Basic Pathology

Lecture 4Tissue Repairs and Healing

By Hermizan Halihanafiah

Introduction to Tissue Repair

• Tissue repair refers to the restoration of tissue structure and function after injury.

• It can be :1. Regeneration: replacement of injured parenchymal

cells with cells of the same type2. Connective tissue (fibrous tissue) replacement :

lead to the scar formation (fibrosis)

Tissue Repairs• Involve cell proliferation, differentiation and

apoptosis• Cell proliferation : • Cell Differentiation :• Cell apoptosis :

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• Several types of cells proliferate during tissue repair including remnants of injured parenchymal cells, vascular endothelial cells fibroblast.

• The proliferation of this cells driven by protein known as growth factors, hormones, cytokines

• It also mediates for cells growth. For examples IGF stimulates hypertrophy of skeletal muscles.

Cell Cycle

• Full regeneration or repair cannot occur without replacing cells lost (due to injury or disease) through the cell cycle

• Cell cycle consist of several steps– Synthesis (S)– Mitosis (M)– Gaps 1 (G1)

– Gaps 2 (G2)

– Gaps 0 (G0)

CELL CYCLE

PROLIFERATIVE CAPACITY OF TISSUE

• The capacity for regeneration varies with tissue and cell type

• Based on the ability of their parenchymal cells to undergo regeneration, body tissue can be divided into:– Labile tissue/cells– Stable tissue/cells– Permanent tissue/cells

Labile tissues• Cells continue to divide

and replicate throughout life, replacing injured/destroyed cells

• Examples: epithelium cells of skin, GIT, vagina etc

Stable Tissues• Cells that normally stop dividing when growth

ceases.• This cells remain in G0 phase in cell cycle, but

capable to undergo regeneration with appropriate stimulus.

• Examples : liver, kidney, smooth muscles cells, vascular endothelium.

Permanent Cells• Do not proliferate• Considered terminally

differentiated (highly specialize)

• Do not undergo mitotic division in postnatal life.

• Example: nerve cells, skeletal muscle cells, cardiac cells

• Once destroyed, it will replaced by fibrous connective tissue (scar formation)

Extracellular Matrix and Cell Matrix Interaction

• ECM – network of spaces surrounding the tissue cells

• 3 basic components of ECF– Fibrous structural

protein (collagen and elastin fiber)

– Water hydrated gel (proteoglycans and hyaluronic acid)

– Adhesive glycoprotein (fibronectin, laminin)

Healing by Connective Tissue Repair (Fibrosis Formation)

• Tissue repair highly associated with tissue regeneration – replacing the injured/destroyed cells with the same type cells

• Tissue regeneration only occur in labile and stable cells

• If the regeneration cant occur, healing process via fibrosis formation (scar formation)

• Fibrosis – extensive the deposition of collagen fiber (lungs, kidney, liver etc) as a results of chronic inflammation or injury

Fibrosis Formation

4 basic processes:• In growth of granulation tissue and Formation

of new blood vessels (angiogenesis)• Migration and proliferation of fibroblast and

Deposition of ECM• Maturation and reorganization of the fibrous

tissue (remodeling)

Ingrowths of granulation tissue• Formation of granulation tissue at the site of injury

area• Granulation tissue : highly vascularized tissue,

composed with newly formed capillaries, proliferating fibroblast and residual inflammatory cells.

• Vascular proliferation, fibroblast and other cells at the site of injury is controlled by growth stimulatory and inhibitory factors (most importantly Vascular Endothelial Cells Growth Factor & Fibroblast Growth Factor)

• Edamotous appearance – leaking of new blood vessels

Migration and proliferation of fibroblast anddeposition of ECM• Migration and proliferation of fibroblast at the

injury site driven by platelet derived growth factor (PDGF)

• Collagen fiber synthesis by fibroblast, is critical to the development of strength in a healing site (days 3 – 5) and may continue to several weeks

• Granulation tissue ------- scar tissue

Maturation and reorganization of the fibroustissue (remodeling)• the collagen content of granulation tissue

progressively increase in time• A young scar tissue consist of granulation

tissues, collagen fiber and moderate number of capillaries and fibroblast

• As the scar matures, the amount of collagen increases and the scar become less cellular and vascular.

Healing of Epithelium Tissue (Wound Healing)

• Involve epithelial cells regeneration and scar formation• Wound healing mechanism can be divided into two ways:

1. Healing by first intention (primary union)• Simple repair, clean incised wound and laceration in

which the edges of the wound are in close apposition.2. Healing by second intention (secondary union)• When the wound can’t be heals by 1st intention• Large wound or Tissue lost more extensive• Maybe due to infarction, inflammatory ulceration,

abscess formation, infections.

Wound Healing Mechanism

• Cutaneous wound healing commonly can be divided into three phases1. Inflammatory phase 2. Proliferative phase3. Remodeling / maturational phase

Inflammatory Phase• Crucial period – it prepares suitable environment for

tissue healing• Hemostasis : constriction of injured blood vessels,

blood clot formation with platelet aggregation• Then vasodilatation, and increase it’s permeability

allowing blood plasma and its component to leak into injured area.

• Then follows by cellular phase ; migration of phagocytic WBC (neutrophil and macrophage)

• Macrophage : release of growth factor – promote epithelial cell growth, angiogenesis and attraction of fibroblast

Proliferative Phase• The major cells during this phase : fibroblast• Synthesizes and secretes collagen and other

intercellular elements that needed for wound healing’

• Fibroblast also produce growth factor (FGF) that needed for angiogenesis, wound contraction and matrix deposition.

• Fibroblast and vascular epithelial cells begin proliferating and form granulation tissue that serves as the foundation for scar tissue development.

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• The final component of proliferation phase is epithelialization, which is the migration, proliferation and differentiation of epithelial cells and the wound edges.

Remodeling Phase• Begins approximately 3 weeks after injury and continue

for 6 months or maybe longer• There is continued remodeling of scar tissue by

synthesis of collagen by fibroblast and lysis by collagenase enzyme.

• As a results the architecture of the scar become reoriented to increase the tensile strength of the wound

• An abnormality in healing by scar tissue repair is keloid formation

• Keloid are benign tumorlike masses caused by excess production of scar tissue (excessive collagen).

Factor That Affect Wound Healing• Failure of collagen synthesis• Excessive collagen production – keloid formation• Local factors : – Foreign or necrotic tissue or blood– Infections– Abnormal blood supply (ischemic)– Decrease viability of cells – irradiation of the

tissue/antimitotic drugs• Diabetes mellitus – poor microcirculation / infections

incidence• Excessive levels of adrenal corticosteroid (depress

WBC function)

• The repair of the bone fracture involves the following steps:

1. Formation of fracture hematoma

2. Fibrocartilaginous callus formation

3. Bony callus formation

4. Bone remodelling

Bone Healing/repairs

1.Formation of fracture hematoma

• Haemorrhage within the bone from ruptured blood vessels and forming blood clot - - - - - -haematoma

• Haematoma facilitates repair and tissue healing

• Forms 6-8 hours after injury

2. Fibrocartilaginous callus formation (soft tissue callus)

• Formation of collagen fiber by fibroblast and fibrocartilage by chondroblast

• Lead to formation of fibrocartilaginous callus and become bridge of the broken area

3. Bony callus formation

• Ossification --- conversation of fibrocartilaginous callus into bony callus

• Osteogenic cells developed into osteoblast and then developed into spongy bone trabeculae

• Begins 3 – 4 weeks after injury

4. Bone remodelling

• Final phase• Remodeling of the bony

callus• Compact bone replace

by spongy bone at the periphery site

• Osteoclast – resorps the fragment of broken bone

Factors That Influence Bone Healing

1. Malunion • Healing with deformity at fracture site• Inadequate reduction or malalignment of

fracture at time of mobilization

2. Delayed union• Failure to unite within normal period• Contributing factors:– Large displaced fracture– Inadequate immobilization– Large hematoma– Infection at fracture site– Excessive lost of bone– Inadequate circulation

3. Nonunion• Failure to produce union / cessation of bone

repairs process• Contributing factors:– Inadequate reduction– Mobility at fracture site– Severe trauma– Soft tissue between bone fragment– Infection– Extensive loss of bone– Inadequate circulation– Malignancy– Bone necrosis