“吸水自膨胀型”生物杂化材料——氧化石墨烯复合PMMA-PAA-PSt的构建及其生物学机制研究

Polymethyl methacrylate (PMMA) cement has been widely used in orthopaedic and neurological surgeries. However, the clinical applications of PMMA cement were limited by several main flaws: cytotoxity, allergic reaction and volume shrinkage. In our previous research, polyacrylic acid (PAA) and polystyrene (PSt) were firstly copolymerized with PMMA and forming a novel trimer: PMMA-PAA-PSt, which is the first injectable self-expandable bone cement in worldwide, and could overcome the imperfection of PMMA. Despite all this, the feature of low mechanical strength and inhomogeneous restrict its further application. Recently, we found adding graphene oxide (GO) in solid phase and hydroxyethyl methacrylate (HEMA) in liquid phase could improve the three-dimensional structure and the mechanical feature of the PMMA-PAA-PSt polymer. In this project, therefore, we will optimize the synthetic process based on this finding to generate homogenous cement with the appropriate mechanical strength for clinical use. Meanwhile, we also will evaluate the biological performance of primary osteocyte co-cultured with the cement component in the medium, by using cellular biological studies, which is also a parameter for evaluation in synthetic procedure. Then, the expansion effect for the osteoblasts growing in the interface between cement and tissue will also be investigated by cell biological experiment in animal model to optimize the cement synthesis. Finally, we will develop novel biocompatibility cement, which is suitable for clinical usage and possess self-owned intellectual property right.

聚甲基丙烯酸甲酯(PMMA)骨水泥是广泛应用于骨科、神经外科等领域的生物填充材料，但其存在细胞毒性、致敏性及固化收缩等缺陷严重影响疗效，亟需改进。申请人前期研制出国际上首个“吸水自膨胀”骨水泥类材料(PMMA-PAA-PSt)，从根本解决上述问题。但该材料的力学强度和均一性不足制约其进一步临床应用。近期，项目组经筛选发现加入氧化石墨烯(GO)和甲基丙烯酸羟乙酯(HEMA)能分别从固液两相优化材料结构和性能。因此，本研究将在此基础上进一步优化合成工艺，提高材料的强度和膨胀后均一性，同时利用细胞生物学研究方法系统评价材料对骨细胞生物学行为的影响，并以此指导材料合成。再利用动物模型检测疗效、分析“膨胀效应”对界面骨组织的生物学影响，得到最优膨胀比率并优化工艺，最终获得一种满足临床需求、生物相容性良好、具有自主知识产权的新型骨水泥材料。本研究具有及其重要的理论和现实意义。

PMMA(polymethyl methacrylate)骨水泥作为黄金标准已经广泛应用于手术中的填充治疗和关节置换术等领域，但是骨水泥固相和液相进行聚合反应存在体积收缩，造成无菌性松动，影响其在人体内的长期稳定性。与此同时，PMMA骨水泥作为一种稳定的药物载体进行抗菌及骨质疏松症治疗，但是疏水性PMMA的包埋造成内部药物的释药率低，释药周期与人体需求不匹配，释药功能单一等缺点。此外，PMMA骨水泥还存在着力学性能过高对人体骨生长造成应力遮蔽，凝固过程中温度过高对人体正常组织造成灼烧，以及生物相容性较差无法促进成骨细胞的生长等缺点。.针对以上问题，本研究在可膨胀P(MMA-AA)骨水泥的研究基础上对其进行改性。通过调整聚合过程的单体配比和交联剂含量对添加物中的亲水基团和三维网状结构进行调控，在PMMA骨水泥内构建由P(MMA-AA)微球构成的吸水通路, 提高吸水动力的同时增加水分向内传递的路径，最高吸水和膨胀倍率分别为60.2%和61.8%；利用二维片层状GO比表面积大的结构优势及亲水性好力学性能优异的性能优势，制备了具有片层-球状的P(MMA-AA)-GO纳米微单元，在复合骨水泥内构建了多级吸水通路，增加了水分传递的通道从而加快水分在聚合物内的扩散，吸水及膨胀倍率最高可达到90.2%和91.3%；在液相中引入了甲基丙烯酸甲酯类衍生物-甲基丙烯酸羟乙酯，可膨胀PMMA基骨水泥内部分PMMA被P(MMA-HEMA)替代， P(MMA-HEMA)微球均匀弥散在骨水泥内与P(MMA-AA)共同形成互穿双吸水网络，加快了凝固前基体对水分的吸收和传递能力，吸水和膨胀倍率可以高达92.5%和97.4%。在成功构建吸水通路的基础上利用其进行药物释放，在骨水泥内加入了硫酸庆大霉素和阿仑膦酸钠，通过调整两种药物的搭载方式以及内部吸水通路的联通情况，得到了能够长效分级释放两种药物的载药可膨胀PMMA基骨水泥，两者的累计释放率最高可达74.67 ± 1.02 %和75.23 ± 1.96 %，释放周期分别为4周及100天，实现了两种药物的分级长效释放。改性骨水泥均具有优于商用PMMA骨水泥的体外细胞活性及体内生物相容性，为其在椎体成形术、骨螺钉、口腔等领域中的应用提供了重要的实验依据。