胶原/羟基磷灰石复合微球的原位合成及其生物性能研究

Collagen/hydroxyapatite (HA) composites have been extensively applied in the biomedical field due to their similar composition and structure to natural bones as well as good biological characteristics. Compared with the other types of materials, the microspheres exhibit unique advantages in terms of small particle size, high specific surface area and good mobility, thus having more pomising perspectives to be used in some fields. However, there has so far been very little published research on the collagen/HA composite microspheres. This project is proposed to synthesize in situ collagen/nano-HA composite microspheres with a narrow paritcle size distribution, a high dispersity and a homogeneous microstructure. The collagen and HA components would be simultaneously precipitated by adjusting the pH values in the emulsion system. The optimal experimental parameters for synthesizing the composite microspheres would be determined, and the possible formation mechanism of the microspheres would be discussed; The influences of the experimental parameters on the osteogenic potential and in vitro drug release behavior of the microspheres would be investigated, and the relationship between the microstructure and the biological properties of the microspheres would be built; The common parameters which influence both the osteogenic potential and drug release behavior of the composite microspheres would be determined and optimized to realize the combination of the biological functions. This project is proposed to not only build a fundation for the preparation of novel bone repair materials but provide new ideas for the investigation of multifunctional biomaterials.

胶原/羟基磷灰石（HA）复合材料因具有与自然骨相类似的组成、结构以及良好的生物学特性而被广泛用于生物医学领域的研究。与其他形式的材料相比，微球材料具有颗粒度小、比表面积大、流动性好等独特的优点，因而在某些领域表现出更诱人的应用前景。然而迄今为止，仅有少数关于胶原/HA复合微球的研究报道。 本项目拟采用原位合成法制备粒径分布窄、分散性好且结构均匀的胶原/纳米HA复合微球；解决在乳液体系中如何通过调节pH值使胶原和HA同时析出的关键问题，确定微球合成的最佳工艺条件，揭示微球的形成机理；探明实验参数对微球的成骨能力和体外释药性能的影响规律，建立结构与生物性能之间的关系；选取影响微球骨修复和药物缓释性能的共同参数，并对其进行合理优化，最终获得具有双重生物功能的胶原/HA复合微球。本项目的研究将不仅为制备新型、实用的骨修复材料奠定科学基础，同时也为具有多重功能的生物材料的研究开发提供新思路。

微球类生物材料在最近几年里得到了迅速的发展，尤其是在药物缓释和骨修复等生物医学领域的应用，更是受到了广泛的关注。羟基磷灰石(HA)因具有良好的生物活性、生物相容性和骨诱导性而成为一种非常重要的生物无机材料。若能将胶原、壳聚糖与HA复合形成微球，则既有望改善HA材料的韧性差和降解速度慢等问题，又可以充分发挥三种成分的性能优势，从而得到一种综合性能优异的复合微球材料。.本研究在油包水(W/O)型乳液体系中原位合成胶原/壳聚糖/HA复合微球。借助FT-IR、XRD、SEM、TEM和TG等表征手段研究了戊二醛预交联用量及时间、NaOH浓度、反应时间、表面活性剂用量、HA含量等实验参数对制备复合微球的影响，确定了最佳制备参数，并最终获得了球形规则、分散性高、结构均匀、平均粒径约为8 μm的胶原/壳聚糖/HA复合微球。以盐酸万古霉素(VH)为药物模型，采用浸泡吸附载药的方式制备胶原/壳聚糖/HA载药复合微球，并通过紫外测试对微球的载药及体外释药性能进行了初步研究。结果表明，复合微球的载药量及包封率均高于胶原/壳聚糖载药微球，且随着HA含量的增加，复合微球的载药量及包封率均有所增加。微球的体外释药研究结果表明，复合微球对盐酸万古霉素具有一定的缓释作用，在60 h时的释药率达到60%左右。结合生物相容性测试结果可以得出，HA含量为40%的胶原/壳聚糖/HA复合微球有望成为兼具药物缓释和骨修复双重功能的一种生物材料。本研究将不仅为制备新型实用的无机/有机复合微球奠定科学基础，同时也为具有多重功能的生物材料的研究开发提供新思路。