Aliphatic and Aromatic Dialdehydes as Chemical Cross-Linkers for Self-Assembled Peptide Gels

Self-assembled peptide-based hydrogels are being developed for a range of biomedical applications conducive to their soft mechanical behavior. Developing methods to enhance their mechanical rigidity would expand their utility to applications demanding stiffer materials. Herein, we systematically study a family of aliphatic and aromatic dialdehydes to establish how their chemical structure determines the formation of covalent cross-links, modulates gel mechanical stiffness, influences macromolecular diffusion within and release from the gel network, and affects material cytocompatibility. We also assess how stoichiometry, buffer composition, pH, and synthetic protocol influence cross-linking potential. Chemical, mechanical, and microscopy experiments show that both aliphatic and aromatic dialdehydes can modulate gel properties but through unexpected different mechanisms. Studies also show that pH and the method of dialdehyde addition significantly influence cross-linking potential. Under appropriate environmental conditions, aliphatic dialdehydes afford significant enhancements (200–300-fold) in gel storage moduli (G′), depending on the identity of the dialdehyde. Surprisingly, small aromatic dialdehydes afford a 250–270-fold enhancement without forming any covalent bonds. Gel properties such as macromolecular diffusion, release, and cytocompatibility are influenced by the extent and nature of covalent cross-linking.