Schiff-Base Cross-Linked Hydrogels Based on Properly Synthesized Poly(ether urethane)s as Potential Drug Delivery Vehicles in the Biomedical Field: Design and Characterization

<i>In situ</i>-forming hydrogels based on the Schiff-base chemistry are promising for drug delivery applications, thanks to their stability under physiological conditions, injectability, self-healing properties, and pH-responsiveness. In this work, two water-soluble poly(ethylene glycol)-based poly(ether urethane)s (PEUs) were engineered. A high-molecular-weight PEU (SHE3350, <i>M̅</i> _n 24 kDa, <i>D</i> 1.7), bearing primary amino groups along each polymeric chain, was synthesized using N-Boc serinol and subjected to an acidic treatment to expose primary amines (<i>ca.</i> 10²⁰ units/g_SHE3350). In parallel, a low-molecular-weight PEU (AHE1500, <i>M̅</i> _n 4 kDa, <i>D</i> 1.5) with aldehyde end groups was synthesized by end-capping an isocyanate-terminated prepolymer with 4-hydroxybenzaldehyde, and the aldehyde groups were quantified to be around 10²⁰ units/g_AHE1500. Hydrogels were prepared by simply mixing SHE3350 and AHE1500 aqueous solutions and characterized to assess their physico-chemical and rheological properties. Schiff-base bond formation was proved through carbon-13 and proton solid-state NMR spectroscopies. Rheological characterization confirmed the formation of gels with high resistance to applied strain (<i>ca.</i> 1000%). Hydrogels exhibited high absorption ability (<i>ca.</i> 270% increase in wet weight) in physiological-like conditions (i.e., 37 °C and pH 7.4) up to 27 days. In contact with buffer at pH 5, enhanced fluid absorption was observed until dissolution occurred starting from 13 days due to Schiff-base hydrolysis in acidic conditions. Conversely, gels showed a reduced absorption ability at pH 9 due to shrinkage phenomena. Furthermore, they exhibited high permeability and controlled, sustained, and pH-triggered release of a model molecule (i.e., fluorescein isothiocyanate dextran) for up to 17 days. Lastly, the hydrogels showed easy injectability and self-healing ability.