The interaction between hyaluronidase and hyaluronic acid gel fillers - a review of the literature and comparative analysis

Abstract

Hyaluronic acid (HA) is the most common component of aesthetic fillers. Many formulations exist, each exhibiting properties that are manifestations of individual molecular modifications. The enzyme hyaluronidase degrades hyaluronic acid and can therefore be injected into soft tissue to reduce suboptimally placed HA fillers or to reverse local ischemic complications. The clinically available varieties of hyaluronidase may be derived from crude animal extracts or genetically engineered from recombinant human DNA. Different HA fillers are not uniformly dissolved by a single source hyaluronidase, and hyaluronidase from different sources may have varying efficacy in the degradation of HA. Previous studies of subsets of HA fillers and hyaluronidases have provided limited and often conflicting data regarding these differences, and a more comprehensive scientific study is needed. In this review, the authors describe commonly available formulations of HA and hyaluronidase and review all studies of HA-hyaluronidase interaction available via a PubMed and Google Scholar search from 2005 to present, exploring trends in the data. Factors determined to confer increased resistance to degradation included higher concentration of HA, higher crosslinking density, and status as monophasic versus biphasic. Fillers of the Juvéderm family were generally found to be more resistant to degradation than members of the Restylane family. Results are less consistent for Belotero Balance. No variety of hyaluronidase was consistently superior at dissolving any variety of HA filler. More research is needed to clarify these clinically relevant relationships.

Comparative Analysis of Hyaluronidase-Mediated Degradation Among Seven Hyaluronic Acid Fillers in Hairless Mice

“…Also, no consensus was established on which type of hyaluronidase is most superior in dissolving HA fillers. 17 A blind randomized study on the reversal of HA filler injection had demonstrated comparable efficacy between the use of 20 and 40 U ovine hyaluronidase in reducing the volume of 0.2 mL HA filler bolus implants based on significantly lower palpation scores compared to non-treated and saline-treated HA filler implants. The study also reported that identical treatments of ovine hyaluronidase showed no clinically significant difference in HA filler volume reduction among different filler implants from three major HA filler manufacturers, despite variability in cohesive properties, HA content and degree of crosslinking.…”

“…The Juvéderm family of products (AbbVie/ Allergan) uses their proprietary "Hylacross" and "Vycross" technology to manufacture monophasic HA fillers, whereas the Restylane family of products (Galderma) manufacture their biphasic HA dermal fillers using their proprietary non-animal stabilized HA (NASHA) and more recently, "XpresHAn" technology. [15][16][17] Another series of BDDE-crosslinked HA dermal fillers was recently introduced in South Korea. The Neuramis family of products (NEU series, Medytox, Inc.) are monophasic HA dermal fillers manufactured using stabilized HA through purification and enhancement (SHAPE) technology, generating products with varying degree of crosslinking to suit specific clinical indication.…”

Comparative Analyses of Inflammatory Response and Tissue Integration of 14 Hyaluronic Acid-Based Fillers in Mini Pigs

“…All HA dermal fillers in the NEU series are manufactured as having a mono-phasic gel phase similar to BEL fillers, 40–42 and is very distinct from the bi-phasic gel phase of RES fillers. 42 , 43 Mono-phasic HA dermal fillers consist of a mixture of high- and low-molecular weight HA, 15 , 19 whereas bi-phasic HA dermal fillers consist of cross-linked HA admixed with non-crosslinked HA. 44 Mono-phasic fillers have been reported to show higher cohesivity (ie, higher affinity between the gel molecules) and lower viscoelasticity than bi-phasic fillers.…”

Evaluating hyaluronic acid dermal fillers: A critique of current characterization methods

“…Many factors can explain these differences: HA concentration, molecular weight, crosslinking technology and amount of free HA present in the final product 23,29 . Many authors report crosslinking density as the factor with the greatest influence on the rheological properties, specifically the stiffness of the gel 25,30,31 …”