JP2011183589A - Sealing apparatus - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a sealing apparatus which determines whether or not a reactor, e.g. a microchip is heat-welded with a lid material at an appropriate sealing temperature immediately after sealing and stops sealing operation at once on anomaly sealing. <P>SOLUTION: The sealing apparatus has a sealing inspection function equipped with a temperature measurement means of measuring a surface temperature of the reactor/lid material, an inspection condition setting means of inspecting the quality of sealing, a measurement data take-in means of taking in temperature measurement data obtained by the temperature measuring means and a determination means of comparing a measurement value taken in by the measurement data take-in means with a quality determination threshold set by the inspection condition setting means. The apparatus is also equipped with an information recording means of recording inspection conditions set by the inspection condition setting means and a control means of outputting a command of stopping the sealing operation when the determination means determines poor sealing. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a sealing device for welding a chip body and a lid of a microchip used for bio-related research and production such as gene analysis. In general, a microchip is a small semiconductor chip in which an integrated circuit is built. Here, a complex chemical system that performs reactions, separation, purification, detection, etc. of chemical substances, DNA, proteins, etc. It shall be the one integrated on one substrate.

  In recent years, μ-Total Analysis System (μ-TAS) technology, which is a micro- and nano-biodevice applying semiconductor microfabrication technology, precision synthesis technology, and microfluidic control technology that perform chemical reaction, DNA reaction, protein reaction, etc. on the chip, Lab-On-Chip technology has been realized, and reaction experiments, which have so far required a large experimental apparatus and a large amount of reagents, can be performed with a small amount of reagents using a microchip.

  Processing in a reaction experiment using such a reaction vessel such as a microchip is usually a detection target in a well-shaped reaction portion (hereinafter, well) having a hollow shape regularly arranged on the vessel. This is performed in a state where a reagent solution containing a specimen is dispensed. In this reagent solution dispensing step, the reagent solution is normally sucked from the test tube into the pipette tip attached to the pipette tip, and the reaction reagent is dispensed into any well-like reaction part. After the repetition, the lid member is joined by thermal welding by heating and pressurization, and each well and a flow path connecting the wells are formed.

  In the above-described reaction experiment using a reaction vessel such as a microchip, it is necessary that the defined well volume and the channel volume between the wells are kept constant and that there is no leakage during reagent feeding. Is done.

  In the thermal welding process using the sealing device, if the sealing temperature is low, a reagent failure from the well and the flow path between the wells when the reagent is fed, or a welding failure that the lid material peels off after sealing occurs, If the sealing temperature is high, the volume of the well and the flow path between the wells will be reduced, and the reaction reagent dispensed before sealing will be deactivated by heat, resulting in a phenomenon that the reaction function deteriorates. .

  In order to eliminate these problems, a method of joining plastics at a relatively low temperature (Patent Document 1) and a joining method that combines adhesion and thermal welding (Patent Document 2) have been devised.

JP 2006-116803 A JP 2008-157644 A

It is possible to reduce the failure rate of seals by devising the above sealing method. It is assumed that there is a case where a bonding failure between the reaction vessel and the cover material occurs due to a mistake in device setting management, a defective shape of the seal member itself, etc. The result of the reaction experiment cannot be obtained. Therefore, the inspection of the sealing state in the sealing process is strongly desired.

  As a means for confirming whether or not the seal is correctly performed, for example, when each member is made of a permeable material, a seal surface inspection by human eyes, that is, a sensory test is performed to confirm whether or not there is unevenness in the welding mark. However, in the sensory test that depends on human sensory, variations in determination results by the inspector cannot be avoided. In particular, since the volume of the well formed on the microchip is often very small, it is very difficult to visually determine the state of thermal welding around the well and the flow path between each well, and workability is low. There is a problem that it is low.

  In addition, a tension test that measures the force required when the bonded lid material is peeled off and a pressure test that measures whether there is a lack of constant pressure in the well flow path and the presence of leakage are performed. Therefore, the inspection is performed by sampling, and the reliability of the inspection result cannot be maintained in a microchip that requires reliability. To compensate for this, it may be possible to increase the number of sampling inspections, but this will increase the manufacturing cost for the number of inspections, and if a defective determination is made in the sampling inspection, the reaction container immediately before the inspection target is treated as a defective product. Therefore, there are problems such as the occurrence of defective products.

  In the conventional sealing device and sealing method, the reaction reagent dispensed into the microchip (injecting the reaction reagent into a predetermined recess on the substrate) is not deactivated and the sealing strength is maintained. Although there is provided a sealing means for maintaining the well volume and the flow path volume between the wells, there is no means for assuring the quality of the seal, and the actual situation is that visual inspection and sampling inspection are performed after the sealing operation.

  The present invention has been made in view of such problems, and determines immediately after sealing whether or not a reaction vessel such as a microchip and a lid material are thermally welded at an appropriate sealing temperature, and immediately stops the sealing operation when the sealing is abnormal. It is an object to provide a sealing device.

As a means for solving the above-mentioned problems, the invention according to claim 1 is characterized in that a well-like reaction part having a depression shape is formed on a substrate, a flow path connecting between the wells and the outlet / delivery liquid port. A sealing device for thermally welding a reaction container in which a predetermined amount of a reaction reagent has been dispensed and a lid for forming the well and the flow path,
Temperature measuring means for measuring the surface temperature of the reaction vessel / cover material;
Inspection condition setting means for inspecting the quality of the seal;
Measurement data acquisition means for acquiring temperature measurement data measured by the temperature measurement means;
A determination processing means that compares the measurement value acquired by the measurement data acquisition means and the pass / fail determination threshold set by the inspection condition setting means, and has a seal inspection function, and
Information recording means for recording the inspection conditions set by the inspection condition setting means;
And a control unit that outputs a sealing operation stop command when the determination processing unit determines that the seal is defective.

  As a means for solving the above-mentioned problem, the invention according to claim 2 is characterized in that the temperature measuring means measures a plurality of times over time in the same measurement region. It is.

As means for solving the above-mentioned problems, the invention according to claim 3 is characterized in that the inspection condition setting means sets an area for performing temperature measurement, an elapsed time setting for determining a timing for taking in temperature measurement data after sealing, The sealing device according to claim 1, wherein a temperature threshold value setting for pass / fail judgment and an abnormal signal output condition setting are performed.

  According to the sealing device of the present invention, whether a reaction vessel such as a microchip and a lid member are thermally welded at an appropriate sealing temperature is measured over time after sealing, and the measurement result is compared with a preset threshold value. Thus, it is possible to suppress the occurrence of a defect by determining the quality and stopping the sealing operation when it is determined that the seal is defective.

(A) is a top view which shows an example of the reaction container before throwing into the sealing device by this invention. (B) is a figure which shows the cross section seen from the cross section 101 of the same top view. It is a block diagram of the part which concerns on the heater which heat-welds the reaction container and lid | cover material of the sealing device by this invention. (A) is a side view of the reaction vessel after sealing the lid plate. (B) is a perspective view of the reaction container after sealing the lid plate. It is a schematic diagram of the surface temperature measurement example of the reaction container after sealing in the present invention. The schematic diagram which shows schematic structure of the part which concerns on the seal | sticker test | inspection function with which the sealing apparatus of this invention was equipped. The flowchart figure which shows the operation | movement flow of the seal | sticker test | inspection function with which the sealing apparatus which concerns on this invention was equipped. The figure which shows transition by the elapsed time of the temperature measurement data which concerns on this invention.

  Below, the form for implementing the sealing device which concerns on this invention is demonstrated.

  FIG. 1A is a plan view showing an example of a reaction container before being put into the sealing device according to the present invention, and FIG. 1B is a cross-sectional view as seen from a cross-section 101 of the same plan view. The reaction container 11 is provided with a recess-shaped well 12, a groove-shaped flow path 14 that connects between the liquid discharge port 13 and the well 12, and between the well 12 and another well 12. A small amount of reaction reagent 15 is spotted in each well 12 and reacts with the reagent injected from the feed / discharge port, and the reaction result is indicated by discoloration or light emission. In addition, since the flow path 14 dislikes the contamination of the reaction reagents 15 between the wells 12, the path may be changed into a bag path.

  FIG. 2 is a configuration diagram of a portion related to a heater for thermally welding the reaction vessel 11 and the lid member 16 of the sealing device according to the present invention. The reaction vessel 11 is placed at a predetermined position of the seal stand 17, the lid member 16 is placed thereon, and from above, the heating member 19 having the heater 18 is heated and pressurized so that it is pressed against the lid member 16 with a constant pressure. The lid 16 and the reaction vessel 11 are thermally welded by the heat of the heating member 19. Further, after a sealing time calculated from the amount of heat necessary for heat welding, the heating member 19 moves away from the lid member 16 and moves upward.

  FIG. 3A is a side view of the reaction vessel after the sealing shown above is completed and the lid plate 16 is sealed. Also. FIG. 3B is a perspective view of the same. By sealing the lid material, the groove-shaped flow path 14 becomes cylindrical, and the well 12 is formed with a lid that covers the reaction reagent 15 to complete the reaction container. The material of the reaction vessel 11 and the lid member 16 may be glass or metal provided with a resin layer suitable for heat welding on the joint surface in addition to plastics suitable for heat welding.

By the way, in the reaction vessel 11 thermally welded by the heating and pressurizing method using the heating member 19, the surface temperature of the lid member 16 with which the heating member 19 is in contact has a temperature difference in the surface direction. On the other hand, also in the thickness direction of the reaction vessel 11, there is a temperature difference because heat conduction is performed from the cover material 16 in contact with the heating member 19 to the bottom surface of the reaction vessel 11 through the joint surface of the reaction vessel 11. Further, when the reaction vessel 11 using a material having a large thickness and low thermal conductivity is used, the surface temperature of the lid 16 gradually decreases, and the surface temperature of the bottom surface of the reaction vessel 11 passes a certain time. Until the temperature rises, the temperature changes at the same measurement location due to the elapsed time after the thermal welding, such as lowering, tends to be remarkable. That is, the temperature of the welded portion after the thermal welding of the reaction vessel is measured at a plurality of elapsed times, and the threshold temperature set for the elapsed time is compared with the temperature measured at the plurality of elapsed times, thereby sealing by thermal welding. The quality can be judged.

  FIG. 4 is a schematic view showing an example of measuring the surface temperature of the reaction container after sealing in the present invention. A measuring device 20 for measuring the temperature of the surface on the lid 16 side, which is a temperature measuring means, and a B measuring device 21 for measuring the temperature of the bottom surface of the reaction vessel 11 are provided at any appropriate position of the sealing device. Measure the temperature. FIG. 4 uses two measuring instruments for convenience of explaining the embodiment for carrying out the present invention. However, when the reaction vessel 11 is thick, one or more measuring devices for measuring the surface temperature of the side surface of the reaction vessel. May be further added. Further, in the case where the thermal conductivity of the reaction vessel 11 is good and heat is easily transmitted, or in the case of a reaction vessel which is easily thermally welded at a low temperature, only the A measuring device 20 may be used. In order to measure two-dimensional temperature instead of the spot, for example, a thermoviewer is preferably used as the measuring instrument, but a plurality of the same non-contact spot thermometers or contact-type thermometers may be used.

  FIG. 5 is a schematic diagram showing a schematic configuration of a portion related to a seal inspection function provided in the sealing device of the present invention. The measurement value capturing means 23 is connected to the A measuring device 20 and transmits temperature measurement data to the determination processing means 24. The determination processing means 24 is connected to the inspection condition setting means 22 and the information recording means 25, and is further connected to the sealing device control unit 27 via the control signal processing means 26. Each means of 22-26 is not restricted to the form taken in to the personal computer 28 as shown in the figure, but a part or all of them may be in the A measuring device 20 or the seal device control unit. For convenience of describing the embodiment according to the present invention, the A measuring device for measuring the temperature of the surface of the lid 16 is illustrated, but each measuring device is connected to the capturing means 23 even when there are a plurality of measuring devices.

  FIG. 6 is a flowchart showing an operation flow of the seal inspection function provided in the seal device according to the present invention. The inspection function includes an inspection condition setting step (indicated by S in the figure, hereinafter abbreviated as S) 22, a measurement value capturing process (S23), a determination process (S24), an information recording (S25), and a control signal process (S26). ), And a series of steps. Hereinafter, the contents of each step will be described in the order of the sealing steps with reference to FIG. 6 and FIG. T0 shown on the horizontal axis of FIG. 7 is the seal start time, T1 is the seal end time, and T2, T3, and T4 indicate the elapsed time after the seal, respectively. M1, M2, M3, and M4 indicate the measured temperatures at the above times, respectively.

  S22 (inspection condition setting) will be described. First, the inspection condition setting means 22 performs setting of an area for temperature measurement, setting of elapsed time for determining the timing for taking in temperature measurement data after sealing, and setting of a temperature threshold value for pass / fail determination. For example, T1, T2, T3, and T4 in FIG. 7 are set as the elapsed time that determines the timing for taking in the temperature measurement data after sealing, and the threshold values for the pass / fail judgment at that time are 120 ° C. to 130 ° C. for T1 and 100 ° C. to 110 ° C. for T2. The temperature is set as 80 ° C. to 90 ° C. for T3 and 60 ° C. to 80 ° C. for T4.

S23 (measurement value acquisition) will be described. The measured value fetching means 23 is a set elapsed time (determined timing for fetching the temperature measurement data of the surface temperature value measured by the A measuring instrument 20 and the temperature of the temperature measurement area set by the inspection condition setting means 22. In accordance with the elapsed times T1, T2, T3, and T4) in FIG. 7, the data is digitally converted into a form that can be used for determination processing (S24), and then determination processing (S24) is performed. Since the temperature measurement is performed according to the elapsed time, it is desirable that the measurement region be an atmosphere that is less affected by the air flow and has a constant ambient temperature.

  S24 (determination process) will be described. The determination processing unit 24 compares the temperature measurement value transferred from the measurement value capturing process S23 with the threshold temperature set in the inspection condition setting S22, and determines a seal failure. For example, if the threshold value of the surface temperature at T1 at an arbitrary position on the circumference having a diameter 1 mm larger than the well diameter is set to 120 ° C. to 130 ° C. and the temperature measurement value does not fall within this range, it is located immediately above the well 12. Judge as abnormal.

  In general, it is desirable to provide a plurality of regions for temperature measurement for one reaction container. For each region, it is determined whether or not the temperature is good. If nine or more regions are determined to be good, the seal of the reaction vessel may be determined to be good.

  S25 (information recording) will be described. The information recording unit 25 records the type of data set in the inspection condition setting S22 out of a series of steps from the inspection condition setting S22 to the determination process 24 on an arbitrary recording medium such as a hard disk. The recorded data is used again later.

  S26 (control signal processing) will be described. The control signal processing means 26 determines the abnormal signal condition setting set in the inspection condition setting S22 based on the determination result in the determination process S24 with respect to the sealing device control unit 27 (for example, three consecutive reaction containers indicate that the seal is defective). If it is determined, a control signal is output), and a control signal corresponding to each abnormality is transmitted. When the seal is abnormal, the operation stops immediately.

  As described above, according to the sealing device and the sealing method of the present invention, it is determined immediately after sealing whether a reaction vessel such as a microchip and a lid material are thermally welded at an appropriate sealing temperature, and immediately operates when a sealing abnormality occurs. Can be stopped and the occurrence of seal defects can be reduced.

  The present invention can be used for research, development, and manufacture of various analysis chips in the pharmaceutical and life science businesses.

11 ... Reaction vessel
DESCRIPTION OF SYMBOLS 12 ... Well 13 ... Feed / discharge port 14 ... Flow path 15 ... Reaction reagent 16 ... Cover material 18 ... Heater 19 ... Heating member 20 ... A measuring device 21 ... B measuring device 22 ... Test condition setting means 23 ... Measurement value taking-in means 24 ... Determination processing means 25 ... Information recording means 26 ... Control signal processing means 27 ... Sealing device control section 28 ... Personal computer 101 ... Cross section

Claims (3)

A reaction vessel in which a predetermined amount of a reaction reagent is dispensed to the well-like reaction portion; and the well and the flow passage. A sealing device for thermally welding a lid material for forming,
Temperature measuring means for measuring the surface temperature of the reaction vessel / cover material;
Inspection condition setting means for inspecting the quality of the seal;
Measurement data acquisition means for acquiring temperature measurement data measured by the temperature measurement means;
A determination processing means that compares the measurement value acquired by the measurement data acquisition means and the pass / fail determination threshold set by the inspection condition setting means, and has a seal inspection function, and
Information recording means for recording the inspection conditions set by the inspection condition setting means;
And a control unit that outputs a seal operation stop command when the determination processing unit determines that the seal is defective.   The sealing device according to claim 1, wherein the temperature measuring unit measures a plurality of times as time passes in the same measurement region.   The inspection condition setting means is characterized by setting the temperature measurement area, setting the elapsed time for determining the timing for capturing the temperature measurement data after sealing, setting the temperature threshold for pass / fail judgment, and setting the abnormal signal output condition. The sealing device according to claim 1 or 2.

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