How do hair follicles and skin occlusion affect transdermal absorption in Franz diffusion vs. real‑world conditions?
Executive summary
Franz diffusion cells are a long-established, standardized in vitro tool that reliably ranks formulations and measures permeation under controlled, static conditions, but they systematically simplify or omit key real‑world features — notably hair follicle appendages and occlusion dynamics — that materially change absorption in vivo [1] [2]. Comparative studies and reviews show excised skin and synthetic membranes can under‑ or overestimate flux depending on model choice, experimental setup and time, while dynamic microphysiological systems and in situ methods reveal different roles for follicular shunts and occlusion not captured by classic Franz tests [3] [4] [5].
1. What Franz cells actually measure — a controlled, largely intercellular snapshot
Franz diffusion cells place a donor formulation against an excised or surrogate membrane and collect permeant in a stirred receptor fluid under fixed temperature, producing reproducible permeation coefficients that are invaluable for early screening and regulatory comparisons [1] [6]; synthetic membranes improve reproducibility by removing biological variability, but that very simplification removes living appendage function and physiologic flows that exist in vivo [6] [2].
2. Hair follicles: minor surface area, outsized local impact in vivo and with particles
Appendages occupy only about 0.1% of skin surface area, so textbooks and reviews treat follicles as a minor “shunt” route overall, but multiple experimental reports show nanoparticles and certain formulations accumulate in hair follicles and can markedly increase local deposition and subsequent permeation compared with intercellular routes — a behavior that static Franz setups with damaged or denuded skin may miss or misrepresent [2] [7].
3. Occlusion in vitro vs. real life: clear effect, variable interpretation
Occlusion—covering the application site to limit evaporation—consistently raises permeation by hydrating stratum corneum and altering lipid fluidity; Franz cell protocols either standardize occlusion or omit it, yet literature and technical discussions show occlusion can change flux markedly and must be considered when extrapolating to uncovered, ambient‑air exposures [8] [2].
4. How excision and time distort follicular and barrier behavior
Excised skin used in Franz cells undergoes structural changes and sub‑lethal injury over hours that may increase permeability; in one direct comparison in vitro vs. in situ, permeation remained comparable for ~4.5 hours but rose in excised tissue thereafter, indicating time‑dependent artefacts that can amplify or mask follicular contributions depending on experiment duration [4] [9].
5. Dynamic systems and in situ methods expose the gaps Franz cells leave
Newer fluidic microphysiological platforms recreate perfusion and flow under the tissue and often predict lipophilic molecule permeation better than static Franz cells, while in situ adapted diffusion cells maintain living skin architecture and show different steady‑state fluxes — together these comparisons underscore that Franz data are informative but not universally predictive without context [3] [5] [4].
6. Sources of variability and why model choice matters for follicles and occlusion
Inter‑laboratory studies attribute large fractions of permeation variability to skin sample differences and experimental conditions rather than the Franz hardware itself, so whether follicles are intact, the membrane is Strat‑M versus porcine or human skin, and whether occlusion or temperature are controlled determines whether follicular or occlusion effects will be captured or lost [2] [3] [10].
7. Practical synthesis and caveats for interpretation
Franz diffusion cells provide a standardized, reproducible platform to compare formulations, but they underrepresent real‑world follicular uptake and dynamic occlusion effects unless deliberately configured to preserve appendages, control occlusion, or be paired with complementary models (dynamic flow devices, in situ tests, imaging of follicular deposition); experts and recent consensus statements urge standardization and triangulation between models rather than blind reliance on a single in vitro readout [11] [2] [5].