JPWO2009069449A1 - Inspection device and control method of inspection device - Google Patents

Abstract

In an inspection apparatus that has a micropump that sends out a liquid by changing the pressure inside the pump chamber with an actuator, injects the liquid from the micropump into the microchip, and reacts the reagent with the sample to measure the reaction result A flow rate measuring means for outputting a signal according to the flow rate of the flow path through which the liquid flows, a flow rate judging means for comparing and judging a signal value and a reference signal value, a pump drive means for driving the micropump, and a drive means And a pump drive control means for controlling the pump drive means, and the pump drive control means controls the pump drive means based on a determination result of the flow rate determination means.

Description

  The present invention relates to an inspection apparatus and a method for controlling the inspection apparatus.

  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 conventional sample preparation, chemical analysis, chemical synthesis, etc. have been miniaturized. A system integrated on a chip 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 / diagnosis field, environmental measurement field, Its application is expected in the field of agricultural production. 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. It can be said that not only the amount of sample and the time required, but also the benefits of enabling analysis at any time and place are great.

  In various types of analysis and inspection, importance is attached to the quantitativeness of analysis, the accuracy of analysis, and the economy of these analysis chips (microchips). For that purpose, it is a problem to establish a highly reliable liquid feeding system with a simple configuration, and there is a demand for a microfluidic control element with high accuracy and excellent reliability. The present applicant discloses, for example, Japanese Patent Application Laid-Open No. H10-228707, the operation principle and control method of a micropump suitable for such a use.

  In addition, the applicant of the present invention encloses a reagent or the like in the microchannel of the microchip, injects the liquid into the microchannel by a micropump, moves the reagent, etc. The inspection apparatus which can measure a reaction result by making it flow to the flow path which comprises is proposed (for example, refer to patent documents 3).

  In such applications, it is necessary to accurately feed a very small amount of reagent or specimen stored in the flow path in the microchip, and it is necessary to perform liquid feed control of the micropump with high accuracy. However, when the fluid is sent to the flow path by the micropump, the flow resistance value changes, so that it is difficult to control to the target flow rate.

  In order to solve such a problem, the present applicant acquires information on the predicted value of the change in the channel resistance based on the change in the amount of fluid in the channel due to the operation of the micropump, and based on the acquired information, A method of controlling an electric signal for driving a pump has been proposed (see Patent Document 4). Patent Document 4 discloses a method for controlling the peak voltage of the trapezoidal wave voltage, since the electric signal for driving the micropump is a trapezoidal wave voltage that repeats at a constant period.

  On the other hand, as a general method, there is a method in which a flow rate sensor is arranged for each flow path to measure the flow rate and feed back to the control of the micropump.

As a flow rate sensor to be arranged for each flow path, a silicon substrate is formed as a flow path lid on a glass substrate on which a plurality of flow paths are formed, and two heaters for fluid flow rate detection are formed thereon, There has been proposed a thermal flow sensor that detects the flow rate from the resistance ratio of the upstream heater and the downstream heater (see, for example, Patent Document 5).
JP 2004-28589 A JP 2001-322099 A JP 2006-149379 A JP 2004-270537 A JP 7-159215 A

  However, since the output voltage of the thermal type flow sensor disclosed in Patent Document 5 is a function of the square root of the flow rate according to King's law, if the output voltage is fed back as it is, the control of the micropump is not stable.

  Therefore, it is necessary to convert the output voltage of the thermal flow sensor to a voltage proportional to a linear function of the flow rate, and to control, for example, the peak voltage of the trapezoidal wave voltage that drives the micropump. In order to convert the output voltage of the thermal flow sensor into a voltage proportional to the linear function of the flow rate in this way, for example, the output voltage of the thermal flow sensor is A / D converted and proportional to the flow rate using a lookup table. It is necessary to convert the output data to D / A conversion and obtain a control voltage. In order to drive a micropump with high control accuracy using such a method, an A / D converter and a D / A converter with high resolution are required, resulting in a complicated circuit with many expensive parts. .

  The present invention has been made in view of the above problems, and an object of the present invention is to provide an inspection apparatus and a control method for the inspection apparatus that can accurately control liquid feeding with a simple circuit configuration.

  The object of the present invention can be achieved by the following constitution.

1.
A testing apparatus that has a micropump for sending a liquid by changing the pressure inside the pump chamber with an actuator, injects the liquid from the micropump into the microchip, and reacts the reagent with the sample to measure the reaction result The flow rate measuring means for outputting a signal in accordance with the flow rate of the flow path through which the liquid flows, the flow rate determining means for comparing and determining the value of the signal and a reference signal value, and the pump drive means for driving the micropump And a pump drive control means for controlling the pump drive means, wherein the pump drive control means controls the pump drive means based on a determination result of the flow rate determination means. .

2.
The pump drive control means controls the flow rate by changing either one or both of a frequency and a duty ratio of a drive voltage for driving the actuator generated by the pump drive means. The inspection device described.

3.
The pump drive control means periodically acquires the determination result from the flow rate determination means, and controls the pump drive means based on the determination result to make the flow rate constant 1 or 2. The inspection apparatus according to 2.

4).
A testing device that has a micropump for sending a liquid by changing the pressure inside the pump chamber with an actuator, injects the liquid from the micropump into the microchip, and reacts the reagent with the sample to measure the reaction result In the control method, a flow rate measuring step of outputting a signal according to a flow rate of the flow path through which the liquid flows, a flow rate determining step of comparing and determining a value of the signal and a reference signal value, and driving the micropump And a pump driving step for setting conditions, and changing the conditions for the pump driving step based on the determination result of the flow rate determination step.

5.
5. The inspection apparatus control method according to 4, wherein the condition is one or both of a frequency and a duty ratio for driving the micropump.

6).
6. The inspection apparatus control method according to 4 or 5, wherein the flow rate is made constant by periodically repeating the flow rate measurement step, the flow rate determination step, and the pump drive step in this order.

  According to the present invention, the output value of the flow rate measuring means is compared with the reference value, and the frequency and / or duty ratio of the drive voltage for driving the pump is changed based on the determination result. Liquid control can be performed.

It is an external view of the test | inspection apparatus 82 in embodiment of this invention. It is explanatory drawing about an example of the micropump unit 5 concerning embodiment of this invention. FIG. 6 is an explanatory diagram showing a relationship between a drive voltage E supplied to an actuator 112 and a flow rate Q. It is explanatory drawing about an example of the microchip 1 concerning embodiment of this invention. It is sectional drawing which shows an example of the internal structure of the test | inspection apparatus 82 in embodiment of this invention. It is a circuit block diagram of the inspection apparatus 82 in the 1st Embodiment of this invention. 3 is a timing chart showing a relationship between a timing signal S1 generated by a timing signal generator 21 and a drive voltage E supplied to an actuator 112. It is a graph for demonstrating an example of the relationship between the drive frequency f of the drive voltage E, and the flow volume Q of micropump MP. It is a graph which shows the relationship between the elapsed time t and the liquid feeding amount U when changing the drive frequency f. 3 is a graph showing a relationship between a flow rate Q and an output voltage E of an amplifier 306. It is a flowchart of the flow control routine in the 1st Embodiment of this invention. It is a circuit block diagram of the test | inspection apparatus 82 in 2nd Embodiment. It is a circuit block diagram of the reaction detection apparatus 82 in the 2nd Embodiment of this invention. It is a flowchart of the flow control routine in the 2nd Embodiment of this invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Microchip 4 Drive liquid 5 Micro pump unit 21 Timing signal generation part 23 Trapezoidal wave generation part 26 Amplifier 80 Microchip inspection system 82 Inspection apparatus 83 Insertion port 84 Display part 90 Packing 91 Drive liquid tank 110 Drive liquid injection part 111 Detection part 112 Actuator 150a Light Emitting Unit 150b Light Receiving Unit 213 Sample Injection Unit 410 Flow Rate Determination Unit 412 Pump Drive Control Unit 500 Pump Drive Unit 510 Flow Rate Measurement Unit MP Micro Pump

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

  FIG. 1 is an external view of an inspection apparatus 82 according to an embodiment of the present invention.

  The inspection system 80 includes an inspection device 82 and the microchip 1. The inspection device 82 is a device that automatically detects the reaction between the specimen previously injected into the microchip 1 and the reagent and displays the result on the display unit 84. The inspection device 82 has an insertion port 83, and the microchip 1 is inserted into the insertion port 83 and set inside the inspection 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 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 inspection device 82, a micropump unit 5 (not shown in FIG. 1) injects a liquid 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. Is called. 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.

  Next, an example of the micropump unit 5 according to the embodiment of the present invention will be described with reference to FIG.

  2A is a plan view of the micropump unit 5 according to the present invention, FIG. 2B is a left side view, and FIG. 2C is a right side view. Moreover, FIG.2 (d) is sectional drawing of the part shown by AA in Fig.2 (a).

  As shown in FIG. 2, the micropump unit 5 includes a first substrate 11 and a second substrate 12. In FIG. 2A, the groove provided in the first substrate 11 is indicated by a dotted line.

  The portion indicated by AA in FIG. 2A constitutes one micropump MP, and the liquid sucked from, for example, the input / output port 145 is discharged from the input / output port 146 by a micropump mechanism described later. Alternatively, the liquid sucked from the input / output port 146 in the reverse direction can be discharged from the input / output port 145. In the example of FIG. 2A, eight micro pumps MP are formed on the first substrate 11. Since these micropumps MP have the same structure, the structure will be described below with reference to FIG.

  The first substrate 11 is, for example, a rectangular sheet having a width of 17 mm, a depth of 35 mm, and a thickness of 0.2 mm. As shown in FIG. 2D, each micropump MP formed on the first substrate 11 includes a pump chamber 121, a diaphragm 122, a first throttle channel 123, a first channel 124, and a second throttle channel. 125 and a second flow path 126.

  The micro pump unit 5 sucks liquid from one input / output port 145 and discharges liquid from the other input / output port 146 by the operation of the micro pump MP described above. Further, by controlling the drive voltage applied to the actuator 112, the direction of liquid suction and discharge can be reversed. For the structure of the first substrate 11 itself, reference can be made to Japanese Patent Application Laid-Open No. 2001-322099 described in the section of the prior art.

  Next, the operation principle of the micropump unit 5 will be described.

  The second throttle channel 125 has a low channel resistance when the differential pressure between the inflow side and the outflow side is close to zero, but the channel resistance increases when the differential pressure increases. That is, the pressure dependency is large. The first throttle channel 123 has a larger channel resistance when the differential pressure is close to zero than that of the second throttle channel 125, but has little pressure dependency, and the channel resistance even when the differential pressure increases. Does not change so much, and when the differential pressure is large, the channel resistance becomes smaller than that of the second throttle channel 125.

  Such flow path resistance characteristics allow the liquid (fluid) flowing through the flow path to be turbulent according to the magnitude of the differential pressure, or always to be laminar regardless of the differential pressure. Or can be obtained by Specifically, for example, the second throttle channel 125 is an orifice having a short channel length, and the first throttle channel 123 is a nozzle having the same inner diameter as the second throttle channel 125 and a long channel length. It is possible to realize.

  By utilizing such flow path resistance characteristics of the first throttle flow path 123 and the second throttle flow path 125, pressure is generated in the pump chamber 121, and the rate of change in the pressure is controlled, thereby providing a flow path. It is possible to realize a pump action that discharges a liquid toward a lower resistance.

  That is, if the pressure in the pump chamber 121 is increased and the rate of change is increased, the differential pressure increases and the flow resistance of the second throttle flow path 125 is greater than the flow of the first throttle flow path 123. It becomes larger than the path resistance, and the liquid in the pump chamber 121 is discharged from the first throttle channel 123 (discharge process). If the pressure in the pump chamber 121 is lowered and the rate of change is reduced, the differential pressure is kept small, and the flow resistance of the first throttle channel 123 is greater than that of the second throttle channel 125. The resistance becomes larger than the resistance, and the liquid flows into the pump chamber 121 from the second throttle channel 125 (suction process).

  On the contrary, if the pressure in the pump chamber 121 is increased and the rate of change is reduced, the differential pressure is maintained smaller, and the flow resistance of the first throttle flow path 123 is greater than that of the second throttle flow path. The flow path resistance of 125 becomes larger, and the liquid in the pump chamber 121 is discharged from the second throttle flow path 125 (discharge process). If the pressure in the pump chamber 121 is lowered and the rate of change is increased, the differential pressure increases, and the flow resistance of the first throttle flow path 123 is greater than that of the second throttle flow path 125. And the liquid flows into the pump chamber 121 from the first throttle channel 123 (suction process).

  Such pressure control of the pump chamber 121 is realized by controlling the driving voltage supplied to the actuator 112 and controlling the deformation amount and timing of the diaphragm 122.

  FIG. 3 is an explanatory diagram showing the relationship between the drive voltage E supplied to the actuator 112 and the flow rate Q. When a high driving voltage is applied to the actuator 112, the pressure in the pump chamber 121 is increased.

  Since T1 <T3 in the waveform shown in FIG. 3A-1, the rate of change when the pressure in the pump chamber 121 rises is greater than the rate of change when the pressure in the pump chamber 121 falls. Therefore, the liquid in the pump chamber 121 is discharged from the first throttle channel 123 as described above.

  FIG. 3A-2 shows an example of the flow rate Q of the liquid discharged from the flow path 123 in the flow path 124. Since the pressure in the pump chamber 121 suddenly rises during the period T1, the flow rate Q flowing through the flow path 124 also suddenly rises. After the suspension period of T2, during the period of T3, when the pressure in the pump chamber 121 gradually decreases, the liquid mainly flows into the pump chamber 121 from the second throttle channel 125, and a part thereof from the first throttle channel 123. It flows into the pump chamber 121. Therefore, the flow rate Q decreases gently. However, the flow rate Q that decreases during the period T3 is less than the flow rate Q that flows during the period T1, and the flow rate Q increases during the idle period of T4 from the initial state. Thus, the flow rate Q increases by repeating the cycle from T1 to T4.

  On the other hand, since T7 <T5 in the waveform shown in FIG. 3B-1, the rate of change when the pressure in the pump chamber 121 increases is smaller than the rate of change when the pressure in the pump chamber 121 decreases. Therefore, the liquid flows into the pump chamber 121 from the first throttle channel 123 as described above.

  FIG. 3B-2 shows an example of the flow rate Q of the liquid sucked from the flow path 123 in the flow path 124. When the pressure in the pump chamber 121 rises gently during the period T 5, the liquid is mainly discharged from the second throttle channel 125 and a part is discharged from the first throttle channel 123. Therefore, the flow rate Q increases gently. On the other hand, if the pressure in the pump chamber 121 suddenly decreases during the period T7 after the pause period T6, the liquid flows into the pump chamber 121 from the first throttle channel 123. Therefore, the flow rate Q decreases rapidly. However, the flow rate Q that increases during the period T5 is smaller than the flow rate Q that is discharged during the period T7, and the flow rate Q decreases during the idle period T8 from the initial state. Thus, the flow rate Q decreases by repeating the cycle from T5 to T8.

  In FIG. 3, the maximum voltage e1 applied to the actuator 112 is about several volts to several tens of volts, and about 100 volts at the maximum. Times T1 and T7 are about 20 μs, times T2 and T6 are about 0 to several μs, and times T3 and T5 are about 60 μs. Times T4 and T8 may be zero. The frequency of the drive voltage E is about 11 kHz. With the drive voltage E shown in FIGS. 3 (a-1) and 3 (b-1), for example, flow rates as shown in FIGS. 3 (a-2) and 3 (b-2) are obtained in the flow path 23. . The flow curves in FIGS. 3 (a-2) and 3 (b-2) schematically show the flow rate obtained by the pump operation, and actually the inertial vibration of the fluid is superimposed. Therefore, a curve obtained by superimposing a vibration component on the flow rate curves shown in these figures indicates the actual flow rate obtained.

  Next, an example of the microchip 1 according to the embodiment of the present invention will be described with reference to FIG.

  4A and 4B are external views of the microchip 1. FIG. In FIG. 4A, an arrow indicates an insertion direction in which the microchip 1 is inserted into an inspection apparatus 82 to be described later, and FIG. 4A illustrates a surface that becomes the upper surface of the microchip 1 when inserted. FIG. 4B is a side view of the microchip 1.

  The detection unit window 111a and the detection unit flow path 111b in FIG. 4A are provided for optically detecting the reaction between the specimen and the reagent, and are configured by a transparent member such as glass or resin. . Reference numerals 110a, 110b, 110c, 110d, and 110e denote driving liquid injection units that communicate with the internal microchannels. The driving liquid 50 is injected from each driving liquid injection unit 110 to drive the internal reagents and the like. Reference numeral 213 denotes a sample injection unit for injecting the sample into the microchip 1.

  As shown in FIG. 4B, the microchip 1 includes a groove forming substrate 108 and a covering substrate 109 that covers the groove forming substrate 108. Next, materials used for the groove forming substrate 108 and the covering substrate 109 constituting the microchip 1 will be described.

  The microchip 1 is desired to be excellent in processability, non-water absorption, chemical resistance, weather resistance, cost and the like. In consideration of the structure, application, detection method, etc. of the microchip 1, The material of chip 1 is selected. Various known materials can be used as the material, and usually the substrate and the flow path element are formed by appropriately combining one or more materials in accordance with individual material characteristics.

  In particular, it is desirable that a chip intended for a large number of measurement specimens, particularly clinical specimens at risk of contamination and infection, be of a disposable type. Therefore, a plastic resin that can be mass-produced, is lightweight, is strong against impact, and can be easily discarded by incineration, for example, polystyrene that is excellent in transparency, mechanical properties, and moldability and is easy to be finely processed is preferable. For example, when it is necessary to heat the chip to near 100 ° C. in analysis, it is preferable to use a resin having excellent heat resistance (for example, polycarbonate). In addition, when protein adsorption becomes a problem, it is preferable to use polypropylene. Resin and glass have low thermal conductivity, and by using these materials in the locally heated region of the microchip, heat conduction in the surface direction is suppressed, and only the heated region is selectively heated. Can do.

  In the case where the detection unit 111 optically detects a color reaction product or a fluorescent substance, at least the substrate of this part uses a light-transmitting material (for example, alkali glass, quartz glass, transparent plastics). It is necessary to allow light to pass through. In the present embodiment, the groove forming substrate that forms the window 111a of the detection unit and at least the flow path 111b of the detection unit is made of a light-transmitting material so that light can pass through the detection unit 111. ing.

  In the microchip 1 according to the embodiment of the present invention, a minute groove-like flow path (fine flow path) and a functional component (flow path element) for performing inspection, sample processing, and the like correspond to applications. It is arranged in an appropriate manner. In the present embodiment, an example of a process for performing amplification and detection of a specific gene performed in the microchip 1 by using these microchannels and channel elements will be described with reference to FIG. The application of the present invention is not limited to the example of the microchip 1 described with reference to FIG. 4C, and can be applied to the microchip 1 for various uses.

  FIG. 4C is an explanatory diagram for explaining the functions of the micro flow channel and the flow channel element inside the microchip 1.

  The microchannel is provided with, for example, a sample storage unit 221 for storing a sample liquid, a reagent storage unit 220 for storing reagents, and the like, so that the reagent storage unit 220 can be quickly examined regardless of location and time. Necessary reagents, washing solution, denaturing treatment solution and the like are stored in advance. In FIG. 4C, the reagent storage unit 220, the sample storage unit 221 and the flow path element are represented by squares, and the fine flow path therebetween is represented by a solid line and an arrow.

  The microchip 1 includes a groove forming substrate 108 in which a fine flow path is formed and a covering substrate 109 that covers the groove-shaped flow path. The fine channel is formed on the order of micrometers, for example, the width is several μm to several hundred μm, preferably 10 to 200 μm, and the depth is about 25 to 500 μm, preferably 25 to 250 μm.

  At least in the groove forming substrate 108 of the microchip 1, the fine flow path is formed. The coated substrate 109 needs to cover at least the fine flow path of the groove forming substrate in close contact, and may cover the entire surface of the groove forming substrate. Note that the microchannel 1 is provided with a part for controlling liquid feeding, such as a liquid feeding control unit (not shown), a backflow prevention unit (a check valve, an active valve, etc.), and the like. In this case, liquid feeding is performed according to a predetermined procedure.

  The sample injection unit 213 is an injection unit for injecting a sample into the microchip 1, and the driving liquid injection unit 110 is an injection unit for injecting the driving liquid 50 into the microchip 1. Prior to performing the test using the microchip 1, the person in charge of the test injects the sample from the sample injection unit 213 using a syringe or the like. As shown in FIG. 4C, the sample injected from the sample injection unit 213 is stored in the sample storage unit 221 through the communicating fine channel.

  Next, when the driving liquid 50 is injected from the driving liquid injection unit 110a, the driving liquid 50 pushes out the sample stored in the sample storage unit 221 through the communicating fine flow path, and sends the sample to the amplification unit 222.

  On the other hand, the driving liquid 50 injected from the driving liquid injection part 110b pushes out the reagent a stored in the reagent storage part 220a through the communicating fine channel. The reagent a pushed out from the reagent storage unit 220 a is sent to the amplification unit 222 by the driving liquid 50. Depending on the reaction conditions at this time, it is necessary to set the amplification unit 222 to a predetermined temperature. As will be described later, the reaction is performed at a predetermined temperature by heating or absorbing heat inside the inspection device 82.

  After a predetermined reaction time, the solution containing the sample after reaction sent out from the amplification unit 222 by the driving liquid 50 is injected into the detection unit 111. The injected solution reacts with the reactants carried on the flow path wall of the detection unit 111 and is immobilized on the flow path wall.

  Next, when the driving liquid 50 is injected from the driving liquid injection section 110c, the driving liquid 50 pushes the reagent b stored in the reagent storage section 220b through the communicating fine flow path, and passes from the fine flow path to the detection section 111. inject.

  Similarly, when the driving liquid 50 is injected from the driving liquid injection unit 110d, the driving liquid 50 pushes the reagent stored in the reagent storage unit 220c through the communicating fine channel and injects the reagent from the micro channel into the detection unit 111. To do.

  Finally, the driving liquid 50 is injected from the driving liquid injection unit 110e, the cleaning liquid is pushed out from the cleaning liquid storage unit 223, and is injected into the detection unit 111. The unreacted solution 41 remaining in the detection unit 111 is washed with the washing liquid.

  After washing, the detected substance such as the amplified gene is detected by optically measuring the concentration of the reactant adsorbed on the flow path wall of the detection unit 111. Thus, a predetermined process is performed inside the microchip 1 by sequentially injecting the driving liquid 50 from the driving liquid injection unit 110.

  FIG. 5 shows a state in which the upper surface of the microchip 1 is in close contact with the temperature adjustment unit 152 and the micropump unit 5. 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. 5, 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 includes a Peltier element, a power supply device, a temperature control device, and the like, and is a unit that adjusts the microchip 1 to a predetermined temperature by generating heat or absorbing heat.

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

  The driving liquid injection part 110 of the microchip 1 is provided at a position that communicates with a corresponding opening 185 provided in the intermediate flow path part 180 when the microchip 1 and the packing 92 are brought into close contact with each other. The intermediate flow path portion 180 includes a transparent first substrate 184 provided with a groove of the intermediate flow path 182 and a transparent second substrate 183 that covers the first substrate 184, and openings 185 are formed at both ends of the intermediate flow path 182. And an opening 186. The opening 186 communicates with the input / output port 146 of the micro pump unit 5 through the packing 90b.

  A driving liquid tank 91 is connected to the suction side of the micropump unit 5 via a packing 90a, and the driving liquid filled in the driving liquid tank 91 is sucked via the packing 90a. On the other hand, the input / output port 146 provided on the discharge-side end face of the micropump unit 5 communicates with the driving liquid injection unit 110 of the microchip 1 through the intermediate flow path 182, and thus is sent out from the micropump unit 5. The driving liquid thus injected is injected from the driving liquid injection part 110 of the microchip 1 into the flow path 250 formed in the microchip 1. In this way, the driving liquid is injected from the micropump unit 5 into the driving liquid injection unit 110.

  For example, a liquid temperature reference resistor 59 and a heating resistor 52 are provided in the intermediate flow path portion 180 in order to measure the flow velocity of the driving liquid 50 flowing through the intermediate flow path 182.

  For example, a glass epoxy substrate can be used for the second substrate 183 by patterning. However, if a low temperature sintered ceramic is used, the liquid temperature reference resistor 59 and the heating resistor 52 can be formed by thick film printing. It can be simplified.

  As shown in the cross-sectional view along the flow path 182 in FIG. 5, the liquid temperature reference resistor 59 and the heating resistor 52 formed on the second substrate 183 are arranged along the flow path 182. In contact with the driving fluid 50 flowing through. The driving liquid 50 is injected from the opening 186 and discharged from the opening 185 through the flow path 182. As will be described in detail later, a bridge circuit detects a change in the resistance value of the liquid temperature reference resistor 59 provided on the upstream side and the heating resistor 52 provided on the downstream side, and a voltage corresponding to the flow rate is obtained. Output.

  In this embodiment, the liquid temperature reference resistor 59 and the heating resistor 52 are provided so as to measure the flow velocity of the intermediate flow path portion 180, but the place where these are provided is limited to the intermediate flow path portion 180. is not. Further, the intermediate flow path portion 180 is not always necessary. For example, the liquid temperature reference resistor 59 and the heating resistor 52 may be provided so as to measure the flow velocity of the first flow path 124 of the micropump unit 5.

  Further, in the example of the micropump unit 5 shown in FIG. 2, eight micropumps MP are provided, but it is not necessary to use all the micropumps MP. In the case of the microchip 1 illustrated in FIG. 3, the driving liquid injection unit 110 may be disposed so that the five micropumps MP communicate with each other.

  In the detection unit 111 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 the present embodiment, as described with reference to FIG. 4, the reaction result of the reagent that occurs in the detection unit 111 is optically detected. The light emitting unit 150a and the light receiving unit 150b are arranged so that light transmitted through the detection unit 111 of the microchip 1 can be detected.

  FIG. 6 is a circuit block diagram of the reaction detection device 82 according to the first embodiment of the present invention. The block diagram of FIG. 6 will be described with reference to FIGS. 7, 8, 9, and 10.

FIG. 7 is a timing chart showing the relationship between the timing signal S1 generated by the timing signal generator 21 and the drive voltage E supplied to the actuator 112. FIG. 8 is a graph for explaining an example of the relationship between the driving frequency f (kHz) of the driving voltage E and the flow rate Q of the micropump MP, and FIG. 9 is an elapsed time t when the liquid is fed while changing the driving frequency f. (Sec) and is a graph showing the relationship between the feed rate U (mm ^3). FIG. 10 is a graph showing the relationship between the flow rate Q (mm ³ / s) and the output voltage E (V) of the amplifier 306.

  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 as a nonvolatile storage unit to the RAM 97. Each part of the reaction detector 82 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 CPU 98 includes a flow rate determination unit 410 and a pump drive control unit 412.

  The pump drive unit 500 is a drive unit that drives the actuator 112 of each micropump MP. The pump drive unit 500 includes a timing signal generation unit 21, a power supply unit 24, a trapezoidal wave generation unit 23, and an amplifier 26.

  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.

Timing signal generator 21, and time T _H of the timing pulse S1 pump drive control unit 412 has commanded the 'H', the timing pulse S1 is in accordance with the time T _L of 'L', for generating a timing pulse S1.

  The trapezoidal wave generator 23 charges the internal capacitor with a constant current when the timing pulse S1 is “H”, and generates a trapezoidal wave by discharging the internal capacitor with a constant current when the timing pulse S1 is “L”. The power supply unit 24 supplies the trapezoidal wave generating unit 23 with a constant voltage that becomes a peak voltage e1 of the trapezoidal wave. The amplifier 26 impedance-converts the voltage of the capacitor inside the trapezoidal wave generator 23 and drives the actuator 112.

  In this manner, the pump drive unit 500 receives the command from the pump drive control unit 412 and generates the drive voltage E having a waveform as shown in FIG. 7 to drive the actuator 112.

  FIGS. 7A and 7C show waveforms of the timing signal S1 output from the timing signal generator 21, and FIGS. 7B and 7D show trapezoids generated by the trapezoidal wave generator 23 to which the timing signal S1 is input. This is a waveform of the drive voltage E that supplies a wave to the actuator 112 via the amplifier 36.

The timing signal S1, FIGS. 7 (a) period T _L as shown in 'L', a rectangular pulse to be the period of T _{H 'H'.} Pump drive control unit 412 sets an initial value of the period T _H of the timing signal S1 to the timing signal generator 21 becomes 'L' in the period T _L becomes 'H' in step S13 described in FIG 10. The timing signal generator 21 generates a pulse of the timing signal S1 at a set time interval.

  When the timing signal S1 is input, the trapezoidal wave generator 23 increases the drive voltage E from the voltage e0 to the voltage e1 during the period T1 from the fall of the timing signal S1. The voltage e1 is a constant voltage supplied from the power supply unit 24. During the period T2, the drive voltage E is a constant voltage e1. The trapezoidal wave generator 23 decreases the drive voltage E from the voltage e1 to the voltage e0 during the period T3 from the rising edge of the timing signal S1. Next, during a period T4 until the timing signal S1 falls, the drive voltage E is a constant voltage e0. T1 and T3 are preset as circuit constants of the trapezoidal wave generator 23. The cycle of the drive voltage E is Tw, and the drive frequency f is 1 / Tw. The duty ratio DT is (T1 + T2 + T3) / Tw.

Next, an example in which the flow rate Q of the micropump MP is controlled by changing the time T _H of the timing signal S1 will be described with reference to FIGS. 7C and 7D.

As shown in FIG. 7C, for example, in response to a command from the pump drive control unit 412, the period during which the timing signal S1 output from the timing signal generator 21 becomes “H” is increased by ΔT and becomes T _H. Then, the rest period T4 of the drive voltage E is increased by ΔT and becomes T4 ′ as shown in FIG. The driving frequency f ′ at this time is 1 / Tw ′, and the duty ratio DT is (T1 + T2 + T3) / Tw ′. In this example, the drive frequency f and the duty ratio DT are lowered, but if the time T _H is shortened, the drive frequency f and the duty ratio DT can be increased.

In this example, since only T _{H of the} timing signal S1 is changed, the driving frequency f and the duty ratio DT are changed. However, the driving frequency f is changed by changing both T _H and T _L of the timing signal S1. Alternatively, only the duty ratio DT can be made variable.

  Next, an example of the flow rate Q of the micropump MP when the drive voltage E of the drive frequency f (kHz) is applied to the actuator 112 will be described.

As shown in the graph of FIG. 8, for example, the flow rate Q increases with the drive frequency f when the drive frequency f is 9.6 KHz to 10.8 KHz, and the flow rate Q is between 10.8 KHz and 11.2 KHz indicated by B in the figure. Becomes a maximum of about 0.7 (mm ³ / s).

  Conventionally, the driving frequency f is set to any frequency in the range of B so that the flow rate Q is maximized, and the flow rate Q is controlled by changing the peak voltage e1 of the trapezoidal wave.

  In the present invention, the flow rate Q is controlled by varying the range in which the flow rate Q increases in proportion to the drive frequency f indicated by A in the figure, that is, the drive frequency f, for example, in the range of 10.3 kHz ± 0.3 KHz. In this way, the flow rate Q changes linearly with respect to the change in the drive frequency f, and since the change amount is small, it is possible to control the target flow rate with high accuracy.

  The straight line indicated by b in FIG. 9 is the case where the drive frequency f is the reference frequency, and in the example of FIG. 8, the drive frequency f is 10.3 kHz. The straight line indicated by “a” in the figure is a case where the drive frequency f is higher than the reference frequency, and for example, the drive frequency f is 10.6 kHz. The straight line indicated by c in the figure is a case where the drive frequency f is lower than the reference frequency. For example, the drive frequency f is 10.0 kHz. As can be seen from the graph, the liquid supply amount U increases in proportion to the frequency in proportion to the time, and can be supplied stably in any case.

  Similarly, when the duty ratio DT of the drive voltage E is made variable, there is a region where the flow rate Q changes linearly, and the duty ratio DT of the center value of such a region is set as a reference value.

  A flow rate measurement unit 510 shown in FIG. 6 includes a bridge circuit and an amplifier 306 in which a heating resistor 52 and a liquid temperature reference resistor 59 for temperature compensation that are kept in equilibrium at a predetermined heating temperature are connected to resistors R3 and R4, respectively. , And a constant current source 305. The flow rate measurement unit 510 is a flow rate measurement unit of the present invention. The voltage difference of the bridge resistance of the bridge circuit is differentially amplified by the amplifier 306, converted into a digital value by the A / D conversion unit 310, and input to the control unit 99.

  As shown in FIG. 10, the output voltage E of the bridge circuit increases in proportion to the square root of the flow rate Q. It is desirable to set each constant so that the change of the output voltage Eo in the vicinity of the target flow rate Qo is close to linear. Note that the flow rate measurement unit 510 of this embodiment is an example, and for example, the temperature of the liquid upstream and downstream of the heating resistor 52 may be detected by a thermistor and the flow rate may be obtained from the temperature difference.

  The flow rate determination unit 410 compares the output value of the amplifier 306 with a reference value and determines the result.

  The CPU 98 shown in FIG. 6 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 the operation of the operation unit 87 or printed by the printer 503.

  FIG. 11 is a flowchart for explaining the inspection procedure by the microchip inspection system 80 in the embodiment of the present invention.

  It is assumed that the temperature adjustment unit 152 is energized when the reaction detector 82 is turned on and has a predetermined temperature.

  S11: This is a step of inserting the microchip 1.

  The person in charge of inspection inserts the microchip 1 from the insertion port 83 until it abuts against a regulating member (not shown).

  S12: A step of lowering the mechanism.

  When the microchip 1 inserted from the insertion port 83 comes into contact with a regulating member (not shown) and the CPU 98 detects a detection signal from the chip detection unit 95, the CPU 98 controls the mechanism driving unit 32, and the packing 92 and the temperature adjustment unit 152. Until it comes into close contact with the appropriate pressure.

  S13: This is a step of injecting the driving liquid into the microchip 1.

  The pump drive control unit 412 instructs the pump drive unit 500 to drive the micropump MP according to a predetermined sequence, and sequentially injects the drive liquid into the drive liquid injection unit 110 of the microchip 1.

  S14: A step of controlling the flow rate of the driving fluid.

  The CPU 98 calls a flow rate control routine, which will be described in detail later, and controls the pump drive unit 500 based on the flow rate of the driving fluid flowing through the intermediate flow path 182 to make the flow rate constant.

  S15: This is a step of determining whether or not the time for injecting the driving liquid has ended.

  The injected driving liquid sends the sample or reagent in the flow path of the microchip 1 to the detection unit 111 in a predetermined sequence, and determines whether or not a predetermined time for reaction has passed.

  When the time to inject | pour is not complete | finished (step S15; No), it returns to step S14.

  When the time to inject | pour is complete | finished (step S104; Yes), it progresses to step S16.

  S16: This is a step of detecting the reaction result of the detection unit 111.

  After a predetermined reaction time has elapsed, the CPU 98 illuminates the detection unit 111 of the microchip 1 by causing the light emission unit 150a to emit light, and the CPU 98 incorporates an input signal from the light reception unit 150b that has received the transmitted light transmitted through the detection unit 111. A / D converter converts the digital value to a digital value to obtain a photometric value.

  S17: This is a step of displaying the reaction result.

  The CPU 98 calculates from the result of photometry performed by the light detection unit 150 and displays the reaction result on the display unit 84.

  This is the end of the inspection procedure.

  Next, the flow rate control routine will be described with reference to FIG. FIG. 12 is a flowchart of a flow rate control routine in the first embodiment of the present invention.

  S101: This is a step of acquiring flow rate data.

  The flow rate determination unit 410 acquires signal voltage data Dn output from the flow rate measurement unit 510. Step S101 is a flow rate measurement process of the present invention.

S102: compared with the data D ₀ of the reference flow rate, a step of determining.

The flow rate determination unit 410 compares and determines the signal voltage data Dn and the reference flow rate data D ₀ . Step S102 is a flow rate determination step of the present invention.

For Dn> D _0, (step S102; Dn> D _0), the process proceeds to step S103.

S103: This is a step of T _Hn = T _Hn-1 + ΔT.

Pump drive control unit 412 sets the timing signal generator 21 so that the period T _Hn timing signal S1 becomes 'H' is the period T _Hn-1 + ΔT previously set, returns to the main routine.

Timing signal generated by timing signal generator 21, a period in which the increasing [Delta] T 'H' as shown in FIG. 7 (c) is T _H '. Then, the rest period T4 of the drive voltage E is increased by ΔT and becomes T4 ′ as shown in FIG. As described above, when the signal voltage data Dn output from the flow rate measuring unit 510 is larger than the reference flow rate data D ₀ , the pause period T4 is lengthened to decrease the flow rate Q.

When Dn = D ₀ (step S102; Dn = D ₀ ), the process proceeds to step S104.

S104: This is a step of setting T _Hn = T _Hn-1 .

Pump drive control unit 412 sets the timing signal generator 21 so that the period T _Hn timing signal S1 becomes 'H' is the period T _Hn-1 previously set returns to the main routine.

If Dn <D ₀ (step S102; Dn <D ₀ ), the process proceeds to step S105.

S105 is a step of setting T _Hn = T _Hn-1 −ΔT.

Pump driving control section 412, the period of the timing signal S1 becomes 'H' sets the timing signal generator 21 so as to be _{T Hn = T Hn-1 -ΔT} . Then, the rest period T4 of the drive voltage E is shortened by ΔT, contrary to FIG. As described above, when the signal voltage data Dn output from the flow rate measuring unit 510 is smaller than the reference flow rate data D ₀ , the pause period T4 is shortened to increase the flow rate Q, and the process returns to the main routine.

  Steps S103, S104, and S105 are the pump driving process of the present invention.

  This completes the description of the flow control routine.

  As described above, in the present invention, since the drive voltage E for driving the micropump MP is controlled according to the determination result of the flow rate, the liquid feeding control can be performed with a simple circuit configuration with high accuracy.

  In the present embodiment, both the frequency and the duty ratio of the drive voltage E are changed by changing the pause period T4 of the drive voltage E, but only the frequency or the duty ratio may be changed. Further, the rising period T1 and the falling period T3 may be changed.

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

  In the second embodiment, the pump drive control unit 412 expands the flow rate control range by controlling the maximum voltage e1 applied to the actuator 112 in addition to the pause period T4 of the drive voltage E.

  FIG. 13 is a circuit block diagram of the reaction detection device 82 according to the second embodiment of the present invention, and FIG. 14 is a flowchart of a flow rate control routine according to the second embodiment of the present invention.

  As shown in the circuit block diagram of FIG. 13, in the second embodiment, the output voltage of the D / A converter 27 is supplied to the trapezoidal wave generator 23 via the amplifier 28. The pump drive controller 412 outputs voltage data to the D / A converter 27 and controls the maximum voltage e1 applied to the actuator 112. The other components are the same as those in the first embodiment shown in FIG.

  Next, the flowchart of FIG. 14 will be described. Steps that perform the same processing as in the first embodiment are given the same numbers, and descriptions thereof are omitted.

  S101: This is a step of acquiring flow rate data.

  The flow rate determination unit 410 acquires signal voltage data Dn output from the flow rate measurement unit 510.

S201: compared with the data D ₀ of the reference flow rate, a step of determining.

The flow rate determination unit 410 compares and determines the signal voltage data Dn and the reference flow rate data D ₀ . In this step, it is determined whether or not the difference between the signal voltage data Dn and the reference flow rate data D ₀ is within a certain range. In the second embodiment, when the difference from the reference flow rate becomes larger than a certain range, the maximum voltage e1 applied to the actuator 112 is changed, and the time until convergence to the reference flow rate is advanced.

If Dn−D ₀ <−Dx (step S201; Dn−D ₀ <−Dx), the process proceeds to step S202.

S202: a step of setting e1 _n = e1 _n-1 + Δe.

The pump drive controller 412 sets the D / A converter 310 so that the maximum voltage e1 _n becomes the previously set e1 _n-1 + Δe, and returns to the main routine.

If | Dn−D ₀ | ≦ Dx (step S201; | Dn−D ₀ | ≦ Dx), the process proceeds to step S203.

S203: a step of setting e1 _n = e1 _n-1 .

The pump drive control unit 412 sets the D / A conversion unit 310 so that the maximum voltage e1 _n becomes the previously set e1 _n−1, and proceeds to step S102.

If Dn−D ₀ > Dx (step S201; Dn−D ₀ > Dx), the process proceeds to step S204.

S204: This is a step of setting e1 _n = e1 _n-1 -Δe.

The pump drive control unit 412 sets the D / A conversion unit 310 so that the maximum voltage e1 _n becomes the previously set e1 _n−1 −Δe, and returns to the main routine.

S102: compared with the data D ₀ of the reference flow rate, a step of determining.

Flow rate determination unit 410 compares the data D ₀ of the data Dn and the reference flow rate of the signal voltage, determines.

For Dn> D _0, (step S102; Dn> D _0), the process proceeds to step S103.

S103: This is a step of T _Hn = T _Hn-1 + ΔT.

Pump drive control unit 412 sets the timing signal generator 21 so that the period T _Hn timing signal S1 becomes 'H' is the period T _Hn-1 + ΔT previously set, returns to the main routine.

When Dn = D ₀ (step S102; Dn = D ₀ ), the process proceeds to step S104.

S104: This is a step of setting T _Hn = T _Hn-1 .

Pump drive control unit 412 sets the timing signal generator 21 so that the period T _Hn timing signal S1 becomes 'H' is the period T _Hn-1 previously set, returns to the main routine.

If Dn <D ₀ (step S102; Dn <D ₀ ), the process proceeds to step S105.

S105 is a step of setting T _Hn = T _Hn-1 −ΔT.

The pump drive control unit 412 sets the timing signal generator 21 so that the period in which the timing signal S1 is “H” is T _Hn = T _Hn−1 −ΔT, and returns to the main routine.

  The flow control routine of the second embodiment has been described above.

  As described above, in the second embodiment, when the difference from the reference flow rate exceeds a certain range, the maximum voltage e1 is controlled to increase or decrease by Δe. Control is performed by increasing or decreasing the drive frequency and duty ratio for driving the MP. In the second embodiment, the D / A converter 27 is required. However, since the adjustment of the maximum voltage e1 does not require much precision, for example, a D / A converter built in the microcomputer can be used. . As described above, in the second embodiment, liquid feeding control can be performed with high accuracy in a wider control range than in the first embodiment with a simple circuit configuration. If the difference from the reference flow rate is within a certain range, control may be performed by increasing or decreasing the drive frequency or duty ratio for driving the micropump MP according to the flow rate determination result.

  As described above, according to the present invention, it is possible to provide an inspection apparatus and a control method for the inspection apparatus that can perform liquid feeding control with high accuracy with a simple circuit configuration.

Claims (6)

A testing device that has a micropump for sending a liquid by changing the pressure inside the pump chamber with an actuator, injects the liquid from the micropump into the microchip, and reacts the reagent with the sample to measure the reaction result The flow rate measuring means for outputting a signal in accordance with the flow rate of the flow path through which the liquid flows, the flow rate determining means for comparing and determining the value of the signal and a reference signal value, and the pump drive means for driving the micropump And a pump drive control means for controlling the pump drive means, wherein the pump drive control means controls the pump drive means based on a determination result of the flow rate determination means. . The pump drive control means controls the flow rate by changing either or both of a frequency and a duty ratio of a drive voltage for driving the actuator generated by the pump drive means. The inspection apparatus according to the first item of the range. The pump drive control unit periodically acquires the determination result from the flow rate determination unit, and controls the pump drive unit based on the determination result to make the flow rate constant. The inspection apparatus according to the first or second range. A testing device that has a micropump for sending a liquid by changing the pressure inside the pump chamber with an actuator, injects the liquid from the micropump into the microchip, and reacts the reagent with the sample to measure the reaction result In the control method, a flow rate measuring step of outputting a signal according to a flow rate of the flow path through which the liquid flows, a flow rate determining step of comparing and determining a value of the signal and a reference signal value, and driving the micropump And a pump driving step for setting conditions, and changing the conditions for the pump driving step based on the determination result of the flow rate determination step. 5. The inspection apparatus control method according to claim 4, wherein the condition is one or both of a frequency and a duty ratio for driving the micropump. 6. The flow rate according to claim 4, wherein the flow rate is made constant by periodically repeating the flow rate measuring step, the flow rate determining step, and the pump driving step in this order. Method of controlling the inspection apparatus.