Model-Based Prediction to Evaluate Residence Time of Hyaluronic Acid Based Dermal Fillers

Abstract

Dermal fillers are gel-type substances for nonsurgical medical-device use to achieve facial rejuvenation. Currently, the most widely used skin fillers are hyaluronic-acid-based dermal fillers. This study aimed to explain the change in the volume of injected dermal fillers by developing a mathematical kinetic model for various dermal fillers. The kinetics of the injected fillers were separated by a biphasic phenomenon. We attributed an increase in filler volume to the hydration of hyaluronic acid molecules and injection-site reaction and a decrease in volume to enzyme-mediated degradation. To explain these in vivo characteristics of dermal fillers, we proposed a two-compartment model, divided into a depot compartment (where the filler was injected) and a subcutaneous compartment (an observation compartment where the fillers swell and degrade), assuming that the swelling and degradation occurred in accordance with the swelling and degradation rate constants, respectively. The model was developed using five hyaluronic-acid-based dermal fillers and NONMEM. We determined that the rate-limiting step for the complete degradation of the dermal fillers in vivo was the swelling phase, as described by the swelling rate constant (K_swell). This study could enable scientists developing novel dermal fillers to predict the in vivo behavior of fillers.

Keywords: HA-based dermal filler; NONMEM; degradation; kinetic model; prediction; swelling.

Figure 1

The schematic kinetic model for dermal fillers; DEPOT, Depot compartment; SC, Subcutaneous compartment, K_swell, Swelling rate constant; K_deg, Degradation rate constant.

Figure 2

Mean volume-time profiles of 5 hyaluronic acid (HA) dermal fillers after injection in hairless mice, (A) 99 fill^®; (B) Juvederm^® VOLUMA with Lidocaine; (C) Neuramis^® VOLUME Lidocaine; (D) Restylane^® Lyft with Lidocaine; (E) YVOIRE^® Contour plus.

Figure 3

Visual predictive check for the final filler’s models of (A) 99 fill^®; (B) Juvederm^® VOLUMA with Lidocaine; (C) Neuramis^® VOLUME Lidocaine; (D) Restylane^® Lyft with Lidocaine; and (E) YVOIRE^® Contour plus.

Figure 4

The Simulated complete decomposition time of (A) 99 fill^®; (B) Juvederm^® VOLUMA with Lidocaine; (C) Neuramis^® VOLUME Lidocaine; (D) Restylane^® Lyft with Lidocaine; (E) YVOIRE^® Contour plus. T_cd, complete decomposition time.

Figure 5

The relationship among the estimated and simulated parameters (K_swell, K_deg, T_cd) from the 5 HA dermal filler’s kinetic model, (A) K_deg vs. K_swell; (B) T_cd vs K_deg; (C) T_cd vs. K_swell. K_swell, swelling rate constant; K_deg, degradation rate constant; T_cd, complete decomposition time.