EM-PCLCol/ EM-PVA纳米纤维管强化磷酸钙治疗骨髓炎的研究

Osteomyelitis still presents a challenge to clinicians. Systemic antibiotic therapy has the disadvantage of not being sufficiently effective due to impaired blood circulation and the need for a high concentration of antibiotics. In addition, long-term antibiotic therapies will bring all kinds of potential side effects and develop the antibiotic- resistant bacteria strains. We believe that a combination of surgical debridement + local antibiotics delivery devices + bone grafting is effective for the treatment of osteomyelitis. The objective of this proposal is to develop a bactericidal bone scaffold capable of controllable and sustained antibiotics delivery. Erythromycin (EM) is a broad spectrum antibiotic against most organisms encountered during osteomyelitis and has additional biological activities, including inhibition of inflammatory bone loss and augmentation of bone formation. We have reported that Coaxial PCL/PVA electrospun nanofibers can be used as osseointegration enhancer and controlled drug release device. We hypothesize that calcium phosphate cement (CPC) scaffold reinforced with a EM-PCLCol/ EM-PVA which produced by 3-D printing will eradicate osteomyelitis by providing a sustained and controllable release of EM encapsulated in the scaffold and enhance osseointegration. The key concepts are to determine the appropriate formulations of the CPC/EM/Coaxial PCL/PVA composites with desired physiochemical and biological properties and determine whether a desired controllable sustained EM release exceeding the minimal inhibitory concentration (MIC) for at least 4 weeks can be reached using our current approach.

骨髓炎治疗非常棘手，全身抗菌素应用常在局部达不到有效药物浓度，且长期大量抗菌素的应用也会带来各种潜在的副作用并导致耐药菌株的出现。局部病灶彻底清除+抗菌素局部缓慢释放+骨替代材料的联合治疗是治疗骨髓炎的有效手段。红霉素是一种广谱抗菌素对绝大多数骨髓炎感染菌种有效，并且其具有一些其他的生物学特性，如阻断炎性骨丢失和促骨形成。我们前期研究证实同轴PCL/PVA静电纺丝纳米管能促进骨整合和作为药物的可控释放载体。因此我们推测使用同轴PCL/PVA对EM载药并与磷酸钙进行三维打印形成的功能型骨支架可作为骨髓炎局部抗菌素治疗的最佳选择；通过体外的药物缓释研究、毒性实验、抗菌实验、成骨能力及骨髓炎治疗的体内多层面研究，对该系统的抗菌性能、机制和骨修复能力进行全面和深入的分析和探讨，从而为骨髓炎的治疗尤其是骨髓炎治疗提供一种新的手段。

课题组在前期对于纳米管混合磷酸钙（CPC）3D打印制备红霉素（EM）缓释支架的基础上，对CPC的结构和3D打印制备方法进行改进，构建了聚磷酸钙（CPP），同时采用医用型PMMA（Simplex P, SP）来加强其力学强度和缓释特性，得到了力学强度满意和具有双重缓释功能的新式骨支架SPC。在本研究中，课题组还通过深入的机制研究发现，局部的炎症微环境含有大量的炎症因子，能通过表观遗传的方式，抑制Wnt/β-catenin信号通路的激活，从而抑制间充质干细胞的成骨分化，损伤干细胞的成骨功能。最后，课题组通过SPC双重缓释这一特点，通过大量药物筛选，及采用大鼠的骨髓炎动物模型，分不同的时间点处死动物，对胫骨进行取材，并进行组织形态学、成软骨和成骨指标检测，发现了姜黄素和EM联用能有效抑制骨髓炎，并且恢复骨髓炎的骨质状态。项目结果显示该骨支架有利于骨髓炎及骨缺损的修复，并揭示了炎症微环境对骨组织工程修复的重要意义。本项目的研究成果为感染性骨复合移植物治疗骨髓炎提供了科学依据。

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