【作者】 王娟；

【导师】 黄楠； Yeoheung Yun；

【作者基本信息】 西南交通大学 ， 材料学， 2015， 博士

【摘要】 目前,医疗植入器械产业正处于从永久型植入物到可吸收再生型植入物的转型。这些可吸收金属材料主要有由镁和镁合金制成。虽然目前关于可吸收金属材料已经开展了大量的研究,但现有的美国材料与试验协会和国际标准化组织已公布的标准不能准确的评价体外降解行为进而预估体内降解行为。发展现行标准的一个关键步骤是在试验系统中明确和测试相关的微环境和参数。此外,针对于可吸收镁基血管支架的临床应用,需要完全理解镁基支架的生物降解机制,同时需要建立可控降解和提高生物相容性的可靠方法。本研究的主要目的是为了更好地认识在模拟血管微环境中流体动力学对镁降解的影响。我们自主开发了一系列血管的生物反应器来模拟体内/临床条件以揭示降解机制,例如体外多流速动态实验与计算机流体动力模拟相结合系统,原位瞬时电化学检测系统,以及模拟血管内皮化前后阶段的镁降解行为的体外猪主动脉生物反应器模型和体内鼠动脉模型评价系统。准确测定腐蚀类型,腐蚀速率和腐蚀产物对预测镁基血管支架的使用寿命起着关键的作用。实验表明流体动力学,流体流速和剪切力对可吸收镁基支架的降解/腐蚀行为起着关键的作用。流体剪切应力加速了质量和电子的转移过程,导致整个腐蚀过程加剧,包括局部腐蚀、均匀腐蚀、点蚀和侵蚀。流体剪切应力提高了平均的均匀腐蚀速率、局部腐蚀的覆盖率和腐蚀深度、以及增加了局部腐蚀区域内部腐蚀产物的去除率。这些结果与电化学测试的均匀腐蚀产物层阻抗、局部腐蚀阻抗以及极化阻抗呈现了一致的相关性。就镁合金血管支架而论,在流体剪切力为0.056 Pa条件下的腐蚀前后体积损失率是0 Pa条件下的两倍。流体运动方向对腐蚀行为有明显的影响,面对流向一侧的腐蚀产物层易从支架筋上剥落。为了认知镁在血管重塑内皮化前后阶段相关的降解行为,本文建立了一个猪主动脉生物反应器模型来研究流体对流和扩散引起的镁的生物降解行为。结果显示管腔表面流体的对流严重加剧了镁的腐蚀,因其增加了镁的质量转移、流体剪切应力、脉动舒张和收缩应力。同时,本文进一步建立了体内鼠动脉模型研究,研究镁的生物降解行为。结果显示无论是管壁还是管腔内的镁丝的降解速率都低于体外模型镁丝的降解速率。管壁内镁丝的降解略快于管腔内的镁丝,同时引起的钙化的富集。考虑到镁基支架的腐蚀和生物相容性的控制,本文设计将表面溶蚀型的聚三亚甲基碳酸酯(PTMC)涂覆在镁合金表面,也对它的动态降解行为、电化学腐蚀、生物相容性和组织相容性进行了研究。在动态降解实验中,PTMC涂层有效地保护了镁合金,减慢其腐蚀速率。经PTMC涂层改性的镁合金的自腐蚀电流密度分别低于参照样未改性镁合金三个数量级和聚己内酯(PCL)改性的镁合金一个数量级。体外静态和动态的血液实验表明相较于对照样附着在PTMC涂层表面的有极少量的血小板粘附和激活,更少的红细胞,更低的溶血率。PTMC改性的镁合金植入到小鼠皮下16个星期后,剩余的PTMC涂层厚度约为其原始厚度的55%,且其均匀平坦的表面证明了是表面侵蚀降解行为；与之形成对比的是,PCL涂层对照组表现出了非均匀的体降解行为。体内试验52周后,与对照组相比,PTMC涂层镁合金的体积减少量更小,腐蚀产物也更少。没有观察到过度的炎症反应,细胞坏死和氢气聚集。PTMC涂层从外部到内部(表面溶蚀行为)均匀的表面侵蚀和中性降解产物促成了其优良的防护性能。总而言之,PTMC作为表面溶蚀型材料是一种对镁基血管支架具有前途的候选涂层材料。本研究强调应充分考虑到流体诱导的降解行为而实现恰当地设计镁基血管支架。这篇论文所展示的数据旨在缩小体内和体外试验结果之间的差距,以及提供更可靠的信息以便更好地理解可吸收金属支架的降解行为。更多还原

【Abstract】 There is currently a paradigm shift in the medical implant device industry where absorbable metallic materials made from Magnesium (Mg) and Mg alloys are being reviewed to replace permanent metal implants. Even with the heavy volume of research that has been conducted, absorbable metals cannot be investigated using the current American Society for Testing and Materials (ASTM) and International Organization for Standards (ISO) standards, since the traditional in vitro test methods cannot predict the in vivo results. A key step of the development of current standards is to identify and test the relevant microenvironments and parameters in test-systems. Furthermore, with respect to clinical applications of absorbable Mg-based vascular stents, there needs to be a full understanding of the mechanisms of biodegradation of Mg-based stents, along with developing reliable methods for controlling degradation and biocompatibility.The main objective of this research is to better understand the effect of fluid dynamics on the Mg degradation, mimicking the vascular environment. We developed a series of vascular bioreactors to simulate in vivo/clinical conditions to reveal degradation mechanisms, such as in vitro varied fluid flow system with computational fluid dynamic calculation, in-situ or real-time electrochemical monitoring system, a porcine aortal bioreactor as well as a rat aortal in vivo system.The accurate determinations of the corrosion types, corrosion rate and corrosion products play a vital part in predicting the fate of magnesium-based stent. Experiments revealed that fluid hydrodynamics, fluid flow velocity, and shear stress play essential roles in the degradation/corrosion behavior of absorbable magnesium-based stent devices. Flow-induced shear stress (FISS) accelerates mass and electron transfer processes, leading to an increase in the entire corrosion, including localized, uniform, pitting and erosion corrosions. FISS increased the average uniform corrosion rate, the localized corrosion coverage ratios and depth, and the removal rate of corrosion products inside of corrosion pits. These results prodived a consistent correlation to the resistance of the uniform corrosion product layer, the resistance of localized corrosion and polarization resistance, which were investigated in the in-situ and real-time electrochemical test. In terms of the stents, the volume loss ratio at a FISS of 0.056 Pa was nearly twice that at a FISS of 0 Pa before and after corrosion. Flow direction has a significant impact on corrosion behavior as the corrosion product layer facing the flow direction peeled off from the stent struts.To understand progressive degradation behaviors of Mg associated to the different vascular remodelling stages, i.e. pre-and post-endothelialization stages, a porcine aortal bioreactor model and a rat aortal in vivo are developed to study flow convection and diffusion induced biodegradation behavior of Mg. The results revealed flow plays a dominant role on the corrosion rate in aortal bioreactor, and biological factors are more important on the corrosion rate in aortal in vivo model. The in vivo degradation was slower than the in vitro degradation. The established porcine aorta porcine aortal bioreactor and a rat aortal in vivo model is expected to provide more information for a better understanding of the degradation behavior of absorbable metallic stents.Concerning the corrosion-control and biocompatiblity of Mg-base stent, a surface-eroding coating of poly(1,3-trimethylene carbonate) (PTMC) on Mg alloy was studied, and its dynamic degradation behavior, electrochemical corrosion, hemocompatiblity and histocompatibility were investigated. The PTMC coating effectively protected the corrosion of the Mg alloy in the dynamic degradation test. The corrosion current density of the PTMC-coated alloy was reduced by three orders and one order of magnitude compared to controls, bare and poly(ε-caprolactone) (PCL)-coated Mg alloy, respectively. Static and dynamic blood tests in vitro indicated that significantly fewer platelets were adherent and activated, and fewer erythrocytes attached on the PTMC-coated surface and showed less hemolysis than on the controls. The PTMC coating after 16 weeks subcutaneous implantation in rats maintained-55%of its original thickness and presented a homogeneously flat surface demonstrating surface erosion; in contrast to the PCL coated control which exhibited non-uniform bulk erosion. The Mg alloy coated with PTMC showed less volume reduction and fewer corrosion products as compared to the controls after 52 weeks in vivo. Excessive inflammation, necrosis or hydrogen gas accumulation were not observed. The homogeneous surface erosion of the PTMC coating from exterior to interior (surface-eroding behavior) and its charge neutral degradation products contribute to its excellent protective performance. It is concluded that PTMC is a promising candidate for a surface-eroding coating applied to Mg-based stents.This study demonstrates that flow-induced corrosion should be understood to properly design Mg-based stents in vascular environments. The experimental data in this dissertation are expected to reduce the gap between in vivo and in vitro test results, as well as, provide more accurate information to better understand degradation behavior of absorbable metallic stents.更多还原