The MDP family provides a diversity of scaffolds that can be designed or used for different bioactivity or specific applications, such as small-molecule and protein delivery, cell support, or tissue engineering. However, non-ionic neutral MDP hydrogels are also formed when steric interactions are used to regulate self-assembly and hydrogelation of these peptides. The most common MDP design utilizes ionic residues such as lysine, arginine or glutamate to modulate molecular assembly and hydrogel formation in response to pH changes or addition of multivalent ions. In aqueous solutions, the amphiphilic core drives aggregation by hydrophobic packing and hydrogen bonding along the peptide backbone, while the N- and C-terminal domains controls self-assembly with ion-ion repulsion or steric constraints. MDPs are composed of a core of alternating hydrophilic and hydrophobic residues which drive assembly and flanking domains which mediate or control assembly. In this category are the self-assembling multidomain peptide (MDP) hydrogels, which rely on the molecular assembly of amphiphilic peptides into nanofibers. Furthermore, hydrogels can be designed to be fully composed of natural amino acids, providing inherent biocompatibility, structural diversity, tunable mechanical properties, degradation without adverse effects, and a platform for the incorporation of bioactive cues. These materials can be designed to form hydrogels - crosslinked fibrous networks with high water content - that provide physical similarity to tissues. Peptide-based materials have shown great promise for biomedical applications because of their capacity to mimic the structure and complexity of the extracellular matrix (ECM), which is usually damaged or lost in injury and disease. This study provides important insights into the potential of MDPs as biomaterials for nerve regeneration and other clinical applications. These results demonstrate that MDPs enhance neurite outgrowth and promote a multicellular pro-regenerative response in peripheral nerve injury. Rats that were injected with the MDP hydrogel K 2 and laminin motif-containing MDPs K 2-IIKDI and K 2-IKVAV were found to have significantly accelerated functional recovery and remyelination compared to those injected with HBSS or other MDPs. MDP hydrogels were found to enhance macrophage recruitment to the injury site and degrade efficiently over time. 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. Using an in vitro screening system, various lysine based MDPs were found to enhance neurite outgrowth. 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. 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. The peripheral nervous system (PNS) substantially recovers after injury, partly due to the abundance of extracellular matrix (ECM) components in its basal lamina. However, their capacity to promote nervous system regeneration remains unknown. Multidomain peptide (MDP) hydrogels are a class of self-assembling materials that have been shown to elicit beneficial responses for soft tissue regeneration.
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