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Page 2 of 8 Gavard Molliard et al. Plast Aesthet Res 2018;5:17 I http://dx.doi.org/10.20517/2347-9264.2018.10

INTRODUCTION
Injectable hydrogels known as fillers are commonly used in aesthetic medicine to shape the face or to treat
signs of facial ageing, e.g., to smooth superficial wrinkles or to palliate age-related atrophy and ptosis by
remodeling some parts of the face. Among these injectable hydrogels, hyaluronic acid (HA) fillers have a
dominant and unchallenged position . In 2016, according to the American Society for Aesthetic Plastic
[1]
Surgery (ASAPS), 2.49 million HA filler treatments were performed only in the USA with a high growth of
16.1% versus the previous year . With the rising interest in the HA treatments and the increasing number of
[2]
available HA fillers on the worldwide market, there is a strong demand from the medical community to better
understand the science behind these products in order to optimize aesthetic outcomes and safety. Available
HA fillers are designed with different manufacturing technologies , different HA concentrations ,
[3,4]
[5]
different crosslinked three-dimensional network structures , different pore size distributions of the fibrous
[6]
HA networks , and different cohesivity levels and rheological properties . Among the proprietary
[7]
[8,9]
[6]
manufacturing technologies, which all allow obtaining specific rheological properties, we can mention the
VYCROSS™ (Allergan Inc., Irvine, CA, USA), the NASHA™ (Galderma Pharma S.A., Lausanne, Switzerland)
and the CPM™ (Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany) technologies. The VYCROSS™
technology uses a combination of low and high molecular weight of HA during the crosslinking to improve
the efficacy of the chemical reaction. The NASHA™ technology uses a step of controlled particle sizing,
after the crosslinking reaction, to obtain specific HA gel textures. The CPM™ technology uses a two-step
process during the crosslinking reaction for obtaining a cohesive gel with different crosslinking densities of
the HA network. Recently, a novel proprietary manufacturing technology for the production of innovative
HA fillers has been discovered. It is the OXIFREE™ technology (Kylane Laboratoires S.A., Plan-les-Ouates,
Switzerland) which is characterized by the extraction of destructive oxygen during the manufacturing
process, including during the crosslinking step, for significantly preserving the intrinsic properties of the
long molecular weight of HA chains. This new technology provides HA fillers with advanced rheological
properties which enable to exhibit strong projection capacities and therefore a high ability to volumize the
facial skin tissues. All the fillers available on the market are designed by the manufacturers with the aim to be
injected by the physicians into the dermal layer, for the superficial ones or into the subcutaneous tissues, for
the products with a higher projection capacity. Due to their clinical applications and the major importance
of their mechanical behavior features to achieve safe and good results, the rheological properties of the HA
fillers are naturally considered key in the field and it is the reason why many articles have been published on
this topic over the past few years [8-12] . Some of these articles emphasize the importance of the science-based
evaluation of HA fillers and more specifically the rheologic tailoring for guiding physicians to identify the
HA fillers that they want to use and to select the most appropriate administration technique and depth of
injection . Nevertheless, to the best of our knowledge, no published article has evaluated the relevance of
[9]
the key rheological parameters of a HA filler during its whole clinical lifetime, i.e., from injection of the HA
gel into skin tissues to its in vivo degradation over the months, as it is the case in this article. In the light of
the assessment of these key rheological parameters, this article also analyzes the mechanical behavior of a
novel HA fillers range, benefiting from the OXIFREE™ technology, in order to better understand the safety
and the performance of these new products from the injection into skin tissues up to the loss of the clinical
effects. Notably, the projection capacity of these new HA fillers is compared to that of the market leader in
the volumizing segment, Juvéderm Voluma™ (Allergan Inc., Irvine, CA, USA), a device produced according
to the VYCROSS™ technology.

METHODS
Materials
Five crosslinked HA fillers intended for facial injection in aesthetic medicine were subjected to flow,
oscillatory shear-stress and compression tests with a DHR-1 rheometer (TA Instruments, New Castle, PA,
USA). Among these 5 HA fillers, four are manufactured according to the novel OXIFREE™ technology
[Table 1], and one is Juvéderm Voluma™, manufactured according to the VYCROSS™ technology.