Medical material and preparation method thereof

Abstract

The invention relates to a medical material and a preparation method thereof. The preparation method of the medical material comprises the following steps: covalently connecting the first anticoagulant layer on the surface of the base material in an atom transfer radical polymerization manner; covalently connecting a second anticoagulant layer on the surface of the first anticoagulant layer by adopting an atom transfer radical polymerization mode to prepare a medical material; one of the first anticoagulant layer and the second anticoagulant layer is a hydrophilic anticoagulant layer, and the other one of the first anticoagulant layer and the second anticoagulant layer is a heparin anticoagulant layer. According to the preparation method of the medical material, the hydrophilic anticoagulation layer with good protein adsorption resistance and the heparin anticoagulation layer with a good anticoagulation effect are combined, and the synergistic anticoagulation effect of the hydrophilic anticoagulation layer and the heparin anticoagulation layer is fully achieved, so that the anticoagulation effect is improved, and meanwhile, the long-term stability of the anticoagulation layer is improved.

Description

Technical Field

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

[0002] Nowadays, blood-contact medical devices are increasingly widely used, such as extracorporeal membrane oxygenation, stents, valves, catheters, etc. However, when the materials used in these medical devices come into contact with blood, they often cause the adsorption of plasma proteins and further trigger platelet coagulation reactions, ultimately leading to the formation of thrombi. Although patients can avoid thrombus formation by taking oral or injectable anticoagulant drugs, such as heparin, clopidogrel, atorvastatin, etc., this will bring the risk of systemic bleeding to patients. Therefore, in order to improve the anticoagulant performance of materials, coating an anticoagulant layer on the material surface is a commonly used method at present.

[0003] Generally speaking, there are two ways to achieve an anticoagulant layer. One is to coat a hydrophilic anticoagulant layer on the material surface, such as hydrophilic polymers like polyethylene glycol, polyvinylpyrrolidone, polyacrylic acid, or zwitterionic polymers like polyphosphorylcholine, polysulfobetaine, polycarboxybetaine. The other is to immobilize an anticoagulant on the material surface, and heparin is one of the most commonly used anticoagulants. In order to further improve the anticoagulant ability of the material surface, some researchers have combined a hydrophilic anticoagulant layer and a heparin anticoagulant layer to prepare a composite anticoagulant layer. However, the traditional method still has the following problems: the stability of the composite anticoagulant layer is poor, and there is a risk of the anticoagulant layer falling off under long-term blood flow scouring. Therefore, how to better combine the hydrophilic anticoagulant layer and the heparin anticoagulant layer to give full play to the synergistic effect of both, so as to improve the anticoagulant effect while improving the long-term stability, is an urgent problem to be solved at present. Summary of the Invention

[0004] Based on this, some embodiments of the present invention provide a medical material and a preparation method thereof that combine a hydrophilic anticoagulant layer and a heparin anticoagulant layer, giving full play to the synergistic anticoagulant effect of both, and improving the long-term stability of the anticoagulant layer while improving the anticoagulant effect.

[0005] A preparation method of a medical material, comprising the following steps:

[0006] Covalently connecting a first anticoagulant layer to the surface of a substrate by means of atom transfer radical polymerization;

[0007] Covalently connecting a second anticoagulant layer to the surface of the first anticoagulant layer to prepare the medical material;

[0008] Wherein, one of the first anticoagulant layer and the second anticoagulant layer is a hydrophilic anticoagulant layer, and the other is a heparin anticoagulant layer.

[0009] In some of these embodiments, the preparation steps of the first anticoagulant layer include:

[0010] Grafting initiator groups on the surface of the substrate, where the initiator groups include halogen groups;

[0011] Treating the substrate grafted with initiator groups with a first solution containing a first anticoagulant monomer, a first catalyst, and a first complexing agent, so that the first anticoagulant monomer undergoes an atom transfer radical polymerization reaction 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 the first anticoagulant layer;

[0012] The preparation steps of the second anticoagulant layer include:

[0013] Treating the substrate grafted with the first anticoagulant layer with a second solution containing a second anticoagulant monomer, a second catalyst, and a second complexing agent, so that the second anticoagulant monomer undergoes an atom transfer radical polymerization reaction on the surface of the first anticoagulant layer under the action of the initiator groups, the second catalyst, and the second complexing agent to prepare the second anticoagulant layer.

[0014] In some of these embodiments, the step of grafting initiator groups on the surface of the substrate includes:

[0015] Obtaining a substrate with a hydroxyl group on its surface;

[0016] Performing a silanization reaction between a silanization reagent containing initiator groups and the hydroxyl groups on the surface of the substrate to graft the initiator groups on the surface of the substrate.

[0017] In some of these embodiments, the step of grafting initiator groups on the surface of the substrate satisfies one or more of the following conditions:

[0018] (1) The silanization reagent containing initiator groups 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;

[0019] (2) The silanization reagent containing initiator groups reacts in the form of a solution, and in the solution, the mass percentage concentration of the silanization reagent containing initiator groups is 5% to 30%;

[0020] (3) The temperature of the silanization reaction is 25°C to 60°C, and the time is 3h to 24h.

[0021] In some of these embodiments, the step of grafting an initiator group onto the surface of the substrate includes:

[0022] obtaining a substrate with an amino group on its surface;

[0023] performing an acylation reaction between an acyl halide reagent containing an initiator group and the amino group on the surface of the substrate.

[0024] In some of these embodiments, the step of grafting an initiator group onto the surface of the substrate satisfies one or more of the following conditions:

[0025] (1) The acyl halide reagent containing an initiator group includes one or a combination of two of chloroacetyl chloride and 2-bromo-2-methylpropionyl bromide;

[0026] (2) 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% - 30%;

[0027] (3) The temperature of the acylation reaction is 0°C - 25°C, and the time is 5h - 48h.

[0028] In some of these embodiments, the first anticoagulant layer is a hydrophilic anticoagulant layer, and the preparation steps of the first anticoagulant layer satisfy one or more of the following conditions:

[0029] (1) In the first solution, the mass percentage concentration of the first anticoagulant monomer is 1% - 50%;

[0030] (2) The molar ratio of the carbon-carbon double bond in the first anticoagulant monomer, the first catalyst, and the first ligand is 1:(0.005 - 0.1):(0.005 - 0.5);

[0031] (3) The first anticoagulant monomer includes one or a combination of more of acrylamide, 2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylamide, potassium 3-sulfopropyl methacrylate, N-vinylpyrrolidone, acrylate-capped oligomer, methacrylate-capped oligomer, and zwitterionic monomer;

[0032] (4) The temperature of the atom transfer radical polymerization reaction is 25°C - 70°C, and the time is 2h - 24h;

[0033] (5) The first catalyst includes one or a combination of more of low-valence salts of copper, iron, molybdenum, chromium, rhenium, ruthenium, rhodium, and nickel;

[0034] (6) The first complexing agent includes one or a combination of more than one of amine substances and phosphine substances. 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;

[0035] (7) The first reducing agent is further contained in the first solution. The first reducing agent includes a high-valent salt corresponding to the metal used in the first catalyst or a free radical thermal initiator.

[0036] In some embodiments, the preparation steps of the first anticoagulant layer satisfy one or several of the following conditions:

[0037] (1) In the first solution, the mass percentage concentration of the first anticoagulant monomer is 5% to 30%;

[0038] (2) The molar ratio of the carbon-carbon double bond in the first anticoagulant monomer, the first catalyst, and the first complexing agent is 1:(0.01 - 0.1):(0.01 - 0.3);

[0039] (3) The first anticoagulant monomer includes an amphoteric ion monomer, and the structural formula of the amphoteric ion monomer is shown as the following formula (II): In formula (II), R 1 includes an amphoteric ion group, R 2 includes -NH- or -O-, R 3 includes -H or -CH 3 , and the amphoteric ion group includes one or several of phosphorylcholine, sulfobetaine, and carboxybetaine;

[0040] (4) The time of the atom transfer radical polymerization reaction is 5 h to 10 h.

[0041] In some embodiments, in the process of preparing the heparin anticoagulant, the anticoagulant monomer is prepared by the following steps: reacting a heparin substance with a modifier containing a carbon-carbon double bond and a reactive group to make the heparin substance carry a carbon-carbon double bond, and the reactive group includes one or several of a carboxylic acid group, an acid anhydride group, an epoxy group, and an amide group.

[0042] In some embodiments, the second anticoagulant layer is a heparin anticoagulant layer, and the preparation steps of the second anticoagulant layer satisfy one or several of the following conditions:

[0043] (1) In the second solution, the mass percentage concentration of the second anticoagulant monomer is 2% to 30%;

[0044] (2) The mass ratio of the second anticoagulant monomer to the second catalyst is 1:(0.005 to 0.05), and the molar ratio of the second catalyst to the second ligand is 1:(1 to 5);

[0045] (3) The temperature of the atom transfer radical polymerization reaction is 25°C to 70°C, and the time is 2 h to 12 h;

[0046] (4) The second catalyst includes one or a combination of low-valent salts of copper, iron, molybdenum, chromium, rhenium, ruthenium, rhodium, and nickel;

[0047] (5) The second 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 substances include triphenylphosphine;

[0048] (6) A second reducing agent is further contained in the second solution. The second reducing agent includes a high-valent salt corresponding to the metal used in the second catalyst or a radical thermal initiator.

[0049] In some embodiments, the steps of preparing the second anticoagulant layer satisfy one or more of the following conditions:

[0050] (1) In the second solution, the mass percentage concentration of the second anticoagulant monomer is 5% to 10%;

[0051] (2) The mass ratio of the second anticoagulant monomer to the second catalyst is 1:(0.005 to 0.01), and the molar ratio of the second catalyst to the second ligand is 1:(1.5 to 2);

[0052] (3) The time of the atom transfer radical polymerization reaction is 2 h to 6 h.

[0053] In some embodiments, after the steps of preparing the second anticoagulant layer, the method further includes: repeating the steps of preparing the first anticoagulant layer and / or the second anticoagulant layer to stack the first anticoagulant layer and the second anticoagulant layer alternately;

[0054] Optionally, in the medical material, the total number of layers of the first anticoagulant layer and the second anticoagulant layer ≤ 6.

[0055] A medical material, comprising a substrate, a first anticoagulant layer disposed on the surface of the substrate, and a second anticoagulant layer disposed on the surface of the first anticoagulant layer away from the substrate;

[0056] Wherein, the first anticoagulant layer is covalently connected to the surface of the substrate by atom transfer radical polymerization, and the second anticoagulant layer is covalently connected to the surface of the first anticoagulant layer by atom transfer radical polymerization;

[0057] One of the first anticoagulant layer and the second anticoagulant layer is a hydrophilic anticoagulant layer, and the other is a heparin anticoagulant layer.

[0058] In some embodiments, the medical material satisfies one or more of the following conditions:

[0059] (1) The material of the hydrophilic anticoagulant layer includes one or a combination of polyethylene glycol, polyvinyl alcohol, polyacrylamide, poly (2-hydroxyethyl methacrylate), poly (2-hydroxyethyl acrylamide), potassium 3-sulfopropyl methacrylate, polyvinylpyrrolidone, and zwitterionic polymers;

[0060] Optionally, the structural formula of the zwitterionic polymer is as follows formula (I):

[0061]

[0062] 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;

[0063] (2) The water contact angle of the surface of the medical material is less than 50°;

[0064] (3) The material of the heparin anticoagulant layer includes a polymer formed by polymerization of one or more of heparin, heparin derivatives, and heparinoids;

[0065] (4) The heparin density on the surface of the medical material is not less than 0.5 μg / cm 2 ;

[0066] (5) The first anticoagulant layer is a hydrophilic anticoagulant layer, and the second anticoagulant layer is a heparin anticoagulant layer;

[0067] (6) In the medical material, the number of the first anticoagulant layers is multiple and / or the number of the second anticoagulant layers is multiple, and the first anticoagulant layers and the second anticoagulant layers are alternately arranged and are covalently connected to the previous layer by atom transfer radical polymerization;

[0068] Optionally, in the medical material, the total number of layers of the first anticoagulant layer and the second anticoagulant layer ≤ 6;

[0069] (7) The material of the substrate includes one or a combination of metal-based biomaterials, silicon-based biomaterials, and polymer-based biomaterials.

[0070] The inventors found in experiments that for traditional composite anticoagulant layers, after grafting one type of anticoagulant layer on the surface of the substrate and then grafting another type of anticoagulant layer, there are few surface binding sites, resulting in a small grafting amount of the other type of anticoagulant layer, affecting the anticoagulant effect. At the same time, it may also lead to a decrease in the stability of the other type of anticoagulant layer, and there is a risk of anticoagulant layer shedding under long-term blood flow scouring. Based on this, the inventors proposed a preparation method for a medical material. By atom transfer radical polymerization (ATRP), the first anticoagulant layer is covalently connected to the surface of the substrate, and then the second anticoagulant layer is covalently connected to the surface of the first anticoagulant layer by the ATRP method. By using the ATRP method, on the one hand, a hydrophilic anticoagulant layer with good anti-protein adsorption performance and a heparin anticoagulant layer with good anticoagulant effect are combined, so that the substrate, the hydrophilic anticoagulant layer, and the heparin anticoagulant layer are all connected by covalent bonds. On the other hand, ATRP is a method of controlled radical polymerization, which has controllability of polymer structure and molecular weight compared with other polymerization methods, enabling the molecular chain to gradually grow. After the polymerization ends, the initiator group remains at the end of the molecular chain, reducing the risk of the initiator group being embedded, ensuring the active sites for grafting the next layer, so that when grafting the second anticoagulant layer, the grafting amount and stability are improved, and it will not fall off under long-term blood flow scouring during the use of the material, achieving long-term stable anticoagulation. Description of the Drawings

[0071] 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 be obtained according to these drawings.

[0072] Figure 1 It is a schematic structural diagram of a medical material in some embodiments of the present invention;

[0073] Figure 2 It is a process flow diagram of a preparation method of a medical material in some embodiments of the present invention;

[0074] Figure 3 is Figure 2 a schematic diagram of the process flow chart shown Specific embodiments

[0075] To facilitate the understanding of the present invention, the present invention will be described more comprehensively below in conjunction 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 of the present invention more thorough and comprehensive.

[0076] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present invention belongs. The terms used in the description of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more of the related listed items.

[0077] Unless otherwise stated or there is a contradiction, the terms or phrases used in the present invention have the following meanings:

[0078] In the present invention, "first" and "second" are only for descriptive purposes and cannot be construed as indicating or implying relative importance or implicitly indicating 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.

[0079] In the description of the present invention, "a plurality of" means at least two, such as two, three, etc., unless otherwise specifically defined.

[0080] In the present 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.

[0081] In the present 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 the component.

[0082] The terms "preferably", "more preferably", etc. in the present invention refer to embodiments of the present invention that can provide certain beneficial effects in certain cases. However, in the same case 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 the present invention.

[0083] When a numerical range is disclosed in the present invention, the above range is considered to be continuous and includes the minimum and maximum values ​​of the range, as well as every value between such minimum and maximum values. Further, when a range refers to an integer, every integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be merged. In other words, unless otherwise indicated, all ranges disclosed in the present invention should be understood to include any and all subranges included therein.

[0084] In the present invention, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0085] The terms "including" and "having" and any variations thereof in the embodiments of the present invention are intended to cover non-exclusive inclusions. 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 may optionally include steps or units that are not listed, or may optionally include other steps or components that are inherent to these processes, methods, products, or devices.

[0086] Reference to "embodiments" in the present invention means that a particular feature, structure, or characteristic described in conjunction with the embodiments may be included in at least one embodiment of the present application. The appearance of the phrase in various places in the specification does not necessarily refer to the same embodiment, nor is it an independent or alternative embodiment that is mutually exclusive with other embodiments. It is explicitly and implicitly understood by those skilled in the art that the embodiments described in the present invention may be combined with other embodiments.

[0087] Several conventional methods disclose the combination of a hydrophilic anticoagulant layer and a heparin anticoagulant layer, but there are still problems such as poor anticoagulant effect and stability to be improved. Based on this, the first aspect of the present invention provides a medical material, see Figure 1 , comprising: a substrate 110, a first anti-coagulation layer 120 disposed on the surface of the substrate 110, and a second anti-coagulation layer 130 disposed on the first anti-coagulation layer 120 away from the surface of the substrate 110;

[0088] The first anti-coagulation layer 120 is covalently connected to the surface of the substrate 110 by atom transfer radical polymerization, and the second anti-coagulation layer 130 is covalently connected to the surface of the first anti-coagulation layer 120 by atom transfer radical polymerization;

[0089] One of the first anticoagulation layer 120 and the second anticoagulation layer 130 is a hydrophilic anticoagulation layer, and the other is a heparin anticoagulation layer.

[0090] The above-mentioned medical material includes a substrate 110, a first anticoagulant layer 120, and a second anticoagulant layer 130. The first anticoagulant layer 120 is covalently connected to the surface of the substrate 110 by means of atom transfer radical polymerization (ATRP), and the second anticoagulant layer 130 is covalently connected to the surface of the first anticoagulant layer 120 by means of atom transfer radical polymerization. By using the method of atom transfer radical polymerization, on the one hand, the substrate 110, the first anticoagulant layer 120, and the second anticoagulant layer 130 are all connected by covalent bonds. On the other hand, atom transfer radical polymerization (ATRP) is a method of controlled radical polymerization, which has controllability of polymer structure and molecular weight compared with other polymerization methods, enables the molecular chain to gradually grow, and the initiator group remains at the end of the molecular chain after the polymerization ends, reducing the risk of being embedded, ensuring the active sites of the next layer, and improving the grafting amount and stability when grafting the second anticoagulant layer 130, so that it will not fall off under the long-term scouring of blood flow during the use of the material, realizing stable anticoagulation.

[0091] In addition, the inventors found in the experiment that if the monomers of the hydrophilic anticoagulant layer and the monomers of the heparin anticoagulant layer are mixed and atom transfer radical polymerization is carried out simultaneously, it will cause mutual embedding of the two, significantly reducing the anticoagulant effect, and even being inferior to the anticoagulant effect of a single heparin anticoagulant layer. Therefore, in the present embodiment, the first anticoagulant layer 120 and the second anticoagulant layer 130 are respectively formed on the surface of the substrate 110 to ensure that the two work together to play an anticoagulant role.

[0092] In some embodiments, the first anticoagulant layer 120 is a hydrophilic anticoagulant layer, and the second anticoagulant layer 130 is a heparin anticoagulant layer. In other embodiments, the first anticoagulant layer 120 is a heparin anticoagulant layer, and the second anticoagulant layer 130 is a hydrophilic anticoagulant layer. Preferably, the first anticoagulant layer 120 is a hydrophilic anticoagulant layer, and the second anticoagulant layer 130 is a heparin anticoagulant layer. The monomer molecular weight of the hydrophilic anticoagulant layer is smaller than the molecular weight of heparin. During the atom transfer radical polymerization process, it can further reduce the risk of the initiator group being embedded, thereby further improving the anticoagulant effect and stability.

[0093] In some embodiments, the material of the substrate 110 includes one or more combinations of metal-based biomaterials, silicon-based biomaterials, and polymer-based biomaterials. It can be understood that when the material of the substrate 110 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 metal-based biomaterial includes but is not limited to medical stainless steel materials. The polymer-based biomaterials include but are not limited to one or several combinations of polyethylene, polypropylene, polycarbonate, polyester, polymethylpentene, and polylactic acid.

[0094] In some embodiments, the material of the hydrophilic anticoagulant layer comprises one or more combinations of polyethylene glycol, polyvinyl alcohol, polyacrylamide, poly(2-hydroxyethyl methacrylate), poly(hydroxyethyl acrylamide), potassium 3-sulfopropyl methacrylate, polyvinylpyrrolidone, and zwitterionic polymers.

[0095] Specifically, the structural formula of the zwitterionic polymer is as follows (Formula I):

[0096]

[0097] In Formula (I), R 1 comprises a zwitterionic group, R 2 comprises -NH- or -O-, R 3 comprises -H or -CH 3 , and the zwitterionic group comprises one or several of phosphorylcholine, sulfobetaine, and carboxybetaine.

[0098] Optionally, the material of the hydrophilic anticoagulant layer comprises one or several combinations of polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), poly(2-hydroxyethyl methacrylate) (PHEMA), and zwitterionic polymers.

[0099] Optionally, the material of the hydrophilic anticoagulant layer comprises a zwitterionic polymer. Using a zwitterionic polymer as the material of the hydrophilic anticoagulant layer can form a hydration layer on the material surface, further effectively hindering the non-specific adsorption of biomolecules such as proteins, thereby further improving the anticoagulant effect.

[0100] In some embodiments, the thickness of the hydrophilic anticoagulant layer is 0.1 μm to 10 μm. For example, the thickness of the hydrophilic anticoagulant coating can be, but is not limited to, 0.1 μm, 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm, or the range formed by any two of these values.

[0101] In some embodiments, the water contact angle of the surface of the medical material is less than 50°. For example, the water contact angle of the surface of the medical material can be, but is not limited to, 48°, 45°, 44°, 42°, 40°, 38°, 36°, 34°, 32°, 30°, 28°, or the range formed by any two of these values.

[0102] In some embodiments, the material of the heparin anticoagulant layer comprises a polymer formed by polymerization of one or more of heparin, heparin derivatives, and heparinoids.

[0103] Optionally, the molecular weight of heparin, heparin derivatives, and heparinoids is 1500 to 10000. For example, the molecular weight 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 medical material 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 medical material 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 medical material is not less than 1 μg / cm 2 . Further, the heparin density on the surface of the medical material is not less than 1.5 μg / cm 2 .

[0105] The above-mentioned medical material includes a substrate 110, a first anticoagulant layer 120, and a second anticoagulant layer 130, enabling the hydrophilic anticoagulant layer and the heparin anticoagulant layer to act synergistically, significantly improving the anticoagulant effect, and being able to meet most anticoagulant requirements. Further, in application scenarios with higher anticoagulant requirements, the medical material can also include multiple first anticoagulant layers 120 and multiple second anticoagulant layers 130.

[0106] In some embodiments, in the medical material, the number of the first anticoagulant layers 120 is multiple and / or the number of the second anticoagulant layers 130 is multiple, and the first anticoagulant layers 120 and the second anticoagulant layers 130 are alternately arranged, and are all covalently grafted into the previous layer by means of atom transfer radical polymerization.

[0107] Optionally, in the medical material, the total number of the first anticoagulant layers 120 and the second anticoagulant layers 130 ≤ 6. For example, the total number of the first anticoagulant layers 120 and the second anticoagulant layers 130 is 2 layers, 3 layers, 4 layers, 5 layers, 6 layers, etc.

[0108] In some embodiments, the medical material comprises a substrate, a first anticoagulant layer and a second anticoagulant layer sequentially laminated on the surface of the substrate, or the medical material comprises a substrate, a first anticoagulant layer, a second anticoagulant layer and a first anticoagulant layer sequentially laminated on the surface of the substrate, or the medical material comprises a substrate, a first anticoagulant layer, a second anticoagulant layer, a first anticoagulant layer and a second anticoagulant layer sequentially laminated on the surface of the substrate, or the medical material comprises a substrate, a first anticoagulant layer, a second anticoagulant layer, a first anticoagulant layer, a second anticoagulant layer and a first anticoagulant layer sequentially laminated on the surface of the substrate, or the medical material comprises a substrate, a first anticoagulant layer, a second anticoagulant layer, a first anticoagulant layer, a second anticoagulant layer, a first anticoagulant layer and a second anticoagulant layer sequentially laminated on the surface of the substrate.

[0109] The second aspect of the present invention provides a method for preparing a medical material, comprising the following steps:

[0110] Covalently connect a first anticoagulant layer to the surface of the substrate by means of atom transfer radical polymerization.

[0111] Covalently connect a second anticoagulant layer to the surface of the first anticoagulant layer to prepare a medical material;

[0112] Wherein, one of the first anticoagulant layer and the second anticoagulant layer is a hydrophilic anticoagulant layer, and the other is a heparin anticoagulant layer.

[0113] In some embodiments, the first anticoagulant layer is a hydrophilic anticoagulant layer and the second anticoagulant layer is a heparin anticoagulant layer. In other embodiments, the first anticoagulant layer is a heparin anticoagulant layer and the second anticoagulant layer is a hydrophilic anticoagulant layer. Preferably, the first anticoagulant layer is a hydrophilic anticoagulant layer and the second anticoagulant layer is a heparin anticoagulant layer. The monomer molecular weight of the hydrophilic anticoagulant layer is smaller than the molecular weight of heparin. During the atom transfer radical polymerization process, the risk of initiator groups being embedded can be further reduced, thereby further improving the anticoagulant effect and stability.

[0114] In some embodiments, please refer to Figure 2 , the method for preparing a medical material comprises the following steps:

[0115] Step S210: Graft initiator groups on the surface of the substrate, and the initiator groups include halogen groups.

[0116] In some embodiments, the initiator groups include one or a combination of several of α-halophenyl compounds, α-halocarbonyl compounds, α-halocyanide compounds, polyhalogen compounds and sulfonyl halides.

[0117] In some embodiments, the material of the substrate includes one or more combinations 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 metal-based biomaterial includes but is not limited to medical stainless steel materials. The polymer-based biomaterial includes but is not limited to one or several combinations of polyethylene, polypropylene, polycarbonate, polyester, polymethylpentene, and polylactic acid.

[0118] The following provides two methods for grafting initiator groups on the surface of the substrate, but is not limited thereto:

[0119] Method 1. In some embodiments, the steps of grafting initiator groups on the surface of the substrate include:

[0120] Obtain a substrate with hydroxyl groups on its surface;

[0121] Perform a silanization reaction between the silanizing reagent containing the initiator group and the hydroxyl groups on the surface of the substrate to graft the initiator group on the surface of the substrate.

[0122] 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 more combinations of plasma treatment, strong oxidant oxidation method, and ultraviolet irradiation method. Among them, the strong oxidant oxidation method can but is not limited to include piranha solution treatment and persulfate oxidation method.

[0123] In some of these embodiments, the silanizing reagent containing the 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.

[0124] In some of these embodiments, the silanizing reagent containing the initiator group reacts in the form of a solution. In the solution, the mass percentage concentration of the silanizing reagent containing the initiator group is 5% - 30%. Optionally, in the solution, the mass percentage concentration of the silanizing reagent containing the initiator group can but is not limited to be 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 the initiator group is 5% - 10%.

[0125] In some of these embodiments, in a solution of a silanizing reagent containing an initiator group, the solvent comprises one or a combination of more of water, methanol, ethanol, isopropanol, butanol, and cyclohexanol. In a specific example, the solvent comprises a mixture of water and ethanol.

[0126] In some of these embodiments, the temperature of the silanization reaction is 25°C to 60°C, and the time is 3 h to 24 h. 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 a range composed of any two of these values. The time of the silanization reaction can be, but is not limited to, 3 h, 6 h, 9 h, 12 h, 15 h, 18 h, 21 h, 24 h, or a range composed of any two of these values.

[0127] In some of these embodiments, the step of grafting an initiator group onto the substrate surface comprises: immersing a substrate with a hydroxyl group on its surface in a solution of a 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 3 h to 24 h to graft an initiator group onto 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%.

[0128] Method 2. In some other embodiments, the step of grafting an initiator group onto the substrate surface comprises:

[0129] Obtaining a substrate with an amino group on its surface;

[0130] Carrying out an acylation reaction between an acyl halide reagent containing an initiator group and the amino group on the substrate surface.

[0131] In some of these embodiments, a substrate with an amino group on its surface is prepared by surface activation of the substrate. Specifically, the method for surface activation of the substrate comprises one or a combination of two of plasma treatment and chemical grafting. In a specific example, the method for surface activation of the substrate comprises ammonia plasma treatment. For example, the substrate is placed in ammonia plasma and treated for 20 min.

[0132] In some of these embodiments, the acyl halide reagent containing an initiator group comprises one or a combination of two of chloroacetyl chloride and 2-bromo-2-methylpropionyl bromide (BiBB).

[0133] In some of these embodiments, the acyl halide reagent containing an initiator group reacts in the form of a solution, in which 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 composed of 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%.

[0134] In some of these embodiments, the acyl halide reagent containing an initiator group reacts in the form of a solution, in which the solvent includes one or a combination of more of water, N,N-dimethylformamide (DMF), tetrahydrofuran (THF), and diethyl ether.

[0135] In some of these embodiments, during the acylation reaction, a third catalyst can also be added. For example, the third catalyst includes triethylamine.

[0136] 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 composed of 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 composed of any two of these values. Optionally, the time of the acylation reaction is 8 h to 24 h.

[0137] In some of these embodiments, the step of grafting an initiator group on the substrate surface includes: immersing the substrate with an amino group on its surface in a solution of the acyl halide reagent containing an initiator group, and carrying out an acylation reaction between the acyl halide group in the acyl halide reagent containing an initiator group and the amino group 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 an initiator group is 5% to 30%.

[0138] Step S220: Treat the substrate grafted with an initiator group with a first solution containing a first anticoagulant monomer, a first catalyst, and a first complexing agent, so that the first anticoagulant monomer undergoes atom transfer radical polymerization on the surface of the substrate grafted with an initiator group under the action of the initiator group, the first catalyst, and the first complexing agent to prepare a first anticoagulant layer.

[0139] In some embodiments, the first anticoagulant layer is a hydrophilic anticoagulant layer, and the first anticoagulant monomer is a hydrophilic anticoagulant monomer. In other embodiments, the first anticoagulant layer is a heparin anticoagulant layer, and the first anticoagulant monomer is a double-bonded heparin-like substance. Hereinafter, the case where the first anticoagulant layer is a hydrophilic anticoagulant layer and the second anticoagulant layer is a heparin anticoagulant layer will be taken as an example for illustration. It can be understood that those skilled in the art can obtain the solution where the first anticoagulant layer is a heparin anticoagulant layer and the second anticoagulant layer is a hydrophilic anticoagulant layer according to the above solution, which will not be elaborated herein.

[0140] In some embodiments, in the first solution, the mass percentage concentration of the first anticoagulant monomer is 1% to 50%. The first anticoagulant monomer is a hydrophilic anticoagulant monomer. For example, the mass percentage concentration of the first anticoagulant monomer can be but is not limited to 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or the range composed of any two of these values. Preferably, in the first solution, the mass percentage concentration of the first anticoagulant monomer is 5% to 30%.

[0141] In some embodiments, the molar ratio of the carbon-carbon double bond, the first catalyst, and the first ligand in the first 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 first 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 composed of any two of these values. The molar ratio of the carbon-carbon double bond to the first ligand in the first 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 composed of any two of these values.

[0142] Preferably, the molar ratio of the carbon-carbon double bond, the first catalyst, and the first ligand in the first anticoagulant monomer is 1:(0.01 to 0.1):(0.01 to 0.3).

[0143] In some embodiments, the first anticoagulant monomer includes one or more combinations of acrylamide, 2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylamide, potassium 3-sulfopropyl methacrylate, N-vinylpyrrolidone, acrylate-capped oligomers, methacrylate-capped oligomers, and zwitterionic monomers.

[0144] Specifically, the acrylate or methacrylate - terminated oligomers include PEG, PHEMA, PHEAA, or PVP, with a molecular weight of 800 - 3000. It can be understood that in the acrylate or methacrylate - terminated oligomers, the acrylate or methacrylate can cap one end or both ends.

[0145] Specifically, the structural formula of the zwitterionic monomer is as follows:

[0146] 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).

[0147] Optionally, the first anticoagulant monomer includes one or more of N - vinylpyrrolidone, 2 - hydroxyethyl methacrylate, polyethylene glycol with methacrylate capping at both ends and a molecular weight of 1000, and the zwitterionic monomer.

[0148] Optionally, the first anticoagulant monomer includes the zwitterionic monomer.

[0149] In a specific example, the zwitterionic monomer includes, but is not limited to, 2 - (methacryloyloxy)ethyl - 2 - (trimethylammonio)ethyl phosphate.

[0150] In some embodiments, the first catalyst includes one or a combination of low - valence salts of copper, iron, molybdenum, chromium, rhenium, ruthenium, rhodium, and nickel. It can be understood that the low - valence 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, +1 and +2, and the low - valence salt of copper refers to the salt formed by +1 - valent copper, such as CuCl. The same applies to the low - valence salts of other metals. Preferably, the first catalyst includes CuCl, FeCl 2 and RuCl 2 or one or several of them.

[0151] In some embodiments, the first ligand includes one or more combinations of amine substances and phosphine substances. Specifically, the amine substances include one or more combinations 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. 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.

[0152] In some embodiments, in the first solution, the solvent includes one or more combinations 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.

[0153] In some embodiments, the first solution further contains a first reducing agent. Adding the first reducing agent can further promote the ATRP reaction. 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 more combinations 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).

[0154] It can be understood that the first reducing agent including a high-valent salt corresponding to the metal used in the first catalyst means, for a metal with variable valence, 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 .

[0155] 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 the range formed by any two of these values.

[0156] In some embodiments, in step S220, the temperature of the atom transfer radical polymerization reaction is 25°C to 70°C, and the time is 2 h to 24 h.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] In some embodiments, step S220 includes:

[0161] Obtaining a first solution including a first anticoagulant monomer, a first catalyst, and a first ligand. In the first solution, the mass percentage concentration of the first 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 first anticoagulant monomer is 1:(0.005 to 0.1):(0.005 to 0.5);

[0162] Immersing the substrate grafted with an initiator group in the first solution, and carrying out an atom transfer radical polymerization reaction of the first anticoagulant monomer on the surface of the substrate grafted with the initiator group at 25°C to 70°C under a closed condition for 2 h to 24 h to prepare a first anticoagulant layer.

[0163] Step S230: Treating the substrate grafted with the first anticoagulant layer with a second solution containing a second anticoagulant monomer, a second catalyst, and a second ligand, so that the second anticoagulant monomer undergoes an atom transfer radical polymerization reaction on the surface of the first anticoagulant layer under the action of the initiator group, the second catalyst, and the second ligand to prepare a second anticoagulant layer.

[0164] In some embodiments, the second anticoagulant monomer is a heparin anticoagulant monomer, and the second anticoagulant layer is a heparin anticoagulant layer.

[0165] In some embodiments, the preparation step of the second anticoagulant monomer includes: modifying a heparin substance with a carboxylic acid containing a carbon-carbon double bond, an acid anhydride containing a carbon-carbon double bond, an amine containing a carbon-carbon double bond, an epoxide containing a carbon-carbon double bond, or an amide compound containing a carbon-carbon double bond to make the heparin substance carry a carbon-carbon double bond, and preparing the second anticoagulant monomer.

[0166] In some of these embodiments, the general formula of the carboxylic acid containing a carbon-carbon double bond is CHX=CY-(L) n -COOZ, where X is hydrogen or phenyl, Y is hydrogen, C 1～ C 6 alkyl or halogen-substituted C 1～ C 6 alkyl, L is a divalent linking group, n is 0 or 1, and Z is hydrogen or sodium. Further, Y is hydrogen, methyl or halogen-substituted methyl. For example, the halogen-substituted methyl can be trifluoromethyl. Preferably, L is an alkylene group. The alkylene group can be straight-chain or branched-chain. For example, the alkylene group is methylene (-CH 2 -), 1,1-ethyl (-CH(CH 3 ))-), 1,2-ethyl (-CH 2 CH 2 -), 1,1-propyl (-CH(CH 2 CH 3 ))-), 1,2-propyl (-CH 2 CH(CH 3 ))-), 1,3-propyl (-CH 2 CH 2 CH 2 -), and 1,4-butyl (-CH 2 CH 2 CH 2 CH 2 -).

[0167] In some of these embodiments, the carboxylic acid containing a carbon-carbon double bond is CH 2 =CH-(L) n -COOH, CH 2 =CH-(L) n -COONa, CH 2 =C(CH 3 )-(L) n -COOH, CH 2 =C(CH 3 )-(L) n -COONa, CH 2 =C(CF 3 )-COOH or C 6 H 5 -CH=CH-COOH, n is 0 or 1, and L is an alkylene group. In a specific example, the carboxylic acid containing a carbon-carbon double bond can be acrylic acid, crotonic acid, pentenoic acid, undecenoic acid, oleic acid, methacrylic acid, methyl crotonic acid, sodium acrylate, sodium crotonate, sodium pentenoate, sodium undecenoate, sodium oleate, sodium methacrylate, sodium methyl crotonate, cinnamic acid, trifluoromethylacrylic acid, etc.

[0168] In some embodiments, the general formula of the anhydride containing a carbon-carbon double bond is R 4 -C(=O)OC(=O)-R 5 , R 4 and R 5 At least one of them is C 2 ~C 6 Alkenyl, or R 4 and R 5 A 5- to 7-membered monocyclic ring is formed, and the 5- to 7-membered monocyclic ring contains a carbon-carbon double bond or has a substituent containing a carbon-carbon double bond. Further, the acid anhydride containing a carbon-carbon double bond is selected from at least one of acrylic anhydride, methacrylic anhydride and maleic anhydride.

[0169] In some of the embodiments, in the step of modifying the heparin-like substance with a carboxylic acid containing a carbon-carbon double bond or an anhydride containing a carbon-carbon double bond, the heparin-like substance and the carboxylic acid containing a carbon-carbon double bond or an anhydride containing a carbon-carbon double bond are reacted in an alkaline solution for 3h to 8h, and the mass ratio of the heparin-like substance to the carboxylic acid containing a carbon-carbon double bond or anhydride containing a carbon-carbon double bond is 1:(0.05 to 0.5).

[0170] It can be understood that after the reaction is completed, dialysis and drying steps are also included, and the drying can be, for example, freeze drying.

[0171] Optionally, the mass ratio of the heparin-like substance to the carboxylic acid containing a carbon-carbon double bond or the anhydride containing a carbon-carbon double bond is 1:0.05, 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5 or a range consisting of any two of these values.

[0172] In some other embodiments, the amine containing a carbon-carbon double bond includes 2-aminoethyl methacrylate.

[0173] Furthermore, in the step of modifying the heparin-like substance with the amine containing a carbon-carbon double bond, the heparin-like substance and the amine containing a carbon-carbon double bond are reacted under the action of an amide catalyst for 3 hours to 24 hours, the mass ratio of the heparin-like substance to the amine containing a carbon-carbon double bond is 1:(0.05-0.5), and the molar ratio of the amine containing a carbon-carbon double bond to the amide catalyst is 1:(0.8-1).

[0174] For example, the mass ratio of the heparin-like substance to the amine containing a carbon-carbon double bond is 1:0.05, 1:0.1, 1:0.15, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5 or a range consisting of any two of these values. The molar ratio of the amine containing a carbon-carbon double bond to the amide catalyst can be, but is not limited to, 1:0.8, 1:0.82, 1:0.85, 1:088, 1:0.9, 1:0.92, 1:0.95, 1:0.98, 1:1 or a range consisting of any two of these values.

[0175] In some other embodiments, the epoxy compound containing a carbon-carbon double bond includes one or more of glycidyl methacrylate, allyl glycidyl ether, epoxybutene and its homologues, 1,2-epoxy-4-vinylcyclohexane, and 3,4-epoxy-1-cyclohexene.

[0176] Further, in the step of modifying the heparin-like substance with the epoxy compound containing a carbon-carbon double bond, the heparin-like substance and the epoxy compound containing a carbon-carbon double bond are reacted in a solution with a pH of 7 to 8 for 3 to 8 days, and the mass ratio of the heparin-like substance to the epoxy compound containing a carbon-carbon double bond is 1:(0.3 to 1).

[0177] Optionally, the mass ratio of the heparin-like substance to the epoxy compound containing a carbon-carbon double bond is 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, or a range composed of any two of these values.

[0178] Optionally, the solution with a pH of 7 to 8 can be a phosphate buffer solution.

[0179] In some other embodiments, the amide compound containing a carbon-carbon double bond includes N-(3-aminopropyl)methacrylamide hydrochloride or N-(3-aminopropyl)methacrylamide.

[0180] Further, in the step of modifying the heparin-like substance with the amide compound containing a carbon-carbon double bond, the heparin-like substance and the amide compound containing a carbon-carbon double bond 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, and the mass ratio of the heparin-like substance, the amide compound containing a carbon-carbon double bond, the activator, and the condensing agent is (1 to 1.2):(0.8 to 1):(0.8 to 1):(0.8 to 1.2).

[0181] Optionally, the mass ratio of the heparin-like substance, the amide compound containing a carbon-carbon double bond, the activator, and the condensing agent is 1.2:1:1:1.

[0182] Optionally, the activator includes NHS (N-hydroxysulfosuccinimide), and the condensing agent includes EDC (1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride).

[0183] The above provides various ways to modify heparin-like substances by double bond formation, enabling the double bond-modified heparin-like substances to directly undergo ATRP reaction and be covalently fixed on the substrate surface through free radical polymerization, achieving the layer-by-layer grafting of heparin and hydrophilic polymers, and also providing the potential for multi-layer grafting, further enhancing the anticoagulant ability of medical materials. Compared with the traditional method of fixing heparin by amide bond, it has a more stable bonding ability. In addition, during the modification process, it is easier to control the density of double bond modification, thereby further adjusting the reaction sites, optimizing the binding firmness while ensuring the activity of heparin-like substances.

[0184] In some embodiments, in the second solution, the mass percentage concentration of the second anticoagulant monomer is 2% - 30%, the mass ratio of the second anticoagulant monomer to the second catalyst is 1:(0.005 - 0.05), and the molar ratio of the second catalyst to the second ligand is 1:(1 - 5).

[0185] Optionally, in the second solution, the mass percentage concentration of the second anticoagulant monomer can be but is not limited to 2%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 15%, 18%, 20%, 22%, 25%, 28%, 30% or the range composed of any two of these values. Preferably, in the second solution, the mass percentage concentration of the second anticoagulant monomer is 5% - 10%.

[0186] Optionally, the mass ratio of the second anticoagulant monomer to the second catalyst can be but is not limited to 1:0.005, 1:0.006, 1:0.007, 1:0.008, 1:0.009, 1:0.01, 1:0.015, 1:0.02, 1:0.025, 1:0.03, 1:0.035, 1:0.04, 1:0.045, 1:0.05 or the range composed of any two of these values. Preferably, the mass ratio of the second anticoagulant monomer to the second catalyst is 1:(0.005 - 0.01).

[0187] Optionally, the molar ratio of the second catalyst to the second ligand can be but is not limited to 1:1, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:3, 1:4, 1:5 or the range composed of any two of these values. Preferably, the molar ratio of the second catalyst to the second ligand is 1:(1.5 - 2).

[0188] Specifically, the second catalyst includes one or more combinations of low-valent salts of copper, iron, molybdenum, chromium, rhenium, ruthenium, rhodium or nickel. Preferably, the second catalyst includes CuCl, FeCl 2 and RuCl 2 and one or several of them.

[0189] The second ligand includes one or a combination of more than one of amine substances and phosphine substances. Among them, 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, or 4,4'-bis(trifluoromethyl)-2,2'-bipyridine. The phosphine substances include triphenylphosphine.

[0190] Preferably, the second ligand includes one or a combination of several of N,N,N,N,N-pentamethyldiethylenetriamine, tris[2-(dimethylamino)ethyl]amine, and 4,4'-di-tert-butyl-2,2'-bipyridine.

[0191] It can be understood that the second catalyst can be the same as or different from the first catalyst. Similarly, the second ligand can be the same as or different from the first ligand.

[0192] In some of these embodiments, the solvent in the second solution includes one or a combination of more than one of water, ethanol, methanol, acetone, tetrahydrofuran, or N,N'-dimethylformamide.

[0193] In some of these embodiments, in the second solution, a second reducing agent is further included. The addition of the second reducing agent promotes the progress of the ATRP reaction. The second reducing agent includes a high-valent salt corresponding to the metal used in the second 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).

[0194] It can be understood that the second reducing agent including a high-valent salt corresponding to the metal used in the second catalyst means, for a metal with variable valence, a salt formed by the metal with a higher valence. For example, the second catalyst includes CuCl, and the second reducing agent includes CuCl 2 。

[0195] Specifically, the molar ratio of the second reducing agent to the second catalyst is (0.1 to 0.3):1. For example, the molar ratio of the second reducing agent to the second 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 the range formed by any two of these values. It can be understood that the second reducing agent can be the same as or different from the first reducing agent.

[0196] Since both the hydrophilic anticoagulant monomer and the double-bonded heparin-like substance can be grafted by ATRP, the ATRP reaction conditions are mild, and the same ATRP reaction system, namely the same catalyst, ligand, solvent, etc., can be more conveniently used during the layer-by-layer grafting process, so as to reduce the cost of industrial production.

[0197] In some embodiments, in the step of treating the substrate grafted with the first anticoagulant layer with a second solution containing a second anticoagulant monomer, a second catalyst, and a second ligand, the substrate grafted with the first anticoagulant layer is immersed in the second solution.

[0198] In some embodiments, in step S230, the temperature of the atom transfer radical polymerization reaction is 25°C to 70°C, and the time is 2 h to 12 h. 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. Optionally, the time of the ATRP reaction can be, but is not limited to, 2 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, or the range formed by any two of these values. Further, the time of the ATRP polymerization reaction is 2 h to 6 h.

[0199] In some embodiments, in step S230, the ATRP polymerization process can be protected by an inert gas or not. Preferably, the ATRP polymerization process is protected by nitrogen or argon.

[0200] In some of these embodiments, step S230 includes:

[0201] Modifying the heparin-like substance with a carboxylic acid containing a carbon-carbon double bond, an acid anhydride containing a carbon-carbon double bond, an amine containing a carbon-carbon double bond, an epoxy compound containing a carbon-carbon double bond, or an amide compound containing a carbon-carbon double bond to make the heparin-like substance carry a carbon-carbon double bond, and preparing a second anticoagulant monomer;

[0202] A second solution including a second anticoagulant monomer, a second catalyst, and a second ligand is obtained. In the second solution, the mass percentage concentration of the second anticoagulant monomer is 5% - 30%, the mass ratio of the second anticoagulant monomer to the second catalyst is 1:(0.005 - 0.05), and the molar ratio of the second catalyst to the second ligand is 1:(1 - 5);

[0203] The substrate grafted with the first anticoagulant layer is immersed in the second solution, and the second anticoagulant monomer is subjected to atom transfer radical polymerization on the surface of the substrate grafted with the first anticoagulant layer for 2h - 12h under closed conditions at 25°C - 70°C to prepare the second anticoagulant layer.

[0204] Please refer to Figure 3 , Figure 3 for Figure 2 a schematic diagram of the process flow chart shown. 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, and then after being treated in step S220, a first anticoagulant layer 120 is grafted on the surface of the substrate 110. Then, through step S230, the second anticoagulant layer 130 is covalently grafted onto the first anticoagulant layer 120 to obtain a medical material.

[0205] The preparation method of the above-mentioned medical material forms the first anticoagulant layer and the second anticoagulant layer by layer grafting through the ATRP method. The first anticoagulant layer and the second anticoagulant layer are sequentially fixed on the surface of the substrate, and they synergistically play the anti-protein adsorption function of the hydrophilic anticoagulant layer and the anticoagulant function of the heparin anticoagulant layer to achieve a more effective anticoagulant effect on the material surface. At the same time, in the above-mentioned medical material, both the hydrophilic anticoagulant layer, the heparin anticoagulant layer and the substrate are connected by covalent bonds. On the other hand, ATRP is a method of controlled radical polymerization, which has better controllability of the polymer structure and molecular weight compared with other polymerization methods. It allows the molecular chain to grow gradually, and the initiator group remains at the end of the molecular chain after the polymerization is completed, reducing the risk of the initiator group being embedded, ensuring the active sites for grafting the next layer, enabling an increase in the grafting amount and stability when grafting the second anticoagulant layer, and preventing it from falling off under long-term blood flow scouring during the use of the material, thus achieving long-term stable anticoagulation.

[0206] The preparation method of the above-mentioned medical material grafts the hydrophilic anticoagulant layer and the heparin anticoagulant layer layer by layer through the SI-ATRP technology, making the polymer structure and molecular weight of each layer controllable, thereby effectively controlling the structure, thickness of each anticoagulant layer in the medical material and the thickness of the total anticoagulant layer. The controllability of the thickness can more effectively reduce the influence of the anticoagulant layer on the material properties itself, and can also more fully exert the synergistic anticoagulant effect of the hydrophilic anticoagulant layer and the heparin anticoagulant layer.

[0207] By the above method, a first anticoagulant layer and a second anticoagulant layer are grafted on the surface of the substrate, enabling the hydrophilic anticoagulant layer and the heparin anticoagulant layer to act synergistically, significantly improving the anticoagulant effect and meeting most anticoagulant requirements. Further, in applications with higher anticoagulant requirements, grafting can be continued on the surface of the second anticoagulant layer.

[0208] In some embodiments, after the step of preparing the second anticoagulant layer, it further includes: repeating the preparation steps of the first anticoagulant layer and / or the second anticoagulant layer to alternately stack the first anticoagulant layer and the second anticoagulant layer.

[0209] Optionally, in medical materials, the total number of layers of the first anticoagulant layer and the second anticoagulant layer ≤ 6. For example, the total number of layers of the first anticoagulant layer and the second anticoagulant layer is 2 layers, 3 layers, 4 layers, 5 layers, 6 layers, etc.

[0210] Due to the ATRP reaction, the ATRP initiating group remains at the end of the polymer chain after initiating the polymerization of the carbon-carbon double bond, reducing the embedding risk. At the same time, it ensures that the second anticoagulant layer is grafted on the surface of the first anticoagulant layer. In addition, the molecular chain end of the second anticoagulant layer also has an initiating group, enabling further grafting. Additionally, considering that the more layers there are, on the one hand, the cost will increase, and on the other hand, the risk of the terminal initiating group being embedded in the polymer will increase, resulting in an impact on the density and thickness of the graftable heparin and hydrophilic anticoagulant materials. Therefore, in some embodiments, preferably, the total number of layers of the first anticoagulant layer and the second anticoagulant layer ≤ 6.

[0211] To make the objectives and advantages of the present invention clearer, the following further elaborates on the medical materials of the present invention and their 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, the following embodiments do not include other components except inevitable impurities. The drugs and instruments used in the embodiments are all conventional selections in the art unless otherwise specified. The experimental methods without specific conditions in the embodiments are carried out under conventional conditions, such as the conditions described in the literature, books, or the methods recommended by the manufacturers.

[0212] The heparin used in the following examples and comparative examples is enoxaparin, with a molecular weight of 3500 - 5000.

[0213] Comparative Example 1

[0214] Comparative Example 1 provides a medical material, including a substrate and a hydrophilic anticoagulant layer grafted on the surface of the substrate. The preparation steps are as follows:

[0215] (1) Place the polyethylene film in ammonia plasma for 20 min to make the polyethylene film carry amino groups, and then 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 with DMF three times first, and then rinse it with pure water three times to obtain a polyethylene film grafted with ATRP initiating groups.

[0216] (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 amounts of CuCl and tris[2-(dimethylamino)ethyl]amine are 2% and 5% of the molar amount of NVP respectively to obtain the first solution. Subsequently, place the polyethylene film grafted with ATRP initiating groups into the first 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 with ethanol three times first, and then rinse it with pure water three times, and dry it to obtain a polyethylene film grafted with a hydrophilic anticoagulant layer.

[0217] Comparative Example 2

[0218] Comparative Example 2 provides a medical material, including a substrate and a heparin anticoagulant layer grafted on the surface of the substrate. The preparation steps are as follows:

[0219] (1) The same as step (1) of Comparative Example 1.

[0220] (2) React 1 g of heparin with 0.1 g of methacrylic anhydride in an aqueous sodium hydroxide solution with a pH value of 8 for 8 hours, and then dialyze and freeze-dry to obtain double-bonded heparin.

[0221] (3) Prepare an aqueous solution of double-bonded heparin with a mass percentage concentration of 8%, add a CuCl catalyst and a tris[2-(dimethylamino)ethyl]amine ligand. Among them, the mass of CuCl is 1% of the mass of double-bonded heparin, and the molar amount of the tris[2-(dimethylamino)ethyl]amine ligand is 120% of the molar amount of CuCl to obtain the second solution. Subsequently, place the polyethylene film grafted with ATRP initiating groups obtained in (1) into the second 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 with pure water three times, and dry it to obtain a polyethylene film grafted with a heparin anticoagulant layer.

[0222] Comparative Example 3

[0223] Comparative Example 3 provides a medical material. The preparation steps are as follows:

[0224] (1) and (2) are the same as steps (1) and (2) of Comparative Example 2 respectively.

[0225] (3) Prepare an ethanol / water solution (V:V = 50:50) containing NVP with a mass percentage concentration of 10% and double-bonded heparin with a mass percentage concentration of 8%. Add a CuCl catalyst and tris[2-(dimethylamino)ethyl]amine ligand. Among them, the molar amounts of CuCl and tris[2-(dimethylamino)ethyl]amine are 2% and 5% of the total molar amounts of NVP and double-bonded heparin respectively to obtain a third solution. Subsequently, place the polyethylene film grafted with the ATRP initiating group into the third 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 pure water, dry it, and obtain a medical material.

[0226] Comparative Example 4

[0227] Comparative Example 4 provides a medical material, including a substrate, a hydrophilic anticoagulant layer grafted on the surface of the substrate, and a heparin anticoagulant layer. The preparation steps are as follows:

[0228] (1) Treat the 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. Among them, the mass percentage concentration of 4,4'-azobis(4-cyanovaleric acid) is 10%. Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole 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 it 3 times with purified water to obtain a polyethylene film grafted with an azo initiator.

[0229] (2) The same as step (2) of Comparative Example 2.

[0230] (3) Prepare an NVP ethanol solution with a mass percentage concentration of 10%. Place the polyethylene film grafted with the 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 obtain a polyethylene film grafted with a hydrophilic anticoagulant layer.

[0231] (4) Prepare an aqueous solution of double-bonded heparin with a mass percentage concentration of 8%. Place the polyethylene film grafted with the hydrophilic anticoagulant layer into the second solution, seal it, purge with nitrogen for 5 min, and then place it in an oven at 80 °C for reaction for 6 h to graft a heparin anticoagulant layer on the surface of the hydrophilic anticoagulant layer. After the reaction is completed, take it out, rinse it 3 times with pure water, dry it, and obtain the medical material of Comparative Example 4.

[0232] Example 1

[0233] This embodiment provides a medical material, which includes a substrate, a hydrophilic anticoagulant layer grafted on the surface of the substrate, and a heparin anticoagulant layer grafted on the surface of the hydrophilic anticoagulant layer. The preparation steps are as follows:

[0234] (1) and (2) are the same as steps (1) and (2) of Comparative Example 2 respectively.

[0235] (3) 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 amounts of CuCl and tris[2-(dimethylamino)ethyl]amine are 2% and 5% of the molar amount of NVP respectively to obtain a first solution. Put the polyethylene film grafted with ATRP initiating groups into the first 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, and then rinse it 3 times with pure water to obtain a polyethylene film grafted with a hydrophilic anticoagulant layer.

[0236] (4) Prepare an aqueous solution of double-bonded heparin with a mass percentage concentration of 8%, add a CuCl catalyst and a tris[2-(dimethylamino)ethyl]amine ligand. Among them, the mass of CuCl is 1% of the mass of double-bonded heparin, and the molar amount of the tris[2-(dimethylamino)ethyl]amine ligand is 120% of the molar amount of CuCl to obtain a second solution. Put the polyethylene film grafted with a hydrophilic anticoagulant layer into the second solution, seal it, purge with nitrogen for 5 min, and then place it in an oven at 30 °C for reaction for 6 h to graft a heparin anticoagulant layer on the surface of the hydrophilic anticoagulant layer. After the reaction is completed, take it out, rinse it 3 times with pure water, and dry it to obtain the medical material of this embodiment.

[0237] Example 2

[0238] This embodiment provides a medical material, which includes a substrate, a heparin anticoagulant layer grafted on the surface of the substrate, and a hydrophilic anticoagulant layer grafted on the surface of the heparin anticoagulant layer. The preparation steps are as follows:

[0239] (1) and (2) are the same as steps (1) and (2) of Comparative Example 2 respectively.

[0240] (3) Prepare an aqueous solution of double-bonded heparin with a mass percentage concentration of 8%, add a CuCl catalyst and a tris[2-(dimethylamino)ethyl]amine ligand. Among them, the mass of CuCl is 1% of the mass of double-bonded heparin, and the molar amount of the tris[2-(dimethylamino)ethyl]amine ligand is 120% of the molar amount of CuCl to obtain a first solution. Put the polyethylene film grafted with ATRP initiating groups into the first 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 pure water, and dry it to obtain a polyethylene film grafted with a heparin anticoagulant layer.

[0241] (4) 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, wherein the molar amounts of CuCl and tris[2-(dimethylamino)ethyl]amine are 2% and 5% of the molar amount of NVP respectively, to obtain a second solution. Immerse the polyethylene film grafted with a heparin anticoagulant layer into the second 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 the medical material of this example.

[0242] Example 3

[0243] This example provides a medical material, including a substrate, a hydrophilic anticoagulant layer grafted on the surface of the substrate, and a heparin anticoagulant layer grafted on the surface of the hydrophilic anticoagulant layer. The preparation steps are as follows:

[0244] (1) and (2) are the same as steps (1) and (2) of Comparative Example 2 respectively.

[0245] (3) Prepare an aqueous solution containing 2-(methacryloyloxy)ethyl-2-(trimethylammonio)ethyl phosphate with a mass percentage concentration of 10%, add a CuCl catalyst and a tris[2-(dimethylamino)ethyl]amine ligand, wherein the molar amounts of CuCl and tris[2-(dimethylamino)ethyl]amine are 2% and 5% of the molar amount of 2-(methacryloyloxy)ethyl-2-(trimethylammonio)ethyl phosphate respectively, to obtain a first solution. Subsequently, immerse the polyethylene film grafted with an ATRP initiating group into the first 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, and then rinse it 3 times with pure water to obtain a polyethylene film grafted with a hydrophilic anticoagulant layer.

[0246] (4) Prepare an aqueous solution of double-bonded heparin with a mass percentage concentration of 8%, add a CuCl catalyst and a tris[2-(dimethylamino)ethyl]amine ligand, wherein the mass of CuCl is 1% of the mass of double-bonded heparin, and the molar amount of the tris[2-(dimethylamino)ethyl]amine ligand is 120% of the molar amount of CuCl, to obtain a second solution. Immerse the polyethylene film in the second solution, seal it, purge with nitrogen for 5 min, and then place it in an oven at 30 °C for reaction for 6 h to graft a heparin anticoagulant layer on the surface of the hydrophilic anticoagulant layer. After the reaction is completed, take it out, rinse it 3 times with pure water, and dry it to obtain the medical material of this example.

[0247] Example 4

[0248] This embodiment provides a medical material, which includes a substrate, a hydrophilic anticoagulant layer grafted on the surface of the substrate, and a heparin anticoagulant layer grafted on the surface of the hydrophilic anticoagulant layer. The preparation steps are as follows:

[0249] (1) and (2) are the same as steps (1) and (2) of Comparative Example 2 respectively.

[0250] (3) Prepare an ethanol / water (V:V = 6:4) solution containing 2-(methacryloyloxy)ethyl-2-(trimethylammonio)ethyl phosphate with a mass percentage concentration of 5% and NVP with a mass percentage concentration of 5%. Add a CuCl catalyst and tris[2-(dimethylamino)ethyl]amine ligand. Among them, the molar numbers of CuCl and tris[2-(dimethylamino)ethyl]amine are 4% and 10% of the total molar numbers of 2-(methacryloyloxy)ethyl-2-(trimethylammonio)ethyl phosphate and NVP respectively to obtain a first solution. Subsequently, immerse the polyethylene film grafted with an ATRP initiating group in the first 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, and then rinse it 3 times with pure water to obtain a polyethylene film grafted with a hydrophilic anticoagulant layer.

[0251] (4) Prepare an aqueous solution of heparin with a double bond with a mass percentage concentration of 8%. Add a CuCl catalyst and tris[2-(dimethylamino)ethyl]amine ligand. Among them, the mass of CuCl is 1% of the mass of heparin with a double bond, and the molar number of the tris[2-(dimethylamino)ethyl]amine ligand is 120% of the molar number of CuCl to obtain a second solution. Immerse the polyethylene film in the second solution, seal it, purge with nitrogen for 5 min, and then place it in an oven at 30 °C for reaction for 6 h to graft a heparin anticoagulant layer on the surface of the hydrophilic anticoagulant layer. After the reaction is completed, take it out, rinse it 3 times with pure water, and dry it to obtain the medical material of this embodiment.

[0252] Example 5

[0253] This embodiment provides a medical material, which includes a substrate, a first hydrophilic anticoagulant layer grafted on the surface of the substrate, a first heparin anticoagulant layer grafted on the surface of the first hydrophilic anticoagulant layer, a second hydrophilic anticoagulant layer grafted on the surface of the first heparin anticoagulant layer, and a second heparin anticoagulant layer grafted on the surface of the second hydrophilic anticoagulant layer. The preparation steps are as follows:

[0254] (1), (2), and (3) are the same as steps (1), (2), and (3) of Example 1 respectively.

[0255] (4) Prepare an aqueous solution of double-bonded heparin with a mass percentage concentration of 8%, and add a CuCl catalyst and tris[2-(dimethylamino)ethyl]amine ligand. Among them, the mass of CuCl is 1% of the mass of double-bonded heparin, and the molar amount of tris[2-(dimethylamino)ethyl]amine ligand is 120% of the molar amount of CuCl to obtain a second solution. Immerse the polyethylene film obtained in (3) in the second 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 and rinse it 3 times with pure water.

[0256] (5) Immerse the polyethylene film obtained in (4) in the first solution prepared in (3), 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, and then rinse it 3 times with pure water.

[0257] (6) Immerse the polyethylene film obtained in (5) in the second solution prepared in (4), 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 pure water, and dry it to obtain the medical material of this example.

[0258] Contact angle test, heparin density test, long-term stability test and platelet adhesion test were carried out on the medical materials obtained in the blank group, Comparative Example 1 to Comparative Example 4, and Example 1 to Example 5 respectively. Among them, the blank group is a polyethylene film cleaned with pure water without grafting any layer. The heparin density test was carried out by the toluidine blue colorimetric method. The long-term stability test means that the sample is immersed in a PBS buffer solution with a pH of 7.4 for 7 days, and then taken out and its heparin density and platelet adhesion are tested again. The platelet adhesion test means that the sample is placed on a 24-well plate, 1 mL of platelet-rich plasma is added to each well, and incubated at 37 °C for 1 h. After incubation, the sample is washed with a PBS buffer solution with a pH of 7.4 to remove unadhered platelets, and the LDH cytotoxicity kit is used to detect the LDH released by cells to indirectly quantify the number of platelets adhered to the surface of the sample. After the reaction is completed, the absorbance at 490 nm is measured with an enzyme-linked immunosorbent assay instrument. Among them, the absorbance at 490 nm measured with pure PBS buffer solution is denoted as A 0 . The relative adhesion of platelets = (absorbance at 490 nm of the experimental group - A 0 ) / (absorbance at 490 nm of the blank group - A 0 ). The experimental group is the samples of Comparative Example 1 to 4 or Example 1 to 5. The blood coagulation time means that the sample is placed in a centrifuge tube, 1 mL of fresh blood is added, and the time of blood coagulation is observed. The test results of each example and comparative example are shown in Table 1.

[0259] Table 1 Test results of each example and comparative example

[0260]

[0261] As can be seen from Table 1 above, the medical materials prepared in the above examples synergistically exerted the hydrophilic effect of the hydrophilic anti-coagulant layer and the anti-coagulant effect of the heparin anti-coagulant layer. The contact angle decreased significantly, the heparin density was also relatively high, the anti-platelet adhesion effect was remarkable, and the blood coagulation time increased significantly, greatly enhancing the anti-coagulant effect of the medical materials. At the same time, through the preparation method of the above examples, the hydrophilic anti-coagulant layer and the heparin anti-coagulant layer can be effectively covalently grafted onto the surface of the substrate, having long-term stability. From the comparison between Example 1 and Comparative Example 3, it can be seen that by grafting the hydrophilic anti-coagulant layer and the heparin anti-coagulant layer separately, it is beneficial to improve the hydrophilic effect and heparin density. This is because the separate grafting of the hydrophilic anti-coagulant layer and the heparin anti-coagulant layer reduces the risk of mutual embedding of the two and is conducive to their respective functions. In addition, by optimizing the material of the hydrophilic anti-coagulant layer and the total number of anti-coagulant layers, the anti-coagulant effect of the medical materials can be further improved. In Comparative Example 4, after the substrate was grafted with an azo initiator, the hydrophilic monomer polymerization and heparin polymerization were sequentially initiated. However, since the azo initiator is different from the ATRP initiator and is consumed during the first hydrophilic monomer polymerization, it will not initiate heparin polymerization again, and the heparin density is significantly lower. In Example 2, after heparin grafting, the hydrophilic layer was grafted. The surface was mainly composed of the hydrophilic layer, so the measured value of heparin density was relatively low. However, in terms of anti-platelet relative adhesion, Example 2 had a better effect than the comparative example.

[0262] Examples 6 to 11

[0263] Examples 6 to 11 respectively provide a medical material, including a substrate, a hydrophilic anti-coagulant layer grafted on the surface of the substrate, and a heparin anti-coagulant layer grafted on the surface of the hydrophilic anti-coagulant layer. The preparation steps are as follows:

[0264] (1) Different substrates in Table 2 were respectively treated by different surface activation methods and fixed with different ATRP initiating groups to obtain substrates grafted with ATRP initiating groups.

[0265] (2) 1 g of heparin and 0.9 g of N-(3-aminopropyl) methacrylamide hydrochloride were stirred and reacted at 0 °C for 6 hours under the action of 0.9 g of NHS and 1.2 g of EDC, and then dialyzed and freeze-dried to obtain double-bonded heparin.

[0266] (3) 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 amounts of CuCl and tris[2-(dimethylamino)ethyl]amine are 2% and 5% of the molar amount of NVP respectively to obtain a first solution. Subsequently, immerse the substrate grafted with an ATRP initiating group in the first 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, and then rinse it 3 times with pure water to obtain a substrate grafted with a hydrophilic anticoagulant layer.

[0267] (4) Prepare an aqueous solution of double-bonded heparin with a mass percentage concentration of 8%, add a CuCl catalyst and a tris[2-(dimethylamino)ethyl]amine ligand. Among them, the mass of CuCl is 1% of the mass of double-bonded heparin, and the molar amount of the tris[2-(dimethylamino)ethyl]amine ligand is 120% of the molar amount of CuCl to obtain a second solution. Subsequently, immerse the substrate grafted with a hydrophilic anticoagulant layer in the second solution, seal it, purge with nitrogen for 5 min, and then place it in an oven at 30 °C for reaction for 6 h to graft a heparin anticoagulant layer on the surface of the hydrophilic anticoagulant layer. After the reaction is completed, take it out, rinse it 3 times with pure water, and dry it to obtain the medical materials of each example.

[0268] Contact angle tests, heparin density tests, platelet adhesion tests, and blood coagulation time tests were respectively carried out on the medical materials prepared in the above examples. The test methods were as described above, and the test results are shown in Table 3.

[0269] Table 2 Substrate types and methods of grafting ATRP initiating groups in each example

[0270]

[0271]

[0272] Table 3 Test results of each example

[0273]

[0274] As can be seen from Tables 2 and 3 above, the preparation methods of the above examples can be applied to a variety of different substrates, and different methods of grafting ATRP initiating groups do not affect the final performance of the medical materials, and excellent anticoagulant effects can be achieved.

[0275] Examples 12 to 16

[0276] Examples 12 to 16 respectively provide a medical material, and the preparation steps are as follows:

[0277] (1) Place the polyethylene film in ammonia plasma for 20 min to make the polyethylene film carry amino groups, and then 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 with DMF three times first, and then rinse it with pure water three times to obtain a polyethylene film grafted with ATRP initiating groups.

[0278] (2) React 5 g of heparin and 0.8 g of glycidyl methacrylate in PBS buffer solution with a pH value of 7.4 for 3 days, and then dialyze and freeze-dry to obtain double-bonded heparin.

[0279] (3) Prepare an ethanol solution of NVP with a mass percentage concentration of 10%, and add the first catalyst and the first ligand shown in Table 4 respectively to obtain the first solution. Subsequently, immerse the polyethylene film grafted with ATRP initiating groups in the first 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 with ethanol three times first, and then rinse it with pure water three times to obtain a polyethylene film grafted with a hydrophilic anticoagulant layer.

[0280] (4) Prepare an aqueous solution of double-bonded heparin with a mass percentage concentration of 8%, and add the second catalyst and the second ligand shown in Table 4 respectively to obtain the second solution. Subsequently, immerse the polyethylene film grafted with a hydrophilic polymer layer in the second solution, seal it, purge with nitrogen for 5 min, and then place it in an oven at 30 °C for reaction for 6 h to graft a heparin anticoagulant layer on the surface of the hydrophilic anticoagulant layer. After the reaction, take it out, rinse it with pure water three times, and dry it to obtain the medical materials of each example.

[0281] Perform contact angle test, heparin density test, platelet adhesion test and blood coagulation time test on the medical materials of each of the above examples respectively, and the results are shown in Table 5.

[0282] Table 4 Catalysts, ligands, reducing agents and dosages of each example

[0283]

[0284] Table 5 Test results of each example

[0285]

[0286]

[0287] In Table 4, the dosages of the first catalyst, the first ligand, and the first reducing agent are all in mole percentages based on NVP, the dosage of the second catalyst is in mass percentage of the second catalyst based on double-bonded heparin, the dosage of the second ligand is in mole percentage of the second ligand based on the second catalyst, and the dosage of the second reducing agent is in mole percentage of the second reducing agent based on the second catalyst.

[0288] As can be seen from Table 4 and Table 5 above, by using the preparation methods of the examples, coatings with excellent anticoagulant effects can be prepared with different catalysts and ligands, and adding a reducing agent can further improve the anticoagulant effect to a certain extent.

[0289] Examples 17 to 25

[0290] Examples 17 to 25 respectively provide a medical material, including a substrate, a hydrophilic anticoagulant layer grafted on the surface of the substrate, and a heparin anticoagulant layer grafted on the surface of the hydrophilic anticoagulant layer. The preparation steps are as follows:

[0291] (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 with DMF three times first, and then rinse with pure water three times to obtain a polyethylene film grafted with an ATRP initiating group.

[0292] (2) React 5 g of heparin and 0.8 g of glycidyl methacrylate in a PBS buffer solution with a pH value of 7.4 for 3 days, then dialyze and freeze-dry to obtain double-bonded heparin.

[0293] (3) Prepare ethanol solutions of NVP with different mass percentage concentrations w1, as shown in Table 6 specifically. Respectively add the first catalyst CuCl and the first ligand tris[2-(dimethylamino)ethyl]amine. The mole percentages of the first catalyst and the first ligand based on NVP are 2% and 5% respectively to obtain the first solution. Subsequently, immerse the polyethylene film grafted with an ATRP initiating group in the first solution, seal it, purge with nitrogen for 5 min, and then place it in an oven at 30 °C to react for different times t1, as shown in Table 6 specifically. After the reaction, take it out, rinse with ethanol three times first, and then rinse with pure water three times to obtain a polyethylene film grafted with a hydrophilic anticoagulant layer, with a thickness of h1.

[0294] (4) Prepare aqueous solutions of heparin with different mass percentages w2, as shown in Table 6 specifically. Add the second catalyst CuCl and the second ligand tris[2-(dimethylamino)ethyl]amine respectively. The mass percentage of the second catalyst in heparin is 1%, and the molar percentage of the second ligand in the second catalyst is 120% to obtain the second solution. Subsequently, immerse the polyethylene film grafted with the hydrophilic anticoagulant layer in the second solution, seal it, purge with nitrogen for 5 min, and then place it in an oven at 30 °C to react for different times t2, as shown in Table 6 specifically, to graft a heparin anticoagulant layer on the surface of the hydrophilic anticoagulant layer with a thickness of h2. After the reaction, take it out, rinse it 3 times with pure water, and dry it to obtain the medical materials of each example.

[0295] Perform contact angle tests, heparin density tests, platelet adhesion tests, and blood coagulation time tests on the medical materials of each of the above examples respectively. The results are shown in Table 6.

[0296] Table 6 Test results of each example

[0297]

[0298]

[0299] As can be seen from Table 6 above, with the increase of the polymerization time and concentration in the preparation process of the hydrophilic anticoagulant layer and the heparin anticoagulant layer, the contact angle decreases, the heparin density increases, thus reducing platelet adhesion and prolonging the blood coagulation time, and improving the anticoagulant performance. However, when the polymerization reaction time of the hydrophilic anticoagulant layer is too long and / or the concentration is too high, although it will increase the thickness of the hydrophilic anticoagulant layer and further decrease the water contact angle and reduce platelet adhesion, it will affect the grafting density of the heparin anticoagulant layer and increase the blood coagulation time to some extent. Similarly, the increase in the thickness of the heparin anticoagulant layer due to the prolongation of the polymerization time and / or the increase in the concentration of the heparin anticoagulant layer will also conversely affect the decrease of the water contact angle and increase platelet adhesion to some extent. Therefore, by optimizing the polymerization process of the hydrophilic anticoagulant layer and the heparin anticoagulant layer, a better synergistic anticoagulant effect can be further achieved.

[0300] The technical features of the above-described examples can be combined arbitrarily. For the sake of concise description, not all possible combinations of the technical features in the above examples are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered to be within the scope described in this specification.

[0301] 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, but 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 deformations 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 on the basis of the technical solutions 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 a medical material, characterized in that, it comprises the following steps: Covalently connecting a first anticoagulant layer on the surface of a substrate by means of atom transfer radical polymerization; Covalently connecting a second anticoagulant layer on the surface of the first anticoagulant layer by means of atom transfer radical polymerization to prepare the medical material; wherein, one of the first anticoagulant layer and the second anticoagulant layer is a hydrophilic anticoagulant layer, and the other is a heparin anticoagulant layer.

2. The preparation method of the medical material according to claim 1, characterized in that, the preparation steps of the first anticoagulant layer include: Grafting an initiator group on the surface of the substrate, and the initiator group includes a halogen group; Treating the substrate grafted with the initiator group with a first solution containing a first anticoagulant monomer, a first catalyst and a first ligand, so that the first anticoagulant monomer undergoes an atom transfer radical polymerization reaction 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 to prepare the first anticoagulant layer; the preparation steps of the second anticoagulant layer include: Treating the substrate grafted with the first anticoagulant layer with a second solution containing a second anticoagulant monomer, a second catalyst and a second ligand, so that the second anticoagulant monomer undergoes an atom transfer radical polymerization reaction on the surface of the first anticoagulant layer under the action of the initiator group, the second catalyst and the second ligand to prepare the second anticoagulant layer.

3. The preparation method of the medical material according to claim 2, characterized in that, the step of grafting the initiator group on the surface of the substrate satisfies one of the following conditions: (1) The step of grafting the initiator group on the surface of the substrate includes: obtaining a substrate with a hydroxyl group on its surface; Performing a silanization reaction between a silanization reagent containing an initiator group and the hydroxyl group on the surface of the substrate to graft the initiator group on the surface of the substrate; Optionally, the silanization 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; 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% - 30%; Optionally, the temperature of the silanization reaction is 25°C - 60°C, and the time is 3h - 24h; (2) The step of grafting the initiator group on the surface of the substrate includes: Obtaining a substrate with an amino group on its surface; Performing an acylation reaction between an acyl halide reagent containing an initiator group and the amino group on the surface of the substrate; Optionally, the acyl halide reagent containing an initiator group includes one or two combinations 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% - 30%; Optionally, the temperature of the acylation reaction is 0°C to 25°C, and the time is 5h to 48h.

4. The method for preparing a medical material according to claim 2, wherein, the first anticoagulant layer is a hydrophilic anticoagulant layer, and the preparation steps of the first anticoagulant layer satisfy one or more of the following conditions: (1) In the first solution, the mass percentage concentration of the first anticoagulant monomer is 1% to 50%; (2) The molar ratio of the carbon-carbon double bond in the first anticoagulant monomer, the first catalyst and the first ligand is 1:(0.005 to 0.1):(0.005 to 0.5); (3) The first anticoagulant monomer includes one or a combination 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 temperature of the atom transfer radical polymerization reaction is 25°C to 70°C, and the time is 2h to 24h; (5) The first catalyst includes one or a combination of low-valent salts of copper, iron, molybdenum, chromium, rhenium, ruthenium, rhodium and nickel; (6) 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 substances include triphenylphosphine; (7) A first reducing agent is further contained in the first solution, and the first reducing agent includes a high-valent salt corresponding to the metal used in the first catalyst or a radical thermal initiator.

5. The method for preparing a medical material according to claim 4, wherein, the preparation steps of the first anticoagulant layer satisfy one or more of the following conditions: (1) In the first solution, the mass percentage concentration of the first anticoagulant monomer is 5% to 30%; (2) The molar ratio of the carbon-carbon double bond in the first anticoagulant monomer, the first catalyst and the first ligand is 1:(0.01 to 0.1):(0.01 to 0.3); (3) The first anticoagulant monomer includes zwitterionic monomers, and the structural formula of the zwitterionic monomer is shown as the following formula (II): 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; (4) The time of the atom transfer radical polymerization reaction is 5h to 10h.

6. The method for preparing a medical material according to claim 2, wherein, in the preparation of the heparin anticoagulant, the anticoagulant monomer is prepared by the following steps: reacting a heparin substance with a modifier containing a carbon-carbon double bond and a reactive group to make the heparin substance carry a carbon-carbon double bond, and the reactive group includes one or several of a carboxylic acid group, an acid anhydride group, an epoxy group and an amide group.

7. The method for preparing a medical material according to claim 2 or 6, wherein, The second anticoagulant layer is a heparin anticoagulant layer, and the steps for preparing the second anticoagulant layer satisfy one or more of the following conditions: (1) In the second solution, the mass percentage concentration of the second anticoagulant monomer is 2% - 30%; (2) The mass ratio of the second anticoagulant monomer to the second catalyst is 1:(0.005 - 0.05), and the molar ratio of the second catalyst to the second ligand is 1:(1 - 5); (3) The temperature of the atom transfer radical polymerization reaction is 25°C - 70°C, and the time is 2h - 12h; (4) The second catalyst includes one or a combination of low-valent salts of copper, iron, molybdenum, chromium, rhenium, ruthenium, rhodium, and nickel; (5) The second 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 substances include triphenylphosphine; (6) The second solution further contains a second reducing agent, and the second reducing agent includes a high-valent salt corresponding to the metal used in the second catalyst or a radical thermal initiator.

8. The method for preparing a medical material according to claim 7, wherein, the steps for preparing the second anticoagulant layer satisfy one or more of the following conditions: (1) In the second solution, the mass percentage concentration of the second anticoagulant monomer is 5% - 10%; (2) The mass ratio of the second anticoagulant monomer to the second catalyst is 1:(0.005 - 0.01), and the molar ratio of the second catalyst to the second ligand is 1:(1.5 - 2); (3) The time of the atom transfer radical polymerization reaction is 2h - 6h.

9. The method for preparing a medical material according to any one of claims 1 - 6 and 8, wherein, after the step of preparing the second anticoagulant layer, it further includes: repeating the steps of preparing the first anticoagulant layer and / or the second anticoagulant layer to alternately stack the first anticoagulant layer and the second anticoagulant layer; Optionally, in the medical material, the total number of layers of the first anticoagulant layer and the second anticoagulant layer ≤ 6.

10. A medical material, wherein, it includes a substrate, a first anticoagulant layer disposed on the surface of the substrate, and a second anticoagulant layer disposed on the surface of the first anticoagulant layer away from the substrate; wherein, the first anticoagulant layer is covalently connected to the surface of the substrate by atom transfer radical polymerization, and the second anticoagulant layer is covalently connected to the surface of the first anticoagulant layer by atom transfer radical polymerization; One of the first anticoagulant layer and the second anticoagulant layer is a hydrophilic anticoagulant layer, and the other is a heparin anticoagulant layer.

11. The medical material according to claim 10, wherein, the medical material meets one or more of the following conditions: (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(2-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 an zwitterionic group, R 2 comprises -NH- or -O-, R 3 comprises -H or -CH 3 , and the zwitterionic group comprises one or more of phosphorylcholine, sulfobetaine and carboxybetaine; (2) The water contact angle on the surface of the medical material is less than 50°; (3) The material of the heparin anticoagulant layer includes a polymer formed by polymerization of one or more of heparin, heparin derivatives and heparinoids; (4) The heparin density on the surface of the medical material is not less than 0.5 μg / cm 2 ; (5) The first anticoagulant layer is a hydrophilic anticoagulant layer, and the second anticoagulant layer is a heparin anticoagulant layer; (6) In the medical material, the number of the first anticoagulant layers is multiple and / or the number of the second anticoagulant layers is multiple, and the first anticoagulant layer and the second anticoagulant layer are alternately arranged and are covalently connected to the previous layer by atom transfer radical polymerization; Optionally, in the medical material, the total number of the first anticoagulant layer and the second anticoagulant layer ≤ 6; (7) The material of the substrate includes a combination of one or more of metal-based biomaterials, silicon-based biomaterials and polymer-based biomaterials.

Images