With a surface of some 2 m2 and a mass equal to around 15% of total body mass, skin is the human body's largest single organ.1 The main functions of human skin are to regulate the temperature, both by insulation and sweating, to be involved in the functioning of the nervous system and the regulation of water content, and to protect the organism from mechanical injuries, microorganisms, substances, and radiation present in the environment.2, 3

The properties and condition of the skin vary with body site and can be influenced by various inherent body‐dependent factors, such as skin type, ethnicity, gender, or even lifestyle and body‐mass index (BMI). Skin can be also influenced by the penetration of various substances to which it is exposed.3, 4 The permeability of skin can be used for cosmetic purposes or drug delivery, which has been a developing technology since the 1970s, but can also lead to harmful effects.5, 6

This review article presents various major factors influencing and determining human skin properties and performance and provides an overview of skin barrier functions and their limitations, focusing on skin‐penetration mechanisms and the methods used to enable or improve drug‐delivery processes. Our aim is to provide readers with an understanding of the complex relationship between specific skin functions. Figure 1 shows an overview of principal body‐dependent factors and penetrating substances that can influence human skin.

Skin properties are also dependent on the body‐mass index (BMI). TEWL is usually higher for obese people. 7 , 67 Obesity is also correlated to elevated sweat gland activity and higher skin blood flow. 67 , 68 Obesity can also increase the risk of various skin disorders 67 , 68 and impaired wound healing. 68 For example, 74% of examined obese people have been found to suffer from acanthosis nigricans , also related to insulin resistance. 68 In another study, 40% of obese children were diagnosed with striae disease. 68

Lifestyle is considered to be one of the factors influencing the extrinsic aging process, which is related to visible aging caused by the exposure to external factors. 60 Proper sun protection prevents accelerated skin aging and the risk of skin cancer and other skin damage. 61 A healthy diet, containing significant amount of fruits and vegetables, as well as a calm, low‐stress lifestyle, leads to a higher concentration of carotenoids and may result in a slower rate of skin aging. 62 , 63 Higher daily vitamin C intake has been connected to a decreased formation of wrinkles, while a higher linoleic acid dose has been associated with a lower level of dryness. 64 A study has shown that smoking is associated with an altered skin condition (wrinkling, larger pores, rougher skin surface, and presence of discoloration). 60 It also significantly increases the risk of skin diseases, such as necrosis after surgery, as it decreases the self‐healing abilities of the skin. 65 , 66

For example, the SC thickness varies significantly with the investigated anatomical site. 20 , 43 It was found that the thickest SC layer is to be found in heels, having 86 ± 36 cell layers, whereas the smallest number of cell layers (6 ± 2) has been observed for genital skin. 20 The thickness of the epidermis depends on the body site in a similar way. 14 , 44 The SC thickness is related to many other phenomena, such as surface morphology, hydration level, and permeability to various substances. 37 , 45 Since the SC acts as a barrier layer, penetration through the skin is higher on body sites with thinner SC. 46 , 47 The roughness (Ra) of the index finger lies within the range of 19‐33 μm, whereas it is lower (12‐20 μm) for the volar forearm. 12 , 48 , 49 Also, sebum secretion varies between different anatomical regions, not only as far as the amount is concerned, but also the chemical composition. 29 , 50 , 51 Due to many reasons, such as exposure to harsh environmental conditions or the frequency of washing with detergents, certain body parts, eg, hands, are more prone to having a lower hydration level of the superficial stratum corneum (SSC). 36 , 52 The highest density of sweat glands can be found on the soles of the feet (620 ± 20 sweat glands per cm 2 ), whereas the lowest density of sweat glands is found on the upper lips (16 sweat glands per cm 2 ). 53 In general, the SC thickness is directly related to the TEWL and anatomical sites characterized by the thickest SC display the lowest TEWL values. 54 However, TEWL levels are also dependent on other factors, such as SC lipid content, blood flow, or skin temperature. 4 , 54 This explains the fact, that the TEWL of the palm (characterized by a thick SC layer but a low level of barrier lipids) is higher than that of the leg. 4 , 29 The elastic properties of skin depend on the collagen structure in the dermis , the local thickness of the skin and other parameters that depend on the anatomical site. 22 , 55 For example, facial skin was found to be less elastic than the skin on the arm and on the back. 24 As the properties of human skin are rarely independent of each other but work as a system, a variation in one property is generally coupled with a variation in others. For example, the frictional behavior of human skin varies with body site because it depends on SC roughness, elastic properties, thickness, hydration level, sweating rate as well as on the presence of hair and sebum. 12 , 36 , 56 - 59

Skin differs not only between different people but also between anatomical sites for the same person. 33 - 35 Table 1 summarizes exemplary characteristics of human skin for different anatomical sites.

Skin type, its pigmentation, hydration, roughness, and many other parameters are very individual. Significant variations can be observed between people from the same ethnic groups, living in the same environment and sharing the same lifestyle, but having different complexions.

Overall, the hydration level of the skin decreases significantly with age, mainly because of the decrease in the amount of natural moisturizers present in the skin, 4 , 10 , 22 but some studies showed contrary results. 23 It was also found that the influence of the skin‐aging processes on skin hydration can vary between different ethnic groups, being the most significant for Caucasians. 9 Furthermore, the elasticity of the skin is also known to decrease, predominantly due to the decreasing collagen production in the dermis and reduction in the resilience of existing collagen and elastin fibers. 4 , 17 , 22 , 24 The thickness of skin initially increases with age, showing a maximum value for women at around 30‐40 years of age and for men at around 40‐50 years, and then significantly decreases with age. 25 , 26 The amount of sebum secretion has been reported to be either independent or slightly decreasing with age. 4 , 16 , 17 The sweating rate slightly decreases with age. 27 , 28 Skin pH has been found to be higher for older subjects, due to an age‐related decrease in the amount of acidic natural moisturizing factors present in the skin. 10 , 29 Skin roughness, the dimensions of the primary lines and anisotropy were all found to increase with age. 12 , 30 - 32

Some researchers found that TEWL is higher for men, explaining this by the fact that they spend more time outdoors and their skin is more damaged and therefore more prone to transepidermal water loss. 4 Sebum secretion is considered to be either independent of gender 16 or slightly higher in males, 4 , 10 , 17 due to a higher testosterone level. 4 , 10 The sweating rate was found to be 30%‐40% higher in males than in females (taking the difference in body surface area into consideration). 18 Results show no clear relationship between gender and SC thickness, 14 , 19 , 20 but it was also found that the cellular epidermis is slightly thicker in males than in females. 14 Measurements have shown no clear and statistically significant difference between the elastic properties and pH of the skin in females and males for the same anatomical sites. 4 , 16 , 21 , 22 Any relationship between gender and skin hydration seems to be outweighed by the individualized factors. 4 , 10 , 16

Caucasians exhibit higher dryness with age than Chinese, which may be caused by different eating habits and avoidance of sun exposure among Chinese. 13 It has been shown that darker skin is more resistant to photo aging processes. 8 Also, the thickness of the SC was found to be greater for darker skin. 13 , 14 Some studies have also indicated differences in the number of layers within comparable SC thickness, suggesting that African‐Americans have more cell layers within the SC than do Caucasians (16 and 9 layers, respectively), the skin thus being more resistant to chemicals and damage. 15 Most studies demonstrated higher transepidermal water loss (TEWL) for African‐Americans than for Caucasians 15 as well as larger gland pore sizes and a higher level of sebum secretion. 7

Skin tone varies among ethnic groups due to different levels of the four chromophores responsible for skin color: hemoglobin and oxyhemoglobin (pinkish tones), melanin (brownish shades), and carotenoids, responsible for yellow‐orange tones. 7 , 8 Ethnicity also influences the natural hydration level of the skin as well as the decrease in hydration level with age. 9 , 10 It has been reported that Caucasians and African‐Americans have slightly drier skin, compared to Chinese, due to the lower levels of SC natural moisturizing factors. 7 , 10 Other experiments have shown no difference in skin hydration level between ethnic groups, 11 which may be due to the significant variations in skin properties among individuals, caused either by different skin types and habits, outweighing the influence of ethnicity. 12

As skin hydration is a very important parameter responsible for skin homeostasis, all deviations from a normal hydration level can result in significant changes in human skin properties and functions. 69 Among the main causes of dry skin, one can list skin aging, 4 the wrong or no skin care 70 or malnutrition. 71 Skin hydration can also be influenced by environmental factors 72 or by anatomical location (eg, skin on the palms and legs is drier than on the forehead). 4 Skin dryness can also be a consequence of various diseases, not only directly related to the skin, such as atopic dermatitis, but also other health problems, eg, hypothyroidism. 73 - 76 A lower hydration level results in a lower elasticity of the skin, 4 faster skin aging and wrinkle creation, 49 higher surface roughness, 77 and lower mechanical resistance. 3 Dry skin is also more susceptible to skin diseases and more prone to redness and itchiness. 45 , 78 The frictional behavior of human skin also depends on hydration. 12 , 79 - 82 It was reported that moist skin shows higher friction‐coefficient values than dry or completely wet skin. Drier skin is more prone to mechanical failure, flakiness, irritation, and other problems. 45 , 78 Irritated skin leads to difficulties in achieving and maintaining an adequate hydration level. This results in drier skin and may lead to more severe skin conditions, if untreated.

Cause and effect chain for the example of the decrease in skin hydration level. “+” and “‐” symbolize positive and negative correlation [Colour figure can be viewed at wileyonlinelibrary.com

It has to be pointed out that several different factors can influence the skin at the same time in everyday life. The same effect can have various origins while the same cause can result in different symptoms, depending on individuals and circumstances. Moreover, human skin characteristics are generally mutually dependent. Therefore, a variation of one parameter will influence interrelated parameters. An example, showing the cause and effect chain connected with the hydration level of skin, is summarized in Figure 2 .

1.3 Penetration through skin

Our skin is constantly in contact with various substances that are either present in the environment or deliberately applied to the surface of the skin.83 Numerous substances have been applied to the skin surface for medical or religious reasons since the beginning of humanity, which provides a hint that the absorption properties of the skin were already known a long time ago.84 Depending on the circumstances, the barrier properties of human skin, given mainly by its horny layer (SC), may be perceived as being either an advantage or an obstacle.85 In everyday life, the skin can be exposed to various substances in the solid, liquid, or gaseous states. Some of them, such as harmful chemicals, allergens, pathogens etc. can be dangerous and lead to irritation, rashes, burns, or other health problems following the topical application or penetration of these substances into deeper layers of the skin.84, 86 Due to the skin's large surface area (around 2 m2), the topical dosage of drugs seems to be an interesting alternative for medication, but, because of the barrier function of the skin, this method is far from straightforward.5, 87, 88

The epidermis and dermis are the skin layers involved in the penetration processes, but the SC composition and properties are mainly responsible for the barrier function of human skin.3 Skin protects the body from penetrating substances through various mechanisms, either mechanically blocking particles from further migration into the skin or neutralizing, attacking, or degrading them.3 Substances that penetrate through the SC barrier layer still have to overcome many other obstacles, such as the antimicrobial barrier and immunological or enzymatic systems.3, 86

There are three different pathways that can be used by substances penetrating the skin mentioned in the literature: intercellular, transcellular, and transappendageal.5 Figure 3 shows a simplified scheme of skin penetration.

The intercellular pathway involves the transport of substances between the cells of the SC layer.5, 89 This mechanism plays a major role in skin permeability and requires the presence of component lipids, such as ceramides, that allow free lateral water diffusion by forming nanometric spaces via short range repulsive forces.89, 90 The diffusion rate depends on the properties of penetrating particles, such as volume, weight, solubility, lipophilicity, or hydrogen‐bonding ability.6 It is assumed that particles with a size of 5‐7 nm can be efficiently transported through the intercellular pathway.3 Although the SC is a thin layer, reaching a thickness of some 20 μm for the volar forearm,14 the intercellular pathway is much longer and reaches 400 μm, which reduces penetration rate significantly.91-93

The transcellular pathway involves keratinocytes in the transport of substances.5 Despite the seemingly short distances involved, this pathway is very selective. Penetrating particles have to overcome various barriers that are repeated many times in the skin structure; lipophilic cell membranes, hydrophilic cellular contents with keratin, and phospholipidic cell barriers.94, 95

The transappendageal pathway involves appendages, such as sweat and sebaceous glands and hair follicles and is a typical route for the penetration of water‐soluble substances.87, 89 Some studies have shown that the size of particles penetrating the skin through aqueous pores can be around 36 nm, whereas trans‐follicularly penetrating particles may potentially have a diameter of up to 210 μm (this being the maximum size of the follicular openings).3 However, other researchers have argued that only particles with sizes up to 40 nm88 or even as small as 20 nm6 can effectively penetrate through follicles into deeper skin layers, whereas bigger particles will only be transported deep into the hair follicle.

The transappendageal pathway used to be considered as the least significant penetration passage, as the appendages cover only 0.1% of the skin surface.5, 91 On the other hand, it is the only penetration pathway for particles larger than few nm.3 In addition, appendages may play a role as reservoirs for topically applied substances and therefore could potentially be an efficient penetration path.5

Consistent with the first part of this paper, the properties of human skin can vary significantly not only between different people but also between anatomical areas. The absorption properties of skin are subject to analogous variations, in particular, when skin barrier properties are altered due to a skin disease. Figure 4 presents the main body‐dependent factors influencing skin permeability.

Figure 4 Open in figure viewer PowerPoint Body‐dependent factors influencing skin permeability. “+” and “‐” symbolize positive and negative correlation between single factors and skin permeability [Colour figure can be viewed at wileyonlinelibrary.com

The barrier properties of human skin vary significantly among body parts, as the anatomical site strongly influences the majority of skin characteristics, such as SC thickness, density of appendages, and hydration level.3, 96 Skin permeability is facilitated when the SC is thinner, due to a smaller distance having to be covered by penetrating substances.3 The distribution, density, and diameter of follicles also have a major influence on skin barrier properties.3 The maximum density of follicles is to be found on the forehead (292 follicles/cm2 compared to 50 follicles/cm2 in other body parts) whereas the maximum diameter of follicles has been reported for the calf (165 ± 45 μm).3 The water‐diffusion rate varies depending on the body site. Diffusion rates of 2.1 mg/cm2/h were reported for the SC on the sole, 0.4 mg/cm2/h on the calf and 0.1 mg/cm2/h on the thigh (isolated dermis showed very poor barrier properties and the diffusion rate persisted at a level of 5 mg/cm2/h).97 The hydration level of skin can vary significantly between body parts. Enhanced hydration leads to an increased penetration rate, since water can act as a penetration enhancer.98 On the other hand, dehydrated skin loses its elasticity, which can lead to surface fracture even during normal everyday activities. Penetration of substances through impaired skin is significantly enhanced.87 For example, eczema (dry and flaky skin) may cause the skin to be 8‐10 times more permeable than is the case for normal, healthy skin.98

It was found that sweating and high skin hydration result in increased water absorption.96, 99 Both these parameters are reduced in older subjects.3, 27, 28

It was found that the presence of hair makes men's faces more permeable than women's.18 Men sweat to a greater extent than women (800 ml/h for men versus 450 ml/h for women during physical activity), which can also result in higher skin permeability in males.18 Sex hormones influence the SC chemical composition and may also influence skin permeability.3

All parameters contributing to personal variations in skin permeability are also dependent on the skin type, as all above‐mentioned characteristics, such as SC thickness, density of appendages, sweat rate, and hydration level can vary among individuals of the same gender and at the same age.

All the above‐mentioned factors influencing human skin barrier properties are interlinked. Therefore, it is impossible to explicitly determine the importance of individual parameters. Moreover, different body‐dependent factors will influence skin permeability to a different extent, depending on the penetration pathway preferable for a certain type of penetrating substance.3 In addition, skin permeability can also be influenced by the climate and environmental conditions.3, 37 Increased hydration level of the skin, which can be caused by increased air humidity as well as increased temperature, for example, can act as penetration enhancers.3, 37 This leads to the conclusion, that transdermal drug delivery should be personalized, taking into account both individual skin characteristics and the living environment of patients.

The transport of substances through the structure of human skin strongly depends on the substances themselves, as well as on the accompanying excipients.3 It has been reported that elastic particles can migrate through human skin more efficiently than rigid ones, and that there are higher dimensional limits for elastic penetrating particles than for rigid ones, due to the difference in deformability.100 In addition, the size and shape of the molecule, pH of the solution, as well as other physicochemical descriptors, eg, water‐octanol partition coefficients and Abraham solute descriptors, are decisive factors for the ability of the substances to migrate through the skin structure and its penetration depth, the possible pathway and the diffusion coefficient.3, 101

As the penetration of substances is quite often desired, (eg, delivery or application of active substances in cosmetics), many compounds have been investigated as potential penetration enhancers: surfactants, esters, fatty acids, alcohols, amines, terpenes, alkanes, phospholipids, sulfoxides, amides, or pyrrolidones.102 The role of such substances is to reversibly decrease the barrier resistance of human skin.103, 104 Besides chemical penetration enhancers, there are also some techniques enhancing skin penetration, such as electroporation, which leads to the creation of aqueous pores by the application of an electric pulse.105 In addition, it has been observed that massage can increase the transappendageal penetration rate.6