Physicochemical Attributes of Solid Hyaluronic Acid Technology Platform-Based Film Drive Rapid Oral Permeation and Barrier Enhancement via LKB1/CaMKKβ-AMPK Signaling

Hyaluronic acid (HA) is widely used in oral film systems; however, the functional interactions of excipient-free HA films with oral epithelial tissues, particularly with respect to permeability and barrier modulation, remain insufficiently understood. In this study, we investigated the physical properties, permeation characteristics, and oral epithelial barrier responses of a solid hyaluronic acid technology platform (SHTP) film composed exclusively of HA, using buccal epithelial TR146 cell layers and a rat model. Compared with a commercial HA film containing excipients, the SHTP film exhibited distinct hydration-driven properties, including rapid water uptake (815% within 60 s) and enhanced swelling capacity. These properties primarily facilitated rapid buccal HA permeation, as reflected by increased transepithelial flux and higher apparent permeability coefficients (Papp). Following this initial permeation-enhancing effect, the SHTP film reinforced epithelial barrier integrity, as evidenced by reduced paracellular transport of fluorescein isothiocyanate-dextran (FD4) and increased transepithelial electrical resistance (TEER). Mechanistic analyses suggested that this barrier-supportive response was associated with the upregulation of tight junction-related gene expression and activation of the LKB1/CaMKKβ-AMPK signaling pathway. In vivo studies further demonstrated rapid oral buccal absorption and subsequent systemic distribution of HA delivered via the SHTP film. Collectively, these findings demonstrate that excipient-free HA films exert a sequential dual effect, facilitating rapid transepithelial permeation, followed by reinforcement of epithelial barrier integrity. This work provides mechanistic insight into hydration-driven interactions between HA and the oral epithelium and supports the application of excipient-free HA films in oral biomedical and epithelial barrier-oriented delivery systems.