Method for monitoring a microneedle biochemical sensor

Abstract

The invention relates to a method of monitoring a biochemical microneedle sensor (2) removably connected to a housing (9), the housing (9) comprising a control unit (7), the sensor (2) comprising several microneedles inserted into the skin of a user to be in contact with an interstitial fluid in which there is an analyte, the microneedles constituting electrodes for measuring the concentration of the analyte, at least one microneedle constituting a working electrode of the sensor (2), the working electrode being coated with a reactive material suitable for reacting with the analyte, the method comprising the following steps implemented by the control unit (7): - supplying the microneedle sensor (2) by means of a sinusoidal excitation voltage having an average value which corresponds to a bias voltage specific to the sensor (2) for measuring the analyte;- determination, during the power supply of the sensor (2) of a first impedance related to the penetration of the electrodes into the skin and to the sensor (2). Figure for the abbreviation: FIGURE 1;

Description

Title of the invention: TITLE OF THE INVENTION

[0001] Method for monitoring a microneedle biochemical sensor Technical field

[0002] The present invention relates to a device for body monitoring via analysis of body fluid, typically interstitial, using a microneedle biochemical sensor.

[0003] More specifically, the present invention relates to the management of the insertion of microneedles into the skin making it possible to measure the presence of an analyte in the body fluid and making it possible to verify whether the microneedles are correctly calibrated. STATE OF THE ART

[0004] Monitoring of many known chronic diseases in humans requires daily recording of biochemical parameters. A concentration level of a body analyte in a body fluid of the organism, for example in blood plasma or in the interstitial fluid of the cells of the organism, can be recorded.

[0005] As a common example, monitoring diabetes in a patient requires an accurate daily reading of the patient's blood sugar.

[0006] A widespread solution for monitoring diabetes consists of performing a puncture, for example at the tip of the finger, to collect a drop of blood, then performing a daily measurement of blood sugar in the drop of blood thus obtained.

[0007] Monitoring systems have been proposed to eliminate the need for manual puncture, so as to make blood glucose measurement less laborious and less invasive. These are called CGM systems, for "Continuous Glucose Monitoring". Some of these CGM systems perform, at regular intervals, a blood glucose measurement at the level of the interstitial fluid between the skin cells. The blood glucose level in the interstitial fluid is very close to the blood glucose level in blood plasma. Measurements at the level of the interstitial fluid allow simple and minimally invasive monitoring of patients' blood glucose levels; these measurements can be carried out using needle sensors, transcutaneously, or non-invasively, such as by iontophoresis or implantable with a measurement by chemo-fluorescence.

[0008] The international application published under number WO 2018 / 104647 describes a body monitoring system, usable in particular for monitoring blood sugar levels. This monitoring system includes an electronic watch attachable to the wrist using a bracelet. The watch comprises a case, into which is inserted an interchangeable removable capsule containing a micro-needle sensor, the micro-needles being inserted into the skin. The sensor is controlled automatically the electronics of the box, to carry out a transcutaneous measurement. The blood sugar measurement by the sensor is an electrochemical measurement.

[0009] However, when such a device includes microneedles, there may be interference related to sweat present on the skin. This interference also depends on the thickness of the epidermis, which varies between individuals: the thickness of the skin to reach the interstitial fluid is then not the same.

[0010] Furthermore, due to the size of the microneedles, there is a risk that these microneedles are not inserted properly into the skin: the resulting measurement is then distorted.

[0011] Furthermore, during the life of the device a drift in the measurement can be observed: here again, the measurement is distorted. Statement of the invention

[0012] The invention makes it possible to control the penetration into the skin of microneedles for measuring an analyte in a bodily fluid.

[0013] The invention also makes it possible to control microneedles if calibration is necessary.

[0014] The invention also makes it possible to monitor the wear of the sensor.

[0015] The invention proposes to overcome at least one of these drawbacks.

[0016] For this purpose, the invention proposes a method for monitoring a biochemical microneedle sensor removably connected to a housing, the housing comprising a control unit, the sensor comprising several microneedles inserted into the skin of a user to be in contact with an interstitial liquid in which an analyte is located, the microneedles constituting electrodes for measuring the concentration of the analyte, at least one microneedle constituting a working electrode of the sensor, the working electrode being covered with a reactive material capable of reacting with the analyte, the method comprising the following steps implemented by the control unit:

[0017] - power supply of the microneedle sensor by means of an excitation voltage if nusoidal having an average value which corresponds to a polarization voltage specific to the sensor for the measurement of the analyte;

[0018] - determination, during the supply of the sensor, of a first linked impedance to the insertion of the electrodes into the skin and to the sensor.

[0019] The invention is advantageously supplemented by the following characteristics, taken alone or in any of their technically possible combinations:

[0020] - the housing comprises surface electrodes in contact with the surface of the skin of the user, the method comprising simultaneously with the power supply of the sensor, a power supply of the surface electrodes by means of a sinusoidal excitation voltage, the method comprising a determination, during the power supply of the surface electrodes of a second impedance linked to the sinking of the electrodes only;

[0021] - the sensor is powered by means of the sinusoidal excitation voltage for a second duration following a first duration during which the sensor is supplied by means of a constant excitation voltage;

[0022] - the sensor is powered for a duration consecutive to a duration during which the sensor is not powered while in contact with the interstitial liquid;

[0023] - the method comprises a supply by means of a direct voltage for first a duration, the sensor being powered by the sinusoidal voltage when the intensity is stabilized for a second duration;

[0024] - the sinusoidal voltage has a frequency between 50 and 500 Hz, of preferably 180 Hz;

[0025] - the sinusoidal voltage oscillates around the bias voltage between 100 mv included from peak to peak and 1 v included from peak to peak;

[0026] - the method comprises a step of processing the first and / or the second impedance to deduce whether the electrodes are inserted correctly.

[0027] - the method comprises a step of processing the first and / or the second impedance to deduce whether the sensor needs to be calibrated or to deduce its wear;

[0028] The invention also relates to a device for detecting an analyte contained in a bodily fluid comprising an electrochemical sensor comprising a working electrode, the device comprising a control unit configured to implement a method according to the invention. PRESENTATION OF FIGURES

[0029] Other characteristics, aims and advantages of the invention will emerge from the following description, which is purely illustrative and non-limiting, and which must be read in conjunction with the appended drawings in which:

[0030] [Fig.l] illustrates a device for measuring an analyte contained in a bodily fluid of an individual;

[0031] [Fig.2] illustrates a method for monitoring a microneedle biochemical sensor according to the invention;

[0032] [Fig. 3] illustrates a timing diagram of a voltage used in the context of the method of the invention according to a first embodiment of the invention;

[0033] [Fig.4] illustrates a timing diagram of a voltage used in the context of the method of the invention according to a second embodiment of the invention;

[0034] [Fig.5] illustrates a timing diagram of a voltage used in the context of the method of the invention according to a third embodiment of the invention.

[0035] Throughout the figures, similar elements bear identical references. DETAILED DESCRIPTION

[0036] Device

[0037] [Fig.l] illustrates device 1 for measuring an analyte contained in a bodily fluid of an individual, preferably glucose contained in the interstitial fluid of an individual. Such a device 1 is notably constituted by an electrochemical sensor 2 comprising a working electrode 3, a reference electrode 4 and preferably a counter electrode 5 which makes it possible to stabilize the chemical reaction occurring at the working electrode when the electrodes are powered.

[0038] The electrodes (i.e., the working electrode 3, the counter electrode 4 and preferably the reference electrode 4) are configured to be implanted in the dermis of a user by one or more microneedles 6 so as to be in contact with the interstitial fluid of the individual. Each electrode consists of one or more microneedles.

[0039] It is noted that in the case of a two-electrode device, the reference electrode plays the role of counter-electrode.

[0040] The device 1 also comprises a control unit 7. The control unit 7 is electrically connected to the electrodes. The control unit 7 may comprise a processor, a memory, an electrical acquisition module and an electrical control module in particular for controlling the electrochemical sensor 2. The control unit 7 is further configured to power the working electrode 3 of the sensor 2 so that it forms a circuit with the reference electrode 4 and possibly the counter electrode 5.

[0041] Each working electrode 3 is covered with a material capable of reacting with the analyte that is to be detected and the quantity of which is to be measured. This may be glucose oxidase (GOx) or any other type of enzyme or reagent capable of reacting with glucose. A redox mediator may optionally be used.

[0042] The device 1 comprises a bracelet 8 or a strap allowing it to be attached to a limb and a housing 9. The housing 9 comprises a display screen (not shown) and the control unit 7 is arranged in the housing 9.

[0043] Method

[0044] A method for monitoring a sensor 2 of the device 1 is implemented by the control unit 7 and is described below in relation to [Fig.2].

[0045] In a preliminary step (step E0), the sensor 2 is positioned on an individual so that the electrodes 3, 4, 5 are in contact with the interstitial liquid in which the analyte is located. The device 1 is in particular arranged around the wrist of an individual, the device 1 preferably being a watch. Thus, the electrodes are pressed into the skin of the individual and are in contact with the skin.

[0046] The microneedles are considered to constitute a working electrode and a counter-electrode (which can also be the reference electrode in a two-electrode sensor).

[0047] The objective of the method is to measure the impedance induced by the insertion of the electrodes into the skin to ensure the correct insertion of the electrodes into the skin and at a sufficient depth. Such an impedance also makes it possible to determine whether the sensor 2 must be calibrated and also makes it possible to determine the wear of the sensor 2.

[0048] The insertion of the electrodes (the micro-needles) into the skin as well as the sensor 2 itself induce a total impedance which can influence the glucose measurement. By knowing the applied voltage and the resulting intensity, we can go back to the measurement of the impedance between the working electrode and the reference electrode.

[0049] To enable the operation of the sensor 2 and in particular the measurement of analyte, the latter is powered by an excitation voltage having a profile dedicated to the measurement of the analyte alone and which is linked to the polarization voltage of the sensor 2. Indeed, when the sensor 2 is put into service, the latter is polarized to enable the measurement of the analyte in a suitable manner.

[0050] For the measurement of the impedance, it is appropriate to supply the sensor 2 with a sinusoidal excitation voltage having an average value which corresponds (preferably equal) to a polarization voltage of the sensor 2 so as not to disturb the chemical reaction between the reactive material and the analyte.

[0051] The sinusoidal excitation voltage therefore oscillates around this bias voltage. For example, the peak-to-peak value around this bias voltage is between 100 mV inclusive from peak to peak and 2.4 V inclusive.

[0052] Also, a frequency sweep between 0.1 and 400 kHz is applied to this sinusoidal voltage.

[0053] While the sensor 2 is supplied by means of this sinusoidal voltage, the resulting intensity is measured by the sensor 2. This is in particular the intensity measured between the working electrode and the counter electrode.

[0054] Figures 3, 4, 5 illustrate three different profiles PI, P2, P3 used for both analyte measurement and impedance measurement. The impedance measurement and analysis are carried out during certain phases of the different profiles PI, P2, P3

[0055] For each of the profiles, during the process the sinusoidal voltage is applied for a time period T2a, T2b, T2c following a time period Tla, Tlb, Tic during which the sensor is supplied by means of an excitation voltage.

[0056] Thus, the method comprises a step of supplying the sensor 2 with a direct voltage (step E1) followed by a step of supplying the sensor 2 with the sinusoidal voltage (step E2). During the supply of the sensor 2, the resulting intensity is measured (step E3).

[0057] Not using a sinusoidal voltage all the time makes it possible to limit energy consumption. Indeed, processing the intensity to deduce the impedance consumes energy, as does applying a sinusoidal voltage instead of a direct voltage which is sufficient for measuring the quantity of analyte.

[0058] According to a first embodiment using a first PI profile illustrated in [Fig.3], the voltage is continuous for a first duration Tla then sinusoidal for a second duration T2a following the first duration Tla. The analyte is measured during the first duration Tla.

[0059] Advantageously, the sum of the durations Tla and T2a is less than 39 minutes. The duration Tla is between 1 and 500 seconds and the duration T2a is between 1 and 30 seconds. The duration T2a is therefore preferably less than the duration Tla. This makes it possible to limit the use of the battery.

[0060] This first embodiment is the chronoamperometric measurement of known type.

[0061] According to a second embodiment using a second profile P2 illustrated in [Fig.4], the direct voltage is applied at the end of a third duration TOb during which the sensor 2 is not powered “sensor disconnected”. At the end of this duration TOb, the sensor 2 is powered by a direct voltage for a first duration Tlb then sinusoidal for a second duration T2b following the first duration Tlb. It is in particular when the measured intensity becomes stable and constant that the sinusoidal voltage is applied. Here again, the analyte is measured during the first duration Tlb.

[0062] This is visible on the intensity curve of [Fig.4] where we see that the succession of periods of power supply to the sensor following a non-power supply to the sensor leads to an intensity which varies in a pulsed manner, showing a decrease over time.

[0063] This second embodiment is a chronoamperometric measurement in pulse mode. This second mode, compared to the first mode, allows energy to be saved since periods of power supply are alternated with periods of non-power supply of the sensor. According to this second embodiment, the non-power supply of the sensor allows glucose and oxygen to diffuse between the electrodes, which makes it possible to smooth out fluctuations due to movement or noise. The duration of non-power supply of the sensor is advantageously sized so that the quantity of analyte (glucose) depends solely on the concentration of analyte (glucose).

[0064] Advantageously, the sum of the durations TOb, Tlb and T2b is less than 10 minutes. Preferably the duration TOb is between 1 and 300 seconds and the sum of the durations Tlb and T2b is between 1 and 300 seconds. Here again, the duration T2b is between 1 and 30 seconds and is less than the duration Tlb.

[0065] According to a third embodiment using a third profile P3 illustrated in [Fig.5]. According to this profile P3, for a duration Tic the voltage is in square waves, the square waves are of amplitude the polarization voltage of the sensor 2. The voltage is sinusoidal for a duration T2c just before disconnecting the sensor 2 for a duration TOc. Then according to this profile P3, the voltage is sawtooth for a duration TOd. During the duration TOd, the peaks are of maximum amplitude the polarization voltage of the sensor 2. The advantage of this third profile P3 is that the sensor 2 is maintained before returning to a sawtooth cycle for the measurement of the analyte for the duration TOd. Here again, the non-powering of the sensor allows the analyte (glucose) and the oxygen to diffuse between the electrodes which makes it possible to smooth out the fluctuations due to movement or noise.Also, the duration of non-powering of the sensor is advantageously dimensioned so that the quantity of analyte (glucose) depends only on the concentration of analyte (glucose).

[0066] According to this third embodiment, the voltage in square waves during the duration Tic makes it possible to consume the residual glucose which burns the effect of oxidation and biological fouling. This therefore makes it possible to ensure that during the non-powering of the sensor, there is no residual glucose on the electrodes which would have already been measured.

[0067] The duration Tic is for example between 1 s and 60 seconds, the duration T2c is between 1 second and 3 seconds, the duration TOc is between 1 second and 500 seconds, the duration TOd is between 1 minute and 10 minutes.

[0068] The intensity measured during the application of the sinusoidal voltage to the sensor 2 is then processed (step E4) to deduce a resulting impedance Zj which is characteristic of the penetration of the electrodes into the skin.

[0069] Such processing is implemented in the frequency domain. Thus, we first calculate a Discrete Fourier Transform (DFT) of the measured intensity to deduce the impedance which is then given by

[0070] । 7 । _ I he |7|

[0071] With |Zj | the modulus of the complex impedance, IUI the complex modulus of the applied voltage and III the complex modulus of the measured voltage (step E41).

[0072] This impedance |Zf | includes both the impedance due to sensor 2 and the insertion of the microneedles. Thus, we have |Z31 — || + \Zenfancement\ with \Zenfom:etnen}\ the impedance linked to the insertion of the microneedles into the skin.

[0073] From the determination of | Z11 and the knowledge | (measurement obtained in the factory during the manufacture of the sensor 2) we can deduce Ideepening\ — “ l^'capteiirl ICiapc CÆZJ.

[0074] According to one embodiment, \Zsinking\ is compared to a threshold set in advance. This is a direct measurement (step E43).

[0075] According to one embodiment, the housing 9 is provided with electrodes 91 in contact with the surface of the skin which make it possible to measure an impedance linked to the skin alone noted |Z?[ • Indeed, the impedance \Zmfmcenu,nt\ is linked to the depression of the electrodes relative to the surface of the user's skin.

[0076] To measure this impedance ] Z2J the electrodes 91 of the housing 9 are also supplied with a sinusoidal voltage which is either identical to that used by the sensor 2 or different (step E2'). It should be noted, however, that the electrodes 91 of the housing 9 are not supplied with a power supply profile used for the sensor. When it is not necessary to measure the impedance, the electrodes 91 of the housing 9 are not supplied with power.

[0077] The resulting intensity is measured (step E3') during the application of the sinusoidal voltage to the electrodes 91 of the box 9 and is then processed (step E4') to deduce the impedance jZ2|-

[0078] In the same way as for Zb Z2 is obtained in the frequency domain by calculating a DFT of the intensity measured for the electrodes 91 of the box 9 (step E41').

[0079] Thus, by calculating |Z | = |Zj - |Z2| we directly obtain the impedance linked to the depression only (step E42'). In this case, the measurement is differential and is more precise than that obtained by direct measurement. Here again Z is compared to a threshold also fixed in advance but which is independent of the user (step E43').

[0080] Alternatively or additionally, from Z ] or Z2 it can be deduced whether the sensor 2 needs to be calibrated (step E5).

[0081] Alternatively or additionally, from Zt or Z2 it can be deduced whether the sensor 2 needs to be changed. In this case its degree of wear is measured (step E6).

[0082] For each comparison, a threshold is set in advance.

[0083] If either of the above comparisons indicates that the electrodes are incorrectly inserted, that the sensor needs to be calibrated or that the sensor needs to be changed then a warning signal is generated (step E7). Such a signal is for example: a change in the display, an audible signal, a vibration of the device etc.

Claims

Claims

1. Method for monitoring a biochemical microneedle sensor (2) removably connected to a housing (9), the housing (9) comprising a control unit (7), the sensor (2) comprising several microneedles inserted into the skin of a user to be in contact with an interstitial liquid in which an analyte is located, the microneedles constituting electrodes for measuring the concentration of the analyte, at least one microneedle constituting a working electrode of the sensor (2), the working electrode being covered with a reactive material capable of reacting with the analyte, the method comprising the following steps implemented by the control unit (7): - supplying (El) the microneedle sensor (2) with a constant excitation voltage for a first duration (Tla, Tlb);- supplying (E2) the microneedle sensor (2) by means of a sinusoidal excitation voltage for a second duration (T2a, T2b, T2c) less than the first duration and consecutive to the first duration, the sinusoidal excitation voltage having an average value which corresponds to a polarization voltage specific to the sensor (2) for the measurement of the analyte; - determining (E3, E4), during the supply of the sensor (2) of a first impedance (Zl) linked to the insertion of the electrodes into the skin and to the sensor (2).;

2. Method according to claim 1, the housing (9) comprising surface electrodes in contact with the surface of the user's skin, the method comprising simultaneously with the power supply (E2) of the sensor (2), a power supply (E2') of the surface electrodes (91) by means of a sinusoidal excitation voltage, the method comprising a determination (E3', E4'), during the power supply of the surface electrodes of a second impedance (Z2) linked to the depression of the electrodes only, the second impedance being measured by means of the surface electrodes.

3. Method according to one of claims 1 to 2, in which the sensor (2) is supplied (E2) by means of the sinusoidal excitation voltage for a second duration (T2a) following a first duration (Tu) during which the sensor is supplied (El) by means of a constant excitation voltage.

4. Method according to one of claims 1 to 2, in which the sensor (2) is powered for a duration (Tu, T2b) following a duration (TOb) during which the sensor (3) is not powered while being in contact with the interstitial liquid.

5. Method according to claim 4, comprising a power supply (El) by means of a direct voltage for a first duration (Tib), the sensor (2) being powered by the sinusoidal voltage when the intensity is stabilized for a second duration (T2b).

6. A method according to any preceding claim, wherein the sinusoidal voltage has a frequency of between 50 and 500 Hz, preferably 180 Hz.

7. A method according to any preceding claim, wherein the sinusoidal voltage oscillates around the bias voltage between 100 mv inclusive peak-to-peak and 1 v inclusive peak-to-peak.

8. A method according to any preceding claim, comprising a step of processing the first and / or second impedance to deduce whether the electrodes are pressed correctly.

9. Method according to one of the preceding claims, comprising a step of processing the first and / or the second impedance to deduce therefrom whether the sensor (2) must be calibrated or to deduce therefrom its wear.

10. Device for detecting an analyte contained in a bodily fluid comprising an electrochemical sensor (2) comprising a working electrode (3), several microneedles inserted into the skin of a user to be in contact with an interstitial liquid in which an analyte is located, the device comprising a control unit (7) configured to implement a method according to any one of the preceding claims.

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