JP7246969B2 - Blood coagulation test device and blood coagulation test method - Google Patents

Description

The present invention relates to a blood coagulation test apparatus and a blood coagulation test method.

The process of blood clotting in order to evaluate the pathology of hemophilia, in which blood clotting factors that clot blood during bleeding, are reduced or lacking, and to evaluate the efficacy of drugs such as hemostatic drugs. In the blood clotting status is examined. As a method for examining the state of blood coagulation, for example, blood to be tested to which a reagent has been added (hereinafter also referred to as a blood sample) is irradiated with light and the amount of scattered light is measured to detect the coagulation and determine the clotting time. An optical inspection method for calculating is known (see Patent Document 1, for example). In addition, by rotating a pin immersed in a cup containing a blood sample back and forth within a certain angle (4.75 degrees) and measuring the decrease in the rotation angle of the pin due to blood coagulation, the state of blood coagulation such as viscosity can be determined. is known (see, for example, Non-Patent Document 1).

JP 2010-217059 A

Naho Suzuki, "Thromboelastography in the operating room and ICU", [online], December 15, 2015, Jikei ICU Study Group, [searched June 3, 2016], Internet <URL: http://www.jikeimasuika .jp/icu_st/151215.pdf＞

When examining the state of blood coagulation using an optical examination method, the amount of scattered light measured may be affected by interfering substances in the blood sample. In addition, depending on the difference in inspection items, that is, the difference in added reagents, etc., the change in the amount of scattered light may not be detected with high accuracy. Being an optical technique, changes in blood viscoelasticity are not accurately measured and data are only acquired at the completion of blood clotting.

In addition, in devices for mechanically examining the state of blood coagulation, such as TEG (registered trademark) and ROTEM (registered trademark), measurement conditions such as the rotation angle of the cup into which the blood sample is injected or the pin immersed in the blood sample is not changed according to differences in blood samples, drugs, test items, and the like. For example, in TEG, the cup is rotated back and forth within a range of ±4.75 degrees (4 degrees 45 minutes). It may be destroyed and the viscoelasticity may not be measured correctly. Further, for example, in ROTEM, a pin is reciprocally rotated at a constant angle by a spring. The rotation angle transmitted to the pin by the spring is fixed at ±4.75 degrees, and when the viscoelasticity increases due to blood coagulation, the pin gradually stops rotating. For this reason, the desired resolution cannot be obtained in measurements in a high viscoelasticity region where blood coagulation has progressed, or in a measurement in a low viscoelasticity region on the contrary, because the rotation angle and rotation speed of the cup or pin are constant. , it was sometimes difficult to assess drug efficacy. In addition, it is difficult to analyze the state of coagulation with a desired resolution from the low viscoelasticity region to the high viscoelasticity region for animal blood, which has a higher amount of platelets and higher viscoelasticity than human blood. there was a case. Furthermore, since these devices are expensive, there has been a demand for lower cost, smaller and lighter devices.

A conventional ROTEM or TEG uses the same spring and the same rotation angle for high viscoelastic coagulation (intrinsic and extrinsic coagulation) and low viscoelastic coagulation (in the presence of antiplatelet drugs). analysis of fibrin gel formation). Therefore, if we use a (weak) spring that is sufficiently sensitive to the increased load on the pin due to the increase in viscoelasticity in low viscoelasticity blood coagulation measurements, then in high viscoelasticity measurements, blood coagulation The accompanying increase in viscoelasticity increases the load on the pin, causing the pin to lose its rotation, and the desired resolution cannot be obtained. Conversely, when a (strong) spring suitable for measuring blood coagulation with high viscoelasticity is used, the load on the pin due to the increase in viscoelasticity of blood coagulation with low viscoelasticity is small. (decrease) becomes small, and the desired sensitivity and reproducibility cannot be obtained. As described above, when the same spring is used and the analysis is performed at the same rotation angle, there is a problem that the sensitivity and accuracy are deteriorated.

SUMMARY OF THE INVENTION An object of the present invention is to provide a technique for obtaining a resolution suitable for a test object in a blood coagulation test.

In order to solve the above problems, the present invention reciprocates an elastic body connected to a stirring section for stirring blood around the axis of the stirring section as a rotation axis, and controls the reciprocating rotation to achieve a predetermined reciprocating motion of the stirring section. I decided to transmit rotational motion. Then, the depth to which the stirring part is immersed in the blood is changed according to the rotation angle of the stirring part.

More specifically, the blood coagulation test apparatus according to the present invention includes a container for holding blood to be tested, a stirring unit for stirring the blood to be tested in the container, a stirring unit connected to the stirring unit, and the blood to be tested from the stirring unit. and an elastic body that can be deformed according to the force received by the stirring, and the elastic body is reciprocally rotated around the axis of the stirring part as a rotation axis, and by controlling the reciprocating rotation, a predetermined reciprocating rotational motion is transmitted to the stirring part, and the stirring is performed. A control unit for reciprocally rotating the part in the circumferential direction, a measuring part for measuring the rotation angle related to the reciprocating rotation of the stirring part, and raising and lowering the stirring part according to the rotation angle measured by the measuring part, and the stirring part is the inspection target. a lift control unit for controlling the depth of immersion in the blood or the distance between the stirring unit and the inner wall of the container.

With the blood coagulation test apparatus described above, it is possible to control the reciprocating rotation of the stirring unit at a predetermined angle. The control unit is, for example, a servomotor that is becoming more and more compact and mass-produced for control of the tail of a radio-controlled airplane, direction control of a camera of a drone, and the like. A servo motor is a motor provided with a servo mechanism that automatically controls the position, orientation, speed, etc. of an object so as to follow target values. Therefore, the servomotor can accurately control rotation at low speed and rotation at a desired angle. Therefore, in the blood coagulation test, the blood coagulation test apparatus can obtain a resolution suitable for the test object by appropriately controlling the rotation speed and rotation angle transmitted to the stirring unit. In addition, the viscoelasticity of the blood in the high viscoelasticity region can be controlled with high accuracy by moving the stirring part up and down and controlling the depth at which the stirring part is immersed in the blood to be tested, or the distance between the stirring part and the inner wall of the container. Measurement becomes possible. In addition, the reduction in size, weight, and cost of the servomotor can reduce the cost of blood coagulation testing. Furthermore, instead of stirring a plurality of blood samples under the same control, by controlling the servo motor for each blood sample, it is possible to perform an examination according to each blood sample. Note that the reciprocating rotary motion is a motion of rotating within a predetermined rotation angle range around the rotation axis.

The rotation angle of the stirring section can be analyzed by capturing an image using a camera or the like of the measurement section. Specifically, for example, a pinhole or the like may be provided at a position where the rotation of the stirring section can be measured, and the rotation angle of the stirring section may be analyzed based on the imaged movement of the pinhole or the like. The rotation angle of the stirring part can also be analyzed by position analysis using a non-contact encoder. An encoder is a sensor that converts a mechanical position change into information indicating a rotational position or a linear displacement position and outputs it as an electrical signal.

The control unit may control the reciprocating rotation of the elastic body at a position separated by a predetermined diameter from the rotation shaft. Further, the control section may change the predetermined reciprocating rotational motion according to the rotation angle measured by the measurement section. With such a blood coagulation test apparatus, for example, when blood coagulation progresses and the stirring unit stops rotating, the rotation angle of the predetermined reciprocating rotary motion transmitted from the servomotor to the stirring unit can be increased. , which enables accurate analysis of the viscoelastic state at higher viscosities. In addition, by changing the predetermined reciprocating rotational motion and controlling the depth at which the agitating part is immersed in the blood to be tested or the distance between the agitating part and the inner wall of the container, the low viscoelasticity region to the high viscoelasticity region can be obtained. It is possible to accurately measure the viscoelasticity of blood in a wide range up to.

In addition, the elevation control unit adjusts the depth at which the stirring unit is immersed in the blood to be tested or the distance between the stirring unit and the inner wall of the container according to the viscoelasticity of the blood to be tested or changes in viscoelasticity associated with blood coagulation. It may determine the distance. Such an elevation control unit enables measurement with appropriate resolution (accuracy) according to the viscoelasticity of blood.

Further, the elevation control section may raise the stirring section when the change rate of the rotation angle measured by the measurement section decreases. With such an elevation control unit, it is possible to improve the resolution when it becomes difficult to measure viscoelasticity in a high viscoelasticity region.

It should be noted that the present invention can also be understood from a method aspect. For example, the present invention includes a stirring step of stirring the blood to be tested put in a container by a stirring part, and an elastic device which is connected to the stirring part and deformable according to the force received by the stirring part from the stirring of the blood to be tested. a control step of reciprocatingly rotating the body about the axis of the stirring part and controlling the reciprocating rotation to transmit a predetermined reciprocating rotational motion to the stirring part and reciprocatingly rotating the stirring part in the circumferential direction; A measurement step of measuring a rotation angle related to reciprocating rotation, and the depth at which the stirring portion is immersed in the blood to be tested by moving the stirring portion up and down according to the rotation angle measured in the measuring step, or the inner wall of the stirring portion and the container. and a lifting control step for controlling the distance to.

Advantageous Effects of Invention According to the present invention, it is possible to obtain a resolution suitable for an object to be examined in a blood coagulation examination.

FIG. 1 is a schematic diagram illustrating the configuration of a blood coagulation test apparatus. FIG. 2 is a diagram illustrating a hardware configuration of a control device according to the embodiment; FIG. 3 is a diagram illustrating a functional configuration of a control device in the embodiment; FIG. 4 is a diagram showing changes in the coagulation state of an agarose solution. FIG. 5 is a flowchart illustrating the flow of test processing in the blood coagulation test apparatus. FIG. 6A is a perspective view showing the appearance of the blood coagulation test apparatus. FIG. 6B is a perspective view showing the inside of the blood coagulation test apparatus. FIG. 7A is a perspective view of the upper unit viewed from above. FIG. 7B is a perspective view of the upper unit viewed from below. FIG. 8A is an exploded perspective view of a stirring motion transmission mechanism. FIG. 8B is a partially exploded view of the stirring motion transmission mechanism and a perspective view of the container. FIG. 9A is a perspective view of the lower unit viewed from the front left side. FIG. 9B is a perspective view of the lower unit viewed from the rear left side. FIG. 10 is a perspective view of the upper unit separated from the lower unit. FIG. 11 is a plan view of the state in which the upper unit and the lower unit are assembled. FIG. 12A is a left side view showing a state in which the upper unit is separated from the lower unit. FIG. 12B is a front view showing a state in which the upper unit is separated from the lower unit. FIG. 13 is a flow chart illustrating the operation flow of the blood coagulation test apparatus according to the second embodiment. FIG. 14A is a diagram showing a state in which the mounting table is housed inside the blood coagulation test apparatus. FIG. 14B is a diagram showing a state in which the mounting table is slid forward and the container can be placed on the mounting table. FIG. 15A is a diagram showing a state in which the holding pin is inserted into the stirring section by lowering the upper unit. FIG. 15B is a diagram showing a state in which the upper unit is lifted to a position where the blood sample in the container can be stirred by the stirring section. 16A and 16B are diagrams illustrating the operation of converting the rotary motion of the gear into the oscillating motion of the oscillating plate by the agitation control mechanism. FIG. 17A is a diagram showing the rotating state of the rocking plate when the sliding plate moves to the front side. FIG. 17B is a diagram showing the rotating state of the rocking plate when the sliding plate is not moving. FIG. 17C is a diagram showing the rotating state of the rocking plate when the sliding plate moves rearward. FIG. 18A is a diagram showing the position of the stirrer during a normal blood coagulation test. FIG. 18B is a diagram showing a state in which the viscoelasticity of the blood sample in the container is increased and the stirrer is raised. Figure 19A is a perspective view of a first variant of the container. Figure 19B is a perspective view of a second variant of the container. FIG. 20A is a diagram showing a state in which the pressing plate does not press the agitator. FIG. 20B is a diagram showing a state in which the holding plate holds the stirring section when the holding pin is pulled out from the stirring section. FIG. 21 is a diagram illustrating a torsion coil spring used in an example of the second embodiment; 22 is a graph showing measurement results in Example 1. FIG. 23 is a graph showing the amplitude of the oscillation measuring pin in Example 1. FIG. 24 is a graph showing measurement results in Comparative Example 1. FIG. 25 is a graph showing the amplitude of the oscillation measuring pin in Comparative Example 1. FIG. 26 is a graph showing measurement results in Example 2. FIG. 27 is a graph showing the amplitude of the oscillation measuring pin in Example 2. FIG. FIG. 28 is a cross-sectional view of a stirring unit used in Examples 1 to 3 and 6. FIG. FIG. 29 is a cross-sectional view of the container used in Examples 1-3 and 6. FIG. FIG. 30 is a diagram for explaining the position of the stirring unit in Example 3. FIG. FIG. 31 is a graph showing measurement results when the stirrer is in the normal measurement position in Example 3. FIG. FIG. 32 is a graph showing measurement results when the stirrer is raised in Example 3. FIG. 33 is a cross-sectional view of a stirring unit used in Examples 4 and 5. FIG. 34 is a cross-sectional view of a stirring unit used in Examples 4 and 5. FIG. 35 is a cross-sectional view of a container used in Examples 4 and 5. FIG. 36 is a graph showing measurement results in Example 4. FIG. 37 is a graph showing the amplitude of the oscillation measuring pin in Example 4. FIG. 38 is a graph showing measurement results in Example 5. FIG. 39 is a graph showing the amplitude of the oscillation measuring pin in Example 5. FIG. 40 is a cross-sectional view of a stirring unit used in Example 6. FIG. FIG. 41 is a graph showing measurement results when the stirrer is in the normal measurement position in Example 6. FIG. FIG. 42 is a graph showing measurement results when the stirring unit is raised in Example 6. FIG. FIG. 43 is a graph showing measurement results when a stirring part with a thinner tip is used in Example 6. FIG.

BEST MODE FOR CARRYING OUT THE INVENTION An embodiment of the present invention will be described below based on the drawings. The configurations of the following embodiments are examples, and the present invention is not limited to the configurations of the embodiments.

[Embodiment]
FIG. 1 is a schematic diagram illustrating the configuration of a blood coagulation test apparatus. A blood coagulation test apparatus 10 includes a control section 1 , an elastic body 2 , a stirring section 3 , a container 4 and a sensor 5 . Blood coagulation test apparatus 10 agitates a blood sample in container 4 with agitator 3 via elastic body 2 under the control of controller 1 . Blood coagulation test apparatus 10 measures the state of blood coagulation and the like by calculating the rotation angle of stirring unit 3 from the image captured by sensor 5 . Blood coagulation test apparatus 10 includes a control device (not shown) that controls processing of control unit 1 and sensor 5 .

The control unit 1 receives commands from the control device and drives the reciprocating rotation of the stirring unit 3 via the elastic body 2 . In FIG. 1, the controller 1 includes a servomotor 1A, an elastic support 1B, and an elastic support shaft 1C. The servomotor 1A causes the elastic body supporting portion 1B to perform a predetermined reciprocating rotational motion with the shaft of the stirring portion 3 as a rotation axis. The predetermined reciprocating rotary motion is, for example, reciprocating rotary motion within a certain angular range. The predetermined reciprocating rotational motion may be a motion controlled so that the rotation angle of the stirring section 3 is constant. That is, the servo motor 1A controls the rotation angle of the stirring unit 3 to be constant by changing the rotation angle according to the coagulation state of the blood sample.

The elastic body support portion 1B performs a predetermined reciprocating rotational motion by being driven by the servomotor 1A. Further, the elastic body support portion 1B supports the elastic body 2 and transmits a predetermined reciprocating rotational motion to the elastic body 2. As shown in FIG. The elastic body support shaft 1C supports the elastic body 2 as a rotating shaft for a predetermined rotational motion transmitted from the elastic body support portion 1B.

Note that the configuration of the control unit 1 is not limited to the example in FIG. The control unit 1 only needs to be able to support the elastic body 2, transmit a predetermined reciprocating rotational motion to the elastic body 2, and control the reciprocating rotational motion at a position separated by a predetermined diameter from the rotation axis. Two wire springs may be supported as the elastic bodies 2 at both ends of the elastic body support portion 1B.

The elastic body 2 transmits the predetermined reciprocating rotational motion transmitted from the elastic body support portion 1B to the stirring portion 3 . In addition, the elastic body 2 can be deformed by receiving force from the stirring section 3 in the circumferential direction of the rotating shaft when the blood coagulation progresses and the stirring section 3 does not follow the predetermined reciprocating rotational motion. In the example of FIG. 1, a coil spring is arranged at a portion where the elastic body 2 is supported by the elastic body support shaft 1C. The coil spring can be deformed by receiving force from the stirring section 3 .

In addition, the elastic body 2 is not limited to the example of FIG. The elastic body 2 may transmit a predetermined reciprocating rotational motion to the stirring section 3 and may be deformed according to the force received from the stirring section 3. For example, a wire spring may be used instead of the coil spring. Moreover, the elastic body 2 may be composed of a plurality of elastic bodies.

Stirrer 3 stirs the blood sample in container 4 by a predetermined reciprocating rotational motion transmitted from controller 1 via elastic body 2 . As the coagulation of blood progresses, the rotation angle of the stirring part 3 becomes smaller than the rotation angle associated with the predetermined reciprocating rotary motion. In FIG. 1, the stirring section 3 includes a rotation transmitting section 3A, a bearing 3B, a stirring pin 3C, and a pinhole 3D.

The rotation transmission part 3A is connected to the elastic body 2 and transmits a predetermined reciprocating rotational motion transmitted from the elastic body 2 to the stirring pin 3C. The rotation transmission part 3A can reciprocate in the circumferential direction with the axis of the stirring pin 3C as the rotation axis. The rotation transmitting portion 3A is connected to the elastic body 2 at a position separated by a predetermined diameter from the rotation shaft, and the rotation is controlled at that position. Since the rotation angle is easily adjusted by controlling the rotation at a position away from the rotation axis, the rotation transmission section 3A can accurately transmit a predetermined reciprocating rotation motion to the stirring pin 3C.

In FIG. 1, the rotation transmission portion 3A is a disk-shaped member arranged perpendicular to the axis of the stirring pin 3C, but the shape of the rotation transmission portion 3A is not limited to a disk shape. The rotation transmission part 3A may be arranged on the shaft of the stirring pin 3C and connected to the elastic body 2 at a position separated from the rotation shaft by a predetermined diameter.

The bearing 3B supports the reciprocating rotation of the stirring pin 3C. In FIG. 1, the bearing 3B is a magnetic bearing using a ring magnet, but it may be a rolling bearing such as a ball bearing, an air bearing, or the like. When a magnetic bearing is used as the bearing 3B, the friction of the bearing portion is reduced, so the rotation transmission portion 3A can transmit a more precise reciprocating rotational motion to the stirring pin 3C.

The agitation pin 3C is immersed in the container 4 and agitates the blood sample in the container 4 by a predetermined reciprocating rotational motion transmitted from the rotation transmission section 3A. As the coagulation of the blood in the container 4 progresses, the rotation angle of the stirring pin 3C becomes smaller due to the reaction force to the predetermined reciprocating rotation. Further, since the rotation transmission portion 3A reciprocates in conjunction with the agitation pin 3C, the rotation angle of the rotation transmission portion 3A is reduced similarly to the agitation pin 3C. When the motion of the rotation transmitting portion 3A no longer follows the predetermined reciprocating rotational motion transmitted from the elastic body 2, the elastic body 2 receives a force opposite to the predetermined reciprocating rotating motion and deforms. Further, the stirring pin 3C can be moved up and down under the control of the control device as the blood in the container 4 coagulates. The control device determines the depth of immersion in the container 4 or the distance between the stirring pin 3C and the inner wall of the container 4 according to the coagulation state of the blood in the container 4, and raises and lowers the stirring pin 3C. The stirring pin 3C is an example of a "stirring part."

The pinhole 3D serves as a mark indicating the reference position of the rotation transmitting portion 3A. By detecting and analyzing the movement of the pinhole 3D by the sensor 5, it is possible to measure the rotation angle of the rotation transmission part 3A, that is, the rotation angle of the stirring pin 3C. In FIG. 1, the pinhole 3D is a hole provided at a position away from the rotating shaft of the rotation transmitting portion 3A. A sensor 5 (for example, a camera) detects light incident from the pinhole 3D and measures the rotation angle of the stirring pin 3C from the movement of the pinhole 3D. The rotation angle can be obtained from the length of the diameter from the rotation axis to the pinhole 3D and the moving distance of the pinhole 3D detected by the sensor 5. FIG.

Note that the pinhole 3D is not limited to the hole provided in the rotation transmitting portion 3A. For example, the pinhole 3D may be a concave portion or a convex portion provided at a position detectable by the sensor 5 . In this case, the sensor 5 can measure the rotation angle of the agitation pin 3C by analyzing the image of the recess or protrusion. That is, the pinhole 3D may be of any form as long as it can be detected by the sensor 5 as a mark indicating the reference position.

A blood sample is placed in the container 4 . The container 4 is arranged so that the stirring pin 3C does not come into contact with the inner surface of the container 4 when the stirring pin 3C reciprocates.

A sensor 5 detects the movement of the pinhole 3D and measures the rotation angle of the stirring pin 3C. Specifically, the sensor 5 may capture an image of the pinhole 3D, transmit the captured image to the control device, and the control device may calculate the rotation angle of the stirring pin 3C. Information on the calculated rotation angle may be displayed on the display unit 17 .

Note that the sensor 5 may be, for example, an electronic device such as a smart phone or a tablet terminal. In this case, the electronic device can image the movement of the pinhole 3D using a camera or the like of the electronic device, analyze the captured image, and calculate the rotation angle of the stirring pin 3C. The electronic device may control the processing of the control section 1 and the sensor 5 as a control device.

<Configuration of control device>
(Hardware configuration)
FIG. 2 is a diagram illustrating a hardware configuration of a control device according to the embodiment; The control device 6 includes a CPU (Central Processing Unit) 11, a RAM (Random Access Memory) 12, a ROM (Read Only Memory) 13, an auxiliary storage device 14 such as a HDD (Hard Disk Drive), and a gateway to the Internet N. It is a computer provided with a connected NIC (Network Interface Card) 15 , an imaging section 16 , a display section 17 and an input section 18 .

The CPU 11 is a central processing unit, and controls the RAM 12, the auxiliary storage device 14 and the like by processing instructions and data of various programs developed in the RAM 12 and the like. The RAM 12 is a main storage device and is controlled by the CPU 11 to write and read various commands and data. The ROM 13 is read-only and stores BIOS (Basic Input/Output System) and firmware as a main storage device. The auxiliary storage device 14 is a non-volatile storage device, in which information requiring persistence such as various programs loaded into the RAM 12 is written and read.

The imaging unit 16 is, for example, a camera having an image sensor such as a CCD (Charge Coupled Device) or a CMOS (Complementary Metal Oxide Semiconductor). When the control device 6 is used as the sensor 5 in FIG. 1 , the imaging section 16 detects the movement of the pinhole 3D of the stirring section 3 .

The display unit 17 displays information and the like based on the measured rotation angle of the stirring unit 3 . The display unit 17 is, for example, a liquid crystal display (LCD). The input unit 18 receives inputs such as information for identifying the elastic body used for inspection and information on the control method of the servomotor 1A. The input unit 18 is, for example, a touch pad, a mouse, a pointing device such as a touch panel, a keyboard, operation buttons, etc., and receives operation input.

(Functional configuration)
FIG. 3 is a diagram illustrating a functional configuration of a control device in the embodiment; The program stored in the auxiliary storage device 14 is read out to the RAM 12 and executed by the CPU 11, so that the control device 6 performs the control information database D11, the correction information database D12, the data reception unit F11, the analysis unit F12 and It functions as a computer having a correction unit F13.

In the present embodiment, each function provided in the control device 6 is executed by the CPU 11, which is a general-purpose processor, but some or all of these functions are implemented by one or more dedicated processors, hardware arithmetic circuits, or the like. may be performed by Here, the hardware arithmetic circuit means, for example, an addition circuit, a multiplication circuit, a flip-flop, or the like, which is a combination of logic gates. Also, part or all of these functions may be executed in a separate computer.

The control information database D11 is a database that stores information for determining an operation related to a predetermined reciprocating rotary motion transmitted from the control unit 1 to the stirring unit 3. FIG. For example, the control information database D11 has a table that stores information for designating a predetermined reciprocating rotational motion by the servomotor 1A, such as angle information relating to a predetermined reciprocating rotational motion. In addition, the control information database D11 includes conditions that trigger the lifting and lowering of the stirring unit 3 when the viscoelasticity of the blood to be tested increases, the depth at which the stirring unit 3 is immersed in the blood, and the relationship between the stirring unit 3 and the container 4. It has a table that stores information such as the distance to the inner wall.

The correction information database D12 is a database that stores information on calibration for each elastic body 2 . Calibration is performed by measuring the deviation from the measurement value of a reference elastic body (hereinafter also referred to as a reference elastic body) for each elastic body 2, and adjusting the measurement accuracy of each elastic body 2 to the reference elastic body. , is a process of correcting the measured value based on the measured deviation. For example, the correction information database D12 has a table that stores information on the difference between the measured value of each elastic body 2 and the reference elastic body.

The control information database D11 and the correction information database D12 are constructed by managing data stored in the auxiliary storage device 14 by a database management system (DBMS) program executed by the CPU 11 . A database management system is, for example, a relational database.

The data receiving section F11 receives data regarding the reciprocating rotational motion of the stirring section 3 detected by the sensor 5 . The received data is, for example, pinhole 3D image information.

The analysis unit F12 analyzes the data received by the data reception unit F11 and calculates the rotation angle of the stirring unit 3 . When controlling the rotation angle of the stirring unit 3 to be constant, the analysis unit F12 controls the servo motor 1A such as the increase rate of the driving force of the servo motor 1A based on the calculated rotation angle of the stirring unit 3. generate information used for Information calculated or generated by the analysis unit F12 is stored in the control information database D11.

The correction unit F13 acquires correction information regarding the deviation from the reference elastic body from the correction information database D12, and corrects the rotation angle of the stirring unit 3 calculated by the analysis unit F12 based on the acquired correction information. The correction information differs for each elastic body 2 used. Therefore, information for identifying the elastic body 2 to be used for inspection may be input from the input unit 18 . The correction unit F13 can acquire correction information related to the elastic body 2 to be used from the correction information database D12 using the input identification information. The information corrected by the correction unit F<b>13 may be displayed on the display unit 17 .

<Elastic Body Calibration>
Now, calibration of the elastic body 2 will be described. The blood coagulation test apparatus 10 may cause variations in measurement accuracy depending on the elastic body 2 used even when testing the same blood sample. Therefore, the blood coagulation test apparatus 10 determines a reference elastic body that serves as a reference for each elastic body 2, and collects measurement results when a predetermined solution is used instead of the blood sample. The blood coagulation test apparatus 10 also measures the coagulation state of each elastic body 2 when a predetermined solution is used, and collects the difference from the measurement result when the reference elastic body is used as correction information. The collected measurement results and correction information of the reference elastic body are stored in the correction information database D12. The blood coagulation test apparatus 10 can correct the detected data for each elastic body 2 based on the correction information stored in the correction information database D12. The predetermined solution is, for example, agarose, gelatin, or the like.

FIG. 4 is a diagram showing changes in the coagulation state of an agarose solution. The gelation temperature of agarose ranges from about 34.5°C to 37.5°C. The vertical axis of each graph shown in FIG. 4 indicates the hardness of the agarose solution, and as the hardness increases, the swelling of the graph increases. The horizontal axis of each graph indicates the time from the start of measurement. FIG. 4 shows graphs for the agarose solution concentrations of 0.5%, 1.0% and 1.5% when the temperature of the agarose solution at the start of measurement is 90° C. and 70° C., respectively. be

When the concentration of the agarose solution is the same, the start of solidification is later when the temperature at the start of measurement is 90°C than when the temperature is 70°C. That is, the higher the temperature at the start of measurement, the later the start of coagulation. In addition, when the temperature of the agarose solution at the start of measurement is the same, the hardness at the time of final gelation increases as the concentration increases. That is, the higher the concentration, the higher the hardness at the final gelation.

The blood coagulation test apparatus 10 collects in advance the correction information of the reference elastic body and each elastic body 2 under various conditions of temperature and concentration at the start of coagulation of the agarose solution, thereby performing measurement for each elastic body 2. Variations in results can be corrected with high accuracy.

<Process flow>
The flow of processing of the blood coagulation test apparatus 10 of this embodiment will be described. In the flow of processing described here, the blood coagulation test apparatus 10 stirs the blood sample in the container 4 with the stirring section 3 by driving the servomotor 1A, and measures the rotation angle of the stirring section 3 . At this time, the servomotor 1A transmits a predetermined reciprocating rotational motion to the stirring section 3 via the elastic body 2. As shown in FIG. In addition, the blood coagulation test apparatus 10 corrects the measurement result based on the correction information regarding the deviation of the elastic body 2 to be used from the reference elastic body measured in advance. Note that the details and order of the processes to be described are only examples, and it is preferable that the details and order of the processes suitable for the embodiment are appropriately adopted.

FIG. 5 is a flowchart illustrating the flow of test processing in the blood coagulation test apparatus. This process flow is triggered, for example, by injection of a blood sample and reagents into container 4 .

First, in step S101, the control device 6 starts the servomotor 1A. The control device 6 controls the servomotor 1A based on the information stored in the control information database D11. The servomotor 1A transmits a predetermined reciprocating rotational motion to the stirring section 3 via the elastic body 2 in accordance with a command from the control device 6 . In the control device 6, for example, the servomotor 1A may transmit reciprocating rotational motion within a certain angular range.

The stirring unit 3 stirs the blood sample in the container 4 by starting the servomotor 1A. As blood coagulation progresses, the reciprocating rotation of the stirring part 3 no longer follows the transmitted predetermined reciprocating rotational motion, and the rotation angle becomes smaller. The sensor 5 detects the reciprocating rotational motion of the stirring unit 3 and transmits data relating to the reciprocating rotational motion, for example, data of the captured image of the pinhole 3D to the control device 6 .

In step S<b>102 , the data receiving section F<b>11 of the control device 6 receives data transmitted from the sensor 5 . In step S<b>103 , the analysis unit F<b>12 of the control device 6 analyzes the received data and calculates the rotation angle of the stirring unit 3 .

Next, in step S104, the correction unit F13 of the control device 6 corrects the rotation angle calculated by the analysis unit F12. Specifically, the correction unit F13 acquires correction information related to the elastic body 2 in use from the correction information database D12. The correction unit F13 corrects the rotation angle calculated by the analysis unit F12 based on the acquired correction information.

In step S105, the control device 6 outputs the rotation angle data corrected by the correction unit F13 as the measurement result. The control device 6 can output the measurement result to the display section 17 . Also, the control device 6 may store the measurement results in the auxiliary storage device 14 . In addition, the control device 6 moves the stirring unit 3 up and down according to the output rotation angle, and controls the depth of the stirring unit 3 immersed in blood, the distance between the stirring unit 3 and the inner wall of the container 4, and the like. may

<Effect>
With the blood coagulation test apparatus 10 of the present embodiment, by appropriately controlling the rotation speed and rotation angle transmitted to the stirring unit 3, it is possible to obtain a resolution suitable for the test object. Also, the cost for the blood coagulation test can be suppressed by reducing the size, weight, and price of the servomotor 1A. In addition, blood coagulation test apparatus 10 does not agitate a plurality of blood samples under the same control, but controls servo motor 1A according to the blood sample, thereby making it possible to perform tests according to each blood sample. be.

Furthermore, blood coagulation test apparatus 10 increases the rotation angle of stirring unit 3 by controlling servo motor 1A when blood coagulation progresses and stirring unit 3 stops reciprocating, thereby increasing the rotation angle of stirring unit 3. Analysis of the elastic state becomes possible. Furthermore, by moving the stirring part 3 up and down and controlling the depth at which the stirring part 3 is immersed in the blood, the distance between the stirring part 3 and the inner wall of the container 4, etc., the resolution is further improved, and the viscosity at high viscosity is improved. It is possible to accurately analyze the elastic state. Thus, the blood coagulation test apparatus 10 acquires data with a desired resolution by changing the predetermined reciprocating rotational motion transmitted from the servomotor 1A to the stirring unit 3 according to the blood sample or preparation to be tested. can do.

Further, by correcting variations in measurement results for each elastic body 2 used based on correction information measured in advance, it is possible to reduce the influence of differences in the elastic bodies 2 used on the measurement results.

[Second embodiment]
<Configuration of blood coagulation test apparatus according to second embodiment>
6A and 6B show the configuration of a blood coagulation test apparatus according to the second embodiment. FIG. 6A is a perspective view showing the appearance of the blood coagulation test apparatus. FIG. 6B is a perspective view showing the inside of the blood coagulation test apparatus. Blood coagulation test apparatus 100 includes housing 110 , upper unit 200 and lower unit 300 . Blood coagulation test apparatus 100 also includes a control device (not shown) that controls the operation of each mechanism included in upper unit 200 and lower unit 300 . A control device according to the second embodiment has the same hardware configuration as the control device 6 according to the above-described embodiment. The operation of each mechanism included in the upper unit 200 and the lower unit 300 is driven by commands from the control device according to the second embodiment.

The housing 110 includes a substantially square bottom plate 111, posts 112 erected at the four corners of the bottom plate 111, panels 113 provided on the front surface, the rear surface, the upper right side, the left side, and the upper surface, and the lower right side. A connection panel 114 having an insertion opening for inserting cables for connection with a power source or an external device is configured in a box shape. The housing 110 accommodates the upper unit 200 and the lower unit 300 . In addition, the housing 110 has a handle 115 on the top panel 113 to enable portability. Furthermore, the front panel 113 is provided with an opening 113A for setting and taking out a container containing a blood sample. Blood samples to be tested also include plasma obtained by centrifugation of blood or the like.

The housing 110 accommodates the upper unit 200 and the lower unit 300, and has an insertion port for connecting each unit to a power source or an external device and an opening that allows insertion and removal of a container containing a blood sample. , the shape of the housing 110, the position and shape of the insertion port for the cables, and the position and shape of the opening for taking in and out the container are not limited to the examples in FIGS. 6A and 6B. The housing 110 may be configured, for example, with a plurality of panels 113 and struts 112 as an integral member to accommodate the upper unit 200 and the lower unit 300 . Further, the housing 110 may be provided with recesses for holding the blood coagulation test apparatus 100 with both hands on the right and left side panels or the front and rear panels 113 without providing the handles 115 on the top panel 113 .

7A and 7B show the configuration of the upper unit 200. FIG. FIG. 7A is a perspective view of the upper unit 200 viewed from above. FIG. 7B is a perspective view of the upper unit 200 as seen from below. The upper unit 200 includes an elevating mechanism 210 , a stirring control mechanism 230 , a stirring motion transmission mechanism 240 and a rotation angle measuring mechanism 270 .

The lifting mechanism 210 includes a lifting motor 211 , a shaft 212 and a support shaft guide 213 . The lifting motor 211 has, for example, a female threaded portion that is screwed together with a fully threaded shaft 212 . The female threaded portion is rotatable around a shaft 212 by being driven by a lifting motor 211 . The upper unit 200 can be raised and lowered to a desired height by rotating the internal thread portion. The support shaft guide 213 is provided with a support shaft insertion hole 213A through which a support shaft (not shown) for the lower unit 300 to support the upper unit 200 is inserted. As shown in FIG. 7B, the support shaft guide 213 has a tubular portion below the upper unit bottom plate 215, and the support shaft is inserted through the support shaft insertion hole 213A. By inserting the support shaft through the support shaft guide 213, the upper unit 200 can be vertically moved up and down. In addition, in the example of FIG. 7A , the support shaft guides 213 are arranged on the right and left sides of the lifting motor 211 . The support shaft guides 213 are not limited to being provided at two locations on the right and left sides of the lifting motor 211. For example, the support shaft guides 213 may be provided at diagonal corners of the upper unit bottom plate 215, or at two or more locations. position.

The stirring control mechanism 230 includes a stirring motor 231 , a gear 232 and a sliding plate 233 . A stirring motor 231 drives rotation of a gear 232 . The gear 232 converts rotary motion into linear motion to slide the sliding plate 233 back and forth. Sliding plate 233 slides back and forth in response to rotation of gear 232 and transmits an operation for stirring the blood sample to stirring motion transmission mechanism 240 . The stirring motion transmission mechanism 240 is detailed in FIG. 8A.

8A and 8B show the configuration of the stirring motion transmission mechanism 240. FIG. 8A is an exploded perspective view of stirring motion transmission mechanism 240. FIG. The stirring motion transmission mechanism 240 includes a swing plate 241, a rotor 242, a washer 243, a rotating shaft 244, a bearing 245A, a bearing 245B, a first pedestal 246, a washer 247A, a washer 247B, a swing transmission portion 248, an elastic body 249, A swing transmission receiving part 250 , a second pedestal 251 and a holding pin 252 are provided.

The oscillating plate 241 performs reciprocating rotational motion (hereinafter also referred to as oscillating motion) about a rotating shaft 244 inserted through the rotating shaft insertion hole 241A in accordance with the reciprocating motion of the sliding plate 233 in the front-rear direction. The rotor 242 is fixed to the rocking plate 241, and the rotating shaft 2 inserted through the rotating shaft insertion hole 241A.
44 to transmit the rocking motion of the rocking plate 241 . The washer 243 suppresses friction with the bearing 245A due to the swinging motion of the rotor 242 . The rotating shaft 244 is rotatably supported by a bearing 245A and a bearing 245B fitted to the bearing 245A. The bearings 245A and 245B are fitted to each other with the first pedestal 246 interposed therebetween. The first pedestal 246 mounts the agitation control mechanism 230 . The rotary shaft 244 is connected to the swing transmission portion 248 via a washer 247A and a washer 247B.

The swing transmission part 248 swings in conjunction with the swing motion of the swing plate 241 . The swing transmission portion 248 includes an elastic body connecting portion 248A for connecting the elastic body 249 . As the elastic body 249, in the example of FIG. 8, a coil spring having a vertical axis is used. One end of the elastic body 249 is connected to the elastic body connecting portion 248A, and the other end of the elastic body 249 is connected to the oscillating transmitted portion 250 . The oscillating transmitted portion 250 includes an elastic body connecting portion 250A for connecting the elastic body 249 . The other end of the elastic body 249 is connected to the elastic body connecting portion 250A. The oscillating transmitted portion 250 further transmits the oscillating motion transmitted via the elastic body 249 to the holding pin 252 . The oscillating transmitted portion 250 includes an oscillating measurement pin 250B for measuring the rotation angle of the oscillating motion of the oscillating transmitted portion 250 . The rotation angle of the swing measurement pin 250B is measured by the rotation angle measurement mechanism 270 shown in FIG. 7A. The second pedestal 251 mounts the oscillating transmitted part 250 thereon. The second pedestal 251 includes a pedestal support portion 251A and a pedestal support portion 251B and supports the first pedestal 246 . The holding pin 252 is connected to the oscillating transmitted portion 250 via an insertion hole (not shown) provided in the second base 251 . The holding pin 252 swings in conjunction with the swing motion of the swing-transmitted portion 250 .

FIG. 8B is a partially exploded view of the stirring motion transmission mechanism 240 and a perspective view of the container. Each member from the rocking plate 241 to the holding pin 252 shown in FIG. 8A is assembled as shown in FIG. 8B. The holding pin 252 holds the stirring unit 30 and rocks the stirring unit 30 to stir the blood sample in the container 40 . The holding pin 252 is inserted into a holding pin insertion hole 30A provided in the upper portion of the stirring section 30. As shown in FIG. Stirrer 30 rotates in conjunction with holding pin 252 to stir the blood sample in container 40 . Due to the coagulation of the blood sample in container 40 , a force that suppresses rocking of holding pin 252 acts, and the rotation angle of holding pin 252 increases or decreases according to the viscosity of the blood sample in container 40 . Further, the stirring section 30 has a flange 30B. The flange 30B is used when the holding pin 252 is pulled out from the stirring section 30 after the blood coagulation test is completed. By lifting the holding pin 252 while pressing the flange 30</b>B, the holding pin 252 can be pulled out from the stirring section 30 .

A rotation angle measurement mechanism 270 in FIG. 7A includes a sensor plate 271 and a light source section 272 . The rotation angle measurement mechanism 270 is a mechanism for measuring the rotation angle of the stirring section 30 . The sensor plate 271 includes an optical sensor in which light receiving elements are linearly arranged. The light source unit 272 includes a light source (not shown) such as an LED (Light Emitting Diode) that irradiates the optical sensor of the sensor plate 271 . In the second embodiment, the rotational angle measuring mechanism 270 detects the rotational motion of the oscillation measuring pin 250B that oscillates on the optical sensor in conjunction with the stirring operation of the blood sample in the container 40. FIG. The rotation angle measurement mechanism 270 can measure the rotation angle of the stirring section 30 that swings in conjunction with the swing measurement pin 250B by measuring the rotation angle of the swing measurement pin 250B. Blood coagulation test apparatus 100 accurately measures the rotation angle of stirring unit 30 by measuring the rotation angle of swing measurement pin 250B that swings at a position away from the rotation axis of stirring unit 30 using rotation angle measurement mechanism 270. can be measured well.

9A and 9B show the configuration of the lower unit 300. FIG. FIG. 9A is a perspective view of the lower unit 300 viewed from the front left side. FIG. 9B is a perspective view of the lower unit 300 as seen from the rear left side. The lower unit 300 includes a mounting table slide mechanism 310 and a holding pin withdrawal mechanism 320 . In addition, the lower unit 300 includes a support shaft 331 and an upper unit support base 332 for connecting with the upper unit 200 . The upper unit support base 332 is provided with a fitting hole 332A for fitting and fixing the lower end of the shaft 212 . 9A and 9B show a state in which the lower unit 300 is arranged on the bottom plate 111 of the housing 110. FIG.

A mounting table slide mechanism 310 shown in FIG. 9B includes a mounting table 311 , a ball screw 312 , a slide motor 313 and a linear guide 314 . The mounting table 311 includes a container setting portion 311A (FIG. 9A), which is a cylindrical concave portion capable of accommodating the container 40 . 9A shows a state in which the container 40 is installed in the container installation section 311A and the stirring section 30 is accommodated in the container 40. FIG. The ball screw 312 is screwed into the mounting table 311 , and the rotation of the ball screw 312 causes the mounting table 311 to slide back and forth. A slide motor 313 drives the rotational motion of the ball screw 312 . The linear guide 314 guides the linear movement of the mounting table 311 in the front-rear direction. The mounting table slide mechanism 310 converts the rotary motion of the motor into a linear motion and slides the mounting table 311 to a position where the container 40 can be installed. Various linear motion mechanisms may be used. Blood coagulation test apparatus 100 may include a heat retaining device (not shown) for keeping container 40 accommodated in mounting table 311 warm. temperature can be maintained.

A holding pin withdrawal mechanism 320 shown in FIG. 9A includes a guide plate 321 , a pressing plate 322 and a solenoid 323 . The guide plate 321 is arranged above the container installation portion 311A of the mounting table 311 and has an opening 321A for inserting the holding pin 252 into the holding pin insertion hole 30A of the stirring portion 30 . When the holding pin 252 is pulled out from the holding pin insertion hole 30A, the holding plate 322 rotates around the end connected to the solenoid 323 to a position where it can hold the flange 30B of the stirring unit 30. As shown in FIG. The pressing plate 322 presses the flange 30B of the stirring unit 30, so that the holding pin 252 can be pulled out from the holding pin insertion hole 30A. The solenoid 323 is energized until the holding pin 252 is pulled out from the holding pin insertion hole 30A. While the solenoid 323 is energized, the presser plate 322 maintains its rotated state to the position where it presses the flange 30</b>B of the stirring section 30 , and the holding pin 252 is pulled out from the stirring section 30 .

The connection between the upper unit 200 and the lower unit 300 will be described with reference to FIGS. 10 to 12. FIG. FIG. 10 is a perspective view of the upper unit 200 separated from the lower unit 300. FIG. The support shafts 331 are arranged vertically on both sides of the rear end of the mounting table 311 . The support shaft 331 supports the upper unit 200 by being inserted through the support shaft guide 213 of the upper unit 200 .

FIG. 11 is a plan view of the state in which the upper unit 200 and the lower unit 300 are assembled. The support shaft guides 213 are arranged at two locations on both sides of the lifting motor 211 at approximately the center between the front and rear surfaces of the blood coagulation test apparatus 100 . Upper unit 200 is supported by support shafts 331 at two locations near the center of blood coagulation test apparatus 100 in a plan view.

12A is a left side view showing a state in which the upper unit 200 is separated from the lower unit 300. FIG. 12B is a front view showing a state in which the upper unit 200 is separated from the lower unit 300. FIG. As shown in FIG. 12A, the support shaft 331 of the lower unit 300 is inserted through the support shaft guide 213 of the upper unit 200. As shown in FIG. When the container 40 and the stirring section 30 are installed on the container installation section 311A of the mounting table 311, the holding pin 252 is inserted into the holding pin insertion hole 30A provided on the upper surface of the stirring section 30 by lowering the upper unit 200. be done. 12B, when the upper unit 200 and the lower unit 300 are assembled, the lower end of the shaft 212 of the upper unit 200 is fitted into the fitting hole 332A provided in the upper unit support base 332 and fixed.

<Flow of operation>
FIG. 13 is a flow chart illustrating the operation flow of the blood coagulation test apparatus according to the second embodiment. 14A to 20B show a lifting mechanism 210, a stirring control mechanism 230, a stirring motion transmission mechanism 240, a rotation angle measuring mechanism 270, a table sliding mechanism 310, and a holding pin extracting mechanism for driving each operation shown in FIG. 320 will be described. The flow of operation shown in FIG. 13 is started when the blood coagulation test apparatus 100 according to the second embodiment receives a test start command from the control device according to the second embodiment.

First, in step S201, the mounting table slide mechanism 310 slides the mounting table 311 to the front side to a position where the container 40 can be installed. The container 40 and the stirring section 30 housed in the container 40 are installed on the container installation section 311A of the mounting table 311 slid to the front side. When the container 40 and the stirring unit 30 are installed, the mounting table slide mechanism 310 slides the mounting table 311 to its original position. Here, the operation of the mounting table 311 by the mounting table slide mechanism 310 will be described with reference to FIGS. 14A and 14B.

14A is a diagram showing a state in which mounting table 311 is housed in blood coagulation test apparatus 100. FIG. FIG. 14B is a diagram showing a state in which the mounting table 311 is slid to the front side and the container 40 can be installed on the mounting table 311. FIG. The mounting table 311 can be slid in the direction of arrow X1 shown in FIGS. The mounting table 311 can move linearly by sliding on the linear guide 314 . In step S201, the mounting table slide mechanism 310 slides the mounting table 311 to the front side to a position where the container 40 can be installed, as shown in FIG. 14B. When the container 40 and the stirring unit 30 are installed, the mounting table slide mechanism 310 slides the mounting table 31 rearward to the position shown in FIG. 14A and returns it to the original position.

Next, in step S<b>202 , the lifting mechanism 210 lowers the upper unit 200 to insert the holding pin 252 into the holding pin insertion hole 30</b>A provided at the top of the stirring section 30 . The holding pin 252 has substantially the same diameter as the holding pin insertion hole 30A, and can hold the stirring section 30 by being inserted into the holding pin insertion hole 30A. Further, in step S<b>203 , the lifting mechanism 210 raises the upper unit 200 so that the stirring section 30 held by the holding pins 252 is removed from the container 40 . The blood sample can be injected into the container 40 by removing the stirring unit 30 from the container 40 . Here, the lifting operation of the upper unit 200 by the lifting mechanism 210 will be described with reference to FIGS. 15A and 15B.

15A is a diagram showing a state in which the holding pin 252 is inserted into the stirring section 30 by lowering the upper unit 200. FIG. FIG. 15B is a diagram showing a state in which upper unit 200 is raised to a position where stirring section 30 can stir the blood sample in container 40 . The lifting mechanism 210 can move the upper unit 200 up and down by driving the lifting motor 211 to rotate a female thread portion screwed with a shaft 212 provided inside the lifting motor 211 . The elevating mechanism 210 can elevate the upper unit 200 to a desired height. In step S<b>202 , the lifting mechanism 210 may lower the upper unit 200 until the holding pins 252 are inserted to a depth at which the stirring section 30 can be held. In step S203, the elevating mechanism 210 further elevates the upper unit 200 from the state of FIG.

At step S204, the upper unit 200 is in a raised state by the process at step S203. The mounting table slide mechanism 310 slides the mounting table 311 to the front side again. Stirrer 30 in container 40 is in a state where it has been taken out by holding pin 252 by the process of step S202, and a blood sample can be injected into container 40. FIG. When the blood sample is injected into the container 40, the mounting table slide mechanism 310 slides the mounting table 311 to the rear surface side and returns it to its original position.

In step S205, the lifting mechanism 210 adjusts the height of the stirring unit 30 so that the blood sample in the container 40 can be stirred. The lifting mechanism 210 may, for example, lower the upper unit 200 to a height where the tip of the stirring section 30 does not contact the bottom of the container 40, as shown in FIG. 15B.

In step S206, a blood coagulation test is performed. First, the stirring control mechanism 230 converts the rotary motion of the stirring motor 231 into the rocking motion of the rocking plate 241 . Next, the stirring motion transmission mechanism 240 transmits the rocking motion of the rocking plate 241 to the rocking transmitted portion 250 . The oscillating transmitted portion 250 further transmits the transmitted oscillating motion to the holding pin 252 . The agitating section 30 held by the holding pin 252 agitates the blood sample in the container 40 by oscillating in conjunction with the holding pin 252 . The rotation angle measurement mechanism 270 measures the rotation angle of the stirring section 30 and transmits the measurement result to the control device according to the second embodiment. Here, the stirring control mechanism 230, the stirring motion transmission mechanism 240, and the rotation angle measuring mechanism 270 will be described with reference to FIGS. 16, 17A, 17B, and 17C.

16A and 16B are diagrams illustrating the operation of converting the rotational motion of the gear 232 into the oscillating motion of the oscillating plate 241 by the stirring control mechanism 230. FIG. The stirring control mechanism 230 rotates a gear 232 by a stirring motor 231 . The rotary motion of the gear 232 is converted into reciprocating motion of the slide plate 233 in the arrow Y direction. By controlling the rotational speed of the stirring motor 231, the amplitude of the reciprocating motion of the sliding plate 233 can be adjusted to a desired width. Further, the reciprocating motion of the sliding plate 233 causes the rocking plate 241 to rock in the Z1 direction about the rotating shaft 244 as the rotating shaft. The rotation angle of the rocking plate 241 can be adjusted to a desired angle by adjusting the amplitude of the reciprocating motion of the sliding plate 233 . Furthermore, by controlling the rotation speed of the stirring motor 231, it is possible to appropriately control the rotation speed of the rocking plate 241, that is, the rotation speed of the stirring motion transmitted to the stirring section 30.

17A to 17C illustrate the operation of transmitting the rocking motion of the rocking plate 241 to the rocking transmitted portion 250 by the stirring motion transmission mechanism 240. FIG. FIG. 17A is a diagram showing the rotating state of the rocking plate 241 when the sliding plate 233 moves to the front side. FIG. 17B is a diagram showing the rotating state of the rocking plate 241 when the sliding plate 233 is not moving. FIG. 17C is a diagram showing the rotating state of the rocking plate 241 when the sliding plate 233 moves rearward. As shown in FIGS. 17A, 17B, 17C, 17B, 17A, 17B, . . . , the rocking plate 241 repeats the states of FIGS.

The stirring motion transmission mechanism 240 transmits the rocking motion of the rocking plate 241 in the Z1 direction to the rocking motion transmission portion 248 . The swing transmission part 248 interlocks with the swing plate 241 via the rotation shaft 244 and swings in the Z2 direction with the rotation shaft 244 as the rotation axis. The stirring motion transmission mechanism 240 transmits the swinging motion of the swinging motion transmitting portion 248 in the Z2 direction to the swinging motion transmitted portion 250 via the elastic body 249 . The oscillating transmitted portion 250 oscillates in the Z3 direction with the holding pin 252 as the rotation axis.

The rotation angle measuring mechanism 270 detects the rotation angle of the oscillation measuring pin 250B on the distal end side of the oscillation transmitted portion 250 by means of an optical sensor 271A provided on the sensor plate 271 . The optical sensor 271A detects the light emitted from the light source section 272 on the upper side by the linearly arranged light receiving elements. The rotation angle measurement mechanism 270 can measure the rotation angle of the oscillation measurement pin 250B from a position where light is not detected due to the movement of the oscillation measurement pin 250B. Since the swing measurement pin 250B swings in conjunction with the holding pin 252, when the rotation angle of the holding pin 252 is reduced due to coagulation of the blood in the container 40, the rotation angle is also reduced. . Therefore, the rotation angle measuring mechanism 270 can measure the rotation angle of the holding pin 252 (and the stirring section 30 held by the holding pin 252) by measuring the rotation angle of the swing measurement pin 250B.

Further, in the blood coagulation test performed in step S206, the rotation angle of the stirring motion transmitted to stirring section 30 (the rotation angle of rocking plate 241) is controlled by stirring control mechanism 230. FIG. When the viscoelasticity of the blood in the container 40 increases, even if the rotation angle of the rocking plate 241 is increased, the stirring unit 30 receives force from the blood in the direction opposite to the rotation of the rocking plate 241 . 30 rotation angle becomes small. In this case, the stirring unit 30 is lifted by the elevating mechanism 210 to reduce the depth at which the stirring unit 30 is immersed in the blood sample, or to increase the distance between the stirring unit 30 and the inner wall of the container 40. The force that the stirring unit 30 receives from the blood sample is suppressed. When the force that the stirring unit 30 receives from the blood is suppressed, when stirring the blood with the same viscoelasticity, the stirring unit 30 raises the stirring unit 30 more than when stirring at a normal depth. can rotate at a larger angle. Therefore, blood coagulation test apparatus 100 can more accurately measure changes in viscoelasticity of blood in a high viscoelasticity region by raising stirring unit 30 . It should be noted that the height of the agitator 30 can be freely set to control the region where the agitator 30 is immersed in blood. For example, the height of the stirring section 30 can be raised between 0.1 mm and 20 mm with a control of 0.1 mm.

Blood coagulation test apparatus 100 measures the viscoelasticity by rotating stirring unit 30 when the viscoelasticity of blood is low, and raises stirring unit 30 at a predetermined timing when the change rate of viscoelasticity decreases. . The predetermined timing can be the timing when the accuracy of measuring the change in viscoelasticity has decreased. Moreover, for a blood sample with high viscoelasticity, the stirring unit 30 can be raised from the timing of starting measurement. It is also possible to measure without changing the depth of immersion in the blood sample with the stirring unit 30 raised. By raising the stirring part 30, it is possible to more accurately measure changes in viscoelasticity even in a high viscoelasticity region. In this manner, the blood coagulation test apparatus 100 uses the elastic body 249 having a stronger elastic force than the elastic body 249 used when measuring the viscoelasticity of blood in the low viscoelasticity region for blood in the high viscoelasticity region. Therefore, the elastic body 249 having the same strength can be used to accurately measure the change in viscoelasticity from the low viscoelasticity region to the high viscoelasticity region.

FIG. 18A is a diagram showing the position of the stirrer during a normal blood coagulation test. FIG. 18B is a diagram showing a state in which the viscoelasticity of the blood sample in the container is increased and the stirring section 30 is raised. In FIG. 18A , the stirring section 30 is in a state where the entire tapered tip is immersed in the blood sample in the container 40 . When the viscoelasticity of the blood sample in the container 40 increases, the rotation angle of the stirring unit 30 or the rate of change in the rotation angle decreases, and measurement of the viscoelasticity becomes difficult, the elevating mechanism 210 is operated as shown in FIG. 18B. You may raise the stirring part 30 by. Alternatively, for a normal human sample, the height of the stirring unit 30 is analyzed at a steady position, and when analyzing the blood of a sample with high viscoelasticity (for example, mouse or rat), the measurement is performed at a position where the stirring unit 30 is elevated. may

Alternatively, when blood viscoelasticity is measured in a state where platelet function is inhibited, such as FIBTEM in ROTEM assay (analysis, evaluation), the height of stirring unit 30 is measured at a steady position, and the height of normal human blood sample is measured. At the time of analysis (for example, EXTEM measurement of ROTEM), the position of the stirring unit 30 is raised for measurement. 30 can also be increased and measured. In this way, by controlling both the elevation and rotation angle of the stirring unit 30, it is possible to analyze blood with a wider range of viscoelasticity. The stirring part 30 is in a state in which a part of the tapered tip part is immersed as it rises. The depth at which the stirring part 30 is immersed in the blood sample in the container 40 becomes shallow, and the rotation angle of the stirring part 30 becomes a measurable size.

19A and 19B are diagrams illustrating a container 40 containing a blood sample. The container 40 is not limited to a cylindrical shape as shown in FIG. 8B. Any shape may be used as long as the depth of the stirring part 30 that accommodates the blood and is immersed in the blood of the container 40 can be changed. Figure 19A is a perspective view of a first variant of the container. In the container 40A shown in FIG. 19A, the diameter of the cylindrical portion 40Ab on the bottom side from the switching portion 40A1 is smaller than the diameter of the cylindrical portion 40Aa on the opening side. Therefore, the distance between the stirring part 30 and the inner wall of the container 40A can be easily changed by moving the stirring part 30 up and down. Figure 19B is a perspective view of a second variant of the container. A container 40B shown in FIG. 19B is a truncated conical container tapered toward the bottom side. By making the shape of the container 40B into a truncated cone shape, it is possible to adjust the distance between the stirring part 30 and the inner wall of the container 40B to a desired distance. Also, striped grooves perpendicular to the circumferential direction may be provided on the inner peripheral surface of the container 40 (40A, 40B).

The shape of the stirring part 30 is not limited to one having a tapered tip as shown in FIG. 18A or 18B. The shape of the stirring part 30 may be rod-like, and the cross section is not limited to a circular shape, and may be polygonal or the like. Also, the outer peripheral surface of the stirring part 30 may be provided with striped grooves or irregularities of various shapes.

In step S207, the holding pin withdrawal mechanism 320 withdraws the holding pin 252 from the stirring section 30 after the inspection is finished. The holding pin pull-out mechanism 320 can pull out the holding pin 252 from the stirring unit 30 by pressing the upper portion of the stirring unit 30 and lifting the upper unit 200 by the lifting mechanism 210 . Here, the operation of pulling out the holding pin 252 from the stirring section 30 by the holding pin pulling out mechanism 320 will be described with reference to FIGS. 20A and 20B. 20A, it is assumed that the holding pin 252 is inserted into the holding pin insertion hole 30A of the stirring section 30. In FIG.

FIG. 20A is a diagram showing a state where the pressing plate 322 does not press the stirring section 30. FIG. FIG. 20B is a diagram showing a state in which the pressing plate 322 presses the stirring section 30 when the holding pin 252 is pulled out from the stirring section 30 . When the solenoid 323 is energized and de-energized, the pressing plate 322 receives force in the direction of the arrow X2, and changes its angle to the states shown in FIGS. 20B and 20A, respectively.

In the state of FIG. 20A, the pressing plate 322 does not overlap the container 40 and the stirring section 30 in plan view. Therefore, the pressing plate 322 does not come into contact with the container 40 and the stirring section 30 . Therefore, the stirring section 30 held by the holding pins 252 is lifted together with the upper unit 200 by the lifting mechanism 210 . On the other hand, in the state of FIG. 20B, the pressing plate 322 overlaps the upper surface of the stirring section 30 in plan view. Since the pressing plate 322 presses the upper portion of the stirring section 30 held by the holding pins 252 , the holding pins 252 are pulled out of the stirring section 30 when the upper unit 200 is lifted by the lifting mechanism 210 . In step S208, the container 40 and the stirring section 30 are taken out, and the process shown in FIG. 13 ends.

With the blood coagulation test apparatus 100 of the second embodiment, the rotation speed and rotation angle transmitted to the stirring section 30 can be appropriately controlled by controlling the rotation speed of the stirring motor 231 . In addition, by moving the stirring part 30 up and down and controlling the depth at which the stirring part 30 is immersed in the blood to be tested, or the distance between the stirring part 30 and the inner wall of the container 40, the range from the low viscoelasticity region to the high viscoelasticity region is controlled. It is possible to accurately measure the viscoelasticity of blood in a wide range up to. Therefore, the examination by the blood coagulation test apparatus 100 can obtain a resolution corresponding to the examination target. Furthermore, the blood coagulation test apparatus 100 is provided with operating mechanisms such as a lifting mechanism 210, a mounting table slide mechanism 310, and a holding pin withdrawal mechanism 320, thereby promoting automation and simplification of the blood coagulation test.

[Example according to the second embodiment]
EXAMPLES Examples according to the second embodiment are shown below to describe the present invention more specifically. However, the present invention is not limited to the following examples.

In the second embodiment, an example is shown in which a spring with greater sensitivity (that is, thinner/weaker) is selected as the elastic body 2 in accordance with the measurement of the low viscoelastic region. In addition, when measuring in a high viscoelastic region, by controlling the rotation speed of the motor and measuring by widening the rotation (amplitude) angle of the stirring unit that stirs the blood sample, measurement in a wide viscoelastic region is possible. becomes possible. For example, a method of analyzing blood viscoelasticity by thromboelastometry in the presence of an antiplatelet agent and measuring the amount of fibrinogen in blood is disclosed (Reference 1: US20090130645 method for assessing the fibrinogen contribution in coagulation). A gel (clot) consisting only of fibrin in the presence of an antiplatelet agent has lower viscoelasticity than a gel (clot) consisting of both activated platelets and fibrin in normal blood. Therefore, a gel consisting only of fibrin in the presence of an antiplatelet agent is suitable for measurement at about ±4-10 degrees due to its thinner/weaker spring.

When the high viscoelasticity region is analyzed under the same high sensitivity spring and amplitude angle conditions as the low viscoelasticity region measurement, sufficient resolution and accuracy cannot be obtained in the high viscoelasticity region. That is, there is a possibility that the movement of the oscillation measuring pin will stop before the blood coagulates and reaches the maximum viscoelasticity. In order to prevent such a situation, for example in the case of hypercoagulable conditions (hyperfibrinogen) or thrombocytosis, for example in the measurement of high viscoelastic regions, even the more sensitive springs should By widening the rotation angle of motion to ±5 degrees or more, preferably ±10 to 20 degrees, a stronger force is applied to the oscillation measurement pin via the spring, enabling highly accurate measurement in the high viscoelasticity region. Become. In addition, even when testing for blood coagulation with high viscoelasticity, the initial rotation angle of the stirrer should be ±4 to 10 degrees, and after confirming the decrease in amplitude due to the start of blood coagulation, it should be increased to ±10 to 20 degrees. is also possible. In this case, even if the rotation angle is widened to ±10 to 20 degrees, the blood viscoelasticity has already started to rise, so the rotation angle of the stirring part can be suppressed to about 5 degrees. It is possible to prevent the gel structure of the blood clot from being broken by the amplitude. If a weak spring that does not break the gel is used, the problem of breaking the fibrin gel does not occur even at a rotation angle of ±10 degrees or more. However, if a weaker spring is used, the analysis of high viscoelasticity requires a higher rotation angle. The angle of rotation of the stirrer is selected according to the sensitivity of the spring and the geometry of the spring and stirrer. In this way, when measuring a high viscoelastic region using the same device (system) using a highly sensitive spring that matches the measurement of the low viscoelastic region, the number of rotations of the motor is controlled, By changing (widening) the rotation angle of the swinging motion transmitted to the spring and the stirrer, it is possible to perform assays (analyses, evaluations) in various viscoelastic regions with high sensitivity. As exemplified in the following examples, the rotation angle of the oscillating motion of the oscillating motion of the oscillating transmission part 248, which is transmitted to the spring and the stirring part, depends on the viscoelasticity of the blood (including plasma) to be tested. It is possible to change for each purpose of measurement according to.

In Examples 1 to 3, the spring and stirring unit 30 are used to measure a blood sample with low viscoelasticity, and the position of the stirring unit 30 is raised when measuring blood coagulation in a high viscoelasticity region. , an example of measuring highly viscoelastic blood coagulation. In Examples 1 to 3, the positional difference at both ends of the oscillating measurement pin 250B is maintained, and the high viscoelasticity region is maintained even when the spring and stirrer 30 for measuring low viscoelasticity blood coagulation are used. It was found that it is possible to measure blood coagulation at

Examples 4 to 6 are examples in which low-viscoelasticity blood coagulation and high-viscoelasticity blood coagulation were measured using stirring units 30 having different tip shapes (thickness and length). . By making the stirrer 30 thicker, the distance to the inner wall of the container 40 becomes shorter, and the load due to the increase in the viscoelasticity of blood is transmitted to the stirrer 30 more strongly, thereby improving the sensitivity for blood samples with low viscoelasticity. . On the other hand, when the stirring part 30 is thin, the distance to the inner wall of the container 40 becomes long, and the load due to the increase in the viscoelasticity of the blood is less likely to be transmitted to the stirring part 30, so that the sensitivity to the highly viscoelastic blood sample is reduced. improves. In the stirring part 30 having a long thick tip part, the area of the part close to the inner wall of the container 40 is large, and the load due to the increase in the viscoelasticity of the blood is transmitted to the stirring part 30 more strongly, resulting in low viscoelasticity. sensitivity to blood samples is improved.

<Example 1>
Example 1 is an example in which a high viscoelasticity sample is analyzed by changing the depth to which the stirring part 30 is immersed in the blood by raising and lowering the upper unit 200 with the raising and lowering mechanism 210 .

Venous blood was collected into a collection tube containing 3.2% sodium citrate. In the container 40, 20 μL of EXTEM reagent (extrinsic blood coagulation activation reagent: Temin innovations Gmbh) and Startem reagent (calcium chloride reagent: Temin innovations
GmbH) and 300 μL of human blood. The container 40 is kept warm at 37 degrees,
By controlling the agitation motor 231, the oscillation transmission part 248 was oscillated within a range of ±10 degrees. The swing motion of the swing motion transmitting portion 248 is transmitted to the stirring portion 30 via the elastic body 249 , the swing-transmitted portion 250 and the holding pin 252 . As the elastic body 249, the following torsion coil spring was used.

FIG. 21 is a diagram illustrating a torsion coil spring used in an example of the second embodiment; Assuming that the wire diameter of the torsion coil spring is d mm and the number of turns of the coil is n, in Examples 1, 2, 3, and 6 of the second embodiment, the spring A has arm length a1=10 mm, arm length a2=10 mm, A torsion coil spring with arm length b=3 mm, center diameter D=2 mm, wire diameter d=0.12 mm, and number of turns=2 was used. The spring constant kTd of the spring A is calculated as 0.0017 Nmm/deg from the following formula (Formula 1). In Examples 4 and 5, the spring B is a torsion coil having arm length a1 = 10 mm, arm length a2 = 10 mm, arm length b = 3 mm, center diameter D = 2 mm, wire diameter d = 0.15 mm, and number of turns = 6. used a spring. The spring constant kTd of the spring B is calculated as 0.0018 Nmm/deg from the following formula (Formula 1).

Ｅ：縦弾性計数（ＳＵＳ、Steel special Use Stainless）＝１８６×１０^３Ｎ／ｍｍ
^２

E: longitudinal elastic modulus (SUS, Steel special Use Stainless) = 186 × 10 ³ N / mm
²

Even when wire springs are used, it is possible to change the spring constant kTd by changing the wire diameter d and the arm lengths _a1 and _a2 . When a torsion coil spring is used, the spring constant kTd can be changed more flexibly by changing the center diameter D and the number of turns n, as shown in the above formula (Formula 1). It becomes possible.

In Example 1, one reciprocation of the amplitude of the oscillation transmission part 248 controlled by the stirring motor 231 was set to 5.2 seconds. The rotation angle of the stirring portion 30 can be calculated from the amplitude of the oscillation measurement pin 250B provided at the tip of the oscillation-transmitted portion 250. As shown in FIG. The amplitude of the oscillation measuring pin 250B is measured four times at intervals of about 0.1 seconds from 0.4 seconds after the rotation of the oscillation transmitting portion 248 stops at both ends, respectively, on the optical sensor 271A of the oscillation measuring pin 250B. was measured, and calculated from the average value of each four times at both ends of the rotation.

The stirring unit 301 and container 40C used in Example 1 will be described with reference to FIGS. 28 and 29. FIG. 28 is a cross-sectional view of the stirring unit 301 used in Example 1. FIG. The total length (height) of the stirring section 301 in the axial direction indicated by the dashed line is 15.2 mm. The thickness of the flange 301B is 1.3 mm. Moreover, the length of the tip for stirring the blood sample (the thickened part on the tip side to be immersed in the container 40C) is 7.1 mm. The diameter of the tip portion on the flange 301B side is 6.2 mm. A holding pin insertion hole 301A is provided at the upper end.

29 is a cross-sectional view of the container 40C used in Example 1. FIG. The height of the container 40C is 16.5 mm. The diameters of the opening surface and the bottom surface of container 40C are 13.5 mm and 10.2 mm, respectively. The inside diameter of the container 40C is 9.5 mm at the opening and 7.6 mm at the bottom. In addition, a switching portion having a narrower inner diameter is provided in the container 40C used in the example, and the inner diameter at the switching portion is 8.0 mm.

22 is a graph showing measurement results in Example 1. FIG. The vertical axis indicates the position of the oscillation measuring pin 250B, and the horizontal axis indicates the number of amplitudes. One amplitude was about 5.2 seconds. The graph of FIG. 22 plots the average value of the distance from a predetermined reference position measured four times at both ends of each amplitude of the oscillation measuring pin 250B.

23 is a graph showing the amplitude of the oscillation measuring pin in Example 1. FIG. The vertical axis indicates the amplitude of the oscillation measuring pin 250B, and the horizontal axis indicates the number of amplitudes. The amplitude of the oscillation measuring pin 250B is the positional difference between the two ends of the oscillation measuring pin 250B shown in FIG. Note that the graph of FIG. 23 is obtained by sequentially plotting average values of three amplitudes in order to level the graph.

In Example 1, as shown in FIG. 23, the amplitude of the oscillation measuring pin 250B (difference between the positions at both ends of the oscillation measuring pin 250B) becomes very small during the process of blood coagulation, and the holding oscillation The measurement pin 250B is in a state where it hardly moves. Therefore, it is difficult to analyze higher viscoelasticity. In Example 1, by raising the stirrer 301, analysis in a higher viscoelastic region becomes possible.

<Comparative Example 1>
In Comparative Example 1, the same device as in Example 1 was used, and 20 μL of EXTEM reagent (extrinsic blood coagulation activation reagent: Temin innovations Gmbh) and 20 μL of FIBTEM reagent (reagent containing antiplatelet drug: Temin innovations Gmbh). , 300 μL of human blood (collected with 3.2% sodium citrate) was placed in the measurement. Since the FIBTEM reagent contains cytochalasin D and platelet function is completely inhibited, a low viscoelastic region is measured to reflect changes in viscoelasticity due to fibrin formation (fibrin clot formation). Amplitude angles were measured as ±10 degrees. In Comparative Example 1, measurement was performed using the same stirrer 301 (FIG. 28) and container 40C (FIG. 29) as in Example 1.

24 is a graph showing measurement results in Comparative Example 1. FIG. The vertical axis indicates the position of the oscillation measuring pin 250B, and the horizontal axis indicates the number of amplitudes. One amplitude was about 5.2 seconds. The graph of FIG. 24 plots the average value of the distance from a predetermined reference position measured four times at both ends of each amplitude of the oscillation measuring pin 250B.

25 is a graph showing the amplitude of the oscillation measuring pin in Comparative Example 1. FIG. The vertical axis indicates the amplitude of the oscillation measuring pin 250B, and the horizontal axis indicates the number of amplitudes. The amplitude of the oscillation measuring pin 250B is the positional difference between both ends of the oscillation measuring pin 250B shown in FIG. Note that the graph of FIG. 25 is obtained by sequentially plotting average values of three amplitudes in order to level the graph.

In Comparative Example 1, in which the blood sample is analyzed in the low viscoelastic region, the amplitude of the oscillating measurement pin 250B (difference in position between both ends of the oscillating measurement pin 250B) is maintained. In Comparative Example 1, analysis in a higher viscoelastic region is also possible without raising the stirrer 30 .

<Example 2>
In Example 2, the same device as in Example 1 was used, and 20 μL of EXTEM reagent (extrinsic blood coagulation activation reagent: Temin innovations Gmbh) and 20 μL of Startem reagent (calcium chloride reagent: Temin innovations Gmbh) and human blood were used. (Blood collection with 3.2% sodium citrate) 300 μL was added and measured. Amplitude angles were measured as ±10 degrees. Before starting the measurement, the stirring part 30 was raised upward by 5 mm, and the measurement was performed in a state in which the stirring part 30 was immersed in the blood to a depth about half of the immersion depth in the first embodiment. In Example 2, measurement was performed using the same stirrer 301 (FIG. 28) and container 40C (FIG. 29) as in Example 1.

26 is a graph showing measurement results in Example 2. FIG. The vertical axis indicates the position of the oscillation measuring pin 250B, and the horizontal axis indicates the number of amplitudes. One amplitude was about 5.2 seconds. The graph of FIG. 26 plots the average value of the distance from a predetermined reference position measured four times at both ends of each amplitude of the oscillation measuring pin 250B.

27 is a graph showing the amplitude of the oscillation measuring pin in Example 2. FIG. The vertical axis indicates the amplitude of the oscillation measuring pin 250B, and the horizontal axis indicates the number of amplitudes. The amplitude of the oscillation measuring pin 250B is the positional difference between the two ends of the oscillation measuring pin 250B shown in FIG. Note that the graph of FIG. 27 is obtained by sequentially plotting average values of three amplitudes in order to level the graph.

In the second embodiment, the amplitude of the oscillation measuring pin 250B (difference between the positions of the oscillation measuring pin 250B at both ends) is maintained by making the depth of the agitator 30 immersed in blood shallow. Therefore, analysis in a higher viscoelasticity region is possible.

<Example 3>
In Example 3, the same device as in Example 1 was used, and the container 40 contained 20 μL of INTEM reagent (intrinsic blood coagulation activation reagent: Temin innovations Gmbh) and 20 μL of Startem reagent (calcium chloride reagent: Temin innovations Gmbh). and 300 μL of rabbit blood (blood was collected with 3.2% sodium citrate), and the measurement was performed. Amplitude angles were measured as ±10 degrees. Before starting the measurement, the measurement was performed with the stirring unit 30 raised 2 mm above the normal measurement position. In Example 3, measurement was performed using the same stirrer 301 (FIG. 28) and container 40C (FIG. 29) as in Example 1.

FIG. 30 is a diagram illustrating the position of the stirring unit 301 in Example 3. FIG. FIG. 30A shows the state where the stirring part 301 is in the normal measurement position. The end face of the stirring part 301 on the side of the flange 301B is located 1 mm higher than the opening face of the container 40C. FIG. 30B shows a state in which the stirrer 301 is elevated by 2 mm from the normal measurement position shown in FIG. 30A in Example 3. FIG. The end face of the stirring part 301 on the side of the flange 301B is located 3 mm higher than the opening face of the container 40C. In FIG. 30B, the volume of blood sample in the bottom portion of container 40C is greater than in FIG. 30A. Further, the liquid level of the blood sample is 11.8 mm in the case of the normal measurement value, whereas it is 11.2 mm in the case of Example 3 in which the stirring section 301 is raised. In Example 3, by raising the stirring unit 301, the depth to which the stirring unit 301 is immersed in the blood sample is reduced, and the liquid level of the blood sample is lowered. In addition, by raising stirring part 301, the area of contact between stirring part 301 and the blood sample in container 40C becomes smaller. Furthermore, since the distance between the stirring part 301 and the bottom surface of the container 40C is increased, the load on the stirring part 301 due to the increase in the viscoelasticity of the blood sample on the bottom side is reduced.

FIG. 31 is a graph showing measurement results when the stirrer is in the normal measurement position in Example 3. FIG. Moreover, FIG. 32 is a graph showing the measurement results when the stirring unit is raised in Example 3. As shown in FIG. That is, FIG. 32 shows the measurement results when the stirring part 301 is raised by 2 mm from the normal measurement position. 31 and 32, the vertical axis indicates the position of the oscillation measuring pin 250B, and the horizontal axis indicates the number of amplitudes. One amplitude was about 6 seconds. The graphs of FIGS. 31 and 32 plot average values of distances from a predetermined reference position measured four times at both ends of each amplitude of the oscillation measuring pin 250B.

In Example 3, the depth at which the stirring unit 301 is immersed in blood is set shallower than in the case of the normal measurement position, so that the amplitude of the oscillation measuring pin 250B (difference between the positions at both ends of the oscillation measuring pin 250B) is maintained. Therefore, analysis in a high viscoelastic region is possible as compared with the case where the measurement is performed with the stirring part 301 at the normal measurement position.

<Example 4>
In Example 4, in order to evaluate the sensitivity of the blood coagulation fibrinolysis system, measurements were performed using a deeper container 40D than in Examples 1 to 3. In addition, the measurement was performed using the agitator 302 and the agitator 303 having different lengths and diameters of the tip (thickened portion on the tip side to be immersed in the container 40D). In this way, a comparative evaluation was made by changing the conditions of the area where each stirring part contacts the blood sample in the container 40D and the distance between each stirring part and the inner wall of the container 40D.

In Example 4, the same device as in Example 1 was used, and 20 μL of INTEM reagent (intrinsic blood coagulation activation reagent: Temin innovations Gmbh) and 20 μL of Startem reagent (calcium chloride reagent: Temin innovations Gmbh) were placed in container 40D. and 300 μL of human blood (blood-collected with 3.2% sodium citrate) were put in and measured. Amplitude angles were measured as ±10 degrees.

The stirring unit 302, the stirring unit 303 and the container 40D used in Example 4 will be described with reference to FIGS. 33 to 35. FIG. In Example 4, two types of stirring units 302 and 303 having a longer overall length than the stirring unit 301 of Example 3, and a container 40D having a depth greater than that of the container 40C of Example 3 were used.

FIG. 33 is a cross-sectional view of the stirring unit 302 used in Example 4. FIG. The total length (height) of the stirring section 302 in the axial direction indicated by the dashed line is 20.6 mm. The thickness of the flange 302B is 1.3 mm. The length of the tip for agitating the blood specimen (the thickened part on the tip side to be dipped into the container) is 7.1 mm. The diameter of the distal end on the flange 302B side is 6.2 mm. A holding pin insertion hole 302A is provided at the upper end.

34 is a cross-sectional view of the stirring unit 303 used in Example 4. FIG. The agitator 303 has the same size as the agitator 302 shown in FIG. 33 except for the length and diameter of the tip. The length of the tip of the stirring part 303 is 16.5 mm. Also, the diameter of the tip on the flange 303B side is 6.6 mm. A holding pin insertion hole 303A is provided at the upper end. Since the stirring part 303 has a longer thick tip part than the stirring part 302 shown in FIG. 33, the area of the part closer to the inner wall of the container 40D becomes larger.

35 is a cross-sectional view of a container 40D used in Example 4. FIG. The container 40D has a height of 22.5 mm, which is higher than the container 40C used in the third embodiment. The diameters of the opening surface and the bottom surface of container 40D are 13.5 mm and 10.2 mm, respectively. The inner diameter inside the container 40D is
The opening surface is 9.0 mm and the bottom surface is 7.6 mm. Similar to the container 40C used in Example 3, the container 40D is provided with a switching portion having a narrower inner diameter, and the inner diameter at the switching portion is 8.0 mm.

36 is a graph showing measurement results in Example 4. FIG. In FIG. 36, the vertical axis indicates the position of the oscillation measuring pin 250B, and the horizontal axis indicates the number of amplitudes. One amplitude was about 7.8 seconds. FIG. 36 shows the result of measurement using the stirring unit 302 of FIG. 33 (graph G411) and the result of measurement using the stirring unit 303 of FIG. 34 (graph G421). Each graph plots the average value of the distance from a predetermined reference position measured four times at both ends of each amplitude of the oscillation measurement pin 250B.

The graph (graph G421) when using the stirring unit 303 with a thick and long tip has a faster waveform closing speed than the graph (graph G411) when using the stirring unit 302 with a short tip. there is

37 is a graph showing the amplitude of the oscillation measuring pin in Example 4. FIG. A graph G412 shows the amplitude when measured using the stirrer 302 of FIG. again. A graph G422 shows the amplitude when measured using the stirrer 303 of FIG. The amplitude graph G422 when using the stirring part 303 with a thick and long tip decreases faster than the amplitude graph 412 when using the stirring part 302, and the final amplitude is also smaller. In FIG. 37, the vertical axis indicates the amplitude of the oscillation measuring pin 250B, and the horizontal axis indicates the number of amplitudes. The amplitude of the oscillation measuring pin 250B is the positional difference between both ends of the oscillation measuring pin 250B shown in FIG.

That is, compared with the case of using the stirring part 302, when using the stirring part 303 with a longer and thicker tip, there was a tendency to detect the increase in viscoelasticity due to blood coagulation with high sensitivity. In this way, in the same device and reagent, by using the stirring part 303 with the thick tip, the distance between the pin of the stirring part 303 and the inner wall of the container 40D becomes short, and the stirring part 303 with the long tip can be used. , the area of the portion where the distance between the pin stirrer 303 and the inner wall of the container 40D is short increases. As a result, the load on the stirring unit 303 due to the increased viscoelasticity of the blood sample is increased, and the coagulation sensitivity can be improved.

<Example 5>
In Example 5, the same apparatus as in Example 1 was used, and 20 μL of EXTEM reagent (extrinsic blood coagulation activation reagent: Temin innovations GmbH) and FIBTEM reagent (including cytochalasin D) were added to the container 40D. A reagent that inhibits fibrin formation and evaluates fibrin formation: 20 μL of human blood (collected with 3.2% sodium citrate) and 300 μL of human blood were added for measurement. Amplitude angles were measured as ±10 degrees.

In Example 5, measurement was performed using the same stirrer 302 (Fig. 33), stirrer 303 (Fig. 34) and container 40D (Fig. 35) as in Example 4. Stirrers 302 and 303 with different tip shapes (thickness and length) were used to evaluate coagulation sensitivity in the low viscoelastic region.

38 is a graph showing measurement results in Example 5. FIG. In FIG. 38, the vertical axis indicates the position of the oscillation measuring pin 250B, and the horizontal axis indicates the number of amplitudes. One amplitude was about 7.8 seconds. FIG. 38 shows the result of measurement using the stirring unit 302 of FIG. 33 (graph G511) and the result of measurement using the stirring unit 303 of FIG. 34 (graph G521). Each graph plots the average value of the distance from a predetermined reference position measured four times at both ends of each amplitude of the oscillation measurement pin 250B.

39 is a graph showing the amplitude of the oscillation measuring pin in Example 5. FIG. A graph G512 shows the amplitude measured using the stirrer 302 of FIG. again. A graph G522 shows the amplitude when measured using the stirring unit 303 of FIG. The amplitude graph G522 when using the stirring part 303 with a thick and long tip decreases faster than the amplitude graph 512 when using the stirring part 302, and the final amplitude is also smaller. In FIG. 39, the vertical axis indicates the amplitude of the oscillation measuring pin 250B, and the horizontal axis indicates the number of amplitudes. The amplitude of the oscillation measuring pin 250B is the positional difference between the two ends of the oscillation measuring pin 250B shown in FIG.

The graph (graph G521) in the case of using the stirring unit 303 with a thick and long tip has a faster waveform closing speed than the graph (graph G511) in the case of using the stirring unit 302 with a short tip. The swing width of the typical swing measurement pin 250B is narrow. That is, compared to the case of using the stirring part 302, when using the stirring part 303 with a thicker and longer tip, the increased load due to the increase in viscoelasticity due to the formation of fibrin is strongly transmitted to the stirring part 303, thereby reducing the A measurement result that reflects the change in viscoelasticity was obtained. In this way, in the same device and reagent, the use of the stirring part 303 with the thick tip shortens the distance between the stirring part 303 and the inner wall of the container 40D, making it possible to use the stirring part 303 with the long tip. , the area of the part where the distance between the stirring part 303 and the inner wall of the container 40D is short increases. As a result, the load due to the increased viscoelasticity of the blood sample is transmitted to the stirring section 303 more strongly, and the coagulation sensitivity can be improved even in the low viscoelasticity region.

<Example 6>
In Example 6, the same apparatus as in Example 1 was used, and the container 40 contained 20 μL of EXTEM reagent (exogenous blood coagulation activation reagent: Temin innovations Gmbh) and 20 μL of Startem reagent (calcium chloride reagent: Temin innovations Gmbh). and 300 μL of human blood (blood-collected with 3.2% sodium citrate) were put in and measured. Amplitude angles were measured as ±10 degrees. Before starting the measurement, the measurement was performed with the stirring unit 30 raised 1.2 mm above the normal measurement position.

In Example 6, the same container 40C (FIG. 29) as in Example 3 was used for measurement. Further, measurement was performed using a stirring unit 301 (FIG. 28) similar to that of Example 3 and a stirring unit 304 shown in FIG. 40 is a cross-sectional view of a stirring unit used in Example 6. FIG. The stirring part 304 has the same size as the stirring part 301 shown in FIG. 28 except for the size of the diameter of the tip. The diameter on the flange 304B side of the tip of the stirring part 304 is 5.2 mm. A holding pin insertion hole 304A is provided at the upper end. The tip portion of the stirring portion 304 is narrower than that of the stirring portion 301, and the distance from the inner wall of the container 40C is increased. Therefore, the load on stirring section 304 due to an increase in the viscoelasticity of the blood sample between stirring section 304 and the inner wall of container 40C is reduced.

FIG. 41 is a graph showing the measurement results when the agitator 301 with a diameter of 6.2 mm at the tip is used and the agitator 301 is in the normal measurement position. Moreover, FIG. 42 shows the measurement results when the stirrer 301 is used and the measurement is performed with the measurement position elevated by 1.2 mm from the normal measurement position. FIG. 43 is a graph showing the measurement results when the agitating part 304 having a tip diameter of 5.2 mm is used and the agitating part 304 is in the normal measurement position. In each graph, the vertical axis indicates the position of the oscillation measuring pin 250B, and the horizontal axis indicates the number of amplitudes. One amplitude was about 6 seconds. Each graph plots the average value of the distance from a predetermined reference position measured four times at both ends of each amplitude of the oscillation measurement pin 250B.

Even when the same blood sample and reagent are used, the difference in the amplitude between both ends of the oscillation measuring pin 250B is maintained by making the depth of the agitator 30 immersed in the blood sample shallow. Also, by using the agitating part 304 with a small diameter at the tip, the difference between both ends is maintained. In other words, measurement in the high viscoelastic region was possible both when the depth of the agitator 301 immersed in the blood sample was shallow and when the diameter of the tip of the agitator 304 was made small.

Even when a spring suitable for measuring a blood sample with low viscoelasticity is used, in measuring a blood sample with high viscoelasticity, the position of the stirring unit 30 is increased and the length of the tip of the stirring unit 30 is increased. , narrowing the diameter of the stirring part 30, and a combination of these, it is possible to measure a blood sample with higher viscoelasticity. Therefore, it becomes possible to deal with measurements in a wide viscoelastic range.

From the results of the above-described examples, in the case of the reagent (FIBTEM) used for measurement in the low viscoelasticity region, the position of the stirring unit 30 is lowered, and the reagents (EXTEM, INTEM) used for measurement in the high viscoelasticity region In this case, it was found that the position of the stirring unit 30 should be raised for measurement. In addition, in the case of reagents used for measurement in the low viscoelasticity region, the stirring part 30 with a thick and long tip is used, and in the case of reagents used for measurement in the high viscoelasticity region, the tip is thin. It has been found that a short stirring section 30 can be used. By using the stirrers 30 having different shapes in this way, it is possible to accurately perform analysis from a high viscoelasticity region to a low viscoelasticity region using the same device.

10 Blood coagulation test apparatus: 1 Control section: 1A Servo motor: 1B Elastic support section: 1C Elastic support shaft: 2 Elastic body: 3 Stirrer: 3A · Rotation transmission part: 3B · Bearing: 3C · Stirring pin: 3D · Pinhole: 4 · Container: 5 · Sensor: 6 · Control device: 11 · CPU: 12 · RAM: 13 · ROM: 14 Auxiliary storage device: 15 NIC: 16 Imaging unit: 17 Display unit: 18 Input unit 30 Stirring unit: 30A Holding pin insertion hole: 30B Flange : 40 Container: 100 Blood coagulation test device: 110 Housing: 111 Bottom plate: 112 Strut: 113 Panel: 114 Connection panel: 200 Upper unit: 210 Lifting mechanism: 211 Lifting motor: 212 Shaft: 213 Support shaft guide: 215 Upper unit bottom plate: 230 Stirring control mechanism: 231 Stirring motor: 232 Gear: 233 Sliding plate: 240 Stirring motion transmission mechanism: 241 Rocking plate: 242 Rotor: 243, 246A, 246B Washer: 244 Rotating shaft: 245A, 245B Bearing: 247 First pedestal: 248 Oscillation transmitting portion: 249 Elastic body: 250 Oscillation transmitted portion: 250A Elastic body connecting portion: 250B Oscillation measuring pin: 251 Second Pedestal: 252 Holding pin: 270 Rotation angle measuring mechanism: 271 Sensor plate: 272 Light source: 300 Lower unit: 310 Mounting table slide mechanism: 311 Mounting table: 311A Container setting part: 312 Ball screw: 313 Slide motor: 314 Linear guide: 320 Holding pin drawing mechanism: 321 Guide plate: 322 Pressing plate: 323 Solenoid: 331 .. Support shaft: 332 .. Upper unit support base

Claims (9)

a container for containing the blood to be tested;
a stirring unit for stirring the blood to be tested in the container;
an elastic body connected to the stirring unit and deformable according to the force received from the stirring unit by stirring the blood to be tested;
A control unit that reciprocates the elastic body about the axis of the stirring unit as a rotation axis, transmits a predetermined reciprocating rotational motion to the stirring unit by controlling the reciprocating rotation, and reciprocates the stirring unit in the circumferential direction. and,
a measurement unit that measures the rotation angle of the reciprocating rotation of the stirring unit;
The stirring unit is moved up and down according to the rotation angle measured by the measurement unit, and the depth at which the stirring unit is immersed in the blood to be tested or the distance between the stirring unit and the inner wall of the container is controlled. a lifting control unit ,
The elevation control unit raises the stirring unit when the change rate of the rotation angle measured by the measurement unit decreases.
Blood coagulation test equipment. a container for containing the blood to be tested;
a stirring unit for stirring the blood to be tested in the container;
an elastic body connected to the stirring unit and deformable according to the force received from the stirring unit by stirring the blood to be tested;
A control unit that reciprocates the elastic body about the axis of the stirring unit as a rotation axis, transmits a predetermined reciprocating rotational motion to the stirring unit by controlling the reciprocating rotation, and reciprocates the stirring unit in the circumferential direction. and,
a measurement unit that measures the rotation angle of the reciprocating rotation of the stirring unit;
The stirring unit is moved up and down according to the rotation angle measured by the measurement unit, and the depth at which the stirring unit is immersed in the blood to be tested or the distance between the stirring unit and the inner wall of the container is controlled. a lifting control unit,
In the measurement in the high viscoelastic region using the extrinsic blood coagulation activating reagent or the endogenous blood coagulation activating reagent, the stirring part has a thinner tip so that the distance from the inner wall of the container increases. having a shape,
Blood coagulation test equipment. a container for containing the blood to be tested;
a stirring unit for stirring the blood to be tested in the container;
an elastic body connected to the stirring unit and deformable according to the force received from the stirring unit by stirring the blood to be tested;
A control unit that reciprocates the elastic body about the axis of the stirring unit as a rotation axis, transmits a predetermined reciprocating rotational motion to the stirring unit by controlling the reciprocating rotation, and reciprocates the stirring unit in the circumferential direction. and,
a measurement unit that measures the rotation angle of the reciprocating rotation of the stirring unit;
The stirring unit is moved up and down according to the rotation angle measured by the measurement unit, and the depth at which the stirring unit is immersed in the blood to be tested or the distance between the stirring unit and the inner wall of the container is controlled. a lifting control unit,
In the measurement in the low viscoelasticity region using a reagent for the purpose of analyzing fibrin clot formation in the presence of a platelet function inhibitor, the stirring part has a tip so that the distance from the inner wall of the container is close. having a thicker and/or longer shape,
Blood coagulation test equipment. a container for containing the blood to be tested;
a stirring unit for stirring the blood to be tested in the container;
an elastic body connected to the stirring unit and deformable according to the force received from the stirring unit by stirring the blood to be tested;
A control unit that reciprocates the elastic body about the axis of the stirring unit as a rotation axis, transmits a predetermined reciprocating rotational motion to the stirring unit by controlling the reciprocating rotation, and reciprocates the stirring unit in the circumferential direction. and,
a measurement unit that measures the rotation angle of the reciprocating rotation of the stirring unit;
The stirring unit is moved up and down according to the rotation angle measured by the measurement unit, and the depth at which the stirring unit is immersed in the blood to be tested or the distance between the stirring unit and the inner wall of the container is controlled. a lifting control unit,
In the measurement in the high viscoelasticity region using the extrinsic blood coagulation activating reagent or the intrinsic blood coagulation activating reagent, the elevation control unit raises the stirring unit so that the stirring unit and the inner wall of the container are separated from each other. increase the distance of
Blood coagulation test equipment. a container for containing the blood to be tested;
a stirring unit for stirring the blood to be tested in the container;
an elastic body connected to the stirring unit and deformable according to the force received from the stirring unit by stirring the blood to be tested;
A control unit that reciprocates the elastic body about the axis of the stirring unit as a rotation axis, transmits a predetermined reciprocating rotational motion to the stirring unit by controlling the reciprocating rotation, and reciprocates the stirring unit in the circumferential direction. and,
a measurement unit that measures the rotation angle of the reciprocating rotation of the stirring unit;
The stirring unit is moved up and down according to the rotation angle measured by the measurement unit, and the depth at which the stirring unit is immersed in the blood to be tested or the distance between the stirring unit and the inner wall of the container is controlled. a lifting control unit,
In a measurement in a low viscoelastic region using a reagent for the purpose of analyzing fibrin clot formation in the presence of a platelet function inhibitor, the elevation control unit lowers the stirring unit to separate the stirring unit and the container. Close the distance to the inner wall,
Blood coagulation test equipment. The blood coagulation test apparatus according to any one of claims 1 to 5 , wherein the controller controls the reciprocating rotation of the elastic body at a position spaced apart from the rotation shaft by a predetermined diameter. The control unit changes the predetermined reciprocating rotational motion according to the rotation angle measured by the measurement unit.
The blood coagulation test apparatus according to any one of claims 1 to 6 . The elevation control unit adjusts the position of the stirring unit and the immersion of the stirring unit in the blood to be inspected according to changes in viscoelasticity of the blood to be inspected or changes in viscoelasticity associated with blood coagulation. Determining the depth or distance between the stirrer and the inner wall of the vessel,
The blood coagulation test apparatus according to any one of claims 1 to 7 . a stirring step of stirring the blood to be tested placed in the container by the stirring part;
reciprocally rotating an elastic body which is connected to the stirring section and is deformable according to the force received from the stirring section by stirring the blood to be examined, about the axis of the stirring section as a rotation axis, and controlling the reciprocating rotation; a control step of transmitting a predetermined reciprocating rotational motion to the stirring unit to reciprocate the stirring unit in a circumferential direction;
a measuring step of measuring a rotation angle related to the reciprocating rotation of the stirring unit;
The stirring part is moved up and down according to the rotation angle measured in the measuring step, and the depth of the stirring part immersed in the blood to be tested or the distance between the stirring part and the inner wall of the container is controlled. a lifting control step ;
In the elevation control step, when the change rate of the rotation angle measured in the measurement step decreases, the stirring unit is raised.
Blood coagulation test method.

Images