Dual-type dynamic covalent chitosan/whey protein/Sr-doped bioactive glass carriers for hydrophobic compounds:...

Chitosan hydrogel-based systems are recognized as versatile platforms for drug delivery and regenerative medicine. However, incorporating hydrophobic bioactive substances remains a significant challenge, typically addressed through complex chemical modifications such as chitosan hydrophobization. This study introduces a straightforward strategy to incorporate lipophilic compounds - retinol and resveratrol - into chitosan hydrogel-based materials using whey protein isolate (WPI) as an amphiphilic carrier. They were developed as preformed injectable hydrogels and porous scaffolds. The hydrogel network was formed using dextran dialdehyde as crosslinking agent, which created dynamic Schiff base linkages with amino groups of chitosan and potentially WPI. The incorporation of WPI was critical, as its hydrophobic pockets stabilized the lipophilic actives. Additionally, strontium-doped silicate bioactive glass (Sr-SBG) contributed to secondary network stabilization; calcium and strontium ions modified electrostatic interactions, while silicate ions were suggested to promote dynamic covalent ester bonding, improving mechanical strength, self-healing, and injectability. The synergy between WPI and Sr-SBG enabled sustained release and reduced burst release, with retinol showing prolonged release. Materials demonstrated high cytocompatibility and reduced intracellular reactive oxygen species in macrophages. These findings highlight the potential of WPI-assisted, Sr-SBG-reinforced chitosan hydrogel-based systems as tunable biomaterials for regenerative therapies and controlled drug delivery.