Understanding Lipid Organization in the Stratum Corneum and Why It Matters for Formulation
In this month’s Formulation Reading Club deep dive, I am going to uncover what I learned from the lipid organization reading list.
If you are new here, welcome to the Formulation Reading Club. A monthly reading challenge designed to get you reading, learning something new and joining in on the discussion. (And yes, nerding out over skin biology absolutely counts as fun).
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Why we Need to Understand the Lipid Mortar
Your skin’s barrier is generally thought of as the outermost layer of the skin, called the Stratum Corneum. It’s the first line of defense against intruders like pollutants and toxins. The main goal of the barrier is to stay as tight as possible even under changes to its environment like pH, temperature and humidity.
While the structural integrity of the stratum corneum is maintained by the corneocytes, which are flattened, dead cells composed mainly of keratin; other key properties like water transport and loss and stress response are maintained by the lipids found within the intercellular space. These lipids make up around 15% by weight of the stratum corneum and their organization is directly related to the barrier properties [1]. Even small changes in composition or pH can affect phase transition temperature of the lipids and ultimately their efficiency [2].
With more and more consumers understanding the importance of protecting this critical component of the skin, we have seen an explosion of skin barrier products hit the market. The more we understand about the barrier in both healthy and diseased states the better formulas we can make. Also, understanding how these lipids organize, helps us strategically overcome it for drug delivery.
For example, lamellar creams have been formulated to better mimic the natural structure of the stratum corneum for less disruption and greater potential for restoration (we will talk more about this next month) [3].
Composition of the Lipid Layer
The oily substance that fills the gaps between the corneocytes, helping to keep water in the skin, has been coined the “mortar.” As keratinocytes gradually make their complex journey upwards through the Epidermis, the production of certain lipids are ramped into high gear.
These lipids get packed into a sack called lamellar bodies. High levels of calcium found within the Stratum Granulosum cause the rupture of these bodies releasing the lipids and enzymes that are needed to break down the lipids and transform them into the cholesterol, free fatty acids and ceramides. The lipids fill the intercellular space in the stratum corneum [4].
The lipid matrix is composed of 50% ceramides, 25% cholesterol and 15% free fatty acids. Research has found 11 subclasses of ceramides that differ by their head-group and fatty acid chain length [1]. The fatty acids are mainly saturated with chain lengths of 16-26. However, higher levels of short chains and unsaturated fatty acids can be found closer to the surface that are thought to be of sebaceous origin that get mixed into the matrix [1].
The heterogeneity amongst the mixture of these lipids forms the basis for the intricate organization of this region of the stratum corneum.
How is the Lipid Layer Organized
These lipids aren’t just hanging out within this intercellular space with no rhyme or reason. There is a distinct organization that is influenced by the chemical and physical properties of the lipids that are present (ex. charge of the head group, the hydration sphere around the head group, the chain length, degree of unsaturation, etc.).
While extensive research has been conducted on this organization there still isn’t a general consensus. However, we do know a few very important things…
Scientists have identified two lamellar phases within the stratum corneum, one with spacing of 6 nm (short periodicity phase) and the other with 13 nm spacing (long periodicity phase) [5].
A second important feature that has been identified is the lateral packing. Scientists have found various packing arrangements throughout the stratum corneum including a liquid phase, hexagonal and orthorhombic packing [5]. These packing arrangements directly affect the barrier properties. For example, the orthorhombic packing is the most dense and contributes heavily to the barrier properties. The more liquid regions are thought to provide flexibility [1]. Like mentioned above, the packing is determined by the lipids present. For example, longer chain lengths will form more crystalline regions while shorter chains give way to greater flexibility and more fluidity. Free fatty acids are thought to provide more fluidity to denser cholesterol/ceramide regions [1].
We also know that this packing isn’t homogenous throughout the stratum corneum. Studies have demonstrated that the hexagonal packing is more concentrated at the top layers of the stratum corneum [5]. It has been theorized that the lipids are found in an orthorhombic structure in the deeper regions because the cells in this region are more compacted forcing the lipids into this specific phase. But because of desquamation, the cells in the upper regions are more spread out, so the lipids are thought to be more fluid and have more disorder and phase separation [1].
In order to make sense of this organization, a few models have been introduced by various scientists over the decades. Two of those models, the Domain Mosaic and Sandwich both describe the bilayer as having both fluid and crystalline phases. While alternatively, Norlen’s model suggests that the bilayer is likely a single gel phase [1]. To my knowledge, no model has been officially deemed "correct", but evidence does point to the bilayer as having both fluid and crystalline regions like we discussed above.
Final Thoughts
While we may not know the exact details of this intricate organization, research has clearly shown that this organization is important. Small shifts in lipid ratios or environmental conditions can push lipids into different phases and packing arrangements which can change the barrier properties.
What stood out most to me is that the stratum corneum isn’t static.
It’s heterogeneous, and dynamic, varying with depth, skin condition, and external stressors. This only adds to the complexity of formulating barrier products and why simply “adding ceramides” is probably not enough.
We still need more data evaluating individual differences and differences between healthy and diseased states to be able to formulate more personalized approaches.
References:
[2] View of A domain mosaic model of the skin barrier.
[4] The mechanisms by which lipids coordinately regulate the formation of the protein and lipid domains of the stratum corneum - PMC (nih.gov)
