Hyaluronic acid as a key modulator of physicochemical, thermal and rheological properties in thermosensitive composite hydrogels for ocular drug delivery

This study investigates the role of hyaluronic acid (HA) in modulating the structure-property relationships of an injectable composite drug delivery system (c-DDS) for ocular drug administration. The c-DDS was designed to behave as a viscous fluid at room temperature, enabling intravitreal injection, and to undergo in situ gelation at physiological ocular temperature. The system consists of a thermosensitive poloxamer-based hydrogel embedding biodegradable poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs). HA was incorporated within the hydrogel and as a surface coating on PLGA NPs to modulate the physicochemical properties of the system and control NP mobility. The hydrogels maintained their rheological properties up to four weeks, also following intravitreal injection through a fine-gauge needle and autoclave sterilization. Swelling and thermal analyses highlighted the contribution of each component to the overall behaviour of the system. Multiple particle tracking (MPT) analysis of NP diffusion within the hydrogels demonstrated a crucial role of HA in tuning NP mobility. In vitro studies using ARPE-19 cells confirmed the biocompatibility of the c-DDS and showed effective NPs internalization. Overall, this preliminary study lays a formulation framework for HA-modulated injectable composite hydrogels. This also upholds their further development as ocular delivery platforms for the loading of diverse therapeutic agents, ranging from hydrophilic to lipophilic and from low- to high-molecular weight, along with the subsequent evaluation of their biological implications.