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WO2025060023A1 - Capteur d'analyte structuralement amélioré - Google Patents

Capteur d'analyte structuralement amélioré Download PDF

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Publication number
WO2025060023A1
WO2025060023A1 PCT/CN2023/120576 CN2023120576W WO2025060023A1 WO 2025060023 A1 WO2025060023 A1 WO 2025060023A1 CN 2023120576 W CN2023120576 W CN 2023120576W WO 2025060023 A1 WO2025060023 A1 WO 2025060023A1
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WO
WIPO (PCT)
Prior art keywords
electrode
substrate
sensor
layer
electrodes
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PCT/CN2023/120576
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English (en)
Inventor
Cuijun YANG
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Medtrum Technologies Inc
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Medtrum Technologies Inc
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Priority to PCT/CN2023/120576 priority Critical patent/WO2025060023A1/fr
Publication of WO2025060023A1 publication Critical patent/WO2025060023A1/fr
Pending legal-status Critical Current
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/1468—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means
    • A61B5/1486—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means using enzyme electrodes, e.g. with immobilised oxidase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue for measuring glucose, e.g. by tissue impedance measurement

Definitions

  • the invention mainly relates to the field of medical devices, in particular to a structurally enhanced analyte sensor.
  • the pancreas in a normal human body can automatically monitor the layer of glucose in the human blood and automatically secrete the required insulin/glucagon.
  • the pancreas does not function properly and cannot produce the insulin the body needs. Therefore, diabetes is a metabolic disease caused by abnormal pancreatic function, and diabetes is a lifelong disease. At present, there is no cure for diabetes with medical technology. The occurrence and development of diabetes and its complications can only be controlled by stabilizing blood glucose.
  • Diabetics need to have their blood glucose measured before they inject insulin into the body. At present, most of the testing methods can continuously measure blood glucose and send the data to a remote device in real time for the user to view. This method is called Continuous Glucose Monitoring (CGM) .
  • CGM Continuous Glucose Monitoring
  • the method requires the device to be attached to the skin and the probe it carries is penetrated into the tissue fluid beneath the skin.
  • the material of the electrode and the substrate are inconsistent, and some areas of the electrode are easy to bubbles and warping. In severe cases, the electrode detaches from the substrate, affecting the service life of the sensor and reducing its detection reliability.
  • the embodiment of the invention discloses a structurally enhanced analyte sensor, which at least one protective layer is set on the surface of the substrate, covering at least a part of the area of the electrode, increasing the degree of adhesion between the electrode and the substrate, which can prevent electrode from warping, bubbling, and detaching, extending the service life of the sensor, and improving the detection reliability of the sensor.
  • the invention discloses an analyte sensor, which comprises: at least one layer of substrate, the substrate comprises an in vivo part and an in vitro part. At least two electrodes are arranged on the surface of the in vivo part for penetrating into the subcutaneous to obtain analyte parameter information. And PADs, which are arranged on the surface of the in vitro part and are electrically connected with the corresponding electrodes through wires.
  • at least one protective layer is arranged on the surface of substrate, and the protective layer at least covers a part area of the electrode.
  • the protective layer covers the edge area of the electrode.
  • the electrode-area covered by the protective layer accounts for 10%to 100%of the area.
  • the area covered by the protective layer in the electrode-area accounts for 100%.
  • the protective layer is a semipermeable membrane.
  • the thickness of the protective layer is 0.1 ⁇ 200um.
  • the thickness of the protective layer is 1 ⁇ 50um.
  • the protective layer also covers a part area of the PAD.
  • At least one layer of insulation material is post manufactured at least a part area of the substrate, which avoiding the PAD-area and electrode-area.
  • the electrode is an electrode array composed of electrode units.
  • the substrate comprises at least two layers of secondary-substrates, and at least one electrode is arranged on the secondary-substrates of different layers.
  • the secondary-substrate of each layer is pasted into a whole after prefabrication.
  • At least one electrode is arranged on the reverse side of the substrate.
  • the obverse side of the substrate is also provided with a secondary-PAD corresponding to the PAD.
  • the obverse side and/or reverse side of the substrate also includes at least two layers of secondary-substrate, with at least two electrodes arranged on different layers of secondary-substrates.
  • electrodes are distributed on the surface of the substrate in a predetermined manner to avoid areas where the substrate is easy to bend.
  • the electrode comprises at least one group of electrodes with the same name.
  • At least one protective layer is set on the substrate when processing sensors, which covers at least a part of the area of the electrode, increasing the adhesion between the electrode and the substrate, which can prevent electrode from warping, bubbling, and detaching, prolonging the service life of the sensor, and improving the detection reliability of the sensor.
  • the protective layer can also fully cover the electrode.
  • the protective layer can choose a semipermeable membrane material.
  • the full coverage of the protective layer on the electrode can further increase the adhesion between the electrode and the substrate, which can prevent electrode from warping, bubbling, and detaching.
  • the use of the semipermeable membrane can allow the analyte to pass through the protective layer without affecting the contact between the electrode and the analyte, and also prevent noise caused by the contact between the interfering substance and the electrode, which can improve detection reliability of sensors.
  • At least one layer of insulation material is set behind at least one area on the sensor substrate.
  • the insulation material avoids the area where the PADs and electrodes are located, increasing the mechanical strength of the sensor substrate.
  • the electrode is an electrode array composed of electrode units.
  • the original whole electrode is made into a smaller electrode unit and laid on the wire, which can avoid the whole electrode being bent or even broken when the sensor is repeatedly bent with the muscle after penetrating into the subcutaneous skin, extending the service life of the electrode and improving the detection reliability of the sensor.
  • the substrate includes at least two layers of secondary-substrates. At least two electrodes are arranged on the secondary-substrates of different layers. The electrodes are located on the secondary-substrates of different layers, which can avoid the wire routing. The electrodes can be made larger, increase the contact area with analytes, enhance the electrode reaction sensitivity, and improve the detection reliability of the sensor.
  • the secondary-substrates of different layers can be prefabricated first, that is, the electrodes, wires and PADs are prefabricated on each layer of substrate, and then pasted and combined into a whole to form a complete sensor.
  • the conventional layer by layer coating process it can avoid insulation failure due to insufficient consolidation of the substrate material, resulting in embrittlement, further causing crosstalk between the electrical signals of the wires or electrodes, and noise in the detection signal, the detection reliability of the sensor is improved.
  • At least one of the multiple electrodes is located on the reverse side of the substrate, and the area of the electrode can be set on the single-sided substrate is limited. Setting one or more electrodes on the reverse side of the substrate can make full use of the two sides of the substrate, so the electrode on each side can be set to a larger area, increasing the contact area with the analyte, improving the electrode reaction sensitivity and improving the detection reliability of the sensor.
  • the penetration depth of the sensor into the subcutaneous skin is fixed.
  • the base is fixed in the area of repeated bending with muscle peristalsis.
  • the electrode is distributed on the substrate of sensor in a predetermined way. The electrode can avoid the area on the substrate of sensor that is easy to bend, avoid the electrode breaking or damage caused by repeated bending with the substrate, extend the service life of the electrode and improve the detection reliability of the sensor.
  • the senor can be equipped with multiple electrodes with the same name, such as two or more working electrodes, two or more counter electrodes, and two or more reference electrodes, to achieve different functions, such as multiple analyte detection, redundant detection, electrode relay use, enhancing electrode detection signal, reducing detection signal noise, and improving the detection reliability of the sensor.
  • multiple electrodes with the same name, such as two or more working electrodes, two or more counter electrodes, and two or more reference electrodes, to achieve different functions, such as multiple analyte detection, redundant detection, electrode relay use, enhancing electrode detection signal, reducing detection signal noise, and improving the detection reliability of the sensor.
  • Fig. 1 is a top view of a planar structure of the sensor according to the embodiment of the invention.
  • Fig. 2 is side A view of the planar structure of the sensor as an embodiment of Fig. 1.
  • Fig. 3 is a sectional view of an electrode according to an embodiment of the invention.
  • Fig. 4 is a schematic diagram of function realization according to the embodiment of the invention.
  • Fig. 5 is a top view of the sensor with a stepped structure according to the embodiment of the invention.
  • Fig. 6 is side A view of the sensor with a stepped structure as an embodiment of Fig. 5.
  • Fig. 7 is a schematic diagram of the sensor having a cylindrical structure according to the embodiment of the invention.
  • Fig. 8 shows a V-V’ section view of the transducer with a cylindrical structure as an embodiment of Fig. 7.
  • Fig. 9 is a schematic diagram of a continuous analyte monitoring device according to an embodiment of the invention.
  • Fig. 10a-Fig. 10j are schematic diagrams of different sensors according to the embodiment of the invention.
  • the electrode of the analyte sensor in existing technology is inconsistent with the material of the substrate, and some areas of the electrode are easy to bubbles and warping. In severe cases, the electrode detaches from the substrate, affecting the service life of the sensor and reducing its detection reliability.
  • the invention provides a structurally enhanced analyte sensor, which at least one protective layer is set on the surface of the substrate, covering at least a part of the area of the electrode to increase the adhesion between the electrode and the substrate, prevent electrode from warping, bubbling, and detaching, extend the service life of the sensor, and improve the detection reliability of the sensor.
  • one or more method steps referred to in the invention do not exclude the possibility that other method steps may exist before and after the combined steps or that other method steps may be penetrated between such explicitly mentioned steps, unless otherwise stated.
  • the combination connection between one or more devices/devices referred to in the invention does not preclude the existence of other devices/devices before and after the said combination devices/devices or the insertion of other devices/devices between the two specifically mentioned devices/devices, unless otherwise stated.
  • Fig. 1 is a top view of a planar structure of the sensor according to the embodiment of the invention.
  • Fig. 2 is side A view of the planar structure of the sensor as an embodiment of Fig. 1.
  • the sensor 11 comprises a substrate 111, which is divided into an in vitro part X and an in vivo part Y by the dotted line shown in Fig. 1.
  • the in vivo part Y is paved with electrodes, comprising at least one working electrode 1131 and at least one additional electrode.
  • the additional electrode comprises a counter electrode 1231 and a reference electrode 1331, thus forming a three-electrode system.
  • the counter electrode 1231 is the other electrode relative to the working electrode 1131, forming a closed loop with the working electrode 1131, so that the current on the electrode can be normally conducted, the reference electrode 1331 is used to provide the reference potential of the working electrode 1131, so the detection potential can be effectively controlled.
  • the additional electrode can also only comprise the counter electrode 1231, thus forming a two-electrode system.
  • the effective area of the working electrode 1131 and the counter electrode 1231 can be increased on the limited area of the in vivo part Y, thereby extending the service life of the electrode.
  • the processing process is simpler, however, the working electrode 1131 does not have the detection potential of the reference electrode as a reference, and the reliability of the analyte detection information will be reduced.
  • the in vitro part X is paved with PADs, which correspond to the electrode one-by-one and are electrically connected through wires, that is, the working PAD 1111 corresponding to the working electrode 1131 is electrically connected through wire 1121.
  • the counter PAD 1211 corresponding to the counter electrode 1231 is electrically connected through wire 1221.
  • reference PAD 1311 corresponding to reference electrode 1331 which is electrically connected through wire 1321.
  • Different PADs, wires and electrodes are insulated from each other to prevent electrical signals from interfering.
  • the sensor 11 is the planar structure, there are two opposite sides, obverse side A and reverse side B.
  • the working electrode 1131, counter electrode 1231 and reference electrode 1331 are laid as one electrode-group on the obverse side A of the sensor.
  • another electrode-group is laid on the reverse side B of the sensor.
  • the electrode-group can be a two-electrode system, a three-electrode system or a double working electrode.
  • it is consistent with the electrode-group on the obverse side A, comprising working electrode 1132, counter electrode 1232 and reference electrode 1332.
  • PADs are also laid on the side B.
  • the electrode with the same name on side B can take over and enter the working state, improving the reliability of the parameter data of the detected analyte and extending the service life of the sensor.
  • the sequence and position of the PADs, wires and electrodes laid on the side A and side B of the sensor can be symmetrically or asymmetrically arranged.
  • the corresponding PADs, wires and electrodes are laid on the same side or on different sides.
  • the corresponding PADs, wires and electrodes are laid on the same side for the convenience of wire routing.
  • the working electrode 1131 on the side A can be reset with the counter electrode 1231, or the counter electrode 1231 on the side A can be reset with the reference electrode 1332 on the side B.
  • the planar structure sensor only has the side A and side B, it can also increase the number of electrode-groups by increasing the sensor area or reducing the electrode-area, so as to further increase the service life of the sensor.
  • too large sensor area may increase the host’s rejection response and cause host discomfort.
  • Too small electrode-area will reduce the sensitivity of electrode and reduce the reliability of detection parameters.
  • Too many electrode-groups will also increase the complexity of the processing process, such as the wiring of the wire will become very dense. Therefore, it is preferred that the number of electrode-groups is two.
  • each electrode-group can also be distributed on the same side of the sensor, such as side A or side B, which is not limited here.
  • the substrate 111 is a material with excellent insulation performance, mainly from inorganic non-metallic ceramics, silica glass, organic Polymers, etc. at the same time, considering the application environment of the implanted electrode, the substrate material is also required to have high impermeability and mechanical strength.
  • the substrate material is selected from one or more combinations of Teflon, PE, PVC, aBS, PMMA, PC, PI, etc.
  • Fig. 3 is a sectional view of the electrode.
  • the working electrode (auxiliary electrode) , counter electrode and reference electrode comprise at least an electron conduction layer a, an anti-interference layer b, an enzyme layer c, an adjustment layer d and a biocompatible layer e.
  • the electron conduction layer a adopts a material with good conductivity and hardening inertia.
  • the working electrode and counter electrode are selected from one of graphite electrode, glassy carbon electrode, noble metal and other materials, and the reference electrode is selected from one of Ag/AgCl or calomel.
  • noble metal electrodes such as gold electrode, platinum electrode and silver electrode have become better choices.
  • both working electrode and counter electrode are platinum electrodes.
  • the anti-interference layer b is located between the enzyme layer and the electron conduction layer.
  • Interferents are molecules or substances that will undergo electrochemical reduction or electrochemical oxidation directly or indirectly through electron transfer agents on the electrode surface, thus generating an error signal that interferes with the detection of analytes.
  • common interferents in the body comprise urea, ascorbic acid, paracetamol, and so on.
  • the anti-interference layer b can prevent one or more interferents from penetrating into the electrolyte around the electrode.
  • the anti-interference layer b will allow the analytes (e.g., hydrogen peroxide) to be measured on the electrode to pass, while at the same time preventing the passage of other substances (e.g., potential interfering substances) .
  • the anti-interference layer b can be a very thin film designed to limit the diffusion of substances with molecular weight greater than 34Da.
  • the anti-interference layer b may be an organic Polymer, which may be made from organosilane and a hydrophilic copolymer.
  • the hydrophilic copolymers more preferably Poly-ethylene glycol (PEG) , Poly-methacrylic acid, 2-hydroxyethyl ester and Poly-lysine.
  • the thickness range of the anti-interference layer b may be 0.1um or less to 10um or more. The more preferred thickness range is 0.5um to 5um.
  • the enzyme layer c is coated with active enzyme, and the corresponding active enzyme is coated according to the type of analyte to be detected.
  • the active enzyme can make the analyte to be detected produce some chemical reactions and generate electrons. According to different concentrations of analyte to be detected, the number of electrons generated is different, and the electrons are collected by the electron conduction layer, thus forming different current intensities. Therefore, the current intensity information can be used to characterize the analyte parameter information.
  • the enzyme layer c is coated with glucose oxidase (Gox) .
  • Gox glucose oxidase
  • the adjustment layer d is located above the enzyme layer.
  • the regulating layer d is mainly used to regulate the transmittance of oxygen and glucose transmitted to the enzyme layer.
  • the glucose content (molar concentration) in body fluid is one order of magnitude higher than that of oxygen.
  • excess oxygen needs to be supplied to ensure that oxygen does not become a limiting substance, so that the sensor can respond linearly to changes in glucose concentration without being affected by oxygen partial pressure.
  • oxygen content becomes a limiting factor, the linear range of glucose oxygen monitoring reaction cannot reach the expected concentration range.
  • the upper limit of the linear response of the sensor to glucose can only reach about 40mg/dL.
  • the upper limit of linear response of blood glucose layer needs to reach about 500mg/dL.
  • the regulating layer d mainly functions as a semipermeable membrane to regulate the amount of oxygen and glucose transmitted to the enzyme layer. More specifically, excess oxygen becomes a non-restrictive factor.
  • the upper limit of the linear response to glucose of the sensor with an adjustment layer can reach a higher layer than that without an adjustment layer.
  • the ratio of oxygen glucose transmittance of the regulating layer d can reach 200: 1, which can ensure that there is enough oxygen for the enzymatic reaction for various glucose and oxygen concentrations that may occur under the skin.
  • the adjustment layer d may be an organic Polymer, which may be manufactured from organosilane and a hydrophilic copolymer. Hydrophilic copolymers, more preferably copolymerized or grafted Poly-ethylene glycol (PEG) . Other hydrophilic copolymers that may be used comprise but are not limited to other diols, such as propylene glycol, esters, amides, carbonates, and Polypropylene glycol. The use of silicone Polymers can significantly improve oxygen transport and effectively control glucose permeation.
  • the thickness range of the adjustment layer d can be 1um or less to 50um or more, and the more preferred thickness range is 1um to 10um.
  • the biocompatible layer e is located at the outermost part of the electrode, aiming to eliminate the body’s rejection of foreign bodies and reduce the formation of a shielding cell layer around the implanted electrode.
  • the biocompatible layer e can be manufactured from organosilane and a hydrophilic copolymer.
  • Hydrophilic copolymers more preferably copolymerized or grafted Poly-ethylene glycol (PEG) .
  • PEG Poly-ethylene glycol
  • Other hydrophilic copolymers comprising but not limited: diols, such as propylene glycol, esters, amides, carbonates, and Polypropylene glycol.
  • the thickness range of the biocompatible layer e may be 1um or less to 100um or more. The more preferred thickness range is 10um to 30um.
  • the thickness of the substrate 11 is 0.01 ⁇ 0.8mm
  • the electrodes are rectangular
  • the width of each electrode is 0.01 ⁇ 1mm
  • the area is 0.1 ⁇ 2mm 2 .
  • the surface of each electrode is also provided with a carbon nanotube layer modification layer.
  • a carbon nanotube layer modification layer Taking advantage of the unique mechanical strength, high specific obverse side Area, rapid electron transfer effect and chemical stability of carbon nanotubes, carbon nanotubes are modified to the electrode surface by physical adsorption, embedding or covalent bonding on the formed electrode surface to improve the electron transfer speed.
  • carbon nanotubes due to its large specific obverse side Area, carbon nanotubes can be used as an excellent catalyst (enzyme) carrier.
  • the carbon nanotube layer modified layer can be fixed on the electrode surface by Nafion solution dispersion method, covalent fixation method, etc.
  • Fig. 4 is the schematic diagram of the function realization of the embodiment of the invention.
  • the in vivo circuit applies voltage to the PAD, and the electrode corresponding to the PAD is activated to enter the working state.
  • the effective working time of the electrode after being activated is 1-14 days. After 14 days, the enzyme activity on the electrode decreases and enters the failure state. At the same time, there may be reasons such as electrode damage or processing errors, and the activated electrode will enter the failure state in advance. If a single group of electrodes is set on the sensor, once a certain electrode enters the failure state, the sensor will fail, and the user needs to replace the sensor, which reduces the user experience and increases the user’s use cost.
  • the in vivo circuit will apply voltage to the PAD corresponding to the electrode with the same name of other electrode-groups, activate the electrode with the same name, make it enter the working state, replace the failed electrode, and make the sensor continue to work normally.
  • the working PAD 1111, the counter PAD 1211 and the reference PAD 1311 on side A are preferentially applied with voltage by the in vivo circuit.
  • the working electrode 1131, the counter electrode 1231 and the reference electrode 1331 on side A enter the working state.
  • the in vivo circuit switches the PAD object to which the voltage is applied, for example, when the working electrode 1131 fails in advance, the in vivo circuit switches to apply voltage to the fourth PAD 1112 on the side B, activates the working electrode 1132 on the side B, and combines it with the counter electrode 1231 and the reference electrode 1331 that have not yet failed to form a new electrode-group to detect the analyte to be tested, thus avoiding the early failure of the sensor 11.
  • the user does not need to replace the sensor because of the early failure of the working electrode 1131, which enhances the user experience, it also reduces the cost of replacing sensors.
  • the above embodiment is not limited to the failure of the working electrode, other electrodes such as the counter electrode and the reference electrode fail, or two or three-electrodes fail at the same time.
  • the method of using the same name electrode to replace the failed electrode in the above embodiment can be adopted.
  • the electrode fails after 14 days in the normal working state, and the preset time t is 2 days.
  • the first electrode-group is energized and activated, after working for 2 days, switch to the second electrode-group, the second electrode-group is activated, and the first electrode-group is no longer energized and enters the sleep state.
  • the second electrode-group works for 2 days, other electrode-groups can be activated or the first electrode-group can be activated again. This cycle is activated until the service life of all electrode-groups ends and all electrode-groups enter the failure state. In this mode, the service life of multiple electrode-groups is superimposed, thus extending the service life of the sensor.
  • the preset time t can be any day within 14 days. If the service life of the electrode is extended to n (n>14) days due to process improvement or other reasons, the preset time t can be any day within n days.
  • Fig. 5 is a top view of the sensor with a stepped structure in the embodiment of the invention.
  • Fig. 6 is side A view of the step structure of the sensor in the embodiment of Fig. 5.
  • the sensor 21 of the step structure comprises side A and side B, and each side is divided into the in vitro part X and the in vivo part Y with the dotted line as the dividing line.
  • the in vivo part Y comprises a first substrate 211, a second substrate 221 and a third substrate 231, forming a step structure with each other.
  • the number and layers of the substrate are consistent with the number of electrodes on the surface. For example, when there is a three-electrode system on the substrate, the substrate is a three-layer step structure. When the side A is a two-electrode system, the substrate is a two-layer step structure.
  • each electrode is electrically connected with the corresponding PAD through the wires distributed on one substrate (such as the third substrate) , that is, a part of the wire is in contact with the electrode, and the main part of the wire is located under the substrate, which can effectively protect the wire.
  • the electrodes are distributed on different layers of substrates.
  • the spacing of electrodes is enlarged, which reduces the influence of the microenvironment on the electrode surface.
  • the electrode distribution of the step structure can effectively inhibit the interference of human response on the electrode response.
  • the width of the whole sensor can be further reduced on the premise that the effective area of each electrode is unchanged.
  • the width of step structure sensor can be reduced by about half on the basis of plane structure sensor.
  • side B and side A are symmetrical step structures.
  • the in vitro part X is paved with PADs, which correspond to the electrode one-by-one and are electrically connected through the wire, that is, the working PAD 2111 corresponding to the working electrode 2131 is electrically connected through the wire 2121.
  • the counter PAD 2211 corresponding to the counter electrode 2231 is electrically connected through wire 2221.
  • the reference PAD 2311 corresponding to the reference electrode 2331 which is electrically connected through wire 2321.
  • Different PADs, wires and electrodes are insulated from each other to prevent electrical signals from interfering.
  • the PADs correspond to the electrodes on the side B one-by-one and are electrically connected through wires, that is, the fourth PAD 2112 corresponding to the working electrode 2132 is electrically connected through wires 2122.
  • the fifth PAD 2212 corresponding to the counter electrode 2232 is electrically connected through wire 2222.
  • the sixth PAD 2312 corresponding to the reference electrode 2332 which is electrically connected through wire 2322.
  • the sequence and position of the PADs, wires and electrodes laid on the side A and side B of the sensor can be symmetrically or asymmetrically arranged.
  • the corresponding PADs, wires and electrodes are laid on the same side or on different sides.
  • the corresponding PADs, wires and electrodes are laid on the same side for the convenience of wire routing.
  • the working electrode 2131 on the side A can be reset with the counter electrode 2231, or the counter electrode 2231 on the side A can be reset with the reference electrode 2332 on the side B.
  • the step structure sensor although the step structure sensor only has the opposite side A and side B, it can also increase the number of electrode-groups by increasing the sensor area or reducing the electrode-area, so as to further increase the service life of the sensor.
  • too large sensor area may increase the host’s rejection response and cause host discomfort.
  • Too small electrode-area will reduce the sensitivity of electrode and reduce the reliability of detection parameters.
  • Too many electrode-groups will also increase the complexity of the processing process, such as the wiring of the wire will become very dense. Therefore, it is preferred that the number of electrode-groups is two.
  • each electrode-group can also be distributed on the same side of the sensor, such as side A or side B, which is not limited here.
  • the first substrate 211, the second substrate 221 and the third substrate 231 are materials with excellent insulation properties, mainly from inorganic non-metallic ceramics, silica glass and organic Polymers.
  • the substrate material is also required to have high water permeability and mechanical strength.
  • the material of the substrate is selected from one or more combinations of Poly-tetrafluoroethylene (Teflon) , Poly-ethylene (PE) , Poly-vinyl chloride (PVC) , acrylonitrile butadiene styrene copolymer (ABS) , Poly-methyl methacrylate (PMMA) , Poly-carbonate (PC) , Poly-imide (PI) , etc.
  • Teflon Poly-tetrafluoroethylene
  • PE Poly-ethylene
  • PVC Poly-vinyl chloride
  • ABS acrylonitrile butadiene styrene copolymer
  • PMMA Poly-methyl methacrylate
  • PC Poly-carbonate
  • PI Poly-imide
  • the working electrode (auxiliary electrode) , counter electrode and reference electrode at least comprise an electron conduction layer a’, an anti-interference layer b’, an enzyme layer c’, an adjustment layer d’ and a biocompatible layer e’, the properties of each layer and their related descriptions can be seen in embodiment 1, and will not be repeated here.
  • Fig. 7 is a schematic diagram of the cylindrical structure of the sensor in the embodiment of the invention.
  • Fig. 8 is the V-V’ sectional view of the cylindrical structure of the sensor in the embodiment of Fig. 7.
  • the columnar sensor 31 is divided by the dotted line on the figure, and its substrate 311 is divided into the in vitro part X and the in vivo part Y.
  • the in vitro part X is planar or cylindrical, preferably planar.
  • the in vivo part Y comprises the substrate 311, which is cylindrical, and each electrode is surrounded on the surface of the substrate. Compared with the planar electrode, the electrode with ring structure does not have sharp edges, which reduces the irritation to human tissues and human rejection reaction, which is conducive to achieving implantable long-term detection and improving the service life of the sensor.
  • the in vivo part Y comprises at least one working electrode 3131 and at least one additional electrode.
  • the additional electrode comprises a counter electrode 3231 and a reference electrode 3331, thereby forming a three-electrode system.
  • the counter electrode 3231 is the other electrode relative to the working electrode 3131, forming a closed loop with the working electrode 3131, so that the current on the electrode can be normally conducted.
  • the reference electrode 3331 is used to provide the reference potential of the working electrode 3131, therefore, the detection potential can be effectively controlled.
  • the additional electrode can also only comprise the counter electrode 3231, thus forming a two-electrode system.
  • the effective area of the working electrode 3131 and the counter electrode 3231 can be increased on the limited area of the in vivo part Y, thereby extending the service life of the electrode. Moreover, because there are two electrodes, the processing process is simpler, however, the working electrode 3131 does not have the detection potential of the reference electrode as a reference, and the reliability of the analyte detection information will be reduced. In another embodiment of the invention, there are two working electrodes 3131, one of which is used to detect the response signal of the interferents or background solution in the host body fluid by electro redox reaction with the analyte to be detected, and the other electrode is the auxiliary electrode.
  • the in vitro part X is paved with PADs, which correspond to the electrode one-by-one and are electrically connected through wires, that is, the working PAD 3111 corresponding to the working electrode 3131 is electrically connected through wire 3121.
  • the counter PAD 3211 corresponding to the counter electrode 3231 is electrically connected through wire 3221.
  • the reference PAD 3311 corresponding to the reference electrode 3331 are electrically connected through the wire 3321.
  • the working electrode 3131, the counter electrode 3231 and the reference electrode 3331 form an electrode-group. Different PADs, wires and electrodes are insulated from each other to prevent electrical signals from being disturbed.
  • each electrode is laid on the in vivo part Y in a semi surrounded manner, so there can be two electrodes at the same place to form an enclosure for the in vivo part Y.
  • the reference electrodes 3331 and 3332 are semicircular rings, respectively, whose inner diameter is equal to the outer diameter of the in vivo part Y, and are in insulated contact with each other, maximizing the obverse side Area of the in vivo part Y.
  • the working electrode 3131 or counter electrode 3231 of the same electrode-group, or the working electrode (not shown in the figure) or counter electrode (not shown in the figure) of other electrode-groups can form an enclosure with the reference electrode 3331, so that in the case of termination or early failure of any electrode, its corresponding electrode of the same name can take over and enter the working state, improve the reliability of the parameter data of the detected analytes and extend the service life of the sensor.
  • the sequence and position of the PADs, wires and electrodes laid on the substrate 311 are not limited.
  • the PADs, wires and electrodes can be symmetrically or asymmetrically arranged. No matter how the order and position of the PADs, wires and electrodes change, it is only necessary to make the PADs, wires and electrodes have a one-to-one correspondence and insulation relationship with each other.
  • the number of electrode-groups can also be increased by increasing the sensor area or reducing the electrode-area, thereby further increasing the service life of the sensor.
  • too large sensor area may increase the host’s rejection response and cause host discomfort.
  • Too small electrode-area will reduce the sensitivity of electrode and reduce the reliability of detection parameters.
  • Too many electrode-groups will also increase the complexity of the processing process, such as the wiring of the wire will become very dense. Therefore, it is preferred that the number of electrode-groups is two.
  • the substrate 311 is a material with excellent insulation performance, mainly from inorganic non-metallic ceramics, silica glass, organic Polymers, etc. at the same time, considering the application environment of the implanted electrode, the substrate material is also required to have high impermeability and mechanical strength.
  • the material of the substrate is selected from one or more combinations of Poly-tetrafluoroethylene (Teflon) , Poly-ethylene (PE) , Poly-vinyl chloride (PVC) , acrylonitrile butadiene styrene copolymer (ABS) , Poly-methyl methacrylate (PMMA) , Poly-carbonate (PC) , Poly-imide (PI) , etc.
  • the outer diameter of the in vivo part Y of the substrate 311 and the inner diameter of the electrode are 0.01 ⁇ 100um, preferably 10 ⁇ 50um.
  • the electrode can be a half ring, a 1/3 ring, a 1/4 ring or other proportion of the ring.
  • the working electrode (auxiliary electrode) , counter electrode and reference electrode at least comprise an electron conduction layer a”, an anti-interference layer b”, an enzyme layer c”, an adjustment layer d”, and a biocompatible layer e”, the properties of each layer and their related descriptions can be seen in embodiment 1, and will not be repeated here.
  • the in vivo part Y of the sensor is not necessarily limited to the shape of the above three embodiments.
  • it can be circular, semi-circular, conical, spiral and other shapes, and the shape of the electrode arranged on it also changes based on the shape of the in vivo part Y.
  • the electrode can be easily laid on the in vivo part Y, there is no limitation here.
  • Fig. 9 is a schematic diagram of a continuous analyte detection device 100 according to an embodiment of the invention.
  • the continuous analyte detection device 100 comprises a bottom shell 101 for mounting on the surface of the host skin.
  • the sensor unit 102 comprises a substrate 1021 and a micro analyte sensor 11 (21/31) as previously described.
  • the micro analyte sensor 11 (21/31) is fixed on the substrate, and the sensor unit 102 is installed on the bottom shell 101 through the substrate.
  • the transmitter unit 103 comprises an in vivo circuit 1031, a transmitter 1032, and an electrical connection area 1033.
  • the electrical connection area 1033 is electrically connected with the sensor unit 102.
  • the in vivo circuit 1031 stores the predetermined conditions for switching electrodes described above.
  • the transmitter 1032 is used to send analyte parameter information to the outside world.
  • the battery 104 is used to provide electric energy.
  • the receiver 105 which is used to receive analyte parameter information and indicate
  • Fig. 10a to Fig. 10j are the schematic diagrams of different schemes of the sensor in the embodiment of the invention.
  • Fig. 10a in order to easily and clearly show the structural characteristics of the sensor 41, the length, width, thickness and curve characteristics of the sensor are expressed in exaggerated form in Fig. 10a.
  • the actual length, width, thickness and curve characteristics of the sensor may be different from those shown in the figure.
  • the length, width, thickness and curve characteristics of the sensor are expressed in the same exaggerated form.
  • the actual length, width, thickness and curve characteristics of the sensor may be different from those in the illustration, and will not be repeated below.
  • wires, PADs and electrodes described above and later are also expressed in the figure in exaggerated form.
  • the wires, PADs and electrodes in the figure are only used as auxiliary examples to express the scheme of the invention, and are not completely equivalent to the wires, PADs and wires in the actual sensor.
  • the wire in the actual sensor is a flat wire with a certain width, which is shown in the form of lines in the illustration.
  • the substrate 411 of the sensor 41 is generally a flexible material, such as one or more combinations selected from Poly-tetrafluoroethylene, Poly-ethylene, Poly-vinyl chloride, acrylonitrile butadiene styrene copolymer, Poly-methyl-methacrylate, Poly-carbonate, Poly-imide, which has good electrical insulation characteristics, and the electrode and electrode, wire and wire set on it can be insulated from each other.
  • the substrate 411 is made of Poly-imide, which has good adaptability to human physiology and will not suffer from excessive rejection due to penetration into the subcutaneous skin.
  • a protective layer 412 is provided on the substrate 411.
  • the protective layer 412 can cover the entire substrate 411, but exposes the central area of PADs 4111/4211/4311 and electrodes 4131/4231/4331 and covers the edges of PADs 4111/4211/4311 and electrodes 4131/4231/4331.
  • Fig. 10a in order to better illustrate the coverage schematic of the protective layer 412 on electrodes 4131/4231/4331, only the working electrode 4131 and the reference electrode 4331 were covered.
  • the protective layer 412 can cover all electrodes.
  • the protective layer 412 can enhance the mechanical strength of the substrate 411 and prolong the time when the substrate 411 is damaged.
  • the protective layer 412 covers the edges of PADs 4111/4211/4311 and electrodes 4131/4231/4331, preventing irregular edges from being exposed and causing signal noise, thereby improving the stability of the detection signal.
  • the electronic conduction layer a of electrodes 4131/4231/4331 is fixed on the substrate 411, due to the repeated bending of the substrate 411 during use, the metal film of the electronic conduction layer a may inevitably detach from the substrate 411 and cause warping, bubbling.
  • the protective layer 412 can also enhance the adhesion between the metal film of the electronic conduction layer a and the substrate 411, avoiding warping, bubbling, and improving the reliability of the sensor.
  • the protective layer 412 not covers the edge area of the electrode only, it can increase the area of the protective layer 412 covering the electrode 4131/4231/4331 to further increase the adhesion degree between the electrode 4131/4231/4331 and the substrate 411. As shown in Fig. 10a, the protective layer 412 covering the working electrode 4131 only exposes a small area in the center area of the electrode, enable the analyte to be tested to come into contact with the electrode through the small area without affecting use. In some embodiments of the invention, the protective layer 412 is thicker than the electrode 4131/4231/4331, such as 0.1-500um. After coating the protective layer 412, pits are formed on the electrode 4131/4231/4331.
  • the anti-interference layer, enzyme layer, regulatory layer, and biocompatible layer of the electrode 4131/4231/4331 are located in the pits, and the pits can accommodate a larger volume of anti-interference layer, enzyme layer, regulatory layer, and biocompatible layer, improved sensitivity of electrodes 4131/4231/4331.
  • the thickness of the protective layer 412 is 0.1-200um. In further preferred embodiments of the invention, the thickness of the protective layer 412 is 1-20um. An excessively thick protective layer 412 will reduce the softness of the substrate 411 and increase the user's discomfort after penetrating the subcutaneous area, while an excessively thin protective layer 412 is easy to damage.
  • the protective layer 412 is made of one or more combinations of Poly-tetrafluoroethylene, Poly-ethylene, Poly-vinyl chloride, acrylonitrile butadiene styrene copolymer, Poly-methyl methacrylate, Poly-carbonate and Poly-imide.
  • the material of the protective layer 412 is Poly-imide. After the Poly-imide is properly heated to form a liquid, it is coated on the substrate 411 which is also Poly-imide material, and the protective layer 412 can be formed after curing.
  • the protective layer 412 of the same material has the same physical characteristics as the substrate 411, which can prevent the protective layer 412 from being damaged or falling off due to uneven stress or stress concentration on the substrate 411.
  • the area covered by the protective layer 412 on the electrode accounts for 10%to 100%.
  • the protective layer 412 when the area of the protective layer 412 covering the electrode accounts for 100%, that is, the protective layer 412 fully covers the electrode 4131/4231/4331.
  • the protective layer 412 covers the reference electrode 4331.
  • the material of the protective layer 412 is a semipermeable membrane, which can allow the analyte to penetrate and come into contact with the electrode, without affecting the use of the electrode. After the protective layer 412 fully covers the electrode, it can further enhance the adhesion between the electrode and substrate 411.
  • the substrate 411 is generally soft, and the soft substrate is repeatedly bent during the repeated peristalsis process of muscles.
  • the substrate 411 is easy to premature reaching the ultimate fatigue (not reaching the designed service life of the sensor 41, such as 14 days) , leading to damage or even breakage, which will cause the electrodes and wires set on the substrate 411 to be exposed and short circuited, or directly broken and damaged, affecting the detection reliability of sensor 41.
  • insulation materials used to strengthen the mechanical strength of the substrate 411 can be post manufactured on some areas of the substrate 411.
  • post manufacture refers to manufacturing at least one layer of insulation material on the substrate 411 after processing the sensor 41, that is, manufacturing electrodes, PADs, and wires on the substrate to form a complete sensor 41.
  • the mechanical strength of substrate 411 in the corresponding area will be improved, and the time to reach ultimate fatigue will also be extended.
  • the number of layers of insulation material installed on the substrate 411 can be multiple, such as 2, 3, or more layers, which can further increase the mechanical strength of the substrate 411.
  • setting multiple layers of insulation material will cause the corresponding area of the substrate to become less soft, and penetrating into the subcutaneous area will increase the user's discomfort.
  • the thicker the insulation material is set the greater the mechanical strength of substrate 411 can also be increased.
  • an excessively thick insulation material will also cause the substrate in the corresponding area to become less soft, which will increase the user's discomfort after penetrating into the subcutaneous area. Therefore, it is necessary to control the number and thickness of insulation materials.
  • the number of layers of the insulation material is 1 to 10, and the thickness of each layer is 0.1um to 200um.
  • the number of layers of insulation material is 1, with a thickness of 25um.
  • setting multiple layers of insulation material will increase the complexity of the processing process. Therefore, setting one layer of insulation material can not only enhance the mechanical strength of substrate 411, but also avoid overly complex processing. Setting a thickness of 25um can maintain sufficient flexibility of substrate 411, it will not increase the user's discomfort by puncturing the base under the skin.
  • the material of the insulation material can be one or more combinations of poly-tetrafluoroethylene, poly-ethylene, poly-vinyl chloride, acrylonitrile butadiene styrene copolymer, poly-methyl methacrylate, poly-carbonate, and poly-imide.
  • the characteristics of the above materials have been described earlier and will not be repeated here.
  • the preferred material for insulation is poly-imide, which is consistent with the material of substrate 411 and has the same physical properties. When extension, contraction, bending, and other actions occur, the insulation material of the same material and substrate 411 have the same extension, contraction, or bending scale, and will not wrinkle or fall off the insulation material on substrate 411 due to different scales.
  • the insulating material can be set on the substrate 411 by coating.
  • the insulating material is made of poly-imide
  • the poly-imide can be heated to a liquid state first, and then coated on the substrate 411.
  • the insulation material can be set on the substrate 411 by pasting.
  • the insulation material is made of poly-imide
  • the poly-imide precursor can be used as the pasting material. After the poly-imide precursor is cured, its physical properties remain consistent with the poly-imide substrate, and it has consistency in extension, contraction, and bending, without causing the insulation material to bulge, wrinkle, fall off, etc. on the substrate 411, improved the yield of sensors.
  • the area where the PADs and electrodes are located should be avoided, otherwise the function of sensor 41 cannot be achieved. Therefore, the area where the insulation material is post manufactured includes at least one of the reverse area 414 of the PAD-area a or the reverse area 415 the electrode-area b. Preferably, both the reverse area 414 and the reverse area 415 are provided with insulation material.
  • the reverse area 414 and the reverse area 415 can be two independent areas as shown in Fig. 10b. In other embodiments of the invention, the reverse area 414 and the reverse area 415 can also be connected into one continuous area.
  • the senor 41 may be installed in a bent form within the analyte detection device, that is, the in vitro part X is bent relative to the in vivo part Y, or the in vivo part Y is bent relative to the in vitro part X. Due to the fixation of the in vitro part X in the analyte detection device, while the in vitro part Y penetrates into the subcutaneous tissue and moves with the user's muscle peristalsis, the in vivo part Y also frequently bends repeatedly relative to the in vitro part X. It is also necessary to install insulation materials in the obverse area 413 of the bending area c of the in vivo part Y relative to the in vitro part X. After bending the obverse area 413, setting insulation materials can not only increase the mechanical strength of the substrate in the corresponding area, but also cover the wires in the corresponding area and provide additional insulation and protection for the wires.
  • the senor 41 adopts a three-electrode system, including a working electrode 4141, a counter electrode 4241 and a reference electrode 4341, and their corresponding working PAD 4111, counter PAD 4211 and reference PAD 4311, as well as wires 4121/4221/4321 connecting each PAD and electrode.
  • the sensor 41 can also adopt a two-electrode system, which does not include the reference electrode 4341 and the corresponding PADs and wires. This is a common general knowledge in the art and will not be described here.
  • the wires 4121/4221/4321 can be set on the surface or inner layer of the substrate 411 through etching, laser welding and other processes.
  • the wires 4121/4221/4321 are arranged on the inner layer of the substrate 411 and are electrically connected with the PADs or electrodes arranged on the surface of the substrate 411, holes 4141/4241/4341 are opened at the corresponding positions of the electrical connection on the substrate 411, and the electrical connection ends of the wires 4121/4221/4321 are led out to the surface of the substrate 411 through holes 4141/4241/4341 to establish electrical connections with the electrodes 4131/4231/4331 respectively.
  • wire 4121/4221/4321 is electrically connected with PAD 4111/4211/4311 through the corresponding hole (not shown in the figure) .
  • the substrate 411 can provide insulation protection for each wire to avoid signal loss or instability caused by short circuit between each wire, but the processing technology is relatively complex.
  • the substrate 411 is a single-layer plane as shown in Fig. 10a.
  • the substrate 411 may also be a multilayer plane as shown in Fig. 10b.
  • the substrate 411 can be composed of multiple layers of secondary-substrates, such as the first secondary-substrate 411d, the second secondary-substrate 411e, and/or the third secondary-substrate 411f.
  • At least one electrode and at least one wire can be arranged on each layer of secondary-substrate 411d/411e/411f.
  • the electrodes 4131/4231/4331 are respectively set on the secondary-substrates 411d/411e/411f of different layers. On the one hand, it can increase the distance between electrodes, reduce the signal interference between electrodes, and improve the detection reliability.
  • the electrode on the substrate of each layer can be made larger, and the electrode with larger area can contact the body fluid more fully, the signal is more stable, and the detection reliability can be improved.
  • the wires 4121/4221/4321 electrically connected with the electrode can also be routed on different secondary-substrates, so the secondary-substrate can also electrically insulate the wires 4121/4221/4321. Based on this, the wires 4121/4221/4321 can be routed on the surface of the secondary-substrates 411d/411e/411f at all layers, simplifying the wire processing technology.
  • the wires 4121/4221/4321 can be laid on the surface of the secondary-substrate 411d/411e/411f of different layers, once the substrate of a certain layer is damaged, the wires of the adjacent two layers may contact and short circuit. Therefore, when laying the wires 4121/4221/4321 on the secondary-substrate 411d/411e/411f, the wires 4121/4221/4321 can be staggered as shown in the top view of Fig. 10b to form a stepped distribution of wires, even if the substrate of a certain layer is damaged, the wires of two adjacent layers will not be short circuited due to contact, which improves the detection reliability.
  • the substrate composed of multi-layer of secondary-substrate has higher mechanical strength, is not easy to be broken or damaged, and extends and improves the detection reliability.
  • the use of a multi-layer of secondary-substrate will inevitably increase the overall thickness of the sensor 41, which may increase the user’s discomfort after penetration into the subcutaneous layer.
  • each electrode on the secondary-substrate is not fixed.
  • the reference electrode 4331 can be set on the secondary-substrate 411f of the top layer.
  • the cost of the reference electrode 4331 is higher than that of the working electrode 4131 and the counter electrode 4231.
  • the reference electrode 4331 on the secondary-substrate 411f of the top layer is manufactured in the final process, which can protect the reference electrode 4331 from damage.
  • the reference electrode 4331 can also be set on the secondary-substrate 411d of the bottom layer.
  • the reference electrode 4331 is thicker than the working electrode and the counter electrode 4231, and is located on the secondary-substrate 411d of the bottom layer, which can improve the thickness consistency of the sensor 41 without making the sensor 41 have too large thickness difference, which is convenient for the storage and use of the sensor 41.
  • the thicknesses of the secondary-substrates 411d/411e/411f and electrodes 4131/4231/4331 of each layer are expressed in exaggerated form. It is understandable that this does not affect the description of this scheme.
  • the secondary-substrates 411d/411e/411f of each layer can be manufactured layer by layer, that is, after the bottom layer of secondary-substrate 411d is manufactured, the middle layer of secondary-substrate 411e is manufactured on the basis of the bottom layer of secondary-substrate 411d. Similarly, after the middle layer of secondary-substrate 411e is manufactured, the top layer of secondary-substrate 411f is manufactured.
  • the secondary-substrate materials such as Poly-imide, are coated on the mold layer by layer after heating to form a complete secondary-substrate after curing.
  • the substrate will be brittle during subsequent use, which will cause the electrodes, wires and PADs on the substrate to be short circuited to each other or even damaged, affecting the detection reliability of the sensor.
  • the secondary-substrates 411d/411e/411f of each layer can be prefabricated first.
  • the prefabrication refers to that after the substrate material of each layer of secondary-substrates 411d/411e/411f is fully cured, the electrodes, wires or PADs are processed on the substrate.
  • the electrodes, wires or PADs set on the substrate of each layer. The wires or PADs may or may not be the same.
  • the secondary-substrates 411d/411e/411f of each layer are combined into a whole by pasting.
  • the precursor of Poly-imide can be used to paste the secondary-substrates 411d/411e/411f of each layer, and finally a complete substrate of sensor can be obtained. Since the secondary-substrates 411d/411e/411f of each layer are pasted as a whole after being fully cured, it can not only avoid the embrittlement problem caused by insufficient curing of materials in the substrate of the same layer, but also avoid the embrittlement problem caused by insufficient curing of materials between secondary-substrates of different layers, which improves the detection reliability of the sensor. In addition, since the secondary-substrates 411d/411e/411f of each layer can be prefabricated independently and then assembled into a whole, the manufacturing efficiency of the sensor 41 can also be increased in the manufacturing process.
  • the PADs 4111/4211/4311 corresponding to each electrode 4131/4231/4331 also need to be prefabricated to achieve the function of the sensor 41.
  • the wires on the secondary-substrate 411d/411e are led to the secondary-substrate 411f of the top layer by drilling to establish an electrical connection with the PADs on the secondary-substrate 411f.
  • the thickness of each layer of secondary-substrate 411d/411e/411f can be 0.1 ⁇ 200um, which is different from the scheme of single-layer substrate shown in Fig. 10a.
  • Each layer of secondary-substrate 411d/411e/411f may need to be made thinner. Otherwise, the superposition of several layers of secondary-substrate is too thick as a whole, and there is not enough softness, which increases the discomfort when stabbing into the user’s skin. Therefore, it is preferred that the thickness of each layer of the secondary-substrate 411d/411e/411f is 0.1 ⁇ 20um.
  • each layer of the secondary-substrate 411d/411e/411f is about 10um, and the thickness of the whole is about 25 ⁇ 35um. This thickness will not be easily damaged or broken because it is too thin, nor will it increase the user’s discomfort because it is too thick. Those skilled in the art can understand that the actual thickness of the secondary-substrate 411d/411e/411f of each layer may deviate due to the error of the processing technology.
  • the material of the secondary-substrates 411d/411e/411f at all layers is preferably Poly-imide.
  • the bonding material can preferably be Poly-imide precursor. After curing, the Poly-imide precursor and Poly-imide can maintain the consistency of physical properties. Such a bonding method can prevent the secondary-substrates 411d/411e/411f at all layers from peeling off or even falling off due to stress concentration or uneven stress.
  • a protective layer 412 can still be set on the surface of the substrate to protect its electrodes or PADs.
  • the thickness and the number of layers of the protective layer 412 are the same as those previously described, and will not be repeated here.
  • At least one electrode may be set on the reverse side B of the substrate 411.
  • a protective layer 412 can be set on both the obverse side A and the reverse side B of the substrate 411 to protect the electrode located on the opposite side of the substrate 411.
  • the protective layer 412 on the reverse side B should also avoid the central area of the electrode on the reverse side B and cover at least its edge.
  • the electrode arranged on the reverse side B of the substrate 411 may be a counter electrode 4231.
  • Setting the counter electrode 4231 on the reverse side B of the substrate 411 can increase the relative distance between the counter electrode 4231 and the working electrode 4131, reduce the current crosstalk between the counter electrode 4231 and the working electrode 4131, and reduce the noise.
  • the area of the counter electrode 4231 can be maximized, so as to reduce the electrochemical polarization and improve the accuracy and sensitivity of the detection signal.
  • the electrode arranged on the reverse side B of the substrate 411 may be a reference electrode 4331.
  • the reference electrode 4331 is set on the reverse side B of the substrate 411.
  • the reference electrode 4331 can be manufactured separately, which will not affect the working electrode 4131 and the counter electrode 4231, improving the yield of finished products.
  • it can reduce the circuit risk caused by the migration of Ag/Cl material of reference electrode 4331 and improve the detection reliability.
  • the electrode arranged on the reverse side B of the substrate 411 may be the working electrode 4131.
  • the working electrode 4131 is set at the reverse side B of the substrate 411. If the counter electrode 4231 is short circuited with the reference electrode 4331, the three-electrode system will become a two-electrode system, which will not affect the detection current, and the detection signal will not change suddenly, improving the detection stability.
  • the obverse side and reverse side of the substrate 411 need to be processed to set electrodes, wires, etc., which will inevitably cause damage to the other side in the processing process.
  • the obverse side and reverse side of the substrate 411 can be processed separately, that is, the obverse side A and reverse side B of the substrate 411 are processed respectively, and then the obverse side A and reverse side B are assembled into a whole, forming a complete sensor can improve the integrity of the double-sided substrate.
  • electrodes, wires and PADs are processed on the obverse side A of substrate 411a, while electrodes and wires are processed on the reverse side B of substrate 411b, the setting positions of the above electrodes, wires and PADs on the substrate 411a and substrate 411b are not limited.
  • at least one protective layer can be processed after the electrodes, wires and PADs are processed.
  • the protective layer can be set as described above, avoiding the central area of the PADs and electrodes and covering the edges of the PADs and electrodes.
  • the substrate 411a and the substrate 411b can be combined into a whole by pasting.
  • the materials of the substrate 411a and the substrate 411b are Poly-imide, and the substrate 411a and the substrate 411b are pasted together using the precursor material of Poly-imide. Refer to Fig. 10c and its description for relevant technical details.
  • the mechanical strength of the substrate 411 can be enhanced by setting a protective layer 412 on the substrate 411, so as to reduce the possibility of electrode damage, in actual use, with the increase of the user’s movement and other reasons, the substrate 411 may be repeatedly bent more than expected, and the electrode may still be damaged. Therefore, some necessary measures can be taken to prevent the electrode from being damaged.
  • changing the whole electrode into an electrode unit array composed of smaller electrode units can prevent the whole electrode from being damaged and improve the detection reliability of the sensor.
  • the original working electrode 4131 is cut into smaller working electrode units 4131a, and then the working electrode units 4131a are assembled into an array to form a working electrode array.
  • Each unit in the working electrode array jointly realizes the detection function of the working electrode 4131, and its function is almost the same as that of the original working electrode 4131.
  • All working electrode units 4131a are laid on wire 4121, and the current of each working electrode unit 4131a during the detection of analytes is transmitted through wire 4121.
  • the electron conduction layer is a hard layer and other structural layers are soft layers
  • the working electrode 4131 when the working electrode 4131 is damaged due to bending, the probability is that the electron conduction layer is bent and broken. Therefore, the working electrode unit 4131a can make the original whole electron conduction layer into an electron conduction layer unit with a smaller area.
  • These electron conduction layer units share an anti-interference layer, an enzyme layer, an adjustment layer and a biocompatible layer.
  • each working electrode unit 4131a can independently realize the detection function, that is, each working electrode unit 4131a contains an independent electron conduction layer, an anti-interference layer, an enzyme layer, a regulation layer, and a biocompatible layer.
  • the electrode unit is a cubic structure as shown in Fig. 10f, which has dimensions of length (L) about 10 ⁇ 100um, width (K) about 1 ⁇ 50um, thickness (H) about 0.05 ⁇ 10um, and the adjacent two electrode units are arranged at intervals of 1 ⁇ 20um.
  • each electrode may contain 10-500 electrode units, which depends on the area of the electrode, the area of the single electrode unit and the spacing of the electrode units.
  • the specific number of electrode units in each electrode is not specially limited here.
  • the area of each electrode in the sensor 41 is different, and there are different numbers of electrode units in the working electrode array, counter electrode array and reference electrode array. For example, there can be 25-120 working electrode units in the working electrode array, 50-150 counter electrode units in the counter electrode array and 15-75 reference electrode units in the reference electrode array.
  • the electrode unit can be other three-dimensional structures, such as cylinder structure, prism structure, cone structure, etc.
  • the length*width*thickness of the electrode unit is 50um*30um*0.2um
  • there are 75 working electrode units 4131 in the working electrode array 110 counter electrode units 4231 in the counter electrode array, 35 reference electrode units 4331 in the reference electrode array, and the spacing of each electrode unit is 10um. If more advanced laser etching technology is adopted, the area of electrode units and the spacing between electrode units can be made smaller, so that the possibility of electrode units being damaged becomes smaller and the detection performance is better.
  • the approximate size of each electrode array is: the length*width*thickness of the working electrode array is 1.08mm*0.18mm*0.2um, the length*width*thickness of the counter electrode array is 1.52mm*0.18mm*0.2um, and the length*width*thickness of the reference electrode array is 0.51mm*0.18mm*0.2um.
  • the protective layer 412 protecting the electrode units and the edge of the PADs can still be set in the corresponding area on the substrate 411.
  • the electrodes located on the substrate 411 can be distributed in a predetermined way to avoid the easy-bending-area 416, so as to prevent the electrodes from being damaged.
  • the easy-bending-area 416 is not limited to one easy-bending-area 416 shown in Fig. 10g, but there may also be multiple easy-bending-areas, which are mainly determined by the material of the substrate 411 and the depth of penetration into the subcutaneous skin. Secondly, it is also related to the location of the substrate penetration into the user’s subcutaneous skin, the user’s movement mode, the thickness of the substrate and other reasons. Generally speaking, for the same substrate material, the penetration depth, the areas with large bending amplitude on the substrate 411 are fixed, and the electrodes should be set away from these easy-bending-areas.
  • the easy-bending-area 416 is the middle section of the in vivo part Y.
  • the easy-bending-area 416 is about 2.5mm away from the end of the substrate 411.
  • the easy-bending-area 416 may be an area 2.1 ⁇ 2.8mm away from the end of the in vivo part Y. The above values are for illustrative purposes only.
  • the substrate 411 when the substrate 411 includes a multi-layer of secondary-substrate or a double-sided substrate, there will also be some easy-bending-areas, which should be avoided when setting electrodes. In some embodiments of the invention, when at least one electrode is arranged on the reverse side of the substrate 411, the electrode arranged on the reverse side of the substrate 411 also avoids these easy-bending-areas.
  • the protective layer 412 protecting the electrode and the edge of the PAD can still be set on the substrate 411.
  • the setting method and setting area have been described in detail previously, and will not be described here.
  • one or more of the working electrode 4131, counter electrode 4231, and reference electrode 4331 may have additional electrodes with the same name, for example, the working electrode 4131 includes the first working electrode 4131 ⁇ and the second working electrode 4131 ⁇ .
  • the working electrode 4131 includes the first working electrode 4131 ⁇ and the second working electrode 4131 ⁇ at the same time
  • the counter electrode 4231 also includes the first counter electrode 4231 ⁇ and the second counter electrode 4231 ⁇ .
  • each electrode may have multiple electrodes with the same name, which can enrich and improve the functions of sensor 41.
  • the first working electrode 4131 ⁇ and the second working electrode 4131 ⁇ can be used as a relay when the first working electrode 4131 ⁇ after being damaged or expired, the second working electrode 4131 ⁇ as a redundant electrode, it can replace the first working electrode 4131 ⁇ by connecting the circuit and continuing the detection function, the lifespan of sensor 41 has been extended and the detection reliability has been improved.
  • the first working electrode 4131 ⁇ and the second working electrode 4131 ⁇ can be different enzyme layers to detect different analytes in the user’s body, such as blood glucose and blood ketone.
  • the first working electrode 4131 ⁇ and the second working electrode 4131 ⁇ can be connected to the circuit simultaneously, and its detection data can be calibrated with each other, improving detection reliability.
  • the first working electrode 4131 ⁇ and the second working electrode 4131 ⁇ can be used interchangeably, reducing the consumption of enzyme layers in each electrode during use, and extending the first working electrode 4131 ⁇ and the second working electrode 4131 ⁇ , and thus the service life of sensor 41 is further extended.
  • each electrode has at least one electrode of the same name.
  • the first working electrode, the first counter electrode, and the first reference electrode form a first electrode group, while the second working electrode, the second counter electrode, and the second reference electrode form a second electrode group.
  • each electrode group can complete and independently perform blood glucose or other analyte detection functions.
  • each electrode group can be used simultaneously or separately.
  • the first working PAD 4111 ⁇ and the second working PAD 4111 ⁇ when the first working electrode 4131 ⁇ and the second working electrode 4131 ⁇ stack the detection signal, the first working PAD 4111 ⁇ and the second working PAD 4111 ⁇ connected to the circuit simultaneously, if the first working PAD 4111 ⁇ and the second working PAD 4111 ⁇ are set the electrical connection area on the circuit separately, which will increase the complexity of the circuit, so the first working PAD 4111 ⁇ and the second working PAD 4111 ⁇ can establish electrical connection on sensor 41 directly, and the circuit only needs to connect to one of the first working PAD 4111 ⁇ and the second working PAD 4111 ⁇ to achieve the function of sensor 41, which reduce the complexity of the circuit.
  • the electrical connection method between the first working PAD 4111 ⁇ and the second working PAD 4111 ⁇ can refer to Fig. 10b and its corresponding description, and will not be repeated here.
  • the first working electrode 4131 ⁇ and the second working electrode 4131 ⁇ share the PADs, specifically, the first working electrode 4131 ⁇ and the second working electrode 4131 ⁇ electrically connected to working PAD 4111 through wire 4121 ⁇ and wire 4121 ⁇ respectively, detection signals of the first working electrode 4131 ⁇ and the second working electrode 4131 ⁇ are transmitted through working PAD 4111, which can achieve signal enhancement function.
  • the first working electrode 4131 ⁇ and the second working electrode 4131 ⁇ share the wire, specifically, the first working electrode 4131 ⁇ and the second working electrode 4131 ⁇ electrically connected to working PAD 4111 through the wire 4121, the detection signals of the first working electrode 4131 ⁇ and the second working electrode 4131 ⁇ are transmitted through wire 4121 and PAD 4111, which can achieve signal enhancement function.
  • the first working electrode 4131 ⁇ shares wire 4121 with the second working electrode 4131 ⁇ , which can reduce the number of wires installed on substrate 411, reduce the possibility of short circuits between wires, and improve detection reliability.
  • electrodes with the same name can be set on the same side of the substrate 411, which can reduce the manufacturing process steps and complexity.
  • electrodes with the same name can be set on the opposite surface of substrate 411 to reduce signal interference between electrodes with the same name.
  • the limited area of the obverse side A of the substrate 411 limits the area of the electrodes. Therefore, it is also necessary to set some of the electrodes on the reverse side B of the substrate 411. For example, setting the first working electrode 4131 ⁇ and the counter electrode 4231 on the reverse side B not only achieves detection function, but also reduces the possibility of short circuit between the counter electrode 4231 and the reference electrode 4331.
  • a protective layer 412 can be set on the substrate 411 to cover the edges of the electrodes or PADs.
  • the setting of the protective layer 412 is not necessary, and without the protective layer 412, sensor 41 can still achieve its detection function.
  • the shape of the protective layer 412 on the substrate 411 is not limited to those shown in Fig. 10a to 10m.
  • the figures are only for illustration, and any simple shape transformation, position transformation, material transformation, quantity transformation, layer number transformation, size transformation, etc. should be included in the scope of protection of the invention.
  • void the area where PADs and electrodes are located can refer to avoiding the structural areas that require electrical conductivity such as PADs and electrodes, or to the surface area where PADs and electrodes are set on the substrate in some embodiments of the invention.
  • the schemes involved in different illustrations may be applicable to each other, such as the electrode unit array scheme in Fig. 10f, which can be applied to the double-sided electrode scheme in Fig. 10e or other schemes, without limitation.
  • the invention discloses a structurally enhanced analyte sensor, which at least one protective layer is set on the surface of the substrate, covering at least a part of the area of the electrode to increase the adhesion between the electrode and the substrate, and prevent electrode from warping, bubbling, and detaching, extend the service life of the sensor, and improve the detection reliability of the sensor.

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Abstract

L'invention concerne un capteur d'analyte structuralement amélioré (11), au moins une couche de protection (412) étant définie sur la surface du substrat (411), recouvrant au moins une partie de la zone de l'électrode (4131/4231/4331), augmentant le degré d'adhérence entre l'électrode (4131/4231/4331) et le substrat (411), la couche de protection (412) pouvant empêcher l'électrode (4131/4231/4331) de se déformer, de former des bulles et de se détacher, prolongeant la durée de vie du capteur (11), et améliorant la fiabilité de détection du capteur (11).
PCT/CN2023/120576 2023-09-22 2023-09-22 Capteur d'analyte structuralement amélioré Pending WO2025060023A1 (fr)

Priority Applications (1)

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PCT/CN2023/120576 WO2025060023A1 (fr) 2023-09-22 2023-09-22 Capteur d'analyte structuralement amélioré

Applications Claiming Priority (1)

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PCT/CN2023/120576 WO2025060023A1 (fr) 2023-09-22 2023-09-22 Capteur d'analyte structuralement amélioré

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100030052A1 (en) * 2008-07-31 2010-02-04 Bommakanti Balasubrahmanya S Analyte sensors comprising plasticizers
CN113820371A (zh) * 2021-10-14 2021-12-21 上海糖简生物传感技术有限公司 一种植入式三电极微型传感器及其制备工艺
CN114778628A (zh) * 2022-04-25 2022-07-22 北京怡成生物电子技术股份有限公司 柔性工作电极及酶传感器
CN115590509A (zh) * 2021-07-08 2023-01-13 上海移宇科技股份有限公司（Cn） 微型分析物传感器
CN115590508A (zh) * 2021-07-08 2023-01-13 上海移宇科技股份有限公司（Cn） 微型分析物传感器
WO2023010539A1 (fr) * 2021-08-06 2023-02-09 Medtrum Technologies Inc. Capteur de micro-analyte

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100030052A1 (en) * 2008-07-31 2010-02-04 Bommakanti Balasubrahmanya S Analyte sensors comprising plasticizers
CN115590509A (zh) * 2021-07-08 2023-01-13 上海移宇科技股份有限公司（Cn） 微型分析物传感器
CN115590508A (zh) * 2021-07-08 2023-01-13 上海移宇科技股份有限公司（Cn） 微型分析物传感器
WO2023010539A1 (fr) * 2021-08-06 2023-02-09 Medtrum Technologies Inc. Capteur de micro-analyte
CN113820371A (zh) * 2021-10-14 2021-12-21 上海糖简生物传感技术有限公司 一种植入式三电极微型传感器及其制备工艺
CN114778628A (zh) * 2022-04-25 2022-07-22 北京怡成生物电子技术股份有限公司 柔性工作电极及酶传感器

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