新型双相兼具自抗炎与自可控降解骨修复复合支架材料的研究

There are technical difficulties in dissolving the accumulation of acid products during degradation process of the degradable polymer composite scaffolds and keeping consistency between degradation speed of the polymer martix and healing speed of new bone tissue. A novel composite scaffold, with self anti-inflammation and self controllable degradation of polymer and inorganic phases, is prepared for bone tissue repairing engineering. The polymer matrix (AMPLLGC) is composed of poly(L-lactide-co-glycolide-co-caprolactone) modified by maleic anhydride and aliphatic diamine, the inorganic phases contain bioactive glass (NBAG) and β-calcium phosphate (β-TCP). The effects of polymerization conditions on the composition, crystallinity and molecular mass of AMPLLGC are investigated, and the effects of grafting conditions on the anhydride and amidogroup content are also studied, The influences of preparation parameters on the size and morphology of the NBAG and β-TCP nanoparticles are performed, and the influences of grafting conditions on the surface modification are also carried out. The influences of molding parameters on the microstructure and mechanical properites of the composite scaffold materials are also investigated. The in-vitro and in-vivo degradation behaviors are carried out and the self anti-inflammation and self controllable degradation machnisms are studied. In addition, the in-vitro and in-vivo biological behaviors of the degradable composite scaffolds are investigated, and the effects of the composition, structure and growth infactors of the composite scaffolds on the bone tissue repairing are disclosed. This project will supply new perspective and important technical support for the designment of novel degradable scaffold materias.

在现有的高分子基复合支架材料中，普遍存在因其降解过程酸性物质累积引起的非细菌性炎症以及降解速率与骨组织愈合速率不匹配等技术瓶颈。基于此，本项目拟构建一种新型兼具自抗炎和自可控降解的高分子/无机复合支架，其中高分子相由马来酸酐和脂肪二胺依次接枝改性聚丙交酯/乙交酯/己内酯（AMPLLGC）组成；无机相由AMPLLGC接枝的纳米生物玻璃和β-磷酸钙组成。研究聚合参数对共聚物组成、结晶度与分子量以及接枝反应参数对接枝率的影响规律；探究合成反应参数对无机纳米粒子形貌与粒径以及接枝条件对其表面修饰效果的影响；探索成型参数对复合支架微结构和力学性能的影响规律，采用体内外降解方法，阐明复合支架体内外的自抗炎和降解机制。研究复合支架在动物体内外的作用模式，揭示复合支架材料组成、结构及生长因子等对骨再生修复的效果的影响规律。通过本项目的研究，可为新型可控降解支架材料的设计提供新思路和重要技术支持。

以L-丙交酯、乙交酯、ε-己内酯为原料，采用熔融共聚法制备三元共聚物PLLGC；采用熔融共聚法制备马来酸酐化PLGA，进一步用丁二胺改性，获得富含碱性基团的聚合物BMPLGA。通过优化制备参数获得分子量、降解速率和对酸性产物的有效中和等可控的聚合物。将PLLGC和BMPLGA复合，获得兼具良好力学性能和富含碱性功能基团的PLLGC/BMPLGA高分子基体。 . 采用溶胶-凝胶法制备不同粒径的纳米NBAG，采用化学沉淀法制备不同尺寸的纳米β-TCP，以带氨基的硅烷偶联剂对NBAG和β-TCP进行表面修饰，获得表面修饰的纳米粒子。. 采用热诱导相分离法制备具有不同孔径（50～200μm），高孔隙率（＞90%）的PLLGC-BMPLGA/NBAG-β-TCP复合支架材料。PLLGC浓度、冷冻温度和无机物含量对支架材料的形貌、孔隙率和抗压强度具有较大影响。聚合物浓度越大，支架材料的孔隙率越低，抗压强度越大；冷冻温度越低，支架材料的孔隙率越低，抗压强度越大；随着NBAG-β-TCP无机粒子含量的增加，支架材料的亲水性能增强，抗压强度先增大后降低。. PLLGC/BMPLGA高分子基体的降解方式为本体降解。与PLLGC/BMPLGA多孔支架降解比较，NBAG和β-TCP的添加降低了复合支架材料的降解速率；与PLLGC/NBAG-β-TCP支架的降解行为比较，BMPLGA的引入加快了高分子基体的降解速率。体内降解呈现出与体外降解相似的变化，但降解速率比体外降解速率较慢。. 生物安全性实验表明PLLGC-BMPLGA/NBAG-β-TCP复合支架材料具有优异的生物相容性。动物体内骨缺损实验以兔子股骨内髁创建软骨缺损模型，采用该复合支架修复缺损区域。20周后软骨缺损愈合，骨界限消失，软骨下支架处可见血管，复合支架材料部分降解。体内骨缺损实验表面该支架材料具有良好的修复能力，NBAG、β-TCP等无机纳米粒子和生长因子的引入有利于软骨组织的修复。. 该新型复合型支架材料兼具双相自抗炎特征和自可控降解的特征，为新型可控降解支架材料的设计提供新思路和重要技术支持。