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• Research article
• Open access
• Published: 12 June 2019

The impact of skin care products on skin chemistry and microbiome dynamics

• Amina Bouslimani 1   na1 ,
• Ricardo da Silva 1   na1 ,
• Tomasz Kosciolek 2 ,
• Stefan Janssen 2 , 3 ,
• Chris Callewaert 2 , 4 ,
• Amnon Amir 2 ,
• Kathleen Dorrestein 1 ,
• Alexey V. Melnik 1 ,
• Livia S. Zaramela 2 ,
• Ji-Nu Kim 2 ,
• Gregory Humphrey 2 ,
• Tara Schwartz 2 ,
• Karenina Sanders 2 ,
• Caitriona Brennan 2 ,
• Tal Luzzatto-Knaan 1 ,
• Gail Ackermann 2 ,
• Daniel McDonald 2 ,
• Karsten Zengler 2 , 5 , 6 ,
• Rob Knight 2 , 5 , 6 , 7 &
• Pieter C. Dorrestein 1 , 2 , 5 , 8  

BMC Biology volume  17 , Article number:  47 ( 2019 ) Cite this article

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Use of skin personal care products on a regular basis is nearly ubiquitous, but their effects on molecular and microbial diversity of the skin are unknown. We evaluated the impact of four beauty products (a facial lotion, a moisturizer, a foot powder, and a deodorant) on 11 volunteers over 9 weeks.

Mass spectrometry and 16S rRNA inventories of the skin revealed decreases in chemical as well as in bacterial and archaeal diversity on halting deodorant use. Specific compounds from beauty products used before the study remain detectable with half-lives of 0.5–1.9 weeks. The deodorant and foot powder increased molecular, bacterial, and archaeal diversity, while arm and face lotions had little effect on bacterial and archaeal but increased chemical diversity. Personal care product effects last for weeks and produce highly individualized responses, including alterations in steroid and pheromone levels and in bacterial and archaeal ecosystem structure and dynamics.

Conclusions

These findings may lead to next-generation precision beauty products and therapies for skin disorders.

The human skin is the most exposed organ to the external environment and represents the first line of defense against external chemical and microbial threats. It harbors a microbial habitat that is person-specific and varies considerably across the body surface [ 1 , 2 , 3 , 4 ]. Recent findings suggested an association between the use of antiperspirants or make-up and skin microbiota composition [ 5 , 6 , 7 ]. However, these studies were performed for a short period (7–10 days) and/or without washing out the volunteers original personal care products, leading to incomplete evaluation of microbial alterations because the process of skin turnover takes 21–28 days [ 5 , 6 , 7 , 8 , 9 ]. It is well-established that without intervention, most adult human microbiomes, skin or other microbiomes, remain stable compared to the differences between individuals [ 3 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ].

Although the skin microbiome is stable for years [ 10 ], little is known about the molecules that reside on the skin surface or how skin care products influence this chemistry [ 17 , 18 ]. Mass spectrometry can be used to detect host molecules, personalized lifestyles including diet, medications, and personal care products [ 18 , 19 ]. However, although the impact of short-term dietary interventions on the gut microbiome has been assessed [ 20 , 21 ], no study has yet tested how susceptible the skin chemistry and Microbiome are to alterations in the subjects’ personal care product routine.

In our recent metabolomic/microbiome 3D cartography study [ 18 ], we observed altered microbial communities where specific skin care products were present. Therefore, we hypothesized that these products might shape specific skin microbial communities by changing their chemical environment. Some beauty product ingredients likely promote or inhibit the growth of specific bacteria: for example, lipid components of moisturizers could provide nutrients and promote the growth of lipophilic bacteria such as Staphylococcus and Propionibacterium [ 18 , 22 , 23 ]. Understanding both temporal variations of the skin microbiome and chemistry is crucial for testing whether alterations in personal habits can influence the human skin ecosystem and, perhaps, host health. To evaluate these variations, we used a multi-omics approach integrating metabolomics and microbiome data from skin samples of 11 healthy human individuals. Here, we show that many compounds from beauty products persist on the skin for weeks following their use, suggesting a long-term contribution to the chemical environment where skin microbes live. Metabolomics analysis reveals temporal trends correlated to discontinuing and resuming the use of beauty products and characteristic of variations in molecular composition of the skin. Although highly personalized, as seen with the microbiome, the chemistry, including hormones and pheromones such as androstenone and androsterone, were dramatically altered. Similarly, by experimentally manipulating the personal care regime of participants, bacterial and molecular diversity and structure are altered, particularly for the armpits and feet. Interestingly, a high person-to-person molecular and bacterial variability is maintained over time even though personal care regimes were modified in exactly the same way for all participants.

Skin care and hygiene products persist on the skin

Systematic strategies to influence both the skin chemistry and microbiome have not yet been investigated. The outermost layer of the skin turns over every 3 to 4 weeks [ 8 , 9 ]. How the microbiome and chemistry are influenced by altering personal care and how long the chemicals of personal care products persist on the skin are essentially uncharacterized. In this study, we collected samples from skin of 12 healthy individuals—six males and six females—over 9 weeks. One female volunteer had withdrawn due to skin irritations that developed, and therefore, we describe the remaining 11 volunteers. Samples were collected from each arm, armpit, foot, and face, including both the right and left sides of the body (Fig.  1 a). All participants were asked to adhere to the same daily personal care routine during the first 6 weeks of this study (Fig.  1 b). The volunteers were asked to refrain from using any personal care product for weeks 1–3 except a mild body wash (Fig.  1 b). During weeks 4–6, in addition to the body wash, participants were asked to apply selected commercial skin care products at specific body parts: a moisturizer on the arm, a sunscreen on the face, an antiperspirant on the armpits, and a soothing powder on the foot (Fig.  1 b). To monitor adherence of participants to the study protocol, molecular features found in the antiperspirant, facial lotion, moisturizer, and foot powder were directly tracked with mass spectrometry from the skin samples. For all participants, the mass spectrometry data revealed the accumulation of specific beauty product ingredients during weeks 4–6 (Additional file  1 : Figure S1A-I, Fig.  2 a orange arrows). Examples of compounds that were highly abundant during T4–T6 in skin samples are avobenzone (Additional file  1 : Figure S1A), dexpanthenol (Additional file  1 : Figure S1B), and benzalkonium chloride (Additional file  1 : Figure S1C) from the facial sunscreen; trehalose 6-phosphate (Additional file  1 : Figure S1D) and glycerol stearate (Additional file  1 : Figure S1E) from the moisturizer applied on arms; indolin (Additional file  1 : Figure S1F) and an unannotated compound ( m/z 233.9, rt 183.29 s) (Additional file  1 : Figure S1G) from the foot powder; and decapropylene glycol (Additional file  1 : Figure S1H) and nonapropylene glycol (Additional file  1 : Figure S1I) from the antiperspirant. These results suggest that there is likely a compliance of all individuals to study requirements and even if all participants confirmed using each product every day, the amount of product applied by each individual may vary. Finally, for weeks 7–9, the participants were asked to return to their normal routine by using the same personal care products they used prior to the study. In total, excluding all blanks and personal care products themselves, we analyzed 2192 skin samples for both metabolomics and microbiome analyses.

Study design and representation of changes in personal care regime over the course of 9 weeks. a Six males and six females were recruited and sampled using swabs on two locations from each body part (face, armpits, front forearms, and between toes) on the right and left side. The locations sampled were the face—upper cheek bone and lower jaw, armpit—upper and lower area, arm—front of elbow (antecubitis) and forearm (antebrachium), and feet—in between the first and second toe and third and fourth toe. Volunteers were asked to follow specific instructions for the use of skin care products. b Following the use of their personal skin care products (brown circles), all volunteers used only the same head to toe shampoo during the first 3 weeks (week 1–week 3) and no other beauty product was applied (solid blue circle). The following 3 weeks (week 4–week 6), four selected commercial beauty products were applied daily by all volunteers on the specific body part (deodorant antiperspirant for the armpits, soothing foot powder for the feet between toes, sunscreen for the face, and moisturizer for the front forearm) (triangles) and continued to use the same shampoo. During the last 3 weeks (week 7–week 9), all volunteers went back to their normal routine and used their personal beauty products (circles). Samples were collected once a week (from day 0 to day 68—10 timepoints from T0 to T9) for volunteers 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, and 12, and on day 0 and day 6 for volunteer 8, who withdraw from the study after day 6. For 3 individuals (volunteers 4, 9, 10), samples were collected twice a week (19 timepoints total). Samples collected for 11 volunteers during 10 timepoints: 11 volunteers × 10 timepoints × 4 samples × 4 body sites = 1760. Samples collected from 3 selected volunteers during 9 additional timepoints: 3 volunteers × 9 timepoints × 4 samples × 4 body sites = 432. See also the “ Subject recruitment and sample collection ” section in the “ Methods ” section

Monitoring the persistence of personal care product ingredients in the armpits over a 9-week period. a Heatmap representation of the most abundant molecular features detected in the armpits of all individuals during the four phases (0: initial, 1–3: no beauty products, 4–6: common products, and 7–9: personal products). Green color in the heatmap represents the highest molecular abundance and blue color the lowest one. Orange boxes with plain lines represent enlargement of cluster of molecules that persist on the armpits of volunteer 1 ( b ) and volunteer 3 ( c , d ). Orange clusters with dotted lines represent same clusters of molecules found on the armpits of other volunteers. Orange arrows represent the cluster of compounds characteristic of the antiperspirant used during T4–T6. b Polyethylene glycol (PEG) molecular clusters that persist on the armpits of individual 1. The molecular subnetwork, representing molecular families [ 24 ], is part of a molecular network ( http://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=f5325c3b278a46b29e8860ec5791d5ad ) generated from MS/MS data collected from the armpits of volunteer 1 (T0–T3) MSV000081582 and MS/MS data collected from the deodorant used by volunteer 1 before the study started (T0) MSV000081580. c , d Polypropylene glycol (PPG) molecular families that persist on the armpits of individual 3, along with the corresponding molecular subnetwork that is part of the molecular network accessible here http://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=aaa1af68099d4c1a87e9a09f398fe253 . Subnetworks were generated from MS/MS data collected from the armpits of volunteer 3 (T0–T3) MSV000081582 and MS/MS data collected from the deodorant used by volunteer 3 at T0 MSV000081580. The network nodes were annotated with colors. Nodes represent MS/MS spectra found in armpit samples of individual 1 collected during T0, T1, T2, and T3 and in personal deodorant used by individual 1 (orange nodes); armpit samples of individual 1 collected during T0, T2, and T3 and personal deodorant used by individual 1 (green nodes); armpit samples of individual 3 collected during T0, T1, T2, and T3 and in personal deodorant used by individual 3 (red nodes); armpit samples of individual 3 collected during T0 and in personal deodorant used by individual 3 (blue nodes); and armpit samples of individual 3 collected during T0 and T2 and in personal deodorant used by individual 3 (purple nodes). Gray nodes represent everything else. Error bars represent standard error of the mean calculated at each timepoint from four armpit samples collected from the right and left side of each individual separately. See also Additional file  1 : Figure S1

To understand how long beauty products persist on the skin, we monitored compounds found in deodorants used by two volunteers—female 1 and female 3—before the study (T0), over the first 3 weeks (T1–T3) (Fig.  1 b). During this phase, all participants used exclusively the same body wash during showering, making it easier to track ingredients of their personal care products. The data in the first 3 weeks (T1–T3) revealed that many ingredients of deodorants used on armpits (Fig.  2 a) persist on the skin during this time and were still detected during the first 3 weeks or at least during the first week following the last day of use. Each of the compounds detected in the armpits of individuals exhibited its own unique half-life. For example, the polyethylene glycol (PEG)-derived compounds m/z 344.227, rt 143 s (Fig.  2 b, S1J); m/z 432.279, rt 158 s (Fig.  2 b, S1K); and m/z 388.253, rt 151 s (Fig.  2 b, S1L) detected on armpits of volunteer 1 have a calculated half-life of 0.5 weeks (Additional file  1 : Figure S1J-L, all p values < 1.81e−07), while polypropylene glycol (PPG)-derived molecules m/z 481.87, rt 501 s (Fig.  2 c, S1M); m/z 560.420, rt 538 s (Fig.  2 c, S1N); m/z 788.608, rt 459 s (Fig.  2 d, S1O); m/z 846.650, rt 473 s (Fig.  2 d, S1P); and m/z 444.338, rt 486 s (Fig.  2 d, S1Q) found on armpits of volunteers 3 and 1 (Fig.  2 a) have a calculated half-life ranging from 0.7 to 1.9 weeks (Additional file  1 : Figure S1M-Q, all p values < 0.02), even though they originate from the same deodorant used by each individual. For some ingredients of deodorant used by volunteer 3 on time 0 (Additional file  1 : Figure S1M, N), a decline was observed during the first week, then little to no traces of these ingredients were detected during weeks 4–6 (T4–T6), then finally these ingredients reappear again during the last 3 weeks of personal product use (T7–T9). This suggests that these ingredients are present exclusively in the personal deodorant used by volunteer 3 before the study. Because a similar deodorant (Additional file  1 : Figure S1O-Q) and a face lotion (Additional file  1 : Figure S1R) was used by volunteer 3 and volunteer 2, respectively, prior to the study, there was no decline or absence of their ingredients during weeks 4–6 (T4–T6).

Polyethylene glycol compounds (Additional file  1 : Figure S1J-L) wash out faster from the skin than polypropylene glycol (Additional file  1 : Figure S1M-Q)(HL ~ 0.5 weeks vs ~ 1.9 weeks) and faster than fatty acids used in lotions (HL ~ 1.2 weeks) (Additional file  1 : Figure S1R), consistent with their hydrophilic (PEG) and hydrophobic properties (PPG and fatty acids) [ 25 , 26 ]. This difference in hydrophobicity is also reflected in the retention time as detected by mass spectrometry. Following the linear decrease of two PPG compounds from T0 to T1, they accumulated noticeably during weeks 2 and 3 (Additional file  1 : Figure S1M, N). This accumulation might be due to other sources of PPG such as the body wash used during this period or the clothes worn by person 3. Although PPG compounds were not listed in the ingredient list of the shampoo, we manually inspected the LC-MS data collected from this product and confirmed the absence of PPG compounds in the shampoo. The data suggest that this trend is characteristic of accumulation of PPG from additional sources. These could be clothes, beds, or sheets, in agreement with the observation of these molecules found in human habitats [ 27 ] but also in the public GNPS mass spectrometry dataset MSV000079274 that investigated the chemicals from dust collected from 1053 mattresses of children.

Temporal molecular and bacterial diversity in response to personal care use

To assess the effect of discontinuing and resuming the use of skin care products on molecular and microbiota dynamics, we first evaluated their temporal diversity. Skin sites varied markedly in their initial level (T0) of molecular and bacterial diversity, with higher molecular diversity at all sites for female participants compared to males (Fig.  3 a, b, Wilcoxon rank-sum-WR test, p values ranging from 0.01 to 0.0001, from foot to arm) and higher bacterial diversity in face (WR test, p  = 0.0009) and armpits (WR test, p  = 0.002) for females (Fig.  3 c, d). Temporal diversity was similar across the right and left sides of each body site of all individuals (WR test, molecular diversity: all p values > 0.05; bacterial diversity: all p values > 0.20). The data show that refraining from using beauty products (T1–T3) leads to a significant decrease in molecular diversity at all sites (Fig.  3 a, b, WR test, face: p  = 8.29e−07, arm: p  = 7.08e−09, armpit: p  = 1.13e−05, foot: p  = 0.002) and bacterial diversity mainly in armpits (WR test, p  = 0.03) and feet (WR test, p  = 0.04) (Fig.  3 c, d). While molecular diversity declined (Fig.  3 a, b) for arms and face, bacterial diversity (Fig.  3 c, d) was less affected in the face and arms when participants did not use skin care products (T1–T3). The molecular diversity remained stable in the arms and face of female participants during common beauty products use (T4–T6) to immediately increase as soon as the volunteers went back to their normal routines (T7–T9) (WR test, p  = 0.006 for the arms and face)(Fig.  3 a, b). A higher molecular (Additional file  1 : Figure S2A) and community (Additional file  1 : Figure S2B) diversity was observed for armpits and feet of all individuals during the use of antiperspirant and foot powder (T4–T6) (WR test, molecular diversity: armpit p  = 8.9e−33, foot p  = 1.03e−11; bacterial diversity: armpit p  = 2.14e−28, foot p  = 1.26e−11), followed by a molecular and bacterial diversity decrease in the armpits when their regular personal beauty product use was resumed (T7–T9) (bacterial diversity: WR test, p  = 4.780e−21, molecular diversity: WR test, p  = 2.159e−21). Overall, our data show that refraining from using beauty products leads to lower molecular and bacterial diversity, while resuming the use increases their diversity. Distinct variations between male and female molecular and community richness were perceived at distinct body parts (Fig.  3 a–d). Although the chemical diversity of personal beauty products does not explain these variations (Additional file  1 : Figure S2C), differences observed between males and females may be attributed to many environmental and lifestyle factors including different original skin care and different frequency of use of beauty products (Additional file  2 : Table S1), washing routines, and diet.

Molecular and bacterial diversity over a 9-week period, comparing samples based on their molecular (UPLC-Q-TOF-MS) or bacterial (16S rRNA amplicon) profiles. Molecular and bacterial diversity using the Shannon index was calculated from samples collected from each body part at each timepoint, separately for female ( n  = 5) and male ( n  = 6) individuals. Error bars represent standard error of the mean calculated at each timepoint, from up to four samples collected from the right and left side of each body part, of females ( n  = 5) and males ( n  = 6) separately. a , b Molecular alpha diversity measured using the Shannon index from five females (left panel) and six males (right panel), over 9 weeks, from four distinct body parts (armpits, face, arms, feet). c , d Bacterial alpha diversity measured using the Shannon index, from skin samples collected from five female (left panel) and six male individuals (right panel), over 9 weeks, from four distinct body parts (armpits, face, arms, feet). See also Additional file  1 : Figure S2

Longitudinal variation of skin metabolomics signatures

To gain insights into temporal metabolomics variation associated with beauty product use, chemical inventories collected over 9 weeks were subjected to multivariate analysis using the widely used Bray–Curtis dissimilarity metric (Fig.  4 a–c, S3A). Throughout the 9-week period, distinct molecular signatures were associated to each specific body site: arm, armpit, face, and foot (Additional file  1 : Figure S3A, Adonis test, p  < 0.001, R 2 0.12391). Mass spectrometric signatures displayed distinct individual trends at each specific body site (arm, armpit, face, and foot) over time, supported by their distinct locations in PCoA (principal coordinate analysis) space (Fig.  4 a, b) and based on the Bray–Curtis distances between molecular profiles (Additional file  1 : Figure S3B, WR test, all p values < 0.0001 from T0 through T9). This suggests a high molecular inter-individual variability over time despite similar changes in personal care routines. Significant differences in molecular patterns associated to ceasing (T1–T3) (Fig.  4 b, Additional file 1 : Figure S3C, WR test, T0 vs T1–T3 p  < 0.001) and resuming the use of common beauty products (T4–T6) (Additional file  1 : Figure S3C) were observed in the arm, face, and foot (Fig.  4 b), although the armpit exhibited the most pronounced changes (Fig.  4 b, Additional file 1 : Figure S3D, E, random forest highlighting that 100% of samples from each phase were correctly predicted). Therefore, we focused our analysis on this region. Molecular changes were noticeable starting the first week (T1) of discontinuing beauty product use. As shown for armpits in Fig.  4 c, these changes at the chemical level are specific to each individual, possibly due to the extremely personalized lifestyles before the study and match their original use of deodorant. Based on the initial use of underarm products (T0) (Additional file  2 : Table S1), two groups of participants can be distinguished: a group of five volunteers who used stick deodorant as evidenced by the mass spectrometry data and another group of volunteers where we found few or no traces suggesting they never or infrequently used stick deodorants (Additional file  2 : Table S1). Based on this criterion, the chemical trends shown in Fig.  4 c highlight that individuals who used stick deodorant before the beginning of the study (volunteers 1, 2, 3, 9, and 12) displayed a more pronounced shift in their armpits’ chemistries as soon as they stopped using deodorant (T1–T3), compared to individuals who had low detectable levels of stick deodorant use (volunteers 4, 6, 7, and 10), or “rarely-to-never” (volunteers 5 and 11) use stick deodorants as confirmed by the volunteers (Additional file  1 : Figure S3F, WR test, T0 vs T1–T3 all p values < 0.0001, with greater distance for the group of volunteers 1, 2, 3, 9, and 12, compared to volunteers 4, 5, 6, 7, 10, and 11). The most drastic shift in chemical profiles was observed during the transition period, when all participants applied the common antiperspirant on a daily basis (T4–T6) (Additional file  1 : Figure S3D, E). Finally, the molecular profiles became gradually more similar to those collected before the experiment (T0) as soon as the participants resumed using their personal beauty products (T7–T9) (Additional file  1 : Figure S3C), although traces of skin care products did last through the entire T7–T9 period in people who do not routinely apply these products (Fig.  4 c).

Individualized influence of beauty product application on skin metabolomics profiles over time. a Multivariate statistical analysis (principal coordinate analysis (PCoA)) comparing mass spectrometry data collected over 9 weeks from the skin of 11 individuals, all body parts, combined (first plot from the left) and then displayed separately (arm, armpits, face, feet). Color scale represents volunteer ID. The PCoA was calculated on all samples together, and subsets of the data are shown in this shared space and the other panels. b The molecular profiles collected over 9 weeks from all body parts, combined then separately (arm, armpits, face, feet). c Representative molecular profiles collected over 9 weeks from armpits of 11 individuals (volunteers 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12). Color gradient in b and c represents timepoints (time 0 to time 9), ranging from the lightest orange color to the darkest one that represent the earliest (time 0) to the latest (time 9) timepoint, respectively. 0.5 timepoints represent additional timepoints where three selected volunteers were samples (volunteers 4, 9, and 10). PCoA plots were generated using the Bray–Curtis dissimilarity matrix and visualized in Emperor [ 28 ]. See also Additional file  1 : Figure S3

Comparing chemistries detected in armpits at the end timepoints—when no products were used (T3) and during product use (T6)—revealed distinct molecular signatures characteristic of each phase (random forest highlighting that 100% of samples from each group were correctly predicted, see Additional file  1 : Figure S3D, E). Because volunteers used the same antiperspirant during T4–T6, molecular profiles converged during that time despite individual patterns at T3 (Fig.  4 b, c, Additional file  1 : Figure S3D). These distinct chemical patterns reflect the significant impact of beauty products on skin molecular composition. Although these differences may in part be driven by beauty product ingredients detected on the skin (Additional file  1 : Figure S1), we anticipated that additional host- and microbe-derived molecules may also be involved in these molecular changes.

To characterize the chemistries that vary over time, we used molecular networking, a MS visualization approach that evaluates the relationship between MS/MS spectra and compares them to reference MS/MS spectral libraries of known compounds [ 29 , 30 ]. We recently showed that molecular networking can successfully organize large-scale mass spectrometry data collected from the human skin surface [ 18 , 19 ]. Briefly, molecular networking uses the MScluster algorithm [ 31 ] to merge all identical spectra and then compares and aligns all unique pairs of MS/MS spectra based on their similarities where 1.0 indicates a perfect match. Similarities between MS/MS spectra are calculated using a similarity score, and are interpreted as molecular families [ 19 , 24 , 32 , 33 , 34 ]. Here, we used this method to compare and characterize chemistries found in armpits, arms, face, and foot of 11 participants. Based on MS/MS spectral similarities, chemistries highlighted through molecular networking (Additional file  1 : Figure S4A) were associated with each body region with 8% of spectra found exclusively in the arms, 12% in the face, 14% in the armpits, and 2% in the foot, while 18% of the nodes were shared between all four body parts and the rest of spectra were shared between two body sites or more (Additional file  1 : Figure S4B). Greater spectral similarities were highlighted between armpits, face, and arm (12%) followed by the arm and face (9%) (Additional file  1 : Figure S4B).

Molecules were annotated with Global Natural Products Social Molecular Networking (GNPS) libraries [ 29 ], using accurate parent mass and MS/MS fragmentation patterns, according to level 2 or 3 of annotation defined by the 2007 metabolomics standards initiative [ 35 ]. Through annotations, molecular networking revealed that many compounds derived from steroids (Fig.  5 a–d), bile acids (Additional file  1 : Figure S5A-D), and acylcarnitines (Additional file  1 : Figure S5E-F) were exclusively detected in the armpits. Using authentic standards, the identity of some pheromones and bile acids were validated to a level 1 identification with matched retention times (Additional file  1 : Figure S6B, S7A, C, D). Other steroids and bile acids were either annotated using standards with identical MS/MS spectra but slightly different retention times (Additional file  1 : Figure S6A) or annotated with MS/MS spectra match with reference MS/MS library spectra (Additional file  1 : Figure S6C, D, S7B, S6E-G). These compounds were therefore classified as level 3 [ 35 ]. Acylcarnitines were annotated to a family of possible acylcarnitines (we therefore classify as level 3), as the positions of double bonds or cis vs trans configurations are unknown (Additional file  1 : Figure S8A, B).

Underarm steroids and their longitudinal abundance. a – d Steroid molecular families in the armpits and their relative abundance over a 9-week period. Molecular networking was applied to characterize chemistries from the skin of 11 healthy individuals. The full network is shown in Additional file  1 : Figure S4A, and networking parameters can be found here http://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=284fc383e4c44c4db48912f01905f9c5 for MS/MS datasets MSV000081582. Each node represents a consensus of a minimum of 3 identical MS/MS spectra. Yellow nodes represent MS/MS spectra detected in armpits samples. Hexagonal shape represents MS/MS spectra match between skin samples and chemical standards. Plots are representative of the relative abundance of each compound over time, calculated separately from LC-MS1 data collected from the armpits of each individual. Steroids detected in armpits are a , dehydroisoandrosterone sulfate ( m/z 369.190, rt 247 s), b androsterone sulfate ( m/z 371.189, rt 261 s), c 1-dehydroandrostenedione ( m/z 285.185, rt 273 s), and d dehydroandrosterone ( m/z 289.216, rt 303 s). Relative abundance over time of each steroid compound is represented. Error bars represent the standard error of the mean calculated at each timepoint from four armpit samples from the right and left side of each individual separately. See also Additional file  1 : Figures S4-S8

Among the steroid compounds, several molecular families were characterized: androsterone (Fig.  5 a, b, d), androstadienedione (Fig.  5 c), androstanedione (Additional file  1 : Figure S6E), androstanolone (Additional file  1 : Figure S6F), and androstenedione (Additional file  1 : Figure S6G). While some steroids were detected in the armpits of several individuals, such as dehydroisoandrosterone sulfate ( m/z 369.19, rt 247 s) (9 individuals) (Fig.  5 a, Additional file  1 : Figure S6A), androsterone sulfate ( m/z 371.189, rt 261 s) (9 individuals) (Fig.  5 b, Additional file  1 : Figure S6C), and 5-alpha-androstane-3,17-dione ( m/z 271.205, rt 249 s) (9 individuals) (Additional file  1 : Figure S6E), other steroids including 1-dehydroandrostenedione ( m/z 285.185, rt 273 s) (Fig.  5 c, Additional file  1 : Figure S6B), dehydroandrosterone ( m/z 289.216, rt 303 s) (Fig.  5 d, Additional file 1 : Figure S6D), and 5-alpha-androstan-17.beta-ol-3-one ( m/z 291.231, rt 318 s) (Additional file  1 : Figure S6F) were only found in the armpits of volunteer 11 and 4-androstene-3,17-dione ( m/z 287.200, rt 293 s) in the armpits of volunteer 11 and volunteer 5, both are male that never applied stick deodorants (Additional file  1 : Figure S6G). Each molecular species exhibited a unique pattern over the 9-week period. The abundance of dehydroisoandrosterone sulfate (Fig.  5 a, WR test, p  < 0.01 for 7 individuals) and dehydroandrosterone (Fig.  5 a, WR test, p  = 0.00025) significantly increased during the use of antiperspirant (T4–T6), while androsterone sulfate (Fig.  5 b) and 5-alpha-androstane-3,17-dione (Additional file  1 : Figure S6E) display little variation over time. Unlike dehydroisoandrosterone sulfate (Fig.  5 a) and dehydroandrosterone (Fig.  5 d), steroids including 1-dehydroandrostenedione (Fig.  5 c, WR test, p  = 0.00024) and 4-androstene-3,17-dione (Additional file  1 : Figure S6G, WR test, p  = 0.00012) decreased in abundance during the 3 weeks of antiperspirant application (T4–T6) in armpits of male 11, and their abundance increased again when resuming the use of his normal skin care routines (T7–T9). Interestingly, even within the same individual 11, steroids were differently impacted by antiperspirant use as seen for 1-dehydroandrostenedione that decreased in abundance during T4–T6 (Fig.  5 c, WR test, p  = 0.00024), while dehydroandrosterone increased in abundance (Fig.  5 d, WR test, p  = 0.00025), and this increase was maintained during the last 3 weeks of the study (T7–T9).

In addition to steroids, many bile acids (Additional file  1 : Figure S5A-D) and acylcarnitines (Additional file  1 : Figure S5E-F) were detected on the skin of several individuals through the 9-week period. Unlike taurocholic acid found only on the face (Additional file  1 : Figures S5A, S7A) and tauroursodeoxycholic acid detected in both armpits and arm samples (Additional file  1 : Figures S5B, S7B), other primary bile acids such as glycocholic (Additional file  1 : Figures S5C, S7C) and chenodeoxyglycocholic acid (Additional file  1 : Figures S5D, S7D) were exclusively detected in the armpits. Similarly, acylcarnitines were also found either exclusively in the armpits (hexadecanoyl carnitines) (Additional file  1 : Figures S5E, S8A) or in the armpits and face (tetradecenoyl carnitine) (Additional file  1 : Figures S5F, S8B) and, just like the bile acids, they were also stably detected during the whole 9-week period.

Bacterial communities and their variation over time

Having demonstrated the impact of beauty products on the chemical makeup of the skin, we next tested the extent to which skin microbes are affected by personal care products. We assessed temporal variation of bacterial communities detected on the skin of healthy individuals by evaluating dissimilarities of bacterial collections over time using unweighted UniFrac distance [ 36 ] and community variation at each body site in association to beauty product use [ 3 , 15 , 37 ]. Unweighted metrics are used for beta diversity calculations because we are primarily concerned with changes in community membership rather than relative abundance. The reason for this is that skin microbiomes can fluctuate dramatically in relative abundance on shorter timescales than that assessed here. Longitudinal variations were revealed for the armpits (Fig.  6 a) and feet microbiome by their overall trend in the PCoA plots (Fig.  6 b), while the arm (Fig.  6 c) and face (Fig.  6 d) displayed relatively stable bacterial profiles over time. As shown in Fig.  6 a–d, although the microbiome was site-specific, it varied more between individuals and this inter-individual variability was maintained over time despite same changes in personal care routine (WR test, all p values at all timepoints < 0.05, T5 p  = 0.07), in agreement with previous findings that individual differences in the microbiome are large and stable over time [ 3 , 4 , 10 , 37 ]. However, we show that shifts in the microbiome can be induced by changing hygiene routine and therefore skin chemistry. Changes associated with using beauty products (T4–T6) were more pronounced for the armpits (Fig.  6 a, WR test, p  = 1.61e−52) and feet (Fig.  6 b, WR test, p  = 6.15e−09), while little variations were observed for the face (Fig.  6 d, WR test, p  = 1.402.e−83) and none for the arms (Fig.  6 c, WR test, p  = 0.296).

Longitudinal variation of skin bacterial communities in association with beauty product use. a - d Bacterial profiles collected from skin samples of 11 individuals, over 9 weeks, from four distinct body parts a) armpits, b) feet, c) arms and d) face, using multivariate statistical analysis (Principal Coordinates Analysis PCoA) and unweighted Unifrac metric. Each color represents bacterial samples collected from an individual. PCoA were calculated separately for each body part. e , f Representative Gram-negative (Gram -) bacteria collected from arms, armpits, face and feet of e) female and f) male participants. See also Additional file  1 : Figure S9A, B showing Gram-negative bacterial communities represented at the genus level

A significant increase in abundance of Gram-negative bacteria including the phyla Proteobacteria and Bacteroidetes was noticeable for the armpits and feet of both females (Fig.  6 e; Mann–Whitney U , p  = 8.458e−07) and males (Fig.  6 f; Mann–Whitney U , p  = 0.0004) during the use of antiperspirant (T4–T6), while their abundance remained stable for the arms and face during that time (Fig.  6 e, f; female arm p  = 0.231; female face p value = 0.475; male arm p = 0.523;male face p  = 6.848751e−07). These Gram-negative bacteria include Acinetobacter and Paracoccus genera that increased in abundance in both armpits and feet of females (Additional file  1 : Figure S9A), while a decrease in abundance of Enhydrobacter was observed in the armpits of males (Additional file  1 : Figure S9B). Cyanobacteria, potentially originating from plant material (Additional file  1 : Figure S9C) also increased during beauty product use (T4–T6) especially in males, in the armpits and face of females (Fig.  6 e) and males (Fig.  6 f). Interestingly, although chloroplast sequences (which group phylogenetically within the cyanobacteria [ 38 ]) were only found in the facial cream (Additional file  1 : Figure S9D), they were detected in other locations as well (Fig.  6 e, f. S9E, F), highlighting that the application of a product in one region will likely affect other regions of the body. For example, when showering, a face lotion will drip down along the body and may be detected on the feet. Indeed, not only did the plant material from the cream reveal this but also the shampoo used for the study for which molecular signatures were readily detected on the feet as well (Additional file  1 : Figure S10A). Minimal average changes were observed for Gram-positive organisms (Additional file  1 : Figure S10B, C), although in some individuals the variation was greater than others (Additional file  1 : Figure S10D, E) as discussed for specific Gram-positive taxa below.

At T0, the armpit’s microflora was dominated by Staphylococcus (26.24%, 25.11% of sequencing reads for females and 27.36% for males) and Corynebacterium genera (26.06%, 17.89% for females and 34.22% for males) (Fig.  7 a—first plot from left and Additional file  1 : Figure S10D, E). They are generally known as the dominant armpit microbiota and make up to 80% of the armpit microbiome [ 39 , 40 ]. When no deodorants were used (T1–T3), an overall increase in relative abundance of Staphylococcus (37.71%, 46.78% for females and 30.47% for males) and Corynebacterium (31.88%, 16.50% for females and 44.15% for males) genera was noticeable (WR test, p  < 3.071e−05) (Fig.  7 a—first plot from left), while the genera Anaerococcus and Peptoniphilus decreased in relative abundance (WR test, p  < 0.03644) (Fig.  7 a—first plot from left and Additional file  1 : Figure S10D, E). When volunteers started using antiperspirants (T4–T6), the relative abundance of Staphylococcus (37.71%, 46.78% females and 30.47% males, to 21.71%, 25.02% females and 19.25% males) and Corynebacterium (31.88%, 16.50% females and 44.15% males, to 15.83%, 10.76% females and 19.60% males) decreased (WR test, p  < 3.071e−05) (Fig.  7 a, Additional file  1 : Figure S10D, E) and at the same time, the overall alpha diversity increased significantly (WR test, p  = 3.47e−11) (Fig.  3 c, d). The microbiota Anaerococcus (WR test, p  = 0.0006018) , Peptoniphilus (WR test, p  = 0.008639), and Micrococcus (WR test, p  = 0.0377) increased significantly in relative abundance, together with a lot of additional low-abundant species that lead to an increase in Shannon alpha diversity (Fig.  3 c, d). When participants went back to normal personal care products (T7–T9), the underarm microbiome resembled the original underarm community of T0 (WR test, p  = 0.7274) (Fig.  7 a). Because armpit bacterial communities are person-specific (inter-individual variability: WR test, all p values at all timepoints < 0.05, besides T5 p n.s), variation in bacterial abundance upon antiperspirant use (T4–T6) differ between individuals and during the whole 9-week period (Fig.  7a —taxonomic plots per individual). For example, the underarm microbiome of male 5 exhibited a unique pattern, where Corynebacterium abundance decreased drastically during the use of antiperspirant (82.74 to 11.71%, WR test, p  = 3.518e−05) while in the armpits of female 9 a huge decrease in Staphylococcus abundance was observed (Fig.  7 a) (65.19 to 14.85%, WR test, p  = 0.000113). Unlike other participants, during T0–T3, the armpits of individual 11 were uniquely characterized by the dominance of a sequence that matched most closely to the Enhydrobacter genera . The transition to antiperspirant use (T4–T6) induces the absence of Enhydrobacter (30.77 to 0.48%, WR test, p  = 0.01528) along with an increase of Corynebacterium abundance (26.87 to 49.74%, WR test, p  = 0.1123) (Fig.  7 a—male 11).

Person-to-person bacterial variabilities over time in the armpits and feet. a Armpit microbiome changes when stopping personal care product use, then resuming. Armpit bacterial composition of the 11 volunteers combined, then separately, (female 1, female 2, female 3, male 4, male 5, male 6, male 7, female 9, male 10, male 11, female 12) according to the four periods within the experiment. b Feet bacterial variation over time of the 12 volunteers combined, then separately (female 1, female 2, female 3, male 4, male 5, male 6, male 7, female 9, male 10, male 11, female 12) according to the four periods within the experiment. See also Additional file  1 : Figure S9-S13

In addition to the armpits, a decline in abundance of Staphylococcus and Corynebacterium was perceived during the use of the foot powder (46.93% and 17.36%, respectively) compared to when no beauty product was used (58.35% and 22.99%, respectively) (WR test, p  = 9.653e−06 and p  = 0.02032, respectively), while the abundance of low-abundant foot bacteria significantly increased such as Micrococcus (WR test, p  = 1.552e−08), Anaerococcus (WR test, p  = 3.522e−13), Streptococcus (WR test, p  = 1.463e−06), Brevibacterium (WR test, p  = 6.561e−05), Moraxellaceae (WR test, p  = 0.0006719), and Acinetobacter (WR test, p  = 0.001487), leading to a greater bacterial diversity compared to other phases of the study (Fig.  7 b first plot from left, Additional file  1 : Figure S10D, E, Fig.  3 c, d).

We further evaluated the relationship between the two omics datasets by superimposing the principal coordinates calculated from metabolome and microbiome data (Procrustes analysis) (Additional file  1 : Figure S11) [ 34 , 41 , 42 ]. Metabolomics data were more correlated with patterns observed in microbiome data in individual 3 (Additional file  1 : Figure S11C, Mantel test, r  = 0.23, p  < 0.001), individual 5 (Additional file  1 : Figure S11E, r  = 0.42, p  < 0.001), individual 9 (Additional file  1 : Figure S11H, r  = 0.24, p  < 0.001), individual 10 (Additional file  1 : Figure S11I, r  = 0.38, p  < 0.001), and individual 11 (Additional file  1 : Figure S11J, r  = 0.35, p  < 0.001) when compared to other individuals 1, 2, 4, 6, 7, and 12 (Additional file  1 : Figure S11A, B, D, F, G, K, respectively) (Mantel test, all r  < 0.2, all p values < 0.002, for volunteer 2 p n.s). Furthermore, these correlations were individually affected by ceasing (T1–T3) or resuming the use of beauty products (T4–T6 and T7–T9) (Additional file  1 : Figure S11A-K).

Overall, metabolomics–microbiome correlations were consistent over time for the arms, face, and feet although alterations were observed in the arms of volunteers 7 (Additional file  1 : Figure S11G) and 10 (Additional file  1 : Figure S11I) and the face of volunteer 7 (Additional file  1 : Figure S11G) during product use (T4–T6). Molecular–bacterial correlations were mostly affected in the armpits during antiperspirant use (T4–T6), as seen for volunteers male 7 (Additional file  1 : Figure S11G) and 11 (Additional file  1 : Figure S11J) and females 2 (Additional file  1 : Figure S11B), 9 (Additional file  1 : Figure S11H), and 12 (Additional file  1 : Figure S11K). This perturbation either persisted during the last 3 weeks (Additional file  1 : Figure S11D, E, H, I, K) when individuals went back to their normal routine (T7–T9) or resembled the initial molecular–microbial correlation observed in T0 (Additional file  1 : Figure S11C, G, J). These alterations in molecular–bacterial correlation are driven by metabolomics changes during antiperspirant use as revealed by metabolomics shifts on the PCoA space (Additional file  1 : Figure S11), partially due to the deodorant’s chemicals (Additional file  1 : Figure S1J, K) but also to changes observed in steroid levels in the armpits (Fig.  5A, C, D , Additional file 1 : Figure S6G), suggesting metabolome-dependant changes of the skin microbiome. In agreement with previous findings that showed efficient biotransformation of steroids by Corynebacterium [ 43 , 44 ], our correlation analysis associates specific steroids that were affected by antiperspirant use in the armpits of volunteer 11 (Fig.  5 c, d, Additional file 1 : Figure S6G) with microbes that may produce or process them: 1-dehydroandrostenedione, androstenedione, and dehydrosterone with Corynebacterium ( r  = − 0.674, p  = 6e−05; r  = 0.671, p  = 7e−05; r  = 0.834, p  < 1e−05, respectively) (Additional file  1 : Figure S12A, B, C, respectively) and Enhydrobacter ( r  = 0.683, p  = 4e−05; r  = 0.581, p  = 0.00095; r  = 0.755, p  < 1e−05 respectively) (Additional file  1 : Figure S12D, E, F, respectively).

Despite the widespread use of skin care and hygiene products, their impact on the molecular and microbial composition of the skin is poorly studied. We established a workflow that examines individuals to systematically study the impact of such lifestyle characteristics on the skin by taking a broad look at temporal molecular and bacterial inventories and linking them to personal skin care product use. Our study reveals that when the hygiene routine is modified, the skin metabolome and microbiome can be altered, but that this alteration depends on product use and location on the body. We also show that like gut microbiome responses to dietary changes [ 20 , 21 ], the responses are individual-specific.

We recently reported that traces of our lifestyle molecules can be detected on the skin days and months after the original application [ 18 , 19 ]. Here, we show that many of the molecules associated with our personal skin and hygiene products had a half-life of 0.5 to 1.9 weeks even though the volunteers regularly showered, swam, or spent time in the ocean. Thus, a single application of some of these products has the potential to alter the microbiome and skin chemistry for extensive periods of time. Our data suggests that although host genetics and diet may play a role, a significant part of the resilience of the microbiome that has been reported [ 10 , 45 ] is due to the resilience of the skin chemistry associated with personal skin and hygiene routines, or perhaps even continuous re-exposure to chemicals from our personal care routines that are found on mattresses, furniture, and other personal objects [ 19 , 27 , 46 ] that are in constant contact. Consistent with this observation is that individuals in tribal regions and remote villages that are infrequently exposed to the types of products used in this study have very different skin microbial communities [ 47 , 48 ] and that the individuals in this study who rarely apply personal care products had a different starting metabolome. We observed that both the microbiome and skin chemistry of these individuals were most significantly affected by these products. This effect by the use of products at T4–T6 on the volunteers that infrequently used them lasted to the end phase of the study even though they went back to infrequent use of personal care products. What was notable and opposite to what the authors originally hypothesized is that the use of the foot powder and antiperspirant increased the diversity of microbes and that some of this diversity continued in the T7–T9 phase when people went back to their normal skin and hygiene routines. It is likely that this is due to the alteration in the nutrient availability such as fatty acids and moisture requirements, or alteration of microbes that control the colonization via secreted small molecules, including antibiotics made by microbes commonly found on the skin [ 49 , 50 ].

We detected specific molecules on the skin that originated from personal care products or from the host. One ingredient that lasts on the skin is propylene glycol, which is commonly used in deodorants and antiperspirants and added in relatively large amounts as a humectant to create a soft and sleek consistency [ 51 ]. As shown, daily use of personal care products is leading to high levels of exposure to these polymers. Such polymers cause contact dermatitis in a subset of the population [ 51 , 52 ]. Our data reveal a lasting accumulation of these compounds on the skin, suggesting that it may be possible to reduce their dose in deodorants or frequency of application and consequently decrease the degree of exposure to such compounds. Formulation design of personal care products may be influenced by performing detailed outcome studies. In addition, longer term impact studies are needed, perhaps in multiple year follow-up studies, to assess if the changes we observed are permanent or if they will recover to the original state.

Some of the host- and microbiome-modified molecules were also detected consistently, such as acylcarnitines, bile acids, and certain steroids. This means that a portion of the molecular composition of a person’s skin is not influenced by the beauty products applied to the skin, perhaps reflecting the level of exercise for acylcarnitines [ 53 , 54 ] or the liver (dominant location where they are made) or gallbladder (where they are stored) function for bile acids. The bile acid levels are not related to sex and do not change in amount during the course of this study. While bile acids are typically associated with the human gut microbiome [ 34 , 55 , 56 , 57 , 58 ], it is unclear what their role is on the skin and how they get there. One hypothesis is that they are present in the sweat that is excreted through the skin, as this is the case for several food-derived molecules such as caffeine or drugs and medications that have been previously reported on the human skin [ 19 ] or that microbes synthesize them de novo [ 55 ]. The only reports we could find on bile acids being associated with the skin describe cholestasis and pruritus diseases. Cholestasis and pruritus in hepatobiliary disease have symptoms of skin bile acid accumulation that are thought to be responsible for severe skin itching [ 59 , 60 ]. However, since bile acids were found in over 50% of the healthy volunteers, their detection on the skin is likely a common phenotype among the general population and not only reflective of disease, consistent with recent reports challenging these molecules as biomarkers of disease [ 59 ]. Other molecules that were detected consistently came from personal care products.

Aside from molecules that are person-specific and those that do not vary, there are others that can be modified via personal care routines. Most striking is how the personal care routines influenced changes in hormones and pheromones in a personalized manner. This suggests that there may be personalized recipes that make it possible to make someone more or less attractive to others via adjustments of hormonal and pheromonal levels through alterations in skin care.

Here, we describe the utilization of an approach that combines metabolomics and microbiome analysis to assess the effect of modifying personal care regime on skin chemistry and microbes. The key findings are as follows: (1) Compounds from beauty products last on the skin for weeks after their first use despite daily showering. (2) Beauty products alter molecular and bacterial diversity as well as the dynamic and structure of molecules and bacteria on the skin. (3) Molecular and bacterial temporal variability is product-, site-, and person-specific, and changes are observed starting the first week of beauty product use. This study provides a framework for future investigations to understand how lifestyle characteristics such as diet, outdoor activities, exercise, and medications shape the molecular and microbial composition of the skin. These factors have been studied far more in their impact on the gut microbiome and chemistry than in the skin. Revealing how such factors can affect skin microbes and their associated metabolites may be essential to define long-term skin health by restoring the appropriate microbes particularly in the context of skin aging [ 61 ] and skin diseases [ 49 ] as has shown to be necessary for amphibian health [ 62 , 63 ], or perhaps even create a precision skin care approach that utilizes the proper care ingredients based on the microbial and chemical signatures that could act as key players in host defense [ 49 , 64 , 65 ].

Subject recruitment and sample collection

Twelve individuals between 25 and 40 years old were recruited to participate in this study, six females and six males. Female volunteer 8 dropped out of the study as she developed a skin irritation during the T1–T3 phase. All volunteers signed a written informed consent in accordance with the sampling procedure approved by the UCSD Institutional Review Board (Approval Number 161730). Volunteers were required to follow specific instructions during 9 weeks. They were asked to bring in samples of their personal care products they used prior to T0 so they could be sampled as well. Following the initial timepoint time 0 and during the first 3 weeks (week 1–week 3), volunteers were asked not to use any beauty products (Fig.  1 b). During the next 3 weeks (week 4–week 6), four selected commercial beauty products provided to all volunteers were applied once a day at specific body part (deodorant for the armpits, soothing foot powder between the toes, sunscreen for the face, and moisturizer for front forearms) (Fig.  1 b, Additional file  3 : Table S2 Ingredient list of beauty products). During the first 6 weeks, volunteers were asked to shower with a head to toe shampoo. During the last 3 weeks (week 7–week 9), all volunteers went back to their normal routine and used the personal care products used before the beginning of the study (Fig.  1 b). Volunteers were asked not to shower the day before sampling. Samples were collected by the same three researchers to ensure consistency in sampling and the area sampled. Researchers examined every subject together and collected metabolomics and microbiome samples from each location together. Samples were collected once a week (from day 0 to day 68—10 timepoints total) for volunteers 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, and 12, and on day 0 and day 6 for volunteer 8. For individuals 4, 9, and 10, samples were collected twice a week. Samples collected for 11 volunteers during 10 timepoints: 11 volunteers × 10 timepoints × 4 samples × 4 body sites = 1760. Samples collected from 3 selected volunteers during 9 additional timepoints: 3 volunteers × 9 timepoints × 4 samples × 4 body sites = 432. All samples were collected following the same protocol described in [ 18 ]. Briefly, samples were collected over an area of 2 × 2 cm, using pre-moistened swabs in 50:50 ethanol/water solution for metabolomics analysis or in Tris-EDTA buffer for 16S rRNA sequencing. Four samples were collected from each body part right and left side. The locations sampled were the face—upper cheek bone and lower jaw, armpit—upper and lower area, arm—front of the elbow (antecubitis) and forearm (antebrachium), and feet—in between the first and second toe and third and fourth toe. Including personal care product references, a total of 2275 samples were collected over 9 weeks and were submitted to both metabolomics and microbial inventories.

Metabolite extraction and UPLC-Q-TOF mass spectrometry analysis

Skin swabs were extracted and analyzed using a previously validated workflow described in [ 18 , 19 ]. All samples were extracted in 200 μl of 50:50 ethanol/water solution for 2 h on ice then overnight at − 20 °C. Swab sample extractions were dried down in a centrifugal evaporator then resuspended by vortexing and sonication in a 100 μl 50:50 ethanol/water solution containing two internal standards (fluconazole 1 μM and amitriptyline 1 μM). The ethanol/water extracts were then analyzed using a previously validated UPLC-MS/MS method [ 18 , 19 ]. We used a ThermoScientific UltiMate 3000 UPLC system for liquid chromatography and a Maxis Q-TOF (Quadrupole-Time-of-Flight) mass spectrometer (Bruker Daltonics), controlled by the Otof Control and Hystar software packages (Bruker Daltonics) and equipped with ESI source. UPLC conditions of analysis are 1.7 μm C18 (50 × 2.1 mm) UHPLC Column (Phenomenex), column temperature 40 °C, flow rate 0.5 ml/min, mobile phase A 98% water/2% acetonitrile/0.1% formic acid ( v / v ), mobile phase B 98% acetonitrile/2% water/0.1% formic acid ( v / v ). A linear gradient was used for the chromatographic separation: 0–2 min 0–20% B, 2–8 min 20–99% B, 8–9 min 99–99% B, 9–10 min 0% B. Full-scan MS spectra ( m/z 80–2000) were acquired in a data-dependant positive ion mode. Instrument parameters were set as follows: nebulizer gas (nitrogen) pressure 2 Bar, capillary voltage 4500 V, ion source temperature 180 °C, dry gas flow 9 l/min, and spectra rate acquisition 10 spectra/s. MS/MS fragmentation of 10 most intense selected ions per spectrum was performed using ramped collision induced dissociation energy, ranged from 10 to 50 eV to get diverse fragmentation patterns. MS/MS active exclusion was set after 4 spectra and released after 30 s.

Mass spectrometry data collected from the skin of 12 individuals can be found here MSV000081582.

LC-MS data processing

LC-MS raw data files were converted to mzXML format using Compass Data analysis software (Bruker Daltonics). MS1 features were selected for all LC-MS datasets collected from the skin of 12 individuals and blank samples (total 2275) using the open-source software MZmine [ 66 ]—see Additional file  4 : Table S3 for parameters. Subsequent blank filtering, total ion current, and internal standard normalization were performed (Additional file  5 : Table S4) for representation of relative abundance of molecular features (Fig.  2 , Additional file  1 : Figure S1), principal coordinate analysis (PCoA) (Fig.  4 ). For steroid compounds in Fig.  5 a–d, bile acids (Additional file  1 : Figure S5A-D), and acylcarnitines (Additional file  1 : Figure S5E, F) compounds, crop filtering feature available in MZmine [ 66 ] was used to identify each feature separately in all LC-MS data collected from the skin of 12 individuals (see Additional file  4 : Table S3 for crop filtering parameters and feature finding in Additional file  6 : Table S5).

Heatmap in Fig.  2 was constructed from the bucket table generated from LC-MS1 features (Additional file  7 : Table S6) and associated metadata (Additional file  8 : Table S7) using the Calour command line available here: https://github.com/biocore/calour . Calour parameters were as follows: normalized read per sample 5000 and cluster feature minimum reads 50. Procrustes and Pearson correlation analyses in Additional file  1 : Figures S10 and S11 were performed using the feature table in Additional file  9 : Table S8, normalized using the probabilistic quotient normalization method [ 67 ].

16S rRNA amplicon sequencing

16S rRNA sequencing was performed following the Earth Microbiome Project protocols [ 68 , 69 ], as described before [ 18 ]. Briefly, DNA was extracted using MoBio PowerMag Soil DNA Isolation Kit and the V4 region of the 16S rRNA gene was amplified using barcoded primers [ 70 ]. PCR was performed in triplicate for each sample, and V4 paired-end sequencing [ 70 ] was performed using Illumina HiSeq (La Jolla, CA). Raw sequence reads were demultiplexed and quality controlled using the defaults, as provided by QIIME 1.9.1 [ 71 ]. The primary OTU table was generated using Qiita ( https://qiita.ucsd.edu/ ), using UCLUST ( https://academic.oup.com/bioinformatics/article/26/19/2460/230188 ) closed-reference OTU picking method against GreenGenes 13.5 database [ 72 ]. Sequences can be found in EBI under accession number EBI: ERP104625 or in Qiita ( qiita.ucsd.edu ) under Study ID 10370. Resulting OTU tables were then rarefied to 10,000 sequences/sample for downstream analyses (Additional file  10 Table S9). See Additional file  11 : Table S10 for read count per sample and Additional file  1 : Figure S13 representing the samples that fall out with rarefaction at 10,000 threshold. The dataset includes 35 blank swab controls and 699 empty controls. The blank samples can be accessed through Qiita ( qiita.ucsd.edu ) as study ID 10370 and in EBI with accession number EBI: ERP104625. Blank samples can be found under the metadata category “sample_type” with the name “empty control” and “Swabblank.” These samples fell below the rarefaction threshold at 10,000 (Additional file  11 : Table S10).

To rule out the possibility that personal care products themselves contained the microbes that induced the changes in the armpit and foot microbiomes that were observed in this study (Fig.  7 ), we subjected the common personal care products that were used in this study during T4–T6 also to 16S rRNA sequencing. The data revealed that within the limit of detectability of the current experiment, few 16S signatures were detected. One notable exception was the most dominant plant-originated bacteria chloroplast detected in the sunscreen lotion applied on the face (Additional file  1 : Figure S9D), that was also detected on the face of individuals and at a lower level on their arms, sites where stable microbial communities were observed over time (Additional file  1 : Figure S9E, F). This finding is in agreement with our previous data from the 3D cartographical skin maps that revealed the presence of co-localized chloroplast and lotion molecules [ 18 ]. Other low-abundant microbial signatures found in the sunscreen lotion include additional plant-associated bacteria: mitochondria [ 73 ], Bacillaceae [ 74 , 75 ], Planococcaceae [ 76 ], and Ruminococcaceae family [ 77 ], but all these bacteria are not responsible for microbial changes associated to beauty product use, as they were poorly detected in the armpits and feet (Fig.  7 ).

To assess the origin of Cyanobacteria detected in skin samples, each Greengenes [ 72 ] 13_8 97% OTU table (per lane; obtained from Qiita [ 78 ] study 10,370) was filtered to only features with a p__Cyanobacteria phylum. The OTU maps for these tables—which relate each raw sequence to an OTU ID—were then filtered to only those observed p__Cyanobacteria OTU IDs. The filtered OTU map was used to extract the raw sequences into a single file. Separately, the unaligned Greengenes 13_8 99% representative sequences were filtered into two sets, first the set of representatives associated with c__Chloroplast (our interest database), and second the set of sequences associated with p__Cyanobacteria without the c__Chloroplast sequences (our background database). Platypus Conquistador [ 79 ] was then used to determine what reads were observed exclusively in the interest database and not in the background database. Of the 4,926,465 raw sequences associated with a p__Cyanobacteria classification (out of 318,686,615 total sequences), at the 95% sequence identity level with 100% alignment, 4,860,258 sequences exclusively recruit to full-length chloroplast 16S by BLAST [ 80 ] with the bulk recruiting to streptophytes (with Chlorophyta and Stramenopiles to a lesser extent). These sequences do not recruit non-chloroplast Cyanobacteria full length 16S.

Half-life calculation for metabolomics data

In order to estimate the biological half-life of molecules detected in the skin, the first four timepoints of the study (T0, T1, T2, T3) were considered for the calculation to allow the monitoring of personal beauty products used at T0. The IUPAC’s definition of biological half-life as the time required to a substance in a biological system to be reduced to half of its value, assuming an approximately exponential removal [ 81 ] was used. The exponential removal can be described as C ( t )  =  C 0 e − tλ where t represents the time in weeks, C 0 represents the initial concentration of the molecule, C ( t ) represents the concentration of the molecule at time t , and λ is the rate of removal [ http://onlinelibrary.wiley.com/doi/10.1002/9780470140451.ch2/summary ]. The parameter λ was estimated by a mixed linear effects model in order to account for the paired sample structure. The regression model tests the null hypothesis that λ is equal to zero and only the significant ( p value < 0.05) parameters were considered.

Principal coordinate analysis

We performed principal coordinate analysis (PCoA) on both metabolomics and microbiome data. For metabolomics, we used MS1 features (Additional file  5 : Table S4) and calculated Bray–Curtis dissimilarity metric using ClusterApp ( https://github.com/mwang87/q2_metabolomics ).

For microbiome data, we used rarefied OTU table (Additional file 10 : Table S9) and used unweighted UniFrac metric [ 36 ] to calculate beta diversity distance matrix using QIIME2 (https://qiime2.org). Results from both data sources were visualized using Emperor ( https://biocore.github.io/emperor/ ) [ 28 ].

Molecular networking

Molecular networking was generated from LC-MS/MS data collected from skin samples of 11 individuals MSV000081582, using the Global Natural Products Social Molecular Networking platform (GNPS) [ 29 ]. Molecular network parameters for MS/MS data collected from all body parts of 11 individuals during T0–T9 MSV000081582 are accessible here http://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=284fc383e4c44c4db48912f01905f9c5 . Molecular network parameters for MS/MS data collected from armpits T0–T3 MSV000081582 and deodorant used by individual 1 and 3 MSV000081580 can be found here http://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=f5325c3b278a46b29e8860ec57915ad and here http://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=aaa1af68099d4c1a87e9a09f398fe253 , respectively. Molecular networks were exported and visualized in Cytoscape 3.4.0. [ 82 ]. Molecular networking parameters were set as follows: parent mass tolerance 1 Da, MS/MS fragment ion tolerance 0.5 Da, and cosine threshold 0.65 or greater, and only MS/MS spectral pairs with at least 4 matched fragment ions were included. Each MS/MS spectrum was only allowed to connect to its top 10 scoring matches, resulting in a maximum of 10 connections per node. The maximum size of connected components allowed in the network was 600, and the minimum number of spectra required in a cluster was 3. Venn diagrams were generated from Cytoscape data http://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=284fc383e4c44c4db48912f01905f9c5 using Cytoscape [ 82 ] Venn diagram app available here http://apps.cytoscape.org/apps/all .

Shannon molecular and bacterial diversity

The diversity analysis was performed separately for 16S rRNA data and LC-MS data. For each sample in each feature table (LC-MS data and microbiome data), we calculated the value of the Shannon diversity index. For LC-MS data, we used the full MZmine feature table (Additional file  5 : Table S4). For microbiome data, we used the closed-reference BIOM table rarefied to 10,000 sequences/sample. For diversity changes between timepoints, we aggregated Shannon diversity values across groups of individuals (all, females, males) and calculated mean values and standard errors. All successfully processed samples (detected features in LC-MS or successful sequencing with 10,000 or more sequences/sample) were considered.

Beauty products and chemical standards

Samples (10 mg) from personal care products used during T0 and T7–T9 MSV000081580 (Additional file  2 : Table S1) and common beauty products used during T4–T6 MSV000081581 (Additional file  3 : Table S2) were extracted in 1 ml 50:50 ethanol/water. Sample extractions were subjected to the same UPLC-Q-TOF MS method used to analyze skin samples and described above in the section “ Metabolite extraction and UPLC-Q-TOF mass spectrometry analysis .” Authentic chemical standards MSV000081583 including 1-dehydroandrostenedion (5 μM), chenodeoxyglycocholic acid (5 μM), dehydroisoandrosterone sulfate (100 μM), glycocholic acid (5 μM), and taurocholic acid (5 μM) were analyzed using the same mass spectrometry workflow used to run skin and beauty product samples.

Monitoring beauty product ingredients in skin samples

In order to monitor beauty product ingredients used during T4–T6, we selected only molecular features present in each beauty product sample (antiperspirant, facial lotion, body moisturizer, soothing powder) and then filtered the aligned MZmine feature table (Additional file  5 : Table S4) for the specific feature in specific body part samples. After feature filtering, we selected all features that had a higher average intensity on beauty product phase (T4–T6) compared to non-beauty product phase (T1–T3). The selected features were annotated using GNPS dereplication output http://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=69319caf219642a5a6748a3aba8914df , plotted using R package ggplot2 ( https://cran.r-project.org/web/packages/ggplot2/index.html ) and visually inspected for meaningful patterns.

Random forest analysis

Random forest analysis was performed in MetaboAnalyst 3.0 online platform http://www.metaboanalyst.ca/faces/home.xhtml . Using LC-MS1 features found in armpit samples collected on T3 and T6. Random forest parameters were set as follows: top 1000 most abundant features, number of predictors to try for each node 7, estimate of error rate (0.0%).

BugBase analysis

To determine the functional potential of microbial communities within our samples, we used BugBase [ 83 ]. Because we do not have direct access to all of the gene information due to the use of 16S rRNA marker gene sequencing, we can only rely on phylogenetic information inferred from OTUs. BugBase takes advantage of this information to predict microbial phenotypes by associating OTUs with gene content using PICRUSt [ 84 ]. Thus, using BugBase, we can predict such phenotypes as Gram staining, or oxidative stress tolerance at each timepoint or each phase. All statistical analyses in BugBase are performed using non-parametric differentiation tests (Mann–Whitney U ).

Taxonomic plots

Rarefied OTU counts were collapsed according to the OTU’s assigned family and genus name per sample, with a single exception for the class of chloroplasts. Relative abundances of each family-genus group are obtained by dividing by overall reads per sample, i.e., 10,000. Samples are grouped by volunteer, body site, and time/phase. Abundances are aggregated by taking the mean overall samples, and resulting abundances are again normalized to add up to 1. Low-abundant taxa are not listed in the legend and plotted in grayscale. Open-source code is available at https://github.com/sjanssen2/ggmap/blob/master/ggmap/snippets.py

Dissimilarity-based analysis

Pairwise dissimilarity matrices were generated for metabolomics and 16S metagenomics quantification tables, described above, using Bray–Curtis dissimilarity through QIIME 1.9.1 [ 71 ]. Those distance matrices were used to perform Procrustes analysis (QIIME 1.9.1), and Mantel test (scikit-bio version 0.5.1) to measure the correlation between the metabolome and microbiome over time. The metabolomics dissimilarities were used to perform the PERMANOVA test to assess the significance of body part grouping. The PCoA and Procrustes plots were visualized in EMPeror. The dissimilarity matrices were also used to perform distance tests, comparing the distances within and between individuals and distances from time 0 to times 1, 2, and 3 using Wilcoxon rank-sum tests (SciPy version 0.19.1) [ 19 ].

Statistical analysis for molecular and microbial data

Statistical analyses were performed in R and Python (R Core Team 2018). Monotonic relationships between two variables were tested using non-parametric Spearman correlation tests. The p values for correlation significance were subsequently corrected using Benjamini and Hochberg false discovery rate control method. The relationship between two groups was tested using non-parametric Wilcoxon rank-sum tests. The relationship between multiple groups was tested using non-parametric Kruskal–Wallis test. The significance level was set to 5%, unless otherwise mentioned, and all tests were performed as two-sided tests.

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Langille MGI, Zaneveld J, Caporaso JG, McDonald D, Knights D, Reyes JA, et al. Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nat Biotech [Computational Biology]. 2013;31(9):814–21.

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Acknowledgements

We thank all volunteers who were recruited in this study for their participation and Carla Porto for discussions regarding beauty products selected in this study. We further acknowledge Bruker for the support of the shared instrumentation infrastructure that enabled this work.

This work was partially supported by US National Institutes of Health (NIH) Grant. P.C.D. acknowledges funding from the European Union’s Horizon 2020 Programme (Grant 634402). A.B was supported by the National Institute of Justice Award 2015-DN-BX-K047. C.C. was supported by a fellowship of the Belgian American Educational Foundation and the Research Foundation Flanders. L.Z., J.K, and K.Z. acknowledge funding from the US National Institutes of Health under Grant No. AR071731. TLK was supported by Vaadia-BARD Postdoctoral Fellowship Award No. FI-494-13.

Availability of data and materials

The mass spectrometry data have been deposited in the MassIVE database (MSV000081582, MSV000081580 and MSV000081581). Molecular network parameters for MS/MS data collected from all body parts of 11 individuals during T0-T9 MSV000081582 are accessible here http://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=284fc383e4c44c4db48912f01905f9c5 . Molecular network parameters for MS/MS data collected from armpits T0–T3 MSV000081582 and deodorant used by individual 1 and 3 MSV000081580 can be found here http://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=f5325c3b278a46b29e8860ec5791d5ad and here http://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=aaa1af68099d4c1a87e9a09f398fe253 , respectively. OTU tables can be found in Qiita ( qiita.ucsd.edu ) as study ID 10370, and sequences can be found in EBI under accession number EBI: ERP104625.

Author information

Amina Bouslimani and Ricardo da Silva contributed equally to this work.

Authors and Affiliations

Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, San Diego, USA

Amina Bouslimani, Ricardo da Silva, Kathleen Dorrestein, Alexey V. Melnik, Tal Luzzatto-Knaan & Pieter C. Dorrestein

Department of Pediatrics, University of California, San Diego, La Jolla, CA, 92037, USA

Tomasz Kosciolek, Stefan Janssen, Chris Callewaert, Amnon Amir, Livia S. Zaramela, Ji-Nu Kim, Gregory Humphrey, Tara Schwartz, Karenina Sanders, Caitriona Brennan, Gail Ackermann, Daniel McDonald, Karsten Zengler, Rob Knight & Pieter C. Dorrestein

Department for Pediatric Oncology, Hematology and Clinical Immunology, University Children’s Hospital, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

Stefan Janssen

Center for Microbial Ecology and Technology, Ghent University, 9000, Ghent, Belgium

Chris Callewaert

Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, 92307, USA

Karsten Zengler, Rob Knight & Pieter C. Dorrestein

Department of Bioengineering, University of California, San Diego, La Jolla, CA, 92093, USA

Karsten Zengler & Rob Knight

Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, 92093, USA

Department of Pharmacology, University of California, San Diego, La Jolla, CA, 92037, USA

Pieter C. Dorrestein

You can also search for this author in PubMed   Google Scholar

Contributions

AB and PCD contributed to the study and experimental design. AB, KD, and TLK contributed to the metabolite and microbial sample collection. AB contributed to the mass spectrometry data collection. AB, RS, and AVM contributed to the mass spectrometry data analysis. RS contributed to the metabolomics statistical analysis and microbial–molecular correlations. GH, TS, KS, and CB contributed to the 16S rRNA sequencing. AB and GA contributed to the metadata organization. TK, SJ, CC, AA, and DMD contributed to the microbial data analysis and statistics. LZ, JK, and KZ contributed to the additional data analysis. AB, PCD, and RK wrote the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Rob Knight or Pieter C. Dorrestein .

Ethics declarations

Ethics approval and consent to participate.

All participants signed a written informed consent in accordance with the sampling procedure approved by the UCSD Institutional Review Board (Approval Number 161730).

Competing interests

Dorrestein is on the advisory board for SIRENAS, a company that aims to find therapeutics from ocean environments. There is no overlap between this research and the company. The other authors declare that they have no competing interests.

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Additional files

Additional file 1:.

Figure S1. Beauty products ingredients persist on skin of participants. Figure S2. Beauty product application impacts the molecular and bacterial diversity on skin of 11 individuals while the chemical diversity from personal beauty products used by males and females on T0 is similar. Figure S3. Longitudinal impact of ceasing and resuming the use of beauty products on the molecular composition of the skin over time. Figure S4. Molecular networking to highlight MS/MS spectra found in each body part. Figure S5. Longitudinal abundance of bile acids and acylcarnitines in skin samples. Figure S6. Characterization of steroids in armpits samples. Figure S7. Characterization of bile acids in armpit samples. Figure S8. Characterization of Acylcarnitine family members in skin samples. Figure S9. Beauty products applied at one body part might affect other areas of the body, while specific products determine stability versus variability of microflora at each body site. Figure S10. Representation of Gram-positive bacteria over time and the molecular features from the shampoo detected on feet. Figure S11. Procrustes analysis to correlate the skin microbiome and metabolome over time. Figure S12. Correlation between specific molecules and bacteria that change over time in armpits of individual 11. Figure S13. Representation of the number of samples that were removed (gray) and those retained (blue) after rarefaction at 10,000 threshold. (DOCX 1140 kb)

Additional file 2:

Table S1. List of personal (T0 and T7–9) beauty products and their frequency of use. (XLSX 30 kb)

Additional file 3:

Table S2. List of ingredients of common beauty products used during T4–T6. (PDF 207 kb)

Additional file 4:

Table S3. Mzmine feature finding and crop filtering parameters. (XLSX 4 kb)

Additional file 5:

Table S4. Feature table for statistical analysis with blank filtering and total ion current normalization. (CSV 150242 kb)

Additional file 6:

Table S5. Feature table for individual feature abundance in armpits. (XLSX 379 kb)

Additional file 7:

Table S6. Feature table for Calour analysis. (CSV 91651 kb)

Additional file 8:

Table S7. Metadata for Calour analysis. (TXT 129 kb)

Additional file 9:

Table S8. feature table with Probabilistic quotient normalization for molecular–microbial analysis. (ZIP 29557 kb)

Additional file 10:

Table S9. OTU table rarefied to 10,000 sequences per sample. (BIOM 9493 kb)

Additional file 11:

Table S10. 16S rRNA sequencing read counts per sample. (TSV 2949 kb)

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Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated.

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Bouslimani, A., da Silva, R., Kosciolek, T. et al. The impact of skin care products on skin chemistry and microbiome dynamics. BMC Biol 17 , 47 (2019). https://doi.org/10.1186/s12915-019-0660-6

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Received : 20 February 2019

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Published : 12 June 2019

DOI : https://doi.org/10.1186/s12915-019-0660-6

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Skin conditions by the numbers

Acne is the most common skin condition in the United States, affecting up to 50 million Americans annually. 1

Acne usually begins in puberty and affects many adolescents and young adults.

Approximately 85 percent of people between the ages of 12 and 24 experience at least minor acne. 2

Acne can occur at any stage of life and may continue into one’s 30s and 40s. 3-5

Acne occurring in adults is increasing, affecting up to 15 percent of women. 3-5

In 2013, the costs associated with the treatment and lost productivity among those who sought medical care for acne exceeded $1.2 billion. 6

More than 5.1 million people sought medical treatment for acne in 2013, primarily children and young adults. 6

The lost productivity among patients and caregivers due to acne was nearly $400 million. 6

One in 10 people will develop atopic dermatitis during their lifetime. 7

It affects up to 25 percent of children and 2 to 3 percent of adults. 8

An estimated 60 percent of people with this condition develop it in their first year of life, and 90 percent develop it before age 5. However, atopic dermatitis can begin during puberty or later. 8-9

In 2013, the costs associated with the treatment and lost productivity among those who sought medical care for atopic dermatitis was $442 million. 6

The total medical cost of treating atopic dermatitis was $314 million, for an average of $101.42 per treated patient. 6

The lost productivity among patients and caregivers due to atopic dermatitis was $128 million. 6

The most common cause of hair loss is hereditary thinning or baldness, also known as androgenetic alopecia. 10

This condition affects an estimated 80 million Americans — 50 million men and 30 million women. 11

Other Potential causes of hair loss, some of which are temporary, include:

Excessive or improper use of styling products such as perms, dyes, gels, relaxers or sprays, which can cause weathering or hair breakage.

Hairstyles that pull on the hair, like ponytails and braids.

Shampooing, combing or brushing hair too much or too hard

Hair pulling, which may be a sign of a disorder called trichotillomania.

A variety of diseases, including thyroid disease and lupus.

Childbirth, major surgery, high fever or severe infection, stress, or even the flu.

Inadequate protein or iron in the diet, or eating disorders such as anorexia and bulimia.

Certain prescription drugs, including blood thinners, high-dose vitamin A, and medicines for arthritis, depression, gout, heart problems and high blood pressure.

Use of birth control pills (usually in women with an inherited tendency for hair thinning).

Hormonal imbalances, especially in women.

Ringworm of the scalp, a contagious fungal infection most common in children.

Some cancer treatments, such as radiation therapy and chemotherapy.

Alopecia areata, a type of hair loss that can affect all ages and causes hair to fall out in round patches. 12

Approximately 7.5 million people in the United States have psoriasis. 13

Psoriasis occurs in all age groups but is primarily seen in adults, with the highest proportion between ages 45 and 64. 6

Approximately 25-30 percent of people with psoriasis experience joint inflammation that produces symptoms of arthritis. This condition is called psoriatic arthritis. 14-16

Approximately 80 percent of those affected with psoriasis have mild to moderate disease, while 20 percent have moderate to severe psoriasis affecting more than 5 percent of the body surface area. 13

The most common form of psoriasis, affecting about 80 to 90 percent of psoriasis patients, is plaque psoriasis. It is characterized by patches of raised, reddish skin covered with silvery-white scale. 13

In 2013, the total direct cost of treatment associated with psoriasis was estimated to be between $51.7 billion and $63.2 billion. 6

Rosacea is a common skin disease that affects 16 million Americans. 17-19

While people of all ages and races can develop rosacea, it is most common in the following groups:

People between age 30 and 60. 20

Individuals with fair skin, blond hair and blue eyes. 20-21

Women, especially during menopause. 20

Those with a family history of rosacea. 21

In 2013, the costs associated with the treatment and lost productivity among those who sought medical care for rosacea was $243 million. 6

More than 1.6 million people sought treatment for rosacea in 2013. 6

The total medical cost of treating rosacea was $165 million, for an average of $102.26 per treated patient. 6

The lost productivity among patients and caregivers due to rosacea was $78 million. 6

Skin cancer

Skin cancer is the most common cancer in the United States. 22-23

It is estimated that more than 9,500 people in the U.S. are diagnosed with skin cancer every day. 24-26

The majority of diagnosed skin cancers are NMSCs. Research estimates that NSMC affects more than 3 million Americans a year. 6, 24

The overall incidence of BCC increased by 145 percent between 1976-1984 and 2000-2010, and the overall incidence of SCC increased 263 percent over that same period. 27

Women had the greatest increase in incidence rates for both types of NMSC. 27

NMSC incidence rates are increasing in people younger than 40. 27

More than 1 million Americans are living with melanoma. 28

It is estimated that 192,310 new cases of melanoma, 95,830 noninvasive (in situ) and 96,480 invasive, will be diagnosed in the U.S. in 2019. 25-26

Invasive melanoma is projected to be the fifth most common cancer for both men (57,220 cases) and  women (39,260 cases) in 2019. 25-26

Melanoma rates in the United States doubled from 1982 to 2011 and have continued to increase. 23, 26

Caucasians and men older than 50 have an increased risk of developing melanoma compared to the general population. 25-26

Skin cancer can affect anyone, regardless of skin color.

Skin cancer in patients with skin of color is often diagnosed in its later stages, when it’s more difficult to treat. 30

Research has shown that patients with skin of color are less likely than Caucasian patients to survive melanoma. 31

People with skin of color are prone to skin cancer in areas that aren’t commonly exposed to the sun, like the palms of the hands, the soles of the feet, the groin and the inside of the mouth. They also may develop melanoma under their nails. 30

Nearly 20 Americans die from melanoma every day. In 2019, it is estimated that 7,230 deaths will be attributed to melanoma — 4,740 men and 2,490 women. 25-26

The five-year survival rate for people whose melanoma is detected and treated before it spreads to the lymph nodes is 98 percent. 25-26

The five-year survival rate for melanoma that spreads to nearby lymph nodes is 64 percent. The five-year survival rate for melanoma that spreads to distant lymph nodes and other organs is 23 percent. 25-26, 29

The annual cost of treating skin cancers in the U.S. is estimated at $8.1 billion — about $4.8 billion for NMSC and $3.3 billion for melanoma. 22

Related AAD resources

Want to know what dermatologists tell their patients about managing conditions that affect the skin, hair, or nails? You’ll find their expertise and insight in Diseases and conditions .

1 Bickers DR, Lim HW, Margolis D, Weinstock MA, Goodman C, Faulkner E et al. The burden of skin diseases: 2004 a joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology. Journal of the American Academy of Dermatology 2006;55:490-500.

2 Bhate K, Williams HC. Epidemiology of acne vulgaris. The British journal of dermatology 2013;168:474-85.

3 Holzmann R , Shakery K. Postadolescent acne in females. Skin pharmacology and physiology 2014;27 Suppl 1:3-8.

4 Khunger N , Kumar C. A clinico-epidemiological study of adult acne: is it different from adolescent acne? Indian journal of dermatology, venereology and leprology 2012;78:335-41.

5 Tanghetti EA, Kawata AK, Daniels SR, Yeomans K, Burk CT , Callender VD. Understanding the Burden of Adult Female Acne. The Journal of Clinical and Aesthetic Dermatology 2014;7:22-30.

6 American Academy of Dermatology/Milliman. Burden of Skin Disease. 2017.  www.aad.org/BSD .

7 Abuabara K, Magyari A, McCulloch CE, Linos E, Margolis DJ, Langan SM. Prevalence of Atopic Eczema Among Patients Seen in Primary Care: Data From The Health Improvement Network. Ann Intern Med. 2018. [Epub ahead of print ] doi: 10.7326/M18-2246.

8 Eichenfield LF, Tom WL, Chamlin SL, Feldman SR, Hanifin JM, Simpson EL, et al. Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 2014 Feb;70(2):338-51. 

9 Beltrani VS, Boguneiwicz M. Atopic dermatitis. Dermatol Online J 2003;9(2):1.

10 Rossi A, Anzalone A, Fortuna MC, Caro G, Garelli V, Pranteda G et al. Multi-therapies in androgenetic alopecia: review and clinical experiences. Dermatologic therapy 2016;29:424-32.​

11 Genetics Home Reference. National Institutes of Health U.S. Library of Medicine.  https://ghr.nlm.nih.gov/condition/androgenetic-alopecia#statistics . Accessed March 30, 2018.​

12 Dainichi T , Kabashima K. Alopecia areata: What's new in epidemiology, pathogenesis, diagnosis, and therapeutic options? Journal of dermatological science 2017;86:3-12.

13 Menter A, Gottlieb A, Feldman SR, Van Voorhees AS et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol 2008 May;58(5):826-50. 

14 Ranza R et al. Prevalence of psoriatic arthritis in a large cohort of Brazilian patients with psoriasis. J Rheumatol. 2015 May;42(5):829-34. doi: 10.3899/jrheum.140474

15 Mease PJ et al. Prevalence of rheumatologist-diagnosed psoriatic arthritis in patients with psoriasis in European/North American dermatology clinics. J Am Acad Dermatol. 2013 Nov;69(5):729-735. doi: 10.1016/j.jaad.2013.07.023

16 Alinaghi F et al. Prevalence of psoriatic arthritis in patients with psoriasis: A systematic review and meta-analysis of observational and clinical studies. Journal of the American Academy of Dermatology. Published online June 18, 2018. https://doi.org/10.1016/j.jaad.2018.06.027.

17 Steinhoff, M., Schauber, J., and Leyden, J.J. New insights into rosacea pathophysiology: a review of recent findings.  J Am Acad Dermatol . 2013; 69: S15–S26

18 Elewski, B.E., Draelos, Z., Dréno, B., Jansen, T., Layton, A., and Picardo, M. Rosacea - global diversity and optimized outcome: proposed international consensus from the Rosacea International Expert Group.  J Eur Acad Dermatol Venereol . 2011; 25: 188–200

19 Okhovat, J.-P. and Armstrong, A.W. Updates in rosacea: epidemiology, risk factors, and management strategies.  Curr Dermatol Rep . 2014; 3: 23–28

20 Rosacea. National Institute of Arthritis and Musculoskeletal and Skin Diseases. https://www.niams.nih.gov/health-topics/rosacea#tab-risk

21 Abram K, Silm H, Maaroos H-I and Oona M. Risk factors associated with rosacea. Journal of the European Academy of Dermatology and Venereology. 2010; 24 (5): 565-571

22 Guy GP, Machlin SR, Ekwueme DU, Yabroff KR. Prevalence and costs of skin cancer treatment in the US, 2002-2006 and 2007-2011. Am J Prev Med. 2015;48:183–7. 

23 Guy GP, Thomas CC, Thompson T, Watson M, Massetti GM, Richardson LC. Vital signs: Melanoma incidence and mortality trends and projections—United States, 1982–2030. MMWR Morb Mortal Wkly Rep. 2015;64(21):591-596. 

24 Rogers HW, Weinstock MA, Feldman SR, Coldiron BM. Incidence estimate of nonmelanoma skin cancer (keratinocyte carcinomas) in the US population. JAMA Dermatol. Published online April 30, 2015. 

25 American Cancer Society. Cancer Facts and Figures 2019. Atlanta: American Cancer Society; 2019.

26 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019; doi: 10.3322/caac.21551.

27 Muzic, JG et al. Incidence and Trends of Basal Cell Carcinoma and Cutaneous Squamous Cell Carcinoma: A Population-Based Study in Olmstead County, Minnesota, 2000-2010. Mayo Clin Proc. Published Online May 15, 2017. http://dx.doi.org/10.1016/j.mayocp.2017.02.015

28 SEER Cancer Stat Facts: Melanoma of the Skin. National Cancer Institute. Bethesda, MD,  http://seer.cancer.gov/statfacts/html/melan.html

29 Noone AM, Howlader N, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2015, National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/csr/1975_2015/, based on November 2017 SEER data submission, posted to the SEER web site, April 2018.

30 Agbai ON, Buster K, Sanchez M, Hernandez C, Kundu RV, Chiu M, Roberts WE, Draelos ZD, Bhushan R, Taylor SC, Lim HW. Skin cancer and photoprotection in people of color: a review and recommendations for physicians and the public. J Am Acad Dermatol. 2014;70(4):748-62.

31 Dawes SM et al. Racial disparities in melanoma survival. J Am Acad Dermatol. 2016 Nov; 75(5):983-991.

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15 Common Skin Conditions

To diagnose skin conditions, healthcare providers typically consider a person's medical history and physical symptoms.

Brendan Camp, MD, FAAD, is a double board-certified dermatologist.

Your skin—the body's biggest organ—shields you from the elements. However, you can sometimes still develop skin conditions, or various problems with your skin. Some common skin conditions include eczema, psoriasis, hives, and vitiligo.

Skin issues can generally be unsightly but harmless, contagious, itchy, painful, or a combination of those features. Here's what else you need to know about 15 common conditions, including treatment options and when to see a healthcare provider.

shironosov/Getty Images

Causes of Skin Conditions

There are various causes of skin conditions, which include:

• Allergens or irritants (e.g., certain metals, poison ivy)
• Germs, including bacteria, fungi, parasites, and viruses
• Immune system problems

Healthcare providers typically consider a person's medical history and physical symptoms to diagnose skin conditions. Assessing the size, shape, location, and color of bumps, blisters, and rashes can help healthcare providers pinpoint the exact cause.

Other non-skin symptoms may offer clues as well. Sometimes, healthcare providers must remove a growth or take a skin sample for examination under a microscope.

Permanent Skin Conditions

There are chronic skin conditions that are incurable and may have treatments to prevent or manage flare-ups. Examples include:

• Hidradenitis suppurativa—an inflammatory skin disorder that consists of bumps or boils that look like pimples
• Lichen planus—a condition where a person has shiny, firm, purplish bumps on their skin

Acne  occurs when oil and dead skin cells clog the pores. Pimples under the skin's surface that erupt with a white center are called whiteheads. Pimples exposed to air are called blackheads and look black.  

Other skin blemishes may form, including:

• Red, pus-filled pimples

Acne usually appears on the face, back, neck, chest, and shoulders. Bacteria ( Cutibacterium acnes ) and inflammation can play a role in determining when pimples crop up, as can changes in hormones. Some hormones trigger excess oil production, resulting in clogged pores. Adolescents are more prone to getting acne than others.

Treatment Options

Treatments will depend on a few factors, such as where the acne appears, the type of acne you have, and your age. However, treatments may include:

• Topical medications, like retinoids or benzoyl peroxide
• Diet changes
• Oral medications, like antibiotics or retinoids
• Corticosteroid injections for large, painful acne breakouts
• Laser or light therapy

2. Cellulitis

DR P. MARAZZI/SCIENCE PHOTO LIBRARY

When bacteria infect skin layers and tissue below the skin, cellulitis is the likely diagnosis. Skin affected by cellulitis may be red, swollen, and tender and feel warm to the touch.

You may have a cellulitis infection anywhere on the skin. However, it typically appears on one lower leg in adults and on the face or neck in children.

The main treatment for cellulitis is an antibiotic, but people may need to take more than one in some cases. Other treatments include wound care, rest, and elevation for cellulitis on the leg.

3. Cold Sore

A viral infection usually causes cold sores, or fever blisters, which are contagious. Cold sores are tiny, painful, fluid-filled blisters. 

Type 1 of the herpes simplex virus (HSV-1) causes cold sores, also called oral herpes. Type 2 of the herpes simplex virus (HSV-2) affects the genital region, but HSV-1 can also spread from the mouth to the genitals.

Cold sores often appear in clusters on or around the lips. People may experience a tingling sensation in the affected area before a breakout. 

There's no cure for cold sores , and they can go away after a few weeks without treatment. However, antiviral medications can speed recovery.

4. Dermatitis

This photo contains medical imagery.

Dermatitis refers to skin rashes that are inflamed and usually red and uncomfortable. The inflammation from dermatitis is an immune system response to germs or other foreign substances coming into contact with your body.

There are various types of dermatitis, such as:

• Atopic dermatitis—also known as eczema
• Contact dermatitis
• Hand and foot dermatitis
• Seborrheic dermatitis

Based on what has caused the rash, options for treatment may include:

• Antihistamines for itch relief
• Cortisone creams for redness, swelling, and itch
• Immunosuppressive medications or injections
• Moisturizers

5. Dry Skin

Dry skin is the result of your skin losing a lot of water. A person may experience dry skin because of environmental factors, like low humidity or spending time exposed to high heat.

You might notice flaky, rough skin or skin that cracks or itches. Some people have dry skin that's painful, stinging, burning, or peeling.

Moisturizers are helpful for healing and hydrating your skin. You may also need to treat any underlying conditions, like eczema or psoriasis, that may be causing your dry skin.

Eczema is a dry, itchy skin condition that can occur anywhere. Atopic dermatitis is the most common type due to an overactive immune system and usually occurs in childhood; more specifically, atopic dermatitis is due to a deficiency in a protein called filaggrin that helps skin maintain water content or moisture.

Eczema can also cause certain types of blistering. The condition may be chronic, but it's not contagious. People with severe eczema are at a higher risk for food allergies and asthma.  

Eczema treatments may include:

• Antihistamines
• Immunosuppressant medicines that reduce immune system response
• Light therapy
• Steroids (used short-term)
• Topical medicines
• Trigger avoidance, where a person avoids the allergens or irritants that cause flares

Hives, also called urticaria , are itchy, raised welts that can be red or skin-colored. About 20% of people experience hives at some point in their lives. Many cases occur due to an allergic reaction. Possible triggers include:

• Insect bites
• Latex exposure
• Medications
• Viral infections

Hives are usually temporary, but some people can develop chronic hives. Healthcare providers often recommend antihistamines to block or reduce the body's allergic response and ease itching. In severe or chronic cases, a healthcare provider may temporarily prescribe corticosteroids to address the inflammation and bring relief.

Lupus  is an autoimmune condition, meaning the body attacks its own tissues and organs. Lupus can affect many parts of the body, so people with lupus can have various symptoms, which include:

• Sensitivity to the sun
• Swelling in the legs or around the eyes
• Abdominal pain

Some forms of lupus only affect the skin. You may notice the following symptoms:

• A butterfly-shaped rash across the cheeks and nose—this is a classic symptom of lupus 
• Painless sores in the nose and mouth
• A raised, disc-shaped red patches on sun-exposed areas 
• Round, scaly rashes anywhere on your body

There's no cure for lupus. However, treatments such as anti-inflammatory drugs, corticosteroids, and immunosuppressants can help manage symptoms and prevent flares.

9. Psoriasis

Courtesy of Dermnet

Psoriasis is a skin condition related to skin cell development. When a person has psoriasis, their body makes skin cells quicker than normal by creating the cells in a few days instead of weeks.

Most people have plaque psoriasis as a result of new cell growth producing piles of skin cells on the skin. The plaques look silvery-white and appear most commonly on the elbows, knees, lower back, and scalp.

Topical medicines, light therapy, and system-wide medicines (ones that work throughout the body) can help treat psoriasis.

10. Ringworm

Ringworm is a fungal skin infection that can be itchy. Ringworm appears as a round patch with a clear center on many areas of the skin. Despite its name, ringworm is not caused by a worm.

Ringworm of the scalp, which is called tinea capitis, can cause scaly, red bald spots. Ringworm of the feet, known as athlete's foot , causes peeling, cracking, and possibly blisters. When ringworm affects the groin, it's called jock itch.

Ringworm is contagious but treatable with antifungal medicines.

11. Rosacea

Some people have rosacea , which is a skin condition that results in facial redness and sometimes burning or stinging. Other symptoms may also include acne-like skin sores, a red nose, and bloodshot, irritated, watery eyes.

There is no known cause for rosacea. However, people who are fair-skinned, aged 30 to 50, and assigned female at birth are more likely to develop rosacea.

Rosacea is incurable but treatable. Potential treatments are trigger avoidance, antibiotics, laser surgery, or nose tissue surgery.

12. Shingles/Chickenpox

A painful rash with blisters is a hallmark sign of shingles . A shingles rash wraps like a band across one side of the face or body.

The virus that causes chickenpox, varicella-zoster virus (VZV), lays dormant in your nerve cells and later reactivates to cause shingles. In other words, shingles only affect people who have previously had chickenpox.

The first signs of shingles include skin sensitivity, itching, tingling, or pain. Days later, a rash of tiny fluid-filled blisters develops. Shingles isn't passed from person to person. People with shingles can give chickenpox to others, usually children, if they've never had the illness.

Healthcare providers usually prescribe antiviral medicines to treat shingles. Those medicines are most effective when started as soon as a rash develops.

13. Skin Cancer

Nonmelanoma skin cancer frequently affects sun-exposed areas, including the head, face, neck, hands, and arms. There are two types of nonmelanoma skin cancer: basal cell carcinomas and squamous cell carcinomas.

Basal cell carcinomas may look like round, flesh-colored growths, a pearl-like bump, or a pink skin patch. Squamous cell carcinomas may form a firm red bump, scaly patch, or a sore.

Melanoma  (above) is a dangerous type of skin cancer because it can metastasize, or spread. Melanoma may cause dark spots, changes in moles , or a bruise that doesn't heal.

Treatment can include surgery, radiation, and chemotherapy, depending on the type of skin cancer and its severity.

14. Vitiligo

There are different types of vitiligo . People with the skin condition develop white or lighter patches of skin, usually on both sides of the body. Some people have localized vitiligo, in which only a few white spots appear, while others can have it on larger swaths of skin.

The cause of vitiligo is not fully understood. Still, some research suggests that vitiligo is an autoimmune disease in which the body's immune system attacks pigment-producing cells.

Healthcare providers may prescribe light therapy and topical creams to ease symptoms.

Common warts  are bumpy skin growths that usually appear on the hands. Foot warts on the soles of the feet, known as plantar warts , tend to be hard and painful when you walk on them.

Warts are caused by human papillomaviruses and can be contagious. Tiny black dots that look like seeds, which are dried blood from tiny blood vessels, may appear on the surface of warts.

Warts often go away on their own, particularly in children. A healthcare provider can remove painful or bothersome warts using peeling medicines, acids, or freezing.

When to See a Healthcare Provider

You'll want to see a board-certified dermatologist or healthcare provider if you have questions or concerns about your skin. You'll also want to consult a healthcare provider if you:

• Experience other symptoms like fever, fatigue, or shortness of breath alongside skin symptoms
• Have rashes that are painful, blistering, or infected
• Have skin problems that don't go away or worsen

A Quick Review

There are many common skin conditions, such as dermatitis, lupus, rosacea, and warts. The causes and treatments for skin conditions vary, so consult a healthcare provider for diagnosis and treatment.

Frequently Asked Questions

Melanoma, a type of skin cancer, is the most serious skin condition. Though the cancer is uncommon, it can spread to other places in the body without early detection and treatment.

Cold sores, psoriasis, rosacea, shingles, and vitiligo cannot be cured.

Older adults may experience dry skin and age spots often. Blemishes, skin tags, and warts are other common skin issues in older adults.

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• Published: 11 November 2021

Defining skin aging and its risk factors: a systematic review and meta-analysis

• Qi Yi Ambrose Wong 1 &
• Fook Tim Chew 1  

Scientific Reports volume  11 , Article number:  22075 ( 2021 ) Cite this article

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• Risk factors
• Skin manifestations

Skin aging has been defined to encompass both intrinsic and extrinsic aging, with extrinsic aging effected by environmental influences and overlaying the effects of chronological aging. The risk factors of skin aging have been studied previously, using methods of quantifying skin aging. However, these studies have yet to be reviewed. To better understand skin aging risk factors and collate the available data, we aimed to conduct a systematic review and meta-analysis. We conducted our systematic review in compliance with Preferred Reporting Item for Systematic Review and Meta-Analyses (PRISMA) guidelines. Embase, PubMed and Web of Science databases were searched in October 2020 using specific search strategies. Where odds ratios were reported, meta-analyses were conducted using the random effects model. Otherwise, significant factors were reported in this review. We identified seven notable risk factors for various skin aging phenotypes: age, gender, ethnicity, air pollution, nutrition, smoking, sun exposure. This review’s results will guide future works, such as those aiming to examine the interaction between genetic and environmental influences.

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Introduction.

Epidemiological evidence of environmentally induced skin changes has existed as early as 1965 1 . However, the concept of skin aging as a superimposition of skin changes induced by both chronologic and environmental factors was only introduced later, after 1983 2 , 3 . Yet, a formally agreed definition of skin aging and its signs is still lacking. There is a rough consensus that skin aging encompasses several phenotypes such as, but not limited to, wrinkling, pigmentation and telangiectasis 3 , 4 , 5 , 6 , 7 , 8 . As such, skin aging has been quantified using different phenotypes and grading systems, allowing the identification of multiple risk factors by various epidemiological studies 9 , 10 .

Definition of skin aging

In this article, skin aging is defined simply as changes to the skin that occur due to aging. Attention was paid to the phrases ‘changes to the skin’, and ‘aging’. With reference to the former, changes to the skin may be categorised as, but not limited to the following: histological, morphological, and physiological. The latter phrase, ‘aging’, requires careful elucidation. Forming an interface between the human body and the external environment, the human skin is constantly subject to both chronologically and environmentally induced changes. Thus, skin aging may be categorised as intrinsic or extrinsic, depending on the epidemiological factors affecting the skin aging process, whereby intrinsic aging is attributed chronological and genetic factors, while extrinsic aging is influenced by environmental factors 11 .

Aim of review

This review examines the association of epidemiological factors with human skin aging signs that are assessable by non-invasive means. We aimed to obtain a broad overview of the epidemiology of skin aging; hence, all participant subjects available in the literature were considered. Although the focus was on modifiable epidemiological factors (extrinsic aging), intrinsic aging factors were included due to their potential interaction or confounding effects with extrinsic factors. The outcome of interest was skin aging signs assessable through non-invasive means, with emphasis on visual assessment methods, owing to the convenience of execution and cosmetic implications of visually evident skin aging phenotypes. Lastly, to maximise the scope of possible associations, we focused on non-experimental observational studies (i.e., cross-sectional, or longitudinal study designs).

Methodology

Search strategy.

This review was conducted in accordance with the Preferred Reporting Item for Systematic Review and Meta-Analyses (PRISMA) guidelines 12 (see Supplementary Table 1 for PRISMA checklist). A primary literature search was performed using the Embase, PubMed and Web of Science databases in October 2020. Search results were restricted to English journal articles published between 1990 and 2020. The search term for all databases included ‘skin aging’ or ‘skin ageing’ in the title or abstract, and ‘risk’, or ‘protective’, or ‘epidemiology’ in all index fields. Full search terms and filters applied for their respective databases are summarised in Table 1 . Eligible articles from the primary search were determined using pre-defined eligibility criteria. A secondary search was conducted by hand-searching references cited by the eligible articles from the primary search. Results obtained in the secondary search were deduplicated and screened using the same eligibility criteria as that applied in the primary search. The hand-search process was repeated for results from the secondary search to ensure a thorough record was obtained (see Fig.  1 for PRISMA flow diagram). A final search, wherein a list of phenotypes collected from the results of the literature search were used as keywords, only returned records that were duplicates of previous results or irrelevant to this review’s aims, ensuring that the literature search illustrated in Fig.  1 was sufficiently thorough.

PRISMA flow diagram (from Moher et al. 12 . Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. https://doi.org/10.1371/journal.pmed1000097 ).

Eligibility criteria

As per our definition of skin aging and stated aims, articles eligible for inclusion in this review examined associations of epidemiological factors, both intrinsic and extrinsic, with skin aging outcomes in any human subjects assessed via non-invasive methods, by means of a non-experimental observational study. Any full-text journal article available in English was included. Articles excluded from the review for met at least one of the following criteria: study pertained to non-human subjects (e.g., in-vitro studies, murine experiments); study did not examine any epidemiological exposure factors; epidemiological exposures examined by study were disease or disorders (e.g., cancers, eczema); study examined skin aging signs as risk factors for other clinical conditions; study pertained to non-epidemiological risk factors (e.g., genetic polymorphisms); study quantified skin aging via invasive methods (e.g., skin biopsy) or instrumental skin parameter measurements (e.g., skin pH, trans-epidermal water loss); article focussed on clinical trials. Several articles reported outcomes measured using various methods (invasive, non-invasive, or instrumental measurement); if outcomes obtained via non-invasive assessment methods were reported, the study was included. Outcomes quantified using digital image analysis were also included. Using this eligibility criteria, a total of 490 records were screened. An initial screening was first performed by selecting articles based on their title and abstract, before retrieving full-text reports for selected articles and re-assessing them for suitability. Full-text articles excluded from the review met at least one of the following criteria: article was a review; article reported insufficient study data; article reported only analysed correlations between skin aging signs. Additionally, quality assessments of included studies were performed using JBI critical appraisal tools 13 .

Data extraction

The following study characteristics were abstracted from the full-text articles: author(s) and year, country, sample size and subject demographics, outcome details (domain, anatomical location, definition if any, and method of quantification), and exposures (protective or risk factor). In several studies, the number of respondents and number of subject data used in statistical analysis differed; the number of subjects included in statistical analysis, if reported, was extracted, and considered as the sample size. To account for varying terminology used by different studies for identical outcomes, we categorised outcomes into 24 individual domains (e.g., pigmentation, wrinkling), including an ‘other’ category which comprised outcomes unique to its study and for which no clear definition was provided (e.g., tear troughs, oral commissures) (Supplementary Table 2 ). For quantitative data, the following were extracted: estimates of effect sizes; confidence interval or standard error, whichever was reported. Where possible, adjusted effect sizes were preferred to non-adjusted ones. If effect sizes were not reported, means and error bars were extracted (Supplementary Dataset). This review focussed primarily on odds ratios.

Statistical analysis

Meta-analyses were conducted on R with the RStudio interface 14 , using the metafor package 15 . Meta-analysis for a given risk factor was conducted when an effect size estimate for association between an outcome of interest and said risk factor was reported by at least two independent studies, using the DerSimonian-Laird random effects meta-analysis method to account for between-study heterogeneity 16 . Pooled odds ratios (pOR) were obtained from the analyses. Odds ratios included in the random effects models were also ensured to compare identical or non-overlapping exposure and reference categories (i.e., subjects grouped in a given exposure category in one study did not qualify to be grouped into the reference category from another study). To avoid possible overlap of study populations and inclusion of duplicate results in the meta-analytic models, each study was only represented once for a given outcome, unless effect sizes reported were for stratified populations. Additionally, it was ensured that each study’s subjects were not drawn from the same study cohort. Where overlapping study subjects were concerned, only the larger study was considered. To assess heterogeneity, the I 2 index was calculated for each meta-analysis; an I 2 value upwards of 50% with p-value < 0.05 was considered as a suggestion of significant heterogeneity. Begg’s funnel plots and Egger’s test were used to assess publication bias; Egger’s test was only performed for meta-analysis of more than 2 studies.

Results and discussion

Literature search.

Thirty-four eligible journal articles were identified during the primary search and screening process (Fig.  1 ). These studies reported on associations between risk factors and outcomes which they linked to skin aging. However, phenotypes considered as skin aging signs or used as measures of skin aging were found to differ between studies. Thus, literature cited by eligible articles from the initial search were retrieved and screened; this citation screening process constituted a secondary literature search. Eligible articles from this secondary search were subjected to the same citation screening process to obtain additional studies, which when deduplicated and included with the results from the secondary search, yielded a total of 74 eligible articles. These articles examined outcomes linked to skin aging by articles from the primary search and reported risk factor associations but did not necessarily link the outcomes to skin aging themselves. The final database search using outcomes from the eligible primary search results did not yield other eligible studies not already included in this review. This paper reviews 109 studies (Supplementary References). Funnel plots, often asymmetrical, and Egger’s test p-values indicated that there was often significant publication bias across all outcomes (Supplementary Figs. 2 – 10 ).

Overview of study characteristics

Study populations originated from 16 countries (Supplementary Table 2 ). Sample sizes and subject characteristics varied between studies, with samples sizes ranging from 24 females only 17 , to 20,295 males and females from the NHANES study 18 . Some studies examined specific races or genders, while others were nationwide cohort studies (e.g., NHANES). The narrowest sample age range reported was 13–15 years 19 and the widest was 18–96 years 20 , with the youngest subject aged one 18 and the oldest aged 101 years 21 .

Overview of skin aging definitions

Twenty-nine articles offered some definition of skin aging, with 11 from the primary search and 18 from the secondary search (Supplementary Table 3 ). Conversely, articles with no clear definition of skin aging generally listed skin aging signs attributable to skin aging, or factors influencing skin aging. Although this review did not identify a formal definition of human skin aging in the literature, the rough consensus in included articles was to attribute human skin aging to both intrinsic aging and aging influenced by external factors. Intrinsic skin aging was attributed to non-modifiable risk factors such as chronological aging and genetic influences, while extrinsic aging was attributed to modifiable extrinsic factors, such as sun exposure and smoking. From the primary search, there were instances of the terms ‘photoaging’ being used in place of or equated to ‘extrinsic aging’ 22 , 23 , 24 , 25 , while others defined extrinsic aging as skin aging influenced by multiple extrinsic risk factors, including skin aging attributed to sun or ultraviolet (UV) exposure which ‘photoaging’ refers to, but not vice versa. This review considers photoaging as a proper subset of extrinsic aging. The visible skin aging phenotype is thus the superimposition of intrinsic and extrinsic skin aging signs—a point that was acknowledged and accounted for by at least two validated skin aging scores that relied on visual grading of outcomes 7 , 11 .

Considering the lack of a standardised definition of skin aging, definitions provided in reviewed studies, and the content of the foregoing studies, we propose the following definition for skin aging: “Skin aging is a superimposition of benign skin phenotypes indicative of histological and morphological changes which are both continuous and inevitable, caused by both intrinsic and extrinsic factors, wherein genetic and chronological influences constitute the former, and environmental influences constitute the latter.” With this definition, we aim to succinctly encompass the relevant definitions identified in the literature while progressing towards a standardised definition of skin aging.

Overview of skin aging signs and non-invasive assessment methods

Fifty-one studies linked their study outcome or outcomes to skin aging, from which 24 skin aging outcomes were identified. These studies examined a variety of phenotypes, the most frequent of which were pigmentation (n = 17), sagging (n = 12), telangiectasia (n = 11), and wrinkling (n = 35). Notably, the term pigmentation often referred to changes in pigmentation, dyspigmentation, or the formation of pigment spots; we henceforth refer to this phenotype as dyspigmentation. Additionally, we observed repeated usage of the Beagley-Gibson photonumeric scale for skin surface microtopography (SSM), wherein a higher score indicated a greater degree of skin aging 26 . Skin aging was also assessed as an outcome comprising a collection of phenotypes (n = 7): overall skin aging using SCINEXA 27 , perceived age 28 , 29 , or photoaging 20 , 30 , 31 , 32 . Overall, most methods of outcome quantification entailed visual assessment by clinicians or researchers according to arbitrary grading scales (Supplementary Table 1 ), such as the Daniell wrinkling scale 33 and the Beagley-Gibson grading scale for SSM 26 , both of which were used recurrently in different studies. Studies used grading scales (n = 68) which were often ordinal wherein higher score values indicated greater severity of skin aging outcome. Text definitions, photographs, or both, were provided as scale references and served as a direct measure of target outcomes. In contrast, three studies assigned grades to their target outcome, then calculated a final score from the assigned grades by applying a formula 34 , 35 , 36 . For discrete outcomes (e.g., seborrheic keratosis), studies assessed subjects by determining presence or absence (n = 14), counting the number of occurrences (n = 10), or both counting, then assigning a grade according to the frequency of outcome (n = 8). Other studies assessed the global face by estimating perceived age (n = 5) or conducted digital image analyses (n = 19) which offered a more precise and objective measure of outcome (e.g., measurement of total wrinkle length). Of note, although SCINEXA was validated as a scale which calculates an overall skin aging score from the individual scores of 23 skin aging signs 7 , most studies using SCINEXA (n = 10) reported individual outcome scores, instead of overall skin aging score, while only one study reported overall SCINEXA score 27 . Since skin aging was most frequently assessed as individual outcomes, this review examined the individual outcomes, or skin aging signs, as proxy measures of overall skin aging. For each skin aging sign, we categorised associated risk factors into two types: non-modifiable and modifiable risk factors. Non-modifiable risk factors are associated with intrinsic skin aging and cannot be altered, such as age and gender. In contrast, modifiable risk factors, such as smoking and sun exposure, influence extrinsic skin aging and can be altered through interventions and lifestyle changes.

Non-modifiable risk factors (intrinsic aging)

Associations with age were obtained for eight skin aging phenotypes: cutis rhomboidalis nuchae, dryness, elastosis, ephelides, facial lentigines, higher SSM score, telangiectasia, and wrinkling (see Fig.  2 ). Significant associations were found for facial lentigines (pOR 1.08, 95% CI 1.05, 1.11), higher SSM score (pOR 1.15, 95% CI 1.12, 1.18), telangiectasia (pOR 1.37, 95% CI 1.09, 1.73), and wrinkling (pOR 3.96, 95% CI 1.75, 8.96). For the significant pooled associations, significant heterogeneity was observed for higher SSM score (I 2  = 75.04%, p = 0.003), telangiectasia (I 2  = 75.04%, p = 0.000), and wrinkling (I 2  = 87.25%, p = 0.000). Since the progression of age results in the inexorable accumulation of effects from intrinsic factors and damage from extrinsic factors 37 , pooled odds ratio for any given skin aging phenotype with chronological age was likely to be significant. Concordant with expectations, we reported four significant pooled estimates above. However, the pooled estimates for cutis rhomboidalis nuchae, dryness, elastosis, and ephelides respectively with age were non-significant.

Forest plot for skin aging phenotypes and age as a continuous variable.

Pooled associations with male gender were obtained for lentigines (pOR 1.26, 95% CI 0.95, 1.67), higher SSM score (pOR 2.48, 95% CI 1.76, 3.49), telangiectasia (pOR 3.86, 95% CI 1.03, 14.49) and wrinkling (pOR 1.25, 95% CI 0.84, 1.88). Significant heterogeneity was observed for higher SSM score (I 2  = 85.75%, p = 0.000), telangiectasia (I 2  = 97.26%, p = 0.000), and wrinkling (I 2  = 78.62%, p = 0.000); heterogeneity for lentigines was non-significant (see Fig.  3 ). Although significant associations were reported for female gender with wrinkling (OR 3.69, 95% CI 1.74, 7.84) 38 and perioral wrinkling 39 , sensitivity analysis by exclusion of each study from the meta-analysis of wrinkling and gender showed that the association with male gender was significantly strengthened when Chung et al. 38 was excluded (pOR 1.50, 95% CI 1.27, 1.77) (Supplementary Fig. 1 ).

Forest plot for skin aging phenotypes and male gender (female gender as reference).

Nonetheless, there appears to be a general male predisposition to increase likelihood of skin aging manifestation. While the pathophysiology is unclear, the role of sex hormones has been implicated and reviewed elsewhere 40 . Additionally, menopausal status and hormone replacement therapy (HRT) use, both factors which interact with increased age and female gender, may influence skin aging manifestation. Although no pooled odds ratio was available for menopausal status and skin aging, individual studies have previously reported a significant association for postmenopausal status with photoaging (OR 1.5, 95% CI 1.2, 1.8) 41 , and no significant association with wrinkling (OR 5.00, 95% CI 0.37, 67.66) 25 . Pooled associations with HRT use was obtained for lentigines (pOR 1.49, 95% CI 0.59, 3.78) and wrinkling (pOR 0.47, 95% CI 0.17, 1.34) (see Fig.  4 ). Notably, although the protective effect of HRT on wrinkling was previously reported 25 , 35 , the pooled association for wrinkling and HRT use was non-significant.

Forest plot for skin aging and HRT use.

Ethnicity and dyspigmentation

Differences in skin aging progression between ethnicities have been reported across several studies. One study evaluating facial skin aging in African-Americans, Caucasians, Chinese, and Indians found that skin aging manifests differently between each ethnicity, with dyspigmentation being the predominant skin aging trait in Asians 42 . Indeed, a comparison between Chinese and French females showed that increased dyspigmentation occurred more frequently in the Chinese than French, and Chinese females exhibit a marked progression in wrinkling severity at a later age than French females 43 . Likewise, Japanese, when compared to Germans, exhibited more lentigines [arithmetic means ratio (AMR) 6.173, 95% CI 2.959–12.88] and decreased wrinkling severity (Wrinkling under the eyes, AMR 0.813, 95% CI 0.639–0.987; Wrinkling on the upper lip, AMR 0.588, 95% CI 0.274–0.901) 44 . Significant associations for decreased forehead, crow’s feet, glabellar, and perioral wrinkling with Asian ethnicity were also identified 45 (Supplementary Dataset).

However, a multi-ethnicity study by Vierkötter et al. 46 concluded that stratification of study subjects by age, anatomical site of skin aging sign, and sub-ethnic group within the Asian category resulted in findings that contradicted the view that skin aging manifestation was specific to ethnicity. In a subject population aged above 30, dyspigmentation was found to be more prevalent in Chinese and Japanese than in Germans only if measured on the cheeks and in subjects up to 60 years old, while wrinkling in Japanese above 60 years old and Chinese of any age were not significantly more severe than that in Germans (Supplementary Dataset). Here, the importance of age in skin aging was underscored, and supported an earlier finding that Chinese have exhibit lower wrinkling severity below 40 years old but show accelerated skin aging from 40 to 50 years old 43 . Indeed, the unequal distribution of subjects within each age range in Vierkötter et al. 46 likely affected the study’s findings. Moreover, the confounding effect of sub-ethnicity on skin aging phenotype cannot be discounted; one study reported a non-significant difference in wrinkling between Mongolians, an Asian ethnic group, and Caucasians (OR 1.014, 95% CI 0.468–2.196) 34 . Nonetheless, ethnic differences in skin aging have been found to be independent of educational level, sun exposure and smoking 46 .

Skin colour has been correlated with ethnicity, with Europeans having the lightest skin, Africans exhibiting the darkest skin, and Chinese and Indian showing lightness values between the two 47 . However, this review identified no clear association between skin colour and skin aging. The categorisation of skin colour and the corresponding associations with skin aging differed between studies (Supplementary Dataset). Moreover, interaction of sun exposure and skin phototype as determinants of skin colour further complicates the categorisation of skin colour and confounds associations with skin aging phenotypes, particularly in studies that did not explicitly differentiate constitutive and facultative pigmentation. Additional pigmentation-related factors identified by this review include hair and eye colour, for which no clear association could be found by this review owing to inter-study differences in categorisation of exposure and significance of associations.

Modifiable factors (extrinsic aging)

Air pollution.

No pooled odds ratio could be obtained for skin aging and air pollution. Each individual study included in this review investigated distinct pollutants in both Asian and Caucasian populations, covering a broad range of air pollutant types overall (Supplementary Table 4 ). Nonetheless, it appeared that dyspigmentation (or lentigines) and wrinkling on the face were significantly associated with various types of air pollution. Significant associations for increased lentigines were found with Air Quality Index (AQI) 48 , 49 , contact with fossil fuels 50 , nitrogen dioxide 51 , particulate matter of diameter 2.5 microns or less (PM2.5) 50 , 52 , 53 , particulate matter of diameter 10 microns or less (PM10) 54 , second hand smoke exposure 50 , soot 54 , and traffic-associated particles 54 . For increased wrinkling, significant associations were found with AQI 48 , 49 , cooking with solid fuels leading to indoor pollution 55 , ozone 56 , PM2.5 53 , PM10 54 , soot 54 , and traffic-associated particles 54 . Other significant associations included sagging with AQI 49 , cooking with solid fuels 55 , and PM2.5 53 ; and greater perceived age than chronological age with AQI 49 . Of note, non-significant associations were reported by one study for both dyspigmentation and wrinkling with carbon monoxide, ozone, PM2.5, PM10, and sulfur dioxide 57 ; these results were attributed to imprecise quantification of air pollutants. Additionally, interaction between pollutants and UV radiation has been reported: nitrogen dioxide, ozone, and UV radiation 56 ; particulate matter and UV radiation 52 . Elaborations on pollutant interactions and mechanistic evidence for skin aging and air pollution (e.g., dyspigmentation and particulate matter; wrinkling and ozone) have been reviewed elsewhere 9 , 10 , 58 , 59 , 60 .

This review found six studies examining the association of skin aging signs with nutritional intake or diet 57 , 61 , 62 , 63 , 64 , 65 . The skin aging phenotypes and nutritional exposures investigated varied widely between studies (Supplementary Table 5 ). A diverse range of food groups and micronutrients were assessed, resulting in different associations being obtained. Only one study used an index to quantify the general dietary intake 63 . Despite the heterogeneity between studies, a healthier dietary intake appears to be associated with less severe skin aging appearance: fatty acids were significantly associated with lower likelihood of dryness, photoaging, and lower SSM score 61 , 62 , 65 ; increased vegetable consumption was significantly associated with decreased wrinkling and lower SSM score 64 , 65 ; the Dutch Healthy Diet Index (DHDI) was associated with decrease wrinkling 63 . The association of alcohol intake was also examined by multiple studies 21 , 23 , 35 , 36 , 57 , 65 , 66 , 67 , 68 , 69 , 70 . As with skin aging and diet associations, no pooled association for skin aging and alcohol consumption could be obtained due to the between-study variation in the quantification of alcohol consumption. Nonetheless, excepting one study which identified a significant association for wrinkling and more than 40 g of alcohol consumed per day (RR 1.35, 95% CI 1.12, 2.97) 35 , all other studies reported non-significant associations for skin aging signs and alcohol consumption.

Smoking was categorised as smoking status or smoking exposure. Studies examining smoking status compared ever smokers to never smokers, or between current, former and non-smokers. In contrast, smoking exposure was quantitative, and measured in units of pack-years, total number of years of smoking, cigarettes per day, or cigarettes in a lifetime. For current smoking, the association with lentigines was non-significant (pOR 1.09, 95% CI 0.76, 1.56) with non-significant heterogeneity (I 2  = 0.00%, p = 0.867). One study reported association for current smoking with photoaging, stratified for gender 41 ; pooling the ORs resulted in a significant association (pOR 1.20, 95% CI 1.01, 1.43). Finally, a significant association found for wrinkling and current smoking (pOR 3.21, 95% CI 1.56, 6.58), with non-significant heterogeneity (I 2  = 49.00%, p = 0.141) (see Fig.  5 a). Conversely, no significant association with former smoking was found for either lentigines (pOR 1.07, 95% CI 0.67, 1.69), photoaging (pOR 1.00, 95% CI 0.89, 1.12) or wrinkling (pOR 1.46, 95% CI 0.70, 3.04) (see Fig.  5 b). Pooling the associations for skin aging with being a smoker, which referred to subjects who indicated they had ever smoked or yes to being a smoker, resulted in a significant association for smoker’s face only (pOR 8.06, 95% CI 1.92, 33.91) with significant heterogeneity (I 2  = 76.43%, p = 0.039). Pooled odds ratios for lentigines and wrinkling with being a smoker were both non-significant (see Fig.  5 c). Nonetheless, there was a dose–response relationship between pack-years of smoking and wrinkling, across four studies, where an increase in number of pack-years of smoking resulted in a stronger association with wrinkling manifestation (Fig.  5 d).

( a ) Forest plot for skin aging and current smoking (non-smoking as reference). ( b ) Forest plot for skin aging and former smoking (non-smoking as reference). ( c ) Forest plot for skin aging and being a smoker (ever smoking or smoker = yes), with non-smoker as reference. ( d ) Forest plot illustrating dose response relationship for smoking (in pack-years) and wrinkling.

UV exposure

The contribution of solar UV exposure to skin aging, resulting in a phenotype termed as photoaging has been established 5 , 6 , 20 . In the literature, sun exposure was quantified using various units (e.g., cumulative lifetime hours, hours per day) and stratified variously by types of sun exposure (e.g., recreational sun exposure, occupational sun exposure). Between studies using identical units, exposure intensity was categorised differently, thus multiple meta-analyses were conducted. When adjusted for smoking exposure, there was significant association between more than 1 h per day of sun exposure and wrinkling (pOR 1.90, 95% CI 1.14, 3.18) with non-significant heterogeneity (I 2  = 23.84%, p = 0.269) (Fig.  6 a, Model 2). For wrinkling due to more than 2 h per day versus less than 2 h per day, due to various categories reported between studies, only meta-analyses considering a sample with a preponderance of higher sun exposure yielded significant pORs (Fig.  6 b). Nonetheless, a dose–response relationship between sun exposure and wrinkling could be discerned. Indeed, for studies that did not report odds ratios, higher degrees of sun exposure were significantly associated with increased wrinkling (Supplementary Table 6 ). Although pORs for other skin aging signs were unavailable, significant associations with higher grades of sun exposure were observed for several notable phenotypes across multiple studies, including lentigines (or dyspigmentation) 18 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , perceived age 29 , 78 , 79 , 80 , sagging 74 , 75 , 76 , 77 . Interestingly, photoaging, often attributed to sun exposure, was not always significantly associated with sun exposure (Supplementary Table 6 ).

( a ) Forest plots for more than 1 h/day of sun exposure and skin aging. The comparison exposure for all odds ratio is 1 h/day of sun exposure. Model 1 and 2: Ernster et al. 36 adjusted for age, BMI, and smoking exposure. Model 3 and 4: Ernster et al. 36 adjusted for age, BMI, and smoking status. ( b ) Forest plots for more than 2 h/day of sun exposure and wrinkling (compared with less than 2 h/day of sun exposure). Model 1 and 2: Ernster et al. 36 excluded from models. Model 3 and 4: included Ernster et al., 1995. ( c ) Forest plots for sunscreen use and skin aging.

A related protective factor, sunscreen use, was significantly associated with wrinkling (pOR 0.50, 95% CI 0.25, 0.98) with non-significant heterogeneity (I 2  = 0.00%, p = 0.387). however, studies that did not report odds ratios found non-significant associations for wrinkling with sunscreen use 39 , 68 , 81 , 82 ; another which stratified sunscreen use by reasons for use reporting findings of inconsistent significance 69 . Likewise, the association of sunscreen use with SSM score was non-significant (Fig.  6 c). Nonetheless, significant associations were reported for sunscreen use with lower perceived age 68 and reduced degree of photoaging 30 . Additional factors, such as a dose–response effect of sunscreen use on skin aging, or interaction between sunscreen use and sun exposure may confound the association between sunscreen use and skin aging.

Several articles not included in this review have examined exposures worth mentioning, such as the impact of stress on skin aging. Financial stress has been found to result in older perceived age 83 , while the mechanistic and phenotypic effects of stress on the skin have been reviewed, a possible link to older looks has been suggested 84 . Previous studies also found that good sleep was associated with lower SCINEXA intrinsic aging score 27 (Supplementary Dataset), while sleep deprivation led to a less healthy and less attractive appearance 85 . Another study also found that sleep deprivation led to a perceived increase in facial signs, including hanging eyelids and wrinkling 86 .

Limitations and conclusion

This review was limited to visible measures of skin aging outcomes, entailing the exclusion of instrumental measurement and biopsy staining methods, which could provide a more accurate measure of phenotype. Dryness has been quantified by skin conductance measured using Skicon-200 87 , while biopsies could permit better quantitative analyses of skin aging via the staining of elastotic tissue 88 , or histologic study 2 . Although studies have taken steps to establish reliability and reproducibility of their various scales by repeating the grading process and assessing the inter-rater reliability, the visual assessment method is inherently subjective and not impervious to cultural perceptions of aged looks. Moreover, since skin aging comprised multiple phenotypes and risk factor exposures were categorised differently between studies, the number of associations obtained by this review for a given skin aging sign and corresponding risk factor were relatively low.

There was a preponderance of cosmetic industry funding and frequent focus on the visuals of skin aging in studies presently reviewed. Although there was no evidence that skin aging phenotypes examined herewith were responsible for functional impairment of the skin nor increased mortality per se, they are nonetheless indicators of histological changes that may contribute to functional impairment of the skin 89 , 90 . For example, aging of the skin is accompanied by degradation of collagen and elastic fibres in the dermis, thinning of the epidermis, impaired fibroblast function, and other changes reviewed elsewhere 91 , 92 , 93 , 94 . These changes have been shown to impair cutaneous integrity, wound healing, and sensory and immune function 94 , 95 , 96 . Moreover, there was an overlap in risk factors for skin aging and skin cancers, with the notable example of UV exposure, thus granting a plausible relevance of skin aging phenotypes as indicators of exposure to risk factors for skin cancer 97 , 98 , 99 , 100 , 101 .

In summary, we have conducted a systematic review and meta-analysis of skin aging phenotypes and their associated risk factors. Through a reasonably comprehensive literature search, this review has collated a record of skin aging signs and their associated risk factors. Considering the variety of skin aging definitions in the literature, this review has proposed standard definition of skin aging. Of the identified skin aging signs, reports on dyspigmentation, sagging, telangiectasia, and wrinkling were predominant in the literature—an observation we attributed to the visibility and noticeability of said phenotypes. Notably, the most important skin aging phenotype was wrinkling, which was frequently used as an indicator of skin aging and a constituent of both validated and non-validated scales in the literature. Of the intrinsic risk factors for skin aging, the primary influence was age, which was highly associated with wrinkling. Conspicuous extrinsic aging factors were smoking and sun exposure, both of which were significantly associated with multiple skin aging signs and exhibited dose-responses relationships with wrinkling.

Finally, this article will serve as a rough directory to the relevant original research publications at bare minimum, while providing readers with an overview of signs linked to skin aging and their associated risk factors. Besides examining risk factors with established significant associations with skin aging, we have also put forward some associations that deserve closer scrutiny. The risk factors identified herewith will guide future research, such as genetic association studies, wherein the interplay between environmental influences and genetics are elucidated.

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F.T.C. conceived and supervised the current review. Q.Y.A.W. conducted the literature review, collated and analysed the data, and wrote the manuscript. All authors read and approved the manuscript.

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Dr. CHEW Fook Tim (Singapore) received grants from the Singapore Ministry of Education Academic Research Fund, Singapore Immunology Network, National Medical Research Council (NMRC) (Singapore), and the Agency for Science Technology and Research (A*STAR) (Singapore); Grant Numbers: N-154-000-038-001; R-154-000-191-112; R-154-000-404-112; R-154-000-553-112; R-154-000-565-112; R-154-000-630-112; R-154-000-A08-592; R-154-000-A27-597; R-154-000-A91-592; R-154-000-A95-592; R154-000-B99-114; BMRC/01/1/21/18/077; BMRC/04/1/21/19/315; BMRC/APG2013/108; SIgN-06-006; SIgN-08-020; NMRC/1150/2008; H17/01/a0/0088; and APG2013/108. The funding agencies had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The other authors declare no other competing interests.

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Wong, Q.Y.A., Chew, F.T. Defining skin aging and its risk factors: a systematic review and meta-analysis. Sci Rep 11 , 22075 (2021). https://doi.org/10.1038/s41598-021-01573-z

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• How psoriasis develops

In psoriasis, the life cycle of your skin cells greatly accelerates, leading to a buildup of dead cells on the surface of the epidermis.

Psoriasis is a skin disease that causes a rash with itchy, scaly patches, most commonly on the knees, elbows, trunk and scalp.

Psoriasis is a common, long-term (chronic) disease with no cure. It can be painful, interfere with sleep and make it hard to concentrate. The condition tends to go through cycles, flaring for a few weeks or months, then subsiding for a while. Common triggers in people with a genetic predisposition to psoriasis include infections, cuts or burns, and certain medications.

Treatments are available to help you manage symptoms. And you can try lifestyle habits and coping strategies to help you live better with psoriasis.

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• Plaque psoriasis

Plaque psoriasis is the most common type of psoriasis. It causes dry, raised skin patches (plaques) covered with scales.

• Guttate psoriasis

Guttate psoriasis, more common in children and young adults, appears as small, water-drop-shaped spots on the trunk, arms or legs. These spots are typically covered by a fine scale.

• Inverse psoriasis

Inverse psoriasis causes smooth patches of inflamed skin in the folds of the skin. It usually appears under the breasts and around the groin and buttocks.

• Nail psoriasis

Psoriasis can affect fingernails and toenails, causing pitting, abnormal nail growth and discoloration.

• Pustular psoriasis

Pustular psoriasis generally develops quickly, with pus-filled blisters appearing just hours after the skin becomes inflamed and tender. It usually appears on the palms or the soles.

• Erythrodermic psoriasis

The least common type of psoriasis, erythrodermic psoriasis can cover the entire body with a peeling, itchy rash.

Common signs and symptoms of psoriasis include:

• A patchy rash that varies widely in how it looks from person to person, ranging from spots of dandruff-like scaling to major eruptions over much of the body
• Rashes that vary in color, tending to be shades of purple with gray scale on brown or Black skin and pink or red with silver scale on white skin
• Small scaling spots (commonly seen in children)
• Dry, cracked skin that may bleed
• Itching, burning or soreness
• Cyclic rashes that flare for a few weeks or months and then subside

There are several types of psoriasis, each of which varies in its signs and symptoms:

• Plaque psoriasis. The most common type of psoriasis, plaque psoriasis causes dry, itchy, raised skin patches (plaques) covered with scales. There may be few or many. They usually appear on the elbows, knees, lower back and scalp. The patches vary in color, depending on skin color. The affected skin might heal with temporary changes in color (post inflammatory hyperpigmentation), particularly on brown or Black skin.
• Nail psoriasis. Psoriasis can affect fingernails and toenails, causing pitting, abnormal nail growth and discoloration. Psoriatic nails might loosen and separate from the nail bed (onycholysis). Severe disease may cause the nail to crumble.
• Guttate psoriasis. Guttate psoriasis primarily affects young adults and children. It's usually triggered by a bacterial infection such as strep throat. It's marked by small, drop-shaped, scaling spots on the trunk, arms or legs.
• Inverse psoriasis. Inverse psoriasis mainly affects the skin folds of the groin, buttocks and breasts. It causes smooth patches of inflamed skin that worsen with friction and sweating. Fungal infections may trigger this type of psoriasis.
• Pustular psoriasis. Pustular psoriasis, a rare type, causes clearly defined pus-filled blisters. It can occur in widespread patches or on small areas of the palms or soles.
• Erythrodermic psoriasis. The least common type of psoriasis, erythrodermic psoriasis can cover the entire body with a peeling rash that can itch or burn intensely. It can be short-lived (acute) or long-term (chronic).

When to see a doctor

If you suspect that you may have psoriasis, see your health care provider. Also seek medical care if your condition:

• Becomes severe or widespread
• Causes you discomfort and pain
• Causes you concern about the appearance of your skin
• Doesn't improve with treatment

Mayo Clinic Minute: Fingernails are clues to your health

Vivien Willliams: Your fingernails are clues to your overall health. Many people develop lines or ridges from the cuticle to the tip.

Rachel Miest, M.D., Department of Dermatology, Mayo Clinic: Those are actually completely fine and just a part of normal aging.

Ms. Williams: But Dr. Rachel Miest says there are other nail changes you should not ignore that may indicate …

Dr. Miest: liver problems, kidney problems, nutritional deficiencies …

Ms. Williams: And other issues. Here are six examples: No. 1 is pitting. This could be a sign of psoriasis. Two is clubbing. Clubbing happens when your oxygen is low and could be a sign of lung issues. Three is spooning. It can happen if you have iron-deficient anemia or liver disease. Four is called "a Beau's line." It's a horizontal line that indicates a previous injury or infection. Five is nail separation. This may happen as a result of injury, infection or a medication. And six is yellowing of the nails, which may be the result of chronic bronchitis.

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Psoriasis is thought to be an immune system problem that causes skin cells to grow faster than usual. In the most common type of psoriasis, known as plaque psoriasis, this rapid turnover of cells results in dry, scaly patches.

The cause of psoriasis isn't fully understood. It's thought to be an immune system problem where infection-fighting cells attack healthy skin cells by mistake. Researchers believe that both genetics and environmental factors play a role. The condition is not contagious.

Psoriasis triggers

Many people who are predisposed to psoriasis may be free of symptoms for years until the disease is triggered by some environmental factor. Common psoriasis triggers include:

• Infections, such as strep throat or skin infections
• Weather, especially cold, dry conditions
• Injury to the skin, such as a cut or scrape, a bug bite, or a severe sunburn
• Smoking and exposure to secondhand smoke
• Heavy alcohol consumption
• Certain medications — including lithium, high blood pressure drugs and antimalarial drugs
• Rapid withdrawal of oral or injected corticosteroids

More Information

Psoriasis care at Mayo Clinic

• What are the risks of vaccinations for people living with psoriasis?

Risk factors

Anyone can develop psoriasis. About a third of instances begin in childhood. These factors can increase the risk of developing the disease:

• Family history. The condition runs in families. Having one parent with psoriasis increases your risk of getting the disease. And having two parents with psoriasis increases your risk even more.
• Smoking. Smoking tobacco not only increases the risk of psoriasis but also may increase the severity of the disease.

Complications

If you have psoriasis, you're at greater risk of developing other conditions, including:

• Psoriatic arthritis, which causes pain, stiffness, and swelling in and around the joints
• Temporary skin color changes (post-inflammatory hypopigmentation or hyperpigmentation) where plaques have healed
• Eye conditions, such as conjunctivitis, blepharitis and uveitis
• Type 2 diabetes
• High blood pressure
• Cardiovascular disease
• Other autoimmune diseases, such as celiac disease, sclerosis and the inflammatory bowel disease called Crohn's disease
• Mental health conditions, such as low self-esteem and depression
• Psoriasis-related health risks
• Psoriasis: What if I get psoriatic arthritis, too?
• AskMayoExpert. Psoriasis. Mayo Clinic; 2021.
• Dinulos JGH. Psoriasis and other papulosquamous diseases. In: Habif's Clinical Dermatology. 7th ed. Elsevier; 2021. https://www.clinicalkey.com. Accessed March 5, 2020.
• Psoriasis clinical guideline. American Academy of Dermatology. https://www.aad.org/member/clinical-quality/guidelines/psoriasis. Accessed March 5, 2020.
• Aloe. Natural Medicines. https://naturalmedicines.therapeuticresearch.com. Accessed March 6, 2020.
• Bolognia JL, et al., eds. Psoriasis. In: Dermatology. 4th ed. Elsevier; 2018. https://www.clinicalkey.com. Accessed March 5, 2020.
• Richard EG. Psoralen plus ultraviolet A (PUVA) photochemotherapy. https://www.uptodate.com/contents/search. Accessed March 16, 2020.
• Feldman SR, et al. Treatment of psoriasis in adults. https://www.uptodate.com/contents/search/. Accessed March 16, 2020.
• Aromatherapy. Natural Medicines. https://naturalmedicines.therapeuticresearch.com. Accessed March 6, 2020.
• Fish oil. Natural Medicines. https://naturalmedicines.therapeuticresearch.com. Accessed March 6, 2020.
• Kermott CA, et al., eds. Psoriasis. In: Mayo Clinic Book of Home Remedies. 2nd ed. Time; 2017.
• Oregon grape. Natural Medicines. https://naturalmedicines.therapeuticresearch.com. Accessed March 16, 2020.
• Bolognia JL, et al., eds. Ultraviolet therapy. In: Dermatology. 4th ed. Elsevier; 2018. https://www.clinicalkey.com. Accessed March 5, 2020.
• Bolognia JL, et al., eds. Systemic immunomodulators. In: Dermatology. 4th ed. Elsevier; 2018. https://www.clinicalkey.com. Accessed March 5, 2020.
• Psoriasis: Causes. American Academy of Dermatology. https://www.aad.org/public/diseases/psoriasis/insider/diet. Accessed March 17, 2020.
• Healthy diet and other lifestyle changes that can improve psoriasis. American Academy of Dermatology. https://www.aad.org/public/diseases/psoriasis/insider/diet. Accessed March 17, 2020.
• Gibson LE (expert opinion). Mayo Clinic. March 26, 2020.
• Sokumbi O (expert opinion). Mayo Clinic. Nov. 1, 2021.
• Kelly AP, et al. Psoriasis. In: Taylor and Kelly's Dermatology for Skin of Color. 2nd ed. McGraw Hill; 2016. https://accessmedicine.mhmedical.com. Accessed Sept. 13, 2021.
• Menter A, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics. Journal of the American Academy of Dermatology. 2018; doi:10.1016/j.jaad.2018.11.057.
• Office of Patient Education. Psoriasis. Mayo Clinic; 2008.
• Managing itch. National Psoriasis Foundation. https://www.psoriasis.org/life-with-psoriasis/managing-itch. Accessed Nov. 12, 2019.
• High WA. Special considerations in skin of color. In: Dermatology Secrets. Elsevier; 2021. https://www.clinicalkey.com. Accessed May 5, 2021.
• Griffiths CEM, et al. A multidimension assessment of the burden of psoriasis: Results from a multinational dermatologist and patient survey. British Journal of Dermatology. 2018; doi:10.111/bjd.16332.
• Feldman SR, et al. Psoriasis: Epidemiology, clinical manifestations, and diagnosis. https://www.uptodate.com/contents/search/. Accessed Sept. 15, 2021.
• Nogueira M, et al. Targeted therapy for pediatric psoriasis. Paediatric Drugs. 2021; doi:10.1007/s40272-021-00443-5.
• Elmets CA, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with topical therapy and alternative medicine modalities for psoriasis severity measures. Journal of the American Academy of Dermatology. 2021; doi.10.1016.j.jaad.2020.07.087.
• Dietary modifications. National Psoriasis Foundation. https://www.psoriasis.org/dietary-modifications/. Accessed Oct. 20, 2021.
• Ford AR, et al. Dietary recommendations for adults with psoriasis or psoriatic arthritis from the medical board of the National Psoriasis Foundation: A systematic review. JAMA Dermatology. 2018; doi:10.1001/jamadermatol.2018.1412.
• 5 signs a psoriasis support group is right for you
• 6 ways to manage itchy skin when you have psoriasis
• Alternative psoriasis treatments
• Can psoriasis make it hard to sleep?
• Ease stress to reduce your psoriasis flares
• Gluten sensitivity and psoriasis: What's the connection?
• Identifying what worsens your psoriasis
• Is the Mediterranean diet good for psoriasis?
• Pregnancy and breastfeeding when you have psoriasis
• Psoriasis and clinical trials
• Psoriasis and intimacy
• Psoriasis and your self-esteem
• Psoriasis treatment options
• Psoriasis: Get the most out of your treatment
• Psoriasis: How can I protect my skin during a workout?
• Psoriasis: What to share with your doctor
• Scalp psoriasis
• Scalp psoriasis vs. seborrheic dermatitis
• Types of psoriasis
• What's the best way to manage scalp psoriasis?

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Cover Story

The link between skin and psychology

How psychologists are helping patients with dermatological problems.

By Rebecca A. Clay

February 2015, Vol 46, No. 2

Print version: page 56

When Rick Fried, MD, PhD, gave a talk at a dermatology conference seven years ago on the relationship between psychological and dermatological problems, at least one dermatologist in the audience was skeptical about the mind/body connection. Then another dermatologist stepped to Fried's defense, telling her colleague that before he attacked Fried he should at least make sure his zipper was up. The skeptic's fly wasn't really down, but his deep blush vividly illustrated the impact that emotions have on the body's largest organ — the skin.

"How amazing is it that a simple cognition — ‘I said or did something foolish' — can cause virtually every blood vessel in the skin to instantaneously open up, causing a blush or flush?" asks Fried, a psychologist turned dermatologist who is the clinical director of Yardley Dermatology Associates and Yardley Clinical Research Associates in Yardley, Pennsylvania. "That's pretty amazing evidence that the mind and body are linked."

These days, dermatologists are much more accepting of the field now known as psychodermatology, and psychologists are getting more involved in helping dermatology patients. They're investigating the role that stress and other psychological issues play in acne, psoriasis, eczema, itching, hives and other skin problems. They're treating the social anxiety, depression and other psychological issues that can arise when people have skin conditions. They're also developing interventions, whether to help dermatology patients deal with psychological issues or to help people avoid melanoma and other skin problems in the first place.

Minding the skin

While psychodermatology is a well-established field in Europe, it has been slower to catch on in the United States, according to a history of the movement on the Association for Psychoneurocutaneous Medicine of North America (APMNA) website. There are just a few psychodermatology clinics in the country, the association reports. Most medical school curricula don't include psychodermatology material. And there are few researchers and limited research funding in this area.

What's more, the field consists primarily of dermatologists and psychiatrists, says Kristina G. Gorbatenko-Roth, PhD, a psychology professor at the University of Wisconsin–Stout. She became interested in psychodermatology when she developed the hair loss condition alopecia areata and discovered that depression, anxiety and other psychological issues were common among participants posting in an alopecia-related Internet chat room.

The APMNA is eager for psychologists to get involved in the field, says Gorbatenko-Roth, who is working with two European psychologists to develop training materials for those interested in developing a clinical competency in psychodermatology.

"The skin is the most noticeable part of our body that could be impacted by psychological factors, yet very few psychologists are studying it," she says. "It's classic health psychology, just in a different area."

Psychologists have roles to play in treating all three types of psychodermatology disorders, says Gorbatenko-Roth. The three types are:

• Skin problems affected by stress or other emotional states.
• Psychological problems caused by disfiguring skin disorders.
• Psychiatric disorders that manifest themselves via the skin, such as delusional parasitosis.

"Psychologists' service provision skills are highly applicable and relevant," she says. "Coupling this with the lack of psychologists with training in psychodermatology, and the growth potential for psychologists becomes more apparent."

Rick Fried is one of the few U.S. clinicians specializing in psychodermatology. Skin problems can be extremely distressing, he says. For one, flare-ups of psoriasis, eczema, acne and other conditions can be unpredictable. Unlike hypertension, diabetes or other health problems, skin problems are usually obvious to onlookers. Plus, patients may have psychological reactions that seem out of proportion to their actual skin conditions.

"We can never presume that the so-called objective severity of a dermatological disorder correlates with the psychological impact," says Fried. "I've see people who have nodulocystic acne who aren't happy but really aren't psychologically distraught; I've also seen patients with one zit on their chin who have attempted suicide."

Having a skin problem can prompt intense distress. In a 2014 National Rosacea Society survey of 1,675 patients with rosacea — a condition that causes facial redness and related symptoms — 90 percent of respondents reported lowered self-esteem and self-confidence, 54 percent reported anxiety and helplessness, and 43 percent reported depression, for example. More than half said they avoided face-to-face contact.

In a vicious circle, stress, depression and other kinds of psychological problems can exacerbate the skin problems. "The common dermatological issues that have been documented to be made worse by stress include acne, rosacea, psoriasis, itching, eczema, pain and hives, just to name a few," says Fried.

Fortunately, he says, treating psychological problems can also improve skin problems.

In a paper published in 2013 in Seminars in Cutaneous Medicine and Surgery , Fried reviewed the evidence for nonpharmacological management of psychodermatalogical conditions. Proven interventions — typically used as complements to traditional dermatological approaches — include hypnosis, support groups, biofeedback, meditation, guided imagery, progressive muscle relaxation, cognitive-behavioral therapy and other forms of psychotherapy.

The key, says Fried, is to give patients a sense of control over their conditions and their reactions to them. Cognitive-behavioral therapy, for example, can help patients manage stress and stop catastrophizing, such as saying they'll kill themselves if their psoriasis acts up on an important day.

Boston psychologist Ted A. Grossbart, PhD, a private practitioner who specializes in psychodermatology, uses a variety of therapies to help people with skin conditions, including imaging and meditation. Hypnosis can be especially helpful, he says. The key is to help patients focus on an image associated with the desired change, whether it's warmer, cooler, dryer, moister or less itchy skin, says Grossbart, who is also an assistant professor of psychology at Harvard Medical School. A patient with eczema, for instance, might zero in on the image of a tropical rainforest to counteract the drying the condition brings.

"Often, people are doing what I call inadvertent negative hypnosis anyway," says Grossbart. "If that very same mechanism can get used in a focused way and in a proper dimension, the results can be quite dramatic."

These kinds of interventions don't just help patients' distress, says Fried. They can also improve patients' skin and their responsiveness to treatment. In one study Fried cites in his literature review, for example, patients who listened to a mindfulness meditation program while undergoing phototherapy treatment for psoriasis needed 40 percent less exposure to ultraviolet light than others.

Fried refers his patients who need more intensive psychological assistance to psychologists, whom he calls "skin-emotion specialists" as a way of reducing stigma and overcoming patients' reluctance to seek mental health care.

In some cases, adds Grossbart, skin problems are the outward manifestation of an underlying mental disorder.

Take skin picking, for example. "Sometimes people would have perfect skin if they would just leave it alone," says Grossbart. "But they can't." Their picking may be a form of addiction, a symptom of attention-deficit disorder or the outward sign of obsessive-compulsive disorder, all of which require different treatment approaches. "You've got to do detective work first," says Grossbart.

Preventing problems

Psychologists are also helping prevent dermatological problems from developing.

Kasey Lynn Morris is investigating the best ways to prevent melanoma and other problems caused by excessive tanning, for instance.

"Tanning is one of those areas where even though people know how bad it is for them, they still do it," says Morris, a graduate student in social psychology at the University of South Florida.

Research has shown that reminding people of tanning's potentially fatal consequences can help curb people's desire to tan, at least temporarily. But as thoughts of death slide into the unconsciousness, which happens very quickly, people's desire to tan actually increases if being tan is relevant to self-esteem, as is often the case for women, says Morris.

"The reason is that non-conscious thoughts of death motivate a desire to maintain self-esteem," Morris explains. "If a person's appearance is relevant to their self-esteem — and being tan is a part of that cultural appearance ideal — then non-conscious thoughts of death will motivate a desire to uphold that ideal by tanning one's skin."

Adding an appearance-related element to the intervention can "re-route" that self-esteem, Morris and colleagues found in two experiments described in a 2014 paper published in Psychology and Health. In the experiments, the researchers exposed women not just to a reminder of mortality via a funeral scene depicting a woman sunbathing on a beach but also to UV-filtered photos of their own skin, a technique that reveals sun damage. "If you've ever seen a UV-filter photo of yourself, you know you look terrible," says Morris. When the death- and appearance-related interventions were combined, they decreased participants' intentions to tan and increased the amount of sunscreen they took from the researchers.

"It relies on the assumption that people value their appearance — and research suggests the majority of women do — and the knowledge that unconscious thoughts of death motivate a desire to maintain self-esteem," says Morris. "If you prime thoughts of death, followed by a delay to give it time to no longer be conscious and then remind people how much sun damage can hurt their appearance, they are subsequently going to try to boost their self-esteem by maintaining their appearance through using sun protection."

Now Morris and her team are exploring whether participants follow through on their intentions in everyday life.

Other psychologists are working on interventions designed to prevent psychological problems from developing among dermatology patients.

Heidi Williamson, DHealth, Psychol, for example, has worked with young people to develop an online interactive intervention called YP Face IT. It's designed for youth ages 12 to 17 who are distressed because of conditions or injuries affecting their appearance, including skin issues such as acne, psoriasis, burns or scars. The seven-week program teaches kids coping strategies and social skills.

"What young people fear most is being judged negatively for their appearance," says Williamson, a senior research fellow at the Centre for Appearance Research at King's College London. And anticipating negative judgments can make young people anxious and self-conscious, which can mean that young people lose their social skills or fail to develop them in the first place.

YP Face IT teaches users how to overcome negative thoughts about their appearance as well as how to handle social situations, such as answering questions about their conditions, coping with teasing and bullying and making the most of their body language and verbal skills. Participants can also find support through a discussion forum. Throughout the program, a psychologist or other health-care professional monitors users' progress and can suggest more intensive help if necessary.

While Williamson and her colleagues are still evaluating YP Face IT, preliminary results suggest that it decreases social anxiety scores and increases assertiveness and social skills.

For Gorbatenko-Roth, all this activity by psychologists is a welcome change.

"Dermatologists and other health-care providers are out there doing the best they can for patients, but they're frustrated, because they see their patients' emotional distress but typically have neither the time nor the tools to fully address it," she says, urging psychologists to attend the APMNA's next annual conference in San Francisco in March. "This is a great role for psychologists."

Rebecca A. Clay is a journalist in Washington, D.C.

Further reading

• Association for Psychoneurocutaneous Medicine of North America. Visit www.psychodermatology.us.
• Bewley, A., Taylor, R. E., Reichenberg, J. S., & Magid, M. (eds). (2014). Practical Psychodermatology . Hoboken, N.J.: Wiley-Blackwell.
• Grossbart, T. A., & Sherman, C. (1992). Skin Deep: A Mind/Body Approach to Healthy Skin . Albuquerque, N.M.: Health Press NA Inc. Free e-book available at www.grossbart.com.
• Kersting, K. (2003). "Psychodermatology's first postdoc." Monitor on Psychology . Washington, D.C.: APA.

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• Open access
• Published: 13 August 2024

Mechanical force regulates the paracrine functions of ADSCs to assist skin expansion in rats

• Zhixin Xue 1 ,
• Delin Hu 1   na1 ,
• Haojing Tang 1 ,
• Mingheng Xue 1 ,
• Yufan Zhu 1 ,
• Ye Li   ORCID: orcid.org/0000-0002-0255-3915 1 &
• Yunjun Liao 1  

Stem Cell Research & Therapy volume  15 , Article number:  250 ( 2024 ) Cite this article

60 Accesses

Metrics details

In the repair of massive tissue defects using expanded large skin flaps, the incidence of complications increases with the size of the expanded area. Currently, stem cell therapy has limitations to solve this problem. We hypothesized that conditioned medium of adipose-derived stem cells (ADSC-CM) collected following mechanical pretreatment can assist skin expansion.

Rat aortic endothelial cells and fibroblasts were cultured with ADSC-CM collected under 0%, 10%, 12%, and 15% stretching force. Ten-milliliter cylindrical soft tissue expanders were subcutaneously implanted into the backs of 36 Sprague-Dawley rats. The 0% and 10% stretch groups were injected with ADSC-CM collected under 0% and 10% stretching force, respectively, while the control group was not injected. After 3, 7, 14, and 30 days of expansion, expanded skin tissue was harvested for staining and qPCR analyses.

Endothelial cells had the best lumen formation and highest migration rate, and fibroblasts secreted the most collagen upon culture with ADSC-CM collected under 10% stretching force. The skin expansion rate was significantly increased in the 10% stretch group. After 7 days of expansion, the number of blood vessels in the expanded area, expression of the angiogenesis-associated proteins vascular endothelial growth factor, basic fibroblast growth factor, and hepatocyte growth factor, and collagen deposition were significantly increased in the 10% stretch group.

Conclusions

The optimal mechanical force upregulates specific paracrine proteins in ADSCs to increase angiogenesis and collagen secretion, and thereby promote skin regeneration and expansion. This study provides a new auxiliary method to expand large skin flaps.

Massive soft tissue defects caused by excision surgery, trauma, burns, and chronic ulcers seriously increase morbidity and mortality, which remains one of the most challenging problems in plastic surgery [ 1 ]. Unfortunately, traditional skin flap transplantation has drawbacks including additional damage of the donor site and functional and aesthetic deficiencies.

Tissue expansion can eliminate donor site complications related to long-distance tissue transplantation, and expanded skin tissue has a similar quality as skin in the defective area. Therefore, this technique has been widely used for breast reconstruction, genitourinary system reconstruction, and treatment of giant congenital naevi and other diseases [ 2 ]. Nevertheless, as the size of the expanded area increases, the blood supply becomes insufficient and the necrosis rate gradually increases [ 3 ]. In addition, some therapeutic factors, such as postoperative radiotherapy for breast cancer, [ 4 ] greatly increase the incidence of complications. Mesenchymal stem cells (MSCs) are a promising treatment option due to their unique tissue regenerative capacity. Compared with other types of MSCs, adipose-derived stem cells (ADSCs) have received much attention due to their abundance and simple isolation procedure. However, although stem cells are promising for tissue repair, their use is hindered by problems such as immune rejection and tumorigenicity [ 5 ]. In addition, the migration ability, survival rate, and differentiation ability of MSCs decrease after transplantation, which limits their therapeutic potential [ 6 ]. Therefore, the development of novel therapies that are safe and effective for expansion of large skin flaps has been intensely pursued.

An increasing body of evidence demonstrates that paracrine function is central to the effects of MSC-based therapy [ 7 ]. MSCs can release a variety of functional molecules such as growth factors, inflammatory cytokines, chemokines, and extracellular matrix components. Some studies have shown that conditioned medium of ADSCs (ADSC-CM) has the potential to promote tissue regeneration [ 8 , 9 ]. However, the composition of the stem cell secretome is affected by numerous factors, including the tissue source, microenvironment, biological behaviors, and physical and chemical stimulation, which hampers its application in regenerative medicine [ 10 ]. It may be possible to customize the secretome and develop a cell-free therapy by modulating these factors [ 11 ].

Many studies have shown that MSCs can be pretreated with hypoxia, genetic engineering, and physical and chemical stimulation to amplify or inhibit specific biomolecules and thereby achieve the desired therapeutic effect [ 12 , 13 ]. Among the numerous pretreatment methods, mechanical force has the advantages of simple application, quantitative comparability, and no by-products. MSCs are sensitive to mechanical induction [ 14 ]. Mechanical stimulation can induce ADSCs to secrete growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which promote angiogenesis [ 15 , 16 ]. Previous study found that mechanical forces regulate the migration, differentiation, and paracrine functions of ADSCs to varying degrees [ 17 ]. Thus, we hypothesized that application of a specific amount of mechanical force can modulate the paracrine functions of ADSCs to promote skin regeneration. Green nanomaterial is a new field that makes use of sustainable processes and non-toxic ingredients, making it an ideal choice for medical applications [ 18 ]. Many studies have shown that nanomaterials can bind to extracellular vesicles obtained by cell paracrine and show great potential in tumor therapy [ 19 ]. In addition, the development of nano-scaffolds highlights their great potential in plastic and reconstructive surgery. Therefore, we expect that the combination of mechanically treated ADSC-CM and nanomaterials will make a breakthrough in repairing massive soft tissue defects in the future.

We hypothesized that ADSC-CM collected under specific mechanical forces can promote skin regeneration by facilitating angiogenesis and collagen secretion. To investigate this, we applied different degrees of mechanical force to ADSCs and explored the relationship between the magnitude of mechanical force and the paracrine functions of ADSCs. A rat skin expansion model was used in which ADSC-CM was subcutaneously injected into the expanded area to explore the role of ADSC-CM in skin expansion and the underlying mechanism (Fig.  1 ).

Schematic presentation of the experimental procedure

Materials and methods

This study was approved by the Nanfang Hospital Animal Ethics Committee and was conducted according to the guidelines of the National Health and Medical Research Council of China. All animals were purchased from Nanfang Hospital Animal Center (Guangzhou, China), without specific pathogens, and were excluded from abnormal or dying animals in the acclimatization period before the experiment. All surgical procedures were performed according to the aseptic principle. The work has been reported in line with the ARRIVE guidelines 2.0.

Cell isolation and culture

ADSCs were isolated as previously described [ 20 ]. After shaving, two male Sprague-Dawley (SD) rats (6-weeks-old, n  = 2) were sacrificed and subcutaneous fat was harvested. Approximately 4 g of fat was acquired from each rat and stored in a sterile 50 mL centrifuge tube. Subsequently, red blood cells were removed by washing three times with phosphate-buffered saline (PBS, pH 7.4). The isolated fat was cut into small pieces and then digested with 0.2% type Ι collagenase (Solarbio Technology Co., Ltd, Beijing, China) for 60 min at 37 °C with continuous stirring. After digestion, the adipose cell suspension was centrifuged at 800 g for 5 min, and then the cell pellet was resuspended in PBS and filtered through a 100 μm mesh cell strainer. After further centrifugation at 800 g for 5 min, the cell pellet was resuspended in complete growth medium, which comprised Dulbecco’s modified Eagle’s medium: Nutrient Mixture F-12 (DMEM/F12; Gibco, Carlsbad Island, NY, USA) supplemented with 10% fetal bovine serum (FBS, Gibco) and 1% penicillin-streptomycin (Gibco). The cell suspension was then placed in 100 mm culture dishes and incubated at 37 °C with 5% CO 2 . The medium was changed every 3 days and cells were passaged when they reached 90% confluency. ADSCs were used at passage 2–5.

Rat aortic endothelial cells and dermal fibroblasts (Procell Life Science & Technology Co., Ltd, Wuhan, China) were cultured in Dulbecco’s modified Eagle medium-low glucose (Gibco) containing 10% FBS and 1% penicillin-streptomycin (Gibco). Cells were maintained at 37 °C in a humidified atmosphere of 5% CO 2 and 95% air.

Cell stretching and conditioned medium collection

ADSCs were seeded in a silicone rubber membrane coated with type I collagen (Col I) at a density of 1 × 10 4 cells/cm 2 in DMEM/F12 supplemented with 10% FBS. After continuous culture for 24 h, the medium was removed and 2 mL of fresh DMEM/F12 was added to starve cells. After cell starvation, all samples were exposed to static stretch for 6 h using a FX-4000T™ Flexcell ® Tension Plus™ unit (Flexcell International Corporation, Burlington, NC, USA), [ 21 ] and the conditioned medium was collected. Before the mechanical stretch experiment, the stretching range, frequency, time, and load model were set using the software, and the equipment automatically calculated the required vertical displacement of the rubber membrane, which ensured that cell length was elongated a certain amount in the circumferential direction. We reviewed various cell stretching experiments and found that when the cell elongation rate was between 10% and 15%, the cells maintained a physiological stretching state and avoided apoptosis. Additionally, this range of elongation induced corresponding changes in paracrine, promoting different cellular functions. Based on these findings, four groups (0% stretch, 10% stretch, 12% stretch, and 15% stretch) were included [ 22 , 23 , 24 , 25 ].

Cell viability assay

The Cell Counting Kit-8 (CCK-8; Shanghai, Biosharp, China) was used to evaluate the effects of ADSC-CM collected under different mechanical forces on endothelial cell proliferation. Serum-free DMEM or ADSC-CM collected under 0%, 10%, 12%, or 15% stretching force was added into the culture medium, and the cells were incubated for 0, 24, 48 h. After incubation, PBS was used to wash cells for 3 times, and CCK-8 solution (10 µL; 1:10 diluted) was added into the fresh culture medium at 37 °C for 2 h. Finally, the optical absorbance for each sample was measured at 450 nm using an ELISA reader (Thermo Fisher, Massachusetts, USA).

Migration assay

The scratch wound assay was performed to evaluate the effect of ADSC-CM collected under different mechanical forces on endothelial cell migration. Rat aortic endothelial cells were seeded in a 6-well plate at a density of 3 × 10 5 cells/well. After the cells had reached 90% confluency, a sterile 200 µL pipette tip was used to scratch them vertically. Each scratch was required to be straight and the same in each well. The cells were then washed twice with PBS, and serum-free DMEM or ADSC-CM collected under 0%, 10%, 12%, or 15% stretching force was added. Images were acquired 0, 12, and 24 h after scratching.

Tube formation assay

To evaluate angiogenesis induced by ADSC-CM, rat aortic endothelial cells were seeded into a 96-well plate coated with Matrigel (BD Biosciences, CA, USA) at a density of 3 × 10 4 cells/well. Matrigel was dissolved overnight at 4°C and placed in each well on ice in advance. ADSC-CM collected under 0%, 10%, 12%, or 15% stretching force or serum-free DMEM was added to each well, and then the cells were cultured for 30 min at 37 °C. The polygonal structures of endothelial cells were observed using an optical microscope 6 h after cell seeding. The tube formation ability was evaluated by calculating the total tube length and total number of nodes.

Collagen secretion assay

To evaluate secretion of collagen induced by ADSC-CM, rat dermal fibroblasts were seeded in a 6-well plate at a density of 5 × 10 5 cells/well. After the cells had reached 90% confluency, the medium was replaced by serum-free DMEM or ADSC-CM collected under 0%, 10%, 12%, or 15% stretching force, and the culture was continued for 24 h. Collagen secretion by fibroblasts was measured by quantitative real-time PCR.

Skin expansion model

Thirty-six SD rats (6-week-old, male, 250–300 g) were used for in vivo experiments. For sample size calculation, we calculated that the sample size of 3 achieves 90.6% power in 1 weeks and the sample size of 3 achieves 95.2% power with a significance level (α) of 0.05 using a two-sided paired t-test in 30 days according to our pre-experimental results. Three samples per time point were selected in 3, 7, 14, and 30 days. Rats were maintained by routine breeding in the Laboratory Animal Center at Southern Medical University and maintained on a standard chow diet ad libitum in a 12-h light/dark cycle. Three rats were housed per cage. All experimental procedures were approved by the Institutional Animal Care and Use Committee, and were in accordance with their recommendations. Rats were anesthetized with 2% isoflurane, and 10 mL silicon expanders (Guangzhou Wanhe Plastic Material, Guangzhou, China) were subcutaneously implanted on the dorsal side. Thereafter, 15 mL of 0.9% saline was injected through the port of the tissue expander to maintain the same expansion tension in all groups. Rats were allocated randomly to the 10% stretch group ( N  = 12), 0% stretch group ( N  = 12), and control group ( N  = 12) by random number table. In the 0% and 10% stretch groups, ADSC-CM collected under 0% and 10% stretching force, respectively, was subcutaneously injected into the expanded area as soon as the expander was implanted. In the control group, the expander was implanted but no injection was performed. In each group, rats were randomly assigned to four time points, namely, 3, 7, 14, and 30 days ( N  = 3 per time point). At each time point, full thickness skin specimens were collected from the expanded area to observe the effect of mechanically preconditioned ADSC-CM on skin regeneration. After the samples were collected, the rats were immediately euthanized by inhaling excessive isoflurane and cervical dislocation, and the respiratory rate and heart rate were monitored.

Histological examination

Skin specimens were fixed in 4% paraformaldehyde overnight at low temperature. Subsequently, samples were washed using precooled PBS, dehydrated with different concentrations of ethyl alcohol, embedded in paraffin, and cut into 4 μm thick sections for hematoxylin and eosin (H&E) staining. A microscope (Olympus Corp., Tokyo, Japan) was used to obtain photomicrographs (magnification, ×5). Five H&E-stained regions per group were randomly selected by author in a single-blinded fashion to measure the full thickness of skin using ImageJ software (NIH, Bethesda, MD, USA).

Immunofluorescence and immunohistochemistry

For immunofluorescence assays, after dewaxing, antigen retrieval, dehydration, and blocking, paraffin sections were incubated with an anti-rat CD31 primary antibody (diluted 1:100; Abcam, Cambridge, England) at 4 °C overnight to investigate the level of newly formed vessels. Then, the secondary antibody was applied and sections were incubated for 1 h in the dark. Finally, nuclei were counterstained with DAPI for 15 min. Stained cells were photographed using a fluorescence microscope. To assess angiogenesis, the central and side regions of each sample were compared. To quantitate angiogenesis, the numbers of new capillaries (CD31-positive) in central regions per sample were counted by author in a single-blinded fashion in 100× magnification field.

For immunohistochemistry assays, the paraffin sections were dewaxed, dehydrated, and incubated overnight at 4 °C with anti-Col I (diluted 1:100, Abcam) and anti-type III collagen (Col III; diluted 1:100, Abcam) primary antibodies. After washing, the secondary antibody (diluted 1:100; Thermo Fisher, Massachusetts, USA) was added, and sections were incubated for 1 h at room temperature. Stained cells were developed with diaminobenzidine and counterstained with hematoxylin. To quantitate collagen deposition, the author calculated the average optical density in five fields per sample in a single blind way in 100× magnification field using ImageJ software (NIH, Bethesda, MD, USA).

Quantitative real-time PCR

The total RNA was extracted from the skin samples and fibroblasts with TRIzol ® Reagent (Invitrogen, Carlsbad, CA, USA). cDNA was synthesized using EasyScript ® First-Strand cDNA Synthesis SuperMix (TransGen Biotech, Beijing, China) according to the manufacturer’s instructions. Quantitative real-time PCR was performed using the PRISM ® 7500 Sequence Detection System (ABI, Massachusetts, USA) and FastStart Universal SYBR Green Master Mix (Vazyme Biotech Co., Ltd., Nanjing, China).

Fibroblast samples were tested for type I collagen (Col I), and type III collagen (Col III), and the skin samples were tested for the following genes: VEGF, bFGF, hepatocyte growth factor (HGF) and platelet-derived growth factor (PDGF). Relative expression normalized to expression of β-actin (endogenous loading control) was calculated using the 2 −ΔΔCt method. The primer–probe sequences were as follows: β-actin (150 bp), forward 5′-AGGGAAATCGTGCGTGACAT-3′ and reverse 5′-GAACCGCTCATTGCCGATAG-3′; Col I (200 bp), forward 5′-CCTGACGGTGCTATTTAACA-3′ and reverse 5′-GGAAAATGGTGCTCTGAAAC-3′; Col III (170 bp), forward 5′-CCTGAAGATGTCCTTGATGTAC-3′ and reverse 5′- GCCTTGAATTCTCCCTCATT-3′; VEGF (232 bp), forward 5′-AGATTCTGCAAGAGCACC-3′ and reverse 5′-AAGGTCCTCCTGAGCTAT-3′; HGF (160 bp), forward 5′-AAACAAGGTCTGGACTCACATG-3′ and reverse 5′- CCAAGGAACGAGAGGATTCC-3′; bFGF (170 bp), forward 5′-AAGGATCCCAAGCGGCTCTA-3′ and reverse 5′-TCGCACACACTCCCTTGATG-3′; and PDGF (190 bp), forward 5′-ACTCCATCCGCTCCTTTGA-3′ and reverse 5′-GTCTTGCACTCGGCGATTAC-3′.

Statistical analysis

Statistical analyses were performed using SPSS version 25.0 (IBM, Inc., Armonk, NY, USA) with a one-way analysis of variance. Two groups were compared using the least significant difference method or Mann-Whitney U-test. p  < 0.05 was considered statistically significant.

ADSC-CM collected under mechanical force promotes migration and angiogenic tube formation of rat aortic endothelial cells

To study the effect of ADSC-CM on angiogenesis and determine the most suitable mechanical pretreatment, we investigated the effects of ADSC-CM collected under different stretching forces on rat aortic endothelial cells. Cells were cultured in ADSC-CM or serum-free DMEM, and the effects of ADSC-CM on proliferation, migration and angiogenic tube formation of these cells were compared. The scratch wound assay demonstrated that migration of these cells was most promoted in the 10% stretch group (8.05 ± 2.20, n  = 3, p  < 0.0001; 15.55 ± 0.70, n  = 3, p  < 0.0001) (Fig.  2 a b) (Additional file 1). The results of the CCK8 experiment showed that the absorbance changes in each stretching group were not significantly different from those in the control group. (0.953 ± 0.112, n = 3 ,  p > 0.05; 0.968 ± 0.121 ,  n = 3 ,  p > 0.05; 0.989 ± 0.147 ,  n = 3 ,  p > 0.05; 0.853 ± 0.073 ,  n = 3 ,  p > 0.05;0.920 ± 0.074 ,  n = 3 ,  p > 0.05 ) (Fig.  2 c) After cells began to form capillaries, calculation of the length of tubes and number of nodes showed that lumen formation at 6 h was best in the 10% stretch group (1554.00 ± 79.6806, n  = 3, p  < 0.01; 47504.33 ± 1742.71, n  = 3, p  < 0.0001) (Fig.  2 d, e, f) (Additional file 2).

Effects of ADSC-CM collected under different mechanical forces on rat aortic endothelial cells and fibroblasts. a Migration of rat aortic endothelial cells at 12 and 24 h in the scratch wound assay. Scale bar, 200 μm. b Quantitative analysis of the scratch wound assay.  c Cell proliferation ability of rat aortic endothelial cells at 24, 48 h in the CCK8 viability assay. d Tube formation ability of rat aortic endothelial cells at 6 h in the tube formation assay. Scale bar, 200 μm. e f Quantitative analysis of the tube formation assay. g qPCR analysis of Col I and Col III secretion by fibroblasts. Each experiment was independently repeated three times. * p  < 0.05, ** p  < 0.01, *** p  < 0.001, **** p  < 0.0001

ADSC-CM collected under mechanical force promotes collagen secretion by rat fibroblasts

To study the effect of ADSC-CM on collagen secretion, we observed the effect of ADSC-CM collected under different stretching forces on rat fibroblasts. Fibroblasts in the 10% stretch group secreted more Col I and Col III (3.19 ± 0.64, n  = 3, p  < 0.0001; 4.79 ± 0.21, n  = 3, p  < 0.0001) (Fig.  2 g).

ADSC-CM collected under mechanical force improves skin expansion

Based on the results of the in vitro experiments, ADSC-CM collected under 0% and 10% stretching force was applied to the expanded area in rats. Gross observation of the expanded tissue is shown in Fig.  3 a. In each group, images of the expanded skin at different time points were superimposed and the expansion rate on day 30 was calculated (58.65 ± 1.44, n  = 3, p  < 0.001) (Fig.  3 b, c) (Additional file 3). The expansion rate was significantly higher in the 10% stretch group than in the other groups, but did not significantly differ between the 0% stretch and control groups.

Macroscopic observation of tissue after expansion in the presence of ADSC-CM collected under mechanical force. a Macroscopic observation of expanded tissue. b Superimposed schematic diagram of expanded skin over 30 days. c Evaluation of the skin expansion rate. *** p  < 0.001

ADSC-CM collected under mechanical force improves vascularization of expanded skin

We performed immunofluorescence staining for CD31 to determine the blood vessel density of central regions. The number of blood vessels was significantly higher in the 10% stretch group than in the other groups at 3 and 7 days, but did not significantly differ among the groups at 14 days (69.50 ± 3.27, n  = 3, p  < 0.0001; 68.17 ± 4.12, n  = 3, p  < 0.0001; 38.17 ± 4.49, n  = 3, p  < 0.05; 37.50 ± 4.18, n  = 3, p  < 0.05) (Fig.  4 ).

Assessment of vascularization in skin after expansion in the presence of ADSC-CM collected under mechanical force. a Evaluation of angiogenesis by immunofluorescence staining for CD31 after 7 days of expansion in the central and side regions respectively. Scale bar, 100 μm. b Quantitative analysis of the capillary density of central regions. * p  < 0.05, ** p  < 0.01, *** p  < 0.001, **** p  < 0.0001

ADSC-CM collected under mechanical force increases expression of angiogenesis-associated proteins

To elucidate the mechanism by which ADSC-CM collected under 10% stretching force improves vascularization of expanded skin, we investigated expression of selected proteins in expanded skin by qPCR. Expression of VEGF, HGF, and bFGF was significantly higher in the 10% stretch group than in the other groups. (8.16 ± 1.40, n  = 3, p  < 0.0001; 3.28 ± 0.03, n  = 3, p  < 0.0001; 2.34 ± 0.20, n  = 3, p  < 0.01; 1.55 ± 0.22, n  = 3, p  > 0.05) (Fig.  5 ).

Gene expression in skin after expansion in the presence of ADSC-CM collected under mechanical force. Evaluation of expression of the angiogenesis-related genes VEGF, bFGF, HGF, and PDGF by qPCR after 7 days of expansion. * p  < 0.05, ** p  < 0.01, *** p  < 0.001, **** p  < 0.0001

ADSC-CM collected under mechanical force increases collagen deposition in expanded skin

To evaluate the amount of collagen in expanded skin, immunohistochemical and histological analyses were performed at each time point. On day 30, the levels of Col I and Col III were increased in the 10% stretch group, but did not significantly differ between the 0% stretch and control groups. (44.54 ± 0.51, n  = 3, p  < 0.0001; 33.33 ± 2.06, n  = 3, p  < 0.0001) (Fig.  6 ) Skin thickness did not significantly differ among the three groups. (2.18 ± 0.39, n  = 3, p  > 0.05) (Additional file 4).

Assessment of collagen deposition in skin after expansion in the presence of ADSC-CM collected under mechanical force. a Immunohistochemistry of Col I after 30 days of expansion. Scale bar, 100 μm. b Immunohistochemistry of Col III after 30 days of expansion. Scale bar, 100 μm. c Quantitative analysis of the levels of Col I and Col III. * p  < 0.05, ** p  < 0.01, *** p  < 0.001, **** p  < 0.0001

In this study, we confirmed that mechanical force can regulate the paracrine functions of ADSCs, determined the best mechanical condition to optimize the secretome of ADSCs in order to promote angiogenesis and collagen deposition, and applied ADSC-CM to an expanded area in order to promote skin regeneration (Fig.  7 ). Our results strongly advocate the application of ADSC-CM collected following mechanical pretreatment for skin expansion because it increases angiogenesis and the collagen content in newly formed skin, does not cause excessive thickening of skin flaps, and thus provides better conditions for expansion of ultra-thin large skin flaps to repair massive soft tissue defects.

An illustration of the possible mechanism by which mechanically preconditioned ADSC-CM assists skin expansion

Tissue expansion plays an important role in reconstruction of massive skin defects [ 26 ]. Application of a tissue expander to exert mechanical force regulates the behavior and function of cells, and thereby promotes tissue regeneration [ 27 ]. However, the expansion process takes a long time when simple mechanical stretching is used to stimulate cell proliferation and tissue regeneration. In addition, excessive pressure may cause tissue necrosis due to insufficient blood supply. Therefore, some studies have used MSCs [ 28 ] or acellular agents, such as cell-free fat extract, [ 29 ] to assist tissue regeneration. However, immune rejection of stem cells and quality control of cell-free liquids hinder their clinical application. Several studies have confirmed that mechanical stimulation is a simple and effective intervention that can control the functions of cells according to its magnitude [ 14 , 30 , 31 ]. Previous studies showed that the paracrine functions of ADSCs can be regulated by changing the mechanical environment to promote wound repair [ 32 ]. In the current study, we demonstrated that the paracrine functions of ADSCs can be regulated by adjusting the degree of mechanical force, the secretome can be altered to achieve the desired therapeutic effect, and a higher skin expansion rate can be achieved using ADSC-CM collected under the most suitable mechanical force. To explore the reasons for the increase in the skin expansion rate, we focused on the level of vascularization, which plays an indispensable role in skin regeneration.

Angiogenesis is key to tissue expansion. Tissue necrosis usually occurs when the speed of neovascularization is insufficient for tissue expansion [ 33 ]. Therefore, a strategy is needed to promote angiogenesis for tissue expansion. Conditioned medium of MSCs exposed to a suitable level of mechanical force has better angiogenic activity. Nasser et al. demonstrated that secretion of VEGF depends on the stiffness of the matrix and is maximal when MSCs are seeded on hydrogel matrices with a stiffness of 5.0 kPa [ 34 ]. Chen et al. found that activation of the Wnt/β-catenin signaling pathway in MSCs exposed to laminar shear stress increases secretion of proteins related to angiogenesis [ 35 ]. Previous studies showed that when a full-thickness skin defect is repaired using a hydrogel containing ADSCs and with a stiffness gradient, expression of VEGF in the wound area, vascularization, and wound healing increase [ 32 ]. In the current study, we confirmed that ADSC-CM collected following mechanical pretreatment promoted angiogenesis during tissue expansion, possibly due to increased expression of the angiogenesis-related proteins VEGF, bFGF, and HGF. Tissue regeneration requires a variety of biological processes in addition to angiogenesis; therefore, we also studied changes of extracellular matrix components during expansion.

Collagen is the main component of the extracellular matrix in skin; therefore, its secretion must increase during expansion of large skin flaps. Previous studies revealed that mechanically stimulated ADSCs promote collagen deposition in newly formed skin [ 32 ]. In the current study, we demonstrated that ADSC-CM collected following mechanical pretreatment promoted collagen expression in regenerated skin. According to histological analysis, the increase of collagen expression did not significantly increase the thickness of the expanded skin flap, which also satisfies the clinical need for construction of an ultra-thin skin flap. These effects may be due to increased expression of growth factors such as bFGF, which promotes proliferation of fibroblasts and regulates expression of collagen [ 36 ]. However, the specific proteins involved and their relationship with the optimal degree of mechanical force must be further confirmed experimentally.

The optimal degree of mechanical force to promote the paracrine functions of ADSCs was determined in this study, and the therapeutic effect of ADSC-CM collected under stretching force was preliminarily confirmed by in vivo experiments. Compared to the method of using a tissue expander alone to promote tissue regeneration, incorporating ADSC-CM enhances blood vessel and collagen production during pre-expansion. This reduces the risk of ischemic necrosis and is more advantageous for pre-expanding super-large skin flaps to repair extensive soft tissue defects and refractory wounds. Currently in clinical practice, we mainly rely on the expansive force of expanders to facilitate skin regeneration and achieve large skin flaps. Based on our research findings, while cell-free therapy cannot completely replace current treatments, its auxiliary application can significantly enhance skin expansion efficacy, decrease necrosis rates, and improve overall treatment outcomes. Meanwhile, in contrast with simple stem cell therapy, application of ADSC-CM obtained following mechanical pretreatment avoids safety problems. ADSC-CM does not require immune compatibility to avoid rejection or strictly controlled sterile conditions for its administration, unlike cell-based treatments. Additionally, it minimizes the potential for tumor formation and embolism development associated with stem cell injections [ 37 ]. In addition, the quantifiable nature of mechanical force ensures the uniformity and consistency of product content and treatment outcomes. Finally, the study also inspires us to explore the relationship between the optimal degree of mechanical force and intracapsular pressure in the expander in order to reduce the incidence of complications during skin expansion and guide the clinical application of tissue expanders. In the future, ADSC-CM can be combined with rapidly developing green nanomaterials to achieve new breakthroughs in plastic surgery. For example, the combination of mechanically treated CM with biodegradable nano-scaffolds offers great potential. nano-scaffolds provide a biocompatible framework for supporting cell adhesion, proliferation and differentiation, while ADSC-CM promotes the production of blood vessels and collagen. This combined method is very effective for repairing massive tissue defects and complex wounds, and represents one of the important future directions of ADSC-CM application.

There are also some issues to be resolved in the mechanical pretreatment of ADSCs to promote their paracrine functions and thereby skin expansion. It is unclear which components of ADSC-CM play a key role; therefore, it is necessary to further analyze these components and explore the underlying molecular mechanism. In addition, expression of growth factors differs according to the degree of mechanical force applied, and the effects on other aspects of tissue regeneration must be studied.

In conclusion, application of mechanical force to ADSCs increases angiogenesis and collagen secretion by regulating their paracrine functions and thereby promotes skin regeneration and assists skin expansion. This study provides a new strategy to optimize cell-free therapy in the field of tissue regeneration.

Data availability

The data used to support the findings of this study are included within the article.

Abbreviations

Conditioned Medium of Adipose-Derived Stem Cells

Adipose-Derived Stem Cells

Mesenchymal Stem Cells

Phosphate-Buffered Saline

Dulbecco’s Modified Eagle’s Medium: Nutrient Mixture F-12

Dulbecco’s modified Eagle’s Medium

Fetal Bovine Serum

Carbon dioxide

Normal Control

Hematoxylin and Eosin

4,6-Diamidino-2-Phenylindole

Complementary DNA

Polymerase Chain Reaction

quantitative Real-Time Polymerase Chain Reaction

Sprague-Dawley

Vascular Endothelial Growth Factor

basic Fibroblast Growth Factor

Hepatocyte Growth Factor

Platelet-Derived Growth Factor

Collagen type 1

Collagen type 3

Wingless/Integrated

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This study was supported by College Students’ Innovative Entrepreneurial Training Plan Program (202312121015, S202312121094, 202312121227, 202312121313, 202312121314, 202312121317, 202312121321), National Nature Science Foundation of China (82202474, 82360615), Clinical Program of Nanfang Hospital, Southern Medical University (2022CR007), First People’s Hospital of Yunnan Province (KHYJ-2023-5-02, 2023-KHRCBZ-B14), Guangdong Basic and Applied Basic Research Foundation (2021A1515110440) and Science and Technology Projects in Guangzhou (2024A04J5192, 2023A04J2350, 2023A04J2349, 2023A04J2347, 2023A04J2271).

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Ye Li and Yunjun Liao contributed equally to this work.

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Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, P. R. China

Zhixin Xue, Delin Hu, Haojing Tang, Mingheng Xue, Yufan Zhu, Ye Li & Yunjun Liao

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ZX carried out the experiments, data analyses and manuscript writing. DH, YZ, participated in the in vitro experiments. MX, HT, participated in the in vivo experiments. YL and YL designed the study and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Ye Li or Yunjun Liao .

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Xue, Z., Hu, D., Tang, H. et al. Mechanical force regulates the paracrine functions of ADSCs to assist skin expansion in rats. Stem Cell Res Ther 15 , 250 (2024). https://doi.org/10.1186/s13287-024-03822-0

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'I feel dismissed': People experiencing colorism say health system fails them

by Chaseedaw Giles, KFF Health News

Jonnae Thompson has felt for a long time that her dark brown skin and natural hair have made finding work in Hollywood especially hard.

"It's like this negative connotation," said the 37-year-old actress, singer, and stand-up comedian, who said she is often asked to audition for villainous roles such as a bully, drug dealer, or pimp.

Her quest for more equitable representation on the big screen isn't just professionally exhausting. Thompson says anxiety about her skin complexion has affected her health.

"It definitely had a negative impact on my self-esteem ," she said. She recalls being called "charcoal" in kindergarten. "It was big, like, your skin is dark and that's a problem."

The term colorism—a form of prejudice and discrimination in which lighter skin is favored over darker skin—was popularized by author Alice Walker in her 1983 book "In Search of Our Mothers' Gardens: Womanist Prose."

Clinicians from various ethnic groups have recently begun to draw a direct line between colorism and poor health. A 2023 KFF survey found that, among Black and Hispanic adults, those with self-described darker skin tones reported more experiences with discrimination in daily life compared with those who have lighter skin tones.

People who feel they experience daily discrimination can be at higher risk for depression, loneliness, increased alcohol and drug use, and anxiety, data shows.

And colorism can also lead to physical health concerns. Hair straighteners and skin lighteners commonly used by women of color, sometimes to conform to racialized beauty standards, increase their exposure to toxic chemicals, research shows.

Because of the potential health implications, the health care system should pay more attention to colorism, said Regina James, a child and adolescent psychiatrist who heads the American Psychiatric Association's Division of Diversity and Health Equity.

"Skin color discrimination is so insidious it can literally get under your skin," she said. "And consciously or subconsciously, it can contribute to low self-esteem and self-confidence, and even be detrimental to one's mental health ."

Conversations about skin complexion can remain overlooked by mental health professionals who do not have expertise about or awareness of a person's cultural context , if the conversations happen at all, said Usha Tummala-Narra, a clinical psychologist and professor in the Department of Counseling, Developmental, and Educational Psychology at Boston College.

"There's no specific training on colorism. Many people are unaware that it exists," Tummala-Narra said.

But the experience can negatively affect a person's self-worth, relationships, sense of belonging, and dignity. "These are all really critically important things as human beings that we all need to secure to have good health, both physically and mentally," she said.

The issue can emerge in childhood for Black and Indigenous people and other people of color, who must navigate fair skin often being seen as superior, a ramification of colonialization. Black children with the darkest complexions experience higher levels of depressive symptoms, found a 2020 study in the journal Society and Mental Health.

Shannon Brown, 34, a former college counselor from the Bronx, New York, who is Black, remembers being called "midnight" by classmates and having family members joke about his skin being difficult to light in family photos. "I've just kind of accepted it and try to find the humor in it," he said. "I feel like most folks aren't intentionally trying to hurt me, but the jokes get tiresome."

Shakun Kaushal, a 26-year-old digital communications specialist at the Johns Hopkins Center for Gun Violence Solutions, is Indian American and has a "darker complexion." She said that in Indian culture one might hear comments like, "Oh, she's so light and beautiful."

"I sometimes feel dismissed by people," said Kaushal, who has searched for an Indian or Black therapist in hopes they might better relate to her lived experience. She believes conversations about colorism should be intergenerational, start early, and get introduced with great care.

"What you say to a child does affect them. They will remember, and it will impact how they feel about themselves and in their skin," Kaushal said. "We must talk about it."

The feeling of shame and embarrassment colorism produces in people is palpable and needs to be acknowledged in health care settings, said Roopal Kundu, a dermatologist who founded and directs the Northwestern Medicine Center for Ethnic Skin and Hair in Chicago.

Kundu, who is of South Asian heritage, opened the center in 2005 and notes that some cases of diseases like psoriasis, skin cancer, and eczema get diagnosed later, or misdiagnosed, because they present differently on diverse skin tones.

"How can we really make sure, as a field, that we're taking care of everybody?" she said. "Healthy skin is beautiful skin. And beauty is across every single skin tone that there is."

Therapists, doctors, and other clinicians from diverse backgrounds say that, in addition to clinical approaches that incorporate cultural competence, more efforts are needed to diversify the pool of mental health practitioners and to collaborate between disciplines.

Without cultural awareness and sensitivity, "you're not going to get all the information that you need to appropriately diagnose and treat someone," James said.

Black people are more likely to report difficulty finding mental health providers who understand their background and experiences, a KFF survey found. At the same time, programs that bolster diversity, equity, and inclusion in medical schools are faltering in the wake of the 2023 Supreme Court decision outlawing affirmative action in higher education.

According to the Association of American Medical Colleges, in 2022, about 5% of active psychiatric physicians identified as Black, 16% as Asian, 6% as Hispanic, and fewer than 1% as American Indian or Alaska Native.

Thompson, Brown, and Kaushal all said they had never been treated by a therapist who looks like them.

Thompson, the L.A. comedian, said she drank bleach when she was 10 years old, thinking it would lighten her skin. Fortunately, it caused only nausea.

If she could speak to her younger self, she would say, "You're beautiful. You're brilliant."

2024 KFF Health News. Distributed by Tribune Content Agency, LLC.

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Adversarial training based domain adaptation of skin cancer images.

1. Introduction

2. related work.

• We present a deep learning-based methodology for unsupervised domain adaptation designed to tackle the drift and bias issues prevalent in skin lesion datasets.
• We compared the performance of AlexNet, VGG-11, and VGG-13 as feature extractors within two state-of-the-art domain adaptation frameworks, finding that VGG-13-based features yielded the best classification results.
• We compared the performance of our model with VGG-11, VGG-13, and AlexNet.

3. Overview of the Proposed Method

4. methadology, 5. experiments and results, 5.1. image generation, 5.2. dann architectures used in this study, 5.3. dataset, 5.3.1. source domain dataset, 5.3.2. target domain dataset, 5.4. experimental settings, 5.5. evaluation metrics, 5.6. results, 5.7. discussion, 6. conclusions, author contributions, data availability statement, conflicts of interest.

• Available online: https://tinyurl.com/ptp97uzv (accessed on 12 March 2024).
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Gilani, S.Q.; Umair, M.; Naqvi, M.; Marques, O.; Kim, H.-C. Adversarial Training Based Domain Adaptation of Skin Cancer Images. Life 2024 , 14 , 1009. https://doi.org/10.3390/life14081009

Gilani SQ, Umair M, Naqvi M, Marques O, Kim H-C. Adversarial Training Based Domain Adaptation of Skin Cancer Images. Life . 2024; 14(8):1009. https://doi.org/10.3390/life14081009

Gilani, Syed Qasim, Muhammad Umair, Maryam Naqvi, Oge Marques, and Hee-Cheol Kim. 2024. "Adversarial Training Based Domain Adaptation of Skin Cancer Images" Life 14, no. 8: 1009. https://doi.org/10.3390/life14081009

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What is Glomerulonephritis?

Table of contents, are there different types of glomerulonephritis, what causes acute glomerulonephritis, what causes chronic glomerulonephritis, how is a diagnosis of glomerulonephritis made, can glomerulonephritis be prevented, what treatment is available for glomerulonephritis, what is nephrotic syndrome, what treatment is available for nephrotic syndrome.

Glomerulonephritis is a group of diseases that injure the part of the kidney that filters blood (called glomeruli). Other terms you may hear used are nephritis and nephrotic syndrome. When the kidney is injured, it cannot get rid of wastes and extra fluid in the body. If the illness continues, the kidneys may stop working completely, resulting in kidney failure.

Yes. There are two types of glomerulonephritis—acute and chronic. The acute form develops suddenly. You may get it after an infection in your throat or on your skin. Sometimes, you may get better on your own. Other times, your kidneys may stop working unless the right treatment is started quickly. The early symptoms of the acute disease are:

• puffiness of your face in the morning
• blood in your urine (or brown urine)
• urinating less than usual.

You may be short of breath and cough because of extra fluid in your lungs. You may also have high blood pressure. If you have one or all of these symptoms, be sure to see your doctor right away.

The chronic form may develop silently (without symptoms) over several years. It often leads to complete kidney failure. Early signs and symptoms of the chronic form may include:

• Blood or protein in the urine (hematuria, proteinuria)
• High blood pressure
• Swelling of your ankles or face (edema)
• Frequent nighttime urination
• Very bubbly or foamy urine

Symptoms of kidney failure include:

• Lack of appetite
• Nausea and vomiting
• Difficulty sleeping
• Dry and itchy skin
• Nighttime muscle cramps

The acute disease may be caused by infections such as strep throat. It may also be caused by other illnesses, including lupus, Goodpasture's syndrome, Wegener's disease, and polyarteritis nodosa. Early diagnosis and prompt treatment are important to prevent kidney failure.

Sometimes, the disease runs in the family. This kind often shows up in young men who may also have hearing loss and vision loss. Some forms are caused by changes in the immune system. However, in many cases, the cause is not known. Sometimes, you will have one acute attack of the disease and develop the chronic form years later.

The first clues are the signs and symptoms. Finding protein and blood cells in your urine is another sign. Blood tests will help the doctor tell what type of illness you have and how much it has hurt your kidneys.

In some cases, a test called a kidney biopsy may be needed. In this test, a tiny piece of your kidney is removed with a special needle, and looked at under a microscope. A biopsy will help the doctor plan the best treatment for you.

Not until more is known about its causes. However, good hygiene, practicing “safe sex” and avoiding IV drugs are helpful in preventing viral infections such as HIV and hepatitis, which could lead to this illness.

If you have the chronic type of glomerulonephritis, it is very important to control your blood pressure since this may slow down kidney damage. Your doctor may tell you to eat less protein. A dietitian trained to work with kidney patients (a renal dietitian) can be very helpful in planning your diet.

The acute form may go away by itself. Sometimes you may need medication or even temporary treatment with an artificial kidney machine to remove extra fluid and control high blood pressure and kidney failure. Antibiotics are not used for acute glomerulonephritis, but they are important in treating other forms of disease related to bacterial infection. If your illness is getting worse rapidly, you may be put on high doses of medicine that affect your immune system. Sometimes, your doctor may order plasmapheresis, a special blood filtering process to remove harmful proteins from your blood.

There is no specific treatment for the chronic form of the illness. You doctor may tell you to:

• Eat less protein, salt and potassium
• Control your blood pressure
• Take diuretics (water pills) to treat puffiness and swelling
• Take calcium supplements

Nephrotic syndrome (also called nephrosis) happens when your kidneys start losing large amounts of protein in your urine. As your kidneys get worse, extra fluids and salt build up in your body. This causes you to have swelling (edema), high blood pressure and higher levels of cholesterol. Nephrotic syndrome may come from kidney diseases or from other illnesses such as diabetes and lupus. Some medicines, IV drug abuse and HIV (the AIDS virus) may also cause it.  Sometimes, nephrotic syndrome goes away after treatment. Other times, this condition may last for many years and eventually lead to kidney failure.

Your doctor may prescribe corticosteroids, such as prednisone. If prednisone does not work, your doctor may suggest other medicines that affect your immune system, such as cyclophosphamide.

Your doctor may also suggest:

• A low salt diet
• Diuretics (water pills)
• Blood pressure medications.

If you would like more information, please contact us .

© 2015 National Kidney Foundation. All rights reserved. This material does not constitute medical advice. It is intended for informational purposes only. Please consult a physician for specific treatment recommendations.

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PolyU researchers invent intelligent soft robotic clothing for automatic thermal adaptation in extreme heat

14 Aug 2024

A team led by Dr Dahua Shou, Limin Endowed Young Scholar in Advanced Textiles Technologies and Associate Professor of the School of Fashion and Textiles of PolyU has developed first-of-its-kind soft robotic clothing that can automatically adapt to changing ambient temperatures, thereby ensuring working safety in hot environments.

As global warming intensifies, people increasingly suffer from extreme heat. For those working in a high-temperature environment indoors or outdoors, keeping thermally comfortable becomes particularly crucial. A team led by   Dr Dahua SHOU, Limin Endowed Young Scholar in Advanced Textiles Technologies and Associate Professor of the School of Fashion and Textiles of The Hong Kong Polytechnic University (PolyU)  has developed first-of-its-kind thermally-insulated and breathable soft robotic clothing that can automatically adapt to changing ambient temperatures, thereby helping to ensure worker safety in hot environments. Their research findings have been published in the international interdisciplinary journal  Advanced Science .

Maintaining a constant body temperature is one of the most critical requirements for living and working. High-temperature environments elevate energy consumption, leading to increased heat stress, thus exacerbating chronic conditions such as cardiovascular disease, diabetes, mental health issues and asthma, while also increasing the risk of infectious disease transmission. According to the World Health Organisation, globally, there were approximately 489,000 heat-related deaths annually between 2000 and 2019, with 45% occurring in Asia and 36% in Europe.

Thermal protective clothing is essential to safeguard individuals in extreme high-temperature environments, such as firefighters who need to be present at fires scenes and construction workers who work outdoors for extended periods. However, traditional gear has been limited by statically fixed thermal resistance, which can lead to overheating and discomfort in moderate conditions, while its heat insulation may not offer sufficient protection in extreme fire events and other high-temperature environments. To address this issue, Dr Shou and his team have developed intelligent soft robotic clothing for automatic temperature adaptation and thermal insulation in hot environments, offering superior personal protection and thermal comfort across a range of temperatures.

Their research was inspired by biomimicry in nature, like the adaptive thermal regulation mechanism in pigeons, which is mainly based on structural changes. Pigeons use their feathers to trap a layer of air surrounding their skin to reduce heat loss to the environment. When the temperature drops, they fluff up their feathers to trap a significant amount of still air, thereby increasing thermal resistance and retaining warmth.

The protective clothing developed by the team uses soft robotic textile for dynamic adaptive thermal management. Soft actuators, designed like a human network-patterned exoskeleton and encapsulating a non-toxic, non-flammable, low-boiling-point fluid, were strategically embedded within the clothing. This thermo-stimulated system turns the fluid from a liquid into a gas when the ambient temperature rises, causing expansion of soft actuators and thickening the textile matrix, thereby enhancing the gap of still air and doubling the thermal resistance from 0.23 to 0.48 Km²/W. The protective clothing can also keep the inner surface temperatures at least 10°C cooler than conventional heat-resistant clothing, even when the outer surface reaches 120°C.

This unique soft robotic textile, made by thermoplastic polyurethane, is soft, resilient and durable. Notably, it is far more skin-friendly and conformable than temperature-responsive clothing embedded with shape-memory alloys and is adjustable for a wide range of protective clothing. The soft actuators have exhibited no signs of leakage after undergoing rigorous standard washing tests. The porous, spaced knitting structure of the material can also significantly reduce convective heat transfer while maintaining high moisture breathability. Not relying on thermoelectric chips or circulatory liquid cooling systems for cooling or heat conduction, the light-weighted, soft robotic clothing can effectively regulate temperature itself without any energy consumption.

Dr Shou said, “Wearing heavy firefighting gear can feel extremely stifling. When firefighters exit a fire scene and remove their gear, they are sometimes drained nearly a pound of sweat from their boots. This has motivated me to develop a novel suit capable of adapting to various environmental temperatures while maintaining excellent breathability. Our soft robotic clothing can seamlessly adapt to different seasons and climates, multiple working and living conditions, and transitions between indoor and outdoor environments to help users experience constant thermal comfort under intense heat.”

Looking forward, Dr Shou finds the innovation to have a wide range of potential applications, from activewear, winter jackets, healthcare apparel and outdoor gear, to sustainable textile-based insulation for construction and buildings, contributing to energy-saving efforts. Supported by the Innovation and Technology Commission and the Hong Kong Research Institute of Textiles and Apparel, Dr Shou and his team have also extended the thermo-adaptive concept to develop inflatable, breathable jackets and warm clothing. This soft robotic clothing is suitable for low-temperature environments or sudden temperature drops to aid those who are stranded in the wilderness to maintain normal body temperature.

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Jamison DT, Breman JG, Measham AR, et al., editors. Disease Control Priorities in Developing Countries. 2nd edition. Washington (DC): The International Bank for Reconstruction and Development / The World Bank; 2006. Co-published by Oxford University Press, New York.

Disease Control Priorities in Developing Countries. 2nd edition.

Chapter 37 skin diseases.

Roderick Hay , Sandra E. Bendeck , Suephy Chen , Roberto Estrada , Anne Haddix , Tonya McLeod , and Antone Mahé .

In assigning health priorities, skin diseases are sometimes thought of, in planning terms, as small-time players in the global league of illness compared with diseases that cause significant mortality, such as HIV/AIDS, community-acquired pneumonias, and tuberculosis. However, skin problems are generally among the most common diseases seen in primary care settings in tropical areas, and in some regions where transmissible diseases such as tinea imbricata or onchocerciasis are endemic, they become the dominant presentation. For instance, the World Health Organization's 2001 report ( Mathers 2006 ) on the global burden of disease indicated that skin diseases were associated with mortality rates of 20,000 in Sub-Saharan Africa in 2001. This burden was comparable to mortality rates attributed to meningitis, hepatitis B, obstructed labor, and rheumatic heart disease in the same region. Using a comparative assessment of disability-adjusted life years (DALYs) from the same report, the World Health Organization recorded an estimated total of 896,000 DALYs for the region in the same year, similar to that attributed to gout, endocrine disease, panic disorders, and war-related injuries. As noted later, those figures require confirmation by more detailed studies, and their practical application to health interventions needs to be tested.

Assessing the impact of skin disease on the quality of life in comparison with that of chronic nondermatological diseases is difficult; however, the study by Mallon and others (1999) , which was not carried out in a developing country, compares the common skin disease acne with chronic disorders such as asthma, diabetes, and arthritis and finds comparable deficits in objective measurements of life quality. Skin disease related to HIV, which may constitute an important component of the skin disease burden in developing countries, particularly in Sub-Saharan Africa, leads to a similar impact on life quality compared with non-HIV-related skin problems, although the use of antiretroviral therapy significantly improves quality of life ( Mirmirani and others 2002 ). Those findings indicate that skin diseases have a significant impact on quality of life.

Although mortality rates are generally lower than for other conditions, people's needs for effective remedies for skin conditions should be met for a number of important reasons.

• First, skin diseases are so common and patients present in such large numbers in primary care settings that ignoring them is not a viable option. Children, in particular, tend to be affected, adding to the burden of disease among an already vulnerable group.
• Second, morbidity is significant through disfigurement, disability, or symptoms such as intractable itch, as is the reduction in quality of life. For instance, the morbidity from secondary cellulitis in lymphatic filariasis, which may lead to progressive limb enlargement, is severe, and subsequent immobility contributes to social isolation.
• Third, the relative economic cost to families of treating even trivial skin complaints limits the uptake of therapies. Generally, families must meet such costs from an overstretched household budget, and such expenses in turn reduce the capacity to purchase such items as essential foods ( Hay and others 1994 ).
• Fourth, screening the skin for signs of disease is an important strategy for a wide range of illnesses, such as leprosy, yet a basic knowledge of the simple features of disease whose presenting signs occur in the skin is often lacking at the primary care level.

A shortage of elementary skills in the management of skin diseases is a further confounding problem. A number of studies assessing success in the management of skin diseases in primary care settings in the developing world find that treatment failure rates of more than 80 percent are common ( Figueroa and others 1998 ; Hiletework 1998 ). An additional point, often overlooked, is that skin diseases in the developing world are often transmissible and contagious but are readily treatable ( Mahé, Thiam N'Diaye, and Bobin 1997 ).

A number of common diseases account for the vast majority of the skin disease burden; therefore implementing effective treatments targeted at those conditions results in significant gains for both personal and public health. Even where eradication is impossible, control measures may be important in reducing the burden of illness; yet few systematic attempts have been made to validate control programs for skin diseases as public health interventions.

• Prevalence of Skin Diseases

Few studies aimed at estimating the prevalence of skin diseases have been carried out in Western societies. However, Rea, Newhouse, and Halil's (1976) study in Lambeth, south London, which used a questionnaire-based, population-centered approach backed by random examination, reveals an overall 52 percent prevalence of skin disease, of which the investigators judged that just over half the cases required treatment. Studies from developing countries have generally adopted a more inclusive approach that uses systematic, community-based surveys backed by examination. Published figures for the prevalence of skin diseases in developing countries range from 20 to 80 percent.

In a study in western Ethiopia, between 47 and 53 percent of the members of two rural communities claimed to have a skin disease ( Figueroa and others 1998 ), but when they were examined, 67 percent of those who denied having skin problems were found to have treatable skin conditions, most of which were infections. However, prevalence alone does not equate with disease burden. For instance, most communities recognize scabies as a problem because of its intractable itching and secondary infection, whereas they may ignore tinea capitis, which is equally common among the same populations, because they are aware that it follows a benign and asymptomatic course in many patients.

Researchers agree about the main risk factors associated with skin disease in developing countries, the most important of which appears to be household overcrowding. In primary schools in western Ethiopia, more than 80 percent of randomly examined schoolchildren had at least one skin disease, which was usually caused by one of four conditions: scabies, pediculosis capitis, tinea capitis, or pyoderma ( Figueroa and others 1996 ). Those figures mirror work carried out elsewhere. For instance, in Tanzania, in a survey of two village communities, Gibbs (1996) found that 27 percent of patients had a treatable skin disease, and once again, infections were the most common diseases. Overcrowding was a major risk factor in that survey. A similar community-based survey in Sumatra, Indonesia, showed a 28 percent prevalence of skin disease ( Saw and others 2001 ). What seems to influence the overall prevalence and pattern of skin conditions in certain areas is the existence of a number of common contagious diseases, notably, scabies and tinea capitis. Hot and humid climatic conditions may also predispose populations to pyoderma, thereby affecting the distribution of disease.

• Patterns of Skin Diseases at the Community Level

A recent (unpublished) survey by the International Foundation of Dermatology designed to provide information about community patterns of skin disease in nine different countries across the world—Australia (Northwest Territory), Ethiopia, Indonesia, Mali, Mexico, Mozambique, Senegal, Tanzania, and Thailand)—and poor regions in other tropical environments from Mexico to Madagascar indicates that the following were the main skin conditions at community level:

• Scabies. Although scabies was often the commonest skin disease, it was completely absent in some regions.
• Superficial mycoses. This group of infections was usually reported as one of the three commonest diseases.
• Pyoderma. This disease was often, but not invariably, associated with scabies.
• Pediculosis. This disease was the subject of much variation but is often overlooked in surveys. Firm, community-level data on the prevalence of pediculosis are deficient; thus, this disease is not discussed further in this chapter.
• Eczema or dermatitis. Although this disease was usually unclassified, irritant dermatitis and chronic lichen simplex were often cited.
• HIV-related skin disease. This disease was reported mainly in Africa. The pruritic papular dermatitis of AIDS is a specific problem.
• Pigmentary anomalies. Three different problems were cited: hypopigmentation, often diagnosed as pityriasis alba, a form of eczema; melasma; and dermatitis caused by cosmetic bleaching agents ( Mahé and others 2003 ).
• Acne. This disease was reported as an emerging and common problem.

These diseases are the same as those recorded in the literature described previously. Other skin conditions cited by different members of the group surveyed follow:

• Tropical ulcer. The incidence was highly variable, but tropical ulcer can account for a huge workload in primary care centers in endemic areas.
• Nonfilarial lymphoedema. This condition was mainly confined to Ethiopia.
• Onchodermatitis, filarial lymphoedema, endemic treponematoses, Buruli ulcers, and leprosy. These conditions are discussed in detail elsewhere in this book, but note that they often present with skin changes and symptoms.

According to World Bank (2002) figures for low-income populations in 2000, the estimated numbers of individuals infected with pyoderma and scabies, based on the highest prevalence figures from community surveys in the developing world, are 400 million and 600 million, respectively. Based on the lowest prevalence figures, these estimated numbers are 40 million and 50 million, respectively. For tinea capitis, the estimated number of cases based on the highest estimates of prevalence for Sub-Saharan Africa alone is 78 million.

Overall, these data suggest that significant changes could be made in reducing the burden of skin diseases by focusing on the small group of conditions, particularly infections, that account for the bulk of the community case load. This chapter concentrates on those conditions for which such a strategy could be implemented—namely, scabies, pyoderma, fungal infections, tropical ulcers, HIV/AIDS-related dermatoses, and pigmentary disorders.

• Effective Therapies

In considering the evidence for effective treatment, a subgroup of the team (Bendeck, Chen, and McLeod) undertook a data search to establish the evidence base for treatment of the common conditions. They carried out comprehensive searches of the MEDLINE (1966–April 2003) and EMBASE (1980–April 2003) databases to identify therapeutic studies on scabies, pyodermas, and superficial mycoses (but note that many of the studies were performed in industrial countries). They used foreign-language articles if an English abstract was provided. Table 37.1 shows search terms for each of the skin diseases common in the developing world and for treatment.

Search Strategy for Therapies.

The team members reviewed study titles and abstracts to select relevant articles and scrutinized the bibliographies of selected articles to identify pertinent studies not captured in the initial literature search. They defined admissible evidence as primary therapeutic studies, based on clinical evaluation, of the treatment of each disease.

• Skin Diseases

Scabies is a common ectoparasitic infestation caused by Sarcoptes scabei, a human-specific mite that is highly prevalent in some areas of the developing world. Scabies is transmitted by direct contact. In industrial societies, it is usually seen in sexually active adults, although it may also appear in the form of clusters of cases among the elderly in residential homes. Peaks of infection in communities may be cyclical. The ease of transmission appears to depend, in part, on the parasitic load, and some patients, including the elderly, may have large numbers of parasites present. By contrast, in healthy adults, the total parasite load may be low, but they, nonetheless, may suffer from highly itchy lesions. The organisms can also reach high densities in patients suffering from a severe depression of immunological responses, as in HIV infection. In this crusted or Norwegian form of scabies, lesions may present with atypical crusted lesions that itch little.

In developing countries, transmission commonly occurs in young children and infants and their mothers and is related to close contact, overcrowding, and shared sleeping areas. Sexual contact is less important as a means of transmission. Scabies is also a scourge of prisons in developing countries, where it is associated with overcrowding ( Leppard and Naburi 2000 ). No evidence exists that transfer is related to inadequate hygiene.

The most important complication of scabies is secondary bacterial infection, usually caused by Group A streptococci. Evidence from studies among the indigenous population of northern Australia indicates that this infection is not always benign and that persistent proteinuria is associated with past scabies infestation, suggesting that nephritis related to secondary infection of scabies may cause long-lasting renal damage ( White, Hoy, and McCredie 2001 ).

The disease presents with itchy papules and sinuous linear tracks in the skin that can be highly pruritic and particularly troublesome at night. Often more than one member of a household has the disease.

The treatments used for scabies are mainly applied topically. Treatment is not based on treating just affected individuals, both because of the ease with which scabies spreads and because symptoms may develop days or weeks after infection. The advice given to patients always includes a recommendation to treat the entire household with a similar medication, a difficult problem when many people live in the same dwelling. The treatments commonly available include the following:

• Sulfur ointments. There are no controlled clinical studies of the use of this cheap medication, which is usually made up in an ointment base. Soap containing sulfur is available in some areas. Anecdotally, sulfur ointment needs to be applied for at least one week to the entire body. Irritation is a common side effect, and lower concentrations, such as 2.5 percent, are applied to infants.
• Benzyl benzoate. A 10 to 25 percent benzyl benzoate emulsion is applied over the entire body and left on the skin for up to 24 hours before washing off. Current recommendations suggest that one to three applications may be sufficient, but consensus on the optimal treatment regimen would be useful. Benzyl benzoate emulsion is an irritant and can lead to secondary eczema in some patients.
• Gamma benzene hexachloride (Lindane). This product is widely available and is used as a single application washed off after 12 to 24 hours. Concerns have arisen about the increasing risk of drug resistance and the absorption of the drug through the skin. It is also not used in children because of reports of neurotoxicity and fits. This product is not available in many countries.
• Malathion (0.5 percent) in an aqueous base. The highly purified commercial forms are effective after a single application, although a second is advised. No data are available on the use of this preparation in developing countries.
• Crotamiton cream or monosulfiram 25 percent. These alternative therapies have highly variable efficacy rates.
• Permethrin 5 percent cream. This effective, nonirritant treatment is usually administered as a cream applied all over the body. A single application washed off after 8 to 12 hours is used. The tubes are small, and adequate quantities should be prescribed. This treatment is also the most costly of the topical therapies.

Treatment failures in developing countries may be related to the lack of a suitable place in many communities where patients can apply treatment effectively over the entire body from the neck down in privacy.

Oral ivermectin, which is an important drug in the treatment of onchocerciasis, has also been used in patients with scabies, particularly those with the crusted form or in places such as prisons, where large numbers of infected individuals live in close proximity. It has also been applied as a community-based treatment and is reported to be effective as such ( Hegazy and others 1999 ). It is not licensed for the treatment of scabies, and the lack of safety data on the use of ivermectin in infants limits its use. In addition, insufficient evaluations of its efficacy and cost-effectiveness in developing countries have been carried out.

Evidence for Effective Therapies

The team identified 56 articles on therapies for scabies and found the following to be the viable ones: oral and topical ivermectin, permethrin, gamma benzene hexachloride, benzyl benzoate, crotamiton, malathion, and topical sulfur. Table 37.2 summarizes the evidence for ivermectin versus a placebo or permethrin and for topical ivermectin, as well as for the less expensive topical sulfur.

Evidence of the Efficacy of Treatments for Scabies.

Community-based Treatments for Scabies

Few studies have addressed the problem of community-administered treatments for scabies, despite the argument that without a community approach to therapy in many developing countries, the successful management of scabies in areas where it affects more than 5 to 6 percent of the population is doomed to failure. Taplin and others' (1991) study of the use of 5 percent permethrin cream in the San Blas Islands, Panama, confirms this view. A three-year program of treatments backed by surveillance reduced the prevalence of scabies from 33 percent to less than 1 percent; however, a three-week break in regular treatment was followed by a rapid increase in prevalence to 3 percent. The results of treatments involving the application of similar protocols, but using other topical agents, are not available. Oral ivermectin lends itself to a community-based treatment approach and has been used in this way ( Hegazy and others 1999 ; Usha and Gopalakrishnan Nair 2000 ), but insufficient follow-up data are currently available to comment further on this approach.

Bacterial Skin Infections or Pyoderma

Bacterial skin infections or pyoderma are common in most developing countries ( Mahé, Thiam N'Diaye, and Bobin 1997 ). Generally these infections arise as primary infections of the skin known as impetigo or as secondary infections of other lesions such as scabies or insect bites. The usual bacterial causes are Group A streptococci or Staphylococcus aureus . Bacterial infections are common in communities. In many cases, no bacteriological confirmation is available from cultures, but surveys show that Group A streptococci account for a substantial number of cases ( Carapetis, Currie, and Kaplan 1999 ; Taplin and others 1973 ), which is not often the case in similar infections in temperate climates, where S. aureus dominates. This finding carries implications for the selection of treatment options. The reasons for this finding are not clear, although humidity and heat are associated with increased risk of bacterial skin infection. In addition to these superficial infections, S. aureus also causes folliculitis, or hair follicle infections and abscesses. Rarer causes of skin infection in developing countries include cutaneous diphtheria and anthrax, as well as necrotizing infection caused by Vibrio vulnificus.

Bacterial infection causes irritation and some discomfort. In some cases, the infection penetrates deep down through the epidermis, causing a necrotic ulcer—a condition known as ecthyma. However, some evidence suggests that streptococcal infection may cause additional long-term damage through the development of prolonged proteinuria, as described earlier in relation to scabies.

Treatment with topical antibacterials, such as fusidic acid or mupirocin, is expensive; thus, the use of cheaper agents, such as antiseptics, is an important option but one that has been evaluated in only a few instances. Chlorhexidine and povidone iodine have both been used, but potassium permanganate is also said to be clinically effective. Gentian violet at concentrations of 0.5 to 1.0 percent is a cheap agent that is widely used, with proven in vitro efficacy against agents commonly involved in pyoderma. Most of those compounds have been used to prevent rather than to treat infections. The most extensively evaluated topical preparations are fusidic acid ointment and mupirocin, which are given daily for up to 10 days. Those drugs are effective in eradicating bacterial infections but, as noted, are not cheap options. Group A streptococci are still sensitive to penicillin, which can be used for treatment, with alternatives for staphylococcal infections being cloxacillin, flucloxacillin, and erythromycin. Industrial countries largely view methicillin resistance among staphylococci as a nosocomial problem, yet it has now spread to the community, and skin infections provide an ideal medium for the spread of resistance, even in developing countries. S. aureus strains isolated from skin sites, even in remote tropical areas, are now resistant to beta-lactam penicillins and tetracyclines through the spread of resistance genes. Tetracycline ointment is still available in many rural pharmacies and is widely used to treat superficial skin lesions, even though some bacterial infections will be unresponsive. Topical neomycin and bacitracin are widely available, are associated with identifiable levels of treatment failure, and also carry a risk of sensitization or adverse effects.

Evidence for Effective Treatment

The team reviewed 727 studies of therapies for pyoderma or bacterial skin infections. These studies could be grouped into either prophylactic regimens or therapeutic trials. For the prevention of pyoderma, the studies surveyed included the following effective therapies: chlorhexidine solution, hexachlorophene scrubbing, and neomycin/polymyxin B-bacitracin (Neosporin) cream. For the treatment of pyodermas, a number of studies reported effective topical therapies, namely: povidone-iodine solution, hydrogen peroxide cream, electrolyzed strong acid aqueous solution, tea ointment, Soframycin ointment, honey, fusidic acid cream, trimethoprim-polymyxin B sulfate cream, rifaximin cream, sulconazole cream, miconazole cream, neomycin/polymyxin B-bacitracin (Neosporin) cream, terbinafine cream, and mupirocin. Systemic agents cited were cephalexin, erythromycin, penicillin, Augmentin, amoxicillin, sultamicillin, (di)cloxacillin, azithromycin, cefadroxil, cefpodoxime, cefaclor, ceftizoxime, clindamycin, clarithromycin, tetracycline, fluoroquinolones, and fusidic acid.

Table 37.3 presents the evidence for commonly used antiseptics and some of the specific antibacterial agents. In practice, topical treatments such as chlorhexidine, povidone, and in some cases neomycin or mupirocin will provide the most cost-effective control measures. For extensive infection, cloxacillin or erythromycin provides alternatives. However, current evaluations are subject to some weaknesses, such as a lack of large, comparative studies, particularly of the topical therapies, including antiseptics, used in developing countries.

Evidence of the Efficacy of Topical Treatments for Pyoderma.

Community-applied measures for managing skin infections have not been evaluated, but measures such as early treatment of scabies or basic wound care of sores might provide significant benefits. In this area, carefully designed pilot control programs would provide extremely valuable data.

Fungal Infections

Fungal infections that affect the skin and adjacent structures are common in all environments. They include infections such as ringworm or dermatophytosis; superficial candidosis and infections caused by lipophilic yeasts and Malassezia species; and some other common causes of foot infection, such as Scytalidium . The clinical and social impact of fungal infections on individuals varies with local conditions. For instance, tinea pedis is a treatable condition that causes cracking and inflammation with itching between the toes. It is generally viewed as a nuisance that only marginally affects the quality of life; however, under certain conditions its significance is far greater. For example, fungal infections of the web spaces and toenails in diabetics provide a portal of entry for S. aureus , an event closely related to the development of serious foot complications in patients with peripheral vascular disease and neuropathy. Similarly, foot infections originally caused by dermatophytes can develop into more serious disabling infections through secondary Gram-negative bacterial infection among certain occupational groups in the tropics, such as workers in heavy industry, the police, or the armed forces. Wearing heavy footwear is a risk factor for the emergence of this problem.

Other infections, such as oropharyngeal candidosis, are important complications of HIV. This commonest infectious complication of AIDS is a potential early marker. Whereas in many patients it may simply have nuisance value, in others it has a more serious impact and leads to dysphagia and loss of appetite. Malassezia infections such as pityriasis versicolor are also common in the developing world and often occur in more than 50 percent of the population; however, they are generally asymptomatic but cause patches of depigmentation, and patients seldom seek treatment.

Some fungal infections are extremely widely distributed or common in defined endemic areas. They include tinea capitis and tinea imbricata.

Tinea capitis

Tinea capitis is a common, contagious disease of childhood that can spread extensively in schools. It is caused by dermatophyte fungi of the genera Trichophyton and Microsporum ( Elewski 2000 ). Infections can spread from child to child ( anthropophilic infections ) or from animals to children ( zoophilic infections ). Anthropophilic infections tend to be endemic or epidemic, whereas the zoophilic forms occur sporadically. The commonest sources and causes of zoophilic infections are cats and dogs ( Microsporum canis ), cattle and camels ( Trichophyton verrucosum ), and rodents ( T. mentagrophytes ). The causes of the anthropophilic form of this infection vary in different areas of the world. Although in areas of the developing world this condition is endemic at high levels, in many parts of Africa it is a common condition affecting more than 30 percent of children in primary schools. The main African species are M. audouinii, T. soudanense , and T. violaceum . The last is also found in the Middle East and India. T. tonsurans , the form of tinea capitis endemic in the United States ( Wilmington, Aly, and Frieden 1996 ) and in parts of Europe, such as France and the United Kingdom ( Hay and others 1996 ), is extremely resistant to treatment. No evidence indicates that this form has spread to Africa yet, although this possibility exists.

Families of children with tinea capitis seldom present for treatment. However, in a small proportion of individuals, tinea capitis produces a highly inflammatory lesion with suppuration on the scalp along with permanent scarring and local hair loss. The numbers of infected individuals showing this highly symptomatic change are not known with any accuracy, but it is believed to occur in about 5 percent of cases, more with T. tonsurans . This factor poses a dilemma in management, because where the disease is common and endemic, a regular source will always exist for new, severe, inflammatory infections in children. Therefore, addressing this issue by tackling individual cases without addressing the reservoir, albeit illogical, may ultimately be the most practical approach.

The diagnosis of tinea capitis is difficult to make clinically in mild cases because the main presenting signs are localized patches of hair loss with fine scaling. In some children, the hair loss is more diffuse. With the inflammatory forms, circumscribed patches of hair loss with erythema and pustulation also occur, and the whole area is raised into a boggy mass. The only way to confirm the diagnosis accurately is to take hair samples for culture and microscopy, which is not possible in many areas because they lack laboratory diagnostic facilities. One specific form of tinea capitis, favus, is clinically recognizable and distinct, because the scalp is covered with white plaques called scutula . The infection is chronic and can develop into permanent, scarring alopecia. Inhabitants of endemic areas often recognize favus as a distinct condition that causes chronic illness, and as a result, the uptake of consultation for treatment is higher.

Highly effective, topically applied treatments for tinea capitis are unavailable, and even though simple remedies such as benzoic acid compound (Whitfield's ointment) may lead to clinical improvements, relapse is almost universal. Nevertheless, the use of topical therapies may limit the spread of tinea capitis. Treatment depends on the use of oral therapies. The most widely available of these is griseofulvin, which is given to children in doses of 10 to 20 milligrams per kilogram daily for a minimum of six weeks. Noncontrolled studies show that a single dose of 1 gram of griseofulvin given under supervision can eradicate infection in more than 70 percent of individuals, but such regimens have not been adequately assessed under trial conditions to determine their effect on community levels of infection, nor are follow-up data available.

Recent years have seen the development of a number of effective, new, oral antifungals, including terbinafine, itraconazole, and fluconazole. Terbinafine is a highly active agent that is effective in the treatment of dermatophyte infections. It is given in doses of 62.5 milligrams for those under 10 kilograms, 125 milligrams for those weighing 10 to 40 kilograms, and 250 milligrams for those over 40 kilograms. Evidence indicates that it is effective after one week of therapy in T. violaceum and T. tonsurans infections, but the best responses are seen when it is used for four weeks. Unfortunately, at these doses it is less effective for Microsporum infections, although some data suggest that responses are significant if the doses are doubled. This drug is, therefore, difficult to administer in standardized protocols when the cause of infection is uncertain. Itraconazole is also effective, but no suitable pediatric formulation is available because it is marketed in a capsule form that is difficult to administer to young children. Fluconazole is also effective, although comparative studies of its use are not available. All three drugs are costly, and a community-based program that uses them would be difficult to fund and implement.

The team found a total of 432 articles for the treatment of tinea capitis. Table 37.4 presents key references for the oral therapies, the mainstay of therapy. The effective treatments included topical therapies (benzoic acid, bifonazole, selenium sulfide, ketaconazole shampoo, and miconazole shampoo) as well as systemic agents (griseofulvin, terbinafine, itraconazole, fluconazole, and ketoconazole). The results of topical treatments appear inferior to those of oral therapy, although they have not been directly compared, and some of the topical agents were applied to prevent transmission rather than to treat infection.

Evidence of the Efficacy of Different Regimens for Tinea Capitis.

Attempts at community control of tinea capitis have been devised but have not been monitored adequately. The methods have been based on surveillance through culture and treatment of all infected children. Culture-based diagnosis is difficult to implement regularly in developing countries. The treatment used for community therapy has been griseofulvin in conventional daily or large single doses, but those approaches have not been compared. In addition, control protocols usually advise treating carriers with topically applied agents such as selenium sulfide (which is relatively cheap) or a miconazole shampoo (which is moderately priced). In practice, some "carriers" are really patients with extremely localized and hard-to-detect infections, and such patients will not respond to topical treatment in the long term. A second problem is the absolute reliance on laboratory confirmation of cultures to direct treatment of carriers. Therefore, other strategies need to be evaluated, such as reducing the community load, perhaps by topical therapy or single-dose griseofulvin, to reduce the risk of spread. An alternative would be to continue with the existing practice of treating individual cases while recognizing that this process ignores the community reservoir.

Tinea imbricata (Tokelau Ringworm)

In many parts of the developing world, tinea imbricata is an exotic and unusual infection, with isolated foci occurring in remote areas of Brazil, India, Indonesia, Malaysia, Mexico, and the western Pacific. However, in some specific locations, it is common and endemic, reaching prevalence rates of more than 30 percent in some communities in the western Pacific. For example, extrapolating from a school survey in Goodenough Island, Papua New Guinea, Hay and others (1984) estimate that more than 7,000 people out of a population of about 20,000 were infected.

The disease presents in the form of widespread scaling, often arranged in concentric rings or with large sheets of desquamation. The infection may develop early in life and persist into old age without the development of effective immunity. Tinea imbricata often affects wide areas of the body, sparing only body folds and scalp skin. In those areas where it is endemic, it can be a significant problem occupying much of the time of health aid post staff.

Individual treatments have depended on the antifungals described earlier, including griseofulvin. Terbinafine and itraconazole are highly effective, but their cost has constrained their use. As table 37.5 shows, the relapse rates after itraconazole are also higher than after terbinafine ( Budimulja and others 1994 ). Topical agents such as benzoic acid compound (Whitfield's ointment) are helpful, but are seldom curative and are difficult to apply over such large areas. Some patients may be treated with locally derived treatments, such as the sipoma paint used in Papua New Guinea, which contains salicylic acid, brilliant green, and kerosene. Traditional treatments have also been used, but never evaluated. The leaves of Cassia alata, for instance, are widely used in the western Pacific.

Evidence of the Efficacy of Terbinafine for Tinea Imbricata.

The team found studies of the use of griseofulvin, terbinafine, and itraconazole for tinea imbricata. Some studies did mention sipoma paint and Cassia alata, but no studies evaluating their efficacy have been performed. The team also found case reports supporting the use of griseofulvin.

Different treatments for use on a community basis need to be evaluated because the impact of this condition on local health services in areas of high prevalence is heavy in terms of both time and staff workload.

Tropical Ulcer

Tropical ulcer is a common condition found mainly in children and teenagers in well-defined tropical regions. It usually affects the lower limbs ( Bulto, Maskel, and Fisseha 1993 ), causing the sudden appearance of regular and deep ulceration. It is mainly seen in Africa, India, and the western Pacific and in parts of Indonesia and the Philippines. The disease is caused by a combined infection of a number of different bacteria together with a fusiform bacterium, Fusobacterium ulcerans , and an as yet unidentified spirochete. The disease is associated with poor living conditions and exposure to water, particularly flood or stagnant water and mud. In endemic areas, it is a constant drain on resources. Morris and others' (1989) study of aid posts in East Sepik province, Papua New Guinea, shows that management of tropical ulcer was occupying a third of the posts' time and almost half their health care budgets.

The lesion usually starts with mild discomfort and overlying hyperpigmentation on the skin that progresses rapidly over a few days until the skin breaks down and sloughs, revealing an underlying ulcer. The lesion is often clean on first presentation and round with smooth edges. It generally starts on the lower leg or ankle, and in about 10 percent of cases, it progresses to become an irregular, enlarged, and chronic ulcer.

The condition heals well in most patients with simple cleansing and treatment with penicillin; however, early grafting may be necessary if healing is delayed. Treatment, therefore, consists of early treatment with penicillin, a strategy that may also fit with a syndromic approach to ulceration, because it will also be effective for yaws. The alternative is oral metronidazole, but no evidence of the comparative efficacy of these two approaches is available.

In searching the literature for effective remedies for tropical ulcer, the team found little evidence. The team did find studies evaluating metronidazole and topical dressings, and several articles mentioned the efficacy of penicillin and split skin grafting, but no randomized controlled trials have been performed. A single case report supports the use of co-trimoxazole. The management strategy thereafter depends on keeping the wound clean to allow appropriate healing using local antisepsis and cleansing, such as potassium permanganate solution, chlorhexidine, or even saline, and protecting the area from further abrasion or secondary infection with sterile dressings. Clinical experience suggests that if this regimen is not followed, the risk of developing chronic leg ulceration is substantial.

No community strategies for preventing tropical ulcer are known, although the process of infection suggests that simple, hygienic measures to disinfect and clean the affected limb, perhaps modified from those used in lymphatic filariasis, might be effective as a simple preventive regimen. The possible use of vaccines has been substantially researched for the animal counterpart, sheep foot rot, which is caused by a similar combination of organisms.

HIV-related Skin Diseases

A wide range of skin conditions may develop as a consequence of HIV infection, but most are beyond the scope of this chapter. They include conditions that are a significant drain on scarce resources. These include Kaposi's sarcoma and toxic epidermal necrolysis, a potentially life-threatening form of skin failure that is often drug induced and requires the level of care and attention that would be deployed for patients with severe burns.

The commonest skin-related complication of HIV, particularly in Africa, is the itchy papular eruption or papular pruritic eruption of HIV. It presents with fiercely itchy multiple papules on the face and upper trunk. It is of unknown etiology and responds only to symptomatic treatment—for instance, antipruritic preparations such as antihistamines—although simple topical preparations, such as calamine or menthol creams, may alleviate the itching. Recognizing this condition is important, because it is seen only in HIV/AIDS cases and is often mistakenly treated as acne. It does not respond to treatments for acne.

Pigmentary Disorders

The development of pigmentary change is an important source of concern in many communities ( Taylor 1999 ). Disorders associated with pigmentary changes are common and range from hereditary defects such as albinism ( Lookingbill, Lookingbill, and Leppard 1995 ) to increased pigmentation, or hyperpigmentation , associated with inflammatory skin lesions such as acne. Albinism is a significant cause of life-threatening skin cancer in the developing world.

For many of these conditions, no effective remedies are available. For instance, hyperpigmentation secondary to inflammation cannot be removed effectively, although it may fade with time. Similarly, no effective cure exists for vitiligo, a common disease involving loss of pigment, although experimental treatments such as melanocyte grafting do produce localized repigmentation. Therefore, advising patients of the current comparative ineffectiveness of treatments for these conditions is important. Preventing the use of therapies that do not lead to effective outcomes should be an important part of the strategy for treating skin diseases.

Some forms of increased pigmentation, such as melasma, which is hyperpigmentation of the cheek and forehead areas and is seen mainly in women, respond to the application of hydroquinone derivatives. However, because such treatments are often misused, they would not be used at the community level and would be used only with advice from a trained practitioner. Depigmenting creams, lotions, and emulsions are widely available as cosmetic preparations in many local markets and shops, and in a study in Dakar, Senegal, more than 50 percent of women questioned stated that they were regularly using bleaching creams ranging from hydroquinones to corticosteroids ( Mahé and others 2003 ). Hydroquinones are potentially damaging to the skin and with continuous use cause patchy increased pigmentation and scarring of the facial skin. Similarly, misuse of corticosteroids is associated with a range of secondary effects from skin thinning to increased infection rates. Warning people about the potential risks of depigmenting creams would be a useful health promotion strategy in many communities.

Skin depigmentation is also a feature of leprosy. Thus, teaching health care workers responsible for leprosy surveillance to recognize skin patterns is a practical strategy of great potential value in continuing progress toward eliminating this disease.

• Economic Assessments and Skin Diseases in Developing Countries

Apart from the studies mentioned here in relation to families' costs for treating community-acquired skin diseases in Mexico ( Hay and others 1994 ) and costs to health posts of managing tropical ulcer in Papua New Guinea ( Morris and others 1989 ), no published studies are available of the economic burden of skin disease. An extensive literature search did reveal some studies related to diseases that affect the skin but discussed elsewhere in this work (Buruli ulcer and onchocercal skin disease), as well as a paper on the direct costs of treating scabies in Italy. These studies are shown in table 37.6 .

Literature Review on the Economic Impact of Skin Diseases.

Examples of drug costs ( tables 37.2 to 37.4 ) for tinea capitis, scabies, and pyoderma can be estimated as follows:

• Treatment of a single case of scalp ringworm using griseofulvin purchased from two differently priced U.S. sources to achieve the published efficacy rates ( table 37.4 ) with a conventional therapeutic course of six weeks, assuming a daily dose of 250 milligrams, would provide between 61 and 92 percent efficacy at a drug cost per individual of US$29 or US$53, depending on the drug source. Alternatively, a single supervised dose of 1 gram would cost US$1.40 or US$2.50. With supervision of treatment, the total cost per cure using daily treatment ranges from US$35 to US$88 per patient.
• Treatment of 100 people with scabies using sulfur ointment, assuming 500 grams per individual, would cost US$58 or US$0.58 per person. This regimen would provide a 71 percent cure rate at three months and a cost per cure of $1.30 per patient.
• Treatment with povidone of an individual with pyoderma would cost US$0.68, assuming that 400 milliliters would treat eight people. This regimen would provide a cure rate of 88 percent at three months and a cost per cure of US$1.10 per patient.

These calculations have taken into account ideal community treatment conditions, where the recurrence rate is negligible. However, if such a community-based scheme is not effectively developed, more than 50 percent of those with scabies are likely to be reinfected. The figures are lower for tinea capitis (15 percent) and pyoderma (10 percent). Table 37.7 shows the costs of treating large populations.

Cost of Cure and Impact on DALYs for the Three Most Common Skin Diseases, Using the Cheapest Effective Treatments.

Although little information is currently available, in particular about the effect of local pricing of medications on overall effective treatment costs, the studies cited in this chapter indicate that the financial burden of skin diseases within families may well be significant and that producing a series of robust analyses of the cost implications of both treatment and failure to provide adequate management strategies for these common conditions is critical.

The 1990 global burden of disease study estimated that the disability weighting associated with skin disease was at least 0.02. However, the disability weighting for severe scabies (25 percent of cases) and patients with ecthyma (10 percent of pyoderma cases) is 0.10. If we take skin cases with the lower disability estimates—for example, mild to moderate scabies and pyoderma—the cost per DALY gained would be about US$1.00 to US$1.50 ( table 37.7 ). For tinea capitis, the cost per DALY gained using daily treatment would be considerably higher, US$175 at the lower drug cost.

The benefits of devising control measures for treatable skin disease are also affected by the high prevalence figures for skin diseases in low-income countries with total populations of between 40 million and 600 million affected, depending on variations in disease prevalence.

• Current Status of Community Control Measures in Dermatology

Despite the logic of developing community-focused services for dermatology, such services have seldom been achieved ( Hay, Andersson, and Estrada 1991 ). Perhaps the best current example of a concerted, community-based approach is the Regional Training Center for Dermatology in Moshi, Tanzania, which focuses on developing a primary care skills base in African countries for the care of patients with skin and sexually transmitted diseases ( Kopf 1993 ). The program has now trained more than 100 medical assistants and nurses, who were placed in 15 different countries at the primary care level and who, in many cases, play key roles in developing local health programs. A key issue is that action proportional to the severity of the problem is needed. For instance, one option would be to help nonspecialized health workers significantly improve their skills in managing common skin diseases. That option would present a new challenge for the teaching of dermatology. Along those lines, a recent initiative to effect change through a control and education program in Mali targeted at pyoderma, scabies, and tinea capitis is currently being evaluated. Early assessments indicate that the teaching methods have been effective in instilling recognition skills among primary care health workers. The effect on community levels of skin diseases is not yet known.

Skin diseases remain a low priority for many health authorities, despite the large demand for services. Addressing the potential for controlling skin problems by means of simple and effective public health measures should be a realistic target for alleviating a common and solvable source of ill health. An effective plan, team, and basic dermatological formulary can do much to improve matters ( Estrada and others 2000 ). This chapter outlines some of the challenges for such programs and some of the deficiencies of current provision.

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