Hydrophilic Macromolecule Transport into Deep Skin Layers through Sweat Ducts Verified through Microscopic Visualization and Flow Simulation

Hydrophilic macromolecules typically exhibit minimal permeability through the skin’s stratum corneum due to their large molecular size and low partition coefficient. However, sweat ducts may present a physically plausible bypass route enabling transdermal delivery. In this study, we examined the inward transport of macromolecular compounds through sweat ducts, despite the natural outward flow of sweat. Fluorescently labeled compounds were visualized penetrating deep dermal layers using tissue clearing and high-resolution confocal microscopy. To elucidate the transport dynamics, we conducted computational fluid dynamics simulations based on anatomically realistic duct geometries. Our analysis incorporated advective and diffusive mechanisms, revealing regimes governed by low Péclet numbers, where diffusion predominates under stagnant or reversed flow conditions. We further characterized the role of duct curvature and constrictions in establishing localized gradients and directional flow reversals. These findings provide quantitative support for the hypothesis that sweat ducts function as microscale detours, allowing hydrophilic macromolecules to bypass conventional diffusion barriers and access subepidermal tissue via an alternative physical route.