Toxicity Assessment of a Single Dose of Poly(ethylene glycol) Diglycidyl Ether (PEGDE) Administered Subcutaneously in Mice

Abstract

Poly(ethylene glycol) diglycidyl ether (PEGDE) is widely used to cross-link polymers, particularly in the pharmaceutical and biomaterial sectors. However, the subcutaneous toxicity of PEGDE has not yet been assessed. PEGDE samples (500–40,000 μg/mouse) were subcutaneously injected into the paraspinal dorsum of BALB/c male mice. Cage-side observations were carried out with measurement of organ weight, body weight variation, and feed intake, as well as histopathological characterization on day 28 post-exposure. Mice that received 40,000 μg of PEGDE showed severe toxic response and had to be euthanized. Subcutaneous injection of PEGDE did not alter feed intake and organ weight; however, the body weight variation of mice injected with 20,000 μg of PEGDE was significantly lower than that of the other groups. Exposure to 10,000 and 20,000 μg of PEGDE induced epidermal ulcer formation and hair loss. The histology of skin tissue in mice administered with 20,000 μg of PEGDE showed re-epithelialized or unhealed wounds. However, the liver, spleen, and kidneys were histologically normal. Collectively, PEGDE, particularly above 10,000 μg/mouse, caused subcutaneous toxicity with ulceration, but no toxicity in the other organs. These results may indicate the optimal concentration of subcutaneously injected PEGDE.

Case Report: Lip Augmentation with Injection of a Novel PEG-crosslinked Hyaluronic Acid Hydrogel

“…Both PEGDE and BDDE have extensive biocompatibility data and a favorable clinical safety profile. Data from in vitro and in vivo studies indicate that PEGDE induces lower levels of dermal toxicity than BDDE [10], [19], and the concentration of residual unreacted PEGDE is estimated at <10 ng/mL; for Food and Drug Administrationapproved HA fillers using BDDE as a cross-linker the residual BDDE content must be inferior to 2 ppm [18]. Histological analysis of skin biopsies obtained 8 months after injection of PEGDE-HA into the hypodermis has revealed no inflammatory cells surrounding the implant or closely associated with it [11], [20].…”

“…While BDDE has been considered the standard cross-linker for the past 20 years, new cross-linking technologies have emerged, potentially bringing novel features to HA fillers. One such strategy utilises poly(ethylene glycol) diglycidyl ether (PEGDE), a water-soluble chemical, widely used in the pharmaceutical and biomaterial sectors to crosslink polymers containing hydroxyl, amine, and carboxyl groups, and now used to crosslink HA in the Neauvia hydrogel product range (PEGDE-HA) [10]. PEGDE is Since 2002 the longest cross-linker employed and it introduces unequal spacers among the HA chains as opposed to simpler molecules such as BDDE.…”

Human dermal fibroblast response to hyaluronic acid-based injectable dermal fillers: an in vitro study

“…Currently, the most common chemical cross-linker used in HA-based IDFs is 1,4-butanediol diglycidyl ether (BDDE) [7]. While being extensively utilized, growing evidence suggests that BDDE is a reactive agent that can be cytotoxic and even mutagenic [8,9]. In this scenario, manufacturers have recently devised novel HA-based IDF formulations with the aim of reducing BDDE content.…”