骨植入用新型可降解鎂合金材料設(shè)計(jì)及生物醫(yī)學(xué)功能研究
發(fā)布時(shí)間：2018-08-31 10:06
【摘要】：鎂合金以其良好的生物相容性、與骨組織匹配的力學(xué)性能以及可以在人體內(nèi)降解吸收等特點(diǎn),成為一類極具臨床應(yīng)用前景的新型生物可降解(吸收)骨植入材料。目前可降解鎂合金在骨科領(lǐng)域應(yīng)用的研究主要集中在鎂合金的力學(xué)性能、降解行為以及生物相容性等方面,然而對于鎂合金的臨床醫(yī)學(xué)功能研究及其相應(yīng)的材料設(shè)計(jì)卻鮮有報(bào)道。本文的研究目的是針對某些具有特定生物醫(yī)學(xué)功能的人體微量金屬元素,將其作為合金化元素加入到鎂中,利用鎂合金在生理環(huán)境中降解形成的堿性環(huán)境以及持續(xù)釋放合金元素離子等特點(diǎn),賦予新型可降解鎂合金促成骨、促血管化和抗細(xì)菌感染等多重生物醫(yī)學(xué)功能,并確保其生物安全性和提供植入后的力學(xué)支撐作用,為發(fā)展新型可降解鎂合金及臨床應(yīng)用提供理論支持和實(shí)驗(yàn)證明。為此,本文對兩種新型可降解鎂合金(鎂鍶合金、鎂銅合金)開展了系統(tǒng)而深入的研究,獲得了許多有意義的研究結(jié)果。本文首先在鎂基體中添加具有促進(jìn)骨骼發(fā)育和類骨質(zhì)形成作用的鍶(Sr)元素,設(shè)計(jì)并制備了不同 Sr 含量的 Mg-Sr 二元合金(Mg-0.25Sr,Mg-1.OSr,Mg-1.5Sr,Mg-2.5Sr)。通過研究Sr含量變化對鑄態(tài)、均勻化退火態(tài)和擠壓態(tài)鎂鍶合金的微觀組織、力學(xué)性能和耐腐蝕性能的影響,表明鎂鍶合金的微觀組織由α-Mg基體和Mg17Sr2第二相組成,Sr在鎂合金基體中固溶度較小,主要以第二相的形式存在于材料中。鑄態(tài)鎂鍶合金中一部分第二相彌散分布在晶粒內(nèi)部,其余沿枝(晶)界分布。鎂鍶合金經(jīng)過擠壓變形之后,晶粒明顯細(xì)化,第二相尺寸減小。與鑄態(tài)鎂鍶合金相比,擠壓態(tài)鎂鍶合金的力學(xué)性能明顯提高,抗壓強(qiáng)度與人體皮質(zhì)骨相匹配,且隨合金中鍶含量的升高先增加后降低(Mg-1.5Sr達(dá)到最大值)。鑄態(tài)鎂鍶合金隨著鍶含量的增加,耐腐蝕性先升高后降低,Mg-1.5Sr的腐蝕速率最低。擠壓態(tài)鎂鍶合金耐腐蝕性與鑄態(tài)相比明顯提高。選擇力學(xué)性能和耐腐蝕性能等綜合性能優(yōu)異的擠壓態(tài)鎂鍶合金作為研究對象,通過溶血實(shí)驗(yàn)、細(xì)胞毒性實(shí)驗(yàn)、細(xì)胞骨架及活死細(xì)胞染色實(shí)驗(yàn)、堿性磷酸酶活性檢測實(shí)驗(yàn)、細(xì)胞外基質(zhì)礦化及膠原蛋白檢測實(shí)驗(yàn)、內(nèi)皮細(xì)胞遷移實(shí)驗(yàn)、體外三維血管化形成實(shí)驗(yàn)、大鼠體外血管環(huán)實(shí)驗(yàn)、成骨和成血管化相關(guān)基因表達(dá)檢測實(shí)驗(yàn)、抗菌實(shí)驗(yàn)等,系統(tǒng)全面地對擠壓態(tài)鎂鍶合金的生物安全性和可能具備的特定生物醫(yī)學(xué)功能進(jìn)行了探索研究。研究結(jié)果表明,擠壓態(tài)鎂鍶合金不會引起溶血現(xiàn)象,而且滿足外科植入材料的細(xì)胞毒性水平要求。在生物功能化方面,擠壓態(tài)鎂鍶合金浸提液對MC3T3-E1細(xì)胞的粘附、增殖和分化有明顯的促進(jìn)作用,其中Mg-1.0Sr和Mg-1.5Sr浸提液的促進(jìn)作用尤為明顯,而且能夠調(diào)控成骨相關(guān)基因的表達(dá)。與此同時(shí),擠壓態(tài)鎂鍶合金浸提液還能夠促進(jìn)HUVECs細(xì)胞的增殖和遷移以及毛細(xì)血管網(wǎng)狀結(jié)構(gòu)的形成,能夠調(diào)控血管化相關(guān)基因的表達(dá)。此外,擠壓態(tài)鎂鍶合金在生理環(huán)境中降解產(chǎn)生的高堿性對骨科常見的金黃色葡萄球菌具有強(qiáng)烈的殺滅作用。上述研究結(jié)果表明,擠壓態(tài)鎂鍶合金具有良好的促成骨、促血管化以及抗細(xì)菌感染等生物醫(yī)學(xué)功能。由于體液的緩沖作用會減弱鎂合金降解產(chǎn)生的堿性環(huán)境,使植入物周圍組織環(huán)境的酸堿度逐漸趨向于人體正常的中性水平,導(dǎo)致堿性環(huán)境抗菌的作用減弱或消失。因此,本文將具有強(qiáng)烈抗菌作用、對人體生物功能有益的銅(Cu)元素添加到鎂中,設(shè)計(jì)并制備不同Cu含量的鎂銅合金(Mg-0.03Cu、Mg-0.19Cu、Mg-0.57Cu),希望能夠在堿性抗菌作用的基礎(chǔ)上實(shí)現(xiàn)銅離子的協(xié)同抗菌效果。通過研究銅含量變化對鑄態(tài)鎂銅合金微觀組織、力學(xué)性能和耐腐蝕性能的影響,表明鎂銅合金的微觀組織由α-Mg基體和Mg2Cu第二相組成。隨著合金中銅含量的增加,鑄態(tài)鎂銅合金的晶粒尺寸變化不大,析出的第二相含量增加,彌散強(qiáng)化作用增強(qiáng),使鑄態(tài)鎂銅合金力學(xué)性能在植入初期能夠滿足骨植入材料的使用要求。鑄態(tài)鎂銅合金在模擬體液中會發(fā)生腐蝕降解,降解速率高于鑄態(tài)純鎂。由于第二相造成的電偶腐蝕作用,鑄態(tài)鎂銅合金的耐腐蝕性隨著銅含量的升高而降低。鑄態(tài)鎂銅合金在降解過程中鎂離子和銅離子不斷溶出,溶出速率在人體能夠承受的范圍之內(nèi),因此不會影響到生物安全性。溶血實(shí)驗(yàn)和細(xì)胞毒性實(shí)驗(yàn)結(jié)果表明,鎂銅合金具有良好的血液相容性和細(xì)胞相容性�？咕鷮�(shí)驗(yàn)結(jié)果表明,鑄態(tài)鎂銅合金對金黃色葡萄球菌具有堿性抗菌和銅離子抗菌相結(jié)合的雙重抗菌作用,表現(xiàn)出優(yōu)異的抗細(xì)菌感染功能。此外,當(dāng)合金中銅的加入量較低時(shí),鎂銅合金還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.
【學(xué)位授予單位】：南京理工大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：TG146.22;R318.08
[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.
【學(xué)位授予單位】：南京理工大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：TG146.22;R318.08
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