Artificial pancreas-like blood glucose sensing and regulating integrated wireless control patch and preparation method thereof

Abstract

The invention discloses an artificial pancreas-like blood glucose sensing and regulating integrated wireless control patch and a preparation method thereof, and belongs to the field of biomedical engineering. The blood glucose sensing and adjusting are integrated, the color sensor and the ultraviolet cut-off filter are integrated, real-time in-situ blood glucose monitoring is achieved, and blood glucose information can be conveniently obtained in time; then the heater controls the temperature-responsive treatment microneedle to release metformin so as to adjust the blood glucose level; according to the invention, wireless energy supply regulation and control and communication are carried out by adopting a near field communication technology. The limitation of a power supply and a battery is eliminated, the size and the weight of the patch are reduced, and the wearing comfort of a patient is improved. According to the invention, monitoring and treatment functions are integrated, and a closed-loop system similar to artificial pancreas is formed. When the hyperglycemia level is monitored, the heater is automatically started for delivering the metformin medicine, the blood glucose level is reduced, and accurate and timely blood glucose regulation is ensured. When at a hypoglycemic level, the heater is not turned on, reducing the risk of hypoglycemia.

Description

Technical Field

[0001] The invention belongs to the field of biomedical engineering, and in particular relates to an artificial pancreas-like blood sugar sensing and regulating integrated wireless control patch and a preparation method thereof. Background Art

[0002] Diabetes is a major global public health challenge, affecting more than 537 million people worldwide. Long-term high blood sugar levels can lead to serious complications such as cardiovascular disease, nephropathy, and retinopathy. Currently, patients need to measure blood sugar levels through invasive methods such as fingertip blood glucose monitoring (SMBG), which uses a blood glucose meter and test strips to collect blood sugar from the fingertip, which is suitable for daily use, especially at key time points such as before and after meals, before and after exercise, and before bedtime. Blood sugar is monitored 3-10 times a day. After obtaining blood sugar data, patients must quickly inject insulin or take oral hypoglycemic drugs. However, these methods often cause discomfort, pose a risk of infection, and the maintenance cost of sensors is high. In addition, frequent monitoring and drug management seriously affect patients' daily lives, and improper drug dosage may also lead to the risk of hypoglycemia. Therefore, it is crucial to monitor glucose concentration in the body minimally invasively and painlessly and adjust drug dosages in a timely and accurate manner.

[0003] At present, people often integrate blood glucose monitoring systems and drug injectors to form a closed-loop system. In this system, the blood glucose monitor monitors blood glucose levels, the insulin delivery device automatically delivers insulin through continuous subcutaneous infusion as needed, and the control algorithm adjusts insulin based on blood glucose data and preset treatment goals. It simulates the body's natural insulin secretion to accurately control blood glucose and provide flexible adjustment of basal infusion and mealtime infusion.

[0004] In the existing closed-loop system technology for diabetes, the glucose monitoring methods for diabetic patients mainly include continuous glucose monitoring system (CGM) and scanning glucose monitoring (FGM). These methods use different technical means to achieve real-time or near real-time monitoring of patients' blood glucose levels, providing data support for individualized blood glucose management. Fingertip blood glucose monitoring (SMBG) is a traditional blood glucose monitoring method. The continuous glucose monitoring system (CGM) continuously monitors the glucose concentration in the interstitial fluid through a sensor implanted under the skin. The data is usually updated every few minutes, which can display the real-time change trend of blood glucose and help identify situations such as nocturnal hypoglycemia or postprandial hyperglycemia, thereby optimizing blood glucose management strategies. In recent years, electrochemical sensors have become an important tool in the field of continuous blood glucose monitoring by detecting the electrical signal of glucose redox reaction to monitor blood glucose levels. At the same time, based on the development of biosensors and microneedle technology, electrochemical microneedle sensors can penetrate the superficial layer of the skin and collect interstitial fluid (ISF), thereby achieving non-invasive or minimally invasive glucose detection. Or after a metal steel needle is inserted into the subcutaneous tissue, the glucose level is monitored using electrochemical impedance spectroscopy (EIS), which is a method for detecting glucose concentration by applying a small AC voltage and measuring its impedance change. In addition, optical detection methods, such as near-infrared spectroscopy, Raman spectroscopy, fluorescence, and colorimetry, can infer blood sugar levels by detecting changes in optical signals generated by the reaction of glucose with specific reagents. Among them, fluorescence detection is to measure blood sugar levels by using changes in fluorescence intensity generated by the reaction of specific fluorescent dyes or fluorescent probes with glucose. The core of this method lies in the design of fluorescent probes and their specific response to glucose. Common fluorescent probes include boric acid compounds, which change their fluorescence properties after binding to glucose, so that glucose concentration can be inferred by changes in fluorescence intensity. Scanning glucose monitoring (FGM) is an improved continuous monitoring technology that obtains instant blood sugar levels by scanning subcutaneous sensors. Although it does not automatically provide continuous data, it is convenient to obtain current blood sugar information through manual scanning, which is suitable for patients who do not need all-day real-time monitoring. In terms of blood sugar regulation, there are also wearable drugs or insulin injection devices. Insulin is mostly delivered through a catheter fixed under the skin, and the injection dose is controlled by a mechanical pump connected to a control system so that insulin can be delivered smoothly into the body.

[0005] Existing blood glucose monitoring and regulation technologies play an important role in diabetes management, but they also have some disadvantages and their causes. The disadvantages of fingertip blood glucose monitoring (SMBG) are that the operation is highly invasive, frequent blood sampling is required, and data can only be provided at specific time points. It cannot continuously track the trend of blood glucose fluctuations. The reason is that it must cause skin incisions and rely on the limitations of manual operation and instantaneous data acquisition; the disadvantages of continuous glucose monitoring systems (CGM) are that the cost of equipment and consumables is high, the accuracy may be affected by the difference between tissue fluid and blood glucose levels, and wearing sensors for a long time may cause skin discomfort. The reasons are complex manufacturing processes, limitations of sensor technology, and the lag between tissue fluid glucose levels and blood glucose levels; the disadvantages of non-invasive detection technology based on optical principles are poor accuracy and stability, and are easily affected by factors such as skin thickness, color, and external light. The reason is that the current technical level is limited and there are many external interference factors. These disadvantages are mainly caused by technical limitations, high costs, dependence on use, and challenges in patient compliance. The disadvantages of Flash Glucose Monitoring (FGM) are that it does not provide automatic continuous data and requires manual scanning to obtain blood sugar information. It cannot monitor blood sugar mutations in real time due to limitations in its technical design and cannot achieve automatic monitoring. The disadvantages of drug therapy (including insulin injections and oral hypoglycemic drugs) are the risk of hypoglycemia, complex dosage adjustments, and possible side effects or contraindications due to the complexity of drug metabolism, the diversity of mechanisms of action, and the limitations of human living conditions and behaviors. The disadvantages of insulin pumps are high equipment costs, possible technical failures, a steep learning curve, and strong dependence on the equipment due to the complexity of the equipment and high technical requirements. Future improvements will focus on integrating glucose concentration monitoring and blood sugar regulation to improve technical accuracy, reduce costs, reduce invasiveness, and enhance patient experience. Summary of the invention

[0006] The purpose of the present invention is to provide an artificial pancreas-like integrated wireless control patch for glucose sensing and regulation for glucose monitoring and blood sugar regulation in diabetic patients. The system can be worn on the surface of human skin, using smartphone near-field communication technology for wireless power supply and regulation, and through glucose-responsive fluorescent materials and temperature-sensitive microneedles, it can achieve real-time and non-invasive glucose monitoring and blood sugar automatic regulation functions. To solve the above technical problems

[0007] In order to solve the above technical problems, the specific technical solution of the artificial pancreas-like blood sugar sensing and regulation integrated wireless control patch of the present invention is as follows:

[0008] An artificial pancreas-like integrated wireless control patch for blood glucose sensing and regulation, comprising a fluorescence-based wireless glucose monitoring unit, a temperature-sensitive blood glucose regulation unit, and a wireless control circuit;

[0009] The wireless glucose monitoring unit includes a flexible hydrogel sensing microneedle array loaded with a glucose concentration-responsive fluorescent material, an ultraviolet cutoff filter, a color sensor, and an ultraviolet lamp; specifically, the flexible hydrogel sensing microneedle array generates fluorescence intensity according to the glucose concentration after receiving ultraviolet light from the ultraviolet lamp, the ultraviolet cutoff filter is fixed on the upper surface of the color sensor and the lower surface of the flexible hydrogel sensing microneedle array, and the upper surface of the flexible hydrogel sensing microneedle array is a microneedle array; the color sensor only receives the fluorescence filtered by the ultraviolet light from the ultraviolet cutoff filter, obtains the fluorescence intensity information, and feeds it back to the wireless control circuit;

[0010] The thermosensitive blood sugar regulation unit comprises a thermosensitive therapeutic microneedle array and a heater; specifically, the substrate of the thermosensitive therapeutic microneedle array is a hydrogel, the surface material of the microneedle needle tip is a temperature phase change material, and the microneedle array is loaded with hypoglycemic drugs; the heater is located on the lower surface of the thermosensitive therapeutic microneedle array, and the upper surface of the thermosensitive therapeutic microneedle array is the microneedle array; the heater heats to melt the temperature phase change material, and the thermosensitive therapeutic microneedle array releases the hypoglycemic drugs;

[0011] The wireless control circuit includes a flexible circuit and a near field communication module; wherein the ultraviolet lamp, the heater, the color sensor, the near field communication module and the flexible circuit are integrated on a flexible polyimide circuit board and encapsulated using polydimethylsiloxane (PDMS);

[0012] The near-field communication module includes an NFC coil, which receives signals and energy from a smart terminal; the flexible circuit includes a wireless control circuit, specifically including an NFC chip and a data processing center MCU; specifically, the NFC coil receives signals and energy from the smart terminal to the NFC chip, and the NFC chip generates an analog voltage output through its integrated energy collection function to power itself, the data processing center, the color sensor, the ultraviolet lamp and the heater; the color sensor receives the fluorescence intensity information and transmits it to the MCU, and after analyzing the fluorescence intensity, the measurement information is transmitted to the smart terminal via NFC, and is also used to determine whether it is in a hyperglycemic state; the data processing center and the NFC chip are connected to the heater to heat the microneedles in a hyperglycemic state and release the blood sugar-lowering material.

[0013] With the UV cutoff filter and heater as the center, recesses for placing sensing microneedles and therapeutic microneedles are reserved on the outer side of the corresponding packaging layer directly above them. The sensing microneedles are embedded in the reserved recesses above the UV cutoff filter, and the therapeutic microneedles are embedded in the reserved recesses above the heater, and then fixed using the viscosity of the hydrogel.

[0014] The temperature phase change material includes tridecanoic acid, tetradecanoic acid, capric acid, etc.; the blood sugar lowering drug is metformin.

[0015] The hydrogel is a biocompatible hydrogel, including one or more of polyvinyl pyrrolidone, polyvinyl alcohol, hyaluronic acid, and polyethylene glycol; the glucose concentration-responsive fluorescent material is specifically 9-anthraceneboric acid.

[0016] The ultraviolet cut-off filter is a 410nm high-pass filter that blocks ultraviolet light from passing through and allows visible light to pass through.

[0017] The heater is a metal heating electrode composed of a 40nm chromium layer and a 200nm gold layer, and the power consumption is 8mW.

[0018] The MCU establishes communication with the color sensor through the I2C protocol, and the color sensor converts the captured light signal into XYZ tristimulus values;

[0019] During the color sensor measurement, the MCU controls the turning on of the ultraviolet light, which is powered by the output voltage of the NFC chip. After the color sensor completes the measurement, it feeds back the information to the MCU, and the MCU controls the turning off of the ultraviolet light. The MCU determines whether to activate the heater based on the predefined XYZ ratio threshold, and transmits the XYZ tristimulus values ​​obtained from the color sensor to the NFC chip through the I2C protocol, and then feeds back to the smart terminal. The calculation method of the XYZ ratio is:

[0020]

[0021] Where i represents x, y or z data collected from the X, Y and Z channels respectively, and P(i) is the percentage of x, y and z in the fluorescence emission signal detected by the color sensor.

[0022] The present invention also provides a method for preparing an artificial pancreas-like blood sugar sensing and regulation integrated wireless control patch, comprising the following steps:

[0023] Step 1: Preparation of a flexible substrate; using software to design a circuit structure, and then patterning a polyimide film to obtain a flexible substrate and a conductor circuit;

[0024] Step 2: Prepare a heater on a flexible substrate using photolithography and electron beam evaporation coating technology, then clean the flexible substrate and blow dry it with nitrogen;

[0025] Specifically, a photoresist is spin-coated on a substrate, and a masked ultraviolet lithography technique is used to determine a serpentine electrode pattern; a chromium attachment layer and a gold attachment layer are sequentially deposited using an electron beam evaporation method, and unnecessary metals and photoresist are removed using ultrasonic waves in acetone, leaving the serpentine electrode on the polyimide film;

[0026] Step 3: Integrate the UV lamp, color sensor, MCU and NFC chip on the flexible substrate using reflow soldering technology, and encapsulate the flexible circuit with PDMS;

[0027] Step 4: Use epoxy resin glue to fix the UV cutoff filter on the color sensor;

[0028] Step 5: preparing sensing microneedles; the microneedle material is a biocompatible hydrogel to prepare a hydrogel solution, and then the 9-anthracene boronic acid solution and the hydrogel solution are mixed and stirred. After the stirring is completed, the solution is poured into a mold, centrifuged and vacuum-treated to allow the solution to fully fill the needle tip and then dried. After the needle tip is solidified, the hydrogel solution is poured into the mold and continued to dry as a microneedle substrate. After the substrate is solidified, the entire microneedle is peeled off in the mold to obtain a sensing microneedle array;

[0029] Step 6: preparing therapeutic microneedles; selecting a biocompatible hydrogel to prepare a hydrogel solution, then adding metformin to the hydrogel solution to a final concentration of 4wt%, mixing and stirring, pouring the solution into a mold after stirring, centrifuging and vacuum treating, so that the solution fully fills the needle tip and dries, after the needle tip is solidified, pouring the hydrogel solution into the mold and continuing to dry as a microneedle substrate; after the substrate is solidified, peeling the entire microneedle in the mold; then heating and melting the temperature phase change material solid, spraying the temperature phase change material liquid on the microneedle in a drying oven at 45°C, and then cooling the microneedle to room temperature to obtain a therapeutic microneedle array;

[0030] Step 7: Encapsulation of the wireless control patch: Use polydimethylsiloxane to encapsulate the flexible substrate, i.e., the device integrated on the surface. At the same time, with the UV cutoff filter and the heater as the center, use the reverse molding method to reserve the placement grooves for the sensing microneedles and the treatment microneedles on the outer side of the corresponding encapsulation layer directly above them, so as to place the microneedle array;

[0031] Step 8: Wet the flat side of the microneedle array substrate with water, embed the microneedle array into the reserved groove and dry it, and fix the microneedles on the PDMS sealing layer.

[0032] Compared with the prior art, the present invention has the following advantages:

[0033] Through the embodiments of the present invention, an artificial pancreas-like integrated wireless control patch for glucose sensing and regulation for glucose monitoring and blood sugar regulation of glucose patients is realized.

[0034] (1) The present invention uses a fluorescence colorimetric method to monitor glucose concentration. The glucose concentration sensing method in the technical solution of the present invention has been improved, and a glucose-responsive fluorescence technology based on 9-anthraceneboronic acid has been adopted. Compared with the traditional electrochemical sensing method, the fluorescence colorimetric method does not require the participation of glucose oxidase, so it is less affected by environmental (humidity and temperature) factors, and has a longer service life and does not require frequent replacement and calibration.

[0035] (2) The present invention prepares hydrogel sensing microneedles to extract interstitial fluid for minimally invasive glucose concentration monitoring. The microneedles are biocompatible. After being inserted into the skin, the microneedles penetrate to a shallow depth without causing pain, while rapidly absorbing interstitial fluid. The 9-anthraceneboric acid in the hydrogel comes into contact with glucose, causing a change in fluorescence intensity. The microneedle substrate is flexible and can better fit the skin than traditional rigid metal microneedles, and is less likely to cause skin damage. At the same time, the microneedles are low in production cost and easy to replace, which reduces the complex replacement steps and improves the comfort of patients.

[0036] (3) The present invention integrates a color sensor and an ultraviolet cutoff filter. Compared with the traditional method of extracting blood sugar and then putting it into the device for detection and the method of using a camera or a fluorescence spectrometer to capture the fluorescence of the material, the integrated color sensor realizes real-time in-situ blood sugar monitoring, which facilitates timely acquisition of blood sugar information. It can also avoid the influence of ambient light and prevent the extracted interstitial fluid sample from being contaminated.

[0037] (4) The present invention prepares a blood sugar regulation unit composed of a temperature-sensitive therapeutic microneedle and a heater. The temperature-responsive therapeutic microneedle is controlled by the heater to release metformin to regulate blood sugar levels. The therapeutic microneedle uses a temperature phase change material tridecanoic acid as a protective film to achieve drug storage at low temperatures and drug delivery at high temperatures (42-45°C) for precise drug release.

[0038] (5) The present invention uses near-field communication technology for wireless power supply regulation and communication. It gets rid of the limitations of power supply and battery, reduces the size and weight of the patch, and improves the wearing comfort of the patient. By wirelessly communicating with a smartphone, the user can keep track of the blood sugar level in a timely manner.

[0039] (6) The present invention integrates monitoring and treatment functions to form a closed-loop system similar to an artificial pancreas. When high blood sugar levels are detected, the heater is automatically turned on for metformin drug delivery to lower blood sugar levels, ensuring accurate and timely blood sugar regulation. When the blood sugar level is low, the heater is not turned on, reducing the risk of hypoglycemia. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 A schematic diagram of the composition of an artificial pancreas-like integrated wireless control patch for blood glucose sensing and regulation;

[0041] Figure 2 Schematic diagram of the change of the fluorescence intensity of the sensing microneedle measured by the color sensor with the glucose concentration;

[0042] Figure 3 It is a schematic diagram of the working performance of the heater at different powers;

[0043] Figure 4 The circuit schematic diagram of the integrated wireless control patch for blood sugar sensing and regulation similar to an artificial pancreas;

[0044] Figure 5 The working principle diagram of the integrated wireless control patch for blood sugar sensing and regulation similar to an artificial pancreas;

[0045] Figure 6 Schematic diagram of the experimental results of using a wireless control patch to monitor changes in glucose concentration in mice;

[0046] Figure 7 Schematic diagram of the experimental results of regulating blood sugar in mice using a wireless control patch. DETAILED DESCRIPTION

[0047] In order to better understand the purpose, structure and function of the present invention, the following is a further detailed description of an artificial pancreas-like blood sugar sensing and regulation integrated wireless control patch and a preparation method thereof in conjunction with the accompanying drawings.

[0048] Example 1

[0049] This embodiment provides an artificial pancreas-like wireless control patch integrating blood sugar sensing and regulation for glucose monitoring and blood sugar regulation in diabetic patients.

[0050] The artificial pancreas-like integrated wireless control patch for glucose sensing and regulation for glucose monitoring and blood sugar regulation in diabetic patients provided in this embodiment realizes painless real-time in-situ glucose concentration monitoring and accurate and timely delivery of hypoglycemic drugs by extracting subcutaneous interstitial fluid.

[0051] This embodiment can use the built-in coil of the smartphone to provide energy and wireless control based on near-field communication technology, thereby realizing wireless battery-free power supply of the wireless control patch and realizing glucose monitoring and blood sugar regulation functions.

[0052] An artificial pancreas-like integrated wireless control patch for glucose sensing and regulation for glucose monitoring and blood sugar regulation in patients with diabetes includes a fluorescence-based wireless glucose monitoring unit, a temperature-sensitive blood sugar regulation unit, and a wireless control circuit. The glucose monitoring unit includes a 1.5×1.5 cm flexible hydrogel sensing microneedle array loaded with glucose-responsive fluorescent material, a UV cutoff filter to ensure the effective transmission of the fluorescence signal, an XYZ (X=red, Y=green and brightness, Z=blue) true color sensor to monitor the change of microneedle fluorescence, a μ-LED that can emit 365 nm ultraviolet light, and related data processing circuits. The temperature-sensitive blood sugar regulation unit includes a temperature-sensitive therapeutic microneedle array (1.5×1.5 cm) made of hydrogel and temperature phase change material, which is loaded with hypoglycemic drugs (metformin) and sprayed with a tridecanoic acid protective layer on the surface, and a heater made of metal heating electrodes (40 nm chromium and 200 nm gold). The wireless control circuit is based on near-field communication technology to achieve glucose monitoring and regulation through a smartphone.

[0053] The wireless control patch in this embodiment is as follows Figure 1 As shown, it is a schematic diagram of the composition of an artificial pancreas-like integrated wireless control patch for blood glucose sensing and regulation, including a sensing microneedle 1-1, a UV cutoff filter 1-2, a color sensor 1-3, a flexible circuit 1-4, a therapeutic microneedle 1-5, a heater 1-6 and a near field communication (NFC) module 1-7, wherein the heater, the color sensor, the near field communication module and the flexible circuit are all integrated on a flexible polyimide (PI) circuit board, the UV cutoff filter is fixed to the upper part of the color sensor and the lower surface of the flexible hydrogel sensing microneedle array by epoxy resin, and the upper surface of the flexible hydrogel sensing microneedle array is a microneedle array; the color sensor only receives the fluorescence filtered by the UV cutoff filter, obtains the fluorescence intensity information, and feeds it back to the wireless control circuit.

[0054] The flexible circuit board and the above-mentioned devices and modules integrated on the circuit board are encapsulated by polydimethylsiloxane, and the UV cut-off filter and the heater are respectively centered, and the placement sites for the sensing microneedles and the therapeutic microneedles are reserved on the outer side of the corresponding encapsulation layer directly above them (two grooves with dimensions of 1.5 cm long, 1.5 cm wide, and 0.2 cm deep). The sensing microneedle is embedded in the reserved groove above the UV cut-off filter, and the therapeutic microneedle is embedded in the reserved groove above the heater, and fixed by the viscosity of the hydrogel. This ensures that the circuit and the device are insulated from the outside world after encapsulation, and have good biocompatibility, bendability and stretchability, and also ensures that the microneedle can smoothly penetrate the surface of the skin.

[0055] The sensing microneedle is made of a biocompatible hydrogel such as polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), hyaluronic acid, polyethylene glycol, etc. as a substrate, and the glucose concentration responsive fluorescent material (9-anthracene boronic acid) is evenly mixed with the hydrogel, and the fluorescent material can be evenly distributed in the microneedle tip after curing. The biocompatible hydrogel can absorb subcutaneous interstitial fluid and be absorbed by organisms. The glucose concentration responsive fluorescent material can produce blue fluorescence under ultraviolet light, and the fluorescence intensity is negatively correlated with the glucose concentration. When the microneedle acts on the skin surface, the hydrogel will quickly absorb the interstitial fluid, and the 9-anthracene boronic acid in the needle tip can contact the glucose molecules in the interstitial fluid. The ultraviolet lamp in the flexible circuit is controlled by a smartphone through the NFC module, and the color sensor module is started. The blue fluorescence intensity produced by 9-anthracene boronic acid shows a good linear negative correlation with the glucose concentration. Figure 2 The relationship between the fluorescence intensity of 9-anthraceneboronic acid and the glucose concentration is shown. As the glucose concentration increases from 50 mg / dL (low blood sugar value) to 400 mg / dL (high blood sugar value), the X-value ratio of the microneedle fluorescence response detected by the XYZ true color sensor decreases by about 13.7%, which has good transdermal glucose concentration capability. The fluorescence intensity measured by the sensor determines the concentration of glucose in the interstitial fluid, which is usually 70% of the glucose concentration in blood sugar, so the interstitial fluid glucose concentration can reflect the blood sugar level.

[0056] The UV cut-off filter is a 410nm high-pass filter that can block UV light from passing through and allow visible light to pass through. The UV cut-off filter is placed directly above the color sensor and directly below the microneedle. The purpose is to filter the color components entering the color sensor, block the UV light generated by the UV LED in the flexible circuit, and allow the 450nm wavelength blue fluorescence generated by the fluorescent material in the microneedle to pass through the filter and enter the color sensor. This ensures that the color sensor can accurately receive the fluorescence emitted by the microneedle.

[0057] The color sensor (AS73211) is a high-performance, low-power and low-noise color sensor. The sensor uses an integrated silicon interference filter as the main sensing area and has a temperature compensation mechanism to give the sensor stable thermal properties. It can provide extremely stable performance over different time and temperature ranges and does not require calibration during its service life. The color sensor is integrated on a flexible polyimide circuit board and placed below the microneedle and UV cutoff filter to collect the fluorescence intensity of the microneedle.

[0058] The flexible circuit is used to provide ultraviolet light source, connect color sensor, manage energy supplied by NFC antenna, analyze and store fluorescence intensity information collected by color sensor, and wirelessly transmit the fluorescence intensity information to smart phone. At the same time, it determines whether the fluorescence intensity meets the high blood sugar state and controls the working state of the heater.

[0059] The therapeutic microneedle is made of a biocompatible hydrogel as a substrate and loaded with a hypoglycemic drug (metformin). A layer of temperature phase change material such as tridecanoic acid, tetradecanoic acid, capric acid, etc. is coated on the surface of the microneedle as a protective film. The protective film of the temperature phase change material changes from solid to liquid as the temperature rises. In the solid state, the film can ensure that the drug in the microneedle does not leak. When the temperature rises, the material becomes liquid, the protective film disappears, and the microneedle tip that pierces the skin surface melts and releases the drug after contacting the interstitial fluid. The therapeutic microneedle is placed above the heater, and the heat generated by the heater can increase the ambient temperature of the therapeutic microneedle, thereby melting the protective film on the surface of the microneedle, and metformin is released from the microneedle tip into the body to play a role in lowering blood sugar.

[0060] The heater, which is made of a 40nm layer of chromium and a 200nm layer of gold, is made using photolithography and electron beam coating processes. When the patch detects high blood sugar levels, the heater automatically starts heating. Figure 3 The heating performance of the heater is demonstrated. Under different powers, the heating effect is different, matching different temperature phase change materials. Here we choose a lower power consumption of 8mW, and the heater can reach 42-45℃ within 5 seconds, melting the tridecanoic acid protective film on the surface of the microneedle to release metformin.

[0061] The near field communication module is composed of an NFC coil, which is used to receive signals and energy from the smartphone, provide energy for the entire patch, and simultaneously realize information transmission between the patch and the smartphone, transmitting the glucose concentration information measured by the patch to the smartphone.

[0062] Figure 4It is a flexible circuit schematic diagram of an integrated wireless control patch for blood sugar sensing and regulation similar to an artificial pancreas, which consists of a sensing circuit 2-1, a treatment circuit 2-2 and a wireless control circuit 2-3. The wireless control circuit includes an NFC antenna, an NFC chip and a data processing center MCU, which are used for wireless power supply and control of smartphones and provide energy for the operation of the entire circuit. The NFC antenna is specifically an NFC coil. The sensing circuit is mainly composed of a color sensor and an ultraviolet LED. The LED and the color sensor are turned on at the same time. The LED is used to excite the sensing microneedle to produce blue fluorescence whose fluorescence intensity is affected by the glucose concentration. The color sensor detects the intensity of red, green and blue light from the three channels of X, Y and Z. The light intensity detected by the channel is converted into a digital signal and transmitted to the MCU data processing center. After analyzing the light intensity, the measurement information is transmitted to the smartphone via NFC, and is also used to determine whether it is in a state of hyperglycemia. The data processing center and the NFC antenna are connected to the heater circuit to heat the microneedle in a state of hyperglycemia and release metformin.

[0063] The wireless control circuit uses NFC technology to achieve wireless power transmission and sensor data communication between the smartphone and the wireless control patch. Initially, the smartphone activates its NFC wireless power transmission function, and then brings the smartphone close to the antenna of the NFC control circuit. The NFC chip generates analog voltage output through its integrated energy collection function to power itself, the data processing center (MCU), the color sensor, the ultraviolet light (UV LED) and the heater. The color sensor receives the fluorescence intensity information and transmits it to the MCU. After analyzing the fluorescence intensity, the measurement information is transmitted to the smart terminal via NFC, and it is also used to determine whether it is in a hyperglycemic state. The data processing center and the NFC chip are connected to the heater to heat the microneedles in a hyperglycemic state and release the hypoglycemic material.

[0064] 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 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.

[0065] During the color sensor measurement, the MCU turns on the UV LED simultaneously through switch S1. The UV LED is powered directly by the NFC output power supply voltage to ensure sufficient optical power. After completing the color data measurement (which takes about 50ms), the MCU commands the color sensor to enter the Power Down state and deactivates the UV LED to minimize power consumption. The MCU then determines whether to activate the heating switch S2 based on the predefined XYZ ratio threshold. The XYZ value obtained from the color sensor is then transmitted to the NFC chip via the I2C protocol. By bringing the smartphone close to the NFC antenna again, the color data stored in the NFC chip can be transmitted via the NFC function. The XYZ ratio is calculated as:

[0066]

[0067] Where i represents x, y or z data collected from the X, Y and Z channels respectively, and P(i) is the percentage of x, y and z in the fluorescence emission signal detected by the sensor. When X accounts for more than 22%, Y accounts for more than 19%, and Z accounts for less than 59%, it is considered to be at a high blood sugar level.

[0068] Figure 5 It is the working / principle diagram of an artificial pancreas-like integrated wireless control patch for blood sugar sensing and regulation, which mainly includes four steps: energy supply, monitoring, judgment, and treatment.

[0069] Reference Figure 5 Steps: When using, attach the 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 use NFC technology 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 and determine whether the blood sugar level reaches the high blood sugar threshold. When the threshold is reached, the heater will be activated to melt the microneedle protective film and release the drug. When the threshold is not reached, there is no need to start the heater.

[0070] Example 2

[0071] This embodiment provides a method for preparing an artificial pancreas-like wireless control patch integrating blood sugar sensing and regulation for glucose monitoring and regulation.

[0072] Step 1: Preparation of flexible substrate: The flexible circuit and near field communication module are structurally designed using CAD, and then the polyimide film is patterned to obtain the flexible substrate and the conductor circuit.

[0073] Step 2: Prepare a heater on a flexible circuit substrate using photolithography and electron beam evaporation coating technology. The polyimide film substrate was cleaned with acetone, isopropanol and deionized water in sequence, and then blown dry with nitrogen. The positive photoresist (S1813) was spin-coated on the substrate at a speed of 4000rpm for 30 seconds to form a 1.5μm thick layer, and then soft-baked at 90°C for 1 minute. The serpentine electrode pattern was determined using masked UV lithography under the condition of 100mJ / cm2 irradiation for 5 seconds. The exposed photoresist was developed in MF-319 developer for 30 seconds, rinsed with deionized water, and dried with nitrogen. After hard baking at 120°C for 2 minutes, a 40nm chromium attachment layer and a 200nm gold attachment layer were deposited in sequence using electron beam evaporation. Unnecessary metals and photoresists were removed using ultrasound in acetone, leaving the serpentine electrodes on the polyimide film.

[0074] Step 3: Integrate the UV lamp, color sensor, MCU and circuit components on the flexible substrate using reflow soldering technology, and encapsulate the flexible circuit with PDMS.

[0075] Step 4: Use epoxy resin glue to fix the UV cutoff filter on the color sensor.

[0076] Step 5, prepare the sensing microneedle, the microneedle material is selected from biocompatible hydrogels, such as polyvinyl pyrrolidone, polyvinyl alcohol, hyaluronic acid, polyethylene glycol, etc. The present invention provides a method for preparing PVP / PVA hydrogel microneedles. First, PVA powder is added to distilled water at a ratio of 12wt%, stirred and heated in a water bath at 95°C and 1000 speed for 3 hours until PVA is completely dissolved to form a viscous transparent solution. After cooling to room temperature, PVP is added to the PVA solution according to the mass ratio of PVA to PVP of 3:4, and stirring is continued until PVP is completely dissolved and the solution is clear to prepare a hydrogel solution, and then 9-anthracene boronic acid is added to 52% ethanol solution to prepare a 0.02mol / L 9-anthracene boronic acid solution, and then the 9-anthracene boronic acid solution and the PVA / PVP solution are mixed at a volume ratio of 1:1, and stirred at 1000 rpm for 15 minutes. After stirring, the solution was poured into the PDMS mold, centrifuged and vacuumed to allow the solution to fully fill the needle tip and dried at 35°C for 24 hours. After the needle tip was solidified, 12wt% PVA solution was poured into the mold and continued to be dried at 35°C for 24 hours as the microneedle substrate. After the substrate was solidified, the entire microneedle was peeled off in the mold to obtain a sensing microneedle.

[0077] Step 6, prepare therapeutic microneedles, and the microneedle material is selected from biocompatible hydrogels, such as polyvinyl pyrrolidone, polyvinyl alcohol, hyaluronic acid, polyethylene glycol, etc. The upper protective film of the microneedle is selected from temperature phase change materials, such as tridecanoic acid, tetradecanoic acid, capric acid, etc. The present invention provides a method for preparing a thermosensitive microneedle. First, a 12wt% PVA solution is prepared according to step 5. Then PVP is added to the PVA solution at a mass ratio of 2:1 (PVA), and stirred until the PVP is completely dissolved to obtain a transparent hydrogel solution. Subsequently, metformin hydrochloride is added to the hydrogel solution to a final concentration of 4wt%. After stirring, the solution is poured into a PDMS mold, centrifuged and vacuum treated, so that the solution fully fills the needle tip and is dried at 35°C for 24 hours. After the needle tip is cured, the 12wt% PVA solution is poured into the mold and continued to be dried at 35°C for 24 hours as a microneedle substrate. After the substrate is cured, the entire microneedle is peeled off in the mold to obtain a therapeutic microneedle. The tridecanoic acid solid was heated to melt, and the tridecanoic acid liquid was sprayed on the microneedles in a drying oven at 45° C. to form a protective layer, and then the microneedles were cooled to room temperature.

[0078] Step 7: Encapsulation of the wireless control patch. The patch is encapsulated with PDMS in small amounts and multiple times (curing conditions: 80°C, 2 hours). Be careful not to encapsulate too much PDMS, which will reduce the deformability of the device. The thickness of the final sealing layer is 0.3-0.5mm. At the same time, a groove is formed above the UV cutoff filter and the heater using the reverse molding method to place the microneedle. The depth of the groove is 1mm.

[0079] Step 8: Wet the flat side of the microneedle substrate 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 control patch is about 1.68g.

[0080] Example 3

[0081] This example applies the wireless control patch to a genetic diabetic mouse model to verify the function of monitoring changes in glucose concentration and regulating blood sugar.

[0082] This embodiment provides an experimental model of monitoring glucose concentration in mice using an artificial pancreas-like wireless control patch integrating blood glucose sensing and regulation.

[0083] Step 1: sterilize the wireless control patch with ultraviolet light.

[0084] Step 2: Depilate the backs of 10 freely moving diabetic mice for patch placement.

[0085] Step 3: First, fast the mice for 8 hours to keep their blood sugar levels low. First, collect blood samples from the tail vein and use a commercial blood glucose meter to measure blood sugar levels. At the same time, apply the patch to the back skin of the mouse. After 20 minutes, use the patch attached to the skin to monitor the interstitial fluid glucose concentration, and read the detected fluorescence data directly with a smartphone. After the measurement, the mice were adaptively raised for 3 days.

[0086] Step 4: After the adaptive feeding, the mice were allowed to eat freely to maintain high blood sugar levels. Blood samples were collected from the tail vein and blood sugar levels were measured using a commercial blood glucose meter. At the same time, the patch was applied to the back skin of the mice. After 20 minutes, the interstitial fluid glucose concentration was monitored using the patch attached to the skin, and the detected fluorescence data was directly read using a smartphone.

[0087] Step 5: Compare the data measured by the commercial blood glucose meter and the data measured by the wireless control patch.

[0088] Figure 6 The results of the experiment of using a wireless control patch to monitor the changes in glucose concentration in mice were shown. It can be seen that under both 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.

[0089] The present invention also provides an experimental model for regulating the blood sugar level of mice using an artificial pancreas-like wireless control patch integrating blood sugar sensing and regulation.

[0090] Step 1: sterilize the wireless control patch with ultraviolet light.

[0091] Step 2: Depilate the backs of 20 freely moving diabetic mice for patch placement.

[0092] Step 3, fast 20 diabetic model mice for 8 hours and randomly divide them into blank group, treatment group, positive control group and control group. In the blank group, mice were allowed to eat freely after two fasting blood glucose measurements. In the treatment group, mice had their blood glucose measured twice on an empty stomach, were allowed to eat freely, and the patch was applied immediately after eating. The positive control group remained fasting throughout the experiment and did not use the patch; the patch control group remained fasting and wore the patch immediately after the second fasting blood glucose measurement.

[0093] Step 4. The blood glucose levels of all mice were measured every hour for 12 hours, and the changes in blood glucose levels were monitored using a commercial blood glucose meter in order to compare blood glucose dynamics and evaluate the therapeutic effects of the patch between different groups. It can be seen that the blood glucose of the blank group mice will rise rapidly after eating, and the blood glucose of the treatment group mice will rise after eating, triggering the patch to release metformin to play a hypoglycemic effect. The mice in the positive control group have lower blood glucose levels due to continuous fasting, and the mice in the control group have lower blood glucose levels due to continuous fasting. Although the patch is worn, it will not trigger the patch to release metformin, and the blood glucose continues to be at a low level. The experimental results show that the patch can play a regulatory role in lowering blood glucose at high blood glucose levels.

[0094] Figure 7 The results of the experiment of regulating the blood sugar of mice with a wireless control patch are shown. It can be seen that in the free-feeding state, the mice wearing the patch (treatment group) have lower blood sugar levels than the mice not wearing the patch (blank group), and can recover from the hypoglycemia state in time after eating and maintain it for 5-6 hours. In the fasting state, the blood sugar of mice wearing the patch (control group) and mice not wearing the patch (positive control group) are in a similar state, indicating that in the hypoglycemic state, the patch did not turn on the heater and did not release hypoglycemic drugs.

[0095] 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. An artificial pancreas-like integrated wireless control patch for blood sugar sensing and regulation, characterized in that: It includes a fluorescence-based wireless glucose monitoring unit, a temperature-sensitive blood glucose regulation unit, and a wireless control circuit; The wireless glucose monitoring unit includes a flexible hydrogel sensing microneedle array loaded with a glucose concentration-responsive fluorescent material, an ultraviolet cutoff filter, a color sensor, and an ultraviolet lamp; specifically, the flexible hydrogel sensing microneedle array generates fluorescence intensity according to the glucose concentration after receiving ultraviolet light from the ultraviolet lamp, the ultraviolet cutoff filter is fixed on the upper surface of the color sensor and the lower surface of the flexible hydrogel sensing microneedle array, and the upper surface of the flexible hydrogel sensing microneedle array is a microneedle array; the color sensor only receives the fluorescence filtered by the ultraviolet light from the ultraviolet cutoff filter, obtains the fluorescence intensity information, and feeds it back to the wireless control circuit; The thermosensitive blood sugar regulation unit comprises a thermosensitive therapeutic microneedle array and a heater; specifically, the substrate of the thermosensitive therapeutic microneedle array is a hydrogel, the surface material of the microneedle needle tip is a temperature phase change material, and the microneedle array is loaded with hypoglycemic drugs; the heater is located on the lower surface of the thermosensitive therapeutic microneedle array, and the upper surface of the thermosensitive therapeutic microneedle array is the microneedle array; the heater heats to melt the temperature phase change material, and the thermosensitive therapeutic microneedle array releases the hypoglycemic drugs; The wireless control circuit includes a flexible circuit and a near field communication module; wherein the ultraviolet lamp, the heater, the color sensor, the near field communication module and the flexible circuit are integrated on a flexible polyimide circuit board and encapsulated using polydimethylsiloxane; The near-field communication module includes an NFC coil, which receives signals and energy from a smart terminal; the flexible circuit includes a wireless control circuit, specifically including an NFC chip and a data processing center MCU; specifically, the NFC coil receives signals and energy from the smart terminal to the NFC chip, and the NFC chip generates an analog voltage output through its integrated energy collection function to power itself, the data processing center, the color sensor, the ultraviolet lamp and the heater; the color sensor receives the fluorescence intensity information and transmits it to the MCU, and after analyzing the fluorescence intensity, the measurement information is transmitted to the smart terminal via NFC, and is also used to determine whether it is in a hyperglycemic state; the data processing center and the NFC chip are connected to the heater to heat the microneedles in a hyperglycemic state and release the blood sugar-lowering material.

2. The artificial pancreas-like wireless control patch for blood sugar sensing and regulation according to claim 1, characterized in that: With the UV cutoff filter and heater as the center, recesses for placing sensing microneedles and therapeutic microneedles are reserved on the outer side of the corresponding packaging layer directly above them. The sensing microneedles are embedded in the reserved recesses above the UV cutoff filter, and the therapeutic microneedles are embedded in the reserved recesses above the heater, and then fixed using the viscosity of the hydrogel.

3. The artificial pancreas-like wireless control patch for blood sugar sensing and regulation according to claim 2, characterized in that: The temperature phase change material is one of tridecanoic acid, tetradecanoic acid and decanoic acid; and the blood sugar lowering drug is metformin.

4. The artificial pancreas-like blood sugar sensing and regulation integrated wireless control patch according to claim 3, characterized in that: The hydrogel is a biocompatible hydrogel, including one or more of polyvinyl pyrrolidone, polyvinyl alcohol, hyaluronic acid, and polyethylene glycol; the glucose concentration-responsive fluorescent material is specifically 9-anthraceneboric acid.

5. The artificial pancreas-like blood sugar sensing and regulation integrated wireless control patch according to claim 4, characterized in that: The ultraviolet cut-off filter is a 410nm high-pass filter that blocks ultraviolet light from passing through and allows visible light to pass through.

6. The artificial pancreas-like wireless control patch for blood sugar sensing and regulation according to claim 5, characterized in that: The heater is a metal heating electrode composed of a 40nm chromium layer and a 200nm gold layer, and the power consumption is 8mW.

7. The artificial pancreas-like wireless control patch for blood sugar sensing and regulation according to claim 6, characterized in that: The MCU establishes communication with the color sensor through the I2C protocol, and the color sensor converts the captured light signal into XYZ tristimulus values; During the color sensor measurement, the MCU controls the turning on of the ultraviolet light, which is powered by the output voltage of the NFC chip. After the color sensor completes the measurement, it feeds back the information to the MCU, and the MCU controls the turning off of the ultraviolet light. The MCU determines whether to activate the heater based on the predefined XYZ ratio threshold, and transmits the XYZ tristimulus values ​​obtained from the color sensor to the NFC chip through the I2C protocol, and then feeds back to the smart terminal. The calculation method of the XYZ ratio is: Where i represents x, y or z data collected from the X, Y and Z channels respectively, and P(i) is the percentage of x, y and z in the fluorescence emission signal detected by the color sensor.

8. A method for preparing an artificial pancreas-like wireless control patch integrating blood sugar sensing and regulation as described in any one of claims 1 to 7, characterized in that: The following steps are involved: Step 1: Preparation of a flexible substrate; using software to design a circuit structure, and then patterning a polyimide film to obtain a flexible substrate and a conductor circuit; Step 2: Prepare a heater on a flexible substrate using photolithography and electron beam evaporation coating technology, then clean the flexible substrate and blow dry it with nitrogen; Specifically, a photoresist is spin-coated on a substrate, and a masked ultraviolet lithography technique is used to determine a serpentine electrode pattern; a chromium attachment layer and a gold attachment layer are sequentially deposited using an electron beam evaporation method, and unnecessary metals and photoresist are removed using ultrasound in acetone, leaving the serpentine electrode on the polyimide film; Step 3: Integrate the UV lamp, color sensor, MCU and NFC chip on the flexible substrate using reflow soldering technology; Step 4: Use epoxy resin glue to fix the UV cutoff filter on the color sensor; Step 5: preparing sensing microneedles; the microneedle material is a biocompatible hydrogel to prepare a hydrogel solution, and then the 9-anthracene boronic acid solution and the hydrogel solution are mixed and stirred. After the stirring is completed, the solution is poured into a mold, centrifuged and vacuum-treated to allow the solution to fully fill the needle tip and then dried. After the needle tip is solidified, the hydrogel solution is poured into the mold and continued to dry as a microneedle substrate. After the substrate is solidified, the entire microneedle is peeled off in the mold to obtain a sensing microneedle array; Step 6: preparing therapeutic microneedles; selecting a biocompatible hydrogel to prepare a hydrogel solution, then adding metformin to the hydrogel solution to a final concentration of 4wt%, mixing and stirring, pouring the solution into a mold after stirring, centrifuging and vacuum treating, so that the solution fully fills the needle tip and dries, after the needle tip is solidified, pouring the hydrogel solution into the mold and continuing to dry as a microneedle substrate; after the substrate is solidified, peeling the entire microneedle in the mold; then heating and melting the temperature phase change material solid, spraying the temperature phase change material liquid on the microneedle in a drying oven at 45°C, and then cooling the microneedle to room temperature to obtain a therapeutic microneedle array; Step 7: Encapsulation of the wireless control patch: Use polydimethylsiloxane to encapsulate the flexible substrate, i.e., the device integrated on the surface. At the same time, with the UV cutoff filter and the heater as the center, use the reverse molding method to reserve the placement grooves for the sensing microneedles and the treatment microneedles on the outer side of the corresponding encapsulation layer directly above them, so as to place the microneedle array; Step 8: Wet the flat side of the microneedle array substrate with water, embed the microneedle array into the reserved groove and dry it, and fix the microneedles on the polydimethylsiloxane sealing layer.

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