scholarly journals An integrated multiscale, multicellular skin model

2019 ◽  
Author(s):  
Ryan Tasseff ◽  
Boris Aguilar ◽  
Simon Kahan ◽  
Seunghwa Kang ◽  
Charles C. Bascom ◽  
...  

ABSTRACTSkin is our primary barrier to the outside world, protecting us from physical, biological and chemical threats. Developing innovative products that preserve and improve skin barrier function requires a thorough understanding of the mechanisms underlying barrier response to topical applications. In many fields, computer simulations already facilitate understanding, thus accelerating innovation. Simulations of software models allow scientists to test hypothesized mechanisms by comparing predicted results to physical observations. They also enable virtual product optimization, without physical experiments, once mechanisms have been validated. The physical accessibility and abundant knowledge of skin structure makes it a prime candidate for computational modeling. In this article, we describe a computational multiscale multicellular skin model used to simulate growth and response of the epidermal barrier. The model integrates several modeling styles and mathematical frameworks including ordinary differential equations, partial differential equations, discrete agent-based modeling and discrete element methods. Specifically, to capture cell biology and physical transport, we combined four distinct sub-models from existing literature. We also implemented methods for elastic biomechanics. Our software implementation of the model is compatible with the high-performance computing simulation platform Biocellion. The integrated model recapitulates barrier formation, homeostasis and response to environmental, chemical and mechanical perturbation. This work exemplifies methodology for integrating models of vastly different styles. The methodology enables us to effectively build on existing knowledge and produce “whole-system” tissue models capable of displaying emergent properties. It also illustrates the inherent technical difficulties associated with the mounting complexity of describing biological systems at high fidelity. Among the challenges are validation of the science, the mathematical representations approximating the science and the software implementing these representations. Responsibility for a discrepancy observed between in silico and in vitro results may as easily lie at one of these three levels as at another, demanding that any sustainable modeling endeavor engage expertise from biology, mathematics and computing.

2021 ◽  
Author(s):  
Adam M. Blanchard ◽  
Ceri E. Staley ◽  
Laurence Shaw ◽  
Sean R Wattegedera ◽  
Christina-Marie Baumbach ◽  
...  

Footrot is a polymicrobial infectious disease in sheep causing severe lameness, leading to one of the industry’s biggest welfare problems. The complex aetiology of footrot makes in-situ or in-vitro investigations difficult. Computational methods offer a solution to understanding the bacteria involved, how they may interact with the host and ultimately providing a way to identify targets for future hypotheses driven investigative work. Here we present the first combined global analysis of the bacterial community transcripts together with the host immune response in healthy and diseased ovine feet during a natural polymicrobial infection state using metatranscriptomics. The intra tissue and surface bacterial populations and the most abundant bacterial transcriptome were analysed, demonstrating footrot affected skin has a reduced diversity and increased abundances of, not only the causative bacteria Dichelobacter nodosus , but other species such as Mycoplasma fermentans and Porphyromonas asaccharolytica . Host transcriptomics reveals a suppression of biological processes relating to skin barrier function, vascular functions, and immunosurveillance in unhealthy interdigital skin, supported by histological findings that type I collagen (associated with scar tissue formation) is significantly increased in footrot affected interdigital skin comparted to outwardly healthy skin. Finally, we provide some interesting indications of host and pathogen interactions associated with virulence genes and the host spliceosome which could lead to the identification of future therapeutic targets. Impact Statement Lameness in sheep is a global welfare and economic concern and footrot is the leading cause of lameness, affecting up to 70% of flocks in the U.K. Current methods for control of this disease are labour intensive and account for approximately 65% of antibiotic use in sheep farming, whilst preventative vaccines suffer from poor efficacy due to antigen competition. Our limited understanding of cofounders, such as strain variation and polymicrobial nature of infection mean new efficacious, affordable and scalable control measures are not receiving much attention. Here we examine the surface and intracellular bacterial populations and propose potential interactions with the host. Identification of these key bacterial species involved in the initiation and progression of disease and the host immune mechanisms could help form the basis of new therapies.


Pharmaceutics ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 255 ◽  
Author(s):  
Lupe Carolina Espinoza ◽  
Rodrigo Vera-García ◽  
Marcelle Silva-Abreu ◽  
Òscar Domènech ◽  
Josefa Badia ◽  
...  

Pioglitazone (PGZ) is a drug used to treat type 2 diabetes mellitus that has been reported to show additional therapeutic activities on diverse inflammatory parameters. The aim of this study was to optimize a topical PGZ-loaded nanoemulsion (PGZ-NE) in order to evaluate its effectiveness for treating atopic dermatitis (AD). The composition of the nanoformulation was established by pseudo-ternary diagram. Parameters such as physical properties, stability, in vitro release profile, and ex vivo permeation were determined. The efficacy study was carried out using oxazolone-induced AD model in hairless mice. PGZ-NE released the drug following a hyperbolic kinetic. Additionally, its properties provided high retention potential of drug inside the skin. Therapeutic benefits of PGZ-NE were confirmed on diverse events of the inflammatory process, such as reduction of lesions, enhancement of skin barrier function, diminished infiltration of inflammatory cells, and expression of pro-inflammatory cytokines. These results were reinforced by atomic force microscope (AFM), which demonstrated the ability of the formulation to revert the rigidification caused by oxazolone and consequently improve the elasticity of the skin. These results suggest that PGZ-NE may be a promising treatment for inflammatory dermatological conditions such as AD.


2020 ◽  
Vol 13 (7) ◽  
pp. 138
Author(s):  
Julian Gorski ◽  
Ehrhardt Proksch ◽  
Jens Malte Baron ◽  
Daphne Schmid ◽  
Lei Zhang

With the availability of new technologies, the number of subjects undergoing medical and cosmetic interventions is increasing. Many procedures (e.g., ablative fractional laser treatment) resulting in superficial/minor wounds require appropriate aftercare to prevent complications in wound healing and poor cosmetic outcome. We review the published evidence of the usefulness of topical dexpanthenol in postprocedure wound healing and the associated mechanisms of action at the molecular level. A search in the PubMed and Embase databases was performed to query the terms dexpanthenol, panthenol, superficial wound, minor wound, wound healing, skin repair, and postprocedure. Search results were categorized as clinical trials and in vitro studies. In vitro and clinical studies provided evidence that topically applied dexpanthenol promotes superficial and postprocedure wound healing. Latest findings confirmed that dexpanthenol upregulates genes that are critical for the healing process. The gene expression data are of clinical relevance as evidenced by prospective clinical studies indicating that topical dexpanthenol accelerates wound healing with rapid re-epithelialization and restoration of skin barrier function following skin injury. It can therefore be inferred that topical dexpanthenol represents an appropriate and state-of-the-art treatment option for superficial postprocedure wounds, especially when applied early after the superficial skin damage.


2020 ◽  
pp. jbc.RA120.016570
Author(s):  
Matthew L. Edin ◽  
Haruto Yamanashi ◽  
William E. Boeglin ◽  
Joan P. Graves ◽  
Laura M. DeGraff ◽  
...  

The mammalian epoxide hydrolase EPHX3 is known from in vitro experiments to efficiently hydrolyze the linoleate epoxides 9,10-epoxyoctadecamonoenoic acid (EpOME) and epoxyalcohol 9R,10R-trans-epoxy-11E-13R-hydroxy-octadecenoate to corresponding diols and triols, respectively. Herein we examined the physiological relevance of EPHX3 to hydrolysis of both substrates in vivo.  Ephx3-/- mice show no deficiency in EpOME-derived plasma diols, discounting a role for EPHX3 in their formation, whereas epoxyalcohol-derived triols esterified in acylceramides of the epidermal 12R-lipoxygenase pathway are reduced. Although the Ephx3-/- pups appear normal, measurements of trans-epidermal water loss detected a modest and statistically significant increase compared to the wild-type or heterozygote mice, reflecting a skin barrier impairment that was not evident in the knockouts of mouse microsomal epoxide hydrolase (EPHX1/mEH) or soluble epoxide hydrolase (EPHX2/sEH). This barrier phenotype in the Ephx3-/- pups was associated with a significant decrease in the covalently bound ceramides in the epidermis (40% reduction, p<0.05), indicating a corresponding structural impairment in the integrity of the water barrier. Quantitative LC-MS analysis of the esterified linoleate-derived triols in the murine epidermis revealed a marked and isomer-specific reduction (~85%) in the Ephx3-/- epidermis of the major trihydroxy isomer 9R,10S,13R-trihydroxy-11E-octadecenoate. We conclude EPHX3 (and not EPHX1 or EPHX2) catalyzes hydrolysis of the 12R-LOX/eLOX3-derived epoxyalcohol esterified in acylceramide, and may function to control flux through the alternative and crucial route of metabolism via the dehydrogenation pathway of SDR9C7. Importantly, our findings also identify a functional role for EPHX3 in transformation of a naturally esterified epoxide substrate, pointing to its potential contribution in other tissues.


2021 ◽  
Vol 22 (23) ◽  
pp. 13091
Author(s):  
Andréa Tremblay ◽  
Mélissa Simard ◽  
Sophie Morin ◽  
Roxane Pouliot

Healthy skin moLEdels produced by tissue-engineering often present a suboptimal skin barrier function as compared with normal human skin. Moreover, skin substitutes reconstructed according to the self-assembly method were found to be deficient in polyunsaturated fatty acids (PUFAs). Therefore, in this study, we investigated the effects of a supplementation of the culture media with docosahexaenoic acid (DHA) on the barrier function of skin substitutes. To this end, 10 μM DHA-supplemented skin substitutes were produced (n = 3), analyzed, and compared with controls (substitutes without supplementation). A Franz cell diffusion system, followed by ultra-performance liquid chromatography, was used to perform a skin permeability to testosterone assay. We then used gas chromatography to quantify the PUFAs found in the epidermal phospholipid fraction of the skin substitutes, which showed successful DHA incorporation. The permeability to testosterone was decreased following DHA supplementation and the lipid profile was improved. Differences in the expression of the tight junction (TJ) proteins claudin-1, claudin-4, occludin, and TJ protein-1 were observed, principally a significant increase in claudin-1 expression, which was furthermore confirmed by Western blot analyses. In conclusion, these results confirm that the DHA supplementation of cell culture media modulates different aspects of skin barrier function in vitro and reflects the importance of n-3 PUFAs regarding the lipid metabolism in keratinocytes.


2020 ◽  
Author(s):  
David Dodds ◽  
Jeffrey L. Bose ◽  
Ming-De Deng ◽  
Gilles Dubé ◽  
Trudy Grossman ◽  
...  

ABSTRACTUsing live microbes as therapeutic candidates is a strategy that has gained traction across multiple therapeutic areas. In the skin, commensal microorganisms play a crucial role in maintaining skin barrier function, homeostasis, and cutaneous immunity. Alterations of the homeostatic skin microbiome are associated with a number of skin diseases. Here, we present the design of an engineered commensal organism, Staphylococcus epidermidis, for use as a live biotherapeutic product (LBP) candidate for skin diseases. The development of novel bacterial strains whose growth can be controlled without the use of antibiotics, or genetic elements conferring antibiotic resistance, enables modulation of therapeutic exposure and improves safety. We therefore constructed an auxotrophic strain of S. epidermidis that requires exogenously supplied D-alanine. The S. epidermidis strain, NRRL B-4268 Δalr1Δalr2Δdat (SEΔΔΔ) contains deletions of three biosynthetic genes: two alanine racemase genes, alr1 and alr2 (SE1674 and SE1079), and the D-alanine aminotransferase gene, dat (SE1423). These three deletions restricted growth in D-alanine deficient media, pooled human blood, and skin. In the presence of D-alanine, SEΔΔΔ colonized and increased expression of human β-defensin 2 in cultured human skin models in vitro. SEΔΔΔ, showed a low propensity to revert to D-alanine prototrophy, and did not form biofilms on plastic in vitro. These studies support the potential safety and utility of SEΔΔΔ as a live biotherapeutic strain whose growth can be controlled by D-alanine.


2002 ◽  
Vol 118 (5) ◽  
pp. 871-875 ◽  
Author(s):  
Robert P. Chilcott ◽  
Christopher H. Dalton ◽  
Andrew J. Emmanuel ◽  
Ceri E. Allen ◽  
Simon T. Bradley

2018 ◽  
Vol 32 (1) ◽  
pp. 8-21 ◽  
Author(s):  
Astrid Pany ◽  
Victoria Klang ◽  
Marion Brunner ◽  
Johanna Ruthofer ◽  
Elisabeth Schwarz ◽  
...  

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