Microbiosensors and their sensing structures
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Patents
- Current Assignee / Owner
- BIONIME
- Filing Date
- 2022-07-22
- Publication Date
- 2026-05-26
Smart Images
Figure 0007866035000001 
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Abstract
Description
Technical Field
[0001] The present invention relates to a micro biosensor and its sensing structure. In particular, the present invention relates to a micro biosensor and its sensing structure that can limit the diffusion distribution of biological fluids.
Background Art
[0002] The basic configuration of a continuous glucose monitoring system includes a biosensor and a transmitter. The biosensor measures physiological signals according to the glucose concentration in the body, and the measurement is mainly based on an electrochemical process. Specifically, glucose undergoes a catalytic reaction with glucose oxidase (GOx) to generate gluconolactone and reduced glucose oxidase, and then hydrogen peroxide (H2O2) is generated as a byproduct through an electron transfer reaction between reduced glucose oxidase and oxygen in the biological fluid. The glucose concentration is obtained from the oxidation reaction of the byproduct H2O2.
[0003] However, interferents with oxidation potentials close to that of H2O2, such as ascorbic acid (the main component of vitamin C), acetaminophen (a common analgesic component), uric acid, proteins, and glucose analogs, are present in blood or tissue fluid, which will have an adverse effect on the measurement of glucose concentration. Therefore, it is difficult to ensure that the physiological parameters of the subject are accurately reflected in the measured values and to maintain the long-term stability of the measurement signal during the operation of the continuous glucose monitoring system.
[0004] Currently, the aforementioned drawbacks are being addressed, for example, by providing polymer membranes for filtering out interfering substances, but completely removing them remains difficult. Alternatively, a potential is applied to multiple working electrodes, each coated with an enzyme or different types of enzymes, and multiple signals are read from the working electrodes. These signals are then processed, such as by subtraction, to accurately obtain the physiological parameters of the target analyte. However, such conventional processes, involving the manufacture and use of working electrodes, are very complex. Furthermore, finding the appropriate subtraction ratio is not easy. [Overview of the project]
[0005] The microbiosensor of the present invention can be implanted under the skin to measure the physiological parameters of a target analyte in a biofluid and comprises a first working electrode for measuring the physiological parameters, a second working electrode for consuming interfering substances, and an isolation layer. The isolation layer is configured to at least shield a portion of the first working electrode to prevent interfering substances in the biofluid from directly diffusing to the first working electrode, and to ensure that the biofluid passes through the second working electrode before reaching the first working electrode, thereby allowing the second working electrode to consume interfering substances in the biofluid that affect the measurement using an electrochemical reaction, and enabling the first working electrode to obtain more accurate measurement results during measurement.
[0006] According to one aspect of the present invention, a microbiosensor for implantation under the skin has been provided to measure the physiological parameters of a target analyte in a biofluid and to reduce interference from interfering substances in the biofluid in measurements by electrochemical reaction. The microbiosensor includes a sheet substrate having a first surface and a second surface arranged opposite to each other; a first working electrode having at least a first sensing section disposed on the first surface of the substrate, wherein the first sensing section of the first working electrode comprises a first conductive material; at least one second working electrode disposed on the first surface of the substrate and having a second sensing section, wherein the second sensing section is disposed adjacent to at least one side of the first sensing section, and the second sensing section of the second working electrode comprises a second conductive material different from the first conductive material; and a first functional membrane covering the first sensing section of the first working electrode and the second sensing section of the second working electrode, wherein the first functional membrane has a small portion of the first conductive material to react with the target analyte in the biofluid to obtain a product. The device includes a chemical reagent that covers and defines the active surface of the first sensing section, and an isolation layer positioned corresponding to at least a portion of the active surface of the first sensing section of the first working electrode to restrict the diffusion pathway of the interfering substance of the biofluid passing through the second sensing section of the second working electrode, wherein the biofluid diffuses into the second sensing section over a period of time, and after passing through the second sensing section, diffuses into the first sensing section, and when the first working electrode is driven by a first working voltage, the first sensing section reacts with the product to output a physiological signal corresponding to the physiological parameters of the target analyte, and when the second working electrode is driven by a second working voltage, the second sensing section consumes the interfering substance of the biofluid by an electrochemical reaction during the period of time to reduce the interference of the interfering substance with the physiological signal, and the remaining portion of the biofluid diffuses into the first sensing section of the first working electrode after passing through the second sensing section.
[0007] According to another aspect of the present invention, a microbiosensor for implantation under the skin has been provided to measure the physiological parameters of a target analyte in a biofluid and to reduce interference from interfering substances in the biofluid in measurements by electrochemical reaction. The microbiosensor includes a substrate having a first surface and a second surface arranged opposite to each other; a first working electrode including at least a first sensing section located on the first surface of the substrate for measuring the physiological parameters of the target analyte; at least one second working electrode located on the first surface of the substrate and including a second sensing section, the at least one second working electrode located adjacent to at least one side of the first sensing section such that the second sensing section consumes the interfering substances by the electrochemical reaction; and a first functional membrane covering the first sensing section of the first working electrode and the second sensing section of the second working electrode, wherein the first functional membrane covers at least a portion of the first conductive material to react with the target analyte in the biofluid to obtain a product. The first sensing section comprises a chemical reagent defining the active surface of the first sensing section, and an isolation layer positioned at least in relation to at least a portion of the active surface to define the diffusion pathway of the interfering substance, thereby increasing the opportunity for the biofluid to interact with the second sensing section of the second working electrode, wherein when the first working electrode is driven by the first working voltage, the first sensing section reacts with the product to output a physiological signal corresponding to the physiological parameters of the target analyte, and when the second working electrode is driven by the second working voltage, the second sensing section consumes the interfering substance in the biofluid by an electrochemical reaction to reduce the interference of the interfering substance with the physiological signal, and the remaining portion of the biofluid passes through the second sensing section and then diffuses into the first sensing section.
[0008] According to another aspect of the present disclosure, a sensing structure for a microbiosensor to be implanted under the skin has been provided to measure the physiological parameters of a target analyte in a biofluid and to reduce interference from interfering substances in the biofluid in measurements by electrochemical reaction. The sensing structure includes a substrate having a surface; a first working electrode disposed on the surface and having an active surface; at least one second working electrode disposed on the surface and adjacent to at least one side of the first working electrode to consume the interfering substances by the electrochemical reaction; and an isolation layer disposed corresponding to at least a portion of the active surface to restrict the diffusion distribution of the interfering substances as the biofluid flows through the second working electrode, wherein at least the interfering substances in the biofluid pass through the second working electrode over a period of time and are consumed by the second working electrode by the electrochemical reaction. [Brief explanation of the drawing]
[0009] The following drawings illustrate embodiments and are merely illustrative of the concept of the present invention. [Figure 1A] This is a schematic front view showing a first embodiment of the microbiosensor of the present invention. [Figure 1B] This is a schematic rear view showing a first embodiment of the microbiosensor of the present invention. [Figure 2A] Figures 1A and 1B show schematic cross-sectional views of the microbiosensor along the cutting line II. [Figure 2B] This is another schematic cross-sectional view of the microbiosensor along the cutting line II in Figures 1A and 1B. [Figure 3] This is a schematic diagram showing the measurement range of the first sensing section and the interference rejection range of the second sensing section after the microbiosensor has been activated. [Figure 4] This is a schematic diagram showing an isolation layer that controls the diffusion pathway of interfering substances within the microbiosensor of the present invention. [Figure 5A] This is a schematic front view showing a second embodiment of the microbiosensor of the present invention. [Figure 5B]This is a schematic rear view showing a second embodiment of the microbiosensor of the present invention. [Figure 6] This is a schematic cross-sectional view of the present invention along the cutting line II-II in Figures 5A and 5B. [Figure 7] This is a schematic diagram showing the configuration of another embodiment of the isolation layer of the microbiosensor of the present invention. [Figure 8] This is another embodiment of the isolation layer of the microbiosensor of the present invention. This is a schematic diagram. [Figure 9] This is a schematic front view showing a third embodiment of the microbiosensor of the present invention. [Figure 10] This is a schematic front view showing the sensing region of the fourth embodiment of the sensing structure in the microbiosensor of the present invention. [Figure 11] Figure 10 shows a schematic cross-sectional view of the microbiosensor along the cutting line IV-IV. [Figure 12] This is a schematic diagram showing the configuration of the second functional membrane of the microbiosensor of the present invention. [Figure 13] This is a schematic diagram showing the arrangement of the packing material in the microbiosensor of the present invention. [Modes for carrying out the invention]
[0010] When reading the following detailed description, refer to all the figures of the present invention. All the figures of the present invention illustrate different embodiments of the invention by example and help those skilled in the art to understand how to carry out the invention. These embodiments provide sufficient embodiments to demonstrate the spirit of the invention, each embodiment is non-contradictory to the others, and new embodiments can be carried out through any combination thereof. That is, the present invention is not limited to the embodiments disclosed herein.
[0011] The microbiosensor of the present invention may be a sensor for a continuous glucose monitoring system that is implanted subcutaneously in a living organism to continuously measure the physiological parameters of a target analyte in a biological fluid. Furthermore, the term “target analyte” as used herein generally refers to any test substance present in a living organism, including, but not limited to, glucose, lactose, and uric acid. The term “biofluid” may be, but not limited to, blood or interstitial fluid (ISF). The term “physiological parameter” may be, but not limited to, concentration.
[0012] Referring to Figures 1A, 1B, and 2A, Figures 1A and 2A show schematic front and rear views of a first embodiment of the microbiosensor of the present invention, respectively, and Figure 2A shows a schematic cross-sectional view of the microbiosensor along the cutting line II of Figures 1A and 1B. In the first embodiment, the microbiosensor 10 of the present invention includes a substrate 110, a first working electrode 120, a second working electrode 130, a counter electrode 210, a first functional film 140, and an isolation layer 150.
[0013] The substrate 110 is a sheet having a first surface 111, a second surface 112 located opposite the first surface 111, a first end 113, and a second end 114. Preferably, both the first surface 111 and the second surface 112 are planar for arranging the following electrodes: a signal output region 115, a sensing region 116, and an insulating region 117 are further defined on the substrate 110. The signal output region 115 is located in the region near the first end 113, the sensing region 116 is located in the region near the second end 114, and the insulating region 117 is covered by a first insulating layer I1 and is located in the region between the signal output region 115 and the sensing region 116. The substrate 110 can be used to manufacture an electrode substrate and can be made of any material having flexibility and insulating properties, such as polyester, polyimide, and other polymer materials, but is not limited to these, and polymer materials may be used alone or in combination. The sensing structure of the present invention comprises at least a first working electrode 120, a second working electrode 130, a first functional film 140, and an isolation layer 150, formed within the sensing region 116 and on the substrate 110.
[0014] The first working electrode 120 and the second working electrode 130 are arranged on the first surface 111 of the substrate 110 and extend from the first end 113 to the second end 114, where a portion of the first working electrode 120 within the sensing region 116 is the first sensing section 121, and a portion of the second working electrode 120 within the sensing region 116 is the second sensing section 131. The first sensing section 121 has at least a first conductive material 1C, and the second sensing section 131 has at least a second conductive material 2C. The first conductive material 1C may be one of the following: carbon, platinum, aluminum, gallium, gold, indium, iridium, iron, lead, magnesium, nickel, molybdenum, osmium, palladium, rhodium, silver, tin, titanium, zinc, silicon, zirconium, their derivatives (alloys, oxides, metallic compounds, etc.), or a combination thereof. The second conductive material 2C can be one of the elements exemplified in the first conductive material 1C or their derivatives.
[0015] In the first embodiment, it should be noted that the first conductive material 1C and the second conductive material 2C are different. To obtain these structures, in the manufacturing process, first, the first conductive material 1C and the second conductive material 2C are respectively formed on the first surface 111 of the substrate 110 and can be patterned into the pattern as shown in FIG. 1A. Subsequently, an insulating layer I1 is formed on the substrate 110 to define a signal output region 115, a sensing region 116, and an insulating region 117. In another embodiment, the second conductive material 2C can be defined as a pattern as shown in FIG. 1A without the pattern of the first sensing section 121 in the patterning step. Specifically, the first working electrode 120 further includes the second conductive material 2C. In this embodiment, it is formed only within the signal output region 115 and the insulating region 117, or at most extends to a part of the sensing region 116. Next, the first conductive material 1C is directly formed on the region of the original first surface 111 where the first sensing section 121 is to be formed, and the first conductive material 1C is electrically connected to the other part (the second conductive material 2C) of the first working electrode 120, and the arrangement of the first sensing section 121 is completed. A cross-sectional schematic view of the sensing region 116 of the micro biosensor 10 in this embodiment is also shown as FIG. 2A.
[0016] However, the structures of the first working electrode 120 and the second working electrode 130 of the present invention are not limited to the structures shown in Figure 2A. Referring to Figure 2B, Figure 2B shows another schematic cross-section of the microbiosensor along the cutting line II of Figures 1A and 1B. As shown in Figure 2B, the second conductive material 2C is first formed on the first surface 111 of the substrate 110 and then patterned into a pattern as shown in Figure 1A. Specifically, the second conductive material 2C is divided into two separate regions, one of which extends from the first end 113 to the second end 114 of the substrate 110 and is bent at the second end 114 to form a U-shaped structure is pre-configured as the second working electrode 130, and the other region extending from the first end 113 to the second end 114 of the substrate 110 and surrounded by the U-shaped structure is pre-configured as the first working electrode 120. After the first insulating layer I1 is covered on the substrate 110 and the signal output region 115 and the sensing region 116 are exposed, the first conductive material 1C is formed on the second conductive material 2C of the first working electrode 120 in the sensing region 116, completing the manufacturing of the first sensing portion 121 of the first working electrode 120. Although not shown in the figure, the first conductive material 1C can also be formed only on the partial second conductive material 2C of the first working electrode 120 in the sensing region 116.
[0017] The second sensing section 131 of the present invention is adjacent to at least one side of the first sensing section 121, and one side of the second sensing section 131 extends along at least one side of the first sensing section 121. In this embodiment, the second sensing section 131 extends along three sides of the first sensing section 121 to form a U-shaped sensing section. Furthermore, the first sensing section 121 and the second sensing section 131 of the present invention maintain their positional relationship only through the first surface 111. Since the first sensing section 121 and the second sensing section 131 of the present invention are directly adjacent, there are no intervening objects such as electrodes or connecting wires between them.
[0018] The first functional film 140 covers at least the first sensing section 121 of the first working electrode 120 and the second sensing section 131 of the second working electrode 130. Specifically, the first functional film 140 of the first embodiment surrounds the substrate 110, the first working electrode 120, the second working electrode 130, and the counter electrode 210. The first functional film 140 contains a chemical reagent that covers at least a part of the first conductive material 1C of the first sensing section 121, whereby the surface of the first sensing section 121 covered by the chemical reagent is defined as an active surface. In other embodiments, the chemical reagent can also cover the second conductive material 2C of the second sensing section 131 of the second working electrode 130, or can cover the second surface 112 of the substrate 110. That is, the chemical reagent can surround the sensing region 116. Basically, the chemical reagent contains at least one enzyme that reacts with or catalyzes the reaction of the target analyte, for example, but not limited to, glucose oxidase, glucose dehydrogenase, etc. In addition to the chemical reagent, different functions of the first functional film 140, such as adjusting the detection sensitivity or preventing bioattachment, can be set as required.
[0019] The first working electrode 120 of the microbiosensor 10 of the present invention is driven to measure the physiological parameters of the target analyte in the biological fluid. When the first working electrode 120 of the microbiosensor 10 is driven by the first working voltage, the first sensing section 121 has a first sensitivity to the product, and as a result, the first conductive material 1C reacts with the product to generate a current signal. If the value of the current signal is in a proportional relationship with the concentration of the product, a physiological signal corresponding to the physiological parameter can be obtained. Therefore, in the range of the active surface of the first sensing section 121, the chemical reagent and the target analyte in the biological fluid react to obtain a product, and this product reacts with the first conductive material 1C of the first sensing section 121. The first sensing section 121 generates a current signal corresponding to the physiological signal of the physiological parameter of the target analyte in the biological fluid, and the physiological signal is transmitted to the signal output region 115 and output.
[0020] Since the biofluid contains the target analyte and interfering substances, the first conductive material 1C reacts not only with these to generate the aforementioned current signal, but also with the interfering substances in the biofluid to generate an interfering current signal. The interfering current signal is mixed with the current signal and output, interfering with the user's determination regarding the physiological signal. Similarly, when the second working electrode 130 is driven by the second working voltage, the second conductive material 2C of the second sensing section 131 has a second sensitivity to the product, and as a result, the second conductive material 2C has the opportunity to react with the product to generate another current signal. That is, the second conductive material 2C consumes the product that should be measured by the first sensing section 121 of the first working electrode 120 to obtain the physiological parameters of the target analyte, and thus affects the physiological parameters that are actually measured. Therefore, in one embodiment, if the target analyte is glucose, its product is hydrogen peroxide, and the physiological parameter is glucose concentration, the first conductive material 1C should preferably be a material that has a first sensitivity to hydrogen peroxide after being driven by the first working voltage. More preferably, the first conductive material 1C is selected from the group consisting of gold, platinum, palladium, iridium, and combinations thereof. The second conductive material 2C is preferably a material that, after being driven by the second working voltage, has a second sensitivity lower than the first sensitivity to hydrogen peroxide. In particular, the second conductive material 2C is a material that, after being driven by the second working voltage, has almost no sensitivity to hydrogen peroxide, i.e., a second sensitivity close to or equal to 0. Furthermore, the second sensing section 131 of the second working electrode 130 of the present invention provides an active surface for consuming interfering substances. Thus, the second conductive material 2C is a material that has almost no sensitivity to hydrogen peroxide and directly and continuously consumes interfering substances by undergoing an oxidation reaction with them. In particular, the second conductive material 2C has sensitivity to interfering substances similar to the first conductive material 1C.
[0021] More specifically, in one embodiment of the present invention, the first conductive material 1C is platinum, and the first operating voltage is in the range of 0.2 volts (V) to 0.8 volts (V), preferably in the range of 0.4V to 0.7V. The second conductive material 2C is carbon, and the second operating voltage is in the range of 0.2V to 0.8V, preferably in the range of 0.4V to 0.7V. In another embodiment of the present invention, the first conductive material 1C is platinum, and the second conductive material 2C is gold. It should be noted that the form of platinum described above may be platinum metal, platinum black, platinum paste, other platinum-containing materials, or a combination thereof. Furthermore, the value of the first operating voltage may be the same as the value of the second operating voltage, but the present invention is not limited thereto.
[0022] In this invention, "driving" means applying a voltage such that the potential of one electrode becomes higher than that of the other electrode, causing the electrode with the higher potential to initiate the oxidation reaction. Therefore, the potential difference between the first working electrode 120 and the counter electrode 210 that drives the first working electrode 120 is the first working voltage, and the potential difference between the second working electrode 130 and the counter electrode 210 that drives the second working electrode 130 is the second working voltage.
[0023] Figure 3 is a schematic diagram showing the measurement range of the first sensing section and the interference rejection range of the second sensing section after the microbiosensor has been driven. When the first working electrode 120 of the microbiosensor 10 is driven by the first working voltage, the first sensing section 121 generates a measurement range 1S, and when the second working electrode 130 of the microbiosensor 10 is driven by the second working voltage, each of the second sensing sections 131 surrounding the first sensing section 121 generates an interference rejection range 2S. Since the second sensing sections 131 are located adjacent to the side of the first sensing section 121 and very close to the first sensing section 121, the interference rejection range 2S can be in contact with the periphery of the first sensing section 121 and can at least partially overlap with the measurement range 1S of the first sensing section 121. The second conductive material 2C can directly and continuously consume the interfering material within the measurement range 1S of the first sensing section 121 by undergoing an electrochemical reaction with the interfering material, thereby reducing the generation of an interfering current signal and reducing the influence of the interfering material on the measurement of the first sensing section 121.
[0024] However, as shown in Figure 3, since the target analyte 310 and interfering substances 320 enter the measurement range 1S of the microbiosensor 10 from all directions, the second sensing section 131, positioned around the first sensing section 121, can consume the interfering substances 320, but there is still a possibility that the interfering substances 320 will be detected by approaching the active surface of the first sensing section 121 from non-overlapping areas.
[0025] Accordingly, the microbiosensor 10 of the present invention includes an isolation layer 150, which is positioned on the first functional film 140. The position of the insulating layer 150 is such that it corresponds to at least a portion of the first sensing section 121 of the first working electrode 120 and extends to shield at least a portion of the active surface or at least a portion of the second sensing section 131. Specifically, the area of the isolation layer 150 may be 0.5 to 10 times the area of the active surface of the first sensing section 121, preferably 1 to 8 times, more preferably 2 to 6 times, and most preferably 4 to 5 times.
[0026] In the first embodiment, as shown in Figure 2A, the isolation layer 150 is positioned to shield the upper parts of the first sensing section 121 and the second sensing section 131. The isolation layer 150 can at least prevent the interfering substance 320 from directly diffusing to the active surface of the first sensing section 121 of the first working electrode 120, or it can also prevent both the target analyte 310 and the interfering substance 320 from directly diffusing. Taking the interfering substance as an example, the isolation layer 150 can isolate the interfering substance 320 and alter its diffusion path or diffusion distribution. Specifically, the isolation layer 150 controls the diffusion path of the interfering substance 320 in the biofluid so that it first passes through the second sensing section 131 of the second working electrode 130, and after the remaining portion and unconsumed interfering substance pass through the second sensing section 131, it diffuses to the first sensing section 121 of the first working electrode 120. Therefore, the diffusion path of the interfering substance 320 is optimized to first pass through the interference removal range 2S of the second sensing section 131, located on the left and right sides of the first sensing section 121, as shown in Figure 4. Furthermore, the biofluid requires a certain period of time to diffuse through the second sensing section 131 of the second working electrode 130 to the first sensing section 121. The term "period" refers to the time required for the interfering substance in the biofluid to diffuse along the diffusion path to the second sensing section 131 of the second working electrode 130, pass through the second sensing section 131, or diffuse to the first sensing section 121. If this period is too short, the second sensing section 131 will not have enough time to consume the interfering substance, affecting the interference removal effect. However, if this period is too long, the subsequent measurement schedule of the biosignal by the first sensing section 121 will be delayed. Moreover, the length of the period can be determined by the length of the diffusion path, the diffusion range or cross-sectional area of the diffusion path, or the properties of the material through which the biofluid passes. Specifically, this ranges from 10 seconds to 15 minutes, preferably 3 to 12 minutes, and more preferably 5 to 8 minutes.
[0027] For the target analyte, whether or not the target analyte can pass through the isolation layer 150 is determined by the material and / or thickness of the isolation layer 150. Therefore, the diffusion pathway of the target analyte 310 is such that (1) it first passes through the second sensing section 131 of the second working electrode 130 and then diffuses to the first sensing section 121 of the first working electrode 120, and / or (2) depending on the state of the isolation layer 150, it diffuses directly from the isolation layer 150 to the active surface of the first sensing section 121 of the first working electrode 120. Due to the different properties of the conductive materials, the interfering substance 320 is directly consumed by the second sensing section 131, and most of the target analyte 310 can pass through the second sensing section 131 or reach the first sensing section 121 directly, so that the target analyte 310 can be measured in the measurement range 1S of the first sensing section 121. Accordingly, the isolation layer 150 of the microbiosensor 10 of the present invention can ensure that interfering substances 320 are consumed by the second sensing section 131 before reaching the first sensing section 121, thereby effectively reducing the interference of interfering substances 320 with the measured physiological signal. The accuracy of the physiological signal by the first sensing section 121 is improved when it is adjusted to an error range of, for example, 20%, preferably 10% or less. Specifically, more than 90% of the interfering substances can be effectively consumed through the sensing structure provided by the present invention.
[0028] Furthermore, the permeability of the insulating layer (such as the object to be insulated and the degree of insulation) can be adjusted by the selection of the material (such as the hydrophilicity or hydrophobicity of the material), the design of the thickness, or a combination thereof, so as to allow substances such as glucose and oxygen to pass through the isolation layer, at least isolating interfering substances, or completely isolating glucose, oxygen, and interfering substances so as not to directly diffuse onto the active surface of the first sensing section 121. For example, when using an isolation layer 150 with high magnetic permeability, the thickness of the isolation layer 150 with high magnetic permeability must be greater than the thickness of the isolation layer 150 with low magnetic permeability. In one embodiment, the isolation layer 150 may contain poly-p-xylylene to block the passage of glucose and interfering substances. In another embodiment, the isolation layer 150 may contain thermoplastic polyurethane such as polycarbonate-based urethane, polyether-based thermoplastic polyurethane, or a combination thereof, to at least block the passage of interfering substances. In yet another embodiment, the isolation layer 150 may also contain a cellulose derivative or a mixture of cellulose derivatives, polyvinyl chloride, Nafion, or a combination thereof. Specifically, the thickness of the isolation layer 150 can be in the range of 1 μm to 80 μm, preferably 3 μm to 24 μm, and more preferably 5 μm to 10 μm, depending on the material used. In the embodiments described above, if the isolation layer 150 is made of poly-p-xylylene, its thickness is 1 μm. If the isolation layer 150 is made of polycarbonate-based urethane or a derivative thereof, such as a polycarbonate-based silicone elastomer, its thickness is in the range of 3 μm to 10 μm. Furthermore, the isolation layer 150 can be manufactured on the first functional film 140 by a spray process or by mask and screen printing, although this is not limited to these methods. It should be further noted that the isolation layer of the present invention is not an insulator between two electrodes on a substrate in the prior art, nor is it an insulator in any manufacturing process.
[0029] The first functional film 140 has a thickness H defined by the distance between the active surface of the first sensing section 121 and the active surface of the second sensing section 131 and the isolation layer 150, so as to have sufficient space for electrochemical reactions between the first sensing section 121 and the target analyte, and between the second sensing section 131 and the interfering substance. The thickness H affects the sensitivity of the sensing. To ensure that the interference removal effect is enhanced, the thickness H is 0.05 μm or more and 50 μm or less, preferably 0.1 μm or more and 20 μm or less, more preferably 2 μm or more and 8 μm or less, and most preferably 3 μm or more and 5 μm or less.
[0030] Referring to Figures 5A, 5B, and 6, Figures 5A and 5B show schematic front and rear views of a second embodiment of the microbiosensor of the present invention, respectively. Figure 6 shows a schematic cross-sectional view of the microbiosensor along the cutting line II-II in Figures 5A and 5B. In the second embodiment, the first working electrode 120 and the second working electrode 130 extend from the first end 113 to the second end 114 of the substrate 110, and in the sensing region, the second sensing section 131 extends along one side of the first working electrode 120. The second sensing section 131 is positioned without bending the first sensing section 121 so as to be adjacent to only one side of the first sensing section 121. The isolation layer 150 is configured on the first functional membrane 140 and covers the top of the first working electrode 120 to restrict and guide at least a portion of the biofluid from passing through the second sensing section 131 before reaching the first sensing section 121. As a result, a portion of the interfering material 320 is consumed. Therefore, sensing the target analyte 310 with a microbiosensor having an isolation layer 150 is more accurate than sensing with a microbiosensor without an isolation layer 150.
[0031] In another embodiment, as shown in Figure 7, the isolation layer 150 can be positioned to enclose the left side of the sensing structure. That is, the isolation layer 150 extends from a position corresponding to the first sensing section 121 along the first functional membrane 140 to the counter electrode 210, isolating the interfering material 320 from directly entering the measurement range from the left side of the first sensing section 121 and affecting the sensing results of the physiological parameters. In another embodiment, as shown in Figure 8, the isolation layer 150 can also be positioned to enclose about two-thirds of the sensing structure. That is, the isolation layer 150 extends from a position corresponding to the first sensing section 121 and part of the second sensing section 131 along the first functional membrane 140 to the counter electrode 210. Specifically, the isolation layer 150 not only completely isolates the interfering substance 320 from directly entering the measurement range from the left side of the first sensing section 121 and the gap between the first sensing section 121 and the second sensing section 131, but also restricts the interfering substance 320 from passing through and being removed from the second sensing section 131 before reaching the first sensing section 121, thereby preventing the interfering substance 320 from affecting the sensing results of physiological parameters.
[0032] Referring to Figure 9, which is a schematic front view of a third embodiment of the microbiosensor 10 of the present invention, the rear view of the third embodiment is the same as that of the first and second embodiments, and therefore the schematic rear view of the third embodiment is omitted. In the third embodiment, the microbiosensor 10 has two second working electrodes 130. The first working electrode 120 and the two second working electrodes 130 extend from the first end 113 to the second end 114 of the substrate 110, and the two second working electrodes 130 each extend along two opposing sides of the first working electrode 120. The III-III cross-sectional view in Figure 9 is the same as in Figure 2, and the two second sensing sections 131 are arranged adjacent to the first sensing section 121.
[0033] Referring to Figures 10 and 11, Figure 10 is a schematic front view of the sensing region of a fourth embodiment of the sensing structure in the microbiosensor of the present invention, and Figure 11 is a schematic cross-sectional view of the microbiosensor along the cutting line IV-IV in Figure 10. Note that in Figure 10, only the sensing region of the microbiosensor 10 is shown, and the signal output region and insulation region are omitted. In the fourth embodiment, the second sensing section 131 of the second working electrode 130 can be arranged adjacent to the four sides of the first sensing section 121 of the first working electrode 120. Specifically, the second sensing section 131 can extend along the first sensing section 121 so as to completely surround it, and has a gap between it and the first sensing section 121. As can be seen from Figure 11, the substrate 110 of the fourth embodiment has a through hole 118, and the first sensing section 121 can extend from the first surface 111 to the second surface 112 of the substrate 110 through the through hole 118, and the insulating layer 150 is arranged to shield at least the upper part of the first sensing section 121. The first working electrode 120 extending from the second surface 112 can return to the first surface 111 through another through hole in the substrate in the signal output region.
[0034] It can be seen that the length of the second sensing section 131 can be changed in correspondence with the first sensing section 121. Therefore, in order to effectively reduce the influence of interfering material on the measurement, the above statement that "the second sensing section 131 is adjacent to at least one side of the first sensing section 121" specifically means that the ratio of the portion of the perimeter of the first sensing section 121 adjacent to the second sensing section 131 to the entire perimeter of the first sensing section 121 is between 30% and 100%.
[0035] Furthermore, as described above, the gap between the second sensing section 131 and the first sensing section 121 in the sensing region 116 of the microbiosensor 10 of the present invention in all the embodiments described above is 0.5 mm or less, preferably the gap between the second sensing section 131 and the first sensing section 121 is 0.2 mm or less, more preferably the gap is in the range of 0.01 mm to 0.2 mm, even more preferably the gap is in the range of 0.01 mm to 0.1 mm, and even more preferably the gap is in the range of 0.02 mm to 0.05 mm.
[0036] In the embodiments described above, the microbiosensor 10 of the present invention further includes a counter electrode 210 disposed on the second surface 112 of the substrate 110 and extending from the first end 113 to the second end 114. The counter electrode 210 is coupled to at least one of the first working electrode 120 and the second working electrode 130, and in cooperation with the first working electrode 120 measures physiological signals and in cooperation with the second working electrode 130 consumes interfering substances. Depending on the material used, the counter electrode 210 can also function as a reference electrode. Specifically, the counter electrode 210 of the present invention forms an electronic circuit with the first working electrode 120 so that current can freely flow through the first working electrode 120. This is to ensure that while electrochemical reactions occur at the first working electrode 120, the counter electrode 210 can also provide a stable relative potential as a reference potential. In another embodiment, the microbiosensor of the present invention may include two counter electrodes, which may be disposed on the first surface 111 of the substrate 110 (not shown). In further embodiments, in addition to the counter electrode, the microbiosensor of the present invention also includes a reference electrode used to provide a reference potential. Specifically, the counter electrode and the reference electrode are separate and not electrically connected, and the counter electrode is coupled to the first working electrode 120 and / or the second working electrode 130. Both the counter electrode and the reference electrode can be placed on a first surface 111 or a second surface 112 of the substrate 110 (not shown), or on different surfaces of the substrate 110, respectively.
[0037] In the embodiments described above, the first conductive material 1C of the first sensing section 121 may be the same as the second conductive material 2C of the second sensing section 131. In this embodiment, the chemical reagent is arranged to cover only the first sensing section 121 of the first working electrode 120, or an interfering substance removal layer may be further added to the second sensing section 131 of the second working electrode 130, and the chemical reagent may be applied to the first sensing section 121 of the first working electrode 120 and the interfering substance removal layer, based on process convenience, etc., which still satisfies the objective of consuming interfering substances through the second sensing section 131 in order to obtain accurate physiological signals.
[0038] In the embodiments described above, the microbiosensor 10 of the present invention further includes a second functional membrane 160, as shown in Figure 12. The second functional membrane 160 is covered by the first functional membrane 140 and the isolation layer 150 so as to enclose the substrate 110, the first sensing section 121, the second sensing section 131, the counter electrode 210, the first functional membrane 140, and the isolation layer 150. The second functional membrane 160 can be used as a protective layer for the microbiosensor 10. The sensing structure of the microbiosensor 10 is a flat plate structure, and because its structure is relatively thin, the stress on its left and right edges becomes stronger. The thickness of the second functional membrane 160 needs to be sufficiently thick on the sides of the sensing structure, for example, between 20 μm and 30 μm, to protect the sensing structure from cracking and prevent leakage current. Therefore, the second functional membrane 160 can further increase the structural strength of the microbiosensor 10. In addition to being a protective layer, the second functional membrane 160 can also be used as a storage layer for a small amount of tissue fluid. When the user engages in strenuous exercise, a large relative displacement occurs between the microbiosensor and the subcutaneous tissue, and the secondary functional membrane can provide a buffering function to prevent signal disturbance.
[0039] In the embodiments described above, the microbiosensor 10 of the present invention further includes a filler material 170 as shown in Figure 13. The filler material 170 is filled between the first working electrode 120 and the second working electrode 130 and has an upper surface. The upper surface of the filler material 170, the upper surface of the first sensing section 121 of the first working electrode 120, and the upper surface of the second sensing section 131 of the second working electrode 130 are on the same plane, so that the first working electrode 120 and the second working electrode 130 are flat, and the coating film on the electrode surfaces thereafter is flat. Furthermore, the material of the filler material 170 is not limited to the same material as the isolation layer 150, and the filler material 170 and the isolation layer 150 are separated by the first functional film 140. However, in another embodiment, if the material of the filler material 170 is the same as the material of the isolation layer 150, the filler material 170 can extend upward and continue to form the isolation layer 150, and as a result the filler material 170 and the isolation layer 150 are formed integrally (not shown).
[0040] In the embodiments described above, the sensing structure of the microbiosensor 10 of the present invention may further include a first working electrode 120, a second working electrode 130, a counter electrode 210, a first functional film 140, an isolation layer 150, a second functional film 160, and a filler 170 formed within the sensing region 116 of the substrate 110. In another embodiment, the sensing structure of the microbiosensor 10 of the present invention may further include a first working electrode 120, a second working electrode 130, a counter electrode 210, a reference electrode, a first functional film 140, an isolation layer 150, a second functional film 160, and a filler 170 formed within the sensing region 116 of the substrate 110.
[0041] In summary, the isolation layer in the microbiosensor of the present invention can isolate at least a portion of the interfering substance, thereby depicting or arranging the diffusion pathway of the interfering substance that first passes through the second working electrode, thereby increasing the opportunity for the interfering substance to interact with and consume the second sensing section of the second working electrode, reducing measurement interference in the first sensing section caused by the interfering substance, and as a result, the microbiosensor can measure physiological parameters with greater accuracy.
[0042] Although the present invention has been described above using embodiments, the technical scope of the present invention is not limited to the scope described in the above embodiments. It will be apparent to those skilled in the art that various modifications or improvements can be made to the above embodiments. It will be clear from the claims that such modified or improved forms may also be included in the technical scope of the present invention. [Explanation of Symbols]
[0043] 10: Microbiosensors 110: Circuit board 111: First surface 112:Second surface 113: First end 114:Second end 115: Signal output area 116: Sensing area 117: Insulated Area 118: Through hole 120: First working electrode 121: First sensing section 130:Second working electrode 131: Second Sensing Section 140:First functional membrane 150: Isolation layer 160:Second functional membrane 170: Filling material 210: Counter electrode 310:Target analyte 320: Interfering substances 1C: First conductive material 2C: Second conductive material 1S: Measurement range 2S: Interference rejection range I1: First insulating layer I2: Second insulating layer H: Thickness
Claims
1. A microbiosensor for implantation under the skin to measure the physiological parameters of a target analyte in a biofluid and to reduce interference from interfering substances in the biofluid during electrochemical reaction measurements, A substrate which is a sheet, having a first surface and a second surface arranged opposite to each other, A first working electrode comprising at least a first sensing section disposed on the first surface of the substrate, wherein the first sensing section of the first working electrode comprises a first conductive material, Displaced on the first surface of the substrate, at least one second working electrode including a second sensing section, wherein the second sensing section is disposed adjacent to at least two sides of the first sensing section, and the second working electrode includes a second conductive material different from the first conductive material. The first working electrode includes a first sensing section and a first functional film covering the second sensing section of the second working electrode, The first functional membrane comprises a chemical reagent that at least covers a portion of the first conductive material and defines the active surface of the first sensing section in order to react with the target analyte of the biological fluid to obtain a product, The first working electrode includes an isolation layer positioned corresponding to the active surface of the first sensing section and a portion of the second sensing section of the first working electrode, to restrict the diffusion path of the interfering substance of the biological fluid passing through the second sensing section of the second working electrode, to shield a portion of the second sensing section and the active surface of the first sensing section, and to isolate the interfering substance from direct diffusion to the active surface, The biological fluid diffuses into the second sensing section over a certain period of time, and after passing through the second sensing section, diffuses into the first sensing section. When the first working electrode is driven by the first working voltage, the first sensing section reacts with the product and outputs a physiological signal corresponding to the physiological parameters of the target analyte. A microbiosensor characterized in that, when the second working electrode is driven by a second working voltage, the second sensing section consumes the interfering substance in the biofluid by an electrochemical reaction over a certain period of time to reduce the interference of the interfering substance with the physiological signal, and the remaining portion of the biofluid diffuses to the first sensing section of the first working electrode after passing through the second sensing section.
2. The isolation layer is arranged in the first functional membrane. The area of the isolation layer is 0.5 to 10 times the area of the active surface of the first sensing section. The thickness of the isolation layer is 1 to 80 μm. The microbiosensor according to claim 1, characterized in that the aforementioned period is 10 seconds to 15 minutes.
3. The first working electrode is driven by the first working voltage so that the first sensing section generates a measurement range. The microbiosensor according to claim 1, characterized in that the second working electrode is driven by the second working voltage to bring the second sensing section into contact with the periphery of the first sensing section, thereby enabling it to have an interference rejection range that at least partially overlaps with the measurement range.
4. The microbiosensor according to claim 1, characterized in that when the first working electrode is driven by the first working voltage, the first conductive material has a first sensitivity to the product, and when the second working electrode is driven by the second working voltage, the second conductive material has a second sensitivity to the product that is smaller than the first sensitivity.
5. The microbiosensor according to claim 1, characterized in that the isolation layer is arranged in the first functional membrane, and the first functional membrane has a thickness defined by the distance between the isolation layer and the active surface of the first sensing section, wherein the thickness is 0.05 μm or more and 50 μm or less.
6. A microbiosensor for implantation under the skin to measure the physiological parameters of a target analyte in a biofluid and to reduce interference from interfering substances in the biofluid during electrochemical reaction measurements, A substrate having a first surface and a second surface arranged opposite to each other, A first working electrode, which includes at least a first sensing section disposed on the first surface of the substrate, to measure the physiological parameters of the target analyte, Displaced on the first surface of the substrate, at least one second working electrode including a second sensing section, wherein the second sensing section is positioned adjacent to at least two sides of the first sensing section such that the second sensing section consumes the interfering substance by the electrochemical reaction, The first working electrode includes a first sensing section and a first functional film covering the second sensing section of the second working electrode, The first functional membrane comprises a chemical reagent that covers at least a portion of the first conductive material and defines the active surface of the first sensing section in order to react with the target analyte of the biological fluid to obtain a product, The system includes a sequencing layer, which is positioned corresponding to the active surface and a portion of the second sensing section, to define the diffusion pathway of the interfering substance, thereby increasing the opportunity for the biological fluid to interact with the second sensing section of the second working electrode, and to shield a portion of the second sensing section and the active surface of the first sensing section, thereby isolating the interfering substance from directly diffusing to the active surface. When the first working electrode is driven by the first working voltage, the first sensing section reacts with the product and outputs a physiological signal corresponding to the physiological parameters of the target analyte. A microbiosensor characterized in that, when the second working electrode is driven by a second working voltage, the second sensing section consumes the interfering substance in the biofluid by an electrochemical reaction to reduce the interference of the interfering substance with the physiological signal, and the remaining portion of the biofluid diffuses to the first sensing section after passing through the second sensing section.
7. The microbiosensor according to claim 6, characterized in that the isolation layer is disposed on the first functional membrane.
8. The microbiosensor according to claim 6, characterized in that the chemical reagent further covers a portion of the second sensing section of the second working electrode.
9. The second sensing section is positioned adjacent to at least one side of the first sensing section via a gap, the gap being 0.5 mm or less. The microbiosensor according to claim 6, characterized in that the side edge of the second sensing section extends along the periphery of the first sensing section, and the portion of the periphery of the first sensing section adjacent to the second sensing section accounts for 30% to 100% of the total length of the periphery of the first sensing section.
10. The number of the second working electrodes is two. The microbiosensor according to claim 6, characterized in that the two second sensing sections of the two second working electrodes are each arranged adjacent to two opposing sides of the first sensing section.
11. At least one counter electrode is positioned on the second surface and coupled to at least one of the first working electrode and the second working electrode, The microbiosensor according to claim 6, further comprising a second functional film that encloses the first surface and the second surface of the substrate and covers the first functional film and the isolation layer.
12. A sensing structure for a microbiosensor to be implanted under the skin to measure the physiological parameters of a target analyte in a biofluid and to reduce interference from interfering substances in the biofluid during electrochemical reaction measurements, A substrate having a surface, A first working electrode, which is disposed on the aforementioned surface and has an active surface, At least one second working electrode is provided, which is positioned on the surface and adjacent to at least two sides of the first working electrode, so as to consume the interfering substance by the electrochemical reaction described above, The system includes an isolation layer positioned corresponding to the active surface and a portion of the second working electrode, which restricts the diffusion distribution of the interfering substance as the biological fluid flows through the second working electrode, shields a portion of the second working electrode and the active surface of the first working electrode, and isolates the interfering substance from directly diffusing onto the active surface. A sensing structure characterized in that at least the interfering substance of the biological fluid passes through the second working electrode over a certain period of time and is consumed by the second working electrode through the electrochemical reaction.
13. The first functional film is located between the first working electrode and the isolation layer and further includes the substrate, the first working electrode and the second working electrode, The first functional membrane includes a chemical reagent that covers a portion of the first working electrode and defines the active surface so as to react with the target analyte of the biological fluid to produce a product, The sensing structure according to claim 12, characterized in that the aforementioned certain period is 10 seconds to 15 minutes.
14. When the first working electrode is driven by the first working voltage, the first working electrode reacts with the product and outputs a physiological signal corresponding to the physiological parameters of the target analyte. When the second working electrode is driven by the second working voltage, the second working electrode consumes the interfering substance by the electrochemical reaction during the specified period in order to reduce the interference of the interfering substance with the physiological signal. The sensing structure according to claim 13, characterized in that the first operating voltage is 0.2 to 0.8 volts and the second operating voltage is 0.2 to 0.8 volts.