Section 1 – Basic science of the lens
Chapter 28 – Anatomy
LISA A. SAXBY
• The lens is a highly organized, transparent structure that has evolved to alter the refractive index of light entering the eye.
• The lens comprises three parts, (1) the capsule, (2) the lens epithelium, and (3) the lens fibers.
• Capsule—an elastic acellular envelope that encloses the epithelium and the lens fibers.
• Lens epithelium—a single layer of cells beneath the anterior capsule which form new fiber cells at the equator.
• Lens fibers—constitute the main mass of the lens and form the basis of the nucleus and cortex and contain high concentrations of crystallin.
GROSS STRUCTURE OF THE ADULT LENS
The adult human lens is an asymmetrical oblate spheroid that does not possess nerves, blood vessels, or connective tissue. The biconvex shape results from the anterior surface being less convex than the posterior surface. The poles represent the center points of these two surfaces—the anteroposterior axis runs from the anterior pole to the posterior pole (polar axis). The equator represents the lateral region of the lens, where the anterior and the posterior surfaces meet. The equatorial axis is at right angles to the anteroposterior axis.     
The lens is located behind the iris and pupil in the anterior compartment of the eye. The anterior surface is in contact with the aqueous on the corneal side; the posterior surface is in contact with the vitreous and faces the retina. The anterior pole of the lens and the front of the cornea are separated by approximately 3.5?mm. The lens is held in place by the zonular fibers (suspensory ligaments), which run between the lens and the ciliary body. These zonular fibers, which originate from the region of the ciliary epithelium, are a series of fibrillin-rich fibers that converge in a circular zone on the lens. Both an anterior and a posterior sheet meet the capsule 1–2?mm from the equator and are embedded into the outer part of the capsule (1–2?µm deep). It also is thought that a series of fibers meets the capsule at the equator. 
Histologically the lens consists of three major components—capsule, epithelium, and lens substance ( Fig. 28-1 ).
The lens is ensheathed by an elastic acellular envelope, which serves to contain the epithelial cells and fibers as a structural unit and allows the passage of small molecules both into and out of the lens. The thickness of the capsule depends upon the region of the capsule being measured and the age of the individual (thickness increases with age).   The thickest region (up to 23?µm) is located close to the equator on both the anterior and the posterior surfaces; the thinnest region is that of the posterior pole (4?µm), while the equator (17?µm) and the anterior pole (9–14?µm) are of intermediate thickness ( Fig. 28-2 ). This basement membrane–like structure is continuously synthesized and represents one of the thickest basement membranes in the body. The capsule is produced anteriorly by the lens epithelium and posteriorly by the elongating fiber cells.
The lens capsule is composed of a number of lamellae stacked on top of each other. The lamellae are narrowest near the outside of the capsule and widest near the cell mass. The anterior capsule also contains linear densities ( Fig. 28-3 ). The major structural proteins (type IV collagen, laminin, heparin sulfate proteoglycan, and entactin) and a small amount of fibronectin are found within the lamellae. Although the precise interactive role of these different components is not known, experiments using lens epithelial cells in culture have shown that collagen IV promotes cellular adhesion and fibronectin promotes migration.
The lens epithelium arises as a single layer of cells beneath the anterior capsule and extends to the equatorial lens bow. These cells have a cuboidal shape, being approximately 10?µm high and 15?µm wide. Their basal surface adheres to the capsule, whereas their anterior surface abuts the newly formed elongating lens fibers. Lens epithelial cells have large, indented nuclei and a normal array of organelles, which include smooth and rough endoplasmic reticulum, polysomes, ribosomes, lysosomes, mitochondria, and Golgi bodies. They also contain dense bodies and glycogen particles. The lateral membranes of epithelial cells (membranes in contact with the adjacent epithelial cells) are highly tortuous ( Fig. 28-4 ). Adjacent cells are attached to each other by adhesion complexes located in the lateral membranes and include both desmosomes and tight junctions.     The desmosomes serve to not only to provide adhesion but also allow the transfer of mechanical stress across the cell sheet via the intermediate filament vimentin. Tight junctions regulate the movement of macromolecules through the extracellular space and, dependent on the number of interlinking strands, can exhibit varying degrees of permeability ranging from impermeable to partially permeable. In the lens this barrier does not appear to restrict the movement of small molecules such as ions and water. Direct communication between lens epithelial cells is via gap junctions that allow the passage of small molecules (less than 1500Da) between cells. These junctions are composed of connexin 43. 
Cytoskeletal elements form a network that serves many important functions within the cell. This network provides structural support; controls cell shape and volume, intracellular compartmentalization, and movement of organelles; enables cell movement, distribution of mechanical stress, and chromosome movement during cell division. Lens epithelial cells are known to contain the three main groups of cytoskeletal elements, which are microfilaments (actin), intermediate filaments (vimentin),
Figure 28-1 Gross anatomy of the adult human lens. Note the different regions are not drawn to scale.
and microtubules (tubulin). The ß- and ?-actins, which are often cell membrane–associated, normally localize with myosin to make polygonal arrays. Lens epithelial cells also express the proteins spectrin and a-actinin, which play an important role in connecting actin to cell adhesion receptors.   Lens epithelial cells are unique in that they contain vimentin and not cytokeratin, an intermediate filament normally associated with epithelial cells. It is thought that the cytokeratin expression is lost after early invagination of the lens placode. Microtubules composed of a- and ß-tubulin are found in small numbers.
The proliferative capacity of epithelial cells varies according to their location (see Fig. 28-1 ) and is greatest at the equator. Most epithelial cells are found in the central zone, a region in which cells normally do not proliferate, although they may do so under pathological circumstances. Cells in this zone are the largest epithelial cells found in the lens. Cells in the pregerminative zone rarely divide, whereas those in the germinative zone constitute the stem cell population of the lens, and therefore are responsible for the formation of all new fibers and the subsequent increase in size and weight of the lens throughout life. Because cells in the germinative zone are dividing constantly, newly formed cells are forced into the transitional zone where they elongate and differentiate to form the fiber mass of the lens.  Although it is known that growth factors in the aqueous and vitreous regulate this proliferation and differentiation, the precise nature of these interactions is not understood fully.
The lens substance, which constitutes the main mass of the lens, is composed of densely packed fibers with very little extracellular space. The adult lens substance consists of the nucleus and the cortex, two regions that often are histologically indistinct. Although the size of these two regions is age dependent, studies of lenses with an average age of 61 years indicate that the nucleus accounts for approximately 84% of the diameter and thickness of the lens and the cortex for the remaining 16%. The nucleus is further subdivided into embryonic, fetal, infantile, and adult nuclei (see Fig. 28-1 ). The embryonic nucleus contains the original primary lens fiber cells that are formed in the lens vesicle. The rest of the nuclei are composed of secondary fibers, which are added concentrically at the different stages of growth by encircling the previously formed nucleus. The fetal nucleus contains the embryonic
Figure 28-2 Changes in thickness of the adult lens capsule with location.
Figure 28-3 High-power transition electron micrograph of the lens capsule. The linear density (LD) exhibits a periodicity of about 60?nm as a result of the axial banding of its constituent fibrils. Electron lucent “bubbles” (arrowheads) occur between the adjacent lamellae. (Courtesy of GE Marshall. From Phelps Brown N, Bron AJ. Lens structure. In: Phelps Brown N, Bron AJ, Phelps Brown NA. Lens disorders. A clinical manual of cataract diagnosis. Oxford: Butterworth-Heinemann; 1996:32–47.)
Figure 28-4 Transmission electron micrograph of lens epithelial cells from a young adult monkey. Montage showing nuclei (n), anterior lens capsule (alc), markedly indented lateral plasma membrane, apical ends of underlying elongating secondary lens fiber cells and perpendicularly sectioned polygonal arrays of actin bundles or geodomes (arrows) immediately subjacent to the apical membranes of lens epithelial cells. (Bar = 1.0?µm.) (From Kuszak JR, Brown HG. Embryology and anatomy of the lens. In: Albert DM, Jakobiec FA, eds. Principles and practice of ophthalmology. Basic sciences. Philadelphia: WB Saunders; 1994:82–96.)
nucleus and all fibers added to the lens before birth. The embryonic and fetal nuclei, together with all the fibers added until 4 years of age, compose the infantile nucleus. The adult nucleus is composed of all fibers added before sexual maturation. The cortex, which is located peripherally, is composed of all the secondary fibers continuously formed after sexual maturation and can be divided into the deep, intermediate, and superficial cortex. The region between the hardened embryonic and fetal nuclear core and the soft cortex (i.e., the fibers added to form the infantile and adult nuclei)
Figure 28-5 Light micrograph of elongating fibers of a rat lens (thick section along the equatorial axis). The arrangement of fibers in radial cell columns and concentric growth shells is apparent. Note that while the fibers are generally hexagonal in cross-section, occasional pentagonal cross-sectional profiles are present. (Bar = 10?µm.) (From Kuszak JR. The ultrastructure of epithelial and fiber cells in the crystalline lens. Int Rev Cytol. 1995;163:305–50.)
sometimes is referred to as the epinucleus. The region between the deep cortex and adult nucleus is sometimes referred to as the perinuclear region. 
Fibers are formed constantly throughout life by the elongation of lens epithelial cells at the equator. Initially, transitional columnar cells are formed but, once long enough, the anterior end moves forward beneath the anterior epithelial cell layer and the posterior end is pushed backward along the posterior capsule. The ends of this U-shaped fiber run toward the poles of both capsular surfaces.      Once fully matured, the fiber detaches from the anterior epithelium and the posterior capsule. Each new layer of secondary fibers formed at the periphery of the lens constitutes a new growth shell. Lens fibers from these concentric shells are aligned so that radial cell columns extend from the center of the lens to the periphery ( Fig. 28-5 ). In some regions, neighboring fibers fuse to maintain these columns and ensure that spaces do not develop between the fibers as the lens grows. The growth shell forming at any one time always has more of these fusion zones than the previous shell to ensure that the correct suture is formed. Because new fibers always are added at the periphery and older fibers are internalized, every fiber formed throughout life needs to be maintained and supported.  
The formation of a new fiber is associated with the production of components of the fiber cell membrane—major intrinsic protein 26 (MIP26 or MP26), lipids, phospholipids, and peripheral proteins. Lens fiber membranes contain similar amounts of proteins and lipids. The major sterol is cholesterol (50–60% of total lipid) and the major phospholipid is sphingomyelin (47–56% of the total phospholipid). The predominant saturated fatty acid is palmitate. The high levels of these three constituents result in a highly ordered membrane with very little fluidity.
The newly formed lens fibers have a consistent hexagonal cross-sectional morphology with six faces, two of which are broad and four of which are narrow. These hexagonal fibers are approximately 2?µm thick, 10?µm wide, and up to 10?mm long. More centrally located fibers lose their uniform shape and adopt an irregular polygonal profile in cross-section.  One study of adult lenses shows that fibers in the embryonic nucleus have an
Figure 28-6 Scanning electron micrograph of polygonal domains of furrowed membranes. They are aligned at acute angles to the long axis of the fibers. (From Kuszak JR. The ultrastructure of epithelial and fiber cells in the crystalline lens. Int Rev Cytol. 1995;163:305–50.)
average cross-sectional area of approximately 80?µm2 , and those added to form the fetal, infantile, and adult nuclei and the cortex have cross-sectional areas of approximately 35, 14, 7, and 24?µm2 , respectively.  Superficial elongating lens fibers still contain most of the organelles present in epithelial cells. As the fibers are internalized and elongate further, the cell nucleus is displaced anteriorly. The cell nucleus of the newest fiber, therefore, always is located more posteriorly, which results in the formation of a lens bow. Organelles also are lost and, as a result, the principal cytoplasmic components of a mature fiber cell are crystallins and the cytoskeleton.  The cytoskeletal components are almost the same as those found in the epithelial cells, except for an additional structure known as the beaded chain, the function of which is of potentially great interest because of its uniqueness to lens fibers. The cytoskeletal components are not distributed evenly throughout the fiber mass. Although actin is found in all fibers, vimentin, tubulin, and myosin are found only in cortical fibers. Beaded chains, which emerge in the differentiating fibers and are found in all mature fibers, may play a role in the loss of the nucleus. 
Lens fibers are held together by the interlocking of the lateral plasma membranes of adjacent fibers to form ball-and-socket and tongue-and-groove joints. These joints, which are found at regular intervals along the length of their membranes, are characterized by square array membranes. Once matured, fibers have polygonal domains of furrowed membranes along both their broad and narrow faces ( Fig. 28-6 ). Both desmosomes and tight junctions are absent from mature lens fibers, although desmosomes are found between elongating fibers.   Of the protein found in lens fiber plasma membranes, 50–60% is MP26 (approximately 26?kDa). Although this protein is thought to be the major gap junction protein, it has no sequence homology with well-known gap junction proteins. It is found also in other regions of the membrane, in which it is thought to promote cell–cell attachment. It has been suggested that MP70 (approximately 70?kDa) may be the major gap junction protein, but this polypeptide is found only in the outer lens cortex. It is degraded to MP38 (approximately 38?kDa) in the more internal regions of the lens.  
Figure 28-7 Increase in complexity of lens sutures with age. Dotted area represents the inferior suture pattern and is drawn only at the Y-suture stage for simplicity.
Sutures are found at both the anterior and the posterior poles. They are formed by the overlap of ends of secondary fibers in each growth shell. No sutures are found between the primary fibers in the embryonic nucleus. Each growth shell of secondary fibers formed before birth has an anterior suture shaped as an “erect Y” and a posterior suture shaped as an “inverted Y.” Each of these symmetrical sutures is composed of three branches, each 120 degrees apart. The anterior and the posterior suture are offset by 60 degrees. After birth, suture pattern complexity increases with increasing age, because of the addition of progressively more fibers and changes in both fiber length and shape ( Fig. 28-7 ). Although discontinuous suture planes are formed after birth, the sutures remain symmetrical until sexual maturation. During childhood a “simple star” suture with six branches is formed. This changes to a “star” suture with nine branches during adolescence and finally to a “complex star” suture with 12 or more branches during adulthood. Observations of the adult lens indicate that these four different types of suture—Y, simple star, star, and complex star—are found in the fetal, infantile, and adult nuclei, and in the lens cortex, respectively. The formation of sutures enables the shape of the lens to change from spherical to that of a flattened biconvex sphere.  
The formation of the different suture patterns corresponds to the localization of the zones of discontinuity, which are found at both the anterior and the posterior of the lens. There are four of these zones, which originate at approximately 4, 9, 19, and 46 years of age. These zones are initiated at the edge of the lens and then internalized as more new fibers are added at the periphery. They represent regions of increased light scatter due to the loss of structural uniformity. 
The growth of the lens throughout life is a unique characteristic not shared with any other internal organ. The growth rate, which is greatest in the young, diminishes with increasing age. During an average lifespan the surface area of the lens capsule increases from 80?mm2 at birth to 180?mm2 by the seventh decade.  The rate of increase in cell numbers parallels the increase in both mass and dimensions of the lens, and therefore decreases dramatically after the second decade. Numbers of both epithelial cells and fibers increase by approximately 45–50% during the first two decades ( Fig. 28-8 ). After this the increase in cell numbers is reduced, with the proportional increase in fibers being very small.
The weight of the lens rapidly increases from 65?mg at birth to 125?mg by the end of the first year. Lens weight then increases at
Figure 28-8 Increase in lens weight and cell numbers with age. Note the correlation between these two parameters. (Lens weight data from Phelps Brown N, Bron AJ. Lens growth. In Phelps Brown N, Bron AJ, Phelps Brown NA. Lens disorders. A clinical manual of cataract diagnosis. Oxford: Butterworth-Heinemann; 1996:17–31. Cell number data from Kuszak JR, Brown HG. Embryology and anatomy of the lens. In: Albert DM, Jakobiec FA, eds. Principles and practices of ophthalmology. Basic sciences. Philadelphia: WB Saunders; 1994:82–96.)
approximately 2.8?mg/year until the end of the first decade, by which time the lens has reached 150?mg. Thereafter, the mass of the lens increases at a slower rate (1.4?mg/year) to reach about 260?mg by the age of 90 years (see Fig. 28-8 ).  The lenses of men are heavier than those of women of the same age, the mean difference being 7.9 ± 2.47?mg (once adjusted for age).
The equatorial diameter of the human lens increases throughout life, although the rate of increase is reduced significantly after the second decade. The diameter increases from approximately 5?mm at birth to 9–10?mm in a 20 year old. The thickness of the lens increases at a much slower rate than does the equatorial diameter. The distance from the anterior to the posterior poles, which is 3.5–4?mm at birth, increases throughout life, reaching up to 4.75–5?mm (unaccommodated).  The thickness of the nucleus decreases with age, as the result of compaction, whereas cortical thickness increases as more fibers are added at the periphery. Because the increase in cortical thickness is greater than the decrease in size of the nucleus, the polar axis of the lens increases with age. The radius of curvature of the anterior surface decreases from 16?mm at the age of 10 years to 8?mm by the age of 80 years as this surface becomes more curved. There is very little change in the radius of curvature of the posterior surface, which remains at approximately 8?mm.
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