TISSUE HEALING AND REPAIR

LECTURE 3
SIAMEBWA OWEN
BIOMEDICAL SCIENTIST
(BSc. CBU-MCS-SOM)
• The inflammatory response sets into motion the process
of repair.

• It occurs by two types :

1. Regeneration
2. Healing by fibrosis
1- Regeneration:
• replace the damaged components
• return to a normal state;

2- Healing by fibrosis: scar formation.

• If the injured tissues are: incapable of complete restitution,

• repair occurs by laying down of connective (fibrous) tissue,
• Although the fibrous scar is not normal, it provides enough
structural stability

both regeneration and scar formation

contribute in varying degrees to the
ultimate repair.
Repair involves :
• 1- the proliferation of various
cells, and
• 2- close interactions between
cells and the extracellular
matrix (ECM).
Mechanisms of
tissue repair. In
this example,
injury to the
liver is repaired
by regeneration
if only the
hepatocytes
are damaged,
or by laying
down of fibrous
tissue if the
matrix is also
injured.
1- THE CONTROL OF
CELL PROLIFERATION
• several cell types proliferate during tissue repair.

• 1- the remnants of the injured tissue

• 2- vascular endothelial cells (to create new vessels)
• 3- fibroblasts

• The proliferation of these cell types is

driven by growth factors.

•
• labile tissues:
• 1- hematopoietic cells in the bone marrow
• 2- epithelia,

• Stable Tissues
• quiescent
• capable of proliferating in response to injury or loss of tissue mass.
• 1- the parenchyma of most solid tissues, such as liver, kidney, and pancreas.
• 2- endothelial cells, fibroblasts, and smooth muscle cells;

• Permanent Tissues
• neurons and cardiac muscle cells
• Skeletal muscle ???
• repair is dominated by scar formation.
 Stem Cells
• Stem cells are characterized by two important
properties:

1. self-renewal capacity and asymmetric replication.

2. Asymmetric replication of stem cells

GROWTH FACTORS
THE NATURE AND MECHANISMS OF ACTION
• There is a huge (and ever-increasing) list of known growth
factors.

• growth factors produced by :

• leukocytes
• parenchymal cells .
• the stromal (connective tissue)
 Growth Factors and Cytokines Involved in Regeneration and Wound Healing

Cytokine Symbol Source Functions

1- Epidermal EGF Activated Mitogenic for keratinocytes
growth factor macrophages, and fibroblasts; stimulates
salivary glands, keratinocyte migration and
keratinocytes, granulation tissue
and many other formation
cells
2- Transforming TGF-α Activated Similar to EGF; stimulates
growth factor α macrophages, T replication of hepatocytes
lymphocytes, and many epithelial cells
keratinocytes,
and many other
cells
3- HGF Mesenchymal Enhances
Hepatocyte cells proliferation of
growth epithelial and
factor endothelial cells, and
(scatter of hepatocytes;
factor) increases cell motility

4- Vascular VEGF Mesenchymal Increases vascular

endothelial cells permeability;
cell growth mitogenic for
factor endothelial cells (see
(isoforms A, text)
B, C, D)
5- Platelet-derived PDGF Platelets, Chemotactic for PMNs, macrophages,
growth factor macrophages, fibroblasts, and smooth muscle cells;
(isoforms A, B, C, D) endothelial activates PMNs, macrophages, and
cells, fibroblasts; mitogenic for fibroblasts,
keratinocytes, endothelial cells, and smooth muscles
smooth cells; stimulates production of MMPs,
muscle cells fibronectin, and HA; stimulates
angiogenesis and wound remodeling;
regulates integrin expression

6- Fibroblast growth FGF-1, Macrophages, Chemotactic for fibroblasts; mitogenic

factor 1 (acidic), -2 -2 mast cells, T for fibroblasts and keratinocytes;
(basic), and family lymphocytes, stimulates keratinocyte migration,
endothelial angiogenesis, wound contraction, and
cells, matrix deposition
fibroblasts,
and many
tissues
7- Transforming TGF-β Platelets, T Chemotactic for PMNs,
growth factor lymphocytes, macrophages, lymphocytes,
β(isoforms 1, 2, macrophages, fibroblasts, and smooth
3) endothelial cells, muscle cells; stimulates
keratinocytes, TIMP synthesis,
smooth muscle angiogenesis, and
cells, fibroblasts fibroplasia; inhibits
production of MMPs and
keratinocyte proliferation;
regulates integrin
expression and other
cytokines

8- Keratinocyte KGF Fibroblasts Stimulates keratinocyte

growth factor migration, proliferation, and
(FGF-7) differentiation
Patterns of
extracellular
signaling,
demonstrating
autocrine,
paracrine, and
endocrine
signaling
 EXTRACELLULAR
MATRIX (ECM) AND
CELL-MATRIX
INTERACTIONS
ECM occurs in two basic forms: interstitial
matrix and basement membrane
• Interstitial Matrix
• This is present in the spaces between cells
• synthesized by mesenchymal cells (e.g., fibroblasts)
• Its major constituents are :
 Fibrillar and nonfibrillar collagens,
 Fibronectin,
 Elastin,
 Proteoglycans,
 Hyaluronate, and
 Other elements
 Basement Membrane
• interstitial matrix in connective tissues becomes highly organized
around epithelial cells, endothelial cells, and smooth muscle cells,
forming the specialized basement membrane.

• Non-fibrillar type IV collagen and laminin

 The major components of the extracellular matrix (ECM), including collagens, proteoglycans, and adhesive
glycoproteins. Note that although there are some overlaps in their constituents, basement membrane and
interstitial ECM have different general compositions and architecture. Both epithelial and mesenchymal cells
(e.g., fibroblasts) interact with ECM via integrins. For the sake of simplification, many ECM components have
been left out (e.g., elastin, fibrillin, hyaluronan, syndecan).
 .
REPAIR BY
CONNECTIVE
TISSUE
• If tissue injury is severe or chronic,
• and results in damage to parenchymal cells
and epithelia as well as the stromal
framework,
• or if non-dividing cells are injured,
• replacement of the non-regenerated cells with
connective tissue, or by a combination of
regeneration of some cells and scar formation.
 granulation tissue
• within 24 hours of injury :
1. emigration of fibroblasts and
2. fibroblast and endothelial cell proliferation.

• 3 to 5 days:
• granulation tissue, is formed
• pink, soft, granular gross appearance
GRANULATION TISSUE
 Granulation tissue is characterized by
1. proliferation of fibroblasts
2. (angiogenesis),
3. a loose ECM
4. eventually resulting in the formation of a scar
 Repair by connective tissue deposition
consists of four sequential processes:
1. Formation of new blood vessels(angiogenesis)
2. Migration and proliferation of fibroblasts
3. Deposition of ECM (scar formation)
4. Maturation and reorganization of the fibrous
tissue (remodeling)
 1- Angiogenesis
Neovascularization: vessels send out capillary sprouts to produce
new vessels
steps
1. Vasodilation :nitric oxide
2. increased permeability by (VEGF)
3. Migration of endothelial cells
4. Proliferation of endothelial cells
5. Inhibition of endothelial cell proliferation and remodeling into
capillary tubes
6. Recruitment of periendothelial cells (pericytes for small
capillaries and smooth muscle cells for larger vessels) to form
the mature vessel
 Angiogenesis resulting from, A, the mobilization of bone marrow endothelial precursor cells (EPCs), and, B, from
preexisting vessels at the site of injury. EPCs can be mobilized from the bone marrow and migrate to a site of injury or
tumor growth. At these sites EPCs differentiate and form a mature network by linking with preexisting vessels. In
angiogenesis from preexisting vessels, endothelial cells from these vessels become motile and proliferate to form capillary
sprouts. Regardless of the mechanism of angiogenesis, vessel maturation requires the recruitment of pericytes and
smooth muscle cells to form the periendothelial layer

• .
2- Migration of Fibroblasts and ECM
Deposition (Scar Formation)
It occurs in two steps:
• (1) migration and proliferation of fibroblasts into
the site of injury

3- DEPOSITION OF ECM BY THESE CELLS.

• growth factors, :
• PDGF (platelet-derived growth factor)
• FGF-2 (fibroblast growth factor- 2)
• TGF-β. (tissue growth factor beta)
 4- Maturation and re-organization of
the fibrous tissue (remodeling)
• Occur by : avascularization
Skin wound healing
 introduction
• This process involves both :
• Epithelial regeneration and
• The formation of connective tissue scar
 Cutaneous wound healing has
4 main phases:
• (1) inflammation,

• (2) formation of granulation tissue,

• (3) ECM deposition and remodeling,

• (4)wounds contraction.
 ,

Healing by
First
Intention
 HEALING BY FIRST INTENTION
(PRIMARY UNION)
• It is the healing of
• a clean,
• uninfected incision
• approximated by surgical sutures
• epithelial regeneration predominates
• A small scar is formed,
• minimal wound contraction.
• The narrow incisional space first fills with:
• fibrin-clotted blood,
• which is rapidly invaded by granulation tissue
and covered by new epithelium
 Within 24 hours,
1. neutrophils are seen migrating toward the
fibrin clot.
2. Basal cells at the cut edge of the epidermis
begin to show increased mitotic activity.
 Within 24 to 48 hours
1. epithelial cells from both edges have begun to
migrate and proliferate
2. meet in the midline beneath the surface scab,
yielding a thin but continuous epithelial layer.
 By day 3,
1. neutrophils have been replaced by macrophages,
2. granulation tissue
3. Epithelial cell proliferation continues,
 By day 5

1. The epidermis recovers its normal thickness

 During the second week,
• The leukocyte infiltrate, edema, and increased
vascularity are substantially diminished.

• The long process of "blanching" begins,

accomplished by increasing collagen deposition
within the incisional scar and the regression of
vascular channels.
 The end of the first month
1. the scar comprises a cellular connective tissue
devoid of inflammatory cells and
2. covered by normal epidermis.
3. the dermal appendages destroyed are
permanently lost.
4. The tensile strength of the wound increases with
time,.
Healing by
Second
Intention
 second-intention healing
(secondary union)
• Large wound
• Dirty Infected
• Not approximated by surgical sutures
 . is more intense,
1. the inflammatory reaction

2. there is abundant development of granulation

tissue,

3. the wound contracts by the action of

myofibroblasts.

4. This is followed by accumulation of ECM and

formation of a large scar.
 Factors
affecting
wound healing
• 1- Infection: prolongs the inflammation
• 2- Nutrition: protein deficiency and vitamin C
deficiency, inhibits collagen synthesis
• 3- Steroids: anti-inflammatory (glucocorticoids)
 4- Mechanical variables
• Mechanical variables such as
• increased local pressure or
• foreign bodies such as
1. fragments of steel,
2. glass, or even bone
 5- Poor perfusion,
• Poor perfusion, due either
• to arteriosclerosis and diabetes or
• to obstructed venous drainage (e.g. in varicose
veins),
• also impairs healing
OUTCOMES OF SKIN WOUND HEALING
1. Complete restoration
2. Scar
3. Keloid: Excess collagen deposition in the skin
forming a raised scar