CN113577377A - 一种活性氧消除抗菌消炎水凝胶皮肤敷料及其制备方法 - Google Patents
一种活性氧消除抗菌消炎水凝胶皮肤敷料及其制备方法 Download PDFInfo
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Abstract
本发明涉及一种活性氧消除抗菌消炎水凝胶皮肤敷料及其制备方法,所述皮肤敷料是由丙酮[双‑(2‑氨基‑乙基)‑二硫缩醇]及3,3’‑二硫代双(丙酰肼)中的氨基与聚(聚乙二醇甲醚甲基丙烯酸酯‑co‑甲基丙烯酸缩水甘油酯)的环氧基团发生开环反应形成主体水凝胶网络,同时聚乙烯醇链段穿插在前述的水凝胶网络中形成半互穿网络,通过将冻干的水凝胶在超支化聚赖氨酸溶液中溶胀实现抗菌物质的负载,即可得到活性氧消除抗菌消炎水凝胶皮肤敷料。本发明的活性氧消除抗菌消炎水凝胶皮肤敷料可用于皮肤损伤修复,起到广谱抗菌、抑菌作用的同时,能通过消除伤口部位过量的活性氧起到调控伤口部位炎症水平,促进伤口愈合及减小瘢痕产生的功效,且不产生耐药性。
Description
技术领域
本发明涉及一种医用促皮肤创面修复抗菌敷料,具体涉及一种活性氧消除抗菌消炎水凝胶皮肤敷料及其制备方法。
背景技术
皮肤是人体最大的器官,在保护人体、组织微生物侵袭、维持体液平衡等方面发挥巨大的功效。皮肤创伤是人们日常生活中最常见的病变,尤其是全层皮肤缺损创面,需要较长的愈合恢复时间。皮肤创面的修复过程有四个阶段:止血期、炎症期、增生期和重塑期,完全愈合常需数月之久。适度的炎症可以激活免疫系统、清除坏死组织,对伤口的愈合速度、瘢痕化程度以及最终的愈合效果有决定性作用。新生成的创口由于暴露在空气中,容易发生细菌感染。由于炎症环境对细菌生长有抑制作用,若不外加干预,人体的免疫系统往往会自发产生过度的炎症反应。但高炎症水平会延长炎症期,增加整体愈合时间,且会影响增生期和重塑期的修复效果,导致较大的疤痕组织的生产。所以,在理想的皮肤损伤的修复过程中,需在减轻炎症进而减小瘢痕化,和抑制细菌生长之间达到平衡。
临床上对创伤敷料的首要要求是快速封闭创面、促进创面愈合、减轻瘢痕化。对比传统的创伤敷料,水凝胶敷料可以维持创面湿度、吸收组织渗出液、增加氧气通透性、冷却创面、减轻患者的痛苦。环境响应性水凝胶在保持水凝胶基本特性的基础上,可以在特定组织微环境发挥更多的功能。已有文献报道了针对皮肤创面的炎症响应性抗菌水凝胶,通过调节伤口位置的炎症水平来促进皮肤的有序愈合。此类水凝胶的抗菌性能通常依靠壳聚糖等天然带抗菌属性的大分子,但由天然分子制备的水凝胶力学性能差,且不易储存;或者依靠传统抗生素实现抗菌,易对细菌产生耐药性;亦有基于金属如银、铜及其纳米粒子的抗菌体系,其存在生物安全性风险,应用受到一定程度的限制。
发明内容
本发明的目的是提供一种活性氧消除抗菌消炎水凝胶皮肤敷料及其制备方法,该水凝胶皮肤敷料具有活性氧响应降解并消除活性氧、广谱抗菌的特性,可促进感染皮肤伤口的杀菌、促进愈合,且能减轻病患的痛苦。
本发明的一种活性氧消除抗菌消炎水凝胶皮肤敷料,包括由聚(聚乙二醇甲醚甲基丙烯酸酯-co-甲基丙烯酸缩水甘油酯)与活性氧响应断裂的小分子交联剂丙酮[双-(2-氨基-乙基)-二硫缩醇]及带动态二硫键的小分子交联剂3,3’-二硫代双(丙酰肼)形成的水凝胶网络,同时聚乙烯醇与上述网络形成半互穿网络,赋予水凝胶合适的力学性能,使之可裁剪成所需的尺寸后冻干保存。冻干后的水凝胶可以在具有抗菌性能的超支化聚赖氨酸溶液中快速吸水溶胀,恢复成水凝胶,即可得到所述活性氧消除抗菌消炎水凝胶材料。
本发明的一种活性氧消除抗菌消炎水凝胶皮肤敷料的制备方法,包括以下步骤:
第一步:在氮气保护下,将聚乙二醇甲醚甲基丙烯酸酯单体(PEGMA),甲基丙烯酸缩水甘油酯单体(GMA)和偶氮二异丁腈(AIBN)溶于甲醇溶剂中,磁力搅拌,50-70摄氏度加热回流若干小时(如10h)。反应结束后将反应液在冰乙醚中沉淀,离心收集产物,干燥后得到粗产物;将粗产物溶于甲醇中,再于冰乙醚中沉降除杂,重复若干次后收集产物,真空干燥得到聚(聚乙二醇甲醚甲基丙烯酸酯-co-甲基丙烯酸缩水甘油酯),即Poly(PEGMA-co-GMA);
第二步:将聚(聚乙二醇甲醚甲基丙烯酸酯-co-甲基丙烯酸缩水甘油酯)、丙酮[双-(2-氨基-乙基)-二硫缩醇]及3,3’-二硫代双(丙酰肼)溶解于聚乙烯醇水溶液中,得到水凝胶预聚溶液;
第三步:将第二步制备的水凝胶预聚溶液注入模具中,密封后加热若干个小时(如置于恒温水浴箱中反应24h)得到水凝胶;
第四步:将第三步制备的水凝胶在0摄氏度以下冷冻若干小时(如24h),再取出放在0摄氏度以上解冻若干小时(如12h),重复若干次;
第五步:将第四步制得的水凝胶切成所需尺寸(如1mm厚的薄片),冷冻干燥得到干燥水凝胶片;
第六步:将第五步制得的干燥水凝胶置于超支化聚赖氨酸溶液中达到溶胀平衡,得到活性氧消除的抗菌消炎水凝胶敷料。
进一步的,所述第一步中聚乙二醇甲醚甲基丙烯酸酯单体和甲基丙烯酸缩水甘油酯单体投料摩尔比为1:1-3:1。
进一步地,所述第一步中单体总摩尔浓度为0.45mol/L-0.75mol/L。
进一步地,所述第一步中引发剂摩尔量占单体总摩尔量的1%-15%。
进一步地,所述第二步中聚乙烯醇水溶液浓度为0.5-1wt%。
进一步地,所述第二步中聚(聚乙二醇甲醚甲基丙烯酸酯-co-甲基丙烯酸缩水甘油酯)与聚乙烯醇溶液的质量体积比为0.1-0.4g/ml;聚(聚乙二醇甲醚甲基丙烯酸酯-co-甲基丙烯酸缩水甘油酯)中环氧基团与丙酮[双-(2-氨基-乙基)-二硫缩醇]的摩尔比例为1:0.5-1:0.8;聚(聚乙二醇甲醚甲基丙烯酸酯-co-甲基丙烯酸缩水甘油酯)中环氧基团与3,3’-二硫代双(丙酰肼)的摩尔比例为1:0.4-1:0.7。
进一步地,所述第三步中成胶温度为30-50摄氏度。
进一步地,所述第六步中超支化聚赖氨酸浓度为0.5-5mg/ml。
本发明的发明原理为:皮肤创面愈合过程中,炎症水平对最终的愈合时间及愈合后瘢痕化程度有极大的影响。由于皮肤常常直接暴露在外界环境中,皮肤创面发生感染的几率大大增加,而创面感染会极大地加剧炎症水平,导致伤口恶化,阻碍伤口的愈合。针对炎症部位大量分泌的高反应活性物质,包括羟基自由基、超氧阴离子自由基、单线态氧等在内的活性氧,已报道众多功能性基团,如酮缩硫醇、苯硼酸酯、二硒键等,能在活性氧刺激下降解的同时消除活性氧。将此类基团引入到水凝胶网络中,可设计对活性氧有响应降解行为的水凝胶,一方面可以清除过剩的活性氧分子,另一方面可促进释放水凝胶网络中的促修复功能物质。由于活性氧消除的水凝胶在抗菌性能上会有局限,水凝胶亦可负载抗菌物质。对比链状聚赖氨酸,超支化聚赖氨酸高度的枝化率可保留大量活性胺基,发挥强大的抗菌功效;此外,其氨基酸类聚合物的本质决定它的生物亲和性,对细菌无耐药性。本发明首次尝试使用含酮缩硫醇键的小分子交联剂丙酮[双-(2-氨基-乙基)-二硫缩醇]和含二硫键的交联剂3,3’-二硫代双(丙酰肼)交联聚(聚乙二醇甲醚甲基丙烯酸酯-co-甲基丙烯酸缩水甘油酯)形成水凝胶网络,同时将聚乙烯醇穿插入此水凝胶形成半互穿网络,增强水凝胶的力学性能。酮缩硫醇基团及二硫键可以与活性氧反应,消除活性氧的同时使凝胶的降解,促进包裹在凝胶网络中的功能物质释放。同时,二硫键的动态键特性能适当地增加水凝胶材料的粘附性能。之后水凝胶可被切割成合适的尺寸后冻干保存。通过将冻干后的水凝胶在超支化聚赖氨酸溶液中重新溶胀,实现抗菌物质的负载,得到活性氧消除抗菌消炎水凝胶皮肤敷料。此水凝胶敷料可在深度感染创面有效地杀死细菌,并调控炎症水平,加速伤口愈合,减轻瘢痕化水平。
本发明的有益效果为:本发明的活性氧消除抗菌消炎水凝胶皮肤敷料具有良好的生物相容性。该水凝胶敷料覆盖皮肤伤口后,可以释放超支化聚赖氨酸达到快速杀菌、抑菌的目的,同时水凝胶敷料可以吸收伤口渗出液,水凝胶网络中的酮缩硫醇基团及二硫键基团可以消除活性氧自由基,大幅度减弱炎症的发展,降低促炎性细胞因子如IL-6、TNF-α的分泌,提高抑炎性细胞因子如IL-10的水平,同时提高伤口区域促生长因子TGF-β的水平,加速伤口愈合、减少瘢痕化,并减轻患者的痛苦。水凝胶网络由带可降解的酮缩硫醇基团和二硫键的小分子交联聚(聚乙二醇甲醚甲基丙烯酸酯-co-甲基丙烯酸缩水甘油酯)得到,在生理条件下及特定活性物质刺激下,酮缩硫醇键和二硫键可断裂,使水凝胶网络降解。与聚乙烯醇形成的半互穿网络能增强水凝胶的力学性能,使水凝胶具有良好的加工性,可裁切成理想的尺寸,且在冻干后依然能维持形状。冻干后的水凝胶储存简易、运输方便,使用前可在溶液中快速溶胀重新形成水凝胶网络。通过将冻干的水凝胶在超支化聚赖氨酸溶液中溶胀,实现抗菌物质的负载,同时抗菌物质易于释放,可在敷于感染部位后快速释放。
附图说明
图1为聚(聚乙二醇甲醚甲基丙烯酸酯-co-甲基丙烯酸缩水甘油酯)的合成路线;
图2为实施例1中的聚(聚乙二醇甲醚甲基丙烯酸酯-co-甲基丙烯酸缩水甘油酯)分子量和核磁氢谱;
图3为含酮缩硫醇键的交联剂丙酮[双-(2-氨基-乙基)-二硫缩醇]和含二硫键的交联剂3,3’-二硫代双(丙酰肼)分子的结构式;
图4为聚(聚乙二醇甲醚甲基丙烯酸酯-co-甲基丙烯酸缩水甘油酯)的环氧基团与小分子交联剂中的氨基反应形成水凝胶的反应机理。
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:在氮气保护下,将25.5g聚乙二醇甲醚甲基丙烯酸酯单体(Mn=300),6.4g甲基丙烯酸缩水甘油酯单体和3.3g偶氮二异丁腈溶于300ml甲醇溶剂中,磁力搅拌,70摄氏度加热回流10h;反应结束后将反应液在冰乙醚中沉淀,离心收集产物,干燥后得到粗产物;将粗产物溶于甲醇中,再于冰乙醚中沉降除杂,重复三次后收集产物,真空干燥得到聚(聚乙二醇甲醚甲基丙烯酸酯-co-甲基丙烯酸缩水甘油酯);
第二步:将0.8g第一步制备的聚(聚乙二醇甲醚甲基丙烯酸酯-co-甲基丙烯酸缩水甘油酯)、82.8mg丙酮[双-(2-氨基-乙基)-二硫缩醇]及51.4mg 3,3’-二硫代双(丙酰肼)溶解于4ml 0.5wt%聚乙烯醇溶液,得到水凝胶预聚溶液;
第三步:将第二步制备的水凝胶预聚溶液注入直径1.1cm的模具中,密封后置于37摄氏度恒温水浴箱中,反应24h得到水凝胶;
第四步:将第三步制备的水凝胶放入-20摄氏度冰箱中冷冻24h,再取出放入4摄氏度冰箱解冻12h,重复3次;
第五步:将第四步制得的水凝胶切成1mm厚的薄片,冷冻干燥得到干燥水凝胶片;
第六步:将第五步制得的干燥水凝胶置于0.5mg/ml的超支化聚赖氨酸溶液中溶胀平衡,得到活性氧消除的抗菌消炎水凝胶敷料。
实施例2:
第一步:在氮气保护下,将14.17g聚乙二醇甲醚甲基丙烯酸酯单体(Mn=300),3.56g甲基丙烯酸缩水甘油酯单体和1.60g偶氮二异丁腈溶于100ml甲醇溶剂中,磁力搅拌,70摄氏度加热回流10h;将反应液在冰乙醚中沉淀,离心收集产物,干燥后得到粗产物;将粗产物溶于甲醇中,再于冰乙醚中沉降除杂,重复三次后收集产物,真空干燥得到聚(聚乙二醇甲醚甲基丙烯酸酯-co-甲基丙烯酸缩水甘油酯);
第二步:将0.2g第一步制备的聚(聚乙二醇甲醚甲基丙烯酸酯-co-甲基丙烯酸缩水甘油酯)、12.9mg丙酮[双-(2-氨基-乙基)-二硫缩醇]及22.5mg 3,3’-二硫代双(丙酰肼)溶解于1ml 1wt%聚乙烯醇溶液,得到水凝胶预聚溶液;
第三步:将第二步制备的水凝胶预聚溶液注入直径1.1cm的模具中,密封后置于37摄氏度恒温水浴箱中,反应24h得到水凝胶;
第四步:将第三步制备的水凝胶放入-20摄氏度冰箱中冷冻24h,再取出放入室温解冻12h,重复3次;
第五步:将第四步制得的水凝胶切成1mm厚的薄片,冷冻干燥得到干燥水凝胶片;
第六步:将第五步制得的干燥水凝胶置于5mg/ml的超支化聚赖氨酸溶液中溶胀平衡,得到活性氧消除的抗菌水凝胶敷料。
以下是用该水凝胶敷料用于小鼠背部皮肤缺损感染模型的实验结果。用C57BL/6小鼠建立皮肤缺损感染模型,即在小鼠背部做直径约0.8cm的全层皮肤缺损,打入0.05ml 2×108CFU/ml耐甲氧西林金葡萄球菌菌液,待菌液完全吸收干燥后,将本申请的实施例1水凝胶敷料覆盖于创面,用3M Tegaderm敷贴对水凝胶进行固定。设阴性对照组,对缺损感染模型不做处理,以3M Tegaderm敷贴覆盖伤口。另设阳性对照组,用百多邦莫匹罗星软膏涂布于缺损感染部位,以3M Tegaderm敷贴覆盖伤口。结果显示,3天后,以阴性对照为参比,本申请的水凝胶敷贴和莫匹罗星阳性对照的杀菌率分别为71.4%和73.1%;8天后的杀菌率为99.1%和98.7%。伤口愈合率结果显示,9天后,阴性对照、阳性对照及本发明水凝胶的伤口面积愈合率分别为-1.9%、49.4%和65.9%。阴性对照、阳性对照及本申请水凝胶对应的平均伤口完全愈合所需时间分别为19.3天、14天和9.6天。
Claims (9)
1.一种活性氧消除抗菌消炎水凝胶皮肤敷料,其特征在于,由丙酮[双-(2-氨基-乙基)-二硫缩醇)及3,3’-二硫代双(丙酰肼)中的氨基与聚(聚乙二醇甲醚甲基丙烯酸酯-co-甲基丙烯酸缩水甘油酯)的环氧基团发生开环反应形成水凝胶网络,聚乙烯醇链段与所述的水凝胶网络形成半互穿网络的水凝胶,通过将水凝胶冻干后再于超支化聚赖氨酸溶液中重新溶胀,得到所述的活性氧消除抗菌消炎水凝胶皮肤敷料。
2.如权利要求1所述的一种活性氧消除抗菌消炎水凝胶皮肤敷料的制备方法,其特征在于,包括如下步骤:
1)在氮气保护下,将聚乙二醇甲醚甲基丙烯酸酯单体、甲基丙烯酸缩水甘油酯单体和偶氮二异丁腈溶于甲醇溶剂中,磁力搅拌,50-70摄氏度加热若干小时;反应结束后将反应液在冰乙醚中沉淀,离心收集产物,干燥后得到粗产物;将粗产物溶于甲醇中,再于冰乙醚中沉降除杂,重复若干次后收集产物,真空干燥得到聚(聚乙二醇甲醚甲基丙烯酸酯-co-甲基丙烯酸缩水甘油酯);
2)将聚(聚乙二醇甲醚甲基丙烯酸酯-co-甲基丙烯酸缩水甘油酯)、丙酮[双-(2-氨基-乙基)-二硫缩醇]及3,3’-二硫代双(丙酰肼)溶解于聚乙烯醇水溶液中,得到水凝胶预聚溶液;
3)将步骤2)制备的水凝胶预聚溶液注入模具中,密封后加热若干小时得到水凝胶;
4)将步骤3)制备的水凝胶放入0摄氏度以下冷冻若干小时,再取出放入0摄氏度以上解冻若干小时,重复若干次;
5)将步骤4)制得的水凝胶切成所需尺寸,冷冻干燥得到干燥水凝胶片;
6)将步骤5)制得的干燥水凝胶置于超支化聚赖氨酸溶液中达到溶胀平衡,得到活性氧消除的抗菌消炎水凝胶敷料。
3.根据权利要求2所述的活性氧消除抗菌消炎水凝胶皮肤敷料的制备方法,其特征在于,步骤1)所述聚乙二醇甲醚甲基丙烯酸酯单体和甲基丙烯酸缩水甘油酯单体投料摩尔比为1:1-3:1。
4.根据权利要求2所述的活性氧消除抗菌消炎水凝胶皮肤敷料的制备方法,其特征在于,步骤1)所述单体总摩尔浓度为0.45mol/L-0.75mol/L。
5.根据权利要求2所述的活性氧消除抗菌消炎水凝胶皮肤敷料的制备方法,其特征在于,步骤1)引发剂偶氮二异丁腈摩尔量占单体总摩尔量的1%-15%。
6.根据权利要求2所述的活性氧消除抗菌消炎水凝胶皮肤敷料的制备方法,其特征在于,步骤2)聚乙烯醇水溶液的浓度为0.5-1wt%。
7.根据权利要求2所述的活性氧消除抗菌消炎水凝胶皮肤敷料的制备方法,其特征在于,步骤2)的聚(聚乙二醇甲醚甲基丙烯酸酯-co-甲基丙烯酸缩水甘油酯)与聚乙烯醇水溶液的质量体积比为0.1-0.4g/ml;聚(聚乙二醇甲醚甲基丙烯酸酯-co-甲基丙烯酸缩水甘油酯)中环氧基团与丙酮[双-(2-氨基-乙基)-二硫缩醇]的摩尔比例为1:0.5-1:0.8;聚(聚乙二醇甲醚甲基丙烯酸酯-co-甲基丙烯酸缩水甘油酯)中环氧基团与3,3’-二硫代双(丙酰肼)的摩尔比例为1:0.4-1:0.7。
8.根据权利要求2所述的活性氧消除抗菌消炎水凝胶皮肤敷料的制备方法,其特征在于,步骤3)中加热温度为30-50摄氏度。
9.根据权利要求2所述的活性氧消除抗菌消炎水凝胶皮肤敷料的制备方法,其特征在于,步骤6)超支化聚赖氨酸浓度为0.5-5mg/ml。
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