CN1920560A - Chips for biological or chemical analysis, apparatus and method for processing fluid - Google Patents

Abstract

A test device is disclosed having a base (22) that is a non-sample surface and sample structures (25 (a,b)) comprising pillars (20 (a,b)).

Description

Be used for the analysis chip of biological or chemical analysis, the device and method of handling of fluids

The application is that denomination of invention is the dividing an application of Chinese patent application 01807348.4 of " chip of lobed sample surfaces ".

The cross reference of related application

The application requires to obtain No. the 60/184th, 381, U.S. Provisional Patent Application of submitting on February 23rd, 2000 and the 60/225th, No. 999 the rights and interests of submitting on August 16th, 2000.The application also with people's such as Paul Jedrzejewski the U.S.'s non-provisional application that is entitled as " microfluidic equipment and method " (Microfluidic Devices and Methods) the _ _ number (application attorney docket 020144-001510) submitting on the same day.All intactly reference is incorporated herein for all purposes for above-mentioned all interim and non-temporary patent applications, and all these applications all are transferred to the assignee identical with the application.

Technical field

The present invention relates to be used for the analysis chip of biological or chemical analysis, the device and method of handling of fluids.

Background technology

In new drug development, the chemical compound that has desirable characteristics by discriminating produces potential drug candidates.Sometimes these compounds are called " lead compound ".In case after finding a kind of lead compound, then can produce the various variants of this lead compound, and they are used as potential drug candidates.

In order to reduce the useful time that drug candidates spent of exploitation, use high flux screening (HTS) method to replace conventional lead compound differential method.The high flux screening method is used the storehouse of containing a large amount of potential required compounds.The amount of the compound in this storehouse is very big, and these compounds can make by the combinatorial chemistry process.In the HTS method, in one or more detections, chemical compound lot is screened, in order that identify member in those storehouses with required feature activity (specifically being chemical species or subspecies).Differentiate that thus these compounds that come out can be used as conventional " lead compound ", perhaps they are used for the treatment of.

Conventional HTS method is used the porous flat plate with many holes.For example, typical porous flat plate can have 96 holes.Each Kong Zhongke is equipped with the different fluid samples that will analyze.Use porous flat plate, can analyze the different fluid sample of many kinds basically simultaneously.

Fig. 1 shows the part of the porous flat plate 10 with substrate 17 and edge 15.Edge 15 extends upward from substrate 17, defines hole 16.One little transfer pipet 11 is arranged on hole 16, and this pipe will contain the liquid droplet distribution of fluid sample 13 in hole 16 and on the sample surfaces 12.Drop can have into the surface of serpentine.And in hole 16, edge 15 is limited in fluid sample 13 on the sample surfaces 12, can analyze it like this.

Be necessary to reduce the volume of porous flat plate mesopore, increase the dull and stereotyped density that goes up the hole.Do like this to make and have more hole on the flat board, thereby more reaction can be carried out basically simultaneously.Equally, because the volume in hole reduces, the volume of fluid sample also reduces.The expense that reduces to have reduced reagent in the HTS method of liquid sample volume.Reduce the amount of the reagent that uses, just can reduce the cost of HTS method.Simultaneously, fluid sample such as biological fluid (as blood) always are not easy to obtain.Under the amount situation seldom of obtainable sample, need to make the sample size in the detection to minimize.

Though need to increase the density in hole on the porous flat plate, the density in hole is subjected to the restriction that the hole upper rim exists.These marginal portions can be removed, make sample surfaces more approaching each other, thereby increase the density of sample surfaces.But, remove these marginal portions after, will not have physical barriers between the adjacent sample surfaces.This has increased, and fluid sample mixes and contamination of heavy mutually on the contiguous sample surfaces.

The volume that reduces fluid sample also may have problems.The volume that detects is reduced to less than 1 microlitre can increase surface area/volume ratio greatly.Increasing surface area/volume ratio can increase in the fluid sample analyte or capture the reformed possibility of agent, thereby has influence on any analysis or the reaction of using described analyte or capturing agent.For example, sex change takes place in protein in the fluid sample easily on liquid/solid and liquid/air interface.When the fluid sample that contains protein formed drop, this drop can have the ratio of the amount of protein in high surface area/drop.If the protein in this fluid sample contacts with liquid/air interface, these protein are with sex change and inactivation.And when the surface area/volume ratio of fluid sample increased, the possibility of this fluid sample evaporation also increased.Sub-micro rises liquid easy rapid evaporation when contacting with air of volume.For example, many sub-micros liquid of rising volume can evaporate in several seconds to a few minutes.This makes the analysis of these liquid or processing is become difficult.In addition, if fluid sample contains protein, then the evaporation of the liquid parts of this fluid sample will produce adverse influence (as sex change) to protein wherein.

Embodiments of the present invention will be at these and other problem.

Summary of the invention

An embodiment of the invention relate to a kind of chip, and it comprises: a) comprise the substrate of non-sample surfaces; B) at least a structure, each structure comprise a post and a sample surfaces, and this surface is protruding with respect to above-mentioned non-sample surfaces, and are adapted to accept the sample that distributes from divider.

Another embodiment of the invention relates to and is adapted to device that liquid is handled, this device comprises: a) comprise a body and the divider that is limited at least one fluid passage in this body, each fluid passage is used to distribute the liquid to one or more sample surfaces; B) chip, it comprises that (i) comprises the substrate of non-sample surfaces; (ii) at least a structure, each structure comprise post and with respect to sample surfaces above-mentioned non-sample surfaces projection and accept sample from described divider.

Another embodiment of the invention relates to a kind of method of treat liquid, and this method comprises: liquid is provided a) for the fluid passage in the divider; B) this liquid is assigned in one or more structures on the chip base, each structure comprises post and with respect to the sample surfaces of non-sample surfaces projection.

Another embodiment of the invention relates to a kind of method of treat liquid, this method comprises: a) many strands of liquid are offered each fluid passage in the divider, comprise passive valve in each fluid passage, each liquid this passive valve place that is flowing in each fluid passage stops; B) sample surfaces of many structures is aimed at many fluid passages, each structure comprises a post; C) when sample surfaces at the port of fluid passage or when being placed in the port of fluid passage, sample surfaces is contacted with liquid in the fluid passage.

Another embodiment of the invention relates to chip piece, and it comprises: a) comprise the substrate of non-sample surfaces; B) line up many structures of array in this substrate, each structure comprises a post and with respect to the sample surfaces of described non-sample surfaces projection, and this sample surfaces is used for accepting the sample that will handle or analyze at described sample surfaces from divider.

Another embodiment of the invention relates to the device that is used for treat liquid, this device comprises: a) chip, it comprises i) comprise the substrate of non-sample surfaces and ii) in this substrate, line up many structures of array, each structure comprises a post and with respect to the sample surfaces of described non-sample surfaces projection, and this sample surfaces is used to accept the sample that will handle or analyze on described this sample surfaces; B) comprise the divider of many fluid passages, a passive valve is arranged in each fluid passage, this divider is assigned to fluid sample on the sample surfaces of described chip.

Hereinafter with these and other embodiment of more detailed description.

Description of drawings

Fig. 1 (a) and 1 (b) show the cross section of little transfer pipet and micropore flat board.

Fig. 2 (a) and 2 (b) show the chip cross section that comprises post.

Fig. 3 and 4 shows the cross section of the post with affine structure.

The skeleton view of Fig. 5 display column array.

The cross section of Fig. 6 (a) and 6 (b) display column.

The skeleton view of dissimilar posts in the substrate of Fig. 6 (c)-6 (h) display chip.

The cross section of Fig. 6 (i)-6 (k) display column.

Fig. 6 (1) shows the cross section of the chip with post, and the fluid passage of passing them is arranged in these posts.

Fig. 7 shows the skeleton view of divider.

Fig. 8 shows the skeleton view of a chip embodiment.

Fig. 9 shows the skeleton view of a device embodiments.

Figure 10-12 shows the cross section of some device embodiments.

Figure 13 is the close up view of fluid sample on the sample surfaces of post.

Figure 14 shows the cross section of a device embodiments.

Figure 15 and 16 shows the cross section of some device embodiments.

Figure 17 (a)-17 (d) shows the cross section of a device embodiments that comprises the chip with post that concave side is arranged.

Figure 18-23 shows the cross section of various divider configurations.

Figure 24 shows the skeleton view of a device embodiments.

Figure 25 shows the part skeleton view of Figure 24 shown device embodiment.

Figure 26 shows the exploded view of a device embodiments.

Figure 27 shows part skeleton view, the fragmentary cross-sectional view of the part of Figure 26 shown device embodiment.

Figure 28 shows the exploded view of a device embodiments.

Figure 29-30 shows the partial cross section of Figure 28 shown device embodiment.

Figure 31 (a) shows the cross section of a device entity.

Figure 31 (b) shows the vertical view of device embodiments shown in Figure 31 (a), and hidden line is represented groove among the figure.

Should be understood that in some example in order to set forth embodiments of the present invention, can simplify above-mentioned accompanying drawing, perhaps they are disproportionate.For example, though Fig. 2 (a) shows the chip with two posts, the chip sample of embodiment of the present invention can have the post of any suitable number.For example, in some embodiment, every chip block can have the post more than 100.

Embodiment

Embodiments of the present invention can be used in many different field.For example, some embodiments of the present invention can be used in pharmaceutical use, as target find and/or confirm usefulness protein (proteomic) etc. research and be used for staging clinically or the diagnosis of progression of disease.Some embodiments of the present invention also can be used in the environmental analysis of tracking of polluting and discriminating.Aspect academic research, some embodiments of the present invention can be used in biology or the medical research.Embodiments of the present invention also can be used with research and clinical microarray system and equipment.

In embodiments of the present invention, for example can analyze between two or more compositions in conjunction with, in conjunction with the incident of inhibition, reaction or catalysis and so on.For example, can use the analyte in the embodiments of the present invention analyzing liquid sample and be attached to the lip-deep interaction of capturing between the agent of post.More particularly, can use embodiments of the present invention to analyze interaction between the following compositions: antibody/antigen, antibody/haptens, enzyme/substrate, carrier protein/matrix, lectin/carbohydrates, acceptor/hormone, acceptor/effector molecules, protein/DNA, protein/RNA, repressor/inducer, DNA/DNA or the like.

I. the chip that has post

An embodiment of the invention relate to a kind of chip.This chip can comprise the substrate that contains non-sample surfaces and contain at least one structure of post.Described at least one structure is the form of array usually on described chip base.Each structure comprises the sample surfaces with respect to the non-sample surfaces projection of described chip.The sample surfaces of described structure can be corresponding with the top surface of described post.In other embodiments, described sample surfaces can be corresponding with the upper surface of coating on the described post.

Each sample surfaces can be used for accepting the sample that will handle or analyze on described sample surfaces.Described sample can be or contain composition combined on described sample surfaces, that adsorb, react etc.For example, described sample can be the liquid that contains analyte and liquid medium.In another embodiment, described sample can be an analyte self.Because on chip, have many sample surfaces, so can handle or analyze many samples simultaneously in embodiments of the present invention.

When sample contacted with described sample surfaces, these samples can be liquid forms.When liquid sample existed on the described sample surfaces, described liquid sample can be the drop form of disperseing.Can on described sample surfaces, place the liquid sample of any suitable volumes.For example, the volume that is placed on the described liquid sample on the described sample surfaces can be about 1 microlitre or still less.In other embodiments, the volume of the liquid sample on the described sample surfaces can approximately be 10 to receive and rise or less (rising or less as 100 skins).

In the other embodiment, the drop of dispersion does not need to stay on the sample surfaces.For example, containing the liquid of capturing agent and liquid medium can be as long as contacts with sample surfaces.This is captured agent and can combine with described sample surfaces, and all basically then liquid mediums are all removed from described sample surfaces, only stays describedly to capture agent on described sample surfaces.As a result, in some embodiments of the present invention, from the liquid of divider with after sample surfaces contacts, liquid medium does not need to be retained on the described sample surfaces.

Can be from biofluid as fluid sample as described in obtaining blood and the urine.In some embodiments, described biofluid can comprise organelle (as cell) or molecule (as protein and nucleic acid chains).When described chip be used for analyzing, when producing or handling a kind of biofluid or biomolecule, described chip can be described as " biochip ".

The liquid that is provided by divider can contain any suitable liquid medium and any appropriate ingredients.Appropriate ingredients can comprise analyte, captures agent (as fixing target) and reactant.Suitable analyte or to capture agent can be organic or inorganic at base by nature also can be a biomolecule, as polypeptide, DNA, RNA, mRNA, antibody etc.Other suitable analyte can be that some may be the chemical compounds of potential drug candidate.Reactant can comprise the reactant that can react with other compositions on the described sample surfaces.Suitable reactant can comprise material biology or chemistry that can handle the composition on the sample surfaces.For example, reagent can be enzyme or other material that protein can be launched, dissociates or derives on described sample surfaces.Suitable liquid medium comprises the solution as damping fluid (as acid, neutral, alkalescence), water, organic solvent etc. and so on.

Sample exists the sample surfaces of projection thereon can have the characteristic of selection.In some embodiments, it is lyophily that described sample surfaces can be made, and these sample surfaces are just more acceptant and retain fluid sample like this.For example, described sample surfaces can be hydrophilic.Perhaps or in addition, can have can be in conjunction with composition in, the absorption fluid sample placed thereon or the molecule that reacts with these compositions for described sample surfaces.For example, can comprise on the sample surfaces one or more can with the agent of capturing of analyte response in the fluid sample.In another embodiment, described sample surfaces can have and can accept and in conjunction with capturing the layer of agent itself.Therefore, in embodiments of the present invention, the character of sample surfaces can change along with the variation of sample structure.

Make sample surfaces be raised with some advantages with respect to non-sample surfaces.For example, by making the sample surfaces projection, the cross pollution that may occur between the different liquids sample on the adjacent structure is reduced as far as possible.Fluid sample on the sample surfaces just is not easy to flow on the contiguous sample surfaces, because these sample surfaces are separated by lowland.In some embodiments, even there is not the marginal portion that fluid sample can be limited on the sample surfaces, but the cross pollution between the sample still obtains reducing on the contiguous sample surfaces.Because do not need sample is limited in marginal portion on their sample surfaces separately, thus the space between the contiguous sample surfaces can be reduced, thus increased the density of sample surfaces.As a result, compare with the method for routine, more fluid sample can be handled and/or analyze to every chip block.In addition, can use the fluid sample of small size in embodiments of the present invention, so just can reduce the amount of employed reagent, thereby reduce cost.

In some embodiments, the side of described structure or the part of this side can provide the selectivity characteristic identical with described sample surfaces, perhaps different with described sample surfaces selectivity characteristics.For example, the side of chip post can provide hydrophobic property, and the sample surfaces of this post can provide hydrophilic feature.The hydrophilic sample surfaces of post attracts fluid sample, and the hydrophobic side of this post then can suppress this fluid sample and flow down along the side of described post.Therefore, in some embodiments, just can be limited on the sample surfaces of post without the edge fluid sample in hole.As a result, in embodiments of the present invention, it is minimum that the cross pollution between adjacent sample surfaces reduces to, and still can increase simultaneously the density of sample surfaces.

In the illustrative example about the chip that how to use one embodiment of the present invention, first divider can be stored in many parts of fluid samples that contain different protein on the sample surfaces of many posts on the described chip base.Described first divider can be the divider of " passive valve " type.Hereinafter will be described in further detail passive valve type divider.Afterwards, different protein (can be to capture agent) can be attached on the different sample surfaces of different separately posts.Can use then and can be assigned on each sample surfaces of described each post with the liquid that identical or different second divider of described first divider will contain analyte.This liquid can be kept with described sample surfaces and contact a preset time, makes analyte in this liquid that the protein interaction (as combining, reacting) on time enough and the sample surfaces be arranged.Preset time can be greater than about 30 seconds (as greater than about 1 minute).But this time can change according to the reaction of concrete generation.After having crossed preset time, can use the sample surfaces of washing, and/or these surfaces are exposed in these liquid, to remove unconjugated analyte or reaction product with liquid or the described post of reagent liquid scrubbing.Can provide described washing with liquid and/or reagent liquid to each post separately or jointly, perhaps these posts be contacted with fluid supply by for example overflow mode.Can analyze these sample surfaces then, determine which analyte has played interaction with the protein that combines in the described liquid.

Can adopt any suitable method to analyze, analysis can be quantitatively or qualitatively to analyze.Can analyze sample surfaces, determine for example which analyte is attached on the described sample surfaces and/or has how many analytes to be incorporated on the described sample surfaces.In one embodiment, can add fluorescent marker, be incorporated into the then unmarked thing of protein on the sample surfaces or contain different labels the analyte in the liquid.Can by as fluorescence, fluorescence polarization, surperficial cytogene resonate (surface plasmon resonance, SPR), the combination between the protein of SPR imaging, ellipsometry or ellipsometry imaging observation or check and analysis thing and combination.

In about another example that how to use the chip in one embodiment of the present invention, can detect potential drug candidates and many kinds of potential drug material standed fors basically simultaneously.For example, can test some synthetic organic compounds as the ability that is fixed on the inhibitor of the receptoroid on the different sample surfaces.Described synthetic compound and can be present in the fluid sample on the sample surfaces that leaves chip at the binding partner of described acceptor.Acceptor corresponding to described part can be fixed on the described sample surfaces.After fluid sample is stored on described sample surfaces, can let alone to place a period of time, any potential interaction between described part and the acceptor is taken place.Can analyze these sample surfaces then, look at whether described part is attached on the described acceptor.If the binding partner in the fluid sample does not have and fixing receptors bind, then the organic compound that distributes with described part may suppress the interaction between described part and described acceptor.Then this organic compound can be differentiated as potential drug candidates.

In another example, the fluid sample that contains protein can be left on the sample surfaces of chip sample structure.When these sample surfaces were accepted described fluid sample, these sample surfaces can be within the fluid passage of divider or near its port.At this moment, each fluid passage can be used as the reaction chamber that reacts.For example, when the sample surfaces of chip during in described fluid passage or near its port, various other reagent in this fluid sample can be stored on the sample of before having deposited.Described reagent can make the protein in the fluid sample of before having deposited launch, dissociate or derive.When the protein in the described fluid sample on (1) described sample surfaces, in (2) drop on described sample surfaces or (3) when described sample surfaces in described fluid passage or when its port, these protein just can be processed.Treated protein transduction can be moved on in the analytical instrument (as mass spectrometer) then.In other embodiments, the protein of depositing in the fluid sample can launch under the situation of the reagent that not deposit later or dissociate.For example, if the protein in the fluid sample of depositing stops preset time on sample surfaces, then they are deployable, dissociate or other variation takes place.

Though what mention in this this example and other example all is protein, also can use other compound as reactant, catalyzer or enzyme.The composition that is incorporated into sample surfaces can be the homologue of reactant, catalyzer or enzyme.Should be appreciated that the protein that this paper quotes from is as exemplary sample and composition, embodiments of the present invention are not limited to handle and analysing protein.Embodiments of the present invention can be analyzed the interaction between any two kinds of homologues.

Fig. 2 (a) has shown the cross section of the chip of one embodiment of the present invention.Shown chip comprises substrate 22, contains sample structure 25 (a) and 25 (b) of post 20 (a) and 20 (b) respectively.Substrate 22 and post 20 (a), 20 (b) can be the one-piece constructions of same material.Substrate 22 can be distinguishing with post 20 (a), 20 (b), promptly is made from a variety of materials.Post 20 (a) and 20 (b) can be made up of homogenous material (as silicon) separately, perhaps can comprise two sections or multistage of different materials.

The substrate 22 of chip can have any suitable feature.For example, the substrate 22 of chip can have any suitable lateral dimension.For example, in some embodiments, substrate 22 can have less than about 2 square inches widthwise size.In the other embodiment, this substrate 22 can have greater than about 2 square inches widthwise size.The non-sample surfaces of substrate 22 generally is flat.But in some embodiments, substrate 22 can have nonplanar surface.For example, substrate 22 can have one or more grooves.The structure that comprises sample surfaces and post can be present in the groove.Any suitable material can be used in the substrate 22.Suitable material comprises glass, silicon or polymeric material.Preferably, substrate 22 is the materials that can carry out micromachining, as silicon.

With respect to substrate 22, the orientation of post 20 (a) and (b) can be vertical substantially.Post 20 (a) and (b) comprise sample surfaces 24 (a), 24 (b) and side 18 (a), 18 (b) separately.The side 18 (a) of post 20 (a), 20 (b), 18 (b) can limit sample surfaces 24 (a), 24 (b) separately.Sample surfaces 24 (a), 24 (b) can be exactly the top surface of post 20 (a), 20 (b), and can be with respect to the non-sample surfaces 23 of chip and projection.Non-sample surfaces 23 and sample surfaces 24 (a), 24 (b) can have identical or different coating or characteristic.Contiguous sample surfaces 24 (a), 24 (b) are separated by the lowland 27 that is formed by contiguous post 20 (a), 20 (b) and non-sample surfaces 23.

Post 20 (a), 20 (b) can have any suitable geometric configuration.For example, the cross section of post (as along radial direction or Width) can be circle or polygon.Post 20 (a), 20 (b) are also microscler.When microscler degree was variable, in one embodiment, post 20 (a), 20 (b) can have greater than about 0.25 or the aspect ratio of above (as 0.25-40).In some other embodiment, the aspect ratio of post can be about 1.0 or bigger.Aspect ratio may be defined as the height H of each post and the ratio of its minimum widith W.Preferably, the height of each post can be greater than about 1 micron.For example, the height of each post can be about the 1-10 micron, perhaps is about the 10-200 micron.Each post can have any suitable width, comprises the width less than about 0.5mm (as 100 microns or littler).

The liquid (not shown) can be the liquid form of discrete volume, and they can be present in respectively on the sample surfaces 24 (a), 24 (b) of post 20 (a), 20 (b).Can in any suitable manner and with any suitable divider (not shown) fluid sample be stored on sample surfaces 24 (a) and 24 (b).Divider can comprise one or more passive valves, and these valves are present in the fluid passage of this divider.Hereinafter will the divider with passive valve be described in detail.

Fluid sample can contain the composition that will analyze, react or deposit (as analyte, target, capture agent) on sample surfaces 24 (a), 24 (b).Perhaps or in addition, described fluid sample can contain the composition that is used for subsequent analysis, detection or processing on the surface that will leave post 20 (a), 20 (b) in.For example, the fluid sample on post 20 (a), 20 (b) can contain protein.Protein in the fluid sample can be incorporated into sample surfaces 24 (a), 24 (b).Can analyze, handle and/or then detect the protein on sample surfaces 24 (a), 24 (b) then, perhaps as capturing the agent of capturing that analyte uses.For example, after protein bound is gone up to sample surfaces 24 (a), 24 (b), can with should in conjunction with protein as capturing agent.Contain and to contact with described surperficial 24 (a), 24 (b) at the liquid of capturing the analyte that agent detects.Then described sample surfaces is analyzed, looked at whether described analyte is incorporated into described protein and captures agent.

Fluid sample on contiguous sample surfaces 24 (a), 24 (b) is separated by the lowland between this proximity structure 27.If for example fluid sample flows out this sample surfaces 24 (a), then this sample will flow on the lowland between the proximity structure, and can not contact with the sample on the contiguous sample surfaces 24 (b) it be polluted.For sample is remained on sample surfaces 24 (a), 24 (b), the side 18 (a) of post 20 (a), 20 (b), 18 (b) can be treated as lyophobicity, perhaps itself are exactly lyophobicity.For example, coat hydrophobic material layer can for side 18 (a), 18 (b), perhaps these sides itself are exactly hydrophobic.In the other embodiment, the side 18 (a) of post, 18 (b) also can coat the material (as alkanethiol or polyglycol) of opposing analyte combination.Non-sample surfaces 23 also can have resistance to combining with analyte, or lyophobicity, perhaps can be partially or completely by making with sample surfaces 24 (a), 24 (b) identical materials.

In some embodiments, post can have one or more wholly or in part around the passage of suprabasil one or more posts.The example of this class passage discusses for the 09/353rd, No. 554 at U.S. Patent application, and this application is transferred to the assignee identical with the application, for all purposes, with the full content of this application with reference to being incorporated into this.This U.S. Patent application has also been discussed and can be used for surface treatment methods more of the present invention and compound exhibits method.

The top area of sample structure 25 (a), 25 (b) can comprise one or more layers material.For example, in the cross section of the chip that Fig. 2 (b) shows, post 20 (a), 20 (b) have the ground floor 26 and the second layer 29 on its top surface 19 (a), 19 (b).In this example, the sample surfaces 24 (a) of structure 25 (a), 25 (b), 24 (b) can be corresponding to the upper surface of the second layer 29.In some embodiments, the top area of structure 25 (a), 25 (b) can intrinsic hydrophobicity or has been processed into hydrophobicity.As hereinafter being further explained in detail, hydrophobic surface is less to the possibility that may be present in structure 25 (a), the protein of 25 (b) top area and have a negative impact.

Described ground floor 26, the second layer 29 can be any suitable materials of any suitable thickness.The described ground floor 26 and the second layer 29 can be dead matter, can be at least a metal or oxide such as metal oxide.Being used for as described, the selection of the second layer 29 (perhaps any other layer on the post or the top layer of post) material can be depending on the molecule that will be incorporated on this second layer 29.For example, metal as platinum, gold, silver and so on is suitable for using with the coupling agent of for example sulfur-bearing coupling agent (as alkanethiol or disulfide coupling agent) and so on, and for example the oxide of monox or titanium dioxide and so on then is suitable for using with the coupling agent of for example silylation coupling agent and so on.Described coupling agent can be used for making the material such as capturing agent to be coupled on the described post.

Illustrate, ground floor 26 can be a kind of adhesiving metal (as a titanium), and its thickness can be less than about 5 nanometers.The second layer 29 is noble metal (as gold), and its thickness is about the 100-200 nanometer.In another embodiment, ground floor 26 is oxide, and as monox or titanium dioxide, the second layer 29 is metal (as noble metal) then, as gold or silver-colored.Though have two-layer material on the top surface 19 (a) of the example display column 20 (a) shown in Fig. 2 (b), 20 (b), 19 (b), can be in these two lip-deep numbers of plies greater or less than 2 (as 1 layers).And, though the ground floor 26 and the second layer 29 are described to have concrete material, it should be understood that, shown in ground floor 26 and the second layer 29 any appropriate combination of some materials.

Can adopt any suitable method on post, to deposit these layers.For example, can adopt the layer above-mentioned as depositions such as electron beam or thermal beam evaporation method, chemical vapour sedimentation method, sputtering method or any other technology known in the art.

In embodiments of the present invention, affine structure can be present on the post separately or with other layer combination.For example, described affine structure can be present on the oxide skin(coating) or metal level of post, perhaps can be the post that does not have intervening layer.Preferably, described affine structure is an organic substance.In some embodiments, described affine structure can be formed in conjunction with the individual layer of the molecule of specific analyte (as protein) by containing.For example, described affine structure can be a single layer to capture agent as the metal level of post or oxide skin(coating) lip-deep.It is described that to capture agent can be for example antibody, antibody fragment, polypeptide, acceptor, DNA chain or fragment, RNA chain or fragment, fit etc.Describedly capture agent and can combine by non-covalent or covalency composition machine-processed and in the fluid matrix.Described affine structure (and element) can be used to increase the top surface (as silicon face) of post and is connected to space between the protein of top surface as described in this post.The protein that is connected can be reduced owing to for example contact and the possibility of inactivation with the solid surface of sample structure in this space.

In some other embodiment, described affine structure can be organic film, affinity tag, adapter molecule and capture a kind of in the agent, perhaps their any suitable combination.When using any of these material together, organic film, affinity tag, adapter molecule and capture agent and can in affine structure, the form with two or more sublevels exist.For example, described affine structure can comprise three sublevels, and each sublevel is respectively organic film, affinity tag and adapter molecule.

Organic film, affinity tag and adapter molecule can have any suitable characteristic." organic film " refers to the normally thin molecule organic layer of one deck, and its thickness is generally less than about 20 nanometers.Preferably, organic film is an individual layer." individual layer " refers to monomolecular molecular layer.In some embodiments, the orientation of these molecules is vertical with respect to the surface of they institute's combinations, and is perhaps angled.Individual layer can similar one " layer " molecule.These molecules in the individual layer can be intensive relatively, so as to make on this individual layer protein not below it the layer contact.Become the way of individual layer to reduce the possibility that the protein on the individual layer contacts with the solid surface of sample structure by this individual layer molecular aggregates." affinity tag " is can directly or indirectly that the composition of for example protein and so on is fixing functionality part.Affinity tag can comprise have with organic film in molecule on the polypeptide of functional group of another functional group reactions.Suitable affinity tag comprises avidin and Streptavidin." linker " can be the material that directly or indirectly affinity tag is connected on the post.In some embodiments, linker can provide between the agent indirectly or directly is connected with capturing at affinity tag.Perhaps or in addition, linker can be at post with affinity tag or capture and provide between the agent indirectly or directly be connected.Describedly capture agent and capture protein in the fluid sample than Canon.In the other embodiment, linker can directly be attached on the post, perhaps with post on the layer directly combine, this linker can also combine with the composition as analyte in the fluid sample and so on.The example of suitable linker is a biotin.At U.S. Patent application the 09/115th, No. 455, the 09/353rd, No. 215 and the 09/353rd, describe organic film, affinity tag, linker in No. 555 and captured the example of agent, for all purposes, all with reference to being incorporated into this, these applications all transfer the assignee identical with the application to the full content of these applications.These U.S. Patent applications have been described the various layer structure that can be used on the post of the present invention.

The use of affinity tag has several advantages.For example, affinity tag can promote combining or reaction of protein and bottom organic film.For example, protein can be fixed to the mode of its stability or the disadvantageous harsh reaction conditions of function not needing.

Can adopt any suitable method to form affine structure and their sublevel, for example chemisorption, physisorption or chemo-selective connection method.The material of sublevel can combine by covalent bond or non-covalent bond layer machine-processed and on other sublevel material, post or the post.

The example of chip structure that has affine structure on post is shown in Fig. 3 and 4.Fig. 3 has shown the cross section of the sample structure of lobed sample surfaces.Shown in sample structure comprise post 60.It on the top surface of post 60 interbed 61 that contains oxide (as monox).Can use interbed 61 that coating 62 is connected on the post 60.Coating 62 can contain another kind of oxide, as titanium dioxide.It on coating 62 affine structure 69.Affine structure 69 can comprise the have organic molecule individual layer 64 of (as polylysine or polyglycol).In some embodiments, the molecule in the individual layer 64 is a linear molecule, the Surface Vertical of the general and coating 62 of their orientation or angled.Molecule in the individual layer 64 all has the functional group that can be connected with other molecule at its two ends.Component that comprises first adapter molecule 65 (as biotin), affinity tag 66 (as avidin or Streptavidin), second adapter molecule 67 (as biotin) and capture agent 68 (as antibody) links together.This component is attached on the individual layer 64.In this example, capture agent 68 and be used for accepting and capturing the analyte that is present in the fluid sample on the post 60.For the sake of simplicity, in Fig. 3, only show component.However, it should be understood that, in embodiments of the present invention, on individual layer 64, can have many such group of molecules.

The embodiment that Fig. 3 shows has an affine structure, and this structure has the several layers sublevel.The affine structure of using in the embodiment of the present invention can comprise the sublevel some more or less than Fig. 3.For example, Fig. 4 shows the cross section of another sample structure, and its affine structure has less sublevel.The structure that Fig. 4 shows comprises post 70.An interbed 71 that comprises certain material such as silicon dioxide is arranged on the top surface of post 70.The individual for example coating 72 of metal oxide (as titanium dioxide) that contains can be arranged on interbed 71.An affine structure 78 can be arranged on coating 72.Affine structure 78 can comprise individual layer 73, affinity tag 74 and adapter molecule 75.Affinity tag 74 can be present on the individual layer 73, and adapter molecule 75 can be connected on the individual layer 73.And adapter molecule 75 can be attached to analyte 76 (as protein) on the affinity tag 74.

The some parts of affine structure separates the top surface of sample surfaces and post.As mentioned above, can inactivation when protein contacts with some solid surface.This affine structure can play to want in post and the fluid sample barrier between captive any composition.This top surface that can reduce post makes the possibility of the protein inactivation in the fluid sample on the post.For example, shown in Fig. 3 and 4, in conjunction with analyte 76 and the agent 68 of capturing of combination unlikely contact with solid surface (as the solid surface of coating 62,72).As a result, the existence of affine structure 69,78 makes sensitive molecule (as protein) reduce owing to contact the possibility that affects adversely with solid surface.In order further to reduce this possibility, can contain the material that unlikely makes protein inactivation in the material of affine structure.

Post can array form be present in the substrate of chip.Fig. 5 has shown the example of the array of post.The array of post can rule or irregular.For example, this array can have evenly distributed pillar, the post array of formation rule.The variable densityization of array center pillar.For example, the density of post can be about 25 pieces/square centimeter or bigger (as 10,000 or 100,000/cm ²Or it is bigger).Though chip can have the post of any suitable number,, in some embodiments, the number of the post of every chip block can be greater than 10,100 or 1000.Post can be 500 microns or nearlyer (as 150 microns) apart from (being the distance of the center to center of adjacent post).

Fig. 6 (a)-6 (b) shows the cross section of the embodiment of some posts.Fig. 6 (a) shows some posts 24 that form an integral body with substrate 22.In this this class embodiment, substrate 22 can be by forming with post 24 identical materials.Fig. 6 (b) shows the post 24 that is present in the substrate 22.Post 24 can comprise the material as porous, as hydrogel materials.In embodiments of the present invention, the factor of porosity of all or part of of post or several portions can similar or different (can have identical or different factor of porosity).For example, the different layers in the post can be a porous, and can have different characteristics.Used porosint, fluid sample can pass through this porosint, and like this, post 24 can hold the fluid sample more more than the post that does not have the hole.As a result, compare, can hold more fluid sample in the porous post with atresia post with similar cross-section size.For example,, then compare, have more fluorescent material and kept by post with the situation of atresia post if this fluid sample contains fluorescent material.Compare with may only there be the atresia post of fluorescent material on the top surface of post, the volume production of the fluorescent material that increases in the porous post has been given birth to the signal (as stronger signal) of better quality.

Other suitable post shapes is presented at Fig. 6 (c) in 6 (k).The embodiment of Fig. 6 (i) is included in the lowland on the top of post.In this embodiment, sample surfaces can be positioned at below the highest part of this post.

Fig. 6 (j) and 6 (k) have shown the post with recessed portion.In the embodiment of Fig. 6 (j), post 410,420 has two recessed parts 400 and 402,400 parts separately near the top, and 402 parts are near the bottom.In this example, two the top surface 406 with post is not vertical basically the side of recessed portion 400,402.Recessed portion 404 is at two not between the recessed portion 400,402.The geometric configuration of each post has precipitous variation in recessed portion 404 beginnings and end.Can adopt as reactive ion-etching and form recessed portion 400,402.Fig. 6 (k) show have at its top surface begin, at the post of the recessed side that its lower surface stops.

The post that use has recessed portion and precipitous structural change is favourable.For example, by recessed part is provided to post, the zone between adjacent post can provide more empty space.For example, try Fig. 6 (j), the volume V between the adjacent post 410,420 can be used to hold any fluid sample that may flow out from the sample surfaces of post 410,420.Has volume V between the adjacent post 410,420 of recessed portion greater than the volume between the adjacent post with substantially parallel side (for example can compare the post that Fig. 6 (a) shows).As a result, produce bigger space and held the liquid that may be not flow out from the sample surfaces of post alertly.And the top non-re-entrant part 400 of the post 410 shown in Fig. 6 (j) has two outstanding in shape marginal portion E1, E2.As further describing of hereinafter will carrying out, when use has the post (shown in Fig. 6 (j)) of two abrupt shape variations, and these change of shape are when together using with the divider with fluid passage of collaborative structure, and they can form two passive valves.These two passive valves help to stop fluid sample to flow downward along the side of post 410,420.In addition, if fluid sample flows out the sample surfaces on the post, the recessed surface of post can provide fluid sample inwardly to flow and away from the passage of adjacent sample surfaces.This has also reduced the possibility of liquid cross pollution between the adjacent sample surfaces.

In some embodiments, also in the post of chip, provide the fluid passage.For example, Fig. 6 (1) shows the post 299 in the substrate 290.Substrate 290 and post 299 are being run through in fluid passage 294.Fluid 292 (as gas) can be removed material from these sample surfaces by the sample surfaces on these fluid passage 294 arrival posts 299.Can above the fluid passage in the post 299 294, place covering chip 291, make these holes above these sample surfaces with corresponding hole.Gas can flow out through fluid passage 294, and sample 295 treated on post 299 upper faces is carried in the analytical instrument (as mass spectrometer).

In the typical method that uses the device shown in Fig. 6 (1), can contact with the sample surfaces on the post of sample chip from the liquid of divider (not shown).But the material on the sample surfaces of this liquid coupled columns is handled.For example, this liquid can contain the reagent of handling protein on the sample surfaces.After processing, chip is separated with divider, will cover chip 291 again and be placed on the sample chip with post 299.Each hole that covers chip 291 lays respectively at each sample surfaces top, makes gas stream cross running through the fluid passage 294 of post 299.This gas is removed treated material from sample surfaces, and through covering the hole in the chip 291, is carried in the analytical instrument (as mass spectrometer).

Sample chip shown in Fig. 6 (1) can otherwise be used.For example, in other embodiment of the present invention, liquid also can upwards pass through fluid passage 294, leaves on the sample surfaces of sample chip (promptly on post).In other embodiment, can use fluid passage 294 to keep composition hydration in the sample surfaces.The gas or the liquid (as water) that can use hydration to use pass through fluid passage 294, to keep any composition hydration on the sample surfaces.For example, kept the protein on the sample surfaces to be in hydration status, these protein are unlikely sex change just.In some embodiments, fluid passage 294 can be connected in the sublevel porous zone of post, used as liquid memory, so that provide liquid to sample surfaces.

Can be in any suitable manner and use the post of any suitable made chip.For example, can adopt embossing, etching or method of moulding in the substrate of chip, to form post.For example, the lip-deep position, column top that will form on silicon substrate forms pattern with photoresist.Can carry out for example dark reactive ion etching then, form many posts thereby on this silicon substrate, etch dark profile.Adjust processing parameter (as the ion energy that uses in the reactive ion-etching) and can revise the side profile of post.If desired, can use the side that is coated with formed post as the material of hydrophobic substance and so on, use this moment photoresist to cover the top surface of post.After coating, photoresist can be removed from the top surface of post.The method of making post is known in semiconductor and MEMS (microelectromechanical systems) industry.

II. install

Other embodiment of the present invention relates to fluid means.The fluid means of embodiment of the present invention can comprise a sample chip and can distribute the divider of a or many component fluids on the sample surfaces of this chip.In some embodiments, can provide many strands of liquid to some fluid passages of divider.The liquid that provides to different fluid passages can be identical, also can be different, can contain identical or different composition.For example, the various liquid in each fluid passage can contain the different analyte that will detect.In another example, the liquid in each fluid passage can contain the difference that is connected on the post of sample chip is captured agent.This divider can provide liquid to sample surfaces abreast.

The chip of using in device can be identical or different with previous described chip.For example, the chip in the device can comprise the structure of the post of lobed sample surfaces.

Divider can have any suitable feature, and in the time will distributing the liquid on the sample chip, it can be placed on the sample chip.Can exert pressure dispense liquid to liquid.For controlling liquid flows, generator can have passive or valve initiatively.

Liquid valve initiatively is known in the art.These valves are by initiatively changing flowing or the position of a physical parameter controlling liquid.Some examples are as follows: 1) heat or light change the lyophile characteristic of polymkeric substance, can be used to the position of controlling liquid; 2) can use electromotive force to induce electronic flowing; 3) can use blocking-up of MEMS structure or unlatching fluid passage; 4) the mobile behavior that can influence liquid of magnetic-particle or feature in the passage.

In some embodiments, each fluid passage of divider has a passive valve at least.Preferably, divider comprises many geats.Basically the while provides the different liquids that contains different compositions to the different sample surfaces of post to these many geats.For example, if the array of 100 sample surfaces is arranged on chip, then divider can have 100 sample geats, and the array of its Pareto diagram and this sample surfaces is similar.In other embodiments, divider can have one or more geats that liquid is provided to the different sample surfaces of series connection.The example of the divider that can use in embodiments of the present invention comprises ring-pin divider, little transfer pipet, capillary divider, ink jet divider, hydrogel stamping machine and the divider that passive valve is arranged.In some embodiments, divider can be the form with chip of many fluid passages.In these embodiments, each fluid passage can have the terminal in the lower surface termination of divider chip.The size of the fluid passage in the divider can change.For example, in the divider sectional dimension of fluid passage be about the 1.0-500 micron (as, be about the 1.0-100 micron).

Can adopt any appropriate method manufacturing known in the art to be used for the divider of embodiment of the present invention.For example, can adopt the method for 3-D stereolithography art, machine drilling, ion etching or reactive ion etching to make divider.

In the embodiment of some devices, the sample surfaces of chip can structurally cooperate to collaborative with the fluid passage in the divider.The sample surfaces of sample structure and their correspondence can be aimed at the fluid passage.Behind the aligning, sample surfaces can be positioned at the fluid passage, perhaps is positioned at the port of fluid passage.Liquid in the fluid passage can contact with the sample surfaces of structure then.For example, but the liquid in the convection cell passage is exerted pressure (producing), liquid is flowed in the fluid passage and contact with sample surfaces as cause wetting (electrowetting) power by gaseous tension, electrophoretic force or electricity.In other embodiments, the distance in sample surfaces and the fluid passage between the liquid can reduce, up to being in contact with one another.Chip and/or divider can move to the other side mutually, to reduce the spacing of liquid in sample surfaces and the fluid passage.In these embodiments, but the liquid in the convection cell passage applies or does not exert pressure.

Fluid passage in the divider can be used as reaction chamber (chamber promptly interacts), and these reaction chambers can be respectively different interactions, provides the space as reaction or binding events.The wall of each sample surfaces and corresponding fluid passage can form a reaction chamber.In typical devices, different incident (as different reactions or binding events) independently can take place in the reaction chamber in each.The incident of same type can take place in the different reaction chamber in other embodiments.

For example, divider can provide liquid to the sample surfaces of chip structure.Liquid can contain and can interactional molecule take place or not take place with the molecule of the sample surfaces that is incorporated into chip.At first, the sample structure that contains sample surfaces can be aimed at the fluid passage.Behind the aligning, sample surfaces can be inserted in the fluid passage, perhaps make they be positioned at these passwaies near.And sample surfaces is near the inside of these fluid passages or its mouthful, and the liquid in the divider fluid passage flows out and contacts with sample surfaces.This makes the molecule be incorporated into sample surfaces and the molecule in the liquid react in almost airtight environment or interacts.Situation in the assorted gaseous environment (as air) of fluid sample minimum exposure that can be on making sample surfaces issues looks interaction or reaction.The result has reduced the possibility of fluid sample evaporation.After having spent the schedule time, can from the fluid passage, withdraw from sample surfaces, and/or chip and divider can be separated from each other.The sample surfaces of chip capable of washing then.Reaction or interactional product can be stayed on the sample surfaces.But the lip-deep product of analytic sample then is to determine for example whether to have taken place reaction.Perhaps or in addition, can further handle the lip-deep product of sample, perhaps they can be separated from chip, transfer to the downstream of sample surfaces then, for further handling or the usefulness of analysis.In other embodiments, the product on the sample surfaces can be the agent of capturing that is used for capturing the liquid analyte.

Embodiments of the present invention can be used to transfer on the sample surfaces of chip containing the liquid of capturing agent, analyte etc., do not form drop in this process.For example, when liquid when divider is transferred on the chip, do not need environment by gaseous state.This makes that the liquid volume that produces big surface area/volume ratio is minimum.In embodiments of the present invention, the liquid of small size can be transferred on the chip, and handles thereon, and the composition change (as protein denaturation) in the transfer liquid is minimized.

Can be in conjunction with some embodiments of Fig. 7-9 tracing device.Fig. 7 shows divider 110, Fig. 8 display chip 105.Chip 105 has many posts 101 on its substrate 105a.Post 101 has top surface 103 and side 104.Sample surfaces 103 is with respect to the non-sample surfaces projection of substrate 105a.

Divider 110 comprises the body 111 with minimum fluid passage 112, and this passage is positioned within this body.In this example, fluid passage 112 is vertical basically.As mentioned above, chemistry or biological respinse or interactional reaction chamber can be played to take place therein in fluid passage 112.The orientation of at least a portion fluid passage 112 is the z directions with respect to the x-y plane of body 111 formation of divider 110.In this example, the fluid passage 112 shown in Fig. 7 is vertical, has a port and a port that stops at the lower surface of body 111 that stops at the upper surface of body 111.

In other embodiment of divider, fluid passage 112 can have level and vertical part.For example, an end of fluid passage can be from the upper surface of body, but then level by the upper surface of body.At certain predetermined point of body, the orientation of fluid passage is become vertically by level, and the lower surface at distributor body stops at last.Though the number of fluid passage 112 equates with the number of Fig. 7 and 8 shown device center pillars 101 in the divider,, the number of fluid passage in other embodiments can be different with the number of post.

Can use the various materials of the behavior (as wetting) that influences liquid in the fluid passage 112 to be coated with the wall of qualification fluid passage 112 and the basal surface 113 of divider 110.For example, can use and increase or reduce in fluidic channel walls and the fluid passage that interactional material is coated with this fluidic channel walls between the liquid.For example, the wall that limits fluid passage 12 can use hydrophobic material coating.For example, if protein contacts with hydrophobic surface, then contact with non-hydrophobic surface and compare, the possibility of its sex change is less.

But be convenient to accept to the structure collaborative of the fluid passage 112 in the divider 110 post 101.For example, as shown in Figure 8, the post 101 of chip 105 can insert in the fluid passage 112 of divider 110 bodies.In this respect, the axial cross section area of each fluid passage 112 can be greater than the axial cross section area of post 101 in the divider 110.After post 101 was inserted in the fluid passage 112 in the divider 110, the sample surfaces 103 of post 101 can be present in the corresponding fluid passage 112.The volume that is limited by the top surface 103 of fluid passage 112 and post 101 can be the reaction chamber that reaction takes place.

Chip 105 and divider 110 can have the parts of one or more alignings separately, make them to aim at mutually, and make post can aim at the fluid passage.Alignment portion can be registration mark or align structures.Representational align structures for example can be pin and corresponding hole.For example at the Bian Shangke of chip 105 one or more pin (not shown) is arranged, it is longer than post 101.These pins can insert the corresponding aperture (not shown) that is positioned on divider 110 limits, thereby post 101 is aimed at the fluid passage.Aligning parts can be optics, machinery or magnetic.For example in some embodiment, aligning parts can be the linear passageway of high aspect ratio, and this passage for example chip and divider has been operated on time, allows light to pass through.For example, when chip and divider in operation on time, also can be that a signal takes place in detecting device a magnetic regions.

Device can be used to carry out various detections.For example, biomolecule such as protein can be incorporated into the top surface 103 of post 101.Can allow post 101 aim at the fluid passage 112 of divider 110 then, make the liquid that contains different potential drug candidates, flow on the sample surfaces of post 101 by different vertical fluid passage 112.Potential interaction or reaction between different drug candidates and the protein can take place in the reaction chamber of post 101 and fluid passage 112 formation.Can keep one section preset time, make any reaction or interact and take place.In some embodiment, the time can be 1 minute or more.In other embodiments, the time of cost can be above 30 minutes or longer.After the reaction or the generation that interacts, allow chip 105 and divider 110 be separated from each other.After chip 105 is separated, on its top surface 103, can there be the drop sample that disperses from divider 110.Then, but the sample surfaces 103 of coupled columns 101 clean.Then sample surfaces 103 is analyzed, combined with protein above it to determine whether to have on these surfaces any potential drug candidate.For helping to differentiate drug candidate, before they being deposited on the sample surfaces 103, can be to their different in addition fluorescent markers in conjunction with it.

In another embodiment, the liquid in the fluid passage 112 can contain the agent of capturing of the top surface that can be attached to post 101.Post 101 removable entering in the fluid passage 112 form little reaction chamber with the inwall of fluid passage, thereby make the molecule in the liquid obtain the chance (for example not staying tangible liquid storage thing on post) of reaction or combination.Perhaps, can be on post 101 with liquid storage, thereby wherein capture the top surface 103 that agent can be incorporated into post 101.Divider 110 can be separated with chip 105 then, the agent of capturing that is incorporated into top surface can be gone to capture the usefulness of analyte for analysis.

Device can comprise one or more passive valves.Passive valve is to use the feature when capillary or little passage to change (for example to change suddenly when the capillary channel cross section, perhaps the material when the structure that limits the fluid passage changes suddenly) time capillary pressure barrier that takes place, make the mobile inwall capillaceous or the port of stopping at of liquid.In following document, be described to passive valve: people such as P.F.Man, " capillary drive of little manufacturing stop valve and sample injector " (" Microfabricated Capillary-Driven Stop Valve and Sample Injector ", IEEE 11 ^ThAnnual Int.MEMS Workshop, Santa Clara, California, in September, 1999,45-50 page or leaf); People such as M.R.McNeely, " hydrophobic Microfluidics " (" Hydrophobic Microfluidics ", SPIE Conf.on Microfluidic Devices and Systems II, Santa Clara, California, in September, 1999, the 3877th volume, the 210-220 page or leaf).For all purposes, the content of these publications is all with reference to being incorporated into this.Passive valve is different with the active valve of using the complete shutoff of physical barrier fluid passage.

Have in the illustrative example of device of passive valve a use, the structure of chip can be inserted in the fluid passage corresponding in the divider.One, two or three and even a plurality of passive valve can be arranged in each fluid passage.For example, each fluid passage can have the passive valve that is formed by the flip-flop of fluid passage on geometric configuration.For example, the wall of fluid passage can form a staircase structural model.When liquid ran into this staircase structural model under predetermined pressure, the mobile of this liquid stopped.

When the structure that contains sample surfaces is present in the fluid passage or during at its port, also can forms passive valve.For example, post can be inserted in the fluid passage, just have a space between the side of the post in this fluid passage and this fluidic channel walls like this around this post.What have in the fluid passage that post exists that part ofly has a ring texture.When the flow direction post, the geometric configuration of this fluid passage is by the cylindrical annular that becomes.At a predetermined pressure, liquid stops to flow in this geometric configuration change place.Make flow of liquid cross this geometric configuration change place and also need extra pressure.Can apply different pressure, make flow of liquid cross each valve in the fluid passage.For example, apply two different big or small pressure can for the fluid in the fluid passage, make this liquid successively flow through two different passive valves.

In a specific example of device, comprise that the chip of post uses with the divider that contains many fluid passages with the divider that has used one or more passive valves.Post can be inserted in the fluid passage, chip can contact with divider.Before or after inserting, apply first pressure for earlier the liquid in the fluid passage, this fluid sample is pushed to (but not passing through basically) first passive valve.Apply second pressure for then this fluid sample, it was pushed away described first valve, so that this liquid contacts with post.This moment, fluid sample did not pass through the second passive valve, and this valve is not limited by post and conduit wall.Liquid in the fluid passage is with after sample surfaces contacts, and the pressure that imposes on this liquid just reduces.Then, allow divider and chip be separated from each other, the main body of liquid in sample surfaces and the fluid passage is separated.In this step, in the fluid passage, withdraw from post, and on sample surfaces, still leave fluid sample.Post withdrawing from the fluid passage can make and may all stop in all incidents that sample surfaces takes place.But after post was withdrawn from the fluid passage, reaction still may take place, and just just stopped carrying out the cleaning step afterreaction.After fluid sample was transferred on the sample surfaces, the process of evaporation and air liquid interface formation and so on to the adverse effect of composition in the fluid sample did not seldom perhaps have.But the solvent or the material rinsing that remain on the sample surfaces are removed, and stay required composition.

In other embodiments, described structure can be inserted in the fluid passage, until contacting with liquid in the passage separately.In these embodiments, need be for liquid in the fluid passage being contacted with the sample surfaces of described structure and additionally exerting pressure to it.

The divider of embodiment of the present invention has lot of advantages.For example, different with the ring pin type divider of routine, embodiments of the present invention can send many strands of liquid to sample surfaces in parallel.For example, in embodiments of the present invention, can use 10,000 or 10,000 parts of fluid samples of more a plurality of fluid passage distribution.Comparatively speaking, each device of Chang Gui ring pin type divider only has the combination of about 30 ring pins.Equally, thus with may to contact the capillary pin type divider that may damage divider and sample surfaces with the sample surfaces material different, the divider of the many embodiments of the present invention does not contact with sample surfaces.And different with the divider of many routines, the device of embodiment of the present invention can reduce the possibility that forms the air liquid interface, because liquid is not being formed drop when divider is transferred to chip.Because the volume of drop becomes less, so that the surface area/volume ratio of this drop becomes is big, the air liquid interface that the result can cause being transferred to molecule and this drop in the liquid of sample surfaces produces interaction.In embodiments of the present invention, need not form drop, thereby make and have the gas/liquid interface and the high fluid sample of surface area/volume ratio forms minimumly.

The object lesson of the device that uses passive valve can be described in conjunction with Figure 10-14.Try Figure 10 and 11, liquid 270 is contained in the fluid passage 112 of divider 118 among the figure.Divider first 120 (a) but water wetted material, divider second portion 120 (b) but hydrophobic material.Then, with the post 101 in 112 aligning chips, 100 substrates 105 of fluid passage, and with in the post 101 insertion fluid passages 112.As shown in figure 11, in post 101 is inserted into fluid passage 112 after, divider 110 and chip 100 are in contact with one another.Before or after post 101 is inserted fluid passage 112, apply first pressure to liquid 270.Described first pressure can be greater than atmospheric pressure.Liquid 270 flows to the first passive valve 114 that limits in the fluid passage 112, but does not flow through.This passive valve 114 can be formed by the flip-flop in 112 cross sections, fluid passage.Perhaps or in addition, passive valve 114 can form because of the unexpected variation (as becoming hydrophobic material by hydrophilic material) of fluid passage wall material.No matter which kind of concrete form passive valve 114 takes, can both stop liquid 270 under the effect of pressure P 1, to flow out fluid passage 112.

Try Figure 12, after post 101 inserts fluid passages 112, can be to liquid 270 P2 that exerts pressure.Pressure P 2 can be greater than sample P 1.Applied pressure P2 makes liquid 270 flow through the first passive valve 114, flow on the material of post 101 top surfaces 103, and flow to by the top surface 103 of post 101 and fluid passage 112 around the second passive valve 115 that wall limited.

Try Figure 13, take place to change suddenly in geometric configuration near flow channel area 109 places of post 101 top surfaces 103.In this example, this zone 109 of fluid passage 112 owing to the cause of post 101 existence ringwise.Material on liquid 270 and post 101 top surfaces 103 reacts.Liquid 270 and composition wherein just place on the top surface 103 of post 101.

Be present on the top surface 103 of post 101 at liquid 270 after, most of liquid 270 can separate with post 101.For example, try Figure 14, liquid 270 is applied pressure (as less than atmospheric pressure) less than pressure P 2, like this, the main part of liquid 270 is to the upper reaches, and stays sub-fraction on post 101.In other embodiments, chip 105 and divider 110 are separated from each other, the main part of liquid 270 and the fraction liquid that leaves on the post 101 are separated.Can withdraw from post 101 in fluid passage 112, this moment, the main part of liquid 270 was still stayed in the fluid passage 112 of divider 110 of separation.In some embodiments, post 101 with can make liquid and post 101 top surfaces separating of fluid passage 112 on any material between interaction stop.In these embodiments, do not need to use pressure that most of liquid 270 is separated with post 101 less than pressure P 2.At divider 110 with after chip separates, the top surface of available another liquid rinse or flushing post 11.This rinsing or rinsing step can make any interaction between any material on liquid and post 101 top surfaces stop, and before separate the words that these interactions are stopped as fruit chip 105 and divider 110.

Figure 15 shows the embodiment of the device with the divider that contains a passive valve.Divider 110 has fluid passage 112, and this passage has the first passage part 112a that is communicated with second channel part 112b.112a is wideer than channel part 112b for the first passage part.In this example, first passage part 112a and second channel part 112b stop in shoulder 113 positions, and this shoulder has formed the restricted area between first passage part 112a and the second channel part 112b.This restricted area (promptly being the preventing property means that prevent that liquid 270 from flowing) plays the effect of passive valve 114.The inwall of passage 112 can have hydrophobic surface 230.The top surface 103 of post 101 can be a water-wetted surface 234.

In embodiment shown in Figure 15, can be with liquid 270 being left on the post 101 with the identical or different mode of method shown in Figure 10-14.For example, post 101 is inserted or is placed on the port (for example, just at the port of fluid passage or just in the outside of this fluid passage port) of the fluid passage 112 of divider 110.In the process that liquid is put on the post 101, divider 110 can contact or not contact with chip 105.When being flowing in the first passive valve place and stopping of liquid 270, liquid 270 can be under the effect of pressure P 1.Apply second pressure P 2 then for liquid 270, make liquid 270 pass through first valve 114, contact until water-wetted surface 234 with the post 101 that is positioned at fluid passage 112 greater than first pressure P 1.The top of post 101 and around fluid passage 112 can form second restricted area, i.e. the second passive valve.Perhaps, the effect of playing the second passive valve with wall and the hydrophobic surface 230 on post 101 sides 104 of second channel part 112b of the water-wetted surface 234 on post 101 top surfaces 103.In above-mentioned these two examples, the upper surface that is flowing in post 101 of liquid 270 stops.The top surface of chip base 105a also can be a hydrophobic surface 230.The lower surface of divider 110 also can be a hydrophobic surface 230.

Can adopt any suitable method to make water-wetted surface 234, and can use any suitable material.For example, can use monox (as SiO ₂) and be that the polymkeric substance of end is made water-wetted surface 234 with hydrophilic radical (as OH or COON).Can adopt the 09/115th, No. 397 disclosed method of U.S. Patent application to make water-wetted surface 234 on the top of post 101, this application is transferred to the assignee identical with the application, and this paper includes its complete reference in.

Figure 16 shows the embodiment of another device.This embodiment and embodiment shown in Figure 15 are similar.But in this example, second channel part 112a is positioned on the top of first passage part 112a, and liquid passed through second channel part 112b earlier before entering first passage part 112a.The wall of passage 112 has water-wetted surface 234 in this example.Apply first pressure P to liquid 270 ₁, make liquid 270 flow through second channel part 112b, but do not flow through the first passive valve 240.In Figure 16, unexpected cross section expansion defines the first passive valve 240.The width moment increase that this unexpected expansion is fluid passage 112 has formed shoulder 113 this moment.Then applying to liquid 270 can be greater than first pressure P ₁Second pressure P ₂, liquid 270 was pushed away and released the first passive valve 240, contact with the water-wetted surface 234 of post 101 up to this liquid.When post was positioned at passage 112, liquid 270 ran into the restricted area that is limited by post 101.This restricted area can play the effect of the second passive valve.Perhaps or in addition, on the top surface 103 and the hydrophobic surface 230 (side 104 that comprise post 101) of water-wetted surface 234 on chip 105 posts on the first passage part 112a inwall can play the effect of the second passive valve.This restriction has stoped liquid 270 effluent fluid passages 112 and has flow on the post of chip 105.

Figure 17 (a) has shown the cross section of the device embodiments that comprises the chip with the post that contains recessed side to 17 (d).Can series of steps on sample surfaces fluid sample can be stored in post be described to 17 (d) in conjunction with Figure 17 (a).

Post 322 in Figure 17 (a) display chip substrate 320.Post 322 comprises sample surfaces 322 (a) and comprises the side of the recessed portion 322 (b) between top non-re-entrant part and bottom non-re-entrant part.First marginal portion 322 (c) and second marginal portion 322 (d) are limiting not recessed portion of this top.Divider 301 is positioned at this chip top, and the fluid passage 341 in the divider 301 is in alignment with post 322 and be positioned at its top.Liquid 340 is present in the fluid passage 341, and staircase structural model 303 is stoping liquid 340 to flow to post 322.Described staircase structural model 303 can play the effect that makes the first passive valve that liquid stops to flow under pressure P 1 effect.

Figure 17 (b) has shown contacting of liquid 340 and post 322 sample surfaces 322 (a).In this example, give liquid 340 P2 that exerts pressure, make it flow through the staircase structural model 303 of divider 301.Pressure P 2 in this example is greater than pressure P 1.Under the effect of pressure P 2, liquid 340 can flow, and runs into edge surface 322 (c), 322 (d) of described top non-re-entrant part up to it.Shown in Figure 17 (b), flowing of liquid 340 can be located to stop in the top edge 322 (c) of post.The part of the wall of edge 322 (c) and qualification fluid passage 341 can form the second passive valve, and this valve makes liquid 340 stop to flow through edge 322 (c) under the effect of pressure P 2.

Perhaps or in addition, shown in Figure 17 (c), when when liquid 340 is exerted pressure P3, flowing of it can be located to stop at the bottom margin 322 (d) of the top of post 322 non-re-entrant part.Edge 322 (d) and around wall can form the 3rd passive valve, this valve makes the liquid 340 unlikely edges 322 (d) that flow through.Pressure P 3 can be greater than pressure P 1 and P2.Though exert pressure for the liquid 340 in the example shown in Figure 17 (b) and 17 (c), in other embodiments, do not need to apply higher pressure for liquid 340 is contacted to it with the sample surfaces 322 (a) of post 322.For example, post 322 and/or divider 301 can move mutually, are in contact with one another up to them.Therefore, in some embodiments, do not need to apply extra pressure the liquid in sample surfaces and the fluid passage is in contact with one another to liquid 340.

Advantageously, the post 322 that shows among Figure 17 (b) and 17 (c) forms two passive valves near its top when being positioned at the fluid passage.Used two passive valves to replace a passive valve and make liquid stop at the way at the top of post 322, helped to guarantee that a large amount of liquid 340 does not flow down along the side of post 322.Liquid 340 is further minimized along the situation about flowing of the side of post 322, and the possibility that fluid sample flows to contiguous sample surfaces also is minimized.This has further reduced on the different sample surfaces possibility of cross pollution between the sample.

Try Figure 17 (d), with after the sample surfaces 322 (a) of post 322 contacts, the part 327 of liquid 340 can leave on the sample surfaces 322 (a) at liquid 340, and the major part of liquid 340 is separated with this sample surfaces.This can accomplish by liquid 340 being applied a less pressure.For example, can apply for liquid 340 can be less than the pressure P 4 of pressure P 2 and P3.This lower pressure makes liquid 340 flow upward in the fluid passage 341.Perhaps or in addition, by chip and/or divider are left mutually divider 301 and chip are separated from each other.If the part of fluid sample 326 does not leave on the sample surfaces, then it can flow downward along the side of post 302 and can not flow on the sample surfaces 327 of adjacent posts 333.Cross pollution between the adjacently situated surfaces sample is minimized.

The divider that is used for embodiment of the present invention can be any form.For example, Figure 18-23 shows the cross section of all kinds divider each several part.Figure 18 shows the geat that similarly can distribute drop with ink jet printer (droplet divider).Figure 19 shows and to be used for liquid is distributed to metal needle on the post.Figure 21 and 23 shows the divider with neck 801.Neck 801 can be corresponding to the port of fluid passage, and can be used to penetrate the outside surface of the drop on the sample surfaces.Can transmit fluid sample by the neck of this divider, and sample is sent to the inside of drop.This makes the contact of the liquid-to-air in the divider minimize.Neck 801 also can be used as the minimized barrier of cross pollution between the liquid that makes in the adjacent flow channels in the divider.

Shown in Figure 18,19 and 23, in some embodiments, the fluid passage of divider can be less than the area of section of post 306 near that part of area of section of post 306, so that post 306 can not enter in the fluid passage of divider.But shown in Figure 22 and previous many figure, the part of divider fluid passage can have the area of section greater than post, and post just can insert in the fluid passage and can come out like this.

Figure 24 and 25 shows the divider 130 that uses with the chip 131 that comprises microscler post 132.Divider 130 comprises microscler (as on x or y direction) divider geat 133, and this geat engages with microscler post 132 or cooperates.Microscler geat 133 respectively has a neck that can be used to stop cross pollution between the adjacent geat 133.The wall 135 that passage 134 is defined passage is limited on the chip 131.Divider 130 is on chip 131 time, and the wall 135 of chip 131 can contact and support divider 130.

Figure 26 and 27 has shown the device with a kind of specific type divider.Such divider can be called the liquid addressing connects and draws equipment 140 (fluid addressing adaptor device 140).This connects and draws equipment 140 and can comprise the fluid storage hole 142 that is connected with fluid passage 143 (being limited by wall 160) via stream 144.Liquid flow path 144 draws horizontal-extending in the equipment 140 connecing.Post 164 on the chip 158 can be aimed at the hole 145 in the diapire that limits fluid passage 143, and inserts.The upper area of post 164 can stretch in the post hole 145.Different with previous institute described many embodiments, but the liquid horizontal flow by fluid passage 143, and since the top surface of post 164 be exposed in the flowing liquid, so this liquid can contact with this top surface.Different liquid can flow out from different separately storage holes 142.These different liquid can flow through different fluid passage 143, and can contact with the top sample surfaces of post.After the sample surfaces with post 164 contacts, can flow to liquid outlet 141 at the liquid of the downstream flow of post 164.Embodiments of the present invention can be used microfluidic equipment, as " laboratory on the chip (labon a chip) " type equipment.

And divider or another equipment can use with other external unit such as mass spectrometer.Suchlike external unit can be used for lip-deep reaction of analytic sample or interaction.This class external unit can be positioned at the downstream of sample surfaces.The people's such as (application attorney docket 020144-001510 number) Paul Jedrzejewski that together submit to this paper the U.S. Patent application that is entitled as " microfluidic equipment and method " (" Microfluidic Devices and Methods ") _ _ _ _ number in further described the use of device with this class external unit.For all purposes, intactly with reference to including in, this application also is transferred to the assignee identical with the present invention to this paper with this application.

Figure 28 shows the divider of another type, can be referred to as " anti-interference contact maker " 172.This anti-interference contact maker 172 can have many holes 180 on its bottom surface.In some embodiments, this anti-interference contact maker 172 can be translucent or full impregnated is bright.As shown in figure 29, the post 178 of chip 170 can insert in the hole 180, and can approach chip 170.Contact maker 172 can comprise fluid passage and liquid inlet 174 and the liquid outlet 176 that is the flow chamber form.The liquid that contacts with the top sample surfaces of the post 178 of chip 170 is arranged in the flow chamber.Liquid in the flow chamber flows in the horizontal direction, and contacts with many sample surfaces simultaneously basically.By using flow orifice contact maker 172, the liquid that contains or do not contain analyte can be injected on a plurality of sample surfaces apace.The non-specific joint of analyte and the side of post 178 is owing to the cause that liquid mainly contacts with the top area of post 178 is minimized.At the sample surfaces of post 178 with after liquid contacts, this anti-interference contact maker 170 can keep and chip 170 contiguous, the feature to sample on the sample surfaces when a little detects.

Chemical reaction between any material on the material that can use some external unit (not shown) such as optical instrument to detect to flow through in the chamber and the top surface of post 178.For example, apply light signal 180 can for the lip-deep sample of post 178, detected reflectance signal determines whether reaction has taken place on this sample surfaces then.

Another embodiment of Figure 31 (a) display device.Try Figure 31 (a), this embodiment comprises the chip 191 with substrate 192, has groove 198 in this substrate, and these grooves are separated by holder 196.Many posts 190 are present on the bottom surface of groove 198.The height of each post 190 can be substantially equal to the depth D of their grooves 198 of living in.In other embodiments, the height of these posts can be less than the depth D of their grooves of living in.Coverture 194 in the substrate 192 of chip 191, can have in the groove 198 such as gas or liquid with post 190 on the sample surfaces fluid in contact.This example has two grooves, in each groove different fluids can be arranged.In other embodiments, the number of groove can be greater or less than two.For example, in some embodiments, 6 (or more) grooves can be arranged, 250 (or more) roots posts are arranged in each groove.

Figure 31 (b) shows the vertical view of the device embodiments shown in Figure 31 (a), and the sidewall that limits groove 198 among the figure is represented with hidden line.Can fluid be injected by the fluid intake 197 (a) in the coverture 194 of groove 198 first ends.Coverture 194 can be thought a divider, because fluid is dispensed on the sample surfaces of post 190.Then, fluid arrives the other end by groove 198, flows out the fluid egress point of coverture 194.In other embodiments, fluid intake and/or fluid egress point can be present in the substrate 192.Because fluid is by groove 198, so fluid contacts with the top sample surfaces and all substances on these sample surfaces of post 190., can analyze with after the sample surfaces of post 190 contacts at fluid, determine whether to have taken place to interact or reaction the top sample surfaces.But c analyzes under the situation that is with or without coverture 194 in the substrate 192.

Figure 31 (a) and (b) shown in embodiment have many advantages.For example, different with previous more described embodiments, the post 190 on the chip 191 does not need to aim at the hole in the divider.Fluid can import the top sample surfaces of post 190 and not need alignment procedures accurately.The liquid or the gas that contain heterogeneity can contact with many sample surfaces basically simultaneously.Therefore, the method such as detecting can use those embodiments shown in Figure 31 (a) and 31 (b) to carry out fast.

In a method, can use any combination of above-mentioned divider/sample chip together.For example, in an exemplary embodiment, the divider (shown in Figure 10-17) with passive valve can be used to capture agent and be stored on the top surface of post of sample chip different.Capturing after agent is attached on the top surface of post, can use divider (shown in Figure 26-30) to distribute the liquid that contains analyte, they are contacted with the agent of capturing on the top surface that is incorporated into post.

Term of Shi Yonging and explanation are descriptive and nonrestrictive in this article, this paper is when using this class term and explanation, shown in not planning to get rid of and the content graph of equal value of described feature or its part, will be appreciated that, in the scope that the present invention advocated, can make various changes.And under the situation that does not depart from the scope of the invention, any one of any embodiment of the present invention or a plurality of feature can combine with any one or a plurality of further feature of any other embodiment of the present invention.For example, under the situation that does not depart from the scope of the invention, any specifically described sample structure embodiment can use with the device described in the embodiment 8-31 among Fig. 2-6.

Claims (50)

1. biochip is characterized in that it comprises:

A) substrate of non-sample surfaces is arranged;

B) at least one structure, each structure comprises post and contains the sample surfaces of capturing agent that wherein, described sample surfaces is with respect to above-mentioned non-sample surfaces projection, be used for accepting to contain the sample of analyte, can analyze this analyte and capture interaction between the agent from divider.

2. biochip as claimed in claim 1 is characterized in that, described biochip comprises many described structures.

3. biochip as claimed in claim 1 is characterized in that, described biochip comprises at least a in silicon, monox, polymkeric substance or the glass.

4. biochip as claimed in claim 1 is characterized in that, described each structure also contains metal, metal oxide, polymkeric substance or gold on its post.

5. biochip as claimed in claim 1 is characterized in that, described each structure contains individual layer on post.

6. biochip as claimed in claim 1 is characterized in that described biochip also contains sample, and wherein said sample is a fluid sample.

7. biochip as claimed in claim 1 is characterized in that described biochip also contains sample, and wherein, described sample is a fluid sample, and described fluid sample and the interaction of described sample surfaces.

8. biochip as claimed in claim 1 is characterized in that the side of described each structure is hydrophobic.

9. biochip as claimed in claim 1 is characterized in that the side of described each structure is hydrophilic.

10. biochip as claimed in claim 1 is characterized in that described post comprises recessed part.

11. biochip as claimed in claim 1 is characterized in that, described post has the aspect ratio greater than about 0.25.

12. biochip as claimed in claim 1 is characterized in that, described post has axially extended fluid passage (294).

13. biochip as claimed in claim 1 is characterized in that, the width of described post is less than about 1.0mm.

14. biochip as claimed in claim 1 is characterized in that, described substrate also comprises the groove (198) that is limited by wall and bottom, and above-mentioned each structure begins to extend from the bottom of described groove (198).

15. biochip as claimed in claim 1 is characterized in that, described substrate also comprises the groove (198) that is limited by wall and bottom, and wherein above-mentioned each structure begins to extend from the bottom of groove (198), and it highly is less than or equal to the degree of depth of this groove (198).

16. biochip as claimed in claim 1 is characterized in that, the described characteristic of stating non-sample surfaces is different from described sample surfaces.

17. biochip as claimed in claim 1 is characterized in that, the characteristic of described non-sample surfaces is identical with described sample surfaces.

18. biochip as claimed in claim 1 is characterized in that, it comprises:

A) substrate of non-sample surfaces is arranged;

B) line up many structures of array in this substrate, each structure comprises post and with respect to the sample surfaces of described non-sample surfaces projection, is used for accepting sample from divider, so that this sample is handled or analyzed it on described sample surfaces the time.

19. biochip as claimed in claim 18 is characterized in that, described biochip also comprises many parts of fluid samples that are present on described many sample surfaces.

20. biochip as claimed in claim 18 is characterized in that, described post and substrate comprise silicon.

21. biochip as claimed in claim 18 is characterized in that, the side of described each structure is hydrophobic.

22. be used for the device of handling of fluids, it is characterized in that described device comprises:

A) divider, this divider comprise body and at least one fluid passage that is limited in this body, and each fluid passage is used to distribute the liquid to one or more sample surfaces;

B) biochip, it comprises that (i) has the substrate of non-sample surfaces; (ii) at least one structure, each structure comprises post and contains the sample surfaces of capturing agent that wherein, described sample surfaces is with respect to above-mentioned non-sample surfaces projection, be used for accepting to contain the sample of analyte, can analyze this analyte and capture interaction between the agent from divider

23. device as claimed in claim 22 is characterized in that, one or more structures of described biochip structurally can be accepted to collaborative in described each fluid passage.

24. device as claimed in claim 22 is characterized in that, described each fluid passage has the passive valve that is partly formed by first passage part and second channel, and described first passage part is wideer than described second channel part.

25. device as claimed in claim 24 is characterized in that, described first passage partly is positioned on the described second channel part.

26. device as claimed in claim 22 is characterized in that, described divider is the inkjet type divider.

27. device as claimed in claim 22 is characterized in that, described at least one fluid passage is a level, and the structure of wherein said biochip can be inserted in the hole in the diapire that limits described at least one fluid passage.

28. device as claimed in claim 22 is characterized in that, described substrate also comprises the groove that is limited by wall and bottom, and described each structure begins to extend from the bottom of this groove, and it highly is less than or equal to the degree of depth of this groove.

29. device as claimed in claim 22 is characterized in that, it comprises:

A) biochip, it comprises i) substrate of non-sample surfaces is arranged and ii) in this substrate, line up many structures of array, each structure comprises post and with respect to the sample surfaces of described non-sample surfaces projection, is used to accept the sample that will handle or analyze thereon;

B) comprise the divider of many fluid passages, each fluid passage comprises passive valve.

30. device as claimed in claim 29 is characterized in that, when each fluid passage of each structure of described biochip and described divider on time, described each fluid passage comprises two or more passive valves.

31. device as claimed in claim 29 is characterized in that, described passive valve is limited by the transient change of the geometric configuration of described fluid passage.

32. device as claimed in claim 29 is characterized in that, it is hydrophobic that the wall that limits described fluid passage has a part at least.

33. device as claimed in claim 29 is characterized in that, it is hydrophilic that the wall that limits described fluid passage has a part at least.

34. device as claimed in claim 29 is characterized in that, the aspect ratio of described each post is approximately greater than 0.25.

35. device as claimed in claim 29 is characterized in that, described each structure comprises the affine structure that is present on the described post.

36. device as claimed in claim 29 is characterized in that, described each structure comprises metal level or the oxide skin(coating) that is present on the described post.

37. device as claimed in claim 29 is characterized in that, the aspect ratio of described post is approximately greater than 1.

38. device as claimed in claim 29 is characterized in that, described fluid sample comprises protein.

39. device as claimed in claim 29 is characterized in that, described post contains silicon.

40. device as claimed in claim 29 is characterized in that, described divider comprises translucent or full material transparent.

41. the method for a treat liquid, this method comprises:

A) liquid is provided for the fluid passage in the divider;

B) this liquid is assigned in the suprabasil one or more structures of biochip, wherein, each structure comprises post and contains the sample surfaces of capturing agent, wherein, described sample surfaces is with respect to above-mentioned non-sample surfaces projection, be used for accepting to contain the sample of analyte, can analyze this analyte and capture interaction between the agent from divider.

42. method as claimed in claim 41 is characterized in that, many fluid passages are arranged in the described divider, the described liquid step that provides comprises:

Many strand liquid are offered in the described divider each fluid passage in many fluid passages.

43. method as claimed in claim 41 is characterized in that, many fluid passages are arranged in the described divider, the described step of liquid that provides comprises:

The different liquids that many thighs is contained heterogeneity offers in the described divider each fluid passage in many fluid passages.

44. method as claimed in claim 43 is characterized in that, described heterogeneity is different separately analyte or different captures agent.

45. method as claimed in claim 41 is characterized in that, described liquid contains reagent.

46. method as claimed in claim 41, it is characterized in that many fluid passages are arranged in the described divider, the described step of liquid that provides comprises, the liquid that many thighs is contained heterogeneity offers each fluid passage in many fluid passages, and this method also comprises:

Described different composition is combined with described sample surfaces.

47. method as claimed in claim 41, it is characterized in that, described divider comprises many fluid passages, the described step of liquid that provides comprises, many strand liquid are offered each fluid passage in many fluid passages, and wherein, this method also comprises, after dispense liquid, many strands of fluid samples are left on each sample surfaces of described biochip.

48. method as claimed in claim 41 is characterized in that, described divider comprises many fluid passages, the described step of liquid that provides comprises, many strand liquid are offered each fluid passage in many fluid passages, and wherein, described allocation step comprises:

Many strand liquid in described divider fluid passage apply first pressure, shift described liquid onto in the described fluid passage the first passive valve;

Place one or more sample surfaces of described biochip in the described fluid passage or at its port, and described divider and biochip are cooperated;

Many strands of liquid in described fluid passage apply second pressure, and these liquid were pushed away the described first passive valve, and it is contacted with described sample surfaces, and described second pressure is greater than described first pressure;

Many strands of liquid in described fluid passage apply the 3rd pressure, and described the 3rd pressure is less than described second pressure.

49. method as claimed in claim 41 is characterized in that, does not form drop when described allocation step is carried out.

50. the method for treat liquid as claimed in claim 41 is characterized in that, described method comprises:

A) many strand liquid are offered each fluid passage in the divider respectively, wherein, each fluid passage comprises passive valve, and each liquid this passive valve place that is flowing in each fluid passage stops;

B) sample surfaces of many structures is aimed at many fluid passages, wherein each structure comprises post;

C), sample surfaces is contacted with liquid in the fluid passage when in the port of sample surfaces in the fluid passage or when being placed in the port of fluid passage.

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