Wireless fluorescent sensing patch for blood glucose monitoring and preparation method thereof

Abstract

The invention discloses a wireless fluorescent sensing patch for blood glucose monitoring and a preparation method thereof, and belongs to the field of biomedical engineering devices. When the wireless fluorescent sensing patch is used, the wireless fluorescent sensing patch is attached to the surface of the skin, and the microneedle is punctured into the epidermis, so that the effects of fixing and extracting interstitial fluid are achieved. After the patch acts on the skin of the human body, firstly, the smart phone is close to the patch to supply energy to the patch, and the patch monitors the glucose concentration and transmits collected data to the smart phone, so that a patient obtains blood glucose level information. The subcutaneous interstitial fluid is extracted through the soft microneedle to achieve painless real-time in-situ glucose concentration monitoring, energy and wireless regulation and control can be provided through a built-in coil of a smart phone based on the near field communication technology, and wireless battery-free energy supply of the flexible microneedle patch is achieved. According to the invention, stable and long-term monitoring is provided, and meanwhile, the convenience and reliability of detection are remarkably improved. The microneedle is low in manufacturing cost and convenient to replace, the operation process is simplified, and the comfort of a patient in long-time use is improved.

Description

Technical Field

[0001] The invention belongs to the field of biomedical engineering devices, and in particular relates to a wireless fluorescent sensor patch for blood sugar monitoring and a preparation method thereof. Background Art

[0002] Diabetes is a metabolic disease characterized by chronic high blood sugar. The number of people suffering from diabetes worldwide has exceeded 500 million and continues to grow. Long-term high blood sugar in diabetes can lead to serious complications such as heart disease, stroke, kidney failure and blindness. Blood sugar monitoring is an important means of diabetes management. It helps patients and doctors develop or adjust treatment plans by detecting blood sugar levels. The most common method of blood sugar monitoring at present is the traditional blood sugar meter that detects blood sugar through fingertip blood samples. In addition, the emerging continuous glucose monitoring (CGM) technology aims to provide real-time, all-weather blood sugar data. The blood sugar monitoring system is constantly developing towards the goal of accuracy and convenience, and can help patients effectively control blood sugar and reduce the risk of complications through data analysis and management.

[0003] The measurement process of a traditional blood glucose meter includes the following steps: First, the user collects blood from the fingertip with a needle and drops it on the detection area on the test strip. The test strip is coated with chemical reagents such as glucose oxidase and catalase. Glucose oxidase catalyzes the reaction of glucose in the blood with oxygen to produce gluconic acid and hydrogen peroxide. Next, catalase catalyzes the reaction of hydrogen peroxide with other reagents to produce electrical signals or color changes. The blood glucose meter detects these signals or changes and converts them into digital results to display blood glucose values. Continuous glucose monitoring (CGM) technology mainly includes the following methods: The puncture sensor measures the glucose level in the interstitial fluid through a probe inserted into the subcutaneous tissue to provide real-time data. The glucose concentration in the subcutaneous interstitial fluid is usually synchronized with the blood glucose level, although the glucose concentration in the interstitial fluid is usually slightly lower than that in the blood because there is a certain delay in the transfer of glucose from the blood to the interstitial fluid, which is usually between a few minutes and half an hour. Therefore, the interstitial fluid glucose concentration measured by the continuous glucose monitoring (CGM) system can effectively reflect the blood glucose level. A fine probe is inserted into the subcutaneous tissue to measure the glucose concentration in the interstitial fluid. The electrochemical element in the sensor reacts with glucose. Such electrochemical elements mostly use enzymes (such as glucose oxidase) to catalyze the reaction of glucose with oxygen to produce hydrogen peroxide. Hydrogen peroxide is oxidized on the electrode to generate current, and the magnitude of the current is proportional to the blood glucose concentration. The sensor converts these current signals into voltage or digital data, which corresponds to the blood glucose concentration and is transmitted wirelessly to an external receiver or smart device. Users can monitor blood glucose levels and trends in real time to better manage blood glucose. In addition, there are laser sensors and fluorescence sensors currently in the research stage. Laser sensors mainly use optical principles to illuminate the skin or sample by emitting a laser beam of a specific wavelength. The laser beam is scattered and absorbed in the skin, and the blood glucose concentration affects the change of this light. The sensor's detector receives and measures the changes in these light signals and converts them into blood glucose values. This method is non-invasive and can provide real-time blood glucose data. The main principle of the fluorescence sensor is to apply chemical reagents containing fluorescent dyes to the sample, which react with glucose molecules. Under the irradiation of excitation light (such as LED light), the dye emits fluorescence of a specific wavelength, and the fluorescence intensity is usually linearly correlated with the glucose concentration. The sensor detects and measures the intensity of this fluorescent signal, which is related to the blood sugar concentration, and finally converts the measured signal into a blood sugar value. Currently, this type of sensor is still in the research and development stage and is rarely used in practice. Summary of the invention

[0004] The purpose of the present invention is to solve the above-mentioned technical problems, and to provide a wireless fluorescent sensor patch for blood sugar monitoring and a preparation method thereof, which is used to analyze the glucose concentration in the interstitial fluid, so as to facilitate diabetic patients to grasp the blood sugar information. The patch is designed to be wearable on the surface of human skin, extract interstitial fluid minimally invasively through its microneedle structure, and monitor the glucose concentration in real time using glucose-responsive fluorescent materials. The patch is equipped with a fluorescent signal detection device, which can convert the fluorescent signal into glucose concentration data, and wirelessly control the monitoring function through the near-field communication technology of a smartphone, and transmit the monitoring results to the smart device at the same time. Users can view blood sugar information in real time through the user interface of the smart device, thereby providing a minimally invasive, real-time and convenient blood sugar monitoring solution for diabetic patients.

[0005] In order to solve the above technical problems, the specific technical solutions of a wireless fluorescent sensor patch for blood glucose monitoring and a preparation method thereof of the present invention are as follows:

[0006] A wireless fluorescent sensor patch for blood glucose monitoring, comprising a sensing microneedle, a fluorescent detection unit and a near field communication wireless control circuit;

[0007] The sensing microneedle 1-1 comprises a soft glucose concentration responsive sensing microneedle array based on fluorescent material, wherein the material of the microneedle sensing array is a bioabsorbable hydrogel and loaded with a glucose concentration responsive fluorescent material, and the fluorescent material is evenly distributed in the microneedle tip;

[0008] The fluorescence detection unit includes an ultraviolet cutoff filter 1-2, an ultraviolet light emitting diode 1-3 and a color sensor 1-4; wherein the ultraviolet light emitting diode 1-3 and the color sensor 1-4 are integrated on a flexible circuit board, the ultraviolet cutoff filter covers the upper surface of the color sensor so that it only receives visible light filtered by the ultraviolet cutoff filter, and the entire flexible circuit board and the ultraviolet cutoff filter 1-2 are encapsulated by polydimethylsiloxane (PDMS); with the ultraviolet cutoff filter as the center, there is a reserved microneedle placement groove on the outer side of the encapsulation layer above it, and the sensing microneedle is embedded in the reserved groove and fixed by the viscosity of the hydrogel; the depth of the groove is equal to the base thickness of the sensing microneedle.

[0009] The near field communication wireless control circuit is specifically an NFC coil, which is used to realize wireless power transmission and receive signals and energy from the smart terminal. The near field communication wireless control circuit is integrated on a flexible circuit board;

[0010] The flexible circuit includes an NFC coil, an NFC chip, a data processing center MCU and its connecting circuit; specifically, the NFC coil is activated by the smart terminal, and the signal and energy from the smart terminal are transmitted to the NFC chip. The NFC chip generates an analog voltage through energy collection to provide power and signal for the flexible circuit board in the patch; the data processing center realizes the color sensor parameter configuration and sensor data acquisition; during the color sensor measurement, the MCU controls the activation of the ultraviolet light emitting diode at the same time, and the light emitting diode is directly powered by the power supply voltage output by the NFC chip; after the microneedle array acts on the skin surface to absorb interstitial fluid, under the irradiation of ultraviolet light, the fluorescence intensity generated by the glucose concentration-responsive fluorescent material based on glucose molecules changes according to the glucose concentration, and the fluorescence intensity is received by the color sensor through the ultraviolet cutoff filter; after the color sensor completes the color data measurement, the MCU commands the color sensor to enter the Power Down state and deactivates the ultraviolet light emitting diode, and transmits the data obtained from the color sensor to the NFC chip. When the smart terminal is close to the NFC coil, the smart terminal obtains the blood glucose concentration through the color data.

[0011] The bioabsorbable hydrogel is specifically one or more of polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol and hyaluronic acid; the glucose concentration responsive fluorescent material is specifically one of 9-anthraceneboric acid, 2-anthraceneboric acid and phenylboric acid. The glucose concentration responsive fluorescent material is in contact with interstitial fluid and produces fluorescence of different colors under ultraviolet light, and the fluorescence intensity is related to the glucose concentration.

[0012] The ultraviolet light emitting diode emits ultraviolet light of 200-400nm to excite the glucose concentration-responsive fluorescent material loaded in the microneedle to generate fluorescence.

[0013] The color sensor is specifically an XYZ true color sensor, which includes three independent photosensitive channels: the X channel is used to detect red light, the Y channel is used to detect green light and brightness, and the Z channel is used to detect blue light; the MCU establishes communication with the color sensor through the I2C protocol and transmits the detected XYZ values ​​to the NFC chip.

[0014] The present invention also provides a method for preparing a wireless fluorescent sensor patch for blood sugar monitoring, which specifically comprises the following steps:

[0015] Step 1: Use computer-aided design software to design the structure of the flexible circuit board and prepare the flexible substrate and wire circuit;

[0016] Step 2: Prepare a flexible printed circuit board with an area of ​​2.0 cm × 2.3 cm by using an immersion gold process;

[0017] Step 3: Integrate the UV lamp, color sensor, data processing center, NFC chip, and NFC coil on the flexible printed circuit board using reflow soldering technology;

[0018] Step 4: Use epoxy resin glue to fix the UV cutoff filter on the color sensor;

[0019] Step 5: encapsulate the patch with polydimethylsiloxane, and use the reverse molding method to form a groove for embedding the sensing microneedle, wherein the groove is located directly above the UV cutoff filter;

[0020] Step 6: Prepare soft glucose concentration responsive fluorescent sensing microneedles; first prepare a bioabsorbable hydrogel solution, then mix the glucose concentration responsive fluorescent material solution with it, stir evenly, pour the resulting mixed solution into a microneedle array mold, centrifuge and vacuum process to ensure that the microneedle tip is completely filled and bubbles are removed, and then put the mold into a drying oven to dry to solidify and form a rigid microneedle tip; after drying, inject the hydrogel solution into the upper layer of the microneedle, and put the mold into the drying oven again to dry to solidify and form a microneedle flexible substrate; after complete curing, demold the microneedle to obtain a microneedle array;

[0021] Step 7: Wet the flat side of the microneedle substrate with water, and use the viscosity of the hydrogel itself to embed the microneedle into the reserved groove and dry it to fix the microneedle on the PDMS encapsulation layer.

[0022] The beneficial effects of the present invention are as follows:

[0023] (1) The present invention provides a method for monitoring glucose concentration based on fluorescence colorimetry. The technical solution of the present invention improves the traditional glucose concentration sensing method, adopts glucose-responsive fluorescence technology based on boric acid, and integrates fluorescent materials and color sensors into one. Compared with traditional electrochemical sensing methods, fluorescence colorimetry does not need to rely on glucose oxidase, so it is not easily affected by environmental factors such as humidity and temperature, has a longer service life, and does not require frequent replacement and calibration. Integrating fluorescent materials and color sensors can avoid the influence of ambient light and realize real-time in-situ blood glucose monitoring. The technical solution of the present invention significantly improves the convenience and reliability of detection while providing stable and long-term monitoring.

[0024] (2) The present invention provides a hydrogel sensing microneedle for minimally invasive monitoring of glucose concentration and a preparation method thereof. The microneedle can realize non-invasive detection of glucose concentration by absorbing interstitial fluid of the skin. The microneedle is made of biocompatible material and can be inserted into the superficial layer of the skin to quickly absorb interstitial fluid while avoiding causing pain. The fluorescent material in the hydrogel interacts with the absorbed glucose molecules to produce changes in fluorescence intensity, thereby realizing the detection of glucose levels. The microneedle substrate designed in the present invention is a flexible material, which can better fit the skin surface and reduce irritation and damage to the skin compared to traditional rigid metal microneedles. In addition, the microneedle has a low production cost and is easy to replace, which simplifies the operation process and improves the comfort of patients during long-term use.

[0025] (3) The present invention realizes wireless power supply and communication functions through near-field communication technology, avoiding dependence on power supply or battery, thereby effectively reducing the size and weight of the patch device and significantly improving the comfort of patients when wearing it. The device can be wirelessly connected to a smartphone, allowing users to view blood sugar data in real time, making it easier to instantly grasp their own blood sugar levels, and improving the convenience and practicality of monitoring. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 A schematic diagram of the composition of a wireless fluorescent sensor patch provided in an embodiment of the present invention;

[0027] Figure 2 A circuit schematic diagram of a wireless fluorescent sensor patch provided by an embodiment of the present invention;

[0028] Figure 3 A schematic diagram of the operation of the wireless fluorescent sensor patch provided by an embodiment of the present invention;

[0029] Figure 4 Schematic diagram of the experimental results of monitoring glucose concentration changes using wireless fluorescent sensor patches;

[0030] Figure 5 Schematic diagram of the experimental results of monitoring changes in glucose concentration in mice using a wireless fluorescent sensor patch. DETAILED DESCRIPTION

[0031] In order to better understand the purpose, structure and function of the present invention, the wireless fluorescent sensor patch for blood glucose monitoring and the preparation method thereof are further described in detail below in conjunction with the accompanying drawings.

[0032] The wireless fluorescent sensor patch of the present invention is used to assist diabetic patients in obtaining blood sugar information, and realizes painless real-time in-situ glucose concentration monitoring by extracting subcutaneous interstitial fluid through soft microneedles.

[0033] Based on near-field communication technology, the present invention can utilize the built-in coil of a smart phone to provide energy and wireless regulation, thereby realizing wireless battery-free energy supply of the flexible microneedle patch and realizing wireless blood glucose monitoring function.

[0034] The invention comprises a fluorescence-based soft glucose concentration response sensing microneedle array, a fluorescence detection unit and a near field communication wireless control circuit.

[0035] The schematic diagram of the wireless fluorescent sensor patch in this embodiment is as follows Figure 1 As shown, it includes a sensing microneedle 1-1, an ultraviolet cutoff filter 1-2, an ultraviolet light emitting diode 1-3, a color sensor 1-4, a flexible circuit 1-5 and a near field communication coil 1-6. The fluorescence detection unit includes an ultraviolet cutoff filter 1-2, an ultraviolet light emitting diode 1-3 and a color sensor 1-4. The fluorescence detection unit and the near field communication wireless control circuit include a near field communication coil 1-6 integrated on a flexible circuit board. The ultraviolet cutoff filter covers the upper surface of the color sensor so that it only receives visible light filtered by the ultraviolet cutoff filter. The entire flexible circuit board and the ultraviolet cutoff filter 1-2 are encapsulated by PDMS to ensure that the device is insulated from the outside after encapsulation, and has good biocompatibility, bendability and stretchability. With the ultraviolet cutoff filter as the center, there is a reserved microneedle placement groove on the outside of the encapsulation layer above it. The sensing microneedle is embedded in the reserved groove and fixed by the viscosity of the hydrogel. The depth of the groove is less than or equal to the substrate thickness of the sensing microneedle.

[0036] The sensing microneedle is a soft glucose concentration responsive sensing microneedle array, which is prepared by a bioabsorbable hydrogel, including one or more of polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol and hyaluronic acid, as a substrate, and loaded with a glucose concentration responsive fluorescent material, including one of 9-anthracene boronic acid, 2-anthracene boronic acid and phenyl boronic acid, and the fluorescent material can be evenly distributed in the microneedle tip. The microneedle substrate of the biocompatible hydrogel can pierce the epidermis, absorb subcutaneous interstitial fluid, and be absorbed by the organism. The glucose concentration responsive fluorescent material can produce fluorescence of different colors under ultraviolet light irradiation, and the fluorescence intensity is related to the glucose concentration. When the microneedle acts on the skin surface to absorb the interstitial fluid, the glucose concentration responsive fluorescent material contacts the glucose molecules, and the generated fluorescence intensity changes. After the fluorescence intensity is detected by the color sensor, the generated electrical signal is converted by the flexible circuit into an XYZ signal value to characterize the fluorescence change, and the concentration of glucose in the interstitial fluid is determined by the change in fluorescence intensity. The glucose concentration in the interstitial fluid is usually about 70% of the blood glucose concentration, so this concentration can be effectively used as an indirect indicator of blood glucose level. .

[0037] The UV cut-off filter is an optical component placed above the color sensor, which is designed to effectively block radiation within the ultraviolet wavelength range while allowing radiation within the visible light wavelength range to pass through. Through this design, the UV cut-off filter of the present invention can ensure that when the color sensor receives the fluorescent signal from the microneedle, it can eliminate the interference of ultraviolet light, thereby achieving accurate detection of the fluorescent signal.

[0038] The ultraviolet light emitting diode is used to emit ultraviolet light of 200-400nm to excite the glucose concentration responsive fluorescent material loaded in the microneedle to produce blue fluorescence. The ultraviolet light emitting diode is specially designed to be used in conjunction with the glucose concentration responsive microneedle to achieve high-precision detection of glucose concentration.

[0039] The color sensor is specifically an XYZ true color sensor (model AS73211), which has the characteristics of low power consumption and low noise, and is particularly suitable for monitoring changes in microneedle fluorescence. The sensor includes three independent photosensitive channels: the X channel is used to detect red light, the Y channel is used to detect green light and brightness, and the Z channel is used to detect blue light. This design enables the sensor to accurately collect and analyze the intensity changes of the fluorescence signal. The color sensor is installed directly above the microneedle array to directly collect the changes in the fluorescence intensity emitted by the microneedles. Through precise sensor positioning and high-sensitivity detection capabilities, the present invention can achieve accurate monitoring of microneedle fluorescence signals, thereby providing a reliable and accurate method for measuring glucose concentration. The low power consumption characteristics of the color sensor make it particularly suitable for portable or long-term monitoring equipment, while the low noise characteristics ensure the accuracy and reliability of the monitoring data.

[0040] The flexible circuit is used to manage the energy supplied by the near field communication coil and analyze and store the fluorescence intensity information collected by the color sensor.

[0041] The near field communication coil is used to achieve wireless power transmission, specifically a near field communication (NFC) coil. The NFC coil is particularly suitable for use with mobile devices such as smartphones to wirelessly transmit processed fluorescence intensity information. The configuration of the coil allows efficient energy and data exchange with the NFC receiver of the mobile device, thereby achieving wireless power supply and data collection for the patch sensor

[0042] Figure 2 This is a circuit schematic diagram of a wireless fluorescent sensor patch, which consists of a sensing circuit 2-1, a data processing circuit 2-2 and a wireless control circuit 2-3. The sensing circuit includes a color sensor and an ultraviolet light emitting diode; the data processing circuit includes an NFC chip and a data processing center (MCU); and the wireless control circuit includes an NFC coil and an NFC chip.

[0043] When testing blood sugar, users only need to bring their smartphones close to the wireless fluorescent sensor patch, and using near-field communication (NFC) technology, the smartphone can wirelessly provide energy to the patch. The microneedles on the patch gently penetrate the skin to absorb interstitial fluid. After the smartphone activates the NFC coil, its built-in NFC chip generates analog voltage through energy collection to power the circuits in the patch. These circuits include the NFC chip itself, the data processing center (MCU), the color sensor, and the ultraviolet light-emitting diode, which work together to achieve fast and accurate blood sugar measurement. The whole process is simple to operate, minimally invasive and painless.

[0044] The data processing center normalizes the fluorescence information data detected by the color sensor. The MCU establishes communication with the color sensor through the I2C protocol to realize sensor parameter configuration and sensor data acquisition. The main function of the color sensor is to convert the captured light signal into XYZ tristimulus values, which conforms to the 1931 color space standard of the International Commission on Illumination (CIE). XYZ represents the tristimulus values ​​of the human color vision system, promoting the standardization and accurate representation of color information. During the color sensor measurement, the MCU controls the activation of the UV light emitting diode at the same time. The light emitting diode is directly powered by the output power supply voltage of the NFC chip to ensure sufficient light power. After completing the color data measurement (which takes about 50ms), the MCU commands the color sensor to enter the Power Down state and deactivate the UV LED to minimize power consumption. The XYZ values ​​obtained from the color sensor are transmitted to the NFC chip through the I2C protocol. By bringing the smartphone close to the NFC antenna again, the color data stored in the NFC chip can be retrieved through the smartphone NFC function, and the color data corresponding to the blood glucose concentration can be transmitted to the smartphone.

[0045] Figure 3 This is a working diagram of the wireless fluorescent sensor patch, which mainly includes four steps: wearing, power supply, monitoring, and transmission.

[0046] Reference Figure 3 Steps: When using, attach the wireless fluorescent sensor patch to the surface of the skin so that the microneedles penetrate the epidermis and play a fixing role. After the patch acts on the human skin, first bring the smartphone close to the patch to power the patch. The patch monitors the glucose concentration. After collecting data, the information can be transmitted to the smartphone so that the patient can obtain blood sugar level information.

[0047] The invention provides a method for preparing a wireless fluorescent sensor patch for blood sugar monitoring.

[0048] Step 1: Use computer-aided design (CAD) software to accurately design the structure of the flexible circuit and near-field communication (NFC) module to facilitate the subsequent patterning of the polyimide film to prepare a flexible substrate and a conductor circuit. The size of the entire flexible circuit is 2.0 cm × 2.3 cm.

[0049] Step 2: The preparation of a flexible printed circuit board (FPCB) using an immersion gold process mainly includes selecting a flexible substrate (such as polyimide), coating a photosensitive material and exposing and developing to form a circuit pattern, then electroplating a copper circuit, and then depositing a layer of gold on the copper circuit to improve conductivity and corrosion resistance, and finally removing the photosensitive material and performing post-processing to complete the preparation of the FPCB.

[0050] Step 3: Use reflow soldering technology to accurately integrate the UV lamp, color sensor, data processing center (MCU), NFC chip, NFC coil and other circuit components on the FPCB.

[0051] Step 4: Use epoxy resin glue to fix the UV cutoff filter on the color sensor.

[0052] Step 5: Use polydimethylsiloxane (PDMS) to encapsulate the patch, and pay attention to controlling the encapsulation thickness within the range of 0.3-0.5 mm to maintain the flexibility of the device. Encapsulate by curing in small amounts multiple times (80°C, 2 hours), and use the reverse molding method to form a groove for embedding the microneedle. The groove depth is 1 mm, and the groove is located directly above the UV cutoff filter.

[0053] Step 6, prepare soft glucose concentration responsive fluorescent sensing microneedles. The microneedle material is selected from biocompatible hydrogel materials, including one or more of polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol and hyaluronic acid. The microneedle tip selects a hydrogel material with a higher hardness after curing, and the microneedle substrate selects a hydrogel material that is flexible after curing. Here we propose a method for preparing microneedle materials. Dissolve polyvinyl alcohol (PVA) powder in distilled water to prepare a solution with a concentration of 12% by weight. Stir the mixture at a speed of 1000 rpm and heat it in a water bath at 95°C for 3 hours until the PVA is completely dissolved to form a viscous and transparent solution. After cooling to room temperature, add polyvinyl pyrrolidone (PVP) to the PVA solution at a mass ratio of 3:4 (PVA), and stir until the PVP is completely dissolved to obtain a transparent hydrogel solution. In addition, 9-anthraceneboric acid (9-ANB) is dissolved in 52% ethanol to prepare a 0.02 mol / L solution. The 9-ANB solution was then mixed with the PVA / PVP hydrogel solution in a volume ratio of 1:1 and stirred at 1000 rpm for 15 minutes. The resulting mixture was poured into a PDMS mold, centrifuged and vacuumed to ensure complete filling of the microneedle tip and removal of bubbles. The mold was then placed in a drying oven and dried at 35°C for 24 hours to form the microneedle tip. Next, the PVA solution was injected into the upper layer of the microneedle, and the mold was dried again at 35°C for 24 hours to form a microneedle substrate. After complete curing, the microneedles were demolded to prepare a microneedle array with a needle length of 650nm and an area of ​​1.5cm×1.5cm.

[0054] Step 7: Wet the flat side of the microneedle slightly with water, and use the viscosity of the hydrogel to embed the microneedle into the reserved groove and dry it. The microneedle will be fixed on the PDMS sealing layer. The final weight of the wireless fluorescent sensor patch is about 1.0g.

[0055] The present invention provides an experimental model for monitoring in vitro glucose concentration using a wireless fluorescent sensor patch. The patch is applied to a genetic diabetic mouse model to verify the function of monitoring blood glucose concentration.

[0056] Step 1. First, prepare a series of glucose aqueous solutions with different concentrations, namely 0, 50, 100, 150, 200, 300 and 450 mg / dL, to establish the relationship between glucose concentration and fluorescence response.

[0057] Step 2: Next, take 150 μL of the above-mentioned glucose aqueous solution of different concentrations and drip it onto the prepared microneedle patch. After dripping, let it stand for 5 minutes. When the patch starts working, the color sensor measures the fluorescence intensity of the microneedle and converts the fluorescence signal into XYZ tristimulus values ​​for subsequent analysis.

[0058] Step 3: Then, place the smartphone close to the patch and use near field communication (NFC) technology to read the fluorescence intensity information measured by the sensor. By analyzing the relationship between fluorescence intensity and glucose concentration, a corresponding relationship between the two is established.

[0059] Step 5: Through data analysis, it is found that as the glucose concentration increases, the stimulation value X will decrease, and the stimulation values ​​Y and Z will increase. Through normalization processing, the processing method is as follows:

[0060]

[0061] After normalization, it was found that there was a significant linear correlation between the change in fluorescence signal and the change in glucose concentration. This finding suggests that the fluorescence signal can be used as an effective indicator of changes in glucose concentration, thereby achieving accurate monitoring of blood sugar levels.

[0062] The invention provides an experimental model of using a wireless fluorescent sensor patch to monitor glucose concentration in mice.

[0063] Step 1: First, the wireless fluorescent sensor patch is strictly sterilized by ultraviolet light to ensure biological safety during the experiment.

[0064] Step 2: 10 diabetic mice with free feeding were selected as experimental subjects, and their backs were depilated to facilitate patch placement.

[0065] Step 3: Before using the patch, first use a commercial blood glucose meter to collect blood from the tail vein of 10 mice to test the blood glucose concentration as the baseline data for subsequent comparison.

[0066] Step 4: After blood collection, apply the sterilized patch to the back skin of the mouse. After 20 minutes, monitor the glucose concentration in the interstitial fluid through the patch attached to the skin. Use a smartphone close to the patch to directly read the detected fluorescence data. After the measurement, the mice were observed for adaptive feeding for 3 days.

[0067] Step 5. Finally, the blood glucose concentration data measured by the commercial blood glucose meter is compared with the data measured by the wireless fluorescent sensor patch. It can be seen that the monitoring of the patch has good accuracy and reliability.

[0068] Figure 4The experimental results of using wireless fluorescent sensor patches to monitor changes in glucose concentration are shown. It can be seen that as the glucose concentration changes, the microneedle fluorescence monitored by the sensor changes. In the converted XYZ tristimulus values, the X ratio decreases with the increase of glucose concentration, and the Y and Z ratios increase with the increase of glucose concentration. The overall visual presentation shows that the blue color decreases with the increase of glucose concentration. There is a significant linear correlation between the change of fluorescence signal and the change of glucose concentration.

[0069] Figure 5 The experimental results of using wireless fluorescent sensor patches to monitor changes in glucose concentration in mice are shown. It can be seen that under high and low blood sugar levels, the patch measurement results have good tracking with the commercial blood glucose meter measurement results, and can accurately express the blood sugar level of mice and realize the glucose concentration monitoring function.

[0070] It is to be understood that the present invention is described by some embodiments, and it is known to those skilled in the art that various changes or equivalent substitutions may be made to these features and embodiments without departing from the spirit and scope of the present invention. In addition, under the teachings of the present invention, these features and embodiments may be modified to adapt to specific circumstances and materials without departing from the spirit and scope of the present invention. Therefore, the present invention is not limited by the specific embodiments disclosed herein, and all embodiments falling within the scope of the claims of this application are within the scope of protection of the present invention.

Claims

1. A wireless fluorescent sensor patch for blood glucose monitoring, characterized in that: It includes a sensing microneedle, a fluorescence detection unit and a near field communication wireless control circuit; The sensing microneedle (1-1) comprises a fluorescence-based soft glucose concentration-responsive sensing microneedle array, wherein the material of the microneedle sensing array is a bioabsorbable hydrogel and loaded with a glucose concentration-responsive fluorescent material, and the fluorescent material is evenly distributed in the microneedle tip; The fluorescence detection unit comprises an ultraviolet cutoff filter (1-2), an ultraviolet light emitting diode (1-3) and a color sensor (1-4); The ultraviolet light emitting diode (1-3) and the color sensor (1-4) are integrated on a flexible circuit board, and the ultraviolet cutoff filter covers the upper surface of the color sensor so that it only receives visible light filtered by the ultraviolet cutoff filter. The entire flexible circuit board and the ultraviolet cutoff filter (1-2) are encapsulated by polydimethylsiloxane (PDMS). With the ultraviolet cutoff filter as the center, a microneedle placement groove is reserved on the outer side of the encapsulation layer above the ultraviolet cutoff filter, and the sensing microneedle is embedded in the reserved groove and fixed by using the viscosity of the hydrogel. The near field communication wireless control circuit is specifically an NFC coil, which is used to realize wireless power transmission and receive signals and energy from the smart terminal. The near field communication wireless control circuit is integrated on a flexible circuit board; The flexible circuit includes an NFC coil, an NFC chip, a data processing center MCU and its connecting circuit; specifically, the NFC coil is activated by the smart terminal, and the signal and energy from the smart terminal are transmitted to the NFC chip. The NFC chip generates an analog voltage through energy collection to provide power and signal for the flexible circuit board in the patch; the data processing center realizes the color sensor parameter configuration and sensor data acquisition; during the color sensor measurement, the MCU controls the activation of the ultraviolet light emitting diode at the same time, and the light emitting diode is directly powered by the power supply voltage output by the NFC chip; after the microneedle array acts on the skin surface to absorb interstitial fluid, under the irradiation of ultraviolet light, the fluorescence intensity generated by the fluorescent material changes according to the glucose concentration, and the fluorescence intensity is received by the color sensor through the ultraviolet cutoff filter; after the color sensor completes the color data measurement, the MCU commands the color sensor to enter the Power Down state and deactivates the ultraviolet light emitting diode, and transmits the data obtained from the color sensor to the NFC chip. When the smart terminal is close to the NFC coil, the smart terminal obtains the blood glucose concentration through the color data.

2. A wireless fluorescent sensor patch for blood glucose monitoring according to claim 1, characterized in that: The depth of the groove is equal to the thickness of the substrate of the sensing microneedle.

3. A wireless fluorescent sensor patch for blood glucose monitoring according to claim 1, characterized in that: The bioabsorbable hydrogel is specifically one or more of polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol and hyaluronic acid; the glucose concentration responsive fluorescent material is specifically one of 9-anthraceneboric acid, 2-anthraceneboric acid and phenylboric acid. The glucose concentration responsive fluorescent material contacts interstitial fluid and generates fluorescence of different colors under ultraviolet light, and the fluorescence intensity is related to the glucose concentration.

4. The wireless fluorescent sensor patch for blood glucose monitoring according to claim 1, characterized in that: The ultraviolet light emitting diode emits ultraviolet light of 200-400nm to excite the glucose concentration-responsive fluorescent material loaded in the microneedle to generate fluorescence.

5. The wireless fluorescent sensor patch for blood glucose monitoring according to claim 1, characterized in that: The color sensor is specifically an XYZ true color sensor, which includes three independent photosensitive channels: the X channel is used to detect red light, the Y channel is used to detect green light and brightness, and the Z channel is used to detect blue light; the MCU establishes communication with the color sensor through the I2C protocol, transmits the detected XYZ values ​​to the NFC chip, and wirelessly transmits blood sugar information to the smart device.

6. A method for preparing a wireless fluorescent sensor patch for blood glucose monitoring according to any one of claims 1 to 5, characterized in that: The following steps are involved: Step 1: Use computer-aided design software to design the structure of the flexible circuit board and prepare the flexible substrate and wire circuit; Step 2: Prepare the flexible printed circuit board using the immersion gold process; Step 3: Integrate the UV lamp, color sensor, data processing center, NFC chip, and NFC coil on the flexible printed circuit board using reflow soldering technology; Step 4: Use epoxy resin glue to fix the UV cutoff filter on the color sensor; Step 5: encapsulate the patch with polydimethylsiloxane, and use the reverse molding method to form a groove for embedding the sensing microneedle, wherein the groove is located directly above the UV cutoff filter; Step 6: Prepare soft glucose concentration responsive fluorescent sensing microneedles; first prepare a bioabsorbable hydrogel solution, then mix it with a glucose concentration responsive fluorescent material solution, stir it evenly, pour the resulting mixed solution into a microneedle array mold, centrifuge and vacuum process to ensure that the microneedle tips are completely filled and bubbles are removed, and then put the mold into a drying oven to dry to solidify and form microneedle tips; after drying, inject the hydrogel solution into the upper layer of the microneedles, and put the mold into the drying oven again to dry to solidify and form a flexible microneedle substrate; after complete solidification, demold the microneedles to obtain a microneedle array; Step 7: Wet the flat side of the microneedle substrate with water, and use the viscosity of the hydrogel itself to embed the microneedle into the reserved groove and dry it to fix the microneedle on the PDMS encapsulation layer.

7. The method for preparing a wireless fluorescent sensor patch for blood glucose monitoring according to claim 6, characterized in that: When the patch is packaged, the packaging thickness is 0.3 to 0.5 mm, and the packaging is performed by curing in small amounts and multiple times.

8. The method for preparing a wireless fluorescent sensor patch for blood glucose monitoring according to claim 6, characterized in that: The needle tips of the microneedle array are specifically mixed with a biocompatible hydrogel and a glucose concentration responsive fluorescent material solution and then dried and solidified to obtain a rigid needle tip; the substrate of the microneedle array is dried and solidified to obtain a flexible substrate through a hydrogel including one of polyvinyl alcohol and hyaluronic acid.

9. The method for preparing a wireless fluorescent sensor patch for blood glucose monitoring according to claim 6, characterized in that: The sensing microneedle array has a needle length of 650 nm and an area of ​​1.5 cm×1.5 cm.

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