A closed-loop insulin control system based on microneedle array patch

Abstract

The application discloses a closed-loop insulin controlled-release system based on a microneedle array patch. The method for realizing the closed-loop insulin controlled-release comprises the following steps: monitoring blood glucose concentration by using a glucose microneedle sensor in the system; when the blood glucose concentration is too high, the subcutaneous release state of insulin is regulated by applying a voltage on the insulin controlled-release microneedle; wherein each insulin controlled-release microneedle has an independent current path, so that each microneedle is individually addressed, and the release of single or multiple insulin can be regulated; and the insulin gel part of the insulin controlled-release microneedle comprises insulin, sodium alginate and metal ions. The closed-loop insulin controlled-release system based on the microneedle array patch discloses an insulin closed-loop system suitable for diabetic patients, can continuously monitor blood glucose, and realizes active control of insulin release by electric triggering when the blood glucose concentration is relatively high, and has the advantages of convenience, minimally invasive and controllability.

Description

Technical Field

[0001] This invention belongs to the field of medical monitoring and treatment instrument technology, specifically relating to a closed-loop insulin controlled release system based on microneedle array patches. Background Technology

[0002] Diabetes mellitus is a chronic disease characterized by hyperglycemia, caused by an absolute or relative deficiency of insulin secretion and impaired utilization. Globally, both the incidence and prevalence of diabetes are on the rise.

[0003] Currently, the main treatment for patients with type 1 diabetes, gestational diabetes, and some types 2 diabetes is to lower blood sugar through insulin injections via pumps or pens before meals and bedtime. Injection dosages are often controlled empirically, making it difficult to ascertain whether blood sugar levels stabilize within the normal range after injection. Furthermore, repeated injections can easily cause pain, fear, and wound infections in patients. Therefore, diabetic patients need less invasive and more precise insulin delivery methods to change this situation. Microneedle technology is a novel drug delivery technique that can penetrate the stratum corneum painlessly and minimally invasively to deliver drugs to the epidermis or upper dermis to exert their pharmacological effects. Microneedle delivery of insulin avoids the destruction of insulin by digestive enzymes associated with oral administration and the skin trauma caused by subcutaneous injection. However, how to accurately control the dosage and timing of administration remains a significant concern. Researchers have already developed insulin-releasing microneedle patches that respond to blood glucose concentrations; insulin release is faster when blood glucose levels are high and slower when blood glucose levels are low. While this patch is convenient and helps stabilize blood sugar to some extent, it cannot determine the remaining amount of insulin in the microneedle patch, when it will run out, or whether it is sufficient. This makes it unsuitable as a tool for long-term, continuous insulin delivery.

[0004] For the widespread application of microneedling technology in the treatment of diabetes, guiding the precise timing of insulin release and effectively controlling the insulin release dose are crucial conditions. Summary of the Invention

[0005] To address the problems existing in the background art, the present invention provides an insulin-controlled release microneedle array patch with electrochemical response, which, combined with a dynamic blood glucose monitoring microneedle array patch, provides guidance on the release timing during hyperglycemia, enabling long-term continuous blood glucose management for diabetic patients.

[0006] The technical solution adopted in this invention is:

[0007] A closed-loop insulin controlled release system based on microneedle array patches includes a control circuit module, an insulin controlled release microneedle array patch, and a dynamic blood glucose monitoring microneedle array patch.

[0008] The insulin-controlled release microneedle array patch includes a first flexible electrode sheet, a first reference electrode, and insulin-controlled release microneedle electrodes distributed in an array on the first flexible electrode sheet. The insulin-controlled release microneedle electrodes use metal needles as a substrate, and a gel network formed by cross-linking sodium alginate with metal ions is covered on the surface of the metal needles. Insulin is encapsulated in the gel network. All electrodes on the first flexible electrode sheet are connected to a control circuit module through an independent first current path. The control circuit module addresses each insulin-controlled release microneedle electrode individually and independently controls the reduction voltage applied to the insulin-controlled release microneedle electrode to release insulin.

[0009] The dynamic blood glucose monitoring microneedle array patch includes a second flexible electrode sheet, a second reference electrode, and dynamic blood glucose monitoring microneedle electrodes distributed in an array on the second flexible electrode sheet. Each electrode on the second flexible electrode sheet is connected to the control circuit module through an independent second current path. The control circuit module addresses each dynamic blood glucose monitoring microneedle electrode individually, independently controls the working voltage applied to the dynamic blood glucose monitoring microneedle electrode, and records the current value on different dynamic blood glucose monitoring microneedle electrodes during the addressing process.

[0010] Preferably, the preparation method of the insulin-controlled release microneedle electrode is as follows: using a metal needle as the working electrode, a silver / silver chloride electrode as the reference electrode, and a platinum electrode as the counter electrode, the three electrodes are immersed in a solution containing sodium alginate, insulin, and ferrous sulfate, and insulin-controlled release microneedles covered with insulin gel are obtained by constant current electrolysis.

[0011] Preferably, the method for preparing the insulin-controlled release microneedle electrode is as follows: a copper-plated metal needle is used as the working electrode, a silver / silver chloride electrode is used as the reference electrode, and a platinum electrode is used as the counter electrode. The three electrodes are immersed in a solution containing sodium alginate and insulin, and insulin-controlled release microneedles covered with insulin gel are obtained by constant current electrolysis.

[0012] Preferably, the reduction voltage applied to the insulin-controlled release microneedle electrode for releasing insulin is -1.0 to -2.0V.

[0013] Preferably, the dynamic blood glucose monitoring microneedle electrode uses a metal needle as the substrate, and the surface of the metal needle is sequentially covered with a platinum layer, an o-phenylenediamine layer, a glucose oxidase layer, a chitosan layer, and a polyurethane layer.

[0014] Preferably, the working voltage applied to the microneedle electrode for dynamic blood glucose monitoring is +0.2 to +1.0V.

[0015] Preferably, the first flexible electrode sheet of the insulin-controlled release microneedle array patch is provided with a first pair of electrodes in addition to the first reference electrode. The first pair of electrodes is also connected to the control circuit module through an independent first current path, thereby forming a three-electrode system with the insulin-controlled release microneedle electrode.

[0016] Preferably, the second flexible electrode of the dynamic blood glucose monitoring microneedle array patch is provided with a second pair of electrodes in addition to the second reference electrode. The second pair of electrodes is also connected to the control circuit module through an independent second current path, thereby forming a three-electrode system with the dynamic blood glucose monitoring microneedle electrode.

[0017] Preferably, the control circuit module has an interactive display interface for displaying control parameters and detection parameters, or a communication module for data interaction with external devices, or a feedback control module for controlling the release of insulin from the insulin-controlled release microneedle array patch based on the blood glucose concentration detected by the dynamic blood glucose monitoring microneedle array patch.

[0018] Preferably, the metal needle is a gold needle, a platinum needle, or a stainless steel needle.

[0019] Compared with the prior art, the beneficial effects of the present invention are:

[0020] 1. The closed-loop insulin controlled release system based on microneedle array patch of the present invention provides a way to regulate insulin release by using an electric field. By adjusting the voltage through a circuit board, metal ions in the insulin controlled release gel are reduced, the degree of gel cross-linking is reduced, and insulin is released into the subcutaneous tissue, thereby realizing automatic and controllable continuous insulin delivery.

[0021] 2. The closed-loop insulin controlled release system based on microneedle array patches of the present invention is equipped with a dynamic blood glucose monitoring module, which, together with the insulin release module, completes the closed-loop management of blood glucose concentration. It is a closed-loop insulin controlled release system that is miniaturized, convenient, comfortable, and minimally invasive.

[0022] 3. The insulin microneedles used in the closed-loop insulin controlled release system based on microneedle array patches of the present invention have metal needles with good mechanical properties, which facilitates subcutaneous drug delivery by puncturing the skin. The replaceable design of the patch ensures the long-term use of the microneedle array patch. Attached Figure Description

[0023] Figure 1 This is a schematic diagram of the overall structure of a closed-loop insulin controlled release system.

[0024] Figure 2 This is a schematic diagram of the structure of an insulin controlled-release microneedle patch.

[0025] Figure 3This is a schematic diagram of the glucose-sensitive microneedles in a dynamic blood glucose monitoring microneedle patch.

[0026] Figure 4 The results are the test results of the current response in the embodiments of the present invention.

[0027] Figure 5 These are the glucose response curves measured by the electrochemical workstation and the flexible circuit board, respectively, in an embodiment of the present invention.

[0028] Figure 6 This is another test result of the current response in an embodiment of the present invention.

[0029] Figure 7 This is the real-time monitoring result of the current signal on the rat in this embodiment of the invention.

[0030] Figure 8 These are images showing the state of the trivalent iron insulin gel at different times after drying in an embodiment of the present invention.

[0031] Figure 9 The results are fluorescence observations under a fluorescence microscope during the insulin release experiment in this embodiment of the invention. Detailed Implementation

[0032] To make the above-mentioned objects, features, and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings. Many specific details are set forth in the following description to provide a thorough understanding of the present invention. However, the present invention can be practiced in many other ways different from those described herein, and those skilled in the art can make similar modifications without departing from the spirit of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below. Technical features in various embodiments of the present invention can be combined accordingly without mutual conflict.

[0033] In the description of this invention, it should be understood that when an element is considered to be "connected" to another element, it can be a direct connection to the other element or an indirect connection, i.e., there is an intermediate element. Conversely, when an element is said to be "directly" connected to another element, there is no intermediate element.

[0034] In the description of this invention, it should be understood that the terms "first" and "second" are used only for descriptive purposes and should not be construed as indicating or implying relative importance or implicitly specifying the number of indicated technical features. Therefore, a feature defined with "first" and "second" may explicitly or implicitly include at least one of those features.

[0035] See Figure 1As shown, in a preferred embodiment of the present invention, a closed-loop insulin controlled-release system based on a microneedle array patch is provided. The system comprises a control circuit module 1, an insulin controlled-release microneedle array patch 2, and a dynamic blood glucose monitoring microneedle array patch 3. The control circuit module 1 serves as the main control module of the entire system, controlling the operating states of the insulin controlled-release microneedle array patch 2 and the dynamic blood glucose monitoring microneedle array patch 3. The insulin controlled-release microneedle array patch 2 releases insulin under the control of the control circuit module 1, while the dynamic blood glucose monitoring microneedle array patch 3 monitors blood glucose concentration in real time under the control of the control circuit module 1. The structural form and working principle of the insulin controlled-release microneedle array patch 2 and the dynamic blood glucose monitoring microneedle array patch 3 are described in detail below.

[0036] See Figure 2 As shown, the insulin-controlled release microneedle array patch 2 includes a first flexible electrode sheet 21, a first reference electrode, and insulin-controlled release microneedle electrodes 22 distributed in an array on the first flexible electrode sheet 21. The insulin-controlled release microneedle electrodes 22 use metal needles as a substrate, with a gel network formed by cross-linking sodium alginate with metal ions covering the surface of the metal needles. Insulin is encapsulated within this gel network. All electrodes on the first flexible electrode sheet 21, including the first reference electrode and the insulin-controlled release microneedle electrodes 22, are each connected to the control circuit module 1 via an independent first current path 23. The control circuit module 1 addresses each insulin-controlled release microneedle electrode 22 individually and independently controls the reduction voltage applied to the insulin-controlled release microneedle electrode 22 for insulin release.

[0037] It should be noted that in the above-mentioned insulin-controlled release microneedle array patch 2, the first reference electrode can form a two-electrode system with each insulin-controlled release microneedle electrode 22. However, in other embodiments, another first pair of electrodes (which can be platinum electrodes) can be provided on the first flexible electrode sheet 21 in addition to the first reference electrode. The first pair of electrodes is also connected to the control circuit module 1 through an independent first current path 23, thereby forming a three-electrode system with the insulin-controlled release microneedle electrodes 22. Both the two-electrode system and the three-electrode system can achieve the technical effects of the present invention.

[0038] In embodiments of the present invention, the preparation method of the above-mentioned insulin-controlled release microneedle electrode 22 can be achieved in two ways. The first method involves immersing a metal needle as the working electrode, a silver / silver chloride electrode (Ag / AgCl) as the reference electrode, and a platinum electrode as the counter electrode in a solution containing sodium alginate, insulin, and ferrous sulfate. Insulin-gel-coated insulin-controlled release microneedles are obtained through constant current electrolysis (preferably 30 μA constant current electroplating for 60 s). The second method involves immersing a copper-plated metal needle as the working electrode, a silver / silver chloride electrode as the reference electrode, and a platinum electrode as the counter electrode in a solution containing sodium alginate and insulin. Insulin-gel-coated insulin-controlled release microneedles are obtained through constant current electrolysis (preferably 30 μA constant current electroplating for 60 s). Both methods can form a gel network on the surface of the metal needle, consisting of sodium alginate cross-linked with metal ions and encapsulating insulin. However, the metal ions are different. In the first method, the metal ions are ferric ions, and in the second method, they are divalent copper ions. These high-valence ions exchange ions with sodium ions in sodium alginate, causing sodium alginate units to stack and form a cross-linked network structure, thereby encapsulating insulin molecules. In this invention, the insulin-releasing gel cross-linked with ferric ions, as described in the first implementation method, is preferred.

[0039] In practical applications, the insulin release method of the aforementioned insulin-controlled release microneedle electrode 22 is as follows: Using the insulin-controlled release microneedle electrode 22 as the working electrode and the silver / silver chloride electrode as the reference and counter electrodes, a two-electrode system is formed (a platinum electrode can also be added to form a three-electrode system). A reduction voltage of -1.0 to -2.0V (relative to the voltage between the working electrode and the silver / silver chloride reference electrode) is applied to the working electrode through the control circuit module 1, thereby reducing ferric ions or divalent copper ions to divalent iron ions or elemental copper. This reduces the cross-linking degree of the sodium alginate gel, releasing the insulin. Since the insulin-controlled release microneedle array patch has multiple insulin microneedles, independent current pathways can release single or multiple insulin microneedles, thereby controlling the release amount and rate. Once all insulin microneedles have been released, the patch can be removed from the interface with the circuit board and replaced with a new patch to complete the continuous supply of insulin.

[0040] See Figure 3As shown, the dynamic blood glucose monitoring microneedle array patch 3 includes a second flexible electrode sheet 31, a second reference electrode, and dynamic blood glucose monitoring microneedle electrodes 32 distributed in an array on the second flexible electrode sheet 31. All electrodes on the second flexible electrode sheet 31, including the second reference electrode and the dynamic blood glucose monitoring microneedle electrodes 32, are each connected to the control circuit module 1 through an independent second current path 33. The control circuit module 1 addresses each dynamic blood glucose monitoring microneedle electrode 32 individually and independently controls the working voltage applied to the dynamic blood glucose monitoring microneedle electrode 32. Simultaneously, the control circuit module 1 also needs to include a microcurrent detection module to detect and record the current values ​​on different dynamic blood glucose monitoring microneedle electrodes 32 during the addressing process. This current value is correlated with blood glucose concentration, and the blood glucose concentration can be calculated using a pre-fitted relationship curve.

[0041] Similarly, in the aforementioned dynamic blood glucose monitoring microneedle array patch 3, the second reference electrode can form a two-electrode system with each dynamic blood glucose monitoring microneedle electrode 32. However, in other embodiments, a second pair of electrodes (which can be platinum electrodes) can be provided on the second flexible electrode sheet 31 in addition to the second reference electrode. The first pair of electrodes is also connected to the control circuit module 1 through an independent second current path 33, thereby forming a three-electrode system with the dynamic blood glucose monitoring microneedle electrodes 32. Both the two-electrode system and the three-electrode system can achieve the technical effects of the present invention.

[0042] The aforementioned dynamic blood glucose monitoring microneedle electrode 32 is based on a series of existing technologies, and theoretically, it can be implemented using any microneedle capable of measuring blood glucose. In the embodiments of the present invention, the dynamic blood glucose monitoring microneedle electrode 32 uses a metal needle as a substrate and has a five-layer composite structure on the outside, namely, a platinum layer, an o-phenylenediamine layer, a glucose oxidase layer, a chitosan layer, and a polyurethane layer are sequentially coated on the surface of the metal needle.

[0043] In an embodiment of the present invention, the preparation method of the glucose-sensitive working electrode of the dynamic blood glucose monitoring microneedle array patch is as follows: using a metal needle as the working electrode, a silver / silver chloride electrode as the reference electrode, and a platinum electrode as the counter electrode, a platinum layer is electroplated at a constant voltage of -0.3V for 300s in a 10mM H2PtCl6 / 1M HCl solution. Then, using the platinum-plated metal needle as the working electrode, the silver / silver chloride electrode as the reference electrode, and the platinum electrode as the counter electrode, an o-phenylenediamine layer is formed by electroplating at a constant voltage of +0.65V for 1200s in a 5mM o-phenylenediamine / 30mg / mL glucose oxidase (GOX) / 10mg / mL bovine serum albumin (BSA) solution. Next, the electrode covered with the o-phenylenediamine layer is immersed in 90mg / mL GOX / 30mg / mL BSA for 10min, and 50μL of glutaraldehyde is added to a 250mL brown cross-linking bottle. The electrode is then placed in the cross-linking bottle and cross-linked at 37°C for 15min to form a glucose oxidase layer. Next, the cross-linked electrode is immersed in a 1% chitosan solution for 30 seconds to form a chitosan layer. Then, a copper ring with a diameter of 3 mm is made using 0.5 mm copper wire. After being immersed in a 1% polyurethane solution, a polyurethane bubble film is formed inside the metal ring. The electrode is then passed through the metal ring and removed, thereby partially transferring the polyurethane bubble film layer to the electrode surface to form a polyurethane layer.

[0044] The working method of this dynamic blood glucose monitoring microneedle array patch 3 is as follows: A dynamic blood glucose monitoring microneedle electrode 32 is used as the working electrode, and a silver / silver chloride electrode is used as the reference and counter electrode, forming a two-electrode system (a platinum electrode can also be added to form a three-electrode system). The working voltage between the working electrode and the silver / silver chloride reference is controlled by the control circuit module 1 to be +0.2 to 1.0V, preferably 0.5V. Glucose in the tissue fluid decomposes into hydrogen peroxide under the action of the glucose oxidase layer of the blood glucose-sensitive microneedle electrode. The platinum layer catalyzes the decomposition of hydrogen peroxide under the working voltage, resulting in electron transfer. The reaction current can be recorded by a microcurrent detection module within the circuit board. Since the glucose concentration in the tissue fluid is highly correlated with the glucose concentration in the blood, the dynamic blood glucose monitoring microneedle array can largely characterize changes in blood glucose levels.

[0045] The current measured by different glucose-sensitive working electrodes in this dynamic glucose monitoring microneedle array patch 3 can be recorded separately, and the data from different groups can be analyzed to obtain more accurate glucose monitoring results. This dynamic glucose monitoring microneedle array patch 3 can also be replaced after it loses its glucose monitoring effect, achieving the purpose of long-term dynamic glucose monitoring.

[0046] Furthermore, in the aforementioned insulin-controlled release microneedle array patch 2 and dynamic glucose monitoring microneedle array patch 3, all microneedles can be arranged arbitrarily, such as an m*n square array, a circle, a ring, or other shapes. The insulin-controlled release microneedle array patch 2 contains only one reference electrode (or one reference electrode and one counter electrode), with the rest being insulin-controlled release microneedle electrodes 22; similarly, the dynamic glucose monitoring microneedle array patch 3 contains only one reference electrode (or one reference electrode and one counter electrode), with the rest being dynamic glucose monitoring microneedle electrodes 32. Both patches are designed to be detachable and replaceable from the control circuit module 1.

[0047] The metal needles used in the preparation of each electrode in this invention are gold needles, platinum needles, or stainless steel needles, etc., and there is no limitation on the type.

[0048] Furthermore, the aforementioned control circuit module 1 serves as the central control hub for realizing the overall functions. However, aside from the individual addressing control of the electrodes on the two patches, other functions can be configured appropriately according to actual needs. For example, in one embodiment, an interactive display interface for displaying control and detection parameters can be provided in the aforementioned control circuit module 1, allowing users to directly interact with the display screen to display and control the data. In another embodiment, a communication module for data interaction with external devices can be provided in the aforementioned control circuit module 1, allowing relevant data to be sent to external mobile devices or other interactive systems for display and control. In yet another embodiment, a feedback control module can be provided in the aforementioned control circuit module 1 for controlling the release of insulin from the insulin-controlled release microneedle array patch 2 based on the blood glucose concentration detected by the dynamic blood glucose monitoring microneedle array patch 3.

[0049] The above will be illustrated through a specific embodiment below. Figures 1-3 The diagram illustrates the specific implementation and technical effects of a closed-loop insulin controlled release system based on a microneedle array patch.

[0050] Example

[0051] In this embodiment, the basic structure and connection method of the control circuit module 1, the insulin-controlled release microneedle array patch 2, and the dynamic blood glucose monitoring microneedle array patch 3 in the closed-loop insulin controlled release system based on microneedle array patches are as described above and will not be repeated here. The specific preparation method and effects are as follows:

[0052] In the insulin-controlled release microneedle array patch 2, the needle body substrate of the insulin-controlled release microneedle electrode 22 is a stainless steel needle with a diameter of 140 μm. The insulin-controlled release microneedle is obtained by electrolysis at a constant current of 30 μA for 60 s in a solution of 1 wt% sodium alginate, 35 mM ferrous sulfate, and 1000 U insulin, using a metal needle as the working electrode, a silver-silver chloride electrode as the reference electrode, and a platinum electrode as the counter electrode (or a two-electrode system). After drying, the insulin-controlled release microneedle is obtained. Alternatively, the stainless steel needle can be electroplated in a 0.4 M copper sulfate solution at a constant current of -3 mA for 10 s to obtain a copper-plated stainless steel needle. Then, the copper-plated stainless steel needle is electrolyzed at a constant current of 30 μA for 60 s in a solution of 1 wt% sodium alginate and 1000 U insulin, and dried to obtain the insulin-controlled release microneedle. In this embodiment, the former method is used, where the outer surface of the insulin-controlled release microneedle electrode 22 is an insulin-releasing gel cross-linked with ferric ions.

[0053] Finally, an insulin-controlled release microneedle array patch with an independent current pathway was designed, as shown in Figure 2. Figure 2 As shown, the insulin-controlled release microneedle electrode 22 and a single silver / silver chloride reference microneedle are connected to the circuit patch via conductive silver paste, and then fixed and insulated with UV adhesive.

[0054] In the dynamic blood glucose monitoring microneedle array patch 3, the needle body substrate of the dynamic blood glucose monitoring microneedle electrode 32 is a stainless steel needle with a diameter of 140 μm. A platinum-plated stainless steel needle is obtained by constant voltage electroplating at -0.3V for 300s in 10mM chloroplatinic acid / 1M hydrochloric acid, using the stainless steel needle as the working electrode, a silver / silver chloride electrode as the reference electrode, and a platinum electrode as the counter electrode. Then, using the platinum-plated stainless steel needle as the working electrode, the silver / silver chloride electrode as the reference electrode, and the platinum electrode as the counter electrode, a constant voltage electroplating at +0.65V for 1200s is performed in a 5mM o-phenylenediamine / 30mg / mL glucose oxidase (GOX) / 10mg / mL bovine serum albumin (BSA) solution. Next, the electrode covered with the o-phenylenediamine layer is immersed in 90mg / mL GOX / 30mg / mL BSA for 10min, and 50μL of glutaraldehyde is added to a 250mL brown crosslinking bottle. The electrode is then placed in the crosslinking bottle and crosslinked at 37℃ for 15min. Next, the electrode was immersed in a 1% chitosan solution for 30 seconds. Then, a copper ring with a diameter of 3 mm was made using a 0.5 mm copper wire. After being immersed in a 1% polyurethane solution, a polyurethane bubble film was formed inside the metal ring. The electrode was then passed through the film and removed.

[0055] Finally, a dynamic blood glucose monitoring microneedle array patch with an independent current path was designed. Figure 3 As shown, the dynamic blood glucose monitoring microneedle electrode 32, the single silver / silver chloride reference microneedle, and the single platinum electrode microneedle are connected to the circuit patch through conductive silver paste, and then fixed and insulated with UV glue.

[0056] Finally, refer to Figure 1As shown, the insulin-controlled release microneedle array patch and the dynamic blood glucose monitoring microneedle array patch are connected to a flexible circuit board via an interface. After connecting a battery to the flexible circuit board, the measured glucose concentration data is transmitted to a mobile phone via Bluetooth. When the glucose concentration exceeds the normal range, the insulin microneedle array patch can be released by applying a reduction voltage, thereby achieving stable control of blood glucose concentration.

[0057] The two patches in the above system were tested and verified separately, and the experimental results are as follows:

[0058] 1) Glucose response experiment of continuous glucose monitoring microneedles:

[0059] For the continuous glucose monitoring microneedle array patch 3, a three-electrode system was constructed using metal microneedles coated with insulin-releasing gel crosslinked with ferric ions as the working electrode, standard Ag / AgCl as the reference electrode, and standard platinum wire as the counter electrode. The patch was immersed in PBS solution with a pH of 7.2–7.4. An electrochemical workstation was used to control the voltage difference between the working and reference electrodes to +0.5V. 2mM glucose was added each time, and the current response was measured. The final results are as follows: Figure 4 As shown, the left figure is the glucose current response curve, and the right figure is the current-concentration relationship.

[0060] In addition, the response of dynamic glucose microneedle monitoring was tested using both an electrochemical workstation and a flexible circuit board. The flexible circuit board served the function of the aforementioned control circuit module 1. Similarly, in a PBS solution with pH = 7.2–7.4, the voltage difference between the working electrode and the reference electrode was controlled at +0.5V, and 2mM glucose was added each time, with the current response measured. The final glucose response curves measured by the electrochemical workstation and the flexible circuit board are shown below. Figure 5 As shown.

[0061] In addition, after connecting the flexible circuit board to the dynamic glucose monitoring microneedle patch, the patch contains four independent dynamic glucose monitoring microneedles. When 2 mM glucose is added to a PBS solution with pH 7.2–7.4 each time, the current response is as follows: Figure 6 As shown (the four microneedles correspond to Channel1, Channel2, Channel3, and Channel4 respectively).

[0062] The continuous glucose monitoring microneedle patch was then inserted into the back of the rat. The rat began to eat, and the real-time monitored current signal was as follows: Figure 7 As shown.

[0063] 2) Response experiment of insulin-controlled release microneedles:

[0064] For the insulin controlled-release microneedle array patch 2, the specific microneedle preparation process is as follows: In a solution containing 1% sodium alginate, 35mM ferrous sulfate, and insulin, using a metal needle as the working electrode, a silver / silver chloride electrode as the reference electrode, and a platinum electrode as the counter electrode, a layer of trivalent iron ion cross-linked insulin-releasing gel is obtained on the surface of the metal needle by electroplating at a constant current of 30μA for 60s. After standing in air for 15 minutes, the gel loses water and tightly coats the needle body. Figure 8 The images show the state of the trivalent iron insulin gel after drying for 0 min, 5 min, 10 min, and 15 min, and it can be seen that the gel gradually shrinks over time.

[0065] In addition, insulin release experiments were conducted based on the prepared microneedles: fluorescent microspheres were used instead of insulin molecules, and fluorescence was observed under a fluorescence microscope after applying a reduction voltage of -1.2V for 5 min and 10 min. Figure 9 As shown in the figure, the left image represents the initial state, the middle image represents the state after 5 minutes of restoration, and the right image represents the state after 10 minutes of restoration. This demonstrates that the insulin-controlled release microneedles prepared in this invention can achieve controlled insulin release under appropriate voltage.

[0066] The embodiments described above are merely some preferred implementations of the present invention and are not intended to limit the invention. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Therefore, all technical solutions obtained through equivalent substitution or transformation fall within the protection scope of the present invention.

Claims

1. A closed-loop insulin controlled release system based on a microneedle array patch, characterized in that, It includes a control circuit module (1), an insulin controlled-release microneedle array patch (2), and a dynamic blood glucose monitoring microneedle array patch (3); The insulin-controlled release microneedle array patch (2) includes a first flexible electrode sheet (21), a first reference electrode, and insulin-controlled release microneedle electrodes (22) distributed in an array on the first flexible electrode sheet (21). The insulin-controlled release microneedle electrodes (22) are based on metal needles, and a gel network formed by cross-linking sodium alginate with metal ions is covered on the surface of the metal needles. Insulin is encapsulated in the gel network. All electrodes on the first flexible electrode sheet (21) are connected to the control circuit module (1) through an independent first current path (23). The control circuit module (1) addresses each insulin-controlled release microneedle electrode (22) individually and independently controls the reduction voltage applied to the insulin-controlled release microneedle electrode (22) to release insulin. The dynamic blood glucose monitoring microneedle array patch (3) includes a second flexible electrode sheet (31), a second reference electrode, and dynamic blood glucose monitoring microneedle electrodes (32) distributed in an array on the second flexible electrode sheet (31). All electrodes on the second flexible electrode sheet (31) are connected to the control circuit module (1) through an independent second current path (33). The control circuit module (1) addresses each dynamic blood glucose monitoring microneedle electrode (32) individually, independently controls the working voltage applied to the dynamic blood glucose monitoring microneedle electrode (32), and records the current value on different dynamic blood glucose monitoring microneedle electrodes (32) during the addressing process.

2. The closed-loop insulin controlled release system based on microneedle array patches as described in claim 1, characterized in that, The preparation method of the insulin-controlled release microneedle electrode (22) is as follows: a metal needle is used as the working electrode, a silver / silver chloride electrode is used as the reference electrode, and a platinum electrode is used as the counter electrode. The three electrodes are immersed in a solution containing sodium alginate, insulin and ferrous sulfate, and insulin-controlled release microneedles covered with insulin gel are obtained by constant current electrolysis.

3. The closed-loop insulin controlled release system based on microneedle array patches as described in claim 1, characterized in that, The preparation method of the insulin-controlled release microneedle electrode (22) is as follows: a copper-plated metal needle is used as the working electrode, a silver / silver chloride electrode is used as the reference electrode, and a platinum electrode is used as the counter electrode. The three electrodes are immersed in a solution containing sodium alginate and insulin, and insulin-controlled release microneedles covered with insulin gel are obtained by constant current electrolysis.

4. The closed-loop insulin controlled release system based on microneedle array patches as described in claim 1, characterized in that, The reduction voltage applied to the insulin-controlled release microneedle electrode (22) for releasing insulin is -1.0 to -2.0V.

5. The closed-loop insulin controlled release system based on microneedle array patches as described in claim 1, characterized in that, The dynamic blood glucose monitoring microneedle electrode (32) uses a metal needle as the base, and a platinum layer, an o-phenylenediamine layer, a glucose oxidase layer, a chitosan layer and a polyurethane layer are sequentially coated on the surface of the metal needle.

6. The closed-loop insulin controlled release system based on microneedle array patches as described in claim 1, characterized in that, The working voltage applied to the dynamic blood glucose monitoring microneedle electrode (32) is +0.2 to +1.0V.

7. The closed-loop insulin controlled release system based on microneedle array patches as described in claim 1, characterized in that, In addition to the first reference electrode, the first pair of electrodes is provided on the first flexible electrode sheet (21) of the insulin controlled-release microneedle array patch (2). The first pair of electrodes is also connected to the control circuit module (1) through an independent first current path (23), thereby forming a three-electrode system with the insulin controlled-release microneedle electrode (22).

8. The closed-loop insulin controlled release system based on microneedle array patches as described in claim 1, characterized in that, In addition to the second reference electrode, the second pair of electrodes is provided on the second flexible electrode sheet (31) of the dynamic blood glucose monitoring microneedle array patch (3). The second pair of electrodes is also connected to the control circuit module (1) through an independent second current path (33), thereby forming a three-electrode system with the dynamic blood glucose monitoring microneedle electrode (32).

9. The closed-loop insulin controlled release system based on microneedle array patches as described in claim 1, characterized in that, The control circuit module (1) has an interactive display interface for displaying control parameters and detection parameters, or a communication module for data interaction with external devices, or a feedback control module for feedback control of insulin release in insulin-controlled release microneedle array patch (2) based on the blood glucose concentration detected by dynamic blood glucose monitoring microneedle array patch (3).

10. The closed-loop insulin controlled release system based on microneedle array patches as described in any one of claims 1 to 9, characterized in that, The metal needle is a gold needle, a platinum needle, or a stainless steel needle.

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