CN106290932A - Comprise the AIDS diagnosis Multichannel device of the Dual Drive coupling of hydrophobic substrate - Google Patents

Abstract

The invention relates to a double-drive coupling multi-channel device for AIDS diagnosis comprising a hydrophobic substrate, which belongs to the field of analysis and testing. There are a series of technical obstacles in using cheap and easy-to-process polydimethylsiloxane (PDMS) to make the substrate of the microfluidic chip for AIDS diagnosis; this case is aimed at this series of obstacles. The main point of this case is that the substrate is selected from PDMS with an original ecological surface, and the link-type electromagnetic fixture equipped with a micro-ultrasonic transducer is socketed and positioned in the vicinity of the sample liquid flow terminal of the microfluidic chip. The interfacial tension is reduced by ultrasonic waves, and the strong absorption ability of PDMS to ultrasonic waves is used to achieve a rapid decrease in the intensity of ultrasonic waves in a short distance, thereby forming a difference in interfacial tension at both ends of the chip, which provides a way to drive the sample liquid flow along the hydrophobic The force of the capillary channel flowing towards the terminal is also coupled and cooperates with the mechanical pumping force of the micropump contained in the structure.

Description

A dual-drive coupled multi-channel device for AIDS diagnosis including a hydrophobic substrate

technical field

The invention relates to a double-drive coupling multi-channel device for AIDS diagnosis comprising a hydrophobic substrate, which belongs to the field of analysis and testing.

Background technique

For the background of multi-channel microfluidic AIDS diagnosis technology, please refer to CN 200910151219.0 and other invention patent applications.

As far as the overall overview of microfluidic technology itself is concerned, you can refer to the monograph "Illustrated Microfluidic Chip Laboratory" published by the famous microfluidic expert Mr. Lin Bingcheng not long ago, which has been published by Science Press. The past, present, and future prospects of microfluidic technology, etc., have detailed and long-form discussions that go deep into specific details.

So, let's talk about the key issues of this case.

The basic structure of a microfluidic chip includes a substrate etched with tiny liquid flow channels and a cover sheet attached to it. The tiny liquid flow channels on the substrate, before the cover sheet is assembled, appear It looks like some microchannels. After the cover sheet is covered on them, the tiny liquid flow channel is really closed and formed. The inner surface of the channel of the microchannel together with the part of the cover sheet surrounding the microchannel constitute the micro-fluid channel together; then, obviously, the micro-fluid channel after the assembly is completed, the main part of its inner surface area is the inner surface area of the micro-groove, in other words, the micro-groove The state or property of the inner surface of the channel basically determines the overall state or property of the micro-fluid channel; therefore, the state or property of the inner surface of the micro-channel built on the substrate is a key factor; in principle, any Any material that can maintain or substantially maintain its solid state can be used to make substrates and cover sheets. For example, materials that can be used as substrates and cover sheets can be single crystal silicon wafers, quartz wafers, glass wafers, high polymer Such as polydimethylsiloxane, polymethyl methacrylate, polycarbonate, etc.; of course, the material selection of the base sheet and the cover sheet can be the same or different; from the perspective of material consumption, production difficulty and application In terms of popularization prospects and other aspects, there are not small differences between these materials, especially the selection of the substrate, which has a greater impact.

Among various materials for making substrates, polydimethylsiloxane, namely PDMS, is relatively easy to form. It is extremely simple to make micro-channels on such substrates, and the material is low in cost. It seems to be an ideal choice to make a substrate made of siloxane-based material, press or etch microchannels on it, and match it with a cover slip made of cheap materials such as glass or polypropylene or other plastic sheets; of course , the cover sheet material can also choose to use cheap polydimethylsiloxane material: then, this kind of substrate material selection is polydimethylsiloxane material, the material is extremely cheap, and the production is extremely simple, it seems that it should be Very easy to popularize and promote.

However, things are not that simple.

First, this polydimethylsiloxane material, the material referred to by the acronym PDMS, is itself a strongly hydrophobic material. Microchannels are built on this material. If the microchannels are not targeted The modification operation of the surface of the channel, then, after the overall assembly is completed, that is, after the cover is covered, because the inner surface of the micro channel in the structure occupies most of the inner surface of the liquid flow channel, then the PDMS micro channel The strong hydrophobic characteristic of the inner surface of the channel is the decisive factor, which will make it very difficult for the polar liquid flow similar to the aqueous solution to pass through, and its flow resistance is so large that even ordinary micropumps are difficult to push. Of course, If the cover sheet also chooses to use the PDMS material, then the problem is basically the same, with little difference; therefore, in the prior art, it is necessary to modify and modify the inner surface of the microchannel on the PDMS material; then , is this modification operation for the inner surface of the PDMS microchannel very troublesome? That's not the problem. What constitutes a serious technical problem is another problem: the PDMS polymer molecules in the bulk phase of the PDMS material substrate have the characteristics of automatic diffusion and migration to the surface. The characteristics of polymer molecules diffusing and migrating to the surface automatically will make the modified state of the inner surface of the microchannel modified by the surface modification unable to maintain for a long enough time, and the microgroove after surface modification The maintenance time of the inner surface state of the channel is roughly only enough to complete the time required for the internal test experiment in the laboratory; in other words, the inner surface of the PDMS microchannel after surface modification or surface modification is formed after modification The surface state of the surface does not last long, but quickly tends to or changes back to the surface state before the surface modification, and returns to the original strongly hydrophobic surface state in a relatively short period of time. Then, just imagine, Can such microfluidic chips be produced in large quantities, stored in large quantities, and widely promoted? The answer is obvious, that is, impossible. If the microchannel on the PDMS material is not surface modified, the micro flow of the polar solution similar to the aqueous solution cannot be pumped through, and the chip cannot be used; and if the surface is modified, the modification cannot be maintained for a long time. In the subsequent state, it is still impossible to promote the application.

Then, how to make substrates with cheap PDMS materials, and remove the modification state of the inner surface of the micro-channel cannot last, chips cannot be mass-produced, a large number of reserves and widely popularized. The long-term entanglement is a difficult problem with obvious technical obstacles that cannot be underestimated.

This difficult problem has existed for many years, and so far, it has not been properly solved.

Second, the PDMS material without surface modification, as mentioned above, its surface is strongly hydrophobic, and there is another problem on the surface of this strongly hydrophobic material, that is, the surface of this strongly hydrophobic PDMS will adsorb biological macromolecules. Molecules, and these adsorbed biological macromolecules will further sink on the PDMS surface, gradually sinking deeper and deeper, until they sink into the bulk phase of the PDMS substrate. In fact, this process, partly It is also caused by the diffusion and migration movement of the polymer molecules inside the bulk phase of the PDMS material to the surface; this situation can also be explained from another perspective, that is, the continuous diffusion and migration from the inside of the bulk phase of PDMS to its surface As a result of the movement of those polymer molecules, those biomacromolecules that have been adsorbed on the surface are gradually involved in the bulk phase of the PDMS substrate. Simply put, these adsorbed biomacromolecules are The bulk phase engulfs; then, the phenomenon of the PDMS substrate engulfing biomacromolecules in bulk will inevitably lead to serious deviations in various experimental test data involving biomacromolecules.

As mentioned above, the problem with the PDMS substrate is that it not only adsorbs biomacromolecules on the surface, but also engulfs biomacromolecules. In this way, the disappearance of biomacromolecules as the experimental test object will not stop due to surface saturation adsorption, but , is constantly being adsorbed, and is also constantly being engulfed.

Regarding the phenomenon that the bulk phase of the PDMS substrate continuously engulfs the relevant biomacromolecules during the relevant experimental testing process, another explanation is that there are a large number of tiny pores in the PDMS bulk phase, and the relevant biomacromolecules sink after being adsorbed by the surface. However, the inventors of this case believe that those tiny pores that can allow tiny-scale air molecules to squeeze into them does not mean that they can also directly allow relatively large-scale biomacromolecules to enter, The scales of the two are so different that they cannot be generalized. Regardless of the explanation, it is a known objective phenomenon that the biomacromolecules, which are the objects of relevant test analysis, are adsorbed by the inner surface of the microchannel of the PDMS substrate, and then continuously engulfed by the bulk phase of the PDMS substrate.

In order to prevent the engulfment of the PDMS substrate body relative to the biomacromolecule, it can be solved by curbing the adsorption of the biomacromolecule on the PDMS surface. The method is to chemically modify the surface of the PDMS material. For PDMS-based In the case of sheet materials, it is to chemically modify the surface of the micro-channel part, and the chemically modified inner surface of the micro-channel can restrain its adsorption to biological macromolecules, thereby avoiding biological macromolecules. Macromolecules are engulfed by the bulk phase of the PDMS substrate; however, there is still the old problem, that is, the surface state after chemical modification on the surface of the PDMS material cannot be maintained for a long time, and the polymer molecules inside the bulk phase of the PDMS substrate The process of automatic diffusion and migration to the surface will quickly change the state of the inner surface of the microchannel modified by surface chemical modification back to the original state of strong hydrophobicity and strong adsorption of biological macromolecules. No matter how the personnel toss, the inner surface of the microchannel of the PDMS substrate always rapidly evolves to a strongly hydrophobic surface state.

Then, how to obtain the advantages of extremely low price of PDMS materials and extremely simple substrate fabrication, and achieve long-term containment of the adsorption process of biomacromolecules on the inner surface of the microchannel of the PDMS substrate, thereby preventing the PDMS substrate from being relatively biomacromolecular. The engulfment of molecules makes it possible for related chip products to maintain a long enough and reasonable shelf life, which is a very difficult problem. This difficult problem, like another difficult problem mentioned above, has caused many professionals in this field to struggle and perplex for a long time. This difficult problem is also a difficult problem with obvious technical obstacles that cannot be underestimated. This problem has also existed for many years, and so far, it has not been properly solved.

Third, as mentioned above, the inner surface of the PDMS microchannel is strongly hydrophobic, and targeted surface chemical modification or surface chemical modification is difficult to last. It is effective to use it within a short period of time; if the relatively short expiration date has passed and it is still used forcibly, since the surface state is already close to the hydrophobic state, there must be a comparison between using the conventional micropump to drive the sample liquid flow. Large flow resistance, in this way, the sample liquid can only be forced to flow in the target direction by increasing the pumping power and pumping pressure of the micropump. Pumping pressure to pump the sample liquid flow will cause bubbling, puffing, twisting, and deformation of the microchannels at the sampling end of the substrate including the area near the sampling end, and, under such high pressure conditions, The microgroove and its periphery at the sample inlet and its vicinity are also prone to peeling between the substrate and the cover slip. In this case, the sample solution will enter between the substrate and the cover slip formed after the peeling. This actually leads to the damage of the microfluidic chip; of course, if the surface modification or the surface modification is not in place, it will also lead to the above-mentioned situation within the short customary validity period; In the case of simply using an external micropump for liquid flow drive, the above-mentioned problem always exists. As mentioned above, if no pre-operations such as surface modification or surface modification have been done at all, then the above-mentioned problem will be more serious, even if the microchannel bubbling at the injection end and its vicinity does not occur , puffing, twisting, deformation, and peeling between the substrate and the cover sheet, just because the flow resistance is too large, the use of a high-pressure micropump may not be able to drive the sample liquid flow toward the terminal.

Contents of the invention

The technical problem to be solved by the present invention is to provide a package solution to simultaneously solve a series of difficult problems that are actually involved in the three aspects mentioned above, and to apply the solution to AIDS diagnosis. In the field of multi-channel microfluidic chips, a new type of multi-channel device for AIDS diagnosis has been formed.

The present invention solves the technical problem through the following solution. The device provided by the solution is a double-drive coupling multi-channel device for AIDS diagnosis including a hydrophobic substrate. The structure of the device includes a multi-channel microfluidic chip. The microfluidic The structure of the control chip includes a base sheet and a cover sheet that are installed together. The base sheet and the cover sheet are both plate-like or sheet-like objects. The channel structure formed by the process or etching process, the substrate and the cover that are installed together to form a microfluidic chip with a pipeline structure, the structure of the pipeline is located between the substrate and the cover The two ends of the pipe are respectively connected to the sampling end and the terminal of the microfluidic chip, the sampling end is the injection end of the sample solution of the microfluidic chip, and the terminal is the microfluidic chip. The terminal of the sample solution flow in the chip during the actual sample injection test of the fluidic chip. The terminal and the sample injection end are far away from each other. The distance between the terminal and the sample injection end is between 3 cm and 10 cm. A working electrode, a counter electrode, and a reference electrode are sequentially installed at different positions in the pipeline, and the working electrode is sensitive to the conductive electrode and the gold colloid embedded in the AIDS-specific antigen attached to the conductive electrode. The structure of the pipeline is a parallel structure, the pipeline in parallel structure is composed of four branch pipelines in parallel, the number of the working electrodes is four, and the installation positions of the four working electrodes are respectively located in the four branch pipelines. In the pipeline, and the specific antigens in the gold colloid sensitive film structure on the surface of the four working electrodes are four AIDS antigen substances that can specifically bind to AIDS antibodies, and the four antigen substances are respectively AIDS-specific antigen p24 , gp41, gp120 and gp36, the material of the working electrode is gold material or thermally decomposed conductive polymer material, the shape of the working electrode is flake or filamentous, and the point is that the material of the substrate is polydimethylformaldehyde Silicone-based material, the surface of the substrate is the surface of the original form, the surface of the original form means the surface of the original form of the material without any surface chemical modification or any surface chemical modification, the device The structure of the chain-ring electromagnetic fixture also includes a chain-ring type electromagnetic fixture. There are six links in the structure of the chain-ring electromagnetic fixture. The links are all in the shape of strips, rods or rods. Its outline is a hexagonal ring structure, and the structural position of each vertex of the hexagonal ring structure is a hinged structure position, and the two links of the hexagonal ring structure at opposite sides are The material is a magnetic material, and the materials of the remaining four links of the hexagonal ring structure are all non-magnetic materials. The non-magnetic material refers to a material that does not strongly respond to an external magnetic field. The two links of the magnetic material One of the links is wound with an exciting coil, and the link wound with the exciting coil is equipped with a pole shoe of a magnetically permeable material on both sides of the exciting coil. There are two pole shoes in total. Each pole piece points to another link of magnetically permeable material, and the link of this other magnetically permeable material is on the surface A miniature ultrasonic transducer is attached and fixed, and the link-type electromagnetic clamp relying on the electromagnetic attraction force is socketed and positioned in the vicinity of the terminal of the microfluidic chip, and the high-frequency oscillating electrical signal transmission cable , one end of the high-frequency oscillating electrical signal transmission cable is connected to the miniature ultrasonic transducer; the link-type electromagnetic clamp provides a function to facilitate disassembly of the device; the main function of the miniature ultrasonic transducer is to During the actual sample injection test of the microfluidic chip, the ultrasonic waves emitted by it are used to reduce the interfacial tension between the sample solution and the inner wall of the internal channel of the microfluidic chip to make it compatible, and, using the described The distance difference between the sample end and the terminal and the installation position of the micro-ultrasonic transducer and the difference in the ultrasonic intensity felt by it induce the formation of the difference between the interfacial tension of the sample injection end and the interfacial tension of the terminal. The difference in interfacial tension between the two ends of the microfluidic chip will form a pressure difference between the two ends of the microfluidic chip, and the pressure difference will drive the sample solution to flow toward the terminal; The function of the micro-ultrasonic transducer also includes preventing the adsorption of biomacromolecules contained in the sample on the inner surface of the internal channel of the microfluidic chip by the ultrasonic waves emitted by it, thereby preventing the polydimethylsiloxane The engulfment effect of the alkane material substrate on the biomacromolecule; the function of the soft and elastic polydimethylsiloxane material includes strong absorption of ultrasonic waves due to its strong absorption of ultrasonic waves. , and thereby realize the rapid decrease of the ultrasonic intensity within a limited short distance between the end of the microfluidic chip and the injection port; and a micropump, which is connected to the injection port; The function of the pump is, under the premise that the interfacial tension between the sample solution and the inner wall of the microfluidic chip is reduced by the action of the ultrasonic wave and the interphase compatibility is increased, the mechanical property of the micropump The pumping force and the driving force brought about by the difference in interfacial tension between the two ends induced by the ultrasonic wave support, adapt to, and couple with each other, and converge into one stream in a cooperative manner to drive the sample liquid to flow to the The force of the flow in the direction of the terminal.

The technical meaning of the term micropump itself is well known to those skilled in the field of microfluidic chips.

The micropump is, for example, a micro piezoelectric pump, a micro peristaltic pump, a micro pneumatic pump, and the like.

The micropump can be an external micropump; the micropump can also be a built-in micropump that is inserted into or embedded in the microfluidic chip at the structural position of the sampling end or the structural position adjacent to the sampling end. Pump.

The technical meaning of the term field coil itself is known.

The technical meaning of the term magnetically permeable material itself is well known; materials belonging to the magnetically permeable material are, for example, pure iron, silicon steel, soft ferrite, and the like.

The non-magnetic material mentioned in this case refers to a material that does not strongly respond to an external magnetic field, and materials belonging to the non-magnetic material include metallic copper, metallic zinc, copper-zinc alloy, metallic aluminum, aluminum-magnesium alloy, and the like.

The technical meaning of the term articulation itself is well known in the field of machine design.

The gold colloid sensitive film is formed by fully mixing the chitosan gold colloid solution and the AIDS-specific antigen solution, spotting or coating a sample with a spotting instrument on a designated structural position, and drying it to form a film. The AIDS-specific antigens in the gold colloid sensitive membrane are all AIDS antigens labeled with horseradish peroxidase or glucose oxidase, and the gold colloid sensitive membrane has contained the AIDS-specific antigens introduced into it for fixing the above-mentioned AIDS-specific antigens. Auxiliary medium, said auxiliary medium such as one of chitosan, cellulose acetate, gelatin or their mixture.

The pipes in the microfluidic chip structure include the branch pipes, and their inner diameters can be any selected size. However, in consideration of using as little liquid samples as possible and reducing reagent loss, etc., The pipeline including the branch pipeline is preferably a capillary-level channel, and the capillary-level channel means a channel whose inner diameter is equivalent to that of a capillary in the usual sense. The cross-sectional shape of the internal channel of the capillary can be any shape, such as a circle, an ellipse, a square, a rectangle, a bar, and of course any curved line, and the The internal shape of the capillary can also be different from the cross-sectional shape of different parts along with the extension of the pipeline. As far as the term capillary is concerned, its technical meaning is known.

The counter electrode and reference electrode involved in the structure are all micro-sized electrodes, and the shape of the electrode can be any selected shape, such as a square sheet shape, a rectangular sheet shape, a strip shape or a circular shape. Flaky and more. The technical meaning of the terms themselves, the counter electrode and the reference electrode, are well known.

Only the technical meaning of the term ultrasonic transducer itself is known to those skilled in the field of ultrasonic technology.

Ultrasonic transducers of various sizes and shapes are commercially available; commercially available miniature ultrasonic transducers can be as small as millimeters in size.

Only the fixing technology of the miniature ultrasonic transducer on the surface of a solid object of general industrial application is a known general technology for professionals in the field of ultrasonic technology. This case does not elaborate on this.

As far as the bare PDMS substrate itself is concerned, the microchannel embossing or etching technology is an extremely simple known technology.

The involved high-frequency oscillating electrical signal transmission cables are available in the industrial product market with various specifications.

The structure of the device may also include a high-frequency oscillating electrical signal generator; the other end of the high-frequency oscillating electrical signal transmission cable may be connected to the high-frequency oscillating electrical signal generator.

The technology of the high-frequency oscillating electrical signal generator itself is simple and well-known to professionals in the field of ultrasonic technology; the high-frequency oscillating electrical signal generator can be customized to professional manufacturers of ultrasonic instruments.

The preferred range of its rated ultrasonic transmission power of the miniature ultrasonic transducer is between 5 milliwatts and 9000 milliwatts; the preferred range of the frequency of the ultrasonic waves emitted by the miniature ultrasonic transducer during operation is between 100KHz and between 12MHz.

Of course, the device of this case may further include some accessories, such as a multi-channel electrochemical workstation, etc. The technical meaning of the multi-channel electrochemical workstation is well known. Each working electrode, counter electrode, and reference electrode involved in the structure of the microfluidic chip in this case can be connected to the corresponding interfaces of the multi-channel electrochemical workstation via corresponding dedicated serial lines. The special serial line is a special cable for interconnecting each electrode and each corresponding interface of the multi-channel electrochemical workstation. The structure of the microfluidic chip in the device of this case can also include microvalves, and the number of the microvalves is not limited. According to actual needs, the microvalves can be installed in any required structure of the microfluidic chip structure. The position of installation; the technical meaning of the word microvalve is known to professionals in the field of microfluidic chip technology; the production technology and use technology of the microvalve itself are also known; the microvalve Not a required component.

The diameter of the working electrode can be allowed to be arbitrarily set to be convenient for installation and use, but the recommended or preferred diameter ranges from 0.1 micron to 2000 micron; the length of the working electrode It is permissible to set the length conveniently for installation and use arbitrarily, but the recommended or preferred length ranges from 1 micron to 15000 microns.

The gold colloid sensitive film installed on the surface layer of the working electrode is coated by spraying or sample spotting or other suitable processes, and its film thickness can be allowed to be arbitrarily set to generate electricity for the sample solution to be tested. The thickness of the signal response, however, is recommended or preferred thickness is between 10nm and 200nm.

The cover sheet in the chip structure can be made of any electrically insulating material, such as polypropylene, glass, polymethyl methacrylate, polydimethylsiloxane, etc., in order to make a more For small-sized microfluidic chips, such as ultra-small microfluidic chips with a length of only 2.0 cm to 3.0 cm, and to achieve extremely fast attenuation of ultrasonic waves within this extremely short distance, polydimethyl Silicone was used as a cover slip. Of course, the choice of using polydimethylsiloxane as the cover sheet on a large-sized microfluidic chip is also allowed by the technical solution of this case.

The thickness of the cover sheet and the base sheet can be set arbitrarily to facilitate assembly, and the recommended or preferred thickness is between 1.0 mm and 5.0 mm. Smaller thickness is beneficial to save material.

The method of using the microfluidic chip in this case:

In this case, the dual-drive coupling operation mode is used to drive liquid flow in the capillary channel of the four-channel microfluidic chip, and the four-channel electrochemical analysis instrument is used to detect four kinds of AIDS antibodies.

Using four AIDS antigens to detect the corresponding four AIDS antibodies, and using four AIDS antibodies to detect the corresponding four AIDS antigens, can also diagnose AIDS; the principle is that AIDS patients Antigens and antibodies must coexist and combine reversibly with each other to form reversible conjugates. Therefore, using antigens to detect antibodies and diagnosing AIDS, and using antibodies to detect antigens and diagnose AIDS can both achieve the purpose of diagnosis. Of course, the corresponding electrode sensitive modification layers of different means are technically different.

The specific detection steps of the microfluidic chip in this case are as follows:

1. Serum sample solution is added to the micropipeline, driven by the dual-drive coupling operation mode, various AIDS antibody molecules are embedded by the corresponding horseradish peroxidase on the electrode surface of each channel by the gold glue sensitive film Labeled HIV-specific antigen capture.

2. The AIDS-specific antigen labeled with horseradish peroxidase forms an immune complex with the AIDS antibody in the serum sample.

3. Use a multi-channel electrochemical analyzer, add catechol and other electronic mediators, and use the amperometric method to detect the current changes caused by the above reactions, thereby obtaining the types and contents of various analytes.

4. Comprehensively analyze the results and make a comprehensive diagnosis of AIDS antibodies.

The advantage of the present invention is that, relying on the electromagnetic attraction force to socket and position the chain-ring type electromagnetic clamp at the adjacent position of the terminal of the microfluidic chip, a magnetically conductive link of the chain-ring type electromagnetic clamp The attached micro-ultrasonic transducer uses the low-power, high-frequency ultrasonic waves emitted by it to make the internal pipe wall of the microfluidic chip that has not undergone surface chemical modification or surface chemical modification and is strongly hydrophobic The compatibility with the aqueous solution of the test object is greatly increased, which provides a realistic possibility for the passage of the sample liquid; at the same time, using the strong absorption capacity of the polydimethylsiloxane sheet for ultrasonic waves, in comparison Within a short distance, that is, within a very short distance of only a few centimeters from the terminal to the sample injection end, a rapid decrease in ultrasonic intensity is achieved, whereby the microfluidic chip The two ends cause said difference in interfacial tension, and this difference in interfacial tension between the two ends results in a driving force that functions as a result of the difference in interfacial tension to drive the sample flow away from the otherwise strongly hydrophobic The capillary channel flows toward the terminal direction; and the micropump existing in the structure at the same time, its function is that the interfacial tension between the sample solution and the inner wall of the microfluidic chip’s internal channel is affected by the ultrasonic wave. Under the premise of decreasing and increasing the compatibility between phases, the mechanical pumping force of the micropump and the driving force brought by the difference in interfacial tension between the two ends induced by the ultrasonic wave support and mutually support each other. Adapted and coupled with each other, they converge into a force that drives the sample liquid to flow in the direction of the terminal in a cooperative manner; the existence of the micropump allows the ultrasonic emission intensity of the miniature ultrasonic transducer to be allowed to be moderately reduced. It is especially suitable for the situation where the detection object contains ultrasonic sensitive components; and due to the existence of the ultrasonic transducer and the ultrasonic radiation it radiates, it can improve the compatibility between phases, reduce the interfacial tension, and provide the interface tension difference between the two ends. In this case, the flow resistance of the sample liquid flow in the microchannel is greatly reduced, and correspondingly, the running resistance of the micropump is greatly reduced. In this way, the micropump can The pumping work for the sample solution is performed at a relatively low pumping pressure, because the mechanical pumping pressure is greatly reduced. Bubbles, expansion, deformation, twisting of the microchannels in the injection port and its vicinity caused by the large size of the microchannel, as well as the peeling between the substrate and the cover sheet in this area; the dual-drive coupling operation scheme in this case Moreover, the controllability of the flow action of the sample liquid flow is increased, and multiple indicators such as ultrasonic intensity, ultrasonic frequency, micropump pumping power, micropump pumping pressure, etc. can be used to control the flow rate and flow action of the flow. Including the multi-parameter precise control of flow actions such as forward flow, pause flow, or accelerated flow; with the dual-drive coupling operation scheme in this case, there is no need for microchannels on the polydimethylsiloxane substrate etc. for any surface chemical modification or surface surface chemical modification, which completely eliminates the troublesome procedures of surface chemical modification or surface chemical modification; Adsorption on the inner surface of the pipeline of the bare polydimethylsiloxane sheet, thereby inhibiting the engulfment of the polydimethylsiloxane sheet relative to the biomacromolecule; the antigen, antibody and antigen Of course, the reversible conjugates with antibodies all belong to the type of biomacromolecule; since the adsorption and engulfment are effectively restrained, the relevant test results will more objectively reflect the actual situation; The role of the low-power, high-frequency ultrasonic waves, of course, also includes promoting the rapid achievement of reversible binding reactions between antigens and antibodies, which enables related testing operations to be completed relatively quickly.

As mentioned above, the existence of the micro-pump allows the ultrasonic emission intensity of the micro-ultrasonic transducer to be reduced moderately, so this feature helps to protect the sensitive coating of the working electrode from ultrasonic damage .

Based on the scheme of this case, there is absolutely no need to carry out surface chemical modification or surface chemical modification operation for the relevant surface of the polydimethylsiloxane sheet, therefore, this surface chemical modification layer or surface chemical modification layer does not need exist, then, the polydimethylsiloxane-based sheet has its bulk internal polymer molecules continuously and automatically diffuse to the surface, and the destructive effect on the surface chemical modification layer or the surface chemical modification layer caused by migration is also no longer exists.

The technical solution of this case solves a series of technical problems related to the application of polydimethylsiloxane-based sheets mentioned above in one package. Based on the proposal of this case, this very cheap and easy-to-process polydimethylsiloxane material may play a greater role in the preparation, production, application and other fields of the microfluidic chip.

The chain-ring type electromagnetic fixture in the structure of this case is attached and fixedly installed with the described micro-ultrasonic transducer on a magnetically conductive link. This structure provides a function to facilitate the disassembly of the device. The clamp and the micro-ultrasonic transducer attached to one of its magnetic links can be easily separated from the microfluidic chip, so that part of the freely detachable component can be reused many times in a virtuous cycle; This structural feature is beneficial to saving the use cost of the device.

Description of drawings

Figure 1 is a rough appearance side view of the link-type electromagnetic clamp of the device in this case when it is socketed with the microfluidic chip, and the illustration also indicates the relative positional relationship between the various components in the socketed state.

Fig. 2 is a side view of the appearance of the device under another viewing angle; the viewing angle of Fig. 2 is perpendicular to that of Fig. 1; components such as infusion hose and micropump are not drawn in Fig. 2 .

In the figure, 1 is a chain-link electromagnetic fixture, 2 is the terminal of the microfluidic chip, 3 is the sampling end of the microfluidic chip, and 4 is a substrate made of polydimethylsiloxane , 5 is a cover sheet, 6 is a micro-ultrasonic transducer, 7 is a high-frequency oscillating electrical signal transmission cable, 8, 15 are two links of magnetically permeable materials located in different structural positions, and the links of these two magnetically permeable materials In this structure, they are opposite to each other, 9 and 22 are two pole shoes located in different structural positions, 10, 12, 14, 17, 19, 21 are six hinge points in six different positions, 11 , 13, 18, and 20 are four non-magnetic material links in four different positions respectively, 16 is an excitation coil, 23 is an infusion hose, and 24 is a micropump; the chain-ring electromagnetic clamp structure in the illustration is only The structure of the schematic illustration, the actual structure of the link-type electromagnetic fixture is not limited to the structure of the link-type electromagnetic fixture of the illustration; the arrow symbol in the illustration indicates that the microfluidic chip is driven by the pressure difference between the two ends during actual operation, and its experimental The flow direction of the sample liquid flow.

detailed description

In this embodiment of the present case shown in Fig. 1 and Fig. 2, the structure of the device includes a multi-channel microfluidic chip, and the structure of the microfluidic chip includes a substrate 4 and a cover sheet 5 that are attached to each other. , the base sheet 4 and the cover sheet 5 are both plates or sheets, and the surface of the base sheet 4 facing the cover sheet 5 contains a channel structure formed by a molding process or an etching process, and is bonded to each other The substrate 4 and the cover sheet 5 installed together constitute a microfluidic chip containing a pipeline structure. The two ends of the microfluidic chip are respectively connected to the sampling port 3 and the terminal 2, the sampling port 3 is the injection port of the sample solution of the microfluidic chip, and the terminal 2 is the actual sample injection port of the microfluidic chip. During the test, the terminal of the sample solution flow in the chip, the terminal 2 and the sampling end 3 are far away from each other, the distance between the terminal 2 and the sampling end 3 is between 3 cm and 10 cm, in the pipeline The working electrode, the counter electrode and the reference electrode are sequentially installed at different positions in the interior, and the working electrode is composed of a conductive electrode and a gold colloid sensitive film embedded in the AIDS-specific antigen attached to the conductive electrode. , the structure of the pipeline is a parallel structure, the pipeline in parallel structure is composed of four branch pipelines connected in parallel, the number of the working electrodes is four, and the installation positions of the four working electrodes are respectively located in the four branch pipelines , and, the specific antigens in the gold colloid sensitive film structure on the surface of the four working electrodes are four AIDS antigen substances that can specifically bind to AIDS antibodies, and the four antigen substances are AIDS-specific antigens p24 and gp41 respectively , gp120 and gp36, the material of the working electrode is gold material or thermally decomposed conductive polymer material, the shape of the working electrode is flake or filamentous, and the point is that the material of the substrate 4 is polydimethyl Silicone material, the surface of the substrate 4 is the surface of the original form, the surface of the original form means the surface of the original form of the material without any surface chemical modification or any surface chemical modification, the device The structure also includes a link type electromagnetic clamp 1, which has six links 8, 11, 13, 15, 18, 20 in its structure, and the links 8, 11, 13, 15, 18, 20 are strip-shaped, rod-shaped or bar-shaped, and each adjacent link is hinged to form a chain link. The outline of the chain link is a hexagonal ring structure, and each vertex 10, 12 , 14, 17, 19, and 21 are all hinged structural positions, and the two links 8 and 15 in the hexagonal annular structure are made of magnetically permeable materials, and the hexagonal annular structure The materials of the remaining four links 11, 13, 18, and 20 of the structure are all non-magnetic materials. The non-magnetic materials refer to materials that do not strongly respond to an external magnetic field. One of the two links of the magnetically permeable material is 15 is wound with an exciting coil 16, and the link 15 wound with the exciting coil 16 is on the adjacent positions on both sides of the exciting coil 16. A pole piece of magnetically permeable material is installed, and there are two pole pieces 9, 22 in total. The two pole pieces 9, 22 all point to another link 8 of magnetically permeable material, and the link 8 of another magnetically permeable material A miniature ultrasonic transducer 6 is attached and fixed on its surface, and the link-type electromagnetic fixture 1 relying on the electromagnetic attraction force is socketed and positioned in the vicinity of the terminal 2 of the microfluidic chip, and the height Frequency oscillation electrical signal transmission cable 7, one end of the high frequency oscillation electrical signal transmission cable 7 is connected with the miniature ultrasonic transducer 6; the link type electromagnetic clamp 1 provides a function to facilitate the disassembly of the device; the The main function of the micro-ultrasonic transducer 6 is to use the emitted ultrasonic waves to reduce the interfacial tension between the sample solution and the inner wall of the internal channel of the microfluidic chip during the actual sample injection test of the microfluidic chip, so that It can be compatible, and, using the distance difference between the sample injection end 3 and the terminal 2 and the installation position of the miniature ultrasonic transducer 6 and the difference in the ultrasonic intensity felt by it, induces the formation of the The difference between the interfacial tension of the sampling end 3 and the interfacial tension of the terminal 2, the difference in interfacial tension between the two ends 2, 3 of the microfluidic chip will be at the two ends 2, 3 of the microfluidic chip 3 to form a pressure difference, which will drive the sample solution to flow in the direction of the terminal 2; the function of the miniature ultrasonic transducer 6 also includes suppressing the biological macromolecules contained in the sample with the ultrasonic waves emitted by it Its adsorption on the inner surface of the internal channel of the microfluidic chip, thereby preventing the engulfment of the polydimethylsiloxane substrate 4 by its body relative to the biomacromolecule; the soft and elastic polydimethylsiloxane The function of the substrate 4 made of methylsiloxane includes strong absorption of ultrasonic waves due to its strong absorption of ultrasonic waves, and thereby the limited distance between the terminal 2 and the sample injection end 3 of the microfluidic chip within a short distance to realize the rapid decrease of the ultrasonic intensity; and, the micropump 24, the micropump 24 is connected with the sample injection port 3; the function of the micropump 24 is, between the sample solution and the microfluidic chip Under the premise that the interfacial tension between the inner walls of the inner channel is reduced by the action of the ultrasonic wave and the interphase compatibility is increased, the mechanical pumping force of the micropump 24 is used to match the two ends 2, 3 induced by the ultrasonic wave. The driving force brought about by the difference in interfacial tension supports, adapts and couples with each other, and converges into a force driving the sample liquid to flow in the direction of the terminal 2 in a cooperative manner.

The arrow symbols in the legend indicate the flow direction of the sample liquid flow of the microfluidic chip driven by the pressure difference between the two ends 2 and 3 during actual operation.

In Fig. 1 and Fig. 2, accessories such as the high-frequency oscillating electrical signal generator are not shown.

Both the permeable magnetic material involved and the non-magnetic material involved are available in the market.

The miniature ultrasonic transducer 6 involved is available in the market; it can also be customized from an ultrasonic transducer manufacturer.

The micropump 24 can be customized to a professional manufacturer.

The involved high-frequency oscillating electrical signal transmission cable 7 is available in the market; it can also be customized from ultrasonic transducer manufacturers or professional cable manufacturers.

The involved high-frequency oscillating electrical signal generator market has products close to the needs available; it can also be customized from relevant manufacturers

The internal channel of the microfluidic chip involved in this case is a hydrophobic capillary-shaped channel.

The technical meaning of the term micropump itself is well known to those skilled in the field of microfluidic chips.

The micropump is, for example, a micro piezoelectric pump, a micro peristaltic pump, a micro pneumatic pump, and the like.

The micropump can be an external micropump; the micropump can also be a built-in micropump that is inserted into or embedded in the microfluidic chip at the structural position of the sampling end or the structural position adjacent to the sampling end. Pump. The micropump in the legend is an external micropump; the micropump can certainly also be a micropump of the built-in type that is inserted into or embedded in the structure of the microfluidic chip or its adjacent structure. The basic structural elements are the same as those of the external micropump.

Each working electrode, counter electrode and reference electrode in the structure of this example can be respectively connected with the corresponding cable interface or serial interface of the multi-channel electrochemical workstation as an accessory via their own dedicated cables or series lines.

The device in this case uses a variety of AIDS antigens to detect a variety of corresponding AIDS antibodies, thereby diagnosing AIDS.

Claims (10)

1. A multi-channel device for AIDS diagnosis with double-drive coupling comprising a hydrophobic substrate. The structure of the device includes a multi-channel microfluidic chip. The structure of the microfluidic chip includes a substrate and a cover that are attached to each other and installed together. The base sheet and the cover sheet are both plates or sheets, and the surface of the base sheet facing the cover sheet contains a channel structure formed by a molding process or an etching process, and they are attached to each other and installed together. The substrate and the cover sheet together constitute a microfluidic chip with a pipe structure, the structure of the pipe is located at the junction area where the substrate and the cover sheet are attached to each other, and the two ends of the pipe are respectively connected to the micro The sampling end of the fluidic chip is connected to the terminal. The sampling end is the injection end of the sample solution of the microfluidic chip, and the terminal is the terminal of the sample solution flow in the chip during the actual sample injection test of the microfluidic chip. , the terminal and the injection end are far away from each other, the distance between the terminal and the injection end is between 3 centimeters and 10 centimeters, a working electrode and a counter electrode are sequentially installed at different positions in the pipeline. The reference electrode, the working electrode is composed of a conductive electrode and a gold colloid sensitive film embedded with AIDS-specific antigen attached to the conductive electrode. The structure of the pipeline is a parallel structure, and the parallel structure The pipeline is composed of four branch pipelines connected in parallel, the number of the working electrodes is four, and the installation positions of the four working electrodes are respectively located in the four branch pipelines, and the gold glue sensitive film structure on the surface of the four working electrodes The specific antigens in the formula are four AIDS antigen substances that can specifically bind to AIDS antibodies. The four antigen substances are AIDS-specific antigens p24, gp41, gp120 and gp36 respectively. The material of the working electrode is gold or The thermally decomposed conductive polymer material, the shape of the working electrode is flake or filament, and it is characterized in that the material of the substrate is polydimethylsiloxane material, and the surface of the substrate is the surface of the original form , the surface of the original form means the surface of the original form of the material without any surface chemical modification or any surface chemical modification. The structure of the device also includes a chain-link electromagnetic clamp, and the chain-link electromagnetic clamp There are six links in its structure, all of which are strip-shaped, rod-shaped or rod-shaped, and the adjacent links are hinged to each other to form a chain ring. The outline of the chain ring is a hexagonal ring structure. The hexagonal ring The structural position of each vertex of the hexagonal structure is the position of the hinged structure. The material of the two links at the opposite sides of the hexagonal ring structure is a magnetic material, and the remaining four of the hexagonal ring structure The material of each link is a non-magnetic material. The non-magnetic material refers to a material that does not strongly respond to an external magnetic field. One of the two links of the magnetically permeable material is wound with an excitation coil, which is wound with an excitation coil. A pole piece of a magnetically permeable material is installed on the adjacent positions on both sides of the excitation coil, and there are two pole pieces in total, and the two pole pieces point to another link made of a magnetically permeable material. The surface of the link made of magnetically conductive material is attached and fixed with a miniature ultrasonic transducer, which relies on the electromagnetic attraction force. The link-type electromagnetic clamp socket is positioned adjacent to the terminal of the microfluidic chip, and a high-frequency oscillating electrical signal transmission cable, one end of the high-frequency oscillating electrical signal transmission cable is connected to the micro-ultrasonic transducer together; the link-type electromagnetic fixture provides a function to facilitate the disassembly of the device; the main function of the micro-ultrasonic transducer is to use the ultrasonic waves emitted by it to reduce the test volume during the actual sample injection test of the microfluidic chip. The interfacial tension between the sample solution and the inner wall of the internal channel of the microfluidic chip makes it compatible, and utilizes the interfacial tension between the sample injection end and the terminal and the installation position of the micro-ultrasonic transducer The difference in distance and the difference in the intensity of the ultrasonic waves felt by it induces the difference between the interfacial tension of the sample injection end and the interfacial tension of the terminal, and the difference in interfacial tension between the two ends of the microfluidic chip will be A pressure difference is formed between the two ends of the microfluidic chip, and the pressure difference will drive the sample solution to flow toward the terminal; the function of the miniature ultrasonic transducer also includes suppressing The adsorption of the contained biomacromolecules on the inner surface of the internal channel of the microfluidic chip prevents the engulfment of the polydimethylsiloxane substrate body relative to the biomacromolecules; it is soft and has The function of the elastic polydimethylsiloxane substrate includes strong absorption of ultrasonic waves due to its strong absorption of ultrasonic waves, thereby creating a gap between the end of the microfluidic chip and the sampling end. Realize the rapid decrease of ultrasonic intensity within the limited short distance; And, micropump, this micropump is connected with this sampling end; Under the premise that the interfacial tension between the inner walls of the micropump is reduced by the action of the ultrasonic wave and the interphase compatibility is increased, the difference in interfacial tension between the two ends induced by the ultrasonic wave is compared with the mechanical pumping force of the micropump The driving forces brought by them support, adapt and couple with each other, and converge into a force driving the sample liquid to flow in the direction of the terminal in a cooperative manner. 2 . The multi-channel device for AIDS diagnosis with double driving coupling comprising a hydrophobic substrate according to claim 1 , wherein the pipelines including the branch pipelines are capillary channels. 3 . 3. The multi-channel device for AIDS diagnosis comprising a hydrophobic substrate according to claim 1, wherein the thermally decomposed conductive macromolecule is made of polyimide or polyacrylonitrile through anaerobic heat treatment Conductive material formed later. 4. The multi-channel device for AIDS diagnosis comprising a hydrophobic substrate according to claim 1, wherein the width or diameter of the working electrode is between 0.1 micron and 2000 micron, and the The length of the working electrodes is between 1 micron and 15000 microns. 5 . The multi-channel device for AIDS diagnosis comprising a hydrophobic substrate with dual drivers coupling according to claim 1 , wherein the thickness of the gold colloid sensitive film is between 10 nanometers and 200 nanometers. 6 . 6 . The multi-channel device for AIDS diagnosis with double driving coupling comprising a hydrophobic substrate according to claim 1 , wherein the material of the cover sheet in the structure is polydimethylsiloxane. 7 . 7 . The multi-channel device for AIDS diagnosis with double driving coupling comprising a hydrophobic substrate according to claim 1 , wherein the micropump is a miniature piezoelectric pump, a miniature peristaltic pump or a miniature pneumatic pump. 8. The multi-channel device for AIDS diagnosis comprising a hydrophobic substrate according to claim 1, wherein the thickness of the cover sheet and the substrate in the structure is between 1.0 mm and 5.0 mm. between. 9. The multi-channel device for AIDS diagnosis comprising a hydrophobic substrate according to claim 1, wherein the structure of the device further comprises a high-frequency oscillating electrical signal generator, and the high-frequency oscillating electrical signal The other end of the transmission cable is connected with the high frequency oscillating electrical signal generator. 10. The multi-channel device for AIDS diagnosis comprising a double-drive coupling of a hydrophobic substrate according to claim 1, wherein the rated ultrasonic transmission power of the miniature ultrasonic transducer is between 5 milliwatts and 9000 milliwatts During operation, the ultrasonic frequency emitted by the miniature ultrasonic transducer is between 100KHz and 12MHz.