Sensor calibration

Abstract

A method of calibrating a sensor including a light-emitting compound having a luminescence that depends on the concentration of an analyte and a detector configured to detect light emitted by the light-emitting compound is provided, the method comprising the steps of: providing a component including the light-emitting compound in a package that maintains exposure of the light-emitting compound to the analyte at a first known concentration; assembling the component into the sensor and measuring a first value of a property of the luminescence of the light-emitting compound while the light-emitting compound is exposed to the analyte at the first concentration; measuring a second value of the property of the luminescence of the light-emitting compound while the light-emitting compound is exposed to the analyte at a second known concentration different from the first concentration; and using the first value and the second value to determine a parameter representing the dependence of the property of luminescence on the concentration of the analyte.

Description

[Technical Field]

[0001] This application relates to a method for calibrating a sensor containing a luminescent compound, and more particularly to the calibration of a sensor for detecting the concentration of an analyte in the environment. [Background technology]

[0002] In many areas, it is desirable to be able to determine the concentration of a specific analyte that may contain a mixture of several different substances in the environment. For example, in some clinical settings such as dialysis treatment or monitoring patients in intensive care, it is important to be able to accurately determine the concentration of carbon dioxide or ions such as potassium or sodium in the patient's blood in real time, and providing clinicians in emergency care settings with continuous real-time measurement data is often extremely useful as a means of guiding treatment management. Another example is the monitoring of a controlled environment in the food industry, where the presence of oxygen or other contaminants can be undesirable as it can cause food spoilage.

[0003] A known type of sensor uses a luminescent compound, such as a fluorescent organic dye having luminescence that depends on the concentration of the target analyte. The concentration of the analyte in the sample can be determined by exciting the luminescent compound while the sample containing the analyte is exposed to the compound and measuring its luminescence. This type of sensor can operate continuously and therefore has the advantage of not requiring periodic sampling of samples, such as blood samples or samples in the atmosphere in which food is stored, for analysis or other similarly cumbersome procedures.

[0004] However, in order to be able to rely on the concentration values reported by the sensor, it is necessary to calibrate the sensor to determine the dependence of the luminescence characteristics on the concentration of the analyte. Conventionally, for example, calibration of a luminescence sensor for measuring the concentration of blood gas has required a complex multi-point calibration procedure that utilizes a dedicated tonometer device to provide a controlled concentration of a specific analyte in order to calibrate the sensor. These devices are complex and costly to maintain and operate, and the multi-point calibration procedure is often time-consuming. These factors mean that the process of calibrating the sensor consumes valuable user time and incurs significant costs. The user may, in situations with time constraints, even perform measurements without calibration at all, which may lead to the risky possibility of using untrustworthy measurement values. Due to recent developments, the size of such devices has been reduced and the number of calibration points required has decreased, but separate calibration devices and calibration procedures are still required, which are costly and time-consuming.

Prior Art Documents

Non-Patent Documents

[0005]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

[0006] Therefore, there is a need for calibration procedures for this type of sensor that reduce or eliminate the need for specialized calibration equipment and shorten the operator time required to perform calibration. One objective of the present invention is to address this problem at least in part. [Means for solving the problem]

[0007] A method is provided for calibrating a sensor comprising a luminescent compound having luminescence dependent on the concentration of an analyte, and a detector configured to detect light emitted by the luminescent compound, the method comprising: preparing a component comprising the luminescent compound in a package that maintains exposure of the luminescent compound to the analyte at a known first concentration; assembling the component to the sensor, measuring a first value of the luminescence property of the luminescent compound while the luminescent compound is exposed to the analyte at the first concentration; measuring a second value of the luminescence property of the luminescent compound while the luminescent compound is exposed to the analyte at a known second concentration different from the first concentration; and using the first and second values, determining a parameter that represents the dependence of the luminescence property on the concentration of the analyte.

[0008] By preparing a sensor component containing a luminescent compound packaged to be exposed to an analyte at a known concentration, a first calibration point can be provided without requiring dedicated equipment or any user preparation. This substantially reduces the time required to calibrate the sensor, eliminates the need for separate equipment to provide the first calibration point, and thereby reduces the time and resource costs for the user operating the system.

[0009] In one embodiment, the step of assembling the component to the sensor is performed while the component is held within the package, and the step of measuring the first value is performed while the component is within the package. The package can be designed so that the sensor can be connected while the component is within the package. Thus, the first calibration point can be measured simply by connecting the component to the sensor before removing the component from the package (an action that would already be performed by the user in existing systems).

[0010] In one embodiment, the step of measuring the first value is performed during a predetermined time period after the component has been removed from the package, while the luminescent compound remains exposed to the analyte at the first concentration. Alternatively, the design of the component and the properties of the luminescent compound may be such that the luminescence properties of the luminescent compound remain substantially unchanged for a predetermined time period after the component has been removed from the packing. Thus, the first calibration point can be measured by connecting the component to the sensor immediately after it has been removed from the package (an action that would similarly be performed by the user in existing systems). In one embodiment, the predetermined time period is at most 5 minutes. This is typical for the embodiments of the component disclosed herein.

[0011] In one embodiment, the first concentration is zero. This is particularly advantageous because it allows the characteristics in the absence of an analyte, i.e., common calibration parameters, to be determined directly rather than being calculated from multiple measurements.

[0012] In one embodiment, the step of measuring the second value is performed while the luminescent compound is exposed to blood containing the analyte at the second concentration. This is a convenient choice for measuring the second value, which the sensor uses to measure the concentration of the analyte in the blood, because the measurement can be performed after the sensor has been set up in the configuration in which it will be used. Thus, the interruption required for calibration purposes is minimized, because for use, the user only needs to assemble the sensor and set up the device, and the calibration measurement is performed automatically at an appropriate stage in the setup procedure.

[0013] In one embodiment, the second concentration is determined by analyzing the blood sample using a blood analyzer. Blood analyzers are generally in clinical settings for analyzing patient samples. Therefore, no further equipment is required to determine the second concentration for calibration purposes.

[0014] In one embodiment, the step of measuring the second value is performed in vivo. As discussed above, this is particularly advantageous because it means that no further setup steps are required before or after measuring the second value.

[0015] In one embodiment, the step of measuring the second value is performed while the luminescent compound is exposed to a pre-prepared fluid containing the analyte at the known second concentration. Using a pre-prepared fluid may be more convenient in some situations because it provides the known second concentration without any further analysis.

[0016] In one embodiment, the method further includes integrating the sensor into a fluid line for biological fluids in a medical device, wherein the pre-prepared fluid is a priming fluid used in setting up the medical device. In some clinical situations, such as dialysis, the priming fluid is used during setup. By providing a second concentration using this priming fluid, calibration is further incorporated into the method step, which would be performed by the user anyway, thereby reducing the additional time required to perform calibration.

[0017] In one embodiment, the luminescence is temperature-dependent of the luminescent compound, and the parameter represents the dependence of the luminescence property on both the concentration of the analyte and the temperature of the luminescent compound. Considering temperature changes that may occur during monitoring enhances the accuracy and reliability of the calibration procedure.

[0018] In one embodiment, the method further includes measuring a first temperature of the luminescent compound when the step of measuring the first value is performed, and measuring a second temperature of the luminescent compound when the step of measuring the second value is performed, wherein the step of determining a parameter representing the dependence of the luminescence property on the concentration of the analyte uses the first temperature and the second temperature in addition to the first and second values. Measuring the temperature at two calibration points makes it possible to adjust the calibration parameter for any difference between the temperatures at two concentrations that may affect the luminescence property, thereby further increasing accuracy and reliability.

[0019] In one embodiment, the above parameters include a temperature parameter representing the dependence of the luminescence property of the luminescent compound on the above temperature. Using a specific temperature parameter means that the temperature dependence can be easily quantified and considered.

[0020] In one embodiment, the temperature parameter has a predetermined value. In some embodiments, the behavior of the component is constant enough that the temperature parameter can be determined during manufacturing. This eliminates the need for the temperature parameter to be determined during calibration, thereby reducing the complexity of calibration.

[0021] In one embodiment, the method further includes measuring a third value of the luminescence property of the luminescent compound while the luminescent compound is exposed to the analyte at a first concentration at a third temperature different from the first temperature, and measuring the third temperature of the luminescent compound when the step of measuring the third value is performed, wherein the step of determining a parameter representing the dependence of the luminescence property on the concentration of the analyte uses the third value and the third temperature in addition to the first value, the second value, the first temperature and the second temperature. Measuring the property values ​​at two temperatures at a first concentration makes it possible to accurately determine the temperature parameter when a predetermined value cannot be relied upon. Nevertheless, this does not require any further steps from the user because the measurement can be performed automatically after the component has been attached to the sensor.

[0022] In one embodiment, the luminescence depends on the temperature of the luminescent compound, and the parameter represents the dependence of the luminescence property on the concentration of the analyte at a given temperature. If the calibration measurement temperature and the operating measurement temperature are approximately the same, no further measurements or parameters are required to quantify the temperature dependence.

[0023] In one embodiment, the luminescence property of the luminescent compound is the intensity of the luminescence. Intensity is a convenient choice of property as it can be directly measured using a photodetector.

[0024] In one embodiment, the luminescence property of the luminescent compound is the ratio of the luminescence intensity at two different wavelengths. Using an intensity ratio is advantageous because it reduces the sensitivity of the measurement to certain types of errors.

[0025] In one embodiment, the above-mentioned dependence of the properties is modeled using a one-to-one host-guest binding model. This model is suitable for modeling many commonly available luminescent compounds.

[0026] In one embodiment, determining the parameter representing the dependency includes using a predetermined value for the strength of the binding between the luminescent compound and the analyte. The strength of this binding of the interaction is referred to as the binding constant. The binding constant is generally constant between components and can thus be determined during manufacture, and the predetermined value is used at the point of use.

[0027] In one embodiment, the dependency of the property C on the concentration [X] of the analyte is given by the following equation, namely, [Number] [[ID=I1]] is modeled using where C0 is the value of the property of the luminescence of the luminescent compound when the concentration of the analyte is zero, and C ∞ is the value of the property of the luminescence of the luminescent compound when the concentration of the analyte is infinite, K is the strength of the binding (binding constant) between the luminescent compound and the analyte, and determining the parameter representing the dependency includes determining C0 and C ∞ . This is a convenient and appropriate specific choice of a mathematical form representing a 1:1 host-guest binding model.

[0028] In one embodiment, the parameter includes a temperature parameter α representing the dependency of the property of the luminescence of the luminescent compound on the temperature, and C0 and C ∞ have the following dependency on the temperature T, namely, C0(T) = C 0c (1 + α(T - T c )) C ∞ (T) = C ∞c (1 + α(T - T c )) is modeled using where C 0c is the value of C0 at temperature T c , and C ∞c is the value of C cC in ∞ This is the value. Using the linear dependence of the luminescence properties on temperature is sufficiently accurate over the temperature range in which this type of sensor is commonly used. Therefore, this is a favorable choice as a simple and effective model.

[0029] In one embodiment, K has the following dependence on the temperature T, namely,

number

[0030] A method for measuring the concentration of an analyte in a sample is provided, using a sensor comprising a luminescent compound having luminescence dependent on the concentration of the analyte, and a detector configured to detect light emitted by the luminescent compound, the method further comprising: calibrating the sensor using an embodiment of the sensor calibration method disclosed above; measuring the value of the luminescence property of the luminescent compound while the luminescent compound is exposed to the sample; and deriving the concentration of the analyte in the sample using the measured value and a determined parameter representing the dependence of the luminescence property on the concentration of the analyte. Performing a concentration measurement method using the aforementioned calibration method is advantageous because it results in accurate concentration measurement and reduces the burden on the user when setting up the sensor.

[0031] In one embodiment, the sample is a biological fluid, and the values ​​of the luminescence properties are measured in vivo. In vivo measurement eliminates the need to periodically collect blood samples for analysis, allowing for continuous monitoring. This provides greater temporal resolution for monitoring, without requiring clinicians to spend time periodically collecting samples.

[0032] In one embodiment, the sample is a biological fluid, and the above-mentioned values ​​of the luminescence properties are measured in vitro (outside the body). This may be more convenient in situations such as dialysis treatment, where the biological fluid is flowing continuously and can be measured in vitro (outside the body). For example, in one embodiment, the method further includes integrating the sensor into a flow line for biological fluid in a medical device, and the sample is located within the flow line.

[0033] In one embodiment, the bodily fluid is either blood or interstitial fluid. Both are suitable samples for measuring the levels of important metabolites in the body and are therefore advantageous choices for monitoring a patient's health.

[0034] In any embodiment of the method, the component is a replaceable component of the sensor. This is advantageous for maintaining the component in a sterile state when used in a clinical setting.

[0035] In any embodiment of the method, the sensor further includes a light source configured to excite the luminescent compound, and measuring the value of the luminescence property of the luminescent compound includes exciting the luminescent compound using the light source and detecting the light emitted by the luminescent compound using the detector. This allows for greater control over the measurement process by controlling the light delivered to the luminescent compound. This improves the accuracy of the lifetime measurement used to derive the concentration.

[0036] In any one embodiment of the method, the analyte is one of carbon dioxide, hydrogen ions, sodium, potassium, magnesium, and calcium. Accurate calibration of the carbon dioxide or oxygen sensor is important to ensure that the patient does not become hypoxic during clinical procedures. Other metabolites are also important targets for measurement in intensive care to ensure the patient's health status.

[0037] In any one embodiment of the method, the luminescent compound includes a fluorescent compound. Fluorescent compounds emit light with a higher intensity than phosphorescent compounds and are therefore more easily detected. In one embodiment, the fluorescent compound includes 8-hydroxypyrene-1,3,6-trisulfonic acid. This is a particularly preferred choice of fluorescent compound for detecting carbon dioxide or pH.

[0038] Herein, embodiments of the present invention will be described as non-limiting examples with reference to the accompanying drawings. [Brief explanation of the drawing]

[0039] [Figure 1] This is a schematic diagram of a sensor device in which the present invention can be implemented. [Figure 2] This is a schematic diagram of possible sensor-probe configurations for in vitro measurement of analyte concentrations in blood. [Figure 3] This is a schematic diagram of possible sensor-probe configurations for intravascular measurement of analyte concentrations in blood. [Figure 4] This is a schematic diagram of possible sensor-probe configurations for subcutaneous measurement of analyte concentrations in blood. [Figure 5] Figure 1 is a flowchart showing a method for calibrating the sensor of the sensor device shown. [Figure 6] This is a schematic diagram of a packaged component that allows a first value to be measured while remaining sealed within the package. [Figure 7] This is a schematic diagram of a component designed and packaged so that a first value can be measured after the component has been removed from the package. [Figure 8] This graph shows the effect of changes in analyte concentration on the measurement of the luminescence properties of luminescent compounds. [Figure 9] This is a graph showing the fit of measured values ​​of luminescence properties to a model of the property's dependence on the concentration of the analyte. [Figure 10] Figure 1 is a flowchart illustrating a method for measuring the concentration of an analyte in a sample using the sensor device shown. [Modes for carrying out the invention]

[0040] This disclosure provides a method for calibrating a sensor. Figure 1 shows a sensor device including a type of sensor 4 in which the method disclosed herein can be used. An example of such a sensor 4 may be a pH sensor for detecting carbon dioxide concentration. The sensor 4 includes a luminescent compound 9 and an analysis system 30.

[0041] Sensor 4 includes a light source 10 configured to excite a luminescent compound. The light source 10 is configured to emit light at a wavelength appropriate for exciting the luminescent compound 9. For example, the light source 10 can be any light source capable of emitting light at the wavelength and intensity required to excite the luminescent compound 9. For example, the light source 10 can include a laser diode or an LED. The light source 10 may be a continuous light source, a light source using vibration intensity, or a pulsed light source.

[0042] Sensor 4 further includes a detector 14 configured to detect light emitted by the luminescent compound 9. The detector 14 can be any device capable of generating a signal in response to receiving light at the wavelength emitted by the luminescent compound 9. For example, the detector 14 may include a charge-coupled device, an energy element sensor, a photodiode, or a photoresistor. The signal output by the detector 14 can represent the intensity of the light received from the luminescent compound 9.

[0043] Sensor 4 includes an optical fiber 16 arranged to guide light to and from a luminescent compound 9. The optical fiber uses total internal reflection to prevent light loss from the fiber. This means that light can be efficiently transmitted to and from the luminescent compound 9, improving the signal and preparing for higher quality and more reliable measurements. They can also be made small and flexible, making them particularly suitable for sensors that must be inserted into a patient's body. For example, the optical fiber 16 may include a PMMA fiber optic component. The optical fiber 16 functions as an optical waveguide, and where appropriate, any other suitable optical waveguide can be used instead of the optical fiber 16.

[0044] A component containing a luminescent compound 9 is prepared and assembled to the sensor 4. In Figure 1, the component is a sensor probe 8 containing the luminescent compound 9. The component is exposed to a sample containing the analyte when the sensor device is in operation. In one embodiment, the sample contains blood. The sensor 4 further includes a connector 21 configured to connect the sensor probe 8 to a light source 10 and a detector 14. In one embodiment, the component is a replaceable component of the sensor 4. Part or all of the sensor 4 may be disposable, and in particular the replaceable component may be disposable. This is convenient in clinical situations where the sensor 4 is used to measure the concentration of the analyte in a patient's body. In such cases, the part of the sensor 4 that is inserted into the patient must be sterile and cannot be reused between patients. For example, only the sensor probe 8 containing the luminescent compound 9 may be disposable, and the detector 14 or light source 10 may not be disposable.

[0045] The analysis system 30 is configured to perform the method by controlling the sensor 4 and processing the signals received from the detector 14. The analysis system 30 may also be configured to calibrate the sensor and / or derive a measured concentration of the analyte based on the measurements from the sensor 4. The analysis system 30 can be connected to the sensor 4 via a wired connection, such as a serial or Ethernet® connection, or another type of interface specifically designed for the sensor device. Alternatively, a wireless connection such as Bluetooth® or Wi-Fi may be used. The analysis system can also receive signals output by the detector 14 and transmit those signals to the sensor 4 to control, for example, the light source 10.

[0046] Figures 2 to 4 show specific examples of the sensor 4 used in clinical settings and when the sensor 4 includes the sensor probe 8.

[0047] Figure 2 shows an embodiment in which sensor 4 is a bypass sensor. Such a sensor can be used in an external blood pump to monitor the concentration of an analyte in the blood being pumped. Measurements of analyte concentrations, particularly oxygen or carbon dioxide, can be used as part of controlling the blood pumping rate by the external blood pump, for example, to maintain an appropriate oxygen supply level to the blood. In this case, the component is a disposable sensor probe 8 attached to a bypass loop 61, so that the luminescent compound 9 is exposed to the blood passing through the bypass loop. A connector 21 connects the disposable sensor probe 8 to the rest of sensor 4. A thermistor or another suitable temperature sensor 20 is mounted inside the sensor probe 8 to measure the temperature of the blood.

[0048] Figure 3 shows an embodiment in which sensor 4 is an intravascular sensor. The luminescent compound 9 is positioned at the tip of an optical fiber 16 that is inserted into the patient via a catheter. The component is a sensor probe 8 which includes the fiber optic component 16 together with a temperature sensor 20. The sensor probe 8 is connected to the rest of sensor 4 via a connector 21.

[0049] Figure 4 shows an embodiment in which sensor 4 is an interstitial fluid sensor. In this case, sensor 4 includes a component containing a sensor probe 8 and an outer component 54. The sensor probe 8 punctures the skin 52 and measures the concentration of analytes in the interstitial fluid. A retractable needle can be used to puncture the skin 52, and sensor 4 is wirelessly connected to an analysis system 30. Alternatively, the analysis system 30 may be located within the outer component 54. A temperature sensor is provided to measure skin temperature. This temperature sensor can be located within the sensor probe 8 that penetrates the skin 52, or it can be located within the outer component 54 near the skin 52.

[0050] The luminescent compound 9 can be any suitable substance having luminescence dependent on the concentration of the analyte. The luminescent compound 9 can be provided within the sensor probe 8 fixed within the polymer layer.

[0051] In some embodiments, the luminescence property measured in the method may be luminescence emission intensity (fluorescence emission intensity or phosphorescence emission intensity, etc.). Alternatively, the luminescence property may be luminescence lifetime (fluorescence lifetime or phosphorescence lifetime, etc.).

[0052] In applications where the amount of luminescent compound 9 is small, it may be difficult to detect absorption by the luminescent compound 9 relative to the background of the excitation light. Therefore, it is preferable that the luminescent compound emits light over a wavelength range different from the wavelength range in which it is excited, because this makes it easy to distinguish between the excitation light and the light emitted from the luminescent compound 9.

[0053] Luminescence can be fluorescence or phosphorescence. However, phosphorescence is generally weaker than fluorescence because it involves spin-forbidden transitions. Therefore, in order to give the luminescent compound 9 a strong photoresponse to excitation light, it is preferable that the luminescent compound 9 is a fluorescent compound that has fluorescence that changes when the luminescent compound interacts with the analyte.

[0054] Therefore, the luminescent compound 9 preferably contains a phosphor. The phosphor is a portion that can absorb and re-emit light through fluorescence emission. Typically, the phosphor absorbs light in the visible region of the electromagnetic spectrum. The phosphor also typically emits light in the visible region of the electromagnetic spectrum. The "visible region of the electromagnetic spectrum" refers to electromagnetic radiation having wavelengths from about 400 nm to about 700 nm. The phosphor can also absorb and / or emit radiation outside the visible region of the electromagnetic spectrum. Therefore, in preferred embodiments, the luminescent compound 9 is a luminescent compound containing a phosphor, and the fluorescence emission spectrum of the phosphor changes in the presence of the analyte.

[0055] Changes in luminescence properties (such as the emission spectrum of luminescent compounds) are caused by interactions with the analyte. Possible forms of interaction between the analyte and the luminescent compound are as follows: Ionic interactions and, The formation of reversible covalent interactions (i.e., the formation of boronic acid esters), Any other non-covalent interactions that result in a 1:1 host-guest complex, namely hydrogen bonding, CH-π interactions, hydrophobic effects, van der Waals interactions, etc. Includes.

[0056] Other forms of interaction are possible. These interactions alter one or more properties of luminescence, which can be detected optically.

[0057] In some cases, the analyte does not bind to the luminescent compound, such as when the interaction between the analyte and the luminescent compound is involved in collision quenching of the luminescent compound. However, in other cases, chemical bonds, such as ionic or covalent bonds, can be formed between the analyte and the luminescent compound. In such cases, the luminescent compound may contain a receptor moiety. The receptor moiety is a portion that can bind to the analyte. It is preferable for the luminescent compound to contain a receptor moiety because the receptor moiety generally conveniently binds to the analyte and not to other chemical species. Therefore, luminescent compounds containing a receptor moiety generally produce an optical signal that is particularly associated with the analyte, and this optical signal has low sensitivity to interference from other species. Many examples of luminescent compounds that can be used for various analytes are listed below for illustrative purposes only.

[0058] For example, a luminescent compound is given by formula (I), that is [ka] It may include a portion of or a derivative thereof. The dashed line indicates a bond point to another portion, which can be, for example, a polymer in a polymer layer, or an organic portion such as an alkyl group. The species of formula (I) is the acceptor (Na + It includes both a cryptand that can be bound to a polycyclic aryl moiety and a phosphor containing a polycyclic aryl moiety. + When it binds to cryptand, the fluorescence emission of this part changes.

[0059] In another example, the luminescent compound is given by formula (II), i.e. [ka] It may include a portion of or a derivative thereof. The dashed line indicates a bond point to another portion, which can be, for example, a polymer in a polymer layer, or an organic portion such as an alkyl group. The species of formula (II) is the acceptor (K +It includes both a cryptand that can be bound to a polycyclic aryl moiety and a phosphor containing a polycyclic aryl moiety. + When it binds to cryptand, the fluorescence emission of this part changes.

[0060] In another example, the luminescent compound is given by formula (III), i.e. [ka] This may include a portion of or a derivative thereof. See, for example, Non-Patent Document 1. The dashed line indicates a bond point to another portion, which can be, for example, a polymer in a polymer layer, or an organic portion such as an alkyl group. The species of formula (III) is the acceptor (Ca 2+ It includes both a portion containing a carboxylate ion pair that can be bonded and a phosphor containing a polycyclic aryl portion. 2+ When it binds to the receptor, the fluorescence emission of this part changes.

[0061] In another example, the luminescent compound is of formula (IV) or (V), i.e. [ka] [ka] This may include a portion of or a derivative thereof. See, for example, Non-Patent Documents 2 or 3. The portion of formula (IV) or (V) can be bonded at any point to the polymer contained in the polymer layer. These compounds are known as Mag-fluo-4 (compound (IV)) and Mag-fura-2 (compound (V)), respectively. The species of formula (IV) and (V) are Mg via the methyl ester portion. 2+ It binds to ions. Therefore, compound (V) is an example of a luminescent compound containing two or more receptors. These compounds also include phosphors containing a polycyclic aryl moiety. Mg 2+ When it binds to any of these compounds, its fluorescence emission changes.

[0062] In another example, the luminescent compound is given by formula (VI), that is, [ka] The portion may include pyranine or a derivative thereof. See, for example, Non-Patent Document 4. This portion can be bonded to the polymer layer at any point other than the hydroxyl group. The compound of formula (VI) does not contain a separate acceptor and phosphor, and the phosphor itself acts as the acceptor. The portion of formula (VI) can be used to detect acid or CO2 because CO2 forms an acid (carbonic acid) in the presence of water. In the presence of an acid (such as carbonic acid formed by CO2), the hydroxyl group of the portion of formula (VI) is protonated. However, as the concentration of the acid or CO2 decreases, the hydroxyl portion is deprotonated, leaving a delocalized negative charge throughout the phosphor and altering the fluorescence emission and fluorescence absorption spectra of the compound. This change is particularly enhanced when the luminescent compound containing the portion of formula (VI) is immobilized in a polymer matrix with a correlation transfer agent. An example of a correlation transfer agent is hexadecyltrimethylammonium hydroxide.

[0063] A suitable pyranine derivative that can be used is of formula (VII), namely, [ka] This is the relevant part.

[0064] For example, see Non-Patent Document 5.

[0065] In another example, a luminescent compound is given by formula (VIII), i.e. [ka] This may include the portion or derivative thereof. This portion can be bonded to the polymer of the polymer layer at any point. The compound of formula (VIII) behaves similarly to the portions of formula (VI) and (VII), i.e., it does not contain a separate acceptor and phosphor, and the phosphor itself acts as the acceptor. In the presence of an acid (such as carbonic acid formed by CO2), the hydroxyl group of the portion of formula (VIII) is protonated. However, as the concentration of the acid or CO2 decreases, the hydroxyl portion is deprotonated, leaving a delocalized negative charge throughout the phosphor and altering the fluorescence emission spectrum and fluorescence absorption spectrum of the compound.

[0066] Other luminescent compounds are known and, in many cases, commercially available, and these compounds can also be used as luminescent compounds. In some examples, the luminescent compound includes 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS). Further examples of luminescent compounds that can be used to detect acids or CO2 are given below, namely [ka] That is the case.

[0067] For example, see Non-Patent Document 6.

[0068] From the above, it should be clear that the sensor can be used for the optical detection of a wide variety of analytes. The analytes may be, for example, ions, gases, inorganic compounds, or organic compounds. The analyte may exist as a gas in the sample, or alternatively, it may be dissolved or suspended in another substance, such as interstitial fluid or blood. If the analyte is an organic compound, it is generally a small organic compound, for example, an organic compound containing fewer than 20 carbon atoms. Specific examples of small organic compounds include sugars, sugar alcohols, and metabolites such as urea or ketones. A particularly preferred example of an analyte is Na + , K + Ca 2+ Mg 2+ , CO2, and acid (H +(i.e., a pH sensor). In one embodiment, the analyte is carbon dioxide.

[0069] Figure 5 shows a flowchart of one embodiment of a method for calibrating the sensor shown in Figure 1.

[0070] In step S10, the method includes preparing a component containing the luminescent compound 9 within a package 31 that maintains exposure of the analyte to the luminescent compound 9 at a known first concentration. In Figure 1, the component is a sensor probe 8. Examples of the package 31 are shown in Figures 6 and 7. By placing the component within the package 31, the package 31 is provided with an analyte at a known first concentration, which is used as a first calibration point during the calibration method. The first concentration can be controlled during the manufacture of the component, so that the user does not need to provide this first concentration by operating a specific calibration device, for example, as required in devices of the prior art. In one embodiment, the first concentration is zero. As will be discussed further below, the value of the property at zero concentration can be precisely a parameter of the property's dependence on the concentration of the analyte. Therefore, having zero concentration as one of the values ​​used for calibration simplifies the determination of the dependence parameter.

[0071] In step S12, the method includes assembling the component to the sensor 4. In Figure 1, this includes connecting the component to the connector 21 of the sensor 4. By assembling the component to the sensor 4, the sensor 4 becomes capable of exciting the luminescent compound 9 and detecting the light emitted by the luminescent compound 9, thereby enabling measurement and calibration of the sensor 4.

[0072] In step S14, the method includes measuring a first value of the luminescence property of the luminescent compound 9 while the luminescent compound 9 is exposed to the analyte at a first concentration. The first concentration represents a known first concentration of the analyte for calibration of the sensor 4. By determining the property value at the first concentration, the analysis system 30 can extrapolate to determine concentrations at other concentrations based on other measurements of the property value. This will be discussed in more detail below. The sensor 4 in Figure 1 includes a light source 10 configured to excite the luminescent compound 9. Step S14 includes exciting the luminescent compound 9 using the light source 10 and detecting the light emitted by the luminescent compound 9 using the detector 14.

[0073] In one embodiment, package 31 is the package shown in Figure 6, step S12 is performed by holding the component inside package 31, and step S14 is performed while the component is inside package 31. This allows exposure to a known first concentration of the luminescent compound 9 to be maintained while the first value is being measured. This embodiment requires that package 31 be designed so that the component can be connected to sensor 4 without opening package 31. In Figure 6, package 31 remains sealed around the fiber optic component 16 of the component, with a portion of the fiber optic component 16 protruding from package 31. Alternatively, an adapter may be provided as part of package 31, with package 31 sealed around this adapter, which is configured to connect to a component inside package 31 and to connect to connector 21 of sensor 4 in step S12.

[0074] In one embodiment, package 31 is the package shown in Figure 7, and step S14 is performed during a predetermined time period after removing the component from package 31, while the luminescent compound 9 remains exposed to the analyte at a first concentration. Depending on the selection of the luminescent compound 9 and the design of the component, the luminescence properties may not change immediately after the component is removed from package 31. Therefore, there may be a time period during which a first value can be measured while the luminescent compound 9 remains exposed to the analyte at a first concentration. In Figure 7, the component is a bypass sensor probe 8 similar to that shown in Figure 2, and includes a section 33 of tubing connected, for example, to a bypass loop in a dialysis system. The tubing 33 is pre-filled with a fluid containing the analyte at a first concentration. After the component is removed from package 31, some time is required for the concentration of the analyte in the fluid to change, and therefore, during this period, step S14 can be performed. In one embodiment, the predetermined time period is at most 5 minutes, preferably at most 3 minutes, and more preferably at most 1 minute.

[0075] The properties of luminescence can be just one of many properties. For example, one property could be the lifespan of luminescence.

[0076] In one embodiment, the luminescence property of the luminescent compound 9 is its luminescence intensity. When the luminescence property is intensity, step S14 includes exciting the luminescent compound 9 with light of a first wavelength and measuring the intensity of the light emitted at a second wavelength. The first wavelength can be selected such that the luminescent compound 9 has the greatest light absorption. The second wavelength can be the wavelength at which the intensity of the emitted light is greatest or the emission spectrum of the luminescent compound 9 has its maximum value. The specific excitation wavelength and detection wavelength are determined according to the selection of the luminescent compound 9.

[0077] In one embodiment, the luminescence property of the luminescent compound 9 is the ratio of the luminescence intensity at two different wavelengths. Using the ratio of the intensity at two different wavelengths would be advantageous in reducing or eliminating the influence of certain types of errors on the measured value of the property. In this case, the value of the luminescence property can be measured in various ways and is determined to some extent depending on the selection of the luminescent compound 9. As described above, the luminescent compound 9 is preferably a fluorescent compound. For example, the sensor 4, which includes the fiber optic component 16 as described above, is deployed with a fluorescent compound having a single absorption peak that yields two overlapping emission peaks when excited by single-wavelength light.

[0078] In embodiments where the fluorescence property is the ratio of the luminescence intensity at two different wavelengths, step S14 includes exciting the luminescent compound 9 with light of a first wavelength and measuring the intensity of the light emitted at each of the two different wavelengths, where the first wavelength is the same for each of the two different wavelengths. This implementation may be preferred in some situations because only single-wavelength light is required to produce two overlapping peaks in the emission spectrum. This reduces the complexity of the light source 10, and furthermore, any change in the output from the light source 10 equally affects both emission peaks. This makes it possible to effectively eliminate changes as errors in the ratio calculation. However, this requires that the detector 14 can distinguish between light at various wavelengths.

[0079] For other luminescent compounds such as HPTS, excitation at various wavelengths results in a single emission peak. For example, the signals obtained by exciting HPTS at 405 nm, 470 nm, and 418 nm result in a single fluorescence emission at 525 nm. Figure 7 shows the absorption spectrum of sensor 4 including HPTS as carbon dioxide concentration increases, with arrows indicating peak shifts as carbon dioxide concentration increases. In such embodiments, where the luminescence characteristic is the ratio of luminescence intensity at two different wavelengths, step S14 includes exciting the luminescent compound 9 with light at one of the two different wavelengths for each of the two different wavelengths, and measuring the intensity of the light emitted by the luminescent compound 9 at the second wavelength, where the second wavelength is the same for each of the two different wavelengths. This would be preferable when the detector 14 can only detect the intensity of light and cannot detect the wavelength, but it is required that the light source 10 can emit light at two different wavelengths.

[0080] Performing step S14 while the component is inside package 31, or immediately after removing the component from package 31, has the advantage that one of the measurements required for calibration is measured as part of the sensor 4 configuration, which would otherwise need to be performed even if calibration is not performed (i.e., steps S10 and S12). This saves user time because it eliminates the need to operate further equipment or take further action to obtain the first calibration value.

[0081] In step S16, the method includes measuring a second value of the luminescence property of the luminescent compound 9 while the luminescent compound 9 is exposed to the analyte at a known second concentration different from the first concentration. The dependence of the property of the luminescent compound 9 on the concentration of the analyte is such that at least two calibration measurements are required to properly calibrate the sensor 4 to ensure reliable concentration measurements during operation. The second value is also preferably measured during a step that is performed as part of setting up the sensor 4, even if calibration is not required.

[0082] In some embodiments, step S16 is performed while the luminescent compound 9 is exposed to blood containing the analyte at a second concentration. Often, the sensor 4 is used to measure the concentration of the analyte in the blood, and in these cases, the sensor 4 must be set up to be exposed to the patient's blood. Therefore, using the concentration of the analyte in the blood to determine the second value also does not require the sensor 4 to be placed in any dedicated calibration device. In one embodiment, the second concentration is determined by analyzing a blood sample using a blood analyzer. Blood analyzers are generally in the clinical setting to analyze blood samples from patients. Therefore, it is likely that the user has convenient access to such an analyzer. The second concentration can be determined from a sample by taking a blood sample at the same time as measuring the second value of the characteristic while the sensor 4 is exposed to blood, and the sensor 4 can be calibrated using the second concentration together with the first value.

[0083] In one embodiment, step S16 is performed in vivo. For example, in the embodiment of the component shown in Figures 2 and 3, the component is at least partially inserted into the patient's body and the luminescent compound 9 is exposed to body fluids. The luminescent compound 9 can be exposed to blood as already described above, or it can be exposed to other fluids such as interstitial fluid, urea, etc.

[0084] In one embodiment, step S16 involves exposing the luminescent compound 9 to a pre-prepared fluid containing the analyte at a known second concentration. Using a pre-prepared fluid has the advantage that the fluid is prepared to have the analyte at a known concentration, thus eliminating the need to separately determine the concentration of the analyte. In one embodiment, step S12 involves assembling the sensor 4 into a fluid line for biological fluids in a medical device, where the pre-prepared fluid is a priming fluid used in the setup of the medical device. This is particularly advantageous for the use of a pre-prepared fluid because the setup of some medical devices (e.g., dialysis systems) requires that a priming fluid pass through the fluid line during the setup of the medical device. Providing a known second concentration using this means that no further steps are required to measure the second value in the setup of the sensor 4.

[0085] In step S18, the method includes determining a parameter that represents the dependence of the luminescence property on the concentration of the analyte using a first value and a second value. The parameter can be a parameter of a mathematical model that describes the dependence of the luminescence property on the concentration of the analyte. As discussed above, the interaction between the analyte and the luminescent compound affects the luminescent compound 9 and its luminescence in various ways. Depending on the specific combination of the analyte and the luminescent compound 9, various models may be appropriate for the specific dependence of the analyte on the concentration. The output of the method is calibration data 40, which includes the determined parameter that represents the dependence of the luminescence property on the concentration of the analyte.

[0086] In one embodiment, the property dependence used in step S18 is modeled using a one-to-one host-guest coupling model. An example of a combination of analyte and luminescent compound 9 for which this model is preferred is the detection of pH (or CO2 concentration) using HPTS. In this model form, a single molecule of the analyte interacts with each molecule of the luminescent compound (H +) or, in the case of carbon dioxide, one molecule of carbon dioxide interacts with the HPTS ion pair. Other combinations, such as the detection of sodium using part (I), the detection of potassium using part (II), and the detection of calcium using part (III), are described in relation to the luminescent compounds disclosed above.

[0087] Equation 1 is an example of a one-to-one host-guest coupling model, and the dependence of characteristic C on the concentration of analyte [X] is given by the following equation, i.e.

number

[0088] Figure 9 shows a comparison of predicted luminescence properties based on Equation 1 with measured property values. In Figure 9, the property is the intensity ratio at two different wavelengths, the luminescent compound is HPTS with an emission spectrum as shown in Figure 8, and the analyte is carbon dioxide. Intensity measurements are made at the wavelengths of the two peaks shown in Figure 8 (405 nm / 470 nm). Figure 9 shows that the luminescence property fits the quadratic one-to-one host-guest coupling model of Equation 1.

[0089] Conventionally, when the model of equation 1 is suitable for calibrating sensor 4, it fits a quadratic curve and C0, C ∞At least three calibration points are required to enable the determination of C0 and K. However, when the component is connected to various sensors, or when sensor 4 is connected to various sensor devices, some parameters remain the same despite the varying luminescence properties measured by sensor 4. In particular, with respect to specific combinations of analytes and luminescent compounds 9, the bond strength should be constant depending on their chemical interaction. Therefore, the bond strength, represented by K in equation 1, can be determined at the time of component manufacturing, and this parameter does not need to be determined at calibration, thereby reducing the number of measurements required to achieve calibration of sensor 4. If the manufacturing process produces a component that functions consistently, C0 and C do not need to be determined at calibration. ∞ It is only necessary to determine this. Therefore, in one embodiment, step S18 includes using a predetermined value for the strength of the bond between the luminescent compound 9 and the analyte.

[0090] The one-to-one host-guest coupling model is a model where the value of the luminescence property at zero analyte concentration, i.e., C0 in equation 1, is the parameter of dependence. Therefore, when the known first concentration is zero, C0 can be directly determined in step S18, as is the value of the property measured in step S14. ∞ The value of can be determined in step S18 using C0, and the characteristic value is given by the following equation, i.e.

number

[0091] For some luminescent compounds, luminescence depends on the temperature of the luminescent compound 9. If steps S14 and S16 are performed at the same temperature at which the subsequent measurement of the analyte concentration is performed after calibration, temperature changes do not need to be considered. This is especially true in situations where the expected temperature change during subsequent operation tends to be small and has little effect on the luminescence properties. Therefore, in some embodiments, luminescence depends on the temperature of the luminescent compound 9, and the parameter obtained in step S18 represents the dependence of the luminescence properties on the concentration of the analyte at a given temperature.

[0092] However, in other cases, significant temperature changes during subsequent operations may be expected, or it may be inconvenient to perform steps S14 and S16 at the same temperature expected for subsequent operations. In these cases, it would be advantageous to consider the effect of temperature on the luminescence properties of the luminescent compound 9. Therefore, in some embodiments, the luminescence is temperature-dependent of the luminescent compound 9, and the parameters determined in step S18 represent the dependence of the luminescence properties on both the analyte concentration and the temperature of the luminescent compound 9. In this case, the calibration data 40 includes the required parameters that represent the dependence of the luminescence properties on both the analyte concentration and the temperature of the luminescent compound 9. Considering temperature changes tends to improve the accuracy and reliability of the reported values.

[0093] In one embodiment, the parameters determined in step S18 include a temperature parameter representing the dependence of the luminescence properties of the luminescent compound 9 on temperature. When the model of the dependence of the luminescence properties is shown by equation 1, the parameters determined in step S18 include a temperature parameter α representing the dependence of the luminescence properties of the luminescent compound 9 on temperature, and C0 and C ∞ This depends on the temperature T as follows: C0(T)=C 0c (1+α(TT c )) equation 3 C ∞ (T=C)∞c (1+α(TT c )) equation 4 It is modeled using, and in the formula, C 0c is, temperature T c This is the value of C0 in C ∞c is, temperature T c C in ∞ This is the value of . This model is advantageous because, even if two of the parameters in equation 1 are temperature-dependent, only one temperature parameter α is needed to model the temperature dependence of the characteristic.

[0094] To determine the parameter values ​​at various temperatures, it is necessary to measure the temperature of the luminescent compound 9. In one embodiment, step S14 includes measuring the first temperature of the luminescent compound 9 when measuring the first value, step S16 includes measuring the second temperature of the luminescent compound 9 when measuring the second value, and step S18 uses the first temperature and the second temperature in addition to the first and second values. In one embodiment, T in equations 3 and 4 c This can be either the first temperature or the second temperature. c Choosing to be the first temperature means that C 0c This is particularly advantageous because it becomes possible to directly measure it as the first value. Therefore, C ∞c The following is, that is

number

[0095] In one embodiment, the temperature parameter α has a predetermined value. Similar to the strength of the bond, in some embodiments, the change in the temperature parameter between components and / or between sensor systems may be small. In particular, the change may be small enough not to significantly affect the accuracy of the value obtained from the model using standard values ​​obtained during manufacturing. This has the advantage that it is not necessary to determine the temperature parameter in step S18, thereby reducing the complexity of calibration and potentially reducing the time required for calibration.

[0096] In some embodiments, the change in the temperature parameter α may be large enough that it is desirable to determine the temperature parameter in step S18 between components or between sensor devices. Alternatively, in some situations, increased accuracy is required, and the level of accuracy achieved by using a given temperature parameter may be insufficient for specific applications. In this case, step S14 further includes measuring a third value of the luminescence property of the luminescent compound 9 while the luminescent compound 9 is exposed to the analyte at a first concentration at a third temperature different from the first temperature, and measuring the third temperature of the luminescent compound 9 when measuring the third value. Step S18 uses the third value and the third temperature in addition to the first value, the second value, the first temperature and the second temperature. Measuring the third value at a known first concentration of the analyte means that convenience is maintained for the user, as there is still no need to prepare any separate calibration device. In this embodiment, α is given by the following equation, i.e.

number

[0097] The strength of the bond may also depend on temperature. In one embodiment where the model of the dependence of luminescence properties is shown by equation 1, K has the following dependence on temperature T, namely,

number

[0098] Here, we provide an example of how to perform the calibration method. The model shown in equations 1-7 above is used for the dependence of luminescence properties on analyte concentration and temperature. c The values ​​of and β are predetermined and therefore do not need to be determined during the calibration of sensor 4. Therefore, the parameter that needs to be determined is C 0c , C ∞c , and α. The component is prepared in step S10 and assembled to the sensor in step S12.

[0099] In step S14, C 0cThis is directly measured at a first temperature T1 (e.g., room temperature) by selecting the first temperature T1 as zero, that is, in equation 1, [X]=0 and T1=T c Therefore, the first value C1 = C(0, T1 = T c )=C 0c C 0c As described above, this can be measured before or immediately after removing the component from the package, depending on the design of the component and package 31.

[0100] Furthermore, in step S14, while the luminescent compound 9 is exposed to the analyte at a first concentration of zero, a third characteristic value is measured at a third temperature. Thus, in step S18, α can be determined from the third value C3 = C(0, T3) by using equation 6.

[0101] After this, C ∞c C is the only remaining parameter to be determined in step S18. In step S16, the second value of the characteristic C2 is measured at a second temperature T2 while the luminescent compound 9 is exposed to the analyte at a second concentration [X2], so C2 = C([X2], T2). Thus, C ∞c This can be found in step S18 using equation 5.

[0102] In this way, all parameters in the temperature-dependent case can be determined from three characteristic values ​​measured at three different temperatures. Table 1 below summarizes the methods for determining the parameters for two variations of this method. [Table 1]

[0103] There are several ways to perform the above optional selection. A suitable calibration method for an interstitial fluid sensor, such as the interstitial fluid sensor in Figure 4, is as follows: 1. C at room temperature 0cBy measuring and using equation 3, we obtain the value for C0(T) and a predetermined value for α at the detection temperature (i.e., the temperature at which the analyte concentration will be subsequently measured). 2. Apply the sensor to the patient and measure the second value of the characteristic. 3. Determine the second concentration of the analyte using a blood sample collected at the same time as the sensor application, and then use equation 2 to determine C ∞c And, K c Determine the default values ​​for α and β.

[0104] Both variations in Table 1 employ a two-point calibration method, meaning that only two different values ​​of analyte concentration are required. The two-point calibration method allows for the rejection of sensors with low modulation and still serves as a performance validation for sensors such as the intravascular sensor in Figure 3. Modulation is given by the following equation, i.e.

number

[0105] After calibrating the sensor using the calibration method discussed above, the concentration of the analyte in the sample can be measured using the sensor. Figure 10 shows an example of a method for measuring the concentration of the analyte in a sample using the sensor device shown in Figure 1. As discussed above, the sensor 4 includes a luminescent compound 9 having luminescence that depends on the concentration of the analyte, and a detector 14 configured to detect the light emitted by the luminescent compound 9.

[0106] In step S20, the method includes measuring the value of the luminescence property of the luminescent compound 9 while the luminescent compound 9 is exposed to the sample. The value of the property can be measured using one of the techniques discussed above, depending on the properties of the luminescent compound and the configuration of the light source and detector. In embodiments in which the luminescence is temperature-dependent of the luminescent compound 9 and the parameter represents the dependence of the luminescence property on both the concentration of the analyte and the temperature of the luminescent compound 9, step S20 further includes measuring the temperature of the luminescent compound 9 while the luminescent compound 9 is exposed to the sample.

[0107] In one embodiment, the sample is a biological fluid, and the luminescence property values ​​are measured in vivo. The biological fluid may be, for example, blood or interstitial fluid. The method is particularly suitable for clinical applications, and therefore blood is a favorable target for determining the concentration of the analyte. The sensors shown in Figures 3 and 4 are suitable for in vivo measurements.

[0108] In alternative embodiments, the sample is a biological fluid, and the luminescence property values ​​are measured in vitro (outside the body). Sensors such as the one shown in Figure 2 are suitable for in vitro (outside the body) measurements where the biological fluid flows outside the patient's body. For example, in one embodiment, the method for measuring concentration may further include integrating sensor 4 into a flow line for biological fluid in a medical device, with the sample in the flow line. This would be particularly advantageous, for example, in monitoring patients undergoing hemodialysis or extracorporeal membrane oxygenation.

[0109] In step S22, the method includes deriving the concentration of the analyte in the sample using the measured value and the determined parameters that represent the dependence of the luminescence properties on the concentration of the analyte. Calibration data 40 is the input to the method and includes parameters obtained from the calibration of sensor 4. When using the above model, the parameters of the model are C 0c , C ∞c , α, K c, and β. Combining equations 1, 3, 4, and 7, we obtain the following equation for concentration, namely

number

number

Claims

1. A method for calibrating a sensor comprising a luminescent compound having luminescence dependent on the concentration of an analyte, and a detector configured to detect light emitted by the luminescent compound, The steps include preparing a component containing the luminescent compound in a package that maintains exposure of the analyte to the luminescent compound at a known first concentration, The steps include: assembling the component into the sensor and measuring a first value of the luminescence property of the luminescent compound while the luminescent compound is exposed to the analyte at a first concentration; The steps include measuring a second value of the luminescence property of the luminescent compound while the luminescent compound is exposed to the analyte at a known second concentration different from the first concentration, A step of determining a parameter that represents the dependence of the luminescence property on the concentration of the analyte using the first and second values. Includes, The step of measuring the first value is performed during a predetermined time period after removing the component from the package, while the luminescent compound remains exposed to the analyte at the first concentration (excluding medical procedures on humans).

2. The method according to claim 1, wherein the predetermined time period is at most 5 minutes.

3. The method according to claim 1 or 2, wherein the first concentration is zero.

4. The step of measuring the second value is performed while the luminescent compound is exposed to blood containing the analyte at the second concentration. a) The method according to any one of claims 1 to 3, wherein the second concentration is determined by analyzing the blood sample using a blood analyzer (excluding medical procedures performed on humans).

5. The step of measuring the second value is performed while the luminescent compound is exposed to a pre-prepared fluid containing the analyte at the known second concentration. The method according to any one of claims 1 to 3, optionally further comprising the step of integrating the sensor into a fluid line for biological fluids in a medical device, wherein the pre-prepared fluid is a priming fluid used in setting up the medical device (excluding medical procedures on humans).

6. The method according to any one of claims 1 to 5, wherein the luminescence depends on the temperature of the luminescent compound, and the parameter represents the dependence of the properties of the luminescence on both the concentration of the analyte and the temperature of the luminescent compound.

7. The aforementioned method, When the step of measuring the first value is performed, the step of measuring the first temperature of the luminescent compound, When the step of measuring the second value is performed, the step of measuring the second temperature of the luminescent compound is performed. It further includes, The method according to claim 6, wherein the step of determining a parameter representing the dependence of the luminescence property on the concentration of the analyte is to use the first temperature and the second temperature in addition to the first value and the second value.

8. The parameters include a temperature parameter representing the dependence of the luminescence property of the luminescent compound on the temperature, Optionally, a) the temperature parameter has a predetermined value, or b) The method described above is The steps include measuring a third value of the luminescence property of the luminescent compound while the luminescent compound is exposed to the analyte at a first concentration at a third temperature different from the first temperature, When the step of measuring the third value is performed, the step of measuring the third temperature of the luminescent compound is performed. It further includes, The method according to claim 7, wherein the step of determining a parameter representing the dependence of the luminescence property on the concentration of the analyte is to use the third value and the third temperature in addition to the first value, the second value, the first temperature, and the second temperature.

9. The method according to any one of claims 1 to 5, wherein the luminescence depends on the temperature of the luminescent compound, and the steps of measuring a first value of the characteristic and measuring a second value of the characteristic are performed at a predetermined temperature, and the parameter represents the dependence of the characteristic of the luminescence on the concentration of the analyte at the predetermined temperature.

10. The method according to any one of claims 1 to 9, wherein the luminescence property of the luminescent compound is a) the intensity of the luminescence or b) the ratio of the intensities of the luminescence at two different wavelengths.

11. The dependency of the aforementioned characteristics is modeled using a one-to-one host-guest coupling model. The method according to any one of claims 1 to 10, wherein the step of determining the parameter representing the dependency optionally includes using a predetermined value for the strength of the bond between the luminescent compound and the analyte.

12. The dependence of characteristic C on the concentration [X] of the analyte is given by the following equation, namely: [Math 1] Modeled using, C ０ This is the value of the luminescence characteristic of the luminescent compound when the concentration of the analyte is zero. C ∞ This is the value of the luminescence property of the luminescent compound when the concentration of the analyte is infinite. K is the strength of the bond between the luminescent compound and the analyte. The step of determining the parameter representing the dependency is C ０ and C ∞ This includes the step of finding the answer, Optionally, the parameter includes a temperature parameter α representing the dependence of the luminescence property of the luminescent compound on the temperature. C ０ and C ∞ This is due to the following dependence on the temperature T, namely, C ０ (T)=C ０c (1+α(T-T c )) C ∞ (T)=C ∞c (1+α(T-T c )) Modeled using, C ０c is, temperature T c C in ０ The value is C ∞c is, temperature T c C in ∞ The method according to claim 11, wherein the value is [value].

13. K has the following dependence on the temperature T, namely, [Math 2] Modeled using, K ｃ is, temperature T ｃ The coupling constant in, The method according to claim 12, wherein β is the bond temperature constant.

14. The method according to any one of claims 1 to 13, wherein the component is a replaceable component of the sensor.

15. A method for measuring the concentration of an analyte in a sample, using a sensor comprising a luminescent compound having luminescence dependent on the concentration of the analyte, and a detector configured to detect light emitted by the luminescent compound, A step of calibrating the sensor using the method according to any one of claims 1 to 14, The steps include measuring the value of the luminescence property of the luminescent compound while the luminescent compound is exposed to the sample, A step of deriving the concentration of the analyte in the sample using the measured value and the obtained parameter that represents the dependence of the luminescence property on the concentration of the analyte. A method that includes this.

16. The sample is a biological fluid, optionally blood or interstitial fluid, and the value of the luminescence characteristic is measured in vitro (outside the body). The method according to claim 15, optionally further comprising the step of integrating the sensor into a fluid line for a biological fluid in a medical device, wherein the sample is located in the fluid line.

17. The method according to any one of claims 1 to 16, wherein the sensor further includes a light source configured to excite the luminescent compound, and the step of measuring the value of the luminescence property of the luminescent compound includes the steps of exciting the luminescent compound using the light source and detecting light emitted by the luminescent compound using the detector.

18. The method according to any one of claims 1 to 17, wherein the analyte is one of carbon dioxide, hydrogen ions, sodium, potassium, magnesium, and calcium.

19. The method according to any one of claims 1 to 18, wherein the luminescent compound comprises a fluorescent compound and optionally 8-hydroxypyrene-1,3,6-trisulfonic acid.

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