[Characterization of sun protection performance: Quo vadis?] / Charakterisierung von Sonnenschutzleistung: Quo vadis?

The task of the first sunscreens was to prevent the development of sunburn and, following the spirit of the 1950/1960s, to not impair the tanning of the skin. The need to quantify the protective performance soon arose. Originally with the help of natural-nowadays artificial-sunlight, a method was developed to determine a sun protection factor (SPF). It is formally defined as a ratio between minimum erythema-effective UV dose on sunscreen-protected skin and minimum erythema-effective UV dose on unprotected skin (ISO 24444:2019). Three observations question the suitability of the method. (1) Interlaboratory variability: Despite strict standardization, results of SPF determinations from different laboratories are subject to large variations. (2) Natural vs. artificial sunlight: The radiation spectrum of artificial sunlight differs from that of natural sunlight. SPFs determined with artificial sunlight (as depicted on all sunscreens currently on the market) are significantly too high compared to SPF determination with natural sunlight. (3) Erythema burden: When determining SPF, subjects are exposed to potentially harmful radiation. Against this background alternative methods-in vitro SPF, hybrid diffuse reflectance spectroscopy (HDRS) and in silico calculations-are presented. These have the potential to replace the current method. As an immediate measure, it is recommended to return to the comprehensible description of low, medium, high, and very high protection and in the future to take into account the spectrum of natural sunlight.

[Nano is big! : Facts and myths about nanoparticulate UV filters]. / Nano ist groß! : Fakten und Mythen über nanopartikuläre UV-Filter.

Sunscreen products containing inorganic micronized titanium dioxide (TiO2) and zinc oxide (ZnO) have been available since the 1950s. Their cosmetic acceptance remained limited as they persist as a white paste on the skin. By reducing the size of the particles into the nano-range below 100 nm, their optical property of reflecting visible light is reduced. After the year 2000, organic filters of this size range were developed. The enthusiasm for nanotechnology that prevailed at the time did not transfer to sunscreen products with nanoparticulate filters. Consumers suspect that the particles permeate the skin, are absorbed by the blood, and spread throughout the body causing illness. Not least due to public pressure, cosmetics-which include sunscreen products-became the first product segment in which accordingly manufactured substances were subjected to strict regulations. Despite advanced regulation and strict approval procedures for nanoparticulate filters, public reservations remained. Possible reasons for this are lack of knowledge or mistrust of the applicable legislation, unclear perception of the behavior of nanoparticles in sunscreen products and as a result unclear perceptions of hazard, risk, and exposure. Against this background, the nature and behavior of nanoparticulate filters in sunscreens on the skin and potentially in the skin, as well as the regulatory framework that ensure that nanoparticulate filters and the products containing them are safe to use are discussed.

The effect of a basic skin care product on the structural strength of the dermo-epidermal junction: An exploratory, randomised, controlled split-body trial.

Skin ageing is associated with various structural alterations including a decreased strength of the dermo-epidermal adhesion increasing the risk for shear type injuries (skin tears). Topical applications of basic skin care products seem to reduce skin tear incidence. The suction blister method leads to the artificial and controlled separation of dermis and epidermis. Therefore, time to blister formation may be used as outcome measuring the strength of dermo-epidermal adhesion. We conducted an exploratory, randomised, controlled trial with a split-body design on forearms in healthy female subjects (n = 12; mean age 70.3 [SD 2.1] years). Forearms assigned to the intervention were treated twice daily with petrolatum for 8 weeks. Suction blisters were induced on forearms after 4 and 8 weeks and time to blister formation was measured. Stratum corneum and epidermal hydration were measured and epidermal thickness was assessed via optical coherence tomography. Time to blistering was longer and stratum corneum as well as epidermal hydration was consistently higher in intervention skin areas. We conclude that topical application of basic skin care products may improve mechanical adhesion of the dermo-epidermal junction and that the parameter "time to blistering" is a suitable outcome to measure dermo-epidermal adhesion strength in clinical research.

Challenges in Sun Protection.

Since time immemorial, people protected themselves from solar radiation. Limiting time in the sun by seeking shade or wearing clothing was a matter of course. In the early 20th century, tanned skin - a result of exposure to sunlight - was associated with good health. At the same time, however, one also had to protect oneself against the potential of excessive exposure to avoid sunburns. Around 1945, the first sunscreen products for protection against solar radiation became available. In the years to follow and up to the recent past, a vast number of different sunscreen filters were developed and incorporated into a wide variety of product formats. Frameworks regulating filter substances and preparations and methods to characterize sunscreen products' performance parameters were developed. Over the past 50-70 years, the perception regarding the tasks of sunscreen products changed several times. It was initially promoted as a lifestyle product and had the task of preventing sun-related erythema (tan without burn). Later, the prevention of skin cancer was added. Only in recent times, sunscreen products have been increasingly advertised and perceived as beauty and lifestyle products again. Also, the use of sunscreen products for antiaging purposes is now commonplace. The different intended purposes (averting harm and prevention) and the widespread use of topical sunscreen products have promoted many investigations and generated a vast and ongoing need for consumer and patient information and education. In the following review, we analyze and discuss current topics from conflicting areas, such as sun protection products (e.g., ideal sun protection products, sun protection metrics), product safety (e.g., nanoparticulate sunscreen filters, regulatory issues), application in everyday life (e.g., wish to tan, vulnerable cohorts), as well as controversies and future challenges (e.g., risks and benefits of UV radiation).

Percutaneous Absorption of Sunscreen Filters: Review of Issues and Challenges.

Although skin is a vital barrier to the outside world, it is permeable to certain substances used in topical pharmacotherapy. It is therefore not surprising that other xenobiotics intentionally or accidentally coming in contact with skin can cross the skin barrier. Long before the turn of the millennium, it became clear that sunscreen filters from sunscreen products can be systemically absorbed and detected in urine and plasma. Against this background, we review issues and challenges with safety assessments related to the possible percutaneous absorption of the sunscreen filters. A reference is made to the Regulation (EC) No. 1223/2009 of the European Parliament and of the Council of 30 November 2009 on cosmetic products (version 1 August 2018) and the concepts of the Maximal Usage Trial (MUsT) and Generally Recognized As Safe and Effective (GRASE), currently discussed in the United States.

Size Matters! Issues and Challenges with Nanoparticulate UV Filters.

Preparations containing pigments have been used since ancient times to protect against negative effects of solar radiation. Since the 1950s, sunscreen products containing micronized TiO2 and ZnO have been marketed. These products were soon regarded as cosmetically unattrac-tive due to their property of remaining as a white paste on the skin, a result of particle sizes. In order to eliminate these unfavourable properties, particle size distribution was lowered into a range below 100 nm, a size threshold for decreasing the particle's optical property to reflect visible light. After 2000, new nanoparticulate organic filters were developed. Effects of both the inorganic and organic nanoparticulate substances - alone or in combination - with non-particulate UV filters were well documented and had shown great effectiveness. At the time, nanotechnology fuelled great hope in the progress of science and technology, including the health sector and cosmetics industry. Instead, influenced by images from the science fiction literature of self-replicating nanorobots destroying all living matter or health and environmental disasters caused by asbestos, fear of this new unknown amongst the general population has hindered acceptance and progress of nano-enabled products. Consumers have started to suspect that the particles permeate through skin, are absorbed by the blood and are distributed throughout the body, causing disease. Not least because of public pressure, cosmetics - which include sunscreen products - became the first product segment in which appropriately manufactured substances were subject to stringent rules. Despite advanced regulation and rigorous approval procedures for nanoparticulate UV filters, widespread reservations remain. Possible reasons could be a lack of knowledge of current legislation and unclear ideas about nature and behaviour of nanoparticles. Against this background, we discuss the nature and behaviour of nanoparticulate UV filters within finished products, on the skin and potentially in the skin, and the regulatory framework that ensures that nanoparticulate UV filters and the sunscreen products containing them are safe to use.

Past, Present, and Future of Sun Protection Metrics.

Since the beginning of the development of sunscreen products, efforts have been made to measure and quantify the protection performance of such products. Early on an in vivo method was established that allowed statements on the sun protection performance in humans. Later, by establishing defined basic and experimental conditions, the method became internationally standardized delivering the well-known sun protection factor (SPF). The method was widely used and is nowadays regarded as a gold-standard method. Further standardized methods were added shortly thereafter. However, shortcomings such as the confined radiation spectra used by the methods, the invasiveness, the complexity in their application, as well as their time- and cost-intensity promoted the development of alternative methods. The shortcomings were recently followed by another, namely, the large interlaboratory variances of the sun protection metrics SPFISO 24444. This all together shows that there is a justifiable need to explore the potential of alternative methods, to complement the existing methods, to serve as equivalents, or even to replace it in the future. Based on the work of Uhlig and coworkers, the authors propose to test the suitability of the alternative methods and their possible equivalency to the reference methods in a broad-based investigation, taking into account possible interlaboratory variances. A research program - developed by a consortium - is in public planning where stakeholders from research, industry, authorities, and the public can come together to facilitate and further advance standardization of the measurement of the sun protection performance. The authors give an insight into historical, technical--conceptual, and future developments of methods for -determining the protective performance of sun protection products.

Skincare interventions in infants for preventing eczema and food allergy: A cochrane systematic review and individual participant data meta-analysis.

OBJECTIVE: Eczema and food allergy start in infancy and have shared genetic risk factors that affect skin barrier. We aimed to evaluate whether skincare interventions can prevent eczema or food allergy. DESIGN: A prospectively planned individual participant data meta-analysis was carried out within a Cochrane systematic review to determine whether skincare interventions in term infants prevent eczema or food allergy. DATA SOURCES: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and trial registries to July 2020. ELIGIBILITY CRITERIA FOR SELECTED STUDIES: Included studies were randomized controlled trials of infants <1 year with healthy skin comparing a skin intervention with a control, for prevention of eczema and food allergy outcomes between 1 and 3 years. RESULTS: Of the 33 identified trials, 17 trials (5823 participants) had relevant outcome data and 10 (5154 participants) contributed to IPD meta-analysis. Three of seven trials contributing to primary eczema analysis were at low risk of bias, and the single trial contributing to primary food allergy analysis was at high risk of bias. Interventions were mainly emollients, applied for the first 3-12 months. Skincare interventions probably do not change risk of eczema by age 1-3 years (RR 1.03, 95% CI 0.81, 1.31; I2 =41%; moderate certainty; 3075 participants, 7 trials). Sensitivity analysis found heterogeneity was explained by increased eczema in a trial of daily bathing as part of the intervention. It is unclear whether skincare interventions increase risk of food allergy by age 1-3 years (RR 2.53, 95% CI 0.99 to 6.47; very low certainty; 996 participants, 1 trial), but they probably increase risk of local skin infections (RR 1.34, 95% CI 1.02, 1.77; I2 =0%; moderate certainty; 2728 participants, 6 trials). CONCLUSION: Regular emollients during infancy probably do not prevent eczema and probably increase local skin infections.

Skin care interventions in infants for preventing eczema and food allergy.

BACKGROUND: Eczema and food allergy are common health conditions that usually begin in early childhood and often occur together in the same people. They can be associated with an impaired skin barrier in early infancy. It is unclear whether trying to prevent or reverse an impaired skin barrier soon after birth is effective in preventing eczema or food allergy. OBJECTIVES: Primary objective To assess effects of skin care interventions, such as emollients, for primary prevention of eczema and food allergy in infants Secondary objective To identify features of study populations such as age, hereditary risk, and adherence to interventions that are associated with the greatest treatment benefit or harm for both eczema and food allergy. SEARCH METHODS: We searched the following databases up to July 2020: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase. We searched two trials registers and checked reference lists of included studies and relevant systematic reviews for further references to relevant randomised controlled trials (RCTs). We contacted field experts to identify planned trials and to seek information about unpublished or incomplete trials. SELECTION CRITERIA: RCTs of skin care interventions that could potentially enhance skin barrier function, reduce dryness, or reduce subclinical inflammation in healthy term (> 37 weeks) infants (0 to 12 months) without pre-existing diagnosis of eczema, food allergy, or other skin condition were included. Comparison was standard care in the locality or no treatment. Types of skin care interventions included moisturisers/emollients; bathing products; advice regarding reducing soap exposure and bathing frequency; and use of water softeners. No minimum follow-up was required. DATA COLLECTION AND ANALYSIS: This is a prospective individual participant data (IPD) meta-analysis. We used standard Cochrane methodological procedures, and primary analyses used the IPD dataset. Primary outcomes were cumulative incidence of eczema and cumulative incidence of immunoglobulin (Ig)E-mediated food allergy by one to three years, both measured by the closest available time point to two years. Secondary outcomes included adverse events during the intervention period; eczema severity (clinician-assessed); parent report of eczema severity; time to onset of eczema; parent report of immediate food allergy; and allergic sensitisation to food or inhalant allergen. MAIN RESULTS: This review identified 33 RCTs, comprising 25,827 participants. A total of 17 studies, randomising 5823 participants, reported information on one or more outcomes specified in this review. Eleven studies randomising 5217 participants, with 10 of these studies providing IPD, were included in one or more meta-analysis (range 2 to 9 studies per individual meta-analysis). Most studies were conducted at children's hospitals. All interventions were compared against no skin care intervention or local standard care. Of the 17 studies that reported our outcomes, 13 assessed emollients. Twenty-five studies, including all those contributing data to meta-analyses, randomised newborns up to age three weeks to receive a skin care intervention or standard infant skin care. Eight of the 11 studies contributing to meta-analyses recruited infants at high risk of developing eczema or food allergy, although definition of high risk varied between studies. Durations of intervention and follow-up ranged from 24 hours to two years. We assessed most of this review's evidence as low certainty or had some concerns of risk of bias. A rating of some concerns was most often due to lack of blinding of outcome assessors or significant missing data, which could have impacted outcome measurement but was judged unlikely to have done so. Evidence for the primary food allergy outcome was rated as high risk of bias due to inclusion of only one trial where findings varied when different assumptions were made about missing data. Skin care interventions during infancy probably do not change risk of eczema by one to two years of age (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.81 to 1.31; moderate-certainty evidence; 3075 participants, 7 trials) nor time to onset of eczema (hazard ratio 0.86, 95% CI 0.65 to 1.14; moderate-certainty evidence; 3349 participants, 9 trials). It is unclear whether skin care interventions during infancy change risk of IgE-mediated food allergy by one to two years of age (RR 2.53, 95% CI 0.99 to 6.47; 996 participants, 1 trial) or allergic sensitisation to a food allergen at age one to two years (RR 0.86, 95% CI 0.28 to 2.69; 1055 participants, 2 trials) due to very low-certainty evidence for these outcomes. Skin care interventions during infancy may slightly increase risk of parent report of immediate reaction to a common food allergen at two years (RR 1.27, 95% CI 1.00 to 1.61; low-certainty evidence; 1171 participants, 1 trial). However, this was only seen for cow's milk, and may be unreliable due to significant over-reporting of cow's milk allergy in infants. Skin care interventions during infancy probably increase risk of skin infection over the intervention period (RR 1.34, 95% CI 1.02 to 1.77; moderate-certainty evidence; 2728 participants, 6 trials) and may increase risk of infant slippage over the intervention period (RR 1.42, 95% CI 0.67 to 2.99; low-certainty evidence; 2538 participants, 4 trials) or stinging/allergic reactions to moisturisers (RR 2.24, 95% 0.67 to 7.43; low-certainty evidence; 343 participants, 4 trials), although confidence intervals for slippages and stinging/allergic reactions are wide and include the possibility of no effect or reduced risk. Preplanned subgroup analyses show that effects of interventions were not influenced by age, duration of intervention, hereditary risk, FLG mutation,  or classification of intervention type for risk of developing eczema. We could not evaluate these effects on risk of food allergy. Evidence was insufficient to show whether adherence to interventions influenced the relationship between skin care interventions and risk of developing eczema or food allergy. AUTHORS' CONCLUSIONS: Skin care interventions such as emollients during the first year of life in healthy infants are probably not effective for preventing eczema, and probably increase risk of skin infection. Effects of skin care interventions on risk of food allergy are uncertain. Further work is needed to understand whether different approaches to infant skin care might promote or prevent eczema and to evaluate effects on food allergy based on robust outcome assessments.

Buffered lidocaine 1%/epinephrine 1:100,000 with sodium bicarbonate (sodium hydrogen carbonate) in a 3:1 ratio is less painful than a 9:1 ratio: A double-blind, randomized, placebo-controlled, crossover trial.

BACKGROUND: Neutralizing (buffering) lidocaine 1%/epinephrine 1:100,000 solution (Lido/Epi) with sodium hydrogen carbonate (NaHCO3) (also called sodium bicarbonate) is widely used to reduce burning sensations during infiltration of Lido/Epi. Optimal mixing ratios have not been systematically investigated. OBJECTIVES: To determine whether a Lido/Epi:NaHCO3 mixing ratio of 3:1 (investigational medicinal product 1) causes less pain during infiltration than a mixing ratio of 9:1 (IMP2) or unbuffered Lido/Epi (IMP3). METHODS: Double-blind, randomized, placebo-controlled, crossover trial (n = 2 × 24) with 4 investigational medicinal products (IMP1-4). RESULTS: The 3:1 mixing ratio was significantly less painful than the 9:1 ratio (P = .044). Unbuffered Lido/Epi was more painful than the buffered Lido/Epi (P = .001 vs IMP1; P = .033 vs IMP2). IMP4 (NaCl 0.9% [placebo]) was more painful than any of the anesthetic solutions (P = .001 vs IMP1; P = .001 vs IMP2; P = .016 vs IMP3). In all cases, the anesthesia was effective for at least 3 hours. LIMITATIONS: Results of this trial cannot be generalized to other local anesthetics such as prilocaine, bupivacaine, or ropivacaine, which precipitate with NaHCO3 admixtures. CONCLUSIONS: Lido/Epi-NaHCO3 mixtures effectively reduce burning pain during infiltration. The 3:1 mixing ratio is significantly less painful than the 9:1 ratio. Reported findings are of high practical relevance, given the extensive use of local anesthesia today.

Metamorphosis of Vehicles: Mechanisms and Opportunities.

The visibility of a skin condition or dermatosis led to the reasonable assumption that the direct application of a therapeutic remedy to the target tissue holds many advantages. Through centuries, the nomenclature of topical preparations has proliferated and finally been moulded into the compulsory nomenclature of official compendia. In everyday life, many terms have been added and have complicated understanding and communication among and between healthcare professionals and laypersons. A large proportion of marketed topical preparations contain significant amounts of volatile vehicle ingredients that evaporate once they are applied onto the skin, that is, the vehicle format as well as the sum of vehicle ingredients in the primary container are different from the vehicle format and the sum of vehicle ingredients on the skin. This phenomenon and the potential consequences have so far been often ignored by many healthcare professionals and laypersons. To gain a better understanding, this phenomenon has been coined as the metamorphosis of the vehicle. The metamorphosis of the vehicle describes the vehicle (a) in the primary container (primary formulation), (b) during and immediately after application onto the skin (secondary formulation) and (c) after all volatile vehicle ingredients have evaporated from the vehicle on top of the skin (tertiary or residual formulation). The secondary and tertiary formulations may offer increased delivery of cosmetic or pharmaceutical actives. This is achieved by (a) an intended post-application creation of supersaturation of actives in the secondary and tertiary formulations or by (b) physico-chemical triggers such as pH.

Influence of Topical Formulations: Lipid Lamella Organization and Lipid Composition of Stratum Corneum as a Surrogate Marker for Barrier Integrity.

Skin barrier repair therapies often involve the use of medicated and non-medicated topical preparations. To measure the effect of topical preparations, clinical (scoring systems, for example, Score of Atopic Dermatitis, Dermatology Quality of Life Index) and biophysical procedures (e.g., trans-epidermal water loss, skin hydration) are widely used. However, the results of these procedures describe the condition of the barrier indirectly. A direct assessment of skin barrier integrity is primarily possible by electron-microscopic examination, visualization and morphometric analysis of the lipid lamellae in the intercellular space of the stratum corneum (SC) and by quantitatively characterizing the composition of key SC lipids. Recently, the combination of a non-invasive lipid barrier visualization (Lipbarvis®) technique (SC sampling and morphometric analysis) and SC lipid composition analysis (chromatographic analysis) has been proposed to directly characterize the skin barrier integrity. Initial experience demonstrates that morphometric analysis of the lipid lamellae organization in the intercellular space of the SC as well as the characterization of the composition of key SC lipids may serve as surrogate marker to study the influence of topical non-medicated preparations including pH-lowered preparations.

Skin Care Products for Healthy and Diseased Skin.

The industry offers a vast armamentarium of skin care products (SCP) to cleanse the skin; to reduce/eliminate unpleasant skin symptoms; to restore, reinforce, fortify and protect undamaged, vulnerable or damaged skin; and to provide a pleasant skin and body feel. Skin care products are readily available and their promotions with a variety of tall claims are omnipresent. This text discusses the various interpretations of skin care, the diversity of its comprehensions and the various groups of receivers and their needs for skin care. Skin care is part of our daily routines, the information on the effects of SCP is omnipresent and the purchase of SCP seems straightforward. However, the true essence of SCP remains concealed to many. This is mainly due to that fact that the "physico-chemical anatomy," the nomenclature and the regulatory classification of SCP as well as the role and the significance of active and inactive ingredients within these products are not well understood. This text addresses the different views, interpretations and comprehensions. The final part highlights the current challenges with SCP and gives an outlook on how to improve our mutual understanding of SCP.

The Acid Mantle: A Myth or an Essential Part of Skin Health?

Ninety years ago - in 1928, the term acid mantle was coined by the physicians Heinrich Schade and Alfred Marchionini in Kiel, Germany. A decade later Marchionini and several coworkers published 5 scientific communications in the Klinische Wochenschrift on "Der Säuremantel der Haut und Bakterienabwehr" (acid mantle and defense against bacteria). They described experimental detail, documented age- and body site as well as skin disease-dependent skin pH shifts, and discussed the significance of the pH and bacterial growth on the skin. In their fourth and fifth communication, they made the first connection between the altered quantitative and qualitative bacterial growth in pathologically modified skin and the shifted skin pH and attributed it partly to the gap in the acid mantle (pathologische Lücke des Säuremantels). They also investigated the pH of several topical dermatologic preparations and concluded that their benefit can at least partly be attributed to their acid character and recommended the systematic investigation of acid treatments in dermatology. At that time, the physiologic role of the acid skin surface was thought to be a protective mechanism against invading organisms. Hence, it seemed reasonable to allocate protection to an easy and conceivable term such as "mantle." Today, "acid mantle" as a term is still a very suitable metaphor to illustrate the protective quality of the "acid" in the skin and the term has become part of colloquial speech. In the meantime, our understanding of the skin pH has broadened, and we know that the acid character and its gradual change within the skin also help to orchestrate epidermal differentiation and corneocyte shedding. For many more biochemical processes within the skin, the compartmental pH is crucial, for example, in pigmentation, ion homeostasis, epidermal (stem) cell behavior, and so on. The often existing difference between the H+ concentration of extra- and intracellular as well as subcellular compartments establishes an ionic, electric, and/or osmotic driving force; hence, H+ concentration per se acts as an extra-, intra,- and subcellular signaling modality affecting and controlling many cellular functions. One may even consider pH a universal signal and effector. It is therefore also no surprise that skin pH shifts have been observed in various skin pathologies. More recently, in carefully controlled trials (acne, atopic dermatitis, incontinence-associated dermatitis, aged skin), the benefits of targeted skin acidification have become evident and the use of topical preparations with reduced pH may be recommended. The currently prevailing formulation concepts for direct acidification are based on a reduced pH of the hydrophilic product phase in combination with a buffer with a sufficiently high buffering capacity within the vehicle.