METHOD FOR DETERMINING AT LEAST ONE MEMBRANE PROPERTY OF AN ANALYTE SENSOR

Abstract

A method for determining a membrane property of an analyte sensor that has at least two measurement electrodes and at least one of the measurement electrodes has a membrane having the membrane property. The method includes generating a fast-transient voltage signal and applying the fast-transient voltage signal to the measurement electrodes. A response signal is measured, and the membrane property is determined by evaluating the response signal.

Claims

1. A method for determining a membrane property of an analyte sensor that has at least two measurement electrodes and at least one of the measurement electrodes has a membrane having the membrane property, the method comprising: a) generating a fast-transient voltage signal and applying the fast-transient voltage signal to the measurement electrodes; b) measuring a response signal; and c) determining the membrane property by evaluating the response signal.

2. The method according to claim 1, wherein the evaluating of the response signal comprises determining equivalent series resistance of the analyte sensor and determining the membrane property from the equivalent series resistance.

3. The method according to claim 1, wherein the analyte sensor is an in vivo sensor.

4. The method according to claim 1, wherein the method is performed during in vivo measurement.

5. The method according to claim 1, wherein the method is performed during manufacturing of the analyte sensor.

6. The method according to claim 1, wherein the method comprises at least one failsafe step that is triggered depending on the determined membrane property.

7. The method according to claim 1, wherein the membrane property is permeability of the membrane.

8. The method according to claim 1, wherein the fast-transient voltage signal has a square wave form or a sine wave signal form.

9. The method according to claim 1, wherein the fast-transient voltage signal comprises a non-continuous signal with a pulse duration selected from the group consisting of ≤20 μs and ≤10 μs.

10. A method for determining concentration of an analyte in body fluid, comprising: performing the method according to claim 1; and completing an analyte measurement step during which a value of the concentration of the analyte is determined.

11. A non-transitory computer readable medium having stored thereon computer executable instructions for performing the method according to claim 1.

12. An analytical system for determining concentration of an analyte in body fluid, comprising: an analyte sensor having at least two measurement electrodes and at least one of the measurement electrodes having a membrane having a membrane property; a signal generator configured for generating a fast-transient voltage signal and applying the fast-transient voltage signal to the two measurement electrodes; a measurement unit configured for receiving a response signal; and an evaluation device configured for determining the membrane property by evaluating of the response signal.

13. The analytical system according to claim 12, wherein the analyte sensor is a two electrode sensor or a three electrode sensor.

14. The analytical system according to claim 12, wherein the measurement electrodes are arranged on opposing sides of the analyte sensor.

15. The analytical system according to claim 12, wherein the analytical system is configured for performing the method according to 1.

16. The analytical system according to claim 12, wherein the analytical system is configured for performing the method according to 10.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0130] The above-mentioned aspects of exemplary embodiments will become more apparent and will be better understood by reference to the following description of the embodiments taken in conjunction with the accompanying drawings, wherein:

[0131] FIG. 1 shows a schematic representing at least one analytical system according to this disclosure;

[0132] FIG. 2 shows an equivalent circuit for measuring equivalent series resistance of at least one analyte sensor using a method according to this disclosure;

[0133] FIGS. 3A to 3C show dependency on temperature of equivalent series resistance of the analyte sensor and time development of response signal and of current for determining of concentration of at least one analyte;

[0134] FIGS. 4A and 4B show a simplified circuit and a fast-transient voltage profile; and

[0135] FIG. 5 shows a simplified circuit.

DESCRIPTION

[0136] The embodiments described below are not intended to be exhaustive or to limit the invention to the precise forms disclosed in the following detailed description. Rather, the embodiments are chosen and described so that others skilled in the art may appreciate and understand the principles and practices of this disclosure.

[0137] FIG. 1 shows a schematic representing at least one analytical system 110 for determining a concentration of at least one analyte in body fluid according to this disclosure. The analytical system 110 comprises at least one analyte sensor 112 shown here as equivalent circuit.

[0138] The analyte may be or may comprise an arbitrary chemical substance or chemical compound which may take part in the metabolism of the user, such as at least one metabolite. As an example, the at least one analyte may be selected from the group consisting of glucose, cholesterol, triglycerides, lactate. Additionally or alternatively, however, other types of analytes may be determined and/or any combination of analytes may be determined.

[0139] In an embodiment, the analyte sensor 112 may be an optical sensor.

[0140] The analyte sensor 112 may be an in vivo sensor. The analyte sensor 112 may be configured for being at least partially implanted into a body tissue of a user. The analyte sensor 112 may be a subcutaneous analyte sensor. The analyte sensor 112 may be configured for implantation into a body tissue of the user. More specifically the analyte sensor 112 may be configured for continuous monitoring of the analyte.

[0141] The analyte sensor 112 comprises at least two measurement electrodes 114. The at least two measurement electrodes 114 may be designed such that an electrochemical reaction may take place at one or more of the electrodes. Thus, the measurement electrodes 114 may be embodied such that an oxidation reaction and/or reduction reaction may take place at one or more of the electrodes.

[0142] One of the measurement electrodes 114 may be designed as working electrode 116. In FIG. 1 for the working electrode 116 a capacitance representing the electric double layer and a resistance representing the charge transfer resistance is shown. The working electrode 116 may comprise at least one test chemical. The working electrode 116 may fully or partially be covered with at least one test chemical, specifically at least one test chemical comprising at least one enzyme for detecting the at least one analyte. As an example, glucose oxidase (GOx) or glucose dehydrogenase (GDH) may be used. The test chemical, further, may comprise additional materials, such as binder materials, electrode particles, mediators or the like. Thus, as an example, the test chemical may comprise at least one enzyme, carbon particles, a polymer binder and MnO.sub.2-particles. In another preferred embodiment, the test chemical may comprise a mediator polymer comprising a polymeric material and a metal containing complex, for example a modified poly(vinylpyridine) backbone loaded with poly(bi-imidizyl) Os complexes covalently coupled through a bidentate linkage. Further, the at least one test chemical may be comprised in a single layer, or the test chemical may comprise a plurality of layers, such as one layer having the at least one enzyme and one or more additional layers having one or more additional functions, such as one or more diffusion barriers and/or one or more biocompatibility layers.

[0143] The other one of the measurement electrodes 114 may be designed as counter electrode 118. The counter electrode may be a part of the implanted or partially implanted analyte sensor, or may be an individual electrode, which is either implanted or partially implanted or placed somewhere else on the body, e.g., on the skin surface. In FIG. 1 for the counter electrode 118 a capacitance representing the electric double layer and a resistance representing the charge transfer resistance is shown. The counter electrode 118 may be configured for performing at least one electrochemical counter reaction and/or configured for balancing a current flow required by the detection reaction at the working electrode 116. In case of the analyte sensor 112 comprises a two electrode system as measurement electrodes 114, the counter electrode 118 may complete the circuit such that charge can flow through an electrochemical cell, also denoted electrochemical system, given by the working electrode 116, the counter electrode 118 and an electrolyte, such as the body fluid, and may maintain a constant counter electrode potential, also referred to as a constant reference potential, regardless of current.

[0144] Additionally, the analyte sensor 112 may comprise at least one reference electrode 120. The reference electrode 120 may be configured for being a reference for measuring and/or controlling a potential of the working electrode 116. The reference electrode 120 may have a stable and well-known electrode potential. The electrode potential of the reference electrode 120 may preferably be highly stable. One of the electrodes may have several functionalities, as for instance, combined reference and counter electrode, which has both, the function of the reference electrode 120 and counter electrode 118, which means it provides a reference potential and balances the current flow from the working electrode 116.

[0145] At least one of the measurement electrodes 114 comprises at least one membrane element 122 having at least one membrane property. In FIG. 1, the resistance of the electrolyte between the working electrode 116 and the reference electrode 120 may be given by an electric resistance R.sub.2 and the resistance of the electrolyte between the counter electrode 118 and the reference electrode 120 may be given by an electric resistance R.sub.1. The resistance R.sub.2 may further be dependent on properties of the membrane element 122 denoted with an arrow and reference number of the membrane element at the electric resistance R.sub.2. Specifically, the membrane element 122 may be applied to the working electrode 116. The membrane element 122 may be configured for controlling and/or limiting diffusion of the analyte to the working electrode 116. Thus, the membrane element 122 may be configured as diffusion limiting membrane. However, the membrane element 122 may have even more functionalities, such as providing biocompatibility. The membrane element 122 may have further functions such as blocking of leakage of components below the membrane element 122 such as of the enzyme or other components comprised in any one of the at least two measurement electrodes. The membrane element 122 may also be configured as a blocking membrane. The blocking may refer to preventing leakage of inner components of a sensitive layer of the working electrode 116 but not to the analyte. The membrane element 122 may be configured for maintaining of sensor integrity, by for instance keeping the enzyme or redox mediator from leaching, thus gradation of the whole sensor. Independently on the role of the membrane element 122, its altering may be compensated.

[0146] The membrane element 122 may comprise at least one polymer. The membrane element 122 may be applied to the working electrode 116 as thin polymer film. For example, the membrane element may be or may comprise Poly-(4-(N-(3-sulfonatopropyl) pyridinium)-co-(4vinyl-pyridine)-co-styrene (5%/90%/5%) or hydrophilic Polyurethane (HP60D20) available from Lubrizol®. For example, the membrane element may comprise at least one of the following polymer classes and/or their copolymer: Poly(4 vinyl pyridine), Polymethacrylate, Polyacrylate, Polyvinyl pyrrolidone, Polyvinyl alcohol (PVA), Polyethylene glycol.

[0147] The analytical system 110 may be configured for determining the at least one membrane property. Permeability of the membrane element 122 for certain compounds may be proportional to the membrane's swelling degree. The swelling degree may correspond to the degree of water uptake. The swelling degree of the membrane 122 may depend on its hydrophilicity. The membrane's swelling degree may directly affect the amount and/or mobility and, thus, the permeability of the membrane for certain compounds. The conductivity of an electrolyte like water or bodily fluid, such as interstitial fluid is directly linked to so-called total dissolved solids whereby ions, such as H+, OH—, Na+, K+, Cl— and other have the most contribution. Therefore, also the conductivity of the membrane 122 which has taken up water or bodily fluid such as interstitial fluid also is directly linked to the total dissolved solids. The more charge carriers are present and the more mobile they are, the lower is the measured electrical resistance, by otherwise constant conditions, such as, e.g., cell geometry. Thus, the electrical resistance, or reversely, electric conductivity of the membrane element 122 may depend on quantity and mobility of ions present in the membrane. The analytical system 110 may be configured for using at least one algorithm configured for determining permeability of the membrane element 122 for a specific analyte, in particular glucose, by evaluating electrical resistance of the membrane element 122. The permeability of the membrane element 122 for a specific analyte p.sub.Analyt may be determined by p.sub.Analyt=f*p, wherein p is the permeability determined via the electrical resistance of the membrane element 122 and f is a conversion factor. The conversion factor may be determined in calibration experiments using known glucose values.

[0148] The membrane property, in particular the permeability, may depend on different parameters such as temperature, composition of interstitial fluid, thickness of the membrane element, aging, swelling degree, mechanical stresses and the like. The analytical system 110 may be configured for performing at least one calibration step, wherein effects of the different parameters on the permeability of the membrane element 122 may be determined. For each of the parameters influencing permeability of the membrane element 122 at least one correction factor may be determined by calibration experiments. The analytical system may be configured for determining correction factors for interdependent parameters. The analytical system 110 may be configured for determining permeability of the membrane element 122 considering the at least one correction factor. The analytical system 110 may be configured for in-operando monitoring of permeability, in particular continuously or in short time intervals. Also temperature monitoring is possible. The analytical system 110 may be configured for performing at least one failsafe step in order to enhance reliability of the determining of the analyte concentration.

[0149] The analytical system 110 comprises at least one signal generator device (or “signal generator”) 124 configured for generating at least one fast-transient voltage signal. The signal generator device 124 is configured for applying the fast-transient voltage signal to the two measurement electrodes 114.

[0150] The fast-transient voltage signal may be at least one arbitrary voltage signal applicable to the at least two measurement electrodes 114 having fast-transient signal flanks, in particular two very steep edges. The fast-transient voltage signal may comprise a square wave form and/or a sine wave form. The fast-transient voltage signal may comprise a non-continuous signal such as a pulse. Specifically, the fast-transient voltage signal may comprise a fast transition square wave. The pulse may have a transient change in the amplitude of the signal from a first value, also denoted baseline value, to a second value, followed by a return to the baseline value or at least approximately to the baseline value. The second value may be a higher or lower value than the baseline value. A pulse duration may be ≤50 μs, preferably ≤20 μs, more preferably ≤10 μs. The duration of the single pulse must be sufficiently long to be able to record its propagation. The duration of the single pulse must be preferentially short, in order to not excite the system electrochemically. The fast-transient voltage signal may be applied during at least one test sequence, for example a time sequence. The fast-transient voltage signal may be applied repeatedly, in particular periodically. The time distance between the cycles must be sufficiently long in order to keep the system at its steady-state. The fast-transient voltage signal may comprise a repeatable cycle, wherein the repeatable cycle comprises at least one signal flank. The signal flank may be a transition of a signal amplitude from low to high signal value or from high to low signal value. The signal flank may be a rising signal flank or a falling signal flank. The signal flank of the fast-transient voltage signal may have a change in signal from the first value of the signal flank to the second value of the signal flank in a microsecond to nanosecond range. The signal flank of the fast-transient voltage signal may have a change in signal from the second value of the signal flank to the first value of the signal flank in a microsecond to nanosecond range. The terms first and second “value” may refer to regions or points of the fast-transient voltage signal, in particular signal amplitude. The first value may be the baseline value. The first value may be a local and/or overall minimum of the fast-transient voltage signal. The first value may be a first plateau of the fast-transient voltage signal. The first value may refer to a time point with no voltage is applied to the measurement electrodes. The first value may be a through or low value of the fast-transient voltage signal. The second value may be a local and/or overall maximum of the fast-transient voltage signal. The second point may be a second plateau of the fast-transient voltage signal, which may be reached during application of the fast-transient voltage signal. The second point may be a peak or high value of the fast-transient voltage signal. The fast-transient voltage signal may have a rising signal flank and a falling signal flank. The fast-transient voltage signal may have steep edges. Specifically, the fast transition square wave may have a change in signal from the first value of the signal flank to the second value of the signal flank below or equal 50 ns, preferably below or equal 20 ns. The change in signal from the first value of the signal flank to the second value of the signal flank may be even faster and may be only limited by electronics such as by an analog-to-digital-converter. The faster the flank and the sharper the transition to the plateau, the more resolution may be between the ohmic part of the system resistance and the capacitive part of the system capacitance. Without wishing to being bound by theory, the fast-transient voltage signal is so short, in particular ultrashort, that no faradaic currents are generated and that an electrochemical system of the analyte sensor 112 is not disturbed and brought out of equilibrium. The ultrashort voltage signal of the fast-transient voltage signal for determining the membrane property may allow that a measurement signal for determining the analyte concentration can be undisturbed determined. The ultrashort voltage signal may prevent that side reaction occur.

[0151] The signal generator device 124 may comprise at least one function generator selected from the group consisting of: at least one square wave generator and at least one sine wave generator. The signal generator device 124 may be part of measurement electronics of the analyte sensor 112 and/or may be connected to the analyte sensor 112 and may be designed as a separate device.

[0152] The analytical system 110 comprises and/or may be directly connectable to at least one measurement unit 126, in particular at least one microcontroller unit (MCU) or an analog front end (AFE), configured for receiving at least one response signal. The analyte sensor 110 may comprise and/or may be directly connectable to the MCU or AFE. For example, the analyte sensor 110 may comprise sensor contacts 128 via which the analyte sensor 112, in particular the measurement electrodes 114 can be connected to the MCU. The signal generator device 124 may be part of the MCU or may be a separate device. The signal generator device 124 may be configured for applying the fast-transient voltage signal to the measurement electrodes 114. The MCU may comprise at least one digital output, in particular a first digital to analog converter DAC output, denoted “Pulse” in FIG. 1, via which the fast-transient voltage signal can be generated and/or applied to the measurement electrodes 114. The fast-transient voltage signal may be applied to at least two measurement electrodes 114 in at least one signal application step. The fast-transient voltage signal may be applied to the working electrode 116.

[0153] The response signal may be a measured propagation of the applied fast-transient voltage signal. The response signal may refer to equivalent series resistance of the analyte sensor 112. The MCU or AFE may be configured for determining the voltage at the working electrode 116 during application of the fast-transient voltage signal.

[0154] The analyte sensor 112 may comprise and/or may be connected to at least one potentiostat 130 and/or may be part of at least one potentiostat 130, in particular at least one analog or digital potentiostat, configured for determining the concentration of the analyte. Operating principles of potentiostats for continuous monitoring of analytes are generally known to the person skilled in the art. The potentiostat 130 may be configured for generating and/or applying of at least one measurement voltage signal, in particular a polarizing potential or voltage. For example, the potentiostat may be based on a MCU which may comprise at least one second Digital to Analog converter (DAC), denoted DAC in FIG. 1, or at least one PWM output, optionally with a low pass filter for generating and/or applying of at least one measurement voltage signal.

[0155] The measurement voltage signal may be a voltage signal used for determining the concentration of the analyte. The measurement voltage signal may be different to the fast-transient voltage signal. In particular, the measurement voltage signal may be longer compared to the fast-transient voltage signal. The measurement voltage signal may be a permanent signal, not a pulsed one. The measurement voltage signal may be adjusted from time to time or continuously in order to give the analyte sensor its polarization voltage, preferably, in order to keep the predefined polarization voltage at the analyte sensor. The measurement voltage signal may a continuous direct current (DC) signal which polarizes the electrochemical cell, and serves as the “motor” for the amperometric measurement of the analyte reducing or oxidizing GO.x across the electrochemical cell. The fast-transient voltage signal may be a voltage pulse with high frequency that only characterizes the capacitive and ohmic parts of the electrochemical cell. Therefore, the measurement voltage signal and the fast-transient voltage signal may not influence each other, since they have completely different time domains.

[0156] The potentiostat 130 may comprise at least two Analog to Digital channels (ADC) for determining voltage output at the two measurement electrodes. In case of using a reference electrode, the potentiostat 130 may comprise four Analog to Digital channels. The MCU may be configured for regulating the output of its “DAC” in order to get a wanted polarization voltage, for example 50 mV, between the reference electrode 120 and the working electrode 116. The measurement voltage signal may be the output signal of the “DAC.” The current flowing through the analyte sensor 112 may be measured on the counter electrode 118 by using an ohmic resistance and at least one first operational amplifier, denoted Amp1 in FIG. 1, connected with the counter electrode 118. The output of said first operational amplifier may be connected to a first ADC channel, denoted ADC1 in FIG. 1. The reference electrode 120 may be a high-impedance electrode and may control the potential of the potentiostat 130. A second operational amplifier, denoted Amp2 in FIG. 1, may be connected to the reference electrode 120 in order to guarantee that no current is flowing out of the reference electrode 120. The potential between the reference electrode 120 and the working electrode 116 may be controlled via a second ADC channel, denoted ADC2 in FIG. 1, and a fourth ADC channel, denoted ADC4 in FIG. 1, wherein, for example, the second ADC channel may be connected to the output of the second operational amplifier and the fourth ADC channel may be connected to the working electrode 116.

[0157] For measuring the response signal to the fast-transient voltage signal the analyte sensor 112 and/or the MUC may comprise further components. For example, the microcontroller unit may comprise two additional capacitors, two additional resistors, one additional ADC channel and the first digital output, as outlined above. One of the additional capacitors, denoted C1 in FIG. 1, may be connected to a non-inverting input of the first operational amplifier connected to the counter electrode 118. The other additional capacitor, denoted C2 in FIG. 1, may be arranged in series with the first digital output of the MUC. The third ADC channel, denoted ADC3 in FIG. 1, may be connected to the working electrode 116 such that the two ADC channels, i.e., the third and the fourth ADC channel, are connected to the working electrode 116. The fourth ADC channel may be connected directly to the working electrode 116. The fast-transient voltage signal may be applied to the working electrode 116 in series with a reference resistance, denoted R.sub.3. R.sub.3 may be a known reference resistance such as a predetermined reference resistance. The reference resistance may be an average value determined, specifically pre-determined, from a plurality of reference measurements. The reference resistance must reflect the measurement range of the cell. This reference resistance may reflect required measurement tolerances which must be maintained for correct system resistances. The reference resistance may be selected suitable for determining a value to be measured such as the electrical resistance of the membrane element. The fast-transient voltage signal may be determined such as by using the third ADC channel which may be placed in series and between the first digital output and the reference resistor R.sub.3. Specifically, before the application of the fast-transient voltage signal an output of the third ADC channel may correspond to the measurement voltage signal. After the application of the fast-transient voltage signal an output of the third ADC channel may correspond to the sum of the measurement voltage signal and the fast-transient voltage signal. The potentiostat 130 may be configured for determining the propagation of the fast-transient voltage signal applied to the working electrode 116. The potentiostat 130 may be configured for determining a change or difference ΔV.sub.ex of the measurement voltage signal at the working electrode 116 before application of the fast-transient voltage signal and during the application of the fast-transient voltage signal. The potentiostat 130 may be configured for determining a change or difference ΔV.sub.prop of voltage at the reference resistor R.sub.3 before application of the fast-transient voltage signal and during the application of the fast-transient voltage signal.

[0158] The analyte sensor may comprise at least one isolating resistor, denoted R.sub.4 configured for isolating the low impedance DAC output, in particular the measurement voltage signal or cell polarization voltage, from the fast transient voltage signal. Without R.sub.4 the pulse would be absorbed by the DAC and not the electrochemical cell. The two additional resistors may be arranged in series. A first additional resistor, denoted R.sub.4, may be connected with the second DAC and with R.sub.3, also denoted second additional resistor. The second additional resistor may be connected to the working electrode 116. The third ADC channel may be arranged between the first additional resistor and the second additional resistor.

[0159] The analytical system 110 comprises at least one evaluation device 132. The evaluation device 132 is configured for determining the at least one membrane property by evaluating of the response signal. The evaluating of the response signal may comprise determining equivalent series resistance of the electrochemical system of the analyte sensor 112 and determining the at least one membrane property from the equivalent series resistance of the electrochemical system of the analyte sensor 112.

[0160] In order to measure the membrane property, in particular equivalent series resistance of the electrochemical system, the fast-transient voltage signal may be sent to the working electrode 116. The edges of the fast-transient voltage signal are very steep such that the additional capacitors and equivalent capacitors of the electrochemical system of the analyte sensor act like short-circuits. The equivalent circuit in this condition is shown in FIG. 2. The equivalent series resistance of the electrochemical system of the analyte sensor 112 may be determined by

[00003]$R_1+R_2=R_3\frac{\Delta V_{\mathrm{prop}}}{\Delta V_{ex}-\Delta V_{\mathrm{prop}}}=R_3\frac{V_{\mathrm{prop},\mathrm{dur}\mathrm{ing}\mathrm{Pulse}}-V_{\mathrm{prop},\mathrm{before}\mathrm{Pulse}}}{\left(V_{\mathrm{ex},\mathrm{during}\mathrm{Pulse}}-V_{\mathrm{ex},\mathrm{before}\mathrm{Pulse}}\right)-\left(V_{\mathrm{prop},\mathrm{during}\mathrm{Pulse}}-V_{\mathrm{prop},\mathrm{before}\mathrm{Pulse}}\right),}$

wherein V.sub.prop,beforePulse refers to the voltage at the working electrode before applying the fast-transient voltage signal, V.sub.ex,beforePulse measurement voltage signal at the reference resistor before applying the fast-transient voltage signal, V.sub.prop,duringPulse refers to the voltage at the working electrode during applying the fast-transient voltage signal, V.sub.ex,duringPulse refers to the measurement voltage signal at the reference resistor during applying the fast-transient voltage signal. Before the application of the fast-transient voltage signal V.sub.ex,beforePulse may correspond to a voltage at the reference resistor in response to the measurement voltage signal. After the application of the fast-transient voltage signal V.sub.ex,duringPulse may correspond to the voltage at the reference resistor in response to the measurement voltage signal and due to the propagation of the fast-transient voltage signal. The method further may comprise at least one subtracting step, wherein from the determined equivalent series resistance a predetermined or known value of the electrolyte resistance R.sub.1+R.sub.2 of the electrolyte is subtracted.

[0161] The analyte sensor 112 may an in vivo sensor, specifically at least one in vivo continuous glucose sensor. The determining of the membrane property may be performed an in-process control. The determining of the membrane property may be performed during in vivo measurement. The determining of the membrane property may be performed in-operando. Specifically, the determining of the membrane property may be performed during determining of the concentration of the analyte. Additionally or alternatively, determining of the membrane property may be performed during manufacturing of the analyte. For example, the manufacturing process may comprise at least one calibration, wherein the analyte sensor 112 may be operated with a sample of known analyte concentration.

[0162] The technical realization of the measurement setup may be simple and requires only a minimum amount of additional components in addition to a known potentiostat. The determined response signal may not require further processing and may can be directly digitalized. The measured response signal may provide absolute values and not relative changes. The determined electrical resistance may be very selective to the membrane property. In particular, the measured electrical resistance may not comprise resistance relating to charge transfer processes of the electrochemical system. Thus, it may be possible to exclude the influences, e.g., of the test chemistry, to the response signal.

[0163] FIGS. 3A to 3C show experimental data. FIG. 3A shows a dependency on temperature of equivalent series resistance of the analyte sensor 112. Specifically, current curve 134 shows the median current I.sub.median in nA as a function of time t in hours, equivalent series resistance curve 136 shows the equivalent series resistance of the analyte sensor 112 in kOhm and temperature curve 138 shows the temperature over time in ° C. A change in equivalent series resistance depending on the temperature is observed.

[0164] FIG. 3B, upper part, shows the sensor current I.sub.sensor measured during a night. The observed rapid signal changes are caused by mechanical stress due to the fact that the patient lies on the sensor patch from time to time. Because of the pressure, the tissue and the by it surrounded sensor are compressed and this alters reversibly the membrane permeability. This effect can be clearly observed by monitoring the membrane resistance R.sub.mem, depicted in the lower part of FIG. 3B, measured using the method according to this disclosure. The abrupt growth of the membrane resistance is observed once the patient lies on the sensor patch and it drops abruptly, once the weight load is removed. Thanks to the fact, that the membrane impedance change preempts the change in the current, it is possible to, e.g., avoid false hypo alarms. FIG. 3C shows a magnified fragment of the both curves, clearly showing, that the resistance change is preempting the current changes for few minutes. The shape of the resistance vs. time curve during the mechanical stress is very specific, which allows easy detection of the event.

[0165] FIGS. 4A and 4B show a further example of an operating principle according to this disclosure. FIG. 4A shows a simplified circuit and FIG. 4B shows a fast-transient voltage profile. Specifically, the method may comprise the following steps: [0166] generating the at least one fast-transient voltage U.sub.gen,pulse and applying it to a membrane comprising circuit serially connected with a reference resistor R.sub.ref, wherein the membrane element has a resistance R.sub.mem; [0167] recording a voltage U.sub.meas,pulse either at the reference resistor R.sub.ref or at the membrane element comprising circuit R.sub.mem; [0168] determining the at least one membrane property by calculating the R.sub.mem from U.sub.gen,pulse, U.sub.meas,pulse and R.sub.ref.

[0169] The simplified circuit comprises a sensor, represented as a simple Randle's circuit, a reference resistor R.sub.ref, a measurement resistor R.sub.meas, a shunt capacitor C.sub.shunt, a signal generator device 124, in this embodiment a voltage source, and a voltmeter V. The Randle's circuit comprises the charge transfer resistance R.sub.ct, which represents the diffusion limited analyte current, double layer capacitance C.sub.dl at the electrode surface and the membrane element resistance R.sub.mem. The signal generator device 124 may be configured for applying a DC base voltage U.sub.gen,base and fast-transient voltage U.sub.gen,pulse. During the U.sub.gen,base is applied, the current flows through all four resistors in the circuit. There is no current flow through the capacitors, as they are charged to the corresponding level. The R.sub.ct may few orders of magnitude larger, than R.sub.mem, thus the voltage drop at the R.sub.mem can be neglected in the first approximation. The same is valid for the R.sub.ref, which is chosen to be roughly the same value as the R.sub.mem. The value for R.sub.meas may be chosen at the way, to get substantial voltage drop at it, which is then measured, e.g., by an additional voltmeter or electrometer is not shown in the scheme, and converted in the sensor current signal, thus the value of the R.sub.meas is roughly of the same order of magnitude as the R.sub.ct. Since the voltage drop at the R.sub.meas is substantial, it is compensated by the voltage source, which is in the feedback with the current measuring unit based on the R.sub.meas.

[0170] In order to measure the R.sub.mem, the signal generator device 124 may generates U.sub.gen,pulse, here exemplarily higher than the DC base voltage. If the U.sub.gen,pulse is applied, the C.sub.di and the C.sub.shunt start to charge causing an art of shortcut at the R.sub.ct and the R.sub.meas respectively. Thus, the whole U.sub.gen,pulse is distributed over the R.sub.ref and the R.sub.mem. Since the R.sub.ref and the R.sub.mem comprise, in the first approximation, a simple voltage divider, the R.sub.mem can be easily calculated, once U.sub.meas,pulse is measured either at the R.sub.ref or at the R.sub.mem by means of the voltmeter. Here, exemplarily, at the R.sub.mem by means of voltmeter V.

[0171] In course of the C.sub.dl and C.sub.shunt charging, U.sub.gen,puls starts to additionally drop at, correspondingly, R.sub.ct and R.sub.meas, which is not desired. Furthermore, the additional voltage at the R.sub.ct means additional undesired current flow through the sensor caused, for instance, by unspecific oxidation of further substances, which must be avoided. Thus, the duration of U.sub.gen,pulse may be kept sufficiently short, in order to exclude the excessive C.sub.dl and C.sub.shunt charging and thus excessive voltage rise at R.sub.ct and R.sub.meas. Correspondingly, the data acquisition rate of the voltmeter V may be sufficiently high, in order to record the U.sub.meas,pulse possibly immediately after applying U.sub.gen,pulse.

[0172] The calculation of the R.sub.mem may be done as

[00004]$R_{mem}=R_{\mathrm{ref}}\frac{U_{\mathrm{meas},\mathrm{pulse}}}{U_{\mathrm{gen},\mathrm{pulse}}-U_{\mathrm{meas},\mathrm{pulse}}}.$

[0173] FIG. 5 shows a simplified circuit of the analytical system 110, in particular similar to FIG. 4A. The simplified circuit comprises a sensor, represented as a simple Randle's circuit, a reference resistor R.sub.ref, a measurement resistor R.sub.meas, a shunt capacitor C.sub.shunt, the signal generator device 124. The Randle's circuit comprises the charge transfer resistance R.sub.ct, which represents the diffusion limited analyte current, double layer capacitance C.sub.di at the electrode surface and the membrane element resistance R.sub.mem.

[0174] The signal generator 124, in this embodiment a voltage source G, is configured for generating the at least one fast-transient voltage signal and applying it to a membrane comprising circuit 112 serially connected with a reference resistor R.sub.ref, wherein the membrane element has a resistance R.sub.mem. In particular, the signal generator device 124 may be configured for applying a measurement voltage signal, in particular a DC base voltage V.sub.gen,base, and fast-transient voltage V.sub.gen,pulse. During the V.sub.gen,base is applied, the current flows through all four resistors in the circuit. There is no current flow through the capacitors, as they are charged to the corresponding level. The R.sub.ct may be few orders of magnitude larger than R.sub.mem, such that the voltage drop at the R.sub.mem can be neglected in the first approximation. The same is valid for the R.sub.ref, which is chosen to be roughly the same value as the R.sub.mem. The value for R.sub.meas may be chosen at the way, to get substantial voltage drop at it, which is then measured, e.g., by an additional voltmeter or electrometer which is not shown in the scheme, and converted in the sensor current signal, thus the value of the R.sub.meas is roughly of the same order of magnitude as the R.sub.ct. Since the voltage drop at the R.sub.meas is substantial, it is compensated by the voltage source, which is in the feedback with the current measuring unit based on the R.sub.meas.

[0175] The voltmeter V may be configured for determining the voltage V.sub.gen,base at the reference resistor before applying the fast-transient voltage signal to the membrane comprising circuit 112. The quantity V.sub.gen,base may be identical to V.sub.ex,beforePulse which was used above. In the ideal case, before the application of the fast-transient voltage signal, the voltage V.sub.gen,base may correspond to a voltage at the reference resistor in response to the measurement voltage signal. At this time point the voltmeter V may further measure at the working electrode 116 the measurement voltage signal V.sub.meas,base. This quantity may be identical to the quantity V.sub.prop,beforePulse which was used above.

[0176] The response signal, i.e., propagated fast-transient voltage signal may be recorded either at the reference resistor R.sub.ref or at the membrane element comprising circuit R.sub.mem using the voltmeter V. During application of the fast-transient voltage signal the voltmeter V may measure at the reference resistor the voltage V.sub.gen,pulse. This quantity may be identical to the quantity V.sub.ex,duringPulse which was used above. At this time point the voltmeter V may be configured for measuring the measurement voltage signal V.sub.meas,pulse. This quantity may be identical to the quantity V.sub.prop,duringPulse which was used above. After the application of the fast-transient voltage signal, the voltage V.sub.gen,pulse may correspond to the voltage at the reference resistor in response to the measurement voltage signal and due to propagation of the fast-transient voltage signal.

[0177] In order to measure the R.sub.mem, the signal generator device 124 may generate V.sub.gen,pulse, here exemplarily higher than the DC base voltage. If the V.sub.gen,pulse is applied, the C.sub.dl and the C.sub.shunt start to charge causing an art of shortcut at the R.sub.ct and the R.sub.meas respectively. Thus, the whole V.sub.gen,pulse is distributed over the R.sub.ref and the R.sub.mem. Since the R.sub.ref and the R.sub.mem comprise, in the first approximation, a simple voltage divider, the R.sub.mem can be easily calculated, once V.sub.meas,pulse is measured either at the R.sub.ref or at the R.sub.mem by means of the voltmeter. Here, exemplarily, at the R.sub.mem by means of voltmeter V.

[0178] In course of the C.sub.dl and C.sub.shunt charging, V.sub.gen,pulse starts to additionally drop at, correspondingly, R.sub.ct and R.sub.meas, which is not desired. Furthermore, the additional voltage at the R.sub.ct means additional undesired current flow through the sensor caused, for instance, by unspecific oxidation of further substances, which must be avoided. Thus, the duration of V.sub.gen,pulse may be kept sufficiently short, in order to exclude the excessive C.sub.dl and C.sub.shunt charging and thus excessive voltage rise at R.sub.ct and R.sub.meas. Correspondingly, the data acquisition rate of the voltmeter V may be sufficiently high, in order to record the V.sub.meas,pulse possibly immediately after applying V.sub.gen,pulse.

[0179] The membrane resistance R.sub.mem may be calculated according to

[00005]$R_{mem}=R_{\mathrm{ref}}\frac{V_{\mathrm{meas},\mathrm{pulse}}-V_{me\mathrm{as},\mathrm{base}}}{\left(V_{\mathrm{gen},\mathrm{pulse}}-V_{\mathrm{gen},\mathrm{base}}\right)-\left(V_{\mathrm{meas},\mathrm{pulse}}-V_{meas,base}\right)}.$

[0180] While exemplary embodiments have been disclosed hereinabove, the present invention is not limited to the disclosed embodiments. Instead, this application is intended to cover any variations, uses, or adaptations of this disclosure using its general principles. Further, this application is intended to cover such departures from the present disclosure as come within known or customary practice in the art to which this invention pertains and which fall within the limits of the appended claims.

LIST OF REFERENCE NUMBERS

[0181] 110 analytical system [0182] 112 analyte sensor [0183] 114 measurement electrode [0184] 116 working electrode [0185] 118 counter electrode [0186] 120 reference electrode [0187] 122 membrane element (membrane) [0188] 124 signal generator device [0189] 126 measurement unit [0190] 128 sensor contacts [0191] 130 Potentiostat [0192] 132 evaluation device [0193] 134 Current curve [0194] 136 equivalent series resistance curve [0195] 138 Temperature curve [0196] 140 equivalent series resistance curve [0197] 142 Current curve [0198] 144 Voltage curve