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WO2024260547A1 - Appareil et procédé de mesure de la concentration de métabolites dans un fluide interstitiel - Google Patents

Appareil et procédé de mesure de la concentration de métabolites dans un fluide interstitiel Download PDF

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Publication number
WO2024260547A1
WO2024260547A1 PCT/EP2023/066751 EP2023066751W WO2024260547A1 WO 2024260547 A1 WO2024260547 A1 WO 2024260547A1 EP 2023066751 W EP2023066751 W EP 2023066751W WO 2024260547 A1 WO2024260547 A1 WO 2024260547A1
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Prior art keywords
skin
impedance
metabolite
cathode
electrodes
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English (en)
Inventor
Matteo CESARINI
Mir Mehdi SEYEDEBRAHIMI
Alexandra ALEXANDROVA
Philippe Maire
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Huawei Technologies Co Ltd
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Huawei Technologies Co Ltd
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Priority to PCT/EP2023/066751 priority Critical patent/WO2024260547A1/fr
Publication of WO2024260547A1 publication Critical patent/WO2024260547A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/14507—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue specially adapted for measuring characteristics of body fluids other than blood
    • A61B5/1451—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid
    • A61B5/14514—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid using means for aiding extraction of interstitial fluid, e.g. microneedles or suction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves
    • A61B5/053—Measuring electrical impedance or conductance of a portion of the body
    • A61B5/0531—Measuring skin impedance
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using optical sensors, e.g. spectral photometrical oximeters

Definitions

  • the disclosure relates generally to a measuring system, and more particularly, the disclosure relates to an apparatus for measuring metabolite concentration in an interstitial fluid and a method of measuring metabolite concentration in an interstitial fluid.
  • the disclosure also relates to a measuring module of a metabolite sensing device.
  • Interstitial Fluid is a water liquid that surrounds cells and tissues throughout bodies, including the skin.
  • the water liquid includes different substances, including metabolites.
  • a composition or mixture of the IF may consist of a water solvent containing sugars, salts, fatty acids, amino acids, coenzymes, hormones, neurotransmitters, white blood cells, cell waste products, and metabolites.
  • the composition or mixture of the IF in the skin relies on an exchange of substances between the cells, tissues, and bloodstream, for a metabolic process occurring in our bodies.
  • Measuring the concentration of the metabolites in the IF may provide information on the substances. For example, tracking glucose levels in the IF can help to track the glucose levels in the blood of diabetic patients.
  • an invasive measuring system and a non-invasive measuring system have been developed. The invasive measuring system involves obtaining a small sample of the IF through an invasive procedure, with a skin prick or micro-dialysis with frequent needle-based methods.
  • the non-invasive measurement system acts as an alternative to the needle-based methods, where the non-invasive measurement system consists of a light source including one or more sensors and readout electronics, which are positioned on the skin to measure a specific molecule or the substance in the blood using the light source that operates within an optical range or an electromagnetic range.
  • the light source stimulates the specific molecule or the substance in the blood, including glucose or other metabolites, and enables the one or more sensors to collect the information on the substances from the stimulation of the specific molecule in the blood.
  • Couplers may also be incorporated into the non-invasive measurement system as an additional component to optimize the transmission of a return signal from the skin to the one or more sensors.
  • the readout electronics are utilized to process, read and display the collected information.
  • a light source emits radiation at specific wavelengths to interact with the specific molecule or substances, such as glucose.
  • the specific molecule or substances can exhibit energy in the form of acoustic waves in a certain frequency range, for example, the Megahertz, MHz, range which are captured by the one or more sensors or microphones through the couplers to monitor the metabolites in the blood.
  • the PA system monitors the metabolism in the blood by analyzing the acoustic waves.
  • the Photoacoustic, PA is a phenomenon by which molecules, when excited by a specific wavelength of light emitted by the light source, release a portion of the collected energy as molecular thermal agitation. The molecular thermal agitation releases mechanical waves i.e. the acoustic waves, which can be collected for the information about the specific molecule or substances.
  • the non-invasive measurement system excites a light source at multiple wavelengths and captures a return signal in various forms, including reflected and scattered light sources, as well as the light emitted by the molecule due to Raman shifts.
  • the Raman shift exhibits an optical response when the light interacts with the molecule or substances.
  • the optical response is the behavior or characteristics of the molecule or substances when the light is emitted on the molecule or substances.
  • the light source may accidentally interact with other substances present in the body, instead of the specific molecule.
  • the existing non-invasive measurement systems utilize the light source as a probing signal which may yield false responses due to the presence of different substances in the skin, leading to a lack of specificity.
  • a Mid-Infrared, Mid-IR Photoacoustic sensing system measures the false response while measuring the glucose from lipids.
  • the Mid-Infrared, Mid- IR is the light source, or equivalently electromagnetic radiation, with wavelengths falling in a range of 3 micrometres to 10 micrometres approximately in a form of photons.
  • the probing signal which is also referred to as an excitation signal, in most cases consists of laser light, which constitutes an optical signal, capable of reaching the target molecule.
  • the existing non-invasive measurement system poses a lack of signal -to-noise ratio, SNR, as within signals received by the one or more sensors, the useful information about the substance of interest is superimposed to other content which results from the interaction of the same probing signal with the environment surrounding the substance, and constitutes a background noise.
  • SNR signal -to-noise ratio
  • the existing non-invasive measurement system poses the attenuation, which arises when light sources or electromagnetic waves are utilized to detect and analyze metabolites in the skin. For example, in the case of Mid-IR systems, the probing signal is able to penetrate with an Effective Penetration Depth, EPD in the skin in a range of 30-50 micrometers depth.
  • the power of the probing signal is attenuated by approximately 1/e, and the concentration of the metabolites is significantly low.
  • the molecule responds with a 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 proportional to the portion of the probing signal which reaches and is effectively absorbed by the targt molecule.
  • the limited power available for the light source in combination with the attenuation occurring in the mentioned scenarios often leads to an SNR for the returning signal which is too low to perform a desired detection.
  • the presence of the water liquid and the manner in which the PA system is connected to the skin can potentially pose challenges to the acoustic waves. If there are any air gaps between the skin and the electrodes used for connection, may impact the probing signal and result in inaccuracy in the information of the substance.
  • the presence of unwanted fluorescence or the emission of the light source is triggered by the probing signal for measurement of the substance.
  • the unwanted fluorescence can create background noise, making it more challenging for the acoustic waves to accurately read the information about the substance.
  • the one or more sensors encounter difficulties in accurately reading information about the substances from the molecule’s response to an energy emission.
  • a process of separating the molecule’s response from the energy emission is known as deconvolution, which is complex due to the presence of various factors like different substances and background noise.
  • determining a desired response which is an accurate measurement of the substance, and a false response which is an inaccurate measurement of the substance is crucial.
  • the desired response and the false response from the water liquid can fluctuate significantly by changes in ambient parameters such as temperature, leading to impacting the reliability of the measurements of the substances.
  • the properties of the skin including thickness and other characteristics, can also rapidly respond to environmental factors leading to variations within a single day.
  • the positioning of the one or more sensors on the skin can be affected by the skin’ s inhomogeneity, such as the presence of hair follicles and sweat glands laterally, as well as different skin layers vertically, which can affect measurement consistency.
  • individuals with different skin types can exhibit variations in lipid levels which can introduce variability in measurements when using a photoacoustic sensing system.
  • directly extracting the IF from the surface of the skin can impact measurement repeatability due to (i) the interstitial fluid that follows multiple pathways, including hair follicles and glands which exhibit intra-day and inter-person variability, affecting the measurement of the substance, and (ii) an outermost layer of the skin, known as Stratum Comeum, SC exhibits continuous variations in thickness, density, and morphology throughout the day. For example, the thickness of the SC can fluctuate significantly, ranging from 0.1 times to 5 times leading to inaccuracies and inconsistencies in the measurements of the substances.
  • the GlucoWatch3 device which was Food and Drug Administration, FDA- approved, utilizes Reverse Iontophoresis, RI electrodes to extract the IF from the skin.
  • the GlucoWatch3 device was discontinued due to issues with non-repeatability measurements.
  • the needles are used to extract the IF from the skin, results in loss of the non-invasiveness of the measurement.
  • all existing solutions focussed on measuring the substances are designed specifically for electrochemical sensing methods, which limits the flexibility to be used with different measurement techniques.
  • the disclosure also relates to a measuring module of a metabolite sensing device. This object is achieved by the features of the independent claims. Further, implementation forms are apparent from the dependent claims, the description, and the figures.
  • an apparatus for measuring metabolite concentration in an interstitial fluid IF.
  • the apparatus includes an electrical device and a metabolite sensing device.
  • the electrical device is configured for determining an impedance of skin at rest at a selected frequency with electrodes placed on the skin.
  • the electrical device is configured for supplying a current to the electrodes for initiating reverse iontophoresis in the interstitial fluid under the skin.
  • the electrical device is configured for monitoring a change of the impedance of the skin with time under an effect of the current.
  • the metabolite sensing device is configured for measuring a metabolite concentration in the interstitial fluid under the skin when a pre-defined condition on the change of the impedance is met.
  • the apparatus improves a signal-to-noise ratio, SNR, and variability in non-invasive measurements of target molecules or substances in the Interstitial Fluid, IF, by combining an apparatus of the electrical device with a non-invasive sensing head.
  • the sensing head may act as a measurement head.
  • the apparatus measures a higher quantity of the target molecules through an optical or electromagnetic light source or beam by lifting and trapping the IF below a Stratum Comeum, SC with Electro-Osmotic Flow or Reverse Iontophoresis, RI, which also improves the SNR by collecting more information on the target substance.
  • the apparatus is designed to detect metabolites by effectively concentrating them laterally in a position accessible by the probing signal.
  • the apparatus targets an area of the highest metabolite concentration i.e. active sensing area by lifting the IF to the SC that applies to the metabolite residing in the IF which leads to an enhanced excitation of the metabolite and reduces the measurement uncertainties caused by the IF extraction pathways variability of the Stratum Comeum, SC.
  • the apparatus actively controls the Electro-Osmotic Flow or Reverse Iontophoresis, RI process that selectively lifts and accumulate the target metabolites or the substances below the SC.
  • the apparatus maintains a consistent distribution of the IF.
  • the mentioned adjusting is possible since, as previously shown in literature, RI parameters like duration, duty cycle, and amplitude of the current injection have an effect on the skin and its impedance.
  • the apparatus enhances the measurement consistency of the target substance by monitoring and reacting to changes in the skin impedance through the current during optical or electromagnetic sensing in the IF.
  • the apparatus enhances the stability of the skin impedance and related skin properties during the measurement of the target substance.
  • the apparatus reduces measurement variability of the target substance when the skin impedance decreases to a pre-determined level while injecting a small current into the skin and while avoiding extraction of the IF.
  • the apparatus ensures a more consistent light loss within the Stratum Comeum, SC resulting in a better repeatability of excitation of the metabolite across measurements, resulting in an improved repeatability in the optical or electromagnetic metabolite sensing, while maintaining the measurements non- invasive.
  • the apparatus utilizes a specific electrode design to spatially impose and control a flow density of the IF in the upper layers of the skin, and thus of the metabolite contained in it, without extracting said fluid from the skin.
  • the apparatus controls some spatial aspects of the light source, optimizing the alignment of the metabolites with an output of the optical probing beam or signal maximizing the metabolite excitation.
  • the electrical device is further configured for adapting one or more of electrical parameters of the current supplied to the electrodes of the electrical device until the pre-defined condition is met.
  • the electrical parameters include an amplitude, a duration, and a duty cycle of the current.
  • the electrical device is further configured for setting the electrical parameters with which the pre-defined condition is met as a setpoint for measuring the metabolite concentration.
  • the electrical device is further configured for obtaining a first set of measurements of the metabolite concentration of the metabolite sensing device with the electrical parameters fixed at the setpoint.
  • the electrical device is further configured for obtaining a second set of measurements of the metabolite concentration of the metabolite sensing device with varying one or more of the electrical parameters around the setpoint.
  • the electrical device is further configured for determining a Figure of Merit for each measurement of the first and second sets.
  • the electrical device is further configured for updating the setpoint for measuring the metabolite concentration with the varied electrical parameters if the varied electrical parameters provide an optimal Figure of Merit among the first and second sets of measurements.
  • the electrical device is further configured for adapting one or more of the electrical parameters of the current supplied to the electrodes of the electrical device with time to maintain the pre-defined condition met within a set precision by keeping the change of the impedance within a target range.
  • the electrical device is configured for supplying the current to the electrodes in cycles and for monitoring the change of the impedance of the skin at the end of each cycle.
  • the pre-defined condition on the change of the impedance is based on a decrease of the impedance of the skin as compared with the determined impedance of the skin at rest and/or a physiological reference dependence of a skin impedance from a current at the selected frequency.
  • the electrodes of the electrical device placed on the skin include the following minimum set of electrodes: a first cathode, a ring-shaped second cathode enclosing the first cathode, and a ring-shaped anode enclosing the second cathode.
  • Further electrodes may be added to ensure matching between constraints in the electrical front-end and, for example, requirements in terms of field distribution profile and/or further case-specific requirements.
  • the metabolite sensing device includes a sensing head arranged in-between the first cathode and the second cathode, and the apparatus is configured for selectively applying a different electrical bias to each of the electrodes.
  • the metabolite sensing device includes two or more sensing heads arranged circumferentially in-between the first cathode and the second cathode.
  • the sensing head of the metabolite sensing device includes a light source, a ringshaped transducer, and an axicon configured for converting a Gaussian light beam generated by the light source into a Bessel light beam passing through the ring-shaped transducer to the skin.
  • a method of measuring metabolite concentration in an interstitial fluid includes determining an impedance of a skin at rest at a selected frequency with electrodes of an electrical device placed on the skin.
  • the method includes supplying a current to the electrodes for initiating reverse iontophoresis in an interstitial fluid under the skin.
  • the method includes monitoring a change in the impedance of the skin with time under an effect of the current.
  • the method includes measuring a metabolite concentration in the interstitial fluid under the skin with a metabolite sensing device when a pre-defined condition on the change of the impedance is met.
  • This method improves a signal -to-noise ratio, SNR, and variability in non-invasive measurements of target molecules or substances in the Interstitial Fluid, IF, by combining an apparatus of the electrical device with a sensing head.
  • the sensing head may act as a measurement head.
  • This method excites and measures a higher quantity of the target molecules through an optical or electromagnetic light source or beam by lifting and trapping the IF below a Stratum Comeum, SC with Electro-Osmotic Flow or Reverse Iontophoresis, RI, which also improves the SNR by collecting more information on the target substance.
  • This method detects metabolites by effectively concentrating them laterally in a position accessible by the probing signal.
  • this method targets an area of the highest metabolite concentration i.e. active sensing area, by lifting the IF to the SC that applies to the metabolite residing in the IF which leads to an enhanced excitation of the metabolite, and reduces the measurement uncertainties caused by the Interstitial Fluid, IF extraction pathways variability of the Stratum Corneum, SC.
  • This method actively controls the Electro-Osmotic Flow or Reverse Iontophoresis, RI process that selectively lifts and accumulates the IF and thus the target metabolites in it or the substances below the SC.
  • This method maintains a consistent distribution of the IF.
  • This method enhances the measurement consistency of the target substance by monitoring and reacting to changes in the skin impedance through the current during optical or electromagnetic sensing in the IF.
  • This method enhances the stability of the skin impedance and related skin properties during the measurement of the target substance.
  • This method reduces measurement variability of the target substances when the skin impedance decreases to a pre-determined level while injecting a small current into the skin and while avoiding extraction of the IF.
  • This method ensures a more consistent light loss within the Stratum Corneum, SC resulting in a better repeatability of excitation of the metabolite across measurements, resulting in an improved repeatability in the optical or electromagnetic metabolite sensing, while maintaining the measurements non- invasive.
  • This method utilizes a specific electrode design to spatially impose and control a flow density of the Interstitial Fluid, IF, in the upper layers of the skin, and thus of the metabolite contained in it, without extracting said fluid from the skin. Moreover, the method controls some spatial aspects of the light source, optimizing the alignment of the metabolites with an output of the optical probing beam or signal maximizing the metabolite excitation.
  • the method further includes adapting one or more of electrical parameters of the current supplied to the electrodes of the electrical device to maintain the pre-defined condition met within a set precision by keeping the change of the impedance within a target range.
  • the electrical parameters include an amplitude, a duration, and a duty cycle of the current.
  • supplying the current to the electrodes includes supplying the current in cycles, and the monitoring of the change of the impedance of the skin with time includes determining the impedance of the skin at the end of each cycle.
  • the pre-defined condition on the change of the impedance is based on a decrease of the impedance of the skin as compared with the determined impedance of the skin at rest and/or a physiological reference dependence of a skin impedance from a current at the selected frequency.
  • a measuring module of a metabolite sensing device is being configured for placing on a skin.
  • the measuring module includes a sensing head and electrodes.
  • the sensing head is configured for measuring a metabolite concentration in an interstitial fluid, IF under the skin.
  • the electrodes are configured for being supplied with a current for initiating reverse iontophoresis in the interstitial fluid under the skin and used to determine an impedance of the skin.
  • the measuring module of the metabolite sensing device enhances an excitation of a target or specific substance using a photonic or electromagnetic light source, which is enhanced by bringing the target or specific substance closer to the sensing head.
  • the measuring module of the metabolite-sensing device is able to collect increased information or signal about the target or specific substance collected from the target or specific substance through the photonic or electromagnetic light source by lifting the target or specific substance in proximity to the sensing head.
  • the measuring module reduces the attenuation of the collected signal by reducing, i.e. lifting, the distance between the target or specific substance and the sensing head.
  • the measuring module aligns a spatial distribution of the target or specific substance below the sensing head within an active region or area of the target or specific substance, which avoids wasting excitation power or active sensing surface.
  • the sensing head effectively excites and detects the molecules or the target or specific substance, thus maximizing sensitivity and accuracy of measurements of the target or specific substance.
  • the measuring module of the metabolite-sensing device incorporates one or more tuning parameters to optimize the performance.
  • the one or more tuning parameters include (i) a voltage difference between multiple electrodes, AVacN > . . . > AVac2 > AVacl, (ii) a distance between electrodes, (iii) a number of electrodes, (iv) a reciprocal 3D placement, and geometry of the number of electrodes, to maximize a steady-state density of a flow of the IF below the active sensing area of the sensing head, for example by maximizing a density of electric field lines or the current below 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, causing the IF to concentrate and flow towards the active sensing area from multiple directions within the skin.
  • the electrodes include a first cathode, a ring-shaped second cathode enclosing the first cathode, and a ring-shaped anode enclosing the second cathode.
  • the sensing head is arranged in-between the first cathode and the second cathode.
  • the measuring module includes two or more sensing heads configured for measuring the metabolite concentration in the interstitial fluid under the skin.
  • the two or more sensing heads are arranged circumferentially in-between the first cathode and the second cathode.
  • the apparatus and the method for measuring the metabolite concentration in the IF improves the consistency of the measurements of the substance in the IF increases the signal-to-noise ratio, SNR, of information about the substance, and stabilizes the impedance of the skin.
  • FIG.1 is a block diagram that illustrates an apparatus for measuring metabolite concentration in an Interstitial Fluid, IF in accordance with an implementation of the disclosure
  • FIG. 2 is a block diagram that illustrates a measuring module of a metabolite sensing device in accordance with an implementation of the disclosure
  • FIG. 3 is an exemplary view of a position of electrodes of an apparatus of FIG. 1 within skin in accordance with an implementation of the disclosure
  • FIG. 4 is an exemplary view of an apparatus of FIG. 1 positioned in skin in accordance with an implementation of the disclosure
  • FIGS. 5 A and 5B illustrate exemplary views of a configuration of a measuring module of a metabolite-sensing device in accordance with an implementation of the disclosure
  • FIGS. 6 A and 6B illustrate exemplary views of an open design parameter of sensing heads in accordance with an implementation of the disclosure
  • FIGS. 7 A and 7B are flowcharts that illustrate a method for measuring metabolite concentration in an Interstitial Fluid, IF in accordance with an implementation of the disclosure
  • FIG. 8 is an illustration of a computer system in which the various architectures and functionalities of the various previous implementations may be implemented.
  • Implementations of the disclosure provide an apparatus and method for measuring metabolite concentration in an interstitial fluid.
  • a process, a method, a system, a product, or a device that includes a series of steps or units is not necessarily limited to expressly listed steps or units but may include other steps or units that are not expressly listed or that are inherent to such process, method, product, or device.
  • Interstitial Fluid is the liquid that surrounds cells and tissues throughout the body (including skin).
  • IF consists of a water solvent containing sugars, salts, fatty acids, amino acids, coenzymes, hormones, neurotransmitters, white blood cells, cell waste-products, and metabolites.
  • IF composition depends on exchanges between cells in the tissue and blood, so it is linked to metabolic processes.
  • Photoacoustic, PA is the phenomenon by which molecules excited with light at specific wavelengths release part of the collected energy in the form of molecular thermal agitation. This agitation releases mechanical (acoustic) waves which can be collected for information.
  • Spectroscopy is a broad set of techniques that use light at specific wavelengths of interaction to excite target molecules.
  • the molecule responds with energy emission in a certain form (heat, light, acoustic waves) and with certain time-domain and frequency-domain characteristics. This energy is collected to obtain information about the molecule, for example, its concentration, or some specificity in its composition, among others.
  • Probing signal is the excitation signal used in spectroscopy, to trigger a characteristic response signal from the molecule, which is then collected.
  • the probing signal consists of laser light (optical signal), and in all cases it must reach the target molecule.
  • Mid-Infrared is light, or equivalently electromagnetic radiation, with wavelengths falling in the approximate range of 3 micrometres to 10 micrometres. It travels in the form of photons.
  • EPD Effective Penetration Depth
  • Signal-to-Noise Ratio is a figure of merit defined as the average value of the physical quantity of interest, divided by the measurement standard deviation, the latter combining all the sources of uncertainty superimposed to the target signal. It provides a quantitative metric of how readable is the signal of interest and which is its minimum detectable variation in a certain measurement system.
  • SC is the first layer of the human skin. It mostly consists of dead cells and does not have a relevant concentration of metabolites in normal conditions.
  • Electro-Osmosis is electro-osmotic flow is the motion of liquid induced by an applied electrical potential across a porous material. It is possible if the liquid globally has a non-zero net electrical charge (positive or negative), for example, due to the presence of ions. The moving mass of the charged particles “drags” the fluid with it due to the creation of an osmotic pressure gradient.
  • RI Reverse Iontophoresis, RI is the practical application of electro-osmosis for the manipulation of interstitial fluid from the upper layers of the skin (transdermal). Electrodes apply a potential difference across the skin surface. The positively charged sodium ions within the IF move towards the negatively charged cathode(s). The resulting concentration gradient within the fluid creates an osmotic pressure gradient that drives IF towards the cathode(s), carrying its components with it, e. g. metabolites.
  • FIG.l is a block diagram that illustrates an apparatus 100 for measuring metabolite concentration in an Interstitial Fluid, IF in accordance with an implementation of the disclosure.
  • the apparatus 100 includes an electrical device 102 and a metabolite sensing device 104.
  • the electrical device 102 is configured for determining an impedance of a skin at rest at a selected frequency with electrodes 106 placed on the skin.
  • the electrical device 102 is configured for supplying a current to the electrodes 106 for initiating reverse iontophoresis in the interstitial fluid under the skin.
  • the electrical device 102 is configured for monitoring a change of the impedance of the skin with time under an effect of the current.
  • the metabolite sensing device 104 is configured for measuring a metabolite concentration in the interstitial fluid under the skin when a pre-defined condition on the change of the impedance is met.
  • the apparatus 100 improves a signal -to-noise ratio, SNR, and variability in non-invasive measurements of target molecules or substances in the Interstitial Fluid, IF, by combining an apparatus of the electrical device 102 with a sensing head.
  • the sensing head may act as a measurement head.
  • the apparatus 100 measures a higher quantity of the target molecules through an optical or electromagnetic light source or beam by lifting and trapping the IF below a Stratum Comeum, SC with Electro-Osmotic Flow or Reverse Iontophoresis, RI, which also improves the SNR by collecting more information on the target substance.
  • the apparatus 100 is designed to detect metabolites by effectively concentrating them laterally between the electrodes 106, i.e. in a position accessible by the probing signal.
  • the apparatus 100 targets an area of the highest metabolite concentration i.e. active sensing area by lifting the IF to the SC that applies to the metabolite residing in the IF which leads to an enhanced excitation of the metabolite and reduces the measurement uncertainties caused by the IF extraction pathways variability of the Stratum Comeum, SC.
  • the apparatus 100 actively controls the Electro-Osmotic Flow or Reverse Iontophoresis, RI process that selectively lifts and accumulates the IF and thus the target metabolites in it or the substances below the SC.
  • the apparatus 100 maintains a consistent distribution of the IF.
  • the apparatus 100 enhances the measurement consistency of the target substance by monitoring and reacting to changes in the skin impedance through the current during optical or electromagnetic sensing in the IF.
  • the apparatus 100 enhances the stability of the skin impedance and related skin properties during the measurement of the target substance.
  • the apparatus 100 reduces measurement variability of the target substance when the skin impedance decreases to a pre-determined level while injecting a small current into the skin and while avoiding extraction of the IF.
  • the apparatus 100 ensures a more consistent light loss within the Stratum Corneum, SC resulting in a better repeatability of excitation of the metabolite across measurements, resulting in an improved repeatability in the optical or electromagnetic metabolite sensing, while maintaining the measurements non-invasive.
  • the apparatus 100 utilizes a specific electrode design to control a flow density of the IF and thus the metabolite in it by controlling some spatial aspects of the light source, optimizing the alignment of the metabolites with an output of the optical probing beam or signal maximizing the metabolite excitation.
  • the electrical device 102 is further configured for adapting one or more of electrical parameters of the current supplied to the electrodes 106 of the electrical device 102 until the pre-defined condition is met.
  • the electrical parameters include an amplitude, a duration, and a duty cycle of the current.
  • the electrical device 102 is further configured for setting the electrical parameters with which the pre-defined condition is met as a setpoint for measuring the metabolite concentration.
  • the electrical device 102 is further configured for obtaining a first set of measurements of the metabolite concentration of the metabolite sensing device 104 with the electrical parameters fixed at the setpoint.
  • the electrical device 102 is further configured for obtaining a second set of measurements of the metabolite concentration of the metabolite sensing device 104 with varying one or more of the electrical parameters around the setpoint.
  • the electrical device 102 is further configured for determining a Figure of Merit for each measurement of the first and second sets.
  • the electrical device 102 is further configured for updating the setpoint for measuring the metabolite concentration with the varied electrical parameters if the varied electrical parameters provide an optimal Figure of Merit among the first and second sets of measurements.
  • the electrical device 102 is further configured for adapting one or more of the electrical parameters of the current supplied to the electrodes 106 of the electrical device 102 with time to 102 maintain the pre-defined condition met within a set precision by keeping the change of the impedance within a target range.
  • the apparatus 100 monitors the skin impedance in the skin i.e. human skin, using the electrodes 106 by measuring the current or electricity that flows through the skin. During monitoring of the skin impedance, the electrical device 102 adjusts the duration and duty cycle of the current or electricity that flows through the skin to maintain the skin impedance within a specific target range. The specific target range may vary for each skin.
  • the apparatus 100 measures a target substance in the skin by performing a sensing process on the skin when the skin impedance is low i.e. the skin does not change its behavior during a certain period, thereby, the apparatus 100 measures the target substance directly in the skin without taking the interstitial fluid, IF upwards towards the outermost layer of the skin.
  • the electrical device 102 is configured for supplying the current to the electrodes 106 in cycles and for monitoring the change of the impedance of the skin at the end of each cycle.
  • the pre-defined condition on the change of the impedance is based on a decrease of the impedance of the skin as compared with the determined impedance of the skin at rest and/or a physiological reference dependence of a skin impedance from a current at the selected frequency.
  • the electrodes 106 of the electrical device 102 placed on the skin include a first cathode, a ring-shaped second cathode enclosing the first cathode, and a ring-shaped anode enclosing the second cathode.
  • the metabolite sensing device 104 includes a sensing head arranged in-between the first cathode and the second cathode, and the apparatus 100 is configured for selectively applying different electrical bias to each of the electrodes 106.
  • the metabolite sensing device 104 includes two or more sensing heads arranged circumferentially in-between the first cathode and the second cathode.
  • the sensing head of the metabolite sensing device 104 includes a light source, a ring-shaped transducer, and an axicon configured for converting a Gaussian light beam generated by the light source into a Bessel light beam passing through the ring-shaped transducer to the skin.
  • FIG. 2 is a block diagram that illustrates a measuring module 202 of a metabolite sensing device 200 in accordance with an implementation of the disclosure.
  • the measuring module 202 is being configured for placing on a skin.
  • the measuring module 202 includes a sensing head 204 and electrodes 206.
  • the sensing head 204 is configured for measuring a metabolite concentration in an interstitial fluid, IF under the skin.
  • the electrodes 206 are configured for being supplied with a current for initiating reverse iontophoresis in the interstitial fluid, IF under the skin and used to determine an impedance of the skin.
  • the measuring module 202 of the metabolite sensing device 200 enhances an excitation of a target or specific substance using a photonic or electromagnetic light source, which is enhanced by bringing the target or specific substance closer to the sensing head 204.
  • the measuring module 202 of the metabolite-sensing device increases information or signal about the target or specific substance collected from the target or specific substance through the photonic or electromagnetic light source by lifting the target or specific substance in proximity to the sensing head 204.
  • the measuring module 202 reduces the attenuation of the collected signal by reducing, i.e. lifting, the distance between the target or specific substance and the sensing head 204.
  • the measuring module 202 aligns a spatial distribution of the target or specific substance below the sensing head 204 within an active region or area of the target or specific substance, which avoids wasting excitation power or active sensing surface.
  • the sensing head 204 effectively excites and detects the molecules or the target or specific substance, thus maximizing sensitivity and accuracy of measurements of the target or specific substance.
  • the measuring module 202 of the metabolite-sensing device incorporates one or more tuning parameters to optimize the performance.
  • the one or more tuning parameters include (i) a voltage difference between multiple electrodes, AVacN > . . . > AVac2 > AVacl, (ii) a distance between electrodes, (iii) a number of electrodes, (iv) a reciprocal 3D placement, and geometry of the number of electrodes, to maximize a steady-state density of a flow of the IF below the active sensing area of the sensing head 204, thereby maximizing a density of electric field lines or the current below 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, causing the IF to concentrate and flow towards the active sensing area from multiple directions within the skin.
  • the measuring module 202 provides flexibility in shaping the electric field lines for accurately sensing the target substance with the sensing head 204, as the number of the electrodes can be increased in a configuration of the measuring module 202 if finer spatial control of the electric field lines is required.
  • the number of electrodes may be designed on a flexible patch like polyamide, PDMS, or textile to maximize patch adherence to the skin.
  • 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 measuring module 202 of the metabolite-sensing device 200.
  • the electrodes 206 include a first cathode, a ring-shaped second cathode enclosing the first cathode, and a ring-shaped anode enclosing the second cathode.
  • the sensing head 204 is arranged in-between the first cathode and the second cathode.
  • the measuring module 202 includes two or more sensing heads configured for measuring the metabolite concentration in the interstitial fluid, IF under the skin.
  • the two or more sensing heads are arranged circumferentially in-between the first cathode and the second cathode.
  • FIG. 3 is an exemplary view 300 of a position of electrodes 302 of an apparatus of FIG. 1 within skin 304 in accordance with an implementation of the disclosure.
  • the apparatus including the electrodes 302 are positioned on an outmost layer of the skin 304.
  • the skin 304 includes the outmost layer which may be called a Stratum Comeum, SC, an inner layer which may be called a Stratum Granulosum, and an inner most layer which may be called a Stratum Spinosum.
  • the electrodes 302 includes an anode 306 and a cathode 308.
  • the apparatus evaluates a skin impedance of the skin 304 by examining the flow of current or electricity through the skin 304 at a rest state or a normal state.
  • the electrodes 302 inject the current into the skin 304 which moves the Interstitial Fluid, IF upwards towards the cathode 308 of the electrodes 302.
  • the skin impedance starts to lower over time, as the Interstitial Fluid, IF moves towards the cathode 308, which enables monitoring of the skin impedance of the skin 304 and tracking the Interstitial Fluid, IF until the apparatus reaches a specific or target substance.
  • FIG. 4 is an exemplary view 400 of an apparatus of FIG. 1 positioned in skin 408 in accordance with an implementation of the disclosure.
  • the exemplary view 400 includes an optical measurement sensing head 402, and a Reverse Iontophoresis, RI electrode 404 that are positioned on the skin 408.
  • the apparatus includes an electromagnetic measurement sensing head.
  • the RI electrode 404 is controlled by a controller 406.
  • the Reverse Iontophoresis, RI current moves the interstitial fluid upwards towards a cathode of the RI electrodes 404.
  • the skin impedance starts to lower over time, as the interstitial fluid moves towards the cathode.
  • the apparatus monitors the skin impedance of the skin 408 and tracks the interstitial fluid until the apparatus reaches a specific or target substance.
  • the apparatus measures the target substance of glucose in the skin 408 when the skin impedance decreases to 20-30% value at the rest of the skin 408.
  • the glucose is getting trapped at the outermost layer of the skin 408 when the skin impedance decreases.
  • the apparatus measures a metabolite concentration of the target or specific substance in the interstitial fluid at the outermost layer of the skin 408 using full spectrum acquisitions and averaging technique, thereby, the apparatus reduces signal-to- noise, SNR ratio in information of the target substance that is collected from the IF.
  • FIGS. 5 A and 5B illustrate exemplary views 500A and 500B of a configuration of a measuring module of a metabolite-sensing device in accordance with an implementation of the disclosure.
  • the exemplary view 500A of the configuration of the measuring module of the metabolitesensing device includes electrodes 502A-N, and sensing heads 504A-N.
  • the electrodes 502A- N include a first cathode 506, a second cathode 508, and an anode 510.
  • the sensing heads 504A-N may be arranged in-between the first cathode 506 and the second cathode 508.
  • the exemplary view 500B of the measuring module of the metabolite-sensing device depicts a rotational geometry view of the first cathode 506, the second cathode 508, the anode 510, and the sensing heads 504A-N.
  • the measuring module provides options to include a more number of sensing heads 504A-N in empty slots.
  • FIGS. 6 A and 6B illustrate exemplary views 600 A and 600B of an open design parameter of sensing heads 602A-N in accordance with an implementation of the disclosure.
  • the exemplary view 600A depicts the sensing heads 602A-N positioned at a skin 606 where the sensing heads 602A-N include optical elements 604 that are arranged in a circular configuration within the sensing head 602A-N to generate a circular shape beam to pass through the skin 606.
  • the geometry of the sensing heads 602A-N can be customized or adjusted to meet requirements that include a maximum matching factor, beam shape, and the like.
  • the maximum matching factor is an alignment between a distribution of the target or specific substance and an active sensing area.
  • the sensing heads 602A-N may be designed with a concentric electrode geometry.
  • the exemplary view 600B depicts a rotational geometry view of the sensing heads 602A-N.
  • the sensing heads 602A-N include a transducer 608 and a light beam 610 that is designed with a toroidal geometry.
  • the sensing heads 602A-N emit a Gaussian beam, which enables the sensing heads 602A-N to transform the shape of the Gaussian beam into a Bessel beam using the optical elements 604.
  • FIGS. 7 A and 7B are flowcharts that illustrate a method for measuring metabolite concentration in an Interstitial Fluid, IF in accordance with an implementation of the disclosure.
  • an impedance of a skin is determined at rest at a selected frequency with electrodes of an electrical device placed on the skin.
  • a current is supplied to the electrodes for initiating reverse iontophoresis in an interstitial fluid under the skin.
  • a change in the impedance of the skin is monitored with time under an effect of the current.
  • a metabolite concentration is measured in the interstitial fluid under the skin with a metabolite sensing device when a pre-defined condition on the change of the impedance is met.
  • This method improves a signal -to-noise ratio, SNR, and variability in non-invasive measurements of target molecules or substances in the Interstitial Fluid, IF, by combining an apparatus of the electrical device with a sensing head.
  • the sensing head may act as a measurement head.
  • This method excites and measures a higher quantity of the target molecules through an optical or electromagnetic light source or beam by lifting and trapping the IF below a Stratum Comeum, SC with Electro-Osmotic Flow or Reverse Iontophoresis, RI, which also improves the SNR by collecting more information on the target substance.
  • This method detects metabolites by effectively concentrating them laterally in a position accessible by the probing signal.
  • this method targets an area of the highest metabolite concentration i.e. active sensing area, by lifting the IF to the SC that applies to the metabolite residing in the IF which leads to an enhanced excitation of the metabolite, and reduces the measurement uncertainties caused by the Interstitial Fluid, IF extraction pathways variability of the Stratum Corneum, SC.
  • This method actively controls the Electro-Osmotic Flow or Reverse Iontophoresis, RI process that selectively lifts and accumulates the If and thus the target metabolites in it or the substances below the SC.
  • This method maintains a consistent distribution of the IF.
  • This method enhances the measurement consistency of the target substance by monitoring and reacting to changes in the skin impedance through the current during optical or electromagnetic sensing in the IF.
  • This method enhances the stability of the skin impedance and related skin properties during the measurement of the target substance.
  • This method reduces measurement variability of the target substances when the skin impedance decreases to a pre-determined level while injecting a small current into the skin and while avoiding extraction of the IF.
  • This method ensures a more consistent light loss within the Stratum Corneum, SC resulting in a better repeatability of excitation of the metabolite across measurements, resulting in an improved repeatability in the optical or electromagnetic metabolite sensing, while maintaining the measurements non- invasive.
  • This method utilizes a specific electrode design to spatially impose and control a flow density of the Interstitial Fluid, IF, in the upper layers of the skin, and thus of the metabolite contained in it, without extracting said fluid from the skin. Moreover, the method controls some spatial aspects of the light source, optimizing the alignment of the metabolites with an output of the optical probing beam or signal maximizing the metabolite excitation.
  • the method further includes adapting one or more of electrical parameters of the current supplied to the electrodes of the electrical device to maintain the pre-defined condition met within a set precision by keeping the change of the impedance within a target range.
  • the electrical parameters include an amplitude, a duration, and a duty cycle of the current.
  • supplying the current to the electrodes includes supplying the current in cycles, and the monitoring of the change of the impedance of the skin with time includes determining the impedance of the skin at the end of each cycle.
  • the pre-defined condition on the change of the impedance is based on a decrease of the impedance of the skin as compared with the determined impedance of the skin at rest and/or a physiological reference dependence of a skin impedance from a current at the selected frequency.
  • FIG. 8 is an illustration of a computer system (i.e. an apparatus) in which the various architectures and functionalities of the various previous implementations may be implemented.
  • the computer system 800 includes at least one processor 804 that is connected to a bus 802, wherein the computer system 800 may be implemented using any suitable protocol, such as PCI (Peripheral Component Interconnect), PCI-Express, AGP (Accelerated Graphics Port), Hyper Transport, or any other bus or point-to-point communication protocol (s).
  • the computer system 800 also includes a memory 806.
  • Control logic (software) and data are stored in the memory 806 which may take a form of random-access memory (RAM).
  • RAM random-access memory
  • a single semiconductor platform may refer to a sole unitary semiconductor-based integrated circuit or chip. It should be noted that the term single semiconductor platform may also refer to multi-chip modules with increased connectivity which simulate on-chip modules with increased connectivity which simulate on- chip operation, and make substantial improvements over utilizing a conventional central processing unit (CPU) and bus implementation. Of course, the various modules may also be situated separately or in various combinations of semiconductor platforms per the desires of the user.
  • the computer system 800 may also include a secondary storage 810.
  • the secondary storage 810 includes, for example, 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.
  • the removable storage drive at least one of reads from and writes to a removable storage unit in a well-known manner.
  • Computer programs, or computer control logic algorithms may 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 in the foregoing.
  • the memory 806, the secondary storage 810, and any other storage are possible examples of computer-readable media.
  • the architectures and functionalities depicted in the various previous figures may be implemented in the context of the processor 804, a graphics processor coupled to a communication interface 812, an integrated circuit (not shown) that is capable of at least a portion of the capabilities of both the processor 804 and a graphics processor, a chipset (namely, a group of integrated circuits designed to work and sold as a unit for performing related functions, and so forth).
  • the architectures and functionalities depicted in the various previous-described figures may be implemented in a context of a general computer system, a circuit board system, a game console system dedicated for entertainment purposes, an application-specific system.
  • the computer system 800 may take the form of a desktop computer, a laptop computer, a server, a workstation, a game console, an embedded system.
  • the computer system 800 may take the form of various other devices including, but not limited to a personal digital assistant (PDA) device, a mobile phone device, a smart phone, a television, and so forth. Additionally, although not shown, the computer system 800 may be coupled to a network (for example, 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, a cable network, or the like) for communication purposes through an I/O interface 808.
  • a network for example, 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, a cable network, or the like.

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Abstract

Pour des mesures non invasives de concentration de métabolites dans un fluide interstitiel avec une cohérence et un rapport signal sur bruit améliorés, un dispositif de détection de métabolite (104, 200) est utilisé en combinaison avec un dispositif électrique (102). Une impédance d'une peau (304, 408, 606) au repos à une fréquence sélectionnée est déterminée par le dispositif électrique avec des électrodes (106 206 302, 502A-N) placées sur la peau, et un courant est fourni aux électrodes permettant d'initier une iontophorèse inverse dans le fluide interstitiel sous la peau. Un changement de l'impédance de la peau avec le temps sous l'effet du courant est ensuite surveillé par le dispositif électrique, et une concentration de métabolites dans le fluide interstitiel sous la peau est mesurée par le dispositif de détection de métabolites lorsqu'une condition prédéfinie sur le changement de l'impédance est satisfaite.
PCT/EP2023/066751 2023-06-21 2023-06-21 Appareil et procédé de mesure de la concentration de métabolites dans un fluide interstitiel Pending WO2024260547A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140155703A1 (en) * 2010-05-20 2014-06-05 University Of Strathclyde Transdermal device
US20180353748A1 (en) * 2015-07-24 2018-12-13 University Of Cincinnati Reverse iontophoresis biosensing with reduced sample volumes
US20190029654A1 (en) * 2016-01-15 2019-01-31 University Of Cincinnati Advanced electroporation devices and methods for analyte access in biofluids

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140155703A1 (en) * 2010-05-20 2014-06-05 University Of Strathclyde Transdermal device
US20180353748A1 (en) * 2015-07-24 2018-12-13 University Of Cincinnati Reverse iontophoresis biosensing with reduced sample volumes
US20190029654A1 (en) * 2016-01-15 2019-01-31 University Of Cincinnati Advanced electroporation devices and methods for analyte access in biofluids

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