Investigation into the safety of perineural application of 1,4-butanediol diglycidyl ether-crosslinked hyaluronan in a rat model

Hyaluronan (HA) is well known for its biocompatibility and has widespread clinical use. To change its mechanical and physiologic properties to adapt to specific clinical scenarios, HA is crosslinked with chemically reactive linker molecules, most of which are toxic chemical reagents. Adverse events related to clinical use of crosslinked HA have been documented. Although approved by the FDA as dermal filler, the safety of perineural application of 1,4-butanediol diglycidyl ether (BDDE)-crosslinked HA has not been assessed critically. Concern exists owing to the vulnerability of neural tissues, because of their elongated morphology, high ratio of membrane surface area to cell volume, and complicated electrophysiologic properties. In this study, we systematically investigated the toxicity profile of BDDE-crosslinked HA, using in vitro and in vivo experiments in a rat model. The in vivo experiments included the evaluation of aspects of histopathology, electrophysiology, and neurobehavior. There were no significant changes in the treatment group compared with the control group in all aspects of the experiments, except for the increased epineurial vascular formation in the 0.5% crosslinked HA-treated group during 2 weeks of observation. Further studies involving perineural application of BDDE-crosslinked HA can be done based on our findings, which ruled out the safety concern of cytotoxicity and adverse changes in electrophysiology and neurobehavior.