Biology of nails
The nail apparatus consists of a horny “dead”
product, the nail plate, and four specialized epithelia: (1) the proximal nail
fold, (2) the nail matrix, (3) the nail bed, and (4) the hyponychium. The nail
apparatus develops during the 9th embryonic week from the epidermis of the
dorsal tip of the digit as a rectangular area, the nail fold that is delineated
by a continuous groove. The proximal border of the nail fold extends downward and proximally into the
dermis to form the nail matrix primordium. By the 15th week the nail matrix is
completely developed and starts to produce the nail plate, which will continue
to grow until death. The nail apparatus lies immediately above the periosteum
of the distal phalanx. The intimate anatomic relationship between the nail and
the bone is responsible for the common occurrence of bone alterations in nail
disorders and vice versa. The shape of the distal phalangeal bone also
determines the shape and the transverse curvature of the nail.
Fingernails usually present a longitudinal
major axis and toenail a transverse major axis. The ratio between length and
width is important for the aesthetic appearance of the nails. The size of the
nails varies in the different digits. The biggest nail is that of the first
toe, which covers approximately 50% of the dorsum of the digit.
Nails have numerous functions. Fingernails
not only contribute to the pleasing appearance of the hands, but are very
important in protecting the distal phalanges and enhancing tactile
discrimination and the capacity to pick up small objects. They are also widely
used for scratching and grooming and are an efficient natural weapon. Toenails
protect the distal toes and contribute to pedal biomechanics.
Nail Plate
The nail plate is a fully keratinized
structure that is continuously produced throughout life. It results from
maturation and keratinization of the nail matrix epithelium and is firmly
attached to the nail bed, which partially contributes to its formation.
Proximally and laterally the nail plate is surrounded by the nail folds, which
cover its proximal third and lateral margins. At the tip of the digit, the nail
plate separates from the underlying tissues at the hyponychium. The nail plate
is rectangular, translucent, and transparent. It is curved in both the
longitudinal and transverse axes, especially in the toes. The nail plate
surface is smooth but frequently shows mild longitudinal ridges that increase
with aging. The pattern of these ridges can be used for forensic
identification. The bottom of the nail plate shows longitudinal ridges that
correspond to the rete ridges of the nail bed. The nail plate is homogeneously
pink, except for its free edge, which is white. The pink color of the nail
plate is due to the nail bed blood vessels.
The proximal part of the fingernails,
especially of the thumbs, shows a whitish, opaque, half-moon-shaped area, the
lunula that is the visible portion of the nail matrix. In this area the nail
plate attachment to the underlying epithelium is loose. The lunula is less apparent, due in part to concealment by the proximal
nail fold, with progression from the second to fifth finger. The lunulae of the
toes are hidden by their relatively prominent proximal nail folds, which may
serve a protective function, and (especially for the great toes) thicker nail
plates. More than 90% of fingernails show a thin distal transverse white
band, the onychocorneal band, better defined as the isthmus, which marks the
most distal portion of firm attachment of the nail plate to the nail bed. This
area represents an important anatomic barrier against environmental hazards,
and its disruption produces nail plate detachment with onycholysis. The
onychocorneal band is separated from the nail plate white free edge by a
1.0–1.5-mm pink band called the onychodermal band.
In transverse sections, the nail plate
consists of three portions: (1) dorsal nail plate, (2) intermediate nail plate,
and (3) ventral nail plate. The dorsal and the intermediate portions of the
nail plate are produced by the nail matrix, whereas its ventral portion is
produced by the nail bed. Above the lunula the nail plate is thinner and
consists only of the dorsal and intermediate portions. There is a natural line
of cleavage between the dorsal and the intermediate nail plate.
The nail plate progressively thickens from
its emergence to its distal margin. The mean toenail thickness at the distal
margin is 1.65 ± 0.43 mm in men and 1.38 ± 0.20 mm in women. Fingernails are
thinner; the mean thickness is 0.6 mm in men and 0.5 mm in women. There is an
increase in nail thickness with age, particularly in the first two decades. Nail
thickness depends on the length of the nail matrix and nail bed. Thinning of
the nails is usually a sign of nail matrix disorders, whereas nail thickening
is most commonly a consequence of nail bed disorders.
Nail folds
The nail plate is surrounded on
three edges by nail folds, one proximal and two laterals. The
proximal nail fold is a skin fold that consists of a dorsal and a ventral
portion. The dorsal portion is anatomically similar to the skin of the dorsum
of the digit but thinner and devoid of pilosebaceous units. The ventral
portion, which cannot be seen from the exterior and proximally continues with
the germinative matrix, covers approximately one-fourth of the nail plate. It
closely adheres to the nail plate surface and keratinizes with a granular
layer. The limit between the proximal nail fold and the nail matrix can be
histologically established at the site of disappearance of the granular layer.
The horny layer of the proximal nail fold
forms the cuticle, which is firmly attached to the superficial nail plate and
prevents the separation of the plate from the nail fold. The integrity of the
cuticle is essential for maintaining the homeostasis of this region.
The longitudinal axis of nail
growth is also guided by the lateral nail folds, which compress the nail plate
from each side and contribute to its transverse curvature. The lateral margins
of the nail bed form deep sulci that follow the curve of the distal phalanx and
then fold back on themselves to produce the lateral nail folds. These sulci
help to attach the nail to the soft tissues and, similar to the proximal nail
fold and cuticle, provide a seal at the nail margin.
The structures bounded by the
nail folds are the nail matrix proximally and the nail bed distally and
medially.
The dermis of the proximal nail fold contains
numerous capillaries that run parallel to the surface of the skin and may
easily be observed in vivo by capillary microscopy. This permits the
observation of both the arterial and the venous limbs of the capillaries, which
are arranged in parallel rows and appear as fine regular loops with a small
space between the afferent and efferent limbs. The morphology of proximal nail
fold capillaries is typically altered in connective tissue diseases.
Nail Matrix
The nail matrix is a specialized epithelial
structure that lies above the mid portion of the distal phalanx. After
elevation of the proximal nail fold, the matrix appears as a distally convex
crescent with its lateral horns extending proximally and laterally.
In longitudinal sections the matrix has a
wedge-shaped appearance and consists of a proximal (dorsal) and a distal
(ventral) portion. Nail matrix keratinocytes divide in the basal cell layer and
keratinize in the absence of a granular zone. The site of keratinization
(keratogenous zone) of nail matrix onychocytes can be clearly distinguished in
histological sections as an eosinophilic area where cells show fragmentation of
their nuclei and condensation of their cytoplasm. In this area, nuclear fragments
are destroyed by deoxyribonuclease and ribonuclease enzymes. In some conditions
nuclear fragments may persist within the intermediate nail plate, producing
leukonychia spots. However, these frequently disappear before reaching the
nail-free edge, due to the persistence of active DNA and RNA lytic enzymes
within the horny nail plate.
Maturation and differentiation of nail matrix
keratinocytes do not follow a vertical axis, as in the epidermis, but occur
along a diagonal axis that is distally oriented. For this reason,
keratinization of the proximal nail matrix cells produces the dorsal nail plate
and keratinization of the distal nail matrix cells produces the intermediate
nail plate.
In some fingers the distal matrix is not
completely covered by the proximal nail fold but is visible through the nail
plate as a white half-moon-shaped area, the lunula. The white color of the
lunula results from two main anatomic factors: (1) the keratogenous zone of the
distal matrix contains nuclear fragments that cause light diffraction; (2)
nail-matrix capillaries are less visible than nail bed capillaries because of
the relative thickness of the nail-matrix epithelium.
Nail Matrix Keratinocytes
The nail matrix cells are able to synthesize
both “soft” or skin-type and “hard” or hair-type keratins. Evaluation of
keratin expression in the different constituents of the nail apparatus showed
that the nail matrix is the sole site of expression of hard keratin proteins,
particularly Ha1 keratin. Data indicate that fibroblasts derived from the nail
matrix may induce hard keratin expression in nonnail-matrix keratinocytes.
Melanocytes
Nail matrix melanocytes are usually quiescent
and therefore not detectable in pathologic sections. However, they possess the
key enzymes that are necessary for melanin production, and may become activated
by a large number of physiologic and pathologic conditions. Nail matrix
melanocyte activation produces diffuse or banded nail pigmentation and is more
common in blacks and Japanese than in Caucasians. DOPA-negative (inactive)
melanocytes are sparsely present in the nail matrix and in the nail bed. DOPA-positive, activable melanocytes are especially seen in the distal nail
matrix, where they are frequently arranged in small clusters among the
suprabasal layers of the nail matrix epithelium.
Langerhans Cells
Langerhans cells are more numerous in the
proximal than in the distal nail matrix. As in normal epidermis, Langerhans
cells are predominantly found in the suprabasal layers. However, they may
occasionally be seen within the basal layer of the nail matrix epithelium.
Merkel Cells
The presence of Merkel cells in the nail
matrix has been demonstrated. Their density is possibly influenced by age, with
these cells being more numerous in fetus than in adult nails.
Nail Bed
The nail bed extends from the distal margin
of the lunula to the isthmus and is completely visible through the nail plate.
The nail bed epithelium is so adherent to the nail plate that it remains
attached to the undersurface of the nail when the latter is avulsed.
The nail bed epithelium is thin and consists
of two to five cell layers. Its rete ridges, which are longitudinally oriented,
interdigitate with the underlying dermal ridges in a “tongue-and-groove”-like
fashion. The nail bed epithelium is a specialized epithelial structure with a
horny layer that interlocks to of the inferior border of the nail plate and is
responsible for the strong attachment between the two tissues. Nail bed horny
layer forms the ventral nail plate, which corresponds to approximately
one-fifth of the terminal nail thickness and mass. In pathologic sections, the
ventral nail plate is easily distinguishable because of its light eosinophilic
appearance. Nail bed keratinization is not associated with the formation of a
granular layer. This may appear, however, when the nail bed becomes exposed
after nail avulsion.
The nail isthmus is a thin transverse distal
band that represents a transitional zone between the nail bed and the
hyponychium and exhibits a unique pattern of keratinization, the onycholemmal
keratinization, with pale, nucleated keratinocytes. The cornified layer of the
nail isthmus closely adheres to the undulating inferior surface of the nail
plate preventing onycholysis; the two grow forward together. Keratin expression
in the nail bed differs from that of the nail matrix since keratins K6, K16,
and K6hf are only expressed in the nail bed. The isthmus differs from nail bed
because of a strong suprabasal expression of K10. Transition from isthmus to
hyponychium is marked by the disappearance of expression of K6hf and K6/16, and
return to expression of K5/17.
Hyponychium
The hyponychium marks the anatomic area
between the nail bed and the distal groove, where the nail plate detaches from
the dorsal digit.
Its anatomic structure is similar to that of plantar and volar skin, and
keratinization occurs through the formation of a granular layer. The horny
layer of the hyponychium partially accumulates under the nail plate free
margin. The hyponychium is normally covered by the distal nail plate, but it
may become visible in nail biters. The architecture of the capillary network of
the hyponychium dermis consists in regular capillary loops arranged
perpendicularly to the skin, visible as red dots with dermoscopy.
Basement Membrane Zone
The antigenic structure of the basement
membrane zone of the nail is identical to that of the epidermis, and there are
no differences in the antigenic composition of the basement membrane zone in
the different portions of the nail apparatus. This may explain the involvement
of the nails in conditions characterized by mutations of basement
membrane-associated genes as well as in autoimmune skin diseases involving the
basement membrane zone antigens.
Dermis
The nail apparatus is devoid of subcutaneous
tissue, and its dermis does not contain pilosebaceous units. The arrangement of
the rete ridges varies in the different portions of the nail apparatus. The
dermis beneath the proximal nail matrix consists of condensed connective tissue
that forms a tendon-like structure connecting the matrix to the periosteum of
the proximal phalangeal bone (posterior ligament). A small amount of subdermal
fat tissue is present close to the periosteum of the base of the phalanx. The
close connection between the lateral horns and the periosteum is possibly
responsible for the nail plate's lateral convexity. The rete ridges of the
dermis underneath the nail matrix are characteristically long and root-like in
shape. The dermis under the distal matrix consists of a loose network of
connective tissue containing numerous blood vessels and rare glomus bodies.
The dermis of the nail bed has a unique
arrangement with longitudinal grooves and ridges that run from the lunula to
the hyponychium. The longitudinal orientation of the capillary vessels within
the nail bed grooves explains the linear pattern of nail bed hemorrhages
(splinter hemorrhages). The nail bed dermis contains abundant connective tissue
networks with connective tissue bundles radiating to the phalangeal periosteum.
It contains numerous glomus bodies.
Blood and Nerve Supply
The nail apparatus has an abundant blood
supply provided by the lateral digital arteries. These run along the sides of
the digits and produce both branches that supply the matrix and the proximal
nail fold and arches that supply the matrix and the nail bed. The nail matrix,
therefore, has two different sources of blood supply. The nail bed is richly
supplied (10–20 cm2) by encapsulated neurovascular structures containing one to
four arteriovenous anastomoses and nerve endings. These glomus bodies are
arteriovenous shunts involved in the regulation of the blood supply to the
digits related to thermoregulation. The cutaneous sensory nerves, which
originate from the dorsal branches of the paired digital nerves, run parallel
to the digital vessels.
Chemical Properties
The nail plate, like hair, consists mainly of
low-sulfur filamentous proteins (keratins) embedded in an amorphous matrix
composed of high-sulfur proteins rich in cysteine.
Other nail constituents include water, lipids, and trace elements. Nail
keratins consist of 80%–90% hard hair-type keratins and 10%–20% soft skin-type
keratins. Hard keratins have been identified as the acidic 44K/46K and basic
56K/60K keratins. Soft keratins have been identified as the 50K/58K and 48K/56K
keratin pairs. Keratin filaments have a transverse orientation that is parallel
to the nail surface. This explains why the nail plate is more susceptible to
transverse fractures than to longitudinal fractures. Specific keratins are
expressed only in some compartments of the nail unit; for instance, K6a and
K6b, K16, and K17 are not expressed in the nail matrix. Mutations of the genes encoding for these keratins are associated with nail
thickening due to nail bed hyperproliferation, as is seen in pachyonychia
congenita (PC). Nail keratin content and composition, measured as the quantity of carbon (C),
nitrogen (N), and sulfur (S) in the fingernails, vary between sexes and in
relation to the aging process. Sulfur content is higher in female than in male
nails and the opposite is for nitrogen. Carbon content is equal in the two
sexes. The carbon content increases with aging, possibly due to loss of
inorganic material, and the nitrogen content decreases, while the sulfur
content remains stable.
Under normal conditions, the water content of
the nail plate is 18%, and most of the water is in the intermediate nail plate.
The average water content of the nail plate is significantly lower in winter
than in summer. and varies significantly in time, due to the high porosity of
the nail plate, which allows it to be rapidly hydrated and dehydrated.
Dehydration is faster when the nails are kept long. When the water content
decreases below 18%, the nail becomes brittle; when it increases above 30%, it becomes
opaque and soft.
The nail contains less than 5% lipids, mainly
cholesterol; the nail plate lipid content is under hormonal control and
decreases after menopause. The nail plate also contains traces of several
inorganic elements, particularly iron, zinc,
and calcium. However, these do not contribute to nail hardness.
Physical Properties
The nail plate is hard, strong, and flexible.
The hardness and strength of the nail plate are due to its high content of hard
keratins and cysteine-rich
high-sulfur proteins, whereas its flexibility depends on its water content and
increases with nail plate hydration.
The double curvature of the nail plate along
its longitudinal and transverse axes enhances nail plate resistance to
mechanical stress.
The physical properties of the nail also
depend on the arrangement and adhesion of onychocytes in the different portions
of the nail plate, as well as on the orientation of the keratin filaments
within the nail plate onychocytes. At the ultrastructural level, the
corneocytes of the dorsal nail plate are flat, with their shorter diameter
perpendicular to the nail plate surface. The average sizes of these cells are
34 μm in length, 64 μm in width, and 2.2 μm in height. Cell adhesion is strong.
This portion of the nail is responsible for nail plate hardness and sharpness.
The onychocytes of the intermediate nail plate show multiple interdigitations
of their cell membranes. The average dimensions of these cells are 40 μm in
length, 53 μm in width, and 5.5 μm in height. Cell adhesion is provided by
desmosomes. This part of the nail plate is responsible for nail pliability and
elasticity. The ventral nail plate is thin and consists of soft keratins. It
provides adhesion to the underlying nail bed.
Nail Growth
The nail plate grows continuously in a
proximal to distal manner throughout life. The nail plate is “pushed” out by
two factors: (1) matrix keratinocytes proliferation and differentiation which
makes a new plate, (2) the nail bed which moves slowly, parallel to the
direction of the nail growth, toward the inferior border of the nail plate.
Fingernails grow two times faster than
toenails, with a mean growth rate in adults of 3.5 mm/month for fingernails and
1.5 mm/month for toenails. The 5th fingernail growth rate is significantly
slower than other fingernails and the growth rate of the great toenail significantly
faster than other toenails.
Complete replacement of a fingernail requires
100–180 days (6 months). When the nail plate is extracted, it is approximately
40 days before the new fingernail first emerges from the proximal nail fold.
After a further 120 days it will reach the fingertip. The total regeneration
time for a toenail is 12–18 months. As a consequence of the slow nail growth
rate, diseases of the nail matrix only become evident a considerable time after
their onset and require a long time to disappear after treatment.
Nail growth rate varies among different
individuals and among the different digits of the same individual. It depends
on the turnover rate of the nail matrix cells and is influenced by several
physiologic and pathologic conditions. Nail growth rate is slow at birth,
increases slightly during childhood, and usually reaches its maximum between
the second and the third decades of life. It sharply decreases after the age of
50 years.
Conditions that have been associated with a
slow growth rate include systemic illness, malnutrition, peripheral vascular or
neurologic diseases, and treatment with antimitotic drugs. Nails affected by
onychomycosis frequently exhibit a slow growth rate. An arrest of nail growth
is a typical feature of yellow nail syndrome. Conditions that have been
associated with accelerated nail growth include pregnancy, finger trauma,
psoriasis, and treatment with oral retinoids or itraconazole.
Accelerated nail growth may cause longitudinal ridging of the nail plate (nail
beading).
Due to their slow growth rate, the nails may
provide information on pathologic conditions that have occurred up to several
months before the time of observation. Drugs, chemicals, and biologic
substances accumulate in nails, where they can be detected and measured.
Advantages of analyzing nail samples include the ease and noninvasiveness of
their collection, the small sample size required for analysis, and the ease of
storage at room temperature. The nail of the big toe is the best site for
investigation because of its size (big toenail length of an adult: 20 mm) and
slow growth rate (about 2 mm/month) permitting to obtain data on exposure to
drugs and chemicals over a period of 10 months.
