表面功能化淀粉基微孔止血材料的构筑及其止血机制探索

Massive hemorrhage and subsequent infection are the leading cause of death, disability and teratogensis after injury. As a novel hemostatic material, releases heat, only suitable for small wounds, rebleeding, no antimicrobial activity and potential toxicity are the main application problems for starch. Surface characteristics of materials had a significant effect on protein adsorption and coagulation reactions involved in blood. Therefore, based on the preparation of the microporous starch by enzymatic degradation, surface functionalization of starch-based porous hemostatic materials are fabricated by chemical modification and self-assembly technique with the functional groups (hydroxyl, carboxyl and amine) and cation (calcium, zinc and silver ion ) as a model. From different levels ( hydrophobicity, surface charge, the degree of substitution of cationic functional groups, species and content, surface roughness etc.), different surfaces involved in the reaction with the effective component of blood, platelet adhesion and the activation of blood coagulation system will be analysized. The surface and interface structure effect of microporous starch will be clearly explained during hemostatic process. The influencing factors of physical and chemical materials played in hemostasis and synergistic effect are to be explored. The hemostatic and antimicrobial activity are evaluated by establishing the animal model. This study will enrich the theory of hemostatic starch, also provide the guidance for the surface design of other materials.

大出血及随之而来的感染是人体受伤后导致死亡、致残和致畸的主要原因。微淀粉作为新型止血材料，只适于小创伤、继发性出血、无抗菌性及其潜在毒性是其应用过程中存在的主要问题。材料表界面对蛋白的吸附和参与血液的凝固反应有显著的影响。为此，项目在酶解制备淀粉微球的基础上，以生物相容性好且与血液有明确作用的官能团（羟基、羧基和胺基）和阳离子（钙、锌和银离子）为模型，通过化学修饰和自组装等技术构筑表面功能化淀粉基微孔止血材料。从不同角度（亲疏水性、表面电荷、官能团种类和取代度、阳离子种类和含量、粗糙度、固载方式等）系统研究不同表面参与血液有形成分反应及对血小板粘附、凝血因子激活的作用机制，明确止血过程中微孔淀粉的表界面结构效应。探索材料发挥物理性止血和化学性止血的影响因素和协同效应，评价材料的止血和抗感染效果，揭示材料用于大出血控制的止血机制。研究将丰富淀粉的止血理论，也为其它材料的表面设计提供实验指导。

不可控的大出血仍然是灾难、战斗、外科手术和交通事故后导致人类死亡的主要原因。项目在酶解制备淀粉微球的基础上，通过化学修饰和自组装等技术构建了不同钙含量的淀粉基止血材料CaOMS和季铵盐基团修饰的阳离子抗菌性淀粉止血材料CS，实现了表面功能化基团及其结构调控材料止血性能的可控制备技术。钙离子引入量为2.2mg/g的CaOMS3有效缩短凝血酶原时间（PT）、部分活化凝血酶时间（APTT）及凝血酶时间（TT），体外凝血时间缩短了约70%；在羧基和钙离子的协同作用下吸水率达到425.29%；降解速度快（7天），细胞相容性良好。CS吸水性和溶胀性优异，分别达到了304.2%和1008%。CS降解速度快，1天的失重率达到72.5%，细胞相容性良好；CS降低了PT和APTT的值，并将TEG中凝血的引发时间r降低到0.1min，体外凝血时间降到55%。同时，CS对E.coli和S.aureus具有持久稳定抑菌杀菌功能，扩大了止血剂的应用范围。构建的两种淀粉基止血材料，对兔耳缘静脉出血、肝脏创伤以及股动脉出血具有快速、高效止血效果。揭示了微孔结构、携带的羟基、功能化装载的基团、材料粘度和亲疏水性等协同参与的多重止血机制。项目团队新获国家自然科学基金面上项目、装备预研教育部联合基金等2项；团队成员6人次获奖。发表论文13篇，其中SCI收录9篇。申请国家发明专利2项，其中1项已授权。参编专著2章。培养研究生8人，3人已毕业。