Comparison of Hyaluronidase-Mediated Degradation Kinetics of Commercially Available Hyaluronic Acid Fillers In Vitro.

BACKGROUND: The ability to degrade hyaluronic acid (HA)-based fillers with hyaluronidase allows for better management of adverse effects and reversal of suboptimal treatment outcomes. OBJECTIVES: The aim of this study was to compare the enzymatic degradation kinetics of 16 commercially available HA-based fillers, representing 6 manufacturing technologies. METHODS: In this nonclinical study, a recently developed in vitro multidose hyaluronidase administration protocol was used to induce degradation of HA-based fillers, enabling real-time evaluation of viscoelastic properties under near-static conditions. Each filler was exposed to repeated doses of hyaluronidase at intervals of 5 minutes to reach the degradation threshold of G' ≤ 30 Pa. RESULTS: Noticeable differences in degradation characteristics were observed based on the design and technology of different filler classes. Vycross fillers were the most difficult to degrade and the Cohesive Polydensified Matrix filler was the least difficult to degrade. Preserved Network Technology products demonstrated proportional increases in gel degradation time and enzyme volume required for degradation across the individual resilient hyaluronic acid (RHA) products and indication categories. No obvious relationship was observed between gel degradation characteristics and the individual parameters of HA concentration, HA chain length, or the degree of modification of each filler when analyzed separately; however, a general correlation was identified with certain physicochemical properties. CONCLUSIONS: Manufacturing technology was the most important factor influencing the reversibility of an HA product. An understanding of the differential degradation profiles of commercially available fillers will allow clinicians to select products that offer a higher margin of safety due to their preferential reversibility.

Multidose Hyaluronidase Administration as an Optimal Procedure to Degrade Resilient Hyaluronic Acid Soft Tissue Fillers.

Minimally invasive hyaluronan (HA) tissue fillers are routinely employed to provide tissue projection and correct age-related skin depressions. HA fillers can advantageously be degraded by hyaluronidase (HAase) administration in case of adverse events. However, clear guidelines regarding the optimal dosage and mode of administration of HAase are missing, leaving a scientific gap for practitioners in their daily practice. In this study, we implemented a novel rheological procedure to rationally evaluate soft tissue filler degradability and optimize their degradation kinetics. TEOSYAL RHA® filler degradation kinetics in contact with HAase was monitored in real-time by rheological time sweeps. Gels were shown to degrade as a function of enzymatic activity, HA concentration, and BDDE content, with a concomitant loss of their viscoelastic properties. We further demonstrated that repeated administration of small HAase doses improved HA degradation kinetics over large single doses. Mathematical analyses were developed to evaluate the degradation potential of an enzyme. Finally, we tuned the optimal time between injections and number of enzymatic units, maximizing degradation kinetics. In this study, we have established a scientific rationale for the degradation of HA fillers by multidose HAase administration that could serve as a basis for future clinical management of adverse events.

Advanced Concepts in Rheology for the Evaluation of Hyaluronic Acid-Based Soft Tissue Fillers.

BACKGROUND: Crosslinked hyaluronic acid (HA)-based soft tissue fillers possess unique viscoelastic properties intended to match specific product indications. Manufacturing has an impact on HA chain integrity and on filler properties. OBJECTIVE: This study introduces 2 new rheological parameters to evaluate the macroscopic characteristics of fillers. METHODS AND MATERIALS: A library of reference commercialized HA fillers was selected to cover the full spectrum of product indications. Gels were assessed in terms of size of released HA fragments as a readout of gel integrity, degree of modification, cohesivity, and rheological properties. RESULTS: The elastic modulus G' often used to characterize fillers was shown not to follow macroscopic mechanical properties. To improve the mechanical characterization of fillers, Strength and Stretch scores were developed and tested. The Strength score defined the ability of a filler to sustain constant viscoelasticity over a wide range of constraints and represented the filler mechanical resilience. The Stretch score measured the propensity of a filler to deform in view to improve implant adaptation to facial animation for natural-looking results. CONCLUSION: Strength and Stretch scores sorted rheological parameters to macroscopic cohesivity assays more accurately than G' and may thus help predict the gel behavior once implanted and submitted to facial dynamics.

Comparative Preclinical Study of Lidocaine and Mepivacaine in Resilient Hyaluronic Acid Fillers.

BACKGROUND: Hyaluronic acid-based filler injections are now well-established aesthetic procedures for the correction of skin tissue defects and volume loss. Filler injections are becoming increasingly popular, with a growing number of injections performed each year. Although classified as a minimally invasive procedure, the introduction of a needle or a canula may remain painful for the patient. A major improvement was achieved with the incorporation of local anesthetics into the formulation for pain relief. METHODS: In this study, two well-known anesthetics, lidocaine and mepivacaine, were systematically compared to assess their influence on filler mechanical and biological features. The impact of each anesthetic was monitored in terms of gel rheological properties, stability, durability, and degradation. The release profiles of each anesthetic were also recorded. Finally, the pharmacokinetics of each anesthetic in rats were assessed. RESULTS: For all the rheological and biological experiments performed, lidocaine and mepivacaine influences were comparable. The addition of either anesthetic into a soft-tissue filler showed no significant modifications of the stability, durability, and degradability of the gel, with similar release profiles and pharmacokinetics at an equivalent concentration. CONCLUSIONS: Substituting lidocaine with mepivacaine does not impact the properties of the gels, and thus both can be equally incorporated as anesthetics in soft-tissue fillers.