Engineered nerve guide conduit enhances peripheral nerve regeneration by modulating the microenvironment through macrophage-triggered cascade reactions

IF 18 1区医学 Q1 ENGINEERING, BIOMEDICAL

Bioactive Materials Pub Date : 2025-05-07 DOI:10.1016/j.bioactmat.2025.04.033

Xindi Yang , Xiao Liang , Binyi Wang , Xing Gao , Wenqiang Yang , Jiajun Li , Huaan Cai , Zan Tong , Yun Chen

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Abstract

Nerve regeneration after peripheral nerve injury (PNI) depends on exogenous and endogenous pro-healing signals in the microenvironment. Maintaining immune system homeostasis and remodeling the regenerative microenvironment are crucial prerequisites for promoting nerve regeneration. Here, a double-layer PSM/Gel-SC(IL-4) nerve guide conduit was fabricated by photocrosslinking poly (ethylene glycol) diacrylate (PEGDA) and methacrylic acid-sodium alginate (SAMA) hydrogel as the outer layer, with GelMA encapsulating IL-4 overexpressing Schwann cells as the inner layer. PSM/Gel-SC(IL-4) conduit enabled the sustained release of IL-4, inducing pro-healing macrophages polarization through JAK1/STAT6 pathway in vitro. The polarized macrophages further triggered the cellular cascade reactions, enhancing the pro-healing characteristics of endothelial cells and Schwann cells. In addition, PSM/Gel-SC(IL-4) conduit significantly promoted functional recovery and nerve regeneration in 12-mm rat sciatic nerve defect model, induced pro-healing macrophage polarization at the early stage and accelerated angiogenesis and myelination at the nerve regeneration stage. This study developed a novel immunomodulatory strategy to remodel the regenerative microenvironment, and explored the underlying cellular and molecular mechanism, demonstrating considerable therapeutic potential for long-distance nerve defect.

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工程神经导管通过巨噬细胞触发级联反应调节微环境，促进周围神经再生

周围神经损伤后的神经再生依赖于微环境中外源性和内源性促愈合信号。维持免疫系统稳态和重塑再生微环境是促进神经再生的重要前提。本实验以聚乙二醇二丙烯酸酯（PEGDA）和甲基丙烯酸-海藻酸钠（SAMA）水凝胶为外层光交联制备双层PSM/Gel-SC（IL-4）神经导管，GelMA包封过表达IL-4的雪旺细胞为内层。PSM/Gel-SC（IL-4）导管使IL-4持续释放，通过JAK1/STAT6途径诱导巨噬细胞促愈合极化。极化后的巨噬细胞进一步触发细胞级联反应，增强内皮细胞和雪旺细胞的促愈合特性。此外，PSM/Gel-SC（IL-4）导管显著促进12mm大鼠坐骨神经缺损模型的功能恢复和神经再生，在早期诱导促愈合的巨噬细胞极化，在神经再生阶段促进血管生成和髓鞘形成。本研究开发了一种新的免疫调节策略来重塑再生微环境，并探索了其潜在的细胞和分子机制，显示出对长距离神经缺损的治疗潜力。

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来源期刊

Bioactive Materials Biochemistry, Genetics and Molecular Biology-Biotechnology

CiteScore

28.00

自引率

6.30%

发文量

436

审稿时长

20 days

期刊介绍： Bioactive Materials is a peer-reviewed research publication that focuses on advancements in bioactive materials. The journal accepts research papers, reviews, and rapid communications in the field of next-generation biomaterials that interact with cells, tissues, and organs in various living organisms. The primary goal of Bioactive Materials is to promote the science and engineering of biomaterials that exhibit adaptiveness to the biological environment. These materials are specifically designed to stimulate or direct appropriate cell and tissue responses or regulate interactions with microorganisms. The journal covers a wide range of bioactive materials, including those that are engineered or designed in terms of their physical form (e.g. particulate, fiber), topology (e.g. porosity, surface roughness), or dimensions (ranging from macro to nano-scales). Contributions are sought from the following categories of bioactive materials: Bioactive metals and alloys Bioactive inorganics: ceramics, glasses, and carbon-based materials Bioactive polymers and gels Bioactive materials derived from natural sources Bioactive composites These materials find applications in human and veterinary medicine, such as implants, tissue engineering scaffolds, cell/drug/gene carriers, as well as imaging and sensing devices.