纳米磷灰石/聚(DTH)碳酸酯自固化骨修复材料的可控制备与作用机理

The unsolved problems of bone cement, such as poor mechanical strength, prohibit their applications for further clinical utilization, especially for load-bearing bone regeneration. In order to solve these problems, based on the principle of biomineralization, a new method of in-situ synthesis and in-situ polymerization will be used in this project to controllably prepare the nano-hydroxyapatite/poly (DTH carbonate) composite materials. By adding the setting liquid,a series of composite biomaterials potentially for load-bearing bone repair can be developed, which showed excellent mechanical properties, rapid self-hardening process and proper biodegradable properties. Moreover, the mechanism of the interface combination between apatite and poly (DTH carbonate), as well as its effect upon the performances of the composites will be investigated by characterizing the physical and chemical properties. Additionally, the process and the principle of composite solidification will be studied and re-modeled. Furthermore, the biocompatibility and bioactivity of the composites will be further tested by in vitro soaking in stimulated body fluid, co-culturing with cells, and thereafter by animal experiment. In the in vivo study, the biodegradability and biocompatibility of the composites in different physical environments, as well as the process of bone reconstruction at the defect sites can be continuously explored by the Micro-CT (u-CT) technology. In conclusion, this project will provide a new method for the preparation of nano-inorganic/organic biological composite material and provide theoretical and experimental basis for the clinical applications of these composite biomaterials.

针对目前医用骨水泥由于强度较低，不能满足临床需要的现状，本项目采用基于生物矿化原理的原位生成-原位聚合法，可控制备出纳米磷灰石/聚(DTH)碳酸酯(n-HA/P(DTH)C)复合骨修复材料，使其在固化液的作用下具有快硬、高强、可降解的优良性能，以满足缺损部位骨修复要求。通过表征其理化性能，探明磷灰石与聚(DTH)碳酸酯的界面结合机制与材料性能间关系。研究该材料的固化过程，揭示其凝结固化机理，建立固化机理模型。通过体外浸泡、细胞共培养及动物体内植入实验，评价该材料的生物相容性和生物活性。采用Micro-CT 技术连续跟踪该材料在不同力学因素作用下的降解过程及其在体内对骨组织的修复和重建过程，探索其降解规律及机理，初步评价其应用于承力骨缺损修复的效果。项目的实施将为纳米无机/有机生物复合材料的研究提供一种新方法，同时可为该材料的临床应用提供理论和实验基础。

自然骨是一种主要由无机纳米羟基磷灰石（n-HA）和有机胶原（collagen）组成的复合材料，模拟骨的结构和功能，充分结合n-HA和高聚物的优良性能，制备纳米羟基磷灰石/高分子复合骨修复材料，是当今国际生物材料研究中的热门课题。本项目主要从n-HA和聚（脱氨基-酪胺酰酪氨酸己酯）碳酸酯 （P(DTH)C）复合材料的设计出发，结合n-HA良好的生物活性与P(DTH)C力学性能优良的优势，分别制备了n-HA、P(DTH)C、n-HA/P(DTH)C复合材料和n-HA/P(DTH)C骨水泥，研究了复合材料的界面结合机理、骨水泥的形成机理以及骨水泥的体内外生物活性。此外，将n-HA/P(DTH)C复合材料和MG-63细胞共培养来探究复合材料的生物活性，将n-HA/P(DTH)C复合骨水泥植入大白兔股骨，研究n-HA/P(DTH)C复合骨水泥的生物相容性、成骨性能等。结果表明，溶液沉淀法合成的n-HA呈棒状，晶粒尺寸为10-25nm×30-45nm，在结构和组成上和人体骨磷灰石相似。合成的P(DTH)C相对重均分子量（Mw）约为47487，相对数均分子量（Mn）约为75698。在n-HA和P(DTH)C制备的基础上，采用溶液共混法制备了n-HA/P(DTH)C复合材料，同时采用适宜浓度的柠檬酸作为固化液制备了n-HA/P(DTH)C复合骨水泥。采用体外模拟体液浸泡测试了n-HA/P(DTH)C复合骨水泥体外生物活性。结果表明，n-HA和P(DTH)C之间以氢键形式结合；n-HA/P(DTH)C复合骨水泥的抗压强度能达到为18.2MPa，能满足松质骨部位的需要。体外浸泡模拟实验证实n-HA/P(DTH)C复合骨水泥表面有羟基磷灰石的生成，说明此材料具有生物活性。细胞共培养实验和动物植入实验结果表明，n-HA/P(DTH)C复合骨水泥具有良好的生物相容性、可降解性和成骨性能。本研究成果为n-HA/P(DTH)C复合材料在骨修复材料领域可能的应用提供了理论依据。