Engineering a self-protecting dermal filler: active hyaluronidase inhibition extends the in vivo persistence of cross-linked hyaluronic acid hydrogels.

Hyaluronic acid (HA) is a naturally occurring polysaccharide with high biocompatibility and an exceptional capacity for water retention, making it a critical component in drug delivery and soft tissue applications. However, native HA exhibits a very short in vivo half-life due to rapid enzymatic degradation. We developed a cross-linked hyaluronic acid (CLHA) hydrogel incorporating active hyaluronidase inhibitors to delay enzymatic degradation and prolong its in vivo persistence. The formulations underwent physicochemical characterisation and rheological profiling to assess their performance. Additionally, in vitro cytotoxicity, in vivo biodegradation, systemic toxicity, and pharmacokinetic evaluations were conducted. Evaluation of several inhibitors identified sodium aurothiomalate (AHM) at a 0.6% (w/w) concentration (AHM0.6) as the most effective formulation, providing sustained resistance against enzymatic erosion while maintaining a favourable safety profile. By limiting hyaluronidase activity, the hydrogel preserves its viscoelastic properties and improves the functional performance of hyaluronic acid. Overall, these findings suggest that localized enzymatic inhibition is a viable strategy for enhancing the durability and performance of HA-based biomaterials in clinical procedures such as soft tissue augmentation.