Method for modifying hydrogel coating on surface of medical base material

Abstract

The invention discloses a method for modifying a hydrogel coating on the surface of a medical base material, and belongs to the technical field of material surface modification. The method comprises the following steps: providing a hydrogel precursor solution; the hydrogel precursor solution is mixed with N, N-methylene bisacrylamide, water-soluble ferrite and ascorbic acid, and a functional modification solution is obtained; loading an organic peroxide and an acrylic acid cross-linking agent on the surface of a medical base material, and soaking the medical base material in the functional modification liquid for grafting reaction to obtain the medical material with the surface modified by the hydrogel coating. According to the method, the bonding effect between the formed hydrogel coating and the medical base material can be effectively enhanced, the hydrogel coating is stable and lasting, and the method has the advantages of being good in universality, mild in reaction condition, simple in preparation process, free of assistance of light / heat and the like and the like, and large-scale batch production is facilitated.

Description

Technical Field

[0001] The present application belongs to the technical field of material surface modification, and in particular relates to a method for modifying a hydrogel coating on the surface of a medical substrate. Background Art

[0002] Biomedical materials are functional materials with excellent biocompatibility and specific biological effects, and are widely used in medical processes such as clinical diagnosis, treatment, and rehabilitation. In clinical applications, the surface properties of biomedical materials, due to their direct interaction with human tissue, become crucial for their overall performance.

[0003] Surface treatment or specific modification is an important means of functionalizing the surface of biomedical materials. It can not only change the physical or chemical properties of the surface, but also impart specific biological functions to the surface, thereby promoting the interaction between biomedical materials and organisms. For example, modifying the surface of biomedical materials with functional hydrogel coatings such as antibacterial and anti-inflammatory, antimicrobial adhesion, and osteogenic properties is one of the common strategies currently used to improve the surface properties of polymer biomedical materials.

[0004] However, the common methods for modifying hydrogel coatings on the surface of biomedical materials currently have some common defects. For example, some non-covalently bonded coatings have weak bonding with the substrate, are easy to fall off during use, and have poor reliability; the commonly used photoinitiated grafting technology cannot achieve the modification of the inner surface of non-transparent pipes, and from an industrial perspective, there are also complex preparation processes, especially in situ polymerization grafting, indiscriminate polymerization of high molecular monomers in the precursor solution, which cannot be reused, and the post-processing process is complicated, which is not conducive to continuous production. Therefore, the development of a simple and efficient strategy to quickly, controllably, and stably construct multifunctional hydrogel coatings with precise bioactivity on the surface of medical polymer materials has great clinical needs and scientific value. Summary of the Invention

[0005] This application discloses a method for modifying a hydrogel coating on the surface of a medical substrate, thereby effectively solving the above-mentioned technical problems existing in the current strategies for modifying a hydrogel coating on the surface of biomedical materials.

[0006] To achieve the above objectives, the present application provides, in a first aspect, a method for modifying a hydrogel coating on the surface of a medical substrate, the method comprising the steps of:

[0007] providing a hydrogel precursor solution;

[0008] mixing the hydrogel precursor solution with N,N-methylenebisacrylamide, a water-soluble ferrous salt, and ascorbic acid to obtain a functional modification solution;

[0009] After the organic peroxide and acrylic acid cross-linking agent are loaded on the surface of the medical substrate, the substrate is immersed in the functional modification solution to carry out a grafting reaction, thereby obtaining a medical material with a surface-modified hydrogel coating.

[0010] In some embodiments, the hydrogel precursor solution is mainly composed of water and a water-soluble polymer dispersed in the water, wherein the water-soluble polymer is at least one selected from polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, sodium polystyrene sulfonate, polyethylene oxide, polyquaternium-11, dextran, polylysine, methylcellulose, and hyaluronic acid.

[0011] In some embodiments, the hydrogel precursor solution is composed of water and a composition of dextran and polylysine dispersed in water.

[0012] In some embodiments, the hydrogel precursor solution is mainly composed of water and a water-soluble monomer dispersed in water, wherein the water-soluble monomer is at least one selected from methacrylic acid, acrylic acid, acrylamide, hydroxyethyl acrylate, hydroxyethyl methacrylate, N-isopropylacrylamide, 2-acrylamido-2-methylpropanesulfonic acid, methacrylic acid sulfonate, dimethylaminoethyl methacrylate, methacryloylethyl carboxybetaine, and methacryloylethyl sulfobetaine.

[0013] In some embodiments, every 100 parts by mass of the hydrogel precursor solution contains: 0.01-1 parts by mass of N,N-methylenebisacrylamide, 0.01-5 parts by mass of a water-soluble ferrous salt, and 1-5 parts by mass of ascorbic acid.

[0014] In some embodiments, the medical substrate is selected from any one of silicone, polyvinyl chloride, polyurethane, polyetheretherketone, polyimide, polyethylene, polypropylene, and ethylene-ethyl acetate copolymer.

[0015] In some embodiments, the organic peroxide is selected from cumene hydroperoxide, t-butyl perbenzoate, or 2-butyl ketone peroxide.

[0016] In some embodiments, the acrylic crosslinker is selected from ethylene glycol dimethacrylate, diethylene glycol diacrylate, or triethylene glycol dimethacrylate.

[0017] In some embodiments, the water-soluble ferrous salt is selected from at least one of ferrous chloride, ferrous sulfate, ferrous fumarate, and ferrous gluconate.

[0018] In some embodiments, the thickness of the hydrogel coating is 10 to 200 μm.

[0019] Compared with the prior art, the advantages or beneficial effects of the embodiments of the present application include at least:

[0020] The preparation method provided in the present application is to load an organic peroxide and an acrylic crosslinker on the surface of a medical substrate, and then immerse it in a functional modification solution mixed with N,N-methylenebisacrylamide, ferrous salt, ascorbic acid and a hydrogel precursor solution for grafting. Such a combination of steps can trigger the generation of free radicals at the interface. On the one hand, it can trigger the grafting and cross-linking of water-soluble polymers to form hydrogels based on hydrogen abstraction to generate polymer free radicals, and it can also trigger the in situ polymerization of water-soluble monomers to form hydrogels. It has the advantages of good universality, mild reaction conditions, simple preparation process, and no need for light / heat assistance, which is convenient for large-scale batch production. On the other hand, the free radicals formed at the interface are limited by the coupling termination and the viscosity of the newly formed hydrogel, and the diffusion range is quite small, which can effectively limit the grafting reaction to the surface of the medical substrate and has the advantage of controllable coating thickness. More importantly, since the acrylic acid crosslinker and N,N-methylenebisacrylamide are respectively present on both sides of the interface, an "interpenetrating polymer network" bridging the two sides of the interface can be formed during the free radical polymerization process, effectively enhancing the bonding effect between the formed hydrogel coating and the medical substrate, so that the hydrogel coating and the medical substrate have a stable bonding effect, and the addition of ascorbic acid can maintain the ferrous ion concentration and keep the reaction going. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] To more clearly illustrate the technical solutions of the embodiments of this application, the following briefly introduces the drawings required for describing the embodiments. Obviously, the drawings described below are only some of the embodiments described in this application. For those skilled in the art, other drawings can be derived from these drawings without inventive effort.

[0022] Figure 1 The physical pictures of the surface functionalized silica gel materials of Example 1 and Comparative Examples 1-3;

[0023] Figure 2 The lap shear strength test results of the surface functionalized silica gel materials of Example 1 and Comparative Example 3;

[0024] Figure 3 This is a cross-sectional SEM image of the surface functionalized silica gel material of Example 1;

[0025] Figure 4 These are the friction coefficient test results of the blank silica gel substrate, the surface functionalized silica gel material of Comparative Example 3, and the surface functionalized silica gel material of Example 1;

[0026] Figure 5 The friction coefficient test results of the polyvinyl pyrrolidone hydrogel coatings formed in Examples 3, 4, and 5;

[0027] Figure 6IR spectra of the hydrogel coatings formed in Examples 7, 8, and 9;

[0028] Figure 7 The oleophobic and oil-repellent properties test results of the polyvinyl alcohol coating surface formed in Example 1;

[0029] Figure 8 The anti-platelet and anti-thrombotic test results of the polyethylene oxide hydrogel coating formed in Example 2 provided in the examples of this application;

[0030] Figure 9 These are the test results of the in vitro osteogenic differentiation ability of the dextran-polylysine hydrogel coating formed in Example 6 provided in the examples of this application. DETAILED DESCRIPTION

[0031] The following will be combined with the accompanying drawings in the embodiments of this application to clearly and completely describe the technical solutions in the embodiments of this application. Obviously, the described embodiments are part of the embodiments of this application, not all of the embodiments. Based on the embodiments in this application, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of this application.

[0032] In the following description, the term "and / or" is used to describe the relationship between associated objects, indicating that three possible relationships exist. For example, "A and / or B" can represent: A alone, B alone, and both A and B. A and B can be singular or plural. The character " / " generally indicates an "or" relationship between the associated objects.

[0033] In the following description, the term "plurality" refers to two or more; the term "at least one" or similar expressions refers to any combination, including any combination of a single or plural number. For example, "at least one of A, B, or C" or "at least one of A, B, and C" refers to any one of A, B, and C, or A+B, A+C, B+C, or A+B+C, where A, B, and C can each be a single or plural number.

[0034] In the following description, the order of serial numbers does not mean the order of execution. Some or all steps can be executed in parallel or sequentially. The execution order of each process should be determined by its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of this application.

[0035] In the following description, numerical ranges should be understood to also specifically disclose each intervening value between the upper and lower limits of the range. Each smaller range between any stated value or intervening value in a stated range and any other stated value or intervening value in the stated range is also encompassed within the invention, and the upper and lower limits of these smaller ranges may independently be included or excluded in the range.

[0036] In the following description, the terms used are for the purpose of describing specific embodiments only and are not intended to limit the present application. The singular forms "a", "an" and "the" used in all application documents are also intended to include the plural forms, unless the context clearly indicates otherwise.

[0037] Unless otherwise indicated, the technical / scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which this application belongs. Although this application describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of this application. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials related to the documents. In the event of any conflict with any incorporated document, the content of this specification shall prevail.

[0038] In a first aspect, the present invention provides a method for modifying a hydrogel coating on the surface of a medical substrate, the method comprising the steps of:

[0039] providing a hydrogel precursor solution;

[0040] mixing the hydrogel precursor solution with N,N-methylenebisacrylamide, a water-soluble ferrous salt, and ascorbic acid to obtain a functional modification solution;

[0041] After the organic peroxide and acrylic acid cross-linking agent are loaded on the surface of the medical substrate, the substrate is immersed in the functional modification solution to carry out a grafting reaction, thereby obtaining a medical material with a surface-modified hydrogel coating.

[0042] It should be noted that the examples of this application do not limit the specific method for loading the organic peroxide and acrylic crosslinker on the surface of the medical substrate. Various surface loading methods known in the art can be used, such as surface adsorption swelling method, solution immersion method, solution spraying method, solution spin coating method, etc. Among them, the examples of this application prefer the surface adsorption swelling method. The surface adsorption swelling method can effectively increase the distribution of the organic peroxide and acrylic crosslinker on the surface of the medical substrate through swelling and diffusion, thereby improving the uniformity of the subsequent grafting reaction.

[0043] The present application embodiment illustratively provides a method for pre-embedding an organic peroxide and an acrylic acid cross-linking agent on the surface of a medical substrate by a solvent swelling method, the steps comprising:

[0044] After dissolving the organic peroxide and acrylic crosslinker in an organic solvent, the resulting solution is used to immerse the medical substrate. The preferred immersion temperature is 10-80°C for 5-60 minutes. To accelerate the swelling reaction and improve dispersibility, the more preferred immersion temperature is 20-40°C for 5-20 minutes.

[0045] It should be noted that the organic solvent used for swelling in the embodiment of the present application is preferably at least one of methanol, ethanol, isopropanol, dichloromethane, dichloroethane, trichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, decahydronaphthalene, ethyl acetate and butyl acetate.

[0046] It should be noted that when the organic peroxide and the acrylic crosslinking agent are dissolved in an organic solvent, the concentration of the organic peroxide or the acrylic crosslinking agent is preferably the same or different, and is preferably 5 to 30 wt %. For example, the concentrations of the organic peroxide and the acrylic crosslinking agent are the same, such as 5 wt %, 15 wt %, and 30 wt %, or the concentrations of the organic peroxide and the acrylic crosslinking agent are different, such as 5 wt % and 30 wt %.

[0047] It should be noted that the specific conditions for the grafting reaction are not particularly limited in the examples of this application and can be reasonably selected based on the characteristics of the free radical polymerization reaction. However, it should be understood in the art that in order to accelerate the free radical polymerization reaction, the preferred temperature is 10-80°C and the reaction time is 0.5-60 minutes; more preferably, the temperature is 20-40°C and the reaction time is 5-20 minutes.

[0048] It should be noted that the examples of the present application do not specifically limit the preparation process of the hydrogel precursor solution, and the preparation can be carried out according to the steps and processes known in the art. The examples of the present application do not specifically limit the ratio and dosage of the hydrogel precursor solution and the medical substrate with the surface loaded with organic peroxide and acrylic crosslinker, as long as the hydrogel precursor solution is in complete contact with the medical substrate with the surface loaded with organic peroxide and acrylic crosslinker.

[0049] The embodiment of the present application combines the above steps, loading an organic peroxide and an acrylic crosslinker on the surface of a medical substrate, and then immersing the substrate in a functional modification solution mixed with N,N-methylenebisacrylamide, ferrous salt, ascorbic acid, and a hydrogel precursor solution for grafting. Such a combination of steps can trigger the generation of free radicals at the interface. On the one hand, it can trigger the grafting and cross-linking of water-soluble polymers to form hydrogels based on hydrogen abstraction to generate polymer free radicals, and it can also trigger the in situ polymerization of water-soluble monomers to form hydrogels. It has the advantages of good universality, mild reaction conditions, simple preparation process, and no need for light / heat assistance, which is convenient for large-scale batch production. On the other hand, the free radicals formed at the interface are limited by the coupling termination and the viscosity of the newly formed hydrogel, and the diffusion range is quite small, which can effectively limit the grafting reaction to the surface of the medical substrate and has the advantage of controllable coating thickness. More importantly, since the acrylic acid crosslinker and N,N-methylenebisacrylamide are respectively present on both sides of the interface, an "interpenetrating polymer network" bridging the two sides of the interface can be formed during the free radical polymerization process, effectively enhancing the bonding effect between the formed hydrogel coating and the medical substrate, so that the hydrogel coating and the medical substrate have a stable bonding effect, and the addition of ascorbic acid can maintain the ferrous ion concentration and keep the reaction going.

[0050] As an example, the main components of the hydrogel precursor solution are water and a water-soluble polymer dispersed in water, wherein the water-soluble polymer is selected from at least one of polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, sodium polystyrene sulfonate, polyethylene oxide, polyquaternium-11, dextran, polylysine, methyl cellulose and hyaluronic acid.

[0051] It should be noted that the embodiment of the present application does not impose any particular restrictions on the mass volume concentration of the water-soluble polymer dispersed in water, and can be set according to the general content of the hydrogel precursor solution configured in the art. For example, the embodiment of the present application is preferably 1-30wt%, exemplified by 1wt%, 15wt%, 30wt% or any one within the said range.

[0052] It should be noted that the above-mentioned water-soluble polymers can form hydrogel coatings with different functions. For example, when selected from polyvinyl pyrrolidone, polyquaternium-11, and methylcellulose, a self-lubricating hydrogel coating can be prepared; when selected from polyethylene glycol, polyethylene oxide, polyvinyl alcohol, and sodium polystyrene sulfonate, a sewage-proof gel coating can be prepared; when selected from hyaluronic acid, an anti-thrombotic hydrogel coating can be prepared; when selected from a combination of dextran or glucose and polylysine, an osteogenic functional hydrogel coating can be prepared. Among them, the embodiment of the present application preferably uses a glucose and polylysine composition with a mass ratio of 1:1, thereby significantly improving the ability to promote osteogenic differentiation in vitro through the synergistic effect of glucose and polylysine.

[0053] Of course, the embodiments of the present application do not particularly limit the specific functions of the hydrogel coating formed by each water-soluble polymer. For example, polyethylene oxide can be used to prepare both a self-lubricating hydrogel coating and a sewage-proof hydrogel coating.

[0054] As an example, the main components of the hydrogel precursor solution are water and a water-soluble monomer dispersed in water, wherein the water-soluble monomer can be selected from at least one of methacrylic acid, acrylic acid, acrylamide, hydroxyethyl acrylate, hydroxyethyl methacrylate, N-isopropylacrylamide, 2-acrylamido-2-methylpropanesulfonic acid, methacrylic acid sulfonate, dimethylaminoethyl methacrylate, methacryloylethyl carboxybetaine and methacryloylethyl sulfobetaine.

[0055] It should be noted that the embodiment of the present application does not impose any particular restrictions on the mass volume concentration of the water-soluble monomer dispersed in water, and can be set according to the general content of the hydrogel precursor solution configured in the art. For example, the embodiment of the present application is preferably 5-60wt%, exemplified by 5wt%, 30wt%, 60wt% or any one within the range.

[0056] It should be noted that the aforementioned water-soluble monomers can form functional hydrogel coatings. For example, when selected from acrylamide, hydroxyethyl acrylate, hydroxyethyl methacrylate, 2-acrylamido-2-methylpropanesulfonic acid, and dimethylaminoethyl methacrylate, a self-lubricating hydrogel coating can be prepared. When selected from methacrylic acid, acrylic acid, N-isopropylacrylamide, methacrylic acid sulfonate, methacryloylethyl carboxybetaine, and methacryloylethyl sulfobetaine, a sewage-resistant gel coating can be prepared. The present examples will not be described in detail here, and appropriate selections can be made in the art based on functional requirements.

[0057] As an example, when preparing the functional modification solution in the embodiment of the present application, 0.01-1 parts by mass of N,N-methylenebisacrylamide, 0.01-5 parts by mass of water-soluble ferrous salt and 1-5 parts by mass of ascorbic acid are mixed into every 100 parts by mass of the hydrogel precursor solution.

[0058] It should be noted that the embodiment of the present application can effectively regulate the process of interfacial free radical generation by mixing the said mass fractions of N,N-methylenebisacrylamide, water-soluble ferrous salt and ascorbic acid into the hydrogel precursor solution, and enable N,N-methylenebisacrylamide to interact with the acrylic acid crosslinker to form an "interpenetrating polymer network" bridging both sides of the interface, thereby enhancing the bonding effect between the formed hydrogel coating and the medical substrate.

[0059] As an example, the medical substrate is preferably selected from at least one of polyimide, polyvinyl chloride, polyurethane, silicone, polyethylene, polypropylene, polyetheretherketone, and ethylene-vinyl acetate copolymer.

[0060] As an example, the organic peroxide described in the embodiments of the present application is preferably selected from any one of cumene hydroperoxide, tert-butyl perbenzoate or 2-methyl ethyl peroxide.

[0061] As an example, in order to ensure good adhesion of the organic peroxide to the surface of the medical substrate and cross-linking with N,N-methylenebisacrylamide to form an interpenetrating polymer network, the acrylic crosslinking agent is preferably selected from any one of ethylene glycol dimethacrylate, diethylene glycol diacrylate, and triethylene glycol dimethacrylate.

[0062] As an example, in order to ensure that the organic peroxide is in full contact with the ferrous ions and the Fenton reaction occurs, the embodiment of the present application preferably uses a water-soluble ferrous salt, which can be selected from at least one of ferrous chloride, ferrous sulfate, ferrous fumarate and ferrous gluconate.

[0063] It should be noted that when two or more water-soluble ferrous salts are selected, the embodiments of the present application do not have any special restrictions on the ratio of different ferrous salts, and any ratio can be selected to meet the actual demand for ferrous ions.

[0064] As an example, in order to at least achieve a good compatibility between the biomedical polymer material and human tissue, the preferred thickness of the hydrogel coating is 10 to 200 μm.

[0065] The technical solution of the present application will be further described below in conjunction with specific embodiments.

[0066] Example 1

[0067] This embodiment provides a method for grafting a polyvinyl alcohol hydrogel coating on the surface of a silica gel substrate, comprising the steps of:

[0068] Step 1: Dissolve 1 mL of cumene hydroperoxide and 1 mL of ethylene glycol dimethacrylate in 10 mL of ethanol to obtain swelling treatment reagent T1;

[0069] Step 2: Immerse the silica gel substrate in swelling reagent T1 at room temperature for 10 minutes to obtain a swollen silica gel substrate;

[0070] Step 3: 1.5 g of polyvinyl alcohol 1799 (PVA-1799, degree of alcoholysis 98-99 mol%, water content ≈1.4 wt%) was added to 10 mL of deionized water and stirred at 60°C until the PVA was completely dissolved. After the solution was cooled to room temperature, 0.04 g of N,N-methylenebisacrylamide, 0.08 g of ferrous chloride, and 0.3 g of ascorbic acid were added and stirred until fully mixed to form a homogeneous solution. The solution was ultrasonicated for 5 min to prepare functional modification solution P1;

[0071] Step 4: Immerse the swollen silica substrate in the functional modification solution P1 and react in situ at 25° C. for 10 minutes to obtain a silica material with a surface modified with a polyvinyl alcohol hydrogel coating.

[0072] Example 2

[0073] This embodiment provides a method for grafting a polyethylene oxide hydrogel coating on the surface of a silica gel substrate, comprising the steps of:

[0074] Step 1: Dissolve 1 mL of cumene hydroperoxide and 1 mL of ethylene glycol dimethacrylate in 10 mL of ethyl acetate to obtain swelling treatment reagent T2;

[0075] Step 2: Immerse the silica gel substrate in a swelling treatment reagent T2 and soak it at room temperature for 10 minutes to obtain a swollen silica gel substrate;

[0076] Step 3: Dissolve 1.5 g of polyethylene oxide (average molecular weight 1000 kDa), 0.04 g of N,N-methylenebisacrylamide, 0.08 g of ferrous chloride, and 0.3 g of ascorbic acid in 10 mL of deionized water, and prepare functional modification solution P2 according to the method of Example 1;

[0077] Step 4: Immerse the treated silica gel substrate in functional modification solution P2 and react in situ at 25° C. for 10 minutes to obtain a silica gel material with a surface modified polyethylene oxide hydrogel coating.

[0078] Example 3

[0079] This embodiment provides a method for grafting a polyvinyl pyrrolidone hydrogel coating on a polyvinyl chloride substrate (PVC), comprising the steps of:

[0080] Step 1: Immerse the polyvinyl chloride substrate in treatment reagent T2 (from Example 2) at room temperature for 10 minutes to obtain a treated polyvinyl chloride substrate;

[0081] Step 2: Dissolve 1.5 g of polyvinylpyrrolidone (average molecular weight 1300 kDa), 0.04 g of N,N-methylenebisacrylamide, 0.08 g of ferrous chloride, and 0.3 g of ascorbic acid in 10 mL of deionized water to prepare functional modification solution P3;

[0082] Step 3: Immerse the treated polyvinyl chloride substrate in functional modification solution P3 and react in situ at 25° C. for 10 minutes to obtain a polyvinyl chloride material with a surface modified polyvinyl pyrrolidone hydrogel coating.

[0083] Example 4

[0084] This embodiment provides a method for grafting a polyvinyl pyrrolidone hydrogel coating on a polyurethane substrate (PU), comprising the steps of:

[0085] Step 1: Dissolve 1 mL of tert-butyl peroxybenzoate and 1 mL of ethylene glycol dimethacrylate in 10 mL of ethyl acetate to obtain swelling treatment reagent T3;

[0086] Step 2: Immerse the polyurethane substrate in a swelling treatment reagent T3 and soak it at room temperature for 10 minutes to obtain a swollen polyurethane substrate;

[0087] Step 3: Immerse the swollen polyurethane substrate in functional modification solution P3 (from Example 3) and react in situ at 25° C. for 10 min to obtain a polyurethane material with a surface modified polyvinyl pyrrolidone hydrogel coating.

[0088] Example 5

[0089] This embodiment provides a method for grafting a polyvinyl pyrrolidone hydrogel coating on the surface of an ultra-high molecular weight polyethylene substrate (UHMWPE), comprising the steps of:

[0090] Step 1: Dissolve 1 mL of 2-butanone peroxide and 1 mL of diethylene glycol diacrylate in 10 mL of ethyl acetate to obtain swelling treatment reagent T4;

[0091] Step 2: Immerse the ultra-high molecular weight polyethylene substrate in a swelling treatment reagent T4 at room temperature for 10 minutes to obtain a swollen ultra-high molecular weight polyethylene substrate;

[0092] Step 3: Immerse the swollen ultrahigh molecular weight polyethylene substrate in functional modification solution P3 (from Example 3) and react in situ at 25° C. for 10 min to obtain an ultrahigh molecular weight polyethylene material with a surface modified polyvinyl pyrrolidone hydrogel coating.

[0093] Example 6

[0094] This embodiment provides a method for grafting a dextran-polylysine hydrogel coating on the surface of a polyetheretherketone substrate, comprising the steps of:

[0095] Step 1: Immerse the polyetheretherketone substrate treated with concentrated sulfuric acid for 5 minutes in a swelling treatment reagent T1 (from Example 1) at room temperature for 10 minutes to obtain a swollen polyetheretherketone substrate;

[0096] Step 2: Dissolve 1.5 g of dextran (average molecular weight 70 kDa), 1.5 g of polylysine (average molecular weight 3500 kDa), 0.04 g of N,N-methylenebisacrylamide, 0.08 g of ferrous chloride, and 0.3 g of ascorbic acid in 10 mL of deionized water to prepare functional modification solution P4;

[0097] Step 3: Immerse the swollen polyetheretherketone substrate in functional modification solution P4 and react in situ at 25° C. for 10 minutes to obtain a polyetheretherketone material with a surface modified dextran-polylysine hydrogel coating.

[0098] Example 7

[0099] This embodiment provides a method for grafting an acrylic acid (AA) hydrogel coating on the surface of a silica gel substrate, comprising the steps of:

[0100] Step 1: Immerse the silica gel substrate in a swelling treatment reagent T1 (from Example 1) at room temperature for 10 minutes to obtain a swollen silica gel substrate;

[0101] Step 2: Dissolve 3.0 g of acrylic acid monomer, 0.04 g of N,N-methylenebisacrylamide, 0.08 g of ferrous chloride, and 0.3 g of ascorbic acid in 10 mL of deionized water to prepare functional modification solution P5;

[0102] Step 3: Immerse the swollen silica gel substrate in the functional modification solution P5 and react in situ at 25° C. for 10 minutes to obtain a silica gel material with a surface modified acrylic hydrogel coating.

[0103] Example 8

[0104] This embodiment provides a method for grafting a hydroxyethyl methacrylate (HEMA) hydrogel coating on the surface of a silica substrate, comprising the steps of:

[0105] Step 1: Immerse the silica gel substrate in a swelling treatment reagent T1 (from Example 1) at room temperature for 10 minutes to obtain a swollen silica gel substrate;

[0106] Step 2: Dissolve 3.0 g of hydroxyethyl methacrylate, 0.04 g of N,N-methylenebisacrylamide, 0.08 g of ferrous chloride, and 0.3 g of ascorbic acid in 10 mL of deionized water to prepare functional modification solution P6;

[0107] Step 3: Immerse the swollen silica gel substrate in the functional modification solution P6 and react in situ at 25° C. for 10 minutes to obtain a silica gel material with a surface modified with hydroxyethyl methacrylate hydrogel coating.

[0108] Example 9

[0109] This embodiment provides a method for grafting an acrylamide (AAM) hydrogel coating on the surface of a silica substrate, comprising the steps of:

[0110] Step 1: Immerse the silica gel substrate in a swelling treatment reagent T1 (from Example 1) at room temperature for 10 minutes to obtain a swollen silica gel substrate;

[0111] Step 2: Dissolve 3 g acrylamide, 0.04 g N,N-methylenebisacrylamide, 0.08 g ferrous chloride, and 0.3 g ascorbic acid in 10 mL deionized water to prepare functional modification solution P7;

[0112] Step 3: Immerse the swollen silica substrate in the functional modification solution P7 and react in situ at 25° C. for 10 minutes to obtain a silica material with a surface modified with an acrylamide hydrogel coating.

[0113] In order to verify the technical effect of the modification method of the present application, the method of Example 1 is used as a control and is described in conjunction with Comparative Examples 1 to 3.

[0114] Comparative Example 1

[0115] The difference between this comparative example and Example 1 is that ethylene glycol dimethacrylate is omitted from the swelling reagent component; and N,N-methylenebisacrylamide is omitted from the functional modification liquid component. The rest remains unchanged. The preparation steps include:

[0116] Step 1: Dissolve 1 mL of cumene hydroperoxide in 10 mL of ethanol to obtain swelling treatment reagent βT1;

[0117] Step 2: Immerse the silica gel substrate in a swelling treatment reagent βT1 and soak it at room temperature for 10 minutes to obtain a swollen silica gel substrate;

[0118] Step 3: Dissolve 1.5 g of polyvinyl alcohol (average molecular weight 1000 kDa), 0.08 g of ferrous chloride, and 0.3 g of ascorbic acid in 10 mL of deionized water to prepare functional modification solution βP1;

[0119] Step 4: Immerse the swollen silica gel substrate in the functional modification solution βP1 and react in situ at 25°C for 10 minutes to obtain a surface functionalized silica gel material.

[0120] Comparative Example 2

[0121] The difference between this comparative example and Example 1 is that N,N-methylenebisacrylamide is omitted from the functional modification liquid components, and the rest remains unchanged. The preparation steps include:

[0122] Step 1: Immerse the silica gel substrate in a swelling treatment reagent T1 (from Example 1) at room temperature for 10 minutes to obtain a swollen silica gel substrate;

[0123] Step 2: Immerse the swollen silica gel substrate in the functional modification solution βP1 (from Comparative Example 1) and react in situ at 25° C. for 10 minutes to obtain a surface functionalized silica gel material.

[0124] Comparative Example 3

[0125] The difference between this comparative example and Example 1 is that ethylene glycol dimethacrylate is omitted from the swelling treatment reagent component, and the rest remains unchanged. The preparation steps include:

[0126] Step 1: Immerse the silica gel substrate in a swelling treatment reagent βT1 (from Comparative Example 1) at room temperature for 10 minutes to obtain a swollen silica gel substrate;

[0127] Step 2: Immerse the swollen silica gel substrate in the functional modification solution P1 (from Example 1) and react in situ at 25° C. for 10 minutes to obtain a surface functionalized silica gel material.

[0128] Test Case

[0129] 1. Surface coating detection of surface functionalized silicone materials

[0130] The surface coating of the surface functionalized silica gel material prepared in Example 1 and Comparative Examples 1-3 was dyed with methylene blue, and the results were as follows: Figure 1 As shown. Among them, a is the surface dyeing result of the surface functionalized silica gel material prepared in Comparative Example 1; b is the surface dyeing result of the surface functionalized silica gel material prepared in Comparative Example 2; c is the surface dyeing result of the surface functionalized silica gel material prepared in Comparative Example 3; d is the surface dyeing result of the surface functionalized silica gel material prepared in Example 1.

[0131] according to Figure 1It can be seen that no hydrogel coating is formed on the surfaces of Comparative Examples 1 and 2, while hydrogel coating is formed on the surfaces of Comparative Example 3 and Example 1. However, the hydrogel coating formed on the surface of Comparative Example 3 is not uniform, while the hydrogel coating formed on the surface of Example 1 is uniform and dense. This indicates that the addition of N,N-methylenebisacrylamide to the functional modification solution is the key to determining the formation of the hydrogel coating, and the addition of an acrylic crosslinker to the swelling treatment reagent component helps to improve the uniformity of the hydrogel coating.

[0132] 2. Lap shear strength

[0133] The surface functionalized silica gel materials of Example 1 and Comparative Example 3 were subjected to lap shear tests using an electronic universal testing machine at a tensile speed of 10 mm / min. The results were as follows: Figure 2 As shown. Among them, Figure 2 These are the lap shear strength test results of the surface functionalized silicone materials of Example 1 and Comparative Example 3.

[0134] according to Figure 2 It can be seen that compared with the surface functionalized silica gel material prepared in Comparative Example 3, the interfacial strength of the hydrogel coating prepared by the method of the present application is significantly improved, indicating that the method of the present application can form an "interpenetrating polymer network" bridging both sides of the interface during the free radical polymerization process by adding an acrylic acid cross-linking agent to the swelling treatment reagent and adding N,N-methylenebisacrylamide to the functional modification liquid, thereby effectively enhancing the bonding effect between the hydrogel coating and the medical substrate.

[0135] 3. Cross-sectional SEM Characterization

[0136] The cross section of the surface functionalized silica gel material of Example 1 was observed using a scanning electron microscope. Figure 3 As shown. Among them, Figure 3 This is a cross-sectional SEM image of the surface functionalized silica gel material of Example 1.

[0137] according to Figure 3 It can be seen that the silicone substrate and the formed polyvinyl alcohol hydrogel coating are densely connected.

[0138] 4. Combined stability test

[0139] The friction coefficients of the blank silica gel substrate, the surface functionalized silica gel material of Comparative Example 3, and the surface functionalized silica gel material of Example 1 were evaluated by rotational rheology. The results were as follows: Figure 4 As shown. Among them, Figure 4 The friction coefficient test results.

[0140] according to Figure 4It can be seen that compared with the hydrogel coating formed in Comparative Example 3, after the hydrogel coating is grafted onto the surface of the silica gel substrate using the method of the present application, the friction coefficient of the surface is significantly reduced and remains stable for a long time, indicating that the method of the present application can enhance the bonding effect between the substrate and the hydrogel coating and is conducive to maintaining the long-term stability of the coating function. It may be that during the hydrogel formation process, N,N-methylenebisacrylamide and the acrylic acid crosslinker undergo cross-linking to form a structure that helps to improve the lubrication performance.

[0141] 5. Universality Experiment

[0142] 5.1 The friction coefficient of the polyvinyl pyrrolidone hydrogel coating formed on the surfaces of different substrates in Examples 3, 4, and 5 was evaluated using a rotational rheometer (ARES / RFSⅡ, TA Instruments). The test conditions were as follows: different test samples were cut into samples with a radius of 5 mm and subjected to a 3.5 s -1 A set of normal pressure (50 kPa) was applied to the sample at a shear rate of 100 μL, water was used as a lubricant, and a 100 μL microsyringe was used to add water at the interface to keep the hydrogel coating wet during the test. Figure 5 shown.

[0143] according to Figure 5 It can be seen that compared with the blank substrate, after the hydrogel lubricating coating is grafted on the surface of different substrates using the method of the present invention, the friction coefficient of the surface is significantly reduced, indicating that the method of the present invention can controllably graft the hydrogel lubricating coating on the surfaces of various materials.

[0144] 5.2 The hydrogel coating samples formed on the surface of the silica gel substrate in Examples 7, 8, and 9 were characterized by infrared spectroscopy using an attenuated total reflection Fourier transform infrared spectrometer (FTIR; Nicoleti S50, Thermal Scientific). The results were as follows: Figure 6 shown.

[0145] according to Figure 6 It can be seen that compared with the original substrate, after the method of the present invention is used to graft hydrogel coatings of different water-soluble monomers on the surface of the silica gel substrate, characteristic peaks of different monomers appear on its surface, indicating that the method of the present application can effectively graft hydrogel coatings formed by different water-soluble monomers on the surface of the substrate.

[0146] 6. Antifouling performance test

[0147] The polyvinyl alcohol hydrogel coating formed on the surface of the surface functionalized silica gel material prepared in Example 1 was subjected to an oil repellency test. The oleophobicity of the polyvinyl alcohol coating surface was demonstrated by the underwater oil contact angle. Nile red was added to the mineral oil to make the oil stain more obvious. The results were as follows: Figure 7 shown.

[0148] according to Figure 7 It can be seen from a that after the hydrogel coating is modified on the surface of the silica gel substrate by the method of the present application, the underwater oil contact angle of the surface is significantly increased; according to Figure 7 b It can be seen that after being fully in contact with mineral oil, there is almost no oil stain attached to the surface, while the surface of the uncoated silicone substrate is seriously contaminated by oil stains, indicating that the hydrogel coating modified on the surface of the silicone substrate by the method of the present application has anti-fouling properties.

[0149] 7. Antiplatelet and antithrombotic tests

[0150] The polyethylene oxide hydrogel coating formed in Example 2 was tested for anti-platelet and anti-thrombotic properties, and an uncoated polyurethane substrate was used as a control sample. The test conditions were as follows: the sample was incubated with rabbit platelet-rich plasma (PRP) or rabbit whole blood at 37°C for 1 hour. After washing, fixation, dehydration and gold spraying, the morphology of platelets or thrombi adhered to the sample surface was observed using a scanning electron microscope. The results were as follows: Figure 8 shown.

[0151] according to Figure 8 It can be seen that compared with a blank substrate, after the polyethylene oxide hydrogel coating is grafted onto the surface of the polyurethane substrate using the method of the present invention, the surface is almost difficult to adhere to activated platelets or form thrombi, indicating that the method of the present invention can successfully form anti-platelet and anti-thrombotic hydrogel coatings on medical polymer materials in biomedical applications.

[0152] 8. In vitro osteogenic differentiation ability test

[0153] The dextran-polylysine hydrogel coating formed in Example 6 was tested for its osteogenic differentiation ability in vitro, and the uncoated polyetheretherketone (PEEK) substrate was used as a control sample. The key sign of osteogenic differentiation is the formation of calcium nodules by osteomineralization. We used Alizarin Red S and Ca 2+ The chelation effect of the material prepared in Example 6 was obtained. After co-culture with human mesenchymal stem cells (hBM-MSCs) for 14 days, qualitative staining was performed. At the same time, the PEEK sheet stained with Alizarin Red S in the above example was dissolved using 10% (v / w) cetylpyridinium chloride (CPC, Sigma-Aldrich) sodium phosphate solution. The eluate was semi-quantitatively analyzed by microplate reader at 570 nm. The results were as follows: Figure 9 shown.

[0154] according to Figure 9It can be seen that compared with uncoated polyetheretherketone, after the method of the present invention is used to modify the polyetheretherketone surface with a dextran-polylysine hydrogel coating, it is beneficial to cell proliferation and differentiation and presents an obvious dark staining reaction. Semi-quantitative analysis shows that it is 45 times that of unmodified PEEK, indicating that the method of the present invention can successfully form a functional hydrogel coating with obvious in vitro osteogenic differentiation ability on medical polymer materials in biomedical applications.

[0155] The various embodiments in this specification are described in a progressive manner. The same or similar parts between the various embodiments can be referenced to each other, and each embodiment focuses on the differences from other embodiments.

[0156] The above embodiments are only used to illustrate the technical solutions of the present application, rather than to limit the present application. Although the present application has been described in detail with reference to the aforementioned embodiments, a person skilled in the art should understand that the technical solutions described in the aforementioned embodiments can still be modified, or some or all of the technical features therein can be replaced by equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the present application.

Claims

1. A method for modifying a hydrogel coating on the surface of a medical substrate, characterized in that the steps include: providing a hydrogel precursor solution; mixing the hydrogel precursor solution with N,N-methylenebisacrylamide, a water-soluble ferrous salt, and ascorbic acid to obtain a functional modification solution; After the organic peroxide and acrylic acid cross-linking agent are loaded on the surface of the medical substrate, the substrate is immersed in the functional modification solution to carry out a grafting reaction, thereby obtaining a medical material with a surface-modified hydrogel coating.

2. The method according to claim 1, characterized in that The main components of the hydrogel precursor solution are water and water-soluble polymers dispersed in the water; The water-soluble polymer is selected from at least one of polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, sodium polystyrene sulfonate, polyethylene oxide, polyquaternium-11, dextran, polylysine, methylcellulose and hyaluronic acid.

3. The method according to claim 2, characterized in that The hydrogel precursor solution is composed of water and a composition of dextran and polylysine dispersed in the water.

4. The method according to claim 1, wherein The main components of the hydrogel precursor solution are water and water-soluble monomers dispersed in water; The water-soluble monomer is selected from at least one of methacrylic acid, acrylic acid, acrylamide, hydroxyethyl acrylate, hydroxyethyl methacrylate, N-isopropylacrylamide, 2-acrylamido-2-methylpropanesulfonic acid, methacrylic acid sulfonate, dimethylaminoethyl methacrylate, methacryloylethyl carboxybetaine and methacryloylethyl sulfobetaine.

5. The method according to claim 1, wherein Every 100 parts by mass of the hydrogel precursor solution is mixed with: 0.01-1 parts by mass of N,N-methylenebisacrylamide, 0.01-5 parts by mass of a water-soluble ferrous salt and 1-5 parts by mass of ascorbic acid.

6. The method according to claim 1, characterized in that The medical substrate is selected from any one of silica gel, polyvinyl chloride, polyurethane, polyetheretherketone, polyimide, polyethylene, polypropylene, and ethylene-ethyl acetate copolymer.

7. The method according to claim 1, characterized in that The organic peroxide is selected from cumene hydroperoxide, tert-butyl perbenzoate or 2-butyl ketone peroxide.

8. The method according to claim 1, characterized in that The acrylic crosslinking agent is selected from ethylene glycol dimethacrylate, diethylene glycol diacrylate or triethylene glycol dimethacrylate.

9. The method according to claim 1, characterized in that The water-soluble ferrous salt is selected from at least one of ferrous chloride, ferrous sulfate, ferrous fumarate and ferrous gluconate.

10. The method according to claim 1, characterized in that The thickness of the hydrogel coating is 10 to 200 μm.

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