Sensor and method of manufacturing the same

Abstract

A sensor having a probe inserted into a living body and measuring an analyte, the probe including: a substrate; an electrode formed on the substrate; and a reference layer formed on the electrode, wherein an upper surface of the reference layer is covered by a thin film, and a side surface is exposed.

Description

Technical Field

[0001] This disclosure relates to sensors and methods for manufacturing the same. Background Technology

[0002] As a representative example of an electrochemical biosensor that uses enzymes, an electrochemical glucose sensor for self-monitoring of blood glucose can be cited. In addition, embedded electrochemical glucose sensors for continuously or semi-continuously measuring glucose concentration in organisms have been developed (for example, see Patent Document 1).

[0003] Existing technical documents

[0004] Patent documents

[0005] Patent Document 1: Japanese Patent Publication No. 2012-519038 Summary of the Invention

[0006] The problem the invention aims to solve

[0007] Electrochemical sensors for measuring analytes such as glucose require higher precision measurements.

[0008] The non-limiting embodiments disclosed herein contribute to providing sensors and methods for manufacturing the same that can measure analytes with higher accuracy.

[0009] Solution to the problem

[0010] One embodiment of the sensor disclosed herein is a sensor having a probe inserted into a biological body to measure an analyte, the probe comprising: a substrate; an electrode formed on the substrate; and a reference layer formed on the electrode, the upper surface of the reference layer being covered by a thin film and the sides being exposed.

[0011] One embodiment of the sensor disclosed herein is a sensor having a probe inserted into a biological body and measuring an analyte. The probe is formed by forming an electrode on a sheet-like substrate, forming a reference layer on the electrode, disposing a thin film on the reference layer, and cutting the substrate into a probe shape. The reference layer is formed by coating the electrode with a paste-like material sprayed from a nozzle across the cutting line.

[0012] One embodiment of the present disclosure is a method for manufacturing a sensor having a probe inserted into a biological body and measuring an analyte. The method involves manufacturing the probe through the following steps: forming an electrode on a sheet-like substrate; forming a reference layer on the electrode; disposing a thin film on the reference layer; and cutting the sheet-like substrate in a shape that forms the probe. In this method, the reference layer is formed by coating the electrode with a paste-like material ejected from a nozzle, and a portion of the reference layer is cut when the sheet-like substrate is cut.

[0013] Invention Effects

[0014] According to one embodiment of this disclosure, analytes can be measured with higher precision.

[0015] Further advantages and effects of one embodiment of this disclosure will be clearly presented by the specification and accompanying drawings. These advantages and / or effects are provided by various embodiments and the features described in the specification and drawings, but not all of them need to be provided to obtain one or more of the same features. Attached Figure Description

[0016] Figure 1 This is a diagram illustrating an application example of the sensor according to the first embodiment.

[0017] Figure 2 This is a cross-sectional view of the sensor.

[0018] Figure 3 This is a planar view of the probe.

[0019] Figure 4A yes Figure 3 A sectional view along the AA line.

[0020] Figure 4B yes Figure 3 BB line sectional view.

[0021] Figure 4C yes Figure 3 CC-line sectional view.

[0022] Figure 5 It is a diagram used to illustrate the positional relationship between the reagent layer and the thin film.

[0023] Figure 6 yes Figure 5 DD-line sectional view.

[0024] Figure 7 This is a three-dimensional view of the reagent layer portion of the probe.

[0025] Figure 8 This is a plan view of the tip of the probe.

[0026] Figure 9 It is a diagram used to illustrate the positional relationship between the reagent layer and the thin film.

[0027] Figure 10 yes Figure 9 EE line sectional view.

[0028] Figure 11 This is a diagram showing an example of the opening shape of a thin film.

[0029] Figure 12 This is an example diagram used to illustrate the size of a sensor.

[0030] Figure 13 This is a perspective view of the probe of the sensor according to the second embodiment.

[0031] Figure 14 Viewed from the third side Figure 13 A partial side view of the probe.

[0032] Figure 15 This is a diagram used to illustrate the shape example of reference layer 24.

[0033] Figure 16 This is a diagram showing an example of Ag / AgCl paste application.

[0034] Figure 17 This is a side view after applying Ag / AgCl paste.

[0035] Figure 18A This is a diagram used to illustrate an example of how a probe is manufactured.

[0036] Figure 18B This is a diagram used to illustrate an example of how a probe is manufactured.

[0037] Figure 18C This is a diagram used to illustrate an example of how a probe is manufactured.

[0038] Figure 19 This diagram illustrates the application of Ag / AgCl paste.

[0039] Figure 20 It is a diagram used to illustrate the shape after applying Ag / AgCl paste.

[0040] Figure 21 It is a diagram used to illustrate the operation of the coating device.

[0041] Figure 22 It is a diagram used to illustrate the operation of the coating device.

[0042] Figure 23 This is a diagram illustrating an example of the shape of a reference layer produced by a single-shot process.

[0043] Figure 24 This is a diagram showing an example of the shape of a reference layer produced by a continuous firing process.

[0044] Figure 25 This is a diagram illustrating an example of the shape of a reference layer produced by a scraper process. Detailed Implementation

[0045] Hereinafter, embodiments of the present disclosure will be described in detail with appropriate reference to the accompanying drawings. However, sometimes unnecessary detailed descriptions will be omitted. For example, detailed descriptions of well-known matters or repetitive descriptions of substantially the same structures will sometimes be omitted. The reason for this is to avoid making the following description unnecessarily lengthy and to facilitate understanding by those skilled in the art.

[0046] Furthermore, the purpose of providing the accompanying drawings and the following description is to enable those skilled in the art to fully understand this disclosure, and there is no intention to limit the subject matter set forth in the claims.

[0047] (First Implementation)

[0048] Figure 1 This is a diagram illustrating an application example of sensor 1 according to the first embodiment. Figure 1 In addition to sensor 1, an organism 2 is also shown. Organism 2 is, for example, a human body.

[0049] Figure 1 The sensor 1 shown is, for example, a biosensor. More specifically, sensor 1 is a CGM (Continuous Glucose Monitor) sensor. Sensor 1 inserts a probe into an organism 2 to continuously or semi-continuously measure the glucose concentration in the blood or interstitial fluid of the organism 2. For example, sensor 1 measures the glucose concentration of the organism 2 over a period of several days to several weeks.

[0050] Figure 2 This is a cross-sectional view of sensor 1. Figure 2 In the middle, to and Figure 1 The same structural elements are marked with the same reference numerals.

[0051] like Figure 2 As shown, sensor 1 includes a body 11 and a probe 12. Probe 12 is inserted into organism 2. Probe 12 has a reagent layer containing an oxidoreductase and outputs an electrical signal based on glucose concentration to body 11. Body 11 stores the electrical signal based on glucose concentration output from probe 12 in a storage device and transmits the electrical signal to other devices (not shown) at predetermined times.

[0052] Figure 3 This is a plan view of probe 12. Figure 3 The entire probe 12 is shown in (A). Figure 3 (B) shows that Figure 3 (A) is an enlarged view of the tip portion of probe 12.

[0053] Figure 3 A portion of region X1 of probe 12 (the head of probe 12) shown in (A) is housed in body 11. The tip of probe 12 protrudes from body 11. The tip of probe 12 is inserted into organism 2. Figure 3 Arrow X2 shown in (A) indicates the insertion direction of probe 12 into organism 2.

[0054] The probe 12 includes a substrate 21, an electrode 22, a reagent layer 23, a reference layer 24, and a thin film 25.

[0055] The manufacturing method of probe 12 is described in summary.

[0056] (1) An electrode 22 is formed on a substrate 21.

[0057] The substrate 21 is, for example, a sheet of synthetic resin. Electrodes 22 are uniformly formed on the substrate 21.

[0058] The material of electrode 22 is, for example, gold (Au). Electrode 22 can also be formed on substrate 21 by sputtering, for example. Electrode 22 can also be referred to as "electrode film" or "electrode layer".

[0059] (2) Divide electrode 22 into three regions.

[0060] Grooves A1 and A2 are formed in the electrode 22 formed on the substrate 21, dividing the electrode 22 into three regions. The electrode 22 is divided into an active electrode 22a, a reference electrode 22b, and a counter electrode 22c by grooves A1 and A2. Grooves A1 and A2 can also be formed, for example, by laser trimming. The active electrode 22a can also be referred to as an "active electrode film" or "active electrode layer". The reference electrode 22b can also be referred to as a "reference electrode film" or "reference electrode layer". The counter electrode 22c can also be referred to as a "counter electrode film" or "counter electrode layer".

[0061] Furthermore, for the active electrode 22a, a potential (a potential referenced to the reference electrode) is supplied sufficient to oxidize the intermediate (containing not only electronic intermediates but also hydrogen peroxide) that has been reduced by the reaction of the oxidoreductase with the analyte (glucose). The glucose concentration is measured by monitoring the current flowing between the active electrode 22a and the counter electrode 22c.

[0062] (3) Forming a reference layer 24.

[0063] A reference layer 24 is formed on the reference electrode 22b at the tip of the probe 12. The material of the reference layer 24 is, for example, silver / silver chloride (Ag / AgCl). For example, Ag / AgCl paste (ink) can also be used to form the reference layer 24 by screen printing or coating process. The reference layer 24 can also be referred to as a "reference film" or "reference electrode".

[0064] (4) Prepare the film 25 and fix it.

[0065] A thin film 25 with openings is disposed on the active electrode 22a, reference electrode 22b, counter electrode 22c, and reference layer 24 formed on the substrate 21. The thin film 25 is sheet-like and has insulating properties. The thin film 25 is disposed such that the opening portion is located at the tip portion of the probe 12 (the portion forming the reagent layer 23). The reagent, described later, is dropped into the opening of the thin film 25. The thin film 25 may also be referred to as a "thin film layer," "insulating layer," or "insulating film." The configuration may also be referred to as a "stack" or "carrier."

[0066] Additionally, the thin film 25 has an opening to allow the upper surface of the counter electrode 22c ( Figure 3 The front and side surfaces of the paper are partially exposed. For example... Figure 3 As shown in region X3 of (B), the opening of the thin film 25 is formed into a notch shape by the cutting process described later in (7). Due to this notch shape, a portion of the counter electrode 22c is exposed on the upper surface. Furthermore, the upper surface can also be understood as the side of the probe 12 forming reagent layer 23.

[0067] Additionally, the thin film 25 has a shape that partially exposes the head of the probe 12. For example, Figure 3 A portion of region X4 in (A) is not covered by the thin film 25. The exposed electrode 22 in region X4 is connected to the circuitry of the body 11.

[0068] In addition, such as Figure 3 As shown in (B), the upper surface of the reference layer 24 is covered by a thin film 25. The reference layer 24 is exposed in the width direction of the probe 12 (the direction perpendicular to the insertion direction indicated by arrow X2). Figure 3 In example (B), the reference layer 24 is exposed on the right side of the tip portion of probe 12 (see also...). Figure 4B Reference layer 24).

[0069] (5) Formation of reagent layer 23.

[0070] A reagent layer 23 is formed on the active electrode 22a at the tip of the probe 12. For example, a reagent is dropped into the opening of the aforementioned thin film 25 and allowed to dry to form the reagent layer 23. Preferably, in… Figure 3The reagent layer 23 is not formed at the tip of the probe 12 indicated by arrow X5 in (B). In other words, it is preferable to form the reagent layer 23 at a distance from the tip of the probe 12. That is, it is preferable not to form the reagent layer 23 within a predetermined distance from the tip of the probe 12. The reason for this is that by forming the reagent layer 23 at a distance from the tip of the probe 12, it is possible to prevent the reagent layer 23 from peeling off (coiling) from the probe 12 when the probe 12 is inserted into the organism 2.

[0071] The reagent layer 23 contains at least an oxidoreductase that can undergo a redox reaction with the analyte (glucose). The reagent layer 23 may also be referred to as a "reagent membrane", "interactive layer", or "interactive electrode".

[0072] Furthermore, the opening of the film 25 may, for example, have a size and shape suitable for forming a reagent layer 23 with a width greater than that of the probe 12. The shape of the reagent layer 23, which is larger than that of the probe 12, is then shaped through a subsequent trimming process.

[0073] (6) Remove reagent layer 23 and electrode 22.

[0074] At the end of the probe 12, whose shape is formed by the cutting process described later (7), along the insertion direction of the probe 12, the reagent layer 23 and the electrode 22 are finely adjusted. Through this fine adjustment, such as... Figure 3 As shown in region X6 of (B), the upper surface of substrate 21 is partially exposed. For example, laser trimming can also be used to fine-tune reagent layer 23 and electrode 22.

[0075] In addition, Figure 3 In (B), the film 25 is also locally (slightly) fine-tuned at both ends of the reagent layer 23 in the insertion direction.

[0076] (7) The probe 12 is cut out from the substrate 21 by cutting.

[0077] The substrate 21, which has undergone the processes described in (1) to (6) above, is cut to cut out... Figure 3 The probe 12 is shown in shape (A).

[0078] The cutting location includes a finely tuned portion. For example, a cut is made near the center (near the center line) of the finely tuned portion (the bottom part of the concave section).

[0079] (8) Form a protective film.

[0080] The tip of the cut probe 12 is, for example, dipped into a liquid that forms a protective film, thus forming a protective film. This protective film prevents or inhibits leakage of substances contained in the reagent layer 23 (primarily oxidoreductases or electron mediators) out of the protective film. The protective film has pores that allow analytes present outside the protective film to permeate into the protective film containing the reagent layer 23. The protective film need only be sufficient to protect (encapsulate) at least a portion of the reagent layer 23 containing the probe 12.

[0081] Figure 4A yes Figure 3 A sectional view along line AA. For example... Figure 4A As shown, for the portion of probe 12 where reagent layer 23 is formed, an active electrode 22a is formed on the substrate 21 (upper surface). Reagent layer 23 is formed on active electrode 22a.

[0082] Through the fine-tuning process described in (6), the reagent layer 23 and the active electrode 22a are removed from both ends of the probe 12 in the width direction (side surface of the probe 12). In the cutting process described in (7), the substrate 21 exposed through the fine-tuning process described in (6) is cut at the position separated from the reagent layer 23 and the active electrode 22a. Thus, as... Figure 4A As shown by arrows 11a and 11b, the side of probe 12 becomes stepped.

[0083] In addition, a protective film is formed around the tip portion of the reagent layer 23 of the probe 12. Figure 4A The illustration of the protective film is omitted.

[0084] Figure 4B yes Figure 3 A sectional view along the BB line. For example... Figure 4B As shown, for the portion of probe 12 where the reference layer 24 is formed, an active electrode 22a and a reference electrode 22b are formed on substrate 21. The active electrode 22a and the reference electrode 22b are physically separated and electrically separated by a groove A1.

[0085] A reference layer 24 is formed on the reference electrode 22b. A thin film 25 is disposed on the active electrode 22a, the reference electrode 22b, and the reference layer 24. Although the upper surface of the reference layer 24 is covered by the thin film 25, the side surface of the probe 12 ( Figure 4B The right side of the middle is exposed.

[0086] Alternatively, the thin film 25 on top of the reference layer 24 may be absent. That is, the upper surface of the reference layer 24 may also be exposed.

[0087] Figure 4C yes Figure 3 A sectional view along the CC line. For example... Figure 4CAs shown, for the exposed portion of the upper surface of the counter electrode 22c, an active electrode 22a, a reference electrode 22b, and a counter electrode 22c are formed on the substrate 21. The active electrode 22a and the reference electrode 22b are physically and electrically separated by a groove A1. The reference electrode 22b and the counter electrode 22c are physically and electrically separated by a groove A2.

[0088] A thin film 25 is formed on the active electrode 22a and the reference electrode 22b. The thin film 25 is not disposed on the counter electrode 22c, and the upper surface of the counter electrode 22c is exposed.

[0089] Examples of each structural component are provided.

[0090] ·Substrate 21

[0091] The substrate 21 is a sheet of synthetic resin. For example, polyethylene terephthalate (PET) can also be used as the substrate 21. However, there are no particular limitations on the resin material, such as a plastic material, as long as it has at least one of the characteristics of flexibility, easy processing, and heat resistance. Other examples include general-purpose plastics such as polyethylene, polypropylene, and polyethylene naphthalate. In addition, polyimide is preferred when high heat resistance is required.

[0092] •Electrode 22

[0093] As mentioned above, gold can also be used as the material for electrode 22. However, there are no particular limitations as long as the material is a metal or carbon that is conductive and stable (e.g., not easily oxidized or salt resistant). Examples of materials for electrode 22 include platinum, palladium, and carbon.

[0094] When using a metal material as electrode 22, the metal material can also be vapor-deposited (including sputtering) onto substrate 21. Other formation methods include printing, plating, and spin coating.

[0095] When carbon is used as electrode 22, carbon paste can also be printed to form electrode 22. In addition, when one of the upper surface and the back surface of probe 12 is set as the active electrode and the other surface is set as the counter electrode, the active electrode and the counter electrode can also be made of different electrode materials.

[0096] ·Reagent layer 23

[0097] As described above, reagent layer 23 contains at least an oxidoreductase capable of undergoing a redox reaction with the analyte. If the oxidoreductase is a dehydrogenase, it also contains an electronic mediator. Alternatively, it can be a system in which an electronic mediator is used even if the oxidoreductase is an oxidase. That is, as long as the system detects hydrogen peroxide produced by the redox reaction of oxidase and glucose by an electrochemical method, an electronic mediator can be used for electrochemical detection even if it is not required. In this case, reagent layer 23 contains an electronic mediator in addition to the oxidase.

[0098] In systems that detect glucose, examples of oxidoreductases include glucose oxidase and glucose dehydrogenase. Regarding glucose dehydrogenase, from the viewpoint of low reactivity to maltose, flavin adenine dinucleotide (FAD)-binding glucose dehydrogenases are preferable, such as enzymes derived from the genera *Aspergillus* (*Oryzae* or *Terreus*) or *Mucor*.

[0099] Examples of electronic mediators include osmium complexes, ruthenium complexes, quinone compounds, phenazine compounds, and ferrocene compounds. Derivatives of these substances can also be listed as electronic mediators.

[0100] • Reference layer 24

[0101] As mentioned above, silver / silver chloride (Ag / AgCl) can also be used as the material for the reference layer 24. Alternatively, the reference layer 24 can be formed by screen printing or coating Ag / AgCl paste (ink) onto the electrode 22 and then drying it.

[0102] Furthermore, for the sensor 1 of this disclosure, an example of a three-electrode structure of an active electrode, a counter electrode, and a reference electrode is shown, which enables better measurement accuracy, but it can also be a two-electrode structure of an active electrode and a counter electrode.

[0103] ·Film 25

[0104] Alternatively, a film 25 can be formed by attaching an adhesive sheet (e.g., acrylic, rubber, or hot-melt type) to a sheet of the same material as the substrate 21. Alternatively, a sheet of a different material from the substrate 21 can be used. Alternatively, the adhesive sheet itself can be used as the film 25. A thermoplastic / photoplastic resist film can also be used as the film 25.

[0105] For the thin film 25, from the viewpoint of reagent coating, it is preferable that the contact angle between the film and the liquid is greater than the contact angle between the film and the liquid at the opening, and the greater the difference between the two contact angles, the better. For example, ideally, the contact angle between the film and the liquid is 90° or more, and the contact angle between the opening and the liquid is 50° or less. Even if the material does not have such a contact angle, it can have such a contact angle by performing at least one of hydrophobic processing on the surface of the film and hydrophilic processing on the opening.

[0106] The film 25 has a thickness of 1 μm or more and 150 μm or less, preferably 3 μm or more and 50 μm or less, and more preferably 5 μm or more and 30 μm or less. The film 25 can also be formed by printing resist ink.

[0107] · Protective film

[0108] The probe 12, having a reagent layer 23, is inserted into the organism 2 for use. Therefore, the protective film covering the surface of the reagent layer 23 preferably has biocompatibility, meaning it does not readily adsorb proteins or cells. Generally, the protective film is preferably formed from a polymer having the properties described above.

[0109] Examples of polymers include copolymers of methyl methacrylate and hydroxyethyl methacrylate, copolymers of butyl methacrylate and hydroxyethyl methacrylate, and poly(2-methacryloyloxyethyl phosphorylcholine-n-butyl methacrylate). Furthermore, (meth)acrylate compounds having the same main chain as these exemplified polymers, but with reactive groups on their side chains capable of reacting with linker peptides, can be used as examples of "vinyl polymers" having methacryloyl or acryloyl groups, listed as specific examples of high molecular weight polymers.

[0110] Figure 5 This is a diagram used to illustrate the positional relationship between reagent layer 23 and film 25. Figure 5 A plan view of the tip portion of probe 12 is shown. Figure 5 In the middle, to and Figure 3 The same structural elements are marked with the same reference numerals.

[0111] Figure 5 A portion of the manufacturing process of probe 12 is shown. Figure 5 The step of “forming a thin film” corresponds to step (4) above. “Applying reagent solution” and “drying the applied reagent solution” correspond to step (5) above. “Fine-tuning” corresponds to step (6) above. “Cutting the sensor” corresponds to step (7) above. “Forming a protective film” corresponds to step (8) above.

[0112] In addition, Figure 5 The descriptions of steps (1) to (3) above are omitted. After steps (1) to (3) above, the process continues... Figure 5 The process of "forming a thin film" is shown. Additionally, in... Figure 5 The illustration of the protective film is omitted in the text.

[0113] Figure 6 yes Figure 5 A DD-line sectional view. A thin film 25 with an opening is disposed on the working electrode 22a. Next, a reagent is dropped into the opening portion of the thin film 25 and allowed to dry. Thus, as... Figure 6 As shown, a reagent layer 23 is formed between thin films 25 in the insertion direction of probe 12. That is, the reagent layer 23 is accommodated and formed within the area defined by the opening of the thin film 25. In other words, the thin film 25 is adjacent to the reagent layer 23 on the electrode 22.

[0114] Alternatively, the thin film 25 on the insertion direction side may not be formed. For example, it may be absent. Figure 5 and Figure 6 The thin film 25 shown on the left.

[0115] Figure 7 This is a three-dimensional view of the reagent layer 23 of probe 12. (See image below.) Figure 7 As shown, the probe 12 includes an upper surface 31 on which a reagent layer 23 is formed, a back surface 32 facing the upper surface 31, a side surface 33 connecting the upper surface 31 and the back surface 32, and a side surface 34 facing the side surface 33 and connecting the upper surface 31 and the back surface 32. Figure 7 The arrow X2 shown indicates the insertion direction of probe 12 into organism 2.

[0116] The upper surface 31 of the probe 12 in the width direction has stepped adjustment portions 35 and 36 at its end, formed by removing the reagent layer 23 and the electrode 22. The adjustment portions 35 and 36 are formed in a positional relationship that at least contacts the reagent layer 23. In other words, the reagent layer 23 extends from one end to the other in the width direction of the upper surface 31, forming the upper surface 31 of the probe 12 and forming a portion of the side surface of the probe 12 (see also...). Figure 4A (Reagent layer 23).

[0117] It can also be understood that the above-mentioned sensor 1 has the following structural elements.

[0118] Sensor 1 has a body 11 and a probe 12. The probe 12 is inserted into the organism 2 to obtain an electrical signal for continuous or semi-continuous measurement of the analyte.

[0119] The substrate 21 has a first surface (e.g., upper surface 31) and a second surface (e.g., back surface 32) facing the first surface. In addition, the substrate 21 has a third surface and a fourth surface (e.g., side surfaces 33, 34) that connect the first surface and the second surface and extend along the insertion direction of the probe 12.

[0120] The active electrode 22a is on the first surface of the substrate 21 and is formed of the first electrode material.

[0121] The reagent layer 23 is disposed on a portion of the active electrode 22a.

[0122] At both ends of the first surface in a direction orthogonal to the insertion direction along which the probe 12 is inserted into the organism 2, the reagent layer 23 and the first electrode material are removed to form fine-tuning sections 35 and 36.

[0123] The reagent layer 23 contains an oxidoreductase. The fine-tuning sections 35 and 36 are formed in a positional relationship that is at least in contact with the reagent layer 23.

[0124] The thin film 25 is adjacent to the reagent layer 23 in the insertion direction of the organism 2, opposite to the tip side of the probe 12.

[0125] The reagent layer 23 does not have a portion sandwiched between the electrode 22 and the thin film 25. In other words, the thin film 25 is not disposed on the reagent layer 23. The thin film 25 may or may not be adjacent to the reagent layer 23 on the tip side of the probe 12. In other words, the thin film 25 may or may not be formed on the tip side of the probe 12.

[0126] It can also be understood that the above-mentioned sensor 1 has the following manufacturing process.

[0127] First, a substrate 21 (substrate sheet) on which an active electrode 22a of a first electrode material is formed on the first surface is prepared.

[0128] Next, at the designated position on the first side, a reagent solution containing oxidoreductase is applied.

[0129] Next, the reagent solution is dried to form reagent layer 23.

[0130] Next, the predetermined position of the reagent layer 23 on the substrate 21 is finely adjusted to form a fine-tuning section formed by removing the reagent layer 23 and the functional electrode 22a formed under the reagent layer 23.

[0131] Next, in the prescribed shape ( Figure 3 The probe 12 shown in (A) is shaped like, for example, a flagpole, to cut the substrate 21. Fine-tuning parts 35 and 36 are included at the cut locations on the substrate 21.

[0132] Alternatively, a protective film may be formed at the tip of the probe 12 that forms the reagent layer 23. The protective film has pores that allow at least the analyte (glucose) to permeate.

[0133] Alternatively, the counter electrode 22c can be formed on either the first or the second surface of the substrate 21. A different counter electrode (second counter electrode) may also be formed on either the first or the second surface of the substrate 21.

[0134] Alternatively, the reference electrode 22b may be formed on at least one of the first to fourth surfaces. When the reference layer 24 is formed on the first surface, a thin film 25 may be disposed on the upper surface, exposing the third surface side.

[0135] Alternatively, the reagent layer 23 may not be formed within a specified distance from the end side (tip of probe 12) of the first surface in the insertion direction of probe 12.

[0136] Alternatively, a portion (end) of the reagent layer 23 may be sandwiched between the electrode 22 and the thin film 25. The reagent layer 23 may also not have a portion sandwiched between the electrode 22 and the thin film 25.

[0137] As described above, the sensor 1 has a probe 12 inserted into the organism 2 to measure the analyte. The probe 12 has a substrate 21, an electrode 22 formed on the substrate 21, and a reagent layer 23 formed on the electrode 22 and containing an oxidoreductase. At at least one end of the probe 12 in the width direction, the reagent layer 23 and the electrode 22 are finely adjusted along the insertion direction of the probe 12 into the organism 2.

[0138] This suppresses performance deviations in sensor 1 caused by the manufacturing process. For example, even if the reagent layer 23 dropped onto electrode 22 is in a "coffee ring state" where the edge portion is thicker than the center portion, it is possible to use the uniform (homogeneous) portion within the ring as the reagent layer 23 by fine-tuning.

[0139] In addition, when cutting according to the shape of probe 12, the tip of the blade can be kept away from the reagent layer 23, thereby reducing the cracks in the reagent layer 23.

[0140] In addition, when cutting according to the shape of probe 12, the tip of the blade can be prevented from contacting the reagent layer 23, thereby suppressing reagent contamination.

[0141] In addition, as described above, the probe 12 of the sensor 1 is manufactured by the following steps: forming an electrode 22 on a substrate 21; forming a reagent layer 23 containing an oxidoreductase on the electrode 22; and fine-tuning the reagent layer 23 and the electrode 22 at at least one end in the width direction of the probe 12 along the insertion direction in which the probe 12 is inserted into the organism 2.

[0142] This suppresses performance deviations in sensor 1 caused by the manufacturing process. For example, even if the reagent layer 23 added to electrode 22 is in a coffee ring state, it is possible to use the uniform (homogeneous) central portion within the ring as the reagent layer 23 by fine-tuning.

[0143] Furthermore, when cutting according to the shape of probe 12, fine adjustments can be made to prevent the blade tip from contacting reagent layer 23, thus reducing cracks in reagent layer 23. Additionally, reagent contamination can be suppressed.

[0144] In addition, as described above, the thin film 25 is disposed on the electrode 22 such that it is adjacent to the reagent layer 23 at both ends in the insertion direction of the reagent layer 23.

[0145] This suppresses performance deviations in sensor 1 caused by the manufacturing process. For example, the position of reagent addition can be determined by the thin film 25, thereby enabling the formation of a uniform reagent layer 23 before fine-tuning.

[0146] (Variation Example 1)

[0147] The probe 12 may also have a fine-tuning section at one end in the width direction. That is, there may be only one fine-tuning section.

[0148] Figure 8 This is a plan view of the tip portion of probe 12. Figure 8 In the middle, to and Figure 3 The same structural elements are marked with the same reference numerals. Figure 8 An example is shown in which the active electrode 22a and the counter electrode 22c are formed side-by-side in the width direction of the probe 12. Figure 8 The illustration of film 25 is omitted in the text.

[0149] A reagent layer 23 is formed on one end of the probe 12 in the width direction, spanning the width of the probe 12. On the other end of the probe 12 in the width direction, a reagent layer 23 is formed without spanning the width of the probe 12. For example, in... Figure 8 In the example, the reagent layer 23 is formed in a manner that spans the right end of probe 12 but does not span the left end of probe 12.

[0150] The probe 12 has a fine-tuning section 41. The fine-tuning section 41 is formed on one side of the reagent layer 23 that spans the width of the probe. Figure 6 (Right side of the image). A fine-tuning section 41 is formed by fine-tuning the reagent layer 23 and the active electrode 22a. The substrate 21 is exposed due to the fine-tuning section 41.

[0151] In this way, probe 12 can also have a fine-tuning section at one end in the width direction. This will also suppress performance deviations of sensor 1 caused by the manufacturing process.

[0152] (Variation Example 2)

[0153] The reagent layer 23 may also extend beyond the area defined by the film 25 in the insertion direction of the probe 12.

[0154] Figure 9 This is a diagram used to illustrate the positional relationship between reagent layer 23 and film 25. Figure 9 A plan view of the tip portion of probe 12 is shown. Figure 9 In the middle, to and Figure 3 The same structural elements are marked with the same reference numerals.

[0155] Figure 9 A portion of the manufacturing process of probe 12 is shown. Figure 9 The steps “applying reagent solution” and “drying the applied reagent solution” shown correspond to the steps in (5) above. “Forming a thin film” corresponds to the steps in (4) above. “Fine-tuning” corresponds to the steps in (6) above. “Cutting the sensor” corresponds to the steps in (7) above. “Forming a protective film” corresponds to the steps in (8) above.

[0156] In addition, Figure 9 The descriptions of steps (1) to (3) above are omitted. After steps (1) to (3) above, the process continues... Figure 9 The procedure of "applying reagent solution" is shown. Additionally, in... Figure 9 The illustration of the protective film is omitted in the text.

[0157] Figure 10 yes Figure 9 A sectional view along the EE line. A thin film 25 with an opening is disposed on the reagent layer 23. The thin film 25 is disposed such that the opening portion is located within the reagent layer 23. The opening of the thin film 25 is formed such that it overlaps with the reagent layer 23 at both ends in the insertion direction (direction of arrow X2). That is, a portion of the thin film 25 overlaps the reagent layer 23 at both ends in the insertion direction. Additionally, a portion of the thin film 25 overlaps the fine-tuning portion at both ends in the insertion direction.

[0158] Alternatively, the thin film 25 on the insertion direction side may not be formed. For example, it may be absent. Figure 9 and Figure 10 The thin film 25 shown on the left.

[0159] Thus, the thin film 25 is disposed on the electrode 22 such that its two ends overlap the reagent layer 23 and the fine-tuning part in the insertion direction of the reagent layer 23.

[0160] This suppresses performance deviations of sensor 1 caused by the manufacturing process. For example, the end of reagent layer 23 in the insertion direction of probe 12 (the edge portion of the coffee ring) can be covered by film 25, while exposing a uniform portion of reagent layer 23.

[0161] (Variation Example 3)

[0162] An example of the opening shape of the film 25 will be explained.

[0163] Figure 11 This is a diagram showing an example of the opening shape of the thin film 25. Figure 11 (A) and Figure 11 The part marked (B) with a shading indicates the fine-tuning section. Figure 11 (A) and Figure 11 The polygonal and circular shapes shown in (B) represent the shape of the opening portion of the film 25. Figure 11 The arrow X2 shown indicates the insertion direction of probe 12 into organism 2.

[0164] exist Figure 11 In (A), thin films 25 are formed at both ends of the reagent layer 23 in the insertion direction (for example, see reference). Figure 5 and Figure 6 ).exist Figure 11 In (B), a thin film 25 is formed at one end of the reagent layer 23 on the side opposite to the tip side (e.g., forming a thin film 25). Figure 5 and Figure 6 (The film 25 on the right side, but not the film 25 on the left side). In this way, the opening shape of the film 25 can also have various shapes.

[0165] (Variation Example 4)

[0166] An example of the size of sensor 1 will be explained.

[0167] Figure 12 This is a diagram illustrating an example of the size of sensor 1. Figure 12 In the middle, to and Figure 3 and Figure 7 The same structural elements are labeled with the same reference numerals. Figure 12 The illustration of film 25 is omitted in the text.

[0168] The width D1 of the tip portion of the probe 12 is, for example, 70 μm or more and 1700 μm or less. The width D1 is preferably 70 μm or more and 600 μm or less, and more preferably 70 μm or more and 400 μm or less.

[0169] The width D2 of the fine-tuning sections 35 and 36 is, for example, 5 μm or more. The width D2 is not particularly limited as long as it meets the condition that the width relative to the tip of the probe 12 is sufficient to ensure the width of the reagent layer 23. Increasing the width D2 of the fine-tuning sections 35 and 36 can be achieved by irradiating the laser multiple times.

[0170] (Second Implementation)

[0171] For example, electrochemical sensors such as CGM sensors continuously or semi-continuously measure analytes in organisms over periods ranging from days to weeks. In such cases, depending on the measurement timing (e.g., days or hours), even with the same analyte concentration, the signal intensity received from the probe can sometimes differ, leading to a decrease in the sensor's measurement accuracy.

[0172] One reason for this is that, due to continuous energization of the reference layer over a long period, the material of the reference layer, namely Ag / AgCl (silver or silver chloride), decomposes, and the decomposed Ag / AgCl flows into the active electrode side. Furthermore, the inventors speculate that the abnormal signal value caused by the inflow of Ag / AgCl into the active electrode side is due to the reaction between silver ions or chloride ions and the reagents on the active electrode side. Therefore, by suppressing the decomposition of Ag / AgCl in the reference layer, the decrease in the sensor's measurement accuracy can be suppressed.

[0173] One way to suppress the decomposition of Ag / AgCl in the reference layer is to miniaturize the reference layer, reducing the area in contact with the analyte. Processes for constructing the Ag / AgCl reference layer include, for example, screen printing and coating processes.

[0174] However, when forming microelectrodes using screen printing, the tiny size of the electrodes makes them prone to clogging the printing plate. Furthermore, the screen printing process involves significant waste of Ag / AgCl paste. Therefore, from the perspective of mass-producing sensors, screen printing is not suitable.

[0175] From the perspective of miniaturizing Ag / AgCl electrodes (reference layers), plating is the preferred process, but it is not suitable for mass production of sensors. The reasons are twofold: first, the management of the chemicals or manufacturing processes used in plating is complex; second, during Ag / AgCl electrode plating, it is difficult to mask the probe portion other than the tiny Ag / AgCl electrode itself, and continuous management of this portion is challenging.

[0176] The following describes a sensor and its manufacturing method that can reduce the contact area between the reference layer and the analyte, thereby enabling higher precision measurement of the analyte.

[0177] Figure 13 This is a perspective view of the probe 12 of the sensor 1 according to the second embodiment. Figure 13 In the middle, to and Figure 2 and Figure 3 The same structural elements are marked with the same reference numerals.

[0178] Figure 13 The probe 12 shown has an electrode 22, similar to the probe 12 described in the first embodiment. Additionally, the probe 12 also has a reagent layer 23, similar to the probe 12 described in the first embodiment. Figure 13 (not shown in the diagram), reference layer 24 ( Figure 13 (not shown in the figure), and a portion of the counter electrode 22c exposed on the first surface ( Figure 13 (Not shown in the image).

[0179] The side of the probe 12 that forms the reagent layer 23 and the reference layer 24 is sometimes referred to as the "first side". The side facing the first side is sometimes referred to as the "second side".

[0180] Additionally, sometimes when connecting the first and second surfaces along the insertion direction of probe 12 ( Figure 13 In the plane extending in the direction of arrow X2, the plane on the right when viewed from the tip of probe 12 is called the "third plane". Sometimes, in the plane connecting the first plane and the second plane and extending along the insertion direction of probe 12, the plane on the left when viewed from the tip of probe 12 is called the "fourth plane".

[0181] In addition, the first surface can also be called the "top surface". The second surface can also be called the "bottom surface". The third and fourth surfaces can also be called the "side surfaces".

[0182] Figure 14 Viewed from the third side Figure 13 A partial side view of probe 12. (See attached image.) Figure 14 As shown, an electrode 22 is formed on the first surface of the substrate 21. The electrode 22 has an active electrode 22a, a reference electrode 22b, and a counter electrode 22c.

[0183] A reagent layer 23 is formed on the first side of the active electrode 22a of electrode 22. A reference layer 24 is formed on the first side of the reference electrode 22b of electrode 22. The Ag / AgCl paste coated on the reference electrode 22b is cured to form the reference layer 24.

[0184] The first side of the reference layer 24 is covered by the thin film 25. In other words, the first side of the reference layer 24 is not exposed. The reference layer 24 is exposed on the third side of the probe 12. In other words, the reference layer 24 is exposed in the width direction of the probe 12 (the direction perpendicular to the insertion direction indicated by arrow X2) (see also...). Figure 4B ).

[0185] Furthermore, the reference layer 24 exposed on the third side, as described in the first embodiment, may also be covered by a protective film. As described in the first embodiment, the protective film has pores that allow at least the analyte (glucose) to permeate. Therefore, the reference layer 24 is at least exposed to the analyte (in contact with, energized).

[0186] The thin film 25 has an opening to expose a portion of the region X3 on the first surface side of the counter electrode 22c. The opening of the thin film 25 has a notch shape (see also...). Figure 3 (Region X3 of (B)). Due to the shape of the notch, a portion of the counter electrode 22c is exposed on the upper surface.

[0187] The shape of the reference layer 24, viewed from the first side in the direction from the third side toward the fourth side, can also be an arc shape or an elliptical arc shape, etc. (e.g., reference). Figure 15 ).

[0188] Furthermore, from the head of probe 12 ( Figure 13 The portion of the active electrode 22a extending from region X1 to reagent layer 23 can also be referred to as a "lead" or "active electrode lead". The portion of the reference electrode 22b extending from the head of probe 12 to reference layer 24 can also be referred to as a "lead" or "reference electrode lead". The portion of the counter electrode 22c extending from the head of probe 12 to the opening (region X3) of thin film 25 can also be referred to as a "lead" or "counter electrode lead".

[0189] Alternatively, the reference layer 24 may also be exposed on the fourth surface side. Furthermore, the reference layer 24 and the counter electrode 22c may also be formed on the second surface side. When the reference layer 24 and the counter electrode 22c are formed on the second surface side, reference electrode leads and counter electrode leads are also formed on the second surface side.

[0190] Figure 15 This is a diagram used to illustrate the shape example of reference layer 24. Figure 15 (A) and Figure 15(B) indicates the reference layer 24 when the probe 12 is viewed from the first side. Figure 15 (A) and Figure 15 In (B), the illustration of film 25 is omitted. Figure 15 (A) and Figure 15 (B) shows the slots A1 and A2 (also see) that separate the active electrode 22a, the reference electrode 22b, and the counter electrode 22c of electrode 22. Figure 3 (B)

[0191] like Figure 15 As shown in (A), the shape of the reference layer 24 in the direction from the third surface to the fourth surface when viewing the probe 12 from the first surface side can also be an arc shape. Alternatively, the shape of the reference layer 24 in the direction from the third surface to the fourth surface when viewing the probe 12 from the first surface side can also be an elliptical arc shape. In other words, the shape of the reference layer 24 can also be such that, when viewed from the first surface side, it tapers in the direction from the exposed surface (third surface) of the reference layer 24 towards the central portion (interior) of the reference layer 24 (from the third surface to the fourth surface).

[0192] The reference layer 24 can also have a shape formed by connecting multiple circular or elliptical arcs. For example, as... Figure 15 As shown in (B), the reference layer 24 can also have a shape formed by two connected arcs. That is, the reference layer 24 can also have a first arc and a second arc, or a first elliptical arc and a second elliptical arc. In addition, the reference layer 24 can also have a shape that combines arcs and elliptical arcs.

[0193] like Figure 15 (A) and Figure 15 As shown in (B), the width (area) of the reference electrode 22b (reference electrode lead) is increased on the tip side of the probe 12. A portion of the increased width of the reference electrode lead is coated with Ag / AgCl paste.

[0194] An overview of the manufacturing method of probe 12 (reference layer 24 of probe 12) is provided.

[0195] Step 1: An electrode 22 is formed on the first side of the sheet-like substrate 21.

[0196] Step 2: Apply Ag / AgCl paste to the specified positions on electrode 22.

[0197] Step 3: Allow the applied Ag / AgCl paste to dry.

[0198] Step 4: Form a thin film 25 in the portion containing the dried Ag / AgCl.

[0199] Step 5: Cut the sheet-like substrate 21 into a probe shape. During cutting, the cutting is performed in a manner that includes a portion of the dried Ag / AgCl.

[0200] Alternatively, step 1a can be performed following step 1. Furthermore, step 2a can be performed instead of step 2.

[0201] Step 1a: Grooves A1 and A2 are formed in the electrodes 22 formed on the substrate 21, thereby forming the active electrode 22a, the reference electrode 22b and the counter electrode 22c.

[0202] Step 2a: Apply Ag / AgCl paste to a specified location on the reference electrode 22b formed in step 1a. For example, apply Ag / AgCl paste to a portion of the area of ​​the reference electrode 22b (reference electrode lead) whose width expands on the tip side of the probe 12.

[0203] Alternatively, step 2 can be performed in the manner described in step 2b below.

[0204] Step 2b: When applying Ag / AgCl paste to the first side of the sheet substrate 21, the application is performed in such a way that a portion of the Ag / AgCl paste includes the reference electrode 22b (reference electrode lead). In other words, the Ag / AgCl paste is applied in such a way that it crosses the portion of the substrate 21 being cut in step 5.

[0205] Figure 16 This is a diagram showing an example of the application of Ag / AgCl paste 51. Figure 16 Electrodes 22 formed on substrate 21 are shown. Figure 16 (The reference numerals are omitted in the attached diagram), trough A1, trough A2, and Ag / AgCl paste 51. Figure 16 The dashed line X11 shown represents the portion that was cut in process 5. Figure 16 The head, tip, reagent layer 23, and film 25 of probe 12 are omitted from the illustration.

[0206] like Figure 16 As shown, Ag / AgCl paste 51 is applied to the end of the reference electrode 22b (the widened portion of the reference electrode 22b) in the insertion direction of the probe 12. Furthermore, Ag / AgCl paste 51 is applied across the portion of the substrate 21 being cut in step 5 (dashed line X11). Therefore, in step 5, the substrate 21 is cut across the portion coated with Ag / AgCl paste 51.

[0207] Furthermore, in step 4, a thin film 25 is formed on the upper surface of the Ag / AgCl paste 51. Therefore, as... Figure 14As explained, the reference layer 24 is not exposed on the upper surface (first surface) of the probe 12, but on the side (third surface).

[0208] Figure 17 This is a side view after applying Ag / AgCl paste 51. Figure 17 The substrate 21, electrode 22, and Ag / AgCl paste 51 are shown.

[0209] The coating process is suitable for forming microelectrodes (Ag / AgCl reference layer 24). However, for the surface of the reference layer 24 formed by the coating process, such as from... Figure 17 As understood from the side view, the reference layer 24 has no flat surface and a large surface area. In addition, the Ag / AgCl paste 51, as shown on the right, sometimes has corners (protrusions) on its surface (in addition, sometimes the corners are removed by cutting in process 5).

[0210] In contrast, in this application, a portion of the Ag / AgCl paste 51 is applied across the cut portion of the substrate 21 and onto the reference electrode 22b. Furthermore, the substrate 21 is cut while the upper surface of the applied Ag / AgCl paste 51 is covered by a thin film 25. This reduces the area of ​​the cross-section (exposed portion) of the reference layer 24.

[0211] In addition, during the coating process, the surface area deviation of Ag / AgCl paste 51 is prone to increase.

[0212] In contrast, in this application, a portion of the Ag / AgCl paste 51 is applied across the cut portion of the substrate 21 and onto the reference electrode 22b. Furthermore, the substrate 21 is cut while the upper surface of the applied Ag / AgCl paste 51 is covered by a thin film 25. This suppresses deviations in the area of ​​the cross-section (exposed portion) of the reference layer 24.

[0213] Therefore, sensor 1 can measure the analyte with high precision. In addition, sensor 1 can be easily mass-produced.

[0214] The detailed manufacturing method of probe 12 is explained. Figures 18A-18C This is a diagram used to illustrate an example of the manufacturing method of probe 12.

[0215] (Process 11)

[0216] like Figure 18A As shown in step 11, an electrode 22 is formed on a sheet-like substrate 21. For example, an electrode material such as gold is sputtered onto a sheet-like substrate 21 such as polyethylene terephthalate (PET) to form the electrode 22.

[0217] (Process 12)

[0218] like Figure 18A As shown in step 12, electrode 22 is finely adjusted to form active electrode 22a, reference electrode 22b, and counter electrode 22c (in Figure 18A (In step 12, the reference numerals are omitted). For example, laser fine-tuning can also be used to fine-tune electrode 22.

[0219] (Process 13)

[0220] like Figure 18A As shown in step 13, Ag / AgCl paste 51 is applied to the reference electrode 22b across the cut portion (cut line) of the substrate 21 and then dried. In other words, Ag / AgCl paste 51 is applied across the reference electrode 22b and the portion outside the probe 12 after the final cut, and then dried. Thus, a reference layer 24 is formed on the electrode 22 (reference electrode 22b).

[0221] also, Figure 18A (Process 13) is to Figure 18A An enlarged view of the dashed box A21 portion of (process 12), and with Figure 16 The same diagram. Figure 18A In step 13, a reference electrode 22b, trench A1, trench A2, and Ag / AgCl paste 51 formed on substrate 21 are shown. Figure 18A In step 13, the head, tip, reagent layer 23 and film 25 of probe 12 are omitted from the illustration.

[0222] (Step 14)

[0223] like Figure 18B As shown in step 14, a thin film 25 is adhered to a substrate 21. The portion of the thin film 25 forming the reagent layer 23 of the active electrode 22a and the region X3 of the counter electrode 22c (see reference) Figure 14 The corresponding portion is open. At this time, the reference electrode 22b (reference layer 24) on the first surface side is covered by the thin film 25 (see reference). Figure 14 ).

[0224] also, Figure 18B Arrow A22 in (step 14) indicates the opening of the thin film 25 where the reagent layer 23 is formed. The region X3 corresponding to the counter electrode 22c (see reference) is omitted. Figure 14 The diagram shows the opening of the corresponding portion of the film 25.

[0225] (Step 15)

[0226] like Figure 18B As shown in step 15, at the opening portion of the thin film 25 used to form the reagent layer 23 ( Figure 18BThe reagent solution is applied to the portion of arrow A22 shown in (step 14) and dried to form reagent layer 23.

[0227] (Step 16)

[0228] like Figure 18C As shown in step 16, the substrate 21 is cut into the shape of the probe 12 in such a manner that it includes a portion of the reagent layer 23 and a portion of the Ag / AgCl paste 51. The reference layer 24 is covered by a thin film 25 on the first side of the probe 12, but exposed on the third side.

[0229] (Step 17)

[0230] like Figure 18C As shown in step 17, for example by impregnation, at least part of the reagent layer 23 of the probe 12 is covered by a protective film.

[0231] Figure 19 This diagram illustrates the application of Ag / AgCl paste 51. Figure 19 A portion of a substrate 21 on which electrodes 22 are formed and a coating apparatus 61 are shown. The coating apparatus 61 has a nozzle 62. Ag / AgCl paste 51 is ejected from the nozzle 62 and coated onto the reference electrode 22b.

[0232] Figure 20 This diagram illustrates the shape after applying Ag / AgCl paste 51. (Example) Figure 20 (A) Figure 20 As shown in (D), the Ag / AgCl paste 51 coated on the substrate 21 can also have a circular or oval shape. Additionally, as... Figure 20 As shown in (E), Ag / AgCl paste 51 can also have a speech balloon shape. The balloon shape is formed, for example, by a scraper process described later.

[0233] Figure 20 The dashed line A31 shown illustrates, for example, the cutting line of the cut performed in process 16 described above. Therefore, the peripheral shape seen when viewing the reference layer 24 from the top surface side can be a shape obtained by cutting the substrate 21 into an arc shape, an elliptical arc shape, or a balloon shape in half, etc. (for example, see reference...) Figure 23 (A) Figure 24 (A) and Figure 25 (A)).

[0234] Figure 21 This diagram illustrates the operation of the coating apparatus 61. (For example...) Figure 21 As shown in (A), the coating apparatus 61 moves to the vicinity of the substrate 21. Then, the coating apparatus 61 sprays Ag / AgCl paste 51 from the nozzle 62.

[0235] After the coating device 61 sprays out the Ag / AgCl paste 51, as follows: Figure 21 (B) and Figure 21 As shown in (C), it rises.

[0236] Thus, Ag / AgCl paste 51 is coated on the reference electrode 22b of substrate 21.

[0237] Furthermore, when the coating apparatus 61 coats the reference electrode 22b on the substrate 21, Figure 21 When the operation shown is performed once, an Ag / AgCl paste 51 is coated on the reference electrode 22b of the substrate 21 (e.g., reference). Figure 20 (A) Figure 20 (B)). Alternatively, the process of coating an Ag / AgCl paste 51 on the reference electrode 22b of the substrate 21 can be called a "single-shot process".

[0238] Additionally, when the coating apparatus 61 coats the reference electrode 22b on the substrate 21, Figure 21 When the operation shown is performed more than twice, two or more Ag / AgCl pastes 51 will be applied to the reference electrode 22b of the substrate 21 (for example, referring to...). Figure 20 (C) Figure 20 (D)). The process of coating two or more Ag / AgCl pastes 51 on the reference electrode 22b of the substrate 21 can also be called a "continuous coating process".

[0239] Figure 22 This diagram illustrates the operation of the coating apparatus 61. (For example...) Figure 22 As shown in (A), the coating apparatus 61 moves to the vicinity of the substrate 21. Then, the coating apparatus 61 sprays Ag / AgCl paste 51 from the nozzle 62.

[0240] Then, the coating device 61 as follows Figure 22 As shown in (B), it moves parallel to the substrate 21 while maintaining the distance between them.

[0241] Next, the coating device 61, as Figure 22 As shown in (C), it rises.

[0242] Therefore, Ag / AgCl ointment 51 Figure 20 As shown in (E), the reference electrode 22b of the substrate 21 is coated in a balloon shape.

[0243] In addition, the following process can also be referred to as the "scraper process", which refers to moving the coating device 61 in parallel while maintaining a distance from the substrate 21, and applying Ag / AgCl paste 51 onto the substrate 21.

[0244] Figure 23 This is a diagram showing an example of the shape of the reference layer 24 produced by a single-shot process. Figure 23 (A) shows an example of the shape of the reference layer 24 when viewed from the first side of the probe 12 after the substrate 21 has been cut. Figure 23 (B) shows an example of the shape of the reference layer 24 when viewed from the third side of the probe 12 after cutting the substrate 21.

[0245] like Figure 23 As shown in (A), when viewed from the first surface of the probe 12, the reference layer 24 can also be formed in an arc shape. For example, the reference layer 24 can also be an arc (semicircle) with a central angle of 180°. Alternatively, the reference layer 24 can also be an arc with a central angle greater than 180°. Furthermore, the reference layer 24 can also be an arc with a central angle less than 180°. Additionally, the reference layer 24 can also be formed in an elliptical arc shape, a quadrilateral shape, or a triangular shape.

[0246] like Figure 23 As shown in (B), when viewed from the third side of the probe 12, the reference layer 24 can also be formed into an arc shape, an elliptical arc shape, an arc shape or an elliptical arc shape with a corner in the center, a shape with a corner around the perimeter, or a quadrilateral shape.

[0247] The shape of the reference layer 24 can be set to various shapes according to the shape of the nozzle 62 of the coating apparatus 61. However, Figure 23 The angular shape around (B) is not a nozzle shape, but is formed by point application.

[0248] Figure 24 This is a diagram showing an example of the shape of the reference layer 24 produced by the continuous firing process. Figure 24 (A) shows an example of the shape of the reference layer 24 when viewed from the first side of the probe 12 after the substrate 21 has been cut. Figure 24 (B) shows an example of the shape of the reference layer 24 when viewed from the third side of the probe 12 after cutting the substrate 21.

[0249] like Figure 24 As shown in (A), when viewed from the first surface side of probe 12, the reference layer 24 can also be formed in an arc shape. The reference layers 24 can be adjacent or separate. Furthermore, the reference layers 24 can also overlap. Although in Figure 24 (A) is not illustrated, but the shape of the reference layer 24 is not limited to an arc shape, but can also be an elliptical arc shape, a quadrilateral shape or a triangular shape.

[0250] like Figure 24 As shown in (B), when viewed from the third side of the probe 12, the reference layer 24 can also be formed into an arc shape, an elliptical arc shape, an arc or elliptical arc shape with corners, a shape with corners in the center, or a quadrilateral shape.

[0251] The shape of the reference layer 24 can be set to various shapes according to the shape of the nozzle 62 of the coating device 61.

[0252] Figure 25 This is a diagram showing an example of the shape of the reference layer 24 produced by the scraper process. Figure 25 (A) shows an example of the shape of the reference layer 24 as viewed from the first side of the probe 12 after the substrate 21 has been cut. Figure 25 (B) shows an example of the shape of the reference layer 24 when viewed from the third side of the probe 12 after cutting the substrate 21.

[0253] like Figure 25 As shown in (A), when viewed from the first side of the probe 12, the reference layer 24 can also be formed into a shape obtained by cutting a balloon shape in half. Alternatively, the reference layer 24 can also be formed by connecting multiple shapes obtained by cutting a balloon shape in half.

[0254] like Figure 25 As shown in (B), when viewed from the third side of the probe 12, the reference layer 24 can also be formed into a shape obtained by cutting the balloon shape in half. The reference layer 24 can also have a corner on a portion of the upper surface of the shape obtained by cutting the balloon shape in half. In addition, when viewed from the third side of the probe 12, the reference layer 24 can also be formed into a quadrilateral shape.

[0255] The Ag / AgCl paste 51 will be described. For example, the Ag / AgCl paste 51 may have a viscosity in the range of 0.1 Pa·s or more and 300 Pa·s or less. More preferably, the Ag / AgCl paste 51 may also have a viscosity in the range of 1 Pa·s or more and 100 Pa·s or less. Even more preferably, the Ag / AgCl paste 51 may also have a viscosity in the range of 10 Pa·s or more and 50 Pa·s or less.

[0256] To set the Ag / AgCl paste 51 to a specified viscosity, organic solvents such as diluents with toluene, xylene, ethyl acetate, butyl acetate, or acetone as the main components can be used.

[0257] The exposed dimensions of the reference layer 24 will be explained. From the viewpoint of suppressing the decomposition of the reference layer 24 over a long period of time, the height of the exposed surface of the reference layer 24 can, for example, be in the range of 1 μm or more and 200 μm or less. More preferably, the height of the exposed surface of the reference layer 24 can also be in the range of 2 μm or more and 50 μm or less. Even more preferably, the height of the exposed surface of the reference layer 24 can also be in the range of 5 μm or more and 15 μm or less.

[0258] Furthermore, the width of the exposed surface of the reference layer 24 can be, for example, in the range of 1 μm or more and 1000 μm or less. More preferably, the width of the exposed surface of the reference layer 24 can also be in the range of 50 μm or more and 800 μm or less. Even more preferably, the width of the exposed surface of the reference layer 24 can also be in the range of 100 μm or more and 600 μm or less. Moreover, the exposed area of ​​the reference layer 24 can, for example, be 0.5 μm. 2 Above and 160,000 μm 2 The following range. More preferably, the exposed area of ​​the reference layer 24 can also be 70 μm. 2 Above and 32000μm 2 The following range. More preferably, the exposed area of ​​the reference layer 24 can also be 390 μm. 2 Above and 7100μm 2 The following range.

[0259] As described above, the probe 12 of the sensor 1, which is inserted into a biological body to measure analytes, includes a substrate 21, an electrode 22 formed on the substrate 21, and a reference layer 24 formed on the electrode 22. The first side of the reference layer 24 is covered by a thin film 25, and the third side is exposed.

[0260] In this way, the first side of the reference layer 24 of sensor 1 is covered by the thin film 25, while the third side is exposed. This reduces the contact area between the reference layer 24 and the analyte, suppressing the decomposition of the reference layer 24 (decomposition of Ag / AgCl). Therefore, sensor 1 can measure the analyte with higher accuracy.

[0261] Furthermore, the reference layer 24 is coated onto the electrode 22 by a coating process and has a shape that tapers in the direction from the third surface toward the interior of the reference layer 24. Thus, the reference layer 24 can be stably and minutely formed on the first surface by the coating process.

[0262] Furthermore, if the tip of the Ag / AgCl paste, which is applied to the electrode 22 in a roughly teardrop shape or a roughly domed shape, is positioned outside the product (outside the probe 12) by means of a scraper action, a reference layer 24 can be formed in a smaller size.

[0263] Furthermore, although the reference layer 24 is formed on the electrode 22 by a coating process, it can also be formed by a screen printing process. Of these two processes, coating is preferred. This is because screen printing results in significant material (Ag / AgCl) loss, and the manufacturing process is more complex due to the need to manage situations where the screen printing plate becomes clogged with Ag / AgCl paste.

[0264] The embodiments have been described above with reference to the accompanying drawings, but this disclosure is not limited to these examples. Those skilled in the art will readily conceive of various modifications or alterations within the scope of the claims. It should be understood that these modifications or alterations also fall within the technical scope of this disclosure.

[0265] Furthermore, the structural elements in the embodiments can be combined arbitrarily without departing from the spirit of this disclosure.

[0266] For example, the probe 12 described in the second embodiment may also have a fine-tuning section in the same way as the probe 12 described in the first embodiment.

[0267] Alternatively, the probe 12 described in the second embodiment may also have a protective film covering the reagent layer 23.

[0268] Alternatively, the probe 12 described in the second embodiment can also be as follows: Figure 10 As described above, a portion of the thin film 25 overlaps the reagent layer 23 at both ends in the insertion direction. Alternatively, the thin film 25 may not be formed on the insertion direction side.

[0269] Furthermore, the materials used for the structural elements of the probe 12 described in the second embodiment can also be the same as those used for the structural elements of the probe 12 described in the first embodiment. Additionally, the size of the probe 12 described in the second embodiment can also be the same as that of the probe 12 described in the first embodiment.

[0270] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 982,939, filed on February 28, 2020, and incorporates the entire contents of U.S. Provisional Application No. 62 / 982,939 by reference.

[0271] Industrial applicability

[0272] This disclosure is useful for biosensors such as CGM sensors.

[0273] Explanation of reference numerals in the attached figures

[0274] 1. Sensor

[0275] 2. Organisms

[0276] 11 Main Body

[0277] 12 probes

[0278] 21 substrate

[0279] 22 electrodes

[0280] 22a Working electrode

[0281] 22b reference electrode

[0282] 22c counter electrode

[0283] 23 Reagent Layer

[0284] 24 Reference Layer

[0285] 25 films

[0286] 31 Upper surface

[0287] 32 Back

[0288] 33, 34 Side View

[0289] 35, 36 Fine-tuning section

[0290] 51 Ag / AgCl ointment

[0291] 61 Coating apparatus

[0292] 62 nozzles

Claims

1. A sensor having a probe inserted into a biological body to measure an analyte, characterized in that, The probe includes: substrate; Electrodes are formed on the substrate; as well as A reference layer is formed on the electrode. The upper surface of the reference layer is covered by a thin film, with the sides exposed. When viewed from the upper surface side, the reference layer has a shape that contracts in a direction from the side towards the interior of the reference layer.

2. The sensor as claimed in claim 1, wherein, The side of the reference layer is exposed to the analyte.

3. The sensor as described in claim 2, wherein, The side of the reference layer is covered by a protective film that the analyte can permeate.

4. A sensor having a probe inserted into a living organism to measure an analyte, characterized in that, The probe includes: substrate; Electrodes are formed on the substrate; as well as A reference layer is formed on the electrode. The upper surface of the reference layer is covered by a thin film, with the sides exposed. The shape of the reference layer from the side toward the interior of the reference layer is an arc shape, an elliptical arc shape, or a triangular shape.

5. The sensor as claimed in claim 4, wherein, The reference layer has multiple circular arc shapes, multiple elliptical arc shapes, or multiple triangular shapes.

6. The sensor as claimed in claim 4, wherein, The side of the reference layer is exposed to the analyte.

7. The sensor as claimed in claim 6, wherein, The side of the reference layer is covered by a protective film that the analyte can permeate.

8. A sensor having a probe inserted into a biological body to measure an analyte, characterized in that, The probe is formed by forming electrodes on a sheet-like substrate, forming a reference layer on the electrodes, disposing a thin film on the reference layer, and cutting the substrate into a probe shape. The reference layer is formed by applying a paste-like material sprayed from a nozzle onto the electrode in a manner that crosses the cutting line.

9. A method for manufacturing a sensor having a probe inserted into a biological body and measuring an analyte, the method being characterized in that, The probe is manufactured through the following process: The process of forming electrodes on a sheet-like substrate; The process of forming a reference layer on the electrode; The process of depositing a thin film on the reference layer; and In the process of cutting the sheet-like substrate in a shape that forms the probe, the reference layer is formed by coating the electrode with a paste-like material ejected from a nozzle. When the sheet-like substrate is cut, a portion of the reference layer is cut.

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