钛表面聚多巴胺、聚乙二醇、聚乳酸-聚羟基乙酸、异烟肼抗结核控释涂层的构建及生物学性能  

Fabrication of the anti-tuberculosis controlled drug delivery system with Ti-PDA-PEG-PLGA-INH and investigation of the biological characteristics

作　　者：马云龙[1] 李力韬 李丹[4] 彭明丽 赵冠人 李大伟 罗展鹏 顾苏熙 杨飞[4] 马远征 

机构地区：[1]河北北方学院,张家口075000 [2]解放军第三○九医院全军骨科中心脊柱外科病区,北京100091 [3]解放军第三○九医院药剂科,北京100091 [4]中国科学院化学研究所高分子物理与化学国家重点实验室,北京100190

出　　处：《中华骨科杂志》2016年第11期725-734,共10页Chinese Journal of Orthopaedics

基　　金：国家自然科学基金面上项目（81071454）;解放军第三○九医院课题重点项目（2014ZD-001）

摘　　要：目的构建钛金属表面聚多巴胺、聚乙二醇、聚乳酸-聚羟基乙酸、异烟肼抗结核控释涂层，评价其表面特征、体内外释药行为、体外抑菌性能及生物相容性。方法合成四臂巯基聚乙二醇（polyethylene glycol，PEG）；通过迈克尔加成反应在钛金属（titanium，Ti）表面构建聚多巴胺（poly dopamine，PDA）涂层；利用多孔淀粉及四臂巯基PEG水凝胶负载异烟肼（isoniazid，INH），通过浇铸法或浸渍-提拉法附着于PDA涂层表面，同法再覆盖一层聚乳酸-聚羟基乙酸[poly lactic-co-glycolic acid，PLGA]，制成Ti-PDA-PEG-PLGA-INH复合涂层；核磁氢谱图（proton nuclear resonance spectroscopy, HNMR）表征四臂巯基PEG末端官能团；扫描电镜（scanning electron microscope, SEM）观察其表面特征，高效液相色谱法（high per-formance liquid chromatography，HPLC）检测Ti-PDA-PEG-PLGA-INH的体外释药行为，并进行体外抑菌实验。取25只新西兰大白兔制作股骨髁骨缺损模型，植入表面构建PDA-PEG-PLGA-INH的钛棒，采用HPLC法于术后检测静脉血以及植入材料周围肌肉组织、骨组织中INH浓度。另取12只兔随机分为实验组和对照组，实验组于背部椎旁肌内及左侧股骨髁分别植入表面构建PDA-PEG-PLGA-INH的钛片和钛棒；对照组于相同部位植入空白钛片及钛棒，术后通过病理组织学观察材料的体内生物相容性。结果 Ti-PDA-PEG-PLGA-INH控释涂层在钛金属表面均匀铺展，呈半透明状，表面光滑。体外药物释放前8 h突释明显，累积释放量占总药量65%，第9天时累积释放量达90%，随后释放趋于平缓，总释放周期达20 d以上。体内释药实验显示材料植入后兔静脉血、材料周围肌肉及骨组织中INH浓度平稳上升，于第28天左右达最高峰；且在第56天时肌肉及骨组织中INH浓度仍高于最低抑菌浓度；体外抑菌实验显示构建Ti-PDA-PEG-PLGA-INH控释涂层的钛片周围形成�Objective To fabricate an anti-tuberculosis controlled drug release coating with Ti-PDA-PEG-PLGA-INH and to investigate its surface characteristics, in vivo and in vitro drug release behavior, and tissue biocompatibility. Methods 4-arm-polyethylene glycol （PEG） was synthesized first. Then cover the surface of titanium （Ti） with a layer of poly dopamine （PDA） by Michael addition reaction. Use porous starch and 4-arm-PEG as a carrier, load with isoniazid （INH）, then attach to the surface of titanium by casting or sol-gel dip coating methods, and then cover with a layer of poly lactic-co-glycolic acid （PLGA） by the＆amp;nbsp;same method, to fabricate the Ti-PDA-PEG-PLGA-INH composite coating finally. The functional group of 4-arm-PEG was charac-terized by proton nuclear resonance spectroscopy （HNMR）. The surface characteristics of Ti-PDA-PEG-PLGA-INH were evaluated by scanning electron microscope （SEM）, while drug release behaviors were detected by high performance liquid chromatography （HPLC） and the cumulative release rate was calculated, and carry out the antibacterial performance in vitro. The animal model of femoral condyle bone defect was established in 25 New Zealand white rabbits. Titanium rods covered with PDA-PEG-PLGA-INH coating were implanted into defect area. INH concentrations were detected by HPLC in venous blood, muscle and bone tissue at each time point postoperatively. Another 12 rabbits were randomly divided into experimental group and control group, the experi-mental group was implanted with titanium tablets and titanium rods coated with PDA-PEG-PLGA-INH in the paraspinous muscle and left femoral condyles respectively, while the control group was implanted with a blank sheet of titanium tablets and titanium rods in the same place. Hematoxylin and Eosin Staining were used to observe the biocompatibility of the composite system in vivo at 28 and 56 days postoperatively. Results Ti-PDA-PEG-PLGA-INH controlled drug release coating uniformly distributed on the surface

关 键 词：结核 异烟肼 乙二醇 迟效制剂 

分 类 号：R943[医药卫生—药剂学]