生物可降解镁合金的制备、表征及体外生物活性评价
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摘要
人们在日常生活中，经常会因为某些意外情况而发生不同程度、不同类型的骨折，以及各种疾病造成的局部或大范围的骨缺损。造成骨缺损的原因有很多，可能是长时间的废用性萎缩，也可能是肿瘤或者外伤，无论哪种原因都使得种植体无法获得良好的初期稳定性，这时就需要植骨来解决这一难题，无论哪种植骨材料应用后都需要骨固定材料将其固定于牙槽骨上，并且这种骨固定材料尤其适用于作为骨折时的内固定材料。目前，临床上常用的骨移植手术固定材料及植骨材料主要有不锈钢、钛合金、可吸收性高分子材料及人工合成材料等，但是，不锈钢和钛合金的弹性模量与骨皮质差异较大，易引起应力遮挡效应，而且，作为植骨材料，不锈钢、钛合金需要二次手术取出，这样就增加了患者的痛苦和费用；可吸收高分子材料如聚乳酸-聚羟基乙酸(PLGA)、聚甲基丙烯酸甲酯(PMMA)等已经应用于临床，但仍存在不足：生物活性较低，力学性能较差，可引起无菌性炎症及周围组织的纤维化等；人工合成材料有PRF、组织工程支架材料等。以上材料各有优缺点。因此，如何合成一种具有良好生物相容性，一定力学性能，可控降解性能的生物材料就成为医学界一项意义重大的任务。
近年来，镁（Mg）及其合金作为一种金属基复合生物材料引起了人们广泛的关注。镁的化学性质极其活泼，在动物体内可短时间降解，镁与其他金属植入物相比，其弹性模量和力学性能更接近皮质骨，这样的物理特性使镁及其合金作为植骨及固定材料应用时能够有效地避免由植入材料引起的应力遮挡效应。因此，镁合金有望成为理想的新型可降解生物医用金属材料。但是，镁合金最大的缺点就是降解过快、产生大量氢气以及由此引起降解环境的碱性化。因此，如何改善镁合金的降解速度，使其与体内成骨的速度相匹配成为现在研究的重点所在。
本研究从体外实验的角度探讨了富含Zn、HA元素的镁合金材料的机械性能和体外降解能力，以及对小鼠前成骨样细胞MC3T3-E1的增殖、黏附和分化的影响，Real time PCR探讨了镁合金材料对成骨相关基因的影响，Western Blot探讨了镁合金材料对RUNX2、FAK、p-FAK及整合素蛋白表达的影响，为其日后临床研究提供理论依据。
通过粉末冶金法及热挤压法制备Mg-4Zn-3HA合金材料，应用扫描电镜表征材料的表面性能，通过压缩试验检测材料的机械性能，浸泡在模拟体液中，持续28天检测材料的降解及由此引起的pH值的变化，通过扫描电镜及能谱定量分析材料降解后的表面性能，及X射线衍射分析降解产物。结果显示：Mg-4Zn-3HA合金的内部疏松多孔，并且它的机械性能与其它植入材料相比更接近于天然骨，使得Mg-4Zn-3HA合金相较于其他金属更加的适合做植入材料。pH值在28天的降解时间内先升高后降低，最后稳定在8.3左右。其腐蚀率在开始的时候最高，随后降低，最后小幅度升高后稳定。降解产物X射线衍射结果分析显示较强的Mg(OH)2衍射峰，还有一定数量其它峰值，例如：HA和Mg-Zn化合物。材料降解后扫描电镜及能谱分析显示材料表面出现大量的裂痕和沉淀，降解产物表面粗糙多孔。能谱分析的结果显示材料的表面腐蚀产物中Mg、Ca、P和O含量丰富。
根据ISO10993-5，制备材料的浸提液，与MC3T3-E1细胞共培养1d、2d、3d，通过CCK-8实验、流式细胞周期实验和碱性磷酸酶（ALP）实验检测细胞毒性、增殖、以及成骨分化能力，通过扫描电镜观察细胞与材料共培养，检测早期细胞的黏附能力。结果显示：三种不同温度处理制备的镁合金都是无毒性的，处理温度为300℃的镁合金与另外两组相比较，有着更好的生物相容性。不同浓度浸提液（100%、50%、10%）对MC3T3-E1细胞的增殖结果表明浓度为50%浸提液组的增殖能力更明显。流式细胞周期的检测结果也证实了镁合金对细胞增殖的促进作用。通过扫描电镜观察，细胞在材料表面没有明显的细胞形态的改变，细胞伸展良好，还可以看到细胞的丝状伪足有的已经伸展到周围的细胞上。通过碱性磷酸酶实验可看出镁合金材料良好的促成骨能力，其中250℃和300℃镁合金组细胞内ALP活力显著高于对照组，300℃处理组差异最明显。
在分子生物学实验中，Real time PCR实验结果显示：BSP的相对表达量在第3天和第7天显著高于对照组，第14天低于对照组；OC的相对表达量在检测时间点低于对照组，但是呈现增长趋势；OPN的相对表达量在第3天显著高于对照组，在第7天和第14天与对照组无显著性差异。Western Blot实验结果显示：RUNX2蛋白的相对表达量在第3天和第14天高于对照组，其中第14天有显著性差异，在第7天，略低于对照组；FAK蛋白的相对表达量在第3天低于对照组，但是在第7天和第14天显著高于对照组；p-FAK蛋白的相对表达量在第3天和第7天显著高于对照组，第14天，略低于对照组；整合素蛋白的相对表达量在三个检测时间点均低于对照组，但是在第7天并无显著性差异。
综上所述，Mg-4Zn-3HA合金的抗腐蚀性能有所提高，在促进细胞增殖和早期成骨分化方面表现良好，并具有良好的生物相容性。本实验为日后镁合金的临床应用提供了理论基础，我们有理由相信Mg-4Zn-3HA合金可以成为理想的医用生物可降解植入材料。
In daily life, because of some unexpected circumstances, people often sufferfrom different kinds of bone fractures, and bone defects. The reasons for bone defectscould be prolonged disuse atrophy, cancer or trauma. No matter what reason makesimplants unable to obtain good initial stability, bone graft are aimed to solve thisproblem. Any bone materials should be fixed on the alveolar bone after theapplication, and should be suitable for internal fixation material of bone fracture. Atpresent, the commonly used clinical bone transplant materials and bone graftmaterials are mainly stainless steel, titanium alloy and absorbable polymer materials,etc. However, elastic modulus of stainless steel and titanium is largely different fromthat of the bone cortex, which could easily cause stress shelter effect. And, as a bonegraft material, stainless steel, and titanium alloy need a second operation, whichincreases the patient's pain and costs. Absorbable polymer materials such aspoly(lactic-co-glycolic) acid (PLGA), poly (methyl methacrylate)(PMMA) has beenused in clinical, but there are still some shortcomings, such as bad biological activity,and poor mechanical performance, which can cause aseptic inflammation and fibrosisof the surrounding tissue. There are sone synthetic materials such as PRF, tissueengineering scaffold material, and so on. The materials above have their advantagesand disadvantages. Therefore, how to synthesize a kind of biological material withgood biocompatibility, certain mechanical properties, controllable degradationperformance has become a focus in the medical community.
In recent years, magnesium and its alloys as a kind of metal matrix compositebiomaterial has attracted much attention. Magnesium is a chemically active metal,which can degradate within a short period in animal. Compared with other metal,magnesium’s elastic modulus and mechanical property is closer to the cortical bone.These physical properties make magnesium and its alloys possible to avoid stress shelter effect as bone graft and fixed material. As a result, the magnesium alloy isexpected to become the ideal new degradable biomedical metal materials. However,the biggest drawback of magnesium alloy is it degrades too fast, and produces a largeamount of hydrogen gas, which causes alkalization of the surrounding environment.Therefore, how to improve the degradation rate of magnesium alloys, and make itmatch that of osteogenesis in vivo now becomes one of the research focuses.
This research investigated mechanical properties and the degradation ability ofmagnesium alloy material rich in Zn and HA in vitro, the effect of the alloy onpreosteoblasts (mice MC3T3-E1) proliferation, adhesion and differentiation. Thisexperiment also studied the influence of magnesium alloy material on the expressionof osteogenesis related genes by Real time PCR, and tested is effect on the expressionof RUNX2, FAK, p-FAK and integrin protein by Western Blot, in order to providetheoretical basis for its clinical studies in the future.
Mg-4Zn-3HA alloy was prepared by powder metallurgy and hot extrusionmethod. Scanning electron microscopy (SEM) was applied to study thecharacterization of the surface of the material. Compression test was used to testmechanical properties of the material. The material had been immersed in simulatedbody fluid, for28days to detect the degradation of it and the change of pH value inthe fluid. Scanning electron microscopy (SEM) and energy spectrum quantitativeanalysis were utilized analyze material surface after degradation. X-ray diffraction(XRD) was used to analye the degradation products. Results showed that theMg-4Zn-3HA was porous, and its mechanical properties is closer to natural bonecompared with other implant materials, making Mg-4Zn-3HA alloy more suitable forimplant materials. During the28days pH values increased first and then went down,finally stabilized at about8.3.The corrosion rates were at the peak in the beginning,then decreased, and remained, stable with a also rise. The results of X-ray diffractionanalysis of degradation products showed a strong diffraction peaks of the Mg(OH)2,there were a number of other peaks, such as HA and Mg-Zn compounds. Materialdegradation after the scanning electron microscopy (SEM) and energy spectrum analysis showed that the material surface appear a lot of cracks and precipitation,degradation product rough surface porous. Spectrum analysis results showed that thesurface of the material corrosion products were rich in Mg, Ca, P and O.
According to the ISO10993-5, leaching solution of material was prepared, andco-cultured with MC3T3-E1for1d,2d,3d, CCK-8cell cycle analisis and alkalinephosphatase detection were used to test cell toxicity, proliferation, and osteogenesisability. Scanning electron microscope was used to observe cells co-cultured withmaterial and to detect cell adhesion ability. Results showed that three differenttemperature treatments of magnesium alloy were non-toxic, processing temperature of300℃of magnesium alloy, have better biocompatibility compared with other twogroups. Leaching solution with different concentrations (100%,50%,10%) haddifferent effects on MC3T3-E1proliferation. The results showed that theconcentration of50%group had the most significant effect on the proliferation abilityof the cells. Flow cytometry cycle test results also confirmed that the magnesiumalloy could promoted cell proliferation. Scanning electron microscope found that thecells in the material surface had no obvious changes in cell morphology, cell stretchwas good, and filiform pseudopodia of cells had been spread to the surrounding cells.Alkaline phosphatase experiment showed the magnesium alloy materials had goodcapability for osteogenesis.250℃and300℃magnesium alloy groups’ intracellularALP activity was significantly higher than that of control group, and300℃treatmentgroup’s difference was most obvious.
In molecular biology experiments, Real time PCR experiment results showedthat the relative expression of BSP in3and7days was significantly higher than thecontrol group,14days was lower than the control group. The relative expression ofOC was lower than the control group at testing time points, but there was a trend ofgrowth. Relative expression of OPN was significantly higher than control group onday3. On day7and14there was no significant difference with control group.Western Blot experiments results showed that the relative expression of RUNX2protein on day3and day14was higher than the control group, and on day14there was a significant difference. On day7, it was slightly lower than the control group;Relative expression of FAK protein was lower than the control group on day3, but onday7and day14was significantly higher than control group; Relative expression ofp-FAK protein awas significantly higher on day3and day7, but on day14, it wasslightly lower than the control group; Relative expression of integrin protein in threetest points were lower than the control group, but there was no significant differenceon day7.
To sum up, Mg-4Zn-3HA alloy’s corrosion resistance had been improved. It hadgood performance in promoting cell proliferation and early osteodifferentiation, andhad good biocompatibility. This experiment provided a theoretical basis for theclinical application of magnesium alloys in the future. We have reason to believe thatrecent Mg-4Zn-3HA alloy can be an ideal medical biodegradable implant material.
近年来，镁（Mg）及其合金作为一种金属基复合生物材料引起了人们广泛的关注。镁的化学性质极其活泼，在动物体内可短时间降解，镁与其他金属植入物相比，其弹性模量和力学性能更接近皮质骨，这样的物理特性使镁及其合金作为植骨及固定材料应用时能够有效地避免由植入材料引起的应力遮挡效应。因此，镁合金有望成为理想的新型可降解生物医用金属材料。但是，镁合金最大的缺点就是降解过快、产生大量氢气以及由此引起降解环境的碱性化。因此，如何改善镁合金的降解速度，使其与体内成骨的速度相匹配成为现在研究的重点所在。
本研究从体外实验的角度探讨了富含Zn、HA元素的镁合金材料的机械性能和体外降解能力，以及对小鼠前成骨样细胞MC3T3-E1的增殖、黏附和分化的影响，Real time PCR探讨了镁合金材料对成骨相关基因的影响，Western Blot探讨了镁合金材料对RUNX2、FAK、p-FAK及整合素蛋白表达的影响，为其日后临床研究提供理论依据。
通过粉末冶金法及热挤压法制备Mg-4Zn-3HA合金材料，应用扫描电镜表征材料的表面性能，通过压缩试验检测材料的机械性能，浸泡在模拟体液中，持续28天检测材料的降解及由此引起的pH值的变化，通过扫描电镜及能谱定量分析材料降解后的表面性能，及X射线衍射分析降解产物。结果显示：Mg-4Zn-3HA合金的内部疏松多孔，并且它的机械性能与其它植入材料相比更接近于天然骨，使得Mg-4Zn-3HA合金相较于其他金属更加的适合做植入材料。pH值在28天的降解时间内先升高后降低，最后稳定在8.3左右。其腐蚀率在开始的时候最高，随后降低，最后小幅度升高后稳定。降解产物X射线衍射结果分析显示较强的Mg(OH)2衍射峰，还有一定数量其它峰值，例如：HA和Mg-Zn化合物。材料降解后扫描电镜及能谱分析显示材料表面出现大量的裂痕和沉淀，降解产物表面粗糙多孔。能谱分析的结果显示材料的表面腐蚀产物中Mg、Ca、P和O含量丰富。
根据ISO10993-5，制备材料的浸提液，与MC3T3-E1细胞共培养1d、2d、3d，通过CCK-8实验、流式细胞周期实验和碱性磷酸酶（ALP）实验检测细胞毒性、增殖、以及成骨分化能力，通过扫描电镜观察细胞与材料共培养，检测早期细胞的黏附能力。结果显示：三种不同温度处理制备的镁合金都是无毒性的，处理温度为300℃的镁合金与另外两组相比较，有着更好的生物相容性。不同浓度浸提液（100%、50%、10%）对MC3T3-E1细胞的增殖结果表明浓度为50%浸提液组的增殖能力更明显。流式细胞周期的检测结果也证实了镁合金对细胞增殖的促进作用。通过扫描电镜观察，细胞在材料表面没有明显的细胞形态的改变，细胞伸展良好，还可以看到细胞的丝状伪足有的已经伸展到周围的细胞上。通过碱性磷酸酶实验可看出镁合金材料良好的促成骨能力，其中250℃和300℃镁合金组细胞内ALP活力显著高于对照组，300℃处理组差异最明显。
在分子生物学实验中，Real time PCR实验结果显示：BSP的相对表达量在第3天和第7天显著高于对照组，第14天低于对照组；OC的相对表达量在检测时间点低于对照组，但是呈现增长趋势；OPN的相对表达量在第3天显著高于对照组，在第7天和第14天与对照组无显著性差异。Western Blot实验结果显示：RUNX2蛋白的相对表达量在第3天和第14天高于对照组，其中第14天有显著性差异，在第7天，略低于对照组；FAK蛋白的相对表达量在第3天低于对照组，但是在第7天和第14天显著高于对照组；p-FAK蛋白的相对表达量在第3天和第7天显著高于对照组，第14天，略低于对照组；整合素蛋白的相对表达量在三个检测时间点均低于对照组，但是在第7天并无显著性差异。
综上所述，Mg-4Zn-3HA合金的抗腐蚀性能有所提高，在促进细胞增殖和早期成骨分化方面表现良好，并具有良好的生物相容性。本实验为日后镁合金的临床应用提供了理论基础，我们有理由相信Mg-4Zn-3HA合金可以成为理想的医用生物可降解植入材料。
In daily life, because of some unexpected circumstances, people often sufferfrom different kinds of bone fractures, and bone defects. The reasons for bone defectscould be prolonged disuse atrophy, cancer or trauma. No matter what reason makesimplants unable to obtain good initial stability, bone graft are aimed to solve thisproblem. Any bone materials should be fixed on the alveolar bone after theapplication, and should be suitable for internal fixation material of bone fracture. Atpresent, the commonly used clinical bone transplant materials and bone graftmaterials are mainly stainless steel, titanium alloy and absorbable polymer materials,etc. However, elastic modulus of stainless steel and titanium is largely different fromthat of the bone cortex, which could easily cause stress shelter effect. And, as a bonegraft material, stainless steel, and titanium alloy need a second operation, whichincreases the patient's pain and costs. Absorbable polymer materials such aspoly(lactic-co-glycolic) acid (PLGA), poly (methyl methacrylate)(PMMA) has beenused in clinical, but there are still some shortcomings, such as bad biological activity,and poor mechanical performance, which can cause aseptic inflammation and fibrosisof the surrounding tissue. There are sone synthetic materials such as PRF, tissueengineering scaffold material, and so on. The materials above have their advantagesand disadvantages. Therefore, how to synthesize a kind of biological material withgood biocompatibility, certain mechanical properties, controllable degradationperformance has become a focus in the medical community.
In recent years, magnesium and its alloys as a kind of metal matrix compositebiomaterial has attracted much attention. Magnesium is a chemically active metal,which can degradate within a short period in animal. Compared with other metal,magnesium’s elastic modulus and mechanical property is closer to the cortical bone.These physical properties make magnesium and its alloys possible to avoid stress shelter effect as bone graft and fixed material. As a result, the magnesium alloy isexpected to become the ideal new degradable biomedical metal materials. However,the biggest drawback of magnesium alloy is it degrades too fast, and produces a largeamount of hydrogen gas, which causes alkalization of the surrounding environment.Therefore, how to improve the degradation rate of magnesium alloys, and make itmatch that of osteogenesis in vivo now becomes one of the research focuses.
This research investigated mechanical properties and the degradation ability ofmagnesium alloy material rich in Zn and HA in vitro, the effect of the alloy onpreosteoblasts (mice MC3T3-E1) proliferation, adhesion and differentiation. Thisexperiment also studied the influence of magnesium alloy material on the expressionof osteogenesis related genes by Real time PCR, and tested is effect on the expressionof RUNX2, FAK, p-FAK and integrin protein by Western Blot, in order to providetheoretical basis for its clinical studies in the future.
Mg-4Zn-3HA alloy was prepared by powder metallurgy and hot extrusionmethod. Scanning electron microscopy (SEM) was applied to study thecharacterization of the surface of the material. Compression test was used to testmechanical properties of the material. The material had been immersed in simulatedbody fluid, for28days to detect the degradation of it and the change of pH value inthe fluid. Scanning electron microscopy (SEM) and energy spectrum quantitativeanalysis were utilized analyze material surface after degradation. X-ray diffraction(XRD) was used to analye the degradation products. Results showed that theMg-4Zn-3HA was porous, and its mechanical properties is closer to natural bonecompared with other implant materials, making Mg-4Zn-3HA alloy more suitable forimplant materials. During the28days pH values increased first and then went down,finally stabilized at about8.3.The corrosion rates were at the peak in the beginning,then decreased, and remained, stable with a also rise. The results of X-ray diffractionanalysis of degradation products showed a strong diffraction peaks of the Mg(OH)2,there were a number of other peaks, such as HA and Mg-Zn compounds. Materialdegradation after the scanning electron microscopy (SEM) and energy spectrum analysis showed that the material surface appear a lot of cracks and precipitation,degradation product rough surface porous. Spectrum analysis results showed that thesurface of the material corrosion products were rich in Mg, Ca, P and O.
According to the ISO10993-5, leaching solution of material was prepared, andco-cultured with MC3T3-E1for1d,2d,3d, CCK-8cell cycle analisis and alkalinephosphatase detection were used to test cell toxicity, proliferation, and osteogenesisability. Scanning electron microscope was used to observe cells co-cultured withmaterial and to detect cell adhesion ability. Results showed that three differenttemperature treatments of magnesium alloy were non-toxic, processing temperature of300℃of magnesium alloy, have better biocompatibility compared with other twogroups. Leaching solution with different concentrations (100%,50%,10%) haddifferent effects on MC3T3-E1proliferation. The results showed that theconcentration of50%group had the most significant effect on the proliferation abilityof the cells. Flow cytometry cycle test results also confirmed that the magnesiumalloy could promoted cell proliferation. Scanning electron microscope found that thecells in the material surface had no obvious changes in cell morphology, cell stretchwas good, and filiform pseudopodia of cells had been spread to the surrounding cells.Alkaline phosphatase experiment showed the magnesium alloy materials had goodcapability for osteogenesis.250℃and300℃magnesium alloy groups’ intracellularALP activity was significantly higher than that of control group, and300℃treatmentgroup’s difference was most obvious.
In molecular biology experiments, Real time PCR experiment results showedthat the relative expression of BSP in3and7days was significantly higher than thecontrol group,14days was lower than the control group. The relative expression ofOC was lower than the control group at testing time points, but there was a trend ofgrowth. Relative expression of OPN was significantly higher than control group onday3. On day7and14there was no significant difference with control group.Western Blot experiments results showed that the relative expression of RUNX2protein on day3and day14was higher than the control group, and on day14there was a significant difference. On day7, it was slightly lower than the control group;Relative expression of FAK protein was lower than the control group on day3, but onday7and day14was significantly higher than control group; Relative expression ofp-FAK protein awas significantly higher on day3and day7, but on day14, it wasslightly lower than the control group; Relative expression of integrin protein in threetest points were lower than the control group, but there was no significant differenceon day7.
To sum up, Mg-4Zn-3HA alloy’s corrosion resistance had been improved. It hadgood performance in promoting cell proliferation and early osteodifferentiation, andhad good biocompatibility. This experiment provided a theoretical basis for theclinical application of magnesium alloys in the future. We have reason to believe thatrecent Mg-4Zn-3HA alloy can be an ideal medical biodegradable implant material.
引文
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