Key considerations from intrinsic properties to context-dependent performance in the preclinical evaluation of crosslinked HA dermal fillers

Abstract Current preclinical evaluation of crosslinked hyaluronic acid (HA) dermal fillers often treats individual assays—rheology, extrusion force, cohesivity, swelling—in isolation, making it difficult to relate intrinsic network properties to context-dependent performance. In this study, five crosslinked HA gels—three commercial BDDE-crosslinked fillers (Juvéderm VOLUMA, Restylane Defyne and Ifresh) and two laboratory-model spermidine-crosslinked HA (SPDHA) gels—were characterized using a multi-assay battery covering extrusion force measurement, rheological characterization (amplitude sweeps, frequency/time sweeps, thixotropy test and flow sweep), cohesivity assessment (drop weight test and dispersion time test), and water uptake evaluation (swelling factor and hydration test). We examined how these different metrics relate to each other. Our results reveal that intrinsic network properties—such as elastic modulus (G′), crossover strain (γ c ) and swelling factor—capture different aspects of gel behavior from context-dependent performance metrics—such as extrusion force, dispersion time (reflecting resistance to hydrodynamic shear), and confined hydration (simulating post-injection spatial constraint). For example, Restylane Defyne exhibited the highest γ c among all products, indicating superior intrinsic resistance to large deformation, yet it showed the shortest dispersion time—a context-dependent outcome. Such discrepancies demonstrate that no single intrinsic parameter can reliably predict context-dependent performance. Interpreting the two sets of metrics in conjunction provides a more comprehensive understanding of each gel’s behavior, which may assist clinicians in product selection and guide future clinical investigation. However, correlations obtained in vitro cannot substitute clinical evidence; further in vivo and clinical studies are necessary to validate these relationships.