Personalized microneedle manufacturing process based on 3D printing technology

Abstract

The invention relates to the technical field of biomedical materials, and discloses a personalized microneedle manufacturing process based on a 3D printing technology, which comprises the following steps: skin feature data acquisition: acquiring skin feature data of a patient through skin scanning equipment, comprise but are not limited to skin thickness, elasticity, pore distribution, skin types and shapes and sizes of skin lesion areas; personalized design and modeling are carried out, and a personalized microneedle array model containing the following parameters is generated by using computer aided design software according to the treatment requirements of the patient and the skin feature data. Skin feature data of a patient is obtained through skin scanning equipment, and a personalized microneedle array model is generated in combination with computer aided design software. According to the model, the length, the diameter, the shape and the spacing of the microneedles can be accurately designed according to the treatment requirements of a patient. According to the process, the individuation degree of the microneedle is remarkably improved, customized design can be carried out according to specific requirements of different patients, and therefore the treatment effect is improved.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedical materials, and particularly to a personalized microneedle manufacturing process based on 3D printing technology. Background Art

[0002] As an emerging minimally invasive technology, microneedles have become a research hotspot in the fields of transdermal drug delivery, disease monitoring and diagnosis, etc. because they can minimally penetrate the stratum corneum of the skin and achieve efficient drug delivery. Currently, the manufacturing methods of microneedles mainly include technologies such as lithography, micro-molding, laser ablation, and droplet blow molding. Lithography patterns a polymer film through a photomask and can manufacture microneedle arrays with high precision and reproducibility, but this process is time-consuming and requires expensive equipment. Micro-molding technology casts microneedles through a mold, which has the advantages of low cost and simple operation, but its design complexity and customizability are limited, and it is difficult to quickly adjust the size and geometric shape of microneedles. Laser ablation technology uses a laser beam to locally melt and vaporize materials and can manufacture microneedles with a high aspect ratio, but it also requires specialized equipment and is costly. Droplet blow molding forms microneedles by stretching and blowing droplets to solidify, with low equipment requirements and fast preparation speed, but there are certain limitations in the control of the geometric shape of microneedles.

[0003] In recent years, 3D printing technology has gradually become a powerful tool in the field of microneedle manufacturing due to its customizability, high precision, and good compatibility with biological materials. However, 3D printing microneedle manufacturing technology still needs to be further optimized in terms of high-precision manufacturing, multi-functional integration, and real-time quality control. For this reason, those skilled in the art have proposed a personalized microneedle manufacturing process based on 3D printing technology to solve the above problems. Summary of the Invention

[0004] In view of the deficiencies of the prior art, the present invention provides a personalized microneedle manufacturing process based on 3D printing technology, which solves the problems raised in the above background art.

[0005] To achieve the above objectives, the present invention is realized through the following technical solutions: A personalized microneedle manufacturing process based on 3D printing technology, comprising the following steps:

[0006] Skin feature data collection, obtaining the skin feature data of the patient through a skin scanning device, including but not limited to skin thickness, elasticity, pore distribution, skin type, and the shape and size of skin lesion areas;

[0007] Personalized design and modeling, using computer-aided design software, according to the treatment needs of the patient and the skin feature data, generating a personalized microneedle array model including the following parameters:

[0008] Printing material preparation: Select a biocompatible printing material and mix the drug into the printing material at a preset concentration and in a preset form according to the treatment requirements to form a drug-loaded printing ink;

[0009] High-precision 3D printing: Use a high-precision 3D printer to print the microneedle array layer by layer according to the personalized microneedle array model, where:

[0010] The movement path of the printing nozzle and the material extrusion rate precisely control the size and shape of the microneedles, with the length error of the microneedles less than ±2% and the diameter error less than ±3%;

[0011] Print microneedles with different sizes, shapes, and drug concentrations in the same array through multi-nozzle printing technology,

[0012] During the printing process, monitor the forming quality of the microneedles in real time and automatically adjust the printing parameters through a feedback control system;

[0013] Post-processing optimization: Perform the following post-processing steps on the printed microneedle array to enhance its performance:

[0014] Drying treatment: Adopt a progressive drying technique to avoid cracks in the microneedle structure due to rapid drying;

[0015] Curing treatment: Enhance the mechanical strength of the microneedles through photocuring, thermal curing, or chemical crosslinking;

[0016] Surface treatment: Modify the surface of the microneedles;

[0017] Quality inspection and verification: Use equipment such as optical microscopes, scanning electron microscopes, and atomic force microscopes to detect the size, shape, surface roughness, drug distribution uniformity, etc. of the microneedles,

[0018] In vivo experiments: Evaluate the safety and therapeutic effect of the microneedles in actual applications;

[0019] Drug release curve optimization: Achieve controlled release or rapid release of the drug by adjusting the composition of the printing material and the drug loading method to meet different treatment requirements.

[0020] Preferably, the skin scanning device includes an optical imaging system, a laser scanning system, an ultrasonic scanning system, or a combination thereof, and the scanning accuracy is not less than 0.01 mm, capable of obtaining detailed data on the skin surface and shallow structures.

[0021] Preferably, the personalized microneedle array model further includes the following parameters: hardness gradient design of the microneedles, partition design of the drug release rate, and degradability design of the microneedles.

[0022] Preferably, the biocompatible material includes one or more combinations of, but is not limited to, natural polymers, inorganic materials, and hydrogels.

[0023] Preferably, the high-precision 3D printer adopts one or more combinations of the following technologies:

[0024] Fused deposition modeling technology, used for thermoplastic biomaterials;

[0025] Inkjet printing technology, used for low-viscosity bioinks;

[0026] Stereolithography technology, used for photosensitive biomaterials;

[0027] Micro-nano 3D printing technology, used for the manufacture of micron-scale precision microneedles;

[0028] And the resolution of the high-precision 3D printer is not less than 10 μm, enabling high-precision forming of microneedles.

[0029] Preferably, the post-processing step further includes the following content:

[0030] Mechanical strengthening treatment, forming micro-nano structures on the surface of microneedles through micro-nano imprinting technology;

[0031] Drug stability treatment, removing solvents in microneedles through freeze-drying or spray-drying technology;

[0032] Biological activity enhancement, embedding bioactive factors on the surface or inside of microneedles.

[0033] Preferably, the quality inspection and verification further include the following steps:

[0034] Drug loading efficiency detection, analyzing the actual drug content in microneedles by high-performance liquid chromatography or mass spectrometry to ensure that the drug loading efficiency is not less than 90%;

[0035] Drug release kinetics analysis, measuring the drug release curve by in vitro release experiments and optimizing the drug release behavior through mathematical models;

[0036] Skin compatibility test, evaluating the biocompatibility and safety of microneedles through in vitro cell experiments and in vivo skin irritation tests.

[0037] Preferably, the personalized design of the microneedle array further includes the following application scenarios:

[0038] Transdermal drug delivery, designing the optimal microneedle length and drug loading method for different drugs;

[0039] Skin beauty, designing the microneedle array according to the degree of skin aging and wrinkle distribution for promoting the absorption of active ingredients;

[0040] Treatment of chronic wounds, customized microneedle arrays according to the shape and size of the wounds, for local delivery of antibiotics, growth factors or stem cells.

[0041] The present invention provides a personalized microneedle manufacturing process based on 3D printing technology. It has the following beneficial effects:

[0042] 1. The present invention obtains the skin characteristic data of patients through a skin scanning device, and generates a personalized microneedle array model in combination with computer-aided design software. This model can accurately design the length, diameter, shape, spacing and drug loading area distribution of microneedles according to the treatment needs of patients. Compared with traditional processes, this process significantly improves the personalization degree of microneedles, can be customized according to the specific needs of different patients, thereby improving the treatment effect and patient comfort.

[0043] 2. The present invention realizes the manufacturing of multifunctional microneedle arrays through multi-nozzle printing technology. Different nozzles can print microneedles of different materials or different drug concentrations respectively, and can also realize the multi-layer structure design of microneedles through nozzle switching. In addition, post-processing steps further optimize the performance of microneedles, making them excellent in mechanical strength, biocompatibility and drug release characteristics. Compared with traditional processes, this process can not only manufacture single-functional microneedles, but also integrate multiple functions in the same array, significantly improving the applicability and treatment effect of microneedles. For example, for different application scenarios such as transdermal drug delivery, skin beautification and chronic wound treatment, microneedle arrays that meet specific requirements can be quickly manufactured, greatly shortening the R & D cycle and manufacturing cost.

[0044] 3. The present invention adopts high-precision 3D printing technology, which can accurately control the size and shape of microneedles, ensuring that the length error of microneedles is less than ±2%, and the diameter error is less than ±3%. Through multi-nozzle printing technology, microneedles of different sizes, shapes and drug concentrations can be printed in the same array to adapt to different skin areas and treatment needs. In addition, the forming quality of microneedles is monitored in real time during the printing process, and the printing parameters are automatically adjusted through a feedback control system to ensure the consistency of product quality. Compared with traditional manufacturing processes, this process significantly improves the manufacturing precision and quality stability of microneedles, reducing the problems of skin puncture failure or uneven drug release caused by size errors. Description of the Drawings

[0045] Figure 1 is the overall flow chart of the present invention;

[0046] Figure 2 is the skin scanning and personalized design flow chart of the present invention;

[0047] Figure 3 is the 3D printing process flow chart of the present invention;

[0048] Figure 4 This is the flowchart of post - processing and quality control for the present invention. Specific embodiments

[0049] Next, in combination with the accompanying drawings of the present invention specification, the technical solutions in the embodiments of the present invention will be clearly and completely described. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts fall within the protection scope of the present invention.

[0050] Embodiment 1:

[0051] Please refer to the attached Figure 1 - attached Figure 4 , the embodiment of the present invention provides a personalized microneedle manufacturing process based on 3D printing technology, including the following steps:

[0052] Skin feature data collection, obtaining the skin feature data of the patient through a skin scanning device, including but not limited to skin thickness, elasticity, pore distribution, skin type, and the shape and size of skin lesion areas; the skin scanning device includes an optical imaging system, a laser scanning system, an ultrasonic scanning system or a combination thereof, and the scanning accuracy is not less than 0.01 mm, capable of obtaining detailed data of the skin surface and shallow - layer structures.

[0053] Personalized design and modeling, using computer - aided design software, according to the treatment requirements of the patient and the skin feature data, generating a personalized microneedle array model including the following parameters: the personalized microneedle array model also includes the following parameters: the hardness gradient design of the microneedles, the partition design of the drug release rate, and the degradability design of the microneedles.

[0054] Specifically, the skin scanning device is used to obtain the skin feature data of the patient, and the data includes skin thickness, elasticity, pore distribution, skin type, and the shape and size of skin lesion areas. The device type can be an optical imaging system, a laser scanning system, an ultrasonic scanning system or a combination thereof, and the scanning accuracy is not less than 0.01 mm to ensure that detailed data of the skin surface and shallow - layer structures can be obtained.

[0055] Among them, the optical imaging system obtains the image data of the skin surface through optical principles and can clearly display information such as skin texture and pore distribution. The laser scanning system scans the skin surface with a laser beam and can accurately measure the skin thickness, elasticity and micro - structures. The ultrasonic scanning system obtains information about the deep - layer structures of the skin, such as the shape and size of skin lesion areas, through the ultrasonic reflection principle.

[0056] Using computer-aided design software, a personalized microneedle array model is generated according to the treatment needs of the patient and the skin characteristic data. The model includes the following parameters:

[0057] Hardness gradient design of microneedles: The hardness gradually increases from the tip to the base to improve the puncture performance of the microneedles and reduce damage to the skin. The hardness gradient can be achieved through material selection and adjustment of printing parameters.

[0058] Partition design of drug release rate: Different drug release rates are designed in different regions of the microneedles to achieve controlled release or rapid release. For example, the outer layer is designed for rapid release and the inner layer is designed for controlled release.

[0059] Degradability design of microneedles: Adjust the degradation time of the microneedles according to the treatment cycle to ensure that the microneedles can be safely degraded after drug release and will not cause residues on the skin.

[0060] Preparation of printing materials, select biocompatible printing materials, and mix the drug into the printing materials at a preset concentration and form according to the treatment needs to form drug-loaded printing inks; biocompatible materials include but are not limited to one or more combinations of natural polymers, inorganic materials, and hydrogels.

[0061] High-precision 3D printing, use a high-precision 3D printer to print the microneedle array layer by layer according to the personalized microneedle array model, where:

[0062] The movement path of the printing nozzle and the material extrusion rate precisely control the size and shape of the microneedles, with the length error of the microneedles less than ±2% and the diameter error less than ±3%;

[0063] Print microneedles with different sizes, shapes, and drug concentrations in the same array through multi-nozzle printing technology,

[0064] Monitor the forming quality of the microneedles in real time during the printing process and automatically adjust the printing parameters through a feedback control system;

[0065] Specifically, the movement path of the printing nozzle is precisely controlled by the personalized microneedle array model generated by computer-aided design software. The path planning ensures that the nozzle can accurately build the microneedle structure layer by layer during the printing process, thus ensuring the dimensional and shape accuracy of the microneedles.

[0066] Material extrusion rate: Precise control of the material extrusion rate is the key to ensuring the size and shape of the microneedles. By adjusting the pressure and speed of the nozzle, the extrusion amount of the material can be precisely controlled, so as to ensure that the length error of the microneedles is less than ±2% and the diameter error is less than ±3%.

[0067] Multi-nozzle printing technology: Through multi-nozzle printing technology, microneedles of different sizes, shapes, and drug concentrations can be printed in the same array. For example, digital light processing (DLP) inkjet printing technology allows the use of multiple materials in a single printing job, enabling the realization of microneedle arrays with different drug concentrations.

[0068] Real-time monitoring and feedback control during the printing process are as follows:

[0069] Real-time monitoring: During the printing process, the forming quality of the microneedles is monitored in real time through sensors and monitoring systems. Through the high-precision optical system and real-time image processing of digital light processing (DLP) technology, the quality of each printed layer is monitored.

[0070] Feedback control system: The feedback control system automatically adjusts the printing parameters according to the data monitored in real time to ensure the forming quality of the microneedles. By precisely controlling the temperature, speed, and trajectory of the nozzle through a fused deposition modeling (FDM) printer, the parameters can be automatically adjusted during the printing process to ensure that the printed model has high precision and good surface quality.

[0071] The high-precision 3D printer adopts one or a combination of the following technologies:

[0072] Fused deposition modeling technology for thermoplastic biomaterials;

[0073] Inkjet printing technology for low-viscosity bioinks;

[0074] Photocuring technology for photosensitive biomaterials;

[0075] Micro-nano 3D printing technology for the manufacture of microneedles with sub-micron precision;

[0076] Moreover, the resolution of the high-precision 3D printer is not less than 10 μm, enabling high-precision forming of microneedles.

[0077] Post-processing optimization: The following post-processing steps are performed on the printed microneedle array to enhance its performance:

[0078] Drying treatment: Progressive drying technology is adopted to avoid cracks in the microneedle structure due to rapid drying;

[0079] Curing treatment: The mechanical strength of the microneedles is enhanced through photocuring, thermal curing, or chemical crosslinking;

[0080] Surface treatment: The surface of the microneedles is modified;

[0081] Quality inspection and verification: The size, shape, surface roughness, drug distribution uniformity, etc. of the microneedles are detected using equipment such as optical microscopes, scanning electron microscopes, and atomic force microscopes.

[0082] In vivo experiments: Evaluate the safety and therapeutic effects of microneedles in practical applications;

[0083] Optimize the drug release curve. By adjusting the composition of the printing material and the drug loading method, achieve controlled or rapid drug release to meet different treatment requirements.

[0084] The post-treatment steps also include the following:

[0085] Mechanical strengthening treatment. Form micro-nano structures on the surface of microneedles through micro-nano imprinting technology;

[0086] Specifically, the mechanical strengthening treatment forms micro-nano structures on the surface of microneedles through micro-nano imprinting technology to improve the mechanical strength and puncture performance of microneedles. Micro-nano imprinting technology is a high-precision processing technology that can form micro- or nano-scale structures on the surface of microneedles. These micro-nano structures can increase the surface area of microneedles, improve their contact efficiency with the skin, and at the same time enhance the mechanical strength of microneedles, making them not easily break during the puncture process.

[0087] Drug stability treatment. Remove the solvent in microneedles through freeze-drying or spray-drying technology;

[0088] Specifically, the drug stability treatment is to remove the solvent in microneedles through freeze-drying or spray-drying technology to ensure the stability of the drug and the performance of microneedles. Freeze-drying is a method of removing the solvent from materials at low temperature and low pressure, which can effectively avoid the decomposition or denaturation of drugs at high temperatures. Spray-drying is to atomize the microneedle material and quickly dry it at high temperature to form a uniform microneedle structure. Both of these technologies can effectively remove the solvent in microneedles, ensure the stability of the drug during storage and use, and avoid skin irritation caused by solvent residues.

[0089] Enhance biological activity. Embed bioactive factors on the surface or inside of microneedles.

[0090] Specifically, enhancing biological activity is to embed bioactive factors on the surface or inside of microneedles to enhance the therapeutic effect of microneedles. Bioactive factors are growth factors, cytokines or other bioactive molecules. These factors can promote skin repair, accelerate wound healing or enhance the therapeutic effect of drugs. Embedding epidermal growth factor (EGF) on the surface of microneedles can promote the proliferation and migration of skin cells and accelerate the skin repair process. Embedding antimicrobial peptides inside microneedles can effectively prevent infection and improve the treatment effect of chronic wounds.

[0091] Quality inspection and verification also include the following steps:

[0092] Detect the drug loading efficiency. Analyze the actual drug content loaded in microneedles by high-performance liquid chromatography or mass spectrometry to ensure that the drug loading efficiency is not less than 90%;

[0093] Specifically, the drug loading efficiency detection aims to determine the actual drug content loaded in the microneedles to ensure that the drug loading efficiency is not less than 90%. The detection method is as follows:

[0094] High-performance liquid chromatography (HPLC): HPLC can accurately measure the drug content in the microneedles. By dissolving the microneedle sample in an appropriate solvent and injecting it into the HPLC system, the separation and quantitative analysis of the drug are achieved by utilizing the differences in the interactions between the drug and the stationary phase and the mobile phase. The detection principle of HPLC is based on the retention time and peak area of the drug in the column. By comparing with the standard sample, the drug content can be accurately determined.

[0095] Mass spectrometry (MS): Mass spectrometry can provide accurate mass information of drug molecules. By ionizing the microneedle sample and detecting the mass-to-charge ratio (m / z) of the ions using a mass spectrometer, the drug molecules can be identified and their content can be quantitatively analyzed.

[0096] Drug release kinetics analysis, using in vitro release experiments to determine the drug release curve and optimizing the drug release behavior through mathematical models;

[0097] Specifically, drug release kinetics analysis is used to study the behavior of drug release from the microneedles. The drug release curve is determined through in vitro release experiments, and the drug release behavior is optimized using mathematical models. The in vitro release experiment is carried out in a buffer solution simulating physiological conditions. By periodically sampling and analyzing, the cumulative release amount of the drug at different time points is determined.

[0098] The formula required is:

[0099] M t / M ∞ =kt

[0100] Where, M t is the cumulative release amount at time t, M ∞ is the total release amount of the drug, and k is the release rate constant.

[0101] Skin compatibility test, evaluating the biocompatibility and safety of the microneedles through in vitro cell experiments and in vivo skin irritation tests.

[0102] Biocompatibility is evaluated through in vitro cell experiments and in vivo skin irritation tests. The evaluation indicators include cell viability and skin irritation score. The calculation formula for cell viability is:

[0103]

[0104] Where the skin irritation score is scored by observing indicators such as skin redness and exudation, with a full score of 5 points. The lower the score, the better the biocompatibility.

[0105] The personalized design of the microneedle array also includes the following application scenarios:

[0106] Transdermal drug delivery, for designing the optimal microneedle length and drug loading method for different drugs;

[0107] Skin beautification, designing the microneedle array according to the degree of skin aging and wrinkle distribution for promoting the absorption of active ingredients;

[0108] Chronic wound treatment, customizing the microneedle array according to the shape and size of the wound for local delivery of antibiotics, growth factors or stem cells.

[0109] Specifically, transdermal drug delivery is a method of delivering drugs into the body through the skin. The application of the microneedle array in transdermal drug delivery is mainly reflected in the following aspects:

[0110] Microneedle length design: The length of the microneedles is optimized according to the thickness of the skin stratum corneum. The microneedle length is slightly greater than the thickness of the stratum corneum (20 - 30 μm), but does not exceed the dermis layer (100 - 150 μm) to avoid causing pain and bleeding.

[0111] The microneedles adopt a hollow design or a drug - loading design. The hollow microneedles connect the drug reservoir and the skin surface to deliver drugs into the skin; the drug - loaded microneedles directly embed the drugs into the microneedle material and gradually release the drugs after penetrating the skin.

[0112] The microneedle array has significant advantages in chronic wound treatment, can locally deliver antibiotics, growth factors or stem cells, and accelerate wound healing. Its application characteristics include:

[0113] Microneedle customization: Customize the microneedle array according to the shape and size of the wound to ensure that the drugs can evenly cover the wound area. For large - area wounds, design a high - density microneedle array; for small - area wounds, adopt a low - density design.

[0114] Drug delivery: The microneedles can be loaded with antibiotics (such as silver ions) to prevent infection, or loaded with growth factors (such as epidermal growth factor) to promote tissue repair.

[0115] To better understand the technical solution of the present invention, the following through comparative test experiments of multiple examples and comparative examples, details the significant advantages of the present invention in aspects such as skin puncture ability, drug release efficiency and biocompatibility.

[0116] Example 2: Application of transdermal drug delivery

[0117] The microneedle design parameters are as follows: microneedle length: 1.5 mm, microneedle diameter: 50 μm, microneedle shape: conical.

[0118] Hardness gradient design: Gradually increase from the tip to the base.

[0119] Drug release rate: Zoned design (rapid release in the outer layer and controlled release in the inner layer).

[0120] Degradability design: Completely degraded within 7 days.

[0121] The printing materials are as follows:

[0122] Substrate: Polylactic acid (PLA), biocompatible additive: Hyaluronic acid, drug: Insulin (concentration 5%).

[0123] The technical type of 3D printing technology: Fused Deposition Modeling (FDM).

[0124] Printer resolution: 10 μm.

[0125] The post-processing operation steps are as follows:

[0126] Drying treatment: Progressive drying (24 hours), curing treatment: Photocuring (ultraviolet irradiation for 5 minutes), surface treatment: Adding a lubricating layer, quality inspection and verification, dimensional inspection: Optical microscope, shape inspection: Scanning electron microscope (SEM), drug distribution uniformity: High performance liquid chromatography (HPLC), in vivo experiment: Skin irritation test.

[0127] Example 3: Skin beauty application

[0128] The micro-needle design parameters are as follows: Micro-needle length: 1.0 mm, micro-needle diameter: 30 μm

[0129] Micro-needle shape: Pyramidal.

[0130] Hardness gradient design: Gradually increasing from the tip to the base.

[0131] Drug release rate: Zoned design (rapid release in the outer layer and controlled release in the inner layer).

[0132] Degradability design: Completely degraded within 5 days.

[0133] The printing materials are as follows:

[0134] Substrate: Poly (lactic-co-glycolic acid) (PLGA), biocompatible additive: Chitosan, drug: Collagen (concentration 3%).

[0135] The technical type of 3D printing technology: Inkjet printing technology.

[0136] Printer resolution: 10 μm.

[0137] The post-processing operation steps are as follows:

[0138] Drying treatment: Progressive drying (12 hours), Curing treatment: Thermal curing (60°C, 10 minutes), Surface treatment: Adding bioactive factors (growth factors).

[0139] The quality inspection and verification operation steps are as follows:

[0140] Size detection: Optical microscope.

[0141] Shape detection: Scanning electron microscope (SEM).

[0142] Drug distribution uniformity: High performance liquid chromatography (HPLC).

[0143] In vivo experiment: Skin irritation test.

[0144] Example 4: Chronic wound treatment application

[0145] The micro - needle design parameters are set as follows: Micro - needle length: 2.0 mm, Micro - needle diameter: 80 μm

[0146] , Micro - needle shape: Cylindrical.

[0147] Hardness gradient design: Gradually increasing from the tip to the base.

[0148] Drug release rate: Zonal design (rapid release in the outer layer and controlled release in the inner layer).

[0149] Degradability design: Completely degraded within 10 days.

[0150] The printing materials are as follows: Substrate: Polycaprolactone (PCL), Biocompatible additive: Collagen, Drug: Antibiotic (concentration 7%).

[0151] The technical type of 3D printing technology: Stereolithography technology.

[0152] Printer resolution: 10 μm.

[0153] The post - processing operation steps are as follows:

[0154] Drying treatment: Progressive drying (36 hours), Curing treatment: Chemical cross - linking (cross - linker treatment for 15 minutes).

[0155] Surface treatment: Adding an antibacterial coating.

[0156] The quality inspection and verification steps are as follows:

[0157] Size detection: Optical microscope.

[0158] Shape detection: Scanning electron microscope (SEM).

[0159] Drug distribution uniformity: High performance liquid chromatography (HPLC).

[0160] In vivo experiment: Skin irritation test.

[0161] Comparative Example 1-1

[0162] Compared with Example 2, the difference lies in removing the hardness gradient design, and the rest are the same.

[0163] Comparative Example 1-2

[0164] Compared with Example 2, the difference lies in canceling the real-time quality monitoring and feedback control system, and the rest are the same.

[0165] Comparative Example 2-1

[0166] Compared with Example 3, the difference lies in removing the drug release rate zoning design, and the rest are the same.

[0167] Comparative Example 2-2

[0168] Compared with Example 3, the difference lies in canceling the multi-nozzle printing technology, and the rest are the same.

[0169] Comparative Example 3-1

[0170] Compared with Example 4, the difference lies in removing the degradability design, and the rest are the same.

[0171] Comparative Example 3-2

[0172] Compared with Example 4, the difference lies in canceling the mechanical strengthening treatment in the post-treatment, and the rest are the same.

[0173] Comparative test experiment

[0174] Test Example 1: Skin puncture ability test

[0175] Test content: Evaluate the skin puncture ability of the microneedles.

[0176] Test method: Use an in vitro skin model to measure the penetration depth and success rate of the microneedles through the skin.

[0177] Test indicators: Penetration depth (mm), penetration success rate (%).

[0178] Test Example 2: Drug release efficiency test

[0179] Test content: Evaluate the drug release efficiency of the microneedles.

[0180] Test method: In vitro release experiment to measure the cumulative release amount of the drug within 24 hours.

[0181] Test indicator: Cumulative release amount (%).

[0182] Test Example 3: Biocompatibility Test

[0183] Test Content: Evaluate the biocompatibility of the microneedles.

[0184] Test Method: In vitro cell experiment (keratinocyte culture) and in vivo skin irritation test.

[0185] Test Indexes: Cell survival rate (%) and skin irritation score.

[0186] The microneedle array of Example 2 showed the best performance in terms of penetration depth and success rate. The penetration depth was 1.45 mm and the success rate was 95%. In Comparative Example 1-1, due to the removal of the hardness gradient design, the mechanical strength of the microneedles decreased, resulting in a decrease in penetration depth and success rate. In Comparative Example 1-2, the real-time quality monitoring and feedback control system was cancelled. Although the penetration depth was slightly higher than that of Comparative Example 1-1, the success rate was still lower than that of Example 2. This indicates that the hardness gradient design and real-time quality control play important roles in ensuring the puncture performance of microneedles.

[0187] The cumulative drug release amount of the microneedle array of Example 2 within 24 hours was 85%, showing good drug release performance. In Comparative Example 1-1, due to the lack of the hardness gradient design, the drug release efficiency decreased to 72%. In Comparative Example 1-2, due to the lack of real-time quality control, the drug release efficiency was 78%. This indicates that the hardness gradient design not only affects the puncture performance but also has an important impact on the drug release behavior.

[0188] The microneedle array of Example 2 showed a cell survival rate of 92% in the in vitro cell experiment and a score of 1.2 (out of 5) in the in vivo skin irritation test, indicating its good biocompatibility. The cell survival rates of Comparative Example 1-1 and Comparative Example 1-2 were 85% and 88% respectively, and the skin irritation scores were 1.8 and 1.5 respectively. This indicates that the hardness gradient design and real-time quality control also have a certain impact on the biocompatibility of microneedles.

[0189] In summary, the microneedle array of Example 2 showed excellent performance in skin puncture ability, drug release efficiency, and biocompatibility, verifying the effectiveness and superiority of the technical solution of the present invention. The test results of the comparative examples further illustrate the key role of the hardness gradient design and real-time quality control in microneedle manufacturing.

[0190] Although the embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principles and spirit of the present invention. The scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A personalized microneedle manufacturing process based on 3D printing technology, characterized in that, It includes the following steps: Skin feature data collection: Obtain the skin feature data of the patient through a skin scanning device, including but not limited to skin thickness, elasticity, pore distribution, skin type, and the shape and size of skin lesion areas; Personalized design and modeling: Use computer-aided design software to generate a personalized microneedle array model containing the following parameters according to the treatment needs of the patient and the skin feature data: Printing material preparation: Select a biocompatible printing material and mix the drug into the printing material at a preset concentration and form according to the treatment needs to form a drug-loaded printing ink; High-precision 3D printing: Use a high-precision 3D printer to print the microneedle array layer by layer according to the personalized microneedle array model, where: The movement path of the printing nozzle and the material extrusion rate precisely control the size and shape of the microneedles, with the length error of the microneedles less than ±2% and the diameter error less than ±3%; Print microneedles with different sizes, shapes, and drug concentrations in the same array through multi-nozzle printing technology; Monitor the forming quality of the microneedles in real time during the printing process and automatically adjust the printing parameters through a feedback control system; Post-processing optimization: Perform the following post-processing steps on the printed microneedle array to enhance its performance: Drying treatment: Adopt a progressive drying technique to avoid cracks in the microneedle structure due to rapid drying; Curing treatment: Enhance the mechanical strength of the microneedles through photocuring, thermal curing, or chemical crosslinking; Surface treatment: Modify the surface of the microneedles; Quality inspection and verification: Use equipment such as optical microscopes, scanning electron microscopes, and atomic force microscopes to detect the size, shape, surface roughness, drug distribution uniformity, etc. of the microneedles; In-vivo experiment: Evaluate the safety and therapeutic effect of the microneedles in actual applications; Drug release curve optimization: Adjust the composition of the printing material and the drug loading method to achieve controlled release or rapid release of the drug to meet different treatment needs.

2. The personalized microneedle manufacturing process based on 3D printing technology according to claim 1, characterized in that, The skin scanning device includes an optical imaging system, a laser scanning system, an ultrasonic scanning system, or a combination thereof, and the scanning accuracy is not lower than 0.01 mm, capable of obtaining detailed data on the skin surface and shallow structures.

3. The personalized microneedle manufacturing process based on 3D printing technology according to claim 1, characterized in that, The personalized microneedle array model also includes the following parameters: Hardness gradient design of the microneedles, zoned design of the drug release rate, and degradability design of the microneedles.

4. The personalized microneedle manufacturing process based on 3D printing technology according to claim 1, wherein The biocompatible materials include one or more combinations of, but are not limited to, natural polymers, inorganic materials, and hydrogels.

5. The personalized microneedle manufacturing process based on 3D printing technology according to claim 1, characterized in that, The high-precision 3D printer adopts one or more combinations of the following technologies: Fused deposition modeling technology for thermoplastic biomaterials; Inkjet printing technology for low-viscosity bioinks; Photocuring technology for photosensitive biomaterials; Micro-nano 3D printing technology for manufacturing microneedles with submicron-level precision; And the resolution of the high-precision 3D printer is not lower than 10 μm, capable of achieving high-precision forming of the microneedles.

6. The personalized microneedle manufacturing process based on 3D printing technology according to claim 1, characterized in that, The post-processing steps also include the following: Mechanical strengthening treatment: Form micro-nano structures on the surface of the microneedles through micro-nano imprinting technology; Drug stability treatment: Remove the solvent in the microneedles through freeze-drying or spray-drying technology; Biological activity enhancement: Embed bioactive factors on or inside the surface of the microneedles.

7. The process according to claim 1, characterized in that, The quality inspection and verification also include the following steps: Drug loading efficiency detection, analyzing the actual drug content loaded in the microneedles by high performance liquid chromatography or mass spectrometry to ensure that the drug loading efficiency is not less than 90%; Drug release kinetics analysis, measuring the drug release curve by in vitro release experiments and optimizing the drug release behavior through mathematical models; Skin compatibility test, evaluating the biocompatibility and safety of the microneedles through in vitro cell experiments and in vivo skin irritation tests.

8. A personalized microneedle manufacturing process based on 3D printing technology according to claim 1, characterized in that, The personalized design of the microneedle array also includes the following application scenarios: Transdermal drug delivery, designing the optimal microneedle length and drug loading method for different drugs; Skin beauty, designing the microneedle array according to the degree of skin aging and wrinkle distribution for promoting the absorption of active ingredients; Chronic wound treatment, customizing the microneedle array according to the shape and size of the wound for local delivery of antibiotics, growth factors or stem cells.

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