Patent Description:
Blood glucose monitoring is a way of testing the concentration of glucose in the blood. Particularly important in the care of diabetes mellitus, a blood glucose test is performed by piercing the skin, typically, on the finger, to draw blood, then applying the blood to a chemically active disposable test strip. Different manufacturers use different technologies, but some systems measure an electrical characteristic, and use this to determine the glucose level in the blood.

Healthcare professionals advise patients with diabetes on the appropriate monitoring regimen for their condition. Most people with Type <NUM> diabetes test at least once per day. Diabetics who use insulin usually test their blood glucose more often, e.g. <NUM> to <NUM> times per day, both to assess the effectiveness of their prior insulin dose and to help determine their next insulin dose. Improved technology for measuring blood glucose is rapidly changing the standards of care for all patients suffering diabetes.

Some methods and devices for monitoring a blood glucose level use test strips that are provided with glucose biosensors. For instance, test strips have been suggested that comprise amperometric enzyme electrodes, based on glucose oxidase (GOx). During a chemical reaction, i.e. during the glucose oxidase, glucose and oxygen convert into gluconic acid and water.

Known amperometric test strips exploit enzymes to convert the analyte of interest, e.g. glucose, into an electrical current. These biosensors are mainly based on an enzyme class called oxidases, that may catalyze the transfer of electrons between two molecules according to the following steps. In a first step, the enzyme binds molecular oxygen and the target compound into its active site and oxidizes the analyte, extracting two electrons in the process. During the oxidation, the electrons are collected by the enzyme's cofactor, which enters in a reduced state. In a further stage the enzyme's cofactor returns to its native state by transferring the electron to a molecule of oxygen and generating hydrogen peroxide as a product allowing a new cycle to start.

The measurement of hydrogen peroxide by chronoamperometry may be highly influenced by the concentration of oxygen in the sample. Some test strips solve this problem by integrating into their composition a mediator, i.e. a chemical compound acting as an electron shuttle between the enzyme's cofactor and the electrode.

Document <NPL> discloses use of a dual-plane impedance tomography system to calculate the mass flow rate of an air-gravel-seawater mixture.

<CIT> discloses a multi-analyte sensor system whereby one or more stimulus signals are applied to a sensor to determine properties of a sensor and/or calibrate sensor data.

It is therefore an aim of the present disclosure to provide an improved method of measuring an analyte in a sample and to provide an improved analyte measurement device for measuring such an analyte or several analytes in a sample.

In one aspect there is provided a method according to independent claim <NUM> of measuring an analyte in a liquid biological sample.

The method comprises the steps of applying an electrical analysis signal to the sample during a measurement time interval. The electrical analysis signal, when transferred into a frequency space, comprises a superposition of two or more non-zero frequency components at least at a sampling time. The method further comprises the step of measuring of at least one electrical response signal from the sample in response to the application of the electrical analysis signal to the sample. Thereafter and in a further step the electrical response signal is analyzed. Based on the analysis of the electrical response signal an amount, a quantity or a concentration of the analyte in the sample is determined, wherein the analyte may be chosen from at least one of: blood glucose, lactate, uric acid, ketones, creatinine, hemoglobin, total cholesterol, oxygen, carbon dioxide, proteins, sodium, potassium, calcium, magnesium, zinc, copper, iron, chromium, nickel or lead.

Since the electrical analysis signal when applied to the sample comprises two or more non-zero frequency components at a given sampling time the sample is exposed to at least two frequency components simultaneously. The electrical response signal derivable from the sample in return can be spectrally analyzed. The electrical response signal therefore also comprises a superposition of at least two non-zero frequency components that are indicative of at least one analyte contained in the sample. In this way and by following this multiple frequency component approach the precision of the electrochemical analysis of the sample can be improved. At a given sample time the sample is exposed to at least two different frequency components of an electrical analysis signal. The electrical response signal can be spectrally analyzed with regards to at least two frequency components. In this way a kind of an electrochemical impedance spectroscopy is applied to the sample for analyte measurement.

It is of particular benefit that a substantially non-varying electrical analysis signal can repeatedly and/or regularly applied to the sample. The respective electrical response signal obtainable from the sample or modified by the sample can then be analyzed differently, e.g. with regard to different spectral ranges or different frequency components. This may have a practical benefit since the sample, e.g. a test strip with a blood sample, is repeatedly exposed to unmodified and non-varying electrical analysis signals. Modifications of the sample over time or modifications and a temporal behavior of the electrochemical reaction taking place in or on the sample can thus be repeatedly monitored and measured under constant and unmodified measurement conditions.

It is even conceivable to constantly apply the electrical analysis signal to the sample, hence to apply the electrical analysis signal to the sample in continues mode or in a cw mode. Independent of the type of application of the electrical analysis signal to the sample spectral ranges of the electrical response signal can be separately analyzed by respective analyzing hardware and software without affecting the sample.

It is particularly conceivable, that during a measurement time interval numerous and a sequence of electrical analysis signals are repeatedly applied to the sample and that for each application of an electrical analysis signal to the sample there is measured at least one electrical response signal from the sample in return. During the measurement time, the sample is subject to an electrochemical reaction that is monitored over time. The measurement time interval may typically range between <NUM> to <NUM> seconds. It may range between <NUM> to <NUM> seconds. In some typical examples the measurement time interval may last about <NUM> seconds.

According to the invention the electrical analysis signal comprises a noise signal comprising one of a white noise frequency spectrum, a pink noise frequency spectrum, a red noise frequency spectrum, a blue noise frequency spectrum, a violet noise frequency spectrum and a grey noise frequency spectrum. The noise signal may be constantly and permanently applied to the sample over the entire measurement time interval. Alternatively, the noise signal may be applied repeatedly at least during selected sampling times within the measurement time interval.

The noise signal comprises a superposition of a multitude of frequency components, wherein each frequency component may be subject to temporal variations or fluctuations. It is even conceivable, that the noise signal comprises an infinitesimal number of different frequency components. In this way, the sample is simultaneously exposed to a large number or even to an infinitesimal number of different frequency components. The electrical response signal obtainable from the sample in return thus carries a respective amount of frequency components that can be selectively and subsequently analyzed for determining the amount or the quantity of the analyte in the sample.

In particular, the noise signal comprises a pink noise frequency spectrum. The pink noise signal comprises a frequency spectrum such that the power spectral density, i.e. the energy or power per frequency interval is inversely proportional to the frequency of the signal. With a pink noise signal, each octave, i.e. halving/doubling in frequency, carries an equal amount of noise energy. The noise signal and in particular the pink noise signal may comprise a frequency range in the region from <NUM> to <NUM>.

When the electrical analysis signal comprises a noise signal or when the electrical analysis signal conditions of a noise signal, e.g. a pink noise signal consists of a noise signal, in particular of a pink noise signal almost any conceivable frequency component is contained in the electrical analysis signal and the sample is excited or exposed to almost any conceivable frequency components. It is then that also the electrical response signal carries a multitude of frequency components.

For analyzing the electrical response signal a suitable or a predetermined frequency spectrum of the electrical response signal can be filtered and can be separately analyzed. Such a filtering, selection or limitation to only one or to several frequency components of the electrical response signal is entirely conducted on the analysis side and leaves the excitation or exposure of the sample with the electrical analysis signal unchanged. The measurement conditions as seen from the sample remain non-amended and unchanged, thus enabling to increase the measurement precision and to improve the reproducibility of the measurement.

According to another example the electrical response signal is filtered by a variable bandpass filter having a center frequency that is varied during the measurement time interval. A portion of the electrical response signal that passes the variable bandpass filter is analyzed for determining the amount of the analyte in the sample. By means of a variable bandpass filter only one or several predetermined frequency components of the electrical response signal can be selected for signal analysis and for the determination of the amount, the quantity or the concentration of the analyte.

A variable bandpass filter can be dynamically tuned or adjusted within a comparatively short time. In this way numerous different frequency components can be filtered from the electrical response signal only by the varying the center frequency of the variable bandpass filter during the measurement time interval. Switching or modifying of the center frequency of the variable bandpass filter can be conducted in a few milliseconds, such as <NUM> or even less. In this way, a rather high sampling rate, e.g. in the range of <NUM> samples per second can be provided. The center frequency of the variable bandpass filter can be modified and varied in accordance to a predefined sampling interval, such as <NUM> or even less. The sampling interval, hence the time interval between two consecutive sampling times, is only governed and limited by the dynamic behavior and the dynamic switching characteristics of the variable bandpass filter.

According to another example, at a first sampling time the variable bandpass filter is tuned to a first center frequency. At a second sampling time the variable bandpass filter is tuned at least to a second center frequency. The first center frequency and the second center frequency are different. Moreover, after each sampling interval the center frequency of the bandpass filter is switched or tuned to a different center frequency. It is conceivable, that the center frequency of the bandpass filter is monotonically increased or decreased step by step at each sampling time. Once a maximum center frequency has been reached, the center frequency may decrease step-by-step or may be abruptly switched to a minimum center frequency. Once a minimum center frequency has been reached, the center frequency may increase step-by-step or may be abruptly switched to a maximum center frequency.

It is conceivable, that the variable bandpass filter is consecutively tuned or switched to <NUM> different center frequencies, <NUM> different center frequencies or even hundred or hundreds of different center frequencies. In this way, the electrical response signal can be analyzed with regard to a respective number of different frequency components. By applying a noise signal as the electrical analysis signal to the sample, a selection of particular center frequency can be exclusively implemented by software and does not require a modification of a hardware setup of a respective analyte measurement device.

Moreover, the number of frequency components as well as the center frequencies of the variable bandpass filter can be easily modified by operating and controlling the variable bandpass filter accordingly. It is even conceivable to modify the number of frequency components and/or the selection of frequency components to be analyzed during the measurement time interval. In this way, the method may dynamically react on specific of a varying measurement conditions.

According to a further example the variable bandpass filter is repeatedly tuned to the first center frequency and to the second center frequency during the measurement time interval. There may be conducted numerous measurement cycles during the measurement time interval, wherein during each measurement cycle each of the predefined center frequencies or frequency components has been selected once. As an example and when for instance <NUM> different frequency components are selected for the analysis of the electrical response signal and with a sampling interval of <NUM>, a measurement cycle may last <NUM>. During a measurement time interval of <NUM> seconds the method and a respective analyte measurement device may conduct <NUM> measurement cycles and may thus collect <NUM> electrical response signals for each one of the <NUM> frequency components.

According to another example the electrical analysis signal comprises a sequence of pulses, wherein a single pulse of the sequence of pulses comprises a peak-shaped pulse or a rectangular-shaped pulse. Other pulse forms are also conceivable. Consecutive pulses are applied to the sample at a predefined repetition rate. The repetition rate of the sequence of pulses may be in a range of a few milliseconds, e.g. in a range of <NUM> or less.

Between two consecutive pulses of the sequence of pulses the electrical analysis signal may comprise a zero amplitude or a constant amplitude. Typically, the electrical response signal is analyzed during pulse-pauses that follow a pulse of the electrical analysis signal. In this way a dynamic response of the sample can be analyzed over time. The electrical response signal following a pulse of the electrical analysis signal may be denoted as a pulse reply signal. The pulse reply signal may be indicative of the amount, the quantity and/or concentration of the analyte in the sample. The pulse reply signal may be further indicative of external or internal factors that have an influence of the measurement of the analyte. The pulse reply signal as well as the electrical response signal in general may be indicative of at least one of hematocrit, ascorbic acid, oxygen, humidity or temperature, just to mention a few.

In another example the electrical response signal is analyzed during the entire measurement time interval and/or during time intervals between consecutive pulses of the sequence of pulses. With both approaches an influence of a pulse-excitation of the sample and a pulse-excitation applied to the electrochemical reaction taking place on or with the sample can be monitored and analyzed.

According to independent claim <NUM> an analyte measurement device for measuring of an analyte in a sample is provided. The analyte measurement device comprises a signal generator configured to generate an electrical analysis signal, wherein the electrical analysis signal, when transferred into a frequency space, comprises a superposition of two or more non-zero frequency components at least at a sampling time. The analyte measurement device further comprises a controller connected to the electrical signal generator and electrically connectable to the sample.

The controller is configured to measure at least one electrical response signal from the sample when the sample is exposed to the electrical analysis signal or when the electrical analysis signal is or has been applied to the sample.

The analyte measurement device is particularly configured to conduct the method of measuring an analyte as described above. Features and effects described above in relation to the method of measuring an analyte equally apply to the analyte measurement device and vice versa.

The controller is also configured to analyze the electrical response signal and to determine the amount of the analyte in the sample on the basis of the analysis of the electrical response signal. Alternatively, the controller may be connected to a separate computing device, such as a computer or a smartphone having a computational unit or a processor configured to conduct the analysis and determination of the amount, the quantity or concentration of the analyte in the sample.

According to the invention the signal generator comprises a noise generator configured to generate at least one of a white noise frequency spectrum, a pink noise frequency spectrum, a red noise frequency spectrum, a blue noise frequency spectrum, a violet noise frequency spectrum and a grey noise frequency spectrum. The signal generator may be configured to constantly and to permanently apply a noise signal to the sample over the entire measurement time interval. Alternatively, the signal generator may be configured to apply the noise signal repeatedly at least during selected sampling times within the measurement time interval. The noise signal comprises a superposition of a multitude of frequency components, wherein each frequency component may be subject to temporal variations or fluctuations. It is even conceivable, that the noise signal comprises an infinitesimal number of different frequency components. In this way, the sample can be simultaneously exposed to a large number or even to an infinitesimal number of different frequency components.

In another example the analyte measurement device comprises a variable bandpass filter connected to the controller and tunable by the controller. The variable bandpass filter is configured to filter the electrical response signal returned from the sample in response to applying the electrical analysis signal to the sample. The variable bandpass filter is particularly configured to filter the electrical response signal when the electrical analysis signal applied to the sample comprises a noise signal, such as a pink noise frequency spectrum. By means of tuning the variable bandpass filter the controller is configured to select predefined frequency components of the electrical response signal during the measurement time interval. In this way, the controller fulfills a double function. In one aspect the controller is configured to select a during each measurement cycle each of the predefined center frequencies or frequency components has been selected once. As an example and when for instance <NUM> different frequency components are selected for the analysis of the electrical response signal and with a sampling interval of <NUM>, a measurement cycle may last <NUM>. During a measurement time interval of <NUM> seconds the method and a respective analyte measurement device may conduct <NUM> measurement cycles and may thus collect <NUM> electrical response signals for each one of the <NUM> frequency components.

According to another aspect an analyte measurement device for measuring of an analyte in a liquid biological sample is provided, wherein the analyte is at least one of: blood glucose, lactate, uric acid, ketones, creatinine, hemoglobin, total cholesterol, oxygen, carbon dioxide, proteins, sodium, potassium, calcium, magnesium, zinc, copper, iron, chromium, nickel or lead. The analyte measurement device comprises a signal generator configured to generate an electrical analysis signal, wherein the electrical analysis signal, when transferred into a frequency space, comprises a superposition of two or more non-zero frequency components at least at a sampling time. The analyte measurement device further comprises a controller connected to the electrical signal generator and electrically connectable to the sample.

In a further example the analyte measurement device comprises a DC offset generator configured to apply a DC offset to the sample. By means of a DC offset, a basic measurement of the electrochemical reaction and a basic estimation of the amount, the quantity or concentration of the analyte in the sample can be conducted. The dynamic contributions to the electrical analysis signal, e.g. the sequence of pulses and the sample's pulse response may be exclusively of predominantly used to conduct a computational compensation of internal or external factors that may have a major impact on the measurement of the analyte in the sample.

According to a further example the controller is configured to deactivate the DC offset generator before activating the pulse generator to generate a sequence of pulses. The DC offset generator and the pulse generator may be operated concurrently so that only one of the DC offset generator and pulse generator is active at a given sampling time.

The above described method of measuring an analyte and the corresponding analyte measurement device may be predominantly configured for measuring blood glucose but are not limited to this application. In general, the method of measuring an analyte and the corresponding analyte measurement device may be configured to measure at least one of the following analytes: lactate, uric acid, ketones, creatinine, hemoglobin, total cholesterol, oxygen, carbon dioxide, proteins, sodium, potassium, calcium, magnesium, zinc, copper, iron, chromium, nickel or lead in a liquid biological sample, such as at least one of blood, urine and sweat.

The analyte measurement device may be implemented as a blood glucose monitoring device to measure a blood glucose concentration of a patient suffering a chronic disease, such as diabetes. The analyte measurement device may be used to determine an amount of a pharmaceutically active substance, hence a drug or medicament to be injected with a separate injection device. The analyte measurement device may be even implemented into an injection device.

Insulin derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyldes(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl- ThrB29LysB30 human insulin; B29-N-(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N-(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin.

Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed in Rote Liste, ed. <NUM>, Chapter <NUM>, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin.

Antibodies are globular plasma proteins (-150kDa) that are also known as immunoglobulins which share a basic structure. As they have sugar chains added to amino acid residues, they are glycoproteins. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentameric with five Ig units, like mammalian IgM.

The disulfide bond of F(ab')<NUM> may be cleaved to obtain Fab'.

It will be further apparent to those skilled in the art that various modifications and variations can be made to the present disclosure without departing from the scope of the claims.

Further, it is to be noted, that any reference numerals used in the appended claims are not to be construed as limiting the scope of the disclosure.

In the following, embodiments of the drive mechanism and the injection device are described in detail by making reference to the drawings, in which:.

In some electrochemical blood glucose monitoring (BGM) measurement schemes the measurement and the measurement results are affected by numerous external and internal factors. Internal factors may be an oxygen pressure in the sample, a level of hematocrit in the sample, or a level ascorbic acid in the sample. Humidity and temperature may be regarded as external factors that may have a substantial influence on the electrochemical analysis of the sample.

By means of elaborate calculations based on measurement signals and based on computational models some of these internal or external factors can be at least approximated, thus allowing to compensate the influence of at least one or some of such internal or external factors, e.g. a hematocrit interference on the measurement result.

It is therefore an aim of the present disclosure to provide an improved method of measuring an analyte in a sample and to provide an improved analyte measurement device for measuring such an analyte or several analytes in a sample. The improved method and the analyte measurement device may provide a rather robust, precise and failure safe measurement of an analyte in a sample. Furthermore, the analyte measurement device and the respective method should support computational compensation of external and internal factors having an influence on the measurement of the analyte.

In <FIG> an analyte measurement device <NUM> is schematically illustrated. The analyte measurement device <NUM> comprises a housing <NUM> and at least one receptacle <NUM> to receive a test strip <NUM>. The test strip <NUM> is configured to receive a liquid medium, such as blood <NUM>. When blood <NUM> is applied to the test strip <NUM> the test strip <NUM> converts into a biosensor or into a kind of an electrochemical cell. Typically and as described above, a test strip <NUM> comprises or is provided with numerous enzymes that start to react with the blood <NUM> as soon as blood <NUM> is applied to the test strip <NUM>. The test strip <NUM> or at least a portion thereof is configured to receive a blood sample <NUM> and thus forms the sample <NUM> that is subject to electrochemical analysis to be conducted by the analyte measurement device <NUM>. For this the receptacle <NUM> of the analyte measurement device <NUM> is formed to receive at least a portion of the test strip <NUM>, namely that portion of the test trip <NUM> that carries the sample <NUM>. The blood <NUM> applied to the test strip <NUM> comprises at least one analyte <NUM>, e.g. blood glucose that is to be measured by the analyte measurement device <NUM>.

The internal structure of the analyte measurement device <NUM> is schematically illustrated in <FIG>. The analyte measurement device <NUM> comprises a controller <NUM> and a signal generator <NUM> both connected or connectable to the sample <NUM>. In the present illustration the sample <NUM> is reproduced as an electrochemical cell. The sample <NUM> is electrically connected to the controller <NUM> as well as to the signal generator <NUM>. The signal generator <NUM> and the controller <NUM> are connected in series. Moreover, the sample <NUM> is connected in series to the signal generator <NUM> and to the controller <NUM>.

The analyte measurement device <NUM> may further comprise an optional DC offset generator <NUM> that is also connected in series to the signal generator <NUM>, the sample <NUM> and to the controller <NUM>. Between the sample <NUM> and the controller <NUM> there is arranged a variable bandpass filter <NUM>. Between the variable bandpass filter <NUM> and the controller <NUM> there is arranged a rectifier and or integrator <NUM> by way of which a signal filtered by the variable bandpass filter <NUM> can be rectified and integrated to be further analyzed by the controller <NUM>.

The controller <NUM> comprises an analog-to-digital converter <NUM>. The controller <NUM> comprises a digital logic unit, such as a processor and a storage, e.g. a microcontroller, to conduct computational compensation of internal or external factors having an influence on the measurement.

The controller <NUM> is connected to the variable bandpass filter <NUM>. The controller <NUM> is also connected to the signal generator <NUM>. The controller <NUM> is configured to control and to tune the variable bandpass filter <NUM>. The controller <NUM> is also configured to control and to operate the signal generator <NUM>. The controller <NUM> is also connected to the DC offset generator <NUM>. The controller <NUM> is configured to control, hence to activate or to deactivate the DC offset generator <NUM>.

Between the signal generator <NUM> and the sample <NUM> there is arranged a resistor <NUM> acting as a reference resistor. The resistor <NUM> acts and behaves as a current to voltage converter.

In the example as illustrated in <FIG> the signal generator <NUM> is implemented as a noise generator <NUM> configured to generate a noise signal as an electrical analysis signal <NUM> as illustrated in <FIG>. A frequency spectrum <NUM> of such a noise signal is shown in <FIG>. The noise generator <NUM> is configured to generate a noise signal <NUM> as shown in the upper graph <NUM> of <FIG>. The signal generator <NUM> and the noise generator thereof <NUM> is configured to generate a pink noise signal <NUM> as a continuous signal over time. Such a noise signal is applied as an electrical analysis signal <NUM> to the sample <NUM>. After the electrochemical reaction on the test strip <NUM> has been activated by applying blood <NUM> thereto the sample <NUM> and the electrochemical cell produces an electrical response signal <NUM> as shown in graph <NUM> in <FIG>. In all graphical representations of signals an amplitude A of the signal is given versus time or versus frequency. The amplitude signal A may represent one of a voltage, a current or an impedance.

The current and hence the electrical response signal generated by the sample <NUM> varies over time. In <FIG> the signals are illustrated over a measurement time interval MT. The measurement time interval MT may have a duration of a few seconds, e.g. <NUM> seconds to <NUM> seconds. It is apparent from the signal, that the response signal <NUM>, hence a current generated by the sample <NUM> when activated with blood <NUM> increases and reaches a maximum after a significant portion of the measurement time interval MT. Thereafter and as time continues the current generated by the sample <NUM> slowly decreases.

In the graph <NUM> of the electrical response signal <NUM> there are illustrated two separate frequency components <NUM>, <NUM> that are measured at sampling times t1 and t2. At these sampling times t1, t2 the electrical response signal <NUM> is measured by the controller <NUM>. In the embodiment of <FIG> the noise generator <NUM> is configured to generate a noise signal <NUM> and to apply the noise signal to the sample <NUM>. The frequency spectrum <NUM> of such this noise signal is for instance shown in <FIG>. There, the amplitude of the noise signal over its frequency components is illustrated. It is apparent from <FIG>, that the electrical analysis signal <NUM> comprises numerous frequency components c1, c2, c3, just to mention a few.

While the electrical analysis signal <NUM> in form of a noise signal is applied to the sample <NUM> continuously and over the entire measurement time interval MT the controller <NUM> is configured to tune the variable bandpass filter <NUM> to a series of different center frequencies f0, f1, f2. In particular, at a first sampling time t1 the bandpass filter <NUM> is tuned to a first center frequency f1. An electrical response signal <NUM> is then obtained from the sample <NUM>. It is filtered by the variable bandpass filter <NUM> and a portion <NUM>, hence a first frequency component <NUM> thereof that passes the variable bandpass filter <NUM> enters the rectifier and integrator <NUM>. Thereafter, the rectified and integrated signal <NUM> is provided to the analog-to-digital converter <NUM> and is then analyzed by the controller <NUM>. In this way and at the sampling time t1 the electrical response signal <NUM> is analyzed with regards to a frequency component with a center frequency f1. This is indicated in the graph <NUM> of <FIG>.

At a second sampling time t2 the variable bandpass filter <NUM> is tuned to a second center frequency f2 by the controller <NUM>. Then, another frequency component <NUM> of the broadband response signal <NUM> is filtered by the variable bandpass filter <NUM>. Correspondingly, the rectifier and integrator <NUM> processes the filtered signal and provides a different signal to the analog-to-digital converter and hence to the controller <NUM>.

The controller <NUM> is configured to repeatedly tune the variable bandpass filter <NUM> to numerous center frequencies and to measure a respective frequency component of the electrical response signal <NUM> for each center frequency of the electrical response signal that is received in response to applying the electrical analysis signal <NUM>, hence the noise signal to the sample <NUM>. The controller <NUM> is configured to repeatedly measure the electrical response signal <NUM> during the measurement time interval MT and to measure the electrical response signal <NUM> for each selected center frequency several times.

The controller <NUM> may conduct numerous measurement cycles during the measurement time interval MT, wherein during each measurement cycle a frequency component of the electrical response signal is only measured once. Each measurement cycle, hence a sweep over numerous frequency components of the electrical response signal <NUM> can be conducted at or during a sampling interval. So for each sampling interval each frequency component of the electrical response signal can be measured. By conducting numerous measurement cycles at numerous sampling times, a temporal evolution of frequency components of the electrical response signal can be derived.

In the graph <NUM> of <FIG> a temporal evolution of a complex impedance Z for three different frequency components f1, f2, f3 is given over the measurement time interval MT. From the temporal behavior of different frequency components f1, f2, f3 of the electrical response signal <NUM> internal and/orexternal factors influencing the measurement of the analyte can be compensated or calculated.

Typically, the variable bandpass sensor can be adjusted within a rather short time interval, e.g. within <NUM>, <NUM>, <NUM> or even faster. This leads to a sampling interval or sampling rate at which different frequency components of the electrical response signal can be selected and separately measured.

In the embodiment as shown in <FIG> the sample <NUM> comprises and represents a two pole electrochemical cell. Alternative, it could be implemented as a three pole cell further comprising a reference electrode.

The further example as shown in <FIG> uses a different type of signal generator <NUM>. Here, the signal generator <NUM> comprises a pulse generator <NUM> configured to generate a sequence of peak- shaped pulses <NUM> as shown in <FIG>. Also here, the controller <NUM> comprises and analog-to-digital converter <NUM>. The controller <NUM> is connected to a DC offset generator <NUM> as well as to the signal generator <NUM>. There are further illustrated switches <NUM>, <NUM> and <NUM> that are also controllable by the controller <NUM>. The switch <NUM> is located between the signal generator <NUM> and the sample <NUM>. The switch <NUM> is connected parallel to the switch <NUM>. The switch <NUM> is located between the DC offset generator <NUM> and the sample <NUM>. The further switch <NUM> is connected parallel to the other two switches <NUM> and <NUM>. By means of the switch <NUM>, an amplifier <NUM> is connectable to one pole of the sample <NUM>. An opposite end of the amplifier <NUM> is finally connected to the analog-to-digital converter <NUM> of the controller <NUM>. The controller <NUM> may comprise a microcontroller so as to control operation of the DC offset generator <NUM> and of the signal generator <NUM>. The controller <NUM> may be also configured to measure and to analyze the electrical response signal <NUM> obtainable from the sample <NUM>.

The graph 280of <FIG> shows the amplitudes or voltages generated by the DC offset generator <NUM> over time. At a time to the blood <NUM> is applied to a test strip <NUM>. As a consequence, the sample <NUM> and the electrochemical cell represented by the sample <NUM> is electrochemically activated. As soon as activation of the electrochemical cell and hence as soon as activation of the sample is detected at the time t0 the controller <NUM> is configured to deactivate the DC offset generator <NUM>. Here, the controller may detect the electrochemical activation of the sample <NUM>. Thereafter or concurrently with the deactivation of the DC of the generator the controller <NUM> activates the signal generator <NUM>. As shown in the graph <NUM> a sequence of peak-shaped pulses of a predefined voltage are applied as an electrical analysis signal <NUM> to the sample <NUM>.

Thereafter and in time intervals between consecutive pulses the amplifier <NUM> is connected to the sample <NUM>. Hence the switch <NUM> is closed during pulse-pauses. The amplifier <NUM> effectively provides a current to voltage converter and the amplifier <NUM> effectively forces the voltage at the terminals of the sample <NUM> to zero. Each pulse of the electrical analysis signal <NUM> in combination with the electromagnetic force generated by the electrochemical behavior of the sample <NUM> leads to a repeated current decay in the electrical response signal <NUM> which is monitored by the controller <NUM>. The temporal behavior and the current decay of the electrical response signal <NUM> following a peak-shaped pulse of the electrical analysis signal <NUM> as shown in the graph <NUM> over time may be characteristic for at least one of the external or internal factors or for the concentration of the analyte in the sample.

By means of a specific algorithm taking into account various parameters such as the above-mentioned internal and external factors the analyte concentration or the amount or quantity of the analyte in the sample can be calculated. For this, a system of n-dimensional equations has to be solved. For solving such equations a neural network may be established by the controller <NUM> or the controller <NUM> may communicate with a separate computing device comprising such a neural network.

The series of peak-shaped pulses used as an electrical analysis signal <NUM> as shown in the time domain in the graph <NUM> of <FIG> is shown in the frequency domain as <NUM> in <FIG>. The sequence of peak -shaped pulses may resemble or may comprise a so-called Dirac comb. It comprises numerous frequency components c1, c2, c3, which in superposition form a tempered distribution constructed from Dirac delta functions.

In the further example as shown in <FIG> a rectangular shaped pulse is applied as an electrical analysis signal <NUM> to the sample <NUM>. The example according to <FIG> resembles the example according to <FIG>. Here, the signal generator <NUM> also comprises a pulse generator <NUM> but contrary to the embodiment as shown in <FIG> the pulse generator <NUM> comprises a current source <NUM>. The analyte measurement device <NUM> as shown in <FIG> also comprises a DC offset generator <NUM> that is connected in parallel to the signal generator <NUM>. Both, the signal generator <NUM> and the DC offset generator <NUM> are connected in series to the sample <NUM> and hence to the electrochemical cell.

In parallel to the signal generator <NUM> and the DC offset generator <NUM> there is provided an amplifier <NUM>. The amplifier <NUM> comprises an amplifying arrangement of an operational amplifier <NUM> and a resistor <NUM>. The amplifier <NUM> is further provided with a separate resistor <NUM> to provide a current to voltage conversion. The resistor <NUM> is connected to an input of the amplifier <NUM>. An input of the amplifier <NUM> is connected to the resistor <NUM>, which is further connected to at least one pole or electrode of the sample <NUM>. An output of the amplifier <NUM> is connected to an analog-to-digital converter <NUM> of the controller <NUM>. The controller <NUM> is connected to the DC offset generator <NUM> as well as to the signal generator <NUM>. The controller <NUM> is further configured to control the DC offset generator <NUM> as well as the signal generator <NUM>.

In a similar way as described in connection to <FIG> and as the sample <NUM> is activated by receiving at least some drops of blood <NUM> a DC offset as shown in graph <NUM> is switched off at a time t0. Here, activation of the sample <NUM> has been detected by the controller <NUM>. Then and after a deactivation of the DC offset the controller <NUM> triggers application of the electrical analysis signal <NUM> to the sample <NUM>.

Here, the electrical analysis signal <NUM> comprises a sequence of current pulses that are of rectangular shape in the time domain. In <FIG> the current pulse is represented in the time domain as <NUM> and its corresponding frequency spectrum is shown as <NUM>. As shown there, the current pulse <NUM> comprises numerous frequency components c1, c2, c3 as illustrated in the corresponding frequency spectrum <NUM> of <FIG>. Concurrently with the application of current pulses to the sample <NUM> a response of the sample <NUM> and hence an electrical response signal 370reflected or produced by the sample <NUM> is measured by the controller <NUM>. The sample <NUM> and the biosensor cell provided or formed by the sample <NUM> delivers a voltage and the current after it has been activated, e.g. by application of blood <NUM> onto the test strip <NUM>.

By means of the current source <NUM> the sample <NUM> and hence the electrochemical cell is loaded and unloaded. During or after application of current pulses as shown in graph <NUM> to the sample <NUM> there evolve characteristic dips or modulations <NUM> in the amplitude of the electrical response signal <NUM> as shown in the graph <NUM>. The size and the shape of the modulations <NUM> is indicative of internal or external factors having an influence on the measurement of the analyte in the sample <NUM>. Moreover the size and shape of the modulations <NUM> can be indicative of the amount, the quantity and/or the concentration of the analyte <NUM> in the sample <NUM>.

In <FIG> a simple flowchart of the method of measuring an analyte <NUM> in a sample <NUM> is illustrated. In a first step <NUM>, the sample is activated, e.g. by applying some drops of blood <NUM> onto a test strip <NUM> and by inserting the test strip <NUM> into an analyte measurement device <NUM> such as a BGM device. Then, in step <NUM> and electrical analysis signal <NUM> is applied to the sample <NUM>. The electrical analysis signal <NUM> comprises a superposition of two or more non-zero frequency components at a sampling time when transferred into a frequency space.

Claim 1:
A method of measuring an analyte (<NUM>) in a sample (<NUM>), the method comprises the steps of:
- applying an electrical analysis signal (<NUM>; <NUM>; <NUM>) to the sample (<NUM>) during a measurement time interval (MT), wherein the electrical analysis signal (<NUM>; <NUM>; <NUM>), when transferred into a frequency space, comprises a superposition of two or more non-zero frequency components (c1, c2, c3) at least at a sampling time (t1, t2),
- measuring of at least one electrical response signal (<NUM>; <NUM>; <NUM>) from the sample (<NUM>),
- analyzing the electrical response signal (<NUM>; <NUM>; <NUM>) and determining an amount of the analyte (<NUM>) in the sample (<NUM>) on the basis of the analysis of the electrical response signal (<NUM>; <NUM>; <NUM>), characterized in that the electrical analysis signal (<NUM>) comprises a noise signal comprising one of a white noise frequency spectrum, a pink noise frequency spectrum, a red noise frequency spectrum, a blue noise frequency spectrum, a violet noise frequency spectrum and a grey noise frequency spectrum.