Schiff-Base Cross-Linked\nHydrogels Based on Properly\nSynthesized Poly(ether urethane)s as Potential Drug Delivery Vehicles\nin the Biomedical Field: Design and Characterization

<i>In situ</i>-forming hydrogels based on the\nSchiff-base\nchemistry are promising for drug delivery applications, thanks to\ntheir stability under physiological conditions, injectability, self-healing\nproperties, and pH-responsiveness. In this work, two water-soluble\npoly(ethylene glycol)-based poly(ether urethane)s (PEUs) were engineered.\nA high-molecular-weight PEU (SHE3350, <i>M̅</i><sub>n</sub> 24 kDa, <i>D</i> 1.7), bearing primary amino groups\nalong each polymeric chain, was synthesized using N-Boc serinol and\nsubjected to an acidic treatment to expose primary amines (<i>ca.</i> 10<sup>20</sup> units/g<sub>SHE3350</sub>). In parallel,\na low-molecular-weight PEU (AHE1500, <i>M̅</i><sub>n</sub> 4 kDa, <i>D</i> 1.5) with aldehyde end groups was\nsynthesized by end-capping an isocyanate-terminated prepolymer with\n4-hydroxybenzaldehyde, and the aldehyde groups were quantified to\nbe around 10<sup>20</sup> units/g<sub>AHE1500.</sub> Hydrogels were\nprepared by simply mixing SHE3350 and AHE1500 aqueous solutions and\ncharacterized to assess their physico-chemical and rheological properties.\nSchiff-base bond formation was proved through carbon-13 and proton\nsolid-state NMR spectroscopies. Rheological characterization confirmed\nthe formation of gels with high resistance to applied strain (<i>ca.</i> 1000%). Hydrogels exhibited high absorption ability\n(<i>ca.</i> 270% increase in wet weight) in physiological-like\nconditions (i.e., 37 °C and pH 7.4) up to 27 days. In contact\nwith buffer at pH 5, enhanced fluid absorption was observed until\ndissolution occurred starting from 13 days due to Schiff-base hydrolysis\nin acidic conditions. Conversely, gels showed a reduced absorption\nability at pH 9 due to shrinkage phenomena. Furthermore, they exhibited\nhigh permeability and controlled, sustained, and pH-triggered release\nof a model molecule (i.e., fluorescein isothiocyanate dextran) for\nup to 17 days. Lastly, the hydrogels showed easy injectability and\nself-healing ability.