A method and system for preparing a hydrogel microneedle array based on electric field stretching

Abstract

This invention discloses a method and system for preparing hydrogel microneedle arrays based on electric field stretching. The preparation method includes preparing a microneedle substrate, preheating and curing, applying an electric field, electrically controlled stretching, and secondary thermal curing. The system includes an electrode array module, a thermosensitive hydrogel microneedle substrate, a high-precision electrically controlled stretching mechanism module, a thermal curing module, an image feedback system module, a substrate fixing mechanism module, an ultrathin ceramic perforated plate groove, and a central control system. This invention achieves flexible control of microneedle geometric parameters and directional arrangement of electrically responsive particles. Precise and controllable drug release can be achieved through dual control of alternating electric field and temperature, significantly improving the functional integration capability and clinical application value of microneedles.

Description

Technical Field

[0001] This invention relates to a method for preparing hydrogel microneedle arrays, specifically a method and system for preparing hydrogel microneedle arrays based on electric field stretching, belonging to the field of biomedical material manufacturing technology. Background Technology

[0002] In the biomedical field, thermosensitive hydrogel microneedles have become a research hotspot in transdermal drug delivery and biosensing due to their excellent biocompatibility, temperature-responsive swelling properties, and minimally invasive percutaneous delivery advantages. Compared to traditional drug delivery methods, thermosensitive hydrogel microneedles can achieve targeted and long-lasting drug delivery, reducing the toxic side effects of systemic drug administration. Furthermore, their temperature-responsive characteristics can adapt to the human physiological environment, further improving the safety and effectiveness of clinical applications. However, current manufacturing technologies for thermosensitive hydrogel microneedles still face many bottlenecks, making it difficult to meet the needs of high-end biomedical applications.

[0003] Currently, the preparation of hydrogel microneedles mainly relies on two major approaches: traditional mold casting process and mechanical drawing technology. For example, CN117919578A discloses a hydrogel microneedle, its preparation mold, preparation method and application. This approach uses a PDMS mold as a molding template, injects the GelMA hydrogel precursor into the mold cavity, and then performs photocuring and cross-linking to form the microneedle array after demolding. 2) Another example is CN114432275A, which discloses a preparation method and microneedle patch for high-adhesion analgesic hydrogel microneedle patch. It also uses a process route of PDMS mold casting combined with vacuum treatment and oven curing. After 2 hours, the hydrogel microneedle patch is obtained by demolding. The above-mentioned mold casting process has two major defects: First, the geometry of the microneedle is completely determined by the shape of the mold, making it impossible to flexibly adjust key parameters such as cone angle and aspect ratio, and making it difficult to adapt to the puncture needs of different skin tissues; Second, during the demolding process, the microneedle tip is prone to breakage and the needle body is prone to sticking to the mold, resulting in a low product qualification rate. In addition, the mold has high processing costs and limited service life, which is not conducive to large-scale industrial production.

[0004] Besides casting, some studies have used 3D printing or mechanical drawing techniques to prepare thermosensitive hydrogel microneedles, but both have significant shortcomings. 3D printing technology is limited by printing resolution, making it difficult to prepare high-precision microneedles with a tip diameter of less than 30 μm. Furthermore, problems such as loose interlayer bonding and uneven internal pore distribution easily occur during printing, resulting in insufficient mechanical properties of the microneedles and making percutaneous puncture impossible. Traditional mechanical drawing techniques lack effective active control methods, relying solely on material surface tension for drawing. This not only fails to precisely control the structural parameters of the microneedles, but also lacks effective constraints on the formation of droplet arrays, leading to poor microneedle size uniformity and chaotic array arrangement. Simultaneously, it is difficult to achieve the directional arrangement of functional components such as electroresponsive components, limiting the functional integration capabilities of the microneedles.

[0005] In addition, existing technologies lack precise molding schemes suitable for thermosensitive hydrogels, and most preparation methods follow the process ideas of photocuring systems, which can easily introduce biosafety risks such as photosensitizer residues. At the same time, problems such as poor connection stability between microneedles and substrates and low pass rate of mass production further restrict the industrial application of thermosensitive hydrogel microneedles. Summary of the Invention

[0006] The purpose of this invention is to provide a method and system for preparing hydrogel microneedle arrays based on electric field stretching, which can achieve regular construction of droplet arrays, precise electrical control of microneedle structures, adaptability to thermosensitive hydrogel systems, and excellent mass production performance, in order to solve at least one of the above-mentioned technical problems.

[0007] This invention achieves the above objective through the following technical solution: a method for preparing hydrogel microneedle arrays based on electric field stretching, the method comprising the following steps: Step 1: Prepare the microneedle substrate. Assemble an ultrathin ceramic well plate groove on the thermosensitive hydrogel-based microneedle substrate, so that the thermosensitive hydrogel precursor containing electroresponsive particles, thermosensitive polymer and crosslinking agent can pass through the ultrathin ceramic well plate to form a regular droplet array on the surface of the thermosensitive hydrogel-based microneedle substrate. Step 2: Preheating and curing treatment. The droplet array of the thermosensitive hydrogel precursor is preheated and cured to form a deformable semi-solid gel structure. Step 3: Apply an electric field, applying an axial gradient electric field to the semi-solid gel structure; Step 4: Electro-controlled stretching. The semi-solid gel structure is simultaneously subjected to electro-controlled stretching. During the stretching process, the electric field gradient is dynamically adjusted to match the stretching process, thereby achieving precise control of the needle tip morphology. Step 5: Secondary thermal curing treatment. The stretched gel structure is subjected to secondary thermal curing treatment to complete the preparation of the thermosensitive hydrogel microneedle array.

[0008] As a further aspect of the present invention: In step one, the pore diameter of the ultrathin ceramic perforated plate groove is 50-200μm, the pore spacing is 300-800μm, and the thickness is 50-100μm, which has the characteristics of high temperature resistance, corrosion resistance and excellent pore diameter uniformity.

[0009] As a further aspect of the present invention: In step one, the electroresponsive particles are conductive nanoparticles with a surface modified by a hydrophilic polymer, which have good water dispersion stability and conductivity. The electroresponsive particles include, but are not limited to, one or more of carboxylated modified carbon nanotubes, carboxylated modified graphene, and conductive ceramic nanoparticles.

[0010] As a further aspect of the present invention: In step one, the thermosensitive polymer is a biocompatible thermosensitive hydrogel material, selected from one or more of N-isopropylacrylamide (NIPAM) copolymers, polyethylene glycol-polypropylene glycol-polyethylene glycol block copolymers (Pluronic), and chitosan-sodium glycerophosphate complexes.

[0011] As a further aspect of the present invention: in step one, a dispersant and a crosslinking agent are added to the thermosensitive hydrogel precursor. The dispersant is used to improve the dispersion uniformity of the electroresponsive particles in the precursor, and the crosslinking agent is used to regulate the thermosetting rate and gel strength.

[0012] As a further aspect of the present invention: in step two, the preheating curing temperature is 30-45℃ and the curing time is 10-30s; the secondary heat curing temperature is 50-65℃ and the curing time is 30-60s, thereby improving the gel crosslinking density and mechanical properties through gradient temperature curing.

[0013] As a further aspect of the present invention: in step three, the axial gradient electric field is generated by an array of multiple sets of parallel electrodes, and the spacing between the electrodes can be adjusted by electronic control to achieve flexible control of the electric field gradient.

[0014] As a further aspect of the present invention: in step four, the stretching process adopts a PID closed-loop control strategy, which combines image feedback to collect stretching shape signals in real time and adjust accordingly, so as to ensure stretching accuracy and shape consistency.

[0015] As a further aspect of the present invention: in step five, the microneedles of the thermosensitive hydrogel microneedle array have a sharp needle tip structure and a stable cone shape, and have excellent drug loading and encapsulation efficiency. They can achieve controlled drug release under the action of an alternating electric field, and also have temperature-responsive swelling characteristics.

[0016] A hydrogel microneedle array fabrication system based on electric field stretching includes an electrode array module, a thermosensitive hydrogel microneedle substrate, a high-precision electrically controlled stretching mechanism module, a thermosetting module, an image feedback system module, a substrate fixing mechanism module, an ultrathin ceramic perforated plate groove, and a central control system. The electrode array module is arranged in two layers, with the thermosensitive hydrogel microneedle substrate and the ultrathin ceramic perforated plate groove positioned between the two electrode array modules. The ultrathin ceramic perforated plate groove is located above the thermosensitive hydrogel microneedle substrate. The thermosensitive hydrogel microneedle substrate is fixedly mounted on the substrate fixing mechanism module. The high-precision electrically controlled stretching mechanism module is also connected to the upper surface of the thermosensitive hydrogel microneedle substrate. The thermosetting module and the image feedback system module are both fixedly connected to the substrate fixing mechanism module, and both the thermosetting module and the image feedback system module are located on one side of the thermosensitive hydrogel microneedle substrate. Both the thermosetting module and the image feedback system module are signal-connected to the central control system.

[0017] The beneficial effects of this invention are: 1) This invention achieves the regular construction of thermosensitive hydrogel precursor droplet array by adding ultra-thin ceramic perforated plate grooves. Combined with the synergistic linkage of electric field regulation and pulling and thermal curing processes, it realizes the flexible control of microneedle geometric parameters, precise control of internal pore structure and functional component arrangement, and improves the connection stability between microneedles and substrate, as well as the stability and pass rate of mass production, avoiding the biosafety risks of photosensitive systems. 2) This invention, through the synergistic linkage of axial gradient electric field and electrically controlled stretching, can precisely program and control the cone angle, aspect ratio and internal pore structure of microneedles, effectively solving the problem of uncontrollable microneedle structure in the prior art; at the same time, the combination of substrate bearing molding and staged thermosetting process enables the microneedles to form a strong cross-linking connection with the substrate, effectively solving the problems of easy microneedle detachment and unstable molding in traditional preparation methods. 3) This invention innovatively adds an ultra-thin ceramic perforated plate groove, which uses its uniform pore size and spacing to constrain the flow of the precursor. Without the need for complex jet parameter control, it can form a neatly arranged and uniformly sized droplet array on the substrate surface. Moreover, the ceramic perforated plate groove is resistant to high temperature and corrosion and can be reused. This not only reduces the cost of production consumables, but also simplifies the droplet array construction process. Combined with multi-array synchronous stretching and thermosetting operations, it further improves the efficiency of batch preparation. 4) This invention employs a thermosensitive hydrogel system, which avoids the biosafety risks associated with photosensitizer residues in photocuring systems. Furthermore, the temperature response characteristics of the thermosensitive hydrogel can be adapted to the human physiological environment, improving the safety of clinical applications. Simultaneously, the electric field guides the electroresponsive particles to be oriented axially within the microneedle, endowing the microneedle with electro-driven response performance. Combined with the temperature response characteristics, precise and controllable drug release can be achieved through dual regulation of alternating electric field and temperature, significantly enhancing the functional integration capability and clinical application value of the microneedle. 5) The directionally arranged electroresponsive particles of this invention can effectively enhance the mechanical strength of the microneedles, enabling them to successfully puncture skin tissues of different hardness with minimal skin damage after puncture. This combination of minimal invasiveness and practicality further broadens its application scenarios in the biomedical field. Attached Figure Description

[0018] Figure 1 This is a schematic diagram of the preparation method of the present invention; Figure 2 This is a schematic diagram of the system structure for preparing the present invention; In the diagram: 1. Electrode array module; 2. Thermosensitive hydrogel microneedle substrate; 3. High-precision electronically controlled stretching mechanism module; 4. Thermosetting module; 5. Image feedback system module; 6. Substrate fixing mechanism module; 7. Ultra-thin ceramic perforated plate groove; 8. Central control system. Detailed Implementation

[0019] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0020] Example 1, as Figure 1 As shown, a method for fabricating hydrogel microneedle arrays based on electric field stretching is disclosed, which includes the following steps: First, a microneedle substrate is prepared, and an ultrathin ceramic well plate groove is assembled on the thermosensitive hydrogel microneedle substrate. The thermosensitive hydrogel precursor containing electrically responsive particles, thermosensitive polymer and crosslinking agent passes through the ultrathin ceramic well plate groove to form a regular droplet array on the surface of the thermosensitive hydrogel microneedle substrate.

[0021] Among them, the pore diameter of the ultrathin ceramic perforated plate groove is 50-200μm, the pore spacing is 300-800μm, and the thickness is 50-100μm. It has the characteristics of high temperature resistance, corrosion resistance and excellent pore size uniformity.

[0022] The electroresponsive particles are conductive nanoparticles with hydrophilic polymers on their surface, exhibiting good water dispersion stability and conductivity. The electroresponsive particles include, but are not limited to, one or more of carboxylated modified carbon nanotubes, carboxylated modified graphene, and conductive ceramic nanoparticles.

[0023] The thermosensitive polymer is a biocompatible thermosensitive hydrogel material selected from one or more of N-isopropylacrylamide (NIPAM) copolymers, polyethylene glycol-polypropylene glycol-polyethylene glycol block copolymers (Pluronic), and chitosan-sodium glycerophosphate complexes.

[0024] The thermosensitive hydrogel precursor also contains a dispersant and a crosslinking agent. The dispersant is used to improve the dispersion uniformity of the electroresponsive particles in the precursor, and the crosslinking agent is used to regulate the thermosetting rate and gel strength.

[0025] Second, a preheating and curing process is performed on the thermosensitive hydrogel precursor droplet array to form a deformable semi-solid gel structure.

[0026] The preheating and curing temperature is 30-45℃, and the curing time is 10-30s.

[0027] Third, apply an electric field, specifically an axial gradient electric field, to the semi-solid gel structure.

[0028] The axial gradient electric field is generated by an array of multiple parallel electrodes. The spacing between the electrodes can be adjusted electronically to achieve flexible control of the electric field gradient.

[0029] Fourth, electro-controlled stretching: the semi-solid gel structure is simultaneously subjected to electro-controlled stretching, and the electric field gradient is dynamically adjusted during the process to match the stretching process, so as to achieve precise control of the needle tip morphology.

[0030] The stretching process employs a PID closed-loop control strategy, combined with real-time acquisition of stretching shape signals via image feedback and subsequent adjustment to ensure stretching accuracy and shape consistency.

[0031] Fifth, a secondary thermal curing treatment is performed on the stretched gel structure to complete the preparation of the thermosensitive hydrogel microneedle array.

[0032] The secondary thermosetting temperature is 50-65℃, and the curing time is 30-60s. Gradient temperature increase during curing improves the gel crosslinking density and mechanical properties.

[0033] The microneedles used to prepare the thermosensitive hydrogel microneedle array have a sharp needle tip structure and a stable cone shape, and have excellent drug loading and encapsulation efficiency. They can achieve controlled drug release under the action of an alternating electric field, and also have temperature-responsive swelling characteristics.

[0034] Example 2, as Figure 2 As shown, this embodiment provides a hydrogel microneedle array fabrication system based on electric field stretching. This hydrogel microneedle array fabrication system is used to implement the hydrogel microneedle array fabrication method in Embodiment 1. Specifically, it includes an electrode array module 1, a thermosensitive hydrogel microneedle substrate 2, a high-precision electrically controlled stretching mechanism module 3, a thermosetting module 4, an image feedback system module 5, a substrate fixing mechanism module 6, an ultrathin ceramic perforated plate groove 7, and a central control system 8. The electrode array module 1 is arranged in two layers, and the thermosensitive hydrogel microneedle substrate 2 and the ultrathin ceramic perforated plate groove 7 are arranged in two layers. Between the electrode array modules 1, the ultrathin ceramic perforated plate groove 7 is located above the thermosensitive hydrogel microneedle substrate 2. The thermosensitive hydrogel microneedle substrate 2 is fixedly mounted on the substrate fixing mechanism module 6. The upper surface of the thermosensitive hydrogel microneedle substrate 2 is also connected to the high-precision electronically controlled stretching mechanism module 3. The thermosetting module 4 and the image feedback system module 5 are both fixedly connected to the substrate fixing mechanism module 6, and the thermosetting module 4 and the image feedback system module 5 are both located on one side of the thermosensitive hydrogel microneedle substrate 2. The thermosetting module 4 and the image feedback system module 5 are both connected to the central control system 8.

[0035] Specific operation: First, the thermosensitive hydrogel microneedle substrate 2 is fixed on the substrate fixing mechanism 6, and an ultra-thin ceramic perforated plate groove 7 is assembled on top of it, so that the thermosensitive hydrogel precursor containing electrically responsive particles passes through the perforated plate groove and forms a regular droplet array on the substrate surface; then, the thermosetting module 4 is activated to preheat and solidify the droplet array, turning it into a semi-solid gel structure and removing the perforated plate groove; next, the central control system 8 drives the electrode array 1 to generate an axial gradient electric field in the semi-solid gel structure region, and at the same time, the high-precision electrically controlled stretching mechanism 3 is activated to perform synchronous electrically controlled stretching operation on the gel structure. During the stretching process, the image feedback system 5 collects the needle tip morphology signal in real time and feeds it back to the central control system. Combined with the PID closed-loop control strategy, the electric field gradient is dynamically adjusted to match the stretching process, realizing precise control of the microneedle cone angle and aspect ratio; after stretching is completed, the electric field state is maintained and the thermosetting module 4 is activated again for secondary thermosetting treatment, finally obtaining a hydrogel microneedle array that is stably connected to the substrate.

[0036] Example 3: A method for preparing a hydrogel microneedle array based on electric field stretching, comprising the following steps: 1. Prepare NIPAM-AM copolymer powder (for preparing the substrate and precursor), carboxyl-modified carbon nanotubes (electrically responsive particles, diameter 20-50 nm, length 500-800 nm, surface modified with polyacrylic acid), crosslinking agent N,N'-methylenebisacrylamide (MBA), crosslinking promoter ammonium persulfate (APS), dispersant hydroxypropyl cellulose (HPC), phosphate buffer (PBS, pH=7.4); ultrathin ceramic well plate groove (pore diameter 100 μm, pore spacing 500 μm, thickness 80 μm, surface treated with hydrophilicity); 2. Add NIPAM-AM copolymer powder to PBS, stir and dissolve at room temperature to prepare a 15% (w / w) base solution, add 0.1% MBA and 0.05% APS, stir evenly and then degas under vacuum; pour the base solution into a petri dish, place it in a constant temperature environment of 40℃ for pre-curing for 20s, and then heat to 60℃ for a second curing for 40s; after curing, cut the base into 20mm×20mm square sheets, wash with deionized water 3 times, and then place them in a vacuum drying oven to dry for later use; 3. Add NIPAM-AM copolymer powder to PBS and stir at room temperature to dissolve, preparing a 20% precursor matrix solution. Add 4% carboxylated carbon nanotubes, 0.2% MBA, 0.1% APS, and 0.3% HPC dispersant to the precursor matrix solution. Place the mixed solution in an ultrasonic cleaner and ultrasonically disperse for 30 min to ensure uniform dispersion of carbon nanotubes. Finally, place the uniformly dispersed mixed solution in a vacuum drying oven and degas at a vacuum of -0.09 MPa for 20 min to remove residual bubbles in the solution, obtaining a uniform and stable thermosensitive hydrogel precursor. 4. Fix the prepared thermosensitive hydrogel microneedle substrate 2 onto the vacuum adsorption platform of the substrate fixing mechanism module 6. Assemble the ultrathin ceramic well plate 7 through the well plate adjustment assembly, adjust the distance between the ultrathin ceramic well plate 7 and the substrate to 80μm, and calibrate the position of the ultrathin ceramic well plate 7 so that the pore size corresponds precisely to the substrate area. Inject the thermosensitive hydrogel precursor into the ultrathin ceramic well plate 7, apply a low pressure of 0.08MPa to allow the precursor to pass through the ultrathin ceramic well plate 7, forming a 6×6 precursor droplet array on the surface of the thermosensitive hydrogel microneedle substrate 2. The volume of a single droplet is 50nL. Let it stand for 8s to allow the droplets to fully wet the substrate. 5. Start the high-precision electronically controlled stretching mechanism module 3 and debug each module; arrange the electrode array module 1 along the direction perpendicular to the thermosensitive hydrogel microneedle substrate 2, and adjust the axial spacing of adjacent electrodes to 20mm; set the pre-curing temperature of the thermosetting module 4 to 40℃ and the curing time to 15s; set the secondary curing temperature to 60℃ and the curing time to 40s; set the stretching speed of the high-precision electronically controlled stretching mechanism module 3 to 5mm / s, calibrate the displacement accuracy to ≤0.1μm, and set the sampling frequency to 100Hz; adjust the microscope magnification of the image feedback system module 5 to 500x to ensure clear acquisition of needle tip morphology images; 6. Start the thermosetting module 4 and preheat and cure the precursor droplet array on the substrate according to the preset parameters. After curing, the droplets are transformed into a semi-solid gel structure with certain mechanical strength and deformability. This structure is tightly connected to the substrate and is not easy to fall off. 7. Start the electrode array module 1 and adjust the input voltage of each group of electrodes through the central control system 8 to build an axial gradient electric field with an electric field strength of 1-5kV / m and a gradient of 50-300kV / m² in the region where the semi-solid gel structure is located. The direction of the electric field is perpendicular to the substrate surface. 8. Activate the high-precision electronically controlled stretching mechanism module 3 to precisely align the array-type stretching fixture with the top of the semi-solid gel structure, and then simultaneously stretch the gel structure at a speed of 5 mm / s. During the stretching process, the image feedback system module 5 acquires real-time images of the needle tip morphology, extracts the needle tip diameter parameters through an image recognition algorithm, and feeds them back to the central control system 8. The central control system 8 dynamically adjusts the voltage of the electrodes based on the real-time data of the needle tip diameter to maintain the electric field gradient within a preset range, ensuring that the needle tip diameter changes according to the preset target (28 μm) and the total stretching length is 30 mm. 9. After stretching, keep the electric field state of electrode array module 1 unchanged, start the thermosetting module 4 to heat up to 60°C, and perform a second thermosetting treatment on the stretched gel structure to make the gel structure completely cross-linked and solidified, while strengthening the connection strength between the microneedles and the substrate; after curing, turn off the electric field and the thermosetting module to obtain a thermosensitive hydrogel microneedle array that is firmly connected to the substrate. 10. Performance testing was conducted on the prepared thermosensitive hydrogel microneedle array. The results showed that the microneedle tip diameter was 28±1.5μm, the cone angle was 29°±1°, and the porosity was 65±3%. The shear strength between the microneedles and the substrate was 1.2MPa, which was much higher than that of microneedles prepared by traditional methods (shear strength <0.5MPa), indicating excellent connection stability. The drug encapsulation rate was 92%, and the cumulative drug release rate was 85% after 12 hours under an alternating electric field of 1-5kV / m and a body temperature of 37℃. The microneedle array was neatly arranged, with excellent uniformity in needle height, a height deviation of <3%, and a pass rate of 98%. The swelling rate increased to 300% at 42℃, demonstrating good temperature response characteristics.

[0037] Example 4: A method for preparing a hydrogel microneedle array based on electric field stretching, comprising the following steps: 1. Prepare Pluronic F127 powder (for preparing the substrate and precursor), carboxylated graphene (electrically responsive particles, thickness 1-5 nm, sheet diameter 200-500 nm, surface modified with polyacrylic acid), crosslinking agent genipin, crosslinking promoter citric acid, dispersant HPC, PBS buffer (pH=7.4); ultrathin ceramic well plate groove (pore diameter 80 μm, pore spacing 400 μm, thickness 60 μm, surface treated with hydrophilicity); 2. Add Pluronic F127 powder to PBS, refrigerate at 4°C and stir to dissolve, prepare a 25% (w / w) base solution, add 0.5% genipin and 0.3% citric acid, stir evenly and then degas under vacuum; pour the base solution into a petri dish, place it in a constant temperature environment of 37°C for pre-curing for 12s, then raise the temperature to 65°C for a second curing for 45s; after curing, cut into 20mm×20mm square sheets, clean and dry for later use; 3. Add Pluronic F127 powder to PBS, refrigerate at 4°C and stir to dissolve, preparing a 30% precursor matrix solution; add 6% carboxylated graphene, 0.8% genipin, 0.5% citric acid and 0.5% dispersant HPC to the precursor matrix solution; after ultrasonic dispersion for 40 min, degas under a vacuum of -0.09 MPa for 30 min to remove bubbles, obtaining a uniform and stable thermosensitive hydrogel precursor; 4. Fix the thermosensitive hydrogel microneedle substrate 2 onto the vacuum adsorption platform of the substrate fixing mechanism module 6, assemble the ultrathin ceramic well plate groove 7, and adjust the distance between the ultrathin ceramic well plate groove 7 and the substrate to 60μm; inject the precursor into the ultrathin ceramic well plate groove 7, apply a low pressure of 0.06MPa to allow the precursor to pass through the ultrathin ceramic well plate groove 7, and form an 8×8 precursor droplet array on the surface of the thermosensitive hydrogel microneedle substrate 2, with a single droplet volume of 30nL, and let it stand for 6s to allow the droplets to fully wet the substrate; 5. Start the system and adjust the parameters. Adjust the adjacent spacing of electrode array module 1 to 15mm; set the pre-curing temperature to 37℃ and the curing time to 12s; set the secondary curing temperature to 65℃ and the curing time to 45s; set the tensile speed to 8mm / s, the displacement accuracy to ≤0.1μm, and the sampling frequency to 150Hz; adjust the microscope magnification of image feedback system module 5 to 800x. 6. Activate the thermosetting module 4 to preheat and cure the droplet array to form a semi-solid gel structure; remove the ultra-thin ceramic perforated plate groove 7; 7. Activate electrode array module 1 and adjust the voltage to form an axial gradient electric field with an electric field strength of 3-8 kV / m and a gradient of 400-600 kV / m² in the semi-solid gel structure region; 8. Start the high-precision electronically controlled stretching mechanism module 3 to synchronously stretch the gel structure at a speed of 8 mm / s. During the stretching process, the electric field gradient is dynamically adjusted through the image feedback system module 5 and the central control system 8 to maintain the gradient stable within the preset range. The total stretching length is 25 mm. 8. After stretching, maintain the electric field state for secondary thermal curing. After curing, turn off the electric field and thermal curing module to obtain a sharp needle-shaped thermosensitive hydrogel microneedle array; 10. The performance of the prepared microneedle array was tested. The results showed that the microneedle tip diameter was 19±0.8μm, the cone angle was 18°±1°, and the porosity was 55±2%. The shear strength between the microneedle and the substrate was 1.5MPa, indicating a stable connection. The drug encapsulation rate was 93%, and the cumulative drug release rate was 92% after 12 hours under an alternating electric field of 3-8kV / m and an environment of 37℃. The mechanical strength of the microneedles was 25% higher than that of Example 1, enabling them to successfully puncture porcine skin tissue with minimal skin damage after puncture, demonstrating good biocompatibility. The swelling rate reached 280% at 40℃, indicating excellent temperature response sensitivity.

[0038] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, all variations falling within the meaning and scope of equivalents of the claims are intended to be included within the present invention. No reference numerals in the claims should be construed as limiting the scope of the claims.

[0039] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A method for preparing an array of hydrogel microneedles based on electric field stretching, characterized in that, The method for preparing the hydrogel microneedle array includes the following steps: Step 1: Prepare the microneedle substrate. Assemble a ceramic perforated plate groove on the top of the thermosensitive hydrogel microneedle substrate, so that the thermosensitive hydrogel precursor containing electrically responsive particles, thermosensitive polymer and crosslinking agent can pass through the ceramic perforated plate groove to form a regular droplet array on the surface of the thermosensitive hydrogel microneedle substrate. Step 2: Preheating and curing treatment. The droplet array of the thermosensitive hydrogel precursor is preheated and cured to form a deformable semi-solid gel structure. Step 3: Apply an electric field, applying an axial gradient electric field to the semi-solid gel structure; Step 4: Electro-controlled stretching. The semi-solid gel structure is simultaneously subjected to electro-controlled stretching. During the stretching process, the electric field gradient is dynamically adjusted to match the stretching process, thereby controlling the needle tip morphology. Step 5: Secondary thermal curing treatment. The stretched gel structure is subjected to secondary thermal curing treatment to complete the preparation of the thermosensitive hydrogel microneedle array.

2. The method of claim 1, wherein: In step one, the diameter of the ceramic perforated plate groove is 50-200μm, the spacing between the holes is 300-800μm, and the thickness is 50-100μm.

3. The method of claim 1, wherein: In step one, the electrically responsive particles are conductive nanoparticles with a surface modified by a hydrophilic polymer, possessing water dispersion stability and conductivity. The electrically responsive particles include, but are not limited to, one or more of carboxylated modified carbon nanotubes, carboxylated modified graphene, and conductive ceramic nanoparticles.

4. The method of claim 1, wherein: In step one, the thermosensitive polymer is a biocompatible thermosensitive hydrogel material, selected from one or more of N-isopropylacrylamide copolymers, polyethylene glycol-polypropylene glycol-polyethylene glycol block copolymers, and chitosan-sodium glycerophosphate complexes.

5. The method of claim 1, wherein the hydrogel microneedle array is prepared by a method comprising: In step one, a dispersant and a crosslinking agent are also added to the thermosensitive hydrogel precursor. The dispersant is used to improve the dispersion uniformity of the electroresponsive particles in the precursor, and the crosslinking agent is used to regulate the thermosetting rate and gel strength.

6. The method of claim 1, wherein the method further comprises: In step two, the preheating curing temperature is 30-45℃ and the curing time is 10-30s; in step five, the secondary heat curing temperature is 50-65℃ and the curing time is 30-60s; gradient temperature curing improves the gel crosslinking density and mechanical properties.

7. The method of claim 1, wherein: In step three, the axial gradient electric field is generated by an array of multiple sets of parallel electrodes. The spacing between the electrodes is adjusted by electronic control to achieve flexible control of the electric field gradient.

8. The method of claim 1, wherein: In step four, the stretching process adopts a PID closed-loop control strategy, which combines image feedback to collect stretching shape signals in real time and adjust accordingly, ensuring stretching accuracy and shape consistency.

9. The method of claim 1, wherein: In step five, the microneedles used to prepare the thermosensitive hydrogel microneedle array have a sharp needle tip structure and a stable cone shape, and have excellent drug loading and encapsulation efficiency. They can achieve controlled drug release under the action of an alternating electric field, and also have temperature-responsive swelling characteristics.

10. A hydrogel microneedle array preparation system based on electric field stretching, which is used to realize the hydrogel microneedle array preparation method of any one of claims 1-9; characterized in that: The hydrogel microneedle array fabrication system includes an electrode array module (1), a thermosensitive hydrogel microneedle substrate (2), a high-precision electrically controlled stretching mechanism module (3), a thermosetting module (4), an image feedback system module (5), a substrate fixing mechanism module (6), an ultra-thin ceramic perforated plate groove (7), and a central control system (8). The electrode array module (1) is arranged in two layers, and the thermosensitive hydrogel microneedle substrate (2) and the ultrathin ceramic well plate groove (7) are arranged between the two electrode array modules (1). The ultrathin ceramic well plate groove (7) is located above the thermosensitive hydrogel microneedle substrate (2). The thermosensitive hydrogel microneedle substrate (2) is fixedly placed on the substrate fixing mechanism module (6), and a high-precision electronically controlled stretching mechanism module (3) is also connected to the upper surface of the thermosensitive hydrogel microneedle substrate (2). The thermosetting module (4) and the image feedback system module (5) are both fixedly connected to the substrate fixing mechanism module (6), and the thermosetting module (4) and the image feedback system module (5) are both located on one side of the thermosensitive hydrogel microneedle substrate (2). The thermosetting module (4) and the image feedback system module (5) are both signal connected to the central control system (8).

Images