ARTICLE: Models to Study Skin Lipids in Relation to the Barrier Function: A Modern Update on Models and Methodologies Evaluating Skin Barrier Function

April 2021 | Volume 20 | Issue 4 | Supplement Individual Articles | s10 | Copyright © April 2021

Published online April 6, 2021

Rebecca Barresi, Hawasatu Dumbuya PhD, Xue Liu PhD, I-Chien Liao PhD

L’Oréal Research and Innovation, Clark, NJ

Stratum Corneum Substitutes
Stratum corneum substitutes (SCS) allow for the in vitro evaluation of barrier function through biophysical, in situ, and permeation studies. These substitutes are made by coating a porous substrate with a uniform composition and thickness of synthetic lipids.7 SCS can be used to predict the permeability of the membrane and allow for the modification of lipid composition in order to study the relationship of barrier function with lipid composition and organization in healthy and diseased-state skin.7,8 To mimic diseased skin structure, an altered lipid composition can be coated on the membrane. To date, there is limited information using modified SCS models to evaluate the effect of supplemented CERs in an impaired barrier state.

Groen et al used a SCS model to evaluate altered FFA composition impact on lamellar and lateral organization through the use of FTIR and small angle x-ray diffraction. It was demonstrated that such changes resulted in hexagonal packing and a disrupted lamellar organization.9 SCS linked shifts in lipids with altered skin permeability.10 SCS models can also be utilized in studying the effect of short chain CERs and FFAs on barrier permeability. Short chain CERs have been found to increase the permeability of the SCS membranes as demonstrated through electrical impedance and flux of small and large molecules.8 It was also found that these short chain CERs induce phase separation and inefficient lipid packing resulting in impaired barrier properties, as compared to native long chain CERs.8

Lipid membrane mixtures and SCS have demonstrated to be an informative means of studying lipid composition and structure on barrier integrity. In respect to the cosmetics, these models can be extended to evaluate supplemental CERs or additional FFAs that may mimic topical application of a skincare product to better understand barrier integrity. One limitation to this model is that it solely demonstrates barrier impairment as a function of lipid changes. It is important to note that the integrity of the skin barrier entails additional structural and molecular changes that occur in conjunction with lipid changes that would not be demonstrated in such models.

Computational Lipid Membrane Simulations
Biological systems have a high level of complexity that have been successfully captured using modern computational and bioinformatics systems. Such systems remove the constraints of in vivo models and permit for a more comprehensive evaluation of essential skin barrier elements and interactions. Different model types, ranging from cellular models to full lipid membranes, can be used to study particular functions of the skin barrier. Each of these simulation types vary in resolution regarding computing time and system size.

Cell-centered agent-based models have been used to study the epidermis in models as simple as mimicking keratinocyte cultures ranging to epidermal homeostasis in full-thickness tissue.11 Atomistic simulations break down systems into subsets to be used with molecular dynamics to better understand SC lipids.12 One simplified atomistic model, lacking lipids such as CHOL and FFAs, elucidated the relationship of CER tail chain length with water permeability.13

Coarse-grained models are ideal for studying skin lipids, as it can undertake long simulation run times with a larger system size needed for visualizing significant lipid rearrangements.14,15 Complex systems are simplified into subsystems of different granularity levels. Unlike atomistic models, this model combats the constraints of system run-time and size by approximating atoms as a group. This reduces molecular detail but permits for the study of more complex systems. Interactions between FFAs with CER[NS] head groups and the self-assembly of large membranes using a CER and FFA mixture have also been studied.14

Computer simulation models aid in understanding SC lipid behavior in relation to barrier integrity. Because of its efficient computational power and run time, coarse-grained models can be used to study larger scale systems, such as more complex lipid membranes, but lack molecular detail evident within atomistic simulations. The level of detail that all-atom models provide can still only be studied with small systems. It is possible to combine these two model types into a multiscale model in order to utilize the benefits of both: high accuracy and molecular detail from atomistic simulations with the computational speed and power of the coarse-grained models. This can be used to not only understand large scale applications of changes to the lipid membrane, but also the specific molecular changes such as the lateral and lamellar lipid organization. Although there is limited incorporation of such models in the cosmetics field, computer simulations can be extended to better understand skin in a diseased state by limiting particular CERs or altering the lipid composition to assess the impact on barrier function.

In Vitro Models
Principle of Generating Biofabricated Skin Tissue Models
Biofabricated tissue is used in research and industry to understand biological mechanisms and develop products. Successful tissue engineering generally includes the following components: keratinocytes or fibroblasts, use of scaffold that recreates the in vivo extracellular matrix to provide mechanical and biological support for epidermis growth, evaluating the tissue quality at all scales.16 Optimized tissue has been used to study skin physical barrier, chemical barrier, immunological barrier, and microbial skin barrier.17 The incorporation of bioengineering further allows the tissue to have specific disease phenotypes. Diseased skin models can be used in developing and evaluating compounds that target specific disease and