CN107345932A - The special cheap cholera diagnosis micro fluidic device of sap flow process mode - Google Patents
The special cheap cholera diagnosis micro fluidic device of sap flow process mode Download PDFInfo
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Abstract
The present invention relates to a kind of special cheap cholera diagnosis micro fluidic device of sap flow process mode, belong to analysis testing field.Serial problem be present if for making the substrate of cholera diagnosis micro-fluidic chip in dimethyl silicone polymer i.e. PDMS that is cheap and easily processing.This case main points are, the selected PDMS with ecosystem surface of substrate, micron silica granule filler is filled up in its pipeline of the chip, its function of the filler includes supporting pipeline inwall, and, with the set of hydrophily fluid channel come the hydrophobic pipeline of compensatory script, and, extruding, cover inner-walls of duct face and thereby reduce the chance that large biological molecule contacts with the internal face, the chip terminal attaches installing miniature ultrasonic transducer units, ultrasonic intensity rapid decrement in short distance is reached to the strong absorption of ultrasonic wave using PDMS, thereby in the both ends induced synthesis interfacial tension difference of the chip, and then sample liquid stream is facilitated to be flowed along its pipeline of chip to the terminal direction.
Description
Technical field
The present invention relates to a kind of special cheap cholera diagnosis micro fluidic device of sap flow process mode, belong to analysis testing field.
Background technology
The micro-fluidic cholera diagnostic techniques background of associated multi-channel, may refer to the invention patent application cases such as CN 200910150930.4.
Only for the microflow control technique overall general picture of itself, it may refer to the monograph " diagram Microfluid based Lab on a chip " that famous micro-fluidic expert Mr. Lin Ping Cheng goes out not long ago, the monograph is published via Science Press, the monograph to past of microflow control technique, now, and, vision of the future etc. etc., suffer from long discussion that is detailed, being deep into detail.
So, the Important Problems of this case that to have a talk below concern.
The basic framework of micro-fluidic chip, including the cover plate for being etched with the substrate of conduit and fitting together therewith, fluid course on the substrate, before upper cover plate is assembled, see to be exactly some conduits on apparent, to wait until after covering cover plate thereon, just really closure forms the fluid course, and the conduit inner surface of the conduit forms described fluid course together with the part cover plate that surround the conduit；So, it is clear that assemble the fluid course after completing, the major part of its inner surface area is the inner surface area of that conduit, and in other words, the state or property of the conduit inner surface substantially determine the integrality or property of the fluid course；Therefore say, the inner surface state or inner surface property of this conduit of the structure on substrate are key factors；In principle, any material that can be kept or keep its solid forms substantially, it can be used to make substrate and cover plate, for example can act as substrate and the material of cover plate can be monocrystalline silicon piece, quartz plate, sheet glass, high polymer such as dimethyl silicone polymer, polymethyl methacrylate, makrolon etc.；Certainly, the selection of substrate and the selection of cover plate be able to can also be differed with identical；From the point of view of material consumption, manufacture difficulty and application popularization prospect etc. etc., not small difference, the especially selection of that substrate between these materials be present, have a great influence.
In various substrate making materials, dimethyl silicone polymer, that is PDMS, comparatively very easily shaping, making conduit is extremely simple on such substrate, and the lower cost for material, substrate is made with the polydimethyl siloxane material, conduit is being suppressed or etched thereon, and is being engaged with the cover plate that the cheap material such as glass or polypropylene or other plastic sheets makes, and is a kind of more satisfactory selection seemingly；Certainly, patch material can also select to use cheap polydimethyl siloxane material：So, this substrate selection is the scheme of polydimethyl siloxane material, and material is extremely cheap, and making is extremely simple, seems and should also be as being extremely easy to popularize, promotes.
But thing is really not so simple.
One, this polydimethyl siloxane material, abridge the material that alphabetical PDMS is referred to, itself it is a kind of strong hydrophobic material, conduit is built on this material, if without being operated for the modified of the conduit surface, so, after overall assembling is completed, after covering cover plate, because the conduit its inner surface in structure occupies the inner surface of most fluid course, so, its strong hydrophobic property of the PDMS conduits inner surface, it is deciding factor, it can cause similar to the aqueous solution the fine liquid stream of polar liquid by becoming very difficult, its flow resistance is big, even in general Micropump is all difficult to promote, certainly, if cover plate also selects to use the PDMS material, so, problem is substantially identical, it is similar；Therefore, among prior art, modification is modified particular for the conduit inner surface on the PDMS material, is necessary operation；So, this is pretty troublesome for the modified operation of PDMS conduit inner surfacesThat falls nor this problem, forms serious technical puzzlement, be another problem：PDMS polymer molecules inside its body phase of this PDMS material substrate have the characteristic for diffusing to the surface, migrating automatically, the characteristic that PDMS polymer molecules are diffused to the surface, migrated automatically inside this substrate body phase, the state after modification by its inner surface of that conduit of surface modifying and decorating will be caused can not to maintain the sufficiently long time, holding time for its inner surface state of the conduit after that is surface-modified is substantially only sufficient to the time needs for completing laboratory internal test experiments；In other words, by surface modification or the PDMS conduit inner surfaces of surface modification, the surface state that is formed can not be lasting after it is modified or after saying modification, but soon automatically tends to or say and become surface state before surface is modified again, and the strong hydrophobic surface state of that script is returned in the shorter time, so, just think, such micro-fluidic chip can largely make, mass storage, be widely popularized, and answer is apparent, it is that is, impossible.Conduit on this PDMS material, if not doing surface modification, it can not pump and pass through similar to the fine liquid stream of polar solvent of the aqueous solution, chip also cannot just use；And if having done surface modification, its state after modifying can not be persistently kept again, or equally can not popularization and application.
According to the literature, there is a kind of expedient solution, be that a small amount of surfactant is added in sample to be tested solution, so as to which during test, dynamic, temporary transient effective surface hydrophilic layer is built temporarily in the PDMS conduits inner surface；However, due to the amphipathic characteristic of surfactant, the introduced surfactant of the program is inevitable also to occur combination with the tested composition in sample solution simultaneously so that tested composition can not be detected normally or it is detected ratio and dubiously reduced；The surfactant is possibly even fully wrapped around by tested composition with micelle form so that tested composition can not be detected or identify；Therefore, this kind adds the scheme of surfactant into sample solution, is far from a preferable solution.
So, how to accomplish that substrate can either be made using cheap PDMS material, and can release the conduit inner surface decorating state can not persistently, chip can not largely make, largely lay in and then be widely popularized such a puzzlement for making the numerous professionals in this area be entangled with for a long time, the highly difficult problem that exactly one its obvious technology barrier can not despise.
Be present many year in the highly difficult problem, so far, not yet properly settled.
Secondly, the PDMS material of non-surface modification, above it is stated that, its surface is strongly hydrophobic, this strong hydrophobic material surface and also another problem, that is exactly, this strong hydrophobic PDMS surfaces can adsorb large biological molecule, also, these adsorbed large biological molecules can also further depression further on PDMS surfaces, gradually fall into gradually deep, until heavy be trapped within the body phase of PDMS substrates, in fact, this process, be partly also due to PDMS material body phase interior polymer molecule have diffuse to the surface, caused by travel motion；Such case, it can also be explained from another angle, i.e., continuously from inside PDMS body phases to those polymer molecules of its diffusion into the surface, migration, its result moved, it is little by little to be involved in those within the body phase of PDMS substrates by the large biological molecule of adsorption, briefly, these adsorbed large biological molecules are exactly to be swallowed up by PDMS substrate body phases；So, this PDMS substrates body phase swallows up the phenomenon of large biological molecule, the influence caused by it, necessarily causes the severe deviations of all kinds of test data of experiment for being related to large biological molecule.
As described above, the problem of PDMS substrates, is, its not only adsorption large biological molecule, and swallow up large biological molecule, so, as the large biological molecule of experiment test object, its disappearance will not stop because surface saturation is adsorbed, but it is constantly adsorbed, also constantly swallowed up.
On PDMS substrates in related experiment test process its body phase constantly swallow up test associated biomolecule macromolecular phenomenon, it is to say that another kind, which is explained, substantial amounts of Minute pores in PDMS body phases be present, associated biomolecule macromolecular is by after adsorption, depression enters these Minute pores, and then is swallowed up；However, inventor thinks, those can allow the air molecule of miniature scale to squeeze into Minute pores therebetween, and not equal to saying that they also can directly allow the large biological molecule of relative large scale to enter, both difference on yardstick are huge, must not make sweeping generalizations.Explanation is bypassed, in any case, the large biological molecule as dependence test analysis object is adsorbed by PDMS substrate conduits inner surface, and then is constantly swallowed up by PDMS substrate body phases, and this is the phenomenon of known objective reality.
In order to prevent swallow up effect of this PDMS substrate bodies relative to large biological molecule, it can be addressed from absorption of the containment PDMS surfaces to large biological molecule, method is chemically modified modification aiming at the PDMS material surface, for in the case of using PDMS as substrate material, modification exactly is chemically modified to the surface of described channel portion, the conduit inner surface being modified by chemical modification, its absorption to large biological molecule can be contained, and then avoid large biological molecule from being swallowed up by PDMS substrate body phases；But, or that old problem, that is exactly, surface state after chemical modification on PDMS material surface is modified can not persistently be kept, its process for diffusing to the surface, migrating automatically of polymer molecule inside the PDMS substrate body phases, that conduit inner surface state being modified by surface chemical modification soon can be become again to strong hydrophobic and strong adsorption large biological molecule the state of script, in other words, no matter how professionals in the field turn from side to side, and its conduit inner surface of the PDMS substrates is always rapidly to strong hydrophobic surface state evolution.
So, how can either obtain that PDMS material price is extremely cheap, substrate makes extremely easy benefit, and can is enough reached contains the absorption process of the PDMS substrate conduit inner surfaces to large biological molecule for a long time, and then prevent the effect of swallowing up of PDMS substrate body Relative biological macromoleculars, so that related chip manufactured goods are able to maintain that a prolonged enough, rational shelf-life, it is exactly a very intractable problem.The problem equally makes the numerous professionals in this area be entangled with, perplex for a long time as another problem addressed above, and the problem is equally the highly difficult problem that its obvious technology barrier can not despise.Also be present many year in the problem, so far, also not yet properly settled.
Thirdly, the polydimethyl siloxane material, namely PDMS material, active force very little wherein between polymer molecule, the polymer molecule of low polymerization degree inside its body phase is in constantly into the dynamic process of surface migration, therefore, chip comprising PDMS substrate materials is after it has been formed, the surface topography in its inner-walls of duct face of chip can change because described low polymerization degree polymer molecule moves about, pours into the surface, the change of its pattern be somewhat similarly to Rheological Deformation, trickling deformation or deformation of creep institute may caused by pattern change；In the higher PDMS material of some low polymerization degree component ratios, this kind is somewhat similarly to the phenomenon of Rheological Deformation, trickling deformation or the deformation of creep, and can show must be than more significant；The dynamic of inner-walls of duct surface topography after its shaping of the chip that this kind includes PDMS substrates changes property, namely the described property for being somewhat similarly to Rheological Deformation or the property of trickling deformation or the property of the deformation of creep, the word of rheology one is applied mechanically in this case, integration, the also referred to as rheological equationm of state or Rheological Deformation property, the dynamic of corresponding inner-walls of duct face pattern changes, and this case is also referred to as rheology；As described above, certain Rheological Deformation property as described above that its own has because of this kind of material, its manufactured goods actually can at leisure Rheological Deformation and cause the manufactured goods total form generation to change；Influence caused by its Rheological Deformation property,It is subtle in terms of macroscopic perspective,But,For the very fine micro-fluidic chip of its internal structure,The rheological equationm of state can but cause bigger influence,Therefore,The fluid course namely the pipeline formed during pre-production,Because the wall of its tube chamber of pipeline is mainly the wall of PDMS materials,So,The cross-sectional area of the pipeline can actually taper into because of rheology over time,In other words,Due to the rheology,It the more can become the more narrow for natively finer its tube chamber of the pipeline that liquid sample flows through,In the case of flow time is sufficiently long,The tube chamber of the even pipeline can partly be closed or fully closed,And then make it that sample fluid course is thoroughly blocked,The degree for closing or fully closing with being even also not reaching to its luminal part of pipeline,Its fluid passage that can be provided of that pipeline narrows because of rheology,So,In the case where pipeline its inner surface is exactly strongly hydrophobic originally,Aqueous sample liquid is just more difficult to by becoming narrower micro-channel so because of rheology,So,How substrate rheology influence is resisted,Maintain the basic framework of the pipeline that gross distortion does not occur for a long time,And,Keep the long-term unobstructed of the pipeline,The problem of being exactly a urgent need to resolve.
The content of the invention
The technical problems to be solved by the invention are, one package solution is provided, solves a series of problems addressed above totally, and, the solution is applied to cholera diagnosis multichannel micro-fluidic chip field, a kind of new cholera diagnosis is formed and uses multichannel micro-fluidic device.
The present invention solves the technical problem by following scheme,The device that the program provides is a kind of special cheap cholera diagnosis micro fluidic device of sap flow process mode,The structure of the micro fluidic device includes multichannel micro-fluidic chip,The structure of the micro-fluidic chip includes being bonded to each other the substrate and cover plate of installing together,The substrate and cover plate are plate object or tablet,Contain the channel structure via mould pressing process or etching technics formation in that face towards the cover plate of the substrate,The substrate also containing be connected with the channel structure and pierce the substrate via mould pressing process,The window structure that etching technics or simple drilling technology are formed,It is bonded to each other the substrate being installed together and has been built into the micro-fluidic chip containing pipeline configuration and the liquid pool structure being attached thereto jointly with the cover plate,The locations of structures of the pipeline is located at the interface zone that the substrate is bonded to each other with the cover plate,Its side of the window is blocked by the cover plate and opposite side opens,The locations of structures of the window is exactly the locations of structures of the liquid pool,The quantity of the liquid pool is three,Its locations of structures of two liquid pools therein is located at the sample introduction end of the micro-fluidic chip,Its locations of structures of a remaining liquid pool is located at the terminal of liquid flowing in its chip when the actual sample introduction of the micro-fluidic chip is tested,The terminal is located remotely from each other with the sample introduction end,One end of the pipeline via be similarly positioned in the manifold shape turnout of the interface zone being bonded to each other respectively with the Liang Ge liquid pools UNICOM positioned at sample introduction end,The other end of the pipeline and a remaining liquid pool UNICOM for the terminal positioned at the micro-fluidic chip,And,The working electrode that is sequentially respectively installed in the pipeline on diverse location and to electrode and reference electrode,The working electrode is made up of conductive electrode and the gold size sensitive membrane for having embedded cholera specific antigen being attached on the conductive electrode,The construction of the pipeline is in parallel construction,The pipeline in parallel construction is made up of four lateral parallel connections,The quantity of the working electrode is four,The installation position of four working electrodes is respectively in four laterals,And,Specific antigen in its top layer gold size sensitivity membrane structure of four working electrodes is the four kinds of cholera antigenic substances that can be specifically bound to cholera antibody respectively,Four kinds of antigenic substances are cholera TP0821 antigens and cholera TP0319 antigens and cholera TP0624 antigens and cholera O139 antigens respectively,Its material of the working electrode is gold material or thermal decomposition conducting polymer material,Sheet or thread is presented in its pattern of the working electrode,Emphasis is,Its material of the substrate is dimethyl silicone polymer material,Its surface of the substrate is the surface of primary form,The surface of the primary form its be intended to refer to the surface of the not primary form of the material by any surface chemical modification or any surface chemical modification,The structure of the micro fluidic device also includes miniature ultrasonic transducer units,And,Higher-order of oscillation electric signal transmission cable,One end of the higher-order of oscillation electric signal transmission cable links together with the miniature ultrasonic transducer units,The miniature ultrasonic transducer units are installed in the position of the cover plate of the micro-fluidic chip or the neighbouring terminal of substrate with attaching；Its major function of the miniature ultrasonic transducer units is in the actual sample introduction test of micro-fluidic chip, utilize the difference on the sample introduction end and the distance between the terminal and the miniature ultrasonic transducer units installation position difference and its ultrasonic intensity experienced, difference between its interfacial tension of sample introduction end described in induced synthesis and the terminal its interfacial tension, interfacial tension difference between the micro-fluidic chip both ends can form pressure gap between the both ends of the micro-fluidic chip, and the pressure gap can drive sample solution to the end flow；Softness simultaneously has its function of the substrate of the dimethyl silicone polymer material of elasticity including with its property to the strong absorption of ultrasonic wave, ultrasonic wave is absorbed strongly, and the rapid decrement of ultrasonic intensity is thereby realized within micro-fluidic chip terminal to the limited short distance between the sample introduction end；And; many silica dioxide granules; many silica dioxide granules are filled in the pipeline; its tube chamber of the pipeline is filled up by many silica dioxide granules; for its particle size range of the silica dioxide granule between 10 microns and 200 microns, the silica dioxide granule is silica crystalline particles, silica glass granule or silica composition its inorganic glass particles of shared percentage by weight more than 80%.
Its particle diameter of the silica dioxide granule can be the particle diameter that the basis between 10 microns and 200 microns is actually needed and is arbitrarily designated, such as 10 microns, 30 microns, 70 microns, 100 microns, 150 microns or 200 microns of the particle diameter, etc..
The scope of further preferred its particle diameter of the silica dioxide granule is between 100 microns and 200 microns.
Its pattern of the silica dioxide granule is unlimited, and the silica dioxide granule for example can be spheric granules, rod-shaped particles, cuboid particle or any amorphous granular.
The various silica dioxide granules manufacturing technology of itself is known technology.
Various forms, the silica dioxide granule market of all size are on sale.
The silica dioxide granule can also customize to specialized factory.
The preferred scope of its internal diameter of pipeline is between 500 microns and 1000 microns；But compared to above-mentioned preferable internal diameter of the pipeline scope, more tiny internal diameter of the pipeline or thicker internal diameter of the pipeline are also what this case was allowed.
The gold size sensitive membrane is to be sufficiently mixed chitosan gold size solution and cholera specific antigen solution uniformly, with point sample instrument point sample or is coated on specified structure position, and form its drying and forming-film.Cholera specific antigen in the gold size sensitive membrane is the cholera antigen of horseradish peroxidase or glucose oxidase mark, the gold size sensitive membrane has been included as fixing above-mentioned each cholera specific antigen and introducing complementary medium therein, and the complementary medium such as chitosan, cellulose acetate, gelatin be therein a kind of or their mixture.
The pipeline and the lateral and the manifold shape turnout in the microfluidic chip structure, its internal diameter size may each be arbitrarily selected size, but, for as far as possible less with the consideration of prepare liquid sample and reduction reagent loss etc., the passage of capillary level is preferably selected on the pipeline and the lateral and the manifold shape turnout, and the passage of the capillary level implies that its internal diameter passage suitable with the internal diameter of the capillary on ordinary meaning.The shape of cross section of its inner passage of capillary can be arbitrary shape, the shape of cross section is for example circular, oval, square, rectangle, bar shaped, can certainly the linear of bending arbitrarily be present, and, with the extension of pipeline, the shape of cross section of different parts can also allow to be different shapes the interior shape of the capillary.Only for the word of capillary one, its art-recognized meanings is known.
What is be related in structure is the electrode of microsize to electrode and reference electrode, and its electrode shape may each be arbitrarily selected shape, the arbitrarily selected shape such as square piece shape, rectangular patch, strip or round sheet etc..The art-recognized meanings to electrode and the reference electrode vocabulary of itself are known.
It is related to several liquid pools in this case microfluidic chip structure, the liquid pool is pond shape or the scrotiform construction for transitional liquid storage, its shape of the inner chamber of each liquid pool may each be arbitrarily selected shape, the cavity shape such as cylindrical empty cavity-like, square column type cavity-like, oblong cavity shape or spherical hollow space shape etc..The size of the liquid pool can be arbitrarily selected size, still, in order to be preferably capable of the liquid pool of the microminiature matched with capillary with prepare liquid sample and reduction reagent loss, the liquid pool less as far as possible.
It is known only for professional of the word of ultrasonic transducer one art-recognized meanings of itself for ultrasonic technology field.
Various sizes, variously-shaped ultrasonic transducer are commercially available；Its size of commercially available miniature ultrasonic transducer units may diminish to the magnitude only calculated with millimeter.
It is known general technology for the professional in ultrasonic technology field for itself only with regard to miniature ultrasonic transducer units its technique for fixing on general industry application solid body surface.This case is not to this expansion superfluous words.
Only with regard to naked PDMS substrates itself conduit molding or lithographic technique for, be open-and-shut known technology；Similarly, the technology of hole-opening is even more known simple technique on naked PDMS substrates.This case is not also to this expansion superfluous words.
The industrial products market of involved its all size of higher-order of oscillation electric signal transmission cable is on sale.
The structure of the micro fluidic device can also include higher-order of oscillation electric signal generator；Its other end of the higher-order of oscillation electric signal transmission cable can be connected with the higher-order of oscillation electric signal generator.
The involved higher-order of oscillation electric signal generator technology of itself, it is simple and known for the professional in ultrasonic technology field；The higher-order of oscillation electric signal generator can customize to ultrasonic instrument specialized factory.
The preferred scope of its specified ultrasonic wave transmission power of the miniature ultrasonic transducer units is between 2 milliwatts and 2000 milliwatts；The preferred scope of the frequency of its ultrasonic wave operationally launched of the miniature ultrasonic transducer units is between 100KHz and 12MHz.
This case device can further include some annexes certainly, and the annex such as multiple tracks electrochemical workstation etc., the art-recognized meanings of the multiple tracks electrochemical workstation are known.Each working electrode for being related in this case microfluidic chip structure and to electrode and reference electrode etc., can respectively via it is corresponding it is special get lines crossed coupled with the corresponding interface of the multiple tracks electrochemical workstation.It is described that special to get lines crossed be private cable for each the corresponding interface of each electrode and the multiple tracks electrochemical workstation is coupled to each other.The micro-fluidic chip in this case device, its structure can also include micro-valve, and the quantity of the micro-valve is unlimited, and according to being actually needed, the micro-valve can be installed in the position of any required installation in the microfluidic chip structure；For the word of micro-valve one for the professional of micro fluidic chip technical field, the art-recognized meanings of itself are known；The micro-valve itself manufacturing technology and the use of technology is also known；The component that the micro-valve is not required.
The diameter of the working electrode can allow to be that any setting is easily installed the suitable diameter used, it is however recommended to or say preferable its scope of the diameter between 0.1 micron to 2000 microns；The length of the working electrode can allow to be that any setting is easily installed the length used, it is however recommended to or to say the preferable length its scope be between 1 micron to 15000 microns.
The gold size sensitive membrane of the working electrode surface layer is installed in by spraying or point sample instrument point sample or the coating of other appropriate process, its thicknesses of layers can allow be any setting treat sample measuring liquid occur electrical signals response thickness, it is however recommended to thickness preferable thickness is between 10 nanometers and 200 nanometers in other words.
The cover plate in chip structure, its material can allow to be any electrical insulating property material, such as：Polypropylene, glass, polymethyl methacrylate, dimethyl silicone polymer, etc., in order to make smaller size of micro-fluidic chip, for example make the micro-fluidic chip of the super-small of only 2.0 centimetres to 3.0 centimetres of length, and extremely fast decay to ultrasonic wave is realized in the extremely short distance, can preferably dimethyl silicone polymer be used as cover plate.Certainly, selection is used as the cover plate using dimethyl silicone polymer on large-sized micro-fluidic chip, and this case technical scheme is allowed.
Positioned at two liquid pools at the sample introduction end of the micro-fluidic chip, itself and the air line distance between a remaining liquid pool for the micro-fluidic chip terminal can be arbitrarily selected suitable distance as needed, but the preferred value of the distance is between 3 centimetres and 7 centimetres.
Described its thickness of cover plate and substrate can allow be any setting the thickness for being easy to assembling, the thickness of recommendation or to say preferable thickness be between 1.0 millimeters and 5.0 millimeters.Less thickness is advantageous to save material.
The application method of this case micro-fluidic chip：
Itd is proposed first based on this case and the first public new liquid stream driving principle, among its application running of this case micro-fluidic chip, the new liquid stream driving method is determined completely without involving any additional Micropump.
The interfacial tension difference that this case is formed between micro-fluidic chip both ends caused by the ultrasonic wave, driving liquid stream is flowed in the capillary channel of the four-way micro-fluidic chip, and four kinds of cholera antibody are detected respectively using four-way electrochemical analytical instrument.
Corresponding four kinds of cholera antibody is detected with four kinds of cholera antigens, and four kinds of cholera antigens corresponding with being detected with four kinds of cholera antibody similarly, can cholera diagnosis；The principle of its foundation is, necessarily antigen, antibody and is deposited in cholera patient, and mutual Reversible binding, reversible conjugate is formed, therefore, antibody and thereby cholera diagnosis are detected with antigen, with being gone to detect antigen and cholera diagnosis with antibody, diagnostic purpose can be reached.Certainly, its corresponding electrode sensitive decorative layer of different means technically and differs.
The specific detection of this case micro-fluidic chip is as follows using step：
1st, blood serum sample liquid is added in micro-pipe road, under ultrasonic wave driving, the cholera specific antigen for the corresponding horseradish peroxidase-labeled that various cholera antibody molecules are embedded by gold size sensitive membrane on electrode surface in each passage captures.
2nd, the cholera specific antigen of horseradish peroxidase-labeled forms immune complex with the cholera antibody in blood serum sample.
3rd, using multi-channel electrochemical analyzer, the electron mediators such as catechol are added, using curent change caused by the above-mentioned reaction of amperometric detection, are derived from the species and content of various analytes.
4th, result is subjected to comprehensive analysis, comprehensive diagnos is carried out to cholera antibody.
It is an advantage of the invention that, in the terminal of the micro-fluidic chip, its close position installs miniature ultrasonic transducer units with attaching, launch low-power with the miniature ultrasonic transducer units, the ultrasonic wave of high-frequency band, simultaneously, utilize its strong absorbability to ultrasonic wave of dimethyl silicone polymer substrate, in shorter distance, namely, in from the terminal to the very short distance of only several centimeters yardsticks the sample introduction end, reach the rapid decrement of ultrasonic intensity, the difference of the interfacial tension is thereby caused at the both ends of the micro-fluidic chip, and then, utilize the pressure gap between its both ends for being formed of the difference of the interfacial tension between the both ends, sample liquid stream is driven to be flowed in the pipeline to the terminal direction.By this case liquid stream drive scheme, the equipment of traditional Micropump etc has been altogether dispensed with；The micro-fluidic chip of Micropump is eliminated, its structure is more succinct, and its production process is less, and its cost of manufacture is lower, and this kind of succinct structure is more beneficial for the low cost application for reaching micro-fluidic chip.
Its scheme of this case and by the pipeline except electrode installation take up space in addition to all clearance spaces all filled up with the silica dioxide granule.Those are filled in the silica dioxide granule in pipeline, this case is to its overall abbreviation silica dioxide granule filler, its function includes support, withstands the tube chamber of the pipeline its inwall, so that the tube chamber of the pipeline because of the rheology from narrowing, prevent its reduced cross-sectional area of the tube chamber of the pipeline or even close, so as to maintain the basic framework of the pipeline that serious deformation does not occur for a long time.
Numerous silica dioxide granule entities are mutually banked up under this case framework together at random in the pipeline, the function of the silica dioxide granule filler, certainly also include with the hydrophilic surface of its silica dioxide granule, there is the space of hydrophilic nmature using mutual formed complications are continuous and its inner surface that is mutually close together by water-wetted surface of each adjacent silicon dioxide particle, in the hydrophilic fluid channel of the pipeline Inner Constitution network morphology, although this fluid channel with hydrophilic nmature that is tortuous but being continuous all the time, so, inside the tube chamber of the pipeline simultaneously and a plurality of fluid channel deposited its synthesis, integrated, the effect of cumulative superposition in other words, it is the equal of the relatively fine hydrophilic capillary channel of caliber；Its presence of the continuous hydrophilic fluid channel of the complications, counteracts the flow resistance for liquid sample caused by the strong hydrophobic property in its surface of the PDMS substrates of the primary form to a large extent；In other words, it is water that because of liquid sample, it, which accounts for the composition of maximum ratio, liquid sample is substantially exactly the aqueous solution, therefore, the presence of the silica dioxide granule filler, can significantly overcome with the unmodified PDMS substrates of hydrophobic property and surface its to the aqueous solution it is incompatible, repel and barrier effect, and then be greatly reduced belong to properties of Aqueous Solution sample liquid stream its be advanced through the resistance of pipeline.
Under this case framework, inside the tube chamber of the pipeline, the area of its lumen wall wall of former pipeline, rigid because of the silica dioxide granule filler ties up, its area of the surface of part hydrophobic property that still can also be exposed on lumen wall wall is already dramatically reduced, and the area on its still exposed part surface for belonging to hydrophobic property has been far smaller than the wall surface area of the hydrophobic property of the lumen wall wall in the presence of no silica dioxide granule filler；So, under this case framework, in its lumen of the pipeline, its remaining hydrophobic surface increases surface newly with hydrophilic part, and that it is superimposed, comprehensive, summation, cumulative technique effect, is to form the surface for tending to be hydrophilic on the whole；In other words, inside the tube chamber of the pipeline, its interfacial tension between sample solution of the part surface of remaining hydrophobic property, its interfacial tension between sample solution of surface is increased newly plus the part of hydrophilic nmature, that it is superimposed, comprehensive, summation, cumulative technique effect, is so that the interfacial tension that the synergy of its solid-liquid interfacial tension inside the tube chamber of the pipeline levels off between its tube chamber inner surface of capillary glass tube and sample solution.
Therefore, exist in the pipeline under this case framework for having stated silica dioxide granule filler, rely on this case sample liquid stream drive scheme simultaneously, it becomes possible to the driving to sample liquid stream is reached with relatively low ultrasonic power, the test liquid flows to the end flow with this case mechanism drives.
On the other hand,Due to its rheological equationms of state of the PDMS as substrate material,The silica dioxide granule filler being filled in the pipeline,Gradually can more tightly it be wrapped up by the pipeline wall of constantly Rheological Deformation and the PDMS materials promoted to arest neighbors free space,This process eventually causes those part silica dioxide granules for pressing close to the lumen wall wall to be stuck in original place or embedded in original place,The part be stuck in original place or silica dioxide granule that embedding in-situ silica dioxide granule is banked up with being mutually closely packed together with remaining is each other together with incarceration,Due to this reason,The silica dioxide granule filler just will not move in the pipeline easily,Silica dioxide granule therein, which is also substantially all, is locked in original place,Therefore the stream framework of the micro-fluidic chip can be kept for a long time.
The particle size range of its particle of this case silica dioxide granule filler is between 10 microns and 200 microns,Compared to general organic molecule,For general large biological molecule,The particle diameter of its particle of this case silica dioxide granule filler can be rated as huge,Due to its huge particle diameter,And the inner surface of the surface of its polarity and the pipeline of strong hydrophobic PDMS materials, which mutually can not perhaps be said, mutually to be melted,So,The huge silica dioxide granule of this kind of particle diameter can not be adsorbed by the inner surface of the pipeline of PDMS materials,It can not more be swallowed up by the inner surface of the pipeline of PDMS materials,The huge silica dioxide granule of this kind of particle diameter surely not be fully sunk in easily or sink to completely PDMS materials its among intrinsic many Minute pores,And because above it is stated that the rheology the reason for,The silica dioxide granule filler can be stuck in original place or perhaps embedded in original place without moving easily.
Inside the tube chamber of the pipeline, its lumen wall wall of former pipeline is entirely the surface of hydrophobic property originally, as described above, under this case framework, rigid because of the silica dioxide granule filler ties up, its area of the surface of part hydrophobic property that still can also be exposed on lumen wall wall is already dramatically reduced, and the area on its still exposed part surface for belonging to hydrophobic property has been far smaller than the wall surface area of the hydrophobic property of the lumen wall wall in the presence of no silica dioxide granule filler；The reason for because of the rheology, it is close to those silica dioxide granules of lumen wall wall, little by little it is partially embedded into or is partly absorbed among the lumen wall wall, silica dioxide granule among the state its towards the part surface of lumen wall wall with having occurred and that the lumen wall wall of matching deformation is brought into close contact, so, the matching is deformed and actually can not contacted with the part wall that silica particles are brought into close contact with flowing through the sample solution of pipeline having occurred and that in lumen wall wall, that is, the wall of this part can not produce suction-operated to the large biological molecule therein that flows through the sample solution of pipeline and organic molecule.Based on above-mentioned mechanism, so, because fill up the pipeline the silica dioxide granule filler its presence, the overwhelming majority of its lumen wall wall of the pipeline is tightly covered, these described walls tightly covered can not contact with flowing through the sample solution of the pipeline, only remaining fraction by silica dioxide granule, its surface is not brought into close contact, the hydrophobic surface tightly covered may contact with sample solution, in other words, under this case framework, its direct touch opportunity with hydrophobic PDMS walls of large biological molecule and organic molecule in sample solution is significantly reduced, thus, its adsorptive hindrance and interference of swallowing up to large biological molecule and organic molecule of the lumen wall face of PDMS materials is greatly reduced；As described above, this case scheme is advantageous to exclude or weakens the adsorptive hindrance and swallow up interference, be advantageous to be lifted the reliability of correlation analysis test data.
As described above,This case silica dioxide granule filler,Its function actually includes the effect for being similar to the inner surface of pipeline progress chemical modification for PDMS materials,Functioning as its this respect of this case is into the surface of hydrophilic nmature by the inner surface of pipeline of the PDMS materials by the surface modification of hydrophobic property,But,With in general,Its hydrophilic chemical decorative layer retention time of usual PDMS surface chemical modifications is short,Hydrophilic effect can not keep situation prolonged enough different,The huge silica dioxide granule filler of particle described in this case,Its particle being stuck by rheology can not both be moved easily,The particle of its huge particle diameter can not more be swallowed up easily by the inner-walls of duct of PDMS materials,Therefore,Its from this respect is similar to from the technique effect of surface chemical modification,Its technique effect of this case,Form permanent,It can not erase,It can not consume,It is not corroded,Do not swallowed up,The hydrophilic surface reforming layer being not dissolved,It is just comparable to a kind of permanent hydrophilic modifying superficial layer built in PDMS base materials its relevant surfaces in effect.
The technical scheme of this case dissolved totally address above to dimethyl silicone polymer substrate its apply a series of related technical barriers.Based on this case scheme, the very cheap polydimethyl siloxane material of this kind is just possible to prepare in the micro-fluidic chip, production, using etc. field play bigger effect.
Brief description of the drawings
Fig. 1 is the schematic diagram of this case micro fluidic device embodiment chip part construction, show the chip internal pipeline and the structural form of each electrode and each related liquid pool under the depression angle of this structure, the miniature ultrasonic transducer units and other annexes are not depicted in the figure.
Fig. 2 is its rough outside side view of this case micro fluidic device.
In figure,1,2,10 be the different liquid pool of three installation positions respectively,3 be manifold shape turnout,4,7,11,14 be that installation position is different but four laterals parallel with one another for forming UNICOM's structure in parallel respectively,5 be working electrode of the specific antigenic substance in its top layer gold size sensitivity membrane structure being installed in lateral 4 for cholera TP0821 antigens,6 be working electrode of the specific antigenic substance in its top layer gold size sensitivity membrane structure being installed in lateral 7 for cholera TP0319 antigens,12 be working electrode of the specific antigenic substance in its top layer gold size sensitivity membrane structure being installed in lateral 11 for cholera TP0624 antigens,13 be working electrode of the specific antigenic substance in its top layer gold size sensitivity membrane structure being installed in lateral 14 for cholera O139 antigens,8 be to electrode,9 be reference electrode,15 be the substrate of dimethyl silicone polymer material,16 be cover plate,17 be higher-order of oscillation electric signal transmission cable,18 be miniature ultrasonic transducer units,19 be the sample introduction end of the micro-fluidic chip,20 be the terminal of the micro-fluidic chip；Arrow in legend indicate the micro-fluidic chip its in actual motion, by pressure at two ends difference drive, the flow direction of its sample liquid stream.
Embodiment
In this case that Fig. 1 and Fig. 2 are shown embodiment,The structure of the micro fluidic device includes multichannel micro-fluidic chip,The structure of the micro-fluidic chip includes being bonded to each other the substrate 15 and cover plate 16 of installing together,The substrate 15 and cover plate 16 are plate object or tablet,Contain the channel structure via mould pressing process or etching technics formation in that face towards the cover plate 16 of the substrate 15,The substrate 15 also containing be connected with the channel structure and pierce the substrate via mould pressing process,The window structure that etching technics or simple drilling technology are formed,It is bonded to each other the substrate 15 being installed together and has been built into the micro-fluidic chip containing pipeline configuration and the liquid pool structure being attached thereto jointly with the cover plate 16,The liquid pool is liquid pool 1,Liquid pool 2,Liquid pool 10,The locations of structures of the pipeline is located at the interface zone that the substrate 15 is bonded to each other with the cover plate 16,Its side of the window is blocked by the cover plate 16 and opposite side opens,The locations of structures of the window is exactly the liquid pool 1,Liquid pool 2,The locations of structures of liquid pool 10,The quantity of the liquid pool is three,Two liquid pools therein are the sample introduction end 19 that liquid pool 1 and liquid pool 2 its locations of structures are located at the micro-fluidic chip,A remaining liquid pool is the terminal 20 of liquid flowing in its chip when liquid pool 10 its locations of structures is located at the micro-fluidic chip actual sample introduction test,The terminal 20 is located remotely from each other with the sample introduction end 19,One end of the pipeline via be similarly positioned in the manifold shape turnout 3 of the interface zone being bonded to each other respectively with the liquid pool 1 positioned at sample introduction end 19 and the UNICOM of liquid pool 2,The other end of the pipeline and a remaining liquid pool for the terminal 20 positioned at the micro-fluidic chip are the UNICOM of liquid pool 10,And,The working electrode that is sequentially respectively installed in the pipeline on diverse location and to electrode 8 and reference electrode 9,The working electrode is made up of conductive electrode and the gold size sensitive membrane for having embedded cholera specific antigen being attached on the conductive electrode,The construction of the pipeline is in parallel construction,The pipeline in parallel construction is made up of four lateral parallel connections,The quantity of the working electrode is four,The installation position of four working electrodes is respectively in four laterals,Four working electrodes are working electrode 5 respectively,Working electrode 6,Working electrode 12,Working electrode 13,And,Specific antigen in its top layer gold size sensitivity membrane structure of four working electrodes is the four kinds of cholera antigenic substances that can be specifically bound to cholera antibody respectively,Four kinds of antigenic substances are cholera TP0821 antigens and cholera TP0319 antigens and cholera TP0624 antigens and cholera O139 antigens respectively,For specifically deploying,5 be working electrode of the specific antigenic substance in its top layer gold size sensitivity membrane structure being installed in lateral 4 for cholera TP0821 antigens,6 be working electrode of the specific antigenic substance in its top layer gold size sensitivity membrane structure being installed in lateral 7 for cholera TP0319 antigens,12 be working electrode of the specific antigenic substance in its top layer gold size sensitivity membrane structure being installed in lateral 11 for cholera TP0624 antigens,13 be working electrode of the specific antigenic substance in its top layer gold size sensitivity membrane structure being installed in lateral 14 for cholera O139 antigens,The working electrode 5,Working electrode 6,Working electrode 12,Its material of working electrode 13 is gold material or thermal decomposition conducting polymer material,The working electrode 5,Working electrode 6,Working electrode 12,Sheet or thread is presented in its pattern of working electrode 13,Emphasis is,Its material of the substrate 15 is dimethyl silicone polymer material,Its surface of substrate 15 is the surface of primary form,The surface of the primary form its be intended to refer to the surface of the not primary form of the material by any surface chemical modification or any surface chemical modification,The structure of the micro fluidic device also includes miniature ultrasonic transducer units 18,And,Higher-order of oscillation electric signal transmission cable 17,One end of the higher-order of oscillation electric signal transmission cable 17 links together with the miniature ultrasonic transducer units 18,The miniature ultrasonic transducer units 18 are installed in the position of the cover plate 16 of the micro-fluidic chip or the neighbouring terminal 20 of substrate 15 with attaching；Its major function of the miniature ultrasonic transducer units 18 is in the actual sample introduction test of micro-fluidic chip, utilize the difference on the sample introduction end 19 and the distance between the terminal 20 and the installation position of miniature ultrasonic transducer units 18 difference and its ultrasonic intensity experienced, difference between its interfacial tension of sample introduction end 19 described in induced synthesis and the terminal 20 its interfacial tension, the micro-fluidic chip both ends are that the interfacial tension difference between sample introduction end 19 and terminal 20 can form pressure gap between the both ends of the micro-fluidic chip i.e. sample introduction end 19 and terminal 20, the pressure gap can drive sample solution to be flowed to the direction of terminal 20；Softness simultaneously has its function of the substrate of the dimethyl silicone polymer material of elasticity including with its property to the strong absorption of ultrasonic wave, ultrasonic wave is absorbed strongly, and the rapid decrement of ultrasonic intensity is thereby realized within micro-fluidic chip terminal to the limited short distance between the sample introduction end；And; many silica dioxide granules; many silica dioxide granules are filled in the pipeline; its tube chamber of the pipeline is filled up by many silica dioxide granules; for its particle size range of the silica dioxide granule between 10 microns and 200 microns, the silica dioxide granule is silica crystalline particles, silica glass granule or silica composition its inorganic glass particles of shared percentage by weight more than 80%.
Arrow in legend indicate the micro-fluidic chip its in actual motion, by pressure at two ends difference drive, the flow direction of its sample liquid stream.
Miniature ultrasonic transducer units 18 and higher-order of oscillation electric signal transmission cable 17 are depicted without in Fig. 1；Also, the associate members such as the higher-order of oscillation electric signal generator and multiple tracks electrochemical workstation are depicted without in Fig. 1 and Fig. 2.
Involved miniature ultrasonic transducer units 18 are commercially available；It can also be customized to ultrasonic transducer producer.
Involved higher-order of oscillation electric signal transmission cable 17 is commercially available；It can also be customized to ultrasonic transducer producer.
Involved higher-order of oscillation electric signal generator market has the product close to needs commercially available；It can also be customized to relevant manufacturers.
Each working electrode in this example structure and electrode and reference electrode can got lines crossed respectively with the corresponding cable interface of the multiple tracks electrochemical workstation as annex or saying interface of getting lines crossed and coupling via each special cable or say respectively.
This case device is that a variety of corresponding cholera antibody are detected with a variety of cholera antigens, thereby cholera diagnosis.
Claims (10)
1. the special cheap cholera diagnosis micro fluidic device of sap flow process mode, the structure of the micro fluidic device includes leading to more
Road micro-fluidic chip, the structure of the micro-fluidic chip include being bonded to each other the substrate and cover plate of installing together, the substrate and lid
Piece is plate object or tablet, and what is formed via mould pressing process or etching technics contained in that face towards the cover plate of the substrate
Channel structure, the substrate also containing be connected with the channel structure and pierce the substrate via mould pressing process, etching technics or letter
The window structure that single drilling technology is formed, it is bonded to each other the substrate being installed together and has been built into jointly with the cover plate and contain pipeline
The micro-fluidic chip of structure and the liquid pool structure being attached thereto, the locations of structures of the pipeline are located at the substrate and mutually pasted with the cover plate
The interface zone of conjunction, its side of the window is blocked by the cover plate and opposite side opens, and the locations of structures of the window is exactly the liquid pool
Locations of structures, the quantity of the liquid pool is three, and its locations of structures of two liquid pools therein is located at the sample introduction of the micro-fluidic chip
End, its locations of structures of a remaining liquid pool are located at the end of liquid flowing in its chip when the actual sample introduction of the micro-fluidic chip is tested
End, the terminal are located remotely from each other with the sample introduction end, and one end of the pipeline is via the manifold for being similarly positioned in the interface zone being bonded to each other
Shape turnout respectively with the Liang Ge liquid pools UNICOM positioned at sample introduction end, the other end of the pipeline with positioned at the micro-fluidic chip the end
A remaining liquid pool UNICOM at end, and, the working electrode that is sequentially respectively installed in the pipeline on diverse location and right
Electrode and reference electrode, the working electrode by conductive electrode and be attached on the conductive electrode embedded cholera spy
The gold size sensitive membrane of heterogenetic antibody is formed, and the construction of the pipeline is in parallel construction, and the pipeline in parallel construction is by four branches
Pipeline is in parallel to be formed, and the quantity of the working electrode is four, and the installation position of four working electrodes is located at described four respectively
In lateral, and, the specific antigen in its top layer gold size sensitivity membrane structure of four working electrodes is that cholera is resisted respectively
Four kinds of cholera antigenic substances of physical efficiency specific binding, four kinds of antigenic substances are cholera TP0821 antigens and cholera respectively
TP0319 antigens and cholera TP0624 antigens and cholera O139 antigens, its material of the working electrode are gold materials
Or sheet or thread is presented in thermal decomposition conducting polymer material, its pattern of the working electrode, it is characterised in that its material of the substrate
Matter is dimethyl silicone polymer material, and its surface of the substrate is the surface of primary form, the surface of the primary form its be meant to
It is not by any surface chemical modification or the surface of the primary form of the material of any surface chemical modification, the micro-fluidic dress
The structure put also includes miniature ultrasonic transducer units, and, higher-order of oscillation electric signal transmission cable, the higher-order of oscillation electric signal passes
One end of transmission cable links together with the miniature ultrasonic transducer units, and the miniature ultrasonic transducer units are installed in the miniflow with attaching
Control the position of the cover plate of chip or the neighbouring terminal of substrate；Its major function of the miniature ultrasonic transducer units is in micro-fluidic core
During the test of piece actual sample introduction, using between the sample introduction end and the terminal and the miniature ultrasonic transducer units installation position away from
Deviation is different and its ultrasonic intensity for being experienced on difference, its interfacial tension of sample introduction end described in induced synthesis and the terminal
Difference between its interfacial tension, interfacial tension difference between the micro-fluidic chip both ends can the micro-fluidic chip this two
Pressure gap is formed between end, the pressure gap can drive sample solution to the end flow；It is soft and have elasticity this poly- two
Its function of the substrate of methylsiloxane material also includes with its property to the strong absorption of ultrasonic wave, and ultrasonic wave is inhaled strongly
Receive, and thereby realize the fast of ultrasonic intensity within micro-fluidic chip terminal to the limited short distance between the sample introduction end
Quick depletion；And many silica dioxide granules, many silica dioxide granules are filled in the pipeline, the pipeline
Its tube chamber is filled up by many silica dioxide granules, and its particle size range of the silica dioxide granule is micro- with 200 between 10 microns
Between rice, the silica dioxide granule is silica crystalline particles, silica glass granule or silica composition its shared weight
Measure inorganic glass particles of the percentage more than 80%.
2. the special cheap cholera diagnosis micro fluidic device of sap flow process mode according to claim 1, its feature
It is, the pipeline and the lateral and the manifold shape turnout are capillary channel.
3. the special cheap cholera diagnosis micro fluidic device of sap flow process mode according to claim 1, its feature
It is, the thermal decomposition conducting polymer is the conductive material formed by polyimides or polyacrylonitrile after anoxybiotic is heat-treated.
4. the special cheap cholera diagnosis micro fluidic device of sap flow process mode according to claim 1, its feature
Be, the width or diameter of the working electrode between 0.1 micron to 2000 microns, and, the working electrode
Length is between 1 micron to 15000 microns.
5. the special cheap cholera diagnosis micro fluidic device of sap flow process mode according to claim 1, its feature
It is, the thickness of the gold size sensitive membrane is between 10 nanometers and 200 nanometers.
6. the special cheap cholera diagnosis micro fluidic device of sap flow process mode according to claim 1, its feature
It is, the cover plate its material in structure is dimethyl silicone polymer material.
7. the special cheap cholera diagnosis micro fluidic device of sap flow process mode according to claim 1, its feature
Be, positioned at the sample introduction end of the micro-fluidic chip two liquid pools its with positioned at the micro-fluidic chip terminal this is remaining
Air line distance between one liquid pool is between 3 centimetres and 7 centimetres；Described its thickness of cover plate and substrate in structure between
Between 1.0 millimeters and 5.0 millimeters.
8. the special cheap cholera diagnosis micro fluidic device of sap flow process mode according to claim 1, its feature
Be, its particle size range of the silica dioxide granule between 100 microns and 200 microns, its inside diameter ranges of the pipeline between
Between 500 microns and 1000 microns.
9. the special cheap cholera diagnosis micro fluidic device of sap flow process mode according to claim 1, its feature
Be, the structure of the micro fluidic device also includes higher-order of oscillation electric signal generator, the higher-order of oscillation electric signal transmission cable its
The other end is connected with the higher-order of oscillation electric signal generator.
10. the special cheap cholera diagnosis micro fluidic device of sap flow process mode according to claim 1, its feature
It is, for its specified ultrasonic wave transmission power of the miniature ultrasonic transducer units between 2 milliwatts and 2000 milliwatts, this is miniature super
The frequency of its ultrasonic wave operationally launched of acoustic wave transducer is between 100KHz and 12MHz.
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Application publication date: 20171114 |