Medical device, functional coating and preparation method of functional coating

Abstract

The invention provides a medical instrument, a functional coating and a preparation method of the functional coating. The medical instrument comprises a base material and a functional coating coated on the surface of the base material. The functional coating comprises a bottom layer, a middle layer and a surface layer, the bottom layer, the middle layer and the surface layer are used for being sequentially coated on a base material, the bottom layer is provided with groups for secondary modification, and the groups of the middle layer and the bottom layer are combined through covalent bonds. The surface of the middle layer is provided with an amino structure, and the aldehyde group structure of the functional substance and the amino structure are covalently bonded to form the surface layer with functional components. The bottom layer and the middle layer of the functional coating are combined through covalent bonds, and the middle layer can be covalently bonded with the surface layer, so that the combination stability of the substrate and the functional coating is improved, the coating is not easy to lose, and the acting effect of the coating can be maintained for a long time.

Description

Technical Field

[0001] This invention relates to the field of medical device technology, and in particular to a medical device, a functional coating, and a method for preparing the functional coating. Background Technology

[0002] In existing technologies, coatings on the surfaces of blood-contact medical devices are typically prepared using physical coating methods. These methods mainly include physical vapor deposition (PVD) and spraying. Because these physical coating methods rely solely on physical adsorption or mechanical intercalation without chemical bonding, the coating adhesion is weak and prone to failure. Furthermore, coatings prepared using physical coating methods are greatly affected by the cleanliness and roughness of the substrate, and are prone to detachment and cracking under long-term blood flow impact or device deformation.

[0003] Specifically, existing devices, when covered with functional coatings, suffer from limitations in processing methods and coating effects due to the lack of reactive groups in the underlying substrate for secondary modification. Furthermore, when coatings are applied to substrates using physical methods, the varying adhesion properties of different substrate materials result in a lack of universal adhesion. Moreover, employing different bonding methods with different substrate materials often poses significant challenges to coating stability.

[0004] Therefore, for those skilled in the art, how to design a functional coating that can improve the adhesion of coatings and its preparation method is a technical problem that urgently needs to be solved. Summary of the Invention

[0005] To address the aforementioned problems, the present invention aims to provide a medical device, a functional coating, and a method for preparing the functional coating. The functional coating has a bottom layer and an intermediate layer bonded by covalent bonds, and the intermediate layer can be covalently bonded to the surface layer, thereby improving the stability of the bonding between the substrate and the functional coating, making the coating less prone to loss, and enabling the coating to maintain its effectiveness for a long time.

[0006] To achieve the above objectives, the present invention provides a functional coating comprising a base layer, an intermediate layer, and a top layer, wherein the base layer, the intermediate layer, and the top layer are sequentially coated on a substrate. The base layer has groups that can be further modified, and the intermediate layer is covalently bonded to the groups of the base layer. The surface of the intermediate layer has an amino structure, and the aldehyde structure of the functionalized substance is covalently bonded to the amino structure to form the top layer with functional components.

[0007] Optionally, the total thickness of the functional coating is 10nm~200nm.

[0008] Optionally, the bottom layer, while bonding the substrate, also provides groups on the surface of the substrate that can be further modified. The groups that can be further modified are one or more of amino, hydroxyl, aldehyde, quinone, and isocyanate groups.

[0009] Optionally, the underlying layer includes one or more of polydopamine and polydopamine analogs, aminosilane coupling agent monolayers, aminosilane coupling agent multilayers, and polyamino polymers.

[0010] Optionally, the underlying layer may further include one of butanol, glutaraldehyde, adipaldehyde, 1,6-hexamethylene diisocyanate, toluene-2,4-diisocyanate, hexamethylene diisocyanate, and isophorone diisocyanate.

[0011] Optionally, the intermediate layer includes polydopamine and polydopamine analogues, polyamino polymers, polyamino compounds with carboxyl groups, or polyamino polymers with carboxyl groups.

[0012] Optionally, the intermediate layer may further include one of butanol, glutaraldehyde, adipaldehyde, 1,6-hexamethylene diisocyanate, toluene-2,4-diisocyanate, hexamethylene diisocyanate, and isophorone diisocyanate.

[0013] Optionally, the amino group density of the intermediate layer ranges from 10 to 200 nmol / cm³. 2 .

[0014] Optionally, the surface layer is an anti-condensation coating.

[0015] Optionally, the surface layer is an anticoagulant coating, which includes one or more of heparin, heparin derivatives, dermatan sulfate, and hyaluronic acid.

[0016] Optionally, the molecular weight of the substance in the anticoating coating is 1800~15000 Da.

[0017] Optionally, the potency of heparin, heparin derivatives, and dermatan sulfate in the anticoagulant coating is 90~200 IU / mg, and the potency ratio is 1.1~3.8.

[0018] Optionally, the active density of heparin, heparin derivatives, and dermatan sulfate in the anticoagulant coating is 0.05~2 IU / cm³. 2 .

[0019] Optionally, the surface of the intermediate layer is reacted with a hydrophilic polymer using a chain extender to adjust the spatial conformation of the surface functional material of the substrate.

[0020] Optionally, the hydrophilic polymer is polyethylene glycol, polypropylene glycol, aminopolyethylene glycolamine, branched polyethyleneimine, polyetheramine, cellulose, methylcellulose, hydroxypropyl methylcellulose, or polyethylene adipate.

[0021] To achieve the above objectives, the present invention also provides a medical device comprising a substrate and any one of the functional coatings described above, the functional coating being used to coat the substrate.

[0022] Optionally, the medical device is a blood contact medical device, including external, semi-external, intravascular implanted, or intravascular interventional medical devices.

[0023] Optionally, the material of the blood contact medical device may be metal, polymer, ceramic, or any combination thereof.

[0024] Optionally, the endovascular implantable medical device includes a blood flow diversion device for treating aneurysms, a coil-assisted stent, a vascular stenosis stent, a covered stent, an artificial blood vessel, or an artificial heart valve; the extracorporeal medical device includes blood collection tubes, blood storage bags, infusion needles, blood collection needles, or hemostatic valves; the semi-extracorporeal medical device includes a hemodialysis machine or an artificial lung membrane; and the endovascular interventional medical device includes a catheter, guidewire, or balloon catheter.

[0025] To achieve the above objectives, the present invention also provides a method for preparing a functional coating, applicable to any of the functional coatings described above, the method comprising the following steps:

[0026] S1: Clean and dry the surface of the substrate, and perform a bottom layer treatment on the dried substrate to cover the surface of the substrate with a bottom layer having groups that can be modified for secondary purposes.

[0027] S2: The substrate having the bottom layer is covalently bonded to the intermediate layer, so that the surface of the bottom layer is covered with an intermediate layer having an amino structure;

[0028] S3: Perform aldehyde-based treatment on the functionalized material to obtain a functionalized material with an aldehyde structure;

[0029] S4: Covalently bond the aldehyde structure of the functionalized substance to the amino structure of the intermediate layer, so that the surface of the intermediate layer is covered with a surface layer containing functional components.

[0030] Optionally, step S1 may be repeated multiple times before step S2, and / or step S2 may be repeated multiple times before step S3.

[0031] Optionally, the specific steps of S1 may include one or a combination of the following:

[0032] The first reactant is subjected to a catalytic oxidation reaction with a catalyst and / or oxidant under weakly alkaline conditions to obtain a reaction solution. The substrate is immersed in the reaction solution for chemical deposition, and groups that can be modified secondary are deposited on the surface of the substrate.

[0033] The substrate is first passivated by immersing it in a strong acid solution, then immersed in a concentrated alkaline solution for a high-temperature reaction, or directly immersed in a concentrated alkaline solution for a high-temperature reaction, or treated with high-purity oxygen in a plasma device to give the substrate surface hydroxyl groups; then the substrate is coated by immersing it in a solvent containing an amino-containing silane coupling agent, and then the substrate is cleaned with the corresponding solvents in sequence, and soaked in purified water to fully hydrolyze the amino-containing silane coupling agent on the surface of the substrate for 2-24 hours, so that the surface of the substrate has groups that can be modified for secondary purposes; the solvent of the amino-containing silane coupling agent is anhydrous methanol or methanol, anhydrous ethanol, ≥50% ethanol, anhydrous toluene or toluene;

[0034] The substrate is treated with high-purity ammonia in a plasma device to form groups on the surface of the substrate that can be further modified.

[0035] Optionally, in step S1, the step following chemical deposition by immersing the substrate in the reaction solution includes:

[0036] The substrate is then subjected to heat treatment at a temperature of 50-200°C for 10-120 minutes, causing the first reactant to undergo intramolecular cyclization to generate an indole derivative structure.

[0037] And / or, in step S1, the step following the complete hydrolysis of the amino-containing silane coupling agent on the substrate surface for 2-24 hours includes:

[0038] The substrate is subjected to heat treatment at a temperature of 50-200°C for 10-120 minutes to further polycondense the hydroxyl groups on the surface of the substrate and the amino-containing silane coupling agent to form stable Si-OX and Si-O-Si covalent bonds on the surface of the substrate, wherein X is the main element of the substrate.

[0039] Optionally, the first reactant is dopamine and a dopamine analogue; the oxidant is air, oxygen, hydrogen peroxide, potassium persulfate, ammonium persulfate, or sodium periodate; the catalyst is copper sulfate pentahydrate, ferric chloride hexahydrate, ferric sulfate heptahydrate, barium chloride dihydrate, or zinc sulfate heptahydrate; and the amino-containing silane coupling agent is KH-550, KH-540, KH-792, KH-602, N,N-diethyl-3-aminopropyltrimethoxysilane, or aminopropyl polyethylene glycol silane.

[0040] Optionally, the specific steps of S2 may include one or a combination of the following:

[0041] The first reactant reacts with a polyamino polymer under weakly alkaline conditions to form an intermediate layer having the amino structure on the surface of the bottom layer.

[0042] A chemical coupling agent is used to coat the bottom layer with a polyamino compound or a polymer with a carboxyl group structure, thereby forming an intermediate layer with the amino structure on the surface of the bottom layer.

[0043] By dissolving a chain extender in an organic solvent, reacting it with the substrate, and then curing it, the molecular chains of the substrate are epitaxial, and reactive sites are obtained on the substrate. Then, the reactive sites on the substrate are reacted with a polyamine polymer, and the substrate is cured, thereby forming an intermediate layer with the amino structure on the surface of the substrate.

[0044] Optionally, in step S2, the steps following the reaction of the first reactant with the polyamine polymer under weakly basic conditions include:

[0045] The substrate is subjected to heat treatment at a temperature of 50-200°C for 10-120 minutes, causing the first reactant to undergo intramolecular cyclization to generate an indole derivative structure.

[0046] In step S2, the steps following the reaction of the chain extender dissolved in an organic solvent with the underlying layer include:

[0047] The substrate is cured at a temperature of 50-200°C for 10-120 minutes.

[0048] Optionally, the chemical coupling agent is any combination of two of N-hydroxysuccinimide ester, imine ester carbodiimide, and dicyclohexylcarbodiimide; the polyamino compound with a carboxyl group is L-lysine, L-histidine, or L-arginine; the polyamino polymer with a carboxyl group is poly-L-lysine, poly-L-histidine hydrochloride, or poly-L-arginine; and the polyamino polymer is branched polyethyleneimine, chitosan, amino-modified hyaluronic acid, or polyamide-amine dendritic polymer.

[0049] Optionally, the chain extender is butadialdehyde, glutaraldehyde, adipaldehyde, 1,6-hexamethylene diisocyanate, toluene-2,4-diisocyanate, hexamethylene diisocyanate, or isophorone diisocyanate; the organic solvent is anhydrous ethanol, anhydrous methanol, toluene, acetone, dimethyl sulfoxide, N,N-dimethylformamide, or tetrahydrofuran.

[0050] Optionally, the functionalized substance is a substance having a 2,5-anhydrous mannose reducing terminal structure.

[0051] The steps in S3 specifically include:

[0052] A substance having a 2,5-anhydrous mannose reducing terminal structure is dissolved in an acidic sodium nitrite aqueous solution to react and obtain an anticoagulant with an aldehyde structure, which is then dialyzed and / or lyophilized for later use; the substance having a 2,5-anhydrous mannose reducing terminal structure is heparin and heparin derivatives, dermatan sulfate or hyaluronic acid.

[0053] Optionally, when the functionalized substance having an aldehyde structure is heparin and heparin derivatives, dermatan sulfate, or hyaluronic acid, the following step is included before step S4:

[0054] The surface of the amino intermediate layer is extended by immersion in a solvent containing a chain extender; then the substrate having the intermediate layer is immersed in a solvent containing a hydrophilic polymer to react, thereby adjusting the spatial conformation of the surface functional material of the substrate; the solvent containing the hydrophilic polymer is anhydrous ethanol, anhydrous methanol, toluene, acetone, dimethyl sulfoxide, N,N-dimethylformamide, or tetrahydrofuran; the hydrophilic polymer is polyethylene glycol, polypropylene glycol, aminopolyethylene glycolamine, branched polyethyleneimine, polyetheramine, cellulose, methylcellulose, hydroxypropyl methylcellulose, or polyethylene adipate.

[0055] Optionally, the specific steps of S4 include:

[0056] An aldehyde-modified anticoagulant functional substance, sodium chloride, and sodium cyanoborohydrin are dissolved in a solvent; a substrate with an intermediate layer is then immersed in the solvent to react, thereby forming an anticoagulant surface layer on the surface of the intermediate layer.

[0057] This invention provides a medical device, a functional coating, and a method for preparing the functional coating. The functional coating has a base layer with groups that can be further modified, allowing the base layer to be covalently bonded to the intermediate layer, thereby improving the adhesion between the base layer and the intermediate layer. Simultaneously, the intermediate layer provides sufficient amino structures for the surface coating. These amino structures can covalently bond with the aldehyde structures of the functionalized substances, enabling the intermediate layer to be stably covalently bonded to the surface layer for efficient surface fixation. The functionalized substances bonded by the intermediate layer through covalent bonding are more stably bonded, ensuring the overall coating adhesion to the substrate surface, preventing coating loss, and maintaining the coating's effectiveness over a long period. Attached Figure Description

[0058] Figure 1 This is a schematic diagram of the cross-sectional structure of a medical device in a preferred embodiment of the present invention.

[0059] Figure 2 for Figure 1 A simplified structural diagram of part a, magnified from the original.

[0060] Figure 3 This is a preferred embodiment of the present invention, which describes a reaction scheme in which dopamine is oxidized to deposit an underlayer on a substrate.

[0061] Figure 4 This is a preferred embodiment of the present invention, which describes a reaction scheme for forming hydroxyl structures on a substrate using concentrated sulfuric acid and sodium hydroxide.

[0062] Figure 5 This is a preferred embodiment of the present invention, which describes a reaction scheme for forming an underlayer on a substrate using an aminosilane coupling agent.

[0063] Figure 6 In a preferred embodiment of the present invention, a reaction scheme is used to form an underlayer on a substrate by sequentially using high-purity oxygen or high-purity ammonia and an aminosilane coupling agent.

[0064] Figure 7 This is a preferred embodiment of the present invention, which involves a reaction scheme in which dopamine and a polyamino polymer are used to form an amino structure on the intermediate layer of the substrate.

[0065] Figure 8 In a preferred embodiment of the present invention, a reaction scheme is used to form an intermediate layer with an amino structure on a substrate by using a chemical coupling agent and a polyamino compound or a polyamino polymer with a carboxyl group.

[0066] Figure 9 In a preferred embodiment of the present invention, a reaction scheme is used to form an intermediate layer with an amino structure on a substrate by using a chain extender and a polyamino polymer.

[0067] Figure 10 This is a preferred embodiment of the present invention, which describes a reaction scheme in which an intermediate layer with an amino structure is formed on a substrate by using a chain extender and a hydrophilic polymer.

[0068] Figure 11 This is a preferred embodiment of the present invention, which describes a reaction scheme for aldehyde treatment of heparin using acidic sodium nitrite.

[0069] Figure 12 This is a preferred embodiment of the present invention, which involves forming a surface layer on a substrate using an aldehyde-modified anticoagulant functionalized substance, sodium chloride, and sodium cyanoborogen.

[0070] Figure 13 This is a reaction scheme in a preferred embodiment of the present invention in which the first reactant on the surface of the substrate undergoes intramolecular cyclization during heat treatment.

[0071] Figure 14In a preferred embodiment of the present invention, a reaction scheme is used to form stable Si-OX and Si-O-Si covalent bonds on the surface of a substrate through heat treatment.

[0072] Figure 15 This is an axial cross-sectional view of a vascular stent in a preferred embodiment of the present invention.

[0073] Figure 16 This is a graph showing the variation of the content of each element in the vascular stent along the direction from the surface to the substrate in a preferred embodiment of the present invention.

[0074] Figure 17 This is a partial schematic diagram of a bare scaffold sample in a preferred embodiment of the present invention.

[0075] Figure 18 This is a partial schematic diagram of a vascular stent with a coating according to a preferred embodiment of the present invention.

[0076] [The annotations in the attached figures are explained below]:

[0077] Substrate 1; Bottom layer 2; Intermediate layer 3; Top layer 4. Detailed Implementation

[0078] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments. The advantages and features of the present invention will become clearer from the following description. It should be noted that the drawings are all in a very simplified form and use non-precise proportions, and are only used to facilitate and clarify the illustration of the embodiments of the present invention.

[0079] The terms “center,” “longitudinal,” “lateral,” “length,” “width,” “thickness,” “upper,” “lower,” “front,” “rear,” “left,” “right,” “vertical,” “horizontal,” “top,” “bottom,” “inner,” “outer,” “clockwise,” “counterclockwise,” “axial,” “radial,” and “circumferential” indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings. They are used only for the convenience of describing the present invention and simplifying the description, and are not intended to indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, they should not be construed as limitations on the present invention.

[0080] In this invention, unless otherwise explicitly specified and limited, the terms "installation," "connection," and "fixation," etc., should be interpreted broadly. For example, they can refer to a fixed connection, a detachable connection, or an integral part; they can refer to a mechanical connection, an electrical connection, or a connection that allows communication between them; they can refer to a direct connection or a connection through an intermediate medium; they can refer to the internal communication of two components or the interaction between two components, unless otherwise explicitly limited. Those skilled in the art can understand the specific meaning of the above terms in this invention according to the specific circumstances. In the description of this invention, "a plurality of" means at least two, such as two, three, or more.

[0081] The present invention will now be described in detail with reference to the accompanying drawings and preferred embodiments. Unless otherwise specified, the following embodiments and features can complement or combine with each other.

[0082] like Figure 1 and Figure 2 As shown, a preferred embodiment of the present invention provides a functional coating comprising a base layer 2, an intermediate layer 3, and a top layer 4, which are sequentially coated onto a substrate 1. The base layer 2 has groups available for secondary modification, and the intermediate layer 3 is covalently bonded to the groups of the base layer 2. The surface of the intermediate layer 3 has an amino structure to expand the active sites on the surface of the intermediate layer 3. The aldehyde structure of the functionalized substance is covalently bonded to the amino structure of the intermediate layer 3 to form the top layer 4 with functional components.

[0083] The purpose of the bottom layer 2 is to form a material that can stably bind and provide reactive sites for secondary modification on the surface of the substrate 1, which has no secondary modification, thus providing anchor points for the subsequent intermediate layer 3. The purpose of the intermediate layer 3 is to amplify the anchor points of the bottom layer 2 and obtain amino structures on the surface of the intermediate layer 3. The multiple amino structures inherent in the intermediate layer 3 will become new and more numerous anchor points, thereby amplifying the anchor points of the top layer 4. The purpose of the top layer 4 is to anchor the intermediate layer 3 with functionalized substances with aldehyde structures. Functionalized substances with aldehyde structures (such as heparin) can be firmly anchored to the surface of the intermediate layer 3 through chemical reactions between the aldehyde structure and the amino structure (such as the Schiff base reaction), forming a stable functional coating and thus exerting anti-coating function. The aldehyde-modification treatment of the functionalized substances can be obtained by pyrolysis of sodium nitrite and sodium periodate under acidic conditions.

[0084] A preferred embodiment of the present invention also provides a medical device, comprising a substrate 1 and any of the functional coatings described in the present invention, the functional coating being used to coat the substrate 1.

[0085] This application provides a functional coating and a medical device. The bottom layer 2 of the medical device has groups that can be further modified, allowing the bottom layer 2 to be covalently bonded to the intermediate layer 3, thereby improving the adhesion between the bottom layer 2 and the intermediate layer 3. Simultaneously, the intermediate layer 3 provides sufficient amino structures for the surface coating. These amino structures can covalently bond with the aldehyde structures of the functionalized material to form new CN covalent bonds, enabling the intermediate layer 3 to be stably covalently bonded to the surface layer 4. This efficiently fixes the surface layer, ensuring the grafting density and activity density of the functionalized coating covalently bonded to the endpoints of the medical device surface. Furthermore, this covalent bonding provides lasting stability for the multifunctionality of the device itself, making the bonding between the substrate 1 and the functionalized material more stable, ensuring the overall coating adhesion of the substrate 1 surface, preventing coating loss, and enabling the vascular stent to maintain the coating's effectiveness over a long period.

[0086] As a preferred embodiment, the medical device is a blood contact medical device, including external medical devices, semi-external medical devices, intravascular implantable medical devices, or intravascular interventional medical devices.

[0087] Furthermore, the materials used in blood contact medical devices are metals, polymers, ceramics, or any combination thereof. The bottom layer 2 of this functional coating is preferably bonded to the surface of the substrate 1 via covalent or non-covalent forces (coordination bonds / hydrogen bonds) to enhance the bonding effect.

[0088] Preferably, endovascular implantable medical devices include flow diversion devices for treating aneurysms such as dense mesh stents, coil-assisted stents, vascular stenosis stents, covered stents, artificial blood vessels, and artificial heart valves; extracorporeal medical devices include blood collection tubes, blood storage bags, infusion needles, blood collection needles, and hemostatic valves; semi-extracorporeal medical devices include hemodialyzers and extracorporeal membrane oxygenation (ECMO); and endovascular interventional medical devices include catheters, guidewires, and balloon catheters.

[0089] It should be noted that substrate 1 is generally a material that does not inherently possess groups (active groups or active sites) suitable for secondary modification. Metal-based biomaterials can be made of 304 stainless steel, cobalt-based alloys, titanium-based alloys, pure titanium, or magnesium-based alloys. Polymer-based biomaterials can be made of polyurethane, expanded polytetrafluoroethylene, silicone rubber, polyvinyl chloride, polypropylene, polyethylene, or polycarbonate.

[0090] Preferably, the total thickness of the functional coating (i.e., the total thickness of the bottom layer 2, the intermediate layer 3 and the top layer 4) is 10nm~200nm.

[0091] Furthermore, while bonding the substrate 1, the bottom layer 2 also provides groups on the surface of the substrate 1 that can be modified for secondary purposes. The groups that can be modified for secondary purposes are one or more of amino, hydroxyl, aldehyde, quinone and isocyanate groups.

[0092] In a preferred embodiment, the bottom layer 2 comprises polydopamine and polydopamine analogues, an aminosilane coupling agent monolayer, and an aminosilane coupling agent multilayer (see reference). Figure 14 (and one or more of the following:) and polyamino polymers.

[0093] In one specific embodiment, the bottom layer 2 also includes, but is not limited to, one of butanedialdehyde, glutaraldehyde, hexamethylene diisocyanate, 1,6-hexamethylene diisocyanate, toluene-2,4-diisocyanate, hexamethylene diisocyanate, and isophorone diisocyanate.

[0094] In some embodiments, the intermediate layer 3 includes polydopamine and polydopamine analogues, polyamino polymers, or polyamino compounds with carboxyl groups.

[0095] For example, the intermediate layer 3 may also include, but is not limited to, one of butanol, glutaraldehyde, hexamethylene diisocyanate, 1,6-hexamethylene diisocyanate, toluene-2,4-diisocyanate, hexamethylene diisocyanate and isophorone diisocyanate.

[0096] In a preferred embodiment, the amino group density of the intermediate layer 3 is in the range of 10~200 nmol / cm³. 2 .

[0097] Furthermore, surface layer 4 is an anti-condensation coating.

[0098] It should be noted that the aldehyde groups in the aldehyde-modified anticoagulant functional materials can undergo addition reactions with the primary or secondary amines (with amino structures) on the intermediate layer 3 to form imine or enamine structures. These are then reduced using sodium cyanoborohydride to generate more stable amide bonds, thereby enhancing the stability of the connection between the intermediate layer 3 and the surface layer 4 on the substrate 1. This is because the stability of amide bonds is much higher than that of the C=N and C=C double bonds of imine / enamine bonds, allowing the functionalized materials to adhere firmly and persistently to the substrate 1, continuously exerting their anticoagulant effect.

[0099] In a preferred embodiment, the surface layer 4 of the functional coating is an anticoagulant coating. This anticoagulant coating can be composed of a substance having a 2,5-anhydrous mannose reducing terminal structure, preferably including one or more of heparin, heparin derivatives, dermatan sulfate, and hyaluronic acid, to improve the stability of the bond between the intermediate layer 3 and the surface layer 4. Since heparin and its derivatives, dermatan sulfate, and hyaluronic acid themselves have good hydrophilicity and carry a large amount of negative charge, and heparin and its derivatives, as well as dermatan sulfate, also possess pentasaccharide sequences that can be mediated by thrombin to inactivate specific coagulation factors in the coagulation cascade reaction, they can reduce the adhesion of platelets and plasma proteins on the surface of the substrate 1 while maintaining an anticoagulant effect, thereby reducing the risk of thrombus formation on the surface of the substrate 1 and achieving both anticoagulant and antithrombotic effects.

[0100] In other examples, the anti-coating coating can also be made of substances such as hyaluronic acid.

[0101] In preferred embodiments, the molecular weight of the substances in the anticoagulant coating is 1800-15000 Da. The potency of heparin, heparin derivatives, and dermatan sulfate in the anticoagulant coating is preferably 90-200 IU / mg, with a potency ratio of 1.1-3.8. The activity density of heparin, heparin derivatives, and dermatan sulfate in the anticoagulant coating is preferably 0.05-2 IU / cm³. 2 .

[0102] When the functionalized substances are heparin, heparin derivatives, dermatan sulfate, and hyaluronic acid, the extended chain conformation can exert a better anticoagulant effect through electrostatic repulsion and better binding with anticoagulant factors; if the molecular chain conformation is coiled, the large number of negative charges and active sites on the molecular chain are blocked, which will greatly reduce its anticoagulant function. To solve the above problems, in a preferred embodiment, when the functionalized substances are heparin, heparin derivatives, dermatan sulfate, and hyaluronic acid, the surface of the intermediate layer 3 is reacted with a hydrophilic polymer through a chain extender to adjust the spatial conformation of the functional substances in the surface layer 4 on the substrate 1.

[0103] Specifically, the intermediate layer 3 undergoes chain extension using a chain extender (dialdehyde / isocyanate) to lengthen the molecular chains on the intermediate layer 3. When the intermediate layer 3 reacts with a hydrophilic polymer (polyethylene glycol), the hydrophilic polymer can be grafted onto the extended molecular chains through reaction, thereby regulating the functional substances on the surface of the intermediate layer 3. The surface layer 4 can then bind with the functional substances on the surface of the intermediate layer 3, thereby reducing the steric hindrance of the functional substances in the surface layer 4 while increasing the hydrophilicity of the material surface and reducing the interfacial energy.

[0104] The hydrophilic polymer can be polyethylene glycol (PEG), polypropylene glycol, aminopolyethylene glycolamine, branched polyethyleneimine, polyetheramine, cellulose, methylcellulose, hydroxypropyl methylcellulose, or polyethylene adipate. The solvent used to dissolve the chain extender can be anhydrous ethanol, anhydrous methanol, toluene, acetone, dimethyl sulfoxide, N,N-dimethylformamide, or tetrahydrofuran.

[0105] like Figures 1-5 As shown, a preferred embodiment of the present invention provides a method for preparing a functional coating, applicable to any of the blood contact device functional coatings described in the present invention. The method for preparing the functional coating includes the following steps:

[0106] S1: Clean and dry the surface of substrate 1, and perform a bottom layer treatment on the dried substrate 1 so that the surface of substrate 1 is covered with a bottom layer 2 having groups that can be modified for secondary purposes.

[0107] S2: The substrate 1 with the bottom layer 2 is covalently bonded to the intermediate layer 3, so that the surface of the bottom layer 2 is covered with the intermediate layer 3 with an amino structure.

[0108] S3: Perform aldehyde-based treatment on the functionalized material to obtain a functionalized material with an aldehyde structure.

[0109] S4: The aldehyde structure of the functionalized substance is covalently bonded to the amino structure of the intermediate layer 3, so that the surface of the intermediate layer 3 is covered with a surface layer 4 containing functional components.

[0110] The method for preparing the functional coating provided in this application is applicable to a variety of substrates and devices, facilitating large-scale production and clinical translation.

[0111] It should be noted that the bottom layer 2 can be generated on the substrate 1 using chemical modification methods to produce groups that can be modified for secondary purposes, or it can be generated on the substrate 1 using physical methods, or it can be a combination of chemical modification methods and physical methods.

[0112] It should also be noted that step S1 can be repeated multiple times before step S2, and / or step S2 can be repeated multiple times before step S3. This setup allows for multiple repetitions depending on the required number of structures on the surface of the bottom layer 2 or the intermediate layer 3, to meet different fabrication requirements.

[0113] Furthermore, the specific steps of step S1 include one of the following methods:

[0114] The first method is chemical modification, specifically: the first reactant is oxidized with a catalyst and / or oxidant under weakly alkaline conditions to obtain a reaction solution. The substrate 1 is then immersed in the reaction solution for chemical precipitation, depositing and forming functional groups on the surface of the substrate 1 that can be further modified. The catalyst or oxidant promotes the oxidation reaction of the first reactant, gradually depositing a uniform coating on the surface of the substrate 1.

[0115] It should be understood that the first reactant is preferably dopamine or a dopamine analogue. Dopamine can form a strong bond with the surface of the substrate 1 and provide active binding sites to deposit on the surface of the substrate 1 and form a sufficient number of groups available for secondary modification.

[0116] In addition, the first reactant can also be melanin and melanin polymer analogs, synthetic melanin, aromatic catechols, or analogs with a catechol structure.

[0117] Meanwhile, the oxidant is preferably air, oxygen, hydrogen peroxide, potassium persulfate, ammonium persulfate, or sodium periodate. The catalyst is preferably copper sulfate pentahydrate, ferric chloride hexahydrate, ferric sulfate heptahydrate, barium chloride dihydrate, or zinc sulfate heptahydrate.

[0118] Preferably, in step S1, the step following chemical deposition of the substrate 1 by immersing it in the reaction solution includes:

[0119] The substrate 1 is heat-treated at a temperature of 50–200 °C for 10–120 min to induce intramolecular cyclization of the first reactant, generating an indole derivative structure (see reference). Figure 13 This configuration improves the biocompatibility of the material surface while enhancing the selectivity of the reaction between the first reactant and the polyamine polymer and chain extender in the subsequent reactions of the bottom layer 2 and the intermediate layer 3, resulting in a denser coating.

[0120] Reference Figure 3 As shown, in a specific example, the first method of chemical modification can be achieved through the following steps.

[0121] First, substrate 1 was sequentially immersed in acetone, purified water, and anhydrous ethanol, ultrasonically cleaned for 10 minutes, and then dried in a forced-air dryer at 50°C to achieve cleaning and drying of substrate 1.

[0122] Next, a 1M Tris-HCl buffer solution with a pH of 8.5 was prepared, using purified water as the reaction solvent, with a contact ratio of substrate 1 surface area to reaction solvent of 1.6-3.3 mL / cm². 2 Determine the reaction solution volume. Add the weighed dopamine and dopamine analogue to the reaction solution to prepare a solution with a concentration of 0.1-4 mg / mL. Then, add a certain volume of 1M Tris-HCl buffer (pH=8.5) to the reaction solution, bringing the final concentration of the Tris-HCl buffer to 10mM-50mM. Stir and adjust the pH of the reaction solution to 7.5-9.5 using 4M hydrochloric acid and 4M sodium hydroxide solutions. React at 25℃ and 150 rpm for 0.5-24 hours. Dopamine polymerizes on the surface of substrate 1 through oxidation and Michael addition / Schiff base reaction, forming a strong polydopamine coating (see...). Figure 3 Then, it is ultrasonically cleaned three times with purified water (1 min / time) and dried with a forced air at 25°C to deposit and form groups on the surface of substrate 1 for secondary modification.

[0123] The second method is chemical modification, which involves immersing the substrate 1 in a concentrated alkaline solution for a high-temperature reaction to obtain functional groups on the surface of the substrate 1 that can be used for secondary modification.

[0124] The third method is chemical modification, specifically: the substrate 1 is first passivated by immersing it in a strong acid solution, then immersed in a concentrated alkaline solution for a high-temperature reaction, or directly immersed in a concentrated alkaline solution for a high-temperature reaction, or treated with high-purity oxygen in a plasma device to obtain hydroxyl groups on the surface of the substrate 1. Then, the substrate 1 is coated by immersing it in a solvent containing an amino-containing silane coupling agent. The substrate 1 is then cleaned sequentially with the corresponding solvent and soaked in purified water to fully hydrolyze the amino-containing silane coupling agent on the surface of the substrate 1 for 2-24 hours, thus obtaining groups on the surface of the substrate 1 that can be used for secondary modification, facilitating the subsequent adhesion of functionalized substances. In this process, the substrate 1 is preferably a metallic or alloy material. The solvent for the amino-containing silane coupling agent is anhydrous methanol or methanol, anhydrous ethanol, ≥50% ethanol, anhydrous toluene or toluene.

[0125] Among them, the amino-containing silane coupling agent is preferably KH-550 (γ-aminopropyltrimethoxysilane), KH-540 (γ-aminopropyltriethoxysilane), KH-792 (N-β-(aminoethyl)-γ-aminopropyltrimethoxysilane), KH-602 (N-β-(aminoethyl)-γ-aminopropylmethyldimethoxysilane), N,N-diethyl-3-aminopropyltrimethoxysilane or aminopropyl polyethylene glycol silane.

[0126] Preferably, in step S1, the step following the complete hydrolysis of the amino-containing silane coupling agent on the surface of substrate 1 for 2-24 hours includes:

[0127] The substrate 1 is subjected to heat treatment at a temperature of 50–200 °C for 10–120 min, which further polycondenses the hydroxyl groups on the surface of the substrate 1 and the amino-containing silane coupling agent to form stable Si-OX and Si-O-Si covalent bonds on the surface of the substrate 1 (refer to...). Figure 14 This improves the bonding strength between the bottom layer 2 and the intermediate layer 3. Here, X represents the main element of the substrate 1 (e.g., the metallic or alloy composition of the substrate 1). Figure 14 In this context, 'n' represents the number of molecular layers of the aminosilane coupling agent perpendicular to the surface of substrate 1.

[0128] In a specific example, the third method of chemical modification can be achieved through the following steps.

[0129] First, refer to Figure 4 First, passivate the substrate 1 in concentrated sulfuric acid. Then, prepare a 2-10M sodium hydroxide solution (the total volume of sodium hydroxide should be calculated as half the volume of the container). Place the passivated substrate 1 in the solution and treat it at 80℃ and 800rpm for 2-24 hours. After treatment, ultrasonically clean the substrate 1 three times with purified water (1min / time) and dry it at 25℃ for later use. This process forms a hydroxyl structure on the surface of the substrate 1.

[0130] Secondly, refer to Figure 5 Prepare an aminosilane coupling agent with a volume ratio of 1%-5% using a 60% ethanol solution. Place substrate 1 in the solution and react at 25°C and 150 rpm for 2-24 hours. After the reaction, ultrasonically clean substrate 1 three times (1 min / time) with 60% ethanol solution and purified water, and then dry it in a forced-air condition at 25°C (see [link to product description]). Figure 5 This leads to the formation of amino-structured groups on the surface of substrate 1 that can be further modified.

[0131] The fourth method is physical modification, which involves treating the substrate 1 with high-purity oxygen or high-purity ammonia in a plasma device to form groups on the surface of the substrate 1 that can be used for secondary modification.

[0132] The fifth method combines physical and chemical modification methods. Specifically, the substrate 1 is first treated with high-purity oxygen or high-purity ammonia in a plasma device to change the molecular structure of the substrate 1 surface and give the substrate 1 surface groups (hydroxyl or amino groups) that can be used for secondary modification. Then, the substrate 1 surface is coated with the first or third method to obtain the bottom layer 2.

[0133] Reference Figure 6 As shown, in a specific example, the fifth method of physical and chemical modification can be achieved through the following steps.

[0134] First, place substrate 1 into a plasma device and treat it with high-purity oxygen / high-purity ammonia at a power of 240W-360W for 5-10 minutes at -97.5kpa±2kpa.

[0135] Then, a silane coupling agent with a volume ratio of 1%-5% is prepared using a 60% ethanol solution. The total volume of the 60% ethanol is 1.6-3.3 mL / cm², based on the surface area of ​​substrate 1 and the contact ratio of the reaction solvent. 2 The sample was measured. Then, substrate 1 was placed in the solution and reacted at 25°C and 150 rpm for 2-24 hours. After the reaction, substrate 1 was ultrasonically cleaned three times (1 min / time) with 60% ethanol solution and purified water, and then dried at 25°C by forced air drying. This process formed amino-structured groups on the surface of substrate 1, which could be used for secondary modification (see...). Figure 6 ).

[0136] Furthermore, the intermediate layer 3 can be amplified by chemical co-deposition of the bottom layer 2 anchor points, or by chemical coupling of the bottom layer 2 anchor points, or by using a chain extender to amplify the bottom layer 2 anchor points.

[0137] Furthermore, the specific steps of S2 include one of the following methods:

[0138] The first method involves anchor point amplification via chemical co-deposition. Specifically, the first reactant reacts with a polyamine polymer under weakly alkaline conditions. The first reactant and the polyamine polymer undergo a Michael addition / Schiff base reaction on the bottom layer 2 and are deposited, thereby forming an intermediate layer 3 with an amino structure on the surface of the bottom layer 2.

[0139] The first reactant is preferably dopamine or a dopamine analogue. The first reactant can also be melanin or a melanin polymer analogue, synthetic melanin, aromatic catechols, or analogues with a catechol structure. The polyamino polymer can be a natural or artificially synthesized amino polymer with more than two amino groups, wherein the amino groups can be located in the main chain or in the branches. For example, the polyamino polymer can be branched polyethyleneimine, amino-modified hyaluronic acid, poly-L-lysine, poly-L-arginine, or a polyamide dendritic polymer, or it can be chitosan, poly-L-histidine hydrochloride, poly-L-arginine, or a polyamide-amine dendritic polymer.

[0140] Preferably, in step S2, the steps following the reaction of the first reactant with the polyamine polymer under weakly alkaline conditions include:

[0141] The substrate 1 is heat-treated at a temperature of 50–200 °C for 10–120 min to induce intramolecular cyclization of the first reactant, generating an indole derivative structure (see reference). Figure 13 This configuration improves the biocompatibility of the material surface while enhancing the selectivity of the reaction between the first reactant and the polyamine polymer and chain extender in the subsequent reactions of the bottom layer 2 and the intermediate layer 3, resulting in a denser coating.

[0142] Reference Figure 7 As shown, the first method of anchor point amplification using the chemical co-deposition method can be achieved through the following steps.

[0143] In a specific example, the volume of purified water is 1.6-3.3 mL / cm², based on the surface area of ​​substrate 1 and the contact ratio with the reaction solvent. 2Take appropriate amounts of the natural / synthetic polyamino polymer (≥2 amino groups) and dissolve it in purified water (to prepare a solution with a concentration of 0.1-4 mg / mL). Add the weighed dopamine and dopamine analogue to the purified water (to prepare a solution with a concentration of 0.1-4 mg / mL). Prepare a 1M Tris-HCl buffer solution with a pH of 8.5. Then, add a certain volume of the 1M Tris-HCl buffer solution with a pH of 8.5 to the buffer solution to bring the final concentration of the Tris-HCl buffer solution to [a specific concentration]. The pH of the reaction solution was adjusted to 7.5-9.5 with 4M hydrochloric acid and 4M sodium hydroxide solution after stirring at 10mM-50mM. The reaction was carried out at 25℃ for 0.5-24 hours. Michael addition / Schiff base reaction occurred between dopamine and dopamine analogues, natural / synthetic polyamino polymers and bottom layer 2 to form an anchor point amplification layer (i.e., intermediate layer 3) on the surface of bottom layer 2. Then, it was ultrasonically cleaned 3 times with purified water (1min / time) and dried with a forced air at 25℃ to form an amino structure on intermediate layer 2.

[0144] The second method involves anchoring amplification using chemical coupling agents. Specifically, a polyamino compound or polyamino polymer with a carboxyl group structure is coated onto the bottom layer 2 using a chemical coupling agent, thereby forming an intermediate layer 3 with an amino structure on the surface of the bottom layer 2.

[0145] The chemical coupling agent is preferably a combination of any two of N-hydroxysuccinimide ester, imine ester carbodiimide, and dicyclohexylcarbodiimide. The polyamino compound with a carboxyl group is preferably L-lysine, L-histidine, or L-arginine. The polyamino polymer with a carboxyl group is preferably poly-L-lysine, poly-L-histidine hydrochloride, or poly-L-arginine. The polyamino polymer is preferably branched polyethyleneimine, chitosan, amino-modified hyaluronic acid, or polyamide-amine dendritic polymer.

[0146] Preferably, in step S2, the steps following the reaction of the chain extender dissolved in an organic solvent with the bottom layer 2 include:

[0147] The substrate 1 is cured at a temperature of 50-200℃ for 10-120 minutes, which causes the molecular chains of the bottom layer 2 to extend and obtain reactive sites on the bottom layer 2.

[0148] Reference Figure 8 As shown, the second method of anchor point amplification via chemical coupling agent can be achieved through the following steps.

[0149] In a specific example, the volume of purified water is 1.6-3.3 mL / cm² based on the surface area of ​​substrate 1 and the contact ratio of purified water. 2First, dissolve the chemical coupling agent in purified water to prepare a 0.1-0.5M solution. Adjust the pH of the reaction solution to 4-7 using 4M hydrochloric acid and 4M sodium hydroxide. Then, dissolve the carboxyl-containing polyamine chemical or polyamine polymer in purified water to prepare a 0.1-4 mg / mL solution. Activate the solution at 25℃ and 150 rpm for 10-60 min. Place the substrate 1 with the bottom layer 2 into the solution and react for 2-24 hours. Wash the substrate 1 three times with purified water (1 min / wash) and dry it at 25℃ using a forced-air drying method (see [link to product description]). Figure 8 ), thereby forming an amino structure on the intermediate layer 3 of the substrate 1.

[0150] The third method involves secondary or multiple anchor point amplification using chain extenders (such as glutaraldehyde). Specifically, the chain extender is dissolved in an organic solvent, reacted with the bottom layer 2, and cured, causing the molecular chains of the bottom layer 2 to epitaxially extend and creating reactive active sites on the bottom layer 2, thereby increasing the number of anchor points. Then, the active sites on the bottom layer 2 are reacted with a polyamine polymer (such as branched polyethyleneimine), and the substrate 1 is cured. The treatment temperature is 50–200°C, and the treatment time is 10–120 min, thereby forming an intermediate layer 3 with an amino structure on the surface of the bottom layer 2.

[0151] The chain extender is preferably a substance containing a dialdehyde group or a diisocyanate group, such as succinal, glutaraldehyde, adipaldehyde, 1,6-hexamethylene diisocyanate, toluene-2,4-diisocyanate, hexamethylene diisocyanate, or isophorone diisocyanate. The organic solvent is preferably anhydrous ethanol, anhydrous methanol, toluene, acetone, dimethyl sulfoxide, N,N-dimethylformamide, or tetrahydrofuran.

[0152] Reference Figure 9 As shown, the second method of anchor point amplification via chemical coupling agent can be achieved through the following steps.

[0153] In a specific example, the total volume of the solvent is set at a contact ratio of 1.6-3.3 mL / cm² based on the surface area of ​​substrate 1 and the solvent. 2 The following steps are performed: First, dissolve the chain extender in a solvent to prepare a solution with a concentration of 0.01-0.05 g / mL. Then, place the substrate 1 with the bottom layer 2 into the solution and react at 50-60℃ and 150 rpm for 0.5-6 hours. Wash three times with the corresponding solvent, then wash three times with purified water (1 min / wash), and dry in a forced-air condition at 25℃. Next, dissolve the natural / synthetic polyamine polymer (amino group ≥ 2) in purified water (preparing a solution with a concentration of 0.1-4 mg / mL). The total volume of purified water should be 1.6-3.3 mL / cm² based on the surface area of ​​substrate 1 and the contact ratio with the solvent. 2Take a sample, place the dried substrate 1 into it, and react at 50-60℃ and 150rpm for 2-24 hours. Wash three times with purified water (1min / wash), and dry in a forced-air condition at 25℃ (see [link to product description]). Figure 9 ), thereby forming an amino structure on the intermediate layer 3.

[0154] Furthermore, the surface layer 4 can be anchored to the intermediate layer 3 using a functionalized substance with an aldehyde structure to achieve the anti-condensation function of the final coating.

[0155] In one alternative embodiment, the functionalized substance is a substance having a 2,5-anhydrous mannose reducing terminal structure, such as heparin and heparin derivatives, dermatan sulfate, or hyaluronic acid.

[0156] When the functionalized substance is a substance with a 2,5-anhydrous mannose reducing terminal structure, step S3 specifically includes:

[0157] A substance with a 2,5-anhydrous mannose reducing terminal structure is dissolved in an acidic aqueous sodium nitrite solution to react and obtain an anticoagulant with an aldehyde structure, which is then dialyzed and / or lyophilized for later use. When the functionalized substance is heparin, this step involves cleaving heparin with sodium nitrite to form low molecular weight heparin with a terminal aldehyde structure, and then reacting the low molecular weight heparin with the amino structure of the intermediate layer 3 to form a covalently bonded heparin surface layer.

[0158] Reference Figure 11 In a specific example, the concentration of the substance with the 2,5-anhydrous mannose reducing terminal structure in the solution was first 10-100 mg / mL, the solubility of sodium nitrite in the solution was 0.02M-0.1M, the pH of the reaction solution was adjusted to 1.5-3.5 with glacial acetic acid, and the reaction was carried out at 0-25℃ for 0.5-3H. The pH was then adjusted to neutral with 4M hydrochloric acid and 4M sodium hydroxide, and precipitation was carried out with anhydrous ethanol at twice the total volume of the reaction solution. The precipitate was collected by centrifugation at 10000 rpm and 4℃ for 10 min. The collected precipitate was dissolved in 20 mL of purified water and dialyzed in a 3500 Da dialysis bag for 24 H. Finally, the dialysate was freeze-dried for later use.

[0159] More preferably, when the functionalized substance with an aldehyde structure is heparin and heparin derivatives or dermatan sulfate, the following is further included before step S4:

[0160] The surface of the amino intermediate layer 3 is subjected to chain extension by immersion in a solvent containing a chain extender, followed by curing of the substrate 1 at a temperature of 50–200°C for 10–120 min. The substrate 1 with the intermediate layer 3 is then immersed in a solvent containing a hydrophilic polymer (such as polyethylene glycol or aminopolyethylene glycolamine) for reaction, followed by curing at a temperature of 50–200°C for 10–120 min. The spatial conformation of the functional material on the surface of the substrate 1 is adjusted to improve the hydrophilicity of the substrate 1 surface and reduce the interfacial energy, thereby optimizing the adhesion environment of the functionalized material in the surface layer 4. The solvent containing the hydrophilic polymer is anhydrous ethanol, anhydrous methanol, toluene, acetone, dimethyl sulfoxide, N,N-dimethylformamide, or tetrahydrofuran. The hydrophilic polymers are polyethylene glycol, polypropylene glycol, aminopolyethylene glycolamine, branched polyethyleneimine, polyetheramine, cellulose, methylcellulose, hydroxypropyl methylcellulose, or polyethylene adipate.

[0161] Reference Figure 10 As shown, the functional material on the surface of the intermediate layer 3 on the substrate 2 can be adjusted in the following ways.

[0162] In some embodiments, the chain extender is first dissolved in a solvent to prepare a solution with a concentration of 0.01-0.05 g / mL. The substrate 1 with the bottom layer 2 is then placed in this solution and reacted at 50-60°C and 150 rpm for 0.5-24 hours. The substrate is then washed three times with the corresponding solvent, followed by three washes with purified water (1 min / wash), and dried in a forced-air conditioner at 25°C. Subsequently, a hydrophilic polymer is dissolved in a solvent to prepare a solution with a concentration of 0.05-0.2 g / mL, with the surface area of ​​the substrate 1 and the solvent contact ratio being 1.6-3.3 mL / cm². 2 Take a sample, place the dried substrate 1 into it, react at 50-60℃ and 150rpm for 2-24 hours, wash 3 times with the corresponding solvent, then wash 3 times with purified water (1min / wash), and dry in a forced-air conditioner at 25℃ (see...). Figure 10 ).

[0163] Furthermore, the specific steps of S4 include the following:

[0164] Specifically, the process involves dissolving an aldehyde-modified anticoagulant functional substance, sodium chloride, and sodium cyanoborohydrin in a solvent (purified water). The substrate 1, containing the intermediate layer 3, is then immersed in the solvent to react, thereby forming an anticoagulant surface layer on the surface of the intermediate layer 3.

[0165] Reference Figure 12As shown, in a specific example, aldehyde-modified anticoagulant, sodium chloride, and sodium cyanoborohydrin were dissolved in purified water to obtain solutions with concentrations of 0.1-1.0 mg / mL, 0.05-0.2 M, and 0.01-0.6 mg / mL, respectively. The pH of the reaction solution was adjusted to 2-4, and the substrate 1 with the intermediate layer 3 was then immersed in it and reacted at 50-60°C and 150 rpm for 2-24 hours. The substrate was washed three times with purified water (1 min / wash) and dried in a forced-air conditioner at 25°C (see [link to product description]). Figure 12 ), so as to obtain an anti-condensation surface layer on the surface of substrate 1.

[0166] The preparation method of the functional coating is described in the following specific embodiments.

[0167] In a non-limiting embodiment, the method for preparing the functional coating on the surface of the nickel-titanium alloy includes:

[0168] (1) The nickel-titanium alloy to be treated was placed in acetone, purified water and anhydrous ethanol in sequence for ultrasonic cleaning for 10 min and then dried at 50℃.

[0169] (2) Prepare a 1M Tris-HCl buffer solution with pH=8.5. Use purified water as the reaction solvent. Add the weighed dopamine and dopamine analogue to the buffer solution to prepare a solution with a concentration of 3.1 mg / mL. Then add a certain volume of 1M Tris-HCl buffer solution with pH=8.5 to make the final concentration of Tris-HCl buffer solution 50 mM. Stir and adjust the pH of the reaction solution to 8.8 with 4M hydrochloric acid solution and 4M sodium hydroxide solution. React at 25℃ and 150 rpm for 4 hours. Dopamine is oxidized by potassium persulfate and polymerized on the surface of nickel-titanium alloy to form a firm bottom layer. Then, ultrasonically clean the bottom layer three times with purified water (1 min / time) and dry it with a forced air at 25℃.

[0170] (3) Dissolve polyamide-amine dendritic polymer in purified water to prepare a solution with a concentration of 3.1 mg / mL. Add weighed dopamine and dopamine analogues to purified water to prepare a solution with a concentration of 3.1 mg / mL. Prepare a 1M Tris-HCl buffer solution with a pH of 8.5. Add a certain volume of 1M Tris-HCl buffer solution with a pH of 8.5 to make the final concentration of Tris-HCl buffer solution 50 mM. Stir and adjust the pH of the reaction solution to 8.8 with 4M hydrochloric acid solution and 4M sodium hydroxide solution. React at 25°C for 5 hours. Dopamine and dopamine analogues react with polyamide-amine dendritic polymer and bottom layer 2 to polymerize on the surface of bottom layer 2 to form intermediate layer 3. Then, ultrasonically clean with purified water 3 times (1 min / time) and dry with a forced air at 25°C.

[0171] (4) First, hexamethylenediamine was dissolved in tetrahydrofuran to prepare a solution with a concentration of 0.04 g / mL. Then, the nickel-titanium alloy with intermediate layer 3 was placed in it and reacted at 58°C and 150 rpm for 4.5 H. The mixture was washed three times with tetrahydrofuran and then three times with purified water (1 min / wash). The mixture was then dried at 25°C by forced air drying. Next, hydroxypropyl methylcellulose was dissolved in tetrahydrofuran to prepare a solution with a concentration of 0.17 g / mL. The dried sample was placed in it and reacted at 58°C and 150 rpm for 18 H. The mixture was washed three times with tetrahydrofuran and three times with purified water (1 min / wash). The mixture was then dried at 25°C by forced air drying. In this way, the intermediate layer 3 was introduced to introduce a function for adjusting the spatial conformation of the surface functional material.

[0172] (5) The aldehyde conversion of heparin can be achieved by preparing an aqueous solution with a concentration of 90 mg / mL, the solubility of sodium nitrite in the solution being 0.1 M, adjusting the pH of the reaction solution to 3.1 with glacial acetic acid, reacting at 20 °C for 2.5 H, adjusting the pH to neutral with 4 M hydrochloric acid and 4 M sodium hydroxide, dialyzing in a 3500 Da dialysis bag for 24 H, and finally lyophilizing the dialysate for later use.

[0173] (6) Dissolve aldehyde-modified heparin, sodium chloride, and sodium cyanoboronide in purified water to obtain concentrations of 0.9 mg / mL, 0.17 M, and 0.45 mg / mL, respectively, and adjust the pH of the reaction solution to 3.6. Then immerse the nickel-titanium alloy with intermediate layer 3 in the solution and react it at 58°C and 150 rpm for 18 hours. Wash it three times with purified water (1 min / time) and dry it in a forced-air conditioner at 25°C to complete the preparation of surface layer 4 functionalization of the nickel-titanium alloy.

[0174] After the experiment, the nickel-titanium alloy and its surface functional coatings were subjected to axial elemental analysis, anticoagulation tests, coating adhesion tests, and dynamic thrombosis tests to evaluate the anticoagulation effect of the functional coatings. Specific details are as follows:

[0175] 1. Axial elemental analysis of the coating

[0176] Reference Figure 15 and Figure 16 As shown, the nickel-titanium alloy along with its functional coating was ion-cut using a FIB (Focused Ion Beam) device. The cut nickel-titanium alloy was then welded onto a six-toothed copper mesh. Axial characteristic element content was scanned using an EDS (Energy Dispersive Spectrometer) (scanning from the coating surface towards substrate 1) to observe the distribution and changes in element content, thus determining whether the functional coating was successfully prepared (see [link to documentation]). Figure 15 and Figure 16 ).

[0177] Figure 15 This is an elemental distribution map of the sample after FIB ion cutting in the embodiment. Figure 16 This graph shows the change in elemental content from the surface layer to substrate 1 along the elemental scanning direction as the detection distance increases. Different colors correspond to different elements. The preparation process reveals that substrate 1 is a nickel-titanium alloy. Dopamine and its analogues, polyamide-amine dendritic polymers, hexamethylenediamine, hydroxypropyl methylcellulose, and aldehyde-modified heparin were sequentially prepared on the nickel-titanium alloy surface. The changing trends of the elements from the surface inwards are consistent with the preparation steps, indicating that the functional coating on the nickel-titanium alloy surface has been successfully prepared.

[0178] 2. Anticoagulation test

[0179] Since the coagulation pathway in contact with blood through the functional coating surface is intrinsic, and the partial thromboplastin time (PTT) test is a commonly used method to determine the activation of intrinsic coagulation pathways, the PTT of plasma after contact with the functional coating can be measured using a coagulation analyzer. This allows the determination of whether the nickel-titanium alloy coating, when coated with an anticoagulant layer, has a prolonging effect on coagulation time. If the PTT of plasma shortens after contact with the functional coating, it indicates activation of the intrinsic coagulation pathway, suggesting a weak anticoagulant effect of the functional coating.

[0180] Blank plasma Example Partial thromboplastin time (bare stent) 258s 149s Partial thromboplastin time (after coating) 258s 272s

[0181] Table 1

[0182] Table 1 shows the partial thromboplastin time (PTT) of the bare stent and the nickel-titanium alloy coated with the functional coating in the examples, using blank plasma as a reference. The data in Table 1 show that the PTT of the nickel-titanium alloy coated with the thromboplastin layer was extended to a limited extent compared to the bare stent. This indicates that the nickel-titanium alloy with the functional coating effectively delayed the activation of the intrinsic coagulation pathway, demonstrating that the anticoagulant coating of the nickel-titanium alloy can effectively prolong clotting time and has a good anticoagulant effect.

[0183] 3. Coating adhesion test

[0184] The above-mentioned nickel-titanium alloy with functional coating was sequentially fixed inside HDPE tubes (polyethylene tubes). DPBS buffer solution (phosphate buffer solution with pH 7.4±0.2) was circulated and flushed for 28 days at a speed of 160 rpm using a peristaltic pump. Samples were collected at 7-day intervals and their clotting time was tested. The collected samples were ultrasonically cleaned 3 times with purified water (1 min / time) and dried in a forced-air oven at 25℃. The test data are shown in Table 2.

[0185] Blank plasma Example Partial thromboplastin time (bare stent) 258s 141s Partial thromboplastin time (7 days after coating) 258s 282s Partial thromboplastin time (14 days after coating) 258s 279s Partial thromboplastin time (21 days after coating) 252s 277s Partial thromboplastin time (28 days after coating) 252s 272s

[0186] Table 2

[0187] By comparing the partial thromboplastin time (PTT) of nickel-titanium alloys with functional coatings over 28 days, it was found that the PTT of nickel-titanium alloys with functional coatings still had a significant effect on prolonging the PTT as the flushing time increased, indicating that nickel-titanium alloys with functional coatings still had a good anticoagulant effect over 28 days.

[0188] 4. Dynamic thrombosis test

[0189] A nickel-titanium alloy with a functional coating was implanted into an HDPE (polyethylene) tube. 30 mL of sodium citrate (Wt%=3.8%) anticoagulated sheep blood was taken and calcified with 2M calcium chloride solution. A certain volume of heparin sodium solution with a concentration of 60 IU / mL was added to make its concentration in sheep whole blood 1.2 IU / mL.

[0190] Then, 5 mL of partially anticoagulated sheep whole blood was injected into the HDPE tube containing the nickel-titanium alloy. After sealing the HDPE tube, it was rotated at 37°C and 60 rpm for 1 hour. The nickel-titanium alloy was then removed, rinsed with DPBS solution until the solution was clear, and photographed and recorded.

[0191] Figure 17 and Figure 18 The images shown are photographs of the bare stent and the coated vascular stent after dynamic thrombosis, respectively, as described in the embodiments. Figure 17 This is a surface structure diagram of the bare support. Figure 18 This is a surface structure diagram of a nickel-titanium alloy with a functional coating. Observation shows that there is less residual sheep whole blood on the inner surface of the nickel-titanium alloy with the functional coating, and the functional coating on the surface of the nickel-titanium alloy has a significant anticoagulation effect.

[0192] In summary, this application provides a medical device, a functional coating, and a method for preparing the functional coating. The bottom layer 2 of the functional coating has groups that can be further modified, allowing the bottom layer 2 to be covalently bonded to the intermediate layer 3, thereby improving the adhesion between the bottom layer 2 and the intermediate layer 3. Simultaneously, the intermediate layer 3 provides sufficient amino structures for coating the surface layer 4. These amino structures can undergo covalent bonding reactions with the aldehyde structures of the functionalized substances, enabling the intermediate layer 3 to be stably covalently bonded to the surface layer 4, thus efficiently fixing the surface layer 4. The functionalized substances bonded by the intermediate layer 3 through covalent bonding are more stably bonded, ensuring the overall coating adhesion on the surface of the substrate 1, preventing coating loss, and maintaining the coating's effectiveness over a long period.

[0193] The above description is merely a description of preferred embodiments of the present invention and is not intended to limit the scope of the present invention in any way. Any changes or modifications made by those skilled in the art based on the above disclosure shall fall within the protection scope of the present invention.

Claims

1. A functional coating, characterized in that, The material comprises a base layer, an intermediate layer, and a top layer, wherein the base layer, the intermediate layer, and the top layer are sequentially coated onto a substrate. The base layer has groups that can be further modified. The groups of the intermediate layer are covalently bonded to the groups of the base layer. The surface of the intermediate layer has an amino structure. The aldehyde structure of the functionalized substance is covalently bonded to the amino structure to form the top layer with functional components.

2. The functional coating as claimed in claim 1, wherein the underlayer provides, while bonding the substrate, a group available for secondary modification on the surface of the substrate, wherein the group available for secondary modification is one or more of amino, hydroxyl, aldehyde, quinone, and isocyanate groups.

3. The functional coating as described in claim 1, wherein the underlying layer comprises one or more of polydopamine and polydopamine analogs, an aminosilane coupling agent monolayer, an aminosilane coupling agent multilayer, and a polyamino polymer.

4. The functional coating as described in claim 3, wherein the underlying layer further comprises one of butanol, glutaraldehyde, adipaldehyde, 1,6-hexamethylene diisocyanate, toluene-2,4-diisocyanate, hexamethylene diisocyanate, and isophorone diisocyanate.

5. The functional coating of claim 1, wherein the intermediate layer comprises polydopamine and polydopamine analogues, polyamino polymers, or polyamino compounds with carboxyl groups.

6. The functional coating of claim 5, wherein the intermediate layer further comprises one of butanol, glutaraldehyde, adipaldehyde, 1,6-hexamethylene diisocyanate, toluene-2,4-diisocyanate, hexamethylene diisocyanate, and isophorone diisocyanate.

7. The functional coating as described in claim 1, characterized in that, The surface layer is an anti-condensation coating.

8. The functional coating as described in claim 1, characterized in that, The surface layer is an anticoagulant coating, which includes one or more of heparin, heparin derivatives, dermatan sulfate, and hyaluronic acid.

9. The functional coating as described in claim 8, characterized in that, The surface of the intermediate layer is reacted with a hydrophilic polymer using a chain extender to adjust the spatial conformation of the surface functional material of the substrate.

10. The functional coating as described in claim 9, characterized in that, The hydrophilic polymer is polyethylene glycol, polypropylene glycol, aminopolyethylene glycolamine, branched polyethyleneimine, polyetheramine, cellulose, methylcellulose, hydroxypropyl methylcellulose, or polyethylene adipate.

11. A medical device, characterized in that, It includes a substrate and a functional coating as described in any one of claims 1 to 10, the functional coating being applied to the substrate.

12. The medical device as described in claim 11, characterized in that, The medical device is a blood contact medical device, including external, semi-external, intravascular implanted or intravascular interventional medical devices.

13. The medical device as described in claim 12, characterized in that, The materials used in the blood contact medical devices are metals, polymers, ceramics, or any combination thereof.

14. The medical device as described in claim 12, characterized in that, The endovascular implantable medical devices include flow diversion devices for treating aneurysms, dense mesh stents, coil-assisted stents, vascular stenosis stents, covered stents, artificial blood vessels, or artificial heart valves; the extracorporeal medical devices include blood collection tubes, blood storage bags, infusion needles, blood collection needles, or hemostatic valves; the semi-extracorporeal medical devices include hemodialyzers or artificial lung membranes; and the endovascular interventional medical devices include catheters, guidewires, or balloon catheters.

15. A method for preparing a functional coating, characterized in that, The functional coating, applicable to any one of claims 1 to 10, is prepared by a method comprising the following steps: S1: Clean and dry the surface of the substrate, and perform a bottom layer treatment on the dried substrate to cover the surface of the substrate with a bottom layer having groups that can be modified for secondary purposes. S2: The substrate having the bottom layer is covalently bonded to the intermediate layer 3, so that the surface of the bottom layer is covered with an intermediate layer having an amino structure; S3: Perform aldehyde-based treatment on the functionalized material to obtain a functionalized material with an aldehyde structure; S4: Covalently bond the aldehyde structure of the functionalized substance to the amino structure of the intermediate layer, so that the surface of the intermediate layer is covered with a surface layer containing functional components.

16. The method for preparing the functional coating as described in claim 15, characterized in that, Step S1 may be repeated multiple times before step S2, and / or step S2 may be repeated multiple times before step S3.

17. The method for preparing the functional coating as described in claim 15, characterized in that, The specific steps of S1 include one or a combination of the following methods: The first reactant is subjected to a catalytic oxidation reaction with a catalyst and / or oxidant under weakly alkaline conditions to obtain a reaction solution. The substrate is immersed in the reaction solution for chemical deposition, and groups that can be modified secondary are deposited on the surface of the substrate. The substrate is first passivated by immersing it in a strong acid solution, then immersed in a concentrated alkaline solution for a high-temperature reaction, or directly immersed in a concentrated alkaline solution for a high-temperature reaction, or treated with high-purity oxygen in a plasma device to give the substrate surface hydroxyl groups; then the substrate is coated by immersing it in a solvent containing an amino-containing silane coupling agent, and then the substrate is cleaned with the corresponding solvents in sequence, and soaked in purified water to fully hydrolyze the amino-containing silane coupling agent on the surface of the substrate for 2-24 hours, so that the surface of the substrate has groups that can be modified for secondary purposes; the solvent of the amino-containing silane coupling agent is anhydrous methanol or methanol, anhydrous ethanol, ≥50% ethanol, anhydrous toluene or toluene; The substrate is treated with high-purity ammonia in a plasma device to form groups on the surface of the substrate that can be further modified.

18. The method for preparing the functional coating as described in claim 17, characterized in that, The first reactant is dopamine and dopamine analogues; the oxidant is air, oxygen, hydrogen peroxide, potassium persulfate, ammonium persulfate, or sodium periodate; the catalyst is copper sulfate pentahydrate, ferric chloride hexahydrate, ferric sulfate heptahydrate, barium chloride dihydrate, or zinc sulfate heptahydrate; the amino-containing silane coupling agent is KH-550, KH-540, KH-792, KH-602, N,N-diethyl-3-aminopropyltrimethoxysilane, or aminopropyl polyethylene glycol silane.

19. The method for preparing the functional coating as described in claim 17, characterized in that, The specific steps of S2 include one or a combination of the following methods: The first reactant reacts with a polyamino polymer under weakly alkaline conditions to form an intermediate layer having the amino structure on the surface of the bottom layer. A carboxyl-containing polyamino compound or carboxyl-containing polyamino polymer is coated onto the substrate by a chemical coupling agent, thereby forming an intermediate layer with the amino structure on the surface of the substrate. By dissolving a chain extender in an organic solvent, reacting it with the underlying layer, and then solidifying it, the molecular chains of the underlying layer are epitaxial, and reactive sites are obtained on the underlying layer. The active sites on the substrate are then reacted with the polyamino polymer, and the substrate is then cured to form an intermediate layer with the amino structure on the surface of the substrate.

20. The method for preparing the functional coating as described in claim 19, characterized in that, The chemical coupling agent is any combination of two of N-hydroxysuccinimide ester, imine ester carbodiimide, and dicyclohexylcarbodiimide; the polyamino compound with a carboxyl group is L-lysine, L-histidine, or L-arginine; the polyamino polymer with a carboxyl group is poly-L-lysine, poly-L-histidine hydrochloride, or poly-L-arginine; the polyamino polymer is branched polyethyleneimine, chitosan, amino-modified hyaluronic acid, or polyamide-amine dendritic polymer.

21. The method for preparing the functional coating as described in claim 19, characterized in that, The chain extender is succinaldehyde, glutaraldehyde, adipaldehyde, 1,6-hexamethylene diisocyanate, toluene-2,4-diisocyanate, hexamethylene diisocyanate, or isophorone diisocyanate; the organic solvent is anhydrous ethanol, anhydrous methanol, toluene, acetone, dimethyl sulfoxide, N,N-dimethylformamide, or tetrahydrofuran.

22. The method for preparing the functional coating as described in claim 15, characterized in that, The functionalized substance is a substance having a 2,5-anhydrous mannose reducing terminal structure; The steps in S3 specifically include: A substance having a 2,5-anhydrous mannose reducing terminal structure is dissolved in an acidic sodium nitrite aqueous solution to react and obtain an anticoagulant with an aldehyde structure, which is then dialyzed and / or lyophilized for later use; the substance having a 2,5-anhydrous mannose reducing terminal structure is heparin and heparin derivatives, dermatan sulfate or hyaluronic acid.

23. The method for preparing the functional coating as described in claim 15, characterized in that, When the functionalized substance with an aldehyde structure is heparin and heparin derivatives, dermatan sulfate, or hyaluronic acid, the process before step S4 further includes: The surface of the amino intermediate layer is extended by immersion in a solvent containing a chain extender; then the substrate having the intermediate layer is immersed in a solvent containing a hydrophilic polymer to react, thereby adjusting the spatial conformation of the surface functional material of the substrate; the solvent containing the hydrophilic polymer is anhydrous ethanol, anhydrous methanol, toluene, acetone, dimethyl sulfoxide, N,N-dimethylformamide, or tetrahydrofuran; the hydrophilic polymer is polyethylene glycol, polypropylene glycol, aminopolyethylene glycolamine, branched polyethyleneimine, polyetheramine, cellulose, methylcellulose, hydroxypropyl methylcellulose, or polyethylene adipate.

24. The method for preparing the functional coating as described in claim 15, characterized in that, The specific steps of S4 include: An aldehyde-modified anticoagulant functionalized substance, sodium chloride, and sodium cyanoborohydrin are dissolved in a solvent; a substrate with an intermediate layer is then immersed in the solvent to react, thereby forming an anticoagulant surface layer on the surface of the intermediate layer.

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