Strong defence

Dr Jennifer Elias takes a deep dive into the stratum corneum, its function and interactions

DR JENNIFER ELIAS

Dr Jennifer Elias is a current internal medical trainee in dermatology at East Surrey Hospital. She read medicine at the University of Cambridge and received her intercalated degree in Pharmacology. She went on to complete her foundation years at Chelsea and Westminster Hospital. Dr Elias has a passion for dermatology and skin care with a particular interest in research.

The stratum corneum (SC) is the outermost layer of the epidermis and is therefore the visible layer of the human skin. The SC plays the essential role of the skin’s barrier and provides protection from external environmental stressors such as infection and UV, chemical, oxidative, and mechanical insult, while preventing excess water loss.1 The SC is also the first point of contact of all topical skincare. Although its role is primarily of a physiochemical barrier, cosmetics and cosmeceuticals are increasingly aiming to include active ingredients to penetrate deeper layers, while other actives such as exfoliators and superficial peels aim to alter the barrier itself.2 It is vital for aesthetic therapists and cosmetic doctors to therefore understand the anatomy and role of the SC in order to promote the use of beneficial, but also safe, skincare routines.

ANATOMY OF THE STRATUM CORNEUM

The anatomy of the SC was described as “brick and mortar” (Elias et al, 1983), where corneocyte cells represent the “brick” and the intracellular lipid represents the “mortar”.3 This analogy is still popular to date. The stratum corneum marks the final stage of keratinocyte maturation and development. Keratinocytes are formed at the stratum basale, the lowest layer of the epidermis. As these cells mature, they migrate upwards to the more superficial layers, while producing keratin. Upon progression to the stratum corneum they reach their final stage of differentiation as enucleated keratinocytes, termed corneocytes.4

Corneocytes continue to migrate to higher levels of the SC which is on average 10-20 µm thick, made up of 10-20 layers dependent on location (the palms of the hands and soles of the feet are far thicker with on average 47 layers).5 Upon reaching the outermost layer, the cells are shed by a process known as desquamation. In healthy skin, a layer of cells is shed every day. Scaling is the most common clinical manifestation of stratum corneum disease and represents inadequate or flawed keratinisation and desquamation. Diseases characterised by scaling, and thus stratum corneum breakdown, include atopic dermatitis, psoriasis, and ichthyoses.

It is well documented that with ageing, desquamation slows, leaving an older layer of corneocytes on the surface resulting in a dull and rough appearance.6 It is therefore desirable to prevent this change through targeting of the desquamation process.

DESQUAMATION AND ACIDS

AHAs and BHAs (alpha hydroxyl acid and beta hydroxyl acid) are widely used topical products that target desquamation through stimulation of cell turnover and corneocyte decohesion, therefore improving appearance by ensuring younger cells are present at the surface.7 Studies continue to show that these actives do not cause stratum corneum thinning, as the increased desquamation is matched by cell generation, and in fact show the overall epidermal thickness to be increased.8

AHAs include glycolic acid, lactic acid and other biosimilar acids. They are good for uneven skin tone, mild hyperpigmentation and fine lines, with the overall aim of producing a more youthful appearance and reversing photodamage. AHAs however are hydrophilic and are therefore poorly absorbed. This results in skin irritation and damage to the SC if not used correctly. Users should slowly increase the concentration and use of AHA products to avoid this. It is also extremely important to note that AHAs increase sun sensitivity, which is reversible on stopping the treatment.9 The use of UV protection is also important.

BHAs, such as salicylic acid, are very similar to AHAs except for the difference in their solubility. BHAs are lipid-soluble in contrast to the water solubility of AHAs10 This results in greatly improved penetration and decreased surface irritancy. BHAs are absorbed well on oily skin and are recognised as a good option for acne-prone skin. The long-term safety aspects of BHAs are being studied by the FDA in the US (Food and Drug Administration) with current guidance similar to that of AHAs in that sun protection is strongly advised and that with any signs of irritancy, use should be stepped down to prevent damage to the skin barrier. It is important for patients to recognise the features of overuse of acid actives on the skin to prevent unknowingly damaging the skin surface barrier. Irritant, dry or erythematous patches all represent skin barrier damage and active overuse, and clients should be counselled with regards to this.

PERMEABILITY AND VITAMIN A DERIVATIVES

The permeability of the skin barrier holds huge importance in not only the level of penetration of a topical and so the level of effect, but also on prevention of SC irritancy and resultant barrier dysfunction, as described with AHAs vs. BHAs. As keratinocytes transform to corneocytes, a tough cell envelope replaces the permeable plasma membranes, greatly reducing intercellular permeability11 The vast majority of molecules that penetrate the skin infiltrate the lipid matrix, or the “mortar”, which has a lamellar organisation that promotes the penetration of lipophilic molecules. The lipid matrix is therefore the target of designed cosmetics, making a lipophilic profile highly desirable. The lipids of the SC are 50% ceramides (CER), 15% free fatty acids (FFAs), and the other 25% comprises predominantly cholesterol and a small percentage of triacylglycerol (TAG) species.12

Other factors affecting penetration are the topical’s concentration, molecular mass and pH alongside biological factors which include skin hydration and age-related changes to the skin structure.

Vitamin A and its derivatives are among the most effective and popular products for the slowing and reversal of agerelated dermatological changes and they demonstrate the permeability of the stratum corneum well13 “Retinoids regulate cell apoptosis, differentiation, and proliferation. Anti-wrinkle properties of retinoids promote keratinocytes proliferation, strengthen the protective function of the epidermis, restrain trans-epidermal water loss and inhibit metalloproteinases activity, protecting against collagen degradation.” (Mukherjee et al, 2006)14

Retinoids come in several forms with retinol being the primary derivative in over-the-counter cosmetics while tretinoin/ retinoic acid and adapalene are popular, prescribed acne formulations. Retinoic acid is some twenty times more potent than retinol, which requires a two-step oxidative process to be converted to the chemically active form of retinoic acid15 Retinol is also extremely unstable and is easily degraded to inactive forms on exposure to light.16 However, retinol, unlike retinoic acid, which is hydrophobic, is lipophilic. Retinol is therefore extremely well absorbed and penetrates the entire epidermis through to the dermis, reaching past the corneocytes in the stratum corneum, to keratinocytes in lower layers. Here retinol can penetrate though the keratinocytes’ permeable membrane and bind to their associated receptors to take effect17

Retinoic acid is hydrophobic and less readily absorbed, with minimum penetration through the stratum corneum. It is not as well tolerated and causes a “retinoid reaction” or “retinoid dermatitis” characterised by pruritus, burning, erythema and desquamation – all signs of barrier damage. This often leads to intolerance and discontinuation of the product. Due to retinoic acid’s greater strength and stability, there is growing interest in finding potential delivery systems of this form of vitamin A to deeper layers, with one possibility being the use of lipid nanoparticle shells18 These nanoparticles have shown promise in not only reducing surface irritancy but in increasing retinoid stability19

OXIDATION

Due to the stratum corneum’s critical location at the interface between the body and the environment, it is continuously exposed to external stressors including oxidative stress. The SC contains several endogenous antioxidants including glutathione peroxidase, superoxide dismutase and catalase, and nonenzymatic low-molecular-weight antioxidants such as vitamin E isoforms, vitamin C, and alpha-tocopherol, which is the major hydrophobic antioxidant20

The production of reactive oxygen species (ROS) through metabolic processes and external aggression is counteracted by these antioxidants in a dynamic balance. However, the antioxidant defence can become overwhelmed and deplete, particularly with acute and chronic UV exposure, resulting in oxidative damage, leading to premature skin ageing and potential skin malignancy21

Antioxidant cosmetic products are widely desired, with vitamin C being one of the most popular antioxidants in production today22 Vitamin C protects the skin from oxidative stress by sequentially donating electrons to neutralise the free radicals. The oxidised forms of vitamin C are relatively non-reactive and can be converted back to vitamin C by the enzyme dehydro-ascorbic acid reductase in the presence of glutathione. Two small double-blind, placebo-controlled trials, the first using 10% topical vitamin C and the second using a 5% formulation found statistically significant improvement in reduction of photoaged scores on their use alongside increased collagen deposition on bio23,24 Further studies are required.

MEASURING SKIN BARRIER FUNCTION

With the importance of this barrier recognised, it is desirable for pharmacologists to be able to measure its function. Transepidermal water loss (TEWL) is the amount of water that passively evaporates through the skin (therefore excluding active sweat gland excretion) to the external environment due to water vapour pressure gradient on both sides of the skin barrier25 The average TEWL is 300-400ml/day. Increased TEWL is a result of skin barrier dysfunction and clinically will be shown by skin dehydration, irritancy, and premature skin ageing. Studies have consistently shown raised TEWL in atopic dermatitis and psoriatic skin, supporting this.26

To conclude, the stratum corneum is continuously exposed to external stressors, which can include inappropriate use of actives. Damage is important to be recognised and includes symptoms of dryness, pruritus and inflammation. The aesthetic therapist or cosmetic doctor advising patients on actives should be knowledgeable around the anatomy of the SC and an active’s properties, in particular the lipophilic-hydrophilic profile. Improving cosmetic penetration of the barrier is of increasing interest and a rapidly advancing field.