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    • 专利摘要:
    centrifugal microfluidic device, and method for analyzing an analyte in a liquid sample are presented a centrifugal microfluidic device for detecting analytes in a liquid sample, and a method for detecting analytes from a liquid sample, using the microfluidic device. the reaction efficiency is high, using a repetitive flow of the liquid sample, induced by an alternating combination of capillary force and centrifugal force, thus increasing the detection sensitivity.
    公开号:BR112012018853B1
    申请号:R112012018853-4
    申请日:2011-01-11
    公开日:2020-12-15
    发明作者:In Wook Kim
    申请人:Nexus Dx, Inc.；
    IPC主号:
    专利说明:

    Technical area
    [0001] Apparatus and methods compatible with exemplary embodiments generally refer to a microfluidic centrifugal device for detecting analytes in a liquid sample and a detection method using the microfluidic device and, more particularly, to a centrifugal microfluidic device for detecting analytes from a liquid sample with improved sensitivity, in which a repeated flow of a liquid sample, induced by centrifugal force and capillary force, increases the efficiency of the reaction, as well as a method to detect analytes in a liquid sample using the device microfluidic. Fundamentals of Technique
    [0002] In order to cause a fluid to drain or move in a microfluidic structure of a microfluidic device, a trigger pressure is generally required. The trigger pressure can be capillary pressure or pressure generated using an additional pump. In recent years, clinical diagnostic analyzers have been proposed, which were designed to allow the detection of a target material present in a small amount of fluid, in a simple and economical way. An example is a centrifugal microfluidic device having a microfluidic structure mounted on a circular disk-type rotating platform, such as a lab-on-disc and / or a lab on a CD.
    [0003] Lab-on-disc, meaning "laboratory on a disc" is a CD-type device, in which different experimental units are integrated for the analysis of biomolecules, used in a laboratory, to perform various experimental processes, including, for example , isolation, purification, mixing, identification, analysis and / or washing of a sample on a small disk. After introducing a biological sample, such as blood, into a microfluidic structure placed on a disk, the CD-type device can advantageously transfer a liquid, such as a biological sample, a chemical reagent, etc. Only centrifugal force can be used to induce the driving pressure and transport the fluid, without additional driving systems.
    [0004] Recently, the use of a 'lap-on-a-chip' for blood analysis has been investigated for its ability to quickly obtain a variety of information from blood samples collected from clinical cases. As a result, a rapid-chip or rapid-kit was developed. For this rapid-chip or rapid-kit, several processes are carried out in just one reaction part of the rapid-chip or a rapid-kit, including: combining a material to be analyzed (that is, an analyte) with a generator of detectable signal; combining an analyte composite and the detectable signal generator (referred to as the "analyte / detectable signal generator complex") with a capture binder and its washing; and so on. However, since the analyte is mainly combined with the identification reagent, a large amount of identification reagent is necessary, although this requirement is rarely satisfied, taking into account practical aspects. In addition, if the analyte does not fully react with the identification reagent, an unmatched portion of the analyte and the detectable signal generator can be combined with a capture binder present on a test line, which in turn competitively inhibits the analyte / signal generator complex detectable to be connected to a control line or test line. In addition, the combination of the analyte and each reagent is terminated within only a single fluid sample flow in one direction, thus resulting in an insufficient combination and causing decreased sensitivity and difficulties in quantitative analysis. The kit does not have an active device to control the rate of redissolution of the detectable signal generator and, therefore, the detectable signal generator is excessively redissolved by a constant volume of a fluid sample flowing into it, thus causing waste of the detectable signal generator at an early stage. On the other hand, the redissolution of the detectable signal generator is drastically reduced at a later stage, thus implying difficulties in the sensitive detection of the analyte. Disclosure of Invention Technical Problem
    [0005] One or more exemplary embodiments provide a microfluidic centrifugal device for detecting analytes, from a liquid sample, with improved sensitivity, in which a repeated flow of the liquid sample induced by a combination of capillary strength and centrifugal force increases reaction efficiency, as well as a method for detecting analytes from a liquid sample using the microfluidic device. Solution to the Problem
    [0006] In accordance with an aspect of an exemplary embodiment, a centrifugal microfluidic device is provided, including: a rotating body; at least one microfluidic structure, including several chambers, at least one channel, through which the various chambers are connected together and at least one valve opening and closing at least one channel; wherein the plurality of chambers includes a reaction chamber, where a detectable signal generator is combined with a liquid sample analyte to create a detectable analyte / signal generator complex, and an analysis chamber located downstream of the reaction; wherein the analysis chamber includes a detection region, where a capture binder is combined with the detectable analyte / signal generator complex; in which the detection region includes one of the porous membranes, micropore and micropillary structures; and a detection unit.
    [0007] According to one aspect of another exemplary embodiment, a centrifugal microfluidic device is provided, including: at least one microfluidic structure having several chambers, at least one channel, through which the various chambers are connected and at least one valve for opening and closing at least one channel; wherein the plurality of chambers make up a reaction chamber, where a detectable signal generator is combined with a liquid sample analyte to create a detectable analyte / signal generator complex, and an analysis chamber located downstream of the reaction; wherein the analysis chamber includes a detection region, where a capture binder is combined with the detectable analyte / signal generator complex; in which at least one valve controls the transport of fluid between the reaction chamber and the analysis chamber; in which the detection region includes one of the porous membranes, micropore and micropillary structures; and a detection unit detects the absorbance of the detection region of the reaction chamber.
    [0008] In accordance with an aspect of another exemplary embodiment, a centrifugal microfluidic device is provided, including: a rotating body; at least one microfluidic structure having several chambers and at least one channel, through which the various chambers are connected to each other; wherein the plurality of chambers includes a reaction chamber, where a detectable signal generator is combined with a liquid sample analyte to create a detectable analyte / signal generator complex, and an analysis chamber located downstream of the reaction; wherein the analysis chamber includes a detection region, where a capture binder is combined with the detectable analyte / signal generator complex; in which the detection region includes one of the porous membranes, micropore and micropillary structures; and a detection unit, which detects the absorbance of the detection region of the reaction chamber.
    [0009] The capture binder and the detectable signal generator can be selected from deoxyribonucleic acid (DNA), oligonucleotide, ribonucleic acid (RNA), RNA aptamer, peptide nucleic acid (PNA), ligand, receptor, hapten, antigen and antibody; however, they are not particularly limited by these.
    [00010] The analysis chamber can also include a support, which conducts a fluid from the reaction chamber.
    [00011] The detection region can contact the support at one end of the support.
    [00012] The detection region can also include a test region, in which the capture binder is attached, as well as a control region located downstream of the test region in relation to a direction for capillary action, spaced at a distance the test region.
    [00013] A section of the detection region, including the test region and the control region, can be tilted in the direction of the capillary action.
    [00014] The plurality of chambers may also include an interruption chamber, which is located downstream of the analysis chamber in relation to a direction of the centrifugal force, to receive the liquid sample from the analysis chamber.
    [00015] The signal generator detectable in the reaction chamber is contained in a liquid or dry solid state.
    [00016] The detectable signal generator may include polymeric granules, metallic colloids, enzymes, fluorescent materials, luminous materials, super paramagnetic materials, materials containing lanthanum (III) chelate, polymeric nanoparticles, or radioactive isotope elements.
    [00017] The detection unit can detect and analyze a detectable analyte / signal generator complex combined with the capture binder.
    [00018] The detection unit can include a light source unit and a light receiving unit, so that the light receiving unit is aligned with the light source unit, to accept the light emitted by the light source unit, that passes through the analysis chamber.
    [00019] In accordance with an aspect of another exemplary embodiment, a method of analyzing an analyte in a liquid sample is provided, including: injection of the liquid sample into a microfluidic structure of the microfluidic device, centrifugation of the liquid sample to obtain a supernatant; transporting the supernatant into a reaction chamber, in which a detectable signal generator is contained; combining the analyte in the supernatant with the detectable signal generator to create an analyte / detectable signal generator complex; subjecting the microfluidic device to centrifugation; transport of the detectable analyte / signal generator complex in an analysis chamber, in which the analysis chamber is located downstream of the reaction chamber, and where the analysis chamber includes a detection region, in which a capture binder is fixed, and where the detection region includes porous membranes, micropore or micropillary structures; moving the supernatant from the analysis chamber, by capillary force, to one end of the analysis chamber; combination of the analyte / signal generator complex detectable in the supernatant with the capture binder in the analysis chamber; applying centrifugal force to the microfluidic device to deliver the supernatant moved to the end of the analysis chamber, to a front end of the analysis chamber and simultaneous combination of the analyte / signal generator complex detectable in the supernatant with the capture agglomerate in the analyze; and detection of the detectable analyte / signal generator complex combined with the capture binder.
    [00020] The movement of the supernatant, from one end of the analysis chamber to the other end of the analysis chamber, can occur at least twice.
    [00021] The analysis chamber can also include a support, which conducts fluid from the reaction chamber.
    [00022] The detection region can contact the support at one end of the support.
    [00023] For the centrifugal microfluidic device, the microfluidic structure may also include an interruption chamber, which is located downstream of the analysis chamber in relation to a direction of the centrifugal force, to receive the liquid sample from the analysis chamber.
    [00024] The signal generator detectable in the reaction chamber is contained in a liquid or dry solid state.
    [00025] The detectable signal generator may include polymeric granules, metallic colloids, enzymes, fluorescent materials, luminous materials, super paramagnetic materials, materials containing lanthanum (III) chelate, polymeric nanoparticles, or radioactive isotope elements.
    [00026] Prior to the detection of the detectable analyte / signal generator complex, the liquid sample contained in the analysis chamber can be transported into the interruption chamber in order to stop a reaction between the detectable analyte / signal generator complex and the capture binder. Favorable Effects of the Invention
    [00027] As is perceived from the description above, compared to any conventional technique using capillary force applied in a single direction, to react the fluid with a fixed reagent, a 2-fold increase in reaction time is achieved, by its time, notably improving reaction sensitivity.
    [00028] In addition, after the fluid is completely displaced to the regions by a second application of capillary action, the fluid can be delivered back into the support, using a second application of centrifugal force generated by the rotation of the microfluidic device, so that a part of the analyte / first reagent complex, which was not combined by the second capillary action, can be repeatedly subjected to the reaction. In an exemplary embodiment, a reaction cycle is repeated for the desired number of repetitions in order to sufficiently carry out the reaction, thereby considerably increasing the sensitivity of detection of the analytes. Brief Description of Drawings
    [00029] The above and / or other aspects will become clear and more easily understood, from the description below of the exemplary embodiments, taken in conjunction with the accompanying drawings, where: Fig. 1 is a schematic view, illustrating the construction of a microfluidic device, according to an exemplary embodiment; Fig. 2 is a schematic view, illustrating the construction of a microfluidic structure in the microfluidic device shown in Fig. 1; Fig. 3 is a detailed view, illustrating a sample chamber; Fig. 4 is a detailed view, showing a sample separation unit; Fig. 5 is an enlarged view, showing micropylons formed in a detection region, according to an exemplary embodiment; Fig. 6 is a side view, showing an analysis chamber, according to another exemplary embodiment; Fig. 7 is a block diagram, illustrating a test system, according to an exemplary embodiment; and Fig. 8 is a flowchart, explaining a method for detecting an analyte in a liquid sample, using a microfluidic device, according to an exemplary embodiment. Best Way to Make the Invention
    [00030] Hereafter, exemplary embodiments and in particular their practical methods will be described, with reference to the accompanying drawings. However, the inventive concept can be incorporated into several other forms, which are not particularly restricted to those described in this document.
    [00031] An exemplary embodiment provides a microfluidic centrifugal device for detecting an analyte in a liquid sample, which includes a rotating body; at least one microfluidic structure having several chambers, at least one channel, through which, several chamber sections are connected together and at least one valve for opening and closing the channel; and a detection unit, in which the device also has a reaction chamber for receiving a detectable signal generator, to be combined with the analyte in the liquid sample, and an analysis chamber that is located downstream of the reaction chamber and includes a detection region, in which a capture binder is attached to be combined with a detectable analyte / signal generator complex, in which a fluid transported between the reaction chamber and the analysis chamber is controlled by the above valve, and the detection region includes porous membranes, micropore or micropillary structures.
    [00032] A test sample may include, for example, DNA, oligonucleotide, RNA, PNA, ligand, receptor, antigen, antibody, milk, urine, saliva, hair, a culture sample, a meat sample, an avian sample , a sample of cattle, a sample of processed food, an oral cell, a sample of tissue, sperm, protein or other biological materials; however, the test sample is not particularly limited by these indications. Such a sample can be used in a liquid or fluid state, by dissolving it using a buffer solution. The analyte can include, for example, protein, antigen, antibody, DNA or RNA, oligonucleotide, receptor and the like; although the analyte is not particularly limited to these indications. For a urine sample, the analyte can be blood, glucose, ascorbic acid, ketone, proteins, sugar, urobilinogen, bilirubin, etc.
    [00033] Fig. 1 is a schematic view, illustrating the construction of a microfluidic device, according to an exemplary embodiment, while Fig. 2 is a schematic view, illustrating the construction of a microfluidic structure, according to an exemplary embodiment.
    [00034] A rotating body 10 used in an exemplary embodiment may include a circular disk-type platform 20 (see FIG. 1). However, a shape of the platform 20 is not particularly limited to a circular disc shape. The platform can be formed using acrylic or other plastic materials, each being easily modelable and having a biologically inactive surface. However, a raw material for manufacturing the rotating body is not particularly limited, and can include any materials with chemical or biological stability, optical transparency and / or mechanical capability.
    [00035] At least one microfluidic structure 30 can be provided on the platform. For example, after partitioning platform 20 into several sections 30, 40, separate microfluidic structures 31, 41 can be placed independently of each other on sections 30, 40, respectively. Fig. 1 shows a particular platform 20 having two microfluidic structures 31, 41, formed on it.
    [00036] The term "microfluidic structure" used here refers to a general structure, which consists of a plurality of chambers, channels and valves, and induces a flow of fluid, rather than a particular structural substance. Therefore, the "microfluidic structure" can form a specific unit with different functions or performances, according to characteristics, such as the arrangement of the chambers, channels, and / or valves, and / or types of materials received in the structure.
    [00037] Therefore, the microfluidic device can be widely used in various applications, such as detection of various chemical compounds, substances harmful to the environment, blood analysis, urine tests, immunological examination based on antigen / antibody reaction, search for new ones. drug candidates based on ligand / receptor binding, DNA / RNA analysis, and so on. In addition, the microfluidic device can simultaneously detect and analyze at least two analytes.
    [00038] The platform can be manufactured with at least one material selected from a variety of materials, such as plastic, polymethylmethacrylate (“PMMA”), glass, mica, silica, a silicone wafer material etc. The plastic material it is used for economical reasons and simple processing. Potential plastic materials can include polypropylene, polyacrylate, polyvinyl alcohol, polyethylene, polymethylmethacrylate, polycarbonate, etc.
    [00039] A fluid sample, a buffer solution, a reactive solution, etc. they can be transported into separate chambers, using the centrifugal force generated by the rotation of the rotating body 10. The rotating body 10 has a rotary actuator D for high speed rotation (see FIG. 7). The centrifugal force generated by the rotation of the rotary actuator D can allow the transport and / or mixing of a sample.
    [00040] Fig. 2 shows a sample chamber 100, a sample separation unit 200, a reaction chamber 300, and an analysis chamber 400.
    [00041] The sample chamber 100 can provide a space for receiving a sample of the fluid type, such as blood. The sample separation unit 200 may allow centrifugation of the sample in a supernatant (i.e., serum, plasma, etc.) and a precipitate (i.e., blood cells). Reaction chamber 300 and analysis chamber 400 are structures for detecting specific protein, glucose, cholesterol, uric acid, creatinine, alcohol, etc. contained in the supernatant by antigen / antibody response, ligand / receptor binding, and so on.
    [00042] Fig. 3 is a detailed display mode, illustrating sample chamber 100. Referring to Fig. 3, sample chamber 100 has a sample input port 110 and a sample receiving unit 120 The sample receiving unit 120 has an output 130 connected to the sample separating unit 200 (not shown). Although not shown in the drawing, outlet 130 can be formed to generate capillary force in order to prevent a fluid sample from moving towards the sample separation unit 200 when centrifugal force is not applied, as described below. Alternatively, in order to control a flow of the fluid sample, a valve can be mounted at outlet 130. In addition, the sample chamber 100 may have an increasing cross section from inlet 110 towards outlet 130, enabling the sample contained in the sample receiving unit 120 to flow easily towards the sample separating unit 200 by the centrifugal force. In order to facilitate the flow of the sample into the sample receiving unit 120 by injection pressure of the sample through the inlet 110 and, in addition, to block an inverted flow of the sample inserted in the sample receiving unit 120 towards the Inlet 110, an alternative structure for generating capillary pressure can be placed between inlet 110 and sample receiving unit 120. This alternative structure, like a capillary valve type structure, will pass the sample through sample chamber 100, only when a desired pressure is applied.
    [00043] The sample receiving unit 120 can have at least one anti-inverting flow unit 140 in one direction, crossing a flow direction of the sample, where the sample flows from inlet 110 to outlet 130. At a anti-inverting flow unit 140 may be rib-shaped. The anti-inverting flow unit 140 creates resistance in the sample flow and, as a result, inhibits an inverted flow of the sample from the sample receiving unit 120 to the inlet 110.
    [00044] Since the transport of the sample from the sample chamber 100 to the sample separation unit 200 uses the centrifugal force per rotation of the rotating body 10, the sample receiving unit 200 is properly located more externally than the sample chamber 100. The sample separation unit 200 for sample centrifugation can be configured in different ways, and an exemplary embodiment of the sample separation unit 200 is shown in Fig. 4. Referring to Fig. 4, the sample separation unit 200 may include a channel type supernatant collector 210 extending out of the sample chamber 100 and a precipitate collector 220, which is a space formed at one end of the supernatant collector 210 to collect a precipitate with relatively high density. The supernatant collector 210 has a sample dispensing channel 230 for distributing the supernatant into the reaction chamber 300 (not shown). The flow of the sample passing through the sample dispensing channel 230 can be controlled by a valve 231. Valve 231 can be any type of microfluidic valve. For example, valve 231 may include a so-called "normally closed valve", in which a channel of the valve is closed to prevent fluid from flowing, unless the valve is opened by an external power supply.
    [00045] Returning to Fig. 2, a supernatant measurement chamber 250 can be placed between the sample separation unit 200 and the reaction chamber 300, in order to measure a quantity of supernatant. One volume of the supernatant measurement chamber 250 may be sufficient to carry a certain amount of supernatant required for testing. A valve 251 is mounted on an outlet of the supernatant measurement chamber 250 in order to control the flow of fluid. Valve 251 can be a normally closed valve, identical to valve 231. The supernatant measurement chamber 250 is connected to the reaction chamber 300, via a channel 252. Although not shown in the drawing, an alternative chamber and an additional channel of fluid can be supplied between the sample dispensing channel 230 and the supernatant measurement chamber 250, in order to receive excess sample in a liquid phase remaining after measurement.
    [00046] The first and second chambers of buffer solution 310 and 320 can receive a reagent (ie, a reactive solution) needed for antigen / antibody response or a biochemical reaction (such as ligand / receptor binding).
    [00047] The first buffer chamber 310 receives a first buffer solution. The first buffer solution may include, for example, a conjugated buffer solution to intercalate immunological examination, a buffer solution containing competitive protein for competitive immunological examination, a buffer solution containing various enzymes, including, for example, polymerase and primer for amplification of DNA and so on.
    [00048] The first buffer chamber 310 is connected to a first ventilation chamber 313. The first ventilation chamber 313 forms a ventilation path to communicate the first buffer chamber 310 with external air, thus easily discharging the first buffer solution contained in the first buffer solution chamber 310. A valve 314 is placed between the first buffer solution 310 and the first ventilation chamber 313. Another valve 311 is mounted on an outlet of the first buffer solution 310. Each such valves 311 and 314 can be normally closed valves, as described above. By introducing the first buffer solution into the first buffer chamber 310 and installing valves 311 and 314, the first buffer chamber 310 can remain closed until valves 311 and 314 are opened. In accordance with another exemplary embodiment, a measuring chamber (not shown) can be provided at the outlet of the first buffer chamber 310, to provide a constant amount of first buffer solution required for testing inside reaction chamber 300. If a valve (not shown) is mounted at the outlet of the measuring chamber (not shown), the first flow of buffer solution can be controlled. If the measuring chamber is not used, the first buffer solution can be directly fed from the first buffer solution 310 to reaction chamber 300, opening valve 311 mounted on the outlet of the first buffer solution 310.
    [00049] The second buffer chamber 320 receives a second buffer solution. The second buffer solution may include, for example, a substrate buffer solution to express a specific color by reacting the substrate with a conjugated or competitive reaction product, a buffer solution containing several enzymes necessary for DNA hybridization and so on. against. The second buffer chamber 320 is substantially the same as the first buffer chamber 310, except that the second buffer solution received therein is different from the first buffer solution and therefore a detailed description of the second buffer chamber 320 will be omitted. for brevity.
    [00050] Although an exemplary embodiment describes the microfluidic structure, which consists of two buffer chambers 310 and 320, such a structure can have only one buffer chamber or at least three buffer chambers, based on reaction types.
    [00051] In the other exemplary embodiment, a washing chamber 330 may contain a washing buffer solution to wash a residue remaining after a reaction from reaction chamber 300. The washing chamber 330 is connected to a third ventilation chamber 333 The third ventilation chamber 333 forms another ventilation path to communicate the wash chamber 330 with external air, thus easily discharging the wash buffer solution contained in the wash chamber 330. A valve 334 is placed between the wash chamber 330 and the third ventilation chamber 333. The wash chamber 330 is connected to the reaction chamber 300, via another valve 331. Each of these valves 331 and 334 can be a normally closed valve, as described above.
    [00052] The reaction chamber 300 receives the supernatant from the supernatant measurement chamber 250, through a channel 252. The reaction chamber 300 may contain a detectable signal generator present in a liquid or solid phase.
    [00053] When the detectable signal generator, in a solid phase, is present in the reaction chamber 300, the detectable signal generator can be temporarily fixed to an internal wall of the reaction chamber 300, or in a porous block fixed to it. That is, the detectable signal generator attached to the reaction chamber 300 is dissolved by penetrating the supernatant, at which point the dissolved binder is combined with an analyte contained in the supernatant. The combined detectable analyte / signal generator becomes a mobile product. If the supernatant flows into reaction chamber 300, the detectable signal generator is excessively redissolved at an early stage, while the redissolution of the detectable signal generator is drastically reduced at a later stage. Conventional technologies have problems with deterioration in the reproducibility of the test results and the characteristics of the signal of response to the concentration of analytes, depending on the variation in the redissolution of the detectable signal generator and / or the flow rate of the detectable signal generator, since a unit capillary force actuator and another unit containing the detectable signal generator are co-present in a physical space. Such technologies also have restrictions, in which the detectable signal generator must be in a solid phase and fixed to the physical space. On the contrary, the exemplary embodiment uses, separately, a reaction chamber 300 containing the detectable signal generator and an analysis chamber 400 for capillary action, described below, thus eliminating re-dissolving influences of a detectable signal generator and / or flow rate of the detectable signal generator on the capillary force. In addition, when a fluid sample (i.e., a liquid sample) is fed into the analysis chamber 400, after completing the combination of the detectable signal generator and the analyte in a physically separate space, the detectable signal generator may be preferably present in a solid or liquid state.
    [00054] A detectable signal generator refers to a material specifically reacted with an analyte fed into reaction chamber 300 by any typical method. Examples of such a detectable signal generator vary, depending on the types of analytes. For example, for antibody A as an analyte, the detectable signal generator may be a conjugate, such as an antigen or antibody pre-bound with an identification material, such as a fluorescent material, where antibody A and the detectable signal generator are first combined in the reaction chamber 300, a conjugate formed from antibody A, and the fluorescent material is fixed in the analysis chamber 400, using an antigen corresponding to antibody A, followed by the use of the conjugate for detection.
    [00055] Detectable signal generator identifiers may include, for example, polymer granules, metallic colloids, such as gold colloids or silver colloids, enzymes such as peroxidase, fluorescent materials, luminous materials, super paramagnetic materials, materials containing chelate of lanthanum (III), polymeric nanoparticles, and radioactive isotope elements. However, the identifiers of the detectable signal generator are not particularly limited to this indication.
    [00056] The reaction chamber 300 may have a residue chamber 360, for storing residues remaining after the reaction, which have been washed, using a washing buffer solution in the washing chamber 330, impurities to be removed, and the like. Impurities, which contain a detectable signal generator and / or non-combined analyte, are moved to the 360 waste chamber. Therefore, for example, for non-competitive analysis, such as detection of specific antibodies, a detectable signal generator or non-combined analyte in reaction chamber 300 is neither moved to analysis chamber 400 nor combined with a capture binder permanently attached to a test region, or to a control region, described below. In this sense, a detectable analyte / signal generator complex is not linked to the test region or the control region, thus avoiding the competitive inhibition of such a connection. In addition, since an unmatched part of the analyte is separated within the residue chamber 360, a "high-dose Hook effect", caused by a high analyte concentration, is not observed. The waste chamber 360 is connected to the reaction chamber 300, through a channel 362. Channel 362 has a valve 361, which can be a normally closed valve, described above.
    [00057] The analysis chamber 400 is connected to the reaction chamber 300, through a valve 305, and receives a fluid from the reaction chamber 300, after the reaction is ended.
    [00058] Analysis chamber 400 is provided for antigen / antibody response or specific biochemical reaction between biomaterials.
    [00059] The analysis chamber 400 includes a support 410 for receiving a fluid from the reaction chamber 300 after the end of a reaction; and a detection region 420 under capillary action, which consists of porous membranes, micropore or micropillary structures. Detection region 420 includes a test region 430, in which a capture binder is directly or indirectly attached, to analyze analytes. The analysis chamber 400 may also have a control region 440, in which another capture binder, independent of the capture binder permanently attached to the test region 430, is permanently attached.
    [00060] One end of the detection region 420 is extended to the support 410 and, when a fluid fed from the reaction chamber 300 fills the support 410, the extended end of the detection region 420 is submerged in the fluid. When fully loading support 410 with fluid, capillary force is applied in Direction A shown in Fig. 2, and a detectable analyte / signal generator complex moves along detection region 420 in the same direction, that is, Direction A. The detectable analyte / signal generator complex is combined with a capture binder, which is permanently attached to test region 430 and control region 440 by antigen / antibody response or specific biochemical reaction between biological materials. As a result, the detectable analyte / signal generator complex is trapped in test region 430 and control region 440. After the fluid is completely displaced to regions 430 and 440 by capillary force, the fluid is returned to the support 410, by centrifugal force applied in Direction B, shown in Fig. 2, in which the centrifugal force is generated by rotation of the microfluidic device. The direction of the centrifugal force, Direction B, is opposite to the direction of the capillary action, Direction A. Thus, compared to any conventional technique using capillary force applied in a single direction to react the fluid with a fixed reagent, a 2-fold increase in reaction time is achieved, in turn, remarkably improving the sensitivity of the reaction.
    [00061] A reaction cycle of applying capillary force (Direction A) and centrifugal force (Direction B) is not limited to just one cycle, but after completely transporting the fluid back to support 410 by centrifugal force and interrupting the rotation of the microfluidic device, a part of the detectable analyte / signal generator complex, which has not been combined with the capture binder, is again combined with another capture binder, permanently attached to the test region 430 and the control region 440 by capillary force in Direction A. After the fluid is completely displaced to regions 430, 440 by a second application of capillary action, the fluid can be returned to support 410, using a second application of the centrifugal force generated by rotation of the microfluidic device , so that a part of the analyte / first reagent complex, which was not combined by the second capillary action, can be repeatedly subjected to the reaction. In an exemplary embodiment, a reaction cycle is repeated for the desired number of repetitions, in order to sufficiently carry out the reaction, considerably increasing the sensitivity of detection of the analytes.
    [00062] The analysis chamber 400 has an interruption chamber 460, to receive a part of the fluid, which was not combined with the capture binder after the reaction of the test region 430 and the control region 440. The interruption chamber 460 is connected to the analysis chamber 400 through a channel 462. A valve 461 is mounted on channel 462. The valve 461 can be a normally closed valve, described above. After the reaction is sufficiently conducted, the valve 461 is opened and the fluid contained in the analysis chamber 400 is completely displaced to the interruption chamber 460, using the centrifugal force generated by the rotation of the microfluidic device, thus ending the reaction.
    [00063] The capture binder refers to a capture test for analysis of analytes and may include various materials, such as antigen, antibody, enzyme, DNA, RNA and the like, depending on the analyte materials in question to be analyzed. For example, if the analyte is a carbamate-based insecticide, the capture binder can be acetylcholine esterase (AChE), whereas, if the analyte is an antigen, the capture binder can be a capture antibody to the antigen.
    [00064] The detection region 420, in which the capillary force is applied, must be optically transparent, and can have a circular or rectangular cross section. For the detection region 420 with a circular section, an inner diameter of a capillary tube can vary from about several micrometers to about 1 millimeter. A capillary tube size can be defined within a desired range sufficient to determine a red blood cell ratio, ie hematocrit. The detection region 420 can be formed of any suitable material, as long as it has a small cavity volume and comprises very fine pores with a high apparent density. Examples of such materials may include porous membranes, micropore, micropylar structures and the like. Fig. 5 shows micropiles 502 used to prepare detection region 420.
    [00065] Fig. 6 shows an analysis chamber 400 ', according to another exemplary embodiment. Referring to Fig. 6, a detection region 420 ', having a test region 430' and a control region 440 ', is partially inclined with respect to Direction A for capillary action. More particularly, one end of the detection region 420 ', in contact with a support 410', forms an upward sloping unit 470, in which the test region 430 'and the control region 440' are present, while the other Unit 480 of detection region 420 'is straight. The reason behind such a configuration is that the 490 end of the detection region 420 ', in contact with the support 410', is located below the test region 430 'and the control region 440', in order to avoid the fluid overflow exceeding the capillary force by force of gravity.
    [00066] Another exemplary embodiment provides a microfluidic centrifugal device for detecting an analyte in a liquid sample, including: at least one microfluidic structure having several chambers, at least one channel, through which the various chambers are connected together, and at least one valve for opening and closing at least one channel; and a detection unit, in which the device also has a reaction chamber for receiving a detectable signal generator to be combined with an analyte in the liquid sample, and an analysis chamber, which is located downstream of the reaction chamber , and includes a detection region, to which a capture binder is attached to be combined with a detectable analyte / signal generator complex, and in which a fluid transported between the reaction chamber and the analysis chamber is controlled by the least one valve, and in which the detection region includes porous membranes, micropore or micropillary structures.
    [00067] This exemplary embodiment is substantially identical to the exemplary embodiment described above, except that the microfluidic structure is mounted on the microfluidic device. Hereafter, particular characteristics and / or technical configurations of the microfluidic device above, other than those described in the previous exemplary embodiment, will be explained, while a detailed description of the same conditions can be omitted for the sake of brevity.
    [00068] After an analyte contained in a fluid sample (ie the liquid sample) has been completely combined with a detectable signal generator in a reaction chamber 300, a valve 305 located between reaction chamber 300 and a analysis chamber 400 is opened. Then, the fluid sample, which contains a detectable analyte / signal generator complex, is delivered to a support 410 of the analysis chamber 400. After filling the support 410 with the fluid sample, the fluid sample moves along a detection region 420 by capillary action, in which one end of the support 410 comes into contact with the detection region 420. When moving along the detection region 420 in Direction A shown in Fig. 2, the complex detectable analyte / signal generator is combined with a capture binder permanently attached to a test region 430 and a control region 440, for example, by antigen / antibody response or a specific biochemical reaction between biomaterials.
    [00069] As described above, the detectable signal generator can be present in a liquid or solid phase in the reaction chamber 300. When the detectable signal generator is present in a solid phase, the detectable signal generator fixed in the reaction chamber 300 is dissolved by penetrating a supernatant, and the dissolved binder is then combined with an analyte contained in the supernatant. The combined detectable signal / analyte generator becomes a mobile product.
    [00070] As described above, the mobile product is separated into a part, which contains the detectable signal generator, and a part of capillary action force by physical separation, in which the part, which contains the detectable signal generator, is inserted in the reaction chamber 300, while the capillary action force part is received in the analysis chamber 400. Consequently, redissolution influences of the detectable signal generator and / or output rate of the detectable signal generator on the capillary force can be excluded favorably. In addition, since the fluid sample is fed into the analysis chamber 400, after completing the combination of the detectable signal generator and the analyte in a physically separate space, the detectable signal generator may preferably be present in a solid state or liquid. The transport of the fluid sample, which contains a detectable analyte / signal generator complex from reaction chamber 300 to analysis chamber 400, is properly controlled by opening and closing a valve 305.
    [00071] Fig. 7 is a block diagram, which illustrates a test system, according to an exemplary embodiment.
    [00072] Such a test system of the exemplary embodiment above includes a rotational driver D for rotating a disk type 1 microfluidic device, an E valve switching unit, a sensing unit 30, an output unit 40, a bank diagnostic data (DB) 50, and a control unit 60 for controlling individual devices described above.
    [00073] The rotational driver D rotates the disk type 1 microfluidic device in order to apply centrifugal force to it, allowing centrifugation of a sample and movement of a fluid, and also stops and rotates the same device 1, in order to move the analysis chamber 400 (see FIG. 2) to a desired position.
    [00074] Although not shown in the drawing, the rotational driver D may still include a motor drive device to control an angular position of the disk-type microfluidic device 1. For example, the motor drive device may have a stepper motor, or a direct current (DC) motor.
    [00075] The E-valve switching unit is designed to open and close at least one valve (not shown) of the disk type 1 microfluidic device, and includes an external power source E1 and a unit an E2 movement to move the source of external energy E1 for any valve, which must be opened.
    [00076] The external energy source E1 can be selected from a laser source, which radiates a laser beam, a light-emitting diode (“LED”) radiating visible or infrared light, a xenon lamp, etc. In particular, the laser source can have at least one laser diode (LD).
    [00077] The movement unit E2 can also include a drive motor (not shown) and a reducer (not shown) equipped with the external energy source E1 to move the external energy source E1 over a valve, which must be opened by drive motor rotation.
    [00078] The detection unit 30 can be installed in several locations to determine the absorbance of the reaction chamber and, in an exemplary embodiment, includes at least one light emitting unit 31 and at least one light receiving unit 32 , which is aligned with the light emitting unit 31 to receive penetrating light in the detection region 420 of the analysis chamber 400 (see FIG. 2), in the microfluidic device 1.
    [00079] The light-emitting unit 31 can be an intermittent light source with a specific frequency, including, for example, a semiconductor, light-emitting device such as an LED or a laser diode (LD), a discharge lamp in gas, like a halogen lamp or a xenon lamp etc ...
    [00080] The light emitting unit 31 is placed above the microfluidic device 1, in which the light emitted by the light emitting unit 31 passes through the analysis chamber 400 and reaches the light receiving unit 32.
    [00081] The light receiving unit 32 generates electrical signals, according to an incident light intensity, and adopts, for example, a photodiode with depletion layer, avalanche photodiode (APD), photomultiplier tube (PMT) etc ..
    [00082] In the present exemplary embodiment, the light-emitting unit 31 is located above the disk-type microfluidic device 1, while the light-receiving unit 32 is positioned below the disk-type microfluidic device 1; however, the positions of these units can be switched. In addition, a light path can be adjusted using a reflecting mirror or a light guide element (not shown).
    [00083] The control unit 60 controls the rotational driver D, the valve switching unit E and / or the detection unit 30, to smoothly conduct the operation of the test system, look for the diagnostic DB 50 and use absorbance detected by the detection unit 30 and a standard curve stored in the diagnostic DB 50, in order to determine the concentration of an analyte in the supernatant contained in the analysis chamber 400 of the microfluidic device 1.
    [00084] Output unit 40 transmits diagnostic results and information on whether or not the diagnosis has been completed and may include a visible output device, such as a liquid crystal display (LCD), an audio output device , such as a speaker, or an audiovisual output device.
    [00085] The following description will be presented of a method of detecting analytes in a liquid sample, using the microfluidic device. Fig. 8 is a flow chart, which illustrates a method of detecting an analyte in a liquid sample, using the microfluidic device, according to an exemplary embodiment. In this exemplary non-limiting embodiment, a process for blood analysis will be described in detail.
    [00086] For example, whole blood collected from a person to be examined is introduced into a sample chamber 100 (S101), and the microfluidic device 1 is mounted on the rotational driver D.
    [00087] Then, by rotating the microfluidic device 1 at low speed, the blood sample is delivered from the sample chamber 100 to the sample separation unit 200. The low speed can, in an exemplary embodiment, be a speed of rotation generating adequate centrifugal force to move a fluid. For example, the microfluidic device 1 can rotate at an accelerated speed of about 1800 revolutions per minute for 11 seconds. By centrifugal force, the sample moves from the sample chamber 100 to the sample separation unit 200. The sample is transported from the sample chamber 100 to the sample separation unit 200 by centrifugal force.
    [00088] Then, a centrifugation process (S102) is conducted. The rotational driver D rotates the microfluidic device 1 at high speed. Such a high speed can be a speed of rotation, separating the blood in a serum or plasma, as a supernatant and a precipitate (blood cells). For example, microfluidic device 1 can rotate at an accelerated speed of about 3600 rpm for about 160 seconds. As a result, relatively heavy blood cells are moved into precipitate collector 220, while the supernatant remains in the supernatant collector 210.
    [00089] Using valve switching unit E, closed valve 231 is opened. The rotational driver D rotates the microfluidic device 1 to generate centrifugal force. This centrifugal force causes the supernatant to move from the supernatant collector 210 to the supernatant measurement chamber 250, through channel 230. Since valve 251 is closed in an outlet outlet of the supernatant measurement chamber 250, the supernatant it fills the supernatant measuring chamber 250. Therefore, if a quantity of the supernatant is sufficient, the supernatant is contained in the supernatant measuring chamber 250 in an amount corresponding to a volume of the supernatant measuring chamber 250.
    [00090] Then, valve 251 is opened, using valve switching unit E, and the supernatant moves from the supernatant measurement chamber 250 to reaction chamber 300, by rotating the microfluidic device 1. The rotational driver D you can shake the microfluidic device 1 several times in the right and left directions (clockwise and counterclockwise), in order to combine the detectable signal generator with the analyte contained in the supernatant. As a result, a fluid sample (ie, a liquid sample), which contains a detectable analyte / signal generator complex, is created in reaction chamber 300 (S103).
    [00091] Subsequently, opening the valve 305 and rotating the microfluidic device, the fluid sample is moved into the support 410 of the analysis chamber 400. After filling the support 410 with the fluid sample, one end of the detection region 420 comes into contact with the fluid sample contained in support 410, allowing, in turn, the capillary transfer of the fluid sample in the detection region 420 or 420 ', which consists of porous membranes, micropore structures, or micropillaries. The fluid sample, which contains the detectable analyte / signal generator complex, moves along the detection region 420 or 420 ', and the detectable analyte / signal generator complex is combined with a capture binder permanently attached to the test region 430 or 430 '(S104). After the fluid sample passes completely through the detection region 420 or 420 ', the rotational driver D rotates the microfluidic device in order to pass the fluid sample back through the detection region 420 or 420' by centrifugal force. Here, a part of the detectable analyte / signal generator complex, which has not been combined with the capillary strength capture binder, can be combined with the capture binder (S105). Therefore, in comparison with the conventional technique, in which an antigen / antibody response and / or a biochemical reaction is terminated only after the fluid flow in a single direction, a reaction time in the present exemplary embodiment is remarkably extended, in turn, increasing the sensitivity of the reaction. In addition, as described above, the application cycle of capillary and centrifugal forces used in the exemplary embodiment is not limited to one cycle, but can be repeated for the desired number of cycles in order to sufficiently conduct the reaction. In other words, when the rotation of the microfluidic device is interrupted, after the complete delivery of the fluid sample to the support 410 by centrifugal force, the fluid sample flows again along the detection region 420 by capillary action (S104). After the complete movement of the fluid sample along the detection region 420, the fluid sample can be returned to the support 410, using, once again, the centrifugal force generated by the rotation of the microfluidic device (S105).
    [00092] When it is determined that the reaction has been sufficiently performed ("YES" in S106), valve 461 connected to support 410 of analysis chamber 400 is opened and the fluid sample is transported into interruption chamber 460 through channel 462, by rotating the microfluidic device. After transporting the fluid sample to the interruption chamber 460, the reaction to combine the detectable analyte / signal generator complex with the capture binder is terminated, and it does not proceed further (S107). Finally, using the detection unit 30, the absorbance of the detection region 420 in the analysis chamber 400 is defined. For extreme point analysis, absorbance is repeatedly measured at defined distances to determine absorbance during a saturated reaction. Based on a relationship between absorbance and concentration stored in the diagnostic DB 340, a concentration of each of the substances to be analyzed is calculated.
    [00093] Although some exemplary embodiments have been shown and described in conjunction with accompanying drawings, it should be clear that the exemplary embodiments have been proposed for illustrative purposes only, and particularly do not restrict the scope of the inventive concept. Thus, it should be realized by those skilled in the art, that various substitutions, variations and / or modifications can be made to these exemplary embodiments, and such exemplary embodiments are not particularly restricted to the specific configurations and / or arrangements, described above or illustrated.
    权利要求:
    Claims (13)
    [0001]
    1. CENTRIFUGAL MICROFLUID DEVICE, characterized by comprising: at least one microfluidic structure composed of a chamber and at least one channel connected in the chamber; and a detection unit (30), where the chamber includes a reaction chamber (300), comprising a detectable signal generator to combine the detectable signal generator with an analyte from a liquid sample to create an analyte / temperature generator complex. detectable signal, and an analysis chamber (400) located downstream of the reaction chamber (300), where the detectable signal generator is in a liquid or solid phase, where the analysis chamber (400) comprises a support (410, 410 ') which conducts a fluid from the reaction chamber (300) and a detection region (420, 420') to combine a capture binder with the detectable analyte / signal generator complex, in which the detection region ( 420, 420 ') includes one of porous membranes, micropore and micropylar structures, in which the detection region (420, 420') comprises a test region (430, 430 '), in which the capture binder is fixed, and a control region (440, 440 '), which is located downstream of the test region ( 430, 430 ') in relation to a capillary action direction A and separated at a distance from the test region (430, 430') and in which the detection region (420, 420 ') is arranged so that the application of a capillary force displaces the fluid along the detection region (420, 420 '), completely changing the fluid to the test region (430, 430') and control region (440, 440 '), and applying a force centrifuge delivers the fluid back to the support (410, 410 '), in which the centrifugal force has a direction B opposite direction A of capillary action.
    [0002]
    2. CENTRIFUGAL MICROFLUID DEVICE, according to claim 1, characterized in that the detection region (420 ') contacts one end of the support (410').
    [0003]
    3. CENTRIFUGAL MICROFLUID DEVICE, according to claim 1, characterized by a section of the detection region (420 '), including the test region (430') and the control region (440 '), being tilted in direction A capillary action.
    [0004]
    4. CENTRIFUGAL MICROFLUID DEVICE, according to claim 1, characterized in that the chamber has an interruption chamber (460) for receiving the fluid sample from the analysis chamber (400), and in which the interruption chamber (460) is located downstream of the analysis chamber (400) with respect to a direction B of the centrifugal force.
    [0005]
    5. CENTRIFUGAL MICROFLUID DEVICE, according to claim 1, characterized in that the detectable signal generator consists of a specific analyte connection element and a detectable signal generating element.
    [0006]
    6. CENTRIFUGAL MICROFLUID DEVICE, according to claim 1, characterized in that the detectable signal generator in the reaction chamber (300) is contained in a dry, solid or liquid state.
    [0007]
    7. CENTRIFUGAL MICROFLUID DEVICE, according to claim 1, characterized in that the detectable signal generator is selected from polymeric granules, metallic colloids, enzymes, fluorescent materials, luminous materials, super paramagnetic materials, materials containing lanthanum chelate (III ), polymeric nanoparticles and radioactive isotopes.
    [0008]
    8. CENTRIFUGAL MICROFLUID DEVICE, according to claim 1, characterized in that the detection unit (30) detects and analyzes the analyte / detectable signal generator complex combined with the capture agglomerate.
    [0009]
    9. CENTRIFUGAL MICROFLUID DEVICE, according to claim 1, characterized in that the detection unit (30) comprises a light source unit (31) and a light receiving unit (32), which is aligned with the light source unit (31) and receives light emitted by the light source unit (31), which passes through the analysis chamber (400).
    [0010]
    10. CENTRIFUGAL MICROFLUID DEVICE, according to claim 1, characterized by the fact that it still comprises a rotating body (10).
    [0011]
    11. CENTRIFUGAL MICROFLUID DEVICE, according to claim 10, characterized by further comprising: at least one valve to close and / or open at least one channel.
    [0012]
    12. CENTRIFUGAL MICROFLUID DEVICE, according to any one of claims 1 to 9, characterized by comprising: at least one valve to close and / or open at least one channel; at least one channel; in which at least one valve controls the transport of the fluid between the reaction chamber (300) and the analysis chamber (400).
    [0013]
    13. CENTRIFUGAL MICROFLUID DEVICE, according to any one of claims 1 to 12, characterized in that the reaction chamber (300) comprises a porous block that includes a detectable signal generator.
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    同族专利:
    公开号 | 公开日
    CN102472739A|2012-05-23|
    EP2529220B1|2016-08-03|
    US20110263030A1|2011-10-27|
    BR112012018853A2|2016-04-12|
    EP2529220A4|2013-06-19|
    JP2013518276A|2013-05-20|
    US20110189701A1|2011-08-04|
    AU2011211319A1|2012-08-23|
    KR20110088746A|2011-08-04|
    CA2788344A1|2011-08-04|
    US9164091B2|2015-10-20|
    WO2011093602A2|2011-08-04|
    SG182770A1|2012-09-27|
    CA2788344C|2016-05-17|
    KR101722548B1|2017-04-03|
    CN102472739B|2015-11-25|
    EP2610618A1|2013-07-03|
    AU2011211319B2|2014-04-24|
    EP2529220A2|2012-12-05|
    WO2011093602A3|2011-12-01|
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    法律状态:
    2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|
    2019-06-11| B25A| Requested transfer of rights approved|Owner name: POLARIS MEDINET, LLC (US) |
    2019-06-25| B25A| Requested transfer of rights approved|Owner name: NEXUS DX, INC. (US) |
    2019-07-09| B06T| Formal requirements before examination|
    2020-10-06| B09A| Decision: intention to grant|
    2020-12-15| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 11/01/2011, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    KR1020100008392A|KR101722548B1|2010-01-29|2010-01-29|Centrifugal Micro-fluidic Device and Method for detecting analytes from liquid specimen|
    KR10-2010-0008392|2010-01-29|
    PCT/KR2011/000192|WO2011093602A2|2010-01-29|2011-01-11|Centrifugal micro-fluidic device and method for detecting analytes from liquid specimen|
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