【作者】 李江波；

【导师】 叶建东；

【作者基本信息】 华南理工大学 ， 材料学， 2010， 硕士

【摘要】 口腔科和整形外科对磷酸钙微球填充修复材料有着迫切的需要,而在临床应用中,磷酸钙微球需要具有良好的生物相容性、生物活性、抗崩解性、可降解、易于操作和方便载入药物等功能性成分。磷酸钙微球的制备工艺有两种:一种是在微球成球后经过烧结处理,另一种是用高分子粘结剂粘结成球,不经烧结处理。这两种方法制备的微球不能同时保证良好的可降解吸收性和抗崩解性,也无法同步载药而导致载药量小、包封率低的问题。针对上述问题,本研究以磷酸钙骨水泥为原料,采用反相乳液法制备了一种新型的自固化磷酸钙微球,微球的粒径范围为100~1000μm,中位径在388~605μm之间,内部有43.4%~66.7%的凝胶孔和微孔。通过正交试验探讨了各种因素对微球粒径的影响,研究表明,随着随着液固比或油液相体积比的增大,微球粒径减小;随着明胶含量的提高,微球粒径增大;随着搅拌速度的提高,微球粒径先减小后增大。获得了稳定制备微球的优化工艺参数为:搅拌速度为200 r/min,明胶浓度为8% (w/v),油水相比例为5∶1,液固比为2.0 mL/g。实验结果表明,所制备微球的自然堆积安息角为28.4~33.0°,说明微球流动性好。设计圆筒状模具表征了微球填充体的抗压性能,结果表明微球有良好的韧性,不易破碎,有利于临床操作。经过充分水化后,微球的抗压性能显著提高。体外抗崩解实验表明,微球在模拟生理条件下微球在模拟生理条件下12小时内不发生崩解,具有良好的抗崩解性。MTT法细胞毒性试验表明,微球有良好的细胞相容性。在微球制备过程中同步复合广谱抗生素药物:硫酸庆大霉素,并进行药物释放试验,研究结果表明,自固化磷酸钙微球的释放呈现明显的三段式释放:第一阶段(前3小时内)出现一定程度的GS快速突释;第二阶段(第3小时到第48小时内),GS的溶出速度较快,是一个减速释放阶段;第三阶段(从第3天到第6天),药物缓慢匀速释放,是一个恒速释放阶段。第6天之后,基本上不再有药物溶出,说明药物释放时间大约为6天。CPC微球的释放动力学特性符合化学控制扩散模型,具有一定的药物缓释效果。所制备的自固化磷酸钙微球有望用作牙槽骨缺损填充修复材料及牙槽嵴增高材料、增宽用材料等;还可用作为药物载体材料。另外,通过液滴冷凝法制备了大粒径的自固化磷酸钙微球,微球的粒径在2~3 mm范围内,表面平整,粒径分布较窄,实验结果表明,当液固比为2.0 mL/g时微球呈椭球状,当液固比为3.0 mL/g时微球呈良好的球形,此方法制备的自固化磷酸钙微球的水化结晶不够完全,力学强度较低。通过挤出滚圆法制备了粒径均一的自固化磷酸钙球粒,可根据网板大小选择粒径在0.5~2 mm之间的微球,微球成球的液固比在0.3~0.6 mL/g之间,研究表明,挤出滚圆法制备的球粒粒径均一,强度较高且制备效率高。更多还原

【Abstract】 Apatite microspheres are in great needs in periodontal surgery and orthopedic surgery. As for clinical use, such microspheres should be good at biocompatibility, bioactivity, biodegradation, anti-disintegration, easy to be operated and be convenient for the incorporation of drugs or other functional components. Generally, there are two ways to fabricate the apatite microspheres, the one is sintering the as-prepared microspheres to form a ceramic apatite microspheres, and the other one is directly using binders of adhesives to form the microspheres. However, microspheres prepared through these two ways don’t perform well in degradation and anti-disintegration at the same time, and drugs cannot be incorporated simultaneously during the preparatioin, which will result in a low drug loading and encapsulation efficiency.In this study, novel self-setting calcium phosphate microspheres were prepared by the employment of a reversed emulsion method, to solve the above problems. The diameter of the microspheres distributed from 100μm to 1000μm with a median diameter between 388-605μm, with a porosity between 43.4%-66.7%. An orthogonal test indicated that the microspheres’s diameter decreased with the increase of the liquid to powder ratio or the oil to water ratio, increased with the gelatin concentration, and increased first and then decreased with the increase of agitating speed. The processing parameters for preparation of the microspheres were optimized to be: an agitating speed of 200 r/min, a gelatin concentration of 8% (w/v), an oil to water ratio of 5:1, and a liquid to powder ratio of 2.0 mL/g. The angle of repose of the microspheres was measured to be 28.4°-31.6°, indicating good flowability. Microspheres with rough surface were figured out by an etching method. The compressive test showed that the microspheres were non-brittle, which is in favor of clinical applications. The compressive performance of the microspheres was significantly improved after full hydration at 37℃and 97% humidity. Anti-disintegration test revealed the microspheres was endurable in simulated physiological conditions and MTT test indicated the microspheres were biocompatible. Gentamicin was incorporated into the microspheres simultaneously during the granulation process, and related drug releasing experiment was carried out, which exhibited drug release form the microspheres demonstrate a typical three-phase release profiles: the drug release profiles exhibited a burst release at the first 3 hours, a deceleration release in the followed 1 and a half days, and a nearly a constant velocity in the third to six days, as a result, the CPC microspheres can be used as slow releaseing drug carrier, and it was a potential candidate for bone defect filling and repair at non-load-bearing sites.Self-setting calcium phosphate microspheres with bigger granule sizes were produced through a droplet-freezing process. The diameter of the microspheres distributed from 2-3 mm, with an even suface. The microspheres with a ellipsoidal shape when the liquid to powder ratio was 2.0 mL/g, while with a spherical shape when the ratio was 3.0 mL/g. Self-setting calcium phosphate microspheres with narrow granule sizes distribution were produced through a extrusion- spheronization process, and the liquid to powder ratio was 0.3-0.6 mL/g, the microspheres had better compressive strength.更多还原