66 JOURNAL OF COSMETIC SCIENCE The lipids are organized in a multilamellar structure and Friberg found that it typically exists as a liquid crystalline phase. However the phase behavior of this liquid crystal lipid structure can be effected by chemical treatment and relative humidity (Froebe et al, J. Soc. Cosmet. Chem. 41, 51-65, 1990 Mattai et al J. Soc. Cosmet. Chem. 44, 89-100, 1993). For example low relative humidity promotes dehydration of the lipid membrane with the formation of crystals in the structure. The lipid bilayers are attached hydrophobically to the comeocyte envelope on the surface of the comeocyte this envelope contains covalently attached co-hydroxyceramide, a lipid which serves as a template for the lipid bilayer attachment (Abraham, above). Moisturization of skin is the mainstay strategy to relieve dry skin. Moisturization can be defined in several ways from simply adding water back to the skin, retaining water inside the skin, elimination of the feeling of dryness of skin, reduction or elimination of dry skin scales, or enhancement of barrier lipid function / repair mechanisms. It can be achieved using a variety of strategies namely with masking emollients, occlusive agents, skin protectants, hygroscopic agents, lipid fluidizing agents, and biological enhancers of barrier repair. Current strategies are briefly summarized here. Simply placing a light emollient on the skin can appear to visibly remove the scales in a superficial way. The end result is apparent softening and smoothing of the skin but it is not a long term effect. Occlusive agents and skin protective agents such as petrolatum can be applied to the skin and these will hold water in the skin by providing a protective barrfer. OTifiemf½one, gfy'c•t-or •&,tr' petrolatum are known for their occlusive protective function and are considered drugs in the US Federal OTC Skin Protectant Monograph. Hydrophilic emollients are used to provide long term benefits on skin by hydrogen bonding to water keeping moisture in skin. Such agents are polymers of ethylene and propylene glycol, e.g .glycerine, propylene glycol, polyethylene glycol. Other hydrating agents affect hydrogen bonding to enhance barrier and such examples of these small molecules are urea and alpha hydroxy acids like lactic acid. These can alter the hydrogen bonding properties of the proteins in skin and result in changing the rheological properties and skin elasticity. Hydroxy acids can also alter cell turnover. The effects are generally longer term and the alpha hydroxy acids can even improve wrinkles and fine lines when used on a daily basis (Smith, Cosmetics and Toiletreis, 109, 41-48, 1994). Lactate and pyrrolidone carboxylic acid are part of the "natural moisturizing factor" identified in stratum corneum, both of which are known to be the most hygroscopic components of the water soluble fraction of the stratum comeurn (Rawlings, A. J. Invest. Derm. 731-740, 1994). They are thought to be derived from breakdown of stratum comeum proteins probably from filaggrin which degrades after the keratin fibers are stacked (Odland, G. in Physiology, Biochemistry, and Molecular Biology of the Skin, Second Edition, L. Goldsmith, Oxford Univ. Press, 1991). Fluidization of the membrane lipid in the epidermis is the contemporary approach being studied to improve barrier. Lipid in skin as mentioned previously assumes a liquid

1999 ANNUAL SCIENTIFIC MEETING 67 crystalline structure. Under conditions of dry relative humidity, a phase change in the lipid to solid crystals may occur. This creates "holes" or defects in the bilayer that can permit moisture to penetrate through the stratum corneum. Application of formulations containing lipid fluidizing agents can slow down the phase change of the lipid to solid crystals under conditions of dry relative humidity. This will maintain the epidermal lipid in the more fluid, liquid crystalline form. Such lipid fluidizers have been identified in the literature and by experimentation with model stratum corneum lipids in vitro (Froebe et al, J. Soc. Cosmet. Chem. 41, 51-65, 1990 Mattai et al J. Soc. Cosmet. Chem. 44, 89- 100, 1993). Using differential scanning calorimetry to track the heat of fusion of the phase changes the above authors determined what materials will reduce the heat of fusion. Lipid fluidizers identified by these in vitro techniques are glycerine and maleated soybean oil (glyceride acid). Glycerine has been reported to be a well known moisturizer / skin protectant for centuries. Perhaps more than its humectant properties, its mechanism of action is via fluidization of stratum corneum lipid. Metabolic Strategies to Repair Aging Skin Barrier Also a more contemporary strategy being explored to repair and enhance barrier is to control the activity of the barrier lipid synthesizing enzymes with mediators of their activity (see review by Harris et al J. Invest. Dermat. 109, 783-7, 1997). The extracellular lipids of the stratum corneum, which are comprised mainly of cholesterol, fatty acids, and ceramides, are essential for epidermal permeability barrier function. Moreover, disruption of the permeability barrier results in increased cholesterol, fatty acid, and ceramide synthesis in the underlying epidermis. This increase in lipid synthesis has been shown to be due to increased activities of HMG-CoA reductase, acetyl-CoA carboxylase, along with fatty acid synthase, and serine palmitoyl transferase, key enzymes of cholesterol, fatty acid, and ceramide synthesis, respectively. It has been determined that the mRNA levels for the key enzymes required for synthesis of these three classes of lipids increase coordinately during barrier recovery. By northern blotting techniques, the steady-state mRNA levels for HMG-CoA reductase, HMG-CoA synthase, farnesyl pyrophosphate synthase, and squalene synthase, key enzymes for cholesterol synthesis, all increased significantly after barrier disruption by either acetone or tape stripping. Additionally, the steady-state mRNA levels of acetyl-CoA carboxylase and fatty acid synthase, required for fatty acid synthesis, as well as serine palmitoyl transferase, the rate-limiting enzyme of de novo ceramide synthesis, also increased. Inhibitors of the activity of these enzymes can also lead to delayed barrier repair. For example application of lovastatin, beta chloroalanine, or TOFA to in vivo to hairless mouse skin with acetone damaged or tape stripped barrier, lead to delayed recovery of TEWL (water loss). These substances inhibit enzymes mentioned above that are involved in cholesterol, sphingolipid, or fatty acid synthesis respectively. It is, therefore, very reasonable that activators of these enzymes should potentiate barrier repair.