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Connective Tissue


A really diverse group of tissues
:

Connective tissue is the most diverse of the four tissue types with a wide variety of functions. It ranges in consistency from the gel-like softness of areolar connective tissue to the hardness of bone. Blood is also a connective tissue. Connective tissue (CT) forms an extensive compartment in the body and can be considered as the "glue" that holds the body together. Chapter 5 of Ross et al. provides an introduction to connective tissue. A number of the specialized connective tissues (adipose tissue; cartilage; bone; blood and hemopoietic tissue) are discussed under separate chapters (ch. 6-9). Another specialized connective tissue, lymphatic tissue, is described in Chapter 13.

Connective tissues have cells and an extracellular matrix:

Connective tissue consists of cells and extracellular material secreted by some of those cells. Thus, unlike the other basic tissues (epithelia, muscle, nervous), the cells in CT may be widely separated from one another within the extracellular matrix. In many types of connective tissue, the matrix-secreting cells are called fibroblasts. Frequently, an abundance of other cell types (eg. macrophages, mast cells, lymphoid cells) may also be present.

The extracellular matrix consists of ground substance and fibres:


Ground substance
:

The ground substance occupies the space between the cells and fibres of connective tissues. It has a high water content, and in specially prepared sections, has an amorphous appearance. In routine preparations, it is lost during the fixation and dehydration process, and only cells and fibres can be seen. Thus, in typical histological sections, the functional importance of ground substance is not at all evident.

Ground substance consists largely of proteoglycans and hyaluronic acid. Proteoglycans are very large macromolecules, consisting of a core protein to which many glycosaminoglycan (GAG) molecules are covalently attached, somewhat like the bristles around the stem of a bottle brush. GAGs, (which used to be called mucopolysaccharides, a name you might still occasionally encounter), are long-chained polysaccharides made up of repeating disaccharide units. One of the sugars in each disaccharide unit is a hexosamine (also called glycosamine), hence the name GAG. Many of the sugars in GAGs have sulfate and carboxyl groups, which makes them highly negatively charged. The high density of negative charges attracts water, forming a hydrated gel. This gel permits the rapid diffusion of water-soluble molecules but inhibits the movement of large molecules and bacteria. A family of seven distinct GAGs is recognized, based on differences in the specific sugar residues, the nature of the linkages and the degree of sulfation. (A reference table of GAG families, Table 5.3, is found on page 107, ch. 5 of Ross et al. A schematic drawing of GAGs and the organization of ground substance is shown on page 108, Fig. 5.11).

Hyaluronic acid (HA) is itself a GAG, but it differs in several respects from typical GAGs. It is extremely long and rigid, consisting of a chain of several thousand sugars, as opposed to several hundred or less in other GAGs. It also does not bind to a core protein to become part of a proteoglycan. Instead, proteoglycans indirectly bind to HA via special linker proteins, to form giant macromolecules. These hydrophilic macromolecules are particularly abundant in cartilage ground substance, and are responsible for the turgor pressure that gives cartilage its shape.


Fibres
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There are three types of fibres secreted by connective tissue cells: collagen fibres, reticular fibres, and elastic fibres. The abundance and preponderance of different types of fibres varies in different CTs. Each type of fibre is formed by proteins made of long peptide chains.


Collagen fibres
: The most common fibre type is the collagen fibre. These are flexible fibres with a high tensile strength. In typical preparations for the light microscope (LM), they appear as wavy lines of variable width and indeterminate length.

With the electron microscope, collagen fibres are seen to be made up of thread-like subunits called collagen fibrils. Each fibril, in turn, is made up of collagen molecules that are aligned, head to tail, in overlapping rows. Within each row, there is a gap beween the tail of one molecule and the head of the next. The fibril's strength is due to covalent bonds between collagen molecules of adjacent rows - not the head to tail attachment within a row.

The collagen molecule (called tropocollagen) is composed of three intertwined polypeptide chains (each of which is called an alpha chain) that form a right-handed triple helix. Except for the ends of the chain, every third amino acid is a glycine. A hydroxyproline frequently precedes each glycine, and a proline frequently follows each glycine. Sugar groups are associated with the triple helix, so collagen is properly called a glycoprotein. (Figure 5.4, pg. 99 in Ross et al. gives a schematic diagram of the structure of collagen.)

The alpha chains that form the helix are not all alike, and, based on differences within the chains, as many as 16 types of collagen have been identified. They are classified by Roman numerals on the basis of chronology of discovery. Type I collagen is the most prevalent type of collagen, and constitutes about 90% of body collagen. It is the collagen found in the dermis of the skin, bone, tendon, organ capsules and many other areas. The fibres found in cartilage are finer, they consist of type II collagen. Type IV collagen is found in the basal lamina (of basement membrane) of epithelia. There is no need to memorize where the different types of collagen are found. A useful table for reference purposes is found in Ross et al. on page 100.


Reticular fibres
: Reticular fibres are closely related to collagen fibres. They are made of type III collagen fibrils (sometimes in association with type IV collagen). The individual fibrils that constitute the reticular fibre are of narrow diameter and typically do not bundle to form thick fibres. Reticular fibres cannot be identified in routine preparations. They can be displayed with special silver preparations or with the periodic acid-Schiff (PAS) reaction because of their relatively high sugar content.

Reticular fibres were given their name because they are arranged in a mesh-like pattern. They provide a supporting framework for the cellular constituents of various tissues and organs, for example the liver. They are also found at the boundary of the CT and epithelium in loose CT, around adipocytes, small blood vessels, nerves and muscle cells.

In most locations, reticular fibres are produced by fibroblasts. However, the reticular fibres that support the stroma of hemopoietic and lymphatic tissue are made by special cells called reticular cells. Each reticular cell maintains a unique relationship to its fibre, surrounding it with its cytoplasm and thereby isolating it from its environment. (The thymus is an exception, it has no reticular fibres.)

Other areas where reticular fibres are not produced by fibroblasts include the endoneurium of peripheral nerves, where they are produced by Schwann cells (discussed under Nervous Tissue below), the tunica media of blood vessels and the muscularis externa of the alimentary canal. The tunica media and muscularis externa are made up of smooth muscle cells (described under Muscle Tissue below), and it is the smooth muscle cells themselves that secrete all the CT fibre types within those structures.


Elastic fibres
: Elastic fibres are thinner than collagen fibres and are arranged in a branching pattern to form a three dimensional network. They give tissue the ability to cope with stretch and distension. Elastic fibres are interwoven with collagen fibres in order to limit distensibility and to prevent tearing.

Elastic fibres are composed of two structural components: elastin and microfibrils. Elastin is a protein related to collagen but with an unusual polypeptide backbone that causes it to coil in a random way. The configuration of one molecule's coiling is not permanent, it oscillates from one shape to another. The coiled elastin molecule can be stretched. When the force causing the stretch is withdrawn, the molecule recoils back to its former state. Two large amino acids unique to elastin, called desmosine and isodesmosine, cause elastin molecules to covalently bond to one another and form an elastin matrix. The entire matrix is engaged during the stretch and recoil of elastic tissue. (For a schematic drawing, see Fig. 5.9, pg. 104 of Ross et al.)

Microfibrils consist of a fibrillar glycoprotein. In developing elastic tissue, they appear before the elastin, and are believed to serve as an organizing structure for it. (Note: Don't confuse microfibrils, an extracellular structure, with microfilaments, an intracellular structure made of actin.)

Elastic material is found in certain ligaments (elastic ligaments), some cartilage (called elastic cartilage) and in large arteries (elastic arteries). In most cases, the elastic fibres are produced by fibroblasts. In the case of elastic arteries, it is produced by the smooth muscle cells of the tunica media. However, the elastic material produced by the smooth muscle cells does not contain microfibrils, only elastin, and as a result does not form elastic fibres. Instead, the elastin is laid down in fenestrated (having gaps or openings) sheets or lamellae arranged in concentric layers between layers of smooth muscle.

Elastic fibres do not stain very well with eosin and in routine preparations usually cannot be distinguished from collagen fibres. (Certain fixatives cause them to become somewhat refractile, and when this occurs, they can be distinguished from collagen fibres even with H&E staining.) Elastic fibres are selectively stained with special dyes such as orcein and resorcin-fuchsin.


The cells of connective tissues
:

As mentioned above, many different kinds of cells can be found in CTs. In some CTs, there is a large diversity of cell types, in others, the diversity is very low. Some of the cells in CTs are fixed, that is, they are permanent residents in the connective tissue. Other cells are wandering, they are transient migrants who have entered the CT from the blood in response to specific stimuli. The list below summarizes some of the cells commonly found in connective tissues.


Fixed Cells
:


Fibroblasts
: Fibroblasts are the principal cells of connective tissue. They are responsible for the secretion of all types of fibres (collagen, reticular, elastin) and the complex carbohydrates of ground substance. A single fibroblast is believed to be able to secrete all the extracellular components, both sequentially and simultaneously. (A diagrammatic representation of collagen secretion by a fibroblast is shown in Fig. 5.5, pg. 101 of Ross et al.) In routine histological preparations, only the nucleus of the fibroblast can be identified, the cytoplasmic processes blend in with the surrounding collagen. The nucleus appears as an elongated or discoid structure. Like the nucleus of any cell, fibroblast nuclei stain blue with H&E, as nucleic acids avidly bind to basic dyes.


Chondroblasts & chondrocytes
: These are the matrix-secreting cells of cartilage.



Osteoblasts & osteocytes: These are the matrix-secreting cells of bone.


Macrophages
: Macrophages, also called histiocytes, are phagocytic cells derived from monocytes.


Adipose cells
: Also called adipocytes, these cells are specialized to store neutral fat.


Mast cells
: Mast cells have granules containing histamine, heparin and anaphylactic factors. When released in response to an antigen, they cause hypersensitivity reactions, allergy and anaphylaxis.


Undifferentiated mesenchyme cells
: These are cells that retain the multiple potentials of embryonic mesenchyme cells. They are found in the tunica adventitia (the outer layer of CT) of venules.


Wandering Cells
:


Lymphocytes
: These are cells responsible for immune responses that circulate in the blood. Normally, only small numbers are found in the CTs throughout the body. The number increases dramatically at certain sites of tissue inflammation. They are also very numerous in the lamina propria of the respiratory and gastrointestinal tracts, where they are involved in immunosurveillance. The lamina propria is a layer of loose CT lying immediately beneath the epithelium.


Plasma cells
: Plasma cells are derived from B-lymphocytes and produce antibodies against a specific antigen. They have a limited migratory ability and a short life.


Neutrophils
: Neutrophils are white blood cells that act as phagocytes in the early stages of acute inflammation.


Eosinophils
: Eosinophils are white blood cells that are found in the lamina propria of the GI tract, and at sites of allergic reaction and parasitic infection.


Basophils
: Basophils are white blood cells that are similar to mast cells in having vasoactive agents released in response to an allergen.


Monocytes
: Monocytes are white blood cells that will give rise to all the phagocytes of the mononuclear phagocytic system (see Ross et al., pg. 110, and Table 5.4, pg. 112). In CT, they give rise to macrophages (histiocytes).


Classification of connective tissues
:

Connective tissues are classified on the basis of types and relative abundance of cells, fibres and ground substance, and on the organization of fibres. The images below will introduce you to the diversity of connective tissues. You will study a number of these connective tissues in greater detail in some of the Blocks.


Loose (or areolar) connective tissue

This is a cellular type of connective tissue, with abundant ground substance and thin and relatively sparse fibres. It has a viscous gel-like consistency and is important for the diffusion of oxygen and nutrients from small vessels, and the diffusion of metabolites back to the vessels. The primary location of loose connective tissue is beneath epithelia that line the internal surfaces of the body, in association with the epithelia of glands and around small vessels. It is the initial site at which antigens, bacteria and other agents that have breached an epithelial surface can be destroyed.



ct01.gif (25933 bytes)Figure 1 shows a whole mount of loose connective tissue stained with a special elastic tissue stain. The small darkly staining nuclei belong to fibroblasts. Most of the larger paler nuclei belong to macrophages. A mast cell with granular cytoplasm and a dark nucleus is seen near the centre in the upper part of the field of view. Thin, dark elastic fibres cross the field at many points. Collagen fibres are larger in diameter and not well stained. The ground substance has been removed. In standard H&E sections, elastin fibres would not be identifiable. Macrophages are very variable in appearance depending on whether they are inactive or active, and what they have been engulfing.


ct02.gif (22688 bytes)Figure 2
shows another example of loose connective tissue, this time from the lamina propria of the duodenum(slide 9 in your collection). The lamina propria is the layer of loose CT underlying the epithelium in certain mucous membranes, such as those of the respiratory and alimentary system. A distinguishing feature of a lamina propria is the abundance of lymphocytes. Other cells, eg. plasma cells, eosinophils etc. are also present. In this figure, the top of one villus is seen at the left, and part of an adjacent villus is seen at the right. The lamina propria (LP) with abundant lymphocytes (and other cells) underlies the epithelium (ep).


Dense irregular connective tissue

In dense irregular CT, collagenous fibres make up the bulk of the tissue. Fibroblasts are scarce and usually the only cell type present. Little ground substance is present. The abundance of collagenous fibres gives the tissue strength. The fibres are typically arranged in bundles in various directions (hence irregular), which enables the tissue to withstand various stresses. Dense irregular CT is found on the outside of many organs, in the dermis of the skin and as a distinct layer, called the submucosa, within various organs.


ct03.gif (24826 bytes)Figure 3
shows the dense irregular CT of the dura mater, the outermost of the meninges that surround the spinal cord. Most of the field is occupied by pink-staining collagen fibres, a few flattened fibroblast nuclei (blue) are seen among the fibres.








Dense regular connective tissue

In dense regular CT, collagenous fibres are packed in dense regular arrays, between which lie rows of cells. Dense regular CT is found in tendons (which connect muscles to bones), ligaments (which connect bones to bones, some also contain large amounts of elastic fibres and are called elastic ligaments), and aponeuroses (broad flattened tendons whose fibres are arranged in multiple layers, within each layer the fibres are regularly arranged).


ct04.gif (20299 bytes)Figure 4
shows a longitudinal section through a tendon. Note the abundance of fibroblast nuclei arragned in orderly rows between the collagen bundles, which stain very pale in this section. The fibroblasts in tendons are often called tendinocytes.







Adipose tissue

Adipocytes, which are specialized to store fat, are found throughout loose connective tissue. When adipocytes are the predominant cell present, the tissue is called adipose tissue. In white or unilocular fat, adipocytes contain a single, large lipid inclusion surrounded by a thin layer of cytoplasm. The lipid mass compresses the nucleus to an eccentric position, producing a "signet ring" appearance.


ct05.gif (27817 bytes)Figure 5
demonstrates adipose tissue in a whole mount of mesentery using a lipid soluble Sudan stain. The lipids are stained red. A faint edge of cytoplasm can be seen around the fat droplets at the right. Fibroblast and other nuclei can be seen within the mesentery. In your paraffin embedded slides, all the fat has been removed and the fat cells appear as empty circles, in which a peripheral nucleus (signet ring) can often be identified.




A different kind of adipose tissue is known as brown or multilocular fat. Brown fat contains fat droplets of varying sizes. The cells are smaller than those of white fat, with an eccentric but not flattened nucleus. Brown fat has a very limited distribution in adult humans, but is found in many animals. In hibernating animals, the oxidation of brown fat warms the blood flowing through it during arousal from hibernation. Human newborns, whose large surface to volume ratio can result in heat loss, also have alot of brown fat. Most of it disappears during the first decade of life.



ct06.gif (27788 bytes)Figure 6
shows a section of brown fat from a gerbil. Fat droplets of varying size lie within the cells. The cells are tightly packed and boundaries are not always distinct. The lower third of the field of view is occupied by a pair of white fat cells.









Cartilage

Cartilage is a connective tissue whose cells, called chondrocytes, secrete a very specialized matrix. The basophilia of the matrix is due to the GAGs in its ground substance, specifically hyaluronic acid, chondroitin sulfate and keratan sulfate. Collagen (type II) fibrils are also present in the matrix, but are not distinguishable as their refractive index is almost identical to that of the ground substance. The chondrocytes sit in spaces called lacunae, which they fill during life. However, during tissue preparation, chondrocytes shrink and frequently fall out, and lacuna appear only partially filled or empty. Cartilage is described in much greater detail in the MSK Block.

 

ct07.gif (28760 bytes)Figure 7 shows the most common type of cartilage, known as hyaline cartilage. The chondrocytes are seen in clusters, called isogenous groups. The outer surface of cartilage is covered with a dense connective tissue called the perichondrium, which is seen at the top of the field of view.






ct08.gif (31304 bytes)Figure 8 shows a section of elastic cartilage, stained with a special elastin stain. This type of cartilage is similar to hyaline cartilage but has, in addition to the other components, abundant elastic fibres and lamellae. The elastic components stain very deeply, other features are a bit more difficult to see than in the previous figure. The shrunken chondrocytes stain very pale within their lacunae. Elastic cartilage is found in a limited number of sites, including the external ear, epiglottis, eustachean tube and larynx.




ct09.gif (25474 bytes)Figure 9 shows a section of fibrocartilage, which consists of chondrocytes in combination with dense connective tissue. The aggregates of isogenous groups are indicative of cartilage, and in this section fibrous "tails" penetrate the matrix between them. Often the chondrocytes in fibrocartilage lie in straight rows between regularly arranged collagen fibres. The amount of cartilage to dense connective tissue can vary. The presence of fibrocartilage indicates that resistance to compression as well as to shear forces is required. Some of the areas where it is found are the intervertebral disks, the symphysis pubis, and certain places where tendons attach to bone.






Bone

Bone is a connective tissue that is characterized by a mineralized extracellular matrix. The matrix is secreted by cells called osteocytes. It consists mostly of mineralized collagen fibres arranged in lamellae. What little ground substance is present is also mineralized. Bone is described in greater detail in the MSK Block.


ct10.gif (32697 bytes)Figure 10
shows a ground section of compact bone, one of the two types of mature bone. Compact bone consists of numerous units called osteons or Haversian systems, one of which is shown entirely, parts of others are seen at the bottom of the figure. Each osteon consists of a central Haversian canal which contains its vascular and nerve supply (the pale central structure in this figure) around which lamellae of collagen fibres are concentrically arrayed. Osteocytes lie in lacunae between the lamellae and make contact with other osteocytes, and ultimately the Haversian canal, via cell processes which they extend in little channels or canaliculi. Here, the lacunae are filled with air and grinding compound (the osteocytes are long gone) and appear black, the canaliculi are seen as fine dark "hairs" extending between lacunae.

Osteons run parallel to the long axis of long bones. Different osteons are connected to one other by transverse channels which run between Haversian canals and ultimately make contact with the bone's marrow cavity. Most of the nourishment for the bone is supplied by vessels in the marrow cavity.


ct11.gif (34656 bytes)Figure 11
shows the other type of mature bone: spongy bone. In spongy bone, the lamellae of collagen run parallel to one another within irregularly shaped spicules or trabeculae. The bone spicules are seen here as solid pink structures, the osteocytes are the little specks within them. The spaces between the spicules are filled with red bone marrow which is actively involved in red blood cell formation. (In older animals, much of the red marrow is replaced with yellow marrow, which consists mainly of adipose tissue.)

Compact and spongy bone are found in specific sites. In long bones, there is a margin of spongy bone around the central marrow cavity, the rest of the long axis or diaphysis consists of compact bone. The ends of the bone, or epiphyses, are filled with spongy bone, with a shell of compact bone around them. Compact and spongy bones should be thought of as different forms of the same tissue (same cells, same matrix, different arrangement). When bone spicules become sufficiently large, osteons start to form within them.


Hemopoietic tissue

The only hemopoietic tissue in the adult is red bone marrow. Red bone marrow gives rise to red blood cells, granulocytes (neutrophils, eosinophils and basophils), monocytes and platelets. Lymphocytes are formed both in the red bone marrow and in lymphatic tissue. Hemopoietic tissue and lymphatic tissue will be studied in greater detail in other Blocks. Red bone marrow (hemopoietic tissue) is seen above in Figure 11.


Blood

Blood is a fluid connective tissue that circulates throught the body. It functions in bringing nutrients and oxygen to tissues, removing waste products, transporting a large number of products including hormones and immunogenic agents, and maintaining homeostasis. The white cells found in blood are shown in the images below.


ct12.gif (30129 bytes)Figure 12
shows a blood smear in which three neutrophils and one basophil are found among the red blood cells. Both neutrophils and basophils are granulocytes. Neutrophils have lobulated nuclei, typically between 2-5 lobes, and small pale granules in their cytoplasm. Neutrophils are the most numerous of the first wave of cells to enter an imflamed site, they engage in phagocytosis. The two lower neutrophils show drumsticks or Barr bodies, indicating female sex. Basophils typically have a "blueberry muffin" appearance. Their abundant, basophilic granules usually obscure the nucleus, which is lobulated. The granules contain hydrolytic enzymes, heparan sulfate, histamine and slow-reacting substance (SRS) of anaphylaxis. Neutrophils are the most abundant (55-60%), and basophils the least abundant (0.5%) of white blood cells.


ct13.gif (22670 bytes)Figure 13
shows the other type of granulocyte, an eosinophil and a few platelets. (There is also an artefact, a brown speck near the middle right.) Eosinophils typically have bilobed nuclei and large, refractile eosinophilic granules in their cytoplasm. They form 2-5% of the WBC population. The granules contain peroxidase, histaminase, arylsulfatase and other hydrolytic enzymes. Eosinophils moderate the potentially deleterious effects of inflammatory vasoactive agents. They also phagocytise antigen-antibody complexes, and large numbers are found in individuals suffering from allergies and parasitic infections. They are also abundant in the lamina propria of the intestinal tract.

Platelets are involved in the clotting of blood. They are membrane-bound, enucleate cytoplasmic fragments that have broken off from large polyploid cells called megakaryocytes, found in bone marrow.


ct14.gif (23263 bytes)Figure 14
shows one small and one medium lymphocyte, one of the two kinds of agranular white blood cells. Three groups of lymphocytes are recognized with respect to size: small, medium and large. Lymphocytes are the main functional cells of the immune system and represent 30-35% of white blood cells. The vast majority of lymphocytes in the bloodstream are small (90%), most of the rest are medium.

Small lymphocytes have an intensely staining, more or less spherical nucleus with a thin blue rim of cytoplasm around it. Larger lymphocytes have a larger, less intensely staining nucleus and a greater amount of cytoplasm.


ct15.gif (24142 bytes)Figure 15
shows a monocyte (the other type of agranulocyte) and other white blood cells. The monocytes is at the right, a neutrophil is in the centre, and a small lymphocytes is at the left. A few platelets are also seen.

Monocytes are the largest of the WBCs in blood, and the precursor of all the cells of the mononuclear phagocytic system (see Ross et al., pg. 110). They represent 3-7% of WBCs. It is sometimes difficult to distinguish monocytes from larger lymphocytes. The nucleus of monocytes is typically more indented than that of lymphocytes. The cytoplasm tends to have a gray or blue tint due to the presence of fine azurophilic granules which contain lysosomes. (Despite these granules, monocytes are classified as agranulocytes).


Lymphatic tissue

ct16.gif (35137 bytes)You will be studying the lymphatic organs in the Immunology Block. Figure 16 shows aggregations of lymphocytes (lymph nodules) separated by sinuses in a lymph node. Cytological detail is not good in this section as it is stained with silver to demonstrate the reticular fibres that form a fine supporting meshwork throughout the parenchyma of the organ. (A gross framework, not seen here, is formed by a capsule of dense connective tissue from which dense CT trabeculae extend into the node.)


Embryonic connective tissue

ct17.gif (22993 bytes)Figure 17 shows mesenchyme, the undifferentiated connective tissue found in the early embryo. Mesenchyme gives rise to all the connective tissue of the body, as well as to some other tissue (muscle, vascular and urogenital systems, and the serous membranes of body cavities). Most mesenchyme is derived from mesoderm. In the head region, some mesenchyme is derived from neural crest cells (and hence from ectoderm). (You will be learning some embryology in the H&D Block, and the terms mesoderm, ectoderm and neural crest will be explained.)

Mesenchyme contains fairly uniform appearing, small spindle-shaped cells whose processes extend and contact those of other cells to form a three dimensional cellular network. Gap junction are present where processes make contact. A semi-fluid ground substance fills the extracellular spaces. Fibres are present, but are very fine and sparse as the embryo is subjected to only limited physical stress.

A slightly different connective tissue, called mucous connective tissue or Wharton's jelly, is present in the umbilical cord and in embryonic subcutaneous tissue. (Its adult counterpart is found in the vitreous body of the eye.) In mucous CT, the ground substance is more viscous or jelly-like than in mesenchyme. Fibroblasts are the predominant cell type, and the number of fibres increases with age.




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