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Structure and function of the epidermal barrier

      The skin is divided into 2 main structural layers: the epidermis and the dermis. The epidermis is generally considered to be subdivided into 5 separate strata: basal, spinous, granular, lucid, and corneum. The vital barrier function of the skin resides primarily in the top stratum of the epidermis, the stratum corneum (SC). The SC is the barrier to the passive diffusion of water out of the skin, allowing us to live in air without suffering from dehydration, and is the barrier to other molecules including irritants into the skin. The epidermis also has immunologic functions and provides some protection of the skin from ultraviolet light via the pigment system. This paper will review the structure and function of the epidermal barrier and the response to environmental challenges such as repeated handwashing. Emphasis will be placed on the SC, the front line of the skin's defense against the insults of the outside world.
      The skin is the largest organ of the human body, accounting for approximately 16% of total body weight. Its vital role is to prevent loss of water and other components of the body to the environment and protect the body from a variety of environmental insults. The skin also has important immune and sensory functions, helps to regulate body temperature, and synthesizes vitamin D. For a review of the overall structure of the skin including the dermis and skin appendages, see Odland.
      • Odland G.F.
      Structure of the skin.
      Any discussion of the structure of skin will necessarily refer to layers. The various layers of the skin work in concert to provide strength and flexibility and perform the multiple functions of the skin. This review will focus on the barrier function residing in the top layer of the skin, the epidermis. The barrier function of the skin has been called “la raison d'etre” of the epidermis.
      • Madison K.C.
      Barrier function of the skin: “la raison d'etre” of the epidermis.
      The epidermal barrier serves to limit passive water loss from the body, reduce the absorption of chemicals from the environment, and prevent microbial infection. These defensive functions reside primarily in the top stratum of the epidermis, the stratum corneum (SC), at which they are integrated with SC formation and homeostasis.
      • Elias P.M.
      • Choi E.H.
      Interactions among stratum corneum defensive functions.
      • Elias P.M.
      Stratum corneum defensive functions: an integrated view.
      Thus, proper development and maintenance of the SC are keys to its remarkable ability to defend the body against both chemical and microbiologic attack as well as dehydration.
      The epidermis is itself divided into several layers or strata starting with the basal layer or stratum basale just above the dermis proceeding upward through the prickle and the granular layers to the top layer, the SC. Figure 1 is a diagram representing the major strata of the epidermis. English and Latin nomenclature of the epidermal strata are given in Table 1.
      Figure thumbnail gr1
      Fig 1Diagram of the epidermis showing the main layers. The clear layer (not shown) is only found in the very thick epidermis of the palms and soles.
      Table 1Nomenclature for epidermal strata
      EnglishLatinAlternative
      Basal cell layerStratum BasaleS Germinativium, Malpighian layer
      Prickle layerS SpinosumMalpighian layer
      Granular layerS GranulosumMalpighian layer
      Clear layerS Lucidum
      Horny layerS Corneum
      The predominant cell type of the epidermis is the keratinocyte. Keratinocytes exist from the basal layer to the granular layer at which they transform into the corneocytes of the SC. Keratinocytes make keratin and many other proteins. Keratins are the major structural proteins of the SC.
      • Steinert P.M.
      Structure, function and dynamics of keratin intermediate filamaments.
      There are 2 other important cell types in the epidermis: melanocytes and Langerhans cells. These 2 cells types are shown in the micrograph in Fig 2.
      Figure thumbnail gr2
      Fig 2Micrograph of the upper dermis and epidermis showing the layers and major cell types. (Figure courtesy of Steve B. Hoath, MD, used with permission.)
      Melanocytes are the pigment-producing cells of the skin and hair in all mammals. In the skin, they are found at the basal layer of the epidermis at which they make pigment granules called melanosomes containing melanin. The melanosomes are transferred from the melanocytes to the epidermal keratinocytes at which they impart some protection to the cell nucleus from ultraviolet (UV) light and give the skin its color. The process of melanin synthesis and transfer of melanosomes occurs continuously as the epidermis renews but can be speeded up in response to UV exposure to produce tanning.
      Another epidermal cell shown in Fig 2 is the Langerhans cell. Langerhans cells are dendritic immune cells that are the antigen-presenting cell of the skin.
      • Cumberbatch M.
      • Dearman R.J.
      • Griffiths C.E.
      • Kimber I.
      Epidermal Langerhans cell migration and sensitisation to chemical allergens.
      • Holikova Z.
      • Hercogova J.
      • Pizak J.
      • Smetana Jr., K.
      Dendritic cells and their role in skin-induced immune responses.
      • Kimber I.
      • Cumberbatch M.
      Dendritic cells and cutaneous immune responses to chemical allergens.
      They are important to the immune barrier of the epidermis and also participate in contact allergy.

      Formation of the SC barrier

      The granular layer or stratum granulosum (SG) is named for the granules that appear in the cells at this point in the epidermis. Although it is only a few cells thick, it is a vital component of the epidermis because it is here that the key transformations that form the SC barrier occur. Two types of granules are formed at the SG: keratohyalin granules,
      • Odland G.F.
      Structure of the skin.
      which are full of protein, and lamellar bodies,
      • Oashi M.
      • Sawada Y.
      • Makita R.
      Odland body and intercellular substances.
      • Odland G.F.
      A submicroscopic granular component in human epidermis.
      which contain lipids. In the SG, the cells are transformed into the corneocytes or squames that form the SC. The nucleus is digested, the cytoplasm disappears, the lipids are released into the intercellular space, the keratin intermediate filaments aggregate to form microfibrils, and the cell membrane is replaced by a cell envelope made of cross-linked protein with lipids covalently attached to its surface. The corneocyte or squame that results from this transformation is a flat cell that tends to be in the shape of either a hexagon or pentagon approximately 25 μm on a side with a surface area of approximately 1000 μm2 and a thickness of approximately 0.5 to 1.0 μm.
      • Mark R.
      • Barton S.P.
      The significance of the size and shape of corneocytes.
      • Plewig G.
      • Scheuber E.
      • Reuter B.
      • Waidelich W.
      Thickness of corneoctyes.
      On most body sites, the SC is 12 to 16 cell layers thick, but it can vary from as little as 9 cell layers of the forehead or eyelids to as much as 25 on the dorsum of the hand and up to 50 or more on the palms or the soles of the feet.
      • Holbrook K.A.
      • Odland G.F.
      The fine structure of developing human epidermis: light, scanning, and transmission electron microscopy of the periderm.
      • Ya-Xian Z.
      • Suetake T.
      • Tagami H.
      Number of cell layers of the stratum corneum in normal skin—relationship to the anatomical location on the body, age, sex and physical parameters.
      To discuss the structure and formation of the SC in more detail, we will refer to a common conceptual model of the SC barrier, the “bricks and mortar” model.
      • Elias P.M.
      • Grayson M.A.
      • Lampe M.A.
      • Williams M.L.
      • Brown B.E.
      The intercorneocyte space.
      • Nemes Z.
      • Steinert P.M.
      Bricks and mortar of the epidermal barrier.

      The bricks and mortar model of the SC barrier

      The SC is often modeled as a brick wall (Fig 3). The SC corneocytes with their resistant cell envelopes and keratin microfibrils are considered to be the bricks, and the layers of lipids found between the cells are considered to be the mortar.
      • Elias P.M.
      • Grayson M.A.
      • Lampe M.A.
      • Williams M.L.
      • Brown B.E.
      The intercorneocyte space.
      The lipid “mortar” is the main barrier to water passing out through the SC.
      • Grubauer G.
      • Feingold K.R.
      • Harris R.M.
      • Elias P.M.
      Lipid content and lipid type as determinants of the epidermal permeability barrier.
      The permeability of lipid soluble molecules is modeled by considering them to wind their way around the corneocyte bricks by diffusing through the lipid mortar.
      • Elias P.M.
      • Cooper E.R.
      • Korc A.
      • Brown B.E.
      Percutaneous transport in relation to stratum corneum structure and lipid composition.
      Both the bricks and the mortar of the SC are produced by keratinocytes at the SG at which keratinocytes release the lipids of the mortar into the space between the cells as they are being transformed into the corneocytes “bricks.” A major difference between the current and the earliest versions of the model is that we now know that the bricks are linked by desomosomes as illustrated in Fig 3 and discussed below.
      Figure thumbnail gr3
      Fig 3A “Bricks and Mortar” model for human stratum corneum illustrating the corneocyte “Bricks,” the Intercellular lipid “Mortar,” and the desmosomes connecting the corneocytes.

      The bricks (corneocytes)

      The SC is approximately 60% keratin by dry weight.
      • Steinert P.M.
      The extraction and characterization of bovine epidermal α-keratin.
      Keratins are members of a family of proteins called intermediate filaments that form part of the cytoskeleton of nucleated cells
      • Steinert P.M.
      Structure, function and dynamics of keratin intermediate filamaments.
      • Dowling L.M.
      • Parry D.A.
      • Sparrow L.G.
      Structural homology between hard α-keratin and the intermediate filament proteins desmin and vimentin.
      • Fuchs E.
      Keratins and the skin.
      and are major structural proteins of skin, hair, and nail. When keratins are made by the cell, an acidic type I keratin is made at the same time as a neutral to basic type II keratin. Acidic proteins have more negatively charged amino acid side chains (aspartic or glutamic acid), and basic proteins have more positively charged side chains (lysine, arginine, or histidine at low pH). This allows the 2 α helical proteins to interact with each other, forming a structure called the coiled-coil.
      • Steinert P.M.
      Structure, function and dynamics of keratin intermediate filamaments.
      • Fuchs E.
      Keratins and the skin.
      • Steinert P.M.
      Organization of coiled-coil molecules in native keratin 1/keratin 10 intermediate filaments: evidence for alternating rows of antiparallel in-register and anti-parallel staggered molecules.
      Coiled-coils are important to the structure of the keratinocyte and help maintain its integrity. Improper assembly of coiled-coils can lead to fragile keratinocytes, which rupture easily causing blistering diseases.
      • Fuchs E.
      Keratins and the skin.
      • Fuchs E.
      • Chan Y.M.
      • Paller A.S.
      • Yu Q.C.
      Cracks in the foundation: keratin filaments and genetic disease.
      • Fuchs E.
      Intermediate filaments and disease: mutations that cripple cell strength.
      • Coulombe P.A.
      • Hutton M.E.
      • Vassar R.
      • Fuchs E.
      A function for keratins and a common thread among different types of epidermolysis bullosa simplex diseases.
      At the SG as keratinocytes are transformed into the corneocyte “bricks,” the coiled-coils aggregate to form structures called microfibrils, which are thought to lie parallel to the surface of the skin serving to reinforce the corneocytes and limit SC swelling in the plane of the skin surface.
      • Norlen L.
      • Emilson A.
      • Forslind B.
      Stratum corneum swelling: biophysical and computer assisted quantitative assessments.
      • Robbins C.R.
      • Fernee K.
      Some observations on the swelling of behavior of human epidermal membrane.
      Two proteins from the keratohyalin granules, filaggrin and loricrin, play key roles in the formation of the “bricks.” Filaggrin is an acronym for filament-aggregating protein.
      • Dale B.A.
      • Holbrook K.A.
      • Kimball J.R.
      • Hoff M.
      • Sun T.T.
      Expression of epidermal keratins and filaggrin during human fetal skin development.
      • Dale B.A.
      Filaggrin, the matrix protein of keratin.
      • Dale B.A.
      • Resing K.A.
      • Lonsdale-Eccles J.D.
      Filaggrin: a keratin filament associated protein.
      • Lynley A.M.
      • Dale B.A.
      The characterization of human epidermal filaggrin: a histidine-rich, keratin filament-aggregating protein.
      Filaggrin contains a high level of positively charge amino acids and participates in the aggregation of the keratin coiled-coils,
      • Dale B.A.
      • Presland R.B.
      • Lewis S.P.
      • Underwood R.A.
      • Fleckman P.
      Transient expression of epidermal filaggrin in cultured cells causes collapse of intermediate filament networks with alteration of cell shape and nuclear integrity.
      which have an overall negative charge. After filaggrin performs this function, it is modified to come off the keratin microfibrils and is then digested by proteolytic enzymes to produce the amino acid components of the natural moisturizing factor (NMF) of the SC.
      • Rawlings A.V.
      • Scott I.R.
      • Harding C.R.
      • Bowser P.A.
      Stratum corneum moisturization at the molecular level.
      • Scott I.R.
      • Harding C.R.
      • Barrett J.G.
      Histidine-rich protein of the keratohyalin granules: source of the free amino acids, urocanic acid and pyrrolidone carboxylic acid in the stratum corneum.
      • Scott I.R.
      • Harding C.R.
      Filaggrin breakdown to water binding compounds during development of the rat stratum corneum is controlled by the water activity of the environment.
      NMF consists of lactate, amino acids from filaggrin breakdown, and pyrollidone carboxylic acid (PCA) formed from the amino acid glutamine.
      • Cler E.J.
      • Fourtanier A.
      L'acide purrolidone caboxylique (PCA) et la peau.
      • Marty J.P.
      NMF and cosmetology of cutaneous hydration.
      • Spier H.W.
      • Pascher G.
      Analytical and functional physiology of the skin surface.
      These natural moisturizers are important to maintain proper hydration of the SC, allowing it to be flexible and to desquamate properly.
      • Jokura Y.
      • Ishikawa S.
      • Tokuda H.
      • Imokawa G.
      Molecular analysis of elastic properties of the stratum corneum by solid-state 13C-nuclear magnetic resonance spectroscopy.
      • Nakagawa N.
      • Sakai S.
      • Matsumoto M.
      • Yamada K.
      • Nagano M.
      • Yuki T.
      • et al.
      Relationship between NMF (lactate and potassium) content and the physical properties of the stratum corneum in healthy subjects.
      • Rawlings A.V.
      • Scott I.R.
      • Harding C.R.
      • Bowser P.A.
      Stratum corneum moisturization at the molecular level.
      • Robinson M.H.
      • Wickett R.R.
      Biochemical and bioengineering analysis of the skin's natural moisturizing factors.
      • Yamamura T.
      • Tezuka T.
      The water-holding capacity of the stratum corneum measured by 1H-NMR.
      In the lower layers of the epidermis, the keratinocyte has a typical phospholipid bilayer cell membrane. Phospholipid membranes are far too permeable to water to survive exposure to air in a dry environment. At the SG, the cell membrane of the keratinocyte is transformed into the resistant cell envelope of the corneocyte.
      • Hohl D.
      Cornified cell envelope.
      The transformation is brought about by the membrane-bound enzyme transglutaminase
      • Yoneda K.
      • McBride O.W.
      • Korge B.P.
      • Kim I.G.
      • Steinert P.M.
      The cornified cell envelope: loricrin and transglutaminases.
      (T-gase). T-gase cross-links 2 proteins together by connecting a glutamine side chain of one to a lysine side chain on the other, resulting in the formation of an isopeptide bond as illustrated in Fig 4.
      Figure thumbnail gr4
      Fig 4Formation of the isopeptide bond by transglutaminase.
      Several proteins participate in cross-linking reactions. The most predominate is loricrin, a globular protein released from the keratohyalin granules that is rich in hydrophobic amino acids and cysteine.
      • Hohl D.
      • Mehrel T.
      • Lichti U.
      • Turner M.L.
      • Roop D.R.
      • Steinert P.M.
      Characterization of human loricrin: structure and function of a new class of epidermal cell envelope proteins.
      • Mehrel T.
      • Hohl D.
      • Rothnagel J.A.
      • Longley M.A.
      • Bundman D.
      • Cheng C.
      • et al.
      Identification of a major keratinocyte cell envelope protein, loricrin.
      • Candi E.
      • Melino G.
      • Mei G.
      • Tarcsa E.
      • Chung S.I.
      • Marekov L.N.
      • et al.
      Biochemical, structural, and transglutaminase substrate properties of human loricrin, the major epidermal cornified cell envelope protein.
      The cytoplasm contains involucrin, a highly helical protein that is also a major substrate for T-gase and an important component of the cell envelope.
      • Eckert R.L.
      • Yaffe M.B.
      • Crish J.F.
      • Murthy S.
      • Rorke E.A.
      • Welter J.F.
      Involucrin—structure and role in envelope assembly.
      • Steinert P.M.
      • Marekov L.N.
      Direct evidence that involucrin is a major early isopeptide cross-linked component of the keratinocyte cornified cell envelope.
      • Yaffe M.B.
      • Beegen H.
      • Eckert R.L.
      Biophysical characterization of involucrin reveals a molecule ideally suited to function as an intermolecular cross-bridge of the keratinocyte cornified envelope.
      An early step in formation of the cell envelope is cross-linking between involucrin and loricrin.
      • Steinert P.M.
      • Marekov L.N.
      Direct evidence that involucrin is a major early isopeptide cross-linked component of the keratinocyte cornified cell envelope.
      Other proteins participate in cross-link formation, especially some small proteins rich in the amino acid proline, known as SPRs.
      • Hohl D.
      • de Viragh P.A.
      • Amiguet-Barras F.
      • Gibbs S.
      • Backendorf C.
      • Huber M.
      The small proline-rich proteins constitute a multigene family of differentially regulated cornified cell envelope precursor proteins.
      • Steinert P.M.
      • Marekov L.N.
      The proteins elafin, filaggrin, keratin intermediate filaments, loricrin, and small proline-rich proteins 1 and 2 are isodipeptide cross-linked components of the human epidermal cornified cell envelope.
      • Steven A.C.
      • Steinert P.M.
      Protein composition of cornified cell envelopes of epidermal keratinocytes.
      Eventually, the entire cell membrane is replaced by cross-linked proteins.
      • Kalinin A.
      • Marekov L.N.
      • Steinert P.M.
      Assembly of the epidermal cornified cell envelope.
      Keratin fibers are also cross-linked to the envelope,
      • Candi E.
      • Tarcsa E.
      • Digiovanna J.J.
      • Compton J.G.
      • Elias P.M.
      • Marekov L.N.
      • et al.
      A highly conserved lysine residue on the head domain of type II keratins is essential for the attachment of keratin intermediate filaments to the cornified cell envelope through isopeptide crosslinking by transglutaminases.
      and lipids (ceramides) are covalently attached to involucrin on the outer surface.
      • Marekov L.N.
      • Steinert P.M.
      Ceramides are bound to structural proteins of the human foreskin epidermal cornified cell envelope.
      • Wertz P.W.
      • Madison K.C.
      • Downing D.T.
      Covalently bound lipids of human stratum corneum.
      These attached ceramides are important to the barrier function of the SC.
      • Meguro S.
      • Arai Y.
      • Masukawa Y.
      • Uie K.
      • Tokimitsu I.
      Relationship between covalently bound ceramides and transepidermal water loss (TEWL).
      The new structure is known as the resistant cell envelope. A schematic of the SC cell envelope based on the work of Peter Steinert is shown in Fig 5.
      Figure thumbnail gr5
      Fig 5The corneocyte envelope as proposed by Steinert.
      • Steinert P.M.
      • Marekov L.N.
      The proteins elafin, filaggrin, keratin intermediate filaments, loricrin, and small proline-rich proteins 1 and 2 are isodipeptide cross-linked components of the human epidermal cornified cell envelope.
      • Steven A.C.
      • Steinert P.M.
      Protein composition of cornified cell envelopes of epidermal keratinocytes.
      • Kalinin A.
      • Marekov L.N.
      • Steinert P.M.
      Assembly of the epidermal cornified cell envelope.
      Recent studies indicate that the cell envelope is not always completely formed in at the SG/SC interface and that some incompletely formed envelopes may persist into the SC.
      • Hirao T.
      • Denda M.
      • Takahashi M.
      Identification of immature cornified envelopes in the barrier-impaired epidermis by characterization of their hydrophobicity and antigenicities of the components.
      Harding et al
      • Harding C.R.
      • Long S.A.
      • Richardson J.
      • Rogers J.
      • Zhang Z.
      • Bush A.
      • et al.
      The cornified cell envelope: an important marker of stratum corneum maturation in healthy and dry skin.
      have classified cell envelopes into 2 types: completely formed robust cell envelopes and incompletely formed fragile envelopes. The ratio of fragile to robust envelopes was reported to increase in dry and damaged skin.

      SC desomosomes

      Desomosomes are structures composed primarily of glycoproteins, which join cells together. The desomosomes joining corneocytes in the SC are modified from those that join epidermal keratinocytes by the addition of a protein called corneodesmosine,
      • Jonca N.
      • Guerrin M.
      • Hadjiolova K.
      • Caubet C.
      • Gallinaro H.
      • Simon M.
      • et al.
      Corneodesmosin, a component of epidermal corneocyte desmosomes, displays homophilic adhesive properties.
      • Lundstrom A.
      • Serre G.
      • Haftek M.
      • Egelrud T.
      Evidence for a role of corneodesmosin, a protein which may serve to modify desmosomes during cornification, in stratum corneum cell cohesion and desquamation.
      • Montezin M.
      • Simon M.
      • Guerrin M.
      • Serre G.
      Corneodesmosin, a corneodesmosome-specific basic protein, is expressed in the cornified epithelia of the pig, guinea pig, rat, and mouse.
      • Simon M.
      • Jonca N.
      • Guerrin M.
      • Haftek M.
      • Bernard D.
      • Caubet C.
      • et al.
      Refined characterization of corneodesmosin proteolysis during terminal differentiation of human epidermis and its relationship to desquamation.
      and SC desmosomes are sometimes referred to as corneodesmosomes. For proper desquamation of the SC to occur, the desmosomes must be digested by proteolytic enzymes.
      • Jonca N.
      • Guerrin M.
      • Hadjiolova K.
      • Caubet C.
      • Gallinaro H.
      • Simon M.
      • et al.
      Corneodesmosin, a component of epidermal corneocyte desmosomes, displays homophilic adhesive properties.
      • Simon M.
      • Jonca N.
      • Guerrin M.
      • Haftek M.
      • Bernard D.
      • Caubet C.
      • et al.
      Refined characterization of corneodesmosin proteolysis during terminal differentiation of human epidermis and its relationship to desquamation.
      • Brattsand M.
      • Stefansson K.
      • Lundh C.
      • Haasum Y.
      • Egelrud T.
      A proteolytic cascade of kallikreins in the stratum corneum.
      • Egelrud T.
      Desquamation in the stratum corneum.
      • Lundstrom A.
      • Egelrud T.
      Stratum corneum chymotryptic enzyme: a proteinase which may be generally present in the stratum corneum and with a possible involvement in desquamation.
      • Simon M.
      • Bernard D.
      • Minondo A.M.
      • Camus C.
      • Fiat F.
      • Corcuff P.
      • et al.
      Persistence of both peripheral and non-peripheral corneodesmosomes in the upper stratum corneum of winter xerosis skin versus only peripheral in normal skin.
      • Rawlings A.V.
      • Watkinson A.
      • Rogers J.
      • Mayo A.
      • Hope J.
      • Scott I.A.
      Abnormalities in stratum corneum structure, lipid composition, and desmosome degradation in soap-induced winter xerosis.
      At least some of the keratin fibers are thought to connect to the desmosomes as illustrated in Fig 4. Figure 5 shows electron micrographs of desmosomes in the SC.
      • Rawlings A.V.
      • Watkinson A.
      • Rogers J.
      • Mayo A.
      • Hope J.
      • Scott I.A.
      Abnormalities in stratum corneum structure, lipid composition, and desmosome degradation in soap-induced winter xerosis.
      In the lower SC, desmosomes are intact, but they are gradually digested by the time the skin surface is reached (Fig 6).
      Figure thumbnail gr6
      Fig 6Electron micrographs of tape strippings of normal skin. Degradation of desmosomes toward the surface of the stratum corneum: (A) First strip; desmosome fully degraded. (B) Second strip; partially degraded and encapsulated by lipid lamella. (C) Second strip; desmosome partially degraded. (D) Third strip; normal desmosome; lipid envelopes in direct contact with desmosome. (magnification, ×200,000) Reprinted from Rawlings et al
      • Rawlings A.V.
      • Watkinson A.
      • Rogers J.
      • Mayo A.
      • Hope J.
      • Scott I.A.
      Abnormalities in stratum corneum structure, lipid composition, and desmosome degradation in soap-induced winter xerosis.
      with permission of the Society of Cosmetic Chemists.
      In SC that is desquamating at its normal rate, corneocytes persist in the SC for approximately 2 weeks, depending on body site, before being shed into the environment.
      • Jansen L.H.
      • Hojyo-Tomoko M.T.
      • Kligman A.M.
      Improved fluorescence technique for estimating stratum corneum turnover time.
      • Marks R.
      • Black D.
      • Hamami I.
      • Caunt A.
      • Marshall R.J.
      A simplified method for measurement of desquamation using dansyl chloride fluorescence.
      • Roberts D.
      • Marks R.
      The determination of regional and age variations in the rate of desquamation: a comparison of four techniques.
      • Jackson S.M.
      • Williams M.L.
      • Feingold K.R.
      • Elias P.M.
      Pathobiology of the stratum corneum.
       On average, about one layer of corneocytes is shed each day from the surface and replaced by keratinocytes at the SG. The corneocytes that are shed each day can have a significant bacterial load and may be a source of contamination of the environment.
      • Jansen L.H.
      • Hojyo-Tomoko M.T.
      • Kligman A.M.
      Improved fluorescence technique for estimating stratum corneum turnover time.
      • Mackintosh C.A.
      Skin scales and microbial contamination.
      • Meers P.D.
      • Yeo G.A.
      Shedding of bacteria and skin squames after handwashing.
      • Noble W.C.
      Dispersal of skin microorganisms.

      The mortar

      The lamellar bodies that appear at the SG contain lipids, which are released into the intercellular space as the SC forms. These lipids are glucosyl ceramides, cholesterol, cholesterol esters, and long-chain fatty acids. In the intercellular space, the glucosyl cermides are converted to ceramides.
      • Holleran W.M.
      • Takagi Y.
      • Menon G.K.
      • Jackson S.M.
      • Lee J.M.
      • Feingold K.R.
      • et al.
      Permeability barrier requirements regulate epidermal beta-glucocerebrosidase.
      • Holleran W.M.
      • Takagi Y.
      • Menon G.K.
      • Legler G.
      • Feingold K.R.
      • Elias P.M.
      Processing of epidermal glucosylceramides is required for optimal mammalian cutaneous permeability barrier function.
      The lipids spontaneously organize into multiple layers between the SC cells.
      • Swartzendruber D.C.
      • Wertz P.W.
      • Kitko D.J.
      • Madison K.C.
      • Downing D.T.
      Molecular models of the intercellular lipid lamellae in mammalian stratum corneum.
      These layers are illustrated in Fig 7, which shows lipid layers in the lower SC after the overlaying SC has been removed by stripping with cellophane tape.
      • Rawlings A.V.
      • Watkinson A.
      • Rogers J.
      • Mayo A.
      • Hope J.
      • Scott I.A.
      Abnormalities in stratum corneum structure, lipid composition, and desmosome degradation in soap-induced winter xerosis.
      Figure thumbnail gr7
      Fig 7Normal lipid lamella at the third tape strip. (magnification, ×200,000) Reprinted from Rawlings et al
      • Rawlings A.V.
      • Watkinson A.
      • Rogers J.
      • Mayo A.
      • Hope J.
      • Scott I.A.
      Abnormalities in stratum corneum structure, lipid composition, and desmosome degradation in soap-induced winter xerosis.
      with permission of the Society of Cosmetic Chemists.
      This lipid “mortar” is critically important to the barrier function of skin, and ceramides are vital to the organization and functioning of the barrier.
      • Bouwstra J.A.
      • Gooris G.S.
      • Dubbelaar F.E.
      • Weerheim A.M.
      • Ijzerman A.P.
      • Ponec M.
      Role of ceramide 1 in the molecular organization of the stratum corneum lipids.
      Ceramides are sphingolipids linked to long-chain fatty acids. There are several ceramides found in the SC, including ceramides 1 and 2 shown in Fig 8.
      The SC contains no phospholipids. The phospholipids from the keratinocytes of the viable layers are broken down by phospholipases
      • Fluhr J.W.
      • Kao J.
      • Jain M.
      • Ahn S.K.
      • Feingold K.R.
      • Elias P.M.
      Generation of free fatty acids from phospholipids regulates stratum corneum acidification and integrity.
      • Mao-Qiang M.
      • Feingold K.R.
      • Jain M.
      • Elias P.M.
      Extracellular processing of phospholipids is required for permeability barrier homeostasis.
      • Mao-Qiang M.
      • Jain M.
      • Feingold K.R.
      • Elias P.M.
      Secretory phospholipase A2 activity is required for permeability barrier homeostasis.
      in the lower SC. This produces fatty acids, which are necessary for the development of a functional SC barrier and may play a role in producing the acid pH of the SC.
      • Fluhr J.W.
      • Kao J.
      • Jain M.
      • Ahn S.K.
      • Feingold K.R.
      • Elias P.M.
      Generation of free fatty acids from phospholipids regulates stratum corneum acidification and integrity.
      The SC has a surface pH of approximately 4 to 5.5, and this acidic pH, the so-called “acid mantle” of the skin,
      • Schmid M.H.
      • Korting H.C.
      The concept of the acid mantle of the skin: its relevance for the choice of skin cleansers.
      • Ohman H.
      • Vahlquist A.
      In vivo studies concerning a pH gradient in human stratum corneum and upper epidermis.
      • Goodman H.
      The acid mantle of the skin surface.
      • Rieger M.M.
      The apparent pH on the skin.
      may play a role in protecting against colonization of the skin surface by harmful bacteria.
      • Elias P.M.
      • Choi E.H.
      Interactions among stratum corneum defensive functions.
      • Elias P.M.
      Stratum corneum defensive functions: an integrated view.
      • Korting H.C.
      • Kober M.
      • Mueller M.
      • Braun-Falco O.
      Influence of repeated washings with soap and synthetic detergents on pH and resident flora of the skin of forehead and forearm: results of a cross-over trial in health probationers.
      Elias et al
      • Elias P.M.
      • Holleran W.M.
      • Calhoun C.J.
      • Quiec D.
      • Brown B.E.
      • Behne M.
      • et al.
      Permeability barrier homeostasis: the role of lipid processing.
      and Schurer and Elias
      • Schurer N.Y.
      • Elias P.M.
      The biochemistry and function of stratum corneum lipids.
      have proposed that the lipids released from lamellar granules in the SG are precursor or probarrier lipids that must be processed in extracellular spaces.
      • Schurer N.Y.
      • Elias P.M.
      The biochemistry and function of stratum corneum lipids.
      The necessity of this extracellular lipid processing emphasizes the dynamic nature of the SC. The SC can no longer be considered as a Saran wrap (SC Johnson, Racine, WI)-like covering of the skin. It is a dynamic tissue that is metabolically active, even if it is not a living tissue in the classic sense. For more details on the dynamic SC and the “updated” bricks and mortar model, see the excellent review by Harding.
      • Harding C.R.
      The stratum corneum: structure and function in health and disease.
      The lamellar bodies of the SC release other important molecules into the intercorneocyte spaces in addition to the lipids that form the permeability barrier. The proteolytic enzymes involved in desmosome hydrolysis
      • Menon G.K.
      • Ghadially R.
      • Williams M.L.
      • Elias P.M.
      Lamellar bodies as delivery systems of hydrolytic enzymes: implications for normal and abnormal desquamation.
      • Sondell B.
      • Thornell L.E.
      • Egelrud T.
      Evidence that stratum corneum chymotryptic enzyme is transported to the stratum corneum extracellular space via lamellar bodies.
      as well as inhibitors of those enzyme to control rates of desquamation
      • Ishida-Yamamoto A.
      • Deraison C.
      • Bonnart C.
      • Bitoun E.
      • Robinson R.
      • O'Brien T.J.
      • et al.
      LEKTI is localized in lamellar granules, separated from KLK5 and KLK7, and is secreted in the extracellular spaces of the superficial stratum granulosum.
      are released by the lamellar bodies, as are antimicrobial peptides called defensins,
      • Oren A.
      • Ganz T.
      • Liu L.
      • Meerloo T.
      In human epidermis, β-defensin 2 is packaged in lamellar bodies.
      which may play a role in protecting the skin from infection.
      • Ali R.S.
      • Falconer A.
      • Ikram M.
      • Bissett C.E.
      • Cerio R.
      • Quinn A.G.
      Expression of the peptide antibiotics human β defensin-1 and human β defensin-2 in normal human skin.
      Production of these peptides is increased in skin with psoriasis but not in skin with atopic dermatitis (eczema).
      • Ong P.Y.
      • Ohtake T.
      • Brandt C.
      • Strickland I.
      • Boguniewicz M.
      • Ganz T.
      • et al.
      Endogenous antimicrobial peptides and skin infections in atopic dermatitis.
      • Nizet V.
      • Ohtake T.
      • Lauth X.
      • Trowbridge J.
      • Rudisill J.
      • Dorschner R.A.
      • et al.
      Innate antimicrobial peptide protects the skin from invasive bacterial infection.
      This may account for the much higher susceptibility of eczema sufferers to skin infection, and eczematous skin may be more likely to spread nocosomial infections.
      • Richards J.
      • Williams H.
      • Warner M.
      • Johnson A.P.
      • Reith S.
      • Woodford N.
      • et al.
      Nosocomial spread of Staphylococcus aureus showing intermediate resistance to methicillin.
      The very specialized “bricks and mortar” of the SC work together to produce a covering for the skin that is both flexible and superbly protective.
      • Elias P.M.
      • Choi E.H.
      Interactions among stratum corneum defensive functions.
      • Elias P.M.
      Stratum corneum defensive functions: an integrated view.
      When the SC is functioning properly, it defends us against dehydration, external toxins, and bacterial assault as well as protecting the more fragile keratinocytes below from mechanical disruption.

      Hand hygiene and epidermal barrier function

      Surfactants

      Most handwash products rely on surfactants for their cleansing action. Surfactants are surface-active molecules. They have a hydrophobic portion referred to as the tail and a hydrophilic portion referred to as the head group. A ball and stick representation of an ionic surfactant is shown in Fig 9.
      Figure thumbnail gr9
      Fig 9Ball and stick representation of a surfactant molecule.
      Surfactants are classified primarily by the characteristics of the head groups. Natural soaps are the metal salts of fatty acids, so the head group is a carboxylic acid and the X is either sodium or potassium. The major classifications of surfactants are anionic, cationic, ampotheric, and nonionic, depending on whether the head group has a negative (anionic) or positive charge (cationic) or both (amphoteric) or is uncharged (nonionic).
      • Rieger M.M.
      Surfactant chemistry and classification.
      The hydrophobic tail can vary in length and structure, but hydrocarbon chains of various lengths are the most common. The structure of one of the most frequently used anionic surfactants, sodium lauryl sulfate (SLS), is shown below. Here, the hydrophobic tail is the 12 carbon hydrocarbon chain, and the head group is the sulfate moiety.
      CH3-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-O-S-O3 NA+
      Surfactants have a wide variety of applications and are especially useful for cleansing. They can form association structures such as micelles, which can dissolve oils directly. The hydrophobic tail can associate with oils on a surface causing it to lift up from the surface, and they can help to break up other types of soil. Nearly all products for cleansing skin or hair contain surfactants.

      Surfactants effects on the bricks and mortar

      Unfortunately, the very characteristics of surfactants that make them so useful for cleaning allow them to damage both the bricks and mortar of protective barrier of the SC. Repeated washing of the skin with soaps and surfactants can negatively impact the multiple functions of the epidermal barrier. The skin problems that can be engendered by the necessity of repeated exposures in a health care environment are multiple. Skin damage from surfactants can be further exacerbated by occlusion from wearing gloves and the mechanical action of scrubbing the hands. The negative effects that soaps and surfactants can have on the epidermal barrier are illustrated in Fig 10.
      Figure thumbnail gr10
      Fig 10Schematic of surfactant interactions with the epidermis. (A) Surfactant molecules enter the SC, binding to proteins and disrupting lipid structures, and eventually reach the viable epidermis. (B) Water depletes NMF after lipid disruption and corneocytes swelling. (C) The formation of the SC is up-regulated by inflammatory factors leading to improper barrier function. (D) Incomplete hydrolysis of desmosomes leads to scale formation.
      Surfactant molecules are well-known to bind to proteins,
      • Blake-Haskins J.C.
      • Scala D.
      • Rhein L.D.
      • Robbins C.R.
      Predicting surfactant irritation from the swelling response of a collagen film.
      • Reynolds J.A.
      • Tanford C.
      Binding of dodecyl sulfate to proteins at high binding ratios: possible implications for the state of proteins in biological membranes.
      • Reynolds J.A.
      • Tanford C.
      The gross conformation of protein-sodium dodecyl sulfate complexes.
      • Tanford C.
      • Nozaki Y.
      • Reynolds J.A.
      • Makino S.
      Molecular characterization of proteins in detergent solutions.
      causing changes in their structure, and have been shown to bind to the SC.
      • Ananthapadmanabhan K.P.
      • Yu K.K.
      • Meyers C.L.
      • Aronson M.P.
      Binding of surfactants to the stratum corneum.
      Surfactants known to be aggressive to the skin such as SLS bind more strongly than milder surfactants such as isethionates. Surfactants cause swelling of the SC in vitro, presumably by interaction with SC proteins,
      • Robbins C.R.
      • Fernee K.
      Some observations on the swelling of behavior of human epidermal membrane.
      • Blake-Haskins J.C.
      • Scala D.
      • Rhein L.D.
      • Robbins C.R.
      Predicting surfactant irritation from the swelling response of a collagen film.
      • Rhein L.D.
      Review of properties of surfactants that determine their interactions with stratum corneum.
      • Rhein L.D.
      • Robbins C.R.
      • Fernee K.
      • Cantore R.
      Surfactant structure effects on swelling of isolated human stratum corneum.
      and the degree of swelling is well correlated with the harshness of either individual or mixtures of surfactant mixtures.
      • Rhein L.D.
      • Robbins C.R.
      • Fernee K.
      • Cantore R.
      Surfactant structure effects on swelling of isolated human stratum corneum.
      • Rhein L.D.
      • Simion F.A.
      • Hill R.L.
      • Cagan R.H.
      • Mattai J.
      • Maibach H.I.
      Human cutaneous response to a mixed surfactant system: role of solution phenomena in controlling surfactant irritation.
      The lipid mortar is the major barrier to permeability of the SC, and surfactants are well-known to increase the ability of exogenous compounds to penetrate the skin
      • Loden M.
      The simultaneous penetration of water and sodium lauryl sulfate through isolated human skin.
      • Scheuplein R.J.
      • Ross L.
      Effects of surfactants and solvents on the permeability of the epidermis.
      and to increase the rate of water loss through the skin,
      • Agner T.
      • Serup J.
      Skin reactions to irritants as assessed by non-invasive bioengineering methods.
      • Berardesca E.
      • Maibach H.I.
      Transepidermal water loss and skin surface hydration in the noninvasive assessment of stratum corneum function.
      • Branco N.
      • Lee I.
      • Zhai H.
      • Maibach H.I.
      Long-term repetitive sodium lauryl sulfate-induced irritation of the skin: an in vivo study.
      • di Nardo A.
      • Sugino K.
      • Wertz P.
      • Ademola J.
      • Maibach H.I.
      Sodium lauryl sulfate (SLS) induced irritant contact dermatitis: a correlation study between ceramides and in vivo parameters of irritation.
      • Fluhr J.W.
      • Praessler J.
      • Akengin A.
      • Fuchs S.M.
      • Kleesz P.
      • Grieshaber R.
      • et al.
      Air flow at different temperatures increases sodium lauryl sulphate-induced barrier disruption and irritation in vivo.
      • Gabard B.
      • Chatelain E.
      • Bieli E.
      • Haas S.
      Surfactant irritation: in vitro corneosurfametry and in vivo bioengineering.
      • Grunewald A.M.
      • Gloor M.
      • Gehring W.
      • Kleesz P.
      Damage to the skin by repetitive washing.
      • Treffel P.
      • Gabard B.
      Measurement of sodium lauryl sulfate-induced skin irritation.
      • Tupker R.A.
      • Pinnagoda J.
      • Nater J.P.
      The transient and cumulative effect of sodium lauryl sulphate on the epidermal barrier assessed by transepidermal water loss: inter-individual variation.
      • Van Neste D.
      • de Brouwer B.
      Monitoring of skin response to sodium lauryl sulphate: clinical scores versus bioengineering methods.
      • Wilhelm K.P.
      • Freitag G.
      • Wolff H.H.
      Surfactant-induced skin irritation and skin repair: evaluation of a cumulative human irritation model by noninvasive techniques.
      presumably because of their effects on the lipid barrier SC.
      • Madison K.C.
      Barrier function of the skin: “la raison d'etre” of the epidermis.
      • Scheuplein R.J.
      • Ross L.
      Effects of surfactants and solvents on the permeability of the epidermis.
      • Grubauer G.
      • Feingold K.R.
      • Harris R.M.
      • Elias P.M.
      Lipid content and lipid type as determinants of the epidermal permeability barrier.
      • Nemes Z.
      • Steinert P.M.
      Bricks and mortar of the epidermal barrier.
      An obvious mechanism for the decrease in barrier function after surfactant treatment could be direct removal of SC lipids and removal of SC lipids by surfactant treatment, an effect that has been reported in some studies.
      • Imokawa G.
      • Akasaki S.
      • Minematsu Y.
      • Kawai M.
      Importance of intercellular lipids in water-retention properties of the stratum corneum: induction and recovery study of surfactant dry skin.
      • Imokawa G.
      Surfactant mildness.
      Other studies on surfactant-induced irritation indicate that, rather than greatly reducing the total lipid content, the main effects are to alter lipid composition
      • Rawlings A.V.
      • Watkinson A.
      • Rogers J.
      • Mayo A.
      • Hope J.
      • Scott I.A.
      Abnormalities in stratum corneum structure, lipid composition, and desmosome degradation in soap-induced winter xerosis.
      • Fulmer A.W.
      • Kramer G.J.
      Stratum corneum lipid abnormalities in surfactant-induced dry scaly skin.
      and disorder the lamellar structure of SC lipids.
      • Rawlings A.V.
      • Watkinson A.
      • Rogers J.
      • Mayo A.
      • Hope J.
      • Scott I.A.
      Abnormalities in stratum corneum structure, lipid composition, and desmosome degradation in soap-induced winter xerosis.
      • Misra M.
      • Ananthapadmanabhan K.P.
      • Hoyberg K.
      • Gurskey R.
      • Prowell S.
      • Aronson M.P.
      Correlation between surfactant-induced ultrastrucural changes in epidermis and transepidermal water loss.
      • Ribaud C.
      • Garson J.C.
      • Doucet J.
      • Leveque J.L.
      Organization of stratum corneum lipids in relation to permeability: influence of sodium lauryl sulfate and preheating.
      • Warner R.R.
      • Boissy Y.L.
      • Lilly N.A.
      • Spears M.J.
      • McKillop K.
      • Marshall J.L.
      • et al.
      Water disrupts stratum corneum lipid lamellae: damage is similar to surfactants.
      • Fartasch M.
      Ultrastructure of the epidermal barrier after irritation.
      • Fartasch M.
      Human barrier formation and reaction to irritants.
      Figure 11 illustrates the extreme disordering of the SC lamellar lipid structure for soap-induced, winter-dry skin.
      • Rawlings A.V.
      • Watkinson A.
      • Rogers J.
      • Mayo A.
      • Hope J.
      • Scott I.A.
      Abnormalities in stratum corneum structure, lipid composition, and desmosome degradation in soap-induced winter xerosis.
      Figure thumbnail gr11
      Fig 11Disordering of lipids in the outer SC in soap induced winter dry skin. Reprinted from Rawlings et al
      • Rawlings A.V.
      • Watkinson A.
      • Rogers J.
      • Mayo A.
      • Hope J.
      • Scott I.A.
      Abnormalities in stratum corneum structure, lipid composition, and desmosome degradation in soap-induced winter xerosis.
      with permission of the Society of Cosmetic Chemists.

      Surfactant effects on the acid mantle

      As discussed above, the SC has a surface pH of approximately 4 to 5.5, and this acidic pH, the so-called “acid mantle” of the SC,
      • Schmid M.H.
      • Korting H.C.
      The concept of the acid mantle of the skin: its relevance for the choice of skin cleansers.
      • Goodman H.
      The acid mantle of the skin surface.
      • Rieger M.M.
      The apparent pH on the skin.
      • Ohman H.
      • Vahlquist A.
      In vivo studies concerning a pH gradient in human stratum corneum and upper epidermis.
      may play a role in protecting against colonization of the skin surface by harmful bacterial.
      • Elias P.M.
      • Choi E.H.
      Interactions among stratum corneum defensive functions.
      • Elias P.M.
      Stratum corneum defensive functions: an integrated view.
      • Korting H.C.
      • Kober M.
      • Mueller M.
      • Braun-Falco O.
      Influence of repeated washings with soap and synthetic detergents on pH and resident flora of the skin of forehead and forearm: results of a cross-over trial in health probationers.
      Bar soaps made from natural soap are alkaline by their very nature and can raise the pH of the skin during washing.
      • Rieger M.M.
      The apparent pH on the skin.
      • Korting H.C.
      • Kober M.
      • Mueller M.
      • Braun-Falco O.
      Influence of repeated washings with soap and synthetic detergents on pH and resident flora of the skin of forehead and forearm: results of a cross-over trial in health probationers.
      • Trobaugh C.M.
      • Wickett R.R.
      Personal care products: effects on skin surface pH.
      Trobaugh and Wickett
      • Trobaugh C.M.
      • Wickett R.R.
      Personal care products: effects on skin surface pH.
      reported that a single washing with typical bars soaps raised the pH from the normal range of 5.0 to 5.5 to approximately 7.5. Washing with a bar soap based on the synthetic detergent sodium cocoyl isethionate did not have this effect. The pH of soap-washed skin gradually declined toward normal over the next several hours because SC has components (fatty acids) that naturally provide buffering capacity.
      • Fluhr J.W.
      • Kao J.
      • Jain M.
      • Ahn S.K.
      • Feingold K.R.
      • Elias P.M.
      Generation of free fatty acids from phospholipids regulates stratum corneum acidification and integrity.
      • Krien P.M.
      • Kermici M.
      Evidence for the existence of a self-regulated enzymatic process within the human stratum corneum—an unexpected role for urocanic acid.
      Trobaugh and Wickett
      • Trobaugh C.M.
      • Wickett R.R.
      Personal care products: effects on skin surface pH.
      further reported that washing 10 times per day with soap overcame the skin's natural buffering capacity to some extent, and, within 3 days, the skin surface pH was consistently above 6.0, suggesting that the mechanism for maintaining the acid mantle was disrupted. In addition, cracking (fissuring) grades increased (worsened) from 1.5 to 3.0 on a 5.0-point scale. The authors interpreted the cracking as due to the harsh nature of natural soap bars and not simply to the high pH of the soap bars. Newman and Seitz
      • Newman J.L.
      • Seitz J.C.
      Intermittent use of an antimicrobial hand gel for reducing soap-induced irritation of health care personnel.
      found similar increases in skin surface pH on repeated soap washing paralleled by similar increases in cracking grade. Korting et al
      • Korting H.C.
      • Kober M.
      • Mueller M.
      • Braun-Falco O.
      Influence of repeated washings with soap and synthetic detergents on pH and resident flora of the skin of forehead and forearm: results of a cross-over trial in health probationers.
      also reported increases in skin pH following the use of natural soaps and a concomitant increase in skin colonization by coagulase-negative staphylococci.

      Surfactant effects on SC hydration and flexibility

      Since the pioneering work of Blank,
      • Blank I.H.
      Factors which influence the water content of the stratum corneum.
      • Blank I.H.
      Further observations on factors which influence the water content of stratum corneum.
      we have known that water is a key factor for maintaining the pliability of the SC. Studies with isolated SC have found that well-hydrated SC is very flexible and dry SC is very stiff and brittle.
      • Blank I.H.
      Factors which influence the water content of the stratum corneum.
      • Van Duzee B.F.
      The influence of water content, chemical treatment and temperature on the rheological properties of stratum corneum.
      • Wickett R.R.
      A review of stratum corneum plasticization mechanisms.
      Many in vivo studies have also found hydration to increase the elasticity of the skin.
      • Murray B.C.
      • Wickett R.R.
      Sensitivity of cutometer data to stratum corneum hydration level.
      • Wickett R.R.
      Stretching the skin surface: skin elasticity.
      • Christensen M.S.
      • Hargens C.W.
      • Nacht S.
      • Gans E.H.
      Viscoelastic properties of intact human skin: instrumentation, hydration effects, and the contribution of the stratum corneum.
      • Cooper E.R.
      • Missel P.J.
      • Hannon D.P.
      • Albright G.B.
      Mechanical Properties of dry, normal and glycerol-treated skin as measured by the gas-bearing electrodynamometer.
      • de Rigal J.
      • Leveque J.L.
      In vivo measurement of the stratum corneum elasticity.
      • Dobrev H.
      Use of Cutometer to assess epidermal hydration.
      • Jemec G.B.
      • Wulf H.C.
      The plasticising effect of moisturizers on human skin in vivo:a measure of moisturizing potency?.
      Loss of elasticity in surfactant-damaged dry skin can lead to cracking of the skin, especially around the knuckles at which stretching and flexing of the skin is required for movement.

      Effects on SC metabolism and desquamation

      In addition to the requirement of water for SC flexibility, we now understand that adequate hydration of the SC is required for the important metabolic processes occurring in the SC, such as conversion of probarrier lipids to barrier lipids
      • Fluhr J.W.
      • Kao J.
      • Jain M.
      • Ahn S.K.
      • Feingold K.R.
      • Elias P.M.
      Generation of free fatty acids from phospholipids regulates stratum corneum acidification and integrity.
      • Elias P.M.
      • Holleran W.M.
      • Calhoun C.J.
      • Quiec D.
      • Brown B.E.
      • Behne M.
      • et al.
      Permeability barrier homeostasis: the role of lipid processing.
      • Holleran W.M.
      • Takagi Y.
      • Menon G.K.
      • Legler G.
      • Feingold K.R.
      • Elias P.M.
      Processing of epidermal glucosylceramides is required for optimal mammalian cutaneous permeability barrier function.
      • Mao-Qiang M.
      • Feingold K.R.
      • Jain M.
      • Elias P.M.
      Extracellular processing of phospholipids is required for permeability barrier homeostasis.
      • Mao-Qiang M.
      • Jain M.
      • Feingold K.R.
      • Elias P.M.
      Secretory phospholipase A2 activity is required for permeability barrier homeostasis.
      to maintain barrier function and the hydrolysis of desmosomes
      • Egelrud T.
      Desquamation in the stratum corneum.
      • Lundstrom A.
      • Egelrud T.
      Stratum corneum chymotryptic enzyme: a proteinase which may be generally present in the stratum corneum and with a possible involvement in desquamation.
      • Simon M.
      • Bernard D.
      • Minondo A.M.
      • Camus C.
      • Fiat F.
      • Corcuff P.
      • et al.
      Persistence of both peripheral and non-peripheral corneodesmosomes in the upper stratum corneum of winter xerosis skin versus only peripheral in normal skin.
      • Rawlings A.V.
      • Watkinson A.
      • Rogers J.
      • Mayo A.
      • Hope J.
      • Scott I.A.
      Abnormalities in stratum corneum structure, lipid composition, and desmosome degradation in soap-induced winter xerosis.
      • Brattsand M.
      • Stefansson K.
      • Lundh C.
      • Haasum Y.
      • Egelrud T.
      A proteolytic cascade of kallikreins in the stratum corneum.
      • Haftek M.
      • Simon M.
      • Kanitakis J.
      • Marechal S.
      • Claudy A.
      • Serre G.
      • et al.
      Expression of corneodesmosin in the granular layer and stratum corneum of normal and diseased epidermis.
      necessary for normal desquamation. Skin in good condition maintains SC water content at approximately 30% by weight (except at the very surface), whereas very dry skin can be as low as 10% to 15% water throughout most of the SC down to nearly the level of the SG.
      • Warner R.R.
      • Lilly N.A.
      Correlation of water content with ultrastructure in the stratum corneum.
      The natural moisturizing factors of the SC are very important to maintaining SC hydration.
      • Rawlings A.V.
      • Scott I.R.
      • Harding C.R.
      • Bowser P.A.
      Stratum corneum moisturization at the molecular level.
      • Robinson M.H.
      • Wickett R.R.
      Biochemical and bioengineering analysis of the skin's natural moisturizing factors.
      • Scott I.R.
      • Harding C.R.
      • Barrett J.G.
      Histidine-rich protein of the keratohyalin granules: source of the free amino acids, urocanic acid and pyrrolidone carboxylic acid in the stratum corneum.
      • Scott I.R.
      • Harding C.R.
      Filaggrin breakdown to water binding compounds during development of the rat stratum corneum is controlled by the water activity of the environment.
      • Visscher M.O.
      • Tolia G.T.
      • Wickett R.R.
      • Hoath S.B.
      Effect of soaking and natural moisturizing factor on stratum corneum water-handling properties.
      NMF is easily lost from the skin, especially after the barrier is perturbed,
      • Robinson M.H.
      • Wickett R.R.
      Biochemical and bioengineering analysis of the skin's natural moisturizing factors.
      • Rawlings A.V.
      • Matts P.J.
      Stratum corneum moisturization at the molecular level: an update in relation to the dry skin cycle.
      • Visscher M.O.
      • Tolia G.T.
      • Wickett R.R.
      • Hoath S.B.
      Effect of soaking and natural moisturizing factor on stratum corneum water-handling properties.
      and it is likely that NMF removal is a major factor in the development of dry skin following repeated hygiene procedures.
      The desmosomes connecting SC cells (Fig 6) are gradually digested by a cascade of proteolytic enzymes.
      • Egelrud T.
      Desquamation in the stratum corneum.
      • Brattsand M.
      • Stefansson K.
      • Lundh C.
      • Haasum Y.
      • Egelrud T.
      A proteolytic cascade of kallikreins in the stratum corneum.
      In dry and in dry, damaged skin, these enzymes are not able to perform their function properly, thereby causing intact desmosomes to persist into the upper SC.
      • Simon M.
      • Bernard D.
      • Minondo A.M.
      • Camus C.
      • Fiat F.
      • Corcuff P.
      • et al.
      Persistence of both peripheral and non-peripheral corneodesmosomes in the upper stratum corneum of winter xerosis skin versus only peripheral in normal skin.
      • Rawlings A.V.
      • Watkinson A.
      • Rogers J.
      • Mayo A.
      • Hope J.
      • Scott I.A.
      Abnormalities in stratum corneum structure, lipid composition, and desmosome degradation in soap-induced winter xerosis.
      This results in shedding of large scales or flakes rather than individual cells. It also increases the surface area of the SC available for bacterial adhesion and may be a factor in the increased presence of colonizing bacteria on damaged hands.
      • Korting H.C.
      • Kober M.
      • Mueller M.
      • Braun-Falco O.
      Influence of repeated washings with soap and synthetic detergents on pH and resident flora of the skin of forehead and forearm: results of a cross-over trial in health probationers.
      • Larson E.L.
      • Hughes C.A.
      • Pyrek J.D.
      • Sparks S.M.
      • Cagatay E.U.
      • Bartkus J.M.
      Changes in bacterial flora associated with skin damage on hands of health care personnel.

      Surfactant effects on cytokines-hyperproliferation

      Surfactants can induce the release of inflammatory cytokines (cell-signaling molecules). Interleukins, particularly interleukin-1α, are released upon surfactant exposure.
      • Berardesca E.
      • Distante F.
      The modulation of skin irritation.
      • Corsini E.
      • Galli C.L.
      Cytokines and irritant contact dermatitis.
      • Perkins M.A.
      • Osterhues M.A.
      • Farage M.A.
      • Robinson M.K.
      A noninvasive method to assess skin irritation and compromised skin conditions using simple tape adsorption of molecular markers of inflammation.
      There are 2 mechanisms that can contribute to this effect. Surfactants are clearly able to penetrate the SC and encounter keratinocytes in the viable layers of the epidermis. The interaction of surfactants with keratinocytes is known to induce cytokine release.
      • Corsini E.
      • Galli C.L.
      Cytokines and irritant contact dermatitis.
      • Gibbs S.
      • Vietsch H.
      • Meier U.
      • Ponec M.
      Effect of skin barrier competence on SLS and water-induced IL-1α expression.
      Interleukin-1α is also released as a natural response of the epidermal barrier to disruption
      • Wood L.C.
      • Elias P.M.
      • Calhoun C.
      • Tsai J.C.
      • Grunfeld C.
      • Feingold K.R.
      Barrier disruption stimulates interleukin-1 α expression and release from a pre-formed pool in murine epidermis.
      as part of the protective process intended to stimulate repair of the barrier. In surfactant-irritated skin, these effects may combine to produce overstimulation, causing the skin to hyperproliferate.
      • Wilhelm K.P.
      • Saunders J.C.
      • Maibach H.I.
      Increased stratum corneum turnover induced by subclinical irritant dermatitis.
      The overstimulated skin has an increased rate of cornification that does not permit sufficient time for the complex events that must occur in the SG to form a fully functional SC. A normal SC lipid profile will not be produced,
      • Rawlings A.V.
      • Watkinson A.
      • Rogers J.
      • Mayo A.
      • Hope J.
      • Scott I.A.
      Abnormalities in stratum corneum structure, lipid composition, and desmosome degradation in soap-induced winter xerosis.
      • Fulmer A.W.
      • Kramer G.J.
      Stratum corneum lipid abnormalities in surfactant-induced dry scaly skin.
      and SC cell envelopes that incompletely formed and are thus “fragile” will form in higher than normal proportion.
      • Harding C.R.
      • Long S.A.
      • Richardson J.
      • Rogers J.
      • Zhang Z.
      • Bush A.
      • et al.
      The cornified cell envelope: an important marker of stratum corneum maturation in healthy and dry skin.
      Cells with fragile envelopes will lose their NMF easily and not have good barrier properties. These effects will combine to lead to SC with impaired barrier function. This resulting barrier will have weaknesses in both the bricks and the mortar. Consequently, it will be increasingly susceptible to further surfactant damage and less able to hold water to allow SC enzymes to function. The result will be a vicious cycle of skin damage.
      • Rawlings A.V.
      • Matts P.J.
      Stratum corneum moisturization at the molecular level: an update in relation to the dry skin cycle.

      Breaking the dry skin cycle

      The challenge in the health care environment is to somehow break this dry skin cycle while meeting hygiene guidelines that require frequent cleansing of the hands. Multiple approaches are required. The first step is to use cleansers formulated with mild surfactants such as isethionates,
      • Ananthapadmanabhan K.P.
      • Moore D.J.
      • Subramanyan K.
      • Misra M.
      • Meyer F.
      Cleansing without compromise: the impact of cleansers on the skin barrier and the technology of mild cleansing.
      amphodiacetates, and sulfosuccinates. Blending surfactants together in appropriate ratios can also significantly improve their mildness.
      • Rhein L.D.
      • Simion F.A.
      • Hill R.L.
      • Cagan R.H.
      • Mattai J.
      • Maibach H.I.
      Human cutaneous response to a mixed surfactant system: role of solution phenomena in controlling surfactant irritation.
      The use of alcohol-based hand sanitizers that contain appropriately formulated emollients may also help to improve hand condition.
      • Larson E.
      • Silberger M.
      • Jakob K.
      • Whittier S.
      • Lai L.
      • Della L.P.
      • et al.
      Assessment of alternative hand hygiene regimens to improve skin health among neonatal intensive care unit nurses.
      • Larson E.
      Hygiene of the skin: when is clean too clean?.
      • Newman J.L.
      • Seitz J.C.
      Intermittent use of an antimicrobial hand gel for reducing soap-induced irritation of health care personnel.
      Although improving the surfactant cleansing system will help reduce skin problems, it is likely to be necessary to use well-formulated therapeutic lotions to help break the cycle and reestablish the formation of normal SC. Glycerin has been shown to be an effective skin-conditioning agent when incorporated into a lotion at 5% or higher.
      • Bissett D.L.
      • McBride J.F.
      Skin conditioning with glycerol.
      • Li F.
      • Visscher M.
      • Conroy E.
      • Wickett R.R.
      The ability of electrical measurements to predict skin moisturization. II. Correlations between one-hour measurements and long-term results.
      It has several positive effects on the physical properties of the SC, including increasing hydration
      • Batt M.D.
      • Davis W.B.
      • Fairhurst E.
      • Gerrard W.A.
      • Ridge B.D.
      Changes in the physical properties of the stratum corneum following treatment with glycerol.
      • Batt M.D.
      • Fairhurst E.
      Hydration of the stratum corneum.
      • Li F.
      • Visscher M.
      • Conroy E.
      • Wickett R.R.
      The ability of electrical measurements to predict skin moisturization. I. Effects of salt and glycerin on short-term measurements.
      and improving elasticity.
      • Cooper E.R.
      • Missel P.J.
      • Hannon D.P.
      • Albright G.B.
      Mechanical Properties of dry, normal and glycerol-treated skin as measured by the gas-bearing electrodynamometer.
      • de Rigal J.
      • Leveque J.L.
      In vivo measurement of the stratum corneum elasticity.
      • Batt M.D.
      • Davis W.B.
      • Fairhurst E.
      • Gerrard W.A.
      • Ridge B.D.
      Changes in the physical properties of the stratum corneum following treatment with glycerol.
      Glycerin has been reported to normalize the rate of desmosome hydrolysis in dry skin,
      • Rawlings A.
      • Harding C.
      • Watkinson A.
      • Banks J.
      • Ackerman C.
      • Sabin R.
      The effect of glycerol and humidity on desmosome degradation in stratum corneum.
      and glycerin has been shown to accelerate the repair of the SC barrier after damage by SLS.
      • Fluhr J.W.
      • Gloor M.
      • Lehmann L.
      • Lazzerini S.
      • Distante F.
      • Berardesca E.
      Glycerol accelerates recovery of barrier function in vivo.
      Petrolatum is an effective treatment for dry skin
      • Kligman A.M.
      Regression method for assessing the efficacy of moisturizers.
      both as a single ingredient and as a component of creams and lotions. Petrolatum is an occlusive agent that reduces the rate of water loss through skin, increasing hydration by causing buildup of water in the upper SC. Petrolatum has been shown to penetrate deeply into damaged skin and enhance recovery of SC barrier function.
      • Ghadially R.
      • Halkier-Sorensen L.
      • Elias P.M.
      Effects of petrolatum on stratum corneum structure and function.
      Use of lotions and creams outside of work may have significant benefits for health care workers and should be stressed as part of the routine hand hygiene practices. Two factors must be considered while using lotions in the health care environment. One is the possibility that oils such as mineral oil and petrolatum in the lotion may compromise the integrity of latex gloves.
      • Beezhold D.H.
      • Kostyal D.A.
      • Wiseman J.
      The transfer of protein allergens from latex gloves: a study of influencing factors.
      The other is that lotions formulated with anionic emulsifiers may inactivate the residual activity of chlorhexidine gluconate on the skin.
      • Benson L.
      • LeBlanc D.
      • Bush L.
      • White J.
      The effects of surfactant systems and moisturizing products on the residual activity of a chlorhexidine gluconate handwash using a pigskin substrate.
      • Frantz S.W.
      • Haines K.A.
      • Azar C.G.
      • Ward J.I.
      • Homan S.M.
      • Roberts R.B.
      Chlorhexidine gluconate (CHG) activity against clinical isolates of vancomycin-resistant Enterococcus faecium (VREF) and the effects of moisturizing agents on CHG residue accumulation on the skin.
      These issues can be addressed by providing lotions that contain lower levels of oils such as petrolatum and mineral oil and that use either nonionic or cationic emulsifers while using latex gloves and chlorhexidine gluconate-containing cleansers.
      • Larson E.
      Skin hygiene and infection prevention: more of the same or different approaches?.
      The consistent use of mild cleansers, alcohol rubs with emollients, and effective skin lotion both during and outside of work should go far to help maintain the protective function of the SC, keeping both the “bricks” and the “mortar” intact while meeting the hand hygiene requirements of the health care worker.

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