In vitro toxicity assessment of crosslinking agents used in hyaluronic acid dermal filler. (February 2021)

• Record Type: Journal Article
• Authors: Jeong, Chang Hee; Kim, Do Hyun; Yune, Jong Hyeok; Kwon, Hyuk Cheol; Shin, Dong-Min; Sohn, Hyejin; Lee, Keyong Ho; Choi, Bokryul; Kim, E Sle; Kang, Ju Hee; Kim, Eun Kyoung; Han, Sung Gu
• Is Part Of: Toxicology in vitro. Volume 70(2021)
• Publication Date: 2021-02
• Subjects: BDDE -- PEGDE -- Crosslinkers -- Dermal filler -- HaCaT cells -- HDF cells; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2020.105034
• Languages: English
• ISSNs: 0887-2333

Abstract

Abstract: 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-α, and IL-1 β) 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. Highlights: Toxicity of crosslinkers for hyaluronic acid dermal fillers (i.e., BDDE and PEGDE) was evaluated in dermal cell lines. Cytotoxicity, oxidative stress and inflammatory responses were higher in BDDE-treated cells than PEGDE-treated cells. At high concentrations (i.e., 50-100 ppm), PEGDE is more safe crosslinker when a large volume of fillers is required.