CN114404648A - 促进糖尿病创面修复可降解抗菌止血水凝胶的制备方法 - Google Patents
促进糖尿病创面修复可降解抗菌止血水凝胶的制备方法 Download PDFInfo
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Abstract
本发明公开了促进糖尿病创面修复可降解抗菌止血水凝胶的制备方法，其由多巴胺(DA)接枝氧化天然多糖、水母胶原蛋白(JC)通过交联剂形成具有三维网络结构水凝胶。本发明所制备的水凝胶不但具有优异的组织粘附性能、抗菌性能、止血性能，而且同时具有很强的保水能力，为糖尿病创面愈合提供湿润环境，加速创面愈合。本发明的优点在于：1、本发明制备的一种具有抗菌、止血功能力的糖尿病创面修复、可降解水凝胶，在治疗糖尿病创面应用时，无需额外加入抗生素，避免产生耐药性；2、所用胶原蛋白来源于水生环境中的浮游生物，与动物源性胶原蛋白相比，避免***共患病(疯牛病、猪布氏杆菌病、吸入性炭疽等)的爆发以及一些潜在病毒传播的风险。
Description
技术领域
本发明涉及糖尿病难愈合创面修复技术领域，具体是指促进糖尿病创面修复可降解抗菌止血水凝胶的制备方法。
背景技术
糖尿病患者由于微小血管受损和免疫***失调引起糖尿病足部难愈合创面是导致截肢的主要原因。由于糖尿病患者创面在临床上缺乏有效的治疗手段，故存在高死亡率；这不仅给患者造成严重心理障碍和经济负担，而且也给社会医疗***带来巨大的负担。尽管临床上伤口愈合材料不断发展，但是现有伤口愈合材料不能满足现代医学对伤口完美再生的预期要求。如传统的伤口敷料材料(绷带、棉花和纱布)表面非常干燥，加剧了受损的组织坏死，并延缓了伤口部位的组织修复机制。此外，由于这些材料的粘性，从患者伤口上取出时感到极度疼痛(Biomater.Sci.,2021,9：7705.)。因此，构建具有创面组织适配功能，促进创面愈合可降解生物材料一直是创面修复领域研究热点。
随着对糖尿病创面愈合的研究不断深入，“湿润伤口愈合理论”得到了广大临床医生和科研者的认可。水凝胶高含水量为伤口提供持续湿润环境，其次具有细胞外基质结构、良好的透气性、可控的力学性能、优异的细胞相容性，在创面修复材料展示出惊人的优势。目前市面上也有创面愈合水凝胶(舒康博、凝必敷、康慧尔等)，但是由于价格过高、且依然存在创面易感染、愈合时间长等的问题。因此，开发新型抗菌、止血、促进糖尿病创面愈合的水凝胶是非常有意义的。
在国家“海洋强国”战略布局下，发展海洋生物资源显得尤为重要。随着全球气候变暖，水母繁殖暴发的趋势越来越加剧，严重影响海洋生态***的结构以及人类生活，已然成为新型的近海海洋生态灾害。如何缓解水母造成的危害是一个亟待解决的新型课题。前期研究发现，JC在创面愈合中能够激活VEGF、bFGF，促进创面胶原纤维形成及胶原沉淀，加速血管生成，提高创面愈合率、缩短愈合时间(Chin.J.Traumatol.，2019,22:12)。因此，JC是制备具有可控力学性能、抗菌性能、可降解、止血、促进糖尿病创面愈合水凝胶理想原材料。
发明内容
为了解决现有治疗糖尿病创面材料及技术存在上述的缺陷，本发明的第一个目的在于提供促进糖尿病创面修复可降解抗菌止血水凝胶的制备方法，其DA接枝氧化天然多糖与JC通过交联剂形成糖尿病创面修复的可降解、抗菌、止血水凝胶。
本发明的第二个目的在于提供采用上述的制备方法制备的促进糖尿病创面修复的可降解、抗菌水凝胶，其在治疗糖尿病创面应用时，无需额外加入抗生素，避免产生耐药性；其次所用的胶原蛋白来源于水生环境中的浮游生物，与动物胶原蛋白相比，避免***共患病(疯牛病、猪布氏杆菌病、吸入性炭疽等)的爆发以及一些潜病毒传播风险。
为了实现上述目标，本发明通过以下技术方案：
促进糖尿病创面修复可降解抗菌止血水凝胶的制备方法，包括如下步骤：
(1)制备氧化天然多糖：将天然多糖搅拌全部溶解在去离子水中，加入高碘酸钠(天然多糖与高碘酸钠摩尔比2:1)，避光反应12h，之后加入适量乙二醇终止反应，反应产物经透析机透析，随后通过冷冻干燥得到氧化天然多糖；
(2)DA接枝氧化天然多糖：将氧化天然多糖和DA加入PBS中，在37℃反应24h得到目标产物；
(3)JC溶解在0.1mol/L冰醋酸水溶液中，利用0.1mol/LNaOH溶液调节pH至中性,通过离心排除气泡，得到JC混合液；之后取(2)制备DA接枝氧化天然多糖，加入去离子水形成溶液，加入交联剂搅拌30min后，转移至培养皿中室温放置一段时间形成促进糖尿病创面修复可降解抗菌止血水凝胶。
作为优选方案：所述步骤(1)中天然多糖为：海藻酸钠、壳聚糖、透明质酸、季铵化壳聚糖、纤维素、羟乙基纤维素其中的。
作为优选方案：所述步骤(2)中DA是氧化醛基天然多糖质量的0.5～10％
作为优选方案：所述步骤(3)中交联剂为戊二醛、京尼平、碳化二亚胺、环氧乙烷、环氧氯丙烷、1,4-二(3,4-羟基苯)-2,3-二甲基丁烷其中的。
作为优选方案：所述步骤(3)中交联剂为京尼平，其浓度为0.05—0.1％，加入量与水母胶原体积比1:1～1:5。
作为优选方案：所述步骤(3)中形成凝胶的时间为24～48h。
作为优选方案：所述步骤(3)中DA接枝氧化天然多糖的浓度为1～10wt.％，水母胶原的浓度为1～5wt.％。
作为优选方案：所述步骤(3)中DA接枝氧化天然多糖和JC的加入体积比为1:1～1:10。
与现有技术相比，本发明具有以下有益效果：
(1)本发明方法制备过程条件温和、未使用有机溶剂、降解过程中不产生有毒物，其降解产物有利于促进细胞增殖、迁移、创伤组织肉芽形成、加速创面愈合。
(2)用于糖尿病创面时，无需额外加入抗生素，避免产生耐药性。
(3)所用的胶原蛋白来源于水生环境中的浮游生物，与动物胶原蛋白相比，避免***共患病(疯牛病、猪布氏杆菌病、吸入性炭疽等)的爆发以及一些潜病毒传播风险。
附图说明
图1实施例1OHEC@DA/JC水凝胶抑制金黄色葡萄球菌繁殖图；
图2实施例3OHEC@DA/JC水凝胶大鼠断尾失血量图；
图3实施例2OHEC@DA/JC水凝胶培养(a)人脐静脉内皮血管细胞和(b)人成纤维细胞的OD值；
图4实施例3OHEC@DA/JC水凝胶负载细胞荧光显微镜图；
图5实施例3OHEC@DA/JC水凝胶负载细胞扫描电镜图；
图6实施例3OHEC@DA/JC水凝胶作用于Ⅱ型糖尿病创面愈合过程图片。
具体实施方式
下面结合具体实施例对本发明进行详细说明。以下实施例将有助于对本领域的技术人员进一步理解本发明，但是不以任何形式限制本发明。应当指出的是，对本领域的普通人员来说，在不脱离本发明构思的前提下，还可以做出若干变性和改进。这都属于本发明保护范围。
实施例1
(1)制备氧化羟乙基纤维素(OHEC)：称取(1.0g,16mmol)羟乙基纤维素(HEC)搅拌全部溶解在300mL去离子水中，加入(1.71g,8mmol)高碘酸钠，避光反应12h，之后加入适量1.5mL乙二醇终止反应，反应产物经透析机透析，随后通过冷冻干燥得到OHEC；
(2)DA接枝OHEC：将1g OHEC和0.05g DA加入PBS中，在37℃反应24h得到目标产物(OHEC@DA)；
(3)JC溶解在0.1mol/L冰醋酸水溶液中，利用0.1mol/LNaOH溶液调节pH至中性,通过离心排除气泡，得到2wt.％JC混合液；之后取OHEC@DA，加入去离子水形成2wt.％溶液，分别取5mL JC混合液和5mL OHEC@DA溶液，加入1mL，0.05％的京尼平搅拌30min后，转移至培养皿中室温放置24h形成促进糖尿病创面修复的可降解、抗菌、止血(OHEC@DA/JC)水凝胶。
实施例2
(1)制备OHEC：称取(1.0g,16mmol)HEC搅拌全部溶解在300mL去离子水中，加入(1.71g,8mmol)高碘酸钠，避光反应12h，之后加入适量1.5mL乙二醇终止反应，反应产物经透析机透析，随后通过冷冻干燥得到OHEC；
(2)DA接枝OHEC：将1g OHEC和0.05g DA加入PBS中，在37℃反应24h得到OHEC@DA；
(3)JC溶解在0.1mol/L冰醋酸水溶液中，利用0.1mol/LNaOH溶液调节pH至中性,通过离心排除气泡，得到2wt.％JC混合液；之后取OHEC@DA，加入去离子水形成2wt.％溶液，分别取10mL JC混合液和5mL OHEC@DA溶液，加入1mL，0.05％的京尼平搅拌30min后，转移至培养皿中室温放置24h形成OHEC@DA/JC水凝胶。
实施例3
(1)制备OHEC：称取(1.0g,16mmol)HEC搅拌全部溶解在300mL去离子水中，加入(1.71g,8mmol)高碘酸钠，避光反应12h，之后加入适量1.5mL乙二醇终止反应，反应产物经透析机透析，随后通过冷冻干燥得到OHEC；
(2)DA接枝OHEC：将1g OHEC和0.05g DA加入PBS中，在37℃反应24h得到OHEC@DA；
(3)JC溶解在0.1mol/L冰醋酸水溶液中，利用0.1mol/LNaOH溶液调节pH至中性,通过离心排除气泡，得到2wt.％JC混合液；之后取OHEC@DA，加入去离子水形成2wt.％溶液，分别取15mL JC混合液和5mL OHEC@DA溶液，加入1mL，0.05％的京尼平搅拌30min后，转移至培养皿中室温放置24h形成OHEC@DA/JC水凝胶。
实施例4
(1)制备OHEC：称取(1.0g,16mmol)HEC搅拌全部溶解在300mL去离子水中，加入(1.71g,8mmol)高碘酸钠，避光反应12h，之后加入适量1.5mL乙二醇终止反应，反应产物经透析机透析，随后通过冷冻干燥得到OHEC；
(2)DA接枝OHEC：将1g OHEC和0.05g DA加入PBS中，在37℃反应24h得到OHEC@DA；
(3)JC溶解在0.1mol/L冰醋酸水溶液中，利用0.1mol/LNaOH溶液调节pH至中性,通过离心排除气泡，得到3wt.％JC混合液；之后取OHEC@DA，加入去离子水形成2wt.％溶液，分别取5mL JC混合液和5mL OHEC@DA溶液，加入1mL，0.05％的京尼平搅拌30min后，转移至培养皿中室温放置24h形成OHEC@DA/JC水凝胶。
对比例1
本对比例与实施例3的区别仅在于，以海藻酸钠代替了HEC进行氧化成醛接枝DA制备水凝胶，其水凝胶也具有良好的止血性能、生物相容性。
对比例2
本对比例与实施例3的区别仅在于，以猪胶明胶代替了JC制备水凝胶，其各种性能不如OHEC@DA/JC。
由实施例3与对比例1、2的对比可知，所制备的材料负载细胞生长情况都比猪胶原的要好，其次与牛或猪胶原蛋白相比JC来源于浮游生物，避免***共患病以及潜在传染病传播风险，因此本发明制备促进糖尿病创面修复的可降解、抗菌、水凝胶在治疗糖尿病难愈合创面等临床应用中更具有开发前景。
以上对本发明的具体实施例进行了描述。需要理解的是，本发明并不局限于上述特定实施方式，本领域技术人员可以在权利要求的范围内做出各种变形或修改，这并不影响本发明的实质内容。
Claims (8)
1.促进糖尿病创面修复可降解抗菌止血水凝胶的制备方法，其特征在于，包括以下步骤：
(1)氧化天然多糖的制备：将天然多糖搅拌全部溶解在去离子水中，加入高碘酸钠，天然多糖与高碘酸钠摩尔比2:1，避光反应12h，之后加入适量乙二醇终止反应，反应产物经透析机透析，随后通过冷冻干燥得到氧化天然多糖；
(2)DA接枝氧化天然多糖：将氧化天然多糖和DA溶于PBS中，在37℃反应24h得到目标产物；
(3)JC溶解在0.1mol/L冰醋酸水溶液中，利用0.1mol/LNaOH溶液调节pH至中性，通过离心排除气泡，得到JC混合液；之后取(2)制备多巴胺接枝氧化天然多糖，加入去离子水形成溶液，加入交联剂搅拌30min后，转移至培养皿中室温放置一段时间形成促进糖尿病创面修复的可降解、抗菌、止血水凝胶。
2.根据权利要求以所述的促进糖尿病创面修复可降解抗菌止血水凝胶的制备方法，其特征在于，所述步骤(1)中天然多糖为：海藻酸钠、壳聚糖、透明质酸、季铵化壳聚糖、纤维素、羟乙基纤维素其中的。
3.根据权利要求以所述的促进糖尿病创面修复可降解抗菌止血水凝胶的制备方法，其特征在于，所述步骤(2)中DA是氧化醛基天然多糖质量的0.5～10％。
4.根据权利要求以所述的促进糖尿病创面修复可降解抗菌止血水凝胶的制备方法，其特征在于，所述步骤(3)中交联剂为戊二醛、京尼平、碳化二亚胺、环氧乙烷、环氧氯丙烷、1,4-二(3,4-羟基苯)-2,3-二甲基丁烷其中的。
5.根据权利要求以所述的促进糖尿病创面修复可降解抗菌止血水凝胶的制备方法，其特征在于，所述步骤(3)中交联剂的浓度为0.05％—0.1％，其加入量与水母胶原体积比1:1～1:5。
6.根据权利要求以所述的促进糖尿病创面修复可降解抗菌止血水凝胶的制备方法，其特征在于，所述步骤(3)中DA接枝氧化天然多糖的浓度为1～10wt.％，水母胶原的浓度为1～5wt.％。
7.根据权利要求以所述的促进糖尿病创面修复可降解抗菌止血水凝胶的制备方法，其特征在于，所述步骤(3)中形成凝胶的时间为24～48h。
8.根据权利要求以所述的促进糖尿病创面修复可降解抗菌止血水凝胶的制备方法，其特征在于，所述步骤(3)中DA接枝氧化天然多糖和JC的加入体积比为1:1～1:10。
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