In vivo measurement system

Abstract

The in vivo measurement system for at least one physiological parameter in a biological fluid comprises a measurement circuit (43; 55) which includes a working electrode (42; 53) and a reference electrode (41; 52), a characterization circuit (46; 65; 69) which includes a working electrode (47; 66; 70), a reference electrode (49; 68; 72) and a counter electrode (48; 67; 71), and a processor (151) which determines the physiological parameter from electrical signals from these circuits. Figure for the abstract: Figure 5

Description

Title of the invention: In vivo measurement system FIELD OF INVENTION

[0001] The present invention relates to an in vivo measurement system for at least one physiological parameter in a biological fluid. technological BACKGROUND

[0002] Chronic kidney disease is a major public health problem, affecting approximately 10% of the world's population. If not managed at an early stage, these diseases can progress to conditions requiring renal replacement therapy, such as regular dialysis or kidney transplantation. These treatments are not only invasive to the body and the daily lives of patients, but also very costly for public health systems. Furthermore, the prospect of progression to an advanced stage of chronic kidney disease discourages physicians from prescribing certain medications, such as antihypertensives, which can cause hyperkalemia. It is therefore crucial to intervene early and ensure continuous patient monitoring to prevent the progression of chronic kidney disease.

[0003] To this end, several techniques are known for monitoring patients, but they rely on occasional, painful, and invasive blood draws. Currently, only patients' blood glucose levels can be recorded continuously, using devices worn on the arm or abdomen. These devices use flexible filaments approximately 1 cm long, placed under the skin's surface, which measure glucose concentration electrochemically. These sensors are used with an injector developed for placing the filament under the skin using a retractable needle. These injectors are for single use only and are systematically discarded after the sensor is placed on the user's skin, thus generating a significant amount of waste.Moreover, during the installation of the sensor in these injectors, there is a high risk of contamination and damage to the sensor, either through exposure to ambient air or through necessary handling by the user, which can distort the measurements obtained.

[0004] A compromise must be made regarding the filament length. A greater length allows access to a deeper area of ​​the patient and provides information more representative of biological phenomena in situ. However, this increased depth can result in greater discomfort for the patient. Therefore, efforts are made to reduce the penetration length, which can negatively impact the interpretation of the measured signal. US 2021 / 321,942 mentions bioimpedance measurements of microneedles or microneedle arrays for measuring or Estimating the depth of microneedle penetration into the skin (i.e., whether the microneedles are in contact with the skin, or the percentage that are) is a problem described in US 11,857,344. However, the proposed solution is to look for correlations in the electrical characteristics measured by the measurement circuit itself.

[0005] The invention aims to remedy these drawbacks. Summary of the invention

[0006] Thus, the invention relates to an in vivo measurement system for at least one physiological parameter in a biological fluid, comprising: - a measurement circuit for an analyte present in the biological fluid, said measurement circuit comprising at least one working electrode and one reference electrode adapted to be disposed at least partially in the biological fluid, - a characterization circuit comprising at least one working electrode, one reference electrode and one counter electrode adapted to be disposed at least partially in the biological fluid, - a processor adapted to receive an electrical signal from the measurement circuit and an electrical signal from the characterization circuit, and to determine said at least one physiological parameter associated with said analyte from these electrical signals.

[0007] Thanks to these arrangements, a more precise measurement of the physiological parameter is obtained.

[0008] Depending on different aspects, it is possible to foresee one and / or the other of the characteristics below taken alone or in combination.

[0009] According to one embodiment, the characterization circuit is a characterization circuit of the reference electrode of the measurement circuit, adapted to deliver a signal characterizing the reference electrode of the measurement circuit.

[0010] According to one embodiment, the characterization circuit is a depth characterization circuit adapted to deliver a signal characterizing the insertion depth of the electrodes.

[0011] According to one embodiment, the characterization circuit is a first characterization circuit, the measurement system further comprising a second characterization circuit, which is a characterization circuit of the reference electrode of the measurement circuit, adapted to deliver a signal characterizing the reference electrode of the measurement circuit.

[0012] According to one embodiment, said analyte is a first analyte, the characterization circuit is a mixed characterization circuit adapted to deliver a signal characterizing either the reference electrode of the measurement circuit or the insertion depth of the electrodes, the mixed characterization circuit further comprising an electrode of specific work of a second analyte present in the biological fluid, and the processor being adapted to receive an electrical signal from the mixed characterization circuit, and to determine a second physiological parameter associated with the second analyte from this electrical signal

[0013] According to one embodiment, the measurement circuit further includes a counter electrode adapted to be disposed at least partially in the biological fluid.

[0014] According to one embodiment, the measurement system further comprises another measurement circuit for another analyte present in the biological fluid, said other measurement circuit comprising at least one working electrode and one reference electrode adapted to be disposed at least partially in the biological fluid, the processor being adapted to receive an electrical signal from the other measurement circuit and an electrical signal from the characterization circuit, and to determine at least one physiological parameter associated with the other analyte from these electrical signals.

[0015] According to one embodiment, a reference electrode is common to several measurement circuits.

[0016] According to one embodiment, a counter electrode is common to several circuits.

[0017] According to one embodiment, the analyte is chosen from the list {potassium, glucose, creatinine, acids, sodium, calcium, lactate, ketone bodies, urea}.

[0018] According to one embodiment, the measurement system comprises a sensor including an electrically insulating base through which extend at least two electrically conductive modules, electrically isolated from each other by the base, and each electrically conductive module includes a plurality of parallel needles forming one of said electrodes.

[0019] According to one embodiment, the measurement circuit comprises: - an electrically insulating base, having a first face intended to be applied from the outside against the skin of a patient, - at least one module comprising a metallic core obtained from a sheet of metal, the metallic core passing through the electrically insulating base, and comprising a rear end adapted to be electrically connected to an electronic sensing system, and a front end portion opposite the rear end, forming at least a part of at least one of said electrodes, protruding from the base, adapted to penetrate the patient, and having a functionalizing coating for the measurement of said physiological parameter.

[0020] According to another aspect, the invention relates to a method for in vivo measurement of at least one physiological parameter in a biological fluid, in which: having a measurement circuit for an analyte present in the biological fluid, said measurement circuit comprising at least one working electrode and one electrode reference materials adapted to be at least partially placed in the biological fluid, having a characterization circuit comprising at least one working electrode, one reference electrode and one counter electrode adapted to be at least partially placed in the biological fluid, - a processor receives an electrical signal from the measurement circuit and an electrical signal from the characterization circuit, and determines said at least one physiological parameter associated with said analyte from these electrical signals.

[0021] According to another aspect, the invention relates to a computer program comprising portions of program code for the execution of the steps of such a process, when said program is executed on a processor. Brief description of the drawings

[0022] Embodiments of the invention will be described below with reference to the drawings, briefly described below:

[0023] [Fig. 1] represents a schematic perspective view of a sensor from the kit according to an example embodiment.

[0024] [Fig.2] represents a schematic side view of an example of a sensor analysis module of [Fig.1].

[0025] [Fig.3] represents a schematic perspective view of the analysis module of the [Fig.2],

[0026] [Fig.4] represents a schematic perspective view of an example of an electronic module of the sensor of [Fig.1].

[0027] [Fig.5] is a functional diagram representing a sensor according to one embodiment.

[0028] [Fig.6] is a view similar to [Fig.5] for a second embodiment.

[0029] [Fig.7] is a view similar to [Fig.5] for a third embodiment.

[0030] [Fig.8] is a view similar to [Fig.5] for a fourth embodiment.

[0031] [Fig.9] is a view similar to [Fig.5] for a fifth embodiment.

[0032] [Fig. 10] is a view similar to [Fig. 5] for a sixth embodiment.

[0033] [Fig. 11] is a view similar to [Fig.5] for a seventh embodiment.

[0034] [Fig. 12] is a view similar to [Fig.5] for an eighth embodiment.

[0035] [Fig. 13] is a view similar to [Fig.5] for a ninth embodiment.

[0036] [Fig. 14] is a view similar to [Fig.5] for a tenth embodiment.

[0037] [Fig. 15] is an example of a cyclic voltammetry curve showing on the abscissa the current measured, expressed in microamperes, when a potential difference expressed in Volts is applied.

[0038] [Fig. 16] is a top view of a plate used for manufacturing modules according to an example embodiment.

[0039] [Fig. 17] is an electron microscopy of a module according to an example embodiment.

[0040] [Fig. 18] is a graph representing, on the abscissa, time, and on the ordinate, the measured concentration of potassium, in millimoles per liter (mmol / 1), during an in vivo experiment, by means of a commercial sensor (points) and a device according to an embodiment of the invention (curve).

[0041] In the drawings, identical references designate identical or similar objects. DETAILED DESCRIPTION

[0042] An example of a system 1 for detecting and / or measuring an analyte and / or a physiological parameter in a biological fluid will now be described. In particular, each of the components of system 1 will be described with reference to the non-limiting embodiment examples shown in Figures 1 to 18.

[0043] The system 1 comprises a sensor 10, an example of which is shown in [Fig. 1]. The sensor 10 comprises an analysis module 12 and an electronic module 14. The analysis module 12 is configured to interface with the patient and is functionalized to perform the desired measurements.

[0044] The analysis module 12 and the housing of the electronic module 14 are, for example, made, at least partially, of a polymer material, in particular an injectable polymer or one usable in 3D printing, such as acrylonitrile butadiene styrene (ABS) or polycarbonate (PC). Of course, the material of the analysis module 12 may be the same as or different from the material of the housing of the electronic module 14.

[0045] As will be detailed, the analysis module 12 and the electronic module are connected to each other, and can in particular be connected to each other in a detachable or permanent manner.

[0046] The analysis module 12 will now be described with reference to Figures 2 and 3.

[0047] The analysis module 12 comprises a base 16. The base 16 comprises a thin plate having a first face 16-1 and a second face 16-2 that are opposite. In the embodiment presented, a plate with two opposite flat faces is shown, but other geometries are possible.

[0048] Base 16 is advantageously made of a non-conductive material. For example, base 16 is made of an electrically insulating polymer material, in particular an injectable or 3D printed polymer, without this being limiting.

[0049] The analysis module 12 further comprises an analysis matrix 18 intended to be brought into contact with the biological fluid in which the analyte and / or the parameter Physiological is measured and / or detected. As seen in [Fig.2], the analysis matrix 18 is linked to the base 16.

[0050] In this example in [Fig. 2], the analysis matrix 18 comprises a plurality of needles 20 intended to be brought into contact with the body fluid in which the analyte and / or physiological parameter is measured and / or detected. More specifically, one tip of each needle 20 is shaped to penetrate the user's skin so as to come into contact with the body fluid, in particular the interstitial fluid, and thus be able to measure and / or detect the analyte and / or physiological parameter in vivo and in real time. Thus, the measurement system 1 is a minimally invasive system, intended to remain outside the patient, with only a portion of the needles penetrating the patient's skin. The system can therefore be installed and used non-surgically.

[0051] According to an example, shown in [Fig.5], the plurality of needles 20 can be configured so that the needles 20 operate in pairs, so that one of the needles 20 of each pair acts as a reference electrode 41, while the other needle 20 of the pair acts as a working electrode 42. The measurement and / or detection of the analyte and / or the physiological parameter is then made between the two needles 20 of each pair, by measuring the voltage between the two corresponding electrodes.

[0052] According to one embodiment, the analyte being measured is the potassium concentration in the interstitial fluid. The working electrode 42 comprises a potassium-specific coating. The chemical reaction takes place between the potassium and the coating at the working electrode and does not occur at the reference electrode. The electrical measuring circuit 43 includes a voltmeter 44, which measures the electrical potential difference between the working electrode 42 and the reference electrode 4L. This potential difference is representative of the potassium concentration at the working electrode 42.

[0053] The sensor 10 further includes a circuit for characterizing the reference electrode 46. The circuit for characterizing the reference electrode 46 includes a working electrode 47, a counter electrode 48, and a reference electrode 49.

[0054] The electrodes of the characterization circuit for the reference electrode 46 are also supported by the base 16, such that these electrodes are sufficiently close to the electrodes of the electrical measurement circuit 43 so that the phenomena of interest occurring in the interstitial fluid are the same or similar at the level of the electrical measurement circuit 43 and the characterization circuit for the reference electrode 46. The electrodes are, for example, circumscribed by a circle of radius 1.5 centimeters (cm), in particular of radius 1 cm, in particular of radius 0.5 cm. The electrodes of the characterization circuit for the reference electrode 46 are also adapted to be in contact with the interstitial fluid. The reference electrode 49 of the characterization circuit of the reference electrode 46 is identical to the reference electrode 41 of the measurement circuit 43.

[0055] By "identical", we mean here, with regard to several electrodes, that the dimensions, locations, chemical, mechanical and physical characteristics of the two electrodes are, from the point of view of a person skilled in the art, identical for the desired measurement function, despite the inevitable dispersion of these characteristics.

[0056] The working electrode 47 has a coating comprising a known redox mediating element, such as, for example, ferrocene, an osmium complex, and / or naphthoquinone. In particular, the working electrode 47 is not functionalized in a manner specific to an analyte contained in the interstitial fluid. The characterization circuit of the reference electrode 46 also includes an ammeter 51 adapted to measure the current flowing between the working electrode 47 and the counter electrode 48.

[0057] A processor 151 receives the electrical signals measured by the electrical measurement circuit 43 and the reference electrode characterization circuit 46, and determines the potassium concentration in the interstitial fluid at the working electrode 42 of the measurement circuit 43 from these signals. For example, the potential of the reference electrode 41 is corrected from the measurement taken on the reference electrode characterization circuit 46, and this corrected value is used in the potential difference analysis used for the potassium concentration measurement.

[0058] More specifically, cyclic voltammetry is implemented in the characterization circuit of the reference electrode 46. During this step, a potential difference is applied between the working electrode 47 and the reference electrode 49. The potential is applied variably over time according to a V-shaped or inverted V-shaped profile, and in particular, repeated cyclically, by means of a suitable potentiostat. One cycle comprises a phase of increasing potential difference between two inversion potentials, and a phase of decreasing potential between these two potentials. During such a cycle, the current flowing between the working electrode 47 and the counter electrode 48 is measured. An example of a measurement is shown in [Fig. 15]. The potential equidistant from the two current peaks on the resulting curve is characteristic of the drift of the reference electrode.Since the redox potential of the working electrode 47 is known, this measurement allows the actual electrical potential of the reference electrode 49 to be determined. If we consider that the reference electrode 41 of the measuring circuit 43 undergoes the same fluctuations or changes over time as the reference electrode 49 of the characterization circuit of the reference electrode 46, the potential of the reference electrode 41 can be considered equal. to the potential of the reference electrode 49, which allows the potential of the working electrode 42 to be determined from the potential difference measured by the measuring circuit 43.

[0059] A potassium concentration measurement can be performed several times per second, for example every second, every two seconds, every five seconds, or every ten seconds. Such frequent measurements are considered real-time measurements for the purposes of this application.

[0060] Alternatively, instead of carrying out a measurement of potassium concentration according to this embodiment, one can alternatively carry out a measurement of calcium, sodium or creatinine concentration or a pH measurement (the acidity of the physiological fluid is then measured) by functionalizing the working electrode to detect this metabolite or physiological parameter.

[0061] According to another example, shown in [Fig. 6], the analysis matrix 18 comprises at least three needles 20 configured to operate in a trio, such that one of the needles acts as a reference electrode 52, another needle acts as a working electrode 53, and the third acts as a counter electrode 54. The working electrode 53 is, for example, functionalized for glucose detection. In this configuration, the electric current flowing between the working electrode 53 and the counter electrode 54 could be measured by means of an ammeter 64, under the application of a voltage difference applied by the measuring circuit 55 between the working electrode 53 and the reference electrode 52.

[0062] In this embodiment, the characterization circuit of the reference electrode 46 as described in the previous embodiment is also used.

[0063] The reference electrode 49 of the characterization circuit of the reference electrode 46 is identical to the reference electrode 52 of the measurement circuit 55.

[0064] The processor 151 receives the electrical signals measured by the electrical measurement circuit 55 and the reference electrode characterization circuit 46, and determines the glucose concentration in the interstitial fluid at the working electrode 53 of the measurement circuit 55 from these signals. More specifically, cyclic voltammetry is implemented at the reference electrode characterization circuit 46, as described previously. This measurement makes it possible to determine the actual electrical potential of the reference electrode 49. If the reference electrode 52 of the measurement circuit 55 is considered to undergo the same fluctuations or changes over time as the reference electrode 49 of the reference electrode characterization circuit 46, the potential of the reference electrode 52 can be considered equal to the potential of the reference electrode 49.A controlled potential difference is then applied between the working electrode 53 and the reference electrode 52, this potential difference being determined from the measurement carried out on the circuit of . characterization of the reference electrode 46, and the current flowing between the working electrode 53 and the counter electrode 54 is measured.

[0065] Alternatively, instead of carrying out a glucose measurement according to this embodiment, a lactate, ketone body or urea measurement can be carried out by functionalizing the working electrode to detect this metabolite.

[0066] According to a third embodiment, as shown in [Fig. 7], the sensor 10 comprises the electrical measurement circuit 43, the electrical measurement circuit 55, and the reference electrode characterization circuit 46, as described above. The reference electrode 49 of the reference electrode characterization circuit 46, the reference electrode 52 of the measurement circuit 55, and the reference electrode 42 of the electrical measurement circuit 43 are identical.

[0067] The processor 151 is adapted to alternately activate the electrical measurement circuit 43, the electrical measurement circuit 55 and the reference electrode characterization circuit 46, so as to successively obtain the measurement signals from these different circuits.

[0068] According to a fourth embodiment, as shown in [Fig. 8], the sensor 10 comprises the electrical measurement circuit 43, the electrical measurement circuit 55, and the reference electrode characterization circuit 46, as described previously, except that the reference electrode 41 of the measurement circuit 43 and the reference electrode 52 of the measurement circuit 55 are one and the same electrode. The sensor 10 includes a switching system 56 controlled to alternately connect the common reference electrode to the measurement circuit 43 or to the measurement circuit 55. Thus, during a first measurement phase, the common reference electrode is part of the measurement circuit 43 for the measurement of the metabolite measured by the measurement circuit 43.Then, in a later phase, the switching of the switching system 56 is commanded, so that the common reference electrode is part of the measuring circuit 55 for the measurement of the metabolite measured by the measuring circuit 55, and this measurement is carried out.

[0069] According to a fifth embodiment, as shown in [Fig. 9], the sensor 10 comprises the electrical measurement circuit 55 and the reference electrode characterization circuit 46, as described previously. The sensor also comprises an electrical measurement circuit 55'. The measurement circuit 55' replicates the characteristics of the measurement circuit 55, and the same numerical references are used with the addition of a single quote. The metabolite measured by the measurement circuit 55' may be different from the metabolite measured by the measurement circuit 55.

[0070] According to a sixth embodiment, as shown in [Fig. 10], the fifth embodiment is repeated, except that the reference electrode 52 of the measuring circuit 55 and the reference electrode 52' of the measuring circuit 55' are a single and same electrode. The sensor 10 includes a switching system 56' controlled to alternately connect the common reference electrode to the measuring circuit 55 or to the measuring circuit 55'. Thus, during a first measurement phase, the common reference electrode is part of the measuring circuit 55 for the measurement of the metabolite measured by the measuring circuit 55. Then, in a subsequent phase, the switching system 56' is controlled so that the common reference electrode is part of the measuring circuit 55' for the measurement of the metabolite measured by the measuring circuit 55', and this measurement is performed.

[0071] According to a seventh embodiment, as shown in [Fig. 11], the fifth embodiment is repeated, except that the counter electrode 54 of the measuring circuit 55 and the counter electrode 54' of the measuring circuit 55' are a single electrode. The sensor 10 includes a switching system 57 controlled to alternately connect the common counter electrode to the measuring circuit 55 or to the measuring circuit 55'. Thus, during a first measurement phase, the counter electrode is part of the measuring circuit 55 for measuring the metabolite measured by the measuring circuit 55. Then, in a subsequent phase, the switching system 57 is controlled so that the common counter electrode is part of the measuring circuit 55' for measuring the metabolite measured by the measuring circuit 55', and this measurement is performed.

[0072] According to an eighth embodiment as shown in [Fig. 12], the fifth embodiment is repeated, except that the counter electrode 54 of the measuring circuit 55 and the counter electrode 54' of the measuring circuit 55' are one and the same electrode, and that the reference electrode 52 of the measuring circuit 55 and the reference electrode 52' of the measuring circuit 55' are one and the same electrode.

[0073] Where applicable, the sensor 10 comprises more than two similar measuring circuits. In this case, one or more reference electrodes and / or one or more counter electrodes may be common to more than two such measuring circuits.

[0074] Regarding the fifth to eighth embodiments, alternatively, the sensor may include an electrical measuring circuit 43. The electrical measuring circuit 43 may be separate from the measuring circuits 55 or 55', or may have a reference electrode 41 common to the reference electrode of either of the measuring circuits 55 or 55', or even to the reference electrode common to both, depending on the embodiments envisaged. A suitable switching system is used to connect the reference electrode to the appropriate measuring circuit.

[0075] According to a ninth embodiment, as shown in [Fig. 13], the embodiment of [Fig. 5] is repeated with a depth characterization circuit 65 which replaces the characterization circuit of the reference electrode 46. The depth characterization circuit 65 includes a working electrode 66, a counter electrode 67, and a reference electrode 68.

[0076] The working electrode 66 is not specific to any metabolite of the interstitial fluid and does not carry any redox mediator. The current measured on the depth characterization circuit 65 is proportional to the contact area between the working electrode 66 and the interstitial fluid, and is therefore representative of the penetration depth of the needles 20 into the skin. The processor 151 receives the electrical signals measured by the electrical measurement circuit 43 and the depth characterization circuit 65, and determines the potassium concentration in the interstitial fluid at the working electrode 42 of the measurement circuit 43 from these signals.For example, the penetration depth of the needles in the depth characterization circuit 65 is estimated using a predetermined rule relating the current measured in the depth characterization circuit 65 to the penetration depth of the needles (this rule is, for example, determined by taking measurements with needles inserted at controlled depths). The penetration depth of the needles in the electrical measurement circuit 43 is estimated from the penetration depth of the needles in the depth characterization circuit 65 (for example, depending on the proximity of the needles, the penetration depths are considered identical, but other, more complex relationships are possible). The electrical potential difference measured between the working electrode 42 and the reference electrode 41 is corrected to account for the penetration depth of these electrodes.

[0077] The sensor 20 may include such a depth characterization circuit 65 in addition to the reference electrode characterization circuit 46.

[0078] Such a depth characterization circuit 65 can also be used instead of or in addition to the reference electrode characterization circuit 46 in the other embodiments above.

[0079] In this case, depending on the variants, the counter electrode 67 of the depth characterization circuit 65 can be shared with one or more counter electrodes of another circuit, as shown above, by means of the use, where appropriate, of dedicated switching systems to successively carry out the circuits.

[0080] Alternatively, the working electrode 66 can carry the redox mediator. In this case, the characterization circuit can be used to characterize both the reference electrode and the penetration depth, according to the two characterization methods presented above.

[0081] According to one embodiment, the sensor 20 comprises a depth characterization circuit 65 and a reference electrode characterization circuit for the depth characterization circuit 65. The electrode characterization circuit of The depth characterization circuit reference works like the reference electrode characterization circuit described above, but is used to characterize the reference electrode of the depth characterization circuit 65.

[0082] According to a tenth embodiment, as shown in [Fig. 14], the sensor comprises the electrical measurement circuit 43, as already described, and a mixed characterization and measurement circuit 69. The mixed characterization and measurement circuit 69 is adapted to provide both a measurement of a metabolite and a characterization of the electrical measurement circuit 43. The mixed characterization and measurement circuit 69 comprises a working electrode 70, as well as a counter electrode 71 and a reference electrode 72. The working electrode 70 comprises, on the one hand, a known redox mediator and, on the other hand, a coating specific to the metabolite to be detected. The counter electrode 70 and the reference electrode are similar to the counter electrode and reference electrode already described. During a measurement by cyclic voltammetry, the measurement can be represented by a diagram, as shown in [Fig. 14].

[15] , relating the measured current to the applied potential difference. A characteristic of the measured electric current is then representative of the metabolite concentration, such as the measured maximum, the value measured for the plateau to the right of potential peak 73a, a shape of part of the curve, or other. The potential peaks 73a, 73b, for example the location of the midpoint between these potential peaks, are representative of the drift of the reference electrode.

[0083] Such a mixed characterization and measurement circuit 69 can also be implemented in the other embodiments presented above, in place of a measurement circuit and / or the characterization circuit, as appropriate. Furthermore, the counter electrode 71 can be shared with the counter electrode of another circuit, as already described above.

[0084] Depending on the embodiment variants, several circuits could be used to detect several metabolites, sharing one or more electrodes if necessary, as shown above.

[0085] The needles 20 extend transversely across the base 16. As shown in Figures 2 and 3, the plurality of needles 20 pass through the base 16 between the first face 16-1 and the second face 16-2. By way of non-limiting example, the needles 20 are installed in the base 16 by overmolding or by press fitting. In some cases, the analysis matrix 18 may additionally or alternatively include a paste for adhering each needle 20 to the base 16, this paste being arranged in contact with the second face 16-2 of the analysis module 12, so as to also facilitate electrical connection to the electronic module 14, when this paste is electrically conductive.

[0086] It is apparent from [Fig. 2] that a first end of each needle 20, which includes the tip of the respective needle 20, protrudes from the first face 16-1, transversely to this first face 16-1. Each needle 20 can therefore be inserted into the user's body until the first face 16-1 of the analysis module 12 comes into contact with the user's skin. In order to hold the analysis module 12 against the skin, and thus the needles 20 inserted into the user's body, the first face 16-1 may include an adhesive. The adhesive may cover all or part of the first face 16-1 of the analysis module 12.

[0087] A second end of the needle 20, opposite the first end of this needle 20, may be flush with the second face 16-2, as in the example of Figures 2 or 3. According to an alternative not shown, the second end of each needle 20 may protrude from the second face 16-2, transversely with respect to this second face 16-2. As will be detailed, the second end of each needle 20 may serve as a connector to electrically connect the analysis module 12 to the electronic module 12.

[0088] Each needle 20 is preferably a microneedle. Advantageously, each needle is made from a metal plate (in particular stainless steel or titanium), preferably of medical grade. The metal plate can be functionalized by depositing one or more additional layer(s) using various methods. Each additional layer can be, for example, a metallic and / or polymeric layer.

[0089] More specifically, as shown in [Fig. 16], a single electrode, designated by the general common reference numeral 58, comprises several needles 20. In particular, the analysis matrix 18 comprises several modules 59. A module 59 is made in one piece. It comprises a base 60 from which the several needles 20 of the same module 59 extend. The needles 20 extend parallel to each other from the base 60 and in the same direction. In the example shown, a module 59 comprises three such needles 20. For example, the modules 59 are identical to each other (apart from the functionalization, which may be specific to each module 59, or to each type of module).

[0090] Thus, as shown in [Fig. 17], starting from a metal plate 62 intended to provide modules 59, the core 61 of each individual module 59 is formed in the plate by chemical etching, the core 61 remaining attached to the plate by a breakable portion. The core 61, in one piece, comprises the core of the base 60 and the core of the needles 20. Then, a coating is applied to one face, or to both faces of this plate, for example by electrodeposition, printing, screen printing, painting, droplet deposition, or other means. For example, to make a potassium-sensitive electrode, a tetrahydrofuran solution is used. comprising an ionophore, an ion exchanger, a polymer, and a plasticizer. For example, the mass proportions of the different species dissolved in the solvent are as follows: ionophore between 1% and 5%, ion exchanger between 0.1% and 1%, polymer between 20% and 50%, plasticizer between 50% and 80%, the sum of these components totaling 100% by mass. The solution is applied twice to the electrode and dries at room temperature in 1 to 24 hours.

[0091] If necessary, the core 61 is separated from the plate 62 and assembled to the base 16. As discussed above, for example, the core 61 is mechanically assembled to the base 16. Alternatively, the cores 61 are arranged and held in a mold, and the base 16 is overmolded around the cores 61. The remaining breakable portion 63 acts as an anchor in the base 16. Thus, the base 60 is held within the base 16, and the needles 20 protrude from the second face of the base 16, as shown above. The base 60 is made of an electrically insulating material, so that two cores 61 separated from each other by the base 60 are electrically insulated from each other. Where appropriate, functionalizing coatings are applied to the different needles 20, masking if necessary the areas of the analysis module 12 which should not then be functionalized.

[0092] Alternatively, a single electrode may comprise a single needle.

[0093] Thus, according to an independent aspect, an invention relates to a transcutaneous sensor for in vivo measurement of at least one physiological parameter in a biological fluid comprising: - an electrically insulating base, having a first face intended to be applied from the outside against the skin of a patient, - at least one module 59 comprising a metallic core 61 obtained from a sheet of metal, the metallic core 61 passing through the electrically insulating base, and comprising a rear end adapted to be electrically connected to an electronic sensing system, and a front end portion opposite the rear end, protruding from the base, adapted to penetrate (non-surgically) into the patient, and having a coating functionalized for the measurement of said physiological parameter.

[0094] This invention also relates to a method for manufacturing a transcutaneous sensor for in vivo measurement of at least one physiological parameter in a biological fluid in which: - at least one module 59 comprising a metallic core 61 is formed from a sheet of metal, - Module 59 is assembled onto an electrically insulating base, having a first face intended to be applied from the outside against the skin of a patient, the metallic core 61 passing through the electrically insulating base, and comprising a rear end adapted to be electrically connected to an electronic system detection, and a front end portion opposite the rear end, protruding from the base, adapted to penetrate (non-surgically) into the patient, and having a functionalizing coating for the measurement of said physiological parameter.

[0095] Alternatively, the electrodes are produced by machining, wafer cutting, molding or other.

[0096] The analysis module 12 further includes coupling means 22 to the electronic module 14. The coupling means 22 extend, according to the example of Figures 2 and 3, transversely to the base 16. In particular, the coupling means 22 protrude transversely from the second face 16-2 of the base 16. Advantageously, the coupling means 22 are made in one piece with the base 16, without this being limiting.

[0097] As can be seen in Figures 2 and 3, the coupling means 22 may include at least one recess 24 and / or at least one projection 26. As will be detailed later, each recess 24 is shaped to receive a projection arranged on the electronic module 14, while each projection 26 is shaped to be received in a recess of the electronic module 14.

[0098] The system 1 further includes an electronic module 14 which will be described below with reference to [Fig.4].

[0099] The electronic module 14 comprises a body 28 including a front edge 28-1, a rear edge 28-2, and two side edges 28-3. In [Fig. 4], the front edge 28-1 and the rear edge 28-2 have different shapes. Although this is not limiting, since the front edge 28-1 and rear edge 28-2 could have the same shape, the difference in shape between the front edge 28-1 and the rear edge 28-2 has the advantage of serving as a guide for correctly positioning the electronic module 14 to a gripping member of the system 1, which will be described later.

[0100] The electronic module 14 is intended to be installed opposite the second face 16-2 of the analysis module 12. In particular, the electronic module 14 is shaped to be removably connected to the analysis module 12, so as to form the sensor 10. For this purpose, the shape of the electronic module 14 is complementary to the shape of the analysis module 12.

[0101] By way of non-limiting example, the electronic module 14 can be connected to the analysis module 12 by snap-fitting. For this purpose, the electronic module 14 includes complementary coupling means 30 for cooperating with the coupling means 22 of the analysis module 12. Thus, as shown in [Fig. 4], the complementary coupling means 30 comprise at least one projection 32 and / or at least one recess 34. Each projection 32 is shaped to be received in a recess 24 respective of the analysis module 12, while each hollow 34 is shaped to receive a respective protrusion 26 of the analysis module 12.

[0102] The electronic module 14 comprises a set of electronic elements used for the operation of the sensor 10, in particular the electronic components of the circuits 43, 46, 55, 55', 65, and 69. The set of electronic elements is advantageously housed inside the body 28. The electronic module 14 advantageously comprises at least one of the following: a battery or a rechargeable battery with a charging circuit (not shown in the figures). The battery provides the electrical energy for the operation of the sensor 10.

[0103] The electronic module 14 may further include at least one of the following: a microcontroller, an antenna, a programming circuit, current measurement components 51, and / or voltage measurement components 44. The antenna allows the electronic module 14 to be wirelessly connected to a device external to the sensor 10, for example, via Bluetooth or Bluetooth Low Energy (BLE). Thus, the transmission and processing of data collected by the analysis module 12 is possible between the electronic module 14 and the external device. The antenna can also communicate other information to the external device, such as the battery level of the electronic module. Therefore, in one embodiment, all or part of the signal processing is performed on the external device.Thus, the processor 151 which receives and processes the measurement and / or characterization signals can be part of one or more external devices.

[0104] In order to electrically connect the analysis module 12 to the electronic module 14, the analysis module 12 includes a first connector, and the electronic module 14 includes a second connector 36, which are connected together when the electronic module 14 is connected to the analysis module 12. As previously stated, the connector of the analysis module 12 is advantageously the end of each module 59 that protrudes from or is flush with the second face 16-2 of the analysis module 12 or, alternatively, a pad disposed on the second face 16-2 to fix each module 59 to the analysis module 12. The connector 36 of the electronic module 14 may include a spring and / or an elastomeric material. For example, the connector 36 may be a spring finger connector, an elastomeric connector, or a pogo pin.

[0105] Furthermore, the electronic module 14 can electrically connect several modules 59 together, so that a single electrode can comprise several modules 59 spaced apart from each other at the level of the analysis matrix 18.

[0106] As can be seen from [Fig. 4], at least one of the lateral edges 28-3 of the electronic module comprises an elongated groove 38. Advantageously, the two edges The lateral ends 28-3 of the electronic module 14 include a respective elongated groove 38. Each elongated groove 38 is shaped to cooperate with the gripping element of kit 1, as will be detailed later. Note that the elongated groove 38 can be extended by another groove 39 arranged on the analysis module 12 (see [Fig. 2]).

[0107] Figure 18 schematically represents the results of an experiment performed on a pig. A blood potassium concentration measurement was carried out using a commercial Siemens Epoc sensor. A measurement was taken every 15 minutes for 3 hours using this sensor, and is represented by the points on the graph. The curve represents the measurements taken using the detection system according to an embodiment of the invention. As can be seen in the figure, the measurement results obtained are very broadly correlated with the measurements taken with the commercial sensor. Furthermore, the sampling rate of measurements using the sensor according to the invention is much higher than with the commercial sensor. List of reference signs

[0108] 1: system

[0109] 10: sensor

[0110] 12: analysis module

[0111] 14: electronic module

[0112] 16: base

[0113] 16-1, 16-2: faces

[0114] 18: analysis matrix

[0115] 20: needles

[0116] 22: coupling means

[0117] 24: hollow

[0118] 26: protrusion

[0119] 28: body

[0120] 28-1 to 28-3: edges

[0121] 30: coupling means

[0122] 32: protrusion

[0123] 34: hollow

[0124] 36: second connector

[0125] 38: throat

[0126] 39: other throat

[0127] 41: reference electrode

[0128] 42: working electrode

[0129] 43: electrical measuring circuit

[0130] 44: voltmeter

[0131] 46: Reference electrode characterization circuit

[0132] 47: working electrode

[0133] 48: counter electrode

[0134] 49: reference electrode

[0135] 50: current generator

[0136] 51: ammeter

[0137] 151: processor

[0138] 52: reference electrode

[0139] 53: working electrode

[0140] 54: counter electrode

[0141] 55: measuring circuit

[0142] 56: switching system

[0143] 57: switching system

[0144] 58: electrode

[0145] 59: module

[0146] 60: base

[0147] 61: Heart

[0148] 62: Plate

[0149] 63: remaining divisible portion

[0150] 64: ammeter

[0151] 65: Depth characterization circuit

[0152] 66: working electrode

[0153] 67: counter electrode

[0154] 68: reference electrode

[0155] 69: Mixed characterization and measurement circuit

[0156] 70: working electrode

[0157] 71: counter electrode

[0158] 72: reference electrode

[0159] 73a, 73b: potential peaks

Claims

Demands

1. An in vivo measurement system for at least one physiological parameter in a biological fluid, comprising: - a measurement circuit (43; 55) for an analyte present in the biological fluid, said measurement circuit (43; 55) comprising at least one working electrode (42; 53) and one reference electrode (41; 52) adapted to be at least partially disposed in the biological fluid, - a characterization circuit (46; 65; 69) comprising at least one working electrode (47; 66; 70), one reference electrode (49; 68; 72), and one counter electrode (48; 67; 71) adapted to be at least partially disposed in the biological fluid, - a processor (151) adapted to receive an electrical signal from the measurement circuit (43; 55) and an electrical signal from the characterization circuit (46; 65; 69), and to determine said at least one physiological parameter associated with said analyte from these electrical signals.

2. The in vivo measurement system according to claim 1, wherein the characterization circuit (46; 65; 69) is a characterization circuit of the reference electrode of the measurement circuit (46), adapted to deliver a signal characterizing the reference electrode (41; 52) of the measurement circuit.

3. The in vivo measurement system according to claim 1, wherein the characterization circuit (46; 65; 69) is a depth characterization circuit (65) adapted to deliver a signal characterizing the insertion depth of the electrodes.

4. The in vivo measurement system according to claim 3, wherein the characterization circuit (65) is a first characterization circuit, the measurement system further comprising a second characterization circuit (46), which is a characterization circuit of the reference electrode of the measurement circuit, adapted to deliver a signal characterizing the reference electrode of the measurement circuit.

5. The in vivo measurement system according to claim 1, wherein said analyte is a first analyte, wherein the characterization circuit (46; 65; 69) is a mixed characterization circuit (69) adapted to deliver a signal characterizing either the electrode of reference of the measurement circuit (43; 55) i.e. the insertion depth of the electrodes, the mixed characterization circuit further comprising a working electrode (70) specific to a second analyte present in the biological fluid, and the processor (151) being adapted to receive an electrical signal from the mixed characterization circuit (69), and to determine a second physiological parameter associated with the second analyte from this electrical signal.

6. The in vivo measurement system according to any one of claims 1 to 5, wherein the measurement circuit (43; 55) further comprises a counter electrode (54) adapted to be disposed at least partially in the biological fluid.

7. The in vivo measurement system according to any one of claims 1 to 6, further comprising another measurement circuit (55') of another analyte present in the biological fluid, said other measurement circuit comprising at least one working electrode (53') and one reference electrode (52') adapted to be disposed at least partially in the biological fluid, the processor (151) being adapted to receive an electrical signal from the other measurement circuit (55') and an electrical signal from the characterization circuit (46; 65; 69), and to determine at least one physiological parameter associated with the other analyte from these electrical signals.

8. The in vivo measurement system according to any one of claims 1 to 7, wherein a reference electrode (41) is common to several measurement circuits.

9. The in vivo measurement system according to any one of claims 1 to 8, wherein a counter electrode (54) is common to several circuits.

10. The in vivo measurement system according to any one of claims 1 to 9, wherein the analyte is selected from the list {potassium, glucose, creatinine, acids, sodium, calcium, lactate, ketone body, urea}.

11. The in vivo measurement system according to any one of claims 1 to 10, comprising a sensor (10) including an electrically insulating base (16) through which extend at least two electrically conductive modules (59), electrically insulated from each other by the base (16), and in which each electrically conductive module comprises a plurality of parallel needles (20) forming one of said electrodes.

12. The measurement system according to any one of claims 1 to 11 in which the measurement circuit comprises: - an electrically insulating base (16), having a first face (16-1) intended to be applied from the outside against the skin of a patient, - at least one module (59) comprising a metallic core (61) obtained from a sheet of metal, the metallic core (61) passing through the electrically insulating base (16), and comprising a rear end adapted to be electrically connected to an electronic sensing system, and a front end portion opposite the rear end, forming at least a part of at least one of said electrodes, protruding from the base (16), adapted to penetrate the patient, and having a functionalizing coating for the measurement of said physiological parameter.

13. A method for in vivo measurement of at least one physiological parameter in a biological fluid, wherein: having a measurement circuit (43; 55) of an analyte present in the biological fluid, said measurement circuit comprising at least one working electrode and one reference electrode adapted to be disposed at least partially in the biological fluid, having a characterization circuit (46; 65; 69) comprising at least one working electrode, one reference electrode and one counter electrode adapted to be disposed at least partially in the biological fluid, - a processor (151) receives an electrical signal from the measurement circuit and an electrical signal from the characterization circuit, and determines said at least one physiological parameter associated with said analyte from these electrical signals.

14. Computer program comprising portions of program code for the execution of the steps of the process according to claim 13, when said program is executed on a processor.

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