异质离子选择性掺杂核-壳结构复相生物陶瓷构建及感染性骨缺损修复的基础研究

It is difficult to treat the infected bone defect which usually leads to delayed union and recurrent infection. Current design of artificial grafts cannot attention simultaneously the bone regeneration and infection control of the implants, and the recurrence of infection is hardly avoided in clinical practice. This proposal is motivated by our previous work on the bioactive microspheres for enhancing the early-stage repair of the pathological bone defect. This work aims to design multifnctional foreign ion selectively doping β-tricalium phosphate (β-TCP) or wollastonite (calcium silicate; CaSi) ceramic phase component in the core-shell-structured microspheres (CaP@CaSi, CaSi@CaP) for the treatment of infected bone defect. This study is based on the optimization of specifically bioactive copper and selenium ions on anti-infection and vascularization improvement, and the component choice that CaSi is biodegradable faster than bone regeneration but β-TCP is slowly biodegradable so that the core-shell CaP@CaSi and CaSi@CaP spheres possess a novel “fast-slow” or “slow-fast” biodegradation characteristic. The first work is to prepare the Cu/Se-doping ceramic phase via wet chemicial appoaches and fabricate the porous structures in the ceramic components in the core or shell layer of CaP@CaSi and CaSi@CaP microspheres, and to evaluate the relationship between foreign ion doping and ion release and biodegradation of CaP and CaSi. The second is to explore the Cu/Se release behavior, biologically active ion dissolution products and surface properties of the CaP@CaSi and CaSi@CaP spheres on inflammatory cell responses and differentiation potential of osteogentic stem cells in vitro. The core-shell spheres developed in our team will be dispersed into the cell culture medium (CCM), on the basis of their compositions and porous structure. The research approach will be guided by inorganic ion dissolution in CCM, and their effects such as the viability, proliferation, and differentiation and the dynamic metabolic behavior of stem cells in CCM will be determined and evaluated in detail. The third is to validate the repair rate in infected bone defect, regulated by the Cu/Se selectively doped CaP@CaSi and CaSi@CaP porous microspheres fillers in vivo. The influence of drug release and shell degradation on the inflammation response and new trabecular regeneration will be monitored to determine the dual-functinoal inorganic ion combination effects from the microspheres. These studies will help to develop dual-functional bioactive materials for bone regeneration and infection control.

感染性骨损伤修复一直是临床的棘手问题，目前的药物控释体系尚不能彻底控制感染并实现高效骨再生修复。本项目拟通过高效抗感染功能铜/硒选择性掺杂、降解显著差异性陶瓷组分及其微孔道分布等的精细设计，探讨一类新的高活性陶瓷颗粒材料解决感染性骨损伤修复的关键科学问题。首先，优化构建铜/硒选择性掺杂硅灰石-磷酸三钙为组分的核-壳结构复相陶瓷(多孔)微球，系统分析异质离子调控核、壳层陶瓷组分的降解特性，以及异质离子缓释规律与微孔道分布的基本关系；再通过细胞生物学和动物模型研究，进一步论证陶瓷组分的核-壳分布、核/壳层内微孔道分布以及掺杂离子释放剂量等的基本特征对骨再生效率、材料降解速率、感染控制的最佳生物学效应和内在机制，阐明高效抗感染无机离子选择性掺杂组分与微结构均精细可调型人工复合材料解决感染性骨损伤修复的有效性和可靠性。本项目的研究还对发展临床众多病理性骨损伤修复生物材料的设计理论具有重要学术意义。

各种原因导致的病理性骨缺损，尤其是感染性骨缺损一直是骨科临床面临的主要难题，虽然目前各种无机材料在骨缺损修复领域广泛应用，但仍存在许多局限。本课题利用自行设计的同轴核-壳结构微球颗粒制备技术平台，成功制备了以β-硅灰石和/或β-磷酸三钙为主要组分的尺度均一的单相和核-壳结构双相生物陶瓷微球。体外评估证实核-壳结构双相微球的生物活性、降解性极为可调可控，实现了波动性降解特性和促成骨活性的有机结合；动物股骨和颅骨缺损模型中系统论证核-壳结构生物活性微球植入物实现降解速率与促成骨速率的匹配性关键问题，证实了核-壳结构型材料组分分布设计与构建可实现材料生物降解和促成骨活性同步，有利于匹配骨缺损修复进程的需求。.其次，本课题进一步通过锶、镁、铜元素选择性掺杂，结合壳层组分内部微孔道精准剪裁，优化制备出一系列降解速率和无机活性离子释放剂量可动态剪裁的核-壳结构生物陶瓷微球。动物实验研究表明，异质离子掺杂于核-壳结构微球特定组分能进一步调控材料生物活性及降解性能，从而满足不同类型骨缺损的需要。其中，研究中通过铜、镁元素掺杂结合微球外壳层造孔的结构设计所制备的微球，被证明具有良好的抗感染和抑菌特性，从而证实了特定离子选择性掺杂对解决感染性骨缺损的再生修复具有重要的应用意义。.本项目通过医工深度合作的多学科协作研究，在解决骨缺损修复方面探索出原材料简单、制备工艺简便的低成本多功能生物材料的设计模式，通过利用钙-磷、钙-硅基材料进行核-壳结构设计、特定组分内部孔道精细剪裁、功能离子选择性掺杂等新技术方案，有效解决了常规无机生物陶瓷材料的性能缺陷，发展出满足骨髓炎等多种临床需求的新型生物活性材料体系。同时，本项目有效凝聚了一支医工协作的研究队伍，在国际高水平SCI收录刊物发表8篇论文，培养5名研究生，并以部分早期成果为支撑取得了相关课题，通过国内外会议的学术交流，显著提升了团队的应用基础研究视野和创新能力。