US20140056580A1 - Microfluidic device and microfluidic apparatus using the same - Google Patents

Microfluidic device and microfluidic apparatus using the same Download PDF

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Publication number
US20140056580A1
US20140056580A1 US14/115,819 US201214115819A US2014056580A1 US 20140056580 A1 US20140056580 A1 US 20140056580A1 US 201214115819 A US201214115819 A US 201214115819A US 2014056580 A1 US2014056580 A1 US 2014056580A1
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resistive element
fluid
flow channel
microfluidic device
temperature
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English (en)
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Hirotomo Taniguchi
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Canon Inc
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Canon Inc
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Publication of US20140056580A1 publication Critical patent/US20140056580A1/en
Abandoned legal-status Critical Current

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    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F24—HEATING; RANGES; VENTILATING
    • F24H—FLUID HEATERS, e.g. WATER OR AIR HEATERS, HAVING HEAT-GENERATING MEANS, e.g. HEAT PUMPS, IN GENERAL
    • F24H9/00—Details
    • 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
    • B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • 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
    • 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
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00783—Laminate assemblies, i.e. the reactor comprising a stack of plates
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00819—Materials of construction
    • B01J2219/00822—Metal
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00819—Materials of construction
    • B01J2219/00824—Ceramic
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00819—Materials of construction
    • B01J2219/00824—Ceramic
    • B01J2219/00826—Quartz
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00819—Materials of construction
    • B01J2219/00831—Glass
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00851—Additional features
    • B01J2219/00853—Employing electrode arrangements
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00873—Heat exchange
    • B01J2219/0088—Peltier-type elements
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00873—Heat exchange
    • B01J2219/00885—Thin film heaters
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00925—Irradiation
    • B01J2219/0093—Electric or magnetic energy
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/0095—Control aspects
    • B01J2219/00952—Sensing operations
    • B01J2219/00954—Measured properties
    • B01J2219/00961—Temperature
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/0095—Control aspects
    • B01J2219/00986—Microprocessor
    • 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
    • B01L2300/18—Means for temperature control
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01K—MEASURING TEMPERATURE; MEASURING QUANTITY OF HEAT; THERMALLY-SENSITIVE ELEMENTS NOT OTHERWISE PROVIDED FOR
    • G01K7/00—Measuring temperature based on the use of electric or magnetic elements directly sensitive to heat ; Power supply therefor, e.g. using thermoelectric elements
    • G01K7/16—Measuring temperature based on the use of electric or magnetic elements directly sensitive to heat ; Power supply therefor, e.g. using thermoelectric elements using resistive elements

Definitions

  • the present invention relates to a microfluidic device having a minute flow channel, specifically, a microfluidic device for performing chemosynthesis, genetic testing, or the like by chemical reaction, biochemical reaction, and physicochemical reaction, or the like. Further, the present invention relates to a microfluidic apparatus using the microfluidic device.
  • Patent Literature 1 There is disclosed a conventional microfluidic device in which a heater is disposed for heating fluid in a micro flow channel on the same substrate as that in which the flow channel is disposed (for example, Patent Literature 1). Moreover, there is disclosed a micro reactor in which a temperature sensor, which is independent from a heater, is disposed as a unit for controlling the heater (for example, Patent Literature 2). Further, apart from the technical field of the microfluidic device, there is disclosed an airflow detection sensor having a heater also functioning as a temperature sensor by using a phenomenon that a resistance value of a resistive element as a heater changes in accordance with temperature (for example, Patent Literature 3).
  • FIG. 5A is a perspective view of a microfluidic device
  • FIG. 5B is a plan view of the microfluidic device
  • FIG. 5C is a cross-sectional view of the microfluidic device cut along the 5 C- 5 C line of FIG. 5B
  • FIG. 5D is an enlarged view of the region B of the microfluidic device of FIG. 5C .
  • the reference symbol D denotes the center of the widths of the flow channel and the heater, and the reference symbol E denotes the width of the flow channel.
  • FIG. 8 is a graph showing temperature distribution along the C-C line in FIG. 5D when the fluid in the micro flow channel is heated by the heater so as to be 94° C.
  • the reference symbol D denotes the center of the widths of the flow channel and the heater
  • the reference symbol E denotes the width of the flow channel, respectively.
  • Patent Literature 4 has an effect of improving temperature distribution of an object to be heated, but does not have a function of measuring the temperature in real time to control the temperature. Accordingly, this is not suitable for a device which needs highly accurate temperature control, such as a microfluidic device which is used for performing genetic testing.
  • an object of the present invention is to provide a microfluidic device and a microfluidic apparatus using the same for achieving uniform temperature of fluid in a flow channel of the microfluidic device, and controlling the temperature with high accuracy.
  • a microfluidic device including: a substrate; a flow channel disposed in the substrate for flowing through fluid therein; a first resistive element for primarily heating the fluid in the flow channel; and multiple second resistive elements for supplementarily heating the fluid in the flow channel, the second resistive elements being disposed at positions different from a position where the first resistive element is disposed.
  • a microfluidic device including: a substrate; multiple flow channels disposed in parallel to one another in the substrate for flowing through fluid therein; first resistive elements for primarily heating the fluid in the multiple flow channels, the first resistive elements being disposed independent from one another so as to correspond to the number of the multiple flow channels; and a second resistive element for supplementarily heating the fluid in the multiple flow channels, the second resistive element being electrically independent from the first resistive elements and disposed in a region of the substrate exterior to an outermost first resistive element in the substrate among the first resistive elements.
  • a microfluidic apparatus including the above-described microfluidic devices for measuring a temperature of the fluid in the flow channel based on a resistance value of the first resistive element and adjusting a heat energy input into the first resistive element to control the temperature of the fluid in the flow channel, in which the microfluidic apparatus stores a relational expression between the temperature of the fluid in the flow channel and the resistance value of the first resistive element, and a fixed value of a ratio between a heat energy input into the first resistive element and a heat energy input into a second resistive element; and the microfluidic apparatus controls the temperature of the fluid in the flow channel in accordance with the relational expression and the fixed value.
  • a microfluidic apparatus further including an arithmetic unit for calculating the fixed value of the ratio between the heat energy input into the first resistive element and the heat energy input into the second resistive element, in which the arithmetic unit calculates the fixed value by using a size of the microfluidic device and an environmental condition of the microfluidic apparatus as input parameters.
  • the second resistive element for supplementarily heating the fluid in the flow channel is disposed at the position different from the position where the first resistive element is disposed.
  • the microfluidic apparatus of the present invention including the above-described microfluidic device stores the relational expression between the temperature of the fluid in the flow channel and the resistance value of the first resistive element, and the fixed value of the ratio between the heat energy input into the first resistive element and the heat energy input into the second resistive element, and controls the temperature of the fluid in the flow channel in accordance with the relational expression and the fixed value. Accordingly, the microfluidic apparatus can provide such advantageous effects that the temperature of fluid in the flow channel can be controlled with high accuracy and the temperature distribution can be improved.
  • the microfluidic apparatus of the present invention further includes the arithmetic unit for calculating the fixed value of the ratio between the heat energy input into the first resistive element and the heat energy input into the second resistive element, and the arithmetic unit can calculate the fixed value by using the size of the microfluidic device and the environmental condition of the microfluidic apparatus as input parameters.
  • the temperature distribution of the microfluidic device can be improved.
  • the present invention includes a method of heating fluid, a method of treating fluid, and a method of controlling a temperature of fluid with use of the above-described microfluidic device.
  • FIG. 1A is a perspective view illustrating an example of an embodiment of a microfluidic device according to the present invention.
  • FIG. 1B is a plan view illustrating the example of the embodiment of the microfluidic device according to the present invention.
  • FIG. 1C is a cross-sectional view cut along the 1 C- 1 C line of FIG. 1B , illustrating the example of the embodiment of the microfluidic device according to the present invention.
  • FIG. 1D is an enlarged view of the region B of FIG. 1C , illustrating the example of the embodiment of the microfluidic device according to the present invention.
  • FIG. 2A is a perspective view illustrating another example of an embodiment of a microfluidic device according to the present invention.
  • FIG. 2B is a plan view illustrating another example of the embodiment of the microfluidic device according to the present invention.
  • FIG. 2C is a cross-sectional view cut along the 2 C- 2 C line of FIG. 2B , illustrating another example of the embodiment of the microfluidic device according to the present invention.
  • FIG. 3A is a perspective view illustrating still another example of an embodiment of a microfluidic device according to the present invention.
  • FIG. 3B is a plan view illustrating the still another example of the embodiment of the microfluidic device according to the present invention.
  • FIG. 3C is a cross-sectional view cut along the 3 C- 3 C line of FIG. 3B , illustrating the still another example of the embodiment of the microfluidic device according to the present invention.
  • FIG. 4A is an exploded view of FIG. 1A illustrating the example of the embodiment of the microfluidic device according to the present invention, and is a perspective view of a substrate in which a flow channel is formed.
  • FIG. 4B is an exploded view of FIG. 1A illustrating the example of the embodiment of the microfluidic device according to the present invention, and is a perspective view of an insulating layer.
  • FIG. 4C is an exploded view of FIG. 1A illustrating the example of the embodiment of the microfluidic device according to the present invention, and is a perspective view of a layer in which first and second resistive elements and electrode wiring of the first and second resistive elements are formed.
  • FIG. 4D is an exploded view of FIG. 1A illustrating the example of the embodiment of the microfluidic device according to the present invention, and is a perspective view of a supporting substrate.
  • FIG. 5A is a perspective view illustrating a microfluidic device to be compared with the microfluidic device according to the present invention.
  • FIG. 5B is a plan view illustrating the microfluidic device to be compared with the microfluidic device according to the present invention.
  • FIG. 5C is a cross-sectional view cut along the 5 C- 5 C line of FIG. 5B , illustrating the microfluidic device to be compared with the microfluidic device according to the present invention.
  • FIG. 5D is an enlarged view of the region B of FIG. 5C , illustrating the microfluidic device to be compared with the microfluidic device according to the present invention.
  • FIG. 6 is a block diagram of a microfluidic apparatus according to the present invention.
  • FIG. 7A is an exploded view of FIG. 5A illustrating the microfluidic device to be compared with the microfluidic device according to the present invention, and is a perspective view of a substrate in which a flow channel is formed.
  • FIG. 7B is an exploded view of FIG. 5A illustrating the microfluidic device to be compared with the microfluidic device according to the present invention, and is a perspective view of an insulating layer.
  • FIG. 7C is an exploded view of FIG. 5A illustrating the microfluidic device to be compared with the microfluidic device according to the present invention, and is a perspective view of a layer in which a resistive element and electrode wiring are formed.
  • FIG. 7D is an exploded view of FIG. 5A illustrating the microfluidic device to be compared with the microfluidic device according to the present invention, and is a perspective view of a supporting substrate.
  • FIG. 8 is a graph showing temperature distribution of fluid in the flow channel in the comparative example of the microfluidic device and a microfluidic apparatus to be compared with the microfluidic device and the microfluidic apparatus according to the present invention.
  • FIG. 9 is a graph showing temperature distribution of fluid in the flow channel in Example 1 of the microfluidic device and the microfluidic apparatus according to the present invention.
  • FIG. 10 is a graph showing temperature distribution of fluid in the flow channel in Example 2 of the microfluidic device and the microfluidic apparatus according to the present invention.
  • a microfluidic device of the present invention is described hereinafter.
  • FIG. 1A is a perspective view illustrating an example of an embodiment of the microfluidic device according to the present invention.
  • FIG. 1B is a plan view of the microfluidic device.
  • FIG. 1C is a cross-sectional view of the microfluidic device, cut along the 1 C- 1 C line of FIG. 1B .
  • FIG. 1D is an enlarged view of the region B of the microfluidic device of FIG. 1C .
  • FIGS. 2A to 2C and FIGS. 3A to 3C are views illustrating other examples of an embodiment of a microfluidic device according to the present invention.
  • a micro flow channel substrate 1 (hereinafter, also referred to as “supporting substrate”), a flow channel 2 , a flow inlet 3 , a flow outlet 4 , a first resistive element 5 for primarily heating fluid in the flow channel, second resistive elements 6 , which are disposed at positions different from the position of the first resistive element 5 , for supplementarily heating the fluid in the flow channel.
  • electrode wiring 7 of the first resistive element electrode wiring 8 of the second resistive elements, and an insulating layer 9 .
  • the first resistive element 5 is disposed on the flow channel 2
  • the second resistive elements 6 are disposed apart from the flow channel.
  • the first resistive element for primarily heating the fluid in the flow channel and the flow channel provided in the substrate are disposed parallel with each other in their longitudinal directions.
  • FIGS. 1A to 1D there are disposed a single flow channel, a single first resistive element, and two second resistive elements which are symmetrically positioned across the first resistive element.
  • FIGS. 2A to 2C there are disposed a single flow channel, a single first resistive element, and four second resistive elements. Two of the second resistive elements are positioned on the same straight line in the longitudinal direction of the flow channel across the first resistive element, and the other two of the second resistive elements are positioned parallel with the longitudinal direction of the first resistive element across the first resistive element, respectively.
  • multiple (three in this configuration) flow channels are disposed in parallel to one another, and the first resistive elements are disposed independent from one another so as to correspond to the number of the multiple flow channels.
  • the second resistive elements are disposed in regions of the substrate exterior to an outermost first resistive element in the substrate so as to be parallel with the longitudinal direction of the first resistive element.
  • FIGS. 4A to 4D are exploded views of FIG. 1A .
  • FIG. 4 A illustrates the substrate in which the flow channel is formed.
  • FIG. 4B illustrates the insulating layer.
  • FIG. 4C illustrates the layer in which the first and second resistive elements and the electrode wiring of the first and second resistive elements are formed.
  • FIG. 4D illustrates the supporting substrate.
  • the insulating layer is disposed so as to insulate the resistive elements, the electrode wiring, and the flow channel from one another. This insulating layer is not essential.
  • a glass material such as quartz
  • a material other than glass such as silicon and ceramics
  • a metal other than glass such as silicon and ceramics
  • the resistive elements a metal, such as platinum, or an oxide, such as ruthenium oxide, are used.
  • the electrode wiring a metal, such as gold and aluminum, is used.
  • an insulating material such as silicon oxide and silicon nitride, is used.
  • the first resistive element and the second resistive elements are individually supplied with energy from different voltage supply systems. That is, the first resistive element and the second resistive elements are preferred to be electrically independent from each other.
  • the second resistive elements for supplementarily heating the fluid in the flow channel contribute to enable the temperature distribution in the flow channel to become uniform.
  • an amount of heat generated by the second resistive elements increases too much, the uniformity of temperature distribution may be deteriorated.
  • the amount of heat generation is preferred to be controlled by a system which regulates an amount of current input into the second resistive element.
  • first resistive element and the second resistive elements may be connected with each other by common wiring.
  • first resistive element and the second resistive elements are independently positioned so that the respective surrounding environments are different from each other.
  • the size of the second resistive element and the positional relationship between the first and second resistive elements are suitably set by performing a thermal diffusion simulation calculation, or the like, so as to dispose the second resistive elements.
  • the microfluidic device of the present invention has the following configurations.
  • the first resistive element and the second resistive element have the same shape and the same area.
  • the first resistive element and the second resistive element have shapes or areas different from each other.
  • a microfluidic apparatus of the present invention is described hereinafter.
  • the microfluidic device illustrated in FIGS. 1A to 1D includes the flow inlet 3 and the flow outlet 4 of the fluid, to which tubes for interfaces are connected so that the fluid flows in and out by an external pump.
  • the fluid in the flow channel provided in the substrate so that the fluid flows therethrough is heated by heat conduction of Joule heat which is generated by applying voltage to the resistive elements.
  • Resistance values of resistive elements, such as platinum, change in accordance with temperature thereof, and hence the resistive elements can also function as temperature sensors.
  • the temperature of fluid is measured based on the changes in resistance value of the resistive element, and the heat energy to be input into the resistive element is adjusted by a control method, such as PID control, so as to adjust the temperature of fluid to a targeted temperature.
  • the heat energy input into the second resistive elements which are independent from the first resistive element and serve as heaters for supplementarily heating the fluid in the flow channel, is the same as the amount of the adjusted heat energy input into the first resistive element for primarily heating the fluid in the flow channel, the heat energy input into the second resistive elements produces an effect of improving the temperature distribution of the fluid.
  • the heat energy needs to be input at an optimum ratio in accordance with the configuration of the microfluidic device.
  • the microfluidic device can be operated so as to optimize the temperature distribution of the fluid in the flow channel by calibrating, in advance before the actual operation of the device, the relationship between the temperature distribution of fluid in the flow channel and the ratio of the heat energy input into the first resistive element and the second resistive elements.
  • the temperature distribution of fluid in the flow channel can be indirectly measured by using a measuring instrument such as a radiation thermometer.
  • the radiation thermometer cannot directly measure the temperature of fluid in the flow channel, but can measure the temperature of the surface of the substrate of the microfluidic device.
  • a physical numerical simulation such as a finite element method, the relationship between the temperature distribution of the substrate surface and the temperature distribution of fluid in the flow channel is obtained in advance.
  • the temperature distribution of fluid in the flow channel can be indirectly measured based on the actually measured temperature distribution of the substrate surface.
  • the microfluidic device which has been calibrated as described above, stores the relational expression between the temperature of fluid in the flow channel and the resistance value of the first resistive element, and the fixed value of the ratio of heat energy input into the first resistive element and the second resistive elements.
  • the temperature of fluid in the flow channel is controlled in accordance with the above-mentioned relational expression and fixed value.
  • the microfluidic apparatus of the present invention includes an arithmetic unit for calculating the above-mentioned fixed value of the ratio between the heat energy input into the first resistive element and the heat energy input into the second resistive elements, and hence the above-mentioned value can be simply obtained. Accordingly, the microfluidic device can be started to operate in a short period of time.
  • the size of microfluidic device means elements including the size of the substrate, the size and positions of the resistive elements, the size and positions of the wiring electrodes, and the size and position of the flow channel.
  • the environmental condition of the apparatus means elements including the temperature at the place where the apparatus is installed, and the heat transfer coefficient when the heat from the device transfers into air.
  • the arithmetic unit includes a numerical calculation program for performing a physical simulation, and a calculator for actually performing the calculation.
  • the arithmetic unit performs two cases of calculation. In one case, a physical simulation is actually performed using an input parameter, and in the other case, a simplified calculation is performed using simulation results which have been pre-stored as a database.
  • the microfluidic device stores the relational expression between the temperature of fluid in the flow channel and the resistance value of the first resistive element, and the fixed value obtained by calculating the heat energy ratio input into the first resistive element and the second resistive elements.
  • the fluid temperature in the flow channel is controlled based on the above-mentioned fixed value of the ratio of heat energy and the above-mentioned relationship between the temperature of fluid in the flow channel and the resistance value of the first resistive element.
  • FIG. 6 is a block diagram of the microfluidic apparatus according to the present invention. The flow of input and output of the above-mentioned microfluidic apparatus is described with reference to FIG. 6 .
  • a microfluidic device 30 and an apparatus environment measuring apparatus 40 for measuring an apparatus environment. Size data 28 of the microfluidic device and parameters 29 of the environmental condition of the apparatus are transmitted to an arithmetic unit 35 . There are also provided calculators 36 , 38 , a numerical calculation program 39 , and a storage area 37 of a database storing simulation results 27 as the database. A value of the heat energy ratio 26 input into the first resistive element and the second resistive elements is obtained by the arithmetic unit 35 . A result calculated by the calculator 38 may be directly transmitted to the storage area 33 storing the fixed value of the heat energy ratio, or alternatively, a value which has been simply calculated by the calculator 36 may be transmitted from the storage area 37 of the database.
  • a temperature distribution measuring apparatus 34 such as a radiation thermometer, for measuring the temperature distribution.
  • the temperature distribution measured by the radiation thermometer 34 and the value of the heat energy ratio 25 input into the first resistive element and the second resistive elements at that time may be transmitted to the arithmetic unit 35 , or alternatively, the value of the heat energy ratio input into the first resistive element and the second resistive elements may be calculated.
  • a storage area 32 stores the relational expression between the fluid temperature in the flow channel and the resistance value of the first resistive element.
  • a resistance value 22 of the first resistive element is output from the microfluidic device 30 to an output control apparatus 31 .
  • the heat energy to be input into the resistive element is calculated based on the relational expression 23 between the fluid temperature in the flow channel and the resistance value of the first resistive element, and the fixed value 24 of the heat energy ratio input into the first resistive element and the second resistive elements. Then, an output value 21 of the heat energy for heating the resistive elements is output to the microfluidic device 30 .
  • FIGS. 1A to 1D illustrate the microfluidic device used in Example 1 of the present invention.
  • the second resistive elements 6 which are independent from the first resistive element, for supplementarily heating the fluid in the flow channel, and their wiring electrodes 8 .
  • the distance between the edge of the first resistive element for primarily heating the fluid in the flow channel and the edge of the second resistive element was set to be 100 ⁇ m.
  • the microfluidic device was manufactured by the same method as that for the comparative example, and PCR reaction was performed similarly to the comparative example. Heat energy identical with the heat energy input into the first resistive element was input into the respective second resistive elements.
  • FIG. 9 shows the temperature distribution along the C-C line of FIG. 1D when the fluid temperature in the flow channel was raised to 94° C. by using the microfluidic device of FIGS. 1A to 1D . Comparing to the comparative example, the amount of lowering in temperature at the edges of fluid in the flow channel was decreased so that the temperature distribution was improved.
  • Example 1 the PCR yield was about 80% of the expected value.
  • the reason why the PCR yield was improved is that a region subjected to a PCR cycle was increased due to the improvement of the temperature distribution of fluid in the flow channel.
  • Example 2 similarly to Example 1, the microfluidic device illustrated in FIGS. 1A to 1D was used. Similarly to Example 1, PCR reaction was performed. In Example 2, before the actual operation, calibration was performed for obtaining the ratio of heat energy input into the first resistive element and the second resistive elements, which optimizes the temperature distribution of fluid in the flow channel. The calibration was performed by using a radiation thermometer. The temperature distribution of the substrate surface of the microfluidic device was measured by the radiation thermometer, and the fluid temperature in the flow channel was estimated based on the relationship between the surface temperature of the substrate of the microfluidic device and the fluid temperature distribution in the flow channel, which had been obtained in advance by a physical simulation of a finite element method.
  • the value for the optimum temperature distribution was obtained by changing the ratio of heat energy input into the above-mentioned resistive elements.
  • the optimum temperature distribution was achieved when the heat energy input into the second resistive elements was about 1.5 to 2.5 times higher than that of the first resistive element.
  • FIG. 10 shows the temperature distribution along the C-C line of FIG. 1D when the fluid temperature in the flow channel was raised to 94° C. by using the microfluidic device of FIGS. 1A to 1D .
  • the heat energy input into the second resistive elements was set to be twice as high as that of the first restive element, and this value and the amount of heat energy input into the resistive elements in accordance with the relational expression between the fluid temperature in the flow channel and the resistance value of the first resistive element were controlled. Comparing to Example 1, the amount of lowering in temperature at the edges of fluid in the flow channel was further decreased so as to improve the temperature distribution.
  • Example 2 the PCR yield was about 95% of the expected value.
  • Example 3 similarly to Examples 1 and 2, the microfluidic device illustrated in FIGS. 1A to 1D was used. Similarly to Examples 1 and 2, PCR reaction was performed. The ratio of heat energy input into the first resistive element and the second resistive elements was obtained by the arithmetic unit.
  • Input parameters were input into the arithmetic unit.
  • the size of the substrate of the microfluidic device, the size and positions of the resistive elements, the size and positions of the wiring electrodes, the size and position of the flow channel, the temperature of the place where the apparatus was installed, and the heat transfer coefficient when the heat of the device is transferred in the air were input.
  • the ratio of heat energy to be input into the first resistive element and the second resistive elements so as to optimize the temperature distribution of fluid in the flow channel was calculated.
  • the optimum temperature distribution was achieved when the above-mentioned value of ratio of heat energy was about 1.5 to 2.5 times. Comparing to Example 2, a calibration operation was omitted so that the time until the start of actual operation of the device was shortened.
  • FIGS. 5A to 5D illustrate the configuration of the microfluidic device used in the comparative example.
  • FIGS. 7A to 7D are exploded views of the microfluidic device of FIGS. 5A to 5D .
  • FIG. 7A illustrates the substrate in which the flow channel is formed
  • FIG. 7D illustrates the supporting substrate.
  • the material was a synthetic silica substrate having a heat conductivity of about 1.4 W/m/K at 20° C.
  • the flow channel of FIG. 7A disposed in the substrate through which fluid flows was formed by sandblast so as to have the width of about 200 ⁇ m and the depth of about 50 ⁇ m.
  • the first resistive element was formed by depositing a platinum film having a thickness of about 100 nm by a sputtering method and adjusting the width to about 300 ⁇ m by a photolithography method.
  • the electrode wiring was formed by continuously depositing a titanium-gold-titanium film having a thickness of about 300 nm by a sputtering method and a photolithography method.
  • the insulating layer was formed by depositing a silicon oxide film having a thickness of about 1 ⁇ m, and finally joined with the substrate of FIG. 7A with an adhesive.
  • PCR polymerase chain reaction
  • the PCR is a method of amplifying DNA in a specific region.
  • the PCR reaction in the microfluidic apparatus is performed by introducing a PCR solution into the flow channel of the microfluidic device, and subjecting the fluid in the flow channel to a temperature cycle.
  • the PCR solution contains ingredients such as DNA to be amplified, a primer, a DNA polymerase, and a buffer solution.
  • a reaction solution is heated to about 94° C. so as to divide double-stranded DNA into single strands.
  • the solution is rapidly cooled to about 50° C. so as to combine a primer with the single-stranded DNA for annealing.
  • DNA is amplified through the repetition of this cycle. It is generally estimated that DNA is amplified by 2 n times after n cycles.
  • FIG. 8 shows the temperature distribution along the C-C line of FIG. 5D when the fluid temperature in the flow channel was raised to 94° C. by using the microfluidic device of FIGS. 5A to 5D .
  • the temperature was below 94° C. by several degrees at the edges of fluid in the flow channel.
  • the present invention can be applied to a microfluidic device for performing chemosynthesis, environment analysis, and clinical specimen analysis, which involves a heating or cooling process.

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