Detection of a new reaction by-product in BDDE cross-linked autoclaved hyaluronic acid hydrogels by LC–MS analysis

Abstract

BackgroundHyaluronic acid (HA), a naturally occurring polysaccharide, is used in the production of dermal fillers for esthetic purposes. As it has a few days of half-life in human tissues, HA-based dermal filler is chemically modified to increase its lifetime in the body. The most common modification used in commercial HA-based filler is the cross-linking of HA chains using 1,4-butanediol diglycidyl ether (BDDE) as cross-linking agent. Residual, or unreacted, BDDE is considered nontoxic when it is <2 parts per million (ppm); therefore, the quantification of residual BDDE in the final dermal filler is mandatory to ensure the safety of the patients.Materials and methodsThe present study describes the detection and characterization of one by-product of the cross-linking reaction between BDDE and HA in alkaline conditions by combining both liquid chromatography and mass spectroscopy (LC–MS).ResultsAfter different analyses, it was found that the alkaline conditions and the high temperatures employed to sterilize the HA–BDDE hydrogel promote the formation of this new by-product, a “propene glicol-like” compound. LC–MS analysis confirmed that this by-product have the same monoisotopic mass as that of BDDE, a different retention time (tR), and also a different UV absorbance (λ=200 nm) pattern. Unlike BDDE, it was observed in the LC–MS analysis that this by-product had a higher detection at 200 nm in the same assay conditions.ConclusionThese results suggest that this new compound does not have an epoxide on its structure. The discussion is open to assess the risk of this new by-product found in the production of HA–BDDE hydrogels (HA dermal fillers) for commercial purposes.

A new nonhydrophilic agarose gel as subdermal filler for facial rejuvenation: Aesthetic results and patient satisfaction

“…When using HA fillers for volume augmentation, we should take into consideration that most of this HA products, especially those that give more volume to the tissue, are made out of reticulated HA. This reticulation can be obtained with different reticulating agents and the toxicity of this molecules in the long term is not clearly understood in most cases 5 . Therefore, agarose can be a good alternative for those patients starting with filler or for those that have already received multiple injections with reticulated HA 12…”

“…One of the problems of reticulated HA fillers is that they include different types of reticulating agents in order to maintain the filler structure, such as 1,4‐butanediol diglycidyl ether (BDDE). Although HA is itself a natural and safe molecule, already present naturally in our normal skin, the reticulating agents can be toxic when deposited in higher concentrations 5 …”

Complication management of hyaluronic acid aesthetic treatments

“…Az oedema lehet lokalizált vagy generalizált, kifejezetten súlyos és elhúzódó. Kezelésében orális kortikoszteroid és antihisztamin jön szóba (28).…”

Comparative Evaluation of the Effectiveness of Novel Hyaluronic Acid-Polynucleotide Complex Dermal Filler

“…The most popular type of filler contains hyaluronic acid (HA). However, the use of HA fillers carries an inherent risk of hypersensitivity reactions because these fillers contain hyaluronan-related proteins and 1,4-butanediol diglycidyl ether (BDDE) 5,6 . In addition, small fragments of HA can cause inflammation and elicit adverse effects that include erythema, slight oedema, hematoma, itching, and pain [7][8][9] .…”

“…In addition, small fragments of HA can cause inflammation and elicit adverse effects that include erythema, slight oedema, hematoma, itching, and pain [7][8][9] . A recent study showed that the biocompatibility of HA-based materials decreases with an increase in the number of modifications to this polysaccharide 5,6,10 .…”