A hydrogel microneedle for sustained release of MCC950 and its application

Abstract

The present invention relates to a hydrogel microneedle for sustained-release MCC950 and its application. The microneedle comprises a needle tip and a substrate, wherein the needle tip is prepared from a GelMA hydrogel solution doped with MCC950 liposomes and coriander nanogold; the substrate is prepared from an ACG solution loaded with nano black phosphorus. The microneedle of the present invention combines nanoparticles with hydrogel technology, and while utilizing nano-nanoparticles to synergistically improve the performance of the drug MCC950, each nanomaterial also cooperates with each other to achieve better sustained-release, antibacterial and therapeutic effects. The microneedle of the present invention can give full play to the therapeutic effect of MCC950 and can be applied to scar-free wound treatment.

Description

Technical Field

[0001] The invention relates to the technical field of medical nanomaterials, and in particular to a hydrogel microneedle for sustained-release of MCC950 and applications thereof. Background Art

[0002] Pathological scars affect 70% of post-traumatic patients and are characterized by abnormally hard ridges, reduced tensile strength, and pigmentation disorders. Patients often experience symptoms such as itching, chronic pain, loss of limb mobility, anxiety, and depression, which have serious physiological and psychological effects on patients. The main cause of scars is the overexpression and disordered deposition of collagen and extracellular matrix caused by fibroblasts.

[0003] As a potent and specific inhibitor of canonical and atypical activation of the NLRP3 inflammasome, MCC950 can reduce inflammatory cytokine levels and activity and specifically inhibit the MAPK / NF-κB pathway, thereby reducing fibrosis and scar formation.

[0004] However, existing treatment methods all involve direct injection of MCC950 liposomes, which affects the therapeutic effect due to the rapid clearance rate and short half-life of MCC950 in the body.

[0005] As an emerging method of topical drug delivery, hydrogel microneedle patches have been proven to have the ability to penetrate the stratum corneum and directly act on the deep tissue of the lesion. The therapeutic drug can be wrapped in the tip of the microneedle and then penetrated into the skin tissue to enhance the drug absorption ability. However, the existing hydrogel microneedle patches lack certain mechanical strength, biocompatibility and light responsiveness, and side effects such as bleeding and inflammatory reactions may occur during the treatment process.

[0006] Therefore, exploring a multifunctional microneedle system that can not only play a synergistic role with MCC950 liposomes in inhibiting inflammation and scarring, but also has analgesic and antibacterial effects is an important issue that needs to be solved in scar-free wound treatment. Summary of the invention

[0007] In view of the above problems, the present invention provides a hydrogel microneedle for sustained-release of MCC950. Nanoparticles are compounded with hydrogel and loaded with MCC950 drug. The obtained microneedle can greatly prolong the sustained-release of MCC950, and can play a synergistic enhancing role in inhibiting inflammation and scars, and has the multifunctional analgesic and antibacterial effects, and can be used for scar-free treatment of wounds.

[0008] The hydrogel microneedle for sustained-release MCC950 of the present invention comprises a needle tip and a substrate, wherein the needle tip is prepared from a GelMA hydrogel solution doped with MCC950 liposomes and coriander nanogold; and the substrate is prepared from an ACG solution loaded with black phosphorus.

[0009] As one of the most commonly used hydrogel materials, gelatin methacrylate (GelMA) has excellent biocompatibility and cell response characteristics, good thermosensitive gel properties and adjustable mechanical properties, and is an excellent basic material for the design of multifunctional microneedles. As a microneedle, GelMA has the characteristics of high water content, low immunogenicity, and strong mechanical properties, and plays a key role in skin wound healing and tissue repair.

[0010] Coriander nanogold is a biological nanogold that is modified with coriander extract on the surface of nanogold particles. It not only has analgesic and anti-inflammatory effects, but also can slowly release ions in hydrogel to produce a strong bactericidal effect. Moreover, studies have shown that surface-modified nanogold particles can play a very important role in many aspects such as cell imaging and drug carriers. And after combining with biological macromolecules, it shows excellent biocompatibility. The drug-carrying system formed by the participation of biological nanogold has the characteristics of increasing drug solubility and stability.

[0011] MCC950, as an effective and specific inhibitor of typical and atypical activation of NLRP3 inflammasome, can reduce the levels of inflammatory cytokines and activity and specifically inhibit the MAPK / NF-κB pathway, thereby reducing fibrosis and scar formation. When encapsulated in liposomes, it can improve its bioavailability and thus enhance the therapeutic efficacy.

[0012] In the process of wound healing, there is the problem of wound infection, and it is also necessary to remove bacteria that damage the wound. Photothermal therapy is considered a potential option for future wound treatment due to its non-pharmacological toxicity and ability to treat a wide range of conditions. Nano-black phosphorus has the characteristics of broad-spectrum light response, narrow band gap, and excellent biocompatibility and biodegradability. The introduction of nano-black phosphorus not only has good biocompatibility and near-infrared (NIR) responsiveness, giving the microneedle the ability to photothermally control drug release, but also prevents the growth of drug-resistant bacteria, thereby inhibiting wound infection.

[0013] In recent years, nanoparticle and hydrogel technologies have made significant progress. Combining the advantages of these individual technologies into a platform can produce composite materials for drug delivery, immunomodulation, detoxification and tissue engineering - nanoparticle-hydrogel. The microneedle of the present invention uses GelMA as a tip substrate, MCC950 liposomes and bio-nano gold are filled into the tip of the needle, and ACG loaded with black phosphorus is prepared as a substrate. The excellent mechanical strength and biocompatibility of GelMA can realize the controlled release of the drug MCC950 loaded on the tip of the microneedle in the dermis, and the drug MCC950 is encapsulated in liposomes, which can improve its bioavailability; coriander nanogold has anti-inflammatory, analgesic and antioxidant effects; at the same time, the drug-carrying system formed by coriander nanogold has the characteristics of increasing drug solubility, increasing drug stability, etc., and the ACG with strong adhesion doped with nano black phosphorus is used as a substrate, providing good photothermal regulation function and antibacterial and anti-infective effects. Further synergizing with the drug in the needle tip can play a better therapeutic effect. The microneedle of the present invention can give full play to the therapeutic effect of MCC950 and be applied to wound scar-free treatment.

[0014] Preferably, the concentration of GelMA in the GelMA hydrogel solution is 10 w / v%, the concentration of MCC950 liposome is 100 μg / mL, and the concentration of coriander nanogold is 200 μg / mL.

[0015] Preferably, the GelMA is prepared by the following method: slowly adding methacrylic anhydride to a 1 g / mL gelatin solution while stirring to maintain the reaction temperature at 50° C., then dialyzing the reaction solution, centrifuging, collecting the supernatant, and freeze-drying to obtain the final product GelMA.

[0016] Preferably, the MCC950 liposome is prepared by the following method: adding an MCC950 aqueous solution to an organic liposome solution, performing a continuous cycle of ultrasound and ice cooling within 10 minutes; then stirring the mixture at 25-30°C to completely evaporate the organic phase; finally, using an extruder to extrude the liposome to obtain the MCC950 liposome, wherein the organic liposome solution includes L-α-phosphatidylcholine, stearylamine and cholesterol.

[0017] Further preferably, the organic liposome solution is formed by mixing a mixed liposome chloroform solution, a DSPE-PEG chloroform solution, and an ether / chloroform solution; in the mixed liposome chloroform solution, the liposome content is 56.09 mg / mL, and the mixed liposome is formed by mixing L-α-phosphatidylcholine / stearylamine / cholesterol in a molar ratio of 7:3:1; the DSPE-PEG concentration in the DSPE-PEG chloroform solution is 0.1 μg / μL, and the volume ratio of ether to chloroform in the ether / chloroform solution is 1:1; the concentration of the MCC950 aqueous solution is 0.1 mg / mL.

[0018] Preferably, the coriander nanogold is prepared by the following method: adding 1wt% chloroauric acid solution to ultrapure water, then adding 1wt% sodium citrate aqueous solution, and finally adding 1g / mL coriander extract aqueous solution, heating to 50°C with stirring, centrifuging the reaction solution, and freeze-drying to obtain the coriander nanogold.

[0019] Further preferably, the volume ratio of the ultrapure water, the chloroauric acid solution, the sodium citrate aqueous solution, and the coriander extract aqueous solution is 90:2:1:10.

[0020] Preferably, the content of the black phosphorus nanosheets in the ACG solution is 0.1 mg / mL, and the content of ACG in the ACG solution is 10 w / v%.

[0021] Further preferably, the ACG is prepared by the following method: slowly dropping a mixture of acryloyl chloride and tetrahydrofuran into a sodium glycine solution under ice bath conditions, continuing the ice bath for 1 hour after the dropwise addition is completed, then adding water to the resulting solution, then washing with ether three times to remove impurities, adjusting the pH of the aqueous phase to 2, then adding NaCl to saturate, and finally extracting with ethyl acetate for several times, drying and concentrating, dissolving the obtained product in water, filtering and freeze-drying to obtain the final product ACG;

[0022] The sodium glycinate solution is obtained by dissolving sodium glycinate in a 6M NaOH solution and stirring under an ice bath. In the acryloyl chloride-tetrahydrofuran mixed solution, the volume ratio of acryloyl chloride to tetrahydrofuran is 1.1:2.

[0023] In addition, the present invention also provides the use of the above-mentioned hydrogel microneedles for sustained-release MCC950 in scar-free wound treatment agents.

[0024] In comparison, the present invention has the following beneficial effects:

[0025] The microneedle of the present invention adopts methacrylate gelatin with good biocompatibility and mechanical strength as the microneedle needle tip material, which can not only penetrate the stratum corneum to release drugs in the dermis layer, but also avoid the potential damage to the skin caused by the fracture of the needle tip, and can directly act on the deep tissue of the lesion to enhance drug absorption. At the same time, MCC950 liposomes and biological nanogold are filled into the tip of the needle tip, and ACG loaded with black phosphorus is used as a substrate. By using the excellent mechanical strength and biocompatibility of GelMA, the drug MCC950 loaded on the tip of the microneedle can be released in a controlled and localized manner in the dermis, and the drug MCC950 is encapsulated in the liposome, which can improve its bioavailability; coriander nanogold has anti-inflammatory, analgesic and antioxidant effects; at the same time, the drug-carrying system formed by coriander nanogold has the characteristics of increasing drug solubility, increasing drug stability, etc., and ACG with strong adhesion doped with nano black phosphorus is used as a substrate, providing good photothermal regulation function and antibacterial and anti-infective effects. Further synergizing with the drug in the needle tip can achieve better therapeutic effects.

[0026] The microneedle of the present invention combines nanoparticles with hydrogel technology to produce a composite microneedle material. While using nanoparticles to synergistically improve the performance of the drug MCC950, each nanomaterial also cooperates with each other to achieve better sustained release, antibacterial and therapeutic effects. The microneedle of the present invention can give full play to the therapeutic effect of MCC950 and can be used for scar-free wound treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The NMR images of GelMA and ACG before and after modification in the embodiments of the present invention;

[0028] Figure 2 Transmission electron microscopy images of liposomes, MCC950 liposomes, and nanogold of the embodiments of the present invention;

[0029] Figure 3 This is a schematic diagram of black phosphorus photothermal testing;

[0030] Figure 4 It is the gel compression curve of different concentrations of GelMA;

[0031] Figure 5 The toxicity of different concentrations of black phosphorus and gold nanoparticles to mouse fibroblasts;

[0032] Figure 6 The results of the evaluation of the antibacterial activity of the microneedles of the embodiments and comparative examples against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus);

[0033] Figure 7 The graphs are the changes in the mRNA expression levels of the microneedle phenotype-related genes iNOS and TNF-α in the examples and comparative examples;

[0034] Figure 8 The figure is a comparison between the drug transdermal sustained release effect of the microneedle of the embodiment of the present invention and the drug sustained release effect of direct injection. DETAILED DESCRIPTION

[0035] In order to facilitate the understanding of the present invention, the present invention will be described more fully below with reference to the relevant drawings. The preferred embodiments of the present invention are given in the drawings. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0036] In the description of the present invention, unless otherwise clearly defined, terms such as heating, cleaning, weighing, freezing, etc. should be understood in a broad sense, and technicians in the relevant technical field can reasonably determine the specific meanings of the above terms in the present invention in combination with the specific content of the technical solution.

[0037] In the description of the present invention, the description with reference to the terms "some embodiments", "examples", etc. means that the specific methods and materials described in conjunction with the embodiments or examples are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific methods and materials described can be combined in any one or more embodiments or examples in a suitable manner.

[0038] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0039] Unless otherwise specified, the reagents, materials, and equipment used in the examples of the present invention are all commercially available; the test methods, unless otherwise specified, are all conventional test methods in the art.

[0040] The nano black phosphorus used in the embodiments of the present invention is a black phosphorus nanosheet, which is usually prepared by an exfoliation method and can also be obtained commercially.

[0041] Example 1: Preparation of MCC950 liposomes

[0042] 1.274 μL of lipid mixed chloroform solution (56.09 mg / mL liposome kit: L-α-phosphatidylcholine / stearylamine / cholesterol, 7:3:1 molar ratio) and 13.5 μL of DSPE-PEG chloroform solution (0.1 μg / μL) were mixed and stirred in 2.738 mL of ether / chloroform (1:1, v / v) solution to obtain an organic liposome solution.

[0043] A 0.1 mg / mL MCC950 aqueous solution (3 mL) was added to the organic liposome solution, and continuous cycles of ultrasound and ice cooling were performed within 10 minutes. The mixture was then stirred at 25°C for 16 hours to completely evaporate the organic phase. Finally, the liposomes were extruded using a manual micro-extruder equipped with 200 and 100 nm filters to obtain the final desired MCC950 liposomes.

[0044] Example 2: Preparation of methacryloyl gelatin (GelMA)

[0045] Weigh 5.0 g of gelatin, add it to 50 mL of deionized water, and dissolve it in a 50°C water bath under magnetic stirring until it is completely transparent. Slowly add 3 mL of methacrylic anhydride to the gelatin solution, stir it magnetically at 700 rpm for 1 hour, maintain the reaction temperature at 50°C, and then transfer the reaction solution to a cellulose dialysis bag with a molecular weight cutoff of 3500 Da, dialyze it in 40°C constant temperature deionized water for 3 days to remove by-products, collect the dialyzed reaction solution, centrifuge it at 5000 rpm for 10 minutes to remove the precipitate, collect the supernatant, and freeze-dry it at -80°C to obtain the final product GelMA.

[0046] Example 3: Preparation of glycine (ACG)

[0047] 5g of sodium glycinate was dissolved in 6M NaOH solution (25mL) and stirred for 20min under ice bath. 5.5mL of acryloyl chloride was added to 10mL of tetrahydrofuran and slowly added dropwise to the sodium glycinate solution after stirring. The addition time lasted for 2h. After the addition was completed, the ice bath was continued for 1h. 10mL of water was added to the resulting solution, and the impurities were removed by washing with ether three times. The aqueous phase was adjusted to pH 2, and then NaCl was added to saturate, and finally extracted with ethyl acetate for many times. After drying and concentration, the obtained product was dissolved in 10mL of water, filtered and freeze-dried to obtain the final product ACG.

[0048] Example 4: Preparation of coriander nanogold

[0049] 2 mL of 1% chloroauric acid solution was added to 90 mL of ultrapure water, followed by 1 mL of 1% sodium citrate aqueous solution. 1 g of coriander extract was dissolved in 10 mL of deionized water and added to the above solution, heated to 50°C and stirred for 20 minutes, the reaction solution was centrifuged at high speed, the supernatant was removed, and coriander nanogold was obtained after freeze-drying.

[0050] Example 5: MCC950 liposomes / coriander nanogold / black phosphorus / GelMA / ACG hydrogel microneedles

[0051] A hydrogel microneedle for sustained release of MCC950, MCC950 liposome / coriander nanogold / black phosphorus / GelMA / ACG, is prepared by the following method:

[0052] A 10 wt % GelMA solution was prepared by using the GelMA prepared in Example 2, and 0.1 wt % LAP was added;

[0053] The coriander nanogold obtained in Example 4 was stirred in a 10% GelMA solution to make the concentration of coriander nanogold 0.2 mg / mL;

[0054] Then, the MCC950 liposomes prepared in Example 1 were added, and the final concentration of the liposomes was 100 μg / mL;

[0055] The obtained solution was added to a microneedle mold, and the mold was placed in a vacuum chamber and evacuated several times at 25° C. until the bubbles were completely removed; the excess solution in the mold base was removed, and the mold was exposed to ultraviolet light (405 nm) for 60 seconds to prepare the needle tip part by cross-linking;

[0056] Then, a 10 wt % ACG solution mixed with 0.1 mg / mL black phosphorus nanosheets was used as a microneedle substrate material, wherein the ACG was the ACG prepared in Example 3, and the microneedles were obtained by gelling.

[0057] Comparative Example 1: Coriander Nanogold / Black Phosphorus / GelMA / ACG Hydrogel Microneedles

[0058] The difference from Example 5 is that there is only coriander nanogold in the needle tip.

[0059] Comparative Example 2: MCC950 liposome / black phosphorus / GelMA / ACG hydrogel microneedles

[0060] The difference from Example 5 is that there are only MCC950 liposomes in the needle tip.

[0061] Comparative Example 3: MCC950 liposomes / coriander nanogold / GelMA / ACG hydrogel microneedles

[0062] The difference from Example 5 is that the microneedle substrate does not contain black phosphorus.

[0063] Test Example 1: NMR Analysis

[0064] Test samples: GelMA of Example 2 and ACG of Example 3

[0065] Test results: Figure 1 As shown, (A) is the NMR image of GelMA; (B) is the NMR image of ACG.

[0066] Test Example 2: Transmission Electron Microscope Analysis

[0067] Test samples: MCC950 liposomes of Example 1 and coriander nanogold of Example 2.

[0068] Test results: Figure 2 As shown, (A) transmission electron microscopy image of liposomes; (B) transmission electron microscopy image of MCC950 liposomes; (C) transmission electron microscopy image of gold nanoparticles.

[0069] Test Example 3: Photothermal Analysis

[0070] Test sample: Black phosphorus nanosheets

[0071] Test results: Figure 3 As shown, (A) the photothermal curve of black phosphorus under different power conditions; (B) the photothermal curve of black phosphorus under different concentration conditions. It shows that with the increase of concentration and power, the photothermal effect of black phosphorus is significantly improved.

[0072] Test Example 4: Gel Strength

[0073] Test sample: GelMA gel of Example 2 at different concentrations

[0074] Test results: Figure 4 As shown, it can be seen that when the concentration is 10 w / v%, the GelMA gel strength is better, so in Example 5, the GelMA hydrogel concentration is selected to be 10 w / v%.

[0075] Test Example 5: Cytotoxicity

[0076] Test samples: black phosphorus nanosheets and coriander nanogold of Example 2

[0077] Test results: Figure 5 As shown, black phosphorus and gold nanoparticles have basically no toxicity to cells, and the concentration has no significant effect on toxicity.

[0078] Test Example 6: Antibacterial Activity

[0079] Test samples: microneedles of Example 5 and Comparative Examples 1-3

[0080] Test results: Figure 6 As shown, the antibacterial activities of the prepared microneedles against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) were evaluated using agar disk diffusion test and surface contact test.

[0081] Escherichia coli and Staphylococcus aureus were revived overnight in Luria-Bertani (LB) broth at 37°C. All microneedle samples were sterilized by ultraviolet irradiation before testing.

[0082] The results are as follows Figure 4 As shown, it can be seen that the hydrogel microneedles of Example 5 can significantly inhibit the growth of Escherichia coli and Staphylococcus aureus and have good antibacterial properties.

[0083] Test Example 7: Wound Healing Function

[0084] Test samples: microneedles of Example 5 and Comparative Example

[0085] Test results: Figure 7 As shown, after the microneedles of Comparative Examples 1, 2, and 3 covered the wound surface, the mRNA expression levels of phenotype-related genes iNOS and TNF-α did not change significantly, while the relative mRNA expression of iNOS and TNF-α was significantly reduced and the relative mRNA expression of Arg1 was significantly increased after the hydrogel microneedles of Example 5 acted. This indicates that the microneedles prepared in the examples are more capable of inducing macrophages to switch from M1 type to M2 type than those in the comparative examples.

[0086] Test Example 8 Drug Sustained Release Effect

[0087] Test sample: Microneedle of Example 5 and MCC950 direct injection

[0088] Test results: Figure 8 As shown, the drug transdermal sustained release effect of the microneedle in the embodiment of the present invention is compared with the drug sustained release effect of direct injection. It can be seen that the drug-loaded needle tip embedded in the skin in the embodiment of the present invention can achieve a steady drug release lasting up to 18 days, which is much longer than the drug release time of direct injection.

[0089] The above-mentioned embodiment has verified through preliminary experiments that the hydrogel microneedles of the sustained-release MCC950 of the present invention have good biocompatibility and antibacterial activity, and can avoid the problems of fast in vivo clearance and short half-life caused by direct injection of MCC950 liposomes by the characteristics of sustained-release drugs through microneedles, thereby significantly improving the therapeutic effect. Moreover, by adding coriander nanogold and black phosphorus to the microneedle system, the synergistic treatment significantly improves the induction of macrophages from M1 to M2 type, which can reduce problems such as inflammation and wound infection during wound healing, and therefore can be used for scar-free wound treatment.

[0090] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0091] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A hydrogel microneedle for sustained release of MCC950, comprising a needle tip and a substrate, characterized in that: The needle tip is prepared from a GelMA hydrogel solution doped with MCC950 liposomes and coriander nano-gold; the substrate is prepared from an ACG solution loaded with nano-black phosphorus; The coriander nano-gold is prepared by the following method: adding 1 wt% chloroauric acid solution to ultrapure water, then adding 1 wt% sodium citrate aqueous solution, and finally adding 1 g / mL coriander extract aqueous solution, heating to 50° C. with stirring, centrifuging the reaction solution, and freeze-drying to obtain the coriander nano-gold; The ACG is prepared by the following method: slowly dropping a mixture of acryloyl chloride and tetrahydrofuran into a sodium glycine solution under ice bath conditions, continuing the ice bath for 1 h after the dropwise addition is completed, then adding water to the resulting solution, then washing with ether three times to remove impurities, adjusting the pH of the aqueous phase to 2, then adding NaCl to saturate, and finally extracting with ethyl acetate for several times, drying and concentrating, dissolving the obtained product in water, filtering and freeze-drying to obtain the final product ACG; The sodium glycinate solution is obtained by dissolving sodium glycinate in a 6 M NaOH solution and stirring in an ice bath. In the acryloyl chloride-tetrahydrofuran mixed solution, the volume ratio of acryloyl chloride to tetrahydrofuran is 1.1:

2.

2. The hydrogel microneedle according to claim 1, characterized in that: The concentration of GelMA in the GelMA hydrogel solution is 10 w / v %, the concentration of MCC950 liposome is 100 μg / mL, and the concentration of coriander nanogold is 200 μg / mL.

3. The hydrogel microneedle according to claim 1, characterized in that: The GelMA is prepared by the following method: slowly dropwise adding methacrylic anhydride into a 1 g / mL gelatin solution, stirring and maintaining the reaction temperature at 50° C., then dialyzing the reaction solution, centrifuging, collecting the supernatant, and freeze-drying to obtain the final product GelMA.

4. The hydrogel microneedle according to claim 1, characterized in that: The MCC950 liposome is prepared by the following method: adding an MCC950 aqueous solution to an organic liposome solution, performing continuous cycles of ultrasound and ice cooling within 10 minutes; then stirring the mixture at 25-30° C. to completely evaporate the organic phase; finally, using an extruder to extrude the liposome to obtain the MCC950 liposome, wherein the organic liposome solution includes L-α-phosphatidylcholine, stearylamine and cholesterol.

5. The hydrogel microneedle according to claim 4, characterized in that: The organic liposome solution is prepared by mixing a mixed liposome chloroform solution, a DSPE-PEG chloroform solution, and an ether / chloroform solution; The liposome content in the mixed liposome chloroform solution is 56.09 mg / mL, and the mixed liposome is formed by mixing L-α-phosphatidylcholine / stearylamine / cholesterol in a molar ratio of 7:3:1; The DSPE-PEG concentration in the DSPE-PEG chloroform solution is 0.1 μg / μL. The volume ratio of ether to chloroform in the ether / chloroform solution is 1:1; The concentration of the MCC950 aqueous solution is 0.1 mg / mL.

6. The hydrogel microneedle according to claim 1, characterized in that: The volume ratio of the ultrapure water, the chloroauric acid solution, the sodium citrate aqueous solution, and the coriander extract aqueous solution is 90:2:1:

10.

7. The hydrogel microneedle according to claim 1, characterized in that: The content of the nano black phosphorus in the ACG solution is 0.1 mg / mL, and the content of ACG in the ACG solution is 10 w / v %.

8. Use of the hydrogel microneedle according to any one of claims 1 to 7 in preparing a scar-free wound treatment agent.

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