CN1432655A - Multilateral biochip - Google Patents
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- CN1432655A CN1432655A CN 02134007 CN02134007A CN1432655A CN 1432655 A CN1432655 A CN 1432655A CN 02134007 CN02134007 CN 02134007 CN 02134007 A CN02134007 A CN 02134007A CN 1432655 A CN1432655 A CN 1432655A
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Abstract
The present invention discloses a multilateral biochip unlike available single-faced ones. In the multilateral biochip, several faces have fixed molecule distinguishing probes, and this can utilize the area of the stereo biochip to raise the utilization efficiency of chip, obviously reduce detection cost and raise detection speed. The present invention also provides devices for preparing and applying the multilateral biochip, especially double-sided biochip, including probe fixing device, reaction operating device and distinguishing read device.
Description
Affiliated technical field:
The present invention relates to a kind of multilateral biochip, particularly a kind of two-sided biochip.This two-sided biochip is all distinguished stationary probe on two largest face of solid phase carrier substrate.
The invention still further relates to and above-mentioned two-sided biochip preparation and use relevant device, comprise a kind of two-sided probe stationary device that can be used for preparing two-sided biochip, a kind of two-sided detection reaction operating gear that can be used for two-sided biochip and a kind ofly can discern the two-sided reading devices that reads the detection reaction result of two-sided biochip.
Background technology:
Biochip, also be called for short chip in the present invention, it 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 specific reaction, and then utilize peripheral equipment or naked eyes that the result of specific reaction is read.In the present invention, in the biochip through activation treatment, be defined as substrate as the parts of the solid phase carrier of stationary probe.
The biochip scope that has a wide range of applications comprises: genetic expression detection, genescreen, drug screening, medical diagnosis on disease treatment, environmental monitoring and fields such as improvement, judicial expertise.
The most frequently used biochip is polypeptide chip and gene chip at present.Polypeptide chip is the biochip for preparing on substrate as probe stationary with a plurality of amino acid whose sequential structures (comprising protein).For example the polypeptide chip based on the Ag-Ab selective reaction is that multiple specific antigen or multiple antibody are fixed on the solid phase substrate in addressable mode, in chip other structure then is in order to corresponding with it antibody or antigen in the test sample.Its basic skills and ELISA are not essentially different, and only will be increased to the microarray of fixing multiple antigen or multiple antibody on solid phase carrier with addressable mode with a kind of antigen of stochastic distribution mode fixed or a kind of antibody on solid phase carrier.Polypeptide chip adopts the fluorescent substance material that serves as a mark usually, and its sensitivity is improved greatly than the ELISA method.Gene chip is with sample amplifying nucleic acid to be checked, Nucleotide and complementary nucleic acid, nucleotide probe hybridization, forms crossbred, or combines with specific antibody, shows the chip of detected result again with color reaction.
Biochip among the present invention comprises the product that is used to detect that all will form based on will there be bioactive material (comprising biotic components such as DNA, polypeptide, protein, cell, tissue) to be fixed on the solid phase carrier in addressable mode.The core of biochip is the reactor on it.The reactor of the biochip among the present invention is defined as: be fixed with probe array in the biochip, reach other dependency structure that is communicated with it with the place of target compound generation specific reaction when detecting.In the present invention, according to the number n of reactor on the biochip, biochip is defined as single reactor biochip (n=l) and multiple reactor biochip (n is equal to or greater than 2).
Among 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 flow reactor and non-current reactor; With flow reactor and non-current reactor is that the biochip of feature is respectively defined as flow biochip and non-current biochip.
Among the present invention, when reading reaction result according to identification, reactor probe top has or not the covering open architecture to be read by external instrument or naked eyes Direct Recognition, is defined as open respectively reactor and the non-open type reactor; With this reactor is the biochip of feature, is respectively defined as open and the non-open type biochip.
The biochip reaction device has the character of above-mentioned several reactors usually simultaneously.Among the present invention, whole character that these reactors are defined as being had with it are the reactor of common trait, are that the biochip of feature is also similarly defined with this reactor.For example: if the liquid phase medium that in testing process, is added can be in reactor directed flow, when reading reaction result, identification covers open architecture for nothing above the probe array, then this reactor is defined as open flow reactor, corresponding biochip is defined as open mobile biochip, or is called for short open mobile chip; Other is analogized in proper order.
The present situation of biochip is as follows:
1, non-current biochip
Non-current biochip comprises non-current biochip of non-open type and open non-current chip, and the most widely used at present is open non-current chip.
Present open non-current chip is the open non-current chip of single reactor, and an example is based on microslide, and the chip of other newly-increased structure is made, do not had to activated, point sample.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 moving medium outside and carry out (for example hydrojet cleaning) under flow state.The shortcoming of this kind chip be when less, the probe array of 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 chip are developed into how open non-current 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, owing to there is not the liquid zone of going out, reaction medium cannot be placed in the directed flow state, thereby can not carry out operate continuously, 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 crossed contamination 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 disrupter with anti-cross-contamination, the disrupter of dismantling during scanning is to adapt to the scanner requirement.
Another example of open non-current multiple reactor biochip is " multiple-sample microarray biochip " (number of patent application 01112783.X).Its probe array, when to be fixed on one be 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 polyester film single face glue material behind application of sample, need remove enclosed material before going out sample, washing, then application of sample, airtight, reaction again, remove airtightly again, finish to detection reaction so repeatedly, operation is complexity very.
2, biochip flows
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 little logical (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 filling hole and the liquid storage tank of a plurality of openings are 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 process, 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, osmosis device for example, 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 the fixed 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 medium flowing continuously, all finish until reaction.
Three-dimensional chip, the i.e. chip that forms in the three-dimensional structure that probe stationary is to form on the chip end face.An example is fixing a lot of " chips " that are added with the small polyvinyl lactam gel strips formation of catching molecule on a slide glass end face, and each gel strips can be used for target DNA, RNA and proteinic analysis.
2) open mobile biochip
Liquid medium can continuous flow react, clean, reaction result does not have the open mobile biochip that the covering open architecture is directly read by peripheral equipment by the probe array top, " a kind of mobile biochip and using method thereof the " (number of patent application: 02133622.9) that example is invented for us.This chip has overcome the structure and the Operating Complexity of non-open type chip, the shortcoming of the medium illiquidity of open chip, brought into play the medium flowable of mobile chip as much as possible, the advantage of the constructional simplicity of open non-current chip and scanning simplification has improved detection sensitivity, has reduced the operating time and reduced the production cost of chip unit reactor and detected cost.
Although above-mentioned various biochip respectively has many good qualities, all are the biochip of probe molecule carrier with the solid substrate at present, all only are fixed with probe on a surface of solid phase carrier substrate.In the present invention, the biochip that only is fixed with probe on a surface of substrate is defined as the single face biochip, is called for short the single face chip.In actual production process, whole outside surfaces of substrate often live through activation treatment again, and the condition of carrying out probe-immobilized reaction is all arranged.Thereby the utilising efficiency of substrate useful area waits to improve in the existing single face chip.
In addition, all are that the biochip preparation and the application apparatus of probe molecule carrier serve as according to invention, design and manufacturing with the single face chip all with the solid substrate at present, have the problem of raising the efficiency similarly.
Summary of the invention:
The object of the present invention is to provide a kind of multilateral biochip, particularly a kind ofly can utilize the substrate surface useful area as much as possible, on the substrate unit volume, fix probe as much as possible and/or form the biochip of reactor as much as possible, detect the cost of required biochip and improve detection efficiency to reduce unit.The invention still further relates to the relative unit of the preparation and the application of corresponding biochip of the present invention.
The object of the present invention is achieved like this:
The present invention is by respectively in the end face of chip stereo structure, bottom surface and side in all, more than one, a plurality of of determining of quantity go up fixing identification molecular probes, utilize the useful area and the volume of solid phase carrier substantially, detect cost and improve detection efficiency to reduce.
In the present invention, substrate is defined as being used as in the biochip parts or the structure of solid phase carrier with stationary probe; Probe tile is defined as parts or the structure that stationary probe forms on substrate in the biochip.Substrate is a three-dimensional arrangement, but usually its all or most surfaces have the activity of stationary probe.The three-dimensional number with surface of substrate depends on its geometrical shape.For example, the spherical shape substrate has only a surface, the surface that square substrates has six areas to equate, and circular sheet (sheet) shape substrate then has end face and bottom surface and area smaller lateral of area maximum, or the like.And the most widely used substrate at present is less highly relatively rectangular thin plate (sheet) shape substrate, has end face and bottom surface and four area smaller lateral (see figure 1)s of area maximum.
In the present invention, the multiaspect probe tile in all in the three-dimensional end face of substrate, bottom surface and side more than one, be fixed with the probe card of probe on the quantity determine a plurality of; Multilateral biochip is called for short the multiaspect chip for containing the biochip of a multiaspect probe card at least.By having active substrate, for example in all of the three-dimensional end face of the cube shaped substrate of activatory, bottom surface and four side more than one a plurality of go up stationary probes, can make the multiaspect probe card, for example six probe cards; By using at least one multiaspect probe card, for example six probe cards can be made one the six thing chip of looking unfamiliar.
A kind of multilateral biochip is characterized in that: in all in the end face of its three-dimensional arrangement, bottom surface and side, more than one, be fixed with the identification molecular probe on the quantity determine a plurality of.
Biochip of the present invention contains a multiaspect probe card at least, promptly in the end face of substrate three-dimensional arrangement, bottom surface and side in all, more than one, be fixed with the probe card of probe on the quantity determine a plurality of.
Probe card of the present invention contains a two-sided probe card that is fixed with probe on two faces of end face and bottom surface of substrate at least.
The structure of biochip of the present invention only contains probe card, or other structure and the parts that contain probe card and connect with probe tile by non-removable or dismountable mode, belong to or do not belong to reactor.
The present invention contains on the end face and bottom surface of the contained two-sided probe card of biochip of probe card, fix one or more a plurality of probe array respectively, and form one or more a plurality of open reactive device or non-open type reactor, flow reactor or non-current reactor with corresponding construction.
End face and the structure on the bottom surface that the present invention contains the biochip of probe card are symmetric or asymmetric, the reactor that is positioned on arbitrary overlaps, partially overlaps or do not overlap with reactor on this face in the projection on its opposite, the structure of arbitrary reactor that it is contained all with the one side, or not entirely with the one side.
The present invention is connected respectively to form the parts of two-sided biochip with two-sided probe card, is two and is separated into two parts or one again with regard to separated components, one after connecting with probe card or probe card substrate still is not separated into two parts after with probe card or probe card substrate connection before connecting with probe card or probe card substrate.
A kind of new bio chip of the present invention comprises that A, its reactor are the open reactive device; Wetting ability by liquid deadweight, mechanical power, water wetted material is arranged in B, its reactor and control mobile liquid phase reaction medium based on one or more effect or combined action of all effects of water-absorbent of the absorbent material of capillary phenomenon; C, described absorbent material and water wetted material is included in or be not included in the chip fluid structure; D, described water wetted material comprise organic hydrophilic material, various hydrophilic coating, natural macromolecular material and derivatives thereof such as inorganic hydrophilic materials such as silicon, aluminum compound, polyacrylamide compounds; E, described absorbent material comprise that all kinds of kapillaries that water-wetted surface arranged, stationery, film class, fibre-bearing are or/and the porous solid phase material of hydrophilic mineral compound; F, described hydrophobic material comprise the material that multiple organic compound and nanometer technology thereof are made.
Magnetic force, the tackiness agent that mechanical force, magnet or the electro-magnet that multiaspect chip of the present invention comprises probe card, reactor isolation structure, can link or remove banded as required provides with gravity, elastic force, screw or anchor clamps provides provides separate a kind of of sticking cohesive force etc. or-kind more than act as the non-irreversible tightness system that realize on the basis.
Multiaspect chip of the present invention comprises: A, its two-sided probe card and forming with it between the parts of reactor connects by tackiness agent; B, according to some step in the testing process to the needs of chip physical dimension, can pass through the aqueous solution, ethanol or/and organic solvent to connecting swelling, the dissolved physics chemical action of tackiness agent, hyperacoustic physical action, described adhering junction is removed in the machine-processed acting in conjunction of one or more of mechanical force etc.; C, according to some step in the testing process to the needs of chip physical dimension, also can excise the parts that form reactor on the two sides with probe card partially or completely by one or more the mechanical technology of grinding, cutting, cutting etc.
The material of substrate of the present invention is made into sheet (film) rear top surface for all and the bottom surface can be activated equally and in order to the material of the probe of fixed biologically chip, comprise: inorganic materials such as glass, silicon and silicon compound etc., organic high molecular polymers such as polypropylene, polyvinyl chloride, polystyrene, nylon and nitrocellulose, and surface coverage has the organic materials of metals such as gold and silver, metallic compound.
The present invention discerns whole process or the part steps that reads in detection reaction with to detected result, and more than one a plurality of two-sided probe cards or two-sided biochip are connected into the combined biochip of a total width less than 35mm by methods such as chimeric, bonding, mechanical location.
The two-sided probe stationary device that two-sided biochip is carried out probe stationary of the present invention comprises: simultaneously or side by side respectively same substrate top surface and bottom surface are not carried out the operation of stationary probes such as point sample or printing, A, in the time can carrying out the operation of two-sided probe stationary simultaneously, its structure comprises the operating system that can carry out probe stationary simultaneously respectively to same substrate at least; B, carry out probe stationary when operation at priority branch face, its structure comprises a system that same substrate top surface and bottom surface can be carried out location swap at least.
The device that two-sided biochip is carried out detection reaction operation of the present invention comprises: A, the reactor that is positioned at end face and bottom surface on the same biochip is carried out detection reaction operations such as application of sample, washing respectively; Its structure includes the structure of reactor generation crossed contamination on the reactor that can avoid on the biochip end face and the bottom surface at least; B, its detection reaction operation to reactor on same biochip end face and the bottom surface can side by side not carried out respectively simultaneously yet; C, in the time can carrying out the operation of two-sided detection reaction simultaneously, its structure comprises the operating system that can carry out the detection reaction operation respectively to the reactor on same biochip end face and the bottom surface at least; D, carry out detection reaction when operation at priority branch face, its structure comprises a transposition system that can carry out location swap to same chip end face and bottom surface at least.
The device that detection reaction result to two-sided biochip of the present invention discerns and reads comprises: A, can be respectively to be positioned at all one's life thing chip end face and the bottom surface on the reaction result of reactor discern and read; Its structure comprises the structure of the consistency that guarantees itself and two-sided biochip structure at least; B, its identification that reaction result that is positioned at the reactor on two faces of biochip is carried out and read can side by side not carried out respectively simultaneously yet; C, when carrying out two-sided identification and read simultaneously, its structure comprises at least and can discern the operating system that reads to the reactor that is positioned on biochip end face and the bottom surface respectively; D, discern when reading at priority branch face, its structure comprises a transposition system that a biological chip end face and bottom surface can be carried out location swap at least.
Of the present invention a kind of with above-mentioned detection reaction operating gear and the detection reaction automated installation combined of reading devices as a result, can be simultaneously or non-ly side by side carry out detection reaction operation and detection reaction result respectively and discern and read to being positioned at reactor on two faces of thing chip in all one's life.
In the present invention, two-sided probe tile is for being fixed with the probe card (see figure 2) of probe on substrate top surface and bottom surface; Two-sided biochip, being called for short two-sided chip is the biochip that contains two-sided probe card.By having active thin plate (sheet) shape substrate, for example two faces of maximum of activatory circle or rectangular thin plate (sheet) shape substrate are stationary probe on end face and the bottom surface, can make the two-sided probe card of circle or rectangle; By two-sided probe card, for example the two-sided probe card of circle or rectangle can be made two-sided biochip.
Two-sided biochip among the present invention, its structure is formed two kinds: A, only contain the two-sided chip of a two-sided probe card, for example form a two-sided chip by the two-sided probe tile that forms at activatory 75mm * 25mm * 1.0mm slide bottom surface commonly used at present and end face stationary probe; B, contain a two-sided probe card and belong to or do not belong to other structure of reactor and the two-sided chip of parts, two-sided probe card and described structure and parts connect by non-removable or dismountable mode, and described structure and examples of members comprise: isolation structure, add spline structure, fluid structure, passage, detection cell, locating device, spacing device, power set, flow rate of liquid formation and control device, tripping device etc.
Can fix one (Fig. 2) or more than one a plurality of probe array on the end face of the two-sided biochip among the present invention and the bottom surface respectively, and form one or more a plurality of reactors (Fig. 3 to Figure 13), thereby form a two-sided biochip of multiple reactor with corresponding construction.Reactor on the two-sided biochip among the present invention can be the open reactive device, also can be non-open reactive device; Can be the narrow sense open reactive device in whole testing process, all opened, also can be open broad sense open reactive device in the part testing process only; Can be the movable reactor of liquid phase medium directed flow is arranged in whole or part testing process, also can be non-movable reactor.For example, fix 16 probe arrays on two-sided biochip end face and the bottom surface respectively, and on each face, form 16 open reactive devices with corresponding construction (for example isolation structure and fluid structure), constitute one the 32 two-sided open biochip of reactor (seeing Fig. 7,8,9).
Two-sided biochip among the present invention, the structure on its end face and the bottom surface can be symmetries, also can be asymmetric that the example of asymmetric two-sided biochip is seen Fig. 4,5.Two-sided biochip among the present invention is positioned at the reactor on arbitrary of its end face and the bottom surface, can overlap, partially overlap or not overlap with reactor on this face in the projection on its opposite, for example arrangement (seeing Fig. 3,4,5,6) that can misplace mutually of the probe array on the two sides.Be positioned at the arbitrary reactor on arbitrary of its end face and the bottom surface in the two-sided biochip among the present invention, its structure can be all with one side, or not entirely with one side, the adding the liquid zone inlet and can drive on the bottom surface of reactor on the end face for example, or the like.
In the two-sided biochip of the present invention, be connected respectively to form the parts of two-sided biochip with the probe card two sides, can be two before connecting with probe card or probe card substrate with regard to separated components, two plastic barrier plates for example; Also can be parts that are separated into two after same substrate connects again, for example one be closed schistose perforated plastic division board, rises respectively and substrate top surface, bottom surface cut syndeton between two pages after bonding again at Zhe; Can also be parts that after same substrate connects, are not separated into two yet, for example can be with the polypropylene fat reactor division board on two faces, injection moulding is bonded on two faces of substrate for closing one of schistose.
In present single face chip, its reactor is that the chip of open reactive device has application widely.In the two-sided biochip of the present invention, its reactor is the chip of open reactive device, also can be widely used owing to simple to operate.Open two-sided biochip of the present invention, the moving of liquid phase reaction medium in its reactor can be the wetting ability by liquid deadweight, power machine, water wetted material and realize based on the formation such as the water-absorbent of the absorbent material of capillary phenomenon and one or more the combined action of effect of controlling all effects of flow velocity; Described absorbent material and water wetted material are included in or are not included in the chip fluid structure; Described water wetted material comprises organic hydrophilic material, various hydrophilic coating, natural macromolecular material and derivatives thereof such as inorganic hydrophilic materials such as silicon, aluminum compound, polyacrylamide compounds; Described absorbent material comprises that all kinds of kapillaries that water-wetted surface arranged, stationery, film class, fibre-bearing are or/and the porous solid phase material of hydrophilic mineral compound.
Two-sided biochip among the present invention can be dismountable two-sided biochip, promptly on its probe tile and Qi Ding, the two sides, the end between the reactor isolation structure, can link or remove the two-sided chip of the non-irreversible connection of banded as required.The non-irreversible tightness system that this class two-sided chip generally includes probe card, reactor isolation structure and probe tile is sealed; Magnetic force, the tackiness agent that described non-irreversible tightness system provides for mechanical force, magnet or the electro-magnet that provides based on gravity, elastic force, screw or anchor clamps provides separates one or more the device (see us another invent " a kind of biochip of detachable use " number of patent application 02113540.1) of mechanism of action of sticking cohesive force etc.
Two-sided biochip among the present invention, its probe card and form with it between the parts of reactor and can connect by tackiness agent, and can remove described adhering junction as required.According to the needs of some step to chip physical dimension, can pass through the aqueous solution, ethanol or/and organic solvent to connecting swelling, dissolved physics, the chemical action of tackiness agent, hyperacoustic physical action, described bonding connection is removed in the machine-processed acting in conjunction of one or more of mechanical force etc.According to the needs of some step to chip physical dimension, also can excise the parts that form reactor on the two sides with probe card partially or completely by one or more the mechanical technology of grinding, cutting, cutting etc., for example during the fluorescent scanning step scanner of some signals to the restriction of chip height.
Two-sided biochip among the present invention is discerned in detection reaction with to detected result in the whole process or part steps that reads, more than one a plurality of two-sided probe card or two-sided biochip can connect the combined biochip of total width of formation less than 35mm by methods such as chimeric, bonding, mechanical location, to raise the efficiency.For example, after detection reaction is finished, be of a size of 75mm * 8.3mm * 1.0mm or two and be of a size of 75mm * 12 by removing bonding three of obtaining, the two-sided probe tile of 5mm * 1.0mm can be entrenched in the rectangular tank that is of a size of 75mm * 25mm * 1.0mm, scans again.
In order to prepare efficiently and to utilize two-sided biochip, the present invention also provides relative unit, comprises a kind of two-sided some model machine that can be used for preparing two-sided biochip, a kind of two-sided detection reaction operating gear that can be used for two-sided biochip and a kind ofly can discern the device that reads to the detection reaction result of two-sided biochip.
The two-sided probe stationary device that carries out probe stationary among the present invention can simultaneously or side by side not carry out the operation of stationary probes such as point sample or printing to same biochip end face and bottom surface respectively.In the time can carrying out two sides probe stationary operation simultaneously, its structure comprises the operating system that can carry out probe stationary simultaneously respectively to same biochip at least, for example with substrate plane perpendicular to horizontal plane, the point sample syringe needle is parallel to horizontal plane point sample on substrate top surface and bottom surface respectively; When carrying out two sides probe stationary operation formerly, its structure comprises a system that same biochip or substrate top surface and bottom surface can be carried out location swap at least, for example earlier substrate top surface is upwards carried out point sample, substrate can be made the device that 180 degree rotate along its major axis by one then, make its bottom surface upwards carry out point sample.
The present invention also provides a kind of device that can carry out two-sided detection reaction operation to the two-sided biochip among the present invention, can carry out detection reaction operations such as application of sample, washing respectively to the reactor that is positioned at end face and bottom surface on the same biochip; Its structure includes the structure of reactor generation crossed contamination on the reactor that can avoid on the biochip end face and the bottom surface, for example water-absorbing material, isolation structure, discharge opeing soleno-, extraction system etc. at least.This two-sided detection reaction operating gear can side by side not carry out the detection reaction operation to the reactor on same biochip end face and the bottom surface respectively simultaneously yet; In the time can carrying out the operation of two-sided detection reaction simultaneously, its structure comprise at least can be respectively the reactor on same biochip end face and the bottom surface be carried out the detection reaction operation operating system for example with the chip plane perpendicular to horizontal plane, sample injector is parallel to horizontal plane and carries out operations such as application of sample, Xian Di respectively on chip end face and bottom surface; When successively carrying out the detection reaction operation respectively, its structure comprises a transposition system that can carry out location swap to same chip end face and bottom surface at least, for example earlier the chip end face is upwards carried out the detection reaction operation, chip can be made the device that 180 degree rotate along its major axis by one then, make its bottom surface upwards carry out the detection reaction operation.
The present invention also provides a kind of can carry out two-sided identification and the device that reads to the detection reaction result of the biochip among the present invention, can discern and read the reaction result that is positioned at the reactor on biochip end face and the bottom surface respectively; Its structure comprises at least and guarantees itself and the structure of the consistency of two-sided biochip structure, for example the sample introduction window of scanner and scanning room's size with scan cooperating of focal length and physical dimension.This two-sided reading devices can yet can side by side not discerned and read the reaction result that is positioned at the reactor on two faces of biochip respectively simultaneously; In the time can carrying out two-sided identification simultaneously and read, its structure comprises at least and can discern the operating system that reads to the reactor that is positioned on biochip end face and the bottom surface respectively; When minute successively carrying out two-sided identification and read, its structure comprises a transposition system that a biological chip end face and bottom surface can be carried out location swap at least.
Multilateral biochip among the present invention with existing single face biochip relatively, has following advantage:
1) utilized the useful area of substrate as much as possible;
2) under the prerequisite of same number of probes and number of reactors, reduced chip volume as much as possible;
3) chip cost that can the unit's of effectively reducing test item and improve the chip service efficiency.
Accompanying drawing and drawing explanation:
Each face synoptic diagram of Fig. 1 substrate
The two-sided probe tile synoptic diagram of a kind of two-sided stationary probe array of Fig. 2
The closed two-sided biochip knot that flows of a kind of independent liquid in-out passage 8 reactors of Fig. 3
Composition
A kind of independent feed liquor of Fig. 4, the closed two-sided biology that flows of common liquid outlet channel 8 reactors
Chip
The closed two-sided biochip that flows of a kind of common liquid in-out passage 8 reactors of Fig. 5
The open non-current two-sided biochip of several multiple reactors of Fig. 6
The open two-sided biochip of 32 reactors that flows of a kind of common liquid outlet channel of Fig. 7
The two-sided biochip of Fig. 8 open two-way flow of a kind of 32 reactors
The two-sided biochip of Fig. 9 open uniflux of a kind of 32 reactors
Two kind of 64 two-sided biochip of the open two-way flow of reactor of Figure 10
A kind of many feed pathway of Figure 11, the closed two-sided biology that flows of single liquid outlet channel 2 reactors
Sheet
The two-sided comobion chip of several flowing-type band of Figure 12 detection cell
The knot that can be undone by a pull formula device of the open two-sided biochip that flows of a kind of 16 reactors of Figure 13
Embodiment:
1 one kinds of non-open types of embodiment two-sided biochip embodiment that flows:
The structure of the two-sided biochip in this example is seen Fig. 3, there is one determining that stationkeeping has the probe card of probe in the middle of the chip, two blocks of moulding plastics plates that pond and groove are arranged on it are pasted on the two sides of probe card, each face of probe card has 4 independently reactors, each reactor comprises a reaction tank and access way independently, imports and exports and is sealed by the single face non-setting adhesive before using.During use, if only use a part of reaction tank, only the pressure sensitive adhesive of used reactor passageway part need be taken off getting final product, remaining reaction tank can use later on.Application of sample and washing use supporting special-purpose loading device or bull application of sample rifle to carry out.Reactor is placed in the unit clamp, is close to water-absorbing material or connects liquid container under the chip outlet.When using 8 reactors at the same time, in each application of sample mouth, add quantified sample according to the speed of setting, target molecule in the sample is combined on the seizure molecule of bag quilt, the unconjugated sample composition of flush away, the affinity molecule that adds the rhodamine mark, the molecule of quantitative rhodamine mark is combined on the target molecule that is captured, after reaction is finished, take the moulding plastics sheet that paste on the probe card two sides off, detect with fluorescent scanning instrument or CCD device, obtain qualitative and quantitative detected result after the Computer Processing.
2 one kinds of open two-sided biochip embodiment of embodiment:
The structure of the two-sided biochip in this example is seen Fig. 4, there is one determining that stationkeeping has the probe card of probe in the middle of the chip, the moulding plastics plate of two porose and grooves on it is pasted on the two sides of probe card, one deck plastic film is reversibly sticked in the outside of plastic plate, each face of probe card has 4 independently reactors, each reactor comprises a reaction tank and independently feed pathway and common liquid outlet channel, imports and exports and is sealed by the single face non-setting adhesive before using.During use, only need reactor passageway part plastic film is taken off and can be used.Application of sample and washing use supporting special-purpose loading device or bull application of sample rifle to carry out.Reactor is placed in the unit clamp, makes its liquid adding hole last, liquid outlet is close to water-absorbing material and is connect liquid container under the chip outlet down.In use, in each application of sample mouth, add quantified sample according to the speed of setting, sample flows downward along the liquid feeding passage bottom, target molecule in the sample is combined on the seizure molecule of bag quilt, the unconjugated sample composition of flush away, add fluorescein-labeled affinity molecule, quantitative rhodamine tagged molecule is combined on the target molecule that is captured, throw off that layer plastic film that stick in the outside of plastic plate, be that available fluorescent scanning instrument or CCD device detect, computer processing data obtains qualitative and quantitative detected result.
Embodiment 3 non-open type biochip embodiment
The structure of the two-sided biochip in this example is seen Fig. 5, there is one determining that stationkeeping has the probe card of probe in the middle of the chip, the moulding plastics plate of two porose and grooves on it is pasted on the two sides of probe card, one deck plastic film is reversibly sticked in the outside of plastic plate, each face of probe card has 4 independently reactors, each reactor comprises a reaction tank and common lead channel, independently liquid in-out passage and one section common liquid outlet channel, and loading slot and liquid outlet are sealed by the single face non-setting adhesive before using.During use, only need reactor passageway part plastic film is taken off, reactor is placed in the unit clamp, make its liquid adding hole last, liquid outlet is close to water-absorbing material and is connect liquid container and can use under the chip outlet down.Use supporting special-purpose loading device or multi-channel loading rifle to carry out during application of sample, adding washings and fluorescent marker only needs that imbibition and fluorescent marker solution are added liquid bath equably and gets final product.In use, in each application of sample mouth, add quantified sample according to the speed of setting, sample flows downward along the liquid feeding passage bottom, target molecule in the sample is combined on the seizure molecule of bag quilt, the unconjugated sample composition of flush away, add the rhodamine mark the quantitative rhodamine tagged molecule of affinity molecule be combined on the target molecule that is captured, throw off that layer plastic film that stick in the outside of plastic plate, be that available fluorescent scanning instrument or CCD device detect, computer processing data obtains qualitative and quantitative detected result.
Embodiment 4 open biochip embodiment:
The structure of the two-sided biochip in this example is seen Fig. 6, and chip is made by the porous organic material plate that glass substrate both sides are stained with different shape.Organic materials plate hole intermediary is determined the stationkeeping probe, and each face of probe card can have a plurality of independently reactors, and each reaction tank is a reactor, no liquid in-out passage.Reaction tank is sealed by the single face non-setting adhesive before using.During use, only the plastic film of the face of use need be taken off getting final product.Application of sample and washing use supporting special-purpose loading device or bull application of sample rifle to carry out.Use operation similar to the ELISA microwell plate, in each reaction tank, add quantified sample, target molecule in the sample is combined on the seizure molecule of bag quilt, the unconjugated sample composition of flush away, add the rhodamine mark affinity molecule, quantitative rhodamine tagged molecule is combined on the target molecule that is captured, and detects with fluorescent scanning instrument or CCD device, and computer processing data obtains qualitative and quantitative detected result.
The embodiment 5 open two-sided biochip embodiment that flow
The structure of the two-sided biochip in this example is seen Fig. 7, there is one determining that stationkeeping has the probe card of probe in the middle of the chip, two blocks of moulding plastics plates that 16 holes and respective channel are arranged on it are pasted on the two sides of probe card, make each face of probe card form 8 reactors of 2 row, each reactor comprises a reaction tank and independently adds the liquid zone, liquid outlet channel, the outside of plastic plate and outlet stick one deck non-setting adhesive plastic film.During use, plastic film taken off getting final product.Application of sample and washing use supporting specific equipment or bull application of sample rifle to carry out.Reactor is placed in the unit clamp, makes it add the liquid zone last, liquid outlet is close to water-absorbing material and is connect liquid container down down.In use, in each application of sample mouth, add quantified sample according to the speed of setting, sample flows downward along the liquid feeding passage bottom, target molecule in the sample is combined on the seizure molecule of bag quilt, the unconjugated sample composition of flush away, add the rhodamine mark affinity molecule, quantitative rhodamine tagged molecule is combined on the target molecule that is captured, throw off that layer plastic film that stick in the outside of plastic plate, be that available fluorescent scanning instrument or CCD device detect, computer processing data obtains qualitative and quantitative detected result.
The embodiment 6 open two-sided biochip embodiment that flow
The structure of the two-sided biochip in this example is seen Fig. 8, there is one determining that stationkeeping has the probe card of probe in the middle of the chip, two blocks of moulding plastics plates that 16 holes and respective channel are arranged on it are pasted on the two sides of probe card, make each face of probe card form 8 reactors of 2 row, each reactor comprises a reaction tank and independently adds the liquid zone, with the opposite liquid outlet channel of outflow direction, respectively there are two isolating trenches the liquid outlet channel both sides, and one deck non-setting adhesive plastic film is sticked in the top of reactor and outlet.During use, plastic film taken off getting final product.Application of sample and washing use supporting specific equipment or bull application of sample rifle to carry out.Reactor water is lain in the unit clamp, make its liquid outlet be close to water-absorbing material, water-absorbing material connects the container of waste liquid.In use, in each application of sample mouth, add quantified sample according to the speed of setting, sample flows along adding liquid zone, reaction tank, liquid outlet channel, enter water-absorbing material, target molecule in the sample is combined on the seizure molecule of bag quilt, the unconjugated sample composition of flush away, add the rhodamine mark affinity molecule, quantitative rhodamine tagged molecule is combined on the target molecule that is captured, detect with fluorescent scanning instrument or CCD device, computer processing data obtains qualitative and quantitative detected result.
Embodiment 7 detachable two-sided biochip embodiment
The structure of the two-sided biochip in this example is seen Fig. 6, respectively is fixed with a plurality of independently reactors that 8 probe arrays form by a glass substrate two sides, and each reactor has only a reaction tank, no liquid in-out passage.The probe card that chip uses preceding two sides to be fixed with probe array is placed in the protection box, takes out during use to be placed on the special electromagnetic worktable.Electromagnetic worktable is provided with the O-ring seal of the non-use face of protection below; there is the rubber plate of the carrying magnetic material of 8 circular holes to cover on the working face by one on it during use; with the solenoid energising of electromagnetic worktable, promptly formed the biochip of single face 8 reactors.Its operation steps is with embodiment 4.
Embodiment can separate the agglutinating biochip for 8 one kinds
The structure of the two-sided biochip in this example is seen Fig. 8, and each fixes a plurality of independently reactors that 16 probe arrays form by a glass substrate two sides, and each reactor has the semicircle of a reaction tank, liquid feeding and fluid ditch to form.The probe card (Fig. 8 intermediary dotted portion) that during making one block length bar shaped two sides is fixed with probe array is bonded in the middle of the polyester sheet in two 16 holes, makes the biochip of one 32 reactor.Its operation steps is substantially with embodiment 6, the different biochips of making one 32 reactor.Its operation steps is substantially with embodiment 6, and different is, before putting into scanner, the plastic molding board of chip both sides reversible adhesive thrown off, and scans to get final product again.
Claims (16)
1, a kind of multilateral biochip is characterized by: in all in the end face of its three-dimensional arrangement, bottom surface and side, more than one, be fixed with the identification molecular probe on the quantity determine a plurality of.
2, according to a kind of multilateral biochip of claim 1, it is characterized in that: described biochip contains a multiaspect probe card at least, promptly in the end face of substrate three-dimensional arrangement, bottom surface and side in all, more than one, be fixed with the probe card of probe on the quantity determine a plurality of.
3, according to a kind of multilateral biochip of claim 1 or 2, it is characterized in that: described probe card contains a two-sided probe card that is fixed with probe on two faces of end face and bottom surface of substrate at least.
4, according to a kind of multilateral biochip of claim 1 or 2, it is characterized in that: the structure of described biochip only contains probe card, or other structure and the parts that contain probe card and connect with probe card by non-removable or dismountable mode, belong to or do not belong to reactor.
5, according to a kind of multilateral biochip of claim 1 or 3, it is characterized in that: on the end face and bottom surface of the described contained two-sided probe card of biochip that contains probe card, fix one or more a plurality of probe array respectively, and form one or more a plurality of open reactive device or non-open type reactor, flow reactor or non-current reactor with corresponding construction.
6, a kind of multilateral biochip according to claim 5, it is characterized in that: the end face and the structure on the bottom surface that contain the biochip of probe card are symmetric or asymmetric, the reactor that is positioned on arbitrary overlaps, partially overlaps or do not overlap with reactor on this face in the projection on its opposite, the structure of arbitrary reactor that it is contained all with the one side, or not entirely with the one side.
7, according to claim 1 or 3 described a kind of multilateral biochips, it is characterized in that: be connected respectively to form the parts of two-sided biochip with two-sided probe card, be two and before connecting, after connecting, be separated into two parts or one again and still be not separated into two parts after with probe card or probe card substrate connection with probe card or probe card substrate with regard to separated components, one with probe card or probe card substrate.
8, a kind of multilateral biochip according to claim 1 and 2 is characterized in that: A, its reactor are the open reactive device; The hydrophobicity of wetting ability by liquid deadweight, mechanical power, water wetted material, hydrophobic material is arranged in B, its reactor and control mobile liquid phase reaction medium based on one or more effect or combined action of all effects of water-absorbent of the absorbent material of capillary phenomenon; C, described absorbent material and water wetted material is included in or be not included in the chip fluid structure; D, described water wetted material comprise organic hydrophilic material, various hydrophilic coating, natural macromolecular material and derivatives thereof such as inorganic hydrophilic materials such as silicon, aluminum compound, polyacrylamide compounds; E, described absorbent material comprise that all kinds of kapillaries that water-wetted surface arranged, stationery, film class, fibre-bearing are or/and the porous solid phase material of hydrophilic mineral compound; F, described hydrophobic material comprise the material that multiple organic compound and nanometer technology thereof are made.
9, a kind of multilateral biochip according to claim 1 and 2 is characterized in that: magnetic force, the tackiness agent that mechanical force, magnet or the electro-magnet that it comprises probe card, reactor isolation structure, can link or remove banded as required provides with gravity, elastic force, screw or anchor clamps provides provides separate a kind of of sticking cohesive force etc. or-kind more than act as the non-irreversible tightness system that realize on the basis.
10, a kind of multilateral biochip according to claim 1 and 2 is characterized in that: A, its two-sided probe card and forming with it between the parts of reactor connects by tackiness agent; B, according to some step in the testing process to the needs of chip physical dimension, can pass through the aqueous solution, ethanol or/and organic solvent to connecting swelling, the dissolved physics chemical action of tackiness agent, hyperacoustic physical action, described adhering junction is removed in the machine-processed acting in conjunction of one or more of mechanical force etc.; C, according to some step in the testing process to the needs of chip physical dimension, also can excise the parts that form reactor on the two sides with probe card partially or completely by one or more the mechanical technology of grinding, cutting, cutting etc.
11, a kind of multilateral biochip according to claim 1 and 2, it is characterized in that: the material of its substrate is made into sheet (film) rear top surface for all and the bottom surface can be activated equally and in order to the material of the probe of fixed biologically chip, comprise: inorganic materials such as glass, silicon and silicon compound etc., organic high molecular polymers such as polypropylene, polyvinyl chloride, polystyrene, nylon and nitrocellulose, and surface coverage has the organic materials of metals such as gold and silver, metallic compound.
12, a kind of multilateral biochip according to claim 1 and 2, it is characterized in that: discern whole process or the part steps that reads in detection reaction with to detected result, more than one a plurality of two-sided probe cards or two-sided biochip are connected into the combined biochip of a total width less than 35mm by methods such as chimeric, bonding, mechanical location.
13, a kind of multilateral biochip according to claim 1, it is characterized in that: the described two-sided probe stationary device that two-sided biochip is carried out probe stationary comprises: simultaneously or side by side respectively same substrate top surface and bottom surface are not carried out the operation of stationary probes such as point sample or printing, A, in the time can carrying out the operation of two-sided probe stationary simultaneously, its structure comprises the operating system that can carry out probe stationary simultaneously respectively to same substrate at least; B, carry out probe stationary when operation at priority branch face, its structure comprises a system that same substrate top surface and bottom surface can be carried out location swap at least.
14, a kind of multilateral biochip according to claim 1 is characterized in that: the described device that two-sided biochip is carried out detection reaction operation comprises: A, the reactor that is positioned at end face and bottom surface on the same biochip is carried out detection reaction operations such as application of sample, washing respectively; Its structure includes the structure of reactor generation crossed contamination on the reactor that can avoid on the biochip end face and the bottom surface at least; B, its detection reaction operation to reactor on same biochip end face and the bottom surface can side by side not carried out respectively simultaneously yet; C, in the time can carrying out the operation of two-sided detection reaction simultaneously, its structure comprises the operating system that can carry out the detection reaction operation respectively to the reactor on same biochip end face and the bottom surface at least; D, carry out detection reaction when operation at priority branch face, its structure comprises a transposition system that can carry out location swap to same chip end face and bottom surface at least.
15, a kind of multilateral biochip according to claim 1 is characterized in that: the device that described detection reaction result to two-sided biochip discerns and reads comprises: A, can be respectively to be positioned at all one's life thing chip end face and the bottom surface on the reaction result of reactor discern and read; Its structure comprises the structure of the consistency that guarantees itself and two-sided biochip structure at least; B, its identification that reaction result that is positioned at the reactor on two faces of biochip is carried out and read can side by side not carried out respectively simultaneously yet; C, when carrying out two-sided identification and read simultaneously, its structure comprises at least and can discern the operating system that reads to the reactor that is positioned on biochip end face and the bottom surface respectively; D, discern when reading at priority branch face, its structure comprises a transposition system that a biological chip end face and bottom surface can be carried out location swap at least.
16, a kind of multilateral biochip according to claim 1, it is characterized in that: described a kind of with above-mentioned detection reaction operating gear and the detection reaction automated installation combined of reading devices as a result, can be simultaneously or non-ly side by side carry out detection reaction operation and detection reaction result respectively and discern and read to being positioned at reactor on two faces of thing chip in all one's life.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02134007 CN1432655A (en) | 2002-11-04 | 2002-11-04 | Multilateral biochip |
| PCT/CN2003/000055 WO2003106999A1 (en) | 2002-06-01 | 2003-01-22 | Biochip with maximization of the reactor number |
| AU2003203334A AU2003203334A1 (en) | 2002-06-12 | 2003-01-22 | Biochip with maximization of the reactor number |
| US10/517,452 US20060057580A1 (en) | 2002-06-12 | 2003-01-22 | Biochip with maximization of the reactor number |
| EP03701458A EP1519191A4 (en) | 2002-06-12 | 2003-01-22 | Biochip with maximization of the reactor number |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02134007 CN1432655A (en) | 2002-11-04 | 2002-11-04 | Multilateral biochip |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1432655A true CN1432655A (en) | 2003-07-30 |
Family
ID=27628625
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 02134007 Pending CN1432655A (en) | 2002-06-01 | 2002-11-04 | Multilateral biochip |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1432655A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100406887C (en) * | 2006-01-10 | 2008-07-30 | 华东理工大学 | Tubular biochip |
| CN102520183A (en) * | 2011-10-20 | 2012-06-27 | 上海裕隆生物科技有限公司 | Sealed protein film chip |
| CN107764994A (en) * | 2017-11-21 | 2018-03-06 | 南京罗岛纳米科技有限公司 | The device spread using magnetic bead control DNA in the sequencing experiment of solid nano hole |
| CN108786941A (en) * | 2018-05-26 | 2018-11-13 | 大连大学 | A kind of preparation method of novel magnetic self assembled three-dimensional paper chip |
-
2002
- 2002-11-04 CN CN 02134007 patent/CN1432655A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100406887C (en) * | 2006-01-10 | 2008-07-30 | 华东理工大学 | Tubular biochip |
| CN102520183A (en) * | 2011-10-20 | 2012-06-27 | 上海裕隆生物科技有限公司 | Sealed protein film chip |
| CN107764994A (en) * | 2017-11-21 | 2018-03-06 | 南京罗岛纳米科技有限公司 | The device spread using magnetic bead control DNA in the sequencing experiment of solid nano hole |
| CN108786941A (en) * | 2018-05-26 | 2018-11-13 | 大连大学 | A kind of preparation method of novel magnetic self assembled three-dimensional paper chip |
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