Device and method for measuring metabolite concentration in interstitial fluid

Abstract

A metabolite sensing device (104, 200) is used in combination with an electrical device (102) for non-invasive measurement of metabolite concentration in interstitial fluid with improved consistency and signal-to-noise ratio. An electrical device determines an impedance of the skin (304, 408, 606) in static state using an electrode (106, 206, 302, 502A to 502N) placed on the skin and provides an electrical current to the electrode to initiate reverse iontophoresis in the interstitial fluid under the skin. Then, the electrical device monitors a change in the impedance of the skin over time under the action of the current, and the metabolite sensing device measures a metabolite concentration in the interstitial fluid under the skin when predefined conditions regarding the change in the impedance are met.

Description

TECHNICAL FIELD

[0001] The present invention relates generally to a measurement system, and more particularly, the present invention relates to a device for measuring the concentration of metabolites in interstitial fluid and a method of measuring the concentration of metabolites in interstitial fluid. The present invention also relates to a measurement module of a metabolite sensing device. BACKGROUND

[0002] Interstitial fluid (IF) is a watery fluid that surrounds the cells and tissues throughout the body, including the skin. The watery fluid includes different substances, including metabolites. The composition or mixture of IF can be comprised of an aqueous solvent containing sugars, salts, fatty acids, amino acids, coenzymes, hormones, neurotransmitters, white blood cells, cellular waste products, and metabolites. The composition or mixture of IF in the skin is dependent on the exchange of substances between the cells, tissues, and blood flow to support the metabolic processes occurring within the human body.

[0003] Measuring the concentration of metabolites in IF can provide information about the substances. For example, tracking the glucose levels in IF can help track the glucose levels in the blood of a diabetic patient. To facilitate the measurement of metabolite concentrations, invasive measurement systems and non-invasive measurement systems have been developed. Invasive measurement systems involve obtaining a small sample of IF through an invasive procedure, using skin pricking or through frequent needle-based methods of microdialysis.

[0004] Non-invasive measurement systems as an alternative to needle-based methods, where the non-invasive measurement systems include a light source comprising one or more sensors and readout electronics positioned on the skin to measure specific molecules or substances in the blood using a light source operating in the optical or electromagnetic range. The light source stimulates the specific molecules or substances in the blood, including glucose or other metabolites, and the one or more sensors collect information about the substances from the stimulation of the specific molecules in the blood. A coupler can also be incorporated as an additional component into the non-invasive measurement system to optimize the transmission of the return signal from the skin to the one or more sensors. The readout electronics are used to process, read, and display the collected information.

[0005] For example, in a photoacoustic (PA) system, a light source emits radiation of a specific wavelength to interact with a specific molecule or substance, such as glucose. The specific molecule or substance can exhibit energy in the form of sound waves in a certain frequency range, such as a Megahertz (MHz) frequency range, which is captured by one or more sensors or microphones through a coupler to monitor metabolites in the blood. The PA system monitors metabolites in the blood by analyzing the sound waves. Photoacoustic (PA) is a phenomenon in which a molecule releases a portion of the collected energy as a molecular thermal agitation when excited by light of a specific wavelength emitted by a light source. The molecular thermal agitation releases mechanical waves (i.e., sound waves) that can be collected to obtain information about the specific molecule or substance.

[0006] Alternatively, a non-invasive measurement system excites a light source of multiple wavelengths and captures various forms of return signals, including reflected and scattered light sources, and light emitted by molecules due to Raman shift. Raman shift exhibits an optical response when light interacts with a molecule or substance. The optical response is the behavior or characteristic of a molecule or substance when light is emitted on the molecule or substance. However, in existing non-invasive measurement systems, the light source can unintentionally interact with other substances present in the body instead of the specific molecule. Existing non-invasive measurement systems utilize a light source as a probe signal, which can produce an erroneous response due to the presence of different substances in the skin, resulting in a lack of specificity. In a PA system, other molecules also produce a response when excitation occurs, which can affect the measurement of the concentration of the specific molecule. For example, a Mid-Infrared (Mid-IR) photoacoustic sensing system measures false responses when measuring glucose in lipids. Mid-Infrared (Mid-IR) is a light source, or equivalent electromagnetic radiation, whose wavelength is in the range of 3 microns to 10 microns, approximately in the form of a photon.

[0007] The probe signal (also referred to as an excitation signal) is composed of a laser in most cases, which constitutes a light signal that can reach the target molecule.

[0008] Moreover, existing non-invasive measurement systems lack signal-to-noise ratio (SNR) because in the signal received by one or more sensors, the useful information about the substance of interest is superimposed on other things that arise due to the same probe signal interacting with the environment around the substance and constitute background noise. Existing non-invasive measurement systems suffer from attenuation when using a light source or electromagnetic waves to detect and analyze metabolites in the skin. For example, in the case of a Mid-IR system, the probe signal is able to penetrate the skin with an effective penetration depth (EPD) in the range of 30 to 50 microns. At a depth of 30 to 50 microns, the power of the probe signal is attenuated by about 1 / e and the concentration of metabolites is significantly lower. Molecules respond to the signal in a specific range of wavelengths within the Mid-IR spectrum, where the molecules exhibit characteristic vibrational modes. The level of this return signal is directly proportional to the portion of the probe signal that reaches and is effectively absorbed by the target molecules. In a practical system, the limited power available for the light source and the attenuation that occurs in the scenario typically results in an SNR of the return signal that is too low to perform the required detection.

[0009] Moreover, in PA systems, the presence of water fluids and the way the PA system is connected to the skin can pose potential challenges to the acoustic waves. If there is any air gap between the skin and the electrodes used for connection, the probe signal can be affected and lead to inaccurate information about the substance.

[0010] In Raman spectroscopy, the probe signal used to measure the substance triggers the presence of unwanted fluorescence or emission of the light source. The unwanted fluorescence creates background noise, making it more difficult for the acoustic waves to accurately read information about the substance.

[0011] Moreover, it is difficult for the one or more sensors to accurately read information about the substance from the response of the molecules to the energy emission. The process of separating the response of the molecules from the energy emission is called deconvolution, which is complex due to the presence of various factors such as different substances and background noise.

[0012] Further, in measuring the substance in the aqueous fluid, it is crucial to determine the desired response (i.e., accurate measurement of the substance) and the erroneous response (i.e., inaccurate measurement of the substance). The desired response and the erroneous response from the aqueous fluid can fluctuate significantly with changes in environmental parameters (e.g., temperature), thereby affecting the reliability of the substance measurement. The properties of the skin, including thickness and other characteristics, can also respond quickly to environmental factors, resulting in changes within a day. Further, the positioning of one or more sensors on the skin can be affected by the unevenness of the skin, such as the presence of hair follicles and sweat glands laterally, and different skin layers longitudinally, which can affect the measurement consistency. Further, individuals with different skin types exhibit differences in lipid levels, which introduces variability in the measurement when using a photoacoustic sensing system.

[0013] In some other existing approaches, the extraction of IF directly from the skin surface affects the measurement repeatability due to (i) the interstitial fluid following multiple paths, including hair follicles and glands exhibiting intra-day and inter-personal variations, thereby affecting the measurement of the substance, and (ii) the outermost layer of the skin, known as the stratum corneum (SC), exhibiting continuous changes in thickness, density, and morphology throughout the day. For example, the thickness of the SC fluctuates significantly, ranging from 0.1 to 5 times, resulting in inaccurate and inconsistent measurement of the substance.

[0014] For example, the food and drug administration (FDA) approved GlucoWatch 3 device utilizes reverse iontophoresis (RI) electrodes to extract IF from the skin. However, the GlucoWatch 3 device was discontinued due to issues with non-reproducible measurements. On the other hand, if a needle is used to extract IF from the skin, it results in the loss of non-invasiveness of the measurement. Further, all existing approaches that focus on measuring the substance are specifically designed for electrochemical sensing methods, which limits the flexibility for different measurement techniques.

[0015] Therefore, there is a need to address the above technical problems / shortcomings in measuring the concentration of metabolites in interstitial fluid (IF) to improve the signal-to-noise ratio (SNR) and consistency in measuring the substance in IF. SUMMARY

[0016] It is an object of the present invention to provide a device for measuring the concentration of metabolites in interstitial fluid, and a method of measuring the concentration of metabolites in interstitial fluid, while avoiding one or more of the shortcomings of the prior art methods. The present invention also relates to a measurement module of a metabolite sensing device.

[0017] This object is achieved by the features of the independent claims. Further implementations are evident from the dependent claims, the description and the figures.

[0018] According to a first aspect, there is provided a device for measuring a concentration of a metabolite in interstitial fluid (IF). The device comprises electrical means and metabolite sensing means. The electrical means are for determining an impedance of a skin at rest at a selected frequency using electrodes placed on the skin. The electrical means are for providing a current to the electrodes to initiate a reverse iontophoresis in the interstitial fluid under the skin. The electrical means are for monitoring a change in the impedance of the skin over time under the influence of the current. The metabolite sensing means are for measuring a concentration of a metabolite in the interstitial fluid under the skin when a predefined condition on the change in the impedance is met.

[0019] The device improves the signal-to-noise ratio (SNR) and variability of non-invasive measurements of target molecules or substances in interstitial fluid (IF) by combining a device of electrical means with a non-invasive sensing head. The sensing head can act as a measurement head. The device uses optical or electromagnetic light sources or beams, with electroosmotic flow or reverse iontophoresis (RI) to lift and trap IF under the stratum corneum (SC), measuring a larger amount of target molecules, which also improves the SNR by gathering more information about the target substances. The device aims to detect metabolites by effectively concentrating them laterally in a position where the probe signal can reach. With the probe signal or light, the device targets the area with the highest concentration of metabolites (i.e. the active sensing area) by lifting the IF to the SC, applying to the metabolites residing in the IF, thus enhancing the excitation of the metabolites and reducing the measurement uncertainty caused by the variability of the IF extraction path of the stratum corneum (SC). The device actively controls the electroosmotic flow or reverse iontophoresis (RI) process to selectively lift and accumulate the target metabolites or substances under the SC. By continuously monitoring and adjusting the skin impedance related to daily changes in the skin, the device maintains a consistent distribution of the IF. The above adjustment is possible because, as previously described in the literature, RI parameters such as the length of the current injection, the duty cycle and the amplitude have an impact on the skin and its impedance. The device enhances the measurement consistency of the target substances by monitoring the changes in the skin impedance through the current during the optical or electromagnetic sensing process in the IF and reacting to them.

[0020] The device enhances the stability of the skin impedance and related skin properties during the measurement of the target substance. When the skin impedance decreases to a predetermined level, the device injects a small current into the skin while avoiding extraction of the IF, which reduces the variability of the measurement of the target substance. The device ensures more consistent light loss within the stratum corneum (SC), which results in better repeatability of the metabolite excitation throughout the measurement, which improves the repeatability of optical or electromagnetic metabolite sensing while maintaining the non-invasive nature of the measurement. The device uses a specific electrode design to spatially apply and control the flow density of the IF in the upper layers of the skin, thereby spatially applying and controlling the flow density of the metabolites contained in the IF without extracting the fluid from the skin. Furthermore, the device controls certain spatial aspects of the light source to optimize the alignment of the metabolites with the output of the optical probing beam or signal, maximizing metabolite excitation.

[0021] Optionally, the electrical device is further configured to adjust one or more of the electrical parameters of the electrical current provided to the electrodes of the electrical device until the predefined condition is met. The electrical parameters include the amplitude, duration, and duty cycle of the electrical current. The electrical device is further configured to set the electrical parameters that satisfy the predefined condition as a setpoint for measuring the concentration of the metabolite. The electrical device is further configured to obtain a first set of measurements of the concentration of the metabolite sensing device with the electrical parameters fixed at the setpoint. The electrical device is further configured to obtain a second set of measurements of the concentration of the metabolite sensing device by varying one or more of the electrical parameters around the setpoint. The electrical device is further configured to determine a figure of merit for each measurement of the first and second sets. The electrical device is further configured to update the setpoint for measuring the concentration of the metabolite with the varied electrical parameters if the varied electrical parameters provide the best figure of merit in the first and second sets of measurements.

[0022] Optionally, the electrical device is further configured to adjust one or more of the electrical parameters of the electrical current provided to the electrodes of the electrical device over time by keeping the variation of the impedance within a target range to maintain the predefined condition to be met with a set precision.

[0023] Optionally, the electrical device is configured to provide the electrical current to the electrodes in cycles and to monitor the variation of the impedance of the skin at the end of each cycle.

[0024] Optionally, the predefined condition regarding the variation of the impedance is based on a decrease in the impedance of the skin compared to the determined impedance of the skin at rest and / or a physiological reference dependence of the skin impedance on the current at the selected frequency.

[0025] Optionally, the electrodes of the electrical device placed on the skin comprise a minimal set of electrodes: a first cathode, a ring-shaped second cathode surrounding the first cathode, and a ring-shaped anode surrounding the second cathode. More electrodes can be added to ensure a match between the constraints in the electrical front-end and e.g. field distribution curves and / or other case-specific requirements. The metabolite sensing device comprises a sensing head arranged between the first cathode and the second cathode, and the apparatus is for selectively applying different electrical bias to each of the electrodes.

[0026] Optionally, the metabolite sensing device comprises two or more sensing heads arranged circumferentially between the first cathode and the second cathode.

[0027] Optionally, the sensing head of the metabolite sensing device comprises a light source, a ring-shaped transducer, and a conical lens for converting a Gaussian light beam generated by the light source into a Bessel light beam, the Bessel light beam passing through the ring-shaped transducer to the skin.

[0028] According to a second aspect, there is provided a method of measuring a metabolite concentration in interstitial fluid (IF). The method comprises determining an impedance of a skin at rest at a selected frequency with electrodes placed on the skin. The method comprises providing an electrical current to the electrodes to initiate a reverse iontophoresis in the interstitial fluid under the skin. The method comprises monitoring a change in the impedance of the skin over time under the influence of the electrical current. The method comprises measuring a metabolite concentration in the interstitial fluid under the skin with a metabolite sensing device when a predefined condition on the change in the impedance is met.

[0029] The method improves the signal-to-noise ratio (SNR) and variability of non-invasive measurements of target molecules or substances in interstitial fluid (IF) by combining a device of an electrical device with a sensing head. The sensing head can act as a measurement head. The method improves the SNR by elevating and trapping IF below the stratum corneum (SC) using electroosmosis or reverse iontophoresis (RI) with optical or electromagnetic light sources or beams, measuring a larger amount of target molecules, which also improves the SNR by gathering more information about the target substances. This method effectively concentrates metabolites laterally in a position where the detection signal can reach to detect the metabolites. With the detection signal or light, this method targets the area with the highest concentration of metabolites (i.e., the active sensing area) by elevating the IF above the SC, applying to metabolites residing in the IF, thereby enhancing the excitation of metabolites and reducing measurement uncertainty caused by the variability of the interstitial fluid (IF) extraction path of the stratum corneum (SC). This method actively controls the electroosmosis or reverse iontophoresis (RI) process to selectively elevate and accumulate IF below the SC and, therefore, target metabolites or substances in the IF. This method maintains a consistent distribution of the IF by continuously monitoring and adjusting the skin impedance related to daily changes in the skin. This method enhances the measurement consistency of target substances by monitoring changes in skin impedance through the current during optical or electromagnetic sensing processes in the IF and reacting to them.

[0030] This method enhances the stability of the skin impedance and related skin properties during the measurement of target substances. When the skin impedance decreases to a predetermined level, this method reduces the measurement variability of target substances by injecting a small current into the skin while avoiding the extraction of IF. This method ensures more consistent light loss within the stratum corneum (SC), resulting in better repeatability of metabolite excitation throughout the measurement, thereby improving the repeatability of optical or electromagnetic metabolite sensing while maintaining the non-invasive nature of the measurement. This method uses a specific electrode design to spatially apply and control the flow density of interstitial fluid (IF) in the upper layers of the skin, thereby spatially applying and controlling the flow density of metabolites contained in the IF without extracting said fluid from the skin. In addition, the method controls certain spatial aspects of the light source to optimize the alignment of the metabolites with the output of the optical detection beam or signal, maximizing metabolite excitation.

[0031] Optionally, the method further comprises adjusting one or more of the electrical parameters of the electrical current provided to the electrode of the electrical device to maintain the predefined condition to satisfy a set accuracy by keeping the change of the impedance within a target range. Optionally, the electrical parameters comprise an amplitude, a duration and a duty cycle of the electrical current.

[0032] Optionally, providing the electrical current to the electrode comprises providing the electrical current in cycles, and the monitoring the change of the impedance of the skin over time comprises determining the impedance of the skin at the end of each cycle.

[0033] Optionally, the predefined condition on the change of the impedance is based on a decrease of the impedance of the skin compared to the determined impedance of the skin at rest, and / or a physiological reference dependence of skin impedance on the electrical current at the selected frequency.

[0034] According to a third aspect, there is provided a measurement module of a metabolite sensing device. The measurement module is for placement on a skin. The measurement module comprises a sensing head and an electrode. The sensing head is for measuring a metabolite concentration in an interstitial fluid (IF) under the skin. The electrode is for being provided with an electrical current to initiate a reverse iontophoresis in the interstitial fluid under the skin, and for determining an impedance of the skin.

[0035] The measurement module of the metabolite sensing device uses a photon or electromagnetic light source to enhance excitation of a target or specific substance by bringing the target or specific substance closer to the sensing head. The measurement module of the metabolite sensing device is able to collect more information or signals about the target or specific substance from the target or specific substance by lifting the target or specific substance near the sensing head with the photon or electromagnetic light source. The measurement module reduces the attenuation of the collected signals by reducing (i.e. lifting) the distance between the target or specific substance and the sensing head. The measurement module aligns the spatial distribution of the target or specific substance under the sensing head within an active zone or region of the target or specific substance, thereby avoiding wasting excitation power or active sensing area. When the target or specific substance is concentrated within the active region, the sensing head effectively excites and detects the molecules or target or specific substance, thereby maximizing the sensitivity and accuracy of the measurement of the target or specific substance.

[0036] The measurement module of the metabolite sensing device comprises one or more tuning parameters to optimize performance. The one or more tuning parameters include (i) the voltage difference between the plurality of electrodes, ΔVacN >... > ΔVac2 > ΔVac1, (ii) the distance between the electrodes, (iii) the number of electrodes, (iv) the symmetric 3D placement, and the geometry of the number of electrodes to maximize the steady state density of the flow of the IF under the active sensing area of the sensing head, for example by maximizing the density of the electric field lines or maximizing the current under the active sensing area of the sensing head. The maximized density of the electric field lines can act as a driving force for the IF to concentrate and flow from multiple directions within the skin towards the active sensing area.

[0037] Optionally, the electrodes comprise a first cathode, an annular second cathode surrounding the first cathode, and an annular anode surrounding the second cathode. The sensing head is arranged between the first cathode and the second cathode.

[0038] Optionally, the measurement module comprises two or more sensing heads for measuring the metabolite concentration in the interstitial fluid under the skin. The two or more sensing heads are arranged circumferentially between the first cathode and the second cathode.

[0039] The technical problem in the prior art is solved, wherein the technical problem is to non-invasively measure the metabolite concentration in the interstitial fluid (IF).

[0040] Thus, unlike the prior art, the apparatus and method for measuring the metabolite concentration in the IF improve the consistency of the measurement of the substance in the IF, increase the signal-to-noise ratio (SNR) of the information about the substance, and stabilize the impedance of the skin.

[0041] These and other aspects of the application are apparent from the following description of one or more implementations. BRIEF DESCRIPTION OF DRAWINGS

[0042] Implementations of the application are described below by way of example only, with reference to the accompanying drawings, in which:

[0043] Figure 1 is a block diagram illustrating an apparatus for measuring a metabolite concentration in the interstitial fluid (IF) according to an implementation of the application;

[0044] Figure 2 is a block diagram illustrating a measurement module of a metabolite sensing device according to an implementation of the application;

[0045] Figure 3is an exemplary view of the device according to an implementation of the present invention Figure 1

[0046] Figure 4 is an exemplary view of the device according to an implementation of the present invention Figure 1

[0047] Figure 5A Figure 5B

[0048] Figure 6A Figure 6B

[0049] Figure 7A Figure 7B is a flowchart illustrating a method for measuring a concentration of a metabolite in interstitial fluid (IF) according to an implementation of the present invention;

[0050] Figure 8 is an illustration of a computer system in which various previously implemented implementations can be implemented. DETAILED DESCRIPTION

[0051] Implementations of the present invention provide a device and a method for measuring a concentration of a metabolite in interstitial fluid.

[0052] The following implementations of the present invention are described in connection with the appended drawings, which are not necessarily drawn to scale.

[0053] The terms "first", "second", "third", and "fourth" (if any) in the description of the present invention, the claims, and the above drawings are used to distinguish similar objects, and are not necessarily used to describe a particular sequence or order. It should be understood that the terms as used in this manner are interchangeable under appropriate circumstances, for example, such that the implementations of the present invention described herein can be implemented in sequences other than those illustrated or described herein. Furthermore, the terms "comprise" and "have" and any variations thereof are intended to cover non-exclusive inclusion. For example, a process, method, system, product, or apparatus that includes a list of steps or units does not necessarily limit the steps or units to only those explicitly listed, but can include other steps or units not explicitly listed or inherent to such a process, method, product, or apparatus.

[0054] Definitions:

[0055] ​​​​​​​Interstitial fluid (IF) is the fluid that surrounds the cells and tissues in the body, including the skin. IF is composed of an aqueous solvent that contains sugars, salts, fatty acids, amino acids, coenzymes, hormones, neurotransmitters, white blood cells, cellular waste products, and metabolites. The composition of IF depends on the exchange between cells in the tissue and blood, and thus it is related to metabolic processes.

[0056] Photoacoustic (PA) refers to the phenomenon of molecules excited by light of a specific wavelength releasing part of the energy collected in the form of molecular thermal perturbation. This perturbation releases a mechanical (acoustic) wave, which can be collected for information.

[0057] Spectroscopy is a broad technique that uses light of a specific wavelength to interact with a target molecule. The molecule emits energy in a certain form (heat, light, acoustic wave) and exhibits certain time and frequency domain characteristics. This energy is collected to obtain information about the molecule, for example, its concentration, or some specificity in its composition, etc.

[0058] The probe signal is the excitation signal used in spectroscopy to trigger a characteristic response signal from the molecule, which is then collected. In most cases, the probe signal consists of a laser (light signal), and in all cases, the probe signal must reach the target molecule.

[0059] Mid-infrared (Mid-IR) is light, or equivalent electromagnetic radiation, whose wavelength is approximately in the range of 3 to 10 microns. It propagates in the form of photons.

[0060] Effective penetration depth (EPD) is the depth of penetration of light in a material or tissue at which the energy (number of photons) is attenuated by a factor of 1 / e. At a propagation distance within the material equal to the EPD, the fraction of light still propagating is reduced almost to one third of the amount that entered the material, the rest being absorbed or scattered.

[0061] The signal-to-noise ratio (SNR) in a measurement is a figure of merit defined as the average value of the physical quantity of interest divided by the measurement standard deviation, which combines together all the sources of uncertainty that will be superimposed on the target signal. It provides a quantitative measure of how readable the signal of interest is, and of the minimum detectable change in the signal of interest in a certain measurement system.

[0062] Stratum corneum (SC) is the first layer of the human skin. It is mainly composed of dead cells, and under normal conditions, there is no relevant concentration of metabolites.

[0063] Electroosmosis, i.e. electroosmotic flow, is the movement of a liquid through a porous material caused by an applied electric potential. It is possible if the liquid has a non-zero net electric charge (positive or negative) globally, e.g. due to the presence of ions. The moving mass of charged particles drags fluid along with it due to the resulting osmotic pressure gradient.

[0064] Reverse iontophoresis (RI) is a practical application of electroosmosis for the treatment of interstitial fluid from the upper layers of the skin (transdermal). Electrodes apply a potential difference at the surface of the skin. Positively charged sodium ions within the IF move towards one or more negatively charged cathodes. The resulting concentration gradient within the fluid creates an osmotic pressure gradient that drives the IF with its components (e.g. metabolites) towards the one or more cathodes.

[0065] Figure 1 is a block diagram illustrating an apparatus 100 for measuring a concentration of a metabolite in interstitial fluid (IF) according to an implementation of the present application. The apparatus 100 comprises electrical means 102 and metabolite sensing means 104. The electrical means 102 are configured to determine an impedance of the skin at rest at a selected frequency using electrodes 106 placed on the skin. The electrical means 102 are configured to provide an electric current to the electrodes 106 to initiate reverse iontophoresis in the interstitial fluid under the skin. The electrical means 102 are configured to monitor a change of the impedance of the skin over time under the influence of the electric current. The metabolite sensing means 104 are configured to measure a concentration of a metabolite in the interstitial fluid under the skin when a predefined condition on the change of the impedance is met.

[0066] The device 100 improves the signal-to-noise ratio (SNR) and variability of non-invasive measurements of target molecules or substances in interstitial fluid (IF) by combining the device of electrical means 102 with a sensing head. The sensing head can act as a measurement head. The device 100 uses optical or electromagnetic light sources or beams, with electroosmosis or reverse iontophoresis (RI), to lift and capture IF under the stratum corneum (SC), measure a larger amount of target molecules, which also improves the SNR by gathering more information about the target substances. The device 100 is designed to detect metabolites by effectively laterally concentrating the metabolites between the electrodes 106, i.e., in a location where the probe signal can reach. With the probe signal or light, the device 100 targets the area with the highest concentration of metabolites (i.e., the active sensing area) by lifting the IF to the SC, applying to metabolites residing in the IF, to enhance the excitation of metabolites and reduce measurement uncertainty caused by the variability of the IF extraction path of the stratum corneum (SC). The device 100 actively controls the electroosmosis or reverse iontophoresis (RI) process to selectively lift and accumulate IF under the SC and, therefore, target metabolites or substances in the IF. The device 100 maintains a consistent distribution of IF by continuously monitoring and adjusting the skin impedance related to daily changes in the skin. The device 100 enhances the measurement consistency of target substances by monitoring changes in skin impedance through the current during optical or electromagnetic sensing processes in the IF and reacting to them.

[0067] The device 100 enhances the stability of the skin impedance and related skin properties during the measurement of target substances. The device 100 reduces the measurement variability of target substances when a small current is injected into the skin while avoiding the extraction of IF when the skin impedance decreases to a predetermined level. The device 100 ensures more consistent light loss within the stratum corneum (SC), resulting in better repeatability of metabolite excitation throughout the measurement, thereby improving the repeatability of optical or electromagnetic metabolite sensing while maintaining the non-invasive nature of the measurement. The device 100 uses a specific electrode design to control the flow density of IF and, therefore, metabolites in IF by controlling some spatial aspects of the light source, thereby optimizing the alignment of metabolites with the output of the optical probe beam or signal or maximizing metabolite excitation.

[0068] Optionally, the electrical device 102 is further configured to adjust one or more of the electrical parameters of the electrical current provided to the electrode 106 of the electrical device 102 until a predefined condition is met. The electrical parameters include the amplitude, the duration, and the duty cycle of the electrical current. The electrical device 102 is further configured to set the electrical parameter that meets the predefined condition as a setpoint for measuring the metabolite concentration. The electrical device 102 is further configured to obtain a first set of measurements of the metabolite concentration of the metabolite sensing device 104, wherein the electrical parameter is fixed at the setpoint. The electrical device 102 is further configured to obtain a second set of measurements of the metabolite concentration of the metabolite sensing device 104 by varying one or more of the electrical parameters around the setpoint. The electrical device 102 is further configured to determine a figure of merit for each measurement of the first and second sets. The electrical device 102 is further configured to update the setpoint for measuring the metabolite concentration with the varied electrical parameter if the varied electrical parameter provides the best figure of merit in the first and second sets of measurements.

[0069] Optionally, the electrical device 102 is further configured to adjust one or more of the electrical parameters of the electrical current provided to the electrode 106 of the electrical device 102 over time by keeping the variation of the impedance within a target range to maintain the predefined condition to be met with a set precision.

[0070] The device 100 uses the electrodes 106 to monitor the skin impedance in the skin (i.e. human skin) by measuring the electrical current or electricity flowing through the skin. During the monitoring of the skin impedance, the electrical device 102 adjusts the duration and the duty cycle of the electrical current or electricity flowing through the skin to keep the skin impedance within a certain target range. The certain target range can be different for each skin. When the skin impedance is low, i.e. the skin does not change its behavior over a certain period of time, the device 100 measures the target substance in the skin by performing a sensing process on the skin, whereby the device 100 directly measures the target substance in the skin without taking interstitial fluid (IF) up towards the outermost layer of the skin.

[0071] Optionally, the electrical device 102 is configured to provide the electrical current to the electrode 106 in cycles and to monitor the variation of the impedance of the skin at the end of each cycle.

[0072] Optionally, the predefined condition regarding the variation of the impedance is based on a decrease of the impedance of the skin compared to the determined impedance of the skin at rest, and / or a physiological reference dependence of the skin impedance on the electrical current at the selected frequency.

[0073] Optionally, the electrodes 106 of the electrical device 102 placed on the skin comprise a first cathode, an annular second cathode surrounding the first cathode, and an annular anode surrounding the second cathode. The metabolite sensing device 104 comprises a sensing head arranged between the first cathode and the second cathode, and the apparatus 100 is configured to selectively apply different electrical bias to each of the electrodes 106.

[0074] Optionally, the metabolite sensing device 104 comprises two or more sensing heads arranged circumferentially between the first cathode and the second cathode.

[0075] Optionally, the sensing head of the metabolite sensing device 104 comprises a light source, an annular transducer, and a conical lens configured to convert a Gaussian light beam generated by the light source into a Bessel light beam that passes through the annular transducer to the skin.

[0076] Figure 2 is a block diagram illustrating a measurement module 202 of a metabolite sensing device 200 according to an implementation of the present application. The measurement module 202 is configured to be placed on the skin. The measurement module 202 comprises a sensing head 204 and an electrode 206. The sensing head 204 is configured to measure a metabolite concentration in interstitial fluid (IF) under the skin. The electrode 206 is configured to be supplied with an electrical current to initiate reverse iontophoresis in the interstitial fluid (IF) under the skin and to determine an impedance of the skin.

[0077] The measurement module 202 of the metabolite sensing device 200 uses a photon or electromagnetic light source to enhance excitation of a target or specific substance by bringing the target or specific substance closer to the sensing head 204. The measurement module 202 of the metabolite sensing device increases the information or signal collected from the target or specific substance about the target or specific substance by lifting the target or specific substance near the sensing head 204 with the photon or electromagnetic light source. The measurement module 202 reduces attenuation of the collected signal by reducing (i.e., lifting) the distance between the target or specific substance and the sensing head 204. The measurement module 202 aligns the spatial distribution of the target or specific substance under the sensing head 204 within an active zone or region of the target or specific substance, thereby avoiding wasting excitation power or active sensing area. When the target or specific substance is concentrated within the active region, the sensing head 204 effectively excites and detects the molecules or target or specific substance, thereby maximizing the sensitivity and accuracy of the measurement of the target or specific substance.

[0078] The measurement module 202 of the metabolite sensing device contains one or more tuning parameters to optimize performance. The one or more tuning parameters include (i) the voltage difference between the plurality of electrodes, AVacN >... > AVac2 > AVac1, (ii) the distance between the electrodes, (iii) the number of electrodes, (iv) the symmetric 3D placement, and the geometry of the number of electrodes to maximize the steady state density of the flow of the IF under the active sensing area of the sensing head 204, thereby maximizing the density of the electric field lines or maximizing the current under the active sensing area of the sensing head 204. The maximized density of the electric field lines acts as a driving force for the IF to concentrate and flow from multiple directions within the skin towards the active sensing area.

[0079] The measurement module 202 provides flexibility in terms of shaping the electric field lines in order to accurately sense the target substance with the sensing head 204, as the number of electrodes can be increased in the configuration of the measurement module 202 if finer spatial control of the electric field lines is required. The number of electrodes can be designed on a flexible patch (such as polyamide, PDMS, or textile) to maximize the adhesion of the patch to the skin. Optionally, the flexible patch can be designed to accommodate multiple elements of a selected sensing head for embedding multiple sensing head configurations within the patch to provide adaptability in the configuration of the measurement module 202 of the metabolite sensing device 200.

[0080] The electrodes 206 include a first cathode, an annular second cathode surrounding the first cathode, and an annular anode surrounding the second cathode. The sensing head 204 is arranged between the first cathode and the second cathode.

[0081] The measurement module 202 includes two or more sensing heads for measuring metabolite concentrations in interstitial fluid (IF) under the skin. The two or more sensing heads are arranged circumferentially between the first cathode and the second cathode.

[0082] Figure 3 is according to an implementation of the present invention Figure 1An exemplary view 300 shows the location of the electrode 302 of the device within the skin 304. The device, including the electrode 302, is positioned on the outermost layer of the skin 304. The skin 304 comprises an outermost layer, which may be referred to as the stratum corneum (SC), an inner layer, which may be referred to as the granular layer, and an innermost layer, which may be referred to as the stratum spinosum. The electrode 302 includes an anode 306 and a cathode 308. The device assesses the skin impedance of the skin 304 by examining the flow of current or electricity through the skin 304 in a static or normal state. The electrode 302 injects current into the skin 304, causing the interstitial fluid (IF) to move upward toward the cathode 308 of the electrode 302. As the interstitial fluid (IF) moves toward the cathode 308, the skin impedance begins to decrease over time, making it possible to monitor the skin impedance of the skin 304 and track the interstitial fluid (IF) until the device reaches a specific or target substance.

[0083] Figure 4 The positioning of the product according to the present invention is in the skin 408 Figure 1 An exemplary view 400 of the device is provided. Exemplary view 400 includes an optical measurement sensing head 402 positioned on skin 408 and a reverse iontophoresis (RI) electrode 404. Optionally, the device includes an electromagnetic measurement sensing head. The RI electrode 404 is controlled by a controller 406. A reverse iontophoresis (RI) current causes interstitial fluid to move upward toward the cathode of the RI electrode 404. As the interstitial fluid moves toward the cathode, skin impedance begins to decrease over time. The device monitors the skin impedance of skin 408 and tracks the interstitial fluid until the device reaches a specific or target substance. For example, when the skin impedance at the rest of skin 408 decreases to a value of 20 to 30%, the device measures glucose, a target substance, in skin 408. When skin impedance decreases, glucose is captured in the outermost layer of skin 408. The device uses full-spectrum acquisition and averaging techniques to measure the concentration of metabolites of a target or specific substance in the interstitial fluid at the outermost layer of the skin 408, thereby reducing the signal-to-noise ratio (SNR) in the information of the target substance collected from the IF.

[0084] Figure 5A and Figure 5BExemplary views 500A and 500B show configurations of a measurement module of a metabolite sensing device according to implementations of the present application. Exemplary view 500A of a configuration of a measurement module of a metabolite sensing device includes electrodes 502A-502N and sensing heads 504A-504N. Electrodes 502A-502N include a first cathode 506, a second cathode 508, and an anode 510. Sensing heads 504A-504N can be arranged between first cathode 506 and second cathode 508. Exemplary view 500B of a measurement module of a metabolite sensing device depicts a rotated geometric view of first cathode 506, second cathode 508, anode 510, and sensing heads 504A-504N. Optionally, the measurement module provides an option to include a larger number of sensing heads 504A-504N in an empty slot.

[0085] Figure 6A and Figure 6B Exemplary views 600A and 600B show open design parameters of sensing heads 602A-602N according to implementations of the present application. Exemplary view 600A depicts sensing heads 602A-602N positioned at skin 606, where sensing heads 602A-602N include optical elements 604 arranged in a circular configuration within sensing heads 602A-602N to produce a circular beam to pass through skin 606. Optionally, the geometry of sensing heads 602A-602N can be customized or adjusted to meet requirements including a maximum matching factor, beam shape, and the like. The maximum matching factor is a match between a target or a specific substance distribution and an active sensing area. Sensing heads 602A-602N can be designed to have a concentric electrode geometry.

[0086] Exemplary view 600B depicts a rotated geometric view of sensing heads 602A-602N. Sensing heads 602A-602N include transducers 608 and a beam 610 designed in a ring geometry. For example, sensing heads 602A-602N emit a Gaussian beam, which enables sensing heads 602A-602N to convert the shape of the Gaussian beam to a Bessel beam using optical elements 604.

[0087] Figure 7A and Figure 7Bis a flowchart illustrating a method for measuring a concentration of a metabolite in interstitial fluid (IF) according to an implementation of the present application. In step 702, the impedance of the skin at rest is determined at a selected frequency using electrodes placed on the skin. In step 704, a current is provided to the electrodes to initiate a reverse iontophoresis in the interstitial fluid under the skin. In step 706, the impedance of the skin is monitored over time under the effect of the current. In step 708, when a predefined condition on the change of impedance is met, the concentration of the metabolite in the interstitial fluid under the skin is measured using a metabolite sensing device.

[0088] The method improves the signal-to-noise ratio (SNR) and variability of non-invasive measurements of target molecules or substances in interstitial fluid (IF) by combining a device of an electrical device with a sensing head. The sensing head can act as a measurement head. The method uses optical or electromagnetic light sources or beams to lift and trap IF under the stratum corneum (SC) using electroosmotic flow or reverse iontophoresis (RI), measures a larger amount of target molecules, which also improves the SNR by gathering more information about the target substances. This method effectively concentrates metabolites laterally in a position where the detection signal can reach to detect the metabolites. Using the detection signal or light, this method targets the area with the highest concentration of metabolites (i.e., the active sensing area) by lifting the IF to the SC, applies to metabolites residing in the IF, thereby enhancing the excitation of metabolites and reducing measurement uncertainty caused by interstitial fluid (IF) extraction path variability of the stratum corneum (SC). This method actively controls the electroosmotic flow or reverse iontophoresis (RI) process to selectively lift and accumulate IF under the SC and thus target metabolites or substances in the IF. By continuously monitoring and adjusting the skin impedance related to daily changes in the skin, this method maintains a consistent distribution of the IF. This method enhances the measurement consistency of the target substances by monitoring the change in skin impedance through the current during the optical or electromagnetic sensing process in the IF and reacting to it.

[0089] This method enhances the stability of the skin impedance and related skin properties during the measurement of the target substance. When the skin impedance decreases to a predetermined level, a small current is injected into the skin while avoiding extraction of the IF, which reduces the variability of the measurement of the target substance. This method ensures more consistent light loss within the stratum corneum (SC), resulting in better reproducibility of the metabolite excitation throughout the measurement, thereby improving the reproducibility of optical or electromagnetic metabolite sensing while maintaining the non-invasive nature of the measurement. This method utilizes a specific electrode design to spatially impose and control the flow density of the interstitial fluid (IF) in the upper layers of the skin, thereby spatially imposing and controlling the flow density of the metabolites contained in the IF, without the need to extract said fluid from the skin. Furthermore, the method controls certain spatial aspects of the light source to optimize the alignment of the metabolites with the output of the optical probing beam or signal, maximizing metabolite excitation.

[0090] Optionally, the method further comprises adjusting one or more of the electrical parameters of the current provided to the electrodes of the electrical device to maintain the predefined condition to meet a set accuracy by keeping the change in the impedance within a target range. The electrical parameters include the amplitude, duration and duty cycle of the current.

[0091] Optionally, providing the current to the electrodes comprises providing the current in cycles, and the monitoring the change in the impedance of the skin over time comprises determining the impedance of the skin at the end of each cycle.

[0092] Optionally, the predefined condition regarding the change in the impedance is based on a decrease in the impedance of the skin compared to the determined impedance of the skin at rest, and / or a physiological reference dependence of the skin impedance on the current at the selected frequency.

[0093] Figure 8 is an illustration of a computer system (i.e., device) in which various previously implemented aspects can be implemented. As shown, computer system 800 includes at least one processor 804 coupled to a bus 802, which can implement any suitable protocol including, for example, peripheral component interconnect (PCI), PCI-Express, accelerated graphics port (AGP), Hyper Transport, or any other bus or point-to-point communication protocol(s). Computer system 800 also includes a memory 806.

[0094] The control logic (software) and data are stored in memory 806, which can take the form of random-access memory (RAM). In the present invention, a single semiconductor platform can refer to a sole unitary semiconductor-based integrated circuit or chip that either contains all or nearly all portions of a system or device, whether a consumer electronic system or device, a computer system or device, or a special- purpose system or device. It should be understood that, as used herein, reference to a single semiconductor platform can also be a reference to a multi-chip system where each of the plurality of chips can be a single semiconductor platform. It should be further understood that, as used herein, references to a single semiconductor platform or chip do not limit the scope of the system or device to a single integrated circuit or chip, but rather, can imply that the system or device can include a single integrated circuit or chip or a plurality of integrated circuits or chips.

[0095] The computer system 800 can also include secondary storage 810. Secondary storage 810 includes a hard disk drive and a removable storage drive, representing a floppy disk drive, a magnetic tape drive, a compact disk drive, digital versatile disk (DVD) drive, recording device, universal serial bus (USB) flash memory, etc. The removable storage drive reads from and / or writes to a removable storage unit in a well-known manner.

[0096] Computer programs (also called computer control logic or software) can be stored in at least one of the memory 806 and the secondary storage 810. Such computer programs, when executed, enable the computer system 800 to perform various functions as described herein. The memory 806, the secondary storage 810, and any other storage are examples of computer-readable storage media.

[0097] In one implementation, the architectures and functionalities described in the various previous figures can be implemented in the context of the processor 804, a graphics processor coupled to the communication interface 812, an integrated circuit (not shown) that can have at least a portion of the capabilities of both the processor 804 and the graphics processor, a chipset (i.e., a group of integrated circuits designed to work and sold as a unit and to perform related functions).

[0098] Further, the architectures and functionalities described in the various previous described figures can be implemented in the context of a general purpose computer system, a circuit board system, a game console system dedicated to entertainment purposes, an application-specific system. For example, the computer system 800 can take the form of a desktop computer, a laptop computer, a server, a workstation, a game console, an embedded system.

[0099] Furthermore, the computer system 800 can take various other forms, including but not limited to a personal digital assistant (PDA) device, a mobile telephone device, a smart phone, a television, and so on. In addition, although not shown, the computer system 800 can be coupled to a network (e.g., a telecommunications network, a local area network (LAN), a wireless network, a wide area network (WAN) such as the Internet, a peer-to-peer network, cable network, and so on) for communication purposes, utilizing I / O interface 808.

[0100] It should be appreciated that the arrangement of components shown in the described figures is exemplary, and other arrangements can be made. It should also be appreciated that the various system components (and modules) defined by the claims below and shown in the various block diagrams represent components in some systems configured in accordance with the subject matter disclosed herein. For example, one or more of these system components (and modules) can be implemented in whole or in part by at least some of the components shown in the arrangements shown in the described figures.

[0101] Furthermore, while at least one of these components is implemented at least partially as an electronic hardware component, and thereby constitutes a machine, other components can be implemented in software, which, when included in an execution environment, constitutes a machine, hardware, or a combination of software and hardware.

[0102] While the present application and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the application as defined by the appended claims.

Claims

1. A device (100) for measuring the concentration of a metabolite in interstitial fluid, characterized in that, The apparatus (100) comprises: electrical means (102) for: determining an impedance of skin (304, 408, 606) at rest at a selected frequency with electrodes (106, 206, 302, 502A-502N) placed on the skin (304, 408, 606), providing a current to the electrodes (106, 206, 302, 502A-502N) to initiate reverse iontophoresis in interstitial fluid (IF) under the skin (304, 408, 606), monitoring a change of the impedance of the skin (304, 408, 606) over time under the effect of the current, metabolite sensing means (104, 200) for measuring a metabolite concentration in the interstitial fluid (304, 408, 606) under the skin when a predefined condition on the change of the impedance is met.

2. The apparatus (100) according to claim 1, characterized in that The electrical means (102) are further for: adjusting one or more of electrical parameters of the current provided to the electrodes (106, 206, 302, 502A-502N) of the electrical means (102) until the predefined condition is met, wherein the electrical parameters include an amplitude, a duration and a duty cycle of the current, setting an electrical parameter at which the predefined condition is met as a setpoint for measuring the metabolite concentration, acquiring a first set of measurements of the metabolite concentration of the metabolite sensing means (104, 200) with the electrical parameter fixed at the setpoint, acquiring a second set of measurements of the metabolite concentration of the metabolite sensing means (104, 200) by varying one or more of the electrical parameters around the setpoint, determining a figure of merit for each measurement of the first and second sets, updating the setpoint for measuring the metabolite concentration with a varying electrical parameter if the varying electrical parameter provides an optimal figure of merit in the first and second sets of measurements.

3. The apparatus (100) according to claim 1 or 2, characterized in that The electrical means (102) are further for: adjusting one or more of the electrical parameters of the current provided to the electrodes (106, 206, 302, 502A-502N) of the electrical means (102) over time by keeping the change of the impedance within a target range to maintain the predefined condition met to a set accuracy.

4. The apparatus (100) according to any one of claims 1 to 3, characterized in that The electrical means (102) are for providing the current to the electrodes (106, 206, 302, 502A-502N) in cycles and for monitoring the change of the impedance of the skin (304, 408, 606) at the end of each cycle.

5. The apparatus (100) according to any one of claims 1 to 4, characterized in that The predefined condition on the change of the impedance is based on a decrease of the impedance of the skin (304, 408, 606) compared to the determined impedance of the skin (304, 408, 606) at rest and / or a physiological reference dependence of skin impedance on the current at the selected frequency.

6. The apparatus (100) according to any one of claims 1 to 5, characterized in that The electrodes (106, 206, 302, 502A-502N) of the electrical device (102) placed on the skin (304, 408, 606) comprise a first cathode (506), an annular second cathode surrounding the first cathode (506), and an annular anode surrounding the second cathode (508), wherein the metabolite sensing device (104, 200) comprises a sensing head (204, 504A-504N, 602A-602N) arranged between the first cathode (506) and the second cathode (508), and the apparatus (100) is configured to selectively apply different electrical bias to each of the electrodes (106, 206, 302, 502A-502N).

7. The apparatus (100) according to claim 6, characterized in that The metabolite sensing device (104, 200) comprises two or more sensing heads (204, 504A-504N, 602A-602N) arranged circumferentially between the first cathode (506) and the second cathode (508).

8. The apparatus (100) according to claim 6, characterized in that The sensing head (204, 504A-504N, 602A-602N) of the metabolite sensing device (104, 200) comprises a light source, an annular transducer, and a conical lens configured to convert a Gaussian beam generated by the light source into a Bessel beam that passes through the annular transducer to the skin (304, 408, 606).

9. A method of measuring a concentration of a metabolite in interstitial fluid, characterized by, The method comprises: determining an impedance of the skin (304, 408, 606) at rest at a selected frequency with electrodes (106, 206, 302, 502A-502N) of an electrical device (102) placed on the skin (304, 408, 606), providing an electrical current to the electrodes (106, 206, 302, 502A-502N) to initiate reverse iontophoresis in interstitial fluid (IF) under the skin (304, 408, 606), monitoring a change in the impedance of the skin (304, 408, 606) over time under the influence of the electrical current, measuring a metabolite concentration in the interstitial fluid (304, 408, 606) under the skin with a metabolite sensing device (104, 200) when a predefined condition on the change in the impedance is met.

10. The method of claim 9, wherein, Further comprising: adjusting one or more of electrical parameters of the electrical current provided to the electrodes (106, 206, 302, 502A-502N) of the electrical device (102) to maintain the predefined condition to be met to a set accuracy by keeping the change in the impedance within a target range, wherein the electrical parameters comprise an amplitude, a duration, and a duty cycle of the electrical current.

11. The method according to claim 9 or 10, characterized in that, The providing of the current to the electrodes (106, 206, 302, 502A-N) comprises providing the current in cycles, and the monitoring of the change of the impedance of the skin (304, 408, 606) over time comprises determining the impedance of the skin (304, 408, 606) at the end of each cycle.

12. The method according to any one of claims 9 to 11, characterized in that, The predefined condition on the change of the impedance is based on a decrease of the impedance of the skin (304, 408, 606) compared to the determined impedance of the skin (304, 408, 606) at rest, and / or a physiological reference dependence of the skin impedance on the current at the selected frequency.

13. A measurement module (202) of a metabolite sensing device (104, 200), characterized by The measurement module is for placement on a skin (304, 408, 606) and comprises: a sensing head (204, 504A-N, 602A-N) for measuring a metabolite concentration in interstitial fluid (IF) under the skin (304, 408, 606), an electrode (106, 206, 302, 502A-N) for being provided with a current to initiate a reverse iontophoresis in the interstitial fluid under the skin (304, 408, 606) and for determining an impedance of the skin (304, 408, 606).

14. The measurement module (202) according to claim 13, characterized in that The electrode (106, 206, 302, 502A-N) comprises a first cathode (506), an annular second cathode surrounding the first cathode (506), and an annular anode surrounding the second cathode (508), wherein the sensing head (204, 504A-N, 602A-N) is arranged between the first cathode (506) and the second cathode (508).

15. The measurement module of claim 14, wherein, The measurement module (104, 200) comprises two or more sensing heads (204, 504A-N, 602A-N) for measuring the metabolite concentration in the interstitial fluid (304, 408, 606) under the skin, wherein the two or more sensing heads (204, 504A-N, 602A-N) are arranged circumferentially between the first cathode (506) and the second cathode (508). The measurement module (104, 200) comprises two or more sensing heads (204, 504A-N, 602A-N) for measuring the metabolite concentration in the interstitial fluid (304, 408, 606) under the skin, wherein the two or more sensing heads (204, 504A-N, 602A-N) are arranged circumferentially between the first cathode (506) and the second cathode (508).

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