Classifications

• • 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, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
  • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
• • 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, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
  • A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
  • A61B5/14551—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters for measuring blood gases
  • A61B5/14552—Details of sensors specially adapted therefor
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
  • A61B5/6801—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
  • A61B5/6802—Sensor mounted on worn items
  • A61B5/681—Wristwatch-type devices

Definitions

• the present invention relates to a device for measuring a body analyte. More specifically, it relates to a body monitoring device by analyzing body fluid, typically interstitial.
• Certain pathologies such as diabetes require daily monitoring of biochemical parameters of the human body, in particular the concentrations of certain compounds (blood sugar in the example of glucose).
• interstitial fluid that is, the fluid that fills the space between blood capillaries and cells. It indeed has an ionic composition close to that of blood plasma.
• Transcutaneous probes have been proposed alternatively in the form of a self-adhesive patch placing a micro-needle sensor just under the skin, so as to put the sensor in permanent fluid communication with the interstitial liquid, for continuous monitoring.
• Some of these patch-type transcutaneous probes include wireless communication means making it possible to send the measurements on the interstitial liquid to a mobile terminal, for storage and / or processing of the measurements (checking thresholds and variations, producing statistics. , triggering alerts if necessary, etc.).
• the sugarBEAT TM or FreeStyle Libre systems will be mentioned.
• the main aim of the invention is to remedy the problems thus posed.
• This aim is achieved in the context of the present invention by virtue of a sensor for a body monitoring system, comprising a plurality of microneedles, each microneedle having a pointed top having a point, the sensor comprising at least one working electrode suitable for measuring.
• the working electrode comprising a first end intended to be electrically connected to a module configured to exploit an electrical signal, and at least a second end defined by an active detection part covering at least part of the surface of the peaked apex, characterized in that each pair of adjacent microneedles is separated by a distance between the tips of the peaked apexes of at least 1 mm and preferably at least 1.5 mm, see where appropriate at least 1.8mm.
• the microneedles form a two-dimensional network having a microneedle density of less than 50 microneedles per cm 2 ,
• each microneedle at its base is less than 400 ⁇ m and preferably less than 250 ⁇ m
• each microneedle is made of a material chosen at least from polycarbonate, silicon, or a metal,
• each microneedle is less than 1100 ⁇ m, preferably less than 900 ⁇ m,
• the microneedle has a central axis of symmetry passing through its point, characterized by the fact that the angle formed between the pointed apex and the central axis is between 7 ° and 35 °,
• the microneedle is made of a material having a Young's modulus greater than 50 GPa
• a body monitoring system comprising a sensor according to the invention and further comprising a module configured to exploit an electrical signal delivered by the sensor and provide information representative of an analyte.
• the monitoring system advantageously comprises a capsule which comprises at least one sensor in accordance with the invention, and also comprises a patch comprising an adhesive for fixing the capsule to the skin of an individual, said system further comprising a housing which houses the module configured to use the electrical signal linked to a bracelet.
• Another aspect of the invention is a method for measuring a body analyte comprising a step of penetrating the microneedles of a sensor according to the invention into the skin of a user.
• the penetration of the microneedles is advantageously implemented by applying a force of less than 50 newtons, in particular less than 25 newtons, and preferably less than 10 newtons, on the sensor.
• the method for measuring body analyte comprises a step of penetrating the microneedles implemented by applying a force of less than 50 newtons on a system in accordance with the invention comprising the sensor, in particular less than 25 newtons, and preferably less than 10 newtons.
• a system according to the invention can include the sensor, and the attachment of the system to a user's body by mechanical attachment means preferentially results in the penetration of the microneedles.
• the present invention also aims to provide a microneedle optimized in terms of its geometry, making it possible to measure a signal representative of the concentration of an analyte without parallelizing the microneedles.
• the present invention relates to a sensor for a body monitoring system, comprising at least one micro-needle for measuring body analyte, characterized in that the micro-needle comprises a base shank and a pointed top arranged on the body.
• the sensor also comprising an active detection part covering at least part of the surface of the pointed top, the active part comprising a face electrically conductive coated of a coating suitable for detecting an analyte, the pointed apex extending exclusively at a distance of between 350 ⁇ m and 1100 ⁇ m from the base of the base barrel, in particular exclusively at a distance of between 600 ⁇ m and 1000 ⁇ m from the base of the barrel, and in that the area of the active part is between 0.04 mm 2 and 0.9 mm 2 .
• the active part covers only at least part of the surface of the peaked apex
• the base barrel tapers towards the top to a point
• the sensor comprises a plurality of microneedles and each pair of adjacent microneedles is separated by a distance between the tips of the peaks of at least 1mm and preferably at least 1.5mm, see where appropriate at less 1, 8mm,
• the microneedle has a square section
• the microneedle has the shape of an obelisk, the base shaft being formed of a quadrangular shaft and the pointed top being in the shape of a pyramid,
• the microneedle has a circular section and the pointed top is conical
• the active part comprises a coating suitable for detecting an analyte, preferably for detecting glycemia by electrochemistry,
• the sensor comprises at least one working electrode, the working electrode comprising a first end intended to be electrically connected to a module configured to use an electrical signal, and at least a second end defined by the active part,
• the sensor comprises between one and fifteen, preferably between one and seven, in particular between one and five and preferentially between one and three active detection parts each covering at least part of the surface of the tip of a different microneedle,
• the sensor comprises a counter-electrode, comprising a first end intended to be electrically connected to a module configured to use an electrical signal, and at least one other end comprising at least one electrically conductive face, the sensor comprising also at least one counter-electrode microneedle comprising a base shank and a pointed top arranged on the base shank, the counter-electrode micro-needle having a slope break between the base shank and the pointed top, the other end covering at least one surface of the pointed apex, the pointed apex extending exclusively at a distance between 100 ⁇ m and 1100 ⁇ m from the base of the base shaft,
• the base shank defines an angle of the order of 7 ° with the central axis, and by the fact that the pointed apex defines an angle between 10 ° and 35 °, preferably approximately equal to 15 °, with the central axis.
• Another aspect of the invention is a body monitoring system characterized by the fact that it comprises a sensor as mentioned above, and that it further comprises a module configured to use an electrical signal delivered by the sensor and provide information. representative of an analyte.
• the invention is advantageously supplemented by the following characteristics, taken individually or in any of their technically possible combinations:
• the system comprises a capsule which comprises at least one sensor in accordance with the invention and, the system also comprising a patch configured to receive the capsule, the patch comprising an adhesive for fixing the capsule to the skin of an individual, said system further comprising a housing which houses the module configured to exploit the electrical signal, the housing also comprising a bracelet.
• the sensor comprises several working electrodes, the system being adapted to individually measure the electric potential of each of the working electrodes,
• At least several working electrodes each comprise an active part suitable for detecting the same analyte.
• Another aspect of the invention is a body monitoring method comprising a step of measuring bodily analyte using a microneedle comprising a base shank, which preferentially tapers towards a peak at the top, said microneedle exhibiting a break in the slope between the base shaft and the peak point, the peak point having a slope greater than that of the base shank, an active part covering at least part of the pointed top and the pointed top extending at a distance of between 350 ⁇ m and 1100 ⁇ m from the base of the base shank.
• the measurement step is advantageously implemented by a sensor comprising at least a plurality of working electrodes, each working electrode comprising a first end intended to be electrically connected to a module configured to use an electrical signal, and at least one second end defined by the active part, the measuring step being implemented independently using each of the working electrodes.
• FIG. 1 is a perspective view of a sensor comprising four microneedles
• FIG. 2 is a perspective view from a different viewing angle from Figure 1 of such a sensor
• FIG. 3 shows a rear view of such a sensor
• FIG. 4 shows a side view of this sensor
• FIG. 5 represents a view from the tip of the sensor
• FIG. 6 shows a side view of a microneedle according to one embodiment of the invention
• FIG. 7 shows a schematic perspective view of a body monitoring system incorporating a sensor according to the present invention
• FIG. 8 shows a view of a capsule adapted to carry a plurality of sensors according to the invention
• FIG. 10 shows schematically an effect observed on the skin of a patient using a network of microneedles in accordance with the state of the art
• FIG. 11 shows the penetration of an array of microneedles according to the present invention into the skin of a patient.
• FIG. 12 schematically illustrates a sensor according to one embodiment of the invention.
• Electrode is understood to mean a conductive device making it possible to pick up variations in electrical potential in a living organism.
• An electrode comprises a terminal having a connection end and at least one sensing end through which an electric potential or an electric current is transmitted, each sensing end being carried by a microneedle.
• the electrode can thus have a single sensing end. It can also include a plurality of detection ends. In this case, it should be noted that the electrode remains single, even though several sensing ends are intended to enter the body of a living organism.
• a sensor comprises a support plate 10 provided with four microneedles 20.
• the contour of the plate can be the subject of many variant embodiments.
• the plate 10 has a square outline.
• the four microneedles are located respectively near the corners of the plate 10.
• the microneedles 20 extend perpendicular to the base plane of the plate 10. In other words, the central axis 21 of each microneedle 20 extends perpendicularly. to the base surface of the plate 10.
• the face of the plate 10 opposite the microneedles 20 comprises four electrically conductive pads 30, each pad 30 being electrically connected to the active part 25 of each microneedle 20.
• the electrically conductive pads 30 allow continuity of 'an electrode when they are electrically connected to a base, for example working or a counter-electrode, in the microneedle 20, and this potentially separately so that each working electrode is independent of the other working electrodes.
• these areas 30 can be integral with the microneedles 20 or electrically connected to the microneedles 20 by any suitable means through or around the plate 10.
• the support plate 10 can be made of any suitable material electrically, for example electrically. insulator or conductor.
• microneedles 20 can be formed from any suitable material.
• the microneedles 20 are suitable for conveying an electrical signal picked up by the active surface 25.
• the microneedles 20 can be formed based on polycarbonate or silicon.
• the microneedle or needles 20 are preferably full, that is to say without any cavity.
• the microneedle can mainly comprise silicon.
• the microneedle has an outer layer of non-conductive protective S1O2, formed by oxidation of the silicon on the surface.
• the microneedle may not include an additional coating to the Si0 2 layer.
• each microneedle 20 comprises a base shank 22 and a pointed apex 24.
• the shank 22 can preferably be thinned towards the apex 24 of the microneedle 20.
• the apex in point 24 has a slope greater than that of the shank 22, that is to say it forms an angle B with the central axis 21 greater than the angle A formed between the base shank 22 and the central axis 21 .
• the microneedle 10 has a break or slope transition 23 between the base shank 22 and the pointed apex. The slope transition 23 can be materialized by an edge.
• the base shank 22 and the pointed top 24 may have a square section.
• the base shank 22 is quadrangular and the point 24 is of the pyramidal type.
• the assembly of the microneedle 20 may preferably have the shape of an obelisk.
• the microneedle 20 may have a circular section.
• the base shank 22 has the shape of a truncated circular cone of revolution and the point 24 is formed of a conical point of revolution.
• the pointed apex 24 preferably extends exclusively at a distance of between 350 ⁇ m and 1100 ⁇ m from the base of the base shank 22 of the microneedle, that is to say from the face 12 of the support plate 10, and preferably between 600 ⁇ m and 1000 ⁇ m from the base of the microneedle and this surface 12 of the support plate 10.
• the expression extends exclusively at a distance of between 350 ⁇ m and 1100 ⁇ m that the portion of the pointed top 24 closest to the base of the base post is arranged at a distance greater than 350 ⁇ m from the base of the base post 22, and that the part furthest from the base of the base post 22 is arranged at a distance of less than 1100 ⁇ m.
• the area of the active detection part 25 must be between 0.04 and 0.9 mm 2 . Consequently, when the measurement is made with a single microneedle 20, the active part 25 of this microneedle 20 is between 0.04 and 0.9 mm 2 .
• the area of the aforementioned active part between 0.04 and 0.9 mm 2 means the total active area micro-needles considered.
• the devices of the prior art comprise much smaller active surfaces and arrays of microneedles comprising for example more than 100 microneedles in order to be able to measure a signal representative of a concentration of analyte with a sufficient signal to noise ratio. From both the surface area of the active part on each microneedle and both the number of active part per electrode, it is possible to diversify the functions of the microneedles on the same device, by treating the microneedles so that they can detect different analytes, and to integrate arrays of a small number of microneedles, for example less than 20, to minimize the costs generated by the rejection of large arrays of microneedles, comprising for example a number of microneedles greater than 100 .
• microneedles 20 or the shape of a similar circular body of revolution but having a break in slope between the base shank 22 and the pointed top 24, makes it possible to solve a problem posed by microneedles 20 known in the state of the art, namely to minimize the diameter of penetration into the skin while maximizing the surface area of the active part 25 present in the part of the skin between the epidermis and nerves.
• microneedles 20 according to the present invention can be made using any suitable microfabrication process.
• the active part 25 comprises an electrically conductive face, preferably covered with a coating which is the subject of various variants depending on the type of measurement sought and the type of analyte to be measured.
• the active part 25 is provided with a coating suitable for carrying out an enzymatic reaction with glucose.
• the active part 25 may also not include a coating specific to a predetermined analyte, for example in the case of the active part 25 of a counter electrode or of a reference electrode.
• the height of the base shaft 22 is of the order of 380 pm
• each microneedle 20 is of the order of 0.25mm
• the width I7 of the microneedle at the level of the slope transition 23 is of the order of 0.2mm
• the angle A of convergence of the base shaft 22 with respect to the central axis 21 is of the order of 7 °
• the angle B of the peak point 24 relative to the central axis 21 is of the order of 30 °.
• a working electrode 70 comprises between one and fifteen, preferably between one and seven, in particular between one and five and preferably between one and three active parts 25 each covering at least part of the surface of the tip top 24 of a different microneedle 20.
• the systems known from the state of the art do not allow the use of so few microneedles.
• each pair of adjacent microneedles 20 is preferably separated by a distance between the tips of the peaks 24 of at least 1mm and preferably at least 1.5mm, or possibly at least 1.8mm.
• This has the effect of preventing a homogeneous deformation of the skin when a network of microneedles 20 is brought into contact with the skin, known in other technical fields under the name of the fakir effect, and on the contrary of promoting a deformation of the skin located around each of the microneedles.
• the pain caused by the penetration of needles into the skin can be significantly reduced, or even eliminated, and the penetration occurs very naturally, the needles having in fact become mechanically independent and come out of the Fakir effect which will be specified with regard to the figures 10 and 11.
• the center distance / between each pair of microneedles 20 is of the order of 1.5 mm.
• the array of microneedles preferably has a density of less than 50 needles per cm 2 .
• FIG. 10 which diagrammatically represents the attempt to penetrate a known array of microneedles 20 ', carried by a substrate 10', into the skin of a patient, when the array of microneedles 20 'exhibits too great a proximity between the neighboring microneedles 20, during the insertion attempt, the microneedles 20 'operate a stress on the skin which tends to deform the latter so that the skin sees a single needle, with a diameter l r equivalent to that of the entire array of microneedles, before the needles penetrate the skin.
• the force exerted between the tips of the two adjacent micro-needles 20 of the needle array takes place over a sufficient distance or gap on the patient's skin to allow direct penetration of the needles into the skin of the patient. patient without going through the painful step illustrated in FIG. 9 of preliminary deformation of the skin to a diameter l r .
• the sensor is preferably suitable for measuring the presence or the concentration of an analyte by electrochemistry.
• a sensor may include a working electrode 70, adapted to assess the presence of an analyte in the body of a user.
• the working electrode 70 comprises at least a first end electrically connected to a module configured to exploit the electrical signal from the working electrode 70, and at least a second end formed by the active part 25. It can also include a plurality. of second ends.
• the active part 25 of the microneedle 20 covers at least part of the surface of the peaked apex 24 and preferably the entire surface of the peaked apex 24.
• the active part 25, at the level of the peaked apex 24 is coated with any coating suitable for the desired measurement, typically a coating suitable for detecting blood glucose electrochemically.
• the sensor can include a counter electrode.
• the counter-electrode may comprise a first end intended to be electrically connected to a module configured to use an electrical signal, and at least one other end making it possible to exploit an electrical signal in the user's body.
• the other end of the counter-electrode may cover a micro-needle against the electrode, for example a micro-needle according to the invention.
• the counter-electrode does not have the same active surface prerequisites as the working electrode.
• the pointed top of the counter electrode can extend exclusively at a distance of between 100 ⁇ m and 1100 ⁇ m from the base shank of the microneedle.
• the other end of the counter electrode may cover the entire surface of the counter electrode microneedle.
• each working electrode can be adapted to detect the same analyte as another working electrode, or be adapted to detect an analyte. different from another working electrode.
• each working electrode may comprise an active part comprising the same type of coating.
• each working electrode may also include different active parts, comprising different coatings, but adapted to detect the same analyte. The concentration of the analyte can thus be detected more accurately than using a single coating for the active part 25.
• Each electrode can also be adapted to detect different analytes. Thus, it is possible to monitor several pathologies with the same monitoring system.
• the microneedle (s) 20 may be arranged on a support plate 10.
• the thickness ei of the support plate is advantageously between 0.1 mm and 1 mm, and preferably of the thickness ei of the support plate. order of 0.2 mm.
• the dimensions of the microneedles 20 can be the subject of numerous variant embodiments. The same is true for the support plate 10.
• the support plate 10 has sides having a width li less than 10mm, advantageously less. at 3mm, for example of the order of 2.3mm.
• the electrically conductive areas 30 are for example square areas having a side I2 of the order of 0.8 mm.
• the support plates 10 can themselves be the subject of different variant embodiments. Some support plates 10 can be adapted to support for example four microneedles while other support plates 10 can be adapted to support only two microneedles 10.
• the present invention can make it possible to measure the blood glucose level independently using a plurality of working electrodes 70. This has an undeniable advantage over the state of the art according to which such an independent measurement using a working electrode comprising a single microneedle was not possible because the measurement signal was too noisy using a single microneedle.
• the sensor preferably comprises several working electrodes 70, the measuring system being adapted to individually measure the electric potential of each of the working electrodes 70.
• the measurement of the potential of each of the working electrodes 70 can be multiplexed.
• the sensor according to the present invention can be implemented in different types of body monitoring system.
• the senor according to the invention is implemented in a monitoring system of the type illustrated in Figures 7 to 9 attached.
• Such a system comprises a case 40 in the form of a watch case comprising a strap 42 adapted to surround the wrist of an individual.
• the housing 40 houses a module configured to use the electrical signal delivered by each microneedle 20 and provide information representative of a physical quantity of the fluid, typically a blood sugar level.
• the body monitoring system preferably used according to the invention comprises a capsule 50 comprising at least one sensor of the aforementioned type, and preferably a plurality of sensors as will be described in more detail later.
• the body monitoring system according to the invention also comprises a patch 60 to which the capsule 50 is linked, the patch 60 itself being provided with an adhesive making it possible to adhere the entire patch and capsule 50 to the skin of the body. 'an individual.
• the capsule 50 preferably has the general shape of a ring comprising a plurality of recessed housings 52 adapted to each respectively receive the support plate 10 of a above-mentioned sensor.
• the capsule 50 may include electrically conductive pads 54 intended to be placed opposite the electrically conductive pads 30 provided on the support plate 10, to provide an electrical connection between the microneedles 20 and the module provided in the box 40 to use the electrical signal thus taken.
• the pads 54 are themselves interconnected with the aforementioned module by electrically conductive tracks 56a.
• some of the pads 54 can be individually connected to the aforementioned processing module by respective tracks 56a while other pads 54 can be connected to the processing module by common tracks 56b .
• the present invention also relates to a method of body monitoring using a sensor comprising a microneedle of the above type.
• the monitoring method comprises a step of measuring bodily analyte using a microneedle 20 in accordance with one embodiment of the invention.
• the sensor can comprise a plurality of working electrodes.
• the measurement can for example be implemented by polarizing the working electrode (s) and the counter-electrode or electrodes at an electrical potential suitable for causing an oxidation-reduction reaction involving the analyte to be measured.
• the measurement step can preferably be carried out at least using two different working electrodes.
• the measuring step can for example be implemented independently, successively on each of the working electrodes 70, or in parallel on each of the working electrodes 70.
• the concentration of the electrolyte can be analyzed more precisely than 'With a system comprising for example a single working electrode having several ends in the form of microneedles.
• Another aspect of the invention is a method for measuring a body analyte comprising a step of penetrating the microneedles of a sensor according to the invention into the skin of a user.
• the sensor needles can be introduced into the skin without an applicator, by the spacing of the microneedles 20.
• a low force compared to the force provided by an applicator can be used for the penetration of the microneedles.
• a force of less than 50 newtons, in particular less than 25 newtons and preferably less than 10 newtons can be used for the penetration of the microneedles 20.
• the penetration of the microneedles can be implemented with the hand, or preferably with mechanical attachment means of the system, for example a bracelet.

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• Health & Medical Sciences (AREA)
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• Physics & Mathematics (AREA)
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• Medical Informatics (AREA)
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• Pathology (AREA)
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• Optics & Photonics (AREA)
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• Animal Behavior & Ethology (AREA)
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• 2019
  • 2019-08-08 EP EP19290066.0A patent/EP3772330A1/de not_active Withdrawn
• 2020
  • 2020-08-07 WO PCT/EP2020/072311 patent/WO2021023883A1/fr unknown
  • 2020-08-07 EP EP20754709.2A patent/EP4009866A1/de active Pending

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