Self-assembling multidomain peptide hydrogels accelerate peripheral nerve regeneration after crush injury

Abstract

Multidomain peptide (MDP) hydrogels are a class of self-assembling materials that have been shown to elicit beneficial responses for soft tissue regeneration. However, their capacity to promote nervous system regeneration remains unknown. The peripheral nervous system (PNS) substantially recovers after injury, partly due to the abundance of extracellular matrix (ECM) components in its basal lamina. However, severe peripheral nerve injuries that significantly damage the ECM continue to be a major clinical challenge as they occur at a high rate and can be extremely detrimental to patients' quality of life. In this study, a panel of eight MDPs were designed to contain various motifs mimicking extracellular matrix components and growth factors and successfully self-assembled into injectable, nanofibrous hydrogels. Using an in vitro screening system, various lysine based MDPs were found to enhance neurite outgrowth. To test their capacity to promote nerve regeneration in vivo, rat sciatic nerve crush injury was performed with MDP hydrogels injected directly into the injury sites. MDP hydrogels were found to enhance macrophage recruitment to the injury site and degrade efficiently over time. Rats that were injected with the MDP hydrogel K₂ and laminin motif-containing MDPs K₂-IIKDI and K₂-IKVAV were found to have significantly accelerated functional recovery and remyelination compared to those injected with HBSS or other MDPs. These results demonstrate that MDPs enhance neurite outgrowth and promote a multicellular pro-regenerative response in peripheral nerve injury. This study provides important insights into the potential of MDPs as biomaterials for nerve regeneration and other clinical applications.

Keywords: Bioactive materials; Peptide hydrogel; Peptide mimics; Peripheral nerve regeneration; Sciatic nerve crush injury.