Stratum Corneum Barrier Function Research Articles

The Chemistry of Skin Cleansers: An Overview for Clinicians

Cleansers and other skin care products can be agents either of stratum corneum damage and skin barrier dysfunction or of maintaining or restoring healthy stratum corneum barrier structure and function. To guide patients toward beneficial choices most suitable for their individual skin conditions and needs, clinicians must be aware of and understand the ingredients in such skin care products and their potential effects on the stratum corneum barrier. In cleansers specifically, clinicians should be aware particularly of the benefits and potential problems associated with chemical components of surfactants, preservatives, and fragrances.

Mechanical Tomography of Human Corneocytes with a Nanoneedle

Atomic force microscopy (AFM) can image biological samples and characterize their mechanical properties. However, the low aspect ratio of standard AFM probes typically limits these measurements to surface properties. Here, the intracellular mechanical behavior of human corneocytes is determined using "nanoneedle" AFM probes. The method evaluates the forces experienced by a nanoneedle as it is pushed into and then retracted from the cell. Indentation loops yield the stiffness profile and information on the elastic and nonelastic mechanical properties at a specific depth below the surface of the corneocytes. A clear difference between the softer ∼50-nm-thick external layer and the more rigid internal structure of corneocytes is apparent, which is consistent with the current understanding of the structure of these cells. There are also significant variations in the mechanical properties of corneocytes from different volunteers. The small diameter of the nanoneedle allows this "mechanical tomography" to be performed with high spatial resolution, potentially offering an opportunity to detect biomechanical changes in corneocytes because of, e.g., environmental factors, aging, or dermatological pathologies.

A Lifetime of Well Skin Care: Practical Recommendations for Clinicians and Patients

The skin is an indicator of overall health throughout life, and the skin's lifelong care and environment are reflected with aging. The goal of skin care education by clinicians is to teach and reinforce habits that will support and maintain optimum stratum corneum barrier function throughout life and, when dermatologic conditions or injuries arise, that will aid in recovery of barrier function.

Impact of intravenous lipid emulsion infusion on the stratum corneum barrier function in patients receiving parenteral nutrition.

The importance of the lipid matrix of stratum corneum (SC) in epidermal barrier function is well documented. Intravenous lipid emulsions (ILE) provide essential fatty acids (EFAs), main components of the SC lipid matrix. The objective of this study was to investigate the influence of ILE upon SC barrier function. The skin barrier was assessed by measuring transepidermal water loss (TEWL). Patients receiving lipid-containing parenteral nutrition (LCPN) were compared to patients receiving lipid-free PN (LFPN). In addition, a before/after LCPN introduction study was set up to limit the influence of inter-individual variability. Twenty-six patients receiving LCPN and seven patients receiving LFPN were included. Medianagewas not significantly different between the two groups. The TEWL of theLCPNgroup(9.05g/m2/h) was significantly lower than the TEWL of the LFPN group(12.1g/m2/h; Wilcoxon test: p=0.016). The relative variation of TEWL before and after ILE treatment of 5studied patients was 21.29±10.28 %. ILE improve epidermal barrier function when compared to lipid-free parenteral treatments. Results of the before/after study confirm this conclusion and the usefulness of ILE intake for preventing excessive TEWL. SC barrier function improvement could be a choice criterion between the different ILE generations, in particular in burn patients and premature neonates.

Tight junction dysfunction in the stratum granulosum leads to aberrant stratum corneum barrier function in claudin-1-deficient mice

BackgroundTight junctions (TJs) contribute to the epithelial barrier function by preventing leakage of solutes through the intercellular space. In the skin, TJs occur in the stratum granulosum (SG), where claudin-1 and claudin-4 are expressed as adhesion molecules of TJs. Claudin-1-deficient (Cldn1−/−) mice die within one day of birth accompanied by excessive transepidermal water loss, indicating a critical role of TJs in the epidermal barrier function. However, it has been debated whether the impaired TJ function in the SG also affects the stratum corneum (SC) barrier function or whether it results in skin barrier defects despite a normal SC barrier. ObjectiveTo clarify whether the impaired TJ function affects the SC barrier function in Cldn1−/− mice. MethodsThe morphology, barrier function and biochemical characteristic of the SC were compared between Cldn1−/− and Cldn1+/+ mice. ResultsScanning electron microscopy demonstrated abnormally wrinkled and rough corneocytes in Cldn1−/− mice. Notably, the X-gal tracer easily permeated into the Cldn1−/− SC, and water evaporation through isolated Cldn1−/− SC sheets was significantly higher than that through Cldn1+/+ SC sheets. Furthermore, the ceramide composition of the SC lipids and filaggrin processing were altered in Cldn1−/− mice. ConclusionCldn1−/− mice exhibited the abnormal SC formation and SC barrier defects. These findings demonstrate for the first time that TJs in the SG play crucial roles in the complete SC formation and SC barrier function.

Bicellar systems as new delivery strategy for topical application of flufenamic acid

In this work, bicellar systems, bilayered disc-shaped nanoaggregates formed in water by phospholipids, are proposed as a novel strategy for delivery of the anti-inflammatory flufenamic acid (FFA) to the skin. A comparative percutaneous penetration study of this drug in bicellar systems and other vehicles was conducted. The effects induced on the skin by the application of FFA in the different vehicles were analyzed by attenuated total reflectance-fourier transform infrared (ATR-FTIR). Additionally, using the microscopic technique freeze-substitution transmission electron microscopy (FSTEM) and X-ray scattering technique using synchrotron radiation (SAXS-SR), we studied the possible microstructural and organizational changes that were induced in the stratum corneum (SC) lipids and the collagen of the skin by the application of FFA bicellar systems. Bicellar systems exhibited a retarder effect on the percutaneous absorption of FFA with respect to the other vehicles without promoting disruption in the SC barrier function of the skin. Given that skin disruption is one of the main effects caused by inflammation, prevention of disruption and repair of the skin microstructure should be prioritized in anti-inflammatory formulations.

In vivo barrier challenge and long‐term recovery in human facial skin

Recently, we developed a biophysical approach to characterize in vivo facial cheek skin as a function of stratum corneum (SC) depth, barrier function and during a 24-h recovery period. The current study extends this work and characterizes the human facial cheek after barrier challenge and, for the first time, facial SC barrier recovery over a 4-week period. Changes in the corneocyte size over the 4-week recovery period, and correlations with changes in Trans-Epidermal Water Loss (TEWL) were monitored. This approach allows complete characterization of SC barrier function after a full biological regeneration of the SC barrier following tape stripping. The structural and compositional changes in facial cheek were investigated using Attenuated Total Reflectance-Fourier Transform Infra Red (ATR-FTIR) spectroscopy, tape stripping, TEWL measurements and image analysis combined with optical microscopy to characterize the SC depth profile during the tape stripping stress and over 4-week recovery period. TEWL increased significantly from baseline after sequential tape stripping. Corneocyte size decreased with successive tape stripping. An inverse direct correlation was determined between TEWL and corneocyte surface area. After 4weeks, the corneocyte size and TEWL for the facial cheek recovered 100% from the tape stripping procedure. The in vivo ATR-FTIR data demonstrated that lipid and sebum components on the surface of the facial cheek SC recovered within 24h post tape stripping, whereas protein (Amide II) and water components recovered after 1week.

Hepatitis B DNA Vaccine-Polycation Nano-Complexes Enhancing Immune Response by Percutaneous Administration with Microneedle

Percutaneous immune method is becoming an attractive alternative for DNA vaccine as a lot of antigen presenting cells are existed in the viable epidermis. However, due to the barrier function of stratum corneum, it would be hard for DNA vaccine to reach the viable epidermis of the skin. In order to deliver the DNA vaccine successfully cross the stratum corneum, pentagram silicon microneedle array was prepared in this study, and fluorescently labeled nanoparticle was taken as the model to observe the situation inside the skin processed by microneedle. Via microneedle nanoparticles could enter the skin through the micro-channel (diameter about 20-30 µm) and its amount is greatly larger than that enter though the hair follicle of intact skin. A new type of gene vector Pluronic P123-modified polyethyleneimine (P123-PEI) was synthesized by high molecular weight polyethylenimine and Pluronic P123 with the molar ratio of 1 : 1 to take the advantage of P123-PEI as low cytotoxicity and high transfection efficiency. Mice were immunized percutaneously with Hepatitis B DNA vaccine/P123-PEI nano-complexes by microneedle. The humoral and cellular immunity generated in percutaneously immunized mice through microneedle array by Hepatitis B DNA vaccine/P123-PEI nano-complex was significantly higher than that of DNA vaccine intramuscular administration.

Influence of niacinamide containing formulations on the molecular and biophysical properties of the stratum corneum

Niacinamide-containing moisturisers are known be efficacious in alleviating dry skin conditions and improving stratum corneum (SC) barrier function. However, the mechanisms of action of niacinamide at the molecular level in the SC are still not well understood. Previously, we have reported the development of novel methods to probe SC barrier properties in vivo. The aim of the present study was to characterise changes in Trans Epidermal Water Loss (TEWL), corneocyte surface area and maturity, selected protease activities and SC thickness after repeated application of a simple vehicle containing niacinamide. A commercial formulation was also included as a reference. The left and right mid-volar forearms of 20 healthy volunteers were used as study sites, to which topical formulations were applied twice daily for 28 days. After successive tape-stripping, corneocyte maturity and surface area were assessed. In addition, activity of the desquamatory kallikrein (KLK) protease enzymes KLK5 and KLK7, and tryptase and plasmin (implicated in inflammatory process) were measured using a fluorogenic probe assay. The amount of protein removed and TEWL were also recorded. SC thickness before and after treatment was determined using Confocal Raman Spectroscopy (CRS). Overall (i) corneocyte maturity and surface area decreased with increasing number of tape strips, (ii) activity of both the desquamatory and inflammatory enzymes was highest in the outer layers of the SC and decreased with depth (iii) TEWL increased as more SC layers were removed. Furthermore, areas treated with formulations containing niacinamide were significantly different to pre-treatment baseline and untreated/vehicle-control treated sites, with larger and more mature corneocytes, decreased inflammatory activity, decreased TEWL and increased SC thickness. These data (a) confirm the utility of measures and metrics developed previously for the non-invasive assay of SC barrier function, (b) present an holistic picture of a SC compartment managing barrier function through dynamic optimisation of pathlength and quality of building materials used, and (c) shed new light on niacinamide as a topical formulation adjunct with unique SC barrier-augmentation properties.

A review of the effects of moisturizers on the appearance of scars and striae

Scars are well known to have a stratum corneum (SC) that is malfunctional. Increases in transepidermal water loss and decreases in SC capacitance and conductance have been reported. Occlusion therapy is a well-known route to improving the signs and symptoms of scarring. Until recently that has been assumed to be totally pressure related. However, studies have demonstrated that the direct effects of hydration on keratinocytes and fibroblasts contribute to the reduction in hypertrophic scarring. Now it is well known that occlusion can regulate epidermal cytokine and growth factor production; changes in profibrotic and anti-fibrotic factors have been established. As a result, it is to be expected that moisturizers may improve the signs and symptoms of scars. As striae have been suggested to be anatomically similar to scars and as it is well established that paracrine signalling occurs in skin, it is expected that striae have similar SC issues. While one cannot exclude the effects of some of the ingredients used in the products, several studies are reported in this review that demonstrates that moisturization is a key component to reducing the clinical signs and symptoms of scars and striae. This is a good example of how knowledge of corneobiology leads to corneotherapies for these skin condition problems. The review is being written in memory of Professor Johann Wiechers who, before he died tragically in November 2011, performed two of the reported studies together with colleagues.

Enhanced transdermal delivery of cyclosporine a by PP electret and ethyl oleate

Transdermal delivery of high molecular weight compound is a great challenge due to the barrier function of the skin's outer stratum corneum (SC) layer. The aim of the present work was to characterize in vitro transdermal delivery of cyclosporine A through rat skin and the drug transdermal enhancing effect of PP electret applied individually and in combination with chemical enhancer. The permeated cumulative amount and steady state flux of the cyclosporine A were determined in following situations: (a) under application of PP electret, (b) after application of ethyl oleate, (c) combination PP electret and ethyl oleate. All the techniques could enhance cyclosporine A transdermal delivery. The combination of PP electret and ethyl oleate proved to be the most effective technique.

In Vivo Barrier Challenge and Initial Recovery in Human Facial Skin

Many in vivo biophysical studies focus on parts of the body which are generally less exposed to the environment compared with facial skin. This study characterizes in vivo changes in the barrier function of cheek stratum corneum (SC) during controlled conditions of damage. The objective was to investigate structural and compositional changes in cheek SC in vivo using tape stripping and Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectroscopy. In vivo ATR-FTIR spectra of the cheek were collected before and after tape stripping. Trans epidermal water loss (TEWL) measurements from the same site were conducted before and after stripping. Data were also collected 24 h after the last tape strip to investigate any initial recovery process. Sequential tape stripping of the cheek progressively increases TEWL to twice baseline values but some barrier recovery is evident 24 h later. ATR-FTIR spectra show increasing water content within the SC with each tape strip with concomitant increase in lipid conformational order. Several structural and compositional parameters have been analyzed for cheek SC and these have been correlated with barrier function. The depth dependent changes in face SC map those in body skin but over a much shorter distance.

Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice

Loss-of-function mutations in filaggrin are major predisposing factors for atopic dermatitis. Although various reports suggest a critical role for filaggrin in stratum corneum (SC) barrier formation, the lack of filaggrin-null (Flg(-/-)) mice has hampered detailed invivo analysis of filaggrin's functions. We sought to generate Flg(-/-) mice and to assess the effect of filaggrin loss on SC barrier function and percutaneous immune responses. We generated Flg(-/-) mice using gene targeting and assessed the morphology, hydration, mechanical strength, and antigen permeability of their SC. Percutaneous immune responses were evaluated through irritant- and hapten-induced contact hypersensitivity studies and by measuring humoral responses to epicutaneous sensitization with protein antigen. Newborn Flg(-/-) mice exhibited dry scaly skin. Despite marked decreases in natural moisturizing factor levels, which are filaggrin degradation products, SC hydration and transepidermal water loss were normal. Microscopic analyses suggested premature shedding of SC layers, and indeed, increased desquamation under mechanical stress was demonstrated. Loss of keratin patterns, which are critical for corneocyte stabilization, is likely attributable to fragility in the Flg(-/-) SC. Antigens penetrated the Flg(-/-) SC more efficiently, leading to enhanced responses in hapten-induced contact hypersensitivity and higher serum levels of anti-ovalbumin IgG(1) and IgE. Complete filaggrin deficiency led to altered barrier integrity and enhanced sensitization, which are important factors in early-phase atopic dermatitis. Flg(-/-) mice should provide a valuable tool to further explore additional factors the dysfunction of which leads to uncontrolled inflammation in patients with atopic diseases.

The matriptase-prostasin proteolytic cascade in epithelial development and pathology

The type II transmembrane serine protease matriptase has an essential role in the integrity and function of multiple epithelial tissues. In the epidermis, matriptase activates the glycosylphosphatidylinositol (GPI) anchored membrane serine protease prostasin to initiate a proteolytic cascade that is required for the development of the stratum corneum barrier function. Accordingly, mice deficient for matriptase phenocopy mice deficient for epidermal prostasin and present with impaired corneocyte differentiation, imparied lipid matrix formation, loss of profilaggrin processing and loss of tight junction formation and function. Together, these defects lead to a compromised epidermal barrier and result in fatal dehydration during the neonatal period. Proteolytic activity of the matriptase-prostasin cascade is regulated in the epidermis via inhibition by the Kunitz-type serine protease inhibitor hepatocyte growth factor activator inhibitor-1 (HAI-1). Importantly, targeted post-natal ablation of matriptase in mice perturbs the function of multiple adult tissues, indicating an ongoing requirement for matriptase proteolysis in the maintenance of diverse types of epithelia. Impaired matriptase proteolytic activity has been linked to human Autosomal Recessive Icthyosis with Hypotrichosis (ARIH), whereas aberrant matriptase activity has been implicated in Netherton's Syndrome. This review will summarize information pertaining to the role of matriptase in epithelial biology and will discuss recent advancements in our understanding of how matriptase activity is regulated and the down-stream effectors of matriptase proteolysis.

Correlation between serum thymus and activation-regulated chemokine levels and stratum corneum barrier function in healthy individuals and patients with mild atopic dermatitis

Serum thymus and activation-regulated chemokine (TARC) levels closely reflect the disease activity of atopic dermatitis (AD). AD is characterized by impaired epidermal barrier function and atopic dry skin. However, dry skin is also a very common problem in healthy individuals. To investigate the relationship between serum TARC levels and epidermal barrier function in healthy subjects and patients with mild AD. This study included 2 groups, 121 healthy subjects (healthy group) and 66 patients with mild AD (mild AD group). Barrier function was assessed by transepidermal water loss (TEWL) and stratum corneum hydration (SCH). Significantly elevated serum TARC levels and TEWL values and significantly decreased SCH values were detected in the mild AD group compared to those in the healthy group. In the mild AD group, serum TARC levels were significantly correlated with TEWL values and were inversely correlated with SCH values. Importantly, serum TARC levels were also inversely correlated with SCH values in the healthy controls. TEWL values in the healthy group tended to be correlated with TARC levels but did not reach statistical significance. Together with TEWL and SCH, serum TARC level is a useful biomarker, reflecting impairment of epidermal function in AD patients as well as healthy subjects.

Evaluation of skin surface hydration state and barrier function of stratum corneum of dorsa of hands and heels treated with PROTECT X2 skin protective cream

Skin roughness is a term commonly used in Japan to describe a poor skin condition related to a rough and dry skin surface that develops as a result of various damaging effects from the environment or skin inflammation. Recovery from skin roughness requires skin care for a long period, thus it is important to prevent development of such skin changes. PROTECT X2 contains agents used for a protective covering of the skin from frequent hand washing or use of alcohol-based disinfectants. These unique components are also thought to be effective to treat skin roughness of the dorsa of the hands and heels. In the present study, we evaluated the effectiveness of PROTECT X2 to increase skin surface hydration state, as well as enhance the barrier function of the stratum corneum of the dorsa of the hands and heels in elderly individuals. A total of 8 elderly subjects and their caretakers without any skin diseases participated in the study. They applied PROTECT X2 by themselves to the dorsum area of 1 hand and heel 3 to 5 times daily for 1 month, while the opposite sides were left untreated. We measured stratum corneum (SC) hydration and transepidermal water loss (TEWL) before beginning treatment, then 1 week and 1 month after the start of treatment to compare between the treated and untreated skin. SC hydration state after applications of PROTECT X2 was 1.5- to 3.0-fold higher than that of the untreated skin in the dorsa of both hands and heels, indicating that the moisturizing ingredients accompanied by water were replenished in those areas where the cream was applied. Also, TEWL in the dorsum of the hands was 17.0-27.9% lower on the treated side, indicating improvement in SC barrier function. On the basis of these findings, we concluded that PROTECT X2 enhances water-holding in the SC and aids the barrier function of the skin in the dorsum of the hands. In addition, we consider that this formulation is useful for not only protecting the hands from the effects of such agents as detergents and alcohol-based disinfectants, but also for protecting heel skin covered by a thick SC from dry and cold conditions such as those encountered in winter. However, since the SC in that area is much thicker than that of the hands, the barrier function was not significantly improved within 1 month of daily treatments.

Barrier-Restoring Therapies in Atopic Dermatitis: Current Approaches and Future Perspectives

Atopic dermatitis is a multifactorial, chronic relapsing, inflammatory disease, characterized by xerosis, eczematous lesions, and pruritus. The latter usually leads to an “itch-scratch” cycle that may compromise the epidermal barrier. Skin barrier abnormalities in atopic dermatitis may result from mutations in the gene encoding for filaggrin, which plays an important role in the formation of cornified cytosol. Barrier abnormalities render the skin more permeable to irritants, allergens, and microorganisms. Treatment of atopic dermatitis must be directed to control the itching, suppress the inflammation, and restore the skin barrier. Emollients, both creams and ointments, improve the barrier function of stratum corneum by providing it with water and lipids. Studies on atopic dermatitis and barrier repair treatment show that adequate lipid replacement therapy reduces the inflammation and restores epidermal function. Efforts directed to develop immunomodulators that interfere with cytokine-induced skin barrier dysfunction, provide a promising strategy for treatment of atopic dermatitis. Moreover, an impressive proliferation of more than 80 clinical studies focusing on topical treatments in atopic dermatitis led to growing expectations for better therapies.

Dendrimer-mediated drug delivery to the skin

Nanoparticles have been increasingly used as carriers for local and systemic drug delivery via the skin. Dendrimers are emerging as the new generation of nanocarriers in skin drug delivery mainly due to their small size, extreme molecular uniformity, and highly functional surfaces. Despite the abundance of investigations which demonstrate the dendrimer-mediated skin delivery enhancement both in vitro and in vivo, there are still controversies over the mechanisms of their action. Based on the critical analysis of currently available data in this field, it is found that the skin delivery enhancement by dendrimers depends on the drug–dendrimer–skin interactions and three potential mechanisms are proposed. Firstly, for some drugs, dendrimers may act as a drug release modifier and speed up the drug dissolution that is the rate-limiting step of percutaneous drug absorption. Secondly, via particle engineering the properties of dendrimers can be tailored to preferably penetrate the skin via the follicular route. Finally, certain low generation dendrimers may impair the stratum corneum barrier function, particularly in the presence of potent vehicles.

Knocking-in the R142C mutation in transglutaminase 1 disrupts the stratum corneum barrier and postnatal survival of mice

Mutations in the gene encoding transglutaminase 1 (TG1) are responsible for various types of autosomal recessive congenital ichthyosis (ARCI), such as lamellar ichthyosis (LI), congenital ichthyosiform erythroderma (CIE) and some minor variants of ARCI. A point mutation of R143C in the β-sandwich domain of TG1 has been often identified in patients with LI or CIE. To elucidate the effect of that point mutation on skin barrier structures and functions, we generated mice with a point mutation of R142C, which corresponds to the R143C mutation in human TG1. A mouse line with the R142C point mutation in TG1 was established using a gene targeting technique and the Cre-loxP system. The skin phenotypes were analyzed in homozygous mutant Tgm1(R142C/R142C) mice. In the skin of Tgm1(R142C/R142C) mice, expression of the mutant transcripts was comparable with wild-type or Tgm1(+/R142C) mice. However, the amount of mutated protein in the skin was markedly decreased in Tgm1(R142C/R142C) mice, and the TG1 activity of Tgm1(R142C/R142C) keratinocytes was almost lost. Tgm1(R142C/R142C) mice exhibited morphological and functional skin barrier defects and neonatal lethality. The stratum corneum of those mice lacked cornified envelopes, and loricrin, the major structural component, failed to assemble at the corneocyte cell periphery. Tgm1(R142C/R142C) mice showed a marked increase in transepidermal water loss and their skin was easily permeable to toluidine blue dye. The intercellular lipid lamellar structures of the stratum corneum were irregular and the 13-nm periodic X-ray diffractions from the stratum corneum lipid molecules were lost in vivo. From these results, we suggest that the R142C mutation of TG1 reduces the enzyme stability which is indispensable for development of the stratum corneum and skin barrier function and for postnatal survival of mice.

Barrier function of intact and impaired skin: percutaneous penetration of caffeine and salicylic acid

Normally, percutaneous absorption tests are carried out using skin biopsies for an apparent and acceptable physiological condition. However, under different pathological conditions, the stratum corneum (SC) barrier function is impaired. The barrier function of the SC was assessed by correlation between the number of repeated applications of tape strips on the skin and its transepidermal water loss (TEWL), as well as by in vitro percutaneous absorption studies of different compounds, using Franz diffusion cells and porcine skin previously stripped. A progressive diminution of the skin barrier function has been detected by TEWL both in vitro and in vivo as the number of skin tape strips increases. On the other hand, the percutaneous absorption of the compounds tested increases in a different way as the number of strips increases. Salicylic acid increases linearly depending on the barrier disturbance. However, percutaneous absorption of caffeine exponentially increased with barrier disturbance. Our results indicate that the barrier impairment of skin always increases the penetration behavior of a given compound; however, the hydrophilic-lipophilic balance of the compounds or formulations used could greatly modify its penetration profile, especially when a modified skin is used. This in vitro protocol may be useful to simulate the percutaneous absorption profile of some drugs applied onto skin with an impaired SC barrier function and could be used to avoid, to some extent, the use of in vivo experimental animal models in the dermopharmaceutical field.