Simultaneous and selective cleaning and detection in an ion-selective electrode analyzer.

Abstract

In most clinical or diagnostic laboratory settings, calibration and compliance services for ion-selective electrode analyzer-based electrolyte measurement devices require a significant amount of time. Users are often forced to make a trade-off between improving diagnostic accuracy and processing a higher workload more quickly and predictably. Current ion-selective electrode-based electrolyte measurement devices are unable to balance the increasing demands for accuracy and speed. The technology claimed and described herein provides an improved device for ion-selective electrode analyzers. The technology claimed and described herein also provides a method for simultaneously and selectively cleaning components of an ion-selective electrode analyzer, and a method for simultaneously and selectively analyzing samples using an ion-selective electrode analyzer in an automated chemical analyzer.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 132,022, filed December 30, 2020, which is incorporated herein by reference in its entirety.

[0002] Field Various aspects of the present disclosure relate to simultaneous and selective cleaning of components of an ion-selective electrode analyzer and simultaneous and selective electrolyte detection using an ion-selective electrode analyzer. Additional aspects include improved ion-selective electrode analyzer devices.

[0003] Background technology Automated chemistry analyzers are commonly used in clinical chemistry collection and analysis applications. Automated instruments, such as automated analytical chemistry workstations, can efficiently perform clinical analyses of large numbers of samples, with tests run simultaneously or at short time intervals. This efficiency is due in part to the use of automated sample identification and tracking. The instruments can automatically prepare the appropriate amount of sample and automatically set the test conditions required for the scheduled test run. Test conditions can be established and tracked independently for different test protocols running simultaneously within a single test station, facilitating the simultaneous execution of multiple different tests based on different chemistries and requiring different reaction conditions. Automated analytical instruments are particularly well-suited for large-scale testing environments, such as those present in many hospitals and centralized testing laboratories, because automated sample handling allows for more accurate sample identification and tracking. Automatic sample handling and tracking significantly reduces the opportunity for human error and accidents, which could lead to either erroneous test results or unwanted contamination.

[0004] Ion-selective electrodes are a key component of automated chemical analyzers. Ion-selective electrodes (ISEs) are typically used to measure electrolyte (ion, such as sodium, potassium, and chloride) concentrations in samples using automated chemical analyzers. Users desire high throughput, reproducibility, and minimal maintenance for ISE-based electrolyte measurement devices. In most clinical or diagnostic laboratory settings, calibration and compliance services for ISE-based electrolyte measurement devices require a significant amount of time. Users are often forced to trade off between improving diagnostic accuracy and processing a higher workload more quickly and predictably. Current ISE-based electrolyte measurement devices are unable to balance the increasing demands for accuracy and speed.

[0005] In a typical ISE method, an internal standard solution (a solution of known concentration) is measured for each sample measurement. The electrolyte concentration of the sample is calculated from the voltage difference between the internal standard solution and the sample dilution solution. It is desirable for the test solution to be retained in the electrode for a long time. If the test solution residence time is short, measurement performance will deteriorate if an electrode with poor response is used.

[0006] In some ISE methods, the measurement operation is performed in one cycle in the following order: voltage measurement of the internal standard solution, voltage measurement of the sample dilution solution, and cleaning operation using the internal standard solution. With this method, the retention time of the test solution inside the electrode needs to be shortened to increase throughput, and achieving both throughput and data reproducibility becomes an issue.

[0007] Furthermore, if measurements are not performed continuously, the initial voltage value becomes unstable due to the drying of the electrode film. Therefore, depending on the measurement interval, it is necessary to perform an electrode conditioning operation (e.g., by flowing an internal standard solution through the electrode) before measurement.

[0008] However, if the conditioning operation is performed before the measurement, the start of the electrolyte measurement will be delayed, and depending on the measurement conditions such as the number of orders for photometric items, the overall processing capacity of the ISE will decrease.

[0009] The prior art described in Japanese Patent No. 3610111 can solve the above problem. In this prior art, the ion-selective analyzer has a bypass line for aspirating the test solution in the dilution pot without passing it through the electrodes. In this method, the reagents used include an internal standard solution and a sample dilution solution, which are always measured alternately without a cleaning operation.

[0010] This measurement method allows the sample dilution solution and internal standard solution to be dispensed and stirred during static potential measurement, ensuring a long period of time for potential measurement within one cycle. Furthermore, because the electrode is always filled with sample dilution solution or internal standard solution, no conditioning operation is required, even if the measurement interval is long. Furthermore, measurements can be started at any time. Therefore, it is possible to provide an analyzer with high throughput regardless of sample measurement conditions such as the number of photometric items.

[0011] However, this method has several problems: it may produce inaccurate data when measuring high / low concentration samples; residual liquid from the previous sample may contaminate the internal standard solution, which may cause poor data reproducibility for samples, especially when the concentration variability is large.

[0012] Another problem is the increased maintenance time required by users. Residual components of the sample dilution solution almost always remain in the dilution pot and / or tube, which can easily accumulate dirt and cause clogging. Dirt and / or clogging can cause calibration errors and abnormal measurements. To prevent this, users must frequently perform a lot of maintenance (cleaning, part replacement, etc.).

[0013] Further limitations and drawbacks of conventional traditional approaches will become apparent to those skilled in the art through comparison with such systems in conjunction with certain aspects of the present disclosure as described in the remainder of this application with reference to the drawings.

[0014] Quick Overview The present inventors have recognized a need for improved ion selective electrode devices and methods for simultaneous and selective cleaning of ion selective electrode components and simultaneous and selective detection of electrolytes using an ion selective electrode analyzer.

[0015] One aspect of the technology disclosed and claimed herein includes an ion-selective electrode analyzer that includes the following elements: at least one reagent supply line further including at least one reagent; a dilution pot for receiving the reagent; a flow-type cell downstream from the dilution pot; a flow-type cell line operably connected to the flow-type cell; a bypass line operably connected to the dilution pot; a drain line; a flushing liquid line; at least three pumps; a first valve, here a three-way valve or pinch valve; a second valve, here a three-way valve; and a third valve, here a two-way valve.

[0016] One aspect of the technology disclosed and claimed herein includes a method of analyzing a biological sample using an ion selective electrode analyzer, the method comprising the steps of: providing an ion selective electrode analyzer, the ion selective electrode analyzer comprising the following elements: at least one reagent supply line further comprising at least one reagent, a dilution pot, a flow cell, optionally a flow cell line, optionally a bypass line, optionally a drain line, and optionally at least two the method includes two pumps, a first pump and a second pump; mixing an amount of biological sample and an amount of reagent in the dilution pot to produce a diluted biological sample; aspirating the diluted biological sample from the dilution pot into a flow cell for analysis; simultaneously analyzing the diluted biological sample in the flow cell while dispensing reagent from a reagent supply line into the dilution pot, where the reagent is used for bypass line cleaning, and then dispensing reagent from the reagent supply line into the dilution pot, where the reagent is used for flow cell line cleaning.

[0017] In some embodiments, reagents are aspirated into the bypass line for bypass line cleaning prior to washing the bypass line. Bypass line cleaning may include, but is not limited to, washing the diluate pot, washing the bypass line, and washing the drain line. In some embodiments, reagents are aspirated into the flow cell line for flow cell line cleaning after the diluted biological sample is analyzed. Flow cell line cleaning may include, but is not limited to, washing the diluate pot, washing the flow cell, washing the flow cell line, and washing the drain line. In some embodiments, the diluted biological sample and / or reagents are aspirated into the bypass line before and / or after aspirating into the flow cell line. In other embodiments, after washing the flow cell line, the method further includes dispensing reagents from the reagent supply line into the diluate pot, aspirating the reagents into the flow cell line, and calibrating the flow cell using the reagents.

[0018] In another aspect of the method, the first pump is configured to pump a reagent from a reagent supply line and the second pump is configured to aspirate the reagent and / or the biological sample. The reagent can include an internal standard solution.

[0019] In another embodiment of the method, the at least one reagent supply line is configured to dispense at least a first reagent and at least a second reagent. Alternatively, the ion-selective electrode analyzer further includes a second reagent supply line, wherein the first reagent supply line includes the first reagent and the second reagent supply line includes the second reagent. In a further embodiment, the first reagent includes an internal standard solution, wherein the internal standard solution is used to wash the flow cell lines and / or calibrate the flow cell, and the second reagent includes a buffer solution, wherein the buffer solution is used to dilute the biological sample and / or wash the bypass line.

[0020] In one embodiment of this method, the ion selective electrode analyzer further comprises at least a first valve, where the first valve is a pinch valve with a Y-connector or a three-way valve, hi another embodiment, the ion selective electrode analyzer further comprises a second valve, where the second valve is a three-way valve.

[0021] In one embodiment of this method, the ion selective electrode analyzer further comprises at least a third pump. In another embodiment, the ion selective electrode analyzer further comprises a flushing liquid line and a third valve, wherein the third valve is a two-way valve.

[0022] In one aspect of the method, the ion selective electrode analyzer further includes a fourth pump. In another aspect, the fourth pump is configured to pump the second reagent from the second reagent supply line.

[0023] One aspect of the technology disclosed and claimed herein includes an ion selective electrode analyzer comprising the following elements: at least one reagent supply line further comprising at least one reagent, a dilution pot, a flow-type cell, a flow-type cell line, a bypass line, optionally an exhaust line, and optionally at least two pumps, a first pump and a second pump, wherein the ion selective electrode analyzer is configured to analyze at least 100 biological samples per hour and is further configured to calibrate the flow-type cell after each biological sample is analyzed.

[0024] One aspect of the technology disclosed and claimed herein includes an ion selective electrode analyzer, the ion selective electrode analyzer comprising the following elements: at least one reagent supply line further comprising at least one reagent; a dilution pot; a flow cell; a flow cell conduit; optionally a bypass line; optionally a discharge line; Optionally, the ion selective electrode analyzer includes at least two pumps, a first pump and a second pump, wherein the ion selective electrode analyzer is configured to continuously wet the flow-type cell conduit or the flow-type cell by alternately aspirating the diluted biological sample from the dilution pot and the reagent from one reagent supply line into the flow-type cell and / or the flow-type cell conduit.

[0025] One aspect of the technology disclosed and claimed herein includes a method for continuous wetting of a flow cell conduit or flow cell, the method comprising the steps of: Providing an ion selective electrode analyzer, the ion selective electrode analyzer comprising the following elements: at least one reagent supply line further comprising at least one reagent; a dilution pot; a flow cell; a flow cell conduit; optionally a bypass line; optionally a discharge line; optionally including at least two pumps, a first pump and a second pump; mixing a quantity of the biological sample and a quantity of the reagent in a dilution pot to generate a diluted biological sample; The method includes alternately aspirating the diluted biological sample from the dilution pot and the reagent from one reagent supply line into the flow-type cell and / or the flow-type cell line.

[0026] These and other advantages, aspects, and novel features of the present disclosure, as well as details of illustrated embodiments thereof, will be more fully understood from the following description and drawings.

[0027] Embodiments of the present disclosure will now be described, by way of example only, with reference to the accompanying drawings, in which: [Brief explanation of the drawings]

[0028] [Figure 1] FIG. 1 illustrates an embodiment of the present disclosure in which an ion selective electrode analyzer includes two three-way valves. [Figure 2] FIG. 1 illustrates an embodiment of the present disclosure in which an ion selective electrode analyzer includes a pinch valve and a Y-connector. [Figure 3] FIG. 10 illustrates a flushing sequence according to an embodiment of the present disclosure. [Figure 4] FIG. 10 illustrates a cleaning sequence according to one embodiment of the present disclosure. [Figure 5] FIG. 1 is a diagram showing a first measurement flow according to an embodiment of the present disclosure. [Figure 6] FIG. 10 is a diagram showing a second measurement flow according to an embodiment of the present disclosure. [Figure 7] FIG. 1 is a diagram illustrating the general configuration of an automated chemical analyzer including an ion-selective electrode analyzer. [Figure 8] FIG. 10 is a diagram illustrating a comparison of a method period according to an embodiment of the present disclosure with a conventional method period. [Figure 9] FIG. 1 shows the carryover rate (%) from a urine sample (high concentration sample) to a serum sample measured with a conventional system, compared with an embodiment of the present disclosure. [Figure 10] FIG. 1 shows the coefficient of variation (CV%) of standard and high concentration samples measured with a conventional system compared to an embodiment of the present disclosure.

[0029] Detailed Description Various embodiments will now be described in detail with reference to the drawings, wherein like reference numerals represent like parts and assemblies throughout the several views. It is understood that the disclosure is not limited to the particular methodology, protocols, and reagents described herein, as such may vary. It is also understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the disclosure or the appended claims.

[0030] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0032] As described herein, an improved ion selective electrode analyzer device and method for simultaneous and selective cleaning of ion selective electrode analyzer components and simultaneous and selective detection of electrolytes using an ion selective electrode analyzer are disclosed.

[0033] Traditional quantitative chemical analysis is typically based on one of two measurement methods: (1) the measurement of light (photometry or spectrophotometry) or (2) the measurement of electrochemical potential (potentiometry). The following examples are based on potentiometry (measurement of electrochemical potential), but other analytical methods, such as photometry or spectrophotometry, may also be used. Potentiometry using an ion-selective electrode analyzer is an analytical technique that determines the activity of ions in aqueous solutions by measuring the potential. Ion-selective electrode analyzers may be used to simultaneously analyze electrolytes in a sample, including, but not limited to, sodium, potassium, calcium, chloride, and carbon dioxide.

[0034] Na + , K. + , and Cl - Ion-selective electrode analyzers for ion selection use crown ether membrane electrodes for sodium and potassium and molecularly oriented PVC membranes for chloride for each specific ion of interest in the sample. A potential is generated according to the Nernst equation for the specific ion. When compared to an internal reference solution, this potential is converted to a voltage, which is then converted to the ion concentration of the sample (Tietz, NW, editor, Fundamentals of Clinical Chemistry, 3rd Edition, WB Saunders, 1987).

[0035] In accordance with at least one embodiment of the technology described and claimed herein, the configuration of an ion-selective electrode analyzer is described below with reference to FIGS. 1 and 2. FIG. 1 illustrates an ion-selective electrode analyzer according to one embodiment of the present disclosure. The ion-selective electrode analyzer 1 includes the following elements: at least one reagent supply line 10 further including at least one reagent; a diluent pot 20 for receiving the reagent; a flow-type cell 30 downstream from the diluent pot 20; a flow-type cell line 35 operably connected to the flow-type cell 30; a bypass line 40 operably connected to the diluent pot 20; a drain line 50; a flushing liquid line 70; at least three pumps 80, 81, and 82; a first valve, here a three-way valve 60; a second valve, here a three-way valve 63; and a third valve, here a two-way valve 64. In some embodiments, the ion-selective electrode analyzer can further include a drain 52 operably connected to the drain line 50.

[0036] Reagent supply line 10 may be configured to dispense at least one reagent, alternatively at least two reagents, alternatively multiple reagents, which may be contained in reagent containers 12. Reagent containers 12 may include one or more compartments for holding one or more different reagents.

[0037] In some embodiments, the ion selective electrode analyzer can further include a second reagent supply line 11 containing at least one reagent. In this embodiment, the second reagent supply line 11 has a reagent container 13 that is separate from the reagent container 12 of the first reagent supply line 10. In this embodiment, the ion selective electrode analyzer further includes a fourth pump 83 connected to the second reagent supply line 11.

[0038] In FIG. 1 , the first valve is a three-way valve 60. This three-way valve 60 is used to select either the flow cell line 35 or the bypass line 40 for aspiration. In FIG. 2 , the first valve is a pinch valve 61. When the ion selective electrode analyzer 1 includes the pinch valve 61, it also includes a Y-connector 62. The pinch valve 61 pinches either the flow cell line 35 or the bypass line 40. The Y-connector 62 operatively connects the flow cell line 35, the bypass line 40, and the discharge line 50.

[0039] To dispense or aspirate fixed or variable volumes, the ion selective electrode analyzer 1 includes at least one pressure-changing mechanism. This pressure-changing mechanism may be a pump, such as a peristaltic pump, a roller pump, or a syringe pump. As shown in FIGS. 1 and 2, at least one of the first pump 80 or the second pump 81 may be a syringe pump. In some embodiments, both the first pump 80 and the second pump 81 are syringe pumps. One advantage of a syringe pump is its ability to dispense or aspirate precise volumes, for example, to minimize reagent consumption.

[0040] In FIGS. 1 and 2 , the second pump 81 is connected to the discharge line 50 via a second valve 63, which is located at or near the middle of the discharge line 50. The position of the second valve 63 separates the discharge line 50 into a pre-flushing portion and a post-flushing portion. In FIGS. 1 and 2 , a third valve 64 is located at or near the middle of the flushing liquid line 70, which connects the second pump 81 to a third pump 82. The third pump may be operably connected to a source of flushing liquid 71, and the third pump 82 may be configured to pump the flushing liquid. The flushing liquid may be any liquid suitable for flushing the lines of an ion-selective electrode analyzer. Non-limiting examples of suitable flushing liquids include deionized water.

[0041] In an ion-selective electrode analyzer according to one embodiment of the present disclosure, the volume of the tubing 90 between the second valve 63 and the second pump 81 is greater than the volume the second pump 81 is configured to aspirate. As shown in FIG. 3, the increased volume ensures that the aspirated mixture does not enter the syringe pump. The flushing step further prevents the mixture from diffusing within the syringe pump. This flushing operation, along with the large volume of the tubing between the syringe and the valve, can reduce problems that can arise due to the accumulation of residual sample on the aspirating syringe, significantly reducing the required aspirating syringe maintenance (cleaning / replacement). Additionally, the tubing shown in FIG. 1 eliminates the need for consumable tubing (e.g., roller pump tubing, pinch valve tubing), reducing the time and effort required to replace the tubing and / or tubing.

[0042] In accordance with at least one embodiment of the technology described and claimed herein, a method for using an ion selective electrode analyzer is described below with reference to FIGS. 4-6.

[0043] In an ion-selective electrode analyzer 1 with a bypass line 40, at least two (2) wash operations may be added to one (1) measurement cycle. In this system, effective use of the bypass line 40 allows at least two (2) wash operations to be added without increasing the measurement cycle time while maintaining the current retention time of the test solution in the flow cell line. Additionally, adding at least two wash operations reduces carryover between reagents and improves data reproducibility for high- and low-concentration samples. It also reduces the amount of sample remaining in the dilution pot / tube after measurement, resulting in shorter maintenance (replacement and cleaning) times for these components (see Figure 4).

[0044] In one embodiment of the present disclosure, carryover is reduced by about 25% compared to conventional ISE methods. In this embodiment, cleaning maintenance only needs to be performed, for example, about once a month, or about once every 30,000 tests. This is in contrast to conventional ISE methods, where cleaning maintenance is performed weekly, or about every 7,500 tests. Furthermore, in this embodiment, ion-selective electrode analyzer components last for at least seven (7) years, and in some embodiments, these components do not require replacement. This is in contrast to conventional methods, where components are replaced monthly. This infrequent maintenance is one of the unexpected results of the improved ion-selective electrode analyzer device and related methods.

[0045] One embodiment of the present disclosure is a method for analyzing a biological sample using an ion selective electrode analyzer 1, the method comprising the following steps: providing an ion selective electrode analyzer 1, the ion selective electrode analyzer 1 including the following elements: at least one reagent supply line 10 further including at least one reagent, a dilution pot 20, a flow-type cell 30, a flow-type cell line 35, a bypass line 40, an exhaust line 50, and at least two pumps, a first pump 80 and a second pump 81; and mixing an amount of the biological sample and an amount of the reagent in the dilution pot 20 to generate a diluted biological sample. and aspirating the diluted biological sample from the diluent pot 20 into the flow-type cell 30 for analysis; and simultaneously analyzing the diluted biological sample in the flow-type cell 30 while dispensing reagents from the reagent supply line 10 into the diluent pot 20 and aspirating the reagents into the bypass line 40, where the reagents are used for bypass line washing to clean the bypass line; and then, after the diluted biological sample is analyzed, dispensing reagents from the reagent supply line 10 into the diluent pot 20 and aspirating the reagents into the flow-type cell line 35, where the reagents are used for flow-type cell line washing to clean the flow-type cell line. In some embodiments, the diluted biological sample is aspirated into the bypass line 40 before being aspirated into the flow-type cell 30. In some embodiments, after washing the flow-type cell line 35, the method further includes dispensing reagents from the reagent supply line 10 into the diluent pot 20, aspirating the reagents into the flow-type cell line 35, and calibrating the flow-type cell 30 using the reagents. In this embodiment, the reagent is an internal standard solution.

[0046] In one embodiment of the present disclosure, these method steps may be performed simultaneously, sequentially, and / or consecutively.

[0047] FIG. 4 illustrates a measurement cycle with two (2) additional washes. In this method, the reagent supply line 10 is configured to dispense at least a first reagent and at least a second reagent. Alternatively, the ion-selective electrode analyzer 1 can include a second reagent supply line 11, where the first reagent supply line 10 contains a first reagent and the second reagent supply line 11 contains a second reagent. In this two-fluid system embodiment, the first reagent includes an internal standard solution, which is used to wash the flow cell line 35 and / or calibrate the flow cell 30, and the second reagent includes a buffer solution. Any suitable buffer solution may be used; non-limiting examples include phosphate-buffered saline, neutral salt, deionized water, or a mixture thereof. In this embodiment, the buffer solution is used to dilute the biological sample and / or to wash the bypass line 40.

[0048] Measurement flows according to at least two embodiments of the present disclosure are shown in Figures 5 and 6. In Figure 5, this measurement flow is simplified and bypass aspiration of diluted sample or reagents is not required when exchanging test solutions in a flow-type cell (e.g., electrodes).

[0049] The biological sample may be from a mammal, preferably a human, and may include, but is not limited to, blood, plasma, serum, saliva, urine, cerebrospinal fluid, tears, sweat, gastrointestinal fluid, amniotic fluid, mucosal fluid, pleural fluid, and sebaceous oil. Prior to analysis, the biological sample is mixed with a reagent, which may include, but is not limited to, an internal standard, a buffer, a sample diluent, and the like. The amount of the biological sample mixed with the reagent is at least about 5 μL, alternatively at least about 10 μL, alternatively at least about 15 μL, or alternatively at least about 20 μL. The amount of the reagent mixed with the biological sample is at least about 300 μL, alternatively at least about 350 μL, alternatively at least about 400 μL, alternatively at least about 450 μL, alternatively at least about 500 μL, alternatively at least about 550 μL, alternatively at least about 600 μL, or alternatively at least about 650 μL.

[0050] 7 illustrates an embodiment of the present disclosure in which the ion selective electrode analyzer 1 is incorporated into an automated chemical analyzer 2. The automated chemical analyzer 2 includes a sample station 14 configured to dispense a biological sample.

[0051] Even with the additional cleaning, the measurement cycle is still relatively short. In some embodiments, the cycle is about 20 seconds, alternatively about 15 seconds, alternatively about 12 seconds, or alternatively about 10 seconds. As shown in FIG. 8, the measurement cycle is about 12 seconds. This short cycle time reduces the need for frequent cleaning maintenance and / or frequent part replacement. FIG. 8 shows a comparison of the cycle of a method according to one embodiment (embodiment 1) of the present disclosure with that of a conventional method.

[0052] Additional examples are provided below.

[0053] Example Example 1: Carryover value (urine sample ⇒ serum sample) The graph in Figure 9 shows the carryover rate (%) from a urine sample (high concentration sample) to a serum sample using a conventional system with a bypass line and the carryover rate (%) from a urine sample (high concentration sample) to a serum sample using the ion selective electrode analyzer of the present disclosure (the "new system").

[0054] The carryover of the double additional wash sequence (with bypass / flow cell wash) was approximately 4 times less than that of the conventional sequence, where no wash was performed.

[0055] When comparing the new system with the conventional system, the accumulation of dirt in the dilution pot and tubes has been reduced to the same extent, but the maintenance frequency / time for the dilution pot and tubes in the new system is expected to be reduced to about one-quarter of that of the conventional system.

[0056] Example 2: Reproducibility Figure 10 shows the data reproducibility CV% (N = 20 × 8 runs) between low-concentration samples and high-concentration samples measured with the conventional system, and the data reproducibility CV% (N = 20 × 8 runs) between low-concentration samples and high-concentration samples measured with the new system with flow cell / bypass line cleaning. Data reproducibility was improved with the new system compared to the conventional system.

[0057] The above description is illustrative and not limiting. Many variations of the invention will become apparent to those skilled in the art upon review of this disclosure. Accordingly, the scope of the invention should not be determined with reference to the above description, but should instead be determined with reference to the appended claims along with their full scope or equivalents.

[0058] All patents, patent applications, publications, and statements cited above are incorporated herein by reference in their entirety.

Claims

1. A method for analyzing a biological sample using an ion-selective electrode analyzer (1), comprising: The method comprises: A step of providing the ion selective electrode analyzer (1), the ion selective electrode analyzer (1) comprising: at least one reagent supply line (10) further containing at least one reagent; a dilution pot (20); A flow-type cell (30); a flow cell line (35); a bypass line (40); a discharge line (50); at least two pumps, a first pump (80) and a second pump (81); mixing an amount of biological sample and an amount of reagent in the dilution pot (20) to produce a diluted biological sample; aspirating the diluted biological sample from the dilution pot (20) into the flow-type cell (30) for analysis; a step of simultaneously analyzing the diluted biological sample in the flow-type cell (30) while dispensing the reagent from the reagent supply line (10) into the dilution pot (20), the reagent being used for washing a bypass line; Then, dispensing the reagent from the reagent supply line (10) into the dilution pot (20), the reagent being used for cleaning the flow cell line; A method comprising:

2. 2. The method of claim 1, wherein the reagent is aspirated into the bypass line (40) prior to rinsing the bypass line (40).

3. The method of claim 2, wherein the bypass line cleaning includes cleaning the diluate pot (20), cleaning the bypass line (40), and cleaning the discharge line (50).

4. 4. The method according to claim 1, wherein the reagent is aspirated into the flow cell line (35) for washing the flow cell line after the diluted biological sample has been analyzed.

5. 5. The method of claim 4, wherein the flow cell line cleaning includes cleaning the dilution pot (20), cleaning the flow cell (30), cleaning the flow cell line (35), and cleaning the discharge line (50).

6. 6. The method according to claim 1, wherein the diluted biological sample and / or the reagent are aspirated into the bypass line (40) before and / or after aspirating into the flow cell line (35).

7. 7. The method of claim 1, further comprising the steps of: dispensing the reagent from the reagent supply line (10) into the dilution pot (20) after cleaning the flow-type cell line (35); aspirating the reagent into the flow-type cell line (35); and calibrating the flow-type cell (30) using the reagent.

8. 8. The method according to claim 1, wherein the first pump (80) is configured to pump the reagent from the reagent supply line (10) and the second pump (81) is configured to aspirate the reagent and / or the biological sample.

9. 9. The method of claim 1, wherein the reagent comprises an internal standard.

10. 10. The method of any one of claims 1 to 9, wherein the reagent supply line (10) is configured to dispense at least a first reagent and at least a second reagent.

11. 11. The method of claim 10, wherein the ion selective electrode analyzer (1) further comprises a second reagent supply line (11), the reagent supply line (10) containing a first reagent and the second reagent supply line (11) containing a second reagent.

12. 12. The method according to claim 10 or 11, wherein the first reagent comprises an internal standard solution, which is used to wash the flow cell line (35) and / or to calibrate the flow cell (30), and the second reagent comprises a buffer solution, which is used to dilute the biological sample and / or to wash the bypass line (40).

13. 13. The method of claim 12, wherein the buffer is phosphate buffered saline, neutral salt, deionized water, or a mixture thereof.

14. 14. The method according to any one of the preceding claims, wherein the at least two pumps (80, 81) are configured to dispense and / or aspirate fixed or variable amounts.

15. 15. The method according to any one of claims 1 to 14, wherein the ion selective electrode analyzer (1) further comprises at least a first valve, the first valve being a three-way valve (60) or a pinch valve (61).

16. 16. The method of claim 15, wherein when the first valve is a pinch valve (61), the ion selective electrode analyzer (1) further comprises a Y-connector (62).

17. 17. The method of claim 15 or 16, wherein the first valve is used to select the flow cell line (35) or the bypass line (40) for aspirating or dispensing the biological sample or for aspirating or dispensing the reagent.

18. 18. The method of any one of claims 15 to 17, wherein the ion selective electrode analyzer (1) further comprises a second valve, the second valve being a three-way valve (63).

19. 19. The method of claim 18, wherein at least one of the at least two pumps (80, 81) is a syringe pump.

20. 20. The method according to claim 18 or 19, wherein at least one of the two pumps (80, 81) is connected to the discharge line (50) via the second valve (63), the second valve (63) being located in or near the middle of the discharge line (50).

21. 21. The method of claim 20, wherein a volume of a tube (90) between the second valve (63) and the second pump (81) is greater than a volume the second pump (81) is configured to draw.

22. 22. The method of claim 20 or 21, wherein the position of the second valve (63) separates the discharge line (50) into a pre-flushing portion and a post-flushing portion.

23. 23. The method of any one of claims 18 to 22, wherein the ion selective electrode analyzer (1) further comprises at least a third pump (82).

24. 24. The method of claim 23, wherein the ion selective electrode analyzer (1) further comprises a flushing liquid line (70) and a third valve, the third valve being a two-way valve (64).

25. 25. The method of claim 24, wherein a flushing liquid line (70) connects the second pump (81) and the third pump (82), and the third valve (64) is located at or near the middle of the flushing liquid line (70).

26. The method of any one of claims 23 to 25, wherein the third pump (82) is further configured to pump flushing liquid.

27. 27. The method of claim 26, wherein the flushing liquid is deionized water.

28. 28. The method of any one of claims 23 to 27, wherein the ion selective electrode analyzer (1) further comprises a fourth pump (83).

29. 29. The method of claim 28, wherein the fourth pump (83) is connected to the second reagent supply line (11).

30. 30. The method of any one of claims 1 to 29, wherein the biological sample is selected from the group consisting of blood, plasma, serum, saliva, urine, cerebrospinal fluid, tears, sweat, gastrointestinal fluid, amniotic fluid, mucosal fluid, pleural fluid, and sebaceous oil.

31. 31. The method of any one of claims 1 to 30, wherein the biological sample is from a mammal.

32. 32. The method of any one of claims 1 to 31, wherein the amount of biological sample mixed with the reagent is at least 5 μL.

33. 33. The method of any one of claims 1 to 32, wherein the volume of reagent mixed with the biological sample is at least 300 μL.

34. 34. The method of any one of claims 1 to 33, wherein the method operates in a cycle of about 20 seconds.

35. An ion-selective electrode analyzer (1), comprising: at least one reagent supply line (10) further containing at least one reagent; a dilution pot (20) for receiving said reagent; a flow-type cell (30) downstream from said dilution pot (20); a flow cell line (35) operatively connected to the flow cell (30); a bypass line (40) operatively connected to said dilution pot (20); a discharge line (50); a flushing liquid line (70); at least three pumps, a first pump (80), a second pump (81), and a third pump (82); a first valve, a three-way valve (60) or a pinch valve (61); a second valve, a three-way valve (63); a third valve, a two-way valve (64); An ion-selective electrode analyzer (1).

36. 36. The ion-selective electrode analyzer (1) according to claim 35, wherein when the first valve is a pinch valve (61), the ion-selective electrode analyzer (1) further comprises a Y-connector (62).

37. 37. An ion selective electrode analyzer (1) according to claim 35 or 36, wherein the ion selective electrode analyzer (1) further comprises a second reagent supply line (11).

38. 38. An ion selective electrode analyzer (1) according to any one of claims 35 to 37, wherein at least one of the first pump (80) or the second pump (81) is a syringe pump.

39. 39. The ion selective electrode analyzer (1) of claim 38, wherein both the first pump (80) and the second pump (81) are syringe pumps.

40. 40. The ion selective electrode analyzer (1) according to any one of claims 35 to 39, wherein at least one of the first pump (80) or the second pump (81) is connected to the discharge line (50) via the second valve (63), and the second valve (63) is located in or near the middle of the discharge line (50).

41. 41. The ion selective electrode analyzer (1) according to any one of claims 35 to 40, wherein the third valve (64) is located in the middle or near the flushing liquid line (70) connecting the second pump (81) and the third pump (82).

42. 42. The ion selective electrode analyzer (1) according to any one of claims 35 to 41, wherein the ion selective electrode analyzer (1) further comprises a fourth pump (83).

43. 43. An ion selective electrode analyzer (1) according to claim 42, wherein the fourth pump (83) is connected to the second reagent supply line (11).

44. 44. The ion-selective electrode analyzer (1) according to any one of claims 35 to 43, wherein the ion-selective electrode analyzer (1) further comprises an exhaust (52), and the exhaust line (50) is operatively connected to the exhaust (52).

45. 36. The ion selective electrode analyzer (1) of claim 35, wherein the ion selective electrode analyzer (1) is configured to analyze at least 200 biological samples per hour.

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