CN117357713A - Preparation method of microenvironment self-response anticoagulation anti-inflammatory self-growth coating for cardiovascular implantation interventional instrument - Google Patents
Preparation method of microenvironment self-response anticoagulation anti-inflammatory self-growth coating for cardiovascular implantation interventional instrument Download PDFInfo
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- CN117357713A CN117357713A CN202311201899.9A CN202311201899A CN117357713A CN 117357713 A CN117357713 A CN 117357713A CN 202311201899 A CN202311201899 A CN 202311201899A CN 117357713 A CN117357713 A CN 117357713A
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Classifications
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- A—HUMAN NECESSITIES
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Abstract
The invention discloses a preparation method of a microenvironment self-response anticoagulation anti-inflammatory self-growth coating for a cardiovascular implantation interventional instrument, which comprises the steps of preparing oxidized polysaccharide nanogel with thrombin-sensitive polypeptide crosslinking and coated with anticoagulation drugs, preparing a gel pre-solution containing zwitterionic monomers, acrylamide phenylboronic acid monomers, a micromolecular crosslinking agent, nanogel and polyphenol, preparing a base coating on the surface of the cardiovascular implantation interventional instrument, immersing the cardiovascular implantation interventional instrument in the pre-solution, and then pulling out the cardiovascular implantation interventional instrument, and irradiating with ultraviolet light. The coating material disclosed by the invention is stable in process, mild in reaction condition, environment-friendly, capable of self-growing from the surface of the material, and uniformly and efficiently coated on the surface of a cardiovascular implantation interventional instrument, and stable and controllable in functional components. The coating prepared by the invention can rapidly release anticoagulant drugs to block the coagulation reaction under the stimulation of thrombin, inhibit oxidative stress and inflammatory cell activation, thereby realizing high-efficiency regulation of the coagulation reaction.
Description
Technical Field
The invention belongs to the field of biomedical engineering functional materials, and particularly relates to a preparation method of a microenvironment self-response anticoagulation anti-inflammatory self-growth coating for a cardiovascular implantation interventional instrument.
Background
After the cardiovascular implantation interventional instrument is implanted into the body, the body immediately generates a coagulation reaction under the participation of platelets and various coagulation factors to form thrombus. Various anti-adhesion polymers, heparin, gas and the like are used for preparing the anti-coagulation modified coating, however, most anti-coagulation coatings are based on passive diffusion of anti-coagulation substances or interfacial enzyme catalysis, and have no feedback function. In order to prolong the action time of the anticoagulant, it is generally necessary to increase the amount of modification of the functional substance, which, however, causes bleeding and toxicity problems. Therefore, on the premise of ensuring the persistence of the anticoagulation effect, the matching of the actual blood coagulation response level is important to the improvement of the blood compatibility of the cardiovascular implantation interventional instrument. The coagulation and inflammatory response caused by the implantation of the cardiovascular implantation interventional instrument are close in relation and causal to each other, and seriously threaten the long-term service capacity of the cardiovascular implantation interventional instrument. Intervention in inflammatory reactions has a positive effect on controlling the coagulation response and subsequent re-endothelialization of materials. Active oxygen over-expressed in tissue surrounding the material activates macrophages, causing damage to biomolecules, resulting in an enhanced host defense response, a key substance for inflammatory reactions. Therefore, the multifunctional modified coating which combines anticoagulation capability and can regulate inflammatory reaction and eliminate active oxygen is an ideal strategy for modifying the function of the cardiovascular implantation interventional instrument.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of a microenvironment self-response anticoagulation anti-inflammatory self-growth coating for a cardiovascular implantation interventional instrument, the prepared coating can effectively control inflammatory reaction by eliminating free radicals and inhibiting inflammatory cell activation, and the nanogel of thrombin-sensitive release anticoagulation medicine in the coating can respond to thrombin in a high-coagulation risk environment and realize self-regulation anticoagulation capacity, thereby providing a mild environment for the re-endothelialization of the surface of the cardiovascular implantation interventional instrument. The invention combines anti-inflammatory and anticoagulation functions organically, and stably modifies the surface of the cardiovascular implantation interventional instrument, and has the advantages of controllable reaction, environmental protection, uniformity, high efficiency and strong universality.
The aim of the invention is achieved by the following technical scheme:
a method for preparing a microenvironment self-response anticoagulation anti-inflammatory self-growth coating for a cardiovascular implantation interventional instrument, which comprises the following steps:
step one: dissolving 1-5mg of anticoagulant drug and 5-10mg of oxidized polysaccharide in dimethyl sulfoxide, slowly dripping the same volume of polypeptide solution dissolved with 5-10mg of thrombin sensitivity into a reaction system at room temperature, and dialyzing with deionized water after full reaction to obtain nanogel;
step two: placing the cardiovascular implantation interventional instrument into an alkaline aqueous solution mixed with 0.1-10mg/ml dopamine methacrylamide and 0.1-10mg/ml azo diisobutylamidine hydrochloride in a volume ratio of 1:1, fully reacting at room temperature, taking out the cardiovascular implantation interventional instrument, and fully cleaning;
step three: immersing the cardiovascular implantation interventional instrument obtained in the step two in a mixed solution of ethanol and water containing zwitterionic monomers, 3-acrylamidophenylboronic acid, a small molecular cross-linking agent, the nanogel of the step one and polyphenol, wherein the concentration of the zwitterionic monomers is 100-300mg/ml, and the molar ratio of the zwitterionic monomers, the 3-acrylamidophenylboronic acid, the small molecular cross-linking agent and the polyphenol is 590:250:21:80; and then taking out the cardiovascular implant interventional instrument, and obtaining the cardiovascular implant interventional instrument with the microenvironment self-response anticoagulation anti-inflammatory self-growth coating after full ultraviolet irradiation.
Further, the anticoagulant drug is selected from any one or a mixture of a plurality of rivaroxaban, apixaban, dabigatran, bivalirudin, clopidogrel, ticagrelor and argatroban according to any proportion.
Further, the oxidized polysaccharide is selected from any one or a mixture of a plurality of oxidized sodium alginate, oxidized glucomannan, oxidized bletilla striata polysaccharide, oxidized fucoidin, oxidized dextran and oxidized hyaluronic acid according to any proportion.
Further, the amino acid sequence of the thrombin-sensitive polypeptide is selected from any one or more of lysine-valine-proline-arginine-glycine, alanine-arginine-serine-tryptophan-glycine, leucine-tyrosine-proline-arginine-glycine-serine, glycine-phenylalanine-proline-arginine-glycine-phenylalanine-proline-alanine-glycine.
Further, the zwitterionic monomer is selected from one or more of 2-methacryloxyethyl phosphorylcholine, 3- [ [2- (methacryloxyethyl ] dimethyl ammonium ] propionate and sulfobetaine methacrylate according to any proportion.
Further, the polyphenol is selected from any one or a mixture of more of dopamine, tannic acid, epigallocatechin gallate EGCG, epicatechin gallate ECG, epicatechin EC, epigallocatechin EGC, catechol and pyrogallol according to any proportion.
Further, the small molecule cross-linking agent is selected from one or a mixture of two of N, N '-methylene bisacrylamide and N, N' -vinyl bisacrylamide according to any proportion.
In the second step, the volume ratio of ethanol to water in the mixed solution of ethanol and water is 1:3-6.
Further, in the first step, the volume of the dimethyl sulfoxide is 1-5ml, and the reaction time of the thrombin-sensitive polypeptide solution is not less than 12 hours;
in the second step, the volume of the alkaline aqueous solution is 2-5ml, the reaction time is 24 hours, and the cleaning times after taking out the cardiovascular implantation interventional instrument are 3-5 times;
in the third step, the volume of the mixed solution of ethanol and water is 2-5ml; the ultraviolet irradiation time is 20-120 minutes.
The cardiovascular implantation interventional instrument with the microenvironment self-response anticoagulation anti-inflammatory self-growth coating prepared by the preparation method.
The beneficial effects of the invention are as follows:
1. the microenvironment self-response anticoagulation anti-inflammatory self-growth coating prepared by the method comprises self-regulating anticoagulation functional components realized by thrombin-sensitive release type drug-loaded nanogel, so that anticoagulation drugs can be released in an environment with high coagulation risk to further inhibit coagulation reaction, feedback control of bionic endothelial cells is realized, efficiency is improved under the condition of avoiding excessive drugs, and accurate anticoagulation of the coating under the premise of matching coagulation response level is realized.
2. The anti-inflammatory function of the invention is realized by the antioxidant polyphenol, the polyphenol not only can be used as a cross-linking agent to participate in the assembly of the coating, but also can fall off under the stimulation of high active oxygen, and fully plays a role on the surface of the material, thereby realizing the multi-way joint regulation and control of the inflammatory microenvironment.
3. The coating of the invention can lead the cardiovascular implantation interventional instrument to show better blood compatibility and milder host reaction, and the modified cardiovascular implantation interventional instrument has ideal re-endothelialization and capability of inhibiting the poor proliferation of intima on the inner surface of the body, thereby being beneficial to long-term service of the cardiovascular implantation interventional instrument in the body.
4. The preparation method and the process are simple and stable, can efficiently assemble functional substances, and have universality and wide application range.
5. The coating is obtained by self-growing and crosslinking from a substrate coating, and is firmly combined with a substrate.
Drawings
Fig. 1 is a surface element composition incorporating an anti-coagulant anti-inflammatory cross-linked coating.
Fig. 2 is a schematic illustration of platelet adhesion and activation of the surface of the material before and after modification of the coating.
FIG. 3 is a schematic representation of the morphology of mononuclear-macrophages modifying the surface of a material before and after coating.
FIG. 4 is a morphology of human umbilical vein endothelial cells modifying the surface of the material before and after coating.
In the above figure, control is unmodified bare material, and DMA-AIBA is the material obtained in step 2. The hydrogel pre-solution in the step 3 of the preparation process of the MA@N group material is composed of a zwitterionic monomer, 3-acrylamidophenylboric acid, a small molecule cross-linking agent and nanogel. The hydrogel pre-solution in the step 3 of the preparation process of the MA@E group material is composed of a zwitterionic monomer, 3-acrylamidophenylboric acid, a small molecule cross-linking agent and polyphenol. The hydrogel pre-solution in the preparation process step 3 of the MA@EN group material is composed of a zwitterionic monomer, 3-acrylamidophenylboric acid, a small molecule cross-linking agent, nanogel and polyphenol.
Detailed Description
The objects and effects of the present invention will become more apparent from the following detailed description of the preferred embodiments and the accompanying drawings, it being understood that the specific embodiments described herein are merely illustrative of the invention and not limiting thereof.
The invention is inspired by the anticoagulation capability of the organism, a self-regulating anticoagulation strategy combined with anti-inflammatory function is constructed, and the coating can replace the anticoagulation function of partial endothelial cells at the early stage of implantation. The anticoagulant component of the coating can rapidly release anticoagulant drugs to block the coagulation cascade under the triggering of environmental thrombin, and the anticoagulant drugs are maintained in an environment without coagulation risk. In addition, the anti-inflammatory polyphenol with the function of free radical removal can fall off under the stimulation of high active oxygen and fully play a role on the surface of the material, thereby realizing multi-way joint regulation and control of inflammatory microenvironment. The invention has the important roles of identifying risk and reducing risk under the double-tube condition, the anticoagulation and anti-inflammatory function modules jointly play, the coagulation and inflammatory reaction are prevented from obstructing the cardiovascular implantation interventional instrument to play an effective function, and a mild environment is provided for the re-endothelialization of the surface of the cardiovascular implantation interventional instrument.
In the following embodiments, the step a and the step B are not sequential, and may be performed simultaneously.
Example 1
A microenvironment self-responsive anticoagulant anti-inflammatory self-growth coating for a vascular stent comprising the steps of:
5mg of apixaban and 10mg of oxidized dextran are dissolved in 1ml of dimethyl sulfoxide, and a thrombin-sensitive polypeptide alanine-arginine-serine-tryptophan-glycine solution with the same volume is slowly dripped into a reaction system at room temperature, and after 12 hours, the solution is dialyzed by deionized water to obtain nanogel;
b, placing the vascular stent in 2ml of alkaline aqueous solution mixed with 2mg/ml of dopamine methacrylamide and 2mg/ml of azo diisobutylamidine hydrochloride in a volume ratio of 1:1, reacting for 24 hours at room temperature, taking out the vascular stent, and cleaning for 3-5 times;
immersing the vascular stent obtained in the step B in a mixed solution of ethanol and water, wherein the volume ratio of the ethanol to the water in the mixed solution is 1:5.6, the concentration of the 2-methacryloxyethyl phosphorylcholine is 168mg/ml, and the mole ratio of the 2-methacryloxyethyl phosphorylcholine, the 3-acrylamidophenylboronic acid, the N, N' -methylenebisacrylamide and the EGCG is as follows: 590:250:21:80. And then taking out the vascular stent, and irradiating with ultraviolet light for 50 minutes to obtain the vascular stent with the microenvironment self-response anticoagulation anti-inflammatory self-growth coating.
Thereafter, the elemental composition of the modified coating was analyzed by X-ray photoelectron spectroscopy, and as can be seen from the results of FIG. 1, representative elements such as boron and phosphorus were detected in the coating. The material was incubated with rabbit platelet rich plasma for 1 hour and the surface of the material was observed with a scanning electron microscope as shown in fig. 2, and the results showed that the material modified with the microenvironment self-responsive anticoagulant anti-inflammatory self-growth coating for vascular stents had optimal anti-platelet adhesion and activation ability. The mononuclear cells are inoculated on the surface of the material, and the phorbol ester of 160nM is added into the culture solution to induce the mononuclear cells into macrophages, and after 48 hours, the cell morphology is observed by a confocal microscope, and the result is shown in figure 3, and the microenvironment self-response anticoagulation anti-inflammatory self-growth coating for the vascular stent can effectively inhibit the activation of the macrophages on the surface of the material. Human umbilical vein endothelial cells are inoculated on the surface of the material, and after 24 hours and 72 hours respectively, the proliferation condition of the cells is observed by a confocal microscope, and the result is shown in figure 4, and the microenvironment self-response anticoagulation anti-inflammatory self-growth coating for the vascular stent can promote the adhesion and proliferation of the endothelial cells and is friendly to the growth of the endothelial cells.
Example 2
A microenvironment self-responsive anticoagulant anti-inflammatory self-growth coating for a vascular stent comprising the steps of:
step A: 1mg of rivaroxaban and 5mg of oxidized sodium alginate are dissolved in 2ml of dimethyl sulfoxide, and a solution of 5mg of thrombin-sensitive polypeptide lysine-valine-proline-arginine-glycine is slowly dripped into the reaction system at room temperature. After 12 hours, dialyzing with deionized water to obtain nanogel;
and (B) step (B): placing the vascular stent into 3ml of alkaline aqueous solution mixed with 0.1mg/ml dopamine methacrylamide and 0.1mg/ml azo diisobutylamidine hydrochloride in a volume ratio of 1:1, reacting for 24 hours at room temperature, taking out the vascular stent, and cleaning for 3-5 times;
immersing the vascular stent obtained in the step B in a mixed solution of ethanol and water containing sulfobetaine methacrylate, 3-acrylamidophenylboronic acid, N '-methylenebisacrylamide, the nanogel obtained in the step A and EGCG, wherein the volume ratio of ethanol to water in the mixed solution of ethanol and water is 1:3, the concentration of the sulfobetaine methacrylate is 100mg/ml, and the molar ratio of the sulfobetaine methacrylate, 3-acrylamidophenylboronic acid, N' -methylenebisacrylamide to dopamine is as follows: 590:250:21:80. And irradiating with ultraviolet light for 60 min to obtain the vascular stent with the microenvironment self-response anticoagulant anti-inflammatory self-growth coating.
Example 3
A microenvironment self-responsive anticoagulant anti-inflammatory self-growth coating for a vascular stent comprising the steps of:
a3 mg of dabigatran and 8mg of oxidized glucomannan are dissolved in 5ml of dimethyl sulfoxide, and a solution of 8mg of thrombin-sensitive polypeptide leucine-tyrosine-proline-arginine-glycine-serine is slowly dripped into a reaction system at room temperature. After 12 hours, dialyzing with deionized water to obtain nanogel;
b, placing the vascular stent in 5ml of alkaline aqueous solution mixed with 5mg/ml dopamine methacrylamide and 5mg/ml azo diisobutylamidine hydrochloride in a volume ratio of 1:1, reacting for 24 hours at room temperature, taking out the vascular stent, and cleaning for 3-5 times;
c, placing the vascular stent obtained in the step B into a mixed solution of ethanol and water, wherein the volume ratio of the ethanol to the water in the mixed solution is 1:6, the concentration of the 2-methacryloxyethyl phosphorylcholine is 300mg/ml, and the mole ratio of the 2-methacryloxyethyl phosphorylcholine, the 3-acrylamidophenylboronic acid, the N, N' -methylenebisacrylamide and the EGCG is as follows: 590:250:21:80. And then taking out the vascular stent, and irradiating with ultraviolet light for 20 minutes to obtain the vascular stent with the microenvironment self-response anticoagulation anti-inflammatory self-growth coating.
Example 4
A microenvironment self-responsive anticoagulant anti-inflammatory self-growth coating for a vascular stent comprising the steps of:
a5 mg of apixaban and 10mg of oxidized hyaluronic acid are dissolved in 10ml of dimethyl sulfoxide, and a solution of the thrombin-sensitive polypeptide leucine-tyrosine-proline-arginine-glycine-serine dissolved in 10mg of the same volume is slowly dripped into a reaction system at room temperature. After 12 hours, dialyzing with deionized water to obtain nanogel;
b, placing the vascular stent in 5ml of alkaline aqueous solution mixed with 10mg/ml dopamine methacrylamide and 10mg/ml azo diisobutylamidine hydrochloride in a volume ratio of 1:1, reacting for 24 hours at room temperature, taking out the material and cleaning for 3-5 times;
c, placing the vascular stent obtained in the step B into a mixed solution of ethanol and water, wherein the volume of the mixed solution contains 3- [ [2- (methacryloyloxy) ethyl ] dimethyl ammonium ] propionate, 3-acrylamidophenylboronic acid, N '-vinyl bisacrylamide, nanogel obtained in the step A and tannic acid, the volume ratio of the ethanol to the water is 1:5, the concentration of the 2-methacryloyloxyethyl phosphorylcholine is 200mg/ml, and the mole ratio of the 2-methacryloyloxyethyl phosphorylcholine, the 3-acrylamidophenylboronic acid, the N, N' -vinyl bisacrylamide and the tannic acid is as follows: 590:250:21:80. And then taking out the vascular stent, and irradiating with ultraviolet light for 120 minutes to obtain the vascular stent with the microenvironment self-response anticoagulation anti-inflammatory self-growth coating.
Example 5
3mg bivalirudin and 8mg of oxidized bletilla striata polysaccharide are dissolved in 5ml of dimethyl sulfoxide, and at room temperature, the same volume of solution of 8mg of thrombin-sensitive polypeptide glycine-phenylalanine-proline-arginine-glycine-phenylalanine-proline-alanine-glycine is slowly dripped into a reaction system. After 12 hours, dialyzing with deionized water to obtain nanogel;
b, placing the vascular stent in 5ml of alkaline aqueous solution mixed with 5mg/ml dopamine methacrylamide and 5mg/ml azo diisobutylamidine hydrochloride in a volume ratio of 1:1, reacting for 24 hours at room temperature, taking out the vascular stent, and cleaning for 3-5 times;
c, placing the vascular stent obtained in the step B into a mixed solution of ethanol and water, wherein the volume ratio of the ethanol to the water in the mixed solution is 1:5, the concentration of the 2-methacryloxyethyl phosphorylcholine is 280mg/ml, and the mole ratio of the 2-methacryloxyethyl phosphorylcholine, the 3-acrylamidophenylboronic acid, the N, N' -methylenebisacrylamide and the EGC is as follows: 590:250:21:80. And then taking out the vascular stent, and irradiating with ultraviolet light for 20 minutes to obtain the vascular stent with the microenvironment self-response anticoagulation anti-inflammatory self-growth coating.
Example 6
A5 mg clopidogrel and 8mg fucoidin are dissolved in 5ml dimethyl sulfoxide, and at room temperature, the same volume of a solution of 8mg thrombin-sensitive polypeptide glycine-phenylalanine-proline-arginine-glycine-phenylalanine-proline-alanine-glycine is slowly dripped into a reaction system. After 12 hours, dialyzing with deionized water to obtain nanogel;
b, placing the vascular stent in 5ml of alkaline aqueous solution mixed with 5mg/ml dopamine methacrylamide and 5mg/ml azo diisobutylamidine hydrochloride in a volume ratio of 1:1, reacting for 24 hours at room temperature, taking out the vascular stent, and cleaning for 3-5 times;
c, placing the vascular stent obtained in the step B into a mixed solution containing 2-methacryloxyethyl phosphorylcholine, 3-acrylamidophenylboronic acid, N '-methylenebisacrylamide, the nanogel obtained in the step A and EC with the volume of 5ml of ethanol and water, wherein the volume ratio of the ethanol to the water in the mixed solution of the ethanol and the water is 1:5, the concentration of the 2-methacryloxyethyl phosphorylcholine is 200mg/ml, and the mole ratio of the 2-methacryloxyethyl phosphorylcholine, the 3-acrylamidophenylboronic acid, the N, N' -methylenebisacrylamide and the EC is as follows: 590:250:21:80. And then taking out the vascular stent, and irradiating with ultraviolet light for 20 minutes to obtain the vascular stent with the microenvironment self-response anticoagulation anti-inflammatory self-growth coating.
Example 7
5mg of ticagrelor and 10mg of oxidized dextran were dissolved in 5ml of dimethyl sulfoxide, and at room temperature, the same volume of a solution of 10mg of thrombin-sensitive polypeptide glycine-phenylalanine-proline-arginine-glycine-phenylalanine-proline-alanine-glycine was slowly dropped into the reaction system. After 12 hours, dialyzing with deionized water to obtain nanogel;
b, placing the vascular stent in 5ml of alkaline aqueous solution mixed with 3mg/ml dopamine methacrylamide and 3mg/ml azo diisobutylamidine hydrochloride in a volume ratio of 1:1, reacting for 24 hours at room temperature, and taking out the vascular stent for cleaning for 3-5 times;
c, placing the vascular stent obtained in the step B into a mixed solution of ethanol and water, wherein the volume ratio of the ethanol to the water in the mixed solution is 1:4, the concentration of the 2-methacryloxyethyl phosphorylcholine is 250mg/ml, and the molar ratio of the 2-methacryloxyethyl phosphorylcholine, the 3-acrylamidophenylboronic acid, the N, N' -methylenebisacrylamide and the ECG is as follows: 590:250:21:80. And then taking out the vascular stent, and irradiating with ultraviolet light for 20 minutes to obtain the vascular stent with the microenvironment self-response anticoagulation anti-inflammatory self-growth coating.
Example 8
A5 mg Argatroban and 10mg oxidized dextran were dissolved in 5ml dimethyl sulfoxide, and at room temperature, the same volume of a solution of 10mg thrombin-sensitive polypeptide glycine-phenylalanine-proline-arginine-glycine-phenylalanine-proline-alanine-glycine was slowly dropped into the reaction system. After 12 hours, dialyzing with deionized water to obtain nanogel;
b, placing the vascular stent in 5ml of alkaline aqueous solution mixed with 2mg/ml dopamine methacrylamide and 2mg/ml azo diisobutylamidine hydrochloride in a volume ratio of 1:1, reacting for 24 hours at room temperature, taking out the vascular stent, and cleaning for 3-5 times;
c, placing the vascular stent obtained in the step B into a mixed solution of ethanol and water, wherein the volume ratio of the ethanol to the water in the mixed solution is 1:4, the concentration of the 2-methacryloxyethyl phosphorylcholine is 250mg/ml, and the molar ratio of the 2-methacryloxyethyl phosphorylcholine, the 3-acrylamidophenylboronic acid, the N, N' -methylenebisacrylamide and the ECG is as follows: 590:250:21:80. And then taking out the vascular stent, and irradiating with ultraviolet light for 20 minutes to obtain the vascular stent with the microenvironment self-response anticoagulation anti-inflammatory self-growth coating.
It will be appreciated by persons skilled in the art that the foregoing description is a preferred embodiment of the invention, and is not intended to limit the invention, but rather to limit the invention to the specific embodiments described, and that modifications may be made to the technical solutions described in the foregoing embodiments, or equivalents may be substituted for elements thereof, for the purposes of those skilled in the art. Modifications, equivalents, and alternatives falling within the spirit and principles of the invention are intended to be included within the scope of the invention.
Claims (10)
1. A method for preparing a microenvironment self-response anticoagulation anti-inflammatory self-growth coating for a cardiovascular implantation interventional instrument, which is characterized by comprising the following steps:
step one: dissolving 1-5mg of anticoagulant drug and 5-10mg of oxidized polysaccharide in dimethyl sulfoxide, slowly dripping the same volume of polypeptide solution dissolved with 5-10mg of thrombin sensitivity into a reaction system at room temperature, and dialyzing with deionized water after full reaction to obtain nanogel;
step two: placing the cardiovascular implantation interventional instrument into an alkaline aqueous solution mixed with 0.1-10mg/ml dopamine methacrylamide and 0.1-10mg/ml azo diisobutylamidine hydrochloride in a volume ratio of 1:1, fully reacting at room temperature, taking out the cardiovascular implantation interventional instrument, and fully cleaning;
step three: immersing the cardiovascular implantation interventional instrument obtained in the step two in a mixed solution of ethanol and water containing zwitterionic monomers, 3-acrylamidophenylboronic acid, a small molecular cross-linking agent, the nanogel of the step one and polyphenol, wherein the concentration of the zwitterionic monomers is 100-300mg/ml, and the molar ratio of the zwitterionic monomers, the 3-acrylamidophenylboronic acid, the small molecular cross-linking agent and the polyphenol is 590:250:21:80; and then taking out the cardiovascular implant interventional instrument, and obtaining the cardiovascular implant interventional instrument with the microenvironment self-response anticoagulation anti-inflammatory self-growth coating after full ultraviolet irradiation.
2. The method for preparing the micro-environment self-response anticoagulation anti-inflammatory self-growth coating for the cardiovascular interventional instrument according to claim 1, wherein the anticoagulation medicine is selected from any one or a mixture of a plurality of rivaroxaban, apixaban, dabigatran, bivalirudin, clopidogrel, ticagrelor and argatroban according to any proportion.
3. The method for preparing the micro-environment self-response anticoagulation anti-inflammatory self-growth coating for the cardiovascular implant interventional instrument according to claim 1, wherein the oxidized polysaccharide is selected from any one or a mixture of a plurality of oxidized sodium alginate, oxidized glucomannan, oxidized bletilla striata polysaccharide, oxidized fucoidan, oxidized dextran and oxidized hyaluronic acid according to any proportion.
4. The method for preparing a microenvironment self-responsive anticoagulant anti-inflammatory self-growth coating for a cardiovascular implant interventional device according to claim 1, wherein the amino acid sequence of the thrombin-sensitive polypeptide is selected from any one or more of lysine-valine-proline-arginine-glycine, alanine-arginine-serine-tryptophan-glycine, leucine-tyrosine-proline-arginine-glycine-serine, glycine-phenylalanine-proline-arginine-glycine-phenylalanine-proline-alanine-glycine in any ratio.
5. The method for preparing the micro-environment self-response anticoagulation anti-inflammatory self-growth coating for the cardiovascular interventional instrument according to claim 1, wherein the zwitterionic monomer is selected from one or more of 2-methacryloxyethyl phosphorylcholine, 3- [ [2- (methacryloxy) ethyl ] dimethyl ammonium ] propionate and sulfobetaine methacrylate according to any proportion.
6. The method for preparing the micro-environment self-responsive anticoagulant anti-inflammatory self-growth coating for the cardiovascular interventional instrument according to claim 1, wherein the polyphenol is selected from any one or more of dopamine, tannic acid, epigallocatechin gallate (EGCG), epicatechin gallate (ECG), epicatechin (EC), epigallocatechin (EGC), catechol and pyrogallol according to any proportion.
7. The method for preparing the micro-environment self-response anticoagulant anti-inflammatory self-growth coating for the cardiovascular interventional instrument according to claim 1, wherein the small molecule cross-linking agent is selected from one or two of N, N '-methylenebisacrylamide and N, N' -vinyl bisacrylamide according to any proportion.
8. The method for preparing the micro-environmental self-responsive anticoagulant anti-inflammatory self-growth coating for the cardiovascular interventional instrument according to claim 1, wherein in the step two, the volume ratio of ethanol to water in the mixed solution of ethanol and water is 1:3-6.
9. The method for preparing the micro-environment self-response anticoagulation anti-inflammatory self-growth coating for the cardiovascular interventional instrument according to claim 1, wherein,
the volume of dimethyl sulfoxide is 1-5ml, and the reaction time of thrombin-sensitive polypeptide solution is not less than 12 hours;
in the second step, the volume of the alkaline aqueous solution is 2-5ml, the reaction time is 24 hours, and the cleaning times after taking out the cardiovascular implantation interventional instrument are 3-5 times;
in the third step, the volume of the mixed solution of ethanol and water is 2-5ml; the ultraviolet irradiation time is 20-120 minutes.
10. A cardiovascular implant interventional instrument with a microenvironment self-responsive anticoagulant anti-inflammatory self-growth coating prepared by the method of any one of claims 1-9.
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