Implantable laminated probe and implantable glucose monitoring probe

Abstract

The invention relates to an implantable laminated probe and an implantable glucose monitoring probe, the implantable laminated probe comprises a flexible substrate, a plurality of functional electrodes and a plurality of insulating layers, each functional electrode comprises a conductive region and a working region, the conductive regions are electrically connected with the working regions, the insulating layers are arranged between the adjacent functional electrodes to realize interlayer isolation, and the insulating layers are arranged between the conductive regions and the working regions. The conductive area of the functional electrode comprises an implanted conductive area implanted into a human body and a non-implanted conductive area not implanted into the human body, the implanted conductive area is a carbon circuit layer, the non-implanted conductive area is a silver circuit layer, and the silver circuit layer and the carbon circuit layer form a series structure. The characteristic of good biocompatibility of the carbon circuit layer and the characteristics of small resistance value and high signal transmission efficiency of the silver circuit layer are fully utilized, the circuit impedance of the functional electrode is effectively reduced, the signal transmission efficiency is improved, the biocompatibility and long-term stability of an implantation area are ensured, the silver circuit layer and the carbon circuit layer form a series structure, and the reliability of the implantation area is improved. The path of the conductive region is ensured.

Description

Technical Field

[0001] The present application relates to the technical field of biosensors, and in particular to an implantable laminated probe and an implantable glucose monitoring probe. Background Art

[0002] As the incidence of diabetes continues to rise, the demand for real-time and accurate blood glucose monitoring is growing. As an efficient diabetes management tool, the implantable continuous glucose monitoring (CGM) system has become the focus of market attention. The CGM system usually relies on an implantable monitoring probe to electrochemically detect the glucose concentration in tissue fluid or blood. The monitoring probe includes a probe sensor, which is usually composed of a working electrode, a reference electrode and a counter electrode. The detection mechanism is based on the current signal generated by the redox reaction between glucose oxidase and glucose. In the prior art, the electrode structure design of the implantable glucose monitoring probe is its core part. The material and structural design of the working electrode, reference electrode and counter electrode directly determine the electrochemical performance and biocompatibility of the monitoring probe, which in turn directly affects the sensitivity, stability and anti-interference performance of the monitoring probe.

[0003] The Chinese patent application with publication number CN112710713A discloses an implantable glucose monitoring probe, the materials and structural designs of its working electrode, reference electrode and counter electrode all have certain technical advantages. The working electrode is usually made of highly conductive materials, such as gold, glassy carbon, graphite, silver or platinum, and coated on its surface with a porous nanoparticle layer that catalyzes the glucose reaction. These particle layers are composed of platinum, titanium, gold or carbon materials, which significantly improve the specific surface area and catalytic performance of the electrode, thereby reducing the catalytic potential of the working electrode; the reference electrode generally uses stable materials such as silver chloride or platinum to form a fixed potential difference with tissue fluid or blood, providing an accurate reference potential for the working electrode; the counter electrode is made of platinum or silver to ensure the efficient closure of the electrochemical circuit. These three electrodes are arranged side by side and adopt a separate layout, which helps to reduce interference between electrodes and enhance the detection stability of the signal.

[0004] A Chinese patent application with publication number CN109765286A discloses a continuous glucose monitoring system sensor and a method for manufacturing the same, wherein conductive layers and insulating layers are alternately stacked on a substrate in a preset order, wherein the conductive layers and insulating layers are made of biocompatible materials; holes are opened in preset areas to obtain holes, wherein the inner walls of the holes expose the corresponding conductive layers, and the inner walls of each of the holes are in contact with only one conductive layer; an enzyme layer is set in the holes obtained after the holes are opened, and the enzyme layer is used to react with glucose to generate current; a membrane layer is set in the holes where the enzyme layer is set, and the membrane layer is permeable to glucose. In this design, three electrodes are stacked to save space.

[0005] However, the above existing technologies still have many limitations in practical applications: 1. The multiple functional electrodes of the probe can be made of materials such as carbon, metal platinum or silver. Metal platinum and silver have low resistance and high signal transmission efficiency, but these metal materials have poor biocompatibility, strong foreign body sensation after implantation, which can easily cause discomfort to patients and have poor adaptability. Carbon has good biocompatibility, weak foreign body sensation after implantation and good adaptability, but carbon has high resistance and low signal transmission efficiency, which will weaken the sensitivity of electrical signals and affect the sensitivity and detection accuracy of blood glucose detection. In addition, if metal impurities (such as silver) are doped in the carbon material, it is easy to generate stray peaks during the electrochemical test, which interferes with the normal signal output of the working electrode and reduces the detection accuracy and stability of the sensor.

[0006] 2. The porous nanoparticle layer often set in the working electrode is one of the keys to improve the electrochemical performance. These nanoparticle layers are usually made of materials such as platinum, carbon nanotubes, gold or graphene, which can not only significantly increase the reaction specific surface area of ​​the electrode, but also catalyze glucose oxidation reaction, effectively reduce the working voltage, and enhance the fixation effect of glucose enzyme. In the prior art, the enzyme modification method mainly adopts the pull-up dip coating method or the coating method. These methods are simple to operate, but the uniformity of electrode surface coating is insufficient. The pull-up dip coating method depends on parameters such as the pulling speed and solution viscosity, resulting in uneven distribution of the enzyme on the electrode surface, and the existence of local concentrations that are too high or too low; and although the coating method has a larger coverage range, it is also difficult to ensure the uniformity of the enzyme layer distribution due to the influence of the coating equipment precision and the electrode surface roughness, which easily causes the waste of enzyme materials. This unevenness also makes the enzyme catalytic efficiency in some electrode areas low, and may even cause signal instability. At the same time, since these processes are mainly based on physical adsorption, the enzymes have weak adhesion and are easily detached during long-term use, especially under the influence of body fluid flushing or mechanical vibration. This further reduces the enzyme catalytic efficiency and affects the service life and stability of the monitoring probe.

[0007] 3. The existing probes lack effective interference shielding design, the electrode structure has weak anti-interference ability, and are easily interfered by impurities in the body such as uric acid and ascorbic acid, resulting in large errors in the test results and insufficient stability.

[0008] 4. The contact area where the functional electrode contacts the external electronic device is prone to wear: The contact design of existing CGM devices generally uses soft carbon or ordinary metal materials, which are easily affected by plugging and unplugging or environmental oxidation during use, resulting in contact wear and performance degradation, thereby shortening the service life of the monitoring probe.

[0009] 5. The structural fixation of the monitoring probe is poor: Some CGM devices rely on flexible materials for fixation or adhesion, lack an effective fixed installation design, and are prone to loosening during implantation or long-term use, affecting the reliability of the connection between the functional electrode and the external device.

[0010] 6. The impact of interference is large: Some technologies fail to effectively block the interference of non-glucose substances, resulting in large signal deviations and difficulty in obtaining stable blood glucose test results. Summary of the invention

[0011] In order to solve the technical problem that the functional electrodes of the monitoring probe in the prior art use a carbon circuit layer, resulting in high resistance, low signal transmission efficiency, weakened sensitivity of the electrical signal, and affecting the sensitivity and detection accuracy of the monitoring probe, an implantable laminated probe and an implantable glucose monitoring probe are proposed.

[0012] On the one hand, the technical solution provided by the present application is as follows: an implantable laminated probe, comprising a flexible substrate, a plurality of functional electrodes and a plurality of insulating layers, the functional electrodes comprising a conductive area and a working area, the conductive area and the working area being electrically connected, the functional electrode stack being arranged on the flexible substrate, the insulating layer being arranged between adjacent functional electrodes to achieve interlayer isolation, the conductive area of ​​the functional electrode comprising an implanted conductive area implanted in a human body and a non-implanted conductive area not implanted in a human body, the implanted conductive area being a carbon circuit layer, the non-implanted conductive area being a silver circuit layer, the silver circuit layer and the carbon circuit layer forming a series structure.

[0013] By adopting the above technical solution, the present application divides the conductive area of ​​the functional electrode into two parts, an implanted conductive area implanted in the human body and a non-implanted conductive area not implanted in the human body. The implanted conductive area is a carbon circuit layer, and the non-implanted conductive area is a silver circuit layer. The carbon circuit layer has good biocompatibility and the silver circuit layer has low resistance and high signal transmission efficiency. The circuit impedance of the functional electrode is effectively reduced, the signal transmission efficiency is improved, and the biocompatibility and long-term stability of the implanted area are ensured. The silver circuit layer and the carbon circuit layer form a series structure to ensure the path of the conductive area. Whether it is a carbon circuit layer or a silver circuit layer, it can be made using silk screen technology, and combined with CCD automatic capture point technology, it can ensure high precision of position, shape and thickness, and effectively reduce the short circuit, circuit breakage or discontinuity problems caused by traditional processes. Functional electrodes with different functions are set on both sides of the flexible substrate of this embodiment. The functional electrodes on the same surface are also laminated to improve the space utilization of the flexible substrate and reduce the width of the laminated probe. High-purity carbon materials are used in the implantation area to reduce the doping of metal impurities, effectively eliminate the interference of miscellaneous peaks in electrochemical testing, and improve the purity of electrochemical signals and detection accuracy.

[0014] Preferably, the multiple functional electrodes include a working electrode, a reference electrode and a counter electrode, the working areas of the working electrode and the reference electrode are provided with sensitive materials, the implanted conductive area of ​​the counter electrode is the working area, the working electrode and the reference electrode are arranged on the front side of the flexible substrate from the inside to the outside, and the counter electrode is arranged on the back side of the flexible substrate.

[0015] Preferably, a contact area for the counter electrode is provided on the front side of the flexible substrate, and the contact area for the counter electrode is a silver layer. A conductive through hole is provided at a position of the flexible substrate corresponding to the contact area for the counter electrode, for accommodating silver paste, so that the counter electrode on the back side of the flexible substrate and the contact area for the counter electrode on the front side are electrically conductive.

[0016] Preferably, the tails of the working electrode and the reference electrode are contact areas electrically connected to external electronic devices, and the contact areas are covered with an anti-oxidation coating.

[0017] Preferably, the flexible substrate is made of polyimide or polyethylene terephthalate; the sensitive material on the working electrode is PEDOT, carbon nanotubes, platinum carbon or gold; the sensitive material on the reference electrode is silver chloride; and the insulating layer is insulating UV light-curing glue.

[0018] Preferably, the surface of the sensitive material of the working electrode is processed by ultraviolet picosecond laser to form a micropore array for loading the enzyme layer, the depth of the micropore array is less than the thickness of the sensitive material, and the sensitive material on the working electrode is also covered with a layer of biocompatible film.

[0019] Preferably, the enzyme layer is made of a mixture of nanowires and a conductive medium.

[0020] Preferably, both sides of the tail of the flexible substrate are also provided with plug-in buckle fixing structures for quick installation and removal with external electronic equipment.

[0021] Preferably, the functional electrodes and the insulating layer are both formed by a laminated silk screen printing process.

[0022] On the other hand, the present application also discloses another technical solution: an implantable glucose monitoring probe, comprising the implantable laminated probe described above.

[0023] In summary, the present application includes at least one of the following beneficial technical effects: 1. In the present application, the conductive area of ​​the functional electrode is divided into two parts, the implanted conductive area is the carbon circuit layer, and the non-implanted conductive area is the silver circuit layer, which fully utilizes the good biocompatibility of the carbon circuit layer and the small resistance and high signal transmission efficiency of the silver circuit layer, effectively reduces the circuit impedance of the functional electrode, improves the signal transmission efficiency, and ensures the biocompatibility and long-term stability of the implanted area. The silver circuit layer and the carbon circuit layer form a series structure to ensure the path of the conductive area.

[0024] 2. In the present application, functional electrodes with different functions are arranged on both sides of the flexible substrate, and the functional electrodes on the same surface are stacked to improve the space utilization of the flexible substrate and reduce the width of the stacked probes.

[0025] 3. The implantable laminated probe of the present application effectively solves the problems of uneven enzyme layer and low enzyme catalytic efficiency through precise array micropore processing and enzyme layer fixation technology, solves the problem of electrochemical impurity peaks by using high-purity carbon ink, and solves the problems of low processing accuracy and insufficient quality control of functional electrodes and probe shapes by high-precision laser processing, thereby ensuring that the electrodes can be mass-produced with high performance and high stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 A front perspective view of the implantable laminated probe described in the embodiment of the present application is depicted; Figure 2 A back stereoscopic view of the implantable laminated probe described in an embodiment of the present application is depicted; Figure 3 Draws Figure 1 Enlarged view of point A in the middle; Figure 4 A schematic diagram of the exploded structure of the implantable laminated probe described in the embodiment of the present application is depicted; Figure 5 A schematic diagram of the action of screen printing the non-implanted conductive area of ​​the counter electrode onto the flexible substrate according to an embodiment of the present application is depicted; Figure 6 A schematic diagram of the action of screen printing the implanted conductive area of ​​the counter electrode onto the flexible substrate in an embodiment of the present application is depicted; Figure 7 A schematic diagram of the action of screen printing an insulating layer onto the back of a flexible substrate according to an embodiment of the present application is depicted; Figure 8 A schematic diagram of the action of screen-printing the contact portion of the counter electrode and the non-implanted conductive area of ​​the working electrode onto the flexible substrate according to an embodiment of the present application is depicted; Fig. 9 A schematic diagram of the operation of screen printing the implanted conductive region of the working electrode onto the flexible substrate in an embodiment of the present application is depicted; Fig.10 A schematic diagram of the action of screen printing an insulating layer onto the front side of a flexible substrate according to an embodiment of the present application is depicted; Fig.11 A schematic diagram of the action of screen-printing the non-implanted conductive area of ​​the reference electrode onto the flexible substrate according to an embodiment of the present application is depicted; Fig.12 A schematic diagram of the action of screen-printing the implanted conductive area of ​​the reference electrode onto the flexible substrate according to an embodiment of the present application is depicted; Fig.13 A schematic diagram of the action of screen printing an insulating layer onto the front side of a flexible substrate according to an embodiment of the present application is depicted; Fig.14 A schematic diagram of the action of screen-printing the working area of ​​the reference electrode onto the front surface of the flexible substrate in an embodiment of the present application is depicted; Fig.15 A schematic diagram of the operation of screen printing the working area of ​​the working electrode onto the front surface of the flexible substrate in an embodiment of the present application is depicted; Fig.16 A schematic diagram showing the processing of the array of micropores in the working area of ​​the working electrode according to the embodiment of the present application is depicted; Fig.17 A schematic diagram of filling an enzyme layer in the micropores of a working electrode according to an embodiment of the present application is depicted; Fig.18 A schematic diagram of the action of screen-printing an anti-oxidation coating on the contact areas of the counter electrode, the working electrode and the reference electrode in an embodiment of the present application is depicted.

[0027] Explanation of the reference numerals: 1. flexible substrate; 11. conductive through hole; 12. plug-in snap-fit ​​fixing structure; 2. working electrode; 21. conductive area; 211. implanted conductive area; 212. non-implanted conductive area; 213. contact area; 22. working area; 221. micropore array; 3. reference electrode; 31. conductive area; 311. implanted conductive area; 312. non-implanted conductive area; 32. working area; 33. contact area; 4. counter electrode; 41. conductive area; 411. implanted conductive area; 412. non-implanted conductive area; 42. contact area; 5. insulating layer; 6. antioxidant coating; 7. enzyme layer. DETAILED DESCRIPTION

[0028] The following is combined with Figures 1 to 18 This application is described in further detail.

[0029] The present application discloses an implantable laminated probe, which is suitable for a detection electrode of a plug-in rapid detection device, such as an implantable continuous glucose monitoring probe.

[0030] Reference Figures 1 to 4 The implantable laminated probe includes a flexible substrate 1, a plurality of functional electrodes and a plurality of insulating layers 5. The functional electrode includes a conductive area and a working area, the conductive area and the working area are electrically connected, the functional electrode stack is arranged on the flexible substrate 1, and the insulating layer 5 is arranged between adjacent functional electrodes to achieve interlayer isolation. The conductive area of ​​the functional electrode includes an implanted conductive area implanted in the human body and a non-implanted conductive area not implanted in the human body. The implanted conductive area is a carbon circuit layer, and the non-implanted conductive area is a silver circuit layer. The silver circuit layer and the carbon circuit layer form a series structure.

[0031] The present application divides the conductive area of ​​the functional electrode into two parts, an implanted conductive area implanted in the human body and a non-implanted conductive area not implanted in the human body. The implanted conductive area is a carbon circuit layer, and the non-implanted conductive area is a silver circuit layer. The carbon circuit layer has good biocompatibility and the silver circuit layer has low resistance and high signal transmission efficiency. The circuit impedance of the functional electrode is effectively reduced, the signal transmission efficiency is improved, and the biocompatibility and long-term stability of the implanted area are ensured. The silver circuit layer and the carbon circuit layer form a series structure to ensure the path of the conductive area. Whether it is a carbon circuit layer or a silver circuit layer, it can be made using silk screen technology, and combined with CCD automatic capture point technology, it can ensure high precision of position, shape and thickness, and effectively reduce the short circuit, circuit breakage or discontinuity problems caused by traditional processes. In this embodiment, functional electrodes with different functions are set on both sides of the flexible substrate 1. The functional electrodes on the same surface are also laminated to improve the space utilization of the flexible substrate 1 and reduce the width of the laminated probe. High-purity carbon materials are used in the implanted area to reduce the doping of metal impurities, effectively eliminate the interference of miscellaneous peaks in electrochemical testing, and improve the purity and detection accuracy of electrochemical signals.

[0032] Reference Figure 4Taking the implantable laminated probe for the implantable continuous glucose monitoring probe as an example, the multiple functional electrodes include a working electrode 2, a reference electrode 3 and a counter electrode 4. The working areas 22 and 32 of the working electrode 2 and the reference electrode 3 are both provided with sensitive materials. The implanted conductive area 411 of the counter electrode 4 is the working area. The working electrode 2 and the reference electrode 3 are arranged on the front side of the flexible substrate 1 from the inside to the outside, and the counter electrode 4 is arranged on the back side of the flexible substrate 1. Since the working principles of the working electrode 2, the reference electrode 3 and the counter electrode 4 and various molding methods have been introduced in the prior art, they will not be described in detail here.

[0033] Reference Figure 4 The front side of the flexible substrate 1 is provided with a contact area 42 of the counter electrode 4, and the contact area 42 of the counter electrode 4 is a silver layer. The flexible substrate 1 is provided with a conductive through hole 11 at a position corresponding to the contact area 42 of the counter electrode 4, which is used to contain silver paste so that the counter electrode 4 on the back side of the flexible substrate 1 and the contact area 42 of the counter electrode 4 on the front side are electrically connected. The silver ink of the contact area 42 of the counter electrode 4 will penetrate into the conductive through hole 11, thereby realizing the conductive connection between the counter electrode 4 on the back side and the contact area 42 on the front side, increasing the integration of functional electrodes, and meeting the requirements of high-density functional electrodes.

[0034] Reference Figure 4 The tails of the working electrode 2 and the reference electrode 3 are contact areas 213 and 33 electrically connected to external electronic devices, and the contact areas 213 and 33 are covered with an anti-oxidation coating 6. The material of the anti-oxidation coating 6 is usually a polymer coating with high chemical stability and anti-oxidation performance, which can enhance the anti-oxidation ability and durability of the functional electrode during long-term use or plug-in test links.

[0035] In this embodiment, the flexible substrate 1 is made of polyimide or polyethylene terephthalate; the sensitive material on the working electrode 2 is PEDOT, carbon nanotubes, platinum carbon or gold; the sensitive material on the reference electrode 3 is silver chloride; the insulating layer 5 is an insulating UV light-curing glue. By superimposing multiple layers of UV light-curing insulating layers 5, effective isolation between the conductive layers is ensured, circuit short circuit and signal interference are prevented, and the electrical stability and overall reliability of the functional electrode structure are improved.

[0036] Reference Figure 3 and Figure 4The surface of the sensitive material of the working electrode 2 is processed by ultraviolet picosecond laser to form a micropore array 221 for loading the enzyme layer 7. The depth of the micropore array 221 is less than the thickness of the sensitive material. The array micropores are evenly distributed and will not burn through the sensitive material of the working electrode 2, and will not damage the flexible substrate 1. The sensitive material on the working electrode 2 is also covered with a layer of biocompatible film, which has excellent biocompatibility, flexibility and chemical resistance, provides good biocompatibility and mechanical protection, effectively reduces immune rejection after implantation, protects the enzyme layer 7 of the working electrode 2, prevents interferences in body fluids (such as uric acid, ascorbic acid) from affecting the detection signal, and can effectively reduce external environmental interference.

[0037] In this embodiment, the enzyme layer 7 is made of a mixture of nanowires and a conductive medium. The nanowires can be conductive nanowires, carbon nanotubes, etc., which can significantly reduce the catalytic potential of the enzyme, improve the reaction sensitivity of the working electrode 2, and enhance the stability of enzyme attachment, effectively reducing the shedding of the enzyme layer 7.

[0038] Reference Figure 1 The two sides of the tail of the flexible substrate 1 are also provided with plug-in buckle fixing structures 12 for quick installation and removal with external electronic devices.

[0039] In this embodiment, the functional electrodes and the insulating layer 5 are both formed by a laminated screen printing process.

[0040] The method for making the implantable laminated probe described in this embodiment is as follows: Figures 5 to 18 , including the following steps: S1, provide a full version of the flexible substrate 1 material, and make conductive through holes 11 on the flexible substrate 1 material. The conductive through holes 11 are arranged in an array, and the number of conductive through holes 11 in each group can be multiple to increase the conductive cross-sectional area. This process has high processing efficiency and can realize mass production of implantable laminated probes. The conductive through holes 11 can be processed by microsecond laser engraving technology. The purpose of setting the conductive through holes 11 is to enable electrical connection between the back and front parts of the electrode 4. The preferred diameter size of the conductive through holes 11 is 50-100μm, and the number is preferably 3. In order to see the detailed structure clearly, the accompanying drawings of this embodiment take a single laminated electrode as an example for illustration.

[0041] S2, reference Figure 5 The non-implanted conductive area 412 of the electrode 4 is screen-printed on the back of the flexible substrate 1 material. The material is silver ink. The thickness of the silver ink is preferably 10-50 μm, and then it is dried and cured. The preferred temperature is 120-150° C. and the time is 5-10 minutes.

[0042] S3, refer to Figure 6, the implanted conductive area 411 of the counter electrode 4 is screen printed on the back of the flexible substrate 1 material, the material is carbon ink, the thickness of the carbon ink is preferably 10-50 μm, and then dried and cured, preferably at a temperature of 90-120° C., for 8-12 minutes. Steps S2 and S3 can be interchanged. Since it is divided into two screen printings, it is preferably combined with CCD capture point technology to ensure high-precision positioning.

[0043] S4, ref. Figure 7 , the insulating layer 5 is screen-printed on the back of the flexible substrate 1 material, and uniform coating should be ensured. The material of the insulating layer 5 is preferably UV light-cured insulating layer 5, and then UV light is irradiated to cure to ensure insulation performance and mechanical protection effect. The insulating layer 5 should cover most of the conductive area 41 of the electrode 4, and only be properly exposed in the working area to avoid short circuit and signal interference. The preferred thickness of the insulating layer 5 is 5-20μm, the wavelength of the UV light source is 365nm, the energy intensity is 100-150mJ / cm², and the illumination time is 10-30 seconds.

[0044] Since this application needs to be divided into multiple screen printings, it is preferred to combine CCD point capture technology to ensure high-precision positioning. Each screen printing must be dried to ensure that the ink cures quickly and has high adhesion. Therefore, after the screen printing and curing steps, quality control steps can be added, such as checking the shape accuracy and integrity of the coating through the AOI system to ensure that the silver circuit layer area is not exposed and the working area is not covered, or adding manual sampling to ensure that the surface is smooth and pinhole-free after UV curing to ensure insulation effect and stability.

[0045] S5, refer to Figure 8 , flip the flexible substrate 1 material, and screen print the contact area 42 of the counter electrode 4 and the non-implanted conductive area 212 of the working electrode 2 on the front side of the flexible substrate 1 material, the material is silver ink, the thickness of the silver ink is preferably 10-50μm, and then dry and solidify, preferably at a temperature of 120-150℃, for 5-10 minutes. The silver ink in the contact area 42 of the counter electrode 4 will penetrate into the conductive through hole 11, thereby achieving the conductive connection between the counter electrode 4 on the back and the contact area 42 on the front, increasing the integration of the functional electrodes and meeting the requirements of high-density functional electrodes.

[0046] S6, ref. Fig. 9 The conductive region 211 of the working electrode 2 is screen printed on the front of the flexible substrate 1. The material is carbon ink. The thickness of the carbon ink is preferably 10-50 μm. The carbon ink is then dried and cured. The preferred temperature is 90-120° C. and the time is 8-12 minutes. Steps S5 and S6 can be interchanged.

[0047] S7, reference Fig.10, the first insulating layer 5 is screen printed on the front of the flexible substrate 1 material. The first insulating layer 5 should cover most of the conductive area 21 of the working electrode 2 and part of the flexible substrate 1, so that the working electrode 2 and the reference electrode 3 can be isolated from each other and uniformly coated. The material of the insulating layer 5 is preferably UV light-cured insulating layer 5, and then UV light is irradiated to cure, to ensure insulation performance and mechanical protection effect, and to avoid short circuit and signal interference. The preferred thickness of the insulating layer 5 is 5-20μm, the wavelength of the UV light source is 365nm, the energy intensity is 100-150mJ / cm², and the illumination time is 10-30 seconds.

[0048] S8, refer to Fig.11 The non-implanted conductive area 312 of the reference electrode 3 is screen-printed on the front side of the flexible substrate 1 material. The material is silver ink. The thickness of the silver ink is preferably 10-50 μm, and then it is dried and cured. The preferred temperature is 120-150° C. and the time is 5-10 minutes.

[0049] S9, reference Fig.12 The conductive region 311 of the reference electrode 3 is screen printed on the front of the flexible substrate 1. The material is carbon ink. The thickness of the carbon ink is preferably 10-50 μm. The carbon ink is then dried and cured. The preferred temperature is 90-120° C. and the time is 8-12 minutes. Steps S8 and S9 can be interchanged.

[0050] S10, refer to Fig.13 , the second insulating layer 5 is screen-printed on the front of the flexible substrate 1 material. The second insulating layer 5 should cover most of the conductive area 31 of the reference electrode 3, exposing the working area 32 of the reference electrode 3, ensuring the insulation performance and mechanical protection effect, and avoiding short circuit and signal interference. To ensure uniform coating, the material of the insulating layer 5 is preferably UV light-cured insulating layer 5, and then UV light is irradiated for curing. The preferred thickness of the insulating layer 5 is 5-20μm, the wavelength of the UV light source is 365nm, the energy intensity is 100-150mJ / cm², and the illumination time is 10-30 seconds.

[0051] S11, reference Fig.14 , the sensitive material is screen-printed in the working area 32 of the reference electrode 3. The sensitive material can be silver chloride, which should be printed evenly and without defects to ensure that the sensitive material is well connected to the conductive area 31 of the reference electrode 3. The thickness of the silver chloride is preferably 10-30 μm, and then it is dried and cured, the temperature is preferably 120-150° C., and the drying time is 5-10 minutes.

[0052] S12, refer to Fig.15, the sensitive material is screen-printed in the working area 22 of the working electrode 2. The sensitive material can be PEDOT, carbon nanotubes, platinum carbon or gold materials. The printing should be uniform, without pinholes, bubbles, stratification or missing. It is necessary to ensure that the sensitive material is well connected with the conductive area 21 of the working electrode 2 to form a functional layer and give high-performance catalytic and electrochemical detection capabilities. The thickness of the sensitive material is preferably 5-20 μm, and then it is dried and cured. The temperature is preferably 90-120°C and the drying time is 5-10 minutes.

[0053] S13, refer to Fig.16 , array micropores are processed in the working area 22 of the working electrode 2, preferably using ultraviolet picosecond laser processing equipment, the array micropores are evenly distributed and will not burn through the sensitive material of the working electrode 2, nor will they damage the flexible substrate 1, and provide a precise area for the attachment of the enzyme layer 7, the diameter of the array micropores is 20-100μm; the depth of the micropores is 0.5-5μm, which can increase the specific surface area, improve the enzyme adhesion and catalytic efficiency. The microporous structure can significantly increase the specific surface area of ​​the working electrode 2, provide a precise area for enzyme attachment, improve adhesion, catalytic efficiency and uniformity of the reaction area, and effectively improve the reaction sensitivity of the working electrode 2.

[0054] S14, refer to Fig.17 , make enzyme layer 7 (enzyme fixation), use CCD grabbing technology combined with high-precision enzyme spotting machine to accurately spot enzyme materials (such as glucose oxidase or peroxidase) in the array micropores to ensure uniform distribution and stable attachment of enzyme layer 7. The enzyme solution is made of conductive nanowires (such as conductive nanowires, carbon nanotubes, etc.) and conductive media, which can significantly reduce the catalytic potential of the enzyme, improve the reaction sensitivity of the working electrode 2, and enhance the stability of enzyme attachment, effectively reduce the shedding of enzyme layer 7, and extend the service life of the probe. The spot coating amount of each micropore is preferably 0.1-0.5μL, the drying temperature is 40℃, and the time is 10 minutes.

[0055] S15, coating the working area 22 of the working electrode 2 with a biocompatible film; the equipment can use a sprayer, a variety of spraying methods, through air spraying, atomization spraying or electrostatic spraying technology, the biocompatible film can use PVP (polyvinyl pyrrolidone), PU (polyurethane), NAFION and other biocompatible films, the film layer has excellent biocompatibility, flexibility and chemical resistance, provides good biocompatibility and mechanical protection, effectively reduces immune rejection after implantation, protects the enzyme layer 7 of the working electrode 2, prevents interference from body fluids (such as uric acid, ascorbic acid) from affecting the detection signal, can effectively reduce external environmental interference, and is very suitable for medical applications such as biosensors to improve the stability and biocompatibility of the working electrode 2 in the biological environment and extend the service life of the probe. The preferred thickness of the biocompatible film is 10-50μm, and the thickness can be adjusted according to actual application requirements to ensure that the film layer is uniform and does not affect the performance of the working electrode 2).

[0056] S16, ref. Fig.18 , the contact areas 213, 33 at the tail of the working electrode 2 and the reference electrode 3, as well as the contact area 42 of the counter electrode 4 are covered with an antioxidant coating 6. The antioxidant coating 6 can enhance the antioxidant ability and durability of the functional electrode during long-term use or plug-in test links. The material of the antioxidant coating 6 is usually a polymer coating with high chemical stability and antioxidant properties, such as epoxy resin, polyvinyl difluoride (PVDF) or other polymer materials. The coating thickness is generally controlled at 5-20μm to ensure that the coating is uniform and does not affect the conductive properties of the functional electrode. After coating, the antioxidant coating 6 needs to be cured to enhance its durability and stability; the curing temperature is preferably 80-120°C, and the curing time is 5-15 minutes to ensure that the antioxidant coating 6 is completely cured to achieve the best antioxidant effect, which is specifically adjusted according to the characteristics of the coating material.

[0057] S17, using the ultraviolet picosecond laser engraving process, the functional electrode of the probe is precisely engraved to ensure the consistency of the size and structure of the functional electrode. This process meets the strict requirements of implantable electrodes for miniaturization and high-precision shape processing and is suitable for large-scale batch production. The laser power is preferably 1-10 W (set according to the substrate material), the engraving accuracy is ±10μm; the engraving speed is 100-300 mm / s.

[0058] S18, dividing the entire stacked probe into individual stacked probes.

[0059] After each layer of conductive material and insulating layer 5 is screen-printed in the present application, it is subjected to high-temperature curing treatment, which can significantly enhance the adhesion and conductivity of the ink, avoid interlayer shedding problems, and enhance the overall structural stability and reliability.

[0060] The implantable laminated probe and its manufacturing method of the present application innovatively introduce a silver-carbon series circuit manufacturing process, an ultraviolet picosecond laser micropore processing process, a precise enzyme point process, a biocompatible film coating process, and an ultraviolet picosecond laser engraving molding process, which comprehensively improves the manufacturing accuracy, enzyme fixation uniformity, electrochemical performance, biocompatibility and production efficiency of the implantable laminated probe. These key technical points not only solve many technical bottlenecks in traditional processes, but also ensure the high performance and high stability of the functional electrodes through multi-level protection measures, thereby realizing the wide application and commercial production of laminated probes in the fields of CGM and plug-in rapid detection. More specifically, by optimizing the conductive material combination of the functional electrode, the problems of high impedance and low signal transmission efficiency in the traditional technology are effectively solved. The problems of uneven enzyme layer 7 and low enzyme catalytic efficiency are effectively solved through precise array micropore processing and enzyme layer 7 fixation technology. By using high-purity carbon ink, the problem of electrochemical impurities is solved. By using high-precision laser processing, the problems of low processing accuracy and insufficient quality control of the functional electrodes and probes are solved, ensuring that the electrodes can be mass-produced with high performance and high stability, and are suitable for medical health monitoring, clinical diagnosis, environmental monitoring and other electrochemical detection applications requiring high sensitivity and high stability.

[0061] In order to further enhance the applicability and flexibility of the present invention, the following material alternatives are provided. These alternatives are mainly aimed at replacing key materials, aiming to adapt to different application requirements and production conditions. Although they may not be better in all cases, they can be selected and adjusted according to specific needs. In addition, the laminated probe of the present invention is not only suitable for the field of continuous glucose monitoring (CGM), but can also be widely used in the field of plug-in rapid detection, such as body fluid analysis, environmental monitoring and clinical diagnosis.

[0062] 1. Alternative options for conductive materials: Pure carbon materials replace carbon-silver mixed materials. In some application scenarios, pure carbon (Pure Carbon) can be used to replace carbon and silver mixed materials. Pure carbon materials have good biocompatibility and conductivity, and are suitable for electrochemical detection applications that need to reduce interference from metal impurities. Although the conductivity of pure carbon materials may be slightly lower than that of carbon-silver mixed materials, they have advantages in reducing electrochemical impurity peaks.

[0063] Alternative silver materials: Copper has excellent electrical conductivity and low cost, and can be used as an alternative to silver for conductive lines in non-implanted areas. However, copper is easily oxidized, so appropriate protective measures must be taken during use to ensure its stability. Gold has excellent electrical conductivity and chemical stability, and can replace silver for conductive lines with high stability requirements. Although gold is more expensive, its corrosion resistance in long-term use gives it a unique advantage in some high-end applications.

[0064] 2. Alternative options for biocompatible membrane materials: Materials that replace PVP, PU, ​​and Nafion, Polyvinyl Alcohol (PVA): PVA has good biocompatibility and controllable film thickness, and is suitable as a biocompatible film material to provide a protective layer and reduce immune response. Polymethyl methacrylate (PMMA), the PMMA film layer has high transparency and good mechanical strength, and can be used to protect the electrode structure while providing the necessary biocompatibility. Biodegradable polymers (such as polylactic acid-glycolic acid copolymer, PLGA): Suitable for sensor designs that need to be gradually degraded in the body, providing short-term protection and naturally degrading after the sensor fails, reducing long-term effects on the human body.

[0065] 3. Alternative options for sensitive materials: Graphene is a material that replaces PEDOT, platinum carbon, carbon nanotubes, and polyaniline. Graphene has extremely high conductivity and flexibility, and is suitable for sensitive materials of working electrodes. Its two-dimensional structure provides a larger specific surface area, which helps to fix enzymes and improve the efficiency of electrochemical reactions. Conductive polymers (such as polypyrrole) have good conductivity and adjustable chemical properties, and are suitable as alternative sensitive materials to meet different electrochemical detection needs.

[0066] 4. Alternative options for insulation materials: Materials that replace UV light-curing polymers: Epoxy resin: Epoxy resin has excellent mechanical strength and chemical stability and can be used as an alternative material for the insulation layer to provide effective electrical isolation and mechanical protection. Silicone rubber: Silicone rubber has good elasticity and chemical resistance and is suitable as a flexible insulation layer material to provide additional flexibility and durability.

[0067] 5. Alternative options for anti-oxidation coating 6 materials: Silicon Nitride (Si3N4) is a material that replaces epoxy resin and polyvinyl difluoride (PVDF). Silicon nitride has excellent oxidation resistance and chemical stability, and is suitable as an antioxidant coating material to provide an efficient protective layer. Aluminum Oxide (Al2O3): Aluminum oxide has good mechanical strength and oxidation resistance, and can be used to replace polyvinyl difluoride (PVDF) to provide strong antioxidant protection.

[0068] 6. Alternative options for flexible substrate materials: Materials that replace polyimide (PI) and polyethylene terephthalate (PET), PolyetherEther Ketone (PEEK): PEEK has excellent mechanical properties and chemical stability, and is suitable for applications that require higher strength and temperature resistance. Polyurethane (PU): Polyurethane provides higher flexibility and elasticity, and is suitable for implantable sensor designs that require greater flexibility and bendability. Stretchable polymers (such as polydimethylsiloxane, Polydimethylsiloxane, PDMS): Suitable for sensors that require highly soft and stretchable properties, providing better fit and comfort.

[0069] VII. Alternatives for enzyme immobilization auxiliary materials Materials that replace cross-linkers, cross-linker-free fixation method: Enzymes are fixed by physical adsorption or charge interaction, without the need for chemical cross-linkers, simplifying process steps and reducing the risk of chemical residues. Biocompatible adhesives: Use natural or synthetic biocompatible adhesives, such as gelatin or chitosan, to assist enzyme fixation and enhance the stability and adhesion of the enzyme layer.

[0070] 8. Expansion of the application field of stacked probes: Plug-in rapid detection field: In addition to continuous glucose monitoring (CGM), the laminated probe of the present invention is also suitable for plug-in rapid detection fields, such as body fluid analysis (blood, urine, etc.), environmental monitoring (air, water quality, etc.) and clinical diagnosis (biomarker detection, etc.). By flexibly adjusting the electrode material and membrane layer design, different detection environments and needs can be met, and the development of multifunctional sensors can be realized.

[0071] The above are all preferred embodiments of the present application, and the protection scope of the present application is not limited thereto. Therefore, any equivalent changes made according to the structure, shape, and principle of the present application should be included in the protection scope of the present application.

Claims

1. An implantable laminated probe, comprising a flexible substrate, a plurality of functional electrodes and a plurality of insulating layers, wherein the functional electrodes comprise a conductive area and a working area, the conductive area and the working area are electrically connected, the functional electrodes are laminated on the flexible substrate, the insulating layer is arranged between adjacent functional electrodes to achieve interlayer isolation, the conductive area of ​​the functional electrodes comprises an implanted conductive area implanted in a human body and a non-implanted conductive area not implanted in a human body, characterized in that: The implanted conductive area is a carbon circuit layer, the non-implanted conductive area is a silver circuit layer, and the silver circuit layer and the carbon circuit layer form a series structure.

2. The implantable laminated probe according to claim 1, characterized in that: The multiple functional electrodes include working electrodes, reference electrodes and counter electrodes. The working areas of the working electrodes and the reference electrodes are provided with sensitive materials. The implanted conductive area of ​​the counter electrode is the working area. The working electrodes and the reference electrodes are arranged on the front side of the flexible substrate from the inside to the outside, and the counter electrode is arranged on the back side of the flexible substrate.

3. The implantable laminated probe according to claim 2, characterized in that: A contact area for an electrode is provided on the front side of the flexible substrate, and the contact area for the electrode is a silver layer. A conductive through hole is provided at a position of the flexible substrate corresponding to the contact area for the electrode, for accommodating silver paste, so that the electrode on the back side of the flexible substrate and the contact area for the electrode on the front side are electrically connected.

4. The implantable laminated probe according to claim 3, characterized in that: The tails of the working electrode and the reference electrode are contact areas electrically connected to external electronic devices, and the contact areas are covered with an anti-oxidation coating.

5. The implantable laminated probe according to claim 2, characterized in that: The flexible substrate is made of polyimide or polyethylene terephthalate; the sensitive material on the working electrode is PEDOT, carbon nanotubes, platinum carbon or gold; the sensitive material on the reference electrode is silver chloride; The insulating layer is insulating UV light-curing glue.

6. The implantable laminated probe according to claim 2, characterized in that: The surface of the sensitive material of the working electrode is processed into a micropore array by ultraviolet picosecond laser for loading the enzyme layer. The depth of the micropore array is less than the thickness of the sensitive material. The sensitive material on the working electrode is also covered with a biocompatible film.

7. The implantable laminated probe according to claim 6, characterized in that: The enzyme layer is made of a mixture of nanowires and a conductive medium.

8. The implantable laminated probe according to claim 1, characterized in that: Both sides of the tail of the flexible substrate are also provided with plug-in buckle fixing structures for quick installation and removal with external electronic equipment.

9. The implantable laminated probe according to claim 1, characterized in that: The functional electrodes and the insulating layer are both formed by a laminated silk screen printing process.

10. An implantable glucose monitoring probe, characterized in that: An implantable laminated probe comprising any one of claims 1 to 9.

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