CN115353647B - 一种自修复海洋源胶原蛋白肽基复合水凝胶及其制备方法 - Google Patents
一种自修复海洋源胶原蛋白肽基复合水凝胶及其制备方法 Download PDFInfo
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- CN115353647B CN115353647B CN202211082911.4A CN202211082911A CN115353647B CN 115353647 B CN115353647 B CN 115353647B CN 202211082911 A CN202211082911 A CN 202211082911A CN 115353647 B CN115353647 B CN 115353647B
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Abstract
本发明涉及功能性天然高分子水凝胶技术领域，特别涉及一种具有自修复功能的海洋源胶原蛋白肽基复合水凝胶及其制备方法。通过化学交联(酰腙键、硼酸酯键、席夫碱、醚键)和物理交联(氢键)的协同作用，形成具有快速自修复功能的互穿网络结构。该复合水凝胶不仅自修复速度快，具有良好的拉伸性和粘附性，而且水凝胶中的小分子活性肽还具有抗菌、促进毛发生长和伤口愈合的功能。除了作为伤口敷料，本发明提供的自修复海洋源胶原蛋白肽基复合水凝胶在人工皮肤、可穿戴器件以及组织工程支架等领域具有潜在的应用。
Description
技术领域
本发明涉及功能性天然高分子水凝胶技术领域，特别涉及一种具有自修复功能的海洋源胶原蛋白肽基复合水凝胶及其制备方法，可作为医用敷料促进伤口创面愈合。
背景技术
慢性伤口导致的溃疡会导致皮肤表皮和真皮全层损伤，使其失去自我修复能力，不但给患者带来巨大痛苦，严重影响患者的工作、生活质量，甚至可能导致患者死亡。传统的干性敷料治疗，如脱脂棉和脱脂纱布，不仅治疗效果有限，频繁换药也会加重患者的痛苦。而湿润的伤口愈合环境有利于肉芽组织的生长并促进皮肤细胞的分裂，从而促进伤口的完全愈合，不仅突破了人们对伤口愈合的认识，更促进了湿性伤口敷料的发展。水凝胶作为一种典型的湿性伤口敷料可以紧密贴合伤口(Advanced Functional Materials,2014,24(25):3933-3943)，减少细菌生长的机率，被认为是一种理想的湿性伤口敷料。
为了提高水凝胶的生物安全性，市面上大多选择壳聚糖、透明质酸、明胶等天然高分子作为水凝胶基体。相关研究表明，胶原蛋白是一种存在于皮肤和软骨中的常见天然纤维蛋白，其基本结构是由三条多肽链互相缠绕形成的螺旋状纤维，是细胞外基质的主要结构。而胶原蛋白肽作为胶原蛋白的水解产物，其小分子肽具有独特的生物活性、良好的生物相容性、高亲水性和低免疫原性等特点，可以促进细胞粘附和增殖，加速伤口愈合(Regenerative biomaterials,2017,4(5):309-314)，胶原蛋白肽不仅利于自然的创面愈合，对于临床上的溃疡病变导致的慢性伤口创面也可起到较好的局部治疗作用。此外，相较于陆生动物(牛、猪、家禽等)来源的胶原蛋白肽，海洋来源的胶原蛋白肽具有重金属和毒素等污染物含量低、没有动物性疾病和病菌的风险以及不受宗教约束等优点，而且从海产品副产物中提取胶原蛋白肽也符合我国开发蓝色海洋经济和绿色可持续发展理念。然而，目前常见的天然高分子水凝胶通常不具有胶原组分或类胶原组分，在一定程度上限制了胶原基自修复水凝胶在生物医学治疗领域的应用。
此外，目前大多数天然高分子水凝胶的三维网络是单向不可逆的定型网络，机械强度低，在使用过程中非常容易破损，对其使用寿命和功能带来很大影响。而自修复水凝胶是一种可以在受到损伤后自动恢复其完整性和自身功能的一类新型智能水凝胶，通过愈合机制自动响应损伤，具有自主修复损伤、保持结构和性能完整性、长期使用功能稳定等独特优点而备受关注(MRS bulletin,2008,33(8):759-765)。该类水凝胶可以匹配不规则的缺陷形状并保持材料的连续性和完整性，可以较好用于具有较大不规则创面的复杂或慢性伤口、溃疡等长期护理康复。同时，作为医用伤口敷料，对水凝胶的抗菌性、粘附性等要求也较为严格，因此，开发以胶原蛋白肽为主要成分的快速自修复、抗菌水凝胶作为伤口敷料，具有极大的生物医学应用价值。
发明内容
为了克服上述现有技术的不足，本发明的主要目的是提供一种具有自修复功能的海洋源胶原蛋白肽基复合水凝胶及其制备方法，通过化学交联(酰腙键、硼酸酯键、席夫碱、醚键) 和物理交联(氢键)的协同作用，形成具有快速自修复功能的互穿网络结构。该复合水凝胶不仅自修复速度快，具有良好的拉伸性和粘附性，而且水凝胶中的小分子活性肽还具有抗菌、促进毛发生长和伤口愈合的功能。除了作为伤口敷料，本发明提供的自修复海洋源胶原蛋白肽基复合水凝胶在人工皮肤、可穿戴器件以及组织工程支架等领域具有潜在的应用。
本发明采用的技术方案是：
一种自修复海洋源胶原蛋白肽基复合水凝胶的制备方法，包括如下步骤：
(1)配制胶原蛋白肽水溶液，加入二酰肼、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐 (EDC)和催化剂，控制反应温度和pH，搅拌反应一段时间后，在去离子水中透析反应液并冷冻干燥，得到酰肼改性的胶原蛋白肽A，通式如下：
其中R为(CH2)n，n＝1-11；
(2)配制不同质量浓度的葡聚糖溶液，加入一定量的氧化剂，在一定温度、避光的条件下搅拌反应。反应一段时间后，加入乙二醇搅拌终止反应，冷冻干燥，即得到氧化葡聚糖产物B：
(3)配置不同质量分数的聚乙烯醇(PVA)水溶液，不同摩尔浓度的硼砂溶液；
(4)将PVA水溶液与A水溶液混合得到混合液C，硼砂溶液滴加在B水溶液中得到混合液D，再添加小分子量的胶原蛋白肽，在室温下搅拌，通过化学、物理交联可以在数秒内迅速成胶，改变C、D混合液的比例，即可得到具有自修复功能的胶原蛋白肽基复合水凝胶，成胶机理如下：
其中代表氧化葡聚糖；R为(CH2)n，n＝1-11。
步骤(1)中的胶原蛋白肽是从海洋鱼类中提取得到的。通常地，本领域技术人员可以通过酸碱、酶切等技术，从鱼类的鱼鳍、鱼头、鱼皮、鱼鳞和内脏中，提取制得分子量在0.3-6 kDa范围内的胶原蛋白肽。
步骤(1)中胶原蛋白肽的浓度范围1-200mg/ml，优选为10-50mg/ml。
步骤(1)中的二酰肼选自含有3-13个碳原子的烷基二酸二酰肼中的至少一种。
步骤(1)中的催化剂选自对二甲氨基吡啶(DMAP)、1-羟基苯并三氮唑(HOBT)、1-羟基-7-氮杂苯并三氮唑(HOAT)、4-吡咯烷基吡啶(4-PPY)、N-羟基琥珀酰亚胺(NHS)等，也可以是它们的混合物。
步骤(1)中的胶原蛋白肽与二酰肼质量比范围1:0.5-1:10，优选为1:2-1:5；反应时间1-24 h，优选为4-10h；反应温度10-45℃，优选为25-35℃；溶液pH范围为3-6。
步骤(2)中的葡聚糖分子量范围在Mw 1.5kDa-500kDa，优选为Mw 10-100kDa；葡聚糖溶液的质量浓度范围0.5-10％，优选为1-5％；氧化剂可选用高碘酸钠、高碘酸钾、氯化铁、过氧化氢中的至少一种或是它们的混合物，葡聚糖与氧化剂的摩尔比为1:1-1:300，优选为1:5-1:150；反应温度为10-50℃，优选为20-40℃；反应时间2-24h，优选为5-12h。
步骤(2)中所制备的氧化葡聚糖是将葡聚糖选择性氧化所得，其氧化度为30-100％。
步骤(3)中的PVA为商品化产品，粘度范围3-50mPa.s，PVA水溶液质量浓度为1-10％；硼砂的摩尔浓度为0.05-2mM。
步骤(4)中的添加的小分子胶原蛋白肽分子量范围Mw 0.3-1kDa，添加量为1-10mg/ml， C与D混合液的体积比为0.5:1-3:1。
通过以上步骤最终得到可以在数秒内迅速成胶，抗拉强度最高达到47kPa，粘附强度最高达到23kPa的胶原蛋白肽基复合水凝胶，该水凝胶具有较高的含水率(60-95％)和保水率 (65-95％)，受到外界破坏后最快可以在1s内迅速修复，且具有良好的细胞生物相容性和抗菌性能，对革兰氏阴性菌大肠杆菌(E.coli DH5α)的抗菌效果尤为显著，能够很好地促进伤口创面愈合。
本发明的有益之处在于：
本发明选择氧化葡聚糖作为柔性大分子交联剂，相对大多数化学交联剂，其生物相容性良好且来源丰富。采用了动态可逆酰腙键、席夫碱、硼酸酯键和醚键以及氢键相互作用的化学、物理交联方式来实现自修复性能，最快可在1s内快速达到自愈合效果，也能进一步限制胶原蛋白肽分子的自由运动以削弱其自组装形成不可逆的胶原纤维，同时，三维网络结构也提供了良好的机械强度和粘附性。该水凝胶涂覆在伤口上之后，可以修复伤口隙缝而最终形成连续的完整凝胶层，对创面起到一定的保护，较高的含水率和保水率有利于维持润湿的微环境，促进伤口愈合。与已有的水凝胶伤口敷料相比，该胶原蛋白肽基复合水凝胶在机械强度、粘附性、可注射性以及细胞生物相容性方面优势明显，小分子肽的加入赋予其良好的免疫原性和抗菌性，同时具有特定生物活性的胶原分子对于伤口创面的愈合表现出促再生功能，在组织工程、生物医学等领域具有广阔的应用前景。
附图说明
图1实施例1中胶原蛋白肽基复合水凝胶的自愈合照片；
图2对比例和实施例1、2、3中胶原蛋白肽基复合水凝胶的抗菌性照片
图中：A图为对比例制备的水凝胶；
B、C、D图分别为实施例1、2、3中制备的水凝胶；
图3实施例1中胶原蛋白肽基复合水凝胶的细胞毒性实验柱状图；
图4大鼠烫伤后三周内的伤口愈合图片
图中A为实施例1中制备的胶原蛋白肽基复合水凝胶；
B为3M公司生产的水胶体敷料TegadermTM 90022T；
C为空白对照(医用纱布)。
具体实施方法
本发明的具体实施方法如下：
实施例1：
1)称取1.106g分子量为3kDa胶原蛋白肽溶于35mL去离子水中，加入催化剂DMAP(0.244 g)，再加入EDC(0.767g)活化羧基，最后加入己二酸二酰肼(ADH)(1.392g)，调节溶液 pH为4.5，搅拌反应12h。透析后冷冻干燥可得白色酰肼化胶原蛋白肽粉末A。
2)称取1g分子量为4万的葡聚糖溶于30mL去离子水中，称取2.14g高碘酸钠加入葡聚糖溶液中搅拌均匀。在室温下避光反应24h后，滴加等摩尔量乙二醇终止反应。利用截留分子量MwCO为500的透析袋进行透析，冷冻干燥可得白色氧化葡聚糖粉末B。
3)将0.1ml质量分数8％的PVA溶液加入0.5ml浓度为100mg/ml的A水溶液中得到混合液C，0.05ml浓度为0.053mM的硼砂滴加在0.5ml浓度为250mg/ml的B水溶液中得到混合液D，添加小分子量0.6kDa的胶原蛋白肽使其浓度为3mg/ml，0.6ml C混合液和0.55ml D 混合液在室温下搅拌可以在1s内得到自修复胶原蛋白肽基抗菌复合水凝胶。该水凝胶抗拉强度为47kPa，粘附强度为23kPa，含水率87.6％，保水率90.4％，在受到外界破坏后在可以3 s内迅速自修复(附图1所示)。其抗菌性能较好，对大肠杆菌有明显的抑菌效果(附图2B 所示)；细胞毒性试验表明复合水凝胶具有良好的细胞生物相容性，可以促进小鼠成纤维细胞增殖(附图3所示)；考查了其作为伤口敷料对大鼠伤口愈合的治疗效果，结果表明复合水凝胶在治疗后期效果优于商业敷料，对伤口创面愈合有明显的促进作用(附图4A所示)。
实施例2：
1)称取0.667g分子量为2kDa胶原蛋白肽溶于35mL去离子水中，加入催化剂DMAP(0.366g)，再加入EDC(0.767g)活化羧基，最后加入ADH(0.696g)，调节溶液pH为4.5，搅拌反应12h。透析后冷冻干燥可得白色酰肼化胶原蛋白肽粉末A。
2)称取1g分子量为2万葡聚糖溶于30mL去离子水中，称取2.14g高碘酸钠加入葡聚糖溶液中搅拌均匀。在室温下避光反应24h后，滴加等摩尔量乙二醇终止反应。利用截留分子量 MwCO为500的透析袋进行透析，冷冻干燥可得白色氧化葡聚糖粉末B。
3)将0.2ml质量分数8％的PVA溶液加入0.5ml浓度为100mg/ml的A水溶液中得到混合液C，0.2ml浓度为0.053mM的硼砂滴加在0.5ml浓度为250mg/ml的B水溶液中得到混合液D，添加小分子量0.6kDa的胶原蛋白肽使其浓度为2mg/ml，0.7ml C混合液和0.7ml D混合液在室温下搅拌可以在1s内得到自修复胶原蛋白肽基抗菌复合水凝胶。该水凝胶抗拉强度32kPa，粘附强度19kPa，含水率和保水率分别为83.4％和68.6％，在受到外界破坏后在可以10s内迅速自修复。对大肠杆菌有一定抑菌效果(附图2C)。
实施例3：
1)称取1.106g分子量为3kDa胶原蛋白肽溶于30mL去离子水中，加入催化剂DMAP(0.244 g)，再加入EDC(0.767g)活化羧基，最后加入ADH(1.392g)，调节溶液pH为5.5，搅拌反应12h。透析后冷冻干燥可得白色酰肼化胶原蛋白肽粉末A。
2)称取1g分子量为2万的葡聚糖溶于30mL去离子水中，称取2.14g高碘酸钠加入葡聚糖溶液中搅拌均匀。在室温下避光反应24h后，滴加等摩尔量乙二醇终止反应。利用截留分子量MwCO为500的透析袋进行透析，冷冻干燥可得白色氧化葡聚糖粉末B。
3)将0.05ml质量分数10％的聚乙烯醇加入0.5ml浓度为100mg/ml的A水溶液中得到混合液C，0.05ml浓度为0.1mM的硼砂滴加在0.5ml浓度为250mg/ml的B水溶液中得到混合液D，添加小分子量0.6kDa的胶原蛋白肽使其浓度为2mg/ml，0.55ml C混合液和0.55ml D混合液在室温下搅拌可以在3s内得到自修复胶原蛋白肽基抗菌复合水凝胶。该水凝胶抗拉强度达45kPa，粘附强度17kPa，含水率和保水率分别为81.2％和77.8％，在受到外界破坏后在可以10s内迅速自修复。对大肠杆菌有一定抑菌效果(附图2D)。
实施例4：
1)称取2.212g分子量为3kDa胶原蛋白肽溶于35mL去离子水中，加入催化剂DMAP(0.366 g)，再加入EDC(0.767g)活化羧基，最后加入ADH(1.392g)，调节溶液pH为4.0，搅拌反应12h。透析后冷冻干燥可得白色酰肼化胶原蛋白肽粉末A。
2)称取1g分子量为3万的葡聚糖溶于30mL去离子水中，称取2.14g高碘酸钠加入葡聚糖溶液中搅拌均匀。在室温下避光反应24h后，滴加等摩尔量乙二醇终止反应。利用截留分子量MwCO为500的透析袋进行透析，冷冻干燥可得白色氧化葡聚糖粉末B。
3)将0.1ml质量分数10％的聚乙烯醇加入0.5ml浓度为100mg/ml的A水溶液中得到混合液 C，0.05ml浓度为0.1mM的硼砂滴加在0.5ml浓度为250mg/ml的B水溶液中得到混合液D，添加小分子量0.6kDa的胶原蛋白肽使其浓度为2mg/ml，0.6ml C混合液和0.55ml D混合液在室温下搅拌可以在1s内得到自修复胶原蛋白肽基抗菌复合水凝胶。该水凝胶抗拉强度37 kPa)，粘附强度15kPa，含水率和保水率分别为78.4％和75.9％，在受到外界破坏后在可以 20s内迅速自修复，对大肠杆菌有一定抑菌效果。
实施例5：
1)称取1.659g分子量为3kDa胶原蛋白肽溶于35mL去离子水中，加入催化剂DMAP(0.306 g)，再加入EDC(0.767g)活化羧基，最后加入ADH(1.392g)，调节溶液pH为4.5，搅拌反应12h。透析后冷冻干燥可得白色酰肼化胶原蛋白肽粉末A。
2)称取1g分子量为10万的葡聚糖溶于30mL去离子水中，称取1.07g氯化铁加入葡聚糖溶液中搅拌均匀。在室温下避光反应24h后，滴加等摩尔量乙二醇终止反应。利用截留分子量MwCO为500的透析袋进行透析，冷冻干燥可得白色氧化葡聚糖粉末B。
3)将0.1ml质量分数10％的聚乙烯醇加入0.5ml浓度为100mg/ml的A水溶液中得到混合液 C，0.05ml浓度为0.1mM的硼砂滴加在0.5ml浓度为250mg/ml的B水溶液中为混合液D，添加小分子量0.6kDa的胶原蛋白肽使其浓度为5mg/ml，0.6ml C混合液和0.55ml D混合液在室温下搅拌可以在3s内得到自修复胶原蛋白肽基抗菌复合水凝胶。该水凝胶抗拉强度42 kPa，粘附强度13kPa，含水率和保水率分别为82.9％和69.4％，在受到外界破坏后在可以30 s内自修复。
对比例：
1)称取1.106g分子量为3kDa胶原蛋白肽溶于35mL去离子水中，加入催化剂DMAP(0.244 g)，再加入EDC(0.767g)活化羧基，最后加入ADH(1.392g)，调节溶液pH为4.5，搅拌反应12h。透析后冷冻干燥可得白色酰肼化胶原蛋白肽粉末A。
2)称取1g分子量为4万葡聚糖溶于30mL去离子水中，称取2.14g高碘酸钠加入葡聚糖溶液中搅拌均匀。在室温下避光反应24h后，滴加等摩尔量乙二醇终止反应。利用截留分子量 MwCO为500的透析袋进行透析，冷冻干燥可得白色氧化葡聚糖粉末B。
3)0.5ml浓度为100mg/ml的A溶液和0.5ml浓度为250mg/ml的B溶液混合，两种混合液在室温下搅拌可以在30s内得到自修复胶原蛋白肽基复合水凝胶。该水凝胶抗拉强度16kPa，粘附强度5.3kPa，含水率和保水率分别为87.9％和73.4％，在受到外界破坏后在可以60s内自修复。
敷料效果实验：
使用自制直径为1.8cm的小型温控电熨斗在24只成年大鼠背部于100℃下烫伤10s，造成深II度烫伤模型。将其平均分为三组，分别用自制胶原蛋白肽基复合水凝胶、商业水胶体敷料(TegadermTM 90022T)和医用纱布(空白对照)处理伤口，单笼饲养大鼠，两天更换一次敷料，观察每组大鼠的伤口愈合情况。
从附图4中可以看出，本发明所制备的胶原蛋白肽复合水凝胶相对商业水胶体敷料和医用纱布处理比较，其具有良好的生物相容性，从14d后伤口愈合面积大幅度增加，21d后伤口愈合面积可达93.4％，在促进伤口快速愈合的同时，大鼠伤口周围的毛发生长速度也明显优于商用水胶体和医用纱布。作为一种湿性伤口敷料，胶原蛋白肽水凝胶敷料从根本上改变伤口的愈合方式，持续保持伤口湿润，防止伤口形成结痂，且具有良好的抗菌性能和一定的机械强度，其保水性较好，可以在更换敷料时不造成二次伤害，是一种很有潜力的伤口敷料。
Claims (8)
1.一种自修复海洋源胶原蛋白肽基复合水凝胶的制备方法，其特征在于步骤包括：
(1)配制胶原蛋白肽水溶液，加入二酰肼、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和催化剂，控制反应温度和pH，搅拌反应一段时间后，在去离子水中透析反应液并冷冻干燥，得到酰肼改性的胶原蛋白肽A，通式如下：
其中R为-(CH2)-n，n＝1-11；
(2)配制不同质量浓度的葡聚糖溶液，加入一定量的氧化剂，在一定温度、避光的条件下搅拌反应；反应一段时间后，加入乙二醇搅拌终止反应，冷冻干燥，即得到氧化葡聚糖产物B；
(3)配置不同质量分数的PVA水溶液，不同摩尔浓度的硼砂溶液；
(4)将PVA水溶液与A水溶液混合得到混合液C；硼砂溶液滴加在B水溶液中得到混合液D，再添加小分子量的胶原蛋白肽；将混合液C、D在室温下搅拌，通过化学、物理交联可以在数秒内迅速成胶，改变C、D混合液的比例，即可得到具有自修复功能的胶原蛋白肽基复合水凝胶；
步骤(1)中的胶原蛋白肽是通过酸碱、酶切技术从海洋鱼类的鱼鳍、鱼头、鱼皮、鱼鳞和内脏中提取得到的，分子量在0.3kDa-6kDa范围内；
步骤(4)中添加的小分子量的胶原蛋白肽Mw分子量范围0.3kDa-1kDa。
2.根据权利要求1所述的自修复海洋源胶原蛋白肽基复合水凝胶的制备方法，其特征在于，步骤(1)中胶原蛋白肽浓度范围1-200mg/ml，胶原蛋白肽与二酰肼质量比范围1:0.5-1:10；反应时间1-24h；反应温度10-45℃；溶液pH范围为3-6。
3.根据权利要求1所述的自修复海洋源胶原蛋白肽基复合水凝胶的制备方法，其特征在于，步骤(1)中催化剂选自对二甲氨基吡啶、1-羟基苯并三氮唑、1-羟基-7-氮杂苯并三氮唑、4-吡咯烷基吡啶、N-羟基琥珀酰亚胺或是它们的混合物。
4.根据权利要求1所述的自修复海洋源胶原蛋白肽基复合水凝胶的制备方法，其特征在于，步骤(2)中葡聚糖Mw分子量范围在1.5kDa-500kDa；葡聚糖溶液的质量浓度范围0.5-10％；氧化葡聚糖的氧化度范围30-100％。
5.根据权利要求1所述的自修复海洋源胶原蛋白肽基复合水凝胶的制备方法，其特征在于，步骤(2)中氧化剂选自高碘酸钠、高碘酸钾、氯化铁、过氧化氢中的至少一种或是它们的混合物，葡聚糖与氧化剂的摩尔比为1:1-1:3000；反应温度为10-50℃；反应时间2-24h。
6.根据权利要求1所述的自修复海洋源胶原蛋白肽基复合水凝胶的制备方法，其特征在于，步骤(3)中的PVA为商品化产品，粘度范围3-50mPa.s，PVA水溶液质量浓度为1-10％；硼砂溶液的摩尔浓度为0.05-2mM。
7.根据权利要求1所述的自修复海洋源胶原蛋白肽基复合水凝胶的制备方法，其特征在于，步骤(4)中小分子量的胶原蛋白肽的添加量为1-10mg/ml，C与D混合液的体积比为0.5:1-3:1。
8.一种由权利要求1所述的制备方法得到的自修复海洋源胶原蛋白肽基复合水凝胶，其特征在于所述水凝胶是由天然高分子复合而成，利用酰腙键、席夫碱、硼酸酯键以及氢键相互作用实现快速自愈合，具有良好的抗拉强度、黏附性能以及抗菌性能。
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