Sensory neuron activation from topical treatments modulates the sensorial perception of human skin.

Neural signaling of skin sensory perception from topical treatments is often reported in subjective terms such as a sensation of skin "tightness" after using a cleanser or "softness" after applying a moisturizer. However, the mechanism whereby cutaneous mechanoreceptors and corresponding sensory neurons are activated giving rise to these perceptions has not been established. Here, we provide a quantitative approach that couples in vitro biomechanical testing and detailed computational neural stimulation modeling along with a comprehensive in vivo self-assessment survey to demonstrate how cutaneous biomechanical changes in response to treatments are involved in the sensorial perception of the human skin. Strong correlations are identified between reported perception up to 12 hours post treatment and changes in the computed neural stimulation from mechanoreceptors residing deep under the skin surface. The study reveals a quantitative framework for understanding the biomechanical neural activation mechanism and the subjective perception by individuals.

Partnering With Faith-Based Organizations to Offer Flu Vaccination and Other Preventive Services.

In 2019, just one-half of Americans received their influenza vaccine, despite it being safe, effective, and important in preventing serious infection, hospitalization, and death. Black children receive fewer influenza vaccines than their White counterparts. Vaccine hesitancy can hinder influenza vaccine uptake and is partially fueled by ongoing systemic racism and historical abuse leading to medical mistrust in communities of color. Building trust may enhance the transfer of reliable vaccine information and may move people along the spectrum of vaccine intention. We sought to partner with faith-based organizations through a community influenza vaccination event to increase vaccination rates. By leveraging the reach and expertise of trusted voices, such as church "first ladies" and local community leaders, we were able to administer 600 pediatric influenza vaccines between 2016 and 2019. In addition, this event served as a platform to assess whether youth attendees had a place for regular medical care ("medical home") (>80% did in each year assessed) and to conduct preventive screenings. Most children, as reported by their caregivers, had recent medical check-ups (85% in 2016, 84% in 2017, and 82% in 2018). Of the children screened, more than one-third had an abnormal body mass index and one-half had abnormal dentition. By partnering with organizations that are well-embedded in the local community, such as faith-based organizations, health care groups may be able to maximize the impact of their health promotion campaigns.

From decoding the perception of tightness to a clinical proof of soothing effects derived from natural ingredients in a moisturizer.

OBJECTIVE: To decode the feeling of skin tightness after application of a cosmetic product and how to soothe this discomfort. To pursue this aim, we considered the ingredient's effect on stratum corneum (SC) biomechanics to differentiate between consumers prone to tightness from those that are not and correlate these effects with mechanoreceptor activation. METHODS: In vivo clinical trials were used to assess the tightness perception dichotomy between groups of Caucasian women; in vitro experiments were used to measure the mechanical stresses induced in the SC after cleanser and moisturizer application; and in silico simulations were used to illustrate how the measured mechanical stresses in the SC result in the development of strains at the depth of cutaneous mechanoreceptors, triggering tightness perceptual responses. RESULTS: Before any cream application, women prone to tightness tend to have a more rigid SC than their less sensitive counterparts, however cleanser application increases SC stiffness in all women. Surprisingly, no correlation was found between tightness perception and hydration measurements by the Corneometer or barrier function, as evaluated by transepidermal water loss. Self-declared tightness and dryness scores were strongly associated with a self-described sensitive skin. After application of the optimized moisturizing formula, Osmoskin® containing natural waxes with good filming properties, consumers report a strong decrease in tightness and dryness perception. These results match with laboratory experiments where the cleanser was shown to increase SC drying stresses by 34%, while subsequent application of Osmoskin® decreased stresses by 48%. Finite element modelling, using experimental results as input, elucidates the differences in perception between the two groups of women. It makes clear that Osmoskin® changes the mechanical status of the SC, producing strains in underlying epidermis that activates multiple cutaneous mechano-receptors at a level correlated with the self-perceived comfort. CONCLUSION: Integration of the in vivo, in vitro and in silico approaches provides a novel framework for fully understanding how skin tightness sensations form and propagate, and how these sensations can be alleviated through the design of an optimized moisturizer.

OBJECTIF: Décoder l'impression de tiraillement de la peau après l'application d'un produit cosmétique et la manière d'apaiser cette sensation désagréable. Pour poursuivre cet objectif, nous avons pris en compte l'effet de l'ingrédient sur la biomécanique de la couche cornée afin de différencier les consommatrices sujettes à un tiraillement de celles qui ne le sont pas et de corréler ces effets avec l'activation des mécanorécepteurs. MÉTHODES: Des essais cliniques in vivo ont été utilisés pour évaluer la dichotomie de perception de tiraillement entre des groupes de femmes de race caucasienne; des expériences in vitro ont été utilisées pour mesurer les contraintes mécaniques induites dans la couche cornée après application d'un produit nettoyant et d'un produit hydratant; et des simulations in silico ont servi à illustrer comment les contraintes mécaniques mesurées dans la couche cornée entraînent le développement de souches à la profondeur des mécanorécepteurs cutanés, qui déclenchent les réponses perceptives de tiraillement. RÉSULTATS: Avant toute application de crème, les femmes sujettes au tiraillement tendent à avoir une couche cornée plus rigide que leurs homologues moins sensibles, mais l'application d'un produit nettoyant augmente la raideur de la couche cornée chez toutes les femmes. Étonnamment, aucune corrélation n'a été observée entre la perception de tiraillement et les mesures d'hydratation réalisées par le cornéomètre ou la fonction barrière, évaluée par la perte d'eau transépidermique. Les scores de tiraillement et de sécheresse auto-déclarés étaient fortement corrélés à une peau décrite par les sujets elles-mêmes comme sensible. Après application de la formule hydratante optimisée, Osmoskin®, qui contient des cires naturelles ayant de bonnes propriétés de dépôt de film, les consommateurs rapportent une forte diminution de la sensation de tiraillement et de sécheresse. Ces résultats concordent avec les expériences en laboratoire où le produit nettoyant s'est avéré augmenter les contraintes de séchage de la couche cornée de 34 %, tandis que l'application ultérieure d'Osmoskin® a réduit les contraintes de 48 %. La modélisation à éléments finis, en utilisant les résultats expérimentaux comme données, élucide les différences de perception entre les deux groupes de femmes. Il est clair qu'Osmoskin® modifie l'état mécanique de la couche cornée, et produit des souches dans l'épiderme sous-jacent qui activent plusieurs mécano-récepteurs cutanés à un niveau corrélé au confort perçu par la patiente. CONCLUSION: La combinaison des approches in vivo, in vitro et in silico fournit un nouveau cadre pour comprendre pleinement comment les sensations de tiraillement de la peau se forment et se propagent, et comment elles peuvent être soulagées en mettant au point une crème hydratante optimisée.

Impact of microstructure on cell behavior and tissue mechanics in collagen and dermal decellularized extra-cellular matrices.

Skin models are used for many applications such as research and development or grafting. Unfortunately, most lack a proper microenvironment producing poor mechanical properties and inaccurate extra-cellular matrix composition and organization. In this report we focused on mechanical properties, extra-cellular matrix organization and cell interactions in human skin samples reconstructed with pure collagen or dermal decellularized extra-cellular matrices (S-dECM) and compared them to native human skin. We found that Full-thickness S-dECM samples presented stiffness two times higher than collagen gel and similar to ex vivo human skin, and proved for the first time that keratinocytes also impact dermal mechanical properties. This was correlated with larger fibers in S-dECM matrices compared to collagen samples and with a differential expression of F-actin, vinculin and tenascin C between S-dECM and collagen samples. This is clear proof of the microenvironment's impact on cell behaviors and mechanical properties. STATEMENT OF SIGNIFICANCE: In vitro skin models have been used for a long time for clinical applications or in vitro knowledge and evaluation studies. However, most lack a proper microenvironment producing a poor combination of mechanical properties and appropriate biological outcomes, partly due to inaccurate extra-cellular matrix (ECM) composition and organization. This can lead to limited predictivity and weakness of skin substitutes after grafting. This study shows, for the first time, the importance of a complex and rich microenvironment on cell behaviors, matrix macro- and micro-organization and mechanical properties. The increased composition and organization complexity of dermal skin decellularized extra-cellular matrix populated with differentiated cells produces in vitro skin models closer to native human skin physiology.

A mechanistic view on the aging human skin through ex vivo layer-by-layer analysis of mechanics and microstructure of facial and mammary dermis.

Age-related changes in skin mechanics have a major impact on the aesthetic perception of skin. The link between skin microstructure and mechanics is crucial for therapeutic and cosmetic applications as it bridges the micro- and the macro-scale. While our perception is governed by visual and tactile changes at the macroscopic scale, it is the microscopic scale (molecular assemblies, cells) that is targeted by topical treatments including active compounds and energies. We report here a large dataset on freshly excised human skin, and in particular facial skin highly relevant for cosmetics and aesthetic procedures. Detailed layer-by-layer mechanical analysis revealed significant age-dependent decrease in stiffness and elastic recoil of full-thickness skin from two different anatomical areas. In mammary skin, we found that the onset of mechanical degradation was earlier in the superficial papillary layer than in the deeper, reticular dermis. These mechanical data are linked with microstructural alterations observed in the collagen and elastic networks using staining and advanced imaging approaches. Our data suggest that with ageing, the earliest microstructural and mechanical changes occur in the top-most layers of dermis/skin and then propagate deeper, providing an opportunity for preventive topical treatments acting at the level of papillary dermis.

A Recruitment Model of Tendon Viscoelasticity That Incorporates Fibril Creep and Explains Strain-Dependent Relaxation.

Soft tissues exhibit complex viscoelastic behavior, including strain-rate dependence, hysteresis, and strain-dependent relaxation. In this paper, a model for soft tissue viscoelasticity is developed that captures all of these features and is based upon collagen recruitment, whereby fibrils contribute to tissue stiffness only when taut. We build upon existing recruitment models by additionally accounting for fibril creep and by explicitly modeling the contribution of the matrix to the overall tissue viscoelasticity. The fibrils and matrix are modeled as linear viscoelastic and each fibril has an associated critical strain (corresponding to its length) at which it becomes taut. The model is used to fit relaxation tests on three rat tail tendon fascicles and predict their response to cyclic loading. It is shown that all of these mechanical tests can be reproduced accurately with a single set of constitutive parameters, the only difference between each fascicle being the distribution of their fibril crimp lengths. By accounting for fibril creep, we are able to predict how the fibril length distribution of a fascicle changes over time under a given deformation. Furthermore, the phenomenon of strain-dependent relaxation is explained as arising from the competition between the fibril and matrix relaxation functions.

Combination of Traction Assays and Multiphoton Imaging to Quantify Skin Biomechanics.

An important issue in tissue biomechanics is to decipher the relationship between the mechanical behavior at macroscopic scale and the organization of the collagen fiber network at microscopic scale. Here, we present a protocol to combine traction assays with multiphoton microscopy in ex vivo murine skin. This multiscale approach provides simultaneously the stress/stretch response of a skin biopsy and the collagen reorganization in the dermis by use of second harmonic generation (SHG) signals and appropriate image processing.

How aging impacts skin biomechanics: a multiscale study in mice.

Skin aging is a complex process that strongly affects the mechanical behavior of skin. This study aims at deciphering the relationship between age-related changes in dermis mechanical behavior and the underlying changes in dermis microstructure. To that end, we use multiphoton microscopy to monitor the reorganization of dermal collagen during mechanical traction assays in ex vivo skin from young and old mice. The simultaneous variations of a full set of mechanical and microstructural parameters are analyzed in the framework of a multiscale mechanical interpretation. They show consistent results for wild-type mice as well as for genetically-modified mice with modified collagen V synthesis. We mainly observe an increase of the tangent modulus and a lengthening of the heel region in old murine skin from all strains, which is attributed to two different origins that may act together: (i) increased cross-linking of collagen fibers and (ii) loss of water due to proteoglycans deterioration, which impedes inner sliding within these fibers. In contrast, the microstructure reorganization upon stretching shows no age-related difference, which can be attributed to opposite effects of the decrease of collagen content and of the increase of collagen cross-linking in old mice.

A novel microstructural interpretation for the biomechanics of mouse skin derived from multiscale characterization.

Skin is a complex, multi-layered organ, with important functions in the protection of the body. The dermis provides structural support to the epidermal barrier, and thus has attracted a large number of mechanical studies. As the dermis is made of a mixture of stiff fibres embedded in a soft non-fibrillar matrix, it is classically considered that its mechanical response is based on an initial alignment of the fibres, followed by the stretching of the aligned fibres. Using a recently developed set-up combining multiphoton microscopy with mechanical assay, we imaged the fibres network evolution during dermis stretching. These observations, combined with a wide set of mechanical tests, allowed us to challenge the classical microstructural interpretation of the mechanical properties of the dermis: we observed a continuous alignment of the collagen fibres along the stretching. All our results can be explained if each fibre contributes by a given stress to the global response. This plastic response is likely due to inner sliding inside each fibre. The non-linear mechanical response is due to structural effects of the fibres network in interaction with the surrounding non-linear matrix. This multiscale interpretation explains our results on genetically-modified mice with a simple alteration of the dermis microstructure. STATEMENT OF SIGNIFICANCE: Soft tissues, as skin, tendon or aorta, are made of extra-cellular matrix, with very few cells embedded inside. The matrix is a mixture of water and biomolecules, which include the collagen fibre network. The role of the collagen is fundamental since the network is supposed to control the tissue mechanical properties and remodeling: the cells attach to the collagen fibres and feel the network deformations. This paper challenges the classical link between fibres organization and mechanical properties. To do so, it uses multiscale observations combined to a large set of mechanical loading. It thus appears that the behaviour at low stretches is mostly controlled by the network structural response, while, at large stretches, the fibre inner-sliding dominate.

Ex vivo multiscale quantitation of skin biomechanics in wild-type and genetically-modified mice using multiphoton microscopy.

Soft connective tissues such as skin, tendon or cornea are made of about 90% of extracellular matrix proteins, fibrillar collagens being the major components. Decreased or aberrant collagen synthesis generally results in defective tissue mechanical properties as the classic form of Elhers-Danlos syndrome (cEDS). This connective tissue disorder is caused by mutations in collagen V genes and is mainly characterized by skin hyperextensibility. To investigate the relationship between the microstructure of normal and diseased skins and their macroscopic mechanical properties, we imaged and quantified the microstructure of dermis of ex vivo murine skin biopsies during uniaxial mechanical assay using multiphoton microscopy. We used two genetically-modified mouse lines for collagen V: a mouse model for cEDS harboring a Col5a2 deletion (a.k.a. pN allele) and the transgenic K14-COL5A1 mice which overexpress the human COL5A1 gene in skin. We showed that in normal skin, the collagen fibers continuously align with stretch, generating the observed increase in mechanical stress. Moreover, dermis from both transgenic lines exhibited altered collagen reorganization upon traction, which could be linked to microstructural modifications. These findings show that our multiscale approach provides new crucial information on the biomechanics of dermis that can be extended to all collagen-rich soft tissues.

Development of human corneal epithelium on organized fibrillated transparent collagen matrices synthesized at high concentration.

Several diseases can lead to opacification of cornea requiring transplantation of donor tissue to restore vision. In this context, transparent collagen I fibrillated matrices have been synthesized at 15, 30, 60 and 90 mg/mL. The matrices were evaluated for fibril organizations, transparency, mechanical properties and ability to support corneal epithelial cell culture. The best results were obtained with 90 mg/mL scaffolds. At this concentration, the fibril organization presented some similarities to that found in corneal stroma. Matrices had a mean Young's modulus of 570 kPa and acellular scaffolds had a transparency of 87% in the 380-780 nm wavelength range. Human corneal epithelial cells successfully colonized the surface of the scaffolds and generated an epithelium with characteristics of corneal epithelial cells (i.e. expression of cytokeratin 3 and presence of desmosomes) and maintenance of stemness during culture (i.e. expression of ΔNp63α and formation of holoclones in colony formation assay). Presence of cultured epithelium on the matrices was associated with increased transparency (89%).

Improving stressful working lives: complementary therapies, counselling and clinical supervision for staff.

The aim of this paper is to briefly examine the contemporary phenomenon of "burnout" within oncology and palliative care. In discussing the suitable interventions to manage stress and avoid burnout, reference will be made to counselling and clinical supervision, but more substantially the paper will report on an innovative subsidised complementary therapy service for staff. The Government's Improving Working Lives Standard will be referred as an initiative that supports the development of supportive services for NHS staff.