INTRODUCTION

Understanding of the structure and functioning of the stratum corneum has advanced greatly in the 4 years since the first edition of this book. Advances in physical and biomolecular techniques are unraveling the dynamic behavior of the bricks and mortar model that skin scientists have long used as their mantra. For the cosmetic scientist hoping to use the new insights to propel cosmeceuticals more effectively through the skin barrier there is disappointment. The recent science does more to explain why the stratum corneum is such an excellent barrier than it does to reveal new strategies to enhance penetration. Delivery of actives across the skin barrier remains a major challenge and continues to limit the physiologic usefulness of topically applied products.

THE STRATUM CORNEUM STRUCTURE AND FUNCTION

The stratum corneum is an essentially impermeable structure with layers of pancake-like cells (corneocytes) embedded in a matrix of lamella lipids (Fig. 2.1). This complex structure is continuously renewed by transformation of cells (keratinocytes) migrating up from the living epidermis. There are four key processes of stratum corneum function (Fig. 2.2). The main features are summarized in Table 2.1. When all four processes are functioning optimally the stratum corneum is an excellent moisture barrier (without which all mammals would quickly dehydrate and perish) and a very effective barrier to micro-organisms and chemicals.

Fig. 2.1 The stratum corneum sitting above the living epidermal layers: (A) a typical bricks and mortar representation that does not reflect the relative proportions of skin cells, and (B) a truer to life representation of the stratum corneum structure with closely opposed and heavily cross-linked corneocytes and intercellular lipids. Corneocyte length is 50–100 times greater than thickness

Fig. 2.2 The four key processes for the formation and functioning of the stratum corneum

THE STRATUM CORNEUM BARRIER AND THE ENVIRONMENT

Although the stratum corneum is an excellent and resilient barrier, the superficial layers are readily disturbed by low humidity, wind, sun, detergents, solvents, and other chemicals. The result is dry skin. What we experience as dry skin is not simply skin that lacks water but dysfunctional skin where aberrant desquamation leads to an accumulation of corneocytes at the skin surface (Fig. 2.3). The skin feels rough; looks dull because light is scattered by the uneven surface; looks pale because the pinky glow from the microcirculation is obscured; may show visible scaling, and is susceptible to irritation. All this is a consequence of dehydration at the skin surface.

Fig. 2.3 (A) Stratum corneum fully hydrated at the skin surface with normal desquamation and release of effete corneocytes. (B) Stratum corneum with reduced hydration in the superficial layers leading to incomplete desquamation and a build up of attached cells at the skin surface (skin dryness)

Water is also important for maintaining the elasticity of the stratum corneum. Without water the skin feels tight and may crack in regions subject to stretching forces (e.g. knuckles). Ultraviolet (UV) radiation, which we mostly associate with sunburn in the short term and photoaging over time, may also damage the stratum corneum by disrupting the conversion of filaggrin to NMF (natural moisturizing factor).

• The stratum corneum intercellular lipids and ceramides

The lipids of the stratum corneum exist as highly ordered lamellae composed of ceramides (50%), cholesterol (30%) and long chain fatty acids (20%). This simple statement hides the complexity of stratum corneum lipid molecular structure and organization, the different phase behaviors of stratum corneum lipids, and the variations between normal and diseased skin. The lipid bilayers are an effective barrier to water and water-soluble chemicals. Disruption of the barrier lipid structure by harsh cleansers leads to loss of moisture and aberrant desquamation.

Lotions containing the three classes of stratum corneum lipids (Fig. 2.4) are claimed to restore normal barrier function, but most are no more effective than products containing the same amount of any emollient lipids. To restore the barrier requires the three lipid types, the correct subspecies of ceramide (there are nine subclasses), the right molar ratio (1 : 1 : 1) delivered into the skin, and an effective amount (well above the low levels present in some cosmetic products). Partial mixtures, cholesterol and fatty acids without ceramides, may disrupt stratum corneum lipid structures rather than improve them.

Fig. 2.4 Three classes of polar lipids, ceramides, fatty acids, and cholesterol, are the main constituents of the lipid matrix of the stratum corneum

NATURAL REJUVENATION OF SKIN

Skin has remarkable ability to repair and compensate for environment insults. The healing of wounds is an example. Many of the skin rejuvenation techniques used in cosmetic dermatology, such as chemical peels, ablative laser therapies, and dermabrasion, involve controlled injury of ‘bad skin’ with the expectation that wound healing processes will replace the damaged skin with new skin that looks and functions better. The biologic mechanisms involved are simple in concept although complex in detail. Injury to skin kills some cells and damages others. Many chemical messengers (cytokines and other mediators) are released and activate/recruit wound-healing cells (immune, inflammatory, hematopoietic) to the damaged area. Scavenger cells remove the debris and tissue remodeling cells rebuild the structure.

THE BARRIER IS A CHALLENGE FOR COSMECEUTICALS

Normal skin is seldom entirely normal because of a daily battery of environmental insults. Minor defects accumulate over time and eventually produce a noticeable deterioration of skin function and appearance. Cosmeceutical products seeking to address these issues must somehow penetrate the stratum corneum barrier.

A route through the corneocytes at their points of intercellular connections (the desmosomes) is the most direct way across the stratum corneum barrier but the corneocyte outer membrane, the cornified envelope, is so extensively cross-linked and insoluble that very few substances are able to penetrate. The main route of penetration of the stratum corneum is a tortuous path through the multiple bilayer lipid matrix between the corneocytes (Fig. 2.5). The lipid bilayers create a formidable barrier to water, microorganisms, and many chemical types.

Fig. 2.5 The stratum corneum lipid matrix has a multiple bilayer organization formed by the spontaneous alignment of polar and nonpolar regions of the ceramide, cholesterol, and fatty acid molecules

There has been extensive research to find methods to enhance delivery of actives through the stratum corneum. The main methods are summarized in Table 2.2. None of these methods is uniformly effective. Chemical penetration enhancers function by temporarily disrupting the lipid bilayer structures of the stratum corneum to allow easier passage of active molecules. The more effective chemical enhancers tend to cause irritation and some are toxic—these are not used in cosmeceuticals. SCOPE is a high-throughput screening system to identify Synergistic Combinations of Penetration Enhancers.

Table 2.2 Strategies to enhance skin penetration

Liposomes are widely used in cosmeceuticals. They are spherical vesicles bounded by a bilayer membrane formed from phospholipid or other polar lipids. This may be a single bilayer (unilamellar) or many layers (multilamellar). The multilamellar membranes are similar in structure to the stratum corneum lipid bilayers but generally less complex (Fig. 2.6). They are claimed to enhance penetration by carrying their hydrophilic contents through the lipid barrier layers as intact vesicles but their effectiveness as penetration enhancers is controversial. It seems likely that most effects of liposomes are due to disruption of the skin lipid bilayers and not to penetration of intact vesicles.

Fig. 2.6 Liposomes—vesicles bounded by a lamellar lipid membrane similar to the lipid bilayers of the stratum corneum. Claimed to enhance penetration by carrying contents through the stratum corneum but any penetration enhancement is likely due to liposome vesicles breaking down and their lipid components interacting with and disrupting the lipid lamellae of the stratum corneum barrier

The challenge to deliver actives beyond the stratum corneum barrier has stimulated renewed interest in physical methods of penetration enhancement such as iontophoresis, sonophoresis, and thermal poration. These methods disturb the normal microstructure of the stratum corneum and create transient microscopic aqueous channels that allow increased penetration of ingredients. The treatment conditions must be controlled to avoid excessive damage, burning, and irritation.

While the focus of this chapter is the stratum corneum barrier, there is increasing interest in transfollicular delivery. Because hair follicles occupy less than 0.1% of the skin surface they have been discounted as a significant route for delivery. This may be true for cosmetically uninteresting sites like the forearm but for sites like the forehead the transfollicular route may be important. Transfollicular penetration depends on the state of the hair follicle which can be open or closed (closed pores are opened by massage).

NANOPARTICLES

Nanoparticles are microscopic particles with one dimension less than 100 nm (Table 2.3). Nanoparticles are not new but the possibility to use submicron size as a strategy to achieve hitherto difficult technical goals has spawned nanotechnology as a new field in medicine and cosmetology. It is no panacea. There are concerns that small particles entering the body may be a hazard to health. Nanoparticles are being promoted for cosmetic applications but optimism that they will overcome the skin barrier to penetration may turn out to be premature. Submicron liposomes penetrate human skin deeper and more rapidly than solid particles the same size that barely penetrate, indicating that permeability is determined by chemistry more than size. Nanoparticles greater than 5 nm do not penetrate the lipid layers of the stratum corneum but can enter the openings of the hair follicle.

Table 2.3 Nanoparticles in perspective

FUTURE PROSPECTS

Although we can expect incremental progress as cosmetic scientists seek ways to increase penetration of cosmeceuticals, it looks likely that the skin barrier will maintain the upper hand. Our safety and well-being are secure!! Perhaps there is a need for a new strategy for skin care. Instead of seeking to propel putative actives to the deeper layers of skin to fix damage, maybe we should concentrate on depositing ingredients in the superficial regions of skin to prevent damage in the first place by protecting from the environmental factors that drive poor skin condition and premature skin aging.