PC polymer, anticoagulant coating, interventional medical device and preparation method of interventional medical device

Abstract

The invention is applicable to the technical field of medical instruments, and provides a PC polymer, an anti-coagulation coating, an interventional medical instrument and a preparation method thereof.The PC polymer comprises the following raw materials: an acrylate derivative containing a phosphorylcholine (PC) functional group, a compound containing sulfydryl and methoxysilane, an anti-coagulation coating, an interventional medical instrument and a preparation method of the anti-coagulation coating, the preparation method of the interventional medical device comprises the following steps: 1) preparing the PC polymer; 2) preparing a coating solution; 3) surface pretreatment; 4) preparing a coating; (5) post-processing and cleaning; a novel PC polymer is synthesized and is used for an anti-coagulation coating of an interventional medical device, the chemical structure of the PC polymer only contains a PC repetitive unit and a methoxy silane end group, the PC polymer is coated without a prime coat liquid, the PC polymer is grafted on the surface of the medical device through chemical bonds, the connection is firmer, the thickness of the coating is in a nanometer level, and the anti-coagulation coating has a good anti-coagulation effect. The influence of the coating on the original performance of the medical instrument is reduced to the greatest extent while the anticoagulation effect of the medical instrument is improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of medical devices, and in particular relates to a PC polymer, an anticoagulant coating, an interventional medical device and a preparation method thereof. Background Art

[0002] In clinical practice, the blood-contact surfaces of blood-contact implantable and interventional medical devices are very likely to trigger multiple coagulation mechanisms such as coagulation factor activation, platelet adhesion and aggregation, red blood cell adhesion and complement activation, causing complications such as coagulation and thrombosis. Therefore, the existing technology adopts the method of coating the surface of medical devices with anticoagulant coatings to reduce the risk of complications such as coagulation and thrombosis caused by implanted devices in the human body.

[0003] At present, the anticoagulant coatings used for Class III implantable medical devices on the market mainly include phosphorylcholine (PC) coating, fibrin-heparin coating, polysaccharide polymer coating (HPC), methoxyethyl acrylate (PMEA) coating, and hydroxy-acrylamide (NTMA) coating. Among them, the PC coating imitates the cell membrane structure, has good biocompatibility, strong hydrophilicity, excellent anticoagulant effect, inert surface, and no drugs. The fibrin-heparin coating uses heparin, which is a drug-device combination product. It is difficult to register, and the coating is not as stable as PC in the body. According to literature reports, the anticoagulant effect of HPC is inferior to that of PC coating. The hydrophilicity of PMEA coating is lower than that of PC, and its anticoagulant effect and biocompatibility are not as good as PC. The NTMA coating is electrochemically grafted, the equipment cost is high, and the hydrophilicity is lower than that of PC, so the anticoagulant effect is poor, and the biocompatibility is not as good as PC. In summary, this application chooses to use PC as the substrate material.

[0004] Limited by the spraying process, most domestic coating suppliers and medical device companies can only make PC coatings at the micron level. Currently, only one company in the world has the ability to prepare nano-level PC coatings. However, it is necessary to first apply a layer of primer on the surface of the sample, and then graft the purchased PC polymer on the primer. There are two disadvantages to introducing the primer. 1. The active functional groups of the purchased PC polymer are on the side chains. Due to the steric hindrance effect of the polymer, some active functional groups do not react with the primer. These unreacted functional groups will affect the anticoagulant effect of the coating and the safety of the product. In addition, the hydrophilic PC molecular chain is stretched in water, and the primer with poor anticoagulant effect will be partially exposed on the surface of the device, thereby reducing the anticoagulant effect of the coating. 2. The use of primer will increase the total coating thickness, which may affect the performance of the product itself. In order to solve the above problems, the present invention independently develops a new type of PC polymer, and the new PC polymer is firmly grafted on the surface of the device through chemical bonds without the introduction of primer to obtain an anticoagulant coating. Summary of the invention

[0005] The present invention provides an anticoagulation coating, aiming to solve the above problems.

[0006] The present invention is achieved in this way: a PC polymer is used for anticoagulation coating of medical devices, comprising the following raw materials: an acrylate derivative containing a phosphorylcholine functional group, and a compound containing a mercapto group and methoxysilane. Preferably, the molar ratio of the acrylate derivative containing a phosphorylcholine functional group to the compound containing a mercapto group and methoxysilane is 10-50:1.

[0007] The present invention also provides a method for preparing the above PC polymer, comprising the following steps: 1.1) Dry all objects that come into contact with the material during the preparation process; 1.2) dissolving an acrylate derivative containing a phosphorylcholine functional group and a compound containing a mercapto group and a methoxysilane in an anhydrous solvent, wherein the molar ratio of the acrylate derivative to the compound containing a mercapto group and a methoxysilane is 10:1 to 50:1, and the ratio of the acrylate derivative to the anhydrous solvent is 2 to 10 ml per gram; 1.3) Stirring while passing inert gas for more than half an hour, then adding a photoinitiator, the amount of the photoinitiator is 0.1 mol% to 2 mol% of the acrylate derivative containing phosphorylcholine functional group, and continuing to pass inert gas for more than half an hour, the photoinitiator includes Benzophenone, Irgacure, Darocure, Esacure, Lucirin, etc.; 1.4) The reaction vessel is sealed and placed under ultraviolet light for reaction under stirring conditions, and a reaction solution is obtained after the reaction is completed; 1.5) Solvent A and solvent B are mixed to obtain a first mixed solvent, and the reaction solution is added dropwise to the first mixed solvent under stirring, and the product is precipitated into a white solid, wherein the solvent A includes but is not limited to dichloromethane, ethyl acetate, and chloroform, and the solvent B includes but is not limited to diethyl ether and n-hexane; 1.6) Transfer the precipitated turbid solution to a centrifuge tube and centrifuge at 2500-3500 rpm for 4-6 min. Pour the supernatant into a waste tank and discard it. Combine the solid obtained from centrifugation with the solid obtained in step 1.5). Repeat steps 1.5) and 1.6) twice; 1.7) Add a mixed solution of anhydrous dichloromethane and ether containing 30% to 100% by volume of anhydrous dichloromethane into a container containing the solid obtained in step 1.6), fill it with inert gas and seal it, stir it at room temperature for 1-18 hours, and after stirring, pour the supernatant into a waste liquid tank and discard it. Repeat this step twice to obtain PC polymer; 1.8) The PC polymer obtained in step 1.7) is subjected to vacuum desolventization at -20 to 60°C for 2 to 96 h, filled with inert gas, and then sealed and stored at -20°C to room temperature away from light.

[0008] In this way, the prepared PC polymer has a chemical structure containing only PC repeating units and methoxysilane end groups, and the chemical structure is simpler, which minimizes the introduction of chemical structures other than functional groups. On the one hand, it avoids the introduction of other chemical structures affecting the anticoagulant effect, and on the other hand, it avoids other chemical structures occupying the effective functional groups on the medical device during subsequent grafting with the surface of the medical device, resulting in a reduction in the number of PC polymers chemically grafted to the surface of the medical device, and the exposure of the device surface during use affects the anticoagulant effect. In addition, the method of first preparing the PC polymer for grafting with the surface of the medical device, compared with the method of directly synthesizing the anticoagulant coating on the medical device, can control the molecular weight of the prepared PC polymer, so that the PC molecular weight of the anticoagulant coating formed on the medical device can be controlled, ensuring the stability of the preparation process of the anticoagulant coating of the medical device and the stability of the anticoagulant effect.

[0009] Preferably, solvent A and solvent B are selected as poor solvents relative to the above-mentioned PC polymer, the ratio of the anhydrous solvent to the first mixed solvent is 1:8 to 1:12; solvent A and solvent B are mixed in a volume ratio of 0:1 to 1:1 to obtain the first mixed solvent, the ultraviolet light wavelength is selected to be 365nm, and the inert gas is selected to be argon.

[0010] Preferably, the intensity of ultraviolet light increases with the volume of the reaction solution, the intensity of the ultraviolet lamp is 300-400 mW / cm2, and the irradiation is performed for 1-18 h under stirring.

[0011] Specifically, the compound containing mercapto and methoxysilane is selected from the following structures: Where n = 1 to 20; or Where n=1~20, m=1~5.

[0012] Preferably, the chemical structure of the PC polymer is: where x = 1-20; or Where x=1-20, y=1-5.

[0013] The present invention also provides an anticoagulation coating for medical devices, which is directly connected to the surface of the medical device through chemical bond grafting. The raw material of the anticoagulation coating includes the above PC polymer or the PC polymer obtained by the preparation method of the above PC polymer.

[0014] The present invention also provides an interventional medical device with an anticoagulant coating, comprising a medical device and an anticoagulant coating on the surface of the medical device, wherein the anticoagulant coating is directly connected to the surface of the medical device by chemical bond grafting, and the raw material of the anticoagulant coating comprises the above-mentioned PC polymer or a PC polymer obtained by the preparation method of the above-mentioned PC polymer.

[0015] Specifically, the interventional medical device is a blood flow guiding dense mesh stent, and the surface of the blood flow guiding dense mesh stent is directly connected to the anticoagulant coating through chemical bond grafting.

[0016] The present invention also provides a method for preparing an interventional medical device having an anticoagulant coating, comprising the following steps: 1) Preparation of the above PC polymer 2) preparing coating solution; 3) Surface pretreatment; 4) Coating preparation; 5) Post-processing and cleaning.

[0017] Preferably, the preparation of the coating solution comprises the following steps: 2.1) Solvent C and solvent D are mixed in a volume ratio of 3:1 to 1:1 to obtain a second mixed solvent, wherein the solvent C includes but is not limited to trifluoroethanol, acetone, tetrahydrofuran, DMSO, and DMF, and the solvent D includes but is not limited to toluene, ethyl acetate, diethyl ether, and n-hexane; 2.2) dissolving the PC polymer product prepared in step 1) in a second mixed solvent at a ratio of 4-6 wt%, and adding a corresponding amount of triethylamine at a ratio of 0.5-1.5 μL triethylamine per mg of PC polymer product; 2.3) After mixing, filter the solution through a filter, fill it with inert gas and package it for later use.

[0018] Preferably, solvent C includes one or more of trifluoroethanol, acetone, tetrahydrofuran, DMSO, and DMF, solvent D includes one or more of toluene, ethyl acetate, ether, and n-hexane, the filter is a PTFE needle filter with a pore size of 0.45 μm, and the inert gas is argon.

[0019] Preferably, the surface pretreatment comprises the following steps: 3.1) Completely immerse the medical device to be coated in the solvent and ultrasonicate for 5-60 min; 3.2) After cleaning, place the medical device on dust-free paper to dry for later use; 3.3) Select appropriate methods to carry out hydroxylation treatment on the surface of medical devices made of different materials.

[0020] Preferably, the coating preparation comprises the following steps: 4.1) The surface pretreated device is completely immersed in the coating solution, filled with argon gas and sealed; 4.2) Place on a shaker at 35-40°C and shake at 50-300 rpm for 2-18 h; In this way, the PC polymer is directly grafted on the surface of the medical device through chemical bonds by surface grafting, and an anticoagulant coating with good coating firmness and nanometer thickness can be formed without introducing a primer (for example, an anticoagulant coating of 1nm, 3nm, 5nm, 10nm, 15nm, 20nm, 25nm, 30nm, 35nm, 40nm, 45nm, and 50nm) to improve the anticoagulant effect of the medical device and ensure the coating firmness while minimizing the impact of the coating on the original performance of the device; at the same time, no primer is required, which reduces production costs, improves production efficiency, and avoids the safety risks caused by the use of primer. The coating thickness of traditional spraying is at the micron level, which will affect the function of some medical devices themselves (such as affecting the push of the blood flow guide device in the sheath and microcatheter), and the use of primer will also increase the total outer diameter of the device. The coating thickness prepared by directly using PC polymer on medical devices through chemical grafting can reach the nanometer level (nanometer-level thickness of 1-50nm), which does not affect the original function of the medical device. In addition, the anticoagulant coating is directly connected to the surface of the medical device through chemical bonds, making the anticoagulant coating more solid; PC polymers have few chemical structures other than functional groups, so more PC polymers can be chemically grafted on the surface of the medical device, and the anticoagulant effect is better.

[0021] Preferably, the post-processing and cleaning comprises the following steps: 5.1) After the reaction is completed, remove the medical device from the coating solution and extract it in a polar solvent for at least 3 times; 5.2) Then place the medical device in an oven and anneal at 45℃~100℃ for 30-90 min; 5.3) After annealing, completely immerse the medical device in a polar solvent and ultrasonicate for 5-15 min. Change the solvent and ultrasonicate 2-3 times. The polar solvent includes, but is not limited to, methanol, ethanol, isopropanol, acetone, tetrahydrofuran, and purified water.

[0022] Preferably, the intensity of the UV light increases with the volume of the reaction solution, and the intensity of the UV light is 300-400 mW / cm 2 , irradiate for 1-18 h with stirring.

[0023] Preferably, before selecting a suitable method to perform hydroxylation treatment on the surface of medical devices of different materials, the surface elements of the PC polymer prepared in step 1) are detected, and a hydroxylation treatment method is selected according to the elements of the PC polymer. The selection of a suitable method to perform hydroxylation treatment on the surface of medical devices of different materials includes selecting one or more of the following methods: Piranha solution method: To prepare piranha solution, you need to wear protective equipment and operate in a fume hood; slowly add 30% hydrogen peroxide to concentrated sulfuric acid in a volume ratio of 7:3; completely immerse the cleaned medical device in the piranha solution for 1-30 minutes until no bubbles are generated on the surface of the material; then remove the medical device with tweezers, rinse it with purified water 3-6 times, and blow dry it with inert gas; UVO method: After cleaning the medical device, place it in a preheated UVO reactor and take it out after reacting for 10-60 minutes; Plasma method: The medical device is suspended in a plasma treatment reactor. After the reactor is evacuated to -12 Pa, oxygen or NH3 is added to an appropriate positive pressure of 50-65 Pa. The oxygen or NH3 pressure is maintained and the plasma surface activation treatment is performed for 10-30 minutes to graft the corresponding hydroxyl or amino group onto the surface of the medical device to make it a base for the activated coating. Compared with the prior art, the embodiments of the present application have the following beneficial effects: The anticoagulation coating provided by the present invention is prepared by synthesizing a new PC polymer, the chemical structure of which only contains PC repeating units and methoxysilane end groups. Compared with the currently existing PC polymer (PC as a functional grafting segment), the chemical structure of this new polymer is purer, and the firmness of the anticoagulation coating is guaranteed without the need for a primer, and the chemical structure other than the functional functional groups is reduced to the maximum extent, avoiding the influence of other chemical structures on the anticoagulation effect, thereby ensuring the anticoagulation effect and firmness of the coating, reducing production costs, improving production efficiency, and avoiding the safety risks brought by the use of a primer.

[0024] The new PC polymer is grafted onto the surface of medical devices (such as blood flow guiding dense mesh stents) through chemical bonds. Compared with the traditional spray coating with a thickness of micron level, which will affect the functions of some devices themselves, the coating prepared by chemical grafting method can reach a thickness of nanometer level, which does not affect the original function of the medical device. The coating is connected to the surface of the device through chemical bonds, and the coating is more firm. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 It is a preparation flow chart of an interventional medical device with an anticoagulant coating provided by the present invention; Figure 2 This is a PC polymer preparation reaction diagram provided by the present invention; Figure 3 This is a PC polymer nuclear magnetic spectrum provided by the present invention; Figure 4 This is a reaction diagram for preparing the anticoagulation coating provided by the present invention; Figure 5 It is a schematic diagram of the structure of the reaction container provided by the present invention; Figure 6 This is a diagram of an in vitro anticoagulation test experiment of the anticoagulation coating provided by the present invention; Figure 7 It is a structural schematic diagram of a blood flow guiding dense mesh stent with an anticoagulant coating provided by the present invention; Notes on the accompanying drawings: 1. fan; 2. Schlenk flask; 3. UV lamp; 4. reaction solution; 5. magnetic stirrer; 6. magnet. DETAILED DESCRIPTION

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by technicians in the technical field of this application; the terms used in the specification of the application herein are only for the purpose of describing specific embodiments and are not intended to limit this application; the terms "including" and "having" and any variations thereof in the specification and claims of this application and the above-mentioned drawings are intended to cover non-exclusive inclusions. The terms "first", "second", etc. in the specification and claims of this application or the above-mentioned drawings are used to distinguish different objects, not to describe a specific order.

[0027] Reference to "embodiments" herein means that a particular feature, structure, or characteristic described in conjunction with the embodiments may be included in at least one embodiment of the present application. The appearance of the phrase in various locations in the specification does not necessarily refer to the same embodiment, nor is it an independent or alternative embodiment that is mutually exclusive with other embodiments. It is explicitly and implicitly understood by those skilled in the art that the embodiments described herein may be combined with other embodiments.

[0028] Example 1 The embodiment of the present invention provides a PC polymer (i.e., phosphorylcholine polymer), comprising the following raw materials: an acrylate derivative containing a phosphorylcholine functional group, and a compound containing a mercapto group and a methoxysilane. In this embodiment, the acrylate derivative containing a phosphorylcholine functional group is selected from 2-methacryloyloxyethyl phosphorylcholine, and the compound containing a mercapto group and a methoxysilane is selected from the following structure: Where n=1~20, in this embodiment, the structure n=3 is selected; In this embodiment, the preparation method of the PC polymer comprises the following steps: 1.1) Dry all objects that come into contact with the material during the preparation process; 1.2) Dissolve 5.4 mmol of an acrylate derivative containing a phosphorylcholine functional group and 0.27 mmol of a compound containing a mercapto group and a methoxysilane in 6.4 mL of anhydrous solvent; 1.3) Add argon gas for more than half an hour while stirring, then add 8 mg of photoinitiator, and continue to add argon gas for more than half an hour. The photoinitiator includes Benzophenone, Irgacure, Darocure, Esacure, Lucirin, etc.; 1.4) The reaction vessel was sealed and placed under 365 nm ultraviolet light under stirring conditions to obtain a reaction solution after the reaction was completed; the intensity of the ultraviolet light increased with the increase of the volume of the reaction solution, and the intensity of the ultraviolet light was 300 mW / cm 2 , irradiated for 1 h under stirring; 1.5) 32 mL of solvent A and 32 mL of solvent B are mixed to obtain a first mixed solvent, and the reaction solution is then added dropwise to the first mixed solvent under stirring, and the product is precipitated into a white solid, wherein the solvent A includes but is not limited to dichloromethane, ethyl acetate, and chloroform, and the solvent B includes but is not limited to diethyl ether and n-hexane; 1.6) Transfer the precipitated turbid solution to a centrifuge tube and centrifuge at 2500 rpm for 4 min. Pour the supernatant into a waste tank and discard it. Combine the solid obtained from centrifugation with the solid obtained in step 1.5). Repeat steps 1.5) and 1.6) twice; 1.7) Add a mixed solution of anhydrous dichloromethane and ether containing 30% to 100% by volume of anhydrous dichloromethane into a container containing the solid obtained in step 1.6), fill it with argon gas and seal it, stir it at room temperature for 1-18 h, and after stirring, pour the supernatant into a waste liquid tank and discard it. Repeat this step twice to obtain PC polymer; 1.8) The product is vacuum-dried for 2 h at -20°C to remove the solvent, filled with argon, and stored in a sealed container away from light at -20°C to room temperature for future use.

[0029] Specifically, the chemical reaction formula for preparing PC polymer is as follows: Figure 2 As shown, the NMR spectrum of the prepared new PC polymer is as follows Figure 3 shown.

[0030] In this way, the chemical structure of the prepared PC polymer only contains PC repeating units and methoxysilane end groups, and the chemical structure is simpler, which minimizes the introduction of chemical structures other than functional groups. On the one hand, it avoids the introduction of other chemical structures affecting the anticoagulant effect, and on the other hand, it avoids other chemical structures occupying the effective functional groups on the medical device during subsequent grafting with the surface of the medical device, resulting in a reduction in the number of PC polymers chemically grafted to the surface of the medical device, and the exposure of the device surface during use affects the anticoagulant effect. In addition, the method of first preparing the PC polymer for grafting with the surface of the medical device, compared with the method of directly synthesizing the anticoagulant coating on the medical device, can control the molecular weight of the prepared PC polymer, so that the PC molecular weight of the anticoagulant coating formed on the medical device can be controlled, ensuring the stability of the preparation process of the anticoagulant coating of the medical device and the stability of the anticoagulant effect.

[0031] Specifically, Figure 5 As shown, a magnetic stirrer 5 is provided at the bottom of the inner cavity of the reaction container, and a Schlenk bottle 2 is provided above the magnetic stirrer 5 for containing raw materials to obtain a reaction solution 4. A magnet 6 cooperating with the magnetic stirrer 5 is provided in the Schlenk bottle 2, a fan 1 is installed at the top of the inner cavity of the reaction container, and ultraviolet lamps 3 are installed on both side walls of the reaction container.

[0032] Specifically, argon is selected in this embodiment, which has a lower water content than other inert gases and is more conducive to the synthesis of the PC polymer.

[0033] Preferably, the chemical structure of PC polymer is: wherein x=1-20, preferably, x=3; or Where x=1-20, y=1-5.

[0034] An embodiment of the present invention provides an anticoagulation coating for medical devices, which is directly connected to the surface of the medical device through chemical bond grafting. The raw material of the anticoagulation coating includes the above-mentioned PC polymer or the PC polymer obtained by the preparation method of the above-mentioned PC polymer.

[0035] An embodiment of the present invention provides an interventional medical device with an anticoagulant coating, including a medical device and an anticoagulant coating on the surface of the medical device, wherein the anticoagulant coating is directly connected to the surface of the medical device by chemical bond grafting, and the raw material of the anticoagulant coating includes the above-mentioned PC polymer or the anticoagulant coating is obtained by the preparation method of the above-mentioned PC polymer.

[0036] In this embodiment, the interventional medical device is selected as a blood flow guiding dense mesh stent (such as Figure 7As shown in FIG. 1 , the surface of the blood flow-directing dense mesh stent is directly connected to the anticoagulant coating via chemical bond grafting.

[0037] The present invention provides a method for preparing an interventional medical device with an anticoagulant coating, such as Figure 1 As shown, the following steps are included: 1) Preparation of PC polymer; 2) preparing coating solution; 3) Surface pretreatment; 4) Coating preparation; 5) Post-processing and cleaning.

[0038] Wherein, step 2) preparing the coating solution comprises the following steps: 2.1) mixing solvent C and solvent D in a volume ratio of 3:1 to obtain a second mixed solvent; 2.2) Dissolve the PC polymer product prepared in step 1) in a second mixed solvent at a ratio of 4 wt%, and add a corresponding amount of triethylamine at a ratio of 0.5 μL triethylamine per mg of PC polymer product; 2.3) After mixing, filter the solution using a 0.45 μm pore size PTFE syringe filter, fill it with argon gas and package it for later use.

[0039] Step 3) Surface pretreatment includes the following steps: 3.1) Completely immerse the medical device to be coated in the solvent and ultrasonicate for 5 min; 3.2) After cleaning, place the medical device on dust-free paper to dry for later use; 3.3) Select appropriate methods to perform hydroxylation treatment on the surface of medical devices made of different materials; The hydroxylation treatment method specifically includes one or more of the following methods. You can first select different methods. After the coating is prepared, detect the surface elements and select the method that detects the most coating elements: Piranha solution method: To prepare piranha solution, you need to wear protective equipment and operate in a fume hood; slowly add 30% hydrogen peroxide to concentrated sulfuric acid at a volume ratio of 7:3; completely immerse the cleaned medical device in the piranha solution for 1 min until no bubbles are generated on the surface of the material; then remove the medical device with tweezers, rinse it with purified water 3 times, and blow dry it with inert gas; UVO method: After cleaning the medical device, place it in a preheated UVO reactor and take it out after reacting for 10 minutes; Plasma method: The medical device is suspended in a plasma treatment reactor. After the reactor is evacuated to -12 Pa, oxygen or NH3 is added to an appropriate positive pressure of 50 Pa. The oxygen or NH3 pressure is maintained and the plasma surface activation treatment is performed for 10 minutes to graft the corresponding hydroxyl or amino group onto the surface of the medical device to make it an activated coating substrate.

[0040] Before selecting a suitable method to perform hydroxylation treatment on the surface of medical devices made of different materials, the surface elements of the PC polymer prepared in step 1) are detected, and a suitable hydroxylation treatment method is selected according to the elements of the PC polymer.

[0041] Step 4) The coating preparation includes the following steps: 4.1) The surface pretreated device is completely immersed in the coating solution, filled with argon gas and sealed; 4.2) Place on a shaker at 35 °C and shake at 50 rpm for 2 h; In this way, the PC polymer is directly grafted on the surface of the medical device through chemical bonds by surface grafting, and an anticoagulant coating with good coating firmness and nanometer thickness can be formed without introducing a primer (for example, an anticoagulant coating of 1nm, 3nm, 5nm, 10nm, 15nm, 20nm, 25nm, 30nm, 35nm, 40nm, 45nm, and 50nm) to improve the anticoagulant effect of the medical device and ensure the coating firmness while minimizing the impact of the coating on the original performance of the device; at the same time, no primer is required, which reduces production costs, improves production efficiency, and avoids the safety risks caused by the use of primer. The coating thickness of traditional spraying is at the micron level, which will affect the function of some medical devices themselves (such as affecting the push of the blood flow guide device in the sheath and microcatheter), and the use of primer will also increase the total outer diameter of the device. The coating thickness prepared by directly using PC polymer on medical devices through chemical grafting can reach the nanometer level (nanometer-level thickness of 1-50nm), which does not affect the original function of the medical device. In addition, the anticoagulant coating is directly connected to the surface of the medical device through chemical bonds, making the anticoagulant coating more solid. Taking nickel-titanium alloy medical devices as an example, the chemical process is as follows Figure 4 As shown, PC polymers have few chemical structures other than functional groups, so more PC polymers can be chemically grafted on the surface of medical devices, and the anticoagulant effect is better.

[0042] Step 5) Post-processing and cleaning includes the following steps; 5.1) After the reaction is completed, remove the medical device from the coating solution and immerse it in a polar solvent for 3 times; 5.2) Then place the medical device in an oven and anneal at 80 °C for 30 min; 5.3) After annealing, completely immerse the medical device in a polar solvent and ultrasonicate it for 5 min. Change the solvent and ultrasonicate it twice; The polar solvent includes, but is not limited to, methanol, ethanol, isopropanol, acetone, tetrahydrofuran, and purified water.

[0043] Example 2 The embodiment of the present invention provides a PC polymer, comprising the following raw materials: an acrylate derivative containing a phosphorylcholine functional group, and a compound containing a mercapto group and a methoxysilane. In this embodiment, the acrylate derivative containing a phosphorylcholine functional group is selected from 2-methacryloyloxyethyl phosphorylcholine, and the compound containing a mercapto group and a methoxysilane is selected from the following structure: Where n=1~20, in this embodiment, the structure n=3 is selected; In this embodiment, the preparation method of the PC polymer comprises the following steps: 1.1) Dry all objects that come into contact with the material during the preparation process; 1.2) Dissolve 128.5 mmol of an acrylate derivative containing a phosphorylcholine functional group and 6.8 mmol of a compound containing a mercapto group and a methoxysilane in 165 mL of anhydrous solvent; 1.3) Add argon gas for more than half an hour while stirring, then add 200 mg of photoinitiator, and continue to add argon gas for more than half an hour. The photoinitiator includes Benzophenone, Irgacure, Darocure, Esacure, Lucirin, etc.; 1.4) The reaction vessel was sealed and placed under 365 nm ultraviolet light under stirring conditions to obtain a reaction solution after the reaction was completed; the intensity of the ultraviolet light increased with the increase of the volume of the reaction solution, and the intensity of the ultraviolet light was 300 mW / cm 2 , irradiated for 1 h under stirring; 1.5) 800 mL of solvent A and 800 mL of solvent B are mixed to obtain a first mixed solvent, and the reaction solution is then added dropwise to the first mixed solvent under stirring, and the product is precipitated into a white solid, wherein the solvent A includes but is not limited to dichloromethane, ethyl acetate, and chloroform, and the solvent B includes but is not limited to diethyl ether and n-hexane; 1.6) Transfer the precipitated turbid solution to a centrifuge tube and centrifuge at 2500 rpm for 4 min. Pour the supernatant into a waste tank and discard it. Combine the solid obtained from centrifugation with the solid obtained in step 1.5). Repeat steps 1.5) and 1.6) twice; 1.7) Add a mixed solution of anhydrous dichloromethane and ether containing 30% to 100% by volume of anhydrous dichloromethane into a container containing the solid obtained in step 1.6), fill it with argon gas and seal it, stir it at room temperature for 1 h, and after stirring, pour the supernatant into a waste liquid tank and discard it. Repeat this step twice to obtain PC polymer; 1.8) Remove the solvent from the product under vacuum at 0℃ for 2 h, fill with argon and store in a sealed container away from light at -20℃ to room temperature for future use.

[0044] Specifically, the chemical reaction formula for preparing PC polymer is as follows: Figure 2 As shown, the NMR spectrum of the prepared new PC polymer is as follows Figure 3 shown.

[0045] Specifically, Figure 5 As shown, a magnetic stirrer 5 is provided at the bottom of the inner cavity of the reaction container, and a Schlenk bottle 2 is provided above the magnetic stirrer 5 for containing raw materials to obtain a reaction solution 4. A magnet 6 cooperating with the magnetic stirrer 5 is provided in the Schlenk bottle 2, a fan 1 is installed at the top of the inner cavity of the reaction container, and ultraviolet lamps 3 are installed on both side walls of the reaction container.

[0046] An embodiment of the present invention provides an anticoagulation coating for medical devices, which is directly connected to the surface of the medical device through chemical bond grafting. The raw material of the anticoagulation coating includes the above-mentioned PC polymer or the PC polymer obtained by the preparation method of the above-mentioned PC polymer.

[0047] An embodiment of the present invention provides an interventional medical device with an anticoagulant coating, including a medical device and an anticoagulant coating on the surface of the medical device, wherein the anticoagulant coating is directly connected to the surface of the medical device by chemical bond grafting, and the raw material of the anticoagulant coating includes the above-mentioned PC polymer or the anticoagulant coating is obtained by the preparation method of the above-mentioned PC polymer.

[0048] In this embodiment, the interventional medical device is selected as a blood flow guiding dense mesh stent (such as Figure 7 As shown in FIG. 1 , the surface of the blood flow-directing dense mesh stent is directly connected to the anticoagulant coating via chemical bond grafting.

[0049] The present invention provides a method for preparing an interventional medical device with an anticoagulant coating, such as Figure 1 As shown, the following steps are included: 1) Preparation of PC polymer; 2) preparing coating solution; 3) Surface pretreatment; 4) Coating preparation; 5) Post-processing and cleaning.

[0050] Wherein, step 2) preparing the coating solution comprises the following steps: 2.1) Solvent C and solvent D are mixed in a volume ratio of 3:1 to obtain a second mixed solvent, wherein the solvent C includes but is not limited to trifluoroethanol, acetone, tetrahydrofuran, DMSO, and DMF, and the solvent D includes but is not limited to toluene, ethyl acetate, diethyl ether, and n-hexane; 2.2) Dissolve the PC polymer product prepared in step 1) in a second mixed solvent at a ratio of 4 wt%, and add a corresponding amount of triethylamine at a ratio of 0.5 μL triethylamine per mg of PC polymer product; 2.3) After mixing, filter the solution using a 0.45 μm pore size PTFE syringe filter, fill it with argon gas and package it for later use.

[0051] Step 3) Surface pretreatment includes the following steps: 3.1) Completely immerse the medical device to be coated in the solvent and ultrasonicate for 5 min; 3.2) After cleaning, place the medical device on dust-free paper to dry for later use; 3.3) Select appropriate methods to perform hydroxylation treatment on the surface of medical devices made of different materials; The hydroxylation treatment method specifically includes one or more of the following methods. You can first select different methods. After the coating is prepared, detect the surface elements and select the method that detects the most coating elements: Piranha solution method: used for medical devices with metal surfaces. To prepare piranha solution, protective equipment must be worn in a fume hood. Slowly add 30% hydrogen peroxide to concentrated sulfuric acid at a volume ratio of 7:3. Immerse the cleaned medical device completely in the piranha solution for 1 min until no bubbles are generated on the surface of the material. Then, remove the medical device with tweezers, rinse it with purified water 3 times, and blow dry it with inert gas. UVO method: for products with metal or polymer surfaces. After cleaning the medical device, place it in a preheated UVO reactor and take it out after reacting for 10 minutes. Plasma method: used for medical devices with metal surfaces. The medical devices are suspended in a plasma treatment reactor. After the reactor is evacuated to -12 Pa, oxygen or NH3 is added to an appropriate positive pressure of 50 Pa. The oxygen or NH3 pressure is maintained and the plasma surface activation treatment is performed for 10 minutes to graft the corresponding hydroxyl or amino group onto the surface of the medical device to make it an activated coating substrate.

[0052] Step 4) The coating preparation includes the following steps: 4.1) The surface pretreated device is completely immersed in the coating solution, filled with argon gas and sealed; 4.2) Place on a shaker at 35 °C and shake at 50 rpm for 2 h; The PC polymer is grafted onto the surface of medical devices through chemical bonds by surface grafting. The coating thickness of traditional spraying is at the micron level, which will affect the functions of some medical devices themselves (such as blood flow guidance devices), while the coating thickness prepared by chemical grafting can reach the nanometer level, which does not affect the original functions of medical devices. In addition, the coating is connected to the surface of medical devices through chemical bonds, making the coating more solid. Taking nickel-titanium alloy medical devices as an example, the chemical process is as follows: Figure 4 shown.

[0053] Step 5) Post-processing and cleaning includes the following steps: 5.1) After the reaction is completed, remove the medical device from the coating solution and immerse it in a polar solvent for 3 times; 5.2) Then place the medical device in an oven and anneal at 80 °C for 30 min; 5.3) After annealing, immerse the medical device completely in a polar solvent and ultrasonicate it for 5 min. Change the solvent and ultrasonicate it twice. The polar solvent includes, but is not limited to, methanol, ethanol, isopropanol, acetone, tetrahydrofuran, and purified water.

[0054] Example 3 The embodiment of the present invention provides a PC polymer, comprising the following raw materials: an acrylate derivative containing a phosphorylcholine functional group, and a compound containing a mercapto group and a methoxysilane. In this embodiment, the acrylate derivative containing a phosphorylcholine functional group is selected from 2-methacryloyloxyethyl phosphorylcholine, and the compound containing a mercapto group and a methoxysilane is selected from the following structure: Where n=1~20, in this embodiment, the structure n=3 is selected; In this embodiment, the preparation method of the PC polymer comprises the following steps: 1.1) Dry all objects that come into contact with the material during the preparation process; 1.2) Dissolve 266 mmol of an acrylate derivative containing a phosphorylcholine functional group and 13.3 mmol of a compound containing a mercapto group and a methoxysilane in 320 mL of anhydrous solvent; 1.3) Add argon gas for more than half an hour while stirring, then add 398 mg of photoinitiator, and continue to add argon gas for more than half an hour. The photoinitiator includes Benzophenone, Irgacure, Darocure, Esacure, Lucirin, etc.; 1.4) The reaction vessel was sealed and placed under 365 nm ultraviolet light under stirring conditions to obtain a reaction solution after the reaction was completed; the intensity of the ultraviolet light increased with the increase of the volume of the reaction solution, and the intensity of the ultraviolet light was 320 mW / cm2 , irradiated for 9.5 h under stirring; 1.5) 1600 mL of solvent A and 1500 mL of solvent B are mixed to obtain a first mixed solvent, and the reaction solution is then added dropwise to the first mixed solvent under stirring, and the product is precipitated into a white solid, wherein the solvent A includes but is not limited to dichloromethane, ethyl acetate, and chloroform, and the solvent B includes but is not limited to diethyl ether and n-hexane; 1.6) Transfer the precipitated turbid solution to a centrifuge tube and centrifuge at 3000 rpm for 5 min. Pour the supernatant into a waste tank and discard it. Combine the solid obtained from centrifugation with the solid obtained in step 1.5). Repeat steps 1.5) and 1.6) twice; 1.7) Add a mixed solution of anhydrous dichloromethane and ether containing 30% to 100% by volume of anhydrous dichloromethane into a container containing the solid obtained in step 1.6), fill it with argon gas and seal it, stir it at room temperature for 9.5 hours, and after stirring, pour the supernatant into a waste liquid tank and discard it. Repeat this step twice to obtain PC polymer; 1.8) The product is vacuum-dried for 25 h at 20°C to remove the solvent, filled with argon, and stored in a sealed container at -20°C to room temperature, away from light, for future use.

[0055] Specifically, the chemical reaction formula for preparing PC polymer is as follows: Figure 2 As shown, the NMR spectrum of the prepared new PC polymer is as follows Figure 3 shown.

[0056] Specifically, Figure 5 As shown, a magnetic stirrer 5 is provided at the bottom of the inner cavity of the reaction container, and a Schlenk bottle 2 is provided above the magnetic stirrer 5 for containing raw materials to obtain a reaction solution 4. A magnet 6 cooperating with the magnetic stirrer 5 is provided in the Schlenk bottle 2, a fan 1 is installed at the top of the inner cavity of the reaction container, and ultraviolet lamps 3 are installed on both side walls of the reaction container.

[0057] An embodiment of the present invention provides an anticoagulation coating for medical devices, which is directly connected to the surface of the medical device through chemical bond grafting. The raw material of the anticoagulation coating includes the above-mentioned PC polymer or the PC polymer obtained by the preparation method of the above-mentioned PC polymer.

[0058] An embodiment of the present invention provides an interventional medical device with an anticoagulant coating, including a medical device and an anticoagulant coating on the surface of the medical device, wherein the anticoagulant coating is directly connected to the surface of the medical device by chemical bond grafting, and the raw material of the anticoagulant coating includes the above-mentioned PC polymer or the anticoagulant coating is obtained by the preparation method of the above-mentioned PC polymer.

[0059] In this embodiment, the interventional medical device is selected as a blood flow guiding dense mesh stent (such as Figure 7As shown in FIG. 1 , the surface of the blood flow-directing dense mesh stent is directly connected to the anticoagulant coating via chemical bond grafting.

[0060] The present invention provides a method for preparing an interventional medical device with an anticoagulant coating, such as Figure 1 As shown, the following steps are included: 1) Preparation of PC polymer; 2) preparing coating solution; 3) Surface pretreatment; 4) Coating preparation; 5) Post-processing and cleaning.

[0061] Wherein, step 2) preparing the coating solution comprises the following steps: 2.1) Solvent C and solvent D are mixed in a volume ratio of 3:1 to obtain a second mixed solvent, wherein the solvent C includes but is not limited to trifluoroethanol, acetone, tetrahydrofuran, DMSO, and DMF, and the solvent D includes but is not limited to toluene, ethyl acetate, diethyl ether, and n-hexane; 2.2) Dissolve the PC polymer product prepared in step 1) in a second mixed solvent at a ratio of 5 wt%, and add a corresponding amount of triethylamine at a ratio of 1 μL triethylamine per mg of PC polymer product; 2.3) After mixing, filter the solution using a 0.45 μm pore size PTFE syringe filter, fill it with argon gas and package it for later use.

[0062] Step 3) Surface pretreatment includes the following steps: 3.1) The medical device to be coated is completely immersed in the solvent and ultrasonicated for 32.5 min; 3.2) After cleaning, place the medical device on dust-free paper to dry for later use; 3.3) Select appropriate methods to perform hydroxylation treatment on the surface of medical devices made of different materials; The hydroxylation treatment method specifically includes one or more of the following methods. You can first select different methods. After the coating is prepared, detect the surface elements and select the method that detects the most coating elements: Piranha solution method: used for medical devices with metal surfaces. To prepare piranha solution, protective equipment must be worn in a fume hood. Slowly add 30% hydrogen peroxide to concentrated sulfuric acid at a volume ratio of 7:3. Immerse the cleaned medical device completely in the piranha solution for 15.5 min until no bubbles are generated on the surface of the material. Then, remove the medical device with tweezers, rinse it with purified water 4 times, and blow dry it with inert gas. UVO method: for products with metal or polymer surface, after cleaning the medical device, put it into the preheated UVO reactor and take it out after 35 minutes of reaction; Plasma method: used for medical devices with metal surfaces. The medical devices are suspended in a plasma treatment reactor. After the reactor is evacuated to -12 Pa, oxygen or NH3 is added to an appropriate positive pressure of 58 Pa. The oxygen or NH3 pressure is maintained for 20 minutes for plasma surface activation treatment. The corresponding hydroxyl or amino group is grafted onto the surface of the medical device to make it an activated coating substrate.

[0063] Step 4) The coating preparation includes the following steps: 4.1) The surface pretreated device is completely immersed in the coating solution, filled with argon gas and sealed; 4.2) Place on a shaker at 38°C and shake at 150 rpm for 10 h; The PC polymer is grafted onto the surface of medical devices through chemical bonds by surface grafting. The coating thickness of traditional spraying is at the micron level, which will affect the functions of some medical devices themselves (such as blood flow guidance devices), while the coating thickness prepared by chemical grafting can reach the nanometer level, which does not affect the original functions of medical devices. In addition, the coating is connected to the surface of medical devices through chemical bonds, making the coating more solid. Taking nickel-titanium alloy medical devices as an example, the chemical process is as follows: Figure 4 shown.

[0064] Step 5) Post-processing and cleaning includes the following steps: 5.1) After the reaction is completed, remove the medical device from the coating solution and immerse it in a polar solvent for 3 times; 5.2) Then place the medical device in an oven and anneal at 80 °C for 60 min; 5.3) After annealing, immerse the medical device completely in a polar solvent and ultrasonicate it for 10 min. Change the solvent and ultrasonicate it twice; The polar solvent includes, but is not limited to, methanol, ethanol, isopropanol, acetone, tetrahydrofuran, and purified water.

[0065] Example 4 The embodiment of the present invention provides a PC polymer, comprising the following raw materials: an acrylate derivative containing a phosphorylcholine functional group, and a compound containing a mercapto group and a methoxysilane. In this embodiment, the acrylate derivative containing a phosphorylcholine functional group is selected from 2-methacryloyloxyethyl phosphorylcholine, and the compound containing a mercapto group and a methoxysilane is selected from the following structure: Where n=1~20, in this embodiment, the structure n=3 is selected; In this embodiment, the preparation method of the PC polymer comprises the following steps: 1.1) Dry all objects that come into contact with the material during the preparation process; 1.2) Dissolve 406 mmol of an acrylate derivative containing a phosphorylcholine functional group and 20.5 mmol of a compound containing a mercapto group and a methoxysilane in 480 mL of anhydrous solvent; 1.3) Add argon gas for more than half an hour while stirring, then add 600 mg of photoinitiator, and continue to add argon gas for more than half an hour. The photoinitiator includes Benzophenone, Irgacure, Darocure, Esacure, Lucirin, etc.; 1.4) The reaction vessel was sealed and placed under 365 nm ultraviolet light under stirring conditions to obtain a reaction solution after the reaction was completed; the intensity of the ultraviolet light increased with the increase of the volume of the reaction solution, and the intensity of the ultraviolet light was 340 mW / cm 2 , irradiated for 18 h under stirring; 1.5) Mix 2400 mL of solvent A and 2500 mL of solvent B to obtain a first mixed solvent, and then add the reaction solution dropwise into the first mixed solvent under stirring, and the product will precipitate into a white solid. The solvent A includes but is not limited to dichloromethane, ethyl acetate, and chloroform, and the solvent B includes but is not limited to diethyl ether and n-hexane; 1.6) Transfer the turbid solution after precipitation to a centrifuge tube and centrifuge at 3500 rpm for 6 min. Pour the supernatant into the waste tank and discard it. Combine the solid obtained by centrifugation with the solid obtained in step 1.5). Repeat steps 1.5) and 1.6) twice; 1.7) Add a mixed solution of anhydrous dichloromethane and ether containing 30% to 100% by volume of anhydrous dichloromethane into a container containing the solid obtained in step 1.6), fill it with argon gas and seal it, stir it at room temperature for 14 h, and after stirring, pour the supernatant into a waste liquid tank and discard it. Repeat this step twice to obtain PC polymer; 1.8) The product was vacuum-dried for 36 h at 40°C to remove the solvent, filled with argon, and stored in a sealed container at -20°C to room temperature, away from light, for future use.

[0066] Specifically, the chemical reaction formula for preparing PC polymer is as follows: Figure 2 As shown, the NMR spectrum of the prepared new PC polymer is as follows Figure 3 shown.

[0067] Specifically, Figure 5 As shown, a magnetic stirrer 5 is provided at the bottom of the inner cavity of the reaction container, and a Schlenk bottle 2 is provided above the magnetic stirrer 5 for containing raw materials to obtain a reaction solution 4. A magnet 6 cooperating with the magnetic stirrer 5 is provided in the Schlenk bottle 2, a fan 1 is installed at the top of the inner cavity of the reaction container, and ultraviolet lamps 3 are installed on both side walls of the reaction container.

[0068] An embodiment of the present invention provides an anticoagulation coating for medical devices, which is directly connected to the surface of the medical device through chemical bond grafting. The raw material of the anticoagulation coating includes the above-mentioned PC polymer or the PC polymer obtained by the preparation method of the above-mentioned PC polymer.

[0069] An embodiment of the present invention provides an interventional medical device with an anticoagulant coating, including a medical device and an anticoagulant coating on the surface of the medical device, wherein the anticoagulant coating is directly connected to the surface of the medical device by chemical bond grafting, and the raw material of the anticoagulant coating includes the above-mentioned PC polymer or the anticoagulant coating is obtained by the preparation method of the above-mentioned PC polymer.

[0070] In this embodiment, the interventional medical device is selected as a blood flow guiding dense mesh stent (such as Figure 7 As shown in FIG. 1 , the surface of the blood flow-directing dense mesh stent is directly connected to the anticoagulant coating via chemical bond grafting.

[0071] The present invention provides a method for preparing an interventional medical device with an anticoagulant coating, such as Figure 1 As shown, the following steps are included: 1) Preparation of PC polymer; 2) preparing coating solution; 3) Surface pretreatment; 4) Coating preparation; 5) Post-processing and cleaning.

[0072] Wherein, step 2) preparing the coating solution comprises the following steps: 2.1) Solvent C and solvent D are mixed in a volume ratio of 3:1 to obtain a second mixed solvent, wherein the solvent C includes but is not limited to trifluoroethanol, acetone, tetrahydrofuran, DMSO, and DMF, and the solvent D includes but is not limited to toluene, ethyl acetate, diethyl ether, and n-hexane; 2.2) The PC polymer product prepared in step 1) is dissolved in a second mixed solvent at a ratio of 6 wt%, and a corresponding amount of triethylamine is added at a ratio of 0.1.5 μL triethylamine per mg of PC polymer product; 2.3) After mixing, filter the solution using a 0.45 μm pore size PTFE syringe filter, fill it with argon gas and package it for later use.

[0073] Step 3) Surface pretreatment includes the following steps: 3.1) The medical device to be coated is completely immersed in the solvent and ultrasonicated for 60 min; 3.2) After cleaning, place the medical device on dust-free paper to dry for later use; 3.3) Select appropriate methods to perform hydroxylation treatment on the surface of medical devices made of different materials; The hydroxylation treatment method specifically includes one or more of the following methods. You can first select different methods. After the coating is prepared, detect the surface elements and select the method that detects the most coating elements: Piranha solution method: used for medical devices with metal surfaces. To prepare piranha solution, protective equipment must be worn in a fume hood. Slowly add 30% hydrogen peroxide to concentrated sulfuric acid at a volume ratio of 7:3. Immerse the cleaned medical device completely in the piranha solution for 30 minutes until no bubbles are generated on the surface of the material. Then, remove the medical device with tweezers, rinse it with purified water 6 times, and blow dry it with inert gas. UVO method: used for products with metal or polymer surfaces. After cleaning the medical device, place it in a preheated UVO reactor and take it out after 60 minutes of reaction. Plasma method: used for medical devices with metal surfaces. The medical devices are suspended in a plasma treatment reactor. After the reactor is evacuated to -12 Pa, oxygen or NH3 is added to an appropriate positive pressure of 65 Pa. The oxygen or NH3 pressure is maintained for 30 minutes for plasma surface activation treatment. The corresponding hydroxyl or amino group is grafted onto the surface of the medical device to make it an activated coating substrate.

[0074] Step 4) The coating preparation includes the following steps: 4.1) The surface pretreated device is completely immersed in the coating solution, filled with argon gas and sealed; 4.2) Place on a shaker at 40 °C and shake at 300 rpm for 18 h; The PC polymer is grafted onto the surface of medical devices through chemical bonds by surface grafting. The coating thickness of traditional spraying is at the micron level, which will affect the functions of some medical devices themselves (such as blood flow guidance devices), while the coating thickness prepared by chemical grafting can reach the nanometer level, which does not affect the original functions of medical devices. In addition, the coating is connected to the surface of medical devices through chemical bonds, making the coating more solid. Taking nickel-titanium alloy medical devices as an example, the chemical process is as follows: Figure 4 shown.

[0075] Step 5) Post-processing and cleaning includes the following steps: 5.1) After the reaction is completed, remove the medical device from the coating solution and immerse it in a polar solvent for 3 times; 5.2) Then place the medical device in an oven and anneal at 80 °C for 90 min; 5.3) After annealing, completely immerse the medical device in a polar solvent and ultrasonicate it for 15 min. Change the solvent and ultrasonicate it 3 times. The polar solvent includes, but is not limited to, methanol, ethanol, isopropanol, acetone, tetrahydrofuran, and purified water.

[0076] Example 5 The embodiment of the present invention provides a PC polymer, comprising the following raw materials: an acrylate derivative containing a phosphorylcholine functional group, and a compound containing a mercapto group and a methoxysilane. In this embodiment, the acrylate derivative containing a phosphorylcholine functional group is selected from 2-methacryloyloxyethyl phosphorylcholine, and the compound containing a mercapto group and a methoxysilane is selected from the following structure: Where n=1~20, in this embodiment, the structure n=3 is selected; In this embodiment, the preparation method of the PC polymer comprises the following steps: 1.1) Dry all objects that come into contact with the material during the preparation process; 1.2) Dissolve 540 mmol of an acrylate derivative containing a phosphorylcholine functional group and 27 mmol of a compound containing a mercapto group and a methoxysilane in 640 mL of anhydrous solvent; 1.3) Add argon gas for more than half an hour while stirring, then add 800 mg of photoinitiator, and continue to add argon gas for more than half an hour. The photoinitiator includes Benzophenone, Irgacure, Darocure, Esacure, Lucirin, etc.; 1.4) The reaction vessel was sealed and placed under 365 nm ultraviolet light under stirring conditions to obtain a reaction solution after the reaction was completed; the intensity of the ultraviolet light increased with the increase of the volume of the reaction solution, and the intensity of the ultraviolet light was 340 mW / cm 2 , irradiated for 18 h under stirring; 1.5) 3200 mL of solvent A and 3200 mL of solvent B are mixed to obtain a first mixed solvent, and the reaction solution is then added dropwise to the first mixed solvent under stirring, and the product is precipitated into a white solid, wherein the solvent A includes but is not limited to dichloromethane, ethyl acetate, and chloroform, and the solvent B includes but is not limited to diethyl ether and n-hexane; 1.6) Transfer the turbid solution after precipitation to a centrifuge tube and centrifuge at 3500 rpm for 6 min. Pour the supernatant into the waste tank and discard it. Combine the solid obtained by centrifugation with the solid obtained in step 1.5). Repeat steps 1.5) and 1.6) twice; 1.7) Add a mixed solution of anhydrous dichloromethane and ether containing 30% to 100% by volume of anhydrous dichloromethane into a container containing the solid obtained in step 1.6), fill it with argon gas and seal it, stir it at room temperature for 18 hours, and after stirring, pour the supernatant into a waste liquid tank and discard it. Repeat this step twice to obtain PC polymer; 1.8) The product is vacuum-dried for 48 h at 60°C to remove the solvent, filled with argon, and stored in a sealed container at -20°C to room temperature, away from light, for future use.

[0077] Specifically, the chemical reaction formula for preparing PC polymer is as follows: Figure 2 As shown, the NMR spectrum of the prepared new PC polymer is as follows Figure 3 shown.

[0078] Specifically, Figure 5 As shown, a magnetic stirrer 5 is provided at the bottom of the inner cavity of the reaction container, and a Schlenk bottle 2 is provided above the magnetic stirrer 5 for containing raw materials to obtain a reaction solution 4. A magnet 6 cooperating with the magnetic stirrer 5 is provided in the Schlenk bottle 2, a fan 1 is installed at the top of the inner cavity of the reaction container, and ultraviolet lamps 3 are installed on both side walls of the reaction container.

[0079] An embodiment of the present invention provides an anticoagulation coating for medical devices, which is directly connected to the surface of the medical device through chemical bond grafting. The raw material of the anticoagulation coating includes the above-mentioned PC polymer or the PC polymer obtained by the preparation method of the above-mentioned PC polymer.

[0080] An embodiment of the present invention provides an interventional medical device with an anticoagulant coating, including a medical device and an anticoagulant coating on the surface of the medical device, wherein the anticoagulant coating is directly connected to the surface of the medical device by chemical bond grafting, and the raw material of the anticoagulant coating includes the above-mentioned PC polymer or the anticoagulant coating is obtained by the preparation method of the above-mentioned PC polymer.

[0081] In this embodiment, the interventional medical device is selected as a blood flow guiding dense mesh stent (such as Figure 7 As shown in FIG. 1 , the surface of the blood flow-directing dense mesh stent is directly connected to the anticoagulant coating via chemical bond grafting.

[0082] The present invention provides a method for preparing an interventional medical device with an anticoagulant coating, such as Figure 1 As shown, the following steps are included: 1) Preparation of PC polymer; 2) preparing coating solution; 3) Surface pretreatment; 4) Coating preparation; 5) Post-processing and cleaning.

[0083] Wherein, step 2) preparing the coating solution comprises the following steps: 2.1) Solvent C and solvent D are mixed in a volume ratio of 3:1 to obtain a second mixed solvent, wherein the solvent C includes but is not limited to trifluoroethanol, acetone, tetrahydrofuran, DMSO, and DMF, and the solvent D includes but is not limited to toluene, ethyl acetate, diethyl ether, and n-hexane; 2.2) The PC polymer product prepared in step 1) is dissolved in a second mixed solvent at a ratio of 6 wt%, and a corresponding amount of triethylamine is added at a ratio of 0.1.5 μL triethylamine per mg of PC polymer product; 2.3) After mixing, filter the solution using a 0.45 μm pore size PTFE syringe filter, fill it with argon gas and package it for later use.

[0084] Step 3) Surface pretreatment includes the following steps: 3.1) The medical device to be coated is completely immersed in the solvent and ultrasonicated for 60 min; 3.2) After cleaning, place the medical device on dust-free paper to dry for later use; 3.3) Select appropriate methods to perform hydroxylation treatment on the surface of medical devices made of different materials; The hydroxylation treatment method specifically includes one or more of the following methods. You can first select different methods. After the coating is prepared, detect the surface elements and select the method that detects the most coating elements: Piranha solution method: used for medical devices with metal surfaces. To prepare piranha solution, protective equipment must be worn in a fume hood. Slowly add 30% hydrogen peroxide to concentrated sulfuric acid at a volume ratio of 7:3. Immerse the cleaned medical device completely in the piranha solution for 30 minutes until no bubbles are generated on the surface of the material. Then, remove the medical device with tweezers, rinse it with purified water 6 times, and blow dry it with inert gas. UVO method: used for products with metal or polymer surfaces. After cleaning the medical device, place it in a preheated UVO reactor and take it out after 60 minutes of reaction. Plasma method: used for medical devices with metal surfaces. The medical devices are suspended in a plasma treatment reactor. After the reactor is evacuated to -12 Pa, oxygen or NH3 is added to an appropriate positive pressure of 65 Pa. The oxygen or NH3 pressure is maintained for 30 minutes for plasma surface activation treatment. The corresponding hydroxyl or amino group is grafted onto the surface of the medical device to make it an activated coating substrate.

[0085] Step 4) The coating preparation includes the following steps: 4.1) The surface pretreated device is completely immersed in the coating solution, filled with argon gas and sealed; 4.2) Place on a shaker at 40 °C and shake at 300 rpm for 18 h; The PC polymer is grafted onto the surface of medical devices through chemical bonds by surface grafting. The coating thickness of traditional spraying is at the micron level, which will affect the functions of some medical devices themselves (such as blood flow guidance devices), while the coating thickness prepared by chemical grafting can reach the nanometer level, which does not affect the original functions of medical devices. In addition, the coating is connected to the surface of medical devices through chemical bonds, making the coating more solid. Taking nickel-titanium alloy medical devices as an example, the chemical process is as follows: Figure 4 shown.

[0086] Step 5) Post-processing and cleaning includes the following steps: 5.1) After the reaction is completed, remove the medical device from the coating solution and immerse it in a polar solvent for 3 times; 5.2) Then place the medical device in an oven and anneal at 80 °C for 90 min; 5.3) After annealing, immerse the medical device completely in a polar solvent and ultrasonicate it for 15 min. Change the solvent and ultrasonicate it 3 times. The polar solvent includes, but is not limited to, methanol, ethanol, isopropanol, acetone, tetrahydrofuran, and purified water.

[0087] The above-mentioned medical devices are interventional medical devices, including blood flow guiding dense mesh stents (such as Figure 7 ), ball-expandable stents, thrombectomy stents and other interventional medical devices. The following takes the blood flow-directed dense mesh stent as an example to compare its Chandler Loop in vitro anticoagulation test: 1. Place the dense mesh stent with anticoagulant coating (test product) and the bare stent of the same specification (control product) into the same silicone tube through a plastic rod; 2. Inject 5 mL of purified water into the silicone tube; 3. Adjust the water bath in the Chandlar Loop System to 37°C and install the silicone tubing on the device; 4. Turn on the Chandlar Loop System and rotate for 10 minutes; 5. Stop the rotation and pour out the purified water in the silicone tube; 6. Add 5 mL of anticoagulated rabbit blood into a 20 mL vial, use a pipette to add 0-100 µL of 0.2M CaCl2 solution into the rabbit blood, stir quickly and add the calcified rabbit blood into the silicone tube placed in the dense mesh holder; 7. Turn on the rotation and continue for 1-30 minutes; 8. Prepare 40 mL of 4 wt% glutaraldehyde aqueous solution, take two 20 mL vials, and fill each with 20 mL of 4 wt% glutaraldehyde aqueous solution; 9. Stop the rotation, remove the silicone tube, pour out the rabbit blood, take out the two dense mesh stents with tweezers (or cut the silicone tube at the position of the dense mesh stent with scissors to keep the dense mesh stent in the silicone tube), and place them in a vial filled with 4 wt% glutaraldehyde aqueous solution and soak for 30 min. Place the test sample and control sample in two vials respectively; 10. Take out the samples respectively and place them in ethanol solution for dehydration; 11. Observe the formation of thrombus on the dense mesh stent and take photos.

[0088] The test results are as follows Figure 6 The dense mesh stent with anticoagulant coating has obvious anticoagulant effect.

[0089] It should be noted that, for the above embodiments, for the sake of simplicity, they are all described as a series of action combinations, but those skilled in the art should know that the present invention is not limited by the described order of actions, because according to the present invention, some steps may be performed in other orders or simultaneously. Secondly, those skilled in the art should also know that the embodiments described in the specification are all preferred embodiments, and the actions and modules involved are not necessarily required by the present invention.

[0090] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the scope of protection of the invention. Obviously, the described embodiments are only some embodiments of the present invention, rather than all embodiments. Based on these embodiments, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention. Although the present invention has been described in detail with reference to the above embodiments, ordinary technicians in this field can still combine, add, delete or make other adjustments to the features in the various embodiments of the present invention according to the circumstances without conflict, without making creative work, so as to obtain different other technical solutions that do not deviate from the concept of the present invention in essence, and these technical solutions also belong to the scope of protection of the present invention.

Claims

1. A PC polymer for anticoagulation coating of medical devices, characterized in that: The invention comprises the following raw materials: an acrylate derivative containing a phosphorylcholine functional group, and a compound containing a mercapto group and a methoxysilane.

2. The method for preparing PC polymer according to claim 1, characterized in that: The steps include: 1.1) Dry all objects that come into contact with the material during the preparation process; 1.2) dissolving an acrylate derivative containing a phosphorylcholine functional group and a compound containing a mercapto group and a methoxysilane in an anhydrous solvent, wherein the molar ratio of the acrylate derivative to the compound containing a mercapto group and a methoxysilane is 10:1 to 50:1, and the ratio of the acrylate derivative to the anhydrous solvent is 2 to 10 ml per gram; 1.3) introducing inert gas for more than half an hour while stirring, then adding a photoinitiator, the amount of the photoinitiator being 0.1 mol% to 2 mol% of the acrylate derivative containing phosphorylcholine functional group, and continuing to introduce inert gas for more than half an hour; 1.4) The reaction vessel is sealed and placed under ultraviolet light for reaction under stirring conditions, and a reaction solution is obtained after the reaction is completed; 1.5) Solvent A and solvent B are mixed to obtain a first mixed solvent, and the reaction solution is then added dropwise to the first mixed solvent under stirring, and the product will precipitate into a white solid; 1.6) Transfer the precipitated turbid solution to a centrifuge tube and centrifuge at 2500-3500 rpm for 4-6 min. Pour the supernatant into a waste tank and discard it. Combine the solid obtained from centrifugation with the solid obtained in step 1.5). Repeat steps 1.5) and 1.6) twice; 1.7) Add a mixed solution of anhydrous dichloromethane and ether containing 30% to 100% by volume of anhydrous dichloromethane into a container containing the solid obtained in step 1.6), fill it with inert gas and seal it, stir it at room temperature for 1-18 hours, and after stirring, pour the supernatant into a waste liquid tank and discard it. Repeat this step twice to obtain PC polymer; 1.8) The PC polymer obtained in step 1.7) is subjected to vacuum desolventization at -20 to 60°C for 2 to 96 h, filled with inert gas, and then sealed and stored at -20°C to room temperature away from light.

3. The method for preparing PC polymer according to claim 2, characterized in that: The solvent A and the solvent B are selected as poor solvents relative to the PC polymer, and the ratio of the anhydrous solvent to the first mixed solvent is 1:8 to 1:12; the solvent A includes one or more of dichloromethane, ethyl acetate, and chloroform, and the solvent B includes one or more of ether and n-hexane. The solvent A and the solvent B are mixed in a volume ratio of 0:1 to 1:1 to obtain the first mixed solvent, the ultraviolet light wavelength is selected to be 365nm, the inert gas is selected to be argon, and the photoinitiator is selected to be Benzophenone, Irgacure, Darocure, Esacure or Lucirin.

4. The method for preparing PC polymer according to claim 2, characterized in that: The intensity of UV light increases with the volume of the reaction solution. The intensity of the UV lamp is 300-400 mW / cm2, and the irradiation is performed for 1-18 h under stirring.

5. The method for preparing PC polymer according to claim 1, characterized in that: The compound containing mercapto and methoxysilane is selected from the following structure: Where n = 1 to 20; or Where n=1~20, m=1~5.

6. The method for preparing PC polymer according to claim 1, characterized in that: The chemical structure of the PC polymer is: where x = 1-20, or Where x=1-20, y=1-5.

7. An anticoagulant coating for medical devices, characterized in that: It is directly connected to the surface of the medical device through chemical bond grafting. The raw material of the anticoagulation coating includes the PC polymer as claimed in claim 1 or the PC polymer obtained by the preparation method of the PC polymer as claimed in any one of claims 2-6.

8. An interventional medical device with an anticoagulant coating, characterized in that: It comprises a medical device and an anticoagulant coating on the surface of the medical device, wherein the anticoagulant coating is directly connected to the surface of the medical device by chemical bond grafting, and the raw material of the anticoagulant coating comprises the PC polymer as claimed in claim 1 or a PC polymer obtained by the preparation method of the PC polymer as claimed in any one of claims 2-6.

9. The interventional medical device with an anticoagulant coating according to claim 8, characterized in that: The interventional medical device is a blood flow guiding dense mesh stent, and the surface of the blood flow guiding dense mesh stent is directly connected to the anticoagulant coating through chemical bond grafting.

10. The method for preparing an interventional medical device with an anticoagulant coating according to claim 8, characterized in that: The steps include: 1) Preparation of PC polymer; 2) preparing coating solution; 3) Surface pretreatment; 4) Coating preparation; 5) Post-processing and cleaning.

11. The method for preparing an interventional medical device with an anticoagulant coating according to claim 10, characterized in that: The preparation of the coating solution comprises the following steps: 2.1) Solvent C and solvent D are mixed in a volume ratio of 3:1 to 1:1 to obtain a second mixed solvent; 2.2) dissolving the PC polymer prepared in step 1) in a second mixed solvent at a ratio of 4-6 wt%, and adding a corresponding amount of triethylamine at a ratio of 0.5-1.5 μL triethylamine per mg of PC polymer; 2.3) After mixing, filter the solution through a filter to obtain a coating solution, fill it with inert gas and package it for later use.

12. The method for preparing an interventional medical device with an anticoagulant coating according to claim 11, characterized in that: The solvent C includes one or more of trifluoroethanol, acetone, tetrahydrofuran, DMSO, and DMF; the solvent D includes one or more of toluene, ethyl acetate, ether, and n-hexane; the filter is a PTFE needle filter with a pore size of 0.45 μm; and the inert gas is argon.

13. The method for preparing an interventional medical device with an anticoagulant coating according to claim 10, characterized in that: The surface pretreatment comprises the following steps: 3.1) Completely immerse the medical device to be coated in the solvent and ultrasonicate for 5-60 min; 3.2) After cleaning, place the medical device on dust-free paper to dry for later use; 3.3) Select appropriate methods to carry out hydroxylation treatment on the surface of medical devices made of different materials.

14. The method for preparing the anticoagulation coating according to claim 10, characterized in that: The coating preparation comprises the following steps: 4.1) The surface pretreated device is completely immersed in the coating solution, filled with argon gas and sealed; 4.2) Place on a shaker at 35-40 ℃ and shake at 50-300 rpm for 2-18 h.

15. The method for preparing an interventional medical device with an anticoagulant coating according to claim 10, characterized in that: The post-processing and cleaning comprises the following steps: 5.1) After the reaction is completed, remove the medical device from the coating solution and extract it in a polar solvent for at least 3 times; 5.2) Then place the medical device in an oven and anneal at 45℃~100℃ for 30-90 min; 5.3) After annealing, completely immerse the medical device in a polar solvent and ultrasonicate for 5-15 min. Change the solvent and ultrasonicate 2-3 times.

16. The method for preparing an interventional medical device with an anticoagulant coating according to claim 13, characterized in that: Before selecting a suitable method to perform hydroxylation treatment on the surface of medical devices of different materials, the surface elements of the PC polymer prepared in step 1) are detected, and a hydroxylation treatment method is selected according to the elements of the PC polymer. The selecting a suitable method to perform hydroxylation treatment on the surface of medical devices of different materials includes selecting one or more of the following methods: Piranha solution method: slowly add 30% hydrogen peroxide to concentrated sulfuric acid at a volume ratio of 7:3; completely immerse the cleaned medical device in the piranha solution for 1-30 minutes until no bubbles are generated on the surface of the material; then remove the medical device with tweezers, rinse it with purified water 3-6 times, and blow dry it with inert gas; UVO method: After cleaning the medical device, place it in a preheated UVO reactor and take it out after reacting for 10-60 minutes; Plasma method: The medical device is suspended in a plasma treatment reactor. After the reactor is evacuated to -12 Pa, oxygen or NH3 is added to an appropriate positive pressure of 50-65 Pa. The oxygen or NH3 pressure is maintained and the plasma surface activation treatment is performed for 10-30 min to graft the corresponding hydroxyl or amino group onto the surface of the medical device to make it an activated coating substrate.

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