WO2022188439A1

WO2022188439A1 - Diabetes monitoring and treating apparatus and system based on mesoporous microneedle

Info

Publication number: WO2022188439A1
Application number: PCT/CN2021/128362
Authority: WO
Inventors: 谢曦; 李湘凌; 黄新烁; 向福森; 王浩; 黄琪琪; 杨成; 张涛; 杭天; 陈惠琄; 胡宁
Original assignee: 中山大学
Priority date: 2021-03-12
Filing date: 2021-11-03
Publication date: 2022-09-15
Also published as: CN113171090B; CN113171090A

Abstract

A diabetes monitoring and treating apparatus and system based on a mesoporous microneedle. The apparatus comprises: a microneedle counter ionophoresis sensor, which is used for extracting glucose and detecting an electrical signal of the glucose concentration; a control circuit module, which is used for sending a control signal to a microneedle ionophoresis module according to the electrical signal of the glucose concentration; and a microneedle ionophoresis module, which is used for releasing insulin according to the control signal, wherein the control circuit module is connected to the microneedle counter ionophoresis sensor and the microneedle ionophoresis module. By means of the treating apparatus, in the case of minimal invasion, fluctuations in glucose can be accurately tracked and insulin can be correspondingly released, such that the glucose concentration is effectively adjusted. The apparatus can be widely applied to the field of biomedicines.

Description

Diabetes monitoring and treatment device and system based on mesoporous microneedles

technical field

The invention relates to the field of biomedicine, in particular to a diabetes monitoring and treatment device and system based on mesoporous microneedles.

Background technique

Diabetes is a common metabolic disease that threatens the health of 463 million people worldwide, can seriously affect the quality of health of patients, and lead to cardiovascular, renal, and neurodegenerative diseases and their complications. At present, the clinical treatment of diabetes is to use a rapid blood glucose meter to obtain the blood glucose value from the blood drawn from the patient's finger, and then to determine whether it is necessary to inject insulin to maintain the balance of blood glucose. However, the method of fingertip blood collection cannot meet the real-time monitoring of blood sugar; in addition, repeated invasive finger puncture brings pain and infection to patients, which seriously restricts the diagnosis and treatment of diabetic patients.

Implantable electrode-based invasive continuous glucose monitors (CGMs) are currently commercialized as sophisticated biosensors, but the long-term nature of implanted CGMs electrodes or insulin pump catheters often leads to undesirable pain, bleeding, and inflammation, and Interference with life activities. On the other hand, non-invasive wearable glucose sensors, including wristbands, contact lenses, and sweat-based sensors, have attracted increasing research interest. However, non-invasive sensors are rarely able to accurately reflect and regulate glucose levels due to insufficient availability of glucose in blood or interstitial fluid due to skin penetration.

SUMMARY OF THE INVENTION

In view of this, the purpose of the embodiments of the present invention is to provide a diabetes monitoring and treatment device and system based on mesoporous microneedles, which can accurately track the fluctuation of glucose and release insulin accordingly in a minimally invasive situation, thereby effectively regulating glucose concentration.

In a first aspect, an embodiment of the present invention provides a diabetes monitoring and treatment device based on mesoporous microneedles, including:

Microneedle counterion electrophoresis sensor, used to extract glucose and detect the electrical signal of glucose concentration;

a control circuit module for sending a control signal to the microneedle ionophoresis module according to the electrical signal of the glucose concentration;

a microneedle ionophoresis module for releasing insulin according to the control signal;

The control circuit module is connected to the microneedle counterionophoresis sensor and the microneedle ionophoresis module.

Optionally, the microneedle counterionophoresis sensor is assembled from counter electrode microneedles, mesoporous microneedle arrays, glucose sensing electrodes and a 3D printed sensing chamber.

Optionally, the glucose sensing electrode is a three-electrode system, the three-electrode system includes a working electrode, a counter electrode and a reference electrode, the working electrode and the counter electrode are carbon electrodes, and the surface of the carbon electrode sequentially includes Metal mask, chromium film layer and gold film layer.

Optionally, the microneedle ionophoresis module is assembled from counter electrode microneedles, a mesoporous microneedle array and a 3D printed sensing chamber.

Optionally, the porosity of the mesoporous microneedle array is 45%-55%.

Optionally, the control circuit module includes an electrical signal adjustment unit for glucose concentration, a first constant current source unit, a second constant current source unit, a controller and a power supply unit; wherein,

the electrical signal adjustment unit of the glucose concentration, for processing the electrical signal of the glucose concentration;

a first constant current source unit for providing a preset constant current to the microneedle counterionophoresis sensor;

a second constant current source unit, configured to provide a preset constant current to the microneedle ionophoresis module;

a controller, configured to send the control signal to the microneedle ionophoresis module according to the electrical signal of the processed glucose concentration;

The power supply unit is used to provide power for the control circuit module.

Optionally, the microneedle reverse ionophoresis sensor shown includes a reference electrode, a counter electrode and a working electrode; the electrical signal adjustment unit of the glucose concentration includes a control amplifier, a reverse follower and a transimpedance amplifier; the reference electrode The reverse follower is connected, the counter electrode is connected to the control amplifier, and the working electrode is connected to the transimpedance amplifier.

Optionally, the control circuit module is a flexible circuit board.

In a second aspect, an embodiment of the present invention provides a system for monitoring and treating diabetes based on mesoporous microneedles, including: the above-mentioned device, a Bluetooth unit, and a display unit; wherein,

the Bluetooth unit for establishing communication between the device and the display unit;

The display unit is used to display glucose concentration information.

Optionally, the system further includes: a filtering unit for filtering the electrical signal of the glucose concentration.

The implementation of the embodiment of the present invention includes the following beneficial effects: the embodiment of the present invention extracts glucose and detects the electrical signal of the glucose concentration through the microneedle counterionphoresis sensor, so as to accurately track the fluctuation of glucose; the control circuit module transmits control according to the electrical signal of the glucose concentration The signal is sent to the microneedle ionophoresis module, and the microneedle ionophoresis module releases insulin according to the control signal to achieve the corresponding release of insulin, thereby effectively regulating the concentration of glucose; Microneedling achieves minimal invasiveness.

Description of drawings

1 is a structural block diagram of a diabetes monitoring and treatment device based on mesoporous microneedles provided by an embodiment of the present invention;

2 is a physical diagram of a diabetes monitoring and treatment device based on mesoporous microneedles provided by an embodiment of the present invention;

3 is a flow chart of the preparation of a microneedle counterionophoresis sensor and a microneedle ionophoresis module provided by an embodiment of the present invention;

FIG. 4 is a photograph and a scanning electron microscope image of a mesoporous microneedle with a porosity of 50% provided by an embodiment of the present invention;

5 is a scanning electron microscope image of a mesoporous microneedle with porosity of 30%, 40% and 60% provided by an embodiment of the present invention;

FIG. 6 is a data diagram of fracture force and yield force of mesoporous microneedles with porosity of 30%, 40%, 50% and 60%, respectively, according to an embodiment of the present invention;

FIG. 7 is a data diagram of the diffusion rate of mesoporous microneedles with porosity of 30%, 40%, 50% and 60%, respectively, according to an embodiment of the present invention;

Fig. 8 is a kind of step flow chart and effect diagram of implanting mesoporous microneedles into the skin for dyeing provided by the embodiment of the present invention;

FIG. 9 is a flow chart of steps for making a glucose electrode provided by an embodiment of the present invention;

10 is a data diagram of the current response of a glucose electrode provided by an embodiment of the present invention;

11 is a schematic structural diagram of a microneedle counterionophoresis sensor provided by an embodiment of the present invention;

12 is a physical diagram and a size diagram of a microneedle counterionophoresis sensor provided by an embodiment of the present invention;

13 is a data diagram of the current response of a microneedle counterionophoresis sensor provided in an embodiment of the present invention;

14 is a data diagram of detecting healthy mice with a microneedle counterionophoresis sensor provided by an embodiment of the present invention;

15 is a data diagram of detecting diabetic mice with a microneedle counterionophoresis sensor according to an embodiment of the present invention;

Figure 16 is a physical diagram of a microneedle ionophoresis module provided in an embodiment of the present invention;

17 is a schematic structural diagram, a physical diagram, and a test data diagram of releasing insulin of a microneedle ionophoresis module provided in an embodiment of the present invention;

Figure 18 is a test data diagram of insulin release in diabetic mice by using a microneedle ionophoresis module provided in an embodiment of the present invention;

19 is a structural block diagram of another diabetes monitoring and treatment device based on mesoporous microneedles provided by an embodiment of the present invention;

20 is a schematic circuit diagram of an electrical signal adjustment unit for glucose concentration provided by an embodiment of the present invention;

21 is a circuit schematic diagram of a first constant current source unit provided by an embodiment of the present invention;

22 is a schematic circuit diagram of a second constant current source unit provided by an embodiment of the present invention;

23 is a circuit schematic diagram of a controller provided by an embodiment of the present invention;

24 is a schematic diagram of a circuit for converting an input voltage to a 5V voltage provided by an embodiment of the present invention;

25 is a schematic diagram of a circuit for converting a 5V voltage to a -5V voltage according to an embodiment of the present invention;

26 is a schematic diagram of a circuit for converting a 5V voltage to a 3.3V voltage according to an embodiment of the present invention;

27 is a schematic diagram of a circuit for converting a 5V voltage to a 20V voltage according to an embodiment of the present invention;

28 is a schematic diagram of a circuit for serial port conversion provided by an embodiment of the present invention;

FIG. 29 is a schematic circuit diagram of a Bluetooth unit provided by an embodiment of the present invention.

Detailed ways

The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments. The numbers of the steps in the following embodiments are only set for the convenience of description, and the sequence between the steps is not limited in any way, and the execution sequence of each step in the embodiments can be adapted according to the understanding of those skilled in the art Sexual adjustment.

Referring to FIG. 1 and FIG. 2 , an embodiment of the present invention provides a diabetes monitoring and treatment device based on mesoporous microneedles, including:

Specifically, a 1-yuan coin in FIG. 2 is a reference object, one end of the 1-yuan coin is a microneedle counter ionophoresis sensor, and the other end is a microneedle ionophoresis module.

The working principle of the diabetes monitoring and treatment device based on mesoporous microneedles is as follows: firstly, the above device is attached to the skin surface; after activation, the microneedle counterionophoresis sensor extracts glucose and detects the electrical signal of the glucose concentration, and the electrical signal of the glucose concentration is transmitted to the control circuit module; the control circuit module sends a control signal to the microneedle ionophoresis module according to the electrical signal of the glucose concentration; the microneedle ionophoresis module releases insulin according to the control signal. Specifically, when the glucose concentration exceeds the preset value, the control signal controls the microneedle ionophoresis module to release insulin; when the glucose concentration is within the normal range, the control signal controls the microneedle ionophoresis module not to release insulin.

Specifically, as shown in Figure 3, a mixture of polydimethylsiloxane and its curing agent was cast on the SU-8 master mold 1 of the microneedle array, and after drying, a PDMS mold 2 with an inverted microneedle structure was formed. PDMS mold 2 prepares PDMS mold 3 with microneedles, separates PDMS mold 3 with microneedles from SU-8 master mold to obtain microneedle patch 4, and uses porogen to obtain mesoporous microneedle array 5; steel sheet 8 After laser cutting, a steel sheet microneedle is formed, and a gold layer is plated on the steel sheet microneedle to form a counter electrode microneedle 9. The counter electrode microneedle 9, the mesoporous microneedle array 5, the glucose sensing electrode and the 3D printing sensor The chambers are assembled to form a microneedle counterionophoresis sensor 6 , and the counter electrode microneedles 9 , the mesoporous microneedle array 5 and the 3D printing sensing chamber are assembled to form a microneedle ionophoresis module 7 .

It should be noted that the specific preparation process of the mesoporous microneedle array is as follows: polydimethylsiloxane (PDMS) and its curing agent are mixed at a ratio of 10:1 and stirred evenly; wherein, the uncured solution is in a vacuum of 4.5Pa Set aside for 30 minutes to remove air bubbles. The PDMS solution was cast on the SU-8 master mold of the microneedle array, and then dried at 60 °C overnight to form a PDMS mold with an inverted microneedle structure. The PDMS mold was then separated from the SU-8 master mold and was ready to be applied as a mold for the fabrication of mesoporous microneedles. Taking the typical preparation process of MMN as an example, trimethylpropane trimethacrylate and triethylene glycol dimethacrylate are used as crosslinking agents for polyglycidyl methacrylate. Polyethylene glycol (10 kDa) was used as porogen. The first step, dissolve 2g polyethylene glycol in 10ml 2-methoxyethanol, dissolve at 50℃ for 1h as the porogen stock solution, make sure the solution is transparent before use. Second step, monomer glycidyl methacrylate (1 ml, 73.3 mmol, 1 equiv.), trimethylpropane trimethacrylate (0.688 ml, 19.4 mmol, 0.26 equiv.) and triethylene glycol dimethacrylate The ester (1.59 ml, 57.6 mmol, 0.79 equiv.) was mixed homogeneously as a monomer stock solution. Third, Irgacure 184 (0.10 g, monomer mass fraction of 1 wt%, as photoinitiator) was added to the mixture of monomer solution and porogen stock solution (1:1, v/v, 6.6 ml in total). Then, the mixed solution was dropped into the PDMS mold and centrifuged at 4000 rpm for 10 minutes to ensure that the mixed solution entered the inverted cavity of the PDMS mold. The microneedle patches were cured by UV light irradiation (INTELLI-RAY 400, Uvitron, USA) at 365 nm for 20 min and then peeled from the PDMS mold. The solid microneedle patches were then soaked in 50% methanol solution for 24 h to remove the PEG porogen.

Optionally, the porosity of the mesoporous microneedle array is 45%-55%.

As shown in Figure 4, the morphological map and SEM image of the mesoporous microneedles with a porosity of 50%; as shown in Figure 5, the SEM images of the mesoporous microneedles with a porosity of 30%, 40% and 60%, respectively Image; stress-strain tests of mesoporous microneedles were performed on the above 30%, 40%, 50% and 60% mesoporous microneedles with a dynamometer, and the critical fracture force and yield force were marked, respectively, as shown in Fig. 6, The critical fracture force and yield force of mesoporous microneedles decrease with the increase of porosity.

As shown in Figure 7, the diffusion rates of the mesoporous microneedles with porosity of 30%, 40%, 50% and 60% were enhanced with the increase of porosity, and the test reagents were FITC-insulin and subunit blue, respectively.

Taking into account the fracture force, yield force and diffusion rate of the mesoporous microneedle array with different porosity, the porosity of the mesoporous microneedle array in the embodiment of the present invention is in the range of 45% to 55%. It should be noted that, according to specific actual needs, mesoporous microneedles with other porosity can be selected.

As shown in Fig. 8, Fig. 8(a) shows that an experiment was performed on the implantation of mesoporous microneedles into the skin: the mesoporous microneedle patch was stained with a red fluorescent dye. The mesoporous microneedles were then inserted into the skin and removed after 5 minutes; the deposition of fluorescent dyes in the skin was then observed with a fluorescence microscope. Figure 8(b) is a cross-section of a fluorescence image showing the deposition of fluorescent dyes mediated by mesoporous microneedles in the skin; the skin tissue was sectioned and imaged with a fluorescence microscope, and the penetration depth was about 400 μm. Figure 8(c) is a fluorescent image of the mesoporous microneedles stained with Rhodamine B, and Figures 8(d) and (e) are fluorescent images showing the deposition of Rhodamine B on pig skin after the penetration of the mesoporous microneedles.

It should be noted that, as shown in Figure 9, the specific preparation process of the glucose sensing electrode is as follows: the three-electrode system screen-printed on the plastic substrate has two carbon electrodes as the working electrode and the counter electrode, and an Ag/AgCl electrode as the reference electrode. A metal mask is covered on the screen-printed carbon electrode, and then a 30-50 nm thick Cr layer and an 80 nm thick Au layer are plated on the working electrode by magnetron sputtering. The Cr layer is the adhesion layer of the Au layer and the carbon electrode. Subsequently, ferrous cyanide (also called ferrocyanide (also called ferrocyanide) was electroplated on the working electrode in 100 mL of solution containing 2.5 mM FeCl ₃ , 100 mM potassium chloride, 2.5 mM K ₃ Fe(CN) ₆ and 100 mM hydrochloric acid in situ at a constant voltage of 0.8 V for 480 seconds. Prussian Blue, PB). After washing and drying the electrode, 4 μl of a mixture solution containing glucose oxidase (50 mg/ml)/bovine serum albumin (80 mg/ml)/glutaraldehyde (2.5% in PBS) was added dropwise and dried. The electrodes were then rinsed with PBS (phosphate buffered saline) to remove non-cross-linked enzymes from the surface, and then air-dried overnight at room temperature. In situ electrodeposition of Prussian blue (PB) on the gold electrode surface as a redox active material provides better selectivity and sensitivity.

As shown in Figure 10, the amperometric response of the planar glucose electrode was tested. As shown in Figure 10(a), the electrode was tested with a series of glucose solutions (0-0.8mM), and the test current increased with the increase of glucose concentration. ; As shown in Figure 10(b), the glucose concentration gradually increased by 0.2mM, and the test current gradually increased; as shown in Figure 10(c), the current signal was linearly related to the corresponding glucose concentration, and the linearity could reach 0.997. It can be seen from Fig. 10 that the glucose electrode can respond well to the glucose concentration.

It should be noted that the specific preparation process of the metal micro-target electrode is as follows: using the laser micro-etching (INNO Laser) technology, a metal MN sheet is prepared on a stainless steel substrate with a thickness of about 100 μm. The base diameter of the metallic manganese is about 225 μm, the length is about 800 μm, and the spacing between adjacent manganese is about 250 μm. Then, an Au layer of about 100 nm was deposited on the MN substrate by magnetron sputtering.

It should be noted that, as shown in FIGS. 11 and 12 , the specific assembly process of the microneedle counterionophoresis sensor is as follows: the counter electrode microneedle 11-4, the mesoporous microneedle array 11-5 (the mesoporous microneedle array 11-4) 5 prepared from the microneedle patch 11-3), the glucose sensing electrode 11-1 and the 3D printed sensing chamber 11-2 are assembled and bonded together using a thin layer of photocurable resin. The resin was cured under UV light irradiation at 365 nm for 2 minutes to achieve seamless integration of the three components. Fig. 12(a) is the actual picture of the microneedle counterionophoresis sensor, and Fig. 12(b) is the CAD drawing of the 3D printed plastic cavity of the actual design size of the microneedle-counterionophoresis glucose sensor (left: top view; right: side view), in which the specific size can be designed according to the actual situation, Figure 12(c) The photo of the actual picture of the glucose electrode.

As shown in Figure 13, the amperometric response test was performed on the microneedle-counterionophoretic glucose sensor. As shown in Figure 13(a), a series of glucose solutions (0-10 mM) were used to test the glucose sensor without microneedle extraction by reverse ion electrophoresis. It can be seen from the figure that the current also increases with the increase of glucose concentration; as shown in Figure 13 (b) The microneedle-counterionphoresis glucose sensor was tested with a series of glucose solutions (0-10 mM). It can be seen from the figure that the current also increases with the increase of glucose concentration. Figure 13(c) The linear relationship between the current signal of the microneedle not passing the counterionophoresis glucose sensor (Iri=0mA) and the microneedle-counterionophoresis glucose sensor (Iri=0.5mA) and the corresponding glucose concentration, it can be seen from the figure The detection sensitivity of glucose not extracted by ionophoresis is 14.1 nA/mM, while the detection sensitivity of glucose extracted by counter ion electrophoresis sensor is 54.2 nA/mM. Therefore, extraction of glucose by counter ion can improve the detection sensitivity of glucose.

As shown in Fig. 14, Fig. 14(a) shows the application of the microneedle-counterionphoresis glucose sensor on anesthetized rats. As shown in Fig. 14(b), for healthy rats, the current signal detected by microneedle-counterionophoresis glucose was converted into glucose concentration, and the actual blood glucose value was measured by standard glucose test strips, asterisks indicate calibration points, Arrows indicate time points of intraperitoneal glucose injection. As shown in Fig. 14(c), statistical analysis shows the detection error between the microneedle-counterionophoresis glucose sensor and the actual blood glucose value at the corresponding time point, the asterisk indicates the calibration point, and the dotted line indicates the clinical standard with an error <15%. As shown in Fig. 14(d), Clarke's error grid analysis shows the comparison of the detection accuracy of the microneedle-counterionophoretic glucose sensor with the actual blood glucose value, and the asterisks indicate the calibration points. Figure 14 shows that the microneedle-counterionophoretic glucose sensor can effectively detect the blood glucose of living animals (normal mice), showing a high degree of agreement (mean error <15%) compared with the commercial tail tip blood glucose.

As shown in Figure 15, Figure 15(a) shows that for diabetic rats, the current signal detected by microneedle-counterionophoresis glucose is converted into glucose concentration, and the actual blood glucose value is measured by standard glucose test strips, asterisks indicate Calibration points, arrows indicate time points for subcutaneous insulin injection. As shown in Fig. 15(b), statistical analysis shows the detection error between the microneedle-counterionophoresis glucose sensor and the actual blood glucose value at the corresponding time point, the asterisk indicates the calibration point, and the dotted line indicates the clinical standard with an error <15%. As shown in Fig. 15(c), Clarke's error grid analysis shows the comparison of the detection accuracy of the microneedle-counterionophoretic glucose sensor with the actual blood glucose value, and the asterisks indicate the calibration points. Figure 15 shows that the microneedle-counterionphoresis glucose sensor can effectively detect the blood glucose of living animals (diabetic mice), showing a high degree of agreement (mean error <15%) compared with the commercial tail tip blood glucose.

It should be noted that, as shown in Fig. 16, Fig. 16(a) is a schematic diagram of a microneedle-ionophoresis device, Fig. 16(b) is a photo of a microneedle-ionophoresis device, and Fig. 16(c) is a counter electrode microneedle optical photographs and SEM images. The specific assembly process of the microneedle ionophoresis module is as follows: Similar to the counter-ionophoretic glucose sensor, the counter electrode microneedles, the mesoporous microneedle array and the 3D printed transfer chamber are assembled and bonded together using a thin layer of photocurable resin. The Au-coated electrode was placed on the MMN surface, the melamine sponge was filled with insulin solution to fill the gap between the electrode surface and the MMN substrate, and then the cavity was sealed with a PDMS layer.

As shown in Fig. 17, Fig. 17(a) is a schematic diagram of the experimental device for in vitro insulin delivery by the microneedle-ionophoresis device, and Fig. 17(b) is a physical photo of the experimental device for the in vitro insulin delivery by the microneedle-ionophoresis device. Figure 17(c) is a graph of quantitative changes in insulin release from the microneedle-ionophoresis device, including constant ion osmotic current (Ii=0.5 mA) and free diffusion (Ii=0 mA). Figure 17 illustrates that the use of the microneedle-ionophoresis device can effectively improve the delivery rate of insulin from the microneedles.

As shown in Fig. 18, Fig. 18(a) shows the application of the microneedle-ionophoresis device on anesthetized rats, and as shown in Fig. 18(b), the diabetic rats were treated with the microneedle-ionophoresis device without ionophoresis. Microneedle-ionophoresis devices and subcutaneous insulin injections were used for treatment, while untreated diabetic rats and healthy rats served as controls. After treatment, blood glucose fluctuations were continuously monitored for 10 hours, and the lower area indicated normal blood glucose. As shown in Fig. 18(c), N=3, that is, the number of tests is 3, and the corresponding durations of different treatments in normal blood sugar and nadir blood sugar were quantitatively analyzed. As shown in Figure 18(d), N=3, that is, the number of tests is 3, the plasma insulin concentration of diabetic rats was measured, treated with the microneedle-ionophoresis device and the microneedle-ionophoresis device without ionophoresis treatment, respectively 2 hours, N=3. Figure 18 shows that the use of the microneedle-ionophoresis device to administer insulin to diabetic mice can effectively increase the transdermal release of insulin.

Optionally, as shown in FIG. 19 , the control circuit module includes an electrical signal adjustment unit for glucose concentration, a first constant current source unit, a second constant current source unit, a controller and a power supply unit; wherein,

an electrical signal adjustment unit for glucose concentration, for processing the electrical signal of glucose concentration;

The power supply unit is used to provide power for the control circuit module.

Optionally, as shown in FIG. 19 , the microneedle reverse ionophoresis sensor includes a reference electrode, a counter electrode and a working electrode; the electrical signal adjustment unit of the glucose concentration includes a control amplifier, a reverse follower and a transimpedance amplifier. ; The reference electrode is connected to the reverse follower, the counter electrode is connected to the control amplifier, and the working electrode is connected to the transimpedance amplifier.

Specifically, the control circuit module is provided with interfaces for the reference electrode, the counter electrode and the working electrode, and the signals detected by the microneedle counterionophoresis sensor are connected to the corresponding interfaces through wires.

Specifically, as shown in Figure 20, the electrical signal adjustment unit for glucose concentration includes a control amplifier (IC2A), an inverse follower (IC2B), and a transimpedance amplifier (IC4), and the reference electrode (RE) is connected to an inverse follower through an interface (IC2B), the counter electrode (CE) is connected to the control amplifier (IC2A), and the working electrode (WE) is connected to the transimpedance amplifier (IC4); among them, the resistance values of R2 and R5 are equal, so the The potential is controlled by the input voltage DAC1, which is output by the controller; the current on the working electrode (WE) is converted into an output voltage by a transimpedance amplifier, and the output voltage is I*R10; the output voltage is sent to the controller.

It should be noted that both the control amplifier and the reverse follower circuit use the dual op amp chip OPA2140AID to realize the function, a total of two pieces; the control amplifier and the reverse follower circuit can also be replaced by the dual op amp chip OPA2227PA, a total of two pieces . In the transimpedance amplifier circuit, the precision single operational amplifier chip TLC2201CD is used to realize the glucose signal amplification function, which can be replaced by the precision operational amplifier chip OPA2227PA.

Specifically, as shown in FIG. 21 , the first constant current source unit includes a digital-to-analog conversion circuit (DAC7311IDCKR) and a constant current transmission circuit (IC8+Q2). The digital-to-analog converter (DAC7311IDCKR) outputs a constant voltage (VOUTA) through the control of the controller, the constant voltage (VOUTA) outputs a constant current through the constant current transmission circuit (IC8+Q2), and the constant current output by the transistor Q2 (current_out) Provides the galvanostatic current required by the microneedle counterionophoresis sensor to extract glucose. Transistor Q2 can choose IRLML2402GTRPBF.

Specifically, as shown in FIG. 22, the input of the second constant current source unit is a constant voltage DAC2, and the constant voltage DAC2 is output by the controller; the output of the second constant current source unit is a constant current (current_out1), a constant current (current_out1) Provides the constant current required to release insulin from the microneedle ionophoresis module.

It should be noted that the chip in the first constant current source unit circuit or the second constant current source unit circuit adopts OPA2140AID, which can be replaced by a precision single operational amplifier chip TLC2201CD or OPA2227PA.

Specifically, as shown in Figure 23, the controller can select STM32 series chips. This embodiment takes STM32F103R8T6 as an example; STM32 includes a power supply, a clock circuit, a debugging interface, a reset circuit, and a single-chip microcomputer; the controller is an electrical signal adjustment for glucose concentration. The unit, the first constant current source unit and the second constant current source unit provide voltage, and the output value of the analog-to-digital converter is specifically controlled by a control command. The controller can also realize the storage and transmission of data, such as sending through Bluetooth.

It should be noted that the voltage values required by different units of the control circuit module may be different. Generally, there is only one input power supply for the device, so the power supply needs to be converted. In the embodiment of the present invention, a 3.7V polymer lithium battery is used as the input power supply, and then the voltage is converted to a required voltage value, such as 5V, -5V, 20V, and 3.3V.

Specifically, as shown in Figure 24, the voltage conversion circuit converts 2.7V to 5V through the boost converter LM2704MF-ADJ/NOPB.

Specifically, as shown in Figure 25, the voltage conversion circuit converts 5V to -5V through the CMOS monolithic voltage converter MAX660ESA+, and the inverter outputs -5V voltage at pin5; the -5V negative voltage is the electrical signal adjustment of glucose concentration An operational amplifier in the unit provides power support.

Specifically, as shown in Figure 26, the voltage conversion circuit converts 5V into 3.3V through the voltage regulator AMS1117, and the inverter outputs a 3.3V voltage at pin2. The 3.3V voltage provides power support for the controller STM32. It should be noted that the linear regulator AMS1117-3.3 is used in the 5V to 3.3V circuit to output a stable 3.3V voltage, which can be replaced by the LDO chip SSP1117-3.3.

Specifically, as shown in Figure 27, the voltage conversion circuit converts 5V to a maximum output voltage of 20V through the boost converter LM2704MF-ADJ/NOPB, and uses the 20V power supply to drive the first constant current source unit and the second constant current source unit.

It should be noted that the controller single-chip microcomputer is parallel data, and the USB transmission data is serial data. If the data is transmitted through the USB, the parallel data needs to be converted into serial data. Specifically, as shown in Figure 28, the serial port circuit transfers the USB to the serial port through the USB bus transmission chip CH340E. The circuit converts the parallel data characters received by the microcontroller into continuous serial data streams and sends them out, and simultaneously converts the received serial data streams into parallel data characters and sends them to the microcontroller.

It should be noted that, if the device needs to communicate with external devices through Bluetooth, a Bluetooth unit needs to be set. Specifically, as shown in FIG. 29 , the Bluetooth circuit realizes the communication between the device and external equipment through RF-BM-4044B4, such as the communication between the device and the mobile phone.

Optionally, the control circuit module is a flexible circuit board.

Specifically, the flexible circuit board realizes wearable design and is convenient to use.

In addition, an embodiment of the present invention provides a diabetes monitoring and treatment system based on mesoporous microneedles, including: the above-mentioned device, a Bluetooth unit, and a display unit; wherein,

The display unit is used to display glucose concentration information.

It should be noted that the Bluetooth unit is provided in the control circuit module of the above device.

It should be noted that the display unit may be different types of electronic devices, including but not limited to terminals such as desktop computers, laptop computers, mobile phones, and electronic watches.

Specifically, the use process of the above system is as follows: firstly, a device connected to Bluetooth is selected for Bluetooth connection, and then the device transmits the test data to the display unit through Bluetooth, and the display unit processes and analyzes the test data and displays it.

It should be noted that the display unit may also include other functions, which are not specifically limited in the embodiment of the present invention. For example, the user can also set a threshold value of glucose concentration related to hyperglycemia, and remind the user in an alarm mode; such as calculating the glucose concentration, blood glucose calibration and triggering childbirth, etc.

It should be noted that, since the above device does not filter the collected analog signal, it is necessary to filter the data before calculating the glucose concentration value to eliminate noise interference. The glucose concentration signal is a slowly changing signal, close to a DC signal; therefore, a Butterworth low-pass filter with a cutoff frequency of 1hz is used to filter the glucose concentration signal, and then the output data of the digital filter is converted into a blood glucose value and displayed in real time On the interface, you can view the history of previous blood glucose values by sliding the display interface.

The implementation of the embodiment of the present invention includes the following beneficial effects: the embodiment of the present invention extracts glucose and detects the electrical signal of the glucose concentration through the microneedle counterionphoresis sensor, so as to accurately track the fluctuation of glucose; the control circuit module transmits control according to the electrical signal of the glucose concentration The signal is sent to the microneedle ionophoresis module, and the microneedle ionophoresis module releases insulin according to the control signal to achieve the corresponding release of insulin, thereby effectively regulating the concentration of glucose; Microneedling achieves minimal invasiveness. The above device communicates with a display device through bluetooth, and the display device displays the glucose concentration information to the user in real time, which is convenient for the user to use.

The above is a specific description of the preferred implementation of the present invention, but the present invention is not limited to the described embodiments, and those skilled in the art can make various equivalent deformations or replacements without departing from the spirit of the present invention. , these equivalent modifications or substitutions are all included within the scope defined by the claims of the present application.

Claims

A diabetes monitoring and treatment device based on mesoporous microneedles, characterized in that it includes:

Microneedle counterion electrophoresis sensor, used to extract glucose and detect the electrical signal of glucose concentration;

a control circuit module for sending a control signal to the microneedle ionophoresis module according to the electrical signal of the glucose concentration;

a microneedle ionophoresis module for releasing insulin according to the control signal;

The control circuit module is connected to the microneedle counterionophoresis sensor and the microneedle ionophoresis module.
The device for monitoring and treating diabetes based on mesoporous microneedles according to claim 1, wherein the microneedle counterionophoresis sensor is composed of counter electrode microneedles, mesoporous microneedle arrays, glucose sensing electrodes and 3D printing electrodes. The sensing chamber is assembled.
The device for monitoring and treating diabetes based on mesoporous microneedles according to claim 2, wherein the glucose sensing electrode is a three-electrode system, and the three-electrode system comprises a working electrode, a counter electrode and a reference electrode, The working electrode and the counter electrode are carbon electrodes, and the surface of the carbon electrode sequentially includes a metal mask, a chromium thin film layer and a gold thin film layer.
The device for monitoring and treating diabetes based on mesoporous microneedles according to claim 1, wherein the microneedle ionophoresis module is assembled from counter electrode microneedles, a mesoporous microneedle array and a 3D printing sensing chamber.
The device for monitoring and treating diabetes based on mesoporous microneedles according to any one of claims 2 to 4, wherein the porosity of the mesoporous microneedle array is 45% to 55%.
The device for monitoring and treating diabetes based on mesoporous microneedles according to claim 1, wherein the control circuit module comprises an electrical signal adjustment unit for glucose concentration, a first constant current source unit, and a second constant current source unit , controller and power supply unit; wherein,

the electrical signal adjustment unit of the glucose concentration, for processing the electrical signal of the glucose concentration;

the first constant current source unit, configured to provide a preset constant current to the microneedle counterionophoresis sensor;

The second constant current source unit is used to provide a preset constant current to the microneedle ionophoresis module;

the controller, configured to send the control signal to the microneedle ionophoresis module according to the electrical signal of the processed glucose concentration;

The power supply unit is used to provide power for the control circuit module.
The device for monitoring and treating diabetes based on mesoporous microneedles according to claim 6, wherein the microneedle counterionophoresis sensor comprises a reference electrode, a counter electrode and a working electrode; the electrical signal adjustment of the glucose concentration The unit includes a control amplifier, a reverse follower and a transimpedance amplifier; the reference electrode is connected to the reverse follower, the counter electrode is connected to the control amplifier, and the working electrode is connected to the transimpedance amplifier.
The device for monitoring and treating diabetes based on mesoporous microneedles according to any one of claims 6-7, wherein the control circuit module is a flexible circuit board.
A diabetes monitoring and treatment system based on mesoporous microneedles, characterized by comprising: the device according to any one of claims 1-8, a Bluetooth unit and a display unit; wherein,

the Bluetooth unit for establishing communication between the device and the display unit;

The display unit is used to display glucose concentration information.
The system for monitoring and treating diabetes based on mesoporous microneedles according to claim 9, wherein the system further comprises: a filtering unit for filtering the electrical signal of the glucose concentration.