A review of hydrophobic modification of chitosan for enhanced transdermal drug delivery and skin repair

Abstract

Chitosan (CS), a linear aminopolysaccharide derived from chitin, exhibits poor solubility in neutral, alkaline, and organic media. This review systematically summarizes recent advances in hydrophobic modification strategies (aldehyde grafting, acylation, and etherification) for CS and their applications in transdermal drug delivery and skin repair. Aldehyde grafting and acylation reactions selectively modified the -NH₂ groups of CS under mild conditions. In contrast, etherification was non selective, yielding higher degrees of substitution up to 1.91. Hydrophobically modified chitosan (HM-CS) exhibited enhanced antioxidant properties, antibacterial and antifungal activities, transdermal permeability, and greater emulsion stability compared with unmodified CS. HM-CS self-aggregated into particles with diameters ranging from 80 to 360 nm, which effectively encapsulated and delivered oil-soluble bioactive compounds. Notably, HM-CS-stabilized microemulsions achieved curcumin loading of 3.41 ± 0.13 mg/mL, which was ≈30,000 times its water solubility. Additionally, these microemulsions achieved a cumulative transdermal delivery of 297.30 ± 18.30 μg/cm² within 24 h in the studied models. HM-CS-stabilized hydrogels accelerated wound re-epithelialization within 5 days, and achieved complete (100 %) wound contraction by day 10, driven by enhanced angiogenesis and collagen deposition. The modification parameters were correlated with self-aggregation behavior and biological efficacy. These findings provide a framework for optimizing CS-based carriers in biomedical applications. This review highlights the potential of HM-CS in transdermal drug delivery and identifies key challenges, including scalable synthesis and clinical validation, to guide future research.