College of Health and sports Sciences

CHS
LFS – 319 General pathology

Tissue repair
 Objectives:
At the end of the chapter, the student must be able to:

1. Describe repair mechanisms by regeneration and scar formation.

2. Identify the factors that impair tissue repair.

3. Highlight some clinical examples of abnormal wound healing and scarring.

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 INTRODUCTION:
• Tissue repair is the body response to tissue injury and represents an attempt
to maintain normal body structure and function.

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 Types of tissue repair:
1. Regeneration: by proliferation of residual (uninjured)
cells and maturation of tissue stem cells. The injured
cells are replaced with cells of the same type leaving no
or minimal residual trace of previous injury.

2. Scar formation: If the injured tissues are incapable of

complete regeneration, or if the supporting structures
are severely damaged, repair occurs by connective
(fibrous) tissue, which leaves a permanent scar.
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 Cell Proliferation: Signals and Control Mechanisms

▪ Several cell types proliferate during tissue repair, that includes:

✓Remnants of the injured tissue (which attempt to restore normal structure)

✓Vascular endothelial cells (to create new vessels to provide nutrients needed for repair)

✓Fibroblasts (the source of the fibrous tissue that forms the scar to fill defects).

▪ Body cells are divided into three types according to their ability to undergo regeneration:

1. Labile cells
2. Stable cells
3. Permanent cells.
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 Labile cells:
▪ Labile cells are those that continue to divide and replicate throughout life or as
long as the pool of stem cells is preserved , replacing cells that are continually
being destroyed.

▪ For example: the surface epithelial cells of the skin, oral cavity, vagina, and
cervix, uterus, the columnar epithelium of the gastrointestinal tract, and bone
marrow cells.

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 Stable cells:
▪ Stable cells are those that normally stop dividing when growth ceases.

▪ However, these cells are capable of undergoing regeneration in response to

injury or loss of tissue mass. cells that multiply only when needed.

▪ Examples: the parenchymal cells of the liver and kidney, smooth muscle cells,
and vascular endothelial cells.

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Permanent cells:

▪ Consist of non-proliferative cells.

▪ These cells do not normally regenerate; once destroyed, they are replaced with
fibrous scar tissue that lacks the functional characteristics of the destroyed tissue

▪ Examples: nerve cells, skeletal muscle cells, and cardiac muscle cells.

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 Signals of cell proliferation:
▪ Cell proliferation is driven by signals provided by:

1. Growth factors:

• Typically produced by cells near the site of damage, in response to injury.

• The most important source is macrophages.

• Growth factors activate signalling pathways that induce changes in gene expression and
support the biosynthesis of molecules and organelles that are needed for cell division.

2. Integrins bind to Extracellular matrix (ECM) proteins, and signals from the integrins can
also stimulate cell proliferation. 9
1. Tissue repair by Regeneration:
• The degree of tissue regeneration varies according to the types of tissues and with the
severity of injury.

• In epithelia of the intestinal tract and skin, injured cells are rapidly replaced by proliferation
of residual cells and differentiation of cells derived from tissue stem cells, providing the
underlying basement membrane is intact.

• The residual epithelial cells produce the growth factors involved in these processes. The
newly generated cells migrate to fill the defect created by the injury, and tissue integrity is
restored.
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• Parenchymal organs; Tissue regeneration can occur in the cells capable of proliferation, but
with the exception of the liver, this is usually a limited process.

• Pancreas, adrenal, thyroid, and lung have some regenerative capacity. The surgical removal
of a kidney elicits in the remaining kidney a compensatory response that consists of both
hypertrophy and hyperplasia under the effect of local production of growth factors and

interactions of cells with the ECM.

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Liver Regeneration
• The human liver has a remarkable capacity to regenerate, as demonstrated by its growth

after partial hepatectomy, (e.g., for tumor resection or liver donation).

• Restoration of normal tissue architecture can occur only if the residual tissue is structurally

intact, for example after partial surgical resection of the liver.

• By contrast, if the entire tissue is damaged by infection or inflammation, regeneration is

incomplete and is accompanied by scarring. For example, extensive destruction of the liver

with collapse of the reticulin framework, as occurs in a liver abscess, leads to scar

formation even though the remaining liver cells have the capacity to regenerate 12
• Regeneration of the liver occurs by two major mechanisms:

1. Proliferation of hepatocytes following partial hepatectomy.

2. Liver regeneration from progenitor stem cells.

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 2. Tissue Repair by Scar formation
▪ 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.

▪ Scarring may happen if the tissue injury is severe or chronic and results in damage to
parenchymal cells and epithelia as well as to the connective tissue framework, or if
nondividing cells are injured.

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 Steps of Scar Formation

1. Inflammatory phase:

The inflammatory phase begins at the time of injury and

includes:

a. Formation of a blood clot

b. Migration of phagocytic white blood cells into the

wound site that is responsible for phagocytosis and
production of growth factors for the proliferative
phase. 15
2. Proliferative phase:

• Includes building of new tissue called granulation tissue to

fill the wound space:

1. Fibroblasts proliferate and migrate to the site of injury

and lay down collagen fibres that form the scar.

2. Endothelial and other vascular cells proliferate to form

new blood vessels, a process known as angiogenesis.

3. Finally, epithelial cells at the wound edges proliferate to

form a new surface layer over the wound to cover it.

• These processes are arranged by locally produced cytokines

and growth factors, including PDGF, FGF-2, and
Transforming growth factor beta (TGF-β).
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3. Remodeling phase:

• This phase includes a decrease in vascularity and remodelling of scar tissue by

simultaneous synthesis of collagen by fibroblasts and lysis by collagenase enzymes.

• As a result of these two processes, the scar increased its tensile strength, and shrinks
so it is less visible.

• Remodeling of the scar tissue is achieved by the balance between:

➢ The degradation of collagens and other ECM components matrix metalloproteinases (MMPs) (e.g.
collagenases, gelatinases).

➢ Tissue inhibitors of metalloproteinases (TIMPs), produced by most mesenchymal cells.

• Thus, a balance of MMPs and TIMPs regulates the size and nature of the scar. 17
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 Healing of skin wounds

Can be classified into:

1. Healing by first intention (primary union): Referring to

epithelial regeneration with minimal scarring, as in well-
apposed surgical incisions.

2. Healing by second intention (secondary union):

Referring to larger wounds that heal by a combination of
regeneration and scarring. 19
Factors That Impair Tissue Repair:
1. Infection it prolongs inflammation and potentially increases the local tissue injury.

2. Impaired inflammatory and immune response: e.g. immunosuppression, Diabetes

3. Nutritional status protein malnutrition and vitamin C deficiency can inhibit collagen synthesis
and retard healing.

4. Poor perfusion (low blood or oxygen supply)

5. Glucocorticoids (steroids) because they inhibit TGF-β production and diminish fibrosis.

6. Mechanical factors: e.g., increased local pressure or torsion may cause wounds to pull apart
(dehisce).

7. Foreign bodies
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8. The type, extent, and site of tissue injury
 Abnormal wound healing and scarring

Deficient scar Excessive Contractures

formation scarring formation

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 1. Deficient scar formation:
a. Venous leg ulcers: as a result of chronic venous hypertension, in severe varicose veins.

These ulcers fail to heal because of poor delivery of oxygen to the site of the ulcer.

b. Arterial ulcers: develop due to ischemia e.g., atherosclerosis of peripheral arteries.

c. Pressure sores: caused by prolonged compression of tissues against a bone, for example,

in bedridden. The lesions are caused by mechanical pressure and local ischemia

d. Diabetic ulcers: due to small vessel disease causing ischemia, neuropathy, systemic

metabolic abnormalities, and secondary infections 22

(A) Venous leg ulcer; (B) arterial ulcer, with more extensive tissue necrosis; (C) diabetic ulcer; and (D) pressure sore.

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 2. Excessive Scarring:
• Due to excessive formation of the components of the repair process

1. Hypertrophic scars:

• raised scar due to accumulation of excessive collagen.

• Often grow rapidly, but they tend to regress over several months.

• Common after thermal or traumatic injury that involves the deep layers of the

dermis.

2. Keloids:

• The scar tissue grows beyond the boundaries of the wound and does not

regress. Certain individuals seem to be predisposed to keloid formation,

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particularly African.
3. Exuberant granulation:

• Characterized by the formation of

excessive amounts of granulation
tissue, which protrudes above the level
of the surrounding skin and blocks re-
epithelialization .

• Excessive granulation must be removed

by cautery or surgical excision to permit
restoration of epithelial continuity. 25
3. Wound contraction :
• An exaggeration of this process gives rise to

contracture and results in deformities of the

wound and the surrounding tissues.

• Common on the palms, the soles, and the anterior

aspect of the thorax.

• Commonly seen after serious burns and can

compromise the movement of joints.

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Fibrosis in Parenchymal Organs:
• Fibrosis is a pathologic process induced by persistent injurious
stimuli such as chronic infections and immunologic reactions and is typically
associated with loss of tissue.

• It may be responsible for substantial organ dysfunction and even organ failure.

• such as liver cirrhosis, systemic sclerosis (scleroderma), pulmonary fibrosis, end-

stage kidney disease, and constrictive pericarditis.

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1. Regeneration: a. The scar tissue grows beyond the boundaries of
the wound and does not regress.

2. Stable cells b. Growth factors and integrins

3. Keloid
4. Healing by first intention (primary
union)
5. Signals for cell proliferation
c. caused by prolonged compression of tissues
against a bone, for example, in bedridden.
d. Proliferation of residual (uninjured) cells to
replace the injured cells with cells of the same
type, sometimes leaving no residual trace of
previous injury.
e. stop dividing when growth ceases but can
undergo regeneration in response to injury.

6. Pressure sores f. Epithelial regeneration with minimal scarring, as

in well-apposed surgical incisions.
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 References:

• Robbins basic pathology, by Vinay Kumar, Abul K. Abbas and Jon C. Aster.
Elsevier; 10 edition (March 8, 2017)

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