WO2023231050A1 - 一种强韧抗菌水凝胶敷料及其制备方法 - Google Patents

一种强韧抗菌水凝胶敷料及其制备方法 Download PDF

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WO2023231050A1
WO2023231050A1 PCT/CN2022/097164 CN2022097164W WO2023231050A1 WO 2023231050 A1 WO2023231050 A1 WO 2023231050A1 CN 2022097164 W CN2022097164 W CN 2022097164W WO 2023231050 A1 WO2023231050 A1 WO 2023231050A1
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hydrogel dressing
strong antibacterial
hydrogel
antibacterial hydrogel
preparation
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高长有
刘笑庆
王秋怡
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浙江大学
浙江大学绍兴研究院
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    • 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
    • A61L26/0009Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0014Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A61L26/0009Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0019Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A61L26/0009Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0023Polysaccharides
    • 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
    • A61L26/0009Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0028Polypeptides; Proteins; Degradation products thereof
    • A61L26/0033Collagen
    • 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
    • A61L26/0009Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0028Polypeptides; Proteins; Degradation products thereof
    • A61L26/0038Gelatin
    • 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
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00Processes of treating or compounding macromolecular substances
    • C08J3/02Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075Macromolecular gels
    • 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
    • A61L2300/21Acids
    • A61L2300/214Amino acids
    • 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
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2389/00Characterised by the use of proteins; Derivatives thereof
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2477/00Characterised by the use of polyamides obtained by reactions forming a carboxylic amide link in the main chain; Derivatives of such polymers
    • C08J2477/04Polyamides derived from alpha-amino carboxylic acids
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08KUse of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00Use of organic ingredients
    • C08K5/04Oxygen-containing compounds
    • C08K5/05Alcohols; Metal alcoholates
    • C08K5/053Polyhydroxylic alcohols
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the technical field of biomedical polymer materials, and in particular to a strong antibacterial hydrogel dressing and a preparation method thereof.
  • Wound healing includes four processes: hemostasis, inflammation, proliferation and remodeling. Depending on the patient's degree of injury, age and health, as well as external factors such as foreign bodies and infections, the entire healing process will last from several days to several years. Skin injuries are common, and skin wound healing is a common clinical problem. The cost of treating wounds, especially chronic wounds, is huge every year, which puts huge economic pressure on patients and the medical system. In order to reduce the cost of wound care and solve the problems of excessive secretion of exudate, susceptibility to infection, and susceptibility to scarring during wound healing, functional wound dressings continue to be developed.
  • Hydrogel is a hydrophilic three-dimensional macromolecular network obtained through cross-linking between polymer chains.
  • the cross-linking method can be divided into physical cross-linking and chemical cross-linking.
  • Chemical cross-linking requires the introduction of cross-linking agents and, in some cases, organic solvents.
  • these cross-linking agents and organic solvents cannot be completely removed from the system, and the residues can easily lead to toxicity problems.
  • Physical cross-linking methods mainly include hydrogen bonding, van der Waals forces, host-guest interactions, electrostatic interactions, and cyclic freezing and thawing.
  • the resulting hydrogel usually has poor mechanical properties and cannot meet the needs of daily activities of skin wounds, or the preparation process is complicated and energy-consuming, such as cyclic freezing and thawing. .
  • How to avoid the residue of cross-linking agents and organic solvents while ensuring that the hydrogel has good mechanical properties and the preparation method is simple and low-cost is a major problem faced by the field of hydrogel dressings.
  • hydrogel dressings can provide a moist and healing environment for the wound, it also provides an excellent place for the growth of bacteria.
  • Most hydrogel dressings currently on the market are powerless against bacterial infections.
  • a common improvement method to address this problem is to add antibacterial agents to give the hydrogel dressing antibacterial capabilities.
  • Antibacterial agents can be divided into natural antibacterial agents, inorganic antibacterial agents and organic antibacterial agents according to different sources. Typical representatives are chitosan, silver ions and antibiotics respectively.
  • Chitosan has a wide range of sources, is green and safe, but the number of effective antibacterial amino groups is small, resulting in weak antibacterial ability; silver ions have a long effective effect and have no drug resistance, but silver ions are mostly added to hydrogels in the form of nanometers. , poor stability, easy to aggregate, and poor killing effect on Gram-positive bacteria; antibiotics are a common and effective antibacterial agent, but their single-target binding mechanism with bacterial surface proteins can easily lead to bacterial resistance. sex. Therefore, researchers are eager to find a new antibacterial hydrogel dressing that is safe, efficient, broad-spectrum antibacterial, stable, easy to obtain, low cost, non-toxic, and difficult to induce drug resistance.
  • One idea is to find a new type of antibacterial hydrogel dressing rich in Amino antibacterial agent, and the antibacterial agent should have the ability to be easily mixed into the hydrogel and quickly released during application.
  • the purpose of the present invention is to provide a strong antibacterial hydrogel dressing and a preparation method thereof.
  • This hydrogel dressing enhances its mechanical properties through salting out on the basis of physical cross-linking, and the preparation process is simple and easy to repeat; it has excellent antibacterial properties by adding a new high-efficiency antibacterial agent, hyperbranched polylysine, for use in skin wounds Antibacterial and healing.
  • a preparation method of strong antibacterial hydrogel dressing which specifically includes the following components:
  • every 100 parts of the material contains 5-20 parts of the host material, 20-50 parts of glycerin, 0.0025-0.3 parts of hyperbranched polylysine, and the rest is water.
  • a method for preparing a strong antibacterial hydrogel dressing is as follows:
  • the molecular weight of hyperbranched polylysine in the process step is 3-7kDa.
  • the main materials in the process steps are chitosan, collagen, alginate, hyaluronic acid, polyethylene glycol, gelatin, polyurethane, polylactic acid, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid, polyurethane, and polyvinyl alcohol.
  • Bohm One or a combination of more than one of Bohm.
  • the heating conditions in the process step are 10-60 minutes at 40-80°C, and the standing conditions are 30-60 minutes at room temperature or 5-15 minutes at 4°C.
  • the composition of the ionic solution in the process step is: the anions are tartrate, acetate, chromate, citrate, sulfate, hydrogen sulfate, carbonate, bicarbonate, dihydrogen phosphate, and thiosulfate.
  • the cation is one of ammonium ions, lithium ions, potassium ions, sodium ions, manganese ions, calcium ions, and barium ions.
  • the present invention has the following beneficial effects:
  • the invention provides a strong antibacterial hydrogel dressing that forms gel through hydrogen bonding of the main material, avoiding toxicity problems caused by the addition of cross-linking agents and still maintaining a blocky shape.
  • the strong antibacterial hydrogel dressing provided by the present invention is enhanced by salting out of the Hofmeister effect, so that the tensile and compressive properties are greatly improved, surpassing the strength level of tens of kPa of existing dressings.
  • the invention provides a strong antibacterial hydrogel dressing with a lower concentration of antibacterial agents than the existing technology; hyperbranched polylysine can destroy bacterial cell membranes and DNA and increase the level of reactive oxygen species in bacterial cells.
  • the mechanism plays an efficient and broad-spectrum antibacterial and bactericidal effect.
  • the preparation method of a strong antibacterial hydrogel dressing provided by the invention has simple process, simple operation, low cost and good repeatability.
  • the obtained hydrogel dressing is suitable for mechanically damaged wounds, thermally damaged wounds, Ulcerative wounds and other types of skin wounds.
  • Figure 1 is a display diagram of the hydrogel dressing prepared by the present invention.
  • Figure 2 shows the mechanical properties of the hydrogel dressing in Example 2 and Comparative Example 1, where (a) and (b) are the compression test curves of the hydrogel dressing in Comparative Example 1 and Example 2 respectively, and (c) ) and (d) are the tensile test curves of the hydrogel dressing in Comparative Example 1 and Example 2 respectively;
  • Figure 3 is an apparent diagram of the inhibition zone of the hydrogel dressing in Example 3.
  • Figure 4 shows the in vitro antibacterial performance of the hydrogel dressing in Example 4 and Comparative Example 2.
  • Step 1 Weigh 25 mg of hyperbranched polylysine (3kDa) and 5g of collagen into a mixed solution of 24.995 mL of ultrapure water and 20 mL of glycerin, and stir for 1 hour at 60°C to dissolve.
  • Step 2 Let the dissolved solution stand at room temperature for 60 minutes to form a gel.
  • Step 3 Cut the hydrogel into slices, immerse it in a 15% sodium dihydrogen phosphate solution for 24 hours, then take it out, rinse with deionized water and dry it.
  • Step 1 Weigh 50 mg of hyperbranched polylysine (3kDa) and 5g of gelatin into a mixed solution of 24.95 mL of ultrapure water and 20 mL of glycerol, and stir for 30 minutes at 50°C to dissolve.
  • Step 2 Let the dissolved solution stand for 20 minutes at 4°C to form a gel.
  • Step 3 Make the hydrogel into a rectangular strip or cylinder, immerse it in a 20% ammonium sulfate solution for 12 hours, then take it out, rinse with deionized water and dry it.
  • the compressive properties of the hydrogel sample were tested at a compression speed of 2mm/min, as shown in Figure 2(b); the tensile properties of the hydrogel sample were tested at a tensile speed of 10mm/min, as shown in Figure 2 (d) is shown.
  • the hydrogel dressing prepared in this example has excellent mechanical properties. It does not break when compressed to 85% strain. The maximum stress reaches 2.8MPa, and the deformation can be restored when the load is removed; and the tensile strength can reach 0.37 MPa, the elongation at break is 397%, and the elastic modulus is 0.17MPa.
  • Step 1 Weigh 25 mg of hyperbranched polylysine (5 kDa) and 5 g of collagen into a mixed solution of 34.95 mL of ultrapure water and 10 mL of glycerin, and stir for 1 hour at 60°C to dissolve.
  • Step 2 Let the dissolved solution stand at room temperature for 60 minutes to form a gel.
  • Step 3 Cut the hydrogel into slices, immerse it in a 15% sodium citrate solution for 12 hours, then take it out, rinse with deionized water and dry it.
  • a hydrogel disk with a diameter of 6 mm was placed on an agar medium coated with 200 ⁇ L of Staphylococcus aureus at a concentration of 10 8 CFU/mL, and cultured at 37°C for 12 hours.
  • the resulting inhibition zone diagram is as follows As shown in Figure 3, it can be seen that an obvious inhibition zone appeared around the hydrogel.
  • Step 1 Weigh 50 mg of hyperbranched polylysine (5 kDa) and 5 g of gelatin into a mixed solution of 34.995 mL of ultrapure water and 10 mL of glycerin, and stir for 30 minutes at 50°C to dissolve.
  • Step 2 Let the dissolved solution stand for 20 minutes at 4°C to form a gel.
  • Step 3 Cut the hydrogel into slices, immerse it in a 20% sodium citrate solution for 12 hours, then take it out, rinse with deionized water and dry it.
  • Step 1 Weigh 50 mg of hyperbranched polylysine (3kDa) and 5g of gelatin into a mixed solution of 24.95 mL of ultrapure water and 20 mL of glycerol, and stir for 30 minutes at 50°C to dissolve.
  • Step 2 Let the dissolved solution stand for 20 minutes at 4°C to form a gel.
  • Step 3 Make the hydrogel into a rectangular strip or cylinder.
  • the compressive properties of the hydrogel sample were tested at a compression speed of 2mm/min, as shown in Figure 2(a); the tensile properties of the hydrogel sample were tested at a tensile speed of 10mm/min, as shown in Figure 2 (c) is shown. It can be seen that the mechanical properties of the hydrogel dressing are poor. It breaks when compressed to 76% strain. The maximum stress is only 13.7kPa; the tensile strength is only 4.0kPa, the elongation at break is 44%, and the elastic modulus is 0.03. MPa.
  • the preparation process disclosed by the present invention introduces the step of salting out enhancement through the Hofmeister effect. From the comparison of mechanical properties shown in Figure 2, it can be seen that the hydrogel dressing obtained by the preparation method disclosed by the present invention has excellent mechanical properties.
  • Step 1 Weigh 5g of gelatin and add it to a mixed solution of 35mL of ultrapure water and 10mL of glycerin, and stir for 30 minutes at 50°C to dissolve.
  • Step 2 Let the dissolved solution stand for 20 minutes at 4°C to form a gel.
  • Step 3 Cut the hydrogel into slices, immerse it in a 20% sodium citrate solution for 12 hours, then take it out, rinse with deionized water and dry it.
  • the hydrogel prepared in this comparative example has no inhibitory effect on Staphylococcus aureus and Escherichia coli at three dosages, and even the number of colonies increases because the added gelatin can provide nutrients for the bacteria, and the water The more gel is added, the greater the number of colonies increases.

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Abstract

涉及一种强韧抗菌水凝胶敷料及其制备方法。该水凝胶敷料是基于聚乙烯醇、明胶、胶原蛋白等成胶骨架的氢键作用成胶,成胶前混入超支化聚赖氨酸,成胶后通过在离子溶液中浸泡增强力学性能。经由氢键作用物理成胶可避免化学交联方法中交联剂残留导致的毒性问题,并且通过霍夫迈斯特效应盐析增强克服了物理交联方法得到的水凝胶力学性能差的缺点。制备的水凝胶敷料具有良好的拉伸、压缩性能和抗菌性能。提供的水凝胶敷料适用于各类皮肤伤口,且制备方法简便、可重复性高、成本低,有望在抗菌皮肤敷料领域获得广泛应用。

Description

一种强韧抗菌水凝胶敷料及其制备方法 技术领域
本发明涉及生物医用高分子材料技术领域,特别涉及一种强韧抗菌水凝胶敷料及其制备方法。
背景技术
皮肤损伤是人体健康的严重威胁,会导致体内水分、热量流失和降低抵御外界病原体侵入的能力。伤口愈合包括止血、炎症、增殖和重塑四个过程。根据患者不同的损伤程度、年龄和健康状况以及异物、感染等外界因素,整个愈合过程将持续数天至数年不等。皮肤损伤多发,皮肤伤口的愈合是临床上的常见问题,每年用于治疗伤口,特别是慢性伤口的花费巨大,这为患者以及医疗系统带来了巨大的经济压力。为降低伤口护理的成本,并解决伤口愈合过程中存在的渗出液大量分泌、易感染、易产生疤痕等问题,继续开发功能性伤口敷料。随着伤口愈合理论的逐渐清晰,伤口敷料的形式也经历了很大的变迁。传统的伤口敷料,如纱布、绷带、棉垫等,为干性敷料,只能为伤口提供物理保护,对伤口愈合和预防感染的作用有限,且取下敷料时对伤口的粘附会造成继发性损伤;而现代敷料,如泡沫、水胶体、水凝胶等,基于潮湿环境的愈合理论,与传统敷料相比具有清创、保湿、防感染、抑制瘢痕化等优点,这其中水凝胶由于具有良好的吸渗性、保湿性、非粘连性、生物相容性以及可作载体等特点而受到广泛关注。
然而水凝胶敷料也具有其局限性。水凝胶是亲水的三维大分子网络,通过聚合物链之间的交联得到,交联方式可以分为物理交联和化学交联。化学交联需要引入交联剂,部分情况下还需要有机溶剂,而这些交联剂、有机溶剂无法从体系中彻底除去,残留物容易导致毒性问题。物理交联手段主要有氢键、范德华力、主客体作用、静电作用和循环冻融等。虽然物理交联避免了交联剂和有机溶剂的残留,但得到的水凝胶通常力学性能较差,不能满足皮肤伤口的日常活动需要,又或者制备过程复杂、能耗高,例如循环冻融。如何在避免交联剂和有机溶剂的残留的同时,保证水凝胶具有良好的力学性能,且制备方法简便、低廉,是水凝胶敷料领域面临的一大难题。
另一方面,水凝胶敷料的保湿性固然可以为伤口提供一个湿润的、有利于愈合的环境,却也为细菌的滋生提供了一个绝佳的场所。目前市面上大部分水凝胶敷料对于细菌感染无能为力,针对这一问题通用的改进方法是加入抗菌剂赋予水凝胶敷料抗菌能力。抗菌剂根据来源不同可分为天然抗菌剂、无机抗菌剂和有机抗菌剂,典型代表分别为壳聚糖、银离子和抗生素。壳聚糖来源广泛、绿色安全,但有效抗菌基团氨基数量较少导致其抗菌能力较弱;银离子有效作用时间长、无耐药性,但银离子多以纳米形式添加到水凝胶中,稳定性差,容易团聚,且对革兰氏阳性菌杀灭效果较差;抗生素是一类常见且有效的抗菌剂,然而其与细菌表面蛋白的单靶点结合作用机理容易导致细菌产生耐药性。因此研究人员迫切希望能够寻找到一种安全、高效、广谱抗菌、性质稳定、易获得、成本低、无毒、不易诱导耐药性的新型抗菌水凝胶敷料,一种思路是寻找富含氨基的抗菌剂,且该抗菌剂应具备能便捷混入水凝胶中并在应用时快速释放的能力。
发明内容
针对上述问题,本发明的目的是提供一种强韧抗菌水凝胶敷料及其制备方法。该水凝胶敷料在物理交联的基础上通过盐析作用增强力学性能,制备过程简单易重复;通过添加新型高效抗菌剂超支化聚赖氨酸而具备优异的抗菌性能,以用于皮肤伤口的抗菌、促愈合。
为实现上述目的,本发明提供以下的技术方案,一种强韧抗菌水凝胶敷料的制备方法,具体包括以下组分:
按重量计,每100份材料中含有5-20份主体材料、20-50份甘油、0.0025-0.3份超支化聚赖氨酸,其余为水。
一种强韧抗菌水凝胶敷料的制备方法,其制备工艺步骤如下:
将超支化聚赖氨酸与主体材料加入水与甘油的混合溶液中,搅拌加热使其充分溶解;溶解后的溶液静置成胶;将固体水凝胶切成所需形状,置于适当体积的重量分数为10-35%的离子溶液中浸泡8-48小时后取出,用水冲洗并擦干。
进一步地,所述工艺步骤中超支化聚赖氨酸分子量为3-7kDa。
进一步地,所述工艺步骤中主体材料为壳聚糖、胶原蛋白、海藻酸盐、透明质酸、聚乙二醇、明胶、聚氨酯、聚乳酸、聚乙烯吡咯烷酮、聚乙烯醇、聚丙烯酸、卡波姆中的一种或多种的组合。
进一步地,所述工艺步骤中加热条件为40-80℃下10-60分钟,静置条件为室温下30-60分钟或4℃下5-15分钟。
进一步地,所述工艺步骤中离子溶液的组成为:阴离子为酒石酸根、醋酸跟、铬酸根、柠檬酸根、硫酸根、硫酸氢根、碳酸根、碳酸氢根、磷酸二氢根、硫代硫酸根、氯离子中的一种,阳离子为铵根离子、锂离子、钾离子、钠离子、锰离子、钙离子、钡离子中的一种。
本发明相对于现有技术具有以下有益效果:
1.本发明提供的一种强韧抗菌水凝胶敷料,通过主体材料的氢键作用成胶,避免了因交联剂的加入而导致的毒性问题,并且仍能保持块状形态。
2.本发明提供的一种强韧抗菌水凝胶敷料,通过霍夫迈斯特效应盐析增强,使拉伸、压缩性能得到大幅提高,超越了已有敷料数十kPa的强度级别。
3.本发明提供的一种强韧抗菌水凝胶敷料,所含抗菌剂的浓度低于现有技术;超支化聚赖氨酸可以通过破坏细菌细胞膜、DNA以及提升细菌细胞内活性氧水平等机理起到高效广谱抑菌、杀菌作用。
4.本发明提供的一种强韧抗菌水凝胶敷料制备方法,工艺简便、操作简单、成本低、可重复性好,得到的水凝胶敷料适用于机械损伤性创面、热损伤性创面、溃疡性创面等各类皮肤创面。
附图说明
图1为本发明制备的水凝胶敷料的展示图;
图2为实施例2及对比例1中该水凝胶敷料的力学性能,其中,(a)、(b)分别为对比例1、实施例2中水凝胶敷料的压缩测试曲线,(c)、(d)分别为对比例1、实施例2中水凝胶敷料的拉伸测试曲线;
图3为实施例3中该水凝胶敷料的抑菌圈表观图;
图4为实施例4及对比例2中该水凝胶敷料的体外抗菌性能。
具体实施方式
以下结合实施例进一步说明本发明的技术方案,但这些实施例并不用于限制本发明。
实施例1:
第一步:称取25mg超支化聚赖氨酸(3kDa)和5g胶原蛋白加入至24.995mL超纯水和20mL甘油的混合溶液中,60℃下搅拌1小时使其溶解。
第二步:溶解后的溶液于室温下静置60分钟成胶。
第三步:将水凝胶切成片状,浸没于重量分数为15%的磷酸二氢钠溶液中24h,随后取出,用去离子水冲洗并擦干。
本实施例制得的水凝胶的展示图如图1所示。
实施例2:
第一步:称取50mg超支化聚赖氨酸(3kDa)和5g明胶加入至24.95mL超纯水和20mL甘油的混合溶液中,50℃下搅拌30分钟使其溶解。
第二步:溶解后的溶液于4℃下静置20分钟成胶。
第三步:将水凝胶制成矩形长条状、圆柱状,浸没于重量分数为20%的硫酸铵溶液中12小时,随后取出,用去离子水冲洗并擦干。
以下是本实施例制得的水凝胶的力学性能测试。在2mm/min的压缩速度下,测试水凝胶样品的压缩性能,如图2(b)所示;在10mm/min的拉伸速度下,测试水凝胶样品的拉伸性能,如图2(d)所示。可知该实施例制得的水凝胶敷料具有优异的力学性能,其在被压缩到85%应变时不发生破坏,最大应力达到2.8MPa,撤去载荷形变即可恢复;而拉伸强度可达到0.37MPa,断裂伸长率为397%,弹性模量为0.17MPa。
实施例3:
第一步:称取25mg超支化聚赖氨酸(5kDa)和5g胶原蛋白加入至34.95mL超纯水和10mL甘油的混合溶液中,60℃下搅拌1小时使其溶解。
第二步:溶解后的溶液于室温下静置60分钟成胶。
第三步:将水凝胶切成片状,浸没于重量分数为15%的柠檬酸钠溶液中12小时,随后取出,用去离子水冲洗并擦干。
以下是本实施例制得的水凝胶的抑菌圈测试。将直径为6mm的水凝胶圆片 置于涂布有200μL浓度为10 8CFU/mL的金黄色葡萄球菌的琼脂培养基上,于37℃下培养12小时,所得抑菌圈表观图如图3所示,可以看到水凝胶周围出现了明显的抑菌圈。
实施例4:
第一步:称取50mg超支化聚赖氨酸(5kDa)和5g明胶加入至34.995mL超纯水和10mL甘油的混合溶液中,50℃下搅拌30分种使其溶解。
第二步:溶解后的溶液于4℃下静置20分钟成胶。
第三步:将水凝胶切成片状,浸没于重量分数为20%的柠檬酸钠溶液中12h,随后取出,用去离子水冲洗并擦干。
以下是本实施例制得的水凝胶的体外抗菌性能测试。将不同质量(25mg、50mg、100mg)的水凝胶与500μL浓度为10 6CFU/mL的金黄色葡萄球菌和大肠杆菌在37℃下共培养12小时,利用涂板法在琼脂板上对菌落数进行定量,所得抑菌率如图4所示。由图4可知,归因于所负载的超支化聚赖氨酸,本实施例制得的水凝胶对于金黄色葡萄球菌在三种用量下均达到了百分百杀灭;而对于大肠杆菌,在25mg、50mg两种用量下即有显著的杀灭效果,在100mg的用量下可以达到百分百杀灭。
对比例1:
第一步:称取50mg超支化聚赖氨酸(3kDa)和5g明胶加入至24.95mL超纯水和20mL甘油的混合溶液中,50℃下搅拌30分钟使其溶解。
第二步:溶解后的溶液于4℃下静置20分钟成胶。
第三步:将水凝胶制成矩形长条状、圆柱状。
以下是本对比例制得的水凝胶的力学性能测试。在2mm/min的压缩速度下,测试水凝胶样品的压缩性能,如图2(a)所示;在10mm/min的拉伸速度下,测试水凝胶样品的拉伸性能,如图2(c)所示。可知该水凝胶敷料力学性能差,其在被压缩到76%应变时即发生破坏,最大应力只有13.7kPa;而拉伸强度只有4.0kPa,断裂伸长率为44%,弹性模量为0.03MPa。
本发明公开的制备工艺中引入了通过霍夫迈斯特效应盐析增强这一步骤,由附图2展示的力学性能对比可见,通过本发明公开的制备方法获得的水凝胶敷料具有优异的力学性能。
对比例2:
第一步:称取5g明胶加入至35mL超纯水和10mL甘油的混合溶液中,50℃下搅拌30分种使其溶解。
第二步:溶解后的溶液于4℃下静置20分钟成胶。
第三步:将水凝胶切成片状,浸没于重量分数为20%的柠檬酸钠溶液中12h,随后取出,用去离子水冲洗并擦干。
以下是本对比例制得的水凝胶的体外抗菌性能测试。将不同质量(25mg、50mg、100mg)的水凝胶与500μL浓度为10 6CFU/mL的金黄色葡萄球菌和大肠杆菌在37℃下共培养12小时,利用涂板法在琼脂板上对菌落数进行定量,所得抑菌率如图4所示。由图4可知,本对比例制得的水凝胶对于金黄色葡萄球菌和大肠杆菌在三种用量下均没有抑制效果,甚至由于添加的明胶可以为细菌提供营养而导致菌落数量增加,且水凝胶的添加量越多则菌落数量增加越多。
由附图3和附图4展示的抗菌性能对比可见,本发明公开的含有HBPL的水凝胶敷料具有优异的抗菌性能。

Claims (8)

  1. 一种强韧抗菌水凝胶敷料,其特征在于,按重量计,每100份材料中含有5-20份主体材料、20-50份甘油、0.0025-0.3份超支化聚赖氨酸,其余为水。
  2. 制备如权利要求1所述的一种强韧抗菌水凝胶敷料的方法,其特征在于,制备方法如下:将主体材料和超支化聚赖氨酸加入水和甘油的混合溶液中,搅拌加热使其充分溶解;溶解后的溶液静置成胶;将固体水凝胶切成所需形状,置于重量分数为10-35%的离子溶液中浸泡8-48小时后取出,用水冲洗并擦干;所述的主体材料为以氢键作用成胶的成胶骨架材料。
  3. 根据权利要求2所述的一种强韧抗菌水凝胶敷料制备方法,其特征在于,所述的主体材料为壳聚糖、胶原蛋白、海藻酸盐、透明质酸、聚乙二醇、明胶、聚氨酯、聚乳酸、聚乙烯吡咯烷酮、聚乙烯醇、聚丙烯酸、卡波姆中的至少一种。
  4. 根据权利要求2所述的一种强韧抗菌水凝胶敷料制备方法,其特征在于,所述的超支化聚赖氨酸分子量为3-7kDa。
  5. 根据权利要求2所述的一种强韧抗菌水凝胶敷料制备方法,其特征在于,所述的加热条件为40-80℃下10-60分钟,静置条件为室温下30-60分钟或4℃下5-15分钟。
  6. 根据权利要求2所述的一种强韧抗菌水凝胶敷料制备方法,其特征在于,所述的离子溶液组成为:阴离子为酒石酸根、醋酸跟、铬酸根、柠檬酸根、硫酸根、硫酸氢根、碳酸根、碳酸氢根、磷酸二氢根、硫代硫酸根、氯离子中的一种,阳离子为铵根离子、锂离子、钾离子、钠离子、锰离子、钙离子、钡离子中的一种。
  7. 根据权利要求1所述的一种强韧抗菌水凝胶敷料,其特征在于,所述的超支化聚赖氨酸通过物理共混方式负载于水凝胶敷料中。
  8. 一种强韧抗菌水凝胶敷料,其特征在于,含有如权利要求1的敷料或2-7任一项所述方法制得的强韧抗菌水凝胶敷料,可应用于机械损伤性创面、热损伤性创面、溃疡性创面等各类创面。
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US11980700B2 (en) 2017-03-08 2024-05-14 Alafair Biosciences, Inc. Hydrogel medium for the storage and preservation of tissue
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101982202A (zh) * 2010-11-02 2011-03-02 华东理工大学 一种医用水凝胶敷料及其制备方法
KR20190114662A (ko) * 2018-03-30 2019-10-10 한양대학교 에리카산학협력단 프로바이오틱스 함유 이중층 상처치유 드레싱제 및 그 제조방법
CN110507845A (zh) * 2019-09-25 2019-11-29 广州沁瀚生物科技有限公司 生物复合透气敷料及其制备方法
CN112190763A (zh) * 2020-06-15 2021-01-08 南京工业大学 透明质酸/ε-聚赖氨酸抗菌水凝胶及其制备方法和应用
CN113577377A (zh) * 2021-08-17 2021-11-02 浙江大学 一种活性氧消除抗菌消炎水凝胶皮肤敷料及其制备方法
CN113621135A (zh) * 2018-01-31 2021-11-09 中国科学院长春应用化学研究所 一种支化聚氨基酸抑菌剂及应用

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8206738B2 (en) * 2001-05-01 2012-06-26 Corium International, Inc. Hydrogel compositions with an erodible backing member
WO2007003028A1 (en) * 2005-07-01 2007-01-11 Kane Biotech Inc. Antimicrobial compositions for inhibiting growth and proliferation of a microbial biofilm on medical devices
CN103656729B (zh) * 2013-12-11 2015-06-17 南京工业大学 一种基于γ-聚谷氨酸与ε-聚赖氨酸交联聚合物的水凝胶及其制备方法
CN105920659A (zh) * 2016-05-11 2016-09-07 温州医科大学 一种创面修复用的抑菌水凝胶敷料及制备方法
CN108066805B (zh) * 2016-11-17 2021-06-01 大连敏慧精益科技有限公司 一种ε-聚赖氨酸仿生抑菌膜及其制备和应用
WO2020165656A1 (en) * 2019-02-11 2020-08-20 Excellgene S.A. Novel eukaryotic cell transfection systems and related methods
CN110680929B (zh) * 2019-09-18 2021-01-01 浙江大学 一种具有广谱活性氧清除功能的微球及其制备方法
CN111035803B (zh) * 2019-11-07 2021-07-06 浙江大学 一种兼具抗感染及促进骨结合功能的钛植入体材料及其制备方法
CN111363171B (zh) * 2020-04-02 2022-10-25 南昌大学第二附属医院 抗菌水凝胶及其制备方法和应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101982202A (zh) * 2010-11-02 2011-03-02 华东理工大学 一种医用水凝胶敷料及其制备方法
CN113621135A (zh) * 2018-01-31 2021-11-09 中国科学院长春应用化学研究所 一种支化聚氨基酸抑菌剂及应用
KR20190114662A (ko) * 2018-03-30 2019-10-10 한양대학교 에리카산학협력단 프로바이오틱스 함유 이중층 상처치유 드레싱제 및 그 제조방법
CN110507845A (zh) * 2019-09-25 2019-11-29 广州沁瀚生物科技有限公司 生物复合透气敷料及其制备方法
CN112190763A (zh) * 2020-06-15 2021-01-08 南京工业大学 透明质酸/ε-聚赖氨酸抗菌水凝胶及其制备方法和应用
CN113577377A (zh) * 2021-08-17 2021-11-02 浙江大学 一种活性氧消除抗菌消炎水凝胶皮肤敷料及其制备方法

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