一维功能化羟基磷灰石纳米材料的制备及其在生物医学领域应用的基础研究

发布时间：2018-07-29 07:57

【摘要】：纳米羟基磷灰石(HAp)由于其化学成分及结构均与人体骨骼中的无机成分高度相似,在生物材料的研究领域中得到了广泛的关注与研究。纳米HAp具有优异的生物相容性、生物活性及骨传导性,因此,被临床应用于硬组织替代与修复方面。目前,人工合成的具有各种形貌与表面性质的纳米HAp材料,也被研究用在药物传递系统中。这主要因为其较大的比表面积,能够吸附更多的药物。将其作为载体负载药物分子用于治疗,可以增加局部药物浓度,延长作用时间并且降低药物对组织器官的损害。其次,纳米HAp在体内具有可降解性,而降解后的钙离子、磷酸根离子是体内天然存在的,这也是纳米HAp作为药物载体的优势之一。基于纳米HAp材料在生物医学领域中的潜在应用价值,本论文采用了不同方法制备了不同形貌的光功能化的一维HAp纳米材料,在药物载体及体外成像等方面进行了一系列探索性的基础研究。采用静电纺丝方法合成了具有多孔结构的Na(Y/Gd)F4:Yb~(3+),Er~(3+)(UCNPs)光/磁功能化的HAp纳米复合纤维(UCNPs@HAp)。上转换纳米颗粒Na(Y/Gd)F4:Yb~(3+),Er~(3+)修饰HAp后,HAp复合纤维在980 nm激光激发下具有明亮的上转换绿光发射,同时Gd~(3+)的引入使得HAp复合纤维具有顺磁性,因此UCNPs@HAp纳米复合纤维可作为生物探针用于细胞成像,我们对材料进行了体外上转换荧光(UCL)成像和T1加权核磁共振(MRI)成像以及相关的细胞吞噬和毒性实验。纳米复合纤维具有的多孔结构可作为药物载体担载药物,以吲哚美辛作为模型药物,考察了其药物吸附/释放性质及体外抗炎效果。通过溶剂热法制备了几种稀土离子Yb~(3+)/Er~(3+)/Gd~(3+)共掺杂的HAp纳米棒。通过一定比例的稀土离子取代HAp中的钙离子,得到在980 nm激光激发下具有上转换绿光发射的HAp:Ln~(3+)纳米材料。而这种上转换发光能够作为一种性能优异的荧光探针,可用于细胞的UCL成像。同时掺杂的Gd~(3+)离子,使HAp纳米棒具有T1 MRI成像效果。通过MTT实验,证实了所合成的HAp纳米棒具有较低的细胞毒性;由于HAp表面对蛋白质具有较强的亲和力,并将HAp:Ln~(3+)纳米棒作为骨形态发生蛋白-2(BMP-2)的载体,并研究了其促进小鼠源成骨前体细胞(MC 3T3-E1)分化的能力,为其作为蛋白载体应用于骨修复方面的研究提供有利依据。对所合成的不同形貌一维羟基磷灰石纳米材料的体内生物相容性进行了考察与比较,主要从材料的小鼠体内生物分布、血生化分析和长期毒性三个方面评价。结果表明材料通过小鼠尾静脉注射后,从HAp纳米材料在小鼠体内分布的变化可以看出,随着时间的增加,纳米材料均能够逐渐从小鼠体内排出;并且通过尾注材料后小鼠的血液生化分析、组织切片和体重结果可以得出,在此注射剂量条件下两种不同形貌的HAp纳米材料对小鼠没有明显的毒性。一维纳米HAp作为药物/蛋白载体材料,在药物控释、疾病诊疗、骨修复等医学领域表现出了潜在的应用价值。
[Abstract]:Nano hydroxyapatite (HAp) has been widely concerned and studied in the field of biomaterials because of its high similar chemical composition and structure with inorganic components in human skeleton. Nano HAp has excellent biocompatibility, bioactivity and bone conductivity. Because of this, it is clinically applied to hard tissue replacement and repair. Before, the synthetic nano HAp materials with various morphologies and surface properties have also been studied in the drug delivery system. This is mainly because of its larger specific surface area, which can adsorb more drugs. Using it as a carrier loaded drug molecule for treatment, it can increase the concentration of local drugs, prolong the time of action and reduce the drug pair. The damage of tissue and organ. Secondly, nano HAp has biodegradability in vivo, and after degradation of calcium ions, phosphate ion is natural in the body. This is one of the advantages of nano HAp as a drug carrier. Based on the potential application value of nano HAp in the biomedical field, different methods have been used to prepare different forms. The photo functionalized one-dimensional HAp nanomaterials have carried out a series of exploratory basic research in drug carrier and in vitro imaging. The electrostatic spinning method has been used to synthesize the porous structure of Na (Y/Gd) F4:Yb~ (3+), Er~ (3+) (UCNPs) light / magnetically functionalized HAp nanocomposite fiber (UCNPs@HAp). (3+), after the Er~ (3+) modification of HAp, the HAp composite fiber has a bright upconversion green light emission under 980 nm laser excitation, while Gd~ (3+) is introduced to make the HAp composite fiber paramagnetic, so UCNPs@HAp nanocomposite fibers can be used as a biological probe for cell imaging. We have carried out the upconversion fluorescence (UCL) imaging and T1 addition of the materials in vitro. Nuclear magnetic resonance (MRI) imaging and related cell phagocytosis and toxicity experiments. The porous structure of nanocomposite fibers can be used as drug carrier drug. Indomethacin is used as a model drug. The properties of its drug adsorption / release and in vitro anti-inflammatory effects are investigated. Several rare earth ions Yb~ (3+) /Er~ (3+) /Gd~ are prepared by solvent thermal method. (3+) Co doped HAp nanorods. By replacing calcium ions in HAp with a certain proportion of rare earth ions, the HAp:Ln~ (3+) nanomaterials with upconversion green emission under 980 nm laser excitation are obtained. The upconversion luminescence can be used as a fluorescent probe with excellent performance, and can be used for UCL imaging of cells. The Gd~ (3+) ions are also doped. The HAp nanorods have the effect of T1 MRI imaging. Through the MTT experiment, it is proved that the synthesized HAp nanorods have lower cytotoxicity; the HAp:Ln~ (3+) nanorods are used as the carrier of -2 (BMP-2) for the bone morphogenetic protein because of the strong affinity to the protein on the surface of the HAp and the promoter of the precursor cells of the mice (MC 3T3-E1) is also studied. The differentiation ability provides a favorable basis for its application in bone repair as a protein carrier. The biocompatibility of the synthesized one-dimensional hydroxyapatite nanomaterials in vivo is investigated and compared, mainly from the three aspects of biological distribution, blood biochemical analysis and long-term toxicity in the mice. The results showed that after the injection of the material through the tail vein of mice, the changes in the distribution of HAp nanomaterials in mice can be seen, as the time increases, the nanomaterials can be gradually discharged from the mice, and the blood biochemical analysis, tissue section and body weight of the mice can be obtained after the tailing material, and the dosage conditions are given here. The next two different morphologies of HAp nanomaterials have no obvious toxicity to mice. One dimensional nano HAp, as a drug / protein carrier material, has shown potential application value in medicine controlled release, disease diagnosis and treatment, bone repair and other medical fields.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R318.08

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