Reply: Evaluation of In Vivo Kinetics and Biostimulatory Effects of Subcutaneously Injected Hyaluronic Acid Filler

Sir: We would like to thank Dr. Andrea Sisti and colleagues for their interest and thoughtful comments regarding our article. As they highlighted, hyaluronic acid fillers have multiple effects. Hyaluronic acid acts not only as a tissue augmenter but also as a biostimulatory inducer (i.e., it enhances the formation of extracellular matrix and the production of new tissue). Physicians dealing with hyaluronic acid fillers should sufficiently understand these pleiotropic properties. We performed this study because we occasionally observed a sustained tissue-volumizing effect in the clinical setting more than 1 year after hyaluronic acid filler treatment when hyaluronic acid was subcutaneously injected using the bolus injection technique. We examined the histologic changes inside and outside the injected hyaluronic acid filler using an in vivo rodent model. This experiment revealed that hyaluronic acid stimulated the surrounding tissues and acted as a scaffold for autologous tissue proliferation, thereby resulting in the development of lattice structures by fibroblasts and induction of collagen fibers. The hyaluronic acid filler–injected space was gradually replaced by autologous tissues composed of fibroblasts, connective tissue, blood vessels, and adipocytes. Therefore, the partial replacement by autologous tissues caused a long-lasting effect despite the hyaluronic acid filler being gradually metabolized and absorbed. In several clinical cases of treatment with hyaluronic acid filler, hyaluronic acid–injected sites could not be recovered to their original condition even when hyaluronidase was injected into the treatment site. Thus, newly generated autologous tissues within the hyaluronic acid filler–injected space may be associated with these irreversible mechanisms. Although there are some differences between an animal model and a human, the results of our experiment can be applied to clinical hyaluronic acid treatments. It may be beneficial to not only inject the hyaluronic acid filler into the intradermal layer but also add a bolus injection into the subcutaneous layer to obtain a long-lasting effect. Furthermore, physicians should consider hydrophilicity (the volume of the hyaluronic acid filler increases by approximately 1.8-fold 4 weeks after injection), shape deformation (the height of the hyaluronic acid filler reduces by two-thirds 4 weeks after injection), and autologous tissue production characteristics over time for controlling the amount of hyaluronic acid filler during the initial treatment. Two concerns are considered as future perspectives. Currently, there are various types of commercially available hyaluronic acid fillers that differ in viscosity, elasticity, and concentration. However, in the present experiment, we elucidated the in vivo kinetics of only one hyaluronic acid filler (Juvéderm Vista ULTRA PLUS; Allergan plc, Dublin, Ireland). Therefore, it is necessary to examine which hyaluronic acid fillers act as a scaffold and which cause calcification or granulation, resulting in a risk of developing a lump in the future. Second, hyaluronic acid fillers may be developed into regenerative medicine in the near future if specific cells (adipocytes or chondrocytes) can be grown in hyaluronic acid–injected spaces by incorporating them into the filler before injection. DISCLOSURE None of the authors has a financial interest in any of the products, devices, or companies mentioned in this communication. No funding was obtained. Noriyuki Aoi, M.D.Masato Mochizuki, M.D.Department of Plastic, Oral, and Maxillofacial SurgeryTeikyo University School of MedicineTokyo, Japan Koichi Gonda, M.D.Department of Plastic SurgeryTohoku Medical and Pharmaceutical University HospitalSendai, Japan Shinichi Hirabayashi, M.D.Yuzo Komuro, M.D.Department of Plastic, Oral and Maxillofacial SurgeryTeikyo University School of MedicineTokyo, Japan