可注射聚合物短纤维的生物学特性及医学功能研究

Electrospun fibers and their biomedical functions have been thoroughly investigated in our previous study. Injectable short fibers are showing significant advantages in eliminating surgery procedures, improving medical outcomes, and simplifying treatment schedules. This proposal is aimed to develop injectable polymeric fibers into a novel platform for biomedical applications through defining their biological profiles and clarifying the principles and methods to realize their biomedical functions. Controllable fabrication processes of short fibers are established to modulate the fiber characteristics and achieve a good injectability. The dynamic distributions and the interactions with cells and tissues after intravenous and local injections are investigated on short fibers with variable characteristics to clarify the modulation mechanism of their biomedical functions. The target capabilities of short fibers to tumor tissues after intravenous and local injections and their synergistic effects of short fibers in regulating independently the drug release behaviors are determined to effectively combat the systemic toxicity, drug resistance effects, and tumor metastases of current anticancer treatment. The short fibers with tailorable surface grafts are designed as the orientation points of anchorage-dependent cells for construction of multicellular spheroid tissues as drug screening molds, to achieve a good correlation coefficient between in vitro tests and in vivo results of drug toxicity, metabolism and therapeutic efficacy. The flexible surface modification and cell attachment abilities are adopted to load cells and growth factors on short fibers, to improve the in situ tissue regeneration and wound repair after injection. In conclusion, the biological profiles and biomedical functions of short fibers as drug carriers and cell scaffolds should enrich the strategies for disease treatment and drug screening.

在前期电纺纤维膜生物医学功能研究的基础上，本申请系统探究可注射聚合物短纤维的生物学特性及医学功能，有望将其发展成一类新的生物医用产品形式,拓展和深化非球形微纳材料与生物体相互作用机制的认知。在建立聚合物短纤维的可控制备和修饰技术、获得特征梯度变化短纤维的基础上，以短纤维的生物学特性研究为中心，全面揭示不同特征短纤维与细胞和组织间发生相互作用的机制、体内动态分布的规律。一方面基于静脉注射长径比较小短纤维的组织靶向性、局部注射长径比较大短纤维的组织滞留效应，利用其独立调控药物释放的能力，探究短纤维共混注射的协同增效，有效应对肿瘤治疗中耐药和转移等问题。另一方面基于长径比大的短纤维作为细胞的着位点，结合水凝胶构筑多细胞球体组织作为药物筛选模型，探究药物及其制剂的毒性、代谢或作用效果等与体内结果的相关性。基于上述可注射短纤维作为药物载体和细胞支架的功能，丰富和发展疾病治疗和药物筛选的机制和手段。

在前期电纺纤维膜生物医学功能研究的基础上，本项目系统探究了可注射聚合物短纤维的生物学特性及医学功能，拓展和深化了非球形微纳材料与生物体相互作用机制的认知，展示了可注射短纤维在减少手术创伤、提升医用效果、简化治疗程序等方面的优势，有望将其发展成一类新的生物医用产品形式。项目研究思路是，基于可注射聚合物短纤维的可控制备，围绕一个中心（研究短纤维的生物学特性，包括与细胞和组织相互作用的机制、经局部组织和静脉注射后体内动态分布的规律），探究三种功能（药物载体、细胞支架、组织修复）的实现机制，为肿瘤治疗、药物筛选、组织修复及再生提供新的策略和技术支撑。项目研究的学术贡献主要有，一是创建了两种短纤维制备方法（冷冻切片和超声处理），均能较好控制短纤维的长径比，短纤维在血液中的循环时间延长，促进了药物在肿瘤组织中的富集，可调控药物在组织中的渗透和分布；二是研究了短纤维释药的刺激响应性和靶向作用机制，可释放自由药物或载药胶束，也可分别释放抗肿瘤药物和作用于肿瘤组织中血管、基质相关细胞的药物等，为实现药物的靶向运送、多重刺激响应性释放、协同作用效果等提供了新的策略；三是通过表面功能化短纤维促进了细胞的粘附，形成多细胞球体组织，建立了肝细胞球和心肌细胞共培养体系作为药物毒性和代谢的筛选模型；四是将携载活性因子的聚合物短纤维、与短纤维共培养的干细胞球注射到修复部分，对局部组织缺血、软骨缺损等实现了组织的原位再生和修复，创伤少、效果好。基于上述研究，项目负责人作为通讯作者在ACS Appl. Mater. Interfaces、Nanoscale和J. Controlled Release等杂志上发表论文30篇。发表论文受到同行广泛关注，对上述工作进行了正面评述，如“…刺激响应性聚合物短纤维为局部靶向治疗提供了颇有吸引力的方案”等。项目研究为提升青年教师、临床研究人员和研究生的理论水平和创新研究能力提供了有力支持。