4.5 Article

In vitro toxicity assessment of crosslinking agents used in hyaluronic acid dermal filler

Journal

TOXICOLOGY IN VITRO
Volume 70, Issue -, Pages -

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tiv.2020.105034

Keywords

BDDE; PEGDE; Crosslinkers; Dermal filler; HaCaT cells; HDF cells

Categories

Funding

  1. Ministry of Trade, Industry and Energy (MOTIE), Korea Institute for Advancement of Technology (KIAT) through the Encouragement Program for The Industries of Economic Cooperation Region [P0010348]

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The study found that BDDE led to higher cytotoxicity, affected cell viability and membrane integrity, increased ROS levels and MMP loss, and elevated inflammatory responses in cells, whereas PEGDE showed lower cytotoxicity, ROS production, and inflammatory responses. The data suggests that PEGDE is safer than BDDE as a crosslinker in HA dermal fillers.
Hyaluronic acid (HA) dermal fillers are produced by crosslinking HA with agents, such as 1,4-butanediol diglycidyl ether (BDDE) and poly (ethylene glycol) diglycidyl ether (PEGDE) to acquire desired properties. Thus, the safety evaluation of these crosslinkers is needed at the cellular level. In the present study, cell viability, cytotoxicity, membrane integrity, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and inflammatory responses were evaluated in the human keratinocyte cell line, HaCaT and human dermal fibroblast cell line, HDF in response to treatment with the crosslinkers. In both the cell lines, BDDE significantly decreased cell viability at 100-1000 ppm, while PEGDE showed a decrease at 500-1000 ppm. In HaCaT cells, BDDE markedly increased cytotoxicity (lactate dehydrogenase release) at 100-1000 ppm, but PEGDE showed an increase at 500-1000 ppm. Cells treated with BDDE (100 ppm) caused alteration in the integrity of cell membrane and shape. In both the cell lines, BDDE-treated cells showed significantly higher ROS levels and MMP loss than PEGDE-treated cells. Also, BDDE-treated cells exhibited higher COX-2 expression at 100 ppm. Expression of inflammatory cytokines (TNF-alpha, and IL-1 beta) was higher in BDDE-treated cells. Taken together, PEGDE-treated cells showed markedly lower cytotoxicity, ROS production, and inflammatory responses than BDDE-treated cells. Our data suggest that PEGDE is safer than BDDE as a crosslinker in HA dermal fillers.

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