CN115025277A - 具有剪切变稀和自愈合性能的可注射型壳聚糖-氧化石墨烯水凝胶创面敷料及其制备方法 - Google Patents
具有剪切变稀和自愈合性能的可注射型壳聚糖-氧化石墨烯水凝胶创面敷料及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种具有剪切变稀和自愈合性能的可注射型壳聚糖‑氧化石墨烯水凝胶创面敷料及其制备方法。该水凝胶利用壳聚糖(CS)这一天然阳离子多糖与带负电的氧化石墨烯(GO)之间的静电相互作用、氢键相互作用以及亲疏水相互作用等实现凝胶化。其制备过程主要包括:将CS与GO混合后,加入到去离子水中,超声分散至少40分钟后,在强烈搅拌下加入乙酸(HAc)溶解。在室温下搅拌至少4h使CS和GO充分混和后,再将混合溶液在95℃下加热4h,自然冷却到室温后即得CSGO水凝胶。本发明制得的水凝胶材料具有优异的剪切变稀可注射性和自愈合性能。与此同时,该水凝胶还具有良好的血液相容性、止血效果以及促进伤口愈合功能,可用作创面敷料。
Description
技术领域
本发明涉及一种具有剪切变稀和自愈合性能的可注射型壳聚糖-氧化石墨烯水凝胶创面敷料及其制备方法。
背景技术
浅层伤口的止血通常是通过机体的先天机制(即激活休眠的血小板和凝血因子,加速血栓形成从而止血)来实现。然而,当面临创伤性损伤导致的大出血时,这种先天止血机制就会变得不那么有效,从而导致高死亡率以及严重的并发症。因此,使用快速有效的止血敷料等止血干预方法对挽救生命至关重要。近年来,包括海绵、纱布、绷带和水凝胶在内的多种止血材料已被开发出来。其中,可注射水凝胶因为具有较高的伤口渗出液吸收能力、可以紧密贴合不规则伤口、易于从伤口处移除等优势,成为一种极具前途的创面敷料。此外,可注射水凝胶还能够作为对抗微生物的物理屏障,在伤口表面保持有利于细胞增殖、表皮生长和皮肤再生的湿润环境,因此可以促进伤口愈合。
可注射水凝胶主要有两种类型:原位形成水凝胶和剪切变稀水凝胶。原位形成水凝胶通常需要在生理条件下混合两种前驱体溶液,使用不便。而且,如果前驱体溶液混合后至发生凝胶化的时间控制不当,会有阻塞注射器或扩散到周围组织的风险。相反,剪切变稀水凝胶在注射前就已经是凝胶状态,这种凝胶在挤压应力下可以流动,离开注射器后则立即自发恢复凝胶状态。这类水凝胶通常通过非共价键交联,由于非共价相互作用可以动态断裂和重组,因此往往还具有自修复性能。这意味着剪切变稀水凝胶在使用过程中可以对断裂的网络进行自我修复,恢复其功能。
因此,制备一种合适的剪切变稀水凝胶具有重要意义。壳聚糖是一种具有抗菌和止血功能的天然阳离子多糖,广泛用于制备水凝胶。氧化石墨烯是石墨烯的一种衍生物,具有良好的亲水性、生物相容性、抗菌性和机械性能。得益于壳聚糖主链上丰富的伯胺和羟基,以及氧化石墨烯片层结构上大量的羧基和羟基,壳聚糖和氧化石墨烯之间可以形成复杂的非共价相互作用,例如静电和氢键相互作用,这些相互作用有利于壳聚糖和氧化石墨烯形成凝胶。尽管已有研究利用这些非共价相互作用制备出了壳聚糖-氧化石墨烯水凝胶,这些研究并未研究壳聚糖分子内和分子间的氢键对于凝胶化过程以及凝胶性能的影响,因此制备出的水凝胶的性能有待改善。与此同时,此前研究也未研究壳聚糖-氧化石墨烯水凝胶在创面敷料上的应用优势。
发明内容
本发明的目的在于提供一种可注射型壳聚糖-氧化石墨烯水凝胶创面敷料及其制备方法。本发明的具有剪切变稀和自愈合性能的可注射型壳聚糖-氧化石墨烯水凝胶创面敷料具有良好的止血效果和促进伤口愈合功能。
本发明的具有剪切变稀和自愈合性能的可注射型壳聚糖-氧化石墨烯水凝胶创面敷料,利用壳聚糖(CS)这一天然阳离子多糖与带负电的氧化石墨烯(GO)之间的静电相互作用、氢键相互作用以及亲疏水相互作用等制备而成。研究发现,加热时间对凝胶化过程起着至关重要的作用,加热4h不仅能驱动壳聚糖大分子链插入氧化石墨烯片层之间,增强两者之间的相互作用力,促成凝胶的形成,且利于改善凝胶力学性能。
其制备方法是:将CS与GO的混合液超声至少40分钟后,在强烈搅拌下加入乙酸(HAc)溶解。在室温下搅拌至少4h后,再将混合溶液在95℃下加热4h,然后自然冷却到室温,即得CSGO水凝胶。
具体的:
1)称取分子量为1~10w、脱乙酰度85%~95%的CS以及GO粉末,加入到去离子水中,超声分散至少40分钟后,得到灰色溶液A;
2)在强烈机械搅拌下(转速大于500rpm)逐滴加入HAc,加入后在室温下继续搅拌至少4h使CS与GO充分混合,得到溶液B;
3)将溶液B在95℃下加热4h,然后自然冷却到室温,即得CSGO水凝胶。
上述技术方案中,进一步地,所述的步骤1)中GO粉末的片层尺寸为0.5~5μm、单片厚度为1~3nm;所述的步骤1)中溶液A中CS、GO的浓度分别为80mg/mL、1~3mg/mL;所述的步骤2)中溶液B中HAc的浓度为0.02~0.05mL/mL。
所述的步骤1)中溶液A中GO的加入量为3mg/mL,此时凝胶的力学性能、吸水能力、止血性能和创面修复性能最佳。
本发明在制备壳聚糖-氧化石墨烯水凝胶过程中,发现加热时间对凝胶化过程起着至关重要的作用,合适的加热时间不仅能驱动壳聚糖大分子链插入氧化石墨烯片层之间,增强两者之间的相互作用力,促成凝胶的形成,且利于改善凝胶力学性能。与此同时,这种水凝胶具有剪切变稀可注射性和优异的自愈合特性,以及良好的止血效果和促进伤口愈合功能,可以用作一种优良的可注射型创面敷料。
本发明利用壳聚糖(CS)与氧化石墨烯(GO)之间的静电相互作用、氢键相互作用以及亲疏水相互作用等非共价键相互作用,制成了具有剪切变稀和自愈合性能的可注射型壳聚糖-氧化石墨烯水凝胶创面敷料。利用加热来削弱CS分子内和分子间的氢键相互作用,驱动CS大分子链插入GO片层之间,增强两者之间的相互作用力,从而形成凝胶网络结构。本发明确定的加热时间,可以使CS和GO之间的物理相互作用,以及与CS链段缠结的协同作用最大化,从而得到性能最优的壳聚糖-氧化石墨烯水凝胶。
本发明制得的水凝胶材料具有优异的剪切变稀可注射性和自愈合性能。与此同时,该水凝胶具有一定的力学强度、吸水能力和黏附性。该水凝胶还具有良好的血液相容性、止血效果以及促进伤口愈合功能,可用作创面敷料。
附图说明
图1是本发明具有剪切变稀和自愈合性能的可注射型壳聚糖-氧化石墨烯水凝胶创面敷料的制备过程与机理示意图;
图2是壳聚糖-氧化石墨烯水凝胶的粘度-剪切速率曲线图;CSGO1,CSGO2,CSGO3分别表示步骤1)中GO的浓度分别为1mg/mL,2mg/mL,3mg/mL;
图3是壳聚糖-氧化石墨烯水凝胶的弹性模量(G’)、储能模量(G”)-振荡应变曲线图(先在0.5%应变下保持3分钟,后在500%应变下保持2分钟,并以5分钟为一个周期扫描4个周期);
图4是壳聚糖-氧化石墨烯水凝胶的储能模量图;
图5是壳聚糖-氧化石墨烯水凝胶的吸水能力图;
图6是壳聚糖-氧化石墨烯水凝胶(i)CSGO1、(ii)CSGO2与(iii)CSGO3的SEM结构对比图;
图7是壳聚糖-氧化石墨烯水凝胶的大鼠肝脏出血时间图(肝脏通过腹部切口暴露);
图8是壳聚糖-氧化石墨烯水凝胶小鼠全层皮肤缺损创面修复情况。
具体实施方式
以下结合附图和具体实例进一步说明本发明。
本发明所述的具有剪切变稀和自愈合性能的可注射型壳聚糖-氧化石墨烯水凝胶创面敷料的制备过程与机理示意图如图1所示。CS通过大分子链上分布的羟基、氨基、N-乙酰氨基相互作用形成各种分子内和分子间氢键,这些氢键不利于CS链段的运动。而通过加热可以削弱CS分子内和分子间氢键,驱动CS大分子链插入GO片层之间,增加CS和GO之间相互接触的几率,从而形成网络结构。在此网络结构中,GO作为交联点可以和CS之间形成多重物理相互作用:一为CS所含的氨基和GO的羧基可以质子化形成静电相互作用;二为氢键相互作用,CS的氨基和羟基与GO的羧基和羟基之间易形成氢键;三为CS链段与GO片层之间的亲疏水相互作用。上述多重物理相互作用与CS链段缠结作用一起协同赋予了凝胶优异的性能。水凝胶的粘度-剪切速率曲线图如图2所示,CSGO水凝胶的黏度均随剪切速率的增加而降低,表现出典型的剪切变稀行为,这赋予凝胶良好的可注射性。水凝胶的弹性模量(G’)、储能模量(G”)-振荡应变曲线图如图3所示,当应变从0.5%增加到500%时,G’<G”,即水凝胶的网络结构被破坏,表现为液体状。相反,一旦应变恢复到0.5%,G’>G”,CSGO液体立即发生溶胶-凝胶转变。在这四个交替重复的循环测试中,凝胶-溶胶转变现象都是可逆的,表明CSGO水凝胶具有良好的自修复性能。水凝胶的储能模量如图4所示,该水凝胶的储能模量随GO含量的增加而增大;图5是壳聚糖-氧化石墨烯水凝胶的吸水能力示意图,CSGO水凝胶被浸泡在37℃的PBS缓冲液中,当浸泡时间相同时,该水凝胶的吸水能力随着GO含量的增加而增大。水凝胶的SEM结构如图6所示,随着GO含量的增加,水凝胶的孔径依次减小,孔隙变得更致密、更均匀。这种现象证明了GO的引入为CS提供了交联点,且GO含量越多交联密度越高,进而改善了水凝胶的力学性能与保水能力。图7是壳聚糖-氧化石墨烯水凝胶的大鼠肝脏出血时间图,空白对照的止血时间为215s,CSGO水凝胶大大降低了止血时间。图8是壳聚糖-氧化石墨烯水凝胶小鼠全层皮肤缺损创面修复情况,10天时皮肤缺口已基本修复。
实施例1:
1)称取8g分子量为1w、脱乙酰度为85%的CS以及0.1g GO粉末,分散在100mL去离子水中,超声分散至少40分钟后,得到灰色溶液A;
2)在强烈机械搅拌下(搅拌转速大于500rpm)逐滴加入2mL HAc,加入后继续在室温下搅拌至少4h使CS与GO充分混合,得到溶液B;
3)将溶液B在95℃下加热4h,然后自然冷却到室温,即得CSGO水凝胶。
本例制得的CSGO水凝胶的储能模量为555Pa。浸泡在PBS缓冲液中90min后,吸水率为80.9%。该水凝胶具有剪切变稀可注射性和自愈合性,还具有优异的止血性能和促进创面修复性能。
实施例2:
1)称取8g分子量为3w、脱乙酰度为90%的CS以及0.2g GO粉末,分散在100mL去离子水中,超声分散至少40分钟后,得到灰色溶液A;
2)在强烈机械搅拌下(搅拌转速大于500rpm)逐滴加入3mL HAc,加入后继续在室温下搅拌至少4h使CS与GO充分混合,得到溶液B;
3)将溶液B在95℃下加热4h,然后自然冷却到室温,即得CSGO水凝胶。
本例制得的CSGO水凝胶的储能模量为747Pa。浸泡在PBS缓冲液中90min后,吸水率为103.3%。该水凝胶具有剪切变稀可注射性和自愈合性,还具有优异的止血性能和促进创面修复性能。
实施例3:
1)称取8g分子量为10w、脱乙酰度为95%的CS以及0.3g GO粉末,分散在100mL去离子水中,超声分散至少40分钟后,得到灰色溶液A;
2)在强烈机械搅拌下(搅拌转速大于500rpm)逐滴加入5mL HAc,加入后继续在室温下搅拌至少4h使CS与GO充分混合,得到溶液B;
3)将溶液B在95℃下加热4h,然后自然冷却到室温,即得CSGO水凝胶。
本例制得的CSGO水凝胶的储能模量为1037Pa。浸泡在PBS缓冲液中90min后,吸水率为117.6%。该水凝胶具有剪切变稀可注射性和自愈合性,还具有优异的止血性能和促进创面修复性能。
Claims (5)
1.一种具有剪切变稀和自愈合性能的可注射型壳聚糖-氧化石墨烯水凝胶创面敷料,其特征在于,所述的水凝胶利用壳聚糖(CS)这一天然阳离子多糖与带负电的氧化石墨烯(GO)之间的静电相互作用、氢键相互作用以及亲疏水相互作用实现凝胶化。
2.如权利要求1所述的具有剪切变稀和自愈合性能的可注射型壳聚糖-氧化石墨烯水凝胶创面敷料的制备方法,其特征在于,具体包括如下制备步骤:
1)称取分子量为1~10w、脱乙酰度85%~95%的CS以及GO粉末,加入到去离子水中,超声分散至少40分钟后,得到灰色溶液A;
2)在强烈机械搅拌下逐滴加入HAc,加入后在室温下继续搅拌至少4h使CS与GO充分混合后,得到溶液B;所述的强烈机械搅拌过程中,搅拌转速大于500rpm;
3)将溶液B在95℃下加热4h,然后自然冷却到室温,即得CSGO水凝胶。
3.如权利要求2所述的具有剪切变稀和自愈合性能的可注射型壳聚糖-氧化石墨烯水凝胶创面敷料的制备方法,其特征在于,所述的步骤1)GO粉末的片层尺寸为0.5~5μm、单片厚度为1~3nm。
4.如权利要求2所述的具有剪切变稀和自愈合性能的可注射型壳聚糖-氧化石墨烯水凝胶创面敷料的制备方法,其特征在于,所述的步骤1)中溶液A中CS、GO的浓度分别为80mg/mL、1~3mg/mL。
5.如权利要求2所述的具有剪切变稀和自愈合性能的可注射型壳聚糖-氧化石墨烯水凝胶创面敷料的制备方法,其特征在于,所述的步骤2)中溶液B中HAc的浓度为0.02~0.05mL/mL。
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