多重载药纳米CaP/聚多巴胺支架的仿生组装及程序化释药研究

In this proposal, nano Calcium Phosphate (CaP) loaded with multiple drugs are designed and developed to carry out the various loaded efficiency and release kinetics, which are controlled by the material characterizations. Furthermore, the mechanisms of controlling of drug release are explored. Poly-dopamine, which is one kind of high adhesive substance similar to that secreted by mussel, is used to bionic assemble the scaffold via the building blocks of nano CaP loaded with multiple drugs. The programmable release kinetics of multiple drugs and biodegradations of the scaffold are investigated by in vitro and in vivo drug release studies. The release is subjected to occur at the bone defect, and at the accurate time, concentration and release speed. Moreover, the key factors and the mechanisms to control the drug programmable release would be revealed. The biological properties and functions of antibacterial properties, cell proliferation and growth enhancement, and osteogenesis of scaffold would be evaluated by antimicrobial testing, cell culture and animal experiment. The present scaffold is combined the features of release drug of nano CaP with the bionic assembly of highly adhesive of poly-dopamine. The attractive advantage of this scaffold is to release multiple drugs programmatically in response to the programmed bone healing and to promote the osteogenesis. The most important studies are bionic assembly and the programmable release in this proposal. The aim is to provide the scaffold with the osteogenesis ability and the higher mechanical strength for clinical application. The expected results have the important scientific meaning, remarkable social significance and prominent economic benefits.

本申请旨在设计和研制具有不同材料学特征的载药纳米磷酸钙（CaP），研究制备工艺和材料学特征对纳米CaP的不同载药率和释药动力学的调控及机理；利用类海洋贻贝分泌的高粘性物质聚多巴胺，以载药纳米CaP为主要组装单元仿生组装多重载药纳米CaP/聚多巴胺支架；通过体内外降解释放试验研究载药支架多重药物的程序化释放动力学及关键控制因素，即定点、定时和定量地精确释放多重药物；研究支架的降解；通过抗菌、细胞体外和动物实验，研究支架的抑菌、促进细胞生长和骨愈合的多重功能作用和生物学性能，揭示其作用机理。该支架结合了纳米CaP的载药特性和高粘性聚多巴胺的仿生组装，其特点是能程序化释放多重药物，响应骨修复中抗感染、治疗骨科疾病和促进骨生长的程序化过程。重点研究支架的仿生组装和程序化释药，目的是为临床提供促进骨修复的高强度支架材料，具有重要的科学价值、显著的社会意义和经济效益。

骨修复材料是临床需求量最大的生物材料之一，骨修复包括一系列程序化的复杂过程，需要多种药物或生长因子治疗骨科疾病和促进骨修复，同时需要一定的力学性能。本项目旨在设计和研制具有不同材料学特征的纳米载药磷酸钙，利用不同的材料学特征调控多重药物的载药率和释药动力学；采用类海洋贻贝分泌的高粘性物质聚多巴胺，以纳米载药磷酸钙为主要组装单元仿生组装多重载药纳米磷酸钙/聚多巴胺支架，提高磷酸钙支架的力学性能。项目开展了纳米载药磷酸钙的设计和合成工艺、有机模板调控纳米载药磷酸钙、体外药物释、聚多巴胺/磷酸钙支架组装和力学性能、体外降解矿化及对蛋白质吸附、抗菌性、细胞毒性和体内植入实验研究。通过使用机械活化结合双膦酸盐的分散可批量合成纳米载药磷酸钙，揭示明胶、纳米晶纤维素等多种有机模板可调控纳米载药磷酸钙的形貌、尺寸、化学组成和结晶度，为进一步构建磷酸钙支架和调控药物释放提供基础。体外释放试验发现载多重药物的磷酸钙支架程序化释放动力学及关键控制因素，实现了抗菌药物和促进骨修复药物分别在前15天和持续100天程序化释放；支架的降解、体外矿化及蛋白质吸附的研究，发现聚多巴胺的加入促进磷酸钙支架的矿化，并在磷酸钙支架表面形成一层微纳多级结构，可促进蛋白质的吸附；抗菌、细胞体外和动物实验表明聚多巴胺增强载抗生素磷酸钙支架的抑菌能力，对细胞无毒性，体内无毒性并能促进新骨生长，增强支架和宿主骨间的结合强度；利用纳米磷酸钙和高粘性聚多巴胺的仿生组装，较空白对照可显著提高多孔磷酸钙支架的力学性能。具有程序化控释多重组份药物、优良生物相容性和生物活性以及较高的力学性能的纳米载药磷酸钙/聚多巴胺支架，具有为临床提供促进骨修复支架的潜能。本项目探明控制程序化释药的关键因素，揭示该支架的性能-结构-组成的关系，丰富和发展载药和骨修复材料的相关理论，为研发具有我国自主知识产权的骨修复材料提供科学依据。