Healing and repair

DR. ONG KC
DEPARTMENT OF BIOMEDICAL SCIENCE, FACULTY OF MEDICINE,
UNIVERSITY OF MALAYA

Healing

To restore the tissue to its normal (preinjury) state, a process termed

resolution.

Removal of debris associated with the inflammatory response is sufficient

to restore a tissue to its normal state if injury has been minor.

After removal of cellular debris, any necrotic parenchymal cells may be

replaced by new parenchymal cell of the same type in a process known
as regeneration.

When resolution & regeneration are not possible, necrotic cells are
replaced with collagen; this term organization, or repair by scar formation.

The process of healing depends on the type of inflammation, the extent of

tissue necrosis, the type of cells involved, & the regenerative ability of
damaged parenchymal cells.

Resolution

Ideal outcome of healing & occurs in acute inflammatory responses to

minor injuries or those with minimal parenchymal cell necrosis.

The tissue is in effect restored to the state it was in before injury occurred.

The fibrinous inflammatory exudate & tissue debris derived from the
inactivated injurious agent or necrotic host cells are liquefied by lysosomal
enzymes liberated by neutrophils & then removed by lymphatic.

Any remaining particulate debris is phagocytosed by macrophages that

enter the area during the late stages of the inflammatory response.

Regeneration

Replacement of lost parenchymal cells by division of adjacent surviving

parenchymal cells (regeneration) can also restore injured tissue to normal.

Whether regeneration occurs depends on:

1)

The regenerative capacity of involved cells (ie, their ability to divide).

2)

The number of surviving viable cells.

3)

The presence of a connective tissue framework that will provide a base

for restoration of normal tissue structure.

Before regeneration can occur, the necrotic cells must be removed.

This involves an acute inflammatory response, liquefaction of cells by

neutrophil enzymes, & removal of debris by lymphatics & macrophages.

The cells of the body can be divided into three groups labile, stable, &
permanent on the basis of their regenerative capacity.

Labile cells

Normally divide actively throughout life to replace cells that are being
continually lost from body.

Exp: basal epithelial stem cells & hematopoietic stem cells (bone marrow).

Mature differentiated cells in these particular tissues cannot divide; their

numbers are maintained by division of their parent labile cells.

Injury to a tissue containing labile parenchymal cells is followed by rapid

regeneration.

Regeneration occurs only when enough labile cells have been spared by
injury.

Stable cells

Have a long life span & are therefore characterized by a low rate of
division.

The parenchymal cells of most solid glandular organs (liver, pancreas) &
mesenchymal cells (fibroblast, endothelial cells) are examples of stable
cells.

Differentiated functional cells that only revert to a dividing mode at need.

Regeneration in tissues composed of stable cells requires

1) Enough viable tissues must remain to provide a source of parenchymal cells
for regeneration.
2) There is an intact connectivity tissue framework for an adequate
connective tissue framework.

Permanent cells

Have no capacity for mitotic division in postnatal life.

Exp: neurons in the central and peripheral nervous systems, cardiac

muscle cells.

Injury to permanent cells is always followed by scar formation.

No regeneration is possible.

Lost of permanent cells is therefore irreversible & if extensive, may result in

a permanent functional deficit.

Repair by scar formation

Mass of collagen that is the end result of repair by organization & fibrosis.

Repair by scar formation occurs:

When resolution fails to occur in an acute inflammatory process.

When there is ongoing tissue necrosis in chronic inflammation.

When parenchymal cell necrosis cannot be repaired by regeneration.

Preparation

The area of injury is prepared for scar formation by removal of

inflammatory exudate, including fibrin, blood & any necrotic tissue.

The debris is liquefied by lysosomal enzymes derived from neutrophils that

have been migrated to the area.

Liquefied material is removed by lymphatics; any particular residue is

removed by macrophage phagocytosis.

The preparatory process is similar to that occurring in resolution and

regeneration.

Ingrowth of granulation tissue

Granulation tissue forms & fills the injured area.

Necrotic debris is being removed.

Granulation tissue is highly vascularized connective tissue composed of

newly formed capillaries, proliferating fibroblasts, & residue inflammatory
cells.

Capillaries are derived by vascular proliferation in healthy tissue at

periphery of the involved injured area.

Fibroblasts migrate with capillaries to the injured area.

Proliferation of capillaries, fibroblasts, & other cells in the healing process is

controlled by a variety of growth-stimulatory or growth-inhibitory factors.

On gross examination, granulation tissue is soft & fleshy (appears pink &
granular) because of the numerous capillaries.

Microscopic examination shows the thin-walled capillaries lined by

endothelium & surrounded by fibroblasts.

Both endothelium & fibroblasts are metabolically very active, with large
nuclei & prominent nucleoli; mitotic figures may been seen.

Production of fibronectin

Glycoprotein that plays a key role in the formation of granulation tissue.

Present in large amounts during wound healing.

In the early phases, it is derived from plasma, but later it is synthesized by

fibroblasts, macrophages, & endothelial cells in granulation tissue.

Fibronectin is chemotactic for fibroblasts & promotes organization of

endothelial cells into capillary vessels.

Collagenization

Collagen is the major fibrillary protein of connective tissue.

It is synthesized by the fibroblasts in the form of a precursor, topocollagen

(procollagen).

Under the light microscope, collagen appears as a fibrillary mass that

stains pink with H&E stain.

Collagen fibers are flexible but inelastic & are responsible for much of the
tensile strength of scar tissue.

A. Types of collagen
Several types of collagen (types I-V) are recognized on the basic of
biochemical variations in the structure of their polypeptide chains.
Type

Primary cell source

Tissue distribution

Structure

Fibroblast (smooth muscle)

Skin, tendon, fascia, bone

fibrillary

II

Chondrocyte

Cartilage

Fibrillary

III

Fibroblast (smooth muscle)

Blood vessels, reticulin fibers in many

tissues

Fibrillary

IV

Endothelial cell

Basement membrane, glomerulus

Amorphous

Fibroblast (smooth muscle)

Basement membrane, blood vessels

Amorphous

B. Turnover of collagen

scar tissue is not inactive; continuous slow removal of collagen in the scar
by the enzyme collagenase is balanced by synthesis of new collagen by
fibroblasts.

Even long-established scars may be weaken if the normal activity of

fibroblast is impaired, as occurs in vitamin c deficiency.

Maturation

The collagen content of granulation tissue progressively increases with

time.

A young scar consists of granulation tissue & abundant collagen together

with a moderate number of capillaries & fibroblasts.

It appears pink on gross examination because of vascularity.

As the scar matures, the amount of collagen increases & the scar
becomes less cellular & vascular.

The mature scar is composed of an avascular, poorly cellular mass of

collagen & white on gross examination.

Contraction & Strengthening

Constitute the final phase of repair by scar formation.

Contraction decreases the size of the scar & enables the surviving cells of
the organ to function with maximal effectiveness.

Contraction begins early in the repair process & continues as the scar
matures.

Early contraction is due to active contraction of actomyosin filaments in

certain specialized myofibril-containing fibroblasts.

Later contraction is a property of the collagen molecular itself.

The tensile strength of a scar is dependent on the amount of collagen &

progressively increases, from about 10% of normal at the end of the first
week to about 80% of normal over several months.

The increasing tensile strength is due to an increase in the amount of the

collagen, change in the type of collagen, & increase in the convalent
linkages between collagen molecules.

The fully formed scar is a firm, inelastic, flexible structure.

Healing of skin wounds

Understanding the mechanisms involved in the healing of skin wounds

provides insight into healing in general.

The skin is composed of epidermis, which is made up of stratified

squamous epithelium-the basal germinative layer of which is composed of
collagen, blood vessels, & skin appendages such as hair follicles, sweet
glands, sebaceous glands, & apocrine glands.

Stable cells make up the dermal connective tissue.

Types of skin injury

Classified on the basic of the severity & nature of involvement:

A.

Abrasion

The mildest form of skin injury

Characterized by removal of the superficial part of the epidermis.

Underlying basal germinative layer of labile cells is intact.

Regenerates from below, & the integrity of the epithelium is restored with
no scarring.

Necrosis & inflammation are minimal.

B. Incision (cut) & laceration (tear):

Involve the full thickness of the skin (epidermis & dermis) but with minimal
loss of germinative cells.

If the skin edges are carefully apposed, as in sutured surgical incision, only
a small gap remains to be repaired.

C. Wounds with epidermal defects:

Severe injuries (eg. crush injuries, extensive lacerations, burn).

Characterized by denudation of large areas of the complete epidermis,

including the basal germinative cells, with variable necrosis of underlying
dermis.

Healing processes
A.

Healing by first intention

1.

Simple repair

The small gap in the epidermis & dermis fills with clotted blood, which forms
a scab & seal the skin opening within 24 h to prevent entry of infectious
agents into the wound.

The epidermis regenerates by rapid division of basal cells at the edges of

the wound.

These cells grow under the scab & reestablish continuity of the epidermis
within 48 h.

As the epidermal cells mature & start shedding the superficial keratinized
layers, the scab separates, usually at the end of the first week.

In the subjacent dermis, the wound fills with clotted blood & heals by scar
formation,

The small amount of clot & tissue debris is liquefied by neutrophilic enzymes
& removed by macrophage phagocytosis.

Neutrophils appear in the wound within 24 h, rapidly complete the

liquefaction process, & are usually replaced by macrophages by day 3.

The growth of fibroblasts & new vessels (granulation tissue) into the
prepared dermal gap begins within 48 h, & collagen can be
demonstrated there within 72 h after injury.

By day 5, dermal gap is filled with a small amount of collagenizing

granulation tissue.

The amount of collagen increases for about 4-6 weeks.

2. The scar:

The young scar that become visible when the scab separates from the skin
is initially pink because of the vascularity of the dermal granulation tissue.

Over the next few weeks the scar turn white as a result of decrease in the
number of blood vessels & an increased amount of collagen in the
maturing scar.

Eventually, the scar assumes normal skin color as the epidermis matures.

3. Tensile strength

In the first postoperative week, a surgical incision is artificially held together

by sutures, clips, or tape.

When the sutures are removed at the end of the first week, the tensile
strength of the young scar is only about 10% that of normal skin.

Skin strength increases to about 30-50% of normal skin by 4 weeks & to 80%
after several months.

B. Healing by second intention

Wound that fail to heal by first intention heal by second intention.

1.

Reasons for failure of the primary healing process

In lacerations characterized by inability to achieve apposition of wound

margins

When foreign material is present

When necrosis is extensive

When infection occurs

2. Process of secondary healing

The processes involved are essentially the same as those in healing by first
intention but take much longer time because of the more extensive
damage.

Infection is controlled by acute inflammation.

The fluid exudate & necrotic tissue are then removed by enzymatic
liquefaction, lymphatic drainage, & macrophage phagocytosis.

Surgical removed of dead tissue & foreign material from the wound greatly
aid this clearing process.

Granulation tissue then grows from the heathy tissue at the base of the
wound & displace the necrotic tissue toward the surface of the skin.

The epidermis regenerates from basal cells at the edges of the wound.

In large wounds, reepithelialization may take several weeks.

When epithelilization of the surface of the wound has occurred,

collagenization transforms the underlying granulation tissue to scar tissue.

The eventual size of the mature scar is much smaller than that of the
original wound as a result of contraction.

Skin appendages such as hail follicles & glands are regenerated if enough
residual cells remain to provide a source of proliferating cells.

In extensive skin wounds with total destruction of skin appendages, the

resulting dermal scar is typically devoid of these structures.

C. Causes of defective wound healing:

Surgeons must recognize the presence of any factors that impair healing
because such adverse factors increase the overall risk of surgery & may
even contraindicate surgery.

1.

Failure of collagen synthesis

Most common causes of defective wound healing & may result from
vitamin C, protein, or zinc deficiency.

2. Excessive collagen production

Synthesis of excessive amounts of collagen in wound healing results in

formation of abnormal nodular masses of collagen at the sites of skin injury.

3. Local factors
Foreign or necrotic tissue or blood
Infection
Abnormal blood supply
Decreased viability of cells
4. Diabetes mellitus

Result of deficient microcirculation & increased incidence of infection.

5. Excessive levels of adrenal corticosteroids

Interfere with neutrophil & macrophage function.