JP2021032824A - Blood coagulation test device and blood coagulation test method - Google Patents

Abstract

To provide a technique capable of obtaining resolution according to the inspection target in the blood coagulation test.SOLUTION: The blood coagulation test device includes: a container for blood to be tested; a stirrer unit that stirs the blood to be tested in the container; an elastic body connected to the stirrer unit, which is deformable according to a force received from the stirrer unit by stirring the blood to be inspected; a control unit that is configured to control the elastic body to reciprocally rotate at a first angle with an axis of the stirrer unit as an axis of rotation and to control the reciprocating rotation of the elastic body in the circumferential direction to thereby transmit the predetermined reciprocating rotary motion to the stirring part; and a measurement unit that measures the rotation angle due to the reciprocating rotation of the stirring unit. The control unit is configured so as to, when the rotation angle of the stirring unit measured by the measurement unit becomes less than or equal to the first measurement angle, expand the rotation angle for reciprocating the elastic body to a second angle larger than the first angle.SELECTED DRAWING: Figure 25

Description

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

The process of blood coagulation in order to evaluate the pathophysiology of hemophilia, in which blood coagulation factors that work to solidify blood during bleeding are reduced or deficient, and to evaluate the efficacy of drugs such as hemostatic agents. In, the state of blood coagulation is examined. As a method for inspecting the state of blood coagulation, for example, by irradiating the blood to be inspected to which a reagent is added (hereinafter, also referred to as a blood sample) with light and measuring the amount of scattered light, a coagulated mass is detected and the coagulation time is determined. An optical inspection method for calculating is known (see, for example, Patent Document 1). In addition, the pin immersed in the cup containing the blood sample is reciprocated within a certain angle (4.75 degrees), and the decrease in the angle of rotation of the pin due to blood coagulation is measured to measure the state of blood coagulation such as viscosity. Is known to be mechanically inspected (see, for example, Non-Patent Document 1).

JP-A-2010-217559

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

When examining the state of blood coagulation using an optical test method, the measured amount of scattered light may be affected by interfering substances in the blood sample. Further, the change in the amount of scattered light may not be detected accurately depending on the difference in the inspection items, that is, the difference in the reagent to be added. Due to the optical technique, changes in blood viscoelasticity are not accurately measured and only data is obtained when blood coagulation is complete.

Further, in a device for dynamically inspecting the state of blood coagulation, for example, TEG (registered trademark) or ROTEM (registered trademark), measurement conditions such as a rotation angle of a cup into which a blood sample is injected or a pin immersed in the blood sample are measured. Is not changed according to the difference in blood sample, drug, test item, etc. For example, in TEG, the cup is reciprocated within the range of ± 4.75 degrees (4 degrees 45 minutes), but if the blood is gelled and then rotated well beyond ± 4.75 degrees, the gel will be rotated. It may be broken and viscoelasticity may not be measured correctly. Further, for example, in ROTEM, the pin is reciprocated at a constant angle by a spring. The rotation angle transmitted to the pin by the spring is fixed at ± 4.75 degrees, and when the viscoelasticity increases due to blood coagulation, the pin gradually stops rotating. Therefore, even in the measurement in the high viscoelastic region where blood coagulation has progressed, or conversely, in the measurement in the 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 the drug. In addition, it is difficult to analyze the coagulation state of animal blood, which has a higher amount of platelets and higher viscoelasticity than human blood, with a desired resolution from the low viscoelastic region to the high viscoelastic region. There was a case. Further, since these devices are expensive, there is a demand for a device that is smaller and lighter at a lower price.

In conventional ROTEM or TEG, the same spring is used, and at the same rotation angle, high viscoelastic blood coagulation (intrinsic blood coagulation or extrinsic blood coagulation) and low viscoelastic blood coagulation (in the presence of antiplatelet drugs). Both (such as analysis of fibrin gel formation) are being analyzed. Therefore, when a spring with sufficient sensitivity (weak) to the increase in the load on the pin due to the increase in viscoelasticity is used in the measurement of low viscoelastic blood coagulation, the measurement in the high viscoelastic region results in blood coagulation. As a result, the load on the pin becomes large due to the increase in viscoelasticity, the rotation of the pin is lost, and the desired resolution cannot be obtained. On the contrary, when a (strong) spring suitable for measuring high viscoelastic blood coagulation is used, the load on the pin due to the increase in viscoelasticity of low viscoelastic blood coagulation is small, so that the rotation angle of the pin changes. (Decrease) becomes small, and the desired sensitivity and reproducibility cannot be obtained. As described above, when the same spring is used and the analysis is performed at the same rotation angle, there is a problem that the sensitivity and accuracy are deteriorated.

An object of the present invention is to provide a technique for obtaining a resolution according 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 unit that agitates blood with the axis of the stirring unit as a rotation axis, and controls the reciprocating rotation to reciprocate a predetermined number of parts to the stirring unit. I decided to transmit the rotational movement. Then, it was decided to change the rotation angle for reciprocating the elastic body during the measurement.

Specifically, the blood coagulation test apparatus according to the present invention is connected to a container for containing the blood to be tested, a stirring unit for stirring the blood to be tested in the container, and a stirring unit, and the blood to be tested is connected to the stirring unit. An elastic body that can be deformed according to the force received by stirring, and the elastic body are reciprocated at a first angle with the axis of the stirring unit as the rotation axis, and the reciprocating rotation of the elastic body is controlled to control the reciprocating rotation of the elastic body. It is equipped with a control unit that transmits reciprocating rotary motion and reciprocates the stirring unit in the circumferential direction, and a measuring unit that measures the rotation angle due to the reciprocating rotation of the stirring unit. The control unit is a stirring unit measured by the measuring unit. When the rotation angle of is equal to or less than the first measurement angle, the rotation angle for reciprocating the elastic body is widened to a second angle larger than the first angle.

With the above blood coagulation tester, it is possible to control the reciprocating rotation of the stirring unit to a predetermined angle. The control unit is, for example, a servomotor that is being mass-produced in small size for controlling the tail of a radio-controlled aircraft, controlling the direction of a drone camera, and the like. A servo motor is a motor provided with a servo mechanism that automatically controls the position, orientation, speed, etc. of an object so as to follow a target value. Therefore, the servomotor can accurately control the rotation at a low speed and the rotation at a desired angle. Therefore, in the blood coagulation test, the blood coagulation tester can obtain the resolution according to the test target by appropriately controlling the rotation speed and the rotation angle transmitted to the stirring unit. In addition, by raising and lowering the stirring unit and controlling the depth at which the stirring unit is immersed in the blood to be inspected or the distance between the stirring unit and the inner wall of the container, the viscoelasticity of blood in the highly viscoelastic region can be accurately controlled. It becomes possible to measure. Further, by reducing the size, weight, and price of the servomotor, it is possible to reduce the cost for performing a blood coagulation test. Further, instead of stirring a plurality of blood samples under the same control, it is possible to perform a test according to each blood sample by controlling a servomotor for each blood sample. The reciprocating rotary motion is a motion that rotates within a range of a predetermined rotation angle about the rotation axis.

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

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 unit may change a predetermined reciprocating rotational motion according to the rotation angle measured by the measurement unit. With such a blood coagulation test device, for example, when blood coagulation progresses and the stirring unit stops rotating, the rotation angle of a predetermined reciprocating rotary motion transmitted from the servomotor to the stirring unit is increased. , It is 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 unit is immersed in the blood to be examined or the distance between the stirring unit and the inner wall of the container, the region from the low viscoelastic region to the high viscoelastic region It is possible to measure the viscoelasticity of blood with high accuracy in a wide range up to.

Further, when the rotation angle of the stirring unit measured by the measurement unit becomes equal to or less than the first measurement angle, the control unit sets 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 for reciprocating the elastic body during the measurement, it is possible to suppress a decrease in resolution in the measurement of viscoelasticity in the high viscoelastic region.

The present invention can also be grasped from the aspect of the method. For example, the present invention has a stirring step of stirring the blood to be tested placed in a container by a stirring section, and elasticity connected to the stirring section and deformable according to the force received from the stirring section by stirring the blood to be tested. By reciprocating the body at the first angle with the axis of the stirring unit as the rotation axis and controlling the reciprocating rotation of the elastic body, a predetermined reciprocating rotational motion is transmitted to the stirring unit, and the stirring unit is reciprocated in the circumferential direction. In the control step, when the rotation angle of the stirring part measured in the measuring step becomes equal to or less than the first measurement angle, the elasticity is included. The rotation angle for reciprocating the body may be widened to a second angle larger than the first angle.

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

FIG. 1 is a schematic view illustrating the configuration of a blood coagulation test device. FIG. 2 is a diagram illustrating a hardware configuration of the control device according to the embodiment. FIG. 3 is a diagram illustrating the functional configuration of the control device according to the embodiment. FIG. 4 is a diagram showing changes in the coagulation state of the agarose solution. FIG. 5 is a flowchart illustrating the flow of the test process in the blood coagulation test device. 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 as viewed from above. FIG. 7B is a perspective view of the upper unit as viewed from below. FIG. 8A is an exploded perspective view of the stirring motion transmission mechanism. FIG. 8B is a partial decomposition view of the stirring motion transmission mechanism and a perspective view of the container. FIG. 9A is a perspective view of the lower unit as viewed from the front left side. FIG. 9B is a perspective view of the lower unit as 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 upper unit and the lower unit assembled. FIG. 12A is a left side view showing a state in which the upper unit is separated from the lower unit. FIG. 12B is a front view showing a state in which the upper unit is separated from the lower unit. FIG. 13 is a flowchart illustrating the flow of operation of the blood coagulation test apparatus according to the second embodiment. FIG. 14A is a diagram showing a state in which the mounting table is housed in the blood coagulation test device. FIG. 14B is a diagram showing a state in which the mounting table is slid to the front side and the container can be installed on the mounting table. FIG. 15A is a diagram showing a state in which the holding pin is inserted into the stirring portion 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 agitated by the stirring unit. FIG. 16 is a diagram illustrating an operation of converting the rotary motion of the gear into the swing motion of the rocking plate by the stirring control mechanism. FIG. 17A is a diagram showing a rotational state of the rocking plate when the sliding plate moves to the front side. FIG. 17B is a diagram showing a rotational state of the rocking plate when the sliding plate is not moving. FIG. 17C is a diagram showing a rotational state of the rocking plate when the sliding plate moves to the rear surface side. FIG. 18A is a diagram showing the position of the stirring unit during a normal blood coagulation test. FIG. 18B is a diagram showing a state in which the viscoelasticity of the blood sample in the container is increased and the stirring portion is increased. 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 portion. FIG. 20B is a diagram showing a state in which the pressing plate presses the stirring portion when the holding pin is pulled out from the stirring portion. FIG. 21 is a diagram illustrating a torsion coil spring used in the embodiment of the second embodiment. FIG. 22 is a perspective view illustrating a double container. FIG. 23 is a cross-sectional view taken along the line AA in a state where the stirring pin is housed in the double container. FIG. 24 is a graph showing the measurement results of blood samples using the same spring. FIG. 25 is a diagram for explaining a 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.

Hereinafter, embodiments of the present invention will be described with reference to the drawings. The configurations of the following embodiments are examples, and the present invention is not limited to the configurations of the embodiments.

[Embodiment]
FIG. 1 is a schematic view illustrating the configuration of a blood coagulation test device. The blood coagulation test device 10 includes a control unit 1, an elastic body 2, a stirring unit 3, a container 4, and a sensor 5. The blood coagulation test device 10 stirs the blood sample contained in the container 4 in the stirring unit 3 via the elastic body 2 under the control of the control unit 1. Then, the blood coagulation test device 10 measures the state of blood coagulation and the like by calculating the rotation angle of the stirring unit 3 from the image captured by the sensor 5. The blood coagulation test device 10 includes a control device (not shown) that controls the processing of the control unit 1 and the sensor 5.

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

The elastic body support portion 1B makes a predetermined reciprocating rotary motion by driving the servomotor 1A. Further, the elastic body support portion 1B supports the elastic body 2 and transmits a predetermined reciprocating rotational motion to the elastic body 2. The elastic body support shaft 1C supports the elastic body 2 as a rotation axis of a predetermined rotational movement transmitted from the elastic body support portion 1B by the elastic body 2.

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

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

The elastic body 2 is not limited to the example of FIG. The elastic body 2 may be deformable according to a force received from the stirring unit 3 by transmitting a predetermined reciprocating rotational motion to the stirring unit 3, and for example, a wire spring may be used instead of the coil spring. Further, the elastic body 2 may be composed of a plurality of elastic bodies.

The stirring unit 3 stirs the blood sample in the container 4 by a predetermined reciprocating rotary motion transmitted from the control unit 1 via the elastic body 2. As blood coagulation progresses, the rotation angle of the stirring unit 3 becomes smaller than the rotation angle related to the predetermined reciprocating rotational movement. In FIG. 1, the stirring unit 3 includes a rotation transmitting unit 3A, a bearing 3B, a stirring pin 3C, and a pinhole 3D.

The rotation transmission unit 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 unit 3A can reciprocate in the circumferential direction with the axis of the stirring pin 3C as the rotation axis. The rotation transmission unit 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 that position. Since the rotation angle can be easily adjusted by controlling the rotation at a position away from the rotation axis, the rotation transmission unit 3A can accurately transmit a predetermined reciprocating rotation motion to the stirring pin 3C.

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

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

The stirring pin 3C is immersed in the container 4 and agitates the blood sample in the container 4 by a predetermined reciprocating rotation operation transmitted from the rotation transmission unit 3A. As the coagulation of blood in the container 4 progresses, the rotation angle of the stirring pin 3C becomes smaller due to the reaction force to the predetermined reciprocating rotation operation. Further, since the rotation transmission unit 3A reciprocates in conjunction with the stirring pin 3C, the rotation angle of the rotation transmission unit 3A becomes small as in the stirring pin 3C. When the movement of the rotation transmission unit 3A does not follow the predetermined reciprocating rotation 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 rotation 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 is coagulated. The control device determines the depth of immersion in the container 4 or the distance between the stirring pin 3C and the inner wall of the container 4 according to the coagulation state of blood in the container 4, and raises and lowers the stirring pin 3C. The stirring pin 3C is an example of a “stirring unit”.

The pinhole 3D serves as a mark indicating the reference position of the rotation transmission unit 3A. By detecting and analyzing the movement of the pinhole 3D by the sensor 5, it is possible to measure the rotation angle of the rotation transmission unit 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 unit 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 obtained from the length of the diameter from the rotation axis to the pinhole 3D and the moving distance of the pinhole 3D detected by the sensor 5.

The pinhole 3D is not limited to the hole provided in the rotation transmission unit 3A. For example, the pinhole 3D may be a concave portion or a convex portion provided at a position detectable from the sensor 5. In this case, the sensor 5 can measure the rotation angle of the stirring pin 3C by analyzing the image in which the concave portion or the convex portion is captured. That is, the pinhole 3D may be in a form that can be detected by the sensor 5 as a mark indicating the reference position.

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

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 and transmit the captured image to the control device so that the control device calculates the rotation angle of the stirring pin 3C. The calculated rotation angle information may be displayed on the display unit 17.

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 with a camera or the like possessed by the electronic device, analyze the captured image, and calculate the rotation angle of the stirring pin 3C. The electronic device may control the processing of the control unit 1 and the sensor 5 as a control device.

<Control device configuration>
(Hardware configuration)
FIG. 2 is a diagram illustrating a hardware configuration of the control device according to the embodiment. The control device 6 is connected to the Internet N via 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, or the like. A computer including a NIC (Network Interface Card) 15, an imaging unit 16, a display unit 17, and an input unit 18 to be connected.

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

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

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

(Functional configuration)
FIG. 3 is a diagram illustrating the functional configuration of the control device according to the embodiment. The control device 6 reads the program stored in the auxiliary storage device 14 into the RAM 12 and executes it by the CPU 11, so that the control information database D11, the correction information database D12, the data receiving unit F11, the analysis unit F12, and the control device 6 are executed. It functions as a computer including the correction unit F13.

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

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

The correction information database D12 is a database that stores information regarding calibration for each elastic body 2. Calibration is performed in order to measure the deviation from the measured value by the reference elastic body (hereinafter, also referred to as the reference elastic body) for each elastic body 2 and to match the measurement accuracy by each elastic body 2 with the reference elastic body. , It is a process of correcting the measured value based on the measured deviation. For example, the correction information database D12 has a table for storing information on the deviation of the measured value from the 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 unit F11 receives data related to the reciprocating rotational movement of the stirring unit 3 detected by the sensor 5. The data to be received is, for example, pinhole 3D image information.

The analysis unit F12 analyzes the data received by the data reception unit F11 and calculates the rotation angle of the stirring unit 3. When controlling the rotation angle of the stirring unit 3 to be constant, the analysis unit F12 controls the servomotor 1A, such as the rate of increase in the driving force of the servomotor 1A, based on the calculated rotation angle of the stirring unit 3. Generate the information used for. The 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, the information for identifying the elastic body 2 used for the inspection may be input from the input unit 18. The correction unit F13 can acquire the correction information related to the elastic body 2 to be used from the correction information database D12 by using the input identification information. The information corrected by the correction unit F13 may be displayed on the display unit 17.

<Calibration of elastic body>
Here, the calibration of the elastic body 2 will be described. Even if the blood coagulation test device 10 tests the same blood sample, the 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 when a predetermined solution is used for each elastic body 2, and collects the difference from the measurement result when the reference elastic body is used as correction information. The collected measurement results and correction information of the reference elastic body are stored in the correction information database D12. The blood coagulation test device 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 the agarose solution. The gelation temperature of agarose ranges from about 34.5 ° C to 37.5 ° C. The vertical axis of each graph shown in FIG. 4 indicates the hardness of the agarose solution, and the bulge of the graph increases as the hardness increases. The horizontal axis of each graph indicates the time from the start of measurement. FIG. 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%, respectively. Is done.

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

The blood coagulation test device 10 measures each elastic body 2 by collecting correction information between the reference elastic body and each elastic body 2 in advance under various conditions of the temperature and concentration at the start of coagulation of the agarose solution. It is possible to correct the variation of the result with high accuracy.

<Processing flow>
The processing flow of the blood coagulation test apparatus 10 of the present embodiment will be described. In the processing flow described here, the blood coagulation test device 10 agitates the blood sample in the container 4 by the stirring unit 3 by driving the servomotor 1A, and measures the rotation angle of the stirring unit 3. At this time, the servomotor 1A transmits a predetermined reciprocating rotary motion to the stirring unit 3 via the elastic body 2. Further, the blood coagulation test device 10 corrects the measurement result based on the correction information regarding the deviation of the elastic body 2 to be used from the reference elastic body measured in advance. The contents and order of the processes described are examples, and it is preferable that the contents and order of the processes appropriately adopted according to the embodiment.

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

First, in step S101, the control device 6 activates the servomotor 1A. The control device 6 controls the servomotor 1A based on the information stored in the control information database D11. The servomotor 1A transmits a predetermined reciprocating rotary motion to the stirring unit 3 via the elastic body 2 in response to a command from the control device 6. The control device 6 may, for example, cause the servomotor 1A to transmit a reciprocating rotary motion within a range of a certain angle.

When the servomotor 1A is started, the stirring unit 3 stirs the blood sample in the container 4. As blood coagulation progresses, the reciprocating rotation of the stirring unit 3 does not follow the transmitted reciprocating rotational movement, and the rotation angle becomes smaller. The sensor 5 detects the reciprocating rotary motion of the stirring unit 3 and transmits data related to the reciprocating rotary motion, 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 the 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 related to the elastic body 2 in use from the correction information database D12. The correction unit F13 corrects the rotation angle calculated by the analysis unit F12 based on the acquired correction information.

In step S105, the control device 6 outputs the rotation angle data corrected by the correction unit F13 as a measurement result. The control device 6 can output the measurement result to the display unit 17. Further, the control device 6 may store the measurement result in the auxiliary storage device 14. Further, the control device 6 raises and lowers the stirring unit 3 according to the output rotation angle, and controls the depth at which the stirring unit 3 is immersed in blood, the distance between the stirring unit 3 and the inner wall of the container 4, and the like. You may.

<Effect>
With the blood coagulation test device 10 of the present embodiment, it is possible to obtain a resolution according to the test target by appropriately controlling the rotation speed and the rotation angle transmitted to the stirring unit 3. Further, by reducing the size, weight, and price of the servomotor 1A, the cost for performing a blood coagulation test can be suppressed. Further, the blood coagulation test apparatus 10 can perform a test according to each blood sample by controlling the servomotor 1A according to the blood sample instead of stirring a plurality of blood samples by the same control. is there.

Further, the blood coagulation test device 10 increases the rotation angle of the stirring unit 3 under the control of the servomotor 1A when the blood coagulation progresses and the stirring unit 3 does not reciprocate, thereby viscoelasticity at high viscosity. It is possible to analyze the elastic state. Further, by raising and lowering the stirring unit 3 and controlling the depth at which the stirring unit 3 is immersed in blood or the distance between the stirring unit 3 and the inner wall of the container 4, the resolution is further improved and the viscoelasticity at high viscosity is achieved. It is 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 a predetermined reciprocating rotary motion transmitted from the servomotor 1A to the stirring unit 3 according to the blood sample or the preparation to be tested. can do.

Further, by correcting the variation in the measurement result for each elastic body 2 to be used based on the correction information measured in advance, it is possible to reduce the influence on the measurement result due to the difference in the elastic body 2 to be used.

[Second Embodiment]
<Structure of blood coagulation test apparatus according to the second embodiment>
6A and 6B show the configuration of the blood coagulation test apparatus according to the 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. The blood coagulation test device 100 includes a housing 110, an upper unit 200, and a lower unit 300. Further, the blood coagulation test device 100 includes a control device (not shown) and controls the operation of each mechanism included 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 operation of each mechanism included in the upper unit 200 and the lower unit 300 is driven by a command of the control device according to the second embodiment.

The housing 110 is provided on a substantially square bottom plate 111, columns 112 erected at the four corners of the bottom plate 111, panels 113 provided on each of the front surface, the rear surface, the upper right surface, the left surface, and the upper surface, and the lower right surface. It is formed in a box shape by a connection panel 114 having an insertion port through which cables for connecting to a power source or an external device are inserted. The housing 110 houses the upper unit 200 and the lower unit 300. Further, the housing 110 is provided with a handle 115 on the upper panel 113 for enabling portability. Further, the front panel 113 is provided with an opening 113A for installing and taking out a container containing a blood sample. The blood sample to be tested includes plasma obtained by centrifugation or the like of blood.

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

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

The elevating mechanism 210 includes an elevating motor 211, a shaft 212, and a support shaft guide 213. The elevating motor 211 has, for example, an internal threaded portion that is screwed with the fully threaded shaft 212. The female thread portion can be rotated around the shaft 212 by driving the elevating motor 211. The upper unit 200 can be raised and lowered to a desired height by rotating the female screw portion. The support shaft guide 213 is provided with a support shaft insertion hole 213A through which a support shaft (not shown) for the lower unit 300 to support the upper unit 200 is inserted. As shown in FIG. 7B, the support shaft guide 213 has a tubular portion on the lower side of the bottom plate 215 of the upper unit, and the support shaft is inserted into the support shaft insertion hole 213A. By inserting the support shaft through the support shaft guide 213, the upper unit 200 can be raised and lowered in the vertical direction. In the example of FIG. 7A, the support shaft guide 213 is arranged on the right side and the left side of the elevating motor 211. The support shaft guides 213 are not limited to the cases where they are provided at two locations on the right side and the left side of the elevating motor 211, and may be provided at, for example, diagonal corners of the upper unit bottom plate 215, or at two or more locations. It may be provided at a position.

The stirring control mechanism 230 includes a stirring motor 231, a gear 232, and a sliding plate 233. The stirring motor 231 drives the rotation of the gear 232. The gear 232 converts the rotary motion into a linear motion and slides the sliding plate 233 back and forth. The sliding plate 233 slides in the front-rear direction in response 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 described in detail with reference to FIG. 8A.

8A and 8B show the configuration of the stirring motion transmission mechanism 240. FIG. 8A is an exploded perspective view of the 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 unit 248, and an elastic body 249. A rocking transmission unit 250, a second pedestal 251 and a holding pin 252 are provided.

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

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

FIG. 8B is a partial decomposition view of the stirring motion transmission mechanism 240 and a perspective view of the container. Each member from the rocking plate 241 to the holding pin 252 shown in FIG. 8A is assembled as shown in FIG. 8B. The holding pin 252 holds the stirring unit 30 and swings the stirring unit 30 to cause the container 4 to swing.
The blood sample in 0 is stirred. The holding pin 252 is inserted into the holding pin insertion hole 30A provided in the upper part of the stirring unit 30. The stirring unit 30 rotates in conjunction with the holding pin 252 to stir the blood sample in the container 40. The coagulation of the blood sample in the container 40 exerts a force for suppressing the swing of the holding pin 252, and the rotation angle of the holding pin 252 increases or decreases according to the viscosity of the blood sample in the container 40. Further, the stirring unit 30 includes a flange 30B. The flange 30B is used when the blood coagulation test is completed and the holding pin 252 is pulled out from the stirring unit 30. By raising the holding pin 252 while holding the flange 30B, the holding pin 252 can be pulled out from the stirring unit 30.

The rotation angle measuring mechanism 270 in FIG. 7A includes a sensor plate 271 and a light source unit 272. The rotation angle measuring mechanism 270 is a mechanism for measuring the rotation angle of the stirring unit 30. The sensor plate 271 includes an optical sensor in which light receiving elements are linearly arranged. The light source unit 272 includes a light source (not shown) such as an LED (Light Emitting Diode) that irradiates the light sensor of the sensor plate 271. In the second embodiment, the rotation angle measuring mechanism 270 detects the rotational movement of the swing measuring pin 250B swinging on the optical sensor in conjunction with the stirring operation of the blood sample in the container 40. The rotation angle measuring mechanism 270 can measure the rotation angle of the stirring unit 30 that swings in conjunction with the swing measuring pin 250B by measuring the rotation angle of the swing measuring pin 250B. The blood coagulation test device 100 accurately measures the rotation angle of the stirring unit 30 by measuring the rotation angle of the swing measuring pin 250B that swings at a position away from the rotation axis of the stirring unit 30 by the rotation angle measuring mechanism 270. It 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 as viewed from the front left side. FIG. 9B is a perspective view of the lower unit 300 as viewed from the left rear side. The lower unit 300 includes a mounting base slide mechanism 310 and a holding pin pull-out mechanism 320. Further, the lower unit 300 includes a support shaft 331 for connecting to the upper unit 200 and an upper unit support base 332. The upper unit support base 332 is provided with a fitting hole 332A for fitting and fixing the lower end of the shaft 212. 9A and 9B show a state in which the lower unit 300 is arranged on the bottom plate 111 of the housing 110.

The mounting table slide mechanism 310 shown in FIG. 9B includes a mounting table 311, a ball screw 312, a slide motor 313, and a linear guide 314. The mounting table 311 includes a container installation portion 311A (FIG. 9A) which is a cylindrical recess capable of accommodating the container 40. FIG. 9A shows a state in which the container 40 is installed in the container installation unit 311A and the stirring unit 30 is housed in the container 40. The ball screw 312 is screwed into the mounting table 311, and the rotation of the ball screw 312 causes the mounting table 311 to slide in the front-rear direction. The slide motor 313 drives the rotary motion of the ball screw 312. The linear guide 314 guides the linear movement of the mounting table 311 in the front-rear direction. The mounting table slide mechanism 310 only needs to be able to convert the rotary motion of the motor into a linear motion and slide the mounting table 311 to a position where the container 40 can be installed. In addition to the ball screw mechanism, a timing belt or the like is used. It may be various linear motion mechanisms. The blood coagulation test device 100 may include a heat retention device (not shown) for keeping the container 40 housed in the mounting table 311 warm, and the heat retention device keeps the blood sample constant during the coagulation test. Can be kept at temperature.

The holding pin pulling mechanism 320 shown in FIG. 9A includes a guide plate 321 and a holding plate 322, and a solenoid 323. The guide plate 321 is arranged above the container installation portion 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 portion 30. When the holding pin 252 is pulled out from the holding pin insertion hole 30A, the holding plate 322 rotates around the end connected to the solenoid 323 to a position where the flange 30B of the stirring portion 30 can be held. When the pressing plate 322 presses the flange 30B of the stirring portion 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 maintains a state of being rotated to a position where the flange 30B of the stirring unit 30 is pressed, and the holding pin 252 is pulled out from the stirring unit 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 in the vertical direction on both sides of the rear end of the mounting table 311. The support shaft 331 supports the upper unit 200 by being inserted through the support shaft guide 213 of the upper unit 200.

FIG. 11 is a plan view of the upper unit 200 and the lower unit 300 in an assembled state. The support shaft guides 213 are arranged at two locations on both sides of the elevating motor 211 at substantially the center of the front surface and the rear surface of the blood coagulation test device 100. The upper unit 200 is supported by support shafts 331 at two locations near the center in the plan view of the blood coagulation test device 100, and the upper unit 200 can be stably moved up and down by the raising and lowering 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 a state in which the upper unit 200 is 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 the stirring unit 30 are installed in the container installation unit 311A of the mounting table 311, the holding pin 252 is inserted into the holding pin insertion hole 30A provided on the upper surface of the stirring unit 30 by lowering the upper unit 200. Will be done. 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 and fixed in the fitting hole 332A provided in the upper unit support base 332.

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

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

FIG. 14A is a diagram showing a state in which the mounting table 311 is housed in the blood coagulation test device 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 installed on the mounting table 311. The mounting table 311 can slide in the direction of the arrow X1 shown in FIGS. 14A and 14B by driving the rotational movement of the ball screw 312 by the slide motor 313. The mounting table 311 can move linearly by sliding on the linear guide 314. In step S201, the mounting table slide mechanism 310 slides the mounting table 311 to the front side to a position where the container 40 can be installed, as shown in FIG. 14B. When the container 40 and the stirring unit 30 are installed, the mounting table slide mechanism 310 slides the mounting table 31 to the rear surface 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 unit 30. The holding pin 252 has substantially the same diameter as the holding pin insertion hole 30A, and the stirring unit 30 can be held 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 unit 30 held by the holding pin 252 is taken out from the container 40. When the stirring unit 30 is taken out from the container 40, the blood sample can be injected into the container 40. Here, the elevating operation of the upper unit 200 by the elevating mechanism 210 will be described 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 unit 30 by lowering the upper unit 200. FIG. 15B is a diagram showing a state in which the upper unit 200 is raised to a position where the blood sample in the container 40 can be agitated by the stirring unit 30. The elevating mechanism 210 can elevate the upper unit 200 by rotating the female screw portion screwed with the shaft 212 provided inside the elevating motor 211 by driving the elevating motor 211. The elevating mechanism 210 can elevate 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 where the stirring unit 30 can be held. In step S203, the elevating mechanism 210 raises the upper unit 200 further than the state shown in FIG. 15B, and raises the stirring unit 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 by the process of step S203. The mounting table slide mechanism 310 slides the mounting table 311 toward the front side again. The stirring unit 30 in the container 40 is in a state of being taken out by the holding pin 252 by 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 slide mechanism 310 slides the mounting table 311 toward the rear surface side and returns it to the original position.

In step S205, the elevating mechanism 210 adjusts the height of the stirring unit 30 so that the blood sample in the container 40 can be stirred. The elevating mechanism 210 may, for example, lower the upper unit 200 to a height at which the tip of the stirring unit 30 does not come into contact with 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 the rocking motion of the rocking plate 241. Next, the stirring motion transmission mechanism 240 transmits the swinging plate 241 swinging motion to the swinging transmitted portion 250. The rocking transmitted portion 250 further transmits the transmitted rocking motion to the holding pin 252. The stirring unit 30 held by the holding pin 252 agitates the blood sample in the container 40 by swinging in conjunction with the holding pin 252. The rotation angle measuring mechanism 270 measures the rotation angle of the stirring unit 30 and transmits the measurement result to the control device according to the second embodiment. Here, the stirring control mechanism 230, the stirring motion transmission mechanism 240, and the rotation angle measuring mechanism 270 will be described with reference to FIGS. 16, 17A, 17B, and 17C.

FIG. 16 is a diagram illustrating an operation of converting the rotational movement of the gear 232 into the swinging motion of the rocking plate 241 by the stirring control mechanism 230. The stirring control mechanism 230 rotationally drives the gear 232 by the stirring motor 231. The rotational motion of the gear 232 is converted into a reciprocating motion of the sliding plate 233 in the arrow Y direction. 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 motion of the sliding plate 233, the rocking plate 241 swings 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. Further, by controlling the rotation speed of the stirring motor 231, it is possible to appropriately control the rotation speed of the rocking plate 241, that is, the rotation speed of the stirring motion transmitted to the stirring unit 30.

17A to 17C illustrate the operation of transmitting the rocking motion of the rocking plate 241 to the rocking transmitted portion 250 by the stirring motion transmitting mechanism 240. FIG. 17A is a diagram showing a rotational state of the rocking plate 241 when the sliding plate 233 is moved to the front side. FIG. 17B is a diagram showing a rotational state of the rocking plate 241 when the sliding plate 233 is not moving. FIG. 17C is a diagram showing a rotational state of the rocking plate 241 when the sliding plate 233 moves to the rear surface side. The rocking plate 241 repeats the states of FIGS. 17A and 17C with the state of FIG. 17B as a base point as shown in FIGS. 17A, 17B, 17C, 17B, 17A, 17B ...

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

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

Further, in the blood coagulation test performed in step S206, the rotation angle of the stirring motion (rotation angle of the rocking plate 241) transmitted to the stirring unit 30 is controlled by the stirring control mechanism 230. When the viscoelasticity of the blood in the container 40 becomes high, even if the rotation angle of the rocking plate 241 is increased, the stirring unit 30 receives a force from the blood in the direction opposite to the rotation of the rocking plate 241. 30 The rotation angle becomes smaller. In this case, the stirring unit 30 is raised by the elevating mechanism 210 to reduce the depth at which the stirring unit 30 is immersed in the blood sample, or increase the distance between the stirring unit 30 and the inner wall of the container 40. The force received by the stirring unit 30 from the blood sample is suppressed. When the force received by the stirring unit 30 from the blood is suppressed, the stirring unit 30 raises the stirring unit 30 when stirring blood having the same viscoelasticity as compared with the case where the stirring unit 30 is stirred at a normal depth. Can rotate at a larger angle. Therefore, the blood coagulation tester 100 can more accurately measure the change in viscoelasticity even for blood in the highly viscoelastic region by raising the stirring unit 30. The height of the stirring unit 30 can be freely set to move up and down, and the region where the stirring unit 30 is immersed in blood can be controlled. For example, the height of the stirring unit 30 can be increased between 0.1 mm and 20 mm under the control of 0.1 mm.

The blood coagulation tester 100 measures the viscoelasticity by rotating the stirring unit 30 when the viscoelasticity of blood is low, and raises the stirring unit 30 at a predetermined timing when the rate of change in the viscoelasticity decreases. .. The predetermined timing can be a timing at which the accuracy of measuring the change in viscoelasticity is lowered. For blood samples with high viscoelasticity, from the timing when measurement is started,
The stirring unit 30 can be raised. It is also possible to measure without changing the depth of immersion in the blood sample with the stirring unit 30 raised. By raising the stirring unit 30, the change in viscoelasticity can be measured more accurately even in the highly viscoelastic region. As described above, the blood coagulation test apparatus 100 uses an elastic body 249 having a stronger elastic force than the elastic body 249 when measuring the viscous elasticity of the blood in the low viscoelastic region with respect to the blood in the high viscoelastic region. Instead, the elastic body 249 having the same strength can be used to accurately measure the change in viscoelasticity from the low viscoelastic region to the high viscoelastic region.

FIG. 18A is a diagram showing the position of the stirring unit 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 is increased and the stirring unit 30 is increased. In FIG. 18A, the stirring unit 30 is in a state in which the entire tapered tip portion is immersed in the blood sample in the container 40. When the viscoelasticity of the blood sample in the container 40 becomes high, the rotation angle of the stirring unit 30 or the rate of change of the rotation angle decreases, and it becomes difficult to measure the viscoelasticity, as shown in FIG. 18B, the elevating mechanism 210 The stirring unit 30 may be raised by the above method. Alternatively, in a normal human sample, the height of the stirring unit 30 is analyzed at a steady position, and when the blood of a blood sample (for example, mouse or rat) that becomes more viscoelastic than a human when the blood coagulates, the blood is analyzed. The measurement may be performed at a position where the stirring unit 30 is raised.

In the analysis of the viscoelasticity of blood coagulation with this device, the following analysis of blood samples with high viscoelasticity and low viscoelasticity is performed.

Any pre-coagulation blood sample (also in humans, rats, mice, and other species) is added to the vessel 40 and the blood coagulation reaction is initiated in the vessel 40. At the start of measurement, it is mixed with the reagent, the blood coagulation reaction of the blood sample is started, and the viscoelasticity is increased. In the container 40, fibrin formation occurs due to the blood coagulation reaction, and thrombin produced by the coagulation reaction activates platelets. Activated platelets change morphology, extend pseudopodia, and platelets aggregate with each other.

For example, when blood coagulation is started by adding an exogenous reagent such as tissue factor or an endogenous reagent such as ellagic acid and calcium chloride to a blood sample anticoagulated with citric acid, it is insoluble with fibrin. Both clot formation (gel formation) and platelet aggregation cause an increase in viscoelasticity.

On the other hand, different viscoelastic regions may be measured depending on the purpose of the inspection. For example, when an inhibitor of platelet aggregation (such as cytochalasin D) is added to blood anticoagulated with citric acid in addition to calcium chloride and an extrinsic or endogenous activation reagent, platelet aggregation occurs. It does not occur, only the formation of fibrin lots occurs.

In this case, the maximum viscoelasticity correlates with the amount of fibrinogen in the blood sample, since the increase in viscoelasticity is not affected by platelets and is caused only by the viscoelasticity of fibrin lott. Naturally, since viscoelasticity reflects only fibrin lot formation, the measurement is in a relatively low viscoelastic region compared to the case where an inhibitor of platelet aggregation is not added, and the maximum viscoelasticity reached during the measurement is also low. Become.

Further, depending on the blood sample, different viscoelastic regions may be measured even if the same reagent is used. 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 blood coagulation is analyzed by adding calcium chloride and an extrinsic or endogenous activation reagent to blood anticoagulated with citric acid, platelet aggregation causes more mice and rats than humans. Since the increase in viscoelasticity occurs more strongly, even when blood coagulation is analyzed using the same reagent, it is required to measure a higher viscoelastic region in mice and rats than in humans. Also, in humans, in diseases such as thrombocytosis, the number of platelets may exceed 1 million / μL, and the measurement of the highly viscoelastic region is performed more accurately than in a normal human blood sample. Is required. On the contrary, in diseases such as thrombocytopenia, the number of platelets may be less than 10,000 / μL, and it is required to accurately measure the low viscoelastic region.

Thus, even for human blood samples, it may be necessary to analyze the high or low viscoelastic region depending on the purpose of the test, and even in different animal species, the change in higher viscoelasticity can be accurately measured. May be required.

When measuring blood viscoelasticity in a state where blood platelet function is inhibited as in FIBTEM of ROTEM assay (analysis, evaluation), the height of the stirring unit 30 is measured at a steady position, and when analyzing a normal human blood sample. For (for example, ROTEM EXTEM measurement), the position of the stirring unit 30 is raised for measurement, and when analyzing a highly viscoelastic blood sample (for example, rat, mouse, etc.), the rotation angle is widened and the stirring unit 30 is used. It can also be raised and measured. By controlling both the elevating and rotating angles of the stirring unit 30 in this way, it is possible to analyze a wider range of viscoelastic blood. As the stirring unit 30 rises, a part of the tapered tip portion is immersed. The depth at which the stirring unit 30 is immersed in the blood sample in the container 40 becomes shallow, and the rotation angle of the stirring unit 30 becomes a measurable size.

19A and 19B are diagrams illustrating a container 40 containing a blood sample. The container 40 is not limited to the cylindrical shape as shown in FIG. 8B. The shape may be any shape as long as it can accommodate the blood and change the depth of the stirring unit 30 that is immersed in the blood of 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 surface side from the switching portion 40A1 is smaller than the diameter of the cylindrical portion 40Aa on the opening side. Therefore, the distance between the stirring unit 30 and the inner wall of the container 40A can be easily changed by raising and lowering the stirring unit 30. FIG. 19B is a perspective view of a second modification of the container. The container 40B shown in FIG. 19B is a truncated cone-shaped container formed in a tapered shape toward the bottom surface side. By making the shape of the container 40B a truncated cone shape, it is possible to adjust the distance between the stirring unit 30 and the inner wall of the container 40B to a desired distance. Further, the inner peripheral surface of the container 40 (40A, 40B) may be provided with a striped groove perpendicular to the circumferential direction.

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

In step S207, the holding pin pulling mechanism 320 pulls out the holding pin 252 from the stirring unit 30 after the inspection is completed. The holding pin pulling mechanism 320 can pull out the holding pin 252 from the stirring unit 30 by holding the upper part of the stirring unit 30 and raising the upper unit 200 by the elevating mechanism 210. Here, the operation of pulling out the holding pin 252 from the stirring unit 30 by the holding pin pulling-out 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 unit 30.

FIG. 20A is a diagram showing a state in which the pressing plate 322 does not press the stirring unit 30. FIG. 20B is a diagram showing a state in which the pressing plate 322 presses the stirring unit 30 when the holding pin 252 is pulled out from the stirring unit 30. The pressing plate 322 receives a force in the direction of arrow X2 by energizing and stopping the energization of the solenoid 323, and changes the angle to the states shown in FIGS. 20B and 20A, respectively.

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

In the blood coagulation test device 100 of the second embodiment, the rotation speed and the rotation angle transmitted to the stirring unit 30 can be appropriately controlled by controlling the rotation speed of the stirring motor 231. Further, by raising and lowering the stirring unit 30 and controlling the depth at which the stirring unit 30 is immersed in the blood to be inspected or the distance between the stirring unit 30 and the inner wall of the container 40, the low viscoelastic region to the high viscoelastic region It is possible to measure the viscoelasticity of blood with high accuracy in a wide range up to. Therefore, the test by the blood coagulation test device 100 can obtain the resolution according to the test target. Further, the blood coagulation test device 100 includes an operation mechanism such as an elevating mechanism 210, a mounting table slide mechanism 310, and a holding pin pull-out mechanism 320, and automation and simplification of the blood coagulation test are promoted.

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

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

(reagent)
Examples of the reagent include a reagent that activates extrinsic blood coagulation (tissue factor, tissue thromboblastin, etc.) and a reagent that activates endogenous blood coagulation (ellagic acid, silica, etc.). In addition, as a reagent, a platelet function inhibitory reagent (cytochalasin D, GPIIbIIIa receptor antagonist abciximab), a fibrinolysis inhibitor (aprotinin), or the like was added to a reagent that activates extrinsic blood coagulation or endogenous blood coagulation. It may be a thing.

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

Further, from the viewpoint of storage, it is desirable that the measuring cup portion 401 for storing the reagent stores the reagent and is sealed and sealed with an aluminum film or the like. It is desirable that the seal that seals the measuring cup portion 401 be easily removed by the measurer before injecting the blood sample to be measured.

(Stirring pin)
The stirring pin housed in the stirring pin accommodating portion 402 is a tip portion for stirring 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 described with reference to FIG.

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

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

When the diameter of the tip of the stirring pin 500 is the same, as in the stirring pin 500A and the stirring pin 500B, the stirring pin 500B having a longer (deeper) tip immersed in the blood sample coagulates even if the blood sample is the same. Due to the increase in viscoelasticity due to the above, a force larger than that of the stirring pin 500A is received. Further, when the length of the tip portion of the stirring pin 500 is the same as in the stirring pin 500A and the stirring pin 500C, the diameter of the tip portion immersed in the blood sample is larger, and the inside of the measuring cup portion 401 is larger than the stirring pin 500A. The stirring pin 500C, which is close to the wall, receives a larger force than the stirring pin 500A due to the increase in viscoelasticity due to coagulation, even for the same blood sample.

That is, when measuring a blood sample having low viscoelasticity, or when measuring the viscoelasticity change of fibrin alone by adding a coagulation activating reagent and a platelet inhibitor as reagents, the tip of the stirring pin 500 is longer. The stirring pin 500 having a larger tip diameter may be arranged in the stirring pin accommodating portion 402. On the other hand, when measuring a highly viscoelastic blood sample, for example, when measuring human fibrinogen hyperplasia or thrombocytosis, or animal (rat, mouse blood), the tip to be immersed in the blood sample. A stirring pin 500 having a shorter tip and a smaller tip diameter may be arranged in the stirring pin accommodating portion 402.

For the measurement of a blood sample having a lower viscoelasticity (for example, evaluation of a change in viscoelasticity due to fibrin formation in a diluted blood state), a stirring pin 500B or a 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 is possible to analyze the decrease in the amplitude of the stirring pin 500.

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

Although the case where the stirring pins 500 having different shapes are used has been described in FIG. 23, the same stirring pins 500 may be used and the measuring cup portion 401 of the container 400 having a different shape may be used. .. For example, for the evaluation of a blood sample having low viscoelasticity, the one having a smaller inner diameter of the measuring cup portion 401 is used, and for the evaluation of a blood sample having high viscoelasticity, the one having a larger inner diameter of the measuring cup portion 401 is used. By doing so, it becomes possible to measure according to the viscoelasticity of the blood sample.

Further, in the first modification, it is assumed that the stirring pin 500 is shaken to measure the decrease in amplitude and the coagulation of the blood sample is examined, but the container 400 is shaken instead of the stirring pin 500. You may. In this case, since the stirring pin 500 follows the swing of the container 400 according to the coagulation of the blood sample, the increase in the amplitude of the stirring pin 500 may be measured.

(Measurement processing)
The measurement process using the two containers is carried out according to the operation flow of the blood coagulation test apparatus shown in FIG. With reference to FIG. 13, a portion of the process using the two containers, which is different from the case where the container having one storage portion is used, will be described.

In step S201, the agitation pin 500 housed in the container 400 and the agitation pin accommodating portion 402 is installed in the container installation portion 311A (FIG. 9A). In this case, the measuring cup portion 401 can store the reagent used for the measurement.

In step S202, the holding pin 252 (FIGS. 8B, 15A, etc.) is inserted into the holding pin insertion hole provided in the upper part of the stirring pin 500 to hold the stirring pin 500. In step S203, the stirring pin 500 rises together with the holding pin 252.

In step S204, the blood sample is injected into the measuring cup portion 401. When the reagent is stored in the measuring cup portion 401 and is sealed with a seal, the measurer may remove the seal, inject a blood sample, and stir by pipetting. Further, the measurer may inject the reagent together with the blood sample when the reagent is not stored in the measurement cup portion 401.

In step S205, the stirring pin 500 is inserted into the measuring cup portion 401 instead of the stirring pin accommodating portion 402, and the height is adjusted 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 the stirring pin 500 are taken out.

In the first modification, 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 in a state of being housed together with the blood sample in the measuring cup portion 401. The used container 400 taken out from the blood coagulation tester 100 is discarded.

(Action effect of modification 1)
In the double container, the shape of the stirring pin 500 is changed according to the type of the reagent stored in the measuring cup portion 401 and the characteristics of the blood sample to be measured. That is, in a blood sample having low viscoelasticity, the shape of the stirring pin 500 may be such that the portion immersed in the blood sample is large. Further, the swing 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 a blood sample having high viscoelasticity, the swing angle of the stirring pin 500 may 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 is possible to measure in a wider viscoelastic region.

Further, the double container 400 has a measurement cup portion 401 and a stirring pin accommodating portion 402, and can store reagents and a stirring pin 500 according to the characteristics of the blood sample in advance. As a result, the measurer can reduce the trouble of injecting the reagent. Further, by accommodating the stirring pin 500 having a shape corresponding to the reagent or the blood sample, the measurer can perform the measurement using an appropriate stirring pin 500.

[Modification 2 of the second embodiment]
In the second embodiment described above, the blood sample is measured according to the viscoelasticity by the height of the stirring unit 30 determined before the measurement, the shape of the stirring unit 30, and the amplitude angle transmitted to the stirring unit 30. .. Moreover, it is assumed that these settings are not changed during the measurement of the blood sample. On the other hand, the modified example 2 shows an example in which the amplitude angle transmitted to the stirring unit 30 is changed during the measurement. The amplitude angle transmitted to the stirring unit 30 is the rotation angle of the rocking plate 241 and the rocking transmission unit 248 controlled by the stirring control mechanism 230, and corresponds to the “rotation angle for reciprocating the elastic body”. .. Although the modified example 2 describes an example in which the stirring unit 30 is used, the stirring pin 500 of the modified example 1 may be used.

Here, the results of measuring high viscoelastic and low viscoelastic blood samples with the same spring will be described with reference to FIG. 24. FIG. 24 is a measurement result of a blood sample using the same spring. FIG. 24A is a graph showing the measurement results of a highly viscoelastic blood sample. FIG. 24B is a graph showing the measurement results of a blood sample having low viscoelasticity. In each graph, the vertical axis is the measured amplitude angle of the stirring unit 30. The horizontal axis is the elapsed time from the start of measurement. In the measurement of a blood sample having high viscoelasticity, the amplitude angle of the stirring unit 30 decreases to the amplitude after coagulation at an early stage, and it is difficult to further measure the change in coagulation. In the measurement of the blood sample with low viscoelasticity, the amplitude angle of the stirring unit 30 does not decrease so much, and the change in amplitude due to blood coagulation is smaller than that of the blood sample with high viscoelasticity.

Therefore, in the measurement of the blood sample having high viscoelasticity, the blood coagulation test device 100 of the second modification increases the amplitude angle transmitted to the stirring unit 30 during the measurement according to the change in viscoelasticity after the start of measurement. Therefore, the change in viscoelasticity can be detected more remarkably.

Specifically, the blood coagulation test apparatus 100 performs measurement by the following measurement algorithm. First, the blood coagulation test apparatus 100 starts the measurement by setting the amplitude angle (corresponding to the "first angle") at the start of the measurement transmitted to the stirring unit 30 to, for example, 10 degrees.

When the amplitude angle of the stirring unit 30 to be measured decreases to an angle for defining the coagulation start time (corresponding to the "second measurement angle"), the blood coagulation test device 100 determines the elapsed time from the start of measurement. Obtained as the coagulation start time. Further, in the blood coagulation test apparatus 100, when the amplitude angle of the stirring unit 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 measurement Is obtained as the coagulation rate. Decreasing to the first measurement angle or the second measurement angle can be determined, for example, by whether or not the average value of the three measurement values before and after is less than these angles.

When the amplitude angle of the stirring unit 30 to be measured becomes equal to or less than the angle for defining the coagulation rate, the blood coagulation test device 100 sets the amplitude angle transmitted to the stirring unit 30 to the amplitude angle at the start of measurement (first). Magnifies to an angle (corresponding to the "second angle") greater than (angle). Whether or not the solidification rate is equal to or less than the angle for defining the solidification rate can be determined, for example, by whether or not the average value of the measured values three times before and after is equal to or less than these angles. The amplitude angle (second angle) after enlargement can be, for example, twice the amplitude angle at the start of measurement.

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

(Action effect of modification 2)
In the measurement of a blood sample having high viscoelasticity, the blood coagulation test apparatus 100 can detect a change in the measured angle of the stirring unit 30 more remarkably by widening the amplitude angle transmitted to the stirring unit 30 during the measurement. Will be. In addition, the blood coagulation test apparatus 100 more prominently detects a change in viscoelasticity with respect to a blood sample having high viscoelasticity, so that the blood sample coagulates and becomes highly viscoelastic, and then fibrinolysis (thrombus dissolves). The reaction also improves sensitivity in the analysis of a condition in which viscoelasticity is slightly reduced.

[Other Embodiments]
Although the details have been described above based on the preferred embodiments of the present invention, the present invention is not limited to these specific embodiments, and various embodiments within the scope of the gist of the present invention are also included in the present invention. Is done. Further, each of the above-described embodiments and modifications merely shows one embodiment of the present invention, and each embodiment can be combined as appropriate.

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

In the second embodiment, an embodiment in which a spring having a higher sensitivity (that is, thinner / weaker) is selected as the elastic body 2 according to the measurement of the low viscoelastic region is shown. In addition, when measuring the high viscoelastic region, by controlling the rotation speed of the motor and programming to widen the rotation (amplitude) angle transmitted to the stirring unit that stirs the blood sample, the measurement can be performed in a wide viscoelastic region. Can be measured. For example, a method for analyzing blood viscoelasticity by thromboelastometry and measuring the amount of fibrinogen in blood in the presence of an antiplatelet agent is disclosed (Reference 1: US20090130645 method for assessing the fibrinogen contribution in coagulation). A gel (clot) consisting only of fibrin in the presence of an antiplatelet agent has lower viscoelasticity than a gel (clot) consisting of both activated platelets and fibrin in normal blood. Therefore, a gel consisting only of fibrin in the presence of an antiplatelet agent is suitable for measurement at about ± 4 to 10 degrees (8 to 20 degrees) with a thinner / weaker spring.

In the following description, the stirring unit indicates the container 40 shown in FIGS. 8, 19A and 19B, and the stirring unit 30 when the container 40A and the container 40B are used. Further, when the double container 400 shown in FIG. 22 is used, the stirring pin 500 is shown. The stirring unit is also referred to as a measuring pin in the examples.

When the high viscoelastic region is analyzed under the conditions of the spring and the amplitude angle having high sensitivity similar to the measurement of the low viscoelastic region, sufficient resolution and accuracy cannot be obtained in the high viscoelastic region. That is, the movement of the swing measuring pin may stop before the blood coagulates and reaches the maximum viscoelasticity. In order to prevent such a state, for example, in the measurement of the hyperviscoelastic region in the case of hypercoagulation (fibrinogen hyperplasia) or thrombocytosis, even a spring with higher sensitivity is transmitted to the stirring part (sway). By expanding the rotation angle of the swing motion (of the motion transmission unit 248) to ± 5 degrees or more, preferably ± 10 to 20 degrees (20 to 40 degrees), a stronger force is applied to the swing measurement pin via the spring. In addition, highly accurate measurement is possible in the highly viscoelastic region. Even in the blood coagulation test that leads to high viscoelasticity, the initial rotation angle of the stirring part should be ± 4 to 10 degrees, and after confirming the decrease in amplitude due to the start of blood coagulation, it should be expanded to ± 10 to 20 degrees. Is also possible. In this case, even if the rotation angle is widened to ± 10 to 20 degrees, the blood viscoelasticity has already started to increase, so that the rotation angle of the stirring part can be suppressed to about 5 degrees, and the stirring part is large. It is possible to prevent the gel structure of blood coagulation from being destroyed by the amplitude. When a weak spring that does not break the gel is used, the problem of breaking the fibrin gel does not occur even at a rotation angle of ± 10 degrees or more. However, when 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 unit is selected according to the sensitivity of the spring and the shape of the spring and the stirring unit. In this way, a device (system) using a highly sensitive spring that matches the measurement of the low viscoelastic region is used, and when the same device is used to measure the high viscoelastic region, the rotation speed of the motor is controlled. By changing (widening) the rotation angle of the oscillating motion transmitted to the spring and the stirring unit, it becomes possible to perform an assay (analysis, evaluation) in various viscoelastic regions with high sensitivity. As illustrated in each of the following examples, the rotation angle of the swing motion of the swing transmission section 248 transmitted to the spring and the stirring section is set to the viscoelastic state of the blood (including plasma) to be tested. It is possible to change it according to the purpose of the measurement.

In the measurement of highly viscoelastic blood samples, the use of more sensitive (ie, thinner / weaker) springs results in a faster decrease in the amplitude of the agitator and less accuracy in detecting changes in viscoelasticity. Therefore, the blood coagulation tester 100 increases the amplitude angle transmitted to the stirring unit at a predetermined timing during measurement in response to the decrease in the amplitude of the stirring unit. By widening the amplitude angle transmitted to the stirring unit, the amplitude of the stirring unit becomes large, and changes in viscoelasticity can be detected with high accuracy. The predetermined timing is, for example, the timing when the amplitude of the stirring unit becomes equal to or less than a predetermined angle. In this way, by widening the amplitude angle transmitted to the stirring unit during the measurement, the amplitude of the stirring unit also increases, and the change in viscoelasticity can be detected accurately even in the highly viscoelastic region.

<Example 1>
Example 1 is an example of a blood sample for the purpose of analyzing high viscoelasticity during blood coagulation, which is analyzed 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 application. Here, the measurement algorithm set by the user will be described with reference to FIG. FIG. 25 is a diagram for explaining a measurement algorithm. The vertical axis represents the amplitude angle (°) and the horizontal axis represents the time (sec). In the following description, the amplitude angle is described as ± 5 degrees (10 degrees), indicating the angle from the center of the amplitude in the positive and negative directions, and the actual swing width in parentheses.

The measurement algorithm is determined by setting various parameters. The various parameters define, for example, the amplitude angle at the start of measurement, the amplitude angle for defining the solidification start time, the amplitude angle for defining the solidification rate, the amplitude angle for defining the maximum viscoelasticity, and fibrinolysis. This is the amplitude angle, etc. In the first embodiment, the following measurement algorithm is 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 (A: solidification start time) when the amplitude drops to ± 4 degrees (8 degrees) (3) ) Measure the time (B: solidification start time + solidification rate) when the amplitude drops to ± 2 degrees (4 degrees) (4) The amplitude transmitted to the measurement pin when the amplitude drops to ± 2 degrees (4 degrees) Expand the angle to ± 10 degrees (20 degrees) (5) Measure the minimum width C of the amplitude (evaluate the maximum viscoelasticity)
(6) Detection of dissolution (fibrinolysis) of coagulated mass (D: re-spread of amplitude)

In the above algorithm, the processes (1) to (3) aim to evaluate the time required for blood to reach a certain viscoelasticity. The time A measured in the process (2) is the coagulation start time, which is the time from the start of the measurement to the start of blood coagulation. The time B measured in the process (3) is the total time of the solidification start time and the solidification rate. The coagulation rate is the time from the start of blood coagulation to the arrival of a certain level of viscoelasticity, and is calculated by subtracting time A from time B.

On the other hand, the treatments (4) to (6) aim to evaluate the minimum viscoelasticity and the subsequent spread (amplitude) of the viscoelasticity. Therefore, in the processes (1) to (3), the amplitude is narrow (10 degrees) and the time per amplitude is shortened to improve the resolution of the solidification time, and in the processes (4) and thereafter, the amplitude is ± 10 degrees. It is expanded to (20 degrees) and the time per amplitude is extended, but by applying a stronger force to the measurement pin, it is possible to improve the sensitivity / resolution of the higher viscoelastic region.

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

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

Next, the container 400 used in Example 1 will be described. In Example 1, the measurement was performed using two containers. First, venous blood was collected in a blood collection tube containing 3.2% sodium citrate. Humans were placed in a container 400 containing 20 μL of lyophilization reagent (INTEM reagent (intrinsic blood coagulation activation reagent: Team innovations GmbH)) and 20 μL of Startem reagent (calcium chloride reagent: Team innovations GmbH) in advance. 300 μL of citrate blood was added. The container 400 was kept warm at 37 degrees, and the swing transmission unit 248 was rocked within a range of ± 5 degrees (10 degrees) by controlling the stirring motor 231. The swing of the swing transmission unit 248 is transmitted to the measurement pin via the elastic body 249, the swing transmission unit 250, and the holding pin 252.

Next, the torsion coil spring used as the elastic body 249 will be described with reference to FIG. FIG. 21 is a diagram illustrating a torsion coil spring used in the embodiment of the second embodiment. Assuming that the wire diameter of the torsion coil spring is dmm and the number of coil turns is n, in Examples 1, 2, 3 and 6 of the second embodiment, the arm length a1 = 10 mm and the arm length a2 = 10 mm are used as the spring A. A torsion coil spring having an arm length b = 3 mm, a center diameter D = 2 mm, a wire diameter d = 0.12 mm, and a number of turns = 2 was used. The spring constant kTd of the spring A is calculated to be 0.0017 Nmm / deg from the following formula (formula 1). In Examples 4 and 5, as the spring B, a torsion coil having an arm length a1 = 10 mm, an arm length a2 = 10 mm, an arm length b = 3 mm, a center diameter D = 2 mm, a wire diameter d = 0.15 mm, and a number of turns = 6. A spring was used. The spring constant kTd of the spring B is calculated to be 0.0018 Nmm / deg from the following formula (formula 1).

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

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

Even with a wire spring, by changing the wire diameter d and arm length a ₁ and a _2, it is possible to change the spring constant KTD. When a torsion coil spring is used, the spring constant kTd can be changed more flexibly by further changing the center diameter D and the number of turns n, as shown by the above formula (Equation 1). It will be possible.

In Example 1, the amplitude of one reciprocation of the swing transmission unit 248 controlled by the stirring motor 231 was set to 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 transmission unit 250. The amplitude of the swing measurement pin 250B is measured four times at intervals of about 0.1 seconds from 0.4 seconds after the rotation of the swing transmission unit 248 is stopped at both ends, on the optical sensor 271A of the swing measurement pin 250B. The position of was measured and calculated from the average value of each of the four times at both ends of the rotation.

The measurement result is shown in FIG. Each measured parameter was as follows.
A: Time when the amplitude decreased to ± 4 degrees (8 degrees) (solidification start time) 2.63 minutes B: Time when the amplitude decreased to ± 2 degrees (4 degrees) (solidification start time + solidification rate) 4.10 Minute C: Minimum amplitude width 2.56 degrees

<Example 2>
Example 2 is an example of comparing the measurement results of different blood samples. In Example 2, the same equipment and container as in Example 1 were used. In Example 2, different blood samples, Specimen A and Specimen B, 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 the time (min). Similar to FIG. 25, in the following description, the amplitude angle is the difference between two positive and negative graphs.

FIG. 26A shows the measurement result when the amplitude angle transmitted to the measurement pin is constant during the measurement. In FIG. 26 (A), the transmitted amplitude angle at the start of measurement was analyzed as ± 5 degrees (10 degrees). In FIG. 26 (B), after the measurement is started with the transmitted amplitude angle set to ± 5 degrees (10 degrees), the transmitted amplitude angle reaches ± 3 degrees (6 degrees) when the actual measurement pin amplitude reaches ± 3 degrees (6 degrees). Was widened to ± 10 degrees (20 degrees).

As shown in FIG. 26 (A), when the transmission angle is constant, the coagulation waveforms of the sample A and the sample B are similar, and the difference in the coagulation ability between the samples is 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). After that, a difference in coagulation ability (particularly maximum viscoelasticity) was observed for each sample. When analyzing the maximum viscoelasticity (minimum amplitude) in this way, by expanding the transmitted amplitude and transmitting a stronger force to the measurement pin, the sensitivity in the measurement of the high viscoelasticity region is improved.

By detecting a decrease in the amplitude angle of the measurement pin during measurement and automatically widening the amplitude angle transmitted to the measurement pin, it is possible to accurately detect changes in viscoelasticity even when measuring a blood sample with high viscoelasticity. I found that I could do it.

<Example 3>
Example 3 was measured using the same equipment and container as in Example 1 under the same measurement conditions as in Example 1. In addition, it was measured using the following reagents. Measurement cup part 401 with reagents (15 μL of tissue factor solution (exogenous blood coagulation activation reagent) extracted from rabbit brain and 20 μL of Startem reagent (calcium chloride reagent: Team innovations GmbH)) in advance.
300 μL of human citrate blood was placed in the container 400 contained therein and analyzed. Furthermore, as a comparison of the lysis reaction of blood coagulation, an analysis was also performed when a thrombolytic drug (tPA: generic name alteplase (product name Glutopa Note) final concentration 100 IU / ml unit) 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 the time (sec). The minimum amplitude width (actual swing width) of C was 1.81 degrees without t-PA addition and 2.20 degrees with tPA addition. The amplitude (actual swing width) about 1 hour after the start of measurement was 2.34 degrees without t-PA addition and 18.64 degrees with tPA addition.

Here, the detection of fibrinolysis will be described. It is recognized that the portion c1 circled is more sensitive to the fibrinolytic reaction. Further, by widening the amplitude angle transmitted to the measurement pin, as shown by the arrow c2, the change in the amplitude due to thrombolysis increases, and the decrease in viscoelasticity is detected with high accuracy. Further, when the amplitude angle is widened and the load on the measuring pin is increased, the sensitivity to the viscoelastic change in the highly viscoelastic region increases. That is, the sensitivity of fibrinolysis at the stage when blood coagulates and begins to dissolve increases. As described above, in the measurement in the high viscoelastic region, the effect of improving the sensitivity to the fibrinolytic reaction was obtained by becoming sensitive to the change in viscoelasticity.

10, 100 ... Blood coagulation tester: 1 ... Control unit: 1A ... Servo motor: 1B ... Elastic body support: 1C ... Elastic body support shaft: 2 ... Elastic body: 3 ... Stirring unit: 3A ・ ・ Rotor transmission part: 3B ・ ・ Bearing: 3C ・ ・ Stirring pin: 3D ・ ・ Pin hole: 4 ・ ・ Container: 5 ・ ・ Sensor: 6 ・ ・ Control device: 11 ・ ・ CPU: 12 ・ ・ RAM: 13 ・ ・ ROM: 14 ・ ・ Auxiliary storage device: 15 ・ ・ NIC: 16 ・ ・ Imaging unit: 17 ・ ・ Display unit: 18 ・ ・ Input unit 30, 500 ・ ・ Stirring unit (stirring pin): 30A ・ ・ Holding Pin insertion hole: 30B ・ ・ Flange: 40, 400 ・ ・ Container: 401 ・ ・ Measuring cup part: 402 ・ ・ Stirring pin housing part 110 ・ ・ Housing: 111 ・ ・ Bottom plate: 112 ・ ・ Support: 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 ... Swing plate: 242 ... Rotor: 243, 246A, 246B ... Washer: 244 ... Rotating shaft: 245A, 245B ... Bearing: 247 ... First pedestal: 248 ... Rocking transmission part: 249 ... Elastic body: 250 ... Rocking transmission part: 250A ... Elastic body Connection part: 250B ・ ・ Swing measurement pin: 251 ・ ・ Second pedestal: 252 ・ ・ Holding pin: 270 ・ ・ Rotor angle measurement mechanism: 271 ・ ・ Sensor plate: 272 ・ ・ Light source part: 300 ・ ・ Lower unit: 310 ・ ・ Mounting stand slide mechanism: 311 ・ ・ Mounting stand: 311A ・ ・ Container mounting part: 312 ・ ・ Ball screw: 313 ・ ・ Slide motor: 314 ・ ・ Linear guide: 320 ・ ・ Holding pin pulling mechanism: 321 ・・ Guide plate: 322 ・ ・ Holding plate: 323 ・ ・ Solvent: 331 ・ ・ Support shaft: 332 ・ ・ Upper unit support base

Claims (8)

A container for the blood to be tested and
A stirring unit that stirs the blood to be tested in the container, and a stirring unit.
An elastic body connected to the stirring unit and deformable according to the force received from the stirring unit by stirring the blood to be inspected.
By reciprocating the elastic body at a first angle with the axis of the stirring unit as a rotation axis and controlling the reciprocating rotation of the elastic body, a predetermined reciprocating rotary motion is transmitted to the stirring unit, and the stirring unit With a control unit that reciprocates in the circumferential direction
A measuring unit for measuring the rotation angle due to the reciprocating rotation of the stirring unit is provided.
When the rotation angle of the stirring unit measured by the measurement unit is equal to or less than the first measurement angle, the control unit causes the rotation angle for reciprocating the elastic body to be larger than the first measurement angle. Spread to the angle of
Blood coagulation tester. The first measurement angle is an angle for defining the solidification rate.
The control unit acquires the solidification rate when the rotation angle of the stirring unit measured by the measurement unit decreases to the first measurement angle.
The blood coagulation test apparatus according to claim 1. The control unit acquires the solidification start time when the rotation angle of the stirring unit measured by the measurement unit decreases to a second measurement angle which is an angle for defining the solidification start time.
The blood coagulation test apparatus according to claim 1 or 2. The second angle is twice the first angle.
The blood coagulation test apparatus 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 apparatus according to any one of claims 1 to 4. The container has a measuring unit for accommodating a reagent added to the blood to be tested and an accommodating unit for accommodating the stirring unit.
The blood coagulation test apparatus according to any one of claims 1 to 5. The container contains the stirring unit having a shape corresponding to the reagent stored in the measuring unit.
The blood coagulation test apparatus according to claim 6. A stirring step of stirring the blood to be tested placed in the container by the stirring part, and
An elastic body connected to the stirring unit and deformable from the stirring unit according to the force received by stirring the blood to be inspected is reciprocated at a first angle with the axis of the stirring unit as the rotation axis, and the elasticity A control step of transmitting a predetermined reciprocating rotary motion to the stirring unit by controlling the reciprocating rotation of the body and reciprocating the stirring unit in the circumferential direction.
Including a measurement step of measuring the rotation angle due to the reciprocating rotation of the stirring unit.
In the control step, when the rotation angle of the stirring unit measured in the measurement step is equal to or less than the first measurement angle, the rotation angle for reciprocating the elastic body is set to be larger than the first angle. Spread to the angle of
Blood coagulation test method.

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