阅读说明：本技术 用于检测生物传感器的体内性质的方法和电子单元 (Method and electronic unit for detecting in vivo properties of a biosensor ) 是由 U.米勒 H.韦德尔 A.波根维施 U.德尔文塔尔 A.克诺尔策 于 2018-06-29 设计创作，主要内容包括：公开了一种用于检测生物传感器(110)的体内性质的方法。本文中,生物传感器(110)与电子单元(202)互操作,适于以电化学方式确定体液(140)的样品中的分析物(136)的至少一个值,其中生物传感器(110)包括至少一个工作电极(120),其中工作电极(120)被膜(132)覆盖并且包括用于提供与分析物(136)的反应的酶(134),其中膜(132)具有电阻,并且工作电极(120)具有电容。此外,电子单元(202)适于测量原始电流和指示生物传感器(110)的导纳的电流响应。在本文中,所述方法包括以下步骤：a)提供生物传感器(110)的灵敏度与导纳的关系；b)测量生物传感器(110)中的原始电流；c)测量指示生物传感器(110)的体内导纳的体内电流响应,其中在至少一个第一操作点(156)和至少一个第二操作点(158)测量体内电流响应,其中选择第一操作点(156)以提供与膜(132)的电阻有关的第一特征值,并且其中选择第二操作点(158)以提供与工作电极(120)的电容有关的第二特征值；d)通过使用原始电流确定体液(140)样品中的分析物(136)值,并通过使用第一特征值来确定灵敏度的实际值来校正原始电流的测量值,从而补偿生物传感器(110)的体内灵敏度漂移,从而考虑在步骤a)期间提供的灵敏度与导纳的关系；以及e)基于第一特征值和/或第二特征值,监测生物传感器(110)的故障安全操作。该方法和包含生物传感器(100)和电子单元(202)的系统(200)可能主要是用于长期监测体液(140)中的分析物(136)的浓度,特别是用于家庭护理领域和专业护理领域的中葡萄糖水平的长期监测。本方法尤其可以允许减少校准程序的数量,并且此外,能够依靠生物传感器(110)的工厂校准。(A method for detecting an in vivo property of a biosensor (110) is disclosed. Herein, a biosensor (110) is interoperable with an electronics unit (202) adapted for electrochemically determining at least one value of an analyte (136) in a sample of a body fluid (140), wherein the biosensor (110) comprises at least one working electrode (120), wherein the working electrode (120) is covered by a membrane (132) and comprises an enzyme (134) for providing a reaction with the analyte (136), wherein the membrane (132) has a resistance and the working electrode (120) has a capacitance. Furthermore, the electronics unit (202) is adapted to measure the raw current and a current response indicative of the admittance of the biosensor (110). Herein, the method comprises the steps of: a) providing a sensitivity versus admittance of the biosensor (110); b) measuring a raw current in the biosensor (110); c) measuring an in vivo current response indicative of in vivo admittance of the biosensor (110), wherein the in vivo current response is measured at least one first operating point (156) and at least one second operating point (158), wherein the first operating point (156) is selected to provide a first characteristic value related to the resistance of the membrane (132), and wherein the second operating point (158) is selected to provide a second characteristic value related to the capacitance of the working electrode (120); d) compensating for in vivo sensitivity drift of the biosensor (110) by determining an analyte (136) value in the sample of bodily fluid (140) using the raw current and correcting the measured value of the raw current by determining an actual value of the sensitivity using the first characteristic value, thereby taking into account the sensitivity versus admittance provided during step a); and e) monitoring the fail-safe operation of the biosensor (110) based on the first characteristic value and/or the second characteristic value. The method and the system (200) comprising the biosensor (100) and the electronic unit (202) may be primarily used for long-term monitoring of the concentration of an analyte (136) in a body fluid (140), in particular for long-term monitoring of glucose levels in the home care field and in the professional care field. The method may in particular allow to reduce the number of calibration procedures and, in addition, to be able to rely on factory calibration of the biosensor (110).)

1. A method for detecting an in vivo property of a biosensor (110), wherein the biosensor (110) is interoperable with an electronics unit (202) adapted to electrochemically determine at least one value of an analyte (136) in a sample of a body fluid (140), wherein the biosensor (110) comprises at least one working electrode (120), wherein the working electrode (120) is covered by a membrane (132) and comprises an enzyme (134) for providing a reaction with the analyte (136), wherein the membrane (132) has a resistance and the working electrode (120) has a capacitance, wherein the electronics unit (202) is adapted to measure a raw current and a current response indicative of an admittance of the biosensor (110), the method comprising the steps of:

a) providing a sensitivity versus admittance of the biosensor (110);

b) measuring a raw current in the biosensor (110);

c) measuring an in vivo current response indicative of in vivo admittance of the biosensor (110), wherein the in vivo current response is measured at least one first operating point (156) and at least one second operating point (158), wherein the first operating point (156) is selected to provide a first characteristic value related to the resistance of the membrane (132), and wherein the second operating point (158) is selected to provide a second characteristic value related to the capacitance of the working electrode (120);

d) determining an analyte (136) value in a sample of the body fluid (140) by using the raw current and compensating for in vivo sensitivity drift in the biosensor (110) by correcting the measured value of the raw current by determining an actual value of the sensitivity by using the first characteristic value, thereby taking into account the sensitivity versus admittance provided during step a); and

e) a fail-safe operation of the biosensor (110) is monitored based on the first and/or second characteristic values.

2. The method of the preceding claim, wherein both the first and second feature values are taken into account for determining the analyte (136) value.

3. The method of the preceding claim, wherein the in vivo current response of the biosensor (110) is determined by applying at least one potential step (150) to the potential difference at the biosensor (110), wherein at least one potential step (150) comprises applying an additional potential between a working electrode (120) and a reference electrode (122) of the biosensor (110) over a time interval.

4. The method according to the preceding claim, wherein the first characteristic value relates to the geometric area of the working electrode (120) carrying the membrane (132), the thickness of the membrane (132), and the permeability of the membrane (132) with respect to at least one ion, and wherein the second characteristic value relates to the actual surface area of the working electrode (120) and the amount of catalyst and/or mediator available in the working electrode (120).

5. The method of any preceding claim, wherein the time constant isτCapacitance from the working electrode (120)CAnd the resistance of the film (132)R _M By passingτ＝R _M ∙ C to determineWherein, inτThe first operating point is selected below and isτThe second operating point is selected above.

6. Method according to the preceding claim, wherein said second operating point is selected higher than3τ。

7. The method of any one of the preceding claims, wherein the capacitance of the working electrode (120) is determined by using the sensitivity versus admittance relationship from the biosensor (110)CResistance of the film (132)R _M To monitor a fail-safe operation of the biosensor (110).

8. The method of the preceding claim, wherein the capacitance of the working electrode (120) is monitored by monitoring a sensitivity determined from a sensitivity versus admittance relationshipCAnd the resistance of the film (132)R _M To determine a structural modification of the biosensor (110).

9. The method according to any of the preceding claims, wherein the sensitivity versus admittance is obtained during a calibration of the biosensor (110), wherein the calibration of the biosensor (110) is selected from at least one of a multiple calibration, an initial calibration and a factory calibration.

10. The method according to any of the preceding claims, wherein in vivo drift of the biosensor (110) is compensated for by using the measured value of the raw current and a corrected value of the sensitivity.

11. The method of any one of the preceding claims, wherein the biosensor (110) is a fully or partially implantable biosensor for continuously monitoring the analyte (136).

12. The method according to any one of the preceding claims, wherein the analyte (136) comprises glucose, wherein the analyte (136) value is determined by using glucose oxidase or glucose dehydrogenase as the enzyme (134).

13. An electronics unit (202) for detecting an in vivo property of a biosensor (110) by performing the method according to any of the preceding method claims, wherein, in interoperation with the biosensor (110), the electronics unit (202) is adapted for electrochemically determining at least one value of an analyte (136) in a sample of a body fluid (140), wherein the biosensor (110) comprises at least one working electrode (120), wherein the working electrode (120) is covered by a membrane (132) and comprises an enzyme (134) for providing a reaction with the analyte (136), wherein the electronics unit (202) is further adapted for measuring a raw current and a current response indicative of an admittance of the biosensor (110), wherein the electronics unit (202) comprises a potential step response measuring unit (206), wherein the potential step response measuring unit (206) is configured for measuring the current response indicative of the admittance of the biosensor (110), wherein the potential step response measurement unit (206) comprises at least one charge counter (218) and at least one peak detector (222), wherein the peak detector (222) is configured to measure a first characteristic value related to the resistance of the membrane (132), and wherein the charge counter (218) is configured to measure a second characteristic value related to the capacitance of the working electrode (120).

14. The electronics unit (202) according to the preceding claim, wherein the electronics unit (202) is further adapted to apply an electrical potential between the working electrode (120) and at least one reference electrode (122) of the biosensor (110) and for measuring a resulting raw current, wherein the electronics unit (202) comprises a direct current measurement unit (204), wherein the direct current measurement unit (204) is configured for measuring the raw current.

15. A system (200) for operating a biosensor (110) for electrochemically detecting at least one analyte (136) value in a sample of a body fluid (140), the system comprising at least one biosensor (110) for electrochemically detecting at least one analyte (136) value in a sample of a body fluid (140), wherein the biosensor (110) is operable by performing a method according to any one of the preceding claims referring to a method and an electronic unit (202) according to any one of the preceding claims referring to an electronic unit.

Technical Field

The present invention relates to a method for detecting an in vivo property of a biosensor, an electronic unit adapted to perform the method and a system comprising a biosensor and such an electronic unit. The electronic unit and the system according to the method of the invention may be used primarily for long term monitoring of the analyte concentration in a body fluid, in particular for long term monitoring of the glucose level or the concentration of one or more other types of analytes in a body fluid. The invention can be applied both in the field of home care and in the field of professional care, such as in hospitals. However, other applications are also possible.

Background

Monitoring certain bodily functions, and more particularly monitoring one or more concentrations of certain analytes, plays an important role in the prevention and treatment of various diseases. Without limiting further possible applications, the invention is described below with reference to glucose monitoring in interstitial fluid. However, the invention may also be applied to other types of analytes. Specifically, blood glucose monitoring can be performed by using an electrochemical biosensor in addition to optical measurement. Examples of electrochemical biosensors for measuring glucose, in particular glucose in blood or other body fluids, are known from US 5,413,690A, US 5,762,770A, US 5,798,031A, US 6,129,823 a or US 2005/0013731A 1.

In addition to "point measurements" in which a body fluid sample is taken from a user (i.e. a human or animal) in a targeted manner and examined with respect to the analyte concentration, continuous measurements are also becoming more and more frequent. Thus, in recent times, continuous measurement of glucose in interstitial tissue (also referred to as "continuous glucose monitoring" or abbreviated "CGM") has been established, for example, as another important method for managing, monitoring and controlling the state of diabetes. Here, the active sensor region is applied directly to a measurement site, which is usually arranged in the interstitial tissue, and glucose can be converted into a modified entity, for example by using an enzyme, in particular glucose oxidase (usually abbreviated as "GOD"). As a result, the detectable current may be related to the glucose concentration and may therefore be used as a measurement variable. Examples of such transcutaneous measurement systems are described in US 6,360,888B 1 or US 2008/0242962 a 1.

US 2012/262298 a1 discloses a method and apparatus for processing sensor data and self-calibration. Herein, methods and devices are provided that enable calibrating a continuous analyte sensor based on an initial sensitivity, and then continuously performing self-calibration without or with reduced use of reference measurements. Also described herein are methods and apparatus for determining properties of an analyte sensor using a stimulation signal, where the properties of the sensor can be used to compensate sensor data for sensitivity drift, or to determine another property associated with the sensor, such as temperature, sensor membrane damage, moisture ingress into sensor electronics, and scaling factor.

Typically, current continuous monitoring systems are transcutaneous or subcutaneous systems. Thus, the actual biosensor or at least the measuring part of the biosensor may be arranged below the skin of the user. However, the evaluation and control portion of the system (which may also be referred to as a "patch") may typically be located outside the user's body. Here, biosensors are generally applied by using an insertion instrument, which is described in an exemplary manner in US 6,360,888B 1. However, other types of insertion instruments are also known. Furthermore, a control part may be generally required, which may be located outside the body tissue and which has to communicate with the biosensor. Typically, communication is established by providing at least one electrical contact between the biosensor and the control portion, wherein the contact may be a permanent electrical contact or a releasable electrical contact. Other techniques for providing electrical contact, such as by suitable spring contact, are generally known and may also be applied.

In a continuous glucose measurement system, the concentration of analyte glucose may be determined by employing an electrochemical sensor that includes an electrochemical cell having at least a working electrode and a counter electrode. Here, the working electrode may have a reagent layer comprising an enzyme having a redox active enzyme cofactor suitable for the oxidation of the analyte in the supporting liquid.

The problem to be solved.

It is therefore an object of the present invention to provide a method for detecting an in vivo property of a biosensor, an electronic unit adapted to perform the method and a system comprising a biosensor and such an electronic unit, which at least partly avoid the disadvantages of such known devices and methods.

In particular, it is desirable that the method is capable of detecting possible in vivo drifts in the biosensor in a reliable and iterative manner, wherein the in vivo drifts subsequently actually detected may be adapted to compensate for the effects of the drifts in the biosensor, in particular in order to be able to reliably and iteratively determine the analyte values.

Furthermore, it is expected that the method according to the invention may be easily implementable in an electronic unit which may be operated with standard biosensors and may thus be applicable to existing biosensor systems without the need for modification.

Disclosure of Invention

This problem is solved by a method for detecting an in vivo property of a biosensor, an electronic unit adapted to perform the method as well as a system comprising a biosensor and such an electronic unit having the features of the independent claims. Preferred embodiments of the invention that can be realized in isolation or in any arbitrary combination are disclosed in the dependent claims.

As used herein, the terms "has," "includes" or "including" or any grammatical variations thereof are used in a non-exclusive manner. Thus, these terms may refer to both the case where there are no other features present in the entities described in this context than the features introduced by these terms and the case where there are one or more other features present therein. As one example, the expressions "a has B", "a includes B", and "a includes B" may refer to both a case in which no other element is present in a other than B (i.e., a case in which a consists only and exclusively of B) and a case in which one or more other elements are present in entity a other than B (such as elements C, elements C and D, or even other elements).

Furthermore, it should be noted that the term "at least one," "one or more," or similar expressions, which indicate that a feature or element may be present one or more times, are generally only used once when introducing the corresponding feature or element. In the following, in most cases, when referring to corresponding features or elements, the expressions "at least one" or "one or more" are not repeated, although corresponding features or elements may be present only once or more than once.

Further, as used in the following, the terms "preferably," "more preferably," "particularly," "more particularly," "specifically," "more specifically," or similar terms are used in connection with optional features without restricting the possibilities of alternatives. Thus, the features introduced by these terms are optional features and are not intended to restrict the scope of the claims in any way. As the skilled person will appreciate, the invention may be carried out by using alternative features. Similarly, features presented by "in an embodiment of the invention" or similar expressions are intended to be optional features, in the absence of any restriction as to the scope of the invention, and in the absence of any restriction as to the possibility of combining features presented in this way with other optional or non-optional features of the invention.

In a first aspect of the invention, a method for detecting an in vivo property of a biosensor is disclosed, wherein the biosensor is interoperable with an electronic unit adapted for electrochemically determining at least one value of an analyte in a sample of bodily fluid, wherein the biosensor comprises at least one working electrode, wherein the working electrode is covered by a membrane and comprises an enzyme for providing a reaction with the analyte, wherein the membrane has a resistance and the working electrode has a capacitance, wherein the electronic unit is adapted for measuring a primary current and a current response indicative of the admittance of the biosensor. The method comprises the following method steps, to name a few:

a) providing a sensitivity-to-acceptance relationship (sensitivity-to-acceptance) of the biosensor;

b) measuring a raw current in the biosensor;

c) measuring an in vivo current response indicative of an in vivo admittance of the biosensor, wherein the in vivo current response is measured at least one first operating point and at least one second operating point, wherein the first operating point is selected for providing a first characteristic value related to a resistance of the membrane, and wherein the second operating point is selected for providing a second characteristic value related to a capacitance of the working electrode; and

d) compensating for in vivo sensitivity drift in the biosensor by determining an analyte value in the body fluid sample using the raw current and correcting the measured value of the raw current by determining an actual value of the sensitivity using the first characteristic value, thereby taking into account the sensitivity versus admittance provided during step a); and

e) a failsafe operation of the sensor is monitored based on the first characteristic value and/or the second characteristic value.

The indicated steps can preferably be carried out in the given sequence, starting with method step a) and ending with method step d), wherein, however, any or all of the indicated steps, in particular method steps b) and c), can be carried out at least partially simultaneously (for example within a defined time period). In addition, any or all of the indicated steps may also be repeated several times to allow detection of in vivo properties of the biosensor (e.g., after a predetermined time or due to the occurrence of a predetermined event). Moreover, additional method steps may also be performed, whether described herein or not.

As generally used, the term "biosensor" may refer to any device configured to perform at least one medical analysis. To this end, the biosensor may be any device configured for performing at least one diagnostic purpose, and in particular, comprises at least one analyte sensor for performing at least one medical analysis. In particular, the biosensor may comprise an assembly of two or more components capable of interacting with each other, for example in order to perform one or more diagnostic purposes, for example in order to perform a medical analysis. In particular, the two or more components may be capable of performing and/or facilitating at least one detection of at least one analyte in a bodily fluid. In general, the biosensor may also be part of at least one of a sensor assembly, a sensor system, a sensor kit or a sensor device. Furthermore, the biosensor may be connectable to an evaluation device, such as an electronic unit.

In a particularly preferred embodiment of the invention, the biosensor may be a fully implantable or partially implantable biosensor, which may be particularly adapted to perform detection of an analyte in a body fluid, in particular in interstitial fluid, in subcutaneous tissue. As used herein, the term "implantable biosensor" or "subcutaneous biosensor" may refer to any biosensor suitable for placement entirely or at least partially within a body tissue of a patient or user. To this end, the biosensor may comprise an insertable portion. In this context, the term "insertable portion" may generally refer to a portion or component of an element that is configured to be insertable into any body tissue. Preferably, the biosensor may fully or partially comprise a biocompatible surface, i.e. a surface that may have as little detrimental effect as possible on the user, the patient or body tissue at least during typical use. To this end, the insertable portion of the biosensor may have a biocompatible surface. According to the invention, the biosensor, in particular the insertable part thereof, is completely or partially covered by at least one biocompatible membrane (e.g. at least one polymer membrane or gel membrane) which on the one hand may be permeable to body fluids or at least to the analyte contained therein and which on the other hand may retain the sensor substance (e.g. one or more test chemicals) in the sensor, thereby preventing its migration into body tissue. Other parts or components of the biosensor may remain outside the body tissue.

As commonly used, the terms "patient" and "user" may refer to a human or animal, independent of the fact that the human or animal may be in a healthy condition or may be suffering from one or more diseases, respectively. As one example, the patient or user may be a human or animal with diabetes. However, the invention may additionally or alternatively be applied to other types of users, patients or diseases.

As further used herein, the term "bodily fluid" may generally refer to a fluid, particularly a liquid, that may be generally present in and/or may be produced by a body or body tissue of a user or patient. Preferably, the body fluid may be selected from the group consisting of blood and interstitial fluid. However, additionally or alternatively, one or more other types of bodily fluids may be used, such as saliva, tears, urine or other bodily fluids. During the detection of the at least one analyte, a body fluid may be present within the body or body tissue. Thus, the biosensor may specifically be configured for detecting at least one analyte within a body tissue.

As further used herein, the term "analyte" may refer to any element, component, or compound present in a bodily fluid, wherein the presence and/or concentration of the analyte may be of interest to a user, patient, or medical professional (e.g., physician). In particular, the analyte may be or may comprise at least one chemical substance or compound that may participate in the metabolism of the user or patient, such as at least one metabolite. As an example, at least one analyte may be selected from the group consisting of glucose, cholesterol, triglycerides, lactate. However, additionally or alternatively, other types of analytes may be used and/or any combination of analytes may be determined. In particular, the detection of the at least one analyte may especially be an analyte-specific detection. Without limiting the further possible applications, the invention is described below with particular reference to the monitoring of glucose in interstitial fluid. As commonly used, at least one property of an analyte may be characterized by a "value" associated with that property, such as the concentration of the analyte. However, other kinds of properties may also be feasible, such as interfering substances or "interferents", i.e. other redox active substances contained in the body fluid, which may be oxidized in a similar manner and may thus generate other electrons which may be detected as additional current.

As further used herein, the term "measuring" refers to a process of generating at least one signal, in particular at least one measurement signal, which is characteristic of the result of at least one measurement. In particular, the at least one signal may be or may comprise at least one electronic signal, such as at least one voltage signal and/or at least one current signal, in particular a raw current signal. The at least one signal may be or may comprise at least one analog signal and/or may be or may comprise at least one digital signal. Especially in electrical systems, it may be necessary to apply a predetermined signal to a specific device in order to be able to record the required measurement signal. For example, especially according to method step b), measuring the raw current may require applying a voltage signal to the device, and vice versa.

In addition, the term "measuring" as used herein also refers to generating additional values related to the measurement signals, wherein each measurement signal may be affected by a variable capable of affecting the measurement signal. As used herein, the raw current of a biosensor can thus be measuredITo measure the sensitivity of a biosensorSFrom which the concentration of an analyte, such as glucose, can be taken into accountc. In an ideal representation, the sensitivity of the biosensorSCan be generally defined by equation (1):

S =（I–I ₀ ）/c， （1）

wherein item I₀Refers to possible zero current that may come from an interferer. In practice, equation (1) may hold for concentrations below the empirical value of 100mg/dl to 150mg/dl glucose, above which the sensitivity of the biosensor isSMore complex curvatures can be exhibited. In fact, the raw current can be measuredIAnd subsequently the sensitivity can be corrected in the case of a sensitivity drift. Alternatively, in this case, the raw current may be correctedIThe value of (c).

Further according to the invention, the in vivo admittance of the indicator biosensor is measured according to method step c)Y（t）In vivo ofThe current response. As generally used, the term "in vivo" refers to the actual state of a biosensor during its application to a patient or user, which may be especially the opposite of the state of the biosensor as manufactured or initially provided to the patient or user. In particular, the time-varying voltage may be applied by applying a time-varying voltage to the biosensorU（t）To determine the current response in vivoI（t）. As is well known, the admittance of biosensorsY（t）Can be defined by equation (2):

Y（t）= I（t）/U（t）=Y'（t）+i Y''（t）， （2）

wherein the termY′（t）AndY″（t）respectively mean complex admittanceY（t）Time-varying real and imaginary parts. Alternatively or additionally, a reciprocal value of the admittance, which is typically expressed as the "impedance" of the biosensor, may be measured. In vivo admittance for actual measurement indicating biosensorY（t）For more details of a preferred procedure of the in-body current response, reference may be made to the following description.

As further used herein, the term "determining" relates to a process of generating at least one representative result, e.g. a plurality of representative results, by using at least one signal, in particular at least one measurement signal, which is characteristic for the measurement result. Thus, as used herein, sensitivity at a biosensor can be measured bySAnd admittanceY（t）Providing at least one selected relationship therebetween to determine a sensitivity to admittance relationship, wherein the sensitivity of the biosensor isSAnd admittance of the biosensorY（t）May be used for this purpose. As generally used, the sensitivity may be determined by measuring at least one first value (e.g., with sensitivity)SRelated) and at least one second value (e.g. related to admittance)Y（t）Related) applying operations (e.g. mathematical operations) between them）To provide two values (e.g., sensitivity)SAnd admittanceY（t））Selected "relationships" between. For example, the mathematical operation may be selected from at least one of a ratio, a weighted ratio, or a functional ratio, wherein a weighted ratio refers to each termA pre-weighted ratio, and wherein a functional ratio refers to a ratio in which each term is subjected to a function such as a polynomial, exponential or logarithmic function before the ratio is formed. However, other kinds of operations and functions are also possible. In a preferred embodiment, the sensitivity to admittance relationship may be a sensitivity to admittance ratioS（t）/Y（t）Which can be preferably formed by forming the sensitivitySRelative to admittanceY（t）Wherein the sensitivity of the biosensor can be usedSAnd admittance of the biosensorY（t）At least one measured value of (a). However, other types of relationships may be possible for this purpose.

As further used herein, the term "monitoring" refers to the process of continuously recording data and deriving the required information therefrom without user interaction. For this purpose, a plurality of measurement signals are generated and evaluated, from which the desired information is determined. In this case, a plurality of measurement signals can be recorded at fixed or variable time intervals or alternatively or additionally upon the occurrence of at least one predetermined event. In particular, the biosensor according to the present invention may be particularly suitable for continuously monitoring one or more analytes, in particular glucose, such as for managing, monitoring and controlling a diabetic condition.

The biosensor according to the invention is an electrochemical or amperometric sensor. As used herein, the term "electrochemical sensor" or "amperometric sensor" each refers to a sensor adapted to perform at least one electrochemical measurement, in particular a plurality or series of electrochemical measurements, for detecting at least one substance contained in a body fluid by using an amperometry method. In particular, the term "electrochemical measurement" or "electrochemical measurement" refers to the detection of an electrochemically detectable property of a substance by employing an amperometric method (e.g., an electrochemical detection reaction). Thus, for example, an electrochemical detection reaction can be detected by applying and comparing one or more electrode potentials. In particular, the electrochemical sensor may be adapted to generate at least one electrical sensor signal, which may be directly or indirectly indicative of the presence and/or extent of an electrochemical detection reaction, such as at least one current signal and/or at least one voltage signal. The measurement may be a qualitative and/or quantitative measurement. However, other embodiments are possible.

For this purpose, an electrochemical sensor as used herein is arranged in the manner of an electrochemical cell, and thus employs at least one pair of electrodes. As used herein, the term "electrode" refers to an entity of the test element adapted to be in contact with a body fluid, either directly or via at least one semi-permeable membrane or layer. With regard to the invention, at least one electrode is covered by a membrane, wherein the electrode may be embodied in such a way that electrochemical reactions may take place on at least one surface of the electrode. In particular, the electrode may be embodied in such a way that oxidation processes and/or reduction processes may occur at selected surfaces of the electrode. In a particularly preferred embodiment as used herein, the biosensor has a working electrode, a reference electrode and a counter electrode, wherein both the working electrode and the reference electrode may be covered by a membrane, wherein the working electrode (as opposed to the reference electrode) further comprises an enzyme, wherein the working electrode may comprise the enzyme or may be covered by an enzyme layer. In addition, the counter electrode may be covered with a film or not. However, other embodiments with a different number of electrodes or a different number of electrodes covered by a film are also possible.

More particularly, the electrochemical sensor may be a multi-domain (field) sensor, wherein the working electrode may cover more than one domain, e.g. 4, 8, 12 or 16 domains, on a substrate such as a polyimide substrate, and the counter electrode may be placed on the back side of the substrate. Preferably, the working electrode may comprise a carbon paste, MnO as a catalyst and/or mediator₂A composition of particles, and Glucose Oxidase (GOD) and/or Glucose Dehydrogenase (GDH) applied to a conductive layer, such as a gold and/or copper layer deposited on a substrate, while the counter electrode may preferably be or comprise a gold electrode and the reference electrode may be an Ag/AgCl electrode. Furthermore, the membrane covering the working electrode may comprise two separate partial membranes, which may be stacked on each other. In this case, the first partial film, which can be positioned adjacent to the working electrode, can form a diffusion barrier, which can be in particular a hydrophilic layer, for exampleSuch as hydrophilic polyurethanes with hydrophilic and hydrophobic side chains. In contrast thereto, the second partial membrane, which may be placed on top of the first partial membrane and may thus adjoin a volume suitable for accommodating body fluids, may be a biocompatible layer, which may preferably comprise a biogel, e.g. a polyacrylate block copolymer having a hydrophobic backbone and hydrophilic side chains. In particular, both partial films may be applied by using a dip coating process.

Furthermore, the working electrode, the reference electrode and the counter electrode may preferably be connected by a potentiostat, wherein a potential difference may be applied between the working electrode and the reference electrode by the potentiostat. Thus, here the detailed course of the redox reaction can be detected by comparing one or more electrode potentials, in particular the potential difference between the working electrode and the reference electrode. As used herein, the term "potentiostat" refers to an electronic device suitable for regulating and/or measuring the potential difference between two electrodes in an electrochemical cell, particularly between a working electrode and a reference electrode. For this purpose, a potentiostat may be implemented in order to be able to inject an electric current into the electrochemical cell via the counter electrode, which is also referred to as auxiliary electrode for this purpose. Such an arrangement of a potentiostat may allow both the adjustment of the potential difference between the working electrode and the reference electrode within the electrochemical cell and the measurement of the original current (preferably between the working electrode and the counter electrode) alternatively or additionallyI. Alternatively, potentiostats may be used as well to measure the raw currentISo that no potential drop can occur due to active current regulation by the potentiostat. As a result, the potentiostat can apply a voltage, for example a direct voltage or an alternating voltage, preferably a direct voltage, between the working electrode and the reference electrode and preferably simultaneously measure a direct or alternatively an alternating primary current, preferably thus generated between the working electrode and the counter electrodeI. As a result, the biosensor may be able to measure the raw current between the working electrode and the reference electrodeI。Furthermore, the current can be derived from the original currentIRelative to the concentration of the analytecThe sensitivity S is obtained. As described in more detail below, preferably, another circuit may be used to determine the in-vivo current response, which is indicative thereofIn vivo admittance of electrochemical cellY（t）Whereby, in addition, the complex admittance of the electrochemical cell can be measuredY（t）Or a value associated therewith.

The working electrode may further comprise an enzyme or may be covered by an enzyme layer, wherein the enzyme or enzyme layer may be or comprise a test chemistry, while the reference electrode and the counter electrode may preferably be kept free of the test chemistry. In general, the term "test chemical" refers to any material or combination of materials suitable for altering at least one detectable property in the presence of at least one analyte, where the detectable property herein is selected from the electrochemically detectable properties mentioned above. In particular, the at least one test chemical may be a highly selective test chemical which only changes properties if the analyte is present in a sample of the bodily fluid applied to the test element, but which does not change if the analyte may not be present. More preferably, the degree or change of the at least one property depends on the concentration of the analyte in the body fluid, so as to allow quantitative detection of the analyte. As used herein, the test chemical may comprise one or more enzymes, such as Glucose Oxidase (GOD) and/or Glucose Dehydrogenase (GDH), preferably adapted to perform an oxidation process or a reduction process with the at least one analyte to be detected by itself and/or in combination with other components of the detector substance. Additionally or alternatively, the test chemical may comprise one or more auxiliary components, for example one or more coenzymes and/or may comprise one or more catalysts and/or redox mediators. Furthermore, the test chemical may comprise one or more dyes, which preferably interact with one or more enzymes, which may change their color in the presence of at least one analyte to be detected.

In a particularly preferred embodiment of the invention, the biosensor may be a diffusion-controlled biosensor, in particular a diffusion-controlled amperometric biosensor. As commonly used, the term "diffuse" refers to the gradient of concentration of a substance (e.g., molecules or particles) in a fluid from a region containing a high concentration of the substance to a region of low concentration of the substanceA net downward motion. Without wishing to be bound by theory, in biosensors, diffusion of an analyte such as glucose from a bodily fluid to the surface of a working electrode can be considered as the rate-limiting step in a typical concentration range. Here, the biosensor may be referred to as "diffusion-controlled" in a situation where the ratio of the diffusion rate to the reaction rate of the analyte may be adjusted in such a manner that the reaction of the analyte reaching the surface of the working electrode with the enzyme, and other steps (e.g., electron transfer) after the reaction may occur rapidly, so that the analyte concentration at the surface of the working electrode may disappear. This solution can be achieved in particular by the enzyme present in excess on the surface of the working electrode in combination with the transport properties of the membrane, in particular the thickness and permeability of the membrane. As a result, a well-tuned diffusion-controlled biosensor can thus exhibit a relative analyte concentration according to equation (1)cWhile high sensitivity can be avoidedSIn particular sensitivity which may occur due to a decrease or loss of enzyme activity as a result of measurement time or storage timeSDrift of (2). Thus, the sensitivity of the biosensorSAnd thus may depend on the transport properties of the membrane, in particular on the thickness and permeability of the membrane. In other words, a change in the properties of the film can be considered to cause sensitivitySThe cause of the change.

On the other hand, it may be feasible to study the properties of the film by exploiting the dielectric properties of the biosensor. In particular, static experiments have shown sensitivitySGood correlation with the resistance or conductance of the film. As commonly used, in the case of a DC circuit, the conductivity of the film and the resistance of the filmR _M Is related to the reciprocal of (c). Here, as long as the enzyme is present in excess, the ion concentration is kept constant, and the temperature is kept constant, a good correlation between ion diffusion and glucose diffusion can be demonstrated in all swollen (swelling) states of the membrane.

Without wishing to be bound by theory, therefore, functional testing of biosensors may provide sensitivitySA trend of (a), wherein the permeability of the membrane with respect to the analyteP _ana Thickness of filmdAnd geometric area of the electrodeACan be considered according to equation (3):

S=（I–I ₀ ）/ _c〜Pana /d∙A（3）

the-symbol represents an aspect sensitivitySPermeability of the other mask with respect to the analyteP _ana Relative to film thicknessdAnd electrode surface areaARatio between the ratios of the products of (a) and (b).

Further, a double-layer capacitance can be formed on the surface of the working electrode, and the double-layer capacitance can be maintained at a frequency of 0.01Hz to 1MHz, preferably 0.1Hz to 100kHz, more preferably 1Hz to 10kHz, particularly 10Hz to 1 kHz. As a result, admittanceY （t）May not be determined by a faraday current, including but not limited to zero current, but may also refer primarily to ions in the film (such as Na)⁺Or Cl^-) The electrical conductivity of (1). Thus, the dielectric property of the biosensor may be admittanceY（t）Trends are provided in which the permeability of the membrane with respect to ionsP _ion Thickness of filmdAnd the actual surface area of the electrodeACan be considered according to equation (4):

Y（t）=〜P _ion /d∙A（4）

therefore, according to equation (5), the sensitivity can be related to the admittanceS（t）/Y（t）Estimated to depend only on the permeability of the respective membrane in relation to the analyte and the ions, respectivelyP _ana ，P _ion The ratio of (A) to (B):

S（t）/Y（t）=〜P _ana /P _ion （5）

as a result, sensitivity versus admittance can be employedS（t）/Y（t）To provide information about the current state of the intrinsic film transport properties, whereas the geometrical properties related to the film, in particular the thickness of the film, can be neglecteddAnd surface area of working electrodeAThe information of (1). Thus, by determining the sensitivity versus admittanceS（t）/Y（t）E.g. by during operation of the biosensorThe change in permeability and thickness of the membrane caused by swelling of the membrane may advantageously be negligible. In other words, the sensitivity can be related to the admittanceS（t）/Y（t）It is assumed to remain constant during operation of the biosensor as long as the biosensor can be considered as a diffusion controlled biosensor. As described above, the term "diffusion-controlled" refers to biosensors in which the reaction rate of an analyte may be much higher compared to the diffusion rate of the analyte. As a result, in vivo drift may not occur in the biosensor, where the term "in vivo drift" relates to a change in the sensitivity of the biosensor due to a change in an in vivo property of the biosensor (such as a membrane property, particularly an intrinsic membrane property) during in vivo operation of the biosensor.

According to step c), a raw current indicative of the in vivo admittance of the biosensor is measured at two different operating points, namely at a first operating point and a second operating pointIAnd in vivo current response. As used herein, the term "operating point" refers to a particular state of the biosensor that can be achieved by applying a determined state of the electronic unit to the biosensor. According to the invention, the first operating point is selected to provide a first characteristic value related to the resistance of the membrane, while the second operating point is selected for providing a second characteristic value related to the capacitance of the working electrode. As further used herein, the term "characteristic value" refers to a numerical value that is related to an operating point and provides representative information of the state of the biosensor at the respective operating point.

As described in more detail below, the first characteristic value may preferably comprise a value which may be related to, in particular proportional to, the electrical resistance of the membrane, in particular proportional to the geometric area (i.e. cross-section) of the working electrode carrying the membrane, the thickness of the membrane and the permeability of the membrane with respect to at least one ion. With respect to the thickness and/or permeability of the membrane, reference may be made to the description elsewhere herein. Similarly, the second characteristic value may comprise a value which may be related to, in particular proportional to, the inverse of the capacitance of the working electrode, in particular proportional to the actual surface area of the working electrode carrying the membrane and proportional to the amount of catalyst and/or mediator available in the membrane. With respect to the catalyst and/or mediator, reference may be made to the description elsewhere herein. However, other kinds of characteristic values may also be possible.

As generally used, the term "geometric area of the electrode" refers to a measured dimension of the electrode that depends on the physical dimensions of the body for the electrode, and therefore is not expected to change during operation of the biosensor. In contrast, the term "actual surface area of the electrode" refers to the partition of the electrode surface of the actual carrier film. As a result, the actual surface area of the electrode may be the same as the geometric area of the electrode, as long as the geometric area of the electrode is completely covered by the membrane. However, the actual surface area of the electrode may change during operation of the biosensor, especially in cases where the electrode chemistry may at least partially separate from the electrode pad, which may be considered as the active electrode surface after detachment of the electrode chemistry. In this case, the ratio of the electrode surface to the diffusion area determined by the electrode pad can be retained, and the influence of the roughness of the electrode paste and the pseudo capacitance can be ignored. Thus, the process allows for different kinds of regions present in the biosensor to be taken into account when determining the respective in vivo properties of the biosensor. In particular, the process advantageously allows the use of values that are independent of the actual area of the electrodes to account for the swelling of the membrane during operation of the biosensor.

According to method step a), the reference sensitivity of the biosensor in relation to the admittance may generally be provided for further reference. To this end, the reference sensitivity versus admittance may preferably be determined at least once by applying a calibration procedure, for which preferably known biosensors, such as common test strips, may be used for the spot measurement. Preferably, the calibration procedure may be performed as a simplified "multiple calibration", in particular in the form of a periodic calibration of the biosensor or a calibration upon event (e.g. a request by the patient to actually wear the biosensor or after a predetermined event). More preferably, the calibration procedure may be performed as an "initial calibration" by calibrating the biosensor during an initial phase (preferably a single time) with respect to a particular patient actually wearing the biosensor before an initial in vivo operation of the biosensor at the patient. Most preferably, however, the calibration procedure may be performed as a "factory calibration" which comprises calibrating the biosensor in the manufacturing facility, in particular by an in vitro operation using the biosensor, independently of the patient to wear the particular biosensor, thus advantageously avoiding invasive point measurements on any patient. However, other possibilities are also conceivable. Irrespective of the chosen calibration procedure, the reference sensitivity-to-admittance relation thus allows to determine intrinsic film properties compared to the intrinsic film properties studied under predetermined conditions, wherein the most recently determined sensitivity-to-admittance relation may preferably be used for the purpose of step d), if applicable.

Thus, according to the present invention, the in vivo properties of the biosensor are detected. As used herein, the term "in vivo property" refers to the actual physical and chemical properties of a particular biosensor, which represent the actual state of the particular biosensor during in vivo determination of an analyte value in a bodily fluid sample, and which may be capable of affecting the analyte value determined by the particular biosensor in the particular state. As noted above, the physical and chemical properties of a particular biosensor may include, but are not limited to, the properties, particularly the intrinsic properties, of the membrane covering the working electrode. Other kinds of properties that may be capable of affecting the analyte value are described in more detail below.

Thus, according to step d), the analyte value in the body fluid sample is determined on the one hand by using the raw current and by compensating for the in vivo drift of the biosensor sensitivity (as described below), and on the other hand by taking into account at least the first characteristic value (but preferably also the second characteristic value). For this purpose, in particular, the first characteristic value and preferably also the second characteristic value are taken into account in the first aspect according to step d), while the failsafe operation of the biosensor is also taken into account in the second aspect according to step e), wherein the failsafe operation is based on at least one of the first characteristic value and the second characteristic value, as described in greater detail below. More specifically, although in any case a first characteristic value related to the reciprocal of the resistance of the membrane is used according to the invention, a second characteristic value related to the capacitance of the working electrode can be useful (since it is independent of the different kinds of regions present in the biosensor, as described above) in particular in improving the correlation between the raw current and the analyte value.

According to the invention, in vivo sensitivity drifts in the biosensor can be compensated by correcting the actually determined value of sensitivity using the first characteristic value of in vivo admittance and preferably also the second characteristic value thereof, thereby taking into account the value of the sensitivity-to-admittance relation provided during step a). According to equation (1), the original currentICan be based on the sensitivity of the biosensorSAnd, among other things, the sensitivity of the biosensor appears to be temperature and time dependentSMay decay over shelf life (shelflife) (e.g., due to membrane reorganization depending on storage conditions), but may increase during in vivo operation of the biosensor (e.g., due to swelling of the membrane). In this way, in vivo sensitivity drift in a biosensor may especially involve changes over time or due to unexpected events in the intrinsic membrane properties of the membrane covering the working electrode of the biosensor and may therefore affect the current flow from the primary currentIAn analyte value is determined.

As further used herein, the term "compensation" relates to a process of modifying a measured value which can be affected by side effects, for which purpose additional considerations are applied by means of which side effects can be reduced or particularly preferably completely eliminated, wherein the additional considerations may in particular be based on additional measurement results on the same biosensor. As used herein, in vivo sensitivity drift in a biosensor can affect the raw currentI，And therefore according to method step d) compensation is carried out by taking into account the first characteristic value and preferably the second characteristic value as described above. To determine both the first and second characteristic values, the in vivo current response indicative of the in vivo admittance of the biosensor is measured at two different operating points, as described elsewhere herein. In a preferred embodimentIn an embodiment, the in vivo sensitivity drift in the biosensor can thus be compensated by correcting the measured value of the raw current by using the first characteristic value and preferably the second characteristic to determine an actual value of the sensitivity, taking into account the value of the sensitivity versus admittance provided during step a). However, other ways of deriving the compensation may also be applied.

However, in contrast to the prior art (in which only the sensitivity can be measured)S（t）And may be after a predetermined time interval has elapsed and/or when the sensitivity is highS（t）May have exceeded a given threshold), the invention allows for the simultaneous consideration of admittanceY（t）Relative to sensitivityS（t）Time variation of the time drift. As particularly described by equation (5), during in vivo operation, the in vivo sensitivity to admittance ratioS（t）/Y（t）May be insensitive to many variations in the biosensor and, therefore, although varying the sensitivity individually and simultaneouslyS（t）And will not change. However, as is particularly indicated by the actual operating regime of the biosensor following equation (5), and therefore at predetermined time intervals and/or sensitivitiesS（t）May thus no longer require recalibration of the biosensor after the time drift of (a) exceeds a given threshold. As a result, the present method may allow for a reduced number of calibrations compared to the prior art, and may also be dependent on an initial calibration of the biosensor or more preferably a factory calibration. Based on these considerations, the present method may furthermore be applied to monitor the fail-safe operation of the biosensor, which will be described in more detail below.

In a particularly preferred embodiment of the invention, the in vivo admittance of the indicator biosensor may be achieved by applying a non-faradaic method, in particular by applying at least one potential step of the potential difference at the biosensor, in particular between the working electrode and the reference electrodeY（t）Measurement of the in-vivo current response. For this purpose, a potentiostat may be preferably used. As used herein, the term "potential step" may refer to a step formed by a process that may be provided in the form of an electrical pulseThe impact of the additional potential of (a) on the working electrode comprising the membrane. Here, the additional potential can preferably be provided by an electrical pulse at a time interval of 10 μ s, more preferably 50 μ s to 1000 μ s, more preferably 250 μ s, in particular about 100 μ s, after the potential step is applied.

Thus, the height of the potential step may be selected so as to define the maximum voltage that can be applied to the membrane of the biosensorU _max Or maximum currentI _max One of them. For example, the potential step may comprise a (previling) potential relative to a prevailing potential on the membraneE ₁ At time intervalsΔtInternal application of increasing or decreasing potentialsE ₂ Thereby proving a potential difference to the filmΔE. In this respect, it may be emphasized that the sign of the potential step may be chosen to be positive or negative. Here, a potential differenceΔEMay preferably be provided with respect to the prevailing potentialE ₁ An additional voltage of 10mV to 500mV, more preferably 50mV to 100 mV.

However, other kinds of measurements are also possible which may be able to provide a time-varying potential to the biosensor. As used herein, the term "potential step" may also include these types of measurements. In particular, the time-varying waveform is a sine wave or a cosine wave or a linear or non-linear combination of sine and/or cosine waves, at least one linear or non-linear scan of at least one periodically varying signal (such as provided by voltammetry) may also be applicable as long as it may allow determining an in vivo admittance indicative of the biosensorY（t）The in vivo current response of (3) is sufficient. As a further alternative, the in vivo current response of the biosensor may be determined by applying an alternating current signal.

Further consider the capacitance of the working electrodeCCurrent after applying a potential stepI（t）The response may follow finger decay

(6)

Or

(7)

WhereinI _max Which is indicative of the maximum current of the current,I ₀ which represents a zero current flow, the current of which,R _M which represents the electrical resistance of the film,R _D representing electron transfer resistance, and

τ=R _M ∙C（8）

represents a time constantτWhich can be assigned to the current decay due to the potential step, thus indicating the in vivo admittance of the biosensorY（t）。

As a further result, the following relationship occurs:

R _M =∆E/I _max ， （9）

C=τ/R _M ， （10）

and is

C=Q/∆E， （11）

Wherein the item

Q=∫I（t）dt （12）

Representing the extra charge provided to the electrode surface by the potential step.

According to the invention, these types of measurements can be performed using two different operating points, which can preferably be selected by observing the in-vivo current response at two different time constants. According to equation (8), the time constant τ is determined by the capacitance C of the working electrode and the resistance R of the membrane_MDetermined by the following equation:

τ=R _M ∙C（8）。

thus, in a particularly preferred embodiment, the first operating point may be chosen to be lower than τ, while the second operating point may be chosen to be higher than τ, preferably higher than 2 τ,3 τ,4 τ or 5 τ. As a result, the first operating point reflects a first characteristic value relating to the electrical resistance of the membrane, thereby providing information about the geometric area of the working electrode supporting the membrane, the thickness of the membrane, and the permeability of the membrane to at least one ion, while the second operating point reflects a second characteristic value relating to the capacitance of the working electrode, thereby providing information about the actual surface area of the working electrode supporting the membrane and the amount of catalyst and/or mediator available in the membrane. Thus, preferably, the second operating point may be selected according to the architecture of the biosensor, depending on the membrane thickness and/or mediator loading. In addition, further considerations may be envisaged. Thus, such measurements may be adapted to take into account all the different film thicknesses that may occur during swelling and deswelling of the film as a whole.

With regard to determining an analyte value in a bodily fluid sample, the present method is simultaneously used for monitoring the fail-safe operation of a biosensor. As generally used, the term "fail-safe operation" refers to a mode of operation of a biosensor that includes detecting a failure in the biosensor that may be capable of affecting an analyte value, where the failure may be due to structural modification of the sensor during its operation over a period of time and/or due to loss of a substance (e.g., a catalyst, mediator, and/or enzyme activity) required for operation of the biosensor. Preferably, the fail-safe operation comprises a mode of operation of the biosensor selected from at least one of an indication of no valid value, a recommendation to recalibrate and a request to shut down the biosensor. For this purpose, the sensitivity can be determinedSCapacitance C of the working electrode and resistance R of the membrane_MWherein the capacitance C of the working electrode and the resistance R of the membrane according to equation (8)_MAre related to each other according to a time constant τ. In particular, it is thus possible to combine sensitivitiesSCapacitance C of the working electrode and resistance R of the membrane_MTo determine a structural modification of the biosensor. Exemplary embodiments particularly suitable for monitoring the fail-safe operation of a biosensor are given below.

In a particularly preferred embodiment, both the analyte value in the bodily fluid sample and information about the fail-safe operation of the biosensor may be presented to the patient or user in a predetermined format. The analyte values can be displayed in a well-defined form, preferably in mg/dl, and/or as a curve illustrating the time course of the analyte values. Instead of indicating or displaying the determination results obtained with respect to the fail-safe operation of the biosensor, the sensitivity drift compensation may be performed without explicit notification to the patient or user, while indicia relating to the proposed reaction may be provided. For example, in the case where the biosensor is in the fail-safe operation mode, a flag indicating "valid value" may be displayed, and in the case where the biosensor is out of the fail-safe operation mode, a flag selected from one of "no valid value", "recalibration required", or "off" may be displayed instead. However, other ways of illustrating the results obtained are also possible.

As further mentioned above, the biosensor as used herein may be a fully implantable biosensor or alternatively a partially implantable biosensor. In particular, the biosensor may be adapted for continuous monitoring of an analyte in a body fluid, preferably for continuous measurement of an analyte in subcutaneous tissue, in particular in interstitial fluid such as blood. However, other kinds of biosensors and applications of the biosensors are also feasible. As further mentioned above, the analyte may preferably comprise glucose, wherein the enzyme may be Glucose Oxidase (GOD). Alternatively, other types of enzymes, such as Glucose Dehydrogenase (GDH), may be used.

In another aspect of the invention, an electronic unit for detecting an in vivo property of a biosensor by performing the method as described above is disclosed. For this purpose, an electronic unit is interoperable with the biosensor, adapted to electrochemically determine at least one value of an analyte in the sample of bodily fluid, wherein the electronic unit is further adapted to measure a raw current and a current response indicative of the admittance of the biosensor.

As used herein, the term "electronic unit" may refer to any device, preferably an electronic device, that may be independent of the biosensor process. The electronic unit may also be particularly adapted to interact with the biosensor to apply a voltage to at least one of the electrodes and to simultaneously or subsequently detect at least one signal generated by one of the electrodes of the biosensor. For this purpose, the electronic unit may be configured to apply at least one electrical pulse and/or to perform at least one impedance measurement, as described above and/or below. To this end, the electronic unit may be adapted in particular to apply an electrical potential between the at least one working electrode and the at least one reference electrode of the biosensor and preferably to measure a resulting primary current between the working electrode and the at least one counter electrode of the biosensor.

The electronic unit may further be configured to perform at least one amperometric measurement by using electrodes of said biosensor, in particular to detect (preferably simultaneously or subsequently) at least one direct current signal and at least one current response. For this purpose, the electronic unit may particularly be configured to be able to apply both the dominant potential and the potential step to the electrodes of the biosensor and detect the response, as described elsewhere herein. In particular, the electronics unit may thus comprise a direct current measurement unit and comprise a potential step response measurement unit, wherein the direct current measurement unit may be configured for measuring a raw current and the potential step response measurement unit may be configured for measuring an in vivo current response indicative of an in vivo admittance of the biosensor. To this end, the potential step response measuring unit comprises at least a charge counter and a peak detector. However, other embodiments are possible.

The electronic unit may further be adapted to derive at least one of the information on the analyte value depending on the analyte in the detected bodily fluid sample. To this end, the electronic unit may comprise at least one electronic evaluation device interacting with the electrodes, in particular in order to derive at least one analyte value from the at least one signal. The electronic unit may thus comprise at least one evaluation device comprising at least one data processing means, such as one or more of a microcontroller, an Application Specific Integrated Circuit (ASIC), a Field Programmable Gate Array (FPGA). However, other types of devices may also be possible.

In another aspect of the invention, a system for operating a biosensor to electrochemically detect at least one analyte value in a bodily fluid sample is disclosed. The system thus comprises at least one biosensor as described above and/or below, which is adapted to detect at least one analyte value in a bodily fluid sample electrochemically, wherein the biosensor can be operated by performing the method as described above and/or below using an electronics unit as described above and/or below, which electronics unit is thus adapted to measure the raw current and to determine the sensitivity and the admittance of the biosensor. For this purpose, the electronics unit is configured for compensating for in vivo sensitivity drift in the biosensor by performing the methods described elsewhere herein.

The method, electronic unit and system according to the invention have a number of advantages over the prior art. The proposed method may in particular allow a reduction of the number of calibrations compared to the prior art, and may also be dependent on the initial calibration of the biosensor, or particularly preferably on the factory calibration of the biosensor, for example by determining the sensitivity versus admittance only once by the manufacturer.

In summary, the following examples are potential embodiments of the present invention. However, other embodiments are possible.

Drawings

Further details of the invention can be taken from the following disclosure of preferred embodiments. The features of the embodiments may be implemented in isolation or in any combination. The invention is not limited to the embodiments. These embodiments are schematically depicted in the drawings. In the drawings, the same reference numerals refer to the same elements or elements having the same function or elements corresponding to each other in terms of their functions.

In the drawings:

FIG. 1 schematically illustrates a circuit suitable for determining the sensitivity of a biosensor;

FIG. 2 illustrates exemplary mechanisms for measuring the sensitivity of a biosensor (FIG. 2A) and the dielectric properties of a biosensor (FIG. 2B), respectively;

FIG. 3 illustrates the application of a potential step to the biosensor (FIG. 3A) and the corresponding process of the current response (FIG. 3B) and associated charge (FIG. 3C) of the biosensor;

fig. 4 illustrates a depiction of the corresponding process of impedance of a biosensor in the form of a bode plot visualizing the frequency behavior of the biosensor;

FIG. 5 illustrates the time course of the sensitivity (FIG. 5A), admittance (FIG. 5B), sensitivity-to-admittance ratio (FIG. 5C), relative deviation of sensitivity-to-admittance ratio from the median value (FIG. 5D) and capacitance (FIG. 5E) of a biosensor;

FIG. 6 illustrates the time course of current (FIG. 6A), admittance (FIG. 6B) and current-to-admittance ratio (FIG. 6C) in a biosensor;

FIG. 7 illustrates a schematic circuit diagram of a system including a biosensor and an electronic device;

FIG. 8 illustrates a preferred example of a circuit particularly suited for charge determination; and

fig. 9 illustrates three preferred examples of circuits particularly suitable for peak determination.

Example 1: a method of determining at least one analyte value in a bodily fluid sample, wherein a biosensor is interoperable with an electronics unit adapted to electrochemically determine at least one value of an analyte in a bodily fluid sample, wherein the biosensor comprises at least one working electrode, wherein the working electrode is covered by a membrane and comprises an enzyme for providing a reaction with the analyte, wherein the membrane has an electrical resistance and the working electrode has a capacitance, wherein the electronics unit is adapted to measure a primary current and a current response indicative of an admittance of the biosensor, the method comprising the steps of:

a) providing a sensitivity to admittance relationship for the biosensor;

b) measuring a raw current in the biosensor;

c) measuring an in vivo current response indicative of an in vivo admittance of the biosensor, wherein the in vivo current response is measured at least one first operating point and at least one second operating point, wherein the first operating point is selected for providing a first characteristic value related to a resistance of the membrane, and wherein the second operating point is selected for providing a second characteristic value related to a capacitance of the working electrode; and

d) compensating for in vivo sensitivity drift in the biosensor by determining an analyte value in the body fluid sample using the raw current and correcting the measured value of the raw current by determining an actual value of the sensitivity using the first characteristic value, thereby taking into account the sensitivity versus admittance provided during step a); and

e) a fail-safe operation of the biosensor is monitored based on the first and/or second characteristic values.