Boosting Supramolecular\nGelation Efficiency and Properties:\nIonic Strength as a Key to Superior Hydrogels

Controlling the minimum gelation concentration (MGC)\nof low molecular\nweight (LMW) hydrogelators is a key for modulating gel properties,\nsuch as mechanical strength, viscoelasticity, and stability, which\nare crucial for applications ranging from drug delivery to tissue\nengineering. However, tweaking the MGC under specific conditions,\nsuch as pH and/or temperature, poses a considerable challenge. Herein,\nwe varied the ionic strength of buffer solutions using NaCl for several\nLMW hydrogelators, including Fmoc-Phe, Fmoc-Tyr, Fmoc-Trp, Fmoc-Met,\nand Fmoc-Cha, and assessed their gelation efficiency at pH 7.4 and\nambient temperature. Interestingly, Fmoc-Phe demonstrated a ∼67%\n(3-fold) MGC reduction, from 0.24 to 0.08 wt %, at 500 mM NaCl, transforming\nit a “super hydrogelator” (MGC < 0.1 wt %), while\nFmoc-Trp showed 60% MGC reduction. Higher ionic strength effectively\nshields the electrostatic repulsion between negatively charged (−COO<sup>–</sup>) groups on the Fmoc-Phe, promoting closer aggregation\nand more efficient self-assembly and allowing for gelation at lower\nconcentrations. In contrast, Fmoc-Met, Fmoc-Cha, and Fmoc-Tyr precipitated\nin the presence of NaCl, suggesting that NaCl specifically modulates\nthe MGC of Fmoc-amino acid gelators containing unsubstituted aromatic\nside chains. Furthermore, these results indicate that cation-π\ninteractions likely play a role, alongside carboxylic acid neutralization.\nWhile Fmoc-Phe forms gels in the presence of other monovalent cations,\nit does not form a hydrogel in the presence of divalent (CaCl<sub>2</sub>) and trivalent (AlCl<sub>3</sub>), indicating that enhancement\nof hydrogelation is specific to monovalent cations. Although the fibrillar\nstructure of Fmoc-Phe hydrogels remained consistent, addition of NaCl\nincreased fibril stickiness, creating densely packed networks that\nmodulate the mechanical strength. Unlike typical cases where increased\nionic strength leads to precipitation, Fmoc-Phe gelation at high NaCl\nconcentrations (150–500 mM) is significant, yielding a robust\nsupramolecular hydrogel that remains stable in high ionic-strength\nenvironments. This outcome suggests that ionic strength could be a\nvaluable factor to enhance the efficient gelation of LMW hydrogelators.