Stratum corneum intercellular lipids

The physical state and molecular organization of the stratum corneum intercellular lipid matrix largely determines the hydration-level of the stratum corneum and thus, indirectly, the mechanical properties and appearance of the skin. A better understanding of stratum corneum lipid organization may thus aid the development of more efficient cosmetic formulations. 

The composition of the stratum corneum intercellular lipids may have profound effects on desquamation. In addition to modifying effects on, for example, proteolytic enzymes and their substrates,34 lipids may also be directly involved in corneocyte cohesion. The effects of cholesterol sulfate have already been mentioned. In addition to RXI, there are a number of other hereditary diseases with disorders of desquamation associated with disturbances in lipid metabolism. Furthermore, scaling as a result of treatment with lipid-lowering drugs has been observed (for review, see References 1 and 2). 

Figure 12 Models for electron density profiles ofhuman and mouse stratum corneum intercellular lipid domains. Fourier transformation of the profiles produce diffracted intensities corisistent with the observed ones. The unit cell spacings of the human and mouse SC are 134 A and 132 A, respectively.

The cornified cell envelope is the outermost layer of a corneocyte, and mainly consists of tightly bundled keratin filaments aligned parallel to the main face of the corneocyte. The envelope consists of both protein and lipid components in that the lipid is attached covalently to the protein envelope. The envelope lies adjacent to the interior surface of the plasma membrane. " The corneocyte protein envelope appears to play an important role in the structural assembly of the intercellular lipid lamellae of the stratum corneum. The corneocyte possesses a chemically bound lipid envelope comprised of A-co-hydroxyceramides, which are ester linked to the numerous glutamate side chains provided possibly by both the ot-helical conformation and p-sheet conformation of involucrin in the envelope protein matrix. In the absence of A-oo-hydro-xyceramides, the stratum corneum intercellular lipid lamellae were abnormal and permeability barrier function was disrupted. 

The stratum corneum intercellular lipids exist as a continuous lipid phase occupying about 20% of the stratum corneum volume and arranged in multiple lamellar structures. They are composed of cholesterol (27 /o) and ceramides (41 /o), together with free fatty acids (9 /o), cholesteryl esters (10 /o) and cholesteryl sulfate (2 /o) (Table 1). Phospholipids, which dominate in the basal layer, are converted to glucosylceramides and subsequently to ceramides and free fatty acids, and are virtually absent in the outer layers of the stratum corneum. Eight classes of ceramides have been isolated and identified in human stratum corneum but the functions of the individual ceramide types are not fully understood. Similarly, the exact function of cholesterol esters within the stratum corneum lamellae is also elusive but it is theoretically possible that cholesterol esters may span adjacent bilayers and serve as additional stabilizing moieties. 

Moghimi H. R., Williams A. C., Barry B. W. (1996). A lamellar matrix model for stratum corneum intercellular lipids. II. Effect of geometry of the stratum corneum on permeation of model drugs 5-fluororouracil and oestradiol. 117-129. 

Of particular interest are membranes prepared of an inert porous support carrying natural or artificial lipids. These coatings may comprise a single component, such as isopropylmyristate or dodecanol [99, 106], or mixtures of comparable composition as the stratum corneum intercellular bilayer [107, 108], Usually, synthetic lipids are used, due to an elaborate isolation procedure for stratum corneum lipids, with limited yield and the necessity of separation of triglycerides, originating from subcutaneous fatty tissue or skin care products [109],... 

Cholesterol sulfate is another intercellular lipid. Addition of low levels of cholesterol sulfate, as observed in normal healthy stratum corneum, to lipid mixtures has little effect on the phase behavior at room temperature. However, addition of high levels of cholesterol sulfate, at levels similar to that observed in the skin disease recessive X-linked ichthyosis, promotes the formation of the long periodicity phase, induces the formation of a fluid phase, and increases the solubility of cholesterol in the lamellar phases [72,80],... 

Dermal and transdermal delivery requires efficient penetration of compounds through the skin barrier, the bilayer domains of intercellular lipid matrices, and keratin bundles in the stratum corneum (SC). Lipid vesicular systems are a recognized mode of enhanced delivery of drugs into and through the skin. However, it is noteworthy that not every lipid vesicular system has the adequate characteristics to enhance skin membrane permeation. Specially designed lipid vesicles in contrast to classic liposomal compositions could achieve this goal. This chapter describes the structure, main physicochemical characteristics, and mechanism of action of prominent vesicular carriers in this field and reviews reported data on their enhanced delivery performance. 

Thewalt, J. et al., Models of stratum corneum intercellular membranes the sphingolipid headgroup is a determinant of phase behaviour in mixed lipid dispersions, Biochem. Biophys. Res. Commun., 188, 1247, 1992. 

To better understand the structure, function, and dynamics of the endogenous lipid matrix of the stratum corneum intercellular space some general principles of lipid phase behavior, dynamics, and structural organization may represent a useful starting point. Further follows a short overview of some basic physico-chemical principles that may be of relevance for stratum corneum lipid research, followed by a presentation of the new technique cryo-transmission electron microscopy of fully hydrated vitreous skin sections and how this technique recently has been applied to the study of the structural organization and formation of the lipid matrix of the stratum corneum intercellular space. 

The elucidation of the molecular genetics RXI has had a major impact on our understanding of stratum corneum turnover. Individuals with RXI lack an enzyme, cholesterol sulfatase,3,4 which catalyzes the transformation of cholesterol sulfate (CS) to cholesterol and free sulfate. As a result there is an accumulation of CS in the stratum corneum intercellular space. Possible mechanisms by which this change in intercellular lipid composition of the stratum corneum can cause disturbances in desquamation, leading to ichthyosis, will be discussed later. 

As mentioned above, the most abundant lipids in the stratum comeum intercellular space are cholesterol and ceramides. Cholesterol is the most abundant lipid species in the stratum corneum intercellular space (see Table 3). It has been... 

Table 1 Lipids of the stratum corneum intercellular space...

As mentioned above, the most abundant lipids in the stratum comeum intercellular space are cholesterol and ceramides. Cholesterol is the most abundant lipid species in the stratum corneum intercellular space. It has been reported that cholesterol is likely to be a key component that determines the barrier capacity for stratum comeum. It has also been reported that cholesterol gives plasticity and increases chain mobility of lipids in the gel and crystalline states (68, 69). Basically, by stabilizing single and coherent gel phases, cholesterol seems to promote the desirable effects of protecting the barrier capacity of stratum corneum against the sudden change in environmental conditions. 

It is a lipophilic compound which removes intercellular lipids that are covalently linked to the cornified envelope surrounding epithelial cells [3]. It also enhances penetration of other agents. Resorcinol (m-dihydroxy benzene) is structurally and chemically similar to phenol. It disrupts the weak hydrogen bonds of keratin [4]. Lactic acid is an alpha hydroxy acid which causes corneocyte detachment and subsequent desquamation of the stratum corneum [5]. 

Salicylic acid (ortho hydroxybenzoic add) is a beta hydroxy acid agent. It is a lipophilic compound which produces desquamation of the stratum corneum via removal of intercellular lipids [3] (see salicylic acid section). Given its keratolytic effects, it has become an increasingly popular superficial peeling agent. Salicylic acid peels induce injury via thinning or removal of the stratum corneum. In addition, salicylic acid potentially enhances the penetration of TCA. 

The intercellular route is considered to be the predominantly used pathway in most cases, especially when steady-state conditions in the stratum corneum are reached. In case of intercellular absorption, substance transport occurs in the bilayer-structured, continuous, intercellular lipid domain within the stratum corneum. Although this pathway is very tortuous and therefore much longer in distance than the overall thickness of the stratum corneum, the intercellular route is considered to yield much faster absorption due to the high diffusion coefficient of most drugs within the lipid bilayer. Resulting from the bilayer structure, the intercellular pathway provides hydrophilic and lipophilic regions, allowing more hydrophilic substances to use the hydrophilic and more lipophilic substances to use the lipophilic route. In addition, it is possible to influence this pathway by certain excipients in the formulation. 

Under normal conditions, the transcellular route is not considered as the preferred way of dermal invasion, the reason being the very low permeability through the corneocytes and the obligation to partition several times from the more hydrophilic corneocytes into the lipid intercellular layers in the stratum corneum and vice versa. The transcellular pathway can gain in importance when a penetration enhancer is used, for example, urea, which increases the permeability of the corneocytes by altering the keratin structure. 

The membrane-coating granules in keratinized epithelia contain electron-dense lipid lamellae [68, 77], and therefore, the intercellular spaces of the stratum corneum are filled with short stacks of lipid lamellae [67, 132], Most of the membrane-coating granules in nonkeratinized epithelia consist of amorphous material [120] however, some studies have shown that a small number of these granules in nonkeratinized epithelia contain lamellae [151]. Therefore,... 

In the first part of this chapter, the formation and structure of the stratum corneum will be discussed. The second part describes the composition and organization of the intercellular stratum corneum lipids in vivo and in vitro. 

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