JP2009008478A - Microchip inspection system - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a microchip inspection system detecting a flow rate in a channel highly accurately with high reliability. <P>SOLUTION: This microchip inspection system comprises: a pump for injecting fluid from the channel into a microchip; a thermal flow rate sensor equipped with a heating resister and a temperature detection member arranged along the fluid channel for outputting a signal corresponding to the flow rate of the fluid; a first flow rate calculation means for calculating the flow rate based on an output from the thermal flow rate sensor; a fluid detection means for detecting existence of the fluid on prescribed two spots in the channel, and outputting a detection signal; a second flow rate calculation means for calculating a calibrated flow rate, based on the detection signal acquired from the fluid detection means; a correction coefficient calculation means for calculating a correction coefficient, based on the calibrated flow rate calculated by the second flow rate calculation means and the flow rate calculated by the first flow rate calculation means; and a correction coefficient table for storing the correction coefficient. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a microchip inspection system.

  In recent years, by making full use of micromachine technology and ultrafine processing technology, devices and means (for example, pumps, valves, flow paths, sensors, etc.) for performing chemical analysis, chemical synthesis, etc. are miniaturized and integrated on one chip. Such a system has been developed (see, for example, Patent Document 1).

  This is also called μ-TAS (Micro total Analysis System), bioreactor, Lab-on-chip, biochip, medical examination, diagnostic field, environmental measurement field, agricultural production Its application is expected in the manufacturing field. In reality, as seen in genetic testing, automated, faster, and simplified microanalysis systems are costly and necessary when complex processes, skilled techniques, and equipment operations are required. The benefits of enabling time-and-location analysis as well as sample size and time are enormous.

  In various types of analysis and inspection, these analysis chips (hereinafter referred to as “microchips”, which are provided with a microchannel in the chip and perform various reactions in the microchannel) are referred to as “microchips”. In many cases, a plurality of flow paths are formed, and since a chemical reaction of a small amount of chemicals is handled, the flow rate of the liquid flowing through these flow paths needs to be strictly managed for each flow path.

  Conventionally, in such a system, liquid feeding is performed using a micropump. When the liquid is sent to a plurality of flow paths, the liquid is sent at a predetermined flow rate for each flow path by a plurality of micro pumps. Since there is variation in the performance of the micropump, it is necessary to arrange a flow rate sensor for each flow path to measure the flow rate and feed it back to the control of the micropump in order to send the liquid accurately at a predetermined flow rate.

  As a method for measuring a minute flow rate, a method is known in which two sensors are provided in close proximity to the outside of a conduit through which liquid flows and along the direction in which the liquid flows, and the flow rate is measured from the temperature difference between the upstream side and the downstream side. (For example, refer to Patent Document 2).

  However, since the sensor is arranged outside the conduit in the method disclosed in Patent Document 2, a member that covers the conduit is necessary to block external heat, and an apparatus for measuring the flow rate from a plurality of conduits is very difficult. It becomes big.

  In addition, a microheater is disposed in the channel tube, a first sensor is disposed upstream of the microheater, and a second sensor is disposed downstream of the microheater, and the flow rate is measured based on the temperature difference between the two sensors. A method has been proposed (see, for example, Patent Document 3).

  However, in the method disclosed in Patent Document 3, since the microheater and the sensor are arranged inside the conduit, the size can be reduced as compared with the method of Patent Document 2. However, since the conduit is used, a member that covers the conduit is also necessary. And the device becomes large.

As a method capable of miniaturization, a silicon substrate is formed as a lid of a flow channel on a glass substrate on which a plurality of flow channels are formed, and two heaters for detecting a fluid flow rate are formed on the silicon substrate. A thermal flow sensor that detects the flow rate from the resistance ratio of the heater on the side and the heater on the downstream side has been proposed (see, for example, Patent Document 4). In the method of Patent Document 4, the heater is formed using a metal material having a large resistance temperature coefficient such as platinum.
JP 2004-28589 A JP-A-62-62221 JP 2005-55317 A JP 7-159215 A

  Noble metals such as platinum used in Patent Document 4 are expensive, and productivity is higher when a heater is formed by thick film printing using an inexpensive material. However, a heater formed by thick film printing using an inexpensive material deteriorates its characteristics when used for a long time, and there is a problem that an error occurs in the measured flow rate.

  This invention is made | formed in view of the said subject, Comprising: It aims at providing the microchip test | inspection system which can detect the flow volume of a flow path with high reliability and high precision.

  In order to solve the above problems, the present invention has the following features.

1.
A pump for injecting fluid from the flow path into the microchip;
A thermal flow sensor that includes a heating resistor and a temperature detection member arranged along the flow path of the fluid, and outputs a signal corresponding to the flow rate of the fluid;
First flow rate calculating means for calculating a flow rate based on the output of the thermal flow sensor;
Fluid detection means for detecting the presence or absence of fluid at two predetermined locations of the flow path and outputting a detection signal;
Second flow rate calculation means for calculating a calibration flow rate based on a detection signal obtained from the fluid detection means;
Correction coefficient calculation means for calculating a correction coefficient based on the calibration flow rate calculated by the second flow rate calculation means and the flow rate calculated by the first flow rate calculation means;
A correction coefficient table for storing the correction coefficient;
Have
The microchip inspection system, wherein the first flow rate calculation unit corrects the flow rate based on the correction coefficient stored in the correction coefficient table.

2.
The first flow rate calculation unit and the second flow rate calculation unit calculate a flow rate and a calibration flow rate at a predetermined timing,
2. The microchip inspection system according to 1, wherein the correction coefficient calculation unit calculates the correction coefficient based on the flow rate and the calibration flow rate, and updates the correction coefficient table.

3.
3. The microchip inspection system according to 1 or 2, wherein at least one of the heating resistor and the temperature detection member is formed by thick film printing.

4).
The fluid detection means includes
A light emitting unit that emits light from the direction orthogonal to the flow path toward the flow path;
A light receiving unit that receives light of the light emitting unit that has passed through the flow path and generates a signal according to the amount of light;
A detection unit that outputs a detection signal by comparing the signal of the light receiving unit with a predetermined value;
The microchip inspection system according to any one of 1 to 3, characterized by comprising:

5).
The fluid detection means includes
A light emitting unit that emits light from the direction substantially orthogonal to the flow path toward the flow path;
A light receiving unit that receives light of the light emitting unit reflected from the flow path and generates a signal according to the amount of light; and
A detection unit that outputs a detection signal by comparing the signal of the light receiving unit with a predetermined value;
The microchip inspection system according to any one of 1 to 3, characterized by comprising:

6).
The fluid detection means includes
A sensor disposed in the flow path;
A detection unit that outputs a detection signal based on an output change when the sensor comes into contact with the fluid;
The microchip inspection system according to any one of 1 to 3, characterized by comprising:

  According to the present invention, the detector for detecting the liquid flowing through the flow path is provided at two locations of the flow path, the correction coefficient is calculated in advance based on the calibration flow rate calculated from the output of the detector, and the output of the thermal flow sensor Since the flow rate obtained from is calibrated based on the correction coefficient, the flow rate of the flow path can be detected with high reliability and high accuracy.

  Hereinafter, embodiments of the present invention will be described with reference to the drawings.

  FIG. 1 is an external view of a microchip inspection system 80 according to an embodiment of the present invention.

  The microchip inspection system 80 of the present invention includes a reaction detection device 82 and a microchip 1. The reaction detection device 82 is a device that automatically detects a reaction between a specimen previously injected into the microchip 1 and a reagent and displays the result on the display unit 84. The reaction detection device 82 has an insertion port 83, and the microchip 1 is inserted into the insertion port 83 and set in the reaction detection device 82.

  The insertion port 83 is sufficiently higher than the thickness of the microchip 1 so that the microchip 1 does not come into contact with the microchip 1 during insertion. Reference numeral 85 denotes a memory card slot, 86 denotes a print output port, 87 denotes an operation panel, and 88 denotes an external input / output terminal.

  The person in charge of inspection inserts the microchip 1 in the direction of the arrow in FIG. 1 and operates the operation panel 87 to start the inspection. Inside the reaction detector 82, a pump 92 (not shown in FIG. 1) injects a fluid such as a driving liquid into the microchip 1 according to a command from the control means, and the reaction in the microchip 1 is automatically inspected. . When the inspection is completed, the result is displayed on the display unit 84 constituted by a liquid crystal panel or the like. The inspection result can be output from the print output port 86 or stored in a memory card inserted into the memory card slot 85 by operating the operation panel 87. Further, data can be stored in the personal computer or the like from the external input / output terminal 88 using, for example, a LAN cable.

  The inspection person takes out the microchip 1 from the insertion port 83 after the inspection is completed.

  FIG. 2 is a cross-sectional view showing an example of the internal configuration of the reaction detection device 82 in the microchip inspection system 80 of the first embodiment. The reaction detection device 82 includes a temperature adjustment unit 152, a light detection unit 150, an intermediate flow path unit 180, a pump 92, packings 90a and 90b, a driving liquid tank 91, and the like. Hereinafter, the same reference numerals are given to the same components as those described so far, and description thereof will be omitted.

  FIG. 2 shows a state in which the upper surface of the microchip 1 is in close contact with the temperature adjustment unit 152 and the pump 92. The microchip 1 is driven by a driving member (not shown) and can move in the vertical direction on the paper.

  In the initial state, the microchip 1 can be inserted / removed in the horizontal direction of FIG. 2, and the person inspecting inserts the microchip 1 from the insertion port 83 until it comes into contact with a regulating member (not shown). When the microchip 1 is inserted to a predetermined position, the chip detection unit 95 using a photo interrupter or the like detects the microchip 1 and is turned on.

  The temperature adjustment unit 152 is a unit that incorporates a Peltier element, a power supply device, a temperature control device, and the like and adjusts the upper surface of the microchip 1 to a predetermined temperature by generating heat or absorbing heat.

  When a control unit (not shown) receives a signal indicating that the chip detection unit 95 is turned on, the microchip 1 is raised by the driving member, and the upper surface of the microchip 1 is intermediately flowed through the temperature adjustment unit 152 and the packing 92. Press against the road portion 180 to bring it into close contact.

  The driving liquid injection part of the microchip 1 is provided at a position where it communicates with the corresponding opening 185 provided in the intermediate flow path part 180 when the microchip 1 and the packing 90a are brought into close contact with each other. The intermediate flow path portion 180 includes a transparent flow path substrate 184 provided with grooves for the intermediate flow path 182a and the intermediate flow path 182b, a sensor substrate 183 that covers the flow path substrate 184, and a covering substrate 189. The intermediate flow path 182 a communicates with the intermediate flow path 182 b provided on the opposite surface of the flow path substrate 184 via the through hole 171 to form one intermediate flow path 182.

  An opening 186 provided at the end of the intermediate flow path 182a communicates with the input / output port 146 of the pump 92 via the packing 90b. The opening 185 provided at the end of the intermediate flow path 182b communicates with the flow path of the microchip 1 through the packing 90a.

  The pump 92 includes a micropump mechanism and discharges the liquid sucked from the driving liquid tank 91 to the intermediate flow path portion 180. Alternatively, the liquid sucked from the intermediate flow path portion 180 in the reverse direction can be discharged from the driving liquid tank 91. In FIG. 2, one cross section of the micropump included in the pump 92 is illustrated, but a plurality of micropumps of the pump 92 are provided and communicated with the intermediate flow path 182.

  A driving liquid tank 91 is connected to the suction side of the pump 92 via a packing 90c, and the driving liquid filled in the driving liquid tank 91 is sucked via the packing 90c. On the other hand, since the discharge side of the pump 92 communicates with the microchip 1 via the intermediate flow path 182, the driving liquid sent from the pump 92 is a flow path formed in the microchip 1 via the packing 90 a. Injected into. In this way, the driving liquid is injected from the pump 92 into the microchip 1.

  The intermediate flow path unit 180 is provided with a liquid detection unit 190 for measuring the flow rate of the driving liquid flowing through the intermediate flow path 182. Further, as will be described later, a thermal flow sensor is provided.

  The liquid detection unit 190 includes a first light emitting unit 193, a first light receiving unit 191, a second light emitting unit 194, a second light receiving unit 192, and a first detection unit 198 and a second detection unit 199 that are not shown in FIG. It is configured (see FIG. 6).

  The first light emitting unit 193 and the second light emitting unit 194 are light emitting elements such as LEDs and lamps. The first light receiving part 191 and the second light receiving part 192 are light receiving elements such as photodiodes, for example, and the intermediate flow path part 180 emits light emitted by the first light emitting part 193 and the second light emitting part 194 that are respectively opposed to each other. The light is received through the transparent part. When the driving liquid flows through the intermediate flow path 182, the amount of light transmitted through the intermediate flow path 182 changes, and the signal currents of the first light receiving unit 191 and the second light receiving unit 192 also change.

  The first detection unit 198 and the second detection unit 199 include an amplifier such as an operational amplifier, a comparator for comparing with a predetermined value, a power supply unit, and the like. The first detection unit 198 and the second detection unit 199 convert the signal currents of the first light receiving unit 191 and the second light receiving unit 192 into voltages, respectively, and compare with a predetermined voltage to output a driving liquid detection signal.

  The first light emitting unit 193, the first light receiving unit 191, the second light emitting unit 194, and the second light receiving unit 192 are arranged at positions apart from the intermediate flow path 182 as shown in FIG. As will be described in detail later, the second flow rate calculation unit 414 (see FIG. 6) (not shown in FIG. 2) generates a driving fluid from the time difference between the times when the first detection unit 198 and the second detection unit 199 generate detection signals. The flow rate is calculated.

  The liquid detection unit 190 is a fluid detection unit of the present invention, and the second flow rate calculation unit 414 is a second flow rate calculation unit of the present invention.

  In the present embodiment, the liquid detection unit 190 is provided so as to measure the flow velocity of the intermediate flow path unit 180, but the location where the liquid detection unit 190 is provided is not limited to the intermediate flow path unit 180. In addition, the intermediate flow path portion 180 is not always necessary. For example, the liquid detection section 190 may be provided so as to measure the flow velocity of the flow path inside the pump 92.

  In the detection part of the microchip 1, the specimen and the reagent stored in the microchip 1 react to cause, for example, coloration, light emission, fluorescence, turbidity, and the like. In this embodiment, the reaction result of the reagent that occurs in the detection unit is optically detected. The light detection unit 150 includes a third light emitting unit 150a and a third light receiving unit 150b, and is arranged so that light transmitted through the detection unit 111 of the microchip 1 can be detected.

  Next, the thermal flow sensor provided in the intermediate flow path portion 180 will be described. The thermal flow sensor is used for a fluid having a minute flow rate.

  FIG. 3 is an explanatory diagram for explaining the structure of a thermal flow sensor according to the present invention. FIG. 3A is a plan view of the thermal flow sensor 280 formed on the sensor substrate 183, and FIG. 3B is a cross-sectional view taken along the line AA in FIG. In the following description of the drawings, the XYZ coordinate axes shown on the right side of FIG. 3 (a) and FIG. 3 (b) are used. In FIG. 3, the illustration of the portion of the intermediate flow path 182b formed in the flow path substrate 184 is omitted.

  The thermal flow sensor 280 according to the present invention includes a heating resistor 52 disposed along the intermediate flow path 182a, a first temperature sensor 53 and a second temperature sensor 51 as temperature detection members, A signal corresponding to the flow rate is output. The thermal flow sensor 280 is formed on the sensor substrate 183 as shown in FIG.

  In this embodiment, a heat transfer type thermal flow sensor will be described, but the application of the present invention is not limited to the heat transfer method, and a heat absorption method or a combination of a heat transfer method and a heat absorption method. May be used.

  FIG. 4 is a plan view of the flow path substrate 184 viewed from the positive direction of the Z-axis in FIG. In the present embodiment, the flow path substrate 184 includes eight groove-shaped intermediate flow paths 182a and 182b, and an opening 186 and an opening 185 are provided at both ends of the groove-shaped intermediate flow path 182, and a through hole 171 is provided in the middle. Is provided. The intermediate flow path 182 b is provided on the surface of the flow path substrate 184 opposite to the surface on which the intermediate flow path 182 a is formed, and communicates with the through hole 171. The flow path substrate 184 is made of, for example, a transparent resin material, and the intermediate flow path 182 has a width of several hundred μm to several mm and a depth of several hundred μm.

  FIG. 5 is a plan view of the sensor substrate 183 viewed from the negative Z-axis direction of FIG. The sensor substrate 183 is provided with a heating resistor 52, a first temperature sensor 53, and a second temperature sensor 51, respectively, along the eight groove-shaped intermediate flow paths 182a. Electrodes 54 are provided at both ends of the heating resistor 52, the first temperature sensor 53, and the second temperature sensor 51, and are wired with a wiring pattern (not shown) of the sensor substrate 183. As the first temperature sensor 53 and the second temperature sensor 51, for example, elements such as a thermistor whose resistance value varies with temperature can be used.

  For example, a glass epoxy substrate or the like can be used as the sensor substrate 183 by patterning. However, when low-temperature sintered ceramics are used, the heating resistor 52, the first temperature sensor 53, and the second temperature sensor 51 are formed by thick film printing. Therefore, the process can be simplified.

  The sensor substrate 183 is laminated and bonded to the flow path substrate 184 as shown in FIG. As shown in the cross-sectional view along the intermediate flow path 182 in FIG. 1B, the heating resistor 52, the first temperature sensor 53, and the second temperature sensor 51 formed on the sensor substrate 183 are connected to the intermediate flow path 182a. It is arrange | positioned so that it may contact | connect the fluid which flows through the intermediate flow path 182a. The fluid is injected from the opening 186 and discharged from the opening 185 through the intermediate flow paths 182a and 182b. As will be described in detail later, for example, the fluid temperature detected by the first temperature sensor 53 provided on the upstream side and the heating resistor 52 detected by the second temperature sensor 51 provided on the downstream side. The flow rate of the fluid flowing through the intermediate flow path 182 is calculated from the temperature difference between the liquid temperatures of the heated fluid.

  As shown in FIG. 3, the slit 50 is provided between the heating resistor 52, the first temperature sensor 53, and the second temperature sensor 51 arranged on the sensor substrate 183 for each intermediate flow path 182. When the slit 50 is provided in this way, the heat generated by the heating resistor 52 is generated by the heating resistor 52, the first temperature sensor 53, the second temperature sensor 51, or the groove-like shape disposed in the adjacent flow path. Conduction to the fluid flowing through the intermediate flow path 182 can be prevented. As a result, even if a plurality of flow paths are arranged close to each other, the flow rate can be accurately calculated without being affected by the heating resistor 52 provided in another flow path.

  Further, when the slit 50 is filled with a heat insulating member, the heat insulating effect can be further enhanced and the flow rate can be calculated more accurately. As the heat insulating member, for example, foamed plastic (polystyrene, polyethylene, polyurethane, polycarbonate foam), foamed ceramics, or the like can be used.

  As described above, since the heat insulating effect is enhanced when the slit 50 is filled with the heat insulating member, even if the heating resistor 52 and the intermediate flow path 182 are arranged closer to each other, the influence of the adjacent intermediate flow path 182 and the heat generating resistance 52 is affected. It is possible to detect the flow rate with a high degree of accuracy.

  FIG. 6 is a circuit block diagram of the microchip inspection system 80 in the first embodiment of the present invention.

  The control unit 99 includes a CPU 98 (central processing unit), a RAM 97 (Random Access Memory), a ROM 96 (Read Only Memory), and the like, and reads a program stored in the ROM 96 which is a nonvolatile storage unit to the RAM 97. Each part of the microchip inspection system 80 is centrally controlled according to the program.

  Hereinafter, functional blocks having the same functions as those described so far are denoted by the same reference numerals, and description thereof is omitted.

  The chip detector 95 transmits a detection signal to the CPU 98 when the microchip 1 comes into contact with the regulating member. When the CPU 98 receives the detection signal, it instructs the mechanism driving unit 32 to lower or raise the microchip 1 according to a predetermined procedure.

  The pump drive unit 500 is a drive unit that drives each micropump mechanism of the pump 92. Based on the program, the pump drive control unit 412 controls the pump drive unit 500 to inject or suck a predetermined amount of drive fluid. The pump drive unit 500 receives a command from the pump drive control unit 412, generates a predetermined drive voltage, and drives the piezoelectric element included in the micropump mechanism of the pump 92.

  The CPU 98 performs inspections in a predetermined sequence and stores the inspection results in the RAM 97. The inspection result can be stored in the memory card 501 by operating the operation unit 87, printed by the printer 503, or output from the external input / output terminal 88.

  The CPU 98 includes a first flow rate calculation unit 410, a temperature calculation unit 411, a pump drive control unit 412, a correction coefficient calculation unit 413, and a second flow rate calculation unit 414.

  As shown in FIG. 6, the first temperature sensor 53 is connected to a resistor R <b> 1 arranged on a surface not shown in FIG. 3 of the sensor substrate 183. A constant voltage Vc is applied to the heating resistor 52 to constantly generate heat.

  A constant voltage Vc is applied to one end of the first temperature sensor 53, and one end of the resistor R1 is grounded. The partial pressure of the first temperature sensor 53 and the resistor R1 is converted into a digital value by the first A / D converter 310 and input to the control unit 99. The temperature calculation unit 411 calculates the temperature T1 of the first temperature sensor 53 with reference to the temperature-voltage conversion table 301 from the output value of the first A / D converter 310.

  Similarly, the second temperature sensor 51 is connected to the resistor R2. A constant voltage Vc is applied to one end of the second temperature sensor 51, and one end of the resistor R2 is grounded. The partial pressure of the second temperature sensor 51 and the resistor R2 is converted into a digital value by the second A / D converter 320 and input to the control unit 99. The temperature calculation unit 411 calculates the temperature T2 of the second temperature sensor 52 with reference to the temperature-voltage conversion table 301 from the output value of the second A / D converter 320. Since the second temperature sensor 51 is provided on the downstream side of the heating resistor 52, the temperature T2 is the fluid temperature of the fluid that has absorbed the heat generated by the heating resistor 52.

  The first flow rate calculation unit 410 calculates a temperature difference ΔT between the upstream liquid temperature T1 calculated by the temperature calculation unit 411 and the downstream liquid temperature T2, and calculates a flow rate from the temperature difference ΔT.

  The pump drive control unit 412 instructs the pump drive unit 500 on the direction in which the driving liquid is fed and the flow velocity. The correction coefficient calculation unit 413 periodically calculates a correction coefficient based on the flow rate calculated by the first flow rate calculation unit 410 and the calibration flow rate calculated by the second flow rate calculation unit 414. The second flow rate calculation unit 414 calculates a reference calibration flow rate based on the detection signal obtained from the liquid detection unit 190.

  The first flow rate calculation unit 410 is a first flow rate calculation unit of the present invention, the correction coefficient calculation unit 413 is a correction coefficient calculation unit of the present invention, and the liquid detection unit 190 is a liquid detection unit of the present invention.

  The ROM 96 stores a temperature / voltage conversion table 301 that refers to the corresponding temperature from the digital value of the voltage, a temperature / flow rate conversion table 302 that refers to the flow rate from the temperature, and a correction coefficient table 303 that stores the correction coefficient calculated by the correction coefficient calculation unit 413. It has.

  The correction coefficient table 303 is a correction coefficient table of the present invention.

  Next, a circuit configuration in which the second flow rate calculation unit 414 calculates the calibration flow rate based on the detection signal of the liquid detection unit 190 will be described.

  The liquid detection unit 190 according to this embodiment includes a first light emitting unit 193, a first light receiving unit 191, a second light emitting unit 194, a second light receiving unit 192, a first detection unit 198, and a second detection unit 199. The first light emitting unit 193 and the second light emitting unit 194 emit light according to a command from the CPU 98. The first detection unit 198 and the second detection unit 199 detect a change in the light amount due to the passage of the driving liquid, generate a detection signal, and input the detection signal to the CPU 98. The second flow rate calculation unit 414 first calculates the flow velocity V from the time difference t between detection signals detected by the first light receiving unit 191 and the second light receiving unit 192.

  When the distance x between the first light receiving part 191 and the second light receiving part 192 is assumed, the flow velocity V is obtained by the following equation (1). It is assumed that the cross-sectional area S of the intermediate flow path 182 is constant.

V = x / t (1)
Assuming that the cross-sectional area S of the intermediate flow path 182 is constant, the flow rate Q is obtained by the following equation (2).

Q = V x S (2)
As described above, the second flow rate calculation unit 414 obtains the calibration flow rate from the time difference between the first light receiving unit 191 and the second light receiving unit 192 when the tip of the driving liquid passes, so that a calibration flow value with less error can be obtained. .

  As will be described in detail later, the correction coefficient calculation unit 413 uses the calibration flow rate thus obtained and the flow rate calculated by the first flow rate calculation unit 410 based on the output of the thermal flow sensor 280 during the calibration flow rate measurement. A correction coefficient is calculated.

  The light detection unit 150 includes a light emitting unit 150a and a light receiving unit 150b, and is arranged so as to be able to detect light transmitted through the detection unit 19 of the microchip 1. In the detection part of the microchip 1, the specimen moved in the flow path by the driving liquid reacts with the reagent stored in the microchip 1 to cause, for example, coloration, light emission, fluorescence, turbidity, and the like. The light detection unit 150 optically detects the reaction result of the reagent that occurs in the detection unit. The reaction result between the reagent and the sample can be analyzed by photometrically or colorimetrically measuring light transmitted through the detection part of the microchip 1.

  Next, a flowchart for calculating the flow rate based on the output of the thermal flow sensor 280 will be described with reference to FIG.

  FIG. 7 is a flowchart for calculating the flow rate using the thermal flow sensor 280 according to the present invention.

  S201: This is a step of calculating the temperature of the first temperature sensor 53.

  The temperature calculation unit 411 obtains the temperature T1 of the first temperature sensor 53 with reference to the temperature-voltage conversion table 301 from the output value of the first A / D converter 310.

  S202: This is a step of calculating the temperature of the second temperature sensor 51.

  The temperature calculation unit 411 obtains the temperature T2 of the second temperature sensor 51 with reference to the temperature-voltage conversion table 301 from the output value of the second A / D converter 320.

  S203: a step of calculating a temperature difference ΔT.

  The temperature calculation unit 411 calculates a temperature difference ΔT from T1 and T2.

  S204: This is a step of calculating the temperature difference ΔT.

  The first flow rate calculation unit 410 refers to the temperature flow rate conversion table 302 to obtain the flow rate.

  This is the end of the process for calculating the flow rate.

  Next, a flowchart for correcting the flow rate calculated based on the output of the thermal flow sensor 280 will be described with reference to FIG.

  S10: This is a step of calculating the flow rate based on the output of the thermal flow sensor 280.

  The subroutine described in FIG. 7 is called to calculate the flow rate.

  S20: A step of correcting the calculated flow rate.

  The first flow rate calculation unit 410 reads the correction coefficient stored in the correction coefficient table 303 according to the flow rate calculated in step S10, and corrects the flow rate calculated in step S10. The correction coefficient stored in the correction coefficient table 303 is calculated based on the calibration flow rate calculated by the second flow rate calculation unit 414 as will be described in detail later.

  This is the end of the procedure for correcting the flow rate.

  The first flow rate calculation unit 410 executes steps S10 and S20 at a constant cycle while the pump drive control unit 412 commands the drive of the pump 92, and feeds back the calculated flow rate to the pump drive control unit 41. . If the flow rate is not a predetermined amount, the pump drive control unit 412 instructs the pump drive unit 500 to have a predetermined flow rate.

  As described above, the flow rate calculated based on the output of the thermal flow sensor 280 is corrected by the correction coefficient based on the calibration flow rate calculated by the second flow rate calculation unit 414. Even if an error occurs in the output, the flow rate can be measured accurately. Thereby, an accurate inspection by the microchip 1 can be performed.

  Next, the procedure of the calibration data acquisition routine for obtaining the correction coefficient will be described with reference to FIGS. 9 and 10. FIG. 9 is a flowchart of the calibration data acquisition routine, and FIG. 10 is an explanatory diagram for explaining the movement of the driving liquid 4 at the time of measuring the calibration flow rate. FIG. 10 is an enlarged cross-sectional view of a portion of the intermediate flow path 180 where the liquid detection unit 190 is provided, and shows the position of the tip of the driving liquid 4 in the intermediate flow path 182b. In the initial state, the tip position of the driving liquid 4 is assumed to be the position shown in FIG.

  Hereinafter, FIG. 10 will be described along the flowchart of FIG. 9.

  S204: This is the step of feeding in the reverse direction.

  The pump drive control unit 412 instructs the pump drive unit 500 to drive the micropump and send liquid in the reverse direction. The reverse direction is opposite to the direction in which the driving liquid 4 is injected into the microchip 1, and is indicated by an arrow B in FIG.

  S205: This is a step of determining whether or not the first detection unit 198 has detected the driving liquid.

  The second flow rate calculation unit 414 determines whether or not the driving fluid has been detected from the output signal of the first detection unit 198.

  When the driving liquid 4 is detected (step S205; Yes), the process returns to step S205.

  When the driving liquid 4 is not detected (step S205; No), the process proceeds to step S206. FIG. 10B illustrates a state in which the driving liquid 4 is supplied in the reverse direction in step S204 and the first detection unit 198 has supplied the liquid until it does not detect the driving liquid 4.

  S206: This is a step of stopping the pump drive.

  The pump drive control unit 412 instructs the pump drive unit 500 to stop driving the pump 92.

  S207: This is the step of feeding in the forward direction.

  The pump drive control unit 412 instructs the pump drive unit 500 to drive the pump 92 and feed liquid in the forward direction. The positive direction is the direction in which the driving liquid is injected into the microchip 1 and is indicated by an arrow F in FIG.

  S208: This is a step of determining whether or not the first detection unit 198 has detected the driving liquid.

  The second flow rate calculation unit 414 determines whether or not the first detection unit 198 has detected the driving fluid.

  When the driving fluid 4 is not detected (step S208; No), the process returns to step S208.

  When the driving fluid 4 is detected (step S208; Yes), the process proceeds to step S209.

  S209: This is a step of starting a counter for measuring time.

  The second flow rate calculation unit 414 initializes an internal counter that measures time and starts counting.

  Since the tip of the driving liquid 4 has passed the position of the first light receiving unit 191 in step S208, time measurement is started by the internal counter. In addition, the first flow rate calculation unit 410 executes a subroutine for calculating a flow rate based on the output of the thermal flow sensor 280 at a constant cycle, and temporarily stores the calculated flow rate in the RAM 97.

  S210: This is a step of determining whether or not the second detection unit 199 has detected the driving fluid.

  The second flow rate calculation unit 414 determines whether or not the second detection unit 199 has detected the driving fluid 4.

  When the driving fluid 4 is not detected (step S210; No), the process returns to step S210.

  When the driving fluid 4 is detected (step S210; Yes), the process proceeds to step S211.

  When the tip of the driving liquid 4 passes through the position of the second light receiving unit 192 as shown in FIG. 10C, the second flow rate calculation unit 414 detects the driving liquid 4.

  S211: This is a step of stopping the counter for measuring time.

  The second flow rate calculation unit 414 stops the internal counter that measures time.

  In step S210, since the tip of the driving liquid 4 has passed the position of the second light receiving unit 192, the internal counter is stopped. Further, the first flow rate calculation unit 410 stops temporarily storing the calculated flow rate in the RAM 97.

  S212: This is a step of stopping the pump drive.

  The pump drive control unit 412 instructs the pump drive unit 500 to stop driving the pump 92.

  S213: This is a step of calculating the flow velocity.

  The second flow rate calculation unit 414 calculates the calibration flow rate C from the value of the internal counter that measures time.

  S214: This is a step of calculating the average flow rate calculated from the output of the thermal flow sensor 280.

  The first flow rate calculation unit 410 calculates an average value q of the flow rate calculated from the output of the thermal flow rate sensor 280 during the temporarily stored steps S209 to S211.

  This completes the subroutine and returns to the main routine. In this way, the average value q of the flow rate calculated from the output of the thermal flow sensor 280 while measuring the calibration flow rate C and the calibration flow rate can be obtained as calibration data.

  Next, a routine for updating the correction coefficient table 303 will be described.

  The correction coefficient calculation unit 413 executes this routine at a predetermined timing, for example, when the reaction detector 82 is turned on, before the start of inspection, or after the end of inspection, and updates the correction coefficient table 303.

  FIG. 11 is a flowchart of the calibration data acquisition routine.

  S501: This is a step of initializing the number of times of measurement n.

  The measurement number n is initialized so that n = 1.

  S502: This is a step of setting the flow velocity Vn of the pump.

  The pump drive control unit 412 instructs the pump drive unit 500 to drive the micro pump at a predetermined flow velocity Vn.

  S503: This is a step of calling a calibration data acquisition routine.

  The calibration data acquisition routine is called to acquire data of the average value qn of the flow rate calculated from the calibration flow rate Cn and the output of the thermal flow sensor 280 while measuring the calibration flow rate.

  S504: This is a step of temporarily storing the acquired calibration data.

  The calibration flow rate Cn and the average value qn of the flow rate are temporarily stored in the RAM 97.

  S505: This is a step of setting n = n + 1.

  Let n be n + 1.

  S506: A step of determining whether n is a predetermined number N or not.

  If the predetermined number N has not been reached (step S506; No), the process returns to step S502.

  In the case of the predetermined number N (step S506; Yes), the process proceeds to step S507.

  S507: A correction coefficient calculation unit 413 calculates a correction coefficient and updates the correction coefficient table 303.

  The correction coefficient calculation unit 413 calculates the correction coefficient H and updates the correction coefficient table 303.

  An example of the average value qn of the flow rate acquired up to this step and the calibration flow rate Cn will be described with reference to FIG. FIG. 12 is a graph showing the relationship between the average flow rate qn and the calibration flow rate Cn.

  The horizontal axis represents the average flow Q1 of the flow calculated from the output of the thermal flow sensor 280 during the calibration flow Cn measurement, and the vertical axis represents the calibration flow Q2. The unit of the horizontal axis and the vertical axis is the flow rate.

  FIG. 12 shows an example in which the flow rate Vn of the pump is changed three times. For example, when the flow rates V1, V2, and V3 of the pump, the measured average flow rates q1, q2, and q3 and calibration flow rates C1, C2, and C3 are graphs. Plotted above.

  Desirably, average flow rate qn = calibration flow rate Cn, but in order to correct an error in flow rate calculated from the output of thermal flow sensor 280, correction coefficient H is obtained from average flow rate qn and calibration flow rate Cn.

  For example, when the flow rate calculated from the output of the thermal flow sensor 280 is 0 to q1, it can be corrected with the correction coefficient H1 obtained by the equation (3).

H1 = C1 / q1 (3)
Similarly, the correction coefficient calculation unit 413 calculates a correction coefficient Hn for the flow rate Q1 between q1 and q2, between q2 and q3, and stores the correction coefficient Hn in the correction coefficient table 303.

  This completes the subroutine and returns to the main routine. In this way, the correction coefficient Hn can be obtained and stored in the correction coefficient table 303 at a predetermined timing, so that the flow rate calculated from the output of the thermal flow sensor 280 can always be accurately corrected.

  Next, a second embodiment of the present invention will be described.

  FIG. 13 is a cross-sectional view showing an example of the internal configuration of the reaction detection device 82 in the microchip inspection system 80 of the second embodiment. The difference from the reaction detection device 82 of the first embodiment described in FIG. 2 is that the driving liquid in the intermediate flow path 182 is detected by transmitted light in the first embodiment, whereas the driving liquid is reflected by reflected light. It is a point that is detected. Therefore, a reflective sensor is used for the liquid detection unit 190.

  The inspection procedure by the microchip inspection system 80 is performed based on the detection signals of the first detection unit 198 and the second detection unit 199 in the same manner as the procedure described with reference to FIGS.

  By doing so, it is not always necessary to be transparent except for the coated substrate 189, so that the selection range of the material of the flow path substrate 184 is widened.

  Next, the liquid detection unit 190 in the microchip inspection system 80 of the third embodiment will be described with reference to FIGS. FIG. 14 is a cross-sectional view illustrating an example of the liquid detection unit 190 in the microchip inspection system 80 of the third embodiment. FIG. 15 is a circuit block diagram of a microchip inspection system 80 in the third embodiment. Hereinafter, the same functional elements described so far are denoted by the same reference numerals, and description thereof is omitted.

  The liquid detection unit 190 according to the present embodiment applies a voltage between the two sensors provided on the inner wall of the intermediate flow path 182 and the sensor. For example, when the driving liquid 4 contacts between the sensors, the liquid detection unit 190 is driven from a change in impedance. It comprises a first detection unit 198 and a second detection unit 199 that detect liquid.

  The sensor 311 and the sensor 312 are electrodes, and the first detection unit 198 includes a power source that applies a voltage between the sensor 311 and the sensor 312 and a circuit that detects a current between the sensor 311 and the sensor 312, and the current is a predetermined value. When it flows above, a detection signal is output. Similarly, the second detection unit 199 includes a power source for applying a voltage between the sensor 321 and the sensor 322 and a circuit for detecting a current between the sensor 321 and the sensor 322, and the current exceeds a threshold value by passing the driving liquid. When there is a change, a detection signal is output.

  The driving liquid detection method of the first detection unit 198 and the second detection unit 199 is not particularly limited to the method of detecting the driving liquid from the change in impedance, and is driven based on the output change when the sensor comes into contact with the fluid. Any method that can detect the liquid 4 may be used. For example, the first detection unit 198 is between the sensor 311 and the sensor 312, and the second detection unit 199 is between the sensor 321 and the sensor 322. May be detected. Alternatively, using the temperature sensor, the first detection unit 198 and the second detection unit 199 may detect an output change of the temperature sensor due to a temperature change when the driving liquid 4 comes into contact with the sensor.

  Detection signals output from the first detection unit 198 and the second detection unit 199 are input to the CPU 98 as shown in FIG.

  The inspection procedure by the microchip inspection system 80 is performed based on the detection signals of the first detection unit 198 and the second detection unit 199 in the same manner as the procedure described with reference to FIGS.

  In the present embodiment, since the sensor is provided on the inner wall of the intermediate flow path 182, the degree of freedom of arrangement of the sensor is large, and the present invention can be applied to an opaque flow path.

  As described above, according to the present invention, it is possible to provide a microchip inspection system that can detect the flow rate of the flow path with high reliability and high accuracy.

It is an external view of the microchip test | inspection system 80 in embodiment of this invention. It is sectional drawing which shows an example of the internal structure of the reaction detection apparatus 82 in the microchip test | inspection system 80 of 1st Embodiment. It is explanatory drawing for demonstrating the structure of the thermal type flow sensor concerning this invention. 3 is a plan view of a flow path substrate 184. FIG. 3 is a plan view of a sensor substrate 183. FIG. 1 is a circuit block diagram of a microchip inspection system 80 in a first embodiment of the present invention. A flowchart for calculating the flow rate based on the output of the thermal flow sensor 280 will be described. 5 is a flowchart for correcting a flow rate calculated based on an output of a thermal flow sensor 280. FIG. 9 is a flowchart of a calibration data acquisition routine. It is explanatory drawing explaining the motion of the driving fluid 4 at the time of calibration flow measurement. It is a flowchart of a calibration data acquisition routine. It is a graph which shows the relationship between the average value qn of flow volume, and the calibration flow volume Cn. It is sectional drawing which shows an example of the internal structure of the reaction detection apparatus 82 in the microchip test | inspection system 80 of 2nd Embodiment. It is sectional drawing which shows an example of the liquid detection part 190 in the microchip test | inspection system 80 of 3rd Embodiment. It is a circuit block diagram of the microchip test | inspection system 80 in 3rd Embodiment.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Microchip 4 Drive liquid 51 2nd temperature sensor 52 Heating resistor 53 1st temperature sensor 80 Microchip test | inspection system 82 Reaction detector 83 Insertion port 84 Display part 90 Packing 91 Drive liquid tank 92 Pump 182 Intermediate flow path 190 Liquid detector 191 First light receiver 192 Second light receiver 193 First light emitter 194 Second light emitter 198 First detector 199 Second detector 280 Thermal flow sensor 310 First A / D converter 320 Second A / D Conversion unit 410 First flow rate calculation unit 411 Temperature calculation unit 412 Pump drive control unit 413 Correction coefficient calculation unit 414 Second flow rate calculation unit

Claims (6)

A pump for injecting fluid from the flow path into the microchip;
A thermal flow sensor that includes a heating resistor and a temperature detection member arranged along the flow path of the fluid, and outputs a signal corresponding to the flow rate of the fluid;
First flow rate calculating means for calculating a flow rate based on the output of the thermal flow sensor;
Fluid detection means for detecting the presence or absence of fluid at two predetermined locations of the flow path and outputting a detection signal;
Second flow rate calculation means for calculating a calibration flow rate based on a detection signal obtained from the fluid detection means;
Correction coefficient calculation means for calculating a correction coefficient based on the calibration flow rate calculated by the second flow rate calculation means and the flow rate calculated by the first flow rate calculation means;
A correction coefficient table for storing the correction coefficient;
Have
The microchip inspection system, wherein the first flow rate calculation unit corrects the flow rate based on the correction coefficient stored in the correction coefficient table. The first flow rate calculation unit and the second flow rate calculation unit calculate a flow rate and a calibration flow rate at a predetermined timing,
2. The microchip inspection system according to claim 1, wherein the correction coefficient calculation unit calculates the correction coefficient based on the flow rate and the calibration flow rate, and updates the correction coefficient table. The microchip inspection system according to claim 1 or 2, wherein at least one of the heating resistor and the temperature detection member is formed by thick film printing. The fluid detection means includes
A light emitting unit that emits light from the direction orthogonal to the flow path toward the flow path;
A light receiving unit that receives light of the light emitting unit that has passed through the flow path and generates a signal according to the amount of light;
A detection unit that outputs a detection signal by comparing the signal of the light receiving unit with a predetermined value;
The microchip inspection system according to claim 1, comprising: The fluid detection means includes
A light emitting unit that emits light from the direction substantially orthogonal to the flow path toward the flow path;
A light receiving unit that receives light of the light emitting unit reflected from the flow path and generates a signal according to the amount of light; and
A detection unit that outputs a detection signal by comparing the signal of the light receiving unit with a predetermined value;
The microchip inspection system according to claim 1, comprising: The fluid detection means includes
A sensor disposed in the flow path;
A detection unit that outputs a detection signal based on an output change when the sensor comes into contact with the fluid;
The microchip inspection system according to claim 1, comprising:

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