WO2013027393A1 - マイクロ流体デバイス - Google Patents
マイクロ流体デバイス Download PDFInfo
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- WO2013027393A1 WO2013027393A1 PCT/JP2012/005236 JP2012005236W WO2013027393A1 WO 2013027393 A1 WO2013027393 A1 WO 2013027393A1 JP 2012005236 W JP2012005236 W JP 2012005236W WO 2013027393 A1 WO2013027393 A1 WO 2013027393A1
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L7/00—Heating or cooling apparatus; Heat insulating devices
- B01L7/52—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/24—Stationary reactors without moving elements inside
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- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
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- 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
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- B01L7/52—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples
- B01L7/525—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples with physical movement of samples between temperature zones
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- C12M1/00—Apparatus for enzymology or microbiology
- C12M1/36—Apparatus for enzymology or microbiology including condition or time responsive control, e.g. automatically controlled fermentors
- C12M1/38—Temperature-responsive control
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- 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
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- G01N35/08—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a stream of discrete samples flowing along a tube system, e.g. flow injection analysis
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- B01J2219/00781—Aspects relating to microreactors
- B01J2219/00783—Laminate assemblies, i.e. the reactor comprising a stack of plates
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- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
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- B01L2300/0893—Geometry, shape and general structure having a very large number of wells, microfabricated wells
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- B01L2300/1805—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks
- B01L2300/1827—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks using resistive heater
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- C12M23/00—Constructional details, e.g. recesses, hinges
- C12M23/02—Form or structure of the vessel
- C12M23/16—Microfluidic devices; Capillary tubes
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- 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
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- G01N27/44708—Cooling
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- G01N27/416—Systems
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- G01N27/44756—Apparatus specially adapted therefor
- G01N27/44791—Microapparatus
Definitions
- the present invention relates to a microfluidic device. More particularly, the present invention relates to microfluidic devices such as microreactors, integrated DNA devices and microelectrophoresis devices.
- microfabrication technology is not limited to the electrical and electronic fields, but has penetrated into all fields such as fluids, machinery, and light, and has been actively researched and developed, and will receive more attention is not. With the development of this microfabrication technology, it is possible to reduce the size of the device, and it is possible to reliably respond to social demands for resource saving and energy saving.
- microfluidic devices which can be said to be representative products of microfabrication technology, react reaction solutions with very small amounts of samples and reagents in fields such as microreactors, integrated DNA devices, and microelectrophoresis devices. It is said that there is much utility value because it can be.
- Patent Document 1 discloses a reaction channel having a meandering shape.
- Patent Document 1 for example, as represented by the PCR (polymerase chain reaction) method, a reaction solution is allowed to undergo at least 5 to 40 cycles in three different temperature regions, and only a portion of DNA (deoxyribonucleic acid) is selected.
- a microchemical device that can be amplified automatically is disclosed.
- the reaction flow path is in a meandering form so that the reaction solution is allowed to undergo at least 5 to 40 cycles in three different temperature regions.
- an object of the present invention is to provide a microfluidic device in which the device can be miniaturized without taking the reaction channel in a meandering form.
- a microfluidic device having a reaction channel according to the present invention A plurality of temperature cycle regions each including at least two temperature regions having different temperatures are provided repeatedly, and the reaction flow path is formed to pass through the plurality of temperature cycle regions.
- the microfluidic device includes a heater portion,
- the heater unit has a plurality of heaters set at different temperatures, A temperature region is formed in the heater peripheral region.
- the microfluidic device comprises a bonded substrate and a lid plate,
- the heater part is formed on at least one of the substrate and the cover plate,
- the reaction channel is formed between the substrate and the cover plate.
- At least two reaction channels are arranged in parallel.
- At least two reaction flow paths arranged in parallel share the same heater section.
- the microfluidic device comprises a sample injection part and a sample discharge part, At least two reaction flow paths arranged in parallel are connected from the same sample injection section.
- the heater is a metal thin film heater.
- a detection electrode for measuring the concentration of the reaction fluid flowing in the reaction channel is included.
- a reaction reagent is supported between the sample injection section and the reaction flow path that passes through the plurality of temperature cycle regions.
- the microfluidic devices are arranged in series or in parallel or a combination thereof.
- the temperature cycle region is repeatedly provided, and the reaction channel is formed in the device so as to pass through the plurality of temperature cycle regions, thereby forming the reaction channel without meandering. This makes it possible to reduce the size of the microfluidic device.
- reaction channels can be formed without meandering, a plurality of reaction channels can be arranged in parallel in one microfluidic device.
- FIG. 1 is an overall perspective view of the microfluidic device of the present invention.
- FIG. 2 is an exploded perspective view of the microfluidic device of the present invention.
- FIG. 3 is a cross-sectional view of a process for forming a substrate in the microfluidic device of the present invention.
- FIG. 4 is a cross-sectional view of a process for forming a lid plate in the microfluidic device of the present invention.
- FIG. 5 is a cross-sectional view of the bonding process of the substrate and the cover plate in the microfluidic device of the present invention.
- the microfluidic device is referred to as “device”.
- the reaction fluid described in the present specification refers to a liquid, a gas, and a mixture thereof that can flow in the reaction channel, but is not particularly limited thereto.
- a slurry in which solid particles are dispersed in a liquid can also be included in the fluid as used herein.
- the device of the present invention includes at least two temperature regions each having different temperatures. This is characterized by repeating the temperature cycle region.
- FIG. 1 is an overall perspective view of a device 1 of the present invention.
- FIG. 2 is an exploded perspective view of the device 1 of the present invention.
- the device 1 of the present invention includes a cover plate 2 and a substrate 3.
- the cover plate 2 includes a through hole, a heater unit 5 and a detection electrode 6 that constitute a part of the sample injection unit 4 and the sample discharge unit 7.
- the heater unit 5 and the detection electrode 6 are formed on the lower surface of the lid plate 2.
- the heater unit 5 includes heaters 5a and 5b arranged alternately, and the heaters 5a and 5b are set to different temperatures.
- the through holes constituting part of the sample injection part 4 and the sample discharge part 7 are formed so as to penetrate from the upper surface to the lower surface.
- the substrate 3 includes a recess that constitutes a part of the sample injection part 4, a recess that constitutes a part of the sample discharge part 7, a reaction channel 8, a reaction reagent carrying part 9, and a detection part 10.
- the reaction channel 8 is located between the reaction reagent carrying part 9 and the detection part 10, and is formed between the channel 14 provided on the substrate 3 and the lid plate 2.
- the reaction channel 8 includes reaction channels 8 a, 8 b, 8 c, 8 d and 8 e in the device 1.
- the reaction channel 8c is linear from the reaction reagent carrying part 9 to the detection part 10.
- the reaction channel 8d is a channel in which the shape of the reaction channel 8b is symmetric.
- the reaction channel 8e is a channel in which the shape of the reaction channel 8a is symmetric.
- the reaction flow paths 8 a, 8 b, 8 c, 8 d and 8 e are at positions passing through the lower part of the heater unit 5.
- the bottom surface of the cover plate 2 configured as described above and the top surface of the substrate 3 are formed by one through hole in the cover plate 2 of the sample injection portion 4 and a concave portion constituting a part of the sample injection portion 4 in the substrate 3. Then, the through hole in the cover plate 2 of the sample discharge portion 7 and the concave portion of the sample discharge portion 7 in the substrate 3 coincide with each other, and the detection electrode 6 is bonded to face the upper portion of the discharge portion 10. .
- the heater 5a and the heater 5b set to different temperatures in the heater unit 5 form a temperature region in each heater peripheral region.
- the temperature region refers to a temperature zone formed in the peripheral region of the heater.
- the temperature region formed in each heater peripheral region is a temperature region having a different temperature, and in this embodiment, two temperature regions having different temperatures alternate from the sample injection unit 4 toward the sample discharge unit 7. Formed.
- a temperature cycle region including the two temperature regions having different temperatures is transferred from the sample injection unit 4 to the sample. It can be considered that a plurality are formed repeatedly in the direction of the discharge portion 7.
- the material of the substrate 3 is, for example, silicon.
- the material of the cover plate 2 is glass.
- the cross-sectional shapes of the sample injection part 4 and the sample discharge part 7 are, for example, circular. However, the shape is not limited to a circle, and may be, for example, an ellipse, a rectangle, a square, or a polygon.
- the reaction channel 8 is a channel for the reaction fluid to flow from the reaction reagent holding unit 9 to the detection unit 10 and passes through a plurality of repeated temperature cycle regions. Further, the reaction channel 8 is a channel in which a portion passing through a plurality of repeated temperature cycle regions is a linear channel.
- the sample injection part 4 is an inlet for injecting a reaction fluid from the outside, and is preferably set at the side end of the device 1, and the sample discharge part 7 is at a position facing the sample injection part 4. .
- the reaction reagent holding part 9 is located between the sample injection part 4 and the reaction flow path 8, and the reaction reagent carried in a dry state is charged.
- the detection unit 10 is provided with the detection electrode 6 for measuring the concentration of the reaction fluid.
- the detection electrode 6 is located between the heater unit 5 and the sample discharge unit 7.
- the detection electrode 6 is a thin film electrode for measuring the concentration of the reaction fluid from the current value obtained by applying a voltage to the electrode.
- the sample discharge unit 7 is an outlet for discharging the reaction fluid in the device 1 to the outside.
- reaction process of the reaction fluid in the device 1 of the present invention will be described.
- a desired reaction solution is injected into the sample injection unit 4, and then this reaction solution is mixed with the reaction reagent charged in the reaction reagent holding unit 9. Since the device 1 of the present invention has the reaction reagent holding part 9, it is possible to quickly react with the reaction reagent without depending on an external reaction apparatus.
- the reaction fluid in which the reaction reagent and the reaction solution are mixed proceeds to the reaction channel 8.
- the reaction fluid traveling in the reaction flow path 8 proceeds toward the detection unit 10 in a plurality of repeated temperature cycle regions.
- the reaction fluid whose reaction has been promoted through the plurality of temperature cycle regions proceeds to the detection unit 10.
- the concentration of the reaction fluid is measured from the current value obtained by applying a voltage to the detection electrode 6.
- the measured reaction fluid is discharged from the sample discharge unit 7.
- FIG. 3 is a cross-sectional view of the process of forming the substrate 3 in the device 1 of the present invention.
- an oxide film 11 is formed on the front and back surfaces of the silicon substrate 12 in a diffusion furnace in an oxygen and hydrogen atmosphere (FIG. 3A).
- a resist is formed on the oxide film 11 by photolithography, and the oxide film 11 is etched by reactive ion etching (RIE) (FIG. 3B).
- RIE reactive ion etching
- the resist is removed, and the portion where the silicon is exposed is etched to form a concave portion that constitutes a part of the sample injection portion 4, the reaction reagent holding portion 9, the reaction flow path 8, the detection portion 10, and a part of the sample discharge portion 7.
- the concave channel 14 is formed (FIG. 3C).
- the front and back oxide films 11 are removed by etching with hydrofluoric acid or the like (FIG. 3D).
- a thermal oxide film 13 is formed to obtain the substrate 3 (FIG. 3E).
- the channel 14 may be formed by a method such as injection molding.
- FIG. 4 is a cross-sectional view of the process of forming the cover plate 2 in the device 1 of the present invention.
- a through hole is formed in the glass plate 15 using sandblasting, drilling, or the like (FIG. 4A).
- the metal 16 such as copper is filled in the through hole by plating or the like (FIG. 4B).
- a metal thin film 17 serving as a heater for example, an aluminum thin film is formed by sputtering.
- the type of the metal thin film is not particularly limited, but for example, aluminum, gold, platinum or the like is preferable (FIG. 4C).
- the aluminum film formed by sputtering is patterned by photolithography and etching (FIG. 4D).
- This metal thin film corresponds to the heaters 5a and 5b in the device 1 of the present invention.
- a silicon oxide film 18 is formed by plasma CVD (FIG. 4E).
- the oxide film 18 formed by chemical mechanical polishing (CMP) is planarized (FIG. 4F).
- CMP chemical mechanical polishing
- the oxide film 18 is removed by photolithography and etching with hydrofluoric acid to form the installation part 19 of the detection electrode 6 (FIG. 4G).
- a detection electrode 6 is formed by sputtering a gold or platinum thin film to obtain the cover plate 2 (FIG. 4 (h)).
- FIG. 5 is a cross-sectional view of the bonding process of the substrate 3 and the cover plate 2 in the device 1 of the present invention.
- the top plate obtained by inverting the cover plate 2 (FIG. 5B) obtained in FIG. 4H is used as the upper plate, and the substrate 3 obtained in FIG. 3E (FIG. 5A).
- the two plates are stacked and heated and held at about 300 ° C. to 400 ° C.
- a voltage of 400 V to 800 V is applied to the lid plate 2 side.
- the substrate 3 and the cover plate 2 are joined by holding for 20 to 60 minutes in a state where a voltage is applied to obtain the device 1 of the present invention (FIG. 5C).
- the bonding method is not limited to anodic bonding. For example, if surface activated bonding or the like is used, bonding can be performed at room temperature.
- the structure and manufacturing method of the device 1 of the present invention and the reaction process of the reaction fluid in the device 1 of the present invention have been described above. And the device 1 of this invention has extended various possibilities to the reaction flow path 8 in the device 1 by taking said embodiment.
- the device 1 of the present invention does not need to meander the reaction flow path 8 because the temperature cycle region is repeated by the required number of temperature cycles. Further, since there is no need to meander the reaction flow path 8, at least two reaction flow paths 8 can be arranged in parallel in one device 1, and the device 1 as a whole can be downsized. Become.
- the shape of the reaction channel 8 in the device 1 may be the same or different.
- reaction flow path 8 in the device 1 of the present invention passes through a plurality of repeated temperature cycle regions, the reaction flow path 8 does not return to the sample injection section 4 and the sample is discharged from the sample injection section 4. It can be directed toward the part 7. Therefore, the liquid feeding resistance of the reaction fluid can be suppressed.
- the reaction channel 8 in the device 1 of the present invention passes through a plurality of temperature cycle regions where the reaction channel 8 is repeated, the reaction channel 8 can be made linear from the reaction reagent carrying unit 9 to the detection unit 10. Thereby, the liquid feeding resistance can be minimized, and the uniform flow of the reaction fluid in the reaction channel 8 can be most stabilized.
- reaction flow paths 8 arranged in parallel can share one heater section 5.
- a plurality of reaction fluids can be reacted under the same temperature change condition, so that the heat transfer to the reaction fluid can be made uniform and the difference in reaction behavior due to the difference in reaction fluid can be objectively observed.
- the device 1 of the present invention is not limited to the above embodiment, and for example, the following embodiment can be adopted.
- the heaters set in the heater unit 5 are set to two different temperatures.
- the present invention is not limited to heaters set at two different temperatures, and may be heaters set at three or more different temperatures.
- the heaters set in the heater unit 5 are set in the same manner as when the two different temperatures are set.
- the heaters form three temperature regions having different temperatures in each heater peripheral region. Three temperature regions having different temperatures are formed in order from the sample injection unit 4 toward the sample discharge unit 7.
- a temperature cycle region including the three temperature regions having different temperatures is formed from the sample injection unit 4 to the sample. It can be considered that a plurality are formed repeatedly in the direction of the discharge portion 7.
- the temperature cycle region in the device 1 of the present invention takes a repetitively continuous form.
- reaction behavior of the reaction fluid in the reaction flow path 8 passing through each temperature region may be changed by changing the position or size of the heater.
- the heater temperature does not necessarily need to be increased or decreased in the order of the direction of the sample discharge section 7, and any combination may be used.
- the heaters do not have to be arranged separately, and for example, one heater may be arranged in a U shape.
- the heater unit 5 is provided on the cover plate 2, the heater unit 5 is not necessarily provided on the cover plate 2 and may be provided on the substrate 3. Further, the sample injection part 4 and the sample discharge part 7 may be formed only on the substrate 3. Moreover, the heater part 5 does not necessarily need to be one, and may be two or more. Therefore, for example, at least two reaction flow paths 8 arranged in parallel may share two different heater portions 5.
- reaction flow path 8 does not necessarily need to be linear in the portion that passes through a plurality of repeated temperature cycle regions, and may have a curved shape such as a semicircle or a semi-ellipse. As a result, the liquid feeding resistance of the reaction fluid can be suppressed, so that a uniform flow of the reaction fluid in the reaction channel 8 can be formed. Moreover, it is preferable that the reaction flow path 8 that crosses the temperature cycle region passes orthogonally.
- At least two reaction flow paths 8 arranged in parallel may be connected from the same sample injection section 4. This allows the same reaction fluid to pass through the at least two reaction channels 8, so that the measured values obtained are reliable.
- the number of sample injection sections 4 and sample discharge sections 7 may be changed according to the number of reaction flow paths 8 arranged in parallel. Further, the number of sample injection sections 4 and sample discharge sections 7 may be the same or different depending on the number of reaction channels 8 arranged in parallel.
- the device 1 of the present invention has the reaction channel 8 formed in the device 1 so as to pass through a plurality of repeated temperature cycle regions, (1)
- the reaction channel 8 can be formed without meandering.
- the reaction channel 8 can be formed without meandering, whereby a plurality of reaction channels 8 are efficiently arranged in parallel in one device 1.
- the device 1 can be downsized.
- At least two devices 1 of the present invention may be arranged.
- the arrangement form of the devices 1 at this time is not limited to the parallel form, and may be in series and / or parallel and / or any combination thereof. This is effective when multiple reaction processes are required while maintaining the miniaturization of each device 1.
- the device of the present invention may be combined with other different devices having various functions and configurations.
- it may be a syringe pump for injecting a sample into the device 1 of the present invention and / or for discharging a sample from the device 1 of the present invention.
- the discharge pressure of the syringe pump is preferably 0.1 MPa to 10 MPa.
- the PCR method is a reaction for amplifying the number of DNA (deoxyribonucleic acid). Specifically, a denaturation temperature (about 95 ° C.), an annealing temperature (about 60 ° C.), an extension temperature (about approx. DNA is increased exponentially by repeating about 30 to 50 cycles at 60 ° C. to 75 ° C.).
- a high temperature range for example, 95 ° C. to 100 ° C.
- a low temperature range for example, 50 ° C. to 75 ° C.
- the time for staying in each temperature region is controlled by controlling the speed of the reaction fluid.
- the speed of the reaction fluid is controlled by changing the width and depth of the reaction channel 8.
- the residence time of the reaction fluid in each temperature region is preferably about 1 to 5 seconds in the high temperature region and about 4 to 20 seconds in the low temperature region, for example, from the viewpoint of increasing the reaction fluid speed.
- the liquid feeding is preferably performed by capillary action from the viewpoint of miniaturization. For example, if the width and depth of the reaction channel 8 are designed in the range of 20 ⁇ m to 100 ⁇ m, a desired flow rate can be obtained.
- the reaction solution injected from the sample injection unit 4 reaches the reaction reagent holding unit 9 on which the reaction reagent is dried and supported, and dissolves the reaction reagent.
- the reaction reagent includes a polymerase enzyme and a primer, and is dry-supported by lyophilization or the like.
- the reaction fluid in which the reaction reagent is dissolved propagates through the reaction flow path 8 by capillary action, and at this time, the PCR is performed by repeatedly passing through the high temperature region and the low temperature region.
- the reaction fluid after the reaction reaches the detection unit 10, and the concentration of the amplified DNA can be known by the interaction with the electrode.
- Substrate 3 This is a formation process of the substrate 3 in the device 1 of the present invention.
- silicon is used as the substrate 3.
- Thermal oxidation A silicon oxide film 11 of about 500 nm to 1 ⁇ m is formed on the front and back surfaces of the silicon substrate 12 in a diffusion furnace in an oxygen and hydrogen atmosphere.
- Removal of silicon oxide film 11 A resist is patterned on the silicon oxide film 11 by photolithography, and the silicon oxide film 11 is etched by reactive ion etching (RIE).
- RIE reactive ion etching
- Si etching The resist is removed, and the silicon exposed portion is etched by, for example, 20 ⁇ m to 100 ⁇ m by deep RIE (DRIE) to form a concave portion that constitutes a part of the sample injection portion 4 of the device, a reaction reagent carrying portion 9.
- DRIE deep RIE
- a recessed channel 14 constituting a part of the reaction channel 8, the detection unit 10 and the sample discharge unit 7 is formed.
- This silicon etching is not limited to DRIE, but may be wet etching using TMAH, for example.
- Removal of silicon oxide film 11 The silicon oxide film 11 on the front and back surfaces is removed by etching with hydrofluoric acid or the like. (5) Thermal oxidation In order to increase the hydrophilicity of the reaction channel 8, an oxide film of about 50 nm to 100 nm is formed.
- Forming process of the cover plate 2 This is a process of forming the cover plate 2 in the device 1 of the present invention.
- glass is used as the cover plate 2.
- Through-hole processing A through-hole is formed in the glass plate 15 using sandblasting, drilling, or the like.
- Metal 16 filling The through hole is filled with metal 16, such as copper, by plating or the like.
- (3) Formation of heater metal thin film A metal thin film 17 to be a heater, for example, an aluminum thin film of about 0.5 ⁇ m to 1.5 ⁇ m is formed by sputtering.
- the type of the metal thin film 17 is not particularly limited. For example, aluminum, gold, platinum and the like are preferable.
- Patterning of the metal thin film 17 Aluminum formed by sputtering is patterned by photolithography and etching. (5) Protective film formation A silicon oxide film 18 of about 1 ⁇ m to 2 ⁇ m is formed by plasma CVD. Prevents the aluminum thin film that becomes the heater from touching the liquid directly. (6) Planarization The formed silicon oxide film 18 is planarized by chemical mechanical polishing (CMP). (7) Oxide film patterning A portion of the oxide film for forming the detection electrode 6 is removed by photolithography and etching with hydrofluoric acid. (8) Formation of detection electrode 6 As the detection electrode 6, a gold or platinum thin film is formed by sputtering.
- Bonding of Substrate 3 and Cover Plate 2 This is a process for bonding the substrate 3 and the cover plate 2 in the device 1 of the present invention.
- a bonding method for example, anodic bonding is used. First, the substrate 3 and the cover plate 2 are stacked, and heated and held at about 300 ° C. to 400 ° C. Next, when the substrate 3 and the cover plate 2 reach a desired temperature, a voltage of 400 V to 800 V is applied to the substrate 3 to the cover plate 2 side. Good bonding can be realized by holding the voltage for 20 minutes to 60 minutes.
- the bonding method is not limited to anodic bonding. For example, if surface activated bonding or the like is used, bonding can be performed at room temperature.
- the device of the present invention is not limited to this, and may be, for example, resin imprint processing.
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Abstract
Description
本発明に係る反応流路を有するマイクロ流体デバイスは、
温度が異なる少なくとも2つの温度領域をそれぞれ含んで成る複数の温度サイクル領域が繰り返し設けられており、反応流路が複数の温度サイクル領域を通過するように形成されることを特徴とする。
マイクロ流体デバイスは、ヒータ部を含んで成り、
ヒータ部は、異なる温度に設定された複数のヒータを有し、
ヒータ周縁域に温度領域が形成される。
ヒータ部は、少なくとも基板と蓋板のいずれか一方に有って成り、
反応流路は、基板と蓋板との間に形成されて成る。
並列に配置された少なくとも2つの反応流路が、同じ試料注入部から接続されている。
<基板3の形成>
図3は、本発明のデバイス1内の基板3の形成プロセス断面図である。まず、酸素および水素雰囲気の拡散炉中でシリコン基板12の表裏面に酸化膜11を形成する(図3(a))。次いで、酸化膜11上にフォトリソグラフィによりレジストを形成し、反応性イオンエッチング(RIE)により酸化膜11をエッチングする(図3(b))。次いで、レジストを除去し、シリコンが露出した部分をエッチングし、試料注入部4の一部を構成する凹部、反応試薬担持部9、反応流路8、検出部10および試料排出部7の一部を構成する凹部のチャンネル14を形成する(図3(c))。次いで、表裏面の酸化膜11をフッ酸等によるエッチングにより除去する(図3(d))。最後に、反応流路8の親水性を高めるため、熱酸化膜13を形成して基板3を得る(図3(e))。上記方法以外に基板3の材質がシリコン以外の例えば樹脂である場合には、チャンネル14の形成方法は射出成形などの方法によって設けられてもよい。
図4は、本発明のデバイス1内の蓋板2の形成プロセス断面図である。まず、サンドブラストやドリル加工等を用いて、ガラス板15に貫通孔を形成する(図4(a))。次いで、メッキ等により貫通孔に金属16、例えば銅を充填する(図4(b))。次いで、ヒータとなる金属薄膜17、例えばアルミニウム薄膜をスパッタリングにより形成する。本発明では特に金属薄膜の種類は限定しないが、例えばアルミニウムや金、白金などが好ましい(図4(c))。次いで、スパッタリングにより成膜したアルミニウムをフォトリソグラフィ、およびエッチングによりパターニングする(図4(d))。この金属薄膜が本発明のデバイス1内のヒータ5aおよび5bに相当する。次いで、ヒータ5aおよびヒータ5bとなるアルミニウム薄膜が直接反応流体に触れるのを防ぐため、プラズマCVDによりシリコン酸化膜18を形成する(図4(e))。次いで、化学機械的研磨(CMP)により成膜した酸化膜18を平坦化する(図4(f))。次いで、検出電極6を設置するため、酸化膜18をフォトリソグラフィ、フッ酸によるエッチングにより除去して、検出電極6の設置部19を形成する(図4(g))。最後に、金または白金薄膜をスパッタリングにより検出電極6を形成して、蓋板2を得る(図4(h))。
図5は、本発明のデバイス1内の基板3と蓋板2の接合プロセス断面図である。まず、図4(h)で得られた蓋板2(図5(b))を上下反転させたものを上板に、又図3(e)で得られた基板3(図5(a))を下板となるようにする。次いで、両板を重ね、300℃~400℃程度に加熱、保持する。次いで、両板が所望の温度になったところで、400V~800Vの電圧を蓋板2側に印加する。電圧を印加した状態で20分~60分保持することで基板3と蓋板2を接合させ、本発明のデバイス1を得る(図5(c))。接合方法は、陽極接合に限るものではなく、例えば表面活性化接合等を用いれば常温で接合することも可能である。
(1)反応流路8を蛇行させることなく形成できること
(2)反応流路8を蛇行させることなく形成できることによって、1つのデバイス1内に複数の反応流路8を効率良く並列に配置することができること
(3)安定な反応流れを実現できることで、反応流体の流動制御および流動操作が容易となること
(4)デバイス1の小型化を図ることができること
の効果を有する。
本発明のデバイス1内の基板3の形成プロセスである。本実施例では、基板3としてシリコンを用いる。
(1)熱酸化
酸素および水素雰囲気の拡散炉中で、シリコン基板12の表裏面に500nm~1μm程度のシリコン酸化膜11を形成する。
(2)シリコン酸化膜11除去
シリコン酸化膜11上にフォトリソグラフィによりレジストをパターニングし、反応性イオンエッチング(RIE)によりシリコン酸化膜11をエッチングする。
(3)Siエッチング
レジストを除去し、シリコンが露出した部分を、深堀りRIE(DRIE)により、例えば20μm~100μmエッチングし、デバイスの試料注入部4の一部を構成する凹部、反応試薬担持部9、反応流路8、検出部10および試料排出部7の一部を構成する凹部のチャンネル14を形成する。このシリコンのエッチングはDRIEに限らず、例えばTMAH等を用いたウェット・エッチングでもよい。
(4)シリコン酸化膜11除去
表裏面のシリコン酸化膜11をフッ酸等によるエッチングにより除去する。
(5)熱酸化
反応流路8の親水性を高めるため、50nm~100nm程度の酸化膜を形成する。
本発明のデバイス1内の蓋板2の形成プロセスである。本実施例では、蓋板2としてガラスを用いる。
(1)貫通孔加工
サンドブラストやドリル加工等を用いて、ガラス板15に貫通孔を形成する。
(2)金属16埋め込み
メッキ等により、貫通孔に金属16、例えば銅を充填する。
(3)ヒータ金属薄膜の形成
ヒータとなる金属薄膜17、例えば0.5μm~1.5μm程度のアルミニウム薄膜をスパッタリングにより形成する。本発明では特に金属薄膜17の種類は限定しないが、例えばアルミニウムや金、白金などが好ましい。
(4)金属薄膜17のパターニング
スパッタリングにより成膜したアルミニウムをフォトリソグラフィ、およびエッチングによりパターニングする。
(5)保護膜形成
プラズマCVDにより、1μm~2μm程度のシリコン酸化膜18を形成する。ヒータとなるアルミニウム薄膜が直接液に触れるのを防ぐ。
(6)平坦化
化学機械的研磨(CMP)により、成膜したシリコン酸化膜18を平坦化する。
(7)酸化膜パターニング
検出電極6を形成する部分の酸化膜をフォトリソグラフィ、フッ酸によるエッチングにより除去する。
(8)検出電極6の形成
検出電極6として、金または白金薄膜をスパッタリングにより形成する。
本発明のデバイス1内の基板3と蓋板2の接合プロセスである。
接合の方法としては、例えば陽極接合によって接合する。まず、基板3と蓋板2とを重ね、300℃~400℃程度に加熱、保持する。次いで、基板3と蓋板2が所望の温度になったところで、基板3に対して400V~800Vの電圧を蓋板2側に印加する。電圧を印加した状態で20分~60分保持することで良好な接合を実現することができる。接合方法は、陽極接合に限るものではなく、例えば表面活性化接合等を用いれば常温で接合することも可能である。
2 蓋板
3 基板
4 試料注入部
5 ヒータ部
5a ヒータ
5b ヒータ
6 検出電極
7 試料排出部
8 反応流路
8a 反応流路
8b 反応流路
8c 反応流路
8d 反応流路
8e 反応流路
9 反応試薬担持部
10 検出部
11 シリコン酸化膜
12 シリコン基板
13 酸化膜
14 チャンネル
15 ガラス板
16 金属
17 金属薄膜
18 シリコン酸化膜
19 検出電極設置部
Claims (10)
- 反応流路を有するマイクロ流体デバイスにおいて、
温度が異なる少なくとも2つの温度領域をそれぞれ含んで成る複数の温度サイクル領域が繰り返し設けられており、前記反応流路が複数の前記温度サイクル領域を通過するように形成されることを特徴とする、
マイクロ流体デバイス。 - 前記マイクロ流体デバイスがヒータ部を含んで成り、
前記ヒータ部は、異なる温度に設定された複数のヒータを有し、
前記ヒータ周縁域に前記温度領域が形成される、
請求項1に記載のマイクロ流体デバイス。 - 前記マイクロ流体デバイスが、結合された基板と蓋板とを含んで成り、
前記ヒータ部は、少なくとも前記基板と前記蓋板のいずれか一方に有って成り、
前記反応流路は、前記基板と前記蓋板との間に形成されて成る、
請求項2に記載のマイクロ流体デバイス。 - 少なくとも2つの前記反応流路が並列に配置されている、請求項1~3のいずれかに記載のマイクロ流体デバイス。
- 並列に配置された少なくとも2つの前記反応流路が、同じ前記ヒータ部を共有する、請求項4に記載のマイクロ流体デバイス。
- 前記マイクロ流体デバイスが、試料注入部および試料排出部を含んで成り、
並列に配置された少なくとも2つの前記反応流路が、同じ前記試料注入部から接続されている、請求項4又は5に記載のマイクロ流体デバイス。 - 前記ヒータが金属薄膜ヒータから成る、請求項2~6のいずれかに記載のマイクロ流体デバイス。
- 前記反応流路内を流れる反応流体の濃度を測定するための検出電極を含んで成る、請求項1~7のいずれかに記載のマイクロ流体デバイス。
- 前記試料注入部と複数の前記温度サイクル領域を通過する前記反応流路との間に、反応試薬が担持されている、請求項6~8のいずれかに記載のマイクロ流体デバイス。
- 請求項1~9のいずれかに記載のマイクロ流体デバイスが、直列に若しくは並列に又はこれらを組み合わせて配列されている、マイクロ流体デバイス。
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Also Published As
Publication number | Publication date |
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EP2749349A1 (en) | 2014-07-02 |
SG11201400130RA (en) | 2014-04-28 |
EP2749349A4 (en) | 2014-07-02 |
TW201323075A (zh) | 2013-06-16 |
JP5965908B2 (ja) | 2016-08-10 |
JPWO2013027393A1 (ja) | 2015-03-05 |
TWI508772B (zh) | 2015-11-21 |
KR101664201B1 (ko) | 2016-10-11 |
CN103781543A (zh) | 2014-05-07 |
IN2014CN01311A (ja) | 2015-08-28 |
US20140220668A1 (en) | 2014-08-07 |
KR20140039079A (ko) | 2014-03-31 |
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