CN114716700A - 一种动态结合天然多酚的可注射双交联水凝胶的制备方法 - Google Patents
一种动态结合天然多酚的可注射双交联水凝胶的制备方法 Download PDFInfo
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- CN114716700A CN114716700A CN202210356269.8A CN202210356269A CN114716700A CN 114716700 A CN114716700 A CN 114716700A CN 202210356269 A CN202210356269 A CN 202210356269A CN 114716700 A CN114716700 A CN 114716700A
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- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
本发明公开了一种动态结合天然多酚的可注射双交联水凝胶的制备方法，该水凝胶材料包括苯硼酸基团和乙烯基团修饰的改性透明质酸、乙烯基团修饰的改性明胶、光引发剂和天然多酚，制备方法包括：将改性透明质酸、改性明胶和光引发剂溶解于磷酸盐缓冲溶液中，与含有天然多酚的磷酸盐缓冲溶液混合均匀，得到单交联水凝胶，然后用紫外光照射，得到双交联水凝胶。该制备过程简单易操作，制备条件温和。该水凝胶可模拟天然的髓核组织，具有良好的力学性能、可注射性、粘附性、pH响应性、生物相容性、抗氧化和抗炎性能，为椎间盘组织工程材料提供了新的设计思路，在其它生物医学领域也具有良好的应用前景。
Description
技术领域
本发明涉及生物医用材料、组织工程和再生医学的技术领域，尤其是指一种用于退变椎间盘再生修复的动态结合天然多酚的可注射双交联水凝胶的制备方法。
背景技术
椎间盘由位于中央含水量极高的髓核、包绕在髓核周围呈分层排列的纤维环及上下软骨终板构成。椎间盘退变大多始于髓核，髓核是一种凝胶状的结构，它的保水性以及多样化的活性分子结合位点在组织稳态的维持中发挥着重要的作用。水凝胶是一种高含水量的交联网络结构，可以实现有效的物质扩散运输，从仿生学的角度出发，水凝胶是具有应用前景的椎间盘再生修复组织工程支架。
透明质酸是脊椎动物中普遍存在的一种多糖，在软骨和椎间盘等组织中被发现，因其具有优异的生物相容性和保水性能而被广泛应用。高分子量的透明质酸还参与多种细胞表面受体相互作用，具有良好的抗血管生成、抗炎和免疫抑制活性。明胶是胶原蛋白部分水解的产物，与透明质酸一样具有良好的生物相容性和生物降解性，且降解产物无毒性。由于含有RGD生物活性序列，明胶能够诱导细胞粘附和增殖。天然多酚具有优异的生物活性，例如抗氧化、抗炎、抗癌和抗菌等，具有巨大的治疗潜力，但较差的生物利用度限制了其临床应用。
与传统手术相比，微创治疗可以减少创伤、手术相关风险、患者疼痛和治疗费用，因此有必要对水凝胶进行可注射设计。可注射水凝胶具有修复不规则形状组织缺损的能力，克服了传统植入式水凝胶的局限性。但可注射水凝胶通常存在力学性能不足、组织粘附性差易脱落、前驱液易泄露到周围组织等问题。
发明内容
本发明的目的在于克服现有技术的缺点与不足，提出了一种用于退变椎间盘再生修复的动态结合天然多酚的可注射双交联水凝胶的制备方法，该水凝胶通过苯硼酸酯和光引发交联的方式制得，具有良好的力学性能、可注射性、粘附性、pH响应性、生物相容性、抗氧化和抗炎性能，具有广泛的应用前景。
为实现上述目的，本发明所提供的技术方案为：一种动态结合天然多酚的可注射双交联水凝胶的制备方法，首先，将透明质酸和明胶进行改性，得到苯硼酸基团和乙烯基团修饰的改性透明质酸(HAMA-PBA)和乙烯基团修饰的改性明胶(GelMA)；然后将HAMA-PBA、GelMA和光引发剂溶解于磷酸盐缓冲溶液中,与含有天然多酚的磷酸盐缓冲溶液混合均匀，形成第一重苯硼酸酯动态共价键交联网络，赋予水凝胶可注射性和粘附性，得到单交联水凝胶；而后用紫外光照射，形成第二重双键交联网络，增强水凝胶的力学性能和稳定性，得到双交联水凝胶。
进一步，所述的动态结合天然多酚的可注射双交联水凝胶的制备方法，包括以下步骤：
1)将透明质酸溶于去离子水中，在冰浴条件下加入甲基丙烯酸酐，之后通过不断加入氢氧化钠维持溶液pH至8，而后继续在冰浴条件下反应12～24小时，将反应产物在去离子水中透析后冻干，得到乙烯基团改性的透明质酸(HAMA)；
2)将步骤1)得到的HAMA溶于吗啉乙磺酸缓冲溶液中，利用羧基活化剂4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐(DMTMM)活化透明质酸分子链上的羧基，而后加入3-氨基苯硼酸反应12～48小时，将反应产物在去离子水中透析后冻干，得到苯硼酸基团和乙烯基团修饰的改性透明质酸(HAMA-PBA)；
3)将明胶溶于磷酸盐缓冲溶液中，加入甲基丙烯酸酐，50℃反应3～6小时，然后加入磷酸盐缓冲溶液稀释以终止反应，将反应产物在去离子水中透析后冻干，得到乙烯基团修饰的改性明胶(GelMA)；
4)将步骤2)得到的HAMA-PBA、步骤3)得到的GelMA和光引发剂溶解于磷酸盐缓冲溶液中，与含有天然多酚的磷酸盐缓冲溶液混合均匀，得到单交联水凝胶，然后用紫外光照射，得到动态结合天然多酚的可注射双交联水凝胶。
进一步，在步骤1)中，所述透明质酸和甲基丙烯酸酐的摩尔比为1：4～8；所述透析是指使用截留分子量为8000～14000的透析袋进行透析，透析时间为3～7天。
进一步，在步骤2)中，HAMA、DMTMM和3-氨基苯硼酸的摩尔比为1：1～2：0.2～0.8；所述透析是指使用截留分子量为8000～14000的透析袋进行透析，透析时间为3～7天。
进一步，在步骤3)中，所述明胶与甲基丙烯酸酐的用量比为10g：5～20mL；所述透析是指使用截留分子量为8000～14000的透析袋进行透析，透析时间为3～7天。
进一步，在步骤4)中，所述单交联水凝胶：HAMA-PBA的质量浓度为1～2％；GelMA的质量浓度为5～10％；所述光引发剂为Irgacure 2959或苯基(2,4,6-三甲基苯甲酰基)磷酸锂盐(LAP)，质量浓度为2～5‰；所述天然多酚为表没食子儿茶素没食子酸酯(EGCG)或迷迭香酸，质量浓度为0.5～5‰。
本发明与现有技术相比，具有如下优点与有益效果：
本发明使用的透明质酸是天然髓核细胞外基质的主要成分之一，具有出色的保水能力，高分子量的透明质酸还参与多种细胞表面受体相互作用，具有良好的抗血管生成、抗炎和免疫抑制活性。
本发明使用的明胶由于含有RGD生物活性序列，能够诱导细胞粘附和增殖，可以解决透明质酸水凝胶细胞粘附能力较弱的问题。
本发明使用的天然多酚既是生物活性药物又充当交联剂，赋予水凝胶抗氧化、抗炎、抗癌和抗菌等性能的同时还能增强水凝胶的力学性能。
本发明利用苯硼酸酯动态共价键赋予水凝胶剪切变稀的特性，拥有可注射性和组织粘附性的同时可避免前驱液注射后泄露造成骨赘等问题，可适应不规则形状缺损；苯硼酸酯动态共价键可以动态结合天然多酚，维持其生物活性，提高生物利用度；苯硼酸酯动态共价键具有pH响应性，针对退变椎间盘微酸性环境的特点，可以实现响应性释放天然多酚。
本发明利用光交联的方式，可以迅速提升水凝胶的力学性能和稳定性，弥补了可注射水凝胶存在的缺陷。
本发明的制备过程简单易操作，制备条件温和。
附图说明
图1为实施例1中所得到的单交联水凝胶和双交联水凝胶的光学照片。
图2为实施例1中所得到的双交联水凝胶的抗疲劳性验证图。
图3为实施例1中所得到的双交联水凝胶的粘附性验证图。
图4为实施例2中所得到的单交联水凝胶的可注射性验证图。
图5为实施例2中所得到的双交联水凝胶的可模塑性验证图。
图6为实施例3中所得到的双交联水凝胶的pH响应性验证图。
图7为实施例3中所得到的双交联水凝胶的抗氧化性验证图。
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)将1g分子量为100～150W的透明质酸溶于300mL去离子水中，充分搅拌溶解后，在冰浴条件下加入1.48mL甲基丙烯酸酐，之后通过不断加入1M氢氧化钠维持溶液pH至8，而后继续在冰浴条件下反应24小时。反应结束后将反应产物装在截留分子量为8000～14000的透析袋中用去离子水透析3天，每天换水3次，透析结束后冷冻干燥，得到白色海绵状固体产物HAMA。
2)将1g HAMA溶于300mL 0.1M吗啉乙磺酸缓冲溶液中，充分搅拌溶解后，加入1.46g DMTMM活化透明质酸分子链上的羧基，半小时后加入0.272g 3-氨基苯硼酸，反应48小时。反应结束后将反应产物装在截留分子量为8000～14000的透析袋中用去离子水透析3天，每天换水3次，透析结束后冷冻干燥，得到白色海绵状固体产物HAMA-PBA。
3)将10g明胶溶于100mL磷酸盐缓冲溶液中，在50℃恒温水浴下充分搅拌溶解后，以0.5mL/min的速率加入5mL甲基丙烯酸酐，50℃反应3小时，然后加入500mL磷酸盐缓冲溶液稀释以终止反应，将反应产物装在截留分子量为8000～14000的透析袋中用去离子水透析3天，每天换水3次，透析结束后弃去沉淀物，将透析液冷冻干燥，得到泡沫状固体产物GelMA。
4)将HAMA-PBA、GelMA和光引发剂LAP溶解于磷酸盐缓冲溶液中，与含有EGCG的磷酸盐缓冲溶液混合均匀，得到可注射单交联水凝胶，其中质量浓度：HAMA-PBA为2％；GelMA为5％；LAP为2‰；EGCG为5‰。
5)用紫外光照射单交联水凝胶30s，得到动态结合EGCG的双交联水凝胶。
参见图1所示的单交联水凝胶和双交联水凝胶的光学照片，图中展示与未添加天然多酚的对照组相比，添加天然多酚可以形成苯硼酸酯动态共价键单交联水凝胶，能够避免直接注射液体易泄露到周围组织等问题。然后用紫外光照射30s得到动态结合EGCG的双交联水凝胶。
参见图2所示的双交联水凝胶的抗疲劳性验证图，图中展示双交联水凝胶连续十个循环的磁滞回线几乎完全重叠，表明双交联水凝胶具有抵抗循环载荷的能力，模拟髓核组织长期承受的力学负荷。
参见图3所示的双交联水凝胶的粘附性验证图，图中展示双交联水凝胶粘附在手指上可以承受手指的来回弯曲而不会脱落，表明其具有出色的实用性。
实施例2
1)将1g分子量为100～150W的透明质酸溶于300mL去离子水中，充分搅拌溶解后，在冰浴条件下加入2.96mL甲基丙烯酸酐，之后通过不断加入1M氢氧化钠维持溶液pH至8，而后继续在冰浴条件下反应24小时。反应结束后将反应产物装在截留分子量为8000～14000的透析袋中用去离子水透析3天，每天换水3次，透析结束后冷冻干燥，得到白色海绵状固体产物HAMA。
2)将1g HAMA溶于300mL 0.1M吗啉乙磺酸缓冲溶液中，充分搅拌溶解后，加入0.73g DMTMM活化透明质酸分子链上的羧基，半小时后加入0.136g 3-氨基苯硼酸，反应24小时。反应结束后将反应产物装在截留分子量为8000～14000的透析袋中用去离子水透析3天，每天换水3次，透析结束后冷冻干燥，得到白色海绵状固体产物HAMA-PBA。
3)将10g明胶溶于100mL磷酸盐缓冲溶液中，在50℃恒温水浴下充分搅拌溶解后，以0.5mL/min的速率加入20mL甲基丙烯酸酐，50℃反应6小时，然后加入500mL磷酸盐缓冲溶液稀释以终止反应，将反应产物装在截留分子量为8000～14000的透析袋中用去离子水透析7天，每天换水3次，透析结束后弃去沉淀物，将透析液冷冻干燥，得到泡沫状固体产物GelMA。
4)将HAMA-PBA、GelMA和光引发剂LAP溶解于磷酸盐缓冲溶液中，与含有EGCG的磷酸盐缓冲溶液混合均匀，得到可注射单交联水凝胶，其中质量浓度：HAMA-PBA为1％；GelMA为10％；LAP为5‰；EGCG为0.5‰。
5)用紫外光照射单交联水凝胶30s，得到动态结合EGCG的双交联水凝胶。
参见图4所示的单交联水凝胶的可注射性验证图，图中展示单交联水凝胶可以通过23G针头进行注射，能够用于微创治疗。
参见图5所示的双交联水凝胶的可模塑性验证图，图中展示将单交联水凝胶注射到模具中用紫外光照射30s，脱模后得到自定义形状的水凝胶。表明其具有修复不规则形状组织缺损的能力，克服了传统植入式水凝胶的局限性。
实施例3
1)将1g分子量为100～150W的透明质酸溶于300mL去离子水中，充分搅拌溶解后，在冰浴条件下加入2.22mL甲基丙烯酸酐，之后通过不断加入1M氢氧化钠维持溶液pH至8，而后继续在冰浴条件下反应12小时。反应结束后将反应产物装在截留分子量为8000～14000的透析袋中用去离子水透析3天，每天换水3次，透析结束后冷冻干燥，得到白色海绵状固体产物HAMA。
2)将1g HAMA溶于300mL 0.1M吗啉乙磺酸缓冲溶液中，充分搅拌溶解后，加入1.095g DMTMM活化透明质酸分子链上的羧基，半小时后加入0.068g 3-氨基苯硼酸，反应24小时。反应结束后将反应产物装在截留分子量为8000～14000的透析袋中用去离子水透析3天，每天换水3次，透析结束后冷冻干燥，得到白色海绵状固体产物HAMA-PBA。
3)将10g明胶溶于100mL磷酸盐缓冲溶液中，在50℃恒温水浴下充分搅拌溶解后，以0.5mL/min的速率加入10mL甲基丙烯酸酐，50℃反应3小时，然后加入500mL磷酸盐缓冲溶液稀释以终止反应，将反应产物装在截留分子量为8000～14000的透析袋中用去离子水透析5天，每天换水3次，透析结束后弃去沉淀物，将透析液冷冻干燥，得到泡沫状固体产物GelMA。
4)将HAMA-PBA、GelMA和光引发剂Irgacure 2959溶解于磷酸盐缓冲溶液中，与含有迷迭香酸的磷酸盐缓冲溶液混合均匀，得到可注射单交联水凝胶，其中质量浓度：HAMA-PBA为2％；GelMA为5％；Irgacure 2959为5‰；迷迭香酸为2‰。
5)用紫外光照射单交联水凝胶60s，得到动态结合迷迭香酸的双交联水凝胶。
参见图6所示的双交联水凝胶的pH响应性验证图，图中展示双交联水凝胶在酸性pH下，天然多酚有更快的释放速率和更高的释放率，能够针对退变椎间盘酸性环境的特点实现pH响应性治疗。
参见图7所示的双交联水凝胶的抗氧化性验证图，图中展示双交联水凝胶与未添加天然多酚的对照组相比，添加天然多酚可以显著提升水凝胶对PTIO自由基的清除能力，具有良好的应用前景。
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它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利要求的保护范围之内。
Claims (6)
1.一种动态结合天然多酚的可注射双交联水凝胶的制备方法，其特征在于：首先，将透明质酸和明胶进行改性，得到苯硼酸基团和乙烯基团修饰的改性透明质酸HAMA-PBA和乙烯基团修饰的改性明胶GelMA；然后将HAMA-PBA、GelMA和光引发剂溶解于磷酸盐缓冲溶液中,与含有天然多酚的磷酸盐缓冲溶液混合均匀，形成第一重苯硼酸酯动态共价键交联网络，赋予水凝胶可注射性和粘附性，得到单交联水凝胶；而后用紫外光照射，形成第二重双键交联网络，增强水凝胶的力学性能和稳定性，得到双交联水凝胶。
2.根据权利要求1所述的一种动态结合天然多酚的可注射双交联水凝胶的制备方法，其特征在于，包括以下步骤：
1)将透明质酸溶于去离子水中，在冰浴条件下加入甲基丙烯酸酐，之后通过不断加入氢氧化钠维持溶液pH至8，而后继续在冰浴条件下反应12～24小时，将反应产物在去离子水中透析后冻干，得到乙烯基团改性的透明质酸HAMA；
2)将步骤1)得到的HAMA溶于吗啉乙磺酸缓冲溶液中，利用羧基活化剂4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM活化透明质酸分子链上的羧基，而后加入3-氨基苯硼酸反应12～48小时，将反应产物在去离子水中透析后冻干，得到苯硼酸基团和乙烯基团修饰的改性透明质酸HAMA-PBA；
3)将明胶溶于磷酸盐缓冲溶液中，加入甲基丙烯酸酐，50℃反应3～6小时，然后加入磷酸盐缓冲溶液稀释以终止反应，将反应产物在去离子水中透析后冻干，得到乙烯基团修饰的改性明胶GelMA；
4)将步骤2)得到的HAMA-PBA、步骤3)得到的GelMA和光引发剂溶解于磷酸盐缓冲溶液中，与含有天然多酚的磷酸盐缓冲溶液混合均匀，得到单交联水凝胶，然后用紫外光照射，得到动态结合天然多酚的可注射双交联水凝胶。
3.根据权利要求2所述的一种动态结合天然多酚的可注射双交联水凝胶的制备方法，其特征在于，在步骤1)中，所述透明质酸和甲基丙烯酸酐的摩尔比为1：4～8；所述透析是指使用截留分子量为8000～14000的透析袋进行透析，透析时间为3～7天。
4.根据权利要求2所述的一种动态结合天然多酚的可注射双交联水凝胶的制备方法，其特征在于，在步骤2)中，HAMA、DMTMM和3-氨基苯硼酸的摩尔比为1：1～2：0.2～0.8；所述透析是指使用截留分子量为8000～14000的透析袋进行透析，透析时间为3～7天。
5.根据权利要求2所述的一种动态结合天然多酚的可注射双交联水凝胶的制备方法，其特征在于，在步骤3)中，所述明胶与甲基丙烯酸酐的用量比为10g：5～20mL；所述透析是指使用截留分子量为8000～14000的透析袋进行透析，透析时间为3～7天。
6.根据权利要求2所述的一种动态结合天然多酚的可注射双交联水凝胶的制备方法，其特征在于，在步骤4)中，所述单交联水凝胶：HAMA-PBA的质量浓度为1～2％；GelMA的质量浓度为5～10％；所述光引发剂为Irgacure 2959或苯基(2,4,6-三甲基苯甲酰基)磷酸锂盐LAP，质量浓度为2～5‰；所述天然多酚为表没食子儿茶素没食子酸酯EGCG或迷迭香酸，质量浓度为0.5～5‰。
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