Perhaps no tissue is so physically maligned by processing for light/electron microscopy as is the stratum corneum (SC). To further complicate matters, no tissue of such critical importance for survival has been so intellectually maligned as well. Because routine microscopic images of normal SC depict loosely attached corneocytes (‘‘basket-weave pattern’’), until the 1960s the barrier was thought to reside not in the SC but rather in the outer stratum granulosum (Table I). The key breakthroughs came from Albert Kligman’s group, who found isolated SC to be not friable but instead extremely durable (Christophers and Kligman, 1964), and from the work of Irvin Blank and Robert Scheuplein in Dr Fitzpatrick’s department at Harvard, who further demonstrated the highly impermeable nature of the SC (Blank, 1969; Scheuplein and Blank, 1971). Because Blank and Scheuplein found the water-transport characteristics of human SC to be similar to plastic wrap, the SC soon was analogized to a sheet of plastic or ‘‘Saran’’wrap (Table I). According to this model, which still dominates the world view of skin biophysicists and physical chemists, hydrophilic and lipophilic molecules traverse a uniform SC ‘‘membrane’’via a transcellular route without regard to tissue architecture or metabolic activity (Blank, 1969). Accordingly, percutaneous penetration is determined by the chemical characteristics of the penetrating molecule, as well as the diffusion path-length across the SC (¼ thickness of the membrane), as embodied in Fick’s law (Scheuplein and Blank, 1971). Although commonsense alone (eg, the hyperpermeability of the thickened SC of the palms and soles to water) immediately invalidates the ‘‘plastic wrap’’model, the seminal work of Blank and Scheuplein nevertheless established the importance of the SC as the critical tissue determinant of the cutaneous permeability barrier. Perhaps of greater importance, it spawned an entirely new industry, devoted to transdermal drug delivery. Developments after 1970 showed that the ‘‘plastic wrap’’model did justice neither to the structural heterogeneity nor to the metabolic activity of the SC. Frozen sections of SC revealed the compression of corneocytes into exquisite geometric stacks of interlocking tetracaidodecahedra (24-sided cells)(Christophers and Kligman, 1964; Menton and Eisen, 1971). Frozen sections and freeze-fracture images revealed lipid stacks, localized to the intercellular spaces (Elias and Friend, 1975), which were shown to derive from the secreted contents of epidermal lamellar or Odland bodies (George Odland first realized the novelty and potential importance of this organelle, previously thought to be an effete mitochondrion; Odland and Holbrook, 1981).

Lipid biochemistry, coupled with lipid histochemistry, revealed a unique extracellular membrane system, devoid of phospholipids, relying instead on an equimolar mixture of ceramides, cholesterol, and nonessential free fatty acids to form extracellular membranes (Gray and Yardley, 1975; Elias et al, 1979), which are riveted into parallel structures by linoleic-acid-bearing o-hydroxy-esterified ceramides (acylceramides)(Wertz and Downing, 1987) À hence, the still-current, two-compartment ‘‘bricks and mortar’’model of the SC (Table I).