【作者】 杨志红；

【导师】 谢长生；

【作者基本信息】 华中科技大学 ， 材料科学与工程， 2007， 博士

【摘要】 含铜宫内节育器（简称Cu-IUD）是目前使用最广泛的活性节育器,具有很高的避孕率,但容易引起经血过多、疼痛、异常出血和炎症等副作用。这些副作用严重影响了Cu-IUD的应用和发展。为了降低Cu-IUD引起的副作用,本课题组在前期工作中制备了铜/低密度聚乙烯（Cu/LDPE）纳米复合材料,在此基础上,本论文引入了能够降低副作用的锌、氧化锌和吲哚美辛等活性物质,制备出了新型的用于IUD的改性Cu/LDPE纳米复合材料。锌和氧化锌溶解后产生的锌离子具有避孕、抗菌、恢复创伤等功能。纳米锌和氧化锌具有很强的抗菌能力,纳米氧化锌还具有优良的抗凝血性能,因此在降低副作用方面,纳米锌和氧化锌具有广阔的应用前景。吲哚美辛（简称IDM）是减轻月经过多副反应的有效药剂。本研究在Cu/LDPE纳米复合材料的基础上加入纳米锌、纳米氧化锌和吲哚美辛,应用热模压法制备了Cu/Zn/LDPE、Cu/ZnO/LDPE和Cu/IDM/LDPE纳米复合材料,并对复合材料的离子释放性能、抗菌性能和血液相容性能进行了研究。模拟宫腔液的血清白蛋白能显著影响锌和氧化锌颗粒的溶解。血清白蛋白通过与锌离子结合形成络合物而促进了锌和氧化锌的溶解,增大了锌离子转化率。但结合了锌离子的血清白蛋白在变性和沉淀之后,对锌离子转化率会产生反作用。通过对Cu/Zn/LDPE和Cu/ZnO/LDPE三元纳米复合材料的Cu²⁺和Zn²⁺释放进行研究后发现,纳米铜和纳米锌（或纳米氧化锌）颗粒既相互抑制对方的溶解,又相互为对方离子的释放提供扩散通道。在经历了初期的快速释放后,复合材料能持续稳定地释放Cu²⁺和Zn²⁺,而且通过调整纳米铜和纳米锌或氧化锌的含量,可以获得合适的Cu²⁺和Zn²⁺释放速率。因此以这种复合材料制备成的IUD在保证避孕率的同时,还可望降低疼痛、生殖系统感染和异常出血等副作用。应用振荡烧瓶法进行的抑菌实验结果表明,对于铜含量35%,锌或氧化锌含量15%的纳米和微米复合材料,Cu/ZnO/LDPE复合材料的抗菌能力最强,其次为Cu/LDPE复合材料,Cu/Zn/LDPE复合材料最差。对纳米复合材料和微米复合材料进行对比后发现,由于纳米抗菌剂具有很强的抗菌活性,纳米复合材料的抑菌能力远高于微米复合材料,其中Cu/ZnO/LDPE和Cu/LDPE纳米复合材料,尤其前者在浸泡一个月后仍能保持较好的抗菌活性。应用血浆复钙化时间实验、溶血率实验和血小板黏附实验对复合材料的血液相容性进行了评估。研究结果表明,在纳米颗粒含量为15%的ZnO/LDPE、Zn/LDPE和Cu/LDPE纳米复合材料中,ZnO/LDPE复合材料的溶血率最低,复钙化时间最长。在纳米铜含量35%的Cu/LDPE纳米复合材料中加入15%的纳米氧化锌后,其溶血率降低,复钙化时间延长。血小板黏附实验结果显示,ZnO/LDPE纳米复合材料表面黏附了少量血小板,而Zn/LDPE纳米复合材料表面黏附了大量血小板,且严重聚集、变形,容易引发血栓的形成。对Cu/IDM/LDPE三元纳米复合材料的性能研究表明,基材中铜溶解后留下的孔道可为吲哚美辛的溶出提供扩散通道,促进吲哚美辛的释放。当IDM在纳米复合材料表层集中分布时,这种纳米复合材料可提高IDM的利用度、延长药效,并能够减轻Cu²⁺暴释带来的副作用。更多还原

【Abstract】 The copper-bearing intrauterine device （Cu-IUD） is the most popularly used IUD at present. However, after Cu-IUDs insertion, some side effects such as pelvic inflammatory disease, pain and bleeding have been observed by some researchers. Concerns about side effects remain stubborn obstacles to a wider use of modern IUDs. In order to decrease the side effects of Cu-IUD, Cu/LDPE nanocomposites were prepared for IUD in our previous study. Further, zinc, zinc oxide and indomethacine were added into Cu/LDPE nanocomposites in this study to decrease the side effects more effectively.Zinc ion has the function of contraceptive action, antibacterial effects, wound healing and tissue repair of the endometrium. Compared with zinc and zinc oxide bulk, zinc and zinc oxide nanoparticles shew much stronger antibacterial properties. Furthermore, the anticoagulant properties of zinc oxide nanoparticles are excellent. It indicates that nanoparticles of zinc and zinc oxide could decrease the side effects of IUD more effectively. At the same time, indomethacine （IDM） can alleviate menorrhagia that is responsible for the extraction of Cu-IUD. Therefore, by using low-density polyethylene as the carrier , composites of Cu/Zn/LDPE、Cu/ZnO/LDPE and Cu/IDM/LDPE were prepared by method of compressing molding. And the properties of the composites were deeply investigated.Investigation on Zn²⁺ transformation ratios of zinc and zinc oxide in the simulated uterine solution shows that the Zn²⁺ transformation ratios are affected by human serum albumin in the simulated uterine solution. By the binding of zinc ions with human serum albumin, the dissolutions of zinc and zinc oxide and the transformation ratio of Zn²⁺ can be obviously accelerated in initial stages. But after denaturalization of human serum albumin in later time, Zn²⁺ transformation ratio becomes lower.It has been found that the release rates of Cu²⁺ and Zn²⁺ of Cu/Zn/LDPE and Cu/ZnO/LDPE nanocomposites can keep stable during the experimentation time after a burst release at beginning. So IUD prepared with this composite should not only have high contraceptive effect but also reduce the side effects like infection, pain and bleeding. With the variation of one kind of nanoparticle content, the ion rate of the other kind of nanoparticles decreases or unchange. The reason is that the copper and zinc nanoparticles （or zinc oxide nanoparticles） can inhibited the dissolution mutually and at the same time provide the pathways for iron release to each other. So the proper release rate of Cu²⁺ and Zn²⁺ in the nanocomposites can be achieved by adjusting the relative contents of copper and zinc.Shake flask test was employed to evaluate the antibacterial activity of the composites with 35wt% copper particles and 15wt% zinc or zinc oxide particles. The results show that the antibacterial activity of these composites, in descending order of strength, is as follows: Cu/ZnO/LDPE composite, Cu/LDPE composite and Cu/Zn/LDPE composite. The antibacterial activity of all the composites becomes worse if they are immersed in the simulated uterine solution for a month. Furthermore, the antibacterial activity of the nanocomposites is better than that of the microcomposites. Among all the composites, only Cu/ZnO/LDPE and Cu/LDPE nanocomposites, especially the latter, can keep good antibacterial activity even for a month.The blood compatibility of the nanocomposites with 15% nanoparticles was evaluated in terms of the plasma recalcification time,the hemolysis rate and platelets adhesion. Among ZnO/LDPE、Zn/LDPE and Cu/LDPE nanocomposites, ZnO/LDPE nanocomposite has the lowest hemolysis rate and the longest plasma recalcification time. The results show that a small amount of platelets on the surface of ZnO/LDPE are detected. However, a lot of activated platelets on the surface of Zn/LDPE aggregate and spread out, which may trigger the formation of thrombus. Consequently, compared with zinc nanoparticles, zinc oxide nanoparticles show good antibacterial effect and blood compatibility. The above results indicated that zinc oxide nanoparticles are more suitable for the material of IUD with low side effects. Cu²⁺ release and IDM release from Cu/IDM/LDPE nanocomposites were studied. IDM in the composites diffuses out through pore channels. Some of the pores created by the dissolution of copper nanoparticles provide diffusion path for IDM release and enhance the release rate of IDM. The preparation process of the nanocomposite was improved in this study by distributing IDM in the surface layer of the nanocomposite. This nanocomposite exhibits much higher release rate of IDM after incubation for 3 months and lower initial burst of Cu²⁺ than the matrix-type nanocomposite, implying that it can enhance the availability ratio of IDM, prolong the service life of IDM, and reduce the burst effect of Cu²⁺.更多还原