Revitalizing the skin: Exploring the role of barrier repair moisturizers

Moisturizers are designed to maintain skin health and treat dermatological conditions associated with impaired skin barrier function. However, differences in their composition account for the differences in their effect.


| INTRODUC TI ON 1.| Skin barrier: Science and importance in health and various skin conditions
An effective skin barrier is vital to protect the body from physical (e.g., temperature, mechanical injury, ultraviolet [UV] radiation), chemical (e.g., irritants, allergens), and microbial (e.g., bacteria, fungi, virus) assaults. 1,2It is also crucial for preventing moisture loss. 3,44][5][6] The lipid lamella comprises equimolar concentrations of ceramides, free fatty acids, and cholesterol. 4e skin barrier is suboptimal at birth; accordingly, newborns and infants are considered to have a physiologically fragile skin with lower resistance to aggression compared with that of adults. 7,8wever, the skin barrier of newborns reaches an adult-like status over a period of several months to years. 7The permeability function of the skin barrier is mainly dependent on the structure and composition of the lipid lamellae. 4Filaggrin and natural moisturizing factor (NMF) also play an important role in maintaining an effective skin barrier. 3,5,9Filaggrin is a matrix protein that aggregates the keratin fibers within corneocytes into tight bundles and thereby promotes flattening of the corneocytes. 3Degradation of filaggrin produces NMF, a natural humectant, within the corneocytes.NMF is a unique hygroscopic moisturizer comprising free amino acids, urocanic acid, pyrrolidone carboxylic acid, simple sugars, and electrolytes. 5laggrin deficiency impairs the skin barrier function, leading to increased trans-epidermal water loss (TEWL), and exposes the skin to infective organisms and environmental allergens, resulting in skin inflammation. 10veral exogenous and/or endogenous factors can disrupt the normal skin barrier (Table S1).When the exogenous insults are acute, the SC usually restores its integrity by incorporating several adaptive mechanisms.However, repetitive/chronic exogenous insults overstress the SC to the extent that it can no longer adopt self-repair mechanisms. 5In the absence of an appropriate intervention, a disrupted skin barrier paves entry to allergens, microbes, and toxins, causing stepwise progression to immunological reactions, inflammation, and dermatitis with associated erythema and pruritus. 5Thus, a disrupted skin barrier is central to the pathogenesis of sensitive skin, acne, allergic dermatitis, psoriasis, rosacea, and atopic dermatitis. 2,11,12As per the International Forum for the Study of Itch (IFSI), sensitive skin is defined as "A syndrome defined by the occurrence of unpleasant sensations (stinging, burning, pain, pruritus, and tingling sensations) in response to stimuli that normally should not provoke such sensations.These unpleasant sensations cannot be explained by lesions attributable to any skin disease.The skin can appear normal or be accompanied by erythema.Sensitive skin can affect all body locations, especially the face." 13

| Moisturizers for skin barrier repair
Moisturizers play an important role in maintaining the appearance and integrity of the skin and improving skin barrier function. 10They are an integral component of the dermatologist's armamentarium for the management of various dermatoses associated with impaired skin barrier function and are the mainstay in the management of atopic dermatitis. 10,14,15However, depending on their composition, moisturizers vary in terms of their effect on maintaining skin barrier integrity and hydration. 16This review aims to (a) discuss the role of barrier repair moisturizers; highlight the role of various components in moisturizers and their role in impaired skin conditions such as dry, itchy, inflamed, sensitive skin; and atopic eczema and empower dermatologists and pediatricians to select the right moisturizer in individuals presenting with barrier dysfunction.

| MATERIAL S AND ME THODS
A literature search was conducted using the PubMed, Embase, and Scopus databases from January 2000 to June 2023 using the search terms "skin barrier," "barrier repair mechanism," "stratum corneum," "endocannabinoid system," "atopic eczema," OR "sensitive skin." Articles focusing on skin barrier repair and the use of barrier repair moisturizers for the treatment of dry, itchy, inflamed, sensitive skin, or atopic eczema in humans were included.Articles for which the full text was not available; that were not written in English; and that focused on systemic, biological, or oral therapies for the treatment of dry, itchy, inflamed, and sensitive skin; and atopic eczema were excluded.A total of 321 articles were found in the literature search.
After selection for eligibility, elimination of duplicates, and scanning for associated references in the relevant articles, 90 articles were identified (Figure 2).

| Moisturizers for disrupted skin barrier repair-Physiological vs. nonphysiological lipids
Moisturizers are mainly classified as emollients, humectants, and occlusives based on their mechanism of action (Table 1), 6,17 and skin barrier repair moisturizers usually contain a combination of either of these. 10aditionally, moisturizers containing nonphysiological lipids (e.g., mineral and vegetable oils) have been used to augment the SC lipid content, occlude the skin surface, and thereby reduce TEWL. 1,18st of the traditional moisturizers containing nonphysiological lipids, however, do not tackle the inherent lipid deficiency, as they are limited to the SC and only form a superficial occlusive barrier on the skin. 19,20Given that a disturbed epidermal differentiation plays a major role in the pathogenesis of dry skin, restoration of normal epidermal differentiation by incorporating physiological lipids (e.g., ceramides, fatty acids, cholesterol) is now being considered for the management of dry skin. 1,19Physiological lipids differ from nonphysiological lipids in that they easily penetrate into the epidermis, where they stimulate the production of normal intercellular lipids in the SC. 1,20Thus, from an efficacy perspective, an "inside-out" approach using physiological lipids is preferred over the "outside-in" approach using nonphysiological lipids. 1,18rrently available moisturizers contain several components (Table 2) that confer benefits other than skin hydration, such as anti-inflammatory, antipruritic, antimitotic, and photo-protective effects. 10,17Components with anti-inflammatory activity are beneficial to control dry, inflamed skin and relieve mild-to-moderate atopic dermatitis; they may even decrease or replace the use of topical corticosteroids and thus lessen the associated adverse effects.
Antipruritic components relieve itch symptoms, whereas antimitotic components are beneficial for skin conditions associated with increased mitotic activity (e.g., psoriasis). 10Some components of a moisturizer improve clinical outcomes by restoring the skin barrier, whereas others may worsen the existing skin condition (Table 3).
Therefore, thorough knowledge of the components is essential. 10

| Attributes of an ideal moisturizer for skin barrier repair
An ideal moisturizer for the management of disrupted skin barrier should 6,17 • Restore the lipid barrier and decrease and avert further TEWL; • Be nonsensitizing, hypoallergenic, and noncomedogenic; • Be fragrance-free, cosmetically elegant, and acceptable; and • Provide immediate and long-lasting hydration.
2][23][24][25] The endocannabinoid system (ECS) balances and regulates the proliferation, differentiation, and survival of skin cells and is thus believed to play an active role in protective mechanisms in skin barrier function. 26Disruption of this balance may therefore lead to the development of cutaneous conditions associated with disrupted barrier function (e.g., acne, allergic dermatitis, seborrhea, psoriasis, itching, pain). 2 Phospholipids such as N-palmitoylethanolamine (PEA) and N-acetylethanolamine (AEA) belong to the functional ECS and are present at high concentrations in the stratum granulosum. 26A acts by markedly augmenting the effects of AEA on cannabinoid receptor subtypes 1 and/or 2 (CB 1 and CB 2 ) and transient receptor potential cation channel, subfamily V, member 1 (Figure 3).PEA also directly activates peroxisome proliferator-activated receptor-alpha (PPARα). 2 Application of phospholipids such as PEA may prevent the degradation of lipids and augment their production in the stratum granulosum, thereby potentially helping in combating dry skin and decreasing the associated itch. 26

Description and mechanism of action Examples
Emollients Chemicals (saturated and unsaturated hydrocarbons) that fill the spaces between corneocytes and improve skin barrier function and maintain the skin condition 6,10,29 Cholesterol, pseudo-ceramides, squalene, fatty alcohols, and fatty acids (lauric, linoleic, linolenic, oleic, and stearic acids), and shea butter 10,29 Humectants Hygroscopic substances that attract water and moisture from the epidermis and environment into the SC 6,10,29 Glycerol, propylene glycol, glycerine, glutamic acid, urea, lactic acid, hyaluronic acid, alpha hydroxy acid, sorbitol, panthenol, sodium lactate, and carnitine 10,29 Occlusives Agents that form an inactive hydrophobic film (occlusive barrier) over the skin to trap water within the uppermost layers of the skin and thereby reduce TEWL 6,10 Petroleum, petrolatum, mineral oil, olive oil, jojoba oil, soybean oil, jelly, beeswax, silicone, dimethicone, and zinc oxide 10,29 Abbreviations: SC, stratum corneum; TEWL, trans-epidermal water loss.

TA B L E 2
Components of moisturizers and their effects.

Component Description and effects
Aloe vera • Contains magnesium lactate, salicylic acid, and gel polysaccharides 10 • Has anti-inflammatory, antipruritic, analgesic, and wound-healing properties 10 • Improves skin hydration through its humectant mechanism 30 Bisabolol • Extracted from the chamomile (Matricaria recutita) plant 10 • Can ameliorate itching 10 • Has anti-inflammatory effects 10 • Promotes formation of granulation tissues to accelerate wound healing 10 Caprylic/capric triglyceride • An emollient that is naturally found in coconut oil 31 • Increases hydration, reduces TEWL, and forms a lipid film over the skin 31 Ceramide • Restores lipid matrix, water permeability, and barrier function in the SC 32 • Improves TEWL and hydrates the skin (ceramide NP [previously ceramide 3]) 33 Cocos nucifera • Reduces TEWL, improves skin hydration, and increases synthesis of skin lipids 34 • Contains monolaurin, which has antimicrobial effects 34

Glycerol
• Degrades desmosomes and thus has keratolytic effects 35 • Protects the skin against irritation and penetration of substances, plasticizes the SC, decreases tissue scattering, stabilizes collagen in the skin, and accelerates the wound healing process 35 Glycyrrhetinic acid • A triterpenoid compound extracted from licorice root 10 • Has anti-inflammatory, antiviral, and antitumor effects 10 Hyaluronic acid • Promotes wound healing 10 • Moisturizes the epidermis and restores barrier function 9 Hydrogenated lecithin • Obtained following controlled hydrogenation of lecithin (a naturally occurring mixture of phosphatidylcholine) 36 • Helps in skin conditioning 36

Niacinamide
• Increases the levels of epidermal ceramides and other intercellular lipids, promotes the upregulation of serine palmitoyltransferase, decreases TEWL, increases the thickness of the SC, and thereby improves the functioning of the skin barrier 10,32 • Has anti-inflammatory effects 32 Palmitoyl-ethanolamide • An endogenous lipid from the fatty acid N-acylethanolamine family, resembling the components of the SC 10 • Has anti-inflammatory and anti-analgesic effects 10 • Prevents skin damage following exposure to UV rays 26

Squalane
• A saturated form of squalene (a natural lipid found in the skin) 10,17 • Although it is an oil, it is not greasy and is noncomedogenic; it is odorless and safe for sensitive skin 17 • Has antibacterial effects 17

CO N FLI C T O F I NTER E S T S TATEM ENT
NM has received consulting fees from Regaliz, Torrent, and Galderma.JD has no conflicts to disclose.KD and RH are employees and shareholders of GSK.BB, VVM, and TS are employees of GSK.
Interestingly, "barrier repair devices" or prescription emollient devices (a class of moisturizing agents) comprising palmitoylethanolamide, fatty acids, ceramides, and glycyrrhetinic acids are developed to target specific deficiencies in the skin barrier composition in individuals with eczematous skin.27

F I G U R E 1
Brick and mortar structure of the stratum corneum-the outermost layer of the epidermis.

A 3 -
week, open-label, noncomparative clinical study evaluated the acceptability of a biomimic moisturizer by the skin in 35 female subjects (aged 18-60 years) with Fitzpatrick phototype classification I-IV and sensitive skin.The biomimic moisturizer consisted of aqua, shea butter, caprylic/capric triglyceride, carbomer, ceramide 3, Cocos nucifera oil, glycerine, hydrogenated lecithin, hydroxyethyl cellulose, pentylene glycol, sodium carbomer, squalane, and xanthan gum. 25 Participants were instructed to apply the moisturizer twice daily at home for 21 ± 2 days and record the usage and any feelings of cutaneous discomfort (e.g., dryness, stinging, prickling, itching) in a diary; any adverse events (AEs) were to be reported to the clinic.By study end, treatment compliance, product acceptability, and final clinical dermatological assessments were performed by the investigator at the clinic.None of the participants experienced cutaneous reactions at the area of moisturizer application or reported any AEs, indicating that the moisturizer was well tolerated and suitable for topical application in individuals with sensitive skin. 25Individuals undergoing hemodialysis usually have dry and itchy skin because of a damaged lipid barrier.Twice-daily application of a moisturizer containing structured physiological and natural lipids (Derma Membrane Structure® [DMS®]) and endocannabinoids such as PEA has been demonstrated to be beneficial in reducing xerosis in such individuals. 283.3.2| Atopic eczema A multinational, observational, noncontrolled, prospective cohort study demonstrated the benefits of a moisturizer based on biomimic technology in 2456 individuals (aged 2-70 years) with mild-to-moderate atopic eczema, dry, or itchy skin.This moisturizer consisted of purified water, Olea europaea, glycerol, pentylene glycol, palm glycerides, Olus oil, hydrogenated lecithin, squalane, F I G U R E 2 Flow diagram.TA B L E 1 Classification of moisturizers.6,10,29