JP7353870B2 - Blood coagulation test device and blood coagulation test method - Google Patents

Description

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

The process by which blood coagulates in order to evaluate the pathological condition of hemophilia, which is a decrease or deficiency of blood coagulation factors that act to solidify blood during bleeding, and to evaluate the efficacy of drugs such as hemostatic drugs. In this step, the state of blood coagulation is examined. As a method for testing the state of blood coagulation, for example, blood to be tested (hereinafter also referred to as blood sample) to which a reagent has been added is irradiated with light and the amount of scattered light is measured to detect clots and determine the clotting time. An optical inspection method for calculation is known (for example, see Patent Document 1). 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, we can measure the state of blood coagulation, such as viscosity. A method for dynamically inspecting is known (for example, see Non-Patent Document 1).

Japanese Patent Application Publication No. 2010-217059

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

When testing the state of blood coagulation using an optical testing method, the amount of scattered light that is measured may be affected by interfering substances in the blood sample. Furthermore, changes in the amount of scattered light may not be detected accurately depending on differences in test items, ie, differences in reagents added. Since it is an optical method, changes in blood viscoelasticity are not accurately measured, and data are only obtained at the completion of blood coagulation.

In addition, in devices that dynamically test 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 are used. are not changed depending on differences in blood samples, drugs, test items, etc. For example, in TEG, the cup is rotated back and forth within a range of ±4.75 degrees (4 degrees 45 minutes), but if the blood is turned into a gel and then rotated much beyond ±4.75 degrees, the gel will It may be destroyed and the viscoelasticity may not be measured correctly. For example, in ROTEM, a pin is rotated reciprocally at a constant angle by a spring. The rotation angle transmitted to the pin by the spring is fixed at ±4.75 degrees, and as the viscoelasticity increases due to blood coagulation, the pin gradually stops rotating. For this reason, even when measuring in a high viscoelastic region where blood coagulation has progressed, or conversely in a low viscoelastic region, the desired resolution cannot be obtained because the rotation angle and rotation speed of the cup or pin are constant. , it was sometimes difficult to evaluate the efficacy of drugs. In addition, animal blood has a higher amount of platelets and higher viscoelasticity than human blood, and it is difficult to analyze the coagulation state with the desired resolution from low viscoelastic to high viscoelastic areas. There was a case. Furthermore, since these devices are expensive, there has been a demand for devices that are smaller and lighter at lower cost.

Conventional ROTEM or TEG uses the same spring and the same rotation angle to detect high viscoelastic blood coagulation (intrinsic blood coagulation and extrinsic blood coagulation) and low viscoelastic blood coagulation (in the presence of antiplatelet drugs). (e.g. analysis of fibrin gel formation). Therefore, when measuring blood coagulation with low viscoelasticity, if a (weak) spring is used that is sufficiently sensitive to the increase in load on the pin due to increased viscoelasticity, when measuring in a high viscoelastic region, blood coagulation will The accompanying increase in viscoelasticity increases the load on the pin, causing the pin to lose its rotation, making it impossible to obtain the desired resolution. On the other hand, when using a (strong) spring suitable for measuring blood coagulation with high viscoelasticity, the load on the pin due to the increase in viscoelasticity of blood coagulation with low viscoelasticity is small, so the change in the rotation angle of the pin is (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 deteriorate.

SUMMARY OF THE INVENTION An object of the present invention is to provide a technique for obtaining a resolution appropriate to 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 part that stirs blood using the axis of the stirring part as a rotation axis, and controls the reciprocating rotation, so that the stirring part is given a predetermined reciprocating effect. I decided to transmit rotational motion. Then, we decided to change the rotation angle at which the elastic body is rotated back and forth during measurement.

Specifically, the blood coagulation test device according to the present invention includes a container containing blood to be tested, a stirring section that stirs the blood to be tested in the container, and a blood coagulation test device connected to the stirring section to allow blood to be tested from the stirring section. An elastic body that can be deformed according to the force received by the stirring of The control unit includes a control unit that transmits reciprocating rotational motion to reciprocate the stirring unit in the circumferential direction, and a measurement unit that measures the rotation angle due to the reciprocating rotation of the stirring unit, and the control unit controls the rotation angle of the stirring unit measured by the measurement unit. When the rotation angle becomes equal to or less than the first measurement angle, the rotation angle for reciprocating the elastic body is increased to a second angle larger than the first angle.

With the blood coagulation test device described above, it is possible to control the reciprocating rotation of the stirring section to a predetermined angle. The control unit is, for example, a servo motor that is being mass-produced in a small size for controlling the tail of a radio-controlled airplane, controlling the direction of a drone camera, and the like. A servo motor is a motor equipped with a servo mechanism that automatically controls the position, direction, speed, etc. of an object so as to follow a target value. Therefore, the servo motor can accurately control rotation at a low speed and rotation at a desired angle. Therefore, in a blood coagulation test, the blood coagulation test apparatus can obtain resolution according to the test object by appropriately controlling the rotational speed and rotation angle transmitted to the stirring section. In addition, by raising and lowering the stirring part 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, the viscoelasticity of blood in the high viscoelastic region can be accurately measured. It becomes possible to measure. Furthermore, by making the servo motor smaller, lighter, and cheaper, it is possible to reduce the cost of blood coagulation tests. 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 a test according to each blood sample. Note that the reciprocating rotational motion is a rotational motion within a predetermined rotational angle range around the rotational axis.

The rotation angle of the stirring section can be analyzed by capturing an image using a camera or the like included in the measuring 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. Further, the rotation angle of the stirring section 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 the information as an electrical signal.

Note that the control unit may control the reciprocating rotation of the elastic body at a position separated by a predetermined diameter from the rotation axis. 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 device, for example, if blood coagulation progresses and the stirring section stops rotating, the rotation angle of the predetermined reciprocating rotational motion transmitted from the servo motor to the stirring section can be increased. , it becomes possible to accurately analyze the viscoelastic state at higher viscosity. In addition, by changing the predetermined reciprocating rotational motion 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, it is possible to change the range from a low viscoelastic region to a high viscoelastic region. It becomes possible to measure blood viscoelasticity with high precision over a wide range of up to

Further, when the rotation angle of the stirring section measured by the measurement section becomes equal to or less than the first measurement angle, the control section changes the rotation angle for reciprocating the elastic body to a second angle larger than the first angle. spread. In this way, by widening the rotation angle at which the elastic body is rotated back and forth during measurement, it is possible to suppress a decrease in resolution in measuring viscoelasticity in a high viscoelastic region.

Note that the present invention can also be understood from the aspect of a method. For example, the present invention includes a stirring process in which blood to be tested placed in a container is stirred by a stirring part, and an elastic material connected to the stirring part and deformable according to the force received from the stirring part by stirring the blood to be tested. By reciprocating the body at a first angle using the axis of the stirring part as the rotation axis and controlling the reciprocating rotation of the elastic body, a predetermined reciprocating rotational motion is transmitted to the stirring part, and the stirring part is reciprocated in the circumferential direction. and a measurement step of measuring the rotation angle due to reciprocating rotation of the stirring section. In the control step, when the rotation angle of the stirring section measured in the measurement step becomes equal to or less than the first measurement angle, the elastic The rotation angle at which the body is rotated back and forth may be expanded to a second angle that is larger than the first angle.

According to the present invention, in a blood coagulation test, it is possible to obtain resolution according to the test object.

FIG. 1 is a schematic diagram illustrating the configuration of a blood coagulation testing apparatus. FIG. 2 is a diagram illustrating the hardware configuration of the control device in the embodiment. FIG. 3 is a diagram illustrating the functional configuration of the 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 testing apparatus. FIG. 6A is a perspective view showing the appearance of the blood coagulation test device. FIG. 6B is a perspective view showing the inside of the blood coagulation test device. 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 the 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 left rear side. FIG. 10 is a perspective view of the upper unit separated from the lower unit. FIG. 11 is a plan view of the assembled upper unit and lower unit. FIG. 12A is a left side view showing the upper unit separated from the lower unit. FIG. 12B is a front view showing the upper unit separated from the lower unit. FIG. 13 is a flowchart illustrating the operation flow of the blood coagulation testing apparatus according to the second embodiment. FIG. 14A is a diagram showing a state in which the mounting table is housed in the blood coagulation test apparatus. FIG. 14B is a diagram showing a state in which the mounting table is slid toward the front side and a 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 raised to a position where the blood sample in the container can be stirred by the stirring section. FIG. 16 is a diagram illustrating an operation in which the rotational motion of the gear is converted into the rocking motion of the rocking plate by the stirring control mechanism. FIG. 17A is a diagram showing the rotational state of the rocking plate when the sliding plate moves toward 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 rotational state of the rocking plate when the sliding plate moves toward the rear side. FIG. 18A is a diagram showing the position of the stirring section 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 has increased and the stirring section has been raised. FIG. 19A is a perspective view of a first modification of the container. FIG. 19B is a perspective view of a second modification of the container. FIG. 20A is a diagram showing a state in which the pressing plate does not press the stirring section. FIG. 20B is a diagram showing a state in which the holding plate presses the stirring part when the holding pin is pulled out from the stirring part. FIG. 21 is a diagram illustrating a torsion coil spring used in an example of the second embodiment. FIG. 22 is a perspective view illustrating two containers. FIG. 23 is a cross-sectional view taken along line AA of a state in which stirring pins are housed in two containers. FIG. 24 is a graph showing the measurement results of blood samples using the same spring. FIG. 25 is a diagram for explaining the measurement algorithm. FIG. 26 is a graph showing the measurement results in Example 2. FIG. 27 is a graph showing the measurement results in Example 3.

Embodiments of the present invention will be described below based on the drawings. The configurations of the following embodiments are illustrative, 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 testing apparatus. The blood coagulation test device 10 includes a control section 1, an elastic body 2, a stirring section 3, a container 4, and a sensor 5. The blood coagulation test apparatus 10 stirs a blood sample placed in a container 4 in a stirring section 3 via an elastic body 2 under the control of a control section 1 . Then, the blood coagulation testing apparatus 10 measures the state of blood coagulation and the like by calculating the rotation angle of the stirring section 3 from the image captured by the sensor 5. The blood coagulation test apparatus 10 includes a control device (not shown) that controls the processing of the control unit 1 and the sensor 5.

The control section 1 receives commands from the control device and drives the reciprocating rotation operation of the stirring section 3 via the elastic body 2 . In FIG. 1, the control section 1 includes a servo motor 1A, an elastic body support section 1B, and an elastic body support shaft 1C. The servo motor 1A causes the elastic body support part 1B to perform a predetermined reciprocating rotational movement using the axis of the stirring part 3 as a rotation axis. The predetermined reciprocating rotational movement is, for example, a reciprocating rotational movement within a certain angle range. The predetermined reciprocating rotational movement may be a movement 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 section 3 to be constant by changing the rotation angle depending on the coagulation state of the blood sample.

The elastic support portion 1B performs a predetermined reciprocating rotational movement by driving the servo motor 1A. Further, the elastic body support section 1B supports the elastic body 2 and transmits a predetermined reciprocating rotational motion to the elastic body 2. The elastic body support shaft 1C supports the elastic body 2 as a rotation axis 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 shown 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, for example, Two wire springs may be supported as the elastic bodies 2 at both ends of the elastic body support section 1B.

The elastic body 2 transmits a predetermined reciprocating rotational motion transmitted from the elastic body support section 1B to the stirring section 3. Further, 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 of the elastic body 2 supported by the elastic body support shaft 1C. The coil spring can be deformed by receiving force from the stirring section 3.

Note that the elastic body 2 is not limited to the example shown in FIG. The elastic body 2 only needs to be capable of transmitting a predetermined reciprocating rotational motion to the stirring section 3 and deforming according to the force received from the stirring section 3. For example, a wire spring may be used instead of a coil spring. Further, the elastic body 2 may be composed of a plurality of elastic bodies.

The stirring section 3 stirs the blood sample in the container 4 by a predetermined reciprocating rotational motion transmitted from the control section 1 via the elastic body 2 . As blood coagulation progresses, the rotation angle of the stirring section 3 becomes smaller than the rotation angle associated with a predetermined reciprocating rotational movement. 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 section 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 section 3A is capable of reciprocating rotation in the circumferential direction using the axis of the stirring pin 3C as a rotation axis. The rotation transmission section 3A is connected to the elastic body 2 at a position separated by a predetermined diameter from the rotation axis, and rotation is controlled at this position. Since the rotation angle can be 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 rotational motion to the stirring pin 3C.

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

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 also 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 part is reduced, so the rotation transmission part 3A can transmit more precise reciprocating rotational motion to the stirring pin 3C.

The stirring pin 3C is immersed in the container 4, and stirs the blood sample in the container 4 by a predetermined reciprocating rotation 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 against the predetermined reciprocating rotational movement. Furthermore, since the rotation transmitting section 3A reciprocates in conjunction with the stirring pin 3C, the rotation angle of the rotation transmitting section 3A becomes small, similarly to the stirring pin 3C. When the movement of the rotation transmitting section 3A no longer follows the predetermined reciprocating rotational motion transmitted from the elastic body 2, the elastic body 2 is deformed by receiving a force in the opposite direction to the predetermined reciprocating rotational motion. Further, the stirring pin 3C can be moved up and down under the control of the control device when the blood in the container 4 has progressed to coagulation. The control device determines the depth of immersion into the container 4 or the distance between the stirring pin 3C and the inner wall of the container 4, depending on 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 section".

The pinhole 3D serves as a mark indicating the reference position of the rotation transmission section 3A. By detecting and analyzing the movement of the pinhole 3D with the sensor 5, it becomes possible to measure the rotation angle of the rotation transmission section 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 rotation axis of the rotation transmission section 3A. The sensor 5 (for example, a camera) detects the 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 determined 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.

Note that the pinhole 3D is not limited to a hole provided in the rotation transmission section 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 stirring pin 3C by analyzing the image of the concave portion or convex portion. That is, the pinhole 3D may have 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 rotates back and forth.

The 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 smartphone or a tablet terminal. In this case, the electronic device can image the movement of the pinhole 3D using a camera or the like included in the electronic device, analyze the captured image, and calculate the rotation angle of the stirring pin 3C. The electronic device may act as a control device to control the processing of the control unit 1 and the sensor 5.

<Configuration of control device>
(Hardware configuration)
FIG. 2 is a diagram illustrating the hardware configuration of the control device in the embodiment. The control device 6 uses 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 an HDD (Hard Disk Drive), a gateway, etc. to internet n The computer includes 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, etc. by processing instructions and data of various programs developed in the RAM 12, etc. The RAM 12 is a main storage device, is controlled by the CPU 11, and various instructions and data are written and read therein. 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 nonvolatile storage device, and information that requires persistence, such as various programs loaded into the RAM 12, is written and read therein.

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 based on the measured rotation angle of the stirring unit 3 and the like. 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 regarding the control method of the servo motor 1A. The input unit 18 is, for example, a pointing device such as a touch pad, a mouse, a touch panel, a keyboard, an operation button, etc., and receives operation input.

(Functional configuration)
FIG. 3 is a diagram illustrating the functional configuration of the control device in the embodiment. The control device 6 has a control information database D11, a correction information database D12, a data reception section F11, an analysis section F12 and It functions as a computer including a correction section F13.

In this embodiment, each function of the control device 6 is executed by the CPU 11, which is a general-purpose processor, but some or all of these functions are executed by one or more dedicated processors, hardware arithmetic circuits, etc. It may be executed by Here, the hardware arithmetic circuit refers to, for example, an adder circuit, a multiplier circuit, a flip-flop, etc., which are combinations of logic gates. Further, some 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 rotational motion transmitted from the control unit 1 to the stirring unit 3. For example, the control information database D11 has a table that stores information for specifying a predetermined reciprocating rotational movement by the servo motor 1A, such as information on angles related to the predetermined reciprocating rotational movement. The control information database D11 also includes conditions that trigger the raising and lowering of the stirring section 3 when the viscoelasticity of the blood to be tested increases, the depth at which the stirring section 3 is immersed in the blood, and the relationship between the stirring section 3 and the container 4. It has a table that stores information such as distance to the inner wall.

The correction information database D12 is a database that stores information regarding calibration for each elastic body 2. Calibration is performed by measuring the deviation from the measurement value of a standard elastic body (hereinafter also referred to as a reference elastic body) for each elastic body 2, and in order to adjust the measurement accuracy of each elastic body 2 to the standard 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 deviations of measured values from a reference elastic body measured for each elastic body 2.

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

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

The analysis section F12 analyzes the data received by the data reception section F11 and calculates the rotation angle of the stirring section 3. In addition, when controlling the rotation angle of the stirring section 3 to be constant, the analysis section 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 section 3. Generate information used in 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 depending on the elastic body 2 used. Therefore, information identifying the elastic body 2 used for the test may be input from the input unit 18. The correction unit F13 can use the input identification information to obtain correction information regarding the elastic body 2 to be used from the correction information database D12. The information corrected by the correction section F13 may be displayed on the display section 17.

<Calibration of elastic body>
Here, the calibration of the elastic body 2 will be explained. Even when the blood coagulation test device 10 tests the same blood sample, measurement accuracy may vary depending on the elastic body 2 used. Therefore, the blood coagulation test apparatus 10 determines a reference elastic body 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 device 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 a 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, a solution of agarose, gelatin, or the like.

FIG. 4 is a diagram showing changes in the coagulation state of an agarose solution. The gelling 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 bulge in the graph increases. Moreover, the horizontal axis of each graph indicates the time from the start of measurement. Figure 4 shows graphs when the agarose solution temperature at the start of measurement is 90°C and 70°C, and the agarose solution concentration is 0.5%, 1.0%, and 1.5%. It will be done.

When the concentration of the agarose solution is the same, the start of coagulation is slower when the temperature at the start of measurement is 90°C than when it is 70°C. That is, as the temperature at the start of measurement becomes higher, the start of solidification becomes slower. Further, when the temperature of the agarose solution at the start of measurement is the same, as the concentration becomes higher, the hardness at the time of final gelation increases. That is, as the concentration increases, the hardness upon final gelation increases.

The blood coagulation test device 10 can perform measurements for each elastic body 2 by collecting correction information for the reference elastic body and each elastic body 2 in advance under various conditions such as the temperature and concentration at the start of coagulation of the agarose solution. It becomes possible to correct variations in results with high precision.

<Processing flow>
The flow of processing of the blood coagulation testing apparatus 10 of this embodiment will be explained. In the process flow described here, the blood coagulation test apparatus 10 stirs the blood sample in the container 4 with the stirring section 3 by driving the servo motor 1A, and measures the rotation angle of the stirring section 3. At this time, the servo motor 1A transmits a predetermined reciprocating rotational motion to the stirring section 3 via the elastic body 2. Furthermore, the blood coagulation testing apparatus 10 corrects the measurement results based on correction information regarding the deviation from the reference elastic body measured in advance for the elastic body 2 to be used. Note that the contents and order of the processes described are merely examples, and it is preferable that the contents and order of the processes be appropriately adopted as appropriate for the embodiment.

FIG. 5 is a flowchart illustrating the flow of test processing in the blood coagulation testing apparatus. This process flow starts, for example, when a blood sample and a reagent are injected into the container 4.

First, in step S101, the control device 6 starts the servo motor 1A. The control device 6 controls the servo motor 1A based on information stored in the control information database D11. The servo motor 1A transmits a predetermined reciprocating rotational motion to the stirring section 3 via the elastic body 2 according to a command from the control device 6. For example, the control device 6 may allow the servo motor 1A to transmit reciprocating rotational motion within a certain angle range.

By starting the servo motor 1A, the stirring section 3 stirs the blood sample in the container 4. As blood coagulation progresses, the reciprocating rotation of the stirring section 3 no longer follows the transmitted predetermined reciprocating rotational motion, and the rotation angle becomes smaller. The sensor 5 detects the reciprocating rotational movement of the stirring section 3 and transmits data regarding the reciprocating rotational movement, for example, data of a captured image of the pinhole 3D to the control device 6.

In step S102, the data receiving unit F11 of the control device 6 receives data transmitted from the sensor 5. In step S103, the analysis unit F12 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 regarding 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 a measurement result. The control device 6 can output the measurement results to the display section 17. Further, the control device 6 may store the measurement results in the auxiliary storage device 14. Further, the control device 6 raises and lowers the stirring section 3 according to the output rotation angle, and controls the depth at which the stirring section 3 is immersed in blood, the distance between the stirring section 3 and the inner wall of the container 4, etc. It's okay.

<Effect>
With the blood coagulation test apparatus 10 of this embodiment, by appropriately controlling the rotational speed and rotational angle transmitted to the stirring section 3, it is possible to obtain resolution according to the test object. Furthermore, the cost for blood coagulation tests can be suppressed by making the servo motor 1A smaller, lighter, and cheaper. Furthermore, the blood coagulation test apparatus 10 can perform tests according to each blood sample by controlling the servo motor 1A according to the blood samples, rather than stirring multiple blood samples under the same control. be.

Furthermore, the blood coagulation test device 10 increases the rotation angle of the stirring unit 3 by controlling the servo motor 1A when blood coagulation progresses and the stirring unit 3 stops rotating back and forth. It becomes possible to analyze the elastic state. Furthermore, by raising and lowering the stirring part 3 and controlling the depth at which the stirring part 3 is immersed in blood or the distance between the stirring part 3 and the inner wall of the container 4, resolution can be further improved and viscosity at high viscosity can be controlled. It becomes possible to analyze the elastic state with high accuracy. In this way, the blood coagulation test device 10 acquires data with a desired resolution by changing the predetermined reciprocating rotational motion transmitted from the servo motor 1A to the stirring section 3 depending on the blood sample or the preparation to be tested. can do.

In addition, 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 on measurement results due to differences in the elastic bodies 2 used.

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

The casing 110 includes a substantially square bottom plate 111, pillars 112 erected at the four corners of the bottom plate 111, panels 113 provided on each of the front, rear, upper right, left, and upper surfaces, and a lower right side. The connection panel 114 has a box-like shape and has an insertion opening through which cables for connection to a power source or an external device are inserted. The housing 110 houses the upper unit 200 and the lower unit 300. Furthermore, the housing 110 includes a handle 115 on the top panel 113 to enable carrying. Further, the front panel 113 is provided with an opening 113A for installing and removing a container containing a blood sample. Note that the blood specimen to be tested also includes plasma obtained by centrifugation of blood or the like.

The housing 110 may accommodate the upper unit 200 and the lower unit 300, and may include an insertion port for connecting each unit to a power source or an external device, and an opening that allows a container containing a blood sample to be taken in and taken out. The shape of the casing 110, the position and shape of the cable insertion port, and the position and shape of the opening for taking in and taking out the container are not limited to the examples shown in FIGS. 6A and 6B. For example, the housing 110 may include a plurality of panels 113 and columns 112 as an integral member, and may accommodate the upper unit 200 and the lower unit 300. Furthermore, the housing 110 may be configured such that the upper panel 113 is not provided with the handle 115, and the left and right side panels 113 or the front and rear panels 113 are provided with recesses for gripping the blood coagulation test device 100 with both hands.

7A and 7B show the configuration of the upper unit 200. 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 viewed from below. The upper unit 200 includes a lifting mechanism 210, a stirring control mechanism 230, a stirring motion transmission mechanism 240, and a rotation angle measuring mechanism 270.

The elevating mechanism 210 includes an elevating motor 211, a shaft 212, and a support shaft guide 213. The lifting motor 211 has, for example, an internally threaded portion that is threadedly engaged with the fully threaded shaft 212 . The female threaded portion is rotatable about a shaft 212 by driving of an elevating motor 211 . The upper unit 200 can be raised and lowered to a desired height by rotating the female threaded 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 cylindrical portion below the upper unit bottom plate 215, and the support shaft is inserted into the support shaft insertion hole 213A. By inserting the support shaft into the support shaft guide 213, the upper unit 200 becomes vertically movable. 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 guide 213 is not limited to being provided at two locations on the right and left sides of the lifting motor 211. For example, the support shaft guide 213 may be provided at a diagonal corner of the upper unit bottom plate 215, or may be provided at two or more locations. It may be provided at any position.

The stirring control mechanism 230 includes a stirring motor 231, a gear 232, and a sliding plate 233. Stirring motor 231 drives gear 232 to rotate. The gear 232 converts rotational motion into linear motion and slides the sliding plate 233 back and forth. The sliding plate 233 slides in the front-back direction according to the rotation of the gear 232, and transmits an operation for stirring the blood sample to the 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. The stirring motion transmission mechanism 240 includes a rocking 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 rocking transmission part 248, an elastic body 249, It includes a swinging transmitted portion 250, a second pedestal 251, and a holding pin 252.

The rocking plate 241 performs a reciprocating rotational movement (hereinafter also referred to as a rocking movement) about a rotating shaft 244 inserted into the rotating shaft insertion hole 241A in response to the reciprocating movement of the sliding plate 233 in the front-rear direction. The rotor 242 is fixed to the rocking plate 241 and transmits the rocking motion of the rocking plate 241 by holding a rotating shaft 244 inserted through the rotating shaft insertion hole 241A. The washer 243 suppresses friction with the bearing 245A due to the rocking motion of the rotor 242. The rotating shaft 244 is rotatably supported by a bearing 245A and a bearing 245B that fits into the bearing 245A. The bearing 245A and the bearing 245B fit into each other with the first pedestal 246 in between. The first pedestal 246 places the stirring control mechanism 230 thereon. The rotating shaft 244 is connected to the swing transmission section 248 via a washer 247A and a washer 247B.

The swing transmission section 248 swings in conjunction with the swing movement of the swing plate 241. The swing transmission section 248 includes an elastic body connecting section 248A for connecting the elastic body 249. In the example shown in FIG. 8, the elastic body 249 uses a coil spring whose axis is in the vertical direction. 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 swinging transmitted portion 250. The swinging 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 swinging transmitted portion 250 further transmits the swinging motion transmitted via the elastic body 249 to the holding pin 252. The oscillating transmitted portion 250 includes a oscillating measurement pin 250B for measuring the rotation angle due to the oscillating movement of the oscillating transmitted portion 250. The rotation angle of the swing measurement pin 250B is measured by a rotation angle measurement mechanism 270 shown in FIG. 7A. The second pedestal 251 places the swinging transmitted portion 250 thereon. The second pedestal 251 includes a pedestal support part 251A and a pedestal support part 251B, and supports the first pedestal 246. The holding pin 252 is connected to the swing transmitted portion 250 via an insertion hole (not shown) provided in the second pedestal 251. The holding pin 252 swings in conjunction with the swing movement 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 part 30 and swings the stirring part 30, so that the container 4
Stir the blood sample in 0. The holding pin 252 is inserted into the holding pin insertion hole 30A provided in the upper part of the stirring section 30. The stirring section 30 rotates in conjunction with the holding pin 252 to stir the blood sample in the container 40. Due to the coagulation of the blood sample in the container 40, a force acts to suppress the swinging of the holding pin 252, and the rotation angle of the holding pin 252 increases or decreases depending on the viscosity of the blood sample in the container 40. Further, the stirring section 30 includes 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 holding down the flange 30B, the holding pin 252 can be pulled out from the stirring section 30.

The rotation angle measuring mechanism 270 in FIG. 7A includes a sensor plate 271 and a light source section 272. The rotation angle measuring 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 arranged linearly. The light source section 272 includes a light source (not shown) such as an LED (Light Emitting Diode) that illuminates the optical sensor of the sensor plate 271. In the second embodiment, the rotation angle measurement mechanism 270 detects the rotational movement of the swing measurement pin 250B swinging on the optical sensor in conjunction with the stirring operation of the blood sample in the container 40. 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. The blood coagulation test apparatus 100 uses the rotation angle measurement mechanism 270 to measure the rotation angle of the swing measurement pin 250B that swings at a position away from the rotation axis of the stirrer 30, thereby accurately determining the rotation angle of the stirrer 30. Can be measured well.

9A and 9B show the configuration of the lower unit 300. 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 viewed from the left rear side. The lower unit 300 includes a mounting table sliding mechanism 310 and a holding pin pulling mechanism 320. Further, the lower unit 300 includes a support shaft 331 and an upper unit support stand 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. Note that FIGS. 9A and 9B show a state in which the lower unit 300 is placed on the bottom plate 111 of the housing 110.

The mounting table slide mechanism 310 shown in FIG. 9B includes a mounting table 311, a ball screw 312, a sliding motor 313, and a linear guide 314. The mounting table 311 includes a container installation part 311A (FIG. 9A) that is a cylindrical recess that can accommodate the container 40. FIG. 9A shows a state in which the container 40 is installed in the container installation part 311A and the stirring part 30 is accommodated in the container 40. The ball screw 312 is screwed onto the mounting table 311, and the rotation of the ball screw 312 causes the mounting table 311 to slide in the front-rear direction. The slide motor 313 drives the rotational movement of the ball screw 312. The linear guide 314 guides the linear motion of the mounting table 311 in the front-rear direction. The mounting table slide mechanism 310 only needs to be able to convert the rotational motion of the motor into a linear motion and slide the mounting table 311 to a position where the container 40 can be installed, and may include a ball screw mechanism, a timing belt, etc. Various types of linear motion mechanisms may be used. The blood coagulation test apparatus 100 may include a heat-retaining device (not shown) for keeping the container 40 housed in the mounting table 311 warm, and the heat-retaining device keeps the blood sample at a constant temperature during the coagulation test. Can be kept at temperature.

The holding pin pulling mechanism 320 shown in FIG. 9A includes a guide plate 321, a holding plate 322, and a solenoid 323. The guide plate 321 is disposed above the container installation part 311A of the mounting table 311, and is provided with an opening 321A for inserting the holding pin 252 into the holding pin insertion hole 30A of the stirring part 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 section 30. When the holding plate 322 presses the flange 30B of the stirring section 30, 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 holding plate 322 remains rotated to the position where it presses the flange 30B 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. 10 is a perspective view of the upper unit 200 separated from the lower unit 300. The support shaft 331 is 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 into the support shaft guide 213 of the upper unit 200.

FIG. 11 is a plan view of the upper unit 200 and lower unit 300 assembled together. The support shaft guides 213 are arranged at two locations on both sides of the lifting motor 211 at substantially the center of the front and rear surfaces of the blood coagulation testing apparatus 100 . The upper unit 200 is supported by support shafts 331 at two locations near the center of the blood coagulation test apparatus 100 in a plan view, and the upper unit 200 can be stably raised and lowered by the lifting mechanism 210.

FIG. 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 the upper unit 200 separated from the lower unit 300. 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. When the container 40 and stirring section 30 are installed in 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 top surface of the stirring section 30 by lowering the upper unit 200. be done. In addition, in FIG. 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 flowchart illustrating the operation flow of the blood coagulation testing apparatus according to the second embodiment. Further, FIGS. 14A to 20B show the elevating mechanism 210, stirring control mechanism 230, stirring motion transmission mechanism 240, rotation angle measuring mechanism 270, mounting table sliding mechanism 310, and holding pin pulling mechanism that drive each operation shown in FIG. 13. The operation of 320 will be explained. The flow of operations shown in FIG. 13 starts when the blood coagulation testing apparatus 100 according to the second embodiment receives a command to start a test from the control device according to the second embodiment.

First, in step S201, the mounting table sliding mechanism 310 slides the mounting table 311 toward the front side to a position where the container 40 can be installed. The container 40 and the stirring part 30 accommodated in the container 40 are installed in the container installation part 311A of the mounting table 311 that is slid toward the front side. When the container 40 and stirring unit 30 are installed, the mounting table sliding mechanism 310 slides the mounting table 311 to the original position. Here, the operation of the mounting table 311 by the mounting table sliding mechanism 310 will be explained with reference to FIGS. 14A and 14B.

FIG. 14A is a diagram showing a state in which the mounting table 311 is accommodated in the blood coagulation test apparatus 100. 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 placed on the mounting table 311. The mounting table 311 can be slid in the direction of the arrow X1 shown in FIGS. 14A and 14B by the sliding motor 313 driving the rotational movement of the ball screw 312. Note that the mounting table 311 can be moved linearly by sliding on the linear guide 314. In step S201, the mounting table slide mechanism 310 slides the mounting table 311 toward the front side to a position where the container 40 can be installed, as shown in FIG. 14B. When the container 40 and stirring section 30 are installed, the mounting table slide mechanism 310 slides the mounting table 31 to the rear side to the position shown in FIG. 14A and returns it to the original position.

Next, in step S202, the elevating mechanism 210 lowers the upper unit 200 to insert the holding pin 252 into the holding pin insertion hole 30A provided in the upper part 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 S203, the elevating mechanism 210 raises the upper unit 200 so that the stirring section 30 held by the holding pin 252 is taken out from the container 40. By removing the stirring unit 30 from the container 40, it becomes possible to inject the blood sample into the container 40. Here, the elevating and lowering operation of the upper unit 200 by the elevating mechanism 210 will be explained with reference to FIGS. 15A and 15B.

FIG. 15A is a diagram showing a state in which the holding pin 252 is inserted into the stirring section 30 as the upper unit 200 is lowered. FIG. 15B is a diagram showing a state in which the upper unit 200 has been raised to a position where the blood sample in the container 40 can be stirred by the stirring section 30. The lifting mechanism 210 can move the upper unit 200 up and down by driving the lifting motor 211 to rotate a female screw portion that is threaded into a shaft 212 provided inside the lifting motor 211. The elevating mechanism 210 is capable of elevating the upper unit 200 to a desired height. In step S202, the elevating mechanism 210 may lower the upper unit 200 until the holding pin 252 is inserted to a depth capable of holding the stirring section 30. In step S203, the elevating mechanism 210 further raises the upper unit 200 than the state shown in FIG. 15B, and raises the stirring section 30 to a height at which the blood sample can be injected into the container 40.

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

In step S205, the elevating mechanism 210 adjusts the height of the stirring section 30 to a height that allows the blood sample in the container 40 to 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 rotational motion of the stirring motor 231 into a swinging motion of the swinging 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 swinging transmitted portion 250 further transmits the transmitted swinging motion to the holding pin 252. The stirring part 30 held by the holding pin 252 stirs the blood sample in the container 40 by performing a rocking motion 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, stirring motion transmission mechanism 240, and rotation angle measuring mechanism 270 will be described with reference to FIGS. 16, 17A, 17B, and 17C.

FIG. 16 is a diagram illustrating an operation in which the stirring control mechanism 230 converts the rotational motion of the gear 232 into the rocking motion of the rocking plate 241. The stirring control mechanism 230 rotates a gear 232 using a stirring motor 231 . The rotational motion of the gear 232 is converted into a reciprocating motion of the sliding plate 233 in the direction of arrow Y. By controlling the rotation 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, due to the reciprocating movement of the sliding plate 233, the swinging plate 241 performs a swinging movement in the Z1 direction with 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 rotational speed of the stirring motor 231, the rotational speed of the rocking plate 241, that is, the rotational speed of the stirring motion transmitted to the stirring section 30, can also be appropriately controlled.

17A to 17C illustrate an operation in which the stirring motion transmission mechanism 240 transmits the rocking motion of the rocking plate 241 to the rocking transmitted portion 250. FIG. 17A is a diagram showing the rotational state of the swing plate 241 when the sliding plate 233 moves to the front side. FIG. 17B is a diagram showing the rotational state of the swing plate 241 when the sliding plate 233 is not moving. FIG. 17C is a diagram showing the rotational state of the swing plate 241 when the sliding plate 233 moves to the rear side. The swing plate 241 repeats the states of FIGS. 17A and 17C, starting from the state of FIG. 17B, as shown in FIGS. 17A, 17B, 17C, 17B, 17A, 17B, and so on.

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

The rotation angle measurement mechanism 270 detects the rotation angle of the swing measurement pin 250B on the tip side of the swing transmitted portion 250 by the optical sensor 271A included in the sensor plate 271. The optical sensor 271A detects light emitted from the upper light source section 272 using light receiving elements arranged in a straight line. The rotation angle measurement mechanism 270 can measure the rotation angle of the swing measurement pin 250B from a position where no light is detected due to the movement of the swing measurement pin 250B. Since the swing measuring pin 250B swings in conjunction with the holding pin 252, when the rotation angle of the holding pin 252 decreases due to coagulation of blood in the container 40, the rotation angle decreases in conjunction with the holding pin 252. . Therefore, the rotation angle measurement mechanism 270 can measure the rotation angle of the holding pin 252 (and the stirring part 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 the stirring section 30 (rotation angle of the rocking plate 241) is controlled by the stirring control mechanism 230. 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 part 30 receives a force from the blood in the direction opposite to the rotation of the rocking plate 241. 30 rotation angle becomes smaller. In this case, the stirring section 30 is raised by the lifting mechanism 210 to reduce the depth at which the stirring section 30 is immersed in the blood sample, or to increase the distance between the stirring section 30 and the inner wall of the container 40. The force that the stirring section 30 receives from the blood sample is suppressed. When the force that the stirring section 30 receives from the blood is suppressed, when stirring blood of the same viscoelasticity, the stirring section 30 becomes lower when the stirring section 30 is raised compared to when stirring at a normal depth. It is possible to rotate at a larger angle. Therefore, by raising the stirring section 30, the blood coagulation test apparatus 100 can more accurately measure changes in viscoelasticity even for blood in a high viscoelastic region. Note that the height at which the stirring section 30 is raised and lowered can be freely set, and the area where the stirring section 30 is immersed in blood can be controlled. For example, the height of the stirring section 30 can be increased by 0.1 mm within a range of 0.1 mm to 20 mm.

Blood coagulation test device 100 measures the viscoelasticity by rotating the stirring section 30 when the viscoelasticity of blood is low, and raises the stirring section 30 at a predetermined timing when the rate of change in viscoelasticity decreases. . The predetermined timing can be a timing at which the accuracy of measuring changes in viscoelasticity has decreased. In addition, for blood samples with high viscoelasticity, from the timing of starting measurement,
The stirring section 30 can be raised. It is also possible to measure without changing the depth of immersion into the blood sample with the stirring unit 30 raised. By raising the stirring part 30, changes in viscoelasticity can be measured more accurately even in a high viscoelastic 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 viscoelastic area for blood in the high viscoelastic area. Therefore, using elastic bodies 249 of the same strength, changes in viscoelasticity from a low viscoelastic region to a high viscoelastic region can be measured with high accuracy.

FIG. 18A is a diagram showing the position of the stirring section during a normal blood coagulation test. Further, FIG. 18B is a diagram showing a state in which the viscoelasticity of the blood sample in the container has increased and the stirring section 30 has been raised. In FIG. 18A, the stirring section 30 is in a state in which 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 becomes high and the rotation angle or the rate of change of the rotation angle of the stirring section 30 decreases, making it difficult to measure the viscoelasticity, as shown in FIG. 18B, the elevating mechanism 210 The stirring section 30 may be raised by Alternatively, for normal human samples, the height of the stirring part 30 is analyzed at a steady position, and when analyzing blood from a blood sample (e.g. mouse, rat) that has higher viscoelasticity than human blood when it coagulates. The measurement may be performed at a position where the stirring section 30 is raised.

In analyzing the viscoelasticity of blood coagulation using this device, the following analyzes of blood samples with high viscoelasticity and low viscoelasticity are performed.

A pre-coagulated blood sample of any human, rat, mouse, or other species is added to the container 40, and a blood coagulation reaction is initiated within the container 40. At the start of measurement, the blood sample is mixed with a reagent, the blood coagulation reaction of the blood sample is started, and the viscoelasticity increases. In the container 40, fibrin formation occurs due to a blood coagulation reaction, and platelets are further activated by thrombin produced by the coagulation reaction. Activated platelets change shape, extend pseudopodia, and aggregate with each other.

For example, if an exogenous reagent such as tissue factor or an endogenous reagent such as ellagic acid and calcium chloride are added to a blood sample anticoagulated with citric acid to initiate blood coagulation, insoluble An increase in viscoelasticity occurs due to both clot formation (gel formation) and platelet aggregation.

On the other hand, depending on the purpose of the inspection, measurements may be performed in different viscoelastic regions. For example, when an inhibitor of platelet aggregation (cytochalasin D, etc.) is added to blood anticoagulated with citric acid in addition to calcium chloride and an extrinsic or intrinsic activation reagent, platelet aggregation is inhibited. does not occur, only the formation of fibrin clots.

In this case, the increase in viscoelasticity is not affected by platelets and is caused only by the viscoelasticity of the fibrin clot, so the maximum viscoelasticity correlates with the amount of fibrinogen in the blood sample. Naturally, since viscoelasticity reflects only fibrin clot formation, the measurement will be in a relatively low viscoelastic region compared to when no platelet aggregation inhibitor is added, and the maximum viscoelasticity reached during the measurement will also be lower. Become.

Furthermore, depending on the blood sample, different viscoelastic regions may be measured using the same reagent. For example, the number of platelets in humans is 150,000 to 300,000/μL, whereas the number of platelets in rats and mice exceeds 1 million/μL. Therefore, when analyzing blood coagulation by adding calcium chloride and an extrinsic or endogenous activating reagent to blood that has been anticoagulated with citric acid, it was found that mice and rats were more susceptible to platelet aggregation than humans. Because the increase in viscoelasticity occurs more strongly, a higher viscoelastic region is required to be measured in mice and rats than in humans, even when analyzing blood coagulation using the same reagent. In addition, in humans, the platelet count can exceed 1 million cells/μL in diseases such as thrombocytosis, so it is possible to measure high viscoelastic regions more accurately than with normal human blood samples. That is required. On the other hand, in diseases such as thrombocytopenia, the platelet count may fall below 10,000/μL, so it is required to accurately measure the low viscoelasticity region.

In this way, even in human blood samples, it may be necessary to analyze high or low viscoelastic regions depending on the purpose of the test, and even in different animal species, it is necessary to accurately measure changes in higher viscoelasticity. Sometimes things are required.

When measuring blood viscoelasticity in a state where platelet function is inhibited, such as FIBTEM in ROTEM assay (analysis, evaluation), the height of the stirring section 30 is measured at a steady position, and when analyzing normal human blood samples. (For example, EXTEM measurement of ROTEM), the position of the stirring section 30 is raised to measure, and when analyzing a highly viscoelastic blood sample (for example, rat, mouse, etc.), the rotation angle is widened and the stirring section 30 is raised. It is also possible to measure it by raising it. In this way, by controlling both the elevation and rotation angle of the stirring section 30, it becomes possible to analyze a wider range of viscoelastic blood. When the stirring part 30 rises, a part of the tapered tip is immersed. The depth at which the stirring section 30 is immersed in the blood sample in the container 40 becomes shallow, and the rotation angle of the stirring section 30 becomes large enough to be measurable.

19A and 19B are diagrams illustrating a container 40 containing a blood sample. The container 40 is not limited to the cylindrical shape shown in FIG. 8B. Any shape may be used as long as it is possible to change the depth of the stirring part 30 that accommodates blood and is immersed in the blood in the container 40. FIG. 19A is a perspective view of a first modification 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, by raising and lowering the stirring part 30, it becomes easy to change the distance between the stirring part 30 and the inner wall of the container 40A. FIG. 19B is a perspective view of a second modification 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 section 30 and the inner wall of the container 40B to a desired distance. Moreover, 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 section 30 is not limited to 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 but may be polygonal or the like. Further, the outer circumferential surface of the agitating section 30 may be provided with striped grooves or irregularities of various shapes.

In step S207, the holding pin pull-out mechanism 320 pulls out the holding pin 252 from the stirring section 30 after the inspection is completed. The holding pin pulling mechanism 320 can pull out the holding pin 252 from the stirring part 30 by pressing the upper part of the stirring part 30 and raising 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 mechanism 320 will be described with reference to FIGS. 20A and 20B. In FIG. 20A, it is assumed that the holding pin 252 is inserted into the holding pin insertion hole 30A of the stirring section 30.

FIG. 20A is a diagram showing a state in which the pressing plate 322 does not press the stirring section 30. FIG. 20B is a diagram showing a state in which the pressing plate 322 presses the stirring part 30 when the holding pin 252 is pulled out from the stirring part 30. When the solenoid 323 is energized and de-energized, the holding plate 322 receives a 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 pin 252 is raised together with the upper unit 200 by the lifting mechanism 210. On the other hand, in the state shown in FIG. 20B, the presser plate 322 overlaps the upper surface of the stirring section 30 in plan view. Since the pressing plate 322 presses down the upper part of the stirring section 30 held by the holding pin 252, when the upper unit 200 is raised by the lifting mechanism 210, the holding pin 252 is pulled out from the stirring section 30. In step S208, the container 40 and stirring section 30 are taken out, and the process shown in FIG. 13 ends.

In the blood coagulation test apparatus 100 of the second embodiment, by controlling the rotation speed of the stirring motor 231, the rotation speed and rotation angle transmitted to the stirring section 30 can be appropriately controlled. In addition, by raising and lowering the stirring section 30 and controlling the depth at which the stirring section 30 is immersed in the blood to be tested or the distance between the stirring section 30 and the inner wall of the container 40, it is possible to change the range from a low viscoelastic region to a high viscoelastic region. It becomes possible to measure blood viscoelasticity with high precision over a wide range of up to Therefore, the test performed by the blood coagulation test apparatus 100 provides a resolution that is appropriate for the test object. Furthermore, the blood coagulation test apparatus 100 includes operating mechanisms such as an elevating mechanism 210, a mounting table sliding mechanism 310, and a holding pin pulling mechanism 320, which promotes automation and simplification of blood coagulation tests.

[Modification 1 of the second embodiment]
The second embodiment described above shows an example in which a container having one storage part is used, such as container 40 in FIG. 8B, container 40A in FIG. 19A, or container 40B in FIG. 19B. On the other hand, Modification 1 is an example in which a container having two storage parts (hereinafter also referred to as a double container) is used for measurement. In the two series of containers, a stirring part (hereinafter also referred to as a stirring pin) and a reagent can be stored in separate storage parts in advance. In this case, the blood sample is injected into the container containing the reagent and stirred by the stirring pin during the testing process in the two series of containers. That is, the step of injecting the reagent can be omitted.

The two series of containers will be explained using FIGS. 22 and 23. FIG. 22 is a perspective view illustrating two containers. The double container 400 has a measuring cup part 401 and a stirring pin accommodating part 402. A blood sample is injected into the measurement cup section 401, and a coagulation test is performed within the cup. The measurement cup section 401 may store a reagent to be added to the blood sample in advance. When storing a reagent, it is desirable that the opening of the measuring cup portion 401 be sealed with an aluminum film or the like to be hermetically sealed. Stirring pin accommodating section 402 accommodates a stirring pin. Further, the stirring pin accommodating section 402 may accommodate stirring pins of different shapes depending on the blood sample to be tested or the reagent stored in the measuring cup section 401. Measuring cup section 401 is an example of a "measuring section". Further, the stirring pin accommodating portion 402 is an example of a “accommodating portion”.

(reagent)
Examples of reagents include reagents that activate extrinsic blood coagulation (tissue factor, tissue thromboblastin, etc.) and reagents that activate intrinsic blood coagulation (ellagic acid, silica, etc.). In addition, the reagents include reagents that activate extrinsic blood coagulation or endogenous blood coagulation, as well as platelet function suppressing reagents (cytochalasin D, GPIIbIIIa receptor antagonist abciximab), fibrinolysis inhibitors (aprotinin), etc. It may be something.

The reagent may be in any form, such as liquid, coated and dried, or freeze-dried, as long as it retains its activity. From the viewpoint of stability, it is desirable that the reagent be stored in a freeze-dried form or in a dried form after application.

In addition, from the viewpoint of storage, it is desirable that the measuring cup section 401 that accommodates the reagent is sealed and hermetically sealed with an aluminum film or the like. It is desirable that the seal that seals the measuring cup portion 401 be easily peeled off by the measurer before injecting the blood sample to be measured.

(stir pin)
The stirring pin accommodated in the stirring pin housing section 402 has a tip portion that stirs the blood sample according to the characteristics of the blood sample, the target assay (analysis, evaluation), and the type of reagent selected according to the assay. It is possible to change the shape of An example of the shape of the stirring pin will be explained with reference to FIG. 23.

FIG. 23 is a sectional view taken along the line AA of the two containers in which the stirring pins are housed in the measuring cup portions 401. The stirring pins 500A to 500C (hereinafter also collectively referred to as stirring pins 500) illustrated in FIGS. 23(A) to 23(C) have a diameter of the tip and a length in the axial direction, respectively. different. The stirring pin 500 corresponds to the stirring section 30 in the second embodiment described above.

In the stirring pin 500A of FIG. 23(A), the diameter of the tip 501A is d1, and the length of the tip 501A is h1. On the other hand, in the stirring pin 500B of FIG. 23(B), the diameter of the tip 501B is d1, which is the same as the diameter of the tip 501A, but the length is h2, which is longer than the tip 501A. Further, in the stirring pin 500C in FIG. 23(C), the length of the tip 501C is h1, which is the same as the length of the tip 501A, but the diameter is d2, which is larger than the tip 501A.

When the diameters of the tips of the stirring pins 500 are the same, such as the stirring pins 500A and 500B, the stirring pin 500B, which has a longer (deeper) tip that is immersed in the blood sample, will not coagulate even if the blood sample is the same. Due to the increase in viscoelasticity, the stirring pin 500A receives a larger force than the stirring pin 500A. In addition, when the length of the tip of the stirring pin 500 is the same as that of the stirring pin 500A and the stirring pin 500C, the diameter of the tip that is immersed in the blood sample is larger, and the length of the tip in the measuring cup portion 401 is larger than that of the stirring pin 500A. The stirring pin 500C, which is closer to the wall, receives a larger force than the stirring pin 500A due to the increase in viscoelasticity due to coagulation, even if the blood sample is the same.

That is, when measuring a blood sample with low viscoelasticity or when measuring viscoelastic changes only in fibrin by adding a coagulation activation reagent and a platelet inhibitor as reagents, the tip of the stirring pin 500 is longer. The stirring pin 500 having a larger diameter at the tip may be placed in the stirring pin accommodating portion 402. On the other hand, when measuring highly viscoelastic blood samples, for example, human fibrinogenemia or thrombocytosis, or animal (rat, mouse blood), the tip is immersed in the blood sample. It is sufficient to arrange the stirring pin 500 having a shorter diameter and a smaller tip diameter in the stirring pin accommodating portion 402.

For measurement of blood samples with lower viscoelasticity (for example, evaluation of changes in viscoelasticity due to fibrin formation in blood dilution), stirring pin 500B or stirring pin 500C may be used. In this case, by making the rotation angle relatively small (for example, ±1.5 to 5 degrees (3 to 10 degrees)), it becomes possible to analyze the decrease in the amplitude of the stirring pin 500.

On the other hand, in the measurement of a blood sample with higher viscoelasticity (for example, analysis of blood coagulation when an exogenous activation reagent is added to mouse or rat blood), the stirring pin 500A, which has a smaller immersed part in the blood sample, is used. Alternatively, a stirring pin 500 having a tip portion shorter in length than the stirring pin 500A may be used. In this case, by making the rotation angle relatively large (for example, ±5 to 15 degrees (10 to 30 degrees)), blood coagulation can be analyzed. In this way, by using stirring pins 500 of different shapes in the same device, it is possible to improve measurement accuracy in a wider viscoelastic region.

Although FIG. 23 describes the case where stirring pins 500 of different shapes are used, it is also possible to use the same stirring pin 500 but with a measuring cup portion 401 of a container 400 having a different shape. . For example, to evaluate a blood sample with low viscoelasticity, a measuring cup part 401 with a smaller inner diameter is used, and to evaluate a blood sample with high viscoelasticity, a measuring cup part 401 with a larger inner diameter is used. By doing so, it becomes possible to perform measurements according to the viscoelasticity of the blood sample.

In addition, in the first modification, it is assumed that the stirring pin 500 is swung to measure the decrease in amplitude and the coagulation of the blood sample is tested. You can. In this case, since the stirring pin 500 follows the rocking of the container 400 as the blood sample coagulates, an increase in the amplitude of the stirring pin 500 may be measured.

(Measurement processing)
The measurement process using two series of containers is carried out according to the flow of operation of the blood coagulation test apparatus shown in FIG. 13. With reference to FIG. 13, the difference between the process using two containers and the process using a container having one storage section will be described.

In step S201, the container 400 and the stirring pin 500 accommodated in the stirring pin accommodating section 402 are installed in the container installation section 311A (FIG. 9A). In this case, the measurement cup section 401 can store reagents used for measurement.

In step S202, the holding pin 252 (FIG. 8B, FIG. 15A, etc.) is inserted into the holding pin insertion hole provided at the top of the stirring pin 500, and holds the stirring pin 500. In step S203, the stirring pin 500 rises together with the holding pin 252.

In step S204, a blood sample is injected into the measurement cup section 401. When a reagent is stored in the measurement cup portion 401 and sealed with a seal, the measurer only has to peel off the seal, inject the blood sample, and stir it by pipetting. Furthermore, if a reagent is not stored in the measuring cup portion 401, the measuring person may inject the reagent together with the blood sample.

In step S205, the stirring pin 500 is inserted into the measuring cup part 401 instead of the stirring pin accommodating part 402, and is adjusted to a height according to the viscoelasticity of the blood sample. In step S206, a blood coagulation test is performed. In step S207, the holding pin 252 is pulled out from the stirring pin 500, and in step S208, the container 400 and stirring pin 500 are taken out.

In Modification 1, the stirring pin 500 is housed in the measuring cup portion 402 of the container 400 before the measurement of the blood coagulation test. Then, at the end of the measurement, the stirring pin 500 is housed in the measurement cup section 401 together with the blood sample. The used container 400 taken out from the blood coagulation test apparatus 100 is discarded.

(Operation and effect of modification 1)
In the case of two containers, the shape of the stirring pin 500 is changed depending on the type of reagent stored in the measurement cup portion 401 and the characteristics of the blood sample to be measured. That is, for a blood sample with low viscoelasticity, the shape of the stirring pin 500 may be such that the portion immersed in the blood sample is large. Further, the swinging angle of the stirring pin 500 (or the container 400) can also be changed according to the type of reagent and the characteristics of the blood sample. That is, in the case of a highly viscoelastic blood sample, the swinging angle of the stirring pin 500 may be set to be large. In this way, by changing the shape of the stirring pin 500 and the swing angle of the stirring pin 500 in combination, it becomes possible to measure in a wider viscoelastic range.

Further, the two containers 400 have a measuring cup portion 401 and a stirring pin accommodating portion 402, and can store reagents and stirring pins 500 in accordance with the characteristics of the blood sample in advance. Thereby, the measurer can reduce the trouble of injecting the reagent. Further, by storing a stirring pin 500 having a shape corresponding to the reagent or blood sample, the measurer can perform measurements using an appropriate stirring pin 500.

[Modification 2 of the second embodiment]
In the second embodiment described above, the blood sample is measured based on the height of the stirring section 30, the shape of the stirring section 30, and the amplitude angle transmitted to the stirring section 30, which are determined before measurement, depending on the viscoelasticity. . Furthermore, it is assumed that these settings will not be changed during blood sample measurement. On the other hand, Modification 2 shows an example in which the amplitude angle transmitted to the stirring section 30 is changed during measurement. The amplitude angle transmitted to the stirring section 30 is the rotation angle of the swing plate 241, the swing transmission section 248, etc. controlled by the stirring control mechanism 230, and corresponds to the "rotation angle for reciprocating the elastic body". . Although the second modification describes an example in which the stirring section 30 is used, the stirring pin 500 of the first modification may also be used.

Here, the results of measuring high viscoelastic and low viscoelastic blood samples using the same spring will be explained using FIG. 24. FIG. 24 shows the measurement results of a blood sample using the same spring. FIG. 24(A) is a graph showing the measurement results of a highly viscoelastic blood sample. FIG. 24(B) is a graph showing the measurement results of a blood sample with low viscoelasticity. In both graphs, the vertical axis is the measured amplitude angle of the stirring section 30. Moreover, the horizontal axis is the elapsed time from the start of measurement. When measuring a highly viscoelastic blood sample, the amplitude angle of the stirring section 30 decreases to the amplitude after coagulation at an early stage, making it difficult to measure further changes in coagulation. When measuring a blood sample with low viscoelasticity, the amplitude angle of the stirring section 30 does not decrease much, and the change in amplitude due to blood coagulation is smaller than that of a blood sample with high viscoelasticity.

Therefore, in the measurement of a blood sample with high viscoelasticity, the blood coagulation test device 100 of the second modified example widens the amplitude angle transmitted to the stirring unit 30 during the measurement according to the change in viscoelasticity after the start of the measurement. With this method, changes in viscoelasticity can be detected more clearly.

Specifically, the blood coagulation test apparatus 100 performs measurements using the following measurement algorithm. The blood coagulation test apparatus 100 first sets the amplitude angle at the start of measurement (corresponding to the "first angle") transmitted to the stirring section 30 to, for example, 10 degrees and starts measurement.

The blood coagulation test apparatus 100 determines the elapsed time from the start of measurement when the measured amplitude angle of the stirring section 30 decreases to an angle for defining the coagulation start time (corresponding to the "second measurement angle"). Obtained as the solidification start time. In addition, in the blood coagulation test apparatus 100, when the amplitude angle of the stirring section 30 to be measured decreases to an angle for defining the coagulation rate (corresponding to the "first measurement angle"), the elapsed time from the start of the measurement is determined. is obtained as the solidification rate. Decreasing to the first measurement angle or the second measurement angle can be determined, for example, based on whether the average value of the three previous and subsequent measurement values has fallen below these angles.

Blood coagulation test apparatus 100 changes the amplitude angle transmitted to stirring section 30 to the amplitude angle at the start of measurement (first (corresponding to the "second angle"). Whether or not the angle has fallen below the angle used to define the solidification rate can be determined, for example, by determining whether the average value of three measurements before and after has fallen below these angles. The amplitude angle after expansion (second angle) can be, for example, twice the amplitude angle at the start of measurement.

The measurement algorithm is determined by the user setting various parameters such as the amplitude angle at the start of measurement, the amplitude angle to define the solidification start time, the amplitude angle to define the solidification rate, and the amplitude angle after expansion. be done. These various parameters are set via an application (hereinafter also referred to as a control application) for controlling blood sample measurement.

(Operation and effect of modification 2)
When measuring a highly viscoelastic blood sample, the blood coagulation test device 100 can detect changes in the measured angle of the stirring section 30 more noticeably by widening the amplitude angle transmitted to the stirring section 30 during the measurement. It becomes like this. In addition, the blood coagulation test device 100 can detect fibrinolysis (dissolution of thrombus) after the blood sample has coagulated and become highly viscoelastic by more markedly detecting changes in viscoelasticity for blood samples with high viscoelasticity. Sensitivity is also improved in the analysis of the state where the viscoelasticity is slightly reduced due to the reaction.

[Other embodiments]
Although the present invention has been described in detail based on the preferred embodiments above, the present invention is not limited to these specific embodiments, and includes various forms without departing from the gist of the present invention. It will be done. Furthermore, each of the embodiments and modifications described above merely shows one embodiment of the present invention, and it is also possible to combine the embodiments as appropriate.

[Example according to the second embodiment]
Hereinafter, an example using the blood coagulation test apparatus 100 according to the second embodiment will be shown, and the present invention will be explained in more detail. However, the present invention is not limited to the following examples.

The second embodiment shows an example in which a spring with greater sensitivity (that is, thinner/weaker) is selected as the elastic body 2 in accordance with the measurement of a low viscoelasticity region. In addition, when measuring in a high viscoelastic region, we can control the rotation speed of the motor and widen the rotation (amplitude) angle transmitted to the stirring part that stirs the blood sample. measurement becomes possible. For example, a method has been disclosed in which blood viscoelasticity is analyzed by thromboelastometry to measure the amount of fibrinogen in the blood in the presence of an antiplatelet agent (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, gels made only of fibrin in the presence of antiplatelet agents are suitable for measurement at about ±4 to 10 degrees (8 to 20 degrees) using thinner/weaker springs.

In addition, in the following description, when using the container 40, container 40A, and container 40B shown in FIG. 8, FIG. 19A, and FIG. 19B, the stirring part 30 is shown as a stirring part. Moreover, when using the two containers 400 shown in FIG. 22, a stirring pin 500 is shown. Further, the stirring section is also referred to as a measuring pin in the examples.

If a high viscoelastic region is analyzed under the same highly sensitive spring and amplitude angle conditions as in the measurement of a low viscoelastic region, sufficient resolution and accuracy cannot be obtained in the high viscoelastic region. That is, the movement of the swing measurement pin may stop before the blood coagulates and reaches its maximum viscoelasticity. In order to prevent such a situation, when measuring a high viscoelastic region in cases such as a hypercoagulable state (increased fibrinogen) or thrombocytosis, even a spring with greater sensitivity should be By widening the rotation angle of the oscillating motion (of the dynamic transmission section 248) to more than ±5 degrees, preferably to ±10 to 20 degrees (20 to 40 degrees), a stronger force can be applied to the oscillation measurement pin via the spring. In addition, highly accurate measurements are possible in the high viscoelastic region. In addition, even when testing for blood coagulation that leads to high viscoelasticity, the initial rotation angle of the stirring section should be ±4 to 10 degrees, and after confirming that the amplitude has decreased due to the start of blood coagulation, increase the rotation angle to ±10 to 20 degrees. is also possible. In this case, even if the rotation angle is increased to ±10 to 20 degrees, the blood viscoelasticity has already started to increase, so the rotation angle of the stirring section can be kept to about 5 degrees, and the rotation angle of the stirring section can be kept large. It is possible to prevent the gel structure of the blood coagulation from being destroyed by the amplitude. If a weak spring that does not break the gel is used, the problem of the fibrin gel breaking does not occur even at a rotation angle of ±10 degrees or more. However, if a weaker spring is used, it is necessary to further increase the rotation angle for analysis of high viscoelasticity. The rotation angle of the stirring part is selected depending on the sensitivity of the spring and the shape of the spring and the stirring part. In this way, if a device (system) using a highly sensitive spring is used to measure a low viscoelastic region, and if the same device is used to measure a high viscoelastic region, the rotation speed of the motor should be controlled, By changing (widening) the rotation angle of the rocking motion transmitted to the spring and the stirring section, it becomes possible to sensitively perform assays (analysis, evaluation) in various viscoelastic regions. As exemplified in the following examples, the rotation angle of the rocking motion of the rocking motion of the rocking transmission section 248 that is transmitted to the spring and the stirring section depends on the state of viscoelasticity, etc. of the blood (including plasma) to be tested. It is possible to change it depending on the purpose of measurement.

When measuring blood samples with high viscoelasticity, if a more sensitive (ie, thinner/weaker) spring is used, the amplitude of the stirring section will decrease more quickly and the accuracy of detecting changes in viscoelasticity will decrease. Therefore, in accordance with the decrease in the amplitude of the stirring section, the blood coagulation testing apparatus 100 widens the amplitude angle transmitted to the stirring section at a predetermined timing during measurement. By widening the amplitude angle transmitted to the stirring section, the amplitude of the stirring section becomes larger, and changes in viscoelasticity can be detected with high accuracy. The predetermined timing is, for example, the timing when the amplitude of the stirring section becomes equal to or less than a predetermined angle. In this way, by widening the amplitude angle transmitted to the stirring section during measurement, the amplitude of the stirring section also increases, making it possible to accurately detect changes in viscoelasticity even in high viscoelastic regions.

<Example 1>
Example 1 is an example in which analysis was performed on a blood sample for the purpose of analyzing high viscoelasticity during blood coagulation by widening the amplitude angle transmitted to the measurement pin at a predetermined timing during measurement.

The predetermined timing is set by the user via the control app. Here, the measurement algorithm set by the user will be explained using FIG. 25. FIG. 25 is a diagram for explaining the measurement algorithm. The vertical axis indicates amplitude angle (°), and the horizontal axis indicates time (sec). In the following description, the amplitude angle is expressed as an angle from the center of the amplitude in a positive or negative direction, such as ±5 degrees (10 degrees), and the actual amplitude of vibration is shown in parentheses.

The measurement algorithm is determined by setting various parameters. The various parameters are, for example, the amplitude angle at the start of the measurement, the amplitude angle to define the solidification start time, the amplitude angle to define the solidification rate, the amplitude angle to define the maximum viscoelasticity, the amplitude angle to define fibrinolysis. The amplitude angle etc. In Example 1, the following measurement algorithm was set by the control application.
(1) Set the amplitude angle transmitted to the measurement pin to ±5 degrees (10 degrees) and start measurement (2) Measure the time when the amplitude drops to ±4 degrees (8 degrees) (A: solidification start time) (3 ) Measure the time when the amplitude has decreased to ±2 degrees (4 degrees) (B: coagulation start time + solidification rate) (4) When the amplitude has decreased to ±2 degrees (4 degrees), measure the amplitude transmitted to the measurement pin Expand the angle to ±10 degrees (20 degrees) (5) Measure the minimum amplitude width C (evaluate maximum viscoelasticity)
(6) Detection of coagulum dissolution (fibrinolysis) (D: broadening of amplitude again)

In the above algorithm, processes (1) to (3) are aimed at evaluating the time it takes for blood to reach a certain viscoelasticity. The time A measured in process (2) is the coagulation start time, which is the time from the start of measurement to the start of blood coagulation. The time B measured in process (3) is the sum of the coagulation start time and the coagulation rate. The coagulation rate is the time from the start of blood coagulation until reaching a certain level of viscoelasticity, and is calculated by subtracting time A from time B.

On the other hand, processes (4) to (6) are aimed at evaluating the minimum viscoelasticity and the subsequent spread (amplitude) of the viscoelasticity. Therefore, in processes (1) to (3), the resolution of the coagulation time is improved by setting a narrow amplitude (10 degrees) and shortening the time per amplitude, and in processes (4) and after, the amplitude is set to ±10 degrees. (20 degrees), the time per amplitude increases, but by applying a stronger force to the measurement pin, it is possible to improve the sensitivity/resolution in the higher viscoelastic region.

In the process (2) above, whether the amplitude decreased to ±4 degrees (8 degrees) was determined by whether the average value of the three measurements before and after was less than 8 degrees. Similarly, in the processes (3) and (4), whether the amplitude decreased to 4 degrees or not was determined based on whether the average value of the three measurements before and after was less than 4 degrees.

Further, regarding various parameters in the above algorithm, the amplitude angle at the start of measurement is ±5 degrees (10 degrees) set in process (1). The amplitude angle for defining the solidification start time is ±4 degrees (8 degrees) as shown in process (2). The amplitude angle for defining the solidification rate is ±2 degrees (4 degrees) as shown in process (3). The amplitude angle for defining the maximum viscoelasticity is the angle indicated by C shown in process (5). The amplitude angle for defining fibrinolysis is the angle indicated by D shown in process (6), and is the angle at which fibrinolysis is detected.

Next, the container 400 used in Example 1 will be explained. In Example 1, measurements were performed using two containers. First, venous blood was collected into a blood collection tube containing 3.2% sodium citrate. A human body was placed in a container 400 in which freeze-dried reagents (20 μL of INTEM reagent (intrinsic blood coagulation activation reagent: Tem innovations Gmbh) and 20 μL of Startem reagent (calcium chloride reagent: Tem innovations Gmbh)) were placed in the measuring cup part 401 in advance. 300 μL of citrated blood was added. The container 400 was kept warm at 37 degrees, and the stirring motor 231 was controlled to swing the swing transmission section 248 within a range of ±5 degrees (10 degrees). The swing of the swing transmitting section 248 is transmitted to the measurement pin via the elastic body 249, the swing transmitted section 250, and the holding pin 252.

Next, the torsion coil spring used as the elastic body 249 will be described using FIG. 21. 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 dmm 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 using the following calculation formula (Formula 1). In Examples 4 and 5, the spring B is a twisted coil with 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. A spring was used. The spring constant kTd of the spring B is calculated as 0.0018 Nmm/deg using the following calculation formula (Formula 1).

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

E: Longitudinal elasticity coefficient (SUS, Steel special use Stainless) = 186 x 10 ³ N/mm
²

Even when a wire spring is used, it is possible to change the spring constant kTd by changing the wire diameter d and the arm lengths a ₁ and a ₂ . 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 calculation formula (Formula 1). It becomes possible.

In Example 1, the amplitude of one round trip of the swing transmission section 248 controlled by the stirring motor 231 was 5.2 seconds. The amplitude (amplitude angle) of the measurement pin can be calculated from the amplitude of the swing measurement pin 250B provided at the tip of the swing transmitted portion 250. The amplitude of the swing measurement pin 250B is measured on the optical sensor 271A of the swing measurement pin 250B four times at approximately 0.1 second intervals starting from 0.4 seconds after the rotation of the swing transmission unit 248 stops at both ends. The position was measured and calculated from the average value of each of the four rotations at both ends of the rotation.

The measurement results are shown in FIG. 25. The parameters measured were as follows.
A: Time when the amplitude decreased to ±4 degrees (8 degrees) (coagulation start time) 2.63 minutes B: Time when the amplitude decreased to ±2 degrees (4 degrees) (coagulation start time + solidification rate) 4.10 Minute C: Minimum width of amplitude 2.56 degrees

<Example 2>
Example 2 is an example in which measurement results of different blood samples are compared. In Example 2, the same equipment and container as in Example 1 were used. In Example 2, sample A and sample B, which are different blood samples, were used. FIG. 26 is a graph showing the measurement results in Example 2. The vertical axis shows the amplitude angle (°) of the measurement pin, and the horizontal axis shows time (min). Similar to FIG. 25, in the following description, the amplitude angle is the difference between two positive and negative graphs.

FIG. 26(A) shows measurement results when the amplitude angle transmitted to the measurement pin is constant during measurement. In FIG. 26(A), the analysis was performed with the transmitted amplitude angle at the start of measurement set to ±5 degrees (10 degrees). In Fig. 26(B), after starting measurement with the transmitted amplitude angle set to ±5 degrees (10 degrees), when the actual amplitude of the measurement pin reaches ±3 degrees (6 degrees), the transmitted amplitude angle was widened to ±10 degrees (20 degrees).

As shown in FIG. 26(A), when the transmission angle is constant, the coagulation waveforms for specimen A and specimen B are similar, and differences in coagulation ability between specimens are not sufficiently detected. On the other hand, as shown in Fig. 26(B), when the amplitude angle of the measurement pin reaches ±3 degrees (6 degrees), the amplitude angle transmitted to the measurement pin is expanded to ±10 degrees (20 degrees). When analyzed, subsequent differences in coagulation ability (particularly maximum viscoelasticity) between samples were observed. When analyzing the maximum viscoelasticity (minimum amplitude) in this way, by widening the transmitted amplitude and transmitting a stronger force to the measurement pin, the sensitivity in measuring high viscoelastic regions is improved.

During measurement, by detecting a decrease in the amplitude angle of the measuring pin and automatically widening the amplitude angle transmitted to the measuring pin, changes in viscoelasticity can be detected accurately even when measuring highly viscoelastic blood samples. I found out that it is possible.

<Example 3>
Example 3 was measured under the same measurement conditions as in Example 1, using the same apparatus and container as in Example 1. In addition, measurements were made using the following reagents. Reagents (15 μL of tissue factor solution extracted from rabbit brain (extrinsic blood coagulation activation reagent) and 20 μL of Startem reagent (calcium chloride reagent: Tem innovations GmbH)) are placed in the measuring cup portion 401 in advance.
Analysis was performed by putting 300 μL of human citrated blood into the container 400 containing the sample. Furthermore, to compare the lysis reaction of blood coagulation, we also conducted an analysis when a thrombolytic drug (tPA: generic name alteplase (product name Glutopa Injection), final concentration 100 IU/ml) was added to the blood sample before the start of measurement. .

FIG. 27 is a graph showing the measurement results in Example 3. The vertical axis shows the amplitude angle (°) of the measurement pin, and the horizontal axis shows time (sec). The minimum width of the amplitude of C (actual amplitude) was 1.81 degrees without the addition of t-PA and 2.20 degrees with the addition of tPA. Further, the amplitude (actual amplitude) approximately 1 hour after the start of the measurement was 2.34 degrees without the addition of t-PA, and 18.64 degrees with the addition of tPA.

Here, detection of fibrinolysis will be explained. It is recognized that the portion c1 surrounded by a circle has improved sensitivity to fibrinolytic reactions. Further, by widening the amplitude angle transmitted to the measurement pin, as shown by arrow c2, the change in amplitude due to thrombolysis increases, and the decrease in viscoelasticity can be detected with high accuracy. Furthermore, when the amplitude angle is widened and the load on the measurement pin is increased, the sensitivity to viscoelastic changes in the high viscoelastic region increases. That is, the sensitivity to fibrinolysis at the stage where blood begins to coagulate and dissolve increases. In this way, in measurements in the high viscoelasticity region, the effect of improving sensitivity to fibrinolytic reactions was achieved by becoming more sensitive to changes in viscoelasticity.

10, 100... Blood coagulation test device: 1... Control section: 1A... Servo motor: 1B... Elastic body support section: 1C... Elastic body support shaft: 2... Elastic body: 3... Stirring section: 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 section: 17... Display section: 18... Input section 30, 500... Stirring section (stirring pin): 30A... Hold Pin insertion hole: 30B...Flange: 40, 400...Container: 401...Measuring cup section: 402...Stirring pin accommodating section 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... Swing transmission part: 249... Elastic body: 250... Oscillation transmitted part: 250A... Elastic body Connecting part: 250B... Swing measurement pin: 251... Second pedestal: 252... Holding pin: 270... Rotation angle measurement mechanism: 271... Sensor plate: 272... Light source section: 300... Lower unit: 310... Placement table slide mechanism: 311... Placement table: 311A... Container installation part: 312... Ball screw: 313... Slide motor: 314... Linear guide: 320... Holding pin pull-out mechanism: 321...・Guide plate: 322・・Press plate: 323・・Solenoid: 331・・Support shaft: 332・・Upper unit support stand

Claims (9)

A container to hold the blood to be tested,
a stirring unit that stirs the blood to be tested in the container;
an elastic body connected to the stirring section and deformable according to the force received from the stirring section by stirring the blood of the test subject;
By reciprocating the elastic body at a first angle about the axis of the stirring section and controlling the reciprocating rotation of the elastic body, a predetermined reciprocating rotational motion is transmitted to the stirring section, and the stirring section a control unit that reciprocates in the circumferential direction;
A measurement unit that measures the rotation angle due to reciprocating rotation of the stirring unit,
The control unit includes:
When the rotation angle of the stirring unit measured by the measurement unit decreases to a first measurement angle that is an angle for defining the solidification rate, obtain the solidification rate,
When the rotation angle of the stirring section measured by the measurement section becomes equal to or less than the first measurement angle, the rotation angle for reciprocating the elastic body is increased to a second angle larger than the first angle. ,
Blood coagulation test device. The control unit obtains the solidification start time when the rotation angle of the stirring unit measured by the measurement unit decreases to a second measurement angle that is an angle for defining the solidification start time.
The blood coagulation test device according to claim 1 . A container to hold the blood to be tested,
a stirring unit that stirs the blood to be tested in the container;
an elastic body connected to the stirring section and deformable according to the force received from the stirring section by stirring the blood of the test subject;
By reciprocating the elastic body at a first angle about the axis of the stirring section and controlling the reciprocating rotation of the elastic body, a predetermined reciprocating rotational motion is transmitted to the stirring section, and the stirring section a control unit that reciprocates in the circumferential direction;
A measurement unit that measures the rotation angle due to reciprocating rotation of the stirring unit,
The control unit includes:
When the rotation angle of the stirring unit measured by the measurement unit decreases to a second measurement angle that is an angle for defining the solidification start time, obtain the solidification start time,
When the rotation angle of the stirring section measured by the measurement section becomes equal to or less than the first measurement angle, which is an angle for defining the solidification rate, the rotation angle for reciprocating the elastic body is changed to the first angle. spread to a second angle greater than
Blood coagulation test device. the second angle is twice the first angle;
The blood coagulation test device according to any one of claims 1 to 3. The first angle and the second angle are set by the user.
The blood coagulation test device according to any one of claims 1 to 4. The container has a measurement section that accommodates a reagent to be added to the blood to be tested, and a storage section that accommodates the stirring section.
The blood coagulation test device according to any one of claims 1 to 5. The accommodating part of the container accommodates the stirring part having a shape according to the reagent stored in the measuring part.
The blood coagulation test device according to claim 6. a stirring step of stirring blood to be tested placed in a container by a stirring section;
An elastic body connected to the stirring section and deformable according to the force received from the stirring section by stirring the blood of the test subject is reciprocated at a first angle about the axis of the stirring section as a rotation axis, and the elastic body a control step of transmitting a predetermined reciprocating rotational motion to the stirring section by controlling the reciprocating rotation of the body, and causing the stirring section to reciprocate in a circumferential direction;
a measuring step of measuring a rotation angle due to reciprocating rotation of the stirring section,
In the control step,
When the rotation angle of the stirring section measured in the measurement step decreases to a first measurement angle that is an angle for defining the solidification rate, obtain the solidification rate,
When the rotation angle of the stirring section measured in the measurement step becomes equal to or less than the first measurement angle, the rotation angle for reciprocating the elastic body is increased to a second angle larger than the first angle. ,
Blood coagulation test method. a stirring step of stirring blood to be tested placed in a container by a stirring section;
An elastic body connected to the stirring section and deformable according to the force received from the stirring section by stirring the blood of the test subject is reciprocated at a first angle about the axis of the stirring section as a rotation axis, and the elastic body a control step of transmitting a predetermined reciprocating rotational motion to the stirring section by controlling the reciprocating rotation of the body, and causing the stirring section to reciprocate in a circumferential direction;
a measuring step of measuring a rotation angle due to reciprocating rotation of the stirring section,
In the control step,
When the rotation angle of the stirring part measured in the measurement step decreases to a second measurement angle that is an angle for defining the solidification start time, obtain the solidification start time,
When the rotation angle of the stirring section measured in the measurement step becomes equal to or less than the first measurement angle, which is an angle for defining the solidification rate, the rotation angle for reciprocating the elastic body is changed to the first angle. spread to a second angle greater than
Blood coagulation test method.

Images