Ultrasound-Enhanced Gelation of Stimuli-Responsive and Biocompatible Phenylalanine-Derived Hydrogels

Stimuli-responsive materials, particularly supramolecular hydrogels, exhibit a dynamic adaptability to external factors such as pH and ultrasound. Among these, phenylalanine (Phe)-derived hydrogels are promising due to their biocompatibility, biodegradability, and tunable properties, making them ideal for biomedical applications. This study explores the effects of pH and ultrasound on the gelation properties of <i>N</i>-substituted Phe derivatives, with a primary focus on the role of ultrasound in optimizing the gelation process. A series of <i>N</i>-substituted Phe derivatives were synthesized via reductive amination and hydrolysis. Hydrogel formation was possible with two of these compounds, namely <b>G1</b> and <b>G2</b>, using the following two methods: heating-cooling (H-C) and heating-ultrasound-cooling (H-US-C). The critical gelation concentration (CGC), gelation kinetics, thermal stability (<i>T</i>_gel), and viscoelastic properties were assessed. Morphological and cytotoxicity analyses were performed to confirm the suitability of these gels for biomedical applications. Both <b>G1</b> and <b>G2</b> derivatives demonstrated enhanced gelation under the H-US-C protocol compared to H-C, with notable reductions in CGC (up to 47%) and gelation time (by over 90%). Ultrasound-induced gels led to an improved network density and stability, while maintaining thermal reversibility and mechanical properties comparable to those of hydrogels formed without ultrasound. Cytotoxicity studies confirmed a high biocompatibility, with cell viability rates above 95% across the tested concentrations. Given the similar rheological and morphological properties of the hydrogels regardless of the preparation method, drug release experiments were performed with representative gel samples and demonstrated the efficient encapsulation and controlled release of 5-fluorouracil and methotrexate from the hydrogels, supporting their potential as pH-responsive drug delivery platforms. This study highlights the role of ultrasound as a powerful tool for accelerating and optimizing the gelation process of supramolecular hydrogels, which is particularly relevant for applications requiring rapid gel formation. The developed Phe-based hydrogels also demonstrate promising characteristics as drug delivery systems.