Medical product and preparation method therefor

Abstract

The present invention relates to a method for modifying surface performance of a material with phosphorylcholine and a resulting medical product. The medical product comprises a substrate surface with a microporous structure or micro-nano topological basal structure feature, and an ultra-thin monomolecular phosphorylcholine layer covalently bonded to at least a part of the substrate. The monomolecular phosphorylcholine layer is configured to maintain over 80% of the basal structure of the substrate surface, as measured by SEM.

Description

Medical product and preparation method thereof Technical Field

[0001] This 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, as well as its preparation method and application. Background Art

[0002] Based on its structure, which mimics the outer layer of the cell membrane, phosphorylcholine coatings are being widely studied for their application in medical device surface modification. Numerous studies have shown that phosphorylcholine coatings can impart excellent biocompatibility and tissue compatibility to materials, leading to extensive research into their potential applications in artificial organs, tissue engineering, soft tissue, and blood purification (Ma Jiani, Gong Ming, Yang Shan, et al. Synthesis and Application of 2-Methacryloxyethyl Phosphorylcholine Monomers and Polymers [J]. Progress in Chemistry, 2008).

[0003] Modification by constructing a phosphorylcholine polymer layer is a common approach to surface modification of biomedical materials. To achieve a good surface coating effect and enhance the binding force of phosphorylcholine polymers to substrates, phosphorylcholine copolymers are generally polymerized by phosphorylcholine monomers, hydrophobic monomers, and cross-linking monomers. However, both single-coating and multi-layer coatings in polymer form have defects such as excessively large coating thickness and uneven coatings, which are particularly evident in the case of medical devices with irregular and / or rough surfaces. In addition, when surface coating is performed on micro-nanostructured and porous substrates such as filamentous devices or braided materials, the polymer, due to its inherent viscosity characteristics, can cause problems such as micropore blockage or uneven pore size in dense mesh devices or fiber materials. Simultaneously, for substrates with infrastructure (e.g., micro-nanostructured) themselves, polymer coatings often inevitably weaken or cover their infrastructure, which is very disadvantageous for maintaining the infrastructure.

[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 the patient's body), uncrosslinked 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-mentioned deficiencies in the prior art, the present invention aims to provide an ultra-thin monolayer phosphorylcholine-modified modified material. The inventors surprisingly discovered that a monolayer phosphorylcholine coating not only achieves uniform and stable coating on the surface of medical biomaterials, but also effectively maintains the underlying structure of substrates / devices with micro-nano and porous structures. The coating also achieves biocompatibility and blood compatibility comparable to existing polymer coatings. Furthermore, the preparation process of this monolayer phosphorylcholine is simpler, facilitating efficient modification of various shapes and special-structured devices, while also improving its binding properties to the substrate surface and durability.

[0007] Solutions for solving problems

[0008] The present invention relates to a medical product comprising a substrate surface having a microporous structure or a micro-nano topological basic structure feature;

[0009] and a monomolecular layer coating material covalently bonded to at least a portion of the substrate, wherein the monomolecular layer coating material has a phosphorylcholine structure and constitutes a functional surface layer; the phosphorylcholine structure contains reactive sites and is bonded to the substrate via the reactive sites;

[0010] The monolayer coating material is configured to resist protein adsorption and anti-thrombotic effects and results in greater than 80% maintenance of the substrate surface infrastructure as measured by SEM.

[0011] 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 thickness change rate caused by the monomolecular layer coating material compared to the substrate itself does not exceed 1%.

[0012] Wherein, the functional surface layer has a thickness of no more than 10 nm; more preferably, the functional surface layer has a thickness of less than 5 nm or even lower.

[0013] In which, in the functional surface layer, the ratio of phosphorus atoms to the total amount of atoms except hydrogen atoms is 0.01 to 2 atomic%, as determined by X-ray photoelectron spectroscopy (XPS); more preferably, in the functional surface layer, the ratio of phosphorus atoms to the total amount of atoms except hydrogen atoms is 0.01 to 1 atomic%, as determined by X-ray photoelectron spectroscopy (XPS).

[0014] The functional surface layer can reduce protein adsorption by at least 20%; preferably, the functional surface layer can reduce protein adsorption by at least 30%; further preferably, the functional surface layer can reduce protein adsorption by at least 40%.

[0015] In the present invention, the compound having a phosphorylcholine structure in the molecule has the general formula shown in the following formula I:

[0016] In the formula, R2 represents a C1-C10 alkylene group, the terminal of the R1 structure contains a functionalized reactive site, and the molecular weight of the compound of the general formula is 1000 or less.

[0017] The compound having a phosphorylcholine structure in the molecule is obtained by functionalizing a raw material of the general formula shown in Formula II or Formula III below:

[0018] In the formula, R2 represents a C1-C10 alkylene group.

[0019] Among them, the medical product described in the present invention also includes a transition layer between the substrate and the functional surface layer, and the transition 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 treatment, silane coupling agent treatment, isocyanate treatment, etc.

[0020] The substrate is a substrate having fibers, pores, filaments, microspheres or a combination thereof.

[0021] The present invention also provides a method for preparing the medical product, characterized by: (1) providing a substrate having a surface with a microporous structure or a micro-nano topological basic structure feature; (2) coating the surface of the substrate with a dispersion containing a compound represented by the following chemical formula I; (3) forming a monomolecular layer of coating material on the surface of the substrate by subjecting the coated substrate to at least one of chemical grafting, solvent evaporation, thermal curing, photocuring, and radiation curing.

[0022] In the formula, R2 represents a C1-C10 alkylene group, the terminal of the R1 structure contains a functionalized reactive site, and the molecular weight of the compound is 1000 or less.

[0023] Furthermore, the concentration of the compound in the dispersion is 0.01 mg / mL to 50 mg / mL.

[0024] Furthermore, the dispersion comprises 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.

[0025] Furthermore, the coating method is selected from at least one of dip coating, spray coating, rod coating, brush coating, spin coating, electrospraying, and combinations thereof.

[0026] Effects of the Invention

[0027] The ultrathin monomolecular phosphorylcholine layer of the present invention can maintain the surface structure of the substrate itself, does not cause the surface of the microporous structure, micro-nano topological structure or woven structure to change significantly during SEM observation, or produces the accumulation of the coating, and does not damage the basic performance of the substrate. Moreover, it has no internal cross-linking sites by covalently linking the end points to the substrate, and has better stability than copolymers containing intramolecular cross-linking sites. Although the coating is ultrathin, it can still obtain the coating function of similar polymer materials and has good durability in use, for example, it has anti-protein adhesion and anti-thrombotic ability substantially equivalent to the polymer coating, and can provide better anti-shedding performance. Therefore, it can be widely used in medical equipment and medical instruments. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1, SEM test images of Example 1, Comparative Example 1 and Comparative Example 2

[0029] Figure 2, SEM test images of Example 2 and Comparative Example 3 DETAILED DESCRIPTION

[0030] To better illustrate the present invention, numerous specific details are provided in the following detailed description. Those skilled in the art will appreciate that the present invention can be practiced without certain 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 main points of the present invention.

[0031] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0032] In this specification, the numerical range expressed using "a numerical value A to a numerical value B" means a range including the endpoints A and B.

[0033] In this specification, the use of "may" includes both the meaning of performing a certain process and the meaning of not performing a certain process.

[0034] It will be understood that as used in this specification and the appended claims, the singular articles "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0035] In this specification, references to "one or some specific / preferred embodiments / solutions," "another or other specific / preferred embodiments / solutions," "one or another embodiment / solution," "one or another technical solution," etc., mean that the specific elements (e.g., features, structures, properties, and / or characteristics) related to the embodiment described are included in at least one embodiment described herein, and may or may not exist in other embodiments. In addition, it should be understood that the elements may be combined in various embodiments in any appropriate manner.

[0036] The term "comprises" and any variations thereof in the description and claims of the present invention are intended to cover non-exclusive inclusions. For example, a process, method, system, product, or apparatus comprising a series of steps or elements is not limited to the listed steps or elements, but may optionally include steps or elements not listed, or may optionally include other steps or elements inherent to the process, method, product, or apparatus.

[0037] In addition, the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of such features. In the description of the invention, the meaning of "multiple" is at least two, such as two, three, etc., unless otherwise clearly and specifically defined. In the description of the present invention, the meaning of "several" is at least one, such as one, two, etc., unless otherwise clearly and specifically defined.

[0038] As used herein, the term "functionalization" and related terms include the process of treating a material to modify its surface properties to meet specific requirements for a particular application, or the process of adding groups to a chemical substance to provide functionality it does not normally possess.

[0039] The medical product of the present invention is characterized by a substrate surface having a microporous structure or a micro-nanotopological basic structure; and a monolayer coating material covalently bonded to at least a portion of the substrate, wherein the monolayer coating material has a phosphorylcholine structure and constitutes 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-thrombotic effects, and the monolayer coating material is configured to maintain the basic structure of the substrate surface to a degree greater than 80%, which can be measured using SEM, for example, by determining the area retention rate of the open holes before and after monolayer treatment in the same area. Furthermore, the monolayer coating material is configured to maintain the basic structure of the substrate surface to a degree greater than 85%; more preferably, the monolayer coating material is configured to maintain the basic structure of the substrate surface to a degree greater than 90%. As for the quantitative method of the surface infrastructure maintenance degree of the present invention, from the perspective of improving the convenience of measurement, the (specific) surface area can also be used for characterization. For example, the ratio of the (specific) surface area S1 of the substrate after monolayer coverage to the (specific) surface area S0 of the original substrate is greater than 80%, preferably greater than 85%, and more preferably greater than 90%.

[0040] Here, the substrate refers to an organic material, an inorganic material, or a metal material, or a combination of any two or more thereof. Preferably, the substrate is generally a polymer material or a metal material, or a composite thereof. In the present invention, there is no particular limitation on the material of the substrate. Polymer materials include polyesters, polytetrafluoroethylene, polyurethane, polyether polyurethane, polyamide, vinyl chloride, polycarbonate, polystyrene, polyethylene, polypropylene, polymethylpentene, polymethyl methacrylate, and various synthetic fibers; inorganic materials include ceramic materials, carbon fiber materials, carbon nanotube materials, and metal materials include stainless steel, titanium and its alloys, cobalt-based alloys, magnesium alloys, and shape memory alloys.

[0041] The microporous structure or micro-nanotopological basic structural features described herein refer to the substrate itself as a feature at a microscopic scale, such as substrates of the size of nanospheres, microfluidic devices, high-precision sensors, chips, and the like. In some specific embodiments, the substrate surface has a micro-nanotopological structure, such as a patterned micro-nanostructure or a surface roughening treatment. In other embodiments, the substrate has a material surface with very small pores formed by weaving, expansion, or overlapping, such as porous expanded polytetrafluoroethylene, a dense mesh scaffold composed of monofilaments or multifilaments, or a fabric structure of warp and weft yarns. The pore size can range from nanometers to micrometers.

[0042] Generally, for substrates with microporous or micro-nanotopological structures, ordinary polymer coatings can impart certain functionality to the surface, but this is at the expense of or destruction of the surface microstructure. For example, the polymer coating may form a web or accumulate at the intersection of the micropores / braided wires, which is very unfavorable for the device.

[0043] Because in the field of medical devices, these devices are usually used to treat or support specific physiological structures, such as blood vessels or other internal organs. They are small in size and complex in shape, so they require high-precision manufacturing processes and extremely small tolerance control. Taking dense mesh stents as an example, the design of this type of device mainly uses a fine mesh structure to provide the necessary mechanical support, and maintains blood flow through these pores, thereby avoiding the formation of thrombi and promoting local tissue regeneration. During the application of dense mesh stents, the size and structural stability of the mesh are key to ensuring its function. If these meshes are affected by the thickness of the coating and blocked, the blood flow function of the stent will be severely weakened, and may even become a source of thrombosis, bringing serious clinical risks. For example, in high-end medical equipment such as ECMO (extracorporeal membrane oxygenation) systems, hollow fiber membranes are one of the key components, especially for the exchange of oxygen and carbon dioxide. Maintaining ventilation rates and effective gas exchange capabilities is crucial for these hollow fibers, and the ultrathin nature of the coating plays a crucial role in this process, ensuring the integrity of the membrane surface structure and the permeability of the pores, maintaining the highest gas exchange efficiency; at the same time, it reduces thrombosis, lowers the mechanical burden and fluid resistance of the membrane, and improves the biocompatibility and long-term durability of the membrane. Therefore, the ultrathin coating not only ensures the functionality and safety of the ECMO system, but also provides more stable therapeutic effects during long-term use.

[0044] However, existing coating technologies are generally unable to effectively control the thickness of the coating. In many cases, excessively thick coatings can lead to blockage of the stent pores. The pores of the stent should remain open to allow blood flow and the growth of endothelial cells, but excessively thick coatings can directly cover or block these pores, hindering blood flow. If this occurs, not only will the stent's original anti-thrombotic function not be fulfilled, but the restricted local blood flow may form a new source of thrombus, leading to more serious complications such as vascular embolism and local thrombosis. In severe cases, it may even lead to stent implantation failure or device removal.

[0045] Furthermore, coating thickness not only affects pore permeability but may also impact the mechanical properties of dense-mesh stents. For example, excessively thick coatings can increase the stent's overall bulk and rigidity, limiting its ability to expand within a vessel or affecting its fit with surrounding tissue. These factors can potentially prevent the medical device from achieving its intended therapeutic effect in practical applications.

[0046] The monolayer coating material refers to a coating material or nanofilm having a thickness on the order of a monolayer molecule, comprising a phosphorylcholine structure and covalently bonded to the surface of the substrate. The monolayer of the present invention is primarily formed by a two-dimensional arrangement of monomolecules. Therefore, its maximum thickness does not exceed 10 nm, preferably does not exceed 5 nm. Generally, the average thickness of the monolayer can be less than 2 nm, or even less than 1 nm, or less than 0.8 nm.

[0047] Because the structure of phosphorylcholine has the characteristics of mimicking the 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.

[0048] The phosphorylcholine structure contains reactive groups, including but not limited to aldehyde, sulfhydryl, 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 strong functional surface layer.

[0049] The monolayer coating material has surprisingly beneficial effects when combined with a substrate. Its thickness is sufficiently small so as not to obscure or cover the original microporous structure or micro-nanostructure features of the substrate, or cause coating accumulation. In the present invention, the monolayer coating material is configured to maintain greater than 80% of the substrate surface structure, as measured by SEM. Furthermore, the monolayer coating material is configured to maintain greater than 85% of the substrate surface structure; more preferably, the monolayer coating material is configured to maintain greater than 90% of the substrate surface structure.

[0050] 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 monolayer coating material does not exceed 5%; when the surface of the substrate has a micro-nano topological structure, the thickness change rate caused by the monolayer coating material compared to the substrate itself does not exceed 1%.

[0051] Because the coating of the present invention chemically bonds to the substrate surface through a single molecular structure to form a monomolecular layer and lacks internal crosslinking sites, its coating thickness can be ultra-thin. Theoretically, the maximum thickness can reach at least 10 nm or less, and even 5 nm or less. Preferably, in the present invention, the functional surface layer has a maximum thickness of no more than 10 nm; more preferably, the functional surface layer has a maximum thickness of less than 5 nm or even less. More preferably, the functional surface layer has an average thickness of no more than 2 nm; even more preferably, the functional surface layer has a thickness of no more than 1 nm.

[0052] In the present invention, in the functional surface layer, the ratio of phosphorus atoms to the total amount of atoms excluding hydrogen atoms is 0.01 to 2 atomic %, as measured by X-ray photoelectron spectroscopy (XPS); more preferably, in the functional surface layer, the ratio of phosphorus atoms to the total amount of atoms excluding hydrogen atoms is 0.01 to 1 atomic %, as measured by X-ray photoelectron spectroscopy (XPS), which can be listed as 0.05 atomic %, 0.10 atomic %, 0.20 atomic %, 0.30 atomic %, 0.40 atomic %, 0.50 atomic %, 0.60 atomic %, 0.70 atomic %, 0.80 atomic %, 0.90 atomic %, 1.10 atomic %, 1.20 atomic %, 1.30 atomic %, 1.40 atomic %, 1.50 atomic %, 1.60 atomic %, 1.70 atomic %, 1.80 atomic %, and 1.90 atomic %.

[0053] Despite its ultrathin nature, the coating still achieves coating properties similar to polymer materials, such as comparable anti-protein adhesion and anti-thrombotic capabilities. The end-point linkage approach, lacking internal crosslinking sites, offers improved stability compared to copolymers containing intramolecular crosslinking sites, allowing for better exposure of the phosphorylcholine structure and its functional performance. In the present invention, the functional surface layer can reduce protein adsorption by at least 20%, more preferably by at least 30%, and even more preferably by at least 40%, compared to an untreated substrate surface.

[0054] The anti-protein adsorption test can be performed by enzyme-linked reaction detection, isotope detection, etc., for example, it can be a fibrinogen adsorption test, an albumin adsorption test, etc.

[0055] Furthermore, the compound having a phosphorylcholine structure in the molecule has the following general formula I:

[0056] In the formula, R2 represents a C1-C10 alkylene group. More preferably, it is a C1-C5 alkylene group. More preferably, it is a C2-C3 alkylene group. Most preferably, it is a C2 alkylene group. The R1 structure terminal contains a functionalized reactive site, and the molecular weight of the compound of general formula (I) is 1000 or less. Furthermore, R1 is a linear or branched structure with a functionality greater than 1. Preferably, it is a linear or branched group with a functionality of 1-3, and more preferably, it is a linear group with a functionality of 1-2.

[0057] The reactive sites of terminal functionalization include, but are not limited to, aldehyde, thiol, hydroxyl, amino, carboxyl, azido, isocyanate, alkynyl, double bond, chlorinated hydrocarbon, acrylate, methacrylate, etc. As long as they can form a covalent bond with the substrate surface, they are within the scope of protection of the present invention.

[0058] The compound having a phosphorylcholine structure in the molecule can be one or a mixture of several of the compounds of the above general formula.

[0059] In some specific embodiments of the present invention, further preferably, the compounds having a phosphorylcholine structure in the molecule according to the present invention include one or more compounds of the following structures:

[0060] Furthermore, the compound having a phosphorylcholine structure in the molecule can be functionalized from a raw material of the following formula II or formula III:

[0061] In the formula, R2 represents a C1-C10 alkylene group, more preferably a C1-C5 alkylene group, more preferably a C2-C3 alkylene group, and most preferably a C2 alkylene group.

[0062] The present invention also includes a transition layer between the substrate and the functional surface layer. The presence of the transition layer can provide reactive sites for certain substrates lacking reactive functional groups, or it can provide more uniform and dense reactive sites on the substrate surface, facilitating the reactive covalent bonding of subsequent monolayer coating materials. The transition layer is obtained by surface activation and coupling agent treatment. Surface activation treatments include acid treatment, alkali treatment, chemical reagent treatment, plasma treatment, corona discharge treatment, radiation treatment, and heat treatment; coupling agent treatments include treatment with catechols, silane coupling agents, and isocyanates.

[0063] The present invention also provides a method for preparing the medical product. (1) Providing a substrate having a surface with a microporous structure or a micro-nanotopological basic structure feature; (2) Applying a dispersion containing a compound represented by the following chemical formula I to the surface of the substrate; (3) Forming a monomolecular layer of coating material on the surface of the substrate by subjecting the coated substrate to at least one of chemical grafting, solvent evaporation, thermal curing, photocuring, and radiation curing.

[0064] In the formula, R2 represents a C1-C10 alkylene group, more preferably a C1-C5 alkylene group. More preferably, it is a C2-C3 alkylene group. Most preferably, it is a C2 alkylene group. The R1 structure terminal contains a functionalized reactive site, and the molecular weight of the compound of the general formula is 1000 or less. Furthermore, R1 is a straight chain or branched structure with a functionality greater than 1. Preferably, it is a straight chain or branched group with a functionality of 1-3, and more preferably a straight chain group with a functionality of 1-2. A higher functionality can obtain more reactive groups, and the chemical grafting efficiency is higher.

[0065] The functionalized reactive sites include, but are not limited to, aldehyde, thiol, hydroxyl, amino, carboxyl, azido, isocyanate, alkynyl, double bond, chlorinated hydrocarbon, acrylate, methacrylate, etc. As long as they can form a covalent bond with the substrate surface, they are within the scope of protection of the present invention.

[0066] The compound having a phosphorylcholine structure in the molecule can be one or a mixture of several of the compounds of the above general formula.

[0067] In the present invention, substrates with microstructured or nanostructured surfaces can be medical products. In one aspect, the substrate itself can have microscopic dimensions or fine structures, such as nanospheres, microfluidic devices, and small-caliber vascular devices. Alternatively, the substrate surface can have micro- or nanoscale topological structures, such as a patterned micro- and nanostructured surface. Furthermore, the substrate surface can have very small pores formed by weaving, expansion, or overlapping, such as porous expanded polytetrafluoroethylene, dense mesh stents composed of monofilaments or multifilaments, or fabric structures composed of warp and weft yarns.

[0068] Of course, the ultrathin monomolecular phosphorylcholine layer of the present invention can also be used to coat almost any medical article, such as a medical device on whose surface it is desired to provide a stable functional coating. Exemplary medical articles include drug delivery vascular stents, other vascular devices (e.g., grafts, catheters, valves, artificial hearts, heart assist devices), implantable defibrillators, blood oxygenator devices (e.g., tubing, membranes), surgical devices, cell culture devices, biosensors, wound treatment devices, endoscopic devices, orthopedic devices, dental devices, urological devices, colostomy bag attachment devices, ophthalmic devices, intraocular lenses, dialysis equipment, and the like.

[0069] In the present invention, the curing method of the coating is not limited, including but not limited to chemical grafting in a dispersion state, solvent volatilization, thermal curing, light curing, radiation curing, etc.

[0070] 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 amount of coating caused by its covalent binding to the substrate is reduced, so it is difficult to obtain high anti-protein adsorption properties and high anti-thrombotic properties, preferably 0.1 mg / mL and above. On the other hand, there are not many restrictions on the upper limit of the compound concentration, preferably below 20 mg / mL, more preferably below 10 mg / mL. Further specific examples of dispersion concentrations include 0.1 mg / mL, 0.5 mg / mL, 1.0 mg / mL, 2.0 mg / mL, 3.0 mg / mL, 4.0 mg / mL, 5.0 mg / mL, 6.0 mg / mL, 7.0 mg / mL, 8.0 mg / mL, 9.0 mg / mL, etc.

[0071] In a preferred embodiment of the present invention, the choice of solvent in the dispersion is not overly limited, including but not limited to 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.

[0072] In a preferred embodiment of the present invention, the coating method can be adaptively selected from at least one of dip coating, spray coating, rod coating, brush coating, spin coating, electrospray coating, and combinations thereof according to the actual sample processing requirements or process.

[0073] Examples

[0074] With reference to the above implementation content, in order to make the technical solution of this application more specific, clear and easy to understand, the technical solution of this application is now given as an example. However, it should be noted that the content to be protected by this application is not limited to the following embodiments.

[0075] Example 1

[0076] Hollow dialysis fibers were cleaned and plasma-treated for 5 minutes. The samples were then immersed in a 1% (v%) KH-550 aqueous solution and allowed to react at 70°C for 2 hours. The surface moisture was then removed by rinsing and drying. The samples were then immersed in a 10 mg / ml methanol solution of 2-methacryloyloxyethyl phosphorylcholine and cured at 60°C for 24 hours. Any residual sample on the surface was then rinsed and dried.

[0077] Example 2

[0078] A PDMS material with a surface microstructure was selected as a sample and cleaned. The microstructure can be produced by one or more methods, such as etching, embossing, inverted molding, or stamping. The PDMS material in this sample has a cylindrical groove structure formed on the surface by the inverted molding method. The sample was then treated with an ozone generator for 10 minutes, immersed in a 1% (v%) KH-550 aqueous solution, reacted at 70°C for 2 hours, and then cleaned to remove residual solution from the sample surface. The surface moisture was then dried at 70°C to obtain a pretreated PDMS material.

[0079] Aldehyde-formyl phosphorylcholine was prepared by the following method: 1.8 g of glycerol phosphorylcholine and 3.0 g of sodium periodate were dissolved in 60 mL of purified water. At 5°C, 0.6 g of ethylene glycol was added dropwise with stirring for 15 hours. After the reaction, the deionized water was removed by freeze drying to obtain the aldehyde-formyl phosphorylcholine. The aldehyde-formyl phosphorylcholine was prepared in 200 mL of a 0.2 mg / mL aqueous solution, and 8 mg of sodium borohydride was added and mixed thoroughly. The pretreated PDMS material was then immersed in the aldehyde-formyl phosphorylcholine solution and cured at 50°C for 2 hours. The sample was then removed, rinsed of any residual solution on the surface, and dried.

[0080] Example 3

[0081] A stainless steel sheet was selected as a sample and cleaned and etched. The sample was then pretreated as in Example 1. Aldehyde-modified phosphorylcholine was prepared according to the method in Example 2. The aldehyde-modified phosphorylcholine was then prepared into 200 mL of a 4 mg / mL aqueous solution, and 8 mg of sodium borohydride was added and mixed thoroughly. The pretreated stainless steel sheet was then immersed in the aldehyde-modified phosphorylcholine solution and cured at 50°C for 2 hours. The sample was then removed, rinsed of any residual solution on the surface, and dried.

[0082] Example 4

[0083] Same as Example 1, except that the sample was replaced with a TPU sheet.

[0084] Comparative Example 1

[0085] Uncoated hollow dialysis fibers.

[0086] Comparative Example 2

[0087] Preparation of phosphorylcholine polymer: Dissolve 2.95 g of 2-methacryloyloxyethyl phosphorylcholine, 5.69 g of butyl methacryloyl ester, and 40 mg of azobisisobutyronitrile in 50 mL of anhydrous ethanol. React at 60°C for 16 h under nitrogen. Post-process with ether precipitation and dry to obtain the phosphorylcholine polymer.

[0088] Preparation of phosphorylcholine polymer coating: 1 g of phosphorylcholine polymer was dissolved in 100 mL of anhydrous ethanol to prepare a coating solution; the cleaned hollow dialysis fiber was then immersed in the coating solution for 20 minutes, and then the hollow dialysis fiber was removed and dried at 50° C. for 2 hours to obtain a phosphorylcholine polymer coating sample.

[0089] Comparative Example 3

[0090] The surface without coating treatment has a microstructured PDMS material.

[0091] Comparative Example 4

[0092] Uncoated stainless steel sheet material.

[0093] Test Example 1 Surface morphology characterization

[0094] The morphology of the sample surface coating was observed by scanning electron microscopy.

[0095] SEM images of Example 1, Comparative Example 1, and Comparative Example 2 are shown in Figure 1. It was found that hollow dialysis fiber samples coated with a monolayer coating significantly maintained the dense network / microporous substrate microstructure compared to hollow dialysis fiber samples coated with a polymer layer. Specifically, after treatment with the ultrathin monolayer of the present invention, the microstructure of the hollow dialysis fiber material was maintained at a rate exceeding 80%. Furthermore, based on statistical analysis of the number or area of ​​micropores per unit area, the change before and after treatment did not exceed 5%.

[0096] SEM images of Example 2 and Comparative Example 3 are shown in Figure 2. The surfaces of the test samples were coated with cylindrical grooves formed by the inverted film method. Similarly, it was found that for PDMS membrane materials with circular micro-nanostructures on their surfaces, the monolayer treatment of the present invention significantly maintained these cylindrical groove microstructures. The coating did not cause topological accumulation, and its thickness did not vary by more than 1% compared to the substrate itself.

[0097] Test Example 2: Surface phosphorus content detection

[0098] X-ray photoelectron spectroscopy was used to detect the phosphorus content on the surface of the material. The test data are shown in Table 1.

[0099] Table 1 Test results of phosphorus content on coating surface

[0100] Test Example 3 Coating Thickness Test

[0101] Scanning electron microscopy was used to observe the coating morphology and measure the coating thickness. The test data are summarized in Table 2. Specifically, the coating of the present invention, because it forms a monolayer by chemically bonding the ends of a single molecular structure to the substrate surface, can achieve an ultra-thin thickness, theoretically at least 10 nm or less, and even 5 nm or less.

[0102] Table 2 Coating thickness test results

[0103] Test Example 4 Protein adsorption test

[0104] Protein adsorption on sample surfaces was tested using a fibrinogen (Fg) protein detection kit. The test data are shown in Table 3 below. Specifically, the coatings of the present invention were used with their respective bare substrates as controls to calculate the reduction in protein adsorption. The tests revealed that the monolayer structure of the present invention can reduce protein adsorption, and despite being an ultrathin coating, it achieves essentially the same level of protein adsorption resistance as polymer coatings.

[0105] Table 3 Protein adsorption

[0106] Test Example 5: Ventilation Rate Test

[0107] Based on ion chromatography, the oxygen permeability is calculated by measuring the permeation rate of oxygen on the material to be tested. The specific method is: 1) Prepare the sample: Cut the material to be tested into appropriate sizes and ensure that there are no obvious defects or contamination on the surface of the material. 2) Install the device: Fix the material to be tested in the test chamber of the oxygen permeator to ensure that there is no air leakage between the material and the test chamber. 3) Pressurization: Pressurize the oxygen in the test chamber to a certain pressure so that the oxygen permeates from the high-pressure side to the low-pressure side. 4) Sampling: Collect a certain volume of oxygen sample from the low-pressure side within a certain time interval. 5) Analysis: Use instruments such as ion chromatographs to analyze the collected oxygen samples and measure the concentration of oxygen. The test results are shown in Table 4 below. The results show that the monolayer ultra-thin coating of the present invention not only ensures the integrity of the membrane surface structure, but also maintains the permeability of the pores to an ultra-high degree, so that the gas exchange efficiency of the device material is maintained at the highest level.

[0108] Table 4 Ventilation rate test results

[0109] Test Example 6: Coating Insoluble Particles Test

[0110] The specific method was tested in accordance with standard YY / T 1556-2017. The results are shown in Table 5 below (N1-N10 represent 10 parallel samples). The results demonstrate that the monolayer ultrathin coating of the present invention, with single molecules arranged two-dimensionally and firmly bonded to the surface, does not cause particle shedding in the in vivo environment. However, in polymer coatings, due to factors such as incomplete internal cross-linking of the coating, the leaching of particulate matter increases significantly, which can have serious consequences, especially for medium- to long-term implantable medical devices.

[0111] Table 5 Coating particle shedding test

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 the change rate of the number or area of micropores per unit area not to exceed 5%; when the substrate surface has a micro-nano topological structure, the monolayer coating material causes the thickness change rate not to exceed 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 existence ratio of phosphorus atoms relative to the existence amount of all atoms except hydrogen atoms is 0.01 to 2 atomic percent, determined 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 percent, 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 Formula I below: In the formula, R2 represents an alkylene group of C1-C10, 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 derived from a raw material of the general formula shown in the following formula II or formula III through functionalization: In the formula, R2 represents an alkylene group of C1-C10.

8. The medical article according to claim 1, wherein, It further includes a transition layer between the substrate and the functional surface layer, and the transition 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.

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 a dispersion containing a compound represented by the following Chemical Formula I on the surface of the substrate; (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, photocuring, or radiation curing on the coated substrate. In the formula, R2 represents an alkylene group of C1-C10, the end of the R1 structure contains a functionalized reactive site, and the molecular weight of the compound is 1000 or less.

11. The method for preparing a medical product according to claim 10, characterized in that, The substrate is subjected to a transition layer treatment before the step (2).

12. The method for preparing a medical product according to any one of claims 10 or 11, characterized in that, The concentration of the compound in the dispersion liquid 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 liquid contains solvents 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 preparation method of the medical product according to any one of claims 10 or 11, characterized in that, The coating method is selected from at least one of dip coating, spray coating, bar coating, brush coating, spin coating, electrospray and combinations thereof.

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