Space-time sequence regulated dual stimulation responsive microneedle and preparation method thereof

Abstract

The invention relates to a spatio-temporal sequence regulated dual stimulation responsive microneedle and a preparation method thereof, and the preparation method comprises the following steps: dispersing piezoelectric nanoparticles in a buffer solution, then adding dopamine hydrochloride, and carrying out a reaction to prepare polydopamine coated piezoelectric nanoparticles; the preparation method comprises the following steps: preparing a dispersion liquid from polydopamine-coated piezoelectric nanoparticles, adding the dispersion liquid into a temperature-sensitive hydrogel prepolymer liquid containing a hydrogel monomer and a drug, and uniformly mixing to obtain a mixed liquid; filling a microneedle mold with the mixed solution, standing for forming, and drying to obtain the dual stimulation responsive microneedle. According to the hydrogel microneedle, a temperature-sensitive material is adopted as a base material of the hydrogel microneedle, and polydopamine coated piezoelectric nanoparticles with photo-thermal and piezoelectric response are doped in the hydrogel microneedle, so that the release rate of a drug loaded in the hydrogel microneedle can be accelerated, and controllable release of the drug can be realized; and the piezoelectric nanoparticles can respond to mechanical stimulation and convert the mechanical stimulation into electric signals so as to synergistically promote tissue repair.

Description

Technical Field

[0001] The present invention relates to the field of biomedical polymer materials, and in particular to a dual-stimulus responsive microneedle regulated in time and space order and a preparation method thereof. Background Art

[0002] Microneedles consist of micron-sized needles (usually less than 1 mm) arranged in an array, which can penetrate the stratum corneum barrier of the skin and form micron-sized pore channels, in which the loaded drugs can penetrate into the surrounding skin tissue through the micropores. Microneedles combine the advantages of traditional intradermal injections and the convenience of transdermal administration, providing a convenient, minimally invasive, and painless transdermal administration method. At the same time, because the microneedle material is mainly hydrogel, and the controlled release duration of hydrogel is relatively long, the loaded active ingredients may be denatured and fail to achieve the therapeutic effect.

[0003] Stimuli-responsive / smart drug delivery systems (DDS) are becoming increasingly popular research topics due to their relatively stable and controlled drug release, lower potential for drug burst release, and improved drug treatment processes. For the human body, temperature is one of the most commonly used stimulus response factors because it can easily change due to inflammation caused by lesions such as wound infection, tumors, or specific external thermal stimuli. On the basis of temperature-responsive release, drug delivery via external photothermal stimulation is necessary and feasible. However, conventional temperature stimulation is usually uncontrollable, and excessively high temperatures can easily cause tissue burns.

[0004] Currently, most wound healing treatments are passive healing processes, and rarely involve stimulating skin cells to control endogenous cell behavior for active wound healing. The skin is one of the most electrically sensitive tissues. Studies have shown that the bioelectricity generated by ion flow can activate cell signaling pathways, regulate the phenotype of macrophages from the M1 subtype (pro-inflammatory) to the M2 subtype (anti-inflammatory), reduce the expression level of inflammatory factors, and enhance the proliferation and migration ability of fibroblasts. At the same time, it promotes epithelial cell regeneration and collagen deposition in wound tissues, induces angiogenesis and nerve function recovery, and ultimately achieves tissue regeneration. Current electrical stimulation therapies usually require an external power supply and have a high risk of infection. Summary of the invention

[0005] The purpose of the present invention is to overcome the above technical deficiencies, provide a dual stimulus responsive microneedle with spatiotemporal sequential regulation and a preparation method thereof, and solve the technical problems of low drug delivery efficiency and single action of microneedles in the prior art.

[0006] In order to achieve the above technical purpose, the technical solution provided by the present invention is: In a first aspect, the present invention provides a method for preparing a dual-stimulus responsive microneedle with spatiotemporal sequential regulation, comprising the following steps: S1, dispersing piezoelectric nanoparticles in a buffer solution, and then adding dopamine hydrochloride to react to obtain polydopamine-coated piezoelectric nanoparticles; S2, preparing the polydopamine-coated piezoelectric nanoparticles into a dispersion, and then adding the dispersion to a thermosensitive hydrogel prepolymer solution containing a hydrogel monomer and a drug, and mixing evenly to obtain a mixed solution; S3, filling the mixed solution into a microneedle mold, allowing it to stand for molding, and drying to obtain a dual-stimulus responsive microneedle.

[0007] In a second aspect, the present invention provides a dual stimulus responsive microneedle prepared by the above preparation method.

[0008] Compared with the prior art, the beneficial effects of the present invention include: The present invention adopts a thermosensitive material as the substrate of the hydrogel microneedle, wherein polydopamine-coated piezoelectric nanoparticles having both photothermal and piezoelectric responses are doped, so as to prepare a dual stimulus responsive microneedle which can be sequentially regulated in time and space. Compared with the traditional microneedle, under the action of external light such as near-infrared irradiation, the present invention uses polydopamine for photothermal conversion to induce thermal contraction of the thermosensitive hydrogel, which can not only accelerate the release rate of the loaded drug therein, but also realize the controllable release of the drug. Moreover, the piezoelectric nanoparticles therein can also respond to mechanical stimulation and convert it into electrical signals to synergistically promote tissue repair, thereby realizing the sequential regulation of tissue defect repair in time and space. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 is a SEM image of BTO nanoparticles of the present invention; Figure 2 is a SEM image of the BTOP nanoparticles of the present invention; Figure 3 is the infrared spectrum of BTO and BTOP nanoparticles of the present invention; Figure 4 is the XRD spectrum of BTO and BTOP nanoparticles of the present invention; Figure 5 This is a physical picture of the dual stimulus responsive microneedle of Example 1 of the present invention; Figure 6 is a micrograph of the dual stimulus responsive microneedle of Example 1 of the present invention; Figure 7 This is a drug release curve diagram of the dual stimulus responsive microneedle under near infrared stimulation in Example 1 of the present invention; Figure 8 This is a conductivity verification diagram of the dual stimulus responsive microneedle of Example 1 of the present invention; Fig. 9 The photothermal properties of hydrogels with different BTOP nanoparticle contents in Example 2 of the present invention. DETAILED DESCRIPTION

[0010] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0011] Currently, hydrogel microneedles deliver hydrogel-loaded drugs or biomolecules deep into the skin or other tissues through physical penetration. Drugs can only be released by diffusion through the swelling of the hydrogel, which has technical problems such as low drug delivery efficiency and single action.

[0012] Specifically, since the microneedle matrix is ​​a hydrogel, its controlled release duration is relatively long, and the loaded active ingredients may denature and fail to achieve the therapeutic effect. Therefore, it is necessary and feasible to deliver drugs through external photothermal stimulation based on temperature-responsive release, but conventional temperature stimulation is usually uncontrollable, and excessive temperature can easily cause tissue burns. The present invention introduces a thermosensitive material into the microneedle system, which can deform under the stimulation of relatively high temperature, and its "sponge effect" can accelerate the release of loaded drugs.

[0013] Considering the non-invasiveness, penetration into soft tissue and high spatial resolution, nanoparticles doped with photothermal materials can be used and near-infrared light can be used as an external stimulus source to induce photothermal therapy. At the same time, the photothermal effect can cause the thermosensitive material to deform, so that the drug loaded therein can be released in a controlled manner. Therefore, for uncontrollable temperature stimulation, in order to avoid tissue burns caused by excessive temperature, the present invention uses low-energy, safe and controllable light-responsive stimulation to achieve controlled drug release. Nanoparticles with good photothermal conversion performance are integrated into thermosensitive materials, and the release of drugs is regulated by the near-infrared effect.

[0014] In addition, most current wound healing treatments are passive healing processes, and electrical stimulation therapy usually requires an external power source and has a higher risk of infection. Piezoelectric materials can directly convert mechanical energy into electrical energy, but pure piezoelectric materials need to be stimulated by ultrasound or pressure to generate electrical signals.

[0015] The present invention introduces piezoelectric materials with electrical responses into the system, which can be used to simulate and amplify endogenous "bioelectricity". When the thermosensitive hydrogel is deformed, it can quickly respond to mechanical stress, generate instant electrical signals, and then synergistically promote tissue repair, playing a role in promoting healing during the wound repair process.

[0016] Therefore, in order to address the defect of low efficiency of the single microneedle drug delivery system, the present invention combines thermosensitive materials with piezoelectric materials, and introduces piezoelectric nanoparticles that can generate electrical stimulation on the basis of simple thermosensitive hydrogel to promote drug release; the introduction of dopamine coating not only increases the biocompatibility of nanoparticles, but also enables them to have heat exchange conversion capabilities, and triggers the deformation of thermosensitive materials through photothermal treatment, thereby generating electrical signals while allowing the drug to be released in a controllable manner, achieving dual response and realizing a tissue regeneration strategy with spatiotemporal sequential regulation.

[0017] Explanation of terms MNs: microneedles; N-isopropylacrylamide (NIPAM) is a temperature-sensitive polymer widely used in biomedicine and bioengineering. The solubility of NIPAM polymers in water changes significantly with temperature. At lower temperatures, NIPAM polymers are hydrophilic, but when the temperature rises above their critical solution temperature (LCST, about 32°C), they become hydrophobic and phase separate, causing deformation. This temperature responsiveness makes it very useful in areas such as drug delivery, cell culture, and bioseparation. NIPAM polymers generally have good biocompatibility, which means they do not cause significant immune responses or toxicity and are suitable for in vivo applications. In addition, NIPAM can be combined with other biodegradable polymers through chemical modification, so that it gradually decomposes in the body, reducing potential risks of long-term existence.

[0018] Barium titanate (BaTiO3, BTO for short) is a piezoelectric material with a very high dielectric constant that can generate electric charge under mechanical stress, which makes them very useful in electrophysiological and electroactive biological applications. BTO NPs are generally considered to be biocompatible and can come into contact with biological tissues without causing significant toxicity or inflammatory responses. The piezoelectric properties of barium titanate nanoparticles can be used to control drug release under the action of an external electric field, achieving site-specific and timed drug release. Barium titanate nanoparticles can be integrated into tissue engineering scaffolds to provide mechanical stimulation to promote cell growth and tissue regeneration.

[0019] Dopamine is a biogenic amine that is widely used in biomaterial surface modification due to its unique adhesion and biocompatibility. Since it is derived from organisms, dopamine has good biocompatibility and is suitable for in vivo applications such as drug delivery and bioimaging. The coating process of dopamine is usually simple, and the coating can be quickly formed under mild conditions through the self-polymerization of dopamine. Dopamine has a high photothermal conversion efficiency and can be combined with photothermal conversion materials to improve the photothermal conversion efficiency for photothermal therapy.

[0020] Spatiotemporal sequential regulation: It is a chain reaction brought about by near-infrared light. The light generates heat, causing the NIPAM to deform, which further causes the piezoelectric nanoparticles (such as barium titanate) loaded in it to generate electrical signals under mechanical force.

[0021] In a first aspect, the present invention provides a method for preparing a dual stimulus responsive microneedle regulated in time and space order, comprising the following steps: S1, dispersing piezoelectric nanoparticles in a buffer solution, and then adding dopamine hydrochloride to react to obtain polydopamine-coated piezoelectric nanoparticles; S2, preparing a dispersion of polydopamine-coated piezoelectric nanoparticles, adding the dispersion to a thermosensitive hydrogel prepolymer solution containing a hydrogel monomer and a drug, and mixing the mixture to obtain a mixed solution; S3, filling the mixed solution into a microneedle mold, allowing it to stand for molding, and drying to obtain dual stimulus responsive microneedles.

[0022] Preferably, in step S1, the piezoelectric nanoparticles are tetragonal barium titanate. The present invention uses tetragonal nanoparticles, which have better piezoelectric effect.

[0023] Further preferably, in step S1, the preparation step of tetragonal barium titanate comprises: mixing a barium source, a titanium source and a solvent, subjecting the mixture to a hydrothermal reaction, and then washing and drying the mixture.

[0024] More preferably, the molar ratio of the barium source to the titanium source is (1-5):1; the barium source includes barium hydroxide, and the titanium source includes titanium dioxide.

[0025] More preferably, the solvent is a mixture of ethanol and deionized water in a volume ratio of (50-90): (10-40); the ratio between the barium source and the solvent is (1-5) mmol: 100 mL. The present invention uses a mixture of ethanol and deionized water as a solvent to control the size, morphology, purity, crystallinity, etc. of the nanoparticles.

[0026] More preferably, the hydrothermal reaction is carried out at 180-250° C. for 18-36 hours.

[0027] Preferably, in step S1, the buffer solution is a tris hydrochloric acid solution with a pH value of 8 to 9.

[0028] Preferably, in step S1, the mass ratio of the piezoelectric nanoparticles to dopamine hydrochloride is (1-5):1.

[0029] Preferably, in step S1, the reaction is carried out at 20-40° C. with stirring for 12-36 hours.

[0030] Preferably, in step S2, the dispersion is prepared by mixing polydopamine-coated piezoelectric nanoparticles with deionized water, and the concentration is 1 to 3 mg / mL.

[0031] Preferably, in step S2, the drug is an anti-inflammatory drug; the thermosensitive hydrogel prepolymer solution is prepared by dissolving a hydrogel monomer, an anti-inflammatory drug, a cross-linking agent, an initiator, and an accelerator in deionized water in sequence.

[0032] Further preferably, in the thermosensitive hydrogel prepolymer solution, the concentration of the hydrogel monomer is 0.01-0.2 g / mL, the concentration of the anti-inflammatory drug is 2-15 mg / mL, the concentration of the cross-linking agent is 0.1-5 mg / mL, the concentration of the initiator is 5-15 mg / mL, and the amount of the accelerator added is 0.1-2 μL / mL.

[0033] Further preferably, the hydrogel monomer comprises one or more of poloxamer 407, hydroxybutyl chitosan and N-isopropylacrylamide.

[0034] Further preferably, the anti-inflammatory drug comprises one or more of glucosamine hydrochloride, curcumin and quercetin.

[0035] Further preferably, the cross-linking agent includes one or more of N,N'-methylenebisacrylamide (MBA), I2959 and LAP.

[0036] More preferably, the initiator includes one or more of ammonium persulfate, sodium persulfate and potassium persulfate.

[0037] Further preferably, the accelerator comprises tetramethylethylenediamine.

[0038] Preferably, in step S2, the mass ratio of polydopamine-coated piezoelectric nanoparticles to hydrogel monomers is (0.5-5) mg: (0.2-2) g.

[0039] Preferably, in step S3, the mixed solution is filled into the microneedle mold by standing, centrifuging or vacuuming.

[0040] Preferably, in step S3, the molding includes photocuring, chemical crosslinking or physical crosslinking; wherein different crosslinking agents can be selected according to actual needs, corresponding to different molding methods.

[0041] Preferably, in step S3, drying includes air drying at room temperature or heating drying.

[0042] In a second aspect, the present invention provides a dual stimulus responsive microneedle prepared by the above preparation method.

[0043] The present invention not only can directly deliver drugs to the desired parts by doping photothermal piezoelectric nanoparticles into the hydrogel microneedle substrate, but also the thermosensitive hydrogel (such as NIPAM) will deform when the temperature is higher than LCST, and the encapsulated drugs will be released, and at the same time, pressure will be generated on the internal piezoelectric particles. Therefore, the present invention can also generate heat by polydopamine in response to near-infrared irradiation, so that the thermosensitive hydrogel will deform and achieve controllable release of drugs. At the same time, the mechanical deformation caused by the contraction of the hydrogel is converted into an electrical signal. Therefore, under the dual response of photothermal and electrical signals, the present invention not only achieves the controllable release of drugs, but also can regulate the repair of tissue defects in a temporal and spatial order.

[0044] The present invention is further described in detail below through specific examples. To avoid redundancy, the preparation method of the BTO nanoparticles used is described here.

[0045] The preparation steps of BTO nanoparticles include: mixing 80 mL of ethanol with 20 mL of deionized water, dissolving 788.65 mg (2.5 mmol) of Ba(OH)2·8H2O, adding 99.84 mg (1.25 mmol) of TiO2 and stirring evenly, transferring the mixed solution to a hydrothermal reactor, and reacting at 210°C for 24 hours. After cooling to room temperature, the BTO nanoparticles (BTO NPs) were collected by centrifugation, washed with deionized water, and dried for later use.

[0046] Figure 1 This is the SEM image of the prepared BTO nanoparticles, showing an obvious tetragonal structure.

[0047] Example 1 A method for preparing a dual stimulus responsive microneedle regulated in time and space sequence, comprising the following steps: (1) Take 20 mg of barium titanate nanoparticles (BTO NPs) and disperse them in 10 mL of tris hydrochloride buffer solution (pH=8.5), then add 5 mg of dopamine hydrochloride (DA), stir vigorously at room temperature for 24 hours after ultrasonic treatment, and collect the nanoparticles (BTOP NPs) by centrifugation. After washing with ethanol, disperse them in deionized water and ultrasonically disperse them evenly to obtain a BTOP dispersion; Figure 2 The SEM image of the prepared polydopamine-coated barium titanate (BTOP) nanoparticles is compared with Figure 1 , with an obvious coating on its surface, indicating the successful preparation of polydopamine.

[0048] Figure 3 and Figure 4 The infrared spectra and XRD spectra of BTO (BaTiO3) and BTOP (BaTiO3@PDA) nanoparticles are shown in Figure 1. Figure 3It can be seen that the 560 cm-1 emission band is observed in the spectra of BTO and BTOP due to the Ti-O vibration of BTO. -1 In the BTOP spectrum, PDA was detected at 1588 cm -1 and 1460cm -1 The characteristic absorption band corresponding to the stretching vibration in the benzene aromatic ring indicates the successful polymerization of PDA. Figure 4 It can be seen that the loading of dopamine does not affect the crystal form of barium titanate, that is, the coating does not affect its piezoelectricity. The above test results all indicate the successful preparation of BTO nanoparticles and the successful coating of PDA nanoparticles.

[0049] (2) Take 1 mL of BTOP dispersion (2 mg / mL) and add it to 8 mL of thermosensitive hydrogel prepolymer containing 1 g of NIPAM monomer and 100 mg of glucosamine hydrochloride, and stir evenly to obtain a mixed solution; the hydrogel also contains 2 mg of MBA cross-linker, 0.1 g of ammonium persulfate initiator, and 5 μL of tetramethylethylenediamine (TEMED) accelerator.

[0050] (3) The mixed solution was filled into a microneedle mold by centrifugation at 5000 rpm for 10 min, dried at room temperature for 12 h, and demolded to obtain microneedles, which were recorded as PNIPAM / BTOP.

[0051] The actual image and micrograph of the microneedle sample are shown in Figure 5 and Figure 6 As shown, it can be clearly seen from the figure that the needle tips are complete, arranged regularly, and have a certain length to facilitate transdermal drug delivery.

[0052] Drug release test: Under different conditions (with or without near-infrared light irradiation), a UV-vis spectrometer with a wavelength of 274 nm was used to observe the in vitro release of PNIPAM / BTOP hydrogel loaded with glucosamine hydrochloride (for ease of testing, there is no need to make microneedles, and the mixed solution obtained in step (2) can be left to stand to form a gel and then freeze-dried). Take 0.5 g of hydrogel sample and put it into 100 mL of PBS solution (pH = 7.4) and place it in a shaker at 100 rpm. At the specified time interval, 2 ml of solution was extracted from the release culture medium, and an equal volume of freshly prepared PBS (pH = 7.4) was added to replenish the culture medium; at the same time, a hydrogel control group was set up. The hydrogel control group did not contain BTOP, and the other conditions were the same as PNIPAM / BTOP, recorded as PNIPAM. The drug release results are shown in the figure. Figure 7 shown.

[0053] Depend on Figure 7 It can be seen that the drug release efficiency of PNIPAM / BTOP of the present invention is significantly improved.

[0054] Conductivity test: The prepared PNIPAM / BTOP hydrogel was connected to a light-emitting LED lamp and powered by a 3V power supply. Figure 8 It can be seen from the results that the LED lamp has bright light, indicating that the PNIPAM / BTOP hydrogel of the present invention has excellent conductive properties and can provide electrical signals during the repair process.

[0055] Example 2 The only difference from Example 1 is that the concentrations of the BTOP dispersion were adjusted to 0, 1 mg / mL, 3 mg / mL, and 5 mg / mL, respectively. The other steps and conditions were the same as those in Example 1.

[0056] The photothermal properties of the above hydrogels were tested using near-infrared lasers, and the temperature was detected in real time using an infrared camera. The results are as follows: Fig. 9 shown.

[0057] Depend on Fig. 9 Photothermal results show that as the concentration of BTOP increases, its relative dosage increases, and the temperature of the hydrogel rises higher. However, when the concentration of BTOP is too low, the thermosensitive hydrogel cannot produce shrinkage deformation, and the purpose of releasing drugs and generating electrical stimulation cannot be achieved; when the concentration is too high, the corresponding hydrogel temperature will rise, causing secondary damage to the skin tissue. Therefore, the present invention preferably has a mass ratio of polydopamine-coated barium titanate nanoparticles to hydrogel monomers of (2-5) mg:1g, further preferably (2-3) mg:1g, and more preferably 2 mg:1g.

[0058] Comparative Example 1 The only difference from Example 1 is that barium titanate nanoparticles and dopamine hydrochloride are directly mixed with the hydrogel prepolymer solution, and the other steps and conditions are the same as those of Example 1; the difference is that: 2 mg of barium titanate nanoparticles and 0.4 mg of dopamine hydrochloride were directly mixed with 8 mL of a thermosensitive hydrogel prepolymer solution containing 1 g of NIPAM monomer and 100 mg of glucosamine hydrochloride. The hydrogel prepolymer solution also contained 2 mg of MBA crosslinker, 0.1 g of ammonium persulfate initiator, and 5 μL of tetramethylethylenediamine (TEMED) accelerator. Microneedles were obtained under the same conditions as step (3) of Example 1.

[0059] The results showed that the obtained nanoparticles did not have the photothermal and conductive properties conferred by dopamine. Not only could they not achieve the purpose of photothermal-induced thermal contraction of the thermosensitive hydrogel and thus trigger drug release, they also could not achieve the synergistic promotion effect of electrical stimulation.

[0060] The specific implementation of the present invention described above does not constitute a limitation on the protection scope of the present invention. Any other corresponding changes and modifications made based on the technical concept of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A method for preparing a dual stimulus responsive microneedle regulated by temporal and spatial sequence, characterized in that: The following steps are involved: S1, dispersing piezoelectric nanoparticles in a buffer solution, and then adding dopamine hydrochloride to react to obtain polydopamine-coated piezoelectric nanoparticles; S2, preparing the polydopamine-coated piezoelectric nanoparticles into a dispersion, adding the dispersion into a thermosensitive hydrogel prepolymer solution containing a hydrogel monomer and a drug, and mixing them evenly to obtain a mixed solution; S3, filling the mixed solution into a microneedle mold, allowing it to stand for molding, and drying to obtain dual stimulus responsive microneedles.

2. The method for preparing the dual stimulus responsive microneedle with spatiotemporal sequential regulation according to claim 1, characterized in that: In step S1, the piezoelectric nanoparticles are tetragonal barium titanate.

3. The method for preparing the dual stimulus responsive microneedle with spatiotemporal sequential regulation according to claim 2, characterized in that: The preparation steps of the tetragonal barium titanate include: mixing a barium source, a titanium source and a solvent, performing a hydrothermal reaction, washing and drying to obtain the tetragonal barium titanate; The molar ratio of the barium source to the titanium source is (1-5):1; The hydrothermal reaction is carried out at 180-250° C. for 18-36 hours.

4. The method for preparing the dual stimulus responsive microneedle with spatiotemporal sequential regulation according to claim 1, characterized in that: In step S1, the buffer solution is a tris hydrochloric acid solution with a pH value of 8 to 9; The mass ratio of the piezoelectric nanoparticles to the dopamine hydrochloride is (1-5):1; The reaction conditions for preparing the polydopamine-coated piezoelectric nanoparticles are: stirring the reaction at 20-40° C. for 12-36 hours.

5. The method for preparing the dual stimulus responsive microneedle with spatiotemporal sequential regulation according to claim 1, characterized in that: In step S2, the dispersion is prepared by mixing polydopamine-coated piezoelectric nanoparticles with deionized water, and the concentration is 1-3 mg / mL.

6. The method for preparing the dual stimulus responsive microneedle with spatiotemporal sequential regulation according to claim 1, characterized in that: In step S2, the drug is an anti-inflammatory drug; The thermosensitive hydrogel prepolymer solution is prepared by dissolving hydrogel monomer, anti-inflammatory drug, cross-linking agent, initiator and accelerator in deionized water in sequence.

7. The method for preparing the dual stimulus responsive microneedle with spatiotemporal sequential regulation according to claim 6, characterized in that: In the thermosensitive hydrogel prepolymer solution, the concentration of the hydrogel monomer is 0.01-0.2 g / mL, the concentration of the anti-inflammatory drug is 2-15 mg / mL, the concentration of the crosslinking agent is 0.1-5 mg / mL, the concentration of the initiator is 5-15 mg / mL, and the addition amount of the accelerator is 0.1-2 μL / mL.

8. The method for preparing the dual stimulus responsive microneedle with spatiotemporal sequential regulation according to claim 6, characterized in that: The hydrogel monomers include one or more of poloxamer 407, hydroxybutyl chitosan and N-isopropyl acrylamide; The anti-inflammatory drug includes one or more of glucosamine hydrochloride, curcumin and quercetin; The cross-linking agent includes one or more of N,N'-methylenebisacrylamide, I2959 and LAP; The initiator includes one or more of ammonium persulfate, sodium persulfate and potassium persulfate; The accelerator includes tetramethylethylenediamine.

9. The method for preparing the dual stimulus responsive microneedle with spatiotemporal sequential regulation according to claim 1, characterized in that: In step S2, the mass ratio of the polydopamine-coated piezoelectric nanoparticles to the hydrogel monomer is (0.5-5) mg: (0.2-2) g.

10. A dual stimulus responsive microneedle prepared by the preparation method according to any one of claims 1 to 9.

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