WO2023087864A1 - 一种通过变色效应指示伤口感染情况的纳米银/双改性壳聚糖抗菌水凝胶敷料及其制备方法 - Google Patents

一种通过变色效应指示伤口感染情况的纳米银/双改性壳聚糖抗菌水凝胶敷料及其制备方法 Download PDF

Info

Publication number
WO2023087864A1
WO2023087864A1 PCT/CN2022/117686 CN2022117686W WO2023087864A1 WO 2023087864 A1 WO2023087864 A1 WO 2023087864A1 CN 2022117686 W CN2022117686 W CN 2022117686W WO 2023087864 A1 WO2023087864 A1 WO 2023087864A1
Authority
WO
WIPO (PCT)
Prior art keywords
modified chitosan
water
double
silver
nano
Prior art date
Application number
PCT/CN2022/117686
Other languages
English (en)
French (fr)
Inventor
金晓强
叶招明
鲍晓炯
滕王锶源
Original Assignee
浙江大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 浙江大学 filed Critical 浙江大学
Priority to US18/306,986 priority Critical patent/US20230255546A1/en
Publication of WO2023087864A1 publication Critical patent/WO2023087864A1/zh

Links

Images

Classifications

    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08BPOLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0024Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
    • C08B37/00272-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
    • C08B37/003Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/44Detecting, measuring or recording for evaluating the integumentary system, e.g. skin, hair or nails
    • A61B5/441Skin evaluation, e.g. for skin disorder diagnosis
    • A61B5/445Evaluating skin irritation or skin trauma, e.g. rash, eczema, wound, bed sore
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L15/00Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/28Polysaccharides or their derivatives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L15/00Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42Use of materials characterised by their function or physical properties
    • A61L15/425Porous materials, e.g. foams or sponges
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L15/00Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42Use of materials characterised by their function or physical properties
    • A61L15/44Medicaments
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L15/00Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42Use of materials characterised by their function or physical properties
    • A61L15/46Deodorants or malodour counteractants, e.g. to inhibit the formation of ammonia or bacteria
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L15/00Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42Use of materials characterised by their function or physical properties
    • A61L15/60Liquid-swellable gel-forming materials, e.g. super-absorbents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L26/00Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0004Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing inorganic materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L26/00Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061Use of materials characterised by their function or physical properties
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L26/00Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061Use of materials characterised by their function or physical properties
    • A61L26/0066Medicaments; Biocides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L26/00Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061Use of materials characterised by their function or physical properties
    • A61L26/008Hydrogels or hydrocolloids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • A61L2300/104Silver, e.g. silver sulfadiazine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/216Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/23Carbohydrates
    • A61L2300/236Glycosaminoglycans, e.g. heparin, hyaluronic acid, chondroitin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404Biocides, antimicrobial agents, antiseptic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/442Colorants, dyes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2400/00Materials characterised by their function or physical properties
    • A61L2400/12Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces

Definitions

  • the invention belongs to the field of medical dressings, and in particular relates to a nano-silver/double-modified chitosan antibacterial hydrogel dressing and a preparation method thereof, which indicate wound infection through a discoloration effect.
  • Wounds generally refer to normal skin or tissue damage caused by internal or external factors. The skin is completely destroyed and the normal tissue is damaged.
  • the common injury wounds in clinical practice and daily life include burn wounds, electrical wounds, and chemical corrosion wounds. wait. Since the wound surface is in direct contact with the external environment, it is extremely prone to infection. Therefore, wound care urgently needs to develop advanced wound dressings with antibacterial functions and healing-promoting effects.
  • chitosan is second only to cellulose in nature reserves, and has excellent biocompatibility, hemostasis, antibacterial and wound healing ability, which has attracted great attention of researchers. .
  • the low molecular weight chitosan after degradation treatment has poor mechanical properties and unstable physical and chemical properties, so it is difficult to meet the actual use requirements.
  • the price of commercialized degraded chitosan is relatively high, and even if the degradation parameters of each batch of chitosan are strictly controlled, it is difficult to obtain degraded chitosan products with the same molecular weight.
  • Raw material grade high molecular weight chitosan has excellent mechanical properties, stable physical and chemical properties, and low price, but the dissolution problem is the main factor affecting its application range. Therefore, the water-soluble modification of chitosan is of great significance for expanding the application range of high molecular weight chitosan.
  • quaternization modification of chitosan is the most extensive, and the quaternary ammonium group can also endow chitosan Antibacterial properties.
  • catecholization can also improve the water solubility of chitosan, and the catechol structure can also provide the possibility for the functionalization of materials.
  • Nano-silver is a common broad-spectrum antibacterial agent, which has good antibacterial effect on Gram-positive bacteria and Gram-negative bacteria.
  • silver nanoparticles often have certain cytotoxicity, and how to balance the relationship between them is very important.
  • the above-mentioned quaternized chitosan can form a synergistic antibacterial effect with nano silver, which can effectively reduce the concentration of silver, and reduce its cytotoxicity while ensuring the antibacterial effect.
  • a chitosan-based hydrogel dressing with high biocompatibility, antibacterial performance and wound infection indication function which can meet the needs of complex use environments and improve the convenience of patients. , to promote the efficiency of wound healing.
  • the purpose of the present invention is to solve the problem that the existing hydrogel wound dressings have low antibacterial efficiency and no wound infection indication function.
  • the synergistic antibacterial effect of quaternized chitosan, silver and curcumin, and the ability of zwitterions to inhibit bacterial adhesion resulted in a novel intelligent color-changing chitosan antibacterial hydrogel dressing.
  • the present invention is specifically realized through the following steps:
  • step 2) Dissolve the quaternized water-soluble modified chitosan obtained in step 1) in deionized water, prepare an aqueous solution with a mass concentration of 0.1 to 1 wt%, and add 3-(2,4-dihydroxy)benzene successively Propionic acid, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, using acetic acid to adjust the pH to 4-5.5 in the whole process, and further reacting for 12 hours to obtain catechol-modified bis Water-soluble modified chitosan, after dialysis and freeze-drying, double water-soluble modified chitosan is obtained. During the dialysis process, acetic acid is used to adjust the pH to 4-5.5;
  • step 2) the double water-soluble modified chitosan obtained in step 2) is dissolved in deionized water, silver nitrate is added, and the reduction of the catechol side chain on the double water-soluble modified chitosan molecular chain is used to avoid Light reaction for 0.5h to prepare nano-silver/double water-soluble modified chitosan solution;
  • the double water-soluble modified chitosan prepared in step 2), the nano silver/double water-soluble modified chitosan prepared in step 3) and curcumin, zwitterion, acrylamide, crosslinking Agent and initiator were dissolved in deionized water, mixed and stirred evenly, poured into a mold after centrifugal defoaming, combined with a one-pot free radical polymerization method at 60°C for 4 hours to obtain a nanocomposite and semi-interpenetrating polymer network structure Hydrogel dressing.
  • the deacetylation degree of the high molecular weight chitosan is 70%-90%, and the molecular weight is 50-3 million; the degree of quaternization of the double water-soluble modified chitosan is between 10%-60%, the degree of catecholization is 5%-60%, and the solubility of double water-soluble modified chitosan is above 25mg/mL.
  • concentration of glycidyltrimethylamine chloride in the above step 1) is 0.025-0.10g/ml
  • concentrations of 3-(2,4-dihydroxy)phenylpropionic acid and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride in the above step 2) were respectively 0.001-0.005g/ml and 0.001-0.005g/ml;
  • concentrations of the double water-soluble modified chitosan and silver nitrate in the above step 3) are respectively 0.015-0.05g/ml and 0.015-0.05g/ml;
  • the zwitterions in the above step 4) include phosphorylcholine (PC), sulfobetaine methacrylate (SBMA) and carboxybetaine methacrylate (CBMA);
  • the crosslinking agent is N, N - Methylenebisacrylamide (MBAA);
  • initiators include ammonium persulfate, sodium persulfate, potassium persulfate, and the like.
  • the concentration of each component is: double water-soluble modified chitosan 0.05-0.1g/ml, nano silver/double water-soluble modified chitosan 0.0002-0.0005g/ml, curcumin 0.001-0.005g/ml ml, zwitterion 0.02-0.1g/ml, acrylamide 0.1-0.5g/ml, crosslinking agent 0.0002-0.0008g/ml, initiator 0.001-0.004g/ml;
  • the hydrogel prepared by the present invention has the following functions:
  • the hydrogel dressing in the present invention also has pH-responsive intelligent discoloration function, excellent biocompatibility, high stretchability, anti-bacterial adhesion function, multi-effect antibacterial anti-adhesion, long-term antibacterial property and skin adhesion .
  • High molecular weight chitosan has excellent mechanical properties and stable physical and chemical properties.
  • high molecular weight chitosan is innovatively modified by quaternization and catecholization.
  • the prepared high molecular weight chitosan has good water solubility and can be used for high
  • the preparation of strength hydrogel expands its application range; at the same time, nano-silver can be prepared by reducing the structure of catechol; the nano-silver is small in size, and the particle size is controlled at 5-25nm; There are also a large number of residual amino groups on the chain, which have a chelating effect on silver and can be used as a stabilizer for nano-silver.
  • the nano-silver/double-modified chitosan solution does not precipitate after standing for more than 10 days.
  • the hydrogel dressing has antibacterial and multiple antibacterial effects: after zwitterionic polymerization, a hydration layer can be formed on the surface of the hydrogel to inhibit the adhesion of bacteria; nano-silver, double water-soluble modified chitosan, and curcumin can Realize synergistic antibacterial function, in which double water-soluble modified chitosan provides contact antibacterial property, curcumin and nano-silver provide external release antibacterial property; due to the physical and chemical interaction with the functional groups of the hydrogel dressing, such as high molecular weight shell The entanglement of polysaccharides with the molecular chains of the main body of the gel dressing (acrylamide and zwitterionic copolymer), the interaction of positively charged silver with electron-rich functional groups, etc., the hydrogel dressing has long-lasting slow-release antibacterial properties.
  • the hydrogel dressing has a certain adhesive effect on the skin by virtue of the combined effect of the catechol structure and the zwitterion, which can make the hydrogel adhere to the surface of the wound skin and can be used without external bandages for fixation.
  • the invention innovatively endows the hydrogel wound dressing with a responsive discoloration indicating function, which is expected to be applied in the fields of intelligent indicating wound repair hydrogel dressing and the like.
  • the hydrogel dressing is blue-yellow; when the pH is greater than 7 (if the pH rises and tends to be alkaline, an infection may have occurred, and the pH of the inflammatory stage is greater than 7), the hydrogel dressing is orange-yellow, which can provide a color visible to the naked eye Changes that directly indicate the infection of the wound.
  • the present invention has the following advantages:
  • the present invention greatly improves its water solubility by carrying out double modification of quaternization and catecholization on high molecular weight chitosan, solves the problem that chitosan is difficult to dissolve, and expands the application range of chitosan ;
  • the present invention uses the catechol structure on the chitosan molecular chain of double water-soluble modification to prepare nano-silver by reduction reaction, and the chitosan molecule after double-modification also has stable dispersion to the prepared nano-silver
  • the nano-silver particle size is 5-25nm, and the nano-silver/double-modified chitosan solution does not precipitate after standing for more than 10 days.
  • acetic acid is used in the whole preparation process, which avoids the generation of silver-containing precipitates, and the prepared nano-silver has small particle size and low cytotoxicity;
  • the present invention aims at the application scene of wound infection.
  • a nano-silver/double modified Antibacterial chitosan hydrogel dressing the above formula is original;
  • the hydrogel dressing in the present invention has a certain adhesion to the skin by virtue of the joint action of the catechol structure and the zwitterion, which can make the hydrogel adhere to the surface of the wound skin, and can be used without external bandages for fixing;
  • the hydrogel prepared in the present invention innovatively uses nano-silver/double water-soluble modified chitosan, double water-soluble modified chitosan, curcumin, zwitterion, acrylamide, etc. as raw materials. Realize the performance complementarity and synergy between various raw materials, so that the hydrogel dressing has the functions and characteristics of preventing bacterial adhesion, antibacterial, intelligent color development, high-strength stretching, and biocompatibility.
  • the polyacrylamide in the hydrogel provides it with high-strength performance
  • zwitterions provide anti-bacterial adhesion performance
  • quaternized chitosan, curcumin, and nano-silver have synergistic antibacterial effects
  • curcumin can be used according to the pH of the wound.
  • the change of the color reaction occurs, which is used to indicate the infection of the wound, so that the hydrogel material designed and prepared in the present invention is expected to be applied in the fields of intelligent hydrogel dressing for wound repair and the like.
  • Fig. 3 is a schematic diagram of the discoloration effect of the hydrogel material prepared by the present invention.
  • the chitosan powder (1,000,000 molecular weight, deacetylation degree 86%) of raw material grade high molecular weight is stirred and dispersed in deionized water, adds the acetic acid of 2.5wt%, is mixed with the chitosan aqueous solution of 0.5wt%; Glycidyl trimethylamine chloride (0.10g/ml) was added in the polysaccharide aqueous solution and reacted for 8h to obtain a quaternized water-soluble modified chitosan aqueous solution, which was dialyzed and freeze-dried to obtain a quaternized water-soluble modified chitosan, The degree of quaternization is 60%;
  • step 2) Dissolve the quaternized water-soluble modified chitosan obtained in step 1) in deionized water, prepare an aqueous solution with a mass concentration of 0.5 wt%, and add 3-(2,4-dihydroxy)phenyl Propionic acid (0.0025g/ml), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.003g/ml), use acetic acid to control the pH of the solution between 4-5.5 During the reaction for 12 hours, the double water-soluble modified chitosan aqueous solution obtained by further catecholization and water-soluble modification was obtained after dialysis and freeze-drying to obtain double water-soluble modified chitosan. During the dialysis process, acetic acid was used to regulate the dialysate pH at 4- 5.5, the degree of product catecholization is 46%;
  • step 3 Dissolve the double water-soluble modified chitosan obtained in step 2) in deionized water (0.05g/ml), add silver nitrate (0.05g/ml), and react in the dark for 0.5h to obtain nano silver/ Double water-soluble modified chitosan solution;
  • step 4) the nano-silver/double water-soluble modified chitosan (0.0005g/ml) obtained in the double water-soluble modified chitosan (0.05g/ml), step 3) obtained in step 2), curcumin (0.005g/ml), SBMA (0.1g/ml), acrylamide (0.25g/ml), MBAA (0.0005g/ml), ammonium persulfate (0.0025g/ml), etc. were added to deionized water in turn, mixed and stirred Uniform, poured after centrifugal defoaming, and made gel by one-pot in-situ free radical copolymerization at 60°C for 4 hours;
  • the prepared hydrogel dressing has a tensile strength of 324.6kPa, an elongation at break of 531%, and an adhesive strength of 8.2kPa; combined with ICP-MS testing, it can be seen that the release of silver in 7 days is 80%; Combining the living dead bacteria staining and antibacterial experiments, it can be seen that the hydrogel dressing can inhibit the adhesion of bacteria, and has a good antibacterial effect on Staphylococcus aureus and Escherichia coli models.
  • step 2) the quaternized water-soluble modified chitosan obtained in step 1) is dissolved in deionized water, and it is prepared into a quaternized water-soluble modified chitosan aqueous solution whose mass concentration is 0.75wt%, and 3- (2,4-dihydroxy)phenylpropionic acid (0.005g/ml), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.005g/ml), the whole process Use acetic acid to regulate the pH of the solution between 4-5.5, react for 12 hours to obtain a double water-soluble modified chitosan aqueous solution that is further catecholized and water-soluble modified, obtain double water-soluble modified chitosan after dialysis and freeze-drying, and dialyze The process uses acetic acid to regulate the pH of the dialysate between 4-5.5, and the degree of catecholization of the product is 21%;
  • step 3 Dissolve the double water-soluble modified chitosan obtained in step 2) in deionized water (0.03g/ml), add silver nitrate (0.025g/ml), and react in the dark for 0.5h to obtain nano silver/ Double water-soluble modified chitosan solution;
  • nano silver/two water-soluble modified chitosan (0.0002g/ml), curcumin obtained in the double water-soluble modified chitosan (0.05g/ml) obtained in step 2), step 3) (0.001g/ml), SBMA (0.04g/ml), acrylamide (0.5g/ml), MBAA (0.0002g/ml), potassium persulfate (0.0035g/ml), etc. were added to deionized water in turn, mixed and stirred Uniform, poured after centrifugal defoaming, and made gel by one-pot in-situ free radical copolymerization at 60°C for 4 hours;
  • the prepared hydrogel dressing has a tensile strength of 167kPa, an elongation at break of 608%, and an adhesive strength of 5.7kPa; combined with ICP-MS testing, it can be seen that the release of silver in 7 days is 64%; Live dead bacteria staining and antibacterial experiments showed that the hydrogel dressing can inhibit the adhesion of bacteria, and has good antibacterial effect on Staphylococcus aureus and Escherichia coli models.
  • step 2) the quaternized water-soluble modified chitosan obtained in step 1) is dissolved in deionized water, and the mass concentration is prepared into a quaternized water-soluble modified chitosan aqueous solution of 0.1 wt%, and 3- (2,4-dihydroxy)phenylpropionic acid (0.001g/ml), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.001g/ml), the whole process Use acetic acid to regulate the pH of the solution between 4-5.5, react for 12 hours to obtain a double water-soluble modified chitosan aqueous solution that is further catecholized and water-soluble modified, obtain double water-soluble modified chitosan after dialysis and freeze-drying, and dialyze The process uses acetic acid to regulate the pH of the dialysate between 4-5.5, and the degree of catecholization of the product is 7.8%;
  • step 3 Dissolve the double water-soluble modified chitosan obtained in step 2) in deionized water (0.015g/ml), add silver nitrate (0.015g/ml), and react in the dark for 0.5h to obtain nano silver/ Double water-soluble modified chitosan solution;
  • nano-silver/two water-soluble modified chitosan (0.0005g/ml) obtained in the double water-soluble modified chitosan (0.1g/ml) obtained in step 2), step 3), curcumin (0.003g/ml), SBMA (0.02g/ml), acrylamide (0.25g/ml), MBAA (0.0008g/ml), sodium persulfate (0.0015g/ml), etc. were added to deionized water in turn, mixed and stirred Uniform, poured after centrifugal defoaming, and made gel by one-pot in-situ free radical copolymerization at 60°C for 4 hours;
  • the obtained hydrogel dressing has a tensile strength of 138kPa, an elongation at break of 431%, and an adhesive strength of 4.4kPa; combined with ICP-MS testing, it can be seen that the release of silver in 7 days is 53%; Live dead bacteria staining and antibacterial experiments showed that the hydrogel dressing can inhibit the adhesion of bacteria, and has good antibacterial effect on Staphylococcus aureus and Escherichia coli models.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Materials Engineering (AREA)
  • Epidemiology (AREA)
  • Dispersion Chemistry (AREA)
  • Hematology (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Dermatology (AREA)
  • Medical Informatics (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pathology (AREA)
  • Biophysics (AREA)
  • Physics & Mathematics (AREA)
  • Surgery (AREA)
  • Biochemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Materials For Medical Uses (AREA)
  • Medicinal Preparation (AREA)

Abstract

一种通过变色效应指示伤口感染情况的纳米银/双改性壳聚糖抗菌水凝胶敷料及其制备方法。所述水凝胶敷料的制备方法为:首先利用高分子量的壳聚糖进行季铵化水溶性改性,再进一步儿茶酚化水溶性改性,制得双水溶性改性壳聚糖;然后利用双水溶性改性壳聚糖还原硝酸银制备纳米银/双水溶性改性壳聚糖溶液;最后将双水溶性改性壳聚糖、纳米银/双水溶性改性壳聚糖、姜黄素、两性离子、丙烯酰胺、交联剂、引发剂依次加入去离子水中,混合搅拌均匀,离心脱泡后浇筑,通过一锅原位自由基聚合法反应制得纳米银/双改性壳聚糖抗菌变色水凝胶敷料。该纳米银/双改性壳聚糖抗菌变色水凝胶敷料在智能指示型创伤修复水凝胶敷料等领域展现出巨大的应用潜力。

Description

一种通过变色效应指示伤口感染情况的纳米银/双改性壳聚糖抗菌水凝胶敷料及其制备方法 技术领域
本发明属于医用敷料领域,具体涉及一种通过变色效应指示伤口感染情况的纳米银/双改性壳聚糖抗菌水凝胶敷料及其制备方法。
背景技术
创面一般指正常的皮肤或组织在内部或外部因素作用下造成损害后皮肤被完整的破坏以及正常组织的损伤缺失,临床上和生活中常见的损伤创面有烧伤创面、电击伤创面、化学腐蚀创面等。由于创面直接与外界环境接触,极易发生感染,因此创面护理迫切需要研制出具有抗菌功能和促愈合效果的先进创面敷料。壳聚糖作为一种天然的高分子,在自然界中的储量仅次于纤维素,具有优异的生物相容性、止血性、抗菌性和促进伤口愈合能力,从而引起了研究者的极大关注。但经过降解处理的低分子量壳聚糖力学性能较差,理化性质不稳定,难以满足实际的使用需求。而商品化的降解壳聚糖价格较高,同时即使严格控制每一批次的壳聚糖降解参数,也难以得到分子量相同的降解壳聚糖产物。原料级高分子量的壳聚糖力学性能优异、理化性质稳定、价格低廉,但溶解问题是目前影响其使用范围的主要因素。因此,对壳聚糖的水溶性改性对于扩大高分子量壳聚糖的使用范围具有重要意义,其中属对壳聚糖进行季铵化改性的研究最为广泛,并且季铵基还能赋予壳聚糖抗菌性能。此外,儿茶酚化也可以提高壳聚糖的水溶性,邻苯二酚结构还可以为材料的功能化提供可能。
纳米银是一种常见的广谱抗菌剂,对革兰氏阳性菌和革兰氏阴性菌等都有很好的抗菌效力。然而纳米银往往存在一定的细胞毒性,如何平衡好两者的关系至关重要。而上述提到的季铵化壳聚糖可以与纳米银形成协同抗菌作用,可以有效降低银的浓度,在保证抗菌效果的同时降低其细胞毒性。
但是截止目前,报道或上市的绝大多数水凝胶敷料仅具备抗菌或抑菌性能, 对于实际伤口的感染情况无指示,医生和患者无法直接获取伤口感染恢复的相关信息,因此对于使用造成了很大的不便。
因此,本发明中计划设计一种同时具有高生物相容性、抗菌性能和伤口感染情况指示功能的壳聚糖基水凝胶敷料,可以满足复杂的使用环境需求,提高病患使用的便捷性,促进伤口愈合的效率。
发明内容
本发明的目的是解决现有水凝胶伤口敷料抗菌效率不高、无伤口感染情况指示功能的问题,通过对于大分子量壳聚糖分子进行季铵化和儿茶酚化双改性,同时结合季铵化壳聚糖、银和姜黄素的协同抗菌作用,以及两性离子的抑制细菌黏附的能力,制得一种新型智能变色壳聚糖抗菌水凝胶敷料。
本发明具体通过以下步骤实现:
1)将高分子量的壳聚糖粉末原料搅拌分散于去离子水中,加入0.1-5wt%的醋酸,配制成0.1~1wt%的壳聚糖水溶液;向壳聚糖水溶液中加入氯化缩水甘油三甲基胺,反应8h制得季铵化水溶性改性壳聚糖,透析冻干后得到季铵化水溶性改性壳聚糖材料;
2)将步骤1)中得到的季铵化水溶性改性壳聚糖溶于去离子水中,配制成质量浓度为0.1~1wt%的水溶液,依次加入3-(2,4-二羟基)苯基丙酸、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐,全程使用醋酸调控pH为4-5.5,进一步反应12h得到儿茶酚化改性的双水溶性改性壳聚糖,通过透析冻干后得到双水溶性改性壳聚糖,透析过程使用醋酸调控pH为4-5.5;
3)将步骤2)中得到的双水溶性改性壳聚糖溶于去离子水中,加入硝酸银,凭借双水溶性改性壳聚糖分子链上的儿茶酚侧链的还原作用,避光反应0.5h,制得纳米银/双水溶性改性壳聚糖溶液;
4)依次将步骤2)中制得的双水溶性改性壳聚糖、步骤3)中制得的纳米银/双水溶性改性壳聚糖与姜黄素、两性离子、丙烯酰胺、交联剂、引发剂溶于去离子水中,混合搅拌均匀,离心脱泡后浇筑于模具中,结合一锅自由基聚合法在60℃下反应4h制得具有纳米复合和半互穿聚合物网络结构的水凝胶敷料。
上述技术方案中,进一步的,所述的高分子量的壳聚糖脱乙酰度为70%-90%,分子量为50-300万;所述的双水溶性改性壳聚糖季铵化程度在10%-60%,儿茶酚化程度在5%-60%,双水溶性改性壳聚糖的溶解度在25mg/mL以上。
进一步的,上述步骤1)中的氯化缩水甘油三甲基胺的浓度为0.025-0.10g/ml;
进一步的,上述步骤2)中的3-(2,4-二羟基)苯基丙酸、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐的浓度分别为0.001-0.005g/ml和0.001-0.005g/ml;
进一步的,上述步骤3)中的双水溶性改性壳聚糖、硝酸银的浓度分别为0.015-0.05g/ml和0.015-0.05g/ml;
进一步的,上述步骤4)中的两性离子包括磷酰胆碱(PC),甲基丙烯酸磺酸甜菜碱(SBMA)和甲基丙烯酸羧酸甜菜碱(CBMA)等;交联剂为N,N-亚甲基双丙烯酰胺(MBAA);引发剂包括过硫酸铵、过硫酸钠、过硫酸钾等。其中,各组分的浓度分别为:双水溶性改性壳聚糖0.05-0.1g/ml、纳米银/双水溶性改性壳聚糖0.0002-0.0005g/ml、姜黄素0.001-0.005g/ml、两性离子0.02-0.1g/ml、丙烯酰胺0.1-0.5g/ml、交联剂0.0002-0.0008g/ml、引发剂0.001-0.004g/ml;
本发明制备的水凝胶具有以下功能:
本发明中的水凝胶敷料同时具有pH响应智能变色功能,优异的生物相容性、高倍拉伸性、抑制细菌黏附功能、多效抗菌抗粘附性、长效抗菌性和皮肤粘附性。
高分子量壳聚糖力学性能优异,理化性质稳定,本发明中创新性地对高分子量进行季铵化和儿茶酚化双重改性,所制得的高分子量壳聚糖水溶性好,可用于高强度水凝胶的制备,拓展其应用范围;同时可以通过儿茶酚结构还原制备纳米银;所述的纳米银尺寸较小,粒径控制在5-25nm;且由于季铵化壳聚糖分子链上还存在大量残余的氨基,对银具有螯合作用,可以作为纳米银的稳定剂,纳米银/双改性壳聚糖溶液静置10天以上不发生沉淀。
所述的水凝胶敷料具有抑菌和多重抗菌作用:其中两性离子聚合以后可以在水凝胶表面形成水合层,抑制细菌的黏附;纳米银、双水溶性改性壳聚糖、姜黄素可以实现协同抗菌功能,其中双水溶性改性壳聚糖提供接触抗菌性,姜黄素、纳米银提供外溶释放抗菌性;由于与水凝胶敷料本体官能团的物理、化学相互作用,如高分子量壳聚糖与凝胶敷料本体分子链(丙烯酰胺和两性离子共聚物)的缠结、带正电的银与富电子功能基团的相互作用等,水凝胶敷料具有长效缓释抗 菌性能。
水凝胶敷料凭借儿茶酚结构和两性离子的共同作用,对皮肤具有一定的黏附作用,可以使水凝胶黏附在伤口皮肤表面,无需外用绷带进行固定即可使用。
本发明创新性地赋予水凝胶伤口敷料以响应性变色指示功能,有望应用于智能指示型创伤修复水凝胶敷料等领域。所述水凝胶敷料的智能变色功能是来源于姜黄素的颜色随着pH的变化而发生变化:pH=5-6时(健康皮肤和愈合伤口呈弱酸性,酸碱度在5-6左右),水凝胶敷料呈青黄色;pH大于7时(如果酸碱度升高,偏向碱性,则说明可能发生了感染,发炎阶段pH大于7),水凝胶敷料呈橘黄色,可提供肉眼可见的颜色变化,直接指示伤口的感染情况。
本发明相对于现有技术具有以下优点:
1)本发明通过对高分子量壳聚糖进行季铵化和儿茶酚化双重改性,极大地提高了其水溶性,解决了壳聚糖难溶解的问题,拓展了壳聚糖的应用范围;
2)本发明使用双水溶性改性的壳聚糖分子链上的儿茶酚结构可以通过还原反应制备纳米银,同时双改性后的壳聚糖分子还对制得的纳米银具有稳定分散的作用,纳米银粒径为5-25nm,纳米银/双改性壳聚糖溶液静置10天以上不发生沉淀。并且整个制备过程中仅使用醋酸,避免了含银沉淀的产生,制得的纳米银粒径小,细胞毒性小;
3)本发明针对伤口感染的应用场景,通过对于原料的精心选择、组合,同时对于水凝胶制备配方进行优化,最终成功制得一种可以通过变色效应指示伤口感染情况的纳米银/双改性壳聚糖抗菌水凝胶敷料,上述配方具有独创性;
4)本发明中的水凝胶敷料凭借儿茶酚结构和两性离子的共同作用,对皮肤具有一定的黏附作用,可以使水凝胶黏附在伤口皮肤表面,无需外用绷带进行固定即可使用;
5)本发明中制备的水凝胶创新性地使用纳米银/双水溶性改性壳聚糖、双水溶性改性壳聚糖、姜黄素、两性离子、丙烯酰胺等作为原料,通过精心设计实现各种原料之间的性能互补和协同增效,使水凝胶敷料同时具备防止细菌黏附、抗菌、智能显色、高倍拉伸、生物相容等功能和特性。其中水凝胶中的聚丙烯酰胺为其提供高倍拉伸性能,两性离子提供抗细菌黏附性能,季铵化壳聚糖、姜黄素、纳米银具有协同抗菌效果,姜黄素更是可以根据伤口pH的变化发生变色反应, 用于指示伤口感染情况,使得本发明中设计制备的水凝胶材料有望应用于创伤修复智能水凝胶敷料等领域。
附图说明
图1本发明制备的纳米银的粒径测试结果和实物图;
图2本发明制备的纳米银/双改性壳聚糖溶液的稳定性测试结果;
图3本发明制备的水凝胶材料变色效应示意图。
具体实施方式
以下结合实例进一步说明本发明。
实施例1:
1)将原料级高分子量的壳聚糖粉末(100万分子量,脱乙酰度86%)搅拌分散于去离子水中,加入2.5wt%的醋酸,配制成0.5wt%的壳聚糖水溶液;向壳聚糖水溶液中加入氯化缩水甘油三甲基胺(0.10g/ml)反应8h得到季铵化水溶性改性壳聚糖水溶液,透析冻干后得到季铵化水溶性改性壳聚糖,季铵化程度为60%;
2)将步骤1)中得到的季铵化水溶性改性壳聚糖溶于去离子水中,配制成质量浓度为0.5wt%的水溶液,依次加入3-(2,4-二羟基)苯基丙酸(0.0025g/ml)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(0.003g/ml),全程使用醋酸调控溶液pH在4-5.5之间,反应12h得到进一步儿茶酚化水溶性改性的双水溶性改性壳聚糖水溶液,透析冻干后得到双水溶性改性壳聚糖,透析过程使用醋酸调控透析液pH在4-5.5之间,产物儿茶酚化程度为46%;
3)将步骤2)中得到的双水溶性改性壳聚糖溶于去离子水中(0.05g/ml),加入硝酸银(0.05g/ml),避光反应0.5h,制得纳米银/双水溶性改性壳聚糖溶液;
4)将步骤2)中得到的双水溶性改性壳聚糖(0.05g/ml)、步骤3)中得到的纳米银/双水溶性改性壳聚糖(0.0005g/ml)、姜黄素(0.005g/ml)、SBMA(0.1g/ml)、丙烯酰胺(0.25g/ml)、MBAA(0.0005g/ml)、过硫酸铵(0.0025g/ml)等依次加入去离子水中,混合搅拌均匀,离心脱泡后浇筑,通过一锅原位自由基共聚法60℃反应4h制得凝胶;
5)所制得的水凝胶敷料,其拉伸强度为324.6kPa,断裂伸长率为531%,黏附强度为8.2kPa;结合ICP-MS测试可知,7天银的释放量为80%;结合活死细菌染色和抗菌实验可知,该水凝胶敷料可以抑制细菌的黏附,对于金黄色葡萄球菌和大肠杆菌模型具有良好的抗菌作用。
实施例2:
1)将原料级高分子量的壳聚糖粉末(180万分子量,脱乙酰度74%)搅拌分散于去离子水中,加入5wt%的醋酸,配制成1wt%的壳聚糖水溶液;向壳聚糖水溶液中加入氯化缩水甘油三甲基胺(0.05g/ml)反应8h得到季铵化水溶性改性壳聚糖水溶液,透析冻干后得到季铵化水溶性改性壳聚糖,季铵化程度为34%;
2)将步骤1)中得到的季铵化水溶性改性壳聚糖溶于去离子水中,配制成质量浓度为0.75wt%的季铵化水溶性改性壳聚糖水溶液,依次加入3-(2,4-二羟基)苯基丙酸(0.005g/ml)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(0.005g/ml),全程使用醋酸调控溶液pH在4-5.5之间,反应12h得到进一步儿茶酚化水溶性改性的双水溶性改性壳聚糖水溶液,透析冻干后得到双水溶性改性壳聚糖,透析过程使用醋酸调控透析液pH在4-5.5之间,产物儿茶酚化程度为21%;
3)将步骤2)中得到的双水溶性改性壳聚糖溶于去离子水中(0.03g/ml),加入硝酸银(0.025g/ml),避光反应0.5h,制得纳米银/双水溶性改性壳聚糖溶液;
4)将步骤2)中得到的双水溶性改性壳聚糖(0.05g/ml)、步骤3)中得到的纳米银/双水溶性改性壳聚糖(0.0002g/ml)、姜黄素(0.001g/ml)、SBMA(0.04g/ml)、丙烯酰胺(0.5g/ml)、MBAA(0.0002g/ml)、过硫酸钾(0.0035g/ml)等依次加入去离子水中,混合搅拌均匀,离心脱泡后浇筑,通过一锅原位自由基共聚法60℃反应4h制得凝胶;
5)所制得的水凝胶敷料,其拉伸强度为167kPa,断裂伸长率为608%,黏附强度为5.7kPa;结合ICP-MS测试可知,7天银的释放量为64%;结合活死细菌染色和抗菌实验可知,该水凝胶敷料可以抑制细菌的黏附,对于金黄色葡萄球菌和大肠杆菌模型具有良好的抗菌作用。
实施例3:
1)将原料级高分子量的壳聚糖粉末(250万分子量,脱乙酰度72%)搅拌分散于去离子水中,加入0.1wt%的醋酸,配制成0.1wt%的壳聚糖水溶液;向壳聚糖水溶液中加入氯化缩水甘油三甲基胺(0.10g/ml)反应8h得到季铵化水溶性改性壳聚糖水溶液,透析冻干后得到季铵化水溶性改性壳聚糖,季铵化程度为56%;
2)将步骤1)中得到的季铵化水溶性改性壳聚糖溶于去离子水中,配制成质量浓度为0.1wt%的季铵化水溶性改性壳聚糖水溶液,依次加入3-(2,4-二羟基)苯基丙酸(0.001g/ml)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(0.001g/ml),全程使用醋酸调控溶液pH在4-5.5之间,反应12h得到进一步儿茶酚化水溶性改性的双水溶性改性壳聚糖水溶液,透析冻干后得到双水溶性改性壳聚糖,透析过程使用醋酸调控透析液pH在4-5.5之间,产物儿茶酚化程度为7.8%;
3)将步骤2)中得到的双水溶性改性壳聚糖溶于去离子水中(0.015g/ml),加入硝酸银(0.015g/ml),避光反应0.5h,制得纳米银/双水溶性改性壳聚糖溶液;
4)将步骤2)中得到的双水溶性改性壳聚糖(0.1g/ml)、步骤3)中得到的纳米银/双水溶性改性壳聚糖(0.0005g/ml)、姜黄素(0.003g/ml)、SBMA(0.02g/ml)、丙烯酰胺(0.25g/ml)、MBAA(0.0008g/ml)、过硫酸钠(0.0015g/ml)等依次加入去离子水中,混合搅拌均匀,离心脱泡后浇筑,通过一锅原位自由基共聚法60℃反应4h制得凝胶;
5)所制得的水凝胶敷料,其拉伸强度为138kPa,断裂伸长率为431%,黏附强度为4.4kPa;结合ICP-MS测试可知,7天银的释放量为53%;结合活死细菌染色和抗菌实验可知,该水凝胶敷料可以抑制细菌的黏附,对于金黄色葡萄球菌和大肠杆菌模型具有良好的抗菌作用。

Claims (4)

  1. 一种通过变色效应指示伤口感染情况的纳米银/双改性壳聚糖抗菌水凝胶敷料的制备方法,其特征在于:首先利用高分子量的壳聚糖进行季铵化水溶性改性,再进一步儿茶酚化水溶性改性,制得双水溶性改性壳聚糖;然后利用双水溶性改性壳聚糖还原硝酸银,制得纳米银/双水溶性改性壳聚糖水溶液;最后将双水溶性改性壳聚糖、纳米银/双水溶性改性壳聚糖、姜黄素、两性离子、丙烯酰胺、交联剂、引发剂依次加入去离子水中,混合搅拌均匀,离心脱泡后浇筑,通过一锅原位自由基聚合法反应制得纳米银/双改性壳聚糖抗菌变色水凝胶敷料;所述的高分子量的壳聚糖脱乙酰度为70%-90%,分子量为100-300万;所述的双水溶性改性壳聚糖季铵化程度在10%-60%,儿茶酚化程度在5%-60%,双水溶性改性壳聚糖的溶解度在25mg/mL以上。
  2. 如权利要求1所述的一种通过变色效应指示伤口感染情况的纳米银/双改性壳聚糖抗菌水凝胶敷料的制备方法,其特征在于:
    具体步骤如下:
    1)将高分子量的壳聚糖粉末原料搅拌分散于去离子水中,加入0.1-5wt%的醋酸,配制成0.1~1wt%的壳聚糖水溶液;向壳聚糖水溶液中加入氯化缩水甘油三甲基胺,反应8h制得季铵化水溶性改性壳聚糖,透析冻干后得到季铵化水溶性改性壳聚糖材料;
    2)将步骤1)中得到的季铵化水溶性改性壳聚糖溶于去离子水中,配制成质量浓度为0.1~1wt%的水溶液,依次加入3-(2,4-二羟基)苯基丙酸、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐,全程使用醋酸调控pH为4-5.5,进一步反应12h得到儿茶酚化改性的双水溶性改性壳聚糖,通过透析冻干后得到双水溶性改性壳聚糖,透析过程使用醋酸调控pH为4-5.5;
    3)将步骤2)中得到的双水溶性改性壳聚糖溶于去离子水中,加入硝酸银,避光反应0.5h,制得纳米银/双水溶性改性壳聚糖溶液;
    4)依次将步骤2)中制得的双水溶性改性壳聚糖、步骤3)中制得的纳米银/双水溶性改性壳聚糖、姜黄素、两性离子、丙烯酰胺、交联剂、引发剂溶于去离子水中,混合搅拌均匀,离心脱泡后浇筑于模具中,结合一锅自由基聚合法在60℃下反应4h制得具有纳米复合和半互穿聚合物网络结构的水凝胶敷料。
  3. 如权利要求2所述的一种通过变色效应指示伤口感染情况的纳米银/双改性壳聚糖抗菌水凝胶敷料的制备方法,其特征在于:
    步骤1)中的氯化缩水甘油三甲基胺的浓度为0.025-0.10g/ml;
    步骤2)中的3-(2,4-二羟基)苯基丙酸、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐的浓度分别为0.001-0.005g/ml和0.001-0.005g/ml;
    步骤3)中的双水溶性改性壳聚糖、硝酸银的浓度分别为0.015-0.05g/ml和0.015-0.05g/ml;
    步骤4)中的两性离子为磷酰胆碱(PC)、甲基丙烯酸磺酸甜菜碱(SBMA)或甲基丙烯酸羧酸甜菜碱(CBMA);交联剂为N,N-亚甲基双丙烯酰胺(MBAA);引发剂为过硫酸铵、过硫酸钠或过硫酸钾;其中,各组分的浓度分别为:双水溶性改性壳聚糖0.05-0.1g/ml、纳米银/双水溶性改性壳聚糖0.0002-0.0005g/ml、姜黄素0.001-0.005g/ml、两性离子0.02-0.1g/ml、丙烯酰胺0.1-0.5g/ml、交联剂0.0002-0.0008g/ml、引发剂0.001-0.004g/ml。
  4. 采用如权利要求1-3任一项所述的方法制备得到的一种通过变色效应指示伤口感染情况的纳米银/双改性壳聚糖抗菌水凝胶敷料。
PCT/CN2022/117686 2021-11-19 2022-09-08 一种通过变色效应指示伤口感染情况的纳米银/双改性壳聚糖抗菌水凝胶敷料及其制备方法 WO2023087864A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US18/306,986 US20230255546A1 (en) 2021-11-19 2023-04-25 Preparation of nano silver/dual modified chitosan antibacterial hydrogel dressing with discoloration effect for wound infection judgement and hydrogel dressing prepared by the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111397963.6A CN113975458B (zh) 2021-11-19 2021-11-19 一种通过变色效应指示伤口感染情况的纳米银/双改性壳聚糖抗菌水凝胶敷料及其制备方法
CN202111397963.6 2021-11-19

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US18/306,986 Continuation US20230255546A1 (en) 2021-11-19 2023-04-25 Preparation of nano silver/dual modified chitosan antibacterial hydrogel dressing with discoloration effect for wound infection judgement and hydrogel dressing prepared by the same

Publications (1)

Publication Number Publication Date
WO2023087864A1 true WO2023087864A1 (zh) 2023-05-25

Family

ID=79750144

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/117686 WO2023087864A1 (zh) 2021-11-19 2022-09-08 一种通过变色效应指示伤口感染情况的纳米银/双改性壳聚糖抗菌水凝胶敷料及其制备方法

Country Status (3)

Country Link
US (1) US20230255546A1 (zh)
CN (1) CN113975458B (zh)
WO (1) WO2023087864A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117224734A (zh) * 2023-11-10 2023-12-15 海门市三德体育用品有限公司 一种伤口张力屏蔽水凝胶敷料及其制备方法

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113975458B (zh) * 2021-11-19 2022-07-26 浙江大学 一种通过变色效应指示伤口感染情况的纳米银/双改性壳聚糖抗菌水凝胶敷料及其制备方法
CN115227866B (zh) * 2022-08-15 2023-03-28 浙江大学 兼具组织黏附、多重杀菌和电刺激组织再生功能的可注射水凝胶伤口敷料及其制备方法
CN115429930A (zh) * 2022-09-01 2022-12-06 西北大学 具有双重纳米酶活性的多功能水凝胶及制备方法
CN116271202A (zh) * 2023-02-20 2023-06-23 河南科技大学 快速自修复可注射纳米复合抗菌水凝胶敷料及其制备方法
CN116870263B (zh) * 2023-09-07 2023-11-21 四川省医学科学院·四川省人民医院 一种具有仿生层结构的角膜绷带镜及其制备方法

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102552964A (zh) * 2012-01-09 2012-07-11 青岛明药堂医药科技开发有限公司 一种纳米银壳聚糖复合抗菌组合物、创口贴及其制备方法
WO2012143788A1 (en) * 2011-04-20 2012-10-26 Diabetes Science International Foundation Wound dressing comprising of silver chitosan
CN105478792A (zh) * 2015-12-05 2016-04-13 浙江大学 一种改性壳聚糖-纳米银溶胶的绿色制备方法
CN106729940A (zh) * 2017-01-24 2017-05-31 浙江大学 一种缓释型长效抗菌载银敷料及其制备方法
CN108524999A (zh) * 2018-05-03 2018-09-14 东华大学 一种慢性伤口用pH敏感型长效修复医用敷膜及其制备方法
CN109260509A (zh) * 2018-11-27 2019-01-25 浙江海洋大学 一种基于聚多巴胺和壳寡糖的自组装接触型抗菌水凝胶敷料及其制备方法
CN109663146A (zh) * 2019-02-01 2019-04-23 浙江大学 一种抗菌、可注射式温敏壳聚糖凝胶敷料及其制备方法
CN112007209A (zh) * 2020-04-29 2020-12-01 浙江大学 一种cs/qcs/两性离子/环氧化两性离子抗杀释菌一体化凝胶敷料及其制备方法
CN113975458A (zh) * 2021-11-19 2022-01-28 浙江大学 一种通过变色效应指示伤口感染情况的纳米银/双改性壳聚糖抗菌水凝胶敷料及其制备方法

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012143788A1 (en) * 2011-04-20 2012-10-26 Diabetes Science International Foundation Wound dressing comprising of silver chitosan
CN102552964A (zh) * 2012-01-09 2012-07-11 青岛明药堂医药科技开发有限公司 一种纳米银壳聚糖复合抗菌组合物、创口贴及其制备方法
CN105478792A (zh) * 2015-12-05 2016-04-13 浙江大学 一种改性壳聚糖-纳米银溶胶的绿色制备方法
CN106729940A (zh) * 2017-01-24 2017-05-31 浙江大学 一种缓释型长效抗菌载银敷料及其制备方法
CN108524999A (zh) * 2018-05-03 2018-09-14 东华大学 一种慢性伤口用pH敏感型长效修复医用敷膜及其制备方法
CN109260509A (zh) * 2018-11-27 2019-01-25 浙江海洋大学 一种基于聚多巴胺和壳寡糖的自组装接触型抗菌水凝胶敷料及其制备方法
CN109663146A (zh) * 2019-02-01 2019-04-23 浙江大学 一种抗菌、可注射式温敏壳聚糖凝胶敷料及其制备方法
CN112007209A (zh) * 2020-04-29 2020-12-01 浙江大学 一种cs/qcs/两性离子/环氧化两性离子抗杀释菌一体化凝胶敷料及其制备方法
CN113975458A (zh) * 2021-11-19 2022-01-28 浙江大学 一种通过变色效应指示伤口感染情况的纳米银/双改性壳聚糖抗菌水凝胶敷料及其制备方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117224734A (zh) * 2023-11-10 2023-12-15 海门市三德体育用品有限公司 一种伤口张力屏蔽水凝胶敷料及其制备方法

Also Published As

Publication number Publication date
CN113975458B (zh) 2022-07-26
US20230255546A1 (en) 2023-08-17
CN113975458A (zh) 2022-01-28

Similar Documents

Publication Publication Date Title
WO2023087864A1 (zh) 一种通过变色效应指示伤口感染情况的纳米银/双改性壳聚糖抗菌水凝胶敷料及其制备方法
Yao et al. Design strategies for adhesive hydrogels with natural antibacterial agents as wound dressings: Status and trends
Mozalewska et al. Chitosan-containing hydrogel wound dressings prepared by radiation technique
CN101982202B (zh) 一种医用水凝胶敷料及其制备方法
CN110551299B (zh) 一种自粘附性聚丙烯酰胺复合水凝胶及其制备方法与应用
BR112017016072B1 (pt) Composição, curativo de ferida, e, método de fabricação de uma composição
CN112480434B (zh) 一种铜离子抗菌水凝胶及制备方法和应用
CN104027833A (zh) 一种壳聚糖水凝胶敷料的制备方法
Huang et al. A tannin-functionalized soy protein-based adhesive hydrogel as a wound dressing
CN112618801B (zh) 一种3d打印制备功能型术后防粘连材料的方法
Wu et al. Conductive dual hydrogen bonding hydrogels for the electrical stimulation of infected chronic wounds
WO2017215610A1 (zh) 一种高效安全的壳聚糖衍生物基消毒液及其制备方法
CN114404646B (zh) CM-β-CD负载鞣酸聚丙烯酰胺型双网络抗菌水凝胶
Wang et al. UV cross-linked injectable non-swelling dihydrocaffeic acid grafted chitosan hydrogel for promoting wound healing
Cheng et al. Biomass-derived ultrafast cross-linked hydrogels with double dynamic bonds for hemostasis and wound healing
CN112480494A (zh) 自抗菌医用手套及其制备方法
Liu et al. Preparation of a nanocomposite hydrogel with high adhesion, toughness, and inherent antibacterial properties by a one-pot method
CN114381083B (zh) 一种角膜接触镜用抗菌抗氧化水凝胶及其制备方法
CN116407674A (zh) 一种载有单宁酸的高强度可自愈抗菌水凝胶的制备方法
CN1569366A (zh) 一种纳米银水溶液制剂其制备方法、用途及其使用方法
CN100488572C (zh) 磺胺嘧啶盐高分子水凝胶敷料及其制备方法
Cao et al. Mechanoactive wound dressing using poly (N-isopropyl acrylamide) based hydrogels
CN115671376B (zh) 一种可注射自愈合甘草酸水凝胶敷料及其制备方法与应用
Yang et al. Fe3+-induced coordination cross-linking gallic acid-carboxymethyl cellulose self-healing hydrogel
CN115537017B (zh) 一种水凝胶及其制备方法和应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22894404

Country of ref document: EP

Kind code of ref document: A1