WO2018126796A1 - 一种在医用材料表面上制备抗菌表面的方法 - Google Patents

一种在医用材料表面上制备抗菌表面的方法 Download PDF

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WO2018126796A1
WO2018126796A1 PCT/CN2017/110895 CN2017110895W WO2018126796A1 WO 2018126796 A1 WO2018126796 A1 WO 2018126796A1 CN 2017110895 W CN2017110895 W CN 2017110895W WO 2018126796 A1 WO2018126796 A1 WO 2018126796A1
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medical material
antibacterial
azide
solution
compound
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French (fr)
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任力
王琳
何精才
王迎军
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华南理工大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B41/00—After-treatment of mortars, concrete, artificial stone or ceramics; Treatment of natural stone
    • C04B41/45—Coating or impregnating, e.g. injection in masonry, partial coating of green or fired ceramics, organic coating compositions for adhering together two concrete elements
    • C04B41/4505—Coating or impregnating, e.g. injection in masonry, partial coating of green or fired ceramics, organic coating compositions for adhering together two concrete elements characterised by the method of application
    • C04B41/4529—Coating or impregnating, e.g. injection in masonry, partial coating of green or fired ceramics, organic coating compositions for adhering together two concrete elements characterised by the method of application applied from the gas phase
    • C04B41/4533—Coating or impregnating, e.g. injection in masonry, partial coating of green or fired ceramics, organic coating compositions for adhering together two concrete elements characterised by the method of application applied from the gas phase plasma assisted
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F292/00—Macromolecular compounds obtained by polymerising monomers on to inorganic materials
    • C—CHEMISTRY; METALLURGY
    • C23—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
    • C23C—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
    • C23C16/00—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes
    • C23C16/44—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes characterised by the method of coating
    • C23C16/455—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes characterised by the method of coating characterised by the method used for introducing gases into reaction chamber or for modifying gas flows in reaction chamber
    • C23C16/45523—Pulsed gas flow or change of composition over time
    • C23C16/45525—Atomic layer deposition [ALD]
    • C23C16/45527—Atomic layer deposition [ALD] characterized by the ALD cycle, e.g. different flows or temperatures during half-reactions, unusual pulsing sequence, use of precursor mixtures or auxiliary reactants or activations
    • C23C16/45536—Use of plasma, radiation or electromagnetic fields
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/25—Peptides having up to 20 amino acids in a defined sequence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/18—Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F2438/00—Living radical polymerisation
    • C08F2438/01—Atom Transfer Radical Polymerization [ATRP] or reverse ATRP

Definitions

  • This invention relates to medical materials, and more particularly to a method of preparing an antimicrobial surface on the surface of a medical material.
  • the problem that the bacterial infection of the implant material is difficult to cure determines the prevention of bacterial infection of the implant, and measures to prevent it from being greater than the treatment. That is, the implant material has excellent tissue compatibility and biocompatibility, and also has excellent antibacterial properties. In order to improve the antibacterial property of the implant material, it is an effective method to modify the surface of the material and construct an antibacterial surface by using various antibacterial agents on the surface thereof.
  • antibacterial agents commonly used in clinical practice include ionic antibacterial agents, such as silver sulfadiazine; and antibiotic antibacterial agents such as tetracycline and vancomycin.
  • the object of the invention is to provide a method for preparing an antibacterial surface on the surface of a medical material, which avoids mutual interference of performance and improves the problem of enzymatic degradation of the antibacterial agent in the body. Better long-lasting antibacterial properties.
  • a method of preparing an antimicrobial surface on a surface of a medical material comprising the steps of:
  • the medical material obtained by the step (1) obtaining the initiator-modified surface is placed in an anti-adhesive monomer radical polymerization mixed solution for graft polymerization to obtain a medical material having an anti-adhesive polymer brush-modified surface;
  • the medical material of the azide surface prepared in the step (3) is placed in a click solution of the antibacterial agent, and a click reaction is performed to obtain an antibacterial surface in which the anti-adhesion polymer layer and the antibacterial layer are co-modified.
  • the oxygen plasma pretreatment in step (1) is specifically:
  • the surface of the medical material is subjected to oxygen plasma pretreatment, and the working parameters are power 20-600 W, pressure 20-120 Pa, gas flow rate 2-300 ml/min, temperature 10-50 ° C, time 2-10 min.
  • step (1) the chemical grafting of the aminosilane on the surface of the medical material is as follows:
  • the pretreated medical material is immersed in an ethanol solution of aminosilane, and reacted for 5-24 hours; wherein, in the ethanol solution of aminosilane, the volume concentration of the aminosilane is 1-20%, and the temperature is 10-40 ° C;
  • the aminosilane is 3-aminopropyltriethoxysilane, 11-aminoundecyltriethoxysilane, 4-aminobutyltriethoxysilane, N-aminoethyl-aminopropylmethyl One or more of dimethoxysilane, N- ⁇ -(aminoethyl)- ⁇ -aminopropyltrimethoxysilane.
  • Step (1) reacting the medical material of the surface aminosilane with the acyl compound, specifically:
  • the medical material of the surface grafted aminosilane is immersed in a dichloromethane solution of the acyl compound for 0.5-24 h; wherein the volume concentration of the acyl compound in the dichloromethane solution of the acyl compound is 2-10%, the acid binding agent Volume concentration 4-20%;
  • the acyl compound is one or more of 2-bromoisobutyryl bromide, 2-bromopropionyl bromide, 4-bromobutyl chloride acid, 3-chloropropionyl chloride, 4-chlorovaleryl chloride, and an acid binding agent. It is one or more of triethylamine, pyridine, and N,N-diisopropylethylamine.
  • step (2) the medical material obtained by the step (1) to obtain the initiator-modified surface is placed in an anti-adhesive monomer radical polymerization mixed solution for graft polymerization, specifically:
  • the medical material obtained by the step (1) to obtain the initiator-modified surface is subjected to graft polymerization in an atom transfer radical polymerization mixed solution; wherein the volume ratio of water to methanol in the mixed solution is 1:0.5-1:3,
  • the anti-adhesion monomer has a mass concentration of 2-20%, the copper compound has a mass concentration of 0.1%-1.2%, the ligand mass concentration is 0.3%-3.6%, the reaction time is 0.5-24h, and the temperature is 10-50°C. ;
  • the anti-adhesion monomer is acryloyloxyphosphocholine, methacryloxyphosphorylcholine, acrylamidophosphorylcholine, methacrylamidophosphocholine, acryloxysulfonic acid betaine , methacryloxysulfonic acid betaine, acrylamidosulfonic acid betaine, methacrylamidosulfonic acid betaine, acryloxylated carboxylic acid betaine, acrylamidocarboxylic acid betaine, methacryl One or more of amidocarboxylic acid betaine and vinylpyrrolidone.
  • Step (3) the medical material of the anti-adhesive polymer brush-modified surface obtained in the step (2) is placed in a solution of an azide compound in dimethylformamide to prepare a medical material of an azide surface, specifically for:
  • the medical material of the anti-adhesive polymer brush-modified surface obtained in the step (2) is placed in a solution of the azide compound in dimethylformamide, and reacted for 4-24 hours to prepare a medical material of the azide surface;
  • the azide compound in dimethylformamide solution the azide compound concentration is 0.5-5%, the temperature is 40-80 ° C;
  • the azide compound is one or both of sodium azide and lithium azide.
  • Step (4) placing the medical material of the azide surface prepared in the step (3) in a click solution of the antibacterial agent, and performing a click reaction, specifically:
  • the medical material of the azide surface prepared in the step (3) is placed in a click solution of the antibacterial agent, and a click reaction is performed, the reaction time is 1-5 h, and the reaction temperature is a temperature of 20-50 ° C;
  • the antibacterial agent concentration is 20-300 ⁇ M
  • the copper compound concentration is 0.5-5 ⁇ M
  • the ligand concentration is 5-50 ⁇ M
  • the ascorbic acid concentration is 25-250 ⁇ M
  • the reaction temperature is 20-50 ° C, time 1 - 5h.
  • the copper compound is one or more of CuCl, CuSO 4 , CuCl 2 , CuBr, CuBr 2 .
  • the ligand is 2,2'-bipyridyl, tetramethylethylenediamine, pentamethyldiethylenetriamine, hexamethyltriethylenetetramine, tris(N,N-dimethylamino One or more of ethyl)amine, N,N,N',N",N"-pentamethyldivinyltriamine, tris[2-(dimethylamino)ethyl]amine.
  • the antibacterial agent is an antibacterial polypeptide, and the sequence is Pra-Lys-Arg-Trp-Trp-Lys-Trp-Trp-Arg-Arg or Pra-Arg-Arg-Trp-Trp-Lys-Trp-Trp-Arg-Lys.
  • the present invention has the following advantages and benefits:
  • the invention introduces an atom transfer radical polymerization initiator on the surface of a medical material, first grafts an anti-adhesion polymer, then introduces an azide group, and finally introduces an antibacterial agent by clicking reaction, thereby preparing an anti-adhesion polymer on the surface of the material.
  • the bottom layer and the upper layer of the antibacterial agent are double-layered bifunctional antibacterial surfaces. Since the anti-adhesive polymer and the antibacterial agent are located in different graft layers, not only the mutual interference of properties is avoided, but also the antibacterial agent is improved.
  • the present invention solves the problem of nosocomial infection caused by medical devices.
  • Figure 1 is a schematic view showing the process of preparing an antibacterial surface on the surface of a silicon wafer according to Example 1 of the present invention.
  • Figure 2 is a water contact angle of the surface of an untreated silicon substrate.
  • Figure 3 is a water contact angle of the surface of the silicon substrate of the anti-adhesive polymer brush-modified surface obtained in the step (3) of Example 1 of the present invention.
  • Example 4 is an antibacterial surface water contact angle of the anti-adhesive polymer primer layer prepared in Example 1 of the present invention and the upper layer of the antibacterial agent.
  • Figure 5 is a surface topography of the surface of an untreated silicon substrate.
  • Figure 6 is a surface topography of an anti-adhesive polymer primer layer prepared in Example 1 of the present invention and an antibacterial agent having a two-layer co-modified antibacterial surface.
  • Figure 7 is a peak of the C element in the X-ray photoelectron spectroscopy of the anti-adhesive polymer primer layer prepared in Example 1 of the present invention and the antibacterial surface of the antibacterial agent.
  • Figure 8 is a partial peak of the N element in the X-ray photoelectron spectroscopy of the anti-adhesive polymer primer layer prepared in Example 1 of the present invention and the antibacterial agent upper layer double-layer co-modified antibacterial surface.
  • Figure 9 shows the bacterial growth of 10 6 CFU/ml bacteria after incubation on the surface of the untreated silicon substrate for 2.5 hours.
  • Fig. 10 shows the bacterial growth condition of 10 6 CFU/ml bacteria in the anti-adhesive polymer brush base layer prepared in Example 1 of the present invention and the antibacterial agent upper layer double-layer co-modified antibacterial surface culture for 2.5 hours.
  • Figure 11 is a graph showing the antibacterial properties of the surface of Comparative Example 1 and Example 1 after treatment with 1 mg/ml trypsin for 1, 3, and 5 minutes.
  • Figure 12 is a water contact angle of the surface of the sample prepared in Comparative Example 1.
  • Figure 13 is a surface topography of the surface of the sample prepared in Comparative Example 1.
  • Fig. 14 is a peak of the C element in the X-ray photoelectron spectroscopy of the surface of the sample prepared in Comparative Example 1.
  • Fig. 15 is a peak of the N element in the X-ray photoelectron spectroscopy of the surface of the sample prepared in Comparative Example 1.
  • the method for preparing an antibacterial surface on the surface of a silicon wafer of the present embodiment includes the following steps:
  • Oxygen plasma pretreatment on the surface of the silicon substrate the working parameters are power 100W, pressure 20Pa, gas flow rate 300ml/min, temperature 30 ° C, time 5 min; the pretreated silicon substrate is immersed in 3-aminopropyl three
  • the aminosilane was chemically grafted on the surface of the silicon substrate at a reaction temperature of 30 ° C for 5 hours; wherein the volume concentration of 3-aminopropyltriethoxysilane was 2%.
  • the silicon substrate of the surface-grafted aminosilane is immersed in a dichloromethane solution of an acyl compound, and reacted with an acyl compound at a temperature of 20 ° C for 3 hours to prepare a silicon substrate modified by an atom transfer radical polymerization initiator.
  • a dichloromethane solution of the acyl compound the volume concentration of 2-bromoisobutyryl bromide was 2%, and the volume concentration of triethylamine was 4%.
  • the silicon substrate of the anti-adhesive polymer brush-modified surface is placed in a solution of an azide compound in dimethylformamide to prepare a silicon substrate on the azide surface;
  • the azide reaction condition is: azide In the dimethylformamide solution of the compound, the surface concentration of sodium azide was 5%, the temperature was 40 ° C, and the time was 8 h to obtain a surface modified by the terminal azide anti-adhesion polymer.
  • an antibacterial agent (sequence is Pra-Lys-Arg-Trp-Trp-Lys-Trp-Trp-Arg-Arg).
  • the reaction the temperature of 37 ° C, the time of 2 h, the anti-adhesive polymer brush bottom layer and the antibacterial agent upper layer double-layer co-modified antibacterial surface; in the click solution, the antibacterial agent concentration is 100 ⁇ M, the copper sulfate concentration is 1 ⁇ M, the ligand three [ The concentration of 2-(dimethylamino)ethyl]amine was 10 ⁇ M, and the concentration of sodium ascorbate was 50 ⁇ M.
  • the water contact angle of the surface of the untreated silicon substrate is as shown in Fig. 2.
  • the water contact angle of the surface of the silicon substrate of the anti-adhesive polymer brush-modified surface obtained in the step (3) of the present embodiment is shown in Fig. 3.
  • the anti-adhesive polymer brush base prepared in this embodiment and the antibacterial agent upper layer double-layer co-modified antibacterial surface water contact angle are shown in FIG. 4 . It can be seen from Figures 2 to 4 that the contact angle after the treatment in each step has a significant change, indicating successful grafting of the anti-adhesive polymer and the antibacterial agent.
  • the surface topography of the untreated silicon substrate surface is as shown in FIG. 5, and the anti-adhesion polymerization prepared in this embodiment
  • the surface topography of the antibacterial surface co-modified by the primer layer and the upper layer of the antibacterial agent is shown in Fig. 6. It can be seen from Figures 5 to 6 that the surface morphology after the treatment in each step has a significant change, indicating successful grafting of the anti-adhesive polymer and the antibacterial agent.
  • the anti-adhesive polymer primer layer prepared in this example and the antibacterial agent upper layer double-layer co-modified antibacterial surface were treated with 1 mg/ml trypsin for 1, 3, and 5 minutes, and the antibacterial properties of the surface were as shown in FIG.
  • This comparative example is the same as Example 1 except that step (3) is not carried out.
  • the water contact angle of the surface of the sample prepared in this comparative example is shown in Fig. 12, and the surface morphology is shown in Fig. 13.
  • the antibacterial property of the surface after treatment with 1 mg/ml trypsin for 1, 3, 5 minutes is shown in Fig. 11;
  • the peak of the C element in the X-ray photoelectron spectroscopy is shown in Fig. 14, and the peak of the N element is shown in Fig. 15.
  • Comparative Example and Comparative Example 1 it was found that the antibacterial agent was successfully grafted to the surface, but the amount of the antibacterial agent grafted in the examples was smaller than that of Comparative Example 1, and the examples had better antibacterial properties and also had better anti-enzymatic hydrolysis. ability.
  • Oxygen plasma pretreatment of medical titanium surface working parameters are power 50W, pressure 30Pa, gas flow rate 30ml/min, temperature 30 ° C, time 3 min; immersed pretreated medical titanium surface into 3-aminopropyl
  • the reaction conditions of grafting aminosilane on the surface of medical titanium 3-aminopropyltriethoxysilane volume concentration is 8%, temperature 25 ° C, time 1 h.
  • reaction conditions are: The volume concentration of 2-bromopropionyl bromide was 8%, the volume concentration of triethylamine was 16%, the temperature was 20 ° C, and the time was 1 h.
  • the medical titanium having the initiator modified surface is placed in an atomic radical polymerization mixed solution for grafting Polymerization reaction, the mixed solution is water, formaldehyde volume ratio 1:05, the mass concentration of the methacrylamidocarboxylic acid betaine monomer aqueous solution is 10%, the copper bromide mass concentration is 0.6%, 2,2'-linked
  • the mass concentration of pyridine is 1.8%, the time is 0.5h, the temperature is 37 ° C; the reaction conditions of azide are: the concentration of sodium azide in the dimethylformamide solution of the azide compound is 2%, the temperature is 70 ° C
  • a terminally azide anti-adhesive polymer modified surface was prepared.
  • an antibacterial agent Pra-Arg-Arg-Trp-Trp-Lys-Trp-Trp-Arg-Lys
  • the antibacterial agent concentration was 200 ⁇ M
  • the sodium chloride concentration was 2 ⁇ M
  • the ligand pentamethyldiethylenetriamine concentration was 20 ⁇ M
  • the ascorbic acid concentration was 100 ⁇ M
  • the temperature was 25 ° C
  • the time was 4 h.
  • test results of the anti-adhesive polymer primer layer prepared in this embodiment and the antibacterial agent upper layer double-layer co-modified antibacterial surface are similar to those in the first embodiment, and will not be described herein.
  • Oxygen plasma pretreatment of medical titanium surface working parameters are power 400W, pressure 60Pa, gas flow rate 250ml/min, temperature 30 ° C, time 10 min; immersed pretreated medical titanium surface into 3-aminopropyl
  • aminosilane was grafted on the surface of medical titanium.
  • the reaction conditions were: 3-aminopropyltriethoxysilane volume concentration was 8%, temperature was 25 ° C, and time was 0.5 h.
  • reaction condition is: 2-bromoisobutyl
  • the volume concentration of the acid bromide is 8%
  • the volume concentration of triethylamine is 16%
  • the temperature is 25 ° C
  • the time is 0.5 h;
  • the medical titanium with the initiator modified surface is placed in an atomic radical polymerization mixed solution for graft polymerization, and the mixed solution is water: methanol volume ratio 1:3, the quality of the acryloyloxycarboxylic acid betaine monomer
  • the concentration is 2%, the mass concentration of copper bromide is 0.2%, the mass concentration of 2,2'-bipyridyl is 0.6%, the time is 18h, the temperature is 20 °C;
  • the reaction condition of azide is: the azide compound In the methylformamide solution, the mass concentration of lithium azide was 1%, the temperature was 50 ° C, and the time was 18 h to obtain a surface modified by the terminal azidation anti-adhesion polymer.
  • the concentration of the antibacterial agent is 50 ⁇ M
  • the concentration of copper sulfate is 1 ⁇ M
  • the ligand three [2-(dimethylamine) Anti-adhesion with a concentration of 10 ⁇ M, an ascorbic acid concentration of 50 ⁇ M, a temperature of 37 ° C, and a time of 3 h.
  • the polymer brush base layer and the antibacterial agent upper layer double-layered co-modified antibacterial surface.
  • test results of the anti-adhesive polymer primer layer prepared in this embodiment and the antibacterial agent upper layer double-layer co-modified antibacterial surface are similar to those in the first embodiment, and will not be described herein.
  • the aminosilane of the present invention may also be 3-aminopropyltriethoxysilane, 11-aminoundecyltriethoxysilane, 4-aminobutyltriethoxysilane, N-aminoethyl-ammonia One or more of propylmethyldimethoxysilane and N- ⁇ -(aminoethyl)- ⁇ -aminopropyltrimethoxysilane.
  • the acyl compound of the present invention may further be one or more of 2-bromoisobutyryl bromide, 2-bromopropionyl bromide, 4-bromobutyl chloride acid, 3-chloropropionyl chloride, 4-chlorovaleryl chloride,
  • the acid binding agent is one or more of triethylamine, pyridine, and N,N-diisopropylethylamine.
  • the anti-adhesion monomer of the present invention may also be acryloyloxyphosphocholine, methacryloxyphosphorylcholine, acrylamidophosphorylcholine, methacrylamidophosphorylcholine, acryloyloxysulfonate.
  • the copper compound of the present invention may also be one or more of CuCl, CuSO 4 , CuCl 2 , CuBr, CuBr 2 .
  • the ligand of the present invention may also be 2,2'-bipyridine, tetramethylethylenediamine, pentamethyldiethylenetriamine, hexamethyltriethylenetetramine, tris(N,N-dimethyl One or more of arylamino)amine, N,N,N',N",N"-pentamethyldivinyltriamine, tris[2-(dimethylamino)ethyl]aminekind.

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Abstract

一种在医用材料表面上制备抗菌表面的方法，包括以下步骤：(1)对医用材料表面进行氧等离子体预处理后，在医用材料表面进行化学接枝氨基硅烷，然后将氨基硅烷表面的医用材料与酰基化合物反应；(2)引发剂修饰表面的医用材料置于抗粘附单体水溶液中进行接枝聚合反应；(3)抗粘附聚合物刷修饰表面的医用材料置于含叠氮化合物的二甲基甲酰胺溶液中；(4)将叠氮化表面的医用材料，置于抗菌剂的点击溶液中，进行点击反应，得到抗粘附聚合物层和抗菌剂层共修饰的抗菌表面。该方法避免了抗粘附能力和杀菌能力的相互干扰，具有优异的长效抗菌性能。

Description

一种在医用材料表面上制备抗菌表面的方法 技术领域
本发明涉及医用材料，特别涉及一种在医用材料表面上制备抗菌表面的方法。
背景技术
我们的健康受到一些微生物威胁，抗菌材料在日常生活中也变得非常重要。随着社会健康意识的提高，植入体材料的应用也越来越广泛，由细菌引起的植入体感染问题也越来越受人们重视。尽管材料的无菌处理和术前抗生素的使用能一定程度减少该类感染的发生，但仍有4％-6％的患者在植入初期因细菌感染而引起植入体失效，给患者带来巨大的痛苦和经济负担。在中国，该类感染临床发生率更是高达15％。因此，植入体材料不仅要求要有良好的生物相容性，还需要具备必要的抗菌能力。硅材料由于表面规整度较好，特异性吸附少，广泛用于表面改性模型的构建。
植入体材料的细菌感染难以治愈的问题决定了对于植入体的细菌感染，要采取预防大于救治的措施。即植入体材料在具备优异的组织相容性和生物相容性的同时，还要具备优异的抗菌性能。为了提高植入体材料的抗菌性能，对材料进行表面改性，在其表面利用各种抗菌剂构建抗菌型表面是一种有效的方法。目前临床常用的抗菌剂包括离子型抗菌剂，如磺胺嘧啶银等；以及抗生素类抗菌剂，如四环素和万古霉素等。尽管添加这些抗菌剂的材料具有很强的抗菌性能，银离子的细胞毒性较大，抗生素类则易使细菌对抗生素产生耐药性，耐药性的细菌已经成为目前临床面临的一大挑战。这些问题使得这些抗菌剂在临床上应用存在一定的限制，人们迫切需要一种新型的抗菌剂。
发明内容
为了克服现有技术中在医用材料表面引入的抗粘附聚合物层和抗菌剂，但抗粘附能力和杀菌能力相互影响从而影响表面抗菌能力，以及多肽类抗菌剂自身不稳定的问题，本发明的目的在于提供一种在医用材料表面上制备抗菌表面的方法，避免了性能相互干扰，而且改善了抗菌剂在体内被酶降解的问题，获 得更优异的长效抗菌性能。
本发明的目的通过以下技术方案实现：
一种在医用材料表面上制备抗菌表面的方法，包括以下步骤：
(1)对医用材料表面进行氧等离子体预处理后，在医用材料表面进行化学接枝氨基硅烷，然后将表面接枝节氨基硅烷的医用材料与酰基化合物反应，制得原子转移自由基聚合的引发剂修饰表面的医用材料；
(2)将步骤(1)得到引发剂修饰表面的医用材料置于抗粘附单体自由基聚合混合溶液中进行接枝聚合反应，制得抗粘附聚合物刷修饰表面的医用材料；
(3)将步骤(2)得到的抗粘附聚合物刷修饰表面的医用材料置于含叠氮化合物的二甲基甲酰胺溶液中，制得叠氮化表面的医用材料；
(4)将步骤(3)制备的叠氮化表面的医用材料，置于抗菌剂的点击溶液中，进行点击反应，得到抗粘附聚合物层和抗菌剂层共修饰的抗菌表面。
步骤(1)所述氧等离子体预处理，具体为：
对医用材料表面进行氧等离子体预处理,工作参数为功率20-600W，压强20-120Pa，气体流速2-300ml/min，温度10-50℃，时间2-10min。
步骤(1)所述在医用材料表面进行化学接枝氨基硅烷，具体为：
将预处理后的医用材料浸入氨基硅烷的乙醇溶液中，反应5-24h；其中，氨基硅烷的乙醇溶液中，氨基硅烷的体积浓度为1-20％，温度10-40℃；
所述氨基硅烷为3-氨基丙基三乙氧基硅烷、11-氨基十一烷基三乙氧基硅烷、4-氨基丁基三乙氧基硅烷、N-氨乙基-氨丙基甲基二甲氧基硅烷、N-β-(氨乙基)-γ-氨丙基三甲氧基硅烷中的一种或多种。
步骤(1)将接表面枝节氨基硅烷的医用材料与酰基化合物反应，具体为：
将表面接枝节氨基硅烷的医用材料浸入酰基化合物的二氯甲烷溶液中，时间为0.5-24h；其中酰基化合物的二氯甲烷溶液中，酰基化合物的体积浓度为2-10％，缚酸剂体积浓度4-20％；
所述酰基化合物为2-溴异丁酰溴、2-溴丙酰溴、4-溴丁基氯酸、3-氯丙酰氯、4-氯戊酰氯中的一种或多种，缚酸剂为三乙胺、吡啶、N,N-二异丙基乙胺中一种或多种。
步骤(2)所述将步骤(1)得到引发剂修饰表面的医用材料置于抗粘附单体自由基聚合混合溶液中进行接枝聚合反应，具体为：
将步骤(1)得到引发剂修饰表面的医用材料置于原子转移自由基聚合混合溶液中进行接枝聚合反应；其中，混合溶液中水、甲醇体积比为1：0.5-1：3， 抗粘附单体的质量浓度为2-20％，铜化合物的质量浓度为0.1％-1.2％，配体质量浓度为0.3％-3.6％，反应时间为0.5-24h，温度为10-50℃；
所述抗粘附单体为丙烯酰氧基磷酸胆碱、甲基丙烯酰氧基磷酸胆碱、丙烯酰胺基磷酸胆碱、甲基丙烯酰胺基磷酸胆碱、丙烯酰氧基磺酸甜菜碱、甲基丙烯酰氧基磺酸甜菜碱、丙烯酰胺基磺酸甜菜碱、甲基丙烯酰胺基磺酸甜菜碱、丙烯酰氧基羧酸甜菜碱、丙烯酰胺基羧酸甜菜碱、甲基丙烯酰胺基羧酸甜菜碱、乙烯基吡咯烷酮中的一种或多种。
步骤(3)所述将步骤(2)得到的抗粘附聚合物刷修饰表面的医用材料置于含叠氮化合物的二甲基甲酰胺溶液中，制得叠氮化表面的医用材料，具体为：
将步骤(2)得到的抗粘附聚合物刷修饰表面的医用材料置于含叠氮化合物的二甲基甲酰胺溶液中，反应4-24h，制得叠氮化表面的医用材料；
其中叠氮化合物的二甲基甲酰胺溶液中，叠氮化合物质量浓度为0.5-5％，温度40-80℃；
所述叠氮化合物为叠氮化钠、叠氮化锂中的一种或两种。
步骤(4)将步骤(3)制备的叠氮化表面的医用材料，置于抗菌剂的点击溶液中，进行点击反应，具体为：
将步骤(3)制备的叠氮化表面的医用材料，置于抗菌剂的点击溶液中，进行点击反应，反应时间1-5h，反应温度为温度20-50℃；
所述抗菌剂的点击溶液中，抗菌剂浓度为20-300μM，铜化合物浓度为0.5-5μM，配体浓度为5-50μM，抗坏血酸浓度为25-250μM；反应温度20-50℃，时间1-5h。
所述铜化合物为CuCl、CuSO4、CuCl2、CuBr、CuBr2中的一种或多种。
所述配体为2,2'-联吡啶、四甲基乙二胺、五甲基二亚乙基三胺、六甲基三亚乙基四胺、三(N,N-二甲基胺基乙基)胺、N,N,N’,N”,N”-五甲基二乙烯基三胺、三[2-(二甲胺基)乙基]胺中的一种或多种。
所述抗菌剂为抗菌多肽，序列为Pra-Lys-Arg-Trp-Trp-Lys-Trp-Trp-Arg-Arg或Pra-Arg-Arg-Trp-Trp-Lys-Trp-Trp-Arg-Lys。
与现有技术相比，本发明具有以下优点和有益效果：
本发明通过在医用材料表面引入原子转移自由基聚合引发剂，先接枝抗粘附聚合物，再引入叠氮基，最后通过点击反应引入抗菌剂，从而在材料表面制备了抗粘附聚合物底层和抗菌剂上层双层双功能抗菌表面。由于抗粘附聚合物与抗菌剂位于不同接枝层内，不仅避免了性能相互干扰，而且改善了抗菌剂在 体内被酶降解的问题，抗粘附聚合物与抗菌剂的协同作用赋予表面更优异的长效抗菌性能，并会减轻杀菌层对血液和体细胞的不良影响，可获得优良的生物相容性。本发明解决了由医疗器械引发的院内感染问题。
附图说明
图1为本发明的实施例1的在硅片表面上制备抗菌表面的方法的过程示意图。
图2为未经处理的硅基底表面的水接触角。
图3为本发明的实施例1的步骤(3)得到的抗粘附聚合物刷修饰表面的硅基底表面的水接触角。
图4为本发明的实施例1制备的抗粘附聚合物刷底层和抗菌剂上层双层共修饰的抗菌表面水接触角。
图5为未经处理的硅基底表面的表面形貌。
图6为本发明的实施例1制备的抗粘附聚合物刷底层和抗菌剂上层双层共修饰的抗菌表面的表面形貌。
图7为本发明的实施例1制备的抗粘附聚合物刷底层和抗菌剂上层双层共修饰的抗菌表面的X射线光电子能谱中C元素的分峰。
图8为本发明的实施例1制备的抗粘附聚合物刷底层和抗菌剂上层双层共修饰的抗菌表面的X射线光电子能谱中N元素的分峰。
图9为106CFU/ml细菌在未经处理的硅基底表面培养2.5小时后细菌滋生情况。
图10为106CFU/ml细菌在本发明的实施例1制备的抗粘附聚合物刷底层和抗菌剂上层双层共修饰的抗菌表面培养2.5小时后细菌滋生情况。
图11为比较例1和实施例1的样品用1mg/ml胰蛋白酶处理1,3,5分钟后表面的抗菌性能。
图12为比较例1制备的样品表面的水接触角。
图13为比较例1制备的样品表面的表面形貌。
图14为比较例1制备的样品表面的X射线光电子能谱中C元素的分峰。
图15为比较例1制备的样品表面的X射线光电子能谱中N元素的分峰。
具体实施方式
下面结合实施例，对本发明作进一步地详细说明，但本发明的实施方式不 限于此。
实施例1
如图1所示，本实施例的在硅片表面上制备抗菌表面的方法，包括以下步骤：
(1)对硅基底表面进行氧等离子体预处理，工作参数为功率100W，压强20Pa,气体流速300ml/min，温度30℃，时间5min；将预处理后的硅基底浸入3-氨基丙基三乙氧基硅烷的乙醇溶液中，在硅基底表面进行化学接枝氨基硅烷，反应温度30℃，时间5h；其中，3-氨基丙基三乙氧基硅烷体积浓度为2％。
(2)将表面接枝氨基硅烷的硅基底浸入酰基化合物的二氯甲烷溶液中，与酰基化合物反应，温度为20℃，时间为3h，制得原子转移自由基聚合引发剂修饰表面的硅基底表面；酰基化合物的二氯甲烷溶液中，2-溴异丁酰溴的体积浓度为2％，三乙胺体积浓度为4％。
(3)将引发剂修饰表面的硅基底置于原子自由基聚合混合溶液中进行接枝聚合反应，时间为2h，温度为25℃，得到抗粘附聚合物刷修饰表面的硅基底表面；混合溶液中水、甲醇体积比为1：1，混合溶液中的甲基丙烯酰氧基磺酸甜菜碱单体水溶液的质量浓度为5％，溴化铜的质量浓度为0.3％，2,2'-联吡啶质量浓度为0.9％。
(4)将抗粘附聚合物刷修饰表面的硅基底置于含叠氮化合物的二甲基甲酰胺溶液中，制得叠氮化表面的硅基底；叠氮化的反应条件为：叠氮化合物的二甲基甲酰胺溶液中，叠氮化钠质量浓度为5％，温度40℃，时间8h，制得末端叠氮化抗粘附聚合物修饰的表面。
(5)将所述叠氮化表面的医用材料经清洗后，置于抗菌剂(序列为Pra-Lys-Arg-Trp-Trp-Lys-Trp-Trp-Arg-Arg)的点击溶液中进行点击反应，温度37℃，时间2h，制得抗粘附聚合物刷底层和抗菌剂上层双层共修饰的抗菌表面；点击液中，抗菌剂浓度为100μM，硫酸铜浓度为1μM，配体三[2-(二甲胺基)乙基]胺浓度为10μM，抗坏血酸钠浓度为50μM。
未经处理的硅基底表面的水接触角如图2所示，本实施例的步骤(3)得到的抗粘附聚合物刷修饰表面的硅基底表面的水接触角如图3所示。本实施例制备的抗粘附聚合物刷底层和抗菌剂上层双层共修饰的抗菌表面水接触角如图4所示。由图2～4可知，经过各步骤处理后的接触角有明显的变化，说明抗粘附聚合物及抗菌剂的成功接枝。
未经处理的硅基底表面的表面形貌如图5所示，本实施例制备的抗粘附聚 合物刷底层和抗菌剂上层双层共修饰的抗菌表面的表面形貌如图6示。由图5～6可知，经过各步骤处理后的表面形貌有明显的变化，说明抗粘附聚合物及抗菌剂的成功接枝。
本实施例制备的抗粘附聚合物刷底层和抗菌剂上层双层共修饰的抗菌表面的X射线光电子能谱中C元素的分峰如图7所示，N元素的分峰如图8所示。可知，抗粘附聚合物与抗菌剂均成功接枝到表面。
106CFU/ml细菌在未经处理的硅基底表面和在本实施例制备的抗粘附聚合物刷底层和抗菌剂上层双层共修饰的抗菌表面培养2.5小时后细菌滋生情况分别如图9～图10所示。
本实施例制备的抗粘附聚合物刷底层和抗菌剂上层双层共修饰的抗菌表面用1mg/ml胰蛋白酶处理1,3,5分钟后表面的抗菌性能如图11所示。
比较例1
本比较例除未进行步骤(3)外，其他步骤均与实施例1同。
本比较例制备的样品表面的水接触角如图12所示，表面形貌如图13所示，用1mg/ml胰蛋白酶处理1,3,5分钟后表面的抗菌性能如图11所示；X射线光电子能谱中C元素的分峰如图14所示，N元素的分峰如图15所示。
对比实施例与比较例1，可知抗菌剂成功接枝到表面，但实施例中的抗菌剂接枝量小于比较例1，实施例具有更好的抗菌性能，同时也具有更好的抗酶解能力。
实施例2
本实施例的医用钛表面上制备抗菌表面的方法，包括以下步骤：
(1)对医用钛表面进行氧等离子体预处理,工作参数为功率50W，压强30Pa,气体流速30ml/min，温度30℃，时间3min；将预处理后的医用钛表面浸入3-氨基丙基三乙氧基硅烷的乙醇溶液中，在医用钛表面接枝氨基硅烷的反应条件：3-氨基丙基三乙氧基硅烷体积浓度为8％，温度25℃，时间1h。
(2)将接枝节氨基硅烷表面的医用钛浸入酰基化合物的二氯甲烷溶液中，与酰基化合物反应，制得原子转移自由基聚合的引发剂修饰表面的硅基底表面；反应的条件为：2-溴丙酰溴体积浓度为8％，三乙胺体积浓度为16％，温度为20℃，时间为1h。
(3)将引发剂修饰表面的医用钛置于原子自由基聚合混合溶液中进行接枝 聚合反应，混合溶液为水、甲醛体积比1：05，甲基丙烯酰胺基羧酸甜菜碱单体水溶液的质量浓度为10％，溴化铜的质量浓度为0.6％，2,2'-联吡啶质量浓度为1.8％，时间为0.5h，温度为37℃；叠氮化的反应条件为：叠氮化合物的二甲基甲酰胺溶液中，叠氮化钠质量浓度为2％，温度70℃，时间8h，制得末端叠氮化抗粘附聚合物修饰的表面。
(4)将所述叠氮化表面的医用材料经清洗后，置于抗菌剂(Pra-Arg-Arg-Trp-Trp-Lys-Trp-Trp-Arg-Lys)的点击溶液中，进行点击反应，抗菌剂浓度为200μM，氯化钠浓度为2μM，配体五甲基二亚乙基三胺浓度为20μM，抗坏血酸浓度为100μM，温度25℃，时间4h，制得抗粘附聚合物刷底层和抗菌剂上层双层共修饰的抗菌表面。
本实施例制备的抗粘附聚合物刷底层和抗菌剂上层双层共修饰的抗菌表面的测试结果与实施例1类似，在此不再赘述。
实施例3
本实施例的医用钛表面上制备抗菌表面的方法，包括以下步骤：
(1)对医用钛表面进行氧等离子体预处理，工作参数为功率400W，压强60Pa,气体流速250ml/min，温度30℃，时间10min；将预处理后的医用钛表面浸入3-氨基丙基三乙氧基硅烷的乙醇溶液中，在医用钛表面接枝氨基硅烷，反应条件：3-氨基丙基三乙氧基硅烷体积浓度为8％，温度25℃，时间0.5h。
(2)将表面接枝节氨基硅烷的医用钛浸入酰基化合物的溶液中，与酰基化合物反应，制得原子转移自由基聚合引发剂修饰表面的硅基底表面；反应条件为：2-溴异丁酰溴的体积浓度为8％，三乙胺体积浓度为16％，温度为25℃，时间为0.5h；
(3)将引发剂修饰表面的医用钛置于原子自由基聚合混合溶液中进行接枝聚合反应，混合溶液为水、甲醇体积比1：3，的丙烯酰氧基羧酸甜菜碱单体质量浓度为2％，溴化铜的质量浓度为0.2％，2,2'-联吡啶质量浓度为0.6％，时间为18h，温度为20℃；叠氮化的反应条件为：叠氮化合物的二甲基甲酰胺溶液中，叠氮化锂的质量浓度为1％，温度50℃，时间18h，制得末端叠氮化抗粘附聚合物修饰的表面。
(4)将所述叠氮化表面的医用材料经清洗后，置于抗菌剂的点击溶液中点击反应，抗菌剂浓度为50μM，硫酸铜浓度为1μM，配体三[2-(二甲胺基)乙基]胺浓度为10μM，抗坏血酸浓度为50μM，温度37℃，时间3h，制得抗粘附 聚合物刷底层和抗菌剂上层双层共修饰的抗菌表面。
本实施例制备的抗粘附聚合物刷底层和抗菌剂上层双层共修饰的抗菌表面的测试结果与实施例1类似，在此不再赘述。
本发明的氨基硅烷还可为3-氨基丙基三乙氧基硅烷、11-氨基十一烷基三乙氧基硅烷、4-氨基丁基三乙氧基硅烷、N-氨乙基-氨丙基甲基二甲氧基硅烷、N-β-(氨乙基)-γ-氨丙基三甲氧基硅烷中的一种或多种。
本发明的酰基化合物还可为2-溴异丁酰溴、2-溴丙酰溴、4-溴丁基氯酸、3-氯丙酰氯、4-氯戊酰氯中的一种或多种，缚酸剂为三乙胺、吡啶、N,N-二异丙基乙胺中一种或多种。
本发明的抗粘附单体还可为丙烯酰氧基磷酸胆碱、甲基丙烯酰氧基磷酸胆碱、丙烯酰胺基磷酸胆碱、甲基丙烯酰胺基磷酸胆碱、丙烯酰氧基磺酸甜菜碱、甲基丙烯酰氧基磺酸甜菜碱、丙烯酰胺基磺酸甜菜碱、甲基丙烯酰胺基磺酸甜菜碱、丙烯酰氧基羧酸甜菜碱、丙烯酰胺基羧酸甜菜碱、甲基丙烯酰胺基羧酸甜菜碱、乙烯基吡咯烷酮中的一种或多种。
本发明的铜化合物还可为CuCl、CuSO4、CuCl2、CuBr、CuBr2中的一种或多种。
本发明的配体还可为2,2'-联吡啶、四甲基乙二胺、五甲基二亚乙基三胺、六甲基三亚乙基四胺、三(N,N-二甲基胺基乙基)胺、N,N,N’,N”,N”-五甲基二乙烯基三胺、三[2-(二甲胺基)乙基]胺中的一种或多种。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受所述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (10)

  1. 一种在医用材料表面上制备抗菌表面的方法，其特征在于，包括以下步骤：
    (1)对医用材料表面进行氧等离子体预处理后，在医用材料表面进行化学接枝氨基硅烷，然后将表面接枝节氨基硅烷的医用材料与酰基化合物反应，制得原子转移自由基聚合的引发剂修饰表面的医用材料；
    (2)将步骤(1)得到引发剂修饰表面的医用材料置于抗粘附单体自由基聚合混合溶液中进行接枝聚合反应，制得抗粘附聚合物刷修饰表面的医用材料；
    (3)将步骤(2)得到的抗粘附聚合物刷修饰表面的医用材料置于含叠氮化合物的二甲基甲酰胺溶液中，制得叠氮化表面的医用材料；
    (4)将步骤(3)制备的叠氮化表面的医用材料，置于抗菌剂的点击溶液中，进行点击反应，得到抗粘附聚合物层和抗菌剂层共修饰的抗菌表面。
  2. 根据权利要求1所述的在医用材料表面上制备抗菌表面的方法，其特征在于，步骤(1)所述氧等离子体预处理，具体为：
    对医用材料表面进行氧等离子体预处理,工作参数为功率20-600W，压强20-120Pa，气体流速2-300ml/min，温度10-50℃，时间2-10min。
  3. 根据权利要求1所述的在医用材料表面上制备抗菌表面的方法，其特征在于，步骤(1)所述在医用材料表面进行化学接枝氨基硅烷，具体为：
    将预处理后的医用材料浸入氨基硅烷的乙醇溶液中，反应5-24h；其中，氨基硅烷的乙醇溶液中，氨基硅烷的体积浓度为1-20％，温度10-40℃；
    所述氨基硅烷为3-氨基丙基三乙氧基硅烷、11-氨基十一烷基三乙氧基硅烷、4-氨基丁基三乙氧基硅烷、N-氨乙基-氨丙基甲基二甲氧基硅烷、N-β-(氨乙基)-γ-氨丙基三甲氧基硅烷中的一种或多种。
  4. 根据权利要求1所述的在医用材料表面上制备抗菌表面的方法，其特征在于，步骤(1)将接表面枝节氨基硅烷的医用材料与酰基化合物反应，具体为：
    将表面接枝节氨基硅烷的医用材料浸入酰基化合物的二氯甲烷溶液中，时间为0.5-24h；其中酰基化合物的二氯甲烷溶液中，酰基化合物的体积浓度为2-10％，缚酸剂体积浓度4-20％；
    所述酰基化合物为2-溴异丁酰溴、2-溴丙酰溴、4-溴丁基氯酸、3-氯丙酰氯、4-氯戊酰氯中的一种或多种，缚酸剂为三乙胺、吡啶、N,N-二异丙基乙胺中一种或多种。
  5. 根据权利要求1所述的在医用材料表面上制备抗菌表面的方法，其特征在于，步骤(2)所述将步骤(1)得到引发剂修饰表面的医用材料置于抗粘附单体自由基聚合混合溶液中进行接枝聚合反应，具体为：
    将步骤(1)得到引发剂修饰表面的医用材料置于原子转移自由基聚合混合溶液中进行接枝聚合反应；其中，混合溶液中水、甲醇体积比为1：0.5-1：3，抗粘附单体的质量浓度为2-20％，铜化合物的质量浓度为0.1％-1.2％，配体质量浓度为0.3％-3.6％，反应时间为0.5-24h，温度为10-50℃；
    所述抗粘附单体为丙烯酰氧基磷酸胆碱、甲基丙烯酰氧基磷酸胆碱、丙烯酰胺基磷酸胆碱、甲基丙烯酰胺基磷酸胆碱、丙烯酰氧基磺酸甜菜碱、甲基丙烯酰氧基磺酸甜菜碱、丙烯酰胺基磺酸甜菜碱、甲基丙烯酰胺基磺酸甜菜碱、丙烯酰氧基羧酸甜菜碱、丙烯酰胺基羧酸甜菜碱、甲基丙烯酰胺基羧酸甜菜碱、乙烯基吡咯烷酮中的一种或多种。
  6. 根据权利要求1所述的在医用材料表面上制备抗菌表面的方法，其特征在于，步骤(3)所述将步骤(2)得到的抗粘附聚合物刷修饰表面的医用材料置于含叠氮化合物的二甲基甲酰胺溶液中，制得叠氮化表面的医用材料，具体为：
    将步骤(2)得到的抗粘附聚合物刷修饰表面的医用材料置于含叠氮化合物的二甲基甲酰胺溶液中，反应4-24h，制得叠氮化表面的医用材料；
    其中叠氮化合物的二甲基甲酰胺溶液中，叠氮化合物质量浓度为0.5-5％，温度40-80℃；
    所述叠氮化合物为叠氮化钠、叠氮化锂中的一种或两种。
  7. 根据权利要求1所述的在医用材料表面上制备抗菌表面的方法，其特征在于，步骤(4)将步骤(3)制备的叠氮化表面的医用材料，置于抗菌剂的点击溶液中，进行点击反应，具体为：
    将步骤(3)制备的叠氮化表面的医用材料，置于抗菌剂的点击溶液中，进行点击反应，反应时间1-5h，反应温度为温度20-50℃；
    所述抗菌剂的点击溶液中，抗菌剂浓度为20-300μM，铜化合物浓度为0.5-5μM，配体浓度为5-50μM，抗坏血酸浓度为25-250μM；反应温度20-50℃，时间1-5h。
  8. 根据权利要求7所述的在医用材料表面上制备抗菌表面的方法，其特征在于，所述铜化合物为CuCl、CuSO4、CuCl2、CuBr、CuBr2中的一种或多种。
  9. 根据权利要求7所述的在医用材料表面上制备抗菌表面的方法，其特征 在于，所述配体为2,2'-联吡啶、四甲基乙二胺、五甲基二亚乙基三胺、六甲基三亚乙基四胺、三(N,N-二甲基胺基乙基)胺、N,N,N’,N”,N”-五甲基二乙烯基三胺、三[2-(二甲胺基)乙基]胺中的一种或多种。
  10. 根据权利要求7所述的在医用材料表面上制备抗菌表面的方法，其特征在于，所述抗菌剂为抗菌多肽，序列为Pra-Lys-Arg-Trp-Trp-Lys-Trp-Trp-Arg-Arg或Pra-Arg-Arg-Trp-Trp-Lys-Trp-Trp-Arg-Lys。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114702624A (zh) * 2022-01-20 2022-07-05 河南科技大学 一种基于多糖聚合物抗菌材料及制备方法
CN115869470A (zh) * 2021-09-27 2023-03-31 齐鲁工业大学 一种用于血管支架的涂层材料及制备方法

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106902396B (zh) 2017-01-05 2021-01-19 华南理工大学 一种在医用材料表面上制备抗菌表面的方法
CN110354303A (zh) * 2018-03-26 2019-10-22 北京化工大学 一种金属钛表面的抗菌修饰方法
CN109517207B (zh) * 2018-11-27 2020-06-16 中国科学院长春应用化学研究所 一种具有抗粘附杀菌功能表面的医用高分子材料及其制备方法
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CN113214526B (zh) * 2021-06-29 2022-11-11 中国人民解放军空军军医大学 一种表面氨基化3d打印聚醚醚酮植入物及其制备方法
CN113755828B (zh) * 2021-09-02 2023-10-24 福建医科大学附属口腔医院 钛表面抗菌修饰并提高其生物活性的方法、涂层、种植体
CN115487361A (zh) * 2022-09-16 2022-12-20 四川大学 一种亲水抗菌抗炎水凝胶薄膜及其制备方法与应用
CN116656236A (zh) * 2023-06-07 2023-08-29 郑州大学 一种医用金属材料的表面润滑改性方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992019289A1 (en) * 1991-04-25 1992-11-12 Polymedica Industries, Inc. Treatment of polyurethane surfaces
FR2905271B1 (fr) * 2006-09-01 2008-10-24 Univ Nice Sophia Antipolis Eta Procede de synthese d'un support a surface a activite biocide
CN102216376A (zh) * 2008-11-17 2011-10-12 帝斯曼知识产权资产管理有限公司 通过表面活性和反应性端基对聚合物的表面改性
CN105601976A (zh) * 2016-03-29 2016-05-25 苏州大学 一种在生物医用材料表面上制备抗菌表面的方法
CN106902396A (zh) * 2017-01-05 2017-06-30 华南理工大学 一种在医用材料表面上制备抗菌表面的方法

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050191270A1 (en) * 2004-02-27 2005-09-01 Hydromer, Inc. Anti-infectious hydrogel compositions
CN100345602C (zh) * 2005-10-14 2007-10-31 浙江大学 改善生物医用材料生物相容性的聚合物刷的制备方法
CN101787136B (zh) * 2010-01-19 2012-01-25 东南大学 一种表面利用聚乙烯基吡咯烷酮修饰的聚氨酯功能材料的制备方法
CN102911378A (zh) * 2012-11-19 2013-02-06 江南大学 一种用于防治化疗性静脉炎的水凝胶膜的制备方法
CN104710644B (zh) * 2015-03-04 2017-09-22 中国科学院长春应用化学研究所 一种在医用高分子材料表面上制备抗菌表面的方法
CN105949322B (zh) * 2016-05-12 2019-08-20 苏州大学附属第一医院 一种适用于“一步法”改性医用钛基材料的生物模拟活性肽

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992019289A1 (en) * 1991-04-25 1992-11-12 Polymedica Industries, Inc. Treatment of polyurethane surfaces
FR2905271B1 (fr) * 2006-09-01 2008-10-24 Univ Nice Sophia Antipolis Eta Procede de synthese d'un support a surface a activite biocide
CN102216376A (zh) * 2008-11-17 2011-10-12 帝斯曼知识产权资产管理有限公司 通过表面活性和反应性端基对聚合物的表面改性
CN105601976A (zh) * 2016-03-29 2016-05-25 苏州大学 一种在生物医用材料表面上制备抗菌表面的方法
CN106902396A (zh) * 2017-01-05 2017-06-30 华南理工大学 一种在医用材料表面上制备抗菌表面的方法

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115869470A (zh) * 2021-09-27 2023-03-31 齐鲁工业大学 一种用于血管支架的涂层材料及制备方法
CN114702624A (zh) * 2022-01-20 2022-07-05 河南科技大学 一种基于多糖聚合物抗菌材料及制备方法
CN114702624B (zh) * 2022-01-20 2024-01-19 河南科技大学 一种基于多糖聚合物抗菌材料及制备方法

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