CN113797386B - 一种负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜及其制备方法 - Google Patents
一种负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜及其制备方法 Download PDFInfo
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Abstract
本发明涉及一种负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜及其制备方法,制备步骤包括:将活性氧响应性聚氨酯与盐酸多西环素溶于六氟异丙醇得到纺丝溶液,通过静电纺丝技术得到负载盐酸多西环素的聚氨酯静电纺丝膜;配制导电水凝胶前体溶液,在载药聚氨酯静电纺丝膜上通过3D打印和紫外光固化,最终形成负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜。本发明利用活性氧响应性聚氨酯和静电纺丝技术得到载药静电纺丝膜,并在上面打印导电水凝胶,结合了水凝胶和聚氨酯两者的特点,所得复合膜具有良好的生物相容性、活性氧响应性、力学性能、药物负载能力,适用于糖尿病等情况导致的慢性炎症皮肤创面治疗。
Description
技术领域
本发明涉及一种水凝胶/聚氨酯复合膜及其制备方法,特别涉及一种负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜及其制备方法。
背景技术
普通的皮肤创面愈合按时间进程主要分为止血期、炎症期、增殖期和重塑期四个阶段。而糖尿病患者的皮肤创面由于其特殊的组织微环境容易形成慢性炎症,难以自行愈合且易遭受感染,基本特征为炎症期的持续存在。当前研究显示,在糖尿病患者创面形成初期,中性粒细胞首先抵达创面并分泌促炎细胞因子基质金属蛋白酶(MMP酶),诱导单核细胞进入创面组织并分化为巨噬细胞。初始阶段,免疫细胞数量少且迁移至伤口的速度非常慢,但该过程一旦开始就会持续加强,尤其对糖尿病创面微环境,炎症细胞促进并维持促炎细胞因子的高表达。其中促炎细胞因子不仅能增加MMP酶的产生,而且降低了组织中MMP酶抑制剂的表达,导致MMP酶和MMP酶抑制剂的动态平衡被打破,进一步导致了相关生长因子和新形成的细胞外基质(ECM)的降解。而ECM分解产物会进一步诱发炎症,促炎因子的诱导作用和ECM的酶解导致了更多的炎症相关细胞迁移到伤口处,从而不断加强、维持创面的炎症反应,产生更多的MMP酶、活性氧(ROS)、活性氮(RNS)等,这将极大地限制创面肉芽组织的形成和成熟,阻止了慢性创面从炎症期过渡到增殖期。
聚氨酯是一种广泛用于生物医用材料的高分子材料,具有良好的力学性能、可加工性和生物相容性,而其结构中软段和硬段化学成分的改变可调节或赋予聚氨酯不同的性能。酮缩硫醇类分子由于其本身的化学特性,可在活性氧作用下发生断裂,本发明中使用的聚氨酯将酮缩硫醇类小分子作为扩链剂,使其具备活性氧响应能力,可清除慢性炎症环境下的活性氧。盐酸多西环素作为一种半合成类四环素药物,近期研究发现其对金属离子的络合作用可起到抑制MMP酶表达的作用,将其用慢性炎症部位可有效改善MMP酶过度表达的情况,从而起到抗炎作用。水凝胶材料作为一种和生物组织相似的高含水量材料,同样具有较好的生物相容性和可调控的物理化学性能。有文献报道称,导电水凝胶对创面愈合具有促进作用,丙烯酰氧乙基三甲基氯化铵是一种生物相容性良好的离子液体,将其与甲基丙烯酰化明胶进行共聚,得到生物相容性良好的导电水凝胶。水凝胶能提供一个和皮肤组织相似的电生理环境用于促进创面再生,但是强度不足;聚氨酯具有良好的强度,但无法提供与皮肤相似的环境供创面愈合。
本发明首次将盐酸多西环素、活性氧响应聚氨酯和导电水凝胶结合,利用静电纺丝技术得到负载盐酸多西环素的活性氧响应性聚氨酯薄膜,再利用3D打印技术在上述薄膜上打印导电水凝胶,制备成一种负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜,相较已报道的敷料,该材料兼具电纺膜和水凝胶两种材料的优点,且具有炎症调控能力以及和皮肤组织相似的电生理活性,可用作敷料治疗包括糖尿病慢性创面在内的皮肤创伤。
发明内容
本发明的目的是针对慢性炎症创面微环境,提供一种负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜及其制备方法,其中含有酮缩硫醇结构的聚氨酯具有活性氧响应功能,负载的盐酸多西环素具有抑制MMP酶表达的作用,在聚氨酯静电纺丝膜表面利用3D打印技术打印一层导电水凝胶网络,促进创面组织修复。
本发明提供一种负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜,其特征在于,包括负载盐酸多西环素的活性氧响应性聚氨酯膜层和打印于其表面的导电水凝胶层。
其中的活性氧响应性聚氨酯包括酮缩硫醇二胺类小分子扩链剂、聚富马酸丙二醇酯(PPF)软段以及饱和脂肪族二异氰酸酯硬段;导电水凝胶成分为甲基丙烯酰化明胶、丙烯酰氧乙基三甲基氯化铵和苯基-2,4,6-三甲基苯甲酰基亚磷酸锂(LAP)。
所述的酮缩硫醇二胺小分子扩链剂(TK)的制备方法如下:
所述的活性氧响应性聚氨酯的制备方法如下:
1)将聚酯二醇加入到干燥容器中,减压除去残余的水分,然后加入无水N,N-二甲基甲酰胺溶剂溶解,再加入二异氰酸酯及催化剂二月桂酸二丁基锡,在氮气保护下65-75℃反应3-4h,得到异氰酸酯基团封端的预聚物;其中二异氰酸酯中异氰酸酯基团与聚酯二醇中羟基的摩尔比为2:1,二月桂酸二丁基锡的物质的量是聚酯二醇的羟基的物质的量的0.2%;
2)在步骤1)制备的异氰酸酯基团封端的预聚物中加入活性氧响应性小分子二胺的稀释液,其中,所述的活性氧响应性小分子二胺的稀释液是将活性氧响应性小分子二胺按10%g/mL用无水N,N-二甲基甲酰胺溶剂进行稀释获得;然后于70℃扩链反应至少7h,得到聚氨酯溶液,活性氧响应性小分子二胺的物质的量与聚酯二醇的物质的量相同,且均为二异氰酸酯物质的量的一半;
3)在步骤2)制备的聚氨酯溶液中加入无水乙醇并保持在70℃封端1h;
4)将经步骤3)处理后的聚氨酯溶液倒入无水乙醇中沉淀,离心、收集,将收集的聚氨酯固体再次溶于N,N-二甲基甲酰胺中,并再次倒入无水乙醇中沉淀,反复数次,最后将所得的聚氨酯固体从无水乙醇中转移到超纯水中,待乙醇除尽后,冷冻干燥,得到活性氧响应性的可降解聚氨酯材料。
进一步地,上述活性氧响应性聚氨酯数均分子量为2~3万。
本发明还提供负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜的制备方法,其特征在于,包括以下步骤:
1)将活性氧响应性聚氨酯与盐酸多西环素按1:(0.05~0.25)的质量比混合后溶于六氟异丙醇中,配置成质量分数8~15%的静电纺丝溶液;
2)将步骤1)所得静电纺丝溶液加入到静电纺丝设备的注射器中,进行单喷头静电纺丝,制得负载盐酸多西环素的活性氧响应性聚氨酯膜层;
3)将甲基丙烯酰化明胶、丙烯酰氧乙基三甲基氯化铵和苯基-2,4,6-三甲基苯甲酰基亚磷酸锂(LAP)溶于水配制成水凝胶前体溶液;
4)将步骤3)配制所得水凝胶前体溶液置于3D打印机中,通过紫外光照交联的方式在步骤2)得到的负载盐酸多西环素的活性氧响应性聚氨酯膜层上进行3D打印,得到导电水凝胶层,导电水凝胶层和负载盐酸多西环素的活性氧响应性聚氨酯膜层共同组成了负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜。
进一步地,所述步骤2)中进行单喷头静电纺丝的条件为:所用针头型号为20G,纺丝电压为10~20kV,纺丝针头距离接收器距离为10~20cm,接收器滚筒转速为200~400rpm,纺丝溶液的给液速度为0.5~1.5mL/h。
进一步地,所述步骤3)中,水凝胶前体溶液中甲基丙烯酰化明胶的质量体积浓度为10~20%,丙烯酰氧乙基三甲基氯化铵的质量体积浓度为1~10%,LAP的质量体积浓度0.05%~0.1%。
进一步地,所述步骤4)中,紫外光照的波长为365-395nm。
进一步地,所述步骤4)中,3D打印的参数如下:3D打印机挤出头直径为0.2~1.0mm,水凝胶网络的面积填充率为30%~60%,层数为2~6层,层高设置为0.1~0.2mm,XY轴在打印时的移动速度为100~400mm/min,3D打印溶液挤出速率为6~60mm/min。
本发明具有如下有益效果:
本发明的负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜具有良好的生物相容性。活性氧响应性聚氨酯中的酮缩硫醇结构在活性氧作用下发生断裂,使该聚氨酯具有活性氧降解性。降解后的聚氨酯电纺膜可以加速所负载的药物释放速率,已知高水平的炎症环境含有大量活性氧物质,从中释放出的盐酸多西环素药物能有效改善创面炎症情况。通过3D打印在表面的导电水凝胶具有组织相似的含水网络结构和电生理活性,并传递组织电信号。上述敷料导电性能、载药量可以通过加工过程中盐酸多西环素和丙烯酰氧乙基三甲基氯化铵离子液体的投料量进行调节。相较于已报道的相关敷料,本发明创造性地将水凝胶和电纺膜进行复合得到了一种多功能非对称创面敷料,其中水凝胶能够模拟组织的结构、含水量以及电生理活性,为创面提供湿润环境,吸收创面渗出液;而载药电纺膜不仅可释药改善炎症,其多孔性能可保证创面的透气性。
附图说明
图1为本发明负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜的制备过程示意图;
图2为实施例1中水凝胶/聚氨酯复合膜的宏观照片;
图3为实施例3中大鼠糖尿病创面愈合实验的创面愈合照片记录;
图4为实施例3中大鼠糖尿病创面愈合实验的第7天各组创面面积统计图。
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
一种负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜,所述复合膜的制备包括以下步骤
第一步:将活性氧响应性聚氨酯与盐酸多西环素按1:0.1的质量比混合后溶于六氟异丙醇溶液中,配置成质量分数10%的纺丝溶液
第二步:将第一步所得静电纺丝溶液加入到静电纺丝设备的注射器中,进行单喷头静电纺丝,纺丝注射器针头为20G,调节纺丝电压为15kV,纺丝针头距离接收器距离为10cm,接收器滚筒转速为200rpm,纺丝溶液的给液速度为1mL/h,保持上述条件直至纺丝结束,得到负载盐酸多西环素的活性氧响应性聚氨酯静电纺丝膜。
第三步:将甲基丙烯酰化明胶、丙烯酰氧乙基三甲基氯化铵和LAP按质量体积浓度10%、2%和0.05%溶于水,配制成水凝胶前体溶液。
第四步:将第三步配制所得水凝胶前体溶液置于3D打印机中,将第二步所得聚氨酯静电纺丝膜置于3D打印机底板上平铺固定。设定3D打印机挤出头直径为0.4mm,3D打印水凝胶网络的面积填充率为30%,层数为4层,层高设置为0.1mm,XY轴在打印时的移动速度为180mm/min,3D打印溶液挤出速率为10mm/min,在聚氨酯电纺膜上打印的水凝胶前体溶液通过365nm紫外光照交联,得到负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜。
实施例2
一种负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜,所述复合膜的制备包括以下步骤
第一步:将活性氧响应性聚氨酯与盐酸多西环素按1:0.15的质量比混合后溶于六氟异丙醇溶液中,配置成质量分数10%的纺丝溶液
第二步:将第一步所得静电纺丝溶液加入到静电纺丝设备的注射器中,进行单喷头静电纺丝,纺丝注射器针头为20G,调节纺丝电压为15kV,纺丝针头距离接收器距离为10cm,接收器滚筒转速为300rpm,纺丝溶液的给液速度为0.8mL/h,保持上述条件直至纺丝结束,得到负载盐酸多西环素的活性氧响应性聚氨酯静电纺丝膜。
第三步:将甲基丙烯酰化明胶、丙烯酰氧乙基三甲基氯化铵和LAP按质量体积浓度10%、5%和0.1%溶于水,配制成水凝胶前体溶液。
第四步:将第三步配制所得水凝胶前体溶液置于3D打印机中,将第二步所得聚氨酯静电纺丝膜置于3D打印机底板上平铺固定。设定3D打印水凝胶网络的面积填充率为60%,层数为4层,层高设置为0.1mm,XY轴在打印时的移动速度为240mm/min,3D打印溶液挤出速率为20mm/min,在聚氨酯电纺膜上打印的水凝胶前体溶液通过365nm紫外光照交联,得到负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜。
实施例3
选取200g雄性SD大鼠若干,按65mg/kg剂量腹腔注射链脲佐菌素(链脲佐菌素按质量分数1%溶于0.1mol/L柠檬酸-柠檬酸钠缓冲液),破坏大鼠胰腺组织得到I型糖尿病大鼠。在大鼠背部两侧对称部位制造直径7mm的圆形全层皮肤缺损。将实施例2中所制得的敷料覆盖在创面部位用于糖尿病大鼠创面治疗,其中打印有水凝胶的一面朝向创面。实施例2所得敷料命名为“导电载药组”。按实施例2相同模式制备敷料,其中不含多西环素盐酸盐的组别命名为“导电组”,不含丙烯酰氧乙基三甲基氯化铵的组别命名为“载药组”。设置导电组、载药组以及无敷料的空白组为对照组,7天后观察记录大鼠背部创面情况。
Claims (10)
1.一种负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜,其特征在于,包括负载盐酸多西环素的活性氧响应性聚氨酯膜层和打印于其表面的导电水凝胶层;
所述的活性氧响应性聚氨酯是利用酮缩硫醇二胺类小分子扩链剂制备得到的含有酮缩硫醇结构的聚氨酯;
所述的导电水凝胶是使用甲基丙烯酰化明胶、丙烯酰氧乙基三甲基氯化铵和苯基-2,4,6-三甲基苯甲酰基亚磷酸锂通过光交联方式制备而成的。
2.负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜的制备方法,其特征在于,包括以下步骤:
1)将活性氧响应性聚氨酯与盐酸多西环素按1:(0.05~0.25)的质量比混合后溶于六氟异丙醇中,配置成总质量分数8~15%的静电纺丝溶液;
2)将步骤1)所得静电纺丝溶液加入到静电纺丝设备的注射器中,进行单喷头静电纺丝,制得负载盐酸多西环素的活性氧响应性聚氨酯膜层;
3)将甲基丙烯酰化明胶、丙烯酰氧乙基三甲基氯化铵和苯基-2,4,6-三甲基苯甲酰基亚磷酸锂(LAP)溶于水配制成水凝胶前体溶液;
4)将步骤3)配制所得水凝胶前体溶液置于3D打印机中,通过紫外光照交联的方式在步骤2)得到的负载盐酸多西环素的活性氧响应性聚氨酯膜层上进行3D打印,得到导电水凝胶层,导电水凝胶层和负载盐酸多西环素的活性氧响应性聚氨酯膜层共同组成了负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜;
其中,所述的活性氧响应性聚氨酯是利用酮缩硫醇二胺类小分子扩链剂制备得到的含有酮缩硫醇结构的聚氨酯。
3.根据权利要求2所述的负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜的制备方法,其特征在于,所述步骤1)中,活性氧响应性聚氨酯合成步骤如下:
1)将聚酯二醇加入到干燥容器中,减压除去残余的水分,然后加入无水N,N-二甲基甲酰胺溶剂溶解,再加入二异氰酸酯及催化剂二月桂酸二丁基锡,在氮气保护下65-75℃反应3-4h,得到异氰酸酯基团封端的预聚物;其中二异氰酸酯中异氰酸酯基团与聚酯二醇中羟基的摩尔比为2:1,二月桂酸二丁基锡的物质的量是聚酯二醇的羟基的物质的量的0.2%;
2)在步骤1)制备的异氰酸酯基团封端的预聚物中加入活性氧响应性小分子二胺的稀释液,其中,所述的活性氧响应性小分子二胺的稀释液是将活性氧响应性小分子二胺按10%g/mL用无水N,N-二甲基甲酰胺溶剂进行稀释获得;然后于70℃扩链反应至少7h,得到聚氨酯溶液,活性氧响应性小分子二胺的物质的量与聚酯二醇的物质的量相同,且均为二异氰酸酯物质的量的一半;
3)在步骤2)制备的聚氨酯溶液中加入无水乙醇并保持在70℃封端1h;
4)将经步骤3)处理后的聚氨酯溶液倒入无水乙醇中沉淀,离心、收集,将收集的聚氨酯固体再次溶于N,N-二甲基甲酰胺中,并再次倒入无水乙醇中沉淀,反复数次,最后将所得的聚氨酯固体从无水乙醇中转移到超纯水中,待乙醇除尽后,冷冻干燥,得到活性氧响应性的可降解聚氨酯材料。
4.根据权利要求2所述的负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜的制备方法,其特征在于,所述步骤1)中,活性氧响应性聚氨酯数均分子量为2~3万。
5.根据权利要求2所述的负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜的制备方法,其特征在于,所述步骤2)中进行单喷头静电纺丝的条件为:所用针头型号为20G,纺丝电压为10~20kV,纺丝针头距离接收器距离为10~20cm,接收器滚筒转速为200~400rpm,纺丝溶液的给液速度为0.5~1.5mL/h。
6.根据权利要求2所述的负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜的制备方法,其特征在于,所述步骤3)中,水凝胶前体溶液中甲基丙烯酰化明胶的质量体积浓度为10~20%。
7.根据权利要求2所述的负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜的制备方法,其特征在于,所述步骤3)中,水凝胶前体溶液中丙烯酰氧乙基三甲基氯化铵的质量体积浓度为1~10%。
8.根据权利要求2所述的负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜的制备方法,其特征在于,所述步骤3)中,水凝胶前体溶液中LAP的质量体积浓度0.05%~0.1%。
9.根据权利要求2所述的负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜的制备方法,其特征在于,所述步骤4)中,紫外光照的波长为365-395nm。
10.根据权利要求2所述的负载盐酸多西环素的导电水凝胶/活性氧响应性聚氨酯复合膜的制备方法,其特征在于,所述步骤4)中,3D打印的参数如下:3D打印机挤出头直径为0.2~1.0mm,水凝胶网络的面积填充率为30%~60%,层数为2~6层,层高设置为0.1~0.2mm,XY轴在打印时的移动速度为100~400mm/min,3D打印溶液挤出速率为6~60mm/min。
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