Computational modelling predicts impaired barrier function and higher sensitivity to skin inflammation following pH elevation.

Skin surface pH has been identified as a key regulator of the epidermal homeostasis through its action on serine protease activity. These enzymes, like kallikreins (KLK), are responsible for the degradation of corneodesmosomes, the protein structures linking together corneocytes, and are regulated by Lympho-Epithelial Kazal-Type-related Inhibitor (LEKTI). KLK activity increases at pH levels higher than physiological. An increase in skin surface pH has been observed in patients suffering from skin diseases characterized by impaired barrier function, like atopic dermatitis. In this work, we introduce an agent-based model of the epidermis to study the impact of a change in skin surface pH on the structural and physiological properties of the epidermis, through the LEKTI-KLK mechanism. We demonstrate that a less acidic pH, compared to the slightly acidic pH observed in healthy skin, is sufficient to significantly affect the water loss at the surface and the amount of irritant permeating through the epidermis. This weakening of the skin barrier function eventually results in a more intense skin inflammation following exposure to an external irritant. This work provides additional evidence that skin surface pH and serine proteases can be therapeutic targets to improve skin barrier integrity.

A Predictive Self-Organizing Multicellular Computational Model of Infant Skin Permeability to Topically Applied Substances.

Computational models of skin permeability are typically based on assumptions of fixed geometry and homogeneity of the whole epidermis or of epidermal strata and are often limited to adult skin. Infant skin differs quantitatively from that of the adult in its structure and its functional properties, including its barrier function to permeation. To address this problem, we developed a self-organizing multicellular epidermis model of barrier formation with realistic cell morphology. By modulating the parameters relating to cell turnover reflecting those in adult or infant epidermis, we were able to generate accordingly two distinct models. Emerging properties of these models reflect the corresponding experimentally measured values of epidermal and stratum corneum thickness. Diffusion of an externally applied substance (e.g., caffeine) was simulated by a molecular exchange between the model agents, defined by the individual cells and their surrounding extracellular space. By adjusting the surface concentration and the intercellular exchange rate, the model can recapitulate experimental permeability data after topical exposure. By applying these parameters to an infant model, we were able to predict the caffeine concentration profile in infant skin, closely matching experimental results. This work paves the way for a better understanding of skin physiology and function during the first years of life.

A 3D self-organizing multicellular epidermis model of barrier formation and hydration with realistic cell morphology based on EPISIM.

The epidermis and the stratum corneum (SC) as its outermost layer have evolved to protect the body from evaporative water loss to the environment. To morphologically represent the extremely flattened cells of the SC - and thereby the epidermal barrier - in a multicellular computational model, we developed a 3D biomechanical model (BM) based on ellipsoid cell shapes. We integrated the BM in the multicellular modelling and simulation platform EPISIM. We created a cell behavioural model (CBM) with EPISIM encompassing regulatory feedback loops between the epidermal barrier, water loss to the environment, and water and calcium flow within the tissue. This CBM allows a small number of stem cells to initiate self-organizing epidermal stratification, yielding the spontaneous emergence of water and calcium gradients comparable to experimental data. We find that the 3D in silico epidermis attains homeostasis most quickly at high ambient humidity, and once in homeostasis the epidermal barrier robustly buffers changes in humidity. Our model yields an in silico epidermis with a previously unattained realistic morphology, whose cell neighbour topology is validated with experimental data obtained from in vivo images. This work paves the way to computationally investigate how an impaired SC barrier precipitates disease.

Geometrical and topological analysis of in vivo confocal microscopy images reveals dynamic maturation of epidermal structures during the first years of life.

Reflectance confocal microscopy is successfully used in infant skin research. Infant skin structure, function, and composition are undergoing a maturation process. We aimed to uncover how the epidermal architecture and cellular topology change with time. Images were collected from three age groups of healthy infants between one and four years of age and adults. Cell centers were manually identified on the images at the stratum granulosum (SG) and stratum spinosum (SS) levels. Voronoi diagrams were used to calculate geometrical and topological parameters. Infant cell density is higher than that of adults and decreases with age. Projected cell area, cell perimeter, and average distance to the nearest neighbors increase with age but do so distinctly between the two layers. Structural entropy is different between the two strata, but remains constant with time. For all ages and layers, the distribution of the number of nearest neighbors is typical of a cooperator network architecture. The topological analysis provides evidence of the maturation process in infant skin. The differences between infant and adult are more pronounced in the SG than SS, while cell cooperation is evident in all cases of healthy skin examined.

Mathematical modeling in metal metabolism: overview and perspectives.

A review of mathematical modeling in metal metabolism is presented. Both endogenous and exogenous metals are considered. Four classes of methods are considered: Petri nets, multi-agent systems, determinist models based on differential equations and stochastic models. For each, a basic theoretical background is given, then examples of applications are given, detailed and commented. Advantages and disadvantages of each class of model are presented. A special attention is given to determinist differential equation models, since almost all models belong to this class.