Methods for the Assessment of Barrier Function.
Antonov Dimitar,Schliemann Sibylle,Elsner Peter
Current problems in dermatology
Due to the ease of skin accessibility, a large variety of invasive and noninvasive in vitro and in vivo methods have been developed to study barrier function. The measurement of the transepidermal water loss (TEWL) is most widely used in clinical studies. The different methods of determining TEWL, as well as skin hydration, skin pH, tape stripping and other modern less widely used methods to assess skin barrier function, are reviewed, including Raman spectroscopy and imaging methods such as optical coherence tomography and laser scanning microscopy. The modern imaging methods are important developments in the last decades which, however, determine the structure and, hence, cannot replace the measurement of TEWL in questions related to function.
10.1159/000441546
How many skin barriers haveth we: Percutaneous egression of ions?
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
INTRODUCTION:Skin provides critical barrier properties that enable terrestrial life. Myriad research has focused on the "water barrier" to transepidermal water loss (TEWL) despite there being a multitude of skin barrier properties. We asked what other barrier properties may have been overlooked and compiled data demonstrating the "electrolyte barrier" to be of potential clinical relevance. METHODS:A literature search was conducted through PubMed, Embase, Google Scholar, and Web of Science databases for the following keywords: "transepidermal" or "epidermal" or "cutaneous" or "skin" or "percutaneous" and "ion" or "sodium" or "chloride" or "potassium" or "electrolyte" and "flux" or "egression." Textbooks at the University of California, San Francisco were also hand reviewed. Experimental studies quantifying in vivo or ex vivo percutaneous egression of ions in response to human skin barrier perturbation were included. RESULTS:Experimental damage to skin, mostly by tape-stripping, frequently induced increased ion flux rates through the epidermis, in addition to increases in TEWL values. Interestingly, barrier perturbation did not always result in a concomitant rise in TEWL and transepidermal ion flux rates, such as in delipidization, indicating a distinction between the two barriers. CONCLUSION:Quantifying the percutaneous egression of ions in response to physical or chemical alterations may offer additional data that are not to be captured with TEWL studies exclusively. Continued efforts should be made to: (1) advance this technique as a method of assessing skin status and (2) enhance our understanding of other barriers and mechanisms.
10.1111/srt.13119
skin optical clearing for improving imaging and light-induced therapy: a review.
Journal of biomedical optics
Significance:Skin is the largest organ and also the first barrier of body. Skin diseases are common, and cutaneous microcirculation is relative to various diseases. Researchers attempt to develop novel imaging techniques to obtain the complex structure, components, and functions of skin. Modern optical techniques provide a powerful tool with non-invasiveness, but the imaging performance suffers from the turbid character of skin. skin optical clearing technique has been proposed to reduce tissue scattering and enhance penetration depth of light and became a hot topic of research. Aim:The aim of this review is to provide a comprehensive overview of recent development of skin optical clearing methods, how skin optical clearing enhances imaging performance, and its applications in study and light therapy of various diseases. Approach:Based on the references published over the last decade, the important milestones on the mechanism, methods, and its fundamental and clinical applications of skin optical clearing technique are provided. Results:With the deepening understanding of skin optical clearing mechanisms, efficient skin optical clearing methods were constantly screened out. These methods have been combined with various optical imaging techniques to improve imaging performances and acquire deeper and finer skin-related information. In addition, skin optical clearing technique has been widely applied in assisting study of diseases as well as achieving safe, high-efficiency light-induced therapy. Conclusions:In the last decade, skin optical clearing technique has developed rapidly and played an important role in skin-related studies.
10.1117/1.JBO.28.6.060901
Sensitive skin: an overview.
Berardesca E,Farage M,Maibach H
International journal of cosmetic science
Sensitive skin is a condition of subjective cutaneous hyper-reactivity to environmental factors. Subjects experiencing this condition report exaggerated reactions when their skin is in contact with cosmetics, soaps and sun screens, and they often report worsening after exposure to dry and cold climate. Although no sign of irritation is commonly detected, itching, burning, stinging and a tight sensation are constantly present. Generally substances that are not commonly considered irritants are involved in this abnormal response.Sensitive skin and subjective irritation are widespread but still far from being completely defined and understood. A correlation between sensitive skin and constitutional anomalies and/or other triggering factors such as occupational skin diseases or chronic exposure to irritants has been hypothesized. Recent findings suggest that higher sensitivity can be due to different mechanisms. Hyper-reactors may have a thinner stratum corneum with a reduced corneocyte area causing a higher transcutaneous penetration of water-soluble chemicals. Alterations in vanilloid receptors and changes in neuronal transmission have been described. Monitoring skin parameters such as barrier function, proclivity to irritation, corneocyte size and sensorial transmission can also be useful to identify regional differences in skin sensitivity.
10.1111/j.1468-2494.2012.00754.x
Drug delivery through the skin: molecular simulations of barrier lipids to design more effective noninvasive dermal and transdermal delivery systems for small molecules, biologics, and cosmetics.
Torin Huzil J,Sivaloganathan Siv,Kohandel Mohammad,Foldvari Marianna
Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology
The delivery of drugs through the skin provides a convenient route of administration that is often preferable to injection because it is noninvasive and can typically be self-administered. These two factors alone result in a significant reduction of medical complications and improvement in patient compliance. Unfortunately, a significant obstacle to dermal and transdermal drug delivery alike is the resilient barrier that the epidermal layers of the skin, primarily the stratum corneum, presents for the diffusion of exogenous chemical agents. Further advancement of transdermal drug delivery requires the development of novel delivery systems that are suitable for modern, macromolecular protein and nucleotide therapeutic agents. Significant effort has already been devoted to obtain a functional understanding of the physical barrier properties imparted by the epidermis, specifically the membrane structures of the stratum corneum. However, structural observations of membrane systems are often hindered by low resolutions, making it difficult to resolve the molecular mechanisms related to interactions between lipids found within the stratum corneum. Several models describing the molecular diffusion of drug molecules through the stratum corneum have now been postulated, where chemical permeation enhancers are thought to disrupt the underlying lipid structure, resulting in enhanced permeability. Recent investigations using biphasic vesicles also suggested a possibility for novel mechanisms involving the formation of complex polymorphic lipid phases. In this review, we discuss the advantages and limitations of permeation-enhancing strategies and how computational simulations, at the atomic scale, coupled with physical observations can provide insight into the mechanisms of diffusion through the stratum corneum.
10.1002/wnan.147
New aspects of the skin barrier organization.
Bouwstra J,Pilgram G,Gooris G,Koerten H,Ponec M
Skin pharmacology and applied skin physiology
In the superficial layer of the skin, the stratum corneum (SC), the lipids form two crystalline lamellar phases with periodicities of 6.4 and 13.4 nm (long-periodicity phase). The main lipid classes in SC are ceramides, free fatty acids and cholesterol. Studies with mixtures prepared with isolated ceramides revealed that cholesterol and ceramides are very important for the formation of the lamellar phases, and the presence of ceramide 1 is crucial for the formation of the long-periodicity phase. This observation and the broad-narrow-broad sequence of lipid layers in the 13.4-nm phase led us to propose a molecular model for this phase. This consists of one narrow central lipid layer with fluid domains on both sides of a broad layer with a crystalline structure. This model is referred to as 'the sandwich model'. While the presence of free fatty acids does not substantially affect the lipid lamellar organization, it is crucial for the formation of the orthorhombic sublattice, since the addition of free fatty acids to cholesterol/ceramide mixtures results in transition from a hexagonal to a crystalline lipid phase. Studies examining lipid organization in SC derived from dry or lamellar X-linked ichthyosis skin revealed that in native tissue the role of ceramide 1 and free fatty acids is similar to that observed with mixtures prepared with isolated SC lipids. From this we conclude that the results obtained with lipid mixtures can be used to predict the SC lipid organization in native tissue.
10.1159/000056391
Effect of tannic acid on skin barrier function.
Nakamura Tomoya,Yoshida Naoki,Yasoshima Mitsue,Kojima Yoshihiko
Experimental dermatology
In this study, we investigated how tannic acid (TA) protects the skin from inflammation caused by external irritation. The effects of TA were evaluated using a mouse 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced skin inflammation model and a reconstructed human epidermal model. We then used Lucifer Yellow for visual confirmation of TA's suppression effect at the stratum corneum (SC) surface. TA treatment of the skin prevented Lucifer Yellow from permeating the skin. This result suggests that TA acts as a barrier against external stimulants such as TPA and artificial sweat on the SC surface.
10.1111/exd.13478
Rosmarinic Acid, as an NHE1 Activator, Decreases Skin Surface pH and Improves the Skin Barrier Function.
International journal of molecular sciences
Stratum corneum (SC) pH regulates skin barrier functions and elevated SC pH is an important factor in various inflammatory skin diseases. Acidic topical formulas have emerged as treatments for impaired skin barriers. Sodium proton exchanger 1 (NHE1) is an important factor in SC acidification. We investigated whether topical applications containing an NHE1 activator could improve skin barrier functions. We screened plant extracts to identify NHE1 activators in vitro and found leaf extract. Rosmarinic acid, a component of leaf extract, significantly increased NHE1 mRNA expression levels and NHE1 production. Immunofluorescence staining of NHE1 in 3D-cultured skin revealed greater upregulation of NHE1 expression by NHE1 activator cream, compared to vehicle cream. Epidermal lipid analysis revealed that the ceramide level was significantly higher upon application of the NHE1 activator cream on 3D-cultured skin, compared to application of a vehicle cream. In a clinical study of 50-60-year-old adult females ( = 21), application of the NHE1 activator-containing cream significantly improved skin barrier functions by reducing skin surface pH and transepidermal water loss and increasing skin hydration, compared to patients who applied vehicle cream and those receiving no treatment. Thus, creams containing NHE1 activators, such as rosmarinic acid, could help maintain or recover skin barrier functions.
10.3390/ijms23073910
Tight junctions in skin inflammation.
Bäsler Katja,Brandner Johanna M
Pflugers Archiv : European journal of physiology
Inflammation of the skin is found after various external stimuli, e.g., UV radiation, allergen uptake, microbial challenge, or contact with irritants, as well as due to intrinsic, not always well-defined, stimuli, e.g., in autoimmune responses. Often, it is also triggered by a combination of both. The specific processes, which mean the kind of cytokines and immune cells involved and the extent of the reaction, depend not only on the trigger but also on the predisposition of the individual. Tight junctions (TJs) in the skin have been shown to form a barrier in the granular cell layer of the epidermis. Furthermore, TJ proteins were found in several additional epidermal layers. Besides barrier function, TJ proteins have been shown to be involved in proliferation, differentiation, cell-cell adhesion, and apoptosis in keratinocytes. In inflamed skin, TJ proteins are often affected. We summarize here the impact of skin inflammation on TJs, e.g., in various forms of dermatitis including atopic dermatitis, in skin infection, and in UV-irradiated skin, and discuss the role of TJs in these inflammatory processes.
10.1007/s00424-016-1903-9
Skin microbiota and human 3D skin models.
Rademacher Franziska,Simanski Maren,Gläser Regine,Harder Jürgen
Experimental dermatology
Although the role of the microbiota in skin homeostasis is still emerging, there is growing evidence that an intact microbiota supports the skin barrier. The increasing number of research efforts that are trying to shed more light on the human skin-microbiota interaction requires the use of suitable experimental models. Three-dimensional (3D) skin equivalents have been established as a valuable tool in dermatological research because they contain a fully differentiated epidermal barrier that reflects the morphological and molecular characteristics of normal human epidermis. In this review, we provide an overview of current 3D skin models and illustrate the potential of 3D skin models to study the human skin-microbiota interplay.
10.1111/exd.13517
Human tissue kallikreins as promiscuous modulators of homeostatic skin barrier functions.
Eissa Azza,Diamandis Eleftherios P
Biological chemistry
Human tissue kallikreins (KLKs) are the largest family of secreted serine protease endopeptidases encoded by 15 genes clustered on chromosome 19q13.4. Multiple KLK enzymes are co-localized in the upper stratum granulosum and stratum corneum of human epidermis, and in associated appendages such as hair follicle epithelia and sweat glands. Until recently, kallikrein proteolytic activity in the skin was exclusively attributed to KLK5 and KLK7. However, wider cutaneous roles of kallikreins became evident in recent years as the proposal of KLK proteolytic activation cascades emerged. We postulate that these proteolytic enzymes may serve as promiscuous mediators of different skin barrier functions, since they are capable of proteolysing different substrates that govern skin desquamation, antimicrobial defense, and lipid permeability. Growing evidence now attests to potential kallikrein involvement in skin inflammation, pigmentation, and tumor suppression via their ability to target proteinase-activated receptor signaling pathways. Current knowledge on kallikrein roles in skin physiology and pathobiology is described in this review.
10.1515/BC.2008.079
TRP channels in the skin.
Tóth Balázs I,Oláh Attila,Szöllősi Attila Gábor,Bíró Tamás
British journal of pharmacology
Emerging evidence suggests that transient receptor potential (TRP) ion channels not only act as 'polymodal cellular sensors' on sensory neurons but are also functionally expressed by a multitude of non-neuronal cell types. This is especially true in the skin, one of the largest organs of the body, where they appear to be critically involved in regulating various cutaneous functions both under physiological and pathophysiological conditions. In this review, we focus on introducing the roles of several cutaneous TRP channels in the regulation of the skin barrier, skin cell proliferation and differentiation, and immune functions. Moreover, we also describe the putative involvement of several TRP channels in the development of certain skin diseases and identify future TRP channel-targeted therapeutic opportunities.
10.1111/bph.12569
Update on the structure and function of the skin barrier: atopic dermatitis as an exemplar of clinical implications.
Elias Peter M,Eichenfield Lawrence F,Fowler Joseph F,Horowitz Paul,McLeod Renee P
Seminars in cutaneous medicine and surgery
The healthy stratum corneum allows optimum permeability of water and provides the first line of defense against pathogenic and environmental assaults. The barrier functions of the stratum corneum are interrelated, coregulated, and interdependent. Research has demonstrated that three lipid species, which usually comprise 10% of the stratum corneum, are crucial to both its structure and its function; these must be present in sufficient quantities and in the correct proportions to provide optimum barrier function. The clinical implications of how the skin barrier works--and is supported and restored--can be seen in the current and emerging understanding of atopic dermatitis management.
10.12788/j.sder.0022
Microspectroscopic Confocal Raman and Macroscopic Biophysical Measurements in the in vivo Assessment of the Skin Barrier: Perspective for Dermatology and Cosmetic Sciences.
Falcone Denise,Uzunbajakava Natallia E,Varghese Babu,de Aquino Santos Gabriela Ricardo,Richters Renée J H,van de Kerkhof Peter C M,van Erp Piet E J
Skin pharmacology and physiology
Skin barrier function, confined to the stratum corneum, is traditionally evaluated using established, noninvasive biophysical methods like transepidermal water loss, capacitance and conductance. However, these methods neither measure skin molecular composition nor its structure, hindering the actual causes of skin barrier change or impairment. At the same time, confocal Raman microspectroscopy (CRS) can directly measure skin molecular composition and structure and has proven itself to be a powerful technique for biomolecular analysis. The aims of this literature review were to evaluate noninvasive biophysical methods in view of CRS and to outline a direction towards more specific and informative skin measurement methods. We address this by investigating, for the first time, the relation between in vivo assessment of the skin barrier using indirect biophysical methods and the actual skin composition and structure as given by CRS, and emphasize the high potential of CRS for dermatology and cosmetic sciences. CRS acceptance in these fields will require close collaboration between dermatologists, skin scientists and spectroscopy experts towards simplifying the technology and creating robust, rapid, easy-to-use and less expensive CRS applications.
10.1159/000439031
An ex vivo human skin model for studying skin barrier repair.
Danso Mogbekeloluwa O,Berkers Tineke,Mieremet Arnout,Hausil Farzia,Bouwstra Joke A
Experimental dermatology
In the studies described in this study, we introduce a novel ex vivo human skin barrier repair model. To develop this, we removed the upper layer of the skin, the stratum corneum (SC) by a reproducible cyanoacrylate stripping technique. After stripping the explants, they were cultured in vitro to allow the regeneration of the SC. We selected two culture temperatures 32 °C and 37 °C and a period of either 4 or 8 days. After 8 days of culture, the explant generated SC at a similar thickness compared to native human SC. At 37 °C, the early and late epidermal differentiation programmes were executed comparably to native human skin with the exception of the barrier protein involucrin. At 32 °C, early differentiation was delayed, but the terminal differentiation proteins were expressed as in stripped explants cultured at 37 °C. Regarding the barrier properties, the SC lateral lipid organization was mainly hexagonal in the regenerated SC, whereas the lipids in native human SC adopt a more dense orthorhombic organization. In addition, the ceramide levels were higher in the cultured explants at 32 °C and 37 °C than in native human SC. In conclusion, we selected the stripped ex vivo skin model cultured at 37 °C as a candidate model to study skin barrier repair because epidermal and SC characteristics mimic more closely the native human skin than the ex vivo skin model cultured at 32 °C. Potentially, this model can be used for testing formulations for skin barrier repair.
10.1111/exd.12579
Skin Metabolism: Relevance of Skin Enzymes for Rational Drug Design.
Pyo Sung Min,Maibach Howard I
Skin pharmacology and physiology
Transdermal therapeutic systems (TTS) have numerous pharmacological benefits. Drug release, for example, is independent of whether a patient is in a fed or a fasted state, and lower doses can be given as gastrointestinal and hepatic first-pass metabolism is avoided. In addition, inter- and intrapatient variability is minimized as the release of the drug is mainly controlled by the system. This makes TTS interesting as alternative systems to the most common dosage form of oral tablets. The difficulty with the dermal administration route is transporting the drug through the skin, since the skin is an efficient barrier against foreign bodies. Various strategies have been reported in the literature of how drug penetration can be improved. Most of them, however, focus on overcoming the stratum corneum as the first (mechanical) skin barrier. However, penetration is much more complex, and the skin's barrier function does not only depend on the stratum corneum; what has been underestimated is the second (biological) skin barrier formed of enzymes. Compared to the stratum corneum, very little is known about these enzymes, e.g., which enzymes are present in the skin and where exactly they are localized. Hence, very few strategies can be found for how to bypass or even use the skin enzyme barrier for TTS development. This review article provides an overview of the skin enzymes considered to be relevant for the biotransformation of dermally applied drugs. Also, we discuss the use of dermal prodrugs and soft drugs and give the stereoselectivity of skin metabolism careful consideration. Finally, we provide suggestions on how to make use of the current knowledge about skin enzymes for rational TTS design.
10.1159/000501732
Antimicrobial peptides activity in the skin.
Herman Anna,Herman Andrzej P
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
This review presents the current state of knowledge regarding multifunctional role of human skin antimicrobial peptides (AMPs), including (a) protection from microbial infection, (b) improvement of skin barrier homoeostasis, (c) modulation of inflammation responses, and (d) promotion of wound healing. In addition, association of AMPs with skin diseases as well as challenges and future prospects for AMP therapeutics has also been discussed.
10.1111/srt.12626
Action of surfactants on the mammal epidermal skin barrier.
Barba Clara,Semenzato Alessandra,Baratto Gianni,Coderch Luisa
Giornale italiano di dermatologia e venereologia : organo ufficiale, Societa italiana di dermatologia e sifilografia
BACKGROUND:Daily skin washing routines can promote undesirable effects on skin barrier function. The stratum corneum (SC) lipid matrix is crucial for skin barrier function. Skin cleansing products are mostly composed of surfactants: surface-active molecules that interact with skin lipids in several ways. The main aim of this work was to investigate the effect produced by surfactants on skin barrier permeability. Porcine skin is a well-accepted and readily available model of the human skin barrier. The effect of two cleansing formulations (based on different surfactant mixtures) on the barrier properties of mammalian skin were evaluated. METHODS:Water sorption/desorption (DVS) experiments were used to measure skin permeability. Attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy and confocal Raman were useful to study SC lipid organization. RESULTS:The results showed that while anionic surfactants (SLS) had a negative impact on the skin barrier, with a clear increase of alkyl chain disorder; cosurfactants present in the shampoo formulation diminished the detrimental effect of their primary ionic surfactant, inducing less modification on lipid intramolecular chain disorder. CONCLUSIONS:The obtained results confirmed that the mild cleansing formulations studied had gentle interaction with skin. The capacity to discriminate between detergent systems was clearly established with both DVS and spectroscopy techniques.
10.23736/S0392-0488.18.05874-1
Skin sensitivity and skin microbiota: Is there a link?
Seite Sophie,Misery Laurent
Experimental dermatology
Sensitive skin is defined by the occurrence of unpleasant sensations, accompanied or not by erythema, in response to stimuli which normally should not provoke such sensations and that cannot be linked to skin disease. Even if its pathophysiology is not completely known, hyper-reactivity of the cutaneous nervous system associated with an abnormal skin barrier has been hypothesized as a primary culprit including more recently a role of the cutaneous microbiota. The objective of this short review is to discuss the relationship between the skin microbiota, skin sensitivity and the skin barrier function.
10.1111/exd.13686
Evidence of Skin Barrier Damage by Cyclic Siloxanes (Silicones)-Using Digital Holographic Microscopy.
Mojsiewicz-Pieńkowska Krystyna,Stachowska Ewa,Krenczkowska Dominika,Bazar Dagmara,Meijer Frans
International journal of molecular sciences
Cyclic siloxanes (D4, D5, D6) are widely used in skin products. They improve skin sensory properties and alleviate dry skin, but there is still one report (published 2019), which regards their effects on the destruction of the skin barrier, by using fluorescence microscopy and attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR). A new skin-imaging technique, digital holographic microscopy (DHM), was used for the first time to investigate the impact of D4, D5, and D6 on the skin barrier. We observed irreversible damage of the stratum corneum due to the interaction with cyclic siloxanes. These substances changed: (a) the first level of the skin barrier through destabilization of the intercellular lipid lamellae and destruction of the corneocyte structure (measured with axial nanometer resolution), (b) the second level by collapse of not only corneocytes but also of a significant part of the clusters, leading to the loss of the stratum corneum integrity and formation of the lacunae, (c) the third level as an effect of the change in the surface geometrical topography of the stratum corneum and disruption of the integrity of this skin layer, measured with lateral micrometer resolution. DHM allowed also to identify an important pathway for substances to penetrate into the skin through canyons surrounding the clusters. Our investigations provide advanced information for understanding the mechanisms by which various substances pass the skin barrier, including uncontrolled diffusion into the skin.
10.3390/ijms21176375
New strategies to improve skin barrier homeostasis.
Denda Mitsuhiro
Advanced drug delivery reviews
The uppermost thin layer, stratum corneum, plays a crucial role as a water impermeable barrier. After acute damage, it recovers automatically, but with aging or psychological stress, the recovery is delayed. Frequent damage, or damage under a dry environment, induces epidermal hyperplasia or inflammation. A specific protease inhibitor, histamine antagonist, and some magnesium salts have been demonstrated to accelerate the barrier recovery. These treatments also mitigated the epidermal hyperplasia induced by repeated barrier disruption or the damage under a dry condition. For the delay of the barrier repair induced by psychological stress, a glucocorticoid receptor antagonist or reduction of the stress by some specific odorant was significantly effective. Recently, the ion flux in the epidermis was found to be crucial for the barrier homeostasis. An external negative electric field accelerated the skin barrier recovery. These new methods to improve skin barrier homeostasis could be useful strategies to solve skin problems.
10.1016/s0169-409x(02)00115-1
A domain mosaic model of the skin barrier.
Forslind B
Acta dermato-venereologica
The skin barrier primarily protects the body against uncontrolled loss of water and in addition prevents water and matter of the environment from indiscriminately entering the living system. The current concept of the skin barrier suggests that permeability is governed by a hydrophilic and a hydrophobic "channel". To account both for the barrier function and the hydrophilic and hydrophobic pathways through this barrier, we propose a new model, "the domain mosaic model of the skin barrier", which depicts the bulk of the lipids as segregated into crystalline/gel domains bordered by "grain borders" where lipids are in the fluid crystalline state. Such an arrangement provides for an effective "water-tight" barrier that allows a minute and controlled loss of water to keep the corneocytes moistened. In addition the model provides for the necessary mechanical properties permitting bending and stress imposed on the skin surface. Furthermore, the fluid character of the "grain borders" represents areas where lipid and hydrophobic molecules may diffuse through the system on down-hill gradients. It is suggested that in the border areas between the crystalline domains, structural transformations of the lipid organization due to permeation promoters may take place without structural changes in the bulk organization of lipids in the crystalline or gel phase.
10.2340/000155557416
[Function of Sacran as an Artificial Skin Barrier and the Development of Skincare Products].
Masaki Hitoshi,Doi Moeko
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan
Sacran, a large molecular-weight polysaccharide isolated from algae, is composed of 11 types of saccharides, including sulfate and carboxylic acid groups. Because of its unique structure, sacran can form a gel-like sheet in the presence of polyols such as 1,3-butanediol. In addition, those sacran gel-like sheets prevent the evaporation of water and the penetration of chemicals. The results of our previous study suggested that sacran can work as an artificial barrier against external stimuli such as air pollutants which increase the stress on humans. Topically applied sacran was localized at the surface of reconstructed human epidermal equivalents. Those results suggested that sacran inhibits excessive water evaporation from the skin and protects against environmental stimuli by forming an artificial barrier at the skin surface. Then, in a clinical study, we examined the activity of sacran in improving skin problems caused by an impaired epidermal barrier. First, we conducted a use test on a serum formulated with sacran on human volunteers who had impaired skin barrier function. The results showed that sacran provided excellent benefits to improve the maturation of corneocytes. These results suggest that sacran could play an important role in providing optimal skin conditions for keratinocytes to progress through their differentiation.
10.1248/yakushi.18-00177-3
Skin barrier dysfunction and systemic sensitization to allergens through the skin.
Strid Jessica,Strobel Stephan
Current drug targets. Inflammation and allergy
Most allergic, atopic and hypersensitive reactions are associated with Th2-biased immune responses and allergen-specific IgE antibodies. Pathological allergic disorders are on an alarming increase in the industrialized world. Understanding the mechanism of primary sensitization to allergens is important in elucidating the pathogenesis of these diseases and for possibly preventing their development. In this article, we review recent information supporting that epidermal allergen exposure may contribute to systemic allergic diseases and that atopy may be secondary to skin barrier dysfunction in some dermatoses. The skin is an active immunological organ, which functions as a primary defence and biosensor to the external environment. The critical permeability barrier function is mediated by the outmost layer of the epidermis, the stratum corneum. Perturbation of the stratum corneum initiates a chain of event, which activates homeostatic responses in the underlying epidermis. Repeated barrier-disruption, whether environmentally or genetically determined, may however stimulate signaling cascades that lead to inflammation and epidermal hyperplasia. Skin barrier dysfunction may also allow entry of allergens, which can lead to primary systemic sensitization. The altered epidermal microenvironment in barrier-disrupted skin appears to be particularly well suited for the induction of potent Th2-type responses with production of allergen-specific IgE. Epidermal exposure to food antigens can prevent the normal induction of oral tolerance and also lead to airway eosinophilia following inhalation. Exposure to allergens on barrier-disrupted skin may as such serve as a natural sensitization pathway for food allergy and respiratory allergic disease.
10.2174/156801005774322199
The role of tight junctions in skin barrier function and dermal absorption.
Bäsler Katja,Bergmann Sophia,Heisig Michael,Naegel Arne,Zorn-Kruppa Michaela,Brandner Johanna M
Journal of controlled release : official journal of the Controlled Release Society
The skin protects our body from external assaults like pathogens, xenobiotics or UV irradiation. In addition, it prevents the loss of water and solutes. To fulfill these important tasks, a complex barrier system has developed which comprises the stratum corneum, tight junctions, the microbiome, the chemical barrier and the immunological barrier. These barriers do not act separately, but influence each other e.g. after external manipulation or in skin diseases. Especially the two mechanical barriers, i.e. stratum corneum and tight junctions, are of great interest for drug delivery, because they are the first interaction partners of drug delivery systems and play the major role in skin absorption. Tight junctions are of special interest, as they are centrally localized in this complex barrier system in the outermost viable layer - the stratum granulosum of the interfollicular epidermis and the companion cell layer of the hair follicle - and because they can react very quickly to stimuli. We summarize here our current knowledge about tight junction barrier function in mammalian interfollicular epidermis and hair follicles, and the interaction of tight junctions with other skin barrier components in health and disease. Furthermore, we discuss their relevance for drug delivery and provide examples for tight junction modulators.
10.1016/j.jconrel.2016.08.007
Oxidative stress in aging human skin.
Rinnerthaler Mark,Bischof Johannes,Streubel Maria Karolin,Trost Andrea,Richter Klaus
Biomolecules
Oxidative stress in skin plays a major role in the aging process. This is true for intrinsic aging and even more for extrinsic aging. Although the results are quite different in dermis and epidermis, extrinsic aging is driven to a large extent by oxidative stress caused by UV irradiation. In this review the overall effects of oxidative stress are discussed as well as the sources of ROS including the mitochondrial ETC, peroxisomal and ER localized proteins, the Fenton reaction, and such enzymes as cyclooxygenases, lipoxygenases, xanthine oxidases, and NADPH oxidases. Furthermore, the defense mechanisms against oxidative stress ranging from enzymes like superoxide dismutases, catalases, peroxiredoxins, and GSH peroxidases to organic compounds such as L-ascorbate, α-tocopherol, beta-carotene, uric acid, CoQ10, and glutathione are described in more detail. In addition the oxidative stress induced modifications caused to proteins, lipids and DNA are discussed. Finally age-related changes of the skin are also a topic of this review. They include a disruption of the epidermal calcium gradient in old skin with an accompanying change in the composition of the cornified envelope. This modified cornified envelope also leads to an altered anti-oxidative capacity and a reduced barrier function of the epidermis.
10.3390/biom5020545
Effect of L-4-Thiazolylalanine (Protinol™) on skin barrier strength and skin protection.
International journal of cosmetic science
OBJECTIVES:Skin barrier properties are critical for maintaining epidermal water content, protecting from environmental factors and providing the first line of defense against pathogens. In this study, we investigated the non-proteinogenic amino acid L-4-Thiazolylalanine (L4) as a potential active ingredient in skin protection and barrier strength. METHODS:L4 on wound healing, anti-inflammatory and anti-oxidant properties were evaluated using monolayers and 3D skin equivalents. The transepithelial electrical resistance (TEER) value was used in vitro as a strong indicator of barrier strength and integrity. Clinical L4 efficacy was assessed for the evaluation of the skin barrier integrity and soothing benefits. RESULTS:In vitro treatments of L4 show beneficial effects in wound closure mechanism, and we demonstrate that L4 anti-oxidant benefits with markedly increased HSP70 and decreased reactive oxygen species production induced by UVs exposure. Barrier strength and integrity were significantly improved by L4, confirmed clinically by an increase in 12R-lipoxygenase enzymatic activity in the stratum corneum. In addition, soothing benefits of L4 have been shown clinically with the decrease in redness after methyl nicotinate application on the inner arm and the significant reduction of the erythema and the skin desquamation on the scalp. CONCLUSION:L4 delivered multiple skin benefits by strengthening the skin barrier, accelerating the skin repair process as well as soothing the skin and the scalp with anti-inflammaging effects. The observed efficacy validates L4 as a desirable skincare ingredient for topical treatment.
10.1111/ics.12881
Overcoming the skin permeation barrier: challenges and opportunities.
Vitorino Carla,Sousa Joao,Pais Alberto
Current pharmaceutical design
Stratum corneum (SC), the outermost layer of the skin, constitutes an excellent protective physiological barrier, and is the main challenge in transdermal drug delivery. Many approaches have been used to enhance the penetration of drugs through this layer, covering passive and active methods or the combination of both. This opens the opportunity to broaden the spectrum of drugs that can be administered through the skin, providing alternatives to existing products, and filling gaps that conventional routes failed to occupy. In this review, an overview of the different permeation enhancing methodologies is carried out, focusing on the combination of lipid nanoparticles with conventional chemical enhancers, as a proof-of-concept of a successful development strategy.
Importance of Tight Junctions in Relation to Skin Barrier Function.
Brandner Johanna M
Current problems in dermatology
Tight junctions (TJs) are complex cell-cell junctions that form a barrier in the stratum granulosum of mammalian skin. Besides forming a barrier themselves, TJs influence other skin barriers, e.g. the stratum corneum barrier, and are influenced by other skin barriers, e.g. by the chemical, the microbiome, or the immunological barrier and likely by the basement membrane. This review summarizes the dynamic interaction of the TJ barrier with other barriers in the skin and the central role of TJs in skin barrier function.
10.1159/000441541
Commensal induce epidermal lipid synthesis important for skin barrier function.
Science advances
Lipid synthesis is necessary for formation of epithelial barriers and homeostasis with external microbes. An analysis of the response of human keratinocytes to several different commensal bacteria on the skin revealed that induced a large increase in essential lipids including triglycerides, ceramides, cholesterol, and free fatty acids. A similar response occurred in mouse epidermis and in human skin affected with acne. Further analysis showed that this increase in lipids was mediated by short-chain fatty acids produced by and was dependent on increased expression of several lipid synthesis genes including . Inhibition or RNA silencing of peroxisome proliferator-activated receptor-α (PPARα), but not PPARβ and PPARγ, blocked this response. The increase in keratinocyte lipid content improved innate barrier functions including antimicrobial activity, paracellular diffusion, and transepidermal water loss. These results reveal that metabolites from a common commensal bacterium have a previously unappreciated influence on the composition of epidermal lipids.
10.1126/sciadv.adg6262
[Improvement of the Skin Barrier Function with Physiologically Active Substances].
Tokudome Yoshihiro
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan
Intercellular lipids in the stratum corneum (SC), including ceramides (CERs), cholesterol, and fatty acids, are important for maintaining the skin barrier function. CERs in the SC have vital roles in water retention and the barrier function. A decrease in intercellular lipids, however, reduces the skin barrier function. In this study, the ability of CER precursors to increase the level of CERs in the SC and improve the skin barrier function was examined. Glucosylceramide and sphingomyelin liposomes were used as CER precursors and prepared with a thin-film method. The particle diameter and surface potential of glucosylceramide liposomes were 120.0 nm and -20 mV, while those of sphingomyelin liposomes were 153.3 nm and -11.4 mV, respectively. Transmission electron microscopy images showed that both liposomes were closed vesicles having a lamellar structure. These liposomes were applied from the SC side of a three-dimensional cultured human epidermis model, and the level of CERs in the epidermis was measured by high-performance thin-layer chromatography. In this study, the application of glucosylceramide or sphingomyelin liposomes increased the amount of CERs. In addition, the precursors of CERs were effective in improving the skin barrier function.
10.1248/yakushi.19-00181-1
3D skin models for 3R research: The potential of 3D reconstructed skin models to study skin barrier function.
Niehues Hanna,Bouwstra Joke A,El Ghalbzouri Abdoelwaheb,Brandner Johanna M,Zeeuwen Patrick L J M,van den Bogaard Ellen H
Experimental dermatology
The skin barrier is an important shield regulating the outside-in as well as inside-out penetration of water, nutrients, ions and environmental stimuli. We can distinguish four different barrier compartments: the physical, chemical, immunological and microbial skin barrier. Well-functioning of those is needed to protect our body from the environment. To better understand the function and the contribution of barrier dysfunction in skin diseases, 3D skin or epidermal models are a valuable tool for in vitro studies. In this review, we summarize the development and application of different skin models in skin barrier research. During the last years, enormous effort was made on optimizing these models to better mimic the in vivo composition of the skin, by fine-tuning cell culture media, culture conditions and including additional cells and tissue components. Thereby, in vitro barrier formation and function has been improved significantly. Moreover, in this review we point towards changes and chances for in vitro 3D skin models to be used for skin barrier research in the nearby future.
10.1111/exd.13531
Skin pH: from basic science to basic skin care.
Ali Saba M,Yosipovitch Gil
Acta dermato-venereologica
The "acid mantle" is a topic not only of historical interest, but also of clinical significance and has recently been linked to vital stratum corneum function. Despite compelling basic science evidence placing skin pH as a key factor in barrier homeostasis, stratum corneum integrity, and antimicrobial defense, application of the acid mantle concept in clinical care is lacking. We review recent basic science investigations into skin pH, discuss skin disorders characterized by aberrant pH, and finally discuss practical application for preservation of the acid mantle. Recognizing factors that alter skin pH and selecting products that preserve the acid mantle is of prime importance in treating dermatologic patients.
10.2340/00015555-1531
Barrier functions of human skin: a holistic view.
Menon G K,Kligman A M
Skin pharmacology and physiology
The fascinating topic of skin barrier continues to engage researchers from diverse disciplines both in academia and industry. Much of the information on the basic biology of barrier formation, its ontogeny as well as repair and homeostasis comes from studies on animal models. A smaller number of human studies have validated the usefulness of animal models, while highlighting some essential differences. We submit that the human skin barrier is unique in several ways, as much due to our adaptive ability as our control over the environment (macro and micro) that none of the other species have exerted. The human skin is not only exposed to the greatest variations of environment due to our phenomenal mobility but also to the largest number of xenobiotics, both chemical and microbial, resulting from human activity. In this overview, we attempt to evaluate the interdependent relation of skin barriers to environmental stressors hoping to raise interest in some of the lesser known or neglected aspects of human skin barriers as they relate to skin health and dysfunctions.
10.1159/000231523
Exogenous Factors in Skin Barrier Repair.
Schwartz Julia,Friedman Adam J
Journal of drugs in dermatology : JDD
The stratum corneum (SC) is the skin's outermost layer and serves the primary function of acting as a shield to keep foreign matter out and to essential elements, such as moisture and water, in. Maintenance of this skin barrier is crucial to healthy functioning skin. A damaged or diseased skin barrier is vulnerable to infection, irritants, and allergens. The cornerstone of skin barrier regulation and repair is through the use of moisturizers. While healthcare providers and patients may underestimate the importance of moisturizers due to their lack of active ingredients, the benefit of a well-planned moisturizer regimen for skin barrier regulation should not be discounted. Dermatologists should be comfortable prescribing and educating about over-the-counter moisturizers to patients with skin barrier is- sues. A general understanding of basic moisturizer ingredients and formulations will aid the dermatologist in providing a personalized moisturizer regimen to their patients. <em>J Drugs Dermatol. 2016;15(11):1289-1294.</em>.
Penetration through the Skin Barrier.
Nielsen Jesper Bo,Benfeldt Eva,Holmgaard Rikke
Current problems in dermatology
The skin is a strong and flexible organ with barrier properties essential for maintaining homeostasis and thereby human life. Characterizing this barrier is the ability to prevent some chemicals from crossing the barrier while allowing others, including medicinal products, to pass at varying rates. During recent decades, the latter has received increased attention as a route for intentionally delivering drugs to patients. This has stimulated research in methods for sampling, measuring and predicting percutaneous penetration. Previous chapters have described how different endogenous, genetic and exogenous factors may affect barrier characteristics. The present chapter introduces the theory for barrier penetration (Fick's law), and describes and discusses different methods for measuring the kinetics of percutaneous penetration of chemicals, including in vitro methods (static and flow-through diffusion cells) as well as in vivo methods (microdialysis and microperfusion). Then follows a discussion with examples of how different characteristics of the skin (age, site and integrity) and of the penetrants (size, solubility, ionization, logPow and vehicles) affect the kinetics of percutaneous penetration. Finally, a short discussion of the advantages and challenges of each method is provided, which will hopefully allow the reader to improve decision making and treatment planning, as well as the evaluation of experimental studies of percutaneous penetration of chemicals.
10.1159/000441549
Skin barrier function.
Current allergy and asthma reports
Like other inflammatory dermatoses, the pathogenesis of atopic dermatitis (AD) has been largely attributed to abnormalities in adaptive immunity. T helper (Th) cell types 1 and 2 cell dysregulation, IgE production, mast cell hyperactivity, and dendritic cell signaling are thought to account for the chronic, pruritic, and inflammatory dermatosis that characterizes AD. Not surprisingly, therapy has been directed toward ameliorating Th2-mediated inflammation and pruritus. Here, we review emerging evidence that inflammation in AD occurs downstream to inherited and acquired insults to the barrier. Therapy based upon this new view of pathogenesis should emphasize approaches that correct the primary abnormality in barrier function, which drives downstream inflammation and allows unrestricted antigen access.
10.1007/s11882-008-0048-0
The dynamic anatomy and patterning of skin.
Wong Richard,Geyer Stefan,Weninger Wolfgang,Guimberteau Jean-Claude,Wong Jason K
Experimental dermatology
The skin is often viewed as a static barrier that protects the body from the outside world. Emphasis on studying the skin's architecture and biomechanics in the context of restoring skin movement and function is often ignored. It is fundamentally important that if skin is to be modelled or developed, we do not only focus on the biology of skin but also aim to understand its mechanical properties and structure in living dynamic tissue. In this review, we describe the architecture of skin and patterning seen in skin as viewed from a surgical perspective and highlight aspects of the microanatomy that have never fully been realized and provide evidence or concepts that support the importance of studying living skin's dynamic behaviour. We highlight how the structure of the skin has evolved to allow the body dynamic form and function, and how injury, disease or ageing results in a dramatic changes to the microarchitecture and changes physical characteristics of skin. Therefore, appreciating the dynamic microanatomy of skin from the deep fascia through to the skin surface is vitally important from a dermatological and surgical perspective. This focus provides an alternative perspective and approach to addressing skin pathologies and skin ageing.
10.1111/exd.12832
Skin barrier in rosacea.
Addor Flavia Alvim Sant'Anna
Anais brasileiros de dermatologia
Recent studies about the cutaneous barrier demonstrated consistent evidence that the stratum corneum is a metabolically active structure and also has adaptive functions, may play a regulatory role in the inflammatory response with activation of keratinocytes, angiogenesis and fibroplasia, whose intensity depends primarily on the intensity the stimulus. There are few studies investigating the abnormalities of the skin barrier in rosacea, but the existing data already show that there are changes resulting from inflammation, which can generate a vicious circle caused a prolongation of flare-ups and worsening of symptoms. This article aims to gather the most relevant literature data about the characteristics and effects of the state of the skin barrier in rosacea.
10.1590/abd1806-4841.20163541
Effect of red light on epidermal proliferation and mitochondrial activity.
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
BACKGROUND/PURPOSE:We previously demonstrated that irradiation with red light accelerates recovery of the epidermal water-impermeable barrier, whereas blue light delays it, and white and green light have no effect. Here, we aimed to examine in detail the effects of red and blue light in a human epidermal-equivalent model and in human skin. METHODS:We used light-emitting diodes (red light, 630 nm, 6.2 mW/cm ; blue light, 463 nm, 6.2 mW/cm ) for irradiation of an epidermal-equivalent model and human skin. Cell proliferation was evaluated by means of BrdU and Ki-67 staining, and mitochondrial activity was quantified with an extracellular flux analyzer. RESULTS:Irradiation of the epidermal-equivalent model with red light for 2 h (44.64 J/cm ) increased both epidermal proliferation in the basal layer and mitochondrial activity. Blue light had no effect on epidermal proliferation. Furthermore, irradiation with red light for 2 h on three consecutive days increased epidermal proliferation in human skin tissue in culture. CONCLUSION:These results suggest that red light accelerates epidermal proliferation in both an epidermal-equivalent model and human skin, and may promote epidermal homeostasis.
10.1111/srt.13447
Assessment of tissue-specific changes in structure and function induced by in vivo skin/skull optical clearing techniques.
Lasers in surgery and medicine
BACKGROUND OBJECTIVES:Newly developed in vivo skin and skull optical clearing techniques can greatly improve the optical imaging performance, showing great advantages and clinical prospects. However, there is a poor understanding of in vivo optical clearing-induced changes in the skin and skull. MATERIALS AND METHODS:Here, we employed in vivo skin/skull optical clearing techniques to improve the optical coherence tomography (OCT) imaging quality. And we also used polarization-sensitive OCT to monitor the dynamic changes in the polarization characteristics of the skin and skull during in vivo optical clearing processes. Two-photon imaging was used to evaluate changes in tissue barrier function and structure. Additionally, Raman spectra were employed for assessing the changes of each component in the skin and skull before and after optical clearing treatment. RESULTS:The results indicated that the polarization states of the skin and skull were altered with the usages of optical clearing agents. And the barrier permeability and collagen fiber distribution of them became disordered. Furthermore, the Raman spectra of tissue demonstrated that the applications of in vivo tissue optical clearing methods could lead to the reduction of proteins, lipids, and inorganic salts in these two organs. Interestingly, after recovery treatment, the structure and function of the skin and skull could almost recover to the initial states. CONCLUSION:In vivo tissue optical clearing can lead to changes in the structure and function of tissue, which was reversible to some extent. This study plays an important role in revealing the underlying mechanisms of tissue optical clearing techniques; moreover, it is conducive to the development and optimization of a novel in vivo tissue optical clearing approaches in future.
10.1002/lsm.23489
Skin Immune Landscape: Inside and Outside the Organism.
Abdallah Florence,Mijouin Lily,Pichon Chantal
Mediators of inflammation
The skin is an essential organ to the human body protecting it from external aggressions and pathogens. Over the years, the skin was proven to have a crucial immunological role, not only being a passive protective barrier but a network of effector cells and molecular mediators that constitute a highly sophisticated compound known as the "skin immune system" (SIS). Studies of skin immune sentinels provided essential insights of a complex and dynamic immunity, which was achieved through interaction between the external and internal cutaneous compartments. In fact, the skin surface is cohabited by microorganisms recognized as skin microbiota that live in complete harmony with the immune sentinels and contribute to the epithelial barrier reinforcement. However, under stress, the symbiotic relationship changes into a dysbiotic one resulting in skin disorders. Hence, the skin microbiota may have either positive or negative influence on the immune system. This review aims at providing basic background information on the cutaneous immune system from major cellular and molecular players and the impact of its microbiota on the well-coordinated immune responses in host defense.
10.1155/2017/5095293
Validation of a novel patient-operated device for measuring skin barrier function in atopic dermatitis.
Grinich Erin E,Topham Christina,Haynes Dylan,Chung Janice,Latour Emile,Simpson Eric L
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
BACKGROUND:Transepidermal water loss (TEWL) and capacitance are used in atopic dermatitis (AD) trials to provide objective data on clinical change and response to therapy. Many barrier devices are costly, limiting their utility. GPSkin is a novel low-cost, patient-operable device that measures both TEWL and capacitance via smartphone application. OBJECTIVE:This validation study investigated the correlation of GPSkin with the AquaFlux and Corneometer, and the reliability of these devices, in patients with AD. METHODS:Fifty AD patients with varying disease severity performed self-measurements with GPSkin, while investigators collected data with all 3 devices, on both nonlesional and lesional skin. CONCLUSION:GPSkin and AquaFlux demonstrated strong correlation for TEWL on nonlesional and lesional skin by Spearman's correlation (r ), independent of device user. For capacitance, GPSkin and the Corneometer showed moderate correlation when obtained by patients, yet a strong correlation when obtained by a clinician. Despite good correlation, GPSkin showed poor agreement with both the AquaFlux and Corneometer in Bland-Altman plots. GPSkin underestimated both TEWL and capacitance. Overall, the devices had good test-retest reliability. None of the devices could discriminate between AD severity states. While GPSkin marks an exciting advancement in barrier technology, further study is needed for validation on AD skin.
10.1111/srt.13027
Construction of a high fidelity epidermis-on-a-chip for scalable irritation evaluation.
Zhang Jing,Chen Zaozao,Zhang Yaoyao,Wang Xingchi,Ouyang Jun,Zhu Jianfeng,Yan Yuchuan,Sun Xiaowei,Wang Fei,Li Xiaoran,Ye Huan,Sun Shiqi,Yu Qingdong,Sun Jiawei,Ge Jianjun,Li Qiwei,Han Qianqian,Pu Yuepu,Gu Zhongze
Lab on a chip
3D skin equivalents have been increasingly used in the pharmaceutical and cosmetic industries, but the troublesome operation procedure and low throughput restricted their applications as safety evaluation models. Organ-on-a-chip, an emerging powerful tool in tissue/organ modeling, could be utilized to improve the function of the skin model compared with that of traditional static skin models, as well as innovate an automatic and modular way for construction or detection. In this research, we grew and differentiated human keratinocytes within a microfluidic chip to construct an integrated epidermis-on-a-chip (iEOC) system, which is specially designed to integrate multi-culture units with integrated bubble removal structures as well as trans-epithelial electrical resistance (TEER) electrodes for barrier function detection . After 14 days of culture at the air-liquid interface (ALI), the constructed epidermis-on-a-chip demonstrated histological features similar to those observed in normal human epidermis: a proliferating basal layer and differentiating spinous, granular, and cornified layers, especially the TEER value reached 3 kΩ cm and prevented more than 99% of Cascade Blue-607 Da permeation owing to the enhanced barrier function. Further immunofluorescence analysis also indicated typical keratin expression including keratin-14, keratin-10, loricrin, involucrin, and filaggrin. With the TEER monitoring integration in the chip, it could be convenient for scale-up high-quality epidermis-on-chip fabrication and correlated investigation. Additionally, the iEOC can distinguish all the 10 known toxins and non-toxins in irritation measurement by MTT assay, which is consistent with animal testing according to the OECD. Preliminarily detection of irritation responses like inflammatory cytokines also predicted different irritation reactions. This high fidelity epidermis-on-a-chip could be a potential alternative in skin irritation evaluation. This microchip and automated microfluidic systems also pave the way for scalable testing in multidisciplinary industrial applications.
10.1039/d1lc00099c
Current Views on Noninvasive in vivo Determination of Physiological Parameters of the Stratum Corneum Using Confocal Raman Microspectroscopy.
Skin pharmacology and physiology
Confocal Raman microspectroscopy is widely used in dermatology and cosmetology for analysis of the concentration of skin components (lipids, natural moisturizing factor molecules, water) and the penetration depth of cosmetic/medical formulations in the human stratum corneum (SC) in vivo. In recent years, it was shown that confocal Raman microspectroscopy can also be used for noninvasive in vivo depth-dependent determination of the physiological parameters of the SC, such as lamellar and lateral organization of intercellular lipids (ICLs), folding properties of keratin, water mobility, and hydrogen bonding states. The results showed that the strongest skin barrier function, which is primarily manifested by the orthorhombic organization of ICLs, is provided at ≈20-40% SC depth, which is related to the maximal bonding state of water with surrounding components in the SC. The secondary and tertiary structures of keratin determine water binding in the SC, which is depth-dependent. This paper shows the technical possibility and advantage of confocal Raman microspectroscopy in noninvasive investigation of the skin and summarizes recent results on in vivo investigation of the human SC.
10.1159/000521416
Noninvasive quantitative analysis of ceramide in skin of healthy Chinese population.
Cheng S-S,Chang Y-L,Fei W-M,Zhai W-F,Cheng H,Yang S,Zhang X-J
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
OBJECTIVE:The objective of this study was to make noninvasive quantitative analysis of ceramide (CER) in skin of healthy Chinese population by high performance liquid chromatography tandem mass spectrometry. METHODS:Seven healthy subjects were selected and the stratified skin samples were available using cyanoacrylate adhesion method. High performance liquid chromatography tandem mass spectrometry, use ceramide Subclass Standard C42H85NO3 Quantification of the 12 corresponding ceramide subclass in the epidermis on the 7 skin samples, which cannot get all the standard of ceramides subclass since the stratum corneum ceramide is complex and diverse. Data were collected and analyzed using full-flow lipid analysis software (LipidSearch). RESULTS:All the seven skin samples contained 12 subclasses of ceramide and the samples were quantitated with ceramide C42H85NO3 standard. The average contents were 33.63, 27.59, 108.57, 220.75, 149.20, 43.06, and 22.78 μg/mL, respectively. CONCLUSION:Ceramide is an important lipid in the epidermis and is closely related to the skin barrier function. There are 12 subtypes of ceramide detected in the skin of Chinese healthy people, and there is a difference in the concentration between individuals. The difference may be associated with the skin barrier condition, and may also be related to the unavoidable error in the process of sampling, treatment, and detection.
10.1111/srt.12457
Phosphorescent Microneedle Array for the Measurement of Oxygen Partial Pressure in Tissue.
ACS sensors
The knowledge of the exact oxygen partial pressure in tissue is crucial for patient care and in the treatment of ischemic medical conditions. However, current methods to assess oxygen partial pressure in tissue suffer from a variety of disadvantages, including complex equipment and procedures that necessitate trained personnel. Additionally, the barrier function of the stratum corneum reduces oxygen exchange and can consequently hamper surface measurements of rapidly changing oxygen partial pressure in tissue. To overcome these challenges, a novel, easy-to-use technique to monitor the oxygen partial pressure in tissue using microneedle arrays (MNAs) has been developed. The MNAs can be made from poly(ethyl methacrylate) and poly(propyl methacrylate) and overcome the skin's barrier function to measure oxygen in the capillary bed and interstitial fluid of the skin. The MNAs' tips are embedded with an oxygen-sensitive phosphorescent metalloporphyrin, where the oxygen partial pressure inversely correlates to changes in both emission intensity and phosphorescence lifetime of the in-house developed red emitting Pt-core porphyrin. It was demonstrated that the oxygen-sensing MNAs are sufficiently robust to puncture human skin via rupture of the stratum corneum, and that the MNAs can detect changes in oxygen partial pressure in skin within the physiologically relevant range (0-160 mmHg). Additionally, the MNAs can be combined with a wearable wireless optical readout system, making these oxygen-sensing MNAs a novel wearable and portable method for user-friendly monitoring of oxygen partial pressure in skin.
10.1021/acssensors.2c01775
How do the skin barrier and microbiome adapt to the extra-uterine environment after birth? Implications for the clinical practice.
International journal of cosmetic science
The multiple protective functions of the skin derive from the interactions between epithelial skin and immune cells as well as the commensal microbiota. Developed in the last trimester of intra-uterine life, the skin barrier adapts dynamically after birth. Specific differences in the structure and physiology have been disclosed between infant and adult skin. The stratum corneum of infants is thinner and structured by thicker corneocytes with a more anisotropic surface in comparison to adult skin. Lower levels of the natural moisturizing factor and its constituents, together with the increased protease activity in the epidermis result in dry baby skin and ongoing adaptation of the desquamation to the extra-uterine environment. Infant epidermis is characterized by an accelerated proliferation rate and clinically competent permeability barrier in term neonates, despite the higher baseline values of transepidermal water loss in infants. The skin surface of newborns is less acidic, which could increase susceptibility to diaper and atopic dermatitis. Immediately after birth, skin is colonized by commensal bacteria-a process dependent on the mode of delivery and of major importance for the maturation of the immune system. Skin bacterial diversity and dysbiosis have been related to different pathology such as atopic and seborrheic dermatitis. This paper focuses on the ongoing structural, functional and biochemical adaptation of the human skin barrier after birth. We discuss the interactions on the 'skin barrier/ microbiota/ immune system' axis and their role in the development of competent functional integrity of the epidermal barrier.
10.1111/ics.12844
Keratinocytes: innate immune cells in atopic dermatitis.
Clinical and experimental immunology
The skin is a unique immune organ that constitutes a complex network of physical, chemical and microbiological barriers against external insults. Keratinocytes are the most abundant cell type in the epidermis. These cells form the physical skin barrier and represent the first line of the host defense system by sensing pathogens via innate immune receptors, initiating anti-microbial responses and producing various cytokines, chemokines and anti-microbial peptides, which are important events in immunity. A damaged epidermal barrier in atopic dermatitis allows the penetration of potential allergens and pathogens to activate keratinocytes. Among the dysregulation of immune responses in atopic dermatitis, activated keratinocytes play a role in several biological processes that contribute to the pathogenesis of atopic dermatitis. In this review, we summarize the current understanding of the innate immune functions of keratinocytes in the pathogenesis of atopic dermatitis, with a special emphasis on skin-derived anti-microbial peptides and atopic dermatitis-related cytokines and chemokines in keratinocytes. An improved understanding of the innate immunity mediated by keratinocytes can provide helpful insight into the pathophysiological processes of atopic dermatitis and support new therapeutic efforts.
10.1111/cei.13575
Permeation pathways through lateral domains in model membranes of skin lipids.
Del Regno Annalaura,Notman Rebecca
Physical chemistry chemical physics : PCCP
An understanding of how molecules permeate the complex lipid matrix of the stratum corneum (SC) skin barrier is important for transdermal drug delivery, preventing the adsorption of toxic chemicals and tackling skin diseases. In this paper we present atomistic molecular dynamics simulations of skin-lipid bilayers composed of ceramides, cholesterol (CHOL) and free fatty acids at different lipid compositions and levels of hydration and investigate both perpendicular and lateral permeation pathways through the systems. We show that in fully hydrated bilayers the lipids are heterogeneously distributed, with CHOL-rich domains emerging spontaneously during the simulations. Potential of mean constraint force calculations reveal that the most favourable permeation pathway for water in the direction normal to the bilayer is through a CHOL-rich region, probably due to the disordering effect of CHOL on lipids in the gel-phase. In systems with a low water content (akin to real skin) we find that rather than forming continuous layers, water forms flattened ellipsoid-shaped pools between the lipid headgroups, which are separated by dry regions. This implies that there is no continuous aqueous lateral pathway in the SC and may help to explain why skin is such an effective barrier. We propose that the most probable permeation pathway for a small polar molecule consists of hopping from the headgroup region of one bilayer to the next via a dry region, followed by permeation along the bilayer normal through a CHOL-rich region to the centre of the bilayer where it can diffuse laterally in the lower-density lipidic environment before encountering another CHOL-rich region through which it can exit the bilayer.
10.1039/c7cp03258g
WASP: Wearable Analytical Skin Probe for Dynamic Monitoring of Transepidermal Water Loss.
ACS sensors
Early diagnosis of skin barrier dysfunction helps provide timely preventive care against diseases such as atopic dermatitis, psoriasis, food allergies, and other atopic skin disorders. Skin barrier function is commonly evaluated by measuring the transepidermal water loss (TEWL) through stratum corneum due to its noninvasive characteristics. However, existing commercial TEWL devices are significantly affected by many factors, such as ambient temperature, humidity, air flow, water accumulation, initial water contents on the skin surface, bulky sizes, high costs, and requirements for well-controlled environments. Here, we developed a wearable closed-chamber hygrometer-based TEWL device (Wearable Analytical Skin Probe, WASP) and the related algorithm for accurate and continuous monitoring of skin water vapor flux. The WASP uses short dry air purges to dry the skin surface and chamber before each water vapor flux measurement. Its design ensures a highly controlled local environment, such as consistent initial dry conditions for the skin surface and the chamber. We further applied WASP to measure the water vapor flux from six different locations of a small group of human participants. It is found that the WASP can not only measure and distinguish between insensible sweating (., TEWL) and sensible sweating (., thermal sweating) but also track skin dehydration-rehydration cycles. Comparisons with a commercial TEWL device, AquaFlux, show that the results obtained by both devices agree well. The WASP will be broadly applicable to clinical, cosmetic, and biomedical research.
10.1021/acssensors.3c01936
Changes in nano-mechanical properties of human epidermal cornified cells depending on their proximity to the skin surface.
Milani Pascale,Chlasta Julien,Abdayem Rawad,Kezic Sanja,Haftek Marek
Journal of molecular recognition : JMR
During formation of the stratum corneum (SC) barrier, terminally differentiated keratinocytes continue their maturation process within the dead superficial epidermal layer. Morphological studies of isolated human corneocytes have revealed differences between cornified envelopes purified from the deep and superficial SC. We used atomic force microscopy to measure the mechanical properties of native human corneocytes harvested by tape-stripping from different SC depths. Various conditions of data acquisition have been tested and optimized, in order to obtain exploitable and reproducible results. Probing at 200 nN allowed us to investigate the total stiffness of the cells (at 50 nm indentation) and that of the cornified envelopes (at 10 to15 nm), and lipid envelopes (at 5 to 10 nm). The obtained data indicated statistically significant differences between the superficial (more rigid) and deep (softer) corneocytes, thus confirming the existence of depth and maturation-related morphological changes within the SC. The proposed approach can be potentially used for minimally invasive evaluation of various skin conditions such as aging, skin hydration, and pathologies linked to SC.
10.1002/jmr.2722
Streamlined Intravital Imaging Approach for Long-Term Monitoring of Epithelial Tissue Dynamics on an Inverted Confocal Microscope.
Journal of visualized experiments : JoVE
Understanding normal and aberrant in vivo cell behaviors is necessary to develop clinical interventions to thwart disease initiation and progression. It is therefore critical to optimize imaging approaches that facilitate the observation of cell dynamics in situ, where tissue structure and composition remain unperturbed. The epidermis is the body's outermost barrier, as well as the source of the most prevalent human cancers, namely cutaneous skin carcinomas. The accessibility of skin tissue presents a unique opportunity to monitor epithelial and dermal cell behaviors in intact animals using noninvasive intravital microscopy. Nevertheless, this sophisticated imaging approach has primarily been achieved using upright multiphoton microscopes, which represent a significant barrier for entry for most investigators. This study presents a custom-designed, 3D-printed microscope stage insert suitable for use with inverted confocal microscopes, streamlining the long-term intravital imaging of ear skin in live transgenic mice. We believe this versatile invention, which may be customized to fit the inverted microscope brand and model of choice and adapted to image additional organ systems, will prove invaluable to the greater scientific research community by significantly enhancing the accessibility of intravital microscopy. This technological advancement is critical for bolstering our understanding of live cell dynamics in normal and disease contexts.
10.3791/65529
Anisotropic cellular forces support mechanical integrity of the Stratum Corneum barrier.
Guo Shuo,Domanov Yegor,Donovan Mark,Ducos Bertrand,Pomeau Yves,Gourier Christine,Perez Eric,Luengo Gustavo S
Journal of the mechanical behavior of biomedical materials
The protective function of biological surfaces that are exposed to the exterior of living organisms is the result of a complex arrangement and interaction of cellular components. This is the case for the most external cornified layer of skin, the stratum corneum (SC). This layer is made of corneocytes, the elementary 'flat bricks' that are held together through adhesive junctions. Despite the well-known protective role of the SC under high mechanical stresses and rapid cell turnover, the subtleties regarding the adhesion and mechanical interaction among the individual corneocytes are still poorly known. Here, we explore the adhesion of single corneocytes at different depths of the SC, by pulling them using glass microcantilevers, and measuring their detachment forces. We measured their interplanar adhesion between SC layers, and their peripheral adhesion among cells within a SC layer. Both adhesions increased considerably with depth. At the SC surface, with respect to adhesion, the corneocyte population exhibited a strong heterogeneity, where detachment forces differed by more than one order of magnitude for corneocytes located side by side. The measured detachment forces indicated that in the upper-middle layers of SC, the peripheral adhesion was stronger than the interplanar one. We conclude that the stronger peripheral adhesion of corneocytes in the SC favors an efficient barrier which would be able to resist strong stresses.
10.1016/j.jmbbm.2018.12.027
Non-invasive method to monitor molecular changes in human stratum corneum during acute barrier disruption using reflectance NIR spectroscopy.
Shin Eui Seok,Lee June-Young,Lee Seung Jun,Nam Sung Hyun
Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference
Stratum corneum is the outer most part of skin for barrier function. Disorder in stratum corneum is related with many skin diseases including acne, atopic dermatitis and psoriasis. In developed countries, about 20% of the population has disorder in the barrier function of stratum corneum. Adhesive tape stripping is a method to disrupt skin barrier function in studying disorder in stratum corneum. In this study, we obtained NIR (Near-Infrared) spectrum of human skin after tape stripping. Changes in skin spectra after barrier disruption were investigated through principal component analysis (PCA) of spectrum. PCA analysis revealed that peaks for -NH stretching and -CH vibration mainly contributed to the spectral variation caused by barrier disruption. Furthermore, second derivative of spectrum revealed that acute barrier disruption contributes to spectral changes in the region related with secondary structure of protein, lipid and water associated with lipid in stratum corneum. We demonstrated that acute barrier disruption affected features in NIR spectrum. These spectral changes revealed that acute barrier disruption affected keratin protein and ceramide in human stratum corneum. These results suggest that NIR spectroscopy can be used to monitor changes in filamentous network and lamellar structure in stratum corneum. NIR spectroscopy can provide non-invasive method to investigate skin disease related with barrier disruption by monitoring disturbance in protein and lipid structure in stratum corneum.
10.1109/EMBC.2018.8512567
[In vivo imaging of cutaneous inflammation: novel insights into cutaneous immune responses revealed by multi-photon microscopic analysis].
Honda Tetsuya,Kabashima Kenji
Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology
Skin is an outermost organ that serves as an interface between the host and the environment. The skin provides not only mechanical barrier functions, but also an active immunological barrier that provides the first line of defense against infections. For the effective clearance of pathogens or antigens in the skin, immune cells, especially effector T cells, must quickly exert their effector functions while avoiding the host damage by their excess activation. Therefore, the quality, magnitude, and the duration of the effector T cell activity must be carefully regulated. Here, we will review our recent findings on the effector T cell dynamics, dendritic cell dynamics, and the regulatory mechanisms for effector T cells activation in the skin, as revealed by the live imaging techniques using multi-photon microscopy.
10.2177/jsci.40.337
Herpes Simplex Virus 1 Can Bypass Impaired Epidermal Barriers upon Infection of Skin from Atopic Dermatitis Patients.
Journal of virology
To infect its human host, herpes simplex virus 1 (HSV-1) must overcome the protective barriers of skin and mucosa. Here, we addressed whether pathological skin conditions can facilitate viral entry via the skin surface and used infection studies to explore viral invasion in atopic dermatitis (AD) skin characterized by disturbed barrier functions. Our focus was on the visualization of the onset of infection in single cells to determine the primary entry portals in the epidermis. After infection of lesional AD skin, we observed infected cells in suprabasal layers indicating successful invasion in the epidermis via the skin surface which was never detected in control skin where only sample edges allowed viral access. The redistribution of filaggrin, loricrin, and tight-junction components in the lesional skin samples suggested multiple defective mechanical barriers. To dissect the parameters that contribute to HSV-1 invasion, we induced an AD-like phenotype by adding the Th2 cytokines interleukin 4 (IL-4) and IL-13 to healthy human skin samples. Strikingly, we detected infected cells in the epidermis, implying that the IL-4/IL-13-driven inflammation is sufficient to induce modifications allowing HSV-1 to penetrate the skin surface. In summary, not only did lesional AD skin facilitate HSV-1 penetration but IL-4/IL-13 responses alone allowed virus invasion. Our results suggest that the defective epidermal barriers of AD skin and the inflammation-induced altered barriers in healthy skin can make receptors accessible for HSV-1. Herpes simplex virus 1 (HSV-1) can target skin to establish primary infection in the epithelium. While the human skin provides effective barriers against viral invasion under healthy conditions, a prominent example of successful invasion is the disseminated HSV-1 infection in the skin of atopic dermatitis (AD) patients. AD is characterized by impaired epidermal barrier functions, chronic inflammation, and dysbiosis of skin microbiota. We addressed the initial invasion process of HSV-1 in atopic dermatitis skin to understand whether the physical barrier functions are sufficiently disturbed to allow the virus to invade skin and reach its receptors on skin cells. Our results demonstrate that HSV-1 can indeed penetrate and initiate infection in atopic dermatitis skin. Since treatment of skin with IL-4 and IL-13 already resulted in successful invasion, we assume that inflammation-induced barrier defects play an important role for the facilitated access of HSV-1 to its target cells.
10.1128/jvi.00864-22
The how, why and clinical importance of stratum corneum acidification.
Elias Peter M
Experimental dermatology
In this article, I review the multiple endogenous mechanisms that contribute to the highly acidic pH of normal stratum corneum (SC). Then, I describe how each mechanism potentially impacts specific defensive functions of the SC. Finally, I review the rapidly expanding, clinical implications and potential therapeutic applications of SC acidification.
10.1111/exd.13329
EGFR inhibitors switch keratinocytes from a proliferative to a differentiative phenotype affecting epidermal development and barrier function.
Joly-Tonetti Nicolas,Ondet Thomas,Monshouwer Mario,Stamatas Georgios N
BMC cancer
BACKGROUND:Cutaneous adverse drug reactions (CADR) associated with oncology therapy involve 45-100% of patients receiving kinase inhibitors. Such adverse reactions may include skin inflammation, infection, pruritus and dryness, symptoms that can significantly affect the patient's quality of life. To prevent severe skin damages dose adjustment or drug discontinuation is often required, interfering with the prescribed oncology treatment protocol. This is particularly the case of Epidermal Growth Factor Receptor inhibitors (EGFRi) targeting carcinomas. Since the EGFR pathway is pivotal for epidermal keratinocytes, it is reasonable to hypothesize that EGFRi also affect these cells and therefore interfere with the epidermal structure formation and skin barrier function. METHODS:To test this hypothesis, the effects of EGFRi and Vascular Endothelial Growth Factor Receptor inhibitors (VEGFRi) at therapeutically relevant concentrations (3, 10, 30, 100 nM) were assessed on proliferation and differentiation markers of human keratinocytes in a novel 3D micro-epidermis tissue culture model. RESULTS:EGFRi directly affect basal keratinocyte growth, leading to tissue size reduction and switching keratinocytes from a proliferative to a differentiative phenotype, as evidenced by decreased Ki67 staining and increased filaggrin, desmoglein-1 and involucrin expression compared to control. These effects lead to skin barrier impairment, which can be observed in a reconstructed human epidermis model showing a decrease in trans-epidermal water loss rates. On the other hand, pan-kinase inhibitors mainly targeting VEGFR barely affect keratinocyte differentiation and rather promote a proliferative phenotype. CONCLUSIONS:This study contributes to the mechanistic understanding of the clinically observed CADR during therapy with EGFRi. These in vitro results suggest a specific mode of action of EGFRi by directly affecting keratinocyte growth and barrier function.
10.1186/s12885-020-07685-5
Dynamics of post-occlusion water diffusion in stratum corneum.
Scientific reports
Diffusion of water through membranes presents a considerable challenge, as the diffusivity often depends on the local concentration of water. One particular example with strong biological relevance is the stratum corneum (SC) as the primary permeability barrier for the skin. A simple alternative for the constant diffusivity model is provided by the Fujita's two-parameter rational approximation, which captures the experimentally observed fact that the SC diffusion constant for water increases with increasing the water concentration. Based on Fick's law of diffusion, a one-dimensional concentration-dependent diffusion model is developed and applied for the analysis of both the steady-state transepidermal water loss (TEWL) and the non-steady-state so-called skin surface water loss (SSWL) occurred after removal of an occlusion patch from the SC surface. It is shown that some of the age-related changes in the SSWL can be qualitatively explained by the variation of the dimensionless Fujita concentration-dependence parameter.
10.1038/s41598-022-22529-x
Evidence for biochemical barrier restoration: Topical solenopsin analogs improve inflammation and acanthosis in the KC-Tie2 mouse model of psoriasis.
Arbiser Jack L,Nowak Ron,Michaels Kellie,Skabytska Yuliya,Biedermann Tilo,Lewis Monica J,Bonner Michael Y,Rao Shikha,Gilbert Linda C,Yusuf Nabiha,Karlsson Isabella,Fritz Yi,Ward Nicole L
Scientific reports
Psoriasis is a chronic inflammatory skin disease affecting 2.5-6 million patients in the United States. The cause of psoriasis remains unknown. Previous human and animal studies suggest that patients with a susceptible genetic background and some stimulus, such as barrier disruption, leads to a coordinated signaling events involving cytokines between keratinocytes, endothelial cells, T cells, macrophages and dendritic cells. Ceramides are endogenous skin lipids essential for maintaining skin barrier function and loss of ceramides may underlie inflammatory and premalignant skin. Ceramides act as a double-edged sword, promoting normal skin homeostasis in the native state, but can be metabolized to sphingosine-1-phosphate (S1P), linked to inflammation and tumorigenesis. To overcome this difficulty, we synthesized solenopsin analogs which biochemically act as ceramides, but cannot be metabolized to S1P. We assess their in vivo bioactivity in a well-established mouse model of psoriasis, the KC-Tie2 mouse. Topical solenopsin derivatives normalized cutaneous hyperplasia in this model, decreased T cell infiltration, interleukin (IL)-22 transcription, and reversed the upregulation of calprotectin and Toll-like receptor (TLR) 4 in inflamed skin. Finally, they stimulated interleukin (IL)-12 production in skin dendritic cells. Thus suggesting barrier restoration has both a biochemical and physical component, and both are necessary for optimal barrier restoration.
10.1038/s41598-017-10580-y
Characterisation of topographical, biomechanical and maturation properties of corneocytes with respect to anatomical location.
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
BACKGROUND:The Stratum Corneum (SC) is the first barrier of the skin. The properties of individual cells are crucial in understanding how the SC at different anatomical regions maintains a healthy mechanical barrier. The aim of the current study is to present a comprehensive description of the maturation and mechanical properties of superficial corneocytes at different anatomical sites in the nominal dry state. MATERIALS AND METHODS:Corneocytes were collected from five anatomical sites: forearm, cheek, neck, sacrum and medial heel of 10 healthy young participants. The surface topography was analysed using Atomic Force Microscopy (AFM) and Scanning Electron Microscopy (SEM). The level of positive-involucrin cornified envelopes (CEs) and desmoglein-1 (Dsg1) were used as indirect measures of immature CEs and corneodesmosomes, respectively. In addition, AFM nanoindentation and stress-relaxation experiments were performed to characterise the mechanical properties. RESULTS:Volar forearm, neck and sacrum corneocytes presented similar topographies (ridges and valleys) and levels of Dsg1 (13-37%). In contrast, cheek cells exhibited circular nano-objects, while medial heel cells were characterized by villi-like structures. Additionally, medial heel samples also showed the greatest level of immature CEs (32-56%, p < 0.001) and Dsg1 (59-78%, p < 0.001). A large degree of inter-subject variability was found for the Young's moduli of the cells (0.19-2.03 GPa), which was correlated with the level of immature CEs at the cheek, neck and sacrum (p < 0.05). CONCLUSION:It is concluded that a comprehensive study of the mechanical and maturation properties of corneocytes may be used to understand the barrier functions of the SC at different anatomical sites.
10.1111/srt.13507
Antagonistic Effects of IL-4 on IL-17A-Mediated Enhancement of Epidermal Tight Junction Function.
Brewer Matthew G,Yoshida Takeshi,Kuo Fiona I,Fridy Sade,Beck Lisa A,De Benedetto Anna
International journal of molecular sciences
Atopic dermatitis (AD) is the most common chronic and relapsing inflammatory skin disease. AD is typically characterized by skewed T helper (Th) 2 inflammation, yet other inflammatory profiles (Th1, Th17, Th22) have been observed in human patients. How cytokines from these different Th subsets impact barrier function in this disease is not well understood. As such, we investigated the impact of the canonical Th17 cytokine, IL-17A, on barrier function and protein composition in primary human keratinocytes and human skin explants. These studies demonstrated that IL-17A enhanced tight junction formation and function in both systems, with a dependence on STAT3 signaling. Importantly, the Th2 cytokine, IL-4 inhibited the barrier-enhancing effect of IL-17A treatment. These observations propose that IL-17A helps to restore skin barrier function, but this action is antagonized by Th2 cytokines. This suggests that restoration of IL-17/IL-4 ratio in the skin of AD patients may improve barrier function and in so doing improve disease severity.
10.3390/ijms20174070
Solubility of Foreign Molecules in Stratum Corneum Brick and Mortar Structure.
Langmuir : the ACS journal of surfaces and colloids
The barrier function of the skin is mainly assured by its outermost layer, stratum corneum (SC). One key aspect in predicting dermal drug delivery and in safety assessment of skin exposure to chemicals is the need to determine the amount of chemical that is taken up into the SC. We here present a strategy that allows for direct measures of the amount of various solid chemicals that can be dissolved in the SC in any environmental relative humidity (RH). A main advantage of the presented method is that it distinguishes between molecules that are dissolved within the SC and molecules that are not dissolved but might be present at, for example, the skin surface. In addition, the method allows for studies of uptake of hydrophobic chemicals without the need to use organic solvents. The strategy relies on the differences in the molecular properties of the added molecules in the dissolved and the excess states, employing detection methods that act as a dynamic filter to spot only one of the fractions, either the dissolved molecules or the excess solid molecules. By measuring the solubility in SC and delipidized SC at the same RHs, the same method can be used to estimate the distribution of the added chemical between the extracellular lipids and corneocytes at different hydration conditions. The solubility in porcine SC is shown to vary with hydration, which has implications for the molecular uptake and transport across the skin. The findings highlight the importance of assessing the chemical uptake at hydration conditions relevant to the specific applications. The methodology presented in this study can also be generalized to study the solubility and partitioning of chemicals in other heterogeneous materials with complex composition and structure.
10.1021/acs.langmuir.2c03092
Take a breath: oxygen sensing of epidermal differentiation.
The FEBS journal
Skin serves as a barrier to protect our body from injury, pathogens and trans-epidermal water loss. It is the only tissue directly exposed to oxygen besides lungs. Air exposure is an essential step of in vitro generation skin graft. However, the role of oxygen in this process remains hitherto unclear. Teshima et al. unveiled the impact of the hypoxia-inducible factor (HIF) pathway on epidermal differentiation in three-dimensional skin models. The authors of this work describe how air-lifting of organotypic epidermal cultures impairs HIFs activity, leading to a proper terminal differentiation of keratinocytes and stratification.
10.1111/febs.16752
Systematic investigation of factors, such as the impact of emulsifiers, which influence the measurement of skin barrier integrity by in-vitro trans-epidermal water loss (TEWL).
International journal of pharmaceutics
Trans-epidermal water loss (TEWL) has been the most widely used method to assess the integrity of the skin barrier and evaluate the irritation potential or the protective properties of topical products for many years. It detects the amount of water that diffuses across the stratum corneum (SC) to the external environment. As one of the most important functions of the skin is to keep water inside the body, an increase in TEWL is used to indicate the skin's impaired barrier function. So far, a variety of commercial instruments are available to measure the TEWL. Their applications mainly focus on the in-vivo TEWL measurements for dermatological examinations or formulation development. Recently, an in-vitro TEWL probe has also been commercially released enabling preliminary tests with excised skin samples. In our study, we first aimed to optimize the experimental procedures for detecting the in-vitro TEWL of porcine skin. Secondly, different kinds of emulsifiers were applied to the skin, including polyethylene glycol-containing emulsifiers (PEG-ylated emulsifiers), sorbitan esters, cholesterol, and lecithin. Sodium lauryl sulfate (SLS) was used as a positive control, and water as a negative control. Based on the findings, we established a protocol for accurately measuring the in-vitro TEWL values, emphasizing that the temperature of the skin sample should be constantly maintained at 32℃. Subsequently, the influences of emulsifiers on the in-vitro TEWL were analyzed. They indicated a significant skin barrier impairment of PEG-20 cetyl ether, PEG-20 stearyl ether, and SLS on in-vitro skin. Furthermore, we interestingly found that there consistently was an alteration of the TEWL values, even after the application of water to the skin. Our findings are of special interest, as the European Medicines Agency (EMA) recommends the use of in-vitro TEWL to determine skin barrier intactness during Franz cell experiments. Thus, this study provides a validated protocol for measuring the in-vitro TEWL and elucidates the impact of emulsifiers on the skin barrier. It also improves the understanding of tolerable variations of in-vitro TEWL and offers recommendations for its use in research.
10.1016/j.ijpharm.2023.122930
Regulation of Tissue Immune Responses by Local Glucocorticoids at Epithelial Barriers and Their Impact on Interorgan Crosstalk.
Merk Verena M,Phan Truong San,Brunner Thomas
Frontiers in immunology
The anti-inflammatory role of extra-adrenal glucocorticoid (GC) synthesis at epithelial barriers is of increasing interest with regard to the search for alternatives to synthetic corticosteroids in the therapy of inflammatory disorders. Despite being very effective in many situations the use of synthetic corticosteroids is often controversial, as exemplified in the treatment of influenza patients and only recently in the current COVID-19 pandemic. Exploring the regulatory capacity of locally produced GCs in balancing immune responses in barrier tissues and in pathogenic disorders that lead to symptoms in multiple organs, could provide new perspectives for drug development. Intestine, skin and lung represent the first contact zones between potentially harmful pathogens or substances and the body, and are therefore important sites of immunoregulatory mechanisms. Here, we review the role of locally produced GCs in the regulation of type 2 immune responses, like asthma, atopic dermatitis and ulcerative colitis, as well as type 1 and type 3 infectious, inflammatory and autoimmune diseases, like influenza infection, psoriasis and Crohn's disease. In particular, we focus on the role of locally produced GCs in the interorgan communication, referred to as gut-skin axis, gut-lung axis or lung-skin axis, all of which are interconnected in the pathogenic crosstalk atopic march.
10.3389/fimmu.2021.672808
Distribution of Domains Formed by Lateral Packing of Intercellular Lipid in the Stratum Corneum.
Chemical & pharmaceutical bulletin
Intercellular lipids fill the interstices of corneocytes and serve a barrier function. The amount of transdermal water evaporation varies depending on the packing structure of intercellular lipids, as this structure is important for maintaining barrier efficacy. This packing structure consists of a mixture of crystals (orthorhombic and hexagonal) and liquid crystals (fluid phase), and the proportion of these phases is thought to affect barrier function. However, there have been no methods to visualize the actual distribution of the domains formed by packing structure in intercellular lipids. In this study, the planar distribution of intercellular lipid structures was determined using focal plane array (FPA)-based Fourier transform (FT) IR imaging analysis of stratum corneum cell units obtained by grid stripping. The lipid composition of ceramides was revealed by electrospray ionization tandem mass spectrometry (ESI-MS/MS)-based shotgun lipidomics. The distribution of domains formed by packing structures and the lipid composition of ceramides was compared in skin with high- or low-transepidermal water loss (TEWL). The orthorhombic proportion was lower in high-TEWL skin than in low-TEWL skin. ESI-MS/MS-based shotgun lipidomics analysis showed that the alpha-hydroxyceramide content in the low- and high-TEWL groups differed regarding the distribution of fatty acid chain lengths. The evaluation of stratum corneum cell units using FPA-based FTIR imaging is an innovative technology that can visualize the distribution of domains formed by intercellular lipid-packing structures. Increased proportions of alpha-hydroxyceramide subclasses such as alpha-hydroxy-sphingosine ceramide and alpha-hydroxy-phytosphingosine ceramide were associated with a reduced proportion of the orthorhombic packing structure domain.
10.1248/cpb.c22-00533
Lipid vesicles: A versatile drug delivery platform for dermal and transdermal applications.
Chacko Indhu A,Ghate Vivek M,Dsouza Leonna,Lewis Shaila A
Colloids and surfaces. B, Biointerfaces
Topical and transdermal application of active pharmaceutical ingredients to the skin is an attractive strategy being explored by formulation scientists to treat disease conditions rather than the oral drug delivery. Several approaches have been attempted, and many of them have emerged with significant clinical potential. However, the delivery of drugs across the skin is an arduous task due to permeation limiting barriers. It, therefore, requires the aid of external agents or carrier systems for efficient permeation. Lipid-based vesicular systems are carriers for the transport of drugs through the stratum corneum (dermal drug delivery) and into the bloodstream for systemic action (transdermal drug delivery) overcoming the barrier properties. This review article describes the various vesicular systems reported for skin delivery of actives with relevant case studies. The vesicular systems presented here are in the order of their advent from conventional systems to the advanced lipid vesicles. The design and development of drugs in vesicular systems have brought a new dimension to the treatment of disease conditions overcoming the permeation limiting barriers, thus improving its efficacy.
10.1016/j.colsurfb.2020.111262
Characterization of a human lesioned-skin model to assess the influence of skin integrity on drug permeability.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
The stratum corneum (SC) is the skin's outermost layer, organized by clusters of corneocytes among a lipid matrix, acting as a barrier. This "brick and mortar" organization is modified in many skin diseases. We proposed a lesioned-skin model for assessing the permeability of topical formulations and the impact of skin integrity on the permeability of molecules. We anticipate that removal of the SC compromises the skin barrier function, making it more permeable, affecting the biopharmaceutics of topical formulations. By stripping with 25 strips (Corneofix®), the thickness of the SC was considerably reduced, exposing the viable epidermis. Transversal and upper views of the skin by electronic microscopy and histology confirm the removal of the SC. After, we evaluated the permeability of tacrolimus (Protopic®, 0.1 % and 0.03 %) by HPLC-UV. The non-lesioned skin presented 20-25 % of tacrolimus in the SC and no drug permeated through the skin's inner layers. Contrary, the lesioned-skin model allowed the permeation of tacrolimus to the epidermis, dermis, and also in the receptor medium. These results highlight the importance of using diseased skin tissue as opposed to normal skin when assessing the permeability of pharmaceutical formulations for local topical delivery, closely mimicking the occurred events in clinical scenario.
10.1016/j.biopha.2023.115841
Transepidermal water loss and stratum corneum hydration in forearm versus hand palm.
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
BACKGROUND:Skin measurements of transepidermal water loss (TEWL) and stratum corneum hydration (SCH) reflect different aspects of skin physiology. Since epidermal water loss depends on epidermal-to-air water vapor gradients, a possible quantitative relationship between TEWL and SCH may exist. This investigation's purpose was to test the possible TEWL-SCH relationship. MATERIALS AND METHODS:SCH and TEWL were measured noninvasively on forearm and palmer thenar eminence (hand) in 40 young adults (20 males) along with total body fat percentage (FAT) via bioimpedance. RESULTS:A significant positive nonlinear correlation (p < 0.001) was detected between SCH and TEWL in hands of the male cohort that occurred when SCH exceeded a threshold level. This threshold level was not exceeded in male or female forearms and forearms did not display a SCH-TEWL correlation. There was a weak inverse dependence of TEWL on FAT on both forearm and hand (p < 0.05), but no SCH-FAT relationship was observed. TEWL values on the forearm and hand were moderately correlated with each other (p = 0.002) but SCH values were not. CONCLUSION:The findings clarify the relationship between forearm and palmer hydration and TEWL values, and their relationship to total body fat percentages in young healthy adults. The significant correlation between palmer stratum corneum hydration and palmer TEWL that was discovered in the male but not the female cohort suggests a threshold hydration level for which TEWL depends both on skin barrier function and stratum corneum hydration. This implies that conditions with increased SCH may in part account for elevated TEWL values.
10.1111/srt.13218
Biomarker Mapping on Skin Tape Strips Using MALDI Mass Spectrometry Imaging.
Hochart Guillaume,Bonnel David,Stauber Jonathan,Stamatas Georgios N
Journal of the American Society for Mass Spectrometry
Keratinocyte organization and biochemistry are important in forming the skin's protective barrier. Intrinsic and extrinsic factors can affect skin barrier function at the cellular and molecular levels. Matrix-assisted laser desorption/ionization (MALDI) mass spectrometric imaging, a technique which combines both molecular aspects and histological details, has proven to be a valuable method in various disciplines including pharmacology, dermatology and cosmetology. It typically requires ex vivo samples, prepared following frozen tissue sectioning. This paper demonstrates the feasibility of performing MALDI analysis on tape strips collected non-invasively on skin. The aim is to obtain molecular imaging of corneocytes on tapes towards novel biological insights. Tapes were collected from two skin sites (volar forearm and cheek) of human volunteers. Ten molecules relating to skin barrier function were detected with a single mode of acquisition at high spatial resolution with a 7 T MALDI-Fourier transform ion cyclotron resonance (FTICR) instrument. The method sensitivity was adequate to create molecular maps which could be overlaid on transmission microscopy images of the same area of the tape. Analysis of the molecular distributions from tapes at the two skin sites was consistent with the known skin properties of the two sites, confirming the validity of the observations. Hierarchical clustering analysis was used to differentiate corneocyte populations based on their molecular profiles. Furthermore, morphological analysis provided a new way of considering statistical populations of corneocytes on the same tape, rather than measuring a single averaged value, providing additional useful information relating to their structure-function relationship.
10.1007/s13361-019-02277-5
Using therapeutic ultrasound to promote irritated skin recovery after surfactant-induced barrier disruption.
Chen Yueh-Chi,Wang Peir-Renn,Lai Te-Jen,Lu Li-Hua,Dai Long-Wei,Wang Chun-Hou
Ultrasonics
BACKGROUND:Surfactant-induced skin barrier disruption can enhance blood flow and water content in the superficial skin. The effect of therapeutic ultrasound on accelerating the recovery of superficial skin after skin barrier disruption has seldom been studied. OBJECTIVE:To understand the effects of therapeutic ultrasound on barrier recovery, we used the sodium lauryl sulfate irritation model and treatment with ultrasound intervention. METHODS:The study allocated 30 healthy subjects into an ultrasound group (n = 15) and a control group (n = 15), each divided into three subgroups (sodium lauryl sulfate at concentrations of 1.0%, 0.5%, and 0%). Pulsed ultrasound (1 MHz, 0.3 W/cm) was applied to ultrasound subgroups. The treatment effect was evaluated by the recovery rate of enhanced blood flow and water content. RESULTS:The results indicated a surfactant dose-dependent effect on blood flow, but not on water content. The recovery rates of enhanced blood flow were higher in the 0.5% and 1.0% ultrasound subgroups than in the control subgroups throughout the experiment. However, recovery rates of water content were higher in the ultrasound subgroups than in the control subgroups only on Day2. CONCLUSIONS:Pulsed ultrasound accelerated the barrier recovery by reducing the enhanced blood flow and water content after skin barrier disruption.
10.1016/j.ultras.2018.08.007
Can a handheld device accurately measure barrier function in ichthyoses?
Murphrey Morgan B,Erickson Taylor,Canter Talia,Rangel Stephanie M,Paller Amy S
Pediatric dermatology
BACKGROUND:Transepidermal water loss (TEWL) is a surrogate measure of skin barrier dysfunction. Historically, devices that measure TEWL are expensive, complex, and require connection to a computer and energy source. Consequently, measurement of skin's TEWL has been limited to the research setting. OBJECTIVES:Evaluate the accuracy of the handheld device gpskin Barrier Light in comparison with a standardly used device, AquaFlux AF200 , for measuring TEWL. METHODS:Transepidermal water loss measurements by gpskin Barrier Light and AquaFlux AF200 in ichthyotic and healthy skin were compared. RESULTS:AquaFlux AF200 TEWL readings were consistently higher than those from gpskin Barrier Light . In the pooled cohort, TEWL values were strongly correlated and both devices had excellent reliability. When subjects and controls were examined separately, there was moderate correlation between devices, with stronger agreement at higher TEWL values. LIMITATIONS:Transepidermal water loss was determined at one time point. There is no formally established industry standard TEWL-assessing device. CONCLUSION:Although gpskin Barrier Light and AquaFlux AF200 devices cannot be used interchangeably, correlation in measuring TEWL was strong in patients with skin disease. This finding suggests that the low-cost, handheld device can accurately capture change in TEWL to track disease improvement.
10.1111/pde.14305
Murine Epidermal Ceramide Synthase 4 Is a Key Regulator of Skin Barrier Homeostasis.
Peters Franziska,Tellkamp Frederik,Brodesser Susanne,Wachsmuth Emmi,Tosetti Bettina,Karow Ulrike,Bloch Wilhelm,Utermöhlen Olaf,Krönke Martin,Niessen Carien M
The Journal of investigative dermatology
Epidermal barrier dysfunction is associated with a wide range of highly prevalent inflammatory skin diseases. However, the molecular processes that drive epidermal barrier maintenance are still largely unknown. Here, using quantitative proteomics, lipidomics, and mouse genetics, we characterize epidermal barrier maintenance versus a newly established barrier and functionally identify differential ceramide synthase 4 protein expression as one key difference. We show that epidermal loss of ceramide synthase 4 first disturbs epidermal lipid metabolism and adult epidermal barrier function, ultimately resulting in chronic skin barrier disease characterized by acanthosis, hyperkeratosis, and immune cell accumulation. Importantly, prolonged barrier dysfunction induced by loss of ceramide synthase 4 induced a barrier repair response that largely recapitulates molecular programs of barrier establishment. Collectively, this study provides an unbiased temporal proteomic characterization of barrier maintenance and disturbed homeostasis and shows that lipid homeostasis is essential to maintain adult skin barrier function to prevent disease.
10.1016/j.jid.2020.02.006
Impact of intercellular crosstalk between epidermal keratinocytes and dermal fibroblasts on skin homeostasis.
Jevtić Marijana,Löwa Anna,Nováčková Anna,Kováčik Andrej,Kaessmeyer Sabine,Erdmann Gerrit,Vávrová Kateřina,Hedtrich Sarah
Biochimica et biophysica acta. Molecular cell research
Dermal fibroblasts seem critical for epidermal maturation and differentiation and recent work demonstrated that diseased fibroblasts may drive pathophysiological processes. Nevertheless, still very little is known about the actual crosstalk between epidermal keratinocytes and dermal fibroblasts and the impact of dermal fibroblasts on epidermal maturation and differentiation. Aiming for a more fundamental understanding of the impact of the cellular crosstalk between keratinocytes and fibroblasts on the skin homeostasis, we generated full-thickness skin equivalents with and without fibroblasts and subsequently analysed them for the expression of skin differentiation markers, their barrier function, skin lipid content and epidermal cell signalling. Skin equivalents without fibroblasts consistently showed an impaired differentiation and dysregulated expression of skin barrier and tight junction proteins, increased skin permeability, and a decreased skin lipid/protein ratio. Most interestingly, impaired Ras/Raf/ERK/MEK signalling was evident in skin equivalents without fibroblasts. Our data clearly indicate that the epidermal-dermal crosstalk between keratinocytes and fibroblasts is critical for adequate skin differentiation and that fibroblasts orchestrate epidermal differentiation processes.
10.1016/j.bbamcr.2020.118722
1-(2-Hydroxyethyl)-2-imidazolidinone, a heparanase and matrix metalloproteinase inhibitor, improves epidermal basement membrane structure and epidermal barrier function.
Iriyama Shunsuke,Yamanishi Haruyo,Kunizawa Naomi,Hirao Tetsuji,Amano Satoshi
Experimental dermatology
Daily exposure to sunlight is known to affect the structure and function of the epidermal basement membrane (BM), as well as epidermal differentiation and epidermal barrier function. The aim of this study is to clarify whether the inhibition of BM-degrading enzymes such as heparanase and matrix metalloproteinase 9 (MMP-9) can improve the epidermal barrier function of facial skin, which is exposed to the sun on a daily basis. 1-(2-hydroxyethyl)-2-imidazolidinone (HEI) was synthesized as an inhibitor of both heparanase and MMP-9. HEI inhibited not only the BM damage at the DEJ but also epidermal proliferation, differentiation, water contents and transepidermal water loss abnormalities resulting from ultraviolet B (UVB). This was determined in this study by the use of UVB-induced human cultured skins as compared with the control without HEI. Moreover, topical application of HEI improved epidermal barrier function by increasing water content and decreasing transepidermal water loss in daily sun-exposed facial skin as compared with non-treated skins. These results suggest that the inhibition of both heparanase and MMP-9 is an effective way to care for regularly sun-exposed facial skin by protecting the BM from damage.
10.1111/exd.13876
Topical dexpanthenol effects on physiological parameters of the stratum corneum by Confocal Raman Microspectroscopy.
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
BACKGROUND:Topical use of dexpanthenol presents well-established moisturizing properties and maintenance and repair of the skin barrier function, however, its exact action mechanisms are not completely elucidated. In this context, Confocal Raman Microspectroscopy is an optical method that enables non-invasive and non-destructive in vivo analysis with the sensitive acquisition of molecular changes in different skin layers. Herein, the aim was to evaluate the effects of topical dexpanthenol on the components and physiological parameters of the stratum corneum (SC). MATERIALS AND METHODS:Ten healthy female subjects underwent skin evaluation by means of a Confocal Raman Spectrometer Skin Analyzer 3510. Spectral data were obtained from the skin of the anterior forearm region, before and 2 h after applying a cosmetic formulation containing or not containing 5% dexpanthenol. RESULTS:Semiquantitative analysis of the natural moisturizing factor showed a significant decrease in content after 2 h of topical dexpanthenol application, while the analysis of the lamellar organization of intercellular lipids and the secondary structure of keratin showed a significant increase in hexagonal organization of lipids at the first half of the SC and a significant increase in β-pleated sheet conformation of keratin. CONCLUSION:Effects of topical dexpanthenol on SC suggest a contribution in increasing fluidity of both lipidic and protein components of the SC and are compatible with dexpanthenol activity in maintaining adequate physiological conditions and preventing transepidermal water loss. This study also contributes to the elucidation of action mechanisms and other concurrent biochemical processes.
10.1111/srt.13317
Hyaluronidase-powered microneedles for significantly enhanced transdermal delivery efficiency.
Journal of controlled release : official journal of the Controlled Release Society
Microneedles (MNs) with enhanced delivery efficiency have revolutionized the transdermal drug delivery system for treating systemic illness. However, the bioavailability of MNs was still far from the clinical requirements by only overcoming the stratum corneum barrier. Herein, hyaluronidase (HAase)-powered MNs were developed as a top-down permeation-enhancement strategy to hijack the sequential transdermal barriers for improved bioavailability. HAase MNs with robust mechanical strength showed excellent skin penetration ability and significantly enhanced the transdermal delivery efficacy of macromolecular drugs as compared to that of HAase-absent MNs, resulting in considerable effect to subcutaneous injection in terms of biodistribution, bioavailability, and therapeutical efficacy. As evidenced from the distribution of trypan blue and fluorescence underlying skin, the positive effects exerted by HAase MNs could be ascribed to the depolymerization of HA that would loosen the subcutaneous space and destruct the extracellular matrix barrier to promote drug diffusion and permeation in larger area and greater depth. Notably, the transient interconversion of keratin from α-helix to β-sheet that might assist the drug residues on the skin surface permeate across the stratum corneum during administration might be another reason not to be ignored. As a labor-saving strategy, HAase-powered MNs offers a promising and painless administration route for macromolecules.
10.1016/j.jconrel.2022.11.046
Regulation of tissue architecture and stem cell dynamics to sustain homeostasis and repair in the skin epidermis.
Seminars in cell & developmental biology
Stratified epithelia are made up of several layers of cells, which act as a protective barrier for the organ they cover. To ensure their shielding effect, epithelia are naturally able to cope with constant environmental insults. This ability is enabled by their morphology and architecture, as well as the continuous turnover of stem and progenitor cells that constitute their building blocks. Stem cell fate decisions and dynamics are fundamental key biological processes that allow epithelia to exert their functions. By focusing on the skin epidermis, this review discusses how tissue architecture is generated during development, maintained through adult life, and re-established during regeneration.
10.1016/j.semcdb.2021.09.008
Lipid gene nanocarriers for the treatment of skin diseases: Current state-of-the-art.
Bellefroid Coralie,Lechanteur Anna,Evrard Brigitte,Piel Géraldine
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V
Nucleic acids carried by non-viral nanovectors have demonstrated high potential as a therapeutic strategy for gene-related diseases. The dermal or transdermal gene delivery allow to target local skin diseases or to reach the blood stream. However, the skin is the first defense barrier of the body and must be overcome to distribute nucleic acids. Many intracellular barriers as cellular uptake, endosomal escape or cytosolic gene trafficking have to be crossed for the gene to achieve its therapeutic action. All hurdles to skin nucleic acid therapy are precisely described. Physical, active or passive methods have been proposed to improve the penetration through the stratum corneum. Lipidic-nanocarriers represent one of the most attractive methods because any skin disruption technique is requested. We give an overview of deformable lipidic-nanocarriers that have been developed to promote the skin penetration of nucleic acids. Moreover, this review describes the potential of deformable liposomes for cutaneous disorders.
10.1016/j.ejpb.2019.02.012
Regulatory T Cells Exhibit Interleukin-33-Dependent Migratory Behavior during Skin Barrier Disruption.
Toyama Sumika,Moniaga Catharina Sagita,Nakae Susumu,Kurosawa Masaru,Ogawa Hideoki,Tominaga Mitsutoshi,Takamori Kenji
International journal of molecular sciences
Regulatory T cells (Tregs) suppress immune responses and maintain immunological self-tolerance and homeostasis. We currently investigated relationships between skin barrier condition and Treg behavior using skin barrier-disrupted mice. Skin barrier disruption was induced by repeated topical application of 4% sodium dodecyl sulfate (SDS) on mice. The number of CD4 forkhead box protein P3 (Foxp3) Tregs was higher in 4% SDS-treated skins than in controls. This increasing was correlated with the degree of acanthosis. The numbers of interleukin (IL)-10 and transforming growth factor (TGF)-β Tregs also increased in 4% SDS-treated skins. Localization of IL-33 in keratinocytes shifted from nucleus to cytoplasm after skin barrier disruption. Notably, IL-33 promoted the migration of Tregs in chemotaxis assay. The skin infiltration of Tregs was cancelled in IL-33 neutralizing antibody-treated mice and IL-33 knockout mice. Thus, keratinocyte-derived IL-33 may induce Treg migration into barrier-disrupted skin to control the phase transition between healthy and inflammatory conditions.
10.3390/ijms22147443
Cytokines and Epidermal Lipid Abnormalities in Atopic Dermatitis: A Systematic Review.
Cells
Atopic dermatitis (AD) is the most common chronic inflammatory skin disease and presents a major public health problem worldwide. It is characterized by a recurrent and/or chronic course of inflammatory skin lesions with intense pruritus. Its pathophysiologic features include barrier dysfunction, aberrant immune cell infiltration, and alterations in the microbiome that are associated with genetic and environmental factors. There is a complex crosstalk between these components, which is primarily mediated by cytokines. Epidermal barrier dysfunction is the hallmark of AD and is caused by the disruption of proteins and lipids responsible for establishing the skin barrier. To better define the role of cytokines in stratum corneum lipid abnormalities related to AD, we conducted a systematic review of biomedical literature in PubMed from its inception to 5 September 2023. Consistent with the dominant T2 skewness seen in AD, type 2 cytokines were featured prominently as possessing a central role in epidermal lipid alterations in AD skin. The cytokines associated with T1 and T17 were also identified to affect barrier lipids. Considering the broad cytokine dysregulation observed in AD pathophysiology, understanding the role of each of these in lipid abnormalities and barrier dysfunction will help in developing therapeutics to best achieve barrier homeostasis in AD patients.
10.3390/cells12242793
Molecular Reorganization during the Formation of the Human Skin Barrier Studied In Situ.
Narangifard Ali,Wennberg Christian L,den Hollander Lianne,Iwai Ichiro,Han HongMei,Lundborg Magnus,Masich Sergej,Lindahl Erik,Daneholt Bertil,Norlén Lars
The Journal of investigative dermatology
In vertebrates, skin upholds homeostasis by preventing body water loss. The skin's permeability barrier is located intercellularly in the stratum corneum and consists of stacked lipid lamellae composed of ceramides, cholesterol, and free fatty acids. We have combined cryo-electron microscopy with molecular dynamics modeling and electron microscopy simulation in our analysis of the lamellae's formation, a maturation process beginning in stratum granulosum and ending in stratum corneum. Previously, we have revealed the lipid lamellae's initial- and end-stage molecular organizations. In this study, we reveal two cryo-electron microscopy patterns representing intermediate stages in the lamellae's maturation process: a single-band pattern with 2.0‒2.5 nm periodicity and a two-band pattern with 5.5‒6.0 nm periodicity, which may be derived from lamellar lipid structures with 4.0‒5.0 nm and 5.5‒6.0 nm periodicity, respectively. On the basis of the analysis of the data now available on the four maturation stages identified, we can present a tentative molecular model for the complete skin barrier formation process.
10.1016/j.jid.2020.07.040
Red light-promoted skin barrier recovery: Spatiotemporal evaluation by transepidermal potential.
Abe Yuina,Konno Hajime,Yoshida Shotaro,Yamauchi Takeshi,Yamasaki Kenshi,Denda Mitsuhiro,Nishizawa Matsuhiko
PloS one
The light-promoted recovery of epidermal barrier of skin was evaluated by the associated recovery of transepidermal potential (TEP), the potential difference between the surface and dermis of skin, by using porcine skin samples. An accelerated recovery of TEP was observed by irradiation of red light with the irradiance of 40 mW/cm2 and a duration of > 10 min. The influence of the light stimulation to the surroundings (~ 20 mm) was also observed. The irradiations of blue and purple lights were ineffective in accelerating the barrier recovery. These characteristics of the light stimulation would be useful for the design of effective and safe phototherapy devices for skin. The present study proves that the TEP can serve as a spatiotemporal indicator of the epidermal barrier function.
10.1371/journal.pone.0219198
Quantitative evaluation of sensitive skin by ANTERA 3D combined with GPSkin Barrier.
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
BACKGROUND:At present, there are many different evaluation methods for sensitive skin, including subjective, semisubjective, and objective evaluation. Various objective tests focus on assessing changes in barrier functions. It is anticipated that the ANTERA 3D®, in combination with GPSkin Barrier®, will provide better evaluation of sensitive skin. METHODS:A total of 20 subjects with sensitive skin and 20 healthy participants were recruited. Sensitive skin subjects were treated with an anti-sensitive moisturizing tolerance-extreme cream which has anti-inflammatory and moisturizing effects, twice daily on the whole face for 28 days. VISIA Skin Detector was used to record clinical images and red area. GPSkin Barrier was used to measure TEWL and SCH. Texture, hemoglobin, and influenced area (mm ) were recorded using ANTERA 3D . Subjects underwent skin tests and recorded changes at D0 and D28. Data were only collected from healthy participants who did not receive treatment as controls. RESULTS:TEWL, texture, hemoglobin, and affected area in sensitive skin group were significantly higher than those in healthy group, while SCH was significantly lower than that in healthy group (p all<0.05). After anti-inflammatory and moisturizing treatment, the texture, hemoglobin, and affected area of sensitive skin decreased, TEWL decreased while SCH increased (p all<0.05). CONCLUSIONS:Based on the results, the combination of the ANTERA 3D with GPSkin Barrier could be used as a new kind of quantitative evaluation method for the detection and diagnosis of sensitive skin.
10.1111/srt.13213
Observation and density estimation of a large number of skin capillaries using wide-field portable video capillaroscopy and semantic segmentation.
Journal of biomedical optics
Significance:Skin capillaries are non-invasively observable; their structure and blood flow can reflect tissue and systemic conditions. Quantitative analysis of video-capillaroscopy images yields novel diagnostic methods. Because the capillary structure is heterogeneous, analyzing more capillaries can increase the evaluation reliability. Aim:We developed a system that can observe and quantify numerous capillaries and verified the performance on human skin. Approach:We developed a portable video-capillaroscope with a spatial resolution higher than and a wide field of view () and a method to evaluate capillary numbers and areas using U-Net. The model was trained and tested with 22 and 11 cropped images () obtained from 11 participants, respectively. They were then applied to the images from four participants. Segmentation results were compared to ground-truth at the pixel level and capillary-region level. Results:Over 1000 capillaries were simultaneously observed using the proposed system. Although pixel-level segmentation performance was low [intersection over union (IoU) = 24.5%], the number and area could be estimated. These values differed among four participants and seven sites, and they changed after skin barrier destruction. Conclusions:The proposed system allows for observing and quantifying numerous skin capillaries simultaneously, suggesting its potential for evaluating tissue and systemic conditions.
10.1117/1.JBO.28.10.106003
Review of Advances in the Measurement of Skin Hydration Based on Sensing of Optical and Electrical Tissue Properties.
Sensors (Basel, Switzerland)
The presence of water in the skin is crucial for maintaining the properties and functions of the skin, in particular its outermost layer, known as the stratum corneum, which consists of a lipid barrier. External exposures can affect the skin's hydration levels and in turn, alter its mechanical and physical properties. Monitoring these alterations in the skin's water content can be applicable in clinical, cosmetic, athletic and personal settings. Many techniques measuring this parameter have been investigated, with electrical-based methods currently being widely used in commercial devices. Furthermore, the exploration of optical techniques to measure hydration is growing due to the outcomes observed through the penetration of light at differing levels. This paper comprehensively reviews such measurement techniques, focusing on recent experimental studies and state-of-the-art devices.
10.3390/s22197151
Film-Forming Properties of Topical Formulations for Skin and Hair: In Vivo and In Vitro Studies Using Biophysical and Imaging Techniques.
AAPS PharmSciTech
The film-forming effect is an important property of formulations for skin improvement and hair protection. Reflectance confocal microscopy, an advanced imaging technique, is an important tool for its evaluation. Thus, the aim of this study was to evaluate the film-forming properties of cosmetic formulations based on starches and containing a Spirulina maxima extract after their application to skin and hair, using sensorial analysis and instrumental measurements, with emphasis on reflectance confocal microscopy. Two formulations based on starches and PEG-75 lanolin containing or not (Vehicle) a Spirulina maxima dry extract were developed. The rheological behavior and sensorial properties of both formulations were evaluated. The film-forming property on the skin was evaluated in terms of skin hydration by RCM imaging analysis and transepidermal water loss (TEWL). The hair tresses were evaluated in terms of mechanical properties and RCM imaging analysis. The formulations showed pseudoplastic behavior and a low hysteresis area. In addition, the presence of Spirulina in the formulation did not interfere in the rheological parameters. Both formulations reduced TEWL and maintained the stratum corneum water content. The protective effect was also observed in the hair, since the application of the formulation with Spirulina showed a better performance in the tensile test when compared to vehicle. Thus, the proposed formulation showed film formation on the skin and hair surface that brought immediate benefits such as a reduction of TEWL. Finally, the formulations were shown to have film-forming effects and their use can be suggested for skin and hair protection against daily damage.
10.1208/s12249-022-02472-w
Direct assessment of individual skin barrier components by electrical impedance spectroscopy.
Mannweiler Roman,Bergmann Sophia,Vidal-Y-Sy Sabine,Brandner Johanna M,Günzel Dorothee
Allergy
BACKGROUND:Expression of the tight junction proteins Cldn1 and 4 is altered in skin diseases such as atopic dermatitis, and Cldn1 deficiency affects skin barrier formation. Impedance spectroscopy (IS) has been proven to allow detection of alterations in the skin barrier but is currently unable to separate effects on viable epidermis (VE) and stratum corneum (SC). METHODS:Effects of siRNA-mediated Cldn1 and 4 knockdown in reconstructed human epidermis (RHE) on VE and SC barrier function were investigated with Ussing chamber-based IS. Barrier components were sequentially altered, employing iron oxide nanoparticles and EGTA, to identify their contribution to the impedance spectrum. Resistance changes due to apically applied hyperosmolar electrolyte were used to identify barrier defects non-invasively. RESULTS:IS of RHE yielded two relaxation frequencies, representing the barrier properties of the SC (~1000 Hz) and VE (~100 Hz). As proof of concept, it was shown that the Cldn1 knockdown-induced resistance drop arises from the impairment of both SC and VE, indicated by a shift of both relaxation frequencies. Hyperosmolar electrolyte penetration allowed non-invasive detection of Cldn1 knockdown via time-dependent frequency shifts. The absence of Cldn4 knockdown-induced changes revealed the weaknesses of transepithelial electrical resistance analysis. CONCLUSION:In conclusion, the present technique allows to separately measure the barrier properties of SC and VE and further evaluate the Cldn1 and 4 knockdown impact on the skin barrier. As the measurement with agarose-embedded electrolyte allowed non-invasive identification of the Cldn1 knockdown, this opens the way to detailed in vivo skin barrier assessment.
10.1111/all.14851
Multiscale Modeling of Skin Electroporation.
Gajula Kishore,Gupta Rakesh,Rai Beena
Langmuir : the ACS journal of surfaces and colloids
Human skin, the largest external organ of the body, provides a selective barrier to therapeutics applied topically. The molecules having specific chemical and physical properties can only penetrate the deeper layer of the skin. However, the lag time for reaching a steady state in the deeper layer is generally of the order of hours. In order to deliver higher-molecular-weight, charged, and hydrophilic therapeutics in the deeper layer, the skin barrier must be breached. Electroporation is one of the methods used to breach the skin barrier for enhancement of drug permeation and reduction of lag time. However, the underlying mechanism responsible for the enhancement of drug permeation is not well understood. In this study, a multiscale model of skin electroporation is developed by connecting molecular phenomena to a macroscopic model. At the atomic scale, molecular dynamics simulations of the lipid matrix of the human stratum corneum (SC) were performed under the influence of an external electric field. The pores get formed during the electroporation process and the transport properties (diffusivity) of drug molecules are computed. The diffusion coefficient obtained during electroporation was found to be higher than passive diffusion. However, this alone could not explain the multifold increase in the drug flux on application of an electric field as observed in the experiments. Hence, a finite element method (FEM) model of the skin SC is also developed. The release of fentanyl through this model is compared with the available experimental results. Both experimental and simulated results of pore formation on application of an electric field and many folds' increase in drug flux are comparable. Once validated, the framework was used for the design of skin electroporation experiments (in silico) by changing the electric pulse parameters such as voltage, pulse duration, and number of pulses. This multiscale modeling framework provides valuable insight at the molecular and macroscopic levels to design the electroporation experiments. The framework can be utilized as a design tool for skin electroporation applications.
10.1021/acs.langmuir.0c00500
Progress in studies of epidermal stem cells and their application in skin tissue engineering.
Stem cell research & therapy
The epidermis, which is the outermost layer of mammalian skin, provides an essential barrier that is essential for maintenance of life. The epidermis is a stratified epithelium, which is maintained by the proliferation of epidermal stem cells (EPSCs) at the basal layer of the epidermis. As a unique cell population characterized by self-renewal and differentiation capabilities, EPSCs ensure the maintenance of adult skin homeostasis and participate in repair of the epidermis after injury. Recently, the utilization of EPSCs for wound healing and tissue regeneration has been attracting increased attention from researchers. In addition, the advances in tissue engineering have increased the interest in applying EPSCs in tissue-engineered scaffolds to further reconstitute injured tissues. In this review, we introduce research developments related to EPSCs, including methods recently used in the culture and enrichment of EPSCs, as well as advanced tools to study EPSCs. The function and mechanism of the EPSC-dermal units in the development and homeostasis of the skin are also summarized. Finally, the potential applications of EPSCs in skin tissue engineering are discussed.
10.1186/s13287-020-01796-3
One Size Does Not Fit All: Diversifying Immune Function in the Skin.
Journal of immunology (Baltimore, Md. : 1950)
Our body's most outward facing epithelial barrier, the skin, serves as the frontline defense against myriad environmental assailants. To combat these motley threats, the skin has evolved a sophisticated immunological arsenal. In this article, I provide an overview of the skin's complex architecture and the distinct microniches in which immune cells reside and function. I review burgeoning literature on the synchronized immune, stromal, epithelial, and neuronal cell responses in healthy and inflamed skin. Next, I delve into the distinct requirement and mechanisms of long-term immune surveillance and tissue adaptation at the cutaneous frontier. Finally, by discussing the contributions of immune cells in maintaining and restoring tissue integrity, I underscore the constellation of noncanonical functions undertaken by the skin immune system. Just as our skin's immune system benefits from embracing diverse defense strategies, so, too, must we in the immunology research community support disparate perspectives and people from all walks of life.
10.4049/jimmunol.2100758
Cytokinocytes: the diverse contribution of keratinocytes to immune responses in skin.
Jiang Yanyun,Tsoi Lam C,Billi Allison C,Ward Nicole L,Harms Paul W,Zeng Chang,Maverakis Emanual,Kahlenberg J Michelle,Gudjonsson Johann E
JCI insight
The skin serves as the primary interface between our body and the external environment and acts as a barrier against entry of physical agents, chemicals, and microbes. Keratinocytes make up the main cellular constitute of the outermost layer of the skin, contributing to the formation of the epidermis, and they are crucial for maintaining the integrity of this barrier. Beyond serving as a physical barrier component, keratinocytes actively participate in maintaining tissue homeostasis, shaping, amplifying, and regulating immune responses in skin. Keratinocytes act as sentinels, continuously monitoring changes in the environment, and, through microbial sensing, stretch, or other physical stimuli, can initiate a broad range of inflammatory responses via secretion of various cytokines, chemokines, and growth factors. This diverse function of keratinocytes contributes to the highly variable clinical manifestation of skin immune responses. In this Review, we highlight the highly diverse functions of epidermal keratinocytes and their contribution to various immune-mediated skin diseases.
10.1172/jci.insight.142067
Regional Differences in the Permeability Barrier of the Skin-Implications in Acantholytic Skin Diseases.
Kapitány Anikó,Medgyesi Barbara,Jenei Adrienn,Somogyi Orsolya,Szabó Lilla,Gáspár Krisztián,Méhes Gábor,Hendrik Zoltán,Dócs Klaudia,Szücs Péter,Dajnoki Zsolt,Szegedi Andrea
International journal of molecular sciences
The chemical milieu, microbiota composition, and immune activity show prominent differences in distinct healthy skin areas. The objective of the current study was to compare the major permeability barrier components (stratum corneum and tight junction (TJ)), investigate the distribution of (corneo)desmosomes and TJs, and measure barrier function in healthy sebaceous gland-rich (SGR), apocrine gland-rich (AGR), and gland-poor (GP) skin regions. Molecules involved in cornified envelope (CE) formation, desquamation, and (corneo)desmosome and TJ organization were investigated at the mRNA and protein levels using qRT-PCR and immunohistochemistry. The distribution of junction structures was visualized using confocal microscopy. Transepidermal water loss (TEWL) functional measurements were also performed. CE intracellular structural components were similarly expressed in gland-rich (SGR and AGR) and GP areas. In contrast, significantly lower extracellular protein levels of (corneo)desmosomes (DSG1 and CDSN) and TJs (OCLN and CLDN1) were detected in SGR/AGR areas compared to GP areas. In parallel, kallikrein proteases were significantly higher in gland-rich regions. Moreover, gland-rich areas were characterized by prominently disorganized junction structures ((corneo)desmosomes and TJs) and significantly higher TEWL levels compared to GP skin, which exhibited a regular distribution of junction structures. According to our findings, the permeability barrier of our skin is not uniform. Gland-rich areas are characterized by weaker permeability barrier features compared with GP regions. These findings have important clinical relevance and may explain the preferred localization of acantholytic skin diseases on gland-rich skin regions (e.g., Pemphigus foliaceus, Darier's disease, and Hailey-Hailey disease).
10.3390/ijms221910428
Vulnerability of the skin barrier to mechanical rubbing.
Kikuchi Kenji,Shigeta Shunsuke,Numayama-Tsuruta Keiko,Ishikawa Takuji
International journal of pharmaceutics
Skin barrier function is the battlefront for preventing permeation of harmful substances and infectious diseases. However, it can be destroyed by mechanical forces, as shown in many studies. Excess rubbing may increase the permeability of the skin to aqueous material. Although the skin barrier plays an important physiological role in humans, the vulnerability of skin to mechanical rubbing is poorly understood. Therefore, we investigated the effects of rubbing on the skin in vitro; skin damage was quantified by laser-induced fluorescence. Microscopic observation showed that keratinocytes in the stratum corneum sustained traumatic damage, which reduced the barrier function in that region. The permeability of the skin to an aqueous solution increased with rubbing frequency and load, and rubbing markedly reduced the barrier function of the stratum corneum. To understand the mechanisms underlying the skin damage, we developed a simple mathematical model assuming that the skin is a viscoelastic material. We hypothesized that the increased skin permeability was caused by the damage sustained by keratinocytes in the stratum corneum, and that the permeability was proportional to the time-averaged strain. Our theoretical results showed quantitative agreement with the experimental results and illustrated that rubbing and strain relaxation play key roles in rubbing-induced permeation.
10.1016/j.ijpharm.2020.119708
Quantifying skin sensitivity caused by mechanical insults: A review.
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
BACKGROUND:Skin sensitivity (SS) is a commonly occurring response to a range of stimuli, including environmental conditions (e.g., sun exposure), chemical irritants (e.g., soaps and cosmetics), and mechanical forces (e.g., while shaving). From both industry and academia, many efforts have been taken to quantify the characteristics of SS in a standardised manner, but the study is hindered by the lack of an objective definition. METHODS:A review of the scientific literature regarding different parameters attributed to the loss of skin integrity and linked with exhibition of SS was conducted. Articles included were screened for mechanical stimulation of the skin, with objective quantification of tissue responses using biophysical or imaging techniques. Additionally, studies where cohorts of SS and non-SS individuals were reported have been critiqued. RESULTS:The findings identified that the structure and function of the stratum corneum and its effective barrier properties are closely associated with SS. Thus, an array of skin tissue responses has been selected for characterization of SS due to mechanical stimuli, including: transepidermal water loss, hydration, redness, temperature, and sebum index. Additionally, certain imaging tools allow quantification of the superficial skin layers, providing structural characteristics underlying SS. CONCLUSION:This review proposes a multimodal approach for identification of SS, providing a means to characterise skin tissue responses objectively. Optical coherence tomography (OCT) has been suggested as a suitable tool for dermatological research with clinical applications. Such an approach would enhance the knowledge underlying the multifactorial nature of SS and aid the development of personalised solutions in medical and consumer devices.
10.1111/srt.13104
Ceramide liposomes for skin barrier recovery: A novel formulation based on natural skin lipids.
Vovesná Aneta,Zhigunov Alexander,Balouch Martin,Zbytovská Jarmila
International journal of pharmaceutics
Diseases related to a disrupted skin barrier are accompanied by lower levels of ceramides in the stratum corneum (SC) lipid matrix. Delivering ceramides directly into damaged skin is a viable alternative to conventional corticosteroids, but is hindered by their low skin bioavailability and limited nanoformulation ability. Here, we developed stable liposomal systems containing ceramides and other SC lipids, and tested their effectiveness in skin barrier repair. Lipid film hydration and high-pressure homogenization were used to prepare different types of liposomes. To determine the stability, the particle size and polydispersity index were measured. The optimal systems were found to include ceramide 3 and 6, cholesterol and stearic acid, with 10% urea in phosphate-buffered saline as the aqueous phase. The ability of the system to repair chemically-damaged porcine skin was tested. While treatment by a standard lipid suspension reduced the passage of a model permeant only to a limited extent, drug flux through the liposomally-treated skin was much closer to permeation through intact skin. The non-homogenized liposomes were more effective than their homogenized version. These findings were also confirmed by FTIR measurements. This suggests that our approach to liposomal development has considerable potential for the repair of a disrupted skin barrier.
10.1016/j.ijpharm.2021.120264
The Sphingosine and Acyl Chains of Ceramide [NS] Show Very Different Structure and Dynamics That Challenge Our Understanding of the Skin Barrier.
Angewandte Chemie (International ed. in English)
The lipid phase of the uppermost human skin layer is thought to comprise highly rigid lipids in an orthorhombic phase state to protect the body against the environment. By synthesizing sphingosine-d deuterated N-lignoceroyl-d-erythro-sphingosine (ceramide [NS]), we compare the structure and dynamics of both chains of that lipid in biologically relevant mixtures using X-ray diffraction, H NMR analysis, and infrared spectroscopy. Our results reveal a substantial fraction of sphingosine chains in a fluid and dynamic phase state at physiological temperature. These findings prompt revision of our current understanding of the skin lipid barrier, where an extended ceramide [NS] conformation is preferred and a possible domain structure is proposed. Mobile lipid chains may be crucial for skin elasticity and the translocation of physiologically important molecules.
10.1002/anie.202003375
Stem Cells as a Target for the Delivery of Active Molecules to Skin by Topical Administration.
Ahmadi-Ashtiani Hamid-Reza,Bishe Parisa,Baldisserotto Anna,Buso Piergiacomo,Manfredini Stefano,Vertuani Silvia
International journal of molecular sciences
Cutaneous stem cells, gained great attention in the field of regenerative medicine as a potential therapeutic target for the treatment of skin and hair disorders and various types of skin cancers. Cutaneous stem cells play a key role in several processes like the renovation of skin structures in the condition of homeostasis and after injuries, the hair follicle growth and the reconstruction and production of melanocytes. Thus, gaining effective access to skin stem cells for therapeutic interventions that often involve active molecules with non-favorable characteristics for skin absorption is a valuable achievement. The topical route with high patient compliance and several other benefits is gaining increasing importance in basic and applied research. However, the major obstacle for topical drug delivery is the effective barrier provided by skin against penetration of the vast majority of exogenous molecules. The research in this field is focusing more and more on new strategies to circumvent and pass this barrier effectively. In this article the existing approaches are discussed considering physical and chemical methods along with utilization of novel drug delivery systems to enhance penetration of drugs to the skin. In particular, attention has been paid to studies finalized to the delivery of molecules to cutaneous stem cells with the aim of transferring signals, modulating their metabolic program, inducing physiological modifications and stem cell gene therapy.
10.3390/ijms21062251
Nod-Like Receptors in Host Defence and Disease at the Epidermal Barrier.
Danis Judit,Mellett Mark
International journal of molecular sciences
The nucleotide-binding domain and leucine-rich-repeat-containing family (NLRs) (sometimes called the NOD-like receptors, though the family contains few bona fide receptors) are a superfamily of multidomain-containing proteins that detect cellular stress and microbial infection. They constitute a critical arm of the innate immune response, though their functions are not restricted to pathogen recognition and members engage in controlling inflammasome activation, antigen-presentation, transcriptional regulation, cell death and also embryogenesis. NLRs are found from basal metazoans to plants, to zebrafish, mice and humans though functions of individual members can vary from species to species. NLRs also display highly wide-ranging tissue expression. Here, we discuss the importance of NLRs to the immune response at the epidermal barrier and summarise the known role of individual family members in the pathogenesis of skin disease.
10.3390/ijms22094677
Transcriptional control and transcriptomic analysis of lipid metabolism in skin barrier formation and atopic dermatitis (AD).
Bhattacharya Nilika,Ganguli-Indra Gitali,Indra Arup K
Expert review of proteomics
: Atopic dermatitis (AD) is a multifactorial ailment associated with barrier breach and intense systemic inflammation. Several studies over the years have shown the complex interplay of a large number of factors in governing the progression and outcome of AD. In addition to the diverse types of AD resulting due to variation in the intrinsic mechanisms giving rise to AD such as single nucleotide polymorphisms (SNPs), epigenetic alterations or transcriptional changes, extrinsic factors such as age, ancestry, ethnicity, immunological background of the subject, the interactions of the subject with environmental stimuli and existing microbiome in the periphery surrounding the subject account for further heterogeneity in the clinical manifestations of the disease. : Here we have selectively discussed transcriptional regulation of genes associated with skin lipid metabolism in the context of AD. Transcriptional control and transcriptomic changes are just one face of this multifaceted disease known to affect humans and a detailed study concerning those will enable us to develop targeted therapies to deal with the disease. : Large-scale integration of different omics approaches (genomics, epigenomics, transcriptomics, lipidomics, proteomics, metabolomics, effect of exposome) will help identify the potential candidate gene(s) associated with the development of various endotypes of AD.
10.1080/14789450.2019.1646128
Immunological fortification at our barrier organs: Protecting us as we age.
Immunology
Our barrier surfaces are fundamental in protecting us from the outside world and segregating key biological processes. The immunological fortifications found at these sites therefore possess many distinct qualities, which are discussed in Immunology's series of reviews on Barrier Immunity. Together these reviews showcase novel biological processes identified through the use of state-of-the-art technologies, and specifically highlight how these change throughout our lives.
10.1111/imm.13197
Research Techniques Made Simple: Lipidomic Analysis in Skin Research.
Sochorová Michaela,Vávrová Kateřina,Fedorova Maria,Ni Zhixu,Slenter Denise,Kutmon Martina,Willighagen Egon L,Letsiou Sophia,Töröcsik Daniel,Marchetti-Deschmann Martina,Zoratto Samuele,Kremslehner Christopher,Gruber Florian
The Journal of investigative dermatology
Although lipids are crucial molecules for cell structure, metabolism, and signaling in most organs, they have additional specific functions in the skin. Lipids are required for the maintenance and regulation of the epidermal barrier, physical properties of the skin, and defense against microbes. Analysis of the lipidome-the totality of lipids-is of similar complexity to those of proteomics or other omics, with lipid structures ranging from simple, linear, to highly complex structures. In addition, the ordering and chemical modifications of lipids have consequences on their biological function, especially in the skin. Recent advances in analytic capability (usually with mass spectrometry), bioinformatic processing, and integration with other dermatological big data have allowed researchers to increasingly understand the roles of specific lipid species in skin biology. In this paper, we review the techniques used to analyze skin lipidomics and epilipidomics.
10.1016/j.jid.2021.09.017
The Effect of UVB Irradiation and Oxidative Stress on the Skin Barrier-A New Method to Evaluate Sun Protection Factor Based on Electrical Impedance Spectroscopy.
Hernández Aura Rocio,Vallejo Bibiana,Ruzgas Tautgirdas,Björklund Sebastian
Sensors (Basel, Switzerland)
Sunlight is vital for several biochemical processes of the skin organ. However, acute or chronic exposure to ultraviolet radiation (UVR) has several harmful effects on the skin structure and function, especially in the case of the failing function of antioxidative enzymes, which may lead to substantial tissue damage due to the increased presence of reactive oxygen species (ROS). The aim of this work was to investigate the combined effect of ultraviolet B (UVB) irradiation and oxidative stress on the skin barrier integrity. For this, we employed electrical impedance spectroscopy (EIS) to characterize changes of the electrical properties of excised pig skin membranes after various exposure conditions of UVB irradiation, oxidative stress, and the inhibition of antioxidative enzymatic processes. The oxidative stress was regulated by adding hydrogen peroxide (HO) as a source of ROS, while sodium azide (NaN) was used as an inhibitor of the antioxidative enzyme catalase, which is naturally present throughout the epidermis. By screening for the combined effect of UVB and oxidative stress on the skin membrane electrical properties, we developed a new protocol for evaluating these parameters in a simple in vitro setup. Strikingly, the results show that exposure to extreme UVB irradiation does not affect the skin membrane resistance, implying that the skin barrier remains macroscopically intact. Likewise, exposure to only oxidative stress conditions, without UVB irradiation, does not affect the skin membrane resistance. In contrast to these observations, the combination of UVB irradiation and oxidative stress conditions results in a drastic decrease of the skin membrane resistance, indicating that the integrity of the skin barrier is compromised. Further, the skin membrane effective capacitance remained more or less unaffected by UVB exposure, irrespective of simultaneous exposure of oxidative stress. The EIS results were concluded to be associated with clear signs of macroscopic tissue damage of the epidermis as visualized with microscopy after exposure to UVB irradiation under oxidative stress conditions. Finally, the novel methodology was tested by performing an assessment of cosmetic sunscreen formulations with varying sun protection factor (SPF), with an overall successful outcome, showing good correlation between SPF value and protection capacity in terms of skin resistance change. The results from this study allow for the development of new skin sensors based on EIS for the detection of skin tissue damage from exposure to UVB irradiation and oxidative stress and provide a new, more comprehensive methodology, taking into account both the influence of UVB irradiation and oxidative stress, for in vitro determination of SPF in cosmetic formulations.
10.3390/s19102376
Role of Omega-Hydroxy Ceramides in Epidermis: Biosynthesis, Barrier Integrity and Analyzing Method.
International journal of molecular sciences
Attached to the outer surface of the corneocyte lipid envelope (CLE), omega-hydroxy ceramides (ω-OH-Cer) link to involucrin and function as lipid components of the stratum corneum (SC). The integrity of the skin barrier is highly dependent on the lipid components of SC, especially on ω-OH-Cer. Synthetic ω-OH-Cer supplementation has been utilized in clinical practice for epidermal barrier injury and related surgeries. However, the mechanism discussion and analyzing methods are not keeping pace with its clinical application. Though mass spectrometry (MS) is the primary choice for biomolecular analysis, method modifications for ω-OH-Cer identification are lacking in progress. Therefore, finding conclusions on ω-OH-Cer biological function, as well as on its identification, means it is vital to remind further researchers of how the following work should be done. This review summarizes the important role of ω-OH-Cer in epidermal barrier functions and the forming mechanism of ω-OH-Cer. Recent identification methods for ω-OH-Cer are also discussed, which could provide new inspirations for study on both ω-OH-Cer and skin care development.
10.3390/ijms24055035
A new topical panthenol-containing emollient: Results from two randomized controlled studies assessing its skin moisturization and barrier restoration potential, and the effect on skin microflora.
Stettler Hans,Kurka Peter,Lunau Nathalie,Manger Caroline,Böhling Arne,Bielfeldt Stephan,Wilhelm Klaus-Peter,Dähnhardt-Pfeiffer Stephan,Dähnhardt Dorothee,Brill Florian H H,Lenz Holger
The Journal of dermatological treatment
PURPOSE:Two randomized, intra-individual comparison studies were performed in healthy subjects to evaluate the skin moisturization and barrier restoration potential of a new topical panthenol-containing emollient (NTP-CE) (Study 1), and its effect on skin microflora (Study 2). METHODS:In Study 1 (N = 23), two skin areas, one challenged with 0.5% sodium dodecyl sulfate (SDS) solution and one unchallenged, were treated with NTP-CE for 3 weeks. Transepidermal water loss (TEWL), skin hydration, and intercellular lipid lamellae (ICLL) organization were measured at regular intervals during the study. In Study 2 (N = 20), quantitative bacterial cultures were obtained over 6 h from a skin area undergoing wash stress with 10% SDS with subsequent single application of NTP-CE. RESULTS:In Study 1, mean AUC for TEWL reduction from baseline was more pronounced with NTP-CE compared with control (-168.36 vs. -123.38 g/m/h, p = 0.023). NTP-CE use was also associated with statistically significant improvements in stratum corneum hydration and an increase in mean ICLL length from baseline (day 22: 120.61 vs. 35.85 nm/1000 nm, p < 0.001). In Study 2, NTP-CE use had no negative impact on bacterial viability. CONCLUSIONS:NTP-CE use has favorable and lasting effects on barrier function and repair as well as skin hydration without negatively influencing bacterial viability.
10.1080/09546634.2016.1214235
Association of Early Clinical Response to Laser Rejuvenation of Photoaged Skin with Increased Lipid Metabolism and Restoration of Skin Barrier Function.
The Journal of investigative dermatology
Laser resurfacing treatments for photoaged skin have improved dramatically over the past decades, but few studies have examined the molecular mechanisms underlying differences in clinical response. Seventeen white female participants with moderate-to-severe photoaging received nonablative fractional laser treatment on the face and forearm once monthly for 6 months. Biopsies for microarray analysis were performed at baseline and 7 days after facial treatment and at baseline and 1, 7, 14, and 29 days after forearm treatment in each participant, resulting in 119 total samples. Participants were stratified into fast (n = 11) and slow (n = 6) responders on the basis of the presence of clinical improvement after the first treatment. Microarray analysis revealed the upregulation of genes associated with matrix metalloproteinases, collagen and extracellular components, TGF-β signaling, double-stranded RNA signaling, and retinoic acid synthesis after treatment that did not differ significantly between fast and slow responders. Cluster and enrichment analyses suggested significantly greater activation of lipid metabolism and keratinocyte differentiation in fast responders, who showed greater upregulation of acyltransferases, fatty acid elongases, fatty acid 2-hydroxylase, fatty acid desaturases, and specific keratins that may contribute to epidermal barrier function. These results create, to our knowledge, a previously unreported atlas of molecular changes that correlate with improvements in photoaging after laser therapy.
10.1016/j.jid.2022.07.024
Assessment of the skin barrier function in the reconstructed human epidermis using a multimodal approach at molecular, tissue and functional levels.
Bakar Joudi,Michael-Jubeli Rime,El Khoury Rindala,Hamla Sabrina,Assi Ali,Baillet-Guffroy Arlette,Tfayli Ali
The Analyst
Reconstructed human epidermis models are used as epidermis alternatives in skin research studies. It is necessary to provide molecular and functional characterization in order to assess these models. Our aim is to establish a link between the barrier function and the structure and composition of the stratum corneum using several complementary techniques. The following three studies were performed on reconstructed human epidermis during the keratinocyte differentiation process: (i) caffeine percutaneous penetration kinetics, (ii) epidermis thickness measurement, stratum corneum formation and lipid organization by Raman microspectroscopy and (iii) lipid composition evolution by liquid chromatography coupled to high-resolution mass spectrometry. The results demonstrated that the caffeine penetration decreased along the differentiation process. Raman in-depth images demonstrated an increase in stratum corneum and RHE thickness accompanied by the evolution of lipid organization. Lipid analysis showed an increase of the ceramide amount and an inverse relationship between ceramide and its precursor levels during the differentiation process. Different behaviors between several ceramide subclasses are highlighted and they relied on the corresponding differentiation stages. The generation of the most important ceramides for the barrier function is closely followed. A period shift between lipid generation and their organization was found. Our analytical data allowed identifying the following 3 groups of maturation days: before day 15, between days 15 and 19, and after day 19. The chemical and physiological states of the barrier function for each group are described thanks to a multimodal approach.
10.1039/d1an00465d
Studies on stratum corneum metabolism: function, molecular mechanism and influencing factors.
Journal of cosmetic dermatology
BACKGROUND:Stratum corneum is located in the outermost layer of the skin and is the most important part of the skin barrier. Stratum corneum mainly contains keratinocytes, lipids, and desmosomes. Their normal metabolic process is closely related to the function of skin barrier. AIMS:This paper reviews the structure and function of stratum corneum, influencing factors, skin diseases, and common solutions. METHODS:An extensive literature search was conducted on the structure and function of stratum corneum, influencing factors, skin diseases, and common solutions. RESULTS:This paper reviews the structure and function of stratum corneum and the influence of various factors on stratum corneum metabolism. At the same time, the existing skin problems, skin diseases, and common solutions are summarized. CONCLUSIONS:This information will help to understand the function, molecular mechanism, and influencing factors of stratum corneum metabolism, and provide new ideas for stratum corneum health management and cosmetic research and development.
10.1111/jocd.15000
Progress and Future Prospectives in Skin-on-Chip Development with Emphasis on the use of Different Cell Types and Technical Challenges.
Stem cell reviews and reports
Understanding the healthy and diseased state of skin is important in many areas of basic and applied research. Although the field of skin tissue engineering has advanced greatly over the last years, current in vitro skin models still do not mimic the complexity of the human skin. Skin-on-chip and induced pluripotent stem cells (iPSC) might be key technologies to improve in vitro skin models. This review summarizes the state of the art of in vitro skin models with regard to cell sources (primary, cell line, iPSC) and microfluidic devices. It can be concluded that iPSC have the potential to be differentiated into many kinds of immunologically matched cells and skin-on-chip technology might lead to more physiologically relevant skin models due to the controlled environment, possible exchange of immune cells, and an increased barrier function. Therefore the combination of iPSC and skin-on-chip is expected to lead to superior healthy and diseased in vitro skin models.
10.1007/s12015-017-9737-1
Development and evaluation of a quality control system based on transdermal electrical resistance for skin barrier function in vitro.
Knoth Katharina,Zäh Ralf-Kilian,Veldung Barbara,Burgio Dominic,Wiegand Birgit,Smola Hans,Bock Udo,Lehr Claus-Michael,Hittinger Marius,Groß Henrik
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
BACKGROUND:In vitro skin permeation experiments are highly relevant for pharmaceutical, cosmetic, agricultural developments, and regulatory evaluation. A key requirement is the skin barrier integrity, that is accompanied by an intact stratum corneum (SC) which implements high skin quality. A variety of integrity tests are currently available, for example, measurement of transepidermal water loss, monitoring the permeation of tritiated water and the measurement of transdermal electrical resistance (TER). MATERIALS AND METHODS:We aimed for a non-destructive examination of barrier integrity as quality control system, based on TER. Therefore, the in-house developed instrument SkinTER measures electrical resistance on excised human skin samples in a non-invasive and easy-to-use pattern. In this proof of concept study, we compared three human in vitro skin models with focus on their TER and permeation properties. The skin integrity was impaired to mimic conditions of skin during age, lifestyle (eg, shaving) or diseases (eg, obesity, psoriasis, and atopic dermatitis). The OECD permeation marker caffeine was correlated to the corresponding TER value. RESULTS:A correlation between both was obtained by having a Pearson coefficient of -0.830. Hereby, a minimum TER value for intact skin samples of ~1.77 kΩ*cm was suggested. Intact samples are significantly different (α = ≤0.05) to their impaired counterparts in flux and TER values. CONCLUSION:The new SkinTER instrument gives a quick and non-invasive feedback on skin quality before a permeation experiment.
10.1111/srt.12998
Soluble mediators in the function of the epidermal-immune-neuro unit in the skin.
Frontiers in immunology
Skin is the largest, environmentally exposed (barrier) organ, capable of integrating various signals into effective defensive responses. The functional significance of interactions among the epidermis and the immune and nervous systems in regulating and maintaining skin barrier function is only now becoming recognized in relation to skin pathophysiology. This review focuses on newly described pathways that involve soluble mediator-mediated crosstalk between these compartments. Dysregulation of these connections can lead to chronic inflammatory diseases and/or pathologic conditions associated with chronic pain or itch.
10.3389/fimmu.2022.1003970
Automating reflectance confocal microscopy image analysis for dermatological research: a review.
Journal of biomedical optics
SIGNIFICANCE:Reflectance confocal microscopy (RCM) is a noninvasive, in vivo technology that offers near histopathological resolution at the cellular level. It is useful in the study of phenomena for which obtaining a biopsy is impractical or would cause unnecessary tissue damage and trauma to the patient. AIM:This review covers the use of RCM in the study of skin and the use of machine learning to automate information extraction. It has two goals: (1) an overview of information provided by RCM on skin structure and how it changes over time in response to stimuli and in disease and (2) an overview of machine learning approaches developed to automate the extraction of key morphological features from RCM images. APPROACH:A PubMed search was conducted with additional literature obtained from references lists. RESULTS:The application of RCM as an in vivo tool in dermatological research and the biologically relevant information derived from it are presented. Algorithms for image classification to epidermal layers, delineation of the dermal-epidermal junction, classification of skin lesions, and demarcation of individual cells within an image, all important factors in the makeup of the skin barrier, were reviewed. Application of image analysis methods in RCM is hindered by low image quality due to noise and/or poor contrast. Use of supervised machine learning is limited by time-consuming manual labeling of RCM images. CONCLUSIONS:RCM has great potential in the study of skin structures. The use of artificial intelligence could enable an easier, more reproducible, precise, and rigorous study of RCM images for the understanding of skin structures, skin barrier, and skin inflammation and lesions. Although several attempts have been made, further work is still needed to provide a definite gold standard and overcome issues related to image quality, limited labeled datasets, and lack of phenotype variability in available databases.
10.1117/1.JBO.27.7.070902
Raman confocal microscopy and biophysics multiparametric characterization of the skin barrier evolution with age.
Rigal Aline,Michael-Jubeli Rime,Nkengne Alex,Baillet-Guffroy Arlette,Bigouret Armelle,Tfayli Ali
Journal of biophotonics
Skin aging is a multifactorial phenomenon that involves alterations at the molecular, cellular and tissue levels. Our aim was to carry out a multiparametric biophysical and Raman characterization of skin barrier between individuals of different age groups (<24 and >70 years old). Our results showed a significant decrease of lipids to proteins ratio overall the thickness of the stratum corneum and higher lateral packing in the outer part of the SC for elderly. This can explain the decrease in trans epidermal water loss measured values rather than only SC thickening. Both age groups showed similar water content at SC surface while elderly presented higher water content in deep SC and viable epidermis. Mechanical measurements showed a decrease in the elasticity and an increase in the fatigability with age and were correlated with partially bound water. Highest correlation and anti-correlation values were observed for the deepest part of the SC and the viable epidermis.
10.1002/jbio.202100107
Potential Therapeutic Approaches through Modulating the Autophagy Process for Skin Barrier Dysfunction.
International journal of molecular sciences
Autophagy is an attractive process to researchers who are seeking novel potential treatments for various diseases. Autophagy plays a critical role in degrading damaged cellular organelles, supporting normal cell development, and maintaining cellular homeostasis. Because of the various effects of autophagy, recent human genome research has focused on evaluating the relationship between autophagy and a wide variety of diseases, such as autoimmune diseases, cancers, and inflammatory diseases. The skin is the largest organ in the body and provides the first line of defense against environmental hazards, including UV damage, chemical toxins, injuries, oxidative stress, and microorganisms. Autophagy takes part in endogenous defense mechanisms by controlling skin homeostasis. In this manner, regulating autophagy might contribute to the treatment of skin barrier dysfunctions. Various studies are ongoing to elucidate the association between autophagy and skin-related diseases in order to find potential therapeutic approaches. However, little evidence has been gathered about the relationship between autophagy and the skin. In this review, we highlight the previous findings of autophagy and skin barrier disorders and suggest potential therapeutic strategies. The recent research regarding autophagy in acne and skin aging is also discussed.
10.3390/ijms22157869
Organic osmolytes increase expression of specific tight junction proteins in skin and alter barrier function in keratinocytes.
El-Chami C,Foster A R,Johnson C,Clausen R P,Cornwell P,Haslam I S,Steward M C,Watson R E B,Young H S,O'Neill C A
The British journal of dermatology
BACKGROUND:The epidermal barrier is important for water conservation, failure of which is evident in dry-skin conditions. Barrier function is fulfilled by the stratum corneum, tight junctions (TJs, which control extracellular water) and keratinocyte mechanisms, such as organic osmolyte transport, which regulate intracellular water homeostasis. Organic osmolyte transport by keratinocytes is largely unexplored and nothing is known regarding how cellular and extracellular mechanisms of water conservation may interact. OBJECTIVES:We aimed to characterize osmolyte transporters in skin and keratinocytes, and, using transporter inhibitors, to investigate whether osmolytes can modify TJs. Such modification would suggest a possible link between intracellular and extracellular mechanisms of water regulation in skin. METHODS:Immunostaining and quantitative polymerase chain reaction of organic osmolyte-treated organ-cultured skin were used to identify changes to organic osmolyte transporters, and TJ protein and gene expression. TJ functional assays were performed on organic osmolyte-treated primary human keratinocytes in culture. RESULTS:Immunostaining demonstrated the expression of transporters for betaine, taurine and myo-inositol in transporter-specific patterns. Treatment of human skin with either betaine or taurine increased the expression of claudin-1, claudin-4 and occludin. Osmolyte transporter inhibition abolished this response. Betaine and taurine increased TJ function in primary human keratinocytes in vitro. CONCLUSIONS:Treatment of skin with organic osmolytes modulates TJ structure and function, which could contribute to the epidermal barrier. This emphasizes a role for organic osmolytes beyond the maintenance of intracellular osmolarity. This could be harnessed to enhance topical therapies for diseases characterized by skin barrier dysfunction.
10.1111/bjd.19162
Assessment of skin barrier function using skin images with topological data analysis.
NPJ systems biology and applications
Recent developments of molecular biology have revealed diverse mechanisms of skin diseases, and precision medicine considering these mechanisms requires the frequent objective evaluation of skin phenotypes. Transepidermal water loss (TEWL) is commonly used for evaluating skin barrier function; however, direct measurement of TEWL is time-consuming and is not convenient for daily clinical practice. Here, we propose a new skin barrier assessment method using skin images with topological data analysis (TDA). TDA enabled efficient identification of structural features from a skin image taken by a microscope. These features reflected the regularity of the skin texture. We found a significant correlation between the topological features and TEWL. Moreover, using the features as input, we trained machine-learning models to predict TEWL and obtained good accuracy (R = 0.524). Our results suggest that assessment of skin barrier function by topological image analysis is promising.
10.1038/s41540-020-00160-8
Evolving Concepts in Psoriasis: Special Considerations for Patients With Skin of Color, Skin Barrier Dysfunction, and the Role of Adjunctive Skin Care.
Journal of drugs in dermatology : JDD
BACKGROUND:Despite considerable advances in our understanding of the pathogenesis and treatment of psoriasis, data pertaining to racial/ethnic variations, effects on barrier function, and the potential role of adjunctive skin care are relatively limited. Knowledge gaps in the clinical presentation, quality-of-life impact, and approach to treating psoriasis in patients with skin color contribute to disparities in care. In addition, small studies suggest that using skincare products can reduce psoriasis symptoms, improve barrier function, and result in higher patient satisfaction, yet patients with psoriasis may underuse skincare products. This manuscript seeks to offer insights into these knowledge gaps and their potential treatment implications. METHODS:A structured literature search followed by a panel discussion and an online review process explored best clinical practices in treating psoriasis patients with skin of color and providing expert guidance for skincare use, including gentle cleansers and moisturizers. RESULTS:Racial/ethnic differences in genetic factors, clinical presentation, and disease burden in psoriasis have been reported. Underrecognition of these differences contributes to racial/ethnic health disparities for psoriasis patients in the US. Several studies have shown a greater quality-of-life impact with psoriasis among patients with skin of color. Although the published data are limited, some studies have identified differences in skin barrier properties and suggest a role for adjunctive skin care in the management of psoriasis. CONCLUSION:Further study is needed to understand racial/ethnic population variations in psoriasis and develop strategies to reduce disparities in care. Addressing alterations in skin barrier function observed in psoriasis may help to improve treatment outcomes and patient satisfaction. J Drugs Dermatol. 2022;21(10):1054-1060. doi:10.36849/JDD.7090.
10.36849/JDD.7090
Inflammatory loops in the epithelial-immune microenvironment of the skin and skin appendages in chronic inflammatory diseases.
Frontiers in immunology
The epithelial-immune microenvironment (EIME) of epithelial tissues has five common elements: (1) microbial flora, (2) barrier, (3) epithelial cells, (4) immune cells, and (5) peripheral nerve endings. EIME provides both constant defense and situation-specific protective responses through three-layered mechanisms comprising barriers, innate immunity, and acquired immunity. The skin is one of the largest organs in the host defense system. The interactions between the five EIME elements of the skin protect against external dangers from the environment. This dysregulation can result in the generation of inflammatory loops in chronic inflammatory skin diseases. Here, we propose an understanding of EIME in chronic skin diseases, such as atopic dermatitis, psoriasis, systemic lupus erythematosus, alopecia areata, and acne vulgaris. We discuss the current treatment strategies targeting their inflammatory loops and propose possible therapeutic targets in the future.
10.3389/fimmu.2023.1274270
Evaluation of a Novel Skin Emollient Cream on Skin Lipidome and Lipid Organization.
Skin pharmacology and physiology
INTRODUCTION:The stratum corneum (SC) matrix is composed of free fatty acids, cholesterol, and ceramides (CERs), which play a key role in the skin barrier function. Changes in the composition and content of skin lipids will affect the function of the skin barrier. The effect of a glycerol/petrolatum-based emollient (G/P-emollient) cream on the lipid profiles of isolated ex vivo human SC and the SC of a reconstructed human epidermis (RHE) model was measured. METHODS:The spatial organization of the cream and the isolated SC intercellular matrix were studied using X-ray diffraction. The inter-bilayer distances in the multi-lamellar lipid structures and lattice type were analyzed using small-angle X-ray scattering and wide-angle X-ray scattering (WAXS), respectively. Lipidomic analysis using shotgun lipidomics was performed on RHE models to quantify CER classes and chain lengths. This technology enables the analysis of thousands of lipids in a single biological sample. RESULTS:The crystallized components of the cream are lipids, which were mainly packed in orthorhombic lattices, as well as hexagonal lattices and were similar to the SC structure. The cream penetrated the SC but did not alter the WAXS profile. It increased the amount of higher carbon number CERs (>42 carbons) and decreased lower carbon number CERs (<42 carbons). All chain length of CERs and acyl-CER classes (CER EOS, EOH, EOP, EOdS) were increased as the total CER classes. A decrease of the CER C34 for hydroxylated and non-hydroxylated CERs was also observed. The cream altered the S and P CER forms (increased the NP/NS and AP/AS ratios), indicating it could reduce the relative feedback mechanism observed in inflammatory pathologies, for example, atopic dermatitis. The cream increased CER NP, which is decreased in dry skin. CONCLUSION:G/P-emollient cream may be beneficial for skin pathologies by modifying SC lipids, balancing CER levels and ratios, and improving the barrier function. Importantly, the cream structure mimics that of the SC and penetrated the lower SC layers without compromising its lamellar structure.
10.1159/000529253
Molecular Mechanism of Epidermal Barrier Dysfunction as Primary Abnormalities.
Lee Ai-Young
International journal of molecular sciences
Epidermal barrier integrity could be influenced by various factors involved in epidermal cell differentiation and proliferation, cell-cell adhesion, and skin lipids. Dysfunction of this barrier can cause skin disorders, including eczema. Inversely, eczema can also damage the epidermal barrier. These interactions through vicious cycles make the mechanism complicated in connection with other mechanisms, particularly immunologic responses. In this article, the molecular mechanisms concerning epidermal barrier abnormalities are reviewed in terms of the following categories: epidermal calcium gradients, filaggrin, cornified envelopes, desquamation, and skin lipids. Mechanisms linked to ichthyoses, atopic dermatitis without exacerbation or lesion, and early time of experimental irritation were included. On the other hand, the mechanism associated with epidermal barrier abnormalities resulting from preceding skin disorders was excluded. The molecular mechanism involved in epidermal barrier dysfunction has been mostly episodic. Some mechanisms have been identified in cultured cells or animal models. Nonetheless, research into the relationship between the causative molecules has been gradually increasing. Further evidence-based systematic data of target molecules and their interactions would probably be helpful for a better understanding of the molecular mechanism underlying the dysfunction of the epidermal barrier.
10.3390/ijms21041194
Keratinocytes: An Enigmatic Factor in Atopic Dermatitis.
Cells
Atopic dermatitis (AD), characterized by rashes, itching, and pruritus, is a chronic inflammatory condition of the skin with a marked infiltration of inflammatory cells into the lesion. It usually commences in early childhood and coexists with other atopic diseases such as allergic rhinitis, bronchial asthma, allergic conjunctivitis, etc. With a prevalence rate of 1-20% in adults and children worldwide, AD is gradually becoming a major health concern. Immunological aspects have been frequently focused on in the pathogenesis of AD, including the role of the epidermal barrier and the consequent abnormal cytokine expressions. Disrupted epidermal barriers, as well as allergic triggers (food allergy), contact allergens, irritants, microbes, aggravating factors, and ultraviolet light directly initiate the inflammatory response by inducing epidermal keratinocytes, resulting in the abnormal release of various pro-inflammatory mediators, inflammatory cytokines, and chemokines from keratinocytes. In addition, abnormal proteinases, gene mutations, or single nucleotide polymorphisms (SNP) affecting the function of the epidermal barrier can also contribute towards disease pathophysiology. Apart from this, imbalances in cholinergic or adrenergic responses in the epidermis or the role played by immune cells in the epidermis such as Langerhans cells or antigen-presenting cells can also aggravate pathophysiology. The dearth of specific biomarkers for proper diagnosis and the lack of a permanent cure for AD necessitate investigation in this area. In this context, the widespread role played by keratinocytes in the pathogenesis of AD will be reviewed in this article to facilitate the opening up of new avenues of treatment for AD.
10.3390/cells11101683
Cutaneous Barriers and Skin Immunity: Differentiating A Connected Network.
Eyerich Stefanie,Eyerich Kilian,Traidl-Hoffmann Claudia,Biedermann Tilo
Trends in immunology
The skin is the outermost barrier of the organism that ensures protection from external harm. Lately, our view of the skin has evolved from an inert mechanical barrier to an active organ that can sense danger signals and mount perfectly adapted defense measures in response to invading pathogens. This Review highlights the different levels of the cutaneous barrier (the microbiome, chemical, physical, and immune barriers), their characteristics, and functional, highly interconnected network of cells and mediators that allow balanced defense measures to protect the body and maintain barrier integrity.
10.1016/j.it.2018.02.004
Value of GPSkin for the measurement of skin barrier impairment and for monitoring of rosacea treatment in daily practice.
Logger Jade G M,Driessen Rieke J B,de Jong Elke M G J,van Erp Piet E J
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
BACKGROUND:Stratum corneum hydration (SCH) and transepidermal water loss (TEWL) provide useful information about skin barrier function. This study aimed to determine the value of GPSkin Pro, a new handheld device determining both SCH and TEWL, to measure skin barrier impairment and to monitor barrier function in rosacea in daily practice. MATERIALS AND METHODS:Two pilots were performed. Pilot 1: in 27 healthy participants, GPSkin SCH and TEWL were compared to Aquaflux and Epsilon values at the forearm before and after skin barrier perturbation via tapestripping. Moreover, GPSkin values were measured at both cheeks without intervention. Pilot 2: in 16 rosacea patients, GPSkin measurements were performed at the forearm, and at both cheeks before and during anti-inflammatory treatment. They were compared to clinical symptoms and to GPSkin values from pilot 1. RESULTS:Pilot 1: after merging data from before and after tapestripping, a strong correlation was observed between GPSkin TEWL and Aquaflux (R = 0.9256), and GPSkin SCH and Epsilon (R = 0.8798). Pilot 2: SCH was significantly lower at the cheeks of rosacea patients compared to controls, with a normalizing trend during successful treatment. TEWL was comparable among patients and controls and did not change during treatment at all locations. CONCLUSION:The GPSkin determines TEWL and SCH accurately in healthy and impaired skin barrier state and can monitor skin barrier function in rosacea during treatment. The GPSkin device is much more practical compared to previous skin barrier tools when used in clinical practice. Its further validation in other inflammatory skin diseases is recommended.
10.1111/srt.12900
The influence of skin barrier impairment on the iontophoretic transport of low and high molecular weight permeants.
Gratieri Taís,Zarhloule Rhita,Dubey Sachin,Kalia Yogeshvar N
International journal of pharmaceutics
The effect of skin barrier impairment on the iontophoretic transport of low (acetaminophen (ACM), lidocaine (LD), ketorolac (KT)) and high molecular weight permeants, (cytochrome c (Cyt c) and ribonuclease T1 (RNase T1)), was evaluated using tape-stripping (TS) and fractional laser ablation for "large-scale" and "localized" barrier disruption. Interestingly, removal of the stratum corneum did not invariably lead to an increase in iontophoretic delivery of the permeants. Decrease of electroosmotic (EO) flow and facilitated transport of Cl ions in the cathode-to-anode direction, which reduced cation electromigration (EM), both impacted cation delivery by anodal iontophoresis but the effects were partly offset by enhanced passive diffusion. Decrease in EO increased cathodal iontophoresis of KT but not that of RNase T1. Permeability coefficients confirmed the superiority of EM over EO for small molecules, LD > KT > ACM. A combination of fractional laser ablation and iontophoresis was advantageous for both positively and negatively charged small molecules as passive penetration was significantly enhanced. In conclusion, results demonstrated that (i) skin ablation prior to anodal iontophoresis decreased EO and EM but could be advantageous for delivery if the ablative technique enhanced passive penetration thereby compensating reduction of electrotransport and (ii) reduced EO favored cathodal electrotransport.
10.1016/j.ijpharm.2021.120607
Corneocytes: Relationship between Structural and Biomechanical Properties.
Évora Ana S,Adams Michael J,Johnson Simon A,Zhang Zhibing
Skin pharmacology and physiology
BACKGROUND:Skin is the interface between an organism and the external environment, and hence the stratum corneum (SC) is the first to withstand mechanical insults that, in certain conditions, may lead to integrity loss and the development of pressure ulcers. The SC comprises corneocytes, which are vital elements to its barrier function. These cells are differentiated dead keratinocytes, without organelles, composed of a cornified envelope and a keratin-filled interior, and connected by corneodesmosomes (CDs). SUMMARY:The current review focusses on the relationship between the morphological, structural, and topographical features of corneocytes and their mechanical properties, to understand how they assist the SC in maintaining skin integrity and in responding to mechanical insults. Key Messages: Corneocytes create distinct regions in the SC: the inner SC is characterized by immature cells with a fragile cornified envelope and a uniform distribution of CDs; the upper SC has resilient cornified envelopes and a honeycomb distribution of CDs, with a greater surface area and a smaller thickness than cells from the inner layer. The literature indicates that this upward maturation process is one of the most important steps in the mechanical resistance and barrier function of the SC. The morphology of these cells is dependent on the body site: the surface area in non-exposed skin is about 1,000-1,200 μm2, while for exposed skin, for example, the cheek and forehead, is about 700-800 μm2. Corneocytes are stiff cells compared to other cellular types, for example, the Young's modulus of muscle and fibroblast cells is typically a few kPa, while that of corneocytes is reported to be about hundreds of MPa. Moreover, these skin cells have 2 distinct mechanical regions: the cornified envelope (100-250 MPa) and the keratin matrix (250-500 MPa).
10.1159/000513054
Effect of compromised skin barrier on delivery of diclofenac sodium from brand and generic formulations via microneedles and iontophoresis.
International journal of pharmaceutics
Application of drugs on skin with compromised barrier can significantly alter permeation of drugs with the possibility of increased adverse side effects or even toxicity. In this study, we tested in vitro delivery of diclofenac sodium from marketed brand and generic formulations across normal and compromised skin using microneedles and iontophoresis, alone and in combination. Ten tape strips on dermatomed human skin were used to create a compromised skin model, as demonstrated by changes in skin resistance and transepidermal water loss. Histology studies further confirmed creation of a compromised skin barrier. There was no significant difference between brand and generic formulations for delivery of diclofenac sodium into and across normal and compromised skin. Compromised skin showed higher total delivery (µg/sq.cm) of diclofenac sodium for all groups - microneedles (brand: 79.45 ± 8.81, generic: 92.15 ± 8.63), iontophoresis (brand: 233.13 ± 8.32, generic: 242.07 ± 11.17), combination (brand: 186.88 ± 6.76, generic: 193.8 ± 5.69) as compared to intact normal skin for same groups, microneedles (brand: 21.83 ± 1.96, generic: 20.38 ± 0.91), iontophoresis (brand: 149.78 ± 18.43, generic: 145.53 ± 12.61), and combination (brand: 80.97 ± 9.86, generic: 70.76 ± 6.56). These results indicate the effect of barrier integrity on delivery of diclofenac sodium which suggests increased absorption and systemic exposure of the drug across skin with compromised skin barrier.
10.1016/j.ijpharm.2022.122271
Specific protection of sensitive skin against environmental stress by maintenance and improvement of barrier function.
Viodé C,Rouquier A,Mias C,Questel E,Bessou-Touya S,Duplan H
Journal of the European Academy of Dermatology and Venereology : JEADV
BACKGROUND:Sensitive skin is a common condition that can severely impact quality of life. Several mechanisms are thought to be involved, including those affecting the skin barrier function, hydration and skin innervation. OBJECTIVES:To investigate the benefit of cream and balm formulations dedicated to sensitive skin and containing Aquaphilus dolomiae extract-G3 (ADE-G3) on skin barrier functions (lipid composition, pH, TEWL), as well as protective responses to dry and pollution stresses. METHODS:In vitro sensitized (using histamine) reconstructed human epidermis (RHE) were subjected to dehydration and pollution stress in the absence and presence of the formulations. Endpoint measurements included transepithelial electric resistance (TEER), stratum corneum protein expression and lipid contents. Clinical measurements included transepithelial water loss (TEWL), skin pH and the lipid index. RESULTS:When applied in cream and balm formulations, ADE-G3, increased the TEER in sensitized RHEs. In non-sensitized dehydrated RHEs, both formulations increased recovery of skin barrier integrity after dehydration, evident as a return of the ratios of filaggrin/profilaggrin and caspase-14/procaspase-14 to values measured in control non-stressed RHEs, as well as reducing the 'natural moisturizing factor' to control levels. In clinical studies performed on dry human skin, the formulations helped to maintain and improve the skin barrier function. This was evident as an intense and sustained moisturization (total lipids and lipid esters were increased), an increase in pH and a decrease in the TEWL by both formulations. When exposed to pollution stress by treating the models with benzo[a]pyrene and airborne particulate matter (PM10), application of both formulations prior to exposure attenuated the induction of CYP1A1, CYP1B1 and UGT1A7 expression, indicating a protective effect. CONCLUSIONS:ADE-G3 cream and balm formulations increased the hydration of the skin but also protected and improved the skin barrier integrity of sensitive skin exposed to dry and cold and airborne pollutant-induced stress environments.
10.1111/jdv.17910
Staphylococcal Biofilms in Atopic Dermatitis.
Gonzalez Tammy,Biagini Myers Jocelyn M,Herr Andrew B,Khurana Hershey Gurjit K
Current allergy and asthma reports
PURPOSE OF REVIEW:Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disorder that is a major public health burden worldwide. AD lesions are often colonized by Staphylococcus aureus and Staphylococcus epidermidis. An important aspect of Staphylococcus spp. is their propensity to form biofilms, adhesive surface-attached colonies that become highly resistant to antibiotics and immune responses, and recent studies have found that clinical isolates colonizing AD skin are often biofilm-positive. Biofilm formation results in complex bacterial communities that have unique effects on keratinocytes and host immunity. This review will summarize recent studies exploring the role of staphyloccocal biofilms in atopic dermatitis and the implications for treatment. RECENT FINDINGS:Recent studies suggest an important role for biofilms in the pathogenesis of numerous dermatologic diseases including AD. S. aureus biofilms have been found to colonize the eccrine ducts of AD skin, and these biofilms influence secretion of keratinocyte cytokines and trigger differentiation and apoptosis of keratinocytes. These activities may act to disrupt barrier function and promote disease pathogenesis as well as allergen sensitization. Formation of biofilm is a successful strategy that protects the bacteria from environmental danger, antibiotics, and phagocytosis, enabling chronic persistence in the host. An increasing number of S. aureus skin isolates are resistant to conventional antibiotics, and staphylococcal biofilm communities are prevalent on the skin of individuals with AD. Staphylococcal colonization of the skin impacts skin barrier function and plays multiple important roles in AD pathogenesis.
10.1007/s11882-017-0750-x
Mechanisms for control of skin immune function by the microbiome.
Current opinion in immunology
The skin represents the largest area for direct contact between microbes and host immunocytes and is a site for constant communication between the host and this diverse and essential microbial community. Coagulase-negative staphylococci are an abundant bacterial genus on the human skin and are regulated through various mechanisms that include the epidermal barrier environment and innate and adaptive immune systems within the epidermis and dermis. In turn, some species and strains of these bacteria produce beneficial products that augment host immunity by exerting specifically targeted antimicrobial, anti-inflammatory, or anti-neoplastic activity while also promoting broad innate and adaptive immune responses. The use of selected skin commensals as a therapeutic has shown promise in recent human clinical trials. This emerging concept of bacteriotherapy is defining mechanisms of action and validating the dependence on the microbiome for maintenance of immune homeostasis.
10.1016/j.coi.2021.09.001
Study of the protective effects of cosmetic ingredients on the skin barrier, based on the expression of barrier-related genes and cytokines.
Ding Wenyu,Fan Linna,Tian Yan,He Congfen
Molecular biology reports
BACKGROUND:Sensitive skin is the result of a complex process that is closely linked to the damage of the skin barrier. There are no recognized methods for evaluating the efficacy of anti-allergy products. METHODS:In this study, a model of skin barrier damage was created by treating HaCaT cells with 60 μg/ml of sodium dodecyl sulfate for 48 h. The protective effects of nine cosmetic ingredients, including oat extract (S1), on the skin barrier were investigated based on the gene expression levels of aquaporin3 (AQP3), filaggrin (FLG), caspase-14 (CASP14), and human tissue kallikrein7 (KLK7), as well as those of various interleukins (IL) and vascular endothelial growth factor (VEGF). RESULTS:Among the nine ingredients, S1 had a good protective effect on the function of the skin barrier. It promoted the expression of AQP3, FLG, and CASP14, while inhibiting the expression of KLK7 in HaCaT cells, at a concentration of 0.06%. It also maintained IL-6, IL-8, and VEGF at appropriate levels while promoting the proliferation and differentiation of HaCaT cells. CONCLUSIONS:The above indicators allow for the preliminary establishment of a method to evaluate the efficacy of the barrier protection ability of sensitive skin.
10.1007/s11033-021-06918-5
The role of skin barrier in occupational contact dermatitis.
Jakasa Ivone,Thyssen Jacob P,Kezic Sanja
Experimental dermatology
Skin diseases represent one of the most common work-related diseases and may have a detrimental effect on social, personal and occupational aspects of life. Contact dermatitis (CD), which comprises predominately irritant contact dermatitis (ICD) and allergic contact dermatitis (ACD), accounts for vast majority of occupational skin diseases, especially in occupations associated with frequent skin contact with irritants and contact allergens. Although ICD and ACD have similar clinical manifestation, their pathophysiology and the role of the skin barrier are different. In ICD, perturbation of the skin barrier is the primary event which sets into motion diverse metabolic processes and triggers activation of innate immunity without the involvement of adaptive immune system. In ACD, a type IV hypersensitivity reaction induced by contact allergens, the skin barrier impairment may evoke innate signalling pathways during the sensitization phase required for the activation of T-cell adaptive response. Thus, skin barrier impairment may increase the risk of ICD or ACD not only because of enhanced permeability and ingress of irritants and allergens but also by the generation of innate immune signal needed for the induction of allergic response. Hence, an efficient way to prevent CD is to avoid skin barrier damage in the workplace. This review focuses on the skin barrier, how it is affected by skin irritants and how its impairment contributes to the development of ICD and ACD.
10.1111/exd.13704
Basics and recent advances in the pathophysiology of atopic dermatitis.
Nakahara Takeshi,Kido-Nakahara Makiko,Tsuji Gaku,Furue Masutaka
The Journal of dermatology
Atopic dermatitis is a common, chronic inflammatory skin disease that is characterized by skin barrier dysfunction, inflammation and intense itch. Although the exact mechanisms behind its pathogenesis remain unclear, it is evident that the complex interplay among barrier dysfunction, inflammation and itch are critical in its development, progression and chronicity. Abnormalities in filaggrin, intercellular lipids and tight junctions induce barrier-disrupted skin, which produces thymic stromal lymphopoietin, interleukin (IL)-25 and IL-33; these in turn promote skin inflammation characterized by type 2 immune deviation. This inflammation then downregulates the expression of filaggrin in keratinocytes and exacerbates epidermal barrier dysfunction. Furthermore, various itch mediators/pruritogens produced during this inflammatory process can act directly on sensory nerves and cause itch. In this review, we summarize the basics and recent advances in our understanding of the pathophysiology of atopic dermatitis focusing on three aspects: barrier dysfunction, skin inflammation and itch.
10.1111/1346-8138.15664
Eavesdropping on the conversation between immune cells and the skin epithelium.
International immunology
The skin epithelium covers our body and serves as a vital interface with the external environment. Here, we review the context-specific interactions between immune cells and the epithelium that underlie barrier fitness and function. We highlight the mechanisms by which these two systems engage each other and how immune-epithelial interactions are tuned by microbial and inflammatory stimuli. Epithelial homeostasis relies on a delicate balance of immune surveillance and tolerance, breakdown of which results in disease. In addition to their canonical immune functions, resident and recruited immune cells also supply the epithelium with instructive signals to promote repair. Decoding the dialogue between immunity and the epithelium therefore has great potential for boosting barrier function or mitigating inflammatory epithelial diseases.
10.1093/intimm/dxy088
Effects of omega--acylceramide structures and concentrations in healthy and diseased skin barrier lipid membrane models.
Opálka Lukáš,Kováčik Andrej,Pullmannová Petra,Maixner Jaroslav,Vávrová Kateřina
Journal of lipid research
Ceramides (Cers) with ultralong (∼32-carbon) chains and ω-esterified linoleic acid, composing a subclass called omega--acylceramides (acylCers), are indispensable components of the skin barrier. Normal barriers typically contain acylCer concentrations of ∼10 mol%; diminished concentrations, along with altered or missing long periodicity lamellar phase (LPP), and increased permeability accompany an array of skin disorders, including atopic dermatitis, psoriasis, and ichthyoses. We developed model membranes to investigate the effects of the acylCer structure and concentration on skin lipid organization and permeability. The model membrane systems contained six to nine Cer subclasses as well as fatty acids, cholesterol, and cholesterol sulfate; acylCer content-namely, acylCers containing sphingosine (Cer EOS), dihydrosphingosine (Cer EOdS), and phytosphingosine (Cer EOP) ranged from zero to 30 mol%. Systems with normal physiologic concentrations of acylCer mixture mimicked the permeability and nanostructure of human skin lipids (with regard to LPP, chain order, and lateral packing). The models also showed that the sphingoid base in acylCer significantly affects the membrane architecture and permeability and that Cer EOP, notably, is a weaker barrier component than Cer EOS and Cer EOdS. Membranes with diminished or missing acylCers displayed some of the hallmarks of diseased skin lipid barriers (i.e., lack of LPP, less ordered lipids, less orthorhombic chain packing, and increased permeability). These results could inform the rational design of new and improved strategies for the barrier-targeted treatment of skin diseases.
10.1194/jlr.RA119000420
Skin-Nerve Co-Culture Systems for Disease Modeling and Drug Discovery.
Schutte Stacey C,Kadakia Feni,Davidson Steve
Tissue engineering. Part C, Methods
Prominent clinical problems related to the skin-nerve interface include barrier dysfunction and erythema, but it is the symptoms of pain and itch that most often lead patients to seek medical treatment. Tissue-engineered innervated skin models provide an excellent solution for studying the mechanisms underlying neurocutaneous disorders for drug screening, and cutaneous device development. Innervated skin substitutes provide solutions beyond traditional monolayer cultures and have advantages that make them preferable to animal studies for certain applications, such as measuring somatosensory transduction. The tissue-engineered innervated skin models replicate the complex stratified epidermis that provides barrier function in native skin, a feature that is lacking in monolayer co-cultures, while allowing for a level of detail in measurement of nerve morphology and function that cannot be achieved in animal models. In this review, the advantages and disadvantages of different cell sources and scaffold materials will be discussed and a presentation of the current state of the field is reviewed. Impact statement A review of the current state of innervated skin substitutes and the considerations that need to be addressed when developing these models. Tissue-engineered skin substitutes are customizable and provide barrier function allowing for screening of topical drugs and for studying nerve function.
10.1089/ten.TEC.2020.0296
Assessing the skin barrier via corneocyte morphometry.
Riethmüller Christoph
Experimental dermatology
The skin barrier is an inevitable physiological function. Virtually all skin diseases exhibit an altered barrier. Because of its diversity, this vital function cannot be assessed adequately by a single method. Preference in both pharmaceutical and cosmetic testing is given to noninvasive assays, mostly macroscopic methods like optical or electrical or mechanical measurements. The present review focuses on advances in ultrastructural assays based on corneocytes obtained via tape stripping-highlighting candidates for automated processing. Among these are electron microscopic (EM) and atomic force microscopic (AFM) analyses, which are discussed with respect to clinical signs and skin hydration, as assessed by Raman spectroscopy or by concentration of natural moisturizing factor.
10.1111/exd.13741
Unraveling Immune-Epithelial Interactions in Skin Homeostasis and Injury.
Mansfield Kody,Naik Shruti
The Yale journal of biology and medicine
The skin serves as a front line of defense against harmful environmental elements and thus is vital for organismal survival. This barrier is comprised of a water-tight epithelial structure reinforced by an arsenal of immune cells. The epithelial and immune components of the skin are interdependent and actively dialogue to maintain health and combat infectious, injurious, and noxious stimuli. Here, we discuss the molecular mediators of this crosstalk that establish tissue homeostasis and their dynamic adaptations to various stress conditions. In particular, we focus on immune-epithelial interactions in homeostatic tissue regeneration, during natural cycling of the hair follicle, and following skin injury. We also highlight the epithelial derived factors that orchestrate immunity. A comprehensive and mechanistic understanding of dynamic interactions between cutaneous immune cells and the epithelium can be leveraged to develop novel therapies to treat of range of skin diseases and boost skin health.
Innate Antiviral Immunity in the Skin.
Handfield Chelsea,Kwock Jeffery,MacLeod Amanda S
Trends in immunology
Barrier sites such as the skin play a critical role in immune defense. They must maintain homeostasis with commensals and rapidly detect and limit pathogen invasion. This is accomplished in part through the production of endogenous antimicrobial peptides and proteins, which can be either constitutive or inducible. Here, we focus particularly on the control of innate antiviral proteins and present the basic aspects of their regulation in the skin by interferons (IFNs), IFN-independent immunity, and environmental factors. We also discuss the activity and (dys-)function of antiviral proteins in the context of skin-tropic viruses and highlight the relevance of the innate antiviral pathway as a potential therapeutic avenue for vulnerable patient populations and skin diseases with high risk for virus infections.
10.1016/j.it.2018.02.003
Effect of sphingosine and phytosphingosine ceramide ratio on lipid arrangement and barrier function in skin lipid models.
Journal of lipid research
The lipids in the uppermost layer of the skin, the stratum corneum (SC), play an important role in the skin barrier function. The three main subclasses in the SC lipid matrix are ceramides (CER), cholesterol, and free fatty acids. In inflammatory skin diseases, such as atopic dermatitis and psoriasis, the SC lipid composition is modulated compared to the composition in healthy SC. One of the main alterations is the molar ratio between the concentration of CER N-(tetracosanoyl)-sphingosine (CER NS) and CER N-(tetracosanoyl)-phytosphingosine (CER NP), which correlated with an impaired skin barrier function. In the present study, we investigated the impact of varying the CER NS:CER NP ratios on the lipid organization, lipid arrangement, and barrier functionality in SC lipid model systems. The results indicate that a higher CER NS:CER NP ratio as observed in diseased skin did not alter the lipid organization or lipid arrangement in the long periodicity phase encountered in SC. The trans-epidermal water loss, an indication of the barrier functionality, was significantly higher for the CER NS:CER NP 2:1 model (mimicking the ratio in inflammatory skin diseases) compared to the CER NS:CER NP 1:2 ratio (in healthy skin). These findings provide a more detailed insight into the lipid organization in both healthy and diseased skin and suggest that in vivo the molar ratio between CER NS:CER NP contributes to barrier impairment as well but might not be the main factor.
10.1016/j.jlr.2023.100400
Heterogeneity of Sweat Gland Stem Cells.
Brandenburger Matthias,Kruse Charli
Advances in experimental medicine and biology
Sweat glands play an important role in skin physiology and are an integral part of the natural skin barrier. In order to maintain functionality throughout life, sweat glands make use of several types of stem cells. This chapter focuses on the classification of different types of stem cells found in the sweat gland and their physiological roles. First, sweat gland formation during skin maturation is addressed in order to give an overview of sweat gland origin and formation in vivo. Then, different kinds of adult sweat gland stem cells are introduced and classified between different potency levels and corresponding physiological roles. Finally, the importance of these cell sources for future developments, including applications in wound healing and cosmetics research, is discussed.
10.1007/978-3-030-24108-7_3
Physiological and Molecular Effects of in vivo and ex vivo Mild Skin Barrier Disruption.
Pfannes Eva K B,Weiss Lina,Hadam Sabrina,Gonnet Jessica,Combardière Béhazine,Blume-Peytavi Ulrike,Vogt Annika
Skin pharmacology and physiology
The success of topically applied treatments on skin relies on the efficacy of skin penetration. In order to increase particle or product penetration, mild skin barrier disruption methods can be used. We previously described cyanoacrylate skin surface stripping as an efficient method to open hair follicles, enhance particle penetration, and activate Langerhans cells. We conducted ex vivo and in vivo measurements on human skin to characterize the biological effect and quantify barrier disruption-related inflammation on a molecular level. Despite the known immunostimulatory effects, this barrier disruption and hair follicle opening method was well accepted and did not result in lasting changes of skin physiological parameters, cytokine production, or clinical side effects. Only in ex vivo human skin did we find a discrete increase in IP-10, TGF-β, IL-8, and GM-CSF mRNA. The data underline the safety profile of this method and demonstrate that the procedure per se does not cause substantial inflammation or skin damage, which is also of interest when applied to non-invasive sampling of biomarkers in clinical trials.
10.1159/000484443
Role of Skin pH in Psoriasis.
Bigliardi Paul L
Current problems in dermatology
Not much is known about the role of skin pH in skin pathophysiology, in particular in psoriasis. However, there is compelling evidence that the epidermal pH can influence the skin homeostasis and affect the skin barrier by changing the activity of cutaneous enzymes and through the modulation of skin inflammation and microbial colonization. This includes the activation of secretory phospholipase A and interaction with the peroxisome proliferators-activated receptor and retinoid pathways. In addition, pH in skin affects the activity of aquaporins and this controls the hydration of the epidermis. Changes in skin homeostasis, differentiation, barrier defects, and inflammation play a crucial role in the pathogenesis of psoriasis. There is evidence that skin pH can affect all of these important factors. However, more studies are needed to examine objectively and precisely the pH in the various skin layers in psoriatic lesional and non-lesional skin and compare it to normal skin. This additional know-how is essential to understand the role of skin pH in psoriasis with ultimately great potential of manipulations of skin pH for topical approaches in the management of psoriasis.
10.1159/000489524
Melanocyte activation and skin barrier disruption induced in melasma patients after 1064 nm Nd:YAG laser treatment.
Gao Ya-Li,Jia Xiao-Xiao,Wang Min,Hua You,Zheng Han,Xiang Wen-Zhong,Song Xiu-Zu
Lasers in medical science
Melasma is a frequently acquired hyperpigmentary skin disorder, for which several therapies are available. Among them, 1064 nm QS Nd:YAG laser therapy is an effective method, but the recurrence rate of laser treatment is still high. The aim of the present study was to elucidate the mechanism of the high relapse rate of melasma after 1064 nm Nd:YAG laser treatment. Twenty-five female melasma patients were treated with 1064 nm Nd:YAG laser for 10 times. The lesional skin and non-lesional skin were evaluated by means of a reflectance confocal laser scanning microscope before and after laser treatment. Melanin content and transepidermal water loss (TEWL) were measured by an MPA9 skin multifunction tester accordingly. The melanin index value was significantly decreased in the lesional skin after laser treatment, while the non-lesional skin had no difference. The dendritic cells were observed at the level of the dermal-epidermal junction (DEJ) in the lesions of 8 patients before laser treatment, while after laser treatment, the dendritic cells were observed in all 25 subjects. Moreover, there was significant difference between the TEWL value of the lesions before and after laser treatment. Furthermore, the TEWL value was higher in lesions of the 8 subjects which had dendritic cells compared with other 17 subjects which had no dendritic cells, no matter before or after laser treatment. The relapse patients of melasma had higher TEWL value compared with the non-relapse patients. Melanocyte activation and skin barrier disruption may be related to the high relapse rate of melasma after laser treatment.
10.1007/s10103-018-2658-7
Protective Barriers Provided by the Epidermis.
International journal of molecular sciences
The skin is the largest organ of the body and consists of an epidermis, dermis and subcutaneous adipose tissue. The skin surface area is often stated to be about 1.8 to 2 m and represents our interface with the environment; however, when one considers that microorganisms live in the hair follicles and can enter sweat ducts, the area that interacts with this aspect of the environment becomes about 25-30 m. Although all layers of the skin, including the adipose tissue, participate in antimicrobial defense, this review will focus mainly on the role of the antimicrobial factors in the epidermis and at the skin surface. The outermost layer of the epidermis, the stratum corneum, is physically tough and chemically inert which protects against numerous environmental stresses. It provides a permeability barrier which is attributable to lipids in the intercellular spaces between the corneocytes. In addition to the permeability barrier, there is an innate antimicrobial barrier at the skin surface which involves antimicrobial lipids, peptides and proteins. The skin surface has a low surface pH and is poor in certain nutrients, which limits the range of microorganisms that can survive there. Melanin and trans-urocanic acid provide protection from UV radiation, and Langerhans cells in the epidermis are poised to monitor the local environment and to trigger an immune response as needed. Each of these protective barriers will be discussed.
10.3390/ijms24043145
The Impact of Ultraviolet Radiation on Barrier Function in Human Skin: Molecular Mechanisms and Topical Therapeutics.
Alhasaniah Abdulaziz,Sherratt Michael J,O'Neill Catherine A
Current medicinal chemistry
A competent epidermal barrier is crucial for terrestrial mammals. This barrier must keep in water and prevent entry of noxious stimuli. Most importantly, the epidermis must also be a barrier to ultraviolet radiation (UVR) from the sunlight. Currently, the effects of ultraviolet radiation on epidermal barrier function are poorly understood. However, studies in mice and more limited work in humans suggest that the epidermal barrier becomes more permeable, as measured by increased transepidermal water loss, in response UVR, at doses sufficiently high to induce erythema. The mechanisms may include disturbance in the organisation of lipids in the stratum corneum (the outermost layer of the epidermis) and reduction in tight junction function in the granular layer (the first living layer of the skin). By contrast, suberythemal doses of UVR appear to have positive effects on epidermal barrier function. Topical sunscreens have direct and indirect protective effects on the barrier through their ability to block UV and also due to their moisturising or occlusive effects, which trap water in the skin, respectively. Some topical agents such as specific botanical extracts have been shown to prevent the loss of water associated with high doses of UVR. In this review, we discuss the current literature and suggest that the biology of UVR-induced barrier dysfunction, and the use of topical products to protect the barrier, are areas worthy of further investigation.
10.2174/0929867324666171106164916
Zooming in across the Skin: A Macro-to-Molecular Panorama.
Deniz Ayşen Aslı Hızlı,Abdik Ezgi Avşar,Abdik Hüseyin,Aydın Safa,Şahin Fikrettin,Taşlı Pakize Neslihan
Advances in experimental medicine and biology
Maintaining integrity of the skin and its appendages still preserves its top-ranking in priorities of survival for the modern human as it probably once did for the ancient individual, -not only- because it is the primary barrier to external assaults, but also because of social and psychological impact of healthy skin during their life-span. Healing wounds in order to shield off the internal organs from infections and damage, restoring its ability to adapt to various environmental stimuli, and slowing-down and reversing aging of the skin in the quest for an everlasting youth can be named as a few of the main drivers behind the multi-million investments dedicated to the advancement of our understanding of skin's physiology. Over the years, these tremendous efforts culminated in the breakthrough discovery of skin stem cells the regenerative capacity of which accounted for the resilience of the skin through their unique capacity as a special cell type that can both self-renew and differentiate into various lineages. In this review, first we summarize the current knowledge on this amazing organ both at a structural and functional level. Next, we provide a comprehensive -in depth- discussion on epidermal as well as dermal stem cells in terms of the key regulatory pathways as well as the main genetic factors that have been implicated in the orchestration of the skin stem cell biology in regards to the shifts between quiescence and entry into distinct differentiation programs.
10.1007/5584_2019_442
Current Understanding of Pathophysiological Mechanisms of Atopic Dermatitis: Interactions among Skin Barrier Dysfunction, Immune Abnormalities and Pruritus.
Fujii Masanori
Biological & pharmaceutical bulletin
Atopic dermatitis (AD) is a common chronic skin disease with multiple pathogenic factors including skin barrier dysfunction, immune abnormalities, and pruritus. This review summarizes components involved in these pathogenic factors. (1) Skin barrier dysfunction in AD could be due to the down-regulation of epidermal barrier components such as filaggrin, acylceramides, cornified envelope precursors, and claudin-1. (2) T helper type 2 (Th2) cell-derived cytokines, such as interleukin (IL)-4 and IL-13, and keratinocyte-derived cytokines, such as thymic stromal lymphopoietin (TSLP) and IL-33, contribute to Th2-mediated skin inflammation in AD. (3) IL-31, TSLP, IL-4, and IL-13 are able to directly activate primary sensory neurons to induce pruritus in AD, and increased susceptibility to itch (so-called alloknesis) is partly due to epidermal hyperinnervation. Importantly, the three key factors (skin barrier dysfunction, immune abnormalities, and pruritis) interact with each other, creating a positive feedback loop that leads to the induction and maintenance of AD. Therefore, a better understanding of not only each pathogenic factor but also their interactions is important to elucidate the complex pathophysiological mechanisms of AD, which will then lead to the development of new therapeutic strategies and drugs for the treatment of this common skin disease.
10.1248/bpb.b19-00088
Effect of altered human exposome on the skin and mucosal epithelial barrier integrity.
Tissue barriers
Pollution in the world and exposure of humans and nature to toxic substances is continuously worsening at a rapid pace. In the last 60 years, human and domestic animal health has been challenged by continuous exposure to toxic substances and pollutants because of uncontrolled growth, modernization, and industrialization. More than 350,000 new chemicals have been introduced to our lives, mostly without any reasonable control of their health effects and toxicity. A plethora of studies show exposure to these harmful substances during this period with their implications on the skin and mucosal epithelial barrier and increasing prevalence of allergic and autoimmune diseases in the context of the "epithelial barrier hypothesis". Exposure to these substances causes an epithelial injury with peri-epithelial inflammation, microbial dysbiosis and bacterial translocation to sub-epithelial areas, and immune response to dysbiotic bacteria. Here, we provide scientific evidence on the altered human exposome and its impact on epithelial barriers.
10.1080/21688370.2022.2133877
The Role of MicroRNAs in Epidermal Barrier.
Lee Ai-Young
International journal of molecular sciences
MicroRNAs (miRNAs), which mostly cause target gene silencing via transcriptional repression and degradation of target mRNAs, regulate a plethora of cellular activities, such as cell growth, differentiation, development, and apoptosis. In the case of skin keratinocytes, the role of miRNA in epidermal barrier integrity has been identified. Based on the impact of key genetic and environmental factors on the integrity and maintenance of skin barrier, the association of miRNAs within epidermal cell differentiation and proliferation, cell-cell adhesion, and skin lipids is reviewed. The critical role of miRNAs in the epidermal barrier extends the use of miRNAs for control of relevant skin diseases such as atopic dermatitis, ichthyoses, and psoriasis via miRNA-based technologies. Most of the relevant miRNAs have been associated with keratinocyte differentiation and proliferation. Few studies have investigated the association of miRNAs with structural proteins of corneocytes and cornified envelopes, cell-cell adhesion, and skin lipids. Further studies investigating the association between regulatory and structural components of epidermal barrier and miRNAs are needed to elucidate the role of miRNAs in epidermal barrier integrity and their clinical implications.
10.3390/ijms21165781
Current insights into skin lipids and their roles in cutaneous health and disease.
Current opinion in clinical nutrition and metabolic care
PURPOSE OF REVIEW:The unique and complex array of cutaneous lipids include essential components of the skin structure and signalling molecules mediating homeostasis and inflammation. Understanding skin lipid biology and metabolism can support our comprehension of health and disease, including systemic conditions with cutaneous involvement. RECENT FINDINGS:Lipids found on the skin surface, produced by both the host and resident microbes, maintain and regulate the skin microbiome and the epidermal barrier, whilst altered contributions from either source can be detrimental to skin health. The unique lipid composition of the epidermal barrier is essential for its function, and recent studies have expanded our understanding of epidermal ceramide production. This has been supported by improved models available for skin research, including organotypic skin models enabling in-vitro production of complex acylceramides for the first time, and model systems facilitating in-silico exploration of the lipid profile changes observed in clinical samples. Studies have revealed further involvement of lipid mediators such as eicosanoids in cutaneous inflammation, as well as immune regulation in both healthy and diseased skin. SUMMARY:Skin lipids offer exciting opportunities as therapeutic targets for many conditions, whether through topical interventions or nutritional supplementation.
10.1097/MCO.0000000000000902
Impact of water exposure on skin barrier permeability and ultrastructure.
Ogawa-Fuse Chie,Morisaki Naoko,Shima Kyoko,Hotta Mitsuyuki,Sugata Keiichi,Ichihashi Toshiki,Oguri Masashi,Yoshida Osamu,Fujimura Tsutomu
Contact dermatitis
BACKGROUND:Skin occlusion caused by the use of diapers or sanitary napkins often results in irritant contact dermatitis. Furthermore, prolonged occlusion and exposure to body fluids are known to increase skin hydration and permeability, thus leading to irritant contact dermatitis. OBJECTIVE:To investigate the effects of water exposure on the skin and its barrier functions, in order to obtain more insights into the mechanisms of irritant contact dermatitis. METHODS:Water patches were applied to the volar forearm skin of 10 human subjects for 3 hours. Permeability of the stratum corneum (SC) was examined with methyl nicotinate (MN). Alterations in the hydration and ultrastructure of the SC were measured with Raman spectroscopy and multiphoton microscopy, respectively. RESULTS:Water profiles found with Raman spectroscopy showed notable increases in water content throughout the SC and skin surface. Multiphoton microscopy showed morphological changes in the intercellular space of the SC. Emerged pools seemed to contribute to increased MN absorption. CONCLUSION:Excessive skin hydration leading to changes in the SC ultrastructure might result in increased skin permeability to skin irritants and allergens.
10.1111/cod.13174
The atopic march: current insights into skin barrier dysfunction and epithelial cell-derived cytokines.
Han Hongwei,Roan Florence,Ziegler Steven F
Immunological reviews
Atopic dermatitis often precedes the development of other atopic diseases. The atopic march describes this temporal relationship in the natural history of atopic diseases. Although the pathophysiological mechanisms that underlie this relationship are poorly understood, epidemiological and genetic data have suggested that the skin might be an important route of sensitization to allergens. Animal models have begun to elucidate how skin barrier defects can lead to systemic allergen sensitization. Emerging data now suggest that epithelial cell-derived cytokines such as thymic stromal lymphopoietin (TSLP), IL-33, and IL-25 may drive the progression from atopic dermatitis to asthma and food allergy. This review focuses on current concepts of the role of skin barrier defects and epithelial cell-derived cytokines in the initiation and maintenance of allergic inflammation and the atopic march.
10.1111/imr.12546
In Vitro Modeling of Skin Barrier Disruption and its Recovery by Ceramide-Based Formulations.
Čuříková-Kindlová Barbora Amélie,Vovesná Aneta,Nováčková Anna,Zbytovská Jarmila
AAPS PharmSciTech
Disrupted skin barrier, one of the severe attributes of inflammatory skin diseases, is caused by lower content and pathological changes of lipids in the uppermost skin layer-stratum corneum (SC). Restoring skin barrier with native skin lipids, especially ceramides (Cers), appears to be a promising therapy with minimum side effects. For testing the efficiency of these formulations, suitable in vitro models of the skin with disrupted barriers are needed. For the similarity with the human tissue, our models were based on the pig ear skin. Three different ways of skin barrier disruption were tested and compared: tape stripping, lipid extraction with organic solvents, and barrier disruption by sodium lauryl sulfate. The level of barrier disruption was investigated by permeation studies, and parameters of each method were modified to reach significant changes between the non-disrupted skin and our model. Fourier transform infrared (FTIR) spectroscopy was employed to elucidate the changes of the skin permeability on the molecular scale. Further, the potential of the developed models to be restored by skin barrier repairing agents was evaluated by the same techniques. We observed a significant decrease in permeation characteristics through our in vitro models treated with the lipid mixtures compared to the untreated damaged skin, which implied that the skin barrier was substantially restored. Taken together, the results suggest that our in vitro models are suitable for the screening of potential barrier repairing agents.
10.1208/s12249-021-02154-z
Homeostatic Control of Sebaceous Glands by Innate Lymphoid Cells Regulates Commensal Bacteria Equilibrium.
Kobayashi Tetsuro,Voisin Benjamin,Kim Do Young,Kennedy Elizabeth A,Jo Jay-Hyun,Shih Han-Yu,Truong Amanda,Doebel Thomas,Sakamoto Keiko,Cui Chang-Yi,Schlessinger David,Moro Kazuyo,Nakae Susumu,Horiuchi Keisuke,Zhu Jinfang,Leonard Warren J,Kong Heidi H,Nagao Keisuke
Cell
Immune cells and epithelium form sophisticated barrier systems in symbiotic relationships with microbiota. Evidence suggests that immune cells can sense microbes through intact barriers, but regulation of microbial commensalism remain largely unexplored. Here, we uncovered spatial compartmentalization of skin-resident innate lymphoid cells (ILCs) and modulation of sebaceous glands by a subset of RORγt ILCs residing within hair follicles in close proximity to sebaceous glands. Their persistence in skin required IL-7 and thymic stromal lymphopoietin, and localization was dependent on the chemokine receptor CCR6. ILC subsets expressed TNF receptor ligands, which limited sebocyte growth by repressing Notch signaling pathway. Consequently, loss of ILCs resulted in sebaceous hyperplasia with increased production of antimicrobial lipids and restricted commensalism of Gram-positive bacterial communities. Thus, epithelia-derived signals maintain skin-resident ILCs that regulate microbial commensalism through sebaceous gland-mediated tuning of the barrier surface, highlighting an immune-epithelia circuitry that facilitates host-microbe symbiosis.
10.1016/j.cell.2018.12.031
Are the Cutaneous Microbiota a Guardian of the Skin's Physical Barrier? The Intricate Relationship between Skin Microbes and Barrier Integrity.
International journal of molecular sciences
The skin is a tightly regulated, balanced interface that maintains our integrity through a complex barrier comprising physical or mechanical, chemical, microbiological, and immunological components. The skin's microbiota affect various properties, one of which is the establishment and maintenance of the physical barrier. This is achieved by influencing multiple processes, including keratinocyte differentiation, stratum corneum formation, and regulation of intercellular contacts. In this review, we summarize the potential contribution of to these events and outline the contribution of bacterially induced barrier defects to the pathogenesis of acne vulgaris. With the combined effects of a Westernized lifestyle, microbial dysbiosis, epithelial barrier defects, and inflammation, the development of acne is very similar to that of several other multifactorial diseases of barrier organs (e.g., inflammatory bowel disease, celiac disease, asthma, atopic dermatitis, and chronic rhinosinusitis). Therefore, the management of acne requires a complex approach, which should be taken into account when designing novel treatments that address not only the inflammatory and microbial components but also the maintenance and strengthening of the cutaneous physical barrier.
10.3390/ijms242115962
Skin-associated adipocytes in skin barrier immunity: A mini-review.
Frontiers in immunology
The skin contributes critically to health its role as a barrier tissue against a multitude of external pathogens. The barrier function of the skin largely depends on the uppermost epidermal layer which is reinforced by skin barrier immunity. The integrity and effectiveness of skin barrier immunity strongly depends on the close interplay and communication between immune cells and the skin environment. Skin-associated adipocytes have been recognized to play a significant role in modulating skin immune responses and infection by secreting cytokines, adipokines, and antimicrobial peptides. This review summarizes the recent understanding of the interactions between skin-associated adipocytes and other skin cells in maintaining the integrity and effectiveness of skin barrier immunity.
10.3389/fimmu.2023.1116548
Melatonin, mitochondria, and the skin.
Slominski Andrzej T,Zmijewski Michal A,Semak Igor,Kim Tae-Kang,Janjetovic Zorica,Slominski Radomir M,Zmijewski Jaroslaw W
Cellular and molecular life sciences : CMLS
The skin being a protective barrier between external and internal (body) environments has the sensory and adaptive capacity to maintain local and global body homeostasis in response to noxious factors. An important part of the skin response to stress is its ability for melatonin synthesis and subsequent metabolism through the indolic and kynuric pathways. Indeed, melatonin and its metabolites have emerged as indispensable for physiological skin functions and for effective protection of a cutaneous homeostasis from hostile environmental factors. Moreover, they attenuate the pathological processes including carcinogenesis and other hyperproliferative/inflammatory conditions. Interestingly, mitochondria appear to be a central hub of melatonin metabolism in the skin cells. Furthermore, substantial evidence has accumulated on the protective role of the melatonin against ultraviolet radiation and the attendant mitochondrial dysfunction. Melatonin and its metabolites appear to have a modulatory impact on mitochondrion redox and bioenergetic homeostasis, as well as the anti-apoptotic effects. Of note, some metabolites exhibit even greater impact than melatonin alone. Herein, we emphasize that melatonin-mitochondria axis would control integumental functions designed to protect local and perhaps global homeostasis. Given the phylogenetic origin and primordial actions of melatonin, we propose that the melatonin-related mitochondrial functions represent an evolutionary conserved mechanism involved in cellular adaptive response to skin injury and repair.
10.1007/s00018-017-2617-7
The Proteome of Hand Eczema Assessed by Tape Stripping.
The Journal of investigative dermatology
Hand eczema (HE) is a prevalent skin disease. However, the classification of HE into different subtypes remains challenging. A limited number of previous studies have employed invasive biopsy-based strategies; yet, studies of the HE proteome using noninvasive tape-stripping methodology have not been reported. In this study, we wanted to assess whether global proteomic analysis of skin tape strip samples can be used for subclassification of patients with HE. Tape strips were collected from patients with HE and healthy skin. Liquid chromatography-mass spectrometry proteomics was performed, and the global protein expression was analyzed. We identified 2,919 proteins in stratum corneum-derived skin cells from tape strip samples. Compared with healthy skin, the lesional samples from patients with HE exhibited increased expression of immune-related markers and a decreased expression of structural barrier proteins. The difference between HE subtypes was restricted to the lesional skin areas and included an increased expression of skin barrier-related proteins independently of the concurrent AD. In conclusion, we found that the noninvasive tape strip method used in combination with liquid chromatography-mass spectrometry proteomics can be used for analysis of skin protein expression in patients with HE. Thus, the method shows potential for assessing the proteomic differences between subtypes of HE and biomarker discovery.
10.1016/j.jid.2022.12.024
Skin barrier damaging and repairing process: A new application field of dermoscopy.
Ye CongXiu,Yi JinLing,Lai Wei,Zheng Yue
Journal of cosmetic dermatology
BACKGROUND:Although more and more noninvasive detection technologies have been used in assessing skin barrier integrity and functions, more accurate, intuitive, and convenient detective methods still needed to be explored and developed. AIMS:To investigate the characteristic image changes under the dermoscopy and to explore the relationship with skin physiological indexes in skin barrier damaging and repairing process. PATIENTS/METHODS:25 healthy subjects with normal skin in forearm were included and divided into different groups according to the operated strips numbers (30, 35, and 40 times). Before tape stripping, and immediately, 3, 7, 14, and 21 days after tape stripping, dermoscopic examination and skin transepidermal water loss (TEWL), surface hydration, and L*a*b* value were simultaneously tested in the same region. RESULTS:Immediately after different times tape stripping, the amount of cuticle cells residues and the microvascular images were different. In skin barrier repairing process, the scab forming time observed under dermoscopy was day 14, day 7, and day 3 on 30 times, 35 times, and 40 times stripped skin, respectively. A small amount of cuticle cells and blurry vessels could be identified in hydration value <40 group, while there was no cuticle cell residue, and the branching vessels were obvious in hydration value >40 group. CONCLUSIONS:Unique manifestations could be observed under dermoscopy in different time points of skin barrier with various degree of injury and in skin barrier repairing process. By combining dermoscopy and skin indexes assessing technologies, the skin barrier integrity and function could be observed and evaluated more accurately and precisely.
10.1111/jocd.13643
The Skin's Barrier: A Cryo-EM Based Overview of its Architecture and Stepwise Formation.
Norlén Lars,Lundborg Magnus,Wennberg Christian,Narangifard Ali,Daneholt Bertil
The Journal of investigative dermatology
A major role of the skin is to serve as a barrier toward the environment. The skin's permeability barrier consists of a lipid structure positioned in the stratum corneum. Recent progress in high-resolution cryo-electron microscopy (cryo-EM) has allowed for elucidation of the architecture of the skin's barrier and its stepwise formation process representing the final stage of epidermal differentiation. In this review, we present an overview of the skin's barrier structure and its formation process, as evidenced by cryo-EM.
10.1016/j.jid.2021.06.037
Profile of skin barrier proteins and cytokines in adults with atopic dermatitis.
Orfali Raquel L,Zaniboni Mariana C,Aoki Valeria
Giornale italiano di dermatologia e venereologia : organo ufficiale, Societa italiana di dermatologia e sifilografia
Atopic dermatitis (AD), an inflammatory skin disorder with chronic course and characterized by intense pruritus, is a dermatosis of high prevalence of childhood. However, persistence of the disease in adolescents and adults may occur, and more studies regarding the interactions of the complex triggering factors, especially between the adaptive and innate immune alterations and skin barrier defects are needed. In this review the authors summarize the major novel findings of a dysfunctional skin barrier in AD, with emphasis on tight junction components, such as claudins and on proteins of the keratinocyte differentiation, such as filaggrin. This review also provides an update on the characterization of immune response in adults with atopic dermatitis. The adaptive immune dysfunction in AD, classically known as a Th2/Th1 model, has changed its profile, with recent reported cytokines such as interleukins 17, 22, and 31; as for the innate immune system scenario in AD, the characterization of skin microbiome opens new frontiers for the understanding of such a complex inflammatory disease.
10.23736/S0392-0488.16.05533-4
Skin Barrier and Autoimmunity-Mechanisms and Novel Therapeutic Approaches for Autoimmune Blistering Diseases of the Skin.
Stevens Natalie E,Cowin Allison J,Kopecki Zlatko
Frontiers in immunology
One of the most important functions of the skin besides regulating internal body temperature includes formation of the barrier between the organism and the external environment, hence protecting against pathogen invasion, chemical and physical assaults and unregulated loss of water and solutes. Disruption of the protective barrier is observed clinically in blisters and erosions of the skin that form in autoimmune blistering diseases where the body produces autoantibodies against structural proteins of the epidermis or the epidermal-dermal junction. Although there is no cure for autoimmune skin blistering diseases, immune suppressive therapies currently available offer opportunities for disease management. In cases where no treatment is sought, these disorders can lead to life threatening complications and current research efforts have focused on developing therapies that target autoantibodies which contribute to disease symptoms. This review will outline the involvement of the skin barrier in main skin-specific autoimmune blistering diseases by describing the mechanisms underpinning skin autoimmunity and review current progress in development of novel therapeutic approaches targeting the underlying causes of autoimmune skin blistering diseases.
10.3389/fimmu.2019.01089
Vitamin C-squalene bioconjugate promotes epidermal thickening and collagen production in human skin.
Gref R,Deloménie C,Maksimenko A,Gouadon E,Percoco G,Lati E,Desmaële D,Zouhiri F,Couvreur P
Scientific reports
Vitamin C (Vit C) benefits to human skin physiology notably by stimulating the biosynthesis of collagen. The main cutaneous collagens are types I and III, which are less synthesized with aging. Vit C is one of the main promotors of collagen formation but it poorly bypasses the epidermis stratum corneum barrier. To address this challenge, we developed a lipophilic version of Vit C for improving skin diffusion and delivery. Vit C was covalently conjugated to squalene (SQ), a natural lipid of the skin, forming a novel Vit C-SQ derivative suitable for cream formulation. Its biological activity was investigated on human whole skin explants in an ex vivo model, through histology and protein and gene expression analyses. Results were compared to Vit C coupled to the reference lipophilic compound palmitic acid, (Vit C-Palmitate). It was observed that Vit C-SQ significantly increased epidermal thickness and preferentially favored collagen III production in human skin after application for 10 days. It also promoted glycosaminoglycans production in a higher extent comparatively to Vit C-Palmitate and free Vit C. Microdissection of the explants to separate dermis and epidermis allowed to measure higher transcriptional effects either in epidermis or in dermis. Among the formulations studied, the strongest effects were observed with Vit C-SQ.
10.1038/s41598-020-72704-1
Peptide-containing nanoformulations: Skin barrier penetration and activity contribution.
Advanced drug delivery reviews
Transdermal drug delivery presents a less invasive pathway, circumventing the need to pass through the gastrointestinal tract and liver, thereby reducing drug breakdown, initial metabolism, and gastrointestinal discomfort. Nevertheless, the unique composition and dense structure of the stratum corneum present a significant barrier to transdermal delivery. This article presents an overview of the current developments in peptides and nanotechnology to address this challenge. Initially, we sum up peptide-containing nanoformulations for transdermal drug delivery, examining them through the lenses of both inorganic and organic materials. Particular emphasis is placed on the diverse roles that peptides play within these nanoformulations, including conferring functionality upon nanocarriers and enhancing the biological efficacy of drugs. Subsequently, we summarize innovative strategies for enhancing skin penetration, categorizing them into passive and active approaches. Lastly, we discuss the therapeutic potential of peptide-containing nanoformulations in addressing a range of diseases, drawing insights from the biological activities and functions of peptides. Furthermore, the challenges hindering clinical translation are also discussed, providing valuable insights for future advancements in transdermal drug delivery.
10.1016/j.addr.2023.115139
Staphylococcus aureus and Atopic Dermatitis: A Complex and Evolving Relationship.
Geoghegan Joan A,Irvine Alan D,Foster Timothy J
Trends in microbiology
Staphylococcus aureus is frequently isolated from the skin of atopic dermatitis (AD) patients during flares. The normal microbiota is disrupted and the diversity of the microorganisms on the skin is reduced. Many species that produce inhibitors of S. aureus growth decline. Strains from S. aureus clonal complex 1 are enriched among AD sufferers whereas the CC30 strains most frequently isolated from nasal carriers in the normal population are much rarer in AD. S. aureus expresses several molecules that contribute to the intensity of symptoms, including δ-toxin which stimulates mast cells, α-toxin which damages keratinocytes, phenol-soluble modulins which stimulate cytokine release by keratinocytes, protein A which triggers inflammatory responses from keratinocytes, superantigens which trigger B cell expansion and cytokine release, and proinflammatory lipoproteins. Proteases contribute to disruption of the epidermal barrier. S. aureus isolated from AD patients adheres to the deformed corneocytes from AD patients in a clumping factor B-dependent fashion. Novel targeted therapies for AD have recently been introduced to clinical practice with many more in development, including monoclonal antibodies that specifically target cytokines and their receptors, and a bacteriophage lysin that eliminates S. aureus from AD skin.
10.1016/j.tim.2017.11.008
The impact of dupilumab on skin barrier function: A systematic review.
Journal of the European Academy of Dermatology and Venereology : JEADV
Skin barrier dysfunction plays an important role in atopic dermatitis (AD) aetiopathogenesis. Dupilumab, a drug that inhibits IL-4 and IL-13, is an effective treatment for AD but there is scarce evidence about its impact on epidermal barrier. The objective of this systematic review is to evaluate the influence of dupilumab on skin barrier in patients with AD using non-invasive tools. A systematic review was designed following PRISMA guidelines. The literature search identified 73 references and, finally, only 6 were selected, including a total of 233 participants. All the studies were prospective observational studies. Dupilumab improved clinical scores in all the research. Skin barrier function parameters were mainly measured on the volar forearm. Transepidermal water loss (TEWL) was the parameter most frequently measured, evaluated in all the studies. Dupilumab decreased TEWL on eczematous lesions and non-involved skin. About 33.6% (2/6) studies reported that dupilumab also increased stratum corneum hydration (SCH) on eczematous lesions while one study did not report any changes in this parameter. This drug also decreased temperature and improved ceramide composition. In conclusion, dupilumab improved skin barrier function in AD patients, mainly reflected in a decreased in TEWL values.
10.1111/jdv.19081
Molecular insights of human skin epidermal and dermal aging.
Journal of dermatological science
Human skin is the most widespread and abundant type of tissue in the human body. With the passage of time, most of our organs, including a substantial part of the skin, tend to undergo a gradual thinning or decrease in size. As we age, there is a gradual and progressive reduction in the thickness of both the epidermis and dermis layers of our skin. This is primarily attributed to the decline of epidermal stem cells and the loss of dermal collagen, which is the most abundant protein in the human body. Age-related alterations of the epidermis and dermis impair skin structure/function and create a tissue microenvironment that promotes age-related skin diseases, such as impaired skin barrier, delayed wound healing, and skin cancer development. This review will examine the current body of literature pertaining to our knowledge of skin epidermal and dermal aging.
10.1016/j.jdermsci.2023.08.006
Overcoming skin barriers through advanced transdermal drug delivery approaches.
Journal of controlled release : official journal of the Controlled Release Society
Upon exhaustive research, the transdermal drug delivery system (TDDS) has appeared as a potential, well-accepted, and popular approach to a novel drug delivery system. Ease of administration, easy handling, minimum systemic exposure, least discomfort, broad flexibility and tunability, controlled release, prolonged therapeutic effect, and many more perks make it a promising approach for effective drug delivery. Although, the primary challenge associated is poor skin permeability. Skin is an intact barrier that serves as a primary defense mechanism to preclude any foreign particle's entry into the body. Owing to the unique anatomical framework, i.e., compact packing of stratum corneum with tight junction and fast anti-inflammatory responses, etc., emerged as a critical physiological barrier for TDDS. Fusion with other novel approaches like nanocarriers, specially designed transdermal delivery devices, permeation enhancers, etc., can overcome the limitations. Utilizing such strategies, some of the products are under clinical trials, and many are under investigation. This review explores all dimensions that overcome poor permeability and allows the drug to attain maximum potential. The article initially compiles fundamental features, components, and design of TDDS, followed by critical aspects and various methods, including in vitro, ex vivo, and in vivo methods of assessing skin permeability. The work primarily aimed to highlight the recent advancement in novel strategies for effective transdermal drug delivery utilizing active methods like iontophoresis, electroporation, sonophoresis, microneedle, needleless jet injection, etc., and passive methods such as the use of liposomes, SLN, NLC, micro/nanoemulsions, dendrimers, transferosomes, and many more nanocarriers. In all, this compilation will provide a recent insight on the novel updates along with basic concepts, the current status of clinical development, and challenges for the clinical translation of TDDS.
10.1016/j.jconrel.2022.09.025
The epidermal lipid barrier in microbiome-skin interaction.
Trends in microbiology
The corneocyte layers forming the upper surface of mammalian skin are embedded in a lamellar-membrane matrix which repels harmful molecules while retaining solutes from subcutaneous tissues. Only certain bacterial and fungal taxa colonize skin surfaces. They have ways to use epidermal lipids as nutrients while resisting antimicrobial fatty acids. Skin microorganisms release lipophilic microbe-associated molecular pattern (MAMP) molecules which are largely retained by the epidermal lipid barrier. Skin barrier defects, as in atopic dermatitis, impair lamellar-membrane integrity, resulting in altered skin microbiomes, which then include the pathogen Staphylococcus aureus. The resulting increased penetration of MAMPs and toxins promotes skin inflammation. Elucidating how microorganisms manipulate the epidermal lipid barrier will be key for better ways of preventing inflammatory skin disorders.
10.1016/j.tim.2023.01.009
Bioengineering the microanatomy of human skin.
Journal of anatomy
Recreating the structure of human tissues in the laboratory is valuable for fundamental research, testing interventions, and reducing the use of animals. Critical to the use of such technology is the ability to produce tissue models that accurately reproduce the microanatomy of the native tissue. Current artificial cell-based skin systems lack thorough characterisation, are not representative of human skin, and can show variation. In this study, we have developed a novel full thickness model of human skin comprised of epidermal and dermal compartments. Using an inert porous scaffold, we created a dermal construct using human fibroblasts that secrete their own extracellular matrix proteins, which avoids the use of animal-derived materials. The dermal construct acts as a foundation upon which epidermal keratinocytes were seeded and differentiated into a stratified keratinised epithelium. In-depth morphological analyses of the model demonstrated very close similarities with native human skin. Extensive immunostaining and electron microscopy analysis revealed ultrastructural details such as keratohyalin granules and lamellar bodies within the stratum granulosum, specialised junctional complexes, and the presence of a basal lamina. These features reflect the functional characteristics and barrier properties of the skin equivalent. Robustness and reproducibility of in vitro models are important attributes in experimental practice, and we demonstrate the consistency of the skin construct between different users. In summary, a new model of full thickness human skin has been developed that possesses microanatomical features reminiscent of native tissue. This skin model platform will be of significant interest to scientists researching the structure and function of human skin.
10.1111/joa.12942
Mesenchymal Stem/Stromal Cell-Derived Exosomes for Immunomodulatory Therapeutics and Skin Regeneration.
Cells
Exosomes are nano-sized vesicles that serve as mediators for cell-to-cell communication. With their unique nucleic acids, proteins, and lipids cargo compositions that reflect the characteristics of producer cells, exosomes can be utilized as cell-free therapeutics. Among exosomes derived from various cellular origins, mesenchymal stem cell-derived exosomes (MSC-exosomes) have gained great attention due to their immunomodulatory and regenerative functions. Indeed, many studies have shown anti-inflammatory, anti-aging and wound healing effects of MSC-exosomes in various in vitro and in vivo models. In addition, recent advances in the field of exosome biology have enabled development of specific guidelines and quality control methods, which will ultimately lead to clinical application of exosomes. This review highlights recent studies that investigate therapeutic potential of MSC-exosomes and relevant mode of actions for skin diseases, as well as quality control measures required for development of exosome-derived therapeutics.
10.3390/cells9051157
Commensal Staphylococcus epidermidis contributes to skin barrier homeostasis by generating protective ceramides.
Cell host & microbe
Previously either regarded as insignificant or feared as potential sources of infection, the bacteria living on our skin are increasingly recognized for their role in benefitting human health. Skin commensals modulate mucosal immune defenses and directly interfere with pathogens; however, their contribution to the skin's physical integrity is less understood. Here, we show that the abundant skin commensal Staphylococcus epidermidis contributes to skin barrier integrity. S. epidermidis secretes a sphingomyelinase that acquires essential nutrients for the bacteria and assists the host in producing ceramides, the main constituent of the epithelial barrier that averts skin dehydration and aging. In mouse models, S. epidermidis significantly increases skin ceramide levels and prevents water loss of damaged skin in a fashion entirely dependent on its sphingomyelinase. Our findings reveal a symbiotic mechanism that demonstrates an important role of the skin microbiota in the maintenance of the skin's protective barrier.
10.1016/j.chom.2022.01.004
Role of Antimicrobial Peptides in Skin Barrier Repair in Individuals with Atopic Dermatitis.
Nguyen Hai Le Thanh,Trujillo-Paez Juan Valentin,Umehara Yoshie,Yue Hainan,Peng Ge,Kiatsurayanon Chanisa,Chieosilapatham Panjit,Song Pu,Okumura Ko,Ogawa Hideoki,Ikeda Shigaku,Niyonsaba François
International journal of molecular sciences
Atopic dermatitis (AD) is a common chronic inflammatory skin disease that exhibits a complex interplay of skin barrier disruption and immune dysregulation. Patients with AD are susceptible to cutaneous infections that may progress to complications, including staphylococcal septicemia. Although most studies have focused on filaggrin mutations, the physical barrier and antimicrobial barrier also play critical roles in the pathogenesis of AD. Within the physical barrier, the stratum corneum and tight junctions play the most important roles. The tight junction barrier is involved in the pathogenesis of AD, as structural and functional defects in tight junctions not only disrupt the physical barrier but also contribute to immunological impairments. Furthermore, antimicrobial peptides, such as LL-37, human b-defensins, and S100A7, improve tight junction barrier function. Recent studies elucidating the pathogenesis of AD have led to the development of barrier repair therapy for skin barrier defects in patients with this disease. This review analyzes the association between skin barrier disruption in patients with AD and antimicrobial peptides to determine the effect of these peptides on skin barrier repair and to consider employing antimicrobial peptides in barrier repair strategies as an additional approach for AD management.
10.3390/ijms21207607
[Functional integrity of aging skin, from cutaneous biology to anti-aging strategies].
Rorteau Julie,Chevalier Fabien P,Fromy Bérengère,Lamartine Jérôme
Medecine sciences : M/S
The skin is a sentinel organ making easily visible the passing of time. Chronological and environmental aging weakens skin structure and functions. The skin barrier, the elastic and mechanical properties of the cutaneous tissue as well as its vascular reactivity are impacted by aging. The barrier dysfunction in aged skin is caused by defects in epidermal keratinocytes renewal and differentiation notably linked to abnormal expression of microRNAs regulating cell death and autophagy. An abnormal balance between synthesis and degradation of matrix proteins modifies the mechanical properties of the dermis in aged skin. Finally, a reduction of the vascular reactivity linked to endothelial dysfunctions is observed in elderly people. These biological processes can be targeted by therapeutic approaches either topical or systemic, especially using anti-oxydants or senolytics. These anti-aging strategies might contribute to restore, at least in part, the functional integrity of aged skin.
10.1051/medsci/2020223
The Roles of Vitamin C in Skin Health.
Nutrients
The primary function of the skin is to act as a barrier against insults from the environment, and its unique structure reflects this. The skin is composed of two layers: the epidermal outer layer is highly cellular and provides the barrier function, and the inner dermal layer ensures strength and elasticity and gives nutritional support to the epidermis. Normal skin contains high concentrations of vitamin C, which supports important and well-known functions, stimulating collagen synthesis and assisting in antioxidant protection against UV-induced photodamage. This knowledge is often used as a rationale for the addition of vitamin C to topical applications, but the efficacy of such treatment, as opposed to optimising dietary vitamin C intake, is poorly understood. This review discusses the potential roles for vitamin C in skin health and summarises the in vitro and in vivo research to date. We compare the efficacy of nutritional intake of vitamin C versus topical application, identify the areas where lack of evidence limits our understanding of the potential benefits of vitamin C on skin health, and suggest which skin properties are most likely to benefit from improved nutritional vitamin C intake.
10.3390/nu9080866
The Epidermal Barrier Structure and Function of Re-Harvested Skin from Non-Scalp Donor Sites.
Journal of investigative surgery : the official journal of the Academy of Surgical Research
AIM:The aim of this study was to explore the epidermal barrier structure and function of re-harvested skin from non-scalp donor sites. METHODS:Six patients with large-area deep burns who met the inclusion and exclusion criteria were subjected to split-thickness skin excision three times on the same healthy non-scalp donor sites, with an interval of 14 days. The donor skin thus harvested was labeled as primary skin (S1), secondary skin (S2), and tertiary skin (S3). The transepidermal water loss (TEWL) and stratum corneum water content (SCH) of donor skin were detected before each surgery, and the donor skin was harvested during the surgery. The donor skin was stained with hematoxylin and eosin (HE) and involucrin, loricrin, filaggrin, small molecule proline-rich protein 3 (SPRR3), ZO-3, JAM-A, and JAM-C, or observed by transmission electron microscopy. RESULTS:The epidermal barrier function of the re-harvested skin from the non-scalp donor sites became impaired. The histopathological structure of the re-harvested skin from non-scalp donor sites became abnormal. The barrier of the epidermal stratum corneum of the re-harvested skin from non-scalp donor sites was damaged. The epidermal tight junction barrier in the re-harvested skin from non-scalp donor sites was damaged. CONCLUSIONS:As the number of harvesting increases, the epidermal barrier function of the skin decreased, and the damage to the barrier structure increased. Hence, it is vitally important to restore the epidermal barrier function for re-harvesting in non-scalp donor sites.
10.1080/08941939.2022.2146318
Natural Oils for Skin-Barrier Repair: Ancient Compounds Now Backed by Modern Science.
Vaughn Alexandra R,Clark Ashley K,Sivamani Raja K,Shi Vivian Y
American journal of clinical dermatology
Natural plant oils are commonly used as topical therapy worldwide. They are usually easily accessible and are relatively inexpensive options for skin care. Many natural oils possess specific compounds with antimicrobial, antioxidant, anti-inflammatory, and anti-itch properties, making them attractive alternative and complementary treatments for xerotic and inflammatory dermatoses associated with skin-barrier disruption. Unique characteristics of various oils are important when considering their use for topical skin care. Differing ratios of essential fatty acids are major determinants of the barrier repair benefits of natural oils. Oils with a higher linoleic acid to oleic acid ratio have better barrier repair potential, whereas oils with higher amounts of irritating oleic acid may be detrimental to skin-barrier function. Various extraction methods for oils exist, including cold pressing to make unrefined oils, heat and chemical distillation to make essential oils, and the addition of various chemicals to simulate a specific scent to make fragranced oils. The method of oil processing and refinement is an important component of selecting oil for skin care, and cold pressing is the preferred method of oil extraction as the heat- and chemical-free process preserves beneficial lipids and limits irritating byproducts. This review summarizes evidence on utility of natural plant-based oils in dermatology, particularly in repairing the natural skin-barrier function, with the focus on natural oils, including Olea europaea (olive oil), Helianthus annus (sunflower seed oil), Cocos nucifera (coconut oil), Simmondsia chinesis (jojoba oil), Avena sativa (oat oil), and Argania spinosa (argan oil).
10.1007/s40257-017-0301-1
Environmental factors in epithelial barrier dysfunction.
Celebi Sözener Zeynep,Cevhertas Lacin,Nadeau Kari,Akdis Mübeccel,Akdis Cezmi A
The Journal of allergy and clinical immunology
The main interfaces controlling and attempting to homeostatically balance communications between the host and the environment are the epithelial barriers of the skin, gastrointestinal system, and airways. The epithelial barrier constitutes the first line of physical, chemical, and immunologic defenses and provides a protective wall against environmental factors. Following the industrial revolution in the 19th century, urbanization and socioeconomic development have led to an increase in energy consumption, and waste discharge, leading to increased exposure to air pollution and chemical hazards. Particularly after the 1960s, biological and chemical insults from the surrounding environment-the exposome-have been disrupting the physical integrity of the barrier by degrading the intercellular barrier proteins at tight and adherens junctions, triggering epithelial alarmin cytokine responses such as IL-25, IL-33, and thymic stromal lymphopoietin, and increasing the epithelial barrier permeability. A typical type 2 immune response develops in affected organs in asthma, rhinitis, chronic rhinosinusitis, eosinophilic esophagitis, food allergy, and atopic dermatitis. The aim of this article was to discuss the effects of environmental factors such as protease enzymes of allergens, detergents, tobacco, ozone, particulate matter, diesel exhaust, nanoparticles, and microplastic on the integrity of the epithelial barriers in the context of epithelial barrier hypothesis.
10.1016/j.jaci.2020.04.024
pH in nature, humans and skin.
Proksch Ehrhardt
The Journal of dermatology
The pH plays an important physiological role in nature and humans. pH varies from 1 to 8 in human organs with tight regulation in blood and epithelia of barrier organs. The physiological pH of the stratum corneum is 4.1-5.8 and several mechanisms contribute to its formation: filaggrin degradation, fatty acid content, sodium-hydrogen exchanger (NHE1) activation and melanosome release. First, the acidic pH of the stratum corneum was considered to present an antimicrobial barrier preventing colonization (e.g. by Staphylococcus aureus and Malassezia). Later on, it was found that the pH influences skin barrier function, lipid synthesis and aggregation, epidermal differentiation and desquamation. Enzymes of ceramide metabolism (e.g. β-glucocerebrosidase or acid sphingomyelinase) as well as proteases (e.g. chymotryptic enzyme or cathepsin D linked to epidermal differentiation and desquamation) are regulated by the pH. Experimental disruption of the physical barrier leads to an increase of pH, returning to normal levels only after many hours. Inflammatory skin diseases and diseases with an involvement of the epidermis exhibit a disturbed skin barrier and an increased pH. This is known for atopic dermatitis, irritant contact dermatitis, ichthyosis, rosacea and acne, but also for aged and dry skin. Normalizing the pH by acidification through topical treatment helps to establish a physiological microbiota, to repair skin barrier, to induce epidermal differentiation and to reduce inflammation.
10.1111/1346-8138.14489
Topical urea in skincare: A review.
Celleno Leonardo
Dermatologic therapy
Alterations in barrier function are associated with a number of skin diseases, including xerosis, atopic dermatitis, and psoriasis. Urea, a component of the natural moisturizing factor of the skin, plays an important role in the preservation of skin hydration and integrity. Several studies have investigated the effects of urea in the clinical setting. Here, we summarize the available clinical evidence regarding the effects of urea in the maintenance of healthy skin and management of skin disorders. At lower doses (≤10%), urea-containing topical formulations act as a skin moisturizer, while at higher concentrations (>10% urea), urea-based preparations exert a keratolytic action. Urea is also useful in combination therapies with anti-inflammatory and anti-fungal drugs, due to its activity as a penetration enhancer.
10.1111/dth.12690
Skin and Its Regenerative Powers: An Alliance between Stem Cells and Their Niche.
Gonzales Kevin Andrew Uy,Fuchs Elaine
Developmental cell
Tissues have a natural capacity to replace dying cells and to heal wounds. This ability resides in resident stem cells, which self-renew, preserve, and repair their tissue during homeostasis and following injury. The skin epidermis and its appendages are subjected to daily assaults from the external environment. A high demand is placed on renewal and regeneration of the skin's barrier in order to protect the body from infection and dehydration and to heal wounds. This review focuses on the epithelial stem cells of skin, where they come from, where they reside, and how they function in normal homeostasis and wound repair.
10.1016/j.devcel.2017.10.001
Neuronal Regulation of Immunity in the Skin and Lungs.
Blake Kimbria J,Jiang Xin Ru,Chiu Isaac M
Trends in neurosciences
The nervous and immune systems are classically studied as two separate entities. However, their interactions are crucial for maintaining barrier functions at tissues constantly exposed to the external environment. We focus here on the role of neuronal signaling in regulating the immune system at two major barriers: the skin and respiratory tract. Barrier tissues are heavily innervated by sensory and autonomic nerves, and are densely populated by resident immune cells, allowing rapid, coordinated responses to noxious stimuli, as well as to bacterial and fungal pathogens. Neural release of neurotransmitters and neuropeptides allows fast communication with immune cells and their recruitment. In addition to maintaining homeostasis and fighting infections, neuroimmune interactions are also implicated in several chronic inflammatory conditions such as atopic dermatitis (AD), chronic obstructive pulmonary disease (COPD), and asthma.
10.1016/j.tins.2019.05.005
The Dynamics of the Skin's Immune System.
Nguyen Alan V,Soulika Athena M
International journal of molecular sciences
The skin is a complex organ that has devised numerous strategies, such as physical, chemical, and microbiological barriers, to protect the host from external insults. In addition, the skin contains an intricate network of immune cells resident to the tissue, crucial for host defense as well as tissue homeostasis. In the event of an insult, the skin-resident immune cells are crucial not only for prevention of infection but also for tissue reconstruction. Deregulation of immune responses often leads to impaired healing and poor tissue restoration and function. In this review, we will discuss the defensive components of the skin and focus on the function of skin-resident immune cells in homeostasis and their role in wound healing.
10.3390/ijms20081811
Skin lipids in health and disease: A review.
Knox Sophie,O'Boyle Niamh M
Chemistry and physics of lipids
Our skin is the interface between us and our environment - a flexible barrier that has evolved for protection, immunity, regulation and sensation. Once regarded as inert, we now know that it is a dynamic environment. Skin lipids are crucial to the structure and function of skin. From deep in the hypodermis, through the ceramide-rich epidermis, to the lipids of the skin surface, there are a vast array of different lipids with important roles to play. This review firstly discusses the lipid composition of human skin and secondly, changes that have been found in skin lipid composition in different skin diseases. Further research into skin lipids facilitated by ever-improving methodologies will no doubt generate new knowledge, paving the way for diagnosis, prevention and treatment of skin disorders and diseases.
10.1016/j.chemphyslip.2021.105055
Epidermal biomarkers of the skin barrier in atopic and contact dermatitis.
Contact dermatitis
Dysfunction of the skin barrier plays a critical role in the initiation and progression of inflammatory skin diseases, such as atopic dermatitis and contact dermatitis. Epidermal biomarkers can aid in evaluating the functionality of the skin barrier and understanding the mechanisms that underlay its impairment. This narrative review provides an overview of recent studies on epidermal biomarkers associated with the function and integrity of the skin barrier, and their application in research on atopic dermatitis and contact dermatitis. The reviewed studies encompass a wide spectrum of molecular, morphological and biophysical biomarkers, mainly obtained from stratum corneum tape strips and biopsies. Lipids, natural moisturizing factors, and structural proteins are the most frequently reported molecular biomarkers. Additionally, corneocyte surface topography and elasticity show potential as biomarkers for assessing the physical barrier of the skin. In contact dermatitis studies, biomarkers are commonly employed to evaluate skin irritation and differentiate between irritant and allergic contact dermatitis. In atopic dermatitis, biomarkers are primarily utilized to identify differences between atopic and healthy skin, for predictive purposes, and monitoring response to therapies. While this overview identifies potential biomarkers for the skin barrier, their validation as epidermal biomarkers for atopic dermatitis and contact dermatitis has yet to be established.
10.1111/cod.14391
The Relation of pH and Skin Cleansing.
Blaak Jürgen,Staib Peter
Current problems in dermatology
Several epidermal barrier functions, like skin barrier regeneration and antimicrobial response, are related to the acidic nature of the skin surface pH (ss-pH). However, the epidermal acidification is known to be fragile and it is commonly accepted that cosmetic products, especially soaps and skin cleansing products, can induce significant changes in ss-pH. As a consequence, epidermal barrier function and skin microflora are affected negatively. ss-pH even increases after a single washing procedure or after rinsing the skin with water alone. The skin pH recovery needs time up to several hours before it can reach the physiological level. For cosmetic-relevant skin conditions, skin disorders and specific consumer groups, maintaining of the acidic ss-pH is beneficial for epidermal physiology and cutaneous microflora. In this context, cleansing and skin care products with a pH level of 4.0-5.0 may be helpful. In addition, combining the acidic product pH level with the ideal mix of surfactants, thereby enhancing product compatibility and minimizing skin irritation and intolerance, is a major challenge for the future. Beyond innovative cleansing technology, further multifaceted cosmetic research is a prerequisite to get deeper knowledge on the interrelation of product pH level, surfactant composition and corneobiology.
10.1159/000489527
Aging of the skin barrier.
Choi Eung Ho
Clinics in dermatology
The skin barrier is mainly present in the stratum corneum (SC), composed of corneocytes surrounded by intercellular lipid lamellae, and attached by corneodesmosome. The tight junction attached to the lateral walls of keratinocytes in the upper part of the stratum granulosum is also included in the skin barrier. During aging, the following structures and functions of the skin barrier are changed or disturbed: (1) skin barrier structure, (2) permeability barrier function, (3) epidermal calcium gradient, (4) epidermal lipid synthesis and SC lipid processing, (5) cytokine production and response after insults, (6) SC acidity, (7) SC hydration, and (8) antimicrobial barrier. Patients with diabetes also show changes in the skin barrier similar to those in aged skin, and the characteristics of the skin barrier are very similar. Understanding the pathogenic mechanisms of the skin barrier in aging will permit us to develop therapeutic strategies for aged or diabetic skin.
10.1016/j.clindermatol.2019.04.009
Skin Barrier Dysregulation in Psoriasis.
International journal of molecular sciences
The skin barrier is broadly composed of two elements-a physical barrier mostly localised in the epidermis, and an immune barrier localised in both the dermis and epidermis. These two systems interact cooperatively to maintain skin homeostasis and overall human health. However, if dysregulated, several skin diseases may arise. Psoriasis is one of the most prevalent skin diseases associated with disrupted barrier function. It is characterised by the formation of psoriatic lesions, the aberrant differentiation and proliferation of keratinocytes, and excessive inflammation. In this review, we summarize recent discoveries in disease pathogenesis, including the contribution of keratinocytes, immune cells, genetic and environmental factors, and how they advance current and future treatments.
10.3390/ijms221910841
The Skin Barrier and Moisturization: Function, Disruption, and Mechanisms of Repair.
Skin pharmacology and physiology
BACKGROUND:The anatomic layers of the skin are well-defined, and a functional model of the skin barrier has recently been described. Barrier disruption plays a key role in several skin conditions, and moisturization is recommended as an initial treatment in conditions such as atopic dermatitis. This review aimed to analyze the skin barrier in the context of the function model, with a focus on the mechanisms by which moisturizers support each of the functional layers of the skin barrier to promote homeostasis and repair. SUMMARY:The skin barrier is comprised of four interdependent layers - physical, chemical, microbiologic, and immunologic - which maintain barrier structure and function. Moisturizers target disruption affecting each of these four layers through several mechanisms and were shown to improve transepidermal water loss in several studies. Occlusives, humectants, and emollients occlude the surface of the stratum corneum (SC), draw water from the dermis into the epidermis, and assimilate into the SC, respectively, in order to strengthen the physical skin barrier. Acidic moisturizers bolster the chemical skin barrier by supporting optimal enzymatic function, increasing ceramide production, and facilitating ideal conditions for commensal microorganisms. Regular moisturization may strengthen the immunologic skin barrier by reducing permeability and subsequent allergen penetration and sensitization. KEY MESSAGES:The physical, chemical, microbiologic, and immunologic layers of the skin barrier are each uniquely impacted in states of skin barrier disruption. Moisturizers target each of the layers of the skin barrier to maintain homeostasis and facilitate repair.
10.1159/000534136
Skin microbiota-host interactions.
Chen Y Erin,Fischbach Michael A,Belkaid Yasmine
Nature
The skin is a complex and dynamic ecosystem that is inhabited by bacteria, archaea, fungi and viruses. These microbes-collectively referred to as the skin microbiota-are fundamental to skin physiology and immunity. Interactions between skin microbes and the host can fall anywhere along the continuum between mutualism and pathogenicity. In this Review, we highlight how host-microbe interactions depend heavily on context, including the state of immune activation, host genetic predisposition, barrier status, microbe localization, and microbe-microbe interactions. We focus on how context shapes the complex dialogue between skin microbes and the host, and the consequences of this dialogue for health and disease.
10.1038/nature25177
Building and Maintaining the Skin.
Cold Spring Harbor perspectives in biology
The skin forms a crucial, dynamic barrier between an animal and the external world. In mammals, three stem cell populations possess robust regenerative potential to maintain and repair the body's protective surface: epidermal stem cells, which maintain the stratified epidermis; hair follicle stem cells, which power the cyclic growth of the hair follicle; and melanocyte stem cells, which regenerate pigment-producing melanocytes to color the skin and hair. These stem cells reside in complex microenvironments ("niches") comprising diverse cellular repertoires that enable stem cells to rejuvenate tissues during homeostasis and regenerate them upon injury. Beyond their niches, skin stem cells can also sense and respond to fluctuations in organismal health or changes outside the body. Here, we review these diverse cellular interactions and highlight how far-reaching signals can be transmitted at the local level to enable skin stem cells to tailor their actions to suit the particular occasion and optimize fitness.
10.1101/cshperspect.a040840
Peripheral itch sensitization in atopic dermatitis.
Allergology international : official journal of the Japanese Society of Allergology
Atopic dermatitis is a skin disorder caused by skin dryness and barrier dysfunction, resulting in skin inflammation and chronic itch (or pruritus). The pathogenesis of atopic dermatitis is thought to be initiated by a lowering of the itch threshold due to dry skin. This lowering of the itch threshold is at least partially due to the increase in intraepidermal nerve fibers and sensitization of sensory nerves by interleukin (IL)-33 produced and secreted by keratinocytes. Such skin is easily prone to itch due to mechanical stimuli, such as rubbing of clothing and chemical stimuli from itch mediators. In patients with atopic dermatitis, once itch occurs, further itch is induced by scratching, and the associated scratching breaks down the skin barrier. Disruption of the skin barrier allows entry into the epidermis of external foreign substances, such as allergens derived from house dust mites, leading to an increased induction of type 2 inflammatory responses. As a result, type 2 cytokines IL-4, IL-13, and IL-31 are mainly secreted by Th2 cells, and their action on sensory nerve fibers causes further itch sensitization. These sequences of events are thought to occur simultaneously in patients with atopic dermatitis, leading to a vicious itch-scratch cycle. This vicious cycle becomes a negative spiral that leads to disease burden. Therefore, controlling itch is essential for the treatment of atopic dermatitis. In this review, we summarize and discuss advances in the mechanisms of peripheral itch sensitization in atopic dermatitis, focusing on skin barrier-neuro-immune triadic connectivity.
10.1016/j.alit.2022.04.003
Skin Barrier Damage and Itch: Review of Mechanisms, Topical Management and Future Directions.
Yosipovitch Gil,Misery Laurent,Proksch Ehrhardt,Metz Martin,Ständer Sonja,Schmelz Martin
Acta dermato-venereologica
Barrier damage, dry skin and itch are intricately linked and form the basis of many common skin diseases. Damage from environmental insults, or genetic or inflammatory causes, can impair the skin barrier, resulting in an increase in transepidermal water loss and activation of itch-associated nerve fibres. The itch-scratch cycle can perpetuate skin barrier damage and itch. Topical therapeutic strategies are utilised to overcome dry skin and itch, primarily in the form of emollients. Recent advances in our understanding of the mechanisms underlying itch have enabled the development of new topical therapies, which may be incorporated into existing treatment regimes. Ultimately, treatment of dry skin and itch must be highly tailored to the individual according to their needs.
10.2340/00015555-3296
Microbiota and maintenance of skin barrier function.
Science (New York, N.Y.)
Human skin forms a protective barrier against the external environment and is our first line of defense against toxic, solar, and pathogenic insults. Our skin also defines our outward appearance, protects our internal tissues and organs, acts as a sensory interface, and prevents dehydration. Crucial to the skin's barrier function is the colonizing microbiota, which provides protection against pathogens, tunes immune responses, and fortifies the epithelium. Here we highlight recent advances in our understanding of how the microbiota mediates multiple facets of skin barrier function. We discuss recent insights into pathological host-microbiota interactions and implications for disorders of the skin and distant organs. Finally, we examine how microbiota-based mechanisms can be targeted to prevent or manage skin disorders and impaired wound healing.
10.1126/science.abo0693