Preparation method and application of soluble bifunctional conductive microneedle patch

Abstract

This invention relates to the field of biomaterials technology, specifically to a method for preparing and applying a soluble bifunctional conductive microneedle patch. The preparation method includes the following steps: (1) adding low molecular weight hyaluronic acid and catalase to deionized water to obtain an HA-CAT solution; (2) adding N,N-dimethylformamide and methacrylic anhydride to the low molecular weight hyaluronic acid solution to obtain methacryloyl hyaluronic acid (HAMA); (3) dissolving a photoinitiator and methacryloyl hyaluronic acid in deionized water, adding black phosphorus nanosheets (BP) to obtain an HAMA-BP solution, filling the needle tip with the HAMA-BP solution, and filling the base with the HA-CAT solution. This conductive microneedle patch possesses excellent mechanical properties and biocompatibility. The black phosphorus nanosheets respond to changes in pH and continuously release reactive oxygen species in hypoxic environments.

Description

Technical Field

[0001] This invention relates to the field of biomaterials technology, specifically to a method for preparing and applying a soluble bifunctional conductive microneedle patch. Background Technology

[0002] Acute myocardial infarction (AMI), also known as myocardial infarction, is a life-threatening disease caused by acute blockage of the coronary arteries, leading to insufficient blood supply to the corresponding myocardial area and resulting in myocardial necrosis. Acute myocardial infarction is a leading cause of death worldwide. After a myocardial infarction, a large number of myocardial cells at the site of coronary artery occlusion are lost due to acute ischemia-reperfusion injury, ultimately leading to heart failure.

[0003] Currently, treatment options for heart failure after myocardial infarction are limited, with heart transplantation being the only effective treatment for end-stage patients. However, heart transplantation still faces numerous challenges, including donor shortages, high surgical risks and technical requirements, and post-transplant immune rejection, limiting its widespread clinical application. Microneedle patches are medical devices that deliver drugs by penetrating the stratum corneum through micron-sized needles. Their core technologies include the preparation of high-drug-load materials and physical permeation enhancement techniques. As an effective transdermal drug delivery device, microneedle patches can painlessly create micron-sized drug delivery channels, enhancing the effects of active substances or drugs on the heart. Soluble microneedle patches are an innovative transdermal drug delivery technology that uses a micron-sized needle array to penetrate the stratum corneum and painlessly deliver drugs or active ingredients. Soluble microneedle patches are made from soluble, biodegradable polymer materials. After the polymer materials dissolve or degrade, the loaded active substances are released to clear excess reactive oxygen species generated after myocardial infarction. The highly biocompatible conductivity of black phosphorus nanosheets can enhance myocardial electrical signal conduction and promote the recovery of electrophysiological function in the infarct area. Combined with modified methacrylamide hyaluronic acid, it provides mechanical support to the myocardium. Therefore, there is a need for a bilayer biodegradable conductive microneedle patch with sustained-release properties. Summary of the Invention

[0004] This invention provides a method for preparing and applying a bilayer biodegradable conductive microneedle patch with sustained-release function to reverse ventricular remodeling after myocardial infarction.

[0005] To achieve the above objectives, this application provides the following technical solution:

[0006] A method for preparing a soluble bifunctional conductive microneedle patch includes the following steps:

[0007] (1) Add low molecular weight hyaluronic acid M and catalase to deionized water, mix well and let stand to remove bubbles to obtain HA-CAT solution for later use.

[0008] (2) Add N,N-dimethylformamide and methacrylic anhydride to a low molecular weight hyaluronic acid solution, then adjust the pH value, add salt, and finally filter, dialyze, and freeze dry to obtain methacrylated hyaluronic acid; graft the methacryl group (containing carbon-carbon double bond C=C) on the methacrylic anhydride onto the backbone of the hyaluronic acid molecule.

[0009] (3) Dissolve the photoinitiator and the methacrylamide hyaluronic acid in deionized water, then add black phosphorus nanosheets to prepare HAMA-BP solution. Then, fill the tip of the mold with HAMA-BP solution, and fill the bottom of the mold with the above HA-CAT solution. Vacuum dry and demold to obtain the final product.

[0010] Preferably, in step (1), the molecular weight of the low molecular weight hyaluronic acid M is 100,000 to 200,000; the mass ratio of the low molecular weight hyaluronic acid M to catalase is 10 to 20:1.

[0011] Preferably, in the HA-CAT solution, the mass concentration of low molecular weight hyaluronic acid M is 75–100 mg / mL, and the mass concentration of catalase is 5–10 mg / mL. More preferably, the mass concentration of low molecular weight hyaluronic acid M is 75 mg / mL, and the mass concentration of catalase is 5 mg / mL.

[0012] Preferably, in step (2), low molecular weight hyaluronic acid N is dissolved in deionized water to prepare a low molecular weight hyaluronic acid solution. N,N-dimethylformamide is slowly added dropwise and stirred until homogeneous. Then, methacrylic anhydride is added, followed by the addition of NaOH to adjust the pH to 8-9. Then, NaCl is added and stirred until completely dissolved. Finally, anhydrous ethanol is added, filtered at least once, and then washed with anhydrous ethanol. After dialyzing the washed solution, it is placed in a freeze dryer and freeze-dried for 48-72 hours to obtain methacrylamide hyaluronic acid.

[0013] More preferably, the molecular weight of the low molecular weight hyaluronic acid N is 20 kDa to 40 kDa, and the mass concentration of the low molecular weight hyaluronic acid N in the low molecular weight hyaluronic acid solution is 15 to 25 mg / mL.

[0014] More preferably, the mass ratio of the low molecular weight hyaluronic acid N to methacrylic anhydride is 1.2 to 1.4:1, and the volume ratio of N,N-dimethylformamide to deionized water is 55 to 70%; the molecular weight of the methacrylated hyaluronic acid retained after filtration is ≥8000 Da.

[0015] Preferably, in step (3), the above-mentioned methacrylamide hyaluronic acid is dissolved in deionized water containing a photoinitiator, and black phosphorus nanosheets are added and vortexed to completely dissolve it to obtain HAMA-BP solution. Then, the HAMA-BP solution is filled into the tip of the PDMS mold, and the excess part is scraped off. Then, the above-mentioned HA-CAT solution is filled into the bottom of the PDMS mold base, and the excess part is scraped off. Vacuuming is performed at least once, each time for 5 to 30 minutes. After drying at room temperature, the mold is demolded by ultraviolet irradiation.

[0016] Preferably, in step (3), the photoinitiator is lithium phenyl-2,4,6-trimethylbenzoylphosphonate, the mass concentration of the photoinitiator in the HAMA-BP solution is 0.1-1.0 mg / mL, the mass concentration of the methacryloyl hyaluronic acid is 50-100 mg / mL, and the mass concentration of the black phosphorus nanosheets is 0.1-5 mg / mL.

[0017] A soluble bifunctional conductive microneedle patch is prepared using the above-mentioned method for preparing soluble bifunctional conductive microneedle patches.

[0018] Application of a soluble bifunctional conductive microneedle patch in the preparation of a medicament for the prevention and / or treatment of myocardial infarction.

[0019] Beneficial effects:

[0020] The conductive microneedle patch provided by this invention includes a base and a tip. The base is made of HA-CAT, a self-crosslinked mixture of highly biocompatible low-molecular-weight hyaluronic acid (HA) and catalase (CAT). Utilizing the natural biodegradability of low-molecular-weight hyaluronic acid, HA-CAT as the base can rapidly degrade, preventing tissue adhesion caused by the base. It also releases catalase to decompose excess ROS generated by ischemia and hypoxia after myocardial infarction into H2O and O2. The tip is made of HAMA (methacryloyl hyaluronic acid), a modified low-molecular-weight hyaluronic acid, mixed with black phosphorus nanosheets (BP), and supplemented with a photoinitiator. Photocuring and crosslinking delay its degradation.

[0021] This invention leverages the unique advantages of microneedle technology for targeted drug delivery. It utilizes biodegradable natural hyaluronic acid as a substrate, which rapidly degrades to release CAT, breaking down excess reactive oxygen species to generate oxygen, thus alleviating the hypoxic environment caused by microenvironmental disturbances following myocardial infarction. Methacrylamide hyaluronic acid forms the microneedle array; the modified hyaluronic acid undergoes chemical cross-linking, resulting in a more stable internal structure and delayed degradation. Black phosphorus, due to its conductivity, meets the electrophysiological needs of the heart while enhancing mechanical strength, providing some mechanical support to the weakened ventricular walls.

[0022] The conductive microneedle patch provided by this invention possesses excellent mechanical properties and biocompatibility. It scavenges ROS to generate oxygen, meeting the electrophysiological needs of the heart. The slowly degrading microneedle array allows the black phosphorus nanosheets to continuously release oxygen in response to changes in pH and hypoxic environments, thus exerting its function of scavenging reactive oxygen species. Fixing the microneedle patch in the myocardial infarction area not only satisfies the electrophysiological function of the myocardium and helps to target drug release and enhance drug efficacy, but also provides excellent mechanical support for the weakened myocardial tissue. Attached Figure Description

[0023] The accompanying drawings, which form part of this application, are used to provide a further understanding of this application. The illustrative embodiments and descriptions of this application are used to explain this application and do not constitute an undue limitation of this application. Wherein:

[0024] Figure 1 Fourier transform infrared spectra of methacryloyl hyaluronic acid (HAMA) and low molecular weight hyaluronic acid (molecular weight of 20Kda~40Kda, HA);

[0025] Figure 2 The images are scanning electron microscope (SEM) images of black phosphorus nanosheets, where the right image is a magnified view of the left image.

[0026] Figure 3 A quantitative graph of hydrogen peroxide scavenging rate;

[0027] Figure 4 Here is a scanning electron microscope image of the microneedle patch prepared in Example 1;

[0028] Figure 5 The mechanical property curve of the microneedle patch prepared in Example 1 is shown.

[0029] Figure 6 CCK8 statistical graph showing the biocompatibility of the microneedle patch prepared in Example 1;

[0030] Figure 7 The image shows the α-actinin immunofluorescence of the microneedle patch prepared in Example 1.

[0031] Figure 8 The image shows the FLUO-4 immunofluorescence pattern of the microneedle patch prepared in Example 1.

[0032] Figure 9 This is a quantitative statistical graph of FLUO-4 immunofluorescence intensity of the microneedle patch prepared in Example 1;

[0033] Figure 10 This is a degradation diagram of the microneedle patch prepared in Example 1. Detailed Implementation

[0034] The present application will now be described in detail with reference to the accompanying drawings and embodiments. Various examples are provided by way of explanation and not by way of limitation. In fact, those skilled in the art will understand that modifications and variations can be made to the present application without departing from the scope or spirit of the present application. For example, a feature shown or described as part of one embodiment may be used in another embodiment to produce yet another embodiment. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention should fall within the scope of protection of the embodiments of the present invention.

[0035] A method for preparing a soluble bifunctional conductive microneedle patch includes the following steps:

[0036] (1) Add low molecular weight hyaluronic acid M and catalase to deionized water, mix evenly, and let stand to remove air bubbles to prepare HA-CAT solution for later use; wherein, the molecular weight of low molecular weight hyaluronic acid M is 100,000 to 200,000; the mass ratio of low molecular weight hyaluronic acid M to catalase is 10 to 20:1; in HA-CAT solution, the mass concentration of low molecular weight hyaluronic acid M is 75 to 100 mg / mL, and the mass concentration of catalase is 5 to 10 mg / mL.

[0037] (2) Dissolve low molecular weight hyaluronic acid N in deionized water to prepare a low molecular weight hyaluronic acid solution. Slowly add N,N-dimethylformamide, stir until homogeneous, then add methacrylic anhydride. Next, add NaOH to adjust the pH to 8-9, then add NaCl and stir until completely dissolved. Finally, add anhydrous ethanol, filter at least once, and wash with anhydrous ethanol. Dialyze the washed solution and place it in a freeze dryer. Freeze-dry for 48-72 hours to obtain methacrylamide hyaluronic acid. The molecular weight of low molecular weight hyaluronic acid N is 20 kDa-40 kDa, and the mass concentration of low molecular weight hyaluronic acid N in the low molecular weight hyaluronic acid solution is 15-25 mg / mL. The mass ratio of low molecular weight hyaluronic acid N to methacrylic anhydride is 1.2-1.4:1, the volume ratio of N,N-dimethylformamide solution is 55-70%, and the molecular weight of the methacrylamide hyaluronic acid retained after filtration is ≥8000 Da.

[0038] (3) Dissolve the above-mentioned methacrylamide hyaluronic acid in deionized water containing a photoinitiator, add black phosphorus nanosheets and vortex to completely dissolve them to obtain a HAMA-BP solution. Then, fill the tip of the PDMS mold with the HAMA-BP solution, scrape off the excess, and then fill the bottom of the PDMS mold with the above-mentioned HA-CAT solution, scrape off the excess, vacuum at least once, each time for 5 to 30 minutes, dry at room temperature, and demold by ultraviolet irradiation. The photoinitiator is lithium phenyl-2,4,6-trimethylbenzoylphosphonate. In the HAMA-BP solution, the mass concentration of the photoinitiator is 0.1 to 1.0 mg / mL, the mass concentration of the methacrylamide hyaluronic acid is 50 to 100 mg / mL, and the mass concentration of the black phosphorus nanosheets is 0.1 to 5 mg / mL.

[0039] Example 1

[0040] A method for preparing a soluble bifunctional conductive microneedle patch includes the following steps:

[0041] (1) Take 75 mg of low molecular weight hyaluronic acid M (molecular weight of 100,000 to 200,000) and add it to 1 mL of deionized water containing 5 mg of catalase. Vortex for 5 min to mix thoroughly, let stand for 10 min to remove bubbles and prepare HA-CAT solution for later use.

[0042] (2) Dissolve 4g of low molecular weight hyaluronic acid N (molecular weight of 20Kda~40Kda) in 200mL of deionized water, slowly add 133.3mL of N,N-dimethylformamide, stir magnetically until uniform, add 4.8mL of methacrylic anhydride solution, then adjust the pH value to 8 with 1mol NaOH, monitor the pH value change in real time, stir magnetically at 300rpm for 24h, add 9.8g of NaCl, continue stirring until completely dissolved, add 500mL of anhydrous ethanol, filter twice, wash with anhydrous ethanol, add the washed solution to a dialysis bag, dialyze with deionized water for 3 days, place in a freeze dryer, freeze dry for 72h to obtain methacrylamide hyaluronic acid, wherein the molecular weight of the methacrylamide hyaluronic acid retained after filtration is ≥8000Da.

[0043] (3) Dissolve 50 mg of methacrylamide hyaluronic acid in 1 mL of deionized water containing 0.5 mg of lithium phenyl-2,4,6-trimethylbenzoylphosphonate, add 1 mg of black phosphorus nanosheets to the above solution and vortex to completely dissolve them to obtain HAMA-BP solution; fill the tip of the PDMS mold with 50 μL of HAMA-BP solution and scrape off the excess, then fill the bottom of the PDMS mold with 200 μL of HA-CAT solution and scrape off the excess. Repeat the vacuuming process 3 times, each time for 15 min, and leave it in a blower box at room temperature overnight. Demold by UV irradiation to obtain the final product.

[0044] Comparative Example 1

[0045] A method for preparing a soluble bifunctional conductive microneedle patch includes the following steps:

[0046] The preparation method of this comparative example differs from that of Example 1 as follows: 50 mg of methacrylamide hyaluronic acid was dissolved in 1 mL of deionized water containing 0.5 mg of photoinitiator (lithium phenyl-2,4,6-trimethylbenzoylphosphonate) to prepare HAMA solution; 50 μL of HAMA solution was filled into the tip of the PDMS mold, and the excess was scraped off. Then, 200 μL of HA-CAT was filled into the bottom of the PDMS mold, and the excess was scraped off. The vacuuming was repeated 3 times, each time for 15 min, and the mold was left overnight in a blower box at room temperature. The mold was then demolded by UV irradiation.

[0047] Characterization and Analysis

[0048] (1) Fourier transform infrared spectroscopy was used to analyze the characteristic peaks of low molecular weight hyaluronic acid (molecular weight of 200Kda~400Kda) and the methacrylamide hyaluronic acid prepared in Example 1. The steps were as follows: The sample to be tested was dried and ground, mixed with potassium bromide (KBr) at a ratio of 1:100, and pressed into a transparent sheet on a tablet press. Before the sample was tested, background correction was required. A blank sheet was used as the background, and the background spectrum was recorded. The prepared sample was placed on the sample holder, ensuring that the sample surface was flat and free of contamination. The position of the sample holder was adjusted so that the sample was located in the center of the beam, ensuring that the beam could uniformly irradiate the sample. The scanning range was set to 4000-400 cm⁻¹, and the resolution was usually 4 cm⁻¹. The characteristic peaks corresponding to the methacrylamide groups attached to the hyaluronic acid were recorded.

[0049] Figure 1 The characteristic peaks of methacryloyl hyaluronic acid (HAMA) were analyzed by Fourier transform infrared spectroscopy and compared with those of hyaluronic acid (HA). The peaks of both peaks were located in the 1715-1720 cm⁻¹ range. -1 The presence of characteristic peaks at all locations proves that the synthesis of methacryloyl hyaluronic acid in this invention was successful.

[0050] (2) A certain amount of black phosphorus nanosheets was dropped onto a silicon wafer. After ensuring the sample was free of moisture, its morphology was characterized using a scanning microscope. Figure 2 It can be seen that the black phosphorus nanosheets have a layered and wrinkled structure and are about 500 nm in size.

[0051] (3) 100 mmol hydrogen peroxide solution and black phosphorus nanosheets (BP) with concentrations of 0, 10, 20, 30, 40 and 50 μg / mL were incubated together in 2 mL of PBS for 24 h. The hydrogen peroxide concentration was detected using a hydrogen peroxide kit. Figure 3 Quantitative analysis was performed on the ability of black phosphorus nanosheets (BP) to scavenge hydrogen peroxide. Figure 3 It can be seen that the hydrogen peroxide removal rate increases with the increase of black phosphorus nanosheet (BP) concentration.

[0052] (4) After drying HA-CAT / HAMA-BP, a certain amount of sample is prepared, placed on conductive adhesive, sputtered with gold, and its morphology is characterized by scanning microscope. Figure 4 The microneedle patch prepared in Example 1 was characterized by... Figure 4 It can be seen that the microneedle patch prepared by the present invention has uniform length, good shape, and flat substrate.

[0053] (5) In order to evaluate whether the addition of black phosphorus nanosheets would affect the mechanical properties of microneedles, mechanical property analysis was performed on HA-CAT / HAMA and HA-CAT / HAMA-BP, and the effect of black phosphorus addition on mechanical properties was evaluated by measuring force-displacement curves.

[0054] Figure 5 The mechanical properties of the microneedle patch were characterized by... Figure 5 It can be seen that the strength of the microneedle patch is 0.41 N / needle, which is sufficient to penetrate myocardial tissue.

[0055] (6) To evaluate the cytotoxicity of HA-CAT / HAMA-BP, the CCK8 assay was used to investigate the cytotoxicity of microneedle patches to H9C2 cells. H9C2 cells were stored in wells at a density of 6 x 10⁶ cells / well. 3 Cells were seeded at a density of 100 μL of DMEM medium containing H9C2 cells in each well of a 96-well plate and cultured at 37 °C and 5% CO2 for 24 h. Cells were then co-cultured with MN for 1, 3, and 7 days, and cell proliferation was assessed using a CCK-8 assay kit.

[0056] Figure 6 To characterize the biocompatibility of microneedle patches using the CCK-8 kit, cell viability was measured at 1, 3, and 7 days. Figure 6 It can be seen that the microneedle patches at 1, 3, and 7 days showed no statistically significant difference compared to the control group, indicating that the microneedle patches have good biocompatibility.

[0057] (7) In order to evaluate the conductivity of the microneedle patch, the cardiomyocyte calcium ion fluorescent probe Fluo-4 is involved in myocardial electrical signal transmission and calcium signal regulation. α-actinin is a key protein of the cardiomyocyte cytoskeleton. Although it is mainly located in the Z disk and does not directly participate in electrical conduction, it indirectly regulates myocardial conductivity by maintaining sarcomere structure and ion channel localization. Electrical conduction capacity has a significant impact on both. After co-culturing the microneedle patch with cardiomyocytes, FLUO-4 detection and α-actinin immunofluorescence staining detection were performed.

[0058] Figure 7 The conductivity of the microneedle patch was assessed by α-actinin immunofluorescence staining. Figure 7 It can be seen that the fluorescence intensity of the microneedle patch group was significantly higher than that of the control group.

[0059] Figure 8 The conductivity of the microneedle patch was assessed using FLUO-4 immunofluorescence staining. Figure 8 It can be seen that, compared with the control group, the calcium ion concentration of the microneedle patch group prepared by the present invention is increased. Figure 9 Quantitative analysis of the fluorescence intensity of FLUO-4 revealed an increase in the fluorescence intensity of the microneedle patch.

[0060] (8) In order to evaluate the degradation performance of the microneedle patch, the prepared microneedle patch was placed in a dish containing PBS. The base began to degrade in 30 seconds and the base was basically completely degraded in 90 seconds, with the needle tip dispersed in PBS.

[0061] Figure 10 The biodegradability of microneedle patches was analyzed, by Figure 10 It can be seen that substrate degradation and needle tip diffusion are visible in PBS after 120 seconds.

[0062] In this invention, the terms "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., refer to a specific feature, structure, material, or characteristic described in connection with that embodiment or example, which is included in at least one embodiment or example of the invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0063] The above description is merely a preferred embodiment of this application and is not intended to limit this application. Various modifications and variations can be made to this application by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the protection scope of this application.

Claims

1. A method for preparing a soluble bi-functional conductive microneedle patch, characterized in that, Includes the following steps: (1) Add low molecular weight hyaluronic acid with a molecular weight of 100,000 to 200,000 Da and catalase to deionized water, mix well and prepare HA-CAT solution for later use. (2) N,N-dimethylformamide and methacrylic anhydride were added to a solution of low molecular weight hyaluronic acid with a molecular weight of 20Kda to 40Kda. Then, the pH value was adjusted first, and then salt was added. Finally, the solution was filtered, dialyzed and freeze-dried to obtain methacrylated hyaluronic acid HAMA. (3) Dissolve the photoinitiator and the methacrylamide hyaluronic acid in deionized water, then add black phosphorus nanosheets (BP) to prepare a HAMA-BP solution. Then, fill the tip of the mold with the HAMA-BP solution, and fill the bottom of the mold with the above-mentioned HA-CAT solution. Dry under vacuum and demold by ultraviolet irradiation.

2. The method of claim 1, wherein the soluble bifunctional conductive microneedle patch is prepared by the steps of: In step (1), the mass ratio of the low molecular weight hyaluronic acid to catalase is 10 to 20:

1.

3. The method for preparing the soluble bifunctional conductive microneedle patch according to claim 1 or 2, characterized in that, In the HA-CAT solution, the mass concentration of low molecular weight hyaluronic acid is 75-100 mg / mL, and the mass concentration of catalase is 5-10 mg / mL.

4. The method for preparing the soluble bifunctional conductive microneedle patch according to claim 3, characterized in that, In step (2), low molecular weight hyaluronic acid is dissolved in deionized water to prepare a low molecular weight hyaluronic acid solution. N,N-dimethylformamide is slowly added dropwise and stirred until homogeneous. Then, methacrylic anhydride is added, followed by NaOH to adjust the pH to 8-9. Then, NaCl is added and stirred until completely dissolved. Finally, anhydrous ethanol is added, filtered at least once, and then washed with anhydrous ethanol. After dialyzing the washed solution, it is placed in a freeze dryer and freeze-dried for 48-72 hours to obtain methacrylamide hyaluronic acid.

5. The method for preparing the soluble bifunctional conductive microneedle patch according to claim 4, characterized in that, In step (2), the mass concentration of low molecular weight hyaluronic acid in the low molecular weight hyaluronic acid solution is 15-25 mg / mL.

6. The method for preparing the soluble bifunctional conductive microneedle patch according to claim 5, characterized in that, In step (2), the mass ratio of the low molecular weight hyaluronic acid to methacrylic anhydride is 1.2 to 1.4:1, and the volume ratio of N,N-dimethylformamide to deionized water is 55 to 70%; the molecular weight of the methacrylated hyaluronic acid retained after filtration is ≥8000 Da.

7. The method for preparing the soluble bifunctional conductive microneedle patch according to claim 4, characterized in that, In step (3), the above-mentioned methacrylamide hyaluronic acid is dissolved in deionized water containing photoinitiator, and black phosphorus nanosheets are added and vortexed to completely dissolve it to obtain HAMA-BP solution. Then, the HAMA-BP solution is filled into the tip of the PDMS mold, and the excess part is scraped off. The above-mentioned HA-CAT solution is then filled into the bottom of the PDMS mold base, and the excess part is scraped off. Vacuuming is performed at least once, each time for 5 to 30 minutes. After drying at room temperature, the mold is demolded by ultraviolet irradiation.

8. The method for preparing the soluble bifunctional conductive microneedle patch according to claim 7, characterized in that, In step (3), the photoinitiator is lithium phenyl-2,4,6-trimethylbenzoylphosphonate, the mass concentration of the photoinitiator in the HAMA-BP solution is 0.1-1.0 mg / mL, the mass concentration of the methacryloyl hyaluronic acid is 50-100 mg / mL, and the mass concentration of the black phosphorus nanosheets is 0.1-5 mg / mL.

9. A soluble bifunctional conductive microneedle patch, characterized in that, The conductive microneedle patch is prepared using the method for preparing a soluble bifunctional conductive microneedle patch as described in claim 1, 3, 4, or 7.

10. An application of the soluble bifunctional conductive microneedle patch as described in claim 9, wherein the conductive microneedle patch is used in the preparation of a medicament for the prevention and / or treatment of myocardial infarction.

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