This document discusses tissue repair through cell growth, fibrosis, and wound healing. It covers the types of cells and their regenerative capabilities, growth factors involved in cell regeneration and fibrosis, wound healing processes, and an overview of the inflammatory reparative response. The key points are that tissue repair involves regeneration of injured tissues by parenchymal cells or replacement by connective tissue fibrosis. The processes of regeneration and fibrosis use similar mechanisms involving cell migration, proliferation, differentiation, and matrix synthesis. Growth factors stimulate processes like fibroblast proliferation, collagen synthesis, and angiogenesis to promote healing.

2. Tissue Repair:
Cell Growth
Fibrosis
And
Wound Healing

3. An Overview
CELL and TISSUE REGENERATION:
•Control of Cell Growth and Differentiation
•Soluble Mediators
•Extracellular Matrix and Cell – Matrix
interactions
REPAIR BY CONNECTIVE TISSUE(FIBROSIS):
•Angiogenesis
•Fibrosis (Scar Formation)
•Scar Remodeling
GROWTH FACTORS IN CELL REGENERATION
AND FIBROSIS:

4. An Overview …. Contd
WOUND HEALING:
•Healing by First Intention (wounds with
opposed edges)
•Healing by second intention ( wounds with
separated edges)
•Wound Strength
•Local and systemic factors that influence
wound healing
 PATHOLOGIC ASPECT OF REPAIR
OVERVIEW OF INFLMMATORY
REPARATIVE RESPONSE

5. Types of cells on the Basis of their
Regenerating Capabilities
1. Labile OR continuously Dividing Cells
2. Stable OR Quiescent Cells
3. No dividing OR Permanent Cells

6. 1. Labile OR Continuously Dividing Cells
These cells proliferate through out life, replacing
those cells that are continuously dying
Examples of Labile Cells:
a) Stratified squamous epithelium of skin, oral
cavity, vagina and cervix
b) Cuboidal epithelium of the ducts draining exocrine
organs e.g., salivary glands, pancreas and
biliary tract.
c) Columnar epithelium of GIT , uterus, and
fallopian tubes
d) Haemopoietic ( blood forming) cells of bone
marrow

7. Stem Cell
Continuously dividing cells (labile cells) contain stem cells
that differentiate to replenish lost cells and maintain tissue
homeostasis .
Stem cells from embryos are pluripotent: they have the
potential to differentiate into almost any cell in the body
Adult tissue, particularly the bone marrow , contain adult
stem cells capable of generating multiple cells lineages
Important properties of stem cell:
(i) Self- renewal
(ii) Replication and differentiation
Clinical applications of stem cells:
(i) Stem cell transplantation for haemopoietic diseases
(ii) Therapeutic cloning
(iii) Stem cell transplantation into haemopoietic diseases.

8. .2. Quiescent OR Stable Cells
These cells have capacity to regenerate but in normal
conditions do not actively replicate. However they can
undergo rapid division in response to a variety of
stimuli and are thus capable of reconstitution of the
tissue of origin.
Examples:
a) Parenchymal cells of liver, kidney and pancreas
b) Mesenchymal cells e.g., smooth muscle cells,
cartilage, connective tissue, fibroblast and vascular
endothelial cells

9. 3. No dividing OR Permanent Cells
These cells are incapable of division and regeneration
If they are destroyed , the loss is permanent and
repair occurs only by the connective tissue ( i.e., by
scar formation.
Examples:
a) Nerve cells (Neurons)
b) Cardiac Cells
c) Skeletal muscle cells

10. With the exception of tissues composed of
non dividing permanent cells (e.g., cardiac
muscle and nerve), most mature tissues
contain variable proportions of three cell
types:continously dividing cells, quiescent
cells that can return to the cell cycle and
nondividing cells

11. KEY POINTS ABOUT HEALING AND REPAIR
►When cells are injured the reparative mechanisms
also set into action.
►Stimuli that induce death in some cells , at the
same time can lead to replication in other cells
►Repair involves two dichotomous processes:
(1) Regeneration of injured tissue by parenchymal cells
of the same type
(2) Replacement by connective tissue (fibrosis) ,
resulting in a scar

12. Regeneration Vs Replacement
Regeneration Replacement
Injured tissue is
regenerated by the
parenchymal cells of the
same type
Injured tissue is replaced
by the fibrous tissue
resulting in Scar formation
Intact basement
membrane and presence of
extracellular matrix is a
prerequisite for
regeneration
Damaged basement
membrane and inadequate
extrallular matrix leads to
replacement
If labile and stable cells
are damaged then
regeneration can take
place
If permanent cells are
damaged then
replacement will take
place

13. Mechanisms of Cell Repair & Regeneration
Injury to liver is repaired by
regeneration if only the
hepatocytes are damaged ,
or by lying down of fibrous
tissue if the matrix is also
injured

14. ►Interestingly Regeneration and scar involve essentially
similar mechanisms including:
(i) Cells migration
(ii) Cells proliferation
(iii) Cells differentiation
(iv) Matrix Synthesis
Significance of Basement membrane(BM)
and Extra Cellular Matrix(ECM)
Intact basement membrane
&
Presence of Extracellular Matrix
Damaged basement membrane
&
Inadequate Extracellular Matrix
Regeneration of inured tissue by
parenchymal cells of the same type
will take place
Replacement by connective tissue
(fibrosis) resulting in scar formation
will take place
KEY POINTS ABOUT HEALING AND REPAIR.. Contd

15. KEY POINTS ABOUT HEALING AND REPAIR…Contd
 The body’s ability to replace injured or dead cells
and to repair tissues after inflammation is critical
to survival.
 Cells can be divided into labile, stable or
permanent populations; only labile and stable cells
can be regenerate if lost.
 Complex tissue architecture may not be reconstructed .
 Healing is restitution with no, or minimal, residual
defect, e.g. superficial skin abrasion, incised wound
healing by first intention

16. Cell
Regeneration

17. Control of Cell Growth and Differentiation
In general , the number of cells
in a given tissue is accumulative
function of the rates at which
new cells enter and existing
cells exit the population
Cells number can be altered by
increased or decreased rate of
cell death (Apoptosis) or by
changes in the rates of
proliferation or differentiation .

18. Cell Cycle
Proliferating cells progress through
a series of checkpoints and defined
phases called the cell cycle
Phases of Cell Cycle
Phase G1
Presynthetic Growth Phase 1
Phase S
DNA synthetic phase
Phase G2
Premitotic Growth Phase 2
Phase M
Mitotic Phase

19. Control
of
Cell Growth

20. Control of Cell Growth
Cellular proliferation is controlled largely by biochemical
factors produced in the local microenvironment that can
either stimulate or inhibit cells growth. The factors
that stimulate cell growth are called growth factors
while those that inhibit growth are called inhibitory
factors

21. FACTORS MEDIATING WOUND HEALING

22. FACTORS MEDIATING WOUND HEALING: A wound is shown
penetrating the skin and entering a blood vessel . (1) Blood
Coagulation and Platelet degranulation , releasing
Growth Factors / Cytokines .(2) These are chemotactitic
for Macrophages, which migrate into the wound to
phagocytose bacteria and necrotic debris (3). In the epidermis :
epidermal basal epithelial cells are activated by released
Growth Factors from the platelets (4), and dermal
myofibroblasts (5); from epidermal cells by Paracrine (6) and
Autocrine (7) mechanisms ; and from saliva (8) (if the
wound is licked) . Nutrients and Oxygen (9) and
Circulating Hormones and Growth Factors diffusing in
myofibroblasts (10), which produce Collagen and
Fibronectin . Fibronectin stimulates migration of dermal
myofibroblasts (11) and epidermal epithelial cells (12) into over
the wound. Angiogenic Growth Factors (not shown)
stimulate the proliferation and migration of new blood vessels
into the area of the wound (13)

23. Growth Factors:
 Cell proliferation is mediated by chemical mediators.
 The most important chemical mediators are
polypeptide growth factors
 These polypeptide growth factors are circulating in
the serum or produced locally by the cells
 At the site of injury there are multiple sources of
these growth factors. Majority of these are formed
by activated macrophages.
 There is an impressing array of growth factors and
new ones are constantly being discovered.

24.  The important growth factors which have a broad
target action or are specifically involved in directing
healing at the site of injury are:
1. Epidermal Growth Factor (EGF)
2. Platelet Derived Growth Factor (PDGF)
3. Fibroblast Growth Factor (FGF)
4. Transforming Growth Factor β (TGF- β)
5. Vascular Endothelial Growth Factor (VEGF)
6. Insulin like Growth Factor (IGF)
7. Tumour Necrosis Factor (TNF)

25. Growth factors involved in Healing and Repair
Growth Factor Abbreviation Functions
Epidermal Growth Factor EGF Regeneration of epithelial cells
Transforming Growth
Factor- β
TGF -β -Stimulates fibroblasts proliferate
and collagen synthesis
-Controls epithelial regeneration
Platelets Derived Growth
Factor
PDGF Mitogenic and chemotactic for
fibroblasts and smooth muscle
cells
Fibroblasts Growth Factor FGF Stimulates fibroblasts proliferation
,angiogenesis and epithelial cell
regeneration
Insulin like Growth Factor IGF Synergistic effect with other
growth factors
Vascular Endothelial
Growth Factor
VEGF Promotes angiogenesis and is
responsible for increase in vascular
permeability
Tumour Necrosis Factor TNF Induce fibroblasts proliferation

26. Growth Factors involved in Healing
and Repair: Summary of functions
Stimulate fibroblasts proliferation and collagen synthesis
Lead to epithelial cells regeneration
Synergistic effect with other growth factors
Promotes Angiogenesis
Are responsible for increasing vascular permeability

27. Signaling by Growth Factors in Healing and Repair
Signaling by growth factors take place in different ways:
1. Signaling through gap junctions
2. Autocrine signaling
3. Paracrine signaling
4. Synaptic Signaling
5. Endocrine signaling

28. 1. Signaling by Gap Junctions
Adjacent cells communicate via gap junctions, narrow
hydrophilic channels that effectively connect two cells’
cytoplasms. The channels permit movement of small ions,
various metabolites and potential second messenger
molecules.

29. 2. Autocrine Signaling
Soluble mediators acts predominantly ( or even exclusively
on the cell that secretes it. This pathway is important in
immune response (cytokines) and in compensatory epithelial
hyperplasia ( i.e., liver regeneration)

30. 3. Paracrine Signaling
Mediators affect cells only in the immediate vicinity .This
pathway is important for recruiting inflammatory cells to
the site of infection and for controlled process of wound
healing

31. 4. Synaptic Signaling
Activated neural tissues secretes neurotransmitters at a
specialized cell junction ( synapse) onto target cells such
as other nerves or muscles.

32. 5. Endocrine Signaling
A regulatory substance such as a hormone is released
into the blood stream and acts on target cell
at a distance

33. Cell Surface Receptors for Growth Factors
Cell surface receptors for growth factors are of
four types:
1. Ion channel receptors
2. Receptors with intrinsic kinase activity
3. G- protein – coupled receptors
4. Receptors without intrinsic enzymatic activity

34. Simplified overview of the major types of cell surface
receptors and their principal signal transduction pathways
leading to transcription factor activation and translocation
into the nucleus

35. 1. Ion channel receptors: Ligand binding alters the
conformation of the receptor so that specific ions can
flow through it.
Example: Acetylcholine receptor at the nerve
muscle junction
2. Receptors with intrinsic kinase activity: These are
transmembrane molecules with an extracellular
ligand- binding domain. Ligand binding activates
(phosphorylation) receptor which in turns then binds to
intracellular proteins.
Example: Intracellular signaling of multiple growth factors

36. 3. G- protein – coupled receptors: These are also
transmembrane receptors. After binding to their
specific ligand these receptors combine with intracellular
GTP – hydrolyzing proteins
Examples: Epinephrine; Glucagon and Chemokines.
4. Receptors without intrinsic enzymatic
activity: Transmembrane molecules with an
extracellular ligand binding domain. Ligand interaction
induces an intracellular conformational change that allows
association with an activation of intracellular protein
kinases.
Example: Rectors involved in cytokines activation in
immune system and erythropoietin receptor .

37. Binding of polypeptide growth factors
with
Receptors
Phosphphorylation of substrates involved in signal transduction
and generation of second messengers
Activation of nuclear transcription factors
Initiation of DNA synthesis
Cell Division

38. Extracellular
Matrix
and
Cell
Matrix
Interactions

39. Extra Cellular matrix is a dynamic constantly
remodeling
macromolecular complex synthesized locally.
It constitutes a significant proportion of any tissue.
Besides providing turgor to soft tissues and rigidity to
bones, Extracellular matrix supplies a substratum for
cell adhesion and critically regulates the growth,
movement and differentiation of the cells living within
it.
Extracellular matrix occurs in two forms:
1. Interstitial Matrix
2. Basement Membrane

40. .Components of Extracellular Matrix
1. Collagen
2. Elastin
3. Proteoglycans and Hyaluronan
4. Adhesive Glycoproteins
5. Fibronectin
6. Laminin
7. Integrins

41. Major Components of Extracellular Matrix

42. Role of Extracellular Matrix
1. Mechanical support for cell anchorage
2. Determination of cell orientation (Polarity)
3. Control of Cell Growth
4. Maintenance of Cell Differentiation
5. Scaffolding for tissue renewal (regeneration) .
6. Establishment of tissue microenvironments
7. Storage and presentation of regulatory molecules

43. Schematic mechanism showing mechanisms by which Extracellular matrix interactions and
growth factors influence cell growth, motility differentiation & protein synthesis.
Integrins bind ECM and interact with the cytoskeleton at focal adhesion complexes.
This can initiate the production of intracellular second messengers or can directly
mediate nuclear signals. Cell surface receptors for growth factors also initiate second
signals. Together, these are integrated by the cell to yield various responses, including
changes in cell growth , locomotion and differentiation.

44. Repair
by
Connective
Tissue
(Fibrosis)

45. Severe or persistent tissue injury with damage
both to parenchymal cells and to the stromal
framework leads to a situation in which repair
can not be accomplished by parenchymal
regeneration alone.
Under these conditions, repair occurs by
replacement of the non – regenerated
parenchymal cells with connective tissue.

46. Conditions in which tissue repair is
achieved by scar formation
Following are the conditions in which tissue repair is
achieved by scar formation:
(1) When resolution (recovery) fails to occur in an acute
inflammation
(2) When parenchymal cell necrosis can not be repaired
by regeneration because:
a) Necrotic cells are permanent cells
b) Necrosis is so extensive that no cells are available
for regeneration

47. • Phases in Scar Formation
• Mechanisms Underlying Scar Formation

48. Phases in Scar Formation
1. Preparation
2. Ingrowth of granulation tissue
3. Production of Fibronectin
4. Collagenization ( Fibrosis)
5. Maturation of scar
6. Contraction and strengthening

49. Phases in Scar Formation
1) Preparation:
The area of injury is prepared for scar formation by removal
of the inflammatory exudate by the lymphatics.
2) Ingrowth of granulation tissue
By 3 to 5 days, a specialized type of tissue that is characteristic
of healing , called Granulation tissue , is apparent.
Granulation tissue forms and fill the injured area while the
necrotic debris is being removed. Granulation tissue is highly
vascularized tissue composed of newly formed capillaries,
proliferating fibroblasts and residual inflammatory cells
Gross Examination findings of granulation tissue: Appears
as soft and pink because of numerous capillaries. The term
granulation tissue derives from the pink , soft , granular appearance,
such as that seen beneath the scab of a skin wound.
Microscopic examination of granulation tissue: Shows
thin walled capillaries lined by endothelium and proliferation of
fibroblasts in a loose extracellular matrix.

50. Phases in Scar Formation….Contd
3) Production of Fibronectin:
Fibronectin is a glycoprotein that plays key role in the formation of
granulation tissue and is present in large amounts during wound healing.
In early phases it is derived from plasma , but later it is synthesized
by fibroblasts, macrophages and endothelial cells in granulation tissue.
4) Collagenization (Fibrosis):
Collagen is the major fibrillary protein of connective tissue. It is
synthesized by fibroblasts and is responsible for much of the tensile
strength of scar tissue. The term fibrous tissue and scar tissues are
synonymous with collagen .
5) Maturation of Scar:
A young scar is consists of granulation tissue and abundant collagen
together with capillaries and fibroblasts. It appears pink on gross
examination because of the vascualrity .
As the scar matures the amount of collagen increases and the scar
becomes less cellular and less vascular.
The mature scar is composed of an avascular , poorly cellular
mass of collagen and is white on gross examination .

51. Phases in Scar Formation….Contd
6) Contraction and strengthening of Scar:
It is the final phase of scar formation . Contraction decreases the size
of scar and enables the surviving cells of the organ to function with
maximum effectiveness

52. Granulation tissue showing mature blood vessels, edema
and a loose extra cellular matrix containing occasional
inflammatory cells. This is a Trichrome stain that stains
collagen blue; minimal collagen can be seen
at this point
Young Scar

53. Trichrome stain of mature scar , showing dense
collagen, with only scattered vascular channels
Mature Scar

54. Mechanisms Underlying Scar Formation
1. Formation of new blood vessels (Angiogenesis)
2. Migration and proliferation of fibroblasts
3. Deposition of Extra - Cellular Matrix (ECM)
4. Maturation and reorganization of the fibrous
tissue (remodeling)

55. Formation of new blood vessels (Angiogenesis)
Blood vessels are assembled by two processes:
1. Vasculogenesis: In this process primitive vascular
net work is assembled from angioblasts (endothelial
cell precursors) during embryonic development
2. Angiogenesis OR Neovascularization: Preexisting
vessels send out capillary sprouts to produce new
vessels.

56. Significance of Angiogenesis
 a) Angiogenesis is a critical process in the healing
at sites of injury and in the development of
collateral circulation at sites of ischemia.
b) Angiogenesis allows tumours to increase in their
size beyond the constraints of their original
blood supply.
Much work has been done in understanding the
mechanisms underlying such Neovascularization and
therapies to:
a) Either augment the process of Angiogenesis as for
example to improve blood flow to a heart ravaged by
atherosclerosis
OR
b) To inhibit tumour growth by stopping angiogenesis

57.  Four general steps occur in the development of a new
capillary vessel:
1. Proteolytic degradation of the parent vessel basement
membrane allowing formation of a capillary sprout
2. Migration of endothelial cells from the original capillary
toward an angiogenic stimulus
3. Proliferation of the endothelial cells behind the leading
edge of migrating cells
4. Maturation of endothelial cells with inhibition of growth
and organization into capillary tubes . This includes
recruitment and proliferation of pericytes(for capillaries)
and smooth muscle cells (for large vessels) to support
the endothelial tube and provide accessory
functions.

58. Steps in the process of angiogenesis
The parent mature blood vessel is on the left
(1) Basement membrane and extracellular matrix degradation
(2) Endothelial migration
(3) Endothelial proliferation (mitosis)
(4) Organization and maturation including the recruitment of vascular
pericytes or smooth muscle cells
(5) Increased permeability due to intercellular gaps and increased transcytosis.
This increased permeability allows deposition of plasma proteins (e.g.,
fibrinogen) in the extracellular matrix and provides a provisional stroma
for fibroblasts and endothelial cell ingrowth. It also leads to the edema
that occurs in granulation tissue.

59. REGULATION OF VASCULAR MORPHOGENESIS
Angioblasts leads to angiogenesis. Then preexisting vessels send out
capillary sprouts to produce new vessels.

60. Growth factors which induce angiogenesis
1 . Basic Fibroblast Growth Factor
2. Vascular Endothelial Growth Factor

61. Fibrosis ( Scar Formation)
 Fibrosis , or scar formation , builds on the granulation
tissue framework of new vessels and loose extracellular
matrix that develops early at the repair site
 Process of fibrosis occurs in two steps:
(1)Emigration and proliferation of fibroblasts into the
site of injury
(2) Deposition of extracellular matrix by fibroblasts.

62. Ultimately , the granulation tissue scaffolding evolves into
a scar composed of largely inactive , spindle – shaped
fibroblasts, dense collagen, fragments of elastic tissue,
and other extracellular matrix components .
As the scar matures , vascular regression eventually
transforms the highly vascularized granulation tissue
into a pale , largely avascular scar.

63. Scar Remodeling
The transition from granulation tissue to scar involves
shifts in the composition of the extracellular matrix.
Even after its synthesis and deposition, scar
extracellular matrix continues to be modified and
remodelled.
The outcome at each stage is a balance between
Extracellular matrix synthesis and degradation
The degradation of collagens and other extracellular
matrix components is accomplished by a family of
Metalloproteinases (MMPs) (Enzymes which
depend upon zinc ions for their activity).

64. Scar Remodeling
Cells responsible to produce MMPs
•Fibroblasts
•Macrophages
•Neutrophils
•Synovial cells
•Some epithelial cells
MMPs include
•interstitial collagenases (cleaves fibrillar collagen),
•Gelatinases (amorphous collagen, fibronectin)
•Stromelysins (proteoglycans, laminin, fibronectin and
amorphous collagen)
Synthesis and secretion of MMPs is regulated by
growth factors,cytokines and other agents

65. Granulation tissue
1- Red granular surface
2- Moist
3- Bleeds easily

66. New capillries
Fibroblast

68. Myocardial Scar

69. Healing myocardial
infarction
Maturation of granulation tissue

70. Section in the myocardium
shows:
•Patches of scar tissue
between cardiac muscle.
•The scar tissue appears
homogenous pink in colour
and shows a number of
dilated capillaries and few
scattered fibroblasts.
•The muscle fibers appear
slightly atrophic with
pyknotic nuclei.
Diagnosis:
Myocardial scar

71. Myocardial Scar
Muscle
bundles
Fibrous tissue

72. Healed infarction
(Myocardial scar)
Complete maturation of granulation tissue to form fibrous tissue

73. Wound
Healing

74. Wound healing is a complex but generally orderly
process.
Sequential waves of specialized cells types first
clear the inciting injury and then progressively
build the scaffolding to fill in any resulting
defect.
The events are orchestrated by an interplay of
soluble growth factors, extra cellular matrix,
physical factors and other elements

75. Processes occurring in wound healing
 Induction of an acute inflammatory response by the
initial injury
Parenchymal cell regeneration
Migration and proliferation of both parenchymal and
connective tissue cells
Synthesis of extra cellular matrix protein
Remodelling of parenchymal elements to restore
tissue function
Remodelling of connective tissue to achieve
wound strength

76. To summarize the healing wound,as a prototype of tissue repair:It is
a dynamic and changing process.The early phase is one of inflammation
followed by granulation and wound contraction.Different mechanisms
occurring at different times trigger the release of chemical signals
that modulate the orderly migration, proliferation and
differentiation of cells.
Orderly phases of wound healing

77. Healing of skin wounds
Healing of skin wounds involve both epithelial regeneration
and the formation of connective tissue scar.
Thus it is illustrative of the general principles that apply
to wound healing in all tissues.
However one should be aware that each different tissue
in the body has specific cells and features that can
modify the basic scheme

78. Healing of Skin Wounds
Healing by First Intention
Healing by Second Intention

79. Healing by First Intention
(Wounds with Opposed Edges)
Wound healing of a clean, uninfected surgical incision approximated
by surgical sutures is referred as Primary union or healing by first
intention .
 The incision causes death of a limited number of epithelial cells and
connective tissue cells as well as there is minimal disruption of
epithelial cells basement membrane continuity.
 The narrow incisional space immediately fills with clotted
blood containing fibrin and blood cells.
 Epithelial regeneration predominates over fibrosis
The narrow incisional space rapidly fills with fibrin– clotted blood;
dehydration at the surface produces a scab to cover and
protect the healing repair site

80. Healing by First intention – Changes in first 24 hours:
Neutrophils appear at the margins of the incision, moving toward the
fibrin clot. The epidermis at its cut edges thickens as a result of
mitotic activity, and within 24 to 48 hours , spurs of epithelial cells
from the edges migrate and grow along the cut margins of the dermis,
depositing basement membrane components. They cells fuse in the
midline beneath the surface scab , thus producing a continuous but
thin epithelial layer.

81. Healing by first intention – changes by day 3: The Neutrophils have been
largely replaced by macrophages. Granulation tissue progressively invades
the incision space. Granulation Tissue consists of proliferating fibroblasts,
and new capillary loops. Progressively this granulation tissue matures into
fibrous tissue by deposition of collagens followed by remodeling. Collagen
fibers are now present in the margins of the incision, but at first these
are vertically oriented and do not bridge the incision . Epithelial cell
proliferation continues, yielding a thin but continuous epithelial layer.
Healing by first intention – changes by day 5: The incisional space is filled
with granulation tissue . Neovascularization is maximal. Collagen fibrils
become more abundant and begin to bridge the incision . The epidermis
recovers its normal thickness, and differentiation of surface cells
yields a mature epidermal architecture with surface keratinization

82. Healing by first intention – changes during second week: There is continued
accumulation of collagen and proliferation of fibroblasts. The leucocytic
infiltrate, edema, and increased vascularity have largely disappeared. At this
time, the long process of blanching begins, accomplished by the increased
accumulation of collagen within the incisional scar, accompanied by
regression of vascular channels
Healing by first intention- changes by the end of first month: The scar
comprises a cellular connective tissue devoid of inflammatory infiltrate,
covered by intact epidermis. It may take months for the wounded area to
obtain its maximal strength.

83. Healing by Second Intention
(Wounds with Separated Edges)
When there is more extensive loss of cells and tissue , as
occurs in infarction , inflammatory ulceration, abscess
formation, and surface wounds that create large defects, the
reparative process is more complicated.
 The common denominator in all these situations is a large
tissue defect that must be filled .
 Regeneration of parenchymal cells cannot completely
reconstitute the original architecture . Abundant granulation
grows in from the margin to complete the repair. This form of
healing is referred to as secondary union or healing by second
intention .

84. Secondary healing differs from primary healing in several
respects:
1. The inflammatory reaction is more intense.
2. Much larger amounts of granulation tissue are formed
3. The feature that most clearly differentiates primary from
secondary healing is the phenomenon of Wound Contraction,
which occurs in large surface wounds . The wound contraction is
due to the presence of altered myofibroblasts .
4. Epithelial proliferation fails to reconstitute the epidermal
covering, except after filling the gap with granulation tissue. By
this time the epidermal cells can grow over the surface of
granulation tissue to complete the process of epidermal
regeneration.
5. The amount of granulation tissue is much larger and
consequently the scar is big. The wound finally consists of a
contracted scar covered by regenerated epidermis without
adenaxae.

85. Stages in wound healing by second intention
(1) Cavity fills with blood and fibrin clot (coagulum)
(2) Coagulum dries on its surface and forms scab
(3) Acute inflammation starts at junction of living tissue
(4) Wound contraction, reducing its size
(5) Formation of granulation tissue is coagulum
(6) Proliferation of adjacent epithelial cells and migration
over the granulation tissue beneath coagulum.
(7) Formation of scar from the granulation tissue

86. WOUND HEALING BY SECONDARY INTENTION

87. Difference between healing by
first and second intention

88. WOUND HEALING BY FIRST
INTENTION
WOUND HEALING BY SECOND
INTENTION
Seen in clean, uninfected surgical
incisions
Seen in ulcers, abscesses and wounds
that create large defects
Inflammatory reaction is less intense Inflammatory reaction is more intense
Formation of granulation tissue is less
as compared with healing with second
intention
Much larger amount of granulation tissue
is formed
No wound contraction is seen Wound contraction due to
myelofiborblasts is a prominent feature
Regeneration predominate over fibrosis Fibrosis predominates over regeneration
Epithelial proliferation completely
recovers the normal thickness of the
area
Epithelial proliferation fails to
reconstitute the epithelial covering
completely
After the completion of healing no
residual defects are seen
After the completion of healing process
some residual defects remain

89. LOCAL AND SYSTEMIC FACTORS
THAT INFLUENCE WOUND HEALING
SYSTEMIC FACTORS:
1. NUTRTION: Protein deficiency and Vitamin C deficiency
inhibit collagen synthesis.
2. CIRCULATORY STATUS: Inadequate blood supply also
retard wound healing
3. ZINC DEFICIENCY: Several enzymes required for DNA and
RNA synthesis are zinc dependent. The deficiency of zinc
impairs DNA and RNA synthesis that leads to impaired wound
healing
4. HORMONES: Glucocortcoids delay repair and they inhibit
wound healing:
(i) Glucocortcoids have strong anti-inflammatory effects, so
the inflammatory cells will not be properly recruited at
the site of wound.
(ii) Glucocortcoids inhibit collagen synthesis

90. 5. GROWTH FACTORS: Different growth factors stimulate cell growth
and repair . The important growth factors for wound healing and repair
are:
(i) Platelet derived growth factors
(ii) Epidermal derived growth factors
(iii) Fibroblast growth factors
(iv) Transforming growth factor -
(v) Transforming growth factor - 
(vi) Interleukin – 1
6. DIABETES MELLITUS: In diabetes:
(a) the Neutrophils have a very low Chemotactic and phagocytic
capacity
(b) Skin of diabetic patient contains high levels of glucose that
favours survival of bacteria
( c) Diabetic develops arterial disease resulting in inadequate blood
supply to the injured area.

91. 7. NEUTROPENIA: Decreased number or defective Neutrophils
increases susceptibility to bacterial infection that hinders the
process of repair.
8. HAEMORRHAGIC DIATHESIS: Extravasation and accumulation of
large amount of blood in the wounded area serves as a good
medium for bacteriological growth thus hindering the repair.
9. ANAEMIA: Low plasma proteins and immunoglobulins in anaemia
impair healing process
10 TEMPARTURE: Wound healing is slow in cold weather , while fast
in hot weather.

92. LOCAL FACTORS:
1. INFECTION: It is the single most important cause of delay in
healing.
2. MECHANICAL FACTORS: Such as early motion of wounds, can delay
healing
3. FOREIGN BODIES: Such as unnecessary sutures or presence of
foreign bodies can delay healing
4. SIZE, LOCATION AND TYPE OF WOUND: Wounds in richly
vascularized areas, such as the face, heal faster than those in poorly
vascularized ones for example in foot.
5. TYPE OF TISSUE INJURED:
Complete repair can occur only in tissues composed of stable and
labile cells. Even in these tissues extensive injury will likely result in
incomplete tissue regeneration and at least partial loss of function.
Injury to tissues composed of permanent cells must result in scarring
with , at most, attempts at functional compensation by the remaining
viable components.

93. COMPLICATIONS OF WOUND HEALING
1. Deficient scar formation leading to wound
dehiscence and ulceration
2. Excessive formation of colloid (Keloid formation)
3. Excessive granulation tissue (Exuberant granulation or
Proud Flesh)
4. Formation of contractures
4. Cosmetic deformities
5. Functional troubles due to contractures
6. Chronic ulcer
7. Chronic fistulas

94. Keloid

96. Overview
of
the
Inflammatory
Reparative
Response

97. Not all injuries result in permanent damage; some
are resolved with almost perfect restoration of
structure and function
Depending upon the type and extent of injury,
the nature of the injured tissue and persistence
of inflammatory stimuli - injury results in some
degree of residual scarring.

98. PATHWAYS OF
REPARATIVE
RESPONSE
AFTER ACUTE
INJURY

99. Questions

100. Q:An American PREDATOR fired two HELL FIRE
missiles on a remote house in North Waziristan.
Many family members died, but a few survived despite
lack of medical or surgical treatment . There was
excessive loss of cells and tissues and large defects
were created on the body surfaces with extensive
loss of normal architecture:
a) What will be this type of healing known as?
b) How does it differ from primary healing ?

101. Q: A 35 – years old female patient of type II
diabetes mellitus cut her hand with a knife in the
kitchen ; the wound failed to heal even after two
weeks ;
a) What cause/ causes of delayed healing you would
suspect in this patient?
b) List four other local / systemic factors that
influence wound healing