WO2023152193A1

WO2023152193A1 - Analyte-detecting patch component and method for producing same

Info

Publication number: WO2023152193A1
Application number: PCT/EP2023/053135
Authority: WO
Inventors: Alexandre Pierre-Marie BOULANGER; Olga CHASHCHINA
Original assignee: Metyos
Priority date: 2022-02-10
Filing date: 2023-02-08
Publication date: 2023-08-17
Also published as: FR3132426B1; FR3132426A1

Abstract

The invention relates to a method for producing an analyte-detecting patch component, the method comprising: - providing a base (9) from which a microneedle (8) extends, which microneedle comprises a hollow body provided with an opening (13) enabling body fluid to enter inside the hollow body; - providing an electronic circuit (14) comprising a flexible printed circuit (15) with an electrical track (18) and a detection unit (35); - joining the electronic circuit (14) to the base (9), a portion of the flexible printed circuit (15) being arranged to flex into the microneedle (8) with the detection unit (35) inside the hollow body.

Description

Analyte detection patch component and method of making same

FIELD OF THE INVENTION

[01] The present invention relates to the components of analyte detection patches and their methods of manufacture.

[02] More specifically, the invention relates to a patch for detecting analyte(s) of a bodily fluid from the animal body (including the human).

TECHNOLOGICAL BACKGROUND

[03] The human body comprises bodily fluids, for example interstitial fluid, in which various analytes can be found. These analytes can for example be metabolites such as in particular glucose, glycerol, free fatty acids or ketone bodies.

[04] It may be of interest to monitor the concentration of analytes in this body fluid. Indeed, this concentration can be an indicator of a person's state of health. Knowing this concentration, and more precisely the evolution of this concentration, can alternatively help everyone to improve their physical performance and/or to achieve well-being or health objectives. To make this estimate, a patch can be used. Such a patch is considered minimally invasive to the human body, as it is applied to the skin, and penetrates very shallowly into the human body. The patch can be described as “micro-invasive”. The main interest of the patch is its minimally invasive aspect, allowing it to obtain information on the human body without bodily sampling, and without heavy medical intervention of implantation. Thus, we can qualify such patches by the Anglicism "wearable" untranslatable in French. Such patches carry out measurements by electrochemistry.

[05] US 2019/388,032 describes an example of a patch performing measurements by electrochemistry, in which a micro-needle extends vertically from an electronic control unit, and an electrode extends from the electronic control unit inside the micro-needle so as to bathe in the interstitial liquid. An electrical circuit is formed with these electrodes, and the electrical quantities measured depend on the metabolite concentration in contact with the electrodes. It is possible to regularly monitor the concentration of the metabolite over time.

[05a] US 2019/233,795 relates to an analyte detection patch which comprises hollow micro-needles provided with a mouthpiece.

[06] However, such patches are difficult to manufacture. In particular, the electrical connection of the electrodes to the electronic circuit is complex. [07] In addition, it is possible that such an embodiment is bulky.

[08] The invention thus aims to facilitate the manufacture and/or implementation of such patches.

SUMMARY OF THE INVENTION

[09] Thus, the invention relates to a process for manufacturing an analyte detection patch component, said manufacturing process comprising:

- a base is provided from which extends at least one micro-needle, said micro-needle comprising a hollow body provided with a mouthpiece adapted to allow the entry of bodily fluid into an interior of the hollow body,

- an electronic circuit is provided comprising a flexible printed circuit comprising at least one electrical track and a detection unit,

- the electronic circuit is assembled at the base, a portion of the flexible printed circuit being arranged flexed in the respective micro-needle with the detection unit inside the hollow body.

[10] Thanks to these provisions, it is possible to use proven two-dimensional manufacturing techniques in order to produce an essentially three-dimensional product. The reliability of the invoiced product is therefore improved.

[11] According to various aspects, it is possible to provide one and/or the other of the characteristics below taken alone or in combination.

[12] According to one embodiment, when the base is supplied, the hollow body of the microneedle comprises a peripheral lateral surface extending from the base to a tip, the mouth being formed at least partially, and in particular totally, in the peripheral side surface, and, when assembled, the detection unit is placed facing the mouthpiece.

[13] According to one embodiment, when the electronic circuit is provided, an electrically insulating flexible matrix is provided, and the at least one electrical track and the detection unit are formed on the electrically insulating flexible matrix.

[14] According to one embodiment, a plurality of electrical tracks that are electrically isolated from each other and individually addressable are formed to measure a concentration of the analyte.

[15] According to one embodiment, the detection unit comprises:

- an electrode, a counter-electrode and optionally a reference electrode each connected to a respective electrical track, and/or

- a gate electrode, a drain electrode, a source electrode each connected to a respective electrical track, a semiconductor channel extending between the drain electrode and the source electrode. [16] According to one embodiment, detection units sensitive to various analytes are formed.

[17] According to one embodiment, a plurality of micro-needles extending from the base are formed.

[18] According to one embodiment, each detection unit extends into a respective microneedle.

[19] According to one embodiment, a pH sensor and/or a body fluid temperature sensor is also provided.

[20] According to one embodiment, an electronic chip is electrically connected to at least one electrical track.

[21] In another aspect, the invention relates to an analyte detection patch component comprising:

- a base from which extends at least one micro-needle, said micro-needle comprising a hollow body provided with a mouth adapted to allow the entry of bodily fluid into an interior of the hollow body,

- an electronic circuit comprising a flexible printed circuit comprising at least one electric track and a detection unit, the electronic circuit being assembled at the base, a portion of the flexible printed circuit being arranged flexed in the respective micro-needle with the detection inside the hollow body.

BRIEF DESCRIPTION OF DRAWINGS

[22] Embodiments of the invention will be described below with reference to the drawings, briefly described below:

[23] [Fig. 1] schematically represents a user wearing a patch.

[24] [Fig. 2] schematically represents a sectional view of a patch as shown in Figure 1 assembled to the user.

[25] [Fig. 3] is a partial perspective view which represents a base of the patch of figure 2.

[26] [Fig. 4] is a perspective view which represents a micro-needle of the patch of figure 3.

[27] [Fig. 5] is a view from the same perspective as Figure 3 of part of an electronic circuit intended to be assembled at the base of Figure 3.

[28] [Fig. 6] is a sectional view of the laminate of a track of the electronic circuit of figure 5.

[29] [Fig. 7] is a cross-sectional view of a tab according to one embodiment.

[30] [Fig. 8] is a detail sectional view of a detection portion of the electronic circuit assembled in a micro-needle. [31] [Fig. 9] is a view similar to Figure 7 for another analyte measurement unit.

[32] [Fig. 10] is a view similar to Figure 7 for a pH measurement unit.

[33] [Fig. 11] is a front view of a tab carrying a measurement unit in the form of a transistor.

[34] [Fig. 12] is a view from the same perspective as Figure 3 of the assembly of the base to the flexible printed circuit according to one embodiment.

[35] [Fig. 13] is an enlarged perspective view of a tab.

[36] [Fig. 14] is a sectional view of a micro-needle according to a second embodiment.

[37] In the drawings, identical references designate identical or similar objects.

DETAILED DESCRIPTION

[38] Figure 1 schematically shows a user 1 wearing a patch 2. The patch 2 is worn next to the skin, for example in a place easy to access for the user himself, which causes the minimum discomfort during movement, and typically hidden from view by others by clothing worn by the user, such as the forearm or upper arm, for example.

[39] The dimensions of patch 2 are for example a few centimeters per side, and less thick, for example, to a thickness of between 0.2 centimeters (cm) and 2 centimeters.

[40] Figure 2 gives an embodiment of a patch 2 assembled to the skin 6 of the user 1. Figure 2 is illustrated with a flat horizontal surface representing the outer surface of the skin of the user. Above this surface is the patch 2 and, below, the skin of the user. In the remainder of the description, to fix ideas, this arrangement and orientation are used. In particular, the terms “upper”, “lower”, “high”, “low”, etc. are used with reference to this orientation. However, in use, the outer surface of the skin, and therefore the patch it wears, could be oriented differently.

[41] As seen in Figure 2, the patch 2 comprises a housing 3. The housing 3 comprises a lower face 4 intended to be turned towards the outer surface 5 of the skin 6 of the user 1. The lower face 4 comprises an adhesive or glue 7 for adhesion to the outer surface 5 of the skin 6 of the user 1.

[42] Patch 2 is intended to carry out, in a repeated manner, an in situ measurement of the concentration of at least one analyte of user 1. That is to say that patch 2 is worn by the user for from a few minutes to several hours, or even up to a few days, and repeatedly measures the concentration of this analyte inside the body of the user. No surgical implantation step is necessary. No extraction of a sample from the body is necessary.

[43] The patch 2 comprises at least one micro-needle 8 which projects from the underside 4 of the casing 3. The length of the micro-needle 8 is for example less than 1 millimeter, so as not to penetrate too deeply into an innervated area of the skin. The patch 2 can comprise several micro-needles 8. In this case, the micro-needles 8 are arranged on the lower face 4 of the casing 3, according to any suitable arrangement. Detailed examples will follow. In Figure 2, there is shown four microneedles 8 aligned, identical, parallel, equi-distributed and centered on the housing 3. However, as a variant, the micro-needles 8 can be different from each other, inclined with respect to each other. to others, and/or distributed differently. In addition, in Figure 2, the micro-needles 8 are presented along a line. As a variant, the patch 2 can comprise other rows of one or more micro-needles in planes parallel to the plane of figure 2.

[44] In the following description, a micro-needle 8 will be described in particular, this description being applicable to other micro-needles 8. The micro-needle 8 is made of a sufficiently rigid material, and with a sufficiently tapered shape to penetrate inside the skin 6 when the patch 2 is assembled to the skin 6. As can be seen in particular in FIG. extend the micro-needles 8. This component, comprising the base and the micro-needles, is for example made by plastic molding. The base 9 takes for example the form of a plate, as shown, from which the micro-needles 8 extend. However, other shapes and manufacturing methods are possible.

[45] Incidentally, Figure 3 shows another example of an arrangement of microneedles 8 than the arrangement of Figure 2. In this example, the microneedles 8 are distributed over the periphery of the lower face 4 of the housing 3 from patch 2.

[46] As shown in Figure 4, according to an exemplary embodiment, a microneedle 8 comprises a peripheral side surface 10, for example frustoconical. The tip angle of the micro-needle 8 is acute. Other geometries are possible, such as for example a cylinder of revolution. In addition, a micro-needle 8 is made in the form of a hollow body, and comprises an interior channel 11 surrounded by the peripheral side surface 10, and extending towards the base 9. According to one embodiment, as shown in the Figure 3, the inner channel 11 can open into a mouth 12 of the upper surface of the base 9. This inner channel 11 can be orthogonal to the support base, or inclined with respect thereto. It can be parallel to the axis of the microneedle or not. [47] The micro-needle 8 also comprises a mouth 13 of the inner channel 11. For example, according to one embodiment, the mouth 13 is made entirely in the peripheral side surface 10 of the micro-needle 8. The mouth 13 is made sufficiently deep so that, once the patch has been correctly applied, the mouth 13 is located in a portion of the skin comprising interstitial liquid. The inner channel 11 receives a portion of the electronic circuit 14, as will be explained in detail later.

[48] Returning now to Figure 2, patch 2 also includes an electronic circuit 14. Electronic circuit 14 is assembled at base 9. Any type of direct or indirect assembly between these two components can be used. The electronic circuit 14 may comprise an electrically insulating support carrying electrically conductive tracks connecting electronic components together, such as an electronic chip 99.

[49] Figure 5 gives an example of an embodiment of an electronic circuit part 14 for patch 2, in a configuration prior to its assembly. In the present case, the electronic circuit 14 comprises a flexible printed circuit 15. As can be seen in FIG. 5, the flexible printed circuit 15 comprises a main surface zone from which several tabs 25 extend. In this example, the zone main is essentially polygonal, and the tabs 25 extend from the same edge of the polygon, and essentially parallel to each other. However, other geometries are possible.

[50] The flexible printed circuit comprises for example a thickness of less than 50 microns, or even less than 40 microns. A flexible printed circuit allows reversible elastic deformation by bending test with a radius of curvature of less than 2 millimeters (mm), for up to at least five consecutive bending tests. The flexible printed circuit 15 comprises a flexible electrically insulating support 16 bearing electrically conductive zones. The flexible electrically insulating support is for example made of polydimethylsiloxane (PDMS), polyethylene terephthalate (PET), polyimide, poly ethylene naphthalate or polyetheretherketone (“PEEK”). As can be seen in FIG. 5, the flexible electrically insulating support 16 carries electrically conductive zones such as electrical contacts 17, electrical tracks 18 or functionalized detection portions 19. In the example shown, each electrical track 18 connects a detection portion 19 to an electrical contact 17.

[51] The electrical contacts 17 are arranged to be assembled with an electronic chip 99 which comprises several components for electrochemical measurement such as a microprocessor, a potentiostat, a battery, etc.... [52] Although Figure 5 shows a particular arrangement of the electronic circuit 14, other arrangements are possible within the scope of the invention.

[53] Alternatively, the electronic components can be individually connected directly to the flexible printed circuit.

[54] According to one embodiment, as also shown in Figure 5, the flexible printed circuit 15 comprises a second flexible electrically insulating support 20 superimposed on the first flexible electrically insulating support 16, so as to protect the electrical tracks. As can be seen in this example, once the two flexible electrically insulating supports 16, 20 have been assembled, only the contacts 17 remain accessible for connection to the electronic chip 99 and the detection portions 19 for the measurement of analytes in the interstitial liquid.

[55] The electrically conductive areas are for example produced by depositing an electrically conductive film 21 according to a predefined geometry, for example by screen printing. The film 21 is for example a film of gold, carbon, carbon ink, with or without inclusion of nanoparticles.

[56] As can still be seen in Figure 6, the flexible printed circuit 15 comprises tabs 25 intended to be inserted bent into the interior channels 11. Thus, the tabs 25 have at least the same laminate as the rest of the flexible printed circuit, with a lower insulating layer 16, electrically conductive zones and an upper insulating layer 20. The tongue 25 comprises a width and a thickness inscribed in the cross section of the inner channel 11.

[57] According to one example, each detection portion 19 of the tab 25 extends in the continuity of an electrical track 18. Certain electrodes may have different geometries.

[58] As seen in Figure 6, at the detection portion 19, the insulating electrical support layer 16 is absent. In addition, the electrically conductive zone is functionalized at the level of at least one of the electrodes of the detection portion.

[59] Depending on the function that one wishes to give to the detection portion, various functionalizations are possible. Several examples will be described below.

[60] FIG. 6 represents an embodiment of a detection portion 19 made in the form of an electrode for detecting a particular analyte. The analyte in question can be a chemical species, such as an ion, an atom, a molecule or a group of molecules (for example, different molecules comprising the same chemical function). The analyte in question may be endogenous or exogenous to the body of the user. Below, the detection of various metabolites is described according to several examples. [61] The detection electrode comprises an enzymatic layer 22 suitable for reacting chemically with the metabolite to generate a derivative product, such as for example nitrogen peroxide (H2O2) or a nicotinamide adenine dinucleotide (NADH) whose concentration depends of the metabolite concentration, and which is detectable by applying a potential to the film 21. The layer 22 is for example produced in the form of a matrix encapsulating the enzymes and co-factors necessary for the enzymatic chemical reaction. This matrix is for example a polymer, such as for example a chitosan, a poly-l-lysine, a polyaniline, a polypyrrole or the like.

[62] One can optionally use a layer of redox mediator or catalyst 23, disposed between the film 21 and the enzymatic layer 22 to improve the yield of the above reaction. On the opposite side to the film 21, a selective porous membrane 24 can be arranged to reserve access to the enzymatic layer 22 for the metabolite, and to limit the access of other species of the tested liquid. The membrane 24 comprises for example polyvinyl chloride or an ethanesulphonyl fluoride.

[63] The catalyst layer 23, the enzymatic layer 22 and the membrane 24 can be applied to the film 21 by droplet deposition or screen printing techniques or another suitable technique.

[64] Figure 7 shows a front view of the tab 25. This comprises the electrode 26 which has just been described, as well as a counter-electrode 27 and a reference electrode 29 separated from each other by an electrically insulating portion 20. The electrode 26, the counter-electrode 27 and the reference electrode 29 are all three formed on the electrically insulating layer 20 while being separated from each other by a space.

[65] An electrode 26 and the counter electrode 27 associated together are called a detection unit 35. Thus, a detection unit 35 is adapted to detect the concentration of a particular analyte.

[66] The reference electrode 29 is for example formed by a layer of silver, silver chloride or iridium oxide, if necessary deposited on the gold layer.

[67] As can be seen in particular in Figure 13, the electrode 26, the counter-electrode 27 and the reference electrode 29 of the tongue 25 (whose electrical insulation is not visible in this figure ) are each addressed by a respective electrical track 18a, 18b, 18c.

[68] Figure 8 shows the insertion of the tab 25 in the channel 11 of the micro-needle. The tongue 25 is bent. The tongue 25 bears against an internal face 28 of the channel 11. In particular, the tongue 25 bears against the internal face 28 of the channel 11 opposite the mouth 13. The tongue 25 is oriented in the channel 11 with the detection unit 35 facing the mouth 13, and the insulating portion facing the internal face 28.

[69] Thus, the base 9 and the flexible printed circuit 15 are designed so that the tabs 25 of the flexible printed circuit 15 fit into the channels 11 of the base 9. According to the arrangement of the micro-needles 8, it is therefore possible to have very different geometries for the flexible printed circuit, with tabs of different length and orientation, for example.

[70] In the example presented, the tongue is bent by around 90° with respect to the base of the flexible printed circuit. According to the embodiments, the tongue is bent by at least 30°, at least 45°, at least 60°, at least 80° with respect to the base of the flexible printed circuit. Typically, the flexion is less than 135°.

[71] Figure 12 shows in particular the assembly of a flexible printed circuit 15 on one side of the base 9. For this basic embodiment 9, another flexible printed circuit 15 can be used for the micro-needles arranged on a other side of the base 9. Different embodiments are possible, such as using only one printed circuit.

[72] The system just described can work as follows. For example, a blood glucose measurement is described.

[73] Layer 22 includes glucose oxidase.

[74] Patch 2 is applied to skin 6, so that microneedle 8 penetrates skin 6 of user 1. Interstitial fluid can then enter the channel

11 through the mouthpiece 13. The fact that the mouthpiece 13 is lateral limits the risks of the mouthpiece being blocked by a solid body during the insertion of the micro-needle 8 into the skin, and of mechanical deterioration of the tab when inserting. In addition, it decreases the flow time of the molecules to the measurement location.

[75] An electric potential difference is applied by a generator (not shown) of the electronic circuit between the electrode 26 and the counter-electrode 27. The generator is for example an electronic component of the patch electrically connected to a contact 17 electrically connected to the electrode 26 via a track 18 and to a contact 17 electrically connected to the counter-electrode 27 via a track 18.

[76] The reaction of interstitial fluid glucose with glucose oxidase generates hydrogen peroxide (H2O2). The electronic circuit continuously measures the electric current flowing between the electrode 26 and the counter-electrode 27. The intensity of the electric current measured depends on the conversion rates of the hydrogen peroxide, and consequently depends on the concentration of ci at the level of the detection unit 35. The concentration of hydrogen peroxide itself depends on the concentration of glucose. Therefore, the intensity of the measured current depends on the concentration in glucose. The reference electrode is used as a reference in the measurement and control of the potential applied to the working electrode. Thus, the functions of supplying the electrons and controlling the potential are implemented by two separate electrodes.

[77] Such a measurement is repeated over time, for example every hour, to obtain a change in concentration over time.

[78] The foregoing description relates to an embodiment for a detection unit 35.

[79] As seen in Figures 2, 3 and 5, several microneedles 8 can be used. As explained above, the microneedles 8 can be distributed according to different configurations. Preferably, the micro-needles 8 are sufficiently spaced from each other to allow the proper insertion of these into the skin. A typical spacing between two micro-needles is for example at least 0.5 millimeters. Thus, chemical or electrical interference between measurement units is reduced. For example, these at least two micro-needles 8 implement the detection which has just been described above. In this case, as can be seen in particular in FIG. 5, the flexible nature of the flexible printed circuit 15 makes it possible to manufacture the electrodes by conventional 2D microelectronic techniques, with a view to producing a three-dimensional product. Connectivity to electronic components or chips is simplified. In addition, it is possible to deport the electronic chip controlling the application of potential differences between the electrode and the corresponding counter-electrode and measuring the electrical intensity. The detection units formed are individually addressable by the electronic chip via tracks 18 to measure the analyte concentrations. The fact of using several detection units 35 makes it possible to improve the overall signal/noise ratio of the measurement, if it is considered that the measurement carried out by the different detection units must give the same result (no local variation of the analyte concentration at the patch scale 2).

[80] According to another embodiment, as shown in Figure 9, the tongue 25 carries the electrode 26 and the counter-electrode 27 excluding the reference electrode 29. This arrangement increases the relative surface of the electrode 26 and of the counter-electrode 27 with respect to the total surface of the tongue 25. Thus, according to this embodiment, another tongue 25 carries the reference electrode 29. According to this embodiment, it It is possible to use several tongues 25 each carrying an electrode 26 and a counter-electrode 27, and a reduced number (for example a single) tongue 25 carrying a common reference electrode 29 for all the electrodes.

[81] According to yet another embodiment, the patch 2 can be configured to measure the concentration of a metabolite in the interstitial fluid other than glucose. [82] For example, the measured metabolite is glycerol. In this case, according to an exemplary embodiment, the layer 22 comprises a glycerol oxidase.

[83] For sensing glycerol concentration, alternatively, layer 22 includes glycerol kinase, glycerol-3P-oxidase, and adenosine triphosphate (ATP).

[84] According to another example, the metabolite measured is free fatty acids (responding to the acronym "NEFA" for their designation "non-esterified fatty acid" in English). In this case, according to an exemplary embodiment, layer 22 comprises a coenzyme 1, ATP, an acyl-coenzyme A synthetase and an acyl-coenzyme A oxidase.

[85] The examples above measure the decomposition of hydrogen peroxide resulting from the reaction of the metabolite with the enzyme layer.

[86] To catalyze the reaction of H2O2, according to one embodiment, an ink containing iron particles (for example an Iron(ll) phthalocyanine) is used for the electrode. Alternatively, a Prussian blue is deposited on the electrode surface. Alternatively, iron nanoparticles are electro-deposited on the electrode surface or within the matrix of the enzymatic layer.

[87] Alternatively, other reactions can be used to electrochemically detect the analyte concentration in the interstitial fluid.

[88] According to an exemplary embodiment, a product derived from the reaction of the analyte of interest with the associated enzymatic layer can be nicotinamide hydride

(“NADH”).

[89] For example, for the detection of glycerol, the enzyme layer 22 comprises a glycerol dehydrogenase and NAD+, so that the reaction of glycerol with this enzyme layer generates NADH whose oxidation is detectable in the same way as described below. above for the decomposition of hydrogen peroxide.

[90] According to another example, the measured metabolite is a ketone body. For example, the measured metabolite is 3-p-hydroxybutyrate. The enzymatic layer 22 then comprises, according to one example, a 3-hydroxybutyrate dehydrogenase and NAD+.

[91] To catalyze the oxidation reaction of NADH, according to one embodiment, Meldola blue is used.

[92] In yet another example, the analyte being measured is an ion, atom, or other molecule of interest.

[93] Thus, a patch 2 can be used to detect any of these analytes in the interstitial fluid.

[94] Alternatively, a patch 2 can be used to detect several of these analytes in the interstitial fluid. Provision can be made, for example, for an electrode 26 to be structured to detect one of the analytes, and another electrode 26 is structured to detect another of the analytes. For example, these two electrodes 26 are arranged in different micro-needles 8. As described above in the case of glucose, one can detect the same analyte in several micro-needles and/or use a dedicated micro-needle for the reference electrode.

[95] According to a variant, the patch 2 also comprises a unit for measuring the pH of the interstitial liquid. The pH measurement unit can be made on a flexible tab inserted into an 8 micro-needle as described above for the metabolite concentration measurement units. For example, an electrochemical measurement unit is produced, as shown in FIG. 10, further comprising an intermediate layer 30 between the electrode and the counter-electrode, and comprising a material whose electrical resistance depends on the pH of the solution. The pH measurement is then carried out by chemical resistance.

[96] Alternatively, a unit of pH measurement can be made by amperometry or voltmetry. In a three-electrode system, as described above in connection with Figure 7, the electrode is functionalized with a layer sensitive to pH changes in the surrounding interstitial fluid. By applying a potential difference between the electrode and the counter-electrode, the variations of the couple { applied potential ; measured current} are indicative of the pH variation of the interstitial fluid.

[97] Among the materials whose electrical properties depend on the pH and which can be used in the embodiments above, one can for example use polyaniline, polypyrrole, an arylamine, a carbazole, an aliphatic or aromatic diaimine, a polythiophene, a polyarylamine, a pentacene or a parylene C.

[98] These polymers can for example be electro-deposited on the working electrode surface in the case of a three-electrode system, or polymerized on the support surface (on the electrode or between two electrodes) by exposure to higher temperature and/or to a polymerizing agent.

[99] In one aspect, patch 2 may include a temperature sensor. For example, the temperature sensor comprises a measuring unit in contact with the interstitial liquid. The measurement unit is for example associated with a micro-needle 8. A tongue can for example carry a thermistor thermometer. In this case, the electrical resistivity of the sensor changes with temperature. Thus, by applying a potential difference between the inputs of the sensor and measuring the current, measuring the change in resistivity provides access to the temperature.

[100] Alternatively, the patch 2 may include a thermocouple. The measurement is carried out thanks to the Seebeck effect describing a potential difference proportional to the temperature obtained at the electrical junction of two different electrical conductors. The pair of metals used for these two conductors can be, for example, titanium (Ti) and gold (Au). For example, a tab inserted into a microneedle comprises these two materials. Alternatively, the thermocouple can be integrated into the surface of a microneedle. In this case, for example, it can be made by sputtering.

[101] According to a variant, a unit of measurement of an analyte or of pH can be implemented in the form of a transistor, as represented in FIG. 11 in the particular case of an organic electrochemical transistor (“OECT ”) coplanar. The flexible support carries a source electrode 31, a drain electrode 32 and a gate electrode 33. In addition, a semiconductor channel 34 connects the drain electrode 32 and the source electrode 31. The grid 33 is functionalized to detect the presence of an analyte, as described above. Detection of analytes at gate electrode 33 changes the voltage thereon which, in turn, changes the charge distribution in the transistor, and causes a change in electrical current in channel 34. measurement of this change in current allows the concentration of the analyte to be defined.

[102] Measurement unit electrodes employing transistor measurement technology can be produced on the same principles as above. Alternatively, an electrically conductive polymer such as poly(3,4-ethylenedioxythiophene): poly(styrene sulfonate) sodium (PEDOT:PSS) can be used.

[103] As material for the channel, polymers such as: PEDOT:PSS, poly(2-(3,3'-bis(2-(2-(2-methoxyethoxy)ethoxy)-ethoxy)-[2, 2'-bithiophen]- 5- yl)thieno[3,2-b] thiophene) (p(g2T-TT)), poly(3,4-ethylenedioxythiophene): poly(3-sulfonyl(trifluoromethanesulfonyl)imide propyl methacrylate of lithium)

(PEDOT:PMATFSI), poly(3,4-ethylenedioxythiophene):poly(styrenesulfonyl(trifluoromethanesulfonyl)lithium imide) (PEDOT:PSTFSI), or the like.

[104] There are many variant embodiments of field-effect or organic electrochemical transistors that can be made on a flexible substrate and using the methods mentioned above. One can for example use the so-called top gate (“top-gated”), coplanar gate (“coplanar gated”), vertical transistor (“vertical transistor”) configurations.

[105] Alternatively, as shown in Figure 14, some micro-needles bear on their outer face the temperature measurement electrodes. These microneedles then do not necessarily include a mouthpiece 13 or a channel 11. In this embodiment, for example, the base 9 comprises through holes 36. The microneedle 8 bears on its surface an electrically conductive layer 37 which is electrically connected to the flexible printed circuit 15 via a first through-hole 36 without covering the other through-hole 36. The micro-needle 8 bears on the first electrical layer 37 an electrically conductive layer 38 which is electrically connected to the circuit flexible print 15 via the second through-hole 36. The temperature sensor, the electrodes of which are not functionalized, can thus be arranged on the outer face of the micro-needle.

[106] The electronic circuit is then programmed to implement the measurements.

[107] The electronic chip 99 may include a clock to clock the measurements. The electronic chip 99 can comprise a memory for storing the measurements carried out, if necessary associated with clock data. The electronic chip 99 can comprise one or more electronic communication modules for transmitting data to a remote electronic device. The electronic communication module can be adapted to communicate by wire with the remote electronic device. For example, the remote electronic device is connected by wire to the electronic circuit 14, and the measurement data is copied to the remote electronic device. As a variant, the electronic communication module can be adapted to communicate wirelessly with the remote electronic device. For example, a short-range communication is implemented, for example according to a Bluetooth standard available on the priority date of the present patent application. The data communication may be timed, for example implemented repeatedly, for example once per hour or otherwise. The remote electronic device may include a processor suitable for processing data.

[108] The electronic chip 99 may include a processor suitable for pre-processing the acquired data. This pre-processing may aim to improve the signal-to-noise ratio (statistical operations on the data, filtration, averaging, etc.) and/or to condense the data with a view to facilitating their transmission.

[109] Patch 2 also includes a power source, such as a coin cell battery, to supply electrical power to the electronic components.

[110] If necessary, a patch component is provided which comprises the base 9 and the flexible printed circuit 15, if necessary in kit form, and the electronic chip and the other electronic components are assembled to the flexible printed circuit 15 by a third party .

[111] Alternatively, the different functions implemented by the electronic chip can be performed by different electronic components that are not not gathered within a chip, but provided individually and electrically connected to the flexible printed circuit 15.

[112] The system just described can be fabricated as follows.

[113] The base 9 carrying the micro-needles 8 is manufactured. Such a component can be manufactured for example by additive manufacturing, by molding, by use, by engraving, and/or by assembly of individual components.

[114] We manufacture the flexible printed circuit. A flexible electrically insulating support 16 is provided, and the electrically conductive layer is provided on this support according to photolithography techniques for example. The support 16 thus designed is covered with the flexible insulating layer 20. If necessary, part of the electrically insulating flexible support 16 and/or 20 is locally removed in the electrically conductive zones intended to be exposed. Alternatively, screen printing, lithography, laser cutting or additive manufacturing methods could be used.

[115] Then, the exposed electrically conductive zones are functionalized according to the analyte to be detected by means of each respective zone. The catalyst layer is for example printed, deposited or electro-deposited. The layer comprising the enzymes is for example produced by applying a drop of matrix in which the enzymes and co-factors have been introduced beforehand, and by causing this layer to polymerize thermally or by drying. The membrane is deposited by drop or by immersion, then polymerized by drying.

[116] The flexible printed circuit is assembled at the base 9, the tabs flexing to fit into the channels of the micro-needles according to the desired orientation.

[117] The product described above can be used to detect the concentration of analytes in body fluids other than interstitial fluid, if present.

LIST OF REFERENCE SIGNS

1: User

2: Patch

3: housing

4: underside

5: outer surface

6: skin

7: adhesive

8: micro needle

9: base

10: peripheral lateral surface

11: inner channel 12: mouthpiece

13: Mouthpiece

14: Electronic circuit

15: Flexible printed circuit

16: electrically insulating support

17: electrical contact

18: electric track

19: detection portion

20: flexible electrically insulating support

21: movie

22: enzyme layer

23: catalyst layer

24: selective porous membrane

25: tongue

26: electrode

27: counter electrode

28: inner wall

29: reference electrode

30: middle layer

31: source electrode

32: drain electrode

33: grid electrode

34: semiconductor channel

35: detection unit

36: through hole

37, 38: Electrically conductive layer

99: Microchip

Claims

1. A method of making an analyte detection patch component, said method of making comprising:

- a base (9) is provided from which extends at least one micro-needle (8), said micro-needle (8) comprising a hollow body provided with a mouth (13) adapted to allow entry of bodily fluid into an interior of the hollow body,

- an electronic circuit (14) comprising a flexible printed circuit (15) comprising at least one electrical track (18) and a detection unit (35) is provided,

- the electronic circuit (14) is assembled on the base (9), a portion of the flexible printed circuit (15) being arranged flexed in the respective micro-needle (8) with the detection unit (35) inside of the hollow body.

2. A method of manufacturing an analyte detection patch component according to claim 1, wherein when providing the base (9), the hollow body of the microneedle (8) has a peripheral side surface (10) extending from the base (9) to a tip, the mouth (13) being formed at least partially, and in particular totally, in the peripheral side surface (10), and in which, when assembling, the detection unit is arranged opposite the mouthpiece (13).

3. A method of manufacturing an analyte detection patch component according to claim 1 or claim 2 wherein, when the electronic circuit (14) is provided, an electrically insulating flexible matrix is provided, and at the at least one electrical track (18) and the detection unit on the electrically insulating flexible die.

4. A method of manufacturing an analyte detection patch component according to any one of claims 1 to 3, in which a plurality of electrical tracks (18) electrically isolated from each other, and individually addressable for measuring a concentration of the analyte.

5. A method of making an analyte detection patch component according to claim 4, wherein the detection unit comprises:

- an electrode (26), a counter-electrode (27) and optionally a reference electrode (29) each connected to a respective electrical track (18), and/or

- a gate electrode (33), a drain electrode (32), a source electrode (31) each connected to a respective electric track (18), a semi- conductor (34) extending between the drain electrode (32) and the source electrode (31).

6. A method of making an analyte detection patch component according to claim 5, wherein detection units sensitive to various analytes are formed.

7. A method of manufacturing an analyte detection patch component according to any one of claims 1 to 6, wherein a plurality of microneedles (8) extending from the base (9) are formed.

8. A method of making an analyte sensing patch component according to claim 7 and claim 5 or 6, wherein each sensing unit extends into a respective microneedle (8).

9. A method of making an analyte-sensing patch component according to any preceding claim, wherein a pH sensor and/or a body fluid temperature sensor is also provided.

10. Method for manufacturing an analyte detection patch component according to one of claims 1 to 9, in which an electronic chip (99) is electrically connected to the at least one electrical track (18).

11. Analyte detection patch component comprising:

- a base (9) from which extends at least one micro-needle (8), said micro-needle (8) comprising a hollow body provided with a mouthpiece (13) adapted to allow the entry of liquid bodily into an interior of the hollow body,

- an electronic circuit (14) comprising a flexible printed circuit (15) comprising at least one electric track (18) and a detection unit (35), the electronic circuit (14) being assembled on the base (9), a portion of the flexible printed circuit being arranged flexed in the respective micro-needle (8) with the detection unit in the interior of the hollow body.