State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Biomedical Materials and Engineering Research Center of Hubei Province, Wuhan University of Technology, Wuhan, 430070, China.
Department of Biomedical Engineering and Hubei Province Key Laboratory of Allergy and Immune-Related Diseases, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.
Biomaterials. 2022 Jan;280:121288. doi: 10.1016/j.biomaterials.2021.121288. Epub 2021 Dec 1.
Delayed injured nerve regeneration remains a clinical problem, partly ascribing to the lack of regulation of regenerative microenvironment, topographical cues, and blood nourishment. Functional electrospun conduits have been established as an efficacious strategy to facilitate nerve regeneration by providing structural guidance, regulating the regenerative immune microenvironment, and improving vascular regeneration. However, the synthetic polymers conventionally used to fabricate electrospinning scaffolds, such as poly(L-lactic acid), poly(glycolic acid), and poly(lactic-co-glycolic acid), can cause aseptic inflammation due to acidic degradation products. Therefore, a poly[3(S)-methyl-morpholine-2,5-dione-co-lactic] [P(MMD-co-LA)] containing alanine units with good mechanical properties and reduced acid degradation products, was obtained by melt ring-opening polymerization (ROP). Here, we aimed to explore the effect of oriented nanofiber/Deferoxamine (DFO, a hydrophilic angiogenic drug) scaffold in the rapid construction of a favorable regenerative microenvironment, including cell bridge, polarized vascular system, and immune microenvironment. In vitro studies have shown that the scaffold can sustainably release DFO, which accelerates the migration and tube formation of human umbilical vein endothelial cells (HUVECs), as well as the expression of genes related to angiogenesis. The physical clues provided by the arranged nanofibers can regulate the polarization of macrophages and reduce the expression of inflammatory factors. Furthermore, the in vivo results demonstrated a higher M2 polarization level of the oriented nanofibrous scaffold treatment group with reducedinflammation reaction in the injured nerve. Moreover, the in-situ release of DFO up-regulated the expression of HIF1-α and SDF-1α genes, as well as the expression of HIF1-α's target gene VEGF, further promoting revascularization and enhancing nerve regeneration at the defect site. The obtained results provide essential insights on accelerating the creation of the nerve regeneration microenvironment by combining the physiological processes of nerve regeneration with topographical cues and chemical signal induction.
神经损伤后的再生仍然是一个临床问题，部分原因是再生微环境、地形线索和血液营养的调节缺乏。功能性静电纺丝导管已被确立为一种有效的策略，通过提供结构指导、调节再生免疫微环境和促进血管再生来促进神经再生。然而，传统上用于制造静电纺丝支架的合成聚合物，如聚（L-乳酸）、聚（乙醇酸）和聚（乳酸-共-乙醇酸），由于酸性降解产物会引起无菌性炎症。因此，通过熔融开环聚合（ROP）获得了一种含有丙氨酸单元的聚[3(S)-甲基吗啉-2,5-二酮-共-乳酸][P(MMD-co-LA)]，具有良好的机械性能和减少的酸性降解产物。在这里，我们旨在探索取向纳米纤维/去铁胺（DFO，一种亲水性血管生成药物）支架在快速构建有利的再生微环境中的作用，包括细胞桥、极化的血管系统和免疫微环境。体外研究表明，支架可以持续释放 DFO，这加速了人脐静脉内皮细胞（HUVEC）的迁移和管形成，以及与血管生成相关的基因的表达。排列纳米纤维提供的物理线索可以调节巨噬细胞的极化，减少炎症因子的表达。此外，体内结果表明，取向纳米纤维支架处理组的炎症反应减轻，M2 极化水平更高。此外，DFO 的原位释放上调了 HIF1-α 和 SDF-1α 基因的表达，以及 HIF1-α 的靶基因 VEGF 的表达，进一步促进了再血管化并增强了损伤部位的神经再生。研究结果为通过结合神经再生的生理过程与地形线索和化学信号诱导来加速神经再生微环境的创建提供了重要的见解。
