JP2009115729A - Microchip inspection device - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a microchip inspection device wherein a fault of liquid sending caused by bubbles in a pump is removed. <P>SOLUTION: This microchip inspection device has; a microchip storage part for storing a microchip having a passage formed therein, in which mixing, reaction or detection of a sample is performed; a detection part provided in correspondence with a part to be detected of the microchip; a micro-pump for injecting driving liquid into the channel of the microchip; and a driving liquid tank for storing the driving liquid. In the device, a dissolved gas concentration detection part is arranged in the channel on the upstream of the micro-pump. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a microchip 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 attracts attention. This is also called μ-TAS (Micro Total Analysis System), and a DNA-treated extraction solution obtained by processing a reagent and a sample (for example, urine, saliva, and blood of a subject to be examined) on a member called a microchip. Etc.) and the characteristics of the sample are examined by detecting the reaction.

  In the microchip, a substrate made of a resin material or a glass material is provided with a fine channel through which a reagent or sample can flow and a liquid reservoir for storing the reagent, and various patterns have been proposed.

  And when examining the characteristics of the sample using these microchips, the driving liquid is sent to the microchannel of the microchip with a micropump, etc., and the reagent or sample contained in the microchip is extruded, The reagent and the sample are reacted and guided to the detected part to perform detection. In the detected portion, the target substance is detected by, for example, an optical detection method.

As such a microchip inspection apparatus, for example, an inspection apparatus as disclosed in Patent Document 1 below is disclosed.
JP 2007-170943 A

  In various types of analysis and inspection, importance is attached to the quantitativeness of analysis, the accuracy of analysis, and the economy of these microchips. For this purpose, it is desired to establish a highly reliable liquid feeding system with a simple configuration.

  However, if bubbles are generated in the pump that feeds the driving liquid to the microchannel of the microchip, there is a problem that the micropump cannot perform accurate liquid feeding.

  In view of the above problems, an object of the present invention is to obtain a microchip inspection apparatus that solves the problem of liquid feeding caused by bubbles in a pump.

  The above object is solved by the following configuration.

  1. A microchip housing portion that houses a microchip in which a channel for mixing, reacting, and detecting a sample is formed, and a detected portion of the microchip housed in the microchip housing portion. A detection unit, a micropump for injecting the driving liquid into the flow path of the microchip, and a driving liquid tank for storing the driving liquid to be supplied to the micropump, the dissolved gas upstream of the micropump A microchip inspection apparatus comprising a concentration detection unit.

  2. 2. The microchip inspection apparatus according to 1, wherein the dissolved gas detected by the dissolved gas concentration detection unit is oxygen.

  3. An intermediate bag between the micropump and the driving liquid tank, and when the dissolved gas concentration by the dissolved gas concentration detection unit exceeds a predetermined value, the driving liquid between the micropump and the intermediate bag; Alternatively, the microchip inspection apparatus according to 1 or 2, wherein the driving liquid between the micropump and the driving liquid tank is replaced.

  4). 3. The microchip inspection apparatus according to 1 or 2, wherein a warning is issued when the concentration of dissolved gas by the dissolved gas concentration detection unit exceeds a predetermined value.

  5). 3. The microchip inspection apparatus according to 1 or 2, wherein the micropump is not driven when the concentration of dissolved gas by the dissolved gas concentration detection unit exceeds a predetermined value.

  6). 6. The microchip inspection apparatus according to any one of 1 to 5, wherein an optical oxygen sensor using quenching by oxygen molecules is used for the dissolved gas concentration detection unit.

  7. 7. The microchip inspection apparatus according to claim 6, wherein a sensor chip of the optical oxygen sensor is disposed in a flow path between the micro pump and the driving liquid tank.

  8). The drive fluid tank to the micro pump can be replaced as an integral cartridge, and the main body of the optical oxygen sensor is disposed outside the cartridge or inserted into and removed from a predetermined position in the cartridge. 8. The microchip inspection apparatus according to 7, wherein the microchip inspection apparatus is made possible.

  According to the present invention, the gas concentration dissolved in the driving liquid can be detected in real time, the generation of bubbles due to an increase in the gas concentration in the pump can be predicted, and the problem of liquid feeding caused by the bubbles has been solved. A microchip inspection apparatus can be obtained.

  Hereinafter, the present invention will be described in detail with reference to embodiments, but the present invention is not limited thereto.

FIG. 1 is a cross-sectional view showing a microchip inspection apparatus according to the present embodiment.
In the figure, reference numeral 1 denotes a microchip inspection apparatus main body, and the microchip 3 is detachable from the microchip insertion port 4 of the apparatus main body 1 in the direction of arrow A. Furthermore, the pump cartridge 2 is configured to be mounted on the upper back side of the apparatus main body 1, and the apparatus main body 1 and the pump cartridge 2 are connected to each other through the connection portion C <b> 1 so that no liquid leaks. Further, the apparatus main body 1 has a power supply part D1 for supplying power to each part of the apparatus, and the pump cartridge 2 is a connector part electrically connected to the power supply part D1 when mounted on the apparatus main body 1. Power is supplied from the power supply unit D1 via C3.

Moreover, the detection part 40 which consists of the light emission part 41, the light-receiving part 42, etc. which detect the reaction state of the test substance in the microchip 3, etc. is provided.
(Pump cartridge)
Next, details of the pump cartridge 2 will be described.

  The pump cartridge 2 includes a driving liquid tank 5 that contains the driving liquid, a tank mounting base 6 on which the driving liquid tank 5 is placed, and a joint part that is connected to the driving liquid tank 5 and sends the driving liquid to a subsequent process. 7. In addition, an electromagnetic valve 8 for controlling the supplied liquid, an extendable intermediate bag 9 for temporarily storing the supplied liquid, a filter unit 10 for removing impurities in the liquid, and a liquid drive for supplying driving liquid There is a pump 11 (referred to as micropump 11), and an intermediate flow path member 12 for sending drive liquid to the microchip 3. Furthermore, the base substrate 13 to which the micropump 11 is attached and the relay substrate 14 that supplies electricity supplied from the connector C3 to each part of the pump cartridge 2 are mainly configured. In the pump cartridge 2, the driving liquid is filled in advance from the driving liquid tank 5 to the intermediate flow path member 12 via the micropump 11, and replacement is performed in this state. .

  In the present embodiment, the driving liquid tank 5 is arranged above the pump cartridge 2 so that the driving liquid fed from the driving liquid tank 5 flows out by the action of gravity. Then, the drive fluid tank 5 can be replaced by opening the lid F and attaching / detaching it in the direction of arrow B. Further, the driving liquid tank 5 is placed inclined as shown in FIG. 1, so that the liquid outlet of the driving liquid tank 5 is at the lowest position.

In order to make the drive fluid tank 5 detachable, in the present embodiment, a female joint is provided on the drive fluid tank 5 side and a male joint is provided on the tank mounting base 6 side. The pair of male and female joints uses a joint that is configured such that the driving fluid does not leak when being removed. Further, if the viscosity of the driving liquid is in the range of 1 to 10 mPa · s (when the ambient temperature is 25 ° C.), an elastic member such as rubber is provided at the liquid outlet on the driving liquid tank 5 side, and the tank mounting base 6 side For example, a thin needle such as an injection needle may be provided so as to be detachable. (Reference Patent Document JP 2005-11187 A)
The electromagnetic valve 8 is disposed at a position lower than the driving liquid tank 5 and higher than the micro pump 11 in the middle of the flow path connecting the driving liquid tank 5 and the micro pump 11. In addition, a liquid amount detection sensor S1 for detecting the liquid amount is provided in the vicinity of the extendable intermediate bag 9, and detects the position where the driving liquid is supplied to the intermediate bag 9 and the bag is inflated. The electromagnetic valve 8 performs ON / OFF control of the passing amount of the driving liquid fed from the tube by opening and closing the valve by the ON / OFF signal of the liquid amount detection sensor S1.

  Further, the difference Δh = (h1−h2) between the water level position h1 in the intermediate bag 9 and the position h2 of the driving liquid inlet of the microchip 3 is called hydrostatic pressure, and the mounting position of the intermediate bag 9 is set up and down. The driving liquid flowing into the microchip 3 is controlled by moving.

  In order to detect the remaining amount of the driving liquid in the driving liquid tank 5, a liquid remaining amount detecting sensor S2 is provided on the tank mounting base 6. The liquid remaining amount detection sensor S2 uses a load cell that transmits weight as signal information. The signal information from the load cell is once input to the control unit of the apparatus main body 1 and, depending on the signal, the remaining amount of liquid is displayed on the display unit of the apparatus main body 1 or a warning buzzer is sounded. The user (person in charge) is informed of the remaining amount of the driving fluid inside.

  The driving liquid tank 5 has a gas barrier formed by, for example, a polyethylene sheet bag or the like whose outer surface is subjected to aluminum vapor deposition or the like, but the other path through which the driving liquid flows is not a gas barrier. For this reason, if oxygen or other gas passes through the wall surface of the path and is left unused for a long time, the dissolved gas concentration will increase.

  Next, the micropump 11 will be described.

  The micropump 11 includes a pump chamber 52, a piezoelectric element 51 that changes the volume of the pump chamber 52, a first throttle channel 53 positioned on the intermediate channel member 12 side of the pump chamber 52, and a filter unit 10 side of the pump chamber 52. The second throttle channel 54 and the like are positioned, and are placed flat in the pump cartridge. The first throttle channel 53 and the second throttle channel 54 are narrow and narrow channels, and the first throttle channel 53 is longer than the second throttle channel 54.

  When the driving liquid is fed in the forward direction (the direction toward the intermediate flow path member 12), first, the piezoelectric element 51 is driven so as to rapidly reduce the volume of the pump chamber 52. Then, a turbulent flow is generated in the second throttle channel 54 that is a short throttle channel, and the channel resistance in the second throttle channel 54 is relatively larger than that of the first throttle channel 53 that is a throttle channel. growing. As a result, the driving liquid 11 in the pump chamber 52 is predominantly pushed toward the first throttle channel 53 and fed. Next, the piezoelectric element 51 is driven so that the volume of the pump chamber 52 is gradually increased. Then, the driving fluid flows from the first throttle channel 53 and the second throttle channel 54 as the volume in the pump chamber 52 increases. At this time, since the length of the second throttle channel 54 is shorter than that of the first throttle channel 53, the channel resistance of the second throttle channel 54 is smaller than that of the first throttle channel 53. Thus, the driving liquid flows into the pump chamber 52 predominantly from the second throttle channel 54. When the piezoelectric element 51 repeats the above operation, the driving liquid is fed in the forward direction.

  On the other hand, when the driving liquid is fed in the reverse direction (the direction toward the filter unit 10), first, the piezoelectric element 51 is driven so that the volume of the pump chamber 52 is gradually reduced. Then, since the length of the second throttle channel 54 is shorter than that of the first throttle channel 53, the channel resistance of the second throttle channel 54 is smaller than that of the first throttle channel 53. . As a result, the driving liquid in the pump chamber 52 is predominantly pushed out toward the second throttle channel 54 and fed. Next, the piezoelectric element 51 is driven so as to rapidly increase the volume of the pump chamber 52. Then, the driving fluid flows from the first throttle channel 53 and the second throttle channel 54 as the volume in the pump chamber 52 increases. At this time, turbulent flow is generated in the second throttle channel 54, which is a short throttle channel, and the channel resistance in the second throttle channel 54 is relatively larger than that of the first throttle channel 53, which is a throttle channel. Become bigger. As a result, the driving fluid flows into the pump chamber 52 predominantly from the first throttle channel 53. When the piezoelectric element 51 repeats the above operation, the driving liquid is fed in the reverse direction.

  In addition, the tube T1 connected upstream of the micropump, which connects the intermediate bag 9 and the filter unit 10, detects the concentration of dissolved gas (for example, oxygen) in the driving liquid flowing in the tube T1. A gas detection unit is arranged.

  FIG. 2 is an enlarged schematic diagram of a dissolved gas detection unit that detects the concentration of dissolved oxygen. An example of measuring the oxygen concentration using the optical oxygen sensor shown in FIGS. 2 and 1 will be described.

  In the driving liquid KE in the tube T1, a reflection type sensor chip ST that causes quenching (quenching phenomenon) due to oxygen molecules is disposed (see FIG. 2). On the other hand, an end portion P of the optical fiber GF that introduces excitation light toward the sensor chip ST and introduces reflected light from the sensor chip ST is disposed outside the tube T1 at a position facing the sensor chip ST. ing. The excitation light irradiated to the sensor chip ST propagates from the control box CB through the optical fiber GF and is irradiated from the end P. The reflected light from the sensor chip ST enters from the end P, propagates through the optical fiber GF, and the amount of light is measured by the control box CB. Based on this reflected light amount, the oxygen concentration in the driving liquid KE in the tube T1 is measured.

  It is preferable that the optical fiber GF and its end P can be inserted into and removed from a predetermined position in the pump cartridge 2 or are arranged outside the region of the pump cartridge 2. In this way, even if the pump cartridge 2 is replaced, only the sensor chip ST is discarded, and the control box CB and the optical fiber GF, which are the main body of the optical oxygen sensor, can be used after replacement. , Cost increase can be suppressed. For example, an oxygen sensor manufactured by PreSens can be used as the sensor chip.

  Further, a drive liquid discharge tube T2 is connected in front of the filter unit 10, and a drive liquid discharge electromagnetic valve DB and a suction pump (not shown) are provided to send the drive liquid to the micropump 11. Without being discharged, the driving liquid in the tube T1 can be replaced with a new liquid.

  A connector CN1 capable of connecting and disconnecting the tube is preferably disposed between the tube T2 and the drive fluid discharge electromagnetic valve DB. By arranging the connector CN1, even if the pump cartridge 2 is replaced, only the tube T2 on the pump cartridge 2 side is discarded, and an increase in cost can be suppressed.

  FIG. 3 is a functional block diagram of the microchip inspection apparatus in the present embodiment.

  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 microchip inspection apparatus 1 is centrally controlled according to the program.

  The operation unit 62 performs various settings of the inspection apparatus, and the display unit 63 displays inspection results, inspection statuses, warnings, and the like. The chip detection unit 61 detects whether or not a microchip is mounted. A detection unit 40 including a light emitting unit and a light receiving unit detects a reaction state between a sample and a reagent in the microchip. The dissolved gas concentration detection unit 64 corresponds to, for example, an optical oxygen sensor that detects the concentration of dissolved oxygen. As shown in FIG. 2, the suction pump KP and the electromagnetic valve DB are for discharging the driving liquid to the outside without sending it to the micropump 11.

  An example of the operation of the microchip inspection apparatus 1 configured as described above will be described.

  FIG. 4 is a flowchart showing an example of the operation of the microchip inspection apparatus according to the present embodiment. Hereinafter, it demonstrates according to a flow. The following flow shows a case where an optical oxygen sensor that detects the concentration of dissolved oxygen is used in the dissolved gas concentration detection unit.

  In the flow shown in the figure, firstly, it waits for a microchip to be inserted (step S101). The insertion detection of the microchip is performed by the chip detection unit 61 (see FIG. 3). When the microchip is inserted (step S101; Yes), the above-described optical oxygen sensor detects and measures the dissolved oxygen concentration of the driving liquid in the tube arranged in the flow path upstream of the micropump (step). S103). Next, it is determined whether or not the detected dissolved oxygen concentration is within a predetermined value (step S104).

  The predetermined value is set to, for example, a dissolved oxygen concentration of 4 ppm in the driving liquid. When oxygen of this concentration or more is dissolved in the driving liquid, bubbles tend to be generated when the driving liquid passes through the micro pump on the downstream side. Then, when bubbles are generated, there is a problem that the liquid feeding performance of the micropump is deteriorated as described above.

  On the other hand, when the detected dissolved oxygen concentration is within a predetermined value (step S104; Yes), the micropump is driven (step S120), the microchip reaction is detected (step S121), and the process is terminated.

  On the other hand, if the detected dissolved oxygen concentration exceeds the predetermined value (step S104; No), the drive liquid discharge electromagnetic valve (DB in FIG. 1) is opened (step S106), and the suction pump is driven (step S107). Then, the driving liquid in the tube disposed in the flow path upstream of the micropump is discharged. As a result, a new driving liquid is filled in the tube from the driving liquid tank, and the driving liquid is replaced. In this replacement of the driving liquid, the driving liquid in the path between the micropump 11 and the intermediate bag 9 or the driving liquid in the path between the micropump 11 and the driving liquid tank 5 is replaced.

  When it is determined in step S108 that the replacement of the driving fluid has been completed (step S108; Yes), the driving fluid discharge solenoid valve is closed (step S109), the suction pump is stopped (step S110), and the processing returns to step S103.

  Next, the dissolved oxygen concentration of the driving liquid in the tube disposed in the flow path upstream of the micropump is detected and measured by the optical oxygen sensor in the same manner as described above (step S103), and the detected dissolved oxygen concentration is detected. Based on the determination of the value (step S104), it is determined whether to move to step S105 or to step S120, and the above operation is performed.

  In this way, the dissolved gas concentration detection unit is arranged in the flow path upstream of the micropump so that the dissolved gas concentration of the driving liquid is detected and the driving liquid is replaced when the detected value exceeds a predetermined value. Thus, it is possible to eliminate the problem of liquid feeding caused by bubbles and obtain a microchip inspection apparatus having a simple structure and a highly reliable liquid feeding system.

  FIG. 5 is a flowchart showing another example of the operation of the microchip inspection apparatus according to the present embodiment. Hereinafter, it demonstrates according to a flow. Steps similar to those in the flow shown in FIG.

  In the flow shown in the figure, firstly, it waits for a microchip to be inserted (step S101). The insertion detection of the microchip is performed by the chip detection unit 61 (see FIG. 3). When the microchip is inserted (step S101; Yes), the above-described optical oxygen sensor detects and measures the dissolved oxygen concentration of the driving liquid in the tube arranged in the flow path upstream of the micropump (step). S103). Next, it is determined whether or not the detected dissolved oxygen concentration is within a predetermined value (step S104).

  If the detected dissolved oxygen concentration is within the predetermined value (step S104; Yes), the micropump is driven (step S120), the microchip reaction is detected (step S121), and the process is terminated.

  On the other hand, if the detected dissolved oxygen concentration exceeds the predetermined value (step S104; No), a warning is displayed on the display unit of the inspection device (step S115), and the process ends without performing the microchip reaction detection. . This warning may be accompanied by a sound such as a buzzer.

  In this way, the dissolved gas concentration detection unit is arranged in the flow path upstream of the micropump so that the dissolved gas concentration of the driving liquid is detected, and a warning is issued when the detected value exceeds a predetermined value. Thus, it is possible to eliminate the problem of liquid feeding caused by bubbles and obtain a microchip inspection apparatus having a simple structure and a highly reliable liquid feeding system.

  FIG. 6 is a flowchart showing another example of the operation of the microchip inspection apparatus according to the present embodiment. Hereinafter, it demonstrates according to a flow. Steps similar to those in the flow shown in FIG.

  In the flow shown in the figure, firstly, it waits for a microchip to be inserted (step S101). The insertion detection of the microchip is performed by the chip detection unit 61 (see FIG. 3). When the microchip is inserted (step S101; Yes), the above-described optical oxygen sensor detects and measures the dissolved oxygen concentration of the driving liquid in the tube arranged in the flow path upstream of the micropump (step). S103). Next, it is determined whether or not the detected dissolved oxygen concentration is within a predetermined value (step S104).

  If the detected dissolved oxygen concentration is within the predetermined value (step S104; Yes), the micropump is driven (step S120), the microchip reaction is detected (step S121), and the process is terminated.

  On the other hand, when the detected dissolved oxygen concentration exceeds the predetermined value (step S104; No), the reaction is terminated without performing the microchip reaction detection.

  In this way, the dissolved gas concentration detection unit is arranged in the flow path upstream of the micro pump, detects the dissolved gas concentration of the driving liquid, and stops the micro pump when the detected value exceeds a predetermined value. By doing so, it is possible to eliminate the problem of liquid feeding caused by bubbles, and to obtain a microchip inspection apparatus having a simple structure and a highly reliable liquid feeding system.

  In the above-described embodiment, the dissolved gas concentration detection is described using the optical oxygen sensor. However, the present invention is not limited to this, and an oxygen meter is directly inserted into the flow path for detection. It may be configured.

It is sectional drawing which shows the microchip test | inspection apparatus which concerns on this Embodiment. It is an expansion schematic diagram of the dissolved gas detection part which detects the density | concentration of dissolved oxygen. It is a functional block diagram of the microchip test | inspection apparatus in this Embodiment. It is a flowchart which shows an example of operation | movement of the microchip test | inspection apparatus which concerns on this Embodiment. It is a flowchart which shows another example of operation | movement of the microchip test | inspection apparatus which concerns on this Embodiment. It is a flowchart which shows another example of operation | movement of the microchip test | inspection apparatus which concerns on this Embodiment.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Microchip test | inspection apparatus 2 Pump cartridge 3 Microchip 4 Microchip insertion port 5 Drive liquid tank 6 Tank mounting stand 7 Joint part 8 Electromagnetic valve 9 Intermediate bag 10 Filter part 11 Liquid drive pump 12 Intermediate flow path member 13 Base base material 14 Relay board C1, C2 connection part C3 connector part D1 power supply part T1 tube T2 tube (for driving liquid discharge)
ST Sensor chip GF Optical fiber CB Control box DB Solenoid valve (for driving fluid discharge)

Claims (8)

A microchip housing part that houses a microchip in which a channel for mixing, reacting, and detecting a sample is formed, and a detection provided corresponding to the detected part of the microchip housed in the microchip housing part A micropump for injecting the driving liquid into the flow path of the microchip, and a driving liquid tank for storing the driving liquid supplied to the micropump,
A microchip inspection apparatus, wherein a dissolved gas concentration detector is disposed upstream of the micropump. The microchip inspection apparatus according to claim 1, wherein the dissolved gas detected by the dissolved gas concentration detection unit is oxygen. An intermediate bag between the micropump and the driving liquid tank, and when the dissolved gas concentration by the dissolved gas concentration detection unit exceeds a predetermined value, the driving liquid between the micropump and the intermediate bag; The microchip inspection apparatus according to claim 1, wherein the driving liquid between the micropump and the driving liquid tank is replaced. The microchip inspection apparatus according to claim 1 or 2, wherein a warning is issued when the concentration of dissolved gas by the dissolved gas concentration detection unit exceeds a predetermined value. 3. The microchip inspection apparatus according to claim 1, wherein the micropump is not driven when the concentration of dissolved gas by the dissolved gas concentration detection unit exceeds a predetermined value. 6. The microchip inspection apparatus according to claim 1, wherein an optical oxygen sensor using quenching by oxygen molecules is used for the dissolved gas concentration detection unit. The microchip inspection apparatus according to claim 6, wherein a sensor chip of the optical oxygen sensor is disposed in a flow path between the micropump and the driving liquid tank. The drive fluid tank to the micro pump can be replaced as an integral cartridge, and the main body of the optical oxygen sensor is disposed outside the cartridge or inserted into and removed from a predetermined position in the cartridge. 8. The microchip inspection apparatus according to claim 7, wherein the microchip inspection apparatus is made possible.

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