An integrated wireless control patch for blood glucose sensing and regulation similar to an artificial pancreas and its preparation method

Abstract

The present invention discloses an integrated wireless control patch for blood glucose sensing and regulation similar to an artificial pancreas and its preparation method, belonging to the field of biomedical engineering. The present invention realizes the integration of blood glucose sensing and regulation, integrates a color sensor and an ultraviolet cut-off filter, and monitors blood glucose in real time in situ, facilitating the timely acquisition of blood glucose information; then, a heater controls the release of metformin by temperature-responsive therapeutic microneedles to regulate blood glucose levels; the present invention uses near-field communication technology for wireless power supply regulation and communication. It gets rid of the limitations of power supplies and batteries, reduces the volume and weight of the patch, and improves the wearing comfort of patients. The present invention integrates monitoring and treatment functions to form a closed-loop system similar to an artificial pancreas. When a high blood glucose level is detected, the heater is automatically turned on for metformin drug delivery to reduce the blood glucose level, ensuring precise and timely blood glucose regulation. When the blood glucose level is low, the heater is not turned on, reducing the risk of hypoglycemia.

Description

Technical Field

[0001] The present invention belongs to the field of biomedical engineering, and particularly relates to an integrated wireless control patch for blood glucose sensing and regulation of an artificial pancreas-like and a preparation method thereof. Background Art

[0002] Diabetes is a major global public health challenge, with over 537 million affected patients worldwide. Prolonged hyperglycemia can lead to severe complications such as cardiovascular diseases, kidney diseases, and retinopathy. Currently, patients need to use invasive methods, such as self-monitoring of blood glucose (SMBG), to measure blood glucose levels by fingerstick blood sampling using a glucometer and test strips, 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 glucose is monitored 3 - 10 times a day. After obtaining the blood glucose data, the patient must promptly inject insulin or take oral hypoglycemic drugs. However, these methods often cause discomfort, pose an infection risk, and have a high maintenance cost for the sensors. In addition, frequent monitoring and medication management seriously affect the patient's daily life, and improper medication dosage may also lead to the risk of hypoglycemia. Therefore, minimally invasive and painless monitoring of the in-vivo glucose concentration and timely and accurate adjustment of the drug dosage are crucial.

[0003] At present, people mostly integrate a blood glucose monitoring system and a drug syringe to form a closed-loop system. In this system, the blood glucose monitor monitors the blood glucose level, the insulin delivery device automatically delivers insulin by continuous subcutaneous infusion as needed, and the control algorithm adjusts the insulin according to the blood glucose data and the preset treatment goal. It simulates the natural insulin secretion of the human body to precisely control blood glucose and provides flexible adjustment of basal infusion and bolus infusion.

[0004] In the existing diabetes closed-loop system technology, the glucose monitoring methods for diabetic patients mainly include continuous glucose monitoring system (CGM) and flash glucose monitoring (FGM). These methods achieve real-time or near-real-time monitoring of the patient's blood glucose level through different technical means, providing data support for individualized blood glucose management. Self-monitoring of blood glucose (SMBG) is a traditional blood glucose monitoring method. The continuous glucose monitoring system (CGM) continuously monitors the glucose concentration in interstitial fluid through a subcutaneous implanted sensor, usually updating data every few minutes, and can display the real-time change trend of blood glucose, which helps to identify situations such as nocturnal hypoglycemia or postprandial hyperglycemia, thus optimizing the blood glucose management strategy. In recent years, electrochemical sensors have become an important tool in the field of continuous glucose monitoring by detecting the electrical signal of the glucose redox reaction. At the same time, based on the development of biosensors and microneedle technology, electrochemical microneedle sensors can penetrate the superficial layer of the skin to collect interstitial fluid (ISF), thus realizing non-invasive or minimally invasive glucose detection. Or after a metal steel needle is inserted subcutaneously, the electrochemical impedance spectroscopy (EIS) technology is used to monitor the glucose level. This is a method of detecting glucose concentration by applying a small alternating voltage and measuring the change in its impedance. In addition, detection methods based on optical principles, such as using near-infrared spectroscopy, Raman spectroscopy, fluorescence method and colorimetry, can infer the blood glucose level by detecting the change in the optical signal generated by the reaction of glucose with a specific reagent. Among them, fluorescence detection measures the blood glucose level by using the change in fluorescence intensity generated after a specific fluorescent dye or fluorescent probe reacts with glucose. The core of this method lies in the design of the fluorescent probe and its specific response to glucose. Common fluorescent probes include boric acid compounds, and the fluorescence characteristics of these compounds will change after binding to glucose, so the glucose concentration can be inferred by the change in fluorescence intensity. Flash glucose monitoring (FGM) is an improved continuous monitoring technology that obtains the immediate blood glucose level by scanning a subcutaneous sensor. Although it does not automatically provide continuous data, the current blood glucose information can be conveniently obtained by manual scanning, which is suitable for patients who do not require all-weather real-time monitoring. In terms of blood glucose regulation, there are also wearable drug or insulin injection devices currently. The insulin delivery is mostly through a fixed catheter under the skin, and the injection dose is controlled by a mechanical pump connected to the control system so that insulin can be smoothly delivered into the body.

[0005] Existing blood glucose monitoring and regulation technologies play an important role in diabetes management, but there are also some drawbacks and their reasons. The drawback of self - monitoring of blood glucose (SMBG) is that it is highly invasive, requires frequent blood sampling, can only provide data at specific time points, and cannot continuously track blood glucose fluctuation trends. The reason is that it must create a skin incision, relying on manual operation and the limitations of instantaneous data acquisition; the drawback of continuous glucose monitoring system (CGM) is that the cost of equipment and consumables is relatively high, the accuracy may be affected by the difference between interstitial fluid and blood glucose levels, and long - term wearing of the sensor may cause skin discomfort. The reasons are the complex manufacturing process, the limitations of sensor technology, and the lag between interstitial fluid glucose level and blood glucose level; the drawback of non - invasive detection technology based on optical principle is that the accuracy and stability are relatively poor, and it is easily affected by factors such as skin thickness, color, and external light. The reason is the limited current technical level and many external interference factors. The emergence of these drawbacks mainly stems from the limitations of technology, high costs, dependence on use, and challenges in patient compliance. The drawback of Flash glucose monitoring (FGM) is that it does not provide automatic continuous data, requires manual scanning to obtain blood glucose information, and cannot monitor blood glucose mutations in real - time. The reason is the limitation of its technical design, unable to achieve automatic monitoring; the drawback of drug treatment (including insulin injection and oral hypoglycemic drugs) is the risk of hypoglycemia, complex dose adjustment, and possible side effects or contraindications. The reason lies in the complexity of drug metabolism, the diversity of action mechanisms, and the limitations of human living state and behavior; the drawback of insulin pump is the high cost of equipment, possible technical failures, a steep learning curve for use, and strong dependence on the equipment. The reason is the complexity of the equipment and high - tech requirements; the future improvement direction will focus on integrating glucose concentration monitoring and blood glucose regulation, improving technical accuracy, reducing costs, reducing invasiveness, and enhancing the patient experience. Summary of the Invention

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

[0007] To solve the above - mentioned technical problems, the specific technical solutions of the integrated wireless control patch for blood glucose sensing and regulation of the artificial - pancreas - like of the present invention are as follows:

[0008] An integrated wireless control patch for blood glucose sensing and regulation of an artificial - pancreas - like, comprising a fluorescence - based wireless glucose monitoring unit, a thermosensitive 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 cut-off filter, a color sensor, and an ultraviolet lamp. Specifically, after receiving ultraviolet light from the ultraviolet lamp, the flexible hydrogel sensing microneedle array generates fluorescence intensity according to the glucose concentration. The ultraviolet cut-off 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 cut-off filter, obtains the fluorescence intensity information, and feeds it back to the wireless control circuit.

[0010] The temperature-sensitive blood glucose regulation unit includes a temperature-sensitive treatment microneedle array and a heater. Specifically, the base of the temperature-sensitive treatment microneedle array is a hydrogel, and the surface material of the microneedle tip is a temperature phase-change material. This microneedle array is loaded with hypoglycemic drugs. The heater is located on the lower surface of the temperature-sensitive treatment microneedle array, and the upper surface of the temperature-sensitive treatment microneedle array is a microneedle array. The heater heats to melt the temperature phase-change material, and the temperature-sensitive treatment microneedle array releases hypoglycemic drugs.

[0011] The wireless control circuit includes a flexible circuit and a near-field communication module. Among them, the ultraviolet lamp, the heater, the color sensor, the near-field communication module, and the flexible circuit are all integrated on a flexible polyimide circuit board and encapsulated with polydimethylsiloxane (PDMS).

[0012] The near-field communication module includes an NFC coil, which receives signals and energy from the smart terminal. The flexible circuit includes a wireless regulation circuit, specifically including an NFC chip and a data processing center MCU. Specifically, the NFC coil receives the signals and energy from the smart terminal to the NFC chip. The NFC chip generates an analog voltage output through its integrated energy harvesting function to supply power to itself, the data processing center, the color sensor, the ultraviolet lamp, and the heater. After receiving the fluorescence intensity information, the color sensor transmits it to the MCU. After analyzing the fluorescence intensity, the measurement information is transmitted to the smart terminal by NFC, and at the same time, it is used to judge whether it is in a hyperglycemic state. The data processing center and the NFC chip are connected to the heater to heat the microneedles and release hypoglycemic materials in a hyperglycemic state.

[0013] Centered on the ultraviolet cut-off filter and the heater, placement grooves for the sensing microneedles and the treatment microneedles are reserved outside the encapsulation layer corresponding to their upper sides. The sensing microneedles are embedded in the reserved grooves above the ultraviolet cut-off filter, and the treatment microneedles are embedded in the reserved grooves above the heater, and are fixed using the viscosity of the hydrogel.

[0014] The temperature phase-change materials include tridecanoic acid, myristic acid, capric acid, etc.; the hypoglycemic drug is metformin.

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

[0016] The ultraviolet cut-off filter is a 410nm high-pass filter that blocks ultraviolet light 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, with a power consumption of 8mW.

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

[0019] During the measurement of the color sensor, the MCU controls to turn on the ultraviolet lamp, which is powered by the voltage output from the NFC chip; after the color sensor completes the measurement, it feeds back the information to the MCU, and the MCU controls to turn off the ultraviolet lamp; the MCU determines whether to activate the heater according to 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 feeds them back to the smart terminal; the calculation method of the XYZ ratio is as follows:

[0020]

[0021] Where i represents the 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 preparation method for an integrated wireless control patch for blood glucose sensing and regulation of an artificial pancreas-like, including the following steps:

[0023] Step 1: Preparation of the flexible substrate; use software for circuit structure design, and then pattern the polyimide film to obtain the flexible substrate and the wire circuit;

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

[0025] Specifically, spin-coat the photoresist on the substrate, use ultraviolet photolithography technology with a mask to determine the serpentine electrode pattern; use electron beam evaporation to sequentially deposit a chromium adhesion layer and a gold adhesion layer, remove the unnecessary metal and photoresist in acetone using ultrasonic waves, and leave the serpentine electrode on the polyimide film;

[0026] Step 3: Integrate the ultraviolet 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: Fix the ultraviolet cut-off filter on the color sensor using epoxy resin glue;

[0028] Step 5: Prepare the sensing microneedles; select a biocompatible hydrogel to prepare a hydrogel solution, then mix and stir the 9-anthracene boronic acid solution and the hydrogel solution. After stirring, pour the solution into a mold, centrifuge and vacuum process it to make the solution fully fill the tip of the needle and then dry it. After the tip is cured, pour the hydrogel solution into the mold and continue to dry it as the microneedle base. After the base is cured, peel the entire microneedle from the mold to obtain a sensing microneedle array;

[0029] Step 6: Prepare the therapeutic microneedles; select a biocompatible hydrogel to prepare a hydrogel solution, then add metformin to the hydrogel solution with a final concentration of 4 wt%, mix and stir. After stirring, pour the solution into a mold, centrifuge and vacuum process it to make the solution fully fill the tip of the needle and dry it. After the tip is cured, pour the hydrogel solution into the mold and continue to dry it as the microneedle base; after the base is cured, peel the entire microneedle from the mold; then heat and melt the solid temperature phase change material, spray the temperature phase change material liquid on the microneedles in a drying oven at 45 °C, and then cool the microneedles to room temperature to obtain a therapeutic microneedle array;

[0030] Step 7: Package the wireless control patch; use polydimethylsiloxane to package the flexible substrate, i.e., the devices integrated on the surface. At the same time, respectively centered on the ultraviolet cut-off filter and the heater, use the reverse molding method to reserve placement grooves for the sensing microneedles and the therapeutic microneedles outside the corresponding packaging layer directly above them to place the microneedle array;

[0031] Step 8: Moisten the flat side of the microneedle array base with water, embed the microneedle array into the reserved groove and then 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, a glucose sensing and regulation integrated wireless control patch for glucose monitoring and blood glucose regulation of glucose patients, similar to an artificial pancreas, is realized.

[0034] (1) The present invention uses the fluorescence colorimetric method to monitor the glucose concentration. The glucose concentration sensing method in the technical solution of the present invention is improved, and the glucose-responsive fluorescence technology based on 9-anthracene boronic acid is 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 need to be frequently replaced and calibrated.

[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 and can rapidly absorb interstitial fluid. 9-anthracene boronic acid in the hydrogel contacts glucose, resulting in a change in fluorescence intensity. The microneedle base is flexible and can better fit the skin compared with traditional rigid metal microneedles, and is not likely to cause skin damage. At the same time, the manufacturing cost of the microneedles is low and they are easy to replace, reducing complex replacement steps and improving the comfort of patients.

[0036] (3) The present invention integrates a color sensor and an ultraviolet cut-off filter. Compared with the traditional method of extracting blood glucose and then detecting it in a device, and the method of capturing the fluorescence of materials using a camera or a fluorometer, the integration of the color sensor enables real-time in-situ blood glucose monitoring, facilitating the timely acquisition of blood glucose information. And it can avoid the influence of ambient light and prevent the extracted interstitial fluid sample from being contaminated.

[0037] (4) The present invention prepares a blood glucose regulation unit composed of temperature-sensitive therapeutic microneedles and a heater. The heater controls the release of metformin by the temperature-responsive therapeutic microneedles to regulate blood glucose levels. The therapeutic microneedles use the 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 supplies and batteries, reduces the volume and weight of the patch, and improves the wearing comfort of patients. Through wireless communication with a smartphone, users can timely grasp their blood glucose levels.

[0039] (6) The present invention integrates monitoring and treatment functions to form a closed-loop system similar to an artificial pancreas. When a high blood glucose level is detected, the heater is automatically turned on for metformin drug delivery to reduce the blood glucose level, ensuring precise and timely blood glucose regulation. When the blood glucose level is low, the heater is not turned on, reducing the risk of hypoglycemia. Description of the Drawings

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

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

[0042] Figure 3 Schematic diagram of the working performance of the heater at different powers;

[0043] Figure 4 Schematic diagram of the circuit principle of the integrated wireless control patch for blood glucose sensing and regulation of an artificial pancreas-like device;

[0044] Figure 5 Working schematic diagram of a glucose-sensing and regulation integrated wireless control patch for an artificial pancreas-like device;

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

[0046] Figure 7 Schematic diagram of the experimental results of regulating blood glucose in mice using a wireless control patch. Detailed implementation manners

[0047] In order to better understand the purpose, structure and function of the present invention, the following further describes in detail a glucose-sensing and regulation integrated wireless control patch for an artificial pancreas-like device and its preparation method according to the present invention with reference to the accompanying drawings.

[0048] Example 1

[0049] This example provides a glucose-sensing and regulation integrated wireless control patch for an artificial pancreas-like device for glucose monitoring and blood glucose regulation in diabetic patients.

[0050] The glucose-sensing and regulation integrated wireless control patch for an artificial pancreas-like device for glucose monitoring and blood glucose regulation in diabetic patients provided in this example realizes painless real-time in-situ glucose concentration monitoring and precise and timely hypoglycemic drug delivery by extracting subcutaneous interstitial fluid.

[0051] Based on near-field communication technology, this example can use the built-in coil of a smart phone to provide energy and wireless regulation, realizing wireless battery-free power supply for the wireless control patch and achieving glucose monitoring and blood glucose regulation functions.

[0052] An integrated wireless control patch for glucose sensing and regulation of an artificial pancreas-like device for diabetes patients includes a fluorescence-based wireless glucose monitoring unit, a temperature-sensitive blood glucose regulation unit, and a wireless control circuit. The glucose monitoring unit includes a flexible hydrogel sensing microneedle array (1.5×1.5 cm) loaded with glucose-responsive fluorescent material, an ultraviolet cut-off filter to ensure effective transmission of the fluorescence signal, an XYZ (X = red, Y = green and luminance, 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 glucose 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 drug (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 and realizes glucose monitoring and regulation through a smart phone.

[0053] The wireless control patch in this embodiment is as Figure 1 shown, which is a schematic diagram of the composition of an integrated wireless control patch for glucose sensing and regulation of an artificial pancreas-like device, including sensing microneedles 1-1, an ultraviolet cut-off filter 1-2, a color sensor 1-3, a flexible circuit 1-4, therapeutic microneedles 1-5, a heater 1-6, and a near-field communication (NFC) module 1-7. Among them, the heater, color sensor, near-field communication module, and flexible circuit are all integrated on a flexible polyimide (PI) circuit board. The ultraviolet cut-off filter is fixed directly above the color sensor and under the lower surface of the flexible hydrogel sensing microneedle array using epoxy resin. The upper surface of the flexible hydrogel sensing microneedle array is the microneedle array. The color sensor only receives the fluorescence filtered by the ultraviolet cut-off filter and obtains the fluorescence intensity information, which is fed 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 respectively centered on the ultraviolet cut-off filter and the heater, and the placement sites for the sensing microneedles and therapeutic microneedles are reserved outside the corresponding encapsulation layer directly above them (two grooves with a size of 1.5 cm in length, 1.5 cm in width, and 0.2 cm in depth). The sensing microneedles are embedded in the reserved groove above the ultraviolet cut-off filter, and the therapeutic microneedles are embedded in the reserved groove above the heater and fixed using the viscosity of the hydrogel. This not only ensures that the circuit and devices are insulated from the outside after encapsulation, with good biocompatibility, bendability, and stretchability, but also ensures that the microneedles can smoothly penetrate the skin surface.

[0055] The sensing microneedles use biocompatible hydrogels such as polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), hyaluronic acid, polyethylene glycol, etc. as the substrate. The glucose concentration-responsive fluorescent material (9-anthracene boronic acid) is uniformly mixed with the hydrogel. After curing, the fluorescent material can be evenly distributed inside the microneedle tips. The biocompatible hydrogel can absorb subcutaneous interstitial fluid and be biodegraded. The glucose concentration-responsive fluorescent material can produce blue fluorescence under ultraviolet light irradiation, and the fluorescence intensity is negatively correlated with the glucose concentration. When the microneedles act on the skin surface, the hydrogel will quickly absorb the interstitial fluid, and the 9-anthracene boronic acid in the needle tips can come into contact with the glucose molecules in the interstitial fluid. The ultraviolet lamp in the flexible circuit is controlled by a smartphone through the NFC module to work, and the color sensor module is activated. The blue fluorescence intensity generated by 9-anthracene boronic acid has a good linear negative correlation with the glucose concentration. Figure 2 It shows the relationship between the fluorescence intensity of 9-anthracene boronic acid and the glucose concentration. As the glucose concentration increases from 50 mg / dL (hypoglycemic value) to 400 mg / dL (hyperglycemic value), the proportion of the X value of the microneedle fluorescence response detected by the XYZ true color sensor decreases by about 13.7%, indicating good ability to transdermally detect glucose concentration. The glucose concentration in the interstitial fluid is determined by the fluorescence intensity measured by the sensor. The glucose concentration in the interstitial fluid is usually 70% of the glucose concentration in the blood sugar, so the interstitial fluid glucose concentration can reflect the blood sugar level.

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

[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 make the sensor have stable thermal characteristics, capable of providing extremely stable performance within different time and temperature ranges, and no further calibration is required during its service life. The color sensor is integrated on a flexible polyimide circuit board and placed below the microneedles and the ultraviolet cut-off filter to collect the fluorescence intensity of the microneedles.

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

[0059] The therapeutic microneedles have a biocompatible hydrogel as the substrate and are loaded with an antidiabetic drug (metformin). A temperature phase change material such as tridecanoic acid, myristic acid, capric acid, etc. is coated on the surface of the microneedles as a protective film. The protective film of the temperature phase change material changes from solid to liquid as the temperature rises. When in the solid state, this film can ensure that the drug in the microneedles does not leak. When the temperature rises, the material becomes liquid, the protective film disappears, and the tips of the microneedles inserted into the skin surface melt and release the drug after contacting the interstitial fluid. The therapeutic microneedles are placed above the heater, and the heat generated by the heater can increase the ambient temperature of the therapeutic microneedles, thereby melting the protective film on the surface of the microneedles, and metformin is released from the tips of the microneedles and enters the body to play a role in lowering blood sugar.

[0060] The heater is composed of a 40nm chromium layer and a 200nm gold layer, and is fabricated using photolithography and electron beam coating processes. When the patch detects a hyperglycemic level, the heater automatically starts heating. Figure 3 The heating performance of the heater is shown. At different powers, the heating effects are different, matching different temperature phase change materials. Here we choose a lower power consumption of 8mW, and the heater can reach 42 - 45°C within 5 seconds, melting the tridecanoic acid protective film on the surface of the microneedles to release metformin.

[0061] The near - field communication module consists of an NFC coil, which is used to receive signals and energy from a smartphone and provide energy for the operation of the entire patch. At the same time, it realizes the information transfer between the patch and the smartphone, and transmits the glucose concentration information measured by the patch to the smartphone.

[0062] Figure 4It is the flexible circuit schematic diagram of a glucose-sensing and regulation integrated wireless control patch similar to an artificial pancreas, which consists of a sensing circuit 2-1, a treatment circuit 2-2 and a wireless regulation circuit 2-3. The wireless regulation circuit includes an NFC antenna, an NFC chip and a data processing center MCU, which are used for wireless power supply and control by a smart phone, providing energy for the operation of the whole 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 stimulate the sensing microneedles to generate blue fluorescence whose fluorescence intensity is affected by the glucose concentration. The color sensor detects the intensities of red, green and blue light from three channels X, Y and Z. The light intensities detected by the channels are converted into digital signals and transmitted to the MCU data processing center. After analyzing the light intensities, the measurement information is transmitted to the smart phone by NFC, and at the same time, it is used to judge whether it is in a hyperglycemic state. The data processing center and the NFC antenna are connected to the heater circuit to heat the microneedles and release metformin in a hyperglycemic state.

[0063] The wireless regulation circuit realizes wireless power transmission and sensing data communication between the smart phone and the wireless control patch through NFC technology. Initially, the smart phone activates its NFC wireless power transmission function, and then brings the smart phone close to the antenna of the NFC control circuit. The NFC chip generates an analog voltage output through its integrated energy harvesting function to supply power to itself, the data processing center (MCU), the color sensor, the ultraviolet lamp (UV LED) and the heater. After receiving the fluorescence intensity information, the color sensor transmits it to the MCU. After analyzing the fluorescence intensity, the measurement information is transmitted to the intelligent terminal by NFC, and at the same time, it is used to judge whether it is in a hyperglycemic state. The data processing center and the NFC chip are connected to the heater to heat the microneedles and release hypoglycemic materials in a hyperglycemic state.

[0064] The MCU establishes communication with the color sensor through the I2C protocol to realize 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.

[0065] During the color sensor measurement, the MCU turns on the UV LED simultaneously through the switch S1. The UV LED is directly powered by the NFC output power voltage 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. Subsequently, the MCU determines whether to activate the heating switch S2 according to the predefined XYZ ratio threshold. Then, 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 transmitted through the NFC function. The calculation method of the XYZ ratio is as follows:

[0066]

[0067] Where i represents the 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 the proportion of X exceeds 22%, the proportion of Y exceeds 19%, and the proportion of Z is less than 59%, it is considered to be in a hyperglycemic state.

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

[0069] Refer to Figure 5 In this step, when in use, the patch is attached to the skin surface so that the microneedles penetrate into 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 energy to the patch using NFC technology. The patch monitors the glucose concentration and, after collecting data, can transmit the information to the smartphone, enabling the patient to obtain blood glucose level information and at the same time judge whether the blood glucose level reaches the hyperglycemic threshold. When the threshold is reached, the heater is activated to melt the microneedle protective film and release the drug. When the threshold is not reached, the heater does not need to be activated.

[0070] Example 2

[0071] This example provides a preparation method for an integrated wireless control patch for blood glucose sensing and regulation of an artificial pancreas-like device for glucose monitoring and regulation.

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

[0073] Step 2: Prepare the heater on the flexible circuit substrate using photolithography and electron beam evaporation coating techniques. Clean the polyimide film substrate successively with acetone, isopropyl alcohol, and deionized water, and then dry it with nitrogen. Spin-coat the positive photoresist (S1813) on the substrate at a speed of 4000 rpm for 30 seconds to form a 1.5-μm-thick layer, and then soft-bake it at 90 °C for 1 minute. Using the ultraviolet photolithography technique with a mask, the serpentine electrode pattern was determined under the condition of irradiating at 100 mJ / cm2 for 5 seconds. The exposed photoresist was developed in the MF-319 developer for 30 seconds, rinsed with deionized water, and dried with nitrogen. After hard-baking at 120 °C for 2 minutes, a 40-nm chromium adhesion layer and a 200-nm gold adhesion layer were successively deposited using the electron beam evaporation method. Remove the unwanted metal and photoresist using ultrasonic waves in acetone, leaving the serpentine electrode on the polyimide film.

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

[0075] Step 4: Fix the ultraviolet cut-off filter on the color sensor using epoxy resin glue.

[0076] Step 5: Prepare the sensing microneedles. The microneedle material is selected as biocompatible hydrogels, such as polyvinylpyrrolidone, polyvinyl alcohol, hyaluronic acid, polyethylene glycol, etc. In the present invention, a preparation method of PVP / PVA hydrogel microneedles is provided. First, add PVA powder to distilled water at a ratio of 12 wt%, stir and heat it in a water bath at 95 °C and 1000 rpm for 3 hours until the PVA is completely dissolved to form a viscous transparent solution. After cooling to room temperature, add PVP to the PVA solution according to the mass ratio of PVA to PVP of 3:4, and continue to stir until the PVP is completely dissolved and the solution is clear to prepare the hydrogel solution. Then, add 9-anthracene boronic acid to a 52% ethanol solution to prepare a 0.02 mol / L 9-anthracene boronic acid solution. Then, mix the 9-anthracene boronic acid solution and the PVA / PVP solution according to a volume ratio of 1:1, and stir at 1000 rpm for 15 minutes. After stirring, pour the solution into the PDMS mold, centrifuge and vacuum-treat it to make the solution fully fill the tip of the needle and dry it at 35 °C for 24 hours. After the tip is cured, pour a 12 wt% PVA solution into the mold and continue to dry it at 35 °C for 24 hours as the microneedle base. After the base is cured, peel the entire microneedle in the mold to obtain the sensing microneedles.

[0077] Step 6: Prepare the therapeutic microneedles. The microneedle material is selected as biocompatible hydrogel, such as polyvinylpyrrolidone, polyvinyl alcohol, hyaluronic acid, polyethylene glycol, etc. The upper protective film of the microneedles is selected as a temperature phase change material, such as tridecanoic acid, myristic acid, capric acid, etc. A preparation method of thermosensitive microneedles is provided in the present invention. First, prepare a 12 wt% PVA solution according to Step 5. Then add PVP to the PVA solution at a mass ratio of 2:1 (PVA), and stir until the PVP is completely dissolved to obtain a transparent hydrogel solution. Subsequently, add metformin hydrochloride to the hydrogel solution, with a final concentration of 4 wt%. After stirring, pour the solution into a PDMS mold, centrifuge and vacuum process it to make the solution fully fill the needle tips and dry it in an environment of 35°C for 24 hours. After the needle tips are cured, pour the 12 wt% PVA solution into the mold and continue to dry it in an environment of 35°C for 24 hours as the microneedle substrate. After the substrate is cured, peel the entire microneedle in the mold to obtain the therapeutic microneedles. Heat and melt the solid tridecanoic acid, and spray the liquid tridecanoic acid on the microneedles in a drying oven at 45°C to form a protective layer. Then cool the microneedles to room temperature.

[0078] Step 7: Package the wireless control patch. The patch is packaged in small amounts and multiple times using PDMS (curing conditions: 80°C, 2 hours). Note that too much PDMS packaging should not be allowed to reduce the deformability of the device. The final thickness of the sealing layer is 0.3 - 0.5 mm. At the same time, above the ultraviolet cut-off filter and the heater, a groove is formed using the reverse molding method to place the microneedles, and the depth of the groove is 1 mm.

[0079] Step 8: Slightly moisten the flat side of the microneedle substrate with water, and use the viscosity of the hydrogel itself to embed the microneedles into the reserved groove and dry them. The microneedles will be fixed on the PDMS sealing layer. The final weight of the wireless control patch is about 1.68 g.

[0080] Example 3

[0081] In this example, the wireless control patch was applied to a genetic diabetes mouse model to verify the functions of monitoring glucose concentration changes and regulating blood glucose.

[0082] This example provides an experimental model for monitoring the glucose concentration of mice using an integrated wireless control patch for blood glucose sensing and regulation of an artificial pancreas-like device.

[0083] Step 1: Sterilize the wireless control patch by ultraviolet light.

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

[0085] Step 3: First, fast the mice for 8 hours to keep them at a low blood glucose level. Collect a blood sample from the tail vein first and measure the blood glucose level using a commercial glucometer. At the same time, apply the patch to the back skin of the mice. After 20 minutes, monitor the interstitial fluid glucose concentration using the patch attached to the skin, and directly read the detected fluorescence data with a smartphone. After the measurement, feed the mice adaptively for 3 days.

[0086] Step 4: After the adaptive feeding period, ensure that the mice are in a state of free access to food to keep them at a high blood glucose level. Collect a blood sample from the tail vein first and measure the blood glucose level using a commercial glucometer. At the same time, apply the patch to the back skin of the mice. After 20 minutes, monitor the interstitial fluid glucose concentration using the patch attached to the skin, and directly read the detected fluorescence data with a smartphone.

[0087] Step 5: Compare the data measured by the commercial glucometer and the data measured by the wirelessly controlled patch.

[0088] Figure 6 The experimental results of monitoring the change of glucose concentration in mice with the wirelessly controlled patch are shown. It can be seen that in both high blood glucose and low blood glucose levels, the measurement results of the patch have good followability with those of the commercial glucometer, can accurately represent the blood glucose level of the mice, and realize the function of glucose concentration monitoring.

[0089] The present invention also provides an experimental model for regulating the blood glucose level of mice with an integrated wirelessly controlled patch for blood glucose sensing and regulation of an artificial pancreas-like.

[0090] Step 1: Sterilize the wirelessly controlled patch by ultraviolet light.

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

[0092] Step 3: Fast 20 diabetic model mice for 8 hours and randomly divide them into a blank group, a treatment group, a positive control group, and a control group on average. In the blank group, the mice are allowed to eat freely after two fasting blood glucose measurements. In the treatment group, the mice are measured for blood glucose on an empty stomach twice, allowed to eat freely, and the patch is applied immediately after eating. In the positive control group, fasting is maintained throughout the experiment and the patch is not used; the patch control group maintains fasting and wears the patch immediately after the second fasting blood glucose measurement.

[0093] Step 4: The blood glucose levels of all mice were measured hourly within 12 hours, and a commercial blood glucose meter was used to monitor the changes in blood glucose levels in order to compare the blood glucose dynamics and evaluate the therapeutic effects of the patches among different groups. It can be seen that the blood glucose of the mice in the blank group increased rapidly after eating. The blood glucose of the mice in the treatment group increased after eating, triggering the release of metformin from the patch to achieve the effect of lowering blood glucose. The blood glucose levels of the mice in the positive control group were relatively low due to continuous fasting, and the blood glucose levels of the mice in the control group were also relatively low due to continuous fasting. Although wearing the patch, it did not trigger the release of metformin from the patch, and the blood glucose remained at a relatively low level. From the experimental results, it can be seen that the patch can play a regulatory role in lowering blood glucose at high blood glucose levels.

[0094] Figure 7 The experimental results of regulating the blood glucose of mice with a wirelessly controlled patch are shown. It can be seen that under the free-feeding state, the mice wearing the patch (treatment group) had lower blood glucose levels than the mice not wearing the patch (blank group), and were able to promptly recover from the hypoglycemic state after eating and maintain it for 5-6 hours. Under the fasting state, the blood glucose levels of the mice wearing the patch (control group) and the mice not wearing the patch (positive control group) were in a similar state, indicating that in the hypoglycemic state, the patch did not turn on the heater and did not release the blood glucose-lowering drug.

[0095] 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. An integrated wireless control patch for blood glucose sensing and regulation of a quasi-artificial pancreas, 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 cut-off filter, a color sensor, and an ultraviolet lamp; specifically, after receiving ultraviolet light from the ultraviolet lamp, the flexible hydrogel sensing microneedle array generates fluorescence intensity according to the glucose concentration. The ultraviolet cut-off 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 cut-off filter to obtain fluorescence intensity information, which is fed back to the wireless control circuit; The temperature-sensitive blood glucose regulation unit includes a temperature-sensitive therapeutic microneedle array and a heater; specifically, the substrate of the temperature-sensitive therapeutic microneedle array is a hydrogel, and the surface material of the microneedle tip is a temperature phase-change material. This microneedle array is loaded with hypoglycemic drugs; the heater is located on the lower surface of the temperature-sensitive therapeutic microneedle array, and the upper surface of the temperature-sensitive therapeutic microneedle array is a microneedle array; the heater heats to melt the temperature phase-change material, and the temperature-sensitive therapeutic microneedle array releases hypoglycemic drugs; The wireless control circuit includes a flexible circuit and a near-field communication module; among them, the ultraviolet lamp, the heater, the color sensor, the near-field communication module, and the flexible circuit are all integrated on a flexible polyimide circuit board and encapsulated with 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 regulation 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. The NFC chip generates an analog voltage output through its integrated energy harvesting function to supply power to itself, the data processing center, the color sensor, the ultraviolet lamp, and the heater; after receiving the fluorescence intensity information, the color sensor transmits it to the MCU. After analyzing the fluorescence intensity, the measurement information is transmitted to the smart terminal by NFC, and at the same time, it is 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 and release hypoglycemic materials in a hyperglycemic state.

2. The integrated wireless control patch for blood glucose sensing and regulation of a quasi-artificial pancreas according to claim 1, characterized in that, Centered on the ultraviolet cut-off filter and the heater, a placement groove for the sensing microneedles and the therapeutic microneedles is reserved on the outside of the corresponding encapsulation layer directly above them. The sensing microneedles are embedded in the reserved groove above the ultraviolet cut-off filter, and the therapeutic microneedles are embedded in the reserved groove above the heater, and are fixed by the viscosity of the hydrogel.

3. The integrated wireless control patch for blood glucose sensing and regulation of a quasi-artificial pancreas according to claim 2, characterized in that, The temperature phase-change material is one of tridecanoic acid, myristic acid, and capric acid; the hypoglycemic drug is metformin.

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

5. The integrated wireless control patch for blood glucose sensing and regulation of a quasi-artificial pancreas according to claim 4, characterized in that, The ultraviolet cut-off filter is a 410nm high-pass filter, which blocks ultraviolet light and allows visible light to pass through.

6. The integrated wireless control patch for blood glucose sensing and regulation of a quasi-artificial pancreas 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, with a power consumption of 8mW.

7. An integrated wireless control patch for blood glucose sensing and regulation of a quasi-artificial pancreas 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 optical signal into XYZ tristimulus values; During the measurement of the color sensor, the MCU controls the turning on of the ultraviolet lamp, which is powered by the voltage output from 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 lamp; the MCU determines whether to activate the heater according to 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 feeds them back to the smart terminal; the calculation method of the XYZ ratio is as follows: where i represents the 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. The preparation method of an integrated wireless control patch for blood glucose sensing and regulation of a kind of artificial pancreas-like, characterized in that, It includes the following steps: Step 1: Preparation of the flexible substrate; use software for circuit structure design, and then pattern the polyimide film to obtain the flexible substrate and the wire circuit; Step 2: Prepare the heater on the flexible substrate using photolithography and electron beam evaporation coating technology, then clean the flexible substrate and dry it with nitrogen; Specifically, spin-coat the photoresist on the substrate, and use ultraviolet photolithography technology with a mask to determine the serpentine electrode pattern; use electron beam evaporation to deposit the chromium adhesion layer and the gold adhesion layer in sequence, remove the unnecessary metal and photoresist in acetone using ultrasonic waves, and leave the serpentine electrode on the polyimide film; Step 3: Integrate the ultraviolet lamp, color sensor, MCU, and NFC chip on the flexible substrate using reflow soldering technology; Step 4: Fix the ultraviolet cut-off filter on the color sensor using epoxy resin glue; Step 5: Prepare the sensing microneedles; select a biocompatible hydrogel as the microneedle material to prepare a hydrogel solution, then mix and stir the 9-anthracene boronic acid solution and the hydrogel solution. After stirring, pour the solution into a mold, centrifuge and vacuum process it to make the solution fully fill the tip of the needle and then dry it. After the tip is cured, pour the hydrogel solution into the mold and continue to dry it as the microneedle base. After the base is cured, peel off the entire microneedle in the mold to obtain the sensing microneedle array; Step 6: Prepare the therapeutic microneedles; select a biocompatible hydrogel to prepare a hydrogel solution, then add metformin to the hydrogel solution with a final concentration of 4wt%, mix and stir. After stirring, pour the solution into a mold, centrifuge and vacuum process it to make the solution fully fill the tip of the needle and dry it. After the tip is cured, pour the hydrogel solution into the mold and continue to dry it as the microneedle base; after the base is cured, peel off the entire microneedle in the mold; then heat and melt the solid temperature phase change material, spray the temperature phase change material liquid on the microneedles in a drying oven at 45°C, and then cool the microneedles to room temperature to obtain the therapeutic microneedle array; Step 7: Encapsulation of the wireless control patch; use polydimethylsiloxane to encapsulate the flexible substrate, i.e., the devices integrated on the surface. At the same time, respectively with the ultraviolet cut-off filter and the heater as the center, use the reverse molding method to reserve placement grooves for the sensing microneedles and the therapeutic microneedles outside the corresponding encapsulation layer directly above them to place the microneedle array; Step 8: Moisten the planar side of the microneedle array substrate with water, embed the microneedle array into the reserved groove and then dry it, and fix the microneedles on the polydimethylsiloxane sealing layer.

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