US20150050721A1 - Chip for analysis of target substance - Google Patents

Chip for analysis of target substance Download PDF

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Publication number
US20150050721A1
US20150050721A1 US14/386,527 US201314386527A US2015050721A1 US 20150050721 A1 US20150050721 A1 US 20150050721A1 US 201314386527 A US201314386527 A US 201314386527A US 2015050721 A1 US2015050721 A1 US 2015050721A1
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US
United States
Prior art keywords
forming non
bonded area
flexible substrate
flow channel
target substance
Prior art date
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Abandoned
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US14/386,527
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English (en)
Inventor
Minoru Asogawa
Hisashi Hagiwara
Yoshinori Mishina
Yasuo Iimura
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NEC Corp
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NEC Corp
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Assigned to NEC CORPORATION reassignment NEC CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ASOGAWA, MINORU, HAGIWARA, HISASHI, IMURA, YASUO, MISHINA, YOSHINORI
Assigned to NEC CORPORATION reassignment NEC CORPORATION CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNOR'S LAST NAME PREVIOUSLY RECORDED ON REEL 033777 FRAME 0781. ASSIGNOR(S) HEREBY CONFIRMS THE CONVEYANCE OF ASSIGNMENT INTEREST. Assignors: ASOGAWA, MINORU, HAGIWARA, HISASHI, IIMURA, Yasuo, MISHINA, YOSHINORI
Publication of US20150050721A1 publication Critical patent/US20150050721A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6844—Nucleic acid amplification reactions
    • C12Q1/686—Polymerase chain reaction [PCR]
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F31/00—Mixers with shaking, oscillating, or vibrating mechanisms
    • B01F31/30—Mixers with shaking, oscillating, or vibrating mechanisms comprising a receptacle to only a part of which the shaking, oscillating, or vibrating movement is imparted
    • B01F31/31—Mixers with shaking, oscillating, or vibrating mechanisms comprising a receptacle to only a part of which the shaking, oscillating, or vibrating movement is imparted using receptacles with deformable parts, e.g. membranes, to which a motion is imparted
    • B01F31/312—Mixers with shaking, oscillating, or vibrating mechanisms comprising a receptacle to only a part of which the shaking, oscillating, or vibrating movement is imparted using receptacles with deformable parts, e.g. membranes, to which a motion is imparted the motion being a transversal movement to one part of the receptacle, e.g. by moving alternatively up and down the opposite edges of a closing lid to cause a pumping action
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502707—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the manufacture of the container or its components
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502715—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
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    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502738—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by integrated valves
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502761—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/416—Systems
    • G01N27/447—Systems using electrophoresis
    • G01N27/44704—Details; Accessories
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/416—Systems
    • G01N27/447—Systems using electrophoresis
    • G01N27/44756—Apparatus specially adapted therefor
    • G01N27/44791—Microapparatus
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/416—Systems
    • G01N27/447—Systems using electrophoresis
    • G01N27/453—Cells therefor
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/72—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating magnetic variables
    • G01N27/74—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating magnetic variables of fluids
    • G01N27/745—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating magnetic variables of fluids for detecting magnetic beads used in biochemical assays
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
    • B01L2200/0668—Trapping microscopic beads
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0645—Electrodes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0864—Configuration of multiple channels and/or chambers in a single devices comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0867—Multiple inlets and one sample wells, e.g. mixing, dilution
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0874—Three dimensional network
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0887—Laminated structure
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/12—Specific details about materials
    • B01L2300/123—Flexible; Elastomeric
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/043—Moving fluids with specific forces or mechanical means specific forces magnetic forces
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0481—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure squeezing of channels or chambers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
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    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01L2400/00—Moving or stopping fluids
    • B01L2400/06—Valves, specific forms thereof
    • B01L2400/0633—Valves, specific forms thereof with moving parts
    • B01L2400/0655—Valves, specific forms thereof with moving parts pinch valves

Definitions

  • the present invention relates to a chip for analysis of a target substance.
  • Patent Document 1 JP 2009-247297 A
  • the present invention is intended to provide a chip for analysis of a target substance that is compact and allows analysis of a target substance such as DNA with less time and effort.
  • the present invention provides a first chip for analysis of a target substance, including:
  • a laminate including: a first flexible substrate; a second flexible substrate; and a third substrate, wherein a flow channel-forming non-bonded area is formed on a bonding surface of the first flexible substrate and the second flexible substrate in a band-like manner and an extraction chamber-forming non-bonded area having a wider band width than the flow channel-forming non-bonded area is formed at a part of the flow channel-forming non-bonded area, the first flexible substrate includes a through-hole that is in contact with the flow channel-forming non-bonded area, a shutter-forming non-bonded area is formed on a bonding surface of the second flexible substrate and the third substrate in a band-like manner at a far side of the through-hole relative to the extraction chamber-forming non-bonded area such that the shutter-forming non-bonded area and the flow channel-forming non-bonded area intersect above and below via the second flexible substrate being interposed therebetween, at least one of both of the first flexible substrate and the second flexible substrate and the third substrate includes a pressure supply port that comes through the substrate(s) so as
  • the present invention also provides a second chip for analysis of a target substance, including:
  • a laminate including: a first flexible substrate; a second flexible substrate; and a third substrate, wherein a flow channel-forming non-bonded area is formed on a bonding surface of the first flexible substrate and the second flexible substrate in a band-like manner and a mixing chamber-forming non-bonded area having a wider band width than the flow channel-forming non-bonded area is formed at a part of the flow channel-forming non-bonded area, the first flexible substrate includes a through-hole that is in contact with the flow channel-forming non-bonded area, shutter-forming non-bonded areas are formed on a bonding surface of the second flexible substrate and the third substrate in a band-like manner (e.g.
  • both of the first flexible substrate and the second flexible substrate and the third substrate includes pressure supply ports that come through the substrate(s) so as to be in contact with the shutter-forming non-bonded areas, a flow channel and a mixing chamber are formable by supplying pressure from the through-hole to raise a site above the flow channel-forming non-bonded area and a site above the mixing chamber-forming non-bonded area, the flow channel is blockable by supplying pressure from the pressure supply ports to raise sites above the shutter-forming non-bonded areas, and a target substance and a reagent are mixable in the mixing chamber by applying pressure to a top surface of the first flexible substrate above the mixing chamber to deform the mixing chamber.
  • the present invention also provides a third chip for analysis of a target substance, including:
  • a laminate including: a first flexible substrate; a second flexible substrate; and a third substrate, wherein a flow channel-forming non-bonded area is formed on a bonding surface of the first flexible substrate and the second flexible substrate in a band-like manner
  • the first flexible substrate includes a through-hole that is in contact with the flow channel-forming non-bonded area
  • a first mixing chamber-forming non-bonded area and a second mixing chamber-forming non-bonded area each having a wider band width than the flow channel-forming non-bonded area are each formed on the bonding surface of the first flexible substrate and the second flexible substrate at a part of the flow channel-forming non-bonded area in this order from the through-hole side
  • shutter-forming non-bonded areas are formed on a bonding surface of the second flexible substrate and the third substrate in a band-like manner (e.g.
  • both of the first flexible substrate and the second flexible substrate and the third substrate includes pressure supply ports that come through the substrate(s) so as to be in contact with the shutter-forming non-bonded areas, a flow channel, a first mixing chamber, and a second mixing chamber are formable by supplying pressure from the through-hole to raise a site above the flow channel-forming non-bonded area, a site above the first mixing chamber-forming non-bonded area, and a site above the second mixing chamber-forming non-bonded area, the flow channel is blockable by supplying pressure from the pressure supply ports to raise sites above the shutter-forming non-bonded areas, and a target substance and a reagent are mixable by moving them between the
  • the present invention it is possible to provide a chip for analysis of a target substance that is compact and allows analysis of a target substance such as DNA with less time and effort.
  • FIG. 1 shows diagrams illustrating an example of the configuration of the first chip for analysis of a target substance of the present invention
  • FIG. 1(A) is a schematic perspective plan view
  • FIG. 1(B) is a schematic cross sectional view of FIG. 1(A) viewed from the line I-I
  • FIG. 1(C) is a schematic cross sectional view of FIG. 1(A) viewed from the line II-II.
  • FIG. 2 shows schematic cross sectional views illustrating an example of the usage of the chip for analysis of a target substance shown in FIG. 1 .
  • FIG. 3 shows schematic cross sectional views illustrating an example of the configuration of the second chip for analysis of a target substance of the present invention.
  • FIG. 4 shows schematic cross sectional views illustrating an example of the configuration of the third chip for analysis of a target substance of the present invention.
  • FIG. 5 is a schematic perspective plan view showing another example of the configuration of the chip for analysis of a target substance of the present invention.
  • FIG. 1 shows an example of the configuration of the first chip for analysis of a target substance of the present invention.
  • FIG. 1(A) is a schematic perspective plan view
  • FIG. 1(B) is a schematic cross sectional view of FIG. 1(A) viewed from the line I-I
  • FIG. 1(C) is a schematic cross sectional view of FIG. 1(A) viewed from the line II-II.
  • a chip for analysis of a target substance 10 includes a laminate in which a first flexible substrate 1 , a second flexible substrate 2 , and a third substrate 3 are laminated. In the laminate, the laminate direction of substrates is referred to as the up-and-down direction (hereinafter, the same applies).
  • a flow channel-forming non-bonded area 11 is formed on the bonding surface of the first flexible substrate 1 and the second flexible substrate 2 in a band-like manner and an extraction chamber-forming non-bonded area 5 having a wider band width than the flow channel-forming non-bonded area 11 is formed at a part of the flow channel-forming non-bonded area 11 .
  • the first flexible substrate 1 includes a through-hole 7 that is in contact with the flow channel-forming non-bonded area 11 .
  • Shutter-forming non-bonded areas 12 a and 12 b are formed on the bonding surface of the second flexible substrate 2 and the third substrate 3 in a band-like manner at the near side and the far side of the through-hole 7 relative to the extraction chamber-forming non-bonded area 5 such that the shutter-forming non-bonded areas 12 a and 12 b and the flow channel-forming non-bonded area 11 intersect above and below via the second flexible substrate 2 being interposed therebetween.
  • the first flexible substrate 1 and the second flexible substrate 2 include pressure supply ports 18 a and 18 b that come through the substrates so as to be in contact with the shutter-forming non-bonded areas 12 a and 12 b respectively.
  • the third substrate 3 includes the pressure supply ports 18 a and 18 b that come through the substrate so as to be in contact with the shutter-forming non-bonded areas 12 a and 12 b respectively.
  • a magnetic particle that binds to a target substance is placed above the extraction chamber-forming non-bonded area 5 .
  • the shutter-forming non-bonded area 12 a and the pressure supply port 18 a are optional components and are not indispensable, although the chip for analysis of a target substance of this Embodiment preferably includes these components.
  • the flow direction of liquid in the flow channel to be formed is along the flow channel-forming non-bonded area 11 and the through-hole 7 side is the upstream side. Therefore, it can be said that the shutter-forming non-bonded area 12 a is formed at the downstream side of the through-hole 7 and the upstream side of the extraction chamber-forming non-bonded area 5 , i.e., between the through-hole 7 and the extraction chamber-forming non-bonded area 5 , and the shutter-forming non-bonded area 12 b is formed at the downstream side of the extraction chamber-forming non-bonded area 5 .
  • one through-hole 7 is provided at the left end of the flow channel-forming non-bonded area 11 .
  • the present invention is not limited thereto.
  • An appropriate number of through-holes may be provided at any place as long as the through-hole is in contact with the flow channel-forming non-bonded area 11 .
  • one pressure supply port 18 a is provided at the end of the shutter-forming non-bonded area 12 a and one pressure supply port 18 b is provided at the end of the shutter-forming non-bonded area 12 b .
  • the present invention is not limited thereto. An appropriate number of pressure supply ports may be provided at any place as long as the pressure supply port is in contact with the shutter-forming non-bonded area.
  • shutter-forming non-bonded areas 12 a and 12 b and the flow channel-forming non-bonded area 11 intersect as long as the shutter-forming non-bonded areas 12 a and 12 b and the flow channel-forming non-bonded area 11 intersect above and below via the second flexible substrate 2 being interposed therebetween.
  • the shutter-forming non-bonded areas 12 a and 12 b and the flow channel-forming non-bonded area 11 intersect at right angles in FIG. 1 , the present invention is not limited thereto.
  • the undersurface of the first flexible substrate 1 and the top surface of the second flexible substrate 2 are bonded with each other at around the flow channel-forming non-bonded area 11 , through-hole 7 , and the extraction chamber-forming non-bonded area 5 .
  • the undersurface of the first flexible substrate 1 and the top surface of the second flexible substrate 2 are bonded with each other at an area excluding the flow channel-forming non-bonded area 11 , the through-hole 7 , and the extraction chamber-forming non-bonded area 5 .
  • the undersurface of the second flexible substrate 2 and the top surface of third substrate 3 are bonded with each other at an area excluding the shutter-forming non-bonded areas 12 a and 12 b and the pressure supply ports 18 a and 18 b.
  • the chip for analysis of a target substance 10 can be produced, for example, as follows. First, the first flexible substrate 1 , the second flexible substrate 2 , and the third substrate 3 are provided. Surface modification treatment for the purpose of increasing the bonding strength between the substrates may be applied to the undersurface of the first flexible substrate 1 , the top surface and the undersurface of the second flexible substrate 2 , and the top surface of the third substrate 3 . Examples of the surface modification treatment include oxygen plasma treatment and excimer UV light irradiation treatment.
  • the oxygen plasma treatment can be performed, for example, using a reactive ion etching (RIE) apparatus and the like in the presence of oxygen.
  • the excimer UV light irradiation treatment can be performed, for example, using a dielectric barrier discharge lamp under an air atmosphere of atmospheric pressure.
  • Examples of the material of the first flexible substrate 1 include a silicone rubber such as polydimethylsiloxane (PDMS); a nitrile rubber; a hydrogenated nitrile rubber; a fluororubber; an ethylene-propylene rubber; a chloroprene rubber; an acrylic rubber; a butyl rubber; an urethane rubber; a chlorosulfonated polyethylene rubber; an epichlorohydrin rubber; a natural rubber; an isoprene rubber; a styrene-butadiene rubber; a butadiene rubber; a polysulfide rubber; a norbornene rubber; and a thermoplastic elastomer.
  • PDMS polydimethylsiloxane
  • a nitrile rubber such as polydimethylsiloxane (PDMS)
  • a nitrile rubber such as polydimethylsiloxane (PDMS)
  • a nitrile rubber such as polydi
  • the thickness of the first flexible substrate 1 is, for example, in the range from 10 ⁇ m to 5 mm in consideration of the strength thereof and the formation of the flow channel and the extraction chamber that will be described below.
  • the through-hole 7 and the pressure supply ports 18 a and 18 b can take any shape such as a cylinder shown in FIG. 1 and a prism, for example.
  • the sizes of the through-hole 7 and the pressure supply ports 18 a and 18 b may be set appropriately, for example, according to the widths of the flow channel-forming non-bonded area and the shutter-forming non-bonded area that will be described below.
  • the material of the second flexible substrate 2 examples include those described for the first flexible substrate 1 . While the material of the second flexible substrate 2 can be the same as or different from the material of the first flexible substrate, the material of the second flexible substrate 2 is preferably the same as the material of the first flexible substrate 1 . Specifically, for example, in the case where the first flexible substrate 1 is silicone rubber, the second flexible substrate 2 is preferably silicone rubber. If the first flexible substrate 1 and the second flexible substrate 2 are both silicone rubber, the first flexible substrate 1 and the second flexible substrate 2 can be bonded by a self adsorption ability without using an adhesive agent.
  • the thickness of the second flexible substrate 2 is, for example, in the range from 10 ⁇ m to 500 ⁇ m in consideration of the strength thereof and the blocking of the flow channel that will be described below.
  • the shapes and the sizes of the pressure supply ports 18 a and 18 b of the second flexible substrate 2 are, for example, the same as those of the pressure supply ports 18 a and 18 b of the first flexible substrate 1 .
  • the flow channel-forming non-bonded area 11 is formed on the top surface of the second flexible substrate 2 in a band-like manner and the extraction chamber-forming non-bonded area 5 having a wider band width than the flow channel-forming non-bonded area 11 is formed at a part of the flow channel-forming non-bonded area 11 .
  • the flow channel-forming non-bonded area 11 and the extraction chamber-forming non-bonded area 5 each can be formed as, for example, an electrode film, a dielectric protective film, a semiconductor film, a fluorescent film, a superconductive film, a dielectric film, a solar cell film, an antireflection film, a wear-resistant film, an optical interference film, a reflection film, an antistatic film, a conductive film, an antifouling film, a hard coating film, a barrier film, an electromagnetic wave shielding film, an infrared shielding film, an ultraviolet absorbing film, a lubricating film, a shape memory film, a magnetic recording film, a light-emitting element film, a biocompatible film, a corrosion-resistant film, a catalyst film, or a gas sensor film, for example, by a conventionally known chemical thin film formation technology.
  • the aforementioned thin film can be formed by a plasma discharge treatment apparatus using an organic fluorine compound or a metal compound as reactive gas.
  • organic fluorine compound examples include fluorocarbon compounds such as fluoromethane, fluoroethane, tetrafluoromethane, hexafluoromethane, 1,1,2,2-tetrafluoroethylene, 1,1,1,2,3,3-hexafluoropropane, hexafluoropropene, and 6-fluoropropylen; fluorohydrocarbon compounds such as 1,1-difluoroethylene, 1,1,1,2-tetrafluoroethane, and 1,1,2,2,3-pentafluoropropane; carbon fluorochloride compounds such as difluorodichloromethane and trifluorochloromethane; fluoroalcohols such as 1,1,1,3,3,3-hexafluoro-2-propanol, 1,3-difluoro-2-propanol, and perfluorobutanol; fluoro carboxylic ester such as vinyltrifluoroacetate and 1,1,1-trifluor
  • the metal compound examples include a single metal compound, a mixed metal compound, and an organic metal compound of Al, As, Au, B, Bi, Ca, Cd, Cr, Co, Cu, Fe, Ga, Ge, Hg, In, Li, Mg, Mn, Mo, Na, Ni, Pb, Pt, Rh, Sb, Se, Si, Sn, Ti, V, W, Y, Zn, and Zr.
  • the aforementioned thin film can be formed, for example, by a reactive ion etching system (RIE), a printing method, and the like in the presence of fluorocarbon (CHF 3 ) via a mask.
  • RIE reactive ion etching system
  • CHF 3 fluorocarbon
  • the printing method for example, conventionally known printing methods such as roll printing, pattern printing, decalcomania, and electrostatic copying can be employed.
  • a metal fine particle, a conductive ink, an insulating ink, a carbon fine particle, a silane agent, parylene, a paint, a pigment, a dye, a water-based dye ink, a water-based pigment ink, an oil dye ink, an oil pigment ink, a solvent ink, a solid ink, a gel ink, a polymer ink, and the like can be used suitably for the material for forming the thin film.
  • the metal fine particle examples include a single metal fine particle of, a mixed metal fine particle of two or more of, an oxide fine particle (for example, ITO fine particle or the like) of the single metal or the mixed metal of, and an organic metal compound fine particle of Al, As, Au, B, Bi, Ca, Cd, Cr, Co, Cu, Fe, Ga, Ge, Hg, In, Li, Mg, Mn, Mo, Na, Ni, Pb, Pt, Rh, Sb, Se, Si, Sn, Ti, V, W, Y, Zn, and Zr.
  • each of the flow channel-forming non-bonded area 11 and the extraction chamber-forming non-bonded area 5 is, for example, in the range from 10 nm to 10 ⁇ m and preferably in the range from 50 nm to 3 ⁇ m in consideration of uniform formation of the flow channel-forming non-bonded area 11 and the extraction chamber-forming non-bonded area 5 and the bonding ability between the first flexible substrate 1 and the second flexible substrate 2 at an area excluding the non-bonded area.
  • the width of the flow channel-forming non-bonded area 11 is, for example, in the range from 10 ⁇ m to 3000 ⁇ m in consideration of the formation of the flow channel that will be described below, a supply amount of each of a reagent and a target substance such as DNA, and the like.
  • the size of the extraction chamber-forming non-bonded area 5 is, for example, in the range from 3 mm 2 to 300 mm 2 and preferably in the range from 16 mm 2 to 50 mm 2 in consideration of the formation of the extraction chamber that will be described below, a supply amount of each of a reagent and a target substance such as DNA, and the like.
  • the shape of the flow channel-forming non-bonded area 11 is not limited to a linear band shown in FIG. 1 , and, for example, various shaped bands such as a Y-shaped band and an L-shaped band can be employed.
  • the shape of the extraction chamber-forming non-bonded area 5 is also not limited to a circle shown in FIG. 1 , and, for example, any shape such as a rectangle can be employed.
  • Examples of the material of the third substrate 3 include acryl, a silicone rubber such as PDMS, glass, polyethylene terephthalate, polyethylene naphthalate, polyethylene, polypropylene, cellophane, cellulose diacetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate phthalate, cellulose triacetate, cellulose nitrate, polyvinylidene chloride, polyvinyl alcohol, ethylene vinyl alcohol, polycarbonate, a norbornene resin, polymethylpentene, polyether ketone, polyimide, polyethersulfone, polyether ketone imide, polyamide, a fluororesin, nylon, polymethyl methacrylate, polyarylate, a polylactic resin, polybutylene succinate, a nitrile rubber, a hydrogenated nitrile rubber, a fluororubber, an ethylene-propylene rubber, a chloroprene rubber, an acrylic rubber, a butyl rubber,
  • surface treatment using a surface treatment agent is applied to the top surface of the third substrate 3 for the purpose of increasing the bonding ability between the top surface of the third substrate 3 and the undersurface of the second flexible substrate 2 at an area excluding the non-bonded area.
  • the surface treatment agent include alkylsilane such as dimethylsilane, tetramethylsilane, and tetraethylsilane; organic silicon compounds of silicon alkoxysilane such as tetramethoxysilane, tetraethoxysilane, tetrapropoxysilane, dimethyldiethoxysilane, methyltrimethoxysilane, and ethyltriethoxysilane; silicon-hydrogen compounds such as monosilane and disilane; halogenated silicon compounds such as dichlorosilane, trichlorosilane, and tetrachlorosilane; silazane such as hexamethyldisilazane; and silicon
  • Shutter-forming non-bonded areas 12 a and 12 b are formed on the top surface of the third substrate 3 in a band-like manner.
  • the shutter-forming non-bonded areas 12 a and 12 b may be formed, for example, using the same material as those used for the flow channel-forming non-bonded area 11 and the extraction chamber-forming non-bonded area 5 such that the shutter-forming non-bonded areas 12 a and 12 b have the same thickness as the flow channel-forming non-bonded area 11 and the extraction chamber-forming non-bonded area 5 .
  • the width of each of the shutter-forming non-bonded areas 12 a and 12 b is, for example, in the range from 10 ⁇ m to 5000 ⁇ m in consideration of the blocking of the flow channel that will be described below and economic efficiency.
  • the first flexible substrate 1 , the second flexible substrate 2 , and the third substrate 3 are laminated.
  • a magnetic particle that binds to a target substance such as DNA is placed above the extraction chamber-forming non-bonded area 5 .
  • “Bonding” may be, for example, direct or indirect bonding of the target substance to the magnetic particle.
  • an example of the direct bonding includes adhesion of the target substance to the magnetic particle itself.
  • examples of the indirect bonding include adsorption or adhesion of the target substance to a predetermined substance to which a magnetic particle coating is applied and bonding of the target substance to the magnetic particle by reaction using a reactive substance.
  • the magnetic particle is, for example, a sphere and the particle size is, for example, in the range from 0.3 ⁇ m to 5 ⁇ m.
  • the magnetic particle for example, a substance having a porous surface or a substance in which at least one of silica gel and cellulose is mixed is suitable.
  • the chip for analysis of a target substance 10 shown in FIG. 1 can be obtained.
  • the first target substance analysis method of the present invention can be performed using the first chip for analysis of a target substance of the present invention.
  • the first target substance analysis method is characterized, for example, by using the first chip for analysis of a target substance of the present invention and including the following steps (a1) to (d1):
  • the steps may be performed in the order from step (a1) to step (d1).
  • the shutter portion formation step (a1) and the flow channel and extraction chamber formation step (b1) may be performed simultaneously or either of the steps (a1) and (b1) may be performed in advance, for example.
  • the analysis sample injection step (c1) may be performed simultaneously with the flow channel and extraction chamber formation step (b1), for example.
  • FIG. 2 As the first target substance analysis method of the present invention, an example of the usage of the chip for analysis of a target substance 10 shown in FIG. 1 will be described with reference to FIG. 2 .
  • the aspect shown in FIG. 2 is an example and the present invention is not limited to this aspect.
  • an adapter 14 is provided at the opening portion of the through-hole 7 serving as an introduction portion of liquid or gas, and an injection tube 15 is connected to the adapter 14 .
  • the shape of the adapter 14 is not limited to that shown in FIG. 2(A) .
  • the adapter 14 may not be in the form of partially inserted in the through-hole 7 but may be in the form of directly fixed to the top surface of the first flexible substrate 1 .
  • the injection tube 15 may be directly connected to the through-hole 7 without using the adapter 14 .
  • the material for the adapter 14 although a silicone rubber such as PDMS is preferable, any other material can be used.
  • an appropriate adhesive agent may be used for fixing the adapter 14 to the top surface of the first flexible substrate 1 .
  • An example of the injection tube 15 includes a Teflon (registered trademark) tube. One end of the injection tube 15 is fixed to the adapter 14 using an appropriate adhesive agent. The other end of the injection tube 15 is connected to an appropriate undiluted solution supply means, an appropriate pressure application means (for example, a micro-pump, a syringe, or the like), and the like although it is not shown.
  • the adapter 14 to which the injection tube 15 is connected is provided also at each of the pressure supply ports 18 a and 18 b although it is not shown. Then, gas is injected at high pressure from the injection tube 15 via the pressure supply port 18 b . Thereby, as shown in FIG. 2(B) , a site above the shutter-forming non-bonded area 12 b is raised to form the shutter-forming void 17 b . Specifically, only a part of the first flexible substrate 1 and a part of the second flexible substrate 2 positioned above the shutter-forming non-bonded area 12 b are raised from the top surface of the third substrate 3 to form the shutter-forming void 17 b .
  • the shutter-forming void 17 b formed by raising is also referred to as a shutter portion (hereinafter, the same applies).
  • the gas is, for example, air or the like, and the level of high pressure is, for example, in the range from 10 kPa to 300 kPa (hereinafter, the same applies).
  • a liquid analysis sample to be analyzed is injected into the chip for analysis of a target substance 10 .
  • the type of the analysis sample there is no particular limitation on the type of the analysis sample, and, for example, the type of the analysis sample can be selected appropriately according to the type of the target substance.
  • the target substance include cells and intracellular components, and specific examples thereof include nucleic acids such as DNA and RNA.
  • the analysis sample may be, for example, a sample in which a target substance is eluted from a cell, i.e., an elution sample of a cell (also referred to as a target substance-eluted sample), or a sample in which a target substance is not eluted from a cell, i.e., a sample that contains a cell.
  • the target substance such as the nucleic acid or the like may be eluted from a cell in the analysis sample in the chip for analysis of a target substance 10 .
  • gas is injected at high pressure from the injection tube 15 after injecting the analysis sample into the through-hole 7 or the analysis sample is injected into the through-hole 7 with application of positive pressure.
  • a site above the flow channel-forming non-bonded area 11 and a site above the extraction chamber-forming non-bonded area 5 are raised and the flow channel 8 and the extraction chamber 6 are formed.
  • only parts of the first flexible substrate 1 positioned above the flow channel-forming non-bonded area 11 and the extraction chamber-forming non-bonded area 5 are raised from the top surface of the second flexible substrate 2 to form the flow channel 8 and extraction chamber 6 .
  • a site above the flow channel-forming non-bonded area 11 positioned further ahead of the shutter-forming void 17 b i.e., a site above the flow channel-forming non-bonded area 11 positioned at the downstream side of the shutter-forming void 17 b is blocked by the shutter-forming void 17 b , and therefore the flow channel is not formed.
  • the target substance contained in the analysis sample that has been injected binds to the magnetic particle 16 .
  • an elution reagent that causes a target substance such as a nucleic acid to be eluted from the cell may be injected into the chip for analysis of a target substance 10 before, at the same time as, or after the injection of the analysis sample.
  • the method of injection is, for example, the same as that described for the analysis sample. Then, the target substance eluted from the cell by the elution reagent binds to the magnetic particle 16 in the extraction chamber 6 .
  • the elution reagent preliminarily place the elution reagent, for example, at the extraction chamber-forming non-bonded area 5 or at the flow channel-forming non-bonded area 11 between the through-hole 7 and the extraction chamber-forming non-bonded area 5 .
  • a washing reagent is injected into the chip for analysis of a target substance 10 .
  • the washing reagent is injected from the injection tube 15 via the through-hole 7 in the same manner as the analysis sample.
  • a magnetic field is generated at the undersurface of the third substrate 3 .
  • a magnetic field is generated at the undersurface of the third substrate 3 directly below the end of the extraction chamber 6 at the opposite side of the through-hole 7 .
  • a target substance such as DNA that is bound to the magnetic particle 16 is captured.
  • the magnetic field may be generated, for example, at the top surface side of the first flexible substrate 1 .
  • the magnetic field may be generated at the top surface side of the first flexible substrate 1 directly above the end of the extraction chamber 6 at the opposite side of the through-hole 7 .
  • a method of generating a magnetic field there is no particular limitation on the method of generating a magnetic field, and an example thereof includes a method of making the chip for analysis of a target substance 10 into contact with a magnet 13 such as an electromagnet or a permanent magnet such as an alnico magnet, a ferrite magnet, a neodymium magnet, or a samarium-cobalt magnet.
  • a magnet 13 such as an electromagnet or a permanent magnet such as an alnico magnet, a ferrite magnet, a neodymium magnet, or a samarium-cobalt magnet.
  • the pressure of the gas injecting from the through-hole 7 and the pressure supply port 18 b is set about atmospheric pressure.
  • the shutter-forming void 17 b and the voids of the flow channel 8 and the extraction chamber 6 are vanished.
  • gas is injected at high pressure from the injection tube 15 via the through-hole 7 .
  • substances excluding the target substance that is bound to the magnetic particle 16 e.g., the washing reagent and the like can be discharged from the flow channel 8 .
  • the chip for analysis of a target substance of this Embodiment allows extraction of a target substance such as DNA from the analysis sample efficiently by the magnetic particle 16 .
  • the extraction chamber can be also referred to as, for example, a separation chamber of the target substance.
  • FIG. 3 shows an example of the configuration of the second chip for analysis of a target substance of the present invention.
  • the aspect shown in FIG. 3 is an example and the present invention is not limited to this aspect.
  • identical parts to those shown in FIGS. 1 and 2 are indicated with identical numerals and symbols.
  • the chip for analysis of a target substance 10 shown in FIG. 3 has the configuration identical to that of the chip for analysis of a target substance 10 shown in FIGS. 1 and 2 except that the extraction chamber-forming non-bonded area 5 has the function of a mixing chamber-forming non-bonded area 9 and does not contain the magnetic particle 16 .
  • the chip for analysis of a target substance of this Embodiment allows mixing of the reagent and the analysis sample or the target substance in the analysis sample in the mixing chamber 19 in the manner described below.
  • the reagent can be selected appropriately according to, for example, the type of the analysis sample, the type of the target substance, and the analysis method.
  • Specific examples of the reagent include the aforementioned elution reagent that causes a target substance to be eluted from the cell, a reaction reagent that reacts with the target substance, and the washing reagent.
  • the second target substance analysis method of the present invention can be performed using the second chip for analysis of a target substance of the present invention.
  • the second target substance analysis method is characterized, for example, by using the second chip for analysis of a target substance of the present invention and including the following steps (a2) to (f2):
  • the steps may be performed in the order from step (a2) to step (f2).
  • the shutter portion formation step (a2) and the flow channel and mixing chamber formation step (b2) may be performed simultaneously or either of the steps (a2) and (b2) may be performed in advance, for example.
  • the analysis sample injection step (c2) and the reagent injection step (d2) may be performed simultaneously or either of the steps (c2) and (d2) may be performed in advance, for example.
  • the analysis sample injection step (c2) and the reagent injection step (d2) may be performed simultaneously with the flow channel and mixing chamber formation step (b2), for example.
  • the steps to the analysis sample injection step are performed in the same manner as in Embodiment 1.
  • the extraction chamber 6 is formed in Embodiment 1 whereas the mixing chamber 19 is formed in this Embodiment.
  • the aforementioned various reagents may be injected into the chip for analysis of a target substance 10 , for example, before, at the same time as, or after the injection of the analysis sample.
  • the method of injection is, for example, the same as that described for the analysis sample.
  • the analysis sample is the sample that contains a cell as described above
  • the elution reagent the reaction reagent that reacts with the eluted target substance, the washing reagent that washes the target substance, and the like may be injected as the reagent.
  • the reaction reagent, the washing reagent, and the like may be injected as the reagent.
  • elution reagent and the reaction reagent for example, at the mixing chamber-forming non-bonded area 9 or at the flow channel-forming non-bonded area 11 between the through-hole 7 and the mixing chamber-forming non-bonded area 9 .
  • gas is injected at high pressure from the injection tube 15 via the pressure supply port 18 a .
  • a site above the shutter-forming non-bonded area 12 a is raised to form the shutter-forming void 17 a .
  • the gas is, for example, air or the like, and the level of high pressure is, for example, in the range from 10 kPa to 300 kPa (hereinafter, the same applies).
  • the pressure of the gas injecting from the through-hole 7 is set about atmospheric pressure. Thereby, as shown in FIG. 3(C) , the void of the flow channel 8 at the upstream side of the shutter-forming void 17 a is vanished.
  • the mixing chamber 19 is deformed by applying pressure to the top surface of the first flexible substrate 1 above the mixing chamber 19 .
  • the target substance and the reagent are mixed in the mixing chamber 19 .
  • There is no particular limitation on the method of applying pressure to the position above the mixing chamber 19 and, for example, gas may be sprayed at high pressure or an object may be pressed.
  • the pressure of the gas injecting from the pressure supply ports 18 a and 18 b is set about atmospheric pressure. Thereby, as shown in FIG. 3(E) , the shutter-forming voids 17 a and 17 b and the void of the mixing chamber 19 are vanished. Thereafter, gas is injected at high pressure from the injection tube 15 via the through-hole 7 . Thereby, the target substance mixed with the reagent can be forwarded to the next step.
  • the same magnetic particle as described in Embodiment 1 may be placed at the mixing chamber-forming non-bonded area 9 .
  • the mixing chamber 19 also has the function of an extraction chamber.
  • the third chip for analysis of a target substance of the present invention as described above, two shutter-forming non-bonded areas are formed on the bonding surface of the second flexible substrate and the third substrate at the near side of the through-hole relative to the first mixing chamber-forming non-bonded area and at the far side of the through-hole relative to the second mixing chamber-forming non-bonded area.
  • the third shutter-forming non-bonded area may be further formed on the bonding surface of the second flexible substrate and the third substrate in a band-like manner such that the third shutter-forming non-bonded area and the flow channel-forming non-bonded area intersect above and below via the second flexible substrate being interposed therebetween.
  • This shutter-forming non-bonded area may be formed at the far side of the through-hole relative to the first mixing chamber-forming non-bonded area, for example.
  • the flow channel at the upstream side and the downstream side of the first mixing chamber can be blocked respectively by the shutter portions.
  • FIG. 4 shows an example of the configuration of the third chip for analysis of a target substance of the present invention.
  • the aspect shown in FIG. 4 is an example and the present invention is not limited to this aspect.
  • identical parts to those shown in FIGS. 1 to 3 are indicated with identical numerals and symbols.
  • the chip for analysis of a target substance 10 shown in FIG. 4 has the configuration identical to that of the chip for analysis of a target substance shown in FIG. 3 except that the chip for analysis of a target substance 10 shown in FIG. 4 includes two mixing chamber-forming non-bonded areas ( 9 a and 9 b ), four shutter-forming non-bonded areas ( 12 a to 12 d ), and four pressure supply ports. Although it is not shown, four pressure supply ports are referred to as pressure supply ports 18 a to 18 d for convenience sake.
  • the shutter-forming non-bonded areas 12 c and 12 d are respectively in contact with the pressure supply ports 18 c and 18 d that come through the first flexible substrate 1 and the second flexible substrate 2 as in the case of the shutter-forming non-bonded areas 12 a and 12 b shown in FIG. 1(A) .
  • the pressure supply ports 18 c and 18 d may be formed on the third substrate 3 in such a manner that they come through the third substrate 3 so as to be in contact with the shutter-forming non-bonded areas 12 c and 12 d .
  • the shutter-forming non-bonded areas 12 b and 12 c and the pressure supply ports 18 b and 18 c are optional components and are not indispensable, although the chip for analysis of a target substance of this Embodiment preferably includes these components. Furthermore, in this Embodiment, the shutter-forming non-bonded areas 12 b and 12 c and the pressure supply ports 18 b and 18 c may be respectively formed as one component, and the number of the non-bonded areas and the pressure supply ports may be respectively three.
  • the third target substance analysis method of the present invention can be performed using the third chip for analysis of a target substance of the present invention.
  • the third target substance analysis method is characterized, for example, by using the third chip for analysis of a target substance of the present invention and including the following steps (a3) to (f3):
  • (a3) a step of forming the flow channel, the first mixing chamber, and the second mixing chamber by supplying pressure from the through-hole to raise a site above the flow channel-forming non-bonded area, a site above the first mixing chamber-forming non-bonded area, and a site above the second mixing chamber-forming non-bonded area; (b3) a step of injecting an analysis sample into the flow channel and the mixing chamber; (c3) a step of injecting a reagent into the flow channel and the mixing chamber; (d3) a step of forming a shutter portion for blocking the flow channel by supplying pressure from the pressure supply port to raise a site above the shutter-forming non-bonded area at the near side of the through-hole relative to the first mixing chamber-forming non-bonded area; (e3) a step of forming a shutter portion for blocking the flow channel by supplying pressure from the pressure supply port to raise a site above the shutter-forming non-bonded area at the far side of the through-hole relative to the second mixing chamber-forming non-bonded area; and (f3)
  • the steps may be performed in the order from step (a3) to step (f3).
  • the step (d3) may be performed, for example, before, at the same time as, or after the step (a3) and is preferably performed before the steps (b3) and (c3).
  • the step (e3) is preferably performed, for example, after the steps (b3) and (c3).
  • the formation of the first mixing chamber and the second mixing chamber in the step (a3) may be performed, for example, as a separated step.
  • the step (a3) may be the steps (a3-1) and (a3-2) described below:
  • (a3-1) a step of forming the flow channel and the first mixing chamber by supplying pressure from the through-hole to raise a site above the flow channel-forming non-bonded area between the through-hole and the first mixing chamber-forming non-bonded area and a site above the first mixing chamber-forming non-bonded area; and (a3-2) a step of forming the flow channel and the second mixing chamber by applying pressure to a site above the first mixing chamber to deform the first mixing chamber so as to raise a site above the flow channel-forming non-bonded area between the first mixing chamber-forming non-bonded area and the second mixing chamber-forming non-bonded and a site above the second mixing chamber-forming non-bonded area.
  • the first mixing chamber formation step (a3-1) is preferably performed before or at the same time as the analysis sample injection step (b3) and the reagent injection step (c3).
  • the second mixing chamber formation step (a3-2) may be performed, for example, before, after, or during the shutter portion formation steps (d3) and (e3).
  • a shutter portion may be formed by raising a site above the third shutter-forming non-bonded area.
  • the chip for analysis of a target substance 10 shown in FIG. 4 is used, for example, as follows. First, as shown in FIG. 4(A) , in the same manner as in Embodiment 1, the adapter 14 to which the injection tube 15 is connected is provided at each of the through-hole 7 and the pressure supply ports 18 a to 18 d.
  • gas is injected at high pressure from the injection tube 15 via the pressure supply port 18 b .
  • a site above the shutter-forming non-bonded area 12 b is raised to form the shutter-forming void 17 b .
  • only a part of the first flexible substrate 1 and a part of the second flexible substrate 2 positioned above the shutter-forming non-bonded area 12 b are raised from the top surface of the third substrate 3 to form the shutter-forming void 17 b .
  • the gas is, for example, air or the like, and the level of high pressure is, for example, in the range from 10 kPa to 300 kPa (hereinafter, the same applies).
  • gas is injected at high pressure from the injection tube 15 after injecting the analysis sample into the through-hole 7 or the analysis sample is injected into the through-hole 7 with application of positive pressure.
  • a site above the flow channel-forming non-bonded area 11 and a site above the first mixing chamber-forming non-bonded area 9 a are raised and the flow channel 8 and the first mixing chamber 19 a are formed.
  • only parts of the first flexible substrate 1 positioned above the flow channel-forming non-bonded area 11 and the first mixing chamber-forming non-bonded area 9 a are raised from the top surface of the second flexible substrate 2 to form the flow channel 8 and the first mixing chamber 19 a .
  • the reagent is injected into the chip for analysis of a target substance 10 .
  • the analysis sample is the sample that contains a cell as described above and the elution reagent is used as the reagent, a target substance such as DNA is eluted from the cell in the first mixing chamber 19 a.
  • gas is injected at high pressure from the injection tube 15 via the pressure supply port 18 a .
  • a site above the shutter-forming non-bonded area 12 a is raised to form the shutter-forming void 17 a .
  • the gas is, for example, air or the like, and the level of high pressure is, for example, in the range from 10 kPa to 300 kPa (hereinafter, the same applies).
  • the pressure of the gas injecting from the through-hole 7 is set about atmospheric pressure. Thereby, as shown in FIG. 4(C) , the void of the flow channel 8 at the upstream side of the shutter-forming void 17 a is vanished.
  • the pressure of the gas injecting from the pressure supply port 18 b is set about atmospheric pressure.
  • the void of the shutter-forming void 17 b is vanished.
  • gas is injected at high pressure from the injection tube 15 via the pressure supply port 18 d .
  • a site above the shutter-forming non-bonded area 12 d is raised to form the shutter-forming void 17 d .
  • only a part of the first flexible substrate 1 and a part of the second flexible substrate 2 positioned above the shutter-forming non-bonded area 12 d are raised from the top surface of the third substrate 3 to form the shutter-forming void 17 d.
  • pressure is alternately applied to the top surface of the first flexible substrate 1 positioned above the first mixing chamber 19 a and the top surface of the first flexible substrate 1 positioned above the second mixing chamber 19 b to alternately deform the first mixing chamber 19 a and the second mixing chamber 19 b .
  • the target substance and the reagent are mixed by moving between the first mixing chamber 19 a and the second mixing chamber 19 b .
  • There is no particular limitation on the method of applying pressure to a site above the first mixing chamber 19 a and a site above the second mixing chamber 19 b and, for example, gas may be sprayed at high pressure or an object may be pressed.
  • the method of mixing the target substance and the reagent by moving them between the first mixing chamber 19 a and the second mixing chamber 19 b is not limited to the method of alternately applying pressure to a site above the first mixing chamber 19 a and a site above the second mixing chamber 19 b to alternately deform the first mixing chamber 19 a and the second mixing chamber 19 b , and any method can be employed.
  • the target substance and the reagent may be mixed by applying air pressure between the first mixing chamber 19 a and the second mixing chamber 19 b to move the target substance and the reagent between the first mixing chamber 19 a and the second mixing chamber 19 b.
  • the pressure of the gas injecting from the through-hole 7 and the pressure supply ports 18 a and 18 d is set about atmospheric pressure.
  • the shutter-forming voids 17 a and 17 d and the voids of the flow channel 8 , the first mixing chamber 19 a , and the second mixing chamber 19 b are vanished.
  • gas is injected at high pressure from the injection tube 15 via the through-hole 7 .
  • the target substance mixed with the reagent can be forwarded to the next step.
  • the same magnetic particle as described in Embodiment 1 may be placed at at least one of the first mixing chamber-forming non-contact (non-bonded) area 9 a and the second mixing chamber-forming non-bonded area 9 b .
  • at least one of the first mixing chamber 19 a and the second mixing chamber 19 b has the function of an extraction chamber.
  • FIG. 5 shows another example of the configuration of the chip for analysis of a target substance of the present invention.
  • the aspect shown in FIG. 5 is an example and the present invention is not limited to this aspect.
  • identical parts to those shown in FIGS. 1 and 2 are indicated with identical numerals and symbols.
  • a chip for analysis of a target substance 20 shown in FIG. 5 includes, in addition to the configuration of the chip for analysis of a target substance 10 shown in FIGS.
  • washing reagent supply portion 30 each include a laminate in which the first flexible substrate 1 , the second flexible substrate 2 , and the third substrate 3 are laminated.
  • each of the first flexible substrate 1 , the second flexible substrate 2 , and the third substrate 3 is the same as that of the chip for analysis of a target substance 10 shown in FIGS. 1 and 2 .
  • the shutter-forming non-bonded area 12 m and the pressure supply port 18 m can be formed in the same manner as the corresponding components of the chip for analysis of a target substance 10 shown in FIGS. 1 and 2 .
  • the washing reagent supply portion 30 includes a through-hole 37 , a flow channel-forming non-bonded area 31 , a shutter-forming non-bonded area 12 e , and a pressure supply port 18 e as main components. These components can be formed in the same manner as the corresponding components of the chip for analysis of a target substance 10 shown in FIGS. 1 and 2 .
  • the flow channel-forming non-bonded area 31 is in contact with the extraction chamber-forming non-bonded area 5 of the chip for analysis of a target substance 10 shown in FIGS. 1 and 2 .
  • the washing reagent supply portion 30 is an optional component and is not indispensable, although the chip for analysis of a target substance 20 preferably includes the washing reagent supply portion 30 .
  • a washing reagent may be supplied from the through-hole 7 of the chip for analysis of a target substance 10 shown in FIGS. 1 and 2 .
  • the PCR reaction reagent supply portion 40 includes a through-hole 47 , a flow channel-forming non-bonded area 41 , a shutter-forming non-bonded area 12 f , and a pressure supply port 18 f as main components. These components can be formed in the same manner as the corresponding components of the chip for analysis of a target substance 10 shown in FIGS. 1 and 2 .
  • the flow channel-forming non-bonded area 41 is in contact with the extraction chamber-forming non-bonded area 5 of the chip for analysis of a target substance 10 shown in FIGS. 1 and 2 .
  • the PCR reagent supply portion 40 is an optional component and is not indispensable, although the chip for analysis of a target substance 20 preferably includes the PCR reagent supply portion 40 .
  • a PCR reagent may be supplied from the through-hole 7 of the chip for analysis of a target substance 10 shown in FIGS. 1 and 2 .
  • the washing reagent recovery portion 70 includes a flow channel-forming non-bonded area 71 , shutter-forming non-bonded areas 12 n and 12 o , pressure supply ports 18 n and 18 o , and a waste tank 78 as main components.
  • the components except for the waste tank 78 can be formed in the same manner as the corresponding components of the chip for analysis of a target substance 10 shown in FIGS. 1 and 2 .
  • the waste tank 78 can be formed in the same manner as the extraction chamber-forming non-bonded area 5 of the chip for analysis of a target substance 10 shown in FIGS. 1 and 2 .
  • the flow channel-forming non-bonded area 11 led out from the chip for analysis of a target substance 10 shown in FIGS. 1 and 2 is split into eight flow channel-forming non-bonded areas 51 a to 51 h via the shutter-forming non-bonded areas 12 g to 12 l and pressure supply ports 18 g to 18 l .
  • the number of the split of the flow channel-forming non-bonded area is not limited to eight and can be increased or decreased appropriately according to a desired analysis accuracy of the target substance.
  • the shutter-forming non-bonded areas 12 g to 12 l , the pressure supply ports 18 g to 18 l , and the flow channel-forming non-bonded areas 51 a to 51 h can be formed in the same manner as the corresponding components of the chip for analysis of a target substance 10 shown in FIGS. 1 and 2 .
  • Eight flow channel-forming non-bonded areas 51 a to 51 h are respectively in contact with eight reaction tanks 52 a to 52 h .
  • shutter-forming non-bonded areas 12 p to 12 z and 12 a to 12 e and pressure supply ports 18 p to 18 z and 18 a to 18 e are respectively formed.
  • a formation method in a conventionally known PCR chip can be employed.
  • the shutter-forming non-bonded areas 12 p to 12 z and 12 a to 12 e and the pressure supply ports 18 p to 18 z and 18 a to 18 e can be formed in the same manner as the corresponding components of the chip for analysis of a target substance 10 shown in FIGS. 1 and 2 .
  • heating means such as heaters are placed.
  • the electrophoresis analysis portion 60 includes reagent tanks 67 a to 67 h , through-holes 68 a to 68 h , flow channel-forming non-bonded areas 61 a to 61 h and 62 a to 62 h , waste tanks 65 a to 65 h and 66 a to 66 h , and electrodes 67 i to 67 p , 68 i to 68 p , 65 i to 65 p , and 66 i to 66 p .
  • the reagent tanks 67 a to 67 h are formed so as to be in contact with the flow channel-forming non-bonded areas 51 a to 51 h of the PCR amplification portion 50 via the shutter-forming non-bonded area 12 m and the pressure supply port 18 m .
  • the flow channel-forming non-bonded areas 61 a to 61 h are formed so as to be in contact with the reagent tanks 67 a to 67 h at one end and be in contact with the waste tanks 65 a to 65 h at the other end.
  • the flow channel-forming non-bonded areas 62 a to 62 h are formed so as to intersect with the flow channel-forming non-bonded areas 61 a to 61 h , be in contact with the through-holes 68 a to 68 h at one end, and be in contact with the waste tanks 66 a to 66 h at the other end.
  • the electrodes 67 i to 67 p , 68 i to 68 p , 65 i to 65 p , and 66 i to 66 p are respectively placed. It is possible to apply voltages to the electrodes 67 i to 67 p , 68 i to 68 p , 65 i to 65 p , and 66 i to 66 p from above the first flexible substrate 1 or below third substrate 3 .
  • the through-holes 67 a to 67 h and the flow channel-forming non-bonded areas 61 a to 61 h and 62 a to 62 h can be formed in the same manner as the corresponding components of the chip for analysis of a target substance 10 shown in FIGS. 1 and 2 .
  • the groove has, for example, a width of about 100 ⁇ m and a depth of about 30 ⁇ m.
  • the reagent tanks 67 a to 67 h and the waste tanks 65 a to 65 h and 66 a to 66 h can be formed in the same manner as the extraction chamber-forming non-bonded area 5 of the chip for analysis of a target substance 10 shown in FIGS. 1 and 2 .
  • As the electrodes 67 i to 67 p , 68 i to 68 p , 65 i to 65 p , and 66 i to 66 p conventionally known ones can be used.
  • optical analysis means such as absorbance measuring apparatuses are placed.
  • the chip for analysis of a target substance 20 of this Embodiment may include the configuration of the chip for analysis of a target substance 10 including the mixing chamber-forming non-bonded area shown in FIG. 3 or FIG. 4 instead of the chip for analysis of a target substance 10 including the extraction chamber-forming non-bonded area 5 shown in FIGS. 1 and 2 . Furthermore, the chip for analysis of a target substance 20 of this Embodiment may further include a through-hole and a flow channel-forming non-bonded area for dry air supply that are formed so as to be in contact with the extraction chamber-forming non-bonded area or the mixing chamber-forming non-bonded area.
  • the size of the chip for analysis of a target substance 20 of this Embodiment is as follows. That is, for example, the length is in the range from 50 mm to 300 mm and the width is in the range from 20 mm to 100 mm. Since the chip for analysis of a target substance of the present invention is compact as described above, it allows a small installation space.
  • the thickness of the chip for analysis of a target substance 20 of this Embodiment excluding the mechanism for generating a magnetic field in the configuration of the chip for analysis of a target substance 10 shown in FIGS. 1 and 2 , the heating means in the PCR amplification portion 50 , and the optical analysis means in the electrophoresis analysis portion 60 is, for example, in the range from 0.5 mm to 5 mm. Therefore, the chip for analysis of a target substance 20 of this Embodiment can be carried around without fixing at a predetermined space.
  • the chip for analysis of a target substance 20 shown in FIG. 5 is used, for example, as follows. First, in the same manner as in Embodiment 1, the target substance such as DNA is extracted from the analysis sample using the configuration of the chip for analysis of a target substance 10 shown in FIGS. 1 and 2 and the washing reagent supply portion 30 .
  • the time required for extracting the target substance is, for example, about 5 minutes.
  • the target substance that is bound to a magnetic particle is transferred to the washing reagent recovery portion 70 by supplying the PCR reaction reagent from the PCR reaction reagent supply portion 40 .
  • a solution obtained by removing the washing reagent from a mixture of the target substance, the washing reagent, the PCR reaction reagent, and the like is transferred to the PCR amplification portion 50 .
  • PCR amplification is performed by a conventionally known method such as a method of applying a temperature cycle to the target substance and the PCR reaction reagent stored in the reaction tanks 52 a to 52 h .
  • the time required for this PCR amplification is, for example, in the range from 10 minutes to 60 minutes and preferably about 15 minutes.
  • electrophoresis analysis is performed by introducing a small amount of amplification products of the target substance from the intersection site of the flow channel-forming non-bonded areas 61 a to 61 h and 62 a to 62 h to the flow channels formed above the flow channel-forming non-bonded areas 62 a to 62 h .
  • the time required for this electrophoresis analysis is, for example, about 5 minutes.
  • Such an electrophoresis analysis method is conventionally known.
  • the chip for analysis of a target substance 20 of this Embodiment allows extraction, amplification, and analysis of a target substance such as DNA with less effort and less time such as from about 20 minutes to about 70 minutes.
  • the chip for analysis of a target substance 20 shown in FIG. 5 includes the PCR amplification portion 50 and the electrophoresis analysis portion 60 .
  • the chip for analysis of a target substance of this Embodiment may be the one that performs electrophoresis analysis without performing PCR amplification.
  • the chip for analysis of a target substance of this Embodiment may be the one that analyzes the target substance by a method other than electrophoresis analysis such as chemiluminescence, fluorescence, or enzyme coloration.
  • analysis of the target substance such as DNA may be performed by a conventional known method such as an intercalation method or a method using a fluorescent-labeled probe.
  • the chip for analysis of a target substance of the present invention is compact and allows analysis of a target substance such as DNA with less time and effort.
  • the chip for analysis of a target substance of the present invention can be applied to a wide range of uses including, for example, DNA analysis in a criminal investigation.

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US10406520B2 (en) 2014-01-24 2019-09-10 The Johns Hopkins University System and device for high throughput generation of combinatorial droplets and methods of use
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JPWO2019146102A1 (ja) * 2018-01-29 2021-02-25 株式会社ニコン 流体デバイス及びその使用
JP6992824B2 (ja) * 2018-01-29 2022-01-13 株式会社ニコン 流体デバイス及びシステム
CN109603942B (zh) * 2019-02-15 2021-12-24 京东方科技集团股份有限公司 微流控装置和微流控方法

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JPWO2013140846A1 (ja) 2015-08-03
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EP2829882B1 (en) 2020-02-19
EP2829882A4 (en) 2015-12-02

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