Long-life analyte sensor integrated with temperature measurement

Abstract

A long-life analyte sensor (11, 21, 31, 41) integrated with temperature measurement. The sensor comprises at least one substrate (111, 211, 311, 411), at least two electrodes (1131, 1231, 1331, 4131, 2131, 2231, 2331), a pin (1111, 1211, 1311, 1411) and a temperature sensor (1431, 2431), wherein the temperature sensor (1431, 2431) is arranged on a surface of an in-vivo part of the substrate (111, 211, 311, 411), and is used for directly measuring the in-vivo temperature of a patient; and at least one layer of insulating material is arranged behind at least one region (312, 313, 314, 315) of the substrate (111, 211, 311, 411), and avoids a central conductive region in which the pin (1111, 1211, 1311, 1411), the electrodes (1131, 1231, 1331, 4131, 2131, 2231, 2331) and the temperature sensor (1431, 2431) are located.

Description

Long-life analyte sensor with integrated temperature detection Technical Field

[0001] The present invention relates generally to the field of medical devices, and in particular to a long-life analyte sensor with integrated temperature detection. Background Art

[0002] In a healthy individual, the pancreas automatically monitors blood glucose levels and secretes the necessary insulin and glucagon. However, in diabetics, the pancreas malfunctions, preventing it from producing the necessary insulin. Therefore, diabetes is a metabolic disease caused by abnormal pancreatic function and is a lifelong condition. Currently, medical technology cannot cure diabetes; the only approach is to control the onset and progression of diabetes and its complications by stabilizing blood sugar levels.

[0003] Diabetic patients need to test their blood sugar before injecting insulin into their bodies. Currently, most detection methods can continuously detect blood sugar and send blood sugar data to remote devices in real time for users to view. This detection method is called continuous glucose monitoring (CGM) method. This method requires the detection device to be attached to the surface of the skin, and the probe it carries is inserted into the subcutaneous tissue fluid to complete the detection. According to the detected blood sugar value, relevant algorithms, such as PID algorithm and MPC algorithm, are used to calculate the amount of insulin that needs to be infused into the patient's body. Excessive insulin infusion may cause the patient to have hypoglycemia, while insufficient insulin infusion may also cause the patient's blood sugar to remain at a high level, causing hyperglycemia. Therefore, the accuracy of the insulin infusion amount is crucial to maintaining the patient's blood sugar stability, and the amount of insulin infused is directly related to the blood sugar value in the patient's body. Therefore, the accuracy of the blood sugar measurement value is crucial to maintaining the patient's blood sugar stability.

[0004] Since temperature changes affect the permeability of the sensor membrane and the activity of active enzymes, it is generally believed that temperature also affects the sensitivity of the sensor. The temperature of the sensor at the factory or when it is calibrated is likely to be different from the temperature during actual use, that is, when it is in the user's body. Therefore, in order to ensure the accuracy of blood glucose measurements, it is necessary to consider the influence of temperature during measurement.

[0005] Currently, some existing technologies integrate temperature sensors into transmitters to measure ambient temperature, while others integrate sensors into housings near the skin to measure skin temperature. However, neither of these methods directly measures the temperature of the sensor during actual use, i.e., the internal body temperature when the sensor is inserted into the body. The temperature measured using existing methods requires further processing through temperature compensation, algorithm correction, and other methods. This process is complex and the results may not be accurate or reliable. When the temperature sensor is placed within the internal body portion of the sensor base, the flexible sensor base will repeatedly bend or flex with muscle peristalsis after subcutaneous insertion. Upon reaching extreme fatigue, the base material may break or damage, exposing the wires or breaking the electrodes or temperature sensor attached to the base, shortening the sensor's service life and reducing its detection reliability.

[0006] Therefore, the prior art urgently needs an analyte sensor that can directly detect the sensor operating temperature, has high blood glucose detection accuracy, and has a long service life.

[0007] Summary of the Invention

[0008] In view of the shortcomings of the above-mentioned prior art, an embodiment of the present invention discloses a long-life analyte sensor with integrated temperature detection. The temperature sensor is arranged on the surface of the internal part of the substrate, and can directly measure the temperature of the analyte sensor during in-vivo detection. There is no need to further calibrate the detected temperature, omitting the temperature processing process, thereby improving the reliability of the detected temperature. According to the detected in-vivo temperature, the analyte value can be directly calibrated to improve the accuracy of analyte detection; at the same time, at least one layer of insulating material is arranged behind at least one area on the substrate to avoid the central conductive area where the pins, electrodes and temperature sensor are located, thereby increasing the mechanical strength of the sensor substrate. After the sensor is inserted into the subcutaneous tissue, when it bends or bends with muscle peristalsis, the time for the substrate to reach extreme fatigue is extended, thereby extending the service life of the sensor.

[0009] The present invention discloses an analyte sensor, comprising: at least one substrate, including an internal part and an external part; at least two electrodes, arranged on the surface of the internal part, for piercing the subcutaneous tissue to obtain analyte parameter information; pins, arranged on the surface of the external part, and electrically connected to corresponding electrodes via wires; and a temperature sensor, arranged on the surface of the internal part, for directly detecting the patient's internal temperature; wherein at least one layer of insulating material is arranged behind at least one area of ​​the surface of the at least one substrate, and the insulating material avoids the central conductive area of ​​the pins, electrodes and temperature sensor.

[0010] According to one aspect of the present invention, the inner portion is bent relative to the outer portion, and the area where the insulating material is disposed further includes the front side of the bent area.

[0011] According to one aspect of the present invention, the area where the insulating material is disposed later includes at least the reverse side of the pin area, the electrode area, and / or the reverse side of the temperature sensor area.

[0012] According to one aspect of the present invention, the area where the insulating material is disposed later also includes an area where the distance between the electrode and the temperature sensor is relatively large.

[0013] According to one aspect of the present invention, the insulating material is disposed on the surface of the substrate by coating or pasting.

[0014] According to one aspect of the present invention, the temperature sensor is one of a metal thin film thermal resistor, a carbon thin film resistor, a metal oxide thin film thermal resistor, and an alloy thin film thermal resistor.

[0015] According to one aspect of the present invention, the temperature sensor is a thin film platinum thermal resistor.

[0016] According to one aspect of the present invention, a temperature sensor includes a polyimide protection layer.

[0017] According to one aspect of the present invention, the at least two electrodes include at least a working electrode and a counter electrode.

[0018] According to one aspect of the present invention, the working electrode and the temperature sensor are at the same height when inserted into the subcutaneous tissue.

[0019] According to one aspect of the present invention, at least one substrate is a single-layer substrate, and the working electrode and the temperature sensor are arranged in parallel on the same surface of the single-layer substrate.

[0020] According to one aspect of the present invention, at least one substrate is a single-layer substrate, and the working electrode and the temperature sensor are arranged on different surfaces of the single-layer substrate.

[0021] According to one aspect of the present invention, the at least one substrate comprises a multi-layer substrate, and the working electrode and the temperature sensor are arranged in parallel on the same surface of the substrate in the same layer.

[0022] According to one aspect of the present invention, the at least one substrate comprises a multi-layer substrate, and the working electrode and the temperature sensor are arranged on different surfaces of the same layer of substrate.

[0023] According to one aspect of the present invention, the at least one substrate comprises a multi-layer substrate, and the working electrode and the temperature sensor are arranged on different surfaces of different layers of substrates.

[0024] According to one aspect of the present invention, the working electrode and the temperature sensor are arranged on different surfaces of adjacent substrates at different levels.

[0025] According to one aspect of the present invention, the working electrode and the temperature sensor are arranged on different surfaces of a spaced-apart substrate at different levels.

[0026] According to one aspect of the present invention, the multi-layered substrate is prefabricated and then glued together to form a whole.

[0027] According to one aspect of the present invention, the temperature sensor is embedded in the working electrode or the counter electrode.

[0028] According to one aspect of the present invention, the conductive lines are provided on the surface of the substrate.

[0029] According to one aspect of the present invention, the conductive lines are provided in an inner layer of the substrate.

[0030] Compared with the prior art, the technical solution of the present invention has the following advantages:

[0031] The present invention discloses an analyte sensor with integrated temperature detection. The temperature sensor is arranged on the surface of the internal part of the substrate, and can directly measure the temperature of the analyte sensor during in-vivo detection. There is no need to further calibrate the detected temperature, omitting the temperature processing process, thereby improving the reliability of the detected temperature. Furthermore, based on the detected in-vivo temperature, the analyte value can be directly calibrated to improve the accuracy of analyte detection. At the same time, at least one layer of insulating material is arranged behind at least one area on the substrate to avoid the central conductive area where the pins, electrodes and temperature sensor are located, thereby increasing the mechanical strength of the sensor substrate. After the sensor is inserted into the subcutaneous tissue, when it bends or folds with muscle peristalsis, the time it takes for the substrate to reach extreme fatigue is prolonged, thereby extending the service life of the sensor.

[0032] Furthermore, the area where the insulating material is later set includes at least the reverse side of the pin area, the reverse side of the electrode area and / or the reverse side of the temperature sensor area, which can enhance the mechanical strength of the sensor substrate while avoiding interference with the electrodes, temperature sensors and pins, thereby increasing the reliability of temperature detection and analyte detection.

[0033] Furthermore, the internal part is bent relative to the external part, and the insulating material can be arranged on the front side of the bending area, which does not affect the electrodes, temperature sensors and pins, and can also enhance the mechanical strength of the bending area of ​​the substrate, reducing the possibility of the substrate in the bending area being damaged due to bending, exposing the wires and causing a short circuit, or breaking and causing sensor failure, thereby improving the detection reliability of the sensor and extending the service life of the sensor.

[0034] Furthermore, the insulating material is set on the surface of the substrate by coating or pasting, which can alleviate the problem of uneven or concentrated stress between the insulating material and the substrate when the two are combined, and can prevent the insulating material from bubbling, warping or detaching from the substrate during use, thereby improving the detection reliability of the sensor and extending the service life of the sensor.

[0035] Furthermore, the temperature sensor and at least one electrode may be arranged in parallel or in sequence on the surface of the internal body part, fully utilizing the area of ​​the substrate and facilitating the miniaturization of the analyte sensor.

[0036] Furthermore, the temperature sensor and at least one electrode are arranged on different surfaces of the substrate, and the temperature sensor and the electrode can be designed with a larger area, thereby improving the reliability of analyte detection and temperature detection.

[0037] Furthermore, the working electrode and the temperature sensor are at the same height when inserted into the subcutaneous tissue, and the operating environment of the temperature sensor is the same as that of the working electrode. Therefore, the temperature measured by the temperature sensor is the operating temperature of the working electrode, and there is no need to further compensate for the measured temperature, making the blood glucose measurement value more accurate.

[0038] Furthermore, the outer layer of the temperature sensor is coated with a liquid polyimide insulating layer as a protective layer, which can reduce or eliminate the stress influence of different material layers and prevent the temperature sensor from being damaged due to uneven stress or stress concentration.

[0039] Furthermore, the substrate includes at least two layers of substrates, and at least two electrodes and temperature sensors are arranged on different layers of sub-substrates. On the one hand, the distance between the electrodes and between the electrodes and the temperature sensors can be increased, the signal interference between the electrodes and between the electrodes and the temperature sensors can be reduced, and the reliability of analyte detection and temperature detection can be improved; on the other hand, the electrodes or temperature sensors on each layer of substrate can be set to a larger area. The electrodes or temperature sensors with a larger area can be in more complete contact with the body fluid, the signals can be more stable, and the reliability of analyte detection and temperature detection can be improved.

[0040] Furthermore, the sub-substrates of different layers can be prefabricated first, that is, the electrodes, wires and pins are prefabricated on each layer of the substrate, and then pasted and combined into a whole to form a complete sensor. Different from the conventional layer-by-layer coating process, it can avoid the insulation failure caused by brittle cracking due to insufficient curing of the substrate material, and further cause crosstalk between the electrical signals of the wires or electrodes, and noise in the detection signal, thereby improving the detection reliability of the sensor.

[0041] Furthermore, at least one protective layer is provided on the sensor substrate, which covers at least the edges of the electrode and / or temperature sensor and avoids the central area of ​​the electrode and / or temperature sensor, thereby preventing the edges of the electrode and / or temperature sensor from warping, bubbling or falling off, thereby increasing the mechanical strength of the sensor substrate and extending the service life of the sensor. At the same time, it can also reduce the signal noise caused by the irregular warping of the edges of the electrode and / or temperature sensor, thereby improving the reliability of the sensor's analyte detection and temperature detection. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figures 1a to 1e are schematic diagrams of an analyte sensor in which a temperature sensor and an electrode are located on the same surface of a substrate according to an embodiment of the present invention;

[0043] 2a-2k are schematic diagrams of analyte sensors in which at least one electrode and a temperature sensor are located on different sides of a substrate according to an embodiment of the present invention;

[0044] 3a-3f are schematic diagrams of an analyte sensor with an integrated temperature sensor having an insulating material disposed thereon in accordance with an embodiment of the present invention;

[0045] 4a-4f are schematic diagrams of an analyte sensor with an integrated temperature sensor and a protective layer according to an embodiment of the present invention. DETAILED DESCRIPTION

[0046] As mentioned above, the temperature sensor of the existing technology cannot directly detect the temperature during electrode operation. The detected temperature needs to be further processed, the processing process is complicated, and the processing results may not be accurate and reliable. At the same time, since the sensor base is soft, it will bend or bend repeatedly with the peristalsis of the muscle after being inserted into the subcutaneous tissue. After reaching the limit of fatigue, the base material may break or break, thereby affecting the service life of the sensor.

[0047] To solve this problem, the present invention provides an analyte sensor with integrated temperature detection. The temperature sensor is arranged on the surface of the internal part of the substrate, and can directly measure the temperature of the analyte sensor during in vivo detection. There is no need to further calibrate the detected temperature, omitting the temperature processing process, thereby improving the reliability of the detected temperature. Further, based on the detected in vivo temperature, the analyte value can be directly calibrated to improve the accuracy of analyte detection. At the same time, at least one layer of insulating material is arranged behind at least one area on the substrate to avoid the central conductive area where the pins, electrodes and temperature sensor are located, thereby increasing the mechanical strength of the sensor substrate. After the sensor is inserted into the subcutaneous tissue, when it bends or folds with muscle peristalsis, the time it takes for the substrate to reach extreme fatigue is extended, thereby extending the service life of the sensor.

[0048] Various exemplary embodiments of the present invention will now be described in detail with reference to the accompanying drawings. It should be understood that unless otherwise specifically stated, the relative arrangement of components and steps, numerical expressions and numerical values ​​set forth in these embodiments should not be construed as limiting the scope of the present invention.

[0049] In addition, it should be understood that for ease of description, the sizes of the various components shown in the drawings are not necessarily drawn according to actual proportional relationships. For example, the thickness, width, length or distance of certain units may be enlarged relative to other structures.

[0050] The following description of exemplary embodiments is merely illustrative and is not intended to limit the present invention, its application, or use in any sense. Technologies, methods, and apparatus known to those skilled in the art may not be discussed in detail herein, but to the extent applicable, such technologies, methods, and apparatuses should be considered part of this specification.

[0051] It should be noted that like reference numerals and letters denote like items in the following figures, and thus, once an item is defined or described in one figure, it will not need to be further discussed in the subsequent figure descriptions.

[0052] Furthermore, it should be understood that the one or more method steps mentioned in the present invention do not exclude the presence of other method steps before or after the combination step, or the insertion of other method steps between these explicitly mentioned steps, unless otherwise specified. It should also be understood that the combination connection relationship between one or more devices / apparatuses mentioned in the present invention does not exclude the presence of other devices / apparatuses before or after the combination device / apparatus, or the insertion of other devices / apparatuses between two explicitly mentioned devices / apparatuses, unless otherwise specified. Furthermore, unless otherwise specified, the numbering of each method step is merely a convenient tool for identifying each method step, and is not intended to limit the order of arrangement of each method step or to define the scope of the present invention. Changes or adjustments to their relative relationships, without substantially changing the technical content, should also be considered within the scope of the present invention.

[0053] Example 1

[0054] 1a to 1d are schematic diagrams of an analyte sensor in which a temperature sensor and an electrode are located on the same surface of a substrate according to an embodiment of the present invention.

[0055] 1a , in order to conveniently and clearly demonstrate the structural features of the sensor 11 , FIG1a expresses the sensor length, width, thickness and curve characteristics in an exaggerated form. The actual length, width, thickness and curve characteristics of the sensor may differ from the illustration.

[0056] In other figures in this article, the sensor length, width, thickness and curve characteristics are also expressed in an exaggerated form. The actual length, width, thickness and curve characteristics of the sensor may be different from the figures, which will not be repeated below.

[0057] Similarly, the wires, pins, electrodes, and temperature sensors described above and below are shown in exaggerated form in the diagrams. The wires, pins, and electrodes shown in the diagrams are merely examples to illustrate the present invention and are not identical to the wires, pins, and wires in actual sensors. For example, the wires in actual sensors are flat wires of a certain width, while the wires in the diagrams are shown as lines.

[0058] The sensor 11 includes a substrate 111, which is divided into an external portion X and an internal portion Y, as shown by the dashed line in Figure 1a. Electrodes are provided on the internal portion Y, including at least one working electrode 1131 (W) and at least one additional electrode. Obviously, in this embodiment, the additional electrodes include a counter electrode 1231 (C) and a reference electrode 1331 (R), thereby forming a three-electrode system. The counter electrode 1231 is the other electrode relative to the working electrode 1131, forming a closed circuit with the working electrode 1131 to ensure normal current conduction through the electrodes. The reference electrode 1331 is used to provide a reference potential for the working electrode 1131, thereby effectively controlling the detection potential. Pins are provided on the external portion X. These pins correspond to electrodes one-to-one and are electrically connected via wires. Specifically, the working pin 1111 corresponding to the working electrode 1131 is electrically connected via wire 1121; the counter pin 1211 corresponding to the counter electrode 1231 is electrically connected via wire 1221; and the reference pin 1311 corresponding to the reference electrode 1331 is electrically connected via wire 1321. The wires are provided on the surface of the substrate, and the different pins, wires, and electrodes are insulated from each other to prevent crosstalk between electrical signals.

[0059] In this embodiment of the present invention, a temperature sensor 1431 (T) is also provided on the internal portion Y, electrically connected to a pin on the external portion X via a wire. It should be noted that the external portion X is provided with two pins, electrically connected to the temperature sensor 1431 via two corresponding wires provided on the internal portion Y. The temperature sensor, its wires, and pins are also insulated from the other electrodes and their pins and wires. To simplify the illustration, only one wire 1421 and one corresponding pin 1411 are shown in the figure. Subsequent embodiments also show only one wire and one corresponding pin (except for FIG. 1e ).

[0060] In some embodiments of the present invention, the substrate 111 of the sensor 11 is generally made of a flexible material, such as a combination of one or more of polytetrafluoroethylene, polyethylene, polyvinyl chloride, acrylonitrile-butadiene-styrene copolymer, polymethyl methacrylate, polycarbonate, and polyimide. These materials exhibit excellent electrical insulation properties, effectively insulating electrodes disposed thereon from one another, electrodes from the temperature sensor, and wires from one another. In a preferred embodiment of the present invention, the substrate 111 is made of polyimide, which exhibits good compatibility with human physiology and prevents excessive rejection upon subcutaneous insertion.

[0061] The temperature sensor 1431 is a thin film thermistor. Preferably, the temperature sensor 1431 is a thin film platinum thermistor. An aluminum oxide layer is prepared as an insulating layer on the substrate 111 by a magnetron sputtering process or vacuum evaporation deposition method, a platinum film layer is prepared on the aluminum oxide layer by a magnetron sputtering process, and a wire is prepared by a magnetron sputtering process. Preferably, the wire is a metal alloy. Finally, a liquid polyimide insulating layer is coated on the outer layer as a protective layer to reduce or eliminate the stress effect of different material layers, thereby obtaining a thin film platinum thermistor, wherein the protective layer avoids the central conductive area of ​​the temperature sensor 1431.

[0062] In other embodiments of the present invention, the thin film thermal resistor is a metal thin film thermal resistor, a carbon thin film resistor, a metal oxide thin film thermal resistor, or an alloy thin film thermal resistor.

[0063] In an embodiment of the present invention, as shown in FIG1a , working electrode 1131 and temperature sensor 1431 are positioned on substrate 111 at the same depth of penetration into the subcutaneous tissue. This means that temperature sensor 1431 and working electrode 1131 operate in the same environment. Therefore, the temperature measured by temperature sensor 1431 is the operating temperature of working electrode 1131, eliminating the need for further temperature compensation and resulting in more accurate blood glucose measurements. In FIG1a , counter electrode 1231 and reference electrode 1331 are also positioned on substrate 111 at the same depth of penetration into the internal body portion, fully utilizing the area of ​​internal body portion Y and enabling a more compact analyte sensor.

[0064] Since the analyte sensor itself is a miniaturized structure and the depth of penetration into the subcutaneous tissue is at the millimeter level, even if the temperature sensor 1431 and the working electrode 1131 are not at the same depth of penetration into the subcutaneous tissue, the difference in their depths is not large, and both are located subcutaneously, it can be considered that the operating environment of the temperature sensor 1431 and the working electrode 1131 is the same, and the temperature measured by the temperature sensor 1431 is the operating temperature of the working electrode 1131. It can also be considered that the temperature measured by the temperature sensor 1431 is the temperature inside the patient's body. Therefore, in other embodiments of the present invention, the positional arrangement relationship of the working electrode 1131, the counter electrode 1231, the reference electrode 1331 and the temperature sensor 1431 is not limited, such as the working electrode 1131, the counter electrode 1231, the reference electrode 1331 and the temperature sensor 1131. 431 can be arranged on the substrate in sequence from the proximal end to the distal end of the internal part. It can be understood that the proximal end of the internal part is the end close to the external part X, and the distal end of the internal part is the end away from the external part X, as shown in Figure 1b; the temperature sensor 1431 can also be at the same depth as the counter electrode 1231 or the reference electrode 1331; or other position arrangement relationships, such as any two of the four components, the temperature sensor and the three electrodes, are located at one depth, and the other two are located at different depths, or any three of the four components are located at one depth, and the other is located at a different depth, etc., as long as the area of ​​the internal part Y is fully utilized while meeting the analyte detection and temperature detection, but preferably, the working electrode 1131 and the temperature sensor 1431 are at the same depth of penetration into the subcutaneous tissue on the substrate 111.

[0065] In Figure 1a, wires 1121 / 1221 / 1321 / 1421 are laid on the surface of substrate 111. In other embodiments of the present invention, the wires may also be arranged in the inner layer of the substrate, as shown in Figure 1b. When wires 1121 / 1221 / 1321 / 1421 are arranged in the inner layer of substrate 111, to electrically connect to pins, electrodes, and temperature sensors arranged on the surface of substrate 111, holes 1141 / 1241 / 1341 / 1441 are opened in substrate 111 at corresponding locations for electrical connection. The electrical connection ends of wires 1121 / 1221 / 1321 / 1421 are led out through holes 1141 / 1241 / 1341 / 1441 to the surface of substrate 111, establishing electrical connections with electrodes 1131 / 1231 / 1331 and temperature sensor 1431, respectively. Similarly, the other ends of wires 1121 / 1221 / 1321 / 1421 are electrically connected to pins 1111 / 1211 / 1311 / 1411 through holes (not shown). When wires 1121 / 1221 / 1321 / 1421 are disposed within the inner layer of substrate 111, substrate 111 can provide insulation protection for each wire, preventing short circuits between the wires that could cause signal loss or instability. However, this process is relatively complex.

[0066] The sensor 11 employs a three-electrode system, comprising a working electrode, a counter electrode, and a reference electrode, corresponding working pins, counter pins, and reference pins, respectively, and wires connecting the pins and electrodes. In other embodiments of the present invention, the sensor may employ a two-electrode system, which does not include a reference electrode and corresponding pins and wires. This is common knowledge in the art and will not be described in detail here.

[0067] As shown in Figure 1c, substrate 111 is composed of four layers of substrates. Each layer of substrates 111a / 111b / 111c / 111d can be provided with at least one electrode or temperature sensor, and each layer of substrates 111a / 111b / 111c / 111d can have at least one conductive wire disposed within its inner layer. In other embodiments of the present invention, the conductive wires can also be laid on the surface of the secondary substrate, as shown in Figure 1a. The electrodes 1131 / 1231 / 1331 and the temperature sensor 1431 are respectively arranged on different layers of sub-substrates 111a / 111b / 111c / 111d. On the one hand, the distance between the electrodes and between the electrodes and the temperature sensor can be increased, the signal interference between the electrodes and between the electrodes and the temperature sensor can be reduced, and the reliability of analyte detection and temperature detection can be improved. On the other hand, the electrodes or temperature sensors on each layer of the substrate can be arranged with a larger area. The electrodes or temperature sensors with a larger area can be in more complete contact with the body fluid, the signal is more stable, and the reliability of analyte detection and temperature detection can be improved. On the other hand, since the electrodes or temperature sensors are arranged on different layers of sub-substrates, the wires 1121 / 1221 / 1321 / 1421 electrically connected to the electrodes or temperature sensors can also be routed on different sub-substrates. Therefore, the sub-substrates can also electrically insulate the wires 1121 / 1221 / 1321 / 1421. Based on this, the wires 1121 / 1221 / 1321 / 1 421 can be respectively routed on the surface of each layer of substrate 111a / 111b / 111c / 111d, which simplifies the processing technology of the wires; Fourthly, although the wires 1121 / 1221 / 1321 / 1421 can be routed on the surface of different layers of sub-substrates 111a / 111b / 111c / 111d, once a layer of substrate is damaged, the wires of the adjacent two layers may come into contact and short-circuit. Therefore, it is necessary to lay the wires on the sub-substrates 111a / 111b / 111c / 111d. When 1121 / 1221 / 1321 / 1421 is used, the wires 1121 / 1221 / 1321 / 1421 can be staggered to form a stepped wire distribution. Even if a certain layer of the substrate is damaged, the wires of the two adjacent layers will not come into contact and short-circuit, thereby improving the reliability of analyte detection and temperature detection. Fifthly, the substrate composed of a combination of multiple layers of substrates has higher mechanical strength than that of a single-layer substrate, is not easily broken or damaged, and extends the service life of the analyte sensor.

[0068] In an embodiment of the present invention, the distribution of the three electrodes 1131 / 1231 / 1331 and the temperature sensor 1431 on each sub-substrate is not fixed and can be randomly distributed on each layer of the substrate or arranged according to actual needs. For example, considering that the reference electrode 1331 is thicker than the working electrode and the counter electrode 1231, the reference electrode 1331 can be placed on the bottom sub-substrate 111a to improve the thickness consistency of the sensor 11, avoid excessive thickness differences in the sensor 11, and facilitate the storage and use of the sensor 11. Figure 1c shows the thickness of each layer of the sub-substrate 111a / 111b / 111c / 111d, electrodes 1131 / 1231 / 1331, and temperature sensor 1431 in an exaggerated manner. It is understood that this does not affect the description of this solution.

[0069] In some embodiments of the present invention, each layer of the sub-substrate can be prepared layer by layer, that is, after preparing the bottom layer substrate 111a, the third layer substrate 111b is prepared on the basis of the bottom layer substrate 111a. Similarly, after preparing the third layer substrate 111b, the second layer substrate 111c is prepared. After preparing the second layer substrate 111c, the top layer substrate 111d is prepared. In a conventional preparation process, when preparing each layer of the substrate, the substrate material, such as polyimide, is heated and coated layer by layer on a mold. After curing, a complete sub-substrate is formed. However, during the curing process, the material may not be fully cured in some areas, or the curing degree of the substrate material at different locations on the sub-substrate may be inconsistent, or the curing degree of the substrate material on different layers of the sub-substrate may be inconsistent, resulting in brittle cracking of the substrate during subsequent use. This may cause the electrodes, wires, and pins provided on the substrate to short-circuit or even be damaged, affecting the detection reliability of the sensor.

[0070] To address the potential for brittle failure of the substrate, in other embodiments of the present invention, each layer of the sub-substrate 111a / 111b / 111c / 111d can be prefabricated. Prefabrication here refers to fully curing the substrate material of each layer of substrate 111a / 111b / 111c / 111d before processing electrodes / temperature sensors, wires, or pins onto the substrate. Depending on the sensor design, the electrodes, wires, or pins provided on each layer of the substrate may be the same or different. After prefabrication, the sub-substrates 111a / 111b / 111c / 111d are assembled into a complete structure by gluing. For example, when polyimide is used as the material for the sub-substrates 111a / 111b / 111c / 111d, a polyimide precursor can be used to gluing the sub-substrates 111a / 111b / 111c / 111d together, ultimately yielding a complete sensor substrate. Because each layer of substrates 111a / 111b / 111c / 111d is fully cured before being bonded together, this prevents brittle cracking caused by insufficiently cured materials within the same layer, as well as brittle cracking caused by insufficiently cured materials between different sub-substrates, thereby improving sensor detection reliability. Furthermore, because each layer of substrates 111a / 111b / 111c / 111d can be prefabricated independently and then assembled into a single unit, sensor production efficiency can be increased.

[0071] It is worth noting that in some embodiments of the present invention, pins 1111 / 1211 / 1311 / 1411 corresponding to the various electrodes and temperature sensors 1131 / 1231 / 1331 / 1431 need to be prefabricated on the top layer of the sub-substrate 111d to complete the functionality of the sensor 11. After the sub-substrates 111a / 111b / 111c / 111d of each layer are pasted, the wires on the sub-substrates 111b / 111c / 111d are led to the top layer of the sub-substrate 111a by punching to establish electrical connection with the pins on the sub-substrate 111a.

[0072] In some embodiments of the present invention, the thickness of each layer of substrate 111a / 111b / 111c / 111d can be 0.1-100 μm. Compared to the single-layer substrate solution shown in Figures 1a and 1b, the thickness of each layer of substrate 111a / 111b / 111c / 111d is thinner. Otherwise, the thickness of the stacked substrates will be too thick and not flexible enough, which will increase the user's discomfort when inserted into the subcutaneous tissue. Therefore, preferably, the thickness of each layer of substrate 111a / 111b / 111c / 111d is 0.1-20 μm. More preferably, the thickness of each layer of substrate 111a / 111b / 111c / 111d is about 10 μm, and the thickness of the entire substrate is about 25-35 μm. This thickness is not too thin and easily damaged or broken, nor is it too thick and increases the user's discomfort. Those skilled in the art will appreciate that due to errors in the manufacturing process, the actual thickness of each layer of the sub-substrate 111 a / 111 b / 111 c / 111 d may vary.

[0073] In some embodiments of the present invention, the material of each layer of substrate 111a / 111b / 111c / 111d is preferably polyimide. In order to stick the various layers of substrate 111a / 111b / 111c / 111d into a whole, the pasting material may preferably be a polyimide precursor. After the polyimide precursor is cured, it can maintain consistency in physical properties with the polyimide. This pasting method can prevent the various layers of substrate 111a / 111b / 111c / 111d from peeling off or even falling off due to stress concentration or uneven stress.

[0074] In Figure 1d, substrate 111 is composed of two layers of substrates 111e and 111f. A working electrode 1131 and a temperature sensor 1431 are arranged side by side on sub-substrate 111e. Conductors 1121 and 1421 are also arranged on the inner layer of sub-substrate 111e. In other embodiments of the present invention, the conductors can also be laid on the surface of the sub-substrate, as shown in Figure 1a. A counter electrode 1231 and a reference electrode 1331 are arranged side by side on sub-substrate 111f. Conductors 1221 and 1321 are also arranged on the inner layer of sub-substrate 111f. In other embodiments of the present invention, the conductors can also be laid on the surface of the sub-substrate, as shown in Figure 1a. The use of a two-layer substrate combines the advantages of the multi-layer substrate described in Figure 1c, improving the reliability of analyte and temperature detection and extending the service life of the analyte sensor. Furthermore, the working electrode and temperature sensor are located at the same subcutaneous depth, posing the same operating environment for the temperature sensor and the working electrode. Therefore, the temperature measured by the temperature sensor is the operating temperature of the working electrode, eliminating the need for further temperature compensation and resulting in more accurate blood glucose measurements. Furthermore, the counter electrode and reference electrode are positioned on the same sub-substrate, fully utilizing the area of ​​the inner portion Y of the sub-substrate 111f while also miniaturizing the analyte sensor.

[0075] As mentioned above, since the analyte sensor itself is a miniaturized structure and the depth of penetration into the subcutaneous tissue is at the millimeter level, even if the temperature sensor and the working electrode are not at the same depth of penetration into the subcutaneous tissue, the depth difference is not large, and both are located subcutaneously. It can also be considered that the operating environment of the temperature sensor and the working electrode is the same, and the temperature measured by the temperature sensor is the operating temperature of the working electrode. Therefore, in other embodiments of the present invention, the positional arrangement relationship of the working electrode, counter electrode, reference electrode and temperature sensor is not limited. For example, the temperature sensor and the reference electrode or the counter electrode are located on the same primary substrate, while the other two electrodes are located on the same primary substrate; or only one of the four components, three electrodes and the temperature sensor, is provided on a certain primary substrate, and the other three are provided on another secondary substrate. Users can set it according to actual needs, and the corresponding wires can be provided on the surface or inner layer of the corresponding secondary substrate.

[0076] In another embodiment of the present invention, the sensor may also include a three-layer substrate, and any two of the four components, namely the three electrodes and the temperature sensor, may be arranged on the same layer of substrate, while the other two may be separately arranged on the other two layers of substrate. The four components are all arranged on the same surface of all sub-substrates, such as surface A, and their corresponding wires may be arranged on the surface or inner layer of the corresponding sub-substrate.

[0077] Generally, the working electrode and the counter electrode are selected from one of the materials such as graphite electrode, glassy carbon electrode, noble metal, etc., and the reference electrode is selected from one of Ag / AgCl or calomel. Considering the requirements of good ductility and surface structure stability, noble metal electrodes such as gold electrode, platinum electrode, silver electrode, etc. become better choices. Preferably, the working electrode and the counter electrode are both platinum electrodes. In the embodiment of the present invention, the temperature sensor is preferably a thin film platinum thermal resistor. Therefore, the temperature sensor can also be embedded in the working electrode or the counter electrode. In addition to realizing the functions of analyte detection and temperature detection at the same time, one electrode can be reduced, making the processing technology simpler. As shown in Figure 1e, the temperature sensor 1431 is embedded in the counter electrode 1231. The temperature sensor 1431 is a thin film platinum thermal resistor strip. One end of the temperature sensor is connected to the dedicated pin of the temperature sensor by a wire, and the other end is connected to the common pin of the temperature sensor and the counter electrode by a wire. Therefore, the function of analyte detection can be realized through the pin of the working electrode, the common pin of the counter electrode and the temperature sensor, and the pin of the reference electrode, while temperature detection can be realized through the common pin of the temperature sensor and the counter electrode and the dedicated pin of the temperature sensor. In the embodiment of the present invention, the resistor strips can be arranged in a reciprocating manner to increase the length of the resistor strips, thereby increasing the resistance of the resistor strips, thereby better realizing analyte detection and temperature detection.

[0078] In other embodiments of the present invention, when the sensor is a dual-electrode system, that is, the sensor includes only a working electrode and a counter electrode, when the temperature sensor can also be embedded in the working electrode or the counter electrode, one electrode can be eliminated, further simplifying the process. Preferably, the temperature sensor is embedded in the counter electrode.

[0079] Example 2

[0080] 2a-2k are schematic diagrams of analyte sensors in which at least one electrode and a temperature sensor are located on different sides of a substrate according to an embodiment of the present invention.

[0081] The sensor has a planar structure, and therefore has two opposing surfaces, namely surface A and surface B. When the three electrodes and the temperature sensor are arranged on surfaces A and B of the substrate, surfaces A and B of the substrate can be fully utilized, and the electrodes and temperature sensors can be set to a larger area. Electrodes with a larger area can make more complete contact with body fluids, and the signals can be more stable, thereby improving the reliability of analyte detection. Temperature sensors with a larger area have a greater resistance, making temperature measurement more sensitive, and on the other hand, they can make more complete contact with body fluids, and the signals can be more stable, thereby improving the reliability of temperature detection. The four components of the three electrodes and the temperature sensor can be arranged in any form on the A and B surfaces of the substrate, such as three components on one side and one component on the other side; or two components on each side. Preferably, the working electrode and the temperature sensor are arranged on the two sides of the substrate and are at the same depth of penetration into the subcutaneous tissue. The temperature measured by the temperature sensor is the operating temperature of the working electrode. There is no need to further compensate for the measured temperature, making the blood glucose measurement value more accurate. As shown in Figures 2a and 2b, the reference electrode and the counter electrode can be arranged on one side of the substrate at the same time according to actual needs, or on both sides of the substrate. The arrangement can be parallel to the working electrode or temperature sensor (as shown in Figure 1a) or arranged in sequence (as shown in Figure 1b). The wires can also be set on the surface of the substrate (as shown in Figure 1a) or in the inner layer (as shown in Figure 1b).

[0082] In Figure 2a, the sensor 21 includes only one substrate 211. The working electrode 2131, the counter electrode 2231, and the reference electrode 2331 are arranged on the A side, and the corresponding pins are also arranged on the A side. The temperature sensor 2431 is arranged on the B side, and the corresponding pins are also arranged on the B side. The temperature sensor 2431 and the working electrode 2131 are at the same depth of penetration into the subcutaneous tissue. The wires 2121 / 2221 / 2321 / 2421 are laid on the surfaces of the A side and the B side. As mentioned above, the wires 2121 / 2221 / 2321 / 2421 can also be arranged in the inner layer of the A side and the B side. When there are substrates on both sides of the substrate and the sensor is inserted into the subcutaneous tissue in a bent manner, it needs to be installed in the analyte detection device in the form of a three-dimensional circuit. The specific technical solution can be referred to the published patent PCT / CN2022 / 080845.

[0083] When the temperature sensor 2431 is located alone on one side of the substrate, the three-electrode system and the temperature sensor can be prepared separately during manufacturing, thereby improving the yield of the finished product. At the same time, the analyte detection signal of the three-electrode system and the temperature detection signal of the temperature sensor do not interfere with each other, thereby improving the accuracy of analyte detection and temperature detection.

[0084] In Figure 2b, sensor 21 comprises a single substrate 211. Working electrode 2131 and reference electrode 2331 are located on surface A, along with corresponding pins. Temperature sensor 2431 and counter electrode 2231 are located on surface B, along with corresponding pins. Temperature sensor 2431 and working electrode 2131 are inserted subcutaneously at the same depth. Leads 2121 / 2221 / 2321 / 2421 are placed on the surfaces of surfaces A and B. As previously described, leads 2121 / 2221 / 2321 / 2421 are placed in the inner layers of surfaces A and B. The counter electrode 2231 and the temperature sensor 2431 are arranged on the same surface of the substrate. On the one hand, a structure in which the temperature sensor 2431 is embedded in the counter electrode 2231 can be selected to make the area of ​​the temperature sensor 2431 larger. As mentioned above, the sensitivity and accuracy of temperature detection can be improved. On the other hand, the relative distance between the counter electrode 2231 and the working electrode 2131 can be increased, the current crosstalk between the counter electrode 2231 and the working electrode 2131 can be reduced, and the noise can be reduced. At the same time, the area of ​​the counter electrode 2231 can be maximized, thereby reducing electrochemical polarization and improving the accuracy and sensitivity of the analyte detection signal.

[0085] In other embodiments of the present invention, the reference electrode 2331 and the temperature sensor 2431 can also be arranged on the same side of the substrate. In this case, on the one hand, the circuit risk caused by the migration of Ag / Cl substances in the reference electrode 2331 can be reduced, thereby improving the reliability of analyte detection. On the other hand, when the reference electrode 2331 fails, the three-electrode system becomes a two-electrode system and can still be used normally, thereby improving the stability of analyte detection.

[0086] The analyte sensor with integrated temperature sensor in FIG. 2 c - FIG. 2 k includes a multi-layer substrate. The benefits of using a multi-layer substrate are as described above and will not be repeated here.

[0087] The sensor in Figures 2c-2f includes two layers of substrates 211a and 211b. Of the four components, three electrodes and a temperature sensor, at least one electrode is positioned on a different surface from the temperature sensor. As shown in Figures 2c and 2d, in Figure 2c, two of the four components, namely, temperature sensor 2431, are positioned on different surfaces from the two electrodes, on surface A of sub-substrate 211a and surface B of sub-substrate 211b, respectively. This arrangement of these four components is not limited in this embodiment of the present invention. Preferably, working electrode 2131 and temperature sensor 2431 are positioned on different surfaces at the same depth of subcutaneous penetration, maximizing the operating environment of the temperature sensor and the working electrode. Consequently, the temperature measured by the temperature sensor is the operating temperature of the working electrode, eliminating the need for further temperature compensation and resulting in more accurate blood glucose measurements. As shown in Figure 2c, the reference electrode 2331 and the working electrode 2131 are arranged in sequence on the sub-substrate 211a, and the counter electrode 2231 and the temperature sensor 2431 are arranged in sequence on the sub-substrate 211b. In other embodiments of the invention, the reference electrode 2331 and the working electrode 2131 can also be arranged in parallel on the sub-substrate 211a (as shown in Figure 1a), and the counter electrode 2231 and the temperature sensor 2431 can be arranged in parallel on the sub-substrate 211b (as shown in Figure 1a), and the wires 2121 / 2221 / 2321 / 2421 can be laid on the surface or inner layer of the sub-substrate.

[0088] In Figure 2d, temperature sensor 2431 and reference electrode 2231 are both located on surface B of sub-substrate 211b, while working electrode 2131 and counter electrode 2331 are located on surfaces A of sub-substrates 211a and 211b, respectively. Leads 2121 / 2221 / 2321 / 2421 can be located on the surface or inner layer of the sub-substrate. In this embodiment of the present invention, there is no restriction on which two of the four components, the three electrodes and the temperature sensor, are located on the same surface, nor is there a restriction on how these two components are arranged on the sub-substrate surface. Preferably, working electrode 2131 and temperature sensor 2431 are located on different surfaces at the same depth of subcutaneous penetration, so that the temperature sensors and the working electrodes are exposed to the same operating environment. Therefore, the temperature measured by the temperature sensor is the operating temperature of the working electrode, eliminating the need for further temperature compensation, resulting in more accurate blood glucose measurements.

[0089] In Figures 2e-2g, the sensor includes two layers of substrates 211a and 211b, one of the three electrodes and the temperature sensor is arranged on one side of a sub-substrate, such as side B, and the other three are arranged on the other side of the sub-substrate, such as side A, including side A of the sub-substrates 211a and 211b. In the embodiment of the present invention, it is not limited which of the three electrodes and the temperature sensor is arranged on one side, nor is it limited how the other three components are arranged on the other side of the sub-substrates 211a and 211b. Preferably, the working electrode 2131 and the temperature sensor 2431 are arranged on different sides at the same depth of penetration under the skin, so that the operating environment of the temperature sensor and the working electrode is the same. Therefore, the temperature measured by the temperature sensor is the operating temperature of the working electrode, and there is no need to further compensate for the measured temperature, so that the blood glucose measurement value is more accurate.

[0090] In Figure 2e, the temperature sensor 2431 is arranged on the B surface of the sub-substrate 211b, the working electrode 2131, the counter electrode 2231 and the reference electrode 2331 are arranged on the A surface of the sub-substrate 211a, and the corresponding pins are arranged on the same surface as the electrodes and the temperature sensor. The wires can be arranged on the surface or inner layer of the sub-substrate. When the temperature sensor 2431 is located alone on one side of the substrate, the three-electrode system and the temperature sensor can be prepared separately on the sub-substrates 211a and 211b during manufacturing, thereby improving the yield of the finished product. At the same time, the analyte detection signal of the three-electrode system and the temperature detection signal of the temperature sensor do not interfere with each other, thereby improving the accuracy of analyte detection and temperature detection. At this time, the temperature sensor and the three electrodes are arranged on different surfaces of the substrate. When the temperature sensor is exchanged with any of the three electrodes, the temperature sensor and one electrode are arranged on different surfaces of the substrate.

[0091] In FIG2f , the temperature sensor 2431 is disposed on the B surface of the sub-substrate 211b, and the working electrode 2131 and the counter electrode 2231 are sequentially disposed on the A surface of the sub-substrate 211b. Of course, the working electrode 2131 and the counter electrode 2231 can also be disposed side by side on the A surface of the sub-substrate 211b, and the reference electrode 2331 is disposed on the A surface of the sub-substrate 211a. In other embodiments of the invention, the working electrode 2131 and the reference electrode 2331 can also be disposed sequentially or side by side on the A surface of the sub-substrate 211b, while the counter electrode 2231 is disposed solely on the A surface of the sub-substrate 211a. Alternatively, the working electrode 2131 can be disposed solely on the A surface of the sub-substrate 211b, while the counter electrode 2231 and the reference electrode 2331 are disposed sequentially or side by side on the A surface of the sub-substrate 211a, as shown in FIG2g .

[0092] In Figures 2h-2j, the sensor includes three layers of substrates 211a, 211b and 211c, one of the four components, the three electrodes and the temperature sensor, is arranged on one side of a sub-substrate, such as side B, and the other three are arranged on the other side of the sub-substrate, such as side A, including side A of sub-substrates 211a, 211b and 211c. In the embodiment of the present invention, it is not limited which of the four components, the three electrodes and the temperature sensor, is arranged on one side, nor is it limited in the arrangement of the other three components on the other side of the sub-substrates 211a, 211b and 211c. Preferably, the working electrode 2131 and the temperature sensor 2431 are arranged on different sides at the same depth of penetration under the skin, so that the operating environment of the temperature sensor and the working electrode is the same. Therefore, the temperature measured by the temperature sensor is the operating temperature of the working electrode, and there is no need to further compensate the measured temperature, so that the blood glucose measurement value is more accurate.

[0093] In Figure 2h, the temperature sensor 2431 is arranged on the B surface of the sub-substrate 211c, and its pins are also arranged on the B surface of the sub-substrate 211c. The other three electrodes are respectively arranged on the A surfaces of the three sub-substrates, and their pins are all arranged on the A surface of the sub-substrate 211a. The wires can be optionally arranged on the surface or inner layer of the sub-substrate.

[0094] In Figure 2i, the temperature sensor 2431 is arranged on the B surface of the sub-substrate 211c, and its pins are also arranged on the B surface of the sub-substrate 211c. The working electrode 2131 and the counter electrode 2231 are arranged in sequence on the A surface of the sub-substrate 211b. Of course, the working electrode 2131 and the counter electrode 2231 can also be arranged in parallel on the A surface of the sub-substrate 211b, and the reference electrode is separately arranged on the A surface of the sub-substrate 211a. The pins of the three electrodes are all arranged on the A surface of the sub-substrate 211a, and the wires can be optionally arranged on the surface or inner layer of the sub-substrate; in other embodiments of the invention, the reference electrode and the working electrode can also be arranged in sequence or in parallel on the A surface of the sub-substrate 211b, and the counter electrode can be separately arranged on the A surface of 211a; or the working electrode can be separately arranged on the A surface of the sub-substrate 211b, and the reference electrode and the counter electrode can be arranged in sequence or in parallel on the A surface of the sub-substrate 211a, and the wires can be optionally arranged on the surface or inner layer of the sub-substrate.

[0095] The difference between Figure 2j and Figure 2i is that the working electrode 2131 is arranged on the A surface of the sub-substrate 211a, the reference electrode 2331 and the counter electrode 2231 are arranged on the A surface of the sub-substrate 211b, and the temperature sensor 2431 is still arranged on the B surface of the sub-substrate 211c. The temperature sensor 2431 and the working electrode 2131 are also at the same depth of penetration into the subcutaneous tissue. At this time, the temperature sensor 2431 and the working electrode 2131 are on different surfaces of the spaced sub-substrate.

[0096] In another embodiment of the present invention, the sensor includes four layers of substrates, one of the three electrodes and the temperature sensor is arranged on one side of a secondary substrate, and the other three components are respectively arranged on the other side of the other three layers of substrates. In this embodiment of the present invention, the arrangement of these four components on the four layers of substrates is not limited. Preferably, the working electrode 2131 and the temperature sensor 2431 are arranged on different surfaces at the same depth of penetration under the skin, so that the operating environment of the temperature sensor and the working electrode is the same. Therefore, the temperature measured by the temperature sensor is the operating temperature of the working electrode, and there is no need to further compensate for the measured temperature, so that the blood glucose measurement value is more accurate. As shown in Figure 2k, the temperature sensor 2431 is arranged on the B surface of the sub-substrate 211d, and its pins are also arranged on the B surface of the sub-substrate 211d. The working electrode is arranged on the A surface of the sub-substrate 211c, at the same depth of penetration into the skin as the temperature sensor 2431. The reference electrode 2331 and the counter electrode 2231 are respectively arranged on the A surfaces of the sub-substrates 211a and 211b. The pins of the three electrodes are all arranged on the A surface of the sub-substrate 211a, and the wires can be optionally arranged on the surface or inner layer of the sub-substrate.

[0097] In various embodiments of the present invention, the counter electrode or the working electrode can be selectively embedded according to the arrangement of the electrodes and the temperature sensor on each substrate.

[0098] Example 3

[0099] 3a-3f are schematic diagrams of an analyte sensor with an integrated temperature sensor having an insulating material disposed thereon according to an embodiment of the present invention.

[0100] In some embodiments of the present invention, after the sensor is inserted subcutaneously, the substrate is generally soft to accommodate the repetitive peristaltic movements of the muscles. However, the soft substrate is repeatedly bent or flexed during the repetitive peristaltic movements of the muscles, and the substrate can easily reach ultimate fatigue prematurely (before reaching the sensor's designed service life, e.g., 14 days), resulting in damage or even breakage. This can expose the electrodes, temperature sensors, or wires disposed on the substrate, causing them to short-circuit or break directly, affecting the sensor's analyte and temperature detection reliability. To improve the sensor's analyte and temperature detection reliability, the mechanical strength of the substrate needs to be enhanced to extend the time it takes for the substrate to reach ultimate fatigue and meet the sensor's designed service life.

[0101] In some embodiments of the present invention, insulating material can be applied post-processing to certain areas of the substrate to enhance the substrate's mechanical strength. "Post-processing" here means applying at least one layer of insulating material to the substrate after the sensor is fabricated—that is, after the electrodes, temperature sensor, pins, and wires are installed on the substrate to complete the sensor. Obviously, adding insulating material improves the mechanical strength of the substrate in the corresponding areas and prolongs the time it takes to reach ultimate stress fatigue.

[0102] In some embodiments of the present invention, multiple layers of insulating material can be applied to the substrate, for example, two, three, or more layers, to further enhance the substrate's mechanical strength. However, applying multiple layers of insulating material can cause the substrate in the corresponding areas to become less flexible, which can increase user discomfort after subcutaneous insertion. Similarly, thicker insulating material can also enhance the substrate's mechanical strength, but excessively thick insulating material can also cause the substrate in the corresponding areas to become less flexible, which can increase user discomfort after subcutaneous insertion. Therefore, the number and thickness of insulating material layers need to be controlled.

[0103] In a preferred embodiment of the present invention, the number of layers of the insulating material is 1 to 10, and the thickness of each layer is 0.1 um to 100 um.

[0104] In a preferred embodiment of the present invention, the number of layers of insulating material is 1, and the thickness thereof is 25 um. During the sensor processing, providing multiple layers of insulating material will increase the complexity of the processing process. Therefore, providing 1 layer of insulating material can both enhance the mechanical strength of the substrate and will not lead to an overly complicated processing process. The thickness thereof is set to 25 um so that the substrate can maintain sufficient softness and will not increase the user's discomfort after the substrate penetrates the user's subcutaneous tissue.

[0105] In some embodiments of the present invention, the insulating material may be made of one or more of polytetrafluoroethylene, polyethylene, polyvinyl chloride, acrylonitrile-butadiene-styrene copolymer, polymethyl methacrylate, polycarbonate, and polyimide. The characteristics of the above materials have been described above and will not be repeated here. Preferably, the insulating material is made of polyimide, which is consistent with the material of the substrate and has the same physical properties. When the insulating material and the substrate are stretched, contracted, or bent, the insulating material and the substrate of the same material have the same stretching, contracting, or bending scale, and the different scales will not cause stress concentration on the insulating material on the substrate, resulting in wrinkling, falling off, etc.

[0106] In some embodiments of the present invention, the insulating material may be disposed on the substrate by coating. When the insulating material is made of polyimide, the polyimide may be heated to a liquid state before being coated on the substrate.

[0107] In other embodiments of the present invention, the insulating material can be set on the substrate by pasting. When the insulating material is polyimide, a polyimide precursor can be used as an adhesive material. After the polyimide precursor is cured, its physical properties are basically consistent with those of polyimide, and it is consistent when extending, shrinking, and bending. The insulating material will not bulge, wrinkle, or fall off on the substrate due to stress concentration or uneven stress, thereby improving the finished product yield of the sensor.

[0108] In the above-mentioned process of setting the insulating material on the substrate by coating or pasting, it is necessary to first ensure that the electrodes, temperature sensors, pins and wires on the substrate establish good electrical connections, and there is good insulation between the electrodes, temperature sensors and electrodes, pins and pins, and wires, so that the sensor function can be effectively realized.

[0109] In some embodiments of the present invention, when the insulating material is applied later to the substrate, it should be placed away from the areas where the pins and electrodes / temperature sensors are located; otherwise, the sensor function will not be realized. Therefore, the area where the insulating material is applied later includes at least one of the pin backside area 312 of the pin area a or the electrode / temperature sensor backside area 313 of the electrode / temperature sensor area b. Preferably, the insulating material is applied to both the pin backside area 312 and the electrode / temperature sensor backside area 313.

[0110] In other embodiments of the present invention, the area where the insulating material is later set may also include the area near the electrode / temperature sensor and the pin, avoiding the central conductive area of ​​the electrode / temperature sensor and the pin. In this case, the insulating material can cover the edges of the electrode / temperature sensor and the pin, increase the adhesion between the electrode / temperature sensor and the pin and the substrate, prevent the edges of the electrode / temperature sensor and the pin from warping, and further prevent the electrode / temperature sensor and the pin from being damaged or even falling off.

[0111] In some embodiments of the present invention, the pin back area 312 and the electrode / temperature sensor back area 313 can be independent areas as shown in Figures 3a-3f. In other embodiments of the present invention, the pin back area 312 and the electrode / temperature sensor back area 313 can also be connected into one piece to form a coherent area.

[0112] In other embodiments of the present invention, the sensor 31 may be installed in a bent form within the analyte detection device, i.e., the external portion X is bent or curved relative to the internal portion Y, or the internal portion Y is bent or curved relative to the external portion X. Since the external portion X is fixed within the analyte detection device, while the external portion Y is inserted subcutaneously and moves with the user's muscle peristalsis, the internal portion Y is frequently and repeatedly bent or curved relative to the external portion X. Therefore, it is necessary to provide insulating material behind the bent front region 314 of the internal portion Y relative to the external portion X. Providing insulating material behind the bent front region 314 can, on the one hand, increase the mechanical strength of the substrate in the corresponding region, and on the other hand, when the wires are provided on the surface of the substrate, it can also cover the wires in the corresponding region and provide additional insulation and protection for the wires.

[0113] It should be noted that in the embodiment of the present invention, in order to make full use of the area of ​​the substrate, the working electrode, the reference electrode, the counter electrode and the temperature sensor are closely arranged in the internal body part Y of the substrate within a safe distance. Therefore, under normal circumstances, the internal body part Y does not need to be provided with insulating material. However, due to other possible reasons, such as the presence of special-shaped electrodes or temperature sensors, there is a large gap between the three electrodes and the temperature sensor, or between these four components and the edge of the substrate. Insulating material can be provided in the gap area to increase the mechanical strength of the corresponding area, as shown in 315 in Figures 3a and 3e.

[0114] In embodiments of the present invention, insulating material can be applied later depending on the number of sensor layers and the arrangement of the electrodes or temperature sensors on the substrate. For example, in FIG3a , the sensor comprises a single-layer substrate, with the electrodes and temperature sensor arranged side by side on the substrate. Insulating material can be applied later in the pin backside region 312 , the electrode / temperature sensor backside region 313 , the bent front region 314 , and / or the widely spaced regions 315 on the internal portion Y. In FIG3b , the sensor comprises a single-layer substrate, with the electrodes and temperature sensor arranged sequentially on the substrate. Insulating material can be applied later in the pin backside region 312 , the electrode / temperature sensor backside region 313 , and / or the bent front region 314 .

[0115] In Figure 3c, the sensor comprises a multi-layer substrate, specifically a four-layer substrate, with three electrodes and a temperature sensor disposed on each of the four layers. Insulating material can be applied to the pin backside region 312, electrode backside region 313 on the B surface of the bottom sub-substrate 311a, and / or the bent front region 314 on the A surface of the top layer 311d. When the sensor comprises another multi-layer substrate, and the temperature sensor and three electrodes are disposed on the same side of all sub-substrates, such as the two-layer or three-layer substrate described in Example 1, insulating material can also be applied to the pin backside region 312, electrode / temperature sensor backside region 313 on the B surface of the bottom sub-substrate, and / or the bent front region 314 on the A surface of the top layer. Furthermore, insulating material can be applied to any areas on both sides of the sub-substrate that are widely spaced apart to increase the mechanical strength of the substrate.

[0116] In Figures 3d-3e, the sensor includes a single-layer substrate, and three electrodes and a temperature sensor are arranged on both sides of the substrate. Insulating materials can be provided on the bent front area 314 of the substrate A side, the electrode back area 313 on the substrate B side, and / or the areas 315 with larger intervals on both sides of the substrate to increase the mechanical strength of the substrate.

[0117] In FIG3f , the sensor includes a multi-layer substrate, specifically, a four-layer substrate. Pins are provided on the surfaces of both the top and bottom substrates. Electrodes and temperature sensors are arranged on different surfaces of the four-layer substrate. Insulating material can be applied to the electrode backside region 313 on the B surface of the bottom sub-substrate 311a and / or the bent front region 314 on the A surface of the top layer 311d. When the sensor includes other multi-layer substrates, and the temperature sensor and at least one electrode are provided on different surfaces of all sub-substrates, such as the two-layer or three-layer substrate described in Example 2, insulating material can also be applied to the electrode / temperature sensor backside region 313 on the B surface of the bottom sub-substrate and / or the bent front region 314 on the A surface of the top layer. Furthermore, insulating material can be applied to any areas on both sides of the sub-substrate that are widely spaced apart to increase the mechanical strength of the substrate.

[0118] In various embodiments of the present invention, the counter electrode or the working electrode can be selectively embedded according to the arrangement of the electrodes and the temperature sensor on each substrate.

[0119] Example 4

[0120] 4a-4g are schematic diagrams of an analyte sensor with an integrated temperature sensor and a protective layer according to an embodiment of the present invention.

[0121] In some embodiments of the present invention, after the electrodes, temperature sensors, wires, and pins are fabricated on the substrate, a protective layer 416 may be provided on the substrate. The protective layer 416 may cover the entire substrate or a certain area of ​​the substrate, but expose the center areas of the pins, electrodes, and temperature sensors and cover the edges of the pins, electrodes, and temperature sensors. First, the protective layer 416 can enhance the mechanical strength of the substrate and prolong the time it takes for the substrate to be damaged; second, the protective layer 416 covers the edges of the pins, electrodes and temperature sensors to prevent irregular edges from being exposed and causing signal noise, thereby improving the stability of the detection signal; third, the electron conduction layer of the electrode is fixed on the substrate. Since the substrate is repeatedly bent during use, the metal film of the electron conduction layer will inevitably separate from the substrate and cause warping, bubbling or even falling off. After the protective layer 416 is set, the protective layer 416 can also enhance the adhesion between the metal film of the electron conduction layer and the substrate, thereby avoiding warping and bubbling of the metal film, thereby improving the reliability of the sensor's analyte detection; the aluminum oxide insulating layer of the temperature sensor is also set on the substrate. Since the substrate is repeatedly bent during use, it may also cause warping, bubbling or even falling off. After the protective layer 416 is set, the protective layer 416 can also enhance the adhesion between the aluminum oxide insulating layer and the substrate, thereby avoiding warping and bubbling of the insulating layer, thereby improving the temperature detection reliability of the sensor.

[0122] In an embodiment of the present invention, a corresponding protective layer 416 can be provided according to the number of layers of the sensor substrate or sub-substrate and the arrangement of the electrodes or temperature sensors on the substrate. Specifically, as long as pins, electrodes or temperature sensors are provided on a certain surface of a certain layer of the substrate or sub-substrate, a protective layer 416 can be provided on that surface, but the central area of ​​the pins, electrodes and / or temperature sensors needs to be exposed and the edges of the pins, electrodes and / or temperature sensors need to be covered.

[0123] As shown in Figures 4a and 4b, the sensor includes a substrate 411, a working electrode 4131, a counter electrode 4231, a reference electrode 4331 and a temperature sensor 4431, which are arranged in parallel or in sequence on the A surface of the substrate 411. Therefore, a protective layer is only provided on the A surface of the substrate 411, exposing the central area of ​​the pins, electrodes and temperature sensor and covering at least the edges of the pins, electrodes and temperature sensor.

[0124] In Figure 4c, the sensor comprises a four-layer substrate, with the electrodes and temperature sensor disposed on the same surface of the four-layer substrate, such as surface A. Therefore, a protective layer 416 is disposed on surface A of each substrate layer, exposing the center areas of the pins, electrodes, and temperature sensor and covering at least the edges of the pins, electrodes, and temperature sensor. When the sensor comprises a two- or three-layer substrate, with the electrodes and temperature sensor disposed on the same surface of different substrate layers, such as in the two- or three-layer substrate described in Example 1, a protective layer may also be disposed on the corresponding surfaces.

[0125] In Figures 4d and 4e, the electrodes and temperature sensors are respectively arranged on different surfaces of the substrate. Figures 4d and 4e are single-layer substrates, and electrodes and / or temperature sensors are arranged on both sides of the substrate 411. Therefore, protective layers 416 are arranged on both sides of the substrate 411, exposing the central areas of the pins, electrodes and / or temperature sensors and covering the edges of the pins, electrodes and / or temperature sensors.

[0126] In Figure 4f, the sensor comprises a multi-layer substrate, specifically a four-layer substrate. The electrodes and temperature sensors are disposed on different surfaces of different sub-substrates. A protective layer 416 is disposed on the surfaces where the electrodes / temperature sensors are disposed, exposing the central areas of the pins, electrodes, and temperature sensors and covering at least the edges of the pins, electrodes, and temperature sensors. When the sensor comprises a two- or three-layer substrate, with at least one electrode and temperature sensor disposed on different surfaces of the sub-substrate, as in the two- or three-layer substrate described in Example 2, a protective layer may also be disposed on the corresponding surfaces.

[0127] In some embodiments of the present invention, in order to reduce the manufacturing process and difficulty of the sensor and save material costs, for the sensor, the electrodes and temperature sensors are more valuable than the pins and are sensitive components. It can be given priority to provide a protective layer 416 to cover the edges of the electrodes and / or temperature sensors, that is, the protective layer 416 does not cover the entire substrate, but covers a part of the substrate.

[0128] In some embodiments of the present invention, the protective layer 416 has a thickness thicker than the electrode and the temperature sensor, for example, 1 to 25 μm. After the protective layer 416 is applied, a pit is formed at the location of the electrode and the temperature sensor. The structural layers of the electrode, such as the anti-interference layer, enzyme layer, regulating layer, and biocompatible layer, are located in the pit. The pit can accommodate a larger volume of anti-interference layer, enzyme layer, regulating layer, and biocompatible layer, thereby improving the sensitivity of the electrode. In a preferred embodiment of the present invention, the thickness of the protective layer 416 is 1 to 20 μm. In a further preferred embodiment of the present invention, the thickness of the protective layer 416 is 4 μm. A protective layer 416 that is too thick will reduce the softness of the substrate and increase the user's discomfort after piercing the user's subcutaneous tissue, while a protective layer 416 that is too thin will be easily damaged.

[0129] In some embodiments of the present invention, the protective layer 416 may have a multi-layer structure. The overall thickness of the multi-layer protective layer 416 still refers to the thickness described above. When the multi-layer protective layer 416 is provided, the thickness of each protective layer 416 will become thinner.

[0130] In some embodiments of the present invention, the material of the protective layer 416 is one or more of polytetrafluoroethylene, polyethylene, polyvinyl chloride, acrylonitrile-butadiene-styrene copolymer, polymethyl methacrylate, polycarbonate, and polyimide.

[0131] In some embodiments of the present invention, the protective layer 416 is made of polyimide. The polyimide is heated to form a liquid, which is then coated onto a polyimide substrate. After curing, the protective layer 416 is formed. The protective layer 416 and the substrate, made of the same material, have consistent physical properties, which prevents the protective layer 416 from breaking or falling off due to uneven stress or stress concentration on the substrate 411.

[0132] In other embodiments of the present invention, the insulating material 414 may be provided after the protective layer 416 is provided. Therefore, the protective layer can prevent the metal film from warping and bubbling while also increasing the strength of the substrate 411. The provision of the protective layer 416 may refer to Figures 4a-4e, that is, no matter how many layers of substrate the sensor includes, whether at least one electrode and temperature sensor are provided on the same surface or different surfaces of the substrate, and whether they are provided in parallel or in sequence on the substrate, as long as an electrode or temperature sensor is provided on a surface of a certain layer of substrate or a secondary substrate, the protective layer 416 may be provided on that surface, but the central area of ​​the pins, electrodes and / or temperature sensors needs to be exposed and at least the edges of the pins, electrodes and / or temperature sensors need to be covered. An insulating material 413 is then applied over the protective layer 416. The placement of the insulating material can be described with reference to Figures 3a-3f, namely, on the bent front region 414 of the topmost layer's A surface and / or the bottommost electrode and / or temperature sensor's back region 413. Furthermore, if the back region of the pins is not provided with pins, or if there are areas with large gaps between the two sides of the substrate, the insulating material can also be applied later. Therefore, the simultaneous placement of the protective layer and insulating layer on the sensor is a combination of Figures 3a-3f and Figures 4a-4e. Figure 4f is used as an example here; other combinations are within the scope of the present invention.

[0133] In Figure 4f, the sensor comprises four sub-substrates, with the three electrodes and the temperature sensor disposed on each of the four sub-substrates. The reference electrode, counter electrode, and working electrode are disposed on the A surfaces of sub-substrates 411d, 411c, and 411b, respectively. The temperature sensor is disposed on the B surface of sub-substrate 411a. The working electrode and temperature sensor are inserted at the same subcutaneous depth, and the leads can be disposed on the surface or inner layer of the corresponding sub-substrates. A protective layer 416 is applied to the A surfaces of sub-substrates 411ab, 411c, and 411d, but this exposes the lead and electrode centers. A protective layer 416 is also applied to the B surface of sub-substrate 411a, but this exposes the lead and temperature sensor centers. An insulating material 414 is applied behind the bent front surface of the A surface of the topmost sub-substrate 411a. An insulating material 413 is applied to the B surface of the bottommost sub-substrate 411d, where the reference and counter electrodes reside.

[0134] In various embodiments of the present invention, the counter electrode or the working electrode can be selectively embedded according to the arrangement of the electrodes and the temperature sensor on each substrate.

[0135] In summary, the present invention discloses a long-life analyte sensor with integrated temperature detection. The temperature sensor is arranged on the surface of the inner part of the substrate, and can directly measure the temperature of the analyte sensor during in-vivo detection. There is no need to further calibrate the detected temperature, omitting the temperature processing process, thereby improving the reliability of the detected temperature. According to the detected in-vivo temperature, the analyte value can be directly calibrated to improve the accuracy of analyte detection. At the same time, at least one layer of insulating material is arranged behind at least one area on the substrate to avoid the central conductive area where the pins, electrodes and temperature sensor are located, thereby increasing the mechanical strength of the sensor substrate. After the sensor is inserted into the subcutaneous tissue, when it bends or bends with muscle peristalsis, the time for the substrate to reach extreme fatigue is extended, thereby extending the service life of the sensor.

[0136] Although some specific embodiments of the present invention have been described in detail by way of example, it should be understood by those skilled in the art that the above examples are for illustration only and are not intended to limit the scope of the present invention. It should be understood by those skilled in the art that modifications may be made to the above embodiments without departing from the scope and spirit of the present invention. The scope of the present invention is defined by the appended claims.

Claims

1. An analyte sensor, characterized in that: include: at least one substrate, including an internal portion and an external portion; At least two electrodes are disposed on the surface of the internal body part and are used to penetrate subcutaneously to obtain analyte parameter information; Pins, the pins are arranged on the surface of the external part and are electrically connected to the corresponding electrodes through wires; and A temperature sensor is arranged on the surface of the internal body part of the substrate, and a user detects the internal temperature of a patient; wherein at least one layer of insulating material is arranged behind at least one area of ​​the surface of at least one layer of the substrate, and the insulating material avoids the pins, the electrodes and the central conductive area of ​​the temperature sensor.

2. The analyte sensor according to claim 1, characterized in that The inner part of the body is bent relative to the outer part, and the area where the insulating material is arranged later also includes the front side of the bent area.

3. The analyte sensor according to claim 2, characterized in that The area where the insulating material is disposed later includes at least the reverse side of the pin area, the reverse side of the electrode area and / or the reverse side of the temperature sensor area.

4. The analyte sensor according to claim 3, characterized in that The area where the insulating material is disposed later also includes an area where the interval between the electrode and the temperature sensor is relatively large.

5. The analyte sensor according to claim 1, characterized in that The insulating material is disposed on the surface of the substrate by coating or pasting.

6. The analyte sensor according to claim 1, characterized in that The temperature sensor is one of a metal film thermal resistor, a carbon film resistor, a metal oxide film thermal resistor, and an alloy film thermal resistor.

7. The analyte sensor according to claim 6, characterized in that The temperature sensor is a thin film platinum thermal resistor.

8. The analyte sensor according to claim 7, characterized in that The temperature sensor includes a polyimide protective layer.

9. The analyte sensor according to any one of claims 1 to 8, characterized in that: The at least two electrodes include at least a working electrode and a counter electrode.

10. The analyte sensor according to claim 9, characterized in that The working electrode and the temperature sensor are at the same depth of penetration into the subcutaneous tissue.

11. The analyte sensor according to claim 10, characterized in that The at least one substrate is a single-layer substrate, and the working electrode and the temperature sensor are arranged in parallel on the same surface of the single-layer substrate.

12. The analyte sensor according to claim 10, characterized in that The at least one substrate is a single-layer substrate, and the working electrode and the temperature sensor are arranged on different surfaces of the single-layer substrate.

13. The analyte sensor according to claim 10, characterized in that The at least one substrate layer comprises a multi-layer substrate, and the working electrode and the temperature sensor are arranged in parallel on the same surface of the sub-substrate in the same layer.

14. The analyte sensor according to claim 10, characterized in that The at least one substrate layer comprises a multi-layer substrate, and the working electrode and the temperature sensor are arranged on different surfaces of the same layer of the secondary substrate.

15. The analyte sensor according to claim 10, characterized in that The at least one substrate layer comprises a multi-layer substrate, and the working electrode and the temperature sensor are arranged on different surfaces of the secondary substrate in different layers.

16. The analyte sensor according to claim 15, characterized in that The working electrode and the temperature sensor are arranged on different surfaces of the secondary substrate in different adjacent layers.

17. The analyte sensor according to claim 15, characterized in that The working electrode and the temperature sensor are arranged on different surfaces of the sub-substrate at different layers.

18. The analyte sensor according to any one of claims 13 to 17, characterized in that: The multi-layered substrate is prefabricated and pasted into a whole.

19. The analyte sensor according to any one of claims 10, characterized in that The temperature sensor is embedded in the working electrode or the counter electrode.

20. The analyte sensor according to claim 1, wherein The conductive wire is disposed on the surface of the substrate.

21. The analyte sensor according to claim 1, wherein The conductive wire is disposed in an inner layer of the substrate.

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