Pushing the Limit of Self-Assembly Ultrashort Peptides Minimum Gelation Concentration for Advanced Biomedical Applications

Ultrashort amphiphilic peptides, characterized by a distinct sequence motif and comprising up to seven natural amino acids, display self-assembling dynamics under physiological conditions. Despite their small size, these peptides can adopt α-helical, β-sheet, and β-turn secondary structures in aqueous solutions. At higher concentrations, they spontaneously organize into nanofibers, resulting in hydrogels characterized by an exceptionally high water content (>99% w/w). Notably, these hydrogels exhibit biocompatibility, biodegradability, and low immunogenicity, making them versatile for various biomedical applications such as 3D cell culture, bioinks for 3D bioprinting, hemostatic agents, drug delivery systems, and materials for soft tissue repair. By strategically substituting certain amino acids in the sequence with non-natural counterparts, we achieved the lowest reported minimum gelation concentration for self-assembling peptides, thereby expanding their potential applications. In-depth analyses using 2D-NMR, Raman spectroscopy, and molecular dynamic (MD) simulations were conducted to further elucidate the self-assembly process. These peptides serve as scaffolds capable of supporting cellular viability and proliferation without compromising the mechanical properties of the hydrogel. The results demonstrate the potential of these scaffolds for advanced biomedical applications. Specifically, we demonstrated the capability of the developed peptide scaffolds to be combined with human platelet lysate up to 40% of its volume without compromising the self-assembly process. This forms a hydrogel scaffold that can self-sustain and promote cellular growth under xenofree 3D culture conditions. The hybrid peptide and platelet lysate hydrogel developed in this study holds immense promise for clinical applications in the field of regenerative medicine.