Degradation of Hylauronic Acid Fillers Using Hyaluronidase in an In Vivo Model

May 2018 | Volume 17 | Issue 5 | Original Article | 548 | Copyright © 2018

Rodrigo Moraes Ferraz MD,a Ulrika Sandkvist MSc,b and Björn Lundgren PhDb

aRodrigo Ferraz Dermatologia, Belo Horizonte, Brazil bGalderma, Uppsala, Sweden

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Abstract

Introduction: Soft tissue fillers manufactured with hyaluronic acid (HA) dominate the filler market around the world and the fact that HA can be dissolved using hyaluronidase contributes to its popularity. Degradation of cross-linked HA products can be performed in situ and access to hyaluronidase is therefore essential for health care professionals (HCP) to perform safe filler treatments. The aim of the present study was to develop an in vivo model where hyaluronidase degradation of HA fillers can be studied in a standardized manner and then secondly, to explore the degradation of marketed HA fillers with different product characteristics. Methods: Intradermal injections of HA fillers were performed and the injection sites were treated with hyaluronidase. The degradation was evaluated by measuring the heights of the injection site bumps during 5-7 days and with histology at day 7 post injection. Results: The results showed that there was a correlation between the hyaluronidase dose and HA filler degradation. The onset of the degradation was fast for all products and the products were easily degraded. Discussion: This standardized animal model proved efficient in the study of in vivo degradation of HA fillers using injected hyaluronidase where products manufactured with different technologies were evaluated. J Drugs Dermatol. 2018;17(5):548-553.

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INTRODUCTION

Historically, many different agents like paraffin, silicon, and collagen have been used for aesthetic purposes to shape and restore the face and body. However, since more than 20 years, cross-linked hyaluronic acid (HA) filler products are used for correction of wrinkles and lines and today HA products dominate the soft tissue filler market. HA is a naturally occurring molecule present in all tissues and a major component of the extracellular matrix (ECM) of the skin. The HA molecules consist of long un-branched chains of alternating units of D-glucuronic acid and N-acetyl-D-glucosamine. This linear polysaccharide can reach a size of 6 to 8 MDa.1 In the body, there is a constant turnover of HA and the half-life in skin is less than one day.2 In order to extend the residence time for the HA based filler products, cross-links are introduced to stabilize the HA molecules into a 3D network and thereby prolonging the duration from days to months or years. The high water-binding capacity of HA together with an excellent safety profile makes it an ideal material for soft tissue filler products.Degradation or de-polymerization of endogenous HA involves primarily enzymatic degradation by hyaluronidases but also degradation by free radicals. In degradation of the HA chains by hyaluronidases, HA fragments are created as the glycosidic bonds between the disaccharides are hydrolyzed. In order for the large HA molecules to be released from the ECM the polymer needs to be at least partially degraded. The HA fragments will then either be further degraded locally or drained from the tissue via the lymphatic system. Local degradation in the skin where HA was synthesized is one of the turnover pathways but the majority of the HA fragments leave the tissue with the lymph and is cleared by endothelial cells in the lymph nodes. What remains after passage through the nodes will reach the circulation and finally be degraded by the liver.3Since hyaluronidase can be used to degrade HA fillers, access to hyaluronidase has become an essential part of the HCP’s toolbox to perform safe filler treatments. Unwanted effects such as overcorrection or nodules may be resolved using hyaluronidase and in case of serious adverse events (AE) such as intravascular injection, hyaluronidase can be used as a rescue therapy. This is a major advantage of HA over other soft tissue filler materials such as poly-L-lactic acid (PLLA), calcium hydroxyapatite (CaHA) and autologous fat.However, there is a common perception among HCPs that some HA products are more difficult to degrade than others, but standardized studies where in vivo degradation was studied are lacking. In vitro tests (performed at the analytical lab of Galderma but not published) have shown that cross-linked HA products can be degraded with hyaluronidase. The modification of the HA molecules that takes place in the cross-linking step does not seem to hinder the degradation with hyaluronidase of the studied products. When comparing degradation behavior of

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