CN2596360Y - Flowing biological chip - Google Patents

Abstract

The utility model discloses a flowing biological chip. At present, the production process of all flowing biological chips using non open type reactors as characteristics is complex, and the operating condition and the scanning condition are harsh, and the application can be limited greatly; at present, as for all biological chips using open type reactors as characteristics, in the detecting process, liquid media can not flow along a definite direction, and the service efficiency is not high. The biological chip of the utility model is characterized in that the utility model comprises an open type flowing reactor that reaction and operation liquid phase media can flow along a definite direction, reaction result can be directly read by an external device or naked eyes through an open structure without coverage arranged above a probe array. The biological chip provided by the utility model has the advantages of simple structure, function and material combination optimization, low cost of unit reactors, quick operation, and easy scan.

Description

A kind of mobile biochip

Technical field

The utility model relates to a kind of biochip, particularly a kind of open mobile biochip.

Background technology

Biochip is a kind of qualitative and/or quantitative testing product, its principle is that micro-probe is fixed on the surface of solid phase carriers in addressable mode, make its under the condition of trace detection with biological sample in target molecule generation idiosyncrasy, and then utilize external unit or naked eyes that the result of idiosyncrasy is read.The probe of fixing on the biochip, its kind is a lot of, comprising: various DNA, RNA, protein, polypeptide, various cell, tissue and drug ingedient etc.The range of size of trace probe: the label area that shows its reaction result usually is less than 1 square millimeter.The biochip scope that has a wide range of applications comprises: gene expression detection, genescreen, drug screening, medical diagnosis on disease treatment, environmental monitoring and fields such as improvement, judicial expertise.

The core of biochip is the reactor on it.In the present invention, the reactor of biochip is defined as: be fixed with probe array in the biochip, reach other dependency structure that is communicated with it with the place of object generation specific reaction when detecting.

Biochip can have reactor of different nature, by the qualitative classification of the characteristic reaction device that it had, it can be defined as dissimilar biochips again.In the present invention, according to the liquid phase medium that is added in the testing process can be in reactor directed flow, reactor is defined as flowing and non-current reactor, and the biochip that is feature with these two kinds of reactors is defined as flow biochip and non-current biochip; Could cover open architecture by the nothing of probe array top according to reaction result is directly read by external instrument or naked eyes, reactor is respectively defined as open and the non-open type reactor, with these two kinds of biochips that reactor is a feature, be respectively defined as open and the non-open type biochip respectively; According to probe array top whether only read rank disconnected just have do not have the covering open architecture, reactor is defined as broad sense and non-broad sense open reactive device, and the biochip that is feature with these two kinds of reactors is defined as broad sense and the open chip of non-broad sense respectively.According to the difference of the structure of the solid phase carrier of stationary probe, biochip also is respectively defined as one dimension chip, two-dimentional chip and three-dimensional chip.In the present invention, according to the number n of reactor on the biochip, biochip is defined as single reactor biochip (n=1) and multiple reactor biochip (n is equal to or greater than 2).In the time will showing reactor character, again reactor character is introduced, for example, and how open flow reactor chip, it is defined as: a biochip that includes the open flow reactor more than two or two.

According to definition of the present utility model, the present situation of biochip is as follows:

1, non-flowing type biochip

The non-flowing type biochip comprises the non-current biochip of non-open type and open non-current

Chip, the most widely used at present is open non-current chip.

Using the widest open non-current chip at present is the open non-current chip of single reactor, and an example is to be the chip that substrate is made, non-structure is transformed with the microslide.Its advantage is simple in structure, and point sample and scan operation are all simple and easy to do, and part operation also can be tried hard to recommend outside under the media flow state under moving and carry out (for example hydrojet cleaning).The shortcoming reaction is to carry out under first valve state.In addition,, probe array less when the probe kind hour, the situation of peptide chips or protein-chip for example, because a reactor only needs the few probe of fixed qty (for example several individual to hundreds of), the single reactor chip just seems that efficient is too low, strengthened and produced and the detection cost, the practical application of biochip has been subjected to considerable restraint in this case.

In order to increase the benefit, manufacturer and scientific worker have carried out a lot of improvement to this class chip, for example single open non-current reactor chip are developed into how open non-current reactor chip.The basic structure of the non-current reactor chip of in the market how open is: the open reactive device that forms a few to tens of circles or square on a substrate with height less than the isolated area of 1.0mm.This open reactive device has the liquid zone of adding and reaction zone, but does not have the liquid zone of going out.During detection, the chip plane is arranged essentially parallel to surface level.Owing to there is not the liquid zone of going out, reaction medium cannot be placed in flow state, thereby can not carry out continued operation, and chip efficient is still treated further raising.In addition, also be owing to there is not a liquid zone of going out, open reactive device isolated area cross pollution between the adjacent reactor occurs as too low meeting, reads as its too high commonplace chip scanner of present use that can not utilize again.At this problem, we have invented " a kind of biochip of detachable use " (number of patent application 02113540.1), when detecting, load onto a sufficiently high reactor spacer assembly with anti-cross-contamination, the spacer assembly of dismantling during scanning is to adapt to the scanner requirement.

Another example of many open non-current reactor organisms chips is " multiple-sample microarray biochip " (number of patent application 01112783.X).Its probe array is fixed on one when being open, reaction when not reacting in the closed reactor that not have import and export.This chip uses the reactor of the airtight original opening of mylar single face glue material behind application of sample, need remove enclosed material before going out sample, washing, then application of sample, more airtight, react, remove again airtight, finish to detection reaction so repeatedly.

2, mobile biochip

Mobile biochip comprises mobile biochip of non-open type and open mobile biochip.

1) the mobile biochip of non-open type

1. the one dimension non-open type chip that flows

The one dimension chip is the chip that probe stationary is formed on the line style solid phase carrier.Its example comprises kapillary biochip device (notification number is CN 2483395Y) and microchannel (microchannel) biochip.The microchannel chip is to make general size to be on the chip slapper base: width is less than 0.05mm, the degree of depth is less than the microchannel of 0.025mm, again with probe stationary in the microchannel, add sample then and make its probe region that flows through the microchannel, adopt corresponding signal detection system to read reaction result at last.An example of microchannel biochip is the detection biochip (www.caliper.com) of Caliper Technologies Inc. company, this chip is made substrate with slide, adopt photoetching and etching technique on substrate, to etch the microchannel, with probe stationary in the microchannel.The liquid storage tank of a plurality of openings is arranged on the chip, and liquid storage tank is connected by the microchannel.The advantage of microchannel chip be highly sensitive, speed is fast.Its shortcoming is: 1), need etch the microchannel earlier in the production run, and probe on the point, and then carry out the microchannel sealing and make, its complex structure, the suitability for industrialized production difficulty is very big; 2), flow rate of liquid need be with the control of special precision equipment during detection, for example electro-osmosis device etc.; 3), after reaction is finished,, detect, can not directly use the common chip scanner to read the result for some test example such as fluorescent marker because fixing probe molecule is surperficial within it.

2. the two-dimentional non-open type chip that flows

The two dimension chip, promptly probe array is distributed in the chip that forms on the solid phase carrier of plane.The two dimension non-open type chip that flows, can lift the invention " a kind of probe card and application thereof that includes closed reactor " (number of patent application 0211364.8) that we have applied for is example.The essential characteristic that this two-dimensional closed formula flows through chip is that probe array is fixed on the plane of a closed reactor that import and export arranged, and operations such as reaction can be carried out under the state of media flow continuously, all finish until reaction.

2), open mobile biochip

New through looking into, liquid medium can continuous flow react, clean, and reaction result can not have the open architecture of covering by the probe array top and be yet there are no by the open mobile biochip that external unit directly reads.Some similar having " virus hepatitis antidiastole biochip " (patent announcement CN 2438121Y) are arranged, but the essence of the biochip in this patent is multi-ribbon fast diagnosis reagent bar, belong to a kind of improved diagnostic reagent bar combination, its reaction zone is absorbent material, for example cellulose acetate membrane or nylon film are with fixedly the canonical biometric chip of microprobe array is different among the present invention.

Although above-mentioned various biochip respectively has many good qualities, produce with use in still have different problems.A main common issue with remains, how each functional areas of chip are being carried out under the condition of economy, technical optimization, utilize liquid transport mechanism or device as far as possible cheaply, realize operation (comprising probe stationary, application of sample, cleaning, scanning etc.) on the simplest, the reliable sheet.

Summary of the invention

The purpose of this utility model is to provide a kind of new biochip and using method thereof, this chip will overcome the shortcoming of existing various biochips as much as possible, (for example structure of non-open type chip and Operating Complexity, the medium illiquidity of open chip) brings into play advantage (the medium flowable of the chip that for example flows that has various biochips now as much as possible, the constructional simplicity of open non-current chip and scanning simplification), to improve detection sensitivity, reduce the production cost of running time and reduction chip unit reactor and to detect cost.

Its essential characteristic of the utility model is for containing a kind of open flow reactor.In open flow reactor of the present invention, reaction and operation liquid phase medium can directed flow, and reaction result can cover open architecture and directly be read by external instrument or naked eyes by the nothing of probe array top.

The purpose of this utility model realizes by implementing following technical proposals:

A kind ofly contain that respond and operate liquid phase medium can directed flow, reaction result can cover the mobile biochip of the open flow reactor that open architecture directly read by external instrument or naked eyes by the nothing of probe array top, it is characterized in that: the basic structure of the open flow reactor that described biochip is contained comprises at least: what liquid phase medium can be by continuous application of sample adds liquid zone (1), liquid phase medium can be under flow state absorb water but the reaction zone (2) of hydrophilic lip-deep probe array effect with being fixed on, liquid phase medium can flow through and leave chip go out liquid zone (3) and the free-pouring isolated area of limits liquid phase medium (4), described open flow reactor add the liquid zone, reaction zone with go out the liquid zone and can directly link to each other, also can link to each other indirectly by other structure example such as passage.The open mobile chip that the utility model provides, the basic structure of contained open flow reactor comprises adding liquid zone (1), reaction zone (2), going out liquid zone (3) and isolated area (4) (see figure 1) at least.Open flow reactor in the described biochip add being characterized as of liquid zone: can reaction and the operation medium carry out application of sample with the continuous flow state.Being characterized as of the reaction zone of the open flow reactor in the described biochip: the surface of stationary probe does not absorb water but the liquid phase medium of possess hydrophilic property, reaction and operation can be under flow state and the effect of immobilization probe array.Open flow reactor in the described biochip go out being characterized as of liquid zone: reaction and operation medium can flow through and leave.Being characterized as of the isolated area of the open flow reactor in the described biochip: limit fluid flows freely.Adding liquid zone, reaction zone and going out the liquid zone of open flow reactor in the biochip of the present invention can directly link to each other, and also can link to each other indirectly by other structure example such as passage.Directly the example of Xiang Lianing as shown in Figure 1.

Biochip in the utility model, only reading the biochip that the reaction result stage has the open flow reactor of broad sense that does not have the covering open architecture above can comprising its probe array, can also comprise its probe array top and not only read the biochip that the reaction result stage has the open flow reactor of non-broad sense that does not have the covering open architecture.The example of the open flow reactor of broad sense is seen example 3.

The open mobile chip that the utility model provides, can also have following feature: open flow reactor can be the capillarity mainly utilizing the water wettability of liquid phase medium deadweight, material surface and/or go out the liquid zone make the liquid phase medium directed flow from flow reactor, can also be mainly to utilize other external force to produce the non-of liquid directed flow from flow reactor.The example of available external force has: mechanical pressure, and the orientation that the electric osmose device provides moves, and the orientation that micro pump provides moves or the like.

It is the unique characteristics of biochip among the present invention that the character of designs such as capillarity in chip of utilizing the water wettability of liquid phase medium deadweight, material surface and/or going out the liquid zone is used as promoting the directed flow of liquid phase medium in reactor.In this case, according to the requirement of biochip test project, can optimize liquid phase medium addition and deadweight, the hydrophilic selection of material in advance and/or go out the design parameters such as selection of liquid zone capillarity, to reach the purpose of effective control flow velocity.For example, (for example add the liquid zone and the reaction zone material is hydrophilic under suitable condition, the water wettability that goes out the liquid zone is not less than and adds liquid zone and reaction zone), select suitable above-mentioned angle, liquid phase medium can mainly rely on its deadweight, flow into reaction zone to the lowland from adding the liquid zone by height, flow out chip by going out the liquid zone again after the reaction.So, just, can make reaction and operation medium flow through successively adds liquid zone, reaction zone and goes out the liquid zone.

In the open mobile biochip of the present utility model, the directed flow of reaction and operation medium both can be that each step is carried out continuously, also can just carry out in individual steps.For example, when the lower or/and reaction medium amount that adds of reaction velocity seldom the time, corresponding reactions steps (for example the reaction of test sample and probe is or/and contain the reagent of label and the reaction of object etc.) can be hatched by noncurrent mode, and other reactions steps (for example cleaning) is then carried out in the mode that flows.In this example, non-current mode can be considered a special case of the type of flow, and promptly flow velocity is zero.For example, under the hydrophilic/water absorptivity that flows out the district is not too high situation, reduce liquid flow and help flowing the effect of component in making a concerted effort or/and increase the effect that liquid flow is unfavorable for the component that flows in making a concerted effort, for example make the angle of chip plane and surface level be tending towards 0 and spend, can realize.Thereby becoming again, above-mentioned angle gives the important parameter of different operating step in the operating process with different in flow rate.

The open mobile chip that the utility model provides, can contain the above open flow reactor, also can contain two or two the above open flow reactors, can also contain one or more described open flow reactor and one or more other type of reactor.When chip contains described open flow reactor more than two or two, its structure can be the multiple reactor chip of fixed sturcture, also can a plurality of single reactors be linked together, form the combined type chip by one or more of draw bails such as wedge head, tenon, fastener, suspension member, plug-in unit.For example shown in Fig. 5.

Described biochip, the water wetted material of the solid phase carrier of its stationary probe comprises: inorganic hydrophilic materials such as glass, silicon, organic hydrophilic materials such as polypropylene, Polyvinylchloride, cellulose nitrate diaphragm; The solid phase material of stationary probe can not be thought absorbent material in the reaction zone, and absorbent material comprises: nitrocellulose membrane, cellulose acetate film class, natural fiber film (paper) etc.The material of other functional areas, can use same material to make according to function-cost relation, also can use different materials to make to reduce the more expensive solid phase material consumption of price, these materials can be a kind of or its combinations of metal, glass, silicon chip, macromolecular material.For example, when being the solid phase body of stationary probe with preactivated slide, its unit area cost is higher than general-purpose plastics far away, is then satisfying under the prerequisite of function, can reduce reaction zone activation slide area as far as possible, to reduce the material cost of unit reactor.

In the open mobile biochip of the present utility model, there is isolated area to flow, prevent cross pollution, in these cases, can also reduces the unit reactor cost with the limit fluid free movement.Plane, isolated area height relative response district is between-10mm to 10mm.The isolated area height is that the connotation of negative value is, one one of reactor reaction zone or all be higher than isolated area, and for example shown in Fig. 5 A.The isolated area height on the occasion of connotation be, one one of reactor reaction zone or all be lower than isolated area, for example shown in Fig. 5 B.The preferred version of isolated area height is between-3.0mm to 3.0mm.The structure that strengthens isolation effect can be arranged on the isolated area, for example, geometry decorative pattern, groove, hole, hydrophobic band or the like.For example, just in case there is liquid to arrive the isolated area top, have on isolated area top or the bottom isolated area along decorative pattern, groove, hole and the absorbent material etc. that add liquid zone, reaction zone and go out the water conservancy diversion of liquid zone direction and can strengthen isolation effect, liquid can be drained very soon, can not enter adjacent reactor.The directed flow and avoid the functional structure of cross pollution between the reactor so chip of the present invention has a good guarantee.

When the isolated area height is negative value, adding the angle of cut place that liquid zone and reaction zone and isolated area form, interrupting appears in the water-wetted surface that adds liquid zone and reaction zone, the surface tension of liquid phase medium makes liquid form the arc with certain altitude and angle in this edge, helps flowing freely of limits liquid phase medium.As this moment chip be in an inclination angle and bigger hydrophilic/water absorptivity arranged or/and go out the liquid zone, then can keep liquid phase medium in reactor along adding liquid zone, reaction zone and going out the directed flow of liquid zone.

Adding liquid zone, reaction zone and going out the liquid zone of open flow reactor in the biochip of the present utility model can be formed by various structures respectively, and these structures can be solid and combinations thereof such as rectangle, circle, ellipse, rhombus.The adding liquid zone, reaction zone and go out the liquid zone of open flow reactor in the biochip of the present invention, can with reaction zone on same plane, also can intersect at angle with it not on same plane, to satisfy in the various detections requirements such as control flow velocity, anti-cross-contaminations with reaction zone.In the example of Fig. 4 E, go out bottom surface, liquid zone and reaction zone bottom surface and form one greater than 90 degree, less than 180 angles of spending.When the reaction zone plane kept level, liquid can not flow and hatch like this; When the reaction zone plane becomes one greater than 0 degree angle with go out the plane, liquid zone when outlet becomes one to spend angle greater than 0 with surface level in outlet with surface level, the liquid outflow is easy to carry out flow operation.

In the biochip of the present utility model, the water wettability of controlling liquid phase medium self gravitation, material surface and/or the structure that goes out the capillarity of liquid zone can be arranged in the described open flow reactor, comprise: add the liquid zone, go out the structure that helps the liquid directed flow (structures such as the ditch of water conservancy diversion layer, flow guide bar, water conservancy diversion rod, diversion rod, water conservancy diversion pin, water conservancy diversion, groove, inclined-plane, tap hole etc.) and the material (for example absorbent material) of liquid zone, the selection of each functional areas surface hydrophilicity in the dynamics size of the control channel of flow velocity and the reactor in each passage on the chip.For example, when adding the liquid zone, reaction zone and go out the surface of liquid zone, more and more favourable liquid phase medium is capillary when reducing, and just helps liquid phase medium along adding liquid zone, reaction zone and going out the directed flow of liquid zone.Biochip of the present utility model, the dynamic form of its open flow reactor can be the permanent structure that forms by moulding or other irreversible connection technology, also can be the dismantled and assembled structure that forms by the non-irreversible connection that physics and/or chemical method obtain.The material of these structural details can be a kind of or its combination of the plate made of inorganic material such as various organic materials such as plastics, rubber and glass, silicon chip or other material, sheet, film, piece.The physics and/or the chemical method that form non-irreversible connection in the dismantled and assembled structure comprise: the bonding agent of mechanical locking device, electromagnetic locking device, reversible bonding, elasticity are chimeric or the like.

A chimeric example of elasticity is: reactor is embedded in the chip shaping aperture plate of being made by resilient material or spring leaf or spring, by elastic force the two is closely pressed together.An example of the bonding agent of reversible bonding is: with in type, contain the plastic plate that adds the liquid zone, goes out liquid zone and isolation region structure, by adhesive sticker with contain the slide of using as reaction zone and be bonded together, be formed with the open mobile chip of a plurality of separate reactors.The example of mechanical locking device, electromagnetic locking device is seen our patent " a kind of biochip of detachable use " (number of patent application 02113540.1).

Advantage of the present utility model is:

1) flow biochip relatively with present non-open type, the biochip simple structure among the present invention, easy to manufacture, easy to use, scanner there is not specific (special) requirements.

2) with the non-current biochip of present non-open type relatively, but the biochip among the present invention can control sample injection rate IR and continued operation thereby have the higher and speed of detection sensitivity advantage faster according to reaction needed,

3) with the open biochip of present single reactor relatively, biochip among the present invention is owing to can there be a plurality of reactors, and each functional areas can be carried out relatively independent cost control and realize optimal combination in selection and making on the chip, thereby when probe array is not very big, when for example the probe array distribution area was less than 8 square centimeters, production cost and use cost were all lower.

Description of drawings

Fig. 1: be the open gravity flow reactor organisms of a kind of list of the utility model chip synoptic diagram

Fig. 2: for the utility model another kind of single open from the flow reactor vertical view

Fig. 3: for the utility model another kind of single open from the flow reactor vertical view

Fig. 4: be the side view of the utility model Fig. 1 and Fig. 2

Fig. 5: be the side view of the utility model Fig. 3

Fig. 6: add the liquid zone vertical view from flow reactor for a kind of list of the utility model is open

Fig. 7: openly add the liquid zone vertical view from flow reactor for the utility model is another kind of single

Fig. 8: openly add the liquid zone vertical view from flow reactor for the utility model is another kind of single

Fig. 9: openly add the liquid zone vertical view from flow reactor for the utility model is another kind of single

Figure 10: add the liquid zone side view from flow reactor for a kind of list of the utility model is open

Figure 11: openly add the liquid zone side view from flow reactor for the utility model is another kind of single

Figure 12: openly add the liquid zone side view from flow reactor for the utility model is another kind of single

Figure 13: openly add the liquid zone side view from flow reactor for the utility model is another kind of single

Figure 14: go out the liquid zone vertical view from flow reactor for a kind of list of the utility model is open

Figure 15: openly go out the liquid zone vertical view from flow reactor for the utility model is another kind of single

Figure 16: go out the liquid zone side view from flow reactor for a kind of list of the utility model is open

Figure 17: openly go out the liquid zone side view from flow reactor for the utility model is another kind of single

Figure 18: openly go out the liquid zone side view from flow reactor for the utility model is another kind of single

Figure 19: openly go out the liquid zone side view from flow reactor for the utility model is another kind of single

Figure 20: openly go out the liquid zone side view from flow reactor for the utility model is another kind of single

Figure 21: for the utility model height is a negative isolated area open reactive device synoptic diagram

Figure 22: for the utility model height is a positive number isolated area open reactive device synoptic diagram

Figure 23: be a kind of inserted type multiple reactor of the utility model biochip synoptic diagram

Figure 24: be the synoptic diagram of a reactor of the another kind of inserted type multiple reactor of the utility model biochip

Figure 25: be the side view of the utility model Figure 24

Figure 26: be the another kind of multiple reactor biochip of the utility model synoptic diagram

Mark among the figure: 1 for add liquid zone 2 for reaction zone 3 be liquid zone 4 for fluid hole 5 for liquid filling hole 6 for isolated area 7 for being that locating slot 10 is a sump pit for isolated area 9 highly highly for positive number for the isolated area 8 of negative

Embodiment

Below in conjunction with some examples of implementation, the invention will be further described.Embodiment 1, and the embodiment of absorbent material additional structure is arranged:

Reactor isolated area height is 0.5mm in the chip, the adding liquid zone 1, reaction zone 2, go out liquid zone 3 and directly link to each other of each reactor, and add liquid zone 1, reaction zone 2 bottom surfaces at grade, have fluid hole 4 going out liquid zone 3, going out liquid zone 3 and fluid hole 4 inwalls have thieving paper.Chip places on the thieving paper.Behind the liquid feeding, liquid is by gravity and surface affinity effect, and through adding liquid zone 1, reaction zone 2, going out liquid zone 3 inflow thieving papers, this moment, thieving paper and thieving paper aperture became control flow velocity principal element.Embodiment 2, a kind of embodiment of composite reaction chamber chip structure

Reactor isolated area height is 0.5mm in the chip, the adding liquid zone 1, reaction zone 2, go out liquid zone 3 and directly link to each other of each reactor, and add liquid zone 1, reaction zone 2 and go out 3 bottom surfaces, liquid zone at grade.Each reactor side has tongue-and-groove, the tenon of a concave, convex respectively, and the tenon of 3 reactor sides is inserted the tongue-and-groove of other reactor respectively, has promptly formed one four combination of reactors chip (Figure 23).Embodiment 3, a kind of biochip example that contains broad sense open flow reactor

The liquid feeding plot structure of this biochip such as Fig. 9, Figure 13, go out structure such as Figure 15, Figure 18 of liquid zone, add the liquid zone and be made up of a liquid filling hole, reaction zone is a square planar, going out the liquid zone is a trapezoidal and square combination, becomes one 25 degree angles by reaction zone with surface level to liquid outlet.During assembling, using pressure sensitive adhesive on isolated area a transparent membrane above the reaction zone.This chip level placed add sample and hatch, hatch finish after, again this chip is placed to add the liquid zone height, to go out the liquid zone low and become miter angle to wash with surface level.Having under the situation of certain inclination angle, institute adds liquid and is easy to flow out the liquid zone.After total overall reaction is finished, tear transparent membrane off, promptly available scanner scans.Film on the open chip reaction zone of this part can the protective reaction district when chip does not use, and reaction zone is worked under certain pressure and prevents cross pollution, when needs are hatched, also has moisture-keeping function.Embodiment 4, and another kind contains the biochip example of broad sense open flow reactor

The liquid feeding plot structure of this biochip such as Fig. 9, Figure 13 go out structure such as Figure 15, Figure 17 of liquid zone, add the liquid zone and are made up of a liquid filling hole, and reaction zone is a square planar, and going out the liquid zone is a trapezoidal and square combination, with reaction zone on same plane.During assembling, using pressure sensitive adhesive on isolated area a transparent membrane above the reaction zone.During use, this chip level is placed, and reaction and cleansing solution add liquid filling hole having under certain external force effect, and institute adds liquid after reaction zone forms certain height, by going out the liquid zone outflow.After total overall reaction is finished, tear transparent membrane off, promptly available scanner scans.Embodiment 5, a kind of open 8 preparations from flow reactor c-hepatitis antibody detection chip

One with 8 holes, 75mm * 25mm * 1.5mm polyphenyl alkene plastics plate, span 5mm, the half slot of a 3mm diameter, dark 0.6mm is done as adding the liquid zone in the hole in liquid feeding side, connect the reach through hole of a 3 * 3mm down, the activation slide of assembling one 3 * 3mm, thick 1mm in each reach through hole, the slit with adhesive closure slide and reactor limit forms a dark 0.6mm reaction zone, the slide bottom surface is lower than plastic plate bottom surface 0.1mm, the benchmark during as scanning.The below of reaction zone meets a wide 2mm, and dark 0.6mm goes out the liquid zone.Go up NS3, NS4, NS5, the CORE antigen of hepatitis C virus (HCV) on each slide with 2 * 2 array point, the diameter of each point is 0.2mm, and dot center is apart from 1mm, apart from pool side 1mm.With the skimmed milk power sealing, make the c-hepatitis antibody detection chip of one 8 reaction tank again.Embodiment 6, a kind of preparation of the open 8 reactors blood transfusion detection chip that flows

One with 8 holes, 75mm * 25mm * 1.5mm polyphenyl alkene plastics plate, pitch of holes 5mm, the half slot of a 3mm diameter, dark 0.6mm is done as adding the liquid zone adding sample prescription in the hole, connect the reach through hole of a 5 * 3mm down, the activation slide of one 5 * 3mm, thick 1mm in the assembling in each reach through hole with the slit of adhesive closure slide and pool side, makes to form a dark 0.6mm reaction zone, the slide bottom surface is lower than plastic plate bottom surface 0.1mm, the benchmark during as scanning.The below of reaction tank meets a wide 2mm, and dark 0.6mm goes out the liquid zone.On each slide, go up NS3, NS4, NS5, CORE fused antigen, HIV 1+2 antigen, HTLV antigen and the syphilis antigen of hepatitis B surface antibody, hepatitis C virus with 3 * 2 array point, the diameter of each point is 0.2mm, dot center is apart from 1mm, apart from pool side 1mm.With the skimmed milk power sealing, make the blood transfusion detection chip of one 8 anti-reaction tank again.Embodiment 7, a kind of application examples of the third liver detection chip of open 8 reaction tanks

This example makes the biochip of use-case 5, and chip reactor plane sample application zone side height during detection, to go out the liquid zone side low, becomes 30 degree angles.8 reaction tanks slowly add 8 each 20ul of different plasma samples that detected with the RIBA method of dilution in 1: 100 separately, each reaction tank adds goat anti-human igg 100ul, the unconjugated labelled antibody of 0.01M phosphate buffer 300ul flush away of the unconjugated impurity of 0.01M phosphate buffer 300ul flush away, rhodamine mark more successively, at last with drying up after the absolute ethyl alcohol 100ul washing, chip scanner (GMS 418 ARRAY SCANNER) is read, the computing machine special software is handled, and obtains table one result:

Table one, the third liver detection chip and RIBA be the open chip detection result of testing result (videing infra) blood serum sample RIBA result relatively

NS3 NS4 NS5 CORE NS3 NS4 NS5 CORE

1 -?— -?— - -?— 88 114 86 99

2 -?— -?— + -?— 124 88 15415 116

3 + + - -?— 15498 16214 111 132

4 ++ -?-- - ++ 18146 106 128 19553

5 ++++ -?— ++ -?— 22051 115 18734 93

6 -?— + - - 91 15426 86 129

7 -?— ++ ++ - 113 19712 19246 127

8 ++ ++ ++ ++ ++ 22,183 18,956 21 179 20132 embodiment 8, a kind of application examples of blood transfusion detection chip of open 8 reaction tanks

This example makes the biochip of use-case 6, chip reactor plane sample application zone side height during detection, it is low to go out the liquid zone side, become miter angle, 8 reactors slowly add 8 each 100ul of different plasma samples that detected with the RIBA method of dilution in 1: 100 separately, each reactor adds the unconjugated impurity of 0.01M phosphate buffer 300ul flush away more successively, the anti-hepatitis B surface specific antibody (HbsAb) of rhodamine mark, third LS antigen (HCV), the HIV specific antigen, the HTLV specific antigen, each 100ul of syphilis specific antigen, 0.01M the unconjugated labelled antibody of phosphate buffer 300ul flush away, antigen, at last with drying up after the absolute ethyl alcohol 100ul washing, chip scanner (GMS 418 ARRAYSCANNER) is read, the computing machine special software is handled, and obtains table 2 result:

Table 2, blood transfusion detection chip and the open chip detection result of RIBA comparative result blood serum sample RIRA result

HbsAb HCV HIV HTLV syphilis HbsAb HCV HIV HTLV syphilis 1----+ 88 114 86 99 158952--+--124 88 15,415 116 1133++---15,498 16,214 111 132 1054 ++--++-18,146 106 128 19,553 1165 ++ ++-++--22,051 115 18,734 93 986-+--+, 91 15,426 86 129 160277-++ ++--113 19,712 19,246 127 1218 ++ ++ ++ ++ ++-22,183 18,956 21,179 20,132 94

Claims (10)

1, a kind ofly contain that respond and operate liquid phase medium can directed flow, reaction result can cover the mobile biochip of the open flow reactor that open architecture directly read by external instrument or naked eyes by the nothing of probe array top, it is characterized in that: the basic structure of the open flow reactor that described biochip is contained comprises at least: what liquid phase medium can be by continuous application of sample adds liquid zone (1), liquid phase medium can be under flow state absorb water but the reaction zone (2) of hydrophilic lip-deep probe array effect with being fixed on, liquid phase medium can flow through and leave chip go out liquid zone (3) and the free-pouring isolated area of limits liquid phase medium (4), described open flow reactor add the liquid zone, reaction zone with go out the liquid zone and can directly link to each other, also can link to each other indirectly by other structure example such as passage.

2, mobile biochip according to claim 1, it is characterized in that: be to contain its probe array top only to read the disconnected biochip in reaction result rank, or not only reading the disconnected biochip in reaction result rank above containing its probe array with the open flow reactor of non-broad sense that does not have the covering open architecture with open flow reactor of broad sense of nothing covering open architecture.

3, mobile biochip according to claim 1, it is characterized in that: be that the capillarity that contains the water wettability of mainly utilizing liquid phase medium deadweight, material surface and/or go out the liquid zone makes the open biochip from flow reactor of liquid phase medium directed flow, or contain the open non-biochip that mainly utilizes other external force to produce the liquid directed flow from flow reactor.

4, mobile biochip according to claim 1, it is characterized in that: be the single reactor biochip that contains a described open flow reactor, or contain the how open flow reactor biochip of two or two the above open flow reactors, or contain the multiple reactor biochip of one or more described open flow reactor and one or more other type of reactor, the multiple reactor chip that above-mentioned how open flow reactor biochip is a fixed sturcture, or by the wedge head, tenon, fastener, the contrary combined type chip that forms that connects of suspension member or plug-in unit.

5, according to claim 1,2,3 or 4 arbitrary described mobile biochips, it is characterized in that: the reaction zone of contained open reactive device in order to stationary probe do not absorb water but hydrophilic solid phase carrier comprises: inorganic hydrophilic materials such as glass, silicon, organic hydrophilic materials such as polypropylene, Polyvinylchloride, cellulose nitrate diaphragm; The material of other functional areas uses same material to make, and perhaps uses a kind of or its combination of metal, glass, silicon chip, macromolecular material.

6, according to claim 1,2,3 or 4 arbitrary described mobile biochips, it is characterized in that: the isolated area of contained open flow reactor, with respect to the reaction zone plane, highly be-10mm to 10mm that how much decorative patterns, ditch, groove, hole, hole or hydrophobic band structures strengthening isolation effect are arranged on the isolated area.

7, mobile biochip according to claim 6 is characterized in that: the isolated area of contained open flow reactor, with respect to the reaction zone plane, height is at-3.0mm to 3.0mm.

8, according to claim 1,2,3 or 4 arbitrary described mobile biochips, it is characterized in that: the adding liquid zone, reaction zone and go out the liquid zone of contained open flow reactor, can be formed by various structures respectively, these structures can be rectangle, circle, ellipse, rhombus or other solids and combination thereof.

9, mobile biochip according to claim 8, it is characterized in that: the described structure that is beneficial to the liquid directed flow comprises water conservancy diversion layer, flow guide bar, water conservancy diversion rod, diversion rod, water conservancy diversion pin, the ditch of water conservancy diversion, groove, inclined-plane, tap hole, and described material is an absorbent material.

10, according to claim 1,2,3 or 4 arbitrary described mobile biochips, it is characterized in that: the dynamic form of its reactor is the permanent structure that forms by moulding or other irreversible connection technology; Or the dismantled and assembled structure that forms by the non-irreversible connection that physics and/or chemical method obtain; Described dismantled and assembled structure comprises: mechanical locking device or electromagnetic locking device, maybe can separate the glued construction or the elasticity embedded structure of bonding.

Images