Preparation method of self-responsive coating for regulating tissue response throughout the entire process of cardiovascular implant interventional devices

Abstract

The present invention discloses a preparation method of a self-responsive coating for the whole process regulation and control tissue reaction of a cardiovascular implant interventional device, wherein 4-carboxylphenylboronic acid, carbodiimide and N-hydroxysuccinimide are dissolved in dimethyl sulfoxide at a molar ratio of 1:1.5:1.2, gelatin is added after sufficient reaction, deionized water is dialyzed, freeze-dried, and the product is dissolved in PBS to obtain a phenylboronic acid gelatin solution, which is then dropped into a mixed solution of polyphenol and dimethyl sulfoxide and fully reacted, and PBS is dialyzed to obtain a nanoparticle solution; the cardiovascular implant interventional device is immersed in an alkaline aqueous solution of dopamine to react, and after taking out and cleaning, it is sequentially immersed in a polycationic electrolyte solution, a nanoparticle solution, an antiplatelet drug, and an oxidized polysaccharide solution to react, and the reaction cycle is repeated multiple times. The coating prepared by the present invention can carry out whole process regulation and control, and the modified cardiovascular implant interventional device shows ideal endothelial regeneration and low intimal hyperplasia, thereby improving its function and long-term service rate.

Description

Technical Field

[0001] The present invention relates to the field of biomedical engineering functional materials, and in particular to a method for preparing a self-responsive coating for regulating tissue response throughout the entire process of cardiovascular implant interventional devices. Background Art

[0002] Cardiovascular implantable devices trigger a variety of complex tissue reactions in the body, such as coagulation and inflammation, delayed endothelial healing, and intimal hyperplasia. These uncontrolled tissue reactions seriously affect the long-term serviceability of the devices. The initial coagulation and inflammatory reactions are interrelated and are risk factors for inducing later endothelial regeneration disorders and intimal hyperplasia. Platelets, as key players in the coagulation reaction, can affect monocyte activation. Platelet-monocyte aggregates further affect cell behaviors such as endothelial cell adhesion and permeability. In addition, intimal hyperplasia is also directly related to endothelial damage and involves the aggregation and activation of cells such as platelets, monocytes, and macrophages. On the basis of effective intervention in coagulation and inflammatory reactions, promoting endothelial regeneration and intervening intimal hyperplasia are key ideas for improving the serviceability of cardiovascular implantable devices. However, the existing technology lacks a surface modification strategy that can accurately inhibit coagulation reactions, regulate inflammatory reactions through multiple pathways, and combine stimulation of endothelial cell regeneration and regulation of smooth muscle cell differentiation to regulate tissue reactions throughout the entire process. Summary of the Invention

[0003] In response to the deficiencies of the prior art, the present invention proposes a method for the preparation of a self-responsive coating for the full-process regulation of tissue reactions in cardiovascular implantable devices. The prepared coating inhibits platelet activation and stimulates endothelial cell proliferation and migration by releasing antiplatelet drugs. The loaded nanoparticles release polyphenols in response to MMP9, which can not only inhibit the function of MMP9 and regulate the behavior of inflammatory cells, but also promote the differentiation of smooth muscle cells into contractile types, thereby regulating the tissue reactions caused by cardiovascular implantable devices throughout the entire process. The present invention realizes the multifunctional modification of the surface of cardiovascular implantable devices, and has the advantages of stability, reliability, environmental friendliness, uniformity, efficiency, and strong versatility.

[0004] The specific technical solutions are as follows:

[0005] A method for preparing a self-responsive coating for regulating tissue response throughout the entire process of cardiovascular implant interventional devices comprises the following steps:

[0006] S1: Dissolve 4-carboxyphenylboronic acid, carbodiimide, and N-hydroxysuccinimide in dimethyl sulfoxide at a molar ratio of 1:1.5:1.2, stir at room temperature until fully reacted, then add 0.1-0.5 g of gelatin and stir until fully reacted; dialyze against deionized water, and freeze-dry to obtain gelatin modified with phenylboronic acid; the mass of the 4-carboxyphenylboronic acid is 30% of the gelatin;

[0007] S2: dissolving 5-10 mg of gelatin modified with phenylboronic acid in 0.5-1 ml of phosphate buffered saline (PBS) to obtain a phenylboronic acid gelatin solution; taking a polyphenol having the same mass as the gelatin modified with phenylboronic acid and a dimethyl sulfoxide solution having the same volume as the PBS, dissolving the polyphenol in the dimethyl sulfoxide solution to obtain a polyphenol system; dripping the phenylboronic acid gelatin solution into the polyphenol system, stirring at room temperature for reaction for 12-24 hours, and then dialyzing against PBS to obtain a nanoparticle solution; the nanoparticle solution is responsive to matrix metalloproteinases;

[0008] The cardiovascular implant device is placed in an alkaline aqueous solution of 0.1 to 10 mg / ml dopamine, and reacted at room temperature for 2 to 4 hours. The cardiovascular implant device is removed and thoroughly cleaned. At this time, the surface of the cardiovascular implant device is modified with a polydopamine coating;

[0009] S3: The cardiovascular implantable device obtained in S2 is immersed in the polycationic electrolyte solution, the nanoparticle solution, the antiplatelet drug and the oxidized polysaccharide solution in turn to react and complete a reaction cycle; within a reaction cycle, each time it is immersed in a solution for reaction for 5 to 20 minutes, and then taken out and thoroughly cleaned; the reaction cycle is repeated 5 to 20 times to complete the preparation of the self-responsive coating of the cardiovascular implantable device.

[0010] Furthermore, in S2, the polyphenols are selected from any one or more of salvianolic acid, dopamine, tannic acid, epigallocatechin gallate EGCG, epicatechin gallate ECG, epicatechin EC, epigallocatechin EGC, catechol and pyrogallol, in any proportion.

[0011] Furthermore, in S3, the polycationic electrolyte is selected from a mixture of any one or more of chitosan, polylysine, polyethyleneimine, polyallylamine hydrochloride, and polyarginine in any proportion.

[0012] Furthermore, in S3, the antiplatelet drug is selected from a mixture of any one or more of aspirin, tirofiban, ticagrelor, and eptifibatide in any proportion.

[0013] Furthermore, in S3, the oxidized polysaccharide is selected from any one or more of oxidized sodium alginate, oxidized glucomannan, oxidized bletilla striata polysaccharide, oxidized fucoidan, oxidized dextran, and oxidized hyaluronic acid, in any proportion.

[0014] Furthermore, in S1, the volume of dimethyl sulfoxide is 8 to 15 ml, and the reaction time for adding gelatin to prepare gelatin modified with phenylboronic acid is not less than 24 hours.

[0015] Furthermore, in said S2, the cardiovascular implantable device is taken out and cleaned 3 to 5 times; in said S3, the cardiovascular implantable device is taken out and cleaned 3 to 5 times after each immersion in the solution for reaction.

[0016] A self-responsive coating for cardiovascular implant interventional devices is prepared by the method for preparing a self-responsive coating for regulating tissue response throughout the entire process of cardiovascular implant interventional devices.

[0017] The beneficial effects of the present invention are:

[0018] (1) The nanoparticles in the self-responsive coating that can regulate tissue response throughout the entire process, prepared by the method of the present invention, can not only enhance the stability of the coating, but also respond to MMP9 overexpressed around inflammatory tissues. The released polyphenols inhibit the function of MMP9, precisely intervene in inflammatory responses through multiple pathways, and regulate the behavior of smooth muscle cells, playing an important role in inhibiting adverse intimal hyperplasia.

[0019] (2) The anti-platelet activation drug released by the coating prepared by the present invention can stimulate the proliferation and migration of endothelial cells, directly promote the re-endothelialization process, inhibit platelet activation, and reduce the degree of inflammatory response.

[0020] (3) The coating prepared by the present invention can regulate the tissue response of cardiovascular implantable devices throughout the entire process. The modified cardiovascular implantable devices exhibit ideal endothelial regeneration and low intimal hyperplasia, effectively improving their functions and long-term service rate, and enhancing the biocompatibility of the devices.

[0021] (4) The preparation method and process of the present invention are simple and stable, the reaction conditions are mild, and it is environmentally friendly. It can be evenly and efficiently coated on the surface of cardiovascular implantable devices, and each functional component is effective and controllable; it can efficiently and easily assemble functional substances and protect the activity of the substances, and has a wide range of applications. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 Schematic diagram of the surface morphology of the coating before and after modification in an embodiment of the present invention, wherein (a) is the surface morphology of the bare material that has not been treated by the method of the present invention, and (b) is the surface morphology of the self-responsive coating of the cardiovascular implantable device after being treated by the method of the present invention. The reaction solutions in step four are, in sequence, polycationic electrolyte solution PEI, nanoparticles GS, antiplatelet drug TIR, and oxidized polysaccharide solution OxHA.

[0023] Figure 2Schematic diagram of platelet adhesion and activation on the surface of the material before and after modification of the coating in an embodiment of the present invention, wherein (a) is the surface morphology of the bare material that has not been treated by the method of the present invention, and (b) is the surface morphology of the self-responsive coating of the cardiovascular implantable device after treatment by the method of the present invention. The reaction solutions in step four are PEI, GS, TIR, and OxHA, respectively.

[0024] Figure 3 Schematic diagram of the morphology of monocytes and macrophages on the surface of the material before and after the modified coating in an embodiment of the present invention, wherein (a) is the surface morphology of the bare material that has not been treated by the method of the present invention, and (b) is the surface morphology of the self-responsive coating of the cardiovascular implantable device after being treated by the method of the present invention. The reaction solutions in step four are PEI, GS, TIR, and OxHA, respectively.

[0025] Figure 4 These are morphological diagrams of endothelial cells and smooth muscle cells on the surface of the material before and after modification of the coating in an embodiment of the present invention, wherein (a) is the surface morphology of the bare material that has not been treated by the method of the present invention, and (b) is the surface morphology of the self-responsive coating of the cardiovascular implantable device after treatment by the method of the present invention. The reaction solutions in step four are PEI, GS, TIR, and OxHA, in sequence. DETAILED DESCRIPTION

[0026] The present invention will be described in detail below based on the accompanying drawings and preferred embodiments. The purpose and effects of the present invention will become more apparent. The present invention will be 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 for explaining the present invention and are not intended to limit the present invention.

[0027] This invention addresses the relationship between materials and tissue responses, aiming to accelerate endothelialization and promote vascular stent-tissue integration. By inhibiting coagulation and inflammation, the coating aids endothelialization and slows intimal proliferation. This not only accelerates endothelial cell migration and proliferation, but also, when the regenerated endothelium is lost, regulates the phenotypic differentiation of smooth muscle cells, thereby inhibiting stent restenosis. This invention addresses the diverse needs of cardiovascular implantable devices and expands the design perspective of functional coatings.

[0028] The present invention is specifically described below by the following examples.

[0029] Example 1

[0030] A method for preparing a self-responsive coating for regulating tissue response throughout the entire process of cardiovascular implant interventional devices, specifically comprising the following steps:

[0031] S1: Dissolve 0.03 g of 4-carboxyphenylboronic acid, 0.052 g of carbodiimide, and 0.025 g of N-hydroxysuccinimide in 8 ml of dimethyl sulfoxide. Stir and react at room temperature for 24 hours. Add 0.1 g of gelatin and stir until fully reacted. After 24 hours, dialyze against deionized water and freeze-dry to obtain gelatin modified with phenylboronic acid.

[0032] S2: This step specifically includes the following two operations. It should be noted that the execution order of operation (1) and operation (2) is not limited and they can be executed one after another or simultaneously.

[0033] (1) Dissolve 5 mg of gelatin modified with phenylboronic acid in 1 ml of PBS to obtain a phenylboronic acid gelatin solution; dissolve the same mass of salvianolic acid as the gelatin modified with phenylboronic acid in the same volume of dimethyl sulfoxide solution as PBS to obtain a salvianolic acid system; slowly drip the phenylboronic acid gelatin solution into the salvianolic acid system, stir at room temperature for 24 hours, and dialyze against PBS to obtain a nanoparticle solution.

[0034] (2) The vascular stent was placed in a 2 ml volume of 2 mg / ml dopamine alkaline aqueous solution and reacted at room temperature for 2 hours. The vascular stent was removed and washed 5 times.

[0035] S3: The vascular stent obtained by S2 operation (2) is immersed in polyethyleneimine solution, nanoparticle solution obtained by S2 operation (1), tirofiban and oxidized hyaluronic acid solution respectively to react and complete a reaction cycle. In one reaction cycle, each time it is immersed in one solution for reaction for 5 minutes, and then taken out and thoroughly washed; the reaction cycle is repeated 10 times to obtain a vascular stent with a self-responsive coating that regulates tissue response throughout the process.

[0036] The surface morphology of the coating before and after modification was observed using a SEM scanning electron microscope. Figure 1 As shown in the figure, it can be seen that the surface morphology of the coating has changed after modification.

[0037] Will Figure 1 The different materials shown were incubated with rabbit platelet-rich plasma for 1 hour, and the surface of the materials was observed using a scanning electron microscope (SEM). Figure 2 As shown, the results show that the self-responsive coating modified material that regulates tissue response throughout the entire process prepared by the method of the present invention has ideal anti-platelet adhesion and activation capabilities.

[0038] Monocytes were seeded in Figure 1 The different material surfaces shown in the figure were coated with water and 160 nM phorbol ester was added to the culture medium to induce monocytes into macrophages. After 48 hours, the cell morphology was observed using a confocal microscope. The results are shown in FIG. Figure 3As shown, it can be seen that the self-responsive coating that regulates tissue response throughout the entire process prepared by the method of the present invention can effectively inhibit the activation of macrophages on the surface of the material.

[0039] Endothelial cells and smooth muscle cells were seeded in Figure 1 After 48 hours, the cell proliferation was observed using a confocal microscope on the different material surfaces shown. Figure 4 As shown, it is shown that the self-responsive coating used for regulating tissue response throughout the entire process of vascular stents can promote the adhesion and proliferation of endothelial cells and is more friendly to endothelial cell growth than smooth muscle cells.

[0040] Example 2

[0041] A method for preparing a self-responsive coating for regulating tissue response throughout the entire process of cardiovascular implant interventional devices, the method comprising the following steps:

[0042] S1: Dissolve 0.09 g of 4-carboxyphenylboronic acid, 0.156 g of carbodiimide, and 0.075 g of N-hydroxysuccinimide in 11 ml of dimethyl sulfoxide. Stir and react at room temperature for 24 hours. Add 0.3 g of gelatin and stir until fully reacted. After 24 hours, dialyze against deionized water and freeze-dry to obtain gelatin modified with phenylboronic acid.

[0043] S2: This step specifically includes the following two operations. It should be noted that the execution order of operation (1) and operation (2) is not limited and they can be executed one after another or simultaneously.

[0044] (1) 8 mg of gelatin modified with phenylboronic acid was dissolved in 0.5 ml of PBS to obtain a phenylboronic acid gelatin solution; the same mass of EGCG as the gelatin modified with phenylboronic acid was dissolved in the same volume of dimethyl sulfoxide solution as PBS to obtain an EGCG system; the phenylboronic acid gelatin solution was slowly dripped into the EGCG system, stirred at room temperature for 24 hours, and dialyzed against PBS to obtain a nanoparticle solution;

[0045] (2) The vascular stent was placed in a 4 ml volume of 1 mg / ml dopamine alkaline aqueous solution and reacted at room temperature for 4 hours. The vascular stent was removed and washed 4 times;

[0046] S3: The vascular stent obtained by S2 operation (2) is immersed in the polylysine solution, the nanoparticle solution obtained by S2 operation (1), the aspirin and the oxidized dextran solution respectively to react and complete a reaction cycle. In one reaction cycle, each time it is immersed in one solution for reaction for 10 minutes, and then taken out and thoroughly washed; the reaction cycle is repeated 20 times to obtain a vascular stent with a self-responsive coating that regulates tissue response throughout the whole process.

[0047] Example 3

[0048] A method for preparing a self-responsive coating for regulating tissue response throughout the entire process of cardiovascular implant interventional devices, the method comprising the following steps:

[0049] S1: Dissolve 0.03 g of 4-carboxyphenylboronic acid, 0.052 g of carbodiimide, and 0.025 g of N-hydroxysuccinimide in 8 ml of dimethyl sulfoxide. Stir and react at room temperature for 24 hours. Add 0.1 g of gelatin and stir until fully reacted. After 24 hours, dialyze against deionized water and freeze-dry to obtain gelatin modified with phenylboronic acid.

[0050] S2: This step specifically includes the following two operations. It should be noted that the execution order of operation (1) and operation (2) is not limited and they can be executed one after another or simultaneously.

[0051] (1) Dissolve 5 mg of gelatin modified with phenylboronic acid in 1 ml of PBS to obtain a phenylboronic acid gelatin solution; dissolve the same mass of salvianolic acid as the gelatin modified with phenylboronic acid in the same volume of dimethyl sulfoxide solution as PBS to obtain a salvianolic acid system; slowly drip the phenylboronic acid gelatin solution into the salvianolic acid system, stir at room temperature for 24 hours, and dialyze against PBS to obtain a nanoparticle solution;

[0052] (2) The vascular stent was placed in a 2 ml volume of 2 mg / ml dopamine alkaline aqueous solution and reacted at room temperature for 2 hours. The vascular stent was removed and washed 5 times;

[0053] S3: The vascular stent obtained by S2 operation (2) is immersed in polyethyleneimine solution, nanoparticle solution obtained by S2 operation (1), tirofiban and oxidized hyaluronic acid solution respectively to react and complete a reaction cycle. In one reaction cycle, each time it is immersed in one solution for reaction for 5 minutes, and then taken out and thoroughly washed; the reaction cycle is repeated 10 times to obtain a vascular stent with a self-responsive coating that regulates tissue response throughout the process.

[0054] Example 4

[0055] A method for preparing a self-responsive coating for regulating tissue response throughout the entire process of cardiovascular implant interventional devices, the method comprising the following steps:

[0056] S1: Dissolve 0.03 g of 4-carboxyphenylboronic acid, 0.052 g of carbodiimide, and 0.025 g of N-hydroxysuccinimide in 10 ml of dimethyl sulfoxide. Stir and react at room temperature for 24 hours. Add 0.1 g of gelatin and stir until fully reacted. After 24 hours, dialyze against deionized water and freeze-dry to obtain gelatin modified with phenylboronic acid.

[0057] S2: This step specifically includes the following two operations. It should be noted that the execution order of operation (1) and operation (2) is not limited and they can be executed one after another or simultaneously.

[0058] (1) Dissolve 5 mg of gelatin modified with phenylboronic acid in 1 ml of PBS to obtain a phenylboronic acid gelatin solution; dissolve the same mass of epigallocatechin-EGC as the gelatin modified with phenylboronic acid in a dimethyl sulfoxide solution with the same volume as PBS to obtain an epigallocatechin-EGC system; slowly drip the phenylboronic acid gelatin solution into the epigallocatechin-EGC system, stir at room temperature for 24 hours, and dialyze against PBS to obtain a nanoparticle solution;

[0059] (2) The vascular stent was placed in a 4 ml volume of 2 mg / ml dopamine alkaline aqueous solution and reacted at room temperature for 2 hours. The vascular stent was removed and washed three times;

[0060] S3: The vascular stent obtained by S2 operation (2) is immersed in the polyallylamine hydrochloride solution, the nanoparticle solution obtained by S2 operation (1), eptifibatide and oxidized bletilla striata polysaccharide solution respectively to react and complete a reaction cycle. In one reaction cycle, each time it is immersed in one solution for reaction for 15 minutes, and then taken out and thoroughly washed; the reaction cycle is repeated 20 times to obtain a vascular stent with a self-responsive coating that regulates tissue response throughout the entire process.

[0061] Example 5

[0062] A method for preparing a self-responsive coating for regulating tissue response throughout the entire process of cardiovascular implant interventional devices, the method comprising the following steps:

[0063] S1: Dissolve 0.03 g of 4-carboxyphenylboronic acid, 0.052 g of carbodiimide, and 0.025 g of N-hydroxysuccinimide in 8 ml of dimethyl sulfoxide. Stir and react at room temperature for 24 hours. Add 0.1 g of gelatin and stir until fully reacted. After 24 hours, dialyze against deionized water and freeze-dry to obtain gelatin modified with phenylboronic acid.

[0064] S2: This step specifically includes the following two operations. It should be noted that the execution order of operation (1) and operation (2) is not limited and they can be executed one after another or simultaneously.

[0065] (1) Dissolve 5 mg of gelatin modified with phenylboronic acid in 0.5 ml of PBS to obtain a phenylboronic acid gelatin solution; dissolve the same mass of salvianolic acid as the gelatin modified with phenylboronic acid in the same volume of dimethyl sulfoxide solution as PBS to obtain a salvianolic acid system; slowly drip the phenylboronic acid gelatin solution into the salvianolic acid system, stir at room temperature for 24 hours, and dialyze against PBS to obtain a nanoparticle solution;

[0066] (2) The vascular stent was placed in a 2 ml volume of 0.1 mg / ml dopamine alkaline aqueous solution and reacted at room temperature for 4 hours. The vascular stent was removed and washed three times;

[0067] S3: The vascular stent obtained by S2 operation (2) is immersed in the polyethyleneimine solution, the nanoparticle solution obtained by S2 operation (1), tirofiban and oxidized hyaluronic acid solution respectively to react and complete a reaction cycle. In one reaction cycle, each time it is immersed in one solution for reaction for 10 minutes, and then taken out and thoroughly washed; the reaction cycle is repeated 5 times to obtain a vascular stent with a self-responsive coating that regulates tissue response throughout the process.

[0068] Example 6

[0069] A method for preparing a self-responsive coating for regulating tissue response throughout the entire process of cardiovascular implant interventional devices, the method comprising the following steps:

[0070] S1: Dissolve 0.09 g of 4-carboxyphenylboronic acid, 0.156 g of carbodiimide, and 0.075 g of N-hydroxysuccinimide in 11 ml of dimethyl sulfoxide. Stir and react at room temperature for 24 hours. Add 0.3 g of gelatin and stir until fully reacted. After 24 hours, dialyze against deionized water and freeze-dry to obtain gelatin modified with phenylboronic acid.

[0071] S2: This step specifically includes the following two operations. It should be noted that the execution order of operation (1) and operation (2) is not limited and they can be executed one after another or simultaneously.

[0072] (1) 8 mg of gelatin modified with phenylboronic acid was dissolved in 0.5 ml of PBS to obtain a phenylboronic acid gelatin solution; the same mass of salvianolic acid as the gelatin modified with phenylboronic acid was dissolved in the same volume of dimethyl sulfoxide solution as PBS to obtain a salvianolic acid system; the phenylboronic acid gelatin solution was slowly dripped into the salvianolic acid system, stirred at room temperature for 24 hours, and dialyzed against PBS to obtain a nanoparticle solution;

[0073] (2) The vascular stent was placed in a 4 ml volume of 1 mg / ml dopamine alkaline aqueous solution and reacted at room temperature for 2 hours. The vascular stent was removed and washed four times;

[0074] S3: The vascular stent obtained by S2 operation (2) is immersed in the polyarginine solution, the nanoparticle solution obtained by S2 operation (1), tirofiban and oxidized fucoidan solution respectively to react and complete a reaction cycle. In one reaction cycle, each time it is immersed in one solution for reaction for 10 minutes, and then taken out and thoroughly washed; the reaction cycle is repeated 10 times to obtain a vascular stent with a self-responsive coating that regulates tissue response throughout the process.

[0075] Example 7

[0076] A method for preparing a self-responsive coating for regulating tissue response throughout the entire process of cardiovascular implant interventional devices, the method comprising the following steps:

[0077] S1: Dissolve 0.15 g of 4-carboxyphenylboronic acid, 0.26 g of carbodiimide, and 0.125 g of N-hydroxysuccinimide in 15 ml of dimethyl sulfoxide. Stir and react at room temperature for 24 hours. Add 0.5 g of gelatin and stir until fully reacted. After 24 hours, dialyze against deionized water and freeze-dry to obtain gelatin modified with phenylboronic acid.

[0078] S2: This step specifically includes the following two operations. It should be noted that the execution order of operation (1) and operation (2) is not limited and they can be executed one after another or simultaneously.

[0079] (1) Dissolve 10 mg of gelatin modified with phenylboronic acid in 1 ml of PBS to obtain a phenylboronic acid gelatin solution; dissolve the same mass of tannic acid as the gelatin modified with phenylboronic acid in the same volume of dimethyl sulfoxide solution as PBS to obtain a tannic acid system; slowly drip the phenylboronic acid gelatin solution into the tannic acid system, stir at room temperature for 24 hours, and dialyze against PBS to obtain a nanoparticle solution;

[0080] (2) The vascular stent was placed in a 4 ml volume of 10 mg / ml dopamine alkaline aqueous solution and reacted at room temperature for 2 hours. The vascular stent was removed and washed 5 times;

[0081] S3: The vascular stent obtained by S2 operation (2) is immersed in the polyethyleneimine solution, the nanoparticle solution obtained by S2 operation (1), ticagrelor and oxidized sodium alginate solution respectively to react and complete a reaction cycle. In one reaction cycle, the vascular stent is immersed in one solution for reaction for 20 minutes each time, and then taken out and thoroughly washed; the reaction cycle is repeated 10 times to obtain a vascular stent with a self-responsive coating that regulates tissue response throughout the entire process.

[0082] Example 8

[0083] A method for preparing a self-responsive coating for regulating tissue response throughout the entire process of cardiovascular implant interventional devices, the method comprising the following steps:

[0084] S1: Dissolve 0.15 g of 4-carboxyphenylboronic acid, 0.26 g of carbodiimide, and 0.125 g of N-hydroxysuccinimide in 15 ml of dimethyl sulfoxide. Stir and react at room temperature for 24 hours. Add 0.5 g of gelatin and stir until fully reacted. After 24 hours, dialyze against deionized water and freeze-dry to obtain gelatin modified with phenylboronic acid.

[0085] S2: This step specifically includes the following two operations. It should be noted that the execution order of operation (1) and operation (2) is not limited and they can be executed one after another or simultaneously.

[0086] (1) Dissolve 10 mg of gelatin modified with phenylboronic acid in 1 ml of PBS to obtain a phenylboronic acid gelatin solution; dissolve the same mass of tannic acid as the gelatin modified with phenylboronic acid in the same volume of dimethyl sulfoxide solution as PBS to obtain a tannic acid system; slowly drip the phenylboronic acid gelatin solution into the tannic acid system, stir at room temperature for 24 hours, and dialyze against PBS to obtain a nanoparticle solution;

[0087] (2) The vascular stent was placed in a 4 ml volume of 10 mg / ml dopamine alkaline aqueous solution and reacted at room temperature for 2 hours. The vascular stent was removed and washed 5 times;

[0088] S3: The vascular stent obtained by S2 operation (2) is immersed in the polyethyleneimine solution, the nanoparticle solution obtained by S2 operation (1), ticagrelor and oxidized glucomannan solution respectively to react and complete a reaction cycle. In one reaction cycle, the vascular stent is immersed in one solution for reaction for 15 minutes each time, and then taken out and thoroughly washed; the reaction cycle is repeated 10 times to obtain a vascular stent with a self-responsive coating that regulates tissue response throughout the entire process.

[0089] Example 9

[0090] A method for preparing a self-responsive coating for regulating tissue response throughout the entire process of cardiovascular implant interventional devices, the method comprising the following steps:

[0091] S1: Dissolve 0.03 g of 4-carboxyphenylboronic acid, 0.052 g of carbodiimide, and 0.025 g of N-hydroxysuccinimide in 8 ml of dimethyl sulfoxide. Stir and react at room temperature for 24 hours. Add 0.1 g of gelatin and stir until fully reacted. After 24 hours, dialyze against deionized water and freeze-dry to obtain gelatin modified with phenylboronic acid.

[0092] S2: This step specifically includes the following two operations. It should be noted that the execution order of operation (1) and operation (2) is not limited and they can be executed one after another or simultaneously.

[0093] (1) 5 mg of gelatin modified with phenylboronic acid was dissolved in 0.5 ml of PBS to obtain a phenylboronic acid gelatin solution; the same mass of epicatechin gallate as the gelatin modified with phenylboronic acid was dissolved in a dimethyl sulfoxide solution with the same volume as PBS to obtain an epicatechin gallate system; the phenylboronic acid gelatin solution was slowly dripped into the epicatechin gallate system, stirred at room temperature for 24 hours, and dialyzed against PBS to obtain a nanoparticle solution;

[0094] (2) The vascular stent was placed in a 2 ml volume of 0.1 mg / ml dopamine alkaline aqueous solution and reacted at room temperature for 2 hours. The vascular stent was removed and washed three times;

[0095] S3: The vascular stent obtained by S2 operation (2) is immersed in the polyethyleneimine solution, the nanoparticle solution obtained by S2 operation (1), tirofiban and oxidized hyaluronic acid solution respectively to react and complete a reaction cycle. In one reaction cycle, each time it is immersed in one solution for reaction for 10 minutes, and then taken out and thoroughly washed; the reaction cycle is repeated 5 times to obtain a vascular stent with a self-responsive coating that regulates tissue response throughout the process.

[0096] Those skilled in the art will understand that the foregoing descriptions are merely preferred embodiments of the invention and are not intended to limit the invention. Although the invention has been described in detail with reference to the foregoing examples, those skilled in the art will still be able to modify the technical solutions described in the foregoing examples or substitute equivalents for some of the technical features therein. Any modifications, equivalent substitutions, etc. made within the spirit and principles of the invention shall be included within the scope of protection of the invention.

Claims

1. A method for preparing a self-responsive coating for regulating tissue response throughout the entire process of cardiovascular implant interventional devices, characterized in that: The following steps are involved: S1: Dissolve 4-carboxyphenylboronic acid, carbodiimide, and N-hydroxysuccinimide in dimethyl sulfoxide at a molar ratio of 1:1.5:1.2, stir at room temperature until fully reacted, then add 0.1-0.5 g of gelatin and stir until fully reacted; dialyze against deionized water and freeze-dry to obtain gelatin modified with phenylboronic acid; the mass of the 4-carboxyphenylboronic acid is 30% of the gelatin; S2: Dissolve 5-10 mg of gelatin modified with phenylboronic acid in 0.5-1 ml of PBS to obtain a phenylboronic acid gelatin solution; take a polyphenol with the same mass as the gelatin modified with phenylboronic acid and a dimethyl sulfoxide solution with the same volume as the PBS, dissolve the polyphenol in the dimethyl sulfoxide solution to obtain a polyphenol system; dropwise add the phenylboronic acid gelatin solution to the polyphenol system, stir at room temperature for 12-24 hours, and then dialyze against PBS to obtain a nanoparticle solution; Place the cardiovascular implant in an alkaline aqueous solution of 0.1-10 mg / ml dopamine and allow it to react at room temperature for 2-4 hours. Remove the cardiovascular implant and rinse thoroughly. S3: The cardiovascular implantable device obtained in S2 is sequentially immersed in a polycationic electrolyte solution, the nanoparticle solution, the antiplatelet drug, and the oxidized polysaccharide solution to react, completing a reaction cycle; within a reaction cycle, each immersion in a solution is reacted for 5 to 20 minutes, and then removed and thoroughly washed; the reaction cycle is repeated 5 to 20 times to complete the preparation of the self-responsive coating for the cardiovascular implantable device; In said S2, the polyphenol is selected from the group consisting of salvianolic acid, dopamine, tannic acid, epigallocatechin gallate, epicatechin gallate, epicatechin, epigallocatechin, catechol and pyrogallol, any one or more of which are mixed in any proportion; In said S3, the polycationic electrolyte is selected from a mixture of any one or more of chitosan, polylysine, polyethyleneimine, polyallylamine hydrochloride, and polyarginine in any proportion; In S3, the antiplatelet drug is selected from a mixture of any one or more of aspirin, tirofiban, ticagrelor, and eptifibatide in any proportion; In the above S3, the oxidized polysaccharide is selected from any one or more of oxidized sodium alginate, oxidized glucomannan, oxidized bletilla striata polysaccharide, oxidized fucoidan, oxidized dextran, and oxidized hyaluronic acid, in any proportion.

2. The method for preparing a self-responsive coating for regulating tissue response throughout the entire process of cardiovascular implantation according to claim 1, characterized in that: In S1, the volume of dimethyl sulfoxide is 8-15 ml, and the reaction time for adding gelatin to prepare gelatin modified with phenylboronic acid is not less than 24 hours.

3. The method for preparing a self-responsive coating for regulating tissue response throughout the entire process of cardiovascular implantation according to claim 1, characterized in that: In said S2, the cardiovascular implant device is taken out and cleaned 3 to 5 times; in said S3, the cardiovascular implant device is taken out and cleaned 3 to 5 times after each immersion in the solution for reaction.

4. A self-responsive coating for cardiovascular implantable interventional devices prepared by the method for preparing a self-responsive coating for regulating tissue response throughout the entire process of cardiovascular implantable interventional devices according to any one of claims 1 to 3.

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