电信号响应特性的骨修复材料及其抗肿瘤细胞作用机制研究

Bone tumors represent one of the greatest threat to patient survival with cancer. Surgery is often required for tumor removal. However, not all tumor can be eliminated by surgery and there is risk of recurrence and metastases in most cases. Besides, the removal of bone tumor leads to destruction of skeletal complication. As a result, radiotherapies and bone grafts are utilized after surgery. To avoid over-use of radiotherapies, lower the risk of recurrence and metastases and improve the skeletal complication, the present work aims to develop new kinds of biomaterials for postoperative bone repair. Taking tumor treating fields and piezoelectricity of nature bone as the reference, we construct the electro-active biomaterials with the use of piezoelectric ceramics and conducting polymers. After controlling the structure, surface property and electric property of the resulting materials, we will evaluate the biocompatibility and investigate the anti-tumor and osteogenesis improval ability of the electro-active biomaterials. Furthermore, the interaction between electro-active biomaterials and osteosarcoma cells / bone marrow mesenchymal stem cells will be studied on molecule, cell and animal levels. The mechanism of electro-active biomaterials inducing tumor elimination and improving osteogenic differentiation will be investigated. The outcome of this work will give a guideline of construction of electro-active biomaterials for the optimal match with the require of tumor elimination and bone repair after surgery.

针对骨肿瘤手术后形成大段骨缺损及可能残留肿瘤细胞而导致大量病人术后复发、肿瘤转移等问题，研制出兼具促成骨和抗肿瘤功能的材料用于切除肿瘤后大段骨缺损修复具有重要意义。研究发现外加电场可促使肿瘤细胞产生细胞核固缩、核蛋白凝固坏死等多种病理性变化，最后导致肿瘤细胞的凋亡。基于此，申请人提出“电信号响应特性的生物材料抗肿瘤”的学术思想，创造性地以生物相容的铌酸钾钠压电陶瓷、聚吡咯导电高分子等为主要成分制备出电信号响应特性的新型骨修复材料，系统研究材料的成分、结构及成型工艺参数对其产生电信号响应的影响规律，构建材料与肿瘤细胞/骨细胞相互作用模型，通过体外实验与动物实验深入研究骨修复材料产生的电信号对肿瘤细胞凋亡的分子机制，包括凋亡的路径、凋亡过程中细胞膜、细胞质或细胞核的变化等作用机理，及其对骨髓间充质干细胞增殖与分化的作用规律，为临床发展具抗肿瘤特性的骨修复材料提供新的思路和途径。

骨肿瘤极大地影响患者的生命健康，同时骨肿瘤本身以及相关治疗手段会造成病灶附近的健康骨组织缺失，且对于肿瘤的二次治疗局限于放射治疗与化学治疗等副作用较大的传统疗法。修复肿瘤或治疗过程引起的骨缺损以及防止肿瘤疾病的复发，对于患者的术后恢复与生活质量有着重要意义。本项目通过固相球磨法制备了具有电信号响应特性的压电陶瓷铌酸钾钠骨修复材料，课题组自主研发的生物医用压电材料极化装置，可以调控铌酸钾钠压电材料的表面电势。研究了不同极化状态的铌酸钾钠表面电学环境对骨肉瘤细胞活性的影响规律，发现正极化面提供的高表面电势电学环境会降低骨肉瘤细胞的细胞活性，其抑制肿瘤细胞活性的途径是通过损伤细胞膜，诱导细胞膜电位去极化以及提高胞内活性氧水平等。铌酸钾钠力-电响应特性对肿瘤细胞活性的影响规律。为模拟铌酸钾钠压电陶瓷在人体体内力学环境中的受力情况以及力-电响应过程中的电信号输出情况，利用动态力学分析仪与皮安表联用的手段，检测到铌酸钾钠压电陶瓷在力-电响应过程中输出电压信号与电流情况；使用自主研发的动态力学加载装置实现对体外细胞培养体系原位施加力学刺激，探讨了压电陶瓷在力学刺激下对于样品表面生长的肿瘤细胞的代谢行为的影响，发现在动态力学作用下具力-电响应特性的极化处理的铌酸钾钠压电陶瓷会抑制细胞的活性，影响细胞的形态，促进细胞凋亡，而不具备力-电响应特性的未极化铌酸钾钠压电陶瓷对细胞则没有类似调控作用。