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Although, drugs are required in the various skin compartments such as viable epidermis, dermis, or hair follicles, to efficiently treat skin diseases, drug delivery into and across the skin is still challenging. An improved understanding of skin barrier physiology is mandatory to optimize drug penetration and permeation. The various barriers of the skin have to be known in detail, which means methods are needed to measure their functionality and outside-in or inside-out passage of molecules through the various barriers. In this review, we summarize our current knowledge about mechanical barriers, i.e., stratum corneum and tight junctions, in interfollicular epidermis, hair follicles and glands. Furthermore, we discuss the barrier properties of the basement membrane and dermal blood vessels. Barrier alterations found in skin of patients with atopic dermatitis are described. Finally, we critically compare the up-to-date applicability of several physical, biochemical and microscopic methods such as transepidermal water loss, impedance spectroscopy, Raman spectroscopy, immunohistochemical stainings, optical coherence microscopy and multiphoton microscopy to distinctly address the different barriers and to measure permeation through these barriers in vitro and in vivo.

The protein von Willebrand factor (VWF) is essential in primary hemostasis, as it mediates platelet adhesion to vessel walls. VWF retains its compact (globule-like) shape in equilibrium due to internal molecular associations, but is able to stretch when a high enough shear stress is applied. Even though the shear-flow sensitivity of VWF conformation is well accepted, the behavior of VWF under realistic blood flow conditions remains poorly understood. We perform mesoscopic numerical simulations together with microfluidic experiments in order to characterize VWF behavior in blood flow for a wide range of flow-rate and hematocrit conditions. In particular, our results demonstrate that the compact shape of VWF is important for its migration (or margination) toward vessel walls and that VWF stretches primarily in a near-wall region in blood flow making its adhesion possible. Our results show that VWF is a highly optimized protein in terms of its size and internal associations which are necessary to achieve its vital function. A better understanding of the relevant mechanisms for VWF behavior in microcirculation provides a further step toward the elucidation of the role of mutations in various VWF-related diseases.

The intravascular formation of neutrophil extracellular traps (NETs) is a trigger for coagulation and blood vessel occlusion. NETs are released from neutrophils as a response to strong inflammatory signals in the course of different diseases such as COVID-19, cancer or antiphospholipid syndrome. NETs are composed of large, chromosomal DNA fibers decorated with a variety of proteins such as histones. Previous research suggested a close mechanistic crosstalk between NETs and the coagulation system involving the coagulation factor XII (FXII), von Willebrand factor (VWF) and tissue factor. However, the direct impact of NET-related DNA fibers on blood flow and blood aggregation independent of the coagulation cascade has remained elusive. In the present study, we used different microfluidic setups in combination with fluorescence microscopy to investigate the influence of neutrophil-derived extracellular DNA fibers on blood rheology, intravascular occlusion and activation of the complement system. We found that extended DNA fiber networks decelerate blood flow and promote intravascular occlusion of blood vessels independent of the plasmatic coagulation. Associated with the DNA dependent occlusion of the flow channel was the strong activation of the complement system characterized by the production of complement component 5a (C5a). Vice versa, we detected that the local activation of the complement system at the vascular wall was a trigger for NET release. In conclusion, we found that DNA fibers as the principal component of NETs are sufficient to induce blood aggregation even in the absence of the coagulation system. Moreover, we discovered that complement activation at the endothelial surface promoted NET formation. Our data envisions DNA degradation and complement inhibition as potential therapeutic strategies in NET-induced coagulopathies.

The application of multiphoton microscopy in the field of biomedical research and advanced diagnostics promises unique insights into the pathophysiology of inflammatory skin diseases. In the present study, we combined multiphoton-based intravital tomography (MPT) and fluorescence lifetime imaging (MPT-FLIM) within the scope of a clinical trial of atopic dermatitis with the aim of providing personalised data on the aetiopathology of inflammation in a non-invasive manner at patients’ bedsides. These ‘optical biopsies’ generated via MPT were morphologically analysed and aligned with classical skin histology. Because of its subcellular resolution, MPT provided evidence of a redistribution of mitochondria in keratinocytes, indicating an altered cellular metabolism. Two independent morphometric algorithms reliably showed an even distribution in healthy skin and a perinuclear accumulation in inflamed skin. Moreover, using MPT-FLIM, detection of the onset and progression of inflammatory processes could be achieved. In conclusion, the change in the distribution of mitochondria upon inflammation and the verification of an altered cellular metabolism facilitate a better understanding of inflammatory skin diseases and may permit early diagnosis and therapy.

IntroductionChronic pruritus (CP) is a symptom of dermatologic, neurologic, systemic and psychosomatic diseases. CP has a prevalence of ~20% in the general population and is therefore a significant burden on society, but the transition from acute pruritus to CP is not well understood. It probably involves interactions between biological and psychosocial factors and pruritus-specific risk factors as well as mechanisms shared with other persistent somatic symptoms addressed in other projects of the SOMACROSS Research Unit (RU). Here we aim to identify psychosocial and biological factors and their interactions which might be associated with the persistence of CP with and without immunologic/inflammatory origin, that is, atopic dermatitis and pruritus on non-inflamed skin. We expect that psychosocial factors relevant to the persistence of symptoms such as fatigue and pain may also show associations to CP.Methods and analysisIn this prospective, exploratory observational study situated in Germany, three cohorts of 40 patients each with acute exacerbation of atopic dermatitis and chronic atopic dermatitis and 40 CP patients with unaffected skin will be recruited for a comprehensive translational investigation including pruritus-specific and the shared psychosocial assessments of the RU SOMACROSS. Pruritus-specific measures will include questionnaires, quantitative sensory testing, cutaneous nerve fibre morphology, skin barrier morphology, epidermal metabolism and pruritogen blood levels. Within 1 year, patients and 80 age-matched and sex-matched healthy controls will be examined at three time points, allowing cross-sectional comparison and a longitudinal investigation of predictive outcome factors in patients under treatment according to existing guidelines.Ethics and disseminationThe study has been approved by the ethics committees of Hamburg (2020-10200-BO-ff) and Münster (2020-676 f-S), Germany. All participants are required to provide written informed consent. Findings will be disseminated through peer-reviewed publications, scientific conferences and involvement of relevant stakeholders, patients and the lay public.Trial registration numberDRKS00026646.

During development and progression of malignant melanoma, an important role has been attributed to alterations of cell-cell adhesions, in particular, to a \"cadherin switch\" from E- to N-cadherin. We have previously shown that a subtype of melanoma cells express the desmosomal cadherin desmoglein 2 as non-junction-bound cell surface protein in addition to classical cadherins. To study the role of desmoglein 2 in melanoma cells, melanoma lines containing high endogenous amounts of desmoglein 2 were depleted of the protein by RNA interference. Transwell migration and scratch wounding assays showed markedly increased migration upon desmoglein 2 suppression whereas proliferation and viability remained unaltered. In gene expression profiles, desmoglein 2 depletion was associated with overexpression of migration-related genes. Strongest overexpression was found for secretogranin II which has not been reported in melanoma cells before. The bioactive peptide derived from secretogranin II, secretoneurin, is known to exert chemoattractive functions and was demonstrated here to stimulate melanoma cell migration. In summary, we show that desmoglein 2 expression attenuates migration of melanoma cells. The mechanism of desmoglein 2 impaired cell migration is mediated by downregulation of secretogranin II. Loss of desmoglein 2 increases expression of secretogranin II, followed by an enhanced migratory activity of melanoma cells. Our data add a new pathway of regulating melanoma cell migration related to a desmoglein 2-secretogranin II axis.

Background It has been demonstrated that von Willebrand factor (VWF) mediated platelet-endothelium and platelet-platelet interactions are shear dependent. The VWF’s mobility under dynamic conditions (e.g. flow) is pivotal to platelet adhesion and VWF-mediated aggregate formation in the cascade of VWF-platelet interactions in haemostasis. Results Combining microfluidic tools with fluorescence and reflection interference contrast microscopy (RICM), here we show, that specific deletions in the A-domains of the biopolymer VWF affect both, adhesion and aggregation properties independently. Intuitively, the deletion of the A1-domain led to a significant decrease in both adhesion and aggregate formation of platelets. Nevertheless, the deletion of the A2-domain revealed a completely different picture, with a significant increase in formation of rolling aggregates (gain of function). We predict that the A2-domain effectively ‘masks’ the potential between the platelet glycoprotein (GP) Ib and the VWF A1-domain. Furthermore, the deletion of the A3-domain led to no significant variation in either of the two functional characteristics. Conclusions These data demonstrate that the macroscopic functional properties i.e. adhesion and aggregate formation cannot simply be assigned to the properties of one particular domain, but have to be explained by cooperative phenomena. The absence or presence of molecular entities likewise affects the properties (thermodynamic phenomenology) of its neighbours, therefore altering the macromolecular function.

Background Picosecond (ps) laser treatments have been widely used for several years to remove unwanted tattoos. It is hypothesized that following the laser‐induced fragmentation of tattoo particles, transepidermal clearance occurs as one of the elimination processes alongside with the renewal of the skin. Nevertheless, the precise microscopic details of the tattoo clearance process following laser treatment remain unclear. Objective To analyze the transepidermal clearance of tattoo particles, along with the morphological and metabolic changes in the surrounding tissue, following ps laser treatment. Material and Methods The study population comprised healthy male and female patients seeking laser‐assisted tattoo removal, who were recruited from the Laser Department at the University Medical Center Hamburg–Eppendorf. Each subject underwent a single ps laser treatment session, and follow‐up assessments were conducted at 6 and 12 weeks post‐treatment using multiphoton tomography with fluorescence lifetime imaging (MPT‐FLIM). Results The study included a total of nine participants with eleven tattoos. In untreated skin, the tattoo particles were observed to be confined to the dermis, situated between collagen bundles. Six weeks following treatment, tattoo particles were observed in both inter‐ and intracellular spaces across all epidermal and the upper dermal layers. By the 12‐week follow‐up, particles were still present in the epidermis and dermis, although their quantity appeared to have decreased. In accordance with the aforementioned findings, the mean fluorescence lifetime measurements demonstrated a decrease across the follow‐up visits, although they remained elevated at 12 weeks. Conclusion Our in vivo, non‐invasive imaging data indicate that the transepidermal clearance of tattoo particles following ps laser treatment can extend over several months. This supports the hypothesis that longer intervals between ps laser treatments may be beneficial. Further prospective clinical studies are required to compare the efficacy and safety of short‐ and long‐term treatment intervals in laser‐assisted tattoo removal. Trial Registration ClinicalTrials.gov identifier: NCT06431464

Blood clotting is a process by which a haemostatic plug is assembled at the site of injury. The formation of such a plug, which is essentially a (bio)polymer–colloid composite, is believed to be driven by shear flow in its initial phase, and contrary to our intuition, its assembly is enhanced under stronger flowing conditions. Here, inspired by blood clotting, we show that polymer–colloid composite assembly in shear flow is a universal process that can be tailored to obtain different types of aggregates including loose and dense aggregates, as well as hydrodynamically induced ‘log’-type aggregates. The process is highly controllable and reversible, depending mostly on the shear rate and the strength of the polymer–colloidbinding potential. Our results have important implications for the assembly of polymer–colloid composites, an important challenge of immense technological relevance. Furthermore, flow-driven reversible composite formation represents a new paradigm in non-equilibrium self-assembly. Blood clotting is caused by biopolymer-mediated aggregation of platelets and is enhanced by fast shear flows. Chen et al . find a similar process that arises during the self-assembly of polymer–colloid composites—a process that can be controlled and even reversed by flow rate and interparticle interaction.

Why was the study undertaken? To investigate the prevalence of the mental comorbidity of somatic symptom disorder (SSD) in patients with chronic pruritus and to study pruritus intensity, psychological distress, quality of life and clinical characteristics in those patients. What does this study add? Using the ‘gold standard’ diagnostic tool, a structured clinical interview employing the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, SSD was diagnosed in about one in seven patients with chronic pruritus. Patients with SSD reported higher pruritus intensity, psychological distress and worse quality of life with large effect sizes. What are the implications of this study for disease understanding and/or clinical care? Somatic symptom disorder is an important and frequent comorbidity of chronic pruritus, both in atopic dermatitis and in chronic pruritus on non‐lesional skin. Patients with this comorbidity are much more burdened and greater emphasis should be placed on psychological aspects in these patients. Excessive health‐related thoughts, feelings, or behaviors associated with chronic pruritus should therefore lead to psychiatric/psychosomatic referral for diagnosis of SSD and interdisciplinary treatment.