Crosslinking hyaluronic acid soft-tissue fillers: current status and perspectives from an industrial point of view

Hyaluronan (HA)-based soft-tissue fillers are injectable crosslinked hydrogels aimed to counteract facial skin aging signs via minimally invasive procedures. The crosslinking step is required to drastically improve HA residence time in vivo and provide the gel with specific viscoelastic properties matching the clinical indications. While HA as a raw material and HA fillers are widely studied, little is reported about crosslinkers themselves used in commercial fillers.This article introduces the specifications of the ideal crosslinker in HA fillers. The properties of commercially used crosslinkers are reviewed. An up-to-date review of innovative hydrogel fabrication alternatives is conducted, and advantages and drawbacks are discussed.HA fillers are predominantly manufactured using 1,4-butanediol diglycidyl ether (BDDE) which is considered as the gold standard crosslinker worldwide due to its proven and unrivaled clinical track record of more than 20 years. Extensive studies have been published covering BDDE-crosslinked HA fillers' chemistry, gel properties, and clinical effectiveness and safety. However, new hydrogel fabrication strategies have emerged, paving the way for innovative alternatives potentially bringing novel features to HA fillers. Nevertheless, major efforts must still be implemented to assess their safety, efficacy, stability and suitability for industrialization.