Method and system for measuring the flow characteristics of a liquid

Abstract

The objective of the present invention is to provide a measuring instrument or the like capable of measuring a flow property of a small amount of a sample.　A measuring instrument 101 for measuring a flow property of a test liquid 5 includes: a pushing-back means for pushing back, to a second opening portion 112 side of a capillary tube 11 having a first opening portion 111 and the second opening portion 112, the test liquid 5, which has flowed into the capillary tube 11 from the second opening portion 112 side toward the first opening portion 111 side; a regulating valve for regulating a flow of liquid in the capillary tube 11; and a measuring portion 6 for measuring an arrival time tn at a liquid surface position Ln in the capillary tube 11.

Description

Method and instrument for measuring flow characteristics of liquid

[0001] The present invention relates to a method and an instrument for measuring the flow properties of a liquid.

[0002] Various experiments using biological samples or biosamples may require precise measurement and comparison of the viscosity of minute amounts of liquid samples, or measurement of viscosity that fluctuates over a short period of time, such as blood coagulation.

[0003] Patent Document 1 discloses a body fluid viscosity measuring device that measures the viscosity of body fluids, characterized by comprising a flow path through which the body fluid flows due to the action of force caused by capillary action, and a calculation means that performs regression analysis based on the distance traveled by the body fluid along the flow path and the time required to travel that distance, and derives the viscosity of the body fluid.

[0004] Patent Document 2 discloses a liquid collection device having a main body having a capillary-shaped fine flow path with a first opening and a second opening, and a switching valve connected to the first opening side, the switching valve having a flow path connected to the main body and a flow path open to the atmosphere and / or a flow path connected to a sealed container.

[0005] Furthermore, Non-Patent Document 1 relates to a method for evaluating viscosity and surface tension of low-volume samples using a glass capillary, and shows that the viscosity coefficients of sucrose solutions of various concentrations can be measured by the methods described in Patent Documents 1 and 2, etc., and values ​​that agree with the literature values ​​can be obtained.

[0006] JP 2020-008342 A JP 2021-001762 A

[0007] Kenji Sakamoto et al 2020 Jpn. J. Appl. Phys. 59 107002

[0008] The techniques described in Patent Documents 1 and 2 and Non-Patent Document 1 make it possible to measure the viscosity and surface tension of a small amount of sample.

[0009] The present inventors considered that the configurations of Patent Documents 1 and 2 and Non-Patent Document 1 could be further applied, and studied configurations for further utilization. Under such circumstances, an object of the present invention is to provide a measuring device, method, etc. that can measure flow characteristics such as viscosity of a small amount of sample.

[0010] The present inventors have conducted extensive research to solve the above problems and have found that the following inventions meet the above objectives, thereby completing the present invention.

[0011] <1> A method for measuring flow characteristics of a test liquid using a measuring instrument including: a push-back means for pushing a test liquid that has flowed into a capillary having a first opening and a second opening from the second opening side toward the first opening side, an adjustment valve for adjusting the flow of liquid in the capillary, and a measuring unit for measuring the arrival time tn at a liquid level position Ln in the capillary. <2> The method according to <1>, wherein the push-back means is a pressure adjusting unit connected to the first opening side and capable of setting a pressure to push the test liquid that has flowed into the capillary back toward the second opening side, the adjustment valve has a switching valve for switching the connection between the pressure adjusting unit and the capillary, and the detecting unit measures the flow characteristics of the test liquid using a measuring instrument including a push-back detecting unit that detects when the test liquid in the capillary has been pushed back toward the second opening side and passed through. <3> The method according to <2>, wherein the pressure adjustment unit includes a container, an adjustment piston connected to the container, and a mechanism that, in conjunction with the switching valve, opens the container to atmospheric pressure until just before isothermal compression and / or isothermal expansion to maintain the inside of the container at atmospheric pressure, and when adjusting the pressure inside the container, after isolating the container from the atmosphere, changes the volume of the container and the adjustment piston using the adjustment piston to adjust the predetermined pressure inside the container using isothermal compression and / or isothermal expansion. <4> The method according to <2> or <3>, wherein the measuring instrument has a liquid reservoir in contact with the second opening side, and measures the flow characteristics inside the capillary of the test liquid contained in the liquid reservoir that has flowed in from the second opening, and includes a first push-back step of connecting the pressure adjustment unit to the first opening at a pressure higher than a critical pressure, sending the test liquid that has flowed into the capillary from the second opening to the liquid reservoir, and stopping the push-back when the test liquid has been pushed back to the push-back detection unit. <5> The method according to any one of <2> to <4>, further comprising, after the first pushing back step, a step of mixing a test component with the test liquid in the liquid reservoir and measuring flow characteristics when the test liquid is allowed to flow into the capillary tube.<6> The method according to any one of <2> to <5>, which measures the flow characteristics of the test liquid contained inside the capillary in an amount less than the capacity of the capillary, and includes a second push-back step of connecting the pressure adjustment unit to the first opening to apply a pressure that pushes the test liquid contained in the capillary back toward the second opening, and stopping the push-back when the test liquid is pushed back to the push-back detection unit. <7> The method according to any one of <2> to <6>, which measures multiple test liquids using the same capillary, and includes connecting the first opening to the pressure adjustment unit adjusted to a pressure that pushes the test liquid in the capillary back toward the second opening, and discharging the test liquid contained in the capillary from the capillary for use in testing another test liquid. <8> The method according to any one of <2> to <7>, wherein the capillary is inclined. <9> The method according to <8>, wherein the pressure adjustment unit is further capable of adjusting the pressure in stages. <10> The method according to any one of <1> to <9>, wherein the push-back means has an inclined platform for positioning the capillary, and can be installed in either an arrangement for allowing the first opening side to be lower than the second opening side for flow, or an arrangement for pushing back the test liquid in the capillary with the second opening side lower than the first opening side. <11> The method according to any one of <1> to <10>, wherein a reagent is installed inside the capillary to be mixed with the test liquid and react. <12> A measuring instrument for measuring flow characteristics of a test liquid, comprising: push-back means for pushing back test liquid that has flowed into a capillary having a first and second opening from the second opening side toward the first opening side, toward the second opening side; an adjustment valve for adjusting the flow of liquid in the capillary; and a measuring unit for measuring the arrival time tn at the liquid level position Ln in the capillary.

[0012] According to the present invention, the flow characteristics of a small amount of sample can be measured.

[0013] FIG. 1 is a schematic diagram of a measuring instrument according to an embodiment of the present invention. FIG. 1 is a schematic diagram for explaining the principle of a first embodiment of the present invention. FIG. 2 is a schematic diagram of a flow in a capillary tube for explaining the principle of a first embodiment of the present invention. FIG. 2 is a schematic diagram for explaining the principle of a pressure adjusting unit that can be used in the present invention. FIG. 3 is a schematic diagram related to differential pressure and flow characteristics for explaining the principle of a first embodiment of the present invention. FIG. 4 is a schematic diagram related to detection of a liquid level position at a sensor by a measuring instrument according to the present invention. FIG. 5 is a flow chart related to a first embodiment of the present invention. FIG. 6 is a schematic diagram of a capillary tube according to a second embodiment of the present invention. FIG. 7 is a flow chart related to a second embodiment of the present invention. FIG. 8 is a schematic diagram related to detection of a liquid level position at a sensor by a measuring instrument according to a second embodiment of the present invention. FIG. 9 is a schematic diagram related to the arrangement of capillaries according to a fifth embodiment of the measuring instrument according to the present invention. FIG. 10 is a schematic diagram related to differential pressure and flow characteristics of a capillary tube according to the fifth embodiment of the present invention. FIG. 11 is a schematic diagram related to the arrangement of capillaries according to a sixth embodiment of the measuring instrument according to the present invention. FIG. 12 is a graph of measurement results of an example of the present invention. FIG. 13 is a graph of measurement results of an example of the present invention. FIG. 14 is a graph of measurement results of an example of the present invention. 10 is a graph showing measurement results of an example of the present invention.

[0014] The following describes in detail an embodiment of the present invention, but the following description of the constituent elements is one example (typical example) of an embodiment of the present invention, and the present invention is not limited to the following content unless the gist of the present invention is changed. Note that when the expression "to" is used in this specification, it is used as an expression including the numerical values ​​before and after it.

[0015] [Measuring Instrument of the Present Invention] The measuring instrument of the present invention is a measuring instrument for measuring the flow characteristics of a test liquid, and comprises: a push-back means for pushing back a test liquid that has flowed into a capillary having a first opening and a second opening from the second opening side toward the first opening side, to the second opening side; an adjusting valve for adjusting the flow of liquid in the capillary; and a measuring unit for measuring the arrival time tn at the liquid level position Ln in the capillary.

[0016] The measuring instrument of the present invention can also be a measuring instrument for measuring the flow characteristics of a test liquid, which comprises, for example, a capillary tube having a first opening and a second opening, a pressure adjustment unit connected to the first opening side and capable of setting a pressure to push the test liquid that has flowed into the capillary tube back to the second opening side, a switching valve for switching the connection between the pressure adjustment unit and the capillary tube, a measuring unit for measuring the arrival time tn at the liquid level position Ln in the capillary tube, and a pushback detection unit for detecting that the test liquid in the capillary tube has been pushed back to the second opening side and passed through.

[0017] [Measurement Method of the Present Invention] The measurement method of the present invention is a method for measuring the flow characteristics of a test liquid using a measuring instrument having: a push-back means for pushing back, to the second opening side, a test liquid that has flowed into a capillary having a first opening and a second opening from the second opening side toward the first opening side; an adjustment valve for adjusting the flow of liquid in the capillary; and a measurement unit for measuring the arrival time tn at the liquid level position Ln in the capillary.

[0018] The measurement method of the present invention can also be a method for measuring the flow characteristics of a test liquid using a measuring instrument having, for example, a capillary tube having a first opening and a second opening, a pressure adjustment unit connected to the first opening side and capable of setting a pressure that pushes the test liquid that has flowed into the capillary tube back toward the second opening side, a switching valve for switching the connection between the pressure adjustment unit and the capillary tube, a measuring unit for measuring the arrival time tn at the liquid level position Ln in the capillary tube, and a pushback detection unit for detecting that the test liquid in the capillary tube has been pushed back toward the second opening side and passed through.

[0019] In the present application, the measuring method of the present invention can also be performed using the measuring device of the present invention, and the corresponding configurations can be used mutually.

[0020] The present invention has a configuration that allows the capillary to be reused repeatedly, which means that the device is not affected by changes in the capillary itself due to changes in the capillary, and therefore allows for accurate detection of flow characteristics such as minute changes in viscosity.

[0021] Pressure is applied to the test liquid sample that has flowed through the capillary, forcing it back to the flow start position and then flowing back into the capillary for flow measurement. Therefore, the same capillary is used repeatedly, resulting in good reproducibility of measurement results. Furthermore, the liquid reservoir can be used as a reaction vessel, and its displacement can be detected. Furthermore, it is possible to track changes over time, such as viscosity, which changes over a short period of time, for example, a half-life of one minute.

[0022] Conventional methods can be affected by the capillary tube itself, making it difficult to track changes over short periods of time.

[0023] Furthermore, in the present invention, the inclination of the capillary tube may be adjusted to perform measurements in an inclined state, or the test liquid may be pushed back into the capillary tube by adjusting the pressure inside the capillary tube or by applying other forces. For example, since the influence of gravity increases when the capillary tube is tilted, the test liquid may be pushed back by using a tilting table that can change the inclination and direction of the capillary tube.

[0024] 1 is a representative schematic diagram of a measuring instrument according to an embodiment of the present invention. The measuring instrument 101 uses a capillary tube 11. The measuring instrument 101 includes the capillary tube 11, a switching valve 2, a pressure adjusting unit 3, a detecting unit 6, and a control unit 8. The mounting table 7 includes a liquid reservoir 4, and can be positioned so that the second opening 112 of the capillary tube 11 comes into contact with the test liquid 5 contained in the liquid reservoir 4.

[0025] [Capillary 11] The capillary 11 has a hollow capillary-shaped microchannel, with a first opening 111 and a second opening 112 at both ends of the microchannel. The first opening 111 is connected to the switching valve 2 via a channel 21. The capillary 11 may be, for example, a commercially available capillary used for attaching a sample point in chromatography or an electrode in electrophysiological experiments. Capillaries include those in which capillary action occurs, such as hydrophilic microchannels.

[0026] The capillary tube 11 has a microscopic capillary flow path and is a flow path of a size that allows capillary action to occur. The amount of liquid that enters the microscopic flow path and its flow are determined by capillary force, which is determined by surface tension, contact angle with the flow path, size of the flow path, etc., as well as pressure within the microscopic flow path space, frictional force, and gravity. The radius of the microscopic flow path suitable for measuring viscosity using such capillary action is approximately 1.0 mm or less, or 0.5 mm or less.

[0027] The present invention is also suitable for use with minute amounts of liquid. For example, it is suitable for measuring blood or saliva, which contain water as the main medium. When measuring such water-containing liquids, it is preferable to use a hydrophilic capillary 11 that is easy to cause capillary action. For liquids containing a large amount of oil, a hydrophobic capillary may be used. The capillary 11 may be made of glass, for example.

[0028] [Switching valve 2] Switching valve 2 is connected to first opening 111 via flow path 21. Switching valve 2 can be opened or closed to the atmosphere, or can be switched to connect to pressure adjustment unit 3. For this switching, flow paths 22 and 23 are used as appropriate. Because capillary action progresses relatively quickly, it is preferable to use an electromagnetic valve as switching valve 2, which can instantly control the start and stop of measurement using an electric signal.

[0029] The switching valve 2 is housed in the liquid reservoir and is linked to a sensor that switches the stop / start of the flow of the liquid that enters the capillary tube from the second opening 112, thereby linking the timing of the flow with the timing of measurement.

[0030] In the measuring instrument 101, the switching valve 2 is preferably an electromagnetic valve. Preferably, a stop sensor for detecting the passage of the liquid level is provided before the first opening 111 of the capillary tube 11, and when the stop sensor detects the liquid level, it sends a signal to close the switching valve 2, thereby closing the switching valve 2 and stopping the flow of liquid within the capillary tube 11. Alternatively, a sensor attached for timing purposes, such as sensor 66, may be used in combination with the stop sensor. The liquid contained in the capillary tube 11 may be discharged, cleaned, or rinsed as needed, and reused.

[0031] In addition to using a signal to stop the flow when the stop sensor detects the liquid level, a signal to stop the flow may be issued when a certain time has elapsed since the start of the flow. The certain time until the flow stops can be set appropriately depending on the length of the capillary tube, the flow rate of the liquid, etc. For example, the upper limit of the stopping time can be set to 10 seconds, 5 seconds, 3 seconds, or 2 seconds.

[0032] [Flow path 21] The first opening 111 of the capillary 11 and the switching valve 2 can be connected by any means. The capillary 11 may be connected using a flexible tube as the flow path 21 to facilitate replacement. It is preferable to use a hydrophobic material for this flow path 21. As partially described above, it is preferable to use a hydrophilic material for the capillary 11 so that capillary action is likely to occur. On the other hand, it is preferable that the test liquid does not excessively flow beyond the first opening 111 of the micro flow path and into the switching valve 2 side. For this reason, by using a hydrophobic tube for the flow path 21, capillary action is unlikely to occur within the flow path 21, and the test liquid stops near the first opening 111.

[0033] [Push-back Means] The measuring device may have a push-back means. In the measuring device 101 of Figure 1, the test liquid 5 first flows into the capillary tube 11 from the second opening 112 side of the capillary tube 11 toward the first opening 111 side. A push-back means is used to push the test liquid 5 back to the second opening 112 side from a state where it has flowed to a predetermined position, in order to perform remeasurement, replace the test liquid, etc. The push-back means of the measuring device 101 is configured using the pressure adjustment unit 3, etc.

[0034] [Adjusting Valve] The measuring instrument has an adjusting valve for adjusting the flow of liquid in the capillary. The adjusting valve is a valve used to stop the flow of liquid in the capillary, push back the liquid, or change the pressure to change the flow rate, etc. In the measuring instrument 101, a switching valve 22 or the like functions as an adjusting valve for changing the state of the pressure on the first opening 111 side when, for example, flowing the test liquid 5 into the capillary 11, pushing back the test liquid 5 by pressure, or stopping the flow of the test liquid 5.

[0035] [Pressure Adjustment Unit 3] The pressure adjustment unit 3 is connected via the switching valve 2 so that it can be connected to the first opening 111 side. The pressure adjustment unit 3 may be maintained at atmospheric pressure except during measurement of the flow time. The pressure adjustment unit 3 can be used by adjusting it to a pressure other than atmospheric pressure when measuring the flow time. The pressure adjustment unit 3 can be configured to recognize that it is adjusted to multiple pressures. The pressure adjustment unit 3 is a part adjusted to negative pressure, positive pressure, or atmospheric pressure. The pressure adjustment unit 3 can be set to at least a pressure that pushes the liquid that has flowed into the capillary 11 back toward the second opening 112 side.

[0036] [Pressure adjustment using an air reservoir container and an adjustment piston] The pressure adjustment unit 3 preferably has an air reservoir container 30 and an adjustment piston 32 connected to the air reservoir, and the adjustment piston changes the total volume of the interior connected to the air reservoir to perform isothermal compression or isothermal expansion. The procedure for pressure adjustment using an air reservoir and piston is described below (FIGS. 4(a) and 4(b)). By performing pressure adjustment in this manner, minute pressure adjustment within a capillary tube, as required by the present invention, can be performed without using a pump, a barometer, or complex control.

[0037] [Combination of pressure adjustment unit 3 and switching valve 2] By combining the pressure adjustment unit 3 and switching valve 2 (hereinafter simply referred to as combination), the following states (1) to (4) can be realized. (1) The pressure adjustment unit 3 is isolated from the atmosphere. The flow path 21 is closed. (2) The pressure adjustment unit 3 is open to the atmosphere. The flow path 21 is closed. (3) The pressure adjustment unit 3 is isolated from the atmosphere. The pressure adjustment unit 3 and the flow path 21 are connected. (4) The pressure adjustment unit 3 is open to the atmosphere. The pressure adjustment unit 3 and the flow path 21 are connected.

[0038] [Administering Sample] With the flow channel 21 closed (combination (1) or (2)), the sample to be tested is administered to the second opening. The sample is drawn into the capillary due to surface tension. The air pressure inside the capillary increases and stops when it balances with the surface tension. Any sample that is not drawn in remains in the reservoir. When the amount of sample is extremely small (up to 5 uL), the entire administered sample is drawn into the capillary and remains near the second opening 112.

[0039] [Pressure setting 1: flow under atmospheric pressure] Sample administration is performed in the combined state (2). The following measurements are possible if a sufficient amount of sample remains in the liquid reservoir. After administration, the switching valve is operated to transition to the combined state (4). The sample flows through the capillary tube driven by surface tension and reaches the first opening 111 of the capillary tube 11. Switching valve 2 is activated to close the flow path 21, transitioning to the combined state (2). Flow stops.

[0040] [Pressure setting 2: positive pressure] Sample administration is performed in combination (2). The pressure inside the pressure adjustment unit is equal to atmospheric pressure. With the adjustment piston pulled out as shown on the left in Figure 4(a), the process moves to combination (1). The pressure adjustment unit is isolated from the atmosphere. The adjustment piston is then pushed in. The pressure inside the pressure adjustment unit increases by ΔP in the following formula. Here, P0 is atmospheric pressure. V0 is the volume of the container. v1 is the volume inside the piston. ΔP = P0 v1 / V0

[0041] From this state, the switching valve is operated to transition to combination (3). Flow recording under positive pressure is achieved. As soon as the flow ends, the switching valve is operated to return to combination (2). The pressure adjustment unit 3 is opened to atmospheric pressure, and the flow path 21 is closed.

[0042] [Pressure setting 3: negative pressure] Sample administration is performed in combination (2). The pressure inside the pressure adjustment unit is equal to atmospheric pressure. With the adjustment piston pushed in as shown on the left in Figure 4 (b), the process moves to combination (1). The pressure adjustment unit 3 is isolated from the atmosphere. The adjustment piston is then pulled out. The internal pressure of the pressure adjustment unit changes by ΔP in the following formula (note that ΔP is negative, so the pressure inside the pressure adjustment unit becomes negative). Here, P0 is atmospheric pressure. V0 is the volume of the container. v1 is the volume inside the piston. ΔP = -P0 v1 / V0

[0043] From this state, the switching valve 2 is operated to transition to combination (3). Flow recording under negative pressure is achieved. As soon as the flow ends, the switching valve 2 is operated to return to combination (2). The pressure adjustment unit 3 is opened to atmospheric pressure, and the flow path 21 is closed.

[0044] [Pressure Gauge 31] It is preferable to attach a pressure gauge 31 to the pressure adjustment unit 3 to measure the pressure. Various pressure gauges that measure atmospheric pressure can be used as the pressure gauge 31. In particular, in the present invention, it is preferable to use a micro-differential pressure gauge that can measure pressures in a measurement range of approximately ±10,000 Pa, ±5,000 Pa, ±1,000 Pa, ±500 Pa, or ±300 Pa relative to atmospheric pressure, and with a scale that is graduated in increments of approximately 10 Pa, 1 Pa, or 0.5 Pa.

[0045] In the present invention, negative pressure is used as the pressure, making it suitable for measuring highly viscous samples. Highly viscous samples have poor flow characteristics due to capillary action, so they can be difficult to measure using atmospheric pressure or positive pressure, but using negative pressure improves the flow characteristics and makes measurement easier. When using negative pressure to measure highly viscous samples, a negative pressure of 5,000 to 10,000 Pa may be used.

[0046] The pressure adjusting unit 3 can be, for example, a unit that connects a pressure vessel and a vacuum pump via a valve and adjusts the pressure according to the degree of opening or closing of the valve. The pressure adjusting unit 3 only needs to be able to grasp and manage the pressure, and as described above, it can be equipped with a pressure gauge 31 to measure the pressure at that time and use the measured pressure to calculate the correlation. Alternatively, the pressure when the conditions related to the pressure vessel, etc. of the pressure adjusting unit 3 are set can be grasped in advance and used as the pressure. Specifically, it is possible to attach a syringe to the vessel and grasp the pressure using the syringe's suction scale.

[0047] [Liquid Reservoir 4] The liquid reservoir 4 contains a sample to be tested. The second opening 112 of the capillary tube 11 comes into contact with the test liquid contained in the liquid reservoir 4.

[0048] The amount of test liquid contained in the liquid reservoir 4 can be set appropriately depending on the type, viscosity, and various conditions that affect surface tension (capillary size), etc., but can be in the range of 500 μL or less, 300 μL or less, 100 μL or less, or 50 μL or less, and the lower limit can be a very small amount of liquid, such as 1 μL or more, 5 μL or more, or 10 μL or more.

[0049] [Test Liquid 5] Any liquid that exhibits capillary action can be used as the test liquid 5. This liquid may contain various dissolved or dispersed components. Biological samples such as blood and saliva can also be used. Emulsions, polymer solutions, particle suspensions, and the like can also be used. The measuring device 101 can measure the flow characteristics of the test liquid 5 in the capillary tube 11. Furthermore, the capillary tube 11 and, if necessary, the flow path 21 can be removed and easily discarded.

[0050] [Measurement Unit 6] The measurement unit 6 measures the arrival time tn at the liquid level position Ln in the capillary tube. The liquid level position Ln is a detection target position at a predetermined distance from the second opening 112, and the arrival time tn is the arrival time from the second opening 112 to the liquid level position Ln. The measurement unit 6 has sensors 61-66 and a timing unit 60. The sensors 61-66 detect the passage of the liquid level of the test liquid flowing through the capillary tube 11. They are used to detect the flow time and passage speed of the liquid flowing through the capillary tube 11 over the flow distance. Multiple sensors 61-66 (six in FIG. 1 ) are arranged side by side in the microchannel of the capillary tube 11 at predetermined intervals. The sensors 61-66 can detect the passage of the liquid level in the microchannel at corresponding positions. The sensors 61-66 are arranged on the mounting table 7.

[0051] For example, sensors 61 to 66 can each be an optical sensor that detects the passage of a liquid surface within the microchannel. When the liquid fluctuates within the microchannel, the liquid surface becomes significantly easier to observe by optical means due to the difference in refractive index and / or light scattering between the liquid and the gas in the space. The presence or absence of the passage of this liquid surface can be detected by each of sensors 61 to 66 corresponding to that position.

[0052] The sensors used in the measuring device of the present invention include those that detect the passage of the liquid surface using a reflection method, those that detect using a transmission method, and those that use a line sensor or area sensor to obtain information on the flow state as a video, etc., and then detect the flow time and passing speed from the video, etc.

[0053] The measuring device 101 detects the time it takes for the liquid to flow over a distance and the speed at which the liquid passes over that distance using sensors 61 to 66. To this end, the measuring device 101 is equipped with a timer 60 that also acquires the time at which the sensors 61 to 66 detect the passage of the liquid surface.

[0054] In the present invention, the flow characteristics may be measured from the flow time corresponding to the inflow direction from the second opening 112 to the first opening 111 and pressure adjustment unit 3 side, or conversely, the flow characteristics may be measured from the flow time corresponding to the push-back direction from the first opening 111 and pressure adjustment unit 3 side to the second opening 112 side by push-back. The arrival time tn at the liquid level position Ln in the capillary tube can be obtained by selecting and using an appropriate sensor according to the orientation at that time.

[0055] [Timer 60] The timer 60 measures the time (flow time) for the liquid surface to pass the positions corresponding to the sensors 61 to 66 and the speed (passing speed) when passing that flow distance. The timer 60 is also connected to the switching valve 2, and measures the detection time of the sensors 61 to 66 when the switching valve 2 is switched.

[0056] The sensors 61 to 66 and the timing unit 60 constitute a measurement unit that measures the flow time tn (t1 to t6) until the liquid surface of the test liquid 5 passes through the flow distance Ln (L1 to L6) of the capillary tube 11, and the passing speed vn (v1 to v6).

[0057] In the measuring device 101, the switching valve 2 is preferably an electromagnetic valve. The measuring device 101 also preferably has a stop sensor that detects the liquid level in the capillary tube 11, and when the stop sensor detects the liquid level, it sends a signal to stop the switching valve 2, closing the switching valve 2 to stop the flow of liquid within the capillary tube 11. This stop sensor may be attached near the first opening 111 of the capillary tube 11 for stopping the flow. Alternatively, a sensor attached for timing, such as sensor 65 or sensor 66, may be used in combination with the stop sensor. If liquid gets into the flow path 21, the measuring device 101 may become contaminated, which may complicate recovery work.

[0058] [Push-back detection unit 69] Push-back detection unit 69 detects when the liquid in capillary tube 11 has been pushed back toward second opening 112 and passed through. Push-back detection unit 69 can be a sensor that detects the liquid level in the same way as sensors 61 to 66. Alternatively, any of sensors 61 to 66, for example sensor 61, may be used as a sensor to be used in conjunction with push-back detection unit 69. Push-back detection unit 69 preferably detects the position within capillary tube 11 to stop the tip of the liquid level within capillary tube 11 and prevent gas from entering liquid reservoir 4 via capillary tube 11.

[0059] [Placement table 7] The placement table 7 supports the capillary tube 11. The capillary tube 11, the liquid reservoir 4, and a substrate on which the sensors 61 to 66 are arranged are provided on the placement table 7. The placement table 7 is configured so that the micro flow path of the capillary tube 11 has a predetermined inclination. The placement table 7 is also configured so that the second opening 112 of the capillary tube 11 comes into contact with the test liquid 5 when the test liquid 5 is contained in the liquid reservoir 4.

[0060] [Controller 8] The controller 8 controls and processes various functions of the measuring device. The controller 8 may include a memory unit 80, a pressure controller 81, a switching valve controller 82, a waveform analyzer 83, a characteristics analyzer 84, a flow controller 85, and the like.

[0061] [Storage Unit 80] The storage unit 80 is a part that stores measurement values ​​obtained when performing the measurement of the present invention, calculation formulas for calculating each processing data, and programs for performing the processing.

[0062] The pressure control unit 81 sets the pressure of the pressure adjustment unit 3 according to the measurement situation. In the present invention, the pressure adjustment unit 3 can be operated while appropriately switching between positive pressure, negative pressure, atmospheric pressure, etc. For this purpose, it adjusts the adjustment piston, cooperates with the switching valve (solenoid valve), and manages the measured values ​​of the pressure gauge.

[0063] The switching valve control unit 82 can appropriately switch the switching valve 2. Depending on the measurement state based on the flow condition in the capillary tube 11, the flow direction, and other purposes, the switching valve 2 connects the capillary tube 11 to the pressure adjustment unit 3, opens it to atmospheric pressure, or connects it to neither and keeps it closed.

[0064] The waveform analysis unit 83 analyzes waveforms such as peaks measured by the measurement unit 6 to analyze the transit time, transit position, flow direction, etc. The characteristic analysis unit 84 analyzes the flow characteristics of the test liquid, such as viscosity and surface tension, from the results of waveform analysis of changes in the liquid level due to flow. The flow control unit 85 controls the operation of the entire measuring device according to the measurement purpose and each flow.

[0065] [Display Unit 91] The display unit 91 is a monitor that displays the measured flow characteristics, various conditions, regression equations for the calculation process, and the like.

[0066] The measuring instrument 101 can be realized by applying a program for causing each part of the control unit 8 to function to a personal computer, tablet terminal, smartphone, or the like.

[0067] [Amount of liquid flowing (penetrating) into capillary] Figure 2 is a schematic diagram for explaining the principle of a first embodiment of the present invention. A capillary with an inner diameter D is placed horizontally. One end of the capillary (the right end in the figure) is in contact with a liquid reservoir (not shown). The liquid reservoir is maintained at atmospheric pressure P0, and the inside of the capillary is maintained at pressure P. The sample liquid in the reservoir, which is the test liquid, penetrates and moves into the capillary, driven by the resultant force of surface tension and pressure difference ΔP. The penetration distance of the sample is defined as l. When ΔP>0, it is called positive pressure, and when ΔP<0, it is called negative pressure.

[0068] The viscosity of the sample is η and the surface tension is σ. The time elapsed from the start of flow is t. The change in the penetration distance l of the sample over time is expressed by equation (1). The coefficient D / 16η (4σ - DΔP) on the right-hand side t is called the "flow coefficient" and is abbreviated as IWs. IWs is expressed by equation (2).

[0069]

[0070]

[0071] The symbols used in the above formula and in this application are as follows: D: inner diameter (mm) of capillary tube; σ: surface tension (mN / m) of sample; η: viscosity of sample (mPa·s); l: length of test liquid entering the tube (mm); t: elapsed time (ms); ΔP (Pa): represents the difference between the internal pressure of the container (standard pressure Pn) and atmospheric pressure (P0) during measurement, ΔP = Pn - P0.

[0072] The measuring device and the measuring method of the present invention evaluate the flow characteristics of the test liquid based on the behavior of the liquid in such a capillary tube, from the liquid level position, flow time, etc. As for the flow characteristics, relative measurements may be made for multiple liquids or the same liquid simply using time as an index, or viscosity may be measured in combination with known values, etc.

[0073] [Pushing back of liquid in capillary tube] Figure 3 is a schematic diagram of the flow in a capillary tube to explain the principle according to the first embodiment of the present invention. The upper row (a) shows the standby state. The middle row (b) shows the state when the flow has ended. The lower row (c) shows the state after the liquid has been pushed back.

[0074] Starting from the standby state shown in Figure 3(a), the switching valve is opened while the pressure inside the container is maintained at a value lower than the critical pressure. The sample is sucked into the capillary tube from the liquid reservoir. The movement of the tip is expressed by equation (1).

[0075] The signal example shown in Figure 6, which will be described later, is the signal of pure water when the inside of the container is pushed back by creating a positive pressure greater than the critical pressure. When the sensor detects that the sample has reached the stop sensor, the switching valve is closed. The pressure inside the capillary tube quickly reaches the critical pressure, and the movement of the test liquid stops.

[0076] [Adjustment of Pressure Regulator] FIG. 4 is a schematic diagram illustrating the principle of the pressure regulator that can be used in the present invention. As shown in FIG. 4(a), the pressure regulator can achieve positive pressure by utilizing isothermal compression. When isothermally compressed, the pressure inside the container before compression is assumed to be equal to atmospheric pressure P0. If the pressure inside the container after compression is P0 + ΔP, then the equation "P0(V0+v1) = (P0+ΔP)V0" holds. From this, it can be determined that "ΔP = P0·v1 / V0." Furthermore, by using the same principle in reverse, negative pressure can also be achieved by isothermal expansion as shown in FIG. 4(b).

[0077] FIG. 5 is a schematic diagram of differential pressure and flow characteristics to explain the principle according to the present invention. When ΔP is 0, the aforementioned IWs is "Dσ / 4η". When ΔP is "4σ / D", IWs becomes 0. In other words, the liquid does not flow. If the pressure is such that IWs becomes a negative value, the liquid can be pushed back. The value of the y-intercept "Dσ / 4η" of this plot represents the movement under atmospheric pressure. From this value, the ratio of the viscosity η to the surface tension σ of the test liquid can be determined. The value of the surface tension of the test liquid can be calculated from the x-intercept "4σ / D" of this plot. The value of the x-intercept "ΔP c1 = 4σ / D” is called the critical pressure in the first embodiment of the present invention.

[0078] [Critical Pressure] If sample remains in the reservoir, a pressure equal to or greater than the critical pressure is required to push it back. For example, if the inner diameter is 0.68 mm, the critical pressure is approximately 400 Pa. This critical pressure value depends on the capillary inner diameter and the surface tension of the sample. However, if the difference from the critical pressure is small, the push-back speed is very slow, so a pressure of 100 Pa or more above the critical pressure is preferable. Typically, a pressure of approximately 600 to 700 Pa can be used for pushing back. On the other hand, if this pressure is too high, the "return" may be too fast, resulting in turbulence and instability.

[0079] FIG. 6 is a schematic diagram of the detection of the liquid level position by a sensor in the measuring device of the present invention. This FIG. 6 shows the signal detected when the liquid is pushed back. When the liquid level passes the sensor, a large change in potential occurs. When the push-back detection unit 69 detects a signal for the selected sensor, it closes the solenoid valve and releases the positive pressure. This stops the flow of liquid within the capillary tube.

[0080] [First embodiment] In the first embodiment of the present invention, the test liquid in the capillary tube is placed horizontally, and the pressure of the pressure adjusting unit is adjusted to a critical pressure ΔP c1 7 is a flow chart showing a first embodiment of the present invention.

[0081] Step S10 is a step of placing liquid in the liquid reservoir. Step S11 is a step of bringing the second opening into contact with the liquid in the liquid reservoir and allowing the liquid to flow into the capillary through the second opening. Step S12 is a step of switching the selector valve to connect the first opening of the capillary to a portion set to the conditions for measuring flow characteristics, allowing the liquid to flow within the capillary, and measuring the flow characteristics during inflow. The first opening can be opened to atmospheric pressure, for example, or it can be set to negative pressure to allow the liquid to flow more actively. Step S13 is a step of adjusting the selector valve on the first opening side to stop the liquid from flowing into the capillary when the inflow stop position is exceeded.

[0082] Step S14 is a step of switching the selector valve on the first opening side to connect the first opening to a pressure adjusting section adjusted to a critical pressure or higher, thereby pushing back the liquid. Step S15 is a step of switching the selector valve to stop the liquid in the capillary tube when it passes through the push-back detecting section.

[0083] Step S20 is a step for determining whether a predetermined number of tests have been performed. If the predetermined number of tests have not yet been completed (No), the process proceeds to step S31. Step S31 is a step for performing processing to appropriately change the test conditions and perform the test, for example, by changing the time, temperature, or reaction with a reagent, etc. to change the physical properties of the liquid in the liquid reservoir. Step S32 is a step for changing the inflow conditions on the first opening side after the predetermined changes have been completed.

[0084] After this, the flow characteristics of the liquid in that state are measured again in steps S11 to S15. Then, in step S20, it is confirmed whether the number of tests has been performed, and this process is repeated until the predetermined number of tests have been performed. If the predetermined number of tests has been performed (Yes), the test is completed.

[0085] In this way, the measurement method according to the first embodiment of the present invention can perform testing in a state where the measuring device has a liquid reservoir in contact with the second opening side, and measures the flow characteristics when the liquid contained in the liquid reservoir flows into the capillary tube through the second opening.

[0086] The method of the present invention can include a first push-back step in which the pressure adjustment unit is connected to a first opening at a positive pressure higher than the critical pressure, the liquid that has flowed into the capillary tube is sent from the second opening to a liquid reservoir unit, and the push-back is stopped when the liquid has been pushed back to the push-back detection unit.

[0087] Furthermore, the method of the present invention may include, after the pushing back step, a displacement measuring step of changing the state of the liquid in the liquid reservoir and measuring the flow characteristics of the liquid in the capillary tube.

[0088] The test of the first embodiment is a technique that allows for rapid, repeated testing. Therefore, even a small amount of test liquid can be used to rapidly measure slight variations in the flow characteristics of the test liquid. For example, the effects of changes in time, temperature, etc. can be measured. Furthermore, a test component can be mixed into the liquid reservoir to change the state of the liquid in the capillary tube, and the effects of the resulting reaction can be measured.

[0089] Second Embodiment Figure 8 is a schematic diagram of a capillary tube according to a second embodiment of the present invention. This second embodiment is intended to measure the flow characteristics of a liquid contained in a horizontally placed capillary tube at a volume less than the capacity of the capillary tube. Because the liquid is contained in the capillary tube, there is a left end (L) and a right end (R) of the liquid. The flow characteristics are measured when the liquid is moved in each direction by adjusting the pressure difference between the first opening side and the second opening side.

[0090] 9 is a flow diagram according to a second embodiment of the present invention. Step S40 is a step of filling the capillary with liquid. This filling may be performed by placing only the amount of liquid that can be filled in the capillary in the liquid reservoir and filling the entire amount, or by bringing the capillary into contact with the test liquid, separating it from the test liquid, and then filling it with air, thereby filling the capillary. Once the amount to be tested has been filled, the inflow of liquid from the second opening is stopped.

[0091] Step S41 is a step of making the pressure on the first opening side more negative than that on the second opening side, switching the first opening side to an inflow condition, and moving the liquid toward the first opening side. Step S42 is a step of measuring the flow characteristics of the flowing liquid. Step S43 is a step of adjusting the switching valve on the first opening side to stop the inflow of liquid when the inflow stop position is exceeded.

[0092] Step S44 is a step of connecting the first opening to a pressure adjustment section that is set to a more positive pressure than the second opening side and pushing back the liquid. The flow characteristics during this pushing back may be measured. Step S45 is a step of switching the switching valve to stop the pushing back when the front end of the liquid passes the push back detection section. Step S50 is a step of checking whether the predetermined number of tests have been performed once the pushing back has stopped. If not completed (No), return to step S41 and perform the test again. If the predetermined number of tests have been completed (Yes), the process ends.

[0093] When the volume of the test sample is less than the volume of the capillary, all of the sample dispensed into the reservoir is absorbed into the capillary, and no sample remains in the reservoir. At this time, equal and opposite surface tensions act on both ends of the test liquid inside the capillary. Therefore, surface tension does not affect the movement of the liquid column inside the capillary.

[0094] When pressure is applied, the liquid column moves at a uniform speed. The speed of the liquid column is proportional to the pressure difference and inversely proportional to the viscosity. The speed of movement, v, is expressed by equation (3). The viscosity of the sample can be determined by measuring the speed of movement. When the test liquid is entirely sealed in the capillary tube, the sample can be made to move back and forth by making the pressure inside the capillary tube either higher or lower than atmospheric pressure.

[0095]

[0096] The symbols used in equation (3) are as follows: v: flow velocity of the liquid column (mm / ms); D: inner diameter of the capillary tube (mm); l: length of the test liquid contained in the tube (mm); η: viscosity of the liquid sample (mPa·s); ΔP: pressure difference between both ends of the liquid column (Pa).

[0097] Fig. 10 is a schematic diagram of the detection of the liquid level position by a sensor in the measuring device of the present invention. Fig. 10 shows a signal of uniform motion to the left due to negative pressure (97 Pa). Fig. 11 is a schematic diagram of the detection of the liquid level position by a sensor in the measuring device of the present invention. Fig. 11 shows a signal of uniform motion to the right due to positive pressure (97 Pa).

[0098] In the tests shown in Figures 10 and 11, a capillary tube with an inner diameter of D was placed horizontally, and three optical sensors were placed at equal intervals close to the capillary tube. The volume of the test liquid sample was approximately 1 / 10 of the internal volume of the capillary tube. When the test liquid was injected from the right end of the capillary tube while the inside of the capillary tube was maintained at atmospheric pressure, the sample was sucked into the capillary tube entirely due to surface tension. The surface tension acting on the L end and R end of the liquid column of the test liquid was equal in value but opposite in direction.

[0099] When P = P0, the liquid column is stationary inside the capillary. When a pressure adjustment unit is connected to the first opening on the left side of the capillary and negative pressure (P < P0) is created, the liquid column moves at a uniform speed to the left inside the capillary. When a pressure adjustment unit is connected to the first opening on the left side of the capillary and positive pressure (P > P0) is created inside the capillary, the liquid column moves at a uniform speed to the right inside the capillary.

[0100] As described above, the second embodiment of the present invention includes a second push-back process in which the pressure adjustment unit is connected to the first opening as a pressure for pushing the liquid contained in the capillary tube back toward the second opening, and the push-back is stopped when the liquid is pushed back to the push-back detection unit. This makes it possible to measure stability when multiple measurements are performed using reciprocating motion, and to measure changes in flow characteristics when temperature, time, pressure, etc. are changed.

[0101] [Pushback Pressure] As in the second embodiment, when an extremely small amount of sample is placed horizontally in a capillary tube as a sample liquid column with a length of approximately 15 mm or less and the entire amount is contained within the capillary tube, it can be moved with a pressure of approximately 100 Pa. Even with such a pressure, the movement is sufficiently fast. Note that this does not depend on the surface tension of the sample.

[0102] In a third embodiment of the present invention, multiple test liquids can be measured using the same capillary tube. The test liquid contained in the capillary tube is connected to a first opening of the capillary tube, and the pressure adjustment unit adjusts the pressure to push the liquid in the capillary tube back toward the second opening of the capillary tube. The test liquid is then discharged from the capillary tube and used to test another test liquid.

[0103] In a fourth embodiment of the present invention, a reagent to be mixed with a liquid and react therewith can be disposed inside the capillary. For example, the reagent can be disposed near the sensor 66 in Fig. 1, and when the reagent first passes through the capillary, the flow characteristics before mixing with the reagent can be measured, and the liquid that has come into contact with the reagent can be pushed back and allowed to flow again, thereby measuring the flow characteristics after mixing with the reagent.

[0104] Fifth Embodiment FIG. 12 is a schematic diagram of the capillary arrangement and other aspects of a fifth embodiment of the measuring instrument of the present invention. This measuring instrument is configured to measure flow characteristics assuming an inclined capillary. The measuring instrument can be configured similarly to the measuring instrument 101 of FIG. 1 , except that the entire test liquid is contained within the capillary, and the capillary is inclined. In this example, the capillary is placed on an inclined platform, and a liquid column of the test liquid is contained within the capillary between the right end R, which is the second opening side, and the left end L, which is the first opening side. Sensors 1 to 3 are arranged along the capillary to detect the end of the liquid column. The left end of the capillary is connected to a pressure adjustment unit, and the pressure control unit is controlled by the control unit. When sensor 3 detects the end of the liquid column, a control valve or the like connected to the pressure adjustment unit can be controlled to close the space around the piping and stop the flow of the test liquid within the capillary.

[0105] The inclination of the capillary in Figure 12 can be adjusted as appropriate, but from the standpoint of making it easier to perform measurements that take into account the effects of the inclination and making it easier to appropriately control the flow of the test liquid within the capillary using an adjustment valve or the like, the angle θ between the horizontal and the axis of the capillary can be set to approximately 10° to 60°, 15° to 50°, or 20° to 40°.

[0106] Here, the capillary is tilted relative to the horizontal. The angle this capillary makes with the horizontal is θ. A solenoid valve is connected to the bottom end of the capillary and closed. A sample of the test liquid (e.g., about 5 μL) is injected from the top end of the capillary. The entire sample enters the capillary and comes to rest at a position where it is in equilibrium with the internal pressure. After that, the solenoid valve is opened to release the inside of the capillary to atmospheric pressure, and the test liquid in the form of a liquid column inside the capillary falls down the capillary due to gravity. The flow velocity v of this liquid column is expressed by equation (4).

[0107]

[0108] The symbols used in equation (4) are as follows: v: flow velocity of the liquid column (mm / ms) D: inner diameter of the capillary tube (mm) ρ: density of the liquid sample (kg / m 3 ) η: Viscosity of the liquid sample (mPa s) g: Gravitational acceleration (m / s 2 ) θ: angle between the capillary and the horizontal

[0109] Here, if the capillary inner diameter, the gravitational acceleration, and the tilt angle are constant, Equation (4) can be expressed as Equation (5) below.

[0110]

[0111] The coefficient K(D, g, θ) in equation (5) is a constant determined by the inner diameter of the capillary, the acceleration of gravity, and the inclination angle of the capillary. Therefore, the liquid flow velocity v is inversely proportional to the dynamic viscosity η / ρ of the liquid sample. Note that the flow velocity v does not depend on the length of the liquid column (i.e., the injection amount).

[0112] Here, the inner diameter of the capillary, the gravitational acceleration, and the tilt angle are constant, and the time it takes for the liquid column to travel a certain distance d is Δt. In this case, since the transit time is inversely proportional to the velocity, equation (5) can be transformed into the following equation (6):

[0113]

[0114] L(D, g, θ, d) is a constant determined by the inner diameter of the capillary, the acceleration due to gravity, the inclination angle of the capillary, and the distance d. Therefore, the flow time Δt of the liquid is proportional to the dynamic viscosity η / ρ of the liquid sample. Note that the flow time Δt does not depend on the length of the liquid column (i.e., the injection amount).

[0115] In equation (6), the coefficient L (D, g, θ, d) is a constant determined by the capillary inner diameter, gravitational acceleration, capillary inclination angle, and distance d. Furthermore, provided that the length of the liquid column is shorter than the length of the capillary, the flow time does not depend on the injection volume (length of the liquid column). Therefore, if the flow time of the first sample (1) is Δt1 and the flow time of the second sample (2) is Δt2, the following equation (7) holds true even if the injection volumes are different. In other words, the ratio of the flow times of the liquid samples is equal to the ratio of their kinematic viscosities. Note that η / ρ in equation (7) is the kinematic viscosity of the first sample, and η / ρ is the kinematic viscosity of the second sample.

[0116]

[0117] [Sixth embodiment] The present invention can be embodied as a sixth embodiment in which the pressure adjusting unit is further configured to adjust the pressure in stages. Fig. 13 is a schematic diagram showing the differential pressure and flow characteristics of a capillary tube according to the present invention.

[0118] This embodiment will be described assuming that the pressure inside the capillary tube is set to a pressure different from atmospheric pressure. Here, atmospheric pressure is P0, and the pressure inside the capillary tube when the solenoid valve is opened is P. The pressure difference is ΔP = P - P0. Assuming that the other conditions are the same as in the fifth embodiment, equation (8) holds.

[0119]

[0120] The symbols used in equation (8) are as follows: v: flow velocity of the liquid column (mm / ms), D: inner diameter of the capillary tube (mm), ΔP: pressure difference between both ends of the liquid column (Pa), ρ: density of the liquid sample (kg / m 3 ) η: viscosity of the liquid sample (mPa·s) l: length of the test liquid contained in the tube (mm) g: gravitational acceleration (m / s 2 ) θ: angle between the capillary and the horizontal

[0121] Figure 13 is a plot of pressure difference ΔP on the horizontal axis and velocity v on the vertical axis. If ΔP = 0, equation (8) reduces to equation (4). That is, the value of the y-intercept of the plot is equal to the velocity value of equation (4).

[0122] The capillary tube is tilted, creating a pressure difference ΔP between the inside and outside of the capillary tube, causing the liquid sample to fall. When the falling velocity v of the liquid column is plotted on the vertical axis and the pressure difference ΔP on the horizontal axis, a straight line sloping downward to the right is obtained, as shown in Figure 13. The dynamic viscosity η / ρ of the sample can be determined from the point where this line intersects with the vertical axis (y-intercept). The density ρ of the sample can be determined from the point where the line intersects with the horizontal axis (x-intercept). The value of the x-intercept of the plot, ΔP c2 = lρgsinθ is named as the critical pressure in the sixth embodiment of the present invention. Under the critical pressure, the test liquid in the inclined capillary tube is stationary. When a positive pressure greater than the critical pressure is applied to the capillary tube, the test liquid in the capillary tube rises against the inclination.

[0123] The sample that has fallen to the bottom of the capillary and stopped there reaches a critical pressure ΔP c2 By applying a larger pressure difference, it can be pushed back to the upper end (the position where the drop starts). As an example, if the test liquid is 5 μL of pure water and the tilt angle is 30°, ΔP c2The value of is about 50 Pa. Therefore, in order to complete the plot in FIG. 13 by repeating the drop measurement, a pressure difference of 100 Pa or less must be created with good reproducibility.

[0124] [Seventh Embodiment] Figure 14 is a schematic diagram of the capillary tube arrangement and other aspects of a seventh embodiment of the measuring device of the present invention. The push-back means has an inclined platform for positioning the capillary tube, and can be installed in two positions: one for allowing the first opening to be lower than the second opening, allowing the flow, and the other for pushing back the test liquid in the capillary, allowing the second opening to be lower than the first opening. By reversing the inclination angle of the capillary tube after the flow measurement is completed, as shown in Figure 14, the sample in the capillary tube can be pushed back to the starting position by gravity without applying pressure. This method of reversing the inclination angle to return to the initial state is equivalent to reversing the signs of v and θ in Equation (4), so it is equivalent to adding an inclination measurement. This configuration does not require pressure adjustment of the positive pressure for push-back. It is preferable to install a pressure adjustment valve at the first and / or second opening to stop the liquid column of the test liquid in the capillary.

[0125] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the following examples as long as the gist of the present invention is not changed.

[0126] [Measurement device] Capillary tube: A capillary tube with a radius r of 0.34 mm (nominal value) was used. The length was 100 mm. As equivalent to the pressure adjustment unit 3, a container (1000 mL sample bottle) and a variable volume container (digital pipette) were used to adjust the negative and positive pressure. The pressure was measured and calibrated with a pressure gauge. A solenoid valve was used as the switching valve.

[0127] Sensor: Multiple optical sensors were placed along the capillary to detect the liquid level. Liquid reservoir: A mounting base with a recessed portion was used so that the tip of the capillary could come into contact with it.

[0128] Standard solution: Pure water was used. Sucrose solution: A mixture of pure water with a sucrose concentration of 30% by mass (30% by mass sucrose aqueous solution) was used. Room temperature was 21°C ± 0.5°C.

[0129] [Test Example 1] Test Examples 1 to 4 are all test examples for the first embodiment. Pure water was used as the test liquid, and the time it took to pass through a 60 mm flow path at atmospheric pressure was measured. After the measurement distance elapsed, when the liquid level reached a position close to the first opening, the test was stopped, and the pressure adjustment unit was switched to a push-back pressure, and the switching valve was switched to push the liquid back to a stop position near the second opening. After that, the first opening side was switched back to the inflow direction, and measurements were taken. The results of measuring the variation when the test was conducted eight times are shown in FIG. 15. It was confirmed that stable results could be obtained by conducting the test eight times.

[0130] [Test Example 2] Similar to Test Example 1, a test was conducted while varying the state of the test liquid in the reservoir during the reciprocating flow. First, during the first inflow, pure water was used, and a flow time test was conducted eight times. Next, the liquid was pushed back to a position where only a small amount remained in the capillary tube, without causing bubbling. Before the second inflow, 2 μL of 30% by mass sucrose solution was added to the reservoir to change the liquid's physical properties, and eight flow time tests were conducted. Next, for the third test, similar to the second test, 2 μL of 30% by mass sucrose solution was added to the reservoir to change the liquid's physical properties, and nine flow time tests were conducted. Then, before the fourth inflow, the liquid in the reservoir was replaced with pure water, and nine flow time tests were conducted. The flow time measurement results for each test are shown in Figure 16 as the average and standard deviation (length of error bars). It was confirmed that changes in flow time due to slight changes in the liquid in the reservoir could be measured, and that by replacing it with pure water, measurements with high reproducibility compared to the results obtained with pure water were possible.

[0131] [Test Example 3] Measurements of flow characteristics were performed with changes in liquid temperature. First, 70 μL of pure water was placed in the liquid reservoir at room temperature to measure the flow characteristics. After the test, the liquid in the capillary was pushed back. Next, 50 μL of ice-cold pure water was mixed with the liquid reservoir, and the same amount of pure water (50 μL) was withdrawn. Repeatedly, 50 μL of ice-cold pure water was mixed with the liquid reservoir, and the same amount of pure water (50 μL) was withdrawn. The flow characteristics were then promptly measured during inflow into the capillary. Once the inflow measurement was completed, the liquid was pushed back. The flow time during inflow was measured approximately every minute. The measurement results are shown in Figure 17. It was confirmed that it was possible to measure the difference in flow time associated with changes in the temperature of the test liquid. Furthermore, it was confirmed that this measurement could track and measure the change in flow characteristics over a short period of time, even if it took only a few minutes for the liquid temperature to return to room temperature.

[0132] Test Example 4: Measurements of flow characteristics were performed with changes in liquid temperature. First, 70 μL of pure water was placed in the reservoir at room temperature to measure the flow characteristics. After the test, the liquid in the capillary was pushed back. Next, 50 μL of pure water at 50°C was mixed with the reservoir, and the same amount of pure water (50 μL) was withdrawn. Repeatedly, 50 μL of pure water at 50°C was mixed with the reservoir, and the same amount of pure water (50 μL) was withdrawn. The flow characteristics were then promptly measured during inflow into the capillary. Once the inflow measurement was completed, the liquid was pushed back. The flow time during inflow was measured approximately every minute. The measurement results are shown in Figure 18. It was confirmed that it was possible to measure the difference in flow time with changes in the temperature of the test liquid. Furthermore, although this measurement is thought to return the liquid temperature to room temperature relatively slowly compared to the low-temperature Test Example 3, it was confirmed that it was possible to track and measure the change in flow characteristics over a short period of time, even within a few minutes.

[0133] Test Example 5: When the entire test liquid was contained in the capillary tube (corresponding to Figure 8), a measurement was performed to confirm that the flow time was proportional to the viscosity. 5 μL of pure water was dispensed into a horizontally placed capillary tube, and negative pressure (97 Pa) was applied to cause the liquid to flow (Figure 19).

[0134] In the signal diagram of Figure 19, the following assumptions are made: - Signal 1 is generated when the R end of the test liquid passes the first sensor; time is t1. - Signal 2 is generated when the L end of the test liquid passes the second sensor; time is t2. - Signal 3 is generated when the R end of the test liquid passes the second sensor; time is t3. - Signal 4 is generated when the L end of the test liquid passes the third sensor; time is t4. In this measurement, the distance between the sensors was fixed at 30 mm. Therefore, the speed at which the liquid column moves through the capillary tube can be calculated from (t3 - t1) or (t4 - t2).

[0135] After measuring the pure water, the sample to be tested in the capillary was pushed out, and 5 μL of a new 30% by mass sucrose solution was added, and the solution was washed back and forth through the capillary. After washing, the sucrose solution was pushed out, and 5 μL of a 30% by mass sucrose solution was added again. Figure 20 shows the signal recorded when a negative pressure of 97 Pa was applied to this sample. The flow time of the 30% by mass sucrose solution was 3.0 times that of pure water. This value is approximately equal to the value expected from the viscosity ratio of 3.17 between the sucrose solution and pure water.

[0136] [Test Example 6] Figure 21 is a graph showing the measurement results of pure water in an example of the present invention. Figure 22 is a graph showing the measurement results of a 30% by mass sucrose solution in an example of the present invention. These measurements are examples of evaluating the flow characteristics of test liquids using the fifth embodiment having the configuration shown in Figure 12. This is particularly suitable for measuring kinematic viscosity.

[0137] The capillary was tilted as shown in Figure 12, with sin θ = 0.57. 5 μL of pure water was injected into the capillary, and the solenoid valve was opened to record the flow time of the liquid column (Figure 21).

[0138] After recording the signal, positive pressure was applied to push the pure water out of the capillary tube, and 5 μL of 30% sucrose solution was injected for co-washing and then discharged. Another 5 μL of 30% sucrose solution was injected, and the flow time was recorded ( FIG. 22 ).

[0139] In the signal records in Figures 21 and 22, the first signal indicates the time when the R end of the liquid column passes the first sensor, the second signal indicates the time when the L end of the liquid column passes the second sensor, the third signal indicates the time when the R end of the liquid column passes the second sensor, and the fourth signal indicates the time when the L end of the liquid column passes the fourth sensor.

[0140] The sample is injected and preparation for measurement is made. The sensors are numbered 1, 2, and 3, starting from the right (closest to the second opening, which serves as the inlet). 5 μL of sample is injected. It is all sucked in by surface tension. Then, the sample is allowed to fall. When sensor 3 detects the passage of the test liquid, it closes the solenoid valve, stopping the flow of the sample liquid.

[0141] After that, positive pressure is applied to push it back. When sensor 1 detects it, the positive pressure is released to stop the sample liquid. The sample stops immediately after passing sensor 1.

[0142] When evaluating flow characteristics, the test liquid is dropped from a state in which the test liquid is present at the top end, as shown in Figure 12. Here, signal 1 is generated when the R end of the sample passes the first sensor; time is t1. Signal 2 is generated when the L end of the sample passes the second sensor; time is t2. Signal 3 is generated when the R end of the sample passes the second sensor; time is t3. Signal 4 is generated when the L end of the sample passes the third sensor; time is t4. The drop time (t3 - t1) or (t4 - t2) is proportional to the kinematic viscosity. Note that this measurement is independent of the amount of liquid injected into the capillary tube.

[0143] According to literature, the density of a 30% by mass sucrose solution is 1.127 times that of pure water (at 20°C). Furthermore, the viscosity of a 30% by mass sucrose solution is 3.17 times that of pure water. Therefore, the kinetic viscosity of a 30% by mass sucrose solution is 2.81 times that of pure water. Based on the actual measurements obtained using this configuration, the flow time of a 30% by mass sucrose solution was 2.7 times that of pure water. Therefore, it was confirmed that the kinetic viscosity of two extremely small amounts (5 μL) of liquid samples can be compared and determined with an accuracy of 5% or less.

[0144] The present invention can be used to measure flow characteristics such as the viscosity of a liquid, and is therefore industrially useful.

[0145] REFERENCE SIGNS LIST 101 Measuring device 11 Capillary tube 111 First opening 112 Second opening 2 Switching valve 21-23 Flow path 3 Pressure adjusting section 30 Container 31 Pressure gauge 32 Adjusting piston 4 Liquid reservoir section 5 Test liquid 6 Measuring section 60 Timer section 61-66 Sensors 69 Push-back detection section 7 Mounting base 8 Control section 91 Display section

Claims

1. A push-back means for pushing back the test liquid that has flowed into the capillary tube from the second opening side toward the first opening side of a capillary tube having a first opening and a second opening, A control valve for adjusting the flow of liquid in the capillary tube, A method for measuring the flow characteristics of a test liquid using a measuring instrument having a measuring unit that measures the time tn to reach the liquid level position Ln in the capillary tube, The push-back means is a pressure adjustment unit connected to the first opening side, which can be set to a pressure that pushes the test liquid flowing into the capillary tube back to the second opening side. The adjustment valve has a switching valve for switching the connection between the pressure adjustment unit and the capillary tube, A measuring instrument is used that includes a pushback detection unit that detects when the test liquid in the capillary tube is pushed back and passes through to the second opening, and has a detection unit that measures the flow characteristics of the test liquid. The method measures the flow characteristics of the test liquid contained inside the capillary tube in an amount less than the capillary tube's capacity, wherein the test liquid contains gas at both the first and second openings inside the capillary tube, and the detection unit can further detect the liquid levels at both ends of the test liquid inside the capillary tube. A method comprising a second pushing step in which the pressure adjustment unit is connected to the first opening as the pressure to push back to the second opening side, the test liquid contained in the capillary tube is pushed back to the second opening side, and the pushing back is stopped when it is pushed back to the pushing back detection unit.

2. A push-back means for pushing back the liquid to be tested that has flowed into the capillary tube from the second opening side toward the first opening side of a capillary tube having a first opening and a second opening, A control valve for adjusting the flow of liquid in the capillary tube, A method for measuring the flow characteristics of a test liquid using a measuring instrument having a measuring unit that measures the time tn to reach the liquid level position Ln in the capillary tube, The push-back means is a pressure adjustment unit connected to the first opening side, which can be set to a pressure that pushes the test liquid flowing into the capillary tube back to the second opening side. The adjustment valve has a switching valve for switching the connection between the pressure adjustment unit and the capillary tube, A measuring instrument is used that includes a pushback detection unit that detects when the test liquid in the capillary tube is pushed back and passes through to the second opening, and has a detection unit that measures the flow characteristics of the test liquid. The method involves measuring the flow characteristics of the test liquid contained inside the capillary tube in an amount less than the capillary tube's capacity. The pressure adjustment unit comprises a container, an adjustment piston connected to the container, and a mechanism that, in conjunction with the switching valve, opens the container to atmospheric pressure until just before isothermal compression and / or isothermal expansion, thereby maintaining the inside of the container at atmospheric pressure. A method for adjusting the internal pressure of the container, wherein, after sealing the container from the atmosphere, the volume of the container and the adjustment piston is changed by the adjustment piston to adjust a predetermined internal pressure of the container using isothermal compression and / or isothermal expansion.

3. The pressure adjustment unit comprises a container, an adjustment piston connected to the container, and a mechanism that, in conjunction with the switching valve, opens the container to atmospheric pressure until just before isothermal compression and / or isothermal expansion, thereby maintaining the inside of the container at atmospheric pressure. The method according to claim 1, wherein when adjusting the pressure inside the container, after the container is isolated from the atmosphere, the volume between the container and the adjustment piston is changed by the adjustment piston to adjust a predetermined pressure inside the container using isothermal compression and / or isothermal expansion.

4. The measuring instrument has a liquid reservoir that is in contact with the second opening side, This method measures the flow characteristics within the capillaries of the test liquid contained in the liquid reservoir that flows in through the second opening. The method according to claim 2, further comprising a first pushback step of connecting the pressure adjustment unit to the first opening at a pressure positive above the critical pressure, sending the test liquid that has flowed into the capillary tube to the liquid reservoir from the second opening, and stopping the pushback when it has been pushed back to the pushback detection unit.

5. The method according to claim 4, further comprising the step of measuring the flow characteristics when the test component is mixed into the test liquid in the liquid reservoir after the first pushback step and introduced into the capillary tube.

6. The method according to any one of claims 1 to 5, wherein the capillary tube is inclined.

7. The method according to claim 6, wherein the pressure adjustment unit can further adjust the pressure in stages.

8. A push-back means for pushing back the liquid of the test that has flowed into the capillary tube from the second opening side toward the first opening side of a capillary tube having a first opening and a second opening, A control valve for adjusting the flow of liquid in the capillary tube, A method for measuring the flow characteristics of a test liquid using a measuring instrument having a measuring unit that measures the time tn to reach the liquid level position Ln in the capillary tube, The push-back means is a pressure adjustment unit connected to the first opening side, which can be set to a pressure that pushes the test liquid flowing into the capillary tube back to the second opening side. The adjustment valve has a switching valve for switching the connection between the pressure adjustment unit and the capillary tube, A measuring instrument is used that includes a pushback detection unit that detects when the test liquid in the capillary tube is pushed back and passes through to the second opening, and has a detection unit that measures the flow characteristics of the test liquid. The measuring instrument has a liquid reservoir that is in contact with the second opening side, This method measures the flow characteristics within the capillaries of the test liquid contained in the liquid reservoir that flows in through the second opening. The pressure adjustment unit is connected to the first opening at a pressure higher than the critical pressure, the test liquid that has flowed into the capillary tube is sent to the liquid reservoir through the second opening, and the first pushback step is to stop the pushback when it has been pushed back to the pushback detection unit. A method comprising, after the first pushback step, a step of measuring the flow characteristics when the test component is mixed into the test liquid in the liquid reservoir and introduced into the capillary tube.

9. A push-back means for pushing back the liquid to be tested that has flowed into the capillary tube from the second opening side toward the first opening side of a capillary tube having a first opening and a second opening, A control valve for adjusting the flow of liquid in the capillary tube, A method for measuring the flow characteristics of a test liquid using a measuring instrument having a measuring unit that measures the time tn to reach the liquid level position Ln in the capillary tube, A method wherein the pushback means has an inclined platform for positioning the capillary tube and can be configured in two ways: one for allowing flow with the first opening side lower than the second opening, and another for pushing back the test liquid in the capillary tube with the second opening side lower than the first opening.

10. A push-back means for pushing back the liquid to be tested that has flowed into the capillary tube from the second opening side toward the first opening side of a capillary tube having a first opening and a second opening, A control valve for adjusting the flow of liquid in the capillary tube, A system for measuring the flow characteristics of a test liquid, comprising a measuring instrument having a measuring unit for measuring the time tn to reach the liquid level position Ln in the capillary tube, The push-back means is a pressure adjustment unit connected to the first opening side, which can be set to a pressure that pushes the test liquid flowing into the capillary tube back to the second opening side. The adjustment valve has a switching valve for switching the connection between the pressure adjustment unit and the capillary tube, A measuring instrument is used that includes a pushback detection unit that detects when the test liquid in the capillary tube is pushed back and passes through to the second opening, and has a detection unit that measures the flow characteristics of the test liquid. The method measures the flow characteristics of the test liquid contained inside the capillary tube in an amount less than the capillary tube's capacity, wherein the test liquid contains gas at both the first and second openings inside the capillary tube, and the detection unit can further detect the liquid levels at both ends of the test liquid inside the capillary tube. A system comprising: a pressure adjustment unit connected to the first opening to apply pressure to push the liquid under test contained in the capillary tube back towards the second opening, and a stop means for a second push-back that stops the push-back when the liquid has been pushed back to the push-back detection unit.

11. A push-back means for pushing back the liquid of test that has flowed into the capillary tube from the second opening side toward the first opening side of a capillary tube having a first opening and a second opening, A control valve for adjusting the flow of liquid in the capillary tube, A system for measuring the flow characteristics of a test liquid, comprising a measuring instrument having a measuring unit for measuring the time tn to reach the liquid level position Ln in the capillary tube, The push-back means is a pressure adjustment unit connected to the first opening side, which can be set to a pressure that pushes the test liquid flowing into the capillary tube back to the second opening side. The adjustment valve has a switching valve for switching the connection between the pressure adjustment unit and the capillary tube, A measuring instrument is used that includes a pushback detection unit that detects when the test liquid in the capillary tube is pushed back and passes through to the second opening, and has a detection unit that measures the flow characteristics of the test liquid. The method involves measuring the flow characteristics of the test liquid contained inside the capillary tube in an amount less than the capillary tube's capacity. The pressure adjustment unit comprises a container, an adjustment piston connected to the container, and a mechanism that, in conjunction with the switching valve, opens the container to atmospheric pressure until just before isothermal compression and / or isothermal expansion, thereby maintaining the inside of the container at atmospheric pressure. A system having an adjustment means for adjusting the internal pressure of a container, wherein, after the container is isolated from the atmosphere, the adjustment piston changes the volume between the container and the adjustment piston, thereby adjusting a predetermined internal pressure of the container using isothermal compression and / or isothermal expansion.

12. A push-back means for pushing back the liquid to be tested that has flowed into the capillary tube from the second opening side toward the first opening side of a capillary tube having a first opening and a second opening, A control valve for adjusting the flow of liquid in the capillary tube, A system for measuring the flow characteristics of a test liquid, comprising a measuring instrument having a measuring unit for measuring the time tn to reach the liquid level position Ln in the capillary tube, The push-back means is a pressure adjustment unit connected to the first opening side, which can be set to a pressure that pushes the test liquid flowing into the capillary tube back to the second opening side. The adjustment valve has a switching valve for switching the connection between the pressure adjustment unit and the capillary tube, A measuring instrument is used that includes a pushback detection unit that detects when the test liquid in the capillary tube is pushed back and passes through to the second opening, and has a detection unit that measures the flow characteristics of the test liquid. The measuring instrument has a liquid reservoir that is in contact with the second opening side, This method measures the flow characteristics within the capillaries of the test liquid contained in the liquid reservoir that flows in through the second opening. The pressure adjustment unit is connected to the first opening at a pressure higher than the critical pressure, and the test liquid that has flowed into the capillary tube is sent to the liquid reservoir through the second opening, and when it is pushed back to the pushback detection unit, the pushback is stopped by a first pushback means. A system comprising, after the first push-back means, a means for measuring the flow characteristics when the test component is mixed into the test liquid in the liquid reservoir and flows into the capillary.

13. A push-back means for pushing back the liquid to be tested that has flowed into the capillary tube from the second opening side toward the first opening side of a capillary tube having a first opening and a second opening, A control valve for adjusting the flow of liquid in the capillary tube, A system for measuring the flow characteristics of a test liquid, comprising a measuring instrument having a measuring unit for measuring the time tn to reach the liquid level position Ln in the capillary tube, The pushback means has an inclined platform for positioning the capillary tube and can be configured in two ways: one for allowing flow with the first opening side lower than the second opening, and another for pushing back the test liquid in the capillary tube with the second opening side lower than the first opening.