Influence of the Macro- and/or Microstructure of Cross-Linked Hyaluronic Acid Hydrogels on the Release of Two Model Drugs

Injectable hyaluronic acid (HA) hydrogels, crosslinked with 1,4-butanediol diglycidyl ether (BDDE), are widely used in aesthetic medicine. Due to their high clinical tolerance, HA hydrogels are thought to be applicable as injectable drug delivery systems. Here, HA matrix structures of BDDE-crosslinked HA hydrogels were analysed, and the effects of the structures on the release of two model drugs were assessed. Seven crosslinked HA hydrogels were observed by optical microscopy and cryo scanning electron microscopy (cryo-SEM). We observed three specific matrix macrostructures under optical microscopy: two had a “spider web”-like structure, three had a particulate structure, and two had an intermediate structure. These differences were less evident under cryo-SEM, where all hydrogels exhibited fibrous microstructures of different homogeneity levels, with pore sizes between 0.5 and 18 μm. Three cross-linked HA hydrogels with different macrostructures were loaded with bovine serum albumin (BSA) and lidocaine to assess their capacities to release drug over 4 days. No differences in drug release were observed between gels, and BSA was released for up to 4 days, which was four times longer than lidocaine. Thus, BDDEcrosslinked HA hydrogels could be applied as an injectable drug delivery system, particularly for the delivery of high-molecular-weight molecules.