A wireless fluorescence sensing patch for blood glucose monitoring and its preparation method

Abstract

A wireless fluorescence sensing patch for blood glucose monitoring and its preparation method belong to the field of biomedical engineering devices. When in use, the wireless fluorescence sensing patch is attached to the skin surface, and the microneedles pierce into the epidermis to play a role in fixing and extracting interstitial fluid. After the patch acts on the human skin, first, the smartphone is brought close to the patch to supply energy to the patch. The patch monitors the glucose concentration and transmits the collected data to the smartphone, enabling the patient to obtain blood glucose level information. Painless real-time in-situ glucose concentration monitoring is achieved by extracting subcutaneous interstitial fluid through soft microneedles. Based on near-field communication technology, the built-in coil of the smartphone can be used to provide energy and wireless control, realizing wireless battery-free power supply for the flexible microneedle patch. While providing stable and long-term monitoring, the present invention significantly improves the convenience and reliability of detection. The production cost of the microneedles is relatively low, and they are easy to replace, simplifying the operation process and improving the comfort of patients during long-term use.

Description

Technical Field

[0001] The present invention belongs to the field of biomedical engineering devices, and particularly relates to a wireless fluorescence sensing patch for blood glucose monitoring and a preparation method thereof. Background Art

[0002] Diabetes is a metabolic disease characterized by chronic hyperglycemia, with the number of patients worldwide exceeding 500 million and continuing to grow. The long-term hyperglycemia in diabetes can lead to serious complications such as heart disease, stroke, kidney failure, and blindness. Blood glucose monitoring is an important means for diabetes management, which helps patients and doctors formulate or adjust treatment plans by detecting blood glucose levels. Currently, the common blood glucose monitoring method is that traditional blood glucose meters detect blood glucose through fingertip blood samples. In addition, the emerging continuous glucose monitoring (CGM) technology aims to provide real-time and all-day blood glucose data. The blood glucose monitoring system is constantly evolving towards the goals of precision and convenience, and can help patients effectively control blood glucose through data analysis and management, reducing the risk of complications.

[0003] The measurement process of traditional blood glucose meters includes the following steps: First, the user collects fingertip blood with a needle and drops it on the test area of 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. Then, catalase catalyzes the reaction of hydrogen peroxide with other reagents to produce an electrical signal or a color change. The blood glucose meter detects these signals or changes and converts them into digital results to display the blood glucose value. Continuous Glucose Monitoring (CGM) technology mainly includes the following methods: The puncture-type sensor measures the glucose level in interstitial fluid through a probe inserted into subcutaneous tissue to provide real-time data. The glucose concentration in subcutaneous interstitial fluid usually shows a synchronous relationship with the blood glucose level. Although the glucose concentration in interstitial fluid is usually slightly lower than that in blood because there is a certain delay in the transfer of glucose from blood to interstitial fluid, this delay is usually between a few minutes and half an hour. Therefore, the glucose concentration in interstitial fluid measured by the Continuous Glucose Monitoring (CGM) system can effectively reflect the blood glucose level. The glucose concentration in interstitial fluid is measured by inserting a thin probe into subcutaneous tissue. 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 at the electrode to generate a 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 transmits it wirelessly to an external receiver or smart device. Users can monitor the blood glucose level and trend in real time, thus better managing their blood glucose. In addition, there are also laser sensors and fluorescence sensors in the research stage at present. Laser sensors mainly use the optical principle. By emitting a laser beam with a specific wavelength to irradiate the skin or sample, the laser beam scatters and absorbs in the skin, and the blood glucose concentration affects this change in light. The detector of the sensor receives and measures the change in these light signals and converts it into a blood glucose value. This method is non-invasive and can provide real-time blood glucose data. The main principle of fluorescence sensors is to apply a chemical reagent containing a fluorescent dye to the sample, and these dyes react with glucose molecules. Under the irradiation of excitation light (such as LED light), the dye emits fluorescence with a specific wavelength, and the fluorescence intensity is usually linearly related to the glucose concentration. The sensor detects and measures the intensity of this fluorescence signal. The fluorescence intensity is associated with the blood glucose concentration, and finally the measured signal is converted into a blood glucose value. At present, such sensors are still in the research and development stage and are less used in actual applications. Summary of the Invention

[0004] The object of the present invention is to solve the above technical problems, and provides a wireless fluorescence sensing patch for blood glucose monitoring and its preparation method, which is used to analyze the glucose concentration in interstitial fluid, and is a wireless fluorescence sensing patch that is convenient for diabetic patients to master blood glucose information. The patch is designed to be worn on the surface of the human skin, minimally invasively extracts interstitial fluid through its microneedle structure, and uses a glucose-responsive fluorescent material to monitor the glucose concentration in real time. The patch is equipped with a fluorescence signal detection device, which can convert the fluorescence signal into glucose concentration data, wirelessly control the monitoring function through the near-field communication technology of a smart phone, and transmit the monitoring result to a smart device at the same time. The user can view the blood glucose information in real time through the user interface of the smart device, thereby providing a minimally invasive, real-time and convenient blood glucose monitoring solution for diabetic patients.

[0005] To solve the above technical problems, the specific technical solutions of a wireless fluorescence sensing patch for blood glucose monitoring and its preparation method of the present invention are as follows:

[0006] A wireless fluorescence sensing patch for blood glucose monitoring, comprising sensing microneedles, a fluorescence detection unit and a near-field communication wireless control circuit;

[0007] Among them, the sensing microneedles 1-1 include a soft glucose concentration-responsive microneedle array based on a fluorescent material. The material of the microneedle sensing array is a bioabsorbable hydrogel, and a glucose concentration-responsive fluorescent material is loaded. The fluorescent material is evenly distributed in the tips of the microneedles;

[0008] The fluorescence detection unit includes an ultraviolet cut-off filter 1-2, an ultraviolet light-emitting diode 1-3 and a color sensor 1-4; among them, the ultraviolet light-emitting diode 1-3 and the color sensor 1-4 are integrated on a flexible circuit board. The ultraviolet cut-off filter covers the upper surface of the color sensor, so that it only receives visible light filtered by the ultraviolet cut-off filter. The entire flexible circuit board and the ultraviolet cut-off filter 1-2 are encapsulated by polydimethylsiloxane (PDMS); centered on the ultraviolet cut-off filter, there is a reserved microneedle placement groove on the outer side of the encapsulation layer above it. The sensing microneedles are 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 microneedles.

[0009] The near-field communication wireless control circuit is specifically an NFC coil, which is used to realize wireless power transmission, receive signals and energy from a smart terminal, and 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 connection circuit; specifically, the NFC coil is activated by the smart terminal, and transmits the signal and energy from the smart terminal to the NFC chip. The NFC chip generates an analog voltage through energy harvesting to provide power and signals for the flexible circuit board in the patch. The data processing center realizes the configuration of color sensor parameters and the acquisition of sensing data. During the measurement of the color sensor, the MCU controls the activation of the ultraviolet light-emitting diode simultaneously, 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 of 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 an ultraviolet cut-off filter. After the color sensor completes the measurement of color data, the MCU commands the color sensor to enter the Power Down state and deactivates the ultraviolet light-emitting diode, transmits the data obtained from the color sensor to the NFC chip, and the smart terminal obtains the blood glucose concentration through the color data by approaching the NFC coil.

[0011] The bioabsorbable hydrogel is specifically one or more of polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol and hyaluronic acid; the glucose concentration-responsive fluorescent material is specifically one of 9-anthracene boronic acid, 2-anthracene boronic acid and phenylboronic acid. The glucose concentration-responsive fluorescent material contacts the interstitial fluid and produces different colors of fluorescence under ultraviolet light irradiation, and the fluorescence intensity is related to the glucose concentration.

[0012] The ultraviolet light-emitting diode emits ultraviolet light with a wavelength of 200 - 400 nm to excite the glucose concentration-responsive fluorescent material loaded in the microneedles to produce 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 preparation method for a wireless fluorescence sensing patch for blood glucose monitoring, which specifically includes the following steps:

[0015] Step 1: Carry out structural design on the flexible circuit board through computer-aided design software to prepare a flexible substrate and a wire circuit;

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

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

[0018] Step 4: Fix the ultraviolet cut-off filter onto the color sensor using epoxy resin glue;

[0019] Step 5: Encapsulate the patch using polydimethylsiloxane and adopt the injection molding method to form a groove for embedding the sensing microneedles, with the groove located directly above the ultraviolet cut-off filter;

[0020] Step 6: Prepare the soft glucose concentration-responsive fluorescent sensing microneedles; first, prepare a bioabsorbable hydrogel solution, then mix it with the glucose concentration-responsive fluorescent material solution, stir evenly, pour the resulting mixed solution into the microneedle array mold, centrifuge and vacuum process to ensure complete filling of the microneedle tips and removal of air bubbles, then place the mold in an oven to dry and cure to form rigid microneedle tips; after drying, inject the hydrogel solution onto the upper layer of the microneedles and place the mold in the oven again to dry and cure to form the flexible microneedle substrate; after complete curing, demold the microneedles to obtain the microneedle array;

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

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

[0023] (1) The present invention provides a glucose concentration monitoring method based on fluorescence colorimetry. The technical solution of the present invention improves the traditional glucose concentration sensing method, adopts a glucose-responsive fluorescence technology based on boric acid, and integrates the fluorescent material and the color sensor into one. Compared with the traditional electrochemical sensing method, fluorescence colorimetry does not rely on glucose oxidase, is thus 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 the fluorescent material and the color sensor into one can avoid the influence of ambient light and achieve real-time in-situ blood glucose monitoring. The technical solution of the present invention provides stable and long-term monitoring while significantly improving the convenience and reliability of detection.

[0024] (2) The present invention provides a hydrogel sensing microneedle for minimally invasive glucose concentration monitoring and a preparation method thereof. The microneedle can achieve non-invasive detection of glucose concentration by absorbing interstitial fluid in the skin. The microneedle is made of biocompatible materials and can be inserted into the shallow surface layer of the skin, quickly absorbing interstitial fluid while avoiding causing pain. The interaction between the fluorescent material in the hydrogel and the absorbed glucose molecules generates a change in fluorescence intensity, thereby realizing the detection of glucose levels. The microneedle base designed in the present invention is a flexible material, which can better fit the skin curve compared with traditional rigid metal microneedles, reducing irritation and damage to the skin. In addition, the microneedle has a low manufacturing cost and is convenient to replace, simplifying the operation process and improving 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 the dependence on power supplies or batteries, thereby effectively reducing the volume and weight of the patch device and significantly improving the comfort of patients when wearing. This device can be wirelessly connected to a smartphone, enabling users to view blood glucose data in real time, facilitating the immediate understanding of their own blood glucose levels and improving the convenience and practicality of monitoring. Brief Description of the Drawings

[0026] Figure 1 Schematic diagram of the composition of the wireless fluorescence sensing patch provided by the embodiment of the present invention;

[0027] Figure 2 Schematic circuit diagram of the wireless fluorescence sensing patch provided by the embodiment of the present invention;

[0028] Figure 3 Schematic working diagram of the wireless fluorescence sensing patch provided by the embodiment of the present invention;

[0029] Figure 4 Schematic diagram of the experimental results of monitoring glucose concentration changes using the wireless fluorescence sensing patch;

[0030] Figure 5 Schematic diagram of the experimental results of monitoring glucose concentration changes in mice using the wireless fluorescence sensing patch. Detailed Description of the Embodiment

[0031] In order to better understand the purpose, structure and function of the present invention, the following further describes in detail a wireless fluorescence sensing patch for blood glucose monitoring and a preparation method thereof in combination with the drawings.

[0032] The wireless fluorescence sensing patch of the present invention for assisting diabetic patients to master blood glucose information realizes painless real-time in-situ glucose concentration monitoring by extracting subcutaneous interstitial fluid with 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, achieving wireless battery-free power supply for a flexible microneedle patch and realizing wireless blood glucose monitoring function.

[0034] The present invention includes a soft glucose concentration-responsive fluorescent sensing microneedle array, a fluorescence detection unit, and a near-field communication wireless control circuit.

[0035] The schematic diagram of the composition of the wireless fluorescent sensing patch in this embodiment is as Figure 1 shown, including sensing microneedles 1-1, an ultraviolet cut-off 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 the ultraviolet cut-off filter 1-2, the ultraviolet light-emitting diode 1-3, and the color sensor 1-4. The fluorescence detection unit and the near-field communication wireless control circuit include the near-field communication coil 1-6 integrated on a flexible circuit board. The ultraviolet cut-off filter covers the upper surface of the color sensor, allowing it to only receive visible light filtered by the ultraviolet cut-off filter. The entire flexible circuit board and the ultraviolet cut-off filter 1-2 are encapsulated by PDMS, ensuring that the device is insulated from the outside after encapsulation and has good biocompatibility, bendability, and stretchability. Centered on the ultraviolet cut-off filter, there is a reserved groove for placing microneedles on the outer side of the encapsulation layer above it. The sensing microneedles are embedded in the reserved groove and fixed using the viscosity of the hydrogel. The depth of the groove is less than or equal to the substrate thickness of the sensing microneedles.

[0036] The sensing microneedles are a soft glucose concentration-responsive fluorescent sensing microneedle array, which is a microneedle array prepared with a bioabsorbable hydrogel, including one or more of polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, and hyaluronic acid, as the substrate, and loaded with a glucose concentration-responsive fluorescent material, including one of 9-anthracene boronic acid, 2-anthracene boronic acid, and phenylboronic acid. The fluorescent material can be evenly distributed within the microneedle tips. The microneedle substrate of the biocompatible hydrogel can pierce the epidermis, absorb subcutaneous interstitial fluid, and be bioabsorbed. The glucose concentration-responsive fluorescent material can produce different colors of fluorescence under ultraviolet light irradiation, and the fluorescence intensity is related to the glucose concentration. When the microneedles act on the skin surface to absorb interstitial fluid, the glucose concentration-responsive fluorescent material comes into contact with glucose molecules, resulting in a change in the fluorescence intensity. After the fluorescence intensity is detected by the color sensor, the generated electrical signal is converted into XYZ signal values by the flexible circuit to characterize the fluorescence change, and the glucose concentration in the interstitial fluid is determined from the change in fluorescence intensity. The glucose concentration in interstitial fluid is usually about 70% of the blood glucose concentration. Therefore, this concentration can effectively serve as an indirect indicator of blood glucose level.

[0037] The ultraviolet cut-off filter is an optical component placed above the color sensor, which is designed to effectively block radiation in the ultraviolet light wavelength range while allowing radiation in the visible light wavelength range to pass through. Through this design, the ultraviolet cut-off filter of the present invention can ensure that when the color sensor receives the fluorescence signal from the microneedle, the interference of ultraviolet light can be excluded, so as to achieve accurate detection of the fluorescence signal.

[0038] The ultraviolet light-emitting diode is used to emit ultraviolet light with a wavelength of 200 - 400 nm to excite the glucose concentration-responsive fluorescent material loaded in the microneedle to generate blue fluorescence. This 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 the fluorescence changes of microneedles. 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 fluorescence intensity changes emitted by the microneedles. Through precise sensor positioning and high-sensitivity detection capabilities, the present invention can achieve accurate monitoring of the microneedle fluorescence signal, thus providing a reliable and accurate method for measuring glucose concentration. The low power consumption characteristic of the color sensor makes it particularly suitable for portable or long-term operating monitoring devices, while the low noise characteristic ensures 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. This NFC coil is particularly suitable for use in conjunction with mobile devices such as smartphones to wirelessly transmit the processed fluorescence intensity information. The configuration of the coil allows for efficient energy and data exchange with the NFC receiver of the mobile device, thus achieving wireless power supply and data collection for the patch sensor.

[0042] Figure 2 is the circuit schematic diagram of the wireless fluorescence sensing patch, which consists of a sensing circuit 2-1, a data processing circuit 2-2, and a wireless control circuit 2-3. Among them, 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); the wireless control circuit includes an NFC coil and an NFC chip.

[0043] When performing blood glucose detection, the user only needs to bring the smartphone close to the wireless fluorescence sensing patch. Using near-field communication (NFC) technology, the smartphone can wirelessly provide power to the patch. The microneedles on the patch gently pierce the skin to absorb interstitial fluid. After the smartphone activates the NFC coil, the built-in NFC chip in the smartphone generates an analog voltage through energy harvesting to power the circuits in the patch. These circuits include the NFC chip itself, a data processing center (MCU), a color sensor, and an ultraviolet light-emitting diode, which work together to achieve fast and accurate blood glucose 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 achieve sensor parameter configuration and sensing data acquisition. The main function of the color sensor is to convert the captured optical signal into XYZ tristimulus values, which conform to the color space standard of the International Commission on Illumination (CIE) in 1931. XYZ represents the tristimulus values of the human color vision system, promoting the standardization and accurate representation of color information. During the measurement of the color sensor, the MCU controls the activation of the ultraviolet light-emitting diode simultaneously. The light-emitting diode is directly powered by the output power voltage of the NFC chip to ensure sufficient optical power. After completing the color data measurement (which takes about 50 ms), the MCU commands the color sensor to enter the Power Down state and deactivates 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's NFC function, and the color data corresponding to the blood glucose concentration is transmitted to the smartphone.

[0045] Figure 3 It is a working schematic diagram of the wireless fluorescence sensing patch, mainly including four steps: wearing, power supply, monitoring, and transmission.

[0046] Refer to Figure 3 In step, when in use, the wireless fluorescence sensing patch is attached to the skin surface, and the microneedles pierce the epidermis to play a fixing role. After the patch acts on the human skin, first bring the smartphone close to the patch to supply power to the patch. The patch monitors the glucose concentration, and after collecting data, the information can be transmitted to the smartphone so that the patient can obtain blood glucose level information.

[0047] The present invention provides a preparation method for a wireless fluorescence sensing patch for blood glucose monitoring.

[0048] Step 1: Use computer-aided design (CAD) software to precisely design the structures of the flexible circuit and the near-field communication (NFC) module, facilitating subsequent patterning of the polyimide film to fabricate the flexible substrate and wire circuits. The size of the entire flexible circuit is 2.0 cm × 2.3 cm.

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

[0050] Step 3: Adopt the reflow soldering technology to precisely integrate the ultraviolet lamp, color sensor, data processing center (MCU), NFC chip, NFC coil, and other circuit components onto the FPCB.

[0051] Step 4: Use epoxy resin glue to fix the ultraviolet cut-off filter on the color sensor.

[0052] Step 5: Package the patch using polydimethylsiloxane (PDMS), paying attention to controlling the packaging thickness within the range of 0.3 - 0.5 mm to maintain the flexibility of the device. The packaging is carried out by curing in small amounts and multiple times (80 °C, 2 hours), and the reverse molding method is used to form a groove for embedding micro needles. The depth of the groove is 1 mm, and the groove is located directly above the ultraviolet cut-off filter.

[0053] Step 6: Prepare soft glucose concentration-responsive fluorescent sensing microneedles. The microneedle material is selected as a biocompatible hydrogel material, including one or more of polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, and hyaluronic acid. The tip of the microneedle is selected as a hydrogel material with a relatively high hardness after curing, and the base of the microneedle is selected as a hydrogel material that shows flexibility after curing. Here, we propose a preparation method for the microneedle material. 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 place it in a water bath at 95 °C for 3 hours until the PVA is completely dissolved, forming a viscous and transparent solution. After cooling to room temperature, add polyvinylpyrrolidone (PVP) to the PVA solution with a mass ratio of 3:4 (PVA), and stir until the PVP is completely dissolved to obtain a transparent hydrogel solution. In addition, dissolve 9-anthracene boronic acid (9-ANB) in 52% ethanol to prepare a 0.02 mol / L solution. Then mix the 9-ANB solution and the PVA / PVP hydrogel solution in a volume ratio of 1:1 and stir at a speed of 1000 rpm for 15 minutes. Pour the resulting mixture into a PDMS mold, centrifuge and vacuum process to ensure complete filling of the microneedle tip and removal of air bubbles. Then place the mold in an oven and dry it at 35 °C for 24 hours to form the microneedle tip. Next, inject the PVA solution onto the upper layer of the microneedle and dry the mold again at 35 °C for 24 hours to form the microneedle substrate. After complete curing, demold the microneedle to prepare a microneedle array with a needle length of 650 nm and an area of 1.5 cm × 1.5 cm.

[0054] Step 7: Slightly moisten one planar side of the microneedle with water, and use the viscosity of the hydrogel itself to embed the microneedle into the reserved groove and then dry it. The microneedle will be fixed on the PDMS sealing layer. The final weight of the wireless fluorescent sensing patch is about 1.0 g.

[0055] The present invention provides an experimental model for monitoring in vitro glucose concentration with a wireless fluorescent sensing patch. The patch is applied to a genetic diabetes 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: Then, respectively take 150 μL of the above glucose aqueous solutions with different concentrations and drop them on the prepared microneedle patch. After dropping, let it stand for 5 minutes. After the patch starts to work, 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. Subsequently, bring 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 the fluorescence intensity and the glucose concentration, establish the corresponding relationship between the two.

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

[0060]

[0061] After normalization processing, it is found that there is a significant linear correlation between the change of the fluorescence signal and the change of the glucose concentration. This finding indicates that the fluorescence signal can be used as an effective indicator of the change of the glucose concentration, so as to realize the accurate monitoring of the blood glucose level.

[0062] The present invention provides an experimental model for monitoring the glucose concentration of mice by a wireless fluorescence sensing patch.

[0063] Step 1. First, perform strict ultraviolet sterilization treatment on the wireless fluorescence sensing patch to ensure biosafety during the experiment.

[0064] Step 2. Select 10 diabetic mice that freely eat food as the experimental subjects, and depilate their backs to facilitate the placement of the patch.

[0065] Step 3. Before using the patch, first use a commercial blood glucose meter to detect the blood glucose concentration of 10 mice by collecting blood from the tail vein, as the reference data for subsequent comparison.

[0066] After blood collection, apply the sterilized patch to the back skin of the mice. After 20 minutes, monitor the glucose concentration in the interstitial fluid through the patch attached to the skin. Use the smartphone to get close to the patch and directly read the detected fluorescence data. After the measurement, conduct an adaptive feeding observation on the mice for 3 days.

[0067] Step 5. Finally, compare and analyze the blood glucose concentration data measured by the commercial blood glucose meter with the data measured by the wireless fluorescence sensing patch, and it can be seen that the monitoring of the patch has good accuracy and reliability.

[0068] Figure 4The experimental results of monitoring the change in glucose concentration using a wireless fluorescence sensing patch are presented. It can be seen that as the glucose concentration changes, the fluorescence of the microneedles monitored by the sensor changes. Among the converted XYZ tristimulus values, the proportion of X decreases with the increase in glucose concentration, while the proportions of Y and Z increase with the increase in glucose concentration. Visually, the blue color weakens as the glucose concentration increases. A significant linear correlation is shown between the change in the fluorescence signal and the change in glucose concentration.

[0069] Figure 5 The experimental results of monitoring the change in glucose concentration in mice using a wireless fluorescence sensing patch are presented. It can be seen that under hyperglycemic and hypoglycemic conditions, the measurement results of the patch have good followability with those of a commercial blood glucose meter, can accurately represent the blood glucose level of mice, and achieve the function of glucose concentration monitoring.

[0070] It can be understood that the present invention is described through some embodiments. Those skilled in the art know that without departing from the spirit and scope of the present invention, various changes or equivalent replacements can be made to these features and embodiments. Additionally, under the teaching of the present invention, these features and embodiments can be modified to adapt to specific situations 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 belong to the scope protected by the present invention.

Claims

1. A wireless fluorescence sensing patch for blood glucose monitoring, characterized in that, It includes sensing microneedles, a fluorescence detection unit, and a near-field communication wireless control circuit; Among them, the sensing microneedles (1-1) include a fluorescence-based soft glucose concentration-responsive microneedle array. The material of the fluorescence-based soft glucose concentration-responsive microneedle array is a bioabsorbable hydrogel, and a glucose concentration-responsive fluorescent material is loaded. The fluorescent material is evenly distributed inside the microneedle tips; The fluorescence detection unit includes an ultraviolet cut-off filter (1-2), an ultraviolet light-emitting diode (1-3), and a color sensor (1-4); Among them, the ultraviolet light-emitting diode (1-3) and the color sensor (1-4) are integrated on a flexible circuit board. The ultraviolet cut-off filter covers the upper surface of the color sensor, enabling it to only receive visible light filtered by the ultraviolet cut-off filter. The entire flexible circuit board and the ultraviolet cut-off filter (1-2) are encapsulated by polydimethylsiloxane (PDMS); centered on the ultraviolet cut-off filter, there is a reserved microneedle placement groove on the outside of the encapsulation layer above it. The sensing microneedles are embedded in the reserved groove and fixed using the viscosity of the hydrogel; The near-field communication wireless control circuit is specifically an NFC coil, which is used to achieve wireless power transmission, receive signals and energy from a smart terminal, and the near-field communication wireless control circuit is integrated on the flexible circuit board; The flexible circuit includes an NFC coil, an NFC chip, a data processing center MCU, and its connection circuit; specifically, the NFC coil is activated by a smart terminal, and transmits the signals and energy from the smart terminal to the NFC chip. The NFC chip generates an analog voltage through energy harvesting to provide power and signals for the flexible circuit board in the patch; the data processing center realizes color sensor parameter configuration and sensing data acquisition; during the measurement of the color sensor, 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 passes through the ultraviolet cut-off filter and is received by the color sensor; after the color sensor completes the color data measurement, the MCU commands the color sensor to enter the Power Down state and deactivate the ultraviolet light-emitting diode, transmits the data obtained from the color sensor to the NFC chip, and by bringing the smart terminal close to the NFC coil, the smart terminal obtains the blood glucose concentration through the color data.

2. The wireless fluorescence sensing patch for blood glucose monitoring according to claim 1, characterized in that The depth of the groove is equal to the base thickness of the sensing microneedles.

3. The wireless fluorescence sensing patch for blood glucose monitoring according to claim 1, wherein The bioabsorbable hydrogel is specifically one or more of polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, and hyaluronic acid; the glucose concentration-responsive fluorescent material is specifically one of 9-anthracene boronic acid, 2-anthracene boronic acid, and phenylboronic acid. The glucose concentration-responsive fluorescent material contacts the interstitial fluid and produces different colors of fluorescence under ultraviolet light irradiation, and the fluorescence intensity is related to the glucose concentration.

4. A wireless fluorescence sensing patch for blood glucose monitoring according to claim 1, characterized in that, The ultraviolet light-emitting diode emits ultraviolet light with a wavelength of 200-400 nm, which is used to excite the glucose concentration-responsive fluorescent material loaded in the microneedles to generate fluorescence.

5. A wireless fluorescence sensing 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 the blood glucose information to the smart device.

6. The preparation method of a wireless fluorescence sensing patch for blood glucose monitoring according to any one of claims 1-5, characterized in that, It includes the following steps: Step 1: Conduct structural design on the flexible circuit board through computer-aided design software to prepare a flexible substrate and a wire circuit; Step 2: Prepare a flexible printed circuit board using the immersion gold process; Step 3: Integrate the ultraviolet lamp, color sensor, data processing center, NFC chip, and NFC coil on the flexible printed circuit board using the reflow soldering technique; Step 4: Fix the ultraviolet cutoff filter on the color sensor using epoxy resin glue; Step 5: Package the patch using polydimethylsiloxane and form a groove for embedding the sensing microneedles by the casting method, with the groove located directly above the ultraviolet cutoff filter; Step 6: Prepare the soft glucose concentration-responsive fluorescent sensing microneedles; first, prepare a bioabsorbable hydrogel solution, then mix it with the glucose concentration-responsive fluorescent material solution, stir evenly, pour the resulting mixed solution into the microneedle array mold, centrifuge and vacuum process to ensure complete filling of the microneedle tips and removal of air bubbles, and then place the mold in an oven to dry and cure to form the microneedle tips; after drying, inject the hydrogel solution onto the upper layer of the microneedles and place the mold in the oven again to dry and cure to form a flexible microneedle substrate; after complete curing, demold the microneedles to obtain a microneedle array; Step 7: Moisten the flat side of the microneedle substrate with water, use the viscosity of the hydrogel itself to embed the microneedles into the reserved groove and dry, and fix the microneedles on the PDMS encapsulation layer.

7. The preparation method of a wireless fluorescence sensing patch for blood glucose monitoring according to claim 6, characterized in that, When packaging the patch, the packaging thickness is 0.3 - 0.5 mm, and the packaging is carried out by curing in small amounts and multiple times.

8. The preparation method of a wireless fluorescence sensing patch for blood glucose monitoring according to claim 6, characterized in that, The tips of the microneedle array are specifically obtained by mixing a biocompatible hydrogel with a glucose concentration-responsive fluorescent material solution and then drying and curing to obtain rigid tips; the substrate of the microneedle array is obtained by drying and curing a hydrogel, including one of polyvinyl alcohol and hyaluronic acid, to obtain a flexible substrate.

9. The preparation method of a wireless fluorescence sensing patch for blood glucose monitoring according to claim 6, characterized in that, The length of the sensing microneedle array is 650 nm, and the area is 1.5 cm × 1.5 cm.

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