可降解温敏物理交联改性甲壳素止血微球的研究

Lethal hemorrhage could endanger lives. Although many hemostatic agents are commercially available with good clinical effect, some issues concerning biological safety, hemostatic efficacy and high cost limit their wide use. Therefore developing new safe and cost effective biodegradable materials to stop severe bleeding rapidly is very necessary. On the previous study of degradable thermosensitive modified chitin based hydrogels, porous microspheres were prepared for the first time via simply heating some aqueous thermosensitive modified chitin solution without using any chemical crosslinker and toxic organic solvent. In the preliminary animal hemostasis experiments, hemostatic efficacy of the porous microsphere crosslinked physically based on the thermosensitive carboxymethyl chitin was superior to the controls chitosan and Yunnan Baiyao powder. . In this work, a series of new thermosensitive modified chitin with low degree of deacetylation will be synthesized homogenously and characterized. The process of the porous microspheres crosslinked physically through heating will be optimized, and the super water absorption and biodegradability, the in vitro and in vivo hemostatic efficacy will be measured for the new thermosensitive modified chitins. In order to provide good strategy and theoretical basis for the development and design of other new polymeric hemostatic materials, the relationship between the structure of the thermosensitive modified chitin (substitution structure, degree of substitution, degree of deacetylation and their distributions) and the hemostatic properties as well as the coagulation function and hemostatic mechanism will be studied. A new suitable effective hemostatic material for Class III medical appliances in clinical services and battlefield first aid will be obtained after evaluation of the biological safety and fast haemostasis.

出血不止危及生命，现有止血材料虽已广泛使用，有不错的临床效果，但都存在一些不足，因此研发快速安全价廉高效的可降解止血新材料非常重要。在研究可降解温敏性改性甲壳素水凝胶时，我们首次发现一些温敏改性甲壳素水溶液通过简单升温可制成多孔微球，不使用任何化学交联剂和有毒的有机溶剂。初步的动物止血实验表明，该类温敏物理交联的羧甲基甲壳素多孔微球粉末具有高效的吸水止血性，优于对照组壳聚糖和云南白药粉末。本项目拟均相合成和表征一系列低脱乙酰度新型温敏改性甲壳素，优化其升温物理交联制备多层次多孔微球的工艺，测试其快速吸水和生物降解特性及体内外止血效果，探索其结构（取代结构，取代度，脱乙酰度）及分布与止血性能之间的关系，研究其凝血机制和止血机理，为研发其它新型高分子止血材料提供思路和理论指导。评价其生物安全性和快速止血的临床效果，研制出可望用于临床医疗和战场急救的新型快速高效止血三类医疗器械材料。

出血不止是外科手术、战伤急救、交通和日常意外事故及自然突害中经常遇到的问题，是战争伤亡中的主要原因，因此快速止血材料的研发和供给非常必要。现有止血材料虽已广泛使用，有不错的临床效果，但都存在一些不足，因此研发快速安全价廉高效的可降解止血新材料非常重要。利用低温尿素碱液水相体系，不使用有机溶剂，均相合成了温敏性羧甲基甲壳素、温敏性可注射羟丙基甲壳素、温敏性季铵化改性甲壳素、温敏性磺酸化改性甲壳素及其温敏可示踪聚集诱导发光改性甲壳素等，并表征了其结构，研究了其改性甲壳素结构与其转变温度之间的规律，发现低温改性反应条件有利于保留较高乙酰基，才能获得具有温敏性改性甲壳素，并随着改性基团的引入增多转变温度会升高。利用这些新型温敏性改性甲壳素，通过低温碱水溶解、中和升温固化、纯化冷冻干燥等步骤分别制得了止血效果优良的羧甲基甲壳素止血微球、凝血酶改性羧甲基甲壳素止血微球、季铵化改性甲壳素多孔止血海绵、羧甲基甲壳素多孔止血海绵和负载了多巴胺和胶原的羧甲基甲壳素多孔海绵材料。开展了系列体外细胞实验、体内生物相容性评价和动物止血和组织修复实验，实验结果表明这些新型的改性甲壳素止血微球和止血海绵具备优良高效的吸水止血性、降解特性和生物相容性，特别是负载了多巴胺和胶原的羧甲基甲壳素多孔海绵和温敏季铵化改性甲壳素海绵材料具备优良高效的吸水止血性、良好的力学强度、降解特性和生物相容性，即使有凝血障碍，也有很好的止血效果，适用于深且窄的伤口、不可压迫性伤口及贯穿性伤口的止血，有望用于临床医疗和战场急救的新型快速高效止血三类医疗器械材料，具有很好的应用开发前景，为研发其它新型可降解高分子止血材料提供了新方法和思路。已发表标注SCI论文15篇，其中1区6篇，影响因子大于10的6篇，大于7的8篇；已获6项中国发明专利授权，申请4项中国发明专利和1项美国发明专利待授权，培养并获硕士学位毕业5名和博士学位4名。