Mechanistic Investigation of Surfactant-Induced Epithelial Barrier Damage and Mitigation through the Delivery of Humectants

Human skin is an important body organ whose function is to protect the body from harmful physical and chemical insults, UV radiation, microbial infection, dehydration, and heat loss. These vital protective functions are attributed to a specialized skin tissue, the keratinizing epithelium, which constitutes the epithelial barrier between the body and the surrounding environment. Certain surfactants, such as, Sodium Dodecyl Sulfate (SDS), which find widespread use in skin cleansers and in skin care formulations, have adverse effects on the epithelial barrier, including enhancing barrier disruption and subsequent pathogen penetration into the deeper, vascularized, skin layers, such as the dermis, and thereby, into the general body circulation. As a result, Epithelial Barrier Damage (EBD) induced by surfactants has the potential to lead to benign, yet debilitating skin disorders, such as atopic dermatitis, as well as to very serious malignant pathological disorders, such as carcinoma. On the other hand, certain skin beneficial agents, in particular humectants, such as Glycerol, can induce mitigation, and in some cases, reversal, of surfactant-induced EBD, thereby preventing penetration of pathogens and chemicals into the body. Understanding the mechanism by which these beneficial agents are delivered to the epithelial barrier can prove critical in the design of better product formulations for the enhanced delivery of these skin beneficial agents.

The objective is to utilize: (a) our expertise in surfactant solution physical chemistry to determine surfactant potency in inducing EBD, (b) transport-kinetic models to determine epithelial barrier transport characteristics of surfactants and humectants, (c) skin conductivity and radioactivity assays to quantify surfactant and humectant epithelial barrier penetration characteristics, and (d) direct visualization of morphological modification of the epithelial barrier upon exposure to surfactant and humectant solutions through a novel application of two-photon fluorescence microscopy, TPM, to elucidate the mechanisms of surfactant-induced epithelial barrier perturbation and mitigation through the delivery of humectants. Knowledge of these mechanisms will then allow the rational, as opposed to the trial-and-error, design of new surfactant- and humectant-containing formulations, or the modification of existing ones, that are milder to the skin.

A recently developed surfactant monomer-and-micelle epithelial barrier penetration model has shown that at total surfactant concentrations that exceed the critical micelle concentration (CMC) of SDS, SDS monomers and SDS micelles contribute to SDS epithelial barrier penetration. The observed SDS dose-dependent response contradicts the widely accepted view that only surfactant monomers penetrate into the epithelial barrier, while surfactant in micellar form does not contribute to penetration into this barrier. Nevertheless, this finding is consistent with previously unexplained observations of a dose-dependent EBD induced by SDS at concentrations above the CMC. Very recently, through the integration of a hindered-transport model combined with our TPM studies of skin exposed to a SDS solution (a chemical enhancer) and to a phosphate-buffer solution (the control), followed by exposure to a hydrophilic probe solution, we were able to determine that skin exposure to SDS may result in: (a) the formation of heterogeneous localized transport regions in the skin epithelial barrier, and (b) an increase in the number of aqueous pores in the epithelial barrier as well as in their average pore radius. Accordingly, our studies suggest that SDS micelles, which have a hydrodynamic radius of 20Å, may be able to penetrate into the epithelial barrier via enhanced aqueous porous pathways which have an average pore radius greater than 28Å, as well as through the localized transport regions that have a much higher permeability than the overall permeability of the skin epithelial barrier.

We have recently observed that mixing an anionic surfactant, such as, SDS, with a non-ionic surfactant, such as, dodecyl hexa(ethylene oxide) (C12E6), leads to reduced EBD relative to the anionic surfactant alone. A possible mechanism that we have proposed to rationalize this finding is as follows: (a) the addition of C12E6 decreases the SDS monomer concentration, thereby reducing the driving force for the penetration of monomeric SDS into the epithelial barrier, and (b) the addition of C12E6 to the SDS solution leads to the formation of mixed (SDS/C12E6) micelles of larger size that are sterically hindered from accessing the aqueous porous pathways, and, hence, cannot penetrate into the epithelial barrier. In addition, we have demonstrated, using TPM skin images, that adding an appropriate amount of C12E6 to the SDS solution can significantly mitigate the ability of SDS to induce heterogeneous localized transport regions in the epithelial barrier, and can also induce an increase in the number and radii of the aqueous pores present in the skin epithelial barrier. Therefore, exposing the skin epithelial barrier to an appropriate SDS/C12E6 surfactant mixture can lead to a reduction in the number of mixed micelles that can penetrate into the skin barrier thereby reducing the amount of surfactant in the skin.

The present investigations are aimed at simultaneously determining the amounts of SDS and C12E6 that have penetrated into the epithelial barrier to verify if C12E6 is, indeed, mild as hypothesized, or if the presence of significant amounts of C12E6 along with SDS in the epithelial barrier may lead to EBD. In addition, our ongoing work showing that appropriate mixtures of Glycerol and SDS may lead to a mitigation of SDS-induced EBD may have important implications for the development of practical strategies to minimize EBD.