Implantable dual channel monitoring sensor and method of making same

Abstract

This application discloses an implantable dual-channel monitoring sensor and its fabrication method. The sensor includes a substrate and an electrode assembly, a sensing component, and a functional component disposed on the substrate. The sensing component includes a glucose sensing layer and a ketone body sensing layer, and the functional component includes a first functional film layer and a second functional film layer. The electrode assembly includes a first working electrode, a second working electrode, a reference electrode, and a counter electrode. The first working electrode has a glucose sensing layer disposed on it, and the second working electrode has a ketone body sensing layer disposed on it. The first functional film layer encapsulates the glucose sensing layer, and the second functional film layer encapsulates the ketone body sensing layer. This application enables dual-channel collaborative continuous monitoring and seamless integration of the two monitoring data. Furthermore, this implantable dual-channel monitoring sensor has low design cost, simple manufacturing process, and mass production advantages.

Description

Technical Field

[0001] This application relates to the field of medical device technology, and in particular to an implantable dual-channel monitoring sensor and its preparation method. Background Technology

[0002] In recent years, continuous glucose monitoring (CGM) products have become increasingly mature. The "Expert Consensus on Clinical Application of Continuous Glucose Monitoring 2024" (Endocrinology Branch of the China International Exchange and Promotion Association for Medical and Health Care) explicitly recommends that patients with type 1 diabetes, type 2 diabetes using insulin, gestational diabetes, and high-risk groups for diabetes prioritize the use of CGM to optimize glycemic control and reduce the risk of complications. According to global epidemiological data, diabetic ketoacidosis (DKA) is one of the most dangerous acute complications of diabetes and a major cause of hospitalization and death in diabetic patients, especially prevalent in type 1 diabetes, insulin therapy interruption, or infections. Its prevention and management remain a key focus and challenge in the clinical diagnosis and treatment of diabetes. The "Expert Consensus on Blood Ketone Monitoring in Diabetes Mellitus in China" (Chinese Society of Endocrinology) states: "Blood ketone monitoring is a key aspect of the diagnosis and treatment of DKA, especially for patients with type 1 diabetes, those who have discontinued insulin therapy, and critically ill patients, who need to dynamically monitor blood ketone levels to assess disease progression." Elevated blood ketones are an early sign of DKA, and when combined with blood glucose monitoring, they can significantly reduce the mortality rate of DKA (from a historically high mortality rate to <5%).

[0003] Traditional blood glucose monitoring products are mainly single-channel continuous glucose monitoring (CGM) products. Conventional blood ketone monitoring devices are mostly extended functions of blood glucose meters and cannot work in conjunction with CGM, resulting in decreased patient compliance. Summary of the Invention

[0004] Therefore, it is necessary to provide an implantable dual-channel monitoring sensor that can achieve dual-channel collaborative continuous monitoring and integration of two types of monitoring data, with low design cost, simple process and mass production advantages.

[0005] One embodiment of this application provides an implantable dual-channel monitoring sensor.

[0006] An implantable dual-channel monitoring sensor includes a substrate and an electrode assembly, a sensing component, and a functional component disposed on the substrate. The sensing component includes a glucose sensing layer and a ketone body sensing layer, and the functional component includes a first functional film layer and a second functional film layer. The electrode assembly includes a first working electrode, a second working electrode, a reference electrode, and a counter electrode. The ketone body sensing layer is disposed on the first working electrode, and the glucose sensing layer is disposed on the second working electrode. The first functional film layer partially encloses the first working electrode, a portion of the reference electrode, a portion of the counter electrode, and the ketone body sensing layer. The second functional film layer partially encloses the second working electrode, a portion of the reference electrode, a portion of the counter electrode, and the glucose sensing layer. The first working electrode, the reference electrode, the counter electrode, the ketone body sensing layer, and the first functional film layer constitute a ketone body monitoring component, and the second working electrode, the reference electrode, the counter electrode, the glucose sensing layer, and the second functional film layer constitute a glucose monitoring component.

[0007] In some embodiments, the glucose sensing layer contains glucose oxidase and a first metal redox polymer.

[0008] In some embodiments, the glucose sensing layer further comprises a first crosslinking agent, a first enzyme protectant, and a first surfactant.

[0009] In some embodiments, the glucose sensing layer is fixed to the second working electrode by chemical cross-linking.

[0010] In some embodiments, the ketone body sensing layer contains β-hydroxybutyrate dehydrogenase, myocardial flavin, coenzyme, and a second metal redox polymer.

[0011] In some embodiments, the ketone body sensing layer further comprises a second crosslinking agent, a second enzyme protectant, and a second surfactant.

[0012] In some embodiments, the ketone body sensing layer is fixed to the first working electrode by chemical cross-linking.

[0013] In some embodiments, the glucose monitoring component and the ketone body monitoring component share the reference electrode and the counter electrode, wherein the first working electrode, the second working electrode, the reference electrode, and the counter electrode are each independently located on the front or back side of the substrate;

[0014] Alternatively, the glucose monitoring component and the ketone body monitoring component are each independently provided with the reference electrode and the counter electrode; wherein, the first working electrode and the corresponding reference electrode and the counter electrode are located on one side surface of the substrate, and the second working electrode and the corresponding reference electrode and the counter electrode are located on the other side surface of the substrate.

[0015] In some embodiments, there is a gap between adjacent electrodes in the electrode assembly.

[0016] In some embodiments, the insulating layer includes a UV insulating layer.

[0017] In some embodiments, each electrode in the electrode assembly is provided with an electrode pin.

[0018] In some embodiments, the substrate is provided with an electrode pad area, and the electrode pins are disposed in the electrode pad area.

[0019] In some embodiments, the electrode pins are connected to the corresponding glucose sensing layer or ketone body sensing layer via electrode leads.

[0020] In some embodiments, the electrode leads comprise carbon leads.

[0021] In some embodiments, the first working electrode, the second working electrode, and the counter electrode are each made of carbon materials independently.

[0022] In some embodiments, the reference electrode is prepared from materials that independently include silver chloride conductive paste.

[0023] In some of these embodiments, the substrate is flexible.

[0024] In some embodiments, the substrate is prepared from a material selected from polyimide and polyethylene terephthalate.

[0025] In some embodiments, the first functional membrane layer and the second functional membrane layer each independently comprise at least two polymer membrane layers, the polymer membrane layers being prepared from biocompatible polymers.

[0026] In some embodiments, the polymer film is prepared from one or more of the following materials: perfluorosulfonic acid polymer, poly(4-vinylpyridine-co-styrene), hydrophilic modified poly(4-vinylpyridine-co-styrene), polyurethane, poly(hydroxyethyl methacrylate), and polyvinyl alcohol.

[0027] In some embodiments, the number of polymer film layers in the first functional film layer is greater than the number of polymer film layers in the second functional film layer.

[0028] An embodiment of this application also provides a method for fabricating an implantable dual-channel monitoring sensor.

[0029] A method for fabricating an implantable dual-channel monitoring sensor includes the following steps:

[0030] An electrode assembly comprising a first working electrode, a second working electrode, at least one reference electrode, and at least one counter electrode is fabricated on a substrate.

[0031] A ketone body sensing layer is prepared on the first working electrode;

[0032] A glucose sensing layer is prepared on the second working electrode;

[0033] A first functional film layer and a second functional film layer are prepared separately. The first functional film layer encapsulates a portion of the first working electrode, a portion of the reference electrode, a portion of the counter electrode, and the ketone body sensing layer. The first working electrode, the reference electrode, the counter electrode, the ketone body sensing layer, and the first functional film layer constitute a ketone body monitoring component. The second functional film layer encapsulates a portion of the second working electrode, a portion of the reference electrode, a portion of the counter electrode, and the glucose sensing layer. The second working electrode, the reference electrode, the counter electrode, the glucose sensing layer, and the second functional film layer constitute a glucose monitoring component.

[0034] In some embodiments, the first working electrode, the second working electrode, the reference electrode, and the counter electrode are each formed independently by printing, baking, and cutting.

[0035] In some embodiments, the first working electrode, the second working electrode, and the counter electrode are each made of carbon materials independently.

[0036] In some embodiments, the reference electrode is prepared from materials that independently include silver chloride conductive paste.

[0037] In some embodiments, the substrate is prepared from a material selected from polyimide and polyethylene terephthalate.

[0038] In some embodiments, the method for preparing the glucose sensing layer includes the following steps:

[0039] The glucose sensing layer is formed by chemically cross-linking glucose oxidase, a first metal redox polymer, and a first cross-linking agent to the surface of the second working electrode.

[0040] In some embodiments, the method for preparing the glucose sensing layer further includes the following steps:

[0041] The first enzyme protectant and the first surfactant are disposed within the glucose sensing layer by at least one of electrostatic interaction, physical encapsulation, and chemical cross-linking.

[0042] In some embodiments, in the method for preparing the glucose sensing layer, the first crosslinking agent includes at least one of polyethylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, trimethylolpropane triglycidyl ether, and glutaraldehyde.

[0043] In some embodiments, the method for preparing the glucose sensing layer includes one or more of citrulline, glycine, bovine serum albumin, and magnesium aspartate.

[0044] In some embodiments, the first surfactant in the method for preparing the glucose sensing layer includes at least one of Triton X-100, Nonidet P-40, Tween-20, Brij-35, and Brij-58.

[0045] In some embodiments, the method for preparing the ketone body sensing layer includes the following steps:

[0046] The ketone body sensing layer is formed by chemically cross-linking β-hydroxybutyrate dehydrogenase, myocardial flavonoid, coenzyme, second metal redox polymer and second cross-linking agent onto the surface of the first working electrode.

[0047] In some embodiments, the method for preparing the ketone body sensing layer further includes the following steps:

[0048] The second enzyme protectant and the second surfactant are disposed within the ketone body sensing layer through at least one of electrostatic interaction, physical encapsulation, and chemical cross-linking.

[0049] In some embodiments, in the method for preparing the ketone body sensing layer, the second crosslinking agent includes at least one of polyethylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, trimethylolpropane triglycidyl ether, and glutaraldehyde.

[0050] In some embodiments, in the method for preparing the ketone body sensing layer, the second enzyme protectant includes at least one of citrulline, glycine, bovine serum albumin, polyethylene glycol, trehalose, glycerol, and sorbitol.

[0051] In some embodiments, the second surfactant in the method for preparing the ketone body sensing layer includes at least one of Triton X-100, Nonidet P-40, Tween-20, Brij-35, and Brij-58.

[0052] In some embodiments, the preparation methods of the first functional film layer and the preparation methods of the second functional film layer each independently include the following steps: immersing a slurry composed of a biocompatible polymer and a third crosslinking agent onto the first working electrode or the second working electrode, and performing a crosslinking and curing reaction to form a polymer film layer.

[0053] In some embodiments, the conditions for dip coating include: dip coating time of 5s to 10s, and air drying for 5min to 20min after dip coating.

[0054] In some embodiments, the conditions satisfied by the crosslinking curing reaction include:

[0055] Curing time is 18-24 hours at a temperature of 20-30℃ and a humidity of 40%-50%RH.

[0056] And, cure at 50℃~60℃ and 10%RH~20%RH for 40h~60h.

[0057] In some embodiments, the biocompatible polymer includes one or more of perfluorosulfonic acid polymers, poly(4-vinylpyridine-co-styrene), hydrophilic modified poly(4-vinylpyridine-co-styrene), polyurethane, poly(hydroxyethyl methacrylate), and polyvinyl alcohol.

[0058] In some embodiments, the third crosslinking agent includes at least one of polyethylene glycol diglycidyl ether and trimethylolpropane triglycidyl ether.

[0059] The aforementioned implantable dual-channel monitoring sensor addresses the clinical pain points of traditional single-channel, discontinuous blood ketone meters and the lack of simultaneous integration of blood glucose and blood ketone data. It integrates glucose and ketone body detection into a single unit, achieving dual-channel collaborative continuous monitoring and data integration. Furthermore, this implantable dual-channel monitoring sensor boasts low design cost, simple manufacturing process, and mass production advantages. Employing dual-channel monitoring of glucose and ketone bodies, the sensor utilizes a charge transfer mechanism when the detected substrate undergoes a redox reaction on the corresponding working electrode surface. This process converts the biochemical signal into an electrical signal, outputting a current signal strongly correlated with the substrate concentration for analysis. This represents a shift from "single-level passive monitoring" to "multi-dimensional proactive prevention and control," becoming a crucial solution for diabetes management.

[0060] Currently, there is only one commercially available ketone body continuous monitoring (CKM) product, and there is a complete lack of dual-channel continuous monitoring products for both glucose and ketone bodies. The core reason for this scarcity is the difficulty in effectively immobilizing ketone bodies using enzymes and coenzymes to achieve long-term, continuous detection. Furthermore, the material and manufacturing costs are significantly higher than those of blood glucose testing products. This application achieves effective immobilization of the coenzyme NAD+ small molecule through a combination of physical action and functional cross-linking, enabling continuous ketone body monitoring, unlike traditional technologies such as blood ketone test strips which use single-point, intermittent monitoring. This application effectively controls ketone body manufacturing costs, and further integrates glucose and ketone body detection into a single unit through a dual-channel electrode design, further controlling detection costs. From technological implementation to manufacturing, this application comprehensively addresses the key challenges in the commercialization of ketone body and dual-channel products.

[0061] In use, the implantable dual-channel monitoring sensor of this application allows glucose in the detection environment to pass through the second functional membrane layer on the sensor surface and reach the glucose sensing layer. Under the catalysis of glucose oxidase, a redox reaction occurs, and the charge is transferred to the electrode through the first metal redox polymer to form a current signal, which is then analyzed to obtain the glucose substrate concentration. When ketone bodies (β-hydroxybutyrate) in the detection environment pass through the first functional membrane layer on the sensor surface and reach the ketone body sensing layer, under the synergistic action of the β-HBDH, coenzyme, and myocardial flavin enzyme coupled enzymatic reaction, the charge is transferred to the electrode through the second metal redox polymer to form a current signal, which is then analyzed to obtain the BHB substrate concentration.

[0062] The fabrication method of the implantable dual-channel monitoring sensor in this application features a simple and mature process, strong operability, excellent consistency, and mass production advantages. This method integrates glucose and ketone body sensors into a single dual-channel sensor, enabling long-term and stable accurate identification and detection of physiological concentrations of glucose and ketone bodies, achieving synergistic analysis. This is of great significance for clinical diabetes management, especially for identifying the risk of ketoacidosis. Simultaneously, it minimizes sensor implantation and simplifies the process, offering advantages such as high mass production capacity and low cost, meeting clinical needs while possessing excellent manufacturability.

[0063] The implantable dual-channel monitoring sensor and its fabrication method disclosed in this application have at least the following beneficial effects:

[0064] (1) In some embodiments, the two channels of the glucose monitoring component and the ketone body monitoring component in the dual-channel monitoring sensor can share the reference electrode and the counter electrode, which simplifies the electrode manufacturing process and reduces costs, and is conducive to improving mass production capacity; at the same time, the electrode size is reduced and the implant volume is reduced.

[0065] (2) In some embodiments, the present application can distribute different electrodes on two surfaces of the substrate to reduce the performance risk and quality control risk caused by single-sided stacking; at the same time, the electrode size is reduced, and the depth and volume of the implant invading the subcutaneous tissue are reduced.

[0066] (3) In some embodiments, the combination of the first functional membrane layer and the second functional membrane layer realizes the integration of two sensing components with different response requirements on one sensor, and improves the stability of the sensor, and ensures the sensor's anti-interference ability and biocompatibility; at the same time, the dual-channel sensor has excellent detection capabilities for both glucose and ketone bodies at physiological concentrations, and the detection limit, resolution, sensitivity, etc. are significantly improved compared with traditional technologies.

[0067] (4) In some embodiments, both sensing components of the glucose monitoring component and the ketone body monitoring component are added with enzyme protectants and surfactants and other related additives. The first functional membrane layer and the second functional membrane layer have good biocompatibility, which can effectively improve the sensor life and stability, and are inexpensive.

[0068] (5) In some embodiments, the first working electrode and the second working electrode can be disposed on the same surface of the substrate, which facilitates the continuous preparation of the glucose sensing layer and the ketone body sensing layer by dispensing process and one-time curing; the combination of the first functional film layer and the second functional film layer can be prepared by dip coating, and when the material composition of the first functional film layer and the second functional film layer is consistent, continuous preparation and one-time curing can be achieved. This design facilitates the simple, efficient and large-scale production of sensor sensing components and functional component combinations. Attached Figure Description

[0069] To more clearly illustrate the technical solutions in the embodiments of this application, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0070] To gain a more complete understanding of this application and its beneficial effects, the following description will be provided in conjunction with the accompanying drawings. In the following description, the same reference numerals denote the same parts.

[0071] Figure 1 This is a schematic diagram of an implantable dual-channel monitoring sensor according to an embodiment of this application;

[0072] Figure 2 This is a schematic diagram of an implantable dual-channel monitoring sensor according to another embodiment of this application;

[0073] Figure 3This is a schematic diagram of an implantable dual-channel monitoring sensor according to another embodiment of this application;

[0074] Figure 4 This is a schematic diagram of an implantable dual-channel monitoring sensor according to another embodiment of this application;

[0075] Figure 5 This is a schematic diagram of an implantable dual-channel monitoring sensor according to another embodiment of this application;

[0076] Figure 6 This is a schematic diagram of an implantable dual-channel monitoring sensor according to another embodiment of this application;

[0077] Figure 7 This is a schematic diagram of an implantable dual-channel monitoring sensor according to another embodiment of this application;

[0078] Figure 8 This is a schematic diagram of an implantable dual-channel monitoring sensor according to another embodiment of this application;

[0079] Figure 9 This is a cross-section of the first or second functional membrane layer and sensor structure of an implantable dual-channel monitoring sensor according to another embodiment of this application.

[0080] Explanation of reference numerals in the attached figures

[0081] 10. Implantable dual-channel monitoring sensor; 100. Substrate; 210. First working electrode; 220. Second working electrode; 230. Reference electrode; 240. Counter electrode; 310. Glucose sensing layer; 320. Ketone sensing layer; 410. First functional film layer; 420. Second functional film layer; 510. Insulating layer; 610. Reference lead. Detailed Implementation

[0082] To make the above-mentioned objectives, features, and advantages of this application more apparent and understandable, the specific embodiments of this application are described in detail below with reference to the accompanying drawings. Many specific details are set forth in the following description to provide a thorough understanding of this application. However, this application can be implemented in many other ways different from those described herein, and those skilled in the art can make similar modifications without departing from the spirit of this application. Therefore, this application is not limited to the specific embodiments disclosed below.

[0083] In this application, unless otherwise expressly specified and limited, the terms "connection," "fixed," etc., should be interpreted broadly. For example, they can refer to a fixed connection, a detachable connection, or an integral part; they can refer to a direct connection or an indirect connection through an intermediate medium; they can refer to the internal communication of two elements or the interaction between two elements, unless otherwise expressly limited. Those skilled in the art can understand the specific meaning of the above terms in this application according to the specific circumstances. In this application, unless otherwise expressly specified and limited, "on" or "below" a second feature can mean that the first and second features are in direct contact, or that the first and second features are in indirect contact through an intermediate medium.

[0084] In the description of this application, "several" means one or more, "multiple" means two or more, "greater than," "less than," and "exceeding" are understood to exclude the number itself, while "above," "below," and "within" are understood to include the number itself. The terms "first" and "second" are used only to distinguish technical features and should not be construed as indicating or implying relative importance, or implicitly specifying the number of technical features indicated, or implicitly specifying the sequential relationship of the technical features indicated.

[0085] In this document, "optionally," "optionally," and "optional" mean that something is optional, meaning that one can choose between two parallel options: "with" or "without." If multiple "options" appear in a technical solution, unless otherwise specified and there are no contradictions or mutual constraints, each "option" is independent. In this application, descriptions such as "optionally contains" and "optionally includes" indicate "contains or does not contain."

[0086] In this application, unless otherwise stated, the sum of the parts of each component in the composition may be 100 parts by weight. Unless otherwise specified, the percentages (including weight percentages) in this application are based on the total weight of the composition, and "wt%" in this document means mass percentage.

[0087] In this document, unless otherwise stated, the reaction steps may be performed in the order described herein or not. For example, other steps may be included between reaction steps, and the order of reaction steps may be appropriately interchanged. This is something that those skilled in the art can determine based on conventional knowledge and experience. Preferably, the reaction methods described herein are performed sequentially.

[0088] In this application, the term "numerical interval" (i.e., numerical range) refers to a range of values. Unless otherwise specified, the distribution of selectable values ​​within this numerical interval is considered continuous, and includes the two endpoints (i.e., the minimum and maximum values) of the interval, as well as every value between these endpoints. Unless otherwise specified, when a numerical interval refers only to integers within that interval, it includes the two endpoints of the range and every integer between them, effectively listing every integer. When multiple numerical ranges are provided to describe features or characteristics, these ranges can be merged. In other words, unless otherwise specified, the numerical ranges disclosed in this application should be understood to include any and all subranges included therein. The "numerical value" in this numerical interval can be any quantitative value, such as a number, percentage, or proportion. The term "numerical interval" can broadly include percentage intervals, proportion intervals, ratio intervals, and other quantitative intervals.

[0089] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein in the specification of this application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0090] One embodiment of this application provides an implantable dual-channel monitoring sensor to address the clinical shortcomings of traditional single-channel breakpoint blood ketone meters and their lack of ability to synchronously integrate blood glucose and blood ketone data. The implantable dual-channel monitoring sensor will be described below with reference to the accompanying drawings.

[0091] An embodiment of this application provides an implantable dual-channel monitoring sensor, exemplarily provided in [reference needed]. Figure 1 , Figure 1 This is a schematic diagram of the implantable dual-channel monitoring sensor provided in one embodiment of this application. The implantable dual-channel monitoring sensor of this application can be used for blood glucose monitoring.

[0092] To more clearly illustrate the structure of the implantable dual-channel monitoring sensor, the following description, in conjunction with the accompanying drawings, will be provided.

[0093] For example, please refer to Figure 1As shown, an implantable dual-channel monitoring sensor 10 includes a substrate 100 and an electrode assembly, a sensing element, and a functional element disposed on the substrate 100. The sensing element includes a glucose sensing layer 310 and a ketone body sensing layer 320. The functional element includes a first functional film layer 410 and a second functional film layer 420. The electrode assembly includes a first working electrode 210, a second working electrode 220, at least one reference electrode 230, and at least one counter electrode 240. The ketone body sensing layer 320 is disposed on the first working electrode 210. The glucose sensing layer 310 is disposed on the second working electrode 220. The first functional film layer 410 covers a portion of the first working electrode 210, a portion of the reference electrode 230, a portion of the counter electrode 240, and the ketone body sensing layer 320. The second functional film layer 420 covers a portion of the second working electrode 220, a portion of the reference electrode 230, a portion of the counter electrode 240, and the glucose sensing layer 310. The first working electrode 210, together with the reference electrode 230, the counter electrode 240, the ketone body sensing layer 320, and the first functional membrane layer 410, constitutes a ketone body monitoring component. The second working electrode 220, together with the reference electrode 230, the counter electrode 240, the glucose sensing layer 310, and the second functional membrane layer 420, constitutes a glucose monitoring component.

[0094] The aforementioned implantable dual-channel monitoring sensor 10 addresses the clinical pain points of traditional single-channel, discontinuous blood ketone meters, as well as the lack of simultaneous integration of blood glucose and blood ketone data. It integrates glucose and ketone body detection into a single unit, achieving dual-channel collaborative continuous monitoring and seamless integration of the two types of data. Furthermore, this implantable dual-channel monitoring sensor 10 boasts low design cost, simple manufacturing process, and mass production advantages. Employing dual-channel monitoring of glucose and ketone bodies, the sensor utilizes a charge transfer mechanism when the detected substrate undergoes a redox reaction on the corresponding working electrode surface. This process converts the biochemical signal into an electrical signal, outputting a current signal strongly correlated with the substrate concentration for analysis. This represents a shift from "single-level passive monitoring" to "multi-dimensional proactive prevention and control," becoming a crucial solution for diabetes management.

[0095] In some embodiments, the glucose sensing layer 310 contains glucose oxidase (GOx) and a first metal redox polymer.

[0096] In some embodiments, the glucose sensing layer 310 further comprises a first crosslinking agent, a first enzyme protectant, and a first surfactant.

[0097] In some embodiments, the glucose sensing layer 310 is chemically cross-linked and fixed to the second working electrode 220. The second working electrode 220 and the corresponding reference electrode 230 form a potential measurement circuit, and the second working electrode 220 and the corresponding counter electrode 240 form a current circuit. When glucose in the detection environment passes through the second functional film layer 420 on the surface of the glucose sensor and reaches the glucose sensing layer 310, a redox reaction occurs under the catalysis of glucose oxidase. The charge is transferred to the electrode through the first metal redox polymer to form a current signal, and the glucose substrate concentration is obtained by analysis.

[0098] In some embodiments, the ketone body sensing layer 320 contains β-hydroxybutyrate dehydrogenase (β-HBDH), myocardial flavin, coenzyme, and a second metal redox polymer.

[0099] In some embodiments, the first metal redox polymer in the glucose sensing layer 310 and the second metal redox polymer in the ketone body sensing layer 320 respectively include one or more of osmium polymer, ruthenium polymer and iron polymer.

[0100] In some embodiments, the coenzyme mentioned above is coenzyme I (NAD+).

[0101] In some embodiments, the ketone body sensing layer 320 further comprises a second crosslinking agent, a second enzyme protectant, and a second surfactant.

[0102] In some embodiments, the ketone body sensing layer 320 is chemically cross-linked and fixed to the first working electrode 210. The second working electrode 220 and the corresponding reference electrode 230 form a potential measurement circuit, and the second working electrode 220 and the corresponding counter electrode 240 form a current circuit. When ketone bodies in the detection environment pass through the first functional film layer 410 on the surface of the ketone body sensor and reach the ketone body sensing layer 320, under the synergistic action of the coupled enzymatic reaction of β-hydroxybutyrate dehydrogenase (β-HBDH), myocardial flavin, and coenzyme, charge transfer is transferred to the electrode through the second metal redox polymer to form a current signal, and the concentration of ketone body substrate is obtained by analysis.

[0103] In some embodiments, the glucose monitoring component and the ketone body monitoring component share the reference electrode 230 and the counter electrode 240. The first working electrode 210, the second working electrode 220, the reference electrode 230, and the counter electrode 240 are all located on the front or back side of the substrate 100, or at least one of the first working electrode 210, the second working electrode 220, the reference electrode 230, and the counter electrode 240 is located on the front side of the substrate 100 and at least one is located on the back side of the substrate 100. In this application, when the glucose monitoring component and the ketone body monitoring component share the reference electrode 230 and the counter electrode 240, the reference electrode 230 and the counter electrode 240 are shared by the two-channel sensors of the glucose monitoring component and the ketone body monitoring component, and simultaneously participate in the formation of the two-channel electrochemical circuit, forming the simplest combination, reducing the electrode size, and reducing the sensor implantation volume.

[0104] In some of these implementations, such as Figure 1 As shown, the first working electrode 210 and the second working electrode 220 are distributed on one surface of the substrate 100, such as the front side, and the counter electrode 240 and the reference electrode 230 are distributed on the other surface of the substrate 100, such as the reverse side, wherein the counter electrode 240 is located at the tip of the electrode needle. The tip of the electrode needle refers to the position shown as 210 and 240.

[0105] In some of these implementations, such as Figure 2 As shown, Figure 2 This is a schematic diagram of an implantable dual-channel monitoring sensor 10 according to another embodiment of this application. The first working electrode 210, the second working electrode 220, the counter electrode 240, and the reference electrode 230 are all distributed on one surface of the substrate 100, such as the front side, wherein the first working electrode 210 and the second working electrode 220 are located at the very end of the electrode needle tip.

[0106] In some of these implementations, such as Figure 3 As shown, Figure 3 This is a schematic diagram of an implantable dual-channel monitoring sensor 10 according to another embodiment of this application. The first working electrode 210, the second working electrode 220, the counter electrode 240, and the reference electrode 230 are all distributed on one surface of the substrate 100, such as the front side, wherein the counter electrode 240 is located between the first working electrode 210 and the second working electrode 220.

[0107] In some of these implementations, such as Figure 4 As shown, Figure 4This is a schematic diagram of an implantable dual-channel monitoring sensor 10 according to another embodiment of this application. The first working electrode 210 and the counter electrode 240 are distributed on one surface of the substrate 100, such as the front side, and the second working electrode 220 and the reference electrode 230 are distributed on the other surface of the substrate 100, such as the back side, wherein the first working electrode 210 and the second working electrode 220 are both located at the tip of the electrode needle.

[0108] In some of these implementations, such as Figure 5 As shown, Figure 5 This is a schematic diagram of an implantable dual-channel monitoring sensor 10 according to another embodiment of this application. The first working electrode 210 and the reference electrode 230 are distributed on one surface of the substrate 100, such as the front side, and the second working electrode 220 and the counter electrode 240 are distributed on the other surface of the substrate 100, such as the back side, wherein both are located at the tip of the electrode needle.

[0109] In some implementations, see Figure 6 , Figure 6 This is a schematic diagram of an implantable dual-channel monitoring sensor 10 according to another embodiment of this application. The first working electrode 210, the second working electrode 220, and the reference electrode 230 are distributed on one surface of the substrate 100, such as the front side, and the counter electrode 240 is distributed on the other surface of the substrate 100, such as the back side. The first working electrode 210 and the second working electrode 220 are both located at the tip of the electrode needle.

[0110] In some implementations, see Figure 7 , Figure 7 This is a schematic diagram of an implantable dual-channel monitoring sensor 10 according to another embodiment of this application. The first working electrode 210, the counter electrode 240, and the reference electrode 230 are distributed on one surface of the substrate 100, such as the front side, and the second working electrode 220 is distributed on the other surface of the substrate 100, such as the back side.

[0111] The first working electrode 210, the second working electrode 220, the reference electrode 230, and the counter electrode 240 can be distributed on the same surface of the substrate 100 or on both sides of the electrode substrate 100, further reducing the sensor implantation depth and volume.

[0112] In some embodiments, the glucose monitoring component and the ketone body monitoring component are each independently provided with a reference electrode 230 and a counter electrode 240, wherein the first working electrode 210 and the corresponding reference electrode 230 and counter electrode 240 are located on one side of the front and back of the substrate 100, and the second working electrode 220 and the corresponding reference electrode 230 and counter electrode 240 are located on the other side of the front and back of the substrate 100.

[0113] In some embodiments, the electrode assembly may include six electrodes: a first working electrode 210, a second working electrode 220, two reference electrodes 230, and two counter electrodes 240, forming two sets of three-electrode systems. Each of the three-electrode systems constitutes a sensor channel, and the electrodes between the two sensor channels are independent and do not share electrodes. This electrode assembly is optimally distributed on both sides of the substrate 100. See also Figure 8 , Figure 8 This is a cross-sectional schematic diagram of an implantable dual-channel monitoring sensor 10 according to another embodiment of this application. A first working electrode 210, one counter electrode 240, and one reference electrode 230 are distributed on one surface of the substrate 100, such as the front side. A second working electrode 220, another counter electrode 240, and another reference electrode 230 are distributed on another surface of the substrate 100, such as the reverse side. The first working electrode 210 and the second working electrode 220 are located at the tip of the electrode needle, and the two counter electrodes 240 are respectively close to the corresponding first working electrode 210 or second working electrode 220.

[0114] In some embodiments, there is a gap between adjacent electrodes in the electrode assembly.

[0115] Specifically, in the electrode assembly, adjacent electrodes located on the same surface of the substrate 100 are provided with an insulating layer 510, or, overlapping electrodes formed by multiple layers of printing on the same surface of the substrate 100 are spaced apart by an insulating layer 510. The electrodes in the electrode assembly are insulated from each other by physical spacing or insulating layers 510, and the electrode assembly is printed layer by layer on the surface of the substrate 100 by screen printing.

[0116] In some embodiments, the insulating layer 510 includes a UV insulating layer, that is, the material used to prepare the insulating layer 510 includes a UV insulating paste.

[0117] In some embodiments, each electrode in the electrode assembly is provided with an electrode pin.

[0118] In some embodiments, the substrate is provided with an electrode pad area, and the electrode pins are provided on the electrode pad area on the substrate 100.

[0119] In some embodiments, the electrode pins are connected to the corresponding glucose sensing layer 310 or ketone body sensing layer 320 via electrode leads. See also Figure 9 , Figure 9 Only the reference lead 610 of the reference electrode 230 is shown; the electrode leads of other electrodes are not shown.

[0120] In some embodiments, the electrode leads comprise carbon leads. That is, the electrode leads are made of carbon materials.

[0121] In some embodiments, the materials used to prepare the first working electrode 210, the second working electrode 220, and the counter electrode 240 each independently include carbon materials.

[0122] In some embodiments, the reference electrode 230 is prepared from materials that independently include silver chloride conductive paste.

[0123] In some of these embodiments, the substrate 100 is flexible.

[0124] In some embodiments, the substrate 100 is prepared from a material comprising polyimide (PI) and polyethylene terephthalate (PET).

[0125] In some embodiments, the first functional membrane layer 410 and the second functional membrane layer 420 each independently comprise at least two polymer membrane layers, the polymer membrane layers being prepared from biocompatible polymers.

[0126] In some embodiments, the materials used to prepare the polymer film include one or more of the following: perfluorosulfonic acid polymer (Nafion), poly(4-vinylpyridine-co-styrene) (P(4VP-co-PVB)), hydrophilic group-modified poly(4-vinylpyridine-co-styrene) (MP(4VP-co-PVB)), polyurethane, poly(hydroxyethyl methacrylate), and polyvinyl alcohol.

[0127] In some embodiments, the first functional film layer 410 has more polymer film layers than the second functional film layer 420.

[0128] One embodiment of this application also provides a method for preparing an implantable dual-channel monitoring sensor 10.

[0129] A method for fabricating an implantable dual-channel monitoring sensor 10 includes the following steps:

[0130] S10. An electrode assembly including a first working electrode 210, a second working electrode 220, a reference electrode 230 and a counter electrode 240 is prepared on a substrate 100.

[0131] S20. A ketone body sensing layer 320 is prepared on the first working electrode 210.

[0132] S30. A glucose sensing layer 310 is prepared on the second working electrode 220.

[0133] S40. Prepare a first functional film layer 410 and a second functional film layer 420 respectively. The first functional film layer 410 encapsulates a portion of the first working electrode 210, a portion of the reference electrode 230, a portion of the counter electrode 240, and the ketone body sensing layer 320. The first working electrode 210, the reference electrode 230, the counter electrode 240, the ketone body sensing layer 320, and the first functional film layer 410 together form a ketone body monitoring component. The second functional film layer 420 encapsulates a portion of the second working electrode 220, a portion of the reference electrode 230, a portion of the counter electrode 240, and the glucose sensing layer 310. The second working electrode 220, the reference electrode 230, the counter electrode 240, the glucose sensing layer 310, and the second functional film layer 420 together form a glucose monitoring component.

[0134] In some embodiments, the first working electrode 210, the second working electrode 220, the reference electrode 230, and the counter electrode 240 are formed independently by printing, baking, and cutting.

[0135] In this application, the first working electrode 210, the second working electrode 220, the reference electrode 230, the counter electrode 240, and the electrode leads are all cured by thermal baking, and the insulating layer 510 is cured by UV. The printed and cured electrodes are then laser-cut to form the electrode contour.

[0136] In some embodiments, taking the simplest four-electrode double-sided printing scheme as an example, after the substrate 100 is cleaned and surface-treated, the first working electrode 210 and its leads are printed and cured on the front side of the substrate 100, followed by the printing and curing of the insulating layer 510, then the printing and curing of the second working electrode 220 and its leads, and finally the printing and curing of another insulating layer 510. On the back side of the substrate 100, the counter electrode 240 and its leads are printed and cured, followed by the printing and curing of the insulating layer 510, then the printing and curing of the reference electrode 230 leads, and finally the printing and curing of the insulating layer 510.

[0137] In some embodiments, the materials used to prepare the first working electrode 210, the second working electrode 220, and the counter electrode 240 each independently include carbon materials.

[0138] In some embodiments, the reference electrode 230 is prepared using materials that independently include silver-silver chloride conductive paste. The mass ratio of silver to silver chloride in the silver-silver chloride conductive paste can be set according to actual needs.

[0139] In some embodiments, the substrate 100 is prepared from a material comprising polyimide (PI) and polyethylene terephthalate (PET).

[0140] In some embodiments, the preparation method of the glucose sensing layer 310 includes the following steps:

[0141] Glucose oxidase (GOx), a first metal redox polymer, and a first crosslinking agent are fixed to the surface of the second working electrode 220 by chemical crosslinking to form a glucose sensing layer 310.

[0142] In some embodiments, the preparation method of the glucose sensing layer 310 further includes the following steps:

[0143] The first enzyme protectant and the first surfactant are disposed in the glucose sensing layer 310 by at least one of electrostatic interaction, physical encapsulation and chemical cross-linking.

[0144] In some embodiments, in the preparation method of glucose sensing layer 310, the first crosslinking agent includes at least one of polyethylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, trimethylolpropane triglycidyl ether, and glutaraldehyde.

[0145] In some embodiments, the first enzyme protectant in the preparation method of glucose sensing layer 310 includes one or more of citrulline, glycine, bovine serum albumin (BSA), and magnesium aspartate.

[0146] In some embodiments, the first surfactant in the preparation method of the glucose sensing layer 310 includes at least one of Triton X-100, Nonidet P-40, Tween-20, Brij-35, and Brij-58.

[0147] In some embodiments, the glucose sensing layer 310 is prepared by uniformly dispersing a solution of glucose oxidase (GOx), a first metal redox polymer, and a first crosslinking agent onto the first working electrode 210 using a dispensing process, and then curing it for 24-28 hours under constant temperature and humidity conditions of 37°C-40°C and 80%-85%RH. The concentration and ratio of the first enzyme solution are selected according to the sensor signal requirements and process conditions. For example, one method for preparing the glucose sensing layer 310 is as follows: first, solutions of glucose oxidase (GOx), the first metal redox polymer, polyethylene glycol diglycidyl ether (first crosslinking agent), citrulline (first enzyme protectant), glycine (first enzyme protectant), bovine serum albumin (BSA) (first enzyme protectant), and magnesium aspartate (first enzyme protectant) are prepared with a concentration of 30 mg / mL using pH 7.4 and 10 mM HEPES buffer as solvents, and then mixed in a volume ratio of 5:5:2:1:1:1:1 to obtain the first enzyme solution.

[0148] In some embodiments, the preparation method of the ketone body sensing layer 320 includes the following steps:

[0149] β-hydroxybutyrate dehydrogenase (β-HBDH), myocardial flavonoids, coenzyme, second metal redox polymer and second crosslinking agent are fixed on the surface of the first working electrode 210 by chemical crosslinking to form ketone body sensing layer 320.

[0150] In some embodiments, the method for preparing the ketone body sensing layer 320 further includes the following steps:

[0151] The second enzyme protectant and the second surfactant are disposed in the ketone body sensing layer 320 by at least one of electrostatic interaction, physical encapsulation and chemical cross-linking.

[0152] In some embodiments, in the method for preparing the ketone body sensing layer 320, the second crosslinking agent includes at least one of polyethylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, trimethylolpropane triglycidyl ether, and glutaraldehyde.

[0153] In some embodiments, the second enzyme protectant in the preparation method of the ketone body sensing layer 320 includes at least one of citrulline, glycine, bovine serum albumin, polyethylene glycol, trehalose, glycerol, and sorbitol.

[0154] In some embodiments, the second surfactant in the preparation method of the ketone body sensing layer 320 includes at least one of Triton X-100, Nonidet P-40, Tween-20, Brij-35, and Brij-58.

[0155] In some embodiments, the ketone body sensing layer 320 is prepared by dispensing a second enzyme solution containing β-hydroxybutyrate dehydrogenase (β-HBDH), myocardial flavin, coenzyme, a second metal redox polymer, and a second crosslinking agent onto the second working electrode 220 using a dispensing process. The solution is then cured for 24-28 hours under constant temperature and humidity conditions of 37°C-40°C and 80%-85%RH. The concentration and ratio of the second enzyme solution are selected based on the sensor signal requirements and process conditions. For example, one method for preparing the ketone body sensing layer 320 involves preparing solutions of β-hydroxybutyrate dehydrogenase (β-HBDH), myocardial flavin, coenzyme, a second metal redox polymer, polyethylene glycol diglycidyl ether (second crosslinking agent), citrulline (second enzyme protectant), and Triton X-100 (second surfactant) at a concentration of 30 mg / mL using a pH 5.5, 10 mM MES buffer as solvent. These solutions are then mixed in a volume ratio of 5:5:5:5:3:5:2 to obtain the second enzyme solution.

[0156] The curing conditions of the glucose sensing layer 310 and the ketone body sensing layer 320 of the present invention should be within the range allowed by enzyme activity. When the curing conditions of the two sensing components are the same, the preparation efficiency of the sensor sensing components can be greatly improved by continuous dispensing and co-curing.

[0157] In some embodiments, the preparation methods of the first functional film layer 410 and the preparation methods of the second functional film layer 420 independently include the following steps: immersing a slurry composed of a biocompatible polymer and a third crosslinking agent onto the first working electrode 210 or the second working electrode 220, and forming a polymer film layer through a crosslinking and curing reaction.

[0158] In some embodiments, the conditions for dip coating include: dip coating time of 5s to 10s, and air drying for 5min to 20min after dip coating.

[0159] In some embodiments, the conditions satisfied by the crosslinking curing reaction include:

[0160] Curing time is 18-24 hours at 20℃~30℃ and 40%RH~50%RH.

[0161] Continue curing at 50℃~60℃ and 10%RH~20%RH for 40h~60h.

[0162] In some embodiments, the multilayer polymer film layers of the first functional film layer 410 or the second functional film layer 420 are respectively set individually or stacked, which can achieve the functions of restricting diffusion of substrate molecules, anti-interference and biocompatibility.

[0163] The multilayer polymer film of the first functional film layer 410 can be the same polymer or different polymers. When different polymers are used, their composition, proportion and film thickness are different.

[0164] The multilayer polymer film of the second functional film layer 420 can be the same polymer or different polymers. When different polymers are used, their composition, proportion and film thickness are different.

[0165] In some embodiments, the biocompatible polymer includes one or more of the following: perfluorosulfonic acid polymer (Nafion), poly(4-vinylpyridine-co-styrene) (P(4VP-co-PVB)), hydrophilic group-modified poly(4-vinylpyridine-co-styrene) (MP(4VP-co-PVB)), polyurethane, poly(hydroxyethyl methacrylate), and polyvinyl alcohol. The perfluorosulfonic acid polymer (Nafion) exhibits excellent selective permeability and stability. The modified poly(4-vinylpyridine-co-styrene) can be sulfonate-modified or polyethylene glycol (PEG)-modified, both of which possess good biocompatibility and can serve as a biocompatible polymer film layer while limiting diffusion.

[0166] In some embodiments, different polymer film layers can cover different areas of the electrode and exist at different levels. For example, in one specific embodiment, the multilayer polymer film combination of the first functional film layer 410 or the second functional film layer 420 is composed of a perfluorosulfonic acid polymer (Nafion) and modified poly(4-vinylpyridine-co-styrene) (MP(4VP-co-PVB)), based on the electrode surface from the inside out in the order of "Nafion, MP(4VP-co-PVB)-1, MP(4VP-co-PVB)-2, Nafion", where Nafion covers the entire implantation area (it should be noted that the above-mentioned implantation area refers to the part of the substrate 100 used for implantation in the user's tissue), MP(4VP-co-PVB)-1, MP(4VP-co-PVB)-2, and MP(4VP-co-PVB)-2. The 4VP-co-PVB coating is applied in two stages. MP(4VP-co-PVB)-1 (used to prepare the first functional film layer 410) is applied to the first working electrode 210 near the tip of the electrode microneedle. MP(4VP-co-PVB)-2 (used to prepare the second functional film layer 420) is superimposed on SP(4VP-co-PVB)-1 to cover the entire implantation area. This results in the first working electrode 210 having more polymer film layers than the second working electrode 220. This is related to the fact that the two channels of the glucose monitoring component and the ketone body monitoring component require different permeability film layers. In comparison, the channel of the ketone body monitoring component may require functional components with stronger confinement or stronger anti-interference performance.

[0167] The polymers of MP(4VP-co-PVB)-1 and MP(4VP-co-PVB)-2 can be exactly the same, for example, both being 10 wt% sulfonate-modified poly(4-vinylpyridine-co-styrene) (10% SP(4VP-co-PVB)). The polymers of MP(4VP-co-PVB)-1 and MP(4VP-co-PVB)-2 can also be different; for example, MP(4VP-co-PVB)-1 is 5 wt% SP(4VP-co-PVB), while MP(4VP-co-PVB)-2 is 10 wt% PEG-P(4VP-co-PVB). The polymer films are applied to the electrode surface via dip coating. The composition of the dip coating solution includes, but is not limited to, the polymer and a third crosslinking agent. After dip coating, crosslinking and curing are completed under specific temperature and humidity conditions. When MP(4VP-co-PVB)-1 and MP(4VP-co-PVB)-2 are the same polymer and the composition of the coating solution is the same, the preparation of the first functional film layer 410 or the second functional film layer 420 can be carried out continuously within a certain range of conditions, improving the preparation efficiency. Figure 1 The electrode structure example shown, the first functional film layer 410 or the second functional film layer 420 and the sensor structure cross-section are shown in the figure. Figure 9 As shown.

[0168] In some embodiments, the preparation methods of the first functional film layer 410 and the second functional film layer 420 include the following steps:

[0169] Prepare a 5 wt% Nafion 117 solution and a 10 wt% SP (4VP-co-PVB) solution at 100 mg / mL using an ethanol:water mixture of 4:1 as the solvent. First, immerse the electrode in a 5 wt% Nafion 117 solution, ensuring the immersion height covers both the first working electrode 210 and the second working electrode 220. After immersion for 5 seconds, remove and air dry for 10 minutes. Then, immerse the electrode in a 10 wt% SP (4VP-co-PVB) solution, ensuring the immersion height covers both the first working electrode 210 and does not touch the second working electrode 220. After immersion for 5 seconds, remove and air dry for 10 minutes. Repeat this process 4 times. Next, immerse the electrode in a 10 wt% SP (4VP-co-PVB) solution, ensuring the immersion height covers the entire implantation area. After immersion for 5 seconds, remove and air dry for 10 minutes. Repeat this process 4 times. Finally, immerse the electrode again in a 5 wt% Nafion 117 solution, ensuring the immersion height covers the entire implantation area. After immersion for 5 seconds, remove and air dry for 10 minutes. The dip-coated electrode is first cured at 25℃-45%RH for 24 hours, and then transferred to 55℃-15%RH for 48 hours to obtain the first functional film layer 410 and the second functional film layer 420.

[0170] In some embodiments, the third crosslinking agent includes one or both of polyethylene glycol diglycidyl ether and trimethylolpropane triglycidyl ether.

[0171] When the implantable dual-channel monitoring sensor 10 of this application is in use, glucose in the detection environment passes through the first functional membrane layer 410 on the sensor surface to reach the glucose sensing layer 310. Under the catalysis of glucose oxidase, a redox reaction occurs, and the charge is transferred to the electrode through the first metal redox polymer to form a current signal, which is then analyzed to obtain the glucose substrate concentration. When ketone bodies (β-hydroxybutyrate, abbreviated as BHB (β-HB)) in the detection environment passes through the second functional membrane layer 420 on the sensor surface to reach the ketone body sensing layer 320, under the synergistic action of the β-HBDH, coenzyme, and myocardial flavin enzyme coupled enzymatic reaction, the charge is transferred to the electrode through the second metal redox polymer to form a current signal, which is then analyzed to obtain the BHB substrate concentration.

[0172] The fabrication method of the implantable dual-channel monitoring sensor 10 in this application features a simple and mature process, strong operability, excellent consistency, and mass production advantages. This method integrates glucose and ketone body sensors into a single dual-channel sensor, enabling long-term and stable accurate identification and detection of physiological concentrations of glucose and ketone bodies, achieving synergistic analysis. This is of great significance for clinical diabetes management, especially for identifying the risk of ketoacidosis. Simultaneously, it minimizes sensor implantation and simplifies the process, offering advantages such as high production capacity and low cost, meeting clinical needs while possessing good manufacturability.

[0173] In summary, the implantable dual-channel monitoring sensor 10 and its preparation method of this application have at least the following beneficial effects:

[0174] (1) In some embodiments, the two channels of the glucose monitoring component and the ketone body monitoring component in the dual-channel monitoring sensor can share the reference electrode 230 and the counter electrode 240, which simplifies the electrode manufacturing process and reduces costs, and is conducive to improving mass production capacity; at the same time, the electrode size is reduced and the implant volume is reduced.

[0175] (2) In some embodiments, the present application can distribute different electrodes on two surfaces of the substrate 100 to reduce the performance risk and quality control risk caused by single-sided stacking; at the same time, the electrode size is reduced, and the depth and volume of the implant invading the subcutaneous tissue are reduced.

[0176] (3) In some embodiments, the combination of the first functional membrane layer 410 and the second functional membrane layer 420 realizes the integration of two sensing components with different response requirements on one sensor, and improves the stability of the sensor, and ensures the sensor's anti-interference ability and biocompatibility; at the same time, the dual-channel sensor has excellent detection capabilities for physiological concentrations of glucose and ketone bodies, and the detection limit, resolution, sensitivity, etc. are significantly improved compared with traditional technologies.

[0177] (4) In some embodiments, both sensing components of the glucose monitoring component and the ketone body monitoring component are added with enzyme protectants and surfactants and other related additives. The first functional membrane layer 410 and the second functional membrane layer 420 have good biocompatibility, which can effectively improve the sensor life and stability, and are inexpensive.

[0178] (5) In some embodiments, the first working electrode 210 and the second working electrode 220 can be disposed on the same surface of the substrate 100, which facilitates the continuous preparation of the glucose sensing layer 310 and the ketone body sensing layer 320 by dispensing process and curing in one step; the combination of the first functional film layer 410 and the second functional film layer 420 can be prepared by dip coating, and when the material composition of the first functional film layer 410 and the second functional film layer 420 is consistent, continuous preparation and one-time curing can be achieved. This design facilitates the simple, efficient and large-scale production of sensor sensing components and functional component combinations.

[0179] In the above embodiments, the descriptions of each embodiment have different focuses. For parts not described in detail in a certain embodiment, please refer to the relevant descriptions in other embodiments.

[0180] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0181] The embodiments described above are merely illustrative of several implementation methods of this application, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of this patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the protection scope of this application. Therefore, the protection scope of this patent application should be determined by the appended claims, and the specification and drawings can be used to interpret the content of the claims.

Claims

1. An implantable dual-channel monitoring sensor, characterized in that, The device includes a substrate and an electrode assembly, a sensing element, and a functional element disposed on the substrate. The sensing element includes a glucose sensing layer and a ketone body sensing layer. The functional element includes a first functional film layer and a second functional film layer. The electrode assembly includes a first working electrode, a second working electrode, a reference electrode, and a counter electrode. The ketone body sensing layer is disposed on the first working electrode, and the glucose sensing layer is disposed on the second working electrode. The first functional film layer partially encloses the first working electrode, part of the reference electrode, part of the counter electrode, and the ketone body sensing layer. The second functional film layer partially encloses the second working electrode, part of the reference electrode, part of the counter electrode, and the glucose sensing layer. The first working electrode, the reference electrode, the counter electrode, the ketone body sensing layer, and the first functional film layer constitute a ketone body monitoring component. The second working electrode, the reference electrode, the counter electrode, the glucose sensing layer, and the second functional film layer constitute a glucose monitoring component.

2. The implantable dual-channel monitoring sensor according to claim 1, characterized in that, It also satisfies at least one of the following conditions: (1) The glucose sensing layer contains glucose oxidase and a first metal redox polymer; (2) The glucose sensing layer is fixed to the second working electrode by chemical cross-linking; (3) The ketone body sensing layer contains β-hydroxybutyrate dehydrogenase, myocardial flavin, coenzyme and second metal redox polymer; (4) The ketone body sensing layer is fixed to the first working electrode by chemical cross-linking.

3. The implantable dual-channel monitoring sensor according to any one of claims 1 to 2, characterized in that, The glucose monitoring component and the ketone body monitoring component share the reference electrode and the counter electrode; wherein the first working electrode, the second working electrode, the reference electrode, and the counter electrode are each independently located on the front or back side of the substrate; Alternatively, the glucose monitoring component and the ketone body monitoring component are each independently provided with the reference electrode and the counter electrode; wherein, the first working electrode and the corresponding reference electrode and the counter electrode are located on one side surface of the substrate, and the second working electrode and the corresponding reference electrode and the counter electrode are located on the other side surface of the substrate.

4. The implantable dual-channel monitoring sensor according to any one of claims 1 to 2, characterized in that, The electrode assembly has a gap between adjacent electrodes.

5. The implantable dual-channel monitoring sensor according to any one of claims 1 to 2, characterized in that, Each electrode in the electrode assembly is provided with an electrode pin; The substrate is provided with an electrode pad area, and each of the electrode pins is disposed in the electrode pad area; Each of the electrode pins is connected to the corresponding glucose sensing layer or ketone body sensing layer via an electrode lead.

6. The implantable dual-channel monitoring sensor according to any one of claims 1 to 2, characterized in that, It also satisfies at least one of the following conditions: (1) The materials used to prepare the first working electrode, the second working electrode, and the counter electrode each independently include carbon materials; (2) The materials used to prepare the reference electrode each independently include silver chloride conductive paste; (3) The substrate is flexible; (4) The substrate is prepared by one of polyimide and polyethylene terephthalate.

7. The implantable dual-channel monitoring sensor according to any one of claims 1 to 2, characterized in that, The first functional membrane layer and the second functional membrane layer each independently comprise at least two polymer membrane layers, and the polymer membrane layers are prepared from biocompatible polymers.

8. The implantable dual-channel monitoring sensor according to claim 7, characterized in that, It also satisfies at least one of the following conditions: (1) The materials used to prepare the polymer film include one or more of the following: perfluorosulfonic acid polymer, poly(4-vinylpyridine-co-styrene), hydrophilic group modified poly(4-vinylpyridine-co-styrene), polyurethane, poly(hydroxyethyl methacrylate), and polyvinyl alcohol; (2) The number of polymer film layers in the first functional film layer is greater than the number of polymer film layers in the second functional film layer.

9. A method for fabricating an implantable dual-channel monitoring sensor, characterized in that, Includes the following steps: An electrode assembly comprising a first working electrode, a second working electrode, a reference electrode, and a counter electrode is fabricated on a substrate. A ketone body sensing layer is prepared on the first working electrode; A glucose sensing layer is prepared on the second working electrode; A first functional film layer and a second functional film layer are prepared separately. The first functional film layer encapsulates a portion of the first working electrode, a portion of the reference electrode, a portion of the counter electrode, and the ketone body sensing layer. The first working electrode, the reference electrode, the counter electrode, the ketone body sensing layer, and the first functional film layer constitute a ketone body monitoring component. The second functional film layer encapsulates a portion of the second working electrode, a portion of the reference electrode, a portion of the counter electrode, and the glucose sensing layer. The second working electrode, the reference electrode, the counter electrode, the glucose sensing layer, and the second functional film layer constitute a glucose monitoring component.

10. The method for preparing the implantable dual-channel monitoring sensor according to claim 9, characterized in that, It also satisfies at least one of the following conditions: (1) The first working electrode, the second working electrode, the reference electrode, and the counter electrode are formed independently by printing, baking, and cutting, respectively; (2) The materials used to prepare the first working electrode, the second working electrode, and the counter electrode each independently include carbon materials; (3) The materials used to prepare the reference electrode each independently include silver chloride conductive paste; (4) The substrate is prepared by one of polyimide and polyethylene terephthalate.

11. The method for preparing the implantable dual-channel monitoring sensor according to any one of claims 9 to 10, characterized in that, The method for preparing the glucose sensing layer includes the following steps: The glucose sensing layer is formed by chemically cross-linking glucose oxidase, a first metal redox polymer, and a first cross-linking agent to the surface of the second working electrode.

12. The method for preparing the implantable dual-channel monitoring sensor according to claim 11, characterized in that, It also satisfies at least one of the following conditions: (1) The preparation method of the glucose sensing layer further includes the following steps: The first enzyme protectant and the first surfactant are disposed in the glucose sensing layer by at least one of electrostatic interaction, physical encapsulation and chemical cross-linking. (2) The first crosslinking agent includes one or more of polyethylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, trimethylolpropane triglycidyl ether, and glutaraldehyde; (3) The first enzyme protectant includes one or more of citrulline, glycine, bovine serum albumin and magnesium aspartate; (4) The first surfactant includes one or more of Triton X-100, Nonidet P-40, Tween-20, Brij-35 and Brij-58.

13. The method for preparing the implantable dual-channel monitoring sensor according to any one of claims 9-10 and 12, characterized in that, The method for preparing the ketone body sensing layer includes the following steps: The ketone body sensing layer is formed by chemically cross-linking β-hydroxybutyrate dehydrogenase, myocardial flavonoid, coenzyme, second metal redox polymer and second cross-linking agent onto the surface of the first working electrode.

14. The method for fabricating the implantable dual-channel monitoring sensor according to claim 13, characterized in that, It also satisfies at least one of the following conditions: (1) The preparation method of the ketone body sensing layer further includes the following steps: The second enzyme protectant and the second surfactant are disposed in the ketone body sensing layer by at least one of electrostatic interaction, physical encapsulation and chemical cross-linking. (2) The second crosslinking agent includes one or more of polyethylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, trimethylolpropane triglycidyl ether, and glutaraldehyde; (3) The second enzyme protectant includes one or more of citrulline, glycine, bovine serum albumin, polyethylene glycol, trehalose, glycerol and sorbitol; (4) The second surfactant includes one or more of Triton X-100, Nonidet P-40, Tween-20, Brij-35 and Brij-58.

15. The method for preparing an implantable dual-channel monitoring sensor according to any one of claims 9-10, 12, and 14, characterized in that, The preparation methods of the first functional membrane and the second functional membrane each independently include the following steps: immersing a slurry composed of a biocompatible polymer and a third crosslinking agent onto the first working electrode or the second working electrode, and then performing a crosslinking and curing reaction to form a polymer membrane.

16. The method for preparing an implantable dual-channel monitoring sensor according to any one of claims 9-10, 12, and 14, characterized in that, It also satisfies at least one of the following conditions: (1) The conditions to be met for dip coating include: dip coating time of 5s~10s, and air drying for 5min~20min after dip coating; (2) The conditions satisfied by the crosslinking curing reaction include: Curing time is 18-24 hours at a temperature of 20-30℃ and a humidity of 40%-50%RH. And, cure at 40℃~60℃ and 10%RH~50%RH for 40h~60h; (3) The biocompatible polymers include one or more of the following: perfluorosulfonic acid polymers, poly(4-vinylpyridine-co-styrene), hydrophilic modified poly(4-vinylpyridine-co-styrene), polyurethane, poly(hydroxyethyl methacrylate), and polyvinyl alcohol; (4) The third crosslinking agent includes one or more of polyethylene glycol diglycidyl ether and trimethylolpropane triglycidyl ether.

Images