Physiologic Development of the Skin

Cornified Envelope and Epidermal Lamellar Bodies

During later gestation, epithelial surfaces at environmental interfaces undergo structural and functional changes, including complex proteolipid synthesis. These highly coordinated events can be influenced by gender and prenatal hormone exposure (rat model), for example, maternal glucocorticoids. The three stages of fetal skin development are stratification, follicular keratinization, and interfollicular epidermal keratinization. Interfollicular keratinization occurs in a rostrocaudal and dorsoventral fashion, beginning at 23 to 24 weeks of GA, coinciding roughly with the time of postnatal viability. The formation of a barrier to water loss and infection is essential for extrauterine survival. Fig. 44.2 illustrates the SC cornified envelope assembly. Synthesis and secretion of epidermal barrier lipids occurs as lamellar bodies, similar to a parallel process in the developing lung ( Table 44.3 ). The intracellular lamellar body fuses with the plasma membrane and extrudes barrier lipids, consisting of free fatty acids, cholesterol, and ceramides, to form the primary barrier to transepidermal water loss (TEWL); the barrier lipids form a regular, bilayer structure that further ensures impermeability to outside agents (see Table 44.3 ). Covalent cross-linking of structural proteins (e.g., keratins) by intracellular transglutaminases and ceramides forms the insoluble, cornified SC envelope, ^, essentially a huge macromolecule. ^, This cross-linked assembly forms the scaffolding for the highly ordered lamellar lipid matrix (see Chapter 43 ). The cells within the stratum spinosum and stratum granulosum are attached to each other in all directions by desmosomes, protein-based materials that provide mechanical integrity (see Fig. 44.2 ).

The Biology of Vernix

Scientifically, the development of epidermal barrier function has many similarities to surfactant production and lung development (see Table 44.3 ). Both epidermal keratinocyte and type II alveolar cells are lipid-synthesizing cells that secrete barrier lipids as lamellar bodies. Both ultimately interface with a gaseous environment and are under similar hormonal control at similar periods of development. The mechanisms by which the lung develops a functionally mature epithelial surface ready for air adaptation and skin surface matures under total aqueous conditions for terrestrial adaptation to a dry environment are analogous. An unanswered question, however, is by which mechanism the epidermal barrier forms under total aqueous immersion. Prolonged exposure of the skin to water in adults is harmful. Vernix caseosa, a complex proteolipid cellular cream, forms during the last trimester, interacts with the epidermis, and facilitates the SC formation ( Fig. 44.3 ).

The barrier forms initially in the region of the pilosebaceous apparatus. ^, This finding strongly supports the hypothesis that vernix caseosa (partly from sebaceous secretions) participates in “waterproofing” the skin surface, allowing cornification initially in the hair follicles and then over the interfollicular skin, perhaps analogous to skin culture systems raised to an air-liquid interface for cornification. Sebaceous glands excrete sebum, a complex nonpolar lipid mixture synthesized de novo by the glands. Sebaceous glands are multiacinar, holocrine-secreting structures that occur over the skin. Their development is closely related to hair follicle differentiation. In neonates, sebaceous glands are hyperplastic and visible in areas such as the nose. The timing of vernix production and the developing pilosebaceous apparatus supports a mechanism by which the surge in sebaceous gland activity leads to production of vernix overlying the developing SC. Sebaceous gland hyperplasia in term infants is putatively secondary to androgenic stimulation from hyperplastic fetal adrenal glands, providing a testable model integrating hyperplasia of sebaceous and adrenal glands during later gestation ( Fig. 44.4 ). This hypothesis explains other clinical observations, such as turbidity of amniotic fluid during the last trimester of pregnancy. In vitro, the addition of physiologically relevant amounts of pulmonary surfactant leads to emulsification and release of immobilized vernix (i.e., a test tube coated with native vernix). This finding is consistent with a mechanism by which the outermost portion of the vernix coating is “removed” from the fetal skin surface by lung-derived surfactant contained in the amniotic fluid (see Fig. 44.4 ). The fetus subsequently swallows the detached vernix (see Fig. 44.4 ). Vernix contains branched chain fatty acids (BCFA), which are trophic and protective factors for the developing gut. ^, A diet enriched with vernix-like BCFA significantly reduced necrotizing enterocolitis in the neonatal rat model and BCFA-enriched vernix-monoacylglycerol decreased inflammatory markers in human enterocytes. Vernix contains antimicrobial agents, including lactoferrin and lysozyme, and antioxidants, providing additional protection at birth. When vernix is retained on the skin surface at birth, the skin is more hydrated and has a lower surface acidity than when it is removed.

Water Loss, Temperature Control, and Blood Flow

A dry environment necessitates protection against dehydration. Barrier formation against TEWL is a function of gestational age ( Fig. 44.5 ), ^, decreasing dramatically and approximating adult values near term. This critical function resides almost entirely in the outermost 20 μm of the skin surface—in the SC. Heat exchange occurs between infant skin and the environment via evaporation, radiation, conduction, and convection. Evaporative heat loss is the primary mode of temperature instability in not only in very low-birth-weight preterm but in all infants and is the primary mode of heat loss at birth. It is important to distinguish between evaporative heat loss from standing water or amniotic fluid on the skin surface and evaporative heat loss secondary to a poorly developed epidermal barrier, which occurs after delivery in very low-birth-weight preterm infants. Evaporative heat and fluid loss are ongoing and are exacerbated in non-humidified, radiant-heated environments.

The periphery is important in temperature control in newborn infants ( Fig. 44.6 ). Given the critical importance of limiting evaporative water and heat loss in temperature control, it is surprising how little attention is given to the role of the SC in thermoregulation. The strategic position of the SC is taken for granted, and focus is placed on more central mechanisms for maintaining body temperature, yet it is essential in organizing, maintaining, and guiding central nervous system development. At 4 hours of age, oxygen consumption is not simply a function of central body temperature, as might be expected with warm-blooded endothermic organisms, but is largely a function of heat exchange at the skin-environment interface, as central homeothermic mechanisms are not well developed at birth. Preterm infants are more vulnerable to environmental heat loss due to a higher surface area to mass ratio, lower endogenous heat generation (e.g., brown adipose tissue), an incompetent epidermal barrier, and inability to self-regulate with flexural positioning. Central control of body temperature requires autonomic mechanisms such as eccrine sweating and vasodilatation/vasoconstriction, which are not well-established at birth. Newborn infants may exhibit vasoconstriction of the extremities (acrocyanosis) and have widely variable hematocrits and blood volumes. Peripheral cooling results in increased blood viscosity and decreased blood flow. In the first 3 months, the cutaneous vascular bed undergoes reorganization, with development of a subpapillary plexus ( Fig. 44.7 ). The formation of a superficial vascular plexus is associated with increased convolution in the epidermis (rete peg formation) a hallmark of the mature epidermis. Abnormal cutaneous vascular development and the role of associated growth factors have been reviewed elsewhere. ^,

Full-Term Neonatal Skin Adaptation

At birth, full-term skin is well-developed and protective, despite having been in a wet environment during gestation. An appropriate level of moisture (hydration) is necessary for flexibility with movement, desquamation of the outer layers during SC self-renewal, and other functions. The level of skin hydration depends upon presence or vernix, environmental temperature, and body site. ^, Hydration decreases rapidly during postnatal day one then increases significantly over the next 2 weeks ( Fig. 44.8 ), but the skin remains drier than older infants and their mothers. Low hydration is likely caused by a delay in the production of water-binding materials, including amino acids, from enzymatic proteolysis of filaggrin in the outer SC layers. These processes are delayed under high humidity in utero and are activated in the drier extrauterine environment.

Factors Influencing Neonatal Skin pH

Full-term skin pH is neutral at birth, decreases markedly over days 1 to 4 and continues to decline for as long as 3 months after birth. ^{, ,} For example, NMF levels were very low at birth in full-term infants but increased over the first postnatal month, ^, contributing to the acid mantle. Vernix plays a role in this process. Full-term skin pH was lower when vernix was retained at delivery than when vernix was removed at 4 or 24 hours after birth.

In low-birth-weight infants, skin pH decreased rapidly over days 1 to 3, more slowly over days 4 to 7, and declined further up to day 28. Individually, GA and day of life did not influence the skin pH but significantly impacted the reduction in combination. A rapid decrease in skin pH occurred in infants 24 to 34 weeks GA during postnatal week 1 then was more gradual. Infants weighing less than 1000 g had a higher skin pH for longer than infants weighing more than 1000 g. Unlike full-term neonates, premature infants less than ∼29 weeks GA have little vernix on the skin surface at birth. Consequently, the premature skin barrier may not experience the benefits of reduced pH and increased hydration observed in full-term infants.

The skin pH can be altered by topical products and items. For example, the pH of skin under the diaper was higher than a non-diapered site in neonates and older infants ( Fig. 44.10 ). ^, Higher diaper skin pH was related to greater irritant contact dermatitis and hydration (wetness). Higher pH may increase the risk of mechanical damage in vulnerable infants (e.g., friction, cleaning) and increase skin permeability to toxins. Higher skin pH may predispose development of inflammatory skin diseases of infancy, including atopic dermatitis and seborrheic dermatitis.