Session 13: Mechanisms of tissue healing and repair

Session 13: Mechanisms of tissue healing and repair

• Alex Simon (MD)

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Learning tasks

Learning tasks

At the end of this session, students are expected to be able to:

Explain processes of regeneration.

Explain processes of repair.

Explain cutaneous wound healing.

Identify factors impair wound healing.

Identify complications of wound healing.

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Healing processes

Healing processes

Healing involves two (2) distinct processes

Regeneration.

Repair.

At times, both the processes take place simultaneously.

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Regeneration

Regeneration

Occurs when some tissues are able to replace the damaged cells and essentially return to a normal state.

A wound in which only the lining epithelium is affected heals exclusively by regeneration.

Regeneration involves two (2) processes

Proliferation of residual (uninjured) cells that retain the capacity to divide.

Replacement from tissue stem cells.

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Regeneration cont…

Regeneration cont…

The capacity of a tissue for regeneration depends on

Proliferative ability.

Degree of damage to stromal framework.

On the type and severity of the damage.

Tissues formed of labile and stable cells can regenerate provided that stromal framework are intact.

It is the typical response to injury in the rapidly dividing epithelia of the skin and intestines, and some parenchymal organs, notably the liver.

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Role of regeneration in tissue repair

Role of regeneration in tissue repair

In labile tissues injured cells are rapidly replaced by proliferation of residual cells and differentiation of tissue stem cells provided the underlying basement membrane is intact.

The growth factors involved in these processes are not defined.

Loss of blood cells is corrected by proliferation of hematopoietic progenitors in the bone marrow and other tissues, driven by colony stimulating factors, which are produced in response to the reduced numbers of blood cells.

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Role of regeneration in tissue repair cont…

Role of regeneration in tissue repair cont…

Tissue regeneration can occur in parenchymal organs with stable cell populations, usually a limited process with the exception of the liver.

Pancreas, adrenal, thyroid, and lung have some regenerative capacity.

Response after surgical removal of one kidney.

The surgical removal of a kidney elicits in the contralateral kidney a compensatory response that consists of both hypertrophy and hyperplasia of proximal duct cells.

The mechanisms underlying this response are not understood.

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Role of regeneration in tissue repair cont…

Role of regeneration in tissue repair cont…

Response after surgical removal of liver tissue.

There is a proliferative response of the remaining hepatocytes (which are normally quiescent), and the subsequent replication of hepatic non parenchymal cells.

It is initiated by cytokines (e.g., TNF, IL-6) that prepare the cells for replication by stimulating the transition from G0 to G1 in the cell cycle.

Progression through the cell cycle is dependent on the activity of growth factors (HGF, TGF-α).

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Role of regeneration in tissue repair cont…

Role of regeneration in tissue repair cont…

Extensive regeneration or compensatory hyperplasia can occur only if the residual connective tissue framework is structurally intact, as after partial surgical resection.

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.

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Repair

Repair

Repair is the replacement of injured tissue by fibrous tissue (scar formation).

Fibrous scar cannot perform the function of lost parenchymal cells, rather provides enough structural stability.

Repair response takes place by participation of

Mesenchymal cells (consisting of connective tissue stem cells, fibrocytes and histiocytes).

Endothelial cells.

Macrophages.

Platelets.

Parenchymal cells of the injured organ.

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Repair cont…

Repair cont…

The term ‘‘fibrosis’’ is most often used to describe extensive deposition of collagen that occurs in the:

Lungs, liver, kidney, and other organs as a consequence of chronic inflammation.

Myocardium after extensive ischemic necrosis (infarction).

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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Repair cont…

Repair cont…

Repair occurs if

Tissue injury is severe or chronic (results in damage to parenchymal cells and epithelia as well as the connective tissue).

Non dividing cells are injured.

Under these conditions, repair occurs by

Replacement of the nonregenerated cells with connective tissue, leading to scar formation.

A combination of regeneration of some cells and scar formation.

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Repair cont…

Repair cont…

Occurs to the wounds that extend through the basement membrane to the connective tissue.

E.g. the dermis in the skin or the sub-mucosa in the gastrointestinal tract, lead to the formation of granulation tissue and eventual scarring.

Tissues containing terminally differentiated (permanent) cells such as neurons and skeletal muscle cells can not heal by regeneration.

Rather the lost permanent cells are replaced by formation of granulation tissue.

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Repair processes

Repair processes

Repair involves two (2) processes

Granulation tissue formation.

Contraction of wounds.

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Granulation tissue formation

Granulation tissue formation

Granular and pink appearance of the tissue.

Each granule has a proliferation of new small blood vessels and thin covering of fibroblasts and young collagen.

It is divided into three (3) phases

Phase of inflammation.

Phase of clearance.

Phase of ingrowth of granulation tissue.

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Phases of Granulation tissue formation

Phases of Granulation tissue formation

Phase of inflammation.

Following trauma, blood clots at the site of injury.

There is acute inflammatory response with exudation of plasma, neutrophils and some monocytes within 24 hours.

Phase of clearance.

Clear off the necrotic tissue, debris and red blood cells by

Proteolytic enzymes liberated from neutrophils.

Autolytic enzymes from dead tissues cells.

Phagocytic activity of macrophages.

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Granulation tissue formation phases cont…

Granulation tissue formation phases cont…

Phase of ingrowth of granulation tissue.

This phase consists of two (2) main processes

Angiogenesis (neovascularisation).

Fibrogenesis.

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Phase of ingrowth of granulation tissue

Phase of ingrowth of granulation tissue

Angiogenesis

A proliferation and formation of new small blood vessels in healing by repair.

From preexisting blood vessel or from stem cells.

Vascular proliferation starts 48 to 72 hours after injury and lasts for several days.

Most important growth factors contribute to angiogenesis are

Vascular Endothelial Growth Factor (VEGF) a

Fibroblast growth factor (FGF-2).

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Phase of ingrowth of granulation tissue

Phase of ingrowth of granulation tissue

Fibrogenesis

Cells responsible for fibrogenesis are fibroblasts.

Fibroblasts actively synthesize and secrete extra-cellular matrix components, including fibronectin, proteoglycans, and collagen types I and III.

The fibronectin and proteoglycans form the ‘scaffolding’ for rebuilding of the matrix.

Fibronectin binds to fibrin and acts as a chemotactic factor for the recruitment of more fibroblasts and macrophages.

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Phase of ingrowth of granulation tissue

Phase of ingrowth of granulation tissue

Fibrogenesis

The synthesis of collagen by fibroblasts begins within 24 hours of the injury although its deposition in the tissue is not apparent until 4 days.

By day 5, collagen type III is the predominant matrix protein being produced.

But by day 7 to 8, collagen type I is prominent, and it eventually becomes the major collagen of mature scar tissue.

Type I collagen is responsible for providing the tensile strength of the matrix in a scar.

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Wound granulation tissue

Wound granulation tissue

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Wound contraction

Wound contraction

It is a mechanical reduction in the size of the wound.

Begins 2 to 3 days after injury, up to 2 weeks.

During this period, the wound is reduced by approximately 70-80% of its original size.

Contracted wound results in rapid healing since lesser surface area of the injured tissue has to be replaced.

If contraction is prevented, healing is slow and a large ugly scar is formed.

Myofibroblasts are the responsible cells for wound contraction.

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Scar formation

Scar formation

The laying down of connective tissue in the scar occurs in two (2) steps:

Migration and proliferation of fibroblasts into the site of injury.

Deposition of ECM proteins produced by these cells.

Many growth factors are involved in these processes, including

Transforming Growth Factor β (TGF-β).

Platelet Derived Growth Factor (PDGF).

Fibroblast Growth Factor (FGF).

Also cytokines (Interleukins -1 and Interleukins -13) are involved in scar formation.

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Steps in scar formation (Repair by connective tissue deposition)

Steps in scar formation (Repair by connective tissue deposition)

It consists of sequential processes that follow the inflammatory response

Formation of new blood vessels (angiogenesis).

Migration and proliferation of fibroblasts (fibrogenesis).

Deposition of Extracellular matrix (connective tissue), which, together with abundant vessels and interspersed leukocytes, has a pink, granular appearance and hence is called granulation tissue.

Maturation and reorganization of the fibrous tissue (remodeling) to produce the stable fibrous scar.

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Remodelling of scar connective tissues

Remodelling of scar connective tissues

After its synthesis and deposition, the connective tissue in the scar continues to be modified and remodeled.

Thus, the outcome of the repair process is a balance between synthesis and degradation of ECM proteins.

The degradation of collagens and other ECM components is accomplished by a family of matrix metalloproteinases (MMPs), which are dependent on zinc ions for their activity.

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Healing of skin wounds (Cutaneous wound healing)

Healing of skin wounds (Cutaneous wound healing)

Cutaneous wound healing is a process that involves both epithelial regeneration (healing of the epidermis) and the formation of connective tissue scar (healing of the dermis).

Depending on the nature and size of the wound, the healing of skin wounds is said to occur by first or second intention.

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Healing of skin wounds (Cutaneous wound healing) cont…

Healing of skin wounds (Cutaneous wound healing) cont…

It is a complex and dynamic process of restoring cellular structures and tissue layers.

Wound healing process can be divided into three (3) distinct phases

Inflammatory phase.

Proliferative phase.

Remodelling phase.

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Types of wound healing

Types of wound healing

Primary wound healing.

Delayed primary wound healing.

Secondary wound healing.

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Primary wound healing(Primary intention/Primary union)

Primary wound healing(Primary intention/Primary union)

Characteristics of wounds which will heal by first intention

Clean.

Uninfected.

Surgically incised.

No much loss of cells and tissues.

Edges of wound are apposed by surgical sutures.

The incision causes only focal disruption of epithelial basement membrane continuity and death of relatively few epithelial and connective tissue cells.

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Primary wound healing(Primary intention/Primary union) cont…

Primary wound healing(Primary intention/Primary union) cont…

As a result, epithelial regeneration is the principal mechanism of healing.

A small scar is formed, but there is minimal wound contraction.

The narrow incisional space first fills with fibrin-clotted blood, which then is rapidly invaded by granulation tissue and covered by new epithelium.

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Delayed primary wound healing

Delayed primary wound healing

Occurs if the wound edges are not reapposed immediately.

By the fourth day, phagocytosis of contaminated tissues is well underway, and the processes of epithelialization, collagen deposition, and maturation are occurring.

Foreign materials are walled off by macrophages that changed into epithelioid cells, which are encircled by mononuclear leukocytes, forming granulomas.

Chronic inflammation can ensue, resulting in prominent scarring.

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Secondary wound healing(Secondary intention/Secondary union)

Secondary wound healing(Secondary intention/Secondary union)

When cell or tissue loss is more extensive, repair process is more complex and involves a combination of regeneration and scarring.

Seen in large wounds, at sites of abscess formation, ulceration, and ischemic necrosis (infarction) in parenchymal organs.

The inflammatory reaction is more intense.

There is development of abundant granulation tissue, with accumulation of ECM and formation of a large scar, followed by wound contraction mediated by the action of myofibroblasts.

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Sequence of events in wound healing

Sequence of events in wound healing

Initial phase (Hemostasis)

Following vasoconstriction, platelets adhere to damaged endothelium and discharge adenosine diphosphate (ADP), promoting thrombocyte clumping, which dams the wound.

Second phase (Inflammation)

Polymorphonuclear leukocytes (Neutrophils) engorge/aggregates at the wound.

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Sequence of events in wound healing cont…

Sequence of events in wound healing cont…

Third phase (Granulation)

This phase consists of subphases which are fibroplasia, matrix deposition, angiogenesis and re-epithelialization.

Fourth phase (Remodelling)

The wound undergoes constant alterations which can last for years after the initial injury occurred.

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Factors impair wound healing

Factors impair wound healing

LOCAL FACTORS.

Local infection.

Poor blood supply.

Excessive movement.

Presence of foreign body.

Ionizing radiation.

SYSTEMIC FACTORS.

Nutrition (lack of proteins, Vitamin C, Zinc).

Diabetes mellitus.

Corticosteroid therapy.

Haematological diseases.

Renal failure.

Systemic infection.

Tumour cachexia.

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Complications of wound healing

Complications of wound healing

Infection of wound.

Deficient scar formation.

Wound dehiscence & Incisional hernia.

Ulceration.

Excessive scar formation.

Hypertrophic scar.

Keloid formation.

Wound contractures (cicatrisation).

Implantation (epidermoid) cyst.

Pigmentation – Haemosiderin deposition.

Marjolin’s ulcer.

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Complications of wound healing cont…

Complications of wound healing cont…

Keloid

Wound contracture

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Key points

Key points

In regeneration, lost cells are replaced by same cells.

Repair involved replacement of a damaged area by a connective tissue scar.

Angiogenesis and fibrogenesis are the processes of granulation tissue growth.

Myofibroblasts are the responsible cells for wound contraction.

Cutaneous wounds can heal by primary union (first intention) or secondary union (second intention).

Complications of cutaneous wound healing include infection, dehiscence, keloids, contractures.

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Review questions

Review questions

List two (2) factors which determine ability of tissue to regenerate.

Mention two (2) process of involved in repair.

List five (5) differences between primary wound healing and secondary wound healing.

Explain sequence of events in wound healing.

Explain factors impair wound healing.

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References

References

Bezabeh M.; Tesfaye A.; Ergicho B. et al (2004): General pathology lecture notes for Health Sciences students. Ethiopia Public Health Training Initiative. Pg. 44-47, 49-56.

Kumar V. ; Abbas A. K. ; Aster J. C.;(2013): Robbins and Contran Pathologic Basis of Disease (9th Ed.) Elsevier Saunders, USA. Pg. 58, 65-72.

Mohan H.;(2010): Text book of Pathology (6th Ed.) Jaypee Brothers Medical Publishers, India. Pg. 165-171.

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