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一系列羟基磷灰石复合材料的合成及生物活性研究
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摘要
本论文主要对纳米羟基磷灰石的合成和性质进行了研究。
     在第二章中,进行了纳米药物/羟基磷灰石复合体的原位组装及浸渍组装的方法、复合体的结构及复合体中的药物含量、药物活性和体外释放量的比较。对于溶菌酶/羟基磷灰石复合体,原位合成法组装酶量为79 mg/g远远大于通过浸渍法组装的酶量15 mg/g。其酶活力为196 F.I.P.-U/mg大于浸渍组装的酶活力56. 8 F.I.P.-U/mg。对于氯霉素/羟基磷灰石复合体,原位合成法组装药量为186.83 mg/g,而通过浸渍法组装的药量为123.8 mg/g。对于原位组装的复合体,药物的组装与HAP的合成同步进行,组装量较大,药物以分子状态均匀存在HAP中,而浸渍组装的药物主要靠吸附作用较多的存在复合体的外部,而复合体内部的药物含量较低。在释放初期,对于原位组装的复合体中药物的释放量低于利用吸附作用组装体,但随着低结晶度HAP在酸性条件逐渐水解,能控制内部的药物的均匀释放,从而高于通过浸渍组装的复合体的释放量。
     在第三章中,利用湿法原位合成了3种未见报道的有机/无机杂化物(RE-HQ/HAP),它是同时具有抗菌功能和骨修复功能的复合材料。本实验选择两种细菌大肠杆菌和金黄葡萄球菌作为抗菌试验的研究对象,通过多种方法进行表征并采用抑菌圈法、最低抑菌浓度(MIC)和最低杀菌浓度(MBC)的测定研究了复合材料对大肠杆菌和金黄葡萄球菌的抑制和杀灭作用,同时探讨了其抗菌机理。
     在第四章中利用湿法合成和水热法合成一系列的RE/HAP复合材料,对其结构进行了表征并且考察了RECL3加入不同量时与单纯的HAP纳米材料的结构和抗肿瘤效应的差异。观察复合材料作用于Hale细胞的形态学,RE/HAP作用后的Hela细胞生长受到干扰,发生细胞变小、脱壁现象,通过细胞生长曲线及细胞生长抑制率的定量研究,发现不同材料浓度和作用时间对Hela细胞都有明显抑制作用,这种抑制作用有一定的剂量和时间依赖关系。从MTT和细胞流式测试结果可以看出,单纯的HAP在各浓度下对细胞生长的抑制率较低,而纳米复合材料RE2a/HAP皆对宫颈癌细胞Hela的生长具有显著的抑制作用,其抑制作用主要是稀土粒子缓慢释放的结果,通过引起肿瘤细胞的凋亡或坏死而抑制了肿瘤细胞的生长率。RE2a/HAP作用细胞后与对照组相比, G1期细胞明显增多,S期细胞相应减少。
When a patient requires an internal fixation device or an artificial joint, bacterial infection after implant placement introduces a significantly rising complication due to the presence of foreign materials inside the body interfering with the host’s defense mechanism. Many studies have shown that delivering antibiotics to bone-implant interface is effective in reducing bacterial adhesion. Among these bacteria, Staphylococcus aureus is a common one in the myelopathy. Although the use of antibiotics has greatly reduced the incidence of infection diseases, it also led to the drug-resistant appearance of bacteria like Staphylococcus aureus (MRSA). In order to overcome the rapid development of this drug-resistance, some new reagents should be synthesized.
     8-hydroxyquinoline (8-HQ) is a well-known lipophilic metal chelator. Its copper chelate has been used as a fungicide in agriculture field and as the preserver for textiles, wood and paper
     In recent years, some new applications of rare earth elements have been found in many areas because of their unique chemical and physical properties. For instance, they have been used as catalysts, glass ceramics, fertilizers, pesticides and so on. The reason to impel us testing this agent is that some lanthanides have been used for clinical treatment as antibacterial agents in wound excision after burn and there was no obvious toxicity in a wide range of concentrations of them.
     J.Z. Ni reported that the rare earth-organism complexes can provide much more effective antibacterial activities than rare earth. Therefore, in the present report three complexes of RE(AC)(HQ)2·H2O (RE = La, Gd or Y) were prepared, which show increased antibacterial activities.
     Though a high concentration of antibiotic at the bone-implant interface should be essential to prevent these bacterial infections, however the concentration of the drug will be low in the bone tissue where a successful blood supply is lack. So it is now recognized that conventional bone treatment using systemic antibiotics is expensive and prone to complications. One management method of utilizing the surgical implantation of antibiotic polymethylmethacrylate (PMMA) bone cements for local delivery of antibiotics makes it possible to reach high local drug levels while maintaining low systemic levels and shows effect on Myelopathy [3,17]. However, PMMA has potential damage to human immune system and need to be taken out with second operation, so PMMA is not very perfect
     Hydroxyapatite(HAP) is a important inorganic component d in human bone and teeth,can form a direct chemical bond with surrounding bone tissue,In the same time, it can be degraded in vivo and supply the requirement of calcium for bone regeneration. therefore has been used extensively in orthopedics and bone regeneration. Nano particles tend to show some unique specialities, nano hydroxyapatite (nano-HAP), therefore has attracted much more attation in recent years.
     The objective of the present research is to synthesize a series of new components of nano-HAP with biological activities, characterizing their physical properties and researching their biological activities.
     1. First, the physical properties of these composites were characterized by means of scanning electron microscopy (SEM), infrared spectroscopy (IR) and X-ray diffraction (XRD). Nano-composite of Hydroxyapatite/Lysozyme was synthesized by chemical wet method in size of 100 nm.It was characterized by nitrongen gas adsorption method、IR、SEM and UV-Visible technique and compared with the dipping-adsorbing composite.The composite by wet method has much more content and activity of Lysozyme than the composite by dipping-adsorbing method.These results suggust the composite by wet method as a controlled released carrier of Lysozyme.
     2. Secondly, the antibacterial activity of three nanoscale organic-inorganic hybrid composites of rare-earth complexes of 8-Hydroxyquinoline (8-HQ) with formulae RE(AC)(HQ)2·H2O (RE=La, Gd or Y) and hydroxyapatite (HAP) were studied. These nanoscale hybrid composites were directly prepared by the wet methods. While the physical properties of these composites were characterized by means of scanning electron microscopy (SEM), infrared spectroscopy (IR) and X-ray diffraction (XRD), the antibacterial activities were tested by minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) methods.
     The results showed, all three composites are less than 50-60nm in size and exhibit stronger bacteriostatic activities against bacteria of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Their antibacterial activities were then tested and all showed higher antibacterial activities against S. aureus than against E. coli. Among these three composites, at a high concentration (> 600μg/mL) all three composites did not show bacteriostatic activities;at a middle concentration (in the range of 169μg/mL to 600μg/mL) they showed obviously bacteriostatic activities;at a low concentration (in the range of 26μg/mL to 169μg/mL) they can almost kill all the bacteria. La-HQ/HAP and Gd-HQ/HAP show stronger antibacterial efficacy than Y-HQ/HAP with the antibacterial activity of La-HQ/HAP comparable to that of ampicillin/HAP. These newly synthesized composites will be promising materials in the treatment of diseases for the musculoskeletal system with their enhanced antibacterial activity and good biocompatibility.
     3. Nano-composite of RE/HAP was synthesized by two method:chemical wet method and hydrothermal synthesis. While the physical properties of these composites were characterized by means of scanning electron microscopy (SEM), infrared spectroscopy (IR) and X-ray diffraction (XRD).The cytotoxic effects on Hela by RE/HAP were determined by the methods of methy1 thiazoly1 tetrazolium(MTT), the difference of cell cycle induced by RE/HAP were investigated by flow cytometry (FCM).
     The results of MTT showed that the inhibition of the pure HAP is very low and was by 5.67 % at a dose of 500 ug/mL. At the same dose, the inhibition of RE2a/HAP were obvious, for example the inhibition of Y2a/HAP、Gd2a/HAP、La2a/HAP were separately 80.31 %、55.43 % and 44.93 %。Comparing with HAP, the effects of RE2a/HAP on Hela cell cycle by flow cytometry the Hela cell numbers in G1 phase were increased obviously and the cell numbers in G1 phase were decreased . The sequence of the effect on Hela cell cycle is La_(2a)/HAP>Y_(2a)/HAP>Gd_(2a)/HAP.
引文
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