Lecture by Dr.AlSoheibany
Inflammation of the
bone and marrow cavity.
be an acute or chronic.
agents arepyogenicbacteria and mycobacterium tuberculosis.
Most cases of acute purulent osteomyelitis are caused by
bacteria. Organisms reach the bone by:
Direct extension from a focus of
acute infection in the adjacent joint or soft tissue.
Traumatic implantation after
compound fractures or orthopedic surgical procedures.
Escherichia coli and
group B streptococci are
important causes of acute
neonates, while Salmonella is an especially
common pathogen responsible for
osteomyelitis occuring in
patients with sickle
anaerobes are responsible for many cases
osteomyelitis developing after bone trauma.
inflammatory infiltrate at the site of
bacterial invasion. The location of infection varies with age.
In children, metaphyses of long bones are typically involved. In
adults, hematogenous osteomyelities primarily affects vertebral
bodies. The involved bone becomes necrotic within a matter of
Developments as a sequela of acute
A repair reaction that includes
osteoclast activation, fibrobastic proliferation and new bone
Residual necrotic bone, termed the
sequestrum, may be resorbed by osteoclastic activity.
Larger sequestra are eventually
surrounded by a rim of reactive bone, termed the involucrum.
may be complicated by the developments of draining sinuses that open
on the overlying skin and by pathologic fractures. Less common
complications of chronic osteo-myelitis include squamous cell
carcinoma developing in long-standing sinus tracts and in exceptional
cases, sarcomas and secon-dary amyloidosis.
Systemic manifestations similar to
those seen in any other acute infection, such as fever, malaise and
Local signs and symptoms of bone
inflammation may be subtle and easily missed, particularly in infants
and young children.
Local pain, swelling and redness may
occur in some adults in the absence of systemic complaints.
Radionuclide scans (e.g. gallium
scans) are helpful in locating the site of infection early in the
course of osteomyelitis.
Infections of the bone demand
vigorous and prolonged antimicrobial therapy and surgical
Complications of osteomyelitis
include pathologic fractures, bacteremia and endocarditis.
Much less common complications are
reactive systemic amyloidosis and squamous cell carcinomas within
chronic sinus tracts.
Mycobacterial infection of bone.
Bone infection complicates an
estimated 1% to 35 of cases of pulmonary tuberculosis.
Reach the bone through the
bloodstream, although direct spread from a contiguous focus of
Long bones and vertebrae are favored
sites of localization.
Pott disease. “ when TB is in
to tissue may result in cell death
and tissue destruction.
Healing on the other hand is the body response to injury in an
attempt to restore normal structure and function.
process of healing involves 2 distinct process:
when healing takes place by proliferation of parenchymal cells and
usually results in complete restoration of the original tissues.
the healing takes place by proliferation of connective tissue
elements resulting in fibrosis and scarring.
times, both the processes take place simultaneously
parenchymal cells are short-lived while others have a longer
lifespan. In order to maintain proper structure of tissues, these
cells are under the constant regulatory control of their cells cycle.
include growth factors such as:
growth factor, fibroblast growth factor, platelet-derived growth
factor, endothelial growth factor, transforming growth factor-β.
cycle is defined as:
the period between two successive cell divisions and is divided into
4 unequal phases.
M (mitosis) phase: Phase of mitosis.
(gap 1) phase: The daughter cell enters G1
phase after mitosis.
S (synthesis) phase: During this
phase, the synthesis of nuclear DNA takes place.
(gap 2) phase: After completion of nuclear DNA duplication, the cell
enters G2 phase.
(gap 0) phase: This is the quiescent or resting phase of the cell
after and M phase
all cells of the body divide at the same pace. Some
mature cells do not divide at all while others complete a cell cycle
every 16-24 hours.
The main difference between slowly-dividing and
rapidly-dividing cells in the duration of G1
upon their capacity to divide, the cell of the body can be divided
into 3 groups:
These cells continue to multiply throughout life under normal
physiologic conditions. These include: surface epithelial cells of
epidermis alimentary tract, respiratory tract, urinary tract, vagina,
cervix, uterine endometrium, haematopoietic cells of bone marrow and
cells of lymph nodes and spleen.
Stable cells: These
cells decrease or lose their ability to proliferate after adolescence
but retain the capacity to multiply in response to stimuli throughout
adult life. These include: parenchymal cells of organs like liver,
pancreas, kidneys, adrenal and thyroid; mesenchymal cells like smooth
muscle cells, fibroblasts, vascular endothelium, bone and cartilage
These cells lose their ability to proliferate around the time of
birth. These include: neurons of nervous system, skeletal muscle and
cardiac muscle cells.
of parenchymal cells with cell cycle
If the three types of parenchymal cells described above
are correlated with the phase of cell cycle, the following inferences
can be derived:
Labile cells which are continuously dividing cells
remain in the cell cycle from one mitosis to the next.
Stable cells are in the resting phase (G0)
but stimulated to enter the cell cycle.
Permanent cells are non-dividing cells which have left
the cell cycle and die after injury.
Regeneration of any type of parenchymal cells involves
the following 2 processes:
Proliferation of original cells from the margin of
injury with migration so as to cover the gap.
Proliferation of migrated cells with subsequent
differentiation and maturation so as to reconstitute the original
Repair is the replacement of injured tissue by fibrous
Two processes are involved in repair:
Granulation tissue formation
Contraction of wounds.
Repairs response takes place by participation of
mesenchymal cells (consisting of connective tissue stem cells,
fibrocytes and histiocytes), endothelial cells, macrophages,
platelets, and the parenchymal cells of the injured organ.
The term granulation tissue derives its name from
slightly granular and pink appearance of the tissue. Each granule
corresponds histologically to proliferation of new small blood
vessels which are slightly lifted on the
surface by thin covering of fibroblasts and young collagen.
The following 3 phases are
observed in the formation of granulation tissue.
Phase of inflammation:
Following trauma, blood clots at the site of injury. There is acute
inflammatory response with exudation of plasma, neutrophils and some
monocytes within 24 hours.
Phase of clearance:
Combination of proteolytic enzymes liberated from neutrophils,
autolytic enzymes from dead tissues cells, and phagocytic activity of
macrophages clear off the necrotic tissue, debris and red blood
Phase of ingrowth of
This phase consists of 2 main processes: angiogenesis or
neovascularisation, and fibrogenesis.
Formation of new blood vessels at
the site of injury takes place by proliferation of endothelial cells
from the margins of severed blood vessels.
Initially, the proliferated
endothelial cells are solid buds but within a few hours develop a
lumen and start carrying blood.
The newly formed blood vessels are
more leaky; accounting for the oedematous appearance of new
Soon, these blood vessels
differentiate into muscular arterioles, thin walled venules and true
process of angiogenesis is stimulated with
proteolytic destruction of basement membrane
and takes place under the influence of the following factors:
Angiogenesis takes place under the
influence of vascular endothelial growth factor (VEGF) elaborated by
mesenchymal cells but its receptors are present in endothelial cells
Platelet-derived growth factor
(PDGF), transforming growth factor-β (TGF-β), basic fibroblast
growth factor (bFGF), other cytokines and surface integrins are the
factors which are associated with cellular proliferation.
The newly formed blood vessels are
present in an amorphous ground substance or matrix. The
new fibroblasts originate from fibrocytes as well as by mitotic
division of fibroblasts. Some of these
fibroblasts have combination of morphologic and functional
characteristics of smooth muscle cells (myofibroblasts).
Collagen fibrils begin to appear by about 6th
day. As maturation proceeds, more and more of collagen is formed
while the number of active fibroblasts and new blood vessels
decreases. This results in formation of inactive looking scar known
The wound starts contracting
after 2-3 days and the process is completed by the 14th
During this period, the wound
is reduced by
approximately 80% of its original size.
Contracted would results in rapid healing since lesser surface area
of the injured tissue has to be replaced.
In order to
explain the mechanism of wound contraction, a number of factors have
been proposed. These are as under:
as a result of removal of fluid by drying of wound was first
suggested but without being substantiated.
of collagen was thought to be responsible for contraction but wound
contraction proceeds at a stage when the collagen content of
granulation tissue is very small.
Discovery of myofibroblasts
appearing in active granulation tissue has resolved the controversy
surrounding the mechanism of wound contraction. These cells have
features intermediate between those of fibroblasts and smooth muscle
cells. Their migration into the wound area and their active
contraction decreases the size of the defect. The evidences in
support of this concept are both morphological as well as functional
characteristics of modified fibroblasts or myofibroblasts as under:
Fibrils present in the cytoplasm of these cells resemble
those seen in smooth muscle cells.
These cells contain actin-myosin similar to that
found in non-striated muscle cells.
The nuclei of these cells have infoldings of nuclear
membrane like in smooth muscle cells.
These cells have basement membrane and desmosomes which
are not seen in ordinary fibroblasts.
The cytoplasm of these modified cells demonstrates
immunofluorescent labelling with anti-smooth muscle antibodies.
The drug response of granulation tissue is similar to
that of smooth muscle.
Healing of skin wounds provides
a classical example of combination of regeneration and repair
described above. This can be accomplished in one of the following
first intention (primary union): and
second intention (Secondary union)
Healing by First Intention (Primary Union)
This is defined as healing of a
wound which has the following characteristics:
loss of cells and tissue; and
wound are approximated by surgical sutures
The sequence of events in primary union are described
Immediately after injury, the space between the approximated surfaces
of incised wound is filled with blood which then clots and seals the
wound against dehydration and infection.
This occurs within 24 hours with appearance of polymorphs from the
margins of incision. By 3rd
day, polymorphs are replaced by macrophages
changes: The basal
cells of epidermis from both the cut margins start proliferating and
migrating towards incisional space in the form of epithelial spurs.
A well-approximated wound is covered by a layer of epithelium in 48
hours. The migrated epidermal cells separate the underlying viable
dermis from the overlying necrotic material and clot, forming scab
which is cast off. The basal cells from the margins continue to
divide. By 5th
day, a multilayered new epidermis is formed which is differentiated
into superficial and
day, fibroblasts also invade the wound area. By 5th
day, new collagen fibrils start forming which dominate till healing
is completed. In 4 weeks, the scar tissue with scanty cellular and
vascular elements, a few inflammatory cells and epithelialised
surface is formed.
tracks: Each suture
track is a separate wound and incites the same phenomena as in
healing of the primary wound i.e. filling the space with haemorrhage,
some inflammatory cell reaction, epithelial cell proliferation along
the suture track from both margins, fibroblastic proliferation and
formation of young collagen. When sutures are removed around 7th
day, much of epithelialised suture track is avulsed and the remaining
epithelial tissue in the track is absorbed. However, sometimes the
suture track gets infected (stitch abscess) or the epithelial cells
may persist in the track (implantation or epidermal cysts).
Thus, the scar formed in a
sutured wound is neat due to close apposition of the margins of
wound; the use of adhesive tapes avoids removal of stitches and its
by Second Intention (Secondary Union)
This is defined as healing of a
wound having the following characteristics:
Open with a
large tissue defect, at times infected;
extensive loss of cells and tissues, and
The wound is
not approximated by surgical sutures but is left open.
basic events in secondary union are similar to primary union but
differ having a larger tissue defect which has to be bridged. Hence
healing takes place from the base upwards as well as from the margins
inwards. The healing by second intention is slow and results in a
large, at times ugly, scar as compared to rapid healing and neat scar
of primary union.
The sequence of events in secondary union are described
a result of injury, the wound space is filled with blood and fibrin
clot which dries.
an initial acute inflammatory response
followed by appearance of macrophages which clear off the debris as
in primary union.
primary healing, the epidermal cells from both the margins of wound
proliferate and migrate into the wound in the form of epithelial
spurs till they meet in the middle and
re-epithelialise the gap completely. However, the proliferating
epithelial cells do not cover the surface
granulation tissue from base has started filling the wound space.
In this way, pre-existing viable connective tissue is separated from
necrotic material and clot of the surface, forming scab which is cast
off. In time, the regenerated epidermis becomes stratified and
The main bulk of secondary
healing is by granulations.
tissue is formed by proliferation of
fibroblasts and neovascularisation from the adjoining viable
newly-formed granulation tissue is deep red, granular and very
fragile. With time, the scar on maturation becomes pale and white
due to increase in collagen and decrease in vascularity. The
specialized structures of skin like hair follicles and sweat glands
are not replaced unless their viable residues remain which may
Contraction of wound is an important feature of secondary healing,
not seen in primary healing. Due to the
action of myofibroblasts present in granulation tissue, the wound
contracts to one-third to one-fourth of its original size.
Wound contraction occurs at a time when active granulation tissue is
Presence of infection:
Bacterial contamination of an open wound delays the process of
healing due to release of bacterial toxins that provoke necrosis,
suppuration and thrombosis. Surgical removal of dead and necrosed
tissue, debridement, helps in preventing the bacterial infection of
of Wound Healing:
During the course of healing, following complications
of wound due to entry of bacteria delays the healing.
cyst formation may occur due to persistence of epithelial cells in
the wound after healing.
Healed wounds may at times have rust-like colour due to staining
with haemosiderin. Some coloured particulate material left in the
wound may persist and impart colour to the healed wound.
Deficient scar formation. This
may occur due to inadequate formation of granulation tissue.
Incisional hernia. A
weak scar, especially after a laparotomy, may be the site of bursting
open of a wound (wound dehiscence) or an incisional hernia.
and keloid formation. At times the scar formed is excessive, ugly
and painful. Excessive formation of collagen in healing may result
in keloid (claw-like) formation, seen more commonly in blacks.
Hypertrophied scars differ from keloid in that they are confined to
the borders of the initial wound while keloids have tumour-like
projection of connective tissue.
An exaggeration of wound contraction may result in formation of
contractures or cicatrisation e.g. Dupuytren’s
(palmar) contracture, plantar contracture and Peyronie’s
disease (contraction of the cavernous tissue of penis).
scar may be the site for development of carcinoma later e.g. squamous
cell carcinoma in marjolin’s
ulcer i.e. a scar following burns on the skin.
Extracellular Matrix –
The wound is strengthened by proliferation of
fibroblasts and myofibroblasts which get structural support from the
extracellular matrix (ECM). In addition to providing structural
support, ECM can direct cell migration, attachment, differentiation
ECM has five main components:
collagens are a family of proteins which provide structural support
to be multicellular organism. It is the main component of tissues
such as fibrous tissue, bone, cartilage, valves of heart, cornea,
basement membrane etc.
Collagen is synthesized and secreted by a complex
biochemical mechanism on ribosomes. The
collagen synthesis is stimulated by various growth factors and is
degraded by collagenase. Regulation of
collagen synthesis and degradation take place by various local and
systemic factors so that the collagen content of normal organs
remains constant. On the other hand, defective
regulation of collagen synthesis leads to hypertrophied scar,
fibrosis, and organ dysfunction.
Depending upon the biochemical
composition, 18 types
of collagen have been identified called collagen type I to XVIII,
many of which are unique for specific tissues.
Type I, III and V are true fibrillar collagen which form the main
portion of the connective tissue during healing of wounds in scars.
Other types of collagen are non-fibrillar and amorphous material
seen as component of the basement membranes.
Morphologically, the smallest
units of collagen are collagen fibrils,
which align together in parallel bundles to form collagen fibers, and
then collagen bundles.
Various adhesive glycoproteins acting as glue for the ECM and the
cells consist of
A- Fibronectin (nectere = to
bind) is the best characterized glycoprotein in ECM and has binding
properties to other cells and ECM. It is of two types –
plasma and tissue fibronectin.
Plasma fibronectin is synthesized by the liver cells and
is trapped in basement membrane such as infiltration through the
Tissue fibronectin is formed by fibroblasts, endothelial
cells and other mesenchymal cells. It is responsible for the
rpimitive matrix such as in the foetus, and in wound healing.
or cytotactin is the glycoprotein associated
with fibroblasts and appears in wound about 48 hours after injury.
It disappears from mature scar tissue.
is mainly synthesised by granules of
platelets. It functions as adhesive protein for keratinocytes and
platelets but is inhibitory to attachment of fibroblasts and
Basement membranes are periodic acid-Schiff (PAS)-positive amorphous
structures that lie underneath epithelia of different organs and
endothelial cells. They consist of collagen type IV and laminin.
While the tensile strength in tissue comes from collagen, the
ability to recoil is provided by elastic fibers. Elastic fibers
consist of 2 components –
elastin glycoprotein and elastic microfibril. Elastases degrade the
elastic tissue e.g. in inflammation, emphysema etc.
These are a group of molecules having 2 components –
and essential carbohydrate polymer (called polysaccharide or
glycosaminoglycan), and a protein bound to it, and hence the name
proteoglycan. Various proteoglycans are distributed in different
tissues as under:
– abundant in cartilage,
Heparan sulphate –
in basement membranes
Dermatan sulphate –
– in cartilage.
– in cartilage, dermis
In would healing, the deposition of proteoglycans
precedes collagen laying
The strength of wound also depends upon factors like
the site of injury, depth of incision and area of wound.
After removal of stitches on around 7th
day, the wound strength is approximately 10% which reaches 80% in
about 3 months.
influencing healing :
Two types of factors influence the wound healing: those
acting locally, and those acting in general.
FACTORS. These include the following
Infection is the most important
factor acting locally which delays the process of healing.
Poor blood supply to wound slows
healing e.g. injuries to face heal quickly due to rich blood supply
while injury to leg with varicose ulcers having poor blood supply
Foreign bodies including sutures
interfere with healing and cause intense inflammatory reaction and
Movement delays wound healing.
Exposure to ionising radiation
delays granulation tissue formation.
Exposure to ultraviolet light
Type, size and location of injury
determines whether healing takes place by resolution or organisation.
FACTORS. These are as under:
healing is rapid in young and somewhat slow in aged and debilitated
people due to poor blood supply to the injured area in the latter.
Deficiency of constituents like proteins, vitamin C (scurvy) and
zinc delays the wound healing.
delays wound healing.
Administration of glucocorticoids
has anti-inflammatory effect.
Uncontrolled diabetics are
more prone to develop infections and hence delay in healing.
Haematologic abnormalities like
defect of neutrophil functions (chemotaxis and phagocytosis), and
neutropenia and bleeding disorders slow the process of wound healing.
fracture is usually accompanied by damage to or haemorrhage into
adjacent soft tissues which are repaired
by the process of organization, while the bone is repaired by
FOLLOWING A FRACTURE:
ends of bone.
soft tissues with hemorrhage
(hematoma) and fibrin
of debris and necrotic
organization: capillaries and
Formation of callus (early bone regeneration
in healthy bone.
callus bridges the gap –
first, osteoid tissue (may include cartilage) then woven bone.
From 3 weeks
healed by ossification.
and osteoclastic activity
Remodelling of callus
weeks into months.
and osteoclasts active.
site may be almost invisible.
may occur in fracture of long bones due to entry of fat from the
marrow cavity into the torn ends of veins.
2- Infection –
if the overlying skin is breached.
break occurs at the site of pre-existing disease of the bone.
condition is a secondary tumor growing in and destroying the bone.
tumor and hematoma –
INFLUENCING HEALING OF FRACTURES
b) Pathological fracture
c) Poor apposition and alignment
d) Continuing movement of bone ends
e) Poor blood supply: This is largely influenced by the
site of the fracture, for example:
Nutrient artery damaged by fracture.
Fracture through area devoid of
periosteum (e.g. neck of femur).
Minimal adjacent soft tissue
2. General factors:
The Main Bulk of
Secondary Healing is caused by?
When Does the Wound
start contracting and when is it completed?
Name the 3 Phases of
formation of Granulation Tissue.
What is Potts Disease?
Depending upon their
capacity to divide, the cell of the body can be divided into 3 groups
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