Iontophoresis-Enhanced Transdermal Delivery of Hyaluronic Acid: Mechanisms, Molecular Weight Effects, and Application Potential

Purpose Hyaluronic acid (HA) is a widely used moisturizing agent, but its strong hydrophilicity and high molecular weight limit its skin permeability. Iontophoresis has been proposed as a strategy to improve HA delivery, but its mechanisms remain unclear. This study aims to investigate how iontophoresis enhances the transdermal transport of HA and to provide a theoretical basis for developing efficient HA delivery systems. Methods Ex vivo pig and rat skin models were used to assess changes in skin electrical properties under iontophoresis. Fluorescein isothiocyanate-labeled HA (FITC-HA) with different molecular weights (3, 10, 35, and 200 kDa) was synthesized to visualize penetration routes and evaluate permeation efficiency. Neutral dextran served as a reference to differentiate the roles of electromigration (EM) and electroosmosis (EO). Results Iontophoresis significantly altered skin electrical behavior, showing polarization and ion accumulation, particularly at the anode with HA. Fluorescence microscopy revealed that HA primarily penetrates through the intercellular pathway, and additionally via hair follicles into the deeper layers of the skin. EM was the primary driving force, with its contribution increasing with applied voltage. Medium-weight HA (10–35 kDa) permeated for 0.5 h under 1 V voltage, showing comparable penetration depth and area to 3 kDa HA under passive conditions. Conclusion Iontophoresis enhances HA transdermal delivery and shows potential as a noninvasive method for skincare and drug delivery applications. Further in vivo studies are needed to support clinical application.