Aligned chitosan nanofiber hydrogel grafted with peptides mimicking bioactive brain-derived neurotrophic factor and vascular endothelial growth factor repair long-distance sciatic nerve defects in rats

Feng Rao^1*, Yanhua Wang^1*, Dianying Zhang^1*, Changfeng Lu^1*, Zheng Cao², Jiajie Sui², Mengjiao Wu³, Yawen Zhang⁴, Wei Pi¹, Bo Wang¹, Yuhui Kou¹, Xiumei Wang^2✉, Peixun Zhang^1✉, Baoguo Jiang^1✉

1. Department of Orthopedics and Trauma, Peking University People's Hospital, Beijing100044, China
2. State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University, Beijing 100084, China
3. Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
4. Department of Orthopedics, Peking University Third Hospital, Beijing100191, China.
* These authors contributed equally to this work.

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Citation:
Rao F, Wang Y, Zhang D, Lu C, Cao Z, Sui J, Wu M, Zhang Y, Pi W, Wang B, Kou Y, Wang X, Zhang P, Jiang B. Aligned chitosan nanofiber hydrogel grafted with peptides mimicking bioactive brain-derived neurotrophic factor and vascular endothelial growth factor repair long-distance sciatic nerve defects in rats. Theranostics 2020; 10(4):1590-1603. doi:10.7150/thno.36272. Available from https://www.thno.org/v10p1590.htm

Abstract

Autologous nerve transplantation, which is the gold standard for clinical treatment of peripheral nerve injury, still has many limitations. In this study, aligned chitosan fiber hydrogel (ACG) grafted with a bioactive peptide mixture consisting of RGI (Ac-RGIDKRHWNSQGG) and KLT (Ac-KLTWQELYQLKYKGIGG), designated as ACG-RGI/KLT, was used as nerve conduit filler to repair sciatic nerve defects in rats.

Methods: Chitosan nanofiber hydrogel was prepared by a combination of electrospinning and mechanical stretching methods, and was then grafted with RGI and KLT, which are peptides mimicking brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), respectively. The physicochemical properties of ACG-RGI/KLT were fully characterized. In vitro, the distribution, proliferation, and secretory activity of Schwann cells were analyzed. Next, the in vivo repair potential for 15-mm rat sciatic nerve defects was examined. The recovery of regenerated nerve, muscle, and motor function was evaluated by neuromuscular histology, electrophysiology, and catwalk gait analysis.

Results: We first constructed directionally aligned chitosan nanofiber hydrogel grafted with RGI/KLT peptide mixture (ACG-RGI/KLT). ACG-RGI/KLT oriented the Schwann cells, and promoted the proliferation and secretion of neurotrophic factors by Schwann cells. At an early injury stage, ACG-RGI/KLT not only enhanced nerve regeneration, but also promoted vascular penetration. At 12 weeks, ACG-RGI/KLT facilitated nerve regeneration and functional recovery in rats.

Conclusions: Aligned chitosan nanofiber hydrogel grafted with RGI/KLT peptide provides an effective means of repairing sciatic nerve defects and shows great potential for clinical application.

Keywords: Peripheral nerve injury, electrospinning, mechanical stretching, chitosan nanofibers, peptides.