CN115068684A - 用于糖尿病慢性创面修复的载姜黄素水凝胶及其制备方法 - Google Patents
用于糖尿病慢性创面修复的载姜黄素水凝胶及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种用于糖尿病慢性创面修复的载姜黄素水凝胶及其制备方法，该水凝胶体系采用一种简单的方式有效的提高姜黄素溶解度，在伤口处该水凝胶能缓慢释放姜黄素起到修复创面的效果。负载姜黄素水凝胶的制备方法包括步骤：1)苯硼酸改性明胶的制备；2)氧化透明质酸的制备；3)苯硼酸改性的明胶增溶姜黄素；4)负载姜黄素的动态水凝胶的制备。该水凝胶具有较好的自愈合性能且易于组织粘附，具有优异的生物相容性，能缓慢释放姜黄素进而减弱创面处的炎症反应，从而达到慢性创面修复的效果。
Description
技术领域
本发明涉及生物医用材料、组织工程的技术领域，尤其是指一种用于糖尿病慢性创面修复的载姜黄素水凝胶及其制备方法。
背景技术
皮肤是人体最大的器官，其中含有复杂的网络结构。皮肤维持着人体的正常生理环境，同时也是使人体免受外来物入侵的一道重要的屏障。正常机体的皮肤受到小范围的损伤后会自发的按止血期、炎症期、增殖期及组织重塑期这四个阶段有序的展开修复，妥善处理的创面愈合周期较短,并无其他并发症产生。慢性疾病如糖尿病、压疮等由于患者组织受损导致局部供血不足，创面处炎症反应严重，愈合过程紊乱，使得皮肤愈合周期延长或不愈合，最终危及患者生命。
目前临床上治疗慢性创面常见的方式是真空辅助闭合式负压引流及湿性敷料，其中多功能水凝胶敷料等湿性敷料是最为经济简便的治疗慢性创面的方式。采用天然高分子构建水凝胶体系保证了材料优良的生物相容性，通过对天然高分子进行特殊基团修饰将会赋予水凝胶体系相应的功能。多功能水凝胶体系通过直接或间接的调控各类细胞的信号通路、上调生长因子表达水平等来调控伤口愈合四个阶段的进程，从而促进伤口的正常愈合。对于慢性创面而言，伤口难以闭合导致创面处细菌滋生，累计过多的活性氧(ROS)将进一步对细胞造成损伤，触发更严重的炎症反应，故对慢性创面修复而言，水凝胶体系的设计需要从抗菌、抗炎及清除过多的ROS出发，促进创面愈合过程的正常进行。
姜黄素(Cur)是一种具有优异抗炎、抗氧化特性的天然化合物，已被广泛应用于治疗各种皮肤疾病，但是其存在水溶性不好、稳定性较差等缺点。为了提高Cur的药用稳定性，研究人员探究了大量的体系，其中水凝胶被认为是良好的载体。较多研究采用胶束或纳米粒子负载Cur，从而提高其水溶性及稳定性，但存在制备过程繁琐，费用较高等问题。
发明内容
本发明的目的在于克服现有技术的缺点与不足，提出了一种用于糖尿病慢性创面修复的载姜黄素水凝胶及其制备方法，采用苯硼酸修饰的明胶和氧化透明质酸作为主体材料，利用席夫碱和苯硼酸酯键作用结合两者形成动态响应水凝胶；苯硼酸和姜黄素上二酮反应形成的苯硼酸酯键，使姜黄素与苯硼酸改性的明胶结合，达到增溶姜黄素的目的；在慢性创面，特别是糖尿病慢性创面的高血糖、酸性环境中，姜黄素能在该动态水凝胶中释放，实现对慢性创面的有效治疗。
为实现上述目的，本发明所提供的技术方案为：一种用于糖尿病慢性创面修复的载姜黄素水凝胶的制备方法，包括以下步骤：
苯硼酸改性明胶的制备：明胶充分加热溶解于2-马啉乙磺酸(MES)缓冲水溶液中，冷却至室温后加入EDC/NHS，随后加入3-氨基苯硼酸，室温搅拌反应，得到反应液A，将反应液A置于透析袋中透析后冻干得到絮状材料，即为苯硼酸改性明胶；
氧化透明质酸的制备：将分子量为100-150W的透明质酸搅拌过夜溶解后加入高碘酸钠，避光搅拌反应，最后加入乙二醇搅拌反应，得到反应液B，将反应液B置于透析袋中透析后冻干得到絮状材料，即为氧化透明质酸；
苯硼酸改性明胶增溶姜黄素：将姜黄素溶于乙醇溶液中备用，将苯硼酸改性明胶溶于1xPBS中备用，将姜黄素的乙醇溶液滴加到溶有改性明胶的PBS溶液中，得到溶液C；其中，苯硼酸改性明胶聚合物材料上的苯硼酸基团能和姜黄素的邻二酮结构络合形成苯硼酸酯动态键，进而起到增溶姜黄素的目的；
负载姜黄素的动态水凝胶的制备：将氧化透明质酸加入1xPBS中充分溶解，然后和溶液C混合搅拌直至形成水凝胶。
进一步，在苯硼酸改性明胶的制备中，明胶和3-氨基苯硼酸的质量比为5：2，EDC的浓度为9.6mg/ml，NHS的浓度为2.3mg/ml。
进一步，在氧化透明质酸的制备中，透明质酸和高碘酸钠加入量均为6mg/ml。
进一步，在氧化透明质酸的制备中，加入的乙二醇和高碘酸钠的质量比为1：1。
进一步，在苯硼酸改性明胶增溶姜黄素中，溶液C中姜黄素的浓度为0.2～1mg/ml。
进一步，在负载姜黄素的动态水凝胶的制备中，苯硼酸改性明胶和氧化透明质酸的质量比为2：1。
本发明也提供了一种由上述方法制备得到的用于糖尿病慢性创面修复的载姜黄素水凝胶。
本发明与现有技术相比，具有如下优点与有益效果：
本发明采用苯硼酸修饰的明胶和氧化透明质酸作为水凝胶的主体材料，两者的主体原料明胶和透明质酸都是细胞外基质的主要成分，生物相容性优良，两者通过席夫碱和苯硼酸酯动态共价键成胶，具有优良的环境响应性，水凝胶在慢性创面的酸性环境中能缓慢断键，是良好的载药体系。同时动态水凝胶能更好的适应慢性创面的复杂伤口形状，对复杂创面进行充分的填充治疗。姜黄素作为一种天然生物活性多酚，具有清除自由基、抗氧化、抗炎、免疫调节等多方面作用，其在各种类型皮肤伤口上都有应用。近年来许多研究表明姜黄素可以通过调控多种细胞信号通路发挥治疗糖尿病创面的作用，但是姜黄素存在稳定性低，水溶性极低等缺点，阻碍了其在皮肤组织工程中的进一步应用。大部分水凝胶体系通过胶束或纳米粒子去包载姜黄素进而提高其在水溶液中的溶解度，但是这样的操作无疑使材料体系复杂化，而本发明采用单一的苯硼酸修饰的明胶负载姜黄素，简单易操作。负载姜黄素的动态水凝胶在慢性创面处缓慢释放姜黄素起到对慢性创面持续有效的修复作用。
附图说明
图1为本发明水凝胶的成型示意图。
图2为实施例1、实施例2、实施例3和实施例4中负载不同浓度姜黄素的水凝胶的压缩模量图。
图3为实施例1、实施例2、实施例3和实施例4中负载不同浓度姜黄素的水凝胶的猪皮剪切拉升模量图。
图4为实施例1、实施例2、实施例3和实施例4中负载不同浓度姜黄素的水凝胶的细胞相容性评价图。
具体实施方式
下面结合附图和实施例对本发明做进一步详细的描述，但本发明的实施方式不限于此。若未特别指明，实施例中所用的技术手段为本领域技术人员所熟知的常规手段。
实施例1
1)明胶以10mg/mL的浓度加热搅拌溶解于PH＝5.5的MES缓冲液中，待其充分溶解后冷却至室温，随后加入4.8g EDC和1.15g NHS，充分搅拌溶解后加入2g 3-氨基苯硼酸，继续搅拌反应48h，得到反应液A1，将反应液A1置于8K-14K透析袋中在去离子水环境中透析，冻干得到聚合物材料，即为苯硼酸改性明胶。
2)3g透明质酸钠在500ml的去离子水中充分搅拌，待其完全溶解后加入3g高碘酸钠继续避光搅拌8h，最后加入3ml乙二醇搅拌1h终止反应，得到反应液B1，将反应液B1置于3k透析袋中在去离子环境中透析，冻干得到聚合物材料，即为氧化透明质酸。
3)将苯硼酸改性明胶溶于500ul的1xPBS中，得到溶液C1，保证最终质量分数为30％。
4)氧化透明质酸以15％的质量分数溶于500ul的1xPBS中，将其和步骤3)中的溶液C1混和搅拌，直至有成胶现象发生，即得到动态水凝胶(GOHA)，其成胶示意图如图1所示。
实施例2
1)明胶以10mg/mL的浓度加热搅拌溶解于PH＝5.5的MES缓冲液中，待其充分溶解后冷却至室温，随后加入4.8g EDC和1.15g NHS，充分搅拌溶解后加入2g 3-氨基苯硼酸，继续搅拌反应48h，得到反应液A2，将反应液A2置于8K-14K透析袋中在去离子水环境中透析，冻干得到聚合物材料，即为苯硼酸改性明胶。
2)3g透明质酸钠在500ml的去离子水中充分搅拌，待其完全溶解后加入3g高碘酸钠继续避光搅拌8h,最后加入3ml乙二醇搅拌1h终止反应，得到反应液B2，将反应液B2置于3k透析袋中在去离子环境中透析，冻干得到聚合物材料，即为氧化透明质酸。
3)制备4mg/ml的姜黄素乙醇溶液备用。将苯硼酸改性明胶溶于500ul的1xPBS中，保证最终质量分数为30％，并加入25ul前述姜黄素的乙醇溶液(混合液中姜黄素浓度为0.2mg/ml)，得到溶液C2，搅拌均匀待用。
4)氧化透明质酸以15％的质量分数溶于500ul的1xPBS中，将其和步骤3)中的溶液C2混和搅拌，直至有成胶现象发生，即得到负载0.1mg姜黄素的水凝胶(GOHA-Cur0.1)。姜黄素含量不同的水凝胶的压缩模量如图2所示。所有组别的水凝胶质地均较为软糯，压缩模量均较低，能很好的贴合创面。
实施例3
1)明胶以10mg/mL的浓度加热搅拌溶解于PH＝5.5的MES缓冲液中，待其充分溶解后冷却至室温，随后加入4.8g EDC和1.15g NHS，充分搅拌溶解后加入2g 3-氨基苯硼酸，继续搅拌反应48h，得到反应液A3，将反应液A3置于8K-14K透析袋中在去离子水环境中透析，冻干得到聚合物材料，即为苯硼酸改性明胶。
2)3g透明质酸钠在500ml的去离子水中充分搅拌，待其完全溶解后加入3g高碘酸钠继续避光搅拌8h,最后加入3ml乙二醇搅拌1h终止反应，得到反应液B3，将反应液B3置于3k透析袋中在去离子环境中透析，冻干得到聚合物材料，即为氧化透明质酸。
3)制备4mg/ml的姜黄素乙醇溶液备用。将苯硼酸改性的明胶溶于500ul的1xPBS中，保证最终质量分数为30％，并加入75ul前述姜黄素的乙醇溶液(混合液中姜黄素浓度为0.6mg/ml)，得到溶液C3，搅拌均匀待用。
4)氧化透明质酸以15％的质量分数溶于500ul的1xPBS中，将其和步骤3)中的溶液C3混和搅拌，直至有成胶现象发生，即得到负载0.3mg姜黄素的水凝胶(GOHA-Cur0.3)。姜黄素含量不同的水凝胶对猪皮的剪切拉升模量如图3所示，负载姜黄素的水凝胶对组织具有良好的粘附性，有利于长久覆盖住创面进而持续给药，起到杀菌消炎的效果。
实施例4
1)明胶以10mg/mL的浓度加热搅拌溶解于PH＝5.5的MES缓冲液中，待其充分溶解后冷却至室温，随后加入4.8g EDC和1.15g NHS，充分搅拌溶解后加入2g 3-氨基苯硼酸，继续搅拌反应48h，得到反应液A4，将反应液A4置于8K-14K透析袋中在去离子水环境中透析，冻干得到聚合物材料，即为苯硼酸改性明胶。
2)3g透明质酸钠在500ml的去离子水中充分搅拌，待其完全溶解后加入3g高碘酸钠继续避光搅拌8h,最后加入3ml乙二醇搅拌1h终止反应，得到反应液B4，将反应液B4置于3k透析袋中在去离子环境中透析，冻干得到聚合物材料，即为氧化透明质酸。
3)制备4mg/ml的姜黄素乙醇溶液备用。将苯硼酸改性的明胶溶于500ul的1xPBS中，保证最终质量分数为30％，并加入125ul前述姜黄素的乙醇溶液(混合液中姜黄素浓度为1mg/ml)，得到溶液C4，搅拌均匀待用。
4)氧化透明质酸以15％的质量分数溶于500ul的1xPBS中，将其和步骤3)中的溶液C4混和搅拌，直至有成胶现象发生，即得到负载0.5mg姜黄素的水凝胶(GOHA-Cur0.5)。姜黄素含量不同的水凝胶均具有优异的生物相容性。如图4所示，成纤维细胞NIH-3T3和不同姜黄素含量的水凝胶共培养1、2、3天后任然表现出较好的增殖趋势，表明所有组别的水凝胶都具有良好的生物安全性。
本发明的实施例仅仅是为清楚地说明本发明所举的例子，而并非是对本发明的实施方式的限定。对于所属领域的专业人员而言，在上述实施例的基础上还可以做出其他不同形式的变化或变动，这里无需也无法对所有的实施方式予以穷举。凡在本发明的精神和原则之内所做的任何修改，等同替换和改进等，均应包含在本发明权力要求的保护范围之内。
Claims (7)
1.用于糖尿病慢性创面修复的载姜黄素水凝胶的制备方法，其特征在于，包括以下步骤：
苯硼酸改性明胶的制备：明胶充分加热溶解于2-马啉乙磺酸(MES)缓冲水溶液中，冷却至室温后加入EDC/NHS，随后加入3-氨基苯硼酸，室温搅拌反应，得到反应液A，将反应液A置于透析袋中透析后冻干得到絮状材料，即为苯硼酸改性明胶；
氧化透明质酸的制备：将分子量为100-150W的透明质酸搅拌过夜溶解后加入高碘酸钠，避光搅拌反应，最后加入乙二醇搅拌反应，得到反应液B，将反应液B置于透析袋中透析后冻干得到絮状材料，即为氧化透明质酸；
苯硼酸改性明胶增溶姜黄素：将姜黄素溶于乙醇溶液中备用，将苯硼酸改性明胶溶于1xPBS中备用，将姜黄素的乙醇溶液滴加到溶有改性明胶的PBS溶液中，得到溶液C；其中，苯硼酸改性明胶聚合物材料上的苯硼酸基团能和姜黄素的邻二酮结构络合形成苯硼酸酯动态键，进而起到增溶姜黄素的目的；
负载姜黄素的动态水凝胶的制备：将氧化透明质酸加入1xPBS中充分溶解，然后和溶液C混合搅拌直至形成水凝胶。
2.根据权利要求1所述的用于糖尿病慢性创面修复的载姜黄素水凝胶的制备方法，其特征在于，在苯硼酸改性明胶的制备中，明胶和3-氨基苯硼酸的质量比为5：2，EDC的浓度为9.6mg/ml，NHS的浓度为2.3mg/ml。
3.根据权利要求1所述的用于糖尿病慢性创面修复的载姜黄素水凝胶的制备方法，其特征在于，在氧化透明质酸的制备中，透明质酸和高碘酸钠加入量均为6mg/ml。
4.根据权利要求1所述的用于糖尿病慢性创面修复的载姜黄素水凝胶的制备方法，其特征在于，在氧化透明质酸的制备中，加入的乙二醇和高碘酸钠的质量比为1：1。
5.根据权利要求1所述的用于糖尿病慢性创面修复的载姜黄素水凝胶的制备方法，其特征在于，在苯硼酸改性明胶增溶姜黄素中，溶液C中姜黄素的浓度为0.2～1mg/ml。
6.根据权利要求1所述的用于糖尿病慢性创面修复的载姜黄素水凝胶的制备方法，其特征在于，在负载姜黄素的动态水凝胶的制备中，苯硼酸改性明胶和氧化透明质酸的质量比为2：1。
7.由权利要求1-6任一项所述的制备方法制得的用于糖尿病慢性创面修复的载姜黄素水凝胶。
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| CN116139331A (zh) * | 2023-01-10 | 2023-05-23 | 华南理工大学 | 负载生物活性玻璃的多功能创面修复敷料及其制备方法 |
| CN116392630A (zh) * | 2023-05-04 | 2023-07-07 | 中山大学附属第一医院 | 一种用于糖尿病创面修复的可注射水凝胶及其制备方法 |
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