Medical product and preparation method thereof
By covalently bonding ultra-thin single-molecular phosphorylcholine coating on the surface of the substrate, the problems of uneven coating and micropore blockage in the prior art are solved, and the stability of the substrate structure and anti-protein adsorption ability are achieved, which is suitable for various medical devices.
Patent Information
- Application Number
- CN202311835992.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-12-28
- Publication Date
- 2025-07-01
AI Technical Summary
In the prior art, when the phosphorylcholine polymer coating is treated with irregular and/or rough surfaces, there are problems such as large coating thickness, unevenness, blocked micropores, weakened or covered by the basic structure, and coating is prone to fall off in implantable interventional medical devices, resulting in an increase in particulate matter in the body.
Ultra-thin single-layer phosphorylcholine coating is used to maintain the micropore or micro-nanostructure integrity of the substrate by covalent bonding to the surface of the substrate, and anti-protein adsorption and anti-thrombosis effects are achieved through reactive sites. The coating thickness does not exceed 10 nm.
The uniformity and stability of the coating are achieved, more than 80% of the substrate structure is maintained, protein adsorption is reduced by at least 20%, and biocompatibility and blood compatibility comparable to polymer coatings are avoided, micropore blockage and structural damage are avoided.
Smart Images
Figure CN120227518A_ABST
Abstract
Description
Technical Field
[0001] The present technology belongs to the field of material surface modification and biomedical materials, and specifically relates to a medical product with an ultra-thin chemical grafting coating that resists protein adsorption, and a preparation method and application thereof. Background Art
[0002] Based on the outer layer structure of the cell membrane, phosphorylcholine coating has been widely studied for its application in the surface modification of medical devices. A large number of studies have shown that phosphorylcholine coating can give materials good biocompatibility and tissue compatibility, and its application potential in artificial organs, tissue engineering, soft tissue, blood purification, etc. has been widely studied (Ma Jiani, Gong Ming, Yang Shan, et al. Synthesis and Application of 2-Methacryloyloxyethyl Phosphorylcholine Monomer and Its Polymer [J]. Progress in Chemistry, 2008).
[0003] Modification by constructing a phosphorylcholine polymer layer is a common idea for surface modification of biomedical materials. In order to achieve a good surface coating effect and enhance the binding force between the phosphorylcholine polymer and the substrate, the phosphorylcholine copolymer is generally polymerized by phosphorylcholine monomers, hydrophobic monomers and cross-linking monomers. However, both single-layer coating and multi-layer coating in the form of polymers have defects such as large coating thickness and uneven coating, which is particularly obvious in the case of medical devices with irregular and / or rough surfaces. In addition, when surface coating is performed on substrates with micro-nano structures and porous substrates such as filament devices or woven materials, the polymer, due to its inherent viscosity characteristics, will cause problems such as micropore blockage or uneven pore size in dense mesh devices or fiber materials. At the same time, for substrates with basic structures (such as micro-nano structures), polymer coatings often inevitably weaken or cover their basic structures, which is very unfavorable for the purpose of maintaining the basic structure.
[0004] Leaching of particulate matter in polymer coatings is another serious problem, especially in medium- to long-term implantable medical devices. After exposure to an aqueous environment (such as in the patient's body), incompletely cross-linked raw materials and shedding of coatings due to delamination or scratching will cause an increase in particulate matter in the body environment, leading to serious consequences.
[0005] Therefore, there is still a need for a coating that can provide complete, uniform and strong coverage of the substrate surface while maximally maintaining the basic structure of the substrate itself. Summary of the invention
[0006] To address the above deficiencies in the existing technologies, the present invention aims to provide an ultra-thin modified material modified with monolayer phosphorylcholine. The inventors surprisingly found that the monolayer phosphorylcholine coating can not only achieve a uniform and stable coating on the surface of medical biomaterials, but also maintain the underlying structure well for substrates / instruments with micro-nano and porous basic structures. In terms of coating performance, it also achieves biocompatibility and blood compatibility comparable to existing polymer coatings. In addition, the preparation process of this monolayer phosphorylcholine is simpler, facilitating the efficient modification of various shaped and special-structured instruments.
[0007] Solution for solving problems The present invention relates to a medical product. It includes a substrate surface having a microporous structure or micro-nano topological basic structure characteristics; and a monolayer coating material covalently bonded to at least a part of the substrate, the monolayer coating material having a phosphorylcholine structure and constituting a functional surface layer; the phosphorylcholine structure contains reactive sites and is bonded to the substrate through the reactive sites; The monolayer coating material is configured to resist protein adsorption and anti-thrombosis effects, and maintain more than 80% of the underlying structure of the substrate surface, measured by SEM.
[0008] When the substrate surface has a microporous structure, the monolayer coating material causes a change rate of the number or area of micropores per unit area not exceeding 5%; when the substrate surface has a micro-nano topological structure, the monolayer coating material causes a thickness change rate not exceeding 1% compared to the substrate itself.
[0009] Among them, the functional surface layer has a thickness of not more than 10 nm; more preferably, the functional surface layer has a thickness less than 5 nm or even lower.
[0010] Among them, in the functional surface layer, the existence ratio of phosphorus atoms relative to the existence amount of all atoms except hydrogen atoms is 0.01 - 2 atomic percentages, measured by X-ray photoelectron spectroscopy (XPS); more preferably, in the functional surface layer, the existence ratio of phosphorus atoms relative to the existence amount of all atoms except hydrogen atoms is 0.01 - 1 atomic percentage, measured by X-ray photoelectron spectroscopy (XPS).
[0011] Among them, the functional surface layer can reduce protein adsorption by at least 20% or more; preferably, the functional surface layer can reduce protein adsorption by at least 30% or more; more preferably, the functional surface layer can reduce protein adsorption by at least 40% or more.
[0012] In the present invention, the compound having a phosphorylcholine structure in the molecule has the general formula shown in Formula I as follows: In the formula, R2 represents an alkylene group having 1 to 10 carbon atoms, the R1 structure has a functionalized reactive site at the end, and the molecular weight of the general formula compound is 1000 or less.
[0013] Among them, the compound having a phosphorylcholine structure in the molecule is functionalized from a raw material represented by the following general formula II or general formula III: In the formula, R2 represents an alkylene group having 1 to 10 carbon atoms.
[0014] Among them, the medical product of the present invention further includes an intermediate layer between the substrate and the functional surface layer, and the intermediate layer is obtained by surface activation treatment and coupling agent treatment; the surface activation treatment includes acid treatment, alkali treatment, plasma treatment, chemical reagent treatment, etc.; the coupling agent treatment includes catechol substance treatment, silane coupling agent treatment, isocyanate treatment, etc.
[0015] Among them, the substrate is a substrate having fibers, pores, filaments, microspheres or a combination thereof.
[0016] The present invention also provides a method for preparing the medical product, which is characterized in that: (1) providing a substrate having a surface with a microporous structure or a micro-nano topological basic structure feature; (2) coating a dispersion liquid containing a compound represented by the following chemical formula I on the substrate surface; (3) and forming a monolayer coating material on the substrate surface by performing at least one treatment of chemical grafting, solvent evaporation, thermal curing, photo-curing, and radiation curing on the coated substrate. In the formula, R2 represents an alkylene group having 1 to 10 carbon atoms, the R1 structure has a functionalized reactive site at the end, and the molecular weight of the general formula compound is 1000 or less.
[0017] Furthermore, the concentration of the compound in the dispersion liquid is 0.01 mg / mL to 50 mg / mL.
[0018] Furthermore, the dispersion liquid contains a solvent selected from methanol, ethanol, isopropanol, n-butanol, water, ethylene glycol, diethylene glycol, polyethylene glycol, glycerol, propylene glycol, pentaerythritol, vinyl alcohol, polyvinyl alcohol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl acetate, toluene, chloroform, dichloromethane and combinations thereof.
[0019] Furthermore, the coating method is selected from at least one of dip coating, spraying, bar coating, brush coating, spin coating, electrospray and combinations thereof.
[0020] Effect of the invention The ultra-thin single-molecule phosphorylcholine layer of the present invention can maintain the surface structure of the substrate itself, without causing obvious changes in the surface of the microporous structure, micro-nano topological structure or woven structure during SEM observation, or generating coating accumulation, and will not damage the basic performance of the substrate. Moreover, it is covalently connected to the substrate through the end points and has no internal cross-linking sites, so it has better stability than the copolymer containing intramolecular cross-linking sites. Although the coating is ultra-thin, it can still obtain coating functions similar to polymer materials, such as having anti-protein adhesion ability and anti-thrombosis ability substantially equivalent to those of polymer coatings. Therefore, it is widely suitable for use in medical devices and medical instruments. Brief Description of the Drawings
[0021] Figure 1 SEM test diagrams of Example 1, Comparative Example 1 and Comparative Example 2 Figure 2 SEM test diagrams of Example 2 and Comparative Example 3 Embodiments
[0022] In order to better illustrate the present invention, numerous specific details are given in the following specific embodiments. Those skilled in the art should understand that the present invention can also be implemented without some specific details. In other instances, methods, means, equipment and steps well known to those skilled in the art are not described in detail in order to highlight the gist of the present invention.
[0023] Unless otherwise defined, the technical and scientific terms used in the present invention have the same meanings as those commonly understood by those of ordinary skill in the technical field to which the present invention belongs.
[0024] In this specification, the numerical range represented by "numerical value A~numerical value B" means a range including the end point numerical values A and B.
[0025] In this specification, the meaning expressed by "can" includes the meanings of both performing a certain process and not performing a certain process.
[0026] It should be understood that the singular form of the article "a" (corresponding to "a", "an" and "the" in English) used in the specification of this application and the appended claims includes plural objects, unless otherwise clearly specified in the text.
[0027] In this specification, the terms "one or some specific / preferred embodiments / schemes", "another or other specific / preferred embodiments / schemes", "one or another embodiment / scheme", "one or another technical scheme", etc. refer to specific elements (e.g., features, structures, properties, and / or characteristics) related to the described embodiment that are included in at least one of the embodiments described herein, and may or may not exist in other embodiments. Additionally, it should be understood that the elements may be combined in any suitable manner in various embodiments.
[0028] The terms "comprise" and any variations thereof in the specification and claims of the present invention are intended to cover non-exclusive inclusion. For example, a process, method, system, product, or device that comprises a series of steps or units is not limited to the listed steps or units, but optionally further comprises steps or units not listed, or optionally further comprises other steps or units inherent to these processes, methods, products, or devices.
[0029] Furthermore, the terms "first" and "second" are used only for descriptive purposes and should not be construed as indicating or implying relative importance or implicitly specifying the quantity of the indicated technical features. Thus, features defined with "first" and "second" may explicitly or implicitly include at least one of such features. In the description of the invention, the meaning of "a plurality of" is at least two, such as two, three, etc., unless otherwise specifically defined. In the description of the present invention, the meaning of "several" is at least one, such as one, two, etc., unless otherwise specifically defined.
[0030] In the present invention, the term "functionalization" and related terms include: a process of treating a material to change its surface properties to meet specific requirements for a particular application, or a process of providing a function that it normally does not have by adding groups to a chemical substance.
[0031] The medical article described in the present invention is characterized in that it has a substrate surface with a microporous structure or a micro-nano topological infrastructure feature; and a monolayer coating material covalently bonded to at least a part of the substrate, the monolayer coating material having a phosphocholine structure and constituting a functional surface layer; the phosphocholine structure contains reactive sites and is bonded to the substrate through the reactive sites; the monolayer coating material is configured to resist protein adsorption and anti-thrombotic effects, and the monolayer coating material is configured to maintain the substrate surface infrastructure by more than 80%, measured by SEM. Further, the monolayer coating material is configured to maintain the substrate surface infrastructure by more than 85%; more preferably, the monolayer coating material is configured to maintain the substrate surface infrastructure by more than 90%.
[0032] Here, the substrate refers to an organic material or an inorganic material, generally a polymer material or a metal material. In the present invention, there is no particular limitation on the material of the substrate, and polymer materials include polyester, polytetrafluoroethylene, polyurethane, polyether polyurethane, polyamide, vinyl chloride, polycarbonate, polystyrene, polyethylene, polypropylene, polymethylpentene, polymethyl methacrylate, various synthetic fibers, etc.; metal materials include stainless steel, titanium and alloys, cobalt-based alloys, magnesium alloys, shape memory alloys, etc.
[0033] The microporous structure or micro-nano topological basic structural feature refers to the characteristics of the substrate itself at a microscopic size, such as nano-microspheres, microfluidic devices, high-precision sensors, chips, etc.; or the micro-nano topological structure on the surface of the substrate, such as micro-nano structure patterning or surface roughening treatment; or the surface of the material with very small pores formed by weaving, expansion, overlapping, etc., such as porous expanded polytetrafluoroethylene, dense mesh stents composed of monofilaments, multifilaments, etc., or warp and weft fabric structures, etc. In general, for such substrates with microporous structures or micro-nano topological structures, although ordinary polymer coatings can give the surface certain functionality, they will sacrifice or destroy its surface microstructure at the expense of, for example, the polymer coating will form a net or accumulate at the overlap of micropores / woven wires, which is very unfavorable to the device.
[0034] The monolayer coating material refers to a coating material or nanofilm with a monolayer molecular thickness, which has a phosphorylcholine structure and is covalently bonded to the surface of the substrate. Since the phosphorylcholine structure has the characteristics of mimicking a cell membrane, it can give the substrate functions such as anti-protein adsorption, anti-bacterial adhesion, anti-thrombosis, and better blood compatibility, meeting the use of the substrate as a device material in contact with human tissues and body fluids for treatment or in vitro testing.
[0035] The phosphorylcholine structure contains reactive groups, including but not limited to aldehyde, thiol, hydroxyl, amino, carboxyl, azido, isocyanate, alkynyl, double bond, chlorinated hydrocarbon, etc. The reactive groups can chemically bond to the surface of the substrate to form a stable and firm functional surface layer.
[0036] The monolayer coating material has a surprising beneficial effect when combined with a substrate. Its thickness is small enough so as not to blur or cover the original microporous structure or micro-nano basic structure features of the substrate, or produce a coating accumulation situation. In the present invention, the monolayer coating material is configured to cause the maintenance of the basic structure of the substrate surface to be greater than 80%, measured by SEM. Further, the monolayer coating material is configured to cause the maintenance of the basic structure of the substrate surface to be greater than 85%; more preferably, the monolayer coating material is configured to cause the maintenance of the basic structure of the substrate surface to be greater than 90%.
[0037] Furthermore, when the surface of the substrate has a microporous structure, the change rate of the number or area of micropores per unit area caused by the monomolecular layer coating material does not exceed 5%; when the surface of the substrate has a micro-nano topological structure, the change rate of the thickness caused by the monomolecular layer coating material compared to the substrate itself does not exceed 1%.
[0038] The coating of the present invention, because it is chemically bonded to the surface of the substrate through a single molecular structure to form a monomolecular layer and has no internal crosslinking sites, the thickness of its coating can reach ultra-thin. Theoretically calculated, it can reach at least below 10 nm, and even reach a thickness of 5 nm or lower. Preferably, in the present invention, the functional surface layer has a thickness of not more than 10 nm; more preferably, the functional surface layer has a thickness of less than 5 nm or even lower. More preferably, the functional surface layer has a thickness of not more than 2 nm; further preferably, the functional surface layer has a thickness of not more than 1 nm.
[0039] In the present invention, in the functional surface layer, the existence ratio of phosphorus atoms relative to the existence amount of all atoms except hydrogen atoms is 0.01 to 2 atomic percentages, measured by X-ray photoelectron spectroscopy (XPS); more preferably, in the functional surface layer, the existence ratio of phosphorus atoms relative to the existence amount of all atoms except hydrogen atoms is 0.01 to 1 atomic percentage, measured by X-ray photoelectron spectroscopy (XPS).
[0040] Although the coating is ultra-thin, it can still obtain coating functions similar to polymer materials, such as having anti-protein adhesion ability and anti-thrombosis ability substantially equivalent to those of polymer coatings. The end-point connection method, without internal crosslinking sites, has better stability compared to copolymers containing intramolecular crosslinking sites, can better expose the phosphocholine structure, and play its function. In the present invention, compared with the untreated substrate surface, the functional surface layer can reduce protein adsorption by at least more than 20%, further preferably can reduce protein adsorption by at least more than 30%, and more preferably can reduce protein adsorption by at least more than 40%.
[0041] The anti-protein adsorption test can be detected by enzyme-linked reaction detection, isotope detection, etc., for example, it can be fibrinogen adsorption test, albumin adsorption test, etc.
[0042] Furthermore, the compound having a phosphocholine structure in the molecule has the following general formula I: In the formula, R2 represents an alkylene group having 1 to 10 carbon atoms. More preferably, it is an alkylene group having 1 to 5 carbon atoms. More preferably, it is an alkylene group having 2 to 3 carbon atoms. Most preferably, it is an alkylene group having 2 carbon atoms. The R1 structure has a functionalized reactive site at the end, and the molecular weight of the general formula compound is 1000 or less. Further, R1 is a linear or branched structure with a functionality greater than 1. Preferably, the functionality is 1 to 3 carbon atoms, and more preferably, it is a linear group with a functionality of 1 to 2.
[0043] The terminal functionalized reactive sites include, but are not limited to, aldehyde groups, mercapto groups, hydroxyl groups, amino groups, carboxyl groups, azide groups, isocyanate groups, alkynyl groups, double bonds, chloroalkanes, acrylate groups, methacrylate groups, etc. As long as it can produce a covalent bonding effect with the substrate surface, it is within the protection scope of the present invention.
[0044] The compound having a phosphocholine structure in the molecule may be one or a mixture of several of the above general formula compounds.
[0045] In some specific embodiments of the present invention, further preferably, the suitable compounds having a phosphocholine structure in the molecule according to the present invention include one or more compounds having the following structures: Further, the compound having a phosphocholine structure in the molecule can be functionalized from raw materials represented by the following formula II or formula III: In the formula, R2 represents an alkylene group having 1 to 10 carbon atoms. More preferably, it is an alkylene group having 1 to 5 carbon atoms. More preferably, it is an alkylene group having 2 to 3 carbon atoms. Most preferably, it is an alkylene group having 2 carbon atoms.
[0046] In the present invention, a transition layer is further included between the substrate and the functional surface layer. The presence of the transition layer can provide reactive sites for some substrates without reactive functional groups, or can provide more uniform and dense reactive sites on the substrate surface, which is beneficial to the reactive covalent bonding of the subsequent monolayer coating material. The transition layer is obtained by surface activation treatment and coupling agent treatment. The surface activation treatment includes acid treatment, alkali treatment, chemical reagent treatment, plasma treatment, corona discharge treatment, radiation irradiation treatment, heat treatment, etc.; the coupling agent treatment includes catechol substance treatment, silane coupling agent treatment, isocyanate treatment, etc.
[0047] The present invention also provides a method for preparing the medical product. (1) Provide a substrate having a surface with a microporous structure or a micro-monomolecular topological basic structure feature; (2) Coat a dispersion liquid containing a compound represented by the following chemical formula I on the substrate surface; (3) And form a monolayer coating material on the substrate surface by performing at least one treatment of chemical grafting, solvent evaporation, thermal curing, photo-curing, and radiation curing on the coated substrate. In the formula, R2 represents an alkylene group having 1 to 10 carbon atoms, more preferably an alkylene group having 1 to 5 carbon atoms, still more preferably an alkylene group having 2 to 3 carbon atoms, and most preferably an alkylene group having 2 carbon atoms. The R1 structure has a functionalized reactive site at its end, and the molecular weight of the general formula compound is 1000 or less. Further, R1 is a straight-chain or branched-chain structure with a functionality greater than 1. Preferably, the functionality is 1 to 3 carbon atoms, and more preferably a straight-chain group with a functionality of 1 to 2. A higher functionality can obtain more reactive groups, and the higher the chemical grafting efficiency. The functionalized reactive sites include, but are not limited to, aldehyde groups, mercapto groups, hydroxyl groups, amino groups, carboxyl groups, azide groups, isocyanate groups, alkynyl groups, double bonds, chloroalkanes, acrylate groups, methacrylate groups, etc. As long as it can produce a covalent bonding effect with the substrate surface, it is within the protection scope of the present invention.
[0048] The compound having a phosphorylcholine structure in the molecule can be one or a mixture of several of the above general formula compounds.
[0049] In the present invention, the substrate having a surface with microstructural or nano-structural features can be some medical products. On the one hand, it can be that the substrate itself has a small size or a fine structure, such as nano microspheres, microfluidic devices, small-diameter vascular devices, etc.; or the substrate surface has a micro-nano topological structure, such as a micro-nano structured patterned surface; or a material surface formed by weaving, expansion, overlapping, etc. with very small pores, such as porous expanded polytetrafluoroethylene, a dense mesh stent composed of monofilaments, multifilaments, etc., or a fabric structure of warp and weft yarns.
[0050] Of course, the ultra-thin single-molecule phosphorylcholine layer of the present invention can also be used to coat almost any medical product, such as a medical device that expects to provide a stable functional coating on its surface. Exemplary medical products include drug delivery vascular stents, other vascular devices (such as: grafts, catheters, valves, artificial hearts, heart assist devices), implantable defibrillators, blood oxygenator devices (such as: pipes, membranes), surgical devices, cell culture equipment, biosensors, wound treatment devices, endoscopic devices, orthopedic equipment, dental instruments, urological instruments, colostomy bag attachment devices, ophthalmic equipment, intraocular lenses, equipment required for dialysis, etc.
[0051] In the present invention, the curing method of the coating is not limited. It includes, but is not limited to, chemical grafting in solution state, solvent evaporation, thermal curing, photo-curing, radiation curing, etc.
[0052] In a preferred embodiment of the present invention, the concentration of the compound in the dispersion is 0.01 mg / mL to 50 mg / mL. When the concentration of the compound is too low, the coating amount caused by its covalent bonding with the substrate decreases, so it is difficult to obtain high anti-protein adsorption properties and high anti-thrombogenicity, and preferably it is 0.1 mg / mL or more. On the other hand, the upper limit of the compound concentration is not overly restricted, preferably 20 mg / mL or less, and more preferably 10 mg / mL or less.
[0053] In a preferred embodiment of the present invention, the selection of the dispersion is not overly restricted, including but not limited to solvents such as methanol, ethanol, isopropanol, n-butanol, water, ethylene glycol, diethylene glycol, polyethylene glycol, glycerol, propylene glycol, pentaerythritol, vinyl alcohol, polyvinyl alcohol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl acetate, toluene, chloroform, dichloromethane and their combinations.
[0054] In a preferred embodiment of the present invention, the coating method can be adaptively selected from at least one of dip coating, spraying, bar coating, brush coating, spin coating, electrospray and their combinations according to the processing requirements or processes of the actual sample. Examples
[0055] Referring to the above implementation content, in order to make the technical solution of the present application more specific, clear and easy to understand, the technical solution of the present application is now exemplified. However, it should be noted that the content to be protected by the present application is not limited to the following examples. Examples
[0056] Select a hollow dialysis fiber as the sample and perform a cleaning treatment. Then, after plasma treatment for 5 minutes, completely immerse the sample in an aqueous solution of KH-550 with a concentration of 1% (v%). After reacting at 70 °C for 2 hours, clean and dry the surface moisture. Then immerse the sample in a methanol solution of 2-methacryloyloxyethyl phosphorylcholine at 10 mg / ml. After curing at 60 °C for 24 hours, rinse the residual sample on the surface and dry it. Examples
[0057] Select a PDMS material with a microstructure on the surface as the sample and perform a cleaning treatment. The microstructure can be prepared by one or more of etching, imprinting, casting, stamping methods. The PDMS material of this sample is a cylindrical groove structure formed on the surface by the casting method. Then, after treating the sample with an ozone generator for 10 minutes, immerse it in an aqueous solution of KH-550 with a concentration of 1% (v%). After reacting at 70 °C for 2 hours, clean to remove the residual solution on the sample surface, and dry the surface moisture at 70 °C to obtain the pretreated PDMS material.
[0058] The aldehyde group-functionalized phosphorylcholine is prepared by the following method: Dissolve 1.8 g of glycerophosphorylcholine and 3.0 g of sodium periodate in 60 mL of purified water. Dropwise add 0.6 g of ethylene glycol at 5 °C and continue stirring for 15 h. After the reaction is completed, freeze-dry to remove the deionized water therein to obtain aldehyde group phosphorylcholine. Prepare an aqueous solution of 200 mL of 0.2 mg / ml with the aldehyde group phosphorylcholine and add 8 mg of sodium borohydride and mix evenly. Then immerse the pretreated PDMS material into the above-mentioned aldehyde group phosphorylcholine solution. After curing at 50 °C for 2 hours, take out the sample, rinse the residual solution on the surface and dry it. Example
[0059] Select a stainless steel sheet as the sample and perform cleaning and etching treatment. Then pretreat the sample in the same manner as in Example 1. Prepare the aldehyde group-functionalized phosphorylcholine according to the method of Example 2. Then prepare an aqueous solution of 200 mL of 4 mg / ml with the aldehyde group phosphorylcholine and add 8 mg of sodium borohydride and mix evenly. Then immerse the pretreated stainless steel sheet material into the above-mentioned aldehyde group phosphorylcholine solution. After curing at 50 °C for 2 hours, take out the sample, rinse the residual solution on the surface and dry it. Example
[0060] Same as Example 1, only replace the sample with a TPU sheet.
[0061] Comparative example 1 Hollow dialysis fibers without coating treatment.
[0062] Comparative example 2 Prepare phosphorylcholine polymer: Weigh 2.95 g of 2-methacryloyloxyethyl phosphorylcholine, 5.69 g of n-butyl methacrylate and 40 mg of azobisisobutyronitrile and dissolve them in 50 mL of absolute ethanol. React at 60 °C for 16 h under a nitrogen atmosphere. Perform post-treatment by precipitation with ether and obtain the phosphorylcholine polymer after drying.
[0063] Prepare a phosphorylcholine polymer coating: Dissolve 1 g of phosphorylcholine polymer in 100 mL of absolute ethanol to prepare a coating solution; then immerse the cleaned hollow dialysis fibers in the coating solution for 20 min, and then take out the hollow dialysis fibers and dry them at 50 °C for 2 hours to obtain a phosphorylcholine polymer coating sample.
[0064] Comparative example 3 PDMS material with a microstructure on the surface without coating treatment.
[0065] Comparative example 4 Stainless steel sheet material without coating treatment.
[0066] Test example 1 Surface topography characterization The surface coating morphology of the sample was observed by scanning electron microscope.
[0067] The SEM test diagrams of Example 1, Comparative Example 1 and Comparative Example 2 are as Figure 1 shown. It has been found that the hollow dialysis fiber sample with the monolayer coating material causes a significant maintenance of the microstructure of the dense mesh / microporous substrate compared to the hollow dialysis fiber sample with the polymer layer. Specifically, after the ultra-thin monolayer treatment of the present invention, the maintenance rate of the microstructure of the hollow dialysis fiber material can reach more than 80%. And according to the number or area of micropores per unit area of statistics, the change before and after is no more than 5%.
[0068] The SEM test diagrams of Example 2 and Comparative Example 3 are as Figure 2 shown. The surface of the test sample has a cylindrical groove structure formed by the casting method. It is also found that for the PDMS membrane material with circular micro-nano structures on the surface, through the monolayer treatment of the present invention, the cylindrical groove microstructure on the surface can be significantly maintained, and the coating will not cause accumulation in the topological structure. Compared with the substrate itself, the thickness change is no more than 1%.
[0069] Test example 2 Detection of surface phosphorus element content The phosphorus element content on the surface of the material was detected by X-ray photoelectron spectroscopy. The test data are as described in Table 1.
[0070] Table 1 Test of phosphorus element content on the coating surface Example 3 Comparative example 4 Phosphorus element content / % 0.3 2.2 Test example 3 Coating thickness measurement The surface coating morphology of the sample was observed by scanning electron microscope and the coating thickness was measured. The test data are as described in Table 2. Specifically, for the coating of the present invention, since it forms a monolayer by chemical bonding of the terminal chemical bond of a single molecular structure to the surface of the substrate, its thickness can reach ultra-thin, and theoretically it can reach at least below 10 nm, and even reach a thickness of 5 nm or lower.
[0071] Table 2 Test of coating thickness Example 2 Example 3 Comparative example 2 Coating thickness / nm Not detected Not detected 736 Test example 4 Protein adsorption test The protein adsorption test on the surface of the sample was carried out by a fibrinogen (Fg) protein detection kit. The test data are shown in Table 3 below. Specifically, for the coating of the present invention, with the respective bare substrates as control samples, the calculation of protein adsorption reduction was carried out. The test found that the monolayer structure of the present invention can reduce protein adsorption, and although it is an ultra-thin coating, it can basically reach the same level of anti-protein adsorption as the polymer coating.
[0072] Table 3 Protein adsorption situation Example 1 Comparative example 1 Comparative example 2 Example 3 Comparative example 4 Protein adsorption amount / OD value 0.46 0.78 0.41 0.44 0.81 Protein adsorption reduction / % 41% / 47% 46% /
Claims
1. A medical product, characterized in that, The medical product includes: a substrate surface having a microporous structure or a micro-nano topological infrastructure feature; and a monolayer coating material covalently bonded to at least a part of the substrate, the monolayer coating material having a phosphorylcholine structure and constituting a functional surface layer; the phosphorylcholine structure contains reactive sites and is bonded to the substrate through the reactive sites; The monolayer coating material is configured to maintain more than 80% of the substrate surface infrastructure, measured by SEM.
2. The medical article according to claim 1, wherein, When the substrate surface has a microporous structure, the monolayer coating material causes a change rate of the number or area of micropores per unit area not exceeding 5%; when the substrate surface has a micro-nano topological structure, the monolayer coating material causes a thickness change rate not exceeding 1% compared to the substrate itself.
3. The medical article according to claim 1 or 2, wherein, The functional surface layer has a thickness of not more than 10 nm; more preferably, the functional surface layer has a thickness of less than 5 nm or even lower.
4. The medical article according to claim 3, wherein, In the functional surface layer, the presence ratio of phosphorus atoms relative to the presence amount of all atoms except hydrogen atoms is 0.01 to 2 atomic percentages, determined by X-ray photoelectron spectroscopy (XPS); more preferably, in the functional surface layer, the presence ratio of phosphorus atoms relative to the presence amount of all atoms except hydrogen atoms is 0.01 to 1 atomic percentage, determined by X-ray photoelectron spectroscopy (XPS).
5. The medical article according to claim 1, wherein The functional surface layer can reduce protein adsorption by more than 20%; preferably, the functional surface layer can reduce protein adsorption by more than 30%; more preferably, the functional surface layer can reduce protein adsorption by more than 40%.
6. The medical article according to claim 1, wherein The compound having a phosphocholine structure in the molecule has the general formula shown in the following formula I: In the formula, R2 represents an alkylene group having 1 to 10 carbon atoms, the end of the R1 structure contains a functionalized reactive site, and the molecular weight of the general formula compound is 1000 or less.
7. The medical article according to claim 6, wherein The compound having a phosphocholine structure in the molecule is functionalized from raw materials represented by the following general formula II or general formula III: In the formula, R2 represents an alkylene group having 1 to 10 carbon atoms.
8. The medical article according to claim 1, wherein It further includes a transition layer between the substrate and the functional surface layer, the transition layer obtained by surface activation treatment and coupling agent treatment; the surface activation treatment includes acid treatment, alkali treatment, plasma treatment, chemical reagent treatment, etc.; the coupling agent treatment includes catechol substance treatment, silane coupling agent treatment, isocyanate treatment, etc.
9. The medical article according to any one of claims 1-8, characterized in that, The substrate is a substrate having fibers, pores, filaments, microspheres or a combination thereof.
10. A method for preparing a medical product according to any one of claims 1-9, characterized in that, (1) Provide a substrate having a surface with a microporous structure or a micro-nano topological infrastructure feature; (2) Coat the surface of the substrate with a dispersion containing a compound represented by the following Chemical Formula I; (3) And form a monolayer coating material on the surface of the substrate by performing at least one treatment of chemical grafting, solvent evaporation, thermal curing, photo-curing, and radiation curing on the coated substrate. In the formula, R2 represents an alkylene group having 1 to 10 carbon atoms, the structure end of R1 contains a functionalized reactive site, and the molecular weight of the general formula compound is 1000 or less.
11. The method for preparing a medical product according to claim 10, wherein, The substrate is subjected to a transition layer treatment before step (2).
12. The preparation method of the medical product according to any one of claims 10 or 11, characterized in that, The concentration of the compound in the dispersion is 0.01 mg / mL to 50 mg / mL.
13. The method for preparing a medical product according to any one of claims 10 or 11, characterized in that, The dispersion contains a solvent selected from methanol, ethanol, isopropanol, n-butanol, water, ethylene glycol, diethylene glycol, polyethylene glycol, glycerol, propylene glycol, pentaerythritol, vinyl alcohol, polyvinyl alcohol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl acetate, toluene, chloroform, dichloromethane and combinations thereof.
14. The method for preparing a medical product according to any one of claims 10 or 11, characterized in that, Wherein the coating method is selected from at least one of dip coating, spray coating, bar coating, brush coating, spin coating, electrospray and combinations thereof.