Skin and its appendages

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CHAPTER 7 Skin and its appendages

In this chapter, the types and functions of skin in different parts of the body are described first, followed by the microstructure of the epidermis and dermis, and the appendages of skin including the pilosebaceous units and the sweat glands and nails. The development of skin, natural skin lines and age-related changes, and clinical aspects of skin, e.g. grafts, surgical skin flaps and wound healing, are also described. The integumental system includes the skin and its derivatives, hairs, nails, sweat and sebaceous glands; subcutaneous fat and deep fascia; the mucocutaneous junctions around the openings of the body orifices; and the breasts. Mucocutaneous junctions and breast tissues are covered in the appropriate regional sections.

TYPES AND FUNCTIONS OF SKIN

The skin covers the entire external surface of the body, including the external auditory meatus, the lateral aspect of the tympanic membrane and the vestibule of the nose. It is continuous with the mucosae of the alimentary, respiratory and urogenital tracts at their respective orifices, where the specialized skin of mucocutaneous junctions is present. It also fuses with the conjunctiva at the margins of the eyelids, and with the lining of the lachrymal canaliculi at the lachrymal puncta. Skin forms 8% of the total body mass. Its surface area varies with height and weight, e.g. in an individual of 1.8 m and weighing 90 kg, the surface area of the skin is approximately 2.2 m². Its thickness ranges from 1.5–4.0 mm, according to its state of maturation, ageing and regional specializations.

The skin forms a self-renewing interface between the body and its environment, and is a major site of intercommunication between the two. Within limits, it forms an effective barrier against microbial invasion, and has properties which can protect against mechanical, chemical, osmotic, thermal and UV radiation damage. It is an important site of immune surveillance against the entry of pathogens and the initiation of primary immune responses. Skin carries out many biochemical synthetic processes, including the formation of vitamin D under the influence of ultraviolet B (UVB) radiation and synthesis of cytokines and growth factors. Skin is the target of a variety of hormones. These activities can affect the appearance and function of individual skin components, such as the sebaceous glands, the hairs and the pigment-producing cells.

Control of body temperature is an important function of skin, and is effected mainly by regulation of heat loss from the cutaneous circulation through the rapid increase or reduction in the flow of blood to an extensive external surface area: the process is assisted by sweating. Skin is involved in sociosexual communication and, in the case of facial skin, can signal emotional states by means of muscular and vascular responses. It is a major sense organ, richly supplied by nerve terminals and specialized receptors for touch, temperature, pain and other stimuli.

Skin has good frictional properties, assisting locomotion and manipulation by its texture. It is elastic, and can be stretched and compressed within limits. The outer surface is covered by various markings, some of them are large and conspicuous and others are microscopic, or are only revealed after manipulation or incision of the skin. These markings are often referred to collectively as skin lines.

The colour of human skin is derived from, and varies with, the amount of blood (and its degree of oxygenation) in the cutaneous circulation, the thickness of the cornified layer, and the activity of specialized cells which produce the pigment melanin. Melanin has a protective role against ultraviolet radiation, and acts as a scavenger of harmful free radicals. Racial variations in colour are mainly due to differences in the amount, type and distribution of melanin, and are genetically determined.

The appearance of skin is affected by many other factors, e.g. size, shape and distribution of hairs and of skin glands (sweat, sebaceous and apocrine), changes associated with maturation, ageing, metabolism, pregnancy. The general state of health is reflected in the appearance and condition of the skin, and the earliest signs of many systemic disorders may be apparent in the skin. Examination of the skin, therefore, is of importance in the diagnosis of more than just skin disease.

CLASSIFICATION OF SKIN

Although skin in different parts of the body is fundamentally of similar structure, there are many local variations in parameters such as thickness, mechanical strength, softness, flexibility, degree of keratinization (cornification), sizes and numbers of hairs, frequency and types of glands, pigmentation, vascularity, innervation. Two major classes of skin are distinguished: they cover large areas of the body and show important differences of detailed structure and functional properties. These are thin, hairy (hirsute) skin, which covers the greater part of the body, and thick, hairless (glabrous) skin, which forms the surfaces of the palms of the hands, soles of the feet, and flexor surfaces of the digits (Fig. 7.1, Fig. 7.2, see Fig. 7.4).

Fig. 7.1 The organization of skin, comparing the structures found in thick, hairless (plantar and palmar) skin with thin, hairy (hirsute) skin. The epidermis has been partially peeled back to show the interdigitating dermal and epidermal papillae.

Fig. 7.2 The interfollicular epidermis of human thin skin. Note the thin cornified layer (C) in comparison with Fig. 7.4 (which is also at a lower magnification).

Fig. 7.4 The epidermis and papillary dermis (P) of human thick skin, showing the thick cornified layer (C, stratum corneum), the eosinophilic clear layer (L, stratum lucidum), the granular layer (G, stratum granulosum), the prickle cell layer (S, stratum spinosum) and the basal layer (B, stratum basale). Capillary loops (arrows) are seen entering the deep papillae (rete ridges) of the dermis, between downward-projecting epidermal rete pegs.

MICROSTRUCTURE OF SKIN AND SKIN APPENDAGES

The epidermis (Fig. 7.2, Fig. 7.3) is a compound tissue consisting mainly of a continuously self-renewing, keratinized, stratified squamous epithelium: the principal cells are called keratinocytes. Nonkeratinocytes within the mature epidermis include melanocytes (pigment-forming cells from the embryonic neural crest), Langerhans cells (immature antigen-presenting dendritic cells derived from bone marrow), and lymphocytes. Merkel cells, which may function as sensory mechanoreceptors or possibly as part of the dispersed neuroendocrine system, are associated with nerve endings. Free sensory nerve endings are sparsely present within the epidermis. In routine histological preparations, the non-keratinocytes and Merkel cells are almost indistinguishable, and appear as clear cells surrounded by a clear space produced by shrinkage during processing. Their cytoplasm lacks prominent filament bundles.

Fig. 7.3 The main features of the epidermis, including its cell layers and different cell types. Melanocytes and Merkel cells are derived from the neural crest and Langerhans cells are derived from bone marrow precursor cells.

The population of keratinocytes undergoes continuous renewal throughout life: a mitotic layer of cells at the base replaces those shed at the surface. As they move away from the base of the epidermis, keratinocytes undergo progressive changes in shape and content. They transform from polygonal living cells to non-viable flattened squames full of intermediate filament proteins (keratins) embedded in a dense matrix of cytoplasmic proteins to form mature keratin. The process is known as keratinization or, more properly, cornification.

The epidermis can be divided into a number of layers from deep to superficial as follows: basal layer (stratum basale), spinous or prickle cell layer (stratum spinosum), granular layer (stratum granulosum), clear layer (stratum lucidum) and cornified layer (stratum corneum) (Fig. 7.4). The first three of these layers are metabolically active compartments through which cells pass and change their form as they progressively differentiate. The more superficial layers of cells undergo terminal keratinization, or cornification, which involves not only structural changes in keratinocytes, but also alterations in their relationships with each other and with non-keratinocytes, and molecular changes within the intercellular space.

The epidermal appendages (pilosebaceous units, sweat glands and nails) are formed developmentally by ingrowth of the general epidermis, and the latter is thus referred to as the interfollicular epidermis.

Keratinocytes

Basal layer

The basal or deepest layer of cells, adjacent to the dermis, is the layer where cell proliferation in the epidermis takes place. This layer contacts a basal lamina (Fig. 7.5, see Fig. 2.7), which is a thin layer of specialized extracellular matrix, not usually visible by light microscopy. By routine electron microscopy the basal lamina appears as a clear lamina lucida (adjacent to the basal cell plasma membrane) and a darker lamina densa. The basal plasma membrane of the basal keratinocytes, together with the extracellular basal lamina (lamina lucida and lamina densa) and anchoring fibrils within the subjacent dermal matrix (the lamina fibroreticularis), which insert into the lamina densa and loop around bundles of collagen, collectively form the basement membrane zone (BMZ) which constitutes the dermo-epidermal junction. This is a highly convoluted interface, particularly in thick, hairless skin, where dermal papillae (rete ridges) project superficially into the epidermal region, interlocking with adjacent downward projections of the epidermis (rete pegs) (Fig. 7.4).

Fig. 7.5 The major features of a hemidesmosome in the basement membrane zone (BMZ) of skin, including some of the important molecular components.

The majority of basal layer cells (Fig. 7.3) are columnar to cuboidal in shape, with large (relative to their cytoplasmic volume) mainly euchromatic nuclei and prominent nucleoli. The cytoplasm contains variable numbers of melanosomes and, characteristically, keratin filament bundles corresponding to the tonofilaments of classic electron microscopy. In the basal keratinocytes these keratins are mostly K5 and K14 proteins. The plasma membranes of apposed cells are connected by desmosomes, and the basal plasma membrane is linked to the basal lamina at intervals by hemidesmosomes (Fig. 7.5, see Fig. 1.5). Melanocytes (see Fig. 7.9), occasional Langerhans cells (see Fig. 7.3) and Merkel cells (see Fig. 3.30) are interspersed among the basal keratinocytes. Merkel cells are connected to keratinocytes by desmosomes, but melanocytes and Langerhans cells lack these specialized contacts. Intraepithelial lymphocytes are present in small numbers.

Fig. 7.9 Melanocytes in the basal layer of thin skin, including that of the follicular epidermis, in a biopsy of periauricular skin in a Caucasian male. The pigmented melanocytes, visualized immunocytochemically using antibody against a differentiation marker (Melan A/MART-1), extend dendritic processes between keratinocytes of the basal and lower prickle cell layers. Melanocytes are relatively inactive in this specimen, with no melanosomes visible in the surrounding keratinocytes.

At any one time the basal layer of the epidermis contains keratinocytes with different fates. These include multipotent stem cells. On division these may self-renew or produce a daughter cell which is committed to differentiate after undergoing further transit amplifying cell divisions. The activity of stem cells and transit amplifying cells in the basal layer provides a continuous supply of differentiating cells which enter the prickle cell layer. The great majority of these cells are postmitotic, although some cell division may occur in the more basal regions of the prickle cell layer. Stem cells are thought to reside mainly in the troughs of rete pegs, and in the outer root sheath bulge of the hair follicle, but they cannot easily be distinguished morphologically. The distribution of stem cells and the size of their proliferative units (see below) may be quite variable in human skin (Ghazizadeh & Taichman 2005).

The organization of the basal layer and overlying progeny cells is thought to form a series of columns. Several layers of prickle and granular cells overlie a cluster of six to eight basal cells, forming a columnar proliferative unit. Each group of basal cells consists of a central stem cell with an encircling ring of transit amplifying proliferative cells and postmitotic maturing cells. From the periphery of this unit, postmitotic cells transfer into the prickle cell layer. The normal total epidermal turnover time is between 52 and 75 days. In some pathologies of skin, turnover rates and transit times can be exceedingly rapid, e.g. in psoriasis, total epidermal turnover time may be as little as 8 days. The control of keratinocyte proliferation and differentiation is beyond the scope of this publication but is reviewed in Niemann & Watt (2002) and Byrne et al (2003).

Prickle cell layer

The prickle cell layer (Fig. 7.3, Fig. 7.6) consists of several layers of closely packed keratinocytes that interdigitate with each other by means of numerous cell surface projections. The cells are anchored to each other by desmosomes that provide tensile strength and cohesion to the layer. These suprabasal cells are committed to terminal differentiation and gradually move upwards towards the cornified layer as more cells are produced in the basal layer. When skin is processed for routine light microscopy, the cells tend to shrink away from each other except where they are joined by desmosomes, which gives them their characteristic spiny appearance. Prickle cell cytoplasm contains prominent bundles of keratin filaments, (mostly K1 and K10 keratin proteins) arranged concentrically around a euchromatic nucleus, and attached to the dense plaques of desmosomes. The cytoplasm also contains melanosomes, either singly or aggregated within membrane-bound organelles (compound melanosomes). Langerhans cells (see Fig. 7.11) and the occasional associated lymphocyte are the only non-keratinocytes present in the prickle cell layer.

Fig. 7.6 The superficial layers of human thick skin at high magnification, showing the deeply stained keratohyalin granule-containing cells of the granular layer (G) between the prickle cell or spinous layer (S) and the clear (or lucid, L) and cornified (C) layers above. Note that the clear layer is only translucent in unstained preparations and appears eosinophilic, as here, after staining.

Fig. 7.11 Langerhans cells immunolabelled for the marker protein S100, extending dendrites between keratinocytes, mainly in the prickle cell layer of human thin skin. Basal layer melanocytes and scattered dermal cells (possibly of neural origin) are also positive for S100, visualized using a peroxidase method.

Granular layer

Extensive changes in keratinocyte structure occur in the three to four layers of flattened cells in the granular layer. The nuclei become pyknotic and begin to disintegrate; organelles such as ribosomes and membrane-bound mitochondria and Golgi bodies degenerate; and keratin filament bundles become more compact and associated with irregular, densely staining keratohyalin granules (Fig. 7.6). Small round granules (100 × 300 nm) with a lamellar internal structure (lamellar granules, Odland bodies, keratinosomes) also appear in the cytoplasm. Keratohyalin granules contain a histidine-rich, sulphur-poor protein (profilaggrin) which, when the cell reaches the cornified layer, becomes modified to filaggrin. The lamellar granules are concentrated deep to the plasma membrane, with which they fuse, releasing their hydrophobic glycophospholipid contents into the intercellular space within the layer and also between it and the cornified layer. They form an important component of the permeability barrier of the epidermis, rendering it relatively waterproof.

Clear layer

The clear layer is only found in thick palmar or plantar skin. It represents a poorly understood stage in keratinocyte differentiation. It stains more strongly than the cornified layer with acidic dyes (Fig. 7.6), is more refractile optically, and often contains nuclear debris. Ultrastructurally, its cells contain compacted keratin filaments and resemble the incompletely keratinized cells which are occasionally seen in the innermost part of the cornified layer of thin skin.

Cornified layer

The cornified layer (Fig. 7.3, Fig. 7.6) is the final product of epidermal differentiation, or cornification. It consists of closely packed layers of flattened polyhedral squames (Fig. 7.7), ranging in surface area from 800 to 1100 μm². These cells overlap at their lateral margins and interlock with cells of apposed layers by ridges, grooves and microvilli. In thin skin this layer may be only a few cells deep, but in thick skin it may be more than 50 cells deep. The plasma membrane of the squame appears thicker than that of other keratinocytes, partly due to the cross-linking of a soluble precursor, involucrin, at the cytoplasmic face of the plasma membrane, in the complex insoluble cornified envelope. The outer surface is also covered by a monolayer of bound lipid. The intercellular region contains extensive lamellar sheets of glycolipid derived from the lamellar granules of the granular layer. The cells lack a nucleus and membranous organelles, and consist solely of a dense array of keratin filaments embedded in a cytoplasmic matrix which is partly composed of filaggrin derived from keratohyalin granules.

Fig. 7.7 The epidermal surface surrounding the aperture of a sweat duct. Several polygonal, scale-like keratinocytes (squames) of the superficial cornified layer are visible in this scanning electron micrograph.

Under normal conditions the production of epidermal keratinocytes in the basal layer is matched by loss of cells from the cornified layer. Desquamation of these outer cells is normally imperceptible. When excessive, it appears in hairy regions as dandruff, and more extensively in certain diseases and, to a lesser extent, after sunburn, as peeling, scaling and exfoliation. The thickness of the cornified layer can be influenced by local environmental factors, particularly abrasion, which can lead to a considerable thickening of the whole epidermis including the cornified layer. The soles of the feet become much thickened if an individual habitually walks barefoot, and cornified pads develop in areas of frequent pressure, e.g. corns from tight shoes, palmar calluses in manual workers, and digital calluses in guitar players.

Keratins

Epidermal keratinization has historically been the term applied to the final stages of keratinocyte differentiation and maturation, during which cells are converted into tough cornified squames. However, this is now regarded as ambiguous because the term keratin is assumed to refer to the protein of epithelial intermediate filaments, rather than (as previously) to the whole complement of proteins in the terminally differentiated cell of the stratum corneum.

Keratins are the intermediate filament proteins found in all epithelial cells. There are two types, type I (acidic) and type II (neutral/basic); they form heteropolymers, are coexpressed in specific pairs and are assembled into 10 nm intermediate filaments. Fifty-four different keratin genes have been recognized and their protein products are numbered. The nomenclature for human keratins and keratin genes has recently been revised and is given in Schweizer et al (2006). Different keratin pairs are expressed according to epithelial cell differentiation; antibodies to individual keratins are useful analytical tools (Fig. 7.8). Keratins K5 and K14 are expressed by basal keratinocytes. New keratins, K1 and K10, are synthesized suprabasally. In the granular layer the filaments become associated with keratohyalin granules containing profilaggrin, a histidine-rich phosphorylated protein. As the cells pass into the cornified layer, profilaggrin is cleaved by phosphatases into filaggrin which causes aggregation of the filaments and forms the matrix in which they are embedded. Other types of keratin expression occur elsewhere, particularly in hair and nails, where highly specialized hard, or trichocyte, keratin is expressed. This becomes chemically modified and is much tougher than in the general epidermis. For a recent review of keratin function see Gu & Coulombe 2007.

Fig. 7.8 Thin skin in the region of a human hair follicle, immunolabelled to detect keratins (including K5) in the basal and suprabasal interfollicular epidermis (between arrowheads), the hair follicle (HF) and associated sebaceous glands (S). The presence of keratins was visualized using a peroxidase technique.

Epidermal lipids

The epidermis serves as an important barrier to the loss of water and other substances through the body surface (apart from in sweating and sebaceous secretion). A variety of lipids are present and synthesized in the epidermis, including triglycerides and fatty acids, phospholipids, cholesterol, cholesterol esters, glycosphingolipids and ceramides. An intermediate in the synthesis of cholesterol, 7-dehydrocholesterol, is the precursor of vitamin D, which is also synthesized in the skin. The content and composition of epidermal lipids change with differentiation. Phospholipids and glycolipids at first accumulate within keratinocytes above the basal layer, but higher up they are broken down and are practically absent from the cornified layer. Cholesterol and its esters, fatty acids and ceramides accumulate towards the surface, and are abundant in the cornified layer. The lamellar arrangement of the extracellular lipids is a major factor in their barrier function.

Melanocytes

Melanocytes are melanin pigment-forming cells derived from the neural crest (Fig. 7.9, Fig. 7.10). They are present in the epidermis and its appendages, in oral epithelium, some mucous membranes, the uveal tract (choroid coat) of the eyeball, parts of the middle and internal ear and in the pial and arachnoid meninges at the base of the brain. The cells of the retinal pigment epithelium, developed from the outer wall of the optic cup, also produce melanin, and neurones in different locations within the brainstem (e.g. the locus coeruleus and substantia nigra) synthesize a variety of melanin called neuromelanin. True melanins are high molecular weight heteropolymers attached to structural protein. In humans there are two classes, the brown-black eumelanin, and the red-yellow phaeomelanin, both derived from the substrate tyrosine. Most natural melanins are mixtures of eumelanin and phaeomelanin, and phaeomelanic pigments, trichochromes, occur in red hair.

Fig. 7.10 Electron micrograph of a basal epidermal melanocyte, showing its nucleus and cytoplasm containing melanosomes (short arrows). There are no desmosomes connecting it with apposed keratinocytes. The cytoplasm of the keratinocytes is full of dense keratin filaments (absent from the melanocyte), as well as transferred melanosomes. The dermo-epidermal junction is indicated (long arrows). Human tissue.

Melanocytes are dendritic cells, and lack desmosomal contacts with apposed keratinocytes, though hemidesmosomal contacts with the basal lamina are present. In routine tissue preparations, melanocytes appear as clear cells in the basal layer of the epidermis; numbers per unit area of epidermis range from 2300 per mm² in cheek skin to 800 per mm² in abdominal skin. It is estimated that a single melanocyte may be in functional contact via its dendritic processes with up to 30 keratinocytes. The nucleus is large, round, and euchromatic, and the cytoplasm contains intermediate filaments, a prominent Golgi complex and vesicles and associated rough endoplasmic reticulum, mitochondria, and coated vesicles, together with a characteristic organelle, the melanosome.

The melanosome is a membrane-bound structure which undergoes a sequence of developmental stages during which melanin is synthesized and deposited within it by a tyrosine–tyrosinase reaction. Mature melanosomes move into the dendrites along the surfaces of microtubules and are transferred to keratinocytes through their phagocytic activity. Keratinocytes engulf and internalize the tip of the dendrite with the subsequent pinching off of melanosomes into the keratinocyte cytoplasm. Here, they may exist as individual granules in heavily pigmented skin, or be packaged within secondary lysosomes as melanosome complexes in lightly pigmented skin. In basal keratinocytes they can be seen to accumulate in a crescent-shaped cap over the distal part of the nucleus. As the keratinocytes progress towards the surface of the epidermis, melanosomes undergo degradation, and melanin remnants in the cornified layer form dust-like particles. Melanosomes are degraded more rapidly in Caucasian skin than in dark-skinned races, where melanosomes persist in cells of the more superficial layers.

Melanin has biophysical and biochemical properties related to its functions in skin. It protects against the damaging effects of UV radiation on DNA and is also an efficient scavenger of damaging free radicals. However a high concentration of melanin may adversely affect synthesis of vitamin D in darker-skinned individuals living in northern latitudes. Melanin pigmentation is both constitutive and facultative. Constitutive pigmentation is the intrinsic level of pigmentation and is genetically determined, whereas facultative pigmentation represents reversible changes induced by environmental agents, e.g. UV and X-radiation, chemicals, and hormones. Racial variations in pigmentation are due to differences in melanocyte morphology and activity rather than to differences in frequency or distribution. In naturally heavily pigmented skins the cells tend to be larger, more dendritic, and to contain more large, late-stage melanosomes than melanocytes of paler skins. The keratinocytes in turn contain more melanosomes, individually dispersed, whereas in light skins, the majority are contained within secondary lysosomes to form melanosome complexes.

Response to UV light includes immediate tanning, pigment darkening, which can occur within a matter of minutes, probably due to photo-oxidation of pre-existing melanin. Delayed tanning occurs after about 48 hours, and involves stimulation of melanogenesis within the melanocytes, and transfer of additional melanosomes to keratinocytes. There may also be some increase in size of active melanocytes, and in their apparent numbers, mainly through activation of dormant cells. Freckles in the skin of red-haired individuals are usually thought to be induced by UV, though they do not appear until several years after birth, despite exposure. Paradoxically, melanocytes are significantly fewer in freckles than in adjacent paler epidermis, but they are larger and more active. What determines the onset of freckles, or their individual location, is not known.

Adrenocorticotrophin (ACTH) is thought to affect melanocyte activity, and is probably responsible for the hyperpigmentation associated with pituitary and adrenal disorders. In pregnancy, higher levels of circulating oestrogens and progesterone are responsible for the increased melanization of the face, abdominal and genital skin, and the nipple and areola, much of which may remain permanently.

In albinism, the tyrosinase required for melanin synthesis is either absent or inactive, and melanocytes, though present, are relatively quiescent cells in an otherwise normal epidermis. Melanocytes decrease significantly in numbers in old age, and are absent from grey-white hair. For further reading on melanocyte function in health and disease, see Goding (2007).

Langerhans cells

Langerhans cells (Fig. 7.11) are immature dendritic antigen-presenting cells (see p. 79) regularly distributed throughout the basal and prickle cell layers of the epidermis and its appendages, apart from the sweat gland. They are also present in other stratified squamous epithelia, including the buccal, tonsillar and oesophageal epithelia, as well as the cervical and vaginal mucosae and the transitional epithelium of the bladder. They are found in the conjunctiva, but not in the cornea. In routine preparations they appear as clear cells, relatively high in the stratified layer. They enter the epidermis from the bone marrow during development to establish the postnatal population (460–1000/mm², 2–3% of all epidermal cells, with regional variations), and this is maintained by continual replacement from the marrow.

The nucleus is euchromatic and markedly indented and the cytoplasm contains a well-developed Golgi complex, lysosomes (which often contain ingested melanosomes), and a characteristic organelle, the Birbeck granule. The latter are discoid, cup-shaped, or have a distended vesicle resembling the head of a tennis racket; in section they often appear as a cross-striated rod 0.5 μm long and 30 nm wide. When stimulated by antigen, Langerhans cells migrate out of the epidermis to lymphoid tissues (see Fig. 4.14). Their numbers are increased in chronic skin inflammatory disorders, particularly of an immune aetiology, such as some forms of dermatitis.

Merkel cells

Merkel cells are present as clear oval cells, singly or in groups, in the basal layer of the epidermis, especially of thick skin. They are also present in the outer root sheath of some large hair follicles. Merkel cells are derived embryologically from the neural crest and are not related developmentally to keratinocytes, as was once thought. They can be distinguished histologically from other clear cells (melanocytes and Langerhans cells) only by immunohistochemical and ultrastructural criteria.

Short, stiff processes of their plasma membrane interdigitate with adjacent basal keratinocytes, to which the Merkel cell is attached by small desmosomes. The cytoplasm contains numerous closely-packed intermediate filaments (simple epithelial keratins, mostly K8 and K18 but also K19 and K20), and characteristic 80–110 μm dense-core granules. The basal plasma membrane is closely apposed to the membrane of an axonal terminal. Merkel cells are thought to function as neuroendocrine sensory receptors, and are slowly adapting mechanoreceptors which respond to directional deformations of the epidermis and direction of hair movement by releasing a transmitter from their dense-core cytoplasmic granules.

DERMIS

The dermis (Fig. 7.1, Fig. 7.4, see Fig. 7.17) is an irregular, moderately dense connective tissue. It has a matrix composed of an interwoven collagenous and elastic network in an amorphous ground substance of glycosaminoglycans, glycoproteins and bound water, which accommodates nerves, blood vessels, lymphatics, epidermal appendages and a changing population of cells. Mechanically, the dermis provides considerable strength to the skin by virtue of the number and arrangement of its collagen fibres (which give it tensile strength), and its elastic fibres (which give it elastic recoil). The density of its fibre meshwork, and therefore its physical properties, varies within an area, in different parts of the body, and with age and sex. The dermis is vital for the survival of the epidermis, and important morphogenetic signals are exchanged at the interface between the two both during development and postnatally. The dermis can be divided into two zones, a narrow superficial papillary layer and a deeper reticular layer: the boundary between them is indistinct.

Fig. 7.17 A sweat duct in thick skin (trichrome-stained), spiralling through the dermis and epidermis, visible most clearly in the cornified superficial layer.

Adult dermal collagen is mainly of types I and III, in proportions of 80–85% and 15–20% respectively. The coarser-fibred type I is predominant in the deeper, reticular dermis, and the finer type III is found in the papillary dermis and around blood vessels. Type IV collagen is found in the basal lamina between epidermis and dermis, around Schwann cells of peripheral nerves and endothelial cells of vessels. Types V, VI and VII are minor collagenous components of the dermis. Elastic fibres form a fibrous network interwoven between the collagen bundles throughout the dermis, and are more prominent in some regions, e.g. the axilla.

Two major categories of cell are present in postnatal dermis, permanent and migrant, as is typical of all general connective tissues (see Ch. 2). The permanent resident cells include cells of organized structures such as nerves, vessels and cells of the arrector pili muscles, and the fibroblasts, which synthesize all components of the dermal extracellular matrix. The migrant cells originate in the bone marrow (Fig. 4.12) and include macrophages, mast cells, eosinophils, neutrophils, T and B cells (including antibody-secreting plasma cells), and dermal interstitial dendritic cells which are capable of immune surveillance and antigen presentation.

Layers of the dermis

Papillary layer

The papillary layer is immediately deep to the epidermis (Fig. 7.4), and is specialized to provide mechanical anchorage, metabolic support, and trophic maintenance to the overlying epidermis, as well as supplying sensory nerve endings and blood vessels. The cytoskeleton of basal epidermal keratinocytes is linked to the fibrous matrix of the papillary dermis through the attachment of keratin filament bundles to hemidesmosomes, then via anchoring filaments of the basal lamina, to the anchoring fibrils of type VII collagen which extend deep into the papillary dermis (Fig. 7.5). This arrangement provides a mechanically stable substratum for the epidermis.

The superficial surface of the dermis is shaped into numerous papillae or rete ridges, which interdigitate with rete pegs in the base of the epidermis and form the dermo-epidermal junction at their interface. The papillae have round or blunt apices which may be divided into several cusps. In thin skin, especially in regions with little mechanical stress and minimal sensitivity, papillae are few and very small, while in the thick skin of the palm and sole of the foot they are much larger, closely aggregated, and arranged in curved parallel lines following the pattern of ridges and grooves on these surfaces (Fig. 7.1). Lying under each epidermal surface ridge are two longitudinal rows of papillae, one on either side of the epidermal rete pegs through which the sweat ducts pass on the way to the surface. Each papilla contains densely interwoven, fine bundles of types I and III collagen fibres and some elastic fibrils. Also present is a capillary loop (Fig. 7.4), and in some sites, especially in thick hairless skin, Meissner’s corpuscle nerve endings.

Reticular layer

The reticular layer merges with the deep aspect of the papillary layer. Its bundles of collagen fibres are thicker than those in the papillary layer and interlace with them and with each other to form a strong but deformable three-dimensional lattice, in which many fibres are parallel to each other, and which contain a variable number of elastic fibres. The predominant orientation of the collagen fibres may be related to the local mechanical forces on the dermis and thus may be involved in the development of skin lines.

Hypodermis

Also known as the superficial fascia, the hypodermis is a layer of loose connective tissue of variable thickness which merges with the deep aspect of the dermis. It is often adipose, particularly between the dermis and musculature of the body wall. It mediates the increased mobility of the skin, and the adipose component contributes to thermal insulation, acts as a shock absorber and constitutes a store of metabolic energy. Subcutaneous nerves, vessels and lymphatics travel in the hypodermis, their main trunks lying in its deepest part, where adipose tissue is scant. In the head and neck, the hypodermis also contains muscles, such as platysma, which are remnants of more extensive sheets of skin-associated musculature found in other mammals.

The quantity and distribution of subcutaneous fat differs in the sexes. It is generally more abundant and widely distributed in females. In males it diminishes from the trunk to the extremities, and this distribution is more obvious in middle age, when the total amount increases in both sexes. The amount of adipose tissue in the hypodermis, as elsewhere, reflects the quantity of lipid stored in its adipocytes rather than a change in the number of cells. There is an association with climate (rather than race), and superficial fat is more abundant in colder geographical regions. The hypodermis is most distinct on the lower anterior abdominal wall, where it contains much elastic tissue and appears many-layered as it passes through the inguinal regions into the thighs. It is similar in the limbs and the perineum, but is thin where it passes over the dorsal aspects of the hands and feet, the sides of the neck and face, around the anus, and over the penis and scrotum. It is almost absent from the external ears but is particularly dense in the scalp, palms and soles, where it is crossed by numerous strong connective tissue bands binding the hypodermis and skin to underlying structures: these are part of the deep fascia, but are known regionally as aponeuroses of the scalp, palm and sole.

PILOSEBACEOUS UNIT

The pilosebaceous unit consists of the hair and its follicle with an associated arrector pili muscle, sebaceous gland, and sometimes an apocrine gland (Fig. 7.1, Fig. 7.12). Not all elements of the unit occur together in all body regions.

Fig. 7.12 A pilosebaceous unit in thin, hairy skin seen at low magnification. The hair follicle, hair shaft and hair root extend almost vertically through the field, the follicle joining the interfollicular epidermis (top). To the left of the follicle are the acini of a sebaceous gland, which is also sectioned tangentially through its capsule (centre bottom, below the portion of the hair follicle in section); the gland opens into the follicle in centre field. The associated arrector pili smooth muscle (thin red fibre bundle) is seen to the left of the sebaceous gland, following its contours.

Hairs

Hairs are filamentous cornified structures present over almost the entire body surface. They grow out of the skin at a slant (Fig. 42.1) as is evident in the sloping of the hairs on the dorsum of forearm, hand and fingers towards the ulnar side. Hairs are absent from several areas of the body, including the thick skin of the palms, soles, the flexor surfaces of the digits, the thin skin of the umbilicus, nipples, glans penis and clitoris, the labia minora and the inner aspects of the labia majora and prepuce. The presence, distribution and relative abundance of hair in certain regions such as the face (in males), pubis and axillae, are secondary sexual characteristics which play subtle roles in sociosexual communication. There are racial variations in density, form, distribution and pigmentation, as well as individual variations. Hairs assist minimally in thermoregulation: on the scalp they provide some protection against injury and the harmful effects of solar radiation. They have a sensory function.

Hairs vary from approximately 600 per cm² on the face to 60 per cm² on the rest of the body. In length they range from less than a millimetre to more than a metre, and in width from 0.005 to 0.6 mm. They vary in form, being straight, coiled, helical or wavy, and differ in colour depending on the type and degree of pigmentation. Curly hairs tend to have a flattened cross-section, and are weaker than straight hairs. In general, body hairs are longest and coarsest in Caucasians and least noticeable in Mongolian races. Over most of the body surface hairs are short and narrow (vellus hairs) and in some areas these hairs do not project beyond their follicles, e.g. in eyelid skin. In other regions they are longer, thicker and often heavily pigmented (terminal hairs); these include the hairs of the scalp, the eyelashes and eyebrows and the postpubertal skin of the axillae and pubis, and the moustache, beard and chest hairs of males. The presence in females of coarse terminal hairs in a male-like pattern is termed hirsutism and is usually a sign of an endocrine disorder and excess androgen production (Azziz 2003).

Hair follicle

The hair follicle (Fig. 7.1, Fig. 7.12, Fig. 7.13A) is a downgrowth of the epidermis containing a hair, which may extend deeply (3 mm) into the hypodermis, or may be more superficial (1 mm) within the dermis. Typically, the long axis of the follicle is oblique to the skin surface; with curly hairs it is also curved. There are cycles of hair growth and loss, during which the follicle presents different appearances. In the anagen phase the hair is actively growing and the follicle is at its maximum extent of development. In the involuting or catagen phase, hair growth ceases and the follicle shrinks. During the resting or telogen phase the inferior segment of the follicle is absent. This is succeeded by the next anagen phase. Further details of the hair growth cycle are given below, after the description of the anagen follicle and hair.

Fig. 7.13 A, The major structural features of the base of a hair follicle, showing the organization of the major layers of the hair and surrounding sheath, arising from the hair bulb. A dermal hair papilla invaginates the bulb, and along the basal layer of the epidermis, at its interface with the dermis, melanocytes insert their dendrites among the keratinocytes forming the hair. B, The hair bulb at the base of the human hair follicle. The dermal hair papilla invaginates the bulb from its fibrous outer sheath, carrying a loop of capillaries. Melanocytes in the germinal matrix (equivalent to the basal layer of interfollicular epidermis) extend dendrites into the adjacent layers of keratinocytes, to which they pass melanosomes. The layers of the hair shaft and root sheaths are also indicated.

Anagen follicle

The anagen follicle has several regions. The deepest is the inferior segment which includes the hair bulb region extending up to the level of attachment of the arrector pili muscle at the follicular bulge. Between this point and the site of entry of the sebaceous duct is the isthmus, above which is the infundibulum, or dermal pilary canal, which is continuous with the intraepidermal pilary canal. Below the sebaceous duct, the hair shaft and follicular wall are intimately connected, and it is only towards the upper end of the isthmus that the hair becomes free in the pilary canal. Below the infundibulum the follicle is surrounded by a thick perifollicular dermal coat containing type III collagen, elastin, sensory nerve fibres and blood vessels, and into which the arrector pili muscle fibres blend. A thick, specialized basal lamina, the glassy membrane, marks the interface between dermis and the epithelium of large hair follicles.

Hair bulb

The hair bulb forms the lowermost portion of the follicular epithelium and encloses the dermal hair papilla of connective tissue cells (Fig. 7.13B). The dermal hair papilla is an important cluster of inductive mesenchymal cells which is required for hair follicle growth in each cycle throughout adult life: it is a continuation of the layer of adventitious mesenchyme that follows the contours of the hair follicle. The hair bulb generates the hair and its inner root sheath. A hypothetical line drawn across the widest part of the hair bulb divides it into a lower germinal matrix and an upper bulb. The germinal matrix is formed of closely packed, mitotically active pluripotential keratinocytes, among which are interspersed melanocytes, and some Langerhans cells. The upper bulb consists of cells arising from the matrix. These migrate apically and differentiate along several lines. Those arising centrally form the hair medulla. Radially, successive concentric rings of cells give rise to the cortex and cuticle of the hair and outside this, to the three layers of the inner root sheath. The latter are, from within out, the cuticle of the inner root sheath, Huxley’s layer and Henle’s layer. Henle’s layer is surrounded by the outer root sheath, which forms the cellular wall of the follicle (Fig. 7.13). Differentiation of cells in the various layers of the hair and its inner root sheath begins at the level of the upper bulb and is asynchronous, beginning earliest in Henle’s layer and Huxley’s layer.

Structure of hair and its sheaths

A fully developed hair shaft consists of three concentric zones which are, from outwards in, the cuticle, cortex and medulla. Each has different types of keratin filament proteins and different patterns of cornification. In finer hairs the medulla is usually absent. The cuticle forms the hair surface and consists of several layers of overlapping cornified squames directed apically and slightly outwards (Fig. 7.14). Immature cuticle cells have dense amorphous granules aligned predominantly along the outer plasma membrane with a few filaments. The cortex forms the greater part of the hair shaft and consists of numerous closely packed, elongated squames which may contain nuclear remnants and melanosomes. Immature cortical cells contain bundles of closely packed filaments but no dense granules, and when fully cornified, they have a characteristic thumb-print appearance with filaments arranged in whorls. The medulla, when present, is composed of loosely aggregated and often discontinuous columns of partially disintegrated cells containing vacuoles, scattered filaments, granular material and melanosomes. Air cavities lie between the cells or even within them.

Fig. 7.14 A scalp hair showing details of surface structure as seen in the scanning electron microscope. Note that the cuticular cells overlap each other; their free ends point towards the apex of the hair.

(By courtesy of Michael Crowder.)

Henle’s layer and Huxley’s layer of the inner root sheath contain irregular dense keratohyalin granules and associated filaments in the precornified state. At the level of the upper bulb, Henle’s layer begins to cornify, as does Huxley’s layer at the middle of the inferior follicle. When fully differentiated, cells of both layers have a thickened cornified envelope enclosing keratin filaments embedded in a matrix. The cells of the inner root sheath cuticle undergo terminal differentiation at a level closer to the hair bulb than that of Huxley’s layer, but lack a clear-cut filament pattern such as is seen in the cortical cells of the hair shaft. As they cornify, the cuticle cells of the inner root sheath and hair become interlocked. At about the level of entry of the sebaceous duct, above the isthmus, the inner root sheath undergoes fragmentation, and the hair then lies free in the pilary canal.

The outer root sheath, beginning at the level of the upper bulb, is a single or double layer of undifferentiated cells containing glycogen. Higher up the follicle it becomes multilayered. At the isthmus all remaining cell layers of the follicle sheath become flattened, compressed and attenuated. On emerging from the isthmus, the outer root sheath assumes the stratified, differentiating characteristics of interfollicular epidermis, with which it becomes continuous. At the level of entry of the sebaceous duct, it forms the wall of the pilary canal.

Hair cycle and growth of hair

Recurrent cyclic activity of hair follicles involves growth, rest, and shedding of hair in phases. In humans, these occur in irregular cycles of variable duration: there are regional and other variations in the length of the individual phases. In the growing or anagen phase, follicle and hair are as described above. Melanocytes are active only in mid-anagen, and are capable of producing both phaeo- and eumelanosomes, which they pass to precortical and medullary keratinocytes. Changes in hair colour of an individual, usually in adolescence, are due to alterations in the dominant type of melanosome produced.

Anagen is followed by the involuting or catagen phase during which mitotic activity of the germinal matrix ceases, the base of the hair condenses into a club which moves upwards to the level of the arrector pili muscle, and the whole inferior segment of the follicle degenerates. The dermal papilla also ascends and remains close to the base of the shortened follicle and its enclosed club hair, a situation which persists during the resting or telogen phase. During telogen, melanocytes become amelanotic and can be identified only ultrastructurally. At the beginning of the next anagen, the epithelial cells at the base of the follicle divide to form a secondary hair rudiment which envelops the dermal papilla to form a new hair bulb. This grows downwards, reforming the inferior segment of the follicle, from which a new hair grows up alongside the club hair, which is eventually shed.

Postnatally, hairs exhibit regional asynchrony of cycle duration and phase leading to an irregular pattern of growth and replacement. In some regions, such as the scalp, the cycle is measured in years; in others, such as general body hair, the cycle is much shorter and hairs are therefore limited in length. At puberty, hair growth and generation of much thicker hairs occurs on the pubes and axillae in both sexes, and on the face and trunk in males. The actions of hormones on hair growth are complex, and involve not only sex hormones, but also those of the thyroid, suprarenal cortex and pituitary glands. Androgens stimulate facial and general body hair formation. After about the first 30 years, they tend to cause the thick terminal hairs of the scalp to change to small vellus hairs, which produces recession from the forehead and sometimes almost complete male pattern baldness. In females, oestrogens tend to maintain vellus hairs: postmenopausal reduction of oestrogens may permit stronger facial and bodily hair growth. In mid-pregnancy, hair growth may be particularly active but later, often post-partum, an unusually large number of hairs enter the telogen phase and are shed before the growth cycle recommences. In older men, growth of hairs on the eyebrows and within the nostrils and external ear canals increases, whereas elsewhere on the body, growth slows and the hairs become much finer.

Measurements of the rate of growth of individual hairs vary considerably, probably because of the influence of the factors mentioned above. A rate of 0.2–0.44 mm per 24 hours in males is usually given: the higher rate occurs on the scalp. Contrary to popular myth, shaving does not appear to affect the growth rate and hair ceases growth after death.

Sebaceous glands

Sebaceous glands are small saccular structures (Fig. 7.1, Fig. 7.12, Fig. 7.15) lying in the dermis; together with the hair follicle and arrector pili muscle, they constitute the pilosebaceous unit. They are present over the whole body except the thick hairless skin of the palm, soles and flexor surfaces of digits. Typically, they consist of a cluster of secretory acini which open by a short common duct into the dermal pilary canal of the hair follicle. They release their lipid secretory product, sebum, into the canal by a holocrine mechanism (see Ch. 2). In some areas of thin skin which lack hair follicles, their ducts open instead directly on to the skin surface, e.g. on the lips and corners of the mouth, the buccal mucosa, nipples, female breast areolae, penis, inner surface of the prepuce, clitoris and labia minora. At the margins of the eyelids, the large complex palpebral tarsal glands (Meibomian glands) are of this type. They are also present in the external auditory meatus.

Fig. 7.15 A sebaceous gland, showing a group of secretory acini opening into a hair follicle (top right). The distended sebocytes are filled with their oily secretion (sebum), which is discharged into the hair follicle by the holocrine disintegration of secretory cells.

In general, numbers of sebaceous glands in any given area reflect the distribution of hair follicles, ranging from an average of 100/cm² over most of the body to as many as 400–900/cm² on the face and scalp. They are also numerous in the midline of the back. Individual sebaceous glands are particularly large on the face, around the external auditory meatus, chest and shoulders, and on the anogenital surfaces. Those on the face are often related to very small vellus hairs whose follicles have particularly wide apertures.

Microscopically, the glandular acini are enclosed in a basal lamina supported by a thin dermal capsule and a rich capillary network. Each acinus is lined by a single layer of small, flat, polygonal epithelial cells (sebocytes) which ultrastructurally resemble undifferentiated basal keratinocytes of interfollicular epidermis. They possess euchromatic nuclei and large nucleoli, scattered keratin filaments, free ribosomes, smooth endoplasmic reticulum and rounded mitochondria, and are attached to each other by desmosomes. Functionally, they are mitotically active stem cells whose progeny move gradually towards the centre of the acinus, increasing in volume and accumulating increasingly large lipid vacuoles. The nuclei become pyknotic as the cells mature. The huge distended cells ultimately disintegrate, filling the central cavity and its duct with a mass of fatty cellular debris (Fig. 7.15). The process takes 2–3 weeks. The secretory products pass through a wide duct lined with keratinized stratified squamous epithelium into the infundibulum of the hair follicle and then to the surface of the hair and the general epidermis.

The normal functions of sebum are the provision of a protective coating on hairs, possibly helping to waterproof the epidermis, discouragement of ectoparasites and contribution to a characteristic body odour. When first formed, sebum is a complex mixture of over 50% di- and triglycerides, with smaller proportions of wax esters, squalene, cholesterol esters, cholesterol and free fatty acids. At birth, sebaceous glands are quite large, regressing later until stimulated again at puberty. At that time, sebaceous gland growth and secretory activity increase greatly in both males and females, under the influence of androgens (testicular and suprarenal), which act directly on the gland. Excessive amounts of sebum may become impacted within the duct, and this, associated with hyperkeratinization, may lead to blockage and formation of a comedone. This may become infected and inflamed, and is the primary lesion of acne. Oestrogens have an effect opposite to that of androgens, and sebum secretion is considerably lower in women, becoming greatly decreased after the age of 50 years.

Apocrine glands

Apocrine glands are particularly large glands of the dermis or hypodermis, classed as a type of sweat gland. Since they develop as outgrowths of the hair follicle and discharge secretion into the hair canal, they are considered here. In the adult, they are present in the axillae, perianal region, areolae, periumbilical skin, prepuce, scrotum, mons pubis and labia minora. Ceruminous glands of the external auditory meatus and the ciliary glands of the palpebral margins (Moll’s glands) are also usually included in this category, but their secretions are quite different and they should be considered as distinct, specialized subtypes.

An apocrine gland consists of a basal secretory coil and a straight duct which opens into either the pilary canal above the duct of the sebaceous gland, or directly onto the skin surface if there is no associated hair. The secretory region may be as much as 2 mm wide and its coils often anastomose to form a labyrinthine network. Each coil is lined by cuboidal secretory cells whose apical cytoplasm projects into the lumen and basally is in contact with a layer of myoepithelial cells within a thick basal lamina. The secretory cells contain vacuoles, vesicles and dense granules of varying size and internal structure: the numbers and character vary with the cycle of synthesis and discharge. The mechanism of secretion is still not clear, but may involve merocrine secretion of granules, apocrine secretion or complete holocrine disintegration of the cells (see Fig. 2.5).

Apocrine activity is minimal before puberty, after which it is androgen dependent and responsive to emotional stimuli. It is controlled by adrenergic nerves, and is sensitive to adrenaline (epinephrine) and noradenaline (norepinephrine). The secretion is initially sterile and odourless, but it undergoes bacterial decomposition to generate potent odorous, musky compounds, including short-chain fatty acids, and steroids such as 5α-androstenone. In many animals these are potent pheromonal signals but their role in humans is less certain. Obstruction of apocrine sweat ducts and associated upper hair follicles in the axillae, breast areolae and pubic region, mainly in women, is thought to underlie Fox–Fordyce disease.

Arrector pili muscles

The arrector pili muscles are small bundles of closely packed smooth muscle cells which form oblique links between the dermal sheaths of hair follicles and the papillary layer of the dermis (Fig. 7.1, Fig. 7.12). They show the typical features of smooth muscle cells and are separated by narrow spaces containing collagen fibres and unmyelinated noradrenergic sympathetic axons.

The muscles are attached to the bulge region of the follicles by elastin fibrils, and are directed obliquely and towards the side to which the hair slopes superficially. The sebaceous gland occupies the angle between the muscle and the hair follicle, and muscle contraction helps to expel the gland contents. Contraction tends to pull the hair into a more vertical position and to elevate the epidermis surrounding it into a small hillock (goose bump), dimpling the skin surface where the muscle is inserted superficially. Arrector pili muscles are absent from facial, axillary, and pubic hairs, from eyelashes and eyebrows, and from the hairs around the nostrils and the external auditory meatuses.

SWEAT GLANDS

The vast majority of sweat glands (Fig. 7.16) are often classified as eccrine, although their mode of secretion includes typical merocrine mechanisms (see Ch. 2). They are long unbranched tubular structures, each with a highly coiled, secretory portion up to 0.4 mm in diameter, situated deep in the dermis or hypodermis. From there, a narrower, straight or slightly helical ductal portion emerges (Fig. 7.1). The walls of the duct fuse with the base of epidermal rete pegs and the lumen passes between the keratinocytes, often in a tight spiral, particularly in thick hairless skin (Fig. 7.17), and opens via a rounded aperture (pore) onto the skin surface (Fig. 7.7). In thick hairless skin, sweat glands discharge along the centres of friction ridges, incidentally providing fingerprint patterns for forensic analysis. Sweat glands have an important thermoregulatory function, they contribute significantly to excretion and their secretion enhances grip and sensitivity of the palms and soles.

Fig. 7.16 The coiled secretory portion of a sweat gland (SG) in the reticular dermis. The deeper-stained profiles (above) are the origins of the duct. An autonomic nerve fibre (NF) and accompanying arteriole (A) and venule (V) are seen below.

Sweat glands are absent from the tympanic membrane, margins of the lips, nail bed, nipple, inner preputial surface, labia minora, penis and clitoris, where apocrine glands are located. Elsewhere they are numerous, their frequency ranging from 80 to over 600/cm², depending on position and genetic variation. The total number lies between 1.6 and 4.5 million, and is greatest on the plantar skin of the feet. There are many sweat glands on the face and flexor aspects of the hands, and fewest on the surfaces of the limbs. Racial groups indigenous to warmer climates tend to have more sweat glands than those indigenous to cooler regions.

Microscopically the secretory coil consists of a pseudostratified epithelium enclosing a lumen. Three types of cell have been described: clear cells from which most of the secretion derives, dark cells which share the same lumen, and myoepithelial cells. Clear cells are approximately pyramidal in shape, and their bases rest on the basal lamina or contact myoepithelial cells. Their apical plasma membranes line lateral intercellular canaliculi which connect with the main lumen. The basolateral plasma membranes are highly folded, interdigitating with apposed clear cells, and they have the basal membrane infoldings typical of cells involved in fluid and ion transport. Their cytoplasm contains glycogen granules, mitochondria, rough endoplasmic reticulum and a small Golgi complex, but few other organelles. The nucleus is round and moderately euchromatic. Dark cells are pyramidal, and lie closer to the lumen such that their broad ends form its lining. Their cytoplasm contains a well-developed Golgi complex, numerous vacuoles and vesicles and dense glycoprotein granules which they secrete by a typical merocrine mechanism. Myoepithelial cells resemble those associated with secretory acini of the salivary glands and breast, and contain abundant myofilaments.

The intradermal sweat duct is formed of an outer basal layer and an inner layer of luminal cells connected by numerous desmosomes. The intraepidermal sweat duct (acrosyringium) is coiled, and consists of two layers of cells which, developmentally, are different from the surrounding keratinocytes and can be distinguished from them by the presence of keratin K19. The outer cells near the surface contain keratohyalin granules and lamellar granules, and undergo typical cornification. The inner cells, from a midepidermal level, contain numerous vesicles, undergo an incomplete form of cornification, and are largely shed into the lumen at the level of the cornified epidermal layer.

Sweat is a clear, odourless fluid, hypotonic to tissue fluid, and contains mainly sodium and chloride ions, but also potassium, bicarbonate, calcium, urea, lactate, amino acids, immunoglobulins and other proteins. Excessive sweating can lead to salt depletion. Heavy metals and various organic compounds are eliminated in sweat, the greater part of which is thought to be produced by the clear cells. When first secreted, the fluid is similar in composition to interstitial fluid. It is modified as it passes along the duct by the action mainly of the basal cells, which resorb sodium and chloride and some water. The hormone aldosterone enhances this activity. The sweat glands are capable of producing up to 10 litres of sweat per day, in response to thermal, emotional and taste stimuli, mediated by unmyelinated sympathetic cholinergic fibres; the glands also respond to adrenaline. Thermoregulation involves a heat centre in the hypothalamus which reacts to changes in blood temperature and afferent stimuli from the skin, by controlling cutaneous blood supply and the rate and volume of sweat secretion for evaporation at the surface.

NAIL APPARATUS

Nails (Fig. 7.18) are homologous with the cornified layer of the general epidermis. They consist of compacted, anucleate, keratin-filled squames in two or three horizontal layers. Ultrastructurally, the squames contain closely packed filaments which lie transversely to the direction of proximodistal growth, and are embedded in a dense protein matrix. Unlike the general epidermis, squames are not shed from the nail plate surface. A variety of mineral elements are present in nail, including calcium. Calcium is not responsible for the hardness of nail: this is determined by the arrangement and cohesion of the layers of squames, and their internal fibres. The water content of nail is low, but nail is 10 times more permeable to water than the general epidermis. The softness and elasticity of the nail plate is related to its degree of hydration.

Fig. 7.18 The organization and terminology of the structures associated with a fingernail.

(By permission from Paus R, Peker S 2003 Biology of hair and nails. In: Bolognia JL, Jorizzo JL, Rapini RP (eds) Dermatology. London: Mosby.)

The nail apparatus consists of the nail plate, proximal and lateral nail folds, nail matrix, nail bed and hyponychium.

Nail plate

The nail plate is embedded within the proximal and lateral nail folds. It is approximately rectangular in shape and is mostly convex in both longitudinal and transverse axes: there is considerable inter- and intra-individual variation (Fig. 7.18). The thickness of the plate increases proximodistally from about 0.7 mm to 1.6 mm: the terminal thickness varies between individuals. The surface of the nail plate may show fine longitudinal ridges, and its undersurface is grooved by corresponding ridges in the nail bed. Disturbances of growth pattern or disease may lead to transverse ridging or grooves, and minute trapped air bubbles may produce white flecks. These defects move distally with growth of the plate.

The nail plate arises from compacted cornified epithelial cells derived from the dorsal, intermediate and ventral nail matrices. It is densely adherent to the matrices on its undersurface, but becomes a free structure distal to the onychodermal band, where it separates from the nail bed. The dorsal aspect of the nail plate originates from the more proximal regions of the germinal matrix, i.e. dorsal and intermediate matrices, whereas the deeper, volar aspect of the plate originates from the ventral matrix.

Nail folds

The sides of the nail plate are bordered by lateral nail folds which are continuous with the proximal fold (Fig. 7.18). The lateral nail folds enclose the lateral free edges of the nail plate and are bounded by the attachment of the skin to the lateral aspect of the distal phalanx margin and the lateral nail. The proximal nail fold provides the visible proximal border to the nail apparatus. It consists of two epidermal layers, superficial and deep, separated by a core of dermis. The epidermis of the superficial layer lacks hair follicles and epidermal ridges: its cornified distal margin extends over the nail plate for a little distance as the cuticle or eponychium. The deep layer merges with the nail matrix.

The eponychium is bounded by the fascial attachment of the skin to the base of the distal phalanx, distal to the insertion of the extensor tendon, and its distal free edge. It adheres to the dorsal aspect of the nail plate and overlies the root of the nail.

Genetic keratin disorders (Irvine & McLean 1999) may lead to nail dystrophies such as pachyonychia, where the nails become grossly thickened.

VASCULAR SUPPLY, LYMPHATIC DRAINAGE AND INNERVATION

VASCULAR SUPPLY AND LYMPHATIC DRAINAGE

The metabolic demands of the skin are not great, and yet, under normal conditions, its blood flow exceeds nutritional requirements by 10 times, and may amount to 5% of the cardiac output. This is because the cutaneous circulation has an important thermoregulatory function, and is arranged so that its capacity can be increased or decreased rapidly by as much as 20 times, in response to the required loss or conservation of heat.

The blood supply to the skin originates from three main sources, the direct cutaneous system, the musculocutaneous system and the fasciocutaneous system. The direct cutaneous system of vessels is derived from the main arterial trunks and accompanying veins. Vessels course in the subcutaneous fat parallel to the skin surface, and are confined to certain areas of the body, e.g. the supraorbital artery, the superficial circumflex iliac artery and the dorsalis pedis artery. The musculocutaneous perforators arise from the intramuscular vasculature, pass through the surface of the muscle, and pierce the deep fascia to reach the skin by spreading out in the subcutaneous tissues. The fasciocutaneous system consists of perforating branches from deeply located vessels (deep to the deep fascia) which pass along intermuscular septa and then fan out at the level of the deep fascia to reach the skin. Examples include the fasciocutaneous perforating vessels from the radial and ulnar arteries.

The direct cutaneous vessels, the musculocutaneous perforators and the fasciocutaneous perforators each contribute to six anastomosing horizontal reticular plexi of arterioles (Fig. 7.19) which have vascular connections between them and which ultimately provide the blood supply to the skin. Three plexi are located in the skin itself and supply all elements including the sweat glands and pilosebaceous units. The subpapillary plexus is located at the junction of the papillary and reticular layers of the dermis. It gives off small branches which form capillary loops in the dermal papillae (usually one loop per papilla) which are perpendicular to the skin surface (Fig. 7.1, Fig. 7.4, Fig. 7.20). The reticular dermal plexus is located in the middle portion of the dermis and is primarily venous. The deep dermal plexus is located in the deepest part of the reticular dermis and on the undersurface of the dermis. The close association between arteriolar and venous plexi permits exchange of heat between blood in vessels at different temperatures flowing in opposite directions (counter-current heat exchange).

Fig. 7.19 Vascular supply to the skin. A, Note the various horizontal plexuses fed by direct cutaneous, fasciocutaneous and musculocutaneous arteries. B, Higher magnification of vascular supply.

(A, redrawn from McCarthy JG (ed) Chapter 9 in Plastic Surgery, Vol 1. Philadelphia: Saunders. B, redrawn from Cormack GC, Lamberty BGH 1994 The Arterial Anatomy of Skin Flaps, 2nd edition. Edinburgh: Churchill Livingstone.)

Fig. 7.20 A thick vertical section through palmar skin, the arteries, arterioles and capillaries of which have been injected with red gelatin to demonstrate the pattern of dermal vascularization. At the base of the dermis a broad, flat arterial plexus supplies a more superficial papillary plexus, which in turn gives off capillary loops which enter the dermal papillae.

The remaining three plexi are the subcutaneous plexus, and two plexi associated with the deep fascia. The deep fascia has a plexus on its deep surface and a more extensive plexus on its superficial surface. This arrangement is much more pronounced in the limbs than it is in the trunk.

The general structure and arrangement of the microvasculature is described in detail in Ch. 6, and so only features particular to skin will be considered here. In the deeper layers of the dermis, arteriovenous anastomoses are common, particularly in the extremities (hands, feet, ears, lips, nose), where, as glomera, they are surrounded by thick muscular coats. Under autonomic vasomotor control, these vascular shunts, when relaxed, divert blood away from the superficial plexus and so reduce heat loss, while at the same time ensuring some deep cutaneous circulation and preventing anoxia of structures such as nerves. Extensive capillary anastomoses are present. Generally, cutaneous blood flow is regulated according to thermoregulatory need, and also, in some areas of the body, according to emotional state. In very cold conditions, the peripheral circulation is greatly reduced by vasoconstriction, but intermittent spontaneous vasodilatation results in periodic increases in temperature which prevent cooling to the level at which frostbite might occur. This is thought to be due to a direct effect of oxygen lack on the arteriolar constrictor muscle, rather than to a neural influence.

The lymphatics of the skin, as elsewhere, are small terminal vessels which collect interstitial fluid and macromolecules for return to the circulation via larger vessels. They also convey lymphocytes, Langerhans cells and macrophages to regional lymph nodes. They begin as blind-ended, endothelial-lined tubes or loops just below the papillary dermis. These drain into a superficial plexus below the subpapillary venous plexus, which drains via collecting vessels into a deeper plexus at the junction of the reticular dermis and subcutis, and this, in turn, drains into the larger subcutaneous channels.

INNERVATION

Skin is a major sensory surface, with regional variations in sensitivity to different stimuli. It has a rich nerve supply, which is also concerned with autonomic functions, particularly related to thermoregulation. Cutaneous sense provides information about the external environment through receptors responsive to stimuli which may be mechanical (rapid or sustained touch, pressure, vibration, stretching, bending of hairs, etc.), thermal (hot and cold), or noxious (perceived as itching, discomfort or pain). Pacinian corpuscles subserve deep pressure and vibrational sensation, and are located deep in the dermis or in the hypodermis, particularly of the digits. Meissner’s corpuscles are located in dermal papillae, close to the dermo-epidermal junction, and are sensitive to touch sensation. These receptors are particularly suited to detecting shape and texture during active exploratory touch as employed most skillfully by readers of Braille text.

The primary input is transmitted by neurones whose cell bodies lie in the spinal and cranial ganglia (see p. 55), and whose myelinated or unmyelinated axons are terminally distributed, mainly within the dermis. Efferent autonomic fibres are unmyelinated and noradrenergic or cholinergic. They innervate the arterioles, arrector pili muscles, and the myoepithelial cells of sweat and apocrine glands. In the scrotum, labia minora, perineal skin and nipples they also supply smooth muscle fasciculi of the dermis and adjacent connective tissue. Except in the nipples and genital area, activity of the autonomic efferent nerves is mainly concerned with regulation of heat loss by vasodilation and vasoconstriction, sweat production, and pilo-erection (although this is a minor function in humans).

On reaching the dermis, nerve fasciculi branch extensively to form a deep reticular plexus which serves much of the dermis, including most sweat glands, hair follicles and the larger arterioles. Many small fasciculi pass from this plexus to ramify in another superficial papillary plexus at the junction between the reticular and papillary layers of the dermis. Branches from this pass superficially into the papillary layer, ramifying horizontally and vertically, and terminate either in relation to encapsulated receptors, or as terminals reaching the level of the basal lamina. In some instances, they enter the epidermis as free endings, responsive to light pressure and touch sensation or to nociceptive stimuli. As these latter fasciculi terminate, they lose their epineurial and perineurial sheaths, leaving Schwann cell axonal complexes or naked axons enveloped by basal lamina, in direct contact with the matrix. These naked distal axonal terminals may be vulnerable to pathogens entering via a skin abrasion. The structure and classification of sensory endings are described in detail Chapter 3.

The segmental arrangement of the spinal nerves is reflected in the sensory supply of the skin: a dermatome is the area supplied by all the cutaneous branches of an individual spinal nerve through its dorsal and ventral rami (see Ch. 15 and Fig. 15.12). Typically, dermatomes extend round the body from the posterior to the anterior median line. The upper half of each zone is supplemented by the nerve above, the lower half by the nerve below. Dermatomes of adjacent spinal nerves overlap markedly, particularly in the segments least affected by development of the limbs.

DEVELOPMENT OF SKIN AND SKIN APPENDAGES

Skin is developed from the surface ectoderm and its underlying mesenchyme. Surface ectoderm gives rise to the cornifying general surface epidermis and its appendages, the pilosebaceous units, sweat glands and nail units, depending on interactions with the mesenchyme. Interactions between ectoderm and mesenchyme also give rise to the internal epithelium of the buccal cavity and the teeth and the nasal epithelia. The differentiated descendants of ectodermal cells are keratinocytes. Immigrant cells of different developmental origin constitute an important component of the epithelial sheet formed by the keratinocytes. The non-keratinocytes are melanocytes and Merkel cells derived from the neural crest, Langerhans cells of bone-marrow origin, and lymphocytes.

The dermis, composed of irregular connective tissue and some of the connective tissue sheaths of peripheral nerves, is derived from somatopleuric mesenchyme (in the limbs and trunk), and possibly somitic mesenchyme (covering the epaxial musculature), and from neural crest (in the head). Angiogenic mesenchyme gives rise to the blood vessels of the dermis. Nerves and associated Schwann cells, of neural crest origin, enter and traverse the dermis to reach their peripheral terminations during development.

EPIDERMIS AND APPENDAGES

General (interfollicular) epidermis

In the first 4–5 weeks, embryonic skin consists of a single layer of ectodermal cells overlying a mesenchyme containing cells of stellate dendritic appearance interconnected by slender processes and sparsely distributed in a loosely arranged microfibrillar matrix (Fig. 7.21). The interface between ectoderm and mesenchyme, known as the basement membrane zone (BMZ), is an important site of mutual interactions upon which the maintenance of the two tissues depends, both in prenatal and postnatal life. Ectodermal cells, which characteristically contain glycogen deposits, contact each other at gap and tight junctions. The layer so formed soon develops into a bilaminar epithelium, and desmosomes also appear. The basal germinative layer gives rise to the definitive postnatal epidermis, and the superficial layer to the periderm, a transient layer confined to fetal life. The periderm maintains itself, expresses different keratin polypeptides, and grows by the mitotic activity of its own cells, independent of those of the germinative layer. Originally flattened, the periderm cells increase in depth: the central area containing the nucleus becomes elevated and projects as a globular elevation towards the amniotic cavity. The plasma membrane develops numerous surface microvilli with an extraneous coat of glycosaminoglycans, and cytoplasmic vesicles become prominent deep to it. These developments reach a peak over the period 12–18 weeks, at which time the periderm is a major source of the amniotic fluid to which it may contribute glucose; it also has an absorptive function. From about 20 weeks onwards, the globular protrusions become undermined and pinched off to float free in the amniotic fluid. The now flattened periderm cells undergo a type of terminal differentiation to form what is regarded as a temporary protective layer for the underlying developing epidermis proper, against an amniotic fluid of changing composition as a result of the accumulation of products of fetal renal excretion. Up to parturition, periderm squames continue to be cast off into the amniotic fluid, and they contribute to the vernix caseosa, a layer of cellular debris which covers the fetal skin at birth.

Fig. 7.21 Development of the skin.

Proliferation in the germinative layer leads to a stratified appearance with successive layers of intermediate cells between it and the periderm. From an early stage, cells of all layers are packed with glycogen granules, presumably a source of energy during this early replicative stage of differentiation. Differentiation of these layers is not synchronous throughout all regions of the developing skin, being more advanced cranially than caudally, and progressing on the body from the midaxillary line ventrally. Reduction in glycogen content of the cells is associated with a shift towards biosynthetic activity connected with terminal (cornifying) differentiation, manifested by the presence of different enzymes and expression of keratins. Simple epithelial keratins present from before implantation (K8 and K18) are replaced by typical keratinocyte basal cell keratins (K5 and K14), followed in the first suprabasal cell layer by those of higher molecular weight associated with differentiation (K1 and K10) at 10–12 weeks. This is soon followed by expression of profilaggrin and filaggrin, and the appearance of keratohyalin granules among filamentous bundles of the uppermost intermediate layer cells at approximately 20 weeks. The first fully differentiated keratinocytes appear shortly afterwards. By 24–26 weeks a definite cornified layer exists in some areas, and by 30 weeks or so, apart from some lingering glycogen in intermediate cells, the interfollicular epidermis is essentially similar to its postnatal counterpart (see Holbrook & Odland 1980, for further details).

Non-keratinocytes are present in developing epidermis from about 8 weeks’ gestation. Langerhans cells can be seen in the epidermis by 5–6 weeks and are fully differentiated by 12–14 weeks. Their numbers increase at least partially by mitotic division in situ, but at 6 months are only 10–20% of those in the adult. It is not known if the Langerhans cell functions in immune surveillance in fetal skin. Melanocytes, of neural crest origin, are present in the bilaminar epidermis of cephalic regions as early as 8 weeks. By 12–14 weeks they can reach a density of 2300 per mm² reducing to 800 per mm² just before birth. Keratinocytes regulate the final ratio between themselves and melanocytes via growth factors, cell surface molecules and other signals. Fetal melanocytes produce melanized melanosomes and transfer them to keratinocytes: these are intrinsic activities clearly independent of ultraviolet (UV) irradiation, and suggest functions of melanin other than photoprotection.

Merkel cells originate from migratory neural crest cells (Szeder et al 2003) and begin to appear in the epidermis of the palm and sole of the foot between 8 and 12 weeks, and later in association with some hairs and with dermal axonal–Schwann cell complexes.

Pilosebaceous unit

Pilosebaceous units develop at about 9 weeks, first in the regions of the eyebrows, lips, and chin, and at progressively later stages elsewhere, proceeding caudally. The first rudiment is a crowding of cells in the basal layer of the epidermis, the hair placode, adjacent to a local concentration of mesenchymal cells which will become the dermal papilla. Further proliferation and elongation of the cells leads to a hair germ, which protrudes downwards into the mesenchyme in association with the primitive dermal papilla during weeks 13–15. With continued downward growth in a slanted direction, the hair germ becomes a hair peg, and when its bulbous lower end envelops the dermal papilla it is known as a bulbous peg. Melanocytes are individually present at the hair peg stage, and abundantly so and quite active in the bulbous peg. At this stage (approximately week 15) two or three swellings appear on the posterior wall. The uppermost is the rudiment of the apocrine gland (present only in some follicles), the middle forms the sebaceous gland and the lower one is the bulb, to which the arrector pili muscle (arising from underlying mesenchyme) later becomes attached, and where it is believed the main reservoir of hair follicle stem cells resides. The cells of the lowermost region of the bulb, the matrix, divide actively and produce a pointed hair cone. This grows upwards to canalize a developing hair tract, along which the fully formed hair, derived by further differentiation of cells advancing from the matrix, reaches the surface at approximately week 18 of gestation.

Sebaceous glands develop independently of hair follicles in the nostrils, eyelids (as tarsal glands) and in the anal region. Apocrine sweat glands are formed at the same time as eccrine (merocrine) sweat glands and are at first distributed widely over the body. Their number diminishes from 5 months’ gestation, producing the distribution seen in the adult.

Hairs produced prenatally are called lanugo hairs; they are short and downy, lack a medulla, and in certain parts of the body are arranged in a vortex-like manner into tracts. Late in pregnancy, lanugo hairs are replaced by vellus hairs, and these in turn by intermediate hairs, which are the predominant type until puberty. New follicles do not develop in postnatal skin.

Eccrine sweat glands

Eccrine (merocrine) sweat glands are one type of sudoriferous gland. Sweat gland rudiments appear in the second and third months as cell buds associated with the primary epidermal ridges of the finger and toe pads of terminal digits. They elongate into the dermis and by 16 weeks the lower end begins to form the secretory coil, within which, by 22 weeks, secretory and myoepithelial cells are evident. The solid cord of cells connecting the coil to the epidermis becomes the intradermal duct, and the lumina of both are formed by dissolution of desmosomal contacts between the cells. The intraepidermal duct is foreshadowed by a coiled column of concentrically arranged inner and outer cells, within which, by fusion of lysosomal vacuoles, a lumen is formed which opens on the surface at 22 weeks. As with hair follicles, no new eccrine sweat glands develop postnatally. Emotional sweating, detected by skin conductance changes, occurs in preterm infants from 29 weeks’ gestational age.

Epidermal ridges

The epidermal ridges are foreshadowed as regularly spaced small downgrowths of epidermal cells which appear in finger and toe pads during the second and third months. They are known as primary epidermal ridges, separated by corresponding dermal ridges. In the fifth month secondary ridges develop, the pattern becomes evident on the surface, and is finalized through further remodelling postnatally.

Nails

Fields of proliferative ectoderm appear on the tips of the terminal segments of the digits. They progressively reach a dorsal position, where at approximately 9 weeks, a flattened nail field limited by proximal, distal, and lateral nail grooves is apparent. The nail field ultimately forms the nail bed, and the primordium of the nail is formed of a wedge of cells which grows diagonally, proximally and deeply into the mesenchyme from the proximal groove towards the underlying terminal phalanx. The deeper cells of this wedge form the primordium of the matrix which gives rise to the nail plate. The latter emerges from under a, now proximal, nail fold at about 14 weeks and grows distally over an already keratinized nail bed. The nail matrix is usually considered to have dorsal and ventral (intermediate) components, but there are conflicting opinions as to the extent to which each contributes to the nail, both in ontogeny and postnatally: it is generally agreed that the ventral matrix contributes the major part. It has been claimed that the nail bed additionally contributes up to 20% of the postnatal nail plate, but embryological studies to date are not clear on this matter. Most texts state that keratohyalin is not involved in the cornification of nail. However, up to at least 16 weeks, the dorsal matrix granular layer cells which contribute cornified cells to the nail plate and eponychium (cuticle) contain typical keratohyalin granules, and the cells of the ventral matrix next to the nail plate contain single and compound granules similar to those present in granular layer cells of oral epithelia. Similar granules have been reported in matrix cells of postnatal human toenail.

At 20 weeks, the nail plate entirely covers the nail field (nail bed), now limited distally by a distal ridge, which, when the plate projects beyond the tip, becomes the hyponychium beneath it. At birth, the microstructure of the main nail unit components is similar to that postnatally; the nail is long and overhanging, and easily falls off during cleansing.

Abnormalities of the epidermis

Anomalous development of the epidermis and its derivatives is relatively common. Excessive or diminished growth, or even complete absence, may affect sebaceous or sudoriferous glands and hair, either locally or generally. Similarly, the epidermis may be excessively pigmented (melanism). Excessive production of the cornified layer leads to ichthyosis. A naevus or mole is a benign proliferation of melanocytes in the basal layer of the epidermis. Ectodermal dysplasia is a rare condition characterized by fine blond and scanty hair, reduced or absent eyelashes and eyebrows. The skin has deficient sweat and sebaceous glands. Teeth are usually peg- or cone-shaped, and absence of major salivary glands may occur. For information on keratin disorders, see Irvine & McLean 1999.

DERMIS

The embryonic dermis is far richer in cells than the adult dermis, and many of these mesenchymal cells are involved in an essential signalling dialogue which regulates ectodermal differentiation. The mesenchymal cells underlying the surface ectoderm and early bi- and trilaminar epidermis contact each other by slender processes to form an intercommunicating network. They secrete a matrix which is rich in ions, water, and macromolecules, proteoglycan/glycosaminoglycans, fibronectin, collagenous proteins of various types and elastin. Further development of these intrinsic components involves the differentiation of individual cell types, fibroblasts, endothelial cells, mast cells, etc. and the assembly of matrix components into organized fibrillar collagen fibres and elastic fibres. During embryogenesis, the matrix is heterogeneous with regard to its biochemical and macromolecular components. The main glycosaminoglycans of embryonic and fetal skin are glycuronic acid and dermatan sulfate. Collagens type I, III, V, and VI are distributed more or less uniformly regardless of fetal age, and there are some local concentrations of III and V, the levels of which are higher than in postnatal skin. Collagens type IV and VII are found predominantly in the BMZ.

The progressive morphological differentiation of the dermis involves its separation from the subcutis at about the third month; changes in composition and size of collagen fibrils and their organization into bundles amongst which cells become relatively fewer; downgrowth of epidermal appendages; the organization of nervous and vascular plexuses, and the relatively late appearance of elastic networks. The papillary and reticular regions are said to be evident as early as 14 weeks, but the overall organization of the dermis continues postnatally.

Vascular supply and lymphatic drainage

The dermal vasculature is generally thought to be developed in situ by transformation of angiogenic mesenchymal cells. Closed endothelial-lined channels containing nucleated red cells are present by 6 weeks underneath the ectoderm, and by the eighth week are arranged in a single plane parallel to the epidermis: they will ultimately form the subpapillary plexus. A second deeper horizontal plexus is evident by 50–70 days. Both plexuses extend by budding as development proceeds, and they give rise to the final patterns of arterioles, venules and capillaries which are established shortly after birth. Pericytes also develop from mesenchymal cells. Lymphatic vessels are formed by mesenchymal cells which become organized to enclose pools of proteinaceous fluid leaking from the developing capillaries.

Innervation

Sensory cutaneous nerves (axons and Schwann cells) are derived by outgrowth from the neural crest (via dorsal root ganglia). Motor fibres to vessels and glands arise from cells of sympathetic ganglia. As individual parts of the embryo grow, the nerves grow and lengthen with them. Small axons are present superficially at a stage when the epidermis is bilaminar, and by 8 weeks gestation there is already a functioning cutaneous plexus. By the fourth gestational month, the dermal plexuses are very richly developed, and Meissner and Pacinian corpuscles have appeared. The outer lamellar cells of Pacinian corpuscles in the dermis are homologous with the perineurium, but the source of the laminar cells of the Meissner corpuscle is unclear.

EPITHELIAL–MESENCHYMAL INTERACTIONS IN DEVELOPING SKIN

Epidermal–mesenchymal (dermal) interactions at the BMZ occur during development and throughout life. At the ectodermal stage, the BMZ consists of the basal plasma membrane of an ectodermal cell, paralleled on its cytoplasmic side by various cytoskeletal filaments, and beneath it, by a layer (0.1–0.2 μm) of microfibrillar-amorphous material deposited by the cell. At the bilaminar stage, a definite continuous lamina densa is present, separated from the basal plasma membrane by a lamina lucida traversed by loosely fibrillar material: similar filaments extend from the lamina densa into the mesenchymal matrix.

Hemidesmosomes begin to appear at 8 weeks as stratification starts, and anchoring fibrils at 9–10 weeks. By the end of the third month the basic morphology of the interfollicular BMZ is essentially similar to that of the postnatal BMZ.

Laminin and collagen type IV are present in the developing basal lamina at 6 weeks, and bullous pemphigoid antigen (BPAG, in hemidesmosomes) and anchoring fibril proteins are expressed later. These immunocytochemical and morphological observations are of importance for prenatal diagnosis of genetically determined diseases, e.g. epidermolysis bullosa. The basal lamina provides a physical supporting substrate and attachment for the developing epidermis, and is thought to be selectively permeable to macromolecules and soluble factors regulating epidermal–dermal morphogenetic interactions.

NEONATAL GROWTH

The surface area of the skin increases with growth. It has been estimated that the surface area of a premature neonate weighing 1505 g is approximately 1266 cm², whereas a neonate of 2980 g has a surface area of 2129 cm². The skin of the neonate is thinner than that of older infants and children. It cornifies over a period of 2–3 weeks which provides protection; however, in the premature infant the thin epidermal layer allows absorption of a variety of substances, e.g. chlorhexidine and boric acid and also permits a significantly higher transepidermal water loss than occurs in full term neonates. At birth the skin is richly vascularized by a dense subepidermal plexus. The mature pattern of capillary loops and of the subpapillary venous plexus is not present at birth but develops as a result of capillary budding with migration of endothelia at some sites and the absorption of vessels from other sites. Some regions mature faster than others. With the exceptions of the palms, soles and nail beds, the skin of the neonate has almost no papillary loops. It has a disordered capillary network which becomes more orderly from the second week when papillary loops appear; defined loops are not present until the fourth or fifth week, and all areas possess loops by 14–17 weeks postnatally.

Neonates exhibit a regional sequence of eccrine gland maturation. The earliest sweating occurs on the forehead, followed by the chest, upper arm and, later, more caudal areas. Acceleration of maturation of the sweating response occurs in premature babies after delivery.

NATURAL SKIN CREASES AND WRINKLES

SKIN LINES

The surface of the skin and its deeper structures show various linear markings, seen as grooves, raised areas and preferred directions of stretching. Some of these are clearly evident in intact skin, others only appear after some sort of intervention.

Surface pattern lines, tension lines and skin creases

Externally visible skin lines are related to various patterns of epidermal creasing, ridge formation, scarring and pigmentation. A simple lattice pattern of lines occurs on all major areas of the body other than the thick skin of volar and plantar surfaces. The lattice pattern typically consists of polygons formed by relatively deep primary creases visible to the naked eye, which are irregularly divided by finer secondary creases into triangular areas (Fig. 7.22, Fig. 7.23). These, in turn, are further subdivided by tertiary creases limited to the cornified layer of the epidermis, and, finally, at the microscopic level, by quaternary lines which are simply the outlines of individual squames (Fig. 7.7). Apart from the quaternary lines, all the others increase the surface area of the skin, permit considerable stretching and recoil and distribute stresses more evenly. Details of the pattern vary according to the region of the body; e.g. on the cheek the primary creases radiate from the hair follicles, on the scalp they form hexagons, while on the calf and thigh they form parallelograms. There is a relationship between type of pattern and local skin extensibility.

Fig. 7.22 The surface of hairless skin from the palm of the hand, showing epidermal friction (papillary) ridges and larger flexure lines (left).

Fig. 7.23 Scanning electron micrograph of the surface of thin skin of the back, showing an interlacing network of fine creases and predominantly triangular areas between them.

Wrinkle lines

Wrinkle lines are caused by contraction of underlying muscles and are usually perpendicular to their axis of shortening. On the face they are known as lines of expression, and with progressive loss of skin elasticity due to ageing, they become permanent. Occupational lines are creases produced by repeated muscular contractions associated with particular trades or skills. Contour lines are lines of division at junctions of body planes, e.g. the cheek with the nose, and lines of dependency are produced by the effect of gravity on loose skin or fatty tissue, e.g. the creases associated with the pendulous fold beneath the chin in older age.

Flexure (joint) lines

Flexure (joint) lines are major markings found in the vicinity of synovial joints, where the skin is attached strongly to the underlying deep fascia (Fig. 7.22). They are conspicuous on the flexor surfaces of the palms, soles, and digits, and in combination with associated skin folds, they facilitate movement. The skin lines do not necessarily coincide with the associated underlying joint line. For example, the flexure lines demarcating the extended fingers from the palm lie approximately half an inch distal to the metacarpophalangeal joints, the positions of which are more closely related to the distal palmar crease (heart-line of palmistry). The patterns of flexure lines on the palms and soles may vary and are to some extent genetically determined. In Down syndrome, the distal and middle palmar creases tend to be united into a prominent single transverse crease, a sign which is of diagnostic importance.

Papillary ridges

Papillary ridges are confined to the palms and soles and the flexor surfaces of the digits, where they form narrow parallel or curved arrays separated by narrow furrows (Fig. 7.24, Fig. 7.25). The apertures of sweat ducts open at regular intervals along the summit of each ridge. The epidermal ridges correspond to an underlying interlocking pattern of dermal papillae, an arrangement which helps to anchor the two layers firmly together. The pattern of dermal papillae determines the early development of the epidermal ridges. This arrangement is stable throughout life, unique to the individual, and therefore significant as a means of identification. The ridge pattern can be affected by certain abnormalities of early development, including genetic disorders such as Down syndrome, and skeletal malformations such as polydactyly. Absence of epidermal ridges is extremely rare. Functionally, epidermal ridges increase the gripping ability of hands and feet, preventing slipping. The great density of tactile nerve endings beneath them means that they are also important sensory structures.