Engineered Neuro-Regenerative Peptide Hydrogel for Directed Neural Lineage Reprograming and Regeneration of Sciatic Nerve Injury.

Abstract

Living systems are distinguished by their ability to self-organization, a phenomenon that drives a range of pattern-forming processes, from sand dunes to cellular assemblies and tissue architectures. Inspired by these natural phenomena and design principles, the fabrication of an engineered nanofibrous, extracellular matrix (ECM) mimicking self-assembling peptide hydrogel is reported. This hydrogel integrates a neuroregenerative motif (NAV) derived from Activity Dependent Neuroprotective Protein (ADNP) with a self-assembling motif (K₂[SL]₆K₂) to enhance neurite outgrowth. Interestingly, it is observed that this engineered hydrogel displays a network of prominent, directed filament-like structures. Remarkably, it supports and promotes the directional differentiation and alignment of stem cells into neuronal lineages. Motivated by this result, its therapeutic potential is evaluated in a rat model of sciatic nerve injury, where guided nerve regeneration is essential. The hydrogel is applied as a nerve guidance matrix, leading to structural repair and significant functional recovery of the injured nerve within two weeks. These findings are further supported by behavioral assessments, histological analysis, and evaluation of gastrocnemius muscle reinnervation. Overall, the results demonstrate that this engineered peptide hydrogel effectively promotes nerve regeneration and functional restoration, highlighting its promise as a therapeutic platform for peripheral nerve injury.