Types o f wounds
Lacerations
 Abrasions
 Contusions
 Avulsions

Wound healing, types of wound
healing
1) first intention-primary wound healing
or primary closure
 2) second intention-secondary wound
healing or spontaneous healing
- reepithelialization and wound contraction by myofibroblasts,

presence of granulation tissue, late wound contracture,
hypertrophic scar

3) third intention-tertiary wound healing
or delayed primary closure
Phases of Healings
Inflammatory(reactive)
- Haemostasis/ inflammation
 Proliferative (Regenerative/reparative)
- Epithelial migration/proliferation/maturation
 Maturational (Remodeling)
- Contraction/scarring/remodeling

Physiologic stages of wound repair
II Cell proliferation and matrix deposition
I Inflammation
III Matrix remodelling
Fibroplasia
Angiogeneisis
Re-epithelialization
ECM synthesis
-collagen,
fibronectin
proteoglycans
Granulocytes
phagocytosis
Bleeding
Coagulation
Platelet activation
Complement activation
Platelet
Neutrophil
Lymphocytes
Macrophages
EPCs
ECM synthesis,
degradation, and remodelling
Tensile strength
Cellularity
Vascularity
Macrophage
Cytokines
Keratinocytes
Endothelial cells
Fibroblasts
Macrophages
EPCs
Myofibroblasts
Macrophages
Early Wound healing events
(Day 1-4)
Inflammatory or reactive phase
- Immediate response to injury
- goals: hemostasis, debridement, sealing of the wound
 Events
1. Increase vascular permeability
2. Chemotaxis
3. Secretion of cytokines
4. Growth factor

Inflammatory phase
Blood vessels are disrupted, resulting in bleeding.
Hemostasis is achieved by formation of platelet plug
and activation of extrinsic (initiation) & intrinsic clotting
(amplification) pathways.
 Formation of a provisional fibrin matirx
 Recruitment of inflammatory cells into the wound by
potent chemoattractants.

Inflammation
Attraction/activation of infiltrating cells
 Neutrophils
- Bacteria and matrix phagocytosis
- Not essential unless wound contaminated
 Macrophages
- Debridement / matrix turnover
- Majour source of stimulatory signals
- Important for wound healing

Inflammatory cells
 PMN(polymorphoneuclear neutrophil)
- Migration of PMN stops when wound contamination
had been controlled
- Don’t survive more than 24hours
- Increase contamination stimulates PMN
resulting to delayed wound healing and destruction
of tissues.
- Not essential for wound healing
Inflammatory cells

-
-
Macrophages
Orchestrate release of cytokines/
process of wound healing/ release of
growth factors
24-48 hours
Source of TNF/interleukin 1,6,8
Role of macrophages in wound healing
Phagocytosis,
Antimicrobial function
Wound
debridement
macrophages
Angiogenesis
Cell recruitment
and activation
Oxygen radicals
H2O2, O2, OH
Nitric oxide
Phagocytosis
Enzymes
-collagenase
-elastase
Matrix synthesis
regulation
Growth factors
- PDGF, TGF-β
EGF, IGF
Cytokines
TNF-α, IL-1, IL-6
Fibronectin
Growth factor
- FGF, VEGF
Cytokines
- TNF-α
Growth factors
- TGF-b, EGF,
PDGF
Cytokines
- TNF-α, IL-1,
IFN-γ
Enzymes
- collagenase,
arginase
Prostaglandins
- PGE2
Cytokine activity in wound healing
Proinflammatory cytokines
Cytokine
Cell source
Biology activity
TNF-α
Macrophages
PMN migration and cytotoxicity, with or without collagen
Synthesis; provides metabolic substrate
IL-1
Macrophages
keratinocytes
Fibroblast and keratinocyte chemotaxis, collagen synthesis
IL-2
T lymphocytes
Increases fibroblast infiltration and metabolism
IL-6
Macrophages
PMNs
Fibroblasts
Fibroblast proliferation, hepatic acute phase protein
synthesis
IL-8
Macrophages
Fibroblasts
Macrophages and PMN chemotaxis, keratinocyte maturation
IFN-γ
T lymphocytes
Macrophages
Activates macrophages and PMNs, retards collagen
synthesis and cross-linking, stimulates collagenase activity
Anti-inflammatory cytokines
IL-4
T lymphocytes
Basophils
Mast cells
Inhibition of TNF, IL-1, IL-6 production; fibroblasts
proliferation, collagen synthesis
IL-10
T lymphocytes
Macrophages
Keratinocytes
Inhibition of TNF, IL-1, IL-6 production; inhibition of
macrophage and PMN activation
Growth factors in wound healing
Cytokine
Source
Functions
Patelet-derived
growth factor
(PDGF)
Platelets,
macrophages,
endothelial cells
keratinocytes
Chemotactic for PMNs, macrophages, fibroblasts; activates PMNs, macrophages, and
fibroblasts; mitogenic for fibroblasts, endothelial cells; stimulates production of MMPs,
fibronectin, and HA; stimulates angiogenesis and wound contraction; remodeling
Transfroming
growth factor-β
(including
isoforms β1, β2
and β3)
(TGF-β)
Platelets,
T lymphocytes,
endothelial cells,
keratinocytes,
fibroblasts
Chemotactic for PMNs, macrophages, lymphocytes, and fibroblasts; stimulates TIMP
synthesis, keratinocyte migration, angiogenesis, and fibroplasia; inhibits production of
MMPs and keratinocyte proliferation; induces TGF-β production.
Epidermal growth
factor (EGF)
Platelets,
macrophages
Mitogenic for keratinocytes and fibroblasts; stimulates keratinocyte migration.
Transforming
growth factor-α
(TGF-α)
Macrophages, T
lymphocytes,
keratinocytes
Similar to EGF
Fibroblast growth
factor-1 and -2
family
(FGF)
Macrophages,mast
cells,T lymphocytes
endothelial cells,
Fibroblasts
Chemotactic for fibroblasts; mitogenic fo fibroblasts and keratinocytes; stimulate
keratinocyte migration, angiogenesis, wound contraction, and matrix deposition
Keratinocyte
growth factor
(also called FGF-7)
(KGF)
Fibroblasts
Stimulates keratinocyte migration, proliferation, and differentiation
Insulin-like
growth factor(IGF1)
Macrophages,
fibroblasts
Stimulates synthesis of sulfated proteoglycans, collagen, keratinocyte migration, and
fibroblast proliferatio; endocrine effects similar to those of growth hormone
Vascular
endothelial cell
growth
factor(VEGF)
Ketatinocytes
Increases vasopermeability; mitogenic for endothelial cells.
Inflammatory cells
Lymphocytes
- Peak on 7th day
- Affect fibroblast
- Stimulate cytokines
- Not essential for acute wound healing

Intemediate events( Days 4-21)

Proliferative phase
Goal: granulation tissue formation
Events:
1. Angiogenesis
2. Fibroplasia
3. Epithelization
Proliferative phase
Granulation tissue formation (composed
of fibroblasts, macrophages and
endothelial cells).
 Contraction
 Re-epithelialization(begins immediately
after injury)
 Decrease collagen synthesis at 4 weeks
after injury.

Proliferative phase
Extracellular matrix
- Scafford for cellular migration
- Composed of fibrin, fibrinogen,
fibronectin, vitronectin
 Fibronectin and Type 3 collagen=early
maxtrix
 Type 1 collagen- wound strength later

Mesencymal cell proliferation



Fibroblasts are the major masenchymal cells
involved in wound healing, although smooth
muscle cells are also involved.
Macrophages products are chemotactic for
fibroblasts. PDGF, EGF, TGF, IL-1, lymphocytes
are as well
Replacement of provisional fibrin matrix with type
III collagen.
Fibroplasia

Fibroblasts are specialized cells that differentiate from resting
mesenchymal cells in connective tissue.
Injury
Stimulation of macrophage &
platelet derived cytokines & growth
factors
Chemoattraction of
fibroblasts to the inflammatory
site
(PDGF, TGF-β), C5 frag
ments, thrombin, TNF-α
, eicosanoids, elastin fr
agments, leukotriene B4
, and fragments of colla
gen and fibronectin
Fibroblasts which are
in G0 phase
Replicate
&proliferate
Components
of ECM
22
Fibroblasts
- They are most common cells of connective tissue
Role of fibroblsats in wound healing
Fibroblasts
Migration,
proliferation
ECM
Production
From
surrounding
Tissues
influenced by
growth
factors/cystokine
s
-PDGF
-EGF
-FGF7
-CTGF
-Activin
Protease
rekase
Angiogenesis
Growth factor/
Cytokine production
Linkage between
actin bundles and
ECM
Serves as
scafford
Tensile strength
PDGF
EGF
FGF-7
CTGF
Activin
Growth
factors/cytokin
es
-FGF7
-EGF
-Activin
ECM remodeling
Disolves
-nonviable
tissue
-fibrin barrier
Angiogenesis



Angiogenesis reconstructs vasculature in areas
damaged by wounding, stimulated by high lactate
levels, acidic pH, decreased O2 Tension in tissues.
Recruitment & assembly of bone marrow derived
progenitor cells by cytokines is the central theme.
FGF-1 is most potent angiogenic stimulant
identified. Heparin important as cofactor, TFG-α, β,
prostaglandins also stimulate.
Epithelialization




Basal cell layer thickening, elongation, detachment &
migration via interaction with ECM proteins via integrin
mediators
Generation of a provisional basement membrane
which includes fibronectin, collagenes type 1 and 5.
Epithelial cells proliferation contribute new cells to the
monolayer. Contact inhibition when edges come
together.
By three keratinocyte functions-migration, proliferation
and differentiation
Role of keratinocytes in wound healing
Migration
Proliferation
Protease
release
Keratinocyte
ECM
production
Angiogenesis
Growth factor/
Cytokine producton
Epiboly
Integrins
Matrix formation
Basement membrane
formation
Dissolves
- nonviable tissue
- fibrin barrier
Chemoattractants
- VEGF
- KCG(FGF-7)
VEGF
TGF-α
PDGF
PD-ECGF
Late wound healing events (Days
21- )


-
Remodeling phase
Goal: scar contraction with collagen cross linking,
shrinking and loss of edema
programmed regression of blood vessels &
granulation tissue.
Wound contraction
Collagen remodeling.
Maturation phase




Wound contraction-centripetal movement of full
thickness of skin
Decreases amount of disorganized scar
Wound contracture, physical restriction, limitation
of function-result of wound contraction
Appearance of stimulated fibroblast known as
myofibroblast
Collagen



19 types identified. Type 1(80-90%) most common,
found in all tissue. The primary collagen in a
healed wound.
Type III(10-20%) seen in early phase of wound
healihng.
Type V (smoth muscle),
Type II, Type XI (cartilage), Type IV(in BM).
Wound contraction



Begins approximately 4-5 days after wounding by
action of myofibroblasts.
Represents centripetal movement of the wound
edge towards the center of the wound.
Maximal contraction occurs for 12-15days,
although it will continue loner if wound remains
open.
Wound contraction



The wound edges move toward each other at an
average rate of 0.6 to 0.75 mm/day.
Wound contraction depends on laxity of tissues, so
a buttock wound will contract faster than a wound
on the scalp or pretibial area.
Wound shape also a factor, square is faster than
circular.
Wound contraction




Contraction of a wound across a joint can cause
contracture.
Can be limited by skin grafts, full better than split
thickness
The earlier the graft the less contraction
Splints temporarily slow contraction
Remodeling


After 21 days, net accumulation of collagen
becomes stable. Bursting stength is only 15% of
normal at this point. Remodeling dramatically
increases this.
3-6 weeks after wounding greates rate of increase,
so at 6 weeks we re at 80% to 90 % of eventual
strength and at 6months 90% of skin breaking
strength.
Remodeling




The number of intra and intermolecular crosslinks
between collagen fibers increases dramatically.
A major contributor to the increase in wound
breaking strength.
Quality of type III collagen decreases replaced by
type I collagen.
Remodeling continues for 12months, so scar
revision should not be done prematurely.
Factors Affecting Wound Healing
Systemic
Local
Age
Mechanical injury
Nutrition
Infection
Trauma
Edema
Metabolic diseases
Ischemia/necrotic tissue
Immunosuppression
Topical agents
Connective tissue disorders
Ionizing radiation
Smoking
Low oxygen tension
Foreign bodies
38
STEROIDS

Large doses or chronic usage of glucocorticoids reduce collagen synthesis
and wound strength.

Inhibit the inflammatory phase of wound healing (angiogenesis, neutrophil
and macrophage migration, and fibroblast proliferation) and the release of
lysosomal enzymes.

Steroids used after the first 3 to 4 days post-injury do not affect wound healing
as severely as when they are used in the immediate postoperative period.

Steroid-delayed healing of cutaneous wounds can be stimulated to
epithelialize by topical application of vitamin A
39
CHEMOTHERAPEUTIC DRUGS

All chemotherapeutic antimetabolite drugs adversely affect wound
healing by inhibiting early cell proliferation and wound DNA and protein
synthesis, all of which are critical to successful repair.

Delay in the use of such drugs for about 2 weeks post injury appears
to lessen the wound healing impairment.
40

The main effect of Arginine on wound healing is to enhance wound
collagen deposition.

Arginine deficiency results in decreased wound-breaking strength
and wound collagen accumulation.

Vitamins most closely involved with wound healing are vitamin C
and vitamin A.

vitamin C deficiency, leads to a defect in wound healing, particularly
via a failure in collagen synthesis and cross-linking.

Biochemically, vitamin C is required for the conversion of proline an
d lysine to hydroxyproline and hydroxylysine, respectively.

Vitamin C deficiency has also been associated with an increased in
cidence of wound infection
41

Vitamin A deficiency impairs wound healing, whereas supplemental
vitamin A benefits wound healing.

Vitamin A increases the inflammatory response in wound healing,
probably by increasing the lability of lysosomal membranes.

Vitamin A directly increases collagen production and epidermal
growth factor receptors when it is added in vitro to cultured fibroblasts.

Supplemental vitamin A can reverse the inhibitory effects of corticos
teroids on wound healing.

Vitamin A also can restore wound healing that has been impaired b
y diabetes, tumor formation, cyclophosphamide, and radiation.

Doses ranging from 25,000 to 100,000 IU per day
42
ZINC

In deficiency states there is decreased fibroblast proliferation, decr
eased collagen synthesis, impaired overall wound strength, and del
ayed epithelialization.
43
IONIZING RADIATION

Causes endothelial cell injury with endarteritis resulting in atrophy, fi
brosis, and delayed tissue repair

Angiogenesis is not initiated

Rapidly dividing cell populations like keratinocytes and fibroblasts a
re most sensitive to radiation.
44
Hypertrophic scar & Keloid

Hypertrophic scars (HTSs) and keloids represent an
overabundance of fibroplasia in the dermal healing process.
vs
Hypertrophic scar
Keloid
HTSs rise above the skin level but stay within the
confines of the original wound and often regress o
ver time
Keloids rise above the skin level as well, but exte
nd beyond the border of the original wound and ra
rely regress spontaneously
HTSs occur after trauma to the skin, and may be t
ender, pruritic, and cause a burning sensation.
keloids occur after trauma to the skin, and may be
tender, pruritic, and cause a burning sensation
HTSs usually develop within 4 weeks after trauma
.
Keloids tend to occur 3 months to years after the
initial insult, and even minor injuries can result in
large lesions.
Keloids can result from surgery, burns, skin inflam
mation, acne, chickenpox, zoster, folliculitis, lacer
ations, abrasions, tattoos, vaccinations, injections
, insect bites, ear piercing, or may arise spontane
ously
They usually occur across areas of tension and fl
exor surfaces, which tend to be at right angles to j
oints or skin creases.
Certain body sites have a higher incidence of
keloid formation, including the skin of the ear lobe
as well as the deltoid, presternal, and upper back
regions.
Initially erythematous and raised, and over time
may evolve into pale, flatter scars.
They vary in size from a few millimetres to large,
pedunculated lesions with a soft to rubbery or har
d consistency
The collagen bundles are flatter, more random, an
d the fibres are in a wavy pattern
Collagen bundles are virtually non-existent, and t
he fibres are connected haphazardly in loose she
ets with a random orientation to the epithelium
46

Underlying mechanisms that cause HTSs and keloids are not know
n.

The immune system appears to be involved in the formation of both
HTSs and keloids.

In both HTSs and keloids, keratinocytes express human leukocyte
antigen-2 and intercellular adhesion molecule-1 receptors, which ar
e absent in normal scar keratinocytes.

Keloids also have increased deposition of immunoglobulin G (IgG),
IgA, and IgM.

Antinuclear antibodies against fibroblasts, epithelial cells, and endot
helial cells are found in keloids, but not HTSs.

HTSs have higher T-lymphocyte and Langerhans cell contents.

Larger number of mast cells –HTSs and keloids.

Other mechanisms
 Mechanical tension
 Prolonged irritation and/or inflammation that may lead to the gen
eration of abnormal concentrations of profibrotic cytokines.
47