Tissue repair occurs through regeneration, replacing damaged cells with the same cell type, or fibrosis, replacing tissue with scar tissue. During fibrosis, blood vessels bleed and mast cells release histamine to promote vasodilation. A clot forms while macrophages remove damaged tissue. Fibroblasts migrate in and produce collagen, forming scar tissue through angiogenesis, fibroblast migration and proliferation, extracellular matrix deposition, and remodeling. Vascular endothelial growth factor is important for angiogenesis and permeability while transforming growth factor promotes fibroblast migration.

1. Fibrosis & Scarring

2. Tissue Repair (Healing)
• Regeneration of injured tissue
(replacement by normal cells of the same kind)
• Replacement by fibrous tissue
(fibrosis, scarring)
• Fibrosis : is the formation of excess fibrous
tissue in an organ or tissue in a reparative
process.

3. • When one suffers a cut to the skin, the
tissue is repaired by two methods:
regeneration and fibrosis.
• Regeneration replaces dead or damaged
cells with the same type of cell, thus
restoring normal function. Fibrosis
replaces damaged tissue with scar
tissue, which holds the tissue together
but does not restore normal function.

4. • Upon damage to the tissue, blood vessels
bleed, and the blood pools in the cut. Mast
cells release histamine, which promotes
vasodilation.
• Vasodilation causes more blood to seep
into the wound; however, it brings with it
antibodies to help prevent infection,
clotting proteins for clot formation.

5. • A clot forms in the tissue. The clot
gently binds together the edges of
the cut to keep and protect the
healthy tissue. The surface of the
clot forms a scab, while
macrophages beneath the scab
remove the damaged tissue.

6. • New blood capillaries grow into the wound.
fibroblasts migrate into the wound. The
macrophages remove the clot, and the fibroblasts
produce collagen fibers, which will form the scar
tissue. This is fibrosis.
• Eventually the scab loosens and falls off. As
fibrosis continues, capillaries withdraw from the
area.

7. Fibrosis progresses through four main stages:
• Angiogenesis
• Migration and proliferation of
fibroblasts
• Deposition of ECM
• Remodeling of ECM

8. Angiogenesis

9.  This process cannot be done without "Endothelial
precursor cells" (EPCs)
Vessels
EPCs are in two places
Bone marrow
network of capillary
plexus
Capillary sprouts

11. • Vascular endothelial growth factor (VEGF): is a
protein that promotes the growth of new blood
vessels by Angiogenesis process.
 Important factors to increase the process
• VEGF forms part of the mechanism that restores the
blood supply to cells and tissues.
• Hypoxia: is an inducing agent for VEGF.
• TGF(α-β ): Transforming growth factor.

12.  Receptors of VEGF:
• VEGFR-1 Most common in the
body.
• VEGFR -2  with the endothelial
cells.
• VEGFR -3  with lymphatic
endothelial cells.

13.  Functions of VEGF
• Promotes angiogenesis.
• Increases vascular permeability.
• Stimulates endothelial cell migration.
• Stimulates endothelial cell proliferation.

14. Migration and proliferation of
fibroblasts

15. • Granulation tissue contains numerous newly formed
blood vessels for transporting of new substances.
• As discussed previously,VEGF promotes angiogenesis
but is also responsible for the increase in vascular
permeability that leads to deposition of plasma proteins,
such as fibrinogen and plasma fibronectin in the ECM
and provides a provisional stroma for fibroblast and
endothelial cell growth.
• Migration of fibroblasts to the site of injury and its
proliferation are caused by multiple growth factors,
including TGF-β, and the cytokines The sources of these
growth factors and cytokines include platelets, is
inflammatory cells and activated endothelium.

16. • We also have Macrophages are important cellular
constituents , clearing extracellular debris, fibrin,
and other foreign material at the site of repair.
• This factor -> TGF-β, helps in migration of
fibroblasts.
• If the appropriate chemotactic stimuli are
present, mast cells, eosinophils, and lymphocytes
may also accumulate.

17. • TGF-β appears to be the most important because
of the effects on fibrous tissue deposition in
grannular tissue.
• TGF-β is produced by most of the cells in
granulation tissue and causes fibroblast migration
and proliferation.
• increased synthesis of collagen and fibronectin,
and decreased degradation of ECM by
metalloproteinases (discussed later).

18. • Increase the permeability of the vessels .
• Increase the deposition of plasma protein .
• Plasma protein will provide provisional
stroma for fibroblasts ingrowth
• Megretion of fibroblasts made under
several factors .
• Macrophages clear the extra cellular
debris, fibrin and some foreign materials
Summary

19. Deposition of ECM

20. Major Components of the ECM:
• Collagen
• Elastic fibers
• Proteoglycans
• Fibronectin
• Laminin
• Integrins

21. • As repair continues, the number of proliferating
endothelial cells and fibroblasts decreases.
• Fibroblasts progressively deposit increased
amounts of ECM. Fibrillar collagens form a
major portion of the connective tissue in repair
sites and are important for the development of
strength in healing wounds.
• collagen synthesis by fibroblasts begins within 3
to 5 days after injury and continues for several
weeks, depending on the size of wound.

22. • Net collagen accumulation, however, depends not
only on increased collagen synthesis but also on
decreased degradation. Ultimately, the
granulation tissue scaffolding is converted into a
scar composed of spindle-shaped fibroblasts,
dense collagen, fragments of elastic tissue, and
other ECM components. As the scar matures,
vascular regression continues, eventually
transforming the richly vascularized granulation
tissue into a pale, avascular scar.

23. Remodeling of ECM

24. • The replacement of granulation tissue with a scar
involves transitions in the composition of the
ECM.
• Some of the growth factors that stimulate
synthesis of collagen and other connective tissue
molecules also modulate the synthesis and
activation of metalloproteinases, enzymes that
degrade these ECM components.

25. • The balance between ECM synthesis and
degradation results in remodeling of the
connective tissue framework an important feature
of both chronic inflammation and wound repair.

26. Thank You

27. Presented by:
Ahmed Kamal Abdallah Hammad
Ahmed Reda Mohamed Edrees
Ahmed Alaa El-Din Mokhtar
Ahmed Emad Mofeed
Ahmed Emad Mounir

28. Reference : Tissue Repair
and
healing, ROBBINS
Chapter 3.