Biological sample analysis device

Abstract

This biological sample analysis device includes: a dilution tank (1) for diluting a biological sample; a discharge nozzle (2) for injecting the biological sample or a cleaning liquid into the dilution tank (1); a flow-through sensor (8) for analyzing the diluted biological sample; and a waste liquid unit (19) for discarding the liquid that has been used for analysis. A cleaning liquid bypass line (13) branched from the dilution tank (1) is connected to the waste liquid unit (19) located downstream of the sensor (8), via a three-way solenoid valve (10) for switching a cleaning bypass line. The cleaning liquid bypass line (13) serves as a replacement for a cleaning block and is a flow path for the cleaning liquid, branches upstream from the sensor (8), is connected via the three-way solenoid valve (10) for switching the cleaning bypass line at a position downstream of the sensor (8), and bypasses the sensor (8).

Description

Biological sample analyzer

[0001] The present invention relates to a technology for an apparatus for analyzing biological samples, and in particular to a technology for preventing a decrease in the quality of analysis due to contamination derived from biological samples that occurs when the apparatus is continuously used.

[0002] Various types of devices for analyzing biological samples have been known. Examples of biological samples include urine, serum, plasma, whole blood, and cerebrospinal fluid. Examples of analytical devices include electrolyte analyzers and sugar analyzers.

[0003] During continuous use of a biological sample analyzer, fouling occurs on the liquid-contacting parts of the device (hereinafter referred to as the "internal surface of the flow path"). The fouling is often derived from organic matter (e.g., proteins) or inorganic substances contained in the biological sample. Initially, the fouling is often simply the adhesion of these substances to the internal surface of the flow path. However, if left unattended, the fouling can grow as microorganisms use the adhesion as a foothold to grow, or as the microorganisms release substances outside their cells (see, for example, Non-Patent Document 1 below). Over time, the fouling can turn into slimy, gel-like, or crystalline deposits, as shown in Figures 7 and 8. Figure 7 shows gel-like fouling that has formed at the top of the dilution tank, and Figure 8 shows cotton-like fouling that has clogged the discharge nozzle.

[0004] The grown dirt has various adverse effects on biological sample analyzers. If it occurs in the dilution section, it can lead to poor dilution ratios and clogged discharge nozzles. Furthermore, if dirt occurs on the inner surface of the flow path upstream of the sensor, it can lead to insufficient rinsing after the previous sample measurement (so-called carryover), which can reduce measurement accuracy. Furthermore, if dirt that has formed on metal parts is left unattended, it can accelerate corrosion of the metal parts (see, for example, Non-Patent Document 1 below). Furthermore, the attached dirt itself can carry an electric charge, which can cause electrical noise.

[0005] To prevent the adverse effects of contamination on the inner surface of the flow path, it is essential to remove the contamination at appropriate times (hereinafter referred to as "cleaning"). However, the cleaning solution used to remove the contamination may also deteriorate the sensor.

[0006] Figure 6 is an enlarged view of the periphery of a cleaning block used in the prior art. Conventionally, cleaning required removing the sensor, replacing it with a cleaning block 30, and then filling the flow path with cleaning liquid. For convenience, the same components as those in the embodiment (Figures 3 and 4) are denoted by the same reference numerals in Figure 6.

[0007] However, replacing the sensor and cleaning block is a very tedious task for users, which often results in insufficient cleaning, leading to a desire for a more user-friendly cleaning method.

[0008] A method for cleaning a flow cell type analyzer has been proposed as a conventional technique (see Patent Document 1 below). However, this method aims to improve the efficiency of the operation of washing away previous samples so as not to affect subsequent samples, thereby improving the processing speed, and is not concerned with cleaning the dirt derived from the biological samples mentioned above.

[0009] Publication number 3-42365

[0010] "Biofilms and Their Industrial Uses," by Hideyuki Kanematsu et al., Yoneda Publishing, 2015.

[0011] In conventional biological component measuring devices, the sensor and cleaning block must be replaced during cleaning to prevent adverse effects caused by dirt on the inner surface of the flow path. However, replacing the sensor and cleaning block is a very tedious task for the user, and there was a problem in that it was not a user-friendly cleaning method.

[0012] In view of the above problems, an object of the present invention is to provide a user-friendly biological sample analyzer that allows the inner surface of a flow channel to be easily cleaned at appropriate times.

[0013] In order to solve the above problems, the biological sample analyzer of the present invention is a biological sample analyzer having a dilution section for diluting a biological sample, an ejection nozzle for injecting the biological sample or a cleaning solution into the dilution section, a flow-through sensor for analyzing the diluted biological sample, and a waste solution section for discarding the solution after use in the analysis, characterized in that a bypass line for cleaning solution branching off from the dilution section is connected via a valve to the waste solution section located downstream of the sensor.

[0014] With the above configuration, when the inner surface of the flow path of the biological sample analyzer becomes soiled, the user can easily clean it at the appropriate time without having to replace the sensor with a cleaning block.

[0015] The flow-through sensor for analyzing a biological sample is characterized by being a flow-through ion-selective electrode.

[0016] With the above configuration, when the inner surface of the flow path of the biological sample analyzer becomes soiled, the user can easily and timely clean the ion selective electrode without having to replace it with a cleaning block.

[0017] The cleaning device also has a control unit that controls each part of the device, including the valve, and the control unit controls the opening and closing of the valve at a predetermined time, thereby automatically performing the cleaning work.

[0018] With this configuration, dirt on the inner surface of the flow path of the biological sample analyzer can be cleaned at the appropriate time without the user having to give any operational instructions.

[0019] The control unit is also characterized in that it automatically executes a cleaning operation when an index related to the quality of measurement detected by the sensor deviates from a threshold value.

[0020] According to the above configuration, when an index related to the quality of analysis deviates from a threshold value, cleaning can be performed at the appropriate time without the user having to give an instruction for operation.

[0021] The present invention has the advantage of being able to prevent, in an easier way than conventional methods, degradation of analytical quality due to contamination from biological samples that occurs when a biological sample analyzer is used continuously.

[0022] FIG. 1 is a fluid system diagram of a biological sample analyzer according to a first embodiment of the present invention. FIG. 2 is an enlarged view of the periphery of a dilution tank of a biological sample analyzer according to a first embodiment of the present invention. FIG. 3 is an enlarged view of the periphery of a washing bypass line of a biological sample analyzer according to a first embodiment of the present invention. (Part 1) FIG. 4 is an enlarged view of the periphery of a washing bypass line of a biological sample analyzer according to a first embodiment of the present invention. (Part 2) FIG. 5 is a diagram showing an example configuration of a control unit of a biological sample analyzer according to a first embodiment of the present invention. FIG. 6 is an enlarged view of the periphery of a washing block used in conventional technology. FIG. 7 is a view showing gel-like stains formed on the top of a dilution tank. FIG. 8 is a view showing cotton-like stains that have clogged a discharge nozzle.

[0023] The following describes in detail an embodiment of the present invention, but the present invention is not limited to this.

[0024] (Biological sample analyzer) The biological sample analyzer of the present invention has a dilution section for diluting the biological sample, an ejection nozzle for injecting the biological sample or cleaning solution into the dilution section, a flow-through sensor for analyzing the diluted biological sample, and a waste liquid section for discarding the liquid after use in the analysis.

[0025] The dilution section consists of a dilution tank, a stirrer, and a dilution solution outlet. Depending on the measurement method, a standard solution outlet or other device may be added. The stirrer can be freely selected as long as it suits the purpose, such as a stirring blade or magnetic stirrer. Considering the efficiency of rinsing off the sample and ease of maintenance, it is desirable to use a small magnetic stirrer. The material of the dilution tank can also be selected appropriately, such as metal, glass, or resin. Among these, it is desirable to use transparent resin from the standpoint of visibility and workability.

[0026] The discharge nozzle has the function of injecting the biological sample or cleaning solution into the dilution tank. If the same discharge nozzle is used for both the biological sample and the cleaning solution, the inner surface of the discharge nozzle can also be cleaned.

[0027] Examples of flow-through sensors include sodium ion-selective electrodes, potassium ion-selective electrodes, chloride ion-selective electrodes, calcium ion-selective electrodes, and magnesium ion-selective electrodes. These are used in conjunction with a reference electrode. Sensors for sugar analysis, amino acid analysis, and the like can also be used. Note that multiple types of ion sensors may be used in combination. Furthermore, sensors for obtaining information other than that of biological sample analysis, such as temperature sensors and pressure sensors, may be added. Using such sensors in combination may contribute to the automation of cleaning operations.

[0028] The waste liquid section is a mechanism for discharging the liquid after it has been used in the analysis (hereinafter referred to as "waste liquid"). If necessary, it can be used in combination with a solenoid valve or a syringe pump. This configuration makes it possible to control the flow direction of the waste liquid and to forcibly discharge it.

[0029] The present invention is characterized in that a flow path for a cleaning solution branches off from the dilution tank of the dilution unit. This flow path for the cleaning solution is arranged in a bypass manner so as to circumvent the sensor and is connected via a valve to a waste solution section located downstream of the sensor (hereinafter, this flow path will be referred to as a "cleaning bypass line"). The cleaning solution tube may branch off from the dilution tank from a side wall surface (a wall surface other than the bottom or top surface) of the dilution tank. For example, it may branch off from the front surface of the device (see FIG. 3 described below) or from the rear surface of the device (see FIG. 4).

[0030] The material of the cleaning bypass line need only be durable enough to withstand the components of the cleaning solution, and can be freely selected from among Teflon (registered trademark), silicone, ceramic, stainless steel, corrosion-coated metal, etc.

[0031] The method for placing the cleaning solution can be selected as appropriate, such as placing it in the same cup as the sample and arranging it on the trajectory of the tip of the discharge nozzle, or setting a bottle of the cleaning solution. It may also be introduced to the specified location via a tube from a bottle or pouch set in another position on the device. It is also possible to use a cassette in which a single dose is individually packaged. If the cleaning component is solid, the cleaning component and liquid component may be mixed inside the device and then used as the cleaning solution.

[0032] The cleaning components can be selected according to the properties of the dirt. Examples of usable cleaning components include alkaline hypochlorites such as sodium hypochlorite and potassium hypochlorite, hypochlorous acid, sodium hydroxide, potassium hydroxide, alkaline percarbonates such as sodium percarbonate and potassium percarbonate, and surfactants. It is also possible to mix multiple cleaning components as long as the components in the cleaning solution do not react with each other to generate harmful substances.

[0033] (Embodiment 1) An embodiment of the biological sample analyzer of the present invention will be described below.

[0034] (Configuration of the Device) Fig. 1 is a fluid system diagram of a biological sample analyzer according to embodiment 1 of the present invention. An electrolyte analyzer (manufactured by A&T Corporation) was used as the biological sample analyzer.

[0035] At the most upstream of the flow path, there are arranged a dilution tank (dilution section) 1 for diluting the biological sample, a discharge nozzle 2 for injecting the biological sample or cleaning solution into the dilution section, a discharge port 3 for the dilution solution, and a discharge port 4 for the standard solution. The structure of the dilution tank 1 and its surroundings is as shown in Figure 2.

[0036] 2 is an enlarged view of the area around dilution tank 1 of the biological sample analyzer according to the first embodiment of the present invention. A flow path 5 leading downstream is provided at the bottom of dilution tank 1, and after bending laterally, heads toward dilution tank outlet 7 (the flow path from the bottom of dilution tank 1 to dilution tank outlet 7 will be referred to as the "diluted sample outlet flow path"). A branch point 6 is located midway along the flow path to dilution tank outlet 7.

[0037] 1, an inlet 14 of a washing bypass line 13 is connected to the branch point 6 via a connector. A magnetic stirrer is provided on the inner wall of the dilution tank 1, and is used to stir and mix the biological sample and diluent when analyzing the biological sample.

[0038] A flow-through sensor 8 was placed downstream of the dilution tank outlet 7. A sodium ion-selective electrode 8c, a potassium ion-selective electrode 8b, and a chlorine ion-selective electrode 8a were used as the flow-through sensor 8, along with a reference electrode 8r and a liquid earth electrode (omitted in FIG. 1 ) (all manufactured by A&T Corporation). These electrodes were connected from upstream to downstream in the order of the liquid earth electrode, chlorine ion-selective electrode 8a, potassium ion-selective electrode 8b, sodium ion-selective electrode 8c, and reference electrode 8r to form a flow path.

[0039] The biological sample analyzer has a signal processing circuit 31 that processes the signals input to these multiple electrodes during biological sample analysis, a differential amplifier circuit 32 that amplifies the signals from each electrode, and a signal input circuit 33 that inputs signals to each electrode. Furthermore, although not shown, the electromotive forces of the liquid earth electrode, chlorine ion selective electrode 8a, potassium ion selective electrode 8b, and sodium ion selective electrode 8c are measured by an arithmetic circuit as potential differences with the potential of reference electrode 8r used as system ground. A control unit 100, described below, has the functions of, for example, the signal processing circuit 31 and the arithmetic circuit, and processes data during biological sample analysis.

[0040] A three-way solenoid valve was placed downstream of the reference electrode 8r (this solenoid valve will be referred to as the "cleaning bypass line switching three-way solenoid valve 10"). One inlet 11 of the cleaning bypass line switching three-way solenoid valve 10 was connected to the outlet 9 of the flow-through sensor, and the other inlet 12 was connected to the outlet 15 of the cleaning bypass line 13. The outlet of the cleaning bypass line switching three-way solenoid valve 10 was connected to a waste liquid line 16 leading to a waste liquid section 19.

[0041] 3 and 4 are enlarged views of the periphery of the washing bypass line of the biological sample analyzer according to the first embodiment of the present invention. In Fig. 3, the washing bypass line 13 branches off from the front of the apparatus, and in Fig. 4, the washing bypass line 13 branches off from the rear of the apparatus. The washing bypass line 13 branches off upstream of the flow-through sensor 8, is arranged in a bypass shape to bypass the flow-through sensor 8, and is connected via a washing bypass line switching three-way solenoid valve 10 downstream of the flow-through sensor 8, and is connected to a waste liquid section 19.

[0042] The flow of liquid from the dilution tank 1 can be controlled by sending an electrical signal from the control unit to the three-way solenoid valve 10 for switching the washing bypass line. When analyzing a diluted biological sample, the control unit issues an instruction to send the biological sample dilution liquid in the dilution tank 1 to the waste liquid section 19 via the flow-through sensor 8. When washing is performed, the control unit issues an instruction to send the washing liquid in the dilution tank 1 to the waste liquid section 19 via the washing bypass line 13.

[0043] 5 is a diagram showing an example of the configuration of the control unit of the biological sample analyzer according to the first embodiment of the present invention. For example, the control unit 100 includes a CPU 101, a ROM 102, a RAM 103, a display 104, and a network I / F (interface) 105. Each of the components 101 to 105 is connected to a bus 110.

[0044] The CPU 101 is responsible for overall control of the biological sample analyzer. The ROM 102 stores various data such as a boot program that starts up the biological sample analyzer, and programs that control measurement processes and various parts such as solenoid valves and pumps. The RAM 103 is used as a work area for the CPU 101.

[0045] Display 104 displays various data. In the present invention, display 104 not only lets the user know the status of the device, but also functions as a human interface for operating and inputting program settings. Network I / F 105 controls data communication between the biological sample analyzer and various external devices.

[0046] The control unit 100 shown in FIG. 5 performs processing related to biological sample analysis based on the detection value of the flow-through sensor 8. Furthermore, the control unit 100 can switch from processing related to biological sample analysis to processing related to cleaning at a predetermined time or other trigger. The cleaning processing described below is not limited to being automatically performed by the control unit 100, but can also be performed manually. Furthermore, the control unit 100 may manage the overall processing, while some operations that require visual confirmation, etc., may be manually performed by the user. Furthermore, as will be described later, the control unit 100 may start processing related to cleaning when an index related to the quality of measurement detected by the flow-through sensor 8 during execution of biological sample analysis deviates from a threshold value.

[0047] (Explanation of cleaning procedure: removal of dirt with cleaning liquid) A container containing cleaning liquid was set on the trajectory of the range of motion of the discharge nozzle 2. A sodium hypochlorite aqueous solution (effective chlorine concentration 5%) was used as the cleaning liquid. Next, under the control of the control unit 100, the cleaning liquid is sucked up from the discharge nozzle 2 and discharged into the dilution tank 1. In addition, the control unit 100 sends an electrical signal to the three-way solenoid valve 10 for switching the cleaning bypass line, causing the cleaning liquid to pass through the cleaning bypass line 13 side, and the syringe pump 20 sucks in the liquid in the flow path, causing the cleaning liquid in the dilution tank 1 to flow in the direction of the cleaning bypass line 13.

[0048] The control unit 100 repeatedly discharges the cleaning solution into the dilution tank 1 and sucks the syringe pump 20, and stops the operation when the cleaning solution fills the dilution tank 1 from the outlet of the washing bypass line 13 (i.e., the connection part 15 with the washing bypass line switching three-way electromagnetic valve 10) to the upper edge of the dilution tank 1, and then leaves the dilution tank 1 to stand for 6 minutes.

[0049] Next, the control unit 100 switches the three-way solenoid valve 17 for waste liquid discharge operation on the waste liquid line 16, while repeatedly discharging the cleaning liquid into the dilution tank 1 and suctioning it with the syringe pump 20, and stops the operation when the liquid is filled from the outlet of the waste liquid section and the syringe pump 20 to the contact point between the diluted sample outlet flow path 5 and the dilution tank 1, and allows the system to stand for 7 minutes. After the system has been left standing, the control unit 100 switches the three-way solenoid valve 17 for waste liquid discharge operation while causing the syringe pump 20 to pump the liquid, and recovers the used cleaning liquid in a waste liquid container.

[0050] (Explanation of cleaning procedure: washing away cleaning solution from the washing bypass line) Since remaining cleaning solution can have a negative effect on the analysis of biological samples, the inner surface of the flow path after cleaning must be washed with a diluent. The process performed automatically by the control unit 100 or manually is as follows. A phosphate buffer solution was used as the diluent.

[0051] First, the control unit 100 discharges the dilution liquid from the dilution liquid outlet 3 into the dilution tank 1. Next, the control unit 100 switches the three-way electromagnetic valve 17 for waste liquid discharge operation while discharging the dilution liquid into the dilution tank 1. When the dilution tank 1 is filled up to the upper edge, the syringe pump 20 sucks and delivers the liquid, recovers the remaining cleaning liquid and dilution liquid in a waste liquid container, and washes the inner surface of the flow path with the dilution liquid. The control unit 100 repeats this process 10 times.

[0052] (Explanation of cleaning procedure: washing away cleaning liquid) The above-mentioned washing cannot wash away the part from the branch point 6 to the dilution tank outlet 7 inside the dilution tank 1. It is necessary to completely wash away even the small amount of cleaning liquid components that have entered the part from the branch point 6 to the dilution tank outlet 7 during washing. The process automatically executed by the control unit 100 or the manual operation is as follows.

[0053] The control unit 100 switches the three-way solenoid valve 10 for switching the washing bypass line so that the liquid flows to the sensor side. Next, the dilution liquid is discharged from the dilution liquid outlet 3 into the dilution tank 1, and when the dilution tank 1 is filled up to the upper edge, the three-way solenoid valve 17 for discharging the waste liquid is switched while the syringe pump 20 sucks and delivers the liquid. The remaining washing liquid and dilution liquid are collected in a waste liquid container, and the dilution liquid is flushed from the branch point 6 to the dilution tank outlet 7. The control unit 100 repeats this process four times.

[0054] In the first embodiment of the present invention, it was possible to clean biological dirt with a simple operation without replacing the sensor and the cleaning block, and the cleaning effect was equivalent to that when the cleaning block was used.

[0055] (Embodiment 2) This embodiment is the same as embodiment 1, except that settings related to the cleaning and washing-off operations are input in advance to the control unit 100. In embodiment 2, the control unit 100 is set to perform the series of operations shown in embodiment 1 at a predetermined date and time, for example, at 18:00 on a Friday of the weekend.

[0056] In the second embodiment of the present invention, cleaning can be performed automatically at a set time without the user having to give instructions each time.

[0057] (Embodiment 3) This embodiment is the same as embodiment 2, except that the operations for cleaning and rinsing off the cleaning solution and the determination of an index related to the quality of the measurement are set and input to the control unit 100 in advance. Here, the number of measurements is used as an index related to the quality of the measurement. The control unit 100 obtains information on the number of measurements from the analysis status at a predetermined date and time, for example, from 18:30 on Friday of the first week to 18:00 on Friday of the second week (the following week), and is set to perform a series of operations similar to embodiment 2 at 18:00 on Friday of the second week if the average number of measurements per day exceeds 100.

[0058] In the third embodiment of the present invention, cleaning can be performed at an appropriate timing depending on the usage status of the biological sample analyzer. Note that although the number of measurements is used here as an index of quality, other indicators can also be used, such as the variation in values ​​or noise generation during biological sample analysis or calibration, the pressure in the flow path, or the status of suspended or attached particles.

[0059] The present invention is suitable for use in an apparatus for analyzing biological samples such as urine, serum, plasma, whole blood, and cerebrospinal fluid.

[0060] 1 Dilution tank 2 Discharge nozzle for injecting biological sample or cleaning solution into dilution section 3 Discharge outlet for dilution solution 4 Discharge outlet for standard solution 5 Flow path for dilution sample extraction 6 Branch point 7 Dilution tank outlet 8 Flow-through sensor 9 Outlet of flow-through sensor 10 Three-way solenoid valve for switching between cleaning bypass lines 13 Cleaning bypass line 14 Cleaning bypass line inlet 15 Cleaning bypass line outlet 16 Waste liquid line 17 Three-way solenoid valve for waste liquid discharge operation 19 Waste liquid section 20 Syringe pump 21 Cleaning solution 30 Cleaning block 101 CPU (control unit) 102 ROM 103 RAM 104 Display 105 Network I / F

Claims

1. A biological sample analyzer having a dilution section for diluting a biological sample, an ejection nozzle for injecting the biological sample or a cleaning solution into the dilution section, a flow-through sensor for analyzing the diluted biological sample, and a waste liquid section for discarding the liquid after use in the analysis, wherein a cleaning solution bypass line branching off from the dilution section is connected via a valve to the waste liquid section located downstream of the sensor.

2. The biological sample analyzer according to claim 1, wherein the flow-through sensor for analyzing the diluted biological sample is an ion-selective electrode.

3. A biological sample analyzer as described in claim 1 or 2, characterized in that it has a control unit that controls each part of the device including the valve, and the control unit controls the opening and closing of the valve at a specified date and time, thereby automatically performing a cleaning operation.

4. The biological sample analyzer according to claim 3, characterized in that the control unit automatically executes a cleaning operation when an index relating to the quality of measurement detected by the sensor deviates from a threshold value.

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