Microneedle system for continuous blood glucose monitoring

Abstract

The invention discloses a microneedle system for continuous blood glucose monitoring, which comprises a microneedle array, an electrode system, a circuit connection and signal acquisition unit and a fixing and packaging structure, the working electrode is used for penetrating into the skin and making contact with intertissue fluid to control the diffusion speed of glucose and prevent glucose oxidase from losing, the surface of the working electrode is wrapped with glucose oxidase cross-linked and fixed through glutaraldehyde, one end of the electrode system is inserted into the microneedle, and the other end of the electrode system is connected with the circuit connection and signal acquisition unit. The fixing and packaging structure is arranged on the outer side of the circuit connecting and signal collecting unit and used for wrapping the electronic device and fixing the microneedle system to the skin surface. According to the microneedle system for continuous blood glucose monitoring, rapid and accurate detection of in-vivo blood glucose level changes is achieved, and minimally invasive property and good patient compliance can be achieved while the detection sensitivity and accuracy are guaranteed.

Description

Technical Field

[0001] This invention relates to the field of percutaneous microneedling technology, and more particularly to a microneedling system for continuous blood glucose monitoring. Background Technology

[0002] Continuous and accurate blood glucose monitoring technology is crucial for blood glucose management, especially for diabetic patients. The precise dosage of essential medications like insulin depends on real-time monitoring of blood glucose levels to avoid the risk of hypoglycemia. However, currently, clinically feasible continuous and accurate blood glucose monitoring primarily relies on invasive methods, involving the collection of blood or endocrine fluids with concentrations close to blood glucose. While these methods offer high sensitivity, they generally suffer from poor patient compliance, require the insertion of a 5 mm probe subcutaneously, and involve a ejector device to insert the glucose sensor probe into the body, causing significant patient resistance. Furthermore, the probe is connected to a sensor chip, which is discarded along with the probe after two weeks of use, making it overly wasteful.

[0003] Non-invasive blood glucose monitoring methods have also been explored extensively. For example, detection is performed using exocrine fluids such as sweat, urine, saliva, and tears, or blood glucose estimation is based on changes in body temperature and near-infrared diffuse reflectance signals. However, because the glucose concentration in exocrine fluids is significantly lower than in blood, even slight detection errors can lead to large deviations, resulting in low accuracy. Optical methods, on the other hand, not only lack sufficient accuracy and specificity, but these devices often rely on complex optical components and prior data modeling, resulting in bulky and expensive equipment. Furthermore, the detection process is easily affected by skin color, temperature, and ambient light, leading to poor stability and hindering long-term wearable applications and frequent daily monitoring.

[0004] To address the aforementioned issues, minimally invasive testing has emerged as a potentially viable approach. For example, Echo Therapeutics in the United States developed a "skin abrasion" method that removes the epidermis, allowing dermal fluid to seep out, and then implants a sensor chip on the wound for detection. This method addresses the sensitivity issue of non-invasive methods to some extent, but still has shortcomings: First, the skin abrasion process may cause patient resistance; second, during sensor construction, glucose oxidase needs to be immobilized on the electrode surface. Due to the limited number of electrode reaction sites, it is difficult to load sufficient enzyme protein, leading to a deviation in reaction kinetics from concentration dependence and an inability to accurately respond to changes in blood glucose levels; furthermore, there is the problem of insufficient protein conformational stability during enzyme immobilization, as the enzyme conformation is easily inactivated during immobilization, affecting long-term stability.

[0005] Other studies have attempted to use ultrasound to collect interstitial fluid through the epidermis and then transport the fluid to an electrochemical reaction cell for detection via a microfluidic channel. Such devices typically require an additional ultrasound acquisition module and a microfluidic transport channel, resulting in complex structures and high manufacturing costs. Furthermore, the amount of interstitial fluid collected through an intact epidermis is limited, making it difficult to maintain stable operation of the electrochemical reaction cell, leading to insufficient signal response and preventing the achievement of high-sensitivity, continuous monitoring. Summary of the Invention

[0006] In view of the aforementioned shortcomings of existing technologies, the technical problem to be solved by this invention is that existing blood glucose monitoring technologies suffer from complex structures, high costs, poor patient compliance, discomfort or damage, and high long-term usage costs. This invention provides a microneedle system for continuous blood glucose monitoring, which utilizes a microneedle array and electrochemical electrodes to construct a stable interstitial fluid detection interface, enabling rapid and accurate detection of changes in blood glucose levels in the body. It ensures both detection sensitivity and accuracy while also being minimally invasive and providing good patient compliance.

[0007] To achieve the above objectives, the present invention provides a microneedle system for continuous blood glucose monitoring, comprising a microneedle array, an electrode system, a circuit connection and signal acquisition unit, and a fixation and encapsulation structure. The microneedle array is made of a biocompatible material and is used to penetrate the skin and contact the interstitial fluid, control the glucose diffusion rate, and prevent glucose oxidase loss. One end of the electrode system is disposed inside the microneedle, and the other end is connected to the circuit connection and signal acquisition unit. The fixation and encapsulation structure is disposed outside the circuit connection and signal acquisition unit and is used to encapsulate electronic devices and fix the microneedle system to the skin surface.

[0008] Furthermore, the microneedle array is made of a highly compatible polyurethane polymer material, and glucose oxidase is immobilized on the electrode surface via glutaraldehyde crosslinking to form a stable enzyme immobilization layer, allowing glucose and its reaction products to diffuse freely and participate in the electrochemical reaction, while inhibiting enzyme loss during continuous monitoring.

[0009] Furthermore, the microneedle array material is a polymer material, polyurethane, which provides sufficient mechanical strength and a stable interstitial fluid contact interface, stabilizes the glucose diffusion rate, and prevents enzymes from being lost from the microneedles.

[0010] Furthermore, the length of the hydrogel microneedles is set to 500-1000 μm, the bottom diameter to 200-300 μm, and the array density to 5-10 microneedles / cm².

[0011] Furthermore, glucose oxidase immobilization methods include covalent immobilization via glutaraldehyde, which is used to cross-link the amino groups of glucose oxidase to improve immobilization stability and detection consistency.

[0012] Furthermore, the electrode system includes one or more working electrodes, a reference electrode, and a control electrode, wherein the electrodes are configured as metal wires or thin-film printed electrodes with a diameter smaller than that of a microneedle; wherein the working electrode contains glucose oxidase, while the control electrode and the reference electrode do not contain glucose oxidase.

[0013] Furthermore, the working electrode is set as a solid metal rod.

[0014] Furthermore, the working electrode is made of one of the following materials: Pt, Au, Ag / AgCl, or carbon-based materials.

[0015] Furthermore, the mechanical strength of a single hydrogel microneedle is greater than 1N, enabling it to be inserted into the skin without breaking and maintain stable contact with the interstitial fluid.

[0016] Technical effect

[0017] This invention provides a microneedle system for continuous blood glucose monitoring, which significantly improves technical, economic, and social benefits. Details are as follows:

[0018] (a) Technical effects

[0019] Minimally invasive and improved compliance: This invention uses a microneedle array, which only needs to penetrate the epidermis to the superficial dermis to come into contact with the interstitial fluid, avoiding the strong discomfort and poor compliance problems caused by traditional 5 mm long probe deep implantation.

[0020] High sensitivity and real-time performance: Glucose oxidase is stably immobilized on the surface of microneedles or working electrodes through glutaraldehyde cross-linking, forming an efficient enzyme reaction interface. This allows glucose to diffuse rapidly and participate in electrochemical reactions, ensuring that the reaction current and blood glucose concentration maintain a good linear correlation within the physiological range, thereby achieving real-time and sensitive detection of blood glucose changes.

[0021] Simplified structure and miniaturization: The electrochemical reaction cell is "embedded" in the microneedle, eliminating the need for large external optical or ultrasonic equipment, making the whole device small and lightweight, and easy to wear for a long time and for continuous monitoring.

[0022] Enhanced signal stability: Covalent fixation of glucose oxidase with glutaraldehyde improves the stability of the enzyme under continuous working conditions and reduces signal drift caused by enzyme shedding and activity decay; at the same time, the reference electrode and control electrode correct background interference, ensuring long-term stable and reliable output current signal.

[0023] (II) Economic Effects

[0024] Reduced usage costs: The microneedles of this invention have sufficient mechanical strength to penetrate the skin without the need for a ejection device.

[0025] The preparation process is simple: microneedles and their electrode structures can be prepared by conventional pressing, injection molding or surface modification processes. The process conditions are mild, the raw materials are common and inexpensive, which is conducive to large-scale production.

[0026] Easy maintenance: The device requires no complex calibration or expensive consumables, and users can attach and replace it themselves, reducing the economic burden on medical systems and individuals.

[0027] (III) Social Impact

[0028] Improving patients' quality of life: Minimally invasive and comfortable continuous monitoring methods improve patient compliance, help diabetic patients better control their blood sugar, and reduce the incidence of complications.

[0029] Facilitating personalized medicine: Real-time blood glucose monitoring data can be applied to insulin pumps and mobile terminals to enable intelligent drug delivery and personalized treatment plans, thereby improving treatment outcomes.

[0030] Social and public health value: By reducing monitoring costs and improving ease of use, this invention is expected to promote the popularization of blood glucose monitoring and reduce the socioeconomic burden caused by diabetes and related metabolic diseases.

[0031] Furthermore, the applications of blood glucose monitoring are not limited to diabetes management. Research in this field shows that patients with malignant tumors such as pancreatic cancer often have glucose metabolism disorders, and continuous glucose monitoring helps in assessing disease progression and treatment efficacy. In addition, continuous glucose monitoring can benefit daily health management, obesity and metabolic syndrome assessment, and the diagnosis and treatment of various endocrine diseases such as thyroid diseases, adrenal diseases, and Cushing's syndrome. Therefore, developing a blood glucose monitoring platform that combines high precision, minimal invasiveness, and applicability to multiple scenarios has significant clinical and social value.

[0032] The following will further explain the concept, specific structure, and technical effects of the present invention in conjunction with the accompanying drawings, so as to fully understand the purpose, features, and effects of the present invention. Attached Figure Description

[0033] Figure 1 This is a schematic diagram of a microneedle system for continuous blood glucose monitoring according to a preferred embodiment of the present invention; A shows the connection between the blood glucose monitoring microneedle and the current sensor; B is a schematic diagram of the blood glucose monitoring microneedle patch, including a working electrode microneedle, a reference electrode microneedle and a control electrode microneedle, wherein the working electrode microneedle contains glucose oxidase and Pt, the reference electrode microneedle contains an Ag / AgCl electrode, and the control electrode microneedle contains only a Pt electrode;

[0034] Figure 2A preferred embodiment of the present invention is a microneedle system for continuous blood glucose monitoring. The current value generated by the reaction with glucose solution at 37 °C shows a good linear relationship with the glucose concentration. Detailed Implementation

[0036] To make the technical problems to be solved, the technical solutions, and the beneficial effects of the present invention clearer, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0037] In the following description, specific details, such as particular internal procedures and techniques, are set forth for illustrative purposes and not for limitation, in order to provide a thorough understanding of the embodiments of the invention. However, those skilled in the art will appreciate that the invention may be practiced in other embodiments without these specific details. In other instances, detailed descriptions of well-known systems, apparatuses, circuits, and methods have been omitted so as not to obscure the description of the invention with unnecessary detail.

[0038] like Figure 1 As shown, this invention provides a microneedle system for continuous blood glucose monitoring, comprising a microneedle array, an electrode system, a circuit connection and signal acquisition unit, and a fixation and encapsulation structure. The microneedle array is made of biocompatible polyurethane and is used to penetrate the skin and contact interstitial fluid, stabilize the glucose diffusion rate, and prevent enzyme loss from the microneedles. The microneedles with working electrodes contain glucose oxidase fixed by glutaraldehyde crosslinking, while the reference and control electrodes do not contain glucose oxidase. One end of the electrode system is disposed within the microneedle array, and the other end is connected to the circuit connection and signal acquisition unit. The fixation and encapsulation structure is disposed outside the circuit connection and signal acquisition unit and is used to encapsulate electronic components and fix the microneedle system to the skin surface.

[0039] The working electrode is composed of platinum, gold, or platinum or gold plated on stainless steel. The electrode array is immersed in a buffer solution containing glutaraldehyde (glutaraldehyde concentration 0.1–2.5 wt%, pH 6.5–7.4) for 30–120 minutes to allow glutaraldehyde molecules to bind to the active groups on the microneedle material or electrode surface. The microneedles are then removed and thoroughly washed with buffer solution to remove unreacted glutaraldehyde. The treated microneedle array is then immersed in a glucose oxidase solution (enzyme concentration 50 mg / mL) and reacted at 4°C for 2–12 hours. Glutaraldehyde molecules undergo a condensation reaction with the amino groups in glucose oxidase molecules to form a covalent cross-linked structure, thereby forming a stable enzyme immobilization layer inside the microneedles or on the working electrode surface. After cross-linking, unimmobilized enzyme molecules are removed by washing with buffer solution. The formation of a stable enzyme immobilization layer on the working electrode surface allows glucose to diffuse from the interstitial fluid to the enzyme reaction interface and participate in the electrochemical reaction, while simultaneously inhibiting enzyme loss during continuous monitoring. The microneedles are set with a length of 500-1000 μm, a base diameter of 200-300 μm, and an array density of 5-10 needles / cm², enabling them to penetrate the epidermis and extend into the superficial dermis, achieving continuous blood glucose monitoring without causing significant pain or tissue damage. Each microneedle has a mechanical strength greater than 1 N, maintaining structural integrity during attachment.

[0040] The outer side of the glucose oxidase immobilization layer on the working electrode surface, as well as the control and reference electrodes, are further coated with a biocompatible polyurethane (PU) polymer material, forming a composite structure of electrode-enzyme layer-polyurethane outer coating. The polyurethane outer coating can be formed by solution coating, dip coating, spraying, and casting, with a thickness of 0.5–10 μm. The polyurethane outer coating limits the diffusion rate of glucose to the electrode reaction interface, prevents enzyme saturation, and maintains the linear relationship between the reaction rate and glucose concentration. Simultaneously, it inhibits the loss of glucose oxidase and blocks electroactive interferences and large protein molecules from entering the reaction interface, thereby improving the stability, repeatability, and biocompatibility of the current signal during long-term monitoring.

[0041] The electrode system includes one or more working electrodes, a reference electrode, and a control electrode. The working electrodes are configured as metal wire or thin-film printed electrodes with a diameter smaller than the microneedles. The working and control electrodes are made of metal wire electrodes (platinum, gold, or platinum or gold plated on stainless steel), and the reference electrode is Ag / AgCl. In this embodiment, the working, control, and reference electrodes are all contained within the microneedles. The working electrodes contain glucose oxidase, while the control and reference electrodes do not. The reaction is based on electrochemical principles; glucose enters the working electrode and reacts with the enzyme to generate electrons. The control electrode does not contain enzymes or electrons and therefore serves as a reference. The working and control electrodes are not connected. In this embodiment, 3-10 microneedles are used for the working electrode, 1-3 microneedles for the control electrode, and 1 microneedle for the reference electrode.

[0042] Working electrode: Inserted into a microneedle loaded with glucose oxidase, electron transfer occurs during the reaction, generating a measurable current; control electrode and reference electrode are inserted into microneedles without enzyme, used for baseline signal reference, and to eliminate other electrochemical interferences.

[0043] Electrochemical reaction: Glucose in the interstitial fluid diffuses into the microneedle where the working electrode is located, and undergoes an oxidation reaction under the catalysis of glucose oxidase to generate gluconolactone and produce electrons. The electrons form a measurable current signal on the surface of the working electrode, and the current intensity is proportional to the blood glucose concentration.

[0044] The other end of the electrodes in the microneedle array is connected to a current sensor for data acquisition and reading, which includes four parts: an amplification module, an analog-to-digital conversion module, a Bluetooth communication module, and a power management module.

[0045] The current sensing circuit is based on the high-performance operational amplifier ADA4530, which amplifies the output voltage of the current sensor. The low-power ADC chip AD7988 digitizes the output analog voltage value and communicates with the subsequent MCU via an SPI interface. The STM32WBA6 is an MCU module that not only contains the core central processing unit, but its wireless subsystem supports 2.4GHz network protocols such as Bluetooth, Zigbee, Thread, and Matter, allowing the device to communicate using multiple protocols simultaneously. The LTC3335 is a low-power DC-DC power supply that converts battery voltage to a constant output voltage. The LTC3335 also includes a coulomb counter to report the accumulated charge from the battery. This information can be read using an I2C interface and then used as a predictor of when the battery might need replacing. The LT6656 is a reference voltage source used to provide a stable reference power to the operational amplifier and ADC. A switch controls the shutdown of the LTC3335, enabling manual shutdown of the module.

[0046] The fixing and encapsulation structure is located on the back of the sensor and is provided with a medical-grade adhesive film to firmly attach the sensor of the present invention to the skin surface, while ensuring electrical contact between the electrodes and the external acquisition unit.

[0047] In this embodiment of the invention, the electrode is placed in the microneedle, and the microneedle, electrode and sensor are replaced together.

[0048] The following specific embodiments will illustrate the preparation and usage methods of a microneedle system for continuous blood glucose monitoring according to the present invention.

[0049] This invention provides a microneedle system for continuous blood glucose monitoring. The microneedles of the continuous blood glucose monitoring microneedle system are inserted into the skin. Glucose from the tissue fluid enters the microneedles and reacts with glucose oxidase and electrodes to generate an electrical signal. This electrical signal is collected by electronic components and transmitted to a mobile phone or other mobile terminal via Bluetooth, allowing the user to directly visualize the blood glucose value. Figure 2 As shown, the microneedle system for continuous blood glucose monitoring of the present invention exhibits a good linear relationship between the current value generated by the reaction with glucose solution at 37 ℃ and the glucose concentration. This indicates that the microneedle system can respond sensitively to changes in glucose concentration within a physiologically relevant range. In this embodiment, the glucose solution concentration range used in the experiment was 1–30 mM, covering the physiological and pathological ranges of hypoglycemia, normal blood glucose, and hyperglycemia; and the steady-state current signal of the working electrode was recorded under a constant temperature of 37 ℃. The current signal monotonically increases with increasing glucose concentration and shows an approximately linear relationship within the concentration range, indicating that the microneedle system of the present invention has good sensitivity and quantitative detection capability. To further verify the effectiveness of the microneedle system of the present invention in actual use, after completing the above calibration experiment, the same microneedle system was repeatedly used in an experiment. Specifically, after completing one glucose detection, the microneedle system was washed with buffer solution and used again for detection of glucose solutions of different concentrations. The obtained current signal remained highly consistent with the initial test results, indicating that the glucose oxidase immobilization layer and the polyurethane outer coating did not experience significant enzyme loss or performance degradation during use. In summary, combined with Figure 2 The experimental results shown demonstrate that the microneedle system for continuous blood glucose monitoring provided by this invention can respond stably and accurately to changes in glucose concentration under physiologically relevant conditions. The method and device have good repeatability, stability, and practicality, and are suitable for continuous blood glucose monitoring applications.

[0050] The preferred embodiments of the present invention have been described in detail above. It should be understood that those skilled in the art can make numerous modifications and variations based on the concept of the present invention without creative effort. Therefore, all technical solutions that can be obtained by those skilled in the art based on the concept of the present invention through logical analysis, reasoning, or limited experimentation on the basis of existing technology should be within the scope of protection defined by the claims.

Claims

1. A microneedle system for continuous blood glucose monitoring, characterized in that, The device includes a microneedle array, an electrode system, a circuit connection and signal acquisition unit, and a fixation and encapsulation structure. The microneedle array is made of a biocompatible material and is used to penetrate the skin and contact the interstitial fluid to control the glucose diffusion rate and prevent glucose oxidase loss. One end of the electrode system is located inside the microneedle array, and the other end is connected to the circuit connection and signal acquisition unit. The fixation and encapsulation structure is located outside the circuit connection and signal acquisition unit and is used to encapsulate electronic devices and fix the microneedle system to the skin surface.

2. The microneedle system for continuous blood glucose monitoring as described in claim 1, characterized in that, The microneedles are formed by compression molding and injection molding. The microneedles are made of a well-compatible polyurethane polymer material. Glucose oxidase is fixed on the electrode surface by glutaraldehyde crosslinking.

3. A microneedle system for continuous blood glucose monitoring as described in claim 2, characterized in that, The microneedle array material is a polymer material used to provide the mechanical strength required for insertion into the skin, a stable interstitial fluid contact interface, control the glucose diffusion rate, and prevent the loss of glucose oxidase.

4. A microneedle system for continuous blood glucose monitoring as described in claim 2, characterized in that, The length of the hydrogel microneedles is set to 500-1000 μm, the bottom diameter to 200-300 μm, and the array density to 5-10 microneedles / cm².

5. A microneedle system for continuous blood glucose monitoring as described in claim 2, characterized in that, The glutaraldehyde is used to covalently immobilize glucose oxidase on the electrode surface to form a stable enzyme immobilization layer. The enzyme immobilization layer maintains catalytic activity and provides a stable electrochemical response signal during continuous blood glucose monitoring.

6. A microneedle system for continuous blood glucose monitoring as described in claim 1, characterized in that, The electrode system includes one or more working electrodes, a reference electrode, and a control electrode, wherein the electrodes are configured as metal wires or thin-film printed electrodes with a diameter smaller than a microneedle; wherein the working electrode contains glucose oxidase that is cross-linked and fixed with glutaraldehyde, while the control electrode and the reference electrode do not contain glucose oxidase.

7. A microneedle system for continuous blood glucose monitoring as described in claim 6, characterized in that, The working electrode is a solid metal rod.

8. A microneedle system for continuous blood glucose monitoring as described in claim 6, characterized in that, The working electrode is made of one of the following materials: Pt, Au, Ag / AgCl, or carbon-based materials.

9. A microneedle system for continuous blood glucose monitoring as described in claim 4, characterized in that, The hydrogel microneedles have a single microneedle mechanical strength greater than 1N, enabling them to be inserted into the skin without breaking and maintain stable contact with the interstitial fluid.

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