Hyaluronic acid-cross-linked filler stimulates collagen type 1 and elastic fiber synthesis in skin through the TGF-β/Smad signaling pathway in a nude mouse model

Compared to pure hyaluronic acid filler, cross-linked hyaluronic acid (HAc) exhibits superior biocompatibility and longevity as a dermal filler. We previously developed composite HAc-hydroxyapatite (HAp) fillers. Herein, we systematically compared the protein-level increase and gene expression between HAc-micro-HAp and HAc-nano-HAp in mice and determined the mechanisms underlying the biological responses to HAc and HAp. Five-week-old female BALB/c-nude mice were classified into five groups: normal skin, Radiesse, Restylane, HAc-nano-HAp, and HAc-micro-HAp. Fillers (200 mu l) were injected to evenly fill the back of mice. Skin biopsies were performed to investigate collagen and elastic fiber synthesis after filler injections. Western blot analysis, real-time polymerase chain reaction analysis, and immunohistochemistry were performed to investigate protein and gene expression changes. Organ (liver, lung, spleen, and kidney) toxicity of HAc-nano-HAp was determined by hematoxylin and eosin staining after 12 weeks. Protein and gene expression analyses indicated that, compared with pure fillers, HAc-nano-HAp and HAc-micro-HAp hydrogels preferentially promoted collagen and elastic fiber formation through the TGF-beta pathway. The composite fillers also exhibited no evidence of organ toxicity. HAc-HAp filler might play an important role in collagen and elastic fiber regeneration. HAc filler stimulates collagen type 1 and elastic fiber synthesis through the TGF-beta/Smad pathway. The role of HAc-HAp composite fillers in photoaging in animal models and their effects on skin, including elasticity and tensile strength, should be investigated. (C) 2019 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.