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. 2023 May 13;29(5):e13346. doi: 10.1111/srt.13346

Directional assessment of the skin barrier function in vivo

Fanny Alsamad 1, Georgios N Stamatas 1,✉
PMCID: PMC10182387  PMID: 37231932

Abstract

Introduction

The fundamental function of the epidermis is to provide an inside‐out barrier to water loss and an outside‐in barrier to penetration of external irritants. Transepidermal water loss (TEWL) has been extensively used as a method of estimating the skin barrier quality, typically without any consideration of directionality. The validity of TEWL as an estimate of skin permeability to external substances has been controversial in vitro and in vivo. The aim of this work was to assess the relationship between TEWL and the penetration of a topically applied external marker (caffeine) in healthy skin in vivo before and following a challenge to the barrier.

Methods

The skin barrier was challenged by application of aqueous solutions of mild cleanser products under occlusion for 3 h on the forearms of nine human participants. Skin barrier quality was evaluated before and after the challenge by measuring the TEWL rate and the permeated amount of topically applied caffeine using in vivo confocal Raman microspectroscopy.

Results

No skin irritation was observed following the skin barrier challenge. TEWL rates and the caffeine penetrated amount in the stratum corneum after the challenge were not correlated. A weak correlation was observed when the changes were corrected to water‐only treatment. TEWL values can be influenced by environmental conditions as well as the skin temperature and water content.

Conclusions

Measuring TEWL rates is not always representative of the outside‐in barrier. TEWL may be useful in differentiating large changes in skin barrier function (e.g., between healthy and compromised skin) but is less sensitive to small variations following topical application of mild cleansers.

Keywords: Caffeine, Confocal Raman, In Vivo, Non‐invasive, skin barrier, TEWL

1. INTRODUCTION

Skin is the largest organ of the human body consisting of three layers: the epidermis, the dermis, and the hypodermis. 1 The principal function of skin is to form an effective barrier between the organism and the environment to ensure protection against: (i) unrestricted water loss due to evaporation (inside‐out direction) and (ii) penetration of external aggressors, such as irritants and/or allergens that could lead to irritation and/or sensitization (outside‐in direction). 2 , 3 , 4 This barrier function is mainly localized in the outermost layer of the epidermis called the stratum corneum (SC). 5 The SC is formed of protein‐enriched cells (corneocytes) embedded in a lipidic cement, mainly composed of ceramides, cholesterol, and cholesteryl esters. 1 In healthy skin, SC lipids and proteins provide a barrier, which among other functions provides protection from the penetration of environmental aggressors such as irritants and allergens. An impairment in the integrity of this layer interferes with the protection provided by the skin barrier in both directions. 6 , 7 , 8

Transepidermal water loss (TEWL) has been extensively used as a method of estimating the skin barrier quality, typically without any consideration of directionality. Prior research has sought to answer if TEWL is an adequate predictor of bi‐directional skin barrier integrity by assessing the potential correlation between TEWL measurements and those gained through various known percutaneous absorption methods with conflicting results.

Dupuis et al. 9 demonstrated a significant linear correlation in vivo between TEWL and benzoic acid percutaneous absorption by measuring six different anatomical skin sites in men. The same group later reported a linear relationship between the permeability of the skin to the outward movement of water and the inward uptake of molecules. 10 Aalto‐Korte and Turpeinen 11 reported a significant correlation between cortisol levels and TEWL values following topical application of 1% hydrocortisone solution on skin in vivo. The authors concluded that the inside‐out measurement represented by TEWL can be a predictor of the outside‐in penetration ability of compounds in normal and compromised skin. Other published reports, however, were not aligned with this conclusion. For instance, Chilcot et al. 12 argued that TEWL rates cannot be used to assess the outside‐in barrier, since no correlation between TEWL and penetration of tritiated water was observed ex vivo on healthy and compromised skin. Zhang et al. 13 reported only a weak correlation between fentanyl delivery rate and TEWL ex vivo. Similarly, Oestmann et al. 14 documented a weak correlation between penetration of hexyl nicotinate and TEWL in vivo on the volar forearm of 21 healthy volunteers. Based on conflicting results from prior studies, the question of whether TEWL measurement is an appropriate predictor of bi‐directional skin barrier integrity remains unanswered.

Confocal Raman microspectroscopy (CRM) can be employed in vivo non‐invasively to assess penetration of topically applied substances as function of skin depth with high specificity and without additional labeling. 15 This method has been used to monitor the skin absorption of penetration enhancers, 16 , 17 , 18 , 19 , 20 , 21 skin moisturizers, 22 other cosmetic ingredients (caffeine, 23 , 24 resveratrol, 17 , 23 hyaluronic acid, 25 retinol, 21 , 26 , 27 , 28 delipidol, 29 niacinamide, 30 salicylic acid, 31 resorcinol 32 ), and drugs (metronidazole, 33 ibuprofen 31 ).

Being able to predictively assess and quantitatively measure the bi‐directional (inside‐out and outside‐in) properties of the skin barrier integrity is important to both fundamental research and understanding of the properties of human skin and to understanding the potential for the environment to impact the skin barrier integrity. In this study, we challenged the concept of TEWL measurement as an adequate measure of bi‐directional skin barrier integrity by employing a validated caffeine penetration model using CRM following a mild topical challenge. 34

2. MATERIALS AND METHODS

2.1. Study population

This study was conducted in accordance with the ethical principles of the Declaration of Helsinki after obtaining signed informed consent from the study volunteers. A total of nine women were recruited. All participants were of Fitzpatrick skin types I–III except one participant of type IV, aged 24–51 years, with no dermatologic conditions on the forearm. Excluded from the study were people with known allergies to adhesives present in patches, cleansers, or caffeine‐containing products. Participants were asked not to apply any leave‐on products to both forearms the night before the study and in the morning on study days.

2.2. Materials

A total of seven marketed mild baby cleansers (designated A–G) from five different manufacturers were used. A volume of 400 µL of each diluted cleanser formulation (50%) was applied to the analyzed skin site via an occlusive patch. The surfactant system of each cleanser is provided in Table S1. Deionized water was used as control. Caffeine (Sigma–Aldrich, USA) was used as an externally applied skin permeability marker. A volume of 400 µL of 1.8% (2 × 10−5 mg/mL) caffeine solution was applied using an occlusive patch to the same spot that was challenged right before with a cleanser. Cleansers and caffeine were diluted in deionized water and prepared freshly before use. Occlusive patches (25 mm chambers, Hill Top Research Inc., USA) were used to apply the cleanser solutions or the caffeine solution on the skin.

2.3. Instruments

All CRM analyses were conducted using a confocal Raman microspectrometer (Model 3510 Skin Composition Analyzer, River Diagnostics, The Netherlands). After instrument calibration, Raman profiles were acquired on the volar forearm in the fingerprint region (400–1800 cm−1) using a 785‐laser source. A total of five Raman profiles (integration time 4 s) were recorded at each skin site at timepoints T 0 and T 2, as shown in Figure 1. Each Raman profile was recorded in the z‐axis direction from skin surface up to 39 µm deep in skin, with 3 µm‐step size, comprising 13 Raman frames. Caffeine concentration profiles were calculated from these spectra using Skin Tools 2.0 software (River Diagnostics, The Netherlands) with the addition of caffeine reference spectrum to the 18 components of the SC as described elsewhere. 24 Caffeine profiles were averaged on the nine participants except for products B (eight participants) and F (seven participants). Outlier profiles were removed before averaging. The total caffeine concentration in the SC was calculated as area under the concentration profile curve from the skin surface up to 18 µm depth in the SC.

FIGURE 1.

FIGURE 1

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Raman baseline measurements ([Caffeine]T0 and TEWLT0) were recorded on the participant's forearm. Diluted cleanser solutions (50%) or water was then applied to skin for 3 h using an occlusive patch. Transepidermal water loss (TEWL) rate values were recorded at T 1 (TEWLT1). Next, caffeine (1.8%) patch was applied to the same area for 30 min before acquiring final Raman measurements ([Caffeine]T2). After each patch removal, skin was gently padded dry and allowed to equilibrate for 10 min.

A calibrated open chamber probe, the TM Hex (latest generation of Tewameter) by Courage + Khazaka Electronic GmbH, Germany, was used to record TEWL rate values. This instrument has been used recently to measure TEWL of psoriatic skin ex vivo. 35 Additionally, the TM Hex probe measures ambient and skin temperature and relative humidity, as well as heat loss by water evaporation and heat loss by heat diffusion. Data were acquired using MPA_CT plus software.

2.4. Clinical study

Skin barrier quality was assessed by measuring TEWL rates and caffeine penetration in the SC using in vivo CRM after applying cleanser or water patches on skin for 3 h. All measurements were conducted in a temperature‐controlled room (21 ± 2.5°C and 48 ± 6% relative humidity). At each visit, volunteers were allowed to acclimate for 30 min. Baseline CRM and TEWL measurements were taken on the volar forearm at time T 0 (Figure 1). TEWL was measured on three different spots of each skin site. On each spot, three TEWL repetitions of 25 s each were recorded and averaged. Diluted cleansers were applied one by one to the analyzed skin sites via the occlusive patches. After 3 h, the patch was removed, and any excess formulation was gently removed using a dry cotton pad and TEWL measurements were taken at time T 1, similar to time T 0. Caffeine was applied to the same spot of skin challenged right before with the cleanser. After 30 min, excess caffeine solution was gently removed with a dry pad and final CRM measurements were taken at time T 2.

For each volunteer, a set of three cleansers was tested on the first day of the study in addition to one skin site treated with water (negative control). The remaining set of four cleansers was tested on the second day. The two measurement days were separated between 1 and 2 weeks to avoid any cross contamination. A total of four skin sites on each volunteer's volar forearms were analyzed per day. This protocol consisting of applying cleanser/caffeine regimen and measuring caffeine penetration to test cleanser mildness has been previously validated. 34

Statistical analysis was conducted using pairwise t‐test using the Jamovi statistical software. Pearson correlation coefficients between parameters were calculated and visualized in the R programming language. Values were considered significant at the level of p < 0.05.

3. RESULTS

3.1. The inside‐out and outside‐in skin barrier following topical challenge

We investigated the relationship between TEWL rates, representing the inside‐out direction of the barrier, and penetration of caffeine in the SC, representing the opposite direction, after challenging skin with topical application of baby cleanser mild formulations. No skin irritation was observed following the skin barrier challenge. The total caffeine concentration within the SC can be calculated by integrating the average caffeine concentration profiles (Figure S1). No significant correlation (p = 0.27) was detected between the amount of caffeine penetrating the SC ([Caffeine]SC, T2) and TEWL values (TEWLT1) following the challenge (Figure 2A). Moreover, after correcting the measured parameters corresponding to treatment of each cleanser solution to that of water‐only treatment (Δ[Caffeine]SC, T2 cleanser – T2 water and ΔTEWLT1 cleanser – T1 water), a weak correlation (R 2 = 0.11, p < 0.05) between the two directions was observed (Figure 2B). Finally, TEWL values recorded after skin treatment were compared to those at baseline (ΔTEWLT1 – T0). This revealed that the change in TEWL correlated weakly to baseline TEWLT0 (R 2 = 0.07, p < 0.05, Figure S2), indicating that the capacity for change in the barrier strength depends weakly on its initial state.

FIGURE 2.

FIGURE 2

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(A) Total caffeine concentration (g/mmol of keratin) in the stratum corneum (SC) and transepidermal water loss (TEWL) rates (g/m2/h) obtained after the skin challenge. No correlation was observed between [Caffeine]SC,T2 and TEWLT1 (p = 0.27). (B) Total caffeine concentration and TEWL rates corrected to the values for water‐only treatment. The values of Δ[Caffeine]SC, T2 cleanser – T2 water and ΔTEWLT1 cleanser – T1 water are weakly correlated (R 2 = 0.11, p < 0.05). Data corresponding to treatments with different cleansing products are coded in different colors. Dotted line indicates significant linear regression.

3.2. TEWL measurement dependence on external and skin‐related factors

We investigated the relationship between TEWL and each of the parameters recorded by the TM Hex Tewameter probe at baseline, namely, total heat loss (total HL) in w/m2, heat loss by heat diffusion (HL HD) or by water evaporation (HL EC), skin surface water vapor concentration (cH2O in g/m3), temperature of skin and ambient air (T in °C), and relative humidity in ambient air (RH in %). Pearson correlation values (Figure 3) showed a positive correlation of TEWL with total HL, ambient temperature, and skin surface water vapor concentration. A stronger correlation was obtained between TEWL and HL by water evaporation than between TEWL and HL by diffusion. TEWL correlated with skin temperature, while it exhibited a weak negative correlation with ambient RH in (the narrow range of 42%–54%).

FIGURE 3.

FIGURE 3

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Pearson correlation heatmap of transepidermal water loss (TEWL) with measured parameters at baseline. HL HD: heat loss by heat diffusion, HL EC: heat loss by water evaporation, skin cH2O: water vapor concentration on skin surface, Amb T°C: ambient temperature, skin T°C: skin temperature, and Amb RH: ambient relative humidity. Values were averaged for the eight skin sites analyzed on the volar forearm of nine participants. The colors of the circles (and their sizes) are indicative of the correlation coefficient values as per colormap. All correlations between TEWL and each of the parameters were statistically significant (p < 0.05).

4. DISCUSSION

The primary aim of this study was to explore whether a potential relationship exists between the two opposite directions of the skin barrier: inside‐out and outside‐in, before and following a topical challenge in vivo. To study the outside‐in direction caffeine was selected as a topically applied skin permeability marker due to its known safety profile and characteristic Raman signature. 23

The finding that there is no correlation in the strength of the two opposite directions of the barrier is in agreement with the work of Chilcott et al. 12 These authors found no correlation between basal TEWL rates and the permeability of ex vivo full thickness skin to topically applied tritiated water. Our results are also in general agreement with the reports by Zhang et al. 13 and Oestmann et al. 14 The former study reported a weak correlation between fentanyl delivery rate and TEWL in excised split‐thickness human cadaver skin, while the latter found that hexyl nicotinate was weakly correlated with TEWL in vivo in 21 volunteers.

However, such findings are contrasted to those of Lotte et al. 36 The authors reported a significant correlation (R 2 = 0.53) between TEWL and percutaneous absorption of caffeine. In that study caffeine was topically applied to four different anatomical sites and its concentrations were measured in human urine samples (n = 6–8). A closer look at their data shows similar ranges in TEWL values and the total amount of penetrated caffeine within 4 days for three sites (arm, abdomen, and postauricular), while for the forehead, these parameters have almost double the values (1.9 and 1.8 times higher). It is therefore questionable whether the correlation would hold for each body site independently. Dupuis et al. 9 from the same group indicated a strong significant correlation (R 2 = 0.94) between TEWL values and in vivo benzoic acid percutaneous absorption measured at six different sites. This strong correlation between TEWL and percutaneous absorption is no longer obtained if the TEWL values collected from the forehead site were excluded from the analysis.

The relationship between TEWL rates and skin permeability to a topically applied substance was also studied in compromised skin barrier. Tsai et al. 37 induced different degrees of barrier disruption by treating ex vivo mouse skin surface with acetone and reported a linear relationship between TEWL and caffeine permeation (R 2 = 0.74). Aalto‐Korte and Turpeinen 11 showed that following application of 1% hydrocortisone cream, the plasma levels of cortisol were significantly correlated in a double log relationship with TEWL rates in patients with widespread dermatitis (three children and six adults). In both studies, the range of barrier disruption is quite large. This can explain the difference between their results and those reported here, since the current study was focused on healthy competent skin barrier and perturbed only by a mild form of barrier challenge. Our results are applicable in the conditions as defined in our study. They cannot be generalized, as this would require a larger study with higher number of volunteers.

Water is constantly diffusing from the inner layers of the epidermis to the skin surface. The total amount of vapor lost through skin and appendages under non‐sweating conditions from a fixed area of SC per unit of time (g/h/m2) corresponds to TEWL. 35 , 36 , 37 The effect of environmental factors on TEWL values has been studied 38 , 39 ; however, discrepant results have been reported regarding the effect of temperature and relative humidity. 40 The results of our present work show that TEWL and skin surface temperature were significantly correlated. This is in agreement with the literature where TEWL was shown to be increased with skin surface temperature, as reported by several studies. 41 , 42 , 43 , 44 Moreover, Lamke and Wedin 45 observed a significant increase in mean evaporation with temperature increase between 15°C and 28°C. Since the mass transfer of water from the SC to the environment increases with temperature, this can explain the increase in water vapor concentration on the skin surface. Grice et al. 42 found that an increase of 7°C–8°C in skin temperature doubles TEWL rates in normal skin. In addition, they reported that TEWL values increase exponentially over the range 25°C–39°C. The skin temperature variation in our study was 19.5°C–23.5°C, which is below the range of exponential increase of TEWL values.

TEWL and RH were negatively correlated in our study, which can be expected from Fick's first law of diffusion assuming everything else remains the same. Although the results by Cravello and Ferri 44 agree with this finding, Hattingh 41 and Grice et al. 46 found a positive correlation between these two parameters. Grice et al. 46 suggested that rising ambient humidity between 3% and 50% increases SC permeability and TEWL. The wide range of values in RH compared to our controlled environment during measurements could explain the difference in results.

Finally, our work shows that TEWL is more dependent on skin and ambient temperature than on RH, which is in accordance with Cravello and Ferri 44 but contrary to what Hattingh 41 reported. TEWL values are dependent on skin surface temperature and water content as the body regulates changes in RH and ambient temperature.

In the present study, a potential relationship for the strength of the skin barrier function in two directions was assessed in vivo on healthy skin before and following a mild challenge. These results show that TEWL values were not correlated with the total caffeine amount that penetrated in the SC after a mild challenge to skin. This work only reflects the movement of molecules with the same properties as caffeine and cannot be generalized to lipophilic compounds or to skin with compromised state, for instance. Although TEWL remains the gold standard method for measuring the inside‐out direction of the skin barrier, for example, in differentiating healthy and compromised skin, it should be used with caution when small variations are studied. Importantly, TEWL should not be unconditionally and indiscriminately ascribed to be a global measure of skin barrier function, especially when investigating the outside‐in direction of the barrier.

CONFLICT OF INTEREST STATEMENT

The authors are employees of Johnson and Johnson Santé Beauté France.

Supporting information

Supporting Information

Click here for additional data file. (154.1KB, docx)

ACKNOWLEDGMENTS

We would like to thank the study volunteers as well as Simarna Kaur and Sonia Terhani for their help with the study protocol, and Imane Lboukili for her help in the data visualization of the Pearson correlation results.

Alsamad F, Stamatas GN. Directional assessment of the skin barrier function in vivo. Skin Res Technol. 2023;29:e13346. 10.1111/srt.13346

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supporting Information

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Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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