Calcium-mediated control of supersaturated L-phenylalanine hydrogel formation: from molecular self-assembly to...

This study systematically investigates the influence of calcium concentration on the structural, rheological, mechanical, and drug release properties of L-phenylalanine (L-Phe) hydrogels prepared from supersaturated L-Phe solutions, without the need for chemical modification. Rheological analyses revealed strain-dependent behavior and robust gel formation, with elasticity decreasing as calcium concentration increased. Mechanical testing showed a non-monotonic relationship between calcium concentration and both hardness and viscosity, peaking at 0.1 M. Microstructural analysis using scanning electron microscope and confocal microscopy demonstrated significant morphological transitions, from linear fibers to entangled structures and aggregated bands, with increasing calcium levels. X-ray diffraction and small-angle X-ray scattering (SAXS) analyses confirmed a shift from ordered crystalline to amorphous structures. SAXS further indicated changes in aggregate size, distribution, and fractal dimensions. Fourier transform infrared spectroscopy revealed enhanced interactions between calcium ions and L-Phe molecules, including hydrogen bonding and coordination. In vitro drug release studies, employing riboflavin as a model drug, demonstrated enzyme-mediated release in simulated intestinal fluid (SIF), with release rates modulated by calcium concentration. Molecular dynamics simulations provided atomic-level insights into the gelation process, highlighting the formation of compact and stable structures mediated by Phe‑calcium interactions and the generation of cavities within the gels. Collectively, these findings underscore the critical role of calcium concentration in tuning the properties of L-Phe hydrogels, offering valuable guidelines for designing these materials for diverse biomedical applications.