氟暴露在钛腐蚀行为中的作用机制及其对种植体骨整合的影响

Endemic fluorosis has a wide distribution in our country and threatened a large number of people. With the recent promotion of dental implants in clinical use, the number of patients who receive dental implant therapies increased rapidly every year in those endemic fluorosis areas. However, our preliminary study found that the clinical success rate of dental implants in patients from the high fluoride region was lower. Our further experiments exihibited that fluoride exposure can damage the titanium surface oxide layer and cause the titanium corrosion. The damage of titanium oxide film not only leads to titanium ions release, but also affects osseointegration of titanium implant. In addition, both the released titanium ions and fluoride exposure have adverse impacts on bone metabolism. Therefore, the mechanism of accelerated titanium corrosion caused by fluoride exposure and its effects on dental implants should be elucidated urgently. In this research, on the basis of our preliminary work, the effects of fluoride on the titanium surface oxide layer and corrosion behavior will be studied to clarify the mechanism of fluoride exposure affecting titanium corrosion behavior. Then, by in vitro and in vivo experiments, including osteogenic gene expression, osteoclastic bone resorption activity, RANKL/OPG levels, etc., the changes of peri-implant osteoblast-osteoclast balance and bone metabolism will be studied to elucidate the influences of titanium behavior on implant osseointegration in the fluoride exposure environment. This research aims to deeply explore the influence of the fluoride exposure on dental implants. It is of great scientific importance to provide foundations for improvement of treatment mode and clinical success rate and early prevention of complications of dental implants in the endemic fluorosis areas.

我国地方性氟中毒病区分布广，人群基数大。随着近年来种植牙技术的推广，地氟病病区内接受种植牙治疗的人数逐年增加。然而，本课题组在前期研究中发现，来自高氟地区患者的种植牙成功率较低。进一步预实验显示，氟暴露会导致钛氧化膜受损和钛腐蚀。而氧化膜受损一方面引发钛离子释放，另一方面抑制钛表面的成骨活性，且钛离子和氟暴露均对骨代谢有不良作用。因此，氟暴露加速钛腐蚀机制及其对种植牙的影响亟待明确。基于前期工作基础，本课题拟研究氟对钛表面氧化膜和腐蚀行为的影响，阐明氟暴露在钛腐蚀行为中的作用机制，再通过成骨基因表达、破骨细胞骨吸收活性、RANKL/OPG水平等检测以及动物实验，研究种植体周围组织的成骨-破骨平衡和骨代谢变化，揭示氟暴露引发的钛腐蚀行为对种植体骨整合的影响。本课题旨在深入探索氟暴露对种植牙的影响，为地氟病病区种植牙治疗模式的改进、临床成功率的提高以及种植牙并发症的早期防治提供理论依据。

我国地方性氟中毒病区分布广，人群基数大。随着近年来种植牙技术的推广，地氟病病区接受种植牙治疗的人数逐年增加。然而，氟暴露加速钛腐蚀及其对种植牙的影响尚不明确。本项目通过扫描电镜、X线光电子能谱（XPS）、钛腐蚀动力学检测、钛离子释放检测、成骨细胞染氟模型、慢病毒转染、氟暴露动物种植体植入模型、Micro-CT以及硬组织切片等体内外实验方法，系统研究了氟暴露在钛腐蚀行为中的作用机制及其对种植体骨整合的影响。实验结果显示：(1) 氟暴露会促进纯钛的晶间腐蚀和钛表面点蚀孔的形成，破坏钛表面微结构和氧化膜，导致表面氧化膜的致密度和保护性下降，进而使纯钛在模拟体液中的腐蚀易感性增强，抗腐蚀性能减弱，加速钛离子的释放，该效应随着血氟浓度的增加而增强，并且在酸性环境中腐蚀程度更加显著。(2) 氟暴露及其引发的钛腐蚀产物对成骨细胞行为具有抑制作用，其分子机制为：氟暴露能抑制MAPK通路关键分子JNK和ERK的表达，进而通过交互作用下调Hippo通路关键分子YAP的核转移，减少YAP入核与成骨相关靶分子结合，最终抑制成骨功能。(3) 饮用水加氟能成功构建慢性氟中毒动物模型，再基于该模型和自主设计的钛种植体，可构建氟暴露动物种植体植入模型；Micro-CT影像学和组织学分析发现，在种植体骨结合早期，氟暴露会增强破骨活性，而在种植体骨结合后期，氟暴露会降低种植体周围骨密度和种植体-骨接触率，影响种植体的骨整合。本项目证实了氟暴露对钛腐蚀行为的促进作用，探索了该现象内在的腐蚀动力学机理，明确了氟暴露对成骨细胞行为的抑制作用及其对种植体骨整合的不良影响，并进一步揭示了氟暴露通过MAPK通路和Hippo/YAP通路的交互对话抑制成骨功能的分子机制。该研究结果有望为地氟病病区种植牙治疗模式的改进以及种植牙并发症的早期防治提供理论和实验依据。