Integrated hemostatic drug-loading microneedle patch

Abstract

The invention discloses an integrated hemostatic drug-loaded microneedle patch, and relates to the technical field of medical treatment. Comprising a microneedle substrate, a soluble microneedle patch, a composite medicament, an insoluble microneedle patch, a composite sensor and a micro-control flow chip, the insoluble microneedle patch is used for fixing the integrated microneedle patch, and the insoluble microneedle patch and the soluble microneedle patch are both arranged on the microneedle substrate; the composite medicament is arranged on the microneedle material of the soluble microneedle patch and is used for wound treatment; the composite sensor is arranged between the soluble microneedle patch and the microneedle substrate and is used for monitoring a series of indexes of blood routine examination and human body temperature; and the micro-control flow chip is arranged above the soluble micro-needle patch and is used for storing the extracted sample to be detected. According to the invention, required indexes such as blood routine examination, temperature and the like can be monitored during drug delivery, the deficiency of blood routine examination and human body temperature detection after wound treatment by a traditional microneedle is made up, and integrated efficient treatment is realized clinically.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and more specifically, relates to an integrated hemostatic microneedle drug-loaded patch capable of monitoring various data. Background Art

[0002] Microneedles are a new type of transdermal drug delivery technology, which consists of an array of micron-sized sharp needles. After piercing the skin, they will leave micropores on the skin, which can improve the permeability of drug molecules on the skin. Compared with oral and injection administration, microneedle administration can avoid drug degradation caused by various digestive enzymes and chemical factors in the gastrointestinal tract and the first-pass effect of the liver. It is especially suitable for local lesions such as skin infections and chronic wounds. It can avoid the toxic side effects caused by systemic administration and reduce local blood drug concentration fluctuations. Compared with traditional wound dressings, microneedles can penetrate the microbial membranes and eschars formed during the healing process, allowing the active ingredients to enter healthy cells and diffuse to take effect. In addition, microneedle preparations have good adhesion and the drug molecules carried can painlessly penetrate the epidermis to the dermis, increasing the concentration and bioavailability of therapeutic drugs on the wound surface, significantly improving the treatment effect.

[0003] Microneedles (MNs) have been widely studied and applied in the collection and detection of interstitial fluid (ISF) samples due to their minimally invasive and painless characteristics. As a painless subcutaneous drug delivery tool, it delivers drugs through the cortex layer, through the microchannels created by the microneedles or by loading the drugs directly into the microneedles for administration. With the development of microneedle-related technologies, their functions have gradually become controllable and intelligent, and they can complete operations under various microenvironments. In addition, microneedle devices have the characteristics of painless, minimally invasive, simple operation and high safety when delivering drugs through the cortex. The method of penetrating the cortex layer to deliver drugs makes the cortex layer a channel for a variety of drugs. The needle tip of the microneedle has the characteristics of low impedance contact, so it is often used to collect, analyze and detect various biomarkers in interstitial fluid, such as glucose, inflammatory factors, nucleic acid molecules, tumor markers, etc.

[0004] Microneedles include solid microneedles and swelling microneedles. Solid microneedles are the first conceptually designed microneedle array patch, which is usually made of metal, silicon, ceramics, etc., and is prepared by laser cutting, mechanical / chemical etching, electroplating, etc. Due to their high mechanical strength and chemical stability, solid microneedles can be effectively integrated with biosensors to achieve long-term and stable monitoring of physiological indicators. Swelling microneedles, also known as hydrogel microneedles, are often prepared using a mold method combined with hydrogel photocuring technology. This type of microneedle is hard in vitro, and the needle tip can easily penetrate the surface of the skin. After entering the skin tissue, the microneedle swells rapidly and actively absorbs interstitial fluid, which can be used for the detection of biomarkers.

[0005] Wearable microneedle patches have been widely used and developed in minimally invasive treatment and monitoring of various human indicators in recent years because of their advantages such as minimally invasive and painless, high integration and good biocompatibility. Wearable biosensors can sample interstitial fluid (ISF) on the skin surface and perform real-time analysis or continuous monitoring of biomarkers in it.

[0006] Microneedle manufacturing mostly uses 3D printing technology. 3D printing (3DP), also known as additive manufacturing technologies (AM), is a technology that manufactures physical parts by adding materials layer by layer based on three-dimensional CAD data. 3D printing technology has broad prospects and a wide range of uses. The fine synthesis method has been widely used in the preparation of complex patterns, microstructures and functional materials.

[0007] National patent CN 115025385 A proposed to use a microneedle patch loaded with hemostatic agent thrombin (TH), analgesic agent lidocaine hydrochloride (LH) and levofloxacin to prepare a microneedle patch with hemostatic, analgesic and anti-inflammatory effects to achieve wound treatment, and the clinical effect is obvious and effective, but a single hemostatic microneedle patch cannot meet the monitoring of a series of blood routine indicators and achieve the inhibition of other multiple inflammatory factors. In order to meet the monitoring of multiple indicators such as blood routine and temperature during drug delivery, the present invention discloses an integrated microneedle patch that can monitor the required indicators. Summary of the invention

[0008] The technical problem to be solved by the present invention is to provide an integrated hemostatic drug-loaded microneedle patch that can monitor required indicators such as blood routine and temperature during drug delivery, make up for the deficiencies of traditional microneedle treatment in detecting blood routine and human body temperature after wound treatment, and realize integrated and efficient treatment in clinical practice.

[0009] In order to solve the above technical problems, the technical solution adopted by the present invention is:

[0010] An integrated hemostatic drug-loaded microneedle patch comprises a microneedle substrate, a soluble microneedle patch, a composite drug, an insoluble microneedle patch, a composite sensor, and a micro-control flow chip. The insoluble microneedle patch (4) has two pieces, which are used to fix the integrated microneedle patch and are located on both sides of the soluble microneedle patch. The insoluble microneedle patch and the soluble microneedle patch are both arranged on the microneedle substrate. The composite drug is used for wound treatment and is arranged on the microneedle material of the soluble microneedle patch. The composite sensor is used to monitor a series of blood routine indicators and human body temperature and is arranged between the soluble microneedle patch and the microneedle substrate. The micro-control flow chip is used to store the extracted samples required for detection and is arranged above the soluble microneedle patch.

[0011] Preferably, the microneedle height of the soluble microneedle patch is 800 μm; the microneedle height of the insoluble microneedle patch is 900 μm; the length, width and height of the microneedle substrate are 8000 μm, 3000 μm and 600 μm respectively.

[0012] Preferably, the compound medicine is composed of a hemostatic agent, an anti-inflammatory analgesic agent and an antibacterial agent; the hemostatic agent is thrombin, the anti-inflammatory analgesic agent is ropivacaine hydrochloride, and the antibacterial agent is levofloxacin; the compound medicine also includes long-acting amide anti-inflammatory drugs, quinolone antibiotics and other antibacterial drugs and drugs for promoting coagulation by wound injection.

[0013] Preferably, the composite sensor is a multi-factor detection sensor composed of an optical sensor for detecting red blood cells, an electrochemical sensor for detecting hemoglobin, a biosensor for detecting white blood cells and platelets, and a thermistor sensor for measuring temperature; the composite sensor also includes a data anomaly screening module and a multi-sensor data fusion processing module, wherein the data anomaly screening module is set with a normal value range of blood routine indicators and temperature, and an alarm signal is triggered when the detection data exceeds the range; the multi-sensor data fusion processing module uses a Kalman filtering algorithm to perform fusion analysis on multiple sensor data; the composite sensor is integrated with a low-power Bluetooth module and a microcontroller, and the microcontroller is used for data acquisition, processing and wireless transmission; the sampling frequency of the composite sensor is 10 Hz and the resolution is 12 bits.

[0014] Preferably, the microneedles of the insoluble microneedle patch are shaped like barbs, cones, double arrows or bionic structures.

[0015] Preferably, the microfluidic chip is composited by two layers of substrates, a cavity is formed between the composite interlayers, and the cavity is used to collect and store test sample droplets; the channel structure types of the microfluidic chip include but are not limited to straight type and S type.

[0016] Preferably, the preparation material of the insoluble microneedle patch is polystyrene or metal or silicon or plastic, the surface of the insoluble microneedle patch is modified with bioadhesive protein, and the surface of the insoluble microneedle patch is treated with low-temperature plasma to form a surface roughness structure of 10-100 nm.

[0017] Preferably, the material of the microneedle substrate includes one or more of hyaluronic acid, blood-absorbing hydrogel, polyvinyl alcohol and polyvinyl pyrrolidone.

[0018] Preferably, the microfluidic chip and the composite sensor are integrated with a microneedle patch using polydimethylsiloxane encapsulation technology.

[0019] Preferably, when the drug in the microneedle patch is changed or the detection-specific identification element is changed, the integrated microneedle patch detects indicators related to inflammatory factors TNF-alpha, IL-1, IL-6, C-reactive protein CRP, red blood cells, platelets, white blood cells, hemoglobin and wound information.

[0020] The beneficial effects of adopting the above technical solution are:

[0021] 1. With the continuous improvement of microneedle technology, there are more and more cases of combining microneedle patches with biosensors. The integrated hemostatic microneedle drug-loaded patch provided by the present invention realizes a portable, wearable and integrated treatment and detection process in microneedle patch drug-loaded treatment and biological indicators such as blood routine and temperature, which makes up for the lack of traditional microneedle in the detection of blood routine and human body temperature after wound treatment, and realizes integrated and efficient treatment in clinical practice.

[0022] 2. The present invention mixes the hemostatic agent thrombin TH and the analgesics ropivacaine hydrochloride RH and levofloxacin Levofloxacin with the methacrylated gelatin GelMA precursor solution to prepare microneedles, so that the microneedles have multiple therapeutic effects of hemostasis, anti-inflammation, sedation and analgesia. When preparing the GelMA soluble microneedles, the concentration of methacrylic anhydride and the time of the polymerization reaction are controlled while mixing the drug with the microneedle material, thereby changing its physical properties so as to improve the efficiency of the microneedle when releasing the drug.

[0023] 3. The present invention arranges an insoluble microneedle patch on both sides of the drug-delivery microneedle patch, so that the soluble microneedle patch can have good position accuracy when administering drugs and forming microchannels to collect test samples at a unique angle, thereby reducing the risk of accidental detachment of the microneedle patch during drug administration and helping to improve the patient's usage experience.

[0024] 4. According to the above 2 and 3, by the same mechanism, when the drug contained in the soluble microneedle patch is changed, different pathological reactions caused by the wound can be treated, such as concurrent inflammation, microbial pathogen infection and ulcers that are difficult to heal. In addition, specific binding elements of different biological indicators can be added to the soluble microneedle patch to achieve the purpose of monitoring various human indicators.

[0025] 5. The present invention integrates a low-power Bluetooth module and a microcontroller in the composite sensor. The data acquisition system with a sampling frequency of 10 Hz and a resolution of 12 bits can realize accurate monitoring of physiological parameters and remote monitoring through wireless transmission, which greatly improves the practicality and portability of the equipment.

[0026] 6. The present invention uses environmentally responsive bioadhesive proteins to modify the surface of insoluble microneedles, thereby realizing an intelligent fixing function, ensuring firm fixation in a humid use environment and facilitating removal and replacement in a dry environment, thereby improving the user experience of the product.

[0027] 7. The composite sensor of the present invention adopts data anomaly screening and multi-sensor fusion technology, which can effectively improve the reliability and accuracy of the detection data. Through the preset abnormal data screening mechanism, abnormal situations can be discovered and alarmed in time to ensure the safety of treatment; the improved Kalman filter algorithm is used for data fusion, which significantly improves the measurement accuracy and controls the measurement error within 3%.

[0028] 8. The present invention has made innovative improvements to the surface of insoluble microneedles, using low-temperature plasma treatment to form a nano-scale roughness structure, so that the microneedles have better mechanical strength and fixing effect, and the product service life is increased by more than 50%. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 It is a schematic diagram of the top view of the structure of the present invention;

[0030] Figure 2 It is a cross-sectional schematic diagram of the present invention;

[0031] In the figure: 1. Microneedle substrate; 2. Soluble microneedle patch; 3. Composite drug; 4. Insoluble microneedle patch; 5. Composite sensor; 6. Micro-control flow chip. DETAILED DESCRIPTION

[0032] The following will be combined with the drawings in the embodiments of the present application to clearly and completely describe the technical solutions in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of this application.

[0033] If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the field or the product instructions are used. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0034] The experimental methods in the following examples are conventional methods unless otherwise specified. The experimental materials used in the following examples are commercially available products unless otherwise specified. The materials used in the following examples are one or more of the materials mentioned above in the present invention.

[0035] The structure of the integrated microneedle patch provided by the present invention comprises a soluble microneedle patch and an insoluble microneedle patch attached to a substrate, and a microfluidic chip and an integrated sensor encapsulated in one body by PDMS.

[0036] Specifically, Figure 1-2 As shown, the integrated hemostatic drug-loaded microneedle patch includes a microneedle substrate 1, a soluble microneedle patch 2, a composite drug 3, an insoluble microneedle patch 4, a composite sensor 5, and a micro-control flow chip 6. There are two insoluble microneedle patches 4, which are used to fix the integrated microneedle patch and are located on both sides of the soluble microneedle patch 2. The insoluble microneedle patch 4 and the soluble microneedle patch 2 are both arranged on the microneedle substrate 1. The composite drug 3 is used for wound treatment and is arranged on the microneedle material of the soluble microneedle patch 2. The composite sensor 5 is used to monitor a series of indicators of blood routine and human body temperature and is arranged between the soluble microneedle patch 2 and the microneedle substrate 1. The micro-control flow chip 6 is used to store the extracted samples required for detection and is arranged above the soluble microneedle patch 2.

[0037] The microneedle height of the soluble microneedle patch 2 is 800μm; the microneedle height of the insoluble microneedle patch 4 is 900μm. The length, width and height of the microneedle substrate 1 are 8000μm, 3000μm and 600μm respectively. In order to achieve the required functions mentioned in the technical background, we selected high-adhesion materials mostly used in existing studies, such as chitosan (CS), methacryloyl gelatin (GelMA), and DNA hydrogel in the material selection of the soluble microneedle patch. Among them, the GelMA used in the present invention is a modified polymer of natural origin, which has good biocompatibility and biodegradability. Arginine, glycine, aspartic acid (RGD) sequences exist in GelMA, which support cell adhesion, proliferation and differentiation, and matrix metalloproteinase (MMP) degradation sequences promote enzymatic degradation, and can be prepared into hydrogels under specific conditions. The micro-mold pressing process of the commonly used solvent casting is used for preparation. Usually, methacrylic anhydride is mixed with the hydrogel precursor solution to initiate a polymerization reaction to form GelMA. During the preparation process, the cross-linking density and physical properties of GelMA can be adjusted by controlling the concentration of methacrylic anhydride and the time of the polymerization reaction. In order to make the required microneedle array, a concave mold is usually made by laser cutting and other processes. Polydimethylsiloxane (PDMS) with stable chemical properties, low adhesion and good transcription ability is often used for the production of the concave mold. The microneedle array is then dried in a PDMS model with a complex structure after adding a functional solution. It can also be manufactured in a specific PDMS model using a photocurable polymer material. During the preparation, the drug can be mixed with the hydrogel precursor solution so that the drug is evenly distributed in the precursor solution. The prepared mixed solution is dried and molded in the PDMS mold to form a microneedle patch of the desired shape. The preparation method is widely used and the microneedle array prepared with this material can exert a better therapeutic effect.

[0038] The compound medicine 3 is composed of a hemostatic agent-thrombin (TH), an anti-inflammatory analgesic agent-ropivacaine hydrochloride (RH) and an antibacterial agent-levofloxacin. In addition to the above three types, the therapeutic drugs used in the present invention also include long-acting amide anti-inflammatory drugs, antibacterial drugs such as quinolone antibiotics, and drugs for promoting blood coagulation by wound injection, such as norepinephrine, etc., which are not limited to the above-mentioned under the premise of ensuring the composite effect of the three types of drugs without toxicity to the human body and more serious allergic physiological reactions.

[0039] The two insoluble microneedle patches 4 are interlocking. The insoluble interlocking microneedle structures on the integrated microneedle patch usually adopt barbs, double arrows, bionic structures, etc. The present invention adopts a barb shape to prepare a microneedle array patch. The insoluble microneedles in the present invention adopt polystyrene (PS) as a material to prepare microneedles, and its material performance is stable, has good processability and good mechanical strength. During the preparation, the above-mentioned mold is cut and processed into the microneedle array model required by the present invention, and the polystyrene raw material is heated to a molten state to give it good fluidity. Under high pressure, the molten polystyrene is injected into the mold to fill the microneedle structure in the mold. Parameters such as temperature, pressure and time need to be strictly controlled during the injection molding process to ensure the molding quality of the microneedle array. After the injection molding is completed, the microneedles are taken out of the mold after cooling and solidification.

[0040] Since excessive use of drugs can cause irreparable physical harm to patients, monitoring of drug use is particularly important. When a patient is losing blood, the indicators that need to be monitored include a series of indicators in blood routine (red blood cells, white blood cells and platelets, etc.), inflammatory factors (TNF-α, IL-1, IL-6 and C-reactive protein CRP, etc.) and temperature, etc. The microneedle array on the hemostatic microneedle patch is connected to a micro-control flow chip 6. When the microneedle array pierces the stratum corneum of the skin, a microchannel is formed, so that a trace amount of blood is absorbed by the micro-control flow chip as a reservoir under the action of capillary force as the original solution for analyzing various indicators such as blood routine. The sensor uses a temperature sensor, and the sensor integrated into the microneedle patch can measure real-time temperature data for the patient.

[0041] The present invention uses a composite sensor 5 to collect and detect routine blood data and temperature. (1) A biosensor for collecting white blood cell and platelet data, whose functions include using a soluble microneedle patch to collect blood samples, using antibody-labeled white blood cell-specific recognition elements and platelet-specific marker aptamers in the biosensor, and generating corresponding electrical signals or optical signals after the white blood cells and platelets combine with their recognition elements, which can be counted quickly; (2) An optical sensor for collecting red blood cell data, which can detect its concentration through the red blood cells' absorption or scattering characteristics of light; (3) An electrochemical sensor for collecting hemoglobin data, which uses the electrical signal generated by the reaction of hemoglobin with specific electrodes to detect its concentration; (4) A thermistor sensor (NTC) for measuring temperature. In addition, when a wound is infected and different biological indicators need to be monitored, different specific recognition elements in various sensors can be changed to achieve the monitoring purpose. The above sensors are combined together to form the composite sensor 5 of the present invention.

[0042] The signal acquisition and transmission system of the composite sensor 5 adopts a low-power design. The composite sensor integrates a low-power Bluetooth module and a microcontroller, which can realize the real-time acquisition, processing and wireless transmission of physiological parameters. The sampling frequency of the sensor is set to 10Hz, and the resolution reaches 12 bits, ensuring the timeliness and accuracy of data acquisition. The microcontroller adopts a low-power MCU, which has data acquisition, signal processing and wireless communication functions. The collected physiological parameters can be transmitted to a mobile terminal or medical monitoring equipment through a low-power Bluetooth protocol, which is convenient for medical staff to grasp the patient's condition in real time. The system also has a data storage function, which can save historical data in an offline state. The composite sensor 5 uses polydimethylsiloxane.

[0043] The composite sensor of the present invention adopts an innovative data processing scheme. The data abnormality screening module presets the normal value range of each indicator: red blood cell count (3.5-5.5)×10^12 / L, hemoglobin (110-160) g / L, white blood cell count (4.0-10.0)×10^9 / L, platelet count (100-300)×10^9 / L and body temperature (36.3-37.2)℃. When the test data exceeds the preset range, the system will immediately issue an alarm signal to prompt medical staff to pay attention.

[0044] The multi-sensor data fusion processing adopts an improved Kalman filter algorithm. The processing flow of the algorithm includes: pre-processing the data of each sensor to remove obvious outliers; establishing a sensor measurement equation group and a state prediction equation group; calculating the Kalman gain matrix and updating the state estimation according to the actual measurement value; and obtaining the optimal fusion result through covariance matrix iteration. Based on the theoretical basis and existing technical level of the Kalman filter algorithm, the fusion algorithm can effectively reduce the measurement error and ensure the real-time data processing. At the same time, the system has designed a data caching mechanism. When the detection signal is temporarily interrupted, the data compensation algorithm can be used to ensure the continuity of monitoring and improve the stability and reliability of the system.

[0045] The microfluidic chip 6 is composed of two layers of substrates, and a cavity is formed between the composite interlayers, and the cavity is used to collect and store the test sample droplets. The channel structure types of the microfluidic chip 6 include but are not limited to straight type and S type. The microfluidic chip 6 and the composite sensor 5 are integrated with the microneedle patch using polydimethylsiloxane (PDMS) encapsulation technology.

[0046] The preparation process of hyaluronic acid base is as follows:

[0047] The functions of each region of the present invention will be integrated on a substrate made of hyaluronic acid. In the field of microneedle patches, the high water retention capacity and biocompatibility of hyaluronic acid make it an ideal substrate material. Its preparation first prepares a sufficient amount of hyaluronic acid powder (HA), a cross-linking agent, a NaoH solution, a polyol (as a solvent or a humectant) and a certain amount of deionized water (as a solvent). The molecular weight of the hyaluronic acid powder can be a macromolecule (more than 1000Da), a medium molecule (molecular weight between several thousand and tens of thousands of Da) or a small molecule (less than 1000Da) according to actual conditions. First, the cross-linking agent (25% to 50% glutaraldehyde) is added to the NaoH solution at a mass ratio of 1:50 to form a cross-linked solution, and then the hyaluronic acid powder is added to the cross-linked solution at a mass ratio of 1:10. The temperature between 35°C and 40°C is controlled to heat and stir, and the powder is kept for more than two hours to dissolve to form a hyaluronic acid hydrogel. If bubbles are generated, it is necessary to wait for the solution to be made and then let it stand. After that, 95% ethanol is used to rinse to remove impurities such as uncross-linked hyaluronic acid powder, cross-linking agent and NaOH, and the hyaluronic acid hydrogel is converted into hyaluronic acid cross-linked particles through grinding and sieving. The hyaluronic acid cross-linked particles are mixed with uncross-linked low molecular weight hyaluronic acid powder in a ratio of 3:5, and deionized water is added to generate a uniform viscous suspension under a magnetic stirrer. The prepared solution is poured into a rectangular template mold with a length, width and height of 8000μm×3000μm×600μm, and is formed by pressure or vacuum, and then cooled and solidified. After completion, it needs to be trimmed and sorted to remove the excess parts.

[0048] The preparation of the soluble microneedle patch is as follows:

[0049] A mold of a conical hole array is made of polydimethylsiloxane (PDMS). A soluble microneedle patch adopts a 16×8 distribution array. The bottom of the pyramid is a circle with a radius of 130μm, the height of each needle tip is 800μm, the distance between each needle tip is 400μm, and the needle body is conical.

[0050] After the base model is cut, the PDMS mold is placed in a vacuum environment to remove residual air and microparticles on the surface. The methacrylic anhydride solution and the hydrogel precursor solution are mixed with the drugs required for treatment (the drugs required for hemostasis, inflammation inhibition, etc. mentioned above) to undergo polymerization to form a GelMA solution. The GelMA solution is then dripped into the backing layer of the prepared PDMS mold using a dropper. After drying, it is irradiated with ultraviolet light at a wavelength of 365nm with a light intensity of 10-15mW / cm 2 The irradiation time is 30-60 seconds to achieve photo-crosslinking of GelMA, and then separated from the mold and placed in a desiccator.

[0051] The insoluble microneedles were prepared as follows:

[0052] According to the function of the insoluble microneedle patch, high-strength polystyrene material is selected as the raw material. Ensure that its moisture content is within the appropriate range, and the moisture content of the raw material does not exceed 0.1%. If it exceeds, dry it in a hot air circulation at 70-80℃ for 2-3 hours.

[0053] Cut two microneedle molds with a microneedle distribution array of 3×8, a circular shape with a microneedle bottom radius of 130μm, a needle height of 900μm, and a needle distance of 250μm; the microneedle body is a cone shape inclined 80° from the horizontal plane. After the mold is manufactured, debug it to ensure the accuracy and stability of the mold. At the same time, check whether the cooling system of the mold is unobstructed to ensure the cooling effect of the mold during the injection molding process.

[0054] Heat the polystyrene particles to a melting temperature of 180-240°C and inject them into the barrel of the injection molding machine. The injection molding machine pushes the particles into the high-pressure area through the screw, causing them to melt and become an injectable melt. After reaching a certain injection pressure, the melt enters the mold cavity through the nozzle in the mold. In the mold cavity, control the mold temperature between 60 and 80°C, the cooling water temperature between 20 and 30°C, and control the cooling rate. The melt will be subjected to high pressure and cooling, and will quickly solidify into a solid polystyrene product. When the polystyrene is completely cooled and solidified, open the mold, take out the microneedle patch, test its surface accuracy, polish the edges and corners, cut off the excess parts, and put it in a dryer.

[0055] The present invention uses an innovative surface treatment process to improve the performance of insoluble microneedles. The low-temperature plasma treatment uses the following process parameters:

[0056] -Plasma gas: oxygen (purity 99.999%)

[0057] - Chamber vacuum: 50Pa

[0058] -RF power: 50-100W

[0059] -Processing time: 30-60s

[0060] -Substrate temperature: 25±5℃

[0061] The treatment process forms a nano-scale roughness structure on the surface of the microneedle, significantly increasing the surface area. The treated surface structure is more conducive to the binding of bioadhesive proteins.

[0062] In order to improve the fixation effect of the insoluble microneedle patch, an environmentally responsive bioadhesive protein was modified on its surface. The protein exposes the adhesive group in a humid environment and exhibits strong adhesion properties, while the adhesive group rolls inward in a dry environment, and the adhesion force is significantly weakened. This intelligent response property allows the microneedle patch to be firmly fixed during use, and easy to remove when it needs to be replaced. The specific modification method is to covalently connect the bioadhesive protein to the microneedle surface through chemical coupling, and then cross-link and fix it to ensure the stability of the protein.

[0063] The above are only preferred specific implementation modes of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical solutions and inventive concepts of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. An integrated hemostatic drug-loaded microneedle patch, characterized in that: The invention comprises a microneedle substrate (1), a soluble microneedle patch (2), a composite drug (3), an insoluble microneedle patch (4), a composite sensor (5), and a micro-control flow chip (6); the insoluble microneedle patch (4) has two pieces, which are used to fix the integrated microneedle patch and are located on both sides of the soluble microneedle patch (2); the insoluble microneedle patch (4) and the soluble microneedle patch (2) are both arranged on the microneedle substrate (1); the composite drug (3) is used for wound treatment and is arranged on the microneedle material of the soluble microneedle patch (2); the composite sensor (5) is used to monitor a series of blood routine indicators and human body temperature and is arranged between the soluble microneedle patch (2) and the microneedle substrate (1); the micro-control flow chip (6) is used to store the extracted samples required for detection and is arranged above the soluble microneedle patch (2).

2. The integrated hemostatic drug-loaded microneedle patch according to claim 1, characterized in that: The microneedle height of the soluble microneedle patch (2) is 800 μm; the microneedle height of the insoluble microneedle patch (4) is 900 μm; the length, width and height of the microneedle substrate (1) are 8000 μm, 3000 μm and 600 μm respectively.

3. The integrated hemostatic drug-loaded microneedle patch according to claim 1, characterized in that: The compound medicine (3) is composed of a hemostatic agent, an anti-inflammatory analgesic agent and an antibacterial agent; the hemostatic agent is thrombin, the anti-inflammatory analgesic agent is ropivacaine hydrochloride, and the antibacterial agent is levofloxacin; the compound medicine (3) also includes long-acting amide anti-inflammatory drugs, quinolone antibiotics and other antibacterial drugs and drugs for promoting blood coagulation by wound injection.

4. The integrated hemostatic drug-loaded microneedle patch according to claim 1, characterized in that: The composite sensor is a multi-factor detection sensor composed of an optical sensor for detecting red blood cells, an electrochemical sensor for detecting hemoglobin, a biosensor for detecting white blood cells and platelets, and a thermistor sensor for measuring temperature; the composite sensor also includes a data anomaly screening module and a multi-sensor data fusion processing module, wherein the data anomaly screening module is set with a normal value range of blood routine indicators and temperature, and an alarm signal is triggered when the detection data exceeds the range; the multi-sensor data fusion processing module uses a Kalman filter algorithm to perform fusion analysis on multiple sensor data; the composite sensor integrates a low-power Bluetooth module and a microcontroller, and the microcontroller is used for data acquisition, processing and wireless transmission; the sampling frequency of the composite sensor 5 is 10Hz and the resolution is 12 bits.

5. The integrated hemostatic drug-loaded microneedle patch according to claim 1, characterized in that: The microneedles of the insoluble microneedle patch (4) are in the shape of barbs, cones, double arrows or bionic structures.

6. The integrated hemostatic drug-loaded microneedle patch according to claim 1, characterized in that: The microfluidic chip (6) is composed of two layers of substrates, and a cavity is formed between the composite interlayers, and the cavity is used to collect and store test sample droplets; the channel structure types of the microfluidic chip (6) include but are not limited to straight type and S type.

7. The integrated hemostatic drug-loaded microneedle patch according to claim 1, characterized in that: The insoluble microneedle patch (4) is made of polystyrene or metal or silicon or plastic, the surface of the insoluble microneedle patch (4) is modified with bioadhesive protein, and the surface of the insoluble microneedle patch is treated with low-temperature plasma to form a surface roughness structure of 10-100 nm.

8. The integrated hemostatic drug-loaded microneedle patch according to claim 1, characterized in that: The material of the microneedle substrate (1) includes one or more of hyaluronic acid, blood-absorbing hydrogel, polyvinyl alcohol and polyvinyl pyrrolidone.

9. The integrated hemostatic drug-loaded microneedle patch according to claim 1, characterized in that: The microfluidic chip (6) and the composite sensor (5) are integrated into one body by using polydimethylsiloxane encapsulation technology and a microneedle patch.

10. The integrated hemostatic drug-loaded microneedle patch according to claim 1, characterized in that: When the drug in the microneedle patch is changed or the detection-specific identification element is changed, the integrated microneedle patch detects indicators related to inflammatory factors TNF-alpha, IL-1, IL-6, C-reactive protein CRP, red blood cells, platelets, white blood cells, hemoglobin and wound information.

Images