CN111307906B - Analyte monitoring probe - Google Patents

Analyte monitoring probe Download PDF

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Publication number
CN111307906B
CN111307906B CN202010247630.4A CN202010247630A CN111307906B CN 111307906 B CN111307906 B CN 111307906B CN 202010247630 A CN202010247630 A CN 202010247630A CN 111307906 B CN111307906 B CN 111307906B
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layer
glucose
monitoring probe
analyte
working electrode
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CN111307906A (en
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方骏飞
夏斌
赵瑜
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Shenzhen Guiji Sensing Technology Co ltd
Shenzhen Silicon Bionics Technology Co ltd
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Shenzhen Guiji Sensing Technology Co ltd
Shenzhen Sibionics Technology Co Ltd
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Priority claimed from CN201811640898.3A external-priority patent/CN110044986B/en
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
    • G01N27/3271—Amperometric enzyme electrodes for analytes in body fluids, e.g. glucose in blood
    • G01N27/3272—Test elements therefor, i.e. disposable laminated substrates with electrodes, reagent and channels
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
    • G01N27/3275—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction
    • G01N27/3278—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction involving nanosized elements, e.g. nanogaps or nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1486—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase
    • A61B5/14865—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/308—Electrodes, e.g. test electrodes; Half-cells at least partially made of carbon
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
    • G01N27/3275—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction
    • G01N27/3277—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction being a redox reaction, e.g. detection by cyclic voltammetry

Abstract

The present disclosure relates to a working electrode for an analyte monitoring probe, comprising: a base layer provided on the flexible substrate, the base layer having conductivity; an enzyme sensing layer formed on the substrate layer and having an enzyme capable of chemically reacting with the analyte; a semi-permeable membrane formed on the enzyme sensing layer, controlling the passage rate of analyte molecules and reducing the number of analyte molecules diffusing into the enzyme sensing layer in a certain ratio; and a biocompatible membrane formed on the semi-permeable membrane, the biocompatible membrane having hydrophilicity, wherein a porous nanoparticle layer catalyzing a reaction of an analyte is disposed between the substrate layer and the enzyme sensing layer, the nanoparticle layer has nanoparticles, and the enzyme permeates the nanoparticle layer to attach the enzyme to the nanoparticles. According to the glucose monitoring probe, the working voltage of the working electrode can be reduced, the interference is reduced, the service life of the glucose monitoring probe is prolonged, and the reaction sensitivity to glucose is improved.

Description

Analyte monitoring probe
Technical Field
The present disclosure relates to the field of analyte monitors, and in particular to an analyte monitoring probe.
Background
Biosensors are analytical devices that tightly bind biological, biologically derived, or biomimetic materials to optical, electrochemical, temperature, piezoelectric, magnetic, or micromechanical physicochemical sensors or sensing microsystems. To date, the most commercially successful biosensor used is the amperometric enzyme glucose sensor. The market share of amperometric enzyme glucose sensors occupies almost 85% of today's global market. Amperometric enzyme glucose sensors are used to detect diabetes, and the larger the market share, the more people with diabetes are reflected.
Diabetes is a series of metabolic disorder syndromes of sugar, protein, fat, water, electrolyte and the like, and is caused by hypofunction of pancreatic islets, insulin resistance and the like caused by the action of various pathogenic factors such as genetic factors, immune dysfunction, microbial infection and toxins thereof on organisms. If diabetes is not well controlled, complications such as ketoacidosis, lactic acidosis, chronic renal failure and retinopathy may arise. With the increasing incidence of diabetes, diabetes has become a public health problem worldwide.
At present, no radical cure method is available for diabetes, and only a control method is available. For diabetic patients, if the patients can monitor glucose continuously in real time on a daily basis, the occurrence of complications such as low glucose and high glucose in insulin-dependent diabetic patients can be reduced and reduced preferentially.
Typically, glucose monitoring is accomplished by a glucose meter in an amperometric enzyme glucose sensor. The sensing probe of a glucose meter is generally implanted in the body to monitor the glucose concentration in interstitial fluid and the rate of change of the glucose concentration in the surrounding blood flow, metabolism and blood vessels. Studies have shown that glucose concentration changes in interstitial fluid are generally delayed from glucose concentration changes in blood by 2-45 minutes with an average delay of about 6.7 minutes. However, when the glucose concentration in the blood begins to decrease, the glucose concentration in the interstitial fluid first decreases compared to the glucose concentration in the blood, indicating that a decrease in glucose concentration in the interstitial fluid can be predicted for an impending low glucose.
With the development of the technological level, various portable glucose monitors are introduced into the eyes of people, and especially some implantable continuous glucose monitoring devices are favored by diabetics and hospitals. However, implantable continuous glucose meters tend to have a short lifetime and are susceptible to immune reactions in the body and to other impurities in the blood that reduce sensitivity. Therefore, how to better construct the detection device, prolong the service life of the sensing probe of the glucose detector and reduce the influence of other factors becomes the biggest problem at present.
Disclosure of Invention
The present disclosure has been made in view of the above circumstances, and an object thereof is to provide a working electrode of an analyte monitoring probe that extends the service life of the probe, reduces interference, and improves sensitivity of a reaction to an analyte.
To this end, one aspect of the present disclosure provides a working electrode of an analyte monitoring probe, comprising: a base layer disposed on a flexible substrate, the base layer having electrical conductivity; an enzyme sensing layer formed on the substrate layer and having an enzyme capable of chemically reacting with an analyte; a semi-permeable membrane formed on the enzyme sensing layer, controlling a passing rate of analyte molecules and reducing the number of analyte molecules diffused to the enzyme sensing layer in a certain ratio; and a biocompatible membrane formed on the semi-permeable membrane, the biocompatible membrane having hydrophilicity, wherein a porous nanoparticle layer that catalyzes a reaction of an analyte is disposed between the substrate layer and the enzyme sensing layer, the nanoparticle layer has nanoparticles, and the enzyme permeates the nanoparticle layer to attach the enzyme to the nanoparticles.
In one aspect of the disclosure, the nanoparticle layer is disposed between the substrate layer and the analyte enzyme sensing layer. Under the condition, the catalytic action of the nano particles on the analyte reaction enables the working voltage required by the normal work of the working electrode to be reduced, and the interference of the current generated by the electrochemical reaction of the electroactive substances under partial high voltage on the working electrode is reduced; meanwhile, the reaction sensitivity of the probe to the analyte is improved, the linear range of the response of the probe to the analyte is enlarged, and the service life of the probe is prolonged.
In a working electrode of an analyte monitoring probe according to an aspect of the present disclosure, the semi-permeable membrane includes a diffusion control layer for controlling diffusion of analyte molecules and an interference prevention layer laminated on the diffusion control layer for blocking an interfering substance. Under the condition, when analyte molecules in interstitial fluid or blood enter the semipermeable membrane, the number of the analyte molecules is reduced in a certain proportion, so that when the analyte reacts with the analyte enzyme sensing layer, the analyte enzyme sensing layer is in an excessive state, the analyte concentration becomes the only factor for limiting the current of the working electrode, the linear range of the analyte monitoring probe in monitoring the analyte concentration is enlarged, in addition, other components in the interstitial fluid or the blood are prevented from entering the semipermeable membrane, and the influence of other electroactive substances which can also generate the current on the working electrode is avoided, so that the analyte detection result is not accurate.
In a working electrode of an analyte monitoring probe according to an aspect of the present disclosure, the base layer is capable of inhibiting an electrochemical reaction on a surface thereof, and the base layer is made of at least one selected from the group consisting of gold, glassy carbon, graphite, silver chloride, palladium, titanium, and iridium. This can improve the stability of the underlayer.
In a working electrode of an analyte monitoring probe according to an aspect of the present disclosure, the analyte is one or more of acetylcholine, amylase, bilirubin, cholesterol, chorionic gonadotropin, creatine kinase, creatine, creatinine, DNA, fructosamine, glucose, glutamine, growth hormone, ketone bodies, lactate, oxygen, peroxide, prostate specific antigen, prothrombin, RNA, thyroid stimulating hormone, or troponin. Thereby, different analytes can be monitored.
In a working electrode of an analyte monitoring probe according to an aspect of the present disclosure, the analyte is glucose, the enzyme sensing layer is a glucolase sensing layer, and the semi-permeable membrane is used to control the passage rate of the glucose molecules and to block interferents. This enables monitoring of glucose.
In a working electrode of an analyte monitoring probe according to an aspect of the present disclosure, the nanoparticle layer includes nanoparticles of at least one of platinum, titanium, gold, and carbon. This can facilitate the reaction of the analyte enzyme with the analyte.
In a working electrode of an analyte monitoring probe according to an aspect of the present disclosure, the flexible substrate is made of at least one of a metal foil, an ultra-thin glass, a single-layer inorganic thin film, a multi-layer organic thin film, or a multi-layer inorganic thin film. This reduces discomfort during implantation.
In a working electrode of an analyte monitoring probe according to an aspect of the present disclosure, a nanofiber three-dimensional network structure is further provided between the analyte enzyme sensing layer and the nanoparticle layer, so that the enzyme is immobilized in the nanofiber three-dimensional network structure. Therefore, a large amount of enzyme can be better fixed, so that the enzyme can be more firmly fixed in a three-dimensional network structure, and the utilization rate of the enzyme is improved.
In a working electrode of an analyte monitoring probe according to an aspect of the present disclosure, the semi-permeable membrane adjusts permeability by a modifier that is a hydrophilic modifier including polyethylene glycol, hydroxyl, or polyhydroxy. Thereby, the semipermeable membrane can be made to have the effect of a biocompatible membrane.
Another aspect of the present disclosure provides an analyte monitoring probe having a working electrode of any one of the analyte monitoring probes described above.
According to the present disclosure, it is possible to provide a working electrode of an analyte monitoring probe that extends the service life of the probe, reduces interference, and improves the reaction sensitivity to an analyte, and an analyte monitoring probe using the working electrode.
Drawings
Fig. 1 is a schematic diagram showing a use state of a glucose monitoring probe according to an embodiment of the present disclosure.
Fig. 2 is a schematic diagram showing the structure of a glucose monitoring probe according to an embodiment of the present disclosure.
FIG. 3 is a schematic diagram showing the glucose monitoring probe of FIG. 2 in a bent state.
Fig. 4 is a schematic diagram showing the structure of the working electrode of the glucose monitoring probe according to the embodiment of the present disclosure.
Fig. 5 is a schematic diagram illustrating a glucose response of a glucose monitoring probe with tissue according to an embodiment of the present disclosure.
Fig. 6 is a schematic diagram showing the structure of a semipermeable membrane of a working electrode of a glucose monitoring probe according to an embodiment of the present disclosure.
Fig. 7 is a schematic diagram illustrating a method of manufacturing a working electrode of a glucose monitoring probe according to an embodiment of the present disclosure.
Fig. 8 is a flowchart illustrating a method for manufacturing a working electrode of a glucose monitoring probe according to an embodiment of the present disclosure.
Fig. 9 is a flowchart illustrating a method for manufacturing a semipermeable membrane for a working electrode of a glucose monitoring probe according to an embodiment of the present disclosure.
Detailed Description
Hereinafter, preferred embodiments of the present disclosure will be described in detail with reference to the accompanying drawings. In the following description, the same components are denoted by the same reference numerals, and redundant description thereof is omitted. The drawings are schematic and the ratio of the dimensions of the components and the shapes of the components may be different from the actual ones.
In addition, the headings and the like referred to in the following description of the present disclosure are not intended to limit the content or scope of the present disclosure, but merely serve as a reminder for reading. Such a subtitle should neither be understood as a content for segmenting an article, nor should the content under the subtitle be limited to only the scope of the subtitle.
Fig. 1 is a schematic diagram showing a use state of a glucose monitoring probe according to an embodiment of the present disclosure. Fig. 2 is a block diagram illustrating a glucose monitoring probe according to an embodiment of the present disclosure. FIG. 3 is a schematic diagram showing the glucose monitoring probe of FIG. 2 in a bent state.
In the present embodiment, the glucose monitoring probe 1 may be referred to as an implantable glucose monitoring probe, a probe 1 of a glucose monitor, or a probe 1.
In this embodiment, the portable glucose monitor G may include a glucose monitoring probe 1 and an electronic system 2 connected to the glucose monitoring probe 1. Through implanting the body surface with the glucose monitoring probe 1 of portable glucose monitor G, with the tissue fluid contact of body surface to can utilize the glucose concentration signal of 1 sensing tissue fluid of glucose monitoring probe, through giving electronic system 2 with this glucose concentration signal transmission, thereby can obtain corresponding glucose concentration.
Specifically, a part (particularly, a sensing part) of the glucose monitoring probe 1 may be implanted on, for example, the body surface of a human body to be in contact with interstitial fluid in the body. In addition, another part of the glucose monitoring probe 1 is also connected with an electronic system 2 positioned on the body surface. When the portable glucose monitor G is in operation, the glucose monitoring probe 1 reacts with tissue fluid in the body to generate a sensing signal (e.g., a current signal) and transmits the sensing signal to the electronic system 2 on the body surface, and the electronic system 2 processes the sensing signal to obtain the glucose concentration. Although fig. 1 shows the arrangement position of the glucose monitoring probe 1, the present embodiment is not limited thereto, and the glucose monitoring probe 1 may be arranged on the abdomen, waist, legs, and the like, for example.
In the present embodiment, although the glucose monitoring probe 1 directly detects glucose in interstitial fluid, the glucose concentration in interstitial fluid and the glucose concentration in blood are strongly correlated, and the glucose concentration in blood can be determined from the glucose in interstitial fluid.
In the present embodiment, the glucose monitoring probe 1 may include a substrate S, and a working electrode 10, a reference electrode 20, and a counter electrode 30 (see fig. 2) provided on the substrate S. In addition, the glucose monitoring probe 1 may further include a contact 40 connected to the working electrode 10 via a lead, a contact 50 connected to the working electrode 20 via a lead, and a contact 60 connected to the working electrode 30 via a lead. In some examples, the glucose monitoring probe 1 may be connected with the electronic system 2 via contacts 40, 50, and 60.
In some examples, the substrate S may be a flexible substrate. The flexible substrate may be substantially made of at least one of Polyethylene (PE), polypropylene (PP), Polyimide (PI), Polystyrene (PS), polyethylene terephthalate (PET), polyethylene naphthalate (PEN). In addition, in other examples, the flexible substrate may also be made of substantially metal foil, ultra-thin glass, a single-layer inorganic thin film, a multi-layer organic thin film, a multi-layer inorganic thin film, or the like.
In some examples, the substrate S may also be a non-flexible substrate. The non-flexible substrate may generally comprise a less conductive ceramic, alumina, silica, or the like. In this case, the glucose monitoring probe 1 with the non-flexible substrate may at the same time have a sharp point or a sharp edge, so that the glucose monitoring probe 1 can be implanted into the skin (e.g., the superficial layer of the skin, etc.) without the need for an auxiliary implantation device (not shown).
In the present embodiment, for convenience of explanation, the glucose monitoring probe 1 may be divided into a connection part 1a and an implantation part 1b (see fig. 3). The line A-A' in FIG. 3 generally shows the approximate location of the skin when the glucose monitoring probe 1 is implanted on the body surface of a tissue.
In addition, in some examples, both the connection portion 1a and the implantation portion 1b may include a flexible substrate, but the present embodiment is not limited thereto, and for example, only the implantation portion 1b may include a flexible substrate while the connection portion 1a includes a non-flexible substrate such as a rigid substrate.
In the present embodiment, the implanted portion 1b of the glucose monitoring probe 1 may be provided in a puncture needle (not shown), and the implanted portion 1b may be separable from the puncture needle. Specifically, it is possible to pierce the piercing needle into the tissue, and then to withdraw and separate the piercing needle from the implanted portion 1b of the glucose monitoring probe 1, whereby the implanted portion 1b is left at the superficial layer of the skin and the electronic system 2 is brought into close contact with the skin surface to which the connection portion 1a (see fig. 3) of the glucose monitoring probe 1 is connected to the electronic system 2 and located.
In this embodiment, the puncture needle may have a notch, and the implanted portion 1b is placed in the notch of the puncture needle. Wherein, the puncture needle is made of stainless steel. In this case, the risk of use of the puncture needle is reduced, and the puncture needle has sufficient hardness to facilitate skin puncture. Is beneficial to the use of patients. Additionally, in some examples, the needle may also be made of plastic, glass, or metal. Thus, the manufacturing cost of the puncture needle can be controlled.
In this embodiment, an auxiliary implanting device (not shown), such as a needle assist device, may be used to pierce the piercing needle into the skin. Under the condition, the puncture depth can be configured in advance by using the needle assisting device, and the purposes of quick puncture, painless puncture and the like are realized by using the needle assisting device, so that the pain of a user is reduced. In addition, one-handed operation is also facilitated by the auxiliary implantation device. However, the present embodiment is not limited to this, and for example, when the glucose monitoring probe 1 is a rigid substrate, the glucose monitoring probe 1 may be implanted in the skin without the use of a puncture needle.
In the present embodiment, the depth of the glucose monitoring probe 1 implanted under the skin is determined according to the position to be penetrated, and when the fat layer is thick, the glucose monitoring probe is implanted to a deep position, such as the abdomen of a human body, and the implantation depth can be about 10mm to 15 mm. When the fat layer is thinner, the implantation depth is shallower, for example, at the arm, and the implantation depth can be about 5mm to 10 mm.
The present embodiment is not limited thereto, and for example, the implanted portion 1b and the connecting portion 1a may be entirely penetrated into the shallow layer of the skin, and in this case, the width of the connecting portion 1a may be limited to about 2mm or less, and in addition, the width of the connecting portion 1a may be limited to about 0.5mm or less. In this case, not only is it possible to make the connecting portion 1a more easily insertable into the skin, but also the width of the implanted portion 1b can be limited by limiting the width of the connecting portion 1 a. Generally, the narrower the width of the glucose monitoring probe 1, the less pain the user will experience during and after implantation.
In the present embodiment, as shown in fig. 2, the glucose monitoring probe 1 may include a working electrode 10, and specifically, as shown in fig. 3, the implanted portion 1b may include the working electrode 10.
Fig. 4 is a schematic diagram showing the structure of the working electrode of the glucose monitoring probe according to the embodiment of the present disclosure. Fig. 5 is a schematic diagram illustrating a glucose response of a glucose monitoring probe with tissue according to an embodiment of the present disclosure. Fig. 6 is a schematic diagram showing the structure of a semipermeable membrane on a working electrode of a glucose monitoring probe according to an embodiment of the present disclosure.
In this embodiment, the working electrode 10 includes a substrate layer 110, a nanoparticle layer 120, a glucolase sensing layer 130, a semi-permeable membrane 140, and a biocompatible membrane 150 (see fig. 4). In some examples, the substrate layer 110, the nanoparticle layer 120, the glucolase sensing layer 130, the semi-permeable membrane 140, and the biocompatible membrane 150 may be sequentially stacked.
In this embodiment, the base layer 110 may be electrically conductive. In some examples, the base layer 110 may be made of at least one selected from gold, glassy carbon, graphite, silver chloride, palladium, titanium, iridium. In this case, the base layer 110 has good conductivity, and the electrochemical reaction of the base layer 110 can be suppressed, thereby improving the stability of the base layer 110.
In the present embodiment, the base layer 110 may be disposed on the substrate by a deposition or plating method in some examples. In some examples, the method of deposition may include physical vapor deposition, chemical vapor deposition, and the like. The plating method may include electroplating, electroless plating, vacuum plating, and the like. Additionally, in some examples, the base layer 110 may also be disposed on the substrate S by screen printing, extrusion, or electrolytic deposition, among others.
In this embodiment, the base layer 110 may be provided on a flexible substrate. Under the condition, the flexible substrate enables the whole product to be light and convenient, has strong shock resistance and reduces foreign body sensation after implantation. In other examples, the base layer 110 may also be disposed on a rigid substrate.
In the present embodiment, as shown in fig. 4, a nanoparticle layer 120 may be disposed on the substrate layer 110. That is, between the substrate layer 110 and the glucosidase sensing layer 130, the nanoparticle layer 120 may be disposed. In this case, the nanoparticles of platinum metal catalyze the reaction of glucose oxidase or dehydrogenase with glucose, reducing the operating voltage required for the reaction and increasing the reaction rate.
In some examples, the nanoparticle layer 120 may be porous. In this case, the glucosidase in the glucosidase sensing layer may penetrate into the nanoparticle layer 120, and thus, the nanoparticle layer 120 may be able to sufficiently contact and catalyze the reaction of a product (e.g., hydrogen peroxide) during the glucose reaction, thereby being able to more effectively promote the glucose reaction.
In some examples, the nanoparticles in the nanoparticle layer 120 are made of metallic platinum. In other examples, the nanoparticle layer 120 may also be composed of at least one of titanium, gold, and carbon. In this case, the nanoparticle layer 120 may also function to catalyze the redox reaction.
In the present embodiment, the thickness of the nanoparticle layer 120 is about 100nm to 2 μm, and preferably 500nm to 2 μm. In one example, the nanoparticle layer 120 may be, for example, about 1 μm.
In the present embodiment, the nanoparticle layer 120 may be disposed on the substrate layer 110 by deposition. However, the present embodiment is not limited to this, and may be provided on the base layer 110 by plating, electroless plating, evaporation, printing, extrusion, or the like.
In the present embodiment, the glucose enzyme sensing layer 130 may be a glucose oxidase sensing layer or a glucose dehydrogenase sensing layer. In some examples, as shown in fig. 4, a glucosidase sensing layer 130 may be coated on the nanoparticle layer 120.
Following, in conjunction with FIG. 5, with GOX(FAD) As an example of glucose oxidase, the reaction occurring in the glucose sensing layer 130 will be described.
In the glucose sensing layer 130, when GOX(FAD) when it encounters glucose in the tissue, the following reactions occur:
glucose + GOx (FAD) → gluconolactone + GOx (FADH)2) … … reaction formula (I)
GOx(FADH2)+O2→GOx(FAD)+H2O2… … reaction formula (II)
As can be seen in the above reaction process, oxygen (O) is generated in the chemical reaction2) Is consumed, O2The reaction rate of the reaction of the formula (II) and the formula (I) is limited by O2The reaction with tissue glucose may slow, resulting in failure of the glucose monitoring probe 1. In addition, in the above reaction process, there may be H in the reaction formula (II)2O2Product of (A), H2O2This accumulation may decrease the enzyme activity in the sensing layer and may also lead to failure of the glucose monitoring probe 1. Therefore, by providing the nanoparticle layer 120 between the base layer 110 and the glucosidase sensing layer 130, H can be caused to react with the nanoparticle layer 120 acting as a catalyst2O2Decomposition reaction occurs, and the specific reaction is as follows:
H2O2→2H++O2+2e-… … reaction formula (III)
The reaction with tissue glucose can be continued by the above reaction formulae (I) to (III). In addition, the nanoparticle layer is used to catalyze the hydrogen peroxide decomposition reaction, thereby accelerating the reaction (III) and reducing the voltage to be applied during the reaction, which is advantageous for improving the sensitivity of the glucose monitoring probe 1, prolonging the service life of the glucose monitoring probe 1, and obtaining a low operating voltage. In other words, through the nanoparticle layer 120, a high-sensitivity sensing signal of tissue glucose can be continuously obtained, the service life of the glucose monitoring probe 1 is prolonged, and meanwhile, the low working voltage is beneficial to improving the anti-interference performance.
In some examples, glucose oxidase or dehydrogenase may also be disposed in the conductive polymer nanofiber three-dimensional network, i.e., the nanofiber three-dimensional network is disposed between the nanoparticle layer 120 and the glucosidase sensing layer 130. This increases the adhesion of glucose oxidase or dehydrogenase to the nanoparticle layer 120, and increases the amount of glucose oxidase or dehydrogenase immobilized.
In some examples, the glucose oxidase or dehydrogenase may also be disposed on carbon nanotubes, wherein the carbon nanotubes are disposed on the nanoparticle layer 120. Thereby, the adhesion and fixation amount of glucose oxidase or dehydrogenase on the nanoparticle layer 120 are increased.
In other examples, the glucose oxidase or dehydrogenase may also be disposed on graphene, porous titanium dioxide, or a conductive organic salt. Thereby, the adhesion and immobilization amount of glucose oxidase or dehydrogenase on the nanoparticle layer 120 is increased.
In the present embodiment, the glucose monitoring probe 1 is implanted in the skin of a human body, and can continuously sample the glucose in the blood, convert the glucose into a corresponding current signal, and transmit the current signal to the electronic system 2 outside the body. In addition, sampling refers to a chemical reaction of glucose oxidase or dehydrogenase on the glucose-enzyme sensing layer 120 with glucose.
In the present embodiment, the thickness of the glucolase sensing layer 130 may be about 0.1 μm to about 100 μm, preferably about 2 μm to about 10 μm, and in one example, the thickness of the glucolase sensing layer 130 may be about 10 μm. Under the condition, the thickness of the glucose oxidase or dehydrogenase is controlled within a certain degree, so that the problems that the adhesion force is reduced due to the fact that the glucose oxidase or dehydrogenase is too much, the materials fall off in vivo, the reaction is insufficient due to the fact that the glucose oxidase or dehydrogenase is too little, and normal glucose concentration information cannot be fed back are solved.
In the present embodiment, as shown in fig. 4 and 6, the semi-permeable membrane 140 may be distributed on the glucolase sensing layer 130, that is, the semi-permeable membrane 140 may be disposed on the glucolase sensing layer 130.
In this embodiment, as shown in fig. 6, the semi-permeable membrane 140 may further include a diffusion-controlled layer 141 and a tamper-resistant layer 142 stacked on the diffusion-controlled layer 141. In some examples, diffusion-control layer 141 may be disposed outside of immunity layer 142. In the semi-permeable membrane 140, the diffusion control layer 141 may control diffusion of glucose molecules, and the interference rejection layer 142 may prevent diffusion of non-glucose species. Thus, tissue fluid or blood components passing through the semipermeable membrane 140 can be reduced, and the interference-preventing layer 142 can block the interfering substance outside the semipermeable membrane 140. Common interferents may include uric acid, ascorbic acid, acetaminophen, etc., which are ubiquitous in the body.
In other examples, not limited to the example of fig. 6, the immunity layer 142 may also be disposed outside the diffusion control layer 141. Therefore, the interference of impurities on the working electrode 10 can be reduced, the detection result is inaccurate, and the service life of the glucose monitoring probe 1 is prolonged.
In this embodiment, the semi-permeable membrane 140 can control the rate of passage of glucose molecules, i.e., the semi-permeable membrane 140 can limit the number of glucose molecules in the interstitial fluid or blood that reach the glucolase sensing layer 130. Specifically, the diffusion-controlling layer 141 of the semi-permeable membrane 140 may effectively reduce the amount of glucose that diffuses into the glucolase sensing layer 130 by a certain ratio.
In the present embodiment, the rate of reducing the amount of the entering matter by the diffusion control layer 141 is 10 to 100 times, preferably 30 to 80 times, for example, 50 times. In this case, the amount of glucose diffusing into the glucose-sensing layer can be reduced, and a sufficient amount of glucose oxidase or dehydrogenase and other substances participating in the reaction can be ensured, while the glucose concentration becomes a factor that mainly (substantially only) limits the magnitude of the electrode current, so that the magnitude of the current can correctly reflect the glucose concentration, and the linear range of the glucose monitoring probe 1 can be increased to a great extent.
In this embodiment, a biocompatible membrane 150 may be disposed on the semi-permeable membrane 140 (see fig. 4).
In some examples, the biocompatible membrane 150 may be made of a plant material. The plant material may be sodium alginate, tragacanth gum, pectin, acacia gum, xanthan gum, guar gum, agar, or derivatives of natural materials including: starch derivatives, cellulose derivatives, and the like.
In other examples, the biocompatible membrane 150 may also be made of a synthetic material. The synthetic material may be a polyolefin: povidone, polyvinyl alcohol, polyisobutylene pressure-sensitive adhesive, ethylene-vinyl acetate copolymer, and the like; it may also be a polyacrylic: acrylic resin, carboxyvinyl-sucrose, carboxyvinyl-pentaerythritol copolymer, polyacrylate pressure-sensitive adhesive and the like; or polyoxyethylenes: polyesters such as polyoxyethylene fatty acid esters and polyoxyethylene-polyoxypropylene copolymers: polylactic acid, polyglycolide-lactide, polynearyl dinonyl sebacate, polycyanoalkyl amino ester, polyether polyurethane, and the like. Therefore, the immune response of the human body to the glucose monitoring probe 1 can be reduced, and the service life of the glucose monitoring probe 1 is prolonged.
Additionally, in some examples, the semi-permeable membrane 140 may also be biocompatible. Thus, the use of the biocompatible film 150 can be avoided, and the manufacturing cost can be reduced.
In other examples, the permeability of the formed membrane to the analyte of interest may be adjusted by a modifying agent. For example, hydrophilic modifiers include: polyethylene glycol, hydroxyl or polyhydroxy modifiers. Thus, the biocompatibility of the film formed by the polymer can be increased, so as to replace the biocompatible film.
In this embodiment, the layer of biocompatible membrane 150 covers the entire glucose monitoring probe 1. This reduces the precision requirements for the process.
In some examples, the biocompatible membrane 150 covers only the implanted portion 1b of the glucose monitoring probe 1 that is implanted in the body. This can reduce the use of raw materials.
In the present embodiment, the glucose monitoring probe 1 may be used for a period of 1 to 24 days, preferably 7 to 14 days. In addition, as described above, the semi-permeable membrane 140 restricts the entrance of some glucose molecules and electroactive interfering substances and effectively expands the linear range of the probe 1, and the glucose oxidase or dehydrogenase is preferably provided in the glucose-enzyme sensing layer 130, so that the life cycle of the glucose monitoring probe 1 can be maintained stably.
In addition, the glucose monitoring probe 1 can also be used in general detection, such as word detection or short-time monitoring. For example, the monitoring time may be 1 hour to 24 hours.
In addition, the addition of the biocompatible membrane 150 enables the use period of the glucose monitoring probe 1 to be maintained from 1 day to 24 days, thereby enabling a user to conveniently select glucose monitors having glucose monitoring probes 1 with different use periods according to different needs (e.g., price, etc.).
In the present embodiment, as described above, the glucose monitoring probe 1 may further include the reference electrode 20 and the counter electrode 30 (see fig. 2). Specifically, as shown in fig. 3, the implanted portion 1b of the glucose monitoring probe 1 may include a reference electrode 20 and a counter electrode 30.
In the present embodiment, the glucose monitoring probe 1 after piercing the skin can generate a current signal by performing an oxidation-reduction reaction between glucose in interstitial fluid or blood and glucose in the working electrode 10 through a glucose oxidase or dehydrogenase, and forming a circuit with the counter electrode 30.
In this embodiment, the reference electrode 20 may form a known and fixed potential difference with the interstitial fluid or blood. In this case, the potential difference between the working electrode 10 and the tissue fluid or blood can be measured by the potential difference formed between the reference electrode 20 and the working electrode 10, so that the voltage generated by the working electrode 10 can be accurately grasped. Therefore, the electronic system 2 can automatically adjust and maintain the stability of the voltage at the working electrode according to the preset voltage value so as to ensure that the measured current signal can accurately reflect the glucose concentration value.
In addition, in the present embodiment, the working electrode 10, the reference electrode 20, and the counter electrode 30 of the implanted portion 1b are disposed in a dispersed manner, but the embodiments of the present disclosure are not limited thereto, and may include a side-by-side (parallel) arrangement.
In addition, in the present embodiment, the glucose monitoring probe 1 is not limited to a planar probe, but may be a linear probe, a probe having stacked electrodes or layered electrodes, and a probe having coplanar electrodes in which electrodes are provided on the same plane.
In some examples, the reference electrode may not be used when the potential difference between the working electrode and the interstitial fluid or blood does not fluctuate much. Thus, the manufacturing cost of the glucose monitoring probe 1 is saved.
In the present embodiment, the counter electrode 30 may be made of platinum, silver chloride, palladium, titanium, or iridium. Thereby, the electrochemical reaction at the working electrode 10 can be not affected with good conductivity. However, the present embodiment is not limited thereto, and in other examples, the counter electrode 30 may be made of at least one selected from gold, glassy carbon, graphite, silver chloride, palladium, titanium, or iridium. This can reduce the influence on the working electrode 10 while having good conductivity.
In addition, in some examples, the same material may be used for working electrode 10, counter electrode 30, and reference electrode 20.
In addition, in the present embodiment, the glucose monitoring probe 1 may include two, or three or more electrodes. For example, glucose monitoring probe 1 may include only two electrodes, working electrode 10 and counter electrode 30, and further, glucose monitoring probe 1 may include additional reference electrodes in addition to working electrode 10, reference electrode 20, and counter electrode 30. In this case, it is possible to obtain the potential difference of the working electrode and grasp the voltage of the working electrode more accurately, thereby obtaining a more accurate current.
In the present embodiment, as described above, the connection portion 1a of the glucose monitoring probe 1 includes a plurality of contacts (feelers). The number of contacts is equal to the number of electrodes of the implanted portion 1b of the glucose monitoring probe 1. The contact is connected with the electrode of the implanted portion 1b through a lead (wire).
In the present embodiment, as shown in fig. 3, the number of electrodes of the implanted portion 1b of the glucose monitoring probe 1 is three. Accordingly, the connection portion 1a includes three contacts (contact tips), which are the contact 40, the contact 50, and the contact 60, respectively. However, the present embodiment is not limited to this, and for example, the number of electrodes of the implanted portion 1b may be two or more than four electrodes, and accordingly, the connection portion 1a may include two or more than four contacts (contacts).
In the present embodiment, the contacts 40, 50, and 60 may each have a disk shape. In other examples, the contacts 40, 50, and 60 may also be rectangular, oval, or other irregular shapes.
In the present embodiment, the current signal generated by the implanted portion 1b of the glucose monitoring probe 1 can be transmitted to the contact of the connection portion 1a through the base layer 110 and the transmission wire. That is, the implanted portion 1b of the glucose monitoring probe 1 is connected to the connection portion 1a, and the connection portion 1a is connected to the electronic system 2 via a plurality of contacts, so that the current signal obtained by the working electrode 10 is transmitted to the electronic system 2 through the contacts of the connection portion 1a for analysis. The electronic system 2 can analyze and process the current signal to obtain a glucose concentration signal. In addition, the electronic system 2 can transmit through wireless communication modes such as Bluetooth, wifi, and the like. An external reading device (not shown) may receive the glucose concentration signal from the electronic system and display the glucose concentration value. Further, since the glucose monitoring probe 1 according to the present embodiment can achieve continuous monitoring, it is possible to achieve the purpose of continuously monitoring the human glucose concentration value for a long period of time (for example, 1 to 24 days). Additionally, in some examples, the reading device may be a reader or a cell phone APP.
In addition, in this embodiment, the glucose monitoring probe 1 and the electronic system 2 may not require calibration during in vivo use. In addition, the glucose monitoring probe 1 and the electronic system 2 may be calibrated in advance at the time of factory shipment. Thus, the user is eliminated from having to calibrate the monitoring system by finger blood on a regular basis, and the potential source of monitoring module reading errors during use is also reduced.
In the present embodiment, the electronic system 2 may be made of a flexible PCB and a flexible battery. Therefore, the skin can be attached to the skin, and the influence on the daily life of the user is reduced. In some examples, the outer shape of the electronic system 2 may be circular. In addition, in some examples, the electronic system 2 may also have a waterproof housing and a waterproof band-aid, thereby enabling use without affecting daily activities such as swimming or bathing.
In the present embodiment, the glucose monitoring probe 1 can acquire the glucose concentration in interstitial fluid or blood. However, the present embodiment is not limited to this, and for example, by changing the sensing layer on the glucose monitoring probe 1, it is possible to acquire body fluid component data other than glucose, and body fluid components such as acetylcholine, amylase, bilirubin, cholesterol, chorionic gonadotropin, creatine kinase, creatine, creatinine, DNA, fructosamine, glucose, glutamine, growth hormone, ketone body, lactate, oxygen, peroxide, prostate-specific antigen, prothrombin, RNA, thyroid stimulating hormone, troponin, and the like.
In other examples, the concentration of a drug in a bodily fluid may also be monitored, such as antibiotics (e.g., gentamicin, vancomycin, and the like), digitoxin, digoxin, theophylline, and warfarin (warfarin), among others.
In this embodiment, first, a nanoparticle layer 120 for catalyzing the reaction of glucose oxidase or dehydrogenase with glucose is disposed on a substrate layer 110 of a working electrode 10, and then a glucose enzyme sensing layer 130 is formed, a semipermeable membrane 140 coating is formed on the glucose enzyme sensing layer 130, and finally a biocompatible membrane 150 is formed on the semipermeable membrane 140 coating. Therefore, the service life of the glucose monitoring probe 1 is prolonged, the interference of other factors is reduced, and the reaction speed of the glucose monitoring probe 1 to glucose is increased.
The method of making the working electrode of the glucose monitoring probe 1 is described in detail below with reference to the accompanying drawings.
Fig. 7 is a schematic diagram illustrating a method of manufacturing a working electrode of a glucose monitoring probe according to an embodiment of the present disclosure. Fig. 8 is a flowchart illustrating a method for manufacturing the working electrode of the glucose monitoring probe 1 according to the embodiment of the present disclosure. Fig. 9 is a flowchart illustrating a method for manufacturing a semipermeable membrane for a working electrode of the glucose monitoring probe 1 according to the embodiment of the present disclosure.
In the present embodiment, the method for manufacturing the working electrode of the glucose monitoring probe 1 may include (see fig. 7 and 8): first, a conductive substrate layer 110 is deposited on a prepared flexible substrate (step S110), a nanoparticle layer 120 for catalyzing a reaction of glucose oxidase or dehydrogenase with glucose is deposited on the substrate layer 110 (step S120), a glucolase sensing layer 130 capable of reacting with glucose is coated on the nanoparticle layer 120 (step S130), a semi-permeable membrane coating 140 is formed on the glucolase sensing layer 130 (step S140), and a biocompatible membrane layer 150 is formed on the semi-permeable membrane coating 140 (step S150). Therefore, the service life of the glucose monitoring probe 1 is prolonged, the interference of external factors is reduced, and the reaction speed of the glucose monitoring probe 1 to glucose is increased.
In the present embodiment, the glucose enzyme sensing layer 130 in step S130 may be a glucose oxidase sensing layer or a glucose dehydrogenase sensing layer.
As shown in fig. 9, the manufacturing method according to the present embodiment further includes, in step S140, forming the interference preventing layer 142 on the glucose sensor layer 130 (step S141), and further forming the diffusion controlling layer 141 on the interference preventing layer (step S142). Thus, the tissue fluid or blood components passing through the semipermeable membrane 140 can be reduced by the tamper resistant layer 142, and the interfering substance can be blocked outside the semipermeable membrane 140 by the diffusion control layer 141.
In some examples, in step S140, the order of step S141 and step S142 may be interchanged. That is, the diffusion control layer may be formed on the glucose oxidase or dehydrogenase layer (step S142), and then the interference suppression layer may be formed on the interference suppression layer (step S141). Therefore, the interference of impurities on the working electrode 10 can be reduced, the inaccurate detection result can be prevented, and the service life of the glucose monitoring probe 1 can be prolonged.
The substrate layer 110 or the nanoparticle layer 120 may be formed by one or more of plating, evaporation, printing, extrusion, or the like.
In addition, the manufacturing method according to the present embodiment further includes providing a nanofiber three-dimensional network structure on the nanoparticle layer 120. Therefore, the glucose oxidase or dehydrogenase can be better attached to the nano-particles with the three-dimensional network structure of the nano-fibers.
In other examples, the nanoparticle layer 120 may be covered with a nanofiber membrane. Thereby, the requirements for the process are reduced, and the glucose oxidase or dehydrogenase can be better attached to the nanoparticles.
While the present disclosure has been described in detail in connection with the drawings and examples, it should be understood that the above description is not intended to limit the disclosure in any way. Those skilled in the art can make modifications and variations to the present disclosure as needed without departing from the true spirit and scope of the disclosure, which fall within the scope of the disclosure.

Claims (9)

1. A working electrode for an analyte monitoring probe,
the method comprises the following steps:
a base layer disposed on a flexible substrate, the base layer having electrical conductivity;
an enzyme sensing layer formed on the substrate layer and having an enzyme capable of chemically reacting with an analyte;
a semi-permeable membrane formed on the enzyme sensing layer, controlling a passing rate of analyte molecules and reducing the number of analyte molecules diffused to the enzyme sensing layer in a certain ratio; and
a biocompatible membrane formed on the semi-permeable membrane, the biocompatible membrane having a hydrophilic property,
wherein a porous nanoparticle layer that catalyzes an analyte reaction is provided between the substrate layer and the enzyme sensing layer, the nanoparticle layer has nanoparticles, and the enzyme permeates the nanoparticle layer to attach the enzyme to the nanoparticles,
and a nanofiber three-dimensional network structure is arranged between the enzyme sensing layer and the nanoparticle layer, and the enzyme is fixed in the nanofiber three-dimensional network structure.
2. The working electrode of claim 1,
the semi-permeable membrane includes a diffusion control layer for controlling diffusion of analyte molecules and an anti-interference layer laminated on the diffusion control layer for blocking an interfering substance.
3. The working electrode of claim 1,
the base layer can inhibit electrochemical reaction on the surface of the base layer, and the base layer is made of at least one of gold, glassy carbon, graphite, silver chloride, palladium, titanium and iridium.
4. The working electrode of claim 1,
the analyte is one or more of acetylcholine, amylase, bilirubin, cholesterol, chorionic gonadotropin, creatine kinase, creatine, creatinine, DNA, fructosamine, glucose, glutamine, growth hormone, hormones, ketone bodies, lactate, oxygen, peroxide, prostate specific antigen, prothrombin, RNA, thyroid stimulating hormone, or troponin.
5. Working electrode according to claim 1 or 4,
the analyte is glucose, the enzyme sensing layer is a glucolase sensing layer, and the semi-permeable membrane is used for controlling the passing rate of the glucose molecules and blocking interferents.
6. The working electrode of claim 1,
the nanoparticle layer comprises nanoparticles of at least one of platinum metal, titanium metal, gold, and carbon.
7. The working electrode of claim 1,
the flexible substrate is made of at least one of a metal foil, ultra-thin glass, a single-layer inorganic thin film, a multi-layer organic thin film, or a multi-layer inorganic thin film.
8. Working electrode according to claim 1 or 2,
the semipermeable membrane is adjusted in permeability by a modifier, which is a hydrophilic modifier including polyethylene glycol, hydroxyl or polyhydroxy.
9. An analyte monitoring probe, comprising,
a working electrode provided with an analyte monitoring probe according to any one of claims 1 to 8.
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CN113083647B (en) * 2019-12-23 2023-06-27 浙江荷清柔性电子技术有限公司 Polymer diffusion limiting membrane layer, preparation method thereof and glucose sensor
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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101018599A (en) * 2004-08-16 2007-08-15 诺和诺德公司 Multiphase biocompatible semi-permeable membrane for biosensors
CN101530327A (en) * 2009-04-20 2009-09-16 湖州艾木奇生物科技咨询服务有限公司 Needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring and manufacturing method thereof
CN202974934U (en) * 2012-10-26 2013-06-05 浙江大学 Glucose sensor
CN103519827A (en) * 2012-06-28 2014-01-22 霍夫曼-拉罗奇有限公司 Device for monitoring at least one body function of a user and method for manufacturing the same
CN105380669A (en) * 2015-10-21 2016-03-09 上海第二工业大学 Long-service-life implantable glucose sensor for continuous glucose monitoring and preparation method thereof
CN105943058A (en) * 2016-05-19 2016-09-21 杭州宇壳科技有限公司 Flexible electrochemical electrode, continuous glucose monitoring sensor and preparation method thereof
CN205607915U (en) * 2016-03-25 2016-09-28 中国科学院重庆绿色智能技术研究院 Glucose sensor based on three -dimensional graphite alkene
CN205758571U (en) * 2016-05-19 2016-12-07 杭州宇壳科技有限公司 Flexible electrochemical electrode and subcutaneous continuous glucose monitoring sensor
CN107422016A (en) * 2017-07-21 2017-12-01 上海第二工业大学 The preparation method of the minimally invasive glucose sensor of spiral shape implantable of PVA/PEG composite aquogel outer membrane structures

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9304306D0 (en) * 1993-03-03 1993-04-21 Univ Alberta Glucose sensor
US7955559B2 (en) * 2005-11-15 2011-06-07 Nanomix, Inc. Nanoelectronic electrochemical test device
JP4359595B2 (en) * 2003-09-02 2009-11-04 広司 早出 Glucose sensor and glucose concentration measuring device
CN1277116C (en) * 2004-03-22 2006-09-27 南开大学 Biological enzyme electrode for biosensor, and its prepn. method
CN102905621A (en) * 2009-12-30 2013-01-30 马奎特急救护理股份公司 Sensor arrangement for continuously measuring analytes in a biological fluid
CN105102972A (en) * 2013-01-11 2015-11-25 东北大学 Saliva glucose monitoring system
CN103995033A (en) * 2014-05-29 2014-08-20 天津大学 Electrochemical glucose sensor based on modification of graphene and nano-particle and application thereof
TWI569007B (en) * 2014-10-28 2017-02-01 國立清華大學 Resistive cholesterol sensor based on conductivity change of conductive polymer and measuring method thereof
KR102423250B1 (en) * 2015-03-04 2022-07-21 삼성전자주식회사 Enzyme-based glucose sensor using potentiometric detection and method for preparing the same
US10324058B2 (en) * 2016-04-28 2019-06-18 Medtronic Minimed, Inc. In-situ chemistry stack for continuous glucose sensors
CN108572208B (en) * 2017-03-09 2023-10-03 深圳先进技术研究院 Flexible stretchable glucose sensor and preparation method and application thereof

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101018599A (en) * 2004-08-16 2007-08-15 诺和诺德公司 Multiphase biocompatible semi-permeable membrane for biosensors
CN101530327A (en) * 2009-04-20 2009-09-16 湖州艾木奇生物科技咨询服务有限公司 Needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring and manufacturing method thereof
CN103519827A (en) * 2012-06-28 2014-01-22 霍夫曼-拉罗奇有限公司 Device for monitoring at least one body function of a user and method for manufacturing the same
CN202974934U (en) * 2012-10-26 2013-06-05 浙江大学 Glucose sensor
CN105380669A (en) * 2015-10-21 2016-03-09 上海第二工业大学 Long-service-life implantable glucose sensor for continuous glucose monitoring and preparation method thereof
CN205607915U (en) * 2016-03-25 2016-09-28 中国科学院重庆绿色智能技术研究院 Glucose sensor based on three -dimensional graphite alkene
CN105943058A (en) * 2016-05-19 2016-09-21 杭州宇壳科技有限公司 Flexible electrochemical electrode, continuous glucose monitoring sensor and preparation method thereof
CN205758571U (en) * 2016-05-19 2016-12-07 杭州宇壳科技有限公司 Flexible electrochemical electrode and subcutaneous continuous glucose monitoring sensor
CN107422016A (en) * 2017-07-21 2017-12-01 上海第二工业大学 The preparation method of the minimally invasive glucose sensor of spiral shape implantable of PVA/PEG composite aquogel outer membrane structures

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
A needle-type glucose biosensor based on PANI nanofibers and PU/E-PU membrane for long-term invasive continuous monitoring;Lu Fang 等;《Biosensors and Bioelectronics》;20170428;第97卷;第196–202页 *
Application of Semipermeable Membranes in Glucose Biosensing;Tanmay Kulkarni 等;《Membranes》;20161214;第6卷(第55期);第1-20页 *
Highly Sensitive Glucose Sensor Based on Pt Nanoparticle/Polyaniline Hydrogel Heterostructures;Dongyuan Zhai 等;《ACS NANO》;20130311;第7卷(第4期);第3540–3546页 *
血糖监测用植入式传感器的研究进展;余江渊 等;《生物医学工程学杂志》;20161030;第33卷(第5期);第991-997页 *

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