CN117462120A - Integrated glucose sensor - Google Patents
Integrated glucose sensor Download PDFInfo
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- CN117462120A CN117462120A CN202311429987.4A CN202311429987A CN117462120A CN 117462120 A CN117462120 A CN 117462120A CN 202311429987 A CN202311429987 A CN 202311429987A CN 117462120 A CN117462120 A CN 117462120A
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Classifications
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- 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
-
- 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
- A61B5/14507—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 specially adapted for measuring characteristics of body fluids other than blood
- A61B5/1451—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 specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid
- A61B5/14514—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 specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid using means for aiding extraction of interstitial fluid, e.g. microneedles or suction
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- 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
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- 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
- A61B5/1468—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 chemical or electrochemical methods, e.g. by polarographic means
- A61B5/1473—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 chemical or electrochemical methods, e.g. by polarographic means invasive, e.g. introduced into the body by a catheter
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
- A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
- A61B5/6847—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
- A61B5/685—Microneedles
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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
- G01N27/3273—Devices therefor, e.g. test element readers, circuitry
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- Health & Medical Sciences (AREA)
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Abstract
The invention discloses an integrated glucose sensor, and belongs to the field of blood glucose measurement. The integrated glucose sensor includes: the glucose sensor is arranged on the back surface of the hollow microneedle array, a gold nanoparticle layer and a carbon nanotube layer are arranged on a working electrode of the glucose sensor, glucose of interstitial fluid is extracted to the surface of the glucose sensor by utilizing the coupling of the microneedles in the hollow microneedle array and counter ion electroosmosis, and glucose molecules are extracted to the surface of the glucose sensor by the hollow microneedles in an electronic control mode under the action of constant current; because the working electrode of the glucose sensor is provided with the gold nanoparticle layer and the carbon nanotube layer, the sensitivity and the detection precision of the integrated glucose sensor for detecting the concentration of glucose are improved.
Description
Technical Field
The invention relates to the field of blood glucose measurement, in particular to an integrated glucose sensor.
Background
With the increasing number of people with diabetes, accurate real-time monitoring of blood glucose levels is urgently needed. Traditional methods of lancing a finger to measure blood glucose in blood are often accompanied by pain, bleeding, and risk of infection. Currently, invasive continuous blood glucose monitors (CGM) based on implanted electrodes are used in the market to track blood glucose in subcutaneous interstitial fluid, but CGM electrodes suffer from the drawbacks of inflammation and interference with vital activity. Therefore, minimally invasive, accurate sensing is of great significance.
Reverse ion electroosmosis technology has recently been integrated into sensor devices for electronically controlling and enhancing the permeation of glucose through the stratum corneum. However, it is difficult to extract a sufficient amount of glucose by only reverse ion electroosmosis, which is hindered by skin barrier, resulting in inaccurate measurement of glucose. Therefore, the conventional counter ion electroosmosis technology has difficulty in meeting the detection requirements of the glucose sensor due to the defects of low extraction flux and consistency.
Microneedles of about 1000 μm in length are the most promising transdermal tools. After being inserted into skin, the skin can not cause bleeding, pain and other symptoms. Most existing microneedle platforms focus on small molecule drug delivery alone, and integrated systems for microneedle-based sensors have not yet been developed. Moreover, integration of microneedle arrays with electrical devices is rarely achieved due to the fabrication and complex structure of the microneedles. Microneedle-based sensors have been used to detect glucose in vivo. However, due to friction and resistance of the skin, the sensitivity of the glucose sensor is reduced, the accuracy is questioned, and the biosafety is low.
Disclosure of Invention
The invention aims to provide an integrated glucose sensor which can improve the accuracy and efficiency of glucose concentration detection.
In order to achieve the above object, the present invention provides the following solutions:
an integrated glucose sensor, the integrated glucose sensor comprising: the device comprises a hollow microneedle array, a solid microneedle array, a glucose sensor, a constant-current adjustable circuit and a signal processing circuit;
the glucose sensor is arranged on the back surface of the hollow microneedle array; the working electrode of the glucose sensor is provided with a gold nanoparticle layer and a carbon nanotube layer;
the current output end of the constant current adjustable circuit is connected with the solid micro-needle array, and the grounding end of the constant current adjustable circuit is connected with the reference electrode of the glucose sensor; the working electrode of the glucose sensor is connected with the signal processing circuit;
when the integrated glucose sensor is used for detecting the concentration of glucose in a body, the hollow microneedle array and the solid microneedle array penetrate through the skin and enter the dermis layer, and the constant current adjustable circuit is used for outputting a stable constant current with adjustable size; the hollow microneedle array is used for enabling glucose of interstitial fluid to reach the surface of the glucose sensor through a microchannel of the microneedle under the action of the constant current; the glucose sensor is used for sensing and detecting glucose of interstitial fluid to generate sensing current; the signal processing circuit is used for converting the sensing current into a sensing voltage; the sensor voltage is used to characterize the glucose concentration.
According to the specific embodiment provided by the invention, the invention discloses the following technical effects:
according to the integrated glucose sensor provided by the embodiment of the invention, glucose in interstitial fluid is extracted to the surface of the glucose sensor by utilizing the coupling of the micro-needles in the hollow micro-needle array and the counter ion electro-osmosis, and under the action of constant current, glucose molecules are extracted to the surface of the glucose sensor by the hollow micro-needles in an electronic control manner, so that the efficiency of extracting glucose by the counter ion electro-osmosis is obviously improved by the synergistic effect; because the working electrode of the glucose sensor is provided with the gold nanoparticle layer and the carbon nanotube layer, the sensitivity and the detection precision of the glucose sensor for detecting the concentration of glucose are improved.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions of the prior art, the drawings that are needed in the embodiments will be briefly described below, it being obvious that the drawings in the following description are only some embodiments of the present invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a schematic diagram of a workflow of an integrated glucose sensor according to an embodiment of the present invention;
FIG. 2 is a schematic diagram of an integrated glucose sensor according to an embodiment of the present invention;
FIG. 3 is a schematic diagram of a constant current adjustable circuit according to an embodiment of the present invention;
fig. 4 is a schematic circuit diagram of a constant current source module according to an embodiment of the present invention;
FIG. 5 is a schematic diagram of a hollow microneedle array according to an embodiment of the present invention;
FIG. 6 is a schematic diagram of a solid microneedle according to an embodiment of the present invention;
FIG. 7 is a schematic view of a planar electrode according to an embodiment of the present invention;
FIG. 8 is a schematic diagram of a modification structure of a working electrode according to an embodiment of the present invention;
FIG. 9 is a schematic diagram of an in vitro test performed by a glucose sensor according to an embodiment of the present invention;
FIG. 10 is a schematic diagram of a COMSOL model for the reverse iontophoresis extraction of glucose provided by an embodiment of the present invention;
FIG. 11 is a graph showing the cumulative amount of reverse iontophoresis extracted to glucose provided in the examples of the present invention;
fig. 12 is a schematic diagram of a signal processing circuit according to an embodiment of the present invention.
Symbol description:
the device comprises a glucose extraction module-1, a glucose sensor-2, a signal processing circuit-3, a voltage stabilizing module-4, a constant current source module-5, a pin header-6, a working electrode-7, a reference electrode-8, a counter electrode-9, a conductive track-10, an electrode port-11, a graphite carbon layer-12, a gold nanoparticle layer-13, a carbon nanotube layer-14, a Prussian blue layer-15, a glucose oxidase layer-16, an electrolyte solution-17, an electrochemical workstation-18, a computer-19, a cuticle-20, an epidermis layer-21, a dermis layer-22, a solid microneedle-23, a transimpedance amplifier-24, an inverter-25 and a filter-26.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In order to realize the extraction of glucose in interstitial fluid and the continuous measurement of glucose, fulfill the requirements of electric control and regulation and meet the physiological requirements of minimally invasive and painless, the invention integrates the micro-needle and counter ion electroosmosis coupling with a glucose sensor. After the hollow microneedles penetrate the skin, the counter ion electroosmosis extracts glucose from the interstitial fluid through the microchannels of the hollow microneedles. The sensing detection is carried out after the glucose reaches the surface of the glucose sensor, so that the efficiency of extracting glucose by reverse ion electroosmosis is greatly improved, and the requirements of high sensitivity and accurate detection are met. In addition, the existing electrochemical detection device cannot directly detect the sensing current as low as several nanoamperes, and the sensing current is unstable and delayed after being interfered by environments such as noise. Therefore, the design of the invention adds a signal processing circuit, ensures the detection of small sensing current and improves the stability of output signals. The invention provides an integrated glucose sensor based on micro-needle and counter ion electroosmosis, which improves the sensitivity, accuracy and reliability of the glucose sensor and realizes painless detection of glucose in vivo.
In order that the above-recited objects, features and advantages of the present invention will become more readily apparent, a more particular description of the invention will be rendered by reference to the appended drawings and appended detailed description.
As shown in fig. 1 and 2, an embodiment of the present invention provides an integrated glucose sensor, including: a hollow microneedle array, a solid microneedle array, a glucose sensor 2, a constant-current adjustable circuit and a signal processing circuit 3.
The glucose sensor 2 is arranged on the back of the hollow microneedle array; the working electrode 7 of the glucose sensor 2 is provided with a gold nanoparticle layer 13 and a carbon nanotube layer 14; the current output end of the constant current adjustable circuit is connected with the solid micro-needle array, and the grounding end of the constant current adjustable circuit is connected with the reference electrode 8 of the glucose sensor 2; the working electrode 7 of the glucose sensor 2 is connected to the signal processing circuit 3.
When the integrated glucose sensor is used for detecting the concentration of glucose in a body, the hollow microneedle array and the solid microneedle array penetrate through the skin and enter the dermis layer 22, and the constant current adjustable circuit is used for outputting stable constant current with adjustable size; the hollow microneedle array is used for enabling glucose of interstitial fluid to reach the surface of the glucose sensor 2 through a microchannel of the microneedle under the action of constant current; the glucose sensor 2 is used for sensing and detecting the glucose of interstitial fluid to generate sensing current; the signal processing circuit 3 is used for converting the sensing current into a sensing voltage; the sensing voltage is used to characterize the glucose concentration.
As shown in fig. 1, a constant current adjustable circuit and a hollow microneedle array form a glucose extraction module 1, glucose in interstitial fluid is extracted, a glucose sensor 2 detects sensing current, and a signal processing circuit 3 amplifies, inverts and filters the sensing current to output stable electric signals, so that the detected glucose concentration is obtained.
The respective structures in the integrated glucose sensor are described in detail below.
(1) Constant current adjustable circuit
Fig. 3 is a schematic structural diagram of a constant current adjustable circuit according to an embodiment of the present invention. The smart phone directly supplies power to the constant current adjustable circuit through the USB port. The voltage stabilizing module 4 is composed of a low dropout voltage regulator (AMS 1117) and two capacitance filters, and the functions of rectification and voltage stabilization are completed. The constant current source module 5 is constituted by a wilson current source circuit, which converts a stable voltage into a constant current output. As shown in fig. 4, an equivalent circuit schematic of the wilson current circuit is shown. It consists essentially of three identical pnp transistors, where T0 and T1 are mirror connected, ib0=ib1, ic1=ic0=ic. The emitter of transistor T2 is connected in series with the base and collector of T1. Since a large equivalent resistance exists between the emitter and the collector, a stable constant current is output. Meanwhile, the equivalent output resistance of the circuit is changed by changing the single-pole three-throw switch S2, so that the circuit finally outputs different constant currents of 1mA, 2mA and 3 mA. The collector of the triode Q3 is an output end, is connected with a reverse ion electroosmosis anode (a gold modified solid microneedle 23), and is grounded and connected with a reverse ion electroosmosis cathode (a reference electrode 8 of the glucose sensor 2).
The specific structure of the constant current adjustable circuit is as follows:
the constant current adjustable circuit includes: the constant voltage module 4, the constant current source module 5 and the pin header 6. The output end of the voltage stabilizing module 4 is connected with the input end of the constant current source module 5, and the output end of the constant current source module 5 is connected with the input end of the pin header 6; the output end of the pin header 6 is connected with the solid micro-needle array, and the grounding end of the pin header 6 is connected with the reference electrode 8 of the glucose sensor 2. The voltage stabilizing module 4 is used for generating a stabilized voltage; the constant current source module 5 is used for converting stable voltage into constant current and transmitting the constant current to the solid micro-needle array through the pin header 6.
Wherein the constant current source module 5 includes: the power supply comprises a Wilson current source circuit, a single-pole three-throw switch, a first resistor and a second resistor. The Wilson current source circuit comprises a triode T0, a triode T1 and a triode T2; the triode T0 is in mirror image connection with the triode T1, and a connection common point of an emitter of the triode T0 and an emitter of the triode T1 is used as an input end of the constant current source module 5 and is connected with an output end of the voltage stabilizing module 4; the emitter of the triode T2 is respectively connected with the base of the triode T1 and the collector of the triode T1 in series, and the collector of the triode T2 is used as the output end of the constant current source module 5 and is connected with the input end of the pin header 6; the common point of the base electrode of the triode T2 and the collector electrode of the triode T0 is connected with the main wiring point of the single-pole three-throw switch. The first movable wiring point of the single-pole three-throw switch is connected with one end of the first resistor, the second movable wiring point of the single-pole three-throw switch is connected with one end of the second resistor, and the third movable wiring point of the single-pole three-throw switch is grounded after being connected with the other end of the first resistor and the other end of the second resistor. The first movable wiring point of the single-pole three-throw switch is connected with one end of the first resistor and then used for outputting a constant current of 1 mA; the second movable wiring point of the single-pole three-throw switch is connected with one end of the second resistor and then used for outputting constant current of 2 mA; the third movable junction point of the single-pole three-throw switch is used for outputting a constant current of 3 mA.
In fig. 3, R3 represents a first resistor, R2 represents a second resistor, S2 represents a single-pole three-throw switch, a main wiring point of the single-pole three-throw switch is denoted by reference numeral 2, a first movable wiring point of the single-pole three-throw switch is denoted by reference numeral 1, a second movable wiring point of the single-pole three-throw switch is denoted by reference numeral 3, and a third movable wiring point of the single-pole three-throw switch is denoted by reference numeral 4. Triode T0 corresponds Q2, triode T1 corresponds Q1, triode T2 corresponds Q3, the port 2 of row needle 6 is the input, the port 1 of row needle 6 is the output, the port 4 of row needle 6 is grounded, the reference electrode 8 of glucose sensor 2 is connected to the port 3 of row needle 6.
(2) Hollow microneedle array
A hollow microneedle array is prepared by 3D printing with biocompatible photosensitive transparent resin, and fig. 5 is a schematic structural diagram of the hollow microneedle array of the present invention. The three-dimensional model of the designed microneedle is hollow conical, the base diameter is about 400 mu m, the pore diameter is about 150 mu m, the height is about 1000 mu m, and the distance between two adjacent microneedles is about 500 mu m. The substrate is made of the same material, has a radius of about 400 μm and a thickness of about 1000 μm. The total number of hollow microneedles on the substrate was 37. The microneedles in the hollow microneedle array are hollow cones, and the bottom surfaces of the hollow cones serve as the back surfaces of the hollow microneedle array.
The hollow microneedles are sufficient to penetrate the skin into the dermis layer 22 so that the glucose of interstitial fluid reaches the surface of the glucose sensor 2 through the microchannels of the microneedles, producing a sensory response and not painful to the user.
Because of the safety and painless characteristics of the micro-needle, the integrated glucose sensor has the function of extracting the glucose of interstitial fluid to the surface of the sensor by utilizing the coupling of the micro-needle and the counter ion electroosmosis to generate sensing current, and then the sensing current passes through the signal processing circuit 3, so that the painless and accurate detection of the glucose concentration is realized.
(3) Solid microneedle array
As shown in fig. 6, a schematic structural view of the solid microneedle 23 of the present invention is shown. The solid microneedles 23 were fabricated on a copper substrate having a thickness of about 1000 μm using a laser micromachining etching technique. The three-dimensional model of copper solid microneedles 23 is a cone with a base diameter of about 400 μm and a height of about 1000 μm, and adjacent microneedles are spaced at a distance of about 500 μm, and the microneedle array is 1×5. The copper substrate has a size of 5000×5000 μm. And sputtering a layer of gold with a thickness of about 200nm on the surface of the copper microneedle by using a magnetron sputtering method. The gold-modified copper solid microneedle 23 is connected with the collector of the Q3 transistor of the constant current adjustable circuit and is used as an anode for reverse ion electroosmosis extraction. Because the gold material has good biocompatibility, the gold-modified copper solid microneedles 23 have little harm to human body after being inserted into the skin.
(4) Glucose sensor 2
Fig. 7 is a schematic view of a planar electrode of a glucose sensor 2 manufactured by screen printing used in the present invention. The planar electrode is formed by a working electrode 7, a reference electrode 8 and a counter electrode 9, and is printed on a plastic PET substrate. The working electrode 7, the reference electrode 8, the conductive track 10 of the counter electrode 9 and the electrode port 11 are printed with silver ink. The working electrode 7 and the counter electrode 9 are printed by using a graphite carbon screen, the working electrode 7 is in a circular sheet structure, and the counter electrode 9 is in a semicircular hook shape. Wherein the working electrode 7 has a radius of 0.2cm and an area of about 0.126cm 2 . Finally, ag/AgCl ink is used for manufacturing a reference electrode 8, and the reference electrode 8 is of an arc-shaped sheet structure. The overall radius of the planar electrode was 0.4cm.
The invention relates to an electrochemical glucose sensor 2 modified by gold nanoparticles, carbon nanotubes, prussian blue and glucose oxidase. As shown in fig. 8, a schematic diagram of the modified structure of the working electrode 7 of the glucose sensor 2 is provided for the present invention. The gold nanoparticle layer 13 is used as an inner conductive layer, has the characteristics of high stability, high conductivity and high biocompatibility, and effectively improves the electrochemical activity of the glucose sensor 2. The carbon nanotube layer 14 increases the contact surface area of the working electrode 7, provides path selection for the flow of electrons, and improves the conductivity of the working electrode 7. The invention introduces the Prussian blue layer 15 of the electron transfer medium, which has rapid electrode dynamics, and the catalytic reduction releases electrons to generate current, thereby providing additional conductivity and electrochemical activity. The present invention utilizes a crosslinking method to fix glucose oxidase on the surface of the working electrode 7 to establish the glucose oxidase layer 16. Thus, the working electrode 7 includes a graphitic carbon layer 12, a gold nanoparticle layer 13, a carbon nanotube layer 14, a Prussian blue layer 15, and a glucose oxidase layer 16. The biological affinity of the film layers, the functions of glucose oxidase fixation and electron transfer and the synergistic effect achieve the aim of improving the detection precision and the sensitivity of the glucose sensor 2. The gold nanoparticle layer 13, the carbon nanotube layer 14, the Prussian blue layer 15 and the glucose oxidase layer 16 are all film layers.
The three-electrode glucose sensor 2 is constructed by taking gold nanoparticles, carbon nanotubes and Prussian blue modified electrodes as working electrodes 7, ag/AgCl as reference electrodes 8 and carbon electrodes as counter electrodes 9. Fig. 9 is a schematic diagram of an in vitro test performed by the glucose sensor 2 of the present invention. In the in vitro test, a phosphate buffer containing glucose was used as the electrolyte solution 17. After the electrochemical workstation 18 applies a voltage to the glucose sensor 2 using a potentiostatic control method, the glucose oxidase contained in the glucose sensor 2 undergoes an oxidation-reduction reaction with glucose to produce a sensing signal current. The working principle of the electrochemical glucose sensor 2 of the invention is: under the action of external constant voltage, glucose is subjected to oxidation reaction under the catalysis of glucose oxidase, and the product of the oxidation reaction and Prussian blue layer 15 of working electrode 7 generate reduction reaction to release free electrons to generate small current. Wherein, the glucose concentration has good linear relation with the current, and the glucose concentration can be identified by the current response.
The gold nanoparticle, the carbon nanotube and the Prussian blue modified glucose sensor 2 are integrated with the hollow microneedle array, the gold modified solid microneedle 23 and the constant current adjustable circuit to realize continuous integration of glucose extraction and detection. Fig. 10 is a schematic diagram of the device structure of the microneedle, constant current adjustable circuit, glucose sensor 2 and electrochemical workstation 18 integrated together. Wherein, the glucose sensor 2 is fixed on the back of the hollow microneedle array by using a medical double faced adhesive tape. The collector output end of the constant current adjustable circuit is connected with a gold modified solid microneedle 23 to serve as an anode of counter ion electroosmosis, and the ground end is connected with a reference electrode Ag/AgCl of the glucose sensor 2 to serve as a cathode of counter ion electroosmosis. The smart phone is powered through the USB charging port so that the circuit outputs constant current. And, the single-pole three-throw switch in the switching circuit can output constant currents of 1mA, 2mA and 3mA respectively. Because the safe current which can be accepted by the human body is 10mA, the current output by the circuit can not harm the human body.
The principle of the reverse ion electroosmosis extraction of glucose is that under the constant current effect, na in interstitial fluid + And Cl - The directional movement is performed respectively, and the subcutaneous tissue generates a current channel. Normally, the skin carries a negative charge. Therefore, na + Is the primary charge carrier of the current path described above. Na (Na) + The directional movement from anode to cathode creates an ion stream that can carry neutral glucose molecules in interstitial fluid to the surface of glucose sensor 2 through the micro-channels of the hollow microneedles. In turn, an electrochemical reaction occurs to produce an electrical current.
As shown in FIG. 10, a COMSOL model of the present invention for reverse iontophoresis extraction of glucose is shown. The extraction of glucose from the dermis layer 22 was simulated using an AC/DC module and a chemical delivery module. Among these, skin tissue is modeled as 3 layers (stratum corneum 20, epidermis layer 21, and dermis layer 22). The hollow microneedle is inserted into the skin, and a gold-modified solid microneedle 23 is placed beside the hollow microneedle to cooperate with the reference electrode 8 of the glucose sensor 2 to provide constant flow for reverse iontophoresis. Wherein the dermis layer 22 is provided with an initial concentration of glucose of 5mM, in the range of normal blood glucose in the human body. The glucose concentration in the other region was 0. After applying a constant current of 1mA for 2min, the cumulative amount of reverse iontophoresis extracted to glucose was observed (see FIG. 11). Wherein the streamline is electric field distribution, and the black contour is glucose concentration distribution. It was found that glucose was present in the glucose sensor 2 after application of a constant current of 1mA for 2min, and its concentration distribution was in the range of 0.2 to 1.5 mmol/L. It has been demonstrated that by applying a constant current, glucose in the interstitial fluid of the dermis layer 22 will reach the surface of the sensor with the ion current formed by na+. The amount of the glucose extracted by the reverse ion electroosmosis is influenced by the extraction time and the extraction constant current, and the change of the constant current can properly adjust the amount of the extracted glucose. The constant current adjustable circuit can provide constant currents of 1mA, 2mA and 3mA, and provides various choices for users.
The invention adopts the mode of the electro-osmotic coupling of the micro needle and the counter ion, thereby improving the efficiency of extracting the glucose in the interstitial fluid. The invention integrates the gold nanoparticle, the carbon nanotube and the Prussian blue modified glucose sensor 2 with the micro-needle, the reverse ion electroosmosis and the constant current adjustable circuit, thereby realizing electrical controllability.
(5) Signal processing circuit 3
Fig. 12 is a schematic circuit diagram of a signal processing circuit 3 according to the present invention. The function of the circuit is to convert the small signal sense current into a stable voltage signal. In the present invention, the direction of the current generated by the glucose sensor 2 is from the Ag/AgCl reference electrode 8 to the working electrode 7, and the output is set to be positive. The sense signal current input into the processing circuit is first converted to a voltage by the transimpedance amplifier 24 and then to a positive voltage signal via the inverter 25. The feedback resistance of the transimpedance amplifier 24 is set to 1mΩ, and the converted signal can be well analyzed. Because the sensor current signal of the glucose sensor 2 may be as low as a few nanoamps, which is much smaller than the minimum signal that can be measured daily (tens of nanoamps). However, the signal processing circuit 3 of the present invention converts the current into a voltage value, lowering the lower limit of the measurement. At the same time, the present invention adds a filter 26. The filter 26 has a gain of-3 dB at a frequency of 1HZ, minimizing noise.
Referring to fig. 12, the signal processing circuit 3 includes: a transimpedance amplifier 24, an inverter 25, and a filter 26. The input end of the transimpedance amplifier 24 is connected with the working electrode 7 of the glucose sensor 2, and the output end of the transimpedance amplifier 24 is connected with the input end of the inverter 25; transimpedance amplifier 24 is used to convert the sense current to a voltage; the inverter 25 is used to convert the voltage into a positive voltage signal. The output end of the inverter 25 is connected with the input end of the filter 26; the filter 26 is used for noise reduction processing of the positive voltage signal.
The signal processing circuit 3 can obtain stable electric signals after the initial unstable sensing current is conditioned by the circuit, so that the measurement of glucose is promoted, and the integration of the sensor and the electric equipment is realized.
In one example, the integrated glucose sensor further comprises: a smart phone. The intelligent mobile phone is connected with the input end of the constant current adjustable circuit through a USB port; the smart phone is used for providing input voltage to the constant current adjustable circuit.
In one example, the integrated glucose sensor further comprises: an electrochemical workstation 18. The power end of the electrochemical workstation 18 is respectively connected with the working electrode 7, the reference electrode 8 and the counter electrode 9 of the glucose sensor 2, the signal input end of the electrochemical workstation 18 is connected with the working electrode 7 of the glucose sensor 2, and the signal output end of the electrochemical workstation 18 is connected with the signal input end of the signal processing circuit 3. The electrochemical workstation 18 is used for applying a voltage to the glucose sensor 2 using a potentiostatic control method, and measuring a sensing current generated by an oxidation-reduction reaction between glucose oxidase and glucose contained in the glucose sensor 2, and simultaneously transmitting the sensing current to the signal processing circuit 3.
Referring to fig. 2, the signal processing circuit 3 is disposed within the electrochemical workstation 18.
In one example, the integrated glucose sensor further comprises: a computer 19. The signal input end of the computer 19 is connected with the signal output end of the signal processing circuit 3; the computer 19 is used for displaying the sensing voltage output by the signal processing circuit 3.
The invention relates to an integrated glucose sensor based on microneedle and reverse ion electroosmosis extraction. As shown in fig. 1, a schematic diagram of the device structure of the microneedle, the constant current adjustable circuit, the glucose sensor 2 and the electrochemical workstation 18 integrated together is provided for the present invention. The invention consists of a constant current adjustable circuit, a hollow microneedle, a gold-modified solid microneedle 23 (copper solid microneedle), a glucose sensor 2 based on a screen printing electrode and a signal processing circuit 3. Wherein the radius of the glucose sensor 2 is about 0.4mm and the radius of the hollow microneedle substrate is about 0.45mm. The glucose sensor 2 is placed on the back of the hollow microneedle. The smart phone supplies power to the constant-current adjustable circuit through the USB port. The gold-modified solid microneedle 23 is used as an anode for reverse ion electroosmosis extraction and is connected with a current output end of the constant current adjustable circuit. The reference electrode 8 of the glucose sensor 2 is connected with the grounding port of the constant-current adjustable circuit and is used as a cathode for the electroosmosis extraction of the counter ions. The glucose sensor 2 based on gold nanoparticles, carbon nanotubes and Prussian blue modification consists of a working electrode 7, a reference electrode 8 and a counter electrode 9. The working electrode 7, the reference electrode 8 and the counter electrode 9 are connected to each other in correspondence with the electrochemical workstation 18. The present invention applies a voltage to the glucose sensor 2 by a potentiostatic control method. Under the synergistic effect of the micro needle and the constant current adjustable circuit, glucose in interstitial fluid is extracted to the surface of the sensor, then oxidation-reduction reaction is carried out on the glucose and the sensor 2 to generate sensing signal current, and the sensing current is input to the signal processing circuit 3.
As shown in fig. 2, a workflow diagram is provided for the present invention. It consists of three parts: 1) A constant current adjustable circuit and a microneedle for reverse ion electroosmosis extraction; 2) A screen-printed electrode-based glucose sensor 2; 3) A signal processing circuit 3 for sensing the signal current. The smart phone provides an input voltage for the constant current adjustable circuit. The invention adopts a low-dropout voltage stabilizing chip (AMS 1117) and two capacitance filters to rectify and stabilize the input voltage. After the stable voltage is obtained, the constant current source is converted into constant current output. The invention uses a wilson current source circuit to form a constant current source. The output end and the grounding end of the constant current adjustable circuit are respectively connected with the gold-modified solid micro needle 23 and the reference electrode 8 of the glucose sensor 2, so that constant current from the solid micro needle 23 to the glucose sensor 2 is generated. The constant current causes glucose molecules to be extracted to the surface of the sensor through the hollow microneedle by a current channel formed by na+. The present invention uses the electrochemical workstation 18 to measure the sensing current produced by glucose under the catalysis of glucose oxidase. The sense signal current inputted into the signal processing circuit 3 is converted into a positive voltage signal by the combined action of the transimpedance amplifier 24 and the inverter. After further processing by the filter 26 (low pass filter), the noise interference is eliminated. This allows very small sense signal currents (as low as a few nanoamps) to be measured as well.
The present invention provides an integrated glucose sensor 2 based on microneedle and counter-ion electroosmotic extraction and provides a signal processing circuit 3 for sensing signal current. Not only improves the sensitivity and precision of the glucose sensor 2, but also eliminates the interference of environmental factors such as noise, realizes the measurement of small sensing current as low as several nanoamperes, realizes the electrical controllability, and develops the glucose sensor 2 with high integration level and low cost.
The integrated glucose sensor based on micro-needle and counter ion electroosmosis extraction belongs to an application of blood sugar measurement, and compared with the traditional blood sugar measurement by puncturing a finger, the integrated glucose sensor provided by the invention overcomes the problems of traditional pain, inconvenience and incapability of continuously measuring blood sugar, and has a larger application potential. Microneedles act as painless skin penetrating tools, and penetration into the skin does not cause bleeding and pain. The use of the microneedle improves the biocompatibility and avoids skin inflammation.
The invention designs and adds the constant current adjustable circuit, and realizes the output of different constant currents of 1, 2 and 3 mA. The invention electroosmotic couples the microneedle with the counter ion. Under the action of constant current, glucose molecules are extracted to the surface of the sensor through the hollow micro needle in an electronic control mode, and the efficiency of extracting glucose by reverse ion electroosmosis is obviously improved through the synergistic effect. And, by varying the intensity of the applied current, the amount of glucose extraction is effectively regulated.
The glucose sensor 2 of the invention improves the sensitivity and the detection precision by utilizing the modification of gold nano particles and carbon nano tubes, and has good stability. The design of the processing circuit aiming at the sensing signal current reduces the measurable lower limit of the traditional sensing current and obtains the voltage signal with stable output. The invention integrates extraction, detection and signal processing, realizes electric control and improves the integration level.
The invention adopts a method of integrating a microneedle, a constant current adjustable circuit, a glucose sensor 2 and a signal processing circuit 3, and adopts a hollow microneedle and counter ion electroosmosis coupling method for extracting glucose. Meanwhile, a user can change the applied constant current, so that the glucose extraction efficiency is improved to a great extent, and the glucose detection is more correct, stable and credible.
In the present specification, each embodiment is described in a progressive manner, and each embodiment is mainly described in a different point from other embodiments, and identical and similar parts between the embodiments are all enough to refer to each other.
The principles and embodiments of the present invention have been described herein with reference to specific examples, the description of which is intended only to assist in understanding the methods of the present invention and the core ideas thereof; also, it is within the scope of the present invention to be modified by those of ordinary skill in the art in light of the present teachings. In view of the foregoing, this description should not be construed as limiting the invention.
Claims (10)
1. An integrated glucose sensor, the integrated glucose sensor comprising: the device comprises a hollow microneedle array, a solid microneedle array, a glucose sensor, a constant-current adjustable circuit and a signal processing circuit;
the glucose sensor is arranged on the back surface of the hollow microneedle array; the working electrode of the glucose sensor is provided with a gold nanoparticle layer and a carbon nanotube layer;
the current output end of the constant current adjustable circuit is connected with the solid micro-needle array, and the grounding end of the constant current adjustable circuit is connected with the reference electrode of the glucose sensor; the working electrode of the glucose sensor is connected with the signal processing circuit;
when the integrated glucose sensor is used for detecting the concentration of glucose in a body, the hollow microneedle array and the solid microneedle array penetrate through the skin and enter the dermis layer, and the constant current adjustable circuit is used for outputting a stable constant current with adjustable size; the hollow microneedle array is used for enabling glucose of interstitial fluid to reach the surface of the glucose sensor through a microchannel of the microneedle under the action of the constant current; the glucose sensor is used for sensing and detecting glucose of interstitial fluid to generate sensing current; the signal processing circuit is used for converting the sensing current into a sensing voltage; the sensor voltage is used to characterize the glucose concentration.
2. The integrated glucose sensor of claim 1, wherein the hollow microneedle array is prepared on the substrate using 3D printing of biocompatible photosensitive transparent resin;
the microneedles in the hollow microneedle array are hollow cones, and the bottom surfaces of the hollow cones serve as the back surfaces of the hollow microneedle array.
3. The integrated glucose sensor of claim 1, wherein the solid microneedle array is fabricated on the copper substrate using a laser micromachining etching technique;
sputtering a layer of gold on the surface of the micro-needle in the solid micro-needle array by adopting a magnetron sputtering method;
the microneedles in the solid microneedle array are cone-shaped.
4. The integrated glucose sensor of claim 1, wherein the constant current adjustable circuit comprises: the device comprises a voltage stabilizing module, a constant current source module and a pin header;
the output end of the voltage stabilizing module is connected with the input end of the constant current source module, and the output end of the constant current source module is connected with the input end of the pin header; the output end of the pin header is connected with the solid micro-needle array, and the grounding end of the pin header is connected with the reference electrode of the glucose sensor;
the voltage stabilizing module is used for generating a stabilized voltage; the constant current source module is used for converting the stable voltage into constant current and transmitting the constant current to the solid micro-needle array through the pin array.
5. The integrated glucose sensor of claim 4, wherein the constant current source module comprises: the power supply comprises a Wilson current source circuit, a single-pole three-throw switch, a first resistor and a second resistor;
the Wilson current source circuit comprises a triode T0, a triode T1 and a triode T2; the triode T0 is in mirror image connection with the triode T1, and a connection common point of an emitter of the triode T0 and an emitter of the triode T1 is used as an input end of the constant current source module and is connected with an output end of the voltage stabilizing module; the emitter of the triode T2 is respectively connected with the base of the triode T1 and the collector of the triode T1 in series, and the collector of the triode T2 is used as the output end of the constant current source module and is connected with the input end of the pin header; the common point of the base electrode of the triode T2 and the collector electrode of the triode T0 is connected with the main wiring point of the single-pole three-throw switch;
the first movable wiring point of the single-pole three-throw switch is connected with one end of a first resistor, the second movable wiring point of the single-pole three-throw switch is connected with one end of a second resistor, and the third movable wiring point of the single-pole three-throw switch is grounded after being connected with the other end of the first resistor and the other end of the second resistor;
the first movable wiring point of the single-pole three-throw switch is connected with one end of the first resistor and then used for outputting a constant current of 1 mA; the second movable wiring point of the single-pole three-throw switch is connected with one end of the second resistor and then used for outputting constant current of 2 mA; the third movable junction point of the single-pole three-throw switch is used for outputting a constant current of 3 mA.
6. The integrated glucose sensor of claim 1, wherein the signal processing circuit comprises: a transimpedance amplifier, an inverter, and a filter;
the input end of the transimpedance amplifier is connected with the working electrode of the glucose sensor, and the output end of the transimpedance amplifier is connected with the input end of the inverter; the transimpedance amplifier is used for converting the sensing current into voltage; the inverter is used for converting the voltage into a positive voltage signal;
the output end of the inverter is connected with the input end of the filter; the filter is used for carrying out noise reduction processing on the positive voltage signal.
7. The integrated glucose sensor of claim 1, wherein the glucose sensor comprises: a working electrode, a reference electrode, and a counter electrode;
printing a working electrode and a counter electrode by using a graphite carbon screen, wherein the working electrode is of a circular sheet structure, and the counter electrode is of a semicircular hook shape;
using Ag/AgCl ink to manufacture a reference electrode, wherein the reference electrode is of an arc-shaped sheet structure;
printing conductive tracks and electrode ports of a working electrode, a reference electrode and a counter electrode by using silver ink;
the working electrode comprises a graphite carbon layer, a gold nanoparticle layer, a carbon nanotube layer, a Prussian blue layer and a glucose oxidase layer which are sequentially connected from bottom to top.
8. The integrated glucose sensor of claim 1, further comprising: a smart phone;
the intelligent mobile phone is connected with the input end of the constant current adjustable circuit through a USB port; the smart phone is used for providing input voltage for the constant current adjustable circuit.
9. The integrated glucose sensor of claim 1, further comprising: an electrochemical workstation;
the power end of the electrochemical workstation is respectively connected with the working electrode, the reference electrode and the counter electrode of the glucose sensor, the signal input end of the electrochemical workstation is connected with the working electrode of the glucose sensor, and the signal output end of the electrochemical workstation is connected with the signal input end of the signal processing circuit;
the electrochemical workstation is used for applying voltage to the glucose sensor by using a potentiostatic control method, measuring sensing current generated by oxidation-reduction reaction of glucose oxidase and glucose contained in the glucose sensor, and transmitting the sensing current to the signal processing circuit.
10. The integrated glucose sensor of claim 1, further comprising: a computer;
the signal input end of the computer is connected with the signal output end of the signal processing circuit; the computer is used for displaying the sensing voltage output by the signal processing circuit.
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