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Tissue Repair and wound Healing
MOLAWORK A. (MD)
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Outline
• Proliferative capacity of cell
• Types of healing process
• Factors affecting healing
• Complications of Wound Healing
2

Wound
Definitions
 Wound is a disruption of the normal structure and
function of the skin and underlying soft tissue.
 Regeneration refers to growth of cells and tissues to
replace lost structures.
 Healing is usually a tissue response to;
 A wound (commonly in the skin),
 Inflammatory processes in internal organs, and
Cell necrosis in organs incapable of regeneration.
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Types of wounds
 Acute vs. chronic
 Open vs. close
 Tidy vs. untidy
Tidy vs untidy wounds
Tidy Untidy
 Incised -Crushed or avulsed
 Clean - Contaminated
 Healthy tissues -Devitalized tissues
 Seldom tissue loss - Often tissue loss
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• The body's ability to repair and replace injured/dead cells and
tissues after inflammation is critical to survival
Healing refers to the body’s replacement of destroyed tissue
• Involves two distinct processes:
1. Regeneration: replacement of lost tissue by similar tissues
2. Repair (healing by scaring)
– the restoration of tissue architecture and function by granulation
tissue which matures to form scar tissue
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• The repair process is influenced by many factors,
including:
- The tissue environment and the extent of tissue
damage
- The intensity and duration of the stimulus
- Adequacy of blood supply
- presence of foreign bodies
- Systemic diseases that inhibit repair
- Steroid therapy
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Types of cells based on proliferative capacity
1. Continuously Dividing(Labile cells)
– cells which have a continuous turn over by programmed
division of stem cells after injury as long as the pool of stem
cells is preserved
– They are found in the surface epithelium of the skin, GIT,,
urinary tract, uterus, lymphoid
– Has excellent regenerative capacity
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2. Stable cells (Quiescent)
• Cells are quiescent and have few stem cells with only minimal
replicative activity in their normal state
• However, these cells are capable of proliferating in response to
injury or loss of tissue mass
– E.g.. mesenchymal cells such as smooth muscle cells,
fibroblasts, osteoblasts and endothelial cells , Liver, endocrine
glands and renal tubular epithelium
– Their chances of regeneration are good
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3. Permanent cells
– They are terminally differentiated cells(non-dividing) in
postnatal life
– Once permanent damaged, cannot be replaced
– For example: adult neurons, striated muscle cells, and cells of
the lens, cardiac myocytes
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Healing by regeneration
• Regeneration is the renewal of a lost tissue in which the lost cells are
replaced by identical ones
• The capacity of a tissue for regeneration depends on its:
– proliferative ability
– degree of damage to stromal framework
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Repair (Healing by connective tissue)
• lost tissue is replaced by a scar
– If tissue injury is severe or chronic that extend through the
basement membrane, stromal framework, to the parenchymal
cells
– Healing by fibro proliferative response "patches" rather than
restores a tissue
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• Repair begins within 24 hours of injury by the emigration of
fibroblasts and the induction of fibroblast and endothelial cell
proliferation
• By 3 to 5 days, a specialized type of tissue that is called
granulation tissue is apparent
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Granulation tissue
• Term derives form its red pink (new capillary loops), soft, moist &
granular appearance on the surface of wounds
• Components
Newly growing blood vessels: provide nutrients, take away
cellular wastes, & transport new leukocytes
Proliferating fibroblasts: new matrix synthesis(collagen initially
type III later type I)
Inflammatory cells e.g., macrophages, neutrophils
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granulation-tissue formation pass through three phases
1. Phase of inflammation
– inflammatory exudate containing polymorphs, platelet
aggregation and fibrin deposition
2. Phase of demolition
– macrophage infiltrate and ingest particulate matter.
– proteolytic enzymes degrade inflammatory cells
3. Ingrowth of granulation tissue
– characterized by proliferation of fibroblasts and In growth of
new blood vessels with a variable number of inflammatory cell
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• Repaire consists of four sequential processes:
– Formation of new blood vessels (angiogenesis)
– Migration and proliferation of fibroblasts
– Deposition of ECM (scar formation)
– Maturation and reorganization of the fibrous tissue
(remodeling)
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Angiogenesis
• Blood vessels are assembled by two processes:
• Vasculogenesis: primitive vascular network is assembled from
angioblasts during embryonic development; and
• Angiogenesis or neovascularization: in which preexisting vessels
send out capillary sprouts to produce new vessels
• Angiogenesis is critical to chronic inflammation and fibrosis,
tumor growth, and vascularization of ischemic tissues
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Angiogenesis (Neovascularization)
• Vascular proliferation starts 48 to 72 hours after injury and lasts for
several days
It occurs because of:
• the branching and extension of adjacent blood vessels
– endothelial cells from these vessels become motile and
proliferate to form capillary beds
• recruitment of endothelial progenitor cells (EPCs) from the bone
marrow which can differentiate and form mature network by
linking with preexisting vessels
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Migration of Fibroblasts and ECM Deposition (Scar Formation)
• Scar formation builds on the granulation tissue framework of new
vessels and loose ECM that develop early at the repair site
• It occurs in two steps:
1. migration and proliferation of fibroblasts into the site of injury
2. deposition of ECM by these cells
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• As healing progresses, the number of proliferating fibroblasts and
new vessels decreases but fibroblasts increase the synthesis and
deposition of ECM
• collagen synthesis by fibroblasts begins early in wound healing
(days 3 to 5) and continues for several weeks
• the granulation tissue evolves into a scar composed of largely
inactive, spindle-shaped fibroblasts, dense collagen, fragments of
elastic tissue, and other ECM components
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ECM and Tissue Remodeling
• The outcome of the repair process is a balance between ECM
synthesis and degradation
• degradation of collagens and other ECM components is
accomplished by a family of matrix metalloproteinase (MMPs)
• MMPs include collagenases(MMP-1,-2 and -3); gelatinases
(MMP-2 and 9) and stromelysins (MMP-3,10, and 11)
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• MMPs are produced by a variety of cell types (fibroblasts,
macrophages, neutrophils, synovial cells, and epithelial cells)
• their synthesis and secretion tightly controlled regulated by
growth factors and cytokines and inhibited by TGF-β and
suppressed by steroids
• elaborated as inactive precursors and activated collagenases can
be rapidly inhibited by specific TIMPs
• They are essential in the debridement of injured sites and in the
remodeling of the ECM
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Wound Healing
• In very superficial wounds, the epithelium is reconstituted and
there may be little scar formation
• Epidermal appendages do not regenerate, and there remains a
connective tissue scar
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Phases of wound healing
• events in wound healing overlap to a great extent and cannot be
completely separated from each other
1. Coagulation phase
induced immediately following injury
characterized by vaso-constriction, clot formation and release
of platelets and other substances necessary for healing and
help as a bridge between the two edges
26

2. Inflammatory phase:
takes place from time of wounding up to three days
 characterized by classical inflammatory response,
vasodilatation and pouring out of fluids, migration of
inflammatory cells and leukocytes and rapid epithelial growth
3. Proliferate Phase(phase of fibroplasia)
 starts around the 3rd day of injury and stays for about three
weeks
 characterized by fibroblast, epithelial and endothelial
proliferation, Collagen synthesis, and ground substance and
blood vessel production
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Maturation phase(phase of remodeling)
 takes the longest period which may extend for up to one year
 Equilibrium between protein synthesis and degradation
leading to slow and continuous increase in tissue strength
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based on the nature of the wound, Skin wounds heal by
– primary intention
–secondary intention or
– Healing by third intention
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Healing by first intention (primary union)
• The incision causes only focal disruption of epithelial basement
membrane and death of a few epithelial & connective tissue cells
• the wounds are sealed immediately with simple suturing, skin
graft placement, or flap closure, such as closure of the wound at
the end of a surgical procedure
• epithelial regeneration predominates over fibrosis
• A small scar is formed, but there is minimal wound contraction
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• dehydration of the surface clot forms the well-known scab that
covers the wound
– E.g. healing of a clean, uninfected surgical incision
approximated by surgical sutures
The healing process follows a series of sequential steps:
• Within 24 hrs.
– neutrophils appear
• In 24 to 48 hours
– spurs of epithelial cells move from the wound edges
– They fuse in the midline beneath the surface scab, producing a
continuous thin epithelial layer that closes the wound
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• By day 3
– the neutrophils largely replaced by macrophages
– Granulation tissue progressively invades the incision space
– Collagen fibers are now present in the margins of the incision
but do not bridge the incision
• By day 5
– the incisional space is filled with granulation tissue
– Neovascularization is maximal
– type III collagen fibrils become more abundant but by day 7 to
8, type I is prominent and becomes the major collagen of
mature scar tissue
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• During the 2nd wk
– continued collagen accumulation and fibroblast
proliferation
– The leukocyte infiltrate, edema, and increased vascularity
are substantially diminished
• By the end of the first month
– the scar is made up of a cellular connective tissue devoid of
inflammatory infiltrate, covered by intact epidermis
– The dermal appendages in the line of the incision are
permanently lost
• Tensile strength of the wound increases thereafter, but it may
take months for the wounded area to obtain its maximal strength
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Wound contraction
 it is a mechanical reduction in the size of the defect
 wound is reduced approximately by 70-80% of its original size
 If contraction is prevented, healing is slow and a large ugly scar is
formed
 Causes of contraction
• It is said to be due to contraction by myofibroblasts which have
the features intermediate between those of fibroblasts and smooth
muscle cells
• Two to three days after the injury they migrate into the wound and
their active contraction decrease the size of the defect
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Healing By Second Intention(secondary union )
• occurs in wounds with widely separated edges, contaminated with
abscess formation which are not primarily closed
• Healing takes place by granulation tissue formation, tissue
contraction and epithelialization
• Closure by secondary, or spontaneous, intention involves no active
intent to seal the wound
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• Secondary healing differs from primary healing in several
respects:
• more intense inflammatory reaction( more necrotic debris
and exudate)
• abundant granulation tissue development
• larger fibrin clot that fills the defect
• formation of a large scar
• the wound contracts
• takes much longer time
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Healing by third intention:
- This occurs in wounds which are left open initially for various
reasons and closed later (delayed primary closure)
- contaminated wound is initially treated by repeated
débridement, or antibiotics for several days to control infection
- Once the wound is being ready for closure approximation will
be performed
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Wound Strength
• Carefully sutured wounds have approximately 70% of the strength
of unwounded skin
• When sutures are removed= strength is approximately10% but
this increases rapidly over the next 4 weeks
• Wound strength reaches approximately 70% to 80% of normal by
3 months but usually does not substantially improve beyond that
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Factors affecting healing
Local factors
• Infection
• Mechanical factors: early motion
• Foreign bodies: sutures, steel, etc
• Size, location
• type of wound
• Adhesions
• Radiation
Systemic factors
• Age
• Nutrition
– Protein, Vitamin C, Zinc
deficiency
• DM
• Circulatory status
• Corticosteroids:
• Granulocytopenia
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Complications In Cutaneous Wound Healing
• Complications in wound healing can arise from abnormalities in
any of the basic components of the repair process
• These aberrations can be grouped into three general categories:
1) Deficient scar formation,
2) Excessive formation of the repair components, and
3) Formation of contractures
Others
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• Inadequate formation of granulation tissue or assembly of a scar
can lead to two types of complications:
wound dehiscence and ulceration
• Dehiscence or rupture of a wound is most common after
abdominal surgery and is due to increased abdominal pressure
• The accumulation of excessive amounts of collagen may give rise
to a raised scar known as a hypertrophic scar; if the scar tissue
grows beyond the boundaries of the original wound and does not
regress, it is called a keloid.
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Postoperative wound dehiscence
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Hypertrophic scar
• Occurs anywhere in the
body
• It is limited to the scar
tissue only and It will not
extend to normal skin.
• Not genetically
predisposed
• Growth usually limits up
to 6 months
44

Keloid
• Grows beyond the
boundaries of the original
wound & does not regress
• Frequently seen on earlobes,
shoulders, upper back and
anterior chest
• Other sites are upper arm,
chest wall, lower neck in
front
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