Introduction

Even as cells and tissues are injured, events that contain the
damage and prepare the surviving cells to replicate are set into motion.
Repair consists of the replacement of dead cells by viable cells.
These new cells may be either derived from the parenchyma or from
the connective tissue stroma of the injured tissue. During the
evolutionary process, mammals lost the capacity to regenerate total
structures, such as limbs, as many of the simpler aquatic and
amphibious animals can. Indeed, the restorative capacity of humans is
quite limited. nly some of their cells are capable of regeneration.
Repair of destroyed cells because usually involves some connective
tissue proliferation with the formation of a fibrous scar. !lthough, the
anatomic continuity of the tissue may be restored thereby, such impair
is obviously imperfect, since it replaces functioning parenchymal cells
with non"speciali#ed connective tissue.
Repair begins very early in the process of inflammation and
involves two processes$
I% Regeneration of the injured tissue.
II% Replacement by connective tissue.
&
I] Regeneration
" 'ome parenchymal cells are short"lived while others have a
longer life span. In order to maintain the proper structure of
tissues, these cells are under the constant regulatory control of
their cell cycle.
which is defined as the period between ( successive cell
divisions and is divided into ) unequal phases.
*a+ *b+ *c+
, *mitosis+ phase
-
&
*gap &+ phase
the daughter cell
enters -
&
phase after
mitosis
' *synthesis phase+
synthesis of
nuclear D.! ta/es
place
*d+
-
(
*gap (+ phase
after completion
of nuclear D.! the
cell enters -
(
phase
*e+
-
0
*gap 0+ phase
is the quiescent or
the resting phase of
the cell after an ,
phase
Regeneration can be divided into$
,ovement of the surviving cells
into the vacant space made
available by loss due to wound 1
necrosis
2roliferation of the surviving cells
to replace the loss
(
The cells of the body have been divided into 3 groups on the basis of
their regenerative capacity and their relationship to the cell"cycle.
(A) Continuously dividing (labile cells)
These cells continue to multiply throughout life under normal
physiologic conditions. These include$
" 'urface epithelial cells of epidermis.
" !limentary tract.
" Respiratory tract.
" 4rinary tract.
" 5agina.
" 6ervi7.
" 4terine endometrium.
" 8aemopoietic cells of bone marrow.
" 6ells of lymph nodes and spleen.
(B)Quiescent (stable cells)
" These cells decrease or lose their ability to proliferate after
adolescence but retain the capacity to multiply in response to
stimuli throughout life.
The growth capacity of stable cells is best e7emplified by the
ability of the liver to regenerate after hepatectomy or following to7ic 1
viral 1 chemical injury. These include$
3
" 2arenchymal cells of organic li/e liver, pancreas, /idneys,
adrenal and thyroid.
" ,esenchymal cells li/e smooth muscle cells
" 9ibroblasts.
" 5ascular endothelium
" :one
" 6artilage cells.
(C)Non-dividing (Permanent cells)
" E7ited the cell cycle at some point in intra"uterine development
and cannot undergo further mitotic division in post"natal life.
These include$
o .eurons of nervous system.
o '/eletal muscle.
o 6ardiac muscle cells.
i.e. why destruction of a neuron whether in central nervous
system 1 ganglia, represents a permanent loss. The perfection of
parenchymal repair of an injury depends on more than the ability of the
cells to regenerate. 2reservation of the stromal architecture of the
injured tissue is also necessary. Thus, the perfection of repair depends
to a considerable e7tent on the survival of the basic framewor/ of the
)
tissue when this is lost, regeneration may restore mass but not
complete function.
Relationship of parenchymal cells to the cell cycle
a. ;abile cells which are continuously dividing cells remain
in the cell cycle from one mitosis to the ne7t.
b. 'table cells are in the resting phase but can be stimulated
to enter the cell cycle.
c. 2ermanent cells leave the cell cycle and die after injury.
II] Repair
" Repair is the replacement of injured tissue by fibrous tissue.
Two processes are involved.
!. -ranulation tissue formation.
:. 6ontraction of wounds.
A. Granulation tissue formation
Refers 1 derived from the pin/, soft, granular gross
appearance such as that seen beneath the scab of a s/in wound.
<
8istologically, each granule corresponds to the proliferation of new
small blood vessels which are slightly lifted on the surface by a thin
covering of fibroblasts and young collagen. There are 3 components
to granulation tissue formation.
i) PHASE O AC!"E #N$A%%A"#ON
" 9ollowing trauma 1 injury, blood clots at the site of injury.
There is acute inflammatory response with e7udation of plasma,
neutrophils and some monocytes within () hours.
ii) PHASE O C$EA&ANCE
" 6ombination of proteolytic en#ymes liberated from neutrophils,
autolytic en#ymes from dead tissue cells, and phagocytic activity
of macrophages clear off the necrotic tissue, debris and red
blood cells.
iii) PHASE O #N'&O("H O '&AN!$A"#ON
"#SS!E
!ngiogenesis 1 .eovasculari#ation 9ormation of fibrous tissue
9ormation of new blood vessels at
the site of injury ta/es place by
proliferation of endothelial cells
from the margins of severed blood
vessels. Initially, the proliferated
endothelial cells are solid buds but
9ormation of fibrous tissue
" !s the granulation tissue
natures, inflammatory cells
decrease in number, fibroblasts
lay down collagen and the
capillaries become much less
=
within a few hours develop a
lumen and start carrying blood.
The newly formed blood vessels
are more lea/y, accounting for the
oedematous appearance of new
granulation tissue.
'ummari#ing$
" 2roteolytic > degeneration
of the parent vessel basement
membrane allowing formation
of a capillary sprout.
" ,igration of the endothelial
cells towards the angiogenic
stimulus.
" 2roliferation of the
endothelial cells.
" ,aturation of the
endothelial cells with
organi#ation.
prominent what emerges is an
avascular, relatively acellular scar
with inactive spindle"shaped
fibroblasts tuc/ed in between
collagen fibres. This is /nown as
6icartrisation.
B. Contraction of wounds
The wound starts contracting after ("3 days and the process is
completed by the &)
th
day. During this time, the wound is reduced
to appro7imately ?0@ of its original si#e. 6ontracted wound results
A
in rapid healing since lesser surface area of the injured tissue has to
be replaced.
In order to e7plain the mechanism of wound healing, a number
of factors have been proposed. These are$
a+ Dehydration as a result of fluid removal by the
drying of the wound but this was not substantiated.
b+ 6ontraction of collagen Bas thought to be
responsible for contraction but wound contraction proceeds at
a stage when the collagen content of the granulation tissue is
very small.
c+ 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 si#e of the defect.
Bith all this bac/ground on granulation tissue, we can now
discuss the two forms of repair.
8ealing by first intention 8ealing by second intention
*primary union+ *secondary union+
?
")e se*uence o+ events are,
&. Initial haemorrhage
Bithin the first post"operative day, after the wound has been
appro7imated by surgical sutures, the line of incision promptly fills
with blood clots which seals the wound against dehydration and
infection.
(. !cute inflammatory response
This occurs within () hours by appearance of polymorphs from
the margins of the incision. :y 3
rd
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. ! well appro7imated wound is covered by a layer of
epithelium in )? hours. The migrated epidermal cells separate the
underlying viable dermis from the overlying necrotic material and
blood clot, forming a scab which is cast off.
:y <
th
day a multilayered new epidermis is formed which is
differentiated into superficial and deeper layer.
C
). rganisation
:y 3
rd
day, fibroblasts also invade the wound area. :y <
th
day,
the acute inflammatory response begins to subside and the neutrophils
are replaced by macrophages which debride the wound margins of
destroyed cells and bits and pieces of fibrin.
In ) wee/s, the scar tissue with scanty cellular and vascular
elements, new inflammatory cells and epitheliali#ed surface is formed.
I] Primary union
This is defined as healing of a wound which has the following
characteristics.
" 6lean and uninfected.
" 'urgically incised.
" Bithout much loss of cells and tissue, and
" Edges of the wound are appro7imated by surgical sutures.
&0
The incised wound as well as sutures trac/
on either side are filled with blood clot and
there is inflammatory response from the
margins.
'purs of epidermal cells migrate along the
incised margin on either side as well as
around the suture trac/. 9ormation of
granulation tissue also begins from below.
Removal of suture at around A
th
day results
in scar tissue at the site of incision and
suture trac/.
Suture tac-s
Each suture trac/ is a separate wound and incites the same
phenomenon as in healing of the primary wound.
Bhen sutures are removed around A
th
day, much of the
epitheliali#ed suture tac/ is avulsed and the remaining epithelial tissue
in the trac/ is absorbed. 8owever, sometimes the suture trac/ gets
infected *'titch absecess+, or the epithelial cells may persist in the
trac/ *implantation 1 epidermal cysts+.
II] Secondary union
This is defined as the healing of the wound having, the following
characteristics$
&&
" pen with a large tissue defectD at times infected.
" 8aving e7tensive loss of cells and tissue and
" The wound is not appro7imated by surgical sutures but is left
open.
" The basic events in secondary union are similar to primary union
but differ in having a larger defect which has to be bridged.
8ence, healing ta/es 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 open wound is filled with blood clot
and there is inflammatory response at the
junction of viable tissue.
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.
!fter contraction of the wound, a scar
smaller than the original wound is left.
&(
")e se*uence o+ events are,
&. Initial haemorrhage
!s a result of injury, the wound space is filled with blood clot
and fibrin clot which dries.
(. Inflammatory phase
There is an initial acute inflammatory phase followed by
appearance of macrophages which clear off the debris as in primary
union.
3. Epithelial changes
!s in 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. 8owever, the proliferating epithelial cells do not cover the
surface fully till granulation tissue from base has started filling the
wound space. In this way, pree7isting viable connective tissue is
separated from necrotic material and clot on the surface, forming seal
which is cast off.
&3
). -ranulation tissue
The main bul/ of secondary healing is by granulations. The
newly"formed granulation tissue is deep red, granular and very fragile.
Bith time, this scar on maturation becomes pale and white due to
increase in collagen and decrease in vascularity.
<. Bound contraction
Due to the action of myofibroblasts present in granulation tissue,
the wound contracts to &13
rd
> Eth of its original si#e.
=. 2resence of infection
:acterial contamination of an open wound delays the process of
healing due to release of bacterial to7ins that provo/e necrosis,
suppuration and thrombosis. 'urgical removal of dead and necrosed
tissue helps in preventing the bacterial infection of open wounds.
Com.lications o+ /ound )ealing,
" Infection *due to entry of bacteria+.
" Implantation cyst.
" 2igmentation *healed wounds may at times have rust li/e colour
due to staining with haemoglobin+.
" Deficient scar formation *due to inadequate -.T. formation+.
&)
" Incisional hermia *a wea/ scar may be site of bursting open of a
wound+ *Bound dehiscence+.
Two main aberrations occur in wound healing whether the
process of &
st
1(
nd
intention.
a+ The accumulation of e7cessive amounts of collagen may give
rise to a protruding, tumorous scar /nown as a /eloid thic/
interlacing bundles of collagen causing mar/ed swelling at the
site of the wound.
b+ The other deviation is the formation of e7cessive amounts of
granulation tissue which protrudes above the level of the
surrounding s/in and in fact bloc/s re"epitheli#ation. This has
been called as Fe7uberant granulation 1 pround fleshG.
PATH!GIC ASP"CTS # R"PAIR $ #actors Influencing
Repair
In wound healing, normal cell growth and fibrosis may be
altered by a variety of influences, frequently reducing the quality and
adequacy of the reparative process.
These factors may be either e7trinsic 1 intrinsic.
&<
Systemic factors% Systemic $ !ocal
01 Hy.o2ia
8ealing is often imperfect in regions with a poor blood
supply e.g., various ulcers in a lower limb made hypo7ic by
varicose veins, often fails to heal.
In contrast to this, mild hypo7ia helps healing by increasing
the differentiation of fibrocytes, collagen formation and the
cross"lin/age of collagen"fibrils.
31 Scurvy
Is a classic cause of defective wound healing though now
rare. 'car that results is wea/ and in the granulation tissue, new
capillaries are few and ill"formed.
41 Severe and .rolonged .rotein de+iciency
Inhibits wound healing. Deficiency of sulfur containing
amino acids li/e cystine and methionine is particularly
important.
51 'lucocorticoids
f the adrenal gland interfere with wound healing when
given in large doses.
&=
61 Age
Bound healing is rapid in young and slow in aged and
debilitated patients due to poor blood supply to the injured area.
=. !ncontrolled diabetic > are more prone to develop infections
and hence delay in healing.
71 $ocal +actors
a+ ,ovement of the injured part.
b+ 9i7ation of the injured tissue to an unyielding object such
as bone, ma/es apposition of the wound edges difficult
and hampers healing.
c+ Bounds made along a line of mechanical stress in the
tissue tend to fall together and heal easily but wound
across a line of stress tend to gape and heal more slowly.
d+ Infection of the wound.
e+ !ny foreign bodies present.
f+ Type, si#e and location of injury determines whether
healing ta/es place by resolution 1 organi#ation.
g+ E7posure to u"v light facilitates healing.
&A
h+ E7posure to ioni#ing radiation delays granulation tissue
formation.
&"CHA'IS&S I'(!(") I' R"PAIR
3 processes
6ell"cell interactions.
6ell"matri7 interactions.
'timulatory hormones 1 growth factors.
01 Cell-cell interactions
!s mentioned earlier, re"epitheliali#ation of wound begins
within () hours of injury and the gap is usually covered within )?
hours. During regeneration of liver, after partial hepatectomy, the liver
cells burst into mitoses but cease to divide when normal liver substance
is restored. Bhat signals these cells to stop dividingH Bhen certain
normal cells are lightly seeded in 2etri dishes to investigate the growth
behaviour of cells, they proliferate migrate and eventually form
confluent monolayers. !t this point cells cease to divide > a process
called contact inhibition. It is proposed that cells are inhibited from
proliferation by interchange of signals or substances at contact point.
31 Cell-matri2 interactions
,uch evidence has accumulated to indicate that the orderly
movement and proliferation of the cells within a healing wound is
&?
influenced not only by signals derived from other cells but also from
the e7tra"cellular matri7, which is an organi#ed comple7 of collagen,
glycosaminoglycans, proteoglycans and glycoproteins. f these much
attention is focused on fibronectins which are a family of adhesive
high molecular weight glycoproteins. E7perimental evidence suggests
that migration of endothelial cells and their organi#ation into
capillaries is also facilitated by fibronectin.
41 'ro/t) actors
Thus far, we have discussed the regeneration migration and
organi#ation of cells in the wound. :ut what triggers these cells to
divide.
Either loss of factors that or release of growth
normally inhibit cell division stimulating factors.
!t one time, the concept that proliferation occurred because of
reduced levels of growth inhibition substance called 6halones, was
popular.
:ut nowadays, the list of growth factors is ever increasing. E.g.,
" Epidermal -.9. *E.-.9.+.
" .erve -.9. *..-.9.+.
" 2latelet derived -.9. *2.D.-.9.+.
" 9ibroblast -.9. *9.-.9.+.
!ll these are polypeptides with hormone li/e structure.
&C
H"A!I'G I' SP"CIA!I*") TISS+"S
a) #nternal sur+aces 8 Endot)elium
The regeneration of the covering epithelium is very similar to
that of the s/in.
b) Bone
Repair of a bone injury is essentially another instance of
connective tissue healing. It differs from soft tissue repair in so far
as formation of the speciali#ed calcified tissues of bone involves the
activity of osteoblasts and osteoclasts.
Repair of a fracture may be ta/en as a model for the process of
bone healing. 8owever, basic events in healing of any type I are
similar and resemble healing of s/in wound to some e7tent.
2rimary 4nion of fractures occurs occasionally in a few special
situations when the ends of fractures are appro7imated because bony
union ta/es place with formation of medullary callus.
'econdary union is the more common process of I healing. It is
described under 3 headings$
" 2rocallus formation.
" sseous callus formation.
" Remodelling.
(0
0) Procallus +ormation
a. 8aematoma
9orms due to bleeding, filling the area surrounding the I.
b. ;ocal inflammatory response
ccurs at the site of injury with e7udation of fibrin, polymorphs
and macrophages. 9ragments of necrosed bone are scavenged by
macrophages and osteoclasts.
c. Ingrowth of granulation tissue
:egins with neovasculari#ation. ! soft tissue callus is that
formed which joins the ends of I bone without much strength.
d. 6allus composed of woven bone and
cartilage
The cells of the inner layer of periosteum have osteogenic
potential and lay down the collagen as well as the osteoid matri7 in the
granulation tissue. The osteoid undergoes calcification and is called
woven bone callus. !t times, callus is composed of woven bone as well
as cartilage, temporarily immobili#ing the bone ends.
This stage is called provisional callus 1 procallus formation and
is arbitrarily divided into$
" E7ternal
(&
" Intermediate.
" Internal procallus.
3) Osseous Callus
The procallus acts as scaffolding on which osseous callus
composed of lamellar bone is formed.
4) &emodelling
During the formation of lamellar bone, osteoblastic laying and
osteoclastic removal are ta/ing place, remodeling the united bone ends,
which after sometime, are indistinguishable from normal bone. The
e7ternal callus is cleared away, compact bone *corte7+ is formed in
place of intermediate callus and the bone marrow cavity develops in
internal callus.
8aematoma formation and local inflammatory
response at the I site.
Ingrowth of granulation tissue with formation of
soft tissue callus.
9ormation of procallus composed of woven bone
and cartilage with its characteristic furiform
appearance and having 3 arbitary components
" E7ternal.
((
" Intermediate.
" Internal callus
9ormation of osseous callus composed of lamellar
bone following clearance of woven bone and
cartilage.
Remodelled bone endD the e7ternal callus cleared
away intermediate callus converted into lamellar
bone and internal callus developing bone marrow
cavity.
5) Nervous tissue
Central 'er,ous System Perip-eral 'er,ous System
Regeneration does not occur. In cases of acute damage, the
initial functional loss often e7ceeds the loss of actual nerve tissue
because of the reactive changes in the surrounding tissue. !s these
changes diminish, functional restoration commences.
Perip-eral 'er,ous System .P'S/
3 types of degenerative processes in the 2.' are$
a) (allerian degeneration
ccurs after transection of the a7on which may be as a result
of /nife wounds, compression, ischaemia. Then, there is initially
(3
accumulation of organelles in the pro7imal and distal end of
transection sites. 'ubsequently, the a7on and myelin sheath
distal to the transection site undergoes disintegration upto the
ne7t node of Ranvier followed by phagocytosis. The process of
regeneration occurs by sprouting of a7ons and proliferation of
'chwann cells from the distal end.
b) A2onal degeneration
Degeneration of the a7on begins at the peripheral terminal
and proceeds bac/wards towards the nerve cell body. 6hanges
similar to those seen in Ballerian degeneration are present but
regenerative reaction is limited 1 absent.
()
c) Segmental demyelination
Is demyelination of the segment between two consecutive
nodes of Ranvier, leaving a denuded a7on segment. The a7on,
however remains intact. 'chwann cells proliferation also occurs.
This results in re"myelination of the affected a7on. Repeated
episodes of demyelination and remyelination are associated with
concentric proliferation of 'chwann cells around a7ons
producing Fonion bulbsG found in hypertrophic neuropathy.
"raumatic Neuroma
.ormally, the injured a7on of a peripheral nerve regenerates
at the rate of appro7imately &mm1day. 8owever, if the process
of regeneration is hampered due to an interposed haematoma or
fibrous scar, the a7onal sprouts together with 'chwann cells and
fibroblasts form a peripheral mass called Traumatic 1 'tump
.euroma.
(<
d) %uscles
,uscle fibres of all 3 types > '/eletal, 6aridac and 5isceral
have only limited capacity to regenerate.
" Bhen a mass of muscle tissue is damaged, repair by scarring
occurs.
" If the damage affects individual muscle fibres diffusely and with
varying severity, then regeneration of the speciali#ed fibres is
possible.
Boo0s referred
" 8arsh ,ohan
" 'tanley *:asic 2athology+
" :oydGs 2athology
" -ovan, ,ac9arlane and 6allendar
" 6ottran, Robin and Billiams
(=
R"PAIR .I' G"'"RA!/
C'T"'TS
Introduction
2rocess Involved in Repair Regeneration
Replacement
Bound 8ealing
2athologic !spects of Repair
,echanisms Involved in Repair
8ealing in 'peciali#ed tissues
(A