Reversing Facial Fillers: Interactions Between Hyaluronidase and Commercially Available Hyaluronic-Acid Based Fillers

September 2014 | Volume 13 | Issue 9 | Original Article | 1053 | Copyright © September 2014

Veena Rao MD,a Sulene Chi MD PhD,a and Julie Woodward MDa,b

aDepartment of Ophthalmology, Duke University Medical Center, Durham, NC
bDepartment of Dermatology, Duke University Medical Center, Durham, NC

INTRODUCTION: Hyaluronidase (HA) degrades hyaluronic acid, allowing flexibility in the use of hyaluronic acid-based fillers commonly used in facial correction. Potentially differing properties of available hyaluronidases and fillers may influence their interaction, leading to important differences in ultimate cosmetic results. This study examines the physical properties of various fillers after exposure to commonly available hyaluronidases in vitro to better inform their in vivo clinical use.
METHODS: Four commonly used HA fillers were exposed to varying concentrations of Vitrase (ovine testicular hyaluronidase) and Hylenex (human recombinant hyaluronidase) in vitro. The gross properties of these fillers were then observed to evaluate time- and dose-response; photographs were obtained to allow visual comparison at 1 minute and 5 minutes post-exposure.
RESULTS: At a concentration of 0.1 mL Vitrase to 0.2 mL filler, Restylane dissipated most followed by Juvéderm; Belotero most retained its form. Hylenex at the same concentration showed similar results, again affecting Restylane most and Belotero least. Response to treatment with both hyaluronidases increased substantially over time, increasing progressively from exposure to 5 minutes post-exposure. When exposed to Hylenex at 15 U and 30 U to 0.2 mL filler, Belotero retained its form most, followed by Juvéderm, Juvéderm Voluma, and then Restylane. The effects on filler structure increased with 30 U concentration vs 15 U concentration of Hylenex.
DISCUSSION: Available hyaluronidases and HA fillers appear to have differing physical properties that influence their interaction in a time and dose-dependent manner. Knowledge of the ways in which specific fillers interact with different hyaluronidases may help achieve desired cosmesis when aiming to adjust delicate facial fillers.

J Drugs Dermatol. 2014;13(9):1053-1056.


Hyaluronic acid (HA) based fillers have gained increasing popularity in cosmetic facial augmentation over the past decade.1 HA fillers are currently the most commonly used facial fillers, accounting for over 1.4 million procedures in 2012.1 The benefits of HA fillers include ease, avoidance of incisional surgery, versatility, relatively instantaneous results, and overall safety.2,3 Nonetheless, as with any pharmacologic agent, complications can occur.2,4–7 Complications of HA fillers that have been reported include: excessively superficial filler placement5; allergy or hypersensitivity4; granulomatous nodules5,8; undesired persistence9; and rarely, focal necrosis.6 Better control of such complications is important for patient satisfaction, especially considering HA fillers are typically used on an elective and aesthetic basis.
HA is a naturally occurring glycosaminoglycan disaccharide present in skin, joint synovia, cartilage, and vitreous.10 For its use as a dermal filler, HA is chemically cross-linked to achieve the manufacturer's desired composition, which determines the filler's structure, longevity, and other properties.11 The properties of HA are adjusted in the manufacturing of different commercially available HA fillers, leading to their differing structural properties. These varying properties may inform clinicians as to which HA filler would be most appropriate for a specific clinical use. For example, a more highly cross-linked HA filler would likely be resilient in its ability to hold its form, making it suitable for the correction of deep wrinkles. Additionally, a more monophasic filler might cleanly retain its form and clinically have a smoother appearance.
Hyaluronidase is a naturally occurring enzyme capable of local degradation of hyaluronic acid, thereby providing a means for correction or alteration of injected fillers. It is FDA approved as a temporary dispersion agent for injectable fluids, typically local anesthetics during retrobulbar blocks.12 It has been used clinically for over 60 years.13–15 In the event of complications with HA fillers, hyaluronidase has been used in attempt to reverse HA fillers.8,16 Hyaluronidase hydrolyzes hyaluronic acid by splitting the bond between C1 of an N-actylglucosamine moiety and C4 of a glucuronic acid moiety.12 It is FDA approved as an agent to increase tissue permeability to facilitate subcutaneous hydration, drug dispersion, and reabsorption of radiopaque dyes so its use to reverse HA fillers is off-label. Different formulations of hyaluronidase are available, including a human recombinant agent12 and an ovine agent.17
Because of their differing structures and properties, various available HA fillers likely interact differently with hyaluronidase. If planning to use hyaluronidase to reverse HA fillers, it is therefore important to optimize our understanding of the interactions between hyaluronidase and the respective filler. Better such