Multi-parameter microneedle array measurement system and implementation method

Abstract

The invention discloses a multi-parameter microneedle array measurement system and an implementation method. The system comprises a multi-parameter microneedle array, a constant potential rectifier and a control module, the multi-parameter microneedle array is connected with the control module through a pluggable socket joint, and the multi-parameter microneedle array is used for continuously collecting a plurality of parameters; the constant potential rectifier is used for receiving an acquisition signal of the multi-parameter microneedle array and amplifying the acquisition signal based on the type of the acquisition signal to obtain a multi-parameter amplified signal; and the control module is used for receiving the multi-parameter amplification signal and determining index information corresponding to the disease based on the multi-parameter amplification signal. According to the embodiment of the invention, continuous acquisition of signals is realized through the multi-parameter microneedle array, the data acquisition process is simple, and the accuracy of index detection is improved. The method can be widely applied to the technical field of electrochemical detection.

Description

Technical Field

[0001] The invention relates to the technical field of electrochemical detection, in particular to a multi-parameter microneedle array measurement system and an implementation method thereof. Background Art

[0002] Gouty arthritis is a common inflammatory joint disease, and its diagnosis and treatment are crucial to patients. In the related art, uric acid monitoring methods mostly rely on intermittent serum uric acid monitoring, which has problems of insufficient timeliness and accuracy in long-term self-management of patients. In other embodiments, uric acid levels are detected based on sweat or saliva. However, sweat or saliva is difficult to consistently reflect the levels of local key joint parameters. Therefore, uric acid detection in the related art has the problems of poor accuracy and difficult implementation. Summary of the invention

[0003] The purpose of the present invention is to solve one of the technical problems existing in the prior art to at least a certain extent.

[0004] Therefore, the object of the present invention is to provide a high-accuracy multi-parameter microneedle array measurement system and implementation method.

[0005] In order to achieve the above technical objectives, the technical solutions adopted by the embodiments of the present invention include:

[0006] On the one hand, an embodiment of the present invention provides a multi-parameter microneedle array measurement system, comprising:

[0007] The multi-parameter microneedle array measurement system of the embodiment of the present invention comprises: a multi-parameter microneedle array, a constant potentiostat, and a control module; wherein the multi-parameter microneedle array is used to continuously collect multiple parameters; the constant potentiostat is used to receive the acquisition signal of the multi-parameter microneedle array, and based on the type of the acquisition signal, amplify the acquisition signal to obtain a multi-parameter amplified signal; the control module is used to receive the multi-parameter amplified signal, and determine the index information corresponding to the disease based on the multi-parameter amplified signal. The embodiment of the present application collects multiple parameters through a multi-parameter microneedle array, selects the amplification processing method for the type of the acquisition signal through the constant potentiostat, determines the multi-parameter amplified signal, and then determines the index information. The embodiment of the present application directly determines the index information by processing the acquisition signal, which is conducive to improving the accuracy of index detection. The embodiment of the present application realizes continuous acquisition of signals through a multi-parameter microneedle array, the data acquisition process is simple, and it is conducive to improving the accuracy of index detection.

[0008] In addition, the multi-parameter microneedle array measurement system according to the above embodiment of the present invention may also have the following additional technical features:

[0009] Furthermore, in the multi-parameter microneedle array measurement system of an embodiment of the present invention, the constant potentiostat includes an acquisition module, and the acquisition module includes a three-electrode detection circuit and a pH detection circuit; the three-electrode detection circuit is used to amplify and process the current signal, and the pH detection circuit is used to amplify and process the voltage signal.

[0010] Furthermore, in one embodiment of the present invention, the pH detection circuit collects voltage signals through an instrument amplifier, the working electrode and the reference electrode of the pH sensing system are connected to the input end of the instrument amplifier, and the reference voltage of the instrument amplifier is grounded.

[0011] Furthermore, in one embodiment of the present invention, the control module is used to provide a reaction potential to a constant potential instrument, and collect current signals for detecting uric acid and ROS through an inverting follower, a control amplifier and a transimpedance amplifier to detect uric acid and ROS.

[0012] Furthermore, in one embodiment of the present invention, the DAC voltage output by the control module realizes negative feedback through an applied potential operational amplifier circuit; the applied potential operational amplifier circuit includes, the DAC voltage is connected to the non-inverting input terminal of the first operational amplifier, the first power supply is connected to the inverting input terminal of the first operational amplifier, and the inverting input terminal of the first operational amplifier is connected to the output terminal of the first operational amplifier through a first resistor.

[0013] Furthermore, in one embodiment of the present invention, the control module is used to output a voltage signal, which passes through a common-mode amplifier and a follower to obtain the voltage of the reference electrode and the working electrode, forming a voltage loop of the three-electrode system; the counter electrode is connected to the amplifier to form a current loop of the three-electrode system.

[0014] Furthermore, in one embodiment of the present invention, the multi-parameter microneedle array is used to penetrate the skin of the subject to be detected and contact the subcutaneous tissue fluid to obtain the collected data.

[0015] On the other hand, an embodiment of the present invention proposes a method for implementing multi-parameter microneedle array measurement, which is applied to the above-mentioned multi-parameter microneedle array measurement system. The method includes:

[0016] The potentiostat receives the acquisition signal of the multi-parameter microneedle array, and amplifies the acquisition signal based on the type of the acquisition signal to obtain a multi-parameter amplified signal;

[0017] The potentiostat sends the multi-parameter amplified signal to the control module, so that the control module determines the index information corresponding to the disease based on the multi-parameter amplified signal.

[0018] Furthermore, in the implementation method based on multi-parameter microneedle array measurement of the embodiment of the present invention, the constant potential instrument includes an acquisition module, and the acquisition module includes a three-electrode detection circuit and a pH detection circuit; the method also includes:

[0019] It is determined that the three-electrode detection circuit amplifies and processes the current signal through an inverting follower, a control amplifier and a transimpedance amplifier, and the pH detection circuit amplifies and processes the voltage signal through an instrument amplifier.

[0020] Furthermore, the implementation method based on multi-parameter microneedle array measurement of the embodiment of the present invention further includes:

[0021] The control module outputs a voltage signal, which passes through a common-mode amplifier and a follower to obtain the voltages of the reference electrode and the working electrode, forming a voltage loop of the three-electrode system; the counter electrode is connected to the amplifier to form a current loop of the three-electrode system.

[0022] On the other hand, an embodiment of the present invention provides a multi-parameter microneedle array measurement device, comprising:

[0023] at least one processor;

[0024] at least one memory for storing at least one program;

[0025] When the at least one program is executed by the at least one processor, the at least one processor implements the above-mentioned method based on multi-parameter microneedle array measurement.

[0026] On the other hand, an embodiment of the present invention provides a storage medium storing a program executable by a processor, wherein the program executable by the processor is used to implement the above-mentioned method based on multi-parameter microneedle array measurement when executed by the processor.

[0027] The measurement system provided by the embodiment of the present invention includes: a multi-parameter microneedle array, a constant potential instrument, and a control module; wherein the multi-parameter microneedle array is connected to the control module through a pluggable socket connector, and the multi-parameter microneedle array is used to continuously collect multiple parameters; the constant potential instrument is used to receive the acquisition signal of the multi-parameter microneedle array, and based on the type of the acquisition signal, the acquisition signal is amplified to obtain a multi-parameter amplified signal; the control module is used to receive the multi-parameter amplified signal, and based on the multi-parameter amplified signal, determine the indicator information corresponding to the disease. The embodiment of the present application collects multiple parameters through a multi-parameter microneedle array, selects the amplification processing method for the type of the acquisition signal through the constant potential instrument, determines the multi-parameter amplified signal, and then determines the indicator information. The embodiment of the present application directly determines the indicator information by processing the acquisition signal, which is conducive to improving the accuracy of indicator detection. The embodiment of the present application realizes continuous signal acquisition through a multi-parameter microneedle array, the data acquisition process is simple, and it is conducive to improving the accuracy of indicator detection. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the embodiments of the present invention or the drawings of related technical solutions in the prior art are introduced below. It should be understood that the drawings introduced below are only for the convenience of clearly describing some embodiments of the technical solutions of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative work.

[0029] Figure 1 A schematic diagram of the structure of an embodiment of a multi-parameter microneedle array measurement system provided in the present application;

[0030] Figure 2 A method of wearing the multi-parameter microneedle array measurement device provided in this application;

[0031] Figure 3a An electrical schematic diagram of an embodiment of a power module provided in the present application;

[0032] Figure 3b An electrical schematic diagram of another embodiment of the power module provided in the present application;

[0033] Figure 3c An electrical schematic diagram of an embodiment of a charging module provided in the present application;

[0034] Figure 3d An electrical schematic diagram of an embodiment of a power switching module provided by the present application;

[0035] Figure 4a An electrical schematic diagram of an embodiment of an inverter provided by the present application;

[0036] Figure 4b An electrical schematic diagram of an embodiment of a transimpedance amplifier circuit provided by the present application;

[0037] Figure 4c An electrical schematic diagram of an embodiment of a three-electrode detection circuit provided by the present application;

[0038] Figure 4d An electrical schematic diagram of an embodiment of an applied potential operational amplifier circuit provided by the present application;

[0039] Figure 4e An electrical schematic diagram of an embodiment of a pH detection circuit provided in the present application;

[0040] Figure 4f An electrical schematic diagram of an embodiment of a transimpedance amplifier circuit provided by the present application;

[0041] Figure 5a An input-output performance diagram of an embodiment of a ROS sensing channel provided in the present application;

[0042] Figure 5b An input-output performance diagram of an embodiment of a uric acid sensing channel provided in the present application;

[0043] Figure 5c An input-output performance diagram of an embodiment of a pH sensing channel provided by the present application;

[0044] Figure 6a A schematic diagram of in vitro electrochemical performance characterization of an embodiment of the ROS sensing channel provided in the present application;

[0045] Figure 6b A schematic diagram of in vitro electrochemical performance characterization of an embodiment of the uric acid sensing channel provided in the present application;

[0046] Figure 6c A schematic diagram of in vitro electrochemical performance characterization of an embodiment of a pH sensing channel provided in the present application;

[0047] Figure 7a A schematic diagram of a display interface of an embodiment of the ROS level display provided in the present application;

[0048] Figure 7b A schematic diagram of a display interface of an embodiment of UA horizontal display provided by the present application;

[0049] Figure 7c A schematic diagram of a display interface of an embodiment of pH value display provided in the present application;

[0050] Figure 8a A schematic diagram of an embodiment of the animal experiment provided in this application;

[0051] Figure 8b A schematic diagram of an embodiment of the animal experiment time map provided in this application;

[0052] Figure 8c A diagram showing an embodiment of swelling changes in relevant parts of an animal provided in the present application;

[0053] Figure 8d A change diagram of an embodiment of the swelling changes in relevant parts of a healthy animal provided in the present application;

[0054] Figure 8e A diagram showing an embodiment of the changes in swelling of relevant parts of an arthritic animal provided in the present application;

[0055] Figure 8f A comparison diagram of an embodiment of in vivo detection of uric acid sensing channels in animal experiments provided in this application;

[0056] Figure 8g A comparison diagram of an embodiment of in vivo detection of ROS sensing channels in animal experiments provided in this application;

[0057] Figure 8h A comparison diagram of an embodiment of in vivo detection of pH sensing channels in animal experiments provided in this application. DETAILED DESCRIPTION

[0058] The embodiments of the present invention are described in detail below, and examples of the embodiments are shown in the accompanying drawings, wherein the same or similar reference numerals throughout represent the same or similar elements or elements having the same or similar functions. The embodiments described below with reference to the accompanying drawings are exemplary and are only used to explain the present invention, and are not to be construed as limitations of the present invention. For the step numbers in the following embodiments, they are only provided for the convenience of explanation, and the order between the steps is not limited in any way, and the execution order of each step in the embodiment can be adaptively adjusted according to the understanding of those skilled in the art.

[0059] The combination of microneedles and biosensors has been widely and deeply studied and applied in recent years. The arrayed device prepared based on the microneedle structure is the microneedle array. The microneedle array can penetrate the skin and directly contact the subcutaneous tissue fluid without causing nerve damage and bleeding. It has a wide range of applications in tissue fluid extraction, marker detection, and drug vaccine delivery. Interstitial fluid is a subcutaneous human body fluid that continuously exchanges substances with blood through capillaries. The material composition and content of each component are close to those of blood. Therefore, microneedle arrays have gradually matured in the application of continuous monitoring of tissue fluid and have become a powerful tool for biomarker sampling and diagnosis. At present, biosensors based on microneedle arrays are particularly outstanding in multi-parameter system integration and in vivo marker analysis through functional modifications such as biological proteases and ion-selective membranes.

[0060] Gouty arthritis is a common inflammatory joint disease, and its diagnosis and treatment are crucial for patients. Existing treatment methods mainly rely on long-term uric acid-lowering treatment and adjust the treatment plan according to the treatment effect. However, existing uric acid monitoring methods mostly rely on intermittent serum uric acid monitoring, which has problems of lack of timeliness and accuracy in long-term self-management of patients. Microneedle arrays realize multi-parameters, which can quickly collect dynamic information of multiple biomarkers and transmit them to mobile applications for real-time display.

[0061] The gold standard for diagnosing gouty arthritis involves collecting synovial fluid or gouty stone samples through joint puncture and examining for the presence of monosodium urate crystals (MSU). However, joint puncture requires anesthesia and bandaging, which can cause great pain to patients. Currently, some technologies are based on sweat or saliva to detect uric acid levels, however, sweat or saliva is difficult to consistently reflect the levels of local key joint parameters. In addition, current strategies for managing gout focus mainly on long-term uric acid-lowering therapy, which may also be accompanied by inflammatory responses caused by gout attacks. Therefore, based on the rapidly developing point-of-care testing technology (POCT; also known as bedside testing; refers to a test method that is performed near the patient and can quickly obtain test results), continuous tracking of multiple gout-related biomarkers, such as uric acid and inflammatory cytokines, can provide rapid and personalized diagnosis for gout treatment.

[0062] The following describes in detail a multi-parameter microneedle array measurement system and an implementation method according to an embodiment of the present invention with reference to the accompanying drawings. First, a multi-parameter microneedle array measurement system according to an embodiment of the present invention is described with reference to the accompanying drawings.

[0063] Figure 1 : is a schematic diagram of the structure of a multi-parameter microneedle array measurement system according to an embodiment of the present invention, wherein the system specifically comprises:

[0064] Multi-parameter microneedle array, potentiostat, and control module;

[0065] Wherein, the multi-parameter microneedle array is connected to the control module via a pluggable socket connector; the multi-parameter microneedle array is used to continuously collect multiple parameters;

[0066] The constant potentiostat is used to receive the acquisition signal of the multi-parameter microneedle array, and based on the type of the acquisition signal, amplify the acquisition signal to obtain a multi-parameter amplified signal;

[0067] The control module is used to receive the multi-parameter amplified signal and determine indicator information corresponding to the disease based on the multi-parameter amplified signal.

[0068] Specifically, the embodiment of the present application can determine different amplification processing methods according to the type of collected signal. For example, different types of amplification circuits are used to amplify the voltage signal and the current signal. This technology is based on a multi-parameter microneedle array (PIMNA) and is integrated into a portable device. The device is miniaturized and low-cost as a whole, and can realize continuous monitoring of multiple parameters such as uric acid, reactive oxygen species (ROS) and pH value in interstitial fluid to comprehensively collect information on acute symptoms of gout. PIMNA is functionally modified based on precious metal materials, biological proteases and ion-selective membranes, and is further combined with pluggable socket connectors to achieve tight electrical connection of the sensor and simple replaceable design. In the in vitro electrochemical experimental characterization of each parameter, PIMNA shows good sensitivity, detection range and specificity. After amplification and processing, the sensor signal collected by the device can be wirelessly transmitted to a mobile application to display the dynamic changes of each parameter in real time. In addition, PIMNA can realize continuous monitoring of three parameters in in vivo experiments, which shows that it has potential application value in clinical evaluation and has the possibility of assisting gout management.

[0069] This technical solution uses a low-cost commercial pluggable interface to prepare the sensor. If the connection interface between the microneedle and the array substrate is customized, it can ensure pluggability while achieving a smaller microneedle array distribution area, stable electrical connection and reliable plug-in replacement. In addition, in some possible implementations, a precision four-channel operational amplifier chip (AD8608) can be used to replace each OPA2140 separation amplifier circuit in the acquisition system to further reduce the system area.

[0070] Optionally, in the multi-parameter microneedle array measurement system in an embodiment of the present invention, the constant potentiostat includes an acquisition module, and the acquisition module includes a three-electrode detection circuit and a pH detection circuit; the three-electrode detection circuit is used to amplify and process the current signal, and the pH detection circuit is used to amplify and process the voltage signal.

[0071] Optionally, in the multi-parameter microneedle array measurement system in the embodiment of the present invention, the pH detection circuit collects voltage signals through an instrument amplifier, the working electrode and reference electrode of the pH sensing system are connected to the input end of the instrument amplifier, and the reference voltage of the instrument amplifier is grounded.

[0072] In some possible implementations, the pH detection circuit adjusts the amplification factor through resistance.

[0073] Optionally, in the multi-parameter microneedle array measurement system in an embodiment of the present invention, the control module is used to provide a reaction potential to the constant potentiostat, and collect current signals for detecting uric acid and ROS through an inverting follower, a control amplifier and a transimpedance amplifier to detect uric acid and ROS.

[0074] In some possible embodiments, the inverting follower includes a control module output terminal connected to the inverting input terminal of the second operational amplifier U11.2, the non-inverting input terminal of the second operational amplifier is grounded, and the inverting input terminal of the second operational amplifier is connected to the output terminal of the second operational amplifier. The transimpedance amplifier is used to convert the current signal between the working electrode and the counter electrode into a voltage signal so as to process the voltage signal through the control module. The control module is used to output a control signal through the output terminal, determine the output of the multiplexer, and then determine the negative feedback resistance of the transimpedance amplifier.

[0075] Optionally, in the multi-parameter microneedle array measurement system in the embodiment of the present invention, the DAC voltage output by the control module realizes negative feedback through an applied potential operational amplifier circuit; the applied potential operational amplifier circuit includes, the DAC voltage is connected to the non-inverting input terminal of the first operational amplifier, the first power supply is connected to the inverting input terminal of the first operational amplifier, and the inverting input terminal of the first operational amplifier is connected to the output terminal of the first operational amplifier through a first resistor.

[0076] Optionally, in the multi-parameter microneedle array measurement system in the embodiment of the present invention, the control module is used to output a voltage signal, which passes through a common-mode amplifier and a follower to obtain the voltage of the reference electrode and the working electrode to form a voltage loop of a three-electrode system; the counter electrode is connected to the amplifier to form a current loop of the three-electrode system.

[0077] Optionally, in the multi-parameter microneedle array measurement system in the embodiment of the present invention, the multi-parameter microneedle array is used to penetrate the skin of the subject to be detected and contact the subcutaneous tissue fluid to obtain the collected data.

[0078] The multi-parameter microneedle array measurement system of the embodiment of the present invention comprises: a multi-parameter microneedle array, a constant potential instrument, and a control module; wherein the multi-parameter microneedle array is connected to the control module through a pluggable socket connector, and the multi-parameter microneedle array is used to continuously collect multiple parameters; the constant potential instrument is used to receive the acquisition signal of the multi-parameter microneedle array, and based on the type of the acquisition signal, the acquisition signal is amplified to obtain a multi-parameter amplified signal; the control module is used to receive the multi-parameter amplified signal, and based on the multi-parameter amplified signal, determine the index information corresponding to the disease. The embodiment of the present application collects multiple parameters through a multi-parameter microneedle array, selects the amplification processing method for the type of the acquisition signal through the constant potential instrument, determines the multi-parameter amplified signal, and then determines the index information. The embodiment of the present application directly determines the index information by processing the acquisition signal, which is conducive to improving the accuracy of index detection. The embodiment of the present application realizes continuous acquisition of signals through a multi-parameter microneedle array, the data acquisition process is simple, and it is conducive to improving the accuracy of index detection.

[0079] Next, a method for implementing multi-parameter microneedle array measurement according to an embodiment of the present invention will be described.

[0080] An implementation method based on multi-parameter microneedle array measurement is provided in an embodiment of the present invention. The implementation method based on multi-parameter microneedle array measurement in the embodiment of the present invention can be applied to a terminal, can be applied to a server, or can be software running in a terminal or a server. The terminal can be a tablet computer, a laptop computer, a desktop computer, etc., but is not limited to this. The server can be an independent physical server, or a server cluster or distributed system composed of multiple physical servers, or a cloud server that provides basic cloud computing services such as cloud services, cloud databases, cloud computing, cloud functions, cloud storage, network services, cloud communications, middleware services, domain name services, security services, CDN, and big data and artificial intelligence platforms. The implementation method based on multi-parameter microneedle array measurement in the embodiment of the present invention is applied to the multi-parameter microneedle array measurement system described above, and mainly includes the following steps:

[0081] The potentiostat receives the acquisition signal of the multi-parameter microneedle array, and amplifies the acquisition signal based on the type of the acquisition signal to obtain a multi-parameter amplified signal;

[0082] The potentiostat sends the multi-parameter amplified signal to the control module, so that the control module determines the index information corresponding to the disease based on the multi-parameter amplified signal.

[0083] Optionally, in the implementation method based on multi-parameter microneedle array measurement in the embodiment of the present invention, the constant potential instrument includes an acquisition module, and the acquisition module includes a three-electrode detection circuit and a pH detection circuit; the method also includes:

[0084] It is determined that the three-electrode detection circuit amplifies and processes the current signal through an inverting follower, a control amplifier and a transimpedance amplifier, and the pH detection circuit amplifies and processes the voltage signal through an instrument amplifier.

[0085] Optionally, the implementation method based on multi-parameter microneedle array measurement in the embodiment of the present invention also includes: the control module outputs a voltage signal, which passes through a common-mode amplifier and a follower to obtain the voltage of the reference electrode and the working electrode to form a voltage loop of the three-electrode system; the counter electrode is connected to the amplifier to form a current loop of the three-electrode system.

[0086] It can be seen that the contents of the above system embodiments are all applicable to the present method embodiments, the functions specifically implemented by the present method embodiments are the same as those of the above system embodiments, and the beneficial effects achieved are also the same as those achieved by the above system embodiments.

[0087] The following is a description of the multi-parameter microneedle array measurement system and implementation method proposed in the embodiment of the present application with a specific embodiment, specifically:

[0088] Reference Figure 2 The wearing method and the composition of the measuring system shown in the figure, the measuring system provided by the present application can be placed on any part of the human body for measurement, and the present application does not make any specific restrictions. At the same time, the measuring system provided by the present application also includes a Bluetooth module for transmitting the measurement data between different modules.

[0089] For the signal acquisition, processing and transmission module, the main control module (i.e., control module) of the multi-parameter microneedle array system in the embodiment of the present application can be selected from MCU STM32F103RCT6, which is based on the ARM Cortex-M3 core, with a maximum operating frequency of 72MHz, 256K bytes of flash memory, 48K bytes of SRAM, and built-in 3 12-bit analog-to-digital converters (ADC) and two 12-bit digital-to-analog converters (DAC). The ADC can convert the collected sensor electrical signals into digital signals for storage and transmission in the next step, and the DAC can provide a reaction potential for the constant potential instrument system. The MCU main control module is the control core of the entire system. First, the MCU is responsible for the control of the multi-channel constant potential instrument module. First, the DAC channel is used to control the potential applied to the three-electrode reaction system to detect uric acid and ROS using the IT method; second, the ADC module transmits the collected signal to the host computer through the communication module for display, which is connected to the chip CH340E to realize the serial port to USB (type-c) to transmit the collected signal to the host computer on the computer. On the other hand, the MCU is also connected to the Bluetooth chip RF-BM-4044B4 (produced by Xinchida Company), and the collected signals are sent to the host computer on the computer or mobile phone through Bluetooth transparent transmission. The RF-BM-4044B4 is a low-power Bluetooth radio frequency module with advantages such as small size (8mm×8mm), long transmission distance, and strong anti-interference ability. The module contains a 32-bit ARM Cortex-M3 processor, which has the same operating frequency of 24MHz as the main processor. It is suitable for connecting external sensors or autonomously collecting analog and digital data when the system is in sleep mode. This architecture can improve overall system performance and power consumption, and release flash memory for applications.

[0090] Refer to the schematic diagram of the power module in the multi-parameter electrochemical monitoring system shown in Figure 3; the power module provides power for the entire circuit through two schemes: lithium battery and USB power supply. There are three main power lines, one is the 3.3V voltage for the MCU to work, and the other is the 5V voltage and -5V voltage for the amplifier in the constant potential instrument to work. Because in the three-electrode system, WE is generally virtual grounded. When the current in the reaction system flows from WE to CE, the voltage will be less than 0V. Therefore, in order for the constant potential instrument to provide reliable and stable functions, 5V and -5V voltages are required. In addition, in the power module, when the system is connected to USB, the USB will charge the lithium battery through the lithium battery charging module; and the switching between USB power supply and lithium battery power supply is realized through three MOS tubes, that is, when the USB is connected, the modules of the system are powered by USB; when the USB is disconnected, the system is powered by lithium batteries. The hardware design of the signal acquisition module depends on the type of signal generated by each sensor.

[0091] Fig. 4 is a schematic diagram of a signal acquisition module (i.e., a constant potential instrument in an embodiment of the present application) in a multi-parameter electrochemical monitoring system; the signal acquisition module is divided into a three-electrode detection circuit and a pH detection circuit, wherein the three-electrode detection circuit is based on a design of a constant potential instrument. The main control module outputs a voltage through a DAC, obtains the voltage required for the reference electrode and the working electrode through a common-mode amplifier, a follower, etc., and realizes a voltage loop in a three-electrode system. On the other hand, the counter electrode is connected to the amplifier to form a current loop of a three-electrode system. The three-electrode system collects current signals, which are connected to a transresistance through a working electrode to convert the current signal into a voltage signal. Since the range of current generated by different biomarkers varies greatly, in the design of the feedback resistor of the transresistance amplifier, different transresistances are selected by a multiplexer to realize different detection ranges of the system. In the pH detection circuit, the voltage signal in the application scenario is collected by an instrument amplifier.

[0092] The power module provides power to the entire PCB through two options: 3.7V lithium battery and USB power supply. The power supply potential includes a 3.3V voltage for the MCU to work (refer to Figure 3b As shown), supply 5V voltage and -5V voltage (refer to Figure 3a In the USB power supply solution, it can charge the lithium battery through the TP5400 charging protection chip (refer to Figure 3c On the other hand, the power switching module composed of three MOS tubes directly outputs 5V (refer to Figure 3d As shown in the figure). In the 3.7V lithium battery power supply solution, it can be directly boosted to 5.0V through the TP5400 charging protection chip. Because the TP5400 does not allow the lithium battery to work during the charging process, the power supply is supplied by the USB when the USB is connected through the power switching module. When the USB is not connected, it is powered by the lithium battery.

[0093] For pH signal detection, the signal collected by the sensor is of voltage type. Therefore, in order to reduce noise and stabilize, an instrument amplifier is used to realize open circuit voltage signal acquisition, such as Figure 4e As shown. First, the working electrode and reference electrode of the pH sensor system are connected to the input of the instrument amplifier. The reference voltage of the instrument amplifier is connected to the analog ground to prevent the open circuit voltage from floating. In order to collect the signal-to-noise ratio, stability and accuracy of the signal, the voltage signal is amplified by 3 times through an external resistor. For the collection of uric acid and ROS signals, the sensing signal is current type. Therefore, an inverting follower ( Figure 4a As shown), control amplifier and transimpedance amplifier are used to realize the acquisition of constant potentiostat signal. Figure 4cAs shown, the inverting follower forms a buffer to stabilize the voltage of the reference voltage, so that a stable potential difference is maintained between the working electrode and the reference electrode connected to the virtual ground of the TIA. In order to enable the constant potential instrument to simultaneously meet the requirements of ROS and UA sensing, the circuit of the DAC applying the potential is designed with negative feedback ( Figure 4d As shown), the DAC output voltage is added or subtracted from the 3.3V voltage to achieve the application of positive and negative voltages. Specifically, the DAC output end of the control module is connected to the positive input end of the first operational amplifier (i.e., U9.1), the output end of the first operational amplifier is connected to the positive input end of the third operational amplifier (i.e., U9.2), and the inverting input end of the third operational amplifier is connected to the output end of the third operational amplifier; the output end of the third operational amplifier is connected to the inverting input end of the fourth operational amplifier (U10.1), the positive input end of the fourth operational amplifier is grounded, the inverting input end of the fourth operational amplifier is connected to the output end of the fourth operational amplifier, and the output end of the fourth operational amplifier is connected to the counter electrode.

[0094] Figure 4b As shown in the figure, the transimpedance amplifier converts the current signal between the working electrode and the counter electrode into a voltage signal and transmits it to the ADC of the MCU for processing. Due to the different magnitudes of the current signals of uric acid and ROS, the negative feedback resistor of the transimpedance amplifier is configured with different resistors through a multiplexer (refer to Figure 4f ) in order to achieve nA to μA current signal accuracy within the ADC input voltage range (0–3.3V).

[0095] Figure 5a , Figure 5b , Figure 5c These are the input and output performance display diagrams of the ROS sensing channel, uric acid sensing channel, and pH sensing channel of the multi-parameter microneedle array system. Figure 6a In vitro electrochemical performance characterization of a multi-parameter microneedle array system for ROS sensing. Figure 6b In vitro electrochemical performance characterization of a multi-parameter microneedle array system for uric acid sensing. Figure 6c The in vitro electrochemical performance characterization of pH sensing of a multi-parameter microneedle array system is shown in FIG.

[0096] FIG. 7 is a schematic diagram of an embodiment of a display module provided in an embodiment of the present application, specifically, displaying a data display interface through a mobile application. Figure 7a , Figure 7b , Figure 7c Dynamic graphs of ROS level, UA level, and pH value are shown respectively.

[0097] In the specific measurement process, it can be understood that the microneedle array in the embodiment of the present application can adopt any form of microneedle array on the market, and can also be customized according to actual needs, and the present application does not make specific restrictions. The multi-parameter microneedle array in the embodiment of the present application can include a gold electrode microneedle plug, H2O2, uric acid and pH sensing electrodes, a counter electrode and a reference electrode. The electrode can be made with a stainless steel needle as the substrate through electroplating, cleaning and other steps.

[0098] The usability of the measurement system proposed in this application is verified by a specific embodiment below, specifically:

[0099] Embodiment 1:

[0100] A. Construction of rat model of gouty arthritis;

[0101] Sprague Dawley (SD) rats (SPF grade, male, 200-250 g) were adapted to the laboratory environment for one week. Before constructing the acute gout model in rats, 0.2 mL of Cefixime 50 was injected to anesthetize the rats, and continuous anesthesia was achieved by injecting 0.06 mL of Cefixime 50. Then, the rat hair in the ankle joint area was shaved with a razor and depilatory cream. The experiment was divided into two groups, one was the experimental group and the other was the control group. For the experimental group, in order to create a gouty arthritis model, 0.2 mL of 50 mg / mL MSU suspension (the dilution solution was normal saline) was injected into the ankle joint of the rat with a syringe. For the control group, it remained normal and no injection was performed. To ensure that the MSU suspension did not clog the syringe needle and cause the injection to fail, the MSU suspension was ultrasonically agitated for 2 hours before injection.

[0102] 1. The width and thickness of the left and right ankle joints of the rats in the control group and the treated group were measured with a vernier caliper. Each ankle joint point was measured three times and the average value was taken.

[0103] 2. Record the activity characteristics of healthy rats and treated rats in the control group (Control) before modeling by video;

[0104] 3. Inject 0.2 mL of Serum-50 into the rats in the control group and the treated group for anesthesia. During the experiment, pay attention to the state of the rats. When the rats are about to wake up, administer about 0.06 mL of Serum-50 for continuous anesthesia.

[0105] 4. Use an electric hair scalpel and depilatory cream to remove hair from the two ankle joints of the rats to make the ankle joints clearly exposed. Pay attention to reducing friction damage to the skin during the depilation process, otherwise it will affect the subsequent observation of the joint inflammation index;

[0106] 5. Treated group: First, puncture the subcutaneous part of the ankle joint of the rat at a 45° angle, insert the injection needle into the joint, and inject 0.2 mL of sodium urate crystal suspension solution (concentration of 50 mg / mL, solvent is normal saline, and ultrasonic oscillation is performed overnight the night before use) into the ankle joint cavity;

[0107] 6. The two ankle joints of the rats in the control group (Control) were not injected and remained normal after hair removal;

[0108] 7. After the injection, the width and thickness of the ankle joint of the test rats were measured with a vernier caliper. Each ankle joint point was measured three times and the average value was taken.

[0109] B. Multi-parameter microneedle array continuous monitoring experiment

[0110] After the experimental rats were anesthetized with Shutai 50, the ankle joints of the modeling rats were kept dry, and the multi-parameter microneedle array was attached to the ankle joints, and the MN penetrated the rat skin layer and contacted the joint fluid. The multi-parameter microneedle array was fixed to the ankle joints of the rats by medical tape to ensure the continuous wearing of the multi-parameter microneedle array. In order to obtain more stable signals in animal experiments, the sensor array was connected to the CHI760E electrochemical workstation. Starting from the 4th hour of modeling injection, acute gout-related physiological parameters, including ROS, UA and pH, were recorded every 30 minutes. For uric acid detection, 0.5V was applied each time, and the it current curve was collected for 150s. For ROS detection, -0.5V was applied each time, and the it current curve was collected for 150s. For pH detection, the open circuit voltage was collected for 40s. The experiment lasted 3h every day, for a total of 3 consecutive days. Finally, the collected voltage and current signals were calibrated by the in vitro standard curve to obtain the actual changes in uric acid, ROS and pH concentrations. In addition, before the start of the experiment each day, we used an inelastic rope to measure the ankle swelling of the experimental and control groups at 0h, 5h, 10h, 24h, 48h and 72h, respectively, for a total of 4 days, and measured the corresponding rope length with a measuring ruler to more accurately obtain the swelling degree of the rat ankle joints.

[0111] The experimental steps are as follows:

[0112] 1. Before anesthetizing the rats, observe the gait activities of the rats in the control group (Control) and the treated group (Treated) and record them by video;

[0113] 2. Place the electrochemical workstation properly, make sure the computer and electrochemical workstation are stably connected, and the software can run normally.

[0114] 3. Anesthetize the rats to be tested by injecting 0.2 mL of Serum-50. Pay attention to the rat's condition during the experiment. If the rat shows signs of awakening during the experiment, administer about 0.06 mL of Serum-50 for continuous anesthesia.

[0115] 4. Parallel experiment electrochemical detection: The anesthetized treated and control rats were placed on their sides. The modified metal microneedle arrays were implanted subcutaneously in the left and right ankle joints of the two groups of rats and fixed with medical tape. The sensor array end was connected to the adapter board through a DuPont line, and the adapter board was directly connected to the three-electrode crocodile head interface of the electrochemical workstation.

[0116] 5. After fixing the microneedle array, start the electrochemical workstation and open the CHI760E software. Perform a round of tests on the three parameters of uric acid (IT method, applying positive pressure of 0.5V for 150s), reactive oxygen (IT method, applying negative pressure of -0.5V for 150s), and pH (open circuit voltage method for 100s) in sequence every 15 minutes. Continue the test for 3 hours.

[0117] 6. At each testing time point, collect 0.5 mL of blood from the tail, let it stand for 1 hour, and then centrifuge it at 5000 rpm for 5 minutes. Extract the supernatant and refrigerate it at -80°C to facilitate the subsequent concentration detection of UA, pH, ROS, etc. using a kit and a biochemical analyzer. After obtaining the results, compare them with the current value or voltage value obtained in step 5.

[0118] 7. Calibration test: After testing the ankle joints of the control group (Control) and the treated group (Treated), the microneedle arrays were implanted into the knee joints of the rats and monitored continuously for 1 hour. The three parameters of uric acid (IT method, applying positive pressure of 0.5V), reactive oxygen (IT method, applying negative pressure of -0.5V), and pH were measured in sequence every 15 minutes.

[0119] At the detection time point in the calibration test, 0.5 mL of blood was collected from the tail, and after standing for 1 hour, it was centrifuged at 5000 rpm for 5 minutes. The supernatant was extracted and refrigerated in a -80°C environment to facilitate the subsequent concentration detection of UA, pH, ROS, etc. using a kit and a biochemical analyzer. After the results are obtained, they are calibrated with the current value or voltage value obtained in step 6.

[0120] FIG8 Multiparametric microneedle array in vivo study for early acute gouty arthritis. Figure 8a The diagrams are animal modeling and multi-parameter microneedle array modeling. The multi-parameter microneedle array can be a plug-in microneedle array. Figure 8bThe animal experiment process includes the injection time of MSU into the rat ankle joint and the detection time. Demonstration diagram of the multi-parameter microneedle array system placed in the gouty ankle joint of the rat to monitor the state of joint inflammation. MSU: monosodium urate crystals. Figure 8c The swelling coefficient of the ankle joint of rats with gout in 4 days is shown in Table 1. The swelling width of the ankle joint at each time point is subtracted from the swelling width at 0h to obtain the difference, and the ratio of the difference to the swelling width of the ankle joint at 0h is the swelling coefficient. Figure 8d This is a graph showing the changes in ankle swelling in healthy rats for three consecutive days. Figure 8e This is a graph showing the changes in ankle joint swelling in rats with gouty arthritis for three consecutive days. Figure 8f This is the in vivo continuous detection of uric acid sensor, where i is a gouty arthritis model rat and ii is a healthy rat. Figure 8g In vivo continuous detection of ROS sensors, i is a gouty arthritis model rat, and ii is a healthy rat. Figure 8h The H sensor is continuously tested in vivo, i is a rat with gouty arthritis model, and ii is a healthy rat. After testing, the multi-parameter microneedle array measurement system proposed in the embodiment of the present application can be used for the measurement of relevant parameters with high accuracy.

[0121] The embodiment of the present application is based on a functionalized microneedle electrode, and a multi-parameter microneedle array is prepared and integrated into a portable device. The device is miniaturized and low-cost as a whole, and can realize continuous monitoring of multiple parameters such as uric acid, ROS and pH value in interstitial fluid to comprehensively collect information on acute symptoms of gout. The multi-parameter microneedle array is functionally modified based on precious metal materials, biological proteases and ion-selective membranes. Through the design of the above materials, the multi-parameter microneedle array can achieve high-sensitivity detection of multiple biomarkers such as ROS, uric acid and pH value. In the in vitro electrochemical experimental characterization of each parameter, the multi-parameter microneedle array showed good sensitivity, detection range and specificity. The sensor signals collected by the device can be wirelessly transmitted to the mobile application after amplification and processing, and the dynamic changes of each parameter can be displayed in real time. In addition, the multi-parameter microneedle array can realize continuous monitoring of three parameters in in vivo experiments, which shows that it has potential application value in clinical evaluation and has the possibility of assisting gout management. Therefore, the measurement system proposed in the embodiment of the present application can be used in a portable POCT device based on a microneedle array to realize a monitoring scheme for multiple parameters such as key factors and inflammatory markers, which has broad application prospects in the rapid assessment and diagnosis of arthritis in the future.

[0122] On the other hand, an embodiment of the present invention provides a multi-parameter microneedle array measurement device, comprising:

[0123] at least one processor;

[0124] at least one memory for storing at least one program;

[0125] When the at least one program is executed by the at least one processor, the at least one processor implements the method based on multi-parameter microneedle array measurement.

[0126] Similarly, the contents of the above method embodiments are all applicable to the present device embodiments. The functions specifically implemented by the present device embodiments are the same as those of the above method embodiments, and the beneficial effects achieved are also the same as those achieved by the above method embodiments.

[0127] An embodiment of the present invention further provides a computer-readable storage medium, in which a program executable by a processor is stored. When the program executable by the processor is executed by the processor, it is used to execute the above-mentioned implementation method based on multi-parameter microneedle array measurement.

[0128] Similarly, the contents of the above method embodiments are all applicable to the present storage medium embodiments. The functions specifically implemented by the present storage medium embodiments are the same as those of the above method embodiments, and the beneficial effects achieved are also the same as those achieved by the above method embodiments.

[0129] In some selectable embodiments, the function / operation mentioned in the block diagram may not occur in the order mentioned in the operation diagram. For example, depending on the function / operation involved, the two boxes shown in succession can actually be executed substantially simultaneously or the boxes can sometimes be executed in reverse order. In addition, the embodiment presented and described in the flow chart of the present invention is provided by way of example, for the purpose of providing a more comprehensive understanding of technology. The disclosed method is not limited to the operation and logic flow presented herein. Selectable embodiments are expected, wherein the order of various operations is changed and the sub-operation of a part for which is described as a larger operation is performed independently.

[0130] In addition, although the present invention is described in the context of functional modules, it should be understood that, unless otherwise specified, one or more of the functions and / or features can be integrated into a single physical device and / or software module, or one or more functions and / or features can be implemented in a separate physical device or software module. It is also understood that a detailed discussion of the actual implementation of each module is unnecessary for understanding the present invention. More specifically, in view of the properties, functions and internal relationships of the various functional modules in the device disclosed herein, the actual implementation of the module will be understood within the conventional skills of the engineer. Therefore, those skilled in the art can implement the present invention set forth in the claims without excessive experimentation using ordinary techniques. It is also understood that the specific concepts disclosed are merely illustrative and are not intended to limit the scope of the present invention, which is determined by the full scope of the appended claims and their equivalents.

[0131] If the functions are implemented in the form of software functional units and sold or used as independent products, they can be stored in a computer-readable storage medium. Based on this understanding, the technical solution of the present invention, or the part that contributes to the prior art or the part of the technical solution, can be embodied in the form of a software product. The computer software product is stored in a storage medium, including several programs to enable a computer device (which can be a personal computer, a server, or a network device, etc.) to perform all or part of the steps of the methods described in each embodiment of the present invention. The aforementioned storage medium includes: U disk, mobile hard disk, read-only memory (ROM, Read-Only Memory), random access memory (RAM, Random Access Memory), disk or optical disk, etc., which can store program codes.

[0132] The logic and / or steps represented in the flowchart or otherwise described herein, for example, may be considered as an ordered list of executable programs for implementing the logical functions, and may be embodied in any computer-readable medium for use by a program execution system, device or apparatus (such as a computer-based system, a system including a processor, or other system that can fetch and execute a program from a program execution system, device or apparatus), or in conjunction with such program execution systems, devices or apparatuses. For purposes of this specification, a "computer-readable medium" may be any device that can contain, store, communicate, propagate or transmit a program for use by a program execution system, device or apparatus, or in conjunction with such program execution systems, devices or apparatuses.

[0133] More specific examples of computer-readable media (a non-exhaustive list) include the following: an electrical connection with one or more wires (electronic device), a portable computer disk case (magnetic device), a random access memory (RAM), a read-only memory (ROM), an erasable and programmable read-only memory (EPROM or flash memory), an optical fiber device, and a portable compact disk read-only memory (CDROM). In addition, the computer-readable medium may even be a paper or other suitable medium on which the program is printed, since the program may be obtained electronically, for example, by optically scanning the paper or other medium, followed by editing, deciphering or, if necessary, processing in another suitable manner, and then stored in a computer memory.

[0134] It should be understood that the various parts of the present invention can be implemented by hardware, software, firmware or a combination thereof. In the above-mentioned embodiments, a plurality of steps or methods can be implemented by software or firmware stored in a memory and executed by a suitable program execution system. For example, if implemented by hardware, as in another embodiment, it can be implemented by any one of the following technologies known in the art or their combination: a discrete logic circuit having a logic gate circuit for implementing a logic function for a data signal, a dedicated integrated circuit having a suitable combination of logic gate circuits, a programmable gate array (PGA), a field programmable gate array (FPGA), etc.

[0135] In the above description of this specification, the description with reference to the terms "one embodiment / example", "another embodiment / example" or "certain embodiments / examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner.

[0136] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the claims and their equivalents.

[0137] 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. Those skilled in the art may make various equivalent modifications or substitutions without violating the spirit of the present invention. These equivalent modifications or substitutions are all included in the scope defined by the claims of the present invention.

Claims

1. A multi-parameter microneedle array measurement system, characterized in that: The measurement system comprises: a multi-parameter microneedle array, a constant potential instrument, and a control module; Wherein, the multi-parameter microneedle array is connected to the control module via a pluggable socket connector; the multi-parameter microneedle array is used to continuously collect multiple parameters; The constant potentiostat is used to receive the acquisition signal of the multi-parameter microneedle array, and based on the type of the acquisition signal, amplify the acquisition signal to obtain a multi-parameter amplified signal; The control module is used to receive the multi-parameter amplified signal and determine indicator information corresponding to the disease based on the multi-parameter amplified signal.

2. The multi-parameter microneedle array measurement system according to claim 1, characterized in that: The constant potential instrument includes an acquisition module, which includes a three-electrode detection circuit and a pH detection circuit; the three-electrode detection circuit is used to amplify and process the current signal, and the pH detection circuit is used to amplify and process the voltage signal.

3. The multi-parameter microneedle array measurement system according to claim 2, characterized in that: The pH detection circuit collects voltage signals through an instrument amplifier. The working electrode and the reference electrode of the pH sensing system are connected to the input end of the instrument amplifier. The reference voltage of the instrument amplifier is grounded.

4. The multi-parameter microneedle array measurement system according to claim 2, characterized in that: The control module is used to provide a reaction potential to the constant potential instrument, and collect current signals for detecting uric acid and ROS through an inverting follower, a control amplifier and a transimpedance amplifier to detect uric acid and ROS.

5. The multi-parameter microneedle array measurement system according to claim 4, characterized in that: The DAC voltage output by the control module realizes negative feedback through an applied potential operational amplifier circuit; the applied potential operational amplifier circuit includes: the DAC voltage is connected to the non-inverting input terminal of the first operational amplifier, the first power supply is connected to the inverting input terminal of the first operational amplifier, and the inverting input terminal of the first operational amplifier is connected to the output terminal of the first operational amplifier through a first resistor.

6. The multi-parameter microneedle array measurement system according to claim 1, characterized in that: The control module is used to output a voltage signal, which passes through a common-mode amplifier and a follower to obtain the voltage of the reference electrode and the working electrode, forming a voltage loop of the three-electrode system; the counter electrode is connected to the amplifier to form a current loop of the three-electrode system.

7. The multi-parameter microneedle array measurement system according to claim 1, characterized in that: The multi-parameter microneedle array is used to penetrate the skin of the subject to be detected and contact the subcutaneous tissue fluid to obtain the collected data.

8. A method for implementing multi-parameter microneedle array measurement, characterized in that: Applied to the multi-parameter microneedle array measurement system as claimed in claim 1, the method comprising: The potentiostat receives the acquisition signal of the multi-parameter microneedle array, and amplifies the acquisition signal based on the type of the acquisition signal to obtain a multi-parameter amplified signal; The potentiostat sends the multi-parameter amplified signal to the control module, so that the control module determines the index information corresponding to the disease based on the multi-parameter amplified signal.

9. The method for realizing multi-parameter microneedle array measurement according to claim 8, characterized in that: The potentiostat includes a collection module, and the collection module includes a three-electrode detection circuit and a pH detection circuit; the method also includes: It is determined that the three-electrode detection circuit amplifies and processes the current signal through an inverting follower, a control amplifier and a transimpedance amplifier, and the pH detection circuit amplifies and processes the voltage signal through an instrument amplifier.

10. The method for realizing multi-parameter microneedle array measurement according to claim 8, characterized in that: The method further comprises: The control module outputs a voltage signal, which passes through a common-mode amplifier and a follower to obtain the voltages of the reference electrode and the working electrode, forming a voltage loop of the three-electrode system; the counter electrode is connected to the amplifier to form a current loop of the three-electrode system.

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