医用抗凝血聚氨酯材料的制备与表征

发布时间：2018-07-14 19:35

【摘要】：从医用导管到人工心脏,聚氨酯(PU)在医疗器械中具有广泛的应用。但是,当PU与血液接触时其凝血问题仍需解决。目前主要有两种改性方法用于改进这一问题：物理方法和化学方法。其中因为物理共混药物改性后的PU只具有中短期抗凝血性；而其他的改性方法主要是针对PU表面的改性,而材料表面的性能在复杂的血液环境中的影响并不确定。因此,本项研究中的PU不仅在表面也在本体内接枝上抗凝血药物肝素,希望改性后的PU可以同时具有持续的抗凝血性。同时这种改性方法制备的聚氨酯抗凝血材料可以制备成任意形状,或作为其他生物医用材料的表面涂层。本项研究采用一种新的方法将肝素共价接枝到聚醚型聚氨酯上以制备医用抗凝血聚氨酯。首先,由异佛尔酮二异氰酸酯、双羟甲基丙二酸二乙酯(DBM)、聚乙二醇、1,6-己二醇合成具有二个脂基侧链的PU。二个脂基是由扩链剂DBM引入。为了比较DBM含量不同对肝素接枝量的影响,本研究合成的两种PU,其一为PU-3DBM:DBM占总单体摩尔分数为12.5at%；另一为PU-6BDM:DBM占总单体摩尔分数为25at%。然后,通过将PU-3DBM和PU-6DBM分别分散于水中,进行水解和羧基化,最后分别接枝了0.49wt.%和0.93wt.%肝素。其中,将水解时间定为30min是为了在保证PU的机械性能没有很大损失的情况下,将二个脂基充分水解。本研究用罗丹明6G法测定了水解和羧基化后PU中羧基的浓度,并用于解释DBM对肝素接枝量的影响。本文还采用傅里叶变换红外光谱和核磁共振氢谱确定肝素的成功接枝；采用化学元素分析分析接枝肝素后的PU的化学组成,结果显示：接枝了肝素的PU-6DBM (PU-6DBM-Hep)中硫元素的含量是接枝了肝素的PU-3DBM (PU-3DBM-Hep)的两倍；化学分析电子能谱显示PU-3DBM-Hep薄膜表面的硫元素含量要高于其本体中硫元素的含量；水接触角测试结果显示接枝有肝素的PU薄膜表面的亲水性能显著提高。在体外肝素释放试验中,本文合成的接枝有肝素的PU可以在生理盐水中持续释放肝素90小时。另外,通过体外血液相容性实验(溶血率和血小板粘附实验)表明,通过本方法合成的接枝有肝素的抗凝血聚氨酯在体外具有很好的血液相容性。但是,将制备的抗凝PU作为血管支架涂层应用于动物体内实验后结果显示,具有涂层的血管支架相对于裸支架,置入动物血管内一个月后会使血管损伤和炎症程度增加,血管壁增生加重。因此,初步认为本项研究制备的抗凝血聚氨酯可作为体外血液接触材料。
[Abstract]:Polyurethane (pu) is widely used in medical instruments from medical catheter to artificial heart. However, the coagulation problem of pu still needs to be solved when it is in contact with blood. At present, there are two main modification methods to improve this problem: physical method and chemical method. The modified pu has only medium and short term anticoagulant effect, while other modification methods are mainly aimed at the surface modification of pu, and the effect of the material surface on the complex blood environment is uncertain. Therefore, the pu in this study not only grafted on the surface but also on the body of anticoagulant drug heparin, it is hoped that the modified pu can also have continuous anticoagulant. At the same time, the polyurethane anticoagulant material prepared by the modified method can be prepared into arbitrary shape or be used as the surface coating of other biomedical materials. In this study, heparin was covalently grafted onto polyether polyurethane to prepare medical anticoagulant polyurethane. Firstly, two aliphatic side chains were synthesized from isophorone diisocyanate, diethyl dimethylol malonate (DBM) and poly (ethylene glycol) 1-hexanediol. Two lipids were introduced by the chain extender DBM. In order to compare the effect of DBM content on the graft capacity of heparin, two kinds of PUM were synthesized, one was that the molar fraction of PU-3DBM: DBM to the total monomer was 12.5 atand the other was PU-6BDM: DBM, the molar fraction of PU-3DBM: DBM was 25atlay. Then, PU-3DBM and PU-6DBM were dispersed in water for hydrolysis and carboxylation respectively. Finally, 0.49wt.% and 0.93wt.% heparin were grafted with PU-3DBM and PU-6DBM, respectively. The hydrolysis time was chosen as 30min in order to fully hydrolyze the two lipids without great loss of the mechanical properties of pu. In this study, the concentration of carboxyl groups in pu after hydrolysis and carboxylation was determined by Rhodamine 6G method, and the effect of DBM on the graft capacity of heparin was explained. The successful grafted heparin was determined by Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR), and the chemical composition of pu grafted with heparin was analyzed by chemical elements. The results show that the content of sulfur in the grafted PU-6DBM (PU-6DBM-Hep) is twice as much as that in the grafted heparin PU-3DBM (PU-3DBM-Hep), and the content of sulfur on the surface of the PU-3DBM-Hep film is higher than that of the PU-3DBM-Hep film. The results of water contact angle test showed that the surface hydrophilicity of pu films grafted with heparin was improved significantly. In vitro heparin release test, the grafted pu grafted with heparin can continuously release heparin in normal saline for 90 hours. In addition, the in vitro blood compatibility test (hemolysis rate and platelet adhesion test) showed that the anticoagulant polyurethane grafted with heparin had good blood compatibility in vitro. However, the application of the prepared anticoagulant pu as a vascular stent coating in vivo showed that compared with the bare stent, the vascular stent with the coating could increase the degree of vascular injury and inflammation one month after the stent was placed in the blood vessel of the animal. The proliferation of vascular wall was aggravated. Therefore, the anticoagulant polyurethane prepared in this study can be used as in vitro blood contact material.
【学位授予单位】：复旦大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R318.08

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