Intercellular lipid matrix

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. 

Water homeostasis is a strict requirement for normal physiological function. The most important task of the human skin is thus to create a watertight enclosure of the body to prevent water loss. It is the intercellular lipid matrix of the outermost keratinized horny layer of the skin (possibly together with recently reported claudin-based tight-junctions Furuse et al., 2002) that represents the skin barrier proper as once this lipid matrix (composed foremostly of saturated long chain ceramides ( 50% wt/wt) and cholesterol (—30% wt/wt) (Wertz and Norlen, 2002)) has been removed, substances diffuse freely into or out of the body system (Blank, 1952 Breathnach et al., 1973 Elias and Friend, 1975). At the same time the intercellular lipid matrix ensures that the stratum corneum remains hydrated and thus the skin surface appears healthy and smooth. 

SECM, was decreased by 8%, 23%, and 65% (from pretreated iontophoretic flux values) for 10-, 20-, and 30-minute pretreatment with SDS, respectively. It was concluded that the penetration enhancement effect of SDS alters the nonporous stmctures of the skin (i.e., keratin-filled comeocytes, intercellular lipid matrix). 

The stratum comeum is composed of flat comeocytes embedded in a continuous intercellular lipid matrix. The intercellular lipid matrix is the main route for percutaneous absorption of many exogenous chemicals. However, it is difficult to use stratum comeum to conduct absorption experiments because of the hair follicles. Synthetic membranes, including lipid and silastic membranes, have been used to simulate the absorption properties of this lipidal layer. 

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. 

In order to maintain water effectively within the skin the epidermis undergoes a process of maturation or terminal differentiation to produce a thin, metabolically inert, barrier, the SC. This heterogeneous structure has been likened to a brick wall in which the anucleated nonviable cells, termed corneocytes are represented as bricks embedded in a continuous matrix of specialized intercellular lipids (mortar).2 Each individual corneocyte can be viewed simplistically as a highly insoluble... 

Figure 35.2. Schematic representation of the barrier property of skin composed of proteinaceous keratinocytes (corneocytes) embedded in an extracellular nonhomogenous matrix of lipid. Arrow depicts intercellular lipid pathway.

In addition to movement through shunts, polar substances may diffuse through the outer surface of the protein filaments of the hydrated stratum corneum, while nonpolar molecules dissolve in and diffuse through the nonaqueous lipid matrix between the protein filaments. The rate of percutaneous absorption through this intercellular lipid pathway is correlated to the partition coefficient of the penetrant, as presented above in Fick s law. 

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 remarkable barrier function of the skin is primarily located in the stratum corneum (SC), the thin, outermost layer of the epidermis. The SC consists of several layers of protein-filled corneocytes (i.e., terminally differentiated keratinocytes) embedded in an extracellular lipid matrix. Attached to the outer cor-neocyte envelope are long-chain covalently bound cer-amides that interact with the lipids of the extracellular space. These lipids are composed primarily of free fatty acids, ceramides, and cholesterol arranged in multiple lamellae.f Passive permeation across the SC is believed to occur primarily via the intercellular... 

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. 

Figure 12.15 Formation of the lipid barrier of human skin. The top layer of the epidermis called stratum corneum is a hornified and inert barrier. Its primary functions are regulation of the skin s moisture content and protection of the underlying tissues against external influences. Due to its structure it is often compared to a brick wall in which the non-viable keratin-filled corneocytes are embedded like bricks in a matrix of intercellular lipids. Synthesis of the stratum corneum lipids starts in deeper skin layers, where lipids (mainly glucosylceramides and sphingomyelin) are produced and packaged in so-called lamellar bodies . During differentiation and maturation, these lipids are enzymatically converted to ceramides and finally assembled into densely packed lamellar structures surrounding the corneocytes and filling the intercellular spaces of the stratum corneum.

The permeability skin barrier, a highly specialized structure responsible for retaining skin moisture, is localized mainly at the stratum corneum (Rudikoff 1998) however, its formation begins deeper in the epidermis and its constituents are progressively modified during the process of keratinization until they reach their highest efficiency in the five layers of the stratum compactum (Rawlings et al. 1994). The modified keratinocytes - the corneocytes - and the intercellular complex lipid matrix in which they are embedded form this specialized structure, which Elias compared to a bricks and mortar model, in which the corneocytes are the bricks and the lipid matrix the mortar (Elias 1983). 

Cal K, Kupiec K, Sznitowska M (2006) Effects of physicochemical properties of cyclic terpenes on their ex vivo skin absorption and elimination kinetics. J Dermatol Sci 41 137-142 Moghimi HR, Williams AC, Barry BW (1996) A lamellar matrix model for stratum comeum intercellular lipids III. Effects of terpene penetration enhancers on the release of 5-fluorouracil and oestradiol from the matrix. Int J Pharm 145 37-47... 

Membranes of plant and animal cells are typically composed of 40-50 % lipids and 50-60% proteins. There are wide variations in the types of lipids and proteins as well as in their ratios. Arrangements of lipids and proteins in membranes are best considered in terms of the fluid-mosaic model, proposed by Singer and Nicolson % According to this model, the matrix of the membrane (a lipid bilayer composed of phospholipids and glycolipids) incorporates proteins, either on the surface or in the interior, and acts as permeability barrier (Fig. 2). Furthermore, other cellular functions such as recognition, fusion, endocytosis, intercellular interaction, transport, and osmosis are all membrane mediated processes. 

Stratum corneum, the nonliving layer of skin, is refractory as a substrate for chemical reactions, hut it has a strong physical affinity for water. The chemical stability of stratum corneum is evident in its mechanical barriers which include insoluble cell membranes, matrix-embedded fibers, specialized junctions between cells, and intercellular cement. The hygroscopic properties of stratum corneum appear to reside in an 80 A-thick mixture of surface-active proteins and lipids that forms concentric hydrophilic interfaces about each fiber. This combination of structural features and surface-active properties can explain how stratum corneum retains body fluids and prevents disruption of living cells by environmental water or chemicals. 

A study related to the buccal bioavailability of testosterone indicated the absorption enhancing effect of hydroxypropyl-p-cyclodextrine with a relative bioavailability of 165% versus the administration without absorption enhancers. This effect was probably due to an increased solubility of testosterone, although cyclodextrins might also extract lipids from the intercellular matrix.f In the same study, sodium tauro-24,25-dihydrofusidate and sodium deoxycholate did not show any enhancing properties. 

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