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The skin consists of several cell populations, including epithelial, immune, and stromal cells. Recently, there has been a significant increase in single-cell RNA-sequencing studies, contributing to the development of a consensus Human Skin Cell Atlas. The aim is to understand skin biology better and identify potential therapeutic targets. The present review utilized previously published single-cell RNA-sequencing datasets to explore human skin's cellular and functional heterogeneity. Additionally, it summarizes the functional significance of newly identified cell subpopulations in processes such as wound healing and aging., Competing Interests: Disclosure A. Mandinova is a co-founder (with equity) of New Frontier Bio, a consumer health company developing skincare and anti-aging products, and has equity in DermBiont, a private company advancing targeted topical therapeutics for dermatologic indications. K. Todorova has a financial interest in New Frontier Bio., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Pruritus, rash, and various other forms of dermatotoxicity are the most frequent adverse events among patients with cancer receiving targeted molecular therapy and immunotherapy. Immune checkpoint inhibitors, macrophage-targeting agents, and epidermal growth factor receptor/MEK inhibitors not only exert antitumor effects but also interfere with molecular pathways essential for skin immune homeostasis. Studying cancer therapy-induced dermatotoxicity helps us identify molecular mechanisms governing skin immunity and deepen our understanding of human biology. This review summarizes new mechanistic insights emerging from the analysis of cutaneous adverse events and discusses knowledge gaps that remain to be closed by future research., Competing Interests: Disclosure J.L. Flesher is supported by NIH, United States T32AR007098 (Dermatology Training Grant). J.M. Park is supported by NIH R01AI177414, has a consulting role with Chong Kun Dang Pharmaceutical, and has received research funding from Pfizer, United States and Evommune., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Wearable alcohol monitoring devices demand noninvasive, real-time measurement of blood alcohol content (BAC) reliably and continuously. A few commercial devices are available to determine BAC noninvasively by detecting transcutaneous diffused alcohol. However, they suffer from a lack of accuracy and reliability in the determination of BAC in real time due to the complex scenario of the human skin for transcutaneous alcohol diffusion and numerous factors (e.g., skin thickness, kinetics of alcohol, body weight, age, sex, metabolism rate, etc.). In this work, a transcutaneous alcohol diffusion model has been developed from real-time captured data from human wrists to better understand the kinetics of diffused alcohol from blood to different skin epidermis layers. Such a model will be a footprint to determine a base computational model in larger studies. Eight anonymous volunteers participated in this pilot study. A laboratory-built wearable blood alcohol content (BAC) monitoring device collected all the data to develop this diffusion model. The proton exchange membrane fuel cell (PEMFC) sensor was fabricated and integrated with an nRF51822 microcontroller, LMP91000 miniaturized potentiostat, 2.4 GHz transceiver supporting Bluetooth low energy (BLE), and all the necessary electronic components to build this wearable BAC monitoring device. The %BAC data in real time were collected using this device from these volunteers' wrists and stored in the end device (e.g., smartphone). From the captured data, we demonstrate how the volatile alcohol concentration on the skin varies over time by comparing the alcohol concentration in the initial stage (= 10 min) and later time (= 100 min). We also compare the experimental results with the outputs of three different input profiles: piecewise linear, exponential linear, and Hoerl, to optimize the developed diffusion model. Our results demonstrate that the exponential linear function best fits the experimental data compared to the piecewise linear and Hoerl functions. Moreover, we have studied the impact of skin epidermis thickness within ±20% and demonstrate that a 20% decrease in this thickness results in faster dynamics compared to thicker skin. The model clearly shows how the diffusion front changes within a skin epidermis layer with time. We further verified that 60 min was roughly the time to reach the maximum concentration, C max , in the stratum corneum from the transient analysis. Lastly, we found that a more significant time difference between BAC max and C max was due to greater alcohol consumption for a fixed absorption time.

Vertebrate skin appendages - particularly avian feathers and mammalian hairs, glands and teeth - are perennially useful systems for investigating fundamental mechanisms of development. The most common type of skin appendage in teleost fishes is the elasmoid scale, yet this structure has received much less attention than the skin appendages of tetrapods. Elasmoid scales are thin, overlapping plates of partially mineralized extracellular matrices, deposited in the skin in a hexagonal pattern by a specialized population of dermal cells in cooperation with the overlying epidermis. Recent years have seen rapid progress in our understanding of elasmoid scale development and regeneration, driven by the deployment of developmental genetics, live imaging and transcriptomics in larval and adult zebrafish. These findings are reviewed together with histological and ultrastructural approaches to understanding scale development and regeneration., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cutaneous damage mechanisms related to dynamic fragment impacts are dependent on the impact angle, impact energy, and fragment characteristics including shape, volume, contact friction, and orientation. Understanding the cutaneous injury mechanism and its relationship to the fragment parameters is lacking compromising damage classification, treatment, and protection. Here we develop a high-fidelity dynamic mechanics-driven model for partial-thickness skin injuries and demonstrate the influence of fragment parameters on the injury mechanism and damage sequence. The model quantitatively predicts the wound shape, area, and depth into the skin layers for selected impact angles, kinetic energy density, and the fragment projectile type including shape and material. The detailed sequence of impact damage including epidermal tearing that occurs ahead of the fragments initial contact location, subsequent stripping of the epidermal/dermal junction, and crushing of the underlying dermis are revealed. We demonstrate that the fragment contact friction with skin plays a key role in redistributing impact energy affecting the extent of epidermal tearing and dermal crushing. Furthermore, projectile edges markedly affect injury severity dependent on the orientation of the edge during initial impact. The model provides a quantitative framework for understanding the detailed mechanisms of cutaneous damage and a basis for the design of protective equipment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: Emotions play an important role in consumers' perception of a sensory experience. The objective of this work was to investigate the ability of basic skin care formulas (i.e. without interference of odour, colour and packaging) and pillar ingredients (i.e. emollients and rheology modifiers) to elicit emotions. Another objective was to track, as claimed by neurocosmetics, the possible effect of formulas to trigger emotions from their direct biochemical effects on the skin., Methods: Standard methodologies were mobilized, combining subjective and behavioural parameters (i.e. verbatim, prosody and gesture). Sense and Story methodology based on a collection of metaphoric verbatim was conducted after an induction phase. In addition, an experimental electrophysiological real-time visualization method was tried as a first experience in cosmetics. Finally, the ability of formulations with emotional benefits to modulate the release of neuropeptides by sensory neurons was evaluated on a 3D human model (epidermis co-cultured with sensory neurons)., Results: Skin care formulas were shown to play a role in emotional potential and the types of emotion generated, while changing one ingredient mostly acted on the intensity of the emotions. Verbatim provided contrasted answers depending on the protocol, highlighting the interest of non-verbal approaches to detect subtle effects. The in vitro model substantiated physiological effects of skin care formulas with emotional potential on human skin sensory neuron activity., Conclusion: Emotions were impacted by the change in ingredients and were better captured through non-verbal methods., (© 2023 The Authors. International Journal of Cosmetic Science published by John Wiley & Sons Ltd on behalf of Society of Cosmetic Scientists and Societe Francaise de Cosmetologie.)

The skin is the largest organ in the human body and serves various functions, including mechanical protection and mechanosensation. Yet, even though skin's biomechanics are attributed to two main layers-epidermis and dermis-computational models have often treated this tissue as a thin homogeneous material or, when considering multiple layers, have ignored the most prominent heterogeneities of skin seen at the mesoscale. Here, we create finite element models of representative volume elements (RVEs) of skin, including the three-dimensional variation of the interface between the epidermis and dermis as well as considering the presence of hair follicles. The sinusoidal interface, which approximates the anatomical features known as Rete ridges, does not affect the homogenized mechanical response of the RVE but contributes to stress concentration, particularly at the valleys of the Rete ridges. The stress profile is three-dimensional due to the skin's anisotropy, leading to high-stress bands connecting the valleys of the Rete ridges through one type of saddle point. The peaks of the Rete ridges and the other class of saddle points of the sinusoidal surface form a second set of low-stress bands under equi-biaxial loading. Another prominent feature of the heterogeneous stress pattern is a switch in the stress jump across the interface, which becomes lower with respect to the flat interface at increasing deformations. These features are seen in both tension and shear loading. The RVE with the hair follicle showed strains concentrating at the epidermis adjacent to the hair follicle, the epithelial tissue surrounding the hair right below the epidermis, and the bulb or base region of the hair follicle. The regions of strain concentration near the hair follicle in equi-biaxial and shear loading align with the presence of distinct mechanoreceptors in the skin, except for the bulb or base region. This study highlights the importance of skin heterogeneities, particularly its potential mechanophysiological role in the sense of touch and the prevention of skin delamination., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Natural products are often friendly and can be used on children's skin after systematic and careful research. Therefore, in this study, the Royal Oji Complex (ROC), a product with natural ingredients, was used to study their effectiveness on keratinocytes taken from the skin of children from 0 to 3 years old., Method: Normal human epidermal keratinocytes and tissue-isolated keratinocytes (TIKC) from young donors were treated with three different concentrations of ROC: 0.1, 1, and 10 ppm. The mRNA expression of the epidermal barrier's essential genes, such as hyaluronic acid synthase 3 (Has3), involucrin (IVL), loricrin (LOR), and claudin-1 (CLD1) was investigated using qRT-PCR. Ceramide content was measured by ELISA, with retinoic acid (R.A.) and amarogentin (AMA) serving as positive controls., Results: ROC significantly elevated HAS3 gene expression in HEKn cells, especially at 10 ppm, indicating potential advantages for skin hydration in young infants. IVL increased at first but decreased as ROC concentrations increased. LOR was upregulated at lower ROC concentrations but reduced at higher doses. CLD1 gene expression increased considerably in HEKn but reduced with increasing ROC doses. Ceramide concentration increased somewhat but not significantly at 10 ppm., Conclusion: ROC shows potential in altering keratinocyte gene expression, with unique responses in HEKn and TIKC from young donors. While changes in ceramide content were insignificant, these results help to comprehend ROC's multiple effects on young children's skin., (© 2024 The Authors. Skin Research and Technology published by John Wiley & Sons Ltd.)

Transdermal drug administration has grown in popularity in the pharmaceutical research community due to its potential to improve drug bioavailability, compliance among patients, and therapeutic effectiveness. To overcome the substantial barrier posed by the stratum corneum (SC) and promote drug absorption within the skin, various physical penetration augmentation approaches have been devised. This review article delves into popular physical penetration augmentation techniques, which include sonophoresis, iontophoresis, magnetophoresis, thermophoresis, needle-free injection, and microneedles (MNs) Sonophoresis is a technique that uses low-frequency ultrasonic waves to break the skin's barrier characteristics, therefore improving drug transport and distribution. In contrast, iontophoresis uses an applied electric current to push charged molecules of drugs inside the skin, effectively enhancing medication absorption. Magnetophoresis uses magnetic fields to drive drug carriers into the dermis, a technology that has shown promise in aiding targeted medication delivery. Thermophoresis is the regulated heating of the skin in order to improve drug absorption, particularly with thermally sensitive drug carriers. Needle-free injection technologies, such as jet injectors (JIs) and microprojection arrays, offer another option by producing temporary small pore sizes in the skin, facilitating painless and effective drug delivery. MNs are a painless, minimally invasive method, easy to self-administration, as well as high drug bioavailability. This study focuses on the underlying processes, current breakthroughs, and limitations connected with all of these approaches, with an emphasis on their applicability in diverse therapeutic areas. Finally, a thorough knowledge of these physical enhancement approaches and their incorporation into pharmaceutical research has the potential to revolutionize drug delivery, providing more efficient and secure treatment choices for a wide range of health-related diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Keratin and lipid structures in the stratum corneum (SC) are closely related to the SC barrier function. The application of penetration enhancers (PEs) disrupts the structure of SC, thereby promoting infiltration. To quantify these PE-induced structural changes in SC, we used confocal Raman imaging (CRI) and polarized Raman imaging (PRI) to explore the integrity and continuity of keratin and lipid structures in SC. The results showed that water is the safest PE and that oleic acid (OA), sodium dodecyl sulfate (SDS), and low molecular weight protamine (LMWP) disrupted the ordered structure of keratin, while azone and liposomes had less of an effect on keratin. Azone, OA, and SDS also led to significant changes in lipid structure, while LMWP and liposomes had less of an effect. Establishing this non-invasive and efficient strategy will provide new insights into transdermal drug delivery and skin health management.

Background: Dermatophytosis has assumed epidemic proportions with rising resistance, recalcitrance and recurrence, especially in tropical regions. While various factors contribute to high prevalence worldwide, yet little is known about the interactions between host defence mechanisms and dermatophytes, particularly in chronic and recalcitrant dermatophytosis., Objectives: We aimed to compare the population of various immune cells in specimens of chronic recurrent dermatophytosis and those with acute superficial dermatophytosis., Methods: We investigated the density of various immune cells-Langerhans cells (CD1a+), macrophages (CD68+), dermal dendrocytes (Factor XIIIa+) in the skin of chronic dermatophytosis patients and those with successfully resolved lesions (controls)., Results: Langerhans cells were significantly decreased in the epidermis of patients, both in affected and unaffected areas in comparison with controls. In the dermis, however, no differences in the density of immune cells (macrophages and fibroblasts) were observed., Limitations: The limited sample size and immune cells evaluated could be expanded further in future research., Conclusion: These results indicate that the decreased number of Langerhans cells could be a potential risk factor for the development of chronic and recurrent dermatophytosis., (© 2024 Wiley-VCH GmbH. Published by John Wiley & Sons Ltd.)

Background: Incontinence-associated dermatitis (IAD) is one of the most common complications of incontinence. Improved diaper designs can minimize the occurrence of IAD., Purpose: To develop a novel diaper design to minimize the damaging effects of incontinence on the epidermal barrier., Methods: An optimized diaper design was tested for surface dryness (ie, rewet), maintenance of a skin-adapted surface pH of 5.5, and ability to protect epidermal barrier function from an alkaline pH 10.7 challenge., Results: The diapers released a mean (standard deviation [SD]) of 1.2 (0.2) mg/cm2 of solution under pressure after the first loading and a mean of 2.9 (1.7) mg/cm2 after the second loading. The surface pH remained between 4.5 and 5.5 over 5 hours. In healthy skin, transepidermal water loss (TEWL) increased by a mean of 3.43 (4.67) g/m2/h after the alkaline urine solution challenge with the new diaper design versus a mean of 8.38 (5.67) g/m2/h with a cellulose patch (P < .001) as a control. The mean erythema readings were 1.18 (1.30) g/m2/h for the new design and 2.56 (1.25) g/m2/h for the cellulose patches (P < .001)., Conclusion: The new diaper design minimizes rewetting, maintains an acidic surface, and protects the epidermal barrier against an alkaline pH challenge. This design may help prevent IAD.

Background: We aimed to investigate the effects of 2 ceramide plus natural moisturizing factor-enriched formulations compared to a ceramide-based cream on skin moisturization., Methods: Two double-blinded comparative studies were conducted, which enrolled 35 (n=29 females, n=6 males) and 33 (n=21 females, n=12 males) participants, respectively. Participants applied ceramide plus natural moisturizer cream or ceramide-based cream (study 1) or applied ceramide plus natural moisturizing factor lotion or ceramide-based cream (study 2) to each of their lower legs for 10 days with a 5-day regression period (no moisturizer applied). Skin hydration by corneometry after bilateral application was conducted once daily for each leg in both groups.&nbsp;&nbsp; Results: An increase in corneometer units vs baseline for the ceramide plus natural moisturizing factor-enriched cream and natural moisturizing factor-enriched lotion were greater than the increase vs baseline for the ceramide-based cream at days 10 and 15; with an overall statistical significance in favor of the ceramide plus natural moisturizing factor-enriched formulations at day 10.&nbsp; Conclusions: The marked improvement in skin moisturization following utilization of the ceramide plus natural moisturizing&nbsp; factor-enriched cream and lotion compared to the ceramide-based cream can be attributed to the inherent properties of the natural moisturizing factors. These properties are known to maintain the humectancy and intercellular lipid membrane of the stratum corneum, which directly improves the permeability barrier function of human skin in reducing transepidermal water loss. J Drugs Dermatol. 2024;23(3):&nbsp; &nbsp; &nbsp;doi:10.36849/JDD.8172.

Objective: This study aims at investigating the difference in facial skin barrier function between rosacea patients and the healthy population of different ages in the Qinghai region and its correlation with age, providing a basis for clinical nursing and treatment., Methods: The data of 216 rosacea patients were collected, and 211 healthy testers were selected as the control group. The skin barrier characteristics of rosacea patients of different ages were evaluated by comparing transepidermal water loss (TEWL), stratum corneum hydration (SCH), sebum content (SC), and pH values between the two groups. Then, the correlation between skin barrier function and age in rosacea patients and the healthy population was analyzed., Results: In all four age groups, the TEWL of the rosacea group was higher than that of the healthy control group, and the epidermal hydration was lower than the healthy control group. In the population aged over 40, the sebum content in rosacea was lower than that in the healthy control group. In the age group of 40-59, the pH value of the rosacea group was higher than the healthy control group. In both the rosacea and the control groups, TEWL was positively correlated with age, and epidermal hydration was negatively correlated with age. The sebum content in rosacea group was negatively correlated with age (p < 0.05)., Conclusion: As age increases, the facial epidermal function of both rosacea patients and the healthy population declines. Therefore, with increasing age, attention should be paid to enhance the epidermal function to slow down the skin aging process., (© 2023 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Skin electroporation for drug delivery involves the application of Pulsed Electric Fields (PEFs) on the skin to disrupt its barrier function in a temporary and non-invasive manner, increasing the uptake of drugs. It represents a potential alternative to delivery methods that are invasive (e.g. injections) or limited. We have developed a drug delivery system comprising nanocomposite hydrogels which act as a reservoir for the drug and an electrode for applying electric pulses on the skin. In this study, we employed a multi-scale approach to investigate the drug delivery system on a mouse skin model, through electrical measurements, numerical modeling and fluorescence microscopy. The Electrical properties indicated a highly non-linear skin conductivity behavior and were used to fine-tune the simulations and study skin recovery after electroporation. Simulation of electric field distribution in the skin showed amplitudes in the range of reversible tissue electroporation (400-1200 V/cm), for 300 V PEF. Fluorescence microscopy revealed increased uptake of fluorescent molecules compared to the non-pulsed control. We reported two reversible electroporation domains for our configuration: (1) at 100 V PEF the first local transport regions appear in the extracellular lipids of the stratum corneum, demonstrated by a rapid increase in the skin's conductivity and an increased uptake of lucifer yellow, a small hydrophilic fluorophore and (2) at 300 V PEF, the first permeabilization of nucleated cells occurred, evidenced by the increased fluorescence of propidium iodide, a membrane-impermeable, DNA intercalating agent., Competing Interests: Declaration of competing interest There are no conflicts to declare., (Copyright © 2024. Published by Elsevier B.V.)

Skin sensitivity and impaired epidermal barrier function are associated with aging and are at least partly due to increased production of reactive oxygen species (ROS). Transient receptor potential vanilloid1 (TRPV1) is expressed in keratinocytes, fibroblasts, mast cells, and endothelial cells in skin. We investigated in skin biopsies of adult and elderly donors whether TRPV1 expression is involved in the skin aging process. We found that aging skin showed a strongly reduced epidermal thickness, strongly increased oxidative stress, protease expression, and mast cell degranulation and strongly increased TRPV1 expression both in epidermis and dermis. Based on our findings, the aging-related changes observed in the epidermis of the skin level are associated with increased ROS production, and hypothesized alterations in TRPV1 expression are mechanistically linked to this process., Competing Interests: Competing InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The morphology and content of stratum corneum (SC) cells provide information on the physiological condition of the skin. Although the morphological and biochemical properties of the SC are known, no method is available to fully access and interpret this information. This study aimed to develop a method to comprehensively decode the physiological information of the skin, based on the SC. Therefore, we established a novel image analysis technique based on artificial intelligence (AI) and multivariate analysis to predict skin conditions., Materials and Methods: SC samples were collected from participants, imaged, and annotated. Nine biomarkers were measured in the samples using enzyme-linked immunosorbent assay. The data were then used to teach machine-learning models to recognize individual SC cell regions and estimate the levels of the nine biomarkers from the images. Skin physiological indicators (e.g., skin barrier function, facial analysis, and questionnaires) were measured or obtained from the participants. Multivariate analysis, including biomarker levels ​​and structural parameters of the SC as variables, was used to estimate these physiological indicators., Results: We established two machine-learning models. The accuracy of recognition was assessed according to the average intersection over union (0.613), precision (0.953), recall (0.640), and F-value (0.766). The predicted biomarker levels significantly correlated with the measured levels. Skin physiological indicators and questionnaire answers were predicted with strong correlations and correct answer rates., Conclusion: Various physiological skin conditions can be predicted from images of the SC using AI models and multivariate analysis. Our method is expected to be useful for dermatological treatment optimization., (© 2024 The Authors. Skin Research and Technology published by John Wiley & Sons Ltd.)

Skin-related immune disorders are a category of diseases that lead to the dysregulation of the body's immune response due to imbalanced immune regulation. These disorders exhibit diverse clinical manifestations and complicated pathogenesis. The long-term use of corticosteroids, anti-inflammatory drugs, and immunosuppressants as traditional treatment methods for skin-related immune disorders frequently leads to adverse reactions in patients. In addition, the effect of external preparations is not ideal in some cases due to the compacted barrier function of the stratum corneum (SC). Microneedles (MNs) are novel transdermal drug delivery systems that have theapparent advantages ofpenetrating the skin barrier, such as long-term and controlled drug delivery, less systemic exposure, and painless and minimally invasive targeted delivery. These advantages make it a good candidate formulation for the treatment of skin-related immune disorders and a hotspot for research in this field. This paper updates the classification, preparation, evaluation strategies, materials, and related applications of five types of MNs. Specific information, including the mechanical properties, dimensions, stability, and in vitro and in vivo evaluations of MNs in the treatment of skin-related immune disorders, is also discussed. This review provides an overview of the advances and applications of MNs in the effective treatment of skin-related immune disorders and their emerging trends., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Wound healing can be influenced by genes that control the circadian cycle, including Per2 and BMAL1, which coordinate the functions of several organs, including the skin. The aim of the study was to evaluate the role of PER2 during experimental skin wound healing. Two groups (control and Per2-KO), consisting of 14 male mice each, were anesthetized by inhalation, and two 6 mm wounds were created on their dorsal skin using a punch biopsy. A silicone ring was sutured around the wound perimeter to restrict contraction. The wound healing process was clinically measured daily (closure index) until complete wound repair. On Day 6, histomorphometric analysis was performed using the length and thickness of the epithelial migration tongue, in addition to counting vessels underlying the lesion by immunofluorescence assay and maturation of collagen fibers through picrosirius staining. Bromodeoxyuridine (BrdU) incorporation and quantification were performed using the subcutaneous injection technique 2 h before euthanasia and through immunohistochemical analysis of the proliferative index. In addition, the qualitative analysis of myofibroblasts and periostin distribution in connective tissue was performed by immunofluorescence. Statistically significant differences were observed in the healing time between the experimental groups (means: 15.5 days for control mice and 13.5 days for Per2-KO; p = 0.001). The accelerated healing observed in the Per2-KO group (p < 0.05) was accompanied by statistical differences in wound diameter and length of the migrating epithelial tongue (p = 0.01) compared to the control group. Regarding BrdU immunoreactivity, higher expression was observed in the intact epithelium of Per2-KO animals (p = 0.01), and this difference compared to control was also present, to a lesser extent, at the wound site (p = 0.03). Immunofluorescence in the connective tissue underlying the wound showed a higher angiogenic potential in the Per2-KO group in the intact tissue area and the wound region (p < 0.01), where increased expression of myofibroblasts was also observed. Qualitative analysis revealed the distribution of periostin protein and collagen fibers in the connective tissue underlying the wound, with greater organization and maturation during the analyzed period. Our research showed that the absence of the Per2 gene positively impacts the healing time of the skin in vivo. This acceleration depends on the increase of epithelial proliferative and angiogenic capacity of cells carrying the Per2 deletion., (© 2024 The Authors. Journal of Cellular Biochemistry published by Wiley Periodicals LLC.)

Dermal uptake is an important and complex exposure route for a wide range of chemicals. Dermal exposure can occur due to occupational settings, pharmaceutical applications, environmental contamination, or consumer product use. The large range of both chemicals and scenarios of interest makes it difficult to perform generalizable experiments, creating a need for a generic model to simulate various scenarios. In this study, a model consisting of a series of four well-mixed compartments, representing the source solution (vehicle), stratum corneum, viable tissue, and receptor fluid, was developed for predicting dermal absorption. The model considers experimental conditions including small applied doses as well as evaporation of the vehicle and chemical. To evaluate the model assumptions, we compare model predictions for a set of 26 chemicals to finite dose in-vitro experiments from a single laboratory using steady-state permeability coefficient and equilibrium partition coefficient data derived from in-vitro experiments of infinite dose exposures to these same chemicals from a different laboratory. We find that the model accurately predicts, to within an order of magnitude, total absorption after 24 h for 19 of these chemicals. In combination with key information on experimental conditions, the model is generalizable and can advance efficient assessment of dermal exposure for chemical risk assessment., Competing Interests: Declaration of competing interest This manuscript is being submitted exclusively to Chemosphere and this research and the results have not been published previously, and if accepted this paper will not be published elsewhere. None of the authors have financial and personal relationships with other people or organizations that could inappropriately influence our work. All authors have approved this manuscript in its submitted version. The research and manuscript have been reviewed, cleared, and approved by U.S. Environmental Protection Agency. Daniel A. Vallero, Ph.D. Corresponding Author., (Published by Elsevier Ltd.)

It is well established that the biomechanical properties of the Stratum Corneum (SC) are influenced by both moisture-induced plasticization and the lipid content. This study employs Atomic Force Microscopy to investigate how hydration affects the surface topographical and elasto-viscoplastic characteristics of corneocytes from two anatomical sites. Volar forearm cells underwent swelling when immersed in water with a 50% increase in thickness and volume. Similarly, medial heel cells demonstrated significant swelling in volume, accompanied by increased cell area and reduced cell roughness. Furthermore, as the water activity was increased, they exhibited enhanced compliance, leading to a decreased Young's modulus, hardness, and relaxation times. Moreover, the swollen cells also displayed a greater tolerance to strain before experiencing permanent deformation. Despite the greater predominance of immature cornified envelopes in plantar skin, the comparable Young's modulus of medial heel and forearm corneocytes suggests that cell stiffness primarily relies on the keratin matrix rather than on the cornified envelope. The Young's moduli of the cells in distilled water are similar to those reported for the SC, which suggests that the corneodesmosomes and intercellular lamellae lipids junctions that connect the corneocytes are able to accommodate the mechanical deformations of the SC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Robust interfacial compliance is essential for long-term physiological monitoring via skin-mountable ionic materials. Unfortunately, existing epidermal ionic skins are not compliant and durable enough to accommodate the time-varying deformations of convoluted skin surface, due to an imbalance in viscosity and elasticity. Here we introduce a self-compliant ionic skin that consistently works at the critical gel point state with almost equal viscosity and elasticity over a super-wide frequency range. The material is designed by leveraging hierarchical hydrogen bond association, allowing for the continuous release of polymer strands to create topological entanglements as complementary crosslinks. By embodying properties of rapid stress relaxation, softness, ionic conductivity, self-healability, flaw-insensitivity, self-adhesion, and water-resistance, this ionic skin fosters excellent interfacial compliance with cyclically deforming substrates, and facilitates the acquisition of high-fidelity electrophysiological signals with alleviated motion artifacts. The presented strategy is generalizable and could expand the applicability of epidermal ionic skins to more complex service conditions., (© 2024. The Author(s).)

Alongside increases in the average lifespan and a growing interest in anti-aging remedies, the demand for at-home skincare devices is rapidly expanding in the cosmetic market. This study aimed to assess the safety and efficacy of a novel home-use handheld multi-energy-based device for skin rejuvenation that simultaneously emits low level light, low-dose radiofrequency, low-energy microcurrent, and low-intensity ultrasonic wave. This prospective, randomized, split-face clinical trial enrolled 36 healthy Korean women. After 8 weeks of device use, parameters associated with skin aging were assessed. Additionally, a preliminary ex vivo study and skin biopsy following device use were performed to confirm safety and efficiency of the device. Parameters associated with skin aging including skin hydration, elasticity, roughness, skin pore size, and eye wrinkle volume showed significant improvements after 8 weeks of the device use, relative to baseline measurements and the control side. No adverse effects were observed during the follow-up period. Results of ex vivo and in vivo skin tissue studies correlated with clinical findings, which showed an increase in the expression of type 1 collagen and a decrease in the expression of matrix metalloproteinase-1, which is related to the skin aging phenotype. The expression of loricrin and involucrin, major components of the epidermal skin barrier, also increased after the use of the device. Multi-energy-based device is effective for skin rejuvenation and tolerable, without any considerable adverse effects., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Specific T cell populations in the skin have been demonstrated as important disease drivers in several dermatoses. Due to the unique skin architecture, these cells are not grouped together in structures but dispersedly spread out throughout the epidermis. Following tissue disruption and isolation, only about 10% of skin T cells are recovered and any in vitro expansion may alter their bona fide phenotype. The Nanostring GeoMx system was developed to address cellular phenotype and protein expression in a tissue spatial context. To do so, regions of interest (ROI) must exceed a certain area threshold (usually 100 μm in diameter) to generate a sufficient signal-to-noise ratio. Here, we present an approach that allows for the pooling of numerous smaller ROIs within the skin, enabling T cell and melanocyte phenotyping. Skin samples from healthy individuals and vitiligo patients were analysed using the GeoMx system and several immune profiling panels. A sufficient signal-to-noise ratio was achieved by pooling smaller ROIs and analysing them as a single group. While this prevents spatial analysis, this method allows for detailed analysis of cells as a population in the context of their physiological environment, making it possible to investigate in situ phenotype of rare cells in different tissue compartments., (© 2023 The Authors. Scandinavian Journal of Immunology published by John Wiley & Sons Ltd on behalf of The Scandinavian Foundation for Immunology.)

Skin is the most prominent tissue and organ, as well as the first line of defence, of the body. Because it is situated on the body's surface, it is constantly exposed to microbial, chemical, and physical factors such as mechanical stimulation. Therefore, skin has evolved substantial immune defences, regenerative ability, and anti-injury capacity. Epidermal cells produce antibacterial peptides that play a role in immune defence under physiological conditions. Additionally, IgG or IgA in the skin also participates in local anti-infective immunity. However, based on the classical theory of immunology, Ig can only be produced by B cells which should be derived from local B cells. This year, thanks to the discovery of Ig derived from non B cells (non B-Ig), Ig has also been found to be expressed in epidermal cells and contributes to immune defence. Epidermal cell-derived IgG and IgA have been demonstrated to have potential antibody activity by binding to pathogens. However, these epidermal cell-derived Igs show different microbial binding characteristics. For instance, IgG binds to Staphylococcus aureus and IgA binds to Staphylococcus epidermidis. Epidermal cells producing IgG and IgA may serve as an effective defense mechanism alongside B cells, providing a novel insight into skin immunity., (© 2024. Springer Nature Singapore Pte Ltd.)

Human skin equivalents (HSEs) serve as important tools for mechanistic studies with human skin cells, drug discovery, pre-clinical applications in the field of tissue engineering and for skin transplantation on skin defects. Besides the cellular and extracellular matrix (ECM) components used for HSEs, physical constraints applied on the scaffold during HSEs maturation influence tissue organization, functionality, and homogeneity. In this study, we introduce a 3D-printed culture insert that exposes bi-layered HSEs to a static radial constraint through matrix adhesion. We examine the effect of various diameters of the ring-shaped culture insert on the HSE's characteristics and compare them to state-of-the-art unconstrained and planar constrained HSEs. We show that radial matrix constraint of HSEs regulates tissue contraction, promotes fibroblast and matrix organization that is similar to human skin in vivo and improves keratinocyte differentiation, epidermal stratification, and basement membrane formation depending on the culture insert diameter. Together, these data demonstrate that the degree of HSE's contraction is an important design consideration in skin tissue engineering. Therefore, this study can help to mimic various in vivo skin conditions and to increase the control of relevant tissue properties., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Tactile sensation plays a crucial role in object manipulation, communication, and even emotional well-being. It has been reported that the deformability of skin (also described as skin compliance) that shows a large mechanical response to stimuli is associated with high tactile sensitivity. However, although the compliance of the stratum corneum, the outermost layer of skin, can change daily due to skin care and environmental factors, few studies have quantified the effect of the stratum corneum on tactile sensation., Aims: We investigated the changes in tactile sensitivity resulting from skin hydration and identified corresponding alterations in the compliance of the stratum corneum., Methods: A randomized controlled trial was conducted. Participants were randomly assigned to an intervention group (n = 20) that had a moisturizing cream applied to their cheeks or a control group (n = 19) that had Milli-Q water applied to their cheeks. Tactile discrimination performance was assessed using psychophysical techniques before and after application. The water content, mechanical response characteristics, and penetration of PEG/PPG-17/4 dimethyl ether from the cream in the stratum corneum were evaluated to identify hydration effects. Skin deformations occurring during tactile sensation were measured concurrently using a suction device employed for tactile stimulation., Results: Tactile sensitivity was increased in participants who had cream applied to the skin surface, while no significant change was observed in participants who received Milli-Q water. The improved discrimination of tactile stimulus intensity was directly related to the magnitude of skin displacement. The higher water content of the stratum corneum due to cream application decreased the dynamic modulus of elasticity of the stratum corneum and increased the skin's extensibility in response to tactile stimuli., Conclusions: Hydrating the stratum corneum significantly enhances tactile sensitivity and is accompanied by an increase in skin extensibility, a factor in tactile intensity perception. The compliance of the thin stratum corneum layer plays a crucial role in tactile experiences that involve skin stretching., (© 2023 Shiseido Co., Ltd and The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

To improve wound healing or treatment of other skin diseases, and provide model cells for skin biology studies, in vitro differentiation of stem cells into keratinocyte-like cells (KLCs) is very desirable in regenerative medicine. This study examined the most recent advancements in in vitro differentiation of stem cells into KLCs, the effect of biofactors, procedures, and preparation for upcoming clinical cases. A range of stem cells with different origins could be differentiated into KLCs under appropriate conditions. The most effective ways of stem cell differentiation into keratinocytes were found to include the co-culture with primary epithelial cells and keratinocytes, and a cocktail of growth factors, cytokines, and small molecules. KLCs should also be supported by biomaterials for the extracellular matrix (ECM), which replicate the composition and functionality of the in vivo extracellular matrix (ECM) and, thus, support their phenotypic and functional characteristics. The detailed efficient characterization of different factors, and their combinations, could make it possible to find the significant inducers for stem cell differentiation into epidermal lineage. Moreover, it allows the development of chemically known media for directing multi-step differentiation procedures.In conclusion, the differentiation of stem cells to KLCs is feasible and KLCs were used in experimental, preclinical, and clinical trials. However, the translation of KLCs from in vitro investigational system to clinically valuable cells is challenging and extremely slow., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Most people are living into their sixties and beyond. Fundamental changes in chronologically aged skin have significant and widespread dermatological implications. This review discusses aging-associated alterations in epidermal function leading to xerosis and related pruritus and the benefits of maintaining or restoring a healthy skin barrier using skincare, specifically ceramide-containing skincare.&nbsp;&nbsp; Methods: A panel of 7 dermatologists convened for a meeting to review aspects of xerosis in mature skin, skin barrier changes, and nuances in the treatment and maintenance of mature skin using gentle cleansers and moisturizers. From the selected literature, 13 statements were drafted. During the meeting, the draft statements underwent the panel's evaluation at a workshop, followed by a plenary discussion adopting 5 statements using evidence from the literature coupled with the panel's opinions and experiences., Results: The exact etiology of xerosis is not entirely understood and likely depends on several genetic and environmental mechanisms. Aging-associated changes in epidermal function include a marked reduction in total lipids in the stratum corneum relative to young skin due to reduced epidermal lipid synthesis. In aging skin, xerosis is significantly associated with pruritus. Studies have shown that lipid-containing skin care, such as a gentle ceramide-containing cleanser and moisturizer, promotes a healthy barrier reducing xerosis and pruritus in individuals with mature skin.&nbsp; Conclusions: The development of xerosis in mature skin involves several genetic and environmental mechanisms. Skincare, including gentle cleansers and moisturizers, has reduced xerosis and pruritus in mature skin individuals.&nbsp; &nbsp;&nbsp; J Drugs Dermatol. 2024;23(1):1253-1259.&nbsp; &nbsp;&nbsp; doi:10.36849/JDD.7560.

I have been studying the improvement of drug solubility using solid dispersion and skin-applied formulations. When preparing solid dispersions using phosphatidylcoline (PC) as a carrier, drug with hydrogen-donating groups interacts with PC to produce amorphous solid dispersions with high drug content; this overcomes improves drug absorption. The drug was solubilized and supersaturated in the oil-based gel formed with hyadrogenated lecithin; this facilitates drug permeation through the skin. The promoting effect differs with the nature of the oil used because of the skin penetration of the oil itself and the accompanying increase in drug solubility and diffusion coefficient in the skin. At actual application volumes of 10 µL/cm 2 or less, the skin penetration of poorly-absorbable drugs depends on the molecular weight and surface tension of the oil. The penetration of the oil vehicle into the upper stratum corneum influences the reach of the drug into the stratum corneum; a high drug concentration near the 7th layer of the stratum corneum promotes migration through the skin by increasing the linear concentration gradient in deeper layers. In addition, we performed a risk assessment, in collaboration with toxicologists, for dermal safety that included the toxicity potential of substances and the parts related to skin transfer.

Physicians and dentists are at risk for chronic hand eczema, but their skin barrier condition has rarely been investigated before. Background: To objectively assess the skin barrier condition among physicians and dentists. Objective: This cross-sectional epidemiological study included an occupational questionnaire, medical examination of hand skin, skin transepidermal water loss (TEWL), and pH measurements, analyzed in 5 groups (N = 37 in each): physicians-nonsurgeons, physicians-surgeons, dentists-nonsurgeons, dentists-surgeons, and control group (unexposed workers). Methods: Critical skin condition (TEWL >30 g/[m Results: Critical skin condition (TEWL >30 g/[m 2 ·h]) was found in 14% of control workers, 14% physicians nonsurgeons, 22% physicians surgeons, 27% dentists nonsurgeons, and 43% dentists surgeons. The latter had the worst stratum corneum ·h) (interquartile range [IQR] 19.24-34.31). Hand skin pH was highest among dentists with nonsurgical specializations, with a median of 5.33 (IQR 5.15-5.60), where 38% of them had pH >5.5. Male sex ( 2 ·h) (interquartile range [IQR] 19.24-34.31). Hand skin pH was highest among dentists with nonsurgical specializations, with a median of 5.33 (IQR 5.15-5.60), where 38% of them had pH >5.5. Male sex ( P  < 0.001) and glove use for >1 h/day ( P  = 0.009) were associated with elevated hand TEWL values, whereas female sex ( P  < 0.001) and glove use for >4 h/day with elevated pH values ( P Prolonged glove usage and dental profession, especially surgical work, significantly affect the skin barrier condition. This study was the first to objectively determine skin barrier condition among dentists and physicians. Conclusions: Prolonged glove usage and dental profession, especially surgical work, significantly affect the skin barrier condition. This study was the first to objectively determine skin barrier condition among dentists and physicians.

Moisturization causes physiological changes that improve the barrier function of human skin and mechanical changes, including skin friction characteristics. This study evaluated petrolatum- or silicone oil-treated human skin to determine the effect of moisturizing on the friction dynamics. The friction force on the human skin was measured using a contact probe with a sinusoidal motion. The contact probe was used to rub the skin of the upper arm of 20 subjects. The water content of the stratum corneum, softness, and barrier function of the skin were measured using a corneometer, cutometer, and tewameter, respectively. Both oils reduce the frictional force on the human skin. Simultaneously, silicone oil also reduced the delay time δ, which is the standardized time difference between the frictional force response to contact probe movement. Three typical friction patterns were also discovered, which were significantly changed by the treatment with oil. These changes were attributed to the lubrication effect and elimination of adhesion at the true contact point between the skin and the contact probe.

Background: The epidermis contains many structurally diverse ceramides, which form the skin permeability barrier (skin barrier). Mutations in genes involved in the synthesis of ω-O-acylceramides (acylceramides) and protein-bound ceramides cause ichthyosis., Objective: We aimed to elucidate the relationship between the degree of skin barrier impairment and changes in epidermal ceramide profiles caused by mutations in acylceramide synthesis genes., Methods: Knockout (KO) mice of three genes-fatty acid (FA) ω-hydroxylase Cyp4f39 (human CYP4F22 ortholog), FA elongase Elovl1, and acyl-CoA synthetase Fatp4-were subjected to transepidermal water loss measurement, toluidine blue staining, and epidermal ceramide profiling via liquid chromatography coupled with tandem mass spectrometry., Results: Transepidermal water loss was highest in Cyp4f39 KO mice, followed by Elovl1 KO and Fatp4 KO mice, and Cyp4f39 KO mice also showed the strongest degree of toluidine blue staining. In Cyp4f39 KO, Elovl1 KO, and Fatp4 KO mice, acylceramide levels were 0.6%, 1.6%, and 12%, respectively, of those in wild-type mice. Protein-bound ceramide levels were 0.2%, 30%, and 33%, respectively, of those in wild-type mice. We also observed a near-complete absence of ω-hydroxy ceramides in Cyp4f39 KO mice, reduced total ceramide levels and shortened FA moieties in Elovl1 KO mice, and increased hydroxylated ceramide levels and slightly shortened FA moieties in Fatp4 KO mice., Conclusions: The degree of reduction in protein-bound ceramide levels is probably related to the severity of skin barrier defects in these three strains. However, reduced acylceramide levels and other changes in ceramide composition unique to each KO strain are also involved., (Copyright © 2023 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Assessing drug disposition in the skin after the application of a topical formulation is difficult. It is hypothesized that reverse iontophoresis (RI), which can extract charged/polar molecules for monitoring purposes, may provide a noninvasive approach for the assessment of local drug bioavailability. The passive and RI extraction of salicylic acid (SA) and nicotine (NIC) from porcine skin in vitro was assessed after a simple solution of the former and a transdermal patch of the latter had been applied for 24 and 8 h, respectively. Immediately after this "passive skin loading", the amount of drug in the stratum corneum (SC) and "viable" tissue (VT) was measured either (a) after tape-stripping and subsequent solvent extraction of both skin layers or (b) following RI extraction over 4 h. Parallel experiments were then performed in vivo in healthy volunteers; in this case, the VT was not sampled and the skin loading period for NIC was only 4 h. RI extraction of both drugs was significantly higher ( in vitro and in vivo ) than that achieved passively, and the cumulative RI extraction profiles as a function of time were mathematically analyzed using a straightforward compartmental model. Best-fit estimates of drug amounts in the SC and VT ( A SC,0 and A VT,0 , respectively) at the end of "loading" and two first-order rate constants describing transfer between the model compartments were then determined. The in vitro predictions of A SC,0 and A results were also similar. In summary, the results provide proof-of-concept that the RI method has the potential to noninvasively assess relevant metrics of drug bioavailability in the skin.VT,0 were in excellent agreement with the experimental results, as was the value of the former in vivo . The rate constants derived from the in vitro and in vivo results were also similar. In summary, the results provide proof-of-concept that the RI method has the potential to noninvasively assess relevant metrics of drug bioavailability in the skin.

The epidermis serves many vital roles, including protecting the body from external influences and healing eventual injuries. It is maintained by an incredibly complex and perfectly coordinated keratinization process. In this process, desquamation is essential for the differentiation of epidermal basal progenitor cells into enucleated corneocytes, which subsequently desquamate through programmed death. Numerous factors control keratinocyte differentiation: epidermal growth factor, transforming growth factor-α, keratinocyte growth factor, interleukins IL-1-β and IL-6, elevated vitamin A levels, and changes in Ca 2+ concentration. The backbone of the keratinocyte transformation process from mitotically active basal cells into fully differentiated, enucleated corneocytes is the expression of specific proteins and the creation of a Ca 2+ and pH gradient at precise locations within the epidermis. Skin keratinization disorders (histologically characterized predominantly by dyskeratosis, parakeratosis, and hyperkeratosis) may be categorized into three groups: defects in the α-helical rod pattern, defects outside the α-helical rod domain, and disorders of keratin-associated proteins. Understanding the process of keratinization is essential for the pathogenesis of many dermatological diseases because improper desquamation and epidermopoiesis/keratinization (due to genetic mutations of factors or due to immune pathological processes) can lead to various conditions (ichthyoses, palmoplantar keratodermas, psoriasis, pityriasis rubra pilaris, epidermolytic hyperkeratosis, and others).

The quantitative determination of topically applied substances in the skin is severely limited and represents a challenging task. The porcine skin ex vivo was topically treated with a gel containing caffeine (CF) and propylene glycol (PG), and depth-resolved Raman spectra were recorded with two confocal Raman microscopes. We applied a novel tailored multivariate curve resolution-alternating least squares method to the selected spectral regions (512-604 and 778-1148 cm -1 ) of gel-treated skin and quantitatively determined the concentrations of CF and PG in the stratum corneum (SC). The highest concentration of CF (181 mg/cm 3 ) was found at the surface, while PG (384 mg/cm 3 ) was found at 10% SC depth, indicating the formation of a reservoir at the superficial SC. The concentrations of CF and PG decreased monotonically and reached the detection limit at ≈60% and ≈80% SC depth, respectively, indicating that neither permeate the SC., (© 2023 Wiley-VCH GmbH.)

Skin expands and regenerates in response to mechanical stretch. This important homeostasis process is critical for skin biology and can be exploited to generate extra skin for reconstructive surgery. Atmospheric oxygen uptake is important in skin homeostasis. However, whether and how cutaneous atmospheric oxygen uptake changes during mechanical stretch remains unclear, and relevant research tools to quantify oxygen flux are limited. Herein, we used the scanning micro-optrode technique (SMOT), a non-invasive self-referencing optical fiber microsensor, to achieve real-time measurement of cutaneous oxygen uptake from the atmosphere. An in vivo mechanical stretch-induced skin expansion model was established, and an in vitro Flexcell Tension system was used to stretch epidermal cells. We found that oxygen influx of skin increased dramatically after stretching for 1 to 3 days and decreased to the non-stretched level after 7 days. The enhanced oxygen influx of stretched skin was associated with increased epidermal basal cell proliferation and impaired epidermal barrier. In conclusion, mechanical stretch increases cutaneous oxygen uptake with spatial-temporal characteristics, correlating with cell proliferation and barrier changes, suggesting a fundamental mechanistic role of oxygen uptake in the skin in response to mechanical stretch. Optical fiber microsensor-based oxygen uptake detection provides a non-invasive approach to understand skin homeostasis., (© 2023 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

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., (© 2023 Society of Cosmetic Scientists and the Société Française de Cosmétologie.)

Poly(methyl methacrylate) (PMMA) is considered an attractive substrate material for fabricating wearable skin sensors such as fitness bands and microfluidic devices. Despite its widespread use, inflammatory and allergic responses have been attributed to the use of this material. Therefore, the main objective of this study was to obtain a comprehensive understanding of potential biological effects triggered by PMMA at non-cytotoxic concentrations using in vitro models of NIH3T3 fibroblasts and reconstructed human epidermis (RhE). It was hypothesized that concentrations that do not reduce cell viability are sufficient to activate pathways of inflammatory processes in the skin. The study included cytotoxicity, cell metabolism, cytokine quantification, histopathological, and gene expression analyses. The NIH3T3 cell line was used as a testbed for screening cell toxicity levels associated with the concentration of PMMA with different molecular weights (MWs) (i.e., MW ~5,000 and ~15,000 g/mol). The lower MW of PMMA had a half-maximal inhibitory concentration (IC 50 ) value of 5.7 mg/cm 2 , indicating greater detrimental effects than the higher MW (IC 50  = 14.0 mg/cm 2 ). Non-cytotoxic concentrations of 3.0 mg/cm 2 for MW ~15,000 g/mol and 0.9 mg/cm 2 for MW ~5,000 g/mol) induced negative metabolic changes in NIH3T3 cells. Cell viability was severely reduced to 7% after the exposure to degradation by-products generated after thermal and photodegradation degradation of PMMA. PMMA at non-cytotoxic concentrations still induced overexpression of pro-inflammatory cytokines, chemokines, and growth factors (IL1B, CXCL10, CCL5, IL1R1, IL7, IL17A, VEGFA, FGF2, IFNG, IL15) on the RhE model. The inflammatory response was also supported by histopathological and gene expression analyses of PMMA-treated RhE, indicating tissue damage and gene overexpression. Results suggested that non-cytotoxic concentrations of PMMA (3.0 to 5.6 mg/cm 2 for MW ~15,000 g/mol and 0.9 to 2.1 mg/cm 2 for MW ~5,000 g/mol) were sufficient to negatively alter NIH3T3 cells metabolism and activate inflammatory events in the RhE skin., (© 2023 Wiley Periodicals LLC.)

Anuran skin is a dynamic organ involved in essential functions that strongly correlate with specific morphological traits. Particularly, gas exchange has been associated with epidermal modifications, such as reduced cell layers and increased vascularization. Here, we describe the epidermal morphology and its association with capillary networks in the dorsal skin of 103 Neotropical anurans (Nobleobatrachia) from different ecomorphs and habitats. Additionally, we examined the lateral and ventral skin for a subset of these species. We report intraepidermal capillaries in (i) dorsal skin of Lepidobatrachus laevis and Lepidobatrachus llanensis (burrowing and semi-aquatic Chacoan species), Hyloscirtus colymba and Hyloscirtus palmeri (arboreal species from humid forests), and Alsodes neuquensis and 15 Telmatobius spp. (aquatic and semi-aquatic species from cold environments); (ii) lateral skin of Boana benitezi and H. colymba (arboreal species from humid forests), and (iii) ventral skin of B. benitezi, H. colymba, Atelognathus patagonicus (aquatic species from cold environments), and four Chacoan species, Chacophrys pierottii, Ceratophrys cranwelli (burrowing/terrestrial species), and Lepidobatrachus asper and L. llanensis (burrowing/semi-aquatic species). Also, verrucae hydrophilicae were observed exclusively in the ventral skin of Leptodactylus fuscus, Leptodactylus laticeps (terrestrial and Chacoan species), and B. benitezi. Regardless of the skin region, the capillaries always penetrate the epidermis from the dermis, while epidermal cell layers are flattened. Our findings support previous hypotheses stating that the environment where species occur influences skin changes related to cutaneous respiration (intraepidermal capillaries in different body regions) and water absorption (intraepidermal capillaries associated with verrucae hydrophilicae within ventral skin). Also, phylogeny might influence the development of these structures, as revealed by the presence of intraepidermal capillaries in almost all analyzed species of Telmatobius. Finally, the co-occurrence of verrucae hydrophilicae in the ventral skin of hylids from humid forests, and leptodactylids from the subhumid Chacoan region suggest an independent origin., (© 2023 Wiley Periodicals LLC.)

Flexible electronic sensors show great potential for health monitoring but are usually limited to single sensing functionality. To enrich their functions, complicated device configurations, sophisticated material systems, and preparation processes are typically involved, obstructing their large-scale deployment and widespread application. Herein, to achieve a good balance between simplicity and multifunctionality, a new paradigm of sensor modality for both mechanical sensing and bioelectrical sensing is presented based on a single material system and a simple solution processing approach. The whole multifunctional sensors are constructed with a pair of highly conductive ultrathin electrodes (WPU/MXene-1) and an elastic micro-structured mechanical sensing layer (WPU/MXene-2), with the human skin serving as the substrate for the whole sensors. The resultant sensors show high pressure sensitivity and low skin-electrode interfacial impedance, enabling to synergetically monitor both physiological pressure (e.g., arterial pulse signals) and epidermal bioelectrical signals (including electrocardiograph and electromyography). The universality and extensibility of this methodology to construct multifunctional sensors with different material systems are also verified. This simplified sensor modality with enhanced multifunctionality provides a novel design concept to construct future smart wearables for health monitoring and medical diagnosis., (© 2023 Wiley-VCH GmbH.)

Chronic, nonhealing wounds remain a clinical challenge and a significant burden for the healthcare system. Skin-resident and infiltrating T cells that recognize pathogens, microbiota, or self-antigens participate in wound healing. A precise balance between proinflammatory T cells and regulatory T cells is required for the stages of wound repair to proceed efficiently. When diseases such as diabetes disrupt the skin microenvironment, T cell activation and function are altered, and wound repair is hindered. Recent studies have used cutting-edge technology to further define the cellular makeup of the skin prior to and during tissue repair. In this review, we discuss key advances that highlight mechanisms used by T cell subsets to populate the epidermis and dermis, maintain skin homeostasis, and regulate wound repair. Advances in our understanding of how skin cells communicate in the skin pave the way for therapeutics that modulate regulatory versus effector functions to improve nonhealing wound treatment., (Copyright © 2023 by The American Association of Immunologists, Inc.)

Background: The world population is growing rapidly and skin problems such as skin tears (STs) are more common in aging skin due to changes in the epidermis and dermis. Identification of ageing related skin properties, which are risk factors for STs, is essential for the development of ST prevention protocols., Objective: The aim of this study was to reveal the skin properties related to epidermal function and dermal associated with STs., Material and Methods: A prospective case-control study was conducted with a sample of 36 older adults, 18 participants with ST and 18 participants without ST, in two elderly care centers. Tewameter TM 210 was used to measure transepidermal water loss, the Sebumeter SM810 was used to measure sebum, and Cutometer Dual MPA 580 was used to measure skin viscoelasticity (R0-R9). The differences of skin properties between groups were analyzed using the independent t-test and Mann-Whitney U test., Results: The case group had a mean age of 77,17 ± 9,7 and the control group had a mean age of 75,33 ± 6,8. It was determined that there were more ecchymosis (p < 0.000), hematoma (p = 0.008), and ST history (p = 0.001) in the case group. Older adults in the case group were more frail than the control group (p = 0.044). Regarding the score of the skin properties, the case group showed that the TEWL levels of the older adults in the case group were lower (p = 0.031) compared to the control groups. There was a significant difference between the groups and R0, R2, R5, and R7. While R0 was higher in the case group, R2, R5, and R7 were lower than the control group., Conclusion: Older adults with ST showed differences in skin properties compared to those without ST, especially transepidermal water loss, and viscoelasticity (R0, R2, R5, R7). The results of this study suggest that some changes in skin properties may be a risk factor for STs., Competing Interests: Declaration of competing interest We have no conflicts of interest to disclose., (Copyright © 2023 Tissue Viability Society / Society of Tissue Viability. Published by Elsevier Ltd. All rights reserved.)

Background: Firstly, confirm penetration of the skin's most exclusive layer, the stratum corneum (SC), by commercially available microneedle patches using reflectance confocal microscopy (RCM). Secondly, determine the deepest layer of the skin penetrated by the microneedle patches., Materials and Methods: In this proof-of-concept study, 3 commercially available dissolving microneedle patches with different active ingredients were included in this study. RCM images of the cheek were taken prior to patch application at 4 different layers of the skin: stratum corneum, stratum spinosum-granulosum, dermal-epidermal junction, and papillary dermis. Patches were then applied to the cheeks of participants according to manufacturer guidelines. Immediately after removal, the same area and layers were imaged using RCM and assessed for features of penetration., Results: Micropores were visualized in RCM images of skin layers post-application of all patches when compared with imaging before application. Characteristics of penetration included uniformly sized, shaped, and spaced well-defined circular areas, which are the created micropores. All 3 patches penetrated the SC to the level of the papillary dermis., Conclusion: This study confirms that the dissolving microneedle patches penetrate the most exclusive layer of the skin, the SC, down to the level of the papillary dermis as visualized through RCM. Confirming penetration with RCM shows the potential of these patches to be used for medication transmission. While future studies are needed to assess the efficacy of microneedle patches applied for their advertised skin conditions, confirming the penetration of the microneedle technology through RCM is a significant first step in this process. J Drugs Dermatol. 2023;22(11):1107-1110&nbsp; &nbsp;&nbsp; doi:10.36849/JDD.6994.

A wealth of specialized cell populations within the skin facilitates its hair-producing, protective, sensory, and thermoregulatory functions. How the vast cell-type diversity and tissue architecture develops is largely unexplored. Here, with single-cell transcriptomics, spatial cell-type assignment, and cell-lineage tracing, we deconstruct early embryonic mouse skin during the key transitions from seemingly uniform developmental precursor states to a multilayered, multilineage epithelium, and complex dermal identity. We identify the spatiotemporal emergence of hair-follicle-inducing, muscle-supportive, and fascia-forming fibroblasts. We also demonstrate the formation of the panniculus carnosus muscle (PCM), sprouting blood vessels without pericyte coverage, and the earliest residence of mast and dendritic immune cells in skin. Finally, we identify an unexpected epithelial heterogeneity within the early single-layered epidermis and a signaling-rich periderm layer. Overall, this cellular and molecular blueprint of early skin development-which can be explored at https://kasperlab.org/tools-establishes histological landmarks and highlights unprecedented dynamic interactions among skin cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Rete ridges consist of undulations between the epidermis and dermis that enhance the mechanical properties and biological function of human skin. However, most human skin models are fabricated with a flat interface between the epidermal and dermal layers. Here, we report a micro-stamping method for producing human skin models patterned with rete ridges of controlled geometry. To mitigate keratinocyte-induced matrix degradation, telocollagen-fibrin matrices with and without crosslinks enable these micropatterned features to persist during longitudinal culture. Our human skin model exhibits an epidermis that includes the following markers: cytokeratin 14, p63, and Ki67 in the basal layer, cytokeratin 10 in the suprabasal layer, and laminin and collagen IV in the basement membrane. We demonstrated that two keratinocyte cell lines, one from a neonatal donor and another from an adult diabetic donor, are compatible with this model. We tested this model using an irritation test and showed that the epidermis prevents rapid penetration of sodium dodecyl sulfate. Gene expression analysis revealed differences in keratinocytes obtained from the two donors as well as between 2D (control) and 3D culture conditions. Our human skin model may find potential application for drug and cosmetic testing, disease and wound healing modeling, and aging studies., (© 2023 IOP Publishing Ltd.)

Bioprinting is a promising alternative method to generate skin substitutes because it can replicate the structural organization of the skin into biomimetic layers in vitro. In this study, six primary human skin cell types were used to bioprint a trilayer skin construct consisting of epidermis, dermis, and hypodermis. Transplantation of the bioprinted skin with human cells onto full-thickness wounds of nu/nu mice promoted rapid vascularization and formation of epidermal rete ridges analogous to the native human epidermis, with a normal-looking extracellular matrix. Cell-specific staining confirmed the integration of the implanted cells into the regenerated skin. Using a similar approach, a 5 centimeter-by-5 centimeter bioprinted autologous porcine skin graft was transplanted onto full-thickness wounds in a porcine excisional wound model. The bioprinted skin graft improved epithelialization, reduced skin contraction, and supported normal collagen organization with reduced fibrosis. Differential gene expression demonstrated pro-remodeling protease activity in wounds transplanted with bioprinted autologous skin grafts. These results demonstrate that bioprinted skin can support skin regeneration to allow for nonfibrotic wound healing and suggest that the skin bioprinting technology may be applicable for human clinical use.

Being the more apparent organ exposed to the outdoor stressors, the effect of pollution on the skin has been widely studied in the last few decades. Although UV light is known as the most aggressive stressor to which our cutaneous tissue is daily exposed, other components of the tropospheric pollution have also shown to affect skin health and functionality. Among them, ozone has been proven to be one of the most toxic due to its high reactivity with the epidermal lipids. Studying the cutaneous effect of pollution in a laboratory setting presents challenges, therefore it becomes critical to employ appropriate and tailored models that aim to answer specific questions. Several skin models are available nowadays: in vitro models (2D cell lines and 3D cutaneous tissues), ex vivo skin explants and in vivo approaches (animals and humans). Although in the last 20 years researchers developed skin models that closely resemble human skin (3D cutaneous tissues), ex vivo skin explants still remain one of the best models to study cutaneous responses. Unfortunately, one important cutaneous property that is not present in the traditional ex vivo human skin explants is the physiological tension, which has been shown to be a cardinal player in skin structure, homeostasis, functional properties and responses to external stimuli. For this reason, in this study, to confirm and further comprehend the harmful mechanism of ozone exposure on the integumentary system, we have performed experiments using the state of art in cutaneous models: the innovative TenSkin™ model in which ex vivo human skin explants are cultured under physiologically relevant tension during the whole experimental procedure. Specifically, we were interested in corroborating previous findings showing that ozone exposure modulates the expression of cutaneous antimicrobial peptides (AMPs). The present work demonstrates that cutaneous exposure to ozone induces AMPs gene and protein levels (CAMP/LL-37, hBD2, hBD3) and that the presence of tension can further modulate their expression. In addition, different responses between tension and non-tension cultured skin were also observed during the evaluation of OxInflammatory markers [cyclooxygenase-2 (COX2), aryl hydrocarbon receptor (AhR), matrix-metallo-proteinase 9 (MMP9) and 4-hydroxy-nonenal (4HNE)]. This current study supports our previous findings confirming the ability of pollution to induce the cutaneous expression of AMPs via redox signaling and corroborates the principle that skin explants are a good and reliable model to study skin responses even though it underlines the need to holistically consider the role of skin tension before extrapolating the data to real life., (© 2023. Springer Nature Limited.)

Stem cells in organoids self-organize into tissue patterns with unknown mechanisms. Here, we use skin organoids to analyze this process. Cell behavior videos show that the morphological transformation from multiple spheroidal units with morphogenesis competence (CMU) to planar skin is characterized by two abrupt cell motility-increasing events before calming down. The self-organizing processes are controlled by a morphogenetic module composed of molecular sensors, modulators, and executers. Increasing dermal stiffness provides the initial driving force (driver) which activates Yap1 (sensor) in epidermal cysts. Notch signaling (modulator 1) in epidermal cyst tunes the threshold of Yap1 activation. Activated Yap1 induces Wnts and MMPs (epidermal executers) in basal cells to facilitate cellular flows, allowing epidermal cells to protrude out from the CMU. Dermal cell-expressed Rock (dermal executer) generates a stiff force bridge between two CMU and accelerates tissue mixing via activating Laminin and β1-integrin. Thus, this self-organizing coalescence process is controlled by a mechano-chemical circuit. Beyond skin, self-organization in organoids may use similar mechano-chemical circuit structures.