CN113384741B - 一种具有主动与被动双重抗菌机理的季铵盐聚膦腈水凝胶伤口敷料及制备方法 - Google Patents
一种具有主动与被动双重抗菌机理的季铵盐聚膦腈水凝胶伤口敷料及制备方法 Download PDFInfo
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Abstract
本发明公开了一种具有主动与被动双重抗菌机理的季铵盐聚膦腈水凝胶伤口敷料及制备方法。本发明的水凝胶伤口敷料是通过含有季铵盐功能基团的亲水性聚膦腈与亲水性1‑乙烯基‑2‑吡咯烷酮在引发剂存在下自由基共聚得到。本发明中的水凝胶伤口敷料通过交联骨架中的阳离子季铵盐功能基团实现被动接触性抗菌,骨架中的可以和游离碘络合的水凝胶网络实现游离碘负载与长效的药物释放;水凝胶伤口敷料能实现抗菌目的,具有良好的溶胀性能,具有较高的机械强度以及较低的溶血率。
Description
技术领域
本发明属于高分子材料技术领域的一种水凝胶伤口敷料及制备方法,具体涉及了一种具有主动与被动双重抗菌机理的季铵盐聚膦腈水凝胶伤口敷料及制备方法。
背景技术
慢性伤口需要频繁换药并且伴有感染、疼痛以及渗出液问题,对人体构成严重的健康风险。伤口感染的发生会导致肉芽组织,生长因子和细胞外基质成分的恶化,损害正常的伤口愈合过程。因此研发更加经济、安全和高效抗感染的伤口敷料成为医药健康关注的问题。与传统的干敷料相比,湿敷料能够加快伤口愈合过程。根据物理形式可分为软膏、薄膜、泡沫和凝胶。同时,抗菌性能是评价伤口敷料的关键因素,其主要是由水凝胶伤口敷料负载具有抗菌能力的药物如抗生素、金属纳米粒子、生物提取物等来实现的,这往往会导致细菌耐药性与较强的生物毒性。在现代伤口管理中,尤其是在耐药菌数量不断增加的背景下,控制感染仍然是一大挑战。
水凝胶是一类富含水的高分子材料。由于含有大量的游离水,水凝胶兼具湿软的特性,且结构与生物组织类似,具有良好的生物相容性。水凝胶伤口敷料具有保持伤口润湿,通过冷却减轻疼痛,吸收组织渗出液,易于更换与移除,机械保护性等优良特性,是目前新型伤口敷料的重要发展方向。在耐药菌数量不断增加的背景下,聚维酮碘、银、氯己定、苯扎氯铵、季铵盐等抗菌剂被认为是解决微生物耐药性的有效方案。
发明内容
为解决现有技术的不足,本发明提供一种具有主动与被动双重抗菌机理的季铵盐聚膦腈水凝胶伤口敷料的制备方法。所述的水凝胶敷料具有优异的被动接触性抗菌性能与药物释放主动抗菌性能,良好的力学性能与溶胀能力等。18h接触性被动抗菌效率能够达到98.6±1.2%,结合碘释放的主动抗菌性能,季铵盐聚膦腈水凝胶伤口敷料的抗菌率能够达到100%。
本发明所采用的技术方案是:
一、一种具有主动与被动双重抗菌机理的季铵盐聚膦腈水凝胶伤口敷料
所述水凝胶伤口敷料是通过含有季铵盐功能基团的亲水性聚膦腈与亲水性1-乙烯基-2-吡咯烷酮在引发剂存在下自由基共聚得到。
所述季铵盐功能基团的亲水性聚膦腈为聚(二甲基-氨乙基-烯丙基溴化铵)膦腈。
所述引发剂为2-羟基-4-(2-羟乙氧基)-2-甲基苯丙酮。
所述含有季铵盐功能基团的亲水性聚膦腈的数均分子量为40000。
二、一种具有主动与被动双重抗菌机理的季铵盐聚膦腈水凝胶伤口敷料的制备方法
方法包括以下步骤:
1)将聚(二甲基-氨乙基-烯丙基溴化铵)膦腈和1-乙烯基-2-吡咯烷酮均充分溶解于去离子水中获得混合溶液,用氩气鼓泡后获得除氧后的溶液;
2)在除氧后的溶液中加入引发剂并充分溶解,得到凝胶前驱溶液;
3)将凝胶前驱溶液注于所需形态的模具中,之后将模具置于紫外灯下进行光引发自由基聚合反应,得到以去离子水为溶剂的有机凝胶;
4)将所得的有机凝胶置于去离子水中,使得有机凝胶中未参加聚合的单体与去离子水充分置换,得到所需形态的水凝胶;
5)将所得的水凝胶置于浓度为2.5mM的标准碘液中24h,使水凝胶充分负载游离碘,得到所需形态的水凝胶伤口敷料。
所述的步骤1)中,以质量份数计,聚(二甲基-氨乙基-烯丙基溴化铵)膦腈为30~70份,1-乙烯基-2-吡咯烷酮为200~300份,去离子水为1500~3000份。
所述的步骤2)中,以质量份数计,引发剂为5~7份。
所述的步骤3)中,光引发自由基聚合反应的紫外光强为100W,光引发自由基聚合反应的时间为0.5h。
所述的模具为任意形状,制成的所述水凝胶伤口敷料为与模具相同的形状。
所述水凝胶对大肠杆菌的生长抑制率达到98.6±1.6%;所述水凝胶伤口敷料对大肠杆菌的生长抑制率达到100%。
所述的水凝胶具有良好的被动接触性抗菌性能以及主动药物释放抗菌性能。
本发明的具有主动与被动双重抗菌机理的水凝胶伤口敷料通过化学交联生成的共价交联点以及游离碘与骨架中的聚乙烯基吡咯烷酮络合作用而成。
本发明所提供的水凝胶伤口敷料的聚合网络中包含能够提供一定阳离子强度的具有抗菌功能的季铵盐基团以及能够与游离碘络合的聚乙烯基吡咯烷酮。季铵盐基团能够通过静电作用、氢键力以及表面活性分子与蛋白质分子之间的疏水结合等作用,吸附带负电的细菌体,导致细菌生长受到抑制而死亡,从而提供高效的被动接触抗菌能力。水凝胶骨架中的聚吡咯烷酮能够游离的碘相结合形成疏松复合物,同时聚乙烯基吡咯烷酮能够提供载体和助溶的作用,提高碘的负载能力,从而能够高效的主动药物释放抗菌能力。
本发明有益效果如下:
1.本发明提供的负载碘后的水凝胶伤口敷料具有良好的溶胀能力,具有足够强度的抗压缩能力以及杨氏模量。
2.本发明提供的水凝胶自身为抗菌性能的材料,其具有的阳离子季铵盐功能基团的水凝胶骨架不存在失效问题,使该水凝胶在使用过程中不会发生因抗菌组分释放时限而产生的时效性问题。
3.本发明提供的水凝胶敷料具有的聚吡咯烷酮组骨架,能够有效的对碘提供载体和助溶作用,提高了碘的负载能力与缓释能力。
4.本发明提供的水凝胶敷料所提供的被动接触性抑菌与主动的碘释放抗菌能力分别从两种不同的抗菌机理出发,协同抗菌效率更强。
附图说明
图1为实施例1制备的负载碘的水凝胶应力-应变曲线图。
图2为实施例1制备的未负载碘与负载碘的水凝胶的接触抑菌率。
图3为实施例2制备的负载碘的水凝胶应力-应变曲线图。
图4为实施例2制备的未负载碘与负载碘的水凝胶的接触抑菌率。
图5为实施例3制备的负载碘的水凝胶应力-应变曲线图。
图6为实施例3制备的未负载碘与负载碘的水凝胶的接触抑菌率。
具体实施方式
下面结合具体实施例对本发明做更详尽的说明,但本发明的实施方式不限于此。
本发明的实施例如下:
实施例1
聚(二甲基-氨乙基-烯丙基溴化铵)膦腈56.1mg,1-乙烯基-2-吡咯烷酮543.2mg,溶于1401.3mg去离子水中获得混合溶液。待充分溶解后向混合溶液中持续通入氩气30min以除去混合溶液中的氧气,之后向混合溶液中加入5.9mg的2-羟基-4-(2-羟乙氧基)-2-甲基苯丙酮并充分溶解得到凝胶前驱溶液。
将凝胶前驱溶液分别注入块状模具(长=1cm,宽=1cm,高=1mm)与柱状模具(内径=1cm)后将块状模具和柱状模具均置于100W紫外灯下进行光引发自由基聚合反应,反应持续30min。反应结束后得到以去离子水为溶剂的片状与柱状有机凝胶。
将片状与柱状有机凝胶分别从块状模具和柱状模具中取出置于足量的水中置换未参加聚合的单体,每隔24h换一次水,连续置换5天使得未参加聚合的单体被去离子水充分置换,之后得到具有被动接触性抗菌的片状和柱状水凝胶。
将所得的片状和柱状水凝胶置于浓度为2.5mM的标准碘液中24h,使片状和柱状水凝胶充分负载游离碘,得到具有主动与被动双重抗菌机理的片状和柱状水凝胶伤口敷料。
所得柱状水凝胶伤口敷料进行体外抗压缩性能评估,实验于25℃下配置有500N张力传感器的万能材料测试仪进行。
将10μL浓度为108CFU/mL的大肠杆菌菌液均匀的涂布在上述负载碘的片状水凝胶伤口敷料与未负载碘的片状水凝胶之上,37℃下孵育18h后将片状水凝胶伤口敷料和片状水凝胶上的菌液稀释用于琼脂平板接种。将琼脂平板孵育过夜以进行CFU计数,计算抑菌率。
将1ml2%红细胞悬液与4mlPBS缓冲液的混合物设为阴性对照组,1ml2%红细胞悬液与4ml去离子水的混合物设为阳性对照组。将上述得到的未负载碘的具有被动接触性抗菌的片状水凝胶在37℃下培养2小时,每15min取细胞混液离心取上清液,在545nm下测量每个样品的吸光度。
本实施例结果如图1~图2所示,图1为所得负载碘的柱状水凝胶伤口敷料的压缩力-应变曲线,由图可见,柱状水凝胶伤口敷料具有优异的力学性能。其抗压缩强度能够到达376kPa,最大压缩应变为57%,杨氏模量达到34kPa。图2为所得负载碘的片状水凝胶伤口敷料与未负载碘的片状水凝胶的接触抑菌性能。由图可见,未负载碘的片状水凝胶由水凝胶表面的阳离子季铵盐基团引起的抑菌效率能够达到86.8%±7.1%,负载碘后的片状水凝胶抗菌敷料通过季铵盐基团的静电相互作用与游离碘的氧化作用,能够达到100%的抗菌效率。该实验体现了该主动与被动双重抗菌机理的季铵盐聚膦腈水凝胶伤口敷料具有非常优异的抗菌性能。此外,未负载碘的片状水凝胶对小鼠红细胞的2h溶血率为-0.8%±1.7%,表现了该水凝胶具有低溶血率,体现了优异的生物相容性。
实施例2
聚(二甲基-氨乙基-烯丙基溴化铵)膦腈104.1mg,1-乙烯基-2-吡咯烷酮495.5mg,溶于1400.5mg去离子水中获得混合溶液。待充分溶解后向混合溶液中持续通入氩气30min以除去混合溶液中的氧气,之后向混合溶液中加入6.3mg的2-羟基-4-(2-羟乙氧基)-2-甲基苯丙酮并充分溶解得到凝胶前驱溶液。
将凝胶前驱溶液分别注入块状模具(长=1cm,宽=1cm,高=1mm)与柱状模具(内径=1cm)后将块状模具和柱状模具均置于100W紫外灯下进行光引发自由基聚合反应,反应持续30min。反应结束后得到以去离子水为溶剂的片状与柱状有机凝胶。
将所得的片状和柱状水凝胶置于浓度为2.5mM的标准碘液中24h,使片状和柱状水凝胶充分负载游离碘,得到具有主动与被动双重抗菌机理的片状和柱状水凝胶伤口敷料。
所得柱状水凝胶伤口敷料进行体外抗压缩性能评估,实验于25℃下配置有500N张力传感器的万能材料测试仪进行。
将10μL浓度为108CFU/mL的大肠杆菌菌液均匀的涂布在上述负载碘的片状水凝胶伤口敷料与未负载碘的片状水凝胶之上,37℃下孵育18h后将片状水凝胶伤口敷料和片状水凝胶上的菌液稀释用于琼脂平板接种。将琼脂平板孵育过夜以进行CFU计数,计算抑菌率。
将1ml2%红细胞悬液与4mlPBS缓冲液的混合物设为阴性对照组,1ml2%红细胞悬液与4ml去离子水的混合物设为阳性对照组。将上述得到的未负载碘的具有被动接触性抗菌的片状水凝胶在37℃下培养2小时,每15min取细胞混液离心取上清液,在545nm下测量每个样品的吸光度。
本实施例结果如图3~图4所示,图3为所得负载碘的柱状水凝胶伤口敷料的压缩力-应变曲线,由图可见,其抗压缩强度能够到达380kPa,最大压缩应变为48%,杨氏模量达88kPa。图4为所得负载碘的片状水凝胶伤口敷料与未负载碘的片状水凝胶的接触抑菌性能。由图可见,未负载碘的片状水凝胶由水凝胶表面的阳离子季铵盐基团引起的抑菌效率能够达到97.5%±1.9%,负载碘的片状水凝胶伤口敷料通过季铵盐基团的静电相互作用与游离碘的氧化作用,能够达到100%的抗菌效率。未负载碘的片状水凝胶对小鼠红细胞的2h溶血率为3.3%±2.7%,表现了该片状水凝胶具有低溶血率。
实施例3
聚(二甲基-氨乙基-烯丙基溴化铵)膦腈141.1mg,1-乙烯基-2-吡咯烷酮460.5mg,溶于1402.5mg去离子水中获得混合溶液。待充分溶解后向混合溶液中持续通入氩气30min以除去混合溶液中的氧气,之后向混合溶液中加入6.0mg的2-羟基-4-(2-羟乙氧基)-2-甲基苯丙酮并充分溶解得到凝胶前驱溶液。
将凝胶前驱溶液分别注入块状模具(长=1cm,宽=1cm,高=1mm)与柱状模具(内径=1cm)后将块状模具和柱状模具均置于100W紫外灯下进行光引发自由基聚合反应,反应持续30min。反应结束后得到以去离子水为溶剂的片状与柱状有机凝胶。
将片状与柱状有机凝胶分别从块状模具和柱状模具中取出置于足量的水中置换未参加聚合的单体,每隔24h换一次水,连续置换5天使得未参加聚合的单体被去离子水充分置换,之后得到具有被动接触性抗菌的片状和柱状水凝胶。
将所得的片状和柱状水凝胶置于浓度为2.5mM的标准碘液中24h,使片状和柱状水凝胶充分负载游离碘,得到具有主动与被动双重抗菌机理的片状和柱状水凝胶伤口敷料。
所得柱状水凝胶伤口敷料进行体外抗压缩性能评估,实验于25℃下配置有500N张力传感器的万能材料测试仪进行。
将10μL浓度为108CFU/mL的大肠杆菌菌液均匀的涂布在上述负载碘的片状水凝胶伤口敷料与未负载碘的片状水凝胶之上,37℃下孵育18h后将片状水凝胶伤口敷料和片状水凝胶上的菌液稀释用于琼脂平板接种。将琼脂平板孵育过夜以进行CFU计数,计算抑菌率。
将1ml2%红细胞悬液与4mlPBS缓冲液的混合物设为阴性对照组,1ml2%红细胞悬液与4ml去离子水的混合物设为阳性对照组。将上述得到的未负载碘的具有被动接触性抗菌的片状水凝胶在37℃下培养2小时,每15min取细胞混液离心取上清液,在545nm下测量每个样品的吸光度。
本实施例结果如图5~图6所示,图5为所得负载碘的柱状水凝胶伤口敷料的压缩力-应变曲线,由图可见,其抗压缩强度能够到达520kPa,最大压缩应变为45%,杨氏模量达到141kPa。图6为所得负载碘的片状水凝胶伤口敷料与未负载碘的片状水凝胶的接触抑菌性能。由图可见,未负载碘的片状水凝胶由片状水凝胶表面的阳离子季铵盐基团引起的抑菌效率能够达到98.6%±1.2%,负载碘的柱状水凝胶伤口敷料通过季铵盐基团的静电相互作用与游离碘的氧化作用,能够达到100%的抗菌效率。未负载碘的片状水凝胶对小鼠红细胞的2h溶血率为6.1%±3.1%。
Claims (9)
1.一种具有主动与被动双重抗菌机理的季铵盐聚膦腈水凝胶伤口敷料,其特征在于:所述水凝胶伤口敷料是通过含有季铵盐功能基团的亲水性聚膦腈与亲水性1-乙烯基-2-吡咯烷酮在引发剂存在下自由基共聚,再通过化学交联生成的共价交联点以及游离碘与骨架中的聚乙烯基吡咯烷酮络合作用而成;
所述含有季铵盐功能基团的亲水性聚膦腈为聚(二甲基-氨乙基-烯丙基溴化铵)膦腈。
2.根据权利要求1所述的一种具有主动与被动双重抗菌机理的季铵盐聚膦腈水凝胶伤口敷料,其特征在于:所述引发剂为2-羟基-4-(2-羟乙氧基)-2-甲基苯丙酮。
3.根据权利要求1所述的一种具有主动与被动双重抗菌机理的季铵盐聚膦腈水凝胶伤口敷料,其特征在于:所述含有季铵盐功能基团的亲水性聚膦腈的数均分子量为40000。
4.根据权利要求1所述的一种具有主动与被动双重抗菌机理的季铵盐聚膦腈水凝胶伤口敷料的制备方法,其特征在于,包括以下步骤:
1)将聚(二甲基-氨乙基-烯丙基溴化铵)膦腈和1-乙烯基-2-吡咯烷酮均充分溶解于去离子水中获得混合溶液,用氩气鼓泡后获得除氧后的溶液;
2)在除氧后的溶液中加入引发剂并充分溶解,得到凝胶前驱溶液;
3)将凝胶前驱溶液注于所需形态的模具中,之后将模具置于紫外灯下进行光引发自由基聚合反应,得到以去离子水为溶剂的有机凝胶;
4)将所得的有机凝胶置于去离子水中,使得有机凝胶中未参加聚合的单体与去离子水充分置换,得到所需形态的水凝胶;
5)将所得的水凝胶置于浓度为2.5mM的标准碘液中24h,使水凝胶充分负载游离碘,得到所需形态的水凝胶伤口敷料。
5.根据权利要求4所述的一种具有主动与被动双重抗菌机理的季铵盐聚膦腈水凝胶伤口敷料的制备方法,其特征在于:所述的步骤1)中,以质量份数计,聚(二甲基-氨乙基-烯丙基溴化铵)膦腈为30~70份,1-乙烯基-2-吡咯烷酮为200~300份,去离子水为1500~3000份。
6.根据权利要求4所述的一种具有主动与被动双重抗菌机理的季铵盐聚膦腈水凝胶伤口敷料的制备方法,其特征在于:所述的步骤2)中,以质量份数计,引发剂为5~7份。
7.根据权利要求4所述的一种具有主动与被动双重抗菌机理的季铵盐聚膦腈水凝胶伤口敷料的制备方法,其特征在于:所述的步骤3)中,光引发自由基聚合反应的紫外光强为100W,光引发自由基聚合反应的时间为0.5h。
8.根据权利要求4所述的一种具有主动与被动双重抗菌机理的季铵盐聚膦腈水凝胶伤口敷料的制备方法,其特征在于:所述的模具为任意形状,制成的所述水凝胶伤口敷料为与模具相同的形状。
9.根据权利要求4所述的一种具有主动与被动双重抗菌机理的季铵盐聚膦腈水凝胶伤口敷料的制备方法,其特征在于:所述水凝胶对大肠杆菌的生长抑制率达到98.6±1.6%;所述水凝胶伤口敷料对大肠杆菌的生长抑制率达到100%。
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