• Injury to cells and tissues sets in

motion a series of events which

contain the damage and initiate
healing.
• This process can be broadly
separated into regeneration and
repair.
 Regeneration :
• Growth of cells and tissues to replace
the lost or damaged tissue
Repair :
• Restores some original structures but
can cause structural derangements.
• In healthy tissues, healing, in the
form of regeneration or repair, occurs
after any insult that causes tissue
destruction, and is essential for the
survival of the organism.
• Regeneration refers to the proliferation
of cells and tissues to replace lost
structures, such as the growth of an
amputated limb in amphibians.
• In mammals, whole organs and
complex tissues rarely regenerate after
injury, and the term is usually applied
to processes such as liver growth after
partial resection or necrosis, but these
processes consist of compensatory
growth rather than true regeneration.
• Tissues with high proliferative capacity,
such as the hematopoietic system and
the epithelia of the skin and
gastrointestinal (GI) tract, renew
themselves continuously and can
regenerate after injury, as long as the
stem cells of these tissues are not
destroyed.
• Repair most often consists of a
combination of regeneration and scar
formation by the deposition of collagen.
• The relative contribution of
regeneration and scarring in tissue
repair depends on the ability of the
tissue to regenerate and the extent of
the injury
• Superficial skin wound heals through
regeneration of the surface
epithelium.
• When the extracellular matrix (ECM)
framework is damaged by severe
injury healing occurs by scar
formation because
ECM components provide the
framework for cell migration, maintain
the correct cell polarity for the re-
assembly of multilayer structures,
and participate in angiogenesis.
Control of Normal Cell Proliferation
and Tissue Growth

• Cell proliferation is largely controlled

by signals from the microenvironment
that either stimulate or inhibit
proliferation. An excess of stimulators
or a deficiency of inhibitors leads to net
growth and, in the case of cancer,
uncontrolled growth.
• The body tissues are divided into
three groups on the basis of the
proliferative activity of their cells:
1) Continuously dividing (labile
tissues)
2) Quiescent (stable tissues)
3) Nondividing (permanent tissues).
 Continuously dividing tissues
Cells proliferate throughout life,
replacing those that are destroyed eg
surface epithelia, columnar
epithelium of the GI tract and uterus;
transitional epithelium of the urinary
tract, and cells of the bone marrow
and hematopoietic tissues.
• Mature cells are derived from adult
stem cells
 Quiescent tissues
• Low level of replication;
• Can undergo rapid division in
response to stimuli and are thus
capable of reconstituting the tissue of
origin,e.g parenchymal cells of liver,
kidneys, and pancreas; mesenchymal
cells such as fibroblasts and smooth
muscle; vascular endothelial cells; and
lymphocytes and other leukocytes.
 Nondividing tissues
• Cells have left the cell cycle and
cannot undergo mitotic division in
postnatal life,e.g. neurons and
skeletal and cardiac muscle cells.
• If neurons in the central nervous
system are destroyed, the tissue is
generally replaced by the
proliferation of the central nervous
system–supportive elements, the
glial cells.
• Mature skeletal muscle cells do not
divide
• Skeletal muscles do have
regenerative capacity, through the
differentiation of the satellite cells
that are attached to the endomysial
sheaths.
 STEM CELLS
• Undifferentiated cells which can
divide and differentiate into different
cell lineages .

Achieved by two mechanisms:

• (a) Obligatory asymmetric replication
Each stem cell divides into one
daughter cell which retains its self-
renewing capacity while the other
enters a differentiation pathway.
(b) Stochastic differentiation
Stem cell population is maintained by
the balance between stem cell divisions
that generate either two self-renewing
stem cells or two cells that will
differentiate
 Potency Definitions
• Totipotent: Can differentiate into
embryonal and extra embryonal tissues
• Pluripotent: Can divide into any cell of
the three germ layers
• Multipotent:Differentiate into a cell of a
closely related family
• Oligopotent:Differentiate into few cells
only eg lymphoid or Myeloid cells
• Unipotent: Can produce their own cell
type only eg Muscle stem cell
 Embryonic Stem Cell
• Derived from inner cell mass of a
blastocyst
• Are pluripotent, that is, they can generate
all tissues of the body.
• Do not form extraembryonic tissues like
placenta

Transdifferentiation indicates a change in

the lineage commitment of a stem cell.
• ES cells may in the future be used to
repopulate damaged organs.
• ES cells may be capable of
differentiating into insulin-producing
pancreatic cells, nerve cells,
myocardial cells, or hepatocytes.
 Adult Stem Cellss

• Lineage specific (multipotent)

• Located in sites called niches
Isthmus of gastric glands
Base of colonic crypts
hair follicles
Limbus of cornea
• Bone marrow contains hematopoietic
stem cells (HSC) and stromal cells
• HSCs can repopulate marrow after
disease or irradiation
• Collected from bone marrow or
peripheral blood of patients receiving
cytokines like GM-CSF
• Bone marrow stromal cells depending
on the enviroment can differentiate into
Chondrocytes
Osteoblasts
Fat cells
Myoblasts
Endothelial cells
ADULT STEM CELLS
 How Stem cells maintain
Homeostasis

• Most organs have got tissue stem cells

( adult stem cells ) which can
generate mature cells of that organ
• Liver contains stem cells (oval cells )
in canals of Hering
• Activated only when hepatocyte
proliferation is blocked
• After hepatectomy or necrotizing
injury hepatocytes divide to replenish
cell population and stem cells are not
activated
• In fulminant hepatic failure , cirrhosis
and liver cancers oval cells become
active because in these situations
hepatocyte proliferationis blocked
 Brain
• Neural stem cells identified in adult
rodent brains in
Olfactory bulb
Dentate gyrus of Hippocampus
These can produce functionally active
neurons
 Skeletal Muscle
• Themselves are non dividing
• Regeneration of injured cells occurs
by replication of stem cells
• If stem cells are placed in different
environment can be osteogenic or
adipogenic
 Epithelium
• Self renewing epithelium
reconstitutes after injury by:
1) Increasing number of dividing stem
cells
2) Increasing number of dividing cells
of epithelium
3) Decreasing cell cycle time
 The Cell Cycle
C/O 4 phases
1) Presynthetic growth phase 1 (G1)
2) DNA synthesis phase (S)
3) Premitotic growth phase 2 (G2)
4) Mitotic phase (M)
• Non dividing cells are in G1 or they
exit cell cycle to enter G0 phase
• Any stimulus for cell proliferation
(growth factors) promotes G0 to G1
transition
• Cell cycle has intrinsic quality control
mechanisms the Checkpoints which
detect DNA damage and prevent
DNA replication of such cells
• Proteins called Cyclins combine with
cyclin dependant kinases (enzymes)
• This promotes progression through
cell cycle
• CDKs are suppressed in G1 by
different mechanisms
• Growth factors release this
suppression
 Growth Factors
• Are proteins which expand cell
population by stimulating cell division
and promoting cell survival
• Also stimulate cell migration ,
differentiation ,contractility and protein
synthesis.
• Act by binding to cell receptors
• Stimulate function of growth control
genes (protooncogenes)
 Signalling Mechanisms of GF
Receptors

1) Autocrine : Important in lymphocytic

proliferation
2) Paracrine :Recruitment of cells in
inflammation and wound healing
3) Endocrine :Hormonal action
 Epidermal GF
• Platelets, Macrophages, salivary
glands,keratinocytes and many other
cells.
• Mitogenic for keratinocytes and
figroblasts
• Stimulates keratinocyte migration and
granulation tissue formation.
 TGF-alpha
• Platelets, Macrophages, T
lymphocytes keratinocytes and many
other cells.
 Stimulates replication of hepatocytes
and most epithelial cells
 Vascular endothelial cell
growth factor

• Mesenchymal cells
• Increases vascular permeability
• Mitogenic for endothelial cells
Platelet-derived growth factor
• Platelets
• Macrophages
• Endothelial cells
• Keratinocytes
• Smooth muscle cells
• Chemotactic for PMNs, macrophages,
fibroblasts, and smooth muscle cells;
• Activates PMNs, macrophages, and
fibroblasts;
• Mitogenic for fibroblasts, endothelial
cells, and smooth muscle cells;
• Stimulates production of MMPs,
• Stimulates angiogenesis and wound
remodelling
 Fibroblast growth factor
 Macrophages mast cells T lymphocytes
endothelial cellsand fibroblasts
 Chemotactic for fibroblasts
 Mitogenic for fibroblasts and
keratinocytes
 Stimulates keratinocyte migration,
angiogenesis, wound contraction and
matrix deposition.
 TGF-beta
• Platelets, T lymphocytes, macrophages,
endothelial cells, keratinocytes, smooth
muscle cells and fibroblasts
• Chemotactic for PMNs, macrophages,
lymphocytes, fibroblasts, and smooth
muscle cells;
• Stimulates angiogenesis, and fibroplasia;
• Inhibits production of MMPs and
keratinocyte proliferation.
 Keratinocyte growth factor
• Fibroblasts
• Stimulates keratinocyte migration,
proliferation, and differentiation
Receptors with Intrinsic Kinase
Activity
• Dimeric transmembrane molecules with
extracellular ligand binding domain
• Binding of ligand causes phosphorylation
of receptor subunits and a cascade of
events leading to entry into cell cycle and
cell cycle progression
• Ligands include Epidermal GF,
VEGF.fibroblast growth factor and
hepatocyte GF
TK
 EGFR Function in Normal Cell

ATP ATP
TK TK

Gene Transcription
Cell Cycle Progression

Cell Proliferation Antiapoptosis

Angiogenesis
 Consequence of proliferation of
Mutation EGFR receptors

Normal Cell
Up Regulation
Cancerous Cell
 Seven Transmembrane G-
protein coupled Receptors

• Contain 7 transmembrane alpha helix

segments
• Binding of ligand causes activation of
GTP binding proteins
• Receptors include epinephrin,
vasopressin, serotonin,histamin,
glucagon and chemokines
 Receptors without Intrinsic
Enzymatic Activity
• Monomeric transmembrane molecules with
extracellular ligand-binding domain
• Ligand binding causes association and
phosphorylation of Jamus Kinases
• Jamus Kinases activate Transcription factors
which enter nucleus and binds to DNA
• Ligands include cytokines, interferones . CSF
growth hormone and erythropoietin
ECM and CELL Matrix
Interactions
ECM is the acellular amorphous gel
surrounding cells. It consists of:
• • Fibers: collagen and elastin, which
provide strength and flexibility.
• • Proteoglycans: protein-saccharide
complexes, providing a voluminous
matrix.
• • Adhesive glycoproteins: which
connect cells and ECM, e.g. fibronectin
and laminin
• Tissue repair and regeneration
depend on interactions between
cells and the components of the
extracellular matrix (ECM).
• The ECM regulates the growth,
proliferation, movement, and
differentiation of the cells living
within it
• ECM is a constantly remodeling
macromolecular complex
• Its synthesis and degradation
accompany regeneration, wound
healing, chronic fibrotic
processes, tumor invasion and
metastasis.
• ECM sequesters water( providing
turgor to soft tissues) and minerals
that give rigidity to bone.
 Functions
1) Mechanical support for cell anchorage
and cell migration and maintenance of
cell polarity
2) Control of cell growth.
ECM components can regulate cell
proliferation by signaling through
cellular receptors of the integrin family.
  
3)   Maintenance of cell
differentiation.
Types of ECM proteins affect the
degree of differentiation of cells in
tissue, acting via cell surface
integrins.
4. Scaffolding for tissue renewal.
Maintenance of normal tissue
structure requires a basement
membrane or stromal scaffold.
Integrity of basement membrane and
stroma of parenchymal cells is
critical for the organized
regeneration of tissues
• Although labile and stable cells are
capable of regeneration, injury to
these tissues results in restitution
of the normal structure only if the
ECM is not damaged. Disruption of
these structures leads to collagen
deposition and scar formation
5) Establishment of tissue
microenvironments.
Basement membrane acts as a
boundary between epithelium and
underlying connective tissue and also
forms part of the filtration apparatus
in the kidney.   
6) Storage and presentation of
Regulatory Molecules
Growth factors like FGF and HGF are
excreted and stored in ECM
Readily available after injury and in
regeneration  
ECM occurs in two basic forms
• The interstitial matrix :
• Found in spaces between cells
• Synthesized by mesenchymal cells
• Forms a 3 dimensional gel
• Consists mostly of fibrillar and
nonfibrillar collagen, elastin,
fibronectin, proteoglycans, and
hyaluronan.
2 ) Basement membranes
• Closely associated with cell
surfaces
• Synthesized by epithelium and
underlying mesenchymal cells
• Consist of nonfibrillar collagen
(mostly type IV), laminin, heparin
sulfate, and proteoglycans.
Extracellular Structures

67
 Components of ECM
COLLAGEN
• Collagen is the most common protein in
the animal world, providing the
extracellular framework for all multicellular
organisms. Without collagen, a human
being would be reduced to a clump of cells
interconnected by a few neurons.
• Currently, 30 different types of collagens
encoded by 41 genes dispersed on at least
14 chromosomes are known.
• Each collagen is composed of three
chains that form a trimer in the shape
of a triple helix.
• The polypeptide is characterized by a
repeating sequence in which glycine
is in every third position (Gly-X-Y, in
which X and Y can be any amino acid
other than cysteine or tryptophan).
• It contains amino acids 4
Hydroxyproline & Hydroxylysine
• Cross linking between triple helices
depends on vitamin C
• Children with vit C deficiency have
skeletal abnormalities , bleed easily
(weak vascular wall BM) and heal poorly
• Genetic defects in collagen causes
diseases as Osteogenesis imperfecta
and Ehlers-Danlos syndrome
• Types I, II, III and V, and XI are the
fibrillar collagens These proteins are
found in extracellular fibrillar
structures.
• Type IV collagens have long triple-
helical domains and form sheets
instead of fibrils; they are the main
components of the basement
membrane, together with laminin.
 ELASTIN
• Tissues such as blood vessels, skin,
uterus,skin and lung require elasticity
for their function.
• Proteins of the collagen family provide
tensile strength, but the ability of these
tissues to expand and recoil depends
on the elastic fibers. These fibers can
stretch and then return to their original
size after release of the tension.
• Morphologically, elastic fibers consist
of a central core made of elastin,
surrounded by a peripheral network of
microfibrils composed of a
glycoprotein called fibrillin
• Inherited defects in fibrillin result in
formation of abnormal elastic fibers in
Marfan syndrome, manifested by
changes in the cardiovascular system
(aortic dissection) and the skeleton.
Elastin
PROTEOGLYCANS and HYALURONAN
• Proteoglycans form hydrated gel which
provide resilience and lubrication esp
in cartilage
• They c/o a protein core with
polysaccharides called
glycosaminoglycans ( dermatan
sulphate and heparan sulphate)
arranged around it
• Hyaluronan : Large molecule c/o
disaccharide units without a protein core
Binds water to form a viscous gel
Adhesive Glycoproteins and
Adhesion Receptors

Molecules involved in
1) Cell to cell adhesion
2) Linkage between cells and ECM
3) Binding between ECM components
 Adhesive Glycoproteins
1) Fibronectin
• Disulphide linked heterodimer
synthesized by many cells as fibroblasts
, monocytes and endothelium
• Bind to a wide variety of ECM
components as collagen, fibrin, heparin
• Also bind to cell integrins via tripeptide
arginine-glycine-aspartic acid(RGD)
molecule
Fibronectin exists in two forms
Tissue Fibronectin which forms fibriller
aggregates at wound healing sites
Plasma Fibronectin which binds to
fibrin and forms blood clot of wound
2) Laminin
• Most abundant glycoprotein of
basement membrane
• Cross shaped heterodimer which
connects cells to ECM components as
type IV collagen and heparan sulphate
(BM)
• Also modulates cell proliferation ,
differentiation and motility
Adhesion Receptors (cell adhesion
molecules)
Four families of CAMs
1) Immunoglobulins
2) Cadherins
3) Selectins
4) Integrins
Integrins
• Transmembrane glycoproteins c/o alpha
and beta chains
• Main receptors for ECM components as
fibronectin and laminin
• Present on all animal cells except RBCs
• Bind to ECM components via RGD motifs
• Affect cell locomotion , proliferation and
differentiation
• Their intracellular domain is linked to actin
filaments
• Utilize same intracellular signalling
pathway used by growth factor
receptors (kinases)
• Convert extracellular mechanical forces
to intracellular synthetic and
transcriptional pathways
Extracellular matrix (e.g., fibronectin
and laminin) and growth factors can
influence cell growth, motility,
differentiation, and protein
synthesis.

Integrins bind ECM components and

interact with the cytoskeleton at
focal adhesion complexes (protein
aggregates that include vinculin,
actin, and talin). This can initiate the
production of intracellular
messengers or can directly mediate
nuclear signals.

Cell-surface receptors for growth

factors may activate signal
transduction pathways that overlap
with those activated by integrins.

Collectively, these are integrated by

the cell to yield various responses,
including changes in cell growth,
locomotion, and differentiation
Repair by Connective Tissue
• Severe or persistent tissue injury with
damage both to parenchymal cells
and to the stromal framework leads to
a situation in which repair cannot be
accomplished by parenchymal
regeneration alone.

• Repair occurs by replacement of the

non regenerated parenchymal cells
with connective tissue.
• General components of this process
are:

 Formation of new blood vessels

(Angiogenesis)
 Migration and proliferation of fibroblast
 Deposition of ECM
 Maturation and reorganization of the
fibrous tissue (Remodeling)
• As early as 24 hr. after injury, fibroblasts
and vascular endothelial cells begin
proliferating to form (by 3-5 days)
granulation tissue – pink granular
appearance on the surface of the wound.
• Histologically : granulation tissue is
composed of :
– Proliferation of new small blood vessels
and
– Proliferation of fibroblasts
 What is granulation tissue?
• The term was used by ancient
surgeons for the red, granular tissue
filling the non healing wounds.
• It is now known that granulation
tissue occurs in all wounds during
healing, and in chronic inflammation
as well
• It c/o fibroblasts surrounded by
abundant extracellular matrix, newly
formed blood vessels, and scattered
macrophages and some other
inflammatory cells
 Angiogenesis from endothelial
precursors
• Common precursor: hemangioblast
that gives rise to angioblast and
hematopoietic stem cells.
• Angioblasts then proliferate and
differentiate into endothelial cells that
form arteries,veins and lymphatics.
• Epcs (angioblast like cells) in the
bone marrow can be recruited into
tissues to initiate angiogenesis.
• What is VASCULOGENESIS?
 Angiogenesis from preexisting
vessel
• Vasodilation in response to nitric acid
and VEGF.
• Increased permeability of pre-existing
vessel.
• Proteolytic degradation of the parent
vessel BM by metalloproteinases and
disruption of cell to cell contact btw
endothelial cells of the vessel by
plasminogen activator.
• Migration of endothelial cells from the
original capillary toward an
angiogenic stimulus.
• Proliferation of the endothelial cells
behind the leading edge of migrating
cells.
• Maturation of endothelial cells with
inhibition of growth and organization
into capillary tubes.
• . The new vessels formed are leaky
because of incomplete
interendothrlial junctions and
increased permeability mediated by
VEGF
• Recruitment and proliferation of
pericytes (for capillaries) and smooth
muscle cells (for larger vessel) to
support the endothelial tube
 How ECM Helps in
Angiogenesis
1) Structural ECM proteins help by
interactions with integrin receptors
on endothelial cells
2) Non structural proteins as
thrombospondin and tenascin C
destablize cell-ECM interactions to
facilitate cell migration and
plasminogen activator and MMPs
degrade ECM for remodelling and
ingrowth of blood vessels
 Growth factors and receptors
involved in angiogenesis

VEGF
 Secreted by mesenchymal cells and
stromal cells (hypoxia)
 Family includes VEGF-A , B , C and D
 Bind to receptors VEGFR-1 , 2 and 3
with tyrosine kinase activity Most
important is VEGFR-2 which is
restricted to endothelial cells
• In angiogenesis from pre-existing
vessels VEGF stimulates proliferation
and motility of endothelial cells

• In angiogenesis from marrow

precursors VEGFR-2 mobilizes the
cells from marrow and induces their
proliferation and motility at site of
angiogenesis
 Angiopoietin 1 and 2 , PDGF and
TGF-beta help in stabilizing and
strengthening newly formed blood
vessels
• Ang 1 recruits periendothelial cells
• PGDF recruits smooth muscle cells
• TGF-beta increases production of
ECM proteins
 FGFs – secreted by many cells and stored
in ECM
• Promotes proliferation of endothelial cells
• Promotes migration of macrophages and
fibroblasts to site of injury
• Stimulates migration of epithelial cells to
cover epidermal wounds
Keratinocyte Growth Factor
• Enhances proliferation and migration of
keratinocytes and protects epithelium of
oral mucosa and GIT
 Scar Formation

Scar forms on granulation tissue framework

.It involves
1) Migration and proliferation of fibroblasts
to site of injury
2) Deposition of ECM by these cells
3) Tissue remodelling
 Fibroblast Migration and
Proliferation
• Exudation and deposition of plasma
protein as fibrinogen and plasma
fibronectin in the ECM of granulation
tissue
• Provides a provisional stroma for
fibroblasts and endothelial cell
ingrowth.
• Migration and proliferation of
Fibroblasts to the site of injury
• Collagen synthesis by fibroblasts begins in 3
to 5 days and continues for several weeks
• Collagen accumulation depends on increased
synthesis and decreased degradation
• Granulation tissue gets replaced by scar
tissue c/o fibroblasts , collagen fibres,elastic
fibres and other ECM components
 Growth Factors involved in
Scar formation
TGF-B appears to be the most
important
It is produced by most of the cells in
granulation tissue .Causes fibroblast
migration and proliferation, increased
synthesis of collagen and fibronectin
• It decreases degradation of ECM by
metalloproteinases by increasing
activity of Tissue Inhibitors of
Proteinases (TIMP)
• Has anti-inflammatory effect by
inhibiting lymphocyte proliferation
PDGF
• Produced by endothelial cells
,activated macrophages, smooth
muscle cells and some tumor cells
• Stored in platelets and released on
platelet activation
• Causes migration and proliferation of
fibroblasts ,smooth muscle cells and
macrophages
Cytokines
• Can function as growth factors
• IL-1 and TNF are chemotactic for
fibroblasts and cause fibroblastic
proliferation and collagen synthesis
ECM and Tissue Remodelling
• The balance between ECM synthesis
and degradation results in remodeling of
the CT framework.
• Degradation of collagen and other ECM
proteins is achieved by a family of
matrix metalloproteinases which are
dependant on zinc ions for their activity.
 MMPs include
1) Interstitial collagenases (MMP1, 2,
3) which cleave the fibrillar collagen
type 1, 2 and 3
2) Gelatinases (MMP2 and 9) degrade
amorphous collagens and fibronectin.
• Stromelysin (MMP-3,10,11) degrades
proteoglycan , laminin, fibronectin and
amorphous collagen.
• MMPS are synthesized as propeptides
that require proteolytic for
• MMPs are produced by different cells as
fibroblasts , macrophages
,neutrophils ,synovial cells and some
epithelial cells

• Synthesized as propeptides (zymogen)

which require proteolytic cleavage for
activation by proteases eg. Plasmin and
free radicals produced in oxidative
burst of leukocytes

• Inhibited by TGF-b and steroids

• Secretion of MMPs is induced by certain
stimuli such as growth factors, cytokines,
and physical stress phagocytosis

• Once formed activated collagenases are

rapidly inhibited by a family of specific
tissue inhibitor of metalloproteinases
(TIMP).
 Cutaneous Wound Healing
• Wound healing is a fibroproliferative
response that is mediated through
growth factors and cytokines.

Healing of Cutaneous wounds involves

1) Epithelial Regeneration
2) Formation of connective tissue scar
 Cutaneous wound healing is divided
into three phases
1) Inflammation (early and late)
2) Granulation tissue formation
3) ECM deposition and remodeling.

• Based on nature of wound ,healing

of cutaneous wound can be by first
or second intention
 Healing by first intention
(wounds with opposed edges
• Common example of wound repair is
healing of a clean, uninfected surgical
incision approximated by sutures.
• Such healing is called primary union
or healing by first intention.
• Incision causes
1) Death of limited number of epithelial
cells and connective tissue.
2) Disruption of epithelial BM.
The narrow incisional space first fills
with clotted blood which is invaded by
granulation tissue and is then
covered by new epithelium
 Within 24 hours;
• Neutrophils appear at the margin of
the incision moving towards the fibrin
clot.
• Basal cells at cut edge of epidermis
show increased mitotic activity
 In 24 to 48 hours
• Epithelial cells from both edges
migrate and proliferate along dermis
depositing BM components as they
move
• These cells finally meet in midline
underneath surface scab forming a
thin but continuous epithelial layer
 Day 3
• Neutrophils are replaced by
macrophages.
• Granulaton tissue invades the
incisional space
• Collagen fibers are present in the
margin of the incision but are oriented
vertically and do not bridge the incision.
• Epithelial cell proliferation thickens the
epidermal layer
 Day 5
• Incisional space filled with granulation
tissue. s
• Neovascularization is maximal
• Abundant collagen fibers ,bridging the
incision.
• Epidermis gains normal thickness
and mature epidermal architecture
with surface kertinization seen
 Second week
• Continued accumulation of collagen
and proliferation of fibroblast .
• Edema ,leukocyte infiltrate and
vascularity are greatly reduced
 End of first month
• Scar is made of cellular C.T
containing no inflammatory cells .It is
now covered by an intact epidermis.
• Dermal appendages that have been
destroyed in the line of incision are
permanently lost.
• Tensile strength of wound increases
with time
 Healing by second intention
(wound with separate edges)
• Extensive tissue loss as in large
wounds , abscess formation and
ulceration
• Inflammatory reaction is more intense
and there is abundant granulation
tissue formation from the margins to
fill the gap
• Wound contracts by action of
myofibroblasts followed by
accumulation of ECM and formation of
large scar
 Difference
• Larger clot
• More severe inflammation due to larger
tissue defect and greater amount of
debris to be cleared
• Much larger amount of granulation
tissue formed resulting in a larger scar
• Wound contraction by myofibroblasts–
May reduce a large skin wound to 10%
of its size in six weeks time
 Wound Strength
• Sutured wounds have about 70% of
strength of unwounded skin
• When sutures are removed at the end
of the first week ,strength is
approximately 10% that of unwounded
skin, but strength increases rapidly
over the next 4 wks.
• At the end of third month the wound
strength is about 70 to 80% of the
unwounded skin
 Factors Affecting Wound
Healing
• Local Factors
1) Infection: Increases tissue damage
and prolongs inflammation
2) Increased local pressure and torsion
may cause wound dehiscence
3) Poor perfusion
4) Foreign bodies (sutures ,fragments of
bone, steel or glass)
• General Factors
1) Nutrition :Deficiency of proteins and
vitamin C inhibits collagen synthesis
and delay healing
2) Steroids: anti-inflammatory ..Poor
wound strength due to decreased
fibrosis
In corneal infections steroids are
administered to decrease chance of
opacity formation by deposition of
collagen
3) Type and volume of tissue injured:
Partial or complete restoration can
occur in labile and stable cells. In case
of permanent cells only scar tissue
forms
• Location of injury: infections of serous
cavities cause formation of exudate
which can resolve or organize and
fibrose
5) Metabolic status, diabetes mellitis
,delayed wound healing,
( microangiopathy)
 Complications
1) Inadequate formation of granulation
tissue.
2) Wound dehiscence
Rupture of a wound is most common
after abdominal surgery and is due to
increased abdominal pressure
Vomiting, coughing , ileus
3) Ulceration of the wounds because
of inadequate vascularization during
healing. (peripheral vascular
diseases)

4) Non healing wounds are also found

in areas of denervation. (diabetic
peripheral neuropathy)
 Excessive formation of the
components of the repair
• Hypertrophic scar : Due to
deposition of excessive amounts of
collagen which gives rise to a raised
scar.  Does not grow beyond the
boundaries of the original wound.
• Proud Flesh: Excessive amount of
granulation tissue which protrudes
above the level of surrounding skin
and prevents re-epithelisation
• Keloid : Is a scar tissue composed mainly
of either type III (early) or type I
(late)collagen which goes beyond the
boundaries of the original wound and
does not regress.
Is benign but can cause itchiness and
pain 
Can occur as a result of severe acne or
chicken pox scarring
More common on central chest, back,
shoulders and ear lobes. 
Frequency of occurrence is 15 times
higher in highly pigmented people
 Contracture
• Exaggeration in the process of
contraction in the wound is called
contracture.
• Severe burns
• Palms,soles ,thorax.