交联透明质酸-阿魏酸缀合物载布昔洛韦纳米粒子促进脊髓损伤后的神经再生。

Cross-Linkable Hyaluronic-Ferulic Acid Conjugate Containing Bucladesine Nanoparticles Promotes Neural Regeneration after Spinal Cord Injury.

机构信息

Department of Pharmaceutical Biomaterials and Medical Biomaterials Research Center (MBRC), Faculty of Pharmacy, Tehran University of Medical Science, Tehran 14176-14411, Iran.

Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 16656-59911, Iran.

出版信息

ACS Appl Mater Interfaces. 2023 Sep 13;15(36):42251-42270. doi: 10.1021/acsami.3c08366. Epub 2023 Aug 30.

Abstract

Dysfunctional clinical outcomes following spinal cord injury (SCI) result from glial scar formation, leading to the inhibition of new axon growth and impaired regeneration. Nevertheless, nerve regeneration after SCI is possible, provided that the state of neuron development in the injured environment is improved. Hence, biomaterial-based therapy would be a promising strategy to endow a desirable environment for tissue repair. Herein, we designed a novel multifunctional injectable hydrogel with antioxidant, neuroprotective, and neuroregenerative effects. Bucladesine-encapsulated chitosan nanoparticles (BCS NPs) were first prepared and embedded in a matrix of thiol-functionalized hyaluronic acid modified with ferulic acid (HASH-FA). The target hydrogel (HSP-F/BCS) was then created through Michael-type addition between HASH-FA containing BCS NPs and four-arm polyethylene glycol-maleimide (4-Arm-PEG-Mal). The obtained hydrogel with shear thinning behavior showed viscoelastic and mechanical properties similar to the normal nerve tissue. FA conjugation significantly improved the antioxidant activity of HA, and suppressed intracellular ROS formation. injection of the HSP-F/BCS hydrogel in a rat contusion model of SCI inhibited glial scar progression, reduced microglia/macrophage infiltration, promoted angiogenesis, and induced myelinated axon regeneration. As a result, a significant improvement in motor performance was observed compared to other experimental groups. Taken together, the HSP-F/BCS hydrogel developed in this study could be a promising system for SCI repair.

摘要

脊髓损伤 (SCI) 后的功能障碍临床结果源于神经胶质瘢痕形成,导致新轴突生长受到抑制和再生受损。然而,SCI 后神经再生是可能的,只要改善损伤环境中神经元发育的状态。因此,基于生物材料的治疗将是为组织修复提供理想环境的有前途的策略。在这里,我们设计了一种具有抗氧化、神经保护和神经再生作用的新型多功能可注射水凝胶。首先制备了包封布昔洛韦的壳聚糖纳米颗粒 (BCS NPs),并将其嵌入到经过阿魏酸修饰的巯基化透明质酸基质中 (HASH-FA)。然后,通过 HASH-FA 中含有 BCS NPs 的迈克尔型加成反应和四臂聚乙二醇-马来酰亚胺 (4-Arm-PEG-Mal) 之间的加成反应,制备了目标水凝胶 (HSP-F/BCS)。所得具有剪切变稀行为的水凝胶表现出与正常神经组织相似的粘弹性和力学性能。FA 缀合显著提高了 HA 的抗氧化活性,并抑制了细胞内 ROS 的形成。SCI 挫伤模型大鼠中 HSP-F/BCS 水凝胶的 注射抑制了神经胶质瘢痕的进展,减少了小胶质细胞/巨噬细胞的浸润,促进了血管生成,并诱导了有髓轴突的再生。与其他实验组相比,运动性能得到了显著改善。总之,本研究开发的 HSP-F/BCS 水凝胶可能是 SCI 修复的有前途的系统。

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