JP2006297257A - Liquid agitating device and measuring device including it - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a liquid agitating device utilizing a surface acoustic wave which eliminates manual operations for introducing a coupling liquid. <P>SOLUTION: The liquid agitating device which agitates a liquid held in a liquid holding plate mounted on a surface acoustic wave agitating board arranged with a surface acoustic wave oscillation element, and is provided with a coupling liquid supply means supplying a coupling liquid to a space between the contact surfaces of the surface acoustic wave agitating board and the liquid holding plate. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a liquid stirring device that stirs a liquid held in a liquid holding plate with a surface acoustic wave stirring board, and a measuring device for measuring the amount or concentration of a specific substance in the liquid, including the liquid stirring device. About.

  In order to quantitatively measure the concentration of a substance in a biological fluid sample, it is desired to thoroughly mix the sample and the measurement reagent. Further, it is desired to stir and mix the measurement reaction system in order to improve the reactivity and to make the temperature of the reaction solution uniform. Large automatic analyzers on the market are capable of high-speed processing and multiple items. These measuring devices include a sample supply unit, a reagent mixing unit, a reaction measurement unit, and a data processing unit, and in addition, a stirring mechanism is provided. The stirring mechanism here is generally a direct stirring means. For example, this is a method in which a stirring part comes into contact with the liquid to be stirred and is stirred by a stirring method such as a stirrer or a stirring bar using a magnet. In addition, a technique in which a stirring part stirs in a non-contact manner with a liquid to be stirred by an indirect stirring means using mechanical vibration, ultrasonic waves (Patent Document 1) or the like has been put into practical use. However, since there is no simple stirring method for medium and small-sized measuring devices, particularly small measuring devices, most devices do not include a stirring mechanism. Research on agitation techniques that can be used in such a small measuring device, for example, research on various agitation to improve the reaction efficiency (Micro Total Analysis System, μ-TAS)) has become popular. However, few of them are practical.

  Among them, one new liquid agitation technology, a liquid agitation method using surface acoustic wave (SAW), has been recently developed and put into practical use. SAW is composed of an oscillation element (IDT electrode = inter-digital transducer) and a high-frequency oscillation circuit. Conventionally, this technique has been often used for measuring physical properties, but recently, attention has also been paid to the movement of liquid droplets and liquid mixing with stirring (Patent Documents 2 and 3). Among them, the liquid on the electrode can be moved by the distance between electrodes of the oscillation element, the frequency, pulse oscillation, etc., and can be applied to liquid mixing (Non-patent Document 1 and Patent Document 4). In particular, since the oscillating element can be very small, it can be applied to a small device.

JP 11-347392 A JP-A-10-327590 Special table 2003-535349 gazette JP-T-2004-534633 Journal of Biomolecular Techniques, 14: 197-204, 2003

  However, in the conventional stirring means, since the stirring part is in direct contact with the liquid to be stirred, sufficient cleaning is required after the measurement is completed. This is a problem for an automatic analyzer that requires high-speed processing. In addition, these agitation devices are unsuitable for small devices because of their size. In the case of stirring by mechanical vibration, there is a problem that it is difficult to reduce the size of the apparatus due to the complexity of the mechanism. In the case of stirring by ultrasonic waves, for example, the stirring method described in Patent Document 1 has problems such as the possibility of damaging a substance, noise, and difficulty in miniaturization. Since each of the above stirring methods is not suitable for stirring a plurality of locations and a minute amount of liquid, it cannot be easily applied to a POCT (point of care testing) simple measuring device for simultaneous measurement of a minute amount sample and multiple items. Is the situation.

  On the other hand, the SAW liquid agitation method has characteristics such as that there is no adverse effect on the substance due to oscillation, that there is no sound, that ultra-small amount of liquid can be agitated, and that no bubbles are generated unlike agitation by ultrasonic waves. In addition, since the SAW oscillation element can be miniaturized and is inexpensive, it is possible to cope with the need for simultaneous stirring at a plurality of locations by using a plurality of oscillation elements. The SAW liquid stirring method can usually be used for both direct and indirect methods. However, the SAW stirring / mixing method or stirring / mixing apparatus described in Patent Document 4 is only of the direct type, that is, the SAW oscillation element is directly brought into contact with the liquid, and the liquid is moved by the oscillation. In this case, as described above, the surface of the SAW element is contaminated, and when it is reused, the surface of the SAW must be sufficiently cleaned. Further, when such a cleaning means is required, it becomes a problem for the realization of the apparatus, particularly for miniaturization. On the other hand, in the case of the indirect type, since the stirring is possible even if the liquid to be stirred is separated from the oscillation element, the liquid is not contaminated and the reaction vessel is not required to be cleaned. However, in this case, the air layer sandwiched between the stirring liquid and the SAW oscillation element absorbs the SAW sound wave and must be removed. For this purpose, it is necessary to make a close contact with a liquid called a coupling liquid. Sample processing apparatuses having such an indirect SAW stirring mechanism are commercially available, but the supply of the coupling liquid is manually introduced when used. However, such an operation of manually supplying the coupling liquid is troublesome, for example, when the coupling liquid is manually added using a micropipette, and it is difficult to ensure the stability of the operation.

  An object of the present invention is to measure the amount or concentration of a specific substance in a liquid stirring apparatus that does not require manual introduction of a coupling liquid in a liquid stirring apparatus using SAW and the liquid equipped with the liquid stirring apparatus. It is to provide a measuring device.

  As a result of earnest research, the inventors of the present application have provided a means for supplying the coupling liquid to the contact surface between the liquid holding plate for storing or placing the liquid and the SAW stirring board, so that the stirring operation is efficiently stabilized. As a result, the present invention has been completed.

  That is, the present invention includes a surface acoustic wave agitation board on which a surface acoustic wave oscillation element is disposed, and a liquid agitation device that agitates a liquid held on a liquid holding plate placed on the surface acoustic wave agitation board And a coupling liquid supply means for supplying a coupling liquid between the contact surface of the surface acoustic wave agitation board and the liquid holding plate. The present invention also provides a measuring device for measuring the amount or concentration of a specific substance in a liquid, comprising a liquid stirring device and means for measuring a signal from the liquid holding plate.

  According to the present invention, a liquid agitating mechanism can be provided even in a small POCT simple measuring apparatus that uses a liquid holding plate such as a disposable inspection tool and targets a small amount of sample. Usually, when measuring the concentration of a component in a biological fluid sample with a small POCT simple measuring device, multiple items may be measured simultaneously. In that case, since it is necessary to provide a plurality of sample processing chambers and a plurality of measurement chambers in the liquid holding plate, it is necessary to perform liquid agitation at a plurality of locations at the same time. According to the present invention, it is possible to easily perform non-contact by providing a stirring mechanism that automatically supplies a coupling liquid and includes a plurality of SAW oscillation elements. By doing so, it is possible to more efficiently perform the mixing of the liquid and the liquid in the sealed small chamber in the liquid holding plate, the dissolution and mixing of the liquid and the solid, and the like. Furthermore, when temperature control is required, heat can be quickly dispersed and uniformed by stirring, so that temperature control can be easily performed.

  As described above, the liquid agitation device of the present invention includes a surface acoustic wave agitation board on which a surface acoustic wave oscillation element is disposed, and the liquid held on the liquid holding plate placed on the surface acoustic wave agitation board. In the liquid agitating apparatus for agitating the liquid, a coupling liquid supply means for supplying a coupling liquid between the contact surface of the surface acoustic wave agitating board and the liquid holding plate is provided.

  Here, the liquid holding plate is, for example, a plate having one or a plurality of recesses (wells) such as a microtiter plate, a chip such as a DNA chip or a peptide chip, and the like. In the case of having a recess, the liquid is accommodated in the recess, and in the case of a chip or the like having no recess, the liquid is placed on the chip. Even when there is no recess, the liquid stays in a certain region due to surface tension. Thus, the liquid stirring apparatus of the present invention can also be applied to stirring of the liquid placed on the chip. Further, when the liquid holding plate has a recess, if the liquid is sealed and accommodated, the liquid holding plate can be arranged horizontally, vertically, or at a certain angle as needed.

  Since SAW is particularly effective in rapidly mixing a small amount of liquid, the liquid held in the liquid holding plate is a minute amount of several μL to several hundred μL in each recess or region. It is preferable that Normally, the amount of biological samples such as clinical specimens is limited, and the ability to efficiently stir such a small amount of liquid is advantageous in that the amount of valuable test sample used can be reduced.

  A liquid agitation device itself that includes a surface acoustic wave agitation board that is vibrated by a surface acoustic wave oscillation element and that agitates a liquid held on a liquid holding plate placed on the surface acoustic wave agitation board is already known. Yes, it is also commercially available. The liquid stirring apparatus of the present invention may be obtained by adding a coupling liquid supply means to such a known liquid stirring apparatus.

  The usage mode of the liquid stirring apparatus of this invention is demonstrated based on FIG. In FIG. 1, reference number 1 is a liquid holding plate, reference number 2 is a SAW stirring board, reference number 3 is a SAW oscillation element (IDT electrode), reference number 4 is a coupling liquid layer, reference number 5 is a liquid holding plate 1 It is the liquid accommodated in the recessed part inside. As described above, normally, the SAW oscillation element is arranged directly under the liquid to be stirred, and the coupling liquid layer 4 is interposed between the upper surface of the SAW stirring board 2 and the bottom surface of the liquid holding plate 1. The SAW oscillation element is activated and the liquid 5 is stirred by SAW. The stirrer according to the present invention comprises a coupling liquid supply means for supplying a coupling liquid between the stirring board and the bottom surface of the liquid holding plate, that is, forming a coupling liquid layer 4. To do.

  In the first aspect, as shown in FIG. 2, the coupling liquid supply means is configured so that the liquid holding plate 1 is contacted with the contact surface (in this example, the bottom surface) when the liquid holding plate 1 is placed on the SAW stirring board. The coupling liquid applying means 7 is disposed at a position in contact with (). The coupling liquid application means 7 preferably extends over, for example, substantially the entire width of the liquid holding plate 1 (in a direction perpendicular to the paper surface of FIG. 2) or the entire width of the portion where the recess or region where the liquid is held exists. A sponge-like porous body may be impregnated with a coupling liquid. Alternatively, the coupling liquid application means 7 may be in the form of a brush or may be in the form of a slit (in the case of a slit, the coupling liquid is supplied from the gap between the slits). In FIG. 2, reference numeral 6 is a coupling liquid storage container that continuously supplies the coupling liquid to the coupling liquid application means 7. In the embodiment shown in FIG. 2, the liquid holding plate 1 is placed on a belt conveyor (not shown), moved in the horizontal direction and placed on the SAW stirring board 2 as indicated by an arrow in FIG. 2. Is done. When placed on the SAW stirring board 2 away from the belt conveyor, the bottom surface of the liquid holding plate 1 comes into contact with the coupling liquid application means 7, and the coupling liquid is applied to the bottom surface of the liquid holding plate 1. When the liquid holding plate 1 is placed on the SAW stirring board 2 in this state, a coupling liquid layer 4 (FIG. 1) is formed between the bottom surface of the liquid holding plate 1 and the upper surface of the SAW stirring board 2. . When the coupling liquid applying means 7 is a sponge-like porous body, it is preferable to provide a cap to prevent the coupling liquid from evaporating when not in use. You may make it.

  A second aspect of the coupling liquid supply means will be described with reference to FIG. FIG. 3 is a plan view, in which the liquid holding plate 1 is placed on the SAW stirring board 2, and the liquid 5 is accommodated in the liquid holding plate 1 as in FIGS. 1 and 2. In the embodiment shown in FIG. 3, the coupling liquid supply means is connected to the nozzle 10 for supplying the coupling liquid to the contact portion between the bottom surface of the liquid holding plate 1 and the SAW stirring board 2, and connected to the nozzle 10 via the pump 9. When the coupling liquid is accommodated in the coupling liquid storage container 8 and the liquid holding plate 1 is placed on the SAW stirring board, a necessary amount of water is supplied by the pump 9. The coupling liquid is supplied from the nozzle 10 to the contact portion between the liquid holding plate 1 and the SAW stirring board 2. The pump 9 is preferably a metering pump capable of transferring a predetermined amount of liquid. The nozzle 10 may be disposed above the end of the liquid holding plate 1 and may drop the coupling liquid onto the end of the liquid holding plate 1 (boundary with the SAW stirring board) when supplying the coupling liquid. Alternatively, the tip of the nozzle 10 may be narrowed, and the coupling liquid may be injected into a boundary portion between the bottom surface of the end portion of the liquid holding plate 1 and the top surface of the SAW stirring board. The coupling liquid dropped or injected spreads by capillary action, and a coupling liquid layer 4 is formed between the bottom surface of the liquid holding plate 1 and the top surface of the SAW stirring board. The amount of coupling liquid to be supplied can be confirmed in advance by preliminary experiments, and the pump can be set to supply a predetermined amount of coupling liquid by computer control. The amount of the coupling liquid to be supplied is not particularly limited and is appropriately determined. Usually, about 0.01 to 0.2 mL is appropriate.

  A third aspect of the coupling liquid supply means will be described with reference to FIG. 4A is a cross-sectional view, and FIG. 4B is a plan view. As the liquid holding plate 1, a breakable bag or container 11 that accommodates the coupling liquid is disposed in the liquid holding plate 1. In the example shown in the figure, the one disposed in the through hole 13 provided in the liquid holding plate 1 is used. The breakable bag or container 11 can be preferably formed of a metal foil such as an aluminum foil or a resin film such as polyethylene. Note that the breakable bag or container 11 is disposed in the liquid holding plate as shown in FIG. For example, a part thereof is disposed in the through hole 13, and the other part extends to the peripheral part of the through hole 13. The breakable bag or the packaging material of the container 11 may be a material that is easily broken in the direction of the coupling liquid flow and a material that is not easily broken on the opposite side. Alternatively, a needle-like object may be provided under the breakable bag or container 11. The amount of the coupling liquid accommodated in the bag or the container 11 is not particularly limited and is appropriately determined. Usually, about 0.01 to 0.2 mL is appropriate as described above. In the embodiment shown in FIG. 4, when the liquid holding plate 1 is placed on the SAW stirring board, the breakable bag or container 11 disposed in the through hole 13 is moved vertically by the breaking member 12 that moves up and down. It is pressed and broken or punctured, and the coupling fluid inside flows out. The coupling liquid that has flowed out spreads by capillary action, and a coupling liquid layer 4 is formed between the liquid holding plate 1 and the contact surface of the SAW stirring board. As shown in FIG. 4, the breaking member 12 has at least a tip inserted into the through hole 13, and is arranged at the tip so that the bag or the container can be easily pressurized. . The breaking member 12 is moved up and down by a computer-controlled motor by a necessary distance.

  FIG. 5 (a) shows the liquid holding plate 1 provided with a plurality of recesses for containing the liquid, and FIG. 5 (b) shows the position of the SAW oscillation element 3 provided on the SAW stirring board 2. Show. As shown in the figure, the SAW oscillation element 3 is disposed directly below each recess in the liquid holding plate 1. As shown in FIG. 5, the liquid holding plate having a plurality of recesses can be applied to multi-item simultaneous measurement, and the SAW stirring board shown in FIG. 5 is a board that supports simultaneous stirring at a plurality of locations. It is. In the POCT biological sample measuring apparatus that simultaneously measures multiple items with a small amount of sample using the liquid holding plate 1, stirring and mixing of the liquid is necessary for processing steps such as sample dilution, reagent dissolution, mixing, and heating. . In that case, a plurality of liquid stirring mechanisms are required for the plurality of sample processing chambers, the plurality of measurement chambers, and the plurality of sample processing chambers / measurement chambers in the liquid holding plate. According to the present invention, it can be easily implemented by providing a plurality of SAW oscillation elements 3. At that time, since the automatically supplied coupling liquid diffuses into a layer, it can be used in the same manner as when a single SAW element is used.

    In each of the embodiments described above, the arrangement of the liquid holding plate and the SAW stirring port is not limited to horizontal, but can be used vertically or arranged with a certain angle as necessary.

  The type of the coupling liquid can be selected according to the purpose of use and the measurement time. For example, when it is desired to use continuously for a long period of time, it is better to use a liquid having a lower boiling point and a higher boiling point. For example, one or more kinds of mixtures selected from the group of high-boiling substances such as glycerol and ethylene glycol can be used. Conversely, when it is desired to remove the liquid immediately after the measurement, a solvent having a lower boiling point may be employed. For example, one or more kinds of mixtures selected from the group of low-boiling substances such as water, alcohol, and acetone can be used. In the case of a POCT biological sample measuring device, usually a short measurement time is required. In that case, it is preferable to use a substance that easily evaporates, such as water, alcohol, and acetone. In some cases, mixtures of these liquids can also be used. If desired, immediately after the measurement is completed, the surface of the SAW stirring board may be heated by a heating device to evaporate the liquid. In some cases, a mechanism for wiping off the liquid remaining on the surface of the SAW stirring board may be provided. For example, the SAW stirring board surface may be automatically wiped and cleaned when the measurement is finished and the liquid holding plate is taken out of the apparatus main body.

  The amount of the coupling liquid to be used is determined by the area of the liquid layer required for the liquid holding plate and the thickness of the liquid layer, and about 0.01 to 0.2 mL is usually appropriate. The thickness of the liquid layer is not particularly limited, but a thin layer is preferable as long as the air layer is not mixed. Usually, it is about 0.005 to 5 mm, desirably about 0.005 to 0.05 mm.

  The liquid stirring device of the present invention may be an independent liquid stirring device, but is usually incorporated in a measuring device that measures a signal from the liquid holding plate. Sample processing apparatuses having an agitation mechanism using a SAW agitation board are already known and are commercially available, but the supply of the coupling liquid is manually introduced when used. However, the operation of supplying the coupling liquid by such manual work is time-consuming and it is difficult to ensure the stability of the operation. For this reason, the liquid stirring device of the present invention described above is preferable as a stirring mechanism in various types of analyzers, particularly medium and small analyzers. The signal to be measured may be, for example, fluorescence or luminescence emitted from the liquid held on the liquid holding plate, the absorbance of the liquid, or the like, and even if the signal is emitted from the liquid itself, the liquid is washed. It may be emitted from a substance bonded to the inner wall of the recess after removal. A signal measured when an electrode or an electrochemical sensor is used as a detection means is an electrical signal. Thus, the “signal from the liquid holding plate” includes a signal emitted from a chemical reaction of a specific substance in the liquid held in the liquid holding plate. Examples of the liquid to be used for measurement include blood for measuring biochemical components, serum, plasma, antigen-antibody reaction solution in immunoassay, binding reaction solution between receptor and ligand in cell surface or solution, DNA chip Examples include, but are not limited to, a reaction solution between a test DNA and a nucleic acid probe, a reaction solution between a peptide and a ligand on a peptide chip, a real-time detection PCR reaction solution, and the like.

  The present invention also provides a measuring device for measuring the amount or concentration of a specific substance in a liquid, comprising a liquid stirring device and means for measuring a signal from the liquid holding plate. The measuring device of the present invention is characterized by the above-described liquid stirring device, and the other parts may be the same as those of various known automatic analyzers. Usually, the liquid holding plate is automatically placed on the SAW stirring board by a transfer means such as a belt conveyor, and the coupling liquid is applied to the contact surface between the SAW stirring board and the liquid holding plate according to the present invention as described above. In between, reactions and measurements are then performed automatically and data processing is performed.

  Hereinafter, the present invention will be described more specifically based on examples. However, the present invention is not limited to the following examples.

  In each of the following examples, the liquid holding plate used was a rectangular parallelepiped having a length of 60 mm, a width of 40 mm, and a thickness of 5 mm, and a recess having a diameter of 10 mm and a depth of 5 mm as a recess for holding the liquid. As the SAW stirring board, a SAW stirring board incorporated as a stirring mechanism in a commercially available automatic analyzer was used. Moreover, isopropanol was used as a coupling liquid, and the supply amount was 0.05 mL in each example.

Example 1
An apparatus having a means for supplying a coupling liquid according to the first embodiment shown in FIG. The sponge was impregnated with the coupling liquid, and the liquid holding plate was placed so that it touched the bottom surface of the liquid holding plate when it was transferred from the belt conveyor onto the SAW stirring board. The dimension of the sponge end face was 40 mm × 10 mm. When the coupling liquid is applied to the bottom surface of the liquid holding plate with a sponge and the liquid holding plate is placed on the SAW stirring board, a coupling liquid layer is formed between the top surface of the SAW stirring board and the bottom surface of the liquid holding plate. It was.

Example 2
An apparatus having a means for supplying a coupling liquid according to the second embodiment shown in FIG. The nozzle was placed above one end of the liquid holding plate, and the pump was operated to drop a predetermined amount (0.05 mL) of coupling liquid near the boundary between one end of the liquid holding plate and the SAW stirring board. The coupling liquid spread between the top surface of the SAW stirring board and the bottom surface of the liquid holding plate due to capillary action, and a coupling liquid layer was formed.

Example 3
An apparatus having a means for supplying a coupling liquid according to the third embodiment shown in FIG. A through hole having a diameter of 4 mm was provided in the liquid holding plate, and an aluminum foil bag containing the coupling liquid was disposed at the bottom thereof. The size of the bag made of aluminum foil was 15 mm × 15 mm × 2 mm, and the portion protruding from the through hole was inserted into the cavity in the liquid holding plate. The breaking member was a rod having a tip of 3 mm in diameter, and was driven up and down by a motor. After the liquid holding plate was placed on the SAW stirring board, the motor was actuated to lower the breaking member, and the aluminum bag was pressed and ruptured at the tip thereof, and the coupling fluid inside was allowed to flow out. The coupling fluid that flowed out spread between the upper surface of the SAW stirring board and the bottom surface of the liquid holding plate due to capillary action, and a coupling liquid layer was formed.

Comparative Example 1
After the liquid holding plate was placed on the SAW stirring board, 0.05 mL of the coupling liquid was quantified with a micropipette, and the coupling liquid was dropped near the boundary between one end of the liquid holding plate and the SAW stirring board. The coupling liquid spread between the top surface of the SAW stirring board and the bottom surface of the liquid holding plate due to capillary action, and a coupling liquid layer was formed.

Comparative Example 2
In the same manner as in the other examples, the liquid holding plate was placed on the SAW stirring board (no coupling liquid was introduced), but the SAW was turned off and no stirring by SAW was performed.

Test example 1
200 μL of water and 5 μL of the dye were quantified with a micropipette in the concave portion of the liquid holding plate, carefully put in, and the coupling solution was supplied by the method described in each example and comparative example. The time required for supplying the coupling liquid was measured. Further, the time from when the SAW oscillation element was operated to when water and the pigment were completely and uniformly mixed was measured visually. The results are shown in Table 1 below.

  As shown in Table 1, when the apparatus of the present invention is used, the coupling liquid can be supplied more quickly than in the case of manual operation (Comparative Example 1). Further, the liquid can be mixed much more rapidly than in the case of no stirring (Comparative Example 2).

It is a figure which shows typically the usage condition of the liquid stirring apparatus of this invention. It is a figure which shows typically the 1st aspect of the coupling liquid supply means of the liquid stirring apparatus of this invention. It is a figure which shows typically the 2nd aspect of the coupling liquid supply means of the liquid stirring apparatus of this invention. It is a figure which shows typically the 3rd aspect of the coupling liquid supply means of the liquid stirring apparatus of this invention. It is a figure which shows arrangement | positioning of the SAW oscillation element of a SAW stirring board in case the recessed part is provided in the liquid holding plate.

Explanation of symbols

1 Liquid holding plate 2 SAW stirring board 3 SAW stirring element 4 Coupling liquid layer 5 Liquid
6 Coupling liquid storage container 7 Coupling liquid application means 8 Coupling liquid storage container 9 Pump 10 Nozzle 11 Breakable bag or container 12 Breaking member 13 Through hole

Claims (13)

  In the liquid agitating apparatus that includes the surface acoustic wave stirring board on which the surface acoustic wave oscillation element is disposed and stirs the liquid held on the liquid holding plate placed on the surface acoustic wave stirring board, the surface acoustic wave A liquid agitation apparatus comprising coupling liquid supply means for supplying a coupling liquid between a stirring board and a contact surface of the liquid holding plate.   The liquid stirring apparatus according to claim 1, wherein the liquid holding plate has one or a plurality of concave portions provided in the liquid holding plate, and the liquid is accommodated in the concave portions.   The liquid surface stirring device according to claim 2, wherein the surface acoustic wave stirring board includes one or a plurality of surface acoustic wave oscillation elements corresponding to the one or the plurality of concave portions, respectively.   The coupling liquid supply means is a coupling liquid application means disposed at a position in contact with the bottom surface of the liquid holding plate when the liquid holding plate is placed on the surface acoustic wave stirring board. Item 4. The liquid stirring device according to any one of Items 1 to 3.   5. The liquid agitating device according to claim 4, wherein the coupling liquid applying means is obtained by impregnating a sponge-like porous body with a coupling liquid.   The coupling liquid supply means includes a nozzle for supplying the coupling liquid to a contact portion between the liquid holding plate and the surface acoustic wave stirring board, and a coupling liquid storage container connected to the nozzle via a pump. When the coupling liquid is contained in the coupling liquid storage container and the liquid holding plate is placed on the surface acoustic wave stirring board, the coupling liquid is supplied from the nozzle by the pump. The liquid stirring apparatus according to any one of claims 1 to 3.   The liquid holding plate is provided with a breakable bag or container for containing the coupling liquid therein, and the coupling liquid supply means includes the liquid holding plate on the surface acoustic wave stirring board. The liquid agitator according to any one of claims 1 to 3, wherein the breakable bag or container is destroyed after being placed on the liquid and the coupling liquid is allowed to flow out.   The liquid stirrer according to claim 7, wherein the breakable bag or container is disposed in a through hole provided in the liquid holding plate.   The liquid agitation device according to any one of claims 1 to 8, wherein the liquid agitation device is incorporated in a measurement device that measures a signal from a liquid holding plate.   10. A measuring apparatus for measuring the amount or concentration of a specific substance in a liquid, comprising the liquid agitating apparatus according to claim 1 and means for measuring a signal from the liquid holding plate. .   The measuring apparatus according to claim 10, further comprising means for placing the liquid holding plate on the surface acoustic wave stirring board.   The liquid holding plate used with the liquid stirring apparatus of Claim 7 or 8 with which the breakable bag or container which accommodates the said coupling liquid was arrange | positioned inside. The liquid holding plate according to claim 12, wherein the breakable bag or container is disposed in a through-hole provided in the liquid holding plate.

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