Formulation and clinical evaluation of hyaluronic acid nanogel in treatment of tear trough: nano-flipping from injectable fillers to topical nanofillers

Tear trough deformity (TTD) is a significant cosmetic concern, with current treatments relying primarily on invasive injectable fillers, which are costly and carry risks of complications. Despite the widespread use of hyaluronic acid (HA) in cosmetic applications, its poor dermal permeation has limited the development of effective topical fillers for TTD. This study aim to develop and evaluate a novel hyaluronic acid nanogel (nanofiller, NF) as a non-invasive topical filler for TTD. The hyaluronic acid NF was formulated and characterized for size, zeta potential, and skin permeation using the Franz diffusion method. The nanofiller demonstrated a particle size of 213.28 ± 4.15 nm and a zeta potential of −22.1 ± 1.07 mV, with a tenfold superior permeation compared to conventional HA gel. Thirty adult female patients aged 21–50 years with TTD were enrolled in a clinical trial and randomly assigned to receive either the NF or a conventional HA gel (control). Participants were randomly assigned to receive either the NF or a conventional HA gel (control). Clinical evaluation included subjective assessments and objective photomorphometric measurements of TTD parameters such as skin roughness (fine lines), indentation index, mean density, and percentage of the affected area. The NF group showed a significant improvement in TTD parameters, including up to a 40-fold reduction in skin roughness and indentation index, with 100% patient satisfaction and no adverse effects, compared to the control group. "To conclude; this study demonstrates the efficacy and safety of the HA nanofiller as the first effective topical treatment for TTD, offering a non-invasive alternative to injectable fillers.

泪沟畸形（Tear trough deformity, TTD）是一类备受关注的美容美学问题，当前主流治疗方式为有创注射填充剂，此类治疗不仅成本高昂，还存在并发症风险。尽管透明质酸（hyaluronic acid, HA）在美容领域应用广泛，但其皮肤渗透性不佳，限制了针对TTD的高效外用填充剂的开发。本研究旨在开发并评估一种新型透明质酸纳米凝胶（nanofiller, NF），作为用于TTD的无创外用填充剂。

研究人员对该透明质酸纳米凝胶进行了配方制备，并通过弗朗兹扩散法（Franz diffusion method）对其粒径、Zeta电位及皮肤渗透性开展表征。结果显示，该纳米填充剂的粒径为213.28±4.15 nm，Zeta电位为-22.1±1.07 mV，皮肤渗透性较传统透明质酸凝胶提升10倍。

本临床试验纳入30名年龄介于21~50岁的成年女性TTD患者，受试者被随机分配至纳米填充剂组或传统透明质酸凝胶对照组。临床评估涵盖主观评价与客观光形态计量学测量两部分，针对TTD相关参数包括皮肤粗糙度（细纹）、凹陷指数、平均密度及受累区域占比进行量化分析。

与对照组相比，纳米填充剂组的TTD相关参数获得显著改善：皮肤粗糙度与凹陷指数最高可降低40倍，患者满意度达100%，且未出现任何不良反应。

综上，本研究证实该透明质酸纳米填充剂具有有效性与安全性，其作为首款针对TTD的有效外用治疗手段，为注射填充剂提供了无创替代方案。