Understanding Clinical and Biophysical Differences Between Non-Cross-Linked and Cross-Linked Hyaluronic Acid Dermal Fillers

Abstract

Background: The rising popularity of injectable soft-tissue fillers in esthetic medicine is driven by their potential to provide facial rejuvenation through minimally invasive techniques. Hyaluronic acid (HA)-based fillers exhibit distinct biophysical characteristics, including rheological properties which are critical for their behavior under mechanical stress. This study aims to compare the viscoelastic properties of commercially available crosslinked (CFs) and non-crosslinked HA fillers (NCFs). Methods: A total of 28 commercially available HA fillers, including both non-cross-linked (n = 3) and cross-linked types (n = 25), were investigated for their rheological properties. Rheological parameters such as storage modulus (G′), loss modulus (G″), loss tangent (tan δ), and complex modulus (G*) were measured over a frequency range of 0.1–10 Hz. Results: NCFs showed greater variation in G′ with a mean of 3263% [range: 1767–4177] compared to crosslinked fillers with 247.60% [range: 85–720]. The calculated difference between the change in percent of CFs versus NCFs was 3016% (755) for G′ with p < 0.001, whereas it was 926% (498) for G″ with p < 0.001, and it was −154% (25.8) for tan-delta with p < 0.001, and 966% (147) for G* with p < 0.001. Conclusions: NCFs and CFs exhibit distinct rheological profiles, with NCFs demonstrating a greater change in their initial rheologic properties when exposed to mechanical stress. This specific biophysical behavior (increase in stiffness and viscosity) predisposes NCFs for dermal structural support with the respective subdermal applications, whereas CFs seem to be more suitable for deep soft tissue injections, offering volumization.