Methods for sensor calibration

Abstract

Disclosed herein is an in vitro diagnostic (IVD) analyzer (200) comprising at least one sensor (212) disposed in a flow-through sensor path (211) of a detection unit and requiring at least one oxygenated calibration fluid (221', 222') for calibration. The IVD analyzer (200) further comprises a fluid supply unit (220) containing at least one deoxygenated calibration fluid (221, 222), a fluid selection valve (230), and at least one oxygenation tube (215, 216) having two ends connected to the fluid selection valve (230) as a loop, the oxygenation tube (215, 216) having an oxygen-permeable wall, and the IVD analyzer (200) comprises a pump (240) and a flow path (240) for supplying the deoxygenated calibration fluid (221, 222) to the oxygenated calibration fluid. and a controller (250) configured to control the pump (240) and the fluid selection valve (230) to transfer the deoxygenated calibration fluid (221, 222) into the tubing (215, 216), wait a predetermined time required for oxygenation of the deoxygenated calibration fluid (221, 222) via uptake of oxygen from ambient air through the walls of the tubing, and transfer the resulting oxygenated calibration fluid (221′, 222′) to the sensor path (211) for calibration of the at least one sensor (212). Respective automatic methods for calibrating the at least one sensor (212) are also disclosed herein.

Description

[Technical Field]

[0001] The present invention relates to an automated method for calibrating sensors placed in a flow-through sensor pathway and requiring at least one oxygenated calibration fluid for calibration, as well as to the respective in-vitro diagnostic analyzer. [Background technology]

[0002] In healthcare, physician diagnoses and patient treatment often rely on the measurement of parameters in patient samples performed by in-vitro diagnostic analyzers. It is crucial that analyzers function properly by providing accurate and reliable measurements. Therefore, implementing workflows that ensure analytical performance is a common requirement for in-vitro diagnostic analyzers. One of these procedures is calibration. In most cases, calibration is performed using standard solutions with known concentrations or parameters. In this way, the measured signal can be related to a quantitative result. Calibration needs to be performed with some frequency, depending on the system and other variables that may affect performance.

[0003] Blood gas and electrolyte tests include partial pressures of blood gases (pO2, pCO2), oxygen saturation (SO2), pH value, and electrolyte concentrations (e.g., Na + , K. + , Mg2 + , Ca2 + , Li + , Cl - ), bicarbonate value (HCO3 - Parameters such as blood glucose, metabolic activity, metabolic activity (e.g., glucose, lactate, urea, creatinine), hemoglobin and hemoglobin derivatives (e.g., tHb, OHb, HHb, COHb, MetHb, SulfHb), bilirubin levels, and hematocrit are determined from the patient sample.

[0004] Typically, these parameters are determined by conductivity, electrochemical, and / or optical measurement principles. Sensors configured to measure such sample parameters based on these measurement principles may be combined, for example, sequentially arranged in one or more flow-through sensor paths. This allows for simultaneous and / or sequential determination of multiple parameters from a single sample in one test run.

[0005] Some metabolite sensors, such as glucose and lactate sensors, require the presence of oxygen to perform measurements. Therefore, to calibrate these sensors, a calibration fluid containing lactate and / or glucose, respectively, and also containing known levels of oxygen, is required. However, glucose / lactate and oxygen cannot be stored together as a ready-to-use calibration fluid because they react with each other, thereby changing their respective contents over storage time. Therefore, glucose / lactate calibration fluids are typically stored without oxygen, and oxygen must be added immediately before sensor calibration in a process called tonometry. This process typically involves drawing a predetermined amount of deoxygenated calibration solution into a fluid line made from a material that allows oxygen from ambient air to pass through, such as silicone, and then drawing this newly oxygenated (tonometered) calibration fluid into the sensor path. Waiting a predetermined time for oxygen to diffuse through the walls of the fluid line into the calibration fluid until the required oxygenation level is reached before calibrating the sensor.

[0006] Tonometry is only one of the steps required to perform the calibration procedure, and because different fluids are transferred sequentially through the same fluid line via the same pump, waiting for diffusion can unduly extend the calibration time. Also, because several calibration fluids that require tonometry may be required, for example, to perform a multi-point calibration, the tonometry process may take additional time. Summary of the Invention

[0007] It is against the above background that aspects of the present disclosure provide certain unobvious advantages and advancements over the prior art. In particular, disclosed herein is a new, automated method for calibrating sensors placed in the flow-through sensor path of a detection unit of an in vitro diagnostic (IVD) analyzer that involves reaction with oxygen in the sample to determine sample parameters and requires at least one oxygenated calibration fluid with a certain level of oxygenation for calibration, which allows for tonometry of deoxygenated calibration fluids without unnecessarily extending calibration time by preventing blocking use of the fluidic system and pumps while waiting for tonometry, and / or by allowing parallel steps during calibration.

[0008] In particular, the method includes controlling a pump and a fluid selection valve with a controller to transfer a deoxygenated calibration fluid from a fluid supply unit into an oxygenation tubing having two ends connected as a loop to a fluid selection valve, the oxygenation tubing having an oxygen permeable wall, the fluid selection valve having one or more fluid input ports for selecting at least one fluid at a time and a common outlet port fluidly connected or connectable to a sensor pathway via a fluid line. The method further includes waiting a predetermined time required to oxygenate the deoxygenated calibration fluid via uptake of oxygen from ambient air through the wall of the tubing until a required level of oxygenation is obtained, thereby obtaining an oxygenated calibration fluid, and transferring the oxygenated calibration fluid thus obtained to the sensor pathway to calibrate at least one sensor.

[0009] Also disclosed herein is an in-vitro diagnostic analyzer configured to perform the automated method and offer the same advantages.

[0010] As used herein, the term "in vitro diagnostic analyzer" or "IVD analyzer" refers to an automated or semi-automated analyzer configured to test samples in vitro to provide information for screening, diagnostic, and treatment monitoring purposes. IVD analyzers are designed and configured according to the medical field of application, the parameters to be determined, and the corresponding laboratory workflow. For example, in point-of-care testing environments, IVD analyzers can range from handheld devices with low throughput, short turnaround times, and a limited number of measurable parameters to compact benchtop instruments with higher throughput and a larger number of measurable parameters. Such IVD analyzers are designed to detect specific types of parameters, such as gases, electrolytes, metabolites, clinical chemistry analytes, immunochemistry analytes, coagulation parameters, hematology parameters, etc. Depending on the parameter of interest, a variety of different analytical methods and different detection technologies can be applied. For example, in the field of blood gas and electrolyte testing, electrochemical measurement principles, conductivity measurement principles, and / or optical detection methods are used. An IVD analyzer typically comprises multiple functional units, each dedicated to a specific task and cooperating with each other to enable automated sample processing and analysis. Such functional units may include, for example, a sample input interface for receiving samples, a fluidic system, an analytical measurement or detection unit, a fluid supply unit, etc. One or more functional units may be integrated into a larger unit or module to simplify the operation of the IVD analyzer.

[0011] In particular, the disclosed in vitro diagnostic (IVD) analyzer includes at least one sensor disposed in a flow-through sensor path of a detection unit that involves reaction with oxygen in the sample to determine a sample parameter and requires at least one oxygenated calibration fluid with a certain level of oxygenation for calibration. The IVD analyzer further includes a fluid supply unit containing at least one deoxygenated calibration fluid, and a fluid selection valve including one or more fluid input ports for selecting at least one fluid at a time and a common outlet port fluidically connected or connectable to the sensor path via a fluid line. The IVD analyzer further includes at least one oxygenation tube having two ends, each connected to the fluid selection valve and thereby forming a loop, the oxygenation tube including an oxygen-permeable wall. The IVD analyzer further comprises a pump and a controller configured to control the pump and the fluid selection valve to transfer at least one deoxygenated calibration fluid from the fluid supply unit into the oxygenation tubing, wait a predetermined time required for oxygenation of the deoxygenated calibration fluid via uptake of oxygen from ambient air through the walls of the tubing until a required level of oxygenation is obtained, and transfer the oxygenated calibration fluid thereby obtained to the sensor path for calibration of the at least one sensor.

[0012] A "detection unit" according to the present disclosure is an analytical measurement unit of an IVD analyzer that includes at least one flow-through sensor path. A "flow-through sensor path" is a fluid conduit that is contacted by a sample flowing through the sensor path and may include one or more sensors, e.g., sequentially arranged along the path, e.g., one sensor for each different parameter / analyte to be detected, and may be embodied in an exchangeable cartridge-like structure with multiple sensors distributed across multiple sensor paths. Alternatively, an IVD analyzer may include multiple detection units, each with a sensor path that includes a sensor dedicated to one parameter / analyte, which may or may not be exchangeable. Thus, a sample may flow through one or more sensor paths, and different parameters / analytes may be determined by the respective sensors. The detection unit may also optionally include a flow-through optical measurement unit. The flow-through sensor path may be an integrated part of the fluidic system of the IVD analyzer, or part of a separate component, e.g., a sensor cartridge, fluidically connected to the fluidic system of the IVD analyzer, such that at least one fluid line and at least one sensor path are fluidly connected.

[0013] The term "sensor" is used generally herein to refer to a detector configured to detect a sample parameter by generating a correlated signal output that can be quantified and digitized. The sensor can be, for example, a biosensor, a chemical sensor, or a physical sensor, and is typically part of a functional unit of an IVD analyzer, such as an analytical measurement unit or a detection unit. A sensor can be selective or specific with respect to one sample parameter of interest, or can be configured to detect and quantify multiple different sample parameters of interest. Depending on the sensor type, a sensor can comprise multiple sensor elements. The term "sensor element" therefore refers to a portion of a sensor (e.g., working electrode, reference electrode, counter electrode) that, in combination with one or more other sensor elements, forms a fully functional sensor.

[0014] According to a particular embodiment, the detection unit includes a pO2 sensor, a pCO2 sensor, a pH sensor, a Na + , K. + , Ca2 + and Cl - and one or more ion selective electrode (ISE) sensors for determining electrolyte values ​​such as ATP, ATP, and one or more metabolite sensors for determining parameters such as lactate and glucose. The sensors may be based, for example, on amperometric, potentiometric, or conductometric principles, respectively.

[0015] For example, pO2 sensors generally function according to the Clark measurement principle. This means that oxygen diffuses through a membrane into a negatively charged gold multi-wire system inside the sensor. There, oxygen is reduced, generating a current proportional to the oxygen content of the sample. This current is measured amperometrically.

[0016] pCO2 sensors are typically Severinghouse-type sensors, meaning that CO2 diffuses through a membrane similar to that of an oxygen sensor. In the sensor, changes in CO2 concentration cause a correlated change in the pH value of an internal buffer system, which is measured potentiometrically.

[0017] A pH sensor typically contains a pH-sensitive membrane. Depending on the pH value of the test sample, a potential is generated at the boundary layer between the membrane and the sample. This potential can be measured potentiometrically by a reference sensor.

[0018] Na + , K. + , Ca 2+ , Cl - ISE sensors usually operate according to the potentiometric measurement principle and differ only in the membrane material that allows them to be sensitive to the respective electrolytes.

[0019] Glucose sensors typically utilize the glucose oxidase enzyme, whereby glucose is oxidized to gluconolactone by oxygen available in the sample. The H2O2 produced in this process is measured amperometrically by a manganese dioxide / carbon electrode.

[0020] Lactate sensors typically utilize the enzyme lactate oxidase, which oxidizes lactate to pyruvate with oxygen available in the sample. The H2O2 produced in this process is measured amperometrically, similar to glucose sensors.

[0021] According to an embodiment, the at least one sensor is a metabolite sensor, including at least one of a glucose sensor and a lactate sensor, or any other biosensor that involves a reaction with oxygen.

[0022] A "fluid line" can include one or more hollow conduits, such as tubing, channels, chambers, or combinations thereof, with one or more components suitable for passing fluid through them in at least a liquid-tight manner, and can have any shape and size, but is typically part of a larger fluid system that is optimized to minimize internal volume and dead volume. Components may be flexible, rigid, elastic, or combinations thereof. One or more fluid lines can be at least partially connected or connectable to one another, for example, via fluid connections and / or valves.

[0023] The term "fluid selection valve" refers to a flow regulation device for controlling, diverting, restricting, or stopping flow, particularly a switching valve or rotary valve, which is a multiport valve that allows for the selection of fluid connections. This is typically accomplished by moving one or more valve conduits to switch communication between different elements. Elements may be fluidly connected via additional conduits, such as pipes, tubing, capillaries, microfluidic channels, etc. For example, the valves may be integrated into a manifold that includes channels and respective input ports for each fluid reservoir, and upon switching of the valve, e.g., by rotation, a fluid connection is established between one fluid reservoir at a time and a common outlet port that is connected or connectable to, for example, a fluid line leading to a flow-through sensor path. Alternatively, the manifold may include input ports for each fluid reservoir that all communicate with a common channel and common fluid input port of the fluid selection valve, in which case individual on / off valves may be positioned corresponding to each fluid reservoir or fluid input port to allow selected fluids from the selected fluid reservoirs to flow to the common channel and fluid selection valve. The valve may include other input ports for other fluids, such as ambient air and / or sample.

[0024] The IVD analyzer also includes at least one pump, such as a peristaltic pump, a syringe pump, a membrane pump, or any other suitable pump, for transporting a sample from a sample container, other fluids from a fluid supply unit, or ambient air through at least one fluid line and past the detection unit. In particular, the pump is used to transport deoxygenated calibration fluid from the fluid supply unit through the fluid selection valve to the oxygenation line and the resulting oxygenated calibration fluid from the oxygenation line to the sensor path. The pump is typically located downstream of the detection unit, but may be located anywhere else and may be connected to the fluid system via additional elements such as valves and switches. The pumping direction may also be reversible.

[0025] As used herein, a "fluid supply unit" is a module or component of an IVD analyzer that includes one or more fluid reservoirs and, optionally, one or more waste containers into which fluids circulating through the fluid system can be discarded at the end of the process. The term "fluid" can refer to either a gas or a liquid or a mixture thereof. The fluid may be, for example, a sample, a reagent, a reference fluid such as a quality control fluid or a calibration fluid, a cleaning fluid, a wetting fluid, air, or another gas.

[0026] The sample typically enters the fluid system via a sample input interface distinct from the fluid supply unit, i.e., a separate module or component of the in-vitro diagnostic analyzer that is typically located in a location conveniently accessible to the operator and configured to transfer the sample into the in-vitro diagnostic analyzer from a sample container lifted by the operator. The sample input interface may, for example, comprise a sample input port having an outer input port side configured to couple, attach, connect, seat, introduce, or plug in, e.g., a capillary- or syringe-type sample container, and an inner input port side for coupling or coupling to one end of a sample input conduit, which is fluidly connected or connectable at its other end to a detection unit / sensor pathway, e.g., directly or via a fluid selection valve. According to embodiments, the sample input conduit is the same fluid line that runs from the fluid selection valve to the sensor path, and is configured to alternately connect by the same end to the inner input port side and the fluid selection valve, for example, directly to the outlet port of the fluid selection valve or via an additional conduit to an additional port connected to the outlet port of the fluid selection valve, to alternately draw sample and non-sample fluids from the sample input port through the fluid selection valve, and the other end is connected to the detection unit / sensor path. According to embodiments, when the fluid line also serves as a sample input conduit, it can be at least partially embodied as a rigid suction needle configured to be coupled to the inner input port side of the sample input port and to the outlet port of the fluid selection valve or an extension thereof. According to embodiments, ambient air can also be aspirated into the fluid line directly through the sample input port or via a dedicated air port of the fluid selection valve.

[0027] A "calibration fluid" is a reference or standard solution, typically provided in a fluid supply unit, that contains known values ​​of one or more calibrants used in calibration and is measured under the same conditions as a biological sample. A calibrant can be the analyte of interest potentially present in a biological sample and detected by a particular sensor; it can be the same as an analyte whose concentration is known or whose reaction produces an analyte identical to the analyte of interest, or it can be any other equivalent concentration substance, such as a dye that optically behaves similarly to the analyte of interest, that mimics a sample parameter of interest or can otherwise be correlated with a particular parameter of interest. Typically, one or two calibration fluids are used for one-point or two-point calibrations, respectively, if the sensor responds linearly to analyte concentration. Three or more calibration fluids may be used if the calibration curve is nonlinear. In particular, calibration fluids may be provided at different levels corresponding to different concentration ranges of the calibrant.

[0028] In particular, at least one deoxygenated calibration fluid is provided in the fluid supply unit according to the present disclosure. The term "deoxygenated" refers to a zero or sufficiently low oxygen level so that the content of any other calibrants in the calibration fluid does not change significantly over storage time as a result of reaction with the oxygen contained therein. In other words, the level or partial pressure of oxygen in the calibration fluid is such that the shelf life of the calibration fluid is not affected by the oxygen level. Deoxygenation can be achieved during manufacturing, for example, by degassing the solvent used in the calibration fluid or by replacing oxygen with another inert gas, or generally by performing the manufacturing process in an oxygen-depleted environment so that oxygen uptake from the air is prevented before the calibration fluid is sealed in a liquid and airtight fluid reservoir. To maintain low or near-zero oxygen levels during storage, for example, a chemical oxygen scavenger can be used in the deoxygenated calibration fluid to interact with and neutralize oxygen that eventually permeates into the fluid reservoir during storage, but whose reaction rate is slow enough not to interfere with the oxygenation process in the fluid lines.

[0029] The deoxygenated calibration fluid is oxygenated in the oxygenation tubing only in the amount required for calibration and immediately before use for calibration. In particular, the "oxygenation tubing" is a fluid conduit that is only liquid-tight and therefore transmits oxygen at least from the ambient air, unlike other parts of the fluid system, which are both liquid-tight and gas-tight to avoid affecting sample parameters during transport. Therefore, the oxygenation tubing includes those with oxygen-permeable walls, i.e., made of an oxygen-permeable material, such as silicone.

[0030] According to an embodiment, the IVD analyzer includes an oxygenation tube for each different deoxygenated calibration fluid to be oxygenated.

[0031] Thus, according to an embodiment, the method includes transferring a different deoxygenated calibration fluid to each oxygenation line to be oxygenated.

[0032] The term "oxygenation" with respect to a calibration fluid refers to the level of oxygenation or oxygen partial pressure obtained after transferring the deoxygenated calibration fluid to the oxygenation tubing and waiting a predetermined time for oxygen uptake from ambient air through the walls of the oxygenation tubing. The predetermined time is the time required to achieve a level near saturation or equilibrium that corresponds to the required level of oxygenation or oxygen partial pressure that is optimally suited and / or sufficient for calibrating at least one sensor; extending this waiting time contributes negligibly to further increasing the level of oxygenation and unnecessarily prolongs the process. The resulting oxygen partial pressure of the oxygenated calibration fluid is typically about 80-90% of the oxygen partial pressure in ambient air, or about 110-170 mmHg, depending, for example, on altitude.

[0033] The only difference between the deoxygenated and oxygenated calibration fluids according to the present disclosure is their different oxygenation levels.

[0034] As used herein, the term "controller" may include any physical or virtual processing device, particularly a programmable logic controller, that executes a computer-readable program with instructions to perform operations according to an operating plan, particularly according to the process of calibrating a sensor disclosed herein. This may include a processor, controller, central processing unit (CPU), microprocessor, microcontroller, reduced instruction set circuit (RISC), application specific integrated circuit (ASIC), logic circuit, or other circuit or processor configured to perform one or more of the functions / methods described herein. In particular, the controller is configured to control a pump and fluid selection valve to transfer deoxygenated calibration fluid from a fluid supply unit to an oxygenation tubing, wait a predetermined time required for oxygenation of the deoxygenated calibration fluid via oxygen uptake from ambient air through the tubing wall, and transfer the resulting oxygenated calibration fluid to a sensor path for calibration of at least one sensor.

[0035] According to an embodiment, the controller is further configured to control the pump and fluid selection valve to transfer any other fluid from the fluid supply unit into the sensor path while at least one oxygenation line is fluidly isolated and the deoxygenated calibration fluid is oxygenated.

[0036] Thus, according to an embodiment, the method includes controlling a pump and a fluid selection valve to transfer any other fluid from the fluid supply unit into the sensor path while at least one oxygenation line is fluidly isolated and the deoxygenated calibration fluid is oxygenated.

[0037] According to an embodiment, the controller is further configured to control the pump and fluid selection valve to transfer oxygenated calibration fluid from the oxygenation tubing into the sensor pathway while introducing fresh deoxygenated fluid into the oxygenation tubing to be oxygenated.

[0038] Thus, according to an embodiment, the method includes controlling a pump and a fluid selection valve to transfer oxygenated calibration fluid from the oxygenation tubing into the sensor pathway while introducing new deoxygenated fluid into the oxygenation tubing to be oxygenated.

[0039] Other and further objects, features and advantages will become apparent from the following description of illustrative embodiments and the accompanying drawings which more particularly explain the principles. [Brief explanation of the drawings]

[0040] [Figure 1A] 1 illustrates a schematic diagram of an in vitro diagnostic analyzer including a flow-through sensor path and a first step of an automated method for calibrating a sensor located within the flow-through sensor path. [Figure 1B] 1B shows the same in vitro diagnostic analyzer as in FIG. 1A and the second step of the same automated method. [Figure 1C] 1A-1B show a schematic representation of the same in vitro diagnostic analyzer and the third step of the same automated method. [Figure 1D] 1A-1C show a schematic representation of the same in vitro diagnostic analyzer and the fourth step of the same automated method. [Figure 1E] 1A-1D show the same in vitro diagnostic analyzer and a fifth step of the same automated method. [Figure 2] 1A-1E show the same in vitro diagnostic analyzer and steps for transferring a sample for analysis after sensor calibration. [Figure 3] 1A-1E show a schematic diagram of the same in vitro diagnostic analyzer and a variation of the steps shown in FIG. 1E. [Figure 4] 1B shows in cross section, in greater detail, portions of the fluid selection valves incorporated into the manifold and oxygenation tubing during the steps shown in FIG. 1A. [Figure 5] 3. It shows the same details as in FIG. 4 during the steps shown in FIG. [Figure 6] It looks similar to FIG. 4 but relates to the steps shown in FIG. 1D. [Figure 7] Due to the oxygen uptake in the oxygenation tube, the progressive levels of oxygenation achieved at different given times are shown.

[0041] Those skilled in the art will appreciate that elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale. For example, the dimensions of some elements in the figures may be exaggerated relative to other elements, while other elements may be omitted or represented in reduced number to improve clarity and to enhance an understanding of aspects of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0042] 1A-1E, taken together, schematically illustrate an example in-vitro diagnostic analyzer 200 including a flow-through sensor pathway 211 according to the present disclosure, as well as an automated method for calibrating a sensor 212 disposed in the flow-through sensor pathway 211. In particular, the in-vitro diagnostic analyzer 200 includes a detection unit 210 including a flow-through sensor pathway 211 that includes at least one sensor 212 that involves reacting with oxygen in the sample to determine a sample parameter and that requires at least one oxygenated calibration fluid with a certain level of oxygenation for calibration. According to an embodiment, the at least one sensor 212 is a metabolite sensor, including at least one of a glucose sensor and a lactate sensor.

[0043] The IVD analytical device 200 further comprises a fluid supply unit 220 containing at least one deoxygenated calibration fluid 221, 222 among other fluids 223, a fluid selection valve 230 for selecting at least one fluid 221, 222, 223 at a time, and a fluid line 213 comprised between the valve 230 and the sensor path 211. The IVD analytical device 200 further comprises a sample input interface 100 comprising a sample input port 10 with an outer input port side 11 and an inner input port side 12 configured to receive the open end of a sample container 1. The sample container 1 is a capillary-shaped sample container in this example. The sample input interface 100 further comprises an aspiration needle 30 with an upstream end 31 and a downstream end 32. The downstream end 32 of the aspiration needle 30 is fluidly connected to the sensor path 211 via a fluid line 213, while the upstream end 31 is configured to alternately couple to the inner input port side 12 for aspirating a sample from a sample container 1 inserted in the outer input port side 11, and to a fluid supply unit port 40 fluidly connected via a further conduit 214 to a common outlet port 231 of the fluid selection valve 230. However, the fluid line 213 may also be connected directly to the outlet port 231 of the fluid selection valve 230, and the sample may be introduced, for example, via different fluid lines separately connected to the fluid selection valve 230. The fluid selection valve also comprises an air port 232. The IVD analyzer 200 further comprises, in this example, two oxygenation tubes 215, 216, each having two ends connected to the fluid selection valve 230 as a loop, the oxygenation tubes comprising oxygen-permeable walls.

[0044] The IVD analysis device 200 further comprises a pump 240, such as a peristaltic pump, arranged downstream of the sensor path 211, and a waste container 224 arranged in the fluid supply unit 220, through which the fluid circulating through the fluid line 213 and the sensor path 211 can be discarded.

[0045] The IVD analyzer 200 further comprises a controller 250 configured to automatically perform any of the method steps disclosed herein.

[0046] 1A schematically illustrates, with fluid locations indicated by bold lines, a first step in an automated method for calibrating at least one sensor 212 disposed in a flow-through sensor path 211 of a detection unit 210 of an in vitro diagnostic (IVD) analyzer 200, which involves reaction with oxygen in the sample to determine sample parameters and requires at least one oxygenated calibration fluid with a certain level of oxygenation for calibration. The method includes controlling a pump 240 and a fluid selection valve 230 by a controller 250 to transfer a first deoxygenated calibration fluid 221 from a fluid supply unit 220 into a first oxygenation line 215.

[0047] The method continues by waiting a predetermined time required to oxygenate the deoxygenated calibration fluid 221 via uptake of oxygen from ambient air through the walls of the oxygenation tubing 215 until a required level of oxygenation is obtained, thereby obtaining a first oxygenated calibration fluid, as shown in Figure 1B. The method further includes transferring a second deoxygenated calibration fluid 222 to be oxygenated to a second respective oxygenation tubing 216 while the first oxygenation tubing 215 is fluidly isolated and the first deoxygenated calibration fluid 221 is being oxygenated.

[0048] As shown in FIG. 1C, the method further includes controlling pump 240 and fluid selection valve 230 to transfer any other fluid 223 from fluid supply unit 220 to sensor path 211 while oxygenation lines 215, 216 are fluidly isolated and the calibration fluid is oxygenated.

[0049] 1D and 1E, the method further includes transferring the resulting first oxygenated calibration fluid 221′ from the oxygenation tubing 215 into the sensor pathway 211 and calibrating at least one sensor 212 while the second deoxygenated calibration fluid 222 continues the oxygenation step. Upon completion of the oxygenation step for the second deoxygenated calibration fluid 222, the method also includes transferring the resulting second oxygenated calibration fluid 222′ from the second oxygenation tubing 216 into the sensor pathway 211 and calibrating at least one sensor 212 (not shown).

[0050] FIG. 2 schematically illustrates the same in-vitro diagnostic analyzer 200 as in FIGS. 1A-1E and the steps of transferring a sample 2 from a sample container 1 inserted into the outer input port side 11 of the sample input port 10 for analysis by the sensor 212 after calibration according to the method of FIGS. 1A-1E, but with the upstream end 31 of the aspiration needle 30 coupled to the inner input port side 12 of the sample input port 10. After calibration and before transferring the sample, an intermediate wash step with another fluid may be performed (not shown). In this case, the controller 250 is also configured to control the aspiration needle 30 to alternately couple to the inner input port side 12 to aspirate the sample from the sample container 1 inserted into the outer input port side 11 into the fluid supply unit port 40 to perform other steps. The steps of transferring the sample and analyzing the sample may also be performed while the calibration fluid is in the oxygenation line and the oxygenation step is ongoing.

[0051] In general, the methods of Figures 1A-1E allow for tonometry of deoxygenated calibration fluids without unnecessarily extending calibration times by preventing the fluid system and pumps from being blocked while waiting for oxygenation, and / or allowing for parallel steps in between.

[0052] Figure 3 shows a schematic diagram of the same in-vitro diagnostic analyzer as Figures 1A-1E and a variation of the steps shown in Figure 1E. This variation of the method involves controlling pump 240 and fluid selection valve 230 to transfer oxygenated calibration fluid 221' from oxygenation tubing 215 into sensor pathway 211 while introducing fresh deoxygenated fluid 221 into oxygenation tubing 215 to be oxygenated.

[0053] 4 shows in more detail perspective and cross-sectional views of components of an embodiment including a fluid selection valve 230 integrated into a manifold 260, an oxygenation tube 215 connected in a loop to the manifold 260, and a fluid reservoir 225 having an on / off valve 226 also connected to the manifold 260. In particular, the manifold 260 includes a channel 261 and respective input ports 262, 263 for each fluid reservoir 225 (only one fluid reservoir is shown for simplicity). The input ports 262, 263 all lead to the same common channel 261 and common fluid input port 233 of the fluid selection valve 230. Each fluid reservoir 225 includes an individual on / off valve 226 that connects the fluid reservoir 225 to the respective input port 262 of the manifold 260 to allow the selected fluid 221 from the selected fluid reservoir 225 to flow to the common channel 261 and fluid selection valve 230. 1A, including the transfer of deoxygenated calibration fluid 221 from fluid reservoir 225 to oxygenation tubing 215 (only one oxygenation tubing is shown for simplicity). In particular, fluid selection valve 230 is in a switch position obtained by rotation of actuation member 234, allowing calibration fluid to flow into fluid selection valve 230 via fluid input port 233, through fluid selection valve 230, through oxygenation tubing 215, and back through fluid selection valve 230 via outlet port 231. On / off valve 226 is in an on state, while all other on / off valves (not shown) in other fluid reservoirs (not shown) are in an off state.

[0054] FIG. 5 is a partial front cross-sectional view of similar details and portions to those shown in FIG. 4 . In particular, FIG. 5 further shows a second fluid reservoir 227 containing a fluid 223, in this example different from the calibration fluid, connected to an input port 263 of a manifold 260 via an on / off valve 228. The on / off valve 228 is in an on state, while the on / off valve 226 and all other on / off valves (not shown) in other fluid reservoirs (not shown) are in an off state. The fluid selection valve 230 is in a switch position obtained by rotation of the actuation member 234, allowing the different fluid 223 to flow into the fluid selection valve 230 via the manifold channel 261 and fluid input port 233, through the fluid selection valve 230 to the outlet port 231, and into the sensor path (not shown in FIG. 5 ), while the oxygenation tube 215, in which the calibration fluid is oxygenated, is fluidically isolated. The oxygenation tubing 215 is made of a material that is permeable to oxygen from the ambient air, for example silicone. Thus, Figure 5 also shows, diagrammatically by arrows, the same step shown in Figure 1C of transferring any other fluid 223 from the fluid supply unit to the sensor path while the oxygenation tubing 215 is fluidly isolated and the deoxygenated calibration fluid is oxygenated.

[0055] Figure 6 is similar to Figure 4, but also illustrates the same steps shown in Figure 3, schematically indicated by arrows, which include transferring oxygenated calibration fluid 221' from oxygenation tubing 215 through outlet port 231 to the sensor path (not shown in Figure 6), while introducing new deoxygenated fluid 221 into oxygenation tubing 215 to be oxygenated.

[0056] Continuing with reference to FIGS. 4-6, a controller (not shown) is configured to control the on / off valves 226, 228 as well as the fluid selection valve 230 and pump 240 to select one fluid at a time.

[0057] FIG. 7 illustrates the progressive level of oxygenation of a calibration fluid achieved over time in an oxygenation tube such as that used in the example above, for example, by measuring the partial pressure of oxygen, pO2, in mmHg, at different times by repeating the process with progressively longer wait times and measuring the pO2 of each of the partially oxygenated calibration fluids in the sensor path. It can be seen that it may be necessary to wait several minutes beyond the time shown in the figure to achieve a sufficient level of oxygenation, i.e., typically about 80-90% of the partial pressure of oxygen in ambient air, i.e., about 110-170 mmHg, depending on the altitude, for example. While not explicitly shown in the example above, it is clear that several other steps may be performed during this time, thanks to the fact that the fluid system and pump remain operational during this time.

[0058] Modifications and variations of the disclosed embodiments are, of course, possible in light of the above description, and it is therefore to be understood that, within the scope of the appended claims, the invention may be practiced otherwise than as specifically devised in the examples above.

[0059] In particular, it should be understood that at least some of the drawings or components are schematic and provided for illustrative purposes only, and that the relationship of elements may be other than as shown, and that components not relevant to the gist of the present disclosure have been omitted.

[0060] Also, throughout the foregoing specification, references to "one example" or "an example" mean that the particular feature, structure, or characteristic described in connection with that aspect or example is included in at least one aspect. Thus, the appearances of the phrase "one example" or "an example" in various places throughout this specification do not necessarily all refer to the same embodiment.

[0061] Furthermore, the particular features, structures or characteristics may be combined in any suitable combinations and / or subcombinations in one or more embodiments or examples.

Claims

1. 1. An in vitro diagnostic (IVD) analyzer (200) comprising at least one sensor (212) disposed in a flow-through sensor path (211) of a detection unit (210) that involves reaction with oxygen in the sample to determine a sample parameter and requires at least one oxygenated calibration fluid (221′, 222′) with a certain level of oxygenation for calibration, the IVD analyzer (200) further comprising a fluid supply unit (220) containing at least one deoxygenated calibration fluid (221, 222), and a fluid selection valve (230) including one or more fluid input ports for selecting at least one fluid (221, 222, 223) at a time and a common outlet port (231) fluidically connected or connectable to the sensor path (211) via fluid lines (214, 213), the IVD analyzer (200) further comprising a fluid selection valve (230) including one or more fluid input ports for selecting at least one fluid (221, 222, 223) at a time and a common outlet port (231) fluidically connected or connectable to the sensor path (211) via fluid lines (214, 213), the fluid selection valve (230) including at least one oxygenated calibration fluid (221′, 222′) having two ends connected as a loop to the fluid selection valve (230). The IVD analyzer (200) further comprises deoxygenated calibration fluids (221, 222) from the fluid supply unit (220) into the oxygenation tubing (215, 216), the oxygenation tubing (215, 216) having oxygen-permeable walls, and the IVD analyzer (200) further comprises a pump (240) and a controller (250) configured to control the pump (240) and the fluid selection valve (230) to transfer deoxygenated calibration fluids (221, 222) from the fluid supply unit (220) into the oxygenation tubing (215, 216) and to permeate the walls of the tubing until a required level of oxygenation is achieved. and a controller (250) configured to control the pump (240) and the fluid selection valve (230) to wait a predetermined time required for oxygenation of the deoxygenated calibration fluid (221, 222) via uptake of oxygen from the ambient air passing therethrough, and to transfer the resulting oxygenated calibration fluid (221′, 222′) into the sensor path (211) for calibration of the at least one sensor (212).

2. The IVD analyzer (200) of claim 1, wherein the at least one sensor (212) is a metabolite sensor including at least one of a glucose sensor and a lactate sensor.

3. 3. The IVD analyzer (200) of claim 1 or 2, comprising an oxygenation tube (215, 216) for each different deoxygenated calibration fluid (221, 222) to be oxygenated.

4. 4. The IVD analysis device (200) of claim 1, wherein the controller is further configured to control the pump (240) and the fluid selection valve (230) to transfer any other fluid (223) from the fluid supply unit (220) into the sensor path (211) while the at least one oxygenation tube (215, 216) is fluidly isolated and the deoxygenated calibration fluid (221, 222) is oxygenated.

5. 5. The IVD analyzer (200) of claim 1, wherein the controller (250) is further configured to control the pump (240) and the fluid selection valve (230) to transfer the oxygenated calibration fluid (221′) from the oxygenation tube (215) into the sensor path (211) while introducing new deoxygenated fluid (221) into the oxygenation tube (215) to be oxygenated.

6. 1. An automatic method for calibrating a sensor (212) disposed in a flow-through sensor path (211) of a detection unit (210) of an in vitro diagnostic (IVD) analyzer (200), which involves reaction with oxygen in a sample to determine a sample parameter and requires at least one oxygenated calibration fluid (221′, 222′) with a certain level of oxygenation for calibration, the method comprising controlling a pump (240) and a fluid selection valve (230) by a controller (250); transporting deoxygenated calibration fluids (221, 222) from a fluid supply unit (220) into oxygenation tubing (215, 216) having two ends fluidly connected as a loop to said fluid selection valve (230), said oxygenation tubing (213) comprising an oxygen permeable wall, said fluid selection valve (230) comprising one or more fluid input ports for selecting at least one fluid (221, 222, 223) at a time, and a common outlet port (231) fluidly connected or connectable to a sensor path (211) via fluid lines (214, 213); waiting a predetermined time required for oxygenation of said deoxygenated calibration fluid (221, 222) via uptake of oxygen from the ambient air through the walls of the tube until a required level of oxygenation is obtained, thereby obtaining an oxygenated calibration fluid (221', 222'); transferring the oxygenated calibration fluid (221', 222') thus obtained to the sensor path (211) to calibrate at least one sensor (212); A method comprising controlling.

7. The method of claim 6, wherein the at least one sensor (212) is a metabolite sensor including at least one of a glucose sensor and a lactate sensor.

8. 8. The method of claim 6 or 7, comprising transporting different deoxygenated calibration fluids (221, 222) to be oxygenated into the respective oxygenation tubes (215, 216).

9. 9. The method of claim 6, further comprising controlling the pump (240) and the fluid selection valve (230) to transfer any other fluid (223) from the fluid supply unit (220) to the sensor path (211) while the at least one oxygenation line (215, 216) is fluidly isolated and the deoxygenated calibration fluid (221, 222) is oxygenated.

10. 10. The method of claim 6, further comprising controlling the pump and the fluid selection valve to transfer the oxygenated calibration fluid from the oxygenation line into the sensor path while introducing fresh deoxygenated fluid into the oxygenation line.

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