Page 392 - Read Online

Page 2 of 11 Paap et al. Plast Aesthet Res 2020;7:36 I http://dx.doi.org/10.20517/2347-9264.2020.121

INTRODUCTION
Hyaluronic acid (HA) in various configurations of density and crosslinking is commonly used as a
substrate for dermal fillers. These widely available and popular fillers augment volume and smooth contour
[1]
irregularities in cosmetic and age-related changes of the face, hands and other anatomic areas . Though
many filler materials, including collagen, autologous fat, calcium hydroxyapatite, and poly-L-lactic acid are
[2]
used in facial rejuvenation, HA accounts for more injections than all other filler varieties combined .
One of the main advantages of HA fillers is their easy reversibility. This quality is useful as a means of
[3]
addressing patient dissatisfaction from superficial or inappropriate placement following filler injection .
Additionally and most importantly, these injections have been associated with rare but serious ischemic
complications including local soft tissue necrosis as well as blindness from possible embolic occlusion of
[3]
the central retinal artery . Hyaluronidase is a naturally occurring enzyme that catalyzes the degradation of
[4,5]
HA by hydrolyzing the bond between N-acetylglucosamine and glucuronic acid . In addition to its off-
label use as a subcutaneous adjuvant that increases the dispersion of drugs, it has been shown to be effective
[6-9]
in both reversing the volumetric effects of HA filler injections and treating local ischemic complications ,
although the reversibility of HA filler associated blindness with hyaluronidase has not been established [10,11] .
Understanding the interactions between the various fillers and the enzymes available for dissolution might
optimize outcomes in the event of a filler misplacement or occlusive event.

Since the first FDA approval in 2003 of the HA-containing filler, Restylane, additional HA formulations
have become commercially available. Aiming to increase stability and longevity, manufacturers of HA fillers
[12]
chemically modify the molecules by crosslinking them into larger conjugated derivatives . The different
HA fillers vary according to the method and extent of crosslinking, concentration of HA, particulate
[13]
size, HA source, and status as monophasic or biphasic . This influences the properties of each gel filler,
[2]
including hydrophilia, cohesivity, hardness, and viscosity . Clinically, knowledge of these differences can
[6]
be used to select the optimal HA filler for a given application . Additionally, the structural differences
between HA fillers are known to alter their response to hyaluronidase [2,6,12,14-18] .
Hyaluronidase, similarly, is available in several formulations, broadly categorized as purified crude extracts
[19]
from ovine or bovine testicular tissue, and products of recombinant technology from human DNA .
Though all major formulations are dosed equivalently, each type has its own optimal pH and is considered
[19]
therapeutically distinct by the FDA .

In the clinical setting, it has been reported that some fillers are more or less responsive to enzymatic
[16]
degradation as compared to others . Thus, the interaction between different HA fillers and the varieties of
hyaluronidase is an area of research with important implications, especially for the choice of reversal agent
in treating suboptimal outcomes or complications from filler injections. Although multiple studies have
explored the effect of hyaluronidase on different types of HA fillers, few have examined more than a single
type of hyaluronidase [6,16] . A comprehensive analysis of the full range of commercially available HA fillers
and hyaluronidases is needed. Unfortunately, the literature to date concerning this topic has been noted
[20]
to exhibit significant and unresolved heterogeneity in both experimentation and results . To address the
incompletely answered question of how different HA fillers respond to different types of hyaluronidase,
the authors first summarize the known literature available on PubMed and Google Scholar of HA-
hyaluronidase interactions. The authors then attempt to clarify, across studies, the relationships between
commercially available HA-based fillers and ovine-, bovine-, and recombinant-sourced hyaluronidase.
Results from experiments using different fillers and hyaluronidases are cross-referenced and information
describing how different HA fillers respond to hyaluronidase will be presented. Additionally, possible
explanations for discrepancies found across studies are explored. Through this review, we attempt to
provide a summary of foundational knowledge and highlight the need for future clarifying studies.