JP2006266925A - Micro-total analyzing system - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a micro-total analyzing system capable of certainly taking a drive liquid mixed with no air bubbles in an inspection chip when the drive liquid is taken in the inspection chip by closely bringing a micropump unit into contact with the inspection chip to accurately perform desired inspection. <P>SOLUTION: The micro-total analyzing system is constituted so that a defoaming mechanism for defoaming the drive liquid sent to the inspection chip is provided to the microchip and the drive liquid not mixed with air bubbles is certainly taken in the inspection chip to accurately perform desired inspection. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  In the present invention, a test chip on which a series of micro flow paths for performing mixing, reaction, and detection of a biological substance and a reagent contained in a specimen is formed is attached to a system body, and the test is performed by a micro pump unit. The present invention relates to a micro total analysis system that automatically performs mixing, reaction, and detection of a reaction between a biological substance and a reagent in a test chip while feeding a liquid in a microchannel of the chip.

  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. Systems integrated on a chip have been developed.

  This is also called μ-TAS (Micro Total Analysis System), bioreactor, Lab-on-chips, biochip, and is used in the medical examination / diagnosis field, environmental measurement field, and agricultural production field. Application is expected.

  In particular, as seen in genetic testing, when a complicated process, skilled technique, and operation of equipment are required, the microreactor as an automated, high-speed and simplified micro-analysis system is cost-effective. The effect of enabling analysis not only in the required sample amount and the required time but also in any time and place is enormous.

  In the field where various tests such as clinical tests are performed in this way, quantitativeness, accuracy of analysis, and the like are regarded as important in measurement using a chip-type microreactor that produces results quickly regardless of location.

In addition, since the microreactor has severe restrictions in terms of its size and form, it is a problem to establish a liquid delivery system having a simple configuration and high reliability.
The present inventors have already proposed a micro total analysis system suitable for gene amplification reaction and its detection (Patent Documents 1 to 6).

The present inventors have already proposed a micropump system suitable for a microfluidic control element having high accuracy and excellent reliability (Patent Documents 7 and 8).
Japanese Patent Application No. 2004-138959 Japanese Patent Application No. 2004-169912 Japanese Patent Application No. 2004-310744 Japanese Patent Application No. 2004-31313 Japanese Patent Application No. 2004-31314 Japanese Patent Application No. 2004-31315 JP 2001-322099 A JP 2004-108285 A

  In the micro comprehensive analysis system as described above, a liquid such as a reagent in a fine flow path of a test chip is fed by a micropump by taking a driving liquid into the test chip.

  Specifically, a micro pump unit in which a plurality of piezo pumps using a piezo element having the configuration disclosed in Patent Documents 7 and 8 are provided on a chip and a test chip, for example, the flow passage openings of each other match. As described above, the chip-side surface of the micropump unit and the chip surface of the inspection chip are brought into close contact with each other so that the flow path on the pump side and the flow path on the inspection chip side are communicated.

Further, the driving liquid can be fed to the inspection chip by the action of the actuator connected to the pump.
However, such a pump used as a micro pump may not be able to accurately deliver a liquid such as a driving liquid if bubbles are mixed in the pump.

  In particular, a piezo pump controls the liquid feeding direction and liquid feeding speed by changing the pump drive voltage and frequency. Therefore, if bubbles are mixed in the liquid, the bubbles are damped in the flow path. The vibration due to the frequency will not be transmitted to the liquid without fail.

Such a problem is an important issue that should be avoided especially in measurement in a microreactor where quantitativeness, an analysis system, etc. are regarded as important.
In view of such a current situation, the present invention makes sure that the micropump unit and the inspection chip are brought into close contact with each other, and when the driving liquid is taken into the inspection chip, the driving liquid not mixed with bubbles is surely taken into the inspection chip. It is an object of the present invention to provide a micro total analysis system capable of accurately performing inspections.

The present invention was invented in order to achieve the problems and objects in the prior art as described above, and the micro total analysis system of the present invention includes:
A biological substance to be measured contained in a specimen or a treatment liquid obtained by treating the specimen in a flow path;
The reagent stored in the reagent storage unit,
Liquid is sent to the flow path that constitutes the reaction site and merged,
After reacting these, the obtained reaction product or its treated substance
A series of fine flow channels are provided to measure by sending liquid to the flow channel constituting the detection site,
A test chip provided with a pump connection part having a channel opening for communicating with the micropump;
A system main body,
The system main body is
A base body,
Multiple micropumps,
A chip connection portion having a flow path opening for communicating with the inspection chip, and
A micropump unit disposed in the base body,
After mounting the test chip in the base body in a state where the pump connection part of the test chip and the chip connection part of the micro pump unit are in close contact with each other, the reaction between the biological substance and the reagent in the test chip and its A micro total analysis system that automatically performs detection,
The micropump unit is
A defoaming mechanism for defoaming the driving liquid fed to the inspection chip is provided.

By configuring in this way, it is possible to reliably remove bubbles in the driving liquid and suppress the generation of bubbles.
Furthermore, since no bubbles are mixed in the driving liquid, the micropump is surely activated, and the driving liquid can be accurately fed into the flow path of the inspection chip to perform a desired inspection accurately.

Moreover, the micro comprehensive analysis system of the present invention includes:
The defoaming mechanism is
It is an ultrasonic defoaming device.

  In this way, if the defoaming mechanism is an ultrasonic defoaming device, bubbles in the liquid such as the driving liquid can be reliably removed by ultrasonic waves, so that the micropump can be started up reliably and the driving liquid can be accurately supplied. It can be sent to the flow path of the inspection chip.

Moreover, the micro comprehensive analysis system of the present invention includes:
The defoaming mechanism is
It is a vacuum degassing apparatus.

  In this way, if the defoaming mechanism is a vacuum degassing mechanism, bubbles in the liquid such as the driving liquid can be surely removed by reducing the pressure, so that the micropump can be started reliably and the driving liquid can be accurately inspected. The desired inspection can be performed accurately.

Moreover, the micro comprehensive analysis system of the present invention includes:
The system main body is
After reacting the biological material and the reagent in the fine flow path of the inspection chip,
A detection device that optically performs detection in the flow path that constitutes the detection site;
A pump control device for controlling liquid feeding by the micropump;
And a temperature control device for controlling the temperature at a predetermined part of the inspection chip.

By configuring in this way, it is possible to reliably perform a desired test on the specimen within the system main body.
Moreover, the micro comprehensive analysis system of the present invention includes:
The micropump is
A first flow path in which the flow path resistance changes according to the differential pressure;
A second flow path whose rate of change in flow path resistance with respect to a change in differential pressure is smaller than the first flow path;
A pressurization chamber connected to the first flow path and the second flow path;
An actuator for changing the internal pressure of the pressurizing chamber;
It is characterized by being a micro pump provided with.

With this configuration, the driving liquid can be reliably taken into the inspection chip.
For this reason, the desired test | inspection with respect to a test substance can be reliably performed within a system main body.

  According to the present invention, when the micropump unit and the inspection chip are brought into close contact with each other and the driving liquid is taken into the inspection chip, the driving liquid without bubbles is reliably taken into the inspection chip to accurately perform the desired inspection. A micro total analysis system that can be performed can be provided.

Hereinafter, embodiments (examples) of the present invention will be described in more detail with reference to the drawings.
FIG. 1 is a schematic perspective view showing an embodiment of the micro total analysis system of the present invention, and FIG. 2 is a schematic diagram of the inside of the base body showing a state in which a test chip is mounted on the base body of the micro total analysis system of FIG. 3 is a schematic perspective view showing a test chip of the micro total analysis system of FIG. 1, and FIG. 4 is a view showing a state where the test chip is mounted on the base body of the micro total analysis system of another embodiment of the present invention. It is the schematic inside the shown base main body.

The micro integrated analysis system 10 shown in FIG. 1 includes a system main body in which a micro pump unit 26, a pump control device 28, a temperature control device 38, a detection device 44 and the like are housed in a base main body 12, and a test chip 50. It is configured.
<Inspection chip>
As schematically shown in FIG. 3, the test chip 50 includes a sample storage unit 52 that stores the sample 54, a reagent storage unit 56 in which a reagent 58 is previously sealed, and the sample storage unit 52 and the reagent storage unit 56. A flow path 60 is provided to continue to the downstream side.

In the flow channel 60 of the inspection chip 50, a valve portion or the like is disposed at an appropriate position, and for example, control such as quantification of a liquid feeding amount and mixing of each liquid is performed.
And in the middle of the flow path 60 of the test | inspection chip 50, the pump connection part 64 for connecting with the micropump shown in FIG. 2 is provided.

Such an inspection chip 50 is a single chip produced by appropriately combining one or more members such as plastic resin, glass, silicon, and ceramics.
Preferably, the fine flow path and the casing of the inspection chip 50 are formed of a plastic resin that is easy to process, inexpensive, and easy to incinerate.

For example, polystyrene resin is excellent in moldability, has a strong tendency to adsorb streptavidin and the like, and can easily form a detection site on a fine channel.
The fine channel is formed to have a width and a depth of, for example, about 10 μm to several hundred μm.

  In addition, in order to optically detect a fluorescent substance or a product of a color reaction, a detection portion that covers at least a detection portion of the fine channel in the surface of the test chip 50 is a transparent member, preferably transparent. It is necessary to be made of plastic.

Typically, each reagent 58 accommodated in a plurality of reagent accommodating portions 56 located at the most upstream part is mixed in the downstream flow path 60, and the mixed reagent is fed to the downstream analysis flow path.
In the analysis flow path, the specimen 54 and the mixed reagent are merged and mixed from the Y-shaped flow path or the like, the reaction is started by temperature rise or the like, and the reaction is detected at a detection site provided in the flow path.

The micro integrated analysis system 10 of the present invention can be suitably used particularly for testing genes or nucleic acids.
In this case, the fine flow path of the test chip 50 is configured to be suitable for PCR amplification, but it can be said that the basic flow path configuration is substantially the same for biological materials other than genetic testing.

Usually, the specimen pretreatment unit, reagents, and probes may be changed. In this case, the arrangement and number of liquid feeding elements will change.
A person skilled in the art can easily select the type of analysis by, for example, mounting reagents necessary for an immunoassay method, etc. on the test chip 50, and making modifications including slight changes in flow path elements and specifications. Can be changed.

Biological substances other than genes mentioned here refer to various metabolites, hormones, proteins (including enzymes and antigens), and the like.
In a preferred embodiment of the test chip 50, a sample storage portion into which a sample or an analyte substance (for example, DNA) extracted from the sample is injected in one chip,
A sample pretreatment unit for preprocessing the sample;
A reagent container for storing reagents used for probe binding reaction, detection reaction (including gene amplification reaction or antigen-antibody reaction);
A positive control accommodating part for accommodating a positive control;
A negative control accommodating portion for accommodating a negative control;
A probe accommodating portion that accommodates a probe (for example, a probe that hybridizes to a gene to be detected amplified by a gene amplification reaction);
A fine flow path communicating with each of these accommodating portions,
A pump connection portion 64 that can be connected to each of the accommodating portions and a separate micropump for feeding the liquid in the flow path is provided.

  A micropump is connected to the test chip 50 via a pump connection unit 64, and the sample 54 stored in the sample storage unit 52 or a biological material extracted from the sample 54 (for example, DNA or other biological material), The reagent 58 housed in the reagent container 56 is fed to the flow channel 60 and mixed and reacted at a reaction site of the fine channel, for example, a site of gene amplification reaction (antigen antibody reaction in the case of protein). Thereafter, the processing liquid 62 processed with the reaction liquid and the probe accommodated in the probe accommodating part are sent to the detection part in the downstream channel, and mixed in the channel and combined with the probe (or Hybridization), and detection of a biological substance is performed based on the reaction product.

  In addition, the above reaction and detection are performed in the same manner for the positive control housed in the positive control housing section and the negative control housed in the negative control.

The sample storage unit 52 in the test chip 50 communicates with the sample injection unit, and temporarily stores the sample 54 and supplies the sample to the mixing unit.
The specimen injection section for injecting the specimen 54 from the upper surface of the specimen storage section 52 is formed with a stopper made of an elastic material such as a rubber-like material in order to prevent leakage, infection and contamination to the outside and to ensure sealing performance. Or covered with a resin such as polydimethylsiloxane (PDMS) or a reinforcing film.

For example, a specimen in a syringe is injected with a needle that has been pierced with a stopper made of the rubber material or a needle that has passed through a pore with a lid.
In the former case, it is preferable that the needle hole is immediately closed when the needle is pulled out.

Alternatively, another specimen injection mechanism may be installed.
The sample 54 injected into the sample storage unit 52 is mixed with, for example, the sample 54 and the treatment liquid 62 in a sample pretreatment unit provided in advance in the flow channel 60 before mixing with the reagent 58 as necessary. It is preprocessed by doing.

Preferred sample pretreatment includes separation or concentration of an analyte (analyte), deproteinization, and the like.
Therefore, the specimen pretreatment unit may include a separation filter, an adsorption resin, beads, and the like.

A predetermined amount of necessary reagents are sealed in the reagent storage portion 56 of the test chip 50 in advance.
Therefore, it is not necessary to fill the necessary amount of the reagent 58 each time it is used, and it can be used immediately.

When analyzing a biological substance in the specimen 54, reagents necessary for the measurement are generally known.
For example, when analyzing an antigen present in the specimen 54, a reagent containing an antibody against it, preferably a monoclonal antibody, is used.

The antibody is preferably labeled with biotin and FITC.
Reagents for gene testing may include various reagents used for gene amplification, probes used for detection, and coloring reagent, as well as pretreatment reagents used for the sample pretreatment if necessary.

  By supplying the driving liquid 31 from the micropump, the sample liquid and the reagent liquid are pushed out from each container and merged to start reactions necessary for analysis such as gene amplification reaction, analyte trap or antigen-antibody reaction. Is done.

  The mixing of the reagent and the reagent and the mixing of the sample and the reagent may be performed at a desired ratio in a single mixing part, or a plurality of merging parts are provided by dividing one or both, and finally You may mix so that it may become a desired mixing ratio.

The mode of such a reactive site is not particularly limited, and various forms and modes are conceivable.
As an example, a micro flow channel in which each liquid is diffused and mixed is provided in advance of a joining portion (flow channel branching point) that joins two or more liquids containing reagents, and from the downstream end of the micro flow channel. The reaction is carried out in a liquid reservoir provided in advance and having a space wider than the fine channel.

As a DNA amplification method, a PCR amplification method that is actively used in various fields can be used.
Various conditions for carrying out the amplification technique have been examined in detail and described in various documents including improvements.

  In the PCR amplification method, it is necessary to manage the temperature by raising and lowering between three temperatures. However, a channel device that enables temperature control suitable for a microchip has already been proposed by the present inventors (Japanese Patent Application Laid-Open No. 2005-318867). 2004-108285).

This device system may be applied to the amplification channel of the chip of the present invention.
As a result, the heat cycle can be switched at high speed, and the micro flow path is a micro reaction cell with a small heat capacity. Therefore, DNA amplification can be performed in a much shorter time than the conventional method that is performed manually.

ICAN (Isothermal chimera) recently developed as an improvement of PCR
The primer initiated nucleic acid amplification) method has a feature that DNA amplification can be performed in a short time at an arbitrary constant temperature of 50 to 65 ° C. (Japanese Patent No. 3343929).

Therefore, the ICAN method is a suitable amplification technique because the inspection chip 50 of the present invention can be simply temperature-controlled.
By hand, the method, which takes one hour, ends with analysis in 10-20 minutes, preferably 15 minutes, in the bioreactor of the present invention.

A detection site for detecting an analyte, for example, an amplified gene, is provided downstream of the reaction site in the fine flow path of the test chip 50.
At least the detection part is made of a transparent material, preferably a transparent plastic, in order to enable optical measurement.

  Furthermore, biotin-affinity protein (avidin, streptavidin, extraavidin (R), preferably streptavidin) adsorbed to the detection site on the microchannel is biotin labeled on the probe substance, or a primer used for gene amplification reaction It specifically binds to biotin labeled at the 5 ′ end of the.

Thereby, the probe labeled with biotin or the amplified gene is trapped at the detection site.
A method for detecting the separated analyte or the amplified DNA of the target gene is not particularly limited, but as a preferred embodiment, it is basically performed in the following steps.

That is,
(1a) A fine channel downstream from these containing portions of a sample or DNA extracted from the sample, or cDNA synthesized by reverse transcription from RNA extracted from the sample or sample, and a primer modified with biotin at the 5 ′ position To liquid.

  The step of amplifying the gene in the microchannel of the reaction site, the amplification reaction solution containing the gene amplified in the microchannel and the denaturing solution are mixed, and the amplified gene is made into a single strand by denaturation treatment. This is hybridized with the probe DNA fluorescently labeled with FITC (fluorescein isothiocyanate).

Next, the solution is sent to the detection site in the microchannel to which the biotin affinity protein is adsorbed, and the amplified gene is trapped in the detection site in the microchannel. (The amplified gene may be trapped at the detection site and then hybridized with a fluorescently labeled probe DNA.)
(1b) A reagent containing an antibody, preferably a monoclonal antibody, specific to an analyte such as an antigen, metabolite or hormone present in the sample is mixed with the sample.

In that case, the antibody is labeled with biotin and FITC.
Therefore, the product obtained by the antigen-antibody reaction has biotin and FITC.
This is sent to a detection site in a microchannel to which a biotin affinity protein (preferably streptavidin) is adsorbed, and is immobilized on the detection site through the binding of biotin affinity protein and biotin.
(2) A colloidal gold solution whose surface has been modified with an anti-FITC antibody that specifically binds to FITC flows through the fine channel, and this hybridizes to the immobilized FITC of the analyte / antibody reaction product or to the gene. The gold colloid is adsorbed to the FITC-modified probe.
(3) Optically measure the concentration of colloidal gold in the fine channel.
<System itself>
As shown in FIG. 1, the base body 12 has a test chip inlet / outlet port 14 for taking the test chip 50 therein and a display unit for outputting a predetermined test result performed in the base body 12. 18 are provided.

After the inspection chip 50 is placed on the chip transport tray 22, the inspection chip 50 is taken into the base body 12 from the inspection chip entrance 14 and attached.
As shown in FIG. 2, various devices for controlling liquid feeding, reaction, detection and the like in the inspection chip 50 placed on the chip transport tray 22 are provided inside the base body 12. .

In the present embodiment, the micro pump unit 26 that is connected to the pump connection portion 64 of the test chip 50 and moves the specimen and the processing liquid to a predetermined location, the pump control device 28 that controls the liquid feeding of the micro pump unit 26, An ultrasonic defoaming device 20 for removing bubbles in the driving liquid 31 in the driving liquid tank 30 is provided.

Furthermore, a temperature control device 38 including a Peltier element 34 and a heater 36 which are in contact with the inspection chip 50 and controls the temperature of the reagent and the like, particularly the temperature in the reaction part flow path, is provided.
In addition, a detection device 44 is provided that includes an LED 40 that emits light and a photodiode 42 that receives the transmitted light in order to detect a substance to be detected present in the detection portion flow path of the inspection chip 50.

  In the system main body of the micro comprehensive analysis system 10, a micro pump unit 26, a pump control device 28 that controls the micro pump, a temperature control device 38 that controls temperature, a detection device 44, and the like are integrated with the base main body 12.

  When a sample liquid is injected into the sample container 52 of the test chip 50 in which the reagent 58 is sealed in advance and the test chip 50 is attached to the system main body, a mechanical connection for operating the micropump for liquid delivery is made. The

Therefore, when the inspection chip 50 is attached to the system body, the flow path 60 of the inspection chip 50 is in an activated state.
Once the analysis is started, the flow of analytes and reagents, gene amplification based on mixing, reactions such as analyte-probe binding, detection of reactants and optical measurements are automatically performed as a series of sequential steps. The measurement data is stored in a file together with necessary conditions and recorded items, and the measurement of the biological material is automatically performed.

A control system related to each control of liquid feeding, temperature and reaction, a unit responsible for optical detection, data collection and processing constitutes a system main body together with a micropump and an optical device.
This system main body is commonly used for each specimen sample by mounting the test chip 50 on the system main body.

  Reactions such as gene amplification and their detection are performed in software installed in the system body as a program along with micropump and temperature control, optical detection data processing, as preset conditions for liquid delivery sequence, volume, timing, etc. It has been incorporated.

  The detection device 44 that detects the reaction in the fine flow path of the inspection chip 50 irradiates the detection site on the analysis flow path for each inspection item with measurement light from, for example, the LED 40, and the like, and a photodiode 42, a photomultiplier tube, and the like. Transmitted light or reflected light is detected by the optical detection means.

  In the micro integrated analysis system 10 of the present invention, all components are miniaturized and are in a form that is convenient to carry. Therefore, the micro integrated analysis system 10 is excellent in workability and operability without being restricted by the place and time of use.

Since the measurement can be made promptly regardless of the place and time, it can be used for emergency medical care or for personal use in home medical care.
Further, since the micro pump unit 26 used for liquid feeding is incorporated on the system main body side, the inspection chip 50 can be suitably used as a disposable type.

  For example, the micropump unit 26 corresponds to the number of parts to be pumped from the upstream side by the driving liquid 31 such as the specimen storage unit 52, the plurality of reagent storage units 56, the positive control storage unit, and the negative control storage unit. A plurality of micropumps are provided.

  By mounting the inspection chip 50 on the system main body, the micropump is connected to the inspection chip 50 via the pump connection portion 64 of the inspection chip 50, and functions as a micropump.

In other words, the micropump unit 26 is provided with a plurality of micropumps and a chip connection part 66 having a channel opening for communicating with the inspection chip 50.
On the other hand, the inspection chip 50 is provided with a pump connection part 64 having a flow path opening for communicating with the micropump. The pump connection part 64 of the inspection chip 50 and the chip connection part 66 of the micropump unit 26 are connected to each other. The micropump is communicated with the flow path 60 of the inspection chip 50 by closely contacting.

  Typically, the pump connection portion 64 in the inspection chip 50 includes a channel opening for communicating with the micropump and a contact surface around the channel opening, and the chip connection portion 66 in the micropump unit 26 is connected to the inspection chip 50. It consists of a channel opening for communication and a surrounding contact surface.

  These are connected by bringing the contact surface on the micropump unit 26 side into contact with the contact surface on the test chip 50 side in a state where the flow path opening on the test chip 50 side matches the flow path opening on the micropump unit 26 side. The

The close contact is performed by pressurizing the inspection chip 50 and the micro pump unit 26, for example.
For example, a sealing member made of a soft resin such as Teflon (registered trademark) is disposed in the chip connecting portion 66 or the pump connecting portion 64, and the sealing surface of the sealing member is used as the inspection chip 50 and the micro pump unit 26. It is good also as a contact surface.

Moreover, it is preferable to use a piezo pump as the micro pump.
In general, the piezo pump has a first flow path in which the flow path resistance changes in accordance with the differential pressure, a second flow path in which the change rate of the flow path resistance with respect to the change in the differential pressure is smaller than the first flow path, A pressurizing chamber connected to the first flow path and the second flow path, and an actuator for changing the internal pressure of the pressurizing chamber are provided. By driving the actuator, the forward direction and the reverse direction are provided. It is a pump that can send liquid.

Details thereof are described in Patent Documents 7 and 8.
According to the above piezo pump, the liquid feeding direction and the liquid feeding speed can be controlled by changing the driving voltage and frequency of the piezo pump.

  As an example, a piezo pump can be manufactured by forming the above pump shape by etching using a silicon substrate obtained by processing a silicon wafer into a predetermined shape by a known photolithography technique and overlaying another substrate thereon. .

The micropump unit 26 in which a large number of piezo pumps are provided on a single silicon substrate can be manufactured by photolithography.
For example, a port is formed on the substrate of the micropump unit 26 and communicates with the pump connection portion 64 of the inspection chip 50 through this port.

  The inspection chip 50 can be connected to the micropump unit 26 by vertically superimposing the substrate with the perforated port and the vicinity of the pump connection portion 64 of the inspection chip 50.

Further, the driving liquid tank 30 is connected to a port opposite to the port connected to the inspection chip 50 via a pump.
When there are a plurality of micropumps, a plurality of ports provided for each of these pumps may be connected to a common drive fluid tank 30.
<Defoaming mechanism>
In the embodiment of the micro total analysis system of the present invention, as shown in FIG. 2, the ultrasonic deaerator 20 is provided in the driving liquid tank 30 in order to remove bubbles contained in the driving liquid 31.

Such an ultrasonic defoaming device 20 is configured to remove bubbles in the driving liquid 31 by applying ultrasonic waves to the driving liquid 31 in the driving liquid tank 30.
The details of the method for removing bubbles in the liquid by the ultrasonic defoaming apparatus 20 have already been disclosed (for example, JP-A-07-80207).

  Since the ultrasonic defoaming device 20 is only added to the driving liquid tank 30, it can be accommodated in the system main body of the micro integrated analysis system 10 that is integrated in a small size, and the cost can be reduced.

  The driving liquid 31 from which bubbles have been removed by the ultrasonic deaerator 20 is reliably taken into the inspection chip 50 by the action of the piezo pump, and the specimen 54 and various reagents 58 in the inspection chip 50 are inspected. The liquid is sent to the flow path 60 downstream of the chip 50.

  Further, the liquid to be detected that has been fed is detected by a detection device 44 that includes an LED 40 that emits light and a photodiode 42 that receives the transmitted light in the detection unit flow path. Become.

Moreover, in the micro comprehensive analysis system 10 of the present invention, as shown in FIG. 4, a vacuum degassing apparatus 21 can be used as another defoaming mechanism.
Such a vacuum degassing device 21 is provided in the driving liquid tank 30 and removes bubbles mixed in the driving liquid 31 in the driving liquid tank 30 by reducing the pressure in the driving liquid tank 30 to a constant pressure. Configured to be able to.

  The vacuum degassing device 21 may be any known vacuum degassing device, but can be installed in a compact system main body, and the volume of the driving fluid tank 30 can be reduced. It is preferable to select the vacuum degassing device 21 having a function capable of quickly performing a desired function.

  Furthermore, when the pressure of the driving liquid tank 30 is constantly reduced, or when the pressure is reduced for a predetermined time by specifying a time, the driving liquid tank 30 may be appropriately selected according to the volume of the driving liquid tank 30 and the amount and type of the driving liquid 31.

As another defoaming mechanism, a method of defoaming dissolved gas in the driving liquid 31 by heating the driving liquid 31 at room temperature to, for example, 200 ° C. can be used.
In the micro comprehensive analysis system 10 of the present invention, these ultrasonic defoaming device 20, vacuum degassing device 21, and defoaming mechanism such as driving liquid heating can be used in appropriate combination, and these are provided side by side. The device can be switched and used accordingly.

Thus, by using the ultrasonic defoaming device 20, the vacuum defoaming device 21, and the driving liquid heating as the defoaming mechanism described above, bubbles mixed in the driving liquid 31 are removed, and only the driving liquid 31 is surely removed. The micropump of the micropump unit 26 can be sent into the inspection chip 50.

  In the above embodiment, an example of the micro total analysis system of the present invention has been shown. However, the present invention is not limited to the embodiment, and various modifications can be made without departing from the object of the present invention. It is.

FIG. 1 is a schematic perspective view showing an embodiment of a micro total analysis system of the present invention. FIG. 2 is a schematic diagram for explaining a state in which a test chip is mounted on the base body of the micro total analysis system of the present invention. FIG. 3 is a schematic perspective view for explaining a test chip of the micro total analysis system of the present invention. FIG. 4 is a schematic diagram illustrating a vacuum degassing apparatus of the micro total analysis system of the present invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 10 Micro comprehensive analysis system 12 Base main body 14 Test | inspection chip inlet / outlet 18 Display part 20 Ultrasonic defoaming apparatus 21 Depressurization defoaming apparatus 22 Test | inspection chip conveyance tray 26 Micro pump unit 28 Pump control apparatus 30 Drive liquid tank 31 Drive liquid 34 Peltier element 36 Heater 38 Temperature control device 40 LED
42 Photodiode 44 Detection Device 50 Test Chip 52 Sample Storage Portion 54 Sample 56 Reagent Storage Portion 58 Reagent 60 Flow Channel 62 Treatment Solution 64 Pump Connection Portion 66 Chip Connection Portion

Claims (5)

A biological substance to be measured contained in a specimen or a treatment liquid obtained by treating the specimen in a flow path;
The reagent stored in the reagent storage unit,
Liquid is sent to the flow path that constitutes the reaction site and merged,
After reacting these, the obtained reaction product or its treated substance
A series of fine flow channels are provided to measure by sending liquid to the flow channel constituting the detection site,
A test chip provided with a pump connection part having a channel opening for communicating with the micropump;
A system main body,
The system main body is
A base body,
Multiple micropumps,
A chip connection portion having a flow path opening for communicating with the inspection chip, and
A micropump unit disposed in the base body,
After mounting the test chip in the base body in a state where the pump connection part of the test chip and the chip connection part of the micro pump unit are in close contact with each other, the reaction between the biological substance and the reagent in the test chip and its A micro total analysis system that automatically performs detection,
The micropump unit is
A micro total analysis system comprising a defoaming mechanism for defoaming the driving liquid fed to the inspection chip. The defoaming mechanism is
2. The micro total analysis system according to claim 1, which is an ultrasonic defoaming apparatus. The defoaming mechanism is
2. The micro total analysis system according to claim 1, which is a vacuum degassing apparatus. The system main body is
After reacting the biological material and the reagent in the fine flow path of the inspection chip,
A detection device that optically performs detection in the flow path that constitutes the detection site;
A pump control device for controlling liquid feeding by the micropump;
The micro integrated analysis system according to claim 1, further comprising a temperature control device that controls a temperature at a predetermined portion of the inspection chip. The micropump is
A first flow path in which the flow path resistance changes according to the differential pressure;
A second flow path whose rate of change in flow path resistance with respect to a change in differential pressure is smaller than the first flow path;
A pressurization chamber connected to the first flow path and the second flow path;
An actuator for changing the internal pressure of the pressurizing chamber;
5. The micro total analysis system according to claim 1, wherein the micro total analysis system is a micro pump equipped with a micro pump.

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