WO2020155708A1 - 一种甲壳素/石墨烯复合海绵及其制备方法与应用 - Google Patents

一种甲壳素/石墨烯复合海绵及其制备方法与应用 Download PDF

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WO2020155708A1
WO2020155708A1 PCT/CN2019/114539 CN2019114539W WO2020155708A1 WO 2020155708 A1 WO2020155708 A1 WO 2020155708A1 CN 2019114539 W CN2019114539 W CN 2019114539W WO 2020155708 A1 WO2020155708 A1 WO 2020155708A1
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chitin
preparation
graphene composite
sponge
graphene
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French (fr)
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王小英
李晓云
黎珊珊
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华南理工大学
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J9/00—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof
    • C08J9/28—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof by elimination of a liquid phase from a macromolecular composition or article, e.g. drying of coagulum
    • C08J9/286—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof by elimination of a liquid phase from a macromolecular composition or article, e.g. drying of coagulum the liquid phase being a solvent for the monomers but not for the resulting macromolecular composition, i.e. macroporous or macroreticular polymers
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    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0042—Materials resorbable by the body
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/0047—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L24/0073—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix
    • A61L24/0078—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix containing fillers of carbon
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/20—Compounding polymers with additives, e.g. colouring
    • C08J3/203—Solid polymers with solid and/or liquid additives
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J9/00—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof
    • C08J9/0061—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof characterized by the use of several polymeric components
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K3/00—Use of inorganic substances as compounding ingredients
    • C08K3/02—Elements
    • C08K3/04—Carbon
    • C08K3/042—Graphene or derivatives, e.g. graphene oxides
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
    • 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
    • A61L2300/108—Elemental carbon, e.g. charcoal
    • 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
    • A61L2300/418—Agents promoting blood coagulation, blood-clotting agents, embolising 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
    • A61L2400/04—Materials for stopping bleeding
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2201/00—Foams characterised by the foaming process
    • C08J2201/02—Foams characterised by the foaming process characterised by mechanical pre- or post-treatments
    • C08J2201/026—Crosslinking before of after foaming
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2201/00—Foams characterised by the foaming process
    • C08J2201/04—Foams characterised by the foaming process characterised by the elimination of a liquid or solid component, e.g. precipitation, leaching out, evaporation
    • C08J2201/048—Elimination of a frozen liquid phase
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2205/00—Foams characterised by their properties
    • C08J2205/02—Foams characterised by their properties the finished foam itself being a gel or a gel being temporarily formed when processing the foamable composition
    • C08J2205/022—Hydrogel, i.e. a gel containing an aqueous composition
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2207/00—Foams characterised by their intended use
    • C08J2207/10—Medical applications, e.g. biocompatible scaffolds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
    • C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Definitions

  • the present invention belongs to the field of functional materials, and specifically relates to a chitin/graphene composite hemostatic sponge and a preparation method thereof, which can be used in medical, sanitary and other related fields.
  • the non-absorbable and degradable hemostatic material needs to be removed by a second operation after use, and there is a risk of rupture of the blood crust and injury by pulling.
  • absorbable and degradable hemostatic materials commonly used hyaluronic acid gel, collagen sponge, etc.
  • the raw materials used have problems such as high cost and complex purification processes. Therefore, the use of low-cost, easily prepared raw materials to develop degradable hemostatic materials has broad application prospects.
  • Chitin is low in price, rich in sources, and simple in extraction process. At the same time, chitin materials with excellent biocompatibility and biodegradability have been confirmed to have good swelling properties and can be used as hemostatic materials. However, pure chitin only causes the aggregation of blood cells through swelling, thereby coagulating blood, which cannot meet the requirements of rapid hemostasis.
  • the purpose of the present invention is to provide a green preparation, low cost, and biological Degradable chitin/graphene hemostatic sponge and preparation method thereof.
  • the present invention combines the swelling ability of chitin and the ability of graphene to absorb and promote blood coagulation, adopts mixing and exfoliating flake graphite and chitin to obtain a chitin/graphene composite material, and prepares it into a composite hemostatic sponge.
  • the flake graphite and chitin are mixed and ball milled to obtain the chitin/graphene composite material, which is dissolved in NaOH/urea solvent, crosslinked with epichlorohydrin crosslinking agent after centrifugal separation, allowed to stand, and lyophilized after dialysis , Get chitin/graphene composite hemostatic sponge.
  • the preparation method of chitin/graphene composite sponge specifically includes the following steps:
  • step (1) The composite material obtained in step (1) is dissolved in NaOH/urea solvent by a freeze-thaw method, and the unstripped graphite sheet is removed by centrifugation and crosslinked Add epichlorohydrin to the solution dropwise, stir at 0 ⁇ 4 °C for 0.2 ⁇ 2 h to obtain a homogeneous solution, and then stand at 0 ⁇ 4 °C for 8 ⁇ 24 h to obtain chitin/graphene hydrogel Glue
  • the mass ratio of chitin to flake graphite in step (1) is 200:1-20:1.
  • the mass ratio of the composite material to the solvent in step (2) is 1:100-6:100.
  • the condition of the ball mill used in step (1) is intermittent operation, with a pause of 10 to 15 minutes every 20 to 30 minutes, and a rotation speed of 180 to 210 r/min.
  • the freezing and thawing method is freezing at -20 ⁇ -40°C, stirring while melting at 20 ⁇ 30°C, and circulating 2 ⁇ 6 times to make the composite material uniformly dispersed in the solvent.
  • the mass fractions of NaOH and urea in the NaOH/urea solvent are 8-15% and 2-8%, respectively
  • the low-speed centrifugal rotation speed is 1800 ⁇ 3000 rpm, and the time is 5-20 min.
  • the amount of crosslinking agent required per 10 g of the solution is 0.5-2 mL.
  • the chitin/graphene composite sponge is used in a degradable wound hemostatic material, and its coagulation index is 9.
  • the present invention has the following advantages:
  • the micromechanical exfoliation method can produce large-scale green and low-cost graphene materials, so the preparation method of the present invention is green, low-cost, and simple;
  • the sponge prepared by the present invention has an excellent hemostatic effect
  • the sponge prepared by the present invention is biodegradable, which greatly reduces the risk of secondary bleeding caused by the removal of hemostatic materials.
  • FIG. 1 is a graph of the coagulation index of different composite hemostatic sponges.
  • FIG. 2 is a graph of the in vitro degradation time of different composite hemostatic sponges.
  • the obtained composite material was added to a 10% NaOH/4% urea solvent at a mass ratio of 2:100, and after being frozen at -40°C, it was stirred while thawing at 23°C. Freeze-thaw 2 times to make it evenly dispersed, after low-speed centrifugation (rotating speed is 1800 rpm, time is 20 min) to remove the unstripped graphite flakes. Add 1 mL of cross-linking agent epichlorohydrin dropwise to every 10 g of the solution, at 0 Stir for 0.2 h at °C to obtain a homogeneous solution. Continue to stand at 2 °C for 12 h to obtain chitin/graphene hydrogel.
  • the above hydrogel was dialyzed at 50°C under heating for 10 d, and then at -40°C: freeze-dried for 48 h to obtain a chitin/graphene composite sponge.
  • the coagulation index of the prepared composite hemostatic sponge is 16.1 ⁇ 2.7, and the degradation rate after 6 hours of degradation exceeds 80%.
  • Embodiment 2 is a diagrammatic representation of Embodiment 1
  • the obtained composite material was added to the 8% NaOH/2% urea solvent at a mass ratio of 1:100, and then frozen at -30 °C, and stirred while thawing at 30 °C.
  • Freeze-thaw 4 Disperse uniformly, and then centrifuge at low speed (rotating speed is 2000 rpm, time is 18 min) to remove unstripped graphite flakes.
  • Add 0.5 mL of cross-linking agent epichlorohydrin dropwise to every 10 g of the solution, and stir for 1.2 h at 4 °C to obtain a uniform solution. Continue to stand at 4 °C for 8 h to obtain chitin/graphene hydrogel.
  • the coagulation index of the prepared composite hemostatic sponge is 11.2 ⁇ 1.6, and the degradation rate exceeds 80% after 8 hours of degradation.
  • the mixed powder of chitin and flake graphite with a mass ratio of 20:1 was dried in a vacuum oven at 80°C for 8 hours. Then, the composite material was obtained by ball milling for 5 h in intermittent operation (15 min pause every 30 min, rotation speed 210 r/min).
  • the obtained composite material was added to a 15% NaOH/8% urea solvent at a mass ratio of 6: 100, and after freezing under the condition of -20 °C, it was stirred while thawing at 20 °C. Freeze-thaw 6 times to make it evenly dispersed, after low-speed centrifugation (rotating speed is 3000 rpm, time is 5 min) to remove the unstripped graphite flakes. 2 mL of crosslinking agent epichlorohydrin was added dropwise to every 10 g of the solution, at 0 Stir at °C 2
  • the coagulation index of the prepared composite hemostatic sponge is 16.0 ⁇ 2.1, and the degradation rate after 12 hours of degradation exceeds 80%.
  • Figure 1 shows the coagulation index of the sponge, PVF ® and blank control group of Examples 1 to 3.
  • 3CH is a pure chitin hemostatic sponge with 3% solid content, that is, it does not contain graphene
  • PVF @ is a commercial medical polyvinyl alcohol sponge.
  • the coagulation index of PVF ® is 27.0 ⁇ 4.7
  • the coagulation index of chitin hemostatic sponge is 23.0 ⁇ 1.5. It can be seen that chitin hemostatic sponge itself has a good coagulation effect.
  • the coagulation index after adding graphene is better than chitin alone, and when the mass ratio of chitin to scaly graphite is 100:1, the coagulation index drops significantly to 11.2, so the hemostatic sponge prepared by the present invention has excellent Hemostatic effect.
  • A The absorption value after adding hemostatic sponge, A is the absorption value of the blank group.
  • BCI value the better the hemostatic performance of the material.
  • Figure 2 shows the degradation time of the sponges and PVF @ prepared in Examples 1 to 3. It can be concluded from Figure 2 that the composite hemostatic sponges with different graphene content prepared in the present invention degrade more than 80% in 12 hours. , And PVF ® degrades less than 10% after 12 hours, which proves that the composite hemostatic sponge of the present invention has excellent biodegradability.
  • the in vitro degradation test was carried out under simulated physiological conditions. Soak 50 mg of the sample in 10 mL of PBS, and add 10 mg of lysozyme to it. Incubate at 37°C and transfer to a dialysis bag at a defined time point. Measure the percentage of weight loss for each time interval.

Abstract

本发明公开了一种甲壳素/石墨烯复合海绵及其制备方法与应用。所述方法为：将一定量的鳞片石墨和甲壳素混合球磨后溶于NaOH/尿素溶剂中，离心分离，分散均匀后使用环氧氯丙烷交联剂交联，静置，透析后冻干，获得甲壳素/石墨烯复合海绵。该复合海绵不仅具有优良的凝血止血效果，而且具有良好的生物可降解性和细胞相容性。与现有技术相比，本发明使用球磨辅助的剥离方法制备甲壳素/石墨烯复合材料，制备方法简单易行；甲壳素和石墨烯的协同作用使止血海绵具有优异的止血性能；由于使用甲壳素作为原料，制备的复合海绵生物可降解，细胞相容性好，避免了止血治疗后止血材料的取出而导致二次出血的风险。

Description

一种甲壳素 /石墨烯复合海绵及其制备方法与应用 技术领域
[0001] 本发明属于功能材料领域， 具体涉及一种甲壳素 /石墨烯复合止血海绵及其制 备方法， 可用于医疗、 卫生等相关领域。
背景技术
[0002] 目前， 不可吸收降解止血材料在使用后需要进行二次手术取出， 存在血痂的破 裂和拉扯伤害的风险。 而可吸收降解性止血材料 （常用的透明质酸凝胶、 胶原 蛋白海绵等） 虽然具有良好生物可降解性， 但是所使用的原料存在成本高、 提 纯工艺复杂等问题。 因此， 使用低成本、 易制备的原料来开发可降解性止血材 料具有广大的应用前景。
[0003] 甲壳素价格低廉， 来源丰富， 提取工艺简单。 同时， 具有优异生物相容性和生 物可降解性能的甲壳素材料已被证实具有良好的润胀性能可以用于止血材料。 然而单纯的甲壳素只是通过润胀来引起血细胞的聚集， 从而凝血， 不能满足快 速止血的要求。
[0004] 目前大部分止血材料通过加入功能性材料来增强止血效果， 常用的功能性材料 包括吸附性粘土、 石墨烯和介孔型生物活性玻璃等。 功能性材料具有大的比表 面积及丰富的孔道结构， 能够吸附血浆、 激活血小板等促进凝血。 粘土在止血 的过程放热， 且存在泄露的问题限制了粘土类止血材料的商品化应用。 石墨烯 拥有较大的比表面积， 易与血液相互作用促进凝血。
[0005] 然而， 常用的石墨烯制备方法存在反应过程冗长， 使用试剂有毒， 环境不友好 ， 高成本， 难以大规模生产等问题。
发明概述
技术问题
问题的解决方案
技术解决方案
[0006] 本发明的目的在于针对现有技术的不足， 提供一种制备绿色， 成本低廉， 生物 可降解的甲壳素 /石墨烯止血海绵及其制备方法。 本发明结合甲壳素的润胀能力 和石墨烯的吸附促凝血的能力， 采用将鳞片石墨和甲壳素混合剥离得到甲壳素 / 石墨烯复合材料， 并将其制备成复合止血海绵。
[0007] 本发明具体通过以下技术方案实现。
[0008] 将鳞片石墨和甲壳素混合球磨后获得甲壳素 /石墨烯复合材料， 溶于 NaOH/尿素 溶剂中， 离心分离后使用环氧氯丙烷交联剂交联， 静置， 透析后冻干， 获得甲 壳素 /石墨烯复合止血海绵。
[0009] 进一步的， 甲壳素 /石墨烯复合海绵的制备方法， 具体包括如下步骤：
[0010] ( 1) 甲壳素 /石墨烯复合材料的制备： 将鳞片石墨和甲壳素混合后在 80~105°C 的真空烘箱中干燥 4~8 h， 然后球磨 4~8 h;
[0011] (2) 甲壳素 /石墨烯复合水凝胶的制备： 将步骤 ⑴ 得到的复合材料通过冻 融法溶于 NaOH/尿素溶剂中， 经过离心除去未剥离的石墨片层后将交联剂环氧氯 丙烷滴加到溶液中， 在 0~4 °C下搅拌 0.2~2 h， 得到均匀的溶液， 然后在 0~4 °C静 置 8~24 h获得甲壳素 /石墨烯水凝胶；
[0012] (3) 甲壳素 /石墨烯复合止血海绵的制备： 将步骤 ⑵ 得到的甲壳素 /石墨烯 水凝胶在 40~60 °(：加热条件下透析 7 ~14 d， 在 -40~-80。(:冷冻干燥 48~72 h。
[0013] 优选的， 步骤 ⑴ 中所述甲壳素与鳞片石墨的质量比为 200: 1~20: 1。
[0014] 优选的， 步骤 (2) 中复合材料与溶剂的质量比为 1: 100~6: 100。
[0015] 优选的， 步骤 ⑴ 用的球磨的条件为间歇式操作， 每 20~30 min停顿 10~15 min ， 转速为 180~210 r/min。
[0016] 优选的， 所述冻融法为在 -20~-40 °C条件下冷冻， 在 20~30 °C环境下边融化边搅 拌， 循环 2~6次使复合材料均匀分散在溶剂中。
[0017] 优选的， 所述 NaOH/尿素溶剂中 NaOH和尿素的质量分数分别为 8~15 %和 2~8 %
[0018] 优选的， 所述的低速离心转速为 1800~3000 rpm， 时间为 5~20 min。
[0019] 优选的， 每 10 g溶液需要的交联剂用量为 0.5~2 mL。
[0020] 所述的甲壳素 /石墨烯复合海绵应用于可降解创伤止血材料中， 其凝血指数在 9.
6~18.8范围内， 在 6~12 h范围内降解了 80%以上。 发明的有益效果
有益效果
[0021] 与现有技术相比， 本发明具有以下优点：
[0022] （1） 微机械剥离法能大规模绿色生产低成本石墨烯材料， 所以本发明制备方 法绿色、 低成本、 简便；
[0023] （2） 结合甲壳素的润胀能力和石墨烯的吸附促凝血的能力， 本发明制备的海 绵具有优良的止血效果；
[0024] （3） 本发明制备的海绵生物可降解， 大大减少因止血材料取出而导致二次出 血的风险。
对附图的简要说明
附图说明
[0025] 图 1为不同复合止血海绵的凝血指数图。
[0026] 图 2为不同复合止血海绵的体外降解时间图。
发明实施例
本发明的实施方式
[0027] 下面结合具体实施例对本发明作进一步说明， 但不限于此。
[0028] 实施例 1:
[0029] 将质量比为 200: 1甲壳素和鳞片石墨混合粉末在 105 °C的真空烘箱中干燥 4 h。 然 后在间歇式操作 （每 20 min停顿 10 min， 转速为 180 r/min） 球磨 8 h得到复合材料
[0030] 将得到的复合材料以质量比为 2: 100加入到 10 % NaOH/4 %尿素溶剂中， 在 -40 °（：条件下冷冻后， 在 23 °C环境下边融化边搅拌， 冻融 2次使其分散均匀， 经过低 速离心 （转速为 1800 rpm， 时间为 20 min） 除去未剥离的石墨片层。 将 1 mL交联 剂环氧氯丙烷滴加到每 10 g溶液中， 在 0 °C下搅拌 0.2 h， 得到均匀的溶液。 继续 在 2 °C静置 12 h获得甲壳素 /石墨烯水凝胶。
[0031] 将上述水凝胶在 50 °（：加热条件下透析 10 d， 然后在 -40。（:冷冻干燥 48 h得到甲壳 素 /石墨烯复合海绵。 [0032] 制备所得的复合止血海绵的凝血指数为 16.1±2.7， 降解 6 h后降解率超 80%。
[0033] 实施例 2:
[0034] 将质量比为 100: 1甲壳素和鳞片石墨混合粉末在 100 °C的真空烘箱中干燥 6 h。 然 后在间歇式操作 （每 25 min停顿 12 min， 转速为 200 r/min） 球磨 4 h得到复合材料
[0035] 将得到的复合材料以质量比为 1: 100加入到 8 % NaOH/2 %尿素溶剂中， 在 -30 °C 条件下冷冻后， 在 30 °C环境下边融化边搅拌， 冻融 4次使其分散均匀， 经过低速 离心 （转速为 2000 rpm， 时间为 18 min） 除去未剥离的石墨片层。 将 0.5 mL交联 剂环氧氯丙烷滴加到每 10 g溶液中， 在 4 °C下搅拌 1.2 h， 得到均匀的溶液。 继续 在 4 °C静置 8 h获得甲壳素 /石墨烯水凝胶。
[0036] 将上述水凝胶在 40 °（：加热条件下透析 14 d， 然后在 -80。（:冷冻干燥 52 h得到甲壳 素 /石墨烯复合海绵。
[0037] 制备所得的复合止血海绵的凝血指数为 11.2±1.6， 降解 8 h后降解率超 80%。
[0038] 实施例 3:
[0039] 将质量比为 20: 1甲壳素和鳞片石墨混合粉末在 80 °C的真空烘箱中干燥 8 h。 然后 在间歇式操作 （每 30 min停顿 15 min， 转速为 210 r/min） 球磨 5 h得到复合材料。
[0040] 将得到的复合材料以质量比为 6: 100加入到 15 % NaOH/8 %尿素溶剂中， 在 -20 °（：条件下冷冻后， 在 20 °C环境下边融化边搅拌， 冻融 6次使其分散均匀， 经过低 速离心 （转速为 3000 rpm， 时间为 5 min） 除去未剥离的石墨片层。 将 2 mL交联 剂环氧氯丙烷滴加到每 10 g溶液中， 在 0 °C下搅拌 2
h， 得到均匀的溶液。 继续在 0°C静置 24 h获得甲壳素 /石墨烯水凝胶。
[0041] 将上述水凝胶在 60 °C加热条件下透析 7 d， 然后在 -50 °C冷冻干燥 72 h得到甲壳 素 /石墨烯复合海绵。
[0042] 制备所得的复合止血海绵的凝血指数为 16.0±2.1， 降解 12h后降解率超 80%。
[0043] 甲壳素 /石墨烯海绵的效果评价
[0044] 1. 凝血指数 （Blood Clotting Index, BCl） : 称量 0.05g甲壳素 /石墨烯海绵， 然 后将凝结剂 10 pL的 CaCl 2 （0.2 M） 溶液与 0.1 mL柠檬酸钠抗凝的兔血快速混合 后滴加到海绵上。 在 37°C下振荡 （30 rpm） 孵育 5分钟后， 然后加入 12.5 mL生理 盐水溶解未凝结的血液。 紫外测定 542 nm处血红蛋白溶液的吸光度值。 测试时 ， 设置空白对照组。 凝血指数通过吸光度值比计算得到： BCI%=A ,/A oXlOO%
[0045] 1. 降解率： 称量 0.05g甲壳素 /石墨烯海绵， 然后浸入 10 mL的 PBS中， 并向其 中加入 10 mg溶菌酶。 在 37°C温度下孵育， 并在确定的时间点转移到透析袋中。 测量每个时间间隔的重量损失百分比， 得出降解率。
[0046] 图 1给出了实施例 1~3的海绵、 PVF ®及空白对照组的凝血指数。 其中 3CH为 3% 固含量的纯甲壳素止血海绵， 即不含石墨烯， PVF @为商品化的医用聚乙烯醇海 绵。 对比发现， PVF ®的凝血指数为 27.0±4.7， 甲壳素止血海绵的凝血指数为 23.0 ±1.5 , 可见甲壳素止血海绵本身具有较好的凝血效果。 加入石墨烯后的凝血指数 比单纯甲壳素的凝血效果更好， 而且当甲壳素与鳞片石墨的质量比为 100: 1时， 凝血指数显著下降至 11.2, 所以本发明制备的止血海绵具有优良的止血效果。
[0047] 为了测量海绵的凝血能力， 将凝结剂 lO pL的 CaCl 2 (0.2 M) 溶液与 0.1 mL柠 檬酸钠抗凝的兔血快速混合后滴加到海绵上。 在 37。(：下振荡 (30 rpm) 孵育 5分 钟后， 然后加入 12.5 mL生理盐水溶解未凝结的血液。 紫外测定 542 nm处血红蛋 白溶液的吸光度值。 测试时， 设置空白对照组。 凝血指数 (Blood Clotting Index, BCI) 通过吸光度值比计算得到：
[0048] BCI%=A i/A 0xl00%
[0049] 其中， A
Figure imgf000007_0001
加入止血海绵后的吸收值， A 为空白组吸收值。 BCI的数值越小， 表明材料的止血性能越好。 图 2给出了实施例 1~3制备的海绵及 PVF @的降解时间 ， 从图 2中可以得出， 本发明中制备的不同石墨烯含量的复合止血海绵几乎在 12 h内降解 80%以上， 而 PVF ®在 12 h后降解不到 10 %， 由此证明了本发明的复合止 血海绵具有优异的生物可降解性。 体外降解试验在模拟的生理条件下进行。 将 5 O mg样品浸入 10 mL的 PBS中， 并向其中加入 10 mg溶菌酶。 在 37°C温育， 并在确 定的时间点转移到透析袋中。 测量每个时间间隔的重量损失百分比。
[0050] 以上实施例仅为本发明较优的实施方式， 仅用于解释本发明， 而非限制本发明
， 本领域技术人员在未脱离本发明精神实质下所作的改变、 替换、 修饰等均应 属于本发明的保护范围。

Claims

权利要求书
[权利要求 1] 一种甲壳素 /石墨烯复合海绵的制备方法， 其特征在于： 首先将鳞片 石墨与甲壳素混合球磨得到甲壳素 /石墨烯复合材料； 甲壳素 /石墨烯 复合材料均匀分散在溶剂中， 经过离心除去未剥离的石墨片层， 与环 氧氯丙烷交联， 透析， 冻干得到所述甲壳素 /石墨烯复合海绵。
[权利要求 2] 根据权利要求 1所述的制备方法， 其特征在于： 具体包括如下步骤：
（1） 甲壳素 /石墨烯复合材料的制备： 将鳞片石墨和甲壳素混合后在 80~105°C的真空烘箱中干燥 4~8 h， 然后球磨 4~8 h;
（2） 甲壳素 /石墨烯复合水凝胶的制备： 将步骤 （1） 得到的复合材 料通过冻融法溶于 NaOH/尿素溶剂中， 经过离心除去未剥离的石墨片 层后将交联剂环氧氯丙烷滴加到溶液中， 在 0~4 °C下搅拌 0.2~2 h， 得 到均匀的溶液， 然后在 0~4 °C静置 8~24 h获得甲壳素 /石墨烯水凝胶；
（3） 甲壳素 /石墨烯复合止血海绵的制备： 将步骤 ⑵ 得到的甲壳 素 /石墨烯水凝胶在 40~60 °（：加热条件下透析 7 ~14 d， 在 -40~-80 °（：冷 冻干燥 48~72 h。
[权利要求 3] 根据权利要求 2所述的制备方法， 其特征在于， 所述步骤 （1） 中所述 甲壳素与鳞片石墨的质量比为 200: 1~20: 1， 所述步骤 （2） 中复合材 料与溶剂的质量比为 1 : 100~6: 100。
[权利要求 4] 根据权利要求 2所述的制备方法， 其特征在于， 所述步骤 （1） 中的球 磨条件为间歇式操作， 每 20~30 min停顿 10~15 min， 转速为 180~210 r/mino
[权利要求 5] 根据权利要求 2所述的制备方法， 其特征在于， 所述冻融法为在 -20~- 40。（:条件下冷冻， 在 20~30。（:环境下边融化边搅拌， 循环 2~6次使复 合材料均匀分散在溶剂中。
[权利要求 6] 根据权利要求 2所述的制备方法， 其特征在于， 所述 NaOH/尿素溶剂 中 NaOH和尿素的质量分数分别为 8~ 15 %和2~8 %。
[权利要求 7] 根据权利要求 2所述的制备方法， 其特征在于， 所述离心的转速为 180
0-3000 rpm, 时间为 5~20 min。
[权利要求 8] 根据权利要求 2所述的制备方法， 其特征在于， 所述步骤 （2） 中， 每 10 g溶液需要的交联剂用量为 0.5~2 mL。
[权利要求 9] 由权利要求 1-8所述的制备方法制备得到的甲壳素 /石墨烯复合海绵。
[权利要求 10] 权利要求 9所述的甲壳素 /石墨烯复合海绵应用于可降解创伤止血材料 中， 其特征在于： 其凝血指数为 9.6 18.8， 在 6~12 h范围内降解了 80%以上。
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