HEALING PROCESS;

REGENERATION
&
Repair

Dr.Yusra Abdulkhaliq
LG-5
16.9..2019
 Healing process
Definition: Is a response to a wound,
inflammation or necrosis trying to restore
tissue architecture & function after injury.
•The healing process starts as the injurious agents
& necrotic cells are cleared & the inflammation
resolves
•So there is always damage after inflammation that
should be followed by a healing process.
Healing occurs by 2 types of reactions:
1- Healing by Regeneration.
2- Healing by repair (Scar formation)
•In many types of injury, both processes
contribute together.
•The healing process involves the
proliferation of cells & interaction between
the cells & the extracellular matrix (ECM).
 Q?
• In wound healing, which type of
tissue undergoes regeneration &
which type of tissue undergoes
repair?
• Answer ----
 the cell cycle controls cell proliferation &
regeneration & is stimulated by growth factors (GF)

•G0 =Quiescent
•G1=PRE-synthetic, but
cell growth is taking place
•S= Cells which have
continuous “turnover”
•G2=PRE-mitotic
•M = (Mitotic)
 Cell types;
According to regenerative activity
Tissues are divided into 3 categories
according to the capacity of turnover of cells
through the cell cycle (proliferative capacity):
1-Labile cell; Continuously dividing cells.
these include hematopoietic cells in the bone
marrow, the surface epithelium of the skin, the
oral cavity, GIT, Genitourinary tract, the duct of
the pancreas (duct epithelia, which is cuboidal,
in general), salivary glands & the biliary tract.
2-Stable cell; Quiescent cells that are
normally capable of proliferation (which
includes most parenchymal organs), e.g., cells
of the liver, pancreas, kidney, endothelial cells,
fibroblasts, smooth muscle.
3-Permanent cell; Non-proliferative cells,
like neurons, skeletal muscles and cardiac
myocytes. Thus, injury to the brain & heart is
irreversible & healing always occurs by scar
formation.
 Regeneration
Definition: the growth of cells to replace the
normal, lost tissue.
•It’s a typical response to injury that is
mediated by proliferation of the
remnants/residual, uninjured tissue that
retains the capacity to divide in an attempt
to restore the normal structure and function
of the damaged tissue
•it’s dependent on the type of cell turnover
of the original tissue.
Regeneration in labile tissue:
•In the epithelia of the intestinal tract & skin,
injured cells are rapidly replaced by the
proliferation of residual cells provided that the
underlying basement membrane (BM) is
intact.
Regeneration in parenchymal organs with
stable cells, like the liver:
•Regeneration occurs only if the residual
connective tissue framework is intact, like
after partial surgical removal.
An example of regeneration by repair (of hepatic tissue)
Hepatic regeneration
the proliferation of hepatocytes
following partial hepatectomy:
A resection of up to 90% of the liver
can be corrected by proliferation of
the residual hepatocytes.
This is driven by the cytokines IL-6,
produced by Kupffer cells, &
hepatocyte growth factor (HGF)
produced by many cell types
(among other growth factors).
• TNF
• IL6
• HGF
• Healing by regeneration depends not only
on cell type, but also on the extent of the
injury or inflammation.
• E.g., if the entire tissue is damaged by
infection or inflammation, then
regeneration occurs by scarring, like in a
liver abscess
 Healing by tissue repair
• Occurs by connective tissue deposition, resulting in
fibrosis & a scar.
• There is no proliferation of parenchymal tissue in
repair.
The steps of repair: There are two major processes:
1. the inflammatory phase: PMN & monocytes that
transform to macrophages predominate to clear
necrotic debris.
2. Granulation tissue formation
3. Wound contraction.
 Sequential Steps in Scar Formation
The mechanisms are the same as those of scar
formation in the skin during tissue repair.
• Vascular endothelial cells (EC) proliferate to create new vessels
(angiogenesis) that provide the nutrients needed for repair.
• Fibroblasts proliferate. They are the source of the fibrous tissue
(scar) that fills defects that cannot be corrected by regeneration.
• Wound contraction: begins within 2-3 days & is completed by 2
weeks. The major contributors are myofibroblasts, which
contract & decrease the size of the wound.
Notes:
• Wound contraction is not the same as contracture (which is
pathologic)
• Inflammatory cells are also among the cells that proliferate
during healing.
• Myofibroblasts are cells with characteristics intermediate
between those of fibroblasts and smooth muscle cells.
 Granulation tissue
• It’s the hallmark of tissue repair
• It looks granular (due to the new capillaries), moist, and soft in
appearance & is edematous.
Note: These new vessels are leaky, allowing the passage of
proteins and red cells into extravascular spaces. Thus the
new granulation tissue are often edematous.
• Granulation tissue is fibro-vascular, proliferative tissue.
• Granulation tissue contains 2 phases: angiogenesis &
fibrogenesis.
1- Angiogenesis: The development of new blood vessels in adult
life from pre-existing blood vessels.
Granulation Tissue

Fibrovascular proliferation
1-ANGIOGENESIS: invades the
site of injury by the action of
growth factors, like epidermal
growth factor (EGF), vascular
endothelial growth factor
(VEGF), platelet derived growth
factor (PDGF), and fibroblast
growth factor (FGF)
2- FIBROGENESIS
• Granulation tissue is NOT a granuloma.
• A Granuloma is a specialized response to an
agent that cannot be eliminated or removed from
the body.
– cellular constituents: giant cells, epithelioid-appearing
macrophages, and lymphocytes.
Note: granulation tissue is present in chronic
inflammation
 Angiogenesis (Neovascularization)
Refers to the process of new blood vessel development
from endothelial precursor cells (EPCs; from the bone
marrow) & pre-existing vessels.
•GFs, especially VEGF, stimulate migration, proliferation &
increased permeability.
•Vasodilation occurs in response to nitric oxide (NO)
Angiogenesis is important in:
•The process of healing
•In the development of collateral circulation at the site of
ischemia
•In allowing tumors to increase in size
 The process of angiogenesis (steps):
The sprouting of new vessels from pre-existing ones:
1.Separation of pericytes & the breakdown of BM (via proteases,
such as collagenases and elastases from WBCs).
2.Migration of endothelial cells toward tissue injury
3.Proliferation of endothelial cells by FGFs
4.Remodeling into capillary tubes
5.Recruitment of pericytes.
6.Suppression of endothelial proliferation & migration
7.Deposition of the basement membrane material
Note: Pericytes are multi-functional mural cells of the
microcirculation that wrap around the endothelial cells that line
the capillaries and venules throughout the body.
• The process of fibrosis occurs by laying down
connective tissue and fibroblast proliferation
with extensive deposition of collagen.
• Fibrosis is one of the 3 possible outcomes of
inflammation and follows healing.
• It’s regulated by cytokines & GFs, including
PDGF, FGF­2, and TGF­β, released from cells
present at site of injury like macrophages, platelets
and endothelial cells.
• As the scar matures, there is progressive
vascular regression, which then transforms
the highly vascularized granulation tissue
that appears pink into a pale, largely
avascular scar.
• In contrast to regeneration, which involves
the restitution of tissue components, scar
formation is a response that appears to
”patch” rather than restore the tissue.
 Example of Fibrotic disorders
Fibrosis is more often used to refer to the abnormal
deposition of collagen that occurs in internal organs in
chronic diseases such as
•Liver cirrhosis
•Systemic sclerosis (scleroderma)
•Fibrosing diseases of the lung (e.g., Idiopathic
pulmonary fibrosis, pneumoconiosis and drug­s- or
radiation­-induced pulmonary fibrosis)
•End­-stage kidney disease (ESKD)
•Constrictive pericarditis
 The role of the ECM in tissue repair
Repair depends on GFs & the interaction between cells &
the ECM.
•The ECM is a complex of proteins forming a network
surrounding cells.
Its Functions:
– Maintain cell differentiation
– “Scaffolding”: Connective tissue holds all the body's
cells, organs and tissue together
– Establishing the microenvironment
– Storage of GFs
•An intact ECM is required for regeneration. If the ECM is
damaged, a scar forms.
 Component of (ECM)
1- Fibrous structural proteins: Collagen(s) &
Elastin.
2- Cell Adhesion Molecules (CAMs):
Adhesive glycoproteins connect the matrix to the
cell. They are of 4 types: immunoglobulins,
cadherins, integrins and selectins.
3- Watery gel, which permits lubrication, such as
Proteoglycans & Hyaluronic Acid
 The Extracellular Matrix
Is of two basic forms:
1) the interstitial matrix: Present between cells in
connective tissue & between epithelia & underlying
supportive vascular & smooth muscle structures. It is
synthesized by fibroblasts, forming an amorphous gel.
Constituents: fibrillar & non-fibrillar collagen,
fibronectin, elastin, etc.
2) The basement membrane: lies beneath the epithelial
cells & above the underlying mesenchymal cells, forming a
plate-like appearance.
Constituents: non-fibrillar type IV collagen & laminin.
Note: a basement membrane is also found beneath
endothelial cells in vessels.
 Collagen
• Is a major component of fibrous tissue,
basement membranes, bone, cartilage, the
cornea, and the heart valves.
• The product of fibroblasts is collagen
• It’s composed of 3 separate polypeptide chains
(forming a triple helix) with lateral cross-linking,
which provides strength to the healing process.
• It depends on vitamin C. This is why a person with
vitamin C deficiency has skeletal deformity, bleeds
easily because of a weak basement membrane &
suffers from poor wound healing.
Examples of Hereditary connective tissue disorders

Collagen Genetic defects: causes many diseases,

including:
Osteogenesis imperfecta
Ehlers-Danlos (E.D) with hyperelastic skin
Marfan’s syndrome
 Marfan’s syndrome (MFS)
• A genetic disorder that affects the body's connective
tissue. It’s caused by a defect in 2 structural proteins of
connective tissue (collagen & elastin) Manifested
clinically by:
• A combination of cardiovascular, musculo-skeletal,
ophthalmic & pulmonary manifestations.
• Progressive dilation of the aorta, accompanied by an
increased risk of aortic dissection
• The affected person having unusually long extremities,
with elongated tapering fingers and toes and joint
hypermobility.
Summary