A review of the metabolism of 1,4-butanediol diglycidyl ether-crosslinked hyaluronic acid dermal fillers

Abstract

Background: Cosmetic procedures are growing ever more common, and the use of soft tissue fillers is increasing. Practicing physicians need to be aware of the biological behavior of these products in tissue to enable them to respond to any safety concerns that their patients raise.

Objectives: To provide an overview of the metabolism of 1,4-butanediol diglycidyl ether (BDDE)-crosslinked hyaluronic acid (HA) dermal fillers and to examine the safety of the resulting byproducts.

Methods: A review of available evidence was conducted.

Results: After reaction with HA, the epoxide groups of BDDE are neutralized, and only trace amounts of unreacted BDDE remain in the product (<2 parts per million). When crosslinked HA, uncrosslinked HA, and unreacted BDDE degrade, they break down into harmless byproducts or into byproducts that are identical to substances already found in the skin.

Conclusion: Clinical and biocompatibility data from longer than 15 years support the favorable clinical safety profile of BDDE-crosslinked HA and its degradation products. Given the strength of the empirical evidence, physicians should be confident in offering these products to their patients.

Figure 1

Metabolism of BDDE.

Figure 2

Schematic showing the crosslinking reaction of hyaluronic acid chains with BDDE. The epoxide groups in BDDE preferentially react with the primary hydroxyl groups in the HA backbone, resulting in “fully reacted crosslinker” (A) or “pendant crosslinker” (B). BDDE that has not reacted with HA can be present in its hydrolyzed form “deactivated crosslinker” (C) or its native form “residual crosslinker” (D). *Since the sum of all four forms of BDDE is <5 mg/mL, or 5,000 ppm, the trace levels of the native form D (<2 ppm) represent a minute fraction of that sum.