Anatomy of Bones

First Edition, 2012
ISBN 978-81-323-1371-7
All rights reserved. Published by: College Publishing House 4735/22 Prakashdeep Bldg, Ansari Road, Darya Ganj, Delhi - 110002 Email: info@wtbooks.com
Table of Contents
Chapter 1 - Frontal Bone and Parietal Bone Chapter 2 - Temporal Bone and Occipital Bone Chapter 3 - Sphenoid Bone and Ethmoid Bone Chapter 4 - Maxilla Chapter 5 - Palatine Bone Chapter 6 - Zygomatic Bone Chapter 7 - Nasal Bone Chapter 8 - Lacrimal Bone Chapter 9 - Vomer Chapter 10 - Stapes and Incus Chapter 11 - Hyoid Bone Chapter 12 - Scapula Chapter 13 - Clavicle Chapter 14 - Rib Chapter 15 - Humerus Chapter 16 - Radius (Bone) Chapter 17 - Anatomy of Bone Marrow Chapter 18 - Types of Stem Cells Chapter 19 - Hematopoietic Stem Cell Transplantation
Chapter 1
Frontal Bone and Parietal Bone
Frontal bone
Bone: Frontal bone
Frontal bone highlighted in red
os frontale subject #33 135 twelve bones: the sphenoid, the ethmoid, the two parietals, the Articulations two nasals, the two maxill, the two lacrimals, and the two zygomatics Frontal+Bone MeSH Latin Gray's The frontal bone is a bone in the human skull that resembles a cockleshell in form, and consists of two portions:

a vertical portion, the squama frontalis, corresponding with the region of the forehead. an orbital or horizontal portion, the pars orbitalis, which enters into the formation of the roofs of the orbital and nasal cavities.
Embryology
The frontal bone is presumed to be derived from neural crest cells.
Borders
The border of the squama frontalis is thick, strongly serrated, bevelled at the expense of the inner table above, where it rests upon the parietal bones, and at the expense of the outer table on either side, where it receives the lateral pressure of those bones; this border is continued below into a triangular, rough surface, which articulates with the great wing of the sphenoid. The posterior borders of the orbital plates are thin and serrated, and articulate with the small wings of the sphenoid.
In other animals
In most vertebrates, the frontal bone is paired, rather than presenting the single, fused structure found in humans. It typically lies on the upper part of the head, between the eyes, but in many non-mammalian animals it does not form part of the orbital cavity. Instead, in reptiles, bony fish and amphibians it is often separated from the orbits by one or two additional bones not found in mammals. These bones, the prefrontals and postfrontals, together form the upper margin of the eye sockets, and lie to either side of the frontal bones.
Parietal bone
Bone: Parietal bone
Figure 1 : Left parietal bone. Outer surface.
Figure 2 : Left parietal bone. Inner surface.
Latin Gray's MeSH
os parietale subject #32 133 Parietal+bone
The parietal bones are bones in the human skull and form, by their union, the sides and roof of the cranium. Each bone is irregularly quadrilateral in form, and has two surfaces, four borders, and four angles. It is named from the Latin pariet-, wall.
Surfaces
External
The external surface [Fig. 1] is convex, smooth, and marked near the center by an eminence, the parietal eminence (tuber parietale), which indicates the point where ossification commenced. Crossing the middle of the bone in an arched direction are two curved lines, the superior and inferior temporal lines; the former gives attachment to the temporal fascia, and the latter indicates the upper limit of the muscular origin of the temporalis. Above these lines the bone is covered by the galea aponeurotica (epicranial aponeurosis); below them it forms part of the temporal fossa, and affords attachment to the temporalis muscle. At the back part and close to the upper or sagittal border is the parietal foramen, which transmits a vein to the superior sagittal sinus, and sometimes a small branch of the occipital artery; it is not constantly present, and its size varies considerably.
Internal
The internal surface [Fig. 2] is concave; it presents depressions corresponding to the cerebral convolutions, and numerous furrows (grooves) for the ramifications of the
middle meningeal artery; the latter run upward and backward from the sphenoidal angle, and from the central and posterior part of the squamous border. Along the upper margin is a shallow groove, which, together with that on the opposite parietal, forms a channel, the sagittal sulcus, for the superior sagittal sinus; the edges of the sulcus afford attachment to the falx cerebri. Near the groove are several depressions, best marked in the skulls of old persons, for the arachnoid granulations (Pacchionian bodies). In the groove is the internal opening of the parietal foramen when that aperture exists.
Borders
The sagittal border, the longest and thickest, is dentated (has toothlike projections) and articulates with its fellow of the opposite side, forming the sagittal suture. The squamous border is divided into three parts: of these: o the anterior is thin and pointed, bevelled at the expense of the outer surface, and overlapped by the tip of the great wing of the sphenoid; o the middle portion is arched, bevelled at the expense of the outer surface, and overlapped by the squama of the temporal; o the posterior part is thick and serrated for articulation with the mastoid portion of the temporal. The frontal border is deeply serrated, and bevelled at the expense of the outer surface above and of the inner below; it articulates with the frontal bone, forming half of the coronal suture. The point where the coronal suture intersects with the sagittal suture forms a T-shape and is called the bregma. The occipital border, deeply denticulated (finely toothed), articulates with the occipital bone, forming half of the lambdoid suture. That point where the sagittal suture intersects the lambdoid suture is called the lambda, because of its resemblance to the Greek letter.
Angles
The frontal angle is practically a right angle, and corresponds with the point of meeting of the sagittal and coronal sutures; this point is named the bregma; in the fetal skull and for about a year and a half after birth this region is membranous, and is called the anterior fontanelle. The sphenoidal angle, thin and acute, is received into the interval between the frontal bone and the great wing of the sphenoid. Its inner surface is marked by a
deep groove, sometimes a canal, for the anterior divisions of the middle meningeal artery.
The occipital angle is rounded and corresponds with the point of meeting of the sagittal and lambdoidal suturesa point which is termed the lambda; in the fetus this part of the skull is membranous, and is called the posterior fontanelle. The mastoid angle is truncated; it articulates with the occipital bone and with the mastoid portion of the temporal, and presents on its inner surface a broad, shallow groove which lodges part of the transverse sinus. The point of meeting of this angle with the occipital and the mastoid part of the temporal is named the asterion.
Ossification
The parietal bone is ossified in membrane from a single center, which appears at the parietal eminence about the eighth week of fetal life. Ossification gradually extends in a radial manner from the center toward the margins of the bone; the angles are consequently the parts last formed, and it is here that the fontanelles exist. Occasionally the parietal bone is divided into two parts, upper and lower, by an anteroposterior suture.
In other animals
In non-human vertebrates, the parietal bones typically form the rear or central part of the skull roof, lying behind the frontal bones. In many non-mammalian tetrapods, they are bordered to the rear by a pair of postparietal bones that may be solely in the roof of the skull, or slope downwards to contribute to the back of the skull, depending on the species. In the living tuatara, and many fossil species, a small opening, the parietal foramen, lies between the two parietal bones. This opening is the location of a third eye in the midline of the skull, which is much smaller than the two main eyes.
Cranial bones
Side view of the skull
Base of the skull. Upper surface.
Sagittal section of skull
Chapter 2
Temporal Bone and Occipital Bone
Temporal bone
Bone: Temporal bone
Cranial bones
Facial bones.
os temporale subject #34 138 occipital, parietal, sphenoid, Articulations mandible and zygomatic Latin Gray's The temporal bones are situated at the sides and base of the skull, and lateral to the temporal lobes of the cerebrum.
The temporal bone supports that part of the face known as the temple.
Parts
The temporal bone consists of four parts:

Squama temporalis Mastoid portion Petrous portion (Petrosal ridge) Tympanic part
Composition
The structure of the squama is like that of the other cranial bones: the mastoid portion is spongy, and the petrous portion dense and hard.
left temporal bone. Prepared and articulate
The skull from the front
Sphenoid bone visible center right
Left infratemporal fossa
Articulation of the mandible. Lateral aspect.
Base of the skull. Upper surface.
In other animals
In evolutionary terms, the temporal bone is derived from the fusion of many bones that are often separate in non-human mammals:
The squamosal bone, which is homologous with the squama, and forms the side of the cranium in many bony fish and tetrapods. Primitively, it is a flattened platelike bone, but in many animals it is narrower in form, for example, where it forms the boundary between the two temporal fenestrae of diapsid reptiles. The petrous and mastoid parts of the temporal bone, which derive from the periotic bone, formed from the fusion of a number of bones surrounding the ear of
reptiles. The delicate structure of the middle ear, unique to mammals, is generally not protected in marsupials, but in placentals, it is usually enclosed within a bony sheath called the auditory bulla. In many mammals this includes a separate tympanic bone derived from the angular bone of the reptilian lower jaw, and, in some cases, an additional entotympanic bone. The auditory bulla is homologous with the tympanic part of the temporal bone. Two parts of the hyoid arch: the styloid process. In the dog the styloid process is represented by a series of 4 articulating bones, from top down tympanohyal, stylohyal, epihyal, ceratohyal; the first two represent the styloid process, and the ceratohyal represents the anterior horns of the hyoid bone and articulates with the basihyal which represents the body of the hyoid bone.
Occipital bone
Bone: Occipital bone
Sagittal section of skull. (Occipital bone is at right, in blue.)
Base of the skull. Upper surface. (Occipital bone is at bottom, in blue.)
os occipitale subject #31 129 the two parietals, the two Articulations temporals, the sphenoid, and the atlas Latin Gray's The occipital bone, a saucer-shaped membrane bone situated at the back and lower part of the cranium, is trapezoidal in shape and curved on itself. It is pierced by a large oval aperture, the foramen magnum, through which the cranial cavity communicates with the vertebral canal.

The curved, expanded plate behind the foramen magnum is named the squama occipitalis. The thick, somewhat quadrilateral piece in front of the foramen is called the basilar part of occipital bone. On either side of the foramen are the lateral parts of occipital bone.
Foramen magnum
The foramen magnum (Latin for large hole) is a large oval aperture with its long diameter antero-posterior; it is wider behind than in front where it is encroached upon by the condyles.
It transmits the medulla oblongata and its membranes, the accessory nerves, the vertebral arteries, the anterior and posterior spinal arteries, and the membrana tectoria and alar ligaments.
Angles
The superior angle of the occipital bone articulates with the occipital angles of the parietal bones and, in the fetal skull, corresponds in position with the posterior fontanelle. The inferior angle is fused with the body of the sphenoid. The lateral angles are situated at the extremities of the grooves for the transverse sinuses: each is received into the interval between the mastoid angle of the parietal and the mastoid part of the temporal.
Borders
The superior borders extend from the superior to the lateral angles: they are deeply serrated for articulation with the occipital borders of the parietals, and form by this union the lambdoidal suture. The inferior borders extend from the lateral angles to the inferior angle; the upper half of each articulates with the mastoid portion of the corresponding temporal, the lower half with the petrous part of the same bone. These two portions of the inferior border are separated from one another by the jugular process, the notch on the anterior surface of which forms the posterior part of the jugular foramen.
Structure
The occipital, like the other cranial has outer and inner tables, between which is the cancellous tissue or diplo; the bone is especially thick at the ridges, protuberances, condyles, and anterior part of the basilar part; in the inferior foss it is thin, semitransparent, and destitute of diplo.
In other animals
The occipital bone is part of the endocranium, the most basal portion of the skull. In Chondrichthyes and Agnathans, the occipital do not form as a separate element, but remain part of the chondrocranium throughout life. In most higher vertebrates, the foramen magnum is surrounded by a ring of four bones. The basioccipital lies in front of the opening, the two exoccipitals lie to either side, and the larger supraoccipital lies to the posterior, and forms at least part of the rear of the cranium. In many bony fish and amphibians, the supraoccipital is never ossified, and remains as cartilage throughout life. In primitive forms the basioccipital and exoccipitals somewhat resemble the centrum and neural arches of a vertebra, and form in a similar manner in the embryo. Together, these
latter bones usually form a single concave circular condyle for the articulation of the first vertebra. In mammals, however, the condyle has divided in two, a pattern otherwise seen only in a few amphibians. Most mammals also have a single fused occipital bone, formed from the four separate elements around the foramen magnum, along with the paired postparietal bones that form the rear of the cranial roof in other vertebrates.
Base of skull. Inferior surface.
Cranial bones
Membrana tectoria, transverse, and alar ligaments
Median sagittal section through the occipital bone and first three cervical vertebr
Muscles connecting the upper extremity to the vertebral column
Upper part of medulla spinalis and hind- and mid-brains; posterior aspect, exposed in situ
Muscles of the pharynx, viewed from behind, together with the associated vessels and nerves.
Chapter 3
Sphenoid Bone and Ethmoid Bone
Sphenoid bone
Bone: Sphenoid bone
Cranial Bones. Only the end of the wing of the sphenoid bone is visible
Sphenoid bone, upper surface.
Latin Gray's MeSH
os sphenoidale subject #35 147 Sphenoid+Bone
The sphenoid bone (from Greek sphenoeides, "wedgelike") is an unpaired bone situated at the base of the skull in front of the temporal bone and basilar part of the occipital bone. The sphenoid bone is one of the seven bones that articulate to form the orbit. Its shape somewhat resembles that of a butterfly or bat with its wings extended.
Portions
It is divided into the following parts:

a median portion, known as the body of sphenoid bone, containing the sella turcica which houses the pituitary gland two greater wings and two lesser wings Pterygoid processes of the sphenoides which project from it posteriorly (below)
Two sphenoidal conchae are situated at the anterior and posterior part of the body.
Seven bones articulate to form the orbit. The sphenoid bone is one of them, labeled with pink
Named features

pterygoid notch pterygoid fossa scaphoid fossa pterygoid hamulus pterygoid canal
pterygospinous process
In other animals
The sphenoid bone of humans is homologous with a number of bones that are often separate in other animals, and have a somewhat complex arrangement. In the early lobe-finned fishes and tetrapods, the pterygoid bones were flat, wing-like bones forming the major part of the roof of the mouth. Above the pterygoids were the epipterygoid bones, which formed part of a flexible joint between the braincase and the palatal region, as well as extending a vertical bar of bone towards the roof of the skull. Between the pterygoids lay an elongated, narrow parasphenoid bone, which also spread over some of the lower surface of the braincase, and connected, at its forward end, with a sphenethmoid bone helping to protect the olfactory nerves. Finally, the basisphenoid bone formed part of the floor of the braincase and lay immediately above the parasphenoid. Aside from the loss of the flexible joint at the rear of the palate, this primitive pattern is broadly retained in reptiles, albeit with some individual modifications. In birds, the epipterygoids are absent and the pterygoids considerably reduced. Living amphibians have a relatively simplified skull in this region; a broad parasphenoid forms the floor of the braincase, the pterygoids are relatively small, and all other related bones except the sphenethmoid are absent. In mammals, these various bones are often (though not always) fused into a single structure; the sphenoid. The basisphenoid forms the posterior part of the base, while the pterygoid processes represent the pterygoid bones. The epipterygoids have extended into the wall of the cranium; they are referred to as alisphenoids when separate in mammals, and form the greater wings of the sphenoid when fused into a larger structure. The sphenethmoid bone forms as three bones: the lesser wings and the anterior part of the base. These two parts of the sphenethmoid may be distinguished as orbitosphenoids and presphenoid, respectively, although there is often some degree of fusion. Only the parasphenoid appears to be entirely absent in mammals. In the dog the sphenoid is represented by 8 bones: basisphenoid, alisphenoids, presphenoid, orbitosphenoids, pterygoids.
Facial bones
Lateral wall of nasal cavity, showing ethmoid bone in position
Lateral view of the skull
Horizontal section of nasal and orbital cavities
Floor of the skull
Roof, floor, and lateral wall of left nasal cavity
The skull from the front. The sphenoid is labeled with yellow to the left of the picture, both in the orbit and behind the zygomatic process
Ethmoid bone
Bone: Ethmoid bone
Cranial bones
The seven bones which articulate to form the orbit. (Ethmoid is brown)
Latin Gray's MeSH
os ethmoidale subject #36 153 Ethmoid+bone
The ethmoid bone (from Greek ethmos, "sieve") is a bone in the skull that separates the nasal cavity from the brain. As such, it is located at the roof of the nose, between the two orbits. The cubical bone is lightweight due to a spongy construction. The ethmoid bone is one of the bones that makes up the orbit of the eye. The ethmoid has three parts: the cribriform plate, the ethmodial labyrinth, and the perpendicular plate
Articulations
The ethmoid articulates with fifteen bones:
four of the neurocraniumthe frontal, and the sphenoid (at the sphenoidal body and at the sphenoidal conchae). eleven of the viscerocranium, two Nasal bones, two maxillae, two lacrimals, two palatines, two inferior nasal conchae, and the vomer
Injuries
Fracture of the lamina papyracea, the lateral plate of the ethmoid labyrinth bone, permits communication between the nasal cavity and the ipsilateral orbit through the inferomedial orbital wall, resulting in orbital emphysema. Increased pressure within the nasal cavity, as seen during sneezing, for example, leads to temporary exophthalmos. The porous, fragile nature of the ethmoid bone makes it particularly susceptible to fractures. The ethmoid is usually fractured from an upward force to the nose. This could occur by hitting the dashboard in a car crash or landing on the ground after a fall. The ethmoid fracture can produce bone fragments that penetrate the cribriform plate. This trauma can lead to a leak of cerebral spinal fluid into the nasal cavity. These openings allow for opportunistic bacteria in the nasal cavity to enter the sterile environment of the central nervous system (CNS). The CNS is usually protected by the blood brain barrier, but holes in the cribriform plate allow bacteria to surpass the barrier. The blood brain barrier makes it extremely difficult to treat such infections because only certain drugs can cross in the CNS. An ethmoid fracture can also sever the olfactory nerve. This injury results in anosmia, or the loss of smell. A reduction in the ability to taste is also a side effect because it is based so heavily on smell. This injury is not fatal.
Role in magnetoception
Some birds and other migratory animals have deposits of biological magnetite in their ethmoid bones which allow them to sense the direction of the Earth's magnetic field. Humans have a similar magnetite deposit, but it is believed to be vestigial.
Ethmoid bone from above
Perpendicular plate of ethmoid
Ethmoid bone (frontal view)
Ethmoid bone from the right side
Medial wall of left orbit
Medial wall of left nasal fossa
Ethmoid bone
Chapter 4
Maxilla
Bone: Maxilla
Side view. Maxilla visible at bottom left, in green.
Front view. Maxilla visible at center, in yellow.
Gray's Precursor MeSH
subject #38 157 1st branchial arch Maxilla
Dorlands / Elsevier
Maxilla
The maxilla (plural: maxillae), also known as the mustache bone, is a fusion of two bones along the palatal fissure that form the upper jaw. This is similar to the mandible (lower jaw), which is also a fusion of two halves at the mental symphysis. Sometimes (e.g. in bony fish), the maxilla is sometimes called "upper maxilla," with the mandible being the "lower maxilla." Conversely, in birds the upper jaw is often called "upper mandible."
Function
The alveolar process of the maxilla holds the upper teeth, and is referred to as the maxillary arch. The maxilla attaches laterally to the zygomatic bones (cheek bones). The maxilla assists in forming the boundaries of three cavities:

the roof of the mouth the floor and lateral wall of the nasal antrum the wall of the orbit
The maxilla also enters into the formation of two fossae: the infratemporal and pterygopalatine, and two fissures, the inferior orbital and pterygomaxillary.
Components
Each half of the fused maxilla consists of:

The body of the maxilla Four processes o The zygomatic process o The frontal process of maxilla o The alveolar process o The palatine process Infraorbital foramen The maxillary sinus
Articulations
The maxilla articulates with nine bones:

two of the cranium: the frontal and ethmoid seven of the face: the nasal, zygomatic, lacrimal, inferior nasal concha, palatine, vomer, and the adjacent fused maxillary bone.
Sometimes it articulates with the orbital surface, and sometimes with the lateral pterygoid plate of the sphenoid.
In other animals
In most vertebrates, the foremost part of the upper jaw, to which the incisors are attached in mammals consists of a separate pair of bones, the premaxillae. These fuse with the maxilla proper to form the bone found in humans, and some other mammals. In bony fish, amphibians, and reptiles, both maxilla and premaxilla are relatively plate-like bones, forming only the sides of the upper jaw, and part of the face, with the premaxilla also forming the lower boundary of the nostrils. However, in mammals, the bones have curved inward, creating the palatine process and thereby also forming part of the roof of the mouth. Birds do not have a maxilla in the strict sense; the corresponding part of their beaks (mainly consisting of the premaxilla) is called "upper mandible." Cartilagenous fish, such as sharks also lack a true maxilla. Their upper jaw is instead formed from a cartilagenous bar that is not homologous with the bone found in other vertebrates.
Facial bones
Left maxilla. Outer surface.
Left maxillary sinus opened from the exterior
Left maxilla. Nasal surface.
Side view of the teeth and jaws
The bony palate and alveolar arch
Articulation of left palatine bone with maxilla
Chapter 5
Palatine Bone
Bone: Palatine bone
Permanent teeth of upper dental arch, seen from below. (Horizontal part of palatine bone visible at bottom.)
Sagittal section of skull. (Palatine bone is labeled at bottom left.)
Gray's MeSH
subject #41 166 Palatine+Bone
The palatine bone is a bone in many species of the animal kingdom, commonly termed the palatum (Latin palatum; unrelated to palatium 'palace', from which other senses of palatine derive).
Human anatomy
It is situated at the back part of the nasal cavity between the maxilla and the pterygoid process of the sphenoid. It contributes to the walls of three cavities: the floor and lateral wall of the nasal cavity, the roof of the mouth, and the floor of the orbit; it enters into the formation of two foss, the pterygopalatine and pterygoid foss; and one fissure, the inferior orbital fissure. The palatine bone somewhat resembles the letter L, and consists of a Horizontal plate of palatine bone and a Perpendicular plate of palatine bone and three outstanding processesviz., the Pyramidal process of palatine bone, which is directed backward and lateralward from the junction of the two parts, and the Orbital process of palatine bone and Sphenoidal process of palatine bone, which surmount the vertical part, and are separated by a deep notch, the sphenopalatine notch. The human palatine articulates with six bones: the sphenoid, ethmoid, maxilla, inferior nasal concha, vomer and opposite palatine.
In other animals
In bony fish the palatine bone consists of the perpendicular plate only, lying on the inner edge of the maxilla. The lower surface of the bone may bear several teeth, forming a second row behind those of the maxilla; in many cases, these are actually larger than the maxillary teeth. Although a similar pattern was present in primitive tetrapods, the palatine bone is reduced in most living amphibians, forming, in frogs and salamanders, only a narrow bar between the vomer and maxilla. Early fossil reptiles retained the arrangement seen in more primitive vertebrates, but in mammals, the lower surface of the palatine became folded over during evolution, forming the horizontal plate, and meeting in the midline of the mouth. This forms the rear of the hard palate, separating the oral and nasal cavities, and making it easier to breathe while eating. A parallel development has occurred to varying degrees in many living reptiles, reaching its greatest extent in crocodilians. In birds, the palatine bones remain separate, long the sides of the rear part of the upper jaw, and typically have a mobile articulation with the cranium. There are numerous variations amongst mammals, amphibians and other species. For example, the palatine bone in many amphibians such as the Rough-skinned Newt manifests as a distinct V-shaped structure. In the case of cat species, the horizontal and a vertical elements join at a forty five degree angle.
Articulation of left palatine bone with maxilla
Chapter 6
Zygomatic Bone
Bone: Zygomatic bone
Left zygomatic bone in situ.
Side view of the teeth and jaws. (Zygomatic visible in center.)
Latin Gray's
os zygomaticum, zygoma subject #40 164
The zygomatic bone (cheekbone, malar bone) is a paired bone of the human skull. It articulates with the maxilla, the temporal bone, the sphenoid bone and the frontal bone.
The zygomatic is homologous to the jugal bone of other tetrapods. It is situated at the upper and lateral part of the face and forms the prominence of the cheek, part of the lateral wall and floor of the orbit, and parts of the temporal and infratemporal fossa. It presents a malar and a temporal surface; four processes, the frontosphenoidal, orbital, maxillary, and temporal; and four borders. The term zygomatic derives from the Greek zygoma meaning "yoke". The zygomatic bone is occasionally referred to as the zygoma, but this term may also refer to the zygomatic arch or the zygomatic process.
Surfaces
The malar surface is convex and perforated near its center by a small aperture, the zygomaticofacial foramen, for the passage of the zygomaticofacial nerve and vessels; below this foramen is a slight elevation, which gives origin to the Zygomaticus. The temporal surface, directed posteriorly and medially, is concave, presenting medially a rough, triangular area, for articulation with the maxilla (articular surface), and laterally a smooth, concave surface, the upper part of which forms the anterior boundary of the temporal fossa, the lower a part of the infratemporal fossa. Near the center of this surface is the zygomaticotemporal foramen for the transmission of the zygomaticotemporal nerve.
Process
The zygomatic process is a protrusion from the rest of the skull, like the bumper of a car. Most of it belongs to the zygomatic bone, but there are other bones contributing to it too, namely the frontal bone, maxilla and temporal bone.
Borders
The antero-superior or orbital border is smooth, concave, and forms a considerable part of the circumference of the orbit. The antero-inferior or maxillary border is rough, and bevelled at the expense of its inner table, to articulate with the maxilla; near the orbital margin it gives origin to the Quadratus labii superioris. The postero-superior or temporal border, curved like an italic letter f, is continuous above with the commencement of the temporal line, and below with the upper border of the zygomatic arch; the temporal fascia is attached to it. The postero-inferior or zygomatic border affords attachment by its rough edge to the Masseter.
Ossification
The zygomatic bone is generally described as ossifying from three centers - one for the malar and two for the orbital portion; these appear about the eighth week and fuse about the fifth month of fetal life. Mall describes it as being ossified from one center which appears just beneath and to the lateral side of the orbit. After birth, the bone is sometimes divided by a horizontal suture into an upper larger, and a lower smaller division. In some quadrumana the zygomatic bone consists of two parts, an orbital and a malar.
Articulations
The zygomatic articulates with four bones: the frontal, sphenoidal, temporal, and maxilla.
In other animals
In non-mammalian vertebrates, the zygomatic bone is referred to as the jugal bone, since these animals have no zygomatic arch. In coelacanths and early tetrapods the bone is relatively large. Here, it is a plate-like bone forming the lower margin of the orbit and much of the side of the face. In ray-finned fishes it is reduced or absent, and the entire cheek region is generally small. The bone is also absent in living amphibians. With the exception of turtles, the jugal bone in reptiles forms a relatively narrow bar separating the orbit from the inferior temporal fenestra, of which it may also form the lower boundary. The bone is similarly reduced in birds. In mammals, it takes on broadly the form seen in humans, with the bar between the orbit and fenestra vanishing entirely, and only the lower boundary of the fenestra remaining, as the zygomatic arch.
Facial bones
Left zygomatic bone. Malar surface.
Left zygomatic bone. Temporal surface.
Human skull side bones numbered
Left orbicularis oculi, seen from behind.
Beauty
Pronounced cheekbones are seen as a sign of beauty in Western culture.
Chapter 7
Nasal Bone
Bone: Nasal bone
Nasal bone visible at center, in dark green.
Cartilages of the nose. Side view. (Nasal bone visible at
upper left.)
Latin Gray's
os nasale subject #37 156
The nasal bones are two small oblong bones, varying in size and form in different individuals; they are placed side by side at the middle and upper part of the face, and form, by their junction, "the bridge" of the nose. Each has two surfaces and four borders.
Surfaces
The outer surface is concavoconvex from above downward, convex from side to side; it is covered by the Procerus and Compressor naris, and perforated about its center by a foramen, for the transmission of a small vein. The inner surface is concave from side to side, and is traversed from above downward, by a groove for the passage of a branch of the nasociliary nerve.
Articulations
The nasal articulates with four bones: two of the cranium, the frontal and ethmoid, and two of the face, the opposite nasal and the maxilla.
In other animals
In primitive bony fish and tetrapods, the nasal bones are the most anterior of a set of four paired bones forming the roof of the skull, being followed in sequence by the frontals, the parietals, and the postparietals. Their form in living species is highly variable, depending on the shape of the head, but they generally form the roof of the snout or beak, running from the nostrils to a position short of the orbits. In most animals, they are generally therefore proportionally larger than in humans or great apes, because of the shortened faces of the latter. Turtles, unusually, lack nasal bones, with the prefrontal bones of the orbit reaching all the way to the nostrils.
Lateral wall of nasal cavity, showing ethmoid bone in position.
Articulation of nasal and lacrimal bones with maxilla
Right nasal bone. Outer surface.
Right nasal bone. Inner surface.
Close up of side view of the skull
Chapter 8
Lacrimal Bone
Bone: Lacrimal bone
Lacrimal bone visible near center.
Orbital bones. Lacrimal bone shown in green.
Latin Gray's
os lacrimale subject #39 164
The lacrimal bone, the smallest and most fragile bone of the face, is situated at the front part of the medial wall of the orbit. It has two surfaces and four borders.
Surfaces
Lateral or orbital surface
The lateral or orbital surface is divided by a vertical ridge, the posterior lacrimal crest, into two parts. In front of this crest is a longitudinal groove, the lacrimal sulcus (sulcus lacrimalis), the inner margin of which unites with the frontal process of the maxilla, and the lacrimal fossa is thus completed. The upper part of this fossa lodges the lacrimal sac, the lower part, the nasolacrimal duct. The portion behind the crest is smooth, and forms part of the medial wall of the orbit. The crest, with a part of the orbital surface immediately behind it, gives origin to the lacrimal part of the Orbicularis oculi and ends below in a small, hook-like projection, the lacrimal hamulus, which articulates with the lacrimal tubercle of the maxilla, and completes the upper orifice of the nasolacrimal canal; the hamulus sometimes exists as a separate piece, and is then called the lesser lacrimal bone.
Medial or nasal surface

The medial or nasal surface presents a longitudinal furrow, corresponding to the crest on the lateral surface. The area in front of this furrow forms part of the middle meatus of the nose; that behind it articulates with the ethmoid, and completes some of the anterior ethmoidal cells.
Borders
Of the four borders:

the anterior articulates with the frontal process of the maxilla; the posterior with the lamina papyracea of the ethmoid; the superior with the frontal bone. The inferior is divided by the lower edge of the posterior lacrimal crest into two parts: o the posterior part articulates with the orbital plate of the maxilla; o the anterior is prolonged downward as the descending process, which articulates with the lacrimal process of the inferior nasal concha, and assists in forming the canal for the nasolacrimal duct.
Ossification
The lacrimal is ossified from a single center, which appears about the twelfth week in the membrane covering the cartilaginous nasal capsule.
Articulations
The lacrimal articulates with four bones: two of the cranium, the frontal and ethmoid, and two of the face, the maxilla and the inferior nasal concha.
In other animals
In early lobe-finned fishes and ancestral tetrapods, the lacrimal bone is a relatively large and robust bone, running from the orbit to the nostrils. It forms part of the side of the face, between the nasal bones and the maxilla. In primitive forms, it is often accompanied by a much smaller septomaxilla bone, lying immediately behind the nasal opening, but this is lost in most modern species. The lacrimal bone is often smaller in living vertebrates, and is no longer always directly associated with the nasal opening, although it retains its connection with the orbit. The bone is entirely absent in living amphibians, as well as some reptilian species.
Left lacrimal bone. Orbital surface.
Chapter 9
Vomer
Vomer
Vomer labeled at left.
Bones and cartilages of septum of nose. Right side. (Vomer visible at bottom left.) Gray's MeSH subject #43 170 Vomer
The vomer is one of the unpaired facial bones of the skull. It is located in the midsagittal line, and articulates with the sphenoid, the ethmoid, the left and right palatine bones, and the left and right maxillary bones.
Biology
The vomeronasal organ, also called Jacobson's organ, is a chemoreceptor organ named for its closeness to the vomer and nasal bones, and is particularly developed in animals such as cats (who adopt a characteristic pose called the Flehmen reaction or flehming when making use of it), and is thought to have to do with the perception of certain pheromones. It has been suggested that by alternately thrusting with the tongue against the roof of the mouth while pressing with the fingers between the eyebrows, one can move the vomer, and if repeated for about 20 seconds, the sinuses will discharge, thus rapidly clearing a stuffy head without the use of drugs. There is no scientific evidence that this procedure actually works.
Anatomical details
The vomer is situated in the median plane, but its anterior portion is frequently bent to one or other side. It is thin, somewhat quadrilateral in shape, and forms the hinder and lower part of the nasal septum; it has two surfaces and four borders. The surfaces are marked by small furrows for blood vessels, and on each is the nasopalatine groove, which runs obliquely downward and forward, and lodges the nasopalatine nerve and vessels.
Borders
The superior border, the thickest, presents a deep furrow, bounded on either side by a horizontal projecting ala of bone; the furrow receives the rostrum of the sphenoid, while the margins of the al articulate with the vaginal processes of the medial pterygoid plates of the sphenoid behind, and with the sphenoidal processes of the palatine bones in front. The inferior border articulates with the crest formed by the maxill and palatine bones. The anterior border is the longest and slopes downward and forward. Its upper half is fused with the perpendicular plate of the ethmoid; its lower half is grooved for the inferior margin of the septal cartilage of the nose. The posterior border is free, concave, and separates the choanae. It is thick and bifid above, thin below.
Articulations
The vomer articulates with six bones:

two of the cranium, the sphenoid and ethmoid. four of the face, the two maxillae; and the two palatine bones.
It also articulates with the septal cartilage of the nose.
In other animals
In bony fish, the vomers are flattened, paired, bones forming the anterior part of the roof of the mouth, just behind the premaxillary bones. In many species, they have teeth, supplementing those in the jaw proper; in some extinct species the teeth on the vomers were actually larger than the primary set. In amphibians and reptiles, the vomers become narrower, due to the presence of the enlarged choanae (the inner part of the nostrils) on either side, and they may extend further back in the jaw. They are typically small in birds, where they form the upper hind part of the beak, again being located between the choanae. In mammals, the vomers have become narrower still, and are fused into a single, vertically oriented bone. The development of the hard palate beneath the vomer means that the bone is now located in a nasal chamber, separate from the mouth.
Median wall of left nasal cavity showing vomer in situ
The vomer
Base of skull. Inferior surface.
Chapter 10
Stapes and Incus
Stapes
Bone: Stapes
A. Left stapes. B. Base of stapes, medial surface.
Chain of ossicles and their ligaments, seen from the front in a vertical, transverse section of the tympanum.
Malleus Tensor Tympani Incus Stapedius Labyrinth Stapes Auditory Canal Tympanic Membrane (Ear Drum) Eustachian Tube Tympanic cavity
Bones and muscles in the tympanic cavity in the middle ear
Latin Precursor MeSH
stapes
2nd branchial arch Stapes
GraySubject
= 231
The stapes or stirrup is the stirrup-shaped small bone or ossicle in the middle ear which is attached through the incudostapedial joint to the incus laterally and to the fenestra ovalis, the "oval window", medially. The oval window is adjacent to the vestibule of the inner ear. The stapes is the smallest and lightest bone in the human body.
Function
The stapes transmits the sound vibrations from the incus to the membrane of the inner ear inside the fenestra ovalis. The stapes is also stabilized by the stapedius muscle, which is innervated by the facial nerve.
Evolutionary variation
In non-mammalian tetrapods, the bone homologous to the stapes is usually called the columella; however, in reptiles, either term may be used. In fish, the homologous bone is
called the hyomandibular, and is part of the gill arch supporting either the spiracle or the jaw, depending on species.
Development
As the stapes first develops embryologically from the 6th to 8th week of life, it surrounds the stapedial artery, which supplies the majority of the vasculature of the embryonic head. After that period, the external carotid artery is generated and takes over for the stapedial artery, which subsequently involutes, leaving the stapes with a windowframelike structure.
Incus
Bone: Incus
Left incus. A. From within. B. From the front.
Auditory tube, laid open by a cut in its long axis.
Malleus Tensor Tympani Incus Stapedius Labyrinth Stapes Auditory Canal Tympanic Membrane (Ear Drum) Eustachian Tube Tympanic cavity
Bones and muscles in the tympanic cavity in the middle ear
Gray's Precursor MeSH
subject #231 1044 1st branchial arch Incus
The incus or anvil is the anvil-shaped small bone or ossicle in the middle ear. It connects the malleus to the stapes. It was first described by Alessandro Achillini of Bologna. The incus transmits sound vibrations from the malleus to the stapes. The incus only exists in mammals, and is derived from a reptilian upper jaw bone, the quadrate bone. Embryologically it is derived from the first pharyngeal arch along with the rest of the bones of mastication, such as the maxilla and mandible.
Head and neck of a human embryo eighteen weeks old, with Meckels cartilage and hyoid bar exposed.
External and middle ear, opened from the front. Right side.
Chain of ossicles and their ligaments, seen from the front in a vertical, transverse section of the tympanum.
Ossicles
Chapter 11
Hyoid Bone
Bone: Hyoid bone
Hyoid bone. Anterior surface. Enlarged.
Anterolateral view of head and neck.
Latin Gray's Precursor MeSH
os hyoideum subject #45 177 2nd and 3rd branchial arch Hyoid+Bone
The hyoid bone (lingual bone) (Latin os hyoideum) is a horseshoe-shaped bone situated in the anterior midline of the neck between the chin and the thyroid cartilage. At rest, it lies at the level of the base of the mandible in the front and the third cervical vertebra behind.
Unlike other bones, the hyoid is only distantly articulated to other bones by muscles or ligaments. The hyoid is anchored by muscles from the anterior, posterior, and inferior directions and aids in tongue movement and swallowing. The hyoid bone provides attachment to the muscles of the floor of the mouth and the tongue above, the larynx below, and the epiglottis and pharynx behind. Its name is derived from the Greek word hyoeides meaning "shaped like the letter upsilon" ().
Segments
The bone consists of a central part, called the body and two pairs of cornua, the greater cornu and the lesser cornu.

Body of hyoid Greater cornu (2) Lesser cornu (2)
Embryology
The second pharyngeal arch gives rise to the lesser cornu of hyoid and the superior part of body of hyoid. The cartilage of the third pharyngeal arch forms the greater cornu of hyoid and the lower portion of the body of hyoid.
Ossification
The hyoid is ossified from six centers: two for the body, and one for each cornu. Ossification commences in the greater cornua toward the end of fetal life, in the body shortly afterward, and in the lesser cornua during the first or second year after birth. Until middle age the connection between the body and greater cornu is fibrous.
Muscle attachments
The following muscles are attached to the hyoid: Superior

Inferior

Middle pharyngeal constrictor muscle Hyoglossus muscle Digastric muscle Stylohyoid muscle Geniohyoid muscle Mylohyoid muscle
Thyrohyoid muscle Omohyoid muscle Sternohyoid muscle
Function
The hyoid bone is present in many mammals, it allows a wider range of tongue, pharyngeal and laryngeal movements by bracing these structures alongside each other in order to produce variation. Its descent in living creatures is not unique to Homo sapiens, and does not allow the production of a wide range of sounds: with a lower larynx, men do not produce a wider range of sounds than women and 2 year old babies. Moreover the larynx position of Neanderthal was not a handicap to producing speech sounds. The discovery of a modern-looking hyoid bone of a Neanderthal man in the Kebara Cave in Palestine led its discoverers to argue that the Neanderthals had a descended larynx, and thus human-like speech capabilities. However, other researchers have claimed that the morphology of the hyoid is not indicative of the larynx's position. It is necessary to take into consideration the skull base, the mandible and the cervical vertebrae and a cranial reference plane.
Fracture and applied anatomy

Due to its position, the hyoid bone is not susceptible to easy fracture. In a suspected case of murder, a fractured hyoid strongly indicates throttling or strangulation. However this is not the case in children and adolescents, where the hyoid bone is still flexible as ossification is yet to be completed.
In other animals
The hyoid bone of a gecko with attached tracheal rings
Hyoid bones of various birds The hyoid bone is derived from the lower half of the second gill arch in fish, which separates the first gill slit from the spiracle, and is often referred to as the hyoid arch. In many animals, it also incorporates elements of other gill arches, and has a correspondingly greater number of cornua. Amphibians and reptiles may have many cornua, while mammals (including humans) have two pairs, and birds only one. In birds, and some reptiles, the body of the hyoid is greatly extended forward, creating a solid bony support for the tongue. The howler monkey Alouatta has a pneumatized hyoid bone, one of the few cases of postcranial pneumatization of bones outside Saurischia.
Larynx
Head and neck of a human embryo eighteen weeks old, with Meckel's cartilage and hyoid bone exposed.
Muscles of the pharynx and cheek
Muscles of the neck. Lateral view.
The internal carotid and vertebral arteries. Right side.
The ligaments of the larynx. Antero-lateral view.
Sagittal section of the larynx and upper part of the trachea
Coronal section of larynx and upper part of trachea
The entrance to the larynx, viewed from behind
Sagittal section of nose mouth, pharynx, and larynx
Extrinsic muscles of the tongue. Left side.
The thyroid gland and its relations
Front view of neck
Chapter 12
Scapula
Bone: shoulder blade
Posterior view of the thorax and shoulder girdle. (Scapula visible at either side.)
Gray's MeSH
subject #50 202 Scapula
In anatomy, the scapula, omo (Medical Latin), or shoulder blade, is the bone that connects the humerus (upper arm bone) with the clavicle (collar bone). The scapula forms the posterior (back) located part of the shoulder girdle. In humans, it is a flat bone, roughly triangular in shape, placed on a posterolateral aspect of the thoracic cage.
Structure
Surfaces
Costal (Front, Ventral, Anterior)

The costal or ventral surface [Fig. 1] presents a broad concavity, the subscapular fossa. The medial two-thirds of this fossa are marked by several oblique ridges, which run lateralward and upward. The ridges give attachment to the tendinous insertions, and the surfaces between them to the shelby, of the Subscapularis. The lateral third of the fossa is smooth and covered by the fibers of this muscle.
| Figure 1 : Left scapula. Costal surface.
| Figure 2 : Left scapula. Dorsal surface.
| Figure 3 : Left scapula. Lateral surface.
At the upper part of the fossa is a transverse depression, where the bone appears to be bent on itself along a line at right angles to and passing through the center of the glenoid cavity, forming a considerable angle, called the subscapular angle; this gives greater strength to the body of the bone by its arched form, while the summit of the arch serves to support the spine and acromion.
Dorsal (Back, Posterior)

The dorsal surface [Fig. 2] is arched from above downward, and is subdivided into two unequal parts by the spine; the portion above the spine is called the supraspinous fossa, and that below it the infraspinous fossa.
The supraspinous fossa, the smaller of the two, is concave, smooth, and broader at its vertebral than at its humeral end; its medial two-thirds give origin to the Supraspinatus. The infraspinous fossa is much larger than the preceding; toward its vertebral margin a shallow concavity is seen at its upper part; its center presents a prominent convexity, while near the axillary border is a deep groove which runs from the upper toward the lower part. The medial two-thirds of the fossa give origin to the Infraspinatus; the lateral third is covered by this muscle.
The dorsal surface is marked near the axillary border by an elevated ridge, which runs from the lower part of the glenoid cavity, downward and backward to the vertebral border, about 2.5 cm above the inferior angle. The ridge serves for the attachment of a fibrous septum, which separates the Infraspinatus from the Teres major and Teres minor. The surface between the ridge and the axillary border is narrow in the upper two-thirds of its extent, and is crossed near its center by a groove for the passage of the scapular circumflex vessels; it affords attachment to the Teres minor. Its lower third presents a broader, somewhat triangular surface, which gives origin to the Teres major, and over which the Latissimus dorsi glides; frequently the latter muscle takes origin by a few fibers from this part. The broad and narrow portions above alluded to are separated by an oblique line, which runs from the axillary border, downward and backward, to meet the elevated ridge: to it is attached a fibrous septum which separates the Teres muscles from each other.
Borders
There are three borders of the scapula:
The superior border is the shortest and thinnest; it is concave, and extends from the medial angle to the base of the coracoid process. It is referred to as the cranial border in animals. The axillary border (or "lateral border") is the thickest of the three. It begins above at the lower margin of the glenoid cavity, and inclines obliquely downward and backward to the inferior angle. It is referred to as the caudal border in animals. The vertebral border (or "medial border") is the longest of the three, and extends from the medial to the inferior angle. It is referred to as the dorsal border in animals.
The acromion
The acromion forms the summit of the shoulder, and is a large, somewhat triangular or oblong process, flattened from behind forward, projecting at first lateralward, and then curving forward and upward, so as to overhang the glenoid cavity.
Development
The larger part of the scapula undergoes membranous ossification.. Some of the outer parts of the scapula are cartilaginous at birth, and would therefore undergo endochondral ossification . The head, processes, and the thickened parts of the bone, contain cancellous tissue; the rest consists of a thin layer of compact tissue. The central part of the supraspinatus fossa and the upper part of the infraspinatous fossa, but especially the former, are usually so thin in humans as to be semitransparent; occasionally the bone is found wanting in this situation, and the adjacent muscles are separated only by fibrous tissue.
Muscular attachments
The following muscles attach to the scapula: Muscle Pectoralis Minor Coracobrachialis Serratus Anterior Direction Region insertion coracoid process origin coracoid process insertion medial border
Triceps Brachii (long head) origin Biceps Brachii (short head) origin Biceps Brachii (long head) origin Subscapularis origin Rhomboid Major insertion Rhomboid Minor insertion Levator Scapulae insertion Trapezius insertion Deltoid origin Supraspinatus origin Infraspinatus origin Teres Minor origin Teres Major origin Latissimus Dorsi (a few fibers) origin Omohyoid origin
infraglenoid tubercle coracoid process supraglenoid tubercle subscapular fossa medial border medial border medial border spine of scapula spine of scapula supraspinous fossa infraspinous fossa lateral border lateral border inferior angle superior border
Movements
Movements of the scapula are brought about by scapular muscles: Elevation, Depression, Protraction, Retraction, Lateral rotation, Medial rotation, Upward Rotation, Downward Rotation, Anterior Tipping, and Posterior Tipping
Injury
Because of its sturdy structure and protected location, scapular fractures are uncommon; when they do occur, they are an indication that severe chest trauma has occurred. A winged scapula is a condition in which the medial border (the side nearest the spine) of a person's scapula is abnormally positioned outward and backward. The resulting appearance of the upper back is said to be wing-like because the inferior angle of the shoulder blade protrudes backward rather than lying mostly flat like in people without the condition.
In other animals
Scapulae, spine and ribs of Myotis lucifugus (Little Brown Bat) In fish, the scapular blade is a structure attached to the upper surface of the articulation of the pectoral fin, and is accompanied by a similar coracoid plate on the lower surface. Although sturdy in cartilagenous fish, both plates are generally small in most other fish, and may be partially cartilagenous, or consist of multiple bony elements. In the early tetrapods, these two structures respectively became the scapula and a bone referred to as the procoracoid (commonly called simply the "coracoid", but not homologous with the mammalian structure of that name). In amphibians, birds, and reptiles, these two bones are distinct, but together form a single structure bearing many of the muscle attachments for the forelimb. In such animals, the scapula is usually a relatively simple plate, lacking the projections and spine that it possesses in mammals. However, the detailed structure of these bones varies considerably in living groups. For example, in frogs, the procoracoid bones may be braced together at the animal's underside to absorb the shock of landing, while in turtles, the combined structure forms a Y-shape in order to allow the scapula to retain a connection to the clavicle (which is part of the shell). In birds, the procoracoids help to brace the wing against the top of the sternum.
In the fossil therapsids, a third bone, the true coracoid, formed just behind the procoracoid. The resulting three-boned structure is still seen in modern monotremes, but in all other living mammals, the procoracoid has disappeared, and the coracoid bone has fused with the scapula, to become the coracoid process. These changes are associated with the upright gait of mammals, compared with the more sprawling limb arrangement of reptiles and amphibians; the muscles formerly attached to the procoracoid are no longer required. The altered musculature is also responsible for the alteration in the shape of the rest of the scapula; the forward margin of the original bone became the spine and acromion, from which the main shelf of the shoulder blade arises as a new structure.
As a shovel
In neolithic times and earlier a large animal's scapula was often used as a crude shovel.
Pectoral girdle - front
Human arm bones diagram
Diagram of the human shoulder joint
Left scapula. Lateral view.
The scapular and circumflex arteries
Chapter 13
Clavicle
Bone: Clavicle
Gray's MeSH
subject #49 200 Clavicle
In human anatomy, the clavicle or collar bone is a long bone of short length that serves as a strut between the scapula and the sternum. It is the only long bone in body that lies horizontally. It makes up part of the shoulder and the pectoral girdle and is palpable in all people, and, in people who have less fat in this region, the location of the bone is clearly visible as it creates a bulge in the skin. It receives its name from the Latin: clavicula ("little key") because the bone rotates along its axis like a key when the shoulder is abducted.
Human anatomy
Right clavicle from below, and from above.
Left clavicle from above, and from below. The clavicle is a doubly curved short bone that connects the arm (upper limb) to the body (trunk), located directly above the first rib. It acts as a strut to keep the scapula in position so the arm can hang freely. Medially, it articulates with the manubrium of the sternum (breast-bone) at the sternoclavicular joint. At its lateral end it articulates with the acromion of the scapula (shoulder blade) at the acromioclavicular joint. It has a rounded medial end and a flattened lateral end. From the roughly pyramidal sternal end, each clavicle curves laterally and anteriorly for roughly half its length. It then forms a smooth posterior curve to articulate with a process of the scapula (acromion). The flat, acromial end of the clavicle is broader than the sternal end. The acromial end has a rough inferior surface that bears prominent line, Trapezoid line and a small rounded projection, Conoid tubercle. These surface features are attachment sites for muscles and ligaments of the shoulder. It can be divided into three parts. Medial end, lateral end and shaft.
Medial End
The medial end is quadrangular and articulates with clavicular notch of menubrium sterni to form sternoclavicular joint. Articular surface extends to anterior aspect for attachment with first costal cartilage. It gives attachments to 1. Fibrous capsule of sternoclavicular joint all around 2. Articular disc superoposteriorly 3. Interclavicular ligament superiorly
Lateral End
The lateral end is flat from above downward downward. It bears a facet for attachment to acromion process of scapula forming acromioclavicular joint. The area surrounding the joint gives attachment to joint capsule.
Shaft
The shaft is divided into medial 2/3rd and lateral 1/3. Medial 2/3rd is thicker than lateral 1/3.
Medial 2/3rd of shaft

Medial 2/3rd of shaft has 4 surfaces and no borders. Anterior surface is convex forward and gives origin to pectoralis major. Posterior surface is smooth and gives origin to sternohyoid muscle at its medial end. Superior surface is rough at its medial part and gives origin to sternocleidomastoid muscle . Inferior surface has an oval impression at its medial end for costoclavicular ligament. At the lateral side of inferior surface, there is a subclavian groove for insertion of subclavius muscle. At the lateral side of subclavian groove, nutrient foramen lies.
Lateral 1/3rd of shaft

It has 2 borders and 2 surfaces. Anterior border is concave forward and gives origin to deltoid muscle. Posterior border is convex backward and gives attachment to trapezius muscle . Superior surface is subcutaneous. Inferior surface has a ridge called trapezoid line and a tubercle, the conoid tubercle for attachment with trapezoid and conoid part of Coracoclavicular ligament that serves to connect the clavicle with the coracoid process of the scapula.
Attachments
Muscles and ligaments that attach to the clavicle include: Attachment on clavicle Muscle/Ligament Other attachment deltoid tubercle, anteriorly on the lateral third posteriorly on the lateral third subclavian groove
Superior surface and Deltoid muscle anterior border Superior surface Inferior surface Inferior surface Inferior surface Anterior border Trapezius muscle
Subclavius muscle Conoid ligament (the medial part of the conoid tubercle coracoclavicular ligament) Trapezoid ligament (the lateral part of trapezoid line the coracoclavicular ligament) medial third (rounded Pectoralis major muscle border)
Posterior border Posterior border Posterior border
Sternocleidomastoid muscle (clavicular superiorly, on the medial head) third inferiorly, on the medial Sternohyoid muscle third Trapezius muscle lateral third
The levator claviculae muscle, present in 23% of people, originates on the transverse processes of the upper cervical vertebrae and is inserted in the lateral half of the clavicle.
Functions
The clavicle serves several functions:
It serves as a rigid support from which the scapula and free limb (arm) are suspended; an arrangement that keeps the upper limb away from the thorax so that the arm has maximum range of movement. Acting as flexible, crane-like strut, it allows the scapula to move freely on the thoracic wall. Covering the cervicoaxillary canal, it protects the neurovascular bundle that supply the upper limb. Transmits physical impacts from the upper limb to the axial skeleton.
Development
The clavicle is the first bone to begin the process of ossification (laying down of minerals onto a preformed matrix) during development of the embryo, during the 5th and 6th weeks of gestation. However, it is one of the last bones to finish ossification, at about 21 25 years of age. It forms by intramembranous ossification. It consists of a mass of cancellous bone surrounded by a compact bone shell. The cancellous bone forms via two ossification centres, one medial and one lateral, which fuse later on. The compact forms as the layer of fascia covering the bone stimulates the ossification of adjacent tissue. The resulting compact bone is known as a periosteal collar. Even though it is classified as a long bone, the clavicle has no medullary (bone marrow) cavity like other long bones. It is made up of spongy (trabecular) bone with a shell of compact bone. It is a dermal bone derived from elements originally attached to the skull.
Variations
The shape of the clavicle varies more than most other long bones. It is occasionally pierced by a branch of the supraclavicular nerve. In manual workers it is thicker and more curved and the sites of muscular attachments are more pronounced. The right clavicle is usually stronger and shorter than the left clavicle.
Common clavicle injuries

Acromioclavicular dislocation Clavicle fractures Degeneration of the clavicle The collarbones are sometimes partly or completely absent in cleidocranial dysostosis Osteolysis Sternoclavicular dislocations
Evolutionary variation
The clavicle first appears as part of the skeleton in primitive bony fish, where it is associated with the pectoral fin; they also have a bone called the cleithrum. In such fish, the paired clavicles run behind and below the gills on each side, and are joined by a solid symphysis on the fish's underside. They are, however, absent in cartilagenous fish and in the vast majority of living bony fish, including all of the teleosts. The earliest tetrapods retained this arrangement, with the addition of a diamond-shaped interclavicle between the base of the clavicles, although this is not found in living amphibians. The cleithrum disappeared early in the evolution of reptiles, and is not found in any living amniotes, but the interclavicle is present in most modern reptiles, and also in monotremes. In modern forms, however, there are a number of variations from the primitive pattern. For example, crocodilians and salamanders lack clavicles altogether (although crocodilians do retain the interclavicle), while in turtles, they form part of the armoured plastron. In birds, the clavicles and interclavicle have fused to form a single Y-shaped bone, the furcula or "wishbone". The interclavicle is absent in marsupials and placental mammals. In many mammals, the clavicles are also reduced, or even absent, to allow the scapula greater freedom of motion, which may be useful in fast-running animals. Though a number of fossil hominin (humans and chimpanzees) clavicles have been found, most of these are mere segments offering limited information on the form and function of the pectoral girdle. One exception is the clavice of AL 333x6/9 attributed to Australopithecus afarensis which has a well-preserved sternal end. One interpretation of this specimen, based on the orientation of its lateral end and the position of the deltoid attachment area, suggests that this clavicle is distinct from those found in extant apes (including humans), and thus that the shape of the human shoulder dates back to less than 3 to 4 million years ago. However, analyses of the clavicle in extant primates suggest that the low position of the scapula in humans is reflected mostly in the curvature of the medial portion of the clavicle rather than the lateral portion. This part of the bone is similar in A. afarensis and it is thus possible that this species had a high shoulder position similar to that in modern humans.
Pectoral girdle front
Sternoclavicular articulation. Anterior view.
The left shoulder and acromioclavicular joints, and the proper ligaments of the scapula
Muscles of the neck. Lateral view.
Muscles of the neck. Anterior view.
Anterolateral view of head and neck
Front view of neck
Chapter 14
Rib
Single human rib-detail
The human rib cage (Source: Gray's Anatomy of the Human Body, 20th ed. 1918) In vertebrate anatomy, ribs (Latin: costae) are the long curved bones which form the rib cage. In most vertebrates, ribs surround the chest, enabling the lungs to expand and thus facilitate breathing by expanding the chest cavity. They serve to protect the lungs, heart, and other internal organs of the thorax. In some animals, especially snakes, ribs may provide support and protection for the entire body.
Human anatomy
Humans have 24 ribs (12 pairs). The first seven sets of ribs, known as "true ribs", are directly attached to the sternum through the costal cartilage. Rib 1 is unique and harder to distinguish from other ribs. It is a short, flat, C-shaped bone. The vertebral attachment
can be found just below the neck and the majority of this bone can be found above the level of the clavicle. Ribs 2 through 7 have a more traditional appearance. The following five sets are known as "false ribs", three of these sharing a common cartilaginous connection to the sternum, while the last two (eleventh and twelfth ribs) are termed floating ribs (costae fluitantes) or vertebral ribs. They are attached to the vertebrae only, and not to the sternum or cartilage coming off of the sternum. Some people are missing one of the two pairs of floating ribs, while others have a third pair. Rib removal is the surgical excision of ribs for therapeutic or cosmetic reasons. In general, human ribs increase in length from ribs 1 through 7 and decrease in length again through rib 12. Along with this change in size, the ribs become progressively oblique (slanted) from ribs 1 through 9, then less slanted through rib 12. The ribcage is separated from the lower abdomen by the thoracic diaphragm which controls breathing. When the diaphragm contracts, the ribcage and thoracic cavity are expanded, reducing intra-thoracic pressure and drawing air into the lungs.
In other animals
Skeleton of a dog showing the location of the ribs
Ribcage of Myotis lucifugus (Little Brown Bat) In fish, there are often two sets of ribs attached to the vertebral column. One set, the dorsal ribs, are found in the dividing septum between the upper and lower parts of the main muscle segments, projecting roughly sideways from the vertebral column. The second set, of ventral ribs arise from the vertebral column just below the dorsal ribs, and enclose the lower body, often joining at the tips. Not all species possess both types of rib, with the dorsal ribs being most commonly absent. Sharks, for example, have no dorsal ribs, and only very short ventral ribs, while lampreys have no ribs at all. In some teleosts, there may be additional rib-like bones within the muscle mass. Tetrapods, however, only ever have a single set of ribs which are probably homologous with the dorsal ribs of fishes. In the early tetrapods, every vertebra bore a pair of ribs, although those on the thoracic vertebrae are typically the longest. The sacral ribs were stout and short, since they formed part of the pelvis, connecting the backbone to the hip bones. In most subsequent forms, many of these early ribs have been lost, and in living amphibians and reptiles, there is great variation in rib structure and number. For example, turtles have only eight pairs of ribs, which are developed into a bony or cartilagenous carapace and plastron, while snakes have numerous ribs running along the full length of
their trunk. Frogs typically have no ribs, aside from a sacral pair, which form part of the pelvis. In birds, ribs are present as distinct bones only on the thoracic region, although small fused ribs are present on the cervical vertebrae. The thoracic ribs of birds possess a wide projection to the rear; this uncinate process is an attachment for the shoulder muscles. Mammals usually also only have distinct ribs on the thoracic vertebra, although fixed cervical ribs are also present in monotremes. In marsupials and placental mammals, the cervical and lumbar ribs are found only as tiny remnants fused to the vertebrae, where they are referred to as transverse processes. In general, the structure and number of the true ribs in humans is similar to that in other mammals. Unlike reptiles, caudal ribs are never found in mammals.
Chapter 15
Humerus
Bone: Humerus
Upper extremity
Gray's MeSH
subject #51 209 Humerus
The humerus (ME from Latin humerus, umerus upper arm, shoulder; Gothic ams shoulder, Greek mos) is a long bone in the arm or forelimb that runs from the shoulder to the elbow. Anatomically, it connects the scapula and the lower arm (consisting of the radius and ulna), and consists of three sections. The upper extremity consists of a rounded head, a narrow neck, and two short processes (tubercles, sometimes called tuberosities.) Its body is cylindrical in its upper portion, and more prismatic below. The lower extremity consists of 2 epicondyles, 2 processes (trochlea & capitulum), and 3 fossae (radial fossa, coronoid fossa, and olecranon fossa). As well as its true anatomical neck, the constriction below the greater and lesser tubercles of the humerus is referred to as its surgical neck due to its tendency to commonly get fractured, thus often becoming the focus of surgeons.
Muscles attached to the humerus

The deltoid originates on the lateral third of the clavicle, acromion and the crest of the spine of the scapula. It is inserted on the deltoid tuberosity of the humerus and has several actions including abduction, extension, and rotation of the shoulder. The supraspinatus also originates on the spine of the scapula. It inserts on the greater tubercle of the humerus, and assists in abduction of the shoulder. The pectoralis major, teres major, and latissimus dorsi insert at the intertubercular groove of the humerus. They work to adduct and medially, or internally, rotate the humerus. The infraspinatus and teres minor insert on the greater tubercle, and work to laterally, or externally, rotate the humerus. In contrast, the subscapularis muscle inserts onto the lesser tubercle and works to medially, or internally, rotate the humerus. The biceps brachii, brachialis, coracobrachialis, and brachioradialis (which attaches distally) act to flex the elbow. (The biceps, however, does not attach to the humerus.) The triceps brachii and anconeus extend the elbow, and attach to the posterior side of the humerus. The four muscles of supraspinatus, infraspinatus, teres minor and subscapularis form a musculo-ligamentous girdle called the rotator cuff. This cuff stabilizes the very mobile but inherently unstable glenohumeral joint. The other muscles are used as counterbalances for the actions of lifting/pulling and pressing/pushing.
Articulations
At the shoulder, the head of the humerus articulates with the glenoid fossa of the scapula. More distally, at the elbow, the capitulum of the humerus articulates with the head of the radius, and the trochlea of the humerus articulates with the olecranon process of the ulna.
Nerves
The axillary nerve is located at the proximal end, against the shoulder girdle. The most common type of shoulder dislocation is an anterior or inferior dislocation of the humerus's glenohumeral joint, which has the potential to injure the axillary nerve or the axillary artery. Signs and symptoms of this dislocation include a loss of the normal shoulder contour and a palpable depression under the acromion. The radial nerve follows the humerus closely. At the midshaft of the humerus, the radial nerve travels from the posterior to the anterior aspect of the bone in the spiral groove. A fracture of the humerus in this region can result in radial nerve injury. The ulnar nerve at the distal end of the humerus near the elbow is sometimes referred to in popular culture as 'the funny bone'. Striking this nerve can cause a tingling sensation ("funny" feeling), and sometimes a significant amount of pain.
In other animals
Primitive fossil amphibians had little, if any, shaft connecting the upper and lower extremities, making their limbs very short. In most living vertebrates, however, the humerus has a similar form to that of humans. In many reptiles and some primitive mammals, the lower extremity includes a large foramen, or opening, into which nerves and blood vessels pass.
Humerus (right) - anterior view
Humerus (right) - posterior view
Left humerus. Anterior view.
Left humerus. Posterior view.
Left humerus with muscle attachments. Anterior view.
Left humerus with muscle attachments. Posterior view.
The left shoulder and acromioclavicular joints, and the proper ligaments of the scapula.
Cross-section through the middle of upper arm
The Supinator
Chapter 16
Radius (Bone)
Bone: Radius (joint)
Upper extremity
Radius is #1
Gray's MeSH
subject #52 219 Radius
The radius is one of the two large bones of the forearm, the other being the ulna. It extends from the lateral side of the elbow to the thumb side of the wrist and runs parallel to the ulna, which exceeds it in length and size. It is a long bone, prism-shaped and slightly curved longitudinally. The radius articulates with the capitulum of the humerus, the radial notch and the head of the ulna. The corresponding bone in the lower leg is the tibia.
The word radius is Latin for "ray". In the context of the radius bone, a ray can be thought of rotating around an axis line extending diagonally from center of capitulum to the center of distal ulna. While the ulna is the major contributor to the elbow joint, the radius primarily contributes to the wrist joint.
Shape
The radius has a body and two extremities. The upper extremity of the radius consists of a somewhat cylindrical head articulating with the humerus and the ulna, a neck, and a single tuberosity. The body of the radius is self-explanatory, and the lower extremity of the radius is roughly quadrilateral in shape, with articular surfaces for the ulna, scaphoid and lunate bones. The distal end of the radius forms a palpable point called the styloid process. Along with the proximal and distal radioulnar articulations, an interosseous membrane originates medially along the length of the body of the radius to attach the radius to the ulna.
Muscle attachments
The biceps muscle inserts on the radial tuberosity of the upper extremity of the bone. The upper third of the body of the bone attaches to the supinator, the flexor digitorum superficialis, and the flexor pollicis longus muscles. The middle third of the body attaches to the extensor ossis metacarpi pollicis, extensor primi internodii pollicis, and the pronator teres muscles. The lower quarter of the body attaches to the pronator quadratus muscle and the tendon of the supinator longus.
Structure
The long narrow medullary cavity is enclosed in a strong wall of compact bone. It is thickest along the interosseous border and thinnest at the extremities, save over the cupshaped articular surface (fovea) of the head. The trabeculae of the spongy tissue are somewhat arched at the upper end and pass upward from the compact layer of the shaft to the fovea capituli (the humerus's cupshaped articulatory notch); they are crossed by others parallel to the surface of the fovea. The arrangement at the lower end is somewhat similar. It is missing in radial aplasia.
Fracture
Specific fracture types of the radius include:
Essex-Lopresti fracture - a fracture of the radial head with concomitant dislocation of the distal radio-ulnar joint with disruption of the interosseous membrane. Distal radius fracture o Galeazzi fracture - a fracture of the radius with dislocation of the distal radioulnar joint
Colles' fracture - a distal fracture of the radius with dorsal (posterior) displacement of the wrist and hand o Smith's fracture - a distal fracture of the radius with volar (ventral) displacement of the wrist and hand o Barton's fracture - an intra-articular fracture of the distal radius with dislocation of the radiocarpal joint.
o
In other animals
In four-legged animals, the radius is the main load-bearing bone of the lower forelimb. Its structure is similar in most terrestrial tetrapods, but it may be fused with the ulna in some mammals (such as horses) and reduced or modified in animals with flippers or vestigial forelimbs.
Right human radius and ulna - post. view
Bones of left forearm - ant. view
Bones of left forearm - post. view
Left elbow-joint, showing anterior and ulnar collateral ligaments
The Supinator
Cross-section through middle of forearm
Transverse section across distal ends of radius and ulna
Chapter 17
Anatomy of Bone Marrow
Illustration of cells in bone marrow Bone marrow is the flexible tissue found in the hollow interior of bones. In humans, marrow in large bones produces new blood cells. It constitutes 4% of the total body weight of humans, i.e. approximately 2.6 kg (5.7 lbs.) in adults. Bone marrow also prevents the backflow of lymph, working as a vital part of the lymphatic system.
Marrow types
A femur with a cortex of cortical bone and medulla of trabecular bone showing its red bone marrow and a focus of yellow bone marrow. There are two types of bone marrow: red marrow (consisting mainly of hematopoietic tissue) and yellow marrow (consisting mainly of fat cells). Red blood cells, platelets and most white blood cells arise in red marrow. Both types of bone marrow contain numerous blood vessels and capillaries. At birth, all bone marrow is red. With age, more and more of it is converted to the yellow type. About half of adult bone marrow is red. Red marrow is found mainly in the flat bones, such as the hip bone, breast bone, skull, ribs, vertebrae and shoulder blades, and in the cancellous ("spongy") material at the epiphyseal ends of the long bones such as the femur and humerus. Yellow marrow is found in the hollow interior of the middle portion of long bones.
In cases of severe blood loss, the body can convert yellow marrow back to red marrow to increase blood cell production.
Stroma
The stroma of the bone marrow is all tissue not directly involved in the primary function of hematopoiesis. The yellow bone marrow belongs here, and makes the majority of the bone marrow stroma, in addition to stromal cells located in the red bone marrow. Yellow bone marrow is found in the Medullary cavity. Still, the stroma is indirectly involved in hematopoiesis, since it provides the hematopoietic microenvironment that facilitates hematopoiesis by the parenchymal cells. For instance, they generate colony stimulating factors, affecting hematopoiesis. Cells that constitute the bone marrow stroma are:

fibroblasts (reticular connective tissue) macrophages adipocytes osteoblasts osteoclasts endothelial cells forming the sinusoids
Macrophages contribute especially to red blood cell production. They deliver iron for hemoglobin-production.
Fibroblast
NIH/3T3 Fibroblasts in cell culture A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework (stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells of connective tissue in animals.
Background information
Fibroblasts and fibrocytes are two states of the same cells, the former being the activated state, the latter the less active state, concerned with maintenance. Currently, there is a tendency to call both forms fibroblasts. The suffix "blast" is used in cellular biology to denote a stem cell or a cell in an activated state of metabolism. Fibroblasts are morphologically heterogeneous with diverse appearances depending on their location and activity. Though morphologically inconspicuous, ectopically transplanted fibroblasts can often retain positional memory of the location and tissue context where they had previously resided, at least over a few generations.
Embryologic origin
The main function of fibroblasts is to maintain the structural integrity of connective tissues by continuously secreting precursors of the extracellular matrix. Fibroblasts secrete the precursors of all the components of the extracellular matrix, primarily the ground substance and a variety of fibers. The composition of the extracellular matrix determines the physical properties of connective tissues. Like other cells of connective tissue, fibroblasts are derived from primitive mesenchyme. Thus they express the intermediate filament protein vimentin, a feature used as a marker to distinguish their mesodermal origin. However, this test is not specific as epithelial cells cultured in vitro on adherent substratum may also express vimentin after some time. In certain situations epithelial cells can give rise to fibroblasts, a process called epithelialmesenchymal transition (EMT). Conversely, fibroblasts in some situations may give rise to epithelia by undergoing a mesenchymal to epithelial transition (MET) and organizing into a condensed, polarized, laterally connected true epithelial sheet. This process is seen in many developmental situations (e.g. nephron and notocord development).
Structure and function

Fibroblasts have a branched cytoplasm surrounding an elliptical, speckled nucleus having one or two nucleoli. Active fibroblasts can be recognized by their abundant rough endoplasmic reticulum. Inactive fibroblasts, which are also called fibrocytes, are smaller and spindle shaped. They have a reduced rough endoplasmic reticulum. Although disjointed and scattered when they have to cover a large space, fibroblasts when crowded often locally align in parallel clusters. Fibroblasts make collagens, glycosaminoglycans, reticular and elastic fibers, and glycoproteins found in the extracellular matrix. Growing individuals' fibroblasts are dividing and synthesizing ground substance. Tissue damage stimulates fibrocytes and induces the mitosis of fibroblasts. Unlike the epithelial cells lining the body structures, fibroblasts do not form flat monolayers and are not restricted by a polarizing attachment to a basal lamina on one side, although they may contribute to basal lamina components in some situations (e.g. subepithelial myofibroblasts in intestine may secrete the -2 chain carrying component of the laminin which is absent only in regions of follicle associated epithelia which lack the myofibroblast lining). Fibroblasts can also migrate slowly over substratum as individual cells, again in contrast to epithelial cells. While epithelial cells form the lining of body structures, it is fibroblasts and related connective tissues which sculpt the "bulk" of an organism.
The life span of a fibroblast, as measured in chick embryos, is 57 3 days.
Secondary actions
Mouse embryonic fibroblasts (MEFs) are often used as "feeder cells" in human embryonic stem cell research. However, many researchers are gradually phasing out MEFs in favor of culture media with precisely defined ingredients of exclusively human derivation. Further, the difficulty of exclusively using human derivation for media supplements is most often solved by the use of "defined media" where the supplements are synthetic and achieve the primary goal of eliminating the chance of contamination from derivative sources.
Macrophage
A macrophage of a mouse stretching its "arms" (Pseudopodia) to engulf two particles, possibly pathogens Macrophages (Greek: big eaters, from makros "large" + phagein "eat"; abbr. M) are white blood cells within tissues, produced by the differentiation of monocytes. Human macrophages are about 21 micrometres (0.00083 in) in diameter. Monocytes and
macrophages are phagocytes, acting in both non-specific defense (innate immunity) as well as to help initiate specific defense mechanisms (adaptive immunity) of vertebrate animals. Their role is to phagocytose (engulf and then digest) cellular debris and pathogens either as stationary or as mobile cells, and to stimulate lymphocytes and other immune cells to respond to the pathogen. They can be identified by specific expression of a number of proteins including CD14, CD11b, F4/80 (mice)/EMR1 (human), Lysozyme M, MAC-1/MAC-3 and CD68 by flow cytometry or immunohistochemical staining. They move by action of Amoeboid movement.
Life cycle
When a leukocyte enters damaged tissue through the endothelium of a blood vessel (a process known as the leukocyte extravasation), it undergoes a series of changes to become a macrophage. Monocytes are attracted to a damaged site by chemical substances through chemotaxis, triggered by a range of stimuli including damaged cells, pathogens and cytokines released by macrophages already at the site. At some sites such as the testis, macrophages have been shown to populate the organ through proliferation. Unlike short-lived neutrophils, macrophages survive longer in the body up to a maximum of several months.
Function
Steps of a macrophage ingesting a pathogen: a. Ingestion through phagocytosis, a phagosome is formed b. The fusion of lysosomes with the phagosome creates a phagolysosome; the pathogen is broken down by enzymes c. Waste material is expelled or assimilated (the latter not pictured)
Parts: 1. Pathogens 2. Phagosome 3. Lysosomes 4. Waste material 5. Cytoplasm 6. Cell membrane
Phagocytosis
One important role of the macrophage is the removal of necrotic cellular debris in the lungs. Removing dead cell material is important in chronic inflammation, as the early stages of inflammation are dominated by neutrophil granulocytes, which are ingested by macrophages if they come of age. The removal of necrotic tissue is, to a greater extent, handled by fixed macrophages, which will stay at strategic locations such as the lungs, liver, neural tissue, bone, spleen and connective tissue, ingesting foreign materials such as pathogens, recruiting additional macrophages if needed. When a macrophage ingests a pathogen, the pathogen becomes trapped in a phagosome, which then fuses with a lysosome. Within the phagolysosome, enzymes and toxic peroxides digest the pathogen. However, some bacteria, such as Mycobacterium tuberculosis, have become resistant to these methods of digestion. Macrophages can digest more than 100 bacteria before they finally die due to their own digestive compounds.
Role in adaptive immunity

Macrophages are versatile cells that play many roles. As scavengers, they rid the body of worn-out cells and other debris. They are foremost among the cells that "present" antigen, a crucial role in initiating an immune response. As secretory cells, monocytes and macrophages are vital to the regulation of immune responses and the development of inflammation; they produce a wide array of powerful chemical substances (monokines) including enzymes, complement proteins, and regulatory factors such as interleukin-1. At the same time, they carry receptors for lymphokines that allow them to be "activated" into single-minded pursuit of microbes and tumour cells. After digesting a pathogen, a macrophage will present the antigen (a molecule, most often a protein found on the surface of the pathogen, used by the immune system for identification) of the pathogen to the corresponding helper T cell. The presentation is done by integrating it into the cell membrane and displaying it attached to an MHC class II molecule, indicating to other white blood cells that the macrophage is not a pathogen, despite having antigens on its surface.
Eventually, the antigen presentation results in the production of antibodies that attach to the antigens of pathogens, making them easier for macrophages to adhere to with their cell membrane and phagocytose. In some cases, pathogens are very resistant to adhesion by the macrophages. The antigen presentation on the surface of infected macrophages (in the context of MHC class II) in a lymph node stimulates TH1 (type 1 helper T cells) to proliferate (mainly due to IL-12 secretion from the macrophage). When a B-cell in the lymph node recognizes the same unprocessed surface antigen on the bacterium with its surface bound antibody, the antigen is endocytosed and processed. The processed antigen is then presented in MHCII on the surface of the B-cell. TH1 receptor that has proliferated recognizes the antigen-MHCII complex (with co-stimulatory factors- CD40 and CD40L) and causes the B-cell to produce antibodies that help opsonisation of the antigen so that the bacteria can be better cleared by phagocytes. Macrophages provide yet another line of defense against tumor cells and somatic cells infected with fungus or parasites. Once a T cell has recognized its particular antigen on the surface of an aberrant cell, the T cell becomes an activated effector cell, chemical mediators known as lymphokines that stimulate macrophages into a more aggressive form. These activated macrophages can then engulf and digest affected cells much more readily. The macrophage does not generate a response specific for an antigen, but attacks the cells present in the local area in which it was activated.
Role in Muscle Regeneration

The first step to understanding the importance of macrophages in muscle repair, growth, and regeneration is that there are two waves of macrophages with the onset of damageable muscle use subpopulations that do and do not directly have an influence on repairing muscle. The initial wave is a phagocytic population that comes along during periods of increased muscle use that are sufficient to cause muscle membrane lysis and membrane inflammation, which that can enter and degrade the contents of injured muscle fibers. These early-invading, phagocytic macrophages reach their highest concentration about 24 hours following the onset of some form of muscle cell injury or reloading. Their concentration rapidly declines after 48 hours. The second group is the non-phagocytic types that are distributed near regenerative fibers. These peak between two and four days and remain elevated for several days during the hopeful muscle rebuilding. The first subpopulation has no direct benefit to repairing muscle, while the second non-phagocytic group does. It is thought that macrophages release soluble substances that influence the proliferation, differentiation, growth, repair, and regeneration of muscle, but at this time the factor that is produced to mediate these effects is unknown. It is known that macrophages involved in promoting tissue repair is not muscle specific; they accumulate in numerous tissues during the healing process phase following injury.
A study conducted in 2006 showcased macrophage influences on muscle repair of soleus muscle on mice. The first procedural step was to make sure macrophages are present in the muscle after onset of muscle injury, and then decrease their presence to see what effects were had on the muscle. By using anti-F4/80 to bind to macrophages and render them useless, it was seen that when the second wave of macrophages were depleted, there were many more lesions in the muscle cell membrane between the second and fourth day showing muscle damage when repairing is suppose to occur. After testing for membrane lesions in both the total amount of muscle fibers present, it was noticed that most of the damage occurred in muscle cells that did not have the second subpopulation of macrophages present. Macrophages depletion prevents muscle membrane repair. When examining muscle regeneration, there was a significant reduction in the amount of myonuclei. Depletion of macrophages caused, between the second and fourth day of repair, much less muscle regeneration compared to muscle with macrophage population. Macrophages promote muscle regeneration between the second and fourth day. To determine the influence of macrophages in muscle growth, muscle cross-sectional area in macrophage-depleted muscle area was measured against two muscle sets: muscle that was injured and had macrophage presence and muscle that was not injured and had macrophage presence. The macrophage-depleted muscle showed less growth after four days, and injured muscle with macrophages nearly grew back to the level of uninjured muscle. Macrophage depletion reduces muscle growth during a growth period. The study attempted to examine the appearances of Pax7 and MyoD, but data was not consistent with previous findings.
Fixed macrophages
Macrophage A majority of macrophages are stationed at strategic points where microbial invasion or accumulation of dust is likely to occur. Each type of macrophage, determined by its location, has a specific name:
Name of cell Location Dust cells/Alveolar macrophages pulmonary alveolus of lungs Histiocytes connective tissue Kupffer cells liver Microglia neural tissue Epithelioid cells granulomas Osteoclasts bone Sinusoidal lining cells spleen Investigations concerning Kupffer cells are hampered because in humans Kupffer cells are only accessible for immunohistochemical analysis from biopsies or autopsies. From rats and mice they are difficult to isolate and after purification only approximately 5 million cells can be obtained from one mouse. Macrophages can express paracrine functions within organs that are specific to the function of that organ. In the testis for example, macrophages have been shown to be able to interact with Leydig cells by secreting 25-hydroxycholesterol, an oxysterol that can be converted to testosterone by neighbouring Leydig cells. Also, testicular macrophages may participate in creating an immune privileged environment in the testis, and in mediating infertility during inflammation of the testis.
Involvement in symptoms of diseases

Due to their role in phagocytosis, macrophages are involved in many diseases of the immune system. For example, they participate in the formation of granulomas, inflammatory lesions that may be caused by a large number of diseases. Some disorders, mostly rare, of ineffective phagocytosis and macrophage function have been described. Macrophages are the predominant cells involved in creating the progressive plaque lesions of atherosclerosis. Macrophages also play a role in Human Immunodeficiency Virus (HIV) infection. Like T cells, macrophages can be infected with HIV, and even become a reservoir of ongoing virus replication throughout the body. Macrophages are believed to help cancer cells proliferate as well. They are attracted to oxygen-starved (hypoxic) tumour cells and promote chronic inflammation. Inflammatory compounds such as Tumor necrosis factor (TNF) released by the macrophage activates the gene switch nuclear factor-kappa B. NF-B then enters the nucleus of a tumour cell and turns on production of proteins that stop apoptosis and promote cell proliferation and inflammation.
Recent investigations point a link between streptococcal infection and autoimmune behaving microglia which cause OCD
Adipocyte
Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. There are two types of adipose tissue, white adipose tissue (WAT) and brown adipose tissue (BAT), which are also known as white fat and brown fat, respectively, and comprise two types of fat cells.
Yellow adipose tissue in paraffin section
White fat cells (unilocular cells)

White fat cells or monovacuolar cells contain a large lipid droplet surrounded by a layer of cytoplasm. The nucleus is flattened and located on the periphery. A typical fat cell is 0.1mm in diameter with some being twice that size and others half that size. The fat stored is in a semi-liquid state, and is composed primarily of triglycerides and cholesteryl ester. White fat cells secrete resistin, adiponectin, and leptin. An average adult has 30 billion fat cells with a weight of 30 lbs or 13.5 kg. If excess weight is gained as an adult,
fat cells increase in size about fourfold before dividing and increasing the absolute number of fat cells present.
Brown fat cells (multilocular cells)

Brown fat cells or plurivacuolar cells are polygonal in shape. Unlike white fat cells, these cells have considerable cytoplasm, with lipid droplets scattered throughout. The nucleus is round, and, although eccentrically located, it is not in the periphery of the cell. The brown color comes from the large quantity of mitochondria. Brown fat, also known as "baby fat," is used to generate heat.
Lineage
Although the lineage of adipocytes is still unclear, preadipocytes are undifferentiated fibroblasts that can be stimulated to form adipocytes. Mesenchymal stem cells can differentiate into adipocytes, connective tissue, muscle or bone. Areolar connective tissue is composed of adipocytes. The term "lipoblast" is used to describe the precursor of the adult cell. The term "lipoblastoma" is used to describe a tumor of this cell type.
Cell Turnover
After marked weight loss, the number of fat cells does not decrease (the cells contain less fat). Fat cells swell or shrink but remain constant in number. However, the number of fat cells may increase once existing fat cells are sufficiently full. Approximately 10% of fat cells are renewed annually at all adult ages and levels of body mass index.
Endocrine functions
Adipocyte produce estrogen, potentially being the reason why underweight or overweight are risk factors for infertility.
Osteoblast
Osteoblasts actively synthesizing osteoid that contains two osteocytes Osteoblasts (from the Greek words for "bone" and "germ" or embryonic) are mononucleate cells that are responsible for bone formation; in essence, osteoblasts are sophisticated fibroblasts that express all genes that fibroblasts express, with the addition of the genes for bone sialoprotein and osteocalcin. Osteoblasts produce osteoid, which is composed mainly of Type I collagen. Osteoblasts are also responsible for mineralization of the osteoid matrix. Zinc, copper and sodium are some of the many minerals produced. Bone is a dynamic tissue that is constantly being reshaped by osteoblasts, which build bone, and osteoclasts, which resorb bone. Osteoblast cells tend to decrease as individuals become elderly, thus decreasing the natural renovation of the bone tissue.
Osteogenesis
Osteoblasts arise from osteoprogenitor cells located in the periosteum and the bone marrow. Osteoprogenitors are immature progenitor cells that express the master regulatory transcription factor Cbfa1/Runx2. Osteoprogenitors are induced to differentiate under the influence of growth factors, in particular the bone morphogenetic proteins (BMPs). Aside from BMPs, other growth factors including fibroblast growth factor (FGF), platelet-derived growth factor (PDGF)
and transforming growth factor beta (TGF-) may promote the division of osteoprogenitors and potentially increase osteogenesis. Once osteoprogenitors start to differentiate into osteoblasts, they begin to express a range of genetic markers including Osterix, Col1, BSP, M-CSF, ALP, osteocalcin, osteopontin, and osteonectin. Although the term osteoblast implies an immature cell type, osteoblasts are in fact the mature bone cells entirely responsible for generating bone tissue in animals and humans.
Morphology and histological staining
Osteoblasts (pointer) lining bone and osteocytes within lacunae of bone Hematoxylin and eosin staining reveals that the cytoplasm of osteoblasts is basophilic due to the presence of a large amount of rough endoplasmic reticulum. A large Golgi apparatus is also present in the centre. The nucleus is spherical and large. Active osteoblasts synthesize, and stain positively for, Type-I collagen and alkaline phosphatase.
Osteoblasts and osteocytes

Osteoblasts that become trapped in the bone matrix become osteocytes. They cease to generate osteoid and mineralized matrix, and instead act in a paracrine manner on active osteoblasts. They are believed to act in a mechanosensory manner.
Osteoclast
Osteoclast, with bone below it, showing typical distinguishing characteristics: a large cell with multiple nuclei and a "foamy" cytosol. An osteoclast (from the Greek words for "bone" () and "broken" ()) is a type of bone cell that removes bone tissue by removing its mineralized matrix and breaking up the organic bone (organic dry weight is 90% collagen). This process is known as bone resorption. Osteoclasts were discovered by Kolliker in 1873. Osteoclasts and osteoblasts are instrumental in controlling the amount of bone tissue: osteoblasts form bone, osteoclasts resorb bone. Osteoclasts are formed by the fusion of cells of the monocyte-macrophage cell line. Osteoclasts are characterized by high expression of tartrate resistant acid phosphatase (TRAP) and cathepsin K.
Morphology
Tartrate resistant acid phosphatase positive osteoclast in cell culture
Illustrated cross-section of an activated osteoclast
An osteoclast is a large cell that is 40 micrometer in diameter. They contain 15-20 closely packed oval-shaped nuclei. They are found in bits in the bone surface which are called resorption bays or Howships Lacunae. Osteoclasts are characterized by a cytoplasm with a homogeneous, "foamy" appearance. This appearance is due to a high concentration of vesicles and vacuoles. These vacuoles are lysosomes filled with acid phophatase. The rough endoplasmic reticulum is sparse. The Golgi complex is extensive. At a site of active bone resorption, the osteoclast forms a specialized cell membrane, the "ruffled border," that touches the surface of the bone tissue. The ruffled border, which facilitates removal of the bony matrix, is a morphologic characteristic of an osteoclast that is actively resorbing bone. The ruffled border increases surface area interface for bone resorption. The mineral portion of the matrix (called hydroxyapatite) includes calcium and phosphate ions. These ions are absorbed into small vesicles, which move across the cell and eventually are released into the extracellular fluid, thus increasing levels of the ions in the blood.
Formation
Since their discovery in 1873 there has been considerable debate about their origin. Three theories were dominant: from 1949 to 1970 the connective tissue origin was popular, which stated that osteoclasts and osteoblasts are of the same lineage, and ostoblasts fuse together to form osteoclasts. At certain times osteoclasts dissociate into osteoblasts, which finally form osteocytes. In the 1970s the biphyletic theory became popular; it states that osteoblasts and osteoclasts are of different lineage. It was in the beginning of 1980 that the monocyte phagocytic system was recognized as precursor of osteoclasts. Osteoclast formation requires the presence of RANK ligand (receptor activator of nuclear factor ) and M-CSF (Macrophage colony-stimulating factor). These membrane bound proteins are produced by neighbouring stromal cells and osteoblasts, thus requiring direct contact between these cells and osteoclast precursors. M-CSF acts through its receptor on the osteoclast, c-fms (colony-stimulating factor 1 receptor), a transmembrane tyrosine kinase-receptor, leading to secondary messenger activation of tyrosine kinase Src. Both of these molecules are necessary for osteoclastogenesis and are widely involved in the differentiation of monocyte/macrophage derived cells. RANKL is a member of the tumour necrosis family (TNF), and is essential in osteoclastogenesis. RANKL knockout mice exhibit a phenotype of osteopetrosis and defects of tooth eruption, along with an absence or deficiency of osteoclasts. RANKL activates NF- (nuclear factor-) and NFATc1 (nuclear factor of activated t cells, cytoplasmic, calcineurin-dependent 1) through RANK. NF- activation is stimulated almost immediately after RANKL-RANK interaction occurs, and is not upregulated. NFATc1 stimulation, however, begins ~2448 hours after binding occurs and its expression has been shown to be RANKL dependent. Osteoclast differentiation is inhibited by osteoprotegerin (OPG), which is produced by osteoblasts and binds to RANKL thereby preventing interaction with RANK.
Function
Once activated, they move to areas of microfracture in the bone by chemotaxis. Osteoclasts lie in a small cavity called Howship's lacunae, formed from the digestion of the underlying bone. The sealing zone is the attachment of the osteoclast's plasmalemma to the underlying bone. Sealing zones are bounded by belts of specialized adhesion structures called podosomes. Attachment to the bone matrix is facilitated by integrin receptors, such as v3, via the specific amino acid motif Arg-Gly-Asp in bone matrix proteins, such as osteopontin. The osteoclast releases hydrogen ions through the action of carbonic anhydrase (H2O + CO2 HCO3- + H+) through the ruffled border into the resorptive cavity, acidifying and aiding dissolution of the mineralized bone matrix into Ca2+, H3PO4, H2CO3, water and other substances. Dysfunction of the carbonic anhydrase has been documented to cause some forms of osteopetrosis. Hydrogen ions are pumped against a high concentration gradient by proton pumps, specifically a unique vacuolarATPase. This enzyme has been targeted in the prevention of osteoporosis. In addition, several hydrolytic enzymes, such as members of the cathepsin and matrix metalloprotease(MMP) groups, are released to digest the organic components of the matrix. These enzymes are released into the compartment by lysosomes. Of these hydrolytic enzymes, cathepsin K is of most importance.
Cathepsin K and other cathepsins

Cathepsin K is a collagenolytic, papain-like, cysteine protease that is mainly expressed in osteoclasts, and is secreted into the resorptive pit. Mutations in the cathepsin K gene are associated with pycnodysostosis, a hereditary osteopetrotic disease, characterised by lack of functional cathepsin K expression. Knockout studies of cathepsin K in mice lead to an osteopetrotic phenotype, which, is partially compensated by increased expression of proteases other that cathepsin K and enhanced osteoclastogenesis. Cathepsin K has an optimal enzymatic activity in acidic conditions. It is synthesized as a proenzyme with a molecular weight of 37kDa, and upon activation by autocatalytic cleavage, is transformed into the mature, active form with a molecular weight of ~27kDa. In the osteoclast, cathepsin K functions in the resorptive process. Upon polarization of the osteoclast over the site of resorption, cathepsin K is secreted from the ruffled border into the resorptive pit. Here, it is the major protease involved in the degradation of type I collagen and other noncollagenous proteins, which have been demineralized by the acidic environment of the resorptive pit. From the resorptive pit, cathepsin K transmigrates across the ruffled border, through the osteoclast via intercellular vesicles and is then released by the functional secretory domain. Within these intercellular vesicles, cathepsin K, along with ROS generation by TRAP further degrades bone resorption products. Numerous other cathepsins are expressed in osteoclasts. These include cathepsin B, C, D, E, G, and L. The function of these cysteine and aspartic proteases is generally unknown within bone, and they are expressed at much lower levels than cathepsin K.
Studies on cathepsin L knockout mice have been mixed, with a report of reduced trabecular bone in homozygous and heterozygous cathepsin L knockout mice compared to wild-type and another report finding no skeletal abnormalities.
Matrix metalloproteinases
The matrix metalloproteinases (MMPs) comprise a family of more that 20 zincdependent endopeptidases. The role of matrix metalloproteinases (MMPs) in osteoclast biology is ill-defined, but in other tissue they have been linked with tumor promoting activities, such as activation of growth factors and are required for tumor metastasis and angiogenesis. MMP-9 is associated with the bone microenvironment. It is expressed by osteoclasts, and is known to be required for osteoclast migration and is a powerful gelatinase. Transgenic mice lacking MMP-9 develop defects in bone development, intraosseous angiogenesis, and fracture repair. MMP-13 is believed to be involved in bone resorption and in osteoclast differentiation, as knockout mice revealed decreased osteoclast numbers, osteopetrosis, and decreased bone resorption. MMPs expressed by the osteoclast include MMP-9, -10, -12, and -14. apart from MMP-9, little is known about their relevance to the osteoclast, however, high levels of MMP-14 are found at the sealing zone.
Regulation
Osteoclasts are regulated by several hormones, including parathyroid hormone (PTH) from the parathyroid gland, calcitonin from the thyroid gland, and growth factor interleukin 6 (IL-6). This last hormone, IL-6, is one of the factors in the disease osteoporosis, which is an imbalance between bone resorption and bone formation. Osteoclast activity is also mediated by the interaction of two molecules produced by osteoblasts, namely osteoprotegerin and RANK ligand. Note that these molecules also regulate differentiation of the osteoclast.
Alternate use of term

An osteoclast can also be an instrument used to fracture and reset bones (the origin is Greek osteon:bone and klastos:broken). To avoid confusion, the cell was originally termed osotoclast. When the surgical instrument went out of use, the cell became known by its present name.
Bone marrow barrier

The blood vessels constitute a barrier, inhibiting immature blood cells from leaving the bone marrow. Only mature blood cells contain the membrane proteins required to attach to and pass the blood vessel endothelium. Hematopoietic stem cells may also cross the bone marrow barrier, and may thus be harvested from blood.
Stem cells
The bone marrow stroma contain mesenchymal stem cells (also called marrow stromal cells). These cells are multipotent stem cells that can differentiate into a variety of cell types. Cell types that MSCs have been shown to differentiate into in vitro or in vivo include osteoblasts, chondrocytes, myocytes, adipocytes, and, as described lately, betapancreatic islets cells. They can also transdifferentiate into neuronal cells.
Compartmentalization
There is biologic compartmentalization in the bone marrow, in that certain cell types tend to aggregate in specific areas. For instance, erythrocytes, macrophages and their precursors tend to gather around blood vessels, while granulocytes gather at the borders of the bone marrow.
Chapter 18
Types of Stem Cells
Hematopoietic precursor cells: promyelocyte in the center, two metamyelocytes next to it and band cells from a bone marrow aspirate. Bone marrow contains three types of stem cells: a) Hematopoietic stem cell b) Mesenchymal stem cell c) Endothelial stem cell
1. Hematopoietic stem cell
Note that some complexity is omitted from the diagram. Lymphocytes come from "Lymphoid" line, whereas granulocytes, monocytes, megakaryocytes, and erythrocytes come from "Myeloid" line. Among myeloid cells, granulocytes and monocytes have a common precursor, "CFU-GM". Hematopoietic stem cells (HSCs) are multipotent stem cells that give rise to all the blood cell types including myeloid (monocytes and macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes/platelets, dendritic cells), and lymphoid lineages (T-cells, B-cells, NK-cells). The definition of hematopoietic stem cells has undergone considerable revision in the last two decades. The hematopoietic tissue contains cells with long-term and short-term regeneration capacities and committed multipotent, oligopotent, and unipotent progenitors. HSCs constitute 1:10.000 of cells in myeloid tissue. Intriguingly, HSC do not form a uniform population. Rather, it was shown in a series of landmark experiments between 2002 and 2004 that HSC fall into 16 classes with distinct repopulation kinetics, and 3 categories of lineage bias distinguished by their ratio of lymphoid to myeloid progeny (L/M) in blood. Myeloid-biased (My-bi) HSC have low L/M ratio (>0, <3), while lymphoid-biased (Ly-bi) HSC show a large ratio (>10). The third category consists of the balanced (Bala) HSC for which 3 L/M 10. Stem cells in all three classes are true HSC, their behavior is epigenetically fixed and, together, they make up the complete hematopoietic stem cell compartment. The finding of diversity among HSC contradicts older models, which postulated a single type of HSC that can be continuously molded into different subtypes of HSCs.
In November of 2010, Mick Bhatia, Ph.D., the scientific director at Canada's McMaster University Michael G. DeGroote School of Medicine's Stem Cell and Cancer Research Institute, announced that he had succeeded in transforming adult skin cells into blood precursor, or hematopoietic, stem cells (to be exact, erythroblasts), by working with a gene necessary for the process. Thankfully, when performed in mice, the experiment did not cause cancer- as has happened in certain cases in related research. The method will be further tweaked and perfected so it can be modified for eventual human trials.
Source
Sketch of bone marrow and its cells HSCs are found in the bone marrow of adults, which includes femurs, hip, ribs, sternum, and other bones. Cells can be obtained directly by removal from the hip using a needle and syringe, or from the blood following pre-treatment with cytokines, such as G-CSF (granulocyte colony-stimulating factors), that induce cells to be released from the bone marrow compartment. Other sources for clinical and scientific use include umbilical cord blood, placenta, mobilized peripheral blood. For experimental purposes, fetal liver, fetal spleen, and AGM (Aorta-gonad-mesonephros) of animals are also useful sources of HSCs.
Functional characteristics
Multipotency and self-renewal
As stem cells, HSC are defined by their ability to replenish all blood cell types (Multipotency) and their ability to self-renew. It is known that a small number of HSCs can expand to generate a very large number of daughter HSCs. This phenomenon is used in bone marrow transplantation, when a small number of HSCs reconstitute the hematopoietic system. This indicates that, subsequent to bone marrow transplantation, symmetrical cell divisions into two daughter HSCs must occur. Stem cell self-renewal is thought to occur in the stem cell niche in the bone marrow, and it is reasonable to assume that key signals present in this niche will be important in selfrenewal. There is much interest in the environmental and molecular requirements for HSC self-renewal, as understanding the ability of HSC to replenish themselves will eventually allow the generation of expanded populations of HSC in vitro that can be used therapeutically.
Stem Cell Heterogeneity

It was originally believed that all HSC were alike in their self-renewal and differentiation abilities. This view was first challenged by the 2002 discovery by the Muller-Sieburg group in San Diego that different stem cells can show distinct repopulation patterns that are epigenetically predetermined intrinsic properties of clonal Thy-1lo SCA-1+ lin- c-kit+ HSC. The results of these clonal studies led to the notion of lineage bias. Using the ratio = L / M of lymphoid (L) to myeloid (M) cells in blood as a quantitative marker, the stem cell compartment can be split into three categories of HSC. Balanced (Bala) HSC repopulate peripheral white blood cells in the same ratio of myeloid to lymphoid cells as seen in unmanipulated mice (on average about 15% myeloid and 85% lymphoid cells, or 310). Myeloid-biased (My-bi) HSC give rise to too few lymphocytes resulting in ratios 0<<3, while lymphoid-biased (Ly-bi) HSC generate too few myeloid cells which results in lymphoid-to-myeloid ratios of 10<<oo. All three types are norm three types of HSC and they do not represent stages of differentiation. Rather, these are three classes of HSC, each with an epigenetically fixed differentiation program. These studies also showed that lineage bias is not stochastically regulated or dependent on differences in environmental influence. My-bi HSC self-renew longer than balanced or Ly-bi HSC. The myeloid bias results from reduced responsiveness to the lymphopoetin Interleukin 7 (IL7). Subsequently, other groups confirmed and highlighted the original findings (refer to the excellent mini-review by Timm Schroeder). For example, the Eaves group confirmed in 2007 that repopulation kinetics, long-term self-renewal capacity and My-bi and Ly-bi are stably inherited intrinsic HSC properties. In 2010, the Goodell group provided additional insights about the molecular basis of lineage bias in side population (SP) SCA-1+ lin- c-
kit+ HSC. As previously shown for IL-7 signaling, it was found that a member of the transforming growth factor family (TGF-beta) induces and inhibits the proliferation of My-bi and Ly-bi HSC, respectively.
Functional assays
Cobble stone area-forming Cell (CAFC) assay: This is a cell culture based empirical assay. When plated onto a confluent culture of stromal feeder layer, a fraction of HSCs creep between the gaps (even though the stromal cells are touching each other) and eventually settle between the stromal cells and the substratum (here the dish surface) or trapped in the cellular processes between the stromal cells. Emperipolesis is the in vivo phenomenon in which one cell is completely engulfed into another (e.g., thymocytes into thymic nurse cells); on the other hand, when in vitro, lymphoid lineage cells creep beneath nurse-like cells, the process is called pseudoemperipolesis. This similar phenomenon is more commonly known in HSC field by the cell culture terminology cobble stone area-forming cells (CAFC), which means areas of cluster of cells that look dull cobblestone-like under phase contrast microscopy, compared to the other HSCs, which are refractile. This happens because the cells that are floating loosely on top of the stromal cells are spherical and thus refractile. However, the cells that creep beneath the stromal cells are flattened and thus not refractile. The mechanism of pseudoemperipolesis is only recently coming to light. It may be mediated by interaction through CXCR4 (CD184) the receptor for CXC Chemokines (e.g., SDF1) and 41 integrins..
Mobility
HSCs have a higher potential than other immature blood cells to pass the bone marrow barrier, and thus may travel in the blood from the bone marrow in one bone to another bone. If they settle in the thymus they'll develop into T cells. In the case of fetuses and other extramedullary hematopoiesis HSCs may also settle in the liver or spleen and develop. This ability is the reason why HSCs may be harvested directly from the blood.
Physical characteristics
With regard to morphology, hematopoietic stem cells resemble lymphocytes. They are non-adherent, and rounded, with a rounded nucleus and low cytoplasm-to-nucleus ratio. Since PHSC cannot be isolated as a pure population, it is not possible to identify them in a microscope. The above description is based on the morphological characteristics of a heterogeneous population, of which PHSC are a component.
Markers
In reference to phenotype, hematopoeitic stem cells are identified by their small size, lack of lineage (lin) markers, low staining (side population) with vital dyes such as rhodamine 123 (rhodamineDULL, also called rholo) or Hoechst 33342, and presence of various antigenic markers on their surface.
Cluster of differentiation and other markers

Many of these markers belong to the cluster of differentiation series, like: CD34, CD38, CD90, CD133, CD105, CD45 and also c-kit- the receptor for stem cell factor. The hematopoietic stem cells are negative for the markers that are used for detection of lineage commitment, and are, thus, called Lin-; and, during their purification by FACS, a bunch of up to 14 different mature blood-lineage marker, e.g., CD13 & CD33 for myeloid, CD71 for erythroid, CD19 for B cells, CD61 for megakaryocytic, etc. for humans; and, B220 (murine CD45) for B cells, Mac-1 (CD11b/CD18) for monocytes, Gr-1 for Granulocytes, Ter119 for erythroid cells, Il7Ra, CD3, CD4, CD5, CD8 for T cells, etc. for mice) antibodies are used as a mixture to deplete the lin+ cells or late multipotent progenitors (MPP)s. There are many differences between the human and mice hematopoietic cell markers for the commonly-accepted type of hematopoietic stem cells..

Mouse HSC: CD34lo/-, SCA-1+, Thy1.1+/lo, CD38+, C-kit+, linHuman HSC: CD34+, CD59+, Thy1/CD90+, CD38lo/-, C-kit/CD117+, lin-
However, not all stem cells are covered by these combinations that nonetheless have become popular. In fact, even in humans, there are hematopoietic stem cells that are CD34-/CD38-.. Also some later studies suggested that earliest stem cells may lack c-kit on the cell surface. For human HSCs use of CD133 was one step ahead as both CD34+ and CD34- HSCs were CD133+. Traditional purification method used to yield a reasonable purity level of mouse hematopoietic stem cells, in general, requires a large(~10-12) battery of markers, most of which were surrogate markers with little functional significance, and thus partial overlap with the stem cell populations and sometimes other closely-related cells that are not stem cells. Also, some of these markers (e.g. Thy1) are not conserved across mouse species, and use of markers like CD34- for HSC purification requires mice to be at least 8 weeks old.
SLAM code
Alternative methods that could give rise to similar or better harvest of stem cells is a hot area of research and are presently emerging. One such method uses a signature of SLAM family of cell surface molecules. SLAM (Signaling lymphocyte activation molecule) family is a group of >10 molecules whose genes are mostly located tandemly in a single
locus on chromosome 1 (mouse), all belonging to a subset of immunoglobulin gene superfamily, and originally thought to be involved in T-cell stimulation. This family includes CD48, CD150, CD244, etc., CD150 being the founding member, and, thus, also called slamF1 i.e. SLAM family member 1. The signature SLAM code for the hemopoietic hierarchy are:

Hematopoietic stem cells (HSC): CD150+CD48-CD244Multipotent progenitor cells (MPPs): CD150-CD48-CD244+ Lineage-restricted progenitor cells (LRPs): CD150-CD48+CD244+ Common myeloid progenitor (CMP): lin-SCA-1-c-kit+CD34+CD16/32mid Granulocyte-macrophage progenitor (GMP): lin-SCA-1-ckit+CD34+CD16/32hi Megakaryocyte-erythroid progenitor (MEP): lin-SCA-1-c-kit+CD34CD16/32low
For HSCs, CD150+CD48- was sufficient instead of CD150+CD48-CD244- because CD48 is a ligand for CD244, and both would be positive only in the activated lineage-restricted progenitors. It seems that this code was more efficient than the more tedious earlier set of the large number of markers, and are also conserved across the mouse strains; however, recent work has shown that this method excludes a large number of HSCs and includes an equally large number of non-stem cells. CD150+CD48- gave stem cell purity comparable to Thy1loSCA-1+lin-c-kit+ in mice.
LT-HSC/ST-HSC/Early MPP/Late MPP

Irving Weissman's group at Stanford University that was the first to isolate mouse hematopoietic stem cells in 1988, was also the first to work out the markers to distinguish the mouse long-term (LT-HSC) and short-term (ST-HSC) hematopoietic stem cells (selfrenew-capable), and the Multipotent progenitors (MPP, low or no self-renew capability the later the developmental stage of MPP, the lesser the self-renewal ability and the more of some of the markers like CD4 and CD135):

LT-HSC: CD34-, SCA-1+, Thy1.1+/lo, C-kit+, lin-, CD135-, Slamf1/CD150+ ST-HSC: CD34+, SCA-1+, Thy1.1+/lo, C-kit+, lin-, CD135-, Slamf1/CD150+, Mac1 (CD11b)lo Early MPP: CD34+, SCA-1+, Thy1.1-, C-kit+, lin-, CD135+, Slamf1/CD150-, Mac-1 (CD11b)lo, CD4lo Late MPP: CD34+, SCA-1+, Thy1.1-, C-kit+, lin-, CD135high, Slamf1/CD150-, Mac-1 (CD11b)lo, CD4lo
Nomenclature of hematopoietic colonies and lineages

Between 1948 and 1950, the Committee for Clarification of the Nomenclature of Cells and Diseases of the Blood and Blood-forming Organs issued reports on the nomenclature
of blood cells. An overview of the terminology is shown below, from earliest to final stage of development:

[root]blast pro[root]cyte [root]cyte meta[root]cyte mature cell name
The root for CFU-E is "rubri", for CFU-GM is "granulo" or "myelo" and "mono", for CFU-L is "lympho" and for CFU-Meg is "megakaryo". According to this terminology, the stages of red blood cell formation would be: rubriblast, prorubricyte, rubricyte, metarubricyte, and erythrocyte. However, the following nomenclature seems to be, at present, the most prevalent:
Committee Lineage CFU Process [root]blast "lympho" Lymphoid CFU-L "rubri" "granulo" or "myelo" Myeloid Myeloid CFUCFU-GEMMCFUGEMMCFU- GM E CFU-G granulocytopoiesis "mono" Myeloid CFUGEMMCFUGMCFU-M "megakaryo" Myeloid CFUGEMMCFUMeg thrombocytomonocytopoiesis poiesis Monoblast Megakaryoblast Promegakaryocyte Megakaryocyte
lymphocytopoiesis erythropoiesis Lymphoblast
Proerythroblast Myeloblast Polychromato pro[root]cyte Prolymphocyte philic Promyelocyte Promonocyte erythrocyte Eosino/neutro/basophilic [root]cyte Normoblast myelocyte Eosinophilic/neutrophilic/ basophilic meta[root] Early monocyte metamyelocyte, Large lymphocyte Reticulocyte cyte Eosinophilic/neutrophilic/ basophilic band cell mature cell granulocytes Small lymphocyte Erythrocyte Monocyte name (Eosino/neutro/basophil)
thrombocytes (Platelets)
Osteoclasts also arise from haemopoietic cells of the monocyte/neutrophil lineage, specifically CFU-GM.
Colony-forming units
There are various kinds of colony-forming units:

Colony-forming unit lymphocyte (CFU-L) Colony-forming unit erythrocyte (CFU-E) Colony-forming unit granulo-monocyte (CFU-GM) Colony-forming unit megakaryocyte (CFU-Me)
Colony-forming unit Basophil (CFU-B) Colony-forming unit Eosinophil (CFU-Eo)
The above CFUs are based on the lineage. Another CFU, the colony-forming unitspleen (CFUS) was the basis of an in vivo clonal colony formation, which depends on the ability of infused bone marrow cells to give rise to clones of maturing hematopoietic cells in the spleens of irradiated mice after 8 to 12 days. It was used extensively in early studies, but is now considered to measure more mature progenitor or Transit Amplifying Cells rather than stem cells.
HSC Repopulation Kinetics

Hematopoietic stem cells (HSC) cannot be easily observed directly and, therefore, their behaviors need to be inferred indirectly. Clonal studies are likely the closest technique for single cell in vivo studies of HSC. Here, sophisticated experimental and statistical methods are used to ascertain that, with a high probability, a single HSC is contained in a transplant administered to a lethally irradiated host. The clonal expansion of this stem cell can then be observed over time by monitoring the percent donor-type cells in blood as the host is reconstituted. The resulting time series is defined as the repopulation kinetic of the HSC. The reconstitution kinetics are very heterogeneous. However, using symbolic dynamics, one can show that they fall into a limited number of classes. To prove this, several hundred experimental repopulation kinetics from clonal Thy-1lo SCA-1+ lin- c-kit+ HSC were translated into symbolic sequences by assigning the symbols "+", "-", "~" whenever two successive measurements of the percent donor-type cells have a positive, negative, or unchanged slope, respectively. By using the Hamming distance, the repopulation patterns were subjected to cluster analysis yielding 16 distinct groups of kinetics. To finish the empirical proof, the Laplace add-one approach was used to determine that the probability of finding kinetics not contained in these 16 groups is very small. By corollary, this result shows that the hematopoietic stem cell compartment is also heterogeneous by dynamical criteria.
2. Mesenchymal stem cell
Mesenchymal stem cell showing typical ultrastructural morphology Mesenchymal stem cells, or MSCs, are multipotent stem cells that can differentiate into a variety of cell types, including: osteoblasts (bone cells), chondrocytes (cartilage cells) and adipocytes (fat cells). This has been shown in ex vivo cultures and in vitro or in vivo.
Definition
While the terms Mesenchymal Stem Cell and Marrow Stromal Cell have been used interchangeably, neither term is sufficiently descriptive as discussed below:
Mesenchyme is embryonic connective tissue that is derived from the mesoderm and that differentiates into hematopoietic and connective tissue, whereas MSCs do not differentiate into hematopoietic cells. Stromal cells are connective tissue cells that form the supportive structure in which the functional cells of the tissue reside. While this is an accurate description for one function of MSCs, the term fails to convey the relatively recently-discovered roles of MSCs in the repair of tissue. Because the cells, called MSCs by many labs today, can encompass multipotent cells derived from other non-marrow tissues, such as adult muscle or the dental pulp of deciduous baby teeth, yet do not have the capacity to reconstitute an entire organ, the term Multipotent Stromal Cell has been proposed as a better replacement. An extremely rich source for mesenchymal stem cells is the developing tooth bud of the mandibular third molar. While considered
multipotent, they may prove to be pluripotent The stem cells eventually form enamel, dentin,blood vessels, dental pulp, nervous tissues, including a minimum of 29 different unique end organs. Because of extreme ease in collection at 810 years of age before calcification and minimal to no morbidity they will probably constitute a major source for personal banking, research and multiple therapies. These stem cells have been shown capable of producing hepatocytes. Additionally, amniotic fluid has been shown to be a very rich source of stem cells. As many as 1 in 100 cells collected from and genetic amniocentesis has been shown to be a pluripotent mesenchymal stem cell.
History
In 1924, Russian-born morphologist Alexander A. Maximow used extensive histological findings to identify a singular type of precursor cell within mesenchyme that develops into different types of blood cells. Scientists Ernest A. McCulloch and James E. Till first revealed the clonal nature of marrow cells in the 1960s. An ex vivo assay for examining the clonogenic potential of multipotent marrow cells was later reported in the 1970s by Friedenstein and colleagues. In this assay system, stromal cells were referred to as colony-forming unit-fibroblasts (CFU-f). Subsequent experimentation revealed the plasticity of marrow cells and how their fate could be determined by environmental cues. Culturing marrow stromal cells in the presence of osteogenic stimuli such as ascorbic acid, inorganic phosphate, and dexamethasone could promote their differentiation into osteoblasts. In contrast, the addition of transforming growth factor-beta (TGF-b) could induce chondrogenic markers.
Characteristics
Morphology
Mesenchymal stem cells are characterized morphologically by a small cell body with a few cell processes that are long and thin. The cell body contains a large, round nucleus with a prominent nucleolus, which is surrounded by finely dispersed chromatin particles, giving the nucleus a clear appearance. The remainder of the cell body contains a small amount of Golgi apparatus, rough endoplasmic reticulum, mitochondria, and polyribosomes. The cells, which are long and thin, are widely dispersed and the adjacent extracellular matrix is populated by a few reticular fibrils but is devoid of the other types of collagen fibrils.
Detection
There is no test that can be performed on a single cell to determine whether that cell is an MSC. There are surface antigens that can be used to isolate a population of cells that have
similar self-renewal and differentiation capacities, yet MSCs, as a population, typically do not all express the proposed markers; and it is not certain which ones must be expressed in order for that cell to be classified as an MSC. It may be that the therapeutic properties attributed to MSCs result from the interaction between the different cells that make up an MSC culture, suggesting that there is no one cell that has all the properties.
Differentiation capacity
MSCs have a large capacity for self-renewal while maintaining their multipotency. Beyond that, there is little that can be definitively said. The standard test to confirm multipotency is differentiation of the cells into osteoblasts, adipocytes, and chondrocytes as well as myocytes and possibly neuron-like cells. However, the degree to which the culture will differentiate varies among individuals and how differentiation is induced, e.g., chemical vs. mechanical; and it is not clear whether this variation is due to a different amount of "true" progenitor cells in the culture or variable differentiation capacities of individuals' progenitors. The capacity of cells to proliferate and differentiate is known to decrease with the age of the donor, as well as the time in culture. Likewise, whether this is due to a decrease in the number of MSCs or a change to the existing MSCs is not known.
Immunomodulatory effects
Numerous studies have demonstrated that human MSC avoid allorecognition, interfere with dendritic cell and T-cell function, and generate a local immunosuppressive microenvironment by secreting cytokines. It has also been shown that the immunomodulatory function of human MSC is enhanced when the cells are exposed to an inflammatory environment characterised by the presence of elevated local interferongamma levels. Other studies contradict some of these findings, reflecting both the highly heterogeneous nature of MSC isolates and the considerable differences between isolates generated by the many different methods under development.
Culturing
The majority of modern culture techniques still take a CFU-f approach, where raw unpurified bone marrow or ficoll-purified bone marrow mononuclears are plated directly into cell culture plates or flasks. Mesenchymal stem cells, but not red blood cells or haematopoetic progenitors, are adherent to tissue culture plastic within 24 to 48 hours. However, at least one publication has identified a population of non-adherent MSCs that are not obtained by the direct-plating technique. Other flow cytometry-based methods allow the sorting of bone marrow cells for specific surface markers, such as STRO-1. STRO-1+ cells are generally more homogenous, and have higher rates of adherence and higher rates of proliferation, but the exact differences between STRO-1+ cells and MSCs are not clear.
Clinical use
The mesenchymal stem cells can be activated and mobilized if needed. However, the efficiency is very low. For instance, damage to muscles heals very slowly. However, if there were a method of activating the mesenchymal stem cells, then such wounds would heal much faster. Direct injection or placement of cells into a site in need of repair may be the preferred method of treatment, as vascular delivery suffers from a "pulmonary first pass effect" where intravenous injected cells are sequestered in the lungs. Clinical case reports in orthopedic applications have been published, though the number of patients treated is small and these methods still lack rigorous study demonstrating effectiveness. Wakitani has published a small case series of nine defects in five knees involving surgical transplantation of mesenchymal stem cells with coverage of the treated chondral defects.
3. Endothelial stem cell
CD34+ endothelial cell among a population of bovine aortic endothelial cells Endothelial stem cells (or endothelial precursor cells) are multipotent stem cells. They are one of the three types of stem cells to be found in bone marrow.
Chapter 19
Hematopoietic Stem Cell Transplantation
Hematopoietic stem cell transplantation (HSCT) is the transplantation of Pluripotential hemopoietic stem cell or blood, often derived from bone marrow, umbilical cord blood or hemopoietic stem cells derived from a placenta. Stem cell transplantation is a medical procedure in the fields of hematology and oncology, most often performed for people with diseases of the blood, bone marrow, or certain cancer. With the availability of the stem cell growth factors GM-CSF and G-CSF, most hematopoietic stem cell transplantation procedures are now performed using stem cells collected from the peripheral blood such as cord blood or placenta derived stem cells, rather than from the bone marrow. Collecting peripheral blood stem cells provides a bigger graft, does not require that the donor be subjected to general anesthesia to collect the graft, results in a shorter time to engraftment, and may provide for a lower long-term relapse rate. Hematopoietic stem cell transplantation remains a risky procedure with many possible complications; it has traditionally been reserved for patients with life-threatening diseases. While occasionally used experimentally in nonmalignant and nonhematologic indications such as severe disabling auto-immune disease and cardiovascular disease, the risk of fatal complications appears too high to gain wider acceptance.
History
Georges Math, a French oncologist, performed the first bone marrow transplant in 1959 on six Yugoslavian nuclear workers whose own marrow had been damaged by irradiation. Math later pioneered the use of bone marrow transplants in the treatment of leukemia. Stem cell transplantation was pioneered using bone-marrow-derived stem cells by a team at the Fred Hutchinson Cancer Research Center from the 1950s through the 1970s led by E. Donnall Thomas, whose work was later recognized with a Nobel Prize in Physiology or Medicine. Thomas' work showed that bone marrow cells infused intravenously could repopulate the bone marrow and produce new blood cells. His work also reduced the likelihood of developing a life-threatening complication called graft-versus-host disease.
The first physician to perform a successful human bone marrow transplant on a disease other than cancer was Robert A. Good at the University of Minnesota in 1968.
Indications for stem cell transplantation

Many recipients of HSCTs are multiple myeloma or leukemia patients who would not benefit from prolonged treatment with, or are already resistant to, chemotherapy. Candidates for HSCTs include pediatric cases where the patient has an inborn defect such as severe combined immunodeficiency or congenital neutropenia with defective stem cells, and also children or adults with aplastic anemia who have lost their stem cells after birth. Other conditions treated with stem cell transplants include sickle-cell disease, myelodysplastic syndrome, neuroblastoma, lymphoma, Ewing's Sarcoma, Desmoplastic small round cell tumor and Hodgkin's disease. More recently non-myeloablative, or socalled "mini transplant," procedures have been developed that require smaller doses of preparative chemo and radiation. This has allowed HSCT to be conducted in the elderly and other patients who would otherwise be considered too weak to withstand a conventional treatment regimen.
Graft types
Autologous
Autologous HSCT requires the extraction (apheresis) of haematopoietic stem cells (HSC) from the patient and storage of the harvested cells in a freezer. The patient is then treated with high-dose chemotherapy with or without radiotherapy with the intention of eradicating the patient's malignant cell population at the cost of partial or complete bone marrow ablation (destruction of patient's bone marrow function to grow new blood cells). The patient's own stored stem cells are then returned to his/her body, where they replace destroyed tissue and resume the patient's normal blood cell production. Autologous transplants have the advantage of lower risk of infection during the immunecompromised portion of the treatment since the recovery of immune function is rapid. Also, the incidence of patients experiencing rejection (graft-versus-host disease) is very rare due to the donor and recipient being the same individual. These advantages have established autologous HSCT as one of the standard second-line treatments for such diseases as lymphoma. However, for others such as Acute Myeloid Leukemia, the reduced mortality of the autogenous relative to allogeneic HSCT may be outweighed by an increased likelihood of cancer relapse and related mortality, and therefore the allogeneic treatment may be preferred for those conditions. Researchers have conducted small studies using non-myeloablative hematopoietic stem cell transplantation as a possible treatment for type I (insulin dependent) diabetes in children and adults. Results have been promising; however, at the time of this writing, it is premature to speculate as to whether these experiments will lead to effective treatments for diabetes.
Allogeneic
Allogeneic HSCT involves two people: the (healthy) donor and the (patient) recipient. Allogeneic HSC donors must have a tissue (HLA) type that matches the recipient. Matching is performed on the basis of variability at three or more loci of the (HLA) gene, and a perfect match at these loci is preferred. Even if there is a good match at these critical alleles, the recipient will require immunosuppressive medications to mitigate graft-versus-host disease. Allogeneic transplant donors may be related (usually a closely HLA matched sibling), syngeneic (a monozygotic or 'identical' twin of the patient necessarily extremely rare since few patients have an identical twin, but offering a source of perfectly HLA matched stem cells) or unrelated (donor who is not related and found to have very close degree of HLA matching). A "savior sibling" may be intentionally selected by preimplantation genetic diagnosis in order to match a child both regarding HLA type and being free of any obvious inheritable disorder. Allogeneic transplants are also performed using umbilical cord blood as the source of stem cells. In general, by transplanting healthy stem cells to the recipient's immune system, allogeneic HCSTs appear to improve chances for cure or long-term remission once the immediate transplant-related complications are resolved. A compatible donor is found by doing additional HLA-testing from the blood of potential donors. The HLA genes fall in two categories (Type I and Type II). In general, mismatches of the Type-I genes (i.e. HLA-A, HLA-B, or HLA-C) increase the risk of graft rejection. A mismatch of an HLA Type II gene (i.e. HLA-DR, or HLA-DQB1) increases the risk of graft-versus-host disease. In addition a genetic mismatch as small as a single DNA base pair is significant so perfect matches require knowledge of the exact DNA sequence of these genes for both donor and recipient. Leading transplant centers currently perform testing for all five of these HLA genes before declaring that a donor and recipient are HLA-identical. Race and ethnicity are known to play a major role in donor recruitment drives, as members of the same ethnic group are more likely to have matching genes, including the genes for HLA.
HSC sources and storage

To limit the risks of transplanted stem cell rejection or of severe graft-versus-host disease in allogeneic HSCT, the donor should preferably have the same human leukocyte antigens (HLA) as the recipient. About 25 to 30 percent of allogeneic HSCT recipients have an HLA-identical sibling. Even so-called "perfect matches" may have mismatched minor alleles that contribute to graft-versus-host disease.
Bone marrow
Bone marrow harvest In the case of a bone marrow transplant, the HSC are removed from a large bone of the donor, typically the pelvis, through a large needle that reaches the center of the bone. The technique is referred to as a bone marrow harvest and is performed under general anesthesia.
Peripheral blood stem cells

Peripheral blood stem cells are now the most common source of stem cells for allogeneic HSCT. They are collected from the blood through a process known as apheresis. The donor's blood is withdrawn through a sterile needle in one arm and passed through a machine that removes white blood cells. The red blood cells are returned to the donor. The peripheral stem cell yield is boosted with daily subcutaneous injections of Granulocyte-colony stimulating factor, serving to mobilize stem cells from the donor's bone marrow into the peripheral circulation.
Amniotic fluid
It is also possible to extract hematopietic stem cells from amniotic fluid for both autologous or heterologous use at the time of childbirth.
Umbilical cord blood

Umbilical cord blood is obtained when a mother donates her infant's umbilical cord and placenta after birth. Cord blood has a higher concentration of HSC than is normally found in adult blood. However, the small quantity of blood obtained from an umbilical cord (typically about 50 mL) makes it more suitable for transplantation into small children than into adults. Newer techniques using ex-vivo expansion of cord blood units or the use of two cord blood units from different donors are being explored to allow cord blood transplants to be used in adults. It is used e.g. in children being born after preimplantation genetic diagnosis (PGD) for human leucocyte antigen (HLA) matching in order to donate to a sick sibling requiring HSCT.
Storage of HSC
Unlike other organs, bone marrow cells can be frozen for prolonged periods (cryopreserved) without damaging too many cells. This is necessary for autologous HSC because the cells must be harvested months in advance of the transplant treatment. In the case of allogeneic transplants fresh HSC are preferred in order to avoid cell loss that might occur during the freezing and thawing process. Allogeneic cord blood is stored frozen at a cord blood bank because it is only obtainable at the time of childbirth. To cryopreserve HSC a preservative, DMSO, must be added and the cells must be cooled very slowly in a control rate freezer to prevent osmotic cellular injury during ice crystal formation. HSC may be stored for years in a cryofreezer which typically utilizes liquid nitrogen because it is non-toxic and it is very cold (boiling point -196C.)
Transplant as a use for treatment of HIV

A bone marrow transplant performed on an American man residing in Germany (Gero Htter) appears to have successfully cured him of both leukemia as well as HIV. Researchers emphasize that this is an unusual case. The donor marrow was selected from 60 matching donors for being [CCR5]-32 homozygous. This genetic trait blocks the primary route by which HIV attaches itself to cells for entry. Roughly 1:100 Europeans and Americans have this inherited mutation but it is rarer in other populations.
Conditioning regimens
Myeloablative transplants
The chemotherapy or irradiation given immediately prior to a transplant is called the conditioning or preparative regimen, the purpose of which is to help eradicate the patient's disease prior to the infusion of HSC and to suppress immune reactions. The bone marrow can be ablated with dose-levels that cause minimal injury to other tissues. In allogeneic transplants a combination of cyclophosphamide with busulfan or total body irradiation is commonly employed. This treatment also has an immunosuppressive effect
which prevents rejection of the HSC by the recipient's immune system. The posttransplant prognosis often includes acute and chronic graft-versus-host disease which may be life-threatening; however in certain leukemias this can coincide with protection against cancer relapse owing to the graft versus tumor effect. Autologous transplants may also use similar conditioning regimens, but many other chemotherapy combinations can be used depending on the type of disease.
Non-myeloablative (or "mini") allogeneic transplants

This is a newer treatment approach using lower doses of chemotherapy and radiation which are too low to eradicate all of the bone marrow cells of a recipient. Instead, nonmyeloablative transplants run lower risks of serious infections and transplant-related mortality while relying upon the graft versus tumor effect to resist the inherent increased risk of cancer relapse. Also significantly, while requiring high doses of immunosuppressive agents in the early stages of treatment, these doses are less than for conventional transplants. This leads to a state of mixed chimerism early after transplant where both recipient and donor HSC coexist in the bone marrow space. Decreasing doses of immunosuppressive therapy then allows donor T-cells to eradicate the remaining recipient HSC and to induce the graft versus tumor effect. This effect is often accompanied by mild graft-versus-host disease, the appearance of which is often a surrogate for the emergence of the desirable graft versus tumor effect, and also serves as a signal to establish an appropriate dosage level for sustained treatment with low levels of immunosuppressive agents. Because of their gentler conditioning regimens, these transplants are associated with a lower risk of transplant-related mortality and therefore allow patients who are considered too high-risk for conventional allogeneic HSCT to undergo potentially curative therapy for their disease. These new transplant strategies are still somewhat experimental, but are being used more widely on elderly patients unfit for myeloablative regimens and for whom the higher risk of cancer relapse may be acceptable.
Engraftment
After several weeks of growth in the bone marrow, expansion of HSC and their progeny is sufficient to normalize the blood cell counts and reinitiate the immune system. The offspring of donor-derived hematopoietic stem cells have been documented to populate many different organs of the recipient, including the heart, liver, and muscle, and these cells had been suggested to have the abilities of regenerating injured tissue in these organs. However, recent research has shown that such lineage infidelities does not occur as a normal phenomenon.
Complications and side effects

HSCT is associated with a high treatment-related mortality in the recipient (10% or higher), which limits its use to conditions that are themselves life-threatening. Major complications are veno-occlusive disease, mucositis, infections (sepsis) and graft-versushost disease.
Infection
Bone marrow transplantation usually requires that the recipient's own bone marrow be destroyed ("myeloablation"). Prior to "engraftment" patients may go for several weeks without appreciable numbers of white blood cells to help fight infection. This puts a patient at high risk of infections, sepsis and septic shock, despite prophylactic antibiotics, and accounts for a large share of treatment-related mortality. The immunosuppressive agents employed in allogeneic transplants for the prevention or treatment of graft-versushost disease further increase the risk of opportunistic infection. Immunosuppressive drugs are given for a minimum of 6-months after a transplantation, or much longer if required for the treatment of graft-versus-host disease. Transplant patients lose their acquired immunity, for example immunity to childhood diseases such as measles or polio. For this reason transplant patients must be re-vaccinated with childhood vaccines once they are off immunosuppressive medications.
Veno-occlusive disease
Severe liver injury is termed hepatic veno-occlusive disease (VOD). Elevated levels of bilirubin, hepatomegaly and fluid retention are clinical hallmarks of this condition. There is now a greater appreciation of the generalized cellular injury and obstruction in hepatic vein sinuses, and it has thus been referred to as sinusoidal obstruction syndrome (SOS). Severe cases are associated with a high mortality. Anticoagulants or defibrotide may be effective in reducing the severity of VOD but may also increase bleeding complications. Ursodiol has been shown to help prevent VOD, presumably by helping the flow of bile.
Mucositis
The injury of the mucosal lining of the mouth and throat and is a common regimenrelated toxicity following ablative HSCT regimens. It is usually not life-threatening but is very painful, and prevents eating and drinking. Mucositis is treated with pain medications plus intravenous infusions to prevent dehydration and malnutrition.
Graft-versus-host disease (GVHD)

Graft-versus-host disease (GVHD) is a common complication of allogeneic bone marrow transplantation in which functional immune cells in the transplanted marrow recognize the recipient as "foreign" and mount an immunologic attack. It can also take place in a blood transfusion under certain circumstances.
Causes
According to the 1966 Billingham Criteria, 3 criteria must be met in order for GVHD to occur.

Administration of an immunocompetent graft, with viable and functional immune cells. The recipient is immunologically disparate - histoincompatible. The recipient is immunocompromised and therefore cannot destroy or inactivate the transplanted cells.
After bone marrow transplantation, T cells present in the graft, either as contaminants or intentionally introduced into the host, attack the tissues of the transplant recipient after perceiving host tissues as antigenically foreign. The T cells produce an excess of cytokines, including TNF- and interferon-gamma (IFN). A wide range of host antigens can initiate graft-versus-host-disease, among them the human leukocyte antigens (HLAs). However, graft-versus-host disease can occur even when HLA-identical siblings are the donors. HLA-identical siblings or HLA-identical unrelated donors often have genetically different proteins (called minor histocompatibility antigens) that can be presented by MHC molecules to the donor's T-cells, which see these antigens as foreign and so mount an immune response. While donor T-cells are undesirable as effector cells of graft-versus-host-disease, they are valuable for engraftment by preventing the recipient's residual immune system from rejecting the bone marrow graft (host-versus-graft). Additionally, as bone marrow transplantation is frequently used to treat cancer, mainly leukemias, donor T-cells have proven to have a valuable graft-versus-tumor effect. A great deal of current research on allogeneic bone marrow transplantation involves attempts to separate the undesirable graft-vs-host-disease aspects of T-cell physiology from the desirable graft-versus-tumor effect.
Types
Clinically, graft-versus-host-disease is divided into acute and chronic forms.
The acute or fulminant form of the disease (aGVHD) is normally observed within the first 100 days post-transplant, and is a major challenge to transplants owing to associated morbidity and mortality. The chronic form of graft-versus-host-disease (cGVHD) normally occurs after 100 days. The appearance of moderate to severe cases of cGVHD adversely influences long-term survival.
This distinction is not arbitrary: acute and chronic graft-versus-host-disease appear to involve different immune cell subsets, different cytokine profiles, somewhat different host targets, and respond differently to treatment. Brandon Schmidt has been credited
with first discovering Graft Versus Host Disease in 1927. Later in 1987, the disease was further described with genetic explanation by Kevin Smith in 'IJ ed. 867-5309'
Clinical manifestation
Classically, acute graft-versus-host-disease is characterized by selective damage to the liver, skin and mucosa, and the gastrointestinal tract. Newer research indicates that other graft-versus-host-disease target organs include the immune system (the hematopoietic systeme.g. the bone marrow and the thymus) itself, and the lungs in the form of idiopathic pneumonitis. Chronic graft-versus-host-disease also attacks the above organs, but over its long-term course can also cause damage to the connective tissue and exocrine glands. Acute GVHD of the GI tract can result in severe intestinal inflammation, sloughing of the mucosal membrane, severe diarrhea, abdominal pain, nausea, and vomiting. This is typically diagnosed via intestinal biopsy. Liver GVHD is measured by the bilirubin level in acute patients. Skin GVHD results in a diffuse maculopapular rash, sometimes in a lacy pattern. Acute GVHD is staged as follows: overall grade (skin-liver-gut) with each organ staged individually from a low of 1 to a high of 4. Patients with grade IV GVHD usually have a poor prognosis. If the GVHD is severe and requires intense immunosuppression involving steroids and additional agents to get under control, the patient may develop severe infections as a result of the immunosuppression and may die of infection.
Transfusion-associated GVHD
This type of GVHD is associated with transfusion of un-irradiated blood to immunocompromised recipients. It can also occur in situations where the blood donor is homozygous and the recipient is heterozygous for an HLA haplotype. It is associated with higher mortality (80-90%) due to involvement of bone marrow lymphoid tissue, however the clinical manifestations are similar to GVHD resulting from bone marrow transplantation. Transfusion-associated GVHD is rare in modern medicine. It is almost entirely preventable by controlled irradiation of blood products to inactivate the white blood cells (including lymphocytes) within.
In thymus transplantation
Thymus transplantation may be said to be able to cause a special type of GVHD because the recipients thymocytes would use the donor thymus cells as models when going through the negative selection to recognize self-antigens, and could therefore still mistake own structures in the rest of the body for being non-self. This is a rather indirect GVHD because it is not directly cells in the graft itself that causes it, but cells in the graft that make the recipient's T cells act like donor T cells. It can be seen as a multiple-organ autoimmunity in xenotransplantation experiments of the thymus between different species. Autoimmune disease is a frequent complication after human allogeneic thymus
transplantation, found in 42% of subjects over 1 year post transplantation. However, this is partially explained by that the indication itself, that is, complete DiGeorge syndrome, increases the risk of autoimmune disease.
Prevention
DNA-based tissue typing allows for more precise HLA matching between donors and transplant patients, which has been proven to reduce the incidence and severity of GVHD and to increase long-term survival. The T-cells of umbilical cord blood (UCB) have an inherent immunological immaturity, and the use of UCB stem cells in unrelated donor transplants has a reduced incidence and severity of GVHD. Methotrexate, ciclosporin and tacrolimus are common drugs used for GVHD prophylaxis. Graft-versus-host-disease can largely be avoided by performing a T-cell depleted bone marrow transplant. However these types of transplants come at a cost of diminished graft-versus-tumor effect, greater risk of engraftment failure or cancer relapse, and general immunodeficiency, resulting in a patient more susceptible to viral, bacterial, and fungal infection. In a multi-center study, disease-free survival at 3 years was not different between T cell depleted and T cell replete transplants.
Treatment of GVHD
Intravenously administered corticosteroids, such as prednisone, are the standard of care in acute GVHD and chronic GVHD. The use of these corticosteroids is designed to suppress the T-cell mediated immune onslaught on the host tissues; however in high doses this immune-suppression raises the risk of infections and cancer relapse. Therefore it is desirable to taper off the post-transplant high level steroid doses to lower levels, at which point the appearance of mild GVHD may be welcome, especially in HLA mis-matched patients, as it is typically associated with a graft-versus-tumor effect.
Investigational therapies for graft-versus-host disease

There are a large number of clinical trials either ongoing or recently completed in the investigation of graft-versus-host disease treatment and prevention.
Graft-versus-tumor effect (GVT)

The beneficial aspect of the Graft-versus-Host phenomenon is known as the "graft versus tumor" or "graft versus leukemia" effect. For example, HSCT patients with either acute and in particular chronic graft-versus-host disease after an allogeneic transplant tend to have a lower risk of cancer relapse. This is due to a therapeutic immune reaction of the grafted donor T lymphocytes against the diseased bone marrow of the recipient. This lower rate of relapse accounts for the increased success rate of allogeneic transplants compared to transplants from identical twins, and indicates that allogeneic HSCT is a
form of immunotherapy. GVT is the major benefit of transplants which do not employ the highest immuno-suppressive regimens. Graft versus tumor is mainly beneficial in diseases with slow progress, e.g. chronic leukemia, low-grade lymphoma, and some cases multiple myeloma. However, it is less effective in rapidly growing acute leukemias. If cancer relapses after HSCT, another transplant can be performed, infusing the patient with even more of the donor's white blood cells.
General prognosis
Prognosis in HSCT varies widely dependent upon disease type, stage, stem cell source, HLA-matched status (for allogeneic HCST) and conditioning regimen. A transplant offers a chance for cure or long-term remission if the inherent complications of graft versus host disease, immuno-suppressive treatments and the spectrum of opportunistic infections can be survived. In recent years, survival rates have been gradually improving across almost all populations and sub-populations receiving transplants. Mortality for allogeneic stem cell transplantation can be estimated using the prediction model created by Sorror et al., using the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI). The HCT-CI was derived and validated by investigators at the Fred Hutchinson Cancer Research Center (Seattle, WA). The HCT-CI modifies and adds to a well-validated comorbidity index, the Charlson Comorbidity Index (CCI) (Charlson et al.) The CCI was previously applied to patients undergoing allogeneic HCT but appears to provide less survival prediction and discrimination than the HCT-CI scoring system.
Risks to Donor following Peripheral Harvesting of Stem Cells

The risks of a complication depend on patient characteristics, health care providers and the apheresis procedure, and the colony-stimulating factor used (G-CSF, GM-CSF). GCSF drugs include Filgrastim (Neupogen, Neulasta), and lenograstim(Graslopin).
Drug risks
Filgrastim is typically dosed in the 10 microgram/kg level for 45 days during the harvesting of stem cells. The documented adverse effects of filgrastim include splenic rupture (indicated by left upper abdominal or shoulder pain, risk 1 in 40000), Adult respiratory distress syndrome (ARDS), alveolar hemorrage, and allergic reactions (usually expressed in first 30 minutes, risk 1 in 300). In addition, platelet and hemoglobin levels dip post-procedure, not returning to normal until one month. The question of whether patients over 65 react the same as patients under 65 has not been sufficiently examined. Coagulation issues and inflammation of atherosclerotic plaques are known to occur as a result of G-CSF injection. G-CSF has also been described to
induce genetic changes in mononuclear cells of normal donors. There is evidence that myelodysplasia (MDS) or acute myeloid leukaemia (AML)can be induced by GCSF in susceptible individuals.
Access risks
Blood was drawn peripherally in a majority of patients, but a central line to jugular/subclavian/femoral veins may be used in 16% of women and 4% of men. Adverse reactions during apheresis were experienced in 20% of women and 8% of men, these adverse events primarily consisted of numbness/tingling, multiple line attempts, and nausea.
Clinical observations
A study involving 2408 donors (1860 years) indicated that bone pain (primarily back and hips) as a result of filgrastim treatment is observed in 80% of donors by day 4 postinjection. This pain responded to acetaminophen or ibuprofen in 65% of donors and was characterized as mild to moderate in 80% of donors and severe in 10%. Bone pain receded post-donation to 26% of patients 2 days post-donation, 6% of patients one week post-donation, and <2% 1 year post-donation.It is recommended for people with back pain history, not to be a donor. Other symptoms observed in more than 40% of donors include myalgia, headache, fatigue, and insomnia. These symptoms all returned to baseline 1 month post-donation, except for some cases of persistent fatigue in 3% of donors. In one metastudy that incorporated data from 377 donors, 44% of patients reported having adverse side effects after peripheral blood HSCT. Side effects included pain prior to the collection procedure as a result of GCSF injections, post-procedural generalized skeletal pain, fatigue and reduced energy.
Severe reactions
A study that surveyed 2408 donors found that serious adverse events (requiring prolonged hospitalization) occurred in 15 donors (at a rate of 0.6%), although none of these events were fatal. Donors were not observed to have higher than normal rates of cancer with up to 48 years of follow up. One study based on a survey of medical teams covered approximately 24,000 peripheral blood HSCT cases between 1993 and 2005, and found a serious cardiovascular adverse reaction rate of about 1 in 1500. This study reported a cardiovascular-related fatality risk within the first 30 days HSCT of about 2 in 10000. For this same group, severe cardiovascular events were observed with a rate of about 1 in 1500. The most common severe adverse reactions were pulmonary edema/deep vein thrombosis, splenic rupture, and myocardial infarction. Haematological malignancy induction was comparable to that observed in the general population with only 15 reported cases within 4 years.
Conditions treated with bone marrow or HSC transplantation

Acquired
Malignancies o Hematological Leukemias Acute lymphoblastic leukemia (ALL) Acute myeloid leukemia (AML) Chronic lymphocytic leukemia (CLL) Chronic myelogenous leukemia (CML), accelerated phase or blast crisis Lymphomas Hodgkin's disease Non-Hodgkin's lymphoma Myelomas Multiple myeloma (Kahler's disease) o Solid tumor cancers Neuroblastoma Desmoplastic small round cell tumor Ewing's sarcoma Choriocarcinoma Hematologic disease o Phagocyte disorders Myelodysplasia o Anemias Paroxysmal nocturnal hemoglobinuria (PNH; severe aplasia) Aplastic anemia Acquired pure red cell aplasia o Myeloproliferative disorders Polycythemia vera Essential thrombocytosis Myelofibrosis Metabolic disorders o Amyloidoses Amyloid light chain (AL) amyloidosis Environmentally-induced diseases o Radiation poisoning Virus diseases o HIV
Congenital
Lysosomal storage disorders o Lipidoses (disorders of lipid storage) Neuronal ceroid lipofuscinoses
Infantile neuronal ceroid lipofuscinosis (INCL, Santavuori disease,) Jansky-Bielschowsky disease (late infantile neuronal ceroid lipofuscinosis) Sphingolipidoses Niemann-Pick disease Gaucher disease Leukodystrophies Adrenoleukodystrophy Metachromatic leukodystrophy Krabbe disease (globoid cell leukodystrophy) o Mucopolysaccharidoses
Hurler syndrome (MPS I H, -L-iduronidase deficiency) Scheie syndrome (MPS I S) Hurler-Scheie syndrome (MPS I H-S) Hunter syndrome (MPS II, iduronidase sulfate deficiency) Sanfilippo syndrome (MPS III) Morquio syndrome (MPS IV) Maroteaux-Lamy syndrome (MPS VI) Sly syndrome (MPS VII) o Glycoproteinoses

Other
Mucolipidosis II (I-cell disease) Fucosidosis Aspartylglucosaminuria Alpha-mannosidosis Wolman disease (acid lipase deficiency)
Immunodeficiencies o T-cell deficiencies Ataxia telangiectasia DiGeorge syndrome o Combined T- and B-cell deficiencies Severe combined immunodeficiency (SCID), all types o Well-defined syndromes Wiskott-Aldrich syndrome o Phagocyte disorders Kostmann syndrome Shwachman-Diamond syndrome o Immune dysregulation diseases Griscelli syndrome, type II o Innate immune deficiencies
NF-Kappa-B Essential Modulator (NEMO) deficiency (Inhibitor of Kappa Light Polypeptide Gene Enhancer in B Cells Gamma Kinase deficiency) Hematologic diseases
Hemoglobinopathies Sickle cell disease thalassemia major (Cooley's anemia) o Anemias Aplastic anemia Diamond-Blackfan anemia Fanconi anemia o Cytopenias Amegakaryocytic thrombocytopenia o Hemophagocytic syndromes Hemophagocytic lymphohistiocytosis (HLH)

Anatomy of Bones

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Anatomy of Bones

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First Edition, 2012

Frontal Bone and Parietal Bone

Frontal bone highlighted in red

Figure 1 : Left parietal bone. Outer surface.

Figure 2 : Left parietal bone. Inner surface.

Latin Gray's MeSH

os parietale subject #32 133 Parietal+bone

Side view of the skull

Base of the skull. Upper surface.

Sagittal section of skull

Temporal Bone and Occipital Bone

left temporal bone. Prepared and articulate

The skull from the front

Sphenoid bone visible center right

Side view of the skull

Left infratemporal fossa

Sagittal section of skull

Articulation of the mandible. Lateral aspect.

Base of the skull. Upper surface.

Sagittal section of skull. (Occipital bone is at right, in blue.)

Base of the skull. Upper surface. (Occipital bone is at bottom, in blue.)

Base of skull. Inferior surface.

Membrana tectoria, transverse, and alar ligaments

Muscles connecting the upper extremity to the vertebral column

Sphenoid Bone and Ethmoid Bone

Sphenoid bone, upper surface.

Latin Gray's MeSH

os sphenoidale subject #35 147 Sphenoid+Bone

Lateral wall of nasal cavity, showing ethmoid bone in position

Sphenoid bone visible center right

Lateral view of the skull

Horizontal section of nasal and orbital cavities

Floor of the skull

Roof, floor, and lateral wall of left nasal cavity

Latin Gray's MeSH

os ethmoidale subject #36 153 Ethmoid+bone

Ethmoid bone from above

Perpendicular plate of ethmoid

Ethmoid bone (frontal view)

Ethmoid bone from the right side

Sphenoid bone visible center right

Side view of the skull

The skull from the front

Medial wall of left orbit

Medial wall of left nasal fossa

Roof, floor, and lateral wall of left nasal cavity

Side view. Maxilla visible at bottom left, in green.

Front view. Maxilla visible at center, in yellow.

Gray's Precursor MeSH

subject #38 157 1st branchial arch Maxilla

Left maxilla. Outer surface.

Left maxillary sinus opened from the exterior

Left maxilla. Nasal surface.

Side view of the teeth and jaws

The bony palate and alveolar arch

Articulation of left palatine bone with maxilla

Bone: Palatine bone

Sagittal section of skull. (Palatine bone is labeled at bottom left.)

subject #41 166 Palatine+Bone

Articulation of left palatine bone with maxilla

Medial wall of left orbit

Roof, floor, and lateral wall of left nasal cavity

Bone: Zygomatic bone