新型ZOL-NPs人工椎体的优化构建及其修复OP椎体缺损的机制研究

Artificial vertebral body replacement is the primary treatment method to the OP vertebral defect patient who is not appropriate to conventional surgery. The key is to implant artificial vertebral body in the spine defect to restore the integrity and provide biomechanical support. However, the artificial vertebral body exist three shortcomings such as "hypofunction, poor biocompatibility and no anti-OP effect", which easily lead to surgical failure and serious complications. Our previous studies have found that: EBM porous titanium scaffold have wonderful bone biomechanical properties and biocompatibility. Thus, bisphosphonates nanospheres (D-NPs) enables local sustained release of drugs in the body with long lasting effect of anti-OP. Its derivatives zoledronic acid (ZOL) also have a certain role in enhancing bone formation under OP conditions. However, its mechanism is not yet clear. Therefore, based on our previous study, we intend to use EBM porous titanium scaffold coated with zoledronic acid nanoparticles (ZOL-NPs) to fabricating novel ZOL-NPs artificial vertebral body. Expound its regular pattern of drug release and repairing effect for OP vertebral defect and reveal its impact to osteoblast and osteoclast function and related molecular mechanisms. In order to constructing a new artificial vertebral body which have good vertebral biomechanical properties, conducive to vertebral defects repair and some role in local anti-OP to providing theoretical and experimental evidence for its clinical application.

人工椎体替代是无法进行常规手术的OP椎体缺损患者最主要的治疗方法，其关键是将人工椎体植入缺损部位恢复脊柱完整性并提供支撑。然而现有人工椎体存在“功能单一、生物相容性差、无抗OP作用”三大缺点，易导致手术失败及严重并发症。我们前期研究发现：EBM多孔钛合金具有良好的生物力学特性和骨生物相容性；而双磷酸盐纳米微球（D-NPs）能使药物在体内局部缓释，具有长期持续抗OP作用，其衍生物唑来磷酸（ZOL）在OP条件下也具有一定的成骨作用，但其作用机制尚不十分清楚。因此，本课题拟在上述基础上，采用唑来磷酸纳米微球（ZOL-NPs）复合EBM多孔钛合金支架构建新型ZOL-NPs人工椎体，进一步明确其载药释放规律和对OP椎体缺损的修复效果，并揭示其对成骨、破骨细胞功能影响和相关分子机制，以期构建一种既符合椎体生物力学特性，又利于椎体缺损修复，还具有一定抗OP作用的新型人工椎体，为其临床应用提供理论依据。

EBM多孔钛合金具有良好的生物力学特性和骨生物相容性；而双磷酸盐纳米微球（D-NPs）能使药物在体内局部缓释，具有长期持续抗OP作用，其衍生物唑来磷酸（ZOL）在OP条件下也具有一定的成骨作用，但其作用机制尚不十分清楚。本课题在上述基础上，采用唑来磷酸纳米微球（ZOL-NPs）复合EBM多孔钛合金支架构建新型ZOL-NPs人工椎体，其具有稳定的载药释放能力，研究表明该新型ZOL-NPs人工椎体具有与人松质骨相似的弹性模量，可有效降低应力遮挡问题。不同浓度ZOL-NPs多孔钛合金支架对成骨、破骨细胞影响的体外研究发现，成骨细胞的增殖、分化、凋亡及成骨关键基因Runx2、BMP-2、OPN、OCN表达都表现出与唑来膦酸浓度呈双向相关。低浓度（1 μmol/L, 10 μmol/L, 50 μmol/L）ZOL-NPs多孔钛合金支架更有利于成骨细胞增殖分化。破骨细胞的凋亡与ZOL呈浓度依赖性，随着浓度增加，破骨细胞凋亡增加。不同浓度ZOL-NPs多孔钛合金支架对 OP 椎体缺损动物模型的体内研究发现低浓度（10 μmol/L, 50 μmol/L）ZOL-NPs多孔钛合金支架更有利于新生骨形成，具有局部抗骨质疏松作用。综合上述结果，本研究构建了一种新型ZOL-NPs人工椎体，探究了其对骨质疏松性椎体缺损的修复效果，为其临床应用提供了理论依据。