可注射生物降解微球骨再生材料的多功能化及成骨机制研究

Demands for bone repairing grafts or materials increase continuously in recent years due to numerous bone defects caused by trauma, tumor and aging, etc.. However, bone repairing remains a big challenge in clinical therapy due to the lack of ideal repairing materials. Traditional bone substitute materials, such as autologous, allologous and heterologous bone grafts, as well as artificial materials, present more or less disadvantages in respect to issues like shortage of donor, secondary surgery, potential immunological rejection and disease transmission, insufficient bioactivity, danger of infection, and so on. Therefore, there is a great and urgent demand for new kinds of bioactive materials that are able to induce and promote bone regeneration. To this end, a kind of multi-functional microspheres made from biodegradable polyesters is proposed as injectable bioactive materials for the purpose to induce bone regeneration. In this project, polylactide-based polymers and copolymers are chosen to prepare the injectable microspheres because they are FDA-approved biomaterials for in vivo applications. These polymers demonstrate flexibility in degradation rate, hydrophilicity/hydrophobility and cell affinity. Besides, other techniques, including surface modification, biomineralization, microencapsulation and time-dependent release of growth factors, and loading of antibacterial and/or antiinfective components, are applicable on these polyester microspheres. In an ideal situation, an injectable bone repairing material can be highly expected, which is able to recruit cells to the defect area to induce bone regeneration via sustained release of proper growth factors when they are injected into the area. This kind of injectable microsphere-based bioactive bone regeneration material is envisioned to have promising application clinically in accordance with the concept of minimal invasive surgery. Basing on in vitro and in vivo evaluations, moreover, qualitative and quantitative correlations between material designs and their osteogenic capacities will be statistically analyzed, which can be a valuable guidance for the design of other bone regeneration materials.

骨创伤、肿瘤切除、骨不连、感染等原因导致的骨缺损日益增多，但目前临床常用的各种骨替代修复材料仍存在着供体有限、潜在免疫排斥和疾病传播、生物活性不足及可能诱发细菌性感染等缺陷。因此，骨科临床治疗对可激活病损骨组织再生修复的生物活性材料需求迫切。本申请提出，基于生物相容性好、降解速率和亲疏水性可调控的脂肪族聚酯，结合表面改性、生物矿化、多生长因子共包埋和顺时控释释放、抑菌抗炎成分引入等多种手段，开展具有诱导成骨促血管并具抗感染功能的可注射微球的制备和体内外生物学评价研究，在阐明该多功能生物活性修复材料与骨再生机制间的定性定量关联基础上，获得一类能够更为有效地促进骨缺损区结构恢复及功能重建的植/介入材料。近年，骨科微创技术及辅助器械发展迅速，为实现材料介入途径和治疗方案的优化提供了可能。本申请的可注射骨缺损再生修复材料，符合临床治疗所提倡的创伤小、手术耗时短、患者恢复快的术式需求，应用前景广阔。

各种原因导致的骨缺损日益增多，其临床治疗对可激活病损骨组织再生修复的生物活性材料需求迫切，但复杂的骨微环境不仅对材料的成血管、成骨活性提出高要求，同时也希望材料具有调节局部活性氧、调控免疫、抑制炎症等功能，以及适应微创介入治疗所期望的可注射骨组织工程微支架。因此，本申请以生物可降解脂肪族聚酯（如乳酸-羟基乙酸共聚物等）为主要基体，同时合成了具有本征性促成骨效应的导电性生物可降解聚膦腈，通过W1/O/W2双乳液法、O/W或W/O单乳液法，复合羟基磷灰石（HA）或生物活性离子掺杂HA、氧化镁/碳酸镁、纳米粘土、骨形态发生蛋白（BMP-2）、淫羊藿苷等活性成分，及纳米银（AgNPs）和万古霉素等抗菌性成分，制备了形貌、组成和活性成分释放可控的功能化改性微球，包括促成骨单功能、促成骨/抗菌双功能、促成血管/促成骨双功能、促成血管/促成骨/抗菌三功能、抗氧化/促成骨等不同功能设计组合的实心微球、多孔微球和纤维微球等，作为可注射微支架开展了骨再生修复和成骨机制的体外/体内系统评价研究，建立了微球型微支架设计与骨再生效率/机制的定性定量关联，尤其是提高了感染情况下的骨再生效率，为实现骨缺损部位的临床治疗方案和支架材料介入途径的优化奠定了可行的材料基础。