The barrier lipid matrix

 

The skin's permeability barrier resides in the stratum corneum and is commonly described by a "bricks-and-mortar" model: corneocytes (the bricks) embedded in an intercellular lipid matrix (the mortar). This lipid matrix, rather than the corneocytes, governs the rate of water loss. By mass it comprises approximately 50% ceramides, 25% cholesterol and 15% free fatty acids, the remainder being minor lipid species (Feingold, K.R., 2007). These lipids are organised into stacked lamellae, including the long-periodicity phase, a lamellar arrangement with a characteristically large repeat spacing of about 13 nm that is considered important for the barrier (Bouwstra, J.A., et al., 1991; Bouwstra, J.A., et al., 2023). The barrier's low permeability derives from this ordered organisation, not from the lipids alone: when the arrangement or the balance of lipids is disrupted, barrier function falls even though the same lipid classes remain present. Replenishing the matrix therefore requires five conditions to be met, each of which Aelon IQ assesses.

 

What Aelon IQ analyses

 

Presence of all three lipid classes

 

Barrier recovery requires all three lipid classes acting together. In the foundational studies, topical application of ceramides alone, or any two of the three classes, interfered with barrier recovery and disrupted it at the level of the lamellar body (the secretory organelle through which the epidermis delivers the lipids that form the intercellular lamellae) producing abnormal intercellular membrane structures; only the complete mixture of ceramides, cholesterol and free fatty acid allowed normal recovery (Man, M.Q., et al., 1993; Mao-Qiang, M., et al., 1996). A formulation supplying ceramides but lacking cholesterol or free fatty acid therefore cannot support barrier recovery in the same way the complete combination does, irrespective of its ceramide content.

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Ceramide subtype and structure
 

Even when all three classes are present, ceramides are not interchangeable. They differ in two structural respects that determine their contribution to the barrier, and neither contribution substitutes for the other.

 

• Building the wide-spaced lamellae. One group, the ω-O-acylceramides (the "EO-type," including ceramide EOS and EOP), carries an unusually long fatty-acid chain with a molecule of linoleic acid attached at its end. This structure is what allows the lipids to assemble into the long-periodicity phase, the wide-spaced layered arrangement that is central to the barrier. When no EO-type ceramide is present, this arrangement does not form properly: the lipids tend to separate out, and the barrier weakens (Opálka, L., et al., 2016; Opálka, L., et al., 2022). A formulation may list several ceramides, but if none is an EO-type, this structure cannot be built.

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• Tightening the bonds between lipid heads. A second group, the phytosphingosine-based ceramides (ceramide NP and AP), carries an extra hydroxyl group on its backbone. This lets the lipid "heads" bond more tightly to one another, forming a denser network. In skin-lipid models, that tighter network is linked to lower water loss, and the researchers attribute this to the stronger bonding between heads rather than to how tightly the chains pack together (Uche, L.E., et al., 2019; Nadaban, A., et al., 2023). Ceramide EOP belongs to this group too, so it contributes on both counts, as an EO-type and as a phytosphingosine ceramide.
   

The barrier-relevant contribution of the ceramides therefore depends on which subtypes are present, not on the presence of ceramides as such.

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Proportion of the lipid classes

 

The three classes must be present in appropriate proportion, though not necessarily in equal amounts. A complete trio supports normal recovery when the classes are approximately equimolar. In young skin, increasing any one class to roughly three times the others accelerated recovery, with the effect peaking near that proportion and declining if the class was increased further (Mao-Qiang, M., et al., 1996). However, in chronologically aged skin, which is relatively cholesterol-deficient, a cholesterol-dominant mixture accelerated recovery, whereas a fatty-acid-dominant mixture delayed it (Zettersten, E.M., et al., 1997).​

 

Delivery and solubilisation

 

Supplying the correct lipids in the correct proportion is not enough; they must also reach the stratum corneum. Ceramides are high-melting, poorly soluble lipids that are difficult to incorporate into a formulation. Unless a product is designed to dissolve and carry them, they can remain as crystalline material that does not integrate properly into the skin's lamellae, and the form in which ceramides are delivered affects how well the barrier recovers (Schild, J., et al., 2024).

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Formulation pH

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Barrier assembly further depends on the pH of the formulation, and the workable range is narrower than the ceramide's own chemical stability would suggest. The ceramide molecule is generally considered stable across roughly pH 4.0 to 7.0, but rebuilding the barrier requires the formulation to sit within the skin's naturally acidic range of about pH 4.5 to 5.5. A product carrying the correct lipids but formulated at neutral or mildly alkaline pH is impaired in two ways. First, it raises the skin's surface pH, which reduces the activity of an acid-dependent enzyme, β-glucocerebrosidase, that converts lipid precursors into finished lamellae; processing stalls, and immature, unassembled membranes persist (Hachem, J.P., et al., 2003). Second, it deprotonates the free fatty acids; in their protonated form these fatty acids assemble more readily into the ordered lipid bilayers, so raising the pH impairs their incorporation into the lamellae. 

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Summary

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Aelon IQ checks each formulation against all five conditions required for replenishing the barrier lipids: presence of all three lipid classes; inclusion of EO-type and phytosphingosine-based ceramide subtypes; appropriate ratios of all classes; adequate solubilisation and delivery of ceramides; and the suitability of the pH environment. Many ceramide-containing products fail one or more of these conditions.​​ 

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References

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Bouwstra, J.A., Gooris, G.S., van der Spek, J.A. and Bras, W. (1991) 'Structural investigations of human stratum corneum by small-angle X-ray scattering', Journal of Investigative Dermatology, 97(6), pp. 1005–1012.

Bouwstra, J.A., Nădăban, A., Bras, W., McCabe, C., Bunge, A.L. and Gooris, G.S. (2023) 'The skin barrier: an extraordinary interface with an exceptional lipid organization', Progress in Lipid Research, 92, 101252.

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Feingold, K.R. (2007) 'Thematic review series: skin lipids. The role of epidermal lipids in cutaneous permeability barrier homeostasis', Journal of Lipid Research, 48(12), pp. 2531–2546.

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Hachem, J.P., Crumrine, D., Fluhr, J., Brown, B.E., Feingold, K.R. and Elias, P.M. (2003) 'pH directly regulates epidermal permeability barrier homeostasis, and stratum corneum integrity/cohesion', Journal of Investigative Dermatology, 121(2), pp. 345–353.

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Man, M.Q., Feingold, K.R. and Elias, P.M. (1993) 'Exogenous lipids influence permeability barrier recovery in acetone-treated murine skin', Archives of Dermatology, 129(6), pp. 728–738.

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Mao-Qiang, M., Feingold, K.R., Thornfeldt, C.R. and Elias, P.M. (1996) 'Optimization of physiological lipid mixtures for barrier repair', Journal of Investigative Dermatology, 106(5), pp. 1096–1101.

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Nadaban, A., Rousel, J., El Yachioui, D., Gooris, G.S., Beddoes, C.M., Dalgliesh, R.M., Malfois, M., Rissmann, R. and Bouwstra, J.A. (2023) 'Effect of sphingosine and phytosphingosine ceramide ratio on lipid arrangement and barrier function in skin lipid models', Journal of Lipid Research, 64(8), 100400.

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Opálka, L., Kováčik, A., Maixner, J. and Vávrová, K. (2016) 'Omega-O-acylceramides in skin lipid membranes: effects of concentration, sphingoid base, and model complexity on microstructure and permeability', Langmuir, 32(48), pp. 12894–12904.
 

​Opálka, L., Meyer, J.M., Ondrejčeková, V., Svatošová, L., Radner, F.P.W. and Vávrová, K. (2022) 'ω-O-Acylceramides but not ω-hydroxy ceramides are required for healthy lamellar phase architecture of skin barrier lipids', Journal of Lipid Research, 63(6), 100226.

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Schild, J., Kalvodová, A., Zbytovská, J., Farwick, M. and Pyko, C. (2024) 'The role of ceramides in skin barrier function and the importance of their correct formulation for skincare applications', International Journal of Cosmetic Science, 46(4), pp. 526–543.

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Uche, L.E., Gooris, G.S., Beddoes, C.M. and Bouwstra, J.A. (2019) 'New insight into phase behavior and permeability of skin lipid models based on sphingosine and phytosphingosine ceramides', Biochimica et Biophysica Acta – Biomembranes, 1861(7), pp. 1317–1328.

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Zettersten, E.M., Ghadially, R., Feingold, K.R., Crumrine, D. and Elias, P.M. (1997) 'Optimal ratios of topical stratum corneum lipids improve barrier recovery in chronologically aged skin', Journal of the American Academy of Dermatology, 37(3), pp. 403–408.