In vivo Bio-Integration of Three Hyaluronic Acid Fillers in Human Skin: A Histological Study

Abstract

Background: Hyaluronic acid (HA) formulations are used for aesthetic applications. Different cross-linking technologies result in HA dermal fillers with specific characteristic visco-elastic properties. Objective: Bio-integration of three CE-marked HA dermal fillers, a cohesive (monophasic) polydensified, a cohesive (monophasic) monodensified and a non-cohesive (biphasic) filler, was analysed with a follow-up of 114 days after injection. Our aim was to study the tolerability and inflammatory response of these fillers, their patterns of distribution in the dermis, and influence on tissue integrity. Methods: Three HA formulations were injected intradermally into the iliac crest region in 15 subjects. Tissue samples were analysed after 8 and 114 days by histology and immunohistochemistry, and visualized using optical and transmission electron microscopy. Results: Histological results demonstrated that the tested HA fillers showed specific characteristic bio-integration patterns in the reticular dermis. Observations under the optical and electron microscopes revealed morphological conservation of cutaneous structures. Immunohistochemical results confirmed absence of inflammation, immune response and granuloma. Conclusion: The three tested dermal fillers show an excellent tolerability and preservation of the dermal cells and matrix components. Their tissue integration was dependent on their visco-elastic properties. The cohesive polydensified filler showed the most homogeneous integration with an optimal spreading within the reticular dermis, which is achieved by filling even the smallest spaces between collagen bundles and elastin fibrils, while preserving the structural integrity of the latter. Absence of adverse reactions confirms safety of the tested HA dermal fillers.

Hyaluronic Acid Filler in HIV-Associated Facial Lipoatrophy: Evaluation of Tissue Distribution and Morphology with MRI

“…Depending on the technological processes used, the cross-linked and negatively charged HA gels can be divided into biphasic gels, also called non-cohesive gels, and monophasic gels, also called cohesive gels [18,29]. Cohesive (monophasic) gels are composed of monodensified HA (single-phase HA cross-linked once) or polydensified HA (single-phase HA cross-linked continuously) [18,21]. Cohesive monodensified fillers are highly cross-linked gels resulting from homogenization of manufacturing technology, whereas cohesive polydensified fillers have variable densities of cross-linked HA, thereby ensuring optimal filling of tissues with variable intercellular space size [18,21,29].…”

“…Cohesive (monophasic) gels are composed of monodensified HA (single-phase HA cross-linked once) or polydensified HA (single-phase HA cross-linked continuously) [18,21]. Cohesive monodensified fillers are highly cross-linked gels resulting from homogenization of manufacturing technology, whereas cohesive polydensified fillers have variable densities of cross-linked HA, thereby ensuring optimal filling of tissues with variable intercellular space size [18,21,29]. Non-cohesive fillers are cross-linked particles suspended in a non-cross-linked HA matrix.…”

“…Non-cohesive fillers are cross-linked particles suspended in a non-cross-linked HA matrix. Histologic studies of forearm, buttock and iliac crest skin in healthy adults showed that different types of cross-linked HAs have different biologic behaviors: while non-cohesive gels show deposition in big pools in the deep reticular dermis, cohesive gels tend to spread in the dermis in a diffuse manner, penetrating the smallest spaces between collagen and elastin bundles [18,21]. Both filler types spare the papillary dermis [18,21].…”

“…Cross-linked hyaluronic acid (HA) derivatives are non-permanent dermal fillers used not only for the correction of HIV-LA, but also for treatment of photodamaged skin [13], facial atrophic scars [14] and other cosmetic purposes [15,16,17]. Histologic analyses of the forearm, buttock and iliac crest skin injected with different types of cross-linked HA have shown that HA implants have the ability to bind water and thereby provide volume and support to the injected tissue for up to 12 months without causing fibrosis or foreign body reactions [18,19,20,21]. Recent studies suggest that these fillers may stimulate dermal collagen anabolism by inducing increased procollagen and tissue inhibitor of matrix-degrading metalloproteinases (TIMP-1) levels [13,22].…”

Migrating Granulomatous Chronic Reaction from Hyaluronic Acid Skin Filler (Restylane): Review and Histopathological Study with Histochemical Stainings

“…This suggests that factors other than an avian protein reactivity, which is to be expected with Hylaform alone, are involved [16]. One recent study [17] analyzed the biointegration of cohesive polydensified filler (Esthelis® Basic), cohesive monodensified filler (JuvedermTM Ultra) and non-cohesive filler (Restylane®). The results of that study showed that the non-cohesive filler forms larger aggregates than either cohesive filler, shifting collagen and elastin fibers and resulting in a less homogenous HA distribution at 8 and 114 days.…”