FR3138295A1 - Method for monitoring a microneedle biochemical sensor - Google Patents

Abstract

The invention relates to a 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 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 covered with a reactive material capable of reacting with the analyte, the method comprising the following steps implemented by the control unit (7): - power supply of the sensor (2) with microneedles 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 supply of the sensor (2), of a first impedance linked to the insertion of the electrodes into the skin and to the sensor (2). Figure for abstract: FIGURE 1

Description

TITLE OF THE INVENTION

Method for monitoring a microneedle biochemical sensor

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

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 check whether the microneedles are properly calibrated.

STATE OF THE ART

Monitoring many known chronic diseases in humans requires daily monitoring of biochemical parameters. A concentration level of a body analyte in a body fluid of the body, for example in blood plasma or in the interstitial fluid of cells of the body, can be measured.

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

A popular solution for monitoring diabetes consists of making a puncture, for example at the tip of the finger, to make a drop of blood appear, then carrying out a daily measurement of blood sugar in the drop of blood thus obtained.

Monitoring systems have been proposed to eliminate the need for a manual puncture, so as to make blood sugar measurement less laborious and less invasive. We are talking about 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. Interstitial fluid glycemia is very close to blood plasma glycemia. Measurements at the interstitial fluid level allow simple and minimally invasive monitoring of patients' blood sugar levels; these measurements can be carried out using needle sensors, transcutaneously, or non-invasively, such as for example iontophoresis or implantable with chemo-fluorescence measurement.

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 that can be attached to the wrist using a bracelet. The watch has a case, into which is inserted an interchangeable removable capsule containing a microneedle sensor, the microneedles being inserted into the skin. The sensor is automatically controlled by the electronics of the box, to carry out a transcutaneous measurement. The blood glucose measurement by the sensor is an electrochemical measurement.

However, when such a device includes microneedles, there may be interference linked to sweat present on the skin. These interferences also depend on the thickness of the epidermis, which varies depending on the individual: the thickness of the skin to reach the interstitial fluid is then not the same.

In addition, due to the size of the microneedles, there is a risk that these microneedles are poorly inserted into the skin: the resulting measurement is then distorted.

In addition, over the life of the device we can observe a drift in the measurement: here again, the measurement is distorted.

The invention makes it possible to control the insertion into the skin of microneedles for measuring an analyte in a body fluid.

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

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

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

To this end, 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 contact with an interstitial liquid 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, the working electrode being covered with a reactive material capable of reacting with the analyte, the process comprising the following steps implemented by the control unit:

- power supply of the microneedle sensor by means of a sinusoidal excitation voltage having an average value which corresponds to a polarization voltage specific to the sensor for measuring the analyte;

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

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

- the housing comprises surface electrodes in contact with the surface of the user's skin, 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 supply of the surface electrodes, of a second impedance linked to the depression of the electrodes only;

- the sensor is powered by means of the sinusoidal excitation voltage for a second duration consecutive to a first duration during which the sensor is powered by means of a constant excitation voltage;

- the sensor is powered for a period consecutive to a period during which the sensor is not powered while being in contact with the interstitial liquid;

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

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

- the sinusoidal voltage oscillates around the bias voltage between 100 mv inclusive from peak to peak and 1 v inclusive from peak to peak;

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

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

The invention also relates to a device for detecting an analyte contained in a body 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

Other characteristics, aims and advantages of the invention will emerge from the description which follows, which is purely illustrative and not limiting, and which must be read with reference to the appended drawings in which:

There illustrates a device for measuring an analyte contained in a bodily fluid of an individual;

There illustrates a method for monitoring a microneedle biochemical sensor according to the invention;

There 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;

There illustrates a timing diagram of a voltage used within the framework of the method of the invention according to a second embodiment of the invention;

There illustrates a timing diagram of a voltage used within the framework of the method of the invention according to a third embodiment of the invention.

In all the figures, similar elements bear identical references.

DETAILED DESCRIPTION

Device

There 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 consists in particular of 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.

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 micro- needles 6 so as to be in contact with the interstitial fluid of the individual. Each electrode consists of one or more microneedles.

Note that in the case of a device with two electrodes, the reference electrode plays the role of counter electrode.

The device 1 also includes 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 electrode of work 3 of the sensor 2 so that it forms a circuit with the reference electrode 4 and possibly the counter electrode 5.

Each working electrode 3 is covered with a material capable of reacting with the analyte that we seek to detect and the quantity of which we seek to measure. 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.

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

Process

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

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 inserted into the skin of the individual and are in contact with the skin.

We consider that the microneedles constitute a working electrode and a counter electrode (which can also be the reference one in a two-electrode sensor).

The objective of the process 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 impedance also makes it possible to determine whether sensor 2 must be calibrated and also makes it possible to determine the wear of sensor 2.

The insertion of the electrodes (the microneedles) 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 measuring the impedance between the working electrode and the reference electrode.

To enable the operation of the sensor 2 and in particular the measurement of the analyte, it is supplied by an excitation voltage having a profile dedicated to the measurement only of the analyte and which is linked to the polarization voltage of the sensor 2. In fact, when sensor 2 is put into service, the latter is polarized to allow measurement of the analyte in a suitable manner.

To measure 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.

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 peak-to-peak and 2.4 v inclusive.

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

While sensor 2 is supplied with this sinusoidal voltage, the resulting intensity is measured by sensor 2. This concerns in particular the intensity measured between the working electrode and the counter electrode.

Figures 3, 4, 5 illustrate three different profiles P1, P2, P3 used for both analyte measurement and impedance measurement. The measurement of impedance and analysis is carried out during certain phases of the different profiles P1, P2, P3

For each of the profiles, during the process the sinusoidal voltage is applied during a time period T2a, T2b, T2c consecutive to a time period T1a, T1b, T1c during which the sensor is powered by means of an excitation voltage.

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). While sensor 2 is powered, the resulting intensity is measured (step E3).

Not using sinusoidal voltage all the time helps limit energy consumption. Indeed, processing the intensity to deduce the impedance consumes energy, as does the application of a sinusoidal voltage instead of a direct voltage which is sufficient to measure the quantity of analyte.

According to a first embodiment using a first profile P1 illustrated on the , the voltage is continuous for a first duration T1a then sinusoidal for a second duration T2a consecutive to the first duration T1a. The analyte is measured during the first duration T1a.

Advantageously, the sum of the durations T1a and T2a is less than 3 9 minutes. The T1a duration is between 1 and 500 seconds and the T2a duration is between 1 and 30 seconds. The duration T2a is therefore preferably less than the duration T1a. This helps limit battery usage.

This first embodiment is the amperometric chrono measurement of known type.

According to a second embodiment using a second profile P2 illustrated on the , the direct voltage is applied after a third duration T0b during which sensor 2 is not powered “sensor unplugged”. At the end of this duration T0b, the sensor 2 is powered by a direct voltage for a first duration T1b then sinusoidal for a second duration T2b consecutive to the first duration T1b. 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 T1b.

This is visible on the intensity curve of the on which we see that the succession of periods of supply of the sensor following a non-supply of the sensor leads to an intensity which varies in an impulse manner presenting a decrease over time.

This second embodiment is an amperometric chrono measurement in pulse mode. This second mode compared to the first mode saves energy since periods of power supply are alternated with periods of no power supply to the sensor. According to this second embodiment, not supplying 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 to the sensor is advantageously dimensioned so that the quantity of analyte (glucose) depends only on the concentration of analyte (glucose).

Advantageously, the sum of the durations T0b, T1b and T2b is less than 10 minutes. Preferably the duration T0b is between 1 and 300 seconds and the sum of the durations T1b and T2b is between 1 and 300 seconds. Here again, the T2b duration is between 1 and 30 seconds and is less than the T1b duration.

According to a third embodiment using a third profile P3 illustrated on the . According to this profile P3, for a duration T1c the voltage is in slots, the slots are of amplitude the polarization voltage of sensor 2. The voltage is sinusoidal for a duration T2c just before disconnecting sensor 2 for a duration T0c. Then according to this profile P3, the tension is sawtooth for a duration T0d. During the duration T0d, the peaks are of maximum amplitude the polarization voltage of the sensor 2. The interest 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 T0d. Here again, not powering the sensor allows the analyte (glucose) and oxygen to diffuse between the electrodes, which helps smooth out fluctuations due to movement or noise. Also, the duration of non-power supply to the sensor is advantageously dimensioned so that the quantity of analyte (glucose) depends only on the concentration of analyte (glucose).

According to this third embodiment, the voltage in slots during the duration T1c makes it possible to consume the residual glucose which burns off the effect of oxidation and biological fouling. This therefore ensures that while the sensor is not powered, there is no residual glucose on the electrodes which would have already been measured.

The duration T1c is for example between 1s and 60 seconds, the duration T2c is between 1second and 3 seconds, the duration T0c is between 1 second and 500 seconds, the duration T0d is between 1 minute to 10 minutes.

The intensity measured during the application of the sinusoidal voltage to sensor 2 is then processed (step E4) to deduce an impedance resulting which is characteristic of the electrodes sinking into the skin.

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

With the module of the complex impedance, |U| the complex module of the applied voltage and |I| the complex module of the measured voltage (step E41).

This impedance includes both the impedance due to sensor 2 and the depression of the microneedles. Thus, we have with the impedance linked to the insertion of the microneedles into the skin.

From the determination of and knowledge (measurement obtained in the factory during the manufacture of sensor 2) we can deduce (step E42).

According to one embodiment, is compared to a threshold fixed in advance. This is a direct measurement (step E43).

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 . In fact, the impedance is linked to the depression of the electrodes relative to the surface of the user's skin.

To measure this impedance the electrodes 91 of the housing 9 are supplied by a sinusoidal voltage which is also either identical to that used by the sensor 2 or different (step E2'). Note, however, that the electrodes 91 of the box 9 are not powered by a power supply profile used for the sensor. When it is not necessary to measure the impedance, the electrodes 91 of the box 9 are not powered.

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 .

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

So, by calculating 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 is compared to a threshold also fixed in advance but which is independent of the user (step E43').

Alternatively or in addition, from Or we can deduce whether sensor 2 needs to be calibrated (step E5).

Alternatively or in addition, from Or we can deduce whether sensor 2 needs to be changed. In this case, its degree of wear is measured (step E6).

For each comparison, a threshold is set in advance.

If any of the above comparisons indicate that the electrodes are inserted incorrectly, 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 (10)

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 embedded in the skin of a user to be in contact with an interstitial liquid 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 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):
- power supply (E2) of the microneedle sensor (2) by means of a sinusoidal excitation voltage having an average value which corresponds to a polarization voltage specific to the sensor (2) for measuring the analyte;
- determination (E3, E4), during the supply of the sensor (2) of a first impedance (Z1) linked to the insertion of the electrodes into the skin and to the sensor (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 ') surface electrodes (91) by means of a sinusoidal excitation voltage, the method comprising a determination (E3', E4'), during the supply of the surface electrodes of a second impedance (Z2 ) linked to the depression of the electrodes only. 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 (T _2a ) consecutive to a first duration (T _1a ) for which the sensor is powered (E1) by means of a constant excitation voltage. Method according to one of claims 1 to 2, in which the sensor (2) is powered for a duration (T _1a , T _2b ) consecutive to a duration (T _0b ) during which the sensor (3) is not powered while being in contact with the interstitial fluid. Method according to claim 4, comprising a power supply (E1) by means of a direct voltage for a first duration (T _1b ), the sensor (2) being powered by the sinusoidal voltage when the intensity is stabilized for a second duration ( T _2b ). Method according to any one of the preceding claims, in which the sinusoidal voltage has a frequency between 50 and 500 Hz, preferably 180 Hz. Method according to any one of the preceding claims, in which the sinusoidal voltage oscillates around the bias voltage between 100 mv inclusive from peak to peak and 1 v inclusive from peak to peak. Method according to any one of the preceding claims, comprising a step of processing the first and/or the second impedance to deduce whether the electrodes are inserted correctly. Method according to one of the preceding claims, comprising a step of processing the first and/or the second impedance to deduce whether the sensor (2) must be calibrated or to deduce its wear. Device for detecting an analyte contained in a body fluid comprising an electrochemical sensor (2) comprising a working electrode (3), the device comprising a control unit (7) configured to implement a method according to any one of the preceding claims.