HEALING

Healing is the body response to injury in an attempt to restore normal structure and function. Healing involves
2 distinct processes:
Regeneration when healing takes place by proliferation of parenchymal cells and usually results in complete
restoration of the original tissues.
Repair when healing takes place by proliferation of connective tissue elements resulting in fibrosis and
scarring.At times, both the processes take place simultaneously.
REGENERATION
Some 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 cell cycle. These include
growth factors such as:
epidermal growth factor, fibroblast growth factor, plateletderived
growth factor, endothelial growth factor,
transforming growth factor-.
Cell cycle (page 26) is defined as the period between two
successive cell divisions and is divided into 4 unequal phases
(Fig. 6.40):
M (mitosis) phase: Phase of mitosis.
G1 (gap 1) phase: The daughter cell enters G1 phase after
mitosis.
S (synthesis) phase: During this phase, the synthesis of
nuclear DNA takes place.
G2 (gap 2) phase: After completion of nuclear DNA
duplication, the cell enters G2 phase.
G0 (gap 0) phase: This is the quiescent or resting phase of
the cell after an M phase.
Not 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 slowlydividing
and rapidly-dividing cells is the duration of G1
phase.
KVIEM’S TEST. It is a useful intradermal diagnostic test.
The antigen prepared from involved lymph node or spleen
is injected intradermally. In a positive test, nodular lesion
appears in 3-6 weeks at the inoculation site which on
microscopic examination shows presence of non-caseating
granulomas.
Depending upon their capacity to divide, the cells of the
body can be divided into 3 groups: labile cells, stable cells,
and permanent cells.
1. Labile cells. These cells continue to multiply throughout
life under normal physiologic conditions. These include:
surface epithelial cells of the epidermis, alimentary tract,
respiratory tract, urinary tract, vagina, cervix, uterine
endometrium, haematopoietic cells of bone marrow and cells
of lymph nodes and spleen.
2. 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 cells.
3. Permanent cells. These cells lose their ability to proliferate
around the time of birth. These include: neurons of
nervous system, skeletal muscle and cardiac muscle cells.
RELATIONSHIP OF PARENCHYMAL CELLS WITH
CELL CYCLE. If the three types of parenchymal cells described
above are correlated with the phase of cell cycle,
following inferences can be derived:
1. Labile cells which are continuously dividing cells remain
in the cell cycle from one mitosis to the next.
2. Stable cells are in the resting phase (G0) but can be stimulated
to enter the cell cycle.
3. 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:
i) Proliferation of original cells from the margin of injury
with migration so as to cover the gap.
ii) Proliferation of migrated cells with subsequent
differentiation and maturation so as to reconstitute the
original tissue.
REPAIR
Repair is the replacement of injured tissue by fibrous tissue.
Two processes are involved in repair:
1. Granulation tissue formation; and
2. Contraction of wounds.
Repair 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.
Granulation Tissue Formation
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 (Fig. 6.41):
1. 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.
2. 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 cells.
Figure 6.40 Parenchymal cells in relation to cell cycle (G0–Resting phase; G1, G2–Gaps; S–Synthesis phase; M–Mitosis phase).
The inner
circle shown with green line represents cell cycle for labile cells; circle shown with yellow-orange line represents cell cycle for stable
cells; and the
circle shown with red line represents cell cycle for permanent cells. Compare them with traffic signals—green stands for ‘go’ applies
here to dividing
labile cells; yellow-orange signal for ‘ready to go’ applies here to stable cells which can be stimulated to enter cell cycle; and red
signal for ‘stop’ here
means non-dividing permanent cells.
Inflammation and Healing
3. PHASE OF INGROWTH OF GRANULATION
TISSUE. This phase consists of 2 main processes: angiogenesis
or neovascularisation, and fibrogenesis.
i) Angiogenesis (neovascularisation). 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 granulation tissue.
Soon, these blood vessels differentiate into muscular
arterioles, thin-walled venules and true capillaries.
The process of angiogenesis is stimulated with proteolytic
destruction of basement membrane. Angiogenesis takes place
under the influence of following factors:
a) Vascular endothelial growth factor (VEGF) elaborated by
mesenchymal cells while its receptors are present in
endothelial cells only.
b) Platelet-derived growth factor (PDGF), transforming
growth factor-(TGF-), basic fibroblast growth factor
(bFGF) and surface integrins are all associated with
cellular proliferation.
ii) Fibrogenesis. 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 as cicatrisation.
Contraction of Wounds
The wound starts contracting after 2-3 days and the process
is completed by the 14th day. During this period, the wound
is reduced by approximately 80% of its original size.
Contracted wound 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:
1. Dehydration as a result of removal of fluid by drying of
wound was first suggested but without being substantiated.
2. Contraction 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.
3. 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:
i) Fibrils present in the cytoplasm of these cells resemble
those seen in smooth muscle cells.
ii) These cells contain actin-myosin similar to that found in
non-striated muscle cells.
iii) Cytoplasm of these modified cells demonstrates
immunofluorescent labelling with anti-smooth muscle
antibodies.
iv) Nuclei of these cells have infoldings of nuclear membrane
like in smooth muscle cells.
v) These cells have basement membrane and desmosomes
which are not seen in ordinary fibroblasts.
vi) Drug response of granulation tissue is similar to that of
smooth muscle.
WOUND HEALING
Healing of skin wounds provides a classical example of
combination of regeneration and repair described above.
Wound healing can be accomplished in one of the following
two ways:
Healing by first intention (primary union)
Healing by second intention (secondary union).
Figure 6.41 Active granulation tissue has inflammatory cell infiltrate, newly formed blood vessels and young fibrous tissue in loose
matrix.
Healing by First Intention (Primary Union)
This is defined as healing of a wound which has the following
characteristics:
i) clean and uninfected;
ii) surgically incised;
iii) without much loss of cells and tissue; and
iv) edges of wound are approximated by surgical sutures.
The sequence of events in primary union is illustrated in
1. Initial haemorrhage. 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.
2. Acute inflammatory response. This occurs within 24
hours with appearance of polymorphs from the margins of
incision. By 3rd day, polymorphs are replaced by
macrophages.
3. Epithelial 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 wellapproximated
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 deeper layers.
4. Organisation. By 3rd 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.
5. Suture 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 complications.
Healing by Second Intention (Secondary Union)
This is defined as healing of a wound having the following
characteristics:
i) open with a large tissue defect, at times infected;
ii) having extensive loss of cells and tissues; and
iii) the wound is not approximated by surgical sutures but
is left open.
The basic events in secondary union are similar to
primary union but differ in 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 is illustrated
in Fig. 6.43 and described below:
1. Initial haemorrhage. As a result of injury, the wound
space is filled with blood and fibrin clot which dries.
2. Inflammatory phase. There is an initial acute inflammatory
response followed by appearance of macrophages
which clear off the debris as in primary union.
3. Epithelial changes. As in primary healing, the epidermal
cells from both the margins of wound proliferate and migrate
Inflammation and Healing
Figure 6.43 Secondary union of skin wounds. A, The open wound is filled with blood clot and there is inflammatory response at the
junction of
viable tissue. B, Epithelial spurs from the margins of wound meet in the middle to cover the gap and separate the underlying viable
tissue from
necrotic tissue at the surface forming scab. C, After contraction of the wound, a scar smaller than the original wound is left.
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 fully until 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
on the surface, forming scab which is cast off. In time, the
regenerated epidermis becomes stratified and keratinised.
4. Granulation tissue. Main bulk of secondary healing is
by granulations. Granulation tissue is formed by proliferation
of fibroblasts and neovascularisation from the adjoining
viable elements. The 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. Specialised structures
of the skin like hair follicles and sweat glands are not replaced
unless their viable residues remain which may regenerate.
5. Wound contraction. 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 onefourth
of its original size. Wound contraction occurs at a time
when active granulation tissue is being formed.
 TABLE 6.6: Differences between Primary and Secondary Union of Wounds.
Feature Primary Union Secondary Union
1. Cleanliness of wound Clean Unclean
2. Infection Generally uninfected May be infected
3. Margins Surgical clean Irregular
4. Sutures Used Not used
5. Healing Scanty granulation tissue at the incised Exuberant granulation tissue
gap and along suture tracks to fill the gap
6. Outcome Neat linear scar Contracted irregular wound
7. Complications Infrequent, epidermal inclusion cyst formation Suppuration, may require debridement
6. 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 open
wounds.
Differences between primary and secondary union of
wounds are given in
Complications of Wound Healing
During the course of healing, following complications may
occur:
1. Infection of wound due to entry of bacteria delays the
healing.
2. Implantation (epidermal) cyst formation may occur due to
persistence of epithelial cells in the wound after healing.
3. Pigmentation. 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.
4. Deficient scar formation. This may occur due to inadequate
formation of granulation tissue.
5. 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.
6. Hypertrophied scars 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.
7. Excessive contraction. 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 tissues of penis).
8. Neoplasia. Rarely, 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— Wound Strength
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 and organisation.
ECM has five main components: collagen, adhesive
glycoproteins, basement membrane, elastic fibres, and
proteoglycans.
1. COLLAGEN. The collagens are a family of proteins
which provide structural support to the multicellular
organism. It is the main component of tissues such as fibrous
tissue, bone, cartilage, valves of heart, cornea, basement
membrane etc.
Collagen is synthesised 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 collagen
is normally present in the skin, bone and tendons and
accounts for 90% of collagen in the body:
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 fibres, and then collagen bundles.
2. ADHESIVE GLYCOPROTEINS. Various adhesive
glycoproteins acting as glue for the ECM and the cells consist
of fibronectin, tenascin (cytotactin) and thrombospondin.
i) Fibronectin (nectere = to bind) is the best characterised
glycoprotein in ECM and has binding properties to other cells
and ECM. It is of two types—plasma and tissue fibronectin.
Plasma fibronectin is synthesised by the liver cells and is
trapped in basement membrane such as in filtration through
the renal glomerulus.
Tissue fibronectin is formed by fibroblasts, endothelial
cells and other mesenchymal cells. It is responsible for the
primitive matrix such as in the foetus, and in wound healing.
ii) Tenascin or cytotactin is the glycoprotein associated with
fibroblasts and appears in wound about 48 hours after injury.
It disappears from mature scar tissue.
iii) Thrombospondin is mainly synthesised by granules of
platelets. It functions as adhesive protein for keratinocytes
and platelets but is inhibitory to attachment of fibroblasts
and endothelial cells.
3. BASEMENT MEMBRANE. 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.
4. ELASTIC FIBRES. While the tensile strength in tissue
comes from collagen, the ability to recoil is provided by elastic
fibres. Elastic fibres consist of 2 components—elastin
glycoprotein and elastic microfibril. Elastases degrade the
elastic tissue e.g. in inflammation, emphysema etc.
5. PROTEOGLYCANS. These are a group of molecules
having 2 components—an essential carbohydrate polymer
(called polysaccharide or glycosaminoglycan), and a protein
bound to it, and hence the name proteo-glycan. Various
proteoglycans are distributed in different tissues as under:
i) Chondroitin sulphate—abundant in cartilage, dermis
ii) Heparan sulphate—in basement membranes
iii) Dermatan sulphate—in dermis
iv) Keratan sulphate—in cartilage
v) Hyaluronic acid—in cartilage, dermis.
In wound 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.
TURNOVER OF ECM. ECM is not a static structure but
the matrix proteins comprising it undergo marked
remodeling during foetal life which slows down in adult
tissues. These matrix proteins are degraded by a family of
metalloproteinases which act under regulatory control of
inhibitors of metalloproteinases.
Factors Influencing Healing
Two types of factors influence the wound healing: those
acting locally, and those acting in general.
A. LOCAL FACTORS:
1. Infection is the most important factor acting locally which
delays the process of healing.
2. 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 heals
slowly.
3. Foreign bodies including sutures interfere with healing and
cause intense inflammatory reaction and infection.
4. Movement delays wound healing.
5. Exposure to ionising radiation delays granulation tissue
formation.
6. Exposure to ultraviolet light facilitates healing.
7. Type, size and location of injury determines whether
healing takes place by resolution or organisation.
B. SYSTEMIC FACTORS:
1. Age. Wound 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.
2. Nutrition. Deficiency of constituents like protein, vitamin
C (scurvy) and zinc delays the wound healing.
3. Systemic infection delays wound healing.
4. Administration of glucocorticoids has anti-inflammatory
effect.
5. Uncontrolled diabetics are more prone to develop infections
and hence delay in healing.
6. Haematologic abnormalities like defect of neutrophil functions
(chemotaxis and phagocytosis), and neutropenia and
bleeding disorders slow the process of wound healing.
HEALING IN SPECIALISED TISSUES
Healing of the skin wound provides an example of general
process of healing by regeneration and repair. However, in
certain specialised tissues, either regeneration or repair may
predominate. Some of these examples are described below.
Fracture Healing
Healing of fracture by callus formation depends upon some
clinical considerations whether the fracture is:
traumatic (in previously normal bone), or pathological (in
previously diseased bone);
complete or incomplete like green-stick fracture; and
simple (closed), comminuted (splintering of bone), or
compound (communicating to skin surface).
However, basic events in healing of any type of fracture
are similar and resemble healing of skin wound to some
extent.
Primary union of fractures occurs in a few special
situations when the ends of fracture are approximated as is
done by application of compression clamps. In these cases,
bony union takes place with formation of medullary callus
without periosteal callus formation. The patient can be made
ambulatory early but there is more extensive bone necrosis
and slow healing.
Secondary union is the more common process of fracture
healing. Though it is a continuous process, secondary bone
union is described under the following 3 headings:
i) Procallus formation
ii) Osseous callus formation
iii) Remodelling
These processes are illustrated in Fig. 6.44 and described
below:
I. PROCALLUS FORMATION. Steps involved in the
formation of procallus are as follows:
1. Haematoma forms due to bleeding from torn blood
vessels, filling the area surrounding the fracture. Loose
meshwork is formed by blood and fibrin clot which acts as
framework for subsequent granulation tissue formation.
2. Local inflammatory response occurs at the site of injury
with exudation of fibrin, polymorphs and macrophages. The
Figure 6.44 Fracture healing. A, Haematoma formation and local inflammatory response at the fracture site. B, Ingrowth of
granulation tissue
with formation of soft tissue callus. C, Formation of procallus composed of woven bone and cartilage with its characteristic fusiform
appearance and
having 3 arbitrary components—external, intermediate and internal callus. D, Formation of osseous callus composed of lamellar
bone following
clearance of woven bone and cartilage. E, Remodelled bone ends; the external callus cleared away. Intermediate callus converted
into lamellar
bone and internal callus developing bone marrow cavity.
macrophages clear away the fibrin, red blood cells,
inflammatory exudate and debris. Fragments of necrosed
bone are scavenged by macrophages and osteoclasts.
3. Ingrowth of granulation tissue begins with neovascularisation
and proliferation of mesenchymal cells from
periosteum and endosteum. A soft tissue callus is thus
formed which joins the ends of fractured bone without much
strength.
4. Callus composed of woven bone and cartilage starts
within the first few days. The cells of inner layer of the
periosteum have osteogenic potential and lay down collagen
as well as osteoid matrix in the granulation tissue (Fig. 6.45).
The osteoid undergoes calcification and is called woven bone
callus. A much wider zone over the cortex on either side of
fractured ends is covered by the woven bone callus and
united to bridge the gap between the ends, giving spindleshaped
or fusiform appearance to the union. In poorly
immobilised fractures (e.g. fracture ribs), the subperiosteal
osteoblasts may form cartilage at the fracture site. At times,
callus is composed of woven bone as well as cartilage, temporarily
immobilising the bone ends.
This stage is called provisional callus or procallus
formation and is arbitrarily divided into external, intermediate
and internal procallus.
II. OSSEOUS CALLUS FORMATION. The procallus acts
as scaffolding on which osseous callus composed of lamellar
bone is formed. The woven bone is cleared away by incoming
osteoclasts and the calcified cartilage disintegrates. In their
place, newly-formed blood vessels and osteoblasts invade,
laying down osteoid which is calcified and lamellar bone is
formed by developing Haversian system concentrically
around the blood vessels.
III. REMODELLING. During the formation of lamellar
bone, osteoblastic laying and osteoclastic removal are taking
place remodelling the united bone ends, which after
sometime, is indistinguishable from normal bone. The
external callus is cleared away, compact bone (cortex) is
formed in place of intermediate callus and the bone marrow
cavity develops in internal callus.
COMPLICATIONS OF FRACTURE HEALING. These are
as under:
1. Fibrous union may result instead of osseous union if the
immobilisation of fractured bone is not done. Occasionally,
a false joint may develop at the fracture site (pseudoarthrosis).
2. Non-union may result if some soft tissue is interposed
between the fractured ends.
3. Delayed union may occur from causes of delayed wound
healing in general such as infection, inadequate blood supply,
poor nutrition, movement and old age.
Healing of Nervous Tissue
CENTRAL NERVOUS SYSTEM. The nerve cells of the
brain, spinal cord and ganglia once destroyed are not
replaced. Axons of CNS also do not show any significant
regeneration. The damaged neuroglial cells, however, may
show proliferation of astrocytes called gliosis.
PERIPHERAL NERVOUS SYSTEM. In contrast to the cells
of CNS, the peripheral nerves show regeneration, mainly
from proliferation of Schwann cells and fibrils from distal
end. The process is discussed in Chapter 30. Briefly, it consists
of the following:
Myelin sheath and axon of the intact distal nerve undergo
Wallerian degeneration up to the next node of Ranvier
towards the proximal end.
Degenerated debris are cleared away by macrophages.
Regeneration in the form of sprouting of fibrils takes place
from the viable end of axon. These fibrils grow along the
track of degenerated nerve so that in about 6-7 weeks, the
peripheral stump consists of tube filled with elongated
Schwann cells.
One of the fibrils from the proximal stump enters the old
neural tube and develops into new functional axon.
Healing of Muscle
All three types of muscle fibres have limited capacity to
regenerate.
SKELETAL MUSCLE. The regeneration of striated muscle
is similar to peripheral nerves. On injury, the cut ends of
muscle fibres retract but are held together by stromal
connective tissue. The injured site is filled with fibrinous
material, polymorphs and macrophages. After clearance of
damaged fibres by macrophages, one of the following two
types of regeneration of muscle fibres can occur:
If the muscle sheath is intact, sarcolemmal tubes
containing histiocytes appear along the endomysial tube
which, in about 3 months time, restores properly oriented
muscle fibres e.g. in Zenker’s degeneration of muscle in
typhoid fever.
If the muscle sheath is damaged, it forms a disorganised
multinucleate mass and scar composed of fibrovascular
tissue e.g. in Volkmann’s ischaemic contracture.
Figure 6.45 Callus formation in fracture healing.
SMOOTH MUSCLE. Non-striated muscle has limited
regenerative capacity e.g. appearance of smooth muscle in
the arterioles in granulation tissue. However, in large
destructive lesions, the smooth muscle is replaced by
permanent scar tissue.
CARDIAC MUSCLE. Destruction of heart muscle is replaced
by fibrous tissue. However, in situations where the
endomysium of individual cardiac fibre is intact (e.g. in
diphtheria and coxsackie virus infections), regeneration of
cardiac fibres may occur in young patients.
Healing of Mucosal Surfaces
The cells of mucosal surfaces have very good regeneration
and are normally being lost and replaced continuously e.g.
mucosa of alimentary tract, respiratory tract, urinary tract,
uterine endometrium etc. This occurs by proliferation from
margins, migration, multilayering and differentiation of
epithelial cells in the same way as in the epidermal cells in
healing of skin wounds.
Healing of Solid Epithelial Organs
Following gross tissue damage to organs like the kidney, liver
and thyroid, the replacement is by fibrous scar e.g. in chronic
pyelonephritis and cirrhosis of liver. However, in
parenchymal cell damage with intact basement membrane
or intact supporting stromal tissue, regeneration may occur.
For example:
In tubular necrosis of kidney with intact basement
membrane, proliferation and slow migration of tubular
epithelial cells may occur to form renal tubules.
In viral hepatitis, if part of the liver lobule is damaged with
intact stromal network, proliferation of hepatocytes may
result in restoration of liver lobule.

❑
Infectious and
Parasitic Diseases
Chapter 7
INTRODUCTION
Microorganisms, namely bacteria, viruses, fungi and
parasites, are present everywhere—in the soil, water, atmosphere
and on the body surfaces, and are responsible for a
large number of infectious diseases in human beings. Some
microorganisms are distributed throughout the world while
others are limited to certain geographic regions only. In
general, tropical and developing countries are specially
affected by infectious diseases than the developed countries.
There are several examples of certain infectious diseases which
are not so common in the developed world now but they
continue to be major health problems in the developing
countries e.g. tuberculosis, leprosy, typhoid fever, cholera,
measles, pertussis, malaria, amoebiasis, pneumonia etc.
Vaccines have, however, been successful in controlling or
eliminating some diseases all over the world e.g. smallpox,
poliomyelitis, measles, pertussis etc. Similarly, insecticides
have helped in controlling malaria to an extent. However,
infections still rank very high as a cause of death in the world.
Reasons for this trend are not difficult to seek:
Development of newer and antibiotic-resistant strains of
microorganisms; classic example is that of methicillinresistant
Staph. aureus (MRSA).
Administration of immunosuppressive therapy to
patients with malignant tumours and transplanted organs
making them susceptible to opportunistic infections
Increasing number of patients reporting to hospital for
different illnesses but instead many developing hospitalacquired
infections.
Lastly, discovery in 1981 of previously unknown deadly
disease i.e. acquired immunodeficiency syndrome (AIDS)
caused by human immunodeficiency virus (HIV).
While talking of microbial infective diseases, let us not
forget the fact that many microorganisms may actually
benefit mankind. Following is the range of host-organism interrelationship,
which may vary quite widely:
1. Symbiosis i.e. cooperative association between two
dissimilar organisms beneficial to both.
2. Commensalism i.e. two dissimilar organisms living
together benefitting one without harming the other.
3. True parasitism i.e. two dissimilar organisms living
together benefitting the parasite but harming the host.
4. Saprophytism i.e. organisms living on dead tissues.
Besides microorganisms, more recently a modified host
protein present in the mammalian CNS has been identified
called prion protein. Prions are transmissible agents similar
to infectious particles but lack nucleic acid. These agents are
implicated in the etiology of spongiform encephalopathy,
(including kuru), bovine spongiform encephalopathy (or mad
cow disease) and Creutzfeldt-Jakob disease (associated with
corneal transplantation). (Dr. Prusiner who discovered prion
protein was awarded Nobel Prize in medicine in 1997).
Transmission of infectious diseases requires a chain of
events and is the consequence of inter