Monitoring electrode for physiological parameters

Abstract

The present disclosure describes a physiological parameter monitoring electrode, comprising a substrate layer, a pattern layer, a conductive layer, and a sensing part, the substrate layer is made of an insulating material, the pattern layer is arranged on the substrate layer and forms a predetermined pattern, the predetermined pattern comprises a plurality of openings, the conductive layer is arranged on the pattern layer as a whole and covers the plurality of openings to form a plurality of limiting grooves, and the sensing part is formed by respectively dropping and coating a sensitive reagent in the plurality of limiting grooves and curing. According to the present disclosure, a complex surface treatment method is not required to obtain the same wetting angle of the liquid drop, but the limiting grooves are formed on the surface of the monitoring electrode, the dropped and coated sensitive reagent is accommodated in the limiting grooves and forms the same topography as the limiting grooves, so that the consistency of the area and topography of the sensing part in the monitoring electrode in mass production can be conveniently controlled, and the sensor with consistent process parameters is obtained.

Description

[0001] This application is a divisional application of the patent application filed on March 11, 2020, with application number 202010168104.9, entitled "Working Electrode of Glucose Sensor". Technical Field

[0002] This disclosure generally relates to the field of biosensors, and more particularly to an electrode for monitoring physiological parameters. Background Technology

[0003] Diabetes is a metabolic disease characterized by high blood sugar. Currently, there is no cure, and diabetic patients often manage their condition by monitoring their blood sugar. The main methods of blood sugar monitoring include traditional blood glucose monitoring and continuous glucose monitoring (CGM). Compared to traditional blood glucose monitoring, CGM technology can typically monitor a patient's blood sugar continuously for at least 24 hours, providing real-time information on the patient's blood sugar levels throughout the day, effectively reflecting hypoglycemia and blood sugar fluctuations. Continuous glucose monitoring can be achieved using glucose sensors.

[0004] A glucose sensor typically consists of a sensor probe and a processing device that records the sensor information. During continuous glucose monitoring (CGM), the sensor probe is often implanted subcutaneously. The working electrode of the probe contains a glucose-sensitive reagent that reacts specifically with glucose molecules at the implantation site to generate an electrical signal. The processing device then processes this signal to obtain the blood glucose level and the patient's blood glucose changes.

[0005] To obtain accurate blood glucose values, the production of glucose sensors requires ensuring that all sensors manufactured in a batch have a consistent initial sensitivity for batch calibration. Therefore, to guarantee consistent initial sensitivity across batches of glucose sensors, consistency in process parameters, such as the area and morphology of the sensing element, is crucial. The sensing element is formed by drop-coating a glucose-sensitive reagent onto the conductive layer of the working electrode and then curing it.

[0006] In existing drop coating processes, the control of the drop coating solution is achieved by improving the surface roughness of the drop coating, thereby ensuring that the droplets have a consistent wetting angle on the surface, and thus controlling the area and morphology of the droplets. However, it is difficult to achieve completely uniform surface roughness in drop coating, which makes it difficult to guarantee the consistency of droplet area and morphology each time drop coating is performed. Consequently, it is difficult to ensure that each glucose sensor produced in batches has a consistently high initial sensitivity. Summary of the Invention

[0007] This disclosure was made in view of the above-mentioned situation, and its purpose is to provide a working electrode for a glucose sensor that can easily and conveniently control the area and morphological consistency of the droplets, which is beneficial to improving the consistency of the sensing parts of various glucose sensors produced in batches, thereby improving the consistency of the initial sensitivity of various glucose sensors produced in batches.

[0008] To this end, a first aspect of this disclosure provides a working electrode for a glucose sensor, comprising: a substrate layer made of an insulating material and pretreated to form a surface with a predetermined roughness; a patterned layer disposed on the substrate layer and having a predetermined pattern, the predetermined pattern including at least one opening arranged along a predetermined direction; a conductive layer disposed on the patterned layer, the conductive layer covering the at least one opening to form at least one limiting groove; and a sensing portion formed by dripping a predetermined amount of glucose-sensitive reagent onto the at least one limiting groove and then curing it.

[0009] In the working electrode of the glucose sensor disclosed in the first aspect, by forming a limiting groove of a certain shape on the surface of the working electrode, a predetermined amount of glucose-sensitive reagent can be contained in the limiting groove and form a morphology with the same shape as the limiting groove. This allows for convenient control of the consistency of the area and morphology of the sensing part in mass-produced working electrodes, resulting in glucose sensors with consistent process parameters. Furthermore, the morphology of the sensing part can be easily changed by altering the volume, shape, and amount of the limiting groove.

[0010] A second aspect of this disclosure provides a working electrode for a glucose sensor, comprising: a substrate layer made of an insulating material and pretreated to form a surface with a predetermined roughness; a conductive layer disposed on the substrate layer and having at least one locating groove arranged along a predetermined direction of the conductive layer, the at least one locating groove being formed by etching a groove to a predetermined depth in the conductive layer; and a sensing portion formed by drop-coating a predetermined amount of glucose-sensitive reagent into the at least one locating groove and then curing it, wherein the predetermined depth is less than the thickness of the conductive layer.

[0011] In the working electrode of the glucose sensor disclosed in the second aspect, by forming a limiting groove of a certain shape on the surface of the working electrode, a predetermined amount of glucose-sensitive reagent can be contained in the limiting groove and form a morphology with the same shape as the limiting groove. This allows for convenient control of the consistency of the area and morphology of the sensing part in mass-produced working electrodes, resulting in glucose sensors with consistent process parameters. Furthermore, the morphology of the sensing part can be easily changed by altering the volume, shape, and amount of the limiting groove.

[0012] Furthermore, in the working electrode of the glucose sensor according to the second aspect of this disclosure, optionally, the at least one limiting groove is formed by etching a groove of a predetermined depth into the conductive layer using a mask with a predetermined pattern. Thus, a limiting groove with a predetermined morphology can be formed by etching the conductive layer.

[0013] Furthermore, in the working electrode of the glucose sensor according to the first aspect of this disclosure, optionally, the thickness of the patterned layer is not less than the thickness of the conductive layer. This facilitates the conductive layer to be recessed at the openings in the patterned layer to form a limiting groove.

[0014] Additionally, in the working electrode of the glucose sensor disclosed herein, optionally, the at least one limiting groove is arranged in a straight line. This improves the drop-coating efficiency.

[0015] Additionally, in the working electrode of the glucose sensor disclosed herein, the limiting groove may optionally be a circular groove or an oval groove. This allows the glucose-sensitive reagent, which is drop-coated, to flow within the limiting groove and fill its edges to form the desired morphology.

[0016] Additionally, in the working electrode of the glucose sensor disclosed herein, optionally, a semi-permeable membrane for controlling the passage of glucose molecules is also covered on the sensing part. This allows for control of the number of glucose molecules passing through the semi-permeable membrane.

[0017] Alternatively, in the working electrode of the glucose sensor disclosed herein, the glucose-sensitive reagent may completely fill the limiting groove. In this case, the glucose-sensitive reagent is confined within the limiting groove, thereby enabling control over the area and morphology of the glucose-sensitive reagent.

[0018] Additionally, in the working electrode of the glucose sensor disclosed herein, optionally, the glucose-sensitive reagent is capable of chemically reacting with glucose, and the glucose-sensitive reagent includes glucosidase, a metal polymer, and a cross-linking agent. Thus, the glucose-sensitive reagent can be easily attached to the conductive layer's limiting groove and specifically react with glucose.

[0019] Additionally, in the working electrode of the glucose sensor disclosed herein, the conductive layer may optionally be made of at least one material selected from glassy carbon, graphite, silver, silver chloride, platinum, palladium, platinum-iridium, titanium, gold, or iridium. This results in good conductivity.

[0020] According to this disclosure, a working electrode for a glucose sensor can be provided that does not require the complex surface treatment methods of the prior art to obtain droplets with the same wetting angle. Instead, a limiting groove with a certain shape is formed on the surface of the working electrode. A predetermined amount of glucose-sensitive reagent can be contained in the limiting groove and form a morphology with the same shape as the limiting groove. This allows for convenient control of the consistency of the area and morphology of the sensing part in mass-produced working electrodes, resulting in a glucose sensor with consistent process parameters. Attached Figure Description

[0021] Figure 1 This is a schematic diagram showing the usage status of a glucose monitoring probe according to an embodiment of the present disclosure.

[0022] Figure 2 This is a planar structural diagram showing the glucose sensor according to an embodiment of the present disclosure.

[0023] Figure 3 It shows Figure 2 A schematic diagram of the glucose monitoring probe in a bent state.

[0024] Figure 4 This is a top view showing the working electrode involved in the embodiments of this disclosure.

[0025] Figure 5 It shows Figure 4 The cross-sectional view along the dashed line B-B' when the working electrode is covered with a semi-permeable membrane.

[0026] Figure 6 This is a cross-sectional view showing the working electrode according to the first embodiment of this disclosure.

[0027] Figures 7(a)-7(d) This is a schematic diagram illustrating the preparation process of the working electrode according to an embodiment of the present disclosure.

[0028] Figure 8 This is a schematic diagram illustrating the drop-coating step involved in an embodiment of the present disclosure.

[0029] Figure 9 This is a cross-sectional view showing the working electrode according to the second embodiment of this disclosure. Detailed Implementation

[0030] Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings. In the following description, the same reference numerals are used for the same parts, and repeated descriptions are omitted. Furthermore, the drawings are merely schematic diagrams, and the proportions of the parts or the shapes of the parts may differ from the actual figures.

[0031] Furthermore, the subheadings and similar terms used in the following description of this disclosure are not intended to limit the content or scope of this disclosure; they are merely intended to serve as reading prompts. Such subheadings should not be construed as dividing the content of the article, nor should the content under a subheading be limited to the scope of that subheading.

[0032] In this disclosure, the glucose sensor can be simply referred to as a "sensor," the probe of the glucose sensor can be simply referred to as a "probe," the working electrode of the glucose sensor can be simply referred to as a "working electrode," and the preparation method of the working electrode of the glucose sensor can be simply referred to as a "preparation method." Furthermore, the working electrode of the glucose sensor and its preparation and drop-coating method disclosed in this disclosure are not only applicable to glucose sensors but also to electrodes for monitoring other physiological parameters, such as uric acid detection sensors for detecting uric acid and cholesterol monitoring sensors for detecting cholesterol, simply by replacing the sensitive reagent in the sensing part of the working electrode with a corresponding enzyme that specifically reacts with its target analyte. In addition to electrodes for monitoring physiological parameters, the method of controlling the drop-coating morphology in this disclosure by forming a limiting groove of a predetermined shape with a volume matching the drop-coating amount at the drop-coating site is also applicable to other production processes requiring control of the drop-coating morphology.

[0033] Figure 1 This is a schematic diagram showing the usage status of a glucose monitoring probe according to an embodiment of the present disclosure. Figure 2 This is a planar structural diagram showing the glucose sensor according to an embodiment of the present disclosure. Figure 3 It shows Figure 2 A schematic diagram of the glucose monitoring probe in a bent state.

[0034] In this embodiment, the glucose sensor probe S may also be referred to as an implantable glucose monitoring probe, the probe S of a glucose monitor, or simply probe S.

[0035] In this embodiment, the portable glucose monitor G may include a glucose sensor probe S and an electronic system S' connected to the probe S. By implanting the probe S of the portable glucose monitor G into the body surface and bringing it into contact with the tissue fluid, the probe S can sense the glucose concentration signal of the tissue fluid. By transmitting this glucose concentration signal to the electronic system S', the corresponding glucose concentration can be obtained.

[0036] Specifically, a portion of the glucose sensor probe S (particularly the sensing part) can be implanted, for example, on the surface of the human body, and come into contact with the tissue fluid within the body. Additionally, another portion of the glucose sensor probe S is connected to an electronic system S' located on the body surface. When the portable glucose monitor G is operating, the glucose sensor probe S reacts with the tissue fluid within the body to generate a sensing signal (e.g., an electrical signal), and transmits this signal to the electronic system S' on the body surface. The electronic system S' processes the sensing signal to obtain the glucose concentration. Although... Figure 1 The location of the glucose sensor probe S is shown, but this embodiment is not limited to this. For example, the glucose sensor probe S can also be configured in the abdomen, waist, legs, etc.

[0037] In this embodiment, although the glucose sensor probe S directly detects glucose in the tissue fluid, the glucose concentration of the tissue fluid is strongly correlated with the glucose concentration of the blood, and the glucose concentration of the blood can be determined by the glucose in the tissue fluid.

[0038] In this embodiment, the glucose sensor probe S may include a working electrode 1, a reference electrode 2, and a counter electrode 3 (see...). Figure 2 In some examples, the working electrode 1, reference electrode 2, and counter electrode 3 may all have an insulating base layer 10 (described later) as a substrate. In some examples, the base layer 10 for the working electrode 1, reference electrode 2, and counter electrode 3 may be a single substrate or partially divided into three parts. Additionally, the glucose sensor probe S may include a contact 4 connected to the working electrode 1 via a lead, a contact 5 connected to the working electrode 2 via a lead, and a contact 6 connected to the reference electrode 3 via a lead. In some examples, the glucose sensor probe S may be connected to the electronic system 2 via contacts 4, 5, and 6.

[0039] In this embodiment, for ease of explanation, the glucose sensor probe S can be divided into a connecting portion Sa and an implanted portion Sb (see...). Figure 3 ). Figure 3 The straight line A-A' in the diagram roughly indicates the approximate location of the glucose sensor probe S in the skin when implanted into the tissue surface. After implantation, the implanted portion Sb is in the superficial layer of the skin, and the electronic system S' is closely attached to the skin surface. The connecting portion Sa of the glucose sensor probe S (see...) Figure 3 It is connected to the electronic system S' and located on the skin surface.

[0040] Figure 4 This is a top view showing the working electrode involved in the embodiments of this disclosure. Figure 5 It shows Figure 4 The cross-sectional view along line B-B' when the working electrode is covered with a semi-permeable membrane.

[0041] In the mass production of glucose sensors, the consistency of process parameters within the same batch is crucial. If the process parameters are consistent, individual calibration of each sensor within the batch is unnecessary; a factory batch calibration of the entire batch is sufficient. To achieve good process parameter consistency, it is necessary to control at least one of the following: the area and morphology of the sensing portion 30 of the working electrode 1, and the film thickness and diffusion coefficient of the conductive layer 20 and the semi-permeable membrane 40 on the sensing portion 30. The sensing portion 30 of the working electrode 1 is primarily formed through a drop-coating process. However, during drop-coating, the morphology and roughness of the drop-coated surface cannot be perfectly uniform, and the drop-coating reagent tends to flow irregularly on the surface, leading to uncontrollable area and morphology of the sensing portion 30 formed by the drop-coating of the glucose-sensitive reagent 310. Therefore, controlling the consistency of the area and morphology of the sensing portion 30 of the working electrode 1 is essential for achieving good process parameter consistency.

[0042] In this embodiment, the working electrode 1 may include: a substrate layer 10, which is made of an insulating material and has a pre-treated surface with a specified roughness; a conductive layer 20 having at least one limiting groove 210; and a sensing portion 30, which is formed by dripping a predetermined amount of glucose-sensitive reagent 310 onto at least one limiting groove 210 and then curing it (see [link]). Figure 4 ).

[0043] According to the working electrode 1 of the glucose sensor disclosed herein, instead of using complex surface treatment methods to obtain droplets with the same wetting angle, a limiting groove 210 of a certain shape is formed on the surface of the working electrode 1. A predetermined amount of glucose-sensitive reagent 310 can be contained in the limiting groove 210 and form a morphology identical to that of the limiting groove 210. This allows for convenient control of the consistency of the area and morphology of the sensing part 30 in mass-produced working electrodes 1, resulting in glucose sensors with consistent process parameters. Furthermore, by changing the volume, shape, and droplet amount of the limiting groove 210, the area and morphology of the sensing part 30 can be easily altered.

[0044] [First Implementation Method]

[0045] Figure 4 This is a top view showing the working electrode 1 according to an embodiment of the present disclosure. Figure 5 It shows Figure 4 The cross-sectional view along line B-B' of the working electrode 1 covered by a semi-permeable membrane. Figure 6 This is a cross-sectional view showing the working electrode 1 according to the first embodiment of the present disclosure.

[0046] (Basal layer 10)

[0047] In this embodiment, as described above, the working electrode 1 may include a substrate layer 10. In some examples, the substrate layer 10 may be made of an insulating material.

[0048] In some examples, the substrate 10 can be selected from flexible insulating materials. The flexible insulating material can be at least one of polyimide (PI), polyethylene terephthalate (PET), parylene, silicone resin, polydimethylsiloxane (PDMS), polyethylene glycol (PEG), or polytetrafluoroethylene resin (Teflon), polyethylene (PE), polypropylene (PP), polystyrene (PS), and polyethylene terephthalate (PEN). This allows the substrate 10 to possess both flexibility and insulation, reducing discomfort after implantation.

[0049] In other examples, the base layer 10 can be made of a non-flexible insulating material. Non-flexible materials can generally include ceramics, polymethyl methacrylate (PMMA), alumina, or silica. In this case, the base layer 10 can have excellent support properties. Furthermore, when the base layer 10 is a non-flexible insulating material, it can be made into an easily implantable shape, such as a needle tip. In this case, the probe including the working electrode 1 can be implanted into the body surface (e.g., superficial skin) without the need for an auxiliary implantation device (not shown) such as a needle applicator.

[0050] In this embodiment, in some examples, the surface of the substrate 10 can be pre-treated to achieve a specified roughness. Pre-treatment may include polishing, plasma gas cleaning, ultrasonic cleaning, nitrogen drying, etc. The specified roughness refers to the fact that the peak and valley dimensions of the uneven surface of the substrate 10 are much smaller than the dimensions of the opening 110 or the limiting groove 210. In some examples, the peak and valley dimensions of the uneven surface of the substrate 10 are two orders of magnitude smaller than the dimensions of the limiting groove 210. This facilitates the formation of the patterned layer 11 and the conductive layer 20 on the substrate 10, reducing the possibility of delamination or slippage.

[0051] (Pattern layer 11)

[0052] In this embodiment, as described above, the working electrode 1 may include a patterned layer 11. In some examples, as described above, the patterned layer 11 may be formed on the surface of the substrate layer 10. In some examples, the patterned layer 11 may be formed on the surface of the substrate layer 10 by means of screen printing, sputtering, plating, etc.

[0053] In some examples, the material of the pattern layer 11 can be the same as the material of the conductive layer 20. This reduces the possibility of delamination between the conductive layer 20 and the pattern layer 11. In other examples, the material of the pattern layer 11 can be different from the material of the conductive layer 20.

[0054] In this embodiment, the pattern layer 11 may have a predetermined pattern. In some examples, the predetermined pattern may be formed by methods such as photolithography, mask printing, and laser engraving.

[0055] In some examples, the predetermined pattern may include at least one opening 110 arranged along a predetermined direction. In some examples, the number of openings 110 may be, for example, 1, 3, 5, or 7. In some examples, the openings 110 may be circular, oval, rectangular, triangular, or irregularly shaped holes. In some examples, the openings 110 may penetrate the entire pattern layer 11.

[0056] In some examples, the size and shape of each opening 110 on the patterned layer 11 (e.g., opening 110a, opening 110b, opening 110c, etc.) can be uniform. In other examples, the size and shape of each opening 110 on the patterned layer 11 may not be completely uniform. However, the patterned layer 11 of different working electrodes 1 in the same batch should be consistent in order to control the consistency of the volume of the glucose-sensitive reagent 310 applied, the overall area of ​​the formed sensing part 30, morphology, etc., thereby facilitating the control of the consistency of the initial sensitivity among different working electrodes 1 in the same batch.

[0057] In some examples, multiple openings 110 on the patterned layer 11 (e.g., openings 110a, 110b, 110c, etc.) are arranged in a straight line. This simplifies the design of the patterned layer 11 and the patterning steps in the manufacturing process.

[0058] In this embodiment, the thickness of the pattern layer 11 can be 1-20 μm, preferably 5-12 μm. This prevents the stacked printed layers from becoming too thick, thus avoiding impact on the bending resistance of the working electrode 1 and the adhesion of the glucose-sensitive reagent 310 to the conductive layer 20.

[0059] (Conductive layer 20)

[0060] In this embodiment, as described above, the working electrode 1 may include a conductive layer 20. The conductive layer 20 may be disposed on the pattern layer 11. The conductive layer 20 may be disposed on the pattern layer 11 by means of screen printing, sputtering, plating, or the like.

[0061] In some examples, the conductive layer 20 can be made of a metallic conductive material. The metallic conductive material can be selected from at least one of silver, platinum, gold, titanium, palladium, iridium, and niobium, or an alloy thereof. This allows the conductive layer 20 to have good conductivity. In other examples, the conductive layer 20 can also be made of a conductive non-metallic material. The conductive non-metallic material can be selected from conductive non-metallic materials such as glassy carbon and graphite.

[0062] In this embodiment, in some examples, the conductive layer 20 can completely cover the entire patterned layer 11. In this case, every surface of the patterned layer 11 is covered by the conductive layer 20, and no surface is exposed. In some examples, the conductive layer 20 can completely cover all the openings 110 of the patterned layer 11, and the conductive layer 20 can be a single, continuous conductive layer without being separated into multiple discontinuous regions. In other words, the conductive layer 20, as a whole, covers all areas of the patterned layer 11 with openings 110 and the areas surrounding the openings 110.

[0063] In some examples, the conductive layer 20 may cover the entire pattern layer 11 by screen printing. In other examples, the conductive layer 20 may cover all openings 110 and the area surrounding the openings 110 by screen printing. In this case, during the screen printing process, a predetermined amount of liquid ink is dispersed throughout the printing area and flows naturally downward at the openings 110, covering the bottom and sidewalls of the openings 110, and forming a complete conductive layer 20 after drying. In this case, the entire conductive layer is complete, and electrons generated by the sensing elements 30 in each limiting groove 210 during the glucose redox reaction can be transferred to the conductive layer 20, and the electrons transferred to the conductive layer 20 can move throughout the conductive layer 20. In this case, the conductive layer 20 may form recessed limiting grooves 210 at the openings 110, for example, limiting groove 210a is formed after the opening 110a is covered by the conductive layer 20.

[0064] In this embodiment, in some examples, the conductive layer 20 formed on the patterned layer 11 may be generally wavy. Specifically, the conductive layer 20 formed on the patterned layer 11, including at least one limiting groove 210, extends from along... Figure 4 The cross-section of the centerline B-B' can be roughly wave-shaped. The part of the conductive layer 20 that contacts the substrate layer 10 at the opening 110 can be roughly the trough of the wave, and the part of the conductive layer 20 that is formed in the patterned layer 11 at the non-opening 110 can be roughly the crest of the wave.

[0065] According to the working electrode 1 of the glucose sensor disclosed herein, it is not necessary to obtain droplets with the same wetting angle using the complex surface treatment methods of the prior art. Instead, a limiting groove 210 with a certain shape is formed on the surface of the working electrode 1. A predetermined amount of glucose-sensitive reagent 310 can be contained in the limiting groove 210 and form a morphology with the same shape as the limiting groove 210. This allows for convenient control of the consistency of the area and morphology of the sensing part 30 in the working electrode 1 of mass production, thereby obtaining a glucose sensor with consistent process parameters.

[0066] In some examples, a nanoparticle layer (not shown) may be further disposed on the surface of the conductive layer 20. Specifically, the nanoparticles may be, for example, gold nanoparticles, platinum nanoparticles, etc. In some examples, the nanoparticle layer may be porous. In some examples, the nanoparticle layer may be disposed on the surface of the conductive layer 20 by means of, for example, electroplating, sputtering, etc. This increases the contact area between the enzyme in the glucose-sensitive reagent 310 of the sensing unit 30 and the conductive layer 20.

[0067] In some examples, the surface of the conductive layer 20 or the surface of the limiting groove 210 may be further provided with a three-dimensional nanofiber network structure (not shown) composed of filamentous nanofibers. In other examples, the three-dimensional nanofiber network structure may be formed on a nanoparticle layer as a base; that is, fine and long filamentous nanofibers may be formed on the nanoparticles by means of conductive materials such as electroplating polyaniline, based on the nanoparticles in the nanoparticle layer, and several filamentous nanofibers intersect each other to form a three-dimensional nanofiber network structure. This can improve the adhesion of glucosamine and provide better conductivity.

[0068] In this embodiment, in some examples, the limiting groove 210 may have a shape substantially the same as that of the opening 110. For example, the limiting groove 210a formed on the opening 110a may have a shape substantially the same as that of the opening 110a (see [link]). Figures 4-6 In other words, when the opening 110 is circular, the resulting limiting groove 210 can be approximately circular.

[0069] In some examples, the limiting groove 210 can be a circular groove or an oval groove. This allows the glucose-sensitive reagent 310, which is readily dispensed, to flow within the limiting groove 210 and fill its edges to form the desired morphology. In other examples, the limiting groove 210 can be a rectangular groove or an irregularly shaped groove.

[0070] In some examples, when the conductive layer 20 has only one limiting groove 210, the surface area of ​​the limiting groove 210 is not less than the surface area of ​​the conductive layer 20. In some examples, multiple limiting grooves 210, for example... Figure 4 The sum of the surface areas of the limiting grooves 210a, 210b, and 210c shown (hereinafter referred to as 210 for ease of explanation) can be no less than 50% of the total surface area of ​​the conductive layer 20, for example, 50%, 60%, 70%, 80%, or 90%. This increases the contact area between glucose molecules in the sensing unit 30 and the conductive layer 20, thereby improving the sensitivity of the glucose sensor.

[0071] In some examples, the thickness of the pattern layer 11 is not less than the thickness of the conductive layer 20. This allows the conductive layer 20 to be recessed at the opening 110 of the pattern layer 11 to form a retaining groove 210. In other examples, the thickness of the conductive layer 20 may be greater than the thickness of the pattern layer 11.

[0072] In some examples, the multiple limiting slots 210 can be arranged in an array. In some examples, the multiple limiting slots 210 can be arranged in a straight line. Additionally, the multiple limiting slots 210 (e.g.) Figure 4 The limiting grooves 210a, 210b, and 210c can also be arranged in other shapes, such as curved or zigzag.

[0073] In some examples, the number and arrangement of the limiting grooves 210 can match the number and arrangement of the openings 110 on the patterned layer 11 (e.g., the predetermined pattern as described above). For example, in some examples, when the number of openings 110 on the patterned layer 11 is, for example, three and arranged in a straight line, the number of limiting grooves 210 on the conductive layer 20 can also be three and arranged in a straight line. For example, in other examples, when the size and shape of each opening 110 on the patterned layer 11 (e.g., opening 110a, opening 110b, opening 110c, etc.) are all the same, the multiple limiting grooves 210 on the conductive layer 20 (e.g., limiting grooves 210a, limiting grooves 210b, limiting grooves 210c, etc.) can also be the same in size and shape.

[0074] In this embodiment, the diameter or maximum width of the limiting groove 210 (e.g., the distance between two adjacent wave crests as described above) can be 100-150 μm. Therefore, the sensing part 30 has a sufficiently large area to give the glucose sensor high sensitivity.

[0075] In this embodiment, the thickness of the conductive layer 20 can be 1-20 μm, preferably 5-12 μm. This ensures that the stacked printed layers are not too thick, thus preventing them from affecting the bending resistance of the probe S and the adhesion of the glucose-sensitive reagent 310.

[0076] (Sensing Unit 30)

[0077] In this embodiment, as described above, the working electrode 1 may include a sensing unit 30. The sensing unit 30 may be disposed on at least one limiting groove 210 of the conductive layer 20. The sensing unit 30 is formed by dripping a predetermined amount of glucose-sensitive reagent 310 into the limiting groove 210 and then curing it. Different sensing units 30 can be obtained depending on the characteristics of different glucose-sensitive reagents 310 and the predetermined amount.

[0078] In some examples, the glucose-sensitive reagent 310 can completely fill the limiting groove 210. In other words, the volume of a predetermined amount of glucose-sensitive reagent 310 can be the same as the volume of the limiting groove 210. In this case, the surface of the sensing part 30 is flush with the line connecting two adjacent peaks of the conductive layer 20 as described above. In this case, the glucose-sensitive reagent 310 can be confined within the limiting groove 210, thereby controlling the area and morphology of the sensing part 30 and preventing undried glucose-sensitive reagent 310 from flowing everywhere and forming an irregular shape.

[0079] In some examples, the sensing element 30 can be slightly protruding within the limiting groove 210. In other words, the volume of the predetermined amount of glucose-sensitive reagent 310 can be slightly larger than the volume of the limiting groove 210. Due to surface tension, the liquid level of the unfixed glucose-sensitive reagent 310 is slightly higher than the upper surface of the conductive layer 20, but it does not diffuse beyond the edge of the side of the limiting groove 210, resulting in a large change in the morphology of the sensing element 30 after curing. Therefore, the area and morphology consistency of the sensing element 30 can still be well controlled.

[0080] In other examples, the surface of the sensing part 30 may be lower than the line connecting two adjacent peaks of the conductive layer 20 as described above, that is, the volume of the predetermined amount of glucose-sensitive reagent 310 is smaller than the volume of the limiting groove 210, and the glucose-sensitive reagent 310 is completely contained in the limiting groove 210.

[0081] In this embodiment, the glucose-sensitive reagent 310 can chemically react with glucose. In some examples, the glucose-sensitive reagent 310 may include a glucose enzyme, a metal polymer, and a cross-linking agent. Thus, the glucose-sensitive reagent 310 can easily adhere to the limiting groove 210 of the conductive layer 20 and react specifically with glucose.

[0082] In some examples, glucose-sensitive reagent 310 may be a mixed solution comprising an enzyme, a cationic polymer, and a redox mediator. For example, glucose-sensitive reagent 310 may be a mixed solution of, for example, glucose oxidase or dehydrogenase with a cationic polymer, a redox mediator such as ferricyanide, diazonium quinone, or ferrocene, and a cross-linking agent.

[0083] In some examples, the glucose-sensitive reagent 310 can be replaced according to the actual target analyte, that is, replaced with a sensitive reagent that can specifically react with the target analyte in the body. This allows for the detection of the concentration of target analytes other than glucose. For example, the glucose-sensitive reagent 310 can be replaced with specific reactants corresponding to acetylcholine, amylase, bilirubin, cholesterol, human chorionic gonadotropin, creatine kinase, creatine, creatine anhydride, DNA, fructosamine, glucose, glutamine, growth hormone, hormones, ketone bodies, lactate, oxygen, peroxides, prostate-specific antigen, prothrombin, RNA, thyroid-stimulating hormone, and troponin.

[0084] In this embodiment, the thickness of the sensing element 30 can be approximately 0.1 μm to 100 μm, preferably approximately 2 μm to 10 μm. In some examples, the thickness of the sensing element 30 can be 10 μm. In this case, controlling the thickness of the sensing element 30 within a certain range avoids a decrease in the adhesion of the glucose-sensitive reagent 310, causing the material to detach from the body. It also avoids problems such as insufficient glucose oxidase in the glucose-sensitive reagent 310 leading to inadequate reaction and inability to provide normal glucose concentration information.

[0085] In some examples, the glucosidase in the glucose-sensitive reagent 310 can be attached to and fixed on the surface of the working electrode 1 by methods such as physical adsorption, covalent cross-linking or embedding.

[0086] In some examples, the glucose-sensitive reagent 310 can be attached to a three-dimensional nanofiber network structure (not shown) formed of a conductive material such as polyaniline. This increases the amount of enzyme attached to the sensing element 30 and provides good electrical signal transmission performance.

[0087] In some examples, the glucose-sensitive reagent 310 may also include carbon nanotubes, with a mass percentage of 5% to 10%. This increases the adhesion of the glucose enzyme and promotes the specific reaction. In other examples, graphene, porous titanium dioxide, or conductive organic salts may be added to the glucose-sensitive reagent 310. This further enhances the promotion of the glucose enzyme reaction.

[0088] (Semi-permeable membrane 40)

[0089] In this embodiment, as described above, the working electrode 1 may further include a semi-permeable membrane 40. In some examples, the semi-permeable membrane 40 may be disposed on the entire exterior of the working electrode 1, that is, covering the entire surface of the working electrode 1 including the conductive layer 20 and the sensing part 30. This provides good diffusion control.

[0090] In other examples, the semi-permeable membrane 40 may be disposed only on the sensing part 30, that is, covering only the entire sensing part 30. This reduces the amount of raw materials used.

[0091] In this embodiment, in some examples, the semipermeable membrane 40 includes a diffusion control layer (not shown) for controlling the diffusion of glucose molecules. In this case, when glucose molecules in tissue fluid or blood enter the semipermeable membrane 40, the number of glucose molecules is reduced proportionally, so that when glucose molecules react with the glucose enzyme in the sensing unit 30, the glucose enzyme in the sensing unit 30 is in an excess state. The glucose concentration becomes the only factor limiting the current of the working electrode 1, thereby expanding the linear range of the glucose sensor when monitoring glucose concentration.

[0092] In some examples, the semipermeable membrane 40 also includes an anti-interference layer (not shown) stacked on top of the diffusion control layer. In other examples, the diffusion control layer may be positioned outside the anti-interference layer. In the semipermeable membrane 40, the diffusion control layer controls the diffusion of glucose molecules, while the anti-interference layer prevents the diffusion of non-glucose substances. In this case, the amount of tissue fluid or blood passing through the semipermeable membrane 40 can be reduced first, and then the anti-interference layer can block interfering substances outside the semipermeable membrane 40. Common interfering substances may include uric acid, ascorbic acid, acetaminophen, etc., which are ubiquitous in the body.

[0093] In some examples, the semi-permeable membrane 40 can be a biocompatible diffusion control material. This extends the lifespan of the sensor probe after implantation. In this embodiment, a sensing element 30 with controllable area and morphology can be obtained, thereby enabling the production of a glucose sensor with consistent process parameters.

[0094] Figure 7 is a schematic diagram illustrating the preparation process of the working electrode 1 according to the embodiments of this disclosure. Figure 8 This is a schematic diagram illustrating the drop-coating step involved in an embodiment of the present disclosure.

[0095] The preparation method of the working electrode 1 of the glucose sensor is described in detail below with reference to Figure 7.

[0096] In this embodiment, in some examples, referring to FIG7(a), a pattern layer 11 of 1-20 μm can first be formed on the substrate layer 10 by means of, for example, screen printing, inkjet printing, vacuum magnetron sputtering, evaporation or plating, the pattern layer 11 having a predetermined pattern.

[0097] In this embodiment, in some examples, referring to FIG7(b), after the pattern layer 11 has stabilized, a complete conductive layer 20 of 1-20 μm can be formed on the pattern layer 11 by methods such as screen printing, inkjet printing, vacuum magnetron sputtering, evaporation, or plating. In some examples, the method for forming the conductive layer 20 can be the same as the method for forming the pattern layer 11, for example, both can be formed by screen printing. This simplifies the process. In some examples, the thickness of the conductive layer 20 can be less than the thickness of the pattern layer 11. This facilitates the formation of a limiting groove 210 at the opening 110 in the conductive layer 20.

[0098] In this embodiment, referring to Figure 7(c), after the limiting groove 210 is formed, a predetermined amount of glucose-sensitive reagent 310 can be drop-coated into the limiting groove 210 to contain the glucose-sensitive reagent 310 within the limiting groove 210. In some examples, the glucose-sensitive reagent 310 can be cross-linked and cured in air at room temperature (e.g., 25°C ± 5°C), preferably for 30 hours or more, for example, 48 hours. This allows the glucose-sensitive reagent 310 to be stably fixed within the limiting groove 210, and the water vapor in the air is beneficial for stable cross-linking. In some examples, cross-linking and curing can be performed in a nitrogen chamber at room temperature. This prevents reaction with reactive gases in the environment during the curing process. In some examples, after cross-linking and curing are completed, the working electrode 1 can be stored in a low-humidity environment, such as in a nitrogen chamber at room temperature. This effectively maintains the enzyme's activity.

[0099] In this embodiment, referring to Figure 7(d), after the glucose-sensitive reagent 310 on the working electrode 1 has solidified, a semi-permeable membrane 40 can be coated on the surface.

[0100] The following, combined with Figure 8 Describe the drop coating process in detail.

[0101] In this embodiment, in some examples, the dosage of the coating liquid dispensed by the dispensing device each time is first pre-adjusted, i.e., a predetermined amount of glucose-sensitive reagent 310 is set to match the volume of the limiting groove 210 (e.g., the predetermined volume is equal to or slightly larger than the volume of the limiting groove 210, but still within the range of surface tension). The stepping distance of the micro-dispensing head is adjusted so that the stepping distance matches the spacing of the plurality of limiting grooves 210 arranged, for example, in a straight line on the conductive layer 20. Then, the micro-dispensing head of the dispensing device is moved to align with the limiting groove 210 of the working electrode 1, and the dispensing head dispenses glucose-sensitive reagent 310 into the limiting groove 210.

[0102] In some examples, the conductive layer 20 contains alignment marks, and the dispensing apparatus has an automated optical inspection (AOI) probe, in which case the micro-dispensing head of the dispensing apparatus can be automatically aligned with the limiting groove 210 of the working electrode 1.

[0103] [Second Implementation]

[0104] Figure 9 This is a cross-sectional view showing the working electrode 1A according to the second embodiment of this disclosure.

[0105] In this embodiment, see Figure 9 The working electrode 1A may include: a substrate layer 10 which may be made of an insulating material and has been pretreated to form a surface with a predetermined roughness. A conductive layer 20 may be disposed on the substrate layer 10 and has at least one limiting groove 210 arranged along a predetermined direction of the conductive layer 20. The at least one limiting groove 210 may be formed by etching a groove to a predetermined depth in the conductive layer 20. The sensing part 30 may be formed by drop-coating a predetermined amount of glucose-sensitive reagent 310 onto the at least one limiting groove 210 and then curing it, wherein the predetermined depth is less than the thickness of the conductive layer 20.

[0106] The difference between the working electrode 1A in this embodiment and the working electrode 1 in the first embodiment is that the working electrode 1A does not include the pattern layer 11, but instead directly etches at least one limiting groove 210 on the conductive layer 20 (see FIG7).

[0107] Furthermore, the preparation method of the working electrode 1A in this embodiment is basically the same as the preparation method of the working electrode 1 in the first embodiment. The preparation method of the working electrode 1 in the first embodiment can be directly adopted. The difference is that during the preparation process, a conductive layer 20 with a thickness of 1-20 μm, for example 12 μm, is directly formed on the substrate layer 10 by means of screen printing, inkjet printing, vacuum magnetron sputtering, evaporation, or plating. Afterwards, the limiting groove 210 can be directly etched on the conductive layer 20.

[0108] In this embodiment, the etching method can be selected from laser etching, plasma etching, or chemical etching.

[0109] In this embodiment, in some examples, the depth of etching the conductive layer 20 may be less than the thickness of the conductive layer 20. In other words, the depth of at least one limiting groove 210 formed by etching the conductive layer 20 is less than the thickness of the conductive layer 20, and the limiting groove 210 does not penetrate the conductive layer 20. In this case, the conductive layer 20 is not blocked by any limiting groove 210, and the electrical signal affecting the electrochemical reaction occurring in the sensing unit 30 is transmitted through the conductive layer 20 to the signal processing device for analysis.

[0110] In this embodiment, at least one limiting groove 210 can be formed by etching a groove of a predetermined depth in the conductive layer 20 using a mask with a predetermined pattern, as described above. A description of the predetermined pattern can be found in the description of the predetermined pattern of the pattern layer 11 in the first embodiment. Thus, the conductive layer 20 can be etched to form the limiting groove 210, and the desired morphology of the limiting groove 210 can be formed on the conductive layer 20.

[0111] In this embodiment, in some examples, since there is no pattern layer 11, that is, the limiting groove 210 is not formed at the opening 110 of the pattern layer 11, the shape of the limiting groove 210 is not related to the shape of the opening 110, but is related to the pattern set during the etching process.

[0112] Although the present invention has been specifically described above in conjunction with the accompanying drawings and embodiments, it is to be understood that the above description does not limit the present invention in any way. Those skilled in the art can make modifications and variations to the present invention as needed without departing from the essential spirit and scope of the invention, and all such modifications and variations fall within the scope of the present invention. Those skilled in the art will understand that, generally speaking, the terminology used in this disclosure is intended to be "open" terminology (e.g., the term "comprising" should be interpreted as "including but not limited to," the term "having" should be interpreted as "at least having," and the term "comprising" should be interpreted as "including but not limited to," etc.).

Claims

1. An electrode for monitoring physiological parameters, characterized in that, include: The substrate layer, pattern layer, conductive layer, and sensing element. The base layer is made of an insulating material. The patterned layer is disposed on the base layer and has a predetermined pattern, the predetermined pattern including a plurality of openings. The conductive layer is disposed as a whole on the pattern layer and covers the multiple openings to form multiple limiting grooves. The sensing unit is formed by dripping sensitive reagents onto the plurality of limiting grooves and then curing them. The sensitive reagents include enzymes that specifically react with the target analyte.

2. The monitoring electrode as described in claim 1, characterized in that, The patterned layer is made of the same material as the conductive layer.

3. The monitoring electrode as described in claim 1, characterized in that, The sensing element is slightly protruding in the limiting groove.

4. The monitoring electrode as described in claim 1, characterized in that, The conductive layer formed on the patterned layer is generally wavy.

5. An electrode for monitoring physiological parameters, characterized in that, include: The substrate, conductive layer, and sensing element. The base layer is made of an insulating material. The conductive layer is integrally disposed on the substrate layer and has multiple positioning grooves. The multiple positioning grooves are formed by etching grooves to a predetermined depth in the conductive layer, the predetermined depth being less than the thickness of the conductive layer. The sensing unit is formed by dripping sensitive reagents onto the plurality of limiting grooves and then curing them. The sensitive reagents include enzymes that specifically react with the target analyte.

6. The monitoring electrode as described in claim 5, characterized in that, It also includes a semi-permeable membrane, which at least covers the sensing element.

7. The monitoring electrode as described in claim 5, characterized in that, The sensitive reagent completely fills the limiting groove.

8. The monitoring electrode as described in claim 5, characterized in that, The multiple limiting grooves are arranged in a straight line.

9. The monitoring electrode as described in claim 5, characterized in that, At least one limiting groove is formed by etching a groove of the predetermined depth in the conductive layer using a mask with a predetermined pattern.

10. The monitoring electrode according to any one of claims 1 to 9, characterized in that, The target analyte is glucose, and the monitoring electrode for the physiological parameters is the working electrode of a glucose sensor.

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