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Introduction
• Injury to human body initiates inflammation ….meant
to eliminate the offender & necrotic debris; additionally
it sets into motion the process of repair.
• Repair of damaged tissues occurs by two types of
reactions:
1. Regeneration
2. Connective tissue deposition (scar formation)
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1. Regeneration
• results in the complete restoration of lost or
damaged tissue and essentially return to a
normal state
– proliferation of cells and tissues to replace lost structures
– Tissues with high proliferative capacity, such as the hematopoietic
system and the epithelia of the skin and gastrointestinal (GI) tract,
renew themselves continuously and can regenerate after injury,
as long as the stem cells of these tissues are not destroyed.
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2. Repair by scar formation
• may restore some original structures but can
cause structural derangements
– often consists of a combination of regeneration and scar
formation by the deposition of collagen
– it may itself cause tissue dysfunction e.g. atherosclerosis
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Major types cell that proliferate during
tissue repair
1. Remnants of the injured tissue → attempt to restore
normal structure
2. Vascular endothelial cells → to create new vessels that
provide the nutrients needed for the repair process
3. Fibroblasts → the source of the fibrous tissue that forms
the scar to fill defects that cannot be corrected by
regeneration
The proliferation of these cell types is driven by proteins
that are collectively called growth factors (polypeptides).
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• The relative contribution of regeneration and
scarring in tissue repair depends on
– the ability of the tissue to regenerate
– the extent of the injury
– persistent injury → chronic inflammation
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• The regeneration of injured cells and tissues involves
cell proliferation, which is driven by growth factors
and is critically dependent on the integrity of the
extracellular matrix, and by the development of
mature cells from stem cells.
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1. continuously dividing
(labile tissues),
2. quiescent (stable tissues),
3. nondividing (permanent
tissues)
TISSUE PROLIFERATIVE ACTIVITY Proliferative Capacities…
1. Continuously Dividing Tissues
(Labile tissues)
• continuously being lost and replaced by maturation
from stem cells and by proliferation of mature cells
• Examples
1. hematopoietic cells in the bone marrow
2. surface epithelia, such as the stratified squamous
surfaces of the skin, oral cavity, vagina, and cervix;
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Proliferative Capacities…
1. Continuously Dividing Tissues (Labile tissues)…
• 3. cuboidal epithelia of the ducts draining exocrine
organs (e.g., salivary glands, pancreas, biliary tract);
• 4. the columnar epithelium of the gastrointestinal tract,
uterus, and fallopian tubes; and the
• 5. transitional epithelium of the urinary tract.
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Proliferative Capacities…
2. Stable Tissues
• Cells in the G0 stage of the cell cycle
• have only minimal replicative activity in their normal state.
• Capable of proliferating in response to injury or loss of
tissue mass.
• constitute the parenchyma of most solid tissues, such as
liver, kidney, and pancreas.
• They also include endothelial cells, fibroblasts, and
smooth muscle cells;
• With the exception of liver, stable tissues have a limited
capacity to regenerate after injury.
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Proliferative Capacities…
3. Permanent Tissues
• considered to be terminally differentiated and
nonproliferative in postnatal life.
• The majority of neurons and cardiac muscle cells belong
to this category.
• Thus, injury to brain or heart or skeletal muscle is
irreversible and results in a scar,
– because neurons and cardiac myocytes do NOT regenerate
or insuffcient to produce tissue regeneration after injury
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Proliferative Capacities…
• it is believed that most mature tissues contain
variable proportions of continuously dividing cells,
quiescent cells and nondividing cells
– it is actually difficult to quantify the proportions of
these cells in any tissue.
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• Cell proliferation is driven by signals provided
by growth factors and from the extracellular
matrix.
– GF are typically produced by cells near the site of
damage.
– Most important source – activated macrophages and
also epithelial and stromal cells
ECM components in wound healing
• Provide the framework for cell migration, maintain the
correct cell polarity for the re-assembly of multilayer
structures, and participate in the formation of new blood
vessels (angiogenesis).
• Cells in the ECM (fibroblasts, macrophages, and other
cell types) produce growth factors, cytokines, and
chemokines that are critical for regeneration and repair.
• Several growth factors bind to ECM proteins and are
displayed at high concentrations.
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Assignment
• Please review the first chapter “The Cell as a Unit
of Health and Disease”
– control of cell proliferation, growth factors and signal
transduction pathways, and functions of ECM
components & regenerative medicine .
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Stem cells
• During development, stem cells give rise to all
the various differentiated tissues;
• in the adult organism, stem cells replace
damaged cells and maintain tissue populations
as individual cells within them undergo replicative
senescence due to attrition of telomeres
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Stem cells…
• important properties of stem cells:
1. self-renewal capacity - permits stem cells to
maintain their numbers
2. asymmetric replication - one daughter cell
enters a differentiation pathway and gives
rise to mature cells, while the other remains
undifferentiated and retains its self-renewal
capacity
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Types of Stem cells…
1. Embryonic stem cells (ES cells)
– are the most undifferentiated
– have virtually limitless cell renewal capacity, and can
give rise to every cell in the body → totipotent
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Types of Stem cells…
2. Tissue stem cells (also called adult stem cells)
– found in intimate association with the differentiated cells
– Found in specialized tissue microenvironments called
stem cell niches
– Soluble factors and other cells within the niches keep
the stem cells quiescent until there is a need for
expansion and differentiation of the precursor pool
– adult stem cells in any given tissue can usually only
produce cells that are normal constituents of that tissue.
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Mechanisms of Tissue Regeneration
• In labile tissues
– E.g. surface epithelium → injured cells are rapidly
replaced by proliferation of residual cells and
differentiation of tissue stem cells provided the
underlying basement membrane is intact.
– Blood loss → production of GF colony stimulating factor
(CSF) → production of blood cells
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Mechanisms of Tissue Regeneration
• in parenchymal organs with stable cell,
– usually limited process except in the liver
• resection of up to 90% of the liver can be corrected by
proliferation of the residual hepatocytes
– Pancreas, adrenal, thyroid, and lung have some
regenerative capacity
Repair by Connective
Tissue Deposition
• If repair cannot be accomplished by
regeneration alone it occurs by
– replacement of the injured cells with connective
tissue, leading to the formation of a scar, or
– by a combination of regeneration of some residual
cells and scar formation.
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• Causes of scaring
– Severe injury
– Chronic process
– Injury to nondividing cells
damage to parenchymal cells
and epithelia as well as to the
connective tissue framework
Steps in Scar Formation
1. Angiogenesis - Formation of new blood vessels
2. Formation of granulation tissue - Migration and
proliferation of fibroblasts and deposition of loose
connective tissue, together with abundant new vessels
and interspersed leukocytes
– Transforming growth factor-β (TGF-β) is the most important
cytokine for the synthesis and deposition of CT proteins
– Collagen synthesis is critical to the development of strength in
a healing wound site.
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Steps in Scar Formation
3. Remodeling of CT - Maturation and reorganization of
the fibrous tissue to produce the stable fibrous scar
– The outcome of the repair process is influenced by a balance
between synthesis and degradation of ECM proteins.
– matrix metalloproteinases (MMPs) /MMP 1 -10/ - degrade a
variety of ECM constituents
• Produced by fbroblasts, macrophages, neutrophils, synovial cells, and
some epithelial cells
• inhibited by specific tissue inhibitors of metalloproteinases (TIMPs)
• fibrosis is the extensive deposition of collagen
various organs (commonly used for internal organs)
in the processes repair
• If fibrosis develops in a tissue space occupied by
an inflammatory exudate it is called organization
(as in organizing pneumonia affecting the lung).
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SELECTED CLINICAL
EXAMPLES OF TISSUE
REPAIR AND FIBROSIS
Cutaneous Wound
Healing
• Wound – is a discontinuity or break in the surface
epithelium.
• wounds can be – accidental or surgical(intentional)
• healing of the epidermis(regeneration) & healing of the
dermis(repair by scaring)
• two patterns of wound healing based on the amount of
tissue damage:
1. healing by first intention (10 intention)
2. healing by second intention (20 union)
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1. Healing by 10 (first) intention /union/
• Occurs in clean incised wound such as surgical
incision wherein there is only a potential space
between the edges.
• It produces a clean, neat, thin scar
1. Healing by 10 (first) intention /union/
• Day 1 = neutrophils;
• Day 2 = basal cell migration – mitotic activity of basal cells
along the cut margins → thickening at the cut edge →
epithelial cells migrate and growth → formation of
continuous thin epithelial layer below the scab
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• Day 3 = macrophages replace PMN and there will
be granulation tissue formation
• By day 5, the incisional space is filled with
granulation tissue. Neovascularization is maximal.
– new vessels are leaky
• 2nd week leukocyte infiltrate, edema and increased
vascularity have largely disappeared.
– Tensile strength is ~10%
• 1st month –remodeling of the wound –
– scar tissue covered by an intact epidermis devoid of
inflammatory infiltrate.
– degradation of type III collagen and replacement by type
I collagen
– Tensile strength increases, reaching ~80% within 3
months (usu. considered as maximum strength)
NB: dermal appendages lost permanently
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2. secondary intention/union/
• more extensive cell and tissue loss → large defect e.g.
- infarction, inflammatory ulceration, abscess
• Abundant granulation tissue grows in from the margin
to complete the repair.
• the difference with 10 union
– large tissue deficits → larger the fibrin clot & necrotic debris
→ → → →
– more intense inflammation
– much granulation tissue formation
– it takes longer time
– greater mass of scar tissue
– there is wound contraction
• myofbroblasts
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Same case eight months later
Summery
Wound = fiber + gel + fluid system
Concrete slab = iron rods + cement + sand + water ++
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FACTORS THAT
INFLUENCE TISSUE
REPAIR
1. local factors
2. systemic factors
Factors Affecting Healing…
Local factors:
• The type and extent (size) of tissue injury
– Complete restoration can occur only in tissues
composed of stable and labile cells; even then,
extensive injury will probably result in incomplete tissue
regeneration and at least partial loss of function.
– Injury to tissues composed of permanent cells must
inevitably result in scarring with, at most, attempts at
functional compensation by the remaining viable
elements. Such is the case with healing of a MI
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Factors Affecting Healing…
Local factors:
• Infection
– is clinically one of the most important causes of delay
in healing;
– prolongs inflammation and potentially increases the
local tissue injury
• → excessive granulation tissue formation (proud flesh)→
large deformed scar
Factors Affecting Healing…
Local factors:
• location
– vascular supply e.g. wounds on the face
heal fast
– inflammation arising in tissue spaces (e.g.,
pleural cavity )
• extensive exudates → digestion of the exudate,
by z leukocytes → resorption of the liquefed
exudate. (resolution = restored normal tissue
architecture)
• larger accumulations→ : granulation tissue
grows into the exudate, → fibrous scar ultimately
(organization exudate)
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Factors Affecting Healing…
Local factors:
• Foreign body such as fragments of steel, glass
– an inoculum of 8 million bacteria is required for
infection of intact skin, 1 million are required for
violated skin, and only 100 are required when foreign
material is present
• Mechanical factors such as
– increased local pressure
– Excess early movement
• ionizing radiation
Factors Affecting Healing…
Systemic Factors:
• circulatory status
• infection
• metabolic status e.g. poorly controlled DM
delayed wound healing (5X non DM)
– Atherosclerosis and diabetic neuropathy interferes with
normal blood supply predisposes to injury respectively.
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Factors Affecting Healing…
Systemic Factors:
• nutritional deficiencies
– ↓ed protein → ↓ed collagen formation
– vitamin deficiency e.g. Vit C → ↓ed collagen synthesis →
scurvy
– zinc deficiency → ↓ed cell proliferation (fibroblasts) → ↓ed
collagen
• Hormones
– e.g. corticosteroids – impair wound healing
↓ed collagen synthesis
anti-inflammatory effect
inhibition of TGFβ production and diminished fibrosis → weak
scar
• anti-inflammatory drugs e.g. steroids, aspirin
Factors Affecting Healing…
Systemic Factors:
• Age
• general immobility
• Obesity
• Smoking
• Anemia
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Complications of wound healing
• Includes
– deficient scar formation,
– excessive formation of the repair components, and
– formation of contractures.
Complications
1. Infection
Complications of wound healing
2. deficient scar formation or Inadequate
formation of granulation tissue
A. wound dehiscence and incisional hernias
• dehiscence occurs in 0.5-5% of abdominal surgeries
• dehiscence can be due to: -
– inappropriate surgical techniques,
– ↑ ed stress on wound (e.g. excessive movment due to ↑
intraabdominal pressure)
– Infection
– Systemic factors
• mortality as high as 30%.
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2. DEFICIENT SCAR FORMATION
Ulceration Wound dehiscence
B. ulceration
• Wounds ulcerate because of an inadequate intrinsic
blood supply or insufficient vascularization during
healing.
– E.g. varicose, DM,
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3. excessive scar formation
• failure in 'maturation arrest' or block in the healing
process
• Keloid – vigorous scar that tends to progress and recur
after excision
– frequent after burns
– scar tissue grows beyond the boundaries
– common on neck & ear lobes.
– Genetic predisposition, repeated trauma, and irritation caused
by foreign body, hair … might be a cause
– Proliferation of immature fibroblasts with immature blood
vessels
• hypertrophic scar – structurally similar to keloid but
never gets worse after 6 months
– Is hypertrophy of mature fibroblasts in hypertrophic scar
– doesn't recur
Keloid
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4. excessive contraction
• exaggeration of contraction → contracture (cicatrisation)
• results in sever deformity
• palms, soles, and anterior thorax are prone for contracture
• follows burn injuries
• it can occur in hollow viscera → stricture e.g. urethra,
esophagus
• palmar contracture – dupuytren disease
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Fracture Healing
• defect is filled by specialized bone forming tissue,
unlike scar formation
• so bone is restored nearly to normal
• bone structure
• bone is composed of calcified osteoid tissue
consists of collagen fibers embedded in a
mucoprotein matrix (osteomucin)
• based on arrangement of collagen fibers there are
two histologic types:
1. woven, immature or non-lamellar bone
– collagen bundles arranged irregularly
– less abundant osteomucin, less calcium
2. lamellar or adult bone
– collagen bundles arranged in parallel sheets
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Stages In Fracture Healing
(Bone Regeneration)
• stage 1-hematoma formation
– Day 1
• stage 2-inflammation
– hematoma attain a fusiform shape
• stage 3-demolition
– macrophages remove clot, fibrin, red cells, exudate &
debris
–fragments of bones by osteoclasts
• stage 4-formation of granulation tissue
– neovascularization, osteogenesis
– Day 2
• stage 5-woven bone& cartilage formation
– osteoblasts- produce both woven bone and cartilage
– callus formation, initially soft but will be hardened
– 3-6W definitive callus orderly bone with haversian
system
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• stage 6 – formation of lamellar bone
– provisional callus removed, osteoid formed and calcified
→ bone
– collagen fibers arranged in lamellar fashion
concentrically around blood vessels → haversian
system formed → definitive lamellar bone merges with
the last stage
• stage 7- remodeling
– osteoclastic removal & osteoblastic lay down of bone
material
– external callus removed
– 8+W
