骨植入用新型可降解镁合金材料设计及生物医学功能研究

发布时间：2018-08-31 10:06

【摘要】：镁合金以其良好的生物相容性、与骨组织匹配的力学性能以及可以在人体内降解吸收等特点,成为一类极具临床应用前景的新型生物可降解(吸收)骨植入材料。目前可降解镁合金在骨科领域应用的研究主要集中在镁合金的力学性能、降解行为以及生物相容性等方面,然而对于镁合金的临床医学功能研究及其相应的材料设计却鲜有报道。本文的研究目的是针对某些具有特定生物医学功能的人体微量金属元素,将其作为合金化元素加入到镁中,利用镁合金在生理环境中降解形成的碱性环境以及持续释放合金元素离子等特点,赋予新型可降解镁合金促成骨、促血管化和抗细菌感染等多重生物医学功能,并确保其生物安全性和提供植入后的力学支撑作用,为发展新型可降解镁合金及临床应用提供理论支持和实验证明。为此,本文对两种新型可降解镁合金(镁锶合金、镁铜合金)开展了系统而深入的研究,获得了许多有意义的研究结果。本文首先在镁基体中添加具有促进骨骼发育和类骨质形成作用的锶(Sr)元素,设计并制备了不同 Sr 含量的 Mg-Sr 二元合金(Mg-0.25Sr,Mg-1.OSr,Mg-1.5Sr,Mg-2.5Sr)。通过研究Sr含量变化对铸态、均匀化退火态和挤压态镁锶合金的微观组织、力学性能和耐腐蚀性能的影响,表明镁锶合金的微观组织由α-Mg基体和Mg17Sr2第二相组成,Sr在镁合金基体中固溶度较小,主要以第二相的形式存在于材料中。铸态镁锶合金中一部分第二相弥散分布在晶粒内部,其余沿枝(晶)界分布。镁锶合金经过挤压变形之后,晶粒明显细化,第二相尺寸减小。与铸态镁锶合金相比,挤压态镁锶合金的力学性能明显提高,抗压强度与人体皮质骨相匹配,且随合金中锶含量的升高先增加后降低(Mg-1.5Sr达到最大值)。铸态镁锶合金随着锶含量的增加,耐腐蚀性先升高后降低,Mg-1.5Sr的腐蚀速率最低。挤压态镁锶合金耐腐蚀性与铸态相比明显提高。选择力学性能和耐腐蚀性能等综合性能优异的挤压态镁锶合金作为研究对象,通过溶血实验、细胞毒性实验、细胞骨架及活死细胞染色实验、碱性磷酸酶活性检测实验、细胞外基质矿化及胶原蛋白检测实验、内皮细胞迁移实验、体外三维血管化形成实验、大鼠体外血管环实验、成骨和成血管化相关基因表达检测实验、抗菌实验等,系统全面地对挤压态镁锶合金的生物安全性和可能具备的特定生物医学功能进行了探索研究。研究结果表明,挤压态镁锶合金不会引起溶血现象,而且满足外科植入材料的细胞毒性水平要求。在生物功能化方面,挤压态镁锶合金浸提液对MC3T3-E1细胞的粘附、增殖和分化有明显的促进作用,其中Mg-1.0Sr和Mg-1.5Sr浸提液的促进作用尤为明显,而且能够调控成骨相关基因的表达。与此同时,挤压态镁锶合金浸提液还能够促进HUVECs细胞的增殖和迁移以及毛细血管网状结构的形成,能够调控血管化相关基因的表达。此外,挤压态镁锶合金在生理环境中降解产生的高碱性对骨科常见的金黄色葡萄球菌具有强烈的杀灭作用。上述研究结果表明,挤压态镁锶合金具有良好的促成骨、促血管化以及抗细菌感染等生物医学功能。由于体液的缓冲作用会减弱镁合金降解产生的碱性环境,使植入物周围组织环境的酸碱度逐渐趋向于人体正常的中性水平,导致碱性环境抗菌的作用减弱或消失。因此,本文将具有强烈抗菌作用、对人体生物功能有益的铜(Cu)元素添加到镁中,设计并制备不同Cu含量的镁铜合金(Mg-0.03Cu、Mg-0.19Cu、Mg-0.57Cu),希望能够在碱性抗菌作用的基础上实现铜离子的协同抗菌效果。通过研究铜含量变化对铸态镁铜合金微观组织、力学性能和耐腐蚀性能的影响,表明镁铜合金的微观组织由α-Mg基体和Mg2Cu第二相组成。随着合金中铜含量的增加,铸态镁铜合金的晶粒尺寸变化不大,析出的第二相含量增加,弥散强化作用增强,使铸态镁铜合金力学性能在植入初期能够满足骨植入材料的使用要求。铸态镁铜合金在模拟体液中会发生腐蚀降解,降解速率高于铸态纯镁。由于第二相造成的电偶腐蚀作用,铸态镁铜合金的耐腐蚀性随着铜含量的升高而降低。铸态镁铜合金在降解过程中镁离子和铜离子不断溶出,溶出速率在人体能够承受的范围之内,因此不会影响到生物安全性。溶血实验和细胞毒性实验结果表明,镁铜合金具有良好的血液相容性和细胞相容性。抗菌实验结果表明,铸态镁铜合金对金黄色葡萄球菌具有碱性抗菌和铜离子抗菌相结合的双重抗菌作用,表现出优异的抗细菌感染功能。此外,当合金中铜的加入量较低时,镁铜合金还兼具一定的促成骨和促血管化功能。
[Abstract]:Magnesium alloys have become a new kind of biodegradable (absorbable) bone implant materials because of their good biocompatibility, matching mechanical properties with bone tissue and biodegradable absorption in human body. Degradation behavior and biocompatibility of magnesium alloys have not been reported yet. The purpose of this study is to add trace metal elements as alloying elements into magnesium and use magnesium alloys in physiological rings for specific biomedical functions. The alkaline environment formed by environmental degradation and the continuous release of alloying elements ions endow the new degradable magnesium alloys with multiple biomedical functions, such as promoting bone formation, promoting vascularization and resisting bacterial infection, and ensure their biological safety and provide mechanical support after implantation, which will provide a new type of degradable magnesium alloys and clinical application. Theoretical support and experimental results show that two kinds of new degradable magnesium alloys (Mg-Sr alloy, Mg-Cu alloy) have been systematically and thoroughly studied in this paper, and many significant results have been obtained. Firstly, strontium (Sr) elements which can promote bone development and osteogenesis have been added to magnesium matrix, and different S-like elements have been designed and prepared. Mg-Sr binary alloys with R content (Mg-0.25Sr, Mg-1.OSr, Mg-1.5Sr, Mg-2.5Sr). The effects of Sr content on microstructure, mechanical properties and corrosion resistance of as-cast, homogenized annealed and extruded Mg-Sr alloys were studied. The results show that the microstructure of Mg-Sr alloys consists of a-Mg matrix and Mg Sr 2 second phase, and Sr is in Mg matrix. Some of the second phases in as-cast Mg-Sr alloys are dispersed in the grains and the others are distributed along the dendritic (grain) boundaries. After extrusion, the grains of Mg-Sr alloys are obviously refined and the size of the second phase decreases. Compared with as-cast Mg-Sr alloys, the mechanical properties of extruded Mg-Sr alloys are better than those of as-cast Mg-Sr alloys. The compressive strength of as-cast Mg-Sr alloy increases firstly and then decreases with the increase of Sr content in the alloy (Mg-1.5Sr reaches the maximum). The corrosion resistance of as-cast Mg-Sr alloy increases first and then decreases with the increase of Sr content, and the corrosion rate of Mg-1.5Sr is the lowest. The extruded magnesium-strontium alloy with excellent mechanical properties and corrosion resistance was selected as the research object. The hemolysis test, cytotoxicity test, cytoskeleton and dying cell staining test, alkaline phosphatase activity test, extracellular matrix mineralization and collagen detection test, endothelial cell migration test, in vitro three-dimensional blood test were carried out. The bio-safety and specific biomedical functions of extruded magnesium-strontium alloys have been systematically and comprehensively studied by tube formation test, rat vascular ring test in vitro, gene expression test related to osteogenesis and vascularization, and antibacterial test. The results show that extruded magnesium-strontium alloys do not cause hemolysis. In the aspect of biological function, extruded magnesium strontium alloy extract can obviously promote the adhesion, proliferation and differentiation of MC3T3-E1 cells, especially the promotion of Mg-1.0Sr and Mg-1.5Sr extracts, and can regulate the expression of osteogenesis-related genes. At the same time, extruded magnesium-strontium alloy extract can promote the proliferation and migration of HUVECs cells and the formation of capillary network structure, which can regulate the expression of angiogenesis-related genes. In addition, the high alkalinity produced by extruded magnesium-strontium alloy degradation in physiological environment has a strong killing effect on orthopedic Staphylococcus aureus. These results indicate that extruded magnesium-strontium alloys have good biomedical functions such as promoting bone formation, promoting vascularization and resisting bacterial infection. The alkaline environment produced by the degradation of magnesium alloys will be weakened due to the buffering effect of body fluid, and the acidity and alkalinity of the tissues around the implants will gradually tend to the normal neutral level of human body, resulting in alkalinity. Therefore, in this paper, copper (Cu) which has strong antibacterial effect and is beneficial to human biological function is added to magnesium to design and prepare magnesium-copper alloys (Mg-0.03Cu, Mg-0.19Cu, Mg-0.57Cu) with different Cu contents, hoping to achieve the synergistic antibacterial effect of copper ions on the basis of basic antibacterial effect. The effect of copper content on microstructure, mechanical properties and corrosion resistance of as-cast Mg-Cu alloy was studied. The results show that the microstructure of as-cast Mg-Cu alloy consists of a-Mg matrix and Mg2Cu secondary phase. The mechanical properties of as-cast Mg-Cu alloy can meet the requirements of bone implant materials at the early stage of implantation by strengthening. As-cast Mg-Cu alloy will undergo corrosion degradation in simulated body fluid, the degradation rate is higher than that of as-cast pure Mg. Due to galvanic corrosion caused by the second phase, the corrosion resistance of as-cast Mg-Cu alloy decreases with the increase of Cu content. The results of hemolysis test and cytotoxicity test show that Mg-Cu alloy has good blood compatibility and cell compatibility. The results of antibacterial test show that as-cast Mg-Cu alloy has good blood compatibility and cell compatibility. Copper alloys have a dual antibacterial effect on Staphylococcus aureus, which combines basic antibacterial and copper ion antibacterial, and exhibit excellent anti-bacterial infective function.
【学位授予单位】：南京理工大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：TG146.22;R318.08

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