Development of Control-Release Materials and Its Applications to Cardiovascular Artificial Organs

本项目旨在开发具有抗凝剂控释功能的生物材料及其在心血管人工器官中的应用。这里选择的基质聚合物是基于聚（乙二醇）的亲水性嵌段聚氨酯。合成的嵌段聚氨酯具有橡胶般的弹性，满足心血管人工器官材料的基本要求，特别是在脉动条件下。发现通过改变作为起始材料的聚（乙二醇）的分子量，可以容易地控制亲水性或吸水能力。分子量越大，吸水率越高。这里使用的抗凝剂是分子设计的合成药物，名为MD-805和FUT-175。前者是对凝血酶高度特异和敏感的凝血酶抑制剂，后者是包括补体抑制在内的广谱合成蛋白酶抑制剂。这些合成的抗凝剂可以很容易地溶解在极性非质子溶剂中，这是嵌段聚氨酯的良好溶剂。采用聚氨酯和抗凝剂的混合溶液一步共铸法制备了均匀分散的共格薄膜。体外实验表明，该体系具有优良的抗凝血性能。抗凝剂的释放速率进行了监测，这与聚合物的吸水能力的增加而增加。抗凝剂的释放速率和持续时间由三个变量控制：1）材料变量（基质聚合物的亲水性），2）制剂变量（载药量）和3）制造变量（涂层厚度）。该系统的研制为高抗凝血材料的控释提供了新的技术途径。

The project aimed at development of biomaterials with control release function of anticoagulants and its applications to cardiovascular artificial organs. The matrix polymers selected here was hydrophilic segmented polyurethanes based on poly(ethylene glycol). This segmented polyurethanes prepared here exhibited rubber-like elasticity which satisfies the basic requirements for materials used for cardiovascular artificial organs especially under pulsatile conditions. The hydrophilicity or water-uptake capability was found to be easily controlled by varying the molecular weight of poly(ethylene glycol) as a starting material. The higher the molecular weight is, the higher water-uptake is obtained. The anticoagulants used here were molecularly-designed synthetic drugs named MD-805 and FUT-175. The former was thrombin inhibitor with highly specific and sensitive to thrombin, and the later was synthetic protease inhibitor with wide spectrum including complement inhibition. These synthetic anticoagulants can be easily dissolved into polar aprotic soluents which are good soluents for segmented polyurethanes. The one-step co-casting from a mixed solution of polyurethane and anticoagulant gave homogeneously-dispersed coherent films. The in vitro experiments showed that the systems developed here exhibited superb anticoagulant behavior. The release rate of anticoagulant was monitored, which increased with an increase in water-uptake capability of polymers. The rate and duration of release of anticoagulant was controlled by three variables; 1) materials's variable (hydrophilicity of matrix polymer), 2) formulation's variable (amount of drug loading) and 3) fabrication's variable (coating's thickness). The developed system will provide a new technology of highly anticoagulant materials with controlled release function.