WO2009107608A1 - Structure de fourniture de liquide et puce de micro-analyse utilisant celle-ci - Google Patents

Structure de fourniture de liquide et puce de micro-analyse utilisant celle-ci Download PDF

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Publication number
WO2009107608A1
WO2009107608A1 PCT/JP2009/053283 JP2009053283W WO2009107608A1 WO 2009107608 A1 WO2009107608 A1 WO 2009107608A1 JP 2009053283 W JP2009053283 W JP 2009053283W WO 2009107608 A1 WO2009107608 A1 WO 2009107608A1
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Prior art keywords
liquid
flow path
liquid reservoir
feeding structure
channel
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PCT/JP2009/053283
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English (en)
Japanese (ja)
Inventor
俊明 北川
理伸 三枝
スンジン チョ
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シャープ株式会社
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Publication of WO2009107608A1 publication Critical patent/WO2009107608A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N2035/1027—General features of the devices
    • G01N2035/1034—Transferring microquantities of liquid
    • G01N2035/1039—Micropipettes, e.g. microcapillary tubes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N2035/1027—General features of the devices
    • G01N2035/1048—General features of the devices using the transfer device for another function
    • G01N2035/1058—General features of the devices using the transfer device for another function for mixing
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N2035/1027—General features of the devices
    • G01N2035/1048—General features of the devices using the transfer device for another function
    • G01N2035/1062—General features of the devices using the transfer device for another function for testing the liquid while it is in the transfer device

Definitions

  • the present invention relates to a liquid feeding structure of a microanalysis chip used for trace chemical analysis of biological materials and substances in the natural environment, and more specifically, relates to a liquid feeding structure using a capillary force as a driving force. Is.
  • Immunoassay is known as an important analysis / measurement method in the medical field, biochemical field, measurement field such as allergen, and the like.
  • the conventional immunoassay has a problem that the operation is complicated and the analysis takes more than a day.
  • micro-analysis chip has been proposed that shortens the analysis time and simplifies the analysis operation by forming a micro-order channel on the substrate and immobilizing antibodies or the like in the micro-channel. Yes.
  • FIG. 18 shows an example of a micro analysis chip using such capillary force.
  • a method of discharging the solution filled in the flow path for example, as shown in Patent Document 2, a method of discharging by installing an absorber that absorbs the solution at the discharge port has been proposed.
  • the liquid 300 is injected into the injection port 413 of the micro analysis chip shown in FIG. 20 (a) (FIG. 20 (b)).
  • the liquid flows through the channels 414, 415, and 416, is absorbed by the absorber provided at the end of the channel 416, and is discharged out of the chip (FIGS. 20C and 20D).
  • FIGS. 20 (e) and 21 (b) when a gas-liquid interface is formed in the channel 415 having a width smaller than that of the main channel 416, the channel having a narrow width from the main channel 416.
  • P is typically expressed by the following equation assuming a flow path having a radius r.
  • the pressure P generated by the surface tension works, and the strong capillary force due to the absorber acts in the direction of the absorber, and each attracts liquid in the opposite direction. Therefore, at the interface between the main channel 416 and the absorber 411 where gas easily enters. The liquid is broken. As a result, the liquid flows backward and becomes stable in a state where a gap is generated between the liquid 300 and the absorber 411. For this reason, even if the absorber 411 having a strong capillary force is provided in the discharge portion, the absorber 411 cannot absorb the liquid 300, and the liquid in the chip cannot be completely discharged (FIG. 21C). reference).
  • the present invention has been made to solve the above-described problem, and an object of the present invention is to provide a liquid feeding structure capable of smoothly discharging a liquid even when a narrow flow path exists. .
  • a first aspect of the present invention for solving the above-described problems is a first flow path connected to an open hole opened to the outside, a liquid reservoir portion continuous with the first flow path, and a continuous portion of the liquid reservoir portion. And at least an absorbent body that is in direct contact with the terminal end of the second flow path, and the pressure due to the surface tension generated in the liquid in the first flow path is P1, and the liquid in the second flow path P3 ⁇ P1 ⁇ P2 is established, where P2 is the pressure due to the surface tension generated in the liquid reservoir and P3 is the pressure due to the surface tension generated in the liquid in the liquid reservoir.
  • the minimum distance between the opposing wall surfaces of the first channel is P2.
  • the minimum distance between the opposing wall surfaces of the second flow path is D2
  • the minimum distance between the opposing wall surfaces of the liquid reservoir is D3, D2 ⁇ D1 ⁇ D3 is adopted. Is simple.
  • a second aspect of the present invention for solving the above-described problems is a first flow path connected to an open hole that is open to the outside, a liquid reservoir portion that is continuous with the first flow path, and a continuous portion of the liquid reservoir portion. At least a second flow path and an absorber that is in direct contact with the end of the second flow path, wherein the first flow path and the second flow path have a hydrophilic contact surface with the liquid,
  • D1 the minimum distance between the opposing wall surfaces of the first channel
  • D2 the minimum distance between the opposing wall surfaces of the second channel
  • the minimum distance between the opposing wall surfaces of the liquid reservoir is D3, D2 ⁇ D1 ⁇ D3 is satisfied.
  • the minimum distance D2 between the opposing wall surfaces of the second channel is equal to or less than the minimum distance D1 between the opposing wall surfaces of the first channel, as shown in FIG.
  • a strong capillary force 501 acts in the reverse flow direction and the liquid flows backward, a gas-liquid interface is generated in the second flow path, and the capillary force 502 acts in the forward flow direction equal to or greater than the reverse flow direction. For this reason, the contact between the liquid and the absorber is maintained, and all the liquid can be discharged to the outside of the structure without remaining in the liquid feeding structure.
  • the first flow path may have two or more.
  • the apparatus further comprises a second liquid reservoir provided on the upstream side of the first flow path, and a third flow path provided on the upstream side of the second liquid reservoir.
  • a second liquid reservoir provided on the upstream side of the first flow path
  • a third flow path provided on the upstream side of the second liquid reservoir.
  • the apparatus further comprises a second liquid reservoir provided on the upstream side of the first flow path, and a third flow path provided on the upstream side of the second liquid reservoir.
  • a second liquid reservoir provided on the upstream side of the first flow path
  • a third flow path provided on the upstream side of the second liquid reservoir.
  • a second liquid reservoir is provided upstream of the liquid reservoir, and the second liquid reservoir is used. It is preferable to carry out the reaction.
  • a liquid feeding structure capable of completely discharging the liquid in the structure can be realized.
  • FIG. 1 is a plan view of a liquid feeding structure according to an embodiment.
  • FIG. 2 is a cross-sectional view of the liquid feeding structure according to the embodiment.
  • FIG. 3 is a conceptual diagram illustrating the flow of the liquid in the liquid feeding structure according to the embodiment.
  • FIG. 4 is a conceptual diagram illustrating a liquid flow in the first flow path and the second flow path of the liquid feeding structure according to the embodiment.
  • FIG. 5 is a plan view of the liquid feeding structure according to the first embodiment.
  • FIG. 6 is a conceptual diagram showing the structure of the electrode.
  • FIG. 7 is a plan view of the liquid feeding structure according to the second embodiment.
  • FIG. 8 is a conceptual diagram showing the operation of the electrowetting valve.
  • FIG. 1 is a plan view of a liquid feeding structure according to an embodiment.
  • FIG. 2 is a cross-sectional view of the liquid feeding structure according to the embodiment.
  • FIG. 3 is a conceptual diagram illustrating the flow of the liquid in the liquid feeding structure according to the embodiment
  • FIG. 9 is a plan view illustrating a modification of the liquid feeding structure according to the first embodiment.
  • FIG. 10 is a plan view showing a liquid feeding structure according to the second embodiment.
  • FIG. 11 is a plan view of a liquid feeding structure according to Comparative Example 1.
  • FIG. 12 is a plan view of a liquid feeding structure according to Comparative Example 2.
  • FIG. 13 is a diagram illustrating the microanalysis chip according to the third embodiment.
  • FIG. 14 is a diagram illustrating the micro-analysis chip according to the fourth embodiment.
  • FIG. 15 is a diagram illustrating the micro-analysis chip according to the fifth embodiment.
  • FIG. 16 is a diagram illustrating the microanalyzer according to the sixth embodiment.
  • FIG. 17 is a diagram illustrating the microanalyzer according to the seventh embodiment.
  • FIG. 18 is a plan view of a liquid feeding structure according to a conventional technique.
  • FIG. 19 is a plan view of a liquid feeding structure according to a conventional technique.
  • FIG. 20 is a conceptual diagram showing the flow of the liquid in the liquid feeding structure shown in FIG.
  • FIG. 21 is a conceptual diagram illustrating a liquid flow in the first flow path and the second flow path of the liquid feeding structure according to the conventional technology.
  • the liquid feeding structure 110 includes a first flow path 115 having an open hole 113 for introducing liquid into the chip, and a liquid reservoir portion continuous with the first flow path. 116, a second flow path 117 that is continuous with the liquid reservoir, and an absorber 111 that is in direct contact with the end of the second flow path.
  • the flow path 114 is not an essential component of the present invention.
  • the second channel 117 is set so that the size of the channel is the same from upstream to downstream.
  • the pressure due to the surface tension generated in the liquid in the first flow path is P1
  • the pressure due to the surface tension generated in the liquid in the second flow path is P2
  • the pressure due to the surface tension generated in the liquid in the liquid reservoir is P3.
  • the pressure due to the surface tension generated in the liquid in the first flow path is P1
  • the pressure due to the surface tension generated in the liquid in the second flow path is P2
  • the pressure due to the surface tension generated in the liquid in the liquid reservoir portion is set so that P3 ⁇ P1 ⁇ P2 is established
  • the minimum distance between the opposing wall surfaces of the first flow path is D1
  • the minimum distance between the opposing wall surfaces of the second flow path is It is preferable to adopt a configuration in which D2 ⁇ D1 ⁇ D3 is established, where D2 is the minimum distance between the opposing wall surfaces of the liquid reservoir. In this embodiment, D2 ⁇ D1.
  • FIG. 2 shows a cross-sectional view of the liquid feeding structure according to the present embodiment.
  • the upper substrate 201 on which the flow path 114, the liquid reservoir 116, the first flow path 115, and the second flow path 117 are formed, the flow path 114, the liquid reservoir 116, and the first flow path. 115, a lower substrate 202 that seals from below the second flow path 117 and on which the absorber 111 is placed.
  • the thickness of the upper substrate 201 is about 0.1 mm to 10 mm, and the thickness of the lower substrate 202 is about 0.01 mm to 10 mm.
  • the open hole 113 may be a through hole having a diameter of 10 ⁇ m or more.
  • the flow path 116 of the liquid feeding structure is used as a detection unit that performs optical detection, as one or both materials used for the substrate 201 and the substrate 202, for example, as proposed in Patent Document 3
  • a transparent or translucent material include glass, quartz, thermosetting resin, thermoplastic resin, and film. Of these, silicon resins, acrylic resins, and styrene resins are preferable from the viewpoints of transparency and moldability.
  • electrochemical detection there are no such restrictions on materials.
  • the substrate 201 and the substrate 202 be a material capable of forming an electrode.
  • a material capable of forming an electrode glass, quartz, silicon and the like are preferable from the viewpoint of productivity and reproducibility. Note that with the current technology, it is difficult to form an electrode on an uneven portion, so it is preferable to form the electrode on a flat substrate 202.
  • the surface of the substrate 201 or 202 that is in contact with the liquid of the material is preferably hydrophilic so that the surface of the substrate material that is in contact with the liquid is easy to flow.
  • hydrophilic oxygen plasma treatment, UV treatment, or the like is used.
  • the hydrophilicity can also be enhanced by applying a surfactant or a reagent having a hydrophilic functional group to the surface.
  • a method of directly processing the substrate 201 for example, a method of machining, a method of laser processing, a method of etching with chemicals or gas, injection molding using a mold, press molding
  • methods such as casting for example, a method using a mold and a method using etching are preferable because of high reproducibility of the shape dimensions.
  • 3 and 4 show the flow of the liquid in the liquid feeding structure according to the present embodiment.
  • 3 (a) to 3 (e) are the same as in the prior art.
  • FIGS. 3E and 4B when the liquid flows back from the liquid reservoir 116 to the first flow path 115 by the capillary force, a gas-liquid interface is generated in the second flow path 117. . Since the channel width L2 of the second channel 117 is less than the channel width L1 of the first channel 115, the capillary force 502 acting on the second channel 117 has a capillary force 501 acting on the first channel 115. Counteract. For this reason, as shown in FIG.3 (f) and FIG.4 (c), a liquid will be discharged
  • the width and height of the flow channel 114, the liquid reservoir 116, the first flow channel 115, and the second flow channel 117 of the liquid feeding structure shown in FIG. 1 are not particularly limited, but the solution is affected by the wetness of the solution and the capillary force. Is set to a dimension that can penetrate.
  • the height is preferably set to about 1 ⁇ m to 5 mm.
  • the width is preferably set to about 1 ⁇ m to 5 mm.
  • an antibody or the like is immobilized in a liquid reservoir, an antigen-containing reaction is performed by flowing a liquid containing an antigen, and an antigen-antibody reaction is performed by flowing a liquid containing a labeled antibody to which a fluorescent dye is attached.
  • an antigen-containing reaction is performed by flowing a liquid containing an antigen
  • an antigen-antibody reaction is performed by flowing a liquid containing a labeled antibody to which a fluorescent dye is attached.
  • It can be used as a micro-analysis chip in which the liquid reservoir is irradiated with excitation light and the amount of antigen is measured by the amount of fluorescence.
  • a valve 140 may be provided in the first flow path.
  • the liquid delivery structure 110 includes an open hole 113, a third flow path 118, a second liquid reservoir 114, a first flow path 115, It has a liquid reservoir 116 that is continuous with one flow path, a second flow path 117 that is continuous with the liquid reservoir, and an absorber 111 that is in direct contact with the end of the second flow path.
  • the flow path 119 is not an essential component of the present invention.
  • the second flow path 117 has a pressure due to the surface tension generated in the liquid in the first flow path as P1, and a pressure due to the surface tension generated in the liquid in the second flow path as P2, and in the liquid reservoir When the pressure due to the surface tension generated in the liquid is P3, P3 ⁇ P1 ⁇ P2 is established. And a third flow path provided on the upstream side of the second liquid reservoir, wherein the pressure due to the surface tension generated in the liquid in the third flow path is P4, and the second liquid reservoir When the pressure due to the surface tension generated in the liquid in the section is P5, P5 ⁇ P4 ⁇ P2 is established.
  • the capillary force acting on the second flow path 117 is equal to or greater than the capillary force acting on the first flow path 115, and the capillary force acting on the second flow path 117 acts on the third flow path 118. Equal to or greater than the capillary force For this reason, similarly to the first embodiment, the liquid feeding is not stopped and the liquid can be smoothly poured.
  • an antibody or the like is fixed to the second liquid reservoir 114, an electrode is provided in the liquid reservoir 116, and the antigen-antibody reaction and enzyme labeling are provided in the second liquid reservoir 114. It can be used as a micro-analysis chip in which the reaction between the antibody and the antigen-antibody complex, the enzyme substrate reaction is performed, and the amount of the electrode active substance generated by the enzyme substrate reaction is detected by the electrode provided in the liquid reservoir 116.
  • FIG. 5 shows a liquid feeding structure according to this example.
  • the liquid feeding structure 110 is a flow connecting two open holes 113a and 113b, a liquid reservoir 116, two first flow paths provided with valves 141 and 142, and the open holes and the first flow path. It has the path
  • the liquid feeding structure is composed of two substrates as in the above embodiment, and is used for the production of the flow path 114, the liquid reservoir 116, the first flow path 115, and the second flow path 117 in the upper substrate.
  • a resist pattern was formed on a silicon substrate by a photolithography method, and then etching was performed by a dry etching process method.
  • the prepared mold form was placed, and silicon rubber (polydimethylsiloxane) (Zill pot 184 manufactured by Toray Dow Corning Co., Ltd.) was poured into the thickness until it became 2 mm, and heated at 100 ° C. for 15 minutes to be cured.
  • the width 103 of the channels 114a and 114b was set to 300 ⁇ m
  • the width of the liquid reservoir 116 was set to 600 ⁇ m
  • the width 100 of the first channels 115a and 115b was set to 50 ⁇ m
  • the width of the second channel 117 was set to 50 ⁇ m.
  • the flow path height was all 50 ⁇ m.
  • the lower substrate was produced by cutting a quartz substrate having a thickness of 600 ⁇ m into a length of 18 mm and a width of 16 mm with a dicing saw.
  • Two inlet holes 113 were formed in the upper substrate by punching to complete the substrate 201.
  • electrodes for the valves 141 and 142 and the detector 151 were prepared in advance.
  • the valves 141 and 142 were prepared by patterning a resist by a photolithography method, forming a titanium layer of 50 nm and a gold layer of 100 nm by a sputtering method, and then forming an electrode patterned by a lift-off method.
  • the valve may be other than the above as long as it can stop or start the inflow of liquid, such as a diaphragm type valve.
  • the detector 151 is manufactured by patterning a resist by a photolithography method, forming a titanium layer 50 nm and a gold layer 100 nm by a sputtering method, and then patterning the electrodes 152, 154, and 155 as shown in FIG. 6 by a lift-off method. 156 was formed.
  • the electrode 153 which is a part of the detection unit 151, after patterning a resist by a photolithography method, a silver layer of 1 ⁇ m is formed by a sputtering method, and a patterned electrode 153 is formed by a lift-off method.
  • the Ag surface was subjected to chlorination treatment to produce an Ag / AgCl layer electrode 153.
  • chlorination treatment a voltage of +100 mV for 50 seconds was applied to the electrode 153 in 0.1 M hydrochloric acid.
  • the upper substrate and the lower substrate are subjected to oxygen plasma treatment under the conditions of 100 W, oxygen flow rate of 30 sccm, and 60 seconds to increase the hydrophilicity of the substrate surface, and then the upper substrate and the lower substrate are bonded to each other by a self-adsorption action.
  • the absorbent body 111 made of cotton was placed on the downstream end of the liquid feeding structure according to the first example.
  • Comparative Example 1 As shown in FIG. 11, a liquid feeding structure 410 according to Comparative Example 1 was produced in the same manner as in Example 1 except that the second flow path was not formed.
  • the test which flows a liquid through the liquid feeding structure concerning Example 1 and Comparative Example 1 was conducted.
  • the liquid delivery structure according to Example 1 when a fluorescent dye (FITC) solution is dropped into the open hole, the solution 300 is filled in the liquid delivery structure by capillary action, and is absorbed from when the solution 300 reaches the absorber 111. The body 111 was able to absorb the solution in the flow channel and absorb it until there was no solution in the flow channel.
  • the absorber 411 started to absorb the solution in the channel from the time when the solution 300 reached the absorber 411, but a gas-liquid interface occurred in the first channel. At that time, the solution returned to the open hole side, and a gap was formed between the absorber 411 and the solution 300. Further liquid feeding stopped, and the solution 300 remained in the flow path.
  • FITC fluorescent dye
  • FIG. 13 is a top view of the micro analysis chip.
  • the liquid feeding structure according to the present embodiment includes an opening hole 2001 for the first liquid, an opening hole 2002 for the second liquid, third liquid reservoirs 2003 and 2004, a mixer 2007, 3 flow channel 2009, second liquid reservoir 2008, first flow channel 2011, first liquid reservoir 2010, second flow channel 2013, and the end of the second flow channel. And an absorber 111.
  • the first liquid When the first liquid is injected from the first liquid opening hole 2001, the first liquid is injected into the third liquid reservoir 2003. Similarly, when the second liquid is injected into the second liquid opening hole 2002, the second liquid is injected into the third liquid reservoir 2004.
  • a first valve 2005 and a second valve 2006 that can stop or start the flow of injected liquid into the mixer 2007 are connected to the first liquid reservoir and the second liquid reservoir, respectively.
  • the mixer 2007 has a configuration capable of sufficiently mixing the first liquid and the second liquid.
  • the second liquid reservoir 2008 is connected via the third flow path 2009.
  • the second liquid reservoir 2008 may have a configuration in which a substance that reacts with the substance to be detected contained in the solution is disposed.
  • the mixer and the reaction unit are connected via the third flow path 2009, but may be directly connected without passing through the third flow path 2009.
  • the first liquid reservoir 2010 is connected to the second liquid reservoir 2008 via the first flow path 2011.
  • the first liquid reservoir 2010 is provided with a detector 2012.
  • the detection unit has a configuration capable of directly or indirectly detecting the substance to be detected.
  • it when it is the structure which can detect a to-be-detected substance directly, it can be set as the structure which does not have the 1st liquid reservoir part 2010.
  • the absorber 2014 is connected to the first liquid reservoir 2010 via the second channel 2013.
  • the second channel 2013 has a capillary force equal to or greater than the capillary force of the first and third channels, and pulling the liquid to the absorber causes the first channel to be absorbed.
  • the liquid can be discharged without staying in the first and third flow paths.
  • an external connection terminal 2015 is provided. Input from the terminal to the power supply chip, input of an electrical control signal, output of a detection signal, and the like are performed.
  • the micro analysis chip itself does not need to be provided with a power supply, and therefore, a micro analysis chip with excellent cost performance can be realized.
  • injection part By injecting the first liquid and the second liquid from the first liquid opening hole 2001 and the second liquid opening hole 2002, respectively, the respective liquids are supplied to the third liquid reservoirs 2003 and 2004, respectively. Is injected.
  • the opening hole may be of such a size that capillary force does not work. In that case, the liquid can be sufficiently injected into the liquid reservoir even when the open hole is hydrophobic.
  • the opening hole may have a size that allows capillary force to work. In that case, by applying hydrophilicity to the open hole, the liquid can be injected into the liquid reservoir by capillary force.
  • the third liquid reservoirs 2003 and 2004 may have a space size that allows capillary force to work.
  • the height direction may be designed to be sufficiently small.
  • the open hole only needs to be open to the atmosphere.
  • the liquid can be injected by connecting a cartridge filled with liquid in advance in the open hole. Even in that case, it is preferable that the cartridge is open to the atmosphere at the connection ports of the open holes 2001 and 2002 or other portions so that the liquid can be sufficiently discharged when the liquid is injected.
  • the case where two open holes are provided will be described, but the number of open holes may be three or more as appropriate.
  • the sample containing the detection target in the first liquid open hole, the reagent in the second liquid open hole, the standard sample in the third liquid open hole, and the fourth liquid use
  • a cleaning liquid may be injected into the open hole.
  • the configuration is such that the cleaning liquid can be injected into the open hole, it can be used repeatedly, so that the cost performance is improved and the environmental load can be reduced.
  • valve The valve may be any valve that can stop or start the inflow of liquid, and may be a diaphragm valve finely formed by using the MEMS technology. When electrowetting valves are used, a working electrode and a reference electrode are required for each valve.
  • the electrowetting valve is a valve having a structure in which the flow of liquid is interrupted when no voltage is applied and the liquid is allowed to flow when a voltage is applied.
  • the principle of the electrowetting valve will be described with reference to FIG.
  • the liquid flows in the flow path 114 while being in contact with the electrowetting valve reference electrode 171.
  • the electrowetting valve working electrode 172 is covered with a hydrophobic film, and when no voltage is applied, the contact angle with the liquid increases to about 60 to 70 degrees.
  • the channel width and height are designed to be 50 ⁇ m, the liquid cannot pass through the first channel 115 due to the resistance of the liquid flowing through the first channel and the surface tension of the liquid.
  • the liquid when a voltage is applied, the liquid is negatively charged by the electrowetting valve reference electrode 171.
  • the liquid via the insulating film forms a virtual capacitor with the working electrode 172, and the liquid is attracted to the working electrode 172 to reduce the contact angle. For this reason, the liquid can pass through the first flow path 115 regardless of the resistance flowing through the flow path.
  • Each flow path of each valve has an optimal flow path space for each valve in order to appropriately stop or start inflow of liquid.
  • the mixer should just be comprised so that a 1st liquid and a 2nd liquid can fully be mixed.
  • a configuration in which mixing is performed by providing a micro-pillar structure in the vicinity of the inflow portion from the first valve and the second valve may be used.
  • There are various modes such as a T-shaped mixer, a Manz mixer, a mixer using a three-dimensional meandering channel, and any configuration may be used as long as it is configured to be sufficiently mixed.
  • the case where two liquids are mixed has been described.
  • three or more liquids may be appropriately mixed.
  • the second liquid reservoir 2008 functions as a reaction part that performs the reaction, and may be any structure as long as molecules that specifically recognize and react with the target substance contained in the sample solution are arranged.
  • the detection substance is an antigen
  • the antibody may be immobilized on the reaction part.
  • a sandwich method of enzyme immunoreaction is used. An antigen is reacted with an enzyme-labeled antibody (secondary antibody) to form a complex in which the antigen and the enzyme-labeled antibody are bound. The aforementioned complex is reacted with an antibody (primary antibody) immobilized in advance in the reaction part.
  • a substrate is introduced, reacted with an enzyme labeled with a secondary antibody, and an electrochemically active substance generated by the reaction is electrochemically detected on an electrode serving as a detection unit.
  • an electrochemically active substance generated by the reaction is electrochemically detected on an electrode serving as a detection unit.
  • a substance that can be detected by the detection part is generated according to the amount of the substance to be detected.
  • the 2nd flow path 2013 may use what kind of member and shape.
  • a hydrophilic material As long as the pressure by the surface tension which generate
  • hydrophilicity may be improved by performing oxygen plasma treatment.
  • a glass substrate is preferable because it has hydrophilicity.
  • the absorbent body may be any material that absorbs liquid, and examples thereof include polymer absorbent bodies, porous substances, hydrophilic meshes, sponge bodies, cotton, and filter paper.
  • the absorber is open to the atmosphere at the connection portion of the absorber and the second flow path or other portions so that the absorber can efficiently absorb.
  • the absorber may protrude partly in the second flow path. In that case, the absorber including the second flow path up to the protruding portion is partly absorbed, and the second flow path is reduced accordingly.
  • An external connection terminal 2015 is provided. Input from the terminal to the power supply chip, input of an electrical control signal, output of a detection signal, and the like are performed. If a gold electrode is used, it may be used in combination with other valves and detection electrodes, and the process may be simplified. Alternatively, a conductive material containing a material such as platinum, aluminum, or copper may be used.
  • the micro analysis chip itself does not need to be provided with a control circuit such as a power source or an IC, and therefore a chip with excellent cost performance can be provided.
  • the micro analysis chip includes an upper layer 2101 and a lower layer 2102.
  • the upper layer preferably has high transparency and processability and is preferably formed using PDMS.
  • the lower layer may be a silicon substrate as a material capable of forming electrodes for electrical control or the like.
  • One or both of the materials used for the upper layer 2101 and the lower layer 2102 are desirably transparent or translucent as proposed in Patent Document 3, for example. This is because, in the case of application to a chip system that detects the fluorescence of the subject by irradiating the subject flowing in the channel with excitation light by using the inside of the microchip channel as the detection unit, the fluorescence that has passed through the reaction unit This is because it is necessary to detect UV and UV.
  • the transparent or translucent material glass, quartz, thermosetting resin, thermoplastic resin, film and the like are preferable. Of these, silicon resins, acrylic resins, and styrene resins are preferable from the viewpoints of transparency and moldability.
  • one or both of the upper layer and the lower layer is a material capable of forming an electrode.
  • materials capable of forming electrodes substrate materials such as glass, quartz, and silicon are preferable from the viewpoint of productivity and reproducibility.
  • a first liquid opening hole 2001 and a second liquid opening hole 2002 are opened upward, and third liquid reservoirs 2003 and 2004, a first valve 2005 and a second liquid hole are opened in the lower part.
  • the flow path for providing the valve 2006, the mixer 2007, the second liquid reservoir 2008, the third flow path 2009, the first liquid reservoir 2010, the first flow path 2011, the second flow path 2013, etc. face downward. Opened and provided.
  • the absorber 2014 is arranged by providing a space opened on the lower side and filling the space. These bottom-opened portions are sealed at the bottom by the lower layer 2102 to form a space.
  • a first valve electrode 2105, a second valve electrode 2106, and a detection electrode 2112 are provided, and each is connected to an external connection terminal 2015.
  • the connection to the first valve electrode 2105 and the second valve electrode 2106 can be two terminals when an electrowetting valve is used and three terminals when a counter electrode is provided.
  • the detection electrode can have three terminals as described above.
  • the upper layer 2201, the middle layer 2202, and the lower layer 2203 are included.
  • the difference from the fourth embodiment is that the first liquid opening hole 2201 and the second liquid opening hole 2202 are divided into upper layers. Both the first liquid opening hole 2201 and the second liquid opening hole 2202 are formed as openings penetrating the 2201 layers.
  • the absorber 2214 is arranged by providing a space opened on the lower side and filling the space.
  • the middle layer can be formed in an open shape except for the second flow path 2213. If necessary, it can be formed in the same manner as the above-described structure opened on the lower side. In that case, the third liquid reservoirs 2203 and 2204 need to be opened on the upper side so as to be connected to the upper layer.
  • the second flow path 2213 is formed with an upper opening so as to connect to the upper layer.
  • the lower layer is the same as in the fourth embodiment.
  • FIG. 16 shows one embodiment of the microanalyzer.
  • the micro analyzer is a portable handy micro analyzer.
  • a chip connection port 2303 which is a connection port of the micro analysis chip 2302 described in the above embodiment is provided below the handy device 2301.
  • An external input / output terminal (not shown) that can be electrically connected to the external connection terminal of the micro analysis chip is provided in the back of the chip connection port 2303 in the handy device 2301, and the micro analysis chip 2302 is connected to the chip connection port 2303. Is inserted between the external input / output terminal in the handy device 2301 and the external connection terminal of the micro analysis chip 2302.
  • a display unit 2304 that can display the amount of a substance to be detected and an input unit 2305 that can input various data for starting and stopping measurement and specifying measurement parameters. Is provided.
  • an information processing system such as a CPU that can process data and an I / O logic circuit that processes input information and output information is built in the handy device.
  • valves such as reagents and samples (samples) that have been prepared in advance on the micro analysis chip and stopped by the valve
  • the inflow is sequentially started, and as a result, an electric signal corresponding to the amount of the substance to be detected detected by the detection unit is output from the external connection terminal of the micro analysis chip.
  • the handy device 2301 can be, for example, a portable electronic device such as a mobile phone or a PDA.
  • a mobile phone will be described as an example.
  • the mobile phone can be operated as a handy device by starting data processing analysis software for a micro analysis chip. That is, the mobile phone is virtually used as a handy device by dedicated software.
  • the external connection terminal of the micro analysis chip may be configured to be connectable to the external input terminal of the mobile phone.
  • the micro analysis chip By connecting the micro analysis chip to the mobile phone, inputting various data from the buttons on the mobile phone, and pressing the button set as the measurement start button, the micro analysis chip is prepared in advance and the flow is stopped by the valve Then, inflow of valves such as reagents and samples (samples) is started sequentially, and as a result, an electrical signal corresponding to the amount of the substance to be detected detected by the detection unit is output from the external connection terminal of the micro analysis chip.
  • the amount or type of the substance to be detected can be specified. Then, the measurement result is displayed on the display screen of the mobile phone.
  • a microanalyzer with excellent cost performance can be provided. Users can also take measurements wherever they need it. Many mobile users can enjoy the benefits when the mobile phone ownership rate rises and mobile phones become sufficiently widespread for the measurers (users). That is, the cost of the handheld device of the mobile phone holder is unnecessary. However, the cost of an electric circuit and data processing analysis software that can be operated on a mobile phone instead is required, but the measurer can download the data processing analysis software on the network, An electric circuit can be mounted in advance by increasing the functionality of the mobile phone. The user can use the mobile phone as a handy device at low cost. As described above, the mobile phone holder can easily prepare the handy device 2301, and after preparing the handy device, the sample (sample) can be analyzed only with the cost of the micro analysis chip 2302.
  • FIG. 17 shows an embodiment of a microanalyzer.
  • This microanalyzer is an independent microanalyzer capable of collecting a sample (sample) independently, analyzing detection data, and outputting.
  • the microanalyzer can independently constitute an independent microanalyzer capable of collecting a sample (sample) to analyzing and outputting detection data. That is, as shown in the figure, the microanalyzer includes a sample collection unit 2401, a liquid channel unit 2402, a drive analysis processing unit 2403, an input / output logic processing unit 2404, and an input / output unit 2405. Each part is sequentially stacked or combined to form a microanalyzer.
  • the sample collection unit 2401 is provided with a needle penetrating a capillary tube, and blood or a sample can be collected by inserting or introducing a needle into a human body or a sample body.
  • a needle is preferable if it is a minimally invasive microprobe because pain is alleviated when a needle is inserted into a subject and a body fluid such as blood is extracted.
  • an absorbent body that collects noninvasive skin surface sweat, saliva in the oral cavity, tears, urine, and the like may be used.
  • the liquid flow path portion 2402 is formed with the flow path structure of the micro analysis chip described in the above embodiment.
  • the structure can be formed using the 2101 layer described in Embodiment 4 and the 2202 layer described in Embodiment 5.
  • the capillary tube of the sample collecting unit is connected to the second liquid reservoir 2414 of the liquid flow channel unit, and is configured such that the sample flows into the liquid reservoir due to the capillary phenomenon of the capillary provided on the needle.
  • the liquid channel part can be made using polydimethylsiloxane (PDMS), polymethyl methacrylate (PMMA), polycarbonate, polytetrafluoroethylene, vinyl chloride or the like. It is also possible to form a flow path structure having a plurality of detection sections in the liquid flow path section. It is also possible to form a plurality of channel structures.
  • PDMS polydimethylsiloxane
  • PMMA polymethyl methacrylate
  • polycarbonate polytetrafluoroethylene
  • vinyl chloride vinyl chloride
  • the drive analysis processing unit 2403 can be configured in the same manner as the micro analysis chip described in the above embodiment, and includes a CPU, a memory, a battery (not shown), and the like, and detects the liquid channel unit 2042. Are connected to an I / O logic circuit, etc., which will be described later, and valve control corresponding to various measurements, processing of measurement data, control of an input / output unit, and the like are possible. Further, the drive analysis processing unit 2403 can be configured using the 2102 layer described in the fourth embodiment and the 2203 layer described in the fifth embodiment. However, in this embodiment, since it can be used independently, a CPU and a data storage unit are provided, and valve control corresponding to various measurements, measurement data processing, and the like are possible.
  • the flow of a valve such as a reagent or sample (sample) that has stopped flowing in at the start of measurement is sequentially started, and as a result, an electric signal corresponding to the amount of the substance to be detected detected by the detection unit is sent to the CPU.
  • the amount or type of the substance to be detected can be specified.
  • data can be output to an I / O logic circuit connected to the CPU described below, and the measurement result can be displayed at the input / output unit.
  • the input / output logic processing unit 2404 has an I / O logic circuit connected to the CPU.
  • An electrical connection line connected to the I / O logic circuit is connected to each button or display unit of the input / output layer and can cooperate with the CPU to appropriately process the I / O data. That is, upon receiving various data and measurement start signals input in the display layer, the electrical signal output according to the non-detected substance of the sample detected in the liquid channel layer is processed, and the amount and type of the detected substance And the information is displayed on the display unit of the input / output layer.
  • the input / output layer 2405 is provided with various data input buttons and a display unit.
  • a liquid crystal display module or an organic EL display module can be used for the display unit. These can perform a display operation by driving the drive driver circuit in cooperation with the I / O logic circuit and the CPU.
  • the display can also be displayed with a time-dependent change using a numerical value display format or a graph. It can also be displayed in a format such as positive or negative.
  • the input / output layer can be provided with a terminal for processing input / output with the outside or a wireless transceiver.
  • a personal computer a PDA terminal, etc.
  • a network so that bidirectional information exchange is also possible.
  • health information obtained from the measurement results of the measurer can be networked with hospitals and health management centers, etc., so that information can be provided in both directions.
  • the measurer can enjoy advice, diagnosis, and treatment directly related to advanced medical care, and the medical provider can make appropriate diagnosis and treatment from abundant health information.
  • the liquid in the chip can be transferred by a simple method using an absorber and a channel having a small cross-sectional area without requiring external power.
  • a liquid-feeding structure can be applied as a micro-analysis chip or the like used for antigen analysis and has great industrial significance.

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  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)

Abstract

La présente invention concerne une structure de fourniture de liquide comprenant des passages étroits et bas, capables de fournir un liquide sans l'aide d'une alimentation externe. La structure de fourniture de liquide comprend au moins un premier passage raccordé à un orifice ouvert sur l'extérieur, une partie réservoir de liquide dotée en permanence du premier passage, un second passage formé en permanence dans la partie réservoir de liquide et un absorbeur en contact direct avec l'extrémité terminale du second passage. La structure de fourniture de liquide se caractérise en ce que la condition P3<P1≤P2 est respectée, où P1 est une pression due à une tension de surface générée dans le liquide dans le premier passage, P2 une pression due à une tension de surface générée dans le liquide dans le second passage et P3 une pression due à une tension de surface générée dans le liquide réservé dans la partie réservoir de liquide.
PCT/JP2009/053283 2008-02-26 2009-02-24 Structure de fourniture de liquide et puce de micro-analyse utilisant celle-ci WO2009107608A1 (fr)

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JP2008044794A JP2009204339A (ja) 2008-02-26 2008-02-26 送液構造体及びこれを用いたマイクロ分析チップ

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JP2011107100A (ja) * 2009-11-20 2011-06-02 Rohm Co Ltd 測定装置および分析チップ
JP2013068546A (ja) * 2011-09-22 2013-04-18 Sharp Corp 送液装置及び送液方法
JP2015172492A (ja) * 2014-03-11 2015-10-01 国立研究開発法人産業技術総合研究所 多孔質媒体を利用したアッセイ装置
KR20180039737A (ko) * 2015-09-04 2018-04-18 노쓰 캐롤라이나 스테이트 유니버시티 미세유체 디바이스용 수동형 펌프
WO2020054704A1 (fr) * 2018-09-10 2020-03-19 地方独立行政法人神奈川県立産業技術総合研究所 Dispositif d'analyse

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JP4949506B2 (ja) * 2010-07-16 2012-06-13 シャープ株式会社 流路構造体及びその製造方法、並びに、分析チップ及び分析装置
JP5688635B2 (ja) * 2010-08-26 2015-03-25 国立大学法人 東京大学 検査用シート、化学分析装置及び検査用シートの製造方法
CN109070075B (zh) * 2016-04-14 2020-12-01 惠普发展公司，有限责任合伙企业 具有毛细腔室的微流体装置
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JP6788247B2 (ja) * 2016-12-28 2020-11-25 国立研究開発法人産業技術総合研究所 Ｎｍｒ測定用混合マイクロチップ
CN115485547A (zh) * 2020-04-28 2022-12-16 电化株式会社 检测装置和检测方法
CN117813514A (zh) * 2021-08-16 2024-04-02 国立研究开发法人产业技术综合研究所 试验装置
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JP2011107100A (ja) * 2009-11-20 2011-06-02 Rohm Co Ltd 測定装置および分析チップ
JP2013068546A (ja) * 2011-09-22 2013-04-18 Sharp Corp 送液装置及び送液方法
JP2015172492A (ja) * 2014-03-11 2015-10-01 国立研究開発法人産業技術総合研究所 多孔質媒体を利用したアッセイ装置
KR20180039737A (ko) * 2015-09-04 2018-04-18 노쓰 캐롤라이나 스테이트 유니버시티 미세유체 디바이스용 수동형 펌프
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WO2020054704A1 (fr) * 2018-09-10 2020-03-19 地方独立行政法人神奈川県立産業技術総合研究所 Dispositif d'analyse
JP7440915B2 (ja) 2018-09-10 2024-02-29 地方独立行政法人神奈川県立産業技術総合研究所 分析デバイス

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