Injectable Hyaluronic Acid Hydrogels Crosslinked by Structure-engineered Aldehyde-functionalized β-Cyclodextrin Derivatives for Long-term Controlled Voriconazole Delivery.

Long-term controlled release in drug-loaded injectable hydrogels is challenging in the injection-based treatments of ocular diseases. Herein, injectable hyaluronic acid (HA)-based hydrogels were synthesized in situ via Schiff base reaction between amino-functionalized hyaluronic acid (NHA) and three aldehyde-functionalized β-cyclodextrin (β-CD) derivatives: aldehyde β-cyclodextrin (ACD), aldehyde linear poly-β-cyclodextrin (ALCD), and aldehyde branched poly-β-cyclodextrin (ABCD). The composition, structure, and properties of the prepared hydrogels were analyzed using Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and dynamic rheometry. The hydrogels exhibited a pore size range of 50-250 μm, a swelling degree of 27.1-45.0%, and a gelation time of 60-300 s, demonstrating suitable microstructural and rheological properties for clinical applications. By leveraging the dual functionality of the aldehyde β-CD derivatives as both crosslinking agents and drug carriers (Voriconazole (VCZ) was as a model drug), the hydrogels achieved long-term controlled release (> 60 days) with quasi-zero-order kinetics in the later stage, alongside excellent cellular compatibility, particularly for NHA/ACD (R2 = 0.99701) and NHA/ABCD (R2 = 0.98931). This study presents the first comparative analysis of the effects of structurally distinct aldehyde β-CD/poly-β-CD derivatives on hydrogel properties. The findings provide novel insights into the structural design of aldehyde-functionalized β-CD derivatives for the development of long-term controlled release injectable hydrogels in about 30-60 days as well as tuned. Simultaneously, the corresponding in vivo animal safety and efficacy experiments could further validate the practical application potential of this gel platform in the future work. Conclusively, the injectable HA-based hydrogels have potential as promising candidates for treating chronic ocular pathologies requiring long-term therapy.