seminar

1. INFLAMMATION AND REPAIR
Darpan Nenava
PG Ist year
1

2. CONTENTS
History
Introduction
Definition
Types of inflammation
Acute inflammation
Chemical mediators
Chronic inflammation
Healing and repair
2

3. HISTORICAL PERSPECTIVES
Earliest reference to inflammation
in medical literature (1650 BC,
Egypt) in the Smith Papyrus
associated inflammation with heat via
symbol of flame
Ancient Greeks used a term which
meant inflammation also indicating a
hot thing
– The greek term persists in our
word "phlegmon" used to
describe internal inflammatory
lesions
Cornelius Celsus(1st century AD
Rome):cardinal signs of
inflammation redness, swelling, heat,
pain
3

4. CARDINAL SIGNS OF (ACUTE)
INFLAMMATION
 Rubor
 Tumor
 Calor
 Dolor
= redness
= swelling
= heat
= pain
(described by Celsus 1st. Century AD)
 Functio laesa = loss of
function
(added by R. Virchow 19th Century)

5. INTRODUCTION
 The inflammatory response is closely intertwined
with the process of repair.
 During repair the injurious tissue is replaced by
regeneration, filling of the defect by fibrous
tissue(scaring).
5

6. INTRODUCTION
The nomenclature used to describe
inflammation in different tissues employs the
tissue name and the suffix “-itis”
e.g
pancreatitis
meningitis
pericarditis
arthritis
6

7. DEFINITION
Inflammation“It is a complex reaction to injurious agents such as
microbes and damaged necrotic cells that consist of
vascular response, migration and activation of leucocytes
and systemic reactions.”
OR
“Inflammation is a complex reaction in tissue that consist
mainly of responses of blood vessels and leukocyte”
7

8. TYPES OF INFLAMMATION
Acute
“The immediate and early response to an injurious agents”
Min to Days
1. Characterized by fluid and protein
2. PMN’s
3. Exudates
4. SG >1.020
8

9. TYPES OF INFLAMMATION
Chronic
“Inflammation of prolonged duration, week or months and
there is active inflammation tissue destruction, with
attempts at repair are proceeding simultaneously”
Week to Year
1. Lymphocytes
2. Macrophages
9

10. Exudates1. Increase vascular permeability
2. High protein and cell debris
3. SG > 1.020
Transudate1. Normal vascular permeability
2. Low protein(mostly albumin)
3. SG < 1.020
10

11. 11

12. Edema1. Exudates and transudate
2. In interstitial or in cavity
12

13. Acute inflammation major components
Transient vasoconstriction
Vasodilatation
Increase epithelial permeability
Extravasations of PMN’s
With five cardinal signs of
inflammation
13

14. Acute inflammation major components
14

15. Inflammatory response consist of
Vascular
reaction
Cellular reaction
15

16. Vascular and cellular changes
Transient vasoconstriction
Vasodilatation
Exudation of protein rich fluid
Blood stasis
Margination
Emigration/ Transmigration
16

17. Vascular changes
Increase intravascular hydrostatic pressure
Endothelial gaps in intercellular junction
Fluid exits vessels
Protein exits vessels
Decrease intravascular osmotic pressure
Immediate transient response
Histamine, bradykinin, leucotrienes and substance P
17

18. Vascular changes
18

19. Lewis experiment of triple response
19

20. Red line appears within seconds resulting from
vasodilatation of capillaries and venules
Flare is a bright reddish appearance or flush surrounding
the red line results from vasodilatation of the adjacent
arterioles
Wheal is the swelling or edema of the skin occurring from
transudation of fluid in extra vascular space
20

21. Vascular permeability
Vasodilatation- increase blood flow
Increased intravascular hydrostatic pressure
Transudate - ultra filtration of blood plasma (contain little
protein, very transient just get the process started)
Exudates- Protein rich with PMNs
Exudates is characteristic of acute inflammation
21

22. Vascular permeability
Intravascular osmotic pressure decreases
Osmotic pressure of interstitial fluid
Outflow of water and ions – edema
22

23. How do endothelial cells become
permeable?
Gap due to Endothelial cell contraction
Direct endothelial cell injury (Immediate system response)
Leukocyte- dependent endothelial injury
Increase transcytosis of fluid
Leakage from new vessels
23

24. Gap due to Endothelial cell contraction
24

25. Direct endothelial cell injury (Immediate
system response)
25

26. Leukocyte- dependent endothelial injury
26

27. Increase transcytosis of fluid
27

28. Leakage from new vessels
28

29. Cellular events
Margination and rolling
Adhesion and transmigration
Migration into interstitial tissue
29

30. Selectin
 Weak and transient binding Results in rolling
Integrins
 Unregulated and activated for increase affinity to
CAMS Results in firm adhesion
30

31. Margination
Normal flow- RBCs and WBCs flow in the center of the
vessels.
A cell poor plasma is flowing adjacent to endothelium
As blood flows slow WBCs collect along the endothelium
Margination
31

32. Endothelium activation
The underlying stimuli causes release of mediators
Activate the endothelium causing selectin and other
mediators to be moved quickly to the surface
32

33. Four families of adhesion molecules are involved in leukocyte migration
Selectins
E-selectin (on endothelium)
P-selectin (on endothelium &
platelets; is preformed and stored in
Weible Palade bodies)
L-selectin (leukocytes)
Ligands for E-and P-Selectins are
sialylated glycoproteins (e.g
Sialylated Lewis X)
Ligands for L-Selectin are Glycanbearing molecules such as
GlyCam-1, CD34, MadCam-1
Integrins (a + b chain)
Heterodimeric molecules
VLA-4 (b1 integrin) binds to
VCAM-1
LFA1 and MAC1
(CD11/CD18) = b2 integrin
bind to ICAM
Expressed on leukocytes
Immunoglobulin family
ICAM-1 (intercellular
adhesion molecule 1)
Mucin-like glycoproteins
Heparan sulfate (endothelium)
VCAM-1 (vascular adhesion
molecule 1)
Ligands for CD44 on
leukocytes
Are expressed on
activated endothelium
Bind chemokines
Ligands are integrins on
leukocytes
33

34. Rolling and Adhesion
Selectin transiently binds to the receptors
PMNs bounces or roll along the endothelium
Mediated by integrins ICAM-1 and VCAM-1
34

35. TRANSMIGRATION
CHEMOTAXIS
• Mediated/assisted by VCAM 1 • Movements towards the site
of injury along a chemical
and ICAM 1(integrins)
gradient
• Chemotactic factor include
• Diapedesis (cell crawling)
1. Components (20 serum
protien)
• Primary in venules
2. Arachadonic acid
metabolites
• Collagenase degrade
3. Soluble bacterial products
basement membrane
4. Chemokines
5. Cytokines
• Increase permeability
35

36. Selectin
s
Integrins
36

37. Inflammatory Cells
The circulating cells includes Neutrophils
 Monocytes
 Eosinophils
 Lymphocytes
 Basophils
 Platelets
The connective tissue cells are Mast cells
 Fibroblast
 Macrophages
 Lymphocytes
37

38. Inflammatory Cells
38

39. Phagocytosis and degranulation
Involves three sequential steps
1. Recognition and attachment of the particle to be
ingested by leucocytes
2. Phagocytosis (engulf and destroys )
3. Killing/degranulation –oxygen dependent :reactive O2
species in Lysosomes
Oxygen independent- bacterial permeability agents ,
Lysosomes , lactoferin
39

40. Leukocyte express several receptors that
recognize external stimuli and deliver activating
signals
• Mannose Receptor
• Receptors for microbial products-toll like
receptors(TLRs)
• G protein-coupled receptors
• Receptors for opsonins
• Receptors for cytokines
40

41. 41

42. Engulfment
After particle is bound to phagocyte receptors, extension of
cytoplasm(pseudopods flows around it)
Plasma membrane pinches off
Forms a vesicle enclosing particle
Phagosome fuses to lysosomal granules
Killing of microbes by lysosomal enzymes in phago
Lysosomes
42

43. 43

44. KILLING AND DEGRANULATION
• Final step
• Microbial killing is accomplished largely by reactive
oxygen species(ROS)also called as reactive
oxygen intermediates
• And reactive nitrogen species mainly derived from
NO
44

45. Chemical mediators in inflammation
Plasma derived-circulating precursors have to be activated
Cell derived-sequestered intracellularly synthesized de
novo
Most mediators bind to receptors on cell surface but some
have direct enzymatic or toxic activity.
Mediators are tightly regulated
45

46. 46

47. Mediators in acute inflammation
47

48. Plasma derived mediators
Complement
Kinin
Clotting
Fibrinolytic
48

49. 49

50. Cell derived mediators-Vasoactive amines
Histamine –
1. Found in mast cells , basophils and platelets
2. Release in response to stimuli
3. Promotes arterioles dilation and venules endothelial
contraction
4. Results in widening of inter-endothelial cell junction
with increase in vascular permeability
50

51. Serotonin/5 hydroxytryptamine-
1. Vaso-active effects similar to histamine but less potent
2. Found in chromaffin cells of GIT, spleen, nervous
system, mast cells and platelets
3. Release when platelet aggregation
51

52. BradykininPotent bio-molecule
1. Vasodilatation
2. Increase vascular permeability
3. Contraction of smooth muscle
4. Short life
52

53. Arachodonic acid/eicosanoids
AA is component of cell membrane phospholipids
AA is activated by some stimuli or mediators like C5a so
as to form AA metabolites
Metabolites of AA –short range hormone
Acts locally at the site of generation
Rapidly decay or destroys
53

54. AA metabolites occurs by two major pathways named for
the enzymes that initiates the reaction,
lypoxygenase and cycloxygenase
Cycloxygense synthesize-prostaglandin, thromboxane
Lypoxygenase synthesize- leucotrines and lipoxins
54

55. Cycloxygense pathway
Cycloxygense is a fatty acid enzyme act on activated AA to
form prostaglandin which further activated by enzyme to
form3 metabolitesProstaglandin-Increase vascular permeability,
vasodilatation, inhibit inflammatory cell function
Prostacyclin- Vasodilatation and inhibits platelet
aggregation
Thromboxane A2-Vasoconstriction,broncoconstriction,
enhances inflammatory cell function Promotes platelet
aggregation
55

56. Lipoxygenase pathway
Enzyme lypoxygenase acts an activator to AA to
form 5-HETE (hydroperoxy eico-astetraeonic acid)
which on further per oxidation forms 2 metabolites
Leucotrines
Lipoxins
Causes
Vasoconstriction
Bronchospasm
Increase vascular permeability
56

57. 57

58. AA metabolites
Participate in every aspect of acute inflammation
Affective anti-inflammatory agent
E.g..
Aspirin, NSAIDS-cycloxygenase pathway
Steroids acts by inhibiting phospolipase A2
58

59. Lysosomal components
Inflammatory cells contains lysosomal granules which
release mediators of inflamation
Granules of neutrophils-2 types azurophil or primary
(myeloperoxidase, acid hydrogenasecollagenase, elastase,
collagenase)
Specific or secondary (lectoferrin, lysozyme, alkaline
phosphatase, collagense) Granules of monocyte-protease,
collagenase, elastase, plasminogen activator
59

60. Platelet activating factor
Another phospholipids derived mediator release by
phospholipase
Induces
Aggregation of platelets
Vasoconstriction
Broncho-constriction
100-1000 times more potent then histamine in
inducing vasodilatation and vascular permeability
Enhances leukocyte adhesion, chemo taxis,
degranulation and oxydative burst
60

61. Cytokines
Polypeptides that are secreted by cells
Act to regulate cell behavior
Autocrine, paracrine, endocrine effects
61

62. IL-1 /TNF
Acute phase reactionIncreases sleep
Acute phase protein hemodynamic effects
Decreases appetite
Endothelial effectsIncreases Leukocyte adhesion, PG synthesis, procoagulants
Decreases anticoagulants
Increases IL-1,IL-8, IL-6
62

63. Neuropeptides
Secreted by sensory nerves and various leucocytes
Role in initiation and propagation of inflammatory
response
Substance P and neurokinnin A are neuropeptides
Has many biological function like transmission of pain
signals, regulation of B.P., increasing vascular
permeability
63

64. Different morphological patterns of acute inflammation can be found
depending on the cause and extend of injury and site of inflammation
Serous inflammation
Fibrinous inflammation
Purulent inflammation
Ulcer
64

65. Outcomes of acute inflammation
Resolution
Fibrosis
Abscess formation
Progression to chronic inflammation
65

66. 66

67. MONONUCLEAR PHAGOCYTES
They are important in acute inflammation, as well as
being a key element in chronic inflammation
Like neutrophils, monocytes bear C3b receptors on
their surfaces famous role as scavengers
67

68. CHRONIC INFLAMMATION
Chronic inflammation is an inflammation of prolonged
duration(weeks or months) in which inflammation,
tissue injury, and attempts at repair co exits, in varying
combination.
It may follow acute inflammation or begin as a low
grade, smoldering response like on rheumatoid
arthritis, atherosclerosis, tuberculosis, pulmonary
inflammation
68

69. Causes of chronic inflammation

Persistent infection-that are difficult to eradicate

Immune mediated inflammatory disease

Prolonged exposure to potentially toxic agents,
either exogenous or endogenous
69

70. Persistent infection-that are difficult
to eradicate

Evoke an immune reaction called delayed –type
hypersensitivity

Sometimes occurs as granulomatous reaction
70

71. Immune mediated inflammatory
disease
Caused by excessive and inappropriate activation of
immune system
Immune reaction develops in individual own tissue
Results in autoimmune disease
Ex. Rheumatoid arthritis, multiple sclerosis
71

72. Prolonged exposure to potentially toxic
agents, either exogenous or endogenous
Exogenous agent: silica results in inflammatory lung
disease called silicosis
Endogenous agent: toxic plasma lipid component
causes atherosclerosis
72

73. Morphological features of chronic
inflammation
1. Infiltration with mononuclear cell-macrophages,
lymphocytes, plasma cell
2. Tissue destruction-induced by persistent
offending agents or by inflammatory cells
3. Attempts at healing, replacement of damaged
tissue
4. (angiogenesis, fibrosis)
73

74. Role of Macrophages
Dominant cell
Component of mononuclear phagocyte system
Scattered in connective tissue or in liver(kuffer cell),
spleen and lymph nodes(sinus histeocytes), lungs
(alveolar macrophages), CNS(microglea)
Journey from bone marrow to tissue macrophages is
regulated by growth and differentiation factors,
cytokines, adhesion molecule and cellular interaction
74

75. Begins to appear in acute inflammation and
predominant after 48 hrs
Extravasations is same like neutrophils
When monocyte reaches to extra vascular tissue
undergo transformation into large phagocytic cell
called macrophage
Macrophages are activated by stimuli including
microbial product that engage TLRs and other cellular
receptors, cytokines(IFN-Y)
75

76. Activated macrophagesServes to eliminate injurious agents
Initiate the process of repair
Responsible for much of the tissue injury
Increases level of lysosomal enzyme
ROS and NOS system
Production of cytokines, growth factors, other
mediators
76

77. 77

78. Other cells in chronic inflammation
LymphocytesMobilized in cell mediated and antibody mediated
immune reaction
Antigen stimulated lymphocytes are – T and B cells
Uses same adherent molecule (selectin, integrin,
ligands) and chemokines to migrate into inflammatory
sites
78

79. 79

80. Plasma cellsDevelops from activated B lymphocytes
Produce antibodies against foreign bodies
Present in germinal center of lymph nodes
EosinophilsAre abundant in immune reaction mediated by IgE
and in parasitic infection
Chemokine toxin is important for eosinophilic
recruitment
They also contribute to tissue damage in immune
reactions such as allergies
80

81. Mast cellsWidely distributed in connective tissue
Contribute in acute and chronic inflammation
Releases mediators such as histamine and
prostaglandin
Responses occurs in allergic reaction to food, insect
venom, or drugs, anaphylaxis
Mast cells also take part in chronic inflammation
As they secrete a plethora of cytokine they have the
ability to promote and limit inflammatory reaction
81

82. Systemic effects of inflammation
Fever Acute phase response increases 1 to 4 degree temp
Produce in response to substance pyrogens that
stimulates the prostaglandin synthesis.
Bacterial products stimulate leukocyte to release IL-1,
TNF which causes increase in the enzyme
cycloxygenase causing conversion of AA into
prostaglandin
Stimulate the production of neurotransmitter (cyclic
adenosine monophosphate) which in turn regulates
the temp
82

83. Acute phase protein –
Are Plasma proteins whose concentration increases
thousand times in inflammation
C reactive protein, amyloid protein, fibrinogen by
hepatocytes
Causes amylodoisis of organ, increases risk of
myocardial infarction, atherosclerosis, thrombosis,
infarction.
83

84. Leukocyte count Usually climbs to 15,000 to 20,000
Bone marrow output is increased
Other systemic effects are –
Increase pulse
Increase blood pressure
Decrease sweating
Shivering, chills
Anorexia
Malaise sometimes in severe bacterial infection =sepsis
84

85. Repair of the damaged tissue is
separated into two processes:
REGENERATION
HEALING
85

86. Definitions:
Regeneration: growth of cells and tissue to replace
lost structures.
Healing: is a tissue response –
to a wound
to inflammatory processes
to cell necrosis
in an organ incapable of regeneration.
It consists of variable proportion of two distinct
processes – regeneration and laying down of fibrous
tissue, or scar formation.
86

87. Regeneration V/s Healing
Regeneration requires an intact tissue scaffold.
By contrast healing with scar formation occurs if the
extracellular matrix (ECM) framework is damaged
causing alteration in tissue architecture.
87

88. Growth factors and cytokines involved in
regeneration and wound healing
Epidermal growth factor (EGF)
Mitogenic; stimulate keratinocytes migration and
granulation tissue formation.
Transforming growth factor alpha (TGF-α)
Similar to EGF; replication of hepatocytes.
Hepatocytes growth factor / Scatter factor (HGF)
Proliferation of hepatocytes & epithelial / endothelial
cells
Vascular endothelial cell growth factor (A,B,C,D)
Increased vascular permeability; mitogenic for
endothelial cells
Platelet deived growth factor (PDGF-A,B,C,D)
Chemotaxis and activation of PMNs, macrophages &
fibroblast; Mitogenic for fibroblast endothelial cells;
stimulates angiogenesis and wound contracture.
Fibroblast growth factor 1,2 and family (FGF-1,2..)
Chemotactic and mitogenic for fibroblast.
Angiogenesis, wound contraction & matrix deposition
Transforming growth factor-beta (TGF-β)
Keratinocyte migration; Angiogenesis & fibroplasia;
regulates integrin expression.
Keratinocyte growth factor (KGF) also called FGF-7
Keratinocyte migration, proliferation & differentiation.
Insulin like growth factor (IGF-1)
Synthesis of sulfated protioglycan, collagen.
Tumour necrosis factor (TNF)
Activates macrophages, regulate other cytokines.
Interleukins (IL-1 etc.)
Synthesis of IL-1 ; Angiogenesis ( IL-8).
Interferon (IFN-α etc.)
Inhibit fibroblast proliferation & synthesis of MMPs.
88

89. There are three general modes of signalingAutocrine
Paracrine
Endocrine
Autocrine: Cells respond to the molecule that they
themselves secrete
Paracrine: One cell type that contains an appropriate
receptor responds to the legand produced by the
adjacent cell.
Juxtacrine: the signaling molecule is anchored in a cell and
bind a receptor in the plasma membrane of another cell.
Endocrine: The signaling molecule, hormone, is
synthesized by cells of endocrine organs and acts on
target cells distant from there site of synthesis.
89

90. 90

91. Extracellular Matrix & Cell Matrix
Interactions
Synthesis & degradation of ECM is involved in
morphogenesis, wound healing, chronic fibrotic
processes & also in tumors invasion and metastasis
Constituent of ECMFibrous structural proteins e.g. collagen & elastin.
Adhesive glycoproteins.
Proteoglycans and hyaluronic acid.
These macromolecules assemble into two forms
Interstitial matrix and Basement membrane
91

92. Interstitial matrix & Basement membrane
IM consists of:-
BM consists of:-
Fibrillar & nonfibrillar collagen
Amorphous nonfibrillar
collagen (type-4)
Elastin
Laminin
Fibronectin
Heparin sulphate
Proteoglycan
Proteoglycan
Hyaluronate
Other glycoproteins
Other components
92

93. Repair by Healing, Scar Formation,
and Fibrosis
Fibro-proliferative response that
“patches” rather than restores a tissue.
Involving a number of processes:
Induction of an inflammatory process
with removal of damaged and dead
tissue.
Proliferation and migration of
parenchymal deposition.
Formation of new blood vessels
(angiogenesis) and granulation tissue.
93

94. Repair by Healing, Scar Formation,
and Fibrosis
Synthesis of ECM proteins and collagen
deposition.
Tissue remodeling
Wound contraction
Acquisition of wound strength
94

95. Inflammatory reaction contain the damage, eliminates
the damaging stimulus, removes injured tissue,
initiates the deposition of ECM components
For tissue that are incapable of regeneration repair is
accomplished by connective tissue deposition ,
producing a scar.
If damages persists, inflammation becomes chronic,
tissue damages and repair may occur concurrently.
Connective tissue deposition in these condition is
usually referred to as FIBROSIS.
95

96. GRANULATION TISSUE
As early as 24 hours fibroblasts and vascular
endothelial cell begin proliferating to form a
specialized type of tissue that is the hallmarks of
healing, called granulation tissue.
Characteristic: the formation of new small blood
vessels (angiogenesis) and the proliferation of
fibroblasts .
96

97. Angiogenesis
Blood vessels are assembled during embryonic
development by vasculogenesis.
Process of blood vessel formation in adults is known
as angiogenesis or neo- vascularization, branching
and extension of adjacent blood vessels also occur by
recruitment of endothelial progenitor cells (EPCs)
from bone marrow.
97

98. Angiogenesis from Endothelial
Precursor Cells
Angio-blasts proliferate, migrate to peripheral sites,
differentiate into endothelial cells that form arteries,
veins, lymphatics . Also can generate pericytes and
smooth muscle cells of vessel wall (periendothelial
cells)
98

99. Angiogenesis from Pre-Existing
Vessels
Major steps:
Vasodilatation increased permeability
Proteolytic degradation of the BM of the parent
vessel ( by metalopoteinase) and disruption of cell-tocell contact between endothelial cell of vessel (by
plasminogen activator).
Migration of endothelial cells
Proliferation of endothelial cells
Maturation of endothelial cells & remodeling into
capillary tube.
Recruitment of periendothelial cells & formation of
mature vessel.
99

100. ANGIOGENESIS FROM PREEXISTING VESSELS
100

101. Scar formation
Scar formation can be divided in three processesEmigration and proliferation of fibroblasts
Deposition of ECM
Tissue remodeling
Fibroblast migration & proliferation
Migration of fibroblast to the site of injury & their
subsequent proliferation are triggered by multiple
growth factors (TGF , PDGF, EGF, FGF)) and the
cytokines (IL-1 & TNF)
Source of these factors are platelets, inflammatory
cells (notably macrophages) & activated
endothelium.
101

102. ECM deposition & Scar formation
As repair continues proliferating endothelial cells and
fibroblasts decreases.
Fibrillar collagen provides the strength in healing
wounds.
Ultimately the granulation tissue scaffolding is
converted into a scar composed of spindle shaped
fibroblasts , dense collagen, fragment of elastic tissue
and other ECM components.
As the scar matures the richly vascularized
granulation tissue is converted into pale avascular
scar.
102

103. Tissue Remodeling
Balance between ECM synthesis and degradation
results in remodeling of the connective tissue.
Degradation is achieved by matrix metaloproteinases
(MMPs).
MMPs includes :Interstitial collagenases(MMP-1,2 &3)
Gelatinases (MMP-2 & 9)
stromelysins (MMP- 3,10 & 11)
Membrane bound MMP
Activated collagenases are rapidly inhibited by tissue
inhibitors of metalloproteinases (TIMPs)
103

104. CUTANEOUS WOUND HEALING
It is divided into three phases-
Inflammation
Granulation tissue formation and re-epithelization
Wound contraction, ECM deposition and
remodeling
Wound healing is by primary or secondary intention
which is based on the nature of the wound rather than
the healing process itself.
104

105. HEALING BY PRIMARY INTENTION
Healing of clean, uninfected surgical incision
approximated by surgical suture is reffered as primary
union or healing by first intension .
Five phases of healing are –
1.Immediately- capillaries of either side of wound are
thrombosed
Gap is filled with blood
Coagulation and sealing of defect
If clot reaches the surface, it dries to form a crust or
scab
105

106. 106

107. Inflammatory phase
2nd dayNeutrophils appear at margins of incision
Acute inflammatory response on either side of narrow
incision space
Swelling, redness, pain at the wound site
Epithelial cells at edge of wound undergo mitosis and
begin to migrate across the wound
107

108. 108

109. Proliferative phase
Cellular proliferation involves three processes
Angiogenesis-the wound surface or edge is relatively
ischemic and healing cannot effectively proceed until
sufficient flow is restored
Also called as neo-vascularisation
Involves formation of new blood vessels by
proliferation and migration of endothelial cells from
preexisting blood vessels
109

110. Epithelial cell proliferation
The epidermis at the cut ends thickens (mitotic
division of basal cells)
Within 48 to 72 hrs epithelial cells from both the
margins grows towards the cut end depositing the
basement membrane as they moves
They fuses in the midline, beneath the scab, thus
producing a continuous but thin epithelial layer
110

111. By day 3:The neutrophils are largely replaced by macrophages.
Granulation tissue progressively invades the incision space.
Collagen at first are vertically oriented, not bridging the
incision site
Epithelial cells proliferation thickens
The thickening of epidermal covering layer yields mature
epidermal architecture with surface keratinisation
111

112. By day 5:Incisional space is filled with granulation tissue.
Neo-vascularization is maximal.
Collagen begin to bridge the incision.
Epidermis recovers its normal thickness.
Surface keratinization starts
Day 7- interstitial matrix production
112

113. 113

114. Day 10th
Fibrous Union phase begins on about 10th day
114

115. Remodeling
Day 30
Scar is largely devoid of inflammatory cells and
covered by an essentially normal epidermis
3 Months
Devascularisation of tissue, remodeling of collagen by
enzyme action , scar is now minimum and merges
with surrounding tissues
115

116. Healing by second intention
Edges are separated.
More extensive loss of cells and tissue.
Prone for infection
Regeneration of parenchymal cells can not
completely restore the original architecture, and
Hence, abundant granulation tissue grows is referred
to as secondary union.
Cannot be brought together by sutures
116

117. Early phase
Edges cannot be brought together and defect remains
Base of wound may covered with plasma
Plasma oozes out from the base of the wound
Wound are filled with the blood from the cut ends of
capillaries, fibrin threads and platelets
117

118. 118

119. One week approximatelyFibrovascular granulation tissue gradually fills the
wound space and epithelium grows over its surface
The exudative inflammatory changes and migration of
neutrophills subsides
Formation of loose connective tissue by fibroblast
Macrophages come to clear the debris
Granulation tissue grows into the wound from the
base
119

120. 120

121. Second weekDuring the second week continuous accumulation of collagen
and proliferation of fibroblast
Leukocyte infiltration, edema, increased vascularity is greatly
reduced
Increased collagen deposition within the incision scar and
disappearance of vascular channels
Months
Contraction of wound by myofibroblast present in granulation
tissue
Wound contraction occur in case of shrinkage of granulation
tissue that pulls the edges together
121

122. 122

123. Wound strength
First week:- 10 % of unwounded
Next 4 weeks:- rapid increase
3rd month:- rate slows down & reaches a plateau at
about 70 % to 80 % of tensile strength.
123

124. Local & Systemic factors that
influence Wound Healing
• Systemic factors:– Nutrition: Vit-c def.
retards healing
– Metabolic state:
Diabetes retards
healing.
– Circulatory status:
atherosclerosis and
venous diseases
retards healing
– Hormones:
glucocorticoids have
anti-inflammatory
effects & inhibits
collagen synthesis.
• Local factors:– Infection (most imp.)
retards healing
– Mechanical factors:early motion retards
healing
– Foreign bodies: inhibits
healing
– Size location & type of
wound: richly
vascularised sites heal
quickly
124

125. Complications In Cutaneous Wound Healing
Deficient scar formation
Excessive formation of the repair components
The accumulation of excessive amounts of
collagen may give to a raised scar known as a
hypertrophic scar
If scar tissue grows beyond the boundaries of the
original wound and does not regress, it is called a
keloid
Exuberant proliferation – Desmoids, or
aggressive fibromatoses (interface between
benign proliferations and malignant tumors)
Formation of contractures: Serious burns.
125

126. 126

127. Healing of extraction socket
The removal of tooth initiates the same sequence of
inflammation, epithelialization, fibroplasia and
remodeling seen in skin wound
Socket heals by secondary intension
After extraction the empty socket consist of cortical
bone(radiographic lamina dura )covered by torn
periodontal ligament with a rim of oral epithelium
127

128. The socket fills with blood clot which seals the socket
from oral environment
During first week inflammatory stage takes place
WBCs enter the socket and clear the microorganism,
begins to break down any debris, bony fragments left
in the socket
Fibro-plasia begins with ingrowths of fibroblast and
capillaries
128

129. The epithelium migrates down the socket wall
Reaches a level at which it contacts the epithelium
Other side of socket
Encounters the bed of granulation tissue under the
clot
Osteoclast accumulates over the crestal bone
129

130. During second week
Large amount of granulation tissue fills the socket
Osteoid deposition along the lining of the socket
The process begin during second week continue
Third and forth week of healing
The cortical bone continues to resorb from the crestal
bone and walls of the socket
130

131. New trabecular bone is laid down across the socket
As bone fills the socket epithelium moves towards the
crest and eventually becomes level with the adjacent
crestal gingiva
131

132. FIBRINOLYTIC ALVEOLITIS
(DRY SOCKET)
Postoperative complication appears 2–3 days after
the extraction.
The blood clot disintegrates and is dislodged, resulting in
delayed healing and necrosis of the bone surface of the
socket.
This disturbance is termed fibrinolytic alveolitis and is
characterized by an empty socket, fetid breath odor, a bad
taste in the mouth, denuded bonewalls, and severe pain that
radiates to other areas of the head
132

133. Clinical photograph of fibrinolytic alveolitis (dry
socket) in the region of the maxillary second molar

134. 134

135. HEALING OF FRACTURED BONE
Phases of fracture healing
There are three major phases of fracture healing, two of which
can be further sub-divided to make a total of five phases;
1. Reactive Phase
i. Fracture and inflammatory phase(immediately)
ii. Granulation tissue formation(24-48 hrs)
2. Reparative Phase
iii. Cartilage Callus formation(2 -3 weeks)
iv. Lamellar bone deposition(external callus removed,
intermediate callus is converted into compact bone, internal
callus into cancellous bone)
3. Remodeling Phase
v. Remodeling to original bone contour(months to year)
135

136. 136

137. REFERENCES
• Robbins and Cotrans.Pathologic basis of diseases,9th edition;
43-108
• Mohan Harsh.Essentials of pathology,4th edition;90-109
• Sant Mrinali. A textbook of pathology,1st edition; 86-90
• Peterson.contemporary oral and maxillofacial surgery,4th
edition;54-55
• Fragiskos D. Fragiskos. Oral Surgery; 199
137

138. THANK YOU
138