Drug delivery system based on microneedle sensor and preparation method thereof

Abstract

The invention discloses a drug delivery system based on a microneedle sensor and a preparation method of the drug delivery system. The drug delivery system comprises a flexible piezoresistive mechanical sensor for detecting a pulse signal; the flexible electrocardio sensor is used for detecting electrocardio signals; the signal identification module is used for converting a blood pressure signal and generating a medicine delivery signal according to the pulse signal and the electrocardiosignal; the drug delivery device comprises a percutaneous drug delivery patch based on a porous microneedle array and a peristaltic pump, the percutaneous drug delivery patch based on the porous microneedle array is used for being attached to the epidermis of a user, the percutaneous drug delivery patch based on the porous microneedle array comprises a porous microneedle patch layer, microneedle arrays are distributed on the porous microneedle patch layer, and the peristaltic pump is arranged on the porous microneedle patch layer. A pipeline opening of the microneedle array is connected with the peristaltic pump; the control unit is used for regulating and controlling the driving rate of the peristaltic pump according to the drug delivery signal so that the drug delivery device can release the corresponding dose of drug. Precise release of the medicine is achieved, the blood pressure state in the body of the user is regulated and controlled in time, and the use feeling of the user is improved.

Description

Technical Field

[0001] The present application relates to the technical field of physiological index monitoring, and in particular to a drug delivery system based on a microneedle sensor and a preparation method thereof. Background Art

[0002] Cardiovascular disease is one of the most common diseases in humans. Among them, hypertension is the most dangerous factor in cardiovascular disease. Due to internal or environmental factors, the blood pressure of people with acute hypertension rises sharply in a short period of time, which can easily cause serious consequences such as aortic dissection and cerebral hemorrhage, threatening life safety. Due to the suddenness of acute hypertension, clinical intervention and control are more complicated and difficult.

[0003] In the related technology, the measurement of routine clinic blood pressure and dynamic blood pressure is achieved by cuff pressurization, which cannot monitor blood pressure frequently for a long time and is difficult to meet the diagnosis and early warning needs of hypertensive emergencies. On the other hand, since oral antihypertensive drugs need to pass through the gastrointestinal barrier and are slow to take effect, the main administration methods for controlling clinical hypertensive emergencies are sublingual administration or intravenous injection. However, when a hypertensive emergency occurs suddenly, the hypertensive emergency population is in a critical state (such as often accompanied by nausea, vomiting, visual impairment, severe headache and other acute symptoms), and oral antihypertensive drugs are slow to take effect, unable to timely regulate the blood pressure status of the hypertensive emergency population, and unable to timely relieve the acute discomfort symptoms of the population, which can easily cause life-threatening danger; in addition, there is no guarantee that the hypertensive emergency population can rush to the hospital for intravenous injection in time when acute symptoms occur, which delays the best time for treatment and has poor treatment effects. Summary of the invention

[0004] The present application aims to solve at least one of the technical problems existing in the prior art. To this end, the present application embodiment provides a drug delivery system based on a microneedle sensor and a preparation method thereof, which is conducive to achieving accurate drug release, can timely regulate the blood pressure state in the user's body, and improve the user's experience.

[0005] In a first aspect, the present application provides a drug delivery system based on a microneedle sensor, comprising:

[0006] Flexible piezoresistive mechanical sensor based on microneedle structure for detecting pulse signals;

[0007] Flexible ECG sensor based on microneedle structure, used to detect ECG signals;

[0008] a signal recognition module, configured to convert a blood pressure signal according to the pulse signal and the electrocardiogram signal, and generate a corresponding drug delivery signal according to the blood pressure signal;

[0009] A drug delivery device, comprising a percutaneous drug delivery patch based on a porous microneedle array and a peristaltic pump, wherein the percutaneous drug delivery patch based on a porous microneedle array is used to be attached to the epidermis of a user, the percutaneous drug delivery patch based on a porous microneedle array comprises a porous microneedle patch layer, a microneedle array is distributed on the porous microneedle patch layer, and a channel opening of the microneedle array of the porous microneedle patch layer is connected to the peristaltic pump;

[0010] The control unit is used to adjust the driving speed of the peristaltic pump according to the drug delivery signal so that the drug delivery device releases a corresponding dose of the drug.

[0011] According to some embodiments of the present application, the peristaltic pump includes a microfluidic cavity formed by the adhesion of a microfluidic cavity negative mold and a barrier layer, an infusion pump and a liquid storage tank; the microfluidic cavity and the pipeline opening of the microneedle array of the porous microneedle patch layer are connected, and the infusion pump is connected to the pipeline between the microfluidic cavity and the liquid storage tank through an infusion tube.

[0012] According to some embodiments of the present application, the drug delivery device also includes a flexible patch cavity, a sponge drug storage layer and an isolation layer. The flexible patch cavity is provided with a groove, and the groove is used to store the sponge drug storage layer. The porous microneedle patch layer and the isolation layer are bonded so that the needles on the porous microneedle patch layer are exposed on the surface of the isolation layer, and the sponge drug storage layer and the porous microneedle patch layer are bonded.

[0013] According to some embodiments of the present application, it also includes a signal modulation module, a wireless communication module and a terminal device, the input end of the signal modulation module is connected to the output end of the signal identification module, and the signal modulation module is used to filter and amplify the pulse signal and the electrocardiogram signal; the wireless communication module is communicatively connected to the medicine delivery device and the signal modulation module, and the terminal device is communicatively connected to the signal modulation module via the wireless communication module.

[0014] According to some embodiments of the present application, the flexible piezoresistive mechanical sensor based on a microneedle structure is formed by an integrated package of two face-to-face stacked polydimethylsiloxane substrates with a composite micro-nanoneedle structure; the composite micro-nanoneedle structure is a zinc oxide / gold nanoneedle structure.

[0015] According to some embodiments of the present application, the microneedle structure-based flexible ECG sensor includes a plurality of ECG monitoring electrodes, and the ECG monitoring electrodes include a polydimethylsiloxane microneedle structure with a gold conductive layer sputtered on the surface.

[0016] According to some embodiments of the present application, the signal identification module is based on the pulse wave conduction time-pulse wave conduction velocity algorithm, calculates the blood flow velocity according to the conduction time of the pulse signal, determines the blood pressure value according to the blood flow velocity, and generates a corresponding blood pressure signal according to the blood pressure value.

[0017] In a second aspect, the present application provides a method for preparing a drug delivery system based on a microneedle sensor, comprising:

[0018] Using flexible polydimethylsiloxane as a substrate, a first microneedle structure is prepared by using micro-nano processing technology;

[0019] Preparing a secondary zinc oxide / gold nanoneedle structure on the surface of the first microneedle structure by magnetron sputtering and hydrothermal growth to form a composite micro-nanoneedle structure;

[0020] Two identical composite micro-nano needle structures are stacked face to face and integrated into a flexible piezoresistive mechanical sensor with a sandwich structure.

[0021] Using flexible polydimethylsiloxane as a substrate, a second microneedle structure is prepared by using micro-nano processing technology;

[0022] Magnetron sputtering a gold conductive layer on the surface of the second microneedle structure, and insulating the non-needle tip area of ​​the second microneedle structure to obtain an electrocardiogram monitoring electrode;

[0023] Multiple ECG monitoring electrodes are integrated and packaged to obtain a flexible ECG sensor based on a microneedle structure;

[0024] The output end of the flexible piezoresistive mechanical sensor, the output end of the flexible electrocardiographic sensor based on the microneedle structure and the input end of the signal recognition module are connected, the output end of the signal recognition module is connected to the drug delivery device, and the drug delivery device is connected to the control unit to construct a drug delivery system based on microneedle sensors.

[0025] According to some embodiments of the present application, the drug delivery device includes a transdermal drug delivery patch based on a porous microneedle array, and the preparation method of the transdermal drug delivery patch based on a porous microneedle array includes:

[0026] Pour polydimethylsiloxane into a preset metal master film and solidify it to obtain a polydimethylsiloxane flexible patch cavity;

[0027] Placing the sponge drug storage layer into the bottom of the polydimethylsiloxane flexible patch cavity;

[0028] A porous microneedle patch layer is prepared using polydimethylsiloxane as a substrate, and a microneedle array is placed in the porous microneedle patch layer;

[0029] preparing an isolation layer, laminating the isolation layer and the porous microneedle patch layer, and exposing the needles on the porous microneedle patch layer on the surface of the isolation layer;

[0030] The porous microneedle patch layer is placed in the polydimethylsiloxane flexible patch cavity to obtain a percutaneous drug delivery patch based on a porous microneedle array.

[0031] According to some embodiments of the present application, after placing the porous microneedle patch layer into the polydimethylsiloxane flexible patch cavity, the method further includes:

[0032] Covering the two polydimethylsiloxane flexible patch cavities and aligning them up and down, and sealing the four sides of the polydimethylsiloxane flexible patch cavity with uncured polydimethylsiloxane;

[0033] The polydimethylsiloxane flexible patch cavity is placed at room temperature to cure for a preset time.

[0034] The drug delivery system based on microneedle sensors and the preparation method thereof provided in the embodiments of the present application have at least the following advantages or beneficial effects: the flexible piezoresistive mechanical sensor based on the microneedle structure can non-invasively monitor the changes in the pulse, thereby obtaining basic information about the cardiovascular system; the flexible ECG sensor based on the microneedle structure can monitor the electrical activity of the heart in real time, providing important data for cardiovascular health. The signal recognition module is responsible for processing the received pulse signal and ECG signal, and converting the pulse signal and ECG signal into a blood pressure signal; by real-time monitoring and analyzing the blood pressure signal, the drug dosage can be adjusted according to the user's specific blood pressure signal and a corresponding drug delivery signal can be generated to achieve precise drug delivery. The drug delivery device includes a transdermal drug delivery patch based on a porous microneedle array, which is used to be attached to the user's epidermis. The microneedle array on the porous microneedle patch layer can penetrate the surface of the skin to form a microchannel for transdermal absorption of the drug, thereby timely regulating the blood pressure state in the user's body and improving the user's experience. The small size of microneedles can minimize skin irritation and pain, achieve painless or slightly painful drug delivery, and allow drugs to enter the blood circulation directly through the skin, avoiding the degradation of oral drugs in the digestive system and improving the bioavailability of drugs. As a wearable device, the drug delivery device is portable and comfortable, making it convenient for users to use it for a long time. The peristaltic pump is connected to the microneedle array pipeline opening of the microneedle patch layer to control the drug delivery rate; the control unit accurately regulates the driving rate of the peristaltic pump according to the drug delivery signal generated by the signal recognition module, thereby achieving the corresponding dose of drug release, which is conducive to the precise release of drugs.

[0035] Other features and advantages of the present application will be described in the following description, and partly become apparent from the description, or understood by practicing the present application. The purpose and other advantages of the present application can be realized and obtained by the structures specifically pointed out in the description, claims and drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 is a schematic structural diagram of a drug delivery system based on a microneedle sensor provided in an embodiment of the present application;

[0037] Figure 2 is a schematic structural diagram of a drug delivery system based on a microneedle sensor provided in another embodiment of the present application;

[0038] Figure 3 is a flow chart of a method for preparing a microneedle sensor-based drug delivery system provided in an embodiment of the present application;

[0039] Figure 4 It is a flow chart of a method for preparing a transdermal drug delivery patch based on a porous microneedle array provided in an embodiment of the present application;

[0040] Figure 5 This is a flow chart of a method for preparing a microneedle sensor-based drug delivery system provided in another embodiment of the present application. DETAILED DESCRIPTION

[0041] This section will describe in detail the specific embodiments of the present application. The preferred embodiments of the present application are shown in the accompanying drawings. The purpose of the accompanying drawings is to supplement the description of the text part of the specification with graphics, so that people can intuitively and vividly understand each technical feature and the overall technical solution of the present application, but it cannot be understood as a limitation on the scope of protection of the present application.

[0042] In the description of this application, "several" means one or more, "more" means more than two, "greater than", "less than", "exceed", etc. are understood to exclude the number itself, "above", "below", "within", etc. are understood to include the number itself, "any one" means one or more, "at least one of the following" and similar expressions refer to any combination of these items, including any combination of single or plural items. If there is a description of the first and the second, it is only used for the purpose of distinguishing the technical features, and cannot be understood as indicating or implying the relative importance or implicitly indicating the number of the indicated technical features or implicitly indicating the order of the indicated technical features.

[0043] It should be noted that the terms such as setting, installing, and connecting in the embodiments of the present application should be interpreted in a broad sense, and the technical personnel in the relevant technical field can reasonably determine the specific meanings of the above terms in the embodiments of the present application in combination with the specific content of the technical solution. For example, the term "connection" can be a mechanical connection, an electrical connection, or mutual communication; it can be directly connected or indirectly connected through an intermediate medium.

[0044] It should be noted that the technical features involved in the various embodiments of the present application described below can be combined with each other as long as they do not conflict with each other.

[0045] Cardiovascular disease is one of the most common diseases in humans. Among them, hypertension is the most dangerous factor in cardiovascular disease. Due to internal or environmental factors, the blood pressure of people with acute hypertension rises sharply in a short period of time, which can easily cause serious consequences such as aortic dissection and cerebral hemorrhage, threatening life safety. Due to the suddenness of acute hypertension, clinical intervention and control are more complicated and difficult.

[0046] At present, the main drug administration methods for controlling clinical hypertensive emergencies are sublingual administration or intravenous injection. Oral antihypertensive drugs are slow to take effect and cannot timely regulate the blood pressure status of people with hypertensive emergencies. Therefore, they cannot timely relieve the acute discomfort symptoms of the people, which can easily cause life-threatening danger. In addition, there is no guarantee that people with hypertensive emergencies can rush to the hospital for intravenous injection in time when acute symptoms occur, which delays the best time for treatment and results in poor treatment effect.

[0047] Based on this, the embodiment of the present application provides a drug delivery system based on a microneedle sensor and a preparation method thereof, which is conducive to the precise release of drugs, can timely regulate the blood pressure status of the user, and improve the user's experience.

[0048] Please refer to the accompanying drawings to further illustrate the drug delivery system based on microneedle sensors and the preparation method thereof provided in the embodiments of the present application.

[0049] Reference Figure 1 As shown, Figure 1 The present invention is a schematic diagram of a drug delivery system based on a microneedle sensor provided in an embodiment of the present invention. The drug delivery system based on a microneedle sensor includes a flexible piezoresistive mechanical sensor based on a microneedle structure, a flexible electrocardiogram sensor based on a microneedle structure, a signal recognition module, a drug delivery device, and a control unit. The flexible piezoresistive mechanical sensor based on a microneedle structure is used to detect a pulse signal; the flexible electrocardiogram sensor based on a microneedle structure is used to detect an electrocardiogram signal; the signal recognition module is used to convert a blood pressure signal according to the pulse signal and the electrocardiogram signal, and generate a corresponding drug delivery signal according to the blood pressure signal; the drug delivery device includes a transdermal drug delivery patch based on a porous microneedle array and a peristaltic pump, the transdermal drug delivery patch based on a porous microneedle array is used to be attached to the epidermis of a user, the transdermal drug delivery patch based on a porous microneedle array includes a porous microneedle patch layer, a microneedle array is distributed on the porous microneedle patch layer, and the pipe opening of the microneedle array of the porous microneedle patch layer is connected to the peristaltic pump; the control unit is used to adjust the driving rate of the peristaltic pump according to the drug delivery signal so that the drug delivery device releases a corresponding dose of the drug.

[0050] In the embodiment of the present application, the flexible piezoresistive mechanical sensor based on the microneedle structure is used to detect the pulse signal based on the microneedle structure. The sensor of this structure can monitor the changes of the pulse non-invasively, so as to obtain the basic information of the cardiovascular system; the flexible ECG sensor based on the microneedle structure is also based on the microneedle structure, and is used to detect the ECG signal. The ECG sensor can monitor the electrical activity of the heart in real time and provide important data for cardiovascular health. The signal recognition module is responsible for processing the pulse signal received from the flexible piezoresistive mechanical sensor based on the microneedle structure and the ECG signal received from the flexible ECG sensor based on the microneedle structure, and converting the pulse signal and the ECG signal into a blood pressure signal. By real-time monitoring and analyzing the blood pressure signal, the drug dosage can be adjusted according to the specific physiological state of the user and the corresponding drug delivery signal can be generated to achieve precise drug delivery. The drug delivery device includes a transdermal drug delivery patch based on a porous microneedle array. This drug delivery patch is designed to be attached to the epidermis of the user. The microneedle array on the porous microneedle patch layer can penetrate the surface of the skin to form a microchannel for transdermal absorption of the drug, so that the blood pressure state in the user's body can be timely regulated, and the user's experience can be improved. The small size of the microneedles can minimize irritation and pain to the skin, achieving painless or slightly painful drug delivery. The drugs directly enter the blood circulation through the skin, avoiding the degradation of oral drugs in the digestive system and improving the bioavailability of the drugs. As a wearable device, the drug delivery device is portable and comfortable, which is convenient for users to use for a long time. The peristaltic pump is connected to the microneedle array pipeline opening of the microneedle patch layer to control the drug delivery rate. The control unit accurately controls the driving rate of the peristaltic pump according to the drug delivery signal generated by the signal recognition module, thereby achieving the corresponding dose of drug release, which is conducive to the precise release of drugs.

[0051] In one embodiment, when the blood pressure signal indicates that the systolic pressure is greater than 180 mmHg and the diastolic pressure is greater than 120 mmHg, the current physiological state of the user is a high-risk blood pressure state. When the blood pressure signal is higher than the high-risk blood pressure state, the trigger signal recognition module generates a drug delivery signal, and the control unit adjusts the drug delivery current intensity of the drug delivery device according to the blood pressure value of the blood pressure signal to control the drug delivery rate.

[0052] In some embodiments of the present application, the peristaltic pump includes a microfluidic cavity formed by the adhesion of a microfluidic cavity negative mold and a barrier layer, an infusion pump and a liquid reservoir; the microfluidic cavity and the pipeline opening of the microneedle array of the porous microneedle patch layer are connected, and the pipeline between the infusion pump and the microfluidic cavity and the liquid reservoir is connected by an infusion tube.

[0053] The microfluidic cavity is formed by the adhesion of the microfluidic cavity female mold and the barrier layer. It is the core part of the dynamic pump and is used to store and transport drug liquid. The design of the microfluidic cavity can ensure the stability of the drug during the delivery process; the infusion pump is connected to the microfluidic cavity and the reservoir, and is responsible for transporting the drug liquid in the reservoir to the microfluidic cavity; the reservoir: used to store the drug liquid to be transported, usually located at one end of the infusion pump, and the capacity of the reservoir is determined according to the need to meet the long-term continuous delivery of drugs. The microfluidic cavity is connected to the microneedle array pipeline opening of the porous microneedle patch layer, so that the drug liquid in the microfluidic cavity can be directly transported to the user's skin surface through the pipeline opening of the microneedle array to achieve transdermal drug administration. This design can improve the transdermal absorption efficiency of the drug and reduce drug waste. The infusion tube connects the infusion pump with the microfluidic cavity and the reservoir. It can be understood that the infusion tube is a connecting channel between the various parts of the dynamic pump, connecting the infusion pump, the microfluidic cavity and the reservoir into a complete drug delivery system.

[0054] In one embodiment, under the instruction of the control unit, the infusion pump starts working, and the drug liquid in the reservoir is delivered to the microfluidic cavity through the infusion tube. The drug liquid in the microfluidic cavity is then delivered to the user's skin surface through the pipeline opening of the microneedle array to achieve transdermal drug administration. Dose adjustment: The control unit adjusts the driving rate of the infusion pump in real time according to the drug delivery signal generated by the signal recognition module, thereby changing the delivery amount of the drug liquid in the microfluidic cavity and achieving the corresponding dose of drug release. This precise dose adjustment can meet the user's medication needs under different physiological conditions and improve the effect and safety of drug treatment. The drug delivery system based on microneedle sensors in this application can achieve painless, minimally invasive, and precise drug delivery, providing users with a more convenient and effective treatment plan.

[0055] In some embodiments of the present application, the drug delivery device also includes a flexible patch cavity, a sponge drug storage layer and an isolation layer. The flexible patch cavity is provided with a groove, the groove is used to store the sponge drug storage layer, the porous microneedle patch layer and the isolation layer are bonded so that the needles on the porous microneedle patch layer are exposed on the surface of the isolation layer, and the sponge drug storage layer and the porous microneedle patch layer are bonded.

[0056] The drug delivery device includes a transdermal drug delivery patch based on a porous microneedle array and a peristaltic pump, wherein the transdermal drug delivery patch based on a porous microneedle array includes a porous microneedle patch layer, a flexible patch cavity, a sponge drug storage layer and an isolation layer. A groove is provided in the flexible patch cavity for storing the sponge drug storage layer, and the structure of the groove can ensure the stable placement of the sponge drug storage layer to prevent it from shifting or falling off during use; the sponge drug storage layer is used to store drugs, and the sponge material has good water absorption and water retention, and can evenly absorb and store drug liquid, providing sufficient drug source for subsequent drug delivery. The isolation layer is bonded to the porous microneedle patch layer to isolate the sponge drug storage layer from the outside world to prevent drug leakage and contamination by external impurities. At the same time, the design of the isolation layer allows the needles on the porous microneedle patch layer to expose their surface, which is convenient for transdermal drug delivery. The porous microneedle patch layer includes a porous microneedle array, and the pipeline opening of the microneedle array is connected to the peristaltic pump. After the microneedle patch layer is attached to the isolation layer, the microneedles can penetrate the surface of the skin to form microchannels, allowing the drug to be delivered from the sponge reservoir layer through the channel openings of the microneedle array into the user's body.

[0057] In one embodiment, the drug is first stored in a sponge drug storage layer. When the drug needs to be administered, the peristaltic pump starts working and transports the drug from the sponge drug storage layer to the microneedle array of the porous microneedle patch layer through an infusion tube. The pipeline opening of the microneedle array is connected to the peristaltic pump to ensure that the drug can be smoothly transported from the drug storage layer to the microneedles. The microneedle patch layer is attached to the user's epidermis, and the microneedles penetrate the surface of the skin to form microchannels. The drug enters the user's body along the microchannel through the pipeline opening of the microneedle array to achieve transdermal administration. The control unit regulates the driving rate of the peristaltic pump according to the drug delivery signal generated by the signal recognition module. The driving rate of the peristaltic pump determines the flow rate of the drug from the sponge drug storage layer to the microneedle patch layer, thereby achieving the corresponding dose of drug release.

[0058] Through the above design and working principle, the drug delivery device can achieve efficient storage, stable delivery and precise drug administration, providing users with more convenient and effective treatment options.

[0059] Reference Figure 2 As shown, Figure 2 This is a structural schematic diagram of a microneedle sensor-based drug delivery system provided by another embodiment of the present application. The microneedle sensor-based drug delivery system also includes a signal modulation module, a wireless communication module and a terminal device. The input end of the signal modulation module is connected to the output end of the signal recognition module. The signal modulation module is used to filter and amplify the pulse signal and the electrocardiogram signal; the wireless communication module is communicatively connected to the drug delivery device and the signal modulation module, and the terminal device is communicatively connected to the signal modulation module via the wireless communication module.

[0060] The input end of the signal modulation module is connected to the output end of the signal recognition module, and the acquired pulse signal and ECG signal are filtered and amplified to improve the quality and accuracy of the signal. Filtering can remove noise and interference components in the signal, and amplification can make the amplitude of the signal reach a level suitable for subsequent processing. The wireless communication module is connected to the signal modulation module of the drug delivery device, and the terminal device is connected to the signal modulation module through the wireless communication module to realize wireless communication between the drug delivery device and the terminal device. The wireless communication module converts the signal processed by the signal modulation module into a wireless signal and sends it to the terminal device, while receiving the command signal of the terminal device to control the working state of the drug delivery device. The terminal device serves as the user interface and control center of the drug delivery system. The terminal device receives physiological signal data from the drug delivery device through the wireless communication module, and displays and analyzes these data. Users can monitor their own physiological status, such as pulse, ECG and blood pressure, in real time through the terminal device, and adjust the dosage and frequency of drug delivery as needed.

[0061] By integrating signal modulation modules, wireless communication modules and terminal devices, the drug delivery system realizes intelligent control and automated management of the drug delivery process, reduces the workload of medical staff and improves the efficiency and safety of treatment.

[0062] In some embodiments of the present application, a flexible piezoresistive mechanical sensor based on a microneedle structure is formed by integrating and packaging two face-to-face stacked polydimethylsiloxane substrates with a composite micro-nanoneedle structure; the composite micro-nanoneedle structure is a zinc oxide / gold nanoneedle structure.

[0063] Microneedle structures were prepared on flexible polydimethylsiloxane substrates using micro-nano processing, and secondary zinc oxide / gold nanoneedle structures were further prepared on the microneedle surface using magnetron sputtering and hydrothermal growth methods to form a composite micro-nanoneedle structure, and the prepared structure was characterized. Two identical flexible polydimethylsiloxane substrates that had been structurally characterized were stacked face to face and integrated into a flexible piezoresistive mechanical sensor with a sandwich structure. Pressure changes the contact between the upper and lower zinc oxide / gold micro-nano structures, thereby changing the resistance between the upper and lower layers of the sensor to produce a measurable signal.

[0064] Polydimethylsiloxane is a commonly used flexible substrate material with good biocompatibility, optical transparency and mechanical flexibility. Zinc oxide has excellent piezoelectric properties and biocompatibility, while gold has good conductivity and stability. This composite structure can improve the sensitivity and response speed of the sensor, and improve the accuracy of obtaining pulse signals by flexible piezoresistive mechanical sensors based on microneedle structures.

[0065] It is understandable that when the flexible piezoresistive mechanical sensor based on the microneedle structure is attached to the skin surface, the micro-nano needle structure can sense the tiny pressure changes on the skin surface, such as the skin vibration caused by the pulse. The piezoelectric properties of zinc oxide enable these pressure changes to be converted into electrical signals, which are transmitted to the sensor's reading circuit through the conductive path of the gold nanoneedle. After signal processing, an accurate pulse signal can be obtained.

[0066] In some embodiments of the present application, a flexible ECG sensor based on a microneedle structure includes a plurality of ECG monitoring electrodes, and the ECG monitoring electrodes include a polydimethylsiloxane microneedle structure with a gold conductive layer sputtered on the surface.

[0067] A microneedle structure is prepared on a flexible polydimethylsiloxane substrate using micro-nano processing, a gold conductive layer is magnetron sputtered on the surface of the microneedle, and the area outside the microneedle tip is further insulated. Finally, the flexible microneedle is integrated and packaged into an ECG monitoring electrode. Gold has excellent conductivity and stability, which can ensure good electrical contact between the electrode and the skin, thereby obtaining a stable ECG signal. The flexible ECG sensor based on the microneedle structure is formed by a combination of multiple ECG monitoring electrodes. Due to the use of the microneedle structure and the gold conductive layer, the sensor can significantly reduce the electrode-skin interface impedance, thereby obtaining high-quality ECG signals. The ECG signal electrode placement in this application adopts a three-lead bipolar detection method, and the three electrodes are placed on the left arm, right arm and left leg (or chest) respectively.

[0068] In some embodiments of the present application, the signal recognition module is based on the pulse wave conduction time-pulse wave conduction velocity algorithm, calculates the blood flow velocity according to the conduction time of the pulse signal, determines the blood pressure value according to the blood flow velocity, and generates a corresponding blood pressure signal according to the blood pressure value.

[0069] The signal recognition module converts the pulse signal and ECG signal into the accuracy of the blood pressure signal based on the pulse wave transmission time-pulse wave transmission velocity algorithm (PTT-PWV). The basic principle of the pulse wave transmission time-pulse wave transmission velocity algorithm is to calculate the blood flow velocity by calculating the pulse wave transmission time (PPT), and then further convert it into a blood pressure value. The pulse wave transmission time represents the time difference from the start of the heartbeat to the blood flow to the test site (such as the radial artery position of the wrist). The pulse wave transmission time is mainly affected by the blood flow velocity, which is mainly affected by the blood pressure.

[0070] Using the pulse wave transmission time and the known blood vessel length, the blood flow velocity is calculated based on the pulse wave transmission velocity formula.

[0071] The formula for pulse wave velocity is:

[0072] Pulse wave velocity = blood vessel length / pulse wave transmission time

[0073] It is understandable that blood flow rate is mainly affected by blood pressure. The higher the blood pressure, the faster the blood flow rate is generally.

[0074] Afterwards, the blood pressure value is determined based on the blood flow velocity and converted into a corresponding blood pressure signal for subsequent monitoring and analysis.

[0075] Reference Figure 3 As shown, Figure 3 is a flow chart of a method for preparing a drug delivery system based on a microneedle sensor provided in an embodiment of the present application. The method for preparing a drug delivery system based on a microneedle sensor includes but is not limited to steps S100 to S700. Specifically,

[0076] Step S100: using flexible polydimethylsiloxane as a substrate and utilizing micro-nano processing technology to prepare a first microneedle structure;

[0077] Step S200: preparing a secondary zinc oxide / gold nanoneedle structure on the surface of the first microneedle structure by magnetron sputtering and hydrothermal growth method to form a composite micro-nanoneedle structure;

[0078] Step S300: stacking two identical composite micro-nano needle structures face to face and integrating and packaging them into a flexible piezoresistive mechanical sensor with a sandwich structure;

[0079] Step S400: using flexible polydimethylsiloxane as a substrate and utilizing micro-nano processing technology to prepare a second microneedle structure;

[0080] Step S500: magnetron sputtering a gold conductive layer on the surface of the second microneedle structure, and performing insulation treatment on the non-needle tip area of ​​the second microneedle structure to obtain an electrocardiogram monitoring electrode;

[0081] Step S600: Integrate and package multiple ECG monitoring electrodes to obtain a flexible ECG sensor based on a microneedle structure;

[0082] Step S700: Connect the output end of the flexible piezoresistive mechanical sensor, the output end of the flexible electrocardiogram sensor based on the microneedle structure and the input end of the signal recognition module, connect the output end of the signal recognition module to the drug delivery device, and connect the drug delivery device to the control unit to construct a drug delivery system based on microneedle sensors.

[0083] In some embodiments of the present application, the preparation method of the drug delivery system based on the microneedle sensor includes using flexible polydimethylsiloxane (PDMS) as a substrate and using micro-nano processing technology to prepare a first microneedle structure. The micro-nano processing technology can accurately control the size and shape of the microneedle, laying the foundation for the subsequent preparation of the composite structure. On the surface of the first microneedle structure, a layer of zinc oxide nanoparticles is first sputtered using magnetron sputtering technology as a seed crystal for hydrothermal growth; then a gold nanoneedle structure is grown on the zinc oxide layer using a hydrothermal growth method to form a composite secondary zinc oxide / gold nanoneedle structure. This composite structure can improve the sensitivity and response speed of the sensor. Two identical composite micro-nano needle structures are stacked face to face, and through appropriate packaging processes, they are integrated and packaged into a flexible piezoresistive mechanical sensor with a sandwich structure. The sandwich structure helps to improve the stability and durability of the sensor.

[0084] The second microneedle structure is also prepared using micro-nano processing technology with flexible PDMS as the substrate; the second microneedle structure is prepared using micro-nano processing technology with flexible PDMS as the substrate. The design of the microneedle needs to consider its contact area with the skin and penetration depth to ensure that the ECG signal can be effectively collected; multiple ECG monitoring electrodes are integrated and packaged to obtain a flexible ECG sensor based on the microneedle structure to achieve multi-channel ECG signal collection.

[0085] The output end of the flexible piezoresistive mechanical sensor and the output end of the flexible ECG sensor based on the microneedle structure are respectively connected to the input end of the signal recognition module, which is responsible for receiving the pulse signal and ECG signal collected by the sensor; the output end of the signal recognition module is connected to the drug delivery device, which converts the blood pressure signal according to the pulse signal and the ECG signal, and generates a corresponding drug delivery signal to control the operation of the drug delivery device; the drug delivery device is connected to the control unit, which controls the driving speed of the peristaltic pump in the drug delivery device according to the drug delivery signal to achieve the release of the corresponding dose of drug; the drug delivery device is connected to the control unit, which controls the driving speed of the peristaltic pump in the drug delivery device according to the drug delivery signal to achieve the release of the corresponding dose of drug.

[0086] Through the above steps, a complete drug delivery system based on microneedle sensors can be constructed to achieve real-time monitoring of human physiological signals and precise drug delivery.

[0087] Reference Figure 4 As shown, Figure 4 : is a flow chart of a method for preparing a transdermal drug delivery patch based on a porous microneedle array provided in an embodiment of the present application. The method for preparing a transdermal drug delivery patch based on a porous microneedle array includes but is not limited to steps S800 to S840. Specifically,

[0088] Step S800: pouring polydimethylsiloxane into a preset metal master film and curing it to obtain a polydimethylsiloxane flexible patch cavity;

[0089] Step S810: placing the sponge drug storage layer at the bottom of the polydimethylsiloxane flexible patch cavity;

[0090] Step S820: preparing a porous microneedle patch layer using polydimethylsiloxane as a substrate, and placing the microneedle array into the porous microneedle patch layer;

[0091] Step S830: preparing an isolation layer, laminating the isolation layer and the porous microneedle patch layer, and exposing the needles on the porous microneedle patch layer on the surface of the isolation layer;

[0092] Step S840: placing the porous microneedle patch layer into the polydimethylsiloxane flexible patch cavity to obtain a transdermal drug delivery patch based on a porous microneedle array.

[0093] In some embodiments of the present application, the preparation method of the percutaneous drug delivery patch based on the porous microneedle array includes: pouring polydimethylsiloxane (PDMS) into a preset metal mother film, PDMS is a flexible substrate material with good biocompatibility and mechanical flexibility. Heat and cure the polydimethylsiloxane at an appropriate temperature to form a stable flexible patch cavity structure. Place a sponge drug storage layer at the bottom of the solidified polydimethylsiloxane flexible patch cavity, the sponge drug storage layer is used to store drugs, and its porous structure is conducive to the release of drugs. Polydimethylsiloxane and a curing agent are prepared into a polydimethylsiloxane solution to be cured, which is transferred to the surface of a microneedle array positive template, heated and cured after vacuum treatment, and peeled off after cooling to obtain a polydimethylsiloxane needle-shaped hole microneedle array template; a microneedle raw material solution and a pore-forming material are mixed to prepare a pore-forming liquid, which is sequentially injected into the polydimethylsiloxane needle-shaped hole microneedle array template step by step, and peeled off after the pore-forming liquid and the microneedle raw material solution are cured; a microneedle patch containing a pore-forming material is reacted with a pore-forming etchant to form holes, thereby obtaining a porous microneedle patch.

[0094] Prepare an isolation layer, which needs to have good mechanical strength and flexibility to protect the microneedle patch layer, fit the isolation layer and the porous microneedle patch layer together, ensure that the needles on the porous microneedle patch layer are exposed on the surface of the isolation layer, and place the porous microneedle patch layer into the polydimethylsiloxane flexible patch cavity so that it fits tightly with the sponge drug storage layer. After the above steps, a transdermal drug delivery patch based on a porous microneedle array is obtained. The transdermal drug delivery patch based on a porous microneedle array can achieve efficient transdermal delivery of drugs. The microneedles penetrate the skin to form microchannels, allowing the drugs to be transported from the sponge drug storage layer through the channel openings of the microneedle array into the body, providing a key drug delivery component for the drug delivery system.

[0095] Reference Figure 5 As shown, Figure 5 is a flowchart of a method for preparing a microneedle sensor-based drug delivery system according to another embodiment of the present invention. The method for preparing a microneedle sensor-based drug delivery system includes but is not limited to steps S841 to S844.

[0096] Step S841: Cover and align the two polydimethylsiloxane flexible patch cavities, and seal the periphery of the polydimethylsiloxane flexible patch cavity with uncured polydimethylsiloxane;

[0097] Step S842: placing the polydimethylsiloxane flexible patch cavity at room temperature for curing for a preset time.

[0098] Cover two polydimethylsiloxane flexible patch cavities face to face and ensure that they are aligned up and down. The purpose of alignment is to ensure that the structure of the encapsulated patch cavity is uniform to avoid structural instability or functional failure caused by misalignment. Use uncured polydimethylsiloxane solution to encapsulate the four sides of the two patch cavities. The uncured polydimethylsiloxane solution has good fluidity and can fill the gaps around the cavity to form a sealed encapsulation layer. Use a syringe or coating tool to evenly apply the polydimethylsiloxane solution around the cavity to ensure that the thickness of the encapsulation layer is uniform, usually between 1-2 mm. Place the encapsulated polydimethylsiloxane flexible patch cavity at room temperature for a preset curing time. The preset curing time is usually determined by the formula and thickness of the polydimethylsiloxane, generally ranging from a few hours to 24 hours.

[0099] By encapsulating and curing the polydimethylsiloxane flexible patch cavity, a polydimethylsiloxane flexible patch cavity with a stable structure and good sealing can be prepared, providing a reliable physical basis for the subsequent drug delivery system.

[0100] Other features and advantages of the present application will be described in the following description, and partly become apparent from the description, or understood by practicing the present application. The purpose and other advantages of the present application can be realized and obtained by the structures specifically pointed out in the description, claims and drawings.

Claims

1. A drug delivery system based on a microneedle sensor, characterized in that: include: Flexible piezoresistive mechanical sensor based on microneedle structure for detecting pulse signals; Flexible ECG sensor based on microneedle structure, used to detect ECG signals; a signal recognition module, configured to convert a blood pressure signal according to the pulse signal and the electrocardiogram signal, and generate a corresponding drug delivery signal according to the blood pressure signal; A drug delivery device, comprising a percutaneous drug delivery patch based on a porous microneedle array and a peristaltic pump, wherein the percutaneous drug delivery patch based on a porous microneedle array is used to be attached to the epidermis of a user, the percutaneous drug delivery patch based on a porous microneedle array comprises a porous microneedle patch layer, a microneedle array is distributed on the porous microneedle patch layer, and a channel opening of the microneedle array of the porous microneedle patch layer is connected to the peristaltic pump; The control unit is used to adjust the driving speed of the peristaltic pump according to the drug delivery signal so that the drug delivery device releases a corresponding dose of the drug.

2. The microneedle sensor-based drug delivery system according to claim 1, characterized in that: The peristaltic pump includes a microfluidic cavity formed by the adhesion of a microfluidic cavity negative mold and a barrier layer, an infusion pump and a liquid storage tank; the microfluidic cavity and the pipeline opening of the microneedle array of the porous microneedle patch layer are connected, and the pipeline between the infusion pump and the microfluidic cavity and the liquid storage tank is connected by an infusion tube.

3. The microneedle sensor-based drug delivery system according to claim 1, characterized in that: The drug delivery device also includes a flexible patch cavity, a sponge drug storage layer and an isolation layer. The flexible patch cavity is provided with a groove, and the groove is used to store the sponge drug storage layer. The porous microneedle patch layer and the isolation layer are bonded so that the needles on the porous microneedle patch layer are exposed on the surface of the isolation layer, and the sponge drug storage layer and the porous microneedle patch layer are bonded.

4. The microneedle sensor-based drug delivery system according to claim 1, characterized in that: It also includes a signal modulation module, a wireless communication module and a terminal device. The input end of the signal modulation module is connected to the output end of the signal identification module. The signal modulation module is used to filter and amplify the pulse signal and the electrocardiogram signal. The wireless communication module is communicatively connected to the medicine delivery device and the signal modulation module. The terminal device is communicatively connected to the signal modulation module via the wireless communication module.

5. The microneedle sensor-based drug delivery system according to claim 1, characterized in that: The flexible piezoresistive mechanical sensor based on microneedle structure is formed by integrated packaging of two layers of polydimethylsiloxane substrates with composite micro-nano needle structures stacked face to face; the composite micro-nano needle structure is a zinc oxide / gold nanoneedle structure.

6. The microneedle sensor-based drug delivery system according to claim 1, characterized in that: The flexible ECG sensor based on the microneedle structure comprises a plurality of ECG monitoring electrodes, and the ECG monitoring electrodes comprise a polydimethylsiloxane microneedle structure with a gold conductive layer sputtered on the surface.

7. The microneedle sensor-based drug delivery system according to claim 1, characterized in that: The signal recognition module is based on the pulse wave conduction time-pulse wave conduction velocity algorithm, calculates the blood flow velocity according to the conduction time of the pulse signal, determines the blood pressure value according to the blood flow velocity, and generates a corresponding blood pressure signal according to the blood pressure value.

8. A method for preparing a drug delivery system based on a microneedle sensor, characterized in that: include: Using flexible polydimethylsiloxane as a substrate, a first microneedle structure is prepared by using micro-nano processing technology; Preparing a secondary zinc oxide / gold nanoneedle structure on the surface of the first microneedle structure by magnetron sputtering and hydrothermal growth to form a composite micro-nanoneedle structure; Two identical composite micro-nano needle structures are stacked face to face and integrated into a flexible piezoresistive mechanical sensor with a sandwich structure. Using flexible polydimethylsiloxane as a substrate, a second microneedle structure is prepared by using micro-nano processing technology; Magnetron sputtering a gold conductive layer on the surface of the second microneedle structure, and insulating the non-needle tip area of ​​the second microneedle structure to obtain an electrocardiogram monitoring electrode; Multiple ECG monitoring electrodes are integrated and packaged to obtain a flexible ECG sensor based on a microneedle structure; The output end of the flexible piezoresistive mechanical sensor, the output end of the flexible electrocardiographic sensor based on the microneedle structure and the input end of the signal recognition module are connected, the output end of the signal recognition module is connected to the drug delivery device, and the drug delivery device is connected to the control unit to construct a drug delivery system based on microneedle sensors.

9. The method for preparing a drug delivery system based on a microneedle sensor according to claim 8, characterized in that: The drug delivery device includes a transdermal drug delivery patch based on a porous microneedle array, and the preparation method of the transdermal drug delivery patch based on a porous microneedle array includes: Pour polydimethylsiloxane into a preset metal master film and solidify it to obtain a polydimethylsiloxane flexible patch cavity; Placing the sponge drug storage layer into the bottom of the polydimethylsiloxane flexible patch cavity; A porous microneedle patch layer is prepared using polydimethylsiloxane as a substrate, and a microneedle array is placed in the porous microneedle patch layer; preparing an isolation layer, laminating the isolation layer and the porous microneedle patch layer, and exposing the needles on the porous microneedle patch layer on the surface of the isolation layer; The porous microneedle patch layer is placed into the polydimethylsiloxane flexible patch cavity to obtain a transdermal drug delivery patch based on a porous microneedle array.

10. The method for preparing a drug delivery system based on a microneedle sensor according to claim 9, characterized in that: After placing the porous microneedle patch layer into the polydimethylsiloxane flexible patch cavity, the method further comprises: Covering the two polydimethylsiloxane flexible patch cavities and aligning them up and down, and sealing the four sides of the polydimethylsiloxane flexible patch cavity with uncured polydimethylsiloxane; The polydimethylsiloxane flexible patch cavity is placed at room temperature to cure for a preset time.

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