Non-invasive blood glucose detection sensor based on anodic aluminum oxide and preparation method thereof

Abstract

The application discloses a non-invasive blood glucose detection sensor based on an anodic aluminum oxide and a preparation method thereof. The sensor comprises, from bottom to top, a flexible substrate, a first electrode layer, an organic insulating layer and a second electrode layer. The second electrode layer comprises a plurality of cavities extending from the upper surface of the second electrode layer to the upper surface of the first electrode layer. The cavities are filled with a honeycomb-shaped anodic aluminum oxide layer. A patterned third electrode layer is arranged on the upper surface of the second electrode layer. Part of the third electrode layer surrounds the upper edge of the cavity. The first electrode layer and the second electrode layer can be respectively connected with the cathode and the anode of a constant-voltage power supply. The first electrode layer, the second electrode layer and the third electrode layer can be connected with a blood glucose detection device. The honeycomb-shaped anodic aluminum oxide is used as a detection cavity, the diameter and the depth of the cavity can be adjusted, the detection performance of the non-invasive blood glucose detection sensor is improved, and the problem of water condensate evaporation of a traditional device is solved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of non-invasive blood glucose monitoring, and particularly relates to a non-invasive blood glucose detection sensor based on anodic aluminum oxide and a preparation method thereof. BACKGROUND

[0002] With the continuous development of science and technology in society, people's life patterns and eating habits are increasingly diversified. Influenced by genetic and environmental factors, the number of diabetes patients continues to rise. According to the data of the International Diabetes Federation, by 2045, the global number of diabetes patients is expected to increase by 46%, reaching a total of about 783 million. As a disease that cannot be cured at present, diabetes can cause blindness, cardiovascular disease, kidney failure and other serious complications, and has become one of the major diseases that endanger human health. Therefore, for diabetes patients, continuous monitoring of blood glucose levels is the key to controlling the disease.

[0003] Current mainstream blood glucose detection technology relies on invasive sampling, that is, through fingertip or venous blood sampling to directly measure blood glucose level. Although this method has high accuracy, frequent needle blood sampling (up to 7 times a day to effectively monitor blood glucose fluctuations) brings significant pain and inconvenience to patients. With the progress of science and technology, minimally invasive blood glucose monitoring technology has emerged. This technology can achieve continuous monitoring of blood glucose while maintaining high accuracy. However, minimally invasive technology still involves minor trauma to the skin, accompanied by mild pain and potential risk of infection. Therefore, the development of a detection method that can achieve continuous blood glucose monitoring without any pain, infection risk, has become an urgent need and important research direction in the field of blood glucose monitoring technology. Through non-invasive means, such as using the optical properties of biological tissues, electromagnetic properties, or non-invasive measurement of metabolic products, accurate, continuous, and painless monitoring of blood glucose is the current mainstream approach. Looking at existing research results, non-invasive blood glucose detection research mainly focuses on optical detection and counter-ion electroosmosis analysis. Although some progress has been made, there are still many challenges. Optical detection is safe, but it is easily disturbed by the human body, resulting in weak monitoring signals, making it difficult to extract effective chemical information from complex spectra. In addition, it involves multidisciplinary knowledge, making research more difficult. At the same time, due to the differences between individuals, the real blood glucose values of users often need to be optimized according to the calculation model for the user, which not only further increases the energy consumption of the device, but also reduces the universal applicability of the device. In contrast, counter-ion electroosmosis analysis exhibits significant advantages such as low cost, simple operation, high sensitivity, and good selectivity. This method uses a weak current to build an electric field between two electrodes, driving the anions in the subcutaneous tissue fluid to move towards the anode, while glucose migrates towards the cathode along with sodium ions under the action of the electric field. At the working electrode, glucose is oxidized to form ions through a catalytic oxidation reaction, and by measuring the number of these ions and converting, the blood glucose concentration can be determined. Counter-ion electroosmosis blood glucose monitoring technology can achieve rapid, convenient, and continuous non-invasive blood glucose monitoring.

[0004] The sensor for non-invasive blood glucose monitoring based on counter-ion electroosmosis generally includes two systems, one is an electroosmosis system, and the other is a blood glucose detection system. In order to combine the two systems together, the traditional sensor of this kind often needs a relatively complex manufacturing process, which not only increases the production cost of the device, but also increases the possible structural deviation of the device in the preparation process. Secondly, the traditional counter-ion electroosmosis device is mostly a planar structure, and the electroosmosis system and the blood glucose detection system are basically located in the same plane. Therefore, a gel medium needs to be added between the skin and the electrode plane during the detection process to carry the glucose separated from the interstitial fluid, so as to realize glucose detection. However, the main component of the gel is water, so the water in the gel will gradually evaporate as the use time increases, resulting in a change in the concentration of the detected glucose, and ultimately leading to errors in subsequent data analysis. Finally, in the non-invasive blood glucose monitoring sensor, the service life of the counter-ion electroosmosis technology device is a problem that cannot be ignored. The electrode and the sensor will gradually wear and age during long-term use, resulting in performance degradation and increased measurement errors. In addition, environmental factors such as humidity, temperature and pollutants can cause additional damage to the electrode and sensor, further shortening their service life. Frequent use and improper cleaning and maintenance can also accelerate the wear and tear of the device. SUMMARY

[0005] In order to solve the above problems existing in the prior art, the present application provides a non-invasive blood glucose detection sensor based on anodic aluminum oxide and a preparation method thereof. The technical problem to be solved by the present application is solved by the following technical scheme:

[0006] One aspect of the present application provides a non-invasive blood glucose detection sensor based on anodic aluminum oxide, comprising: a flexible substrate, a first electrode layer, an organic insulating layer and a second electrode layer arranged in order from bottom to top, wherein,

[0007] The second electrode layer comprises a plurality of cavities extending downward from the upper surface of the second electrode layer to the upper surface of the first electrode layer, and the cavities are filled with a honeycomb-shaped anodic aluminum oxide layer inside;

[0008] A patterned third electrode layer is further provided on the upper surface of the second electrode layer, and a part of the third electrode layer surrounds the upper edge of the cavity;

[0009] The first electrode layer and the second electrode layer can be respectively connected to the cathode and the anode of a constant voltage power supply, and the honeycomb-shaped anodic aluminum oxide layer forms an electric field environment for the hydrogel in the subcutaneous tissue to move glucose, so that the glucose in the subcutaneous tissue is concentrated in the cathode region under the electroosmosis effect;

[0010] The first electrode layer, the second electrode layer and the third electrode layer can also be connected to a blood glucose detection device for generating an electrical signal of the reaction glucose concentration.

[0011] Another aspect of the present application provides a preparation method of a non-invasive blood glucose detection sensor based on anodic aluminum oxide, characterized in that the preparation method is used for preparing the non-invasive blood glucose detection sensor described in the above embodiments, and the preparation method comprises the following steps:

[0012] S1: selecting a flexible substrate and forming a first electrode layer on the flexible substrate;

[0013] S2: forming an organic insulating layer on the upper surface of the first electrode layer and etching a plurality of cavities on the organic insulating layer;

[0014] S3: depositing an aluminum metal layer in the plurality of cavities, and the thickness of the aluminum metal layer is slightly less than or equal to the thickness of the organic insulating layer;

[0015] S4: forming a second electrode layer on the upper surface of the organic insulating layer, and a plurality of holes corresponding to the cavities are formed on the second electrode layer;

[0016] S5: forming a patterned third electrode layer on the upper surface of the second electrode layer;

[0017] S6: preparing the aluminum metal layer into a honeycomb-shaped anodic aluminum oxide layer.

[0018] Compared with the prior art, the present application has the following beneficial effects:

[0019] 1. The non-invasive blood glucose detection sensor based on anodic aluminum oxide of the present application uses a special electrode structure to wrap the traditional water film (hydrogel) on the outer layer inside the electrode, so that the water film does not gradually evaporate with the use of the sensor, effectively prolonging the service life of the sensor and improving the detection accuracy of glucose. At the same time, the preparation process is simple, the cost is low, it is convenient for industrial production, and it is more suitable for daily use of diabetic patients.

[0020] 2. The honeycomb-shaped anodic aluminum oxide is used as a detection cavity, and the diameter and depth of the honeycomb-shaped cavity can be adjusted by controlling the thickness of the aluminum layer and the reaction parameters of anodic oxidation, thereby further improving the detection performance of the non-invasive blood glucose detection sensor. The device structure and preparation process are simple, and can be mass-produced. At the same time, the honeycomb-shaped anodic aluminum oxide can provide a chamber for glucose detection, solving the problem of evaporation of the traditional water film.

[0021] The present application will be further described in detail below with reference to the accompanying drawings and embodiments. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 is a structure schematic diagram of a counter-ion electro-osmotic glucose electro-osmotic sensor provided by an embodiment of the present application;

[0023] Figure 2 is a cross-sectional view taken along line A-A in Figure 1 ;

[0024] Figure 3 is a connection diagram of a counter-ion electro-osmotic glucose electro-osmotic sensor and external equipment provided by an embodiment of the present application;

[0025] Figure 4 is a working principle diagram of a counter-ion electro-osmotic glucose electro-osmotic sensor provided by an embodiment of the present application;

[0026] Figures 5a to 5f is a preparation process diagram of a counter-ion electro-osmotic glucose electro-osmotic sensor provided by an embodiment of the present application;

[0027] Figure 6 is an SEM photo of a honeycomb-shaped anodic aluminum oxide provided by an embodiment of the present application;

[0028] Figure 7 is a modification process diagram of an enzyme layer provided by an embodiment of the present application;

[0029] Figure 8 is an SEM photo of a MWCNT-Au structure provided by an embodiment of the present application.

[0030] Explanation of reference signs:

[0031] 1-flexible substrate; 2-first electrode layer; 3-organic insulating layer; 4-second electrode layer; 5-cavity; 6-third electrode layer; 7-anodic aluminum oxide layer; 8-constant voltage power supply; 9-electrochemical detector; 10-aluminum metal layer. DETAILED DESCRIPTION

[0032] In order to further illustrate the technical means and effects taken by the present application to achieve the predetermined purposes, the following will combine the drawings and specific embodiments to specifically describe a non-invasive blood glucose detection sensor based on anodic aluminum oxide and a preparation method thereof according to the present application.

[0033] The foregoing and other technical contents, features and effects of the present application can be clearly presented in the following specific embodiment description with the aid of the drawings. Through the description of the specific embodiments, the technical means and effects taken by the present application to achieve the predetermined purposes can be more deeply and specifically understood. However, the attached drawings are provided for reference and explanation only, and are not used to limit the technical solutions of the present application.

[0034] It should be noted that the relational terms herein, such as first and second, and the like, are used solely to distinguish one from another entity or action without necessarily requiring or implying any actual relationship or order between such entities or actions. Moreover, the terms "comprises", "comprising", or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a vesicle or an apparatus that comprises a list of elements does not include only those elements but can include other elements not expressly listed or inherent to such vesicle or apparatus. An element proceeded by "comprises a... " does not, without more constraints, exclude the presence of additional identical elements in the vesicle or apparatus that includes the stated element.

[0035] Embodiment one

[0036] Please refer to Figure 1 , Figure 1 is a structure diagram of a non-invasive blood glucose detection sensor based on anodic aluminum oxide provided by the embodiment of the present application. The non-invasive blood glucose detection sensor comprises, from bottom to top, a flexible substrate 1, a first electrode layer 2, an organic insulating layer 3 and a second electrode layer 4, wherein the second electrode layer 4 comprises a plurality of cavities 5, the cavities 5 extend from the upper surface of the second electrode layer 4 to the upper surface of the first electrode layer 2, and the cavities 5 are filled with a honeycomb-shaped anodic aluminum oxide layer 7; a patterned third electrode layer 6 is further arranged on the upper surface of the second electrode layer 4, and a part of the third electrode layer 6 is adjacent to the edge of the cavity 5; the first electrode layer 2 and the second electrode layer 4 can be respectively connected to the cathode and the anode of a constant voltage power supply 8, and the honeycomb-shaped anodic aluminum oxide layer 7 enables the hydrogel to form an electric field environment for glucose movement in the subcutaneous tissue, so that the glucose in the subcutaneous tissue is concentrated in the cathode region under the electroosmosis effect; the first electrode layer 2, the second electrode layer 4 and the third electrode layer 6 can be further connected to a blood glucose detection device 9 for generating an electrical signal of the reaction glucose concentration.

[0037] In the embodiment, the material of the flexible substrate 1 is PI (Polyimide, polyimide), and the thickness is 75-125 μm. The first electrode layer 2 comprises, from bottom to top, 10-30 nm of chromium (Cr) and 100-250 nm of platinum (Pt). Preferably, the thickness of the chromium is 25 nm, and the thickness of the platinum is 100 nm. The first electrode layer 2 serves as a first electroosmotic electrode in the electroosmosis process and as a working electrode in the detection process, and the working electrode can be modified by an enzyme modification process or an enzyme-free modification process. If the enzyme modification process is adopted, the enzyme solution can be dropped into the cavity 5 before detection, and then the gel is added to complete the process. The material of the organic insulating layer 3 is a cured photoresist, specifically an organic resin, which can be selected from PDMS, SU-8 or PI, etc., and the thickness of the organic insulating layer 3 is 100-150 nm.

[0038] The second electrode layer 4 comprises 10-30 nm of chromium and 100-250 nm of platinum from bottom to top. Preferably, the thickness of chromium is 25 nm and the thickness of platinum is 100 nm. The second electrode layer 4 serves as the second electro-osmotic electrode in the electro-osmotic process and as the counter electrode in the glucose detection process. The anodic aluminum oxide layer 7 is in a honeycomb shape, as shown in Figure 6 The diameter and depth of the honeycomb cavities can be adjusted by controlling the thickness of the aluminum layer and the anodic oxidation reaction parameters during the preparation process. The detailed preparation process is described in Example 2.

[0039] In a specific embodiment, the cavities 5 are in a cylindrical structure with a diameter of 1-10 mm and a spacing of 3-5 mm. Alternatively, the cavities 5 are in a stepped structure composed of multiple cylindrical segments with different diameters, and the diameters decrease from top to bottom. Preferably, the second electrode layer 4 comprises four cavities 5, as shown in Figure 1 The upper surfaces of the four cavities 5 are circular, and the centers of the four circles are arranged in a square.

[0040] The anodic aluminum oxide layer 7 is arranged inside the cavities 5, and the lower surface of the anodic aluminum oxide layer 7 is in contact with the upper surface of the first electrode layer 2. Further, the thickness of the anodic aluminum oxide layer 7 in this embodiment is equal to or slightly smaller than the thickness of the organic insulating layer 3.

[0041] The third electrode layer 6 is an AgCl / Ag metal layer. The third electrode layer 6 is a reference electrode and is in working state during the glucose detection process. During use, the surface of the third electrode layer 6 and the anodic aluminum oxide layer 7 in the cavities 5 are filled with hydrogel, which serves as the carrier medium of glucose during the electro-osmotic and glucose detection processes.

[0042] The third electrode layer 6 in this embodiment comprises an integral main stem, connecting portions, and multiple terminal portions in a semi-ring shape. The main stem is in a long strip shape and extends to the edge of the second electrode layer 4 at one end, and the multiple cavities 5 are symmetrically arranged on both sides of the main stem. The number of terminal portions is equal to the number of cavities 5, and each terminal portion surrounds the upper edge of one cavity 5. Each terminal portion is connected to the main stem through a connecting portion.

[0043] Please refer to Figure 3 , Figure 3is a connection diagram of a reverse ion electro-osmotic glucose electro-osmotic sensor and external equipment provided by the embodiment of the present application. The second electrode layer 4 acts as a second electro-osmotic electrode in the electro-osmotic process and as a counter electrode in the glucose detection process, and is connected with the constant voltage source 8 and the electrochemical detector 9 at the same time, and the constant voltage source 8 and the electrochemical detector 9 do not work at the same time; the first electrode layer 2 acts as a first electro-osmotic electrode in the electro-osmotic process and as a working electrode in the detection process, and is connected with the constant voltage source 8 and the electrochemical detector 9 at the same time; the third electrode layer 5 is a reference electrode and is connected with the electrochemical detector 9.

[0044] Further, please refer to Figure 4 , Figure 4 is a working principle diagram of a reverse ion electro-osmotic glucose electro-osmotic sensor provided by the embodiment of the present application. In the use process, one side of the second electrode layer 4 is coated with a hydrogel, the hydrogel covers the upper surface of the second electrode layer 4 and the inside of the cavity 5, then the side coated with the hydrogel is closely attached to the skin surface, the constant voltage source 8 is turned on, the constant voltage source 8 starts to work, the first electrode layer 2 (negative electrode) and the second electrode layer 4 (positive electrode) are attracted, the hydrogel coated on the upper surface forms an electric field with the subcutaneous tissue through the honeycomb structure of the anodic aluminum layer 7, so that the glucose in the subcutaneous tissue is concentrated in the area where the anodic aluminum layer is located under the action of electro-osmosis; after the electro-osmosis is completed, the constant voltage source 8 is turned off, the second electrode layer 4 acts as a counter electrode and a reference electrode (the third electrode layer 5) and a working electrode (the first electrode layer 2) form an electrochemical loop in the hydrogel in the cavity 5; wherein the reference electrode provides a reference potential, and the working electrode generates an electrical signal reflecting the glucose concentration under the oxidation of glucose in the electrochemical loop with the reference potential as the reference.

[0045] The non-invasive blood glucose detection sensor based on anodic aluminum of the present application uses a special electrode structure to wrap the traditional water film (hydrogel) in the outer layer inside the electrode, so that the water film does not gradually evaporate with the use of the sensor, effectively prolonging the service life of the sensor and improving the detection accuracy of glucose. At the same time, the preparation process is simple, the cost is low, it is convenient for industrial production, and it is more suitable for daily use of diabetic patients. The present application uses a honeycomb anodic aluminum as a detection cavity, and the diameter and depth of the honeycomb cavity can be adjusted by controlling the thickness of the aluminum layer and the reaction parameters of anodic oxidation, thereby further improving the detection performance of the non-invasive blood glucose detection sensor; the device structure and preparation process are simple, and can be mass-produced, and the honeycomb anodic aluminum can provide a chamber for glucose detection, solving the problem of evaporation of the traditional water film.

[0046] Example two

[0047] Based on the embodiment one, the embodiment provides a preparation method of an anodic aluminum oxide-based non-invasive blood glucose detection sensor, as shown in Figures 5a to 5f The method of the embodiment is an enzyme sensor. The preparation method comprises the following steps:

[0048] S1: a flexible substrate 1 is selected and a first electrode layer 2 is formed on the flexible substrate 1.

[0049] A PI film with a thickness of 75-125 μm is selected as the flexible substrate 1, and the thickness is selected according to actual needs. The PI film is cut into a size slightly smaller than a 4-inch silicon wafer, and the PI film is fixed on the silicon wafer by a PI tape.

[0050] Subsequently, the first electrode layer 2 is formed on the PI film by metal sputtering. In an embodiment, 25 nm of chromium (Cr) and 100 nm of platinum (Pt) are sequentially sputtered on the PI film by a metal sputtering process to form the first electrode layer 2, as shown in Figure 5a Specifically, first, the flexible substrate 1 is cleaned and the surface is subjected to oxygen plasma treatment to improve the surface activity. Subsequently, the flexible substrate 1 is placed in a sputtering system and vacuumized to a base pressure (about 0.133 Pa). Then, the argon pressure is set to 0.5-2 Pa, the sputtering power is set to 100 W, the rotation speed of the flexible substrate 1 is set to 20 rpm, and the temperature is kept at room temperature. First, a chromium layer with a thickness of 25 nm is sputtered by using a chromium target, which takes about 50 seconds. Then, the platinum target is replaced, and a platinum layer with a thickness of 100 nm is continuously sputtered under the same conditions. Finally, the sample is naturally cooled and ready for use.

[0051] S2: an organic insulating layer 3 is formed on the upper surface of the first electrode layer 2, and a plurality of cavities 5 are etched on the organic insulating layer 3.

[0052] Specifically, the flexible substrate 1 with the first electrode layer 2 is subjected to ultrasonic cleaning using an acetone solvent to remove surface contaminants and dried. Then, a spin coater is used to uniformly coat photoresist on the upper surface of the first electrode layer 2, and the photoresist is cured by soft baking. Subsequently, the sample coated with the photoresist is placed in a photoetching machine, aligned with a pre-designed mask, and exposed to ultraviolet light to form the required pattern. After exposure, the sample is placed in a developing solution to develop, remove the unexposed part (if the photoresist used is positive photoresist) or the exposed part (if the photoresist used is negative photoresist), and form a clear pattern. After development, the sample is washed with deionized water and dried. Then, organic glue is uniformly coated on the patterned photoresist by using a spin coating or other methods, and the organic glue is cured by baking to a thickness of 150-300 nm. Finally, the remaining photoresist is removed using a stripping solution, leaving a patterned organic glue film, i.e., forming an organic insulating layer 3 with a plurality of cavities 5, as shown in Figure 5bAs shown, the material of the photoresist can be selected from PDMS, SU-8, PI and other relatively stable gels, and PI is preferred.

[0053] S3: depositing an aluminum metal layer 10 in the cavities 5, the thickness of the aluminum metal layer 10 being slightly less than or equal to the thickness of the organic insulating layer 3, as shown. Figure 5c

[0054] In one embodiment of the present application, the step specifically comprises the following steps:

[0055] S3.1: cleaning the substrate: ultrasonic cleaning of the current sample using acetone solvent for about 8 min. Then rinse with deionized water and dry or bake.

[0056] S3.2: glueing: select AZ 1514H photoresist, use a spin coater to uniformly coat the photoresist on the platinum film inside the cavities 5, usually the thickness is between 1-2 μm.

[0057] S3.3: pre-baking: pre-baking at a temperature of 90-110°C for 3-5 min to remove the solvent and solidify the photoresist.

[0058] S3.4: exposure: place the substrate coated with photoresist in a photoetching machine and use a pre-designed mask for UV exposure. The exposure time is between a few seconds and a few tens of seconds.

[0059] S3.5: post-baking, the temperature is generally between 120-150°C for a few minutes to further solidify the remaining photoresist.

[0060] S3.6: development: use AZ 300MIF developer to develop the exposed photoresist to remove the unexposed part. The development time is between a few tens of seconds and a few minutes.

[0061] S3.7: place the developed substrate into a sputtering system. Vacuumize to the base pressure, set the sputtering parameters: argon pressure is 0.5-2 Pascal (Pa). Sputtering power: 50-200 watts (W). The rotation speed is 10-30 revolutions per minute (rpm) to ensure uniform deposition. The substrate temperature is kept at room temperature or slightly heated, such as 30°C-80°C. The sputtering rate is / s, it takes about 400 seconds (about 6.6 minutes) to deposit a 200 nm aluminum film.

[0062] S3.8: after the aluminum deposition is completed, use a stripping agent (such as acetone or a special stripping agent) to remove the photoresist and the aluminum film on it, leaving only the required aluminum pattern.

[0063] S3.9: cleaning: thoroughly clean the substrate with deionized water and other solvents to remove residual stripping agent and other impurities.​

[0064] In another embodiment of the present application, step S3 employs FIB-induced deposition, which specifically includes the following steps:

[0065] S'3.1: Place the sample on the sample stage of the FIB (Focused Ion beam) system and ensure that the sample surface is clean and flat.

[0066] S'3.2: Select a metal organic compound of aluminum, the selection basis being whether the metal organic compound can be decomposed and deposited on the sample surface under the bombardment of the ion beam.

[0067] S'3.3: Adjust the electrostatic lens and other components of the FIB system to focus the ion beam into a beam of appropriate size, so as to accurately control the deposition area.

[0068] S'3.4: Start the gas injection system to introduce the gaseous precursor of the metal organic compound into the deposition area. The gaseous precursor is uniformly adsorbed on the sample surface to form a thin film. Start the FIB system to bombard the sample surface with the focused ion beam. The energy of the ion beam will excite the chemical reaction on the sample surface, so that the gaseous precursor is decomposed and deposited on the sample surface, specifically inside the plurality of grooves 10, to form an aluminum metal layer 11. By accurately controlling the scanning path, dwell time and other parameters of the ion beam, as well as the flow rate and concentration of the gaseous precursor, the thickness and uniformity of the aluminum metal layer 11 can be accurately controlled. During the deposition process, the imaging function of the FIB system is used to monitor the growth of the deposited layer (i.e. the aluminum metal layer 11) in real time, to ensure the accuracy of the deposition pattern.

[0069] S4: Form a second electrode layer 4 on the upper surface of the organic insulating layer 3, and a plurality of holes corresponding to the cavities are formed in the second electrode layer 4, as shown in Figure 5d .

[0070] In this step, the second electrode layer 4 needs to be patterned, and there are many process methods to achieve it, two of which are listed below.

[0071] In one embodiment of the present application, step S5 includes the following steps:

[0072] The patterned second electrode layer 4 is formed using conventional lift-off technology. Specifically, a layer of photoresist (e.g., AZ1512) is first formed using photolithography. After patterning the photoresist, 25nm of chromium and 100nm of platinum are sequentially deposited. The chromium serves as a connecting layer, and the specific thickness of each metal layer is determined by actual conditions. Platinum is then deposited using a process such as electron beam deposition, preferably at room temperature. Finally, excess metal and photoresist are removed using a stripping solvent such as Remover PG.

[0073] In another embodiment of the present invention, the specific execution process of this step is:

[0074] A patterned second electrode layer 4 is formed by inkjet printing. First, a platinum ink suitable for inkjet printing is selected or formulated. The sample is cleaned and surface treated to improve the ink adhesion and printing effect. Make sure that the printer is correctly set up and calibrated. Adjust the printing parameters, such as nozzle temperature, printing voltage, substrate temperature, etc., to adapt to the characteristics of the platinum ink. The pattern graphic information of the second electrode layer 4 stored in the computer is transferred to the printing system. The printer sprays extremely small droplets of platinum ink onto the surface of the sample according to the settings to form the required pattern. After printing is completed, the pattern is cured to enhance its adhesion and stability. The curing method may include heat treatment, ultraviolet light irradiation or other chemical methods. Use an appropriate solvent to clean the substrate to remove uncured ink and impurities. Dry the sample to ensure the clarity and durability of the platinum pattern. Depending on the application requirements, the platinum pattern may need to be further processed and treated, such as etching, polishing, etc.

[0075] S5: forming a patterned third electrode layer 6 on the upper surface of the second electrode layer 4, such as Figure 5e shown.

[0076] First, a stable silver chloride ink is prepared by mixing silver chloride powder with ethanol, a dispersant (polyvinyl pyrrolidone (PVP)), and a surfactant (Triton X-100) to form a uniform suspension, i.e., the desired silver chloride ink. Next, a high-precision inkjet printer (such as a piezoelectric inkjet printer) is used to precisely print the silver chloride ink onto the upper surface of the clean second electrode layer 4 to form a patterned third electrode layer 6. The resolution is set to 600 dpi, the ink droplet size is set to 10 picoliters, and the number of printed layers is approximately 10. After printing, the substrate is placed in an oven for drying and curing.

[0077] S6: The aluminum metal layer 11 is prepared into a honeycomb anodized aluminum layer, such as Figure 5f shown.

[0078] The first electrode layer 2 is connected to a direct current power source to anodize the aluminum. The anodization process can be either a one-step anodization process or a two-step anodization process.

[0079] For the one-step anodization process, the second electrode layer is connected to a direct current power source and the cavity is immersed in a 0.3 Mol / L oxalic acid solution to anodize at 45V direct current voltage and 2°C (either one-step or two-step process). The pore size can be adjusted by adjusting the anodization time. The surface is then rinsed thoroughly with deionized water and dried.

[0080] For the two-step anodization process, the second electrode layer is connected to a direct current power source and the cavity is immersed in a 0.3 Mol / L oxalic acid solution for a first step anodization of 5-15 minutes (preferably 10 minutes), then the sample is etched in a 0.4 Mol / L phosphoric acid solution and 0.2 Mol / L chromic acid solution at 65°C for 20-40 minutes, followed by a second step anodization in a 0.3 Mol / L oxalic acid solution at 65°C for 20-40 minutes. The surface is then rinsed thoroughly with deionized water and dried. In practice, the time for each step can be adjusted according to the thickness of the aluminum layer.

[0081] S7: The surface of the first electrode layer 2 is modified to have a response to glucose.

[0082] Specifically, the electrode modification can be performed by an enzymatic modification process or a non-enzymatic modification process.

[0083] The enzymatic modification process includes:

[0084] Mixing appropriate amount of glucose oxidase and deionized water, and preparing 100 U / μL glucose oxidase solution. Mixing 1960 μL of deionized water, 26.6 mg of BSA bovine serum albumin and 13.4 μL of GDH glutaraldehyde (25% in water) and centrifuging at 4000 rpm for 30 seconds to prepare a cross-linking agent. After taking the glucose oxidase solution and placing it in a 4-degree Celsius refrigerator for thawing, taking 2 mL and adding it to 1.5 mL of the cross-linking agent, and placing it in a centrifuge for 4000 rpm centrifugal treatment for 30 seconds to form a mixed solution. Taking a syringe, dropping the mixed solution into cavity 5, and allowing it to cover the entire electrode under the action of gravity, i.e. covering the upper surface of the second electrode layer 4, cavity 5 and the third electrode layer 6, repeating 25-45 times with a drop interval of 50-90 seconds, and placing the electrode sample in a 4-degree Celsius refrigerator for 48 hours, waiting for the electrode to air dry. Connecting the second electrode layer to a direct current power supply (specifically, the above constant voltage power supply), immersing the sample in a mPD solution (containing 1 M NaCl and 10 mM mPD) by means of electropolymerization, and performing voltammetric cyclic scanning for 100-150 cycles, applying a voltage interval of -0.2 V-0.8 V and a scanning speed of 50 mV / s, covering the entire electrode surface with an mPD thin film, and placing it in a 4-degree Celsius refrigerator for at least 48 hours. It should be noted that the process parameters can be adjusted according to specific circumstances, and all parameter settings are not unique and can be optimized according to actual conditions.

[0085] The enzyme-free modification process includes:

[0086] First, disperse MWCNTs (carbon nanotubes) in a mixture of Nafion solution (5 wt%) and ethanol at a volume ratio of 1:9, ultrasonically disperse for 30 min, and form a MWCNT mixed solution with a concentration of 10 mg ml -1 Connect the second electrode layer to a direct current power supply, arrange several electrodes in order on a heating table, keep the MWCNT mixed solution in an ultrasonic state at all times, take about 3 ul at a time and drop it into the cavity, heat and evaporate for 30-60 min, and repeat the dropping three to five times on the working electrode surface (specifically, the inside of the cavity), so that a uniform carbon nanometer film is formed on the surface of the second electrode in the cavity. Then, in a mixed solution of 0.5 Mol / L H2SO4 and 0.5 mMol / L HAuCl4, use a Gamry electrochemical workstation to apply a constant voltage of -0.3 V, and deposit Au nanoparticles on the carbon nanometer film for 50 s. Form a MWCNT-Au structure as shown in Figure 8 , where the white particles are Au, and finally, clean and dry the electrode. The MWCNT-Au plays a catalytic role in the blood glucose detection process.

[0087] It should be noted that the above scheme is only a single enzyme-free process, and the device structure is suitable for various enzyme-free modification processes and is not limited to the above one.

[0088] The counter-ion electro-osmotic glucose electro-osmotic sensor prepared by the preparation method of the embodiment of the application can reduce the manufacturing cost of the counter-ion electro-osmotic blood glucose sensor, simplify the preparation process, prevent water gel from being exposed for a long time to cause evaporation, affect the detection efficiency and accuracy of the sensor, and improve the service life of the sensor.

[0089] In several embodiments provided in the present application, it should be understood that the disclosed devices and methods can be implemented in other ways. For example, the above-described device embodiments are only illustrative, for example, the division of the modules is only a logical function division, and actual implementation can have another division manner, for example, multiple modules or components can be combined or integrated into another system, or some features can be ignored or not executed.

[0090] In addition, each function module in each embodiment of the present application can be integrated in a processing module, or each module can exist physically, or two or more modules can be integrated in one module. The above integrated module can be realized in the form of hardware or in the form of hardware plus software function module.

[0091] The above is a further detailed description of the present application in combination with specific preferred embodiments, and the specific implementation of the present application cannot be limited to these descriptions. For ordinary skilled persons in the technical field to which the present application belongs, several simple deductions or replacements can be made without departing from the concept of the present application, and all of them should be regarded as falling within the protection scope of the present application.

Claims

1. An anodized aluminum oxide based non-invasive blood glucose detection sensor, characterized by, The non-invasive blood glucose sensor comprises a flexible substrate (1), a first electrode layer (2), an organic insulating layer (3) and a second electrode layer (4) arranged in sequence from bottom to top, wherein a plurality of cavities (5) are formed on the second electrode layer (4), the cavities (5) extend downward from the upper surface of the second electrode layer (4) to the upper surface of the first electrode layer (2), and the cavities (5) are filled with a honeycomb-shaped anodic aluminum oxide layer (7); a patterned third electrode layer (6) is further arranged on the upper surface of the second electrode layer (4), and a part of the third electrode layer (6) surrounds the upper edge of the cavity (5); the first electrode layer (2) and the second electrode layer (4) can be respectively connected to the cathode and the anode of a constant voltage power supply (8), and the honeycomb-shaped anodic aluminum oxide layer (7) forms an electric field environment for the hydrogel in the subcutaneous tissue, so that the glucose in the subcutaneous tissue is concentrated in the cathode area under the electroosmosis effect; the first electrode layer (2), the second electrode layer (4) and the third electrode layer (6) can also be connected to a blood glucose detection device (9) for generating an electrical signal corresponding to the reaction glucose concentration. The first electrode layer (2) and the second electrode layer (4) each comprise a chromium layer with a thickness of 10-30 nm and a platinum layer with a thickness of 100-250 nm arranged in sequence from bottom to top.

2. The non-invasive blood glucose detection sensor based on anodized aluminum oxide according to claim 1, characterized in that, The first electrode layer (2) is modified by an enzyme modification process or an enzyme-free modification process.

3. The non-invasive blood glucose detection sensor based on anodized aluminum oxide according to claim 1, characterized in that, The cavities (5) are in the form of a cylindrical structure with a diameter of 1-10 mm and a spacing of 3-5 mm, or the cavities (5) are in the form of a stepped structure composed of multiple cylindrical segments with different diameters, and the diameter decreases from top to bottom.

4. The non-invasive blood glucose detection sensor based on anodized aluminum oxide according to claim 1, characterized in that, The thickness of the anodic aluminum oxide layer (7) is equal to or less than the thickness of the organic insulating layer (3).

5. The non-invasive blood glucose detection sensor based on anodized aluminum oxide according to claim 1, characterized in that, The third electrode layer (6) comprises a main body, a connecting portion and a plurality of terminal portions in the form of a semi-ring, wherein 6. The non-invasive blood glucose detection sensor based on anodized aluminum oxide according to claim 1, characterized in that, the main body is in the form of a long strip and extends to the edge of the second electrode layer (4) at one end, and the plurality of cavities (5) are symmetrically arranged on both sides of the main body; the number of the plurality of terminal portions is equal to the number of the cavities (5), and each terminal portion surrounds the upper edge of one cavity (5); each terminal portion is connected to the main body by a connecting portion. The non-invasive blood glucose sensor of any one of claims 1-6 is prepared by the following method:

7. A method for preparing an anodized aluminum oxide-based non-invasive blood glucose detection sensor, characterized by, S1: selecting a flexible substrate and forming a first electrode layer on the flexible substrate; S2: forming an organic insulating layer on the upper surface of the first electrode layer and etching a plurality of cavities on the organic insulating layer; S3: depositing an aluminum metal layer in the cavities, and the thickness of the aluminum metal layer is slightly less than or equal to the thickness of the organic insulating layer; S4: forming a second electrode layer on the upper surface of the organic insulating layer, and a plurality of holes corresponding to the cavities are formed on the second electrode layer; S5: forming a patterned third electrode layer on the upper surface of the second electrode layer; S6: preparing the aluminum metal layer into a honeycomb-shaped anodic aluminum oxide layer. The S6 comprises:

8. The method for preparing an anodic aluminum oxide-based non-invasive blood glucose measurement sensor according to claim 7, characterized by, ​ The second electrode layer is connected to a direct current power supply, the cavity is immersed in 0.3Mol / L oxalic acid solution, and anodic oxidation treatment is performed by using direct current voltage, and then the surface is rinsed with deionized water and dried; Or, the second electrode layer is connected to a direct current power supply, the cavity is immersed in 0.3Mol / L oxalic acid solution for 5-15min for first-step anodic oxidation, and then the sample is etched in a mixed solution of 0.4Mol / L phosphoric acid and 0.2Mol / L chromic acid at a temperature of 65℃ for 20-40min, and then second-step anodic oxidation is performed in 0.3Mol / L oxalic acid solution for 20-40min, and then the surface is rinsed with deionized water and dried.

9. The method for preparing a non-invasive blood glucose detection sensor based on anodized aluminum according to claim 7, characterized in that: After step S6, the following steps are further included: An appropriate amount of glucose oxidase and deionized water are mixed to form a glucose oxidase solution, and an appropriate amount of deionized water, bovine serum albumin and glutaraldehyde are mixed and centrifuged to form a crosslinking agent; An appropriate amount of the glucose oxidase solution is added to the crosslinking agent and centrifuged to obtain a mixed solution; the mixed solution is dropped into the cavity, and each drop is repeated 25-45 times with an interval of 50-90s, and then placed in a refrigerator for cold storage and waiting for air drying; The second electrode layer is connected to a direct current power supply, the sample is immersed in mPD solution by electro-polymerization, a voltage of-0.2V-0.8V is applied, a layer of mPD thin film is formed on the surface of the second electrode in the cavity, and then placed in a refrigerator for cold storage.

10. The method of claim 7, wherein the anodized aluminum oxide-based non-invasive blood glucose sensor is prepared by the steps of: After step S6, the following steps are further included: ​ An appropriate amount of carbon nanotubes is dispersed in a mixed solution of Nafion solution and ethanol, and ultrasonic dispersion is performed to form a carbon nanotube mixed solution; The sample is placed on a heating table, the carbon nanotube mixed solution is kept in an ultrasonic state, 3ul is dropped into the cavity, and heating evaporation is performed for 30-60min, and the dropping is repeated 3-5 times to form a uniform carbon nanotube film on the surface of the second electrode in the cavity; The second electrode layer is connected to a direct current power supply, the sample is immersed in a mixed solution of H2SO4 and HAuCl4, a constant voltage of-0.3V is applied, Au nanoparticles are deposited on the carbon nanotube film to form a MWCNT-Au structure.

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