p^{*}-{\mathrm{\&epsiv;}}_m^{*}}{{\mathrm{\&epsiv;}}_p^{*}+{2\mathrm{\&epsiv;}}_m^{*}}\right)$

Here Re refers to real, symbol ε _x ^*=ε _x-j σ _x/ (2 π f) is compound dielectric coefficient (wherein x=p is corresponding to particulate, and x=m is corresponding to medium).Parameter ε _p, σ _pBe respectively effective dielectric coefficient and conductivity (may be relevant) of particulate with impressed frequency.For example, typical biological cell will have conductivity and the dielectric coefficient (is because the cytoplasma membrane polarization causes) with frequency dependence to small part.

The formula of more than describing dielectrophoresis force also can be expressed as

$F_{\mathrm{DEP\; z}}=2{\mathrm{\&pi;\&epsiv;}}_{\mathrm{<figure-callout\; id="3"\; label="m\; r"\; filenames="A0312082100521.png"\; state="\{\{state\}\}">m</figure-callout>}}{r}^{}{}^3{\mathrm{\&chi;}}_{\mathrm{DEP}}{V}^{2}p\left(z\right){\stackrel{\mathrm{\&rho;}}{a}}_z$

Wherein p (z) is the distribution of the electric field value square of unit voltage excitation on the electrode (voltage V=1V), and V is an impressed voltage.

The dielectrophoresis that two kinds of forms are arranged usually, forward dielectrophoresis and negative sense dielectrophoresis.In the forward dielectrophoresis, particulate is moved to strong field by the effect of dielectrophoresis force.In the negative sense dielectrophoresis, particulate is subjected to the effect of dielectrophoresis force to the feeble field regional movement.It still is the negative sense dielectrophoresis that particulate is made forward, is by the relative degree of polarization decision of particulate and medium.

Row ripple dielectrophoresis force refers to that entity molecule (particulate or molecule) is in the capable ripple electric field and the power that is subjected to.The characteristics of row ripple electric field are that the phase value of its AC field component is a uneven distribution.

At this, we analyze the capable ripple dielectric electric field force of a desirable capable ripple electric field.The ripple electric field of being expert at $E_{\mathrm{TWD}}=E\cos \left(2\mathrm{\&pi;}(\mathrm{ft}-z/{\mathrm{\&lambda;}}_0)\right){\stackrel{\mathrm{\&rho;}}{a}}_x$ Act on the dielectrophoresis force F that radius is the particle of r in when the z direction is moved (for example the electric field of an x direction along) _TWDDielectrophoresis can be by formula $F_{\mathrm{TWD}}=-2\mathrm{\&pi;}{\mathrm{\&epsiv;}}_{\mathrm{<figure-callout\; id="3"\; label="m\; r"\; filenames="A0312082100521.png"\; state="\{\{state\}\}">m</figure-callout>}}{r}^{}{}^3{\mathrm{\&zeta;}}_{\mathrm{TWD}}{\mathrm{<figure-callout\; id="2"\; label="E"\; filenames="A0312082100521.png"\; state="\{\{state\}\}">E</figure-callout>}}^2\&CenterDot;{\stackrel{\mathrm{\&rho;}}{a}}_z$ Provide, wherein E is field intensity, ε _mBe specific inductive capacity, the ζ of medium _TWDBe the polarization factor of particle, ζ _TWDProvide by following formula ${\mathrm{\&zeta;}}_{\mathrm{TWD}}=\mathrm{Im}\left(\frac{{\mathrm{\&epsiv;}}_p^{*}-{\mathrm{\&epsiv;}}_m^{*}}{{\mathrm{\&epsiv;}}_p^{*}+2{\mathrm{\&epsiv;}}_m^{*}}\right),$ Wherein Im refers to the imaginary part of plural number, symbol ε _x ^*=ε _x-j σ _x/ 2 π f are (particle x=p and medium x=m) composite dielectric constants, parameter ε _pAnd σ _pBe respectively the conductivity of effective dielectric constant and particle, these parameters are frequency dependences.

Have different dielectric properties particle (defined) as biological cell etc. and will show different dielectrophoresis forces as specific inductive capacity, conductivity.Concerning the capable ripple dielectrophoresis of particle (comprising biological cell) was handled, the capable ripple dielectrophoresis force that loads on a diameter and be on 10 microns the particle can change between 0.01-10000pN.

On the microelectrode that is arranged on the chip, apply suitable AC signal and just can produce capable ripple electric field.In order to produce capable ripple electric field, on electrode, should apply the electric signal of three groups of out of phase values at least.In the example of a capable ripple electric field, used the electric signal (being respectively 0,90,180,270 degree) of four kinds of out of phase values, be applied on the parallel pole that is arranged in chip surface of four wire, four such electrodes can be used as a basic repetitive in order to chip design.Needs according to using can get up unit cell arrangement such more than two, thus above the electrode or near generation row ripple electric field.As long as electrode unit is spatially lined up according to certain order, the signal of the out of phase that adds just can produce row ripple electric field at the electrode near zone.

The dielectrophoresis force that is subjected on the particulate (microdevice, microdevice-entity molecule compound or microdevice-bond-entity molecule compound) is not only relevant with Electric Field Distribution (electric field magnitude, phase place, frequency etc.) with the situation of row ripple dielectrophoresis force, and relevant with the dielectric properties of particulate and medium.If particulate is than dielectric polorization degree height (for example under certain frequency, particulate has bigger conductivity and polarizability), particulate is subjected to the effect of forward dielectrophoresis force and moves to strong field.If particulate is lower than dielectric polorization degree, particulate is subjected to the effect of negative sense dielectrophoresis force to the feeble field regional movement.It still is the negative sense dielectrophoresis that particulate is made forward, is by the relative degree of polarization decision of particulate and medium.Be expert in the ripple dielectrophoresis, particulate is subjected to dielectrophoresis force, according to polarization factor ζ _TWDDifference, particulate can along or move against the direction of row ripple electric field.Following document has provided some basic theories about dielectrophoresis and row ripple dielectrophoresis: Huang, et al., J.Phys.D:Appl.Phys.26:1528-1535 (1993); Wang, et al., Biochim.Biophys.Acta.1243:185-194 (1995); Wang, et al., IEEE Trans.Ind.Appl.33:660-669 (1997).

Particulate (microdevice, microdevice-entity molecule compound or microdevice-bond-entity molecule compound) can be handled by the sound field radiant force, for example is among the sound field.If the reflection wave by a sound field source and it has produced a standing-wave sound field in the space, be in wherein particulate according to the difference of the sound damping coefficient of itself and surrounding medium, can be subjected to the effect of sound field radiant force.Acoustic damping is relevant with the density of material itself, is the velocity of propagation of sound wave in this material.If particulate has higher acoustic damping than surrounding medium, will be subjected to pointing to the sound field radiant force of position of the node of standing-wave sound field.Sound field distributes not simultaneously, and particulate is subjected to different sound field radiant forces.

Can use piezoelectric to produce sound field,, can be delivered in the material medium on every side and go so that piezoelectric produces mechanical vibration when the electric signal that on piezoelectric, applies appropriate frequency.Piezoelectric ceramics is so a kind of piezoelectric.Microelectrode can be produced on the piezoelectric ceramics makes piezoelectric ceramics produce sound field to apply electric signal.According to different application needs, can design the microelectrode of different size and geometric configuration.In order to produce standing-wave sound field, also need reflecting wall.Can use the sound field of different frequency among the present invention, for example from several kHz to hundreds of MHz.Except standing-wave sound field, can also use non-standing-wave sound field, for example capable wave sound field.Row wave sound field also can be so that particulate wherein be subjected to the effect of power, can be referring to " Acoustic radiation pressure on a compressible sphere, by K.Yoshioka and Y.Kawashima in Acustica, 1955; Vol.5, pages 167-173 ".Particulate not only itself is subjected to the effect of sound field, also is subjected to the acting force of surrounding fluid medium simultaneously, be expert at the down motion of effect of wave sound field of fluid media (medium).Use sound field, can be to operations such as particulate carry out enrichment, focuses on, catches, promotes and transports under microfluidic environment.Another mechanism that makes particulate in the sound field be subjected to the effect of power is that the convection current of the fluid media (medium) that brings out by sound field produces.Such convection current is by the distribution of sound field itself, the character of fluid and the volume and the structures shape of the residing cavity of fluid.Thereby the such convection current of fluid can apply the manipulation of the effect realization of power to particulate to particulate wherein.This manipulation can be used to promote the immixture of fluid and particulate wherein.In the present invention, such convection current can strengthen the interaction of bond and entity molecule in order to promote to be connected the bond on the microdevice and the mixing of the entity molecule in the fluid.

Can produce the plane of ultrasound standing wave by on piezoelectric transducer, applying AC signal.For example, suppose that standing wave is to be based upon in the liquid on the specific direction (for example, Z direction).The variation of standing wave on the Z direction can be shown with following table:

Δp(z)＝p ₀?sin(kz)cos(ωt)

Wherein Δ p represents the sound field pressure on the Z direction, p ₀Represent the sound field pressure intensity, k represents wave number (2 π/λ, wherein λ is a wavelength), and z represents the distance of pressure node, and ω represents angular frequency, and t represents the time.According to the theory that Yoshiokaand Kawashima nineteen fifty-five proposes, in the stationary field of a static state, the sound field radiant force that acts on a spherical particle can be represented with following formula, referring to K.Yoshioka and Y.Kawashima at Acustica, 1955, Vol.5, pages 167-173; " Acoustic radiation pressure on a compressible sphereand electrostatic force by Yasuda K.et al.in Jpn.J.Appl.Physics, 1996, Volume 35, pages 3295-3299 ":

$F_{\mathrm{acoustic}}=-\frac{4\mathrm{\&pi;}}{3}{r}^{3}k{E}_{\mathrm{acoustic}}A\sin \left(2\mathrm{kz}\right)$

Wherein r is the radius of particulate, E _AcousticBe the mean energy density of sound field, A is a constant, represents with following formula:

$A=\frac{5{\mathrm{\&rho;}}_p-{2\mathrm{\&rho;}}_{\mathrm{<figure-callout\; id="2"\; label="m"\; filenames="A0312082100521.png"\; state="\{\{state\}\}">m</figure-callout>}}}{{2\mathrm{\&rho;}}_p+{\mathrm{\&rho;}}_m}-\frac{{\mathrm{\&gamma;}}_p}{{\mathrm{\&gamma;}}_m}$

ρ wherein _mAnd ρ _pRepresent particulate and density of medium, γ _mAnd γ _pRepresent the acoustic impedance of particulate and medium.A represents the sound field polarization parameter here.Acoustic impedance is defined as the density (ρ of material _mAnd ρ _pRepresent particulate and density of medium) and the velocity of sound (C _mAnd C _pRepresent medium and particulate in the velocity of sound) product (γ _m=ρ _mC _mAnd γ _p=ρ _pC _p).

When A＞0, particulate is located to move to the pressure node (z=0) of standing wave.

When A＜0, particulate is located to move to the pressure node (z=0) away from standing wave.

Clearly, when being placed on the particulate of different densities and acoustic impedance in the stationary field, they are subjected to different sound field radiant forces.For example: according to the sound field energy distribution of having set up, diameter is that the sound field radiant force that 10 microns particulate is subjected to changes from 0.01 to 1000pN.

Piezoelectric transducer is made with piezoelectric.When making it that deformation takes place when from the outside piezoelectric being applied mechanical force, piezoelectric can produce electric field (this is called piezoelectric effect or generator effect).Opposite, piezoelectric is applied electric field can produce a mechanical stress (this is called electricity and causes blockage effect or engine effect).Piezoelectric effect is found in 1880 by Pierre Curie and his fraternal Jacques.The reason of explaining is the electric polarization that the displacement of ion has caused the material structure unit.When applying electric field, ion is replaced by electrostatic force, causes the mechanical sex change of whole material.Like this, in a sound field-field flow separation or sound field-electrophoresis-field flow separation or sound field-dielectrophoresis-field flow tripping device, piezoelectric transducer is applied AC signal, and the vibrations that produce on the converter just are coupled in the liquid in the reaction tank so, cause producing in the reaction tank sound wave.Such sound wave may have capable ripple and standing wave component.

Particulate (microdevice, microdevice-entity molecule compound or microdevice-bond-entity molecule compound) can be handled in DC electric field.DC electric field can apply the effect of electrostatic force to charged particulate.Electrostatic force is relevant with polarity with a particulate charged quantity itself, and is simultaneously also relevant with direction with the field intensity of electric field itself.The particulate that has positive charge will move to electrode direction under the effect of negative potential; The particulate that has negative charge then will move to electrode direction under the effect of positive potential.Design is during microelectrode in microfluidic device, consider to make electric field correct in space distribution.In DC electric field, the particulate in the microfluidic device can be by enrichment, focus on and transport.Also to cover one deck suitable insulation layer at electrode surface, preventing or to reduce undesirable surface electrochemistry phenomenon as far as possible, thus the surface of guard electrode.

At electric field F _EIn act on a direct current field force on the particulate

Provide by following formula:

$F_E=Q_p{E}_z{\stackrel{\mathrm{\&rho;}}{a}}_z$

Q wherein _pIt is the effective charge on particulate.The direction that acts on the direct current field force on the charged corpuscle is decided by the polarity of particulate electric charge and the direction that applies electric field.

If set up a thermograde in medium, such thermograde will cause flowing of medium, thereby form a velocity field in medium.Make particulate (microdevice, microdevice-entity molecule compound or microdevice-bond-entity molecule compound) be subjected to the effect of power.The mobile part of this medium produces owing to thermal diffusion makes medium tend to reach thermal equilibrium, in addition, for aqueous solution, the Temperature Distribution of solution is tended to consistent with corresponding Density Distribution, and a kind of like this distribution of density can cause flowing of medium equally and reach balance.The media flow that thermograde causes is also referred to as thermal convection sometimes.Thermal convection can occur in the relatively large whole medium of scale, and it can be used to promote the mixing of liquid, also can be used as a kind of power molecule is taken to a certain specific response location from place far away.

By being installed, heating and/or cooling element also can in based on the reactor of chip or instrument, set up temperature gradient distribution in chip structure.This heating element can be simple joule heating resistor, and this joule of heating resistor can be machined in the chip.With an impedance is that 10 ohm well heater is an example, and the electric current that passes to 0.2A will produce 0.4W joule heat energy, if this coil is mounted in a zone less than 100 square microns, and its will effectively raise local temperature and in medium, produce thermograde.Equally, cooling element can be one and passes to semiconductor Pa Er card (Peltier) element that can cause that environment temperature descends behind the electric current.

In actual applications, chip can have the array of a gateable heating element, thereby these elements must place in a certain order or carry out structural design so as to make when wherein each, can set up thermograde when some or all elements are activated and produce desirable thermal convection, and therefore in the medium of introducing the instrument that constitutes by chip, set up velocity field.For example, when a heating element is activated or switches on, raising in the temperature of this component ambient adjacent media will produce a localized temperature gradients, the generation thermal convection.In another practical application, chip can comprise a plurality of, interconnective heating unit, so that make these unit can be by synchronous switch.In same another practical application, chip can only comprise a heating element, and its local temperature that can raise produces thermal convection in medium when passing to electric current.Equally, chip also can comprise an array of the cooling element of gating one by one, or single cooling element.

Except above-mentioned physical force, other physical force also can be used for the present invention.For example, mechanical force (fluid force) can be in order to transport particulate (microdevice, microdevice-entity molecule compound or microdevice-bond-entity molecule compound).Light field power or optical radiation power are used for " light pincers " and come particulate is carried out polymerization, catches, floats and handles.When a kind of refractive index material different with its surrounding medium (as particulate etc.) light field power suffered when being placed in the gradient light field is exactly so-called gradient force.When light passes through polarizable material, it will produce the moment dipole.These dipoles and electromagnetic field gradient interact, when the refractive index of these materials will produce a power of pointing to the bright areas of light during greater than its surrounding medium.On the contrary, when the refractive index of certain material during less than surrounding medium, it will be subjected to one it will be pulled to the power in the darker zone of light.About the theory of the various biological applications of light pincers and example has been undertaken describing in detail by many documents as: " Making light work with optical tweezers; by Block S.M., in Nature, 1992; Volume 360, pages 493-496 "; " Forces of a single-beamgradient laser trap on a dielectric sphere in the ray optics regime, by Ashkin, A., in Biophys.J., 1992, Volume 61, pages 569-582 "; " Laser trapping in cellbiology, by Wright et al., in IEEE J.of Quantum Electronics, 1990, Volume26, pages 2148-2157 "; " Laser manipulation of atoms and particles, by ChuS.in Science, 1991, Volume 253, pages 861-866 ".In order in based on the reactor of chip or instrument, to produce the light field radiant force, need to produce light field and/or light intensity field, for example can pass through built-in optical element and the array and the external light source of chip or pass through the built-in photovalve of chip and the electric signal source of array and external structure.In the previous case, when the light of optical signal source generation passed through built-in optical element and array, light was just handled by reflection, focusing, interference etc. by these element/arrays, and light field is handled the chips peripheral region in many power and produced.Under latter event, after electric signal that external electric signal source produces was absorbed by built-in photovalve and array, they will produce light, just produce light field around chip.Also available other method makes many power handle chip and produces light field, thereby produces light field power.

Described microdevice can only contain a functional unit, also can contain a plurality of functional units in order to high throughput analysis, each functional unit can so that a kind of specific physical force microdevice is handled.For example, functional unit can be the magnetisable material that available magnetic field force is handled, insulating material or conductive material that available dielectrophoresis force is handled, the high/low acoustic damping material that available sound field radiant force is handled, the charged materials that can be handled by electrostatic force etc.

In actual applications, have on the microdevice can in conjunction with or the bond of specific bond entity molecule to be separated, to be detected, to be handled and be convenient to microdevice/entity molecule-microdevice compound is handled or making microdevice/entity molecule-microdevice compound handled becomes possible unit.Also can have on the microdevice can in conjunction with or one group of bond of the different entity molecule to be separated, to be detected, to be handled of specific bond with different physical force easy to use microdevice/entity molecule-microdevice compound is handled or is made that using different physical force that microdevice/entity molecule-microdevice compound is handled becomes one group of possible unit.

Can also have on the described microdevice can be detected mark or a kind of molecular label.Like this can be detected mark can be dyestuff, radiomaterial and fluorescent material or the like.Such molecular label can be nucleic acid, nucleic acid oligomer, protein or polypeptide.

In actual applications, microdevice of the present invention can be thin rectangular shape, and the ratio of main shaft (length) and secondary axes (width) is 1.2 at least, preferably is 1.5 at least, and the thickness of microdevice (highly) is all littler than main shaft and secondary axes.In another practical application, microdevice of the present invention comprises at least two rectangular-shaped or approaching rectangular-shaped list structures of being made by paramagnet (club shaped structure).Strip (bar-shaped) structure that these at least two paramagnets are made preferably is separated out, and lays respectively at the both sides of the main shaft of microdevice, but the middle metal film that is had light recognition coding pattern separates.Preferably this metal film contains aluminium.Can have the rectangular configuration that the different paramagnet of quantity is made in the main shaft both sides of microdevice.Microdevice also can have the rectangular configuration that two paramagnets are made along main shaft, and the rectangular configuration that these two paramagnets are made all has the outstanding structure of finger-shaped at two ends.Also can be that paramagnet forms the rectangular configuration along the major axes orientation of microdevice, this rectangular configuration all has the outstanding structure of finger-shaped at two ends.

Another object of the present invention provides a kind of system that constitutes the microdevice array.

A kind of system that constitutes the microdevice array comprises: 1) one group of microdevice, and this microdevice comprises: a) magnetizable base material; B) but be produced on the coding pattern of the light identification on the above-mentioned base material; C) magnetized axis; With 2) the minitype channel array formed by one group of minitype channel; The width of described minitype channel is: when described microdevice was in the externally-applied magnetic field, single microdevice can rotate freely in passage, can not form the microdevice chain when the main shaft of described microdevice main shaft and minitype channel is vertical.

In a certain practical application, the coded portion of microdevice of the present invention is not realized by platinum, palladium, nickel, cobalt, silver, copper or gold.In another practical application, the composition material of microdevice of the present invention does not comprise platinum, palladium, nickel, cobalt, silver, copper or gold.

When described microdevice is handled in minitype channel, microdevice keeps the plane upwards or the state that makes progress of basic plane, but so that by optical means by with the length of the minitype channel direction vertical with wide residing plane on the optical identification coding is detected.Height by minitype channel and/or should make that to the adjusting of the restrictive condition of microdevice microdevice is unlikely to erect in minitype channel by magnetic field.For example, the height of minitype channel can be not more than 70% of microdevice main axis length.

Can also comprise a field generator for magnetic on the minitype channel array apparatus, can handle microdevice turnover minitype channel, make microdevice in minitype channel, rotate required magnetic field so that produce.Such field generator for magnetic can use any proper device, for example can use permanent magnet, movable magnet, electromagnetic unit, ferromagnetic material or little electromagnetic unit etc.The magnetic field that produces can act on the certain location of minitype channel array, for example minitype channel array below, middle, top and neighbouring etc.

The 3rd purpose of the present invention provides the method for making the microdevice array.

The method of making the microdevice array has two kinds.First kind of method of making the microdevice array may further comprise the steps:

(1) provide one group of above-mentioned microdevice, this microdevice comprises a) magnetizable base material; B) but be produced on the coding pattern of the light identification on the above-mentioned base material; C) magnetized axis;

(2) provide a minitype channel array of forming by one group of minitype channel; The width of described minitype channel is: when described microdevice was in the externally-applied magnetic field, single microdevice can rotate freely in passage, can not form the microdevice chain when the main shaft of described microdevice main shaft and minitype channel is vertical;

(3) described one group of microdevice is introduced described minitype channel;

(4) rotate described microdevice by the magnetic field force that adds in minitype channel, the acting in conjunction of the magnetized axis by described magnetic field force and described microdevice makes and disperses mutually between the described microdevice.

In a certain practical application, the coded portion of microdevice of the present invention is not realized by platinum, palladium, nickel, cobalt, silver, copper or gold.In other practical application, the composition material of microdevice of the present invention does not comprise platinum, palladium, nickel, cobalt, silver, copper or gold.

When described microdevice is handled in described minitype channel, microdevice keeps the plane upwards or the state that makes progress of basic plane, but so that by optical means by with the length of the described minitype channel direction vertical with wide residing plane on the optical identification coding is detected.Height by described minitype channel and/or should make that to the adjusting of the restrictive condition of microdevice microdevice is unlikely to erect in minitype channel by magnetic field.For example, the height of minitype channel can be not more than 70% of microdevice main axis length.

Described microdevice can use any suitable acting force to introduce minitype channel.For example, can use magnetic field force, fluid force or the two combination that microdevice is introduced minitype channel.There is several different methods microdevice can be introduced passage.In concrete enforcement, microdevice can be a kind of certain thickness miniature disc that two main planes are arranged that has.Earlier miniature disc is placed near minitype channel or feeder connection place, use a neodymium system magnetisable material with miniature disc suction passage at the endpiece of passage.Can be with the magnetisable material rotation so that with miniature disc suction passage.In concrete an enforcement of the present invention, the interarea of miniature disc is of a size of 90 microns * 70 microns, the about several microns of thickness.Use above-mentioned method, can be in 3 minutes, completely miniature disc is filled among the passage of 52 centimeter length (about 120 to 160 microns wide).The magnetic strip or the length and width of club shaped structure and high in the miniature disc all along the length and width of the residing miniature disc of magnetic material and high direction.Because rate-limiting step is to fill miniature disc along the major axis of passage, can't prolong the required time of filling significantly so increase the quantity of passage, can within 3 minutes, finish among for example 50,000 miniature discs being packed into the passage of 200 2 centimeter length.When the direction of magnetic direction that adds and passage is vertical, make to fill in this way to make the miniature disc of " homeotropic alignment " overlap.The overlapping phenomenon of miniature disc can be by eliminating the direction of externally-applied magnetic field to the vertical direction conversion from parallel direction several times.Like this can be so that the distance between " chain " that the miniature hdd sheet is arranged in increases.When miniature disc was introduced passage, the short transverse of best miniature disc and the short transverse of minitype channel were consistent, and miniature like this disc can keep the plane upwards in minitype channel.

Described microdevice can be a kind of certain thickness miniature disc that two main planes are arranged that has.Described miniature disc is filled according to above-mentioned method, the efficient that keeps constant flow velocity to fill with raising simultaneously.When described miniature disc was introduced described passage, the short transverse of best miniature disc and the short transverse of minitype channel were consistent, and miniature like this disc can keep the plane upwards in minitype channel.

In concrete enforcement, described microdevice can be a kind of certain thickness miniature disc that two main planes are arranged that has.The length and width of magnetic strips or magnetism stick and high in the miniature disc all along the length and width of the residing miniature disc of magnetic material and high direction.Earlier miniature disc is placed near described minitype channel or feeder connection place, the neodymium system magnetisable material that uses a large size at the endpiece of passage is with miniature disc suction passage, and the magnetic direction of this piece magnetisable material generation is vertical with channel direction.Above the inlet end of passage or below use the neodymium system magnetisable material of a trumpet, rotate so that with miniature disc suction passage.The efficient that keeps constant flow velocity to fill simultaneously with raising.Miniature disc is packed into passage according to the pattern (magnetized axis that is miniature disc is vertical with the direction of passage major axis) of " vertically arranging ", and this mode can reduce the phenomenon of the overlapping arrangement of miniature disc in the passage, makes the arrangement of miniature disc keep homogeneous.Above-mentioned this loading and the method for arranging miniature disc will make on the miniature disc or the magnetic list structure in the miniature disc is vertical with the direction of passage major axis, on the promptly miniature disc or the magnetic list structure in the miniature disc or the long axis direction of the long axis direction of club shaped structure and passage is vertical or vertical substantially.When miniature disc was introduced passage, the short transverse of best miniature disc and the short transverse of minitype channel were consistent, and miniature like this disc can keep the plane upwards in minitype channel.

Described microdevice or miniature disc can be introduced described minitype channel according to certain angle.For example, can use the magnetic field of pointing to a certain direction that microdevice is packed into minitype channel, the magnetic field of this direction makes the angle between the main shaft of the main shaft of microdevice and minitype channel be not more than 45 degree.The direction in magnetic field can influence the direction of microdevice or the location of miniature disc and microdevice main shaft.Usually, when microdevice can rotate freely or reorientate, the magnetized axis of microdevice will be substantially along the direction of externally-applied magnetic field.For microdevice or miniature disc, their magnetized axis is consistent with major axes orientation, thus magnetized axis consistent with the externally-applied magnetic field direction be exactly that the main shaft of microdevice is consistent with the externally-applied magnetic field direction.Like this, can use the magnetic field of pointing to a certain direction that microdevice is packed into minitype channel, the magnetic field of this direction makes the angle between the length direction of the main shaft of microdevice and minitype channel be not more than 45 degree.Be more preferably, can use the magnetic field of pointing to a certain direction that microdevice is packed into minitype channel, the magnetic field of this direction makes the angle between the length direction of the main shaft of microdevice and minitype channel be not more than 40,35,30,25,20,15,10,5 or 0 degree.

Method of the present invention further is included in the microdevice of introducing before the described microdevice or interrupting catenation simultaneously in described minitype channel.Can realize this purpose by any suitable method, for example the method by the direction of rotating magnetic field between the main shaft of microdevice and secondary axes.

After described microdevice or miniature disc were introduced described minitype channel or passage, microdevice or miniature disc kept the plane upwards.Microdevice or miniature disc can rotate in passage and make microdevice or miniature disc separate each other.Described microdevice or miniature disc are separated each other, can realize by the rotation of a wide-angle, also can be by repeatedly low-angle rotation realization.The microdevice or the anglec of rotation of miniature disc are rotated 45 degree at least; Best, the microdevice or the anglec of rotation of miniature disc are 90 degree.

In concrete enforcement of the present invention, at least one microdevice can be in conjunction with an entity molecule, and perhaps one group of microdevice can be respectively in conjunction with a group object molecule.Method of the present invention can be in order to carrying out any suitable manipulation to entity molecule, such manipulation can be transport, focusing, enrichment, concentrate, assemble, catch, the moving of the entity molecule on repulsion, suspension, separation, fractionation, isolation, linearity or other direction.Thereby, method of the present invention determines the entity molecule of being handled on this microdevice but also comprising the coding pattern that uses optical means to detect light identification on the microdevice.To by parameters such as the ratio of the entity molecule of determining to comprise that acquisition is handled of the entity molecule kind handled, content.

Method of the present invention also comprises by the entity molecule on the quantivative approach analysis microdevice further to obtain being handled the quantitative information of entity molecule.To parameters such as the quantity that comprised the entity molecule that acquisition is handled by the quantitative test of the entity molecule handled, concentration.Method of the present invention also comprises by endpiece collects the microdevice that is combined with entity molecule.Method of the present invention also comprises the method for collecting entity molecule from the microdevice of collecting.

Second kind of method of making the microdevice array provided by the invention may further comprise the steps:

(1) provide one group of above-mentioned microdevice, this microdevice comprises: a) magnetizable base material; B) but be produced on the coding pattern of the light identification on the above-mentioned base material; C) magnetized axis.

(2) they are positioned on the plane that is beneficial to microdevice rotation;

(3) rotate described microdevice by the magnetic field force that adds on described surface, the acting in conjunction of the magnetized axis by described magnetic field force and described microdevice makes and disperses mutually between the described microdevice.

In a certain practical application, the coded portion of microdevice of the present invention is not realized by platinum, palladium, nickel, cobalt, silver, copper or gold; The composition material of microdevice of the present invention does not comprise platinum, palladium, nickel, cobalt, silver, copper or gold in another practical application.

The present invention has provided a minitype channel array of being made up of one group of minitype channel, when above-mentioned microdevice is in the externally-applied magnetic field, this minitype channel needs enough wide, make single microdevice in passage, to rotate freely, this passage also needs enough narrowly simultaneously, makes above-mentioned microdevice be unlikely to form the microdevice string under the main shaft situation vertical with the main shaft of minitype channel; C) one group of above-mentioned microdevice is introduced above-mentioned minitype channel; D) rotate above-mentioned microdevice by the magnetic field force that adds in minitype channel, the acting in conjunction of the preferred magnetisable axle by above-mentioned magnetic field force and above-mentioned microdevice makes and disperses mutually between the above-mentioned microdevice.In concrete enforcement of the present invention, described microdevice is suspended in and is introduced into the plane in the solution.The suspending liquid of microdevice can be incorporated on the plane by the whole bag of tricks, for example by application of sample, or by pump suspending liquid is introduced in the minitype channel on the plane.Also can produce earlier wide (size than microdevice is wide) in the plane) groove of back narrow (size than microdevice is narrow), the suspending liquid that adds microdevice in the plane, by the time after microdevice is arranged in the plane, the liquid of the residing suspending liquid of microdevice can pass through several different methods, for example aspirates or the mode that pumps is removed.

The present invention can on the chip or on the non-chip in order to analyze, separate, to handle or detect the entity molecule of any kind of that carries out some processing, these entity molecules can carry out physics, chemistry, biological, biophysics or biochemical processing.Entity molecule to be handled can be cell, organelle, virus, molecule or their complex.Entity molecule to be handled can be pure material, or exists with the form of potpourri, only is a component in the potpourri at this potpourri entity molecule that hits.For example, the cancer cell in cancer cell, the cancer patient tissue in the blood of leukemia patient, the fetal cell in the maternal blood can be as entity molecule to be separated, that handle or detect.Similarly, different blood cells, for example red blood cell in the blood and leucocyte can be used as entity molecule to be separated, that handle or detect.The protein of dna molecular, mRNA molecule, particular types or the total protein in the cell pyrolysis liquid can be as entity molecules to be separated, that handle or detect.

The entity molecule that cell can be used as is to be separated, handle or detect.Such cell comprises, but is not limited only to zooblast, vegetable cell, fungal cell, bacterial cell, recombinant cell or cultured cells.A certain kind or subspecies that zooblast to be handled, vegetable cell, fungal cell and bacterial cell derive from the animal kingdom, plantage, mycota and bacterium circle respectively belong to.The cell that belongs to infusorians, Slime fungi, flagellates, little spore class also can be handled.Come from birds such as chicken, vertebrate for example fish and mammal for example rat, mouse, rabbit, cat, dog, pig, milk cow, bull, sheep, goat, horse, monkey and other anthropoid cape and human cell can be as entity molecules to be separated, that handle or detect.

For zooblast, the cell that comes from specific tissue or organ can be as entity molecule to be separated, that handle or detect.For example, the cell of connective tissue, epithelial tissue, musculature or nerve fiber.Similarly, the cell in the various organs also can be handled, as the eye accessory organ, and toroidal helical organ (annulospiral organ), ear's organ, Qi Weici device, circumventricular organs official, Ke Ti Shi, critical organ, enamel, end organ, female external genital organs official, the male genitalia official, reproductive organs, Golgi tendon organ, gustatory organ, the hearing organ, female internal reproductive organ, male internal reproductive organ inserts organ, Jacobson's organ, neurohaemal organ, neurotendinal spindle, olfactory organ, the otolith device, organ of Rosenmuller, sense organ, olfactory organ, spiral organ, subcommissural organ, subfornical organ, antennal organ, target organ, gustatory organ, tactile organ, urinary organ, vestibular organ, vestibulocochlear organ, vestige, the organs of vision, vomeronasal organ, migration device, weber's organ and glomus aorticum.From animal internal such as brain, lung, liver, spleen, marrow, thymus gland, heart, lymph, blood, bone, cartilage, pancreas, kidney, gall-bladder, stomach, intestines, testis, ovary, the uterus, rectum, nervous system, the cell of blood vessel or the like is easier to handle in the body of gland, body.Furtherly, can be from the cell of any plant, fungi (as saccharomycete), bacterium (as eubacteria or archeobacteria) as entity molecule to be separated, that handle or detect.From any eucaryon or procaryotic recombinant cell, as animal, plant, fungi or bacterium can be as entity molecule to be separated, that handle or detect.The body fluid that comes from parts of body, as the cell in blood, urine, saliva, marrow, seminal fluid or other ascites, and their component such as serum and blood plasma can be as entity molecules to be separated, that handle or detect.

Can be transported or comprised nucleus, mitochondria, chloroplast, ribosomes, endoplasmic reticulum, golgiosome, lysosome, proteasome, vesica, vacuole or microbody as the organelle of bond.Can be transported or can be from such as first kind virus, second viroid, the 3rd viroid, the 4th viroid, the 5th viroid or the 6th viroid in its life cycle as the virus (no matter being complete virus or any virus structure) of bond.

Can be inorganic molecule such as ion by the molecule of manipulation, separation or detection, organic molecule or their complex.The example of steerable ion comprises, but be not limited only to sodion, potassium ion, magnesium ion, calcium ion, chlorion, ferric ion, copper ion, zinc ion, manganese ion, vanadium ion, nickel ion, chromium ion, fluorine ion, silicon ion, tin ion, boron ion or arsenic ion.The example of organic molecule comprises, but is not limited only to amino acid, peptide, protein, nucleosides, nucleotide, oligonucleotides, nucleic acid, vitamin, monose, oligosaccharides, carbohydrates, lipid or their complex.

Any amino acid can use method of the present invention to detect, separate or handle as D-with L-amino acid.In addition, all of naturally occurring peptide and protein make up composition, comprise alanine (A), arginine (R), asparagine (N), aspartic acid (D), halfcystine (C), glutamine (Q), glutamic acid (E), glycocoll (G), histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), proline (P), serine (S), threonine (T), tryptophane (W), tyrosine (Y) can use method of the present invention to detect, separate or handle with valine (V).

Any protein can use method of the present invention to detect, separate or handle with peptide.For example, the memebrane protein on the cell membrane (as receptor protein), enzyme, transport albumen (as ion channel and ionic pump), nutrition or storage protein, contraction or motion albumen (as actin and myosin), structural proteins, Buchner's bodies or regulate albumen (as antibody, hormone and auxin).Antigen protein or peptide can use method of the present invention to detect, separate or handle.

Any nucleic acid comprises that strand, two strands and three chain nucleic acid can use method of the present invention to detect, separate or handle.The example of such nucleic acid comprises DNA (as A-, B-, Z-type DNA) and RNA (as mRNA, tRNA and rRNA).

Any nucleosides can use method of the present invention to detect, separate or handle.The example of such nucleosides comprises adenosine, guanosine, cytidine, thymidine, uridine.Any nucleotide can use method of the present invention to detect, separate or handle, and the example of such nucleotide comprises AMP, GMP, CMP, UMP, ADP, GDP, CDP, UDP, ATP, GTP, CTP, UTP, dAMP, dGMP, dCMP, dTMP, dADP, dGDP, dCDP, dTDP, dATP, dGTP, dCTP and dTTP.

Any vitamin can use method of the present invention to detect, separate or handle.For example, water soluble vitamin such as vitamin B1, vitamin B2, niacin, vitamin B3, vitamin B6, biotin, folic acid, cobalamin and vitamin C can use method of the present invention to detect, separate or handle.Similarly, liposoluble vitamin such as vitamin A, vitamin D, vitamin E and vitamin K can use method of the present invention to detect, separate or handle.

Any monose (no matter be D-or L one monose, also no matter be aldose or ketose) can use method of the present invention to detect, separate or handle.The example of monose comprises that trisaccharide (as glyceraldehyde), tetrose (as erythrose and threose), pentose are (as ribose, arabinose, wood sugar, lyxose and ribulose), hexose (as allose, altrose, glucose, mannose, gulose, idose, galactose, talose and fructose) and heptose (as sedoheptulose).

Any lipid can use method of the present invention to detect, separate or handle.The example of lipid comprises triacylglycerol (as tristerin, tripalmitin and olein), paraffin, phosphoglyceride (as phosphatidyl-ethanolamine, lecithin, phosphatidylserine, the pure and mild cardiolipin of phosphatidyl-4), sheath ester class (as sphingomyelins, cerebroside and gangliosides), sterol (as cholesterol and stigmasterol) and solid polyol fatty acid ester.Fatty acid can be saturated fatty acid (as dodecylic acid, myristic acid, palmitic acid, stearic acid, arachidic acid and lignoceric acid), can also be non-saturated fatty acid (as palmitoleic acid, oleic acid, linoleic acid, leukotrienes and arachidonic acid).

The 4th purpose of the present invention provides the method in synthetic compound storehouse.

The method in synthetic compound provided by the invention storehouse has two kinds.The method in first kind of synthetic compound storehouse may further comprise the steps:

1) provide one group of microdevice, this microdevice comprises: (a) base material that can be magnetized; (b) but be produced on the coding pattern of the light identification on the above-mentioned base material; (c) magnetized axis; But the coding pattern correspondence of described light identification the product that will carry out synthetic reaction on described microdevice;

2) synthetic described compound library: synthetic reaction realizes by a series of synthesis steps; In per step synthetic in, but according to the light recognition coding pattern on the described microdevice, carry out corresponding synthetic reaction; Behind the single step reaction, but, described microdevice is classified, carry out next step synthetic reaction more again according to the light recognition coding pattern on the described microdevice.But thereby on microdevice, synthesize and the corresponding product of light recognition coding pattern according to design in advance.

This method can be used to preestablish compound library synthetic of step

The present invention has provided simultaneously and has used the synthetic compound library of said method.

In a certain practical application, the coded portion of microdevice of the present invention is not realized by platinum, palladium, nickel, cobalt, silver, copper or gold; The composition material of microdevice of the present invention does not comprise platinum, palladium, nickel, cobalt, silver, copper or gold in another practical application.

The method in second kind of synthetic compound storehouse provided by the invention may further comprise the steps:

1) provide one group of microdevice, this microdevice comprises: (a) base material that can be magnetized; (b) but be produced on the coding pattern of the light identification on the above-mentioned base material; (c) magnetized axis; But the coding pattern correspondence of described light identification the product that will carry out synthetic reaction on described microdevice;

2) synthetic described compound library: synthetic reaction realizes by a series of synthesis steps; In per step synthetic after, but according to the light recognition coding pattern on the described microdevice, write down corresponding synthetic reaction, carry out next step synthetic reaction again.But thereby obtain corresponding relation between the product synthetic on light recognition coding pattern on the microdevice and the microdevice.

This method can be used for synthesizing of compound library at random.

The present invention has provided simultaneously and has used the synthetic compound library of said method.

In a certain practical application, the coded portion of microdevice of the present invention is not realized by platinum, palladium, nickel, cobalt, silver, copper or gold; The composition material of microdevice of the present invention does not comprise platinum, palladium, nickel, cobalt, silver, copper or gold in another practical application.

Described microdevice can use any suitable method to carry out sorting.For example, can use the minitype channel array that constitutes by one group of minitype channel to carry out sorting.Enough wide of this minitype channel makes that single microdevice can rotation freely in passage, and also enough narrow of this passage simultaneously makes above-mentioned microdevice be unlikely to form the microdevice string under the main shaft situation vertical with the main shaft of minitype channel.The acting in conjunction of the magnetized axis by the magnetic field force that adds and above-mentioned microdevice disperses between the above-mentioned microdevice mutually.The height of minitype channel and/or the restriction of microdevice is made that microdevice is unlikely to erect in minitype channel wherein by magnetic field.The height of minitype channel is not more than 70% of microdevice main axis length.When microdevice in minitype channel, arrange good after, but just can use the method for optical analysis to determine light recognition coding pattern on the single microdevice.Can use the method for handling single microdevice to handle microdevice, but and they are sorted into different area/location/reaction chambers according to the light recognition coding pattern that carries on the microdevice.For example, can use little electromagnetism tip to carry out sorting.Little electromagnetism tip can produce magnetic field at the place, tip, in order to from the passage that is arranged with microdevice, to draw specific microdevice (this occasion, the top of passage must be open), move with the single microdevice of conveying/distribution in different area/location, reaction chamber.In concrete an enforcement of the present invention, microdevice shifts out minitype channel under magnetic field force and hydrokinetic acting in conjunction, and at the endpiece of passage, microdevice can be transported to different zones under magnetic field force and hydrokinetic acting in conjunction.

Above-mentioned sorting also can be by using magnetic field force, after each step reaction, special catches required microdevice, and they are sent in the suitable reaction chamber.Can make with photoresist in the upper surface of arranging good microdevice or the arrangement chamber that lower surface is produced microdevice.When the irradiation of the light that is subjected to specific wavelength, can dissolved flush away by the photoresist in the zone that shone, the microdevice that was capped just now just comes out, and can be removed by magnetic field force.Can use a miniature light microscopic array of programmable numeral (Singh-Gasson et al.Maskless fabrication oflight-directed oligonucleotides microarrays using a digital micromirror array.Nature Biotechnology, 17:974-978 (1999)) or other similar maskless array synthesizer guides light source.

Using magnetic field force to carry out sorting can also realize by sort channel.Microdevice with magnetized axis, in magnetic field, can be aligned, and under the effect of magnetic field force, separated from one another, under the promotion of liquid, be filled in the passage with the form of " vertically arranging " (long axis direction of magnetized axis and passage is vertical).By default suitable liquid-liquid (immiscible liquid, for example hexane and water) or gas-liquid interface, can increase the surface tension of solution, the moving of the microdevice in the restriction solution.In concrete enforcement of the present invention, introduce the passage of microdevice and in order to separate by little valve (design, make and use valve be the interior general knowledge of association area) between the passage of sorting.Can introduce a bubble in passage by being produced near the hole on the correct position of the endpiece of the passage of introducing microdevice, this bubble is just between last and penult microdevice.Open valve can only last microdevice be introduced sort channel with magnetic field force, and other microdevice is blocked in the rear of the bubble of introducing then.Valve-off then uses magnetic field force, fluid force or other suitable physical force (for example dielectrophoresis force) that this is in microdevice in the sort channel and is sorted in the suitable reaction chamber and goes.Re-use fluid force (for example pumping liquid) and will make that the microdevice position in the passage moves forward to endpiece, repeat the operation of above-mentioned sorting again in order to the hole of the endpiece of the bubble passing away of the channel end of introducing microdevice.Must be significantly smaller than the size of microdevice in order to the hole of introducing and discharging bubble.The scheme of sorting more fast similarly be in passage all microdevices all introduce a bubble between any two, regulate suitable magnetic field force and fluid force, make the mode that microdevice flows with segmentation pass through passage.The widely used segmentation current method of institute of this method and Technicon company similar (can referring to United States Patent (USP) Pat.Nos.2,797,149 and 3,109,713).When the method for using segmentation to flow, magnetic field force and fluid force all are the significant effects factors, in addition the 3rd influence factor is the surface tension of liquid, and the surface tension of liquid can be regulated by interpolation solvent or adjuvant (for example detergent) in solution.Carry out common technology in the capillary adjusting employing association area by adding solvent.

Microdevice can also use the device (for example particulate switch) that can handle particulate to carry out sorting.As shown in Figure 7, the minitype channel array apparatus can comprise one can so that the zone that microdevice is handled therein, one in order to go up the last sample district that adds the microdevice sample to device and in order to exit passageway, collecting region and the fluid line bound fraction of discharge microdevice.U.S. Patent application " Apparatus for switching and manipulatingparticles and methods of use thereof " (application number: No.09/678,263, submit October 3 2000 date) in provided that concentrate can be in order to handle and the device of sorting particulate.These devices and equipment and their using method can be applied to the sorting of microdevice of the present invention.For example, can on the particulate switching device, carry out sorting by row ripple dielectrophoresis.At least the electrode group that has three groups of separate loading electric signal on the particulate switching device.The unit that has a plurality of branched structures on the particulate switching device, these branched structures have public bonding pad, when these three groups or three groups load the out of phase electric signal on the top electrode group, particulate is subjected to different capable ripple dielectrophoresis forces, can move along the branch of device, arrive the another one component by the common bonding pad of each branch from a branch.The end of these branches (a bonding pad opposite end public with branch) can be used as import or outlet.In concrete enforcement the of the present invention, the particulate switching device has 3 imports (outlet).Can be with one of them port as import, two other port is as outlet.Microdevice of the present invention can be introduced the particulate switching device by import, transports along branch under action of electric signals, again from one of them outlet output device.But can in the particulate switch, carry out optical detection to the light recognition coding pattern on the microdevice, but then according to the light recognition coding pattern that carries on the microdevice, on the electrode of particulate switching device, apply suitable electric signal, so that microdevice is by sorting, from an outlet output device.The array apparatus that is made of such particulate switching device can be sorted into microdevice plural outlet.The description of relevant such particulate sorting device array can be referring to U.S. Patent application No.09/678,263.

Microdevice also can carry out sorting by the fluid system that use has an import and a plurality of outlets.Fluid system can be transported to any one outlet from import with microdevice.Each microdevice optical decoder device in the fluid system of all can flowing through, but demoder can be discerned the light recognition coding pattern on the microdevice, then according to coding, by changing type of fluid microdevice is transported to different outlets.

But other also can use according to the method that the light recognition coding pattern on the microdevice carries out sorting.

Can on a kind of described microdevice, synthesize any multiple compound, for example, can on a kind of microdevice, synthesize a kind of or one group of compound.Best, only synthetic a kind of compound on a kind of microdevice.

Method of the present invention can be in order to the storehouse of synthetic any kind of.The composition in storehouse can be polypeptide, protein, nucleic acid oligomer, nucleic acid, vitamin, oligosaccharides, carbohydrates, fat, micromolecule or their aggregation and compound.Synthetic compound library wherein comprises one group of entity molecule relevant with a certain biological pathway, this group object molecule has identical or similar biological function, all express in the same cell cycle, in same cell type, express, in same types of organization, express, in same organ, express, in the same stage of development, express.The expression of entity molecule can be owing to disease changes or active, or changes along with disease type and advancing of disease stage, or is subjected to medicine or other processing and changes.

Synthetic storehouse can be a nucleic acid library, contains multiple nucleic acid molecules, for example the DNA of covering gene group (for example human genome) or RNA molecule segment.Preferably each nucleic acid fragment in the storehouse comprises at least 10,15,20,25,50,75,100,200 or 500 nucleotide.

Synthetic storehouse can be albumen/peptide library also, contains multiple protein/peptide molecule, for example covers all albumen or the albumen/polypeptide fragments of peptide sequence (for example human protein or peptide sequence) in the encoding human body.Preferably each the albumen/polypeptide fragments in the storehouse comprises at least 10,15,20,25,50,75,100,200 or 500 amino acid residues.

Compound library can adopt above-mentioned method synthetic.

The present invention can be widely used in the synthetic field of separation, detection, manipulation and compound library of entity molecule/molecule.

Description of drawings

Fig. 1 is microdevice (miniature disc) structural representation.

Fig. 2 is a plurality of miniature discs under the action of a magnetic field of the diagram direction of arrow, is limited issuable in the plane arrangement mode.

Fig. 3 is a plurality of miniature discs under the action of a magnetic field of the diagram direction of arrow, is limited to be introduced into then in the plane the short chain shape arrangement architecture in the passage.

Fig. 4 turns over the later arrangement situation of 90 degree for miniature disc short chain shown in Figure 3 as shown by arrows at magnetic direction.

Fig. 5 is the example with miniature disc of different bar magnet types.

Fig. 6 is the different coding patterns of two classes.

Fig. 7 has provided one and has included the minitype channel device that sample district, minitype channel, collecting region and fluid line bound fraction are formed.

Fig. 8 is the example of 4 miniature discs.

Fig. 9 is under the externally-applied magnetic field effect shown in the figure arrow, and miniature disc forms the wire chain type at glass surface and arranges.

Figure 10 is under the externally-applied magnetic field effect shown in the figure arrow, and miniature disc forms the wire chain type with branch at glass surface and arranges.

Figure 11 is presented under the externally-applied magnetic field effect shown in the figure arrow, and it is in 130 microns the passage that miniature disc is limited in width.

Embodiment

Definition

Unless add definition in addition, otherwise the used scientific and technical terminology of the present invention is understood according to the General Definition in field under it all.General, the nomenclature of this paper and manufacturing described below and experimentation are all very general, and usually are cited in this technical field.These processes are all used classic method, and are the same with what mention in this technology and the common document.The direction term such as " on " D score " top " " following " and the similar direction of some term finger devices each several part when using.The nomenclature of this paper is very general, and usually is used in this technical field.Definition herein should be used in the unified discrepant place of term and definition in term and definition and the document.Following term among the present invention is not if there is other explanation all should understand according to following explanation.

" magnetisable material/material " is meant the material with magnetic, can be subjected to the effect of magnetic force.

" magnetisable material/material " is meant that those can be subjected to the material of the action of a magnetic field, when they are placed in the magnetic field, can be subjected to magnetization, generates magnetic dipole.Magnetisable material comprises, but is not limited only to paramagnetism, ferromagnetism or ferrimagnetism material.

" paramagnet/material " is meant the material with such character, and its atom, iron or molecule wherein all has permanent magnetic dipole.Because the atom or the thermal motion of molecule self in the material, the direction of these magnetic dipoles is to point to all directions at random, so this material does not have magnetic generally.But in externally-applied magnetic field, the magnetic dipole that pointed to all directions originally can point to the direction parallel with magnetic field under the effect in magnetic field, and is lower than the energy that does not point to parallel direction because these magnetic dipoles point to the energy of magnetic field parallel direction, just more stable.Like this, the direction parallel in magnetic field just produced clean magnetic, also increased the coefficient of magnetization of material.Can consult many relevant documents about the further data of " paramagnet ", for example Page 169-page 171, and Chapter 6, in " Electricity and Magnetism " by B.I Bleaney and B.Bleaney, Oxford, 1975.

" ferromagnetic material/material " have bigger (on the occasion of) coefficient of magnetization, relevant with externally-applied magnetic field intensity.In addition, after externally-applied magnetic field removes, ferromagnetic material also residual a part of magnetic, be called " remanent magnetism ".Can consult many relevant documents about the further data of " ferromagnetic material ", for example Page 171-page 174, and Chapter 6, in " Electricity and Magnetism " by B.I Bleaney and B.Bleaney, Oxford, 1975.

" ferrimagnetism material/material " is similar with ferromagnetic material, has spontaneous magnetic and remanent magnetism.But the spontaneous magnetic dipole of this material does not also reach original desired all magnetic dipoles all according to the value of a direction permutation calculation gained, so be called " ferrimagnetism material ".Can consult many relevant documents about the further data of " foundary weight magnetisable material ", Page 519-524 for example, Chapter 16, in " Electricity andMagnetism " by B.I Bleaney and B.Bleaney, Oxford, 1975.

" but light identification coding pattern " is meant any coding pattern that can identify and analyze by method of optics.Any can be as the feature of coding pattern by the character that light is discerned.For example, but the pattern of light identification can provide by the composition of material itself: the hole of getting on base material is with certain form arrangement; On the base material according to certain mode fixing on and substrate other material with different optical character.But the coded system of the coding pattern of optical identification can be based on the hole of getting in substrate itself or the substrate or figure, numeral, position distribution, optical property, the material of fixing, be placed on the material of base material form or the combination of aforesaid way.For the ease of the optical encoding pattern is carried out optical analysis, be preferably with the mark of location usefulness on the microdevice.For example,, when microdevice keeps flat, be difficult to differentiate the front or the reverse side of microdevice, will cause difficulty to identification like this for discoid microdevice.And just can determine that by telltale mark which face is the front with coding pattern.In the present invention, but can use one dimension or the bar code of two dimension coding pattern as light identification.

Be meant that the optical encoding pattern is arranged in the top of base material or is produced on base material, carries out optical detection as long as be convenient to coding but " be produced on the light recognition coding pattern on the base material ".For example, but the coding pattern of light identification can be positioned on the surface or surface of substrate, also can be embedded in the middle of the substrate.If substrate is made up of the multilayer material, but the coding pattern of light identification can be positioned at above the superficial layer or on the superficial layer, also can be produced on one deck or multilayer material wherein.

Be produced on the base material but " be produced on the base material " but be meant by the coding pattern of micro-processing technology with light identification by the coding pattern of micro-processing technology with light identification.Can use various semiconducter process, for example photoengraving, wet etching, mask, reactive ion etching and deep reaction ion etching or the like.

" main shaft of microdevice " is meant the longest one dimension in the microdevice three-dimensional dimension.If microdevice is the disc-shaped structure that approaches, the height of microdevice is exactly the thickness of microdevice.In the microdevice of this thin disc-shaped structure, main shaft just is meant any and the parallel plane diameter of a circle of dish disk.In the practical application of a this microdevice with disc-shaped structure, but the coding pattern of light identification be positioned on the plane parallel with card, can be on the surface of card or in the zone between the card up and down.If microdevice is thin rectangular configuration, the three-dimensional of this device of definition is respectively main shaft (for example length), secondary axes (for example width) and height (thickness of rectangle disc) earlier.In this case, the main shaft of microdevice should be than secondary axes and highly all big.Secondary axes also should equal or greater than the thickness of microdevice.Microdevice is except above-mentioned shape, and card can also be other shape.

" described microdevice has magnetized axis " is meant, when microdevice is placed magnetic field, the difference of the angle when inserting between each of magnetic direction and microdevice, it is also different that microdevice is subjected to the effect in magnetic field, suppose that microdevice is placed into and has less frictional resistance in the medium of (no frictional resistance or have less frictional resistance), or be placed on and have less frictional resistance on the plane of (no frictional resistance or have less frictional resistance), microdevice can rotate or be positioned at a certain position, so that self is in energy minimum state or stable state in externally-applied magnetic field.In have less frictional resistance when microdevice the is placed into medium of (no frictional resistance or have less frictional resistance), or be placed on and have less frictional resistance on the plane of (no frictional resistance or have less frictional resistance), and be in the minimum state of such energy, the axle that microdevice is corresponding with magnetic direction just is called the magnetized axis of microdevice.Magnetized axis is by the decision of the geometric configuration of microdevice, for example with the ratio of the main shaft and the secondary axes of microdevice, or the The Nomenclature Composition and Structure of Complexes parameter correlation of microdevice.According to the geometric configuration of microdevice, magnetized axis can be the independent axle on the direction, or is positioned at a plurality of axles of a plurality of directions, also can be the axle arbitrarily that is positioned at a certain plane.Induced after magnetized process finishes when the microdevice that is arranged in magnetic field, when reaching the minimum energy state, induce the magnetization (its absolute value) more than or equal to the magnetization of inducing that produces at other direction of principal axis what the magnetized axis direction produced.Microdevice of the present invention can produce in externally-applied magnetic field and induce magnetization phenomenon, and the interaction in induced magnetic moment and the magnetic field that adds makes microdevice rotate in magnetic field or is positioned at a certain position in the magnetic field.The magnetization (its absolute value) of inducing that produces along the magnetized axis direction in the microdevice should be at least induces the magnetization big by 20% than what at least one the direction at other produced.Be more preferably in the microdevice along the magnetized axis direction produce induce the magnetization (its absolute value) should be at least than at least one the direction at other produce induce the magnetization big by 50% respectively, 70% and 90%.Best is, big 1 times, 2 times, 5 times, 10 times, 20 times, 50 times even the hundred times of inducing the magnetization of inducing the magnetization (its absolute value) should be at least to produce than at least one the direction at other that produce along the magnetized axis direction in the microdevice.When microdevice was placed in the externally-applied magnetic field, microdevice was from original state to the energy minimum state or steady state (SS) is a dynamic process, needs the regular hour.Friction force or other acting force (for example gravity) are being arranged when existing, when microdevice reached steady state (SS), the direction of magnetized axis and externally-applied magnetic field may not fit like a glove.Many factors, for example the direction of the geometric configuration of microdevice, externally-applied magnetic field and intensity and other factor (for example when microdevice was positioned at supporting dielectric surperficial, the friction force that is produced by the supporting dielectric surface can be such factor) all can influence the magnetized axis of microdevice.By changing and adjust these factors, can be so that microdevice be when reaching steady state (SS), magnetized axis can be substantially along the direction of externally-applied magnetic field.For example, a thin discoid microdevice wherein contains thin discoid magnetisable material.The magnetized axis of this microdevice should be arranged in and the parallel plane of microdevice disc surface (disc surface of the magnetisable material of disc just).When such microdevice is inserted in the magnetic field, even the microdevice of this thin plate-like initially is positioned at the plane vertical with the externally-applied magnetic field direction, microdevice can rearrange, and makes that the plane of microdevice of chip shape is parallel or substantially parallel with the direction of externally-applied magnetic field.If microdevice is the rectangular configuration that approaches, the length and width of the magnetic force structural unit (for example magnetic rectangular bar) that magnetisable material wherein constitutes is with high consistent with high orientation with the length and width of microdevice respectively.The sensing of the length of magnetisable material is consistent in the sensing of the direction of the magnetized axis of the microdevice of this spline structure and the length of microdevice and the microdevice.

" magnetized axis can be substantially along the direction of externally-applied magnetic field " be meant that the direction of magnetized axis and the angle between the externally-applied magnetic field direction are smaller or equal to 45 degree.Better, the angle between the direction of magnetized axis and the externally-applied magnetic field direction is smaller or equal to 15 degree; Best situation is, the direction of magnetized axis is fully along the direction of externally-applied magnetic field.When the magnetized axis of a microdevice was exactly its main shaft, " magnetized axis can be substantially along the direction of externally-applied magnetic field " be meant that the direction of main shaft and the angle between the externally-applied magnetic field direction are smaller or equal to 45 degree.For being shaped as thin rectangular configuration, magnetized axis is exactly the microdevice of main shaft, and under the effect of externally-applied magnetic field, microdevice can be arranged in chain along main shaft.In the time of more than the direction rotation 45 of externally-applied magnetic field is spent (for example revolve and turn 90 degrees), microdevice also takes place identical or the rotation of the close number of degrees, just separates mutually between each microdevice in the chain microdevice like this.

" magnetized axis of microdevice can be substantially along the direction of the main shaft of microdevice " be meant that angle between the main shaft of the direction of magnetized axis of microdevice and microdevice is smaller or equal to 45 degree.Better, the angle between the main shaft of the direction of the magnetized axis of microdevice and microdevice is smaller or equal to 15 degree; Best situation is, the direction of the magnetized axis of microdevice is fully along the direction of the main shaft of microdevice.

" microdevice of catenation is separated each other substantially " but be meant that microdevice is separated mutually substantially and make and can read to determine microdevice or microdevice is analyzed by coding pattern the light identification of carrying on the microdevice to each microdevice.The degree that each microdevice is separated determines jointly by many factors, but but for example the geometric configuration of the distribution of the type of microdevice, quantity light recognition coding pattern, microdevice, read light recognition coding method of patterning and microdevice identified or the purpose of analyzing etc.Only however influence but the coding pattern of the light identification of carrying on the microdevice is read to determine microdevice or microdevice is analyzed that being in contact with one another or overlapping of may existing between the microdevice all is acceptable.Under some occasion, be that any contact or overlapping separation completely do not take place between the microdevice preferably.

" width of described minitype channel is: when described microdevice was in the externally-applied magnetic field, single microdevice can rotate freely in passage, can not form the microdevice chain when the main shaft of described microdevice main shaft and minitype channel is vertical." width that is meant minitype channel equals or greater than the longest size of microdevice, for example when microdevice be rectangular configuration, the width of minitype channel is got the cornerwise size of rectangle, just can be so that microdevice is free to rotate in passage.The width of pipeline can not be greater than 150% of microdevice longest dimension simultaneously, and for example working as microdevice is rectangular configuration, and the width of minitype channel is got the cornerwise size of rectangle.When if the main shaft of the main shaft of microdevice and minitype channel is vertical substantially like this, minitype channel can prevent that the microdevice in the passage is arranged in chain (chain that contains two microdevices at least).Best situation is that the width of pipeline can not be greater than 140%, 130%, 120%, 110%, 105% or 102% of microdevice longest dimension." when the main shaft of described microdevice main shaft and minitype channel is vertical, can not form the microdevice chain." be meant after rotation, arrange catenulate microdevice and separate substantially each other.The width of each minitype channel in the minitype channel array can be identical, but this not necessarily.Each minitype channel in the minitype channel array will make that all microdevice can rotate in passage.Here, the main shaft of minitype channel is the direction along the length of minitype channel.

" main shaft of microdevice is vertical substantially with the main shaft of minitype channel " is meant the main shaft of microdevice and has angle between the main shaft of minitype channel of microdevice more than or equal to 45 degree.Better, the main shaft of microdevice and have angle between the main shaft of minitype channel of microdevice more than or equal to 50,55,60,65,70,75,80,85 and 90 degree.Here, the main shaft of minitype channel is the direction along the length of minitype channel.

" height of described minitype channel and/or by magnetic field the restriction of microdevice is made that described microdevice is unlikely to erect in described minitype channel " is meant only by the height of restriction minitype channel or only by the magnetic confinement microdevice, or, be enough to make that the substantially parallel situation of short transverse of main shaft and minitype channel can not appear in microdevice in minitype channel by above-mentioned both sums.The size of minitype channel comprises length and width and Senior Three part.Long corresponding its main shaft of minitype channel.The height of minitype channel along with the vertical direction in the residing plane of minitype channel.The wide of minitype channel is the third dimension size of minitype channel." short transverse of main shaft and minitype channel is substantially parallel " is meant that angle between the short transverse of the main shaft of microdevice and minitype channel is smaller or equal to 45 degree.Iff just preventing that by the method for using magnetic confinement microdevice from forming the generation of above-mentioned arrangement, just can not consider the height of minitype channel itself.

" but the coding pattern correspondence of described light identification the product that will carry out synthetic reaction on described microdevice " but be meant that the compound that synthesizes on the microdevice is to be predetermined according to the light recognition coding on the microdevice.Coding has determined the mode of synthetic compound on the microdevice.For example, coding can comprise a plurality of numerals, each specific synthesis step of one step of digitized representation, and the such set of number in the coding has just been represented a synthetic step, synthesizes required product.Also can determine synthetic route by the part of whole coding rather than coding.

But " encode according to optical identification; each the step synthetic reaction after microdevice carry out sorting again " but be meant that the synthesis step of the compound on each microdevice is identified by the light recognition coding on it in advance, after the previous step synthetic reaction finishes, according to the coding on the microdevice, microdevice is carried out sorting, carry out next step reaction again.

" electricity lead or can be by the dielectric polarization material " be meant any material that can be subjected to the dielectrophoresis force effect under given conditions.According to the electrical properties and the dielectric properties of material itself, under given conditions, this material can be subjected to the forward or the dielectrophoresis force of negative sense.Such certain conditions comprises, but is not limited only to the extra electric field of characteristic frequency, the medium with certain electricity and dielectric properties.

" optical labeling substance " is meant the entity molecule that the visible material of those optics can be transported in order to mark.Quantum dot is a kind of like this optical labeling substance.

" but scattered light detection of particles " is meant under given conditions with after the rayed, can produces the particulate of unique distinguishable scattered light.Particulate with nano-scale of " resonant light scattering (resonance light scattering (RLS)) " character is exactly a class such " but scattered light detection of particles ".

" quantum dot " is the fluorescent marker that a class is made of water miscible semiconductor nanocrystal.The character of a uniqueness of quantum dot is that its fluorescence spectrum is by the decision of the diameter of nanocrystal." water-soluble " is meant that here material can have enough solubleness or can be suspended in these solution in aqueous solution (formulated in the water or by water solution or physiological condition solution).Information about quantum dot can be further referring to document.Usually, can prepare the quantum dot with better monodispersity, the deviation of the diameter of the kernel of the quantum dot of for example preparing is within 10%.

" chip " is meant the surface that can carry out at least a processing or manipulation thereon.Such as: transfer, separation, gathering, enrichment, concentrate, physics is broken, mix, in conjunction with, analyze or the like.Chip can be made by solid or semisolid, and material can be porous or fine and close.Particular procedure can carry out thereon, such as physics, chemistry, biological, biophysics or biochemical process.Be shaped on the chip or be integrated with such as the little processing structure of groove, passage, electrode unit and piezoelectric sensor or the like, can carry out reaction or processing physics, biophysics, biological, chemistry thereon.Chip is a thin slice.Requirement to the chip surface area size is not harsh, such as from 1mm ²To 0.25m ²Can.Preferably used chip surface area is from 4mm ²To 25cm ²About.Chip can have difformity, shape such as rectangle, circle, ellipse or other irregular shape of rule.Chip surface can be flat, also can be uneven.The chip that has a non-planar surface should comprise from the teeth outwards by processing at chip surface or structures such as the groove that etching gets, cavity.

The mode of physical field " on the described chip produce " is meant any can generation on chip, or and in build material, structural unit or their combination that the structural unit acting in conjunction of chip produces required physical field in.

" physical field ", other saying also have " physical field in the certain space scope " or " physical field that produces in the certain space scope " to be meant a spatial dimension with following feature.(just enter in the physical field) when an entity molecule with suitable character is placed in this space, as the result of this entity molecule and field interactions, entity molecule has been subjected to the effect of power.Entity molecule is handled by the power that the field applies thereon in the field.Typical field comprises electric field, magnetic field, sound field, light field and velocity field.In the present invention, physical field always is present in the medium in the certain space scope, and these entity molecules of being handled normally are suspended in or are dissolved in, or is more typically and is placed in the medium.Typical medium is liquid such as water or on-aqueous liquid, or gas.According to the character of field, electric field can apply electrophoretic force to charged entity molecule, or charged or neutral entity molecule is applied conventional dielectrophoresis force and/or row ripple dielectrophoresis force.Magnetic field can apply magnetic field force to the magnetic entity molecule; Sound field can apply the sound field radiant force to entity molecule; Light field can apply the light field radiant force to entity molecule.Velocity field in the medium in the certain space scope is meant the velocity distribution that medium moves in this spatial dimension.Various mechanism can cause moving of medium and reveal different speed in the media table of diverse location, so produced a velocity field.Velocity field can apply mechanical force to entity molecule.

" medium " is meant fluid carrier, for example liquid or gas.Wherein suspend, comprise or be dissolved with entity molecule or the entity molecule that links to each other with microdevice.

" microfluidic applications " is meant the employing micro devices, the size of its basic structural unit in sub-micron to centimetre magnitude, be used for fluid actuated, handle and carry out special biological, biochemistry or chemical reaction.These special fields are including, but not limited to biochip (as being used for and biological relevant reaction and the microchip of operation), chemical chip (microchip that is used for chemical reaction) or compound chip.The characteristic dimension of the elementary cell in the device is meant the size of certain one dimension in the device.For example, the characteristic dimension of the unit of a circular configuration (for example circular electrode plates) is meant the diameter of this circular configuration.If structural unit is the line of the rectangular shape that approaches, its feature structure is meant the length or the width of line.

" suprabasil built-in structural unit " is meant that these structural units are embedded in the substrate or these structural units are positioned in the substrate and with substrate and link to each other.In actual applications, so built-in structural unit is that directly processing is suprabasil.For example, the same as what describe in " Dielectrophoretic manipulation of cells using spiralelectrodes by Wang et al.; Biophys.J., 72:1887-1899 (1997) ", the little processing of spiral helicine electrode is on substrate of glass.Here, screw electrode " built-in " structural unit on substrate of glass.In actual applications, this built-in structure can be processed earlier in a substrate, and this substrate that contains built-in structure can be connected with another sheet substrate more then.This like this " built-in " structure has in two substrates.In actual applications, this built-in structure can directly be connected on the one side of substrate.For example, thin electrical lead can be used as electrode and produce electric field.These electrodes can directly be connected on the substrate of glass.In this example, electrical lead is " built-in " structure on the substrate of glass.Among the present invention, be described in chip or substrate, have the ability to produce physical force and or the built-in structure of physical field, can be connected with outside source.

The characteristic dimension of " microstructure " is between 1 micron to 20 millimeters, and the size in order to the inner structure that produces required physical force on the device should be coordinated mutually with the requirement of microfluidic applications.

" entity molecule " is meant any material that can analyze, separate, handle, measure and detect on microdevice of the present invention.In general, the characteristic dimension of these materials should be above 1 centimetre.For example, if these materials are sphere or subglobular, its characteristic dimension is meant the diameter of ball or almost spherical.If these materials are cube or approximate cube, then its characteristic dimension is meant the cube or the approximate cubical length of side.If these materials have irregular shape, then its characteristic dimension is meant its greatest axis and the mean value of minimum shaft length.Entity molecule can be, but be not limited only to cell, organelle, virus, particulate, molecule (as protein, DNA and RNA), or their aggregation or compound.

Can be analyzed, separate, handle, the entity molecule of measuring and detecting can comprise---solid is (for example: beaded glass, emulsion particle, magnetic bead), liquid (for example: drop) or gas particles (for example: bubble), the particulate of dissolving (for example: molecule, albumen, antibody, antigen, grease, DNA, RNA, molecular complex), suspended particulates (for example: beaded glass, emulsion particle, polystyrene bead), the particulate molecular complex (for example: by the dna molecular magnetic bead compound that forms at magnetic bead surfaces fixed dna molecule, or the protein-polystyrene bead compound that is formed by polystyrene bead with the protein molecule bag).Particulate can be organically (for example: mammalian cell or other cell, bacterium, virus or other microorganism), also can be inorganic (for example: metal particle).Particulate can have different shape (for example: spherical, ellipsoid shape, cubic, discus shape, needle-like) and different sizes (for example: nanoscale gold goal, micron-sized cell, millimetre-sized microparticle polymer).Particulate comprises, but is not restricted to biomolecule (as DNA, RNA, chromosome), protein molecule (as antibody), cell, colloidal particles (as polystyrene bead, magnetic bead) and other biomolecule (as enzyme, antigen, hormone or the like).

" plant " is meant that plant any in belonging to carries out photosynthetic eucaryon multicellular organisms, it is characterized by and can produce the embryo, comprises chloroplast, has the cell membrane of cellulose components, can't move.

" animal " is meant any multicellular organisms in the animal genus, it is characterized by to have mobile ability, and unglazed cooperation has tangible reaction with mechanism to stimulation, has the limited development degree and the body structure of almost fixed.Examples of animals comprises, but is not limited only to birds (as chicken), vertebrate (as fish and mammal, as rat, mouse, rabbit, cat, dog, pig, milk cow, bull, sheep, goat, horse, monkey and other anthropoid cape) or the like.

" bacterium " is meant little prokaryotes (characteristic dimension is approximately about 1 micron), has ribosomes and closed hoop DNA that sedimentation coefficient is approximately 70s.The synthesis mode of bacterioprotein is different with eucaryote.Many antibiotic suppress the synthetic of bacterioprotein but do not influence infected host.

" eubacteria " is meant the big subclass of another except that archeobacteria in the bacterium.Most grampostive bacteria, cyanobacteria, mycoplasma, enterobacteria, pseudomonad and chloroplasts all are eubacterias.Eubacterial cytoplasma membrane contains ester and connects lipid, if cell membrane is arranged, it contains peptide glycan; Unit in not finding in the eubacterial genome.

" archeobacteria " is meant the another big subclass except eubacteria in the bacterium.Mainly contain the three major types archeobacteria: Halophiles, methanobacteria and a kind of very thermophilic mushroom that relies on sulphur existence.Archeobacteria and eubacterial difference mainly are the difference on Ribosome Structure and the cell membrane component, and the genome of (in some example) archeobacteria has interior unit.

" virus " is a kind of biosome that lives in host cell, does not have the architectural feature of cell, has the shell of DNA or RNA and protein.Virus range of size from about 20 to about 300 nanometers.The genome of first kind virus (Baltimore classification) is a double-stranded DNA; The genome of second viroid is a single stranded DNA; The genome of the 3rd viroid is a double-stranded RNA; The genome of the 4th viroid is the positive chain RNA of strand, and genome oneself is as the mRNA of virus; The genome of the 5th viroid is the anti-chain RNA of strand, and genome is the template of synthetic mRNA; The genome of the 6th viroid is the positive chain RNA of strand, but duplicate with mRNA synthetic in all with DNA as medium.Most of viruses be by them plant, animal and prokaryotes go up that caused disease discerns.Procaryotic virus is called as bacteriophage.

" fungi " is the class in the eucaryote, and they are grown with irregular accumulation shape, do not have root, stem or leaf, and lack chlorophyll or other can carry out photosynthetic pigment.Each fungi (bluff body) is a single celled filamentous, and has the mycelia of branch-like, is surrounded by cell membrane (containing glucosan and chitin or both has), contains real nucleus.

" bond " is meant any any material that can link to each other with specificity with certain compatibility with entity molecule.Bond can be, but is not limited only to, cell, organelle, virus, particulate, condensate or complex, and perhaps the condensate of molecule or complex also can be specific molecule, for example antibody, single stranded DNA etc.Bond also can be the surface coated material of the microdevice among the present invention.Bond also can be the ingredient of microdevice.In the composition material of microdevice of the present invention,, can also have affine to some entity molecule, can directly play the function of bond in conjunction with active except itself being the substrate of microdevice.

" be beneficial to/make the material that microdevice or entity molecule/the microdevice compound is handled " and be meant material itself that can be handled and make that entity molecule/microdevice compound can be handled by physical force.Such material can be, but is not limited only to, for example the compound of molecule, cell, organelle, virus, particulate or above-mentioned substance.Such material also can be, but is not limited only to, the material of making by deposition or other technology with specific physical chemical property.Such material can be the metal film of being made by metals such as gold, chromium, titanium or platinum, and they not only can be used as the composition material of microdevice, can also increase the conductivity of microdevice.Such material can also be these megohmite insulants of plastic polymer such as polystyrene, and they not only can be used as the composition material of microdevice, can also reduce the conductivity of microdevice.

" particulate " is meant Any shape, and any composition has the particulate of any composite structure, can handle in microfluidic device by corresponding physical force.An example of particulate is the magnetic bead of handling with magnetic field force.Another example of particulate is to use the cell of handling such as electric field forces such as row ripple dielectrophoresis forces.The particle size of using in this method can be from about 0.01 micron to about 10 centimetres.More suitably be, the size of the particulate in this method from about 0.01 micron to about several thousand microns.The example of particulate comprises, but is not limited only to the particulate of plastic particles, ps particle, beaded glass, magnetic bead, hollow glass ball, composite parts, little non-built-in microstructure that is processed to form etc.Other particulate comprises cell, organelle, big biomolecule such as DNA, RNA and protein etc.

" manipulation " is meant and moves and handle these entity molecule/microdevices, thereby cause entity molecule/microdevice on the chip (be included on the single-chip or on many integrated chips or between, between a plurality of substrates in the substrate or in device) do the motion on one dimension, two dimension or the three-dimensional.Manipulation to these entity molecules also can be to carry out in liquid container." manipulation " comprise, but be not limited only to, transport, focusing, enrichment, concentrate, assemble, catch, the moving of the entity molecule on repulsion, suspension, separation, fractionation, isolation, linearity or other direction.In order to realize handling efficiently, entity molecule to be handled and the physical force that is applied thereto should be coordinated.For example, the entity molecule with magnetic can apply with magnetic field force.Similar, the entity molecule with electric charge can apply with direct current field force (being electrophoretic force).In the situation of handling microdevice, these physical force that are used for the microdevice manipulation must be coordinated.For example, microdevice has certain magnetic, can be handled by magnetic field force.Microdevice can be made of one or more magnetisable materials, for example ferromagnetism or ferrimagnetism material.Ferromagnetism or ferrimagnetism material can be nickel or CoTaZr (Cobalt-Tantalum-Zirconium) alloy.Similar, the microdevice that has net charge can use electrostatic force to handle.In the situation of handling microdevice-bond-entity molecule compound, the character of these microdevice-bonds-entity molecule and the physical force that is used to handle must be coordinated.For example, entity molecule or its bond or microdevice has certain dielectric properties can be used dielectrophoresis force to handle by dielectric polarization.

" the not directly entity molecule of Cao Zonging " be meant under the effect of specific physical force, when these entity molecules not with it bond or microdevice is when linking to each other, do not observe any visible motion.

" physical force " is meant a kind of like this usefulness so that entity molecule or its bond or the power of microdevice motion, it not with or with entity molecule or its bond or microdevice chemistry, biological respinse take place hardly, do not influence or influence hardly entity molecule or its bond or the biology of microdevice, chemical property.Term " power " or " physical force " always are meant " power " or " physical force " that acts on these entity molecules, bond or the microdevice, " power " or " physical force " is that the effect by the field produces, and is determined by the character of entity molecule, bond or microdevice itself.Therefore, when a given field or physical field, in order to produce physical force on entity molecule, these entity molecules must have certain character.The field of some type can be in multiple effect with the power that all produces on the entity molecule of different nature, and the field of some type is perhaps only to apply the effect of power at the entity molecule to some limited types.For example, magnetic field can only or have generation power or magnetic field force on the entity molecule of certain magnetic at the magnetic entity molecule, and is not suitable for the particulate of other type, as polystyrene bead.And on the other hand, the electric field of a non-homogeneous can apply the effect of physical force on the dissimilar entity molecule of many kinds, as polystyrene bead, cell, also has magnetic bead or the like.In fact, the effect that does not necessarily require physical field on dissimilar entity molecules, all to produce power, but physical field must can produce the effect of power at least at least one entity molecule, bond or the microdevice of a kind of entity molecule, bond or microdevice.

" electric field force " is the power that electric field applies entity molecule, bond or microdevice.

" magnetic field force " is the power that magnetic field applies entity molecule, bond or microdevice.

" sound field power (sound field radiant force) " is meant the power that sound field applies entity molecule, bond or microdevice.

" light field power (optical radiation power) " is the power that light field applies entity molecule, bond or microdevice.

" mechanical force " is the power that velocity field applies entity molecule, bond or microdevice.

" sample " is meant any material that comprises the entity molecule that can separate, analyze, handle, measure by microdevice of the present invention or method of the present invention.Sample can be a biological sample, biological example fluid or biological tissue.The example of biofluid has urine, blood, blood plasma, serum, saliva, seminal fluid, ight soil, phlegm, brain liquid, spinal fluid, tear, mucus, amniotic fluid or the like.Biological tissue is the aggregation of one group of cell, can form biological structural unit, and tissue can be conjunctive tissue, peripheral tissues, musculature and nerve fiber etc.The example of biological tissue comprises organ, tumour, lymph node and artery etc.Sample can be the target material of external preparation or the potpourri of enzyme liquid.

" liquid (fluid) sample " is meant the sample that exists with liquid or fluid form, the body fluid of biological example body." fluid sample " can also refer to those originally was not to exist with liquid form, as gas or solid state, but the sample of preparation in liquid, fluid or solution.For example, can or be suspended in the liquid (fluid) the histolysis of biosome and be prepared into fluid sample.

" mensuration " is specified amount or composition and/or the quantity of determining entity molecule qualitatively, and for example whether certain nucleic acid or the existence of protein can also be measured ratio, form or the like other parameter in the working sample.Mensuration can be undertaken by direct method, also can be undertaken by round-about way.Mensuration can be quantitative, also can be qualitatively.

Preferred design

The present invention uses magnetic field force that microdevice (miniature disc) is arranged in certain geometric configuration.Miniature disc is a kind of particulate of size between 1 to 1000 micron of produced by micro processing, contains strip or the club shaped structure that or a plurality of magnetisable material are made in its side.These strips or the magnetisable material of club shaped structure all has magnetized axis.Magnetized axis is by the decision of the geometric configuration of magnetic material.Usually the length breadth ratio of the film of being made by magnetic material (usually less than 1 micron) is not less than 3.Usually the magnetized axis of these structures is exactly their main shaft.Fig. 1 has provided a synoptic diagram that has the miniature disc of two magnetic strips (bar-shaped) structure.Magnetic direction such as arrow indication, miniature hdd sector-meeting rotate or navigate to a certain position makes the magnetized axis direction of self parallel or substantially parallel with the externally-applied magnetic field direction.The direction of the magnetized axis of the miniature disc here is consistent with the direction of main shaft, perhaps is exactly it self main shaft.If these miniature discs are not limited in certain locus by other effect, they can be arranged in as shown in Figure 2 chain or bunch shape (arrow among the figure has been pointed out the direction in magnetic field).In Fig. 3, arrange catenulate microdevice and be limited in the minitype channel.Magnetic direction revolved turn 90 degrees, arrange catenulate microdevice and will rotate, thereby separate mutually, as shown in Figure 4.Step shown in Fig. 2 to 4 has been formed " magnetic alignment ".

After having loaded magnetic field, microdevice can be arranged in chain or bunch shape voluntarily.For microdevice is introduced passage, the microdevice that must earlier bunch shape be arranged scatter.This can realize by the direction of rotating magnetic field.Can use guide post (specifically discussing in the description of general's minitype channel hereinafter) for bunch shape or the microdevice of chain of rotation provide fulcrum, help their reorganization.One group of suitable guide post can guide microdevice to be arranged in a chain, and the length of chain should be longer than the width of single microdevice.

The chain that microdevice is arranged in can be introduced passage by magnetic field force or fluid force.Chain will move towards the direction that magnetic field intensity strengthens.If the long axis direction of chain (being consistent with the magnetized axis direction of microdevice basically) is consistent with direction of motion, the resistance of the liquid that is subjected on the chain is less relatively, thereby makes chain have movement velocity faster.For single microdevice, if the direction of magnetized axis is vertical or vertical substantially with direction of motion (towards the direction of magnetic field intensity increase), microdevice can be subjected to bigger magnetic field force.In sum, when the angle between the direction that the long axis direction of chain and magnetic field intensity increase was not more than 90 degree, the motion of chain was the most efficiently, and best angle is about 45 degree, and chain also can be along other angular movement certainly.Such magnetic field gradient can pass through in the passage in the plane or near big permanent magnet of use or electromagnet, or one group of small electrical magnet is realized.When the residing magnetic field of miniature disc rotates (direction in magnetic field is vertical with chain), miniature disc also can rotate, to keep consistent with the variation in magnetic field.

Among the present invention, it is very important selecting the miniature disc and the passage of suitable dimension.The overlapping degree of the miniature disc of catenation and the thickness of miniature disc are relevant with the magnetic strip or the shape of club shaped structure on the miniature disc.Miniature disc among Fig. 1 approximately has the overlapping of 20-30% degree when arrangement is catenulate.When the length breadth ratio of miniature disc was 1.22 (90 microns/70 microns), when magnetic field rotates, miniature disc also can rotate in passage, but the relative centre of gravity place of the miniature disc in the passage does not have big change.In contrast, discoid miniature disc still keeps overlapping when magnetic field rotates, or under the repulsion effect in magnetic field, is dispersed in the flank of passage.

The optimum width of passage is determined by two factors.Passage needs enough wide, makes that single microdevice can rotation freely in passage, among Fig. 1 width of channel must be at least greater than 114 micron (90 of the cornerwise width of miniature disc ²+ 70 ²Square root), this is the minimum widith of passage.This passage also needs enough narrowly simultaneously, makes above-mentioned microdevice be unlikely to form the microdevice string under the main shaft situation vertical with the main shaft of minitype channel.Like this in Fig. 1, the size of the principal plane of miniature disc is 90 microns * 70 microns, the overlapping degree of supposing two miniature discs approximately is 30%, and two length of arranging catenulate miniature disc are 153 microns (=90+90-90 * 30%) so, and this is the most wide degree that passage can allow.When the overlapping degree of two miniature discs is respectively 10% and 20%, two length of arranging catenulate miniature discs are respectively 171 microns and 162 microns so.In order to prevent that miniature disc from holding up in passage, the height of passage also should be taken into account.If magnetic field is enough strong to the restriction of miniature disc, can avoid miniature disc to hold up the appearance of situation, can consider the height problem of passage itself.The process that Fig. 2-4 provides is the situation that the miniature disc of hypothesis is limited in moving on the plane.The height of passage should be less than the length of the minor face of miniature disc.If minitype channel has top cover or sealed from the top, should be the upright state that can keep stable with miniature disc that passage bottom becomes to be slightly less than an angle of 90 degrees.Can be so that the weight of the stable minimum angles of erectting of miniature hdd sheet and the intensity in magnetic field, the amount of magnetisable material and their saturated magnetization rate, miniature disc be relevant with the density of density and liquid medium.This numerical value can obtain by experience or Model Calculation, but can make miniature disc trend towards keeping horizontality in passage less than 45 angles of spending usually.Like this, the height of the residing passage of miniature disc shown in Fig. 1 must be no more than 50 microns (=70 microns * Sin45 °), can prevent that just miniature disc from keeping reaching stable upright state.

The shape of the magnetic on the miniature disc bar-shaped (strip) structure can influence miniature disc and be arranged in chain or bunch shape, influences the overlapping degree between the miniature disc.Fig. 5 has provided strip (bar-shaped) structure Design of concentrating other type.

Miniature disc can make in all sorts of ways and encode with mutual differentiation.First-selected coded system is the coding of making up in the miniature disc of produced by micro processing, but for example two-dimensional bar or embedding light identification character, as shown in Figure 6, among the figure, the left side is the matrix pattern of 2D, the right be the coding pattern of four characters that can optical identification.

The miniature disc that has coding can use any existing technology to make.Typical miniature disc shown in Figure 1 comprises 4 parts: magnetic bar-shaped (strip) structure 1; Code area 2 (for example making) by aluminum; Peripheral regions 3 surrounds magnetic area and code area 2, provides for the surface of modifying; Arrow points be the direction in outside magnetic field.This peripheral regions can be used any simple material, for example silica-base material, pottery and metal or the like.First-selected here material is a silicon dioxide.These different zones are produced on the different-thickness layer of miniature disc.Magnetic bar-shaped (strip) structure 1 and code area 2 are produced on the middle layer of miniature disc, are clipped between the material shown in the peripheral regions 3.These different areal distribution are on the different aspects of microdevice thickness.Bar magnet and code area are positioned at the middle layer, are wrapped in by the material of top layer and bottom.In a kind of example of microdevice, so miniature disc comprises the bar magnet of being made up of soft magnetic material (as CoTaZr or NiFe), is of a size of 90 microns long, and 70 microns wide, 3.2 micron thickness.

Magnetic bar-shaped (strip) structure that is produced in the miniature disc can use any magnetic material to make.Preferably by low remanent magnetism rate, the material of high magnetic susceptibility is made, and cobalt-tantalum-zircaloy satisfies above-mentioned requirement.But the nickel with higher remanent magnetism rate also can be in order to the present invention.The coding layer can use any nonmagnetic substance to make, for example materials such as aluminium, gold or copper.With to use fluorescein different as the encoded beads body of coded system, the magnetic of produced by micro processing shown in Figure 6 bar-shaped (strip) structure is a kind of coding of physics mode, and the group/cording quantity that can produce is not limited to the character of material itself.4 character code modes shown in Figure 6, if oneself only get the capital and small letter and the numeral (62 kinds altogether) of English alphabet, the quantity of possible coding surpasses 10 ⁷Kind.

Miniature disc of the present invention can be arranged in array, and making becomes possibility to reading fast of miniature hdd slice encode information, can also avoid using complicated optical detection system.Such array also is easy to long-term preservation.With traditional capture molecules to be fixed on same lip-deep method different, every kind of different capture molecules is fixed on a kind of surface of miniature disc in the array that miniature disc forms.Like this, can carry out the analysis of sequential successively to single miniature disc.For example, after a certain class disc in the miniature hdd chip arrays was initially screened, miniature disc can further react with other detection molecules or carry out the analysis of another form, for example order-checking or mass spectrophotometry.Isolate specific miniature disc and the molecule of catching on the miniature disc is carried out purifying with regard to being equivalent to.Like this, when miniature disc and sorting technology combination, can be in order to the purifying entity molecule, for example protein, DNA, cell etc.

After in entering minitype channel, miniature disc can be along single the moving of passage, also can be with the mode mass motion of chain.Can use magnetic field force that miniature disc is transported to corresponding collecting chamber by the passage that is connected to different collecting chambers.For example, in the synthetic process of DNA, each passage can be connected in A, T, C and four reaction tubes of G.Such passage can also be isolated required type and carry out follow-up analysis (referring to U.S. Patent application No.09/924,428, submit August 7 calendar year 2001) from miniature disc.Other method for separating that this paper summary of the invention partly provides also can be in order to the sorting of miniature disc.

The shape of " magnetic club shaped structure " can also be shaft-like or other has the slightly irregular shape of magnetized axis except the rectangle of selective rule, the taper that has for example elongated.The example that provides above is plane particulate (miniature disc) mostly, and microdevice can take shape arbitrarily to comprise the form of spherical beads body in fact.The simplest microdevice is the scrambler that has a magnetic club shaped structure, this coding is to make up when making microdevice, for example by the photochemistry photoetching or connect behind the bar-shaped structure fabrication of magnetic, for example connects fluorescein.

But can being arranged in neat form, reads microdevice the light recognition coding on the microdevice.The arrangement mode of first-selected microdevice is by microdevice is introduced passage, make that the long axis direction of the magnetized axis of microdevice and minitype channel is vertical, as shown in Figure 9, but just can conveniently read the light recognition coding of catenation at the miniature disc of glass surface.In Figure 10, the bar-shaped coding of the 2D on the miniature disc is presented at the outside of chain fully, and light source shines from the below, and enlargement factor is approximately 400 times.Though first-selected mode is to make miniature disc arrange (as Fig. 4 and shown in Figure 11) in passage, such arrangement also can be carried out in the plane, for example in slide surface (as Fig. 9, shown in Figure 10).Even it is necessarily overlapping that the miniature hdd sector-meeting that closes on takes place, miniature disc still can effectively be arranged in chain.Can add " assisting " miniature disc in the potpourri of miniature disc, these miniature discs do not comprise coding pattern, itself are transparent yet.Before miniature disc is arranged in chain, add " assisting " miniature disc, can reduce by two close probabilities of miniature disc that have coding pattern.Like this, by using magnetic field, the chain that the miniature disc that just can effectively obtain encoding is arranged in.

When particulate was by passage, coding pattern and out of Memory were read.Coding pattern and out of Memory can use any suitable sorting instrument, for example flow cell sorter.

Except can arranging, the microdevice that has magnetized axis can also rotate in the mode of determining in passage according to the variation of external magnetic field.This rotation helps to mix, accelerated reaction and make solution trend homogeneous.

Embodiment

Embodiment 1, protein spectrum

The surface that has the miniature disc of coding is an earth silicon material, can make the surface with the functional group of going up activation by silanization, and it is amino for example to use the 3-aminoproplytrimethoxysilane treatment surface to make the surface be with.Functional group can further be activated in order to coupling, it is amino for example can to use N-hydroxysulfosuccinimide and 1-ethyl-3-(3-dimethylaminopropyl) carb-odiimide to activate, again with capture antibody on the coupling reaction of amino group generation covalency.Prepare many so miniature discs that are connected with capture antibody in advance, all be connected with a kind of different biotinylated capture antibody that has on each miniature disc.With the potpourri of so miniature disc that has antibody and to be detected containing the to be hunted down antigen or the protein solution reaction of antibody recognition.After the fundamental reaction, add and have fluorescently-labeled Streptavidin molecule, further reaction.Then miniature disc is lined up, detect the type of miniature disc, use fluorescence detector to determine the level of the antigen of combination on the miniature disc (albumen) simultaneously by fluorescence detector.

Embodiment 2, mRNA/cDNA express spectra

The surface that has the miniature disc of coding is an earth silicon material, can make the surface with going up first-selected group--the aldehyde radical (referring to " Comparison between different strategiesof covalent attachment of DNA to glass surfaces to build DNA microarrays " byZammatteo et.al.Anal.Biochem., 280:143-150 (2000)) that connects synthetic oligonucleotides by silanization.Can be by using 3-glycidoxyproplytrimethoxysilane, hydrolysis epoxy radicals again forms glycol, re-use periodate and handle and to make glycol be converted into aldehyde radical, the surface that is connected to miniature disc that the synthetic oligonucleotides that has amino labeled so just can covalency.Prepare many so miniature discs that are connected with capture probe in advance, all be connected with a kind of not homotactic capture probe on each miniature disc.With the potpourri of so miniature disc that has capture probe and to be detected containing and having of capture probe complementation of fluorescently-labeled cDNA solution reaction.After fundamental reaction is finished and cleaned, then miniature disc is lined up, detect the type of miniature disc, use fluorescence detector to determine the level of the cDNA of combination on the miniature disc simultaneously by fluorescence detector.

Embodiment 3, compound library synthesize

When equipment that does not have miniature disc sorting or instrument, the synthetic of storehouse is at random.Use " split and pool " method compound library directly to synthesize on miniature disc.After synthetic the finishing of each step, before next step reaction, miniature disc is arranged, the identification of encoding.For example in the time of synthetic DNA, miniature disc is mixed, be divided into four parts, put into four reaction chamber A, G, T and C respectively.These miniature discs of participating in reaction all are arranged and carry out optical detection and note corresponding information.Each step is all carried out the such identification and the operation of record when reacting, and waits until that like this reaction finishes, and the sequence of the DNA that is synthesized on each miniature disc all has record, is known.In the method in this synthetic compound at random storehouse, but the light recognition coding that carries on each miniature disc all should be different, otherwise two miniature discs with same-code may enter different reaction chambers, and different reactions takes place, thereby synthesize different compounds, do not have the method difference.In such example, the coding that has on any two miniature discs all should be different in other words, and two miniature discs that have different coding might experience same reaction, have identical compound.Such compound library can be used for screening, and such technology is given an example in order to the synthetic DNA storehouse except top, can also be in order to synthetic peptide library.Any can on so miniature disc, synthesizing at compound library synthetic on the pearl body.In combinatorial chemistry, there are a large amount of such storehouses (can be referring to " Comprehensivesurvey of combinatorial library synthesis; 1999 " by Dolle Journal ofCombinatorial Chemistry, 2:383-433 (2000)).The method in this synthetic compound at random storehouse requires each miniature disc all to have unique encoding.

Second kind and be to use sorting unit after more useful compound library synthetic need be in each step synthetic.In this method, the kind of the compound that each will be synthesized after having been specified in advance before synthesizing above the miniature disc and having synthesized.After each step reaction, miniature disc all carries out sorting and sends corresponding reaction chamber to and carry out follow-up reaction.With a designated composition sequence of miniature disc is that the dna molecular of ATCAGTCATGCG (SEQ ID NO:1) is an example, this miniature disc is introduced into the test tube that is numbered A and synthesizes in building-up process so, entering the test tube that is numbered T again, to carry out for second step synthetic, entering the test tube that is numbered C again, to carry out for the 3rd step synthetic, and the rest may be inferred.Storage capacity just determined before synthetic, and storehouse to be synthesized can only be the part wherein in the storehouse that possible synthesize.For example, can synthesize one and have 10 ⁷Planting long is the dna library of 50 nucleotide, and these are 10 years old ⁷It is corresponding with the sequence in the human genome to plant dna molecular, though this storehouse is the dna library (10 that 50 complete nucleotide constitute ³⁰Kind, 4 ⁵⁰) sub-fraction; Can synthesize one and have 10 ⁷Planting long is 20 amino acid whose peptide libraries, and these are 10 years old ⁷The peptide species molecule is corresponding with the peptide sequence in the human genome, though this storehouse is the peptide library (10 that 20 complete nucleotide constitute ²⁶Kind, 20 ²⁰) sub-fraction.Since all carry out sorting when synthesizing in each step, thus can in once synthesizing, produce identical compound, because the miniature hdd sector-meeting that has same-code synthesizes identical compound together by sorting.This can strict control with regard to the copy number that means single miniature disc.The more important thing is that the storehouse mixing that the compound library that synthesizes can be divided into littler part and other known array just can obtain new storehouse.

The synthetic research focus of compound library is to synthesize the storehouse that has the variable region on template or skeleton now.Many researchers and company are (as Affibody, Phylos, Ribozyme Pharmaceuticals, Somalogic) all use such method synthesize antibody, enzyme or other can discern other molecule (as nucleic acid antibody, aptamer), carry out enzyme function (as ribozyme) or can produce the molecule of signal (transforming) function as fluorescence, fluorescent energy.The common ground of these methods is all to need to use enzyme to produce the secondary storehouse, and explains final result.For example in the screening of nucleic acid antibody, nucleic acid antibody is normally by SELEX (Systematic Evolution ofLigands by Exponential enrichments--e.g.U.S.Pat.No.6,048,698) process produces, this needs advanced row stochastic synthetic, by screening, obtain to have required Ya Ku then in conjunction with character.This inferior storehouse is exaggerated and randomization by PCR's again, screens again, and such step carries out reaching the specificity of requirement in advance and the nucleic acid antibody of compatibility up to obtaining generation repeatedly.

Use miniature disc of the present invention to screen and amplification has two big advantages.The first, the amplification of polymkeric substance is not needed to use enzyme.The second, because being chemosynthesis by repeatedly, the polymkeric substance in the storehouse obtains, compound can be the combination of following any composition, nucleic acid, amino acid, little organic molecule, glycosyl, protein-nucleic acid compound etc.Along with the increase of the compound library storage capacity that uses miniature disc to synthesize, increased and synthesized possibility with the molecule that under extreme conditions has special nature, for example synthesize can be under the sex change condition molecule of capture protein.These compound libraries also can use the method for traditional pearl bodily form formula to synthesize, and are the steps of speed limit but further screen and produce.In traditional chemical synthesis process, method that can the operational analysis chemistry is analyzed the part molecule in the storehouse, for example uses mass spectrum.The character of all compounds is unpractical in the storehouse but analyze.But each miniature disc of the present invention all has optical encoding, and all the components in the miniature hdd valut can be analyzed.For example, contain 10 for one ¹⁰Plant the storehouse of compound, the joint efficiency of all compounds can be analyzed, can be starting point with a word bank in this storehouse then, synthetic once more new compound library.Because in each screening process, the metrical information of each compound in the storehouse all goes on record, the method for numerology easy to use designs next step screening.When using the miniature hdd chip technology, each takes turns a large amount of information that the screening storehouse all obtains, and makes traditional random device become a systems approach that guidance is arranged.

Claims (93)

1, a kind of microdevice comprises: a) magnetizable base material; B) but be produced on the coding pattern of the light identification on the above-mentioned base material; C) magnetized axis.

2, according to the microdevice described in the claim 1, it is characterized in that: described magnetizable base material is paramagnetism, ferromagnetism or ferrimagnetism material.

3, according to the microdevice described in the claim 1, it is characterized in that: the absolute value of inducing the magnetization that described microdevice produces along described magnetized axis direction is induced the magnetization big at least 20% than what at least one the direction at other produced.

4, according to the microdevice described in the claim 1, it is characterized in that: the absolute value of inducing the magnetization that described microdevice produces along described magnetized axis direction induces the magnetization big at least by 50%, 70% or 90% than what at least one the direction at other produced.

5, according to the microdevice described in the claim 1, it is characterized in that: the absolute value of inducing the magnetization that described microdevice produces along described magnetized axis direction than at least one the direction at other produce induce the magnetization big at least 1 times, 2 times, 5 times, 10 times, 20 times or 50 times.

6, according to the microdevice described in the claim 1, it is characterized in that: the basic or complete direction of described magnetized axis along main shaft.

7, according to the microdevice described in the claim 1, it is characterized in that: described microdevice is thin discoid shape, and described magnetized axis is positioned at the principal plane of disc.

8, according to the microdevice described in the claim 1, it is characterized in that: described microdevice is the thin rectangular shape shape, and the direction of described magnetized axis is along the direction of the major axis of microdevice.

9, microdevice according to claim 1 is characterized in that: the described base material that is magnetized comprises metal ingredient.

10, microdevice according to claim 9 is characterized in that: described metal ingredient is metal ingredient or its alloy material of transition group.

11, microdevice according to claim 10 is characterized in that: the metal ingredient of described transition group or its alloy material are iron, nickel, copper, cobalt, tungsten, tantalum, zirconium or nickel-ferro alloy and cobalt-tantalum-zircaloy.

12, microdevice according to claim 9 is characterized in that: described metal ingredient is Fe ₃O ₄

13, microdevice according to claim 1 is characterized in that: described microdevice comprises the substrate that a non-magnetisable material is made.

14, according to the microdevice described in the claim 13, it is characterized in that: described base material is silica-base material, plastics, pottery, rubber, polymer or their compound.

15, according to the microdevice described in the claim 14, it is characterized in that: described silica-base material is silicon dioxide or silicon nitride.

16, according to the microdevice described in the claim 13, it is characterized in that: the surface of described substrate is hydrophobic or hydrophilic.

17, according to the microdevice described in the claim 1, it is characterized in that: but the composition of described light recognition coding pattern by the material of described microdevice own provides, the structure of described microdevice itself provides or use the optical markings thing to provide.

18, according to the microdevice described in the claim 17, but the diversity of light recognition coding pattern wherein is made up of shape, quantity, position distribution, chemical property and the material of the structure of substrate, substrate and optical markings thing or their combining case provides.

19, according to the microdevice described in the claim 17, it is characterized in that: but the structure that described light recognition coding pattern is one group of microdevice is arranged or one group of optical markings thing.

20, according to the microdevice described in the claim 1, it is characterized in that: but described light recognition coding pattern is to use general processing technology or micro fabrication is produced on the microdevice.

21, according to the microdevice described in the claim 1, it is characterized in that: but described light recognition coding pattern is to use the mask etching fabrication techniques.

22, according to the microdevice described in the claim 21, it is characterized in that: described mask etching technology is photoengraving, electron beam lithography or X ray etching.

23, according to the microdevice described in the claim 17, it is characterized in that: described optical markings thing is placed on the described microdevice.

24, according to the microdevice described in the claim 17, it is characterized in that: described optical markings thing is the part of described microdevice.

25, according to the microdevice described in the claim 17, it is characterized in that: described optical markings thing is vapour deposition or sputters on the microdevice.

26, according to the microdevice described in the claim 17, it is characterized in that: but described optical markings thing is particulate or quantum dot that the fluorescent material scattered light detects.

27, according to the microdevice described in the claim 26, it is characterized in that: described quantum dot is cadmium-X (Cd-X) core texture, and wherein X represents selenium (Se), sulphur (S) or tellurium (Te).

28, according to the microdevice described in the claim 27, it is characterized in that: described quantum dot is realized passivation by parcel one deck inorganics.

29, according to the microdevice described in the claim 28, it is characterized in that: described integument is a Y-Z type structure, and wherein Y represents cadmium or zinc, and Z represents sulphur or selenium.

30, according to the microdevice described in the claim 26, it is characterized in that: described quantum dot comprises a cadmium-X (Cd-X) core texture, and wherein X represents selenium (Se), sulphur (S) or tellurium (Te); With a Y-Z type integument, wherein Y represents cadmium or zinc, and Z represents sulphur or selenium; In addition, the skin of described microdevice wraps up one deck trialkyl phosphine oxide again.

31, according to the microdevice described in the claim 17, it is characterized in that: but described light recognition coding pattern is the bar coding of one dimension and/or two dimension.

32, according to the microdevice described in the claim 1, it is characterized in that: described microdevice also comprises the bond that can combine with entity molecule to be handled.

33, according to the microdevice described in the claim 32, it is characterized in that: described bond is antibody or nucleotide sequence.

34, according to the microdevice described in the claim 32, it is characterized in that: described microdevice has one group of bond, and every kind of bond can be special in conjunction with a kind of entity molecule to be handled.

35, according to the microdevice described in the claim 1, it is characterized in that: described microdevice has one and is convenient to microdevice/entity molecule-microdevice compound manipulation or feasible to microdevice/entity molecule-possible unit of microdevice compound manipulation becoming.

36, according to the microdevice described in the claim 35, it is characterized in that: described unit is conductive material, insulating material, have the material and the charged materials of high/low acoustic damping character.

37, according to the microdevice described in the claim 35, it is characterized in that: described unit is handled by dielectrophoresis force, row ripple dielectrophoresis force, sound field power, electrostatic force, mechanical force, optical radiation power or thermal convection power.

38, according to the microdevice described in the claim 35, it is characterized in that: described unit is handled by physical force.

39, the microdevice described in according to Claim 8, it is characterized in that: the main shaft of described microdevice and the ratio of secondary axes are at least 1.2.

40, the microdevice described in according to Claim 8, it is characterized in that: described microdevice comprises the rectangular configuration that two paramagnets are made at least.

41, according to the microdevice described in the claim 40, it is characterized in that: described rectangular configuration is separated by metal level.

42, according to the microdevice described in the claim 41, it is characterized in that: described metal level comprises aluminium.

43, according to the microdevice described in the claim 41, it is characterized in that: described microdevice has the rectangular configuration that the different paramagnet of quantity is made in the main shaft both sides.

44, the microdevice described in according to Claim 8, it is characterized in that: described microdevice has the rectangular configuration that two paramagnets are made along main shaft.

45, according to the microdevice described in the claim 40, it is characterized in that: described paramagnet forms the rectangular configuration along the major axes orientation of described microdevice, and this rectangular configuration all has the outstanding structure of finger-shaped at two ends.

46, according to the microdevice described in the claim 44, it is characterized in that: the rectangular configuration that described two paramagnets are made all has the outstanding structure of finger-shaped at two ends.

47, according to the microdevice described in the claim 1, it is characterized in that: described microdevice also comprises in order to synthetic, combination and the functional group that is connected usefulness.

48, according to the microdevice described in the claim 47, it is characterized in that: described functional group is carboxyl, amino, hydroxyl, sulfydryl, epoxy radicals, ester group, thiazolinyl, alkynyl, alkyl, aromatic radical, aldehyde radical, ketone group or their derivant.

49, according to the microdevice described in the claim 17, it is characterized in that: the structure of described microdevice itself is the hole of getting on described microdevice.

50, according to the microdevice described in the claim 40, it is characterized in that: the rectangular configuration that described at least two paramagnets are made is arranged in strip.

51, a kind of system that can constitute the microdevice array comprises a) microdevice described in one group of claim 1; B) the minitype channel array of forming by one group of minitype channel; The width of described minitype channel is: when described microdevice was in the externally-applied magnetic field, single microdevice can rotate freely in passage, can not form the microdevice chain when the main shaft of described microdevice main shaft and minitype channel is vertical.

52, according to the system described in the claim 51, it is characterized in that: the height of described minitype channel and/or the restriction of microdevice is made that microdevice is unlikely to erect in minitype channel by magnetic field.

53, according to the system described in the claim 51, it is characterized in that: the height of described minitype channel is not more than 70% of microdevice main axis length.

54, according to the system described in the claim 51, it is characterized in that: described minitype channel array comprises one can be so that the zone that microdevice is handled therein.

55, according to the system described in the claim 51, it is characterized in that: described minitype channel array comprises one in order to discharge the exit passageway of microdevice.

56, according to the system described in the claim 51, it is characterized in that: described minitype channel array comprises the field generator for magnetic that can handle microdevice turnover minitype channel.

57, according to the system described in the claim 56, it is characterized in that: described field generator for magnetic is ferromagnetic material or little electromagnetic unit.

58, according to the system described in the claim 56, it is characterized in that: described field generator for magnetic below the described minitype channel array, middle, above and near.

59, a kind of method of making the microdevice array may further comprise the steps:

(a) provide one group of microdevice described in the claim 1;

(b) provide a minitype channel array of forming by one group of minitype channel; The width of described minitype channel is: when described microdevice was in the externally-applied magnetic field, single microdevice can rotate freely in passage, can not form the microdevice chain when the main shaft of described microdevice main shaft and minitype channel is vertical;

(c) described one group of microdevice is introduced described minitype channel;

(d) rotate described microdevice by the magnetic field force that adds in minitype channel, the acting in conjunction of the magnetized axis by described magnetic field force and described microdevice makes and disperses mutually between the described microdevice.

60, according to the method described in the claim 59, it is characterized in that: the height of described minitype channel and/or the restriction of microdevice is made that microdevice is unlikely to erect in minitype channel by magnetic field.

61, according to the method described in the claim 59, it is characterized in that: the height of described minitype channel is not more than 70% of microdevice main axis length.

62, according to the method described in the claim 59, it is characterized in that: described microdevice is introduced minitype channel by magnetic field force, fluid force or both combinations.

63, according to the method described in the claim 59, it is characterized in that: described microdevice is introduced minitype channel by magnetic field force, and the direction of introducing makes the angle between microdevice main shaft and the minitype channel main shaft be not more than 45 degree.

64, according to the method described in the claim 59, it is characterized in that: described method is included in minitype channel the microdevice of introducing before the microdevice or interrupting catenation when introducing.

65, according to the method described in the claim 59, it is characterized in that: the rotation of described microdevice is no less than 45 degree.

66, according to the method described in the claim 65, it is characterized in that: described microdevice revolves and turn 90 degrees.

67, according to the method described in the claim 59, it is characterized in that: at least one is in conjunction with a kind of entity molecule in described one group of microdevice; Handle this entity molecule with described method.

68, according to the method described in the claim 59, it is characterized in that: described one group of microdevice is respectively in conjunction with a group object molecule; Handle this group object molecule with described method.

69, according to the method described in the claim 67, it is characterized in that: described manipulation be transport, focusing, enrichment, concentrate, assemble, catch, the moving of the entity molecule on repulsion, suspension, separation, fractionation, isolation, linearity or other direction.

70, according to the method described in the claim 67, it is characterized in that: but thereby described method comprises the coding pattern that uses optical means to detect light identification on the microdevice determines the entity molecule of being handled on this microdevice.

71, according to the method described in the claim 59, it is characterized in that: described one group of microdevice combines with a group object molecule; Described method realizes the detection by quantitative to entity molecule by the physical parameter of the described entity molecule of detection or by detecting and the interaction of described entity molecule or the physical parameter of the mark-up entity molecule that is connected.

72, according to the method described in the claim 71, it is characterized in that: the physical parameter of described physical parameter or mark-up entity molecule is the response to second quasi-molecule of fluorescence, radioactive isotope, quality, reflectivity, absorptivity, chemiluminescence or described parameter.

73, according to the method described in the claim 72, it is characterized in that: described second quasi-molecule is an enzyme.

74, according to the method described in the claim 67, it is characterized in that: described method also comprises by collect the step of the microdevice that combines entity molecule at endpiece.

75, according to the method described in the claim 74, it is characterized in that: described method also comprises the step that discharges entity molecule from the microdevice of collecting.

76, a kind of method of making the microdevice array may further comprise the steps:

(a) provide one group of microdevice described in the claim 1, they are positioned on the plane that is beneficial to microdevice rotation;

(b) rotate described microdevice by the magnetic field force that adds on described surface, the acting in conjunction of the magnetized axis by described magnetic field force and described microdevice makes and disperses mutually between the described microdevice.

77, according to the method described in the claim 76, it is characterized in that: be manufactured with width on the described surface and be not more than the described microdevice groove structure of the width of one dimension at least.

78, according to the method described in the claim 76, it is characterized in that: described method comprises introduces described surface with described microdevice with the form of liquid suspension, removes the step of described liquid then by groove.

79, the method in a kind of synthetic compound storehouse may further comprise the steps:

1) provide one group of microdevice, this microdevice comprises: (a) base material that can be magnetized; (b) but be produced on the coding pattern of the light identification on the above-mentioned base material; (c) magnetized axis; But the coding pattern correspondence of described light identification the product that will carry out synthetic reaction on described microdevice;

2) synthetic described compound library: synthetic reaction realizes by a series of synthesis steps; In per step synthetic in, but according to the light recognition coding pattern on the described microdevice, carry out corresponding synthetic reaction; Behind the single step reaction, but, described microdevice is classified, carry out next step synthetic reaction more again according to the light recognition coding pattern on the described microdevice.

80, according to the method described in the claim 79, it is characterized in that: of the minitype channel array sorting of described microdevice by constituting by one group of minitype channel; The width of described minitype channel is: when described microdevice was in the externally-applied magnetic field, single microdevice can rotate freely in passage, can not form the microdevice chain when the main shaft of described microdevice main shaft and minitype channel is vertical; The acting in conjunction of the magnetized axis by the magnetic field force that adds and described microdevice makes between the described microdevice and disperses mutually.

81, the method described in 0 according to Claim 8 is characterized in that: the height of described minitype channel and/or the restriction of microdevice is made that described microdevice is unlikely to erect by magnetic field in described minitype channel.

82, the method described in 0 according to Claim 8, it is characterized in that: the height of described minitype channel is not more than 70% of microdevice main axis length.

83, according to the method described in the claim 79, it is characterized in that: connected a kind of synthetic compound on described each microdevice.

84, according to the method described in the claim 79, it is characterized in that: described synthetic compound is peptide, protein, nucleic acid oligomer, nucleic acid, vitamin, oligosaccharides, carbohydrates, fat, micromolecule or their compound.

85, according to the described method of claim 79, it is characterized in that: described compound library comprises one group of entity molecule relevant with a certain biological pathway, this group object molecule has identical or similar biological function, all express in the same cell cycle, in same cell type, express, in same types of organization, express, in same organ, express, in the same stage of development, express; The expression of entity molecule can be owing to disease changes or active, or changes along with disease type and advancing of disease stage, or is subjected to medicine or other processing and changes.

86, according to the described method of claim 79, it is characterized in that: described synthetic compound library comprises one group of nucleic acid fragment.

87,6 described methods according to Claim 8 is characterized in that: the nucleic acid fragment in the described synthetic compound library comprises 2,10,15,20,25,50,75,100,200 or 500 nucleotide at least.

88, according to the described method of claim 79, it is characterized in that: described synthetic compound library comprises a histone matter or a polypeptide fragments.

89,8 described methods according to Claim 8 is characterized in that: protein or polypeptide fragments in the described synthetic compound library comprise 2,10,15,20,25,50,75,100,200 or 500 amino acid at least.

90, a kind of according to the synthetic compound library of the described method of claim 79.

91, the method in a kind of synthetic compound storehouse may further comprise the steps:

1) provide one group of microdevice, this microdevice comprises: (a) base material that can be magnetized; (b) but be produced on the coding pattern of the light identification on the above-mentioned base material; (c) magnetized axis; But the coding pattern correspondence of described light identification the product that will carry out synthetic reaction on described microdevice;

2) synthetic described compound library: synthetic reaction realizes by a series of synthesis steps; In per step synthetic after, but according to the light recognition coding pattern on the described microdevice, write down corresponding synthetic reaction, carry out next step synthetic reaction again; But thereby on described microdevice, synthesize and the corresponding product of light recognition coding pattern.

92, according to the described method of claim 91, it is characterized in that: described microdevice is after the synthetic reaction in each step, under the interaction of self magnetized axis and externally-applied magnetic field, be arranged in together, but, determine the kind of microdevice by discerning the coding pattern of the specific light identification that has on the described microdevice.

93, a kind of compound library synthetic according to the described method of claim 91.

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