Double-crosslinkable poly(urethane)-based hydrogels relying on supramolecular interactions and light-initiated polymerization: promising tools for advanced applications in drug delivery

Physical and chemical hydrogels are promising platforms for tissue engineering/regenerative medicine (TERM). In particular, physical hydrogels are well-suitable to design drug delivery systems due to their reversibility and responsiveness to applied stimuli and external environment. Differently, chemical hydrogels represent the best strategy to produce stable 3D constructs in the TERM field. In this work, these two strategies were combined to develop multi-functional formulations integrating both drug delivery potential with TERM approaches into a single device. Specifically, a novel photo-sensitive poly(ether urethane) (PEU) was developed to form supramolecular networks with α-cyclodextrins (α-CDs). The PEU was successfully synthesized using Poloxamer® 407, 1,6-diisocyanatohexane and 2-hydroxyethyl methacrylate, as assessed by infrared spectroscopy, size exclusion chromatography and proton nuclear magnetic resonance (1H NMR) spectroscopy. Thermo-responsiveness was characterized through critical micellar temperature evaluation and dynamic light scattering analyses which suggested the achievement of a good balance between molecular mass and overall hydrophobicity. Consequently, the formation of supramolecular domains with α-CDs was demonstrated through X-Ray diffraction and 1H NMR spectroscopies. Supramolecular hydrogels with remarkably fast gelation kinetics (i.e., few minutes) were designed at low PEU concentration (≤ 5% w/v). All formulations resulted cytocompatible according to ISO 10993-5 regulation. Noteworthy, mechanical properties and self-healing ability were observed by rheological tests, while fast photo-crosslinking was evidenced (<60 s) by photo-rheology. A high curcumin payload (570 μg ml-1) was encapsulated within the hydrogels, which was released with highly tunable and progressive kinetics in physiological-simulated environment up to 5 weeks. Finally, a preliminary evaluation of printability was performed through an extrusion-based bioprinter obtaining 3D-printed structures showing good morphological fidelity to the original design. Overall, the developed hydrogel platform showed promising properties for application in the emerging field of regenerative pharmacology as (i) easily-injectable drug-loaded formulations suitable for post-application stabilization through light irradiation, and (ii) biomaterial inks for the fabrication of patient-specific drug-loaded patches