WOUND HEALING

AND TISSUE REPAIR

GROUP 14
 Introduction
 Wound healing is the process whereby the skin or any injured organ repairs itself after injury.
 The main aim of wound healing is to prevent or limit further damage, to clean and seal the wound
against infection, to restore tissue strength and tissue function.

 Wound healing is complex and can be influenced by various factors such as age, nutrition, location
of the injury and underlying medical conditions i.e, diseases

 Wound healing can be divided into four overlapping processes namely;

• Maintenance of homeostasis
• An inflammatory response
• A proliferative phase
• Remodeling
 Cont….
1. Hemostasis
 This phase involves the formation of a blood clot to stop bleeding from the wound. Platelets
and cytokines form a clot to stop bleeding from the wound
2. Inflammation
 During this phase, white blood cells and other immune cells migrate to the wound site to
fight off any pathogens and remove debris
3. Proliferation
 In this phase, new blood vessels form and new cells grow to replace the damaged tissue
4. Remodeling
 This phase involves the maturation of the new tissue and the removal of any excess cells
 1. EXTRACELLULAR MATRIX AND CELL
MATRIX INTERACTION
 The extracellular matrix (ECM) is a complex network of proteins, glycoprotein and
polysaccharides that provides biochemical and structural support as well as signaling cues
for cells.
 The ECM includes collagen, fibronectin, elastin, laminin etc
 During wound healing, ECM plays a crucial role in providing a scaffold for cell migration
and proliferation, deposition of new matrix components as well as regulating cell behavior
and tissue formation + remodeling.

 The components of extracellular matrix may support cell migration necessary for wound
healing as well as triggering the inflammation process
The components of extracellular matrix
 The roles of ECM components
1. Collagens
Structure: formed as fibrils within the ECM (types I, II, III, V and XI)
Function:
Provide tensile strength
Influence cell processes eg. Adhesion and migration

2. Elastin
Structure: composed of single tropoelastin subunits cross-linked with an outer layer of fibrillin microfibrils making up
an elastic fibre.

Function:
closely linked to collagens
Allows tissues such as the skin and tendon to recover/recoil
3. Fibronectin
Structure: Arranged into a mesh of fibrils similar to collagen and is linked to cell surface receptors (integrins)
Function: found in basement membrane of the ECM
Plays a role in cell adhesion, embryonic development and the healing process following wound injury

4. Laminins
Structure: a glycoprotein with trimeric structure, has three different chains ie, alpha, beta and gamma which exist in
various genetically distinct forms.
Function: plays a role in several cell processes including differentiation and migration via their integrins

5. MMPs
Structure: occurs as zinc-dependent endopeptides
Function: capable of disintegrating the ECM, associated with many different processes including angiogenesis and
wound repair [are key modulators for tissue remodelling]
 ECM DEGRADATION
 The degradation of collagens and other ECM components is accomplished by a family of matrix
metalloproteinases (MMPs), so called because they are dependent on metal ions (e.g. zinc) for their
enzymatic activity.

 MMPs are produced by a variety of cell types (fibroblasts, macrophages, neutrophils, synovial cells,
and some epithelial cells), and their synthesis and secretion are regulated by growth factors,
cytokines, and other agents.

 The aim is to get free fibrillar collagens and elastin that contribute the major tensile strength and
viscoelasticity of the tissue as well as fibronectin, laminin and nidogen that are matrix connectors or
linking proteins

 In addition, activated collagenases can be rapidly inhibited by specific tissue inhibitors of

metalloproteinases (TIMPs), produced by most mesenchymal cells.
 Cont…
 The ECM interacts with the cell through various cell surface receptors, such as integrins, which
mediate cell adhesion, migration, proliferation, survival and signaling processes.
 Integrins, in this case for wound healing beta-1 integrin is necessary for keratinocyte migration in
vivo and in experimental wounds also the alpha-3 integrin regulates reepithelialisation.

 Matrikines are peptides derived from extracellular matrix degradation , released by partial
proteolysis which are able to modulate many cell activities that helps to control wound repair and
wound healing.
 The ECM also regulates the activity of growth factors, cytokines and enzymes that influence wound
healing
 This interaction is essential for coordinating the activities of different cell types involved in wound
healing, such as fibroblasts, endothelial cells and immune cells.
2. REPAIR BY FIRST AND SECOND
INTENTION
 REPAIR BY FIRST INTENTION
[REPAIR BY CELL & TISSUE REGENERATION]

 Repair by first intention (primary closure) occurs when the wound edges are
brought together and sutured, stapled/glued. This minimizes tissue loss and
scarring.
 Mostly occurs in parenchymal organs whose cells are 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.
 In this process, the wound is cleaned and closed with sutures or staples and the
healing occurs primarily through the formation of a thin scar. The inflammatory
response is minimal and the healing process is relatively rapid.
 Cont…
 Haemostasis: the action of platelets and cytokines forms a haematoma and causes
vasoconstriction, limiting blood loss at the affected area

 The close proximity of the wound edges allows for ease of clot formation and prevents
infection by forming a scab

 Inflammation: a cellular inflammatory response [by WBCs and cytokines] acts to

remove any cell debris and pathogens present

 Proliferation: cytokines released by inflammatory cells drive the proliferation of the

fibroblasts and the formation of granulation tissue
 Cont…
 Angiogenesis is promoted by the presence of growth mediators (VEGF
“VASCULAR ENDOTHELIAL GROWTH FACTOR”), allowing for further
maturation of the granulation tissue; the production of collagen by fibroblasts
allows for closure of the wound after around a week.
 Remodeling: collagen fibres are deposited within the wound to provide
strength in the region, with the fibroblasts subsequently undergoing apoptosis
 The end result of healing by primary intention is (in most cases) a complete
return to function, with minimal scarring and loss of skin appendages.
Tissue regeneration
 ANGIOGENESIS
Angiogenesis is the process of new blood vessel development from existing
vessels.
It involves sprouting of new vessels from existing ones, and consists of the
following steps
• Vasodilation in response to NO and increased permeability induced by VEGF
• Separation of pericytes from the abluminal surface and breakdown of the
basement membrane to allow formation of a vessel sprout
• Migration of endothelial cells toward the area of tissue injury
• Proliferation of endothelial cells just behind the leading front (“tip”) of
migrating cells
• Remodeling into capillary tubes
• Recruitment of periendothelial cells (pericytes for small capillaries and
smooth muscle cells for larger vessels) to form the mature vessel
• Suppression of endothelial proliferation and migration and deposition of the
basement membrane.
 REPAIR BY SECOND INTENTION
[REPAIR BY SCARRING]
 Repair by second intention (secondary closure) occurs when the wound edges are not close
together, such as in larger or contaminated wounds.

 The wound is left open to heal by granulation, contraction and epithelialization. This results in
more tissue loss and scarring also requires longer healing time.
 In this process, bottom up and the healing involves a more extensive inflammatory response,
granulation tissue formation and re epithelization. The resulting scar is often larger and more
prominent compared to repair by first intention.

NB:Repair occurs by deposition of connective tissue and scar formation if the injured tissue is not capable of
regeneration or if the structural framework is damaged and cannot support regeneration
 CONT…
 It occurs in the same four stages as primary intention:

 Haemostasis: Within minutes after injury, a hemostatic plug comprised of platelets is formed, which
stops bleeding and provides a scaffold for infiltrating inflammatory cells, a large fibrin mesh forms,
which fills the wound.

 Inflammation: an inflammatory response acts to remove any cell debris and pathogens present
 There is a larger amount of cell debris present, and the inflammatory reaction tends to be more intense
than in primary intention.
 Macrophages are the central cellular players in the repair process. M1 macrophages clear microbes and
necrotic tissue and promote inflammation in a positive feedback loop, and M2 macrophages produce
growth factors that stimulate the proliferation of many cell types in the next stage of repair.
 CONT…
 Proliferation: granulation tissue forms at the bottom of the wound

 It takes up to 10 days, several cell types, including epithelial cells, endothelial and other vascular cells, and
fibroblasts, proliferate and migrate to close the wound.
 Epithelial cells respond to locally produced growth factors and migrate over the wound to cover it.
 Endothelial and other vascular cells proliferate to form new blood vessels (angiogenesis).
 Fibroblasts proliferate and migrate into the site of injury and lay down collagen fibers that form the scar.

 The combination of proliferating fibroblasts, loose connective tissue, new blood vessels and scattered
chronic inflammatory cells, forms a type of tissue that is unique to healing wounds and is called
granulation tissue.
 Remodeling: the inflammatory response begins to resolve, and
wound contraction can occur.

 Myofibroblasts are vital cells in secondary intention. They are

modified smooth muscle cells that contain actin and myosin, and act
to contract the wound; decreasing the space between the dermal
edges. They also can deposit collagen for scar healing

 This process begins 2 to 3 weeks after injury and may continue for
months or years.
(A) Granulation tissue showing numerous blood vessels, edema, and a loose extracellular matrix containing occasional
inflammatory cells. Collagen is stained blue by the trichrome stain; minimal mature collagen can be seen at this
point.
(B) Trichrome stain of mature scar, showing dense collagen (stained blue) and scattered vascular channels.
 FIBROSIS
The term fibrosis is used to denote the excessive deposition of
collagen and other ECM components to replace the normal
tissue.
The major cytokine involved in fibrosis is TGF-β. The cell
death by necrosis or apoptosis and the production of ROS are
the important triggers.

The cells that produce collagen in response to TGF-β

stimulation may vary depending on the tissue. Ie,
myofibroblasts are the main source of collagen in lungs, but
stellate cells are the major collagen producers in liver cirrhosis.

Mechanisms of fibrosis. Persistent tissue injury leads to

chronic inflammation and loss of tissue architecture. Cytokines
produced by macrophages and other leukocytes stimulate the
migration and proliferation of fibroblasts and myofibroblasts
and the deposition of collagen and other extracellular matrix
proteins.
 EXCESSIVE SCARRING
 An uncommon complication from wound healing
(particularly in people with darker skin), are keloid
scars, whereby there is excessive collagen production,
leading to extensive scarring. [ Excessive production of
ECM ]
 Hypertrophic scars generally develop after thermal or
traumatic injury that involves the deep layers of the
dermis

 This can occur in both primary and secondary intention

healing.
 Clinical examples of excessive scarring and collagen
deposition.
(A) Hypertrophic scar.
(B) Keloid.
(C) Microscopic appearance of a keloid.
Note the thick connective tissue deposition in the
dermis.
THE DIFFERENCES BTN 1ST & 2ND INTENTION
 REFERENCES;
 Robbins and Cotran Pathologic Basis of Disease, 9 th edition
 BRS pathology 5th edition
 Internet
THANK YOU