半胱氨酸功能化的透明质酸结合物的合成及其在可注射原位形成的共价交联水凝胶中的应用

发布时间：2018-04-30 09:29

本文选题：透明质酸 + 可注射原位形成　；参考：《海南大学》2014年硕士论文

【摘要】：透明质酸是一种生物相容、生物可降解的直链高分子多糖聚合物。它广泛分布于人体各部位,并且发挥着重要的生理作用。本课题研究探索了一种新的、高效的、在温和条件下通过透明质酸的羟基修饰和功能化透明质酸的方法,并且合成得到了一种半胱氨酸透明质酸结合物。通过修饰透明质酸的羟基,得到通过稳定的醚键连接的半胱氨酸透明质酸结合物。本课题研究的重大突破是在透明质酸的修饰反应中引入了四丁基氢氧化铵作为助溶剂与催化剂。据查阅文献结果表明,此方法是一种新的并且第一次应用于多糖的修饰方法中,大大提高了透明质酸的溶解度,并且提高了反应的修饰率,克服了以往修饰透明质酸的过程中溶解度受限,并且反应需要在有机溶剂中进行等一系列导致修饰失败的问题。本课题研究所得到的半胱氨酸透明质酸结合物不修饰其结构中的羧基功能团,保留了其具有细胞CD44受体识别能力而通过稳定的醚健修饰其羟基得到了具有巯基活性基团的结合物。这些巯基基团可被进一步功能化,将会扩大透明质酸在医药与生物材料领域的应用。合成得到的半胱氨酸透明质酸结合物可用于制备可注射的原位形成的共价交联透明质酸水凝胶,延长透明质酸在体内的滞留时间,发挥更广泛的作用。本课题研究运用两种交联方法得到了共价交联的水凝胶：(1)使用半胱氨酸透明质酸结合物与聚乙二醇丙烯酸酯结合物运用迈克尔加成反应得到可注射的原位形成的共价交联透明质酸水凝胶；(2)使用半胱氨酸透明质酸结合物与不同分支的聚乙二醇硫酯结合物运用自然化学连接反应得到的共价交联透明质酸水凝胶。通过这两种方法都能在短时间内获得水凝胶。水凝胶的形成过程和形成的水凝胶的流变学研究表明,该水凝胶可在十分钟内形成,并且所形成的水凝胶为共价交联、具有高度的粘弹性。本研究获得的水凝胶可注射原位形成,不经过手术而通过针管注射,以最小程度地对机体组织侵入填充任意形状的缺损,且能与治疗药物混合注射发挥药物缓释作用,预期将可广泛地应用于外科封闭剂和粘合剂、药物释放、组织填充、组织修复和组织工程。
[Abstract]:Hyaluronic acid is a biocompatible, biodegradable polymer with straight chain polysaccharides. It is widely distributed in various parts of the human body and plays an important physiological role. In this paper, a new and efficient method of modification and functionalization of hyaluronic acid by hydroxyl group of hyaluronic acid under mild conditions was studied, and a cysteine hyaluronic acid conjugate was synthesized. By modifying the hydroxyl group of hyaluronic acid, a stable cysteine hyaluronic acid bond was obtained. An important breakthrough in this research is the introduction of tetra ammonium hydroxide as a co-solvent and catalyst in the modification of hyaluronic acid. According to the results of literature review, this method is a new and first time applied to the modification of polysaccharides, which greatly improves the solubility of hyaluronic acid and the modification rate of the reaction. It overcomes a series of problems that lead to the failure of modification, such as the limited solubility in the process of modification of hyaluronic acid and the reaction needs to be carried out in organic solvents. In this study, the cysteine hyaluronic acid conjugate did not modify the carboxyl functional group in its structure. The conjugate with mercapto active group was obtained by modifying its hydroxyl group with stable ether binding. These mercapto groups can be further functionalized, which will expand the application of hyaluronic acid in medicine and biomaterials. The synthesized cysteine hyaluronic acid conjugate can be used in the preparation of injectable covalent crosslinked hyaluronic acid hydrogels, which can prolong the retention time of hyaluronic acid in vivo and play a more extensive role. In this study, two cross-linking methods were used to obtain covalent crosslinked hydrogel: 1) by using cysteine hyaluronic acid conjugate and polyethylene glycol acrylate conjugate, the injectable in situ formation was obtained by Michael addition reaction. The covalent crosslinked hyaluronic acid hydrogels were obtained by using cysteine hyaluronic acid conjugate and polyethylene glycol sulfur ester conjugate with different branches. Hydrogels can be obtained in a short time by both methods. The hydrogel formation process and the rheology of the formed hydrogel show that the hydrogel can be formed in ten minutes and the hydrogel formed is covalent crosslinked with high viscoelasticity. The hydrogel obtained in this study can be injected in situ and injected through needle tube without operation to minimize the invasion of the body tissue to fill any shape defect, and can be combined with the treatment drug injection to play a drug release effect. It is expected to be widely used in surgical sealants and adhesives, drug release, tissue filling, tissue repair and tissue engineering.
【学位授予单位】：海南大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5

【参考文献】