Accelerated commissioning of a microneedle sensor

Abstract

TITLE: Accelerated commissioning of a microneedle sensor The invention relates to a method for monitoring the concentration of body analyte in an individual, the method being implemented by a processing unit of a body monitoring device comprising a biochemical microneedle sensor, the microneedles being in contact with an interstitial fluid in which the analyte is located, at least one microneedle constituting a working electrode, the working electrode being coated with a reactive material capable of reacting with the analyte, the method comprising: - a commissioning phase corresponding to a first period following a power supply to the sensor following a period during which the sensor is not powered;- an acceleration step of the sensor commissioning phase during which the sensor is supplied by means of a commissioning voltage profile comprising at least one lobe consisting of an increasing cycle and a decreasing cycle; - a functional analyte measurement phase following the commissioning phase; the method comprising a switching step from the commissioning phase to the functional phase as soon as a current measured by the sensor shows a variation less than or equal to a convergence threshold, the sensor being functional more quickly than in the absence of the acceleration phase of the sensor commissioning.

Description

Description Title of the invention: Accelerated commissioning of a mid-range sensor cross-shaped needles technical field

[0001] = The invention relates to ready-to-wear or "wearable" devices used in body monitoring systems, for example for recording and tracking pa- biochemical parameters of the human body.

[0002] The invention relates in particular to the commissioning of a sensor comprising mi- cross-needles, the sensor being configured to provide a concentration measurement of body analyte. STATE OF THE ART

[0003] The monitoring of many known chronic diseases in humans requires a daily record of biochemical parameters. A concentration level of a body analyte in a body fluid of the organism, for example in the plasma blood or in the interstitial fluid of the body's cells, can be detected.

[0004] As a common example, monitoring diabetes in a patient requires a detection precise daily blood glucose readings of the patient.

[0005] = One solution for monitoring diabetes is to perform a puncture, by for example, at the tip of the finger, to make a drop of blood bead, then to perform a Daily measurement of blood glucose in the drop of blood thus obtained.

[0006] Monitoring systems have been proposed to eliminate the need for a blood draw. manual, so as to make blood glucose measurement less laborious and less invasive. These are called CGM systems, for "Continuous Glucose Monitoring".

[0007] — Some of these CGM systems perform, at regular intervals, a measurement of Blood glucose levels in the interstitial fluid between skin cells. Blood glucose levels of Interstitial fluid is very close to blood plasma glucose levels. Measurements at Interstitial fluid levels allow for simple and minimally invasive blood glucose monitoring patients; these measurements can be performed using needle probes, in transcutaneous, or non-invasively, such as by iontophoresis or by implantable with measurement by chemo-fluorescence.

[0008] — The international application published under number WO 2019 / 141743 describes a body monitoring system, usable in particular for blood glucose monitoring. This monitoring system includes an electronic watch that can be attached to the wrist. with the help of a bracelet. The watch has a case into which a capsule is inserted. removable interchangeable containing a microneedle sensor and an adhesive patch allowing the sensor to be held against the wrist. The case includes... The sensor is powered and automatically controlled by the electronics in the housing to perform a transcutaneous measurement. The blood glucose measurement by the sensor is an electrochemical measurement. The body monitoring system described in the above-mentioned document has the significant advantage of providing autonomous calibration measurement by measuring a reference concentration of a body analyte in the user. The number of steps the user needs to take to obtain their daily measurements is significantly reduced. Specifically, the user needs to perform very few manual punctures (for example, a single weekly puncture), or even none at all. Another advantage of this system is its low hygiene risk, as the sensor needles are not in contact with the external environment once inserted into the skin. Furthermore, the aforementioned system is easy to maintain, as replacing a faulty sensor simply requires removing the removable capsule and inserting a new one. Additionally, when the user needs to remove the case (to shower, recharge the device, or for any other reason), they can do so without removing the capsule, which remains attached to the wrist. One problem is that when the sensor is inserted into the capsule, for example, when using a new capsule or after a period of inactivity, it cannot provide a reliable glucose reading. Therefore, after the capsule has been filled, no glucose reading is taken until a certain amount of time has elapsed. Specifically, it is necessary to wait between 1 and 10 hours. These waiting periods can vary between manufacturers and countries depending on their specific requirements. This problem is even more pronounced with a device that can be removed at will (for example, for showering, charging, at night, etc.). Indeed, when the user removes the device with its battery, leaving the capsule attached to their limb, the needles are inserted into the skin, and the sensor is then not powered. Description of the invention One aim of the invention is to accelerate the availability of the needle sensor so that it provides a reliable measurement. To this end, the invention proposes a method for monitoring the concentration of a bodily analyte in an individual, the method being implemented by a processing unit of a body monitoring device comprising a microneedle biochemical sensor, the microneedles being in contact with an interstitial fluid in which the analyte is located, at least one microneedle constituting a working electrode, the working electrode being coated with a reactive material capable of reacting with the analyte, the process comprising: - a commissioning phase corresponding to an initial period following the powering of the sensor after a period during which the sensor is not powered: - an acceleration step of the sensor commissioning phase during which the sensor is powered by means of a commissioning voltage profile comprising at least one lobe consisting of an increasing cycle and a decreasing cycle; - a functional phase of analyte measurement following the commissioning phase; - the process comprising a step of switching from the commissioning phase to the functional phase as soon as a current measured by the sensor shows a variation less than or equal to a convergence threshold, the sensor being functional more rapidly than in the absence of the acceleration phase of the commissioning of the sensor. The invention is advantageously complemented by the following features, taken alone or in any technically feasible combination thereof: - the commissioning voltage profile is a succession of lobes; - the commissioning voltage profile includes at least one alternation of at least one positive voltage lobe and at least one negative voltage lobe; - the increasing and decreasing cycles of a lobe of the commissioning voltage evolve in steps; - each step of the commissioning voltage profile is a voltage that increases or decreases between 10mV and 1500mV; - each lobe of the commissioning voltage profile is triangular or rectangular or sinusoidal; - a lobe of the commissioning voltage profile has a maximum amplitude between -1500 mV and +1500 mV and a frequency between ImHz and 1KHz; - the convergence threshold corresponds to a derivative of the current over time close to zero or corresponds to a threshold less than or equal to 10nA / s. The invention also relates to a body monitoring device comprising a microneedle biochemical sensor, the sensor comprising a processing unit configured to implement a process according to the invention. PRESENTATION OF THE FIGURES Other features, purposes, and advantages of the invention will become apparent from the following description, which is purely illustrative and not limiting, and which should be read in regarding the attached drawings on which: -Fig. 1 illustrates an overview of a device for monitoring a bodily analyte - Figure [2] illustrates a schematic view of a needle sensor according to the invention; - Figure [3] illustrates a method for monitoring the concentration of a body analyte in an individual according to the invention: - Fig. 4a and Fig. 4b illustrate variations in the measured intensity as a function of time; -Figures 5a, 5b, 5c illustrate different successions of lobes of a commissioning voltage implemented during the process of the invention; - Figure [6] illustrates different configurations for a lobe of a commissioning voltage implemented during the process of the invention -Fig.7 illustrates a lobe of a commissioning voltage implemented during the process of the invention comprising several stages. Throughout the figures, similar elements bear identical references. DETAILED DESCRIPTION The sensor is designed to provide a measurement of glucose concentration within the wearer's interstitial fluid. The electronic watch, together with the sensor, forms a body monitoring device. By "body monitoring," we mean the verification of biochemical constants of the wearer of the monitoring system, typically the concentration of the wearer's interstitial fluid of a protein, hormone, biomarker, oxygen, nutrients, etc. A person skilled in the art will readily understand that other physical quantities can be monitored by the system, such as lactate concentration, hydration, etc. Throughout this text, the biochemical constant to be monitored is, for example, the glucose concentration (or blood glucose) within the interstitial fluid of the skin. The blood glucose level in the interstitial fluid is considered representative of the blood plasma glucose level. Furthermore, the sensor needle(s) could be designed to be inserted into a bodily fluid other than interstitial fluid, for example, into the blood. Furthermore, the wearable device, as described below, is an electronic watch configured to display information to its wearer. However, the sensor preparation kit described below can be used, with the same advantages, in conjunction with any other type of wearable device: bracelet, tracker, electronic patch, electronic radio reader, etc. General architecture of a body surveillance device Figure 1 illustrates a body monitoring device 1 comprising a housing 2, a sensor 3 and an adhesive patch 4. In this case, sensor 3 is a needle sensor designed to provide an electrical current measurement within the interstitial fluid of the wearer of device 1. Needles 5 are advantageously arranged on an inner face 31 of the sensor 3. This inner face 31 is intended to be placed on the skin of the wearer. The sensor 3 is assembled with the adhesive patch 4, together forming a capsule. The sensor 3 can also be removable from the patch 4. Such a capsule is advantageously mounted as removable with the housing 2. In particular, the capsule, and therefore the sensor 3, preferably engages in a cavity 21 of the housing 2 located on its face intended to be in contact with the skin. The sensor 3 comprises an outer face 32 opposite the inner face 31. Housing 2 and the capsule may have complementary shapes, which limits the effort required for proper insertion of the capsule against housing 2. Patch 4 has an adhesive layer, or is itself made of an adhesive material. The patch thus allows the capsule to attach to the wearer's skin and helps retain the needles 5 in the interstitial fluid. Patch 4, for example, has a ring shape and covers the capsule. The sensor 3 shown here is circular with a central opening 33, but it can take other shapes: rectangular, oblong, ellipsoidal, with or without a central opening. The central opening 33 allows the sensor 3 to be correctly positioned in the cavity 21 of the housing, which includes a central positioning pin (not shown). Sensor 3 therefore includes elements which allow the liquid to be collected or the signals detected by each microneedle to be brought to housing 2 for processing (not described here). The sensor 3 can take the form of a plastic plate, a printed circuit board (rigid or flexible silicon), a non-conductive metal plate such as aluminum. The adhesive patch 4 is designed to adhere to the skin and supports the sensor 3, allowing the housing 2 to be detached without removing the sensor 3, keeping it attached to the body. This configuration avoids removing the sensor for certain operations that only involve the housing: battery charging, repair, replacement, and data transfer to a computer. The housing 2 is advantageously shaped like a watch case and includes means 23 for attaching the device to a user's wrist. This includes a suitable strap to encircle the user's wrist. The strap is preferably adjustable. Housing 2 contains several components for analyzing or extracting interstitial fluid. In this regard, reference can be made to document WO 2019 / 141743 in the name of the applicant, which describes in detail the measurement and detection of a physical quantity using microneedles in contact with a bodily fluid that may or may not be sampled. Advantageously, the watch also includes a wireless communication interface, for example via a 3G and / or 4G and / or 5G and / or Wi-Fi and / or Bluetooth and / or NFC and / or DECT type telecommunications network. Also, the watch may include a light indicator such as an LED, which can be used to signal the end of a sensor preparation operation. The needles 5 are advantageously microneedles. The sensor 3 preferably comprises between four and fifty microneedles, or even four hundred microneedles. Of course, a different number can be considered without limiting the description of the invention given here. A microneedle is defined as a needle with a small height, preferably between 10 µm and 1000 µm, and preferably between 0.3 mm and 0.8 mm. The height of the microneedles is sufficiently small to avoid contact with a mechanical pain nerve in the wearer when the device is worn. The 5 microneedles allow for the measurement of body fluid. The 5 microneedles are solid for direct liquid analysis. To analyze liquid, the microneedles do not draw up any liquid and instead incorporate the sensor on their surface in the form of a coating such as a biochemical material capable of reacting with the analysis to be performed on the liquid. The length of the needles 5 is thus sufficiently reduced to avoid contact with a nerve of the user, to limit the pain caused by wearing the device 1. Each needle, for example, has a pyramidal shape. In this example, each needle 5 has on its surface at least one chemical or biochemical material capable of reacting with the body analyte whose measurement is to be obtained (i.e., glucose in this case). A material capable of reacting with the body analyte is, for example, an enzyme capable of oxidizing the body analyte. In an alternative example, each needle 5 includes an internal cavity located at the rear of the tip, and the chemical or biochemical material suitable for reacting with the analyte is located in this internal cavity. In another alternative example, the sensor 3 may include cavities located at the rear of the needles 5, and / or within the needles 5. For example, one or more needles 5 may include an open channel. The cavities contain the chemical or biochemical material capable of reacting with the analyte. The needles 5 are then capable of conveying the body fluid to said cavities. Advantageously, sensor 3 includes several microneedles which They consist of a network of microneedles, electrically connected to each other in groups. The microneedles pierce the skin to come into contact with the interstitial fluid when the sensor is in contact with the skin. The sensor 3 illustrated in [Fig.2] comprises, in addition to the needles 5, a substrate 311 having a plurality of metallic tracks 312, a working conductivity electrode 313, a reference conductivity electrode 314. During the use of sensor 3 to perform a measurement, a voltage is generated between several needles. At least some of the needles 5 of sensor 3 are at least partially immersed in the interstitial fluid. The chemical or biochemical material present on the surface of the needles 5 reacts with the glucose in the interstitial fluid. Sensor 3 thus provides an electrical current measurement, representative of the glucose concentration in the interstitial fluid. The substrate 311 and the needles 5 are preferentially arranged on a single face of the sensor 3, which is the face facing upwards according to the orientation of [Fig.2]. This upper face is intended to be positioned facing the user's skin. Each needle extends from the upper face in a Z direction, from its base to its tip. The Z direction is preferably orthogonal to a plane of the upper face. The central aperture 33 is circular in shape. The sensor 3 thus has, in this example, a generally annular shape. For a detailed example of the structure of sensor 3, reference may be made to the international application published under number WO 2020 / 025822 and in particular to the description relating to figures 1 and 2 of this document. A support for sensor 3 (e.g. the removable capsule) preferably includes a patch (not shown) that can be attached to the user's skin. Sensor 3 is intended to be controlled by the processing unit 14 of watch 10. Process During a body analyte concentration monitoring process, implemented in processing unit 14, a user inserts sensor 3 into housing 2 (step E0) and the sensor is then powered for the first time (step El). Thus, two phases can be distinguished. - a P1 commissioning phase corresponding to the initial period following the powering of sensor 3. This is the phase following the insertion of sensor 3 into housing 2, during which the sensor is powered. This commissioning phase occurs after the insertion of sensor 3 into housing 2: when using a new capsule or after a period during which the sensor, while attached to the wrist, has not been powered. This latter case occurs when the user removed case 2, for example, to recharge it, to take a shower, etc. - a functional P2 phase of analyte measurement which is therefore consecutive to the commissioning phase of sensor 3. Usually, the functional P2 phase arrives after an arbitrarily fixed duration that varies from 1 hour to 10 hours depending on the case. After the sensor 3 is inserted into the housing 2, the latter energizes the sensor 3 (step E1). Then, to accelerate commissioning, the process includes supplying the average sensor with a commissioning voltage profile Vmes comprising at least one lobe consisting of an increasing cycle and a decreasing cycle (step E2). It has been highlighted and defined that applying a start-up voltage profile with at least one lobe allows equilibrium to be reached more quickly than simply turning on the sensor 3 using a voltage dedicated to measuring the analyte. During the commissioning phase P1 and while the sensor 3 is powered by means of the commissioning voltage, the sensor 3 measures a current I (step E3) resulting from the application of the commissioning voltage profile Vmes and the sensor 3 switches (step E4) from the commissioning phase P1 to the functional phase P2 as soon as the measured current I has a variation less than or equal to a convergence threshold (denoted S). In this way, sensor 3 is operational more quickly than in the absence of the acceleration phase of the commissioning of sensor 3. By "functional," we mean that the sensor provides a reliable measurement of the analyte. Specifically, during this functional phase, the analyte measurement is available to the user accurately. In this case, the chemical reaction at sensor 3 is representative of the amount of analyte in the liquid, for example, glucose. Furthermore, the term "convergence threshold" refers to the threshold at which the Test current stabilizes. Indeed, at the beginning of the acceleration phase, the current varies rapidly and tends to stabilize (progression less than 10%). It has been observed that the sensor can reliably provide this measurement by accelerating the commissioning phase of known sensors by 20% to 80%. Depending on the configuration, the commissioning phase can thus be reduced to between 30 and 10 minutes. Preferably, the convergence threshold S corresponds to a time derivative of the current close to zero or to a threshold less than or equal to 10 nA / s. Figures 4a and 4b illustrate possible variations of the measured current over time. In these figures, the commissioning and functional switching phases are shown. starting from the convergence threshold S, they were identified. We see that during the functional phase the current is representative of the amount of glucose. The commissioning voltage profile is preferably a succession of lobes. This succession can be a succession of positive voltage lobes or negative voltage lobes. The number of lobes is greater than or equal to one. Advantageously, a lobe has a maximum amplitude between -1500 mV and +1500 mV and a frequency between 11Hz and 1KHz. Figure 5a illustrates a succession of positive voltage lobes and Figure 5b illustrates a succession of negative voltage lobes. Alternatively, the sequence can be an alternation of a positive voltage lobe followed by a negative voltage lobe, and so on. Figure 5c illustrates such an alternation. Also, one or more positive lobes may be followed by one or more negative lobes or vice versa. The alternating start-up voltage profile helps to improve the speed at which the convergence threshold is reached. Alternatively, as seen in [Fig.6], the lobes present several profiles: sinusoidal portion, triangular, square. Advantageously, the rising and falling cycles of a lobe evolve in steps. For example, each step is a voltage that rises or falls between 10 mV and 1500 mV. Figure 7 illustrates a lobe with several steps. Each step preferably has a frequency between 1 mHz and 1 kHz. To determine the maximum voltage value, the sensor's oxidation voltage is taken into account. Indeed, beyond a certain voltage, the sensor can be damaged and its aging is accelerated. Setting one or more steps, as well as the slope and frequency of each, allows for either slow or rapid growth. More generally, to fix the profile of the commissioning voltage Vmes, a compromise must be found between the speed at which the convergence threshold is reached and the accuracy of the functional phase.

Claims

Demands

1. Method for monitoring the concentration of corporcl analyte in a individual, the process being implemented by a processing unit (9) of a body monitoring device (1) comprising a sensor (3) biochemical microneedle injection, the microneedles being in contact with a interstitial fluid in which the analyte is located, at least half- a needle forming a working electrode, the working electrode being coated with a reactive material capable of reacting with the analyte, the process comprising: - a commissioning phase (P1) corresponding to a first period following a sensor power supply (El) following a period during which the sensor is not powered; - a step (E2) to accelerate the commissioning phase of the sensor during which the sensor is powered by means of a profile of commissioning voltage (Vmes) comprising at least one lobe consisting of an increasing cycle and a decreasing cycle; - a functional phase (P2) of analyte measurement following the commissioning phase; the process comprising a phase (P1) switching step (E4) commissioning to the functional phase (P2) as soon as a current (I) measured by the sensor (3) shows a variation less than or equal to one convergence threshold (S), the sensor (3) being functional more ra- quickly than in the absence of the acceleration phase of the implementation sensor service.

2. Method according to claim !, wherein the tension profile of commissioning (Views) is a succession of lobes.

3. A method according to any one of claims 1 to 2, wherein the the commissioning voltage profile (Vmes) includes at least one any alternation of at least one lobe with positive tension and of minus one lobe with negative tension.

4. A method according to any one of claims 1 to 3, wherein the ascending and descending cycles of a lobe of the commissioning voltage {Vmes) evolve in stages.

5. A method according to claim 4, wherein each bearing of the profile of The commissioning voltage (Vmes) is a voltage that increases or decreases. between 100 mV and 1500 mV.

6. A method according to any one of the preceding claims, in which each lobe of the commissioning voltage profile (Vmes) is triangular, rectangular, or sinusoidal.

7. A method according to any one of claims 1 to 6, wherein a lobe of the commissioning voltage profile (Vmes) exhibits a maximum amplitude between -1500 mV and +1500 mV and a frequency between 1000Hz and 1kHz.

8. A method according to any one of the preceding claims, in which the convergence threshold (S) corresponds to a derivative of the current {D over time close to zero or corresponds to a lower threshold or equal to lOnA / s.

9. Body monitoring device (1) comprising a bio- sensor chemical microneedle sensor, comprising a unit (9) of processing configured to implement a process according to one any of the preceding claims.