Medical anticoagulant device and preparation method thereof

Abstract

The invention relates to an anticoagulant medical device and a preparation method thereof. The preparation method of the anticoagulant medical device comprises the following steps: covalently connecting the hydrophilic anticoagulant layer on the surface of the base material in an atom transfer radical polymerization manner; a heparin anticoagulation layer is covalently connected to the surface of a hydrophilic anticoagulation layer to prepare the anticoagulation medical device, and the heparin anticoagulation layer and the hydrophilic anticoagulation layer are connected through one or more covalent bonds of a triazole bond, an amido bond, a carbon-nitrogen single bond and a carbon-sulfur single bond. According to the preparation method of the anticoagulation medical device, the anti-protein adsorption effect of the hydrophilic anticoagulation layer and the anticoagulation effect of the heparin anticoagulation layer can be synergistically exerted, the anticoagulation effect is improved, and meanwhile, the anticoagulation stability is improved.

Description

Technical Field

[0001] The present invention relates to the field of medical materials, and particularly to an anticoagulant medical device and a preparation method thereof. Background Art

[0002] Blood-contact medical devices include extracorporeal membrane oxygenation, valves, artificial blood vessels, vascular stents, and various catheters and guide wires. The blood compatibility of their constituent materials is often poor. When in contact with blood, plasma proteins are easily adsorbed on the surface of medical devices, thereby causing platelet coagulation reactions and further leading to the formation of thrombi. Currently, the main way to reduce the thrombus risk of such medical devices is to coat an anticoagulant coating on the surface of medical device materials to achieve a local anticoagulant effect. However, traditional anticoagulant coatings still have problems in that their anticoagulant effects and anticoagulant stabilities need to be improved. Summary of the Invention

[0003] Based on this, some embodiments of the present invention provide an anticoagulant medical device and a preparation method thereof, which can synergistically exert the anti-protein adsorption effect of the hydrophilic anticoagulant layer and the anticoagulant effect of the heparin anticoagulant layer, improve the anticoagulant effect, and at the same time improve the anticoagulant stability.

[0004] A preparation method of an anticoagulant medical device includes the following steps:

[0005] Covalently connect a hydrophilic anticoagulant layer to the surface of a substrate by atom transfer radical polymerization;

[0006] Covalently connect a heparin anticoagulant layer to the surface of the hydrophilic anticoagulant layer to prepare an anticoagulant medical device, and the heparin anticoagulant layer is covalently connected to the hydrophilic anticoagulant layer through one or several covalent bonds among triazole bonds, amide bonds, carbon-nitrogen single bonds, and carbon-sulfur single bonds.

[0007] In some of these embodiments, the step of covalently connecting a heparin anticoagulant layer to the surface of the hydrophilic anticoagulant layer includes:

[0008] Introduce one or several groups among azide groups, amino groups, and thiol groups at the end of the polymer in the hydrophilic anticoagulant layer to obtain a functionalized hydrophilic anticoagulant layer;

[0009] Perform one or several reactions among azide-alkyne reaction, amide reaction, aldehyde-amine condensation reaction, and thiol-ene reaction on the functionalized hydrophilic anticoagulant layer and heparin substances, so that the heparin substances are covalently grafted onto the surface of the functionalized hydrophilic anticoagulant layer to prepare a heparin anticoagulant layer.

[0010] In some of these embodiments, the step of introducing an azide group at the end of the polymer in the hydrophilic anticoagulant layer includes: immersing the substrate with the hydrophilic anticoagulant layer in a solution containing an azidating reagent, and reacting at 10°C to 50°C for 3 h to 24 h;

[0011] Optionally, in the solution containing the azidating reagent, the mass percentage concentration of the azidating reagent is 1% to 10%;

[0012] Optionally, the azidating reagent includes one or a combination of several of sodium azide, trimethylsilyl azide, and diphenylphosphate azide.

[0013] In some of these embodiments, the step of performing an azide-alkyne reaction between the functionalized hydrophilic anticoagulant layer and a heparin-like substance includes: immersing the substrate with the azidated hydrophilic anticoagulant layer in a second solution containing an alkynylated heparin-like substance, a copper(I) catalyst, and a second ligand, and reacting at 20°C to 35°C for 5 h to 12 h;

[0014] Optionally, in the second solution, the mass percentage concentration of the alkynylated heparin-like substance is 0.1% to 10%, the mass percentage concentration of the copper(I) catalyst is 0.01% to 1%, and the molar ratio of the second ligand to the copper(I) catalyst is (1 to 1.2):1;

[0015] Optionally, the copper(I) catalyst includes one or a combination of several of CuBr, CuCl, and CuI;

[0016] Optionally, the second ligand includes one or a combination of several of N,N,N',N',N''-pentamethyldiethylenetriamine, 2,2'-bipyridine, tris(2-dimethylaminoethyl)amine, and tripropylene glycol methyl ether acetate.

[0017] In some of these embodiments, the step of introducing an amino group at the end of the polymer in the hydrophilic anticoagulant layer includes:

[0018] introducing an azide group at the end of the polymer in the hydrophilic anticoagulant layer;

[0019] immersing the substrate with the azidated hydrophilic anticoagulant layer in an anhydrous diethyl ether solution containing a second reducing agent, and reacting at 25°C to 50°C for 1 h to 5 h to make the end of the polymer in the hydrophilic anticoagulant layer carry an amino group;

[0020] Optionally, in the anhydrous diethyl ether solution containing the second reducing agent, the mass percentage concentration of the second reducing agent is 0.1% to 5%.

[0021] In some of these embodiments, the step of subjecting the functionalized hydrophilic anticoagulant layer to an amide reaction with a heparin-like substance includes: immersing a substrate with an aminated hydrophilic anticoagulant layer in a third solution containing a heparin-like substance, an activator, and a condensing agent, and reacting at 0°C to 25°C for 1 h to 6 h;

[0022] Optionally, in the third solution, the mass percentage concentration of the heparin-like substance is 0.1% to 10%, and the mass ratio of the activator, the condensing agent, and the heparin-like substance is (1 to 1.2):(1 to 1.2):1.

[0023] In some of these embodiments, the step of subjecting the functionalized hydrophilic anticoagulant layer to an aldehyde-amine condensation reaction with a heparin-like substance includes: immersing a substrate with an aminated hydrophilic anticoagulant layer in a solution containing an aldehyde-group-containing heparin-like substance, and reacting at 20°C to 40°C for 1 h to 6 h, and then continuously reacting the reaction product with sodium cyanoborohydride for 1 h to 3 h;

[0024] Optionally, in the aqueous solution containing the aldehyde-group-containing heparin-like substance, the mass percentage concentration of the aldehyde-group-containing heparin-like substance is 0.1% to 10%, and the mass percentage of sodium cyanoborohydride in the aldehyde-group-containing heparin-like substance is 1% to 10%.

[0025] In some of these embodiments, the step of introducing a thiol group at the end of the polymer in the hydrophilic anticoagulant layer includes: immersing a substrate with the hydrophilic anticoagulant layer in a thiourea solution, and reacting at 80°C to 100°C under inert gas protection for 8 h to 24 h, and then continuously reacting the reaction product with a basic reagent at 90°C to 110°C for 8 h to 24 h;

[0026] Optionally, in the thiourea solution, the mass percentage concentration of thiourea is 0.1% to 1%.

[0027] In some of these embodiments, the step of subjecting the functionalized hydrophilic anticoagulant layer to a thiol-ene reaction with a heparin-like substance includes: immersing a substrate with a thiolated hydrophilic anticoagulant layer in a fourth solution containing a double-bond-containing heparin-like substance and an auxiliary agent, and reacting at 20°C to 80°C for 0.5 h to 5 h;

[0028] Wherein, in the fourth solution, the mass percentage concentration of the double-bond-containing heparin-like substance is 0.1% to 10%, the mass percentage concentration of the auxiliary agent is 0.01% to 2%, and the auxiliary agent includes one or more of a thermal initiator, a photoinitiator, and a basic catalyst.

[0029] In some of these embodiments, the step of covalently connecting a hydrophilic anticoagulant layer to the substrate surface by atom transfer radical polymerization includes:

[0030] Graft an initiator group on the surface of the substrate, and the initiator group includes a halogen group;

[0031] Obtain a first solution including a hydrophilic anticoagulant monomer, a first catalyst, and a first complexing agent, and treat the substrate grafted with the initiator group with the first solution, so that the hydrophilic anticoagulant monomer undergoes atom transfer radical polymerization on the surface of the substrate grafted with the initiator group under the action of the initiator group, the first catalyst, and the first complexing agent.

[0032] In some embodiments, the step of grafting an initiator group on the surface of the substrate includes:

[0033] Obtain a substrate with hydroxyl groups on its surface;

[0034] Perform a silanization reaction between a silanizing reagent containing an initiator group and the hydroxyl groups on the surface of the substrate to graft the initiator group on the surface of the substrate.

[0035] In some embodiments, the step of grafting an initiator group on the surface of the substrate satisfies one or more of the following graphic conditions:

[0036] (1) The silanizing reagent containing an initiator group includes one or a combination of more than one of (3-bromopropyl)trimethoxysilane, (3-bromopropyl)triethoxysilane, (3-chloropropyl)trimethoxysilane, (3-bromopropyl)trichlorosilane, 1-bromo-4-(trimethoxysilyl)benzene, and (3-chloropropyl)trichlorosilane;

[0037] (2) The silanizing reagent containing an initiator group reacts in the form of a solution, and in the solution, the mass percentage concentration of the silanizing reagent containing an initiator group is 5% to 30%;

[0038] (3) The temperature of the silanization reaction is 25°C to 60°C, and the time is 3h to 24h.

[0039] In some embodiments, the step of grafting an initiator group on the surface of the substrate includes:

[0040] Obtain a substrate with amino groups on its surface;

[0041] Perform an acylation reaction between an acyl halide reagent containing an initiator group and the amino groups on the surface of the substrate.

[0042] In some embodiments, the step of grafting an initiator group on the surface of the substrate satisfies one or more of the following conditions:

[0043] (1) The acyl halide reagent containing an initiator group includes one or a combination of two of chloroacetyl chloride and 2-bromo-2-methylpropanoyl bromide;

[0044] (2) The acyl halide reagent containing an initiator group reacts in the form of a solution. In the solution, the mass percentage concentration of the acyl halide reagent containing an initiator group is 5% - 30%;

[0045] (3) The temperature of the acylation reaction is 0°C - 25°C, and the time is 5h - 48h.

[0046] In some of the embodiments, the process parameters for preparing the hydrophilic anticoagulant layer satisfy one or more of the following conditions:

[0047] (1) In the first solution, the mass percentage concentration of the hydrophilic anticoagulant monomer is 1% - 50%;

[0048] (2) The molar ratio of the carbon - carbon double bond in the hydrophilic anticoagulant monomer, the first catalyst, and the first ligand is 1:(0.005 - 0.1):(0.005 - 0.5);

[0049] (3) The hydrophilic anticoagulant monomer includes one or more of acrylamide, 2 - hydroxyethyl methacrylate, 2 - hydroxyethyl acrylamide, potassium 3 - sulfopropyl methacrylate, N - vinylpyrrolidone, acrylate - terminated oligomer, methacrylate - terminated oligomer, and zwitterionic monomer;

[0050] (4) The first catalyst includes one or a combination of low - valence salts of copper, iron, molybdenum, chromium, rhenium, ruthenium, rhodium, and nickel;

[0051] (5) The first ligand includes one or a combination of amine substances and phosphine substances. The amine substances include one or a combination of N,N,N,N,N - pentamethyldiethylenetriamine, 1,1,4,7,10,10 - hexamethyltriethylenetetramine, tris[2 - (dimethylamino)ethyl]amine, tris(2 - pyridylmethyl)amine, 1,4,8,11 - tetraazacyclotetradecane, 2,2'-bipyridine, 4,4'-di - tert - butyl - 2,2'-bipyridine, 4,4'-dimethyl - 2,2'-bipyridine, and 4,4'-bis(trifluoromethyl)-2,2'-bipyridine. The phosphine substance includes triphenylphosphine;

[0052] (6) The first solution further contains a first reducing agent. The first reducing agent includes the high - valence salt corresponding to the metal used in the first catalyst or a free - radical thermal initiator. The molar ratio of the first reducing agent to the first catalyst is (0.1 - 0.3):1;

[0053] (7) The temperature of the atom transfer radical polymerization reaction is 25°C - 70°C, and the time is 2h - 24h.

[0054] In some of these embodiments, the process parameters for preparing the hydrophilic anticoagulant layer satisfy one or more of the following conditions:

[0055] (1) In the first solution, the mass percentage concentration of the hydrophilic anticoagulant monomer is 5% to 30%;

[0056] (2) The molar ratio of the carbon-carbon double bond in the hydrophilic anticoagulant monomer, the first catalyst, and the first ligand is 1:(0.01 - 0.1):(0.01 - 0.3);

[0057] (3) The hydrophilic anticoagulant monomer includes one or more of N-vinylpyrrolidone, 2-hydroxyethyl methacrylate, polyethylene glycol dimethacrylate with a molecular weight of 1000 capped at both ends with methacrylate, and zwitterionic monomers. The structural formula of the zwitterionic monomer is as follows:

[0058] In formula (II), R 1 includes a zwitterionic group, R 2 includes -NH- or -O-, R 3 includes -H or -CH 3 , and the zwitterionic group includes one or more of phosphorylcholine, sulfobetaine, and carboxybetaine;

[0059] (4) The first catalyst includes one or more of CuCl, FeCl 2 and RuCl 2 ;

[0060] (5) The first ligand includes one or more of N,N,N,N,N-pentamethyldiethylenetriamine, tris[2-(dimethylamino)ethyl]amine, and 4,4'-di-tert-butyl-2,2'-bipyridine;

[0061] (6) The time for the atom transfer radical polymerization reaction is 5 h to 10 h.

[0062] An anticoagulant medical device includes a substrate, a hydrophilic anticoagulant layer disposed on the surface of the substrate, and a heparin anticoagulant layer disposed on the surface of the hydrophilic anticoagulant layer;

[0063] Wherein, the hydrophilic anticoagulant layer is covalently connected to the surface of the substrate by atom transfer radical polymerization, and the heparin anticoagulant layer is connected to the hydrophilic anticoagulant layer by a covalent bond, and the covalent bond includes one or more of a triazole bond, an amide bond, a carbon-nitrogen single bond, and a carbon-sulfur single bond.

[0064] In some of these embodiments, the anticoagulant medical device satisfies one or more of the following conditions:

[0065] (1) The material of the hydrophilic anticoagulant layer includes one or a combination of more than one of polyethylene glycol, polyvinyl alcohol, polyacrylamide, poly(2-hydroxyethyl methacrylate), poly(hydroxyethyl acrylamide), potassium 3-sulfopropyl methacrylate, polyvinylpyrrolidone, and zwitterionic polymers;

[0066] Optionally, the structural formula of the zwitterionic polymer is as follows (Formula I):

[0067]

[0068] In Formula (I), R 1 includes a zwitterionic group, R 2 includes -NH- or -O-, R 3 includes -H or -CH 3 , and the zwitterionic group includes one or several of phosphorylcholine, sulfobetaine, and carboxybetaine;

[0069] (2) The water contact angle of the surface of the anticoagulant medical device is less than 50°;

[0070] (3) The material of the heparin anticoagulant layer includes one or a combination of more than one of heparin, heparin derivatives, and heparinoids, and the molecular weight of the material of the heparin anticoagulant layer is 1500 - 10000;

[0071] (4) The heparin density on the surface of the anticoagulant medical device is not less than 0.5 μg / cm 2 ;

[0072] (5) The material of the substrate includes one or a combination of more than one of metal-based biomaterials, silicon-based biomaterials, and polymer-based biomaterials;

[0073] Optionally, the material of the substrate includes one or several of polyethylene, polypropylene, polycarbonate, polyester, polymethylpentene, and polylactic acid.

[0074] The inventor found in experiments that although the traditional method discloses the way of combining a hydrophilic anticoagulant layer and a heparin anticoagulant layer, usually after grafting the hydrophilic anticoagulant layer, there are fewer active sites and less grafting amount of the anticoagulant layer. On the one hand, it affects the anticoagulant effect. On the other hand, the stability of the heparin anticoagulant layer is poor and it is easy to fall off. And the above-mentioned anticoagulant medical device includes a substrate and a hydrophilic anticoagulant layer and a heparin anticoagulant layer formed on the surface of the substrate. The hydrophilic anticoagulant layer is covalently connected to the surface of the substrate by means of atom transfer radical polymerization (ATRP). On the one hand, it makes the hydrophilic anticoagulant layer and the substrate covalently connected with good stability. On the other hand, compared with other polymerization methods, ATRP technology has controllability of polymer structure and molecular weight, making the molecular chain grow gradually, and the initiator remains at the end of the molecular chain, reducing the risk of the initiating group being buried. And ATRP technology usually uses organic halides as initiators. After using ATRP to prepare the hydrophilic anticoagulant layer, terminal functionalization is carried out to achieve covalent grafting of heparin, making full use of its reactivity, so that the heparin anticoagulant layer and the hydrophilic anticoagulant layer are connected by one or several covalent bonds among triazole bonds, amide bonds, carbon-nitrogen single bonds and carbon-sulfur single bonds, and it is not easy to fall off under the scouring of blood flow during use, having excellent long-term stability and realizing long-term anticoagulation. BRIEF DESCRIPTION OF THE DRAWINGS

[0075] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the following will briefly introduce the drawings required for the description of the embodiments. Obviously, the following drawings are only some embodiments of the present application. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained according to these drawings.

[0076] Figure 1 It is a schematic structural diagram of an anticoagulant medical device in some embodiments of the present invention;

[0077] Figure 2 It is a process flow chart of a preparation method of an anticoagulant medical device in some embodiments of the present invention;

[0078] Figure 3 is Figure 2 a schematic diagram of the process flow chart shown. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0079] In order to facilitate the understanding of the present invention, the following will describe the present invention more comprehensively in combination with specific embodiments. Preferred embodiments of the present invention are given in the specific embodiments. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure content of the present invention more thorough and comprehensive.

[0080] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field to which this invention belongs. The terms used in the description of this invention herein are for the purpose of describing specific embodiments only and are not intended to limit the invention.

[0081] Unless otherwise stated or in case of contradiction, the terms or phrases used in this invention have the following meanings:

[0082] In this invention, "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the quantity of the indicated technical features. Thus, features defined with "first" and "second" may explicitly or implicitly include at least one of such features.

[0083] In the description of this invention, "a plurality of" means at least two, such as two, three, etc., unless otherwise specifically defined.

[0084] In this invention, "one or several" means any one, any two or any two or more of the listed items. Among them, "several" means any two or any two or more.

[0085] In this invention, the percentage concentration involved, unless otherwise specified, refers to the final concentration. The final concentration refers to the proportion of the added component in the system after adding this component.

[0086] The terms "preferably", "more preferably", etc. in this invention refer to embodiments of this invention that can provide certain beneficial effects in certain cases. However, in the same or other cases, other embodiments may also be preferred. In addition, the description of one or more preferred embodiments does not imply that other embodiments are not available, nor is it intended to exclude other embodiments from the scope of this invention.

[0087] When a numerical range is disclosed in this invention, the above range is considered continuous and includes the minimum and maximum values of the range, as well as every value between such minimum and maximum values. Further, when the range refers to integers, it includes every integer between the minimum and maximum values of the range. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be combined. In other words, unless otherwise specified, all ranges disclosed in this invention should be understood to include any and all sub-ranges subsumed therein.

[0088] In this invention, among the technical features described in an open-ended manner, it includes a closed technical solution composed of the listed features, and also includes an open technical solution containing the listed features.

[0089] The terms "comprising" and "having" and any variations thereof in the embodiments of the present invention are intended to cover non-exclusive inclusion. For example, a process, method, system, product or device that includes a series of steps or units is not limited to the listed steps or units, but optionally further includes steps or units not listed, or optionally further includes other steps or components inherent to these processes, methods, products or devices.

[0090] Reference to "embodiment" in the present invention means that a specific feature, structure or characteristic described in connection with the embodiment may be included in at least one embodiment of the present application. The phrase appears in various places in the specification and does not necessarily refer to the same embodiment, nor is it an independent or alternative embodiment mutually exclusive with other embodiments. It is explicitly and implicitly understood by those skilled in the art that the embodiments described in the present invention may be combined with other embodiments.

[0091] Traditional anticoagulant coatings such as hydrophilic coatings include hydrophilic polymer coatings such as polyethylene glycol, polyvinylpyrrolidone, and polyacrylic acid, or zwitterionic polymer coatings such as polyphosphorylcholine, poly(sulfobetaine), and poly(carboxybetaine). The above hydrophilic coatings all have good hydrophilic ability, can effectively avoid non-specific adsorption of proteins in the blood, and thus reduce the risk of thrombus formation. However, the anticoagulant effect of a single hydrophilic coating is limited. Heparin-based anticoagulant coatings are also a type of coating that has been relatively maturely studied at present, but there are still problems of heparin detachment and failure during long-term use of such coatings.

[0092] Based on this, a first aspect of the present invention provides an anticoagulant medical device. Please refer to Figure 1 , including a substrate 110, a hydrophilic anticoagulant layer 120, and a heparin anticoagulant layer 130;

[0093] Among them, the hydrophilic anticoagulant layer 120 is covalently connected to the surface of the substrate 110 by means of atom transfer radical polymerization, and the heparin anticoagulant layer 130 is connected to the hydrophilic anticoagulant layer 120 by a covalent bond, and the covalent bond includes one or several of a triazole bond, an amide bond, a carbon-nitrogen single bond, and a carbon-sulfur single bond.

[0094] Atom transfer radical polymerization (ATRP) is a method of controlled radical polymerization, which has the characteristics of controllable polymer structure, narrow molecular weight distribution, and mild reaction conditions. Therefore, it is easy to prepare a hydrophilic anticoagulant layer 120 on the material surface by ATRP technology to achieve the anti-non-specific adsorption ability of the material. In addition, the hydrophilic anticoagulant layer 120 prepared by ATRP technology still has a structure with an alkyl halide or aryl halide at the end. The halogen is an easily leaving group and can undergo various substitution reactions to achieve further functionalization. Based on this, the inventor found that a heparin can be further grafted using the end-functionalized hydrophilic anticoagulant layer to prepare an anticoagulant medical device.

[0095] In some embodiments, the material of the substrate 110 includes one or a combination of more than one of a metal-based biomaterial, a silicon-based biomaterial, and a polymer-based biomaterial. It can be understood that when the material of the substrate 110 includes a combination of multiple materials among a metal-based biomaterial, a silicon-based biomaterial, and a polymer-based biomaterial, it can be obtained by laminating multiple materials or by mixing multiple materials and then preparing. Optionally, the material of the substrate 110 includes a polymer-based biomaterial. Optionally, the material of the substrate 110 includes one or a combination of several of polyethylene, polypropylene, polycarbonate, polyester, polymethylpentene, and polylactic acid.

[0096] In some embodiments, the material of the hydrophilic anticoagulant layer 120 includes one or a combination of more than one of polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyacrylamide (PAAm), poly(2-hydroxyethyl methacrylate) (PHEMA), poly(2-hydroxyethyl acrylamide) (PHEAA), potassium 3-sulfopropyl methacrylate (PSMP), polyvinylpyrrolidone (PVP), and zwitterionic polymers. Among them, the zwitterionic polymer has the following general formula (I) structure:

[0097]

[0098] In formula (I), R 1 includes a zwitterionic group, R 2 includes -NH- or -O-, R 3 includes -H or -CH 3 .

[0099] Specifically, the zwitterionic group includes phosphorylcholine (PC), sulfobetaine (SB), or carboxybetaine (CB).

[0100] Optionally, the material of the hydrophilic anticoagulant layer 120 includes one or several of polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), poly(2-hydroxyethyl methacrylate) (PHEMA), and the polymer of 2-(methacryloyloxy)ethyl-2-(trimethylammonio)ethyl phosphate.

[0101] In some embodiments, the thickness of the hydrophilic anticoagulant layer 120 is 0.1 μm to 10 μm.

[0102] In some embodiments, the water contact angle on the surface of the anticoagulant medical device is less than 50°. For example, the water contact angle on the surface of the anticoagulant medical device can be, but is not limited to, 48°, 46°, 44°, 42°, 40°, 38°, 36°, 34°, 32°, 30°, 28°, or the range formed by any two of these values.

[0103] In some embodiments, the material of the heparin anticoagulant layer 130 includes one or more combinations of heparin, heparin derivatives, and heparinoids. Optionally, the molecular weight of the material of the heparin anticoagulant layer 130 is 1500-10000. For example, the molecular weight of the material of the heparin anticoagulant layer can be, but is not limited to, 1500, 2000, 4000, 5000, 6000, 8000, 10000, or the range composed of any two of these values.

[0104] In some embodiments, the heparin density on the surface of the anticoagulant medical device is not less than 0.5 μg / cm 2 . It can be understood that not less than 0.5 μg / cm 2 means ≥0.5 μg / cm 2 . For example, the heparin density on the surface of the anticoagulant medical device can be, but is not limited to, 0.5 μg / cm 2 , 0.6 μg / cm 2 , 0.8 μg / cm 2 , 1 μg / cm 2 , 1.2 μg / cm 2 , 1.4 μg / cm 2 , 1.6 μg / cm 2 , 1.8 μg / cm 2 , 2 μg / cm 2 or the range composed of any two of these values. Optionally, the heparin density on the surface of the anticoagulant medical device is not less than 1 μg / cm 2 . Further, the heparin density on the surface of the anticoagulant medical device is not less than 1.5 μg / cm 2 .

[0105] The above anticoagulant medical device has at least the following advantages:

[0106] (1) The above anticoagulant medical device includes a substrate 110 and a hydrophilic anticoagulant layer 120 and a heparin anticoagulant layer 130 formed on the surface of the substrate 110, which can respectively exert the anti-protein adsorption of the hydrophilic anticoagulant layer 120 and the anticoagulant function of the heparin anticoagulant layer 130. The two work together to further improve the anticoagulant performance. At the same time, the hydrophilic anticoagulant layer 120 is covalently connected to the surface of the substrate 110 by atom transfer radical polymerization (ATRP), and the covalent grafting of heparin is realized by using the terminal halogen functionalization of ATRP, making full use of its reactivity, so that the heparin anticoagulant layer 130 and the hydrophilic anticoagulant layer 120 are connected by one or several covalent bonds among triazole bonds, amide bonds, carbon-nitrogen single bonds, and carbon-sulfur single bonds, and are not easily detached under the scouring of blood flow during use, having excellent long-term stability and enabling long-term anticoagulation.

[0107] (2) The hydrophilic anticoagulant layer 120 in the above-mentioned anticoagulant medical device is prepared by ATRP technology, which can effectively control the structure and molecular weight of the hydrophilic anticoagulant layer 120. Thus, for the constituent materials of different instruments, the thickness of the hydrophilic anticoagulant layer 120 can be effectively adjusted, and the influence of the hydrophilic anticoagulant layer 120 on the performance of the material itself can be reduced. When preparing the hydrophilic anticoagulant layer by other polymerization methods, there are uncontrollable situations, and the polymer is prone to form a cross-linked network structure, embedding the active centers and making it impossible to graft the heparin anticoagulant layer.

[0108] The second aspect of the present invention provides a preparation method of an anticoagulant medical device, including the following steps:

[0109] Covalently connect a hydrophilic anticoagulant layer on the surface of the substrate by atom transfer radical polymerization;

[0110] Covalently connect a heparin anticoagulant layer on the surface of the hydrophilic anticoagulant layer to prepare an anticoagulant medical device. The heparin anticoagulant layer and the hydrophilic anticoagulant layer are covalently connected by one or more of covalent bonds such as triazole bond, amide bond, carbon-nitrogen single bond, and carbon-sulfur single bond.

[0111] In some embodiments, the step of covalently connecting a hydrophilic anticoagulant layer on the surface of the substrate by atom transfer radical polymerization includes:

[0112] Graft an initiator group on the surface of the substrate, and the initiator group includes a halogen group;

[0113] Obtain a first solution including a hydrophilic anticoagulant monomer, a first catalyst, and a first ligand, and treat the substrate grafted with the initiator group with the first solution, so that the hydrophilic anticoagulant monomer undergoes atom transfer radical polymerization on the surface of the substrate grafted with the initiator group under the action of the initiator group, the first catalyst, and the first ligand.

[0114] Specifically, in the step of covalently connecting a hydrophilic anticoagulant layer on the surface of the substrate by atom transfer radical polymerization, the end of the hydrophilic anticoagulant layer is provided with an initiator group, and the initiator group includes a halogen group.

[0115] In some embodiments, the step of covalently connecting a heparin anticoagulant layer on the surface of the hydrophilic anticoagulant layer includes:

[0116] Introduce one or more of an azide group, an amino group, and a thiol group at the end of the polymer in the hydrophilic anticoagulant layer to obtain a functionalized hydrophilic anticoagulant layer;

[0117] Perform one or more of an azide-alkyne reaction, an amide reaction, an aldehyde-amine condensation reaction, and a thiol-ene reaction on the functionalized hydrophilic anticoagulant layer and a heparin substance, so that the heparin substance is covalently grafted onto the surface of the functionalized hydrophilic anticoagulant layer to prepare a heparin anticoagulant layer.

[0118] Please refer to Figure 2 , in some embodiments, the method for preparing an anticoagulant medical device includes the following steps S210 to S240:

[0119] Step S210: Graft initiator groups on the surface of the substrate.

[0120] It can be understood that the initiator groups are initiator groups for atom transfer radical polymerization. In some embodiments, the initiator groups include halogen groups. Specifically, the initiator groups include one or a combination of several of α-halophenyl compounds, α-halocarbonyl compounds, α-halonitrile compounds, polyhalogen compounds, and sulfonyl halides.

[0121] In some embodiments, the material of the substrate includes a combination of one or more of metal-based biomaterials, silicon-based biomaterials, and polymer-based biomaterials. It can be understood that when the material of the substrate includes a combination of multiple metal-based biomaterials, silicon-based biomaterials, and polymer-based biomaterials, it can be a multi-layer obtained by laminating multiple materials or a single layer prepared by mixing multiple materials. Optionally, the material of the substrate includes polymer-based biomaterials. Optionally, the material of the substrate includes a combination of one or several of polyethylene, polypropylene, polycarbonate, polyester, polymethylpentene, and polylactic acid.

[0122] The following provides two methods for grafting initiator groups on the surface of the substrate, but is not limited thereto:

[0123] Method 1. In some embodiments, the step of grafting initiator groups on the surface of the substrate includes:

[0124] Obtain a substrate with hydroxyl groups on its surface;

[0125] Perform a silanization reaction between the silanization reagent containing initiator groups and the hydroxyl groups on the surface of the substrate to graft initiator groups on the surface of the substrate.

[0126] In some of these embodiments, the preparation steps of the substrate with hydroxyl groups on its surface include: obtaining a substrate with hydroxyl groups on its surface by surface activation of the substrate. Specifically, the methods for surface activation of the substrate include one or a combination of plasma treatment, strong oxidant oxidation method, and ultraviolet light irradiation method. Among them, the strong oxidant oxidation method can include, but is not limited to, piranha solution treatment and persulfate oxidation method.

[0127] In some of these embodiments, the silanizing reagent containing an initiator group includes one or more combinations of (3-bromopropyl)trimethoxysilane, (3-bromopropyl)triethoxysilane, (3-chloropropyl)trimethoxysilane, (3-bromopropyl)trichlorosilane, 1-bromo-4-(trimethoxysilyl)benzene, and (3-chloropropyl)trichlorosilane.

[0128] In some of these embodiments, the silanizing reagent containing an initiator group reacts in the form of a solution, in which the mass percentage concentration of the silanizing reagent containing an initiator group is 5% to 30%. Optionally, in the solution, the mass percentage concentration of the silanizing reagent containing an initiator group can be but is not limited to 5%, 8%, 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, or the range composed of any two of these values. Optionally, in the solution, the mass percentage concentration of the silanizing reagent containing an initiator group is 5% to 10%.

[0129] In some of these embodiments, in the solution of the silanizing reagent containing an initiator group, the solvent includes one or more combinations of water, methanol, ethanol, isopropanol, butanol, and cyclohexanol. In a specific example, the solvent includes a mixture of water and ethanol.

[0130] In some of these embodiments, the temperature of the silanization reaction is 25°C to 60°C, and the time is 3h to 24h. Optionally, the temperature of the silanization reaction can be but is not limited to 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, or the range composed of any two of these values. The time of the silanization reaction can be but is not limited to 3h, 6h, 9h, 12h, 15h, 18h, 21h, 24h, or the range composed of any two of these values.

[0131] In some of these embodiments, the step of grafting an initiator group on the substrate surface includes: immersing the substrate with a hydroxyl group on its surface in a solution of the silanizing reagent containing an initiator group, and carrying out a silanization reaction between the silanizing reagent containing an initiator group and the hydroxyl group on the substrate surface at 25°C to 60°C for 3h to 24h to graft an initiator group on the substrate surface. Among them, in the solution of the silanizing reagent containing an initiator group, the mass percentage concentration of the silanizing reagent containing an initiator group is 5% to 30%.

[0132] Method 2. In some other embodiments, the step of grafting an initiator group on the substrate surface includes:

[0133] Obtaining a substrate with an amino group on its surface;

[0134] Carrying out an acylation reaction between the acyl halide reagent containing an initiator group and the amino group on the substrate surface.

[0135] In some of these embodiments, the substrate is surface-activated to prepare a substrate with amino groups on its surface. Specifically, the method for surface-activating the substrate includes one or a combination of two of plasma treatment and chemical grafting. In a specific example, the method for surface-activating the substrate includes ammonia plasma treatment. For example, the substrate is placed in ammonia plasma and treated for 20 min.

[0136] In some of these embodiments, the acyl halide reagent containing an initiator group includes one or a combination of two of chloroacetyl chloride and 2-bromo-2-methylpropionyl bromide (BiBB).

[0137] In some of these embodiments, the acyl halide reagent containing an initiator group reacts in the form of a solution. In the solution, the mass percentage concentration of the acyl halide reagent containing an initiator group is 5% to 30%. Optionally, in the solution, the mass percentage concentration of the acyl halide reagent containing an initiator group can be but is not limited to 5%, 8%, 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30% or the range formed by any two of these values. Optionally, in the solution, the mass percentage concentration of the acyl halide reagent containing an initiator group is 5% to 10%.

[0138] In some of these embodiments, the acyl halide reagent containing an initiator group reacts in the form of a solution. In the solution, the solvent includes one or a combination of more of water, N,N-dimethylformamide (DMF), tetrahydrofuran (THF), and diethyl ether.

[0139] In some of these embodiments, in the step of acylation reaction, a third catalyst can also be added. For example, the third catalyst includes triethylamine.

[0140] In some of these embodiments, the temperature of the acylation reaction is 0°C to 25°C, and the time is 5 h to 48 h. Optionally, the acylation reaction temperature can be but is not limited to 0°C, 2°C, 5°C, 8°C, 10°C, 12°C, 15°C, 18°C, 20°C, 22°C, 25°C or the range formed by any two of these values. Optionally, the acylation reaction time can be but is not limited to 5 h, 10 h, 12 h, 15 h, 20 h, 24 h, 30 h, 36 h, 40 h, 48 h or the range formed by any two of these values. Optionally, the time of the acylation reaction is 8 h to 24 h.

[0141] In some of these embodiments, the step of grafting initiator groups onto the substrate surface includes: immersing the substrate with amino groups on its surface in a solution of an acyl halide reagent containing initiator groups, and allowing the acyl halide groups in the acyl halide reagent containing initiator groups to undergo an acylation reaction with the amino groups on the substrate surface at 0°C to 25°C for 5 h to 48 h. In the solution, the mass percentage concentration of the acyl halide reagent containing initiator groups is 5% to 30%.

[0142] Step S220: Treat the substrate grafted with initiator groups with a first solution including a hydrophilic anticoagulant monomer, a first catalyst, and a first complexing agent, so that the hydrophilic anticoagulant monomer undergoes atom transfer radical polymerization on the surface of the substrate grafted with initiator groups under the action of the initiator groups, the first catalyst, and the first complexing agent to prepare a hydrophilic anticoagulant layer.

[0143] In some embodiments, in the first solution, the mass percentage concentration of the hydrophilic anticoagulant monomer is 1% to 50%. For example, the mass percentage concentration of the hydrophilic anticoagulant monomer can be, but is not limited to, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or the range formed by any two of these values. Preferably, in the first solution, the mass percentage concentration of the hydrophilic anticoagulant monomer is 5% to 30%.

[0144] In some embodiments, the molar ratio of the carbon-carbon double bond, the first catalyst, and the first complexing agent in the hydrophilic anticoagulant monomer is 1:(0.005 to 0.1):(0.005 to 0.5). For example, the molar ratio of the carbon-carbon double bond to the first catalyst in the hydrophilic anticoagulant monomer is 1:0.005, 1:0.008, 1:0.01, 1:0.02, 1:0.03, 1:0.04, 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.1, or the range formed by any two of these values. The molar ratio of the carbon-carbon double bond to the first complexing agent in the hydrophilic anticoagulant monomer can be, but is not limited to, 1:0.005, 1:0.008, 1:0.01, 1:0.02, 1:0.04, 1:0.05, 1:0.06, 1:0.08, 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, or the range formed by any two of these values.

[0145] Preferably, the molar ratio of the carbon-carbon double bond, the first catalyst, and the first complexing agent in the hydrophilic anticoagulant monomer is 1:(0.01 to 0.1):(0.01 to 0.3).

[0146] In some embodiments, the hydrophilic anticoagulant monomer includes one or a combination of more than one of acrylamide, 2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylamide, potassium 3-sulfopropyl methacrylate, N-vinylpyrrolidone, acrylate-capped oligomers, methacrylate-capped oligomers, and zwitterionic monomers.

[0147] Specifically, the acrylate-capped or methacrylate-capped oligomer includes PEG, PHEMA, PHEAA, or PVP, with a molecular weight of 800 to 3000. It can be understood that in the acrylate-capped or methacrylate-capped oligomer, the acrylate or methacrylate can cap one end or both ends.

[0148] Specifically, the structural formula of the zwitterionic monomer is as follows:

[0149] In formula (II), R 1 includes a zwitterionic group, R 2 includes -NH- or -O-, R 3 includes -H or -CH 3 , and the zwitterionic group includes phosphorylcholine (PC), sulfobetaine (SB), or carboxybetaine (CB).

[0150] Optionally, the hydrophilic anticoagulant monomer includes one or several of N-vinylpyrrolidone, 2-hydroxyethyl methacrylate, polyethylene glycol with methacrylate capping at both ends and a molecular weight of 1000, and zwitterionic monomers.

[0151] Optionally, the hydrophilic anticoagulant monomer includes zwitterionic monomers.

[0152] In a specific example, the zwitterionic monomer includes, but is not limited to, 2-(methacryloyloxy)ethyl-2-(trimethylammonio)ethyl phosphate.

[0153] In some embodiments, the first catalyst includes one or a combination of more than one of low-valent salts of copper, iron, molybdenum, chromium, rhenium, ruthenium, rhodium, and nickel. It can be understood that the low-valent salt of a metal refers to, for a metal with variable valences, the salt formed by the metal with a lower valence. For example, copper has two valences of +1 and +2, and the low-valent salt of copper refers to the salt formed by +1-valent copper, such as CuCl. The same applies to the low-valent salts of other metals. Preferably, the first catalyst includes one or several of CuCl, FeCl 2 and RuCl 2 .

[0154] In some embodiments, the first ligand includes one or a combination of more than one of amine substances and phosphine substances. Specifically, the amine substances include one or a combination of more than one of N,N,N,N,N-pentamethyldiethylenetriamine, 1,1,4,7,10,10-hexamethyltriethylenetetramine, tris[2-(dimethylamino)ethyl]amine, tris(2-pyridylmethyl)amine, 1,4,8,11-tetraazacyclotetradecane, 2,2'-bipyridine, 4,4'-di-tert-butyl-2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, and 4,4'-bis(trifluoromethyl)-2,2'-bipyridine. The phosphine substances include triphenylphosphine. Preferably, the first ligand includes one of N,N,N,N,N-pentamethyldiethylenetriamine, tris[2-(dimethylamino)ethyl]amine, and 4,4'-di-tert-butyl-2,2'-bipyridine.

[0155] In some embodiments, in the first solution, the solvent includes one or a combination of more than one of benzene, toluene, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, N,N'-dimethylformamide, ethanol, methanol, isopropanol, and water. In a specific example, in the first solution, the solvent includes ethanol or a mixture of ethanol and water.

[0156] In some embodiments, the first solution further contains a first reducing agent. By adding the first reducing agent, the progress of the ATRP reaction can be further promoted. The first reducing agent includes a high-valent salt corresponding to the metal used in the first catalyst or a radical thermal initiator. Among them, the radical thermal initiator includes one or a combination of more than one of azobisisobutyronitrile (AIBN), azobisisoheptonitrile (AIVN), benzoyl peroxide (BPO), di-tert-butyl peroxide (DTBP), tert-butyl perpivalate (BPP), bis(4-tert-butylcyclohexyl) peroxydicarbonate (TBCP), and diisobutyl peroxydicarbonate (IBP).

[0157] It can be understood that the first reducing agent includes a high-valent salt corresponding to the metal used in the first catalyst means that for a metal with variable valence, it is a salt formed by the metal with a higher valence. For example, the first catalyst includes CuCl, and the first reducing agent includes CuCl 2 。

[0158] Specifically, the molar ratio of the first reducing agent to the first catalyst is (0.1 - 0.3):1. For example, the molar ratio of the first reducing agent to the first catalyst can be but is not limited to 0.1:1, 0.12:1, 0.15:1, 0.18:1, 0.2:1, 0.22:1, 0.25:1, 0.28:1, 0.3:1, or a range composed of any two of these values.

[0159] In some embodiments, the step of treating the substrate grafted with an initiator group with a first solution to cause atom transfer radical polymerization of a hydrophilic anticoagulant monomer on the surface of the substrate grafted with an initiator group includes: immersing the substrate grafted with an initiator group in the first solution, and causing the hydrophilic anticoagulant monomer to undergo atom transfer radical polymerization on the surface of the substrate grafted with an initiator group at 25°C to 70°C for 2 h to 24 h under airtight conditions.

[0160] Optionally, the time of the ATRP reaction can be, but is not limited to, 2 h, 5 h, 10 h, 12 h, 15 h, 18 h, 20 h, 24 h, or the range formed by any two of these values. Further, the time of the ATRP polymerization reaction is 5 h to 10 h.

[0161] Optionally, the reaction temperature can be, but is not limited to, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, or the range formed by any two of these values.

[0162] It can be understood that the ATRP polymerization process can be protected by an inert gas or not. Preferably, the ATRP polymerization process is protected by nitrogen or argon.

[0163] In some embodiments, step S220 includes:

[0164] Obtaining a first solution including a hydrophilic anticoagulant monomer, a first catalyst, and a first ligand. In the first solution, the mass percentage concentration of the hydrophilic anticoagulant monomer is 1% to 50%, and the molar ratio of the carbon-carbon double bond, the first catalyst, and the first ligand in the hydrophilic anticoagulant monomer is 1:(0.005 to 0.1):(0.005 to 0.5);

[0165] Immersing the substrate grafted with an initiator group in the first solution, and causing the hydrophilic anticoagulant monomer to undergo atom transfer radical polymerization on the surface of the substrate grafted with an initiator group at 25°C to 70°C for 2 h to 24 h under airtight conditions to prepare a hydrophilic anticoagulant layer.

[0166] Step S230: Introducing one or more of an azide group, an amino group, and a thiol group at the end of the polymer in the hydrophilic anticoagulant layer to obtain a functionalized hydrophilic anticoagulant layer.

[0167] In some embodiments, the step of introducing an azide group at the end of the polymer in the hydrophilic anticoagulant layer includes: immersing the substrate with the hydrophilic anticoagulant layer in a solution containing an azidating reagent and reacting at 10°C to 50°C for 3 h to 24 h.

[0168] Specifically, in the solution containing the azide reagent, the mass percentage concentration of the azide reagent is 1% to 10%. Optionally, in the solution containing the azide reagent, the mass percentage concentration of the azide reagent can be, but is not limited to, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or the range composed of any two of these values.

[0169] Optionally, the temperature for reacting with the azide reagent can be, but is not limited to, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, or the range composed of any two of these values. Optionally, the reaction time with the azide reagent can be, but is not limited to, 3 h, 5 h, 10 h, 12 h, 15 h, 18 h, 20 h, 24 h, or the range composed of any two of these values.

[0170] In some embodiments, the azide reagent is a reagent containing an azide group. Specifically, the azide reagent includes one or a combination of several of sodium azide, trimethylsilyl azide, and diphenylphosphate azide.

[0171] In some embodiments, in the solution containing the azide reagent, the solvent includes a combination of one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, tetrahydrofuran, and dimethylformamide. Preferably, in the solution containing the azide reagent, the solvent is an anhydrous solvent.

[0172] It can be understood that during the reaction with the azide reagent, it can be protected by an inert gas or not. Preferably, it is protected by nitrogen or argon during the reaction with the azide reagent.

[0173] In other embodiments, the step of introducing an amino group at the end of the polymer in the hydrophilic anticoagulant layer includes:

[0174] Introducing an azide group at the end of the polymer in the hydrophilic anticoagulant layer;

[0175] Immersing the substrate with the azide-functionalized hydrophilic anticoagulant layer in an anhydrous ether solution containing a second reducing agent, and reacting at 25°C to 50°C for 1 h to 5 h to make the end of the polymer in the hydrophilic anticoagulant layer carry an amino group.

[0176] Specifically, in the anhydrous ether solution containing the second reducing agent, the mass percentage concentration of the second reducing agent is 0.1% to 5%. Optionally, in the anhydrous ether solution containing the second reducing agent, the mass percentage concentration of the second reducing agent can be, but is not limited to, 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, or the range composed of any two of these values.

[0177] Optionally, the second reducing agent includes LiAlH 4 .

[0178] It can be understood that during the process of introducing amino groups at the ends of the polymers in the hydrophilic anticoagulant layer, it can be protected by an inert gas or not. Preferably, during the process of introducing amino groups at the ends of the polymers in the hydrophilic anticoagulant layer, it is protected by nitrogen or argon.

[0179] In some other embodiments, the step of introducing thiol groups at the ends of the polymers in the hydrophilic anticoagulant layer includes: immersing the substrate with the hydrophilic anticoagulant layer in a thiourea solution, reacting at 80°C to 100°C under the protection of an inert gas for 8h to 24h, and then reacting the reaction product with a basic reagent at 90°C to 110°C for 8h to 24h.

[0180] Specifically, in the thiourea solution, the mass percentage concentration of thiourea is 0.1% to 1%. For example, in the thiourea solution, the mass percentage concentration of thiourea can be but is not limited to 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1% or the range composed of any two of these values.

[0181] Optionally, in the thiourea solution, the solvent includes DMF (N,N-dimethylformamide).

[0182] In some of these embodiments, the molar ratio of the basic reagent to thiourea is 1:1.

[0183] In some of these embodiments, the basic reagent is added in the form of a solution, and in the solution containing the basic reagent, the concentration of the basic reagent is 3mol / L to 5mol / L. Optionally, in the solution containing the basic reagent, the concentration of the basic reagent can be but is not limited to 3mol / L, 3.2mol / L, 3.5mol / L, 3.8mol / L, 4mol / L, 4.2mol / L, 4.5mol / L, 4.8mol / L, 5mol / L or the range composed of any two of these values.

[0184] During the ATRP polymerization process, the ends will contain halogen functional groups. Utilizing the reactivity of the halogen functional groups, it can have a variety of groups that can react with heparin, so that heparin can be covalently grafted on the surface of the hydrophilic anticoagulant layer, improving the anticoagulant ability while also improving the long-term stability.

[0185] Step S240: React the functionalized hydrophilic anticoagulant layer with heparin-like substances through one or more of the azide-alkyne reaction, amide reaction, aldehyde-amine condensation reaction, and thiol-ene reaction, so that the heparin-like substances are covalently grafted onto the surface of the functionalized hydrophilic anticoagulant layer to form a heparin anticoagulant layer.

[0186] In some embodiments, the step of performing an azide-alkyne reaction between a functionalized hydrophilic anticoagulant layer and a heparin-like substance includes: immersing a substrate with an azide-functionalized hydrophilic anticoagulant layer in a second solution containing an alkynylated heparin-like substance, a copper(I) catalyst, and a second ligand, and reacting at 20°C to 35°C for 5 h to 12 h.

[0187] For example, the temperature of the azide-alkyne reaction can be, but is not limited to, 20°C, 22°C, 25°C, 28°C, 30°C, 32°C, 35°C, or a range composed of any two of these values. The time of the azide-alkyne reaction can be, but is not limited to, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, or a range composed of any two of these values.

[0188] In some of these embodiments, in the second solution, the mass percentage concentration of the alkynylated heparin-like substance is 0.1% to 10%, the mass percentage concentration of the copper(I) catalyst is 0.01 to 1%, and the molar ratio of the second ligand to the copper(I) catalyst is (1 to 1.2):1. For example, in the second solution, the mass percentage concentration of the alkynylated heparin-like substance can be, but is not limited to, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or a range composed of any two of these values. In the second solution, the mass percentage concentration of the copper(I) catalyst can be, but is not limited to, 0.01%, 0.05%, 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1%, or a range composed of any two of these values.

[0189] Optionally, in the second solution, the mass percentage concentration of the alkynylated heparin-like substance is 0.5% to 5%.

[0190] In some of these embodiments, in the second solution, the solvent includes one or more combinations of water, methanol, ethanol, isopropanol, and acetone.

[0191] In some of these embodiments, the copper(I) catalyst includes one or more combinations of CuBr, CuCl, and CuI. The second ligand includes one or more combinations of N,N,N',N',N''-pentamethyldiethylenetriamine, 2,2'-bipyridine, and tris(2-dimethylaminoethyl)amine-based tripropylene glycol methyl ether acetate.

[0192] It can be understood that the azide-alkyne reaction process can be protected by an inert gas or not. Preferably, the azide-alkyne reaction process is protected by nitrogen or argon.

[0193] In some of these embodiments, the alkynylated heparin-like substances can be prepared by the following steps: modifying heparin-like substances with a carboxylic acid containing a carbon-carbon triple bond, an acid anhydride containing a carbon-carbon triple bond, or an amine containing a carbon-carbon triple bond to prepare alkynylated heparin-like substances. Or modifying aldehyde-group-containing heparin-like substances with an amine containing a carbon-carbon triple bond to prepare alkynylated heparin-like substances.

[0194] Specifically, in the step of modifying heparin-like substances with a carboxylic acid containing a carbon-carbon triple bond or an acid anhydride containing a carbon-carbon triple bond, the heparin-like substances are reacted with the carboxylic acid containing a carbon-carbon triple bond or the acid anhydride containing a carbon-carbon triple bond in an alkaline solution for 3 h to 8 h, and the mass ratio of the heparin-like substances to the carboxylic acid containing a carbon-carbon triple bond or the acid anhydride containing a carbon-carbon triple bond is 1:(0.05 - 0.5).

[0195] Specifically, in the step of modifying heparin-like substances with an amine containing a carbon-carbon triple bond, the heparin-like substances are reacted with the amine containing a carbon-carbon triple bond under the action of an amide catalyst for 3 h to 24 h, the mass ratio of the heparin-like substances to the amine containing a carbon-carbon triple bond is 1:(0.05 - 0.5), and the molar ratio of the amide catalyst to the amine containing a carbon-carbon triple bond is 1:(0.8 - 1). Through the above steps, an amide reaction is carried out between the heparin-like substances and the amine containing a carbon-carbon triple bond, and alkynyl groups are introduced on the side of the main chain of the heparin-like substances.

[0196] Specifically, in the step of modifying aldehyde-group-containing heparin-like substances with an amine containing a carbon-carbon triple bond, the aldehyde-group-containing heparin-like substances are reacted with the amine containing a carbon-carbon triple bond in a solution with a pH of 3 - 6 at 0 °C to 40 °C for 1 h to 6 h, and then sodium cyanoborohydride is added and the reaction continues for 1 h to 3 h. The mass ratio of the aldehyde-group-containing heparin-like substances to the amine containing a carbon-carbon triple bond is 1:(0.05 - 0.5):(0.01 - 0.1). Through the above steps, an aldehyde-amine condensation reaction is carried out between the aldehyde-group-containing heparin-like substances and the amine containing a carbon-carbon triple bond, and alkynyl groups are introduced at the end of the main chain of the heparin-like substances.

[0197] In some other embodiments, the step of carrying out an amide reaction between the functionalized hydrophilic anticoagulant layer and the heparin-like substances includes: immersing a substrate with an aminated hydrophilic anticoagulant layer in a third solution containing heparin-like substances, an activator, and a condensing agent, and reacting at 0 °C to 25 °C for 1 h to 6 h.

[0198] For example, the temperature of the amide reaction can be but is not limited to 0 °C, 5 °C, 10 °C, 15 °C, 20 °C, 25 °C, or the range composed of any two of these values. The time of the amide reaction can be but is not limited to 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, or the range composed of any two of these values.

[0199] Among them, in the third solution, the mass percentage concentration of heparin-like substances is 0.1% to 10%. For example, the mass percentage concentration of heparin-like substances can be but is not limited to 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% or the range composed of any two of these values. Optionally, in the third solution, the mass percentage concentration of heparin-like substances is 0.5% to 5%.

[0200] In some of these embodiments, the mass ratio of the activator, the condensing agent, and the heparin-like substance is (1 to 1.2):(1 to 1.2):1.

[0201] In some of these embodiments, the solvent used in the third solution includes water or a buffer solution with a pH of 6 to 10.

[0202] In some of these embodiments, the activator includes one or more of N-hydroxysulfosuccinimide, 1-hydroxybenzotriazole, and 4-dimethylaminopyridine. The condensing agent includes one or more of dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, O-(7-azabenzotriazol-1-yl)-bis(dimethylamino)carbenium hexafluorophosphate, O-(benzotriazol-1-yl)-bis(dimethylamino)carbenium hexafluorophosphate, O-(5-chlorobenzotriazol-1-yl)-bis(dimethylamino)carbenium hexafluorophosphate, O-(benzotriazol-1-yl)-bis(dimethylamino)carbenium tetrafluoroborate, O-(N-succinimidyloxy)-bis(dimethylamino)carbenium tetrafluoroborate, and O-(N-endo-5-norbornene-2,3-dicarboximide)-bis(dimethylamino)carbenium tetrafluoroborate.

[0203] The heparin-like substance itself contains carboxyl groups and can undergo an amide reaction with the aminated hydrophilic anticoagulant layer, thereby connecting through an amide bond.

[0204] In some other embodiments, the step of performing an aldehyde-amine condensation reaction between the functionalized hydrophilic anticoagulant layer and the heparin-like substance includes: immersing the substrate with the aminated hydrophilic anticoagulant layer in a solution containing aldehyde-functionalized heparin-like substance, reacting at 20°C to 40°C for 1 h to 6 h, and continuing to react the reaction product with sodium cyanoborohydride for 1 h to 3 h.

[0205] In some of these embodiments, in an aqueous solution containing an aldehyde-group heparin-like substance, the mass percentage concentration of the aldehyde-group heparin-like substance is 0.1% to 10%. For example, in an aqueous solution containing an aldehyde-group heparin-like substance, the mass percentage concentration of the aldehyde-group heparin-like substance can be, but is not limited to, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or the range formed by any two of these values. Preferably, in an aqueous solution containing an aldehyde-group heparin-like substance, the mass percentage concentration of the aldehyde-group heparin-like substance is 0.5% to 5%.

[0206] Optionally, the mass percentage of sodium cyanoborohydride in the aldehyde-group heparin-like substance is 1% to 10%. For example, the mass percentage of sodium cyanoborohydride in the aldehyde-group heparin-like substance is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or the range formed by any two of these values.

[0207] In some of these embodiments, the preparation steps of the aldehyde-group heparin-like substance include: mixing and reacting the heparin-like substance with an oxidant under the conditions of a temperature of 0°C to 20°C and a pH of 2.5 to 4 to prepare the aldehyde-group heparin-like substance. Among them, the mass ratio of the heparin-like substance to the oxidant is 100:(0.1 to 5), and the oxidant includes any one or several of sodium nitrite, nitrous acid, periodic acid, and sodium periodate.

[0208] In some other embodiments, the step of performing a thiol-ene reaction between the functionalized hydrophilic anticoagulant layer and the heparin-like substance includes: immersing a substrate with a thiolated hydrophilic anticoagulant layer in a fourth solution containing a double-bonded heparin-like substance and an auxiliary agent, and reacting at 20°C to 80°C for 0.5 h to 5 h.

[0209] Among them, in the fourth solution, the mass percentage concentration of the double-bonded heparin-like substance is 0.1% to 10%, and the mass percentage concentration of the auxiliary agent is 0.01% to 2%. For example, in the fourth solution, the mass percentage concentration of the double-bonded heparin-like substance can be, but is not limited to, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or the range formed by any two of these values. The mass percentage concentration of the auxiliary agent can be, but is not limited to, 0.01%, 0.05%, 0.1%, 0.2%, 0.5%, 0.8%, 1%, 1.5%, 2%, or the range formed by any two of these values.

[0210] Optionally, in the fourth solution, the mass percentage concentration of the double-bonded heparin-like substance is 0.5% to 5%.

[0211] In some of these embodiments, the adjuvants include initiators and basic catalysts. The initiators include one or more of water-soluble thermal initiators and water-soluble photoinitiators. Among them, the water-soluble thermal initiators include one or more of potassium persulfate, ammonium persulfate, potassium persulfate / ferrous chloride, potassium persulfate / sodium sulfite, potassium persulfate / sodium thiosulfate, 2,2'-azobis(2-methyl-N-(2-hydroxyethyl)propionamide), 2,2'-azobis(2-methylpropionamidine) dihydrochloride, 2,2'-azobis(2-methylimidazoline) dihydrochloride, 2,2'-azobis(2-cyanovaleric acid), and 2,2'-azobis(isopropylimidazoline). It can be understood that potassium persulfate / ferrous chloride refers to a class of redox initiators composed of the oxidant potassium persulfate and the reductant ferrous chloride. Other potassium persulfate / sodium sulfite and potassium persulfate / sodium thiosulfate have similar meanings and will not be elaborated further.

[0212] Among them, the water-soluble photoinitiators include one or more combinations of 2-hydroxy-2-methyl-1-[4-(2-hydroxyethoxy)phenyl]-1-propanone, diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide, lithium phenyl(2,4,6-trimethylbenzoyl)phosphate, lithium bis(2,4,6-trimethylbenzoyl)phosphate, 2,2'-azobis(2-methyl-N-(2-hydroxyethyl)propionamide), riboflavin, and eosin Y.

[0213] Among them, the basic catalysts include one or more combinations of triethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, and triethylenediamine.

[0214] In some of these embodiments, the preparation steps of the double-bonded heparin-like substances include: modifying the heparin-like substances with a carboxylic acid containing a double bond, an acid anhydride containing a double bond, an epoxide containing a double bond, an amine containing a double bond, or an amide compound containing a double bond to prepare the double-bonded heparin-like substances. Or modifying the aldehyde-group heparin-like substances with an amine containing a double bond to prepare the double-bonded heparin-like substances.

[0215] Specifically, in the step of modifying the heparin-like substances with a carboxylic acid containing a double bond or an acid anhydride containing a double bond, the heparin-like substances are reacted with the carboxylic acid containing a double bond or the acid anhydride containing a double bond in an alkaline solution for 3 h to 8 h, and the mass ratio of the heparin-like substances to the carboxylic acid containing a double bond or the acid anhydride containing a double bond is 1:(0.05 - 0.5).

[0216] Specifically, in the step of modifying the heparin-like substances with an epoxide containing a double bond, the heparin-like substances are reacted with the epoxide containing a double bond in a solution with a pH of 7 to 8 for 3 days to 8 days, and the mass ratio of the heparin-like substances to the epoxide containing a double bond is 1:(0.3 - 1).

[0217] Specifically, in the step of modifying heparin-like substances with amines containing carbon-carbon double bonds, the heparin-like substances and the amines containing carbon-carbon double bonds are reacted for 3 h to 24 h under the action of an amide catalyst. The mass ratio of the heparin-like substances to the amines containing carbon-carbon double bonds is 1:(0.05 - 0.5), and the molar ratio of the amines containing carbon-carbon double bonds to the amide catalyst is 1:(0.8 - 1). Through the above steps, carbon-carbon double bonds are introduced on the side chain of the main chain of the heparin-like substances. Specifically, in the step of modifying heparin-like substances with amide compounds containing double bonds, the heparin-like substances and the amide compounds containing double bonds are stirred and reacted at 0 °C to 4 °C for 3 h to 8 h under the action of an activator and a condensing agent. The mass ratio of the heparin-like substances, the amide compounds containing double bonds, the activator, and the condensing agent is (1 - 1.2):(0.8 - 1):(0.8 - 1):(0.8 - 1).

[0218] Specifically, in the step of modifying aldehyde-group-containing heparin-like substances with amines containing double bonds, the aldehyde-group-containing heparin-like substances and the amines containing double bonds are reacted at 0 °C to 40 °C for 1 h to 6 h in a solution with a pH of 3 - 6, and then sodium cyanoborohydride is added and the reaction continues for 1 h to 3 h. The mass ratio of the aldehyde-group-containing heparin-like substances to the amines containing double bonds is 1:(0.05 - 0.5):(0.01 - 0.1). Through the above steps, carbon-carbon double bonds are introduced at the end of the main chain of the heparin-like substances.

[0219] Please refer to Figure 3 , Figure 3 which shows a schematic flow chart of a preparation method of the above anticoagulant medical device. After the substrate 110 is treated in step S210, an initiator 102 for atom transfer radical polymerization is grafted on the surface of the substrate 110. After further treatment in step S220, a hydrophilic anticoagulant layer 120 is grafted on the surface of the substrate 110. Then, after treatment in step S230 and step S240, a heparin anticoagulant layer 130 is covalently grafted onto the hydrophilic anticoagulant layer 120 to obtain the anticoagulant medical device.

[0220] The preparation method of the above anticoagulant medical device has at least the following advantages:

[0221] (1) In the preparation method of the above anticoagulant medical device, the hydrophilic anticoagulant layer and the heparin anticoagulant layer are grafted onto the substrate surface layer by layer, which can respectively exert the anti-protein adsorption of the hydrophilic anticoagulant layer and the anticoagulant function of heparin. The two work together to further improve the anticoagulant performance of the surface of the instrument. At the same time, both the hydrophilic anticoagulant layer and the substrate, and the hydrophilic anticoagulant layer and the heparin anticoagulant layer are chemically connected by covalent bonds, and are not likely to fall off under the scouring of blood flow during use, and have excellent long-term stability, and can truly achieve long-term anticoagulation.

[0222] (2) The preparation method of the above-mentioned anticoagulant medical device prepares a hydrophilic anticoagulant layer through ATRP technology. The structure and molecular weight of the hydrophilic anticoagulant layer can be effectively controlled, so that for different substrates, the thickness of the hydrophilic anticoagulant layer can be effectively adjusted, and the influence of the hydrophilic anticoagulant layer on the performance of the material itself can be reduced.

[0223] (3) The preparation method of the above-mentioned anticoagulant medical device utilizes the terminal halogen functionalization of ATRP to achieve the grafting of heparin. Making full use of its reactivity, after functionalizing it, heparin is covalently fixed on the hydrophilic anticoagulant layer through various chemical reactions, improving the anticoagulant ability while also improving the long-term stability.

[0224] (4) The preparation method of the above-mentioned anticoagulant medical device provides a series of functionalization methods and corresponding methods for grafting heparin, and different methods can be selected according to different materials, heparin density requirements, etc.

[0225] In order to make the purpose and advantages of the present invention clearer, the following further elaborates in detail on the anticoagulant medical device of the present invention and its effects in combination with specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and shall not be used to limit the present invention. Unless otherwise specified in the following examples, other components are not included except for inevitable impurities. The drugs and instruments used in the examples are all conventional selections in the art unless otherwise specified. The experimental methods without specific conditions noted in the examples are carried out according to conventional conditions, such as the conditions described in the literature, books, or the methods recommended by the manufacturers.

[0226] The heparin used in the following examples and comparative examples is enoxaparin, with a molecular weight of 3500 - 5000.

[0227] Comparative Example 1

[0228] Comparative Example 1 provides an anticoagulant medical device, and the preparation steps are as follows:

[0229] (1) Treat a polyethylene film in ammonia plasma for 20 min to make its surface carry amino groups, and then react with an aqueous solution of 4,4'-azobis(4-cyanovaleric acid) at room temperature for 24 h. The mass percentage concentration of 4,4'-azobis(4-cyanovaleric acid) is 10%, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole are added as catalysts. The molar ratio of the catalyst to 4,4'-azobis(4-cyanovaleric acid) is 0.5:1. After the reaction is completed, rinse with purified water 3 times to obtain a polyethylene film grafted with an azo initiator.

[0230] (2) Prepare an NVP ethanol solution with a mass percentage concentration of 10%. Put the polyethylene film grafted with an azo initiator into the solution, seal it, purge with nitrogen for 5 min, and then place it in an oven at 80 °C for reaction for 6 h. After the reaction is completed, take it out, rinse it 3 times with ethanol, and then rinse it 3 times with purified water to form a hydrophilic anti-coagulant layer on the surface of the polyethylene film, obtaining the anti-coagulant medical device of Comparative Example 1. Comparative Example 2

[0231] Comparative Example 2 provides an anti-coagulant medical device, and the preparation steps are as follows:

[0232] (1) Place the polyethylene film in ammonia plasma for treatment for 20 min to make the polyethylene film carry amino groups. Subsequently, react with a DMF solution of BiBB at 20 °C for 12 h. In the DMF solution of BiBB, the mass percentage concentration of BiBB is 10%. After the reaction is completed, first rinse it 3 times with DMF, and then rinse it 3 times with pure water to obtain a polyethylene film grafted with an ATRP initiator.

[0233] (2) Prepare an ethanol solution of NVP (N-vinylpyrrolidone) with a mass percentage concentration of 10%, add a CuCl catalyst and a tris[2-(dimethylamino)ethyl]amine ligand. Among them, the molar addition amounts of CuCl and tris[2-(dimethylamino)ethyl]amine are 2% and 5% of the molar amount of NVP, respectively. Subsequently, immerse the polyethylene film grafted with the ATRP initiator in the above solution, seal it, purge with nitrogen for 5 min, and then place it in an oven at 30 °C for reaction for 6 h. After the reaction is completed, take it out, first rinse it 3 times with ethanol, then rinse it 3 times with pure water, and dry it to form a hydrophilic anti-coagulant layer on the surface of the polyethylene film, obtaining the anti-coagulant medical device of Comparative Example 2.

[0234] Comparative Example 3

[0235] Comparative Example 3 provides an anti-coagulant medical device, and the preparation steps are as follows:

[0236] (1) Place the polyethylene film in ammonia plasma for treatment for 20 min to make the polyethylene film carry amino groups. Subsequently, react with a DMF solution of BiBB at 20 °C for 12 h. In the DMF solution of BiBB, the mass percentage concentration of BiBB is 10%. After the reaction is completed, first rinse it 3 times with DMF, and then rinse it 3 times with pure water to obtain a polyethylene film grafted with an ATRP initiator.

[0237] (2) Prepare an anhydrous methanol solution of sodium azide with a mass percentage concentration of 1%, purge with nitrogen for 5 min, then put the polyethylene film grafted with the ATRP initiator prepared in step (1), react at 20 °C for 8 h, first rinse it 3 times with anhydrous methanol, and then rinse it 3 times with pure water. Then, prepare a 1% LiAlH 4Put the anhydrous ether solution into the above polyethylene film. After reacting at 35 °C for 1 h, take it out, rinse it three times with anhydrous ether, and dry it to obtain an aminated polyethylene film.

[0238] (3) Prepare an aqueous heparin solution with a mass percentage concentration of 1%. Add N-hydroxysulfosuccinimide with the same mass as heparin and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide with the same mass as heparin. After maintaining at 0 °C for 5 min, add the aminated polyethylene film prepared in step (2). After carrying out an amide reaction at 25 °C for 2 h, take it out, rinse it three times with pure water, and graft a heparin anticoagulant layer on the polyethylene film to obtain the anticoagulant medical device of Comparative Example 3.

[0239] Example 1

[0240] This example provides an anticoagulant medical device, and the preparation steps are as follows:

[0241] (1) Place the polyethylene film in ammonia plasma for 20 min to make the polyethylene film carry amino groups. Subsequently, react with a DMF solution of BiBB at 20 °C for 12 h. In the DMF solution of BiBB, the mass percentage concentration of BiBB is 10%. After the reaction is completed, rinse it three times with DMF first, and then rinse it three times with pure water to obtain a polyethylene film grafted with an ATRP initiator.

[0242] (2) Prepare an ethanol solution of NVP with a mass percentage concentration of 10%. Add a CuCl catalyst and a tris[2-(dimethylamino)ethyl]amine ligand. Among them, the molar numbers of CuCl and tris[2-(dimethylamino)ethyl]amine are 2% and 5% of the molar number of NVP respectively. Subsequently, immerse the polyethylene film grafted with the ATRP initiator in the solution, seal it, purge with nitrogen for 5 min, and then put it into an oven at 30 °C for reaction for 6 h. After the reaction is completed, take it out, rinse it three times with ethanol first, and then rinse it three times with pure water, and dry it to obtain a polyethylene film grafted with a hydrophilic anticoagulant layer.

[0243] (3) Prepare an anhydrous methanol solution of sodium azide with a mass percentage concentration of 1%. After purging with nitrogen for 5 min, put the polyethylene film grafted with the hydrophilic anticoagulant layer prepared in step (2). After reacting at 20 °C for 8 h, take it out, rinse it three times with anhydrous methanol first, and then rinse it three times with pure water to obtain a polyethylene film grafted with an azide hydrophilic anticoagulant layer.

[0244] (4) Dissolve 1 g of aldehyde group heparin in 50 mL of purified water, adjust the pH to 3.5 with HCl, add 0.1 g of propargylamine, react at room temperature for 1 h, then add 0.05 g of sodium cyanoborohydride, and continue to react for 2 h. After the reaction is completed, adjust the pH = 7.0 with NaOH, dialyze, and freeze-dry to obtain alkynylated heparin

[0245] (5) Prepare a solution of alkynylated heparin with a mass percentage concentration of 1% (the solvent is a mixture of water and ethanol with a volume ratio of 8:2). Add CuCl accounting for one-tenth of the mass of alkynylated heparin and tris(2-dimethylaminoethyl)amine with an equimolar amount to CuCl. Bubble nitrogen for 5 min, then place the polyethylene film grafted with an azide-functionalized hydrophilic anticoagulant layer prepared in step (3). Conduct an azide-alkyne reaction at 30 °C for 8 h, then take it out and rinse it 3 times with pure water to obtain the anticoagulant medical device of this example.

[0246] Example 2

[0247] This example provides an anticoagulant medical device, and the preparation steps are as follows:

[0248] (1) Place the polyethylene film in ammonia plasma for 20 min to make the polyethylene film carry amino groups. Subsequently, react with a DMF solution of BiBB at 20 °C for 12 h. In the DMF solution of BiBB, the mass percentage concentration of BiBB is 10%. After the reaction, rinse it 3 times with DMF first, and then rinse it 3 times with pure water to obtain a polyethylene film grafted with an ATRP initiator.

[0249] (2) Prepare an ethanol solution of NVP with a mass percentage concentration of 10%, and add a CuCl catalyst and a tris[2-(dimethylamino)ethyl]amine complexing agent. Among them, the molar addition amounts of CuCl and tris[2-(dimethylamino)ethyl]amine are 2% and 5% of the molar amount of NVP respectively. Subsequently, place the polyethylene film grafted with an ATRP initiator into the solution, seal it, bubble nitrogen for 5 min, and then place it in an oven at 30 °C for 6 h. After the reaction, take it out, rinse it 3 times with ethanol first, then rinse it 3 times with pure water, and dry it to obtain a polyethylene film grafted with a hydrophilic anticoagulant layer.

[0250] (3) Prepare an anhydrous methanol solution of sodium azide with a mass percentage concentration of 1%. After bubbling nitrogen for 5 min, place the polyethylene film grafted with a hydrophilic anticoagulant layer prepared in step (2). React at 20 °C for 8 h, then take it out and rinse it 3 times with anhydrous methanol first, and then rinse it 3 times with pure water. Then, prepare an anhydrous ether solution of LiAlH 4 and place the above polyethylene film into it. React at 35 °C for 1 h, then take it out and rinse it 3 times with anhydrous ether, and dry it in an oven to obtain a polyethylene film grafted with an amino-functionalized hydrophilic anticoagulant layer.

[0251] (4) Prepare an aqueous heparin solution with a mass percentage concentration of 1%. Add N-hydroxysulfosuccinimide with the same mass as heparin and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide with the same mass as heparin. After maintaining at 0 °C for 5 min, add the polyethylene film grafted with an amino-functionalized hydrophilic anticoagulant layer prepared in step (3). Carry out an amide reaction at 25 °C for 2 h, then take it out and rinse it 3 times with pure water to obtain the anticoagulant medical device of this example.

[0252] Example 3

[0253] This example provides an anticoagulant medical device, and the preparation steps are as follows:

[0254] (1) Place the polyethylene film in ammonia plasma for treatment for 20 min to make the polyethylene film carry amino groups. Subsequently, react with a DMF solution of BiBB at 20 °C for 12 h. In the DMF solution of BiBB, the mass percentage concentration of BiBB is 10%. After the reaction, rinse it 3 times with DMF first, and then rinse it 3 times with pure water to obtain a polyethylene film grafted with an ATRP initiator.

[0255] (2) Prepare an ethanol solution of NVP with a mass percentage concentration of 10%, and add a CuCl catalyst and a tris[2-(dimethylamino)ethyl]amine complexing agent. Among them, the molar addition amounts of CuCl and tris[2-(dimethylamino)ethyl]amine are 2% and 5% of the molar amount of NVP respectively. Subsequently, immerse the polyethylene film grafted with the ATRP initiator in the above solution, seal it, purge with nitrogen for 5 min, and then place it in an oven at 30 °C for reaction for 6 h. After the reaction, take it out, rinse it 3 times with ethanol first, then rinse it 3 times with pure water, and dry it to obtain a polyethylene film grafted with a hydrophilic anticoagulant layer.

[0256] (3) Prepare an anhydrous methanol solution of sodium azide with a mass percentage concentration of 1%. After purging with nitrogen for 5 min, put the polyethylene film grafted with the hydrophilic anticoagulant layer prepared in step (2) into it. After reacting at 20 °C for 8 h, take it out and rinse it 3 times with anhydrous methanol first, and then rinse it 3 times with pure water. Then, prepare an anhydrous ether solution of LiAlH 4 with a mass percentage concentration of 1%, put the above polyethylene film into it, after reacting at 35 °C for 1 h, take it out and rinse it 3 times with anhydrous ether, and dry it to obtain a polyethylene film grafted with an amino-functionalized hydrophilic anticoagulant layer.

[0257] (4) Dissolve 1 g of heparin in purified water. At 0 °C, adjust the pH to 3.0 with HCl, then slowly add 0.01 g of sodium nitrite, and continue to stir and react for 3 h. After the reaction, adjust the pH = 7.0 with a NaOH solution, dialyze, and freeze-dry to obtain aldehyde-functionalized heparin.

[0258] (5) Prepare a solution of aldehyde - heparin with a mass percentage concentration of 1%, put the polyethylene film grafted with an amino - modified hydrophilic anticoagulant layer prepared in step (3) into it, react at 30 °C for 2 h, then add sodium cyanoborohydride accounting for 5% of the mass of aldehyde - heparin, continue to react for 2 h, take it out, and rinse it 3 times with pure water to obtain the anticoagulant medical device of this example.

[0259] Example 4

[0260] This example provides an anticoagulant medical device, and the preparation steps are as follows:

[0261] (1) Place the polyethylene film in ammonia plasma for 20 min to make the polyethylene film carry amino groups. Subsequently, react with the DMF solution of BiBB at 20 °C for 12 h. In the DMF solution of BiBB, the mass percentage concentration of BiBB is 10%. After the reaction, rinse it 3 times with DMF first, and then rinse it 3 times with pure water to obtain the polyethylene film grafted with ATRP initiator.

[0262] (2) Prepare an NVP ethanol solution with a mass percentage concentration of 10%, add CuCl catalyst and tris[2 - (dimethylamino)ethyl]amine ligand. Among them, the molar addition amounts of CuCl and tris[2 - (dimethylamino)ethyl]amine are 2% and 5% of the molar amount of NVP respectively. Subsequently, put the polyethylene film grafted with ATRP initiator into the above solution, seal it, purge with nitrogen for 5 min, and then put it into an oven at 30 °C for reaction for 6 h. After the reaction, take it out, rinse it 3 times with ethanol first, then rinse it 3 times with pure water, and dry it to obtain the polyethylene film grafted with a hydrophilic anticoagulant layer.

[0263] (3) Prepare a thiourea DMF solution with a mass percentage concentration of 1%, put the polyethylene film grafted with a hydrophilic anticoagulant layer prepared in step (2) into it, purge with nitrogen for 5 min, and react at 85 °C for 12 h. Then, add a NaOH solution with a concentration of 4 mol / L that is equimolar to thiourea, and continue to react at 100 °C for 12 h to obtain the polyethylene film grafted with a thiolated hydrophilic anticoagulant layer.

[0264] (4) Dissolve 1 g of heparin in purified water, adjust the pH = 8.0 with NaOH, then slowly add 0.1 g of methacrylic anhydride. After the reaction, dialyze and freeze - dry to obtain double - bond - heparin.

[0265] (5) Prepare an aqueous solution of double - bond - heparin with a mass percentage concentration of 1%, add potassium persulfate and sodium sulfite accounting for one - tenth of the mass of double - bond - heparin, carry out a thiol - ene reaction at 35 °C for 1 h, then take it out and rinse it 3 times with pure water to obtain the anticoagulant medical device of this example.

[0266] Example 5

[0267] This embodiment provides an anticoagulant medical device, and the preparation steps are as follows:

[0268] (1) Place the polyethylene film in an aqueous solution of potassium persulfate with a mass percentage concentration of 20%, and irradiate it with ultraviolet light at 50 °C for 10 min to make the polyethylene film carry hydroxyl groups. Subsequently, react it with an ethanol / water (V:V = 8:2) solution of (3-bromopropyl)trimethoxysilane with a mass percentage concentration of 10% at 25 °C for 8 h. After the reaction is completed, rinse it with pure water three times to obtain a polyethylene film grafted with an ATRP initiator.

[0269] Steps (2) to (4) are the same as steps (2) to (4) in Embodiment 2 and will not be elaborated here. Finally, the anticoagulant medical device of this embodiment is obtained.

[0270] Embodiments 6 to 8

[0271] Embodiments 6 to 8 respectively provide an anticoagulant medical device, and the preparation steps are as follows:

[0272] (1) The same as step (1) in Embodiment 2 to obtain a polyethylene film grafted with an ATRP initiator.

[0273] (2) Prepare a solution of a hydrophilic anticoagulant monomer with a mass percentage concentration of 10% as shown in Table 1 below, add a CuCl catalyst and a tris[2-(dimethylamino)ethyl]amine ligand. Among them, the molar addition amounts of CuCl and tris[2-(dimethylamino)ethyl]amine are 2% and 5% of the molar amount of the hydrophilic anticoagulant monomer, respectively. Subsequently, place the polyethylene film grafted with the ATRP initiator into the solution, seal it, purge with nitrogen for 5 min, and then place it in an oven at 30 °C for reaction for 6 h. After the reaction is completed, take it out, rinse it with ethanol three times first, then rinse it with pure water three times, and dry it to obtain a polyethylene film grafted with a hydrophilic anticoagulant layer.

[0274] Steps (3) to (4) are the same as steps (3) to (4) in Embodiment 2 and will not be elaborated here. Finally, the anticoagulant medical devices of Embodiments 6 to 8 are obtained.

[0275] Table 1 Hydrophilic anticoagulant monomers of Embodiment 2, Embodiments 6 to 8

[0276]

[0277] Embodiments 9 to 13

[0278] Examples 9 to 13 respectively provide an anticoagulant medical device. The preparation steps are similar to those of Example 2, except that: step (2) is different, and steps (1), (3) and (4) are the same as the corresponding steps in Example 2 and will not be described in detail. The step (2) of Examples 9 to 13 is as follows:

[0279] (2) Prepare an NVP ethanol solution with a mass percentage concentration of 10%, and add the first catalyst, the first ligand and optionally the first reducing agent as shown in Table 2 below. Subsequently, place the polyethylene film grafted with the ATRP initiator into the solution, seal it, purge with nitrogen for 5 min, and then place it in an oven at 30 °C for reaction for 6 h. After the reaction is completed, take it out, rinse it 3 times with ethanol first, then rinse it 3 times with pure water, and dry it to obtain a polyethylene film grafted with a hydrophilic anticoagulant layer.

[0280] Table 2 The first catalyst, the first ligand, the first reducing agent and their dosages in each example

[0281]

[0282] Examples 14 to 20

[0283] Examples 14 to 20 respectively provide an anticoagulant medical device. The preparation steps are similar to those of Example 2, except that step (1) is different, and steps (2) to (4) are the same as the corresponding steps in Example 2 and will not be described in detail. Examples 14 to

[0284] The step (1) of Example 18 is as follows:

[0285] (1) Place the films of different materials as shown in Table 3 below in ammonia plasma for treatment for 20 min to make the films carry amino groups. Subsequently, react with the DMF solution of BiBB at 20 °C for 12 h. In the DMF solution of BiBB, the mass percentage concentration of BiBB is 10%. After the reaction is completed, rinse it 3 times with DMF first, and then rinse it 3 times with pure water to obtain films of different materials grafted with the ATRP initiator.

[0286] Table 3 The base materials of each example

[0287] Example Material type Example 2 Polyethylene Example 14 Polypropylene Example 15 Polycarbonate Example 16 Polyester Example 17 Polymethylpentene Example 18 Polylactic acid

[0288] The step (1) of Examples 19 to 20 is as follows:

[0289] The stainless steel (Example 19) and nitinol alloy (Example 20) were placed in piranha solution for 1 min to make their surfaces hydroxyl - group - bearing. Subsequently, they were reacted with an ethanol / water (V:V = 8:2) solution of (3 - bromopropyl)trimethoxysilane with a mass percentage concentration of 10% at 25 °C for 8 h. After the reaction ended, they were rinsed 3 times with pure water to obtain thin films of different materials grafted with ATRP initiators.

[0290] Examples 21 - 23

[0291] Examples 21 - 23 respectively provide an anticoagulant medical device. The preparation steps are similar to those of Example 2, with the difference being that steps (3) and (4) are different. Steps (1)-(2) are the same as the corresponding steps in Example 2 and will not be elaborated here.

[0292] Steps (3) and (4) of Examples 21 - 23 are as follows:

[0293] (3) Prepare an azide reagent solution with the mass percentage concentration shown in Table 4 below. After purging with nitrogen for 5 min, place the polyethylene film grafted with a hydrophilic anticoagulant layer prepared in step (2). After reacting at a certain temperature T1 for a period of time t1, first rinse 3 times with the solvent used in the azide reagent solution, and then rinse 3 times with pure water. Then, prepare an anhydrous ether solution of LiAlH 4 and place the polyethylene film in it. After reacting at a certain temperature T2 for a period of time t2, rinse 3 times with anhydrous ether and dry to obtain a polyethylene film grafted with an amino - modified hydrophilic anticoagulant layer. The reaction temperature and time are both shown in Table 4 below.

[0294] (4) Prepare an aqueous heparin solution with the mass percentage concentration shown in Table 4 below, add the activator and condensing agent shown in Table 4 below. After maintaining at 0 °C for 5 min, add the polyethylene film grafted with an amino - modified hydrophilic anticoagulant layer prepared in step (3). After carrying out an amide reaction at 25 °C for 2 h, take it out and rinse 3 times with pure water to obtain the anticoagulant medical devices of Examples 21 - 23.

[0295] Table 4 Process parameters of each example

[0296]

[0297] The following is the specific test part:

[0298] 1. Basic performance detection

[0299] (1) Contact angle measurement

[0300] The water contact angles of the uncoated polyethylene film, Comparative Examples 1-2, and the anticoagulant medical devices prepared in Examples 1-23 were measured using a contact angle tester, and the test results are shown in Table 5.

[0301] (2) Heparin content determination

[0302] The heparin contents in the uncoated polyethylene film, Comparative Examples 1-2, and the anticoagulant medical devices prepared in Examples 1-23 were measured using the toluidine blue colorimetric method, and the test results are shown in Table 5.

[0303] Table 5 Water contact angles and heparin contents of the anticoagulant medical devices in each example and comparative example

[0304]

[0305]

[0306] As shown in Table 5, the introduction of the hydrophilic anticoagulant layer significantly reduced the contact angle of the material surface, improved the hydrophilicity, and was beneficial to anti-nonspecific protein adsorption. At the same time, heparin could be effectively immobilized through the reaction of the end-functionalized hydrophilic anticoagulant layer with heparin, achieving a high heparin density and enabling effective anticoagulation.

[0307] 2. Stability test

[0308] The polyethylene films with heparin anticoagulant coatings prepared in Comparative Examples 1-3 and Examples 1-4 were respectively immersed in hydrochloric acid solution with a pH value of 1, sodium hydroxide solution with a pH value of 12, and physiological saline for 1 hour, 24 hours, and 7 days. After taking them out, they were washed with purified water, and then their contact angles were measured using a contact angle tester and their heparin contents were measured using the toluidine blue colorimetric method. The results are shown in Table 6.

[0309] Table 6 Stability results of the anticoagulant medical devices in each example and comparative example

[0310]

[0311]

[0312] As shown in Table 6, the anticoagulant medical devices prepared in the examples all showed very excellent long-term stability. After being immersed in acid, alkali, or physiological saline for 7 days, there were only small changes in the contact angle and a decrease in the heparin density, which proved that the anticoagulant medical devices prepared in the examples had the potential for long-term anticoagulation.

[0313] The above stability test only took Examples 1-4 as examples, and other examples had stability equivalent to that of Examples 1-4 and will not be elaborated.

[0314] 3. Human Whole Blood Test

[0315] Samples of 1 cm × 1 cm were cut from the anticoagulant medical devices prepared in Comparative Examples 1 to 3 and Examples 1 to 4, and the polyethylene film without coating (control group). After washing with physiological saline at 37°C for 30 minutes and soaking for 7 days respectively, they were placed into 10 mL centrifuge tubes. After adding sodium heparin injection at 0.5 U / mL to fresh human blood, the blood was added to the centrifuge tubes, with the addition amount of 2 mL, and incubated at 37°C for 2 hours. Subsequently, the films were taken out, rinsed with PBS buffer, dried, and the weight of the attached thrombus was quantified. Among them, the thrombus weight was obtained from the difference between the dry weights of the samples before measurement and after rinsing. Each sample and the control group were each tested 3 times, and the average value was taken. Then, according to these values, the relative value was calculated according to the following formula, and the results are shown in Table 7.

[0316] Relative value of thrombus weight (%) = thrombus weight of sample / thrombus weight of control group × 100%.

[0317] Table 7 Results of Human Whole Blood Test for Each Coating

[0318]

[0319] As shown in Table 7, after coating the coating, thrombus formation was significantly inhibited. Both the hydrophilic anticoagulant layer and the heparin anticoagulant layer could effectively inhibit thrombus formation, reducing the relative value of thrombus weight by more than 80%. After combining the hydrophilic anticoagulant layer and the heparin anticoagulant layer to prepare an anticoagulant medical device, the relative value of thrombus weight decreased by 95%, effectively inhibiting thrombus formation and having very excellent anticoagulant ability. In addition, after soaking in physiological saline for seven days, the anticoagulant medical device of the present invention could still exhibit a very strong anticoagulant effect, with almost no obvious decrease compared to without soaking.

[0320] The above human whole blood test only takes Examples 1 to 4 as examples, and other examples have anticoagulant effects equivalent to those of Examples 1 to 4, so they will not be elaborated.

[0321] The technical features of the above-mentioned embodiments can be combined arbitrarily. For the sake of concise description, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as the scope recorded in this specification.

[0322] The above-described embodiments merely represent several implementation manners of the present invention, facilitating the specific and detailed understanding of the technical solution of the present invention. However, it should not be construed as a limitation on the protection scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all fall within the protection scope of the present invention. It should be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments based on the technical solution provided by the present invention are all within the protection scope of the appended claims of the present invention. Therefore, the protection scope of the present invention patent shall be subject to the content of the appended claims, and the description and drawings can be used to explain the content of the claims.

Claims

1. A preparation method of an anticoagulant medical device, characterized in that, it comprises the following steps: Covalently connecting a hydrophilic anticoagulant layer on the surface of a substrate by atom transfer radical polymerization; Covalently connecting a heparin anticoagulant layer on the surface of the hydrophilic anticoagulant layer to prepare an anticoagulant medical device, and the heparin anticoagulant layer is covalently connected to the hydrophilic anticoagulant layer through one or more of covalent bonds such as triazole bond, amide bond, carbon-nitrogen single bond and carbon-sulfur single bond.

2. The preparation method of the anticoagulant medical device according to claim 1, characterized in that, the step of covalently connecting a heparin anticoagulant layer on the surface of the hydrophilic anticoagulant layer comprises: Introducing one or more of azide group, amino group and thiol group at the end of the polymer in the hydrophilic anticoagulant layer to obtain a functionalized hydrophilic anticoagulant layer; Performing one or more of azide-alkyne reaction, amide reaction, aldehyde-amine condensation reaction and thiol-ene reaction on the functionalized hydrophilic anticoagulant layer and heparin-like substances, so that the heparin-like substances are covalently grafted on the surface of the functionalized hydrophilic anticoagulant layer to prepare a heparin anticoagulant layer.

3. The preparation method of the anticoagulant medical device according to claim 2, characterized in that, the step of introducing an azide group at the end of the polymer in the hydrophilic anticoagulant layer comprises: immersing the substrate with the hydrophilic anticoagulant layer in a solution containing an azidating reagent, and reacting at 10°C to 50°C for 3h to 24h; Optionally, in the solution containing the azidating reagent, the mass percentage concentration of the azidating reagent is 1% to 10%; Optionally, the azidating reagent comprises one or more combinations of sodium azide, trimethylsilyl azide and diphenylphosphate azide.

4. The preparation method of the anticoagulant medical device according to claim 2 or 3, characterized in that, the step of performing an azide-alkyne reaction on the functionalized hydrophilic anticoagulant layer and heparin-like substances comprises: immersing the substrate with an azidated hydrophilic anticoagulant layer in a second solution containing an alkynylated heparin-like substance, a copper(I) catalyst and a second ligand, and reacting at 20°C to 35°C for 5h to 12h.

5. The preparation method of the anticoagulant medical device according to claim 4, characterized in that, the step of the azide-alkyne reaction satisfies one or more of the following conditions: (1) In the second solution, the mass percentage concentration of the alkynylated heparin-like substance is 0.1% to 10%, the mass percentage concentration of the copper(I) catalyst is 0.01 to 1%, and the molar ratio of the second ligand to the copper(I) catalyst is (1 to 1.2):1; (2) The copper(I) catalyst comprises one or more combinations of CuBr, CuCl and CuI; (3) The second ligand comprises one or more combinations of N,N,N',N',N”-pentamethyldiethylenetriamine, 2,2'-bipyridine, tris(2-dimethylaminoethyl)amine and tripropylene glycol methyl ether acetate.

6. The preparation method of the anticoagulant medical device according to claim 2, characterized in that, The step of introducing an amino group at the end of the polymer in the hydrophilic anticoagulant layer includes: introducing an azide group at the end of the polymer in the hydrophilic anticoagulant layer; immersing the substrate with the azide-functionalized hydrophilic anticoagulant layer in an anhydrous ether solution containing a second reducing agent, and reacting at 25°C to 50°C for 1 h to 5 h to make the end of the polymer in the hydrophilic anticoagulant layer carry an amino group; Optionally, in the anhydrous ether solution containing the second reducing agent, the mass percentage concentration of the second reducing agent is 0.1% to 10%.

7. The method for preparing an anticoagulant medical device according to claim 2 or 6, characterized in that the step of performing an amide reaction between the functionalized hydrophilic anticoagulant layer and a heparin-like substance includes: immersing the substrate with the amino-functionalized hydrophilic anticoagulant layer in a third solution containing a heparin-like substance, an activator, and a condensing agent, and reacting at 0°C to 25°C for 1 h to 6 h; Optionally, in the third solution, the mass percentage concentration of the heparin-like substance is 0.1% to 10%, and the mass ratio of the activator, the condensing agent, and the heparin-like substance is (1 to 1.2):(1 to 1.2):

1.

8. The method for preparing an anticoagulant medical device according to claim 2 or 6, characterized in that the step of performing an aldehyde-amine condensation reaction between the functionalized hydrophilic anticoagulant layer and a heparin-like substance includes: immersing the substrate with the amino-functionalized hydrophilic anticoagulant layer in a solution containing an aldehyde-functionalized heparin-like substance, and reacting at 20°C to 40°C for 1 h to 6 h, and then continuing to react the reaction product with sodium cyanoborohydride for 1 h to 3 h; Optionally, in the aqueous solution containing the aldehyde-functionalized heparin-like substance, the mass percentage concentration of the aldehyde-functionalized heparin-like substance is 0.1% to 10%, and the mass percentage of sodium cyanoborohydride in the aldehyde-functionalized heparin-like substance is 1% to 10%.

9. The method for preparing an anticoagulant medical device according to claim 2, characterized in that the step of introducing a thiol group at the end of the polymer in the hydrophilic anticoagulant layer includes: immersing the substrate with the hydrophilic anticoagulant layer in a thiourea solution, and reacting at 80°C to 100°C under inert gas protection for 8 h to 24 h, and then continuing to react the reaction product with a basic reagent at 90°C to 110°C for 8 h to 24 h; Optionally, in the thiourea solution, the mass percentage concentration of thiourea is 0.1% to 1%.

10. The method for preparing an anticoagulant medical device according to claim 2 or 9, characterized in that the step of performing a thiol-ene reaction between the functionalized hydrophilic anticoagulant layer and a heparin-like substance includes: immersing the substrate with the thiol-functionalized hydrophilic anticoagulant layer in a fourth solution containing a double-bond-functionalized heparin-like substance and an auxiliary agent, and reacting at 20°C to 80°C for 0.5 h to 5 h; wherein, in the fourth solution, the mass percentage concentration of the double-bond-functionalized heparin-like substance is 0.1% to 10%, the mass percentage concentration of the auxiliary agent is 0.01% to 2%, and the auxiliary agent includes one or more of a thermal initiator, a photoinitiator, and a basic catalyst.

11. The preparation method of the anticoagulant medical device according to claim 1, characterized in that, the step of covalently connecting a hydrophilic anticoagulant layer to the substrate surface by atom transfer radical polymerization includes: grafting an initiator group on the substrate surface, and the initiator group includes a halogen group; treating the substrate grafted with the initiator group with a first solution including a hydrophilic anticoagulant monomer, a first catalyst and a first ligand, so that the hydrophilic anticoagulant monomer undergoes atom transfer radical polymerization on the surface of the substrate grafted with the initiator group under the action of the initiator group, the first catalyst and the first ligand.

12. The preparation method of the anticoagulant medical device according to claim 11, characterized in that, the step of grafting an initiator group on the substrate surface satisfies one of the following conditions: (1) The step of grafting an initiator group on the substrate surface includes: obtaining a substrate with a hydroxyl group on the surface; performing a silanization reaction between a silanization reagent containing an initiator group and the hydroxyl group on the substrate surface to graft the initiator group on the substrate surface; Optionally, the silanization reagent containing an initiator group includes one or a combination of more than one of (3-bromopropyl)trimethoxysilane, (3-bromopropyl)triethoxysilane, (3-chloropropyl)trimethoxysilane, (3-bromopropyl)trichlorosilane, 1-bromo-4-(trimethoxysilyl)benzene and (3-chloropropyl)trichlorosilane; Optionally, the silanization reagent containing an initiator group reacts in the form of a solution, and in the solution, the mass percentage concentration of the silanization reagent containing an initiator group is 5% to 30%; Optionally, the temperature of the silanization reaction is 25°C to 60°C, and the time is 3h to 24h; (2) The step of grafting an initiator group on the substrate surface includes: obtaining a substrate with an amino group on the surface; performing an acylation reaction between an acyl halide reagent containing an initiator group and the amino group on the substrate surface; Optionally, the acyl halide reagent containing an initiator group includes one or a combination of two of chloroacetyl chloride and 2-bromo-2-methylpropionyl bromide; Optionally, the acyl halide reagent containing an initiator group reacts in the form of a solution, and in the solution, the mass percentage concentration of the acyl halide reagent containing an initiator group is 5% to 30%; Optionally, the temperature of the acylation reaction is 0°C to 25°C, and the time is 5h to 48h.

13. The preparation method of the anticoagulant medical device according to claim 11, characterized in that, the process parameters for preparing the hydrophilic anticoagulant layer satisfy one or several of the following conditions: (1) In the first solution, the mass percentage concentration of the hydrophilic anticoagulant monomer is 1% to 50%; (2) The molar ratio of the carbon-carbon double bond in the hydrophilic anticoagulant monomer, the first catalyst and the first ligand is 1:(0.005 to 0.1):(0.005 to 0.5); (3) The hydrophilic anticoagulant monomer includes one or more of acrylamide, 2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylamide, potassium 3-sulfopropyl methacrylate, N-vinylpyrrolidone, acrylate-capped oligomer, methacrylate-capped oligomer, and zwitterionic monomer; (4) The first catalyst includes a combination of one or more of low-valent salts of copper, iron, molybdenum, chromium, rhenium, ruthenium, rhodium, and nickel; (5) The first ligand includes a combination of one or more of amine substances and phosphine substances. The amine substances include a combination of one or more of N,N,N,N,N-pentamethyldiethylenetriamine, 1,1,4,7,10,10-hexamethyltriethylenetetramine, tris[2-(dimethylamino)ethyl]amine, tris(2-pyridylmethyl)amine, 1,4,8,11-tetraazacyclotetradecane, 2,2'-bipyridine, 4,4'-di-tert-butyl-2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, and 4,4'-bis(trifluoromethyl)-2,2'-bipyridine. The phosphine substances include triphenylphosphine; (6) The first solution further contains a first reducing agent. The first reducing agent includes a high-valent salt corresponding to the metal used in the first catalyst or a radical thermal initiator. The molar ratio of the first reducing agent to the first catalyst is (0.1 - 0.3):1; (7) The temperature of the atom transfer radical polymerization reaction is 25°C to 70°C, and the time is 2 h to 24 h.

14. The method for preparing an anticoagulant medical device according to claim 13, wherein, the process parameters for preparing the hydrophilic anticoagulant layer satisfy one or more of the following conditions: (1) In the first solution, the mass percentage concentration of the hydrophilic anticoagulant monomer is 5% to 30%; (2) The molar ratio of the carbon-carbon double bond in the hydrophilic anticoagulant monomer, the first catalyst, and the first ligand is 1:(0.01 - 0.1):(0.01 - 0.3); (3) The hydrophilic anticoagulant monomer includes one or more of N-vinylpyrrolidone, 2-hydroxyethyl methacrylate, polyethylene glycol with a molecular weight of 1000 and blocked with methacrylate at both ends, and zwitterionic monomers. The structural formula of the zwitterionic monomer is as follows: In formula (II), R 1 includes zwitterionic groups, R 2 includes -NH- or -O-, R 3 includes -H or -CH 3 , and the zwitterionic groups include one or more of phosphorylcholine, sulfobetaine, and carboxybetaine; (4) The first catalyst includes one or more of CuCl, FeCl 2 and RuCl 2 ; (5) The first ligand includes one or more of N,N,N,N,N-pentamethyldiethylenetriamine, tris[2-(dimethylamino)ethyl]amine, and 4,4'-di-tert-butyl-2,2'-bipyridine; (6) The time of the atom transfer radical polymerization reaction is 5 h to 10 h.

15. An anticoagulant medical device, wherein, it includes a substrate, a hydrophilic anticoagulant layer provided on the surface of the substrate, and a heparin anticoagulant layer provided on the surface of the hydrophilic anticoagulant layer; wherein, the hydrophilic anticoagulant layer is covalently connected to the surface of the substrate by atom transfer radical polymerization, and the heparin anticoagulant layer is connected to the hydrophilic anticoagulant layer by a covalent bond, and the covalent bond includes one or more of a triazole bond, an amide bond, a carbon-nitrogen single bond, and a carbon-sulfur single bond.

16. The anticoagulant medical device according to claim 15, wherein, the anticoagulant medical device satisfies one or more of the following conditions: (1) The materials of the hydrophilic anticoagulant layer include one or a combination of polyethylene glycol, polyvinyl alcohol, polyacrylamide, poly(2-hydroxyethyl methacrylate), poly(hydroxyethyl acrylamide), potassium 3-sulfopropyl methacrylate, polyvinylpyrrolidone, and zwitterionic polymers; Optionally, the structural formula of the zwitterionic polymer is as follows (Formula I): In formula (I), R 1 comprises zwitterionic groups, R 2 comprises -NH- or -O-, R 3 comprises -H or -CH 3 , and the zwitterionic groups include one or more of phosphorylcholine, sulfobetaine, and carboxybetaine; (2) The water contact angle of the surface of the anticoagulant medical device is less than 50°; (3) The materials of the heparin anticoagulant layer include one or a combination of heparin, heparin derivatives, and heparinoids, and the molecular weight of the materials of the heparin anticoagulant layer is 1500 - 10000; (4) The heparin density on the surface of the anticoagulant medical device is not less than 0.5 μg / cm 2 ; (5) The materials of the substrate include one or a combination of metal-based biomaterials, silicon-based biomaterials, and polymer-based biomaterials; Optionally, the materials of the substrate include one or a combination of polyethylene, polypropylene, polycarbonate, polyester, polymethylpentene, and polylactic acid.

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