JP2007327931A - Micro reactor and microreactor system, and liquid transmission method of the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a microreactor and a microreactor system for transmitting a liquid without remaining a gas within a reaction tank and efficiently implementing a preprocess for immobilizing a ligand, and to provide its liquid transmission method. <P>SOLUTION: The micro reactor is composed by laminating a first flow path substrate having a sensor and a second flow path substrate having a protrusion, and has a structure carrying the reactor tank whose volume is changed by moving the protrusion and discharging the residual gas remaining within the reactor tank. The preprocessing for immobilizing the ligand can be implemented by immersing the first flow path substrate. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a disposable microreactor and microreactor system for immobilizing a biochemical substance and measuring a chemical substance such as an enzyme, an antibody, a protein, a hormone, a sugar chain, or a compound that specifically adsorbs or binds to the biochemical substance, and its The present invention relates to a liquid feeding method.

Conventionally, there is a method of measuring the concentration of a specific component in a solution by changing the oscillation frequency of a piezoelectric vibrator. Since the crystal is often used for the piezoelectric vibrator, a conventional example using the crystal will be described below.
First, the quartz crystal is cut by a specific crystal orientation, and electrodes such as gold and silver are formed on both sides thereof by a vacuum deposition method or the like to produce a quartz crystal resonator. Then, a voltage is applied to the crystal resonator to oscillate at a frequency unique to the resonator. When a substance adheres to the surface of the electrode of the crystal resonator by adsorption or the like and the weight of the electrode changes, the oscillation frequency changes with the change in weight. Therefore, a change in weight can be detected by measuring a change in oscillation frequency. Examples of such a microbalance sensor include an immunosensor and a DNA sensor (see Non-Patent Document 1, for example). Conventionally, there is a sensor called a QCM (Quartz Crystal Microbalance) sensor as a weight change detection sensor using such a crystal.

  On the other hand, there is a method for detecting 2-MIB that uses antigen-antibody reaction to quantify 2-methylisoborneol (hereinafter abbreviated as 2-MIB), which is a musty odor substance in tap water (see Patent Document 1). ). This is also an example of a technique that applies a crystal resonator in a liquid phase system. In this detection method, a camphor-ovalbumin complex in which camphor having a structure similar to 2-MIB is bound to ovalbumin is immobilized on the electrode surface of a crystal resonator, and this is mixed with an antibody mixed with a known concentration. It is immersed in a measurement solution, and camphor and 2-MIB in the solution to be measured are reacted competitively with the antibody.

  Since the amount of anti-2-MIB antibody bound to the camphor-ovalbumin complex is detected as the amount of change in the oscillation frequency of the crystal resonator, it is contained in the solution by measuring the amount of change in the oscillation frequency. -The concentration of MIB can be measured. In this method, in order to oscillate the crystal resonator in a liquid phase system having conductivity, it is necessary to electrically insulate one of the electrodes. As shown in FIG. A quartz oscillator 1011 having gold electrodes on both sides is held between a holding substrate 1014 made of the above and a cover 1012 having a solution inflow passage 1016 and a discharge passage 1017 via a pair of silicone rubbers 1015. .

  The center part of the silicone rubber 1015 on the cover 1012 side is removed, and the cover 1012, the crystal oscillator 1011 and the silicone rubber 1015 constitute a flow-through cell, which becomes a reaction tank part for causing a reaction for detection. ing. The solution supplied from the inflow passage 1016 is circulated on the electrode of the crystal unit 1011 and comes into contact with the electrode, and then is discharged from the outflow passage 1017 side. Lead wires are connected to the upper and lower gold electrodes of the crystal resonator 1011, respectively. In addition, platinum black is formed on the surface of the electrode in contact with the solution of the crystal resonator 1011.

In addition, the flow-through cell type reaction vessel shown in the conventional example is built in a disposable flow path substrate, which is called a microreactor, and a pump or valve that controls liquid feeding to the microreactor is added. This is called a microreactor system.
JP-A-10-90270 Okahata Megumi, DNA sensor using crystal resonator as a device, protein nucleic acid enzyme (Kyoritsu Shuppan) Vol. 40, No2, 165-172, 1995

Since the reaction tank section as described above is made of acrylic resin or silicone rubber, the reaction tank section shows hydrophobicity, bubbles tend to remain in the reaction tank section, and the inflow continues to the reaction tank section. Even if the solution is simply poured from the passage, it is difficult to cause the solution to flow out into the outflow passage while filling the entire reaction tank section.
Further, for example, a flow path substrate may be manufactured using a hydrophilic material such as glass. However, if a disposable microreactor is to be realized, an inexpensive flow path substrate using a plastic resin is required. .
Furthermore, when a protein-protein interaction such as an antigen-antibody reaction is measured using a microreactor, a pretreatment for immobilizing a protein serving as a ligand on the sensor electrode must be performed in advance. Performing ligand pre-treatment with a sensor in the reaction vessel section in which the flow path is configured significantly reduces measurement efficiency and is wasteful. The reason is that since the reaction for pretreatment takes several to several tens of hours, it is inefficient and it is necessary to use the reactor system unnecessarily when the microreactor is continuously reacted for several tens of hours.

  Therefore, the present invention can carry out liquid feeding without gas remaining in the reaction tank part of the microreactor, and can efficiently carry out pretreatment for ligand fixation. The purpose is to realize the method.

  In order to achieve the above object, the microreactor of the present invention has a reaction tank unit for measuring the weight of a second chemical substance that specifically adsorbs or binds to the immobilized first chemical substance, In a microreactor formed in a flat plate shape, a hold substrate having a through-hole portion, and a sensor made of a piezoelectric vibrator provided on the hold substrate so as to cover one side of the hole portion of the hold substrate, And a second flow path substrate having a convex shape portion that fits into the hole portion from the other side of the hole portion, and the convex shape portion is inserted into the hole portion. The reaction vessel section is formed by superimposing the first flow path substrate and the second flow path substrate in this order while being fitted together.

  Moreover, the volume of the said reaction tank part is variable with the insertion amount of the said convex-shaped part of a said 2nd flow-path board | substrate.

  Further, a packing made of an elastic member sheet is provided between the first flow path substrate and the second flow path substrate, and the volume of the reaction vessel portion depends on the thickness of the packing, and the packing The thickness is formed such that the amount of insertion varies according to an external force applied to at least one of the first flow path substrate and the second flow path substrate. Is.

  Further, the flow path for sending the solution to the reaction vessel is formed so as to penetrate the first flow path substrate, the previous packing, and the second flow path substrate. .

  The microreactor system of the present invention drives the microreactor, pump means connected to the microreactor, liquid feed control means for controlling the liquid feed in the microreactor, and a sensor in the microreactor. And a moving means for moving the convex portion of the second flow path substrate inserted into the hole of the first flow path substrate to change the volume of the reaction vessel. It is characterized by this.

  Furthermore, in the liquid feeding method for feeding a solution using the microreactor of the present invention, the step of feeding the solution to the reaction tank part and the volume of the reaction tank part are changed so as to be reduced. Discharging the bubbles existing in the reaction tank, and after discharging the bubbles, changing the volume of the reaction tank to increase, thereby pouring the solution into the reaction tank. And a step.

  According to the present invention, the reaction tank part is formed by inserting the convex part of the second flow path substrate into the hole of the first flow path substrate having the reaction tank part. When the convex portion moves, the volume of the reaction vessel changes, and when the convex portion enters the entire reaction vessel, the reaction vessel volume becomes zero and at this point the gas and liquid in the reaction vessel Is discharged from the reaction vessel. Furthermore, when the solution is fed while moving the convex portion so as to increase the reaction tank part volume, the reaction tank part is filled with the liquid, and no gas remains in the reaction tank part. Since this operation prevents bubbles from remaining, a hydrophobic material such as an inexpensive plastic resin or silicone rubber can be used for the flow path substrate.

  In addition, since the first flow path substrate having the sensor can be separated from the second flow path substrate having the external connection port and the flow path, directly from the hole formed in the reaction tank portion of the first flow path substrate. A pretreatment agent can be applied to the sensor electrode. In other words, by immersing the first flow path substrate in a container containing a pretreatment agent, it is possible to efficiently perform ligand pretreatment on a number of first flow path substrates simultaneously in batch processing. it can.

Hereinafter, the present invention will be described in detail with reference to the drawings. In addition, this invention is not limited by the following embodiment.
(Embodiment 1)
FIG. 1 is an external view of a first flow path substrate 1 of the present invention, FIG. 1 (a) is a view from the sensor 3 side, and FIG. 1 (b) is a view from the back hole 8 side. It is a figure. The first flow path substrate 1 includes a hold substrate 2 having a hole 8 and a sensor 3 disposed on the hold substrate 2. The sensor 3 includes electrodes disposed on both sides of the quartz substrate and the quartz substrate (see FIG. Not shown.)

  FIG. 2 is a diagram illustrating the configuration of the first flow path substrate 1. FIG. 2 shows a cross-sectional view taken along the plane A shown in FIG. As shown in this figure, the first flow path substrate 1 is more specifically a QCM sensor (hereinafter referred to as a sensor) comprising a hold substrate 2 made of plastic resin and a quartz substrate having electrodes on both sides. 3 and a silicone rubber packing 7 disposed between the hold substrate 2 and the quartz substrate.

  As described above, the reaction electrode 6 is formed on the surface of the sensor 3 on the reaction tank section 9 side, and the back electrode 5 is formed on the back surface side. Both the reaction electrode 6 and the back electrode 5 use gold films. The packing 7 is bonded to the sensor 3 and the hold substrate 2, and the sensor 3 and the hold substrate 2 are not detached. The first flow path substrate 1 is formed with a liquid inlet / outlet 4 for introducing the solution to the reaction tank. By sending a buffer solution or a sample solution to be measured from the liquid inlet / outlet 4 to the reaction tank 9, the sensor 3 detects a change in the weight of a substance adsorbed on the reaction electrode 6 due to a chemical reaction occurring on the reaction electrode 6. be able to.

  FIG. 3 shows an enlarged view of the reaction tank portion 9 and the surrounding portion thereof in the first flow path substrate 1. The sensor unit 3 made of a quartz substrate is not shown. For the hold substrate 2, only a part of the periphery of the reaction vessel 9 is shown. The size of the reaction vessel 9 is determined by the size of the hole 8 and the size of the packing 7. As an example, the diameter of the reaction vessel 9 was 4 mm, and the liquid inlet / outlet 4 was prepared with 500 μm. Then, the liquid is supplied from the liquid inlet / outlet 4 to the reaction tank 9 via a flow path formed by the packing 7. The first flow path 1 is manufactured by attaching a packing 7 to a plastic hold substrate 2 having a hole 8 and a liquid inlet / outlet 4, and forming a sensor 3 made of a quartz substrate on which gold electrode patterning is performed. Glued. The sensor 3 was 8 mm square, and the electrodes were prepared with the reaction electrode 6 having a diameter of 3 mm and the back electrode 5 having a diameter of 5 mm. The plastic resin hold substrate 2 was made of acrylic resin.

  Next, the configuration of the second flow path substrate 10 will be described with reference to FIG. FIG. 4A is a top view of the second flow path substrate 10 as viewed from above. The second flow path substrate 10 has an external connection port 11, a liquid feeding port 12, and a convex portion 13. FIG. 4B is a B-B ′ cross-sectional view shown in FIG. The external connection port 11 and the liquid supply port 12 are connected inside the second flow path substrate 10. As an example, the second flow path substrate 10 is made of a plastic resin in the same manner as the first flow path substrate 1. A substrate having the convex portion 13 and the flow path portion 14 was molded by injection molding, and then a flat plastic substrate 15 was bonded thereto. The liquid feeding port 12 was designed to have a diameter of 500 μm, and the flow path 14 was designed to have a width of 500 μm and a depth of 50 μm. The external connection port 11 is φ1 mm. An acrylic resin substrate was used as the second flow path substrate 10 made of plastic resin. As for the second channel substrate material, any resin may be used, and PET, COP, PES resin, etc. may be used.

  Next, the microreactor 17 formed by inserting the convex portion 13 of the second flow path substrate 10 into the hole 8 of the first flow path substrate 1 will be described below. The external view is shown in FIG. FIG. 5A is an external view before the first flow path substrate 1 and the second flow path substrate 10 are overlapped. FIG. 5B is an external view after the convex portion 13 is inserted into the hole 8 and the two substrates are overlaid. An elastic member packing 16 is sandwiched between the first flow path substrate 1 and the second flow path substrate 10.

  Next, a cross-sectional view cut in the longitudinal direction at the center of the microreactor 17 is shown in FIG. A reaction tank portion 9 is formed by the tip portions of the convex portion 13 of the first flow path substrate 1 and the second flow path substrate 10. As described above, the first flow path substrate 1 and the second flow path substrate 10 are fixed with the elastic member packing 16 interposed therebetween. The elastic member packing 16 is provided with a flow path for connecting the liquid inlet / outlet port 4 of the first flow path substrate 1 and the liquid feed port 12 of the second flow path substrate 13, and a hole for the convex portion 13 to enter. It has been. As an example, silicone rubber was used as the material of the elastic member packing 16 and was formed to a thickness of 150 μm. In this microreactor 17, the convex portion 13 moves up and down in the reaction tank portion 9 by pressurizing the first flow path substrate 1 and the second flow path substrate 10 so as to compress and compress the elastic member packing 16. The volume of the reaction tank part 9 can be changed.

  Next, the microreactor system will be described with reference to FIG. FIG. 7 is a diagram illustrating the configuration of the microreactor system. A chemical tank 18 is connected to the IN side port of the external connection port 11 of the microreactor 17, and a liquid feed pump 20 is connected to the OUT side port via a valve 19. In addition, a waste liquid tank 21 is connected to the tube discharged from the pump so that the waste liquid is accumulated. The moving means 24 of the convex portion 13 is connected to the first flow path substrate 1 of the microreactor 17. Further, a liquid feeding control means 22 is connected to the moving means 24, the liquid feeding pump 20 and the valve 19 via a control signal line 26. Further, a sensor circuit means 23 is connected to the quartz sensor 3 constituting the first flow path substrate 1 via a lead electrode 27.

  Next, a liquid feeding method for discharging bubbles remaining in the reaction tank using the microreactor system will be described. The liquid feeding method will be described with reference to the flowchart of FIG. 9, and the operation of the system will be described with reference to FIG. FIG. 8 is a cross-sectional view of the microreactor 17 and the moving means 24. Portions connected to the outside from the external connection port 11 such as the liquid feed pump 20 and the valve 19 are omitted.

  First, as shown in FIG. 8A, the microreactor 17 is fixed by the moving means 24 with the first flow path substrate 1 and the second flow path substrate 10 sandwiching the elastic member packing 16. . Then, a signal is sent from the liquid feeding control means 22 to operate the liquid feeding pump 20, the valve 19 is opened, and the buffer solution 25 is fed to the reaction tank 9 in the microreactor 17 (FIG. 9, step). S1). Here, before the liquid is fed, the flow path 14 and the reaction tank 9 of the microreactor 17 are in a state of air, and the plastic resin, which is the flow path substrate material, exhibits hydrophobicity, so that it is very wet with the buffer solution 25. Does not show sex.

Therefore, as shown in FIG. 8B, the bubbles 28 remain in the flow path 14, particularly in the reaction tank portion 9. In this state, a signal is sent from the liquid feeding control means 22 to the moving means 24 and the moving means 24 is pushed down. Then, when pressed, the elastic member packing 16 contracts, and the top of the convex portion 13 in the reaction tank portion 9 relatively moves to the sensor 3 side. The liquid feeding control means 22 moves the convex-shaped part 13 until the volume of the reaction tank part 9 becomes zero (FIG. 9, step S2).
By this operation, as shown in FIG. 8C, when the movement of the convex portion 13 is finished, all the bubbles 28 interposed in the reaction tank portion 9 are discharged to the OUT-side flow path 14. Since the liquid supply control means 22 keeps the valve 19 open and the liquid supply pump 20 is kept operating while the convex portion 13 is moving, the buffer solution 25 continues to flow, and the bubbles 28 remain on the OUT side. Are discharged into the flow path 14. The liquid sending control means 22 immediately raises the moving means 24 after reducing the volume of the reaction tank section 9 to zero, and flows the buffer solution 25 into the reaction tank section 9 (step S3 in FIG. 9).

  Thereby, as shown in FIG. 8D, in this state, the bubbles 28 do not remain in the reaction tank section 9, and the reaction tank section 9 is filled with the buffer solution 25. As an example, the height position of the top part of the convex-shaped part 13 was adjusted so that the depth of the reaction tank part 9 in the state shown in FIG.8 (d) might be set to 80 micrometers. Once the degassing of the reaction tank 9 is completed, the state in which the bubbles 28 remain does not occur even if the sample solution to be measured other than the buffer solution 25 is flowed.

  Next, since the reaction measurement was actually performed using the above-described microreactor and the present microreactor system, it will be described. In this measurement, an antigen-antibody reaction measurement will be described as an example.

  First, the ligand fixation pretreatment method will be described. As a ligand immobilization pretreatment, SAM (Self-assembled Monolayer) was modified on the surface of the reaction electrode 6 of the sensor 3, and then an antibody was immobilized on the SAM as a ligand. The method will be described with reference to FIG.

  FIG. 10 shows a method of simultaneously modifying a plurality of first flow path substrates 1 in batches. An immersion container 30 is prepared, and a chemical solution 29 is put therein. The chemical solution 29 is a solution in which a chemical to be modified is dissolved. In this reaction experiment, first, since the SAM modification is performed on the reaction electrode 6 part of the first flow path substrate 1 using the thiol reaction, the alkanethiol solution for forming the SAM is filled with the immersion container 30, Five flow path substrates 1 are immersed at the same time.

Then, after the SAM is formed on the reaction electrode 6 in the first flow path substrate 1, one first flow path substrate 1 is taken out, and then, to modify the antibody as a ligand on the SAM The first flow path substrate 1 is immersed in the antibody solution. After the antibody is fixed on the SAM, the first flow path substrate 1 is taken out from the antibody solution. In this state, the second flow path substrate 10 is inserted into the hole 8 of the first flow path substrate 1. Assemble the elastic member packing so that the convex portion 13 is inserted.
Then, each flow path substrate is fixed by the moving means 24 to form the microreactor 17. Then, a tube is attached to the external connection port 11 and the lead electrode 27 is connected to the electrode of the sensor 3. By using this pretreatment method, ligand fixation pretreatment can be quickly performed on a plurality of sensors.

  Next, an actual antigen-antibody reaction measurement method will be described. The chemical solution in the chemical solution tank 18 is switched to the buffer solution, the liquid supply control unit 22 operates the liquid supply pump 20, the valve 19 is opened, and the buffer solution is supplied to the reaction tank 9 in the microreactor 17. And the moving means 24 is lowered | hung from the liquid feeding control means 22, and the convex-shaped part 13 top part in the reaction tank part 9 is moved to the sensor 3 side. And after making the volume of the reaction tank part 9 zero, the moving means 24 is raised and the reaction tank part 9 is filled with a buffer solution. Here, after the flow rate of the liquid feed pump 19 is controlled by the liquid feed control means 22 and stabilized at about 1 μl / min, the chemical solution in the chemical solution tank 18 is switched to the antigen solution of the sample solution to be measured and the pump solution is continued. Then, about 20 μl of the antigen solution is fed.

  Then, when the antigen solution enters the reaction tank 9, the frequency reduction signal generated by the binding reaction (antigen-antibody reaction) of the antigen in the solution with the antibody fixed to the reaction electrode 6 is detected by the sensor circuit means 23. To detect. (Note that there was no disturbance such as residual bubbles in the signal actually measured and detected.) Then, about 20 minutes after starting the antigen solution delivery (after flowing 20 μl), again Then, the chemical solution in the chemical solution tank 18 is switched to the buffer solution and the liquid feeding is continued. Thereafter, when a buffer solution is passed through the reaction tank unit 9, a frequency increase signal generated by the dissociation of the antigen adsorbed on the antibody is detected by the sensor circuit means 23.

  The reaction rate and dissociation multiplier can be obtained from the antigen-antibody reaction data obtained in the first embodiment. Further, each time one measurement is completed, the tube connected to the external connection port 11 is removed, and the first flow path substrate 1 and the second flow path substrate 10 forming the microreactor 17 are exchanged. The microreactor 17 can be used in a disposable manner.

    As described above, according to the present invention, the first flow path substrate subjected to the sensor pretreatment is placed on the second flow path substrate, the convex portion of the second flow path substrate, and the first flow path substrate. Set so that the hole in the reaction vessel fits and move the convex part while feeding the liquid, all residual bubbles in the reaction vessel can be eliminated, and stable measurement becomes possible, A pretreatment for rapid ligand fixation and a liquid feeding method that does not leave residual bubbles in the reaction vessel 9 can be realized. In addition, the antigen-antibody reaction can be measured in real time, and it is possible not only to quantify the reaction, but also to quickly measure affinity characteristics related to the reaction rate such as binding constant and dissociation constant. Although an antigen-antibody reaction has been described as an example, it can also be used for various biochemical reactions such as DNA hybridization reaction, protein binding, and enzyme reaction.

  The sensor 3 including the quartz substrate and the electrodes 5 and 6 is not limited to the shape and size described above. For example, the shape may be various shapes such as a circle, an ellipse, and a polygon. Any size can be used as long as it satisfies the above-mentioned constitutional condition that the reaction tank unit 9 can be formed, and the size can be manufactured from the viewpoint of manufacturing cost, number of pieces to be taken, and yield. In view of the above efficiency, it is preferable to use the sensor 3 using the quadrangular crystal substrate as illustrated in the first embodiment.

Further, even when the sensor 3 made of such a square crystal substrate is used, the arrangement of the sensor 3 in which the two opposite sides are arranged in the vicinity of the liquid inlet / outlet port 4 as illustrated in the first embodiment. The present invention is not limited to the method and can be arranged in various modes, and an example thereof will be described in the second embodiment.
(Embodiment 2)
FIG. 11 is an explanatory view for explaining the first flow path substrate 1 in which the sensor 3 is arranged on the hold substrate 2. FIG. 12 shows the first flow path substrate 1 and the second flow path substrate 1 in FIG. FIG. 12B is a perspective view of the first flow path substrate 1 and the second flow path substrate 10 stacked together by inserting the convex portion 13 into the hole 8. It is the figure which showed the match | combined external view.

  The microreactor 17 of the present invention according to the second embodiment is different from the microreactor 17 of the present invention according to the first embodiment described above only in the arrangement method of the sensor 3, and has the same configuration in other points. . Therefore, in order to avoid duplication of explanation, the same reference numerals are given, explanation thereof is omitted, and explanation will be given below with an emphasis on different points.

As shown in FIGS. 11 and 12, particularly FIG. 11, the quartz substrate constituting the sensor 3 has a square shape close to a square, and the liquid inlet / outlet 4 is located on the diagonal of the square or in the vicinity of the diagonal of the square. This is characterized in that the sensor 3 is arranged. When the quartz substrate is arranged in this way, the shape in the vicinity of the reaction vessel 8 and the liquid inlet / outlet 4 is formed in a streamline shape as shown in FIG. 3, and therefore the pressing portion 153 is placed at a position close to each side of the quartz substrate. It can be provided.
As shown in FIG. 11, the pressing portion 153 can be provided at four places because the quartz substrate is substantially square, and the four pressing portions 153 are evenly and simultaneously sent by the moving means 24. By pressing in the thickness direction of the road substrate 1, the convex shape portion 13 can be moved while maintaining parallelism with the second flow path substrate without tilting the first flow path substrate. .

Further, since the four pressing portions 153 can be provided in the vicinity of the reaction tank portion 8 and the liquid inlet / outlet port 4, sufficient pressing force is obtained, and unnecessary unnecessary pressing force is not required, and the minimum necessary amount. The convex shape portion 13 can be moved with a limited pressing force.
FIG. 13 is a diagram illustrating the microreactor system according to the second embodiment configured to be operated by the moving means 24 via the four pressing portions 153, and the microreactor system according to the first embodiment shown in FIG. The difference between the microreactor system according to the second embodiment and the microreactor system according to the second embodiment is that only the number of provided pressing portions and the number of moving means 24 corresponding thereto are different, and the other configurations and functions are basically the same. For this reason, the same reference numerals are used, and the description thereof is omitted.

  On the other hand, a lead electrode for connection with the electrodes 5 and 6 is required on the quartz substrate. As described above, for example, the quartz substrate is about 8 mm square and is formed on the quartz substrate. Since the size of the electrodes 5 and 6 is a very small sensor 3 such as φ5 mm to φ3 mm, the sensor lead electrode 154 has a certain length when the resonance characteristics of the sensor 3 and the liquid leakage from the joint are taken into consideration. For that purpose, the sensor lead electrode 154 is extended to the apex portion by using any apex portion of the quartz substrate, and external wiring and solder connection are performed at the apex portion. If the quartz substrate is arranged as in the second embodiment, the sensor lead electrode 154 is formed on a diagonal line different from the diagonal line where the liquid inlet / outlet port 4 is located as shown in FIG. In It is possible to connect the formed substrate lead electrode 152 at the apex angle portion of the quartz substrate, and the wiring to the sensor 3 can be easily formed.

BRIEF DESCRIPTION OF THE DRAWINGS It is an external view of the 1st flow-path board | substrate concerning this invention, (a) is the figure seen from the sensor side, (b) is the figure seen from the back hole part side. It is sectional drawing of the 1st flow-path board | substrate concerning this invention. The enlarged view which shows the reaction tank part and surrounding part of the 1st flow-path board | substrate which concerns on this invention is shown. It is explanatory drawing explaining the structure of the 2nd flow-path board | substrate concerning this invention, (a) is a top view, (b) is sectional drawing. BRIEF DESCRIPTION OF THE DRAWINGS It is an external view of the microreactor concerning this invention, (a) is an external view before superimposing the 1st flow path board | substrate and the 2nd flow path board | substrate, (b) is a convex-shaped part as a hole. It is the external view which inserted and overlapped two board | substrates. It is sectional drawing of the microreactor concerning this invention. It is a block diagram which shows the microreactor system structure concerning this invention. It is explanatory drawing explaining operation | movement of the microreactor and microreactor system concerning this invention. It is a flowchart figure which shows the liquid feeding method concerning this invention. It is explanatory drawing which shows the ligand fixation pre-processing method concerning this invention. It is a figure which shows the structure of the microreactor concerning this invention. BRIEF DESCRIPTION OF THE DRAWINGS It is an external view of the microreactor concerning this invention, (a) is an external view before superimposing the 1st flow path board | substrate and the 2nd flow path board | substrate, (b) is a convex-shaped part as a hole. It is the external view which inserted and overlapped two board | substrates. It is a block diagram which shows the microreactor system structure concerning this invention. It is explanatory drawing which shows the conventional flow through cell type reaction tank part.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 1st flow path substrate 2 Hold substrate 3 Sensor 4 Liquid inlet / outlet 5 Back electrode 6 Reaction electrode 7 Packing 8 Hole part 9 Reaction tank part 10 Second flow path board 11 External connection port 12 Liquid supply port 13 Convex-shaped part 14 Flow path portion 15 Substrate 16 Elastic member packing 17 Microreactor 18 Chemical liquid tank 19 Valve 20 Liquid feed pump 21 Waste liquid tank 22 Liquid feed control means 23 Sensor circuit means 24 Moving means 25 Buffer solution 26 Control signal line 27 Lead electrode 28 Bubble 29 Chemical solution 30 Immersion container 152 Substrate lead electrode 153 Pressing part 154 Sensor lead electrode 1011 Quartz crystal resonator 1014 Holding substrate 1015 Silicone rubber

Claims (6)

In a microreactor having a reaction tank section that measures the weight of a second chemical substance that specifically adsorbs or binds to the immobilized first chemical substance, and is formed in a flat plate shape,
A first flow path substrate comprising: a hold substrate having a through-hole portion; and a sensor made of a piezoelectric vibrator provided on the hold substrate so as to cover one side of the hole portion of the hold substrate;
A second flow path substrate having a convex portion that fits into the hole from the other side of the hole,
The reaction vessel portion is formed by overlapping the first flow path substrate and the second flow path substrate in this order while inserting and fitting the convex portion into the hole. Microreactor to do. 2. The microreactor according to claim 1, wherein the volume of the reaction tank unit is variable depending on an insertion amount of the convex portion of the second flow path substrate.   A packing made of an elastic member sheet is provided between the first flow path substrate and the second flow path substrate, and the volume of the reaction vessel portion depends on the thickness of the packing, and the packing The thickness is formed so that the amount of insertion varies according to an external force applied to at least one of the first flow path substrate and the second flow path substrate. 3. The microreactor according to 1 or 2.   The flow path for sending a solution to the reaction vessel is formed so as to penetrate the first flow path substrate, the packing, and the second flow path substrate. The microreactor according to any one of the above. 5. The microreactor according to claim 1, pump means connected to the microreactor, liquid feed control means for controlling liquid feed in the microreactor, and a sensor in the microreactor are driven. And a moving means for moving the convex portion of the second flow path substrate inserted into the hole of the first flow path substrate to change the volume of the reaction vessel. A microreactor system characterized by that. It has a reaction tank that measures the weight of the second chemical substance that specifically adsorbs or binds to the immobilized first chemical substance, and feeds the solution in a plate-shaped microreactor. A liquid method,
Feeding the solution to the reaction vessel,
Discharging air bubbles present in the reaction vessel by changing the volume of the reaction vessel to be small; and
And a step of pouring and filling a solution into the reaction vessel by changing the volume of the reaction vessel to be larger after discharging the bubbles.

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