Healing and repair

1. HEALING BY REPAIR, SCAR FORMATION AND FIBROSIS
Dr. Suhad Faisal Hatem

2. Healing is the ability to repair the damage caused by injurious agents & inflammation.Its
occurs by Regeneration of injured tissue and Repair by connective tissue (healing by
scaring).Usually tissue repairinvolves both processesand associated with acute
inflammatory diseases.
The healing process involves two distinct processes:
1-Regeneration: complete reinstitution of the damaged components of the affected tissueby
tissues similar in type, the tissueessentially returns to a normal state(ex. Superficial wounds ,
Remove half of the liver: it will grow back)
2-Repair (healing by scaring):the replacement of lost tissue bygranulation tissue
whichmatures to form scar tissue .Itsa process characterized by laying down of new
connective (fibrous) tissue that results inscarformation(ex. Deep wounds healingin the skin),
This mode occurs when:
1. The injured tissues are incapable of complete regeneration, or
2. The supporting structures of the tissue are severely damagedresulting fibrous scar and
make granulation tissue.

4. scar
is most often used in connection to wound healing in the skin, but
is also used to describe the replacement of parenchymal cells in
any tissue by collagen, as in the heart after Myocardial infarction.
Repair by connective tissue deposition consists of four equential
processes:
1-inflammation
2-Formation of new blood vessels (angiogenesis)
3-Migration and proliferation of fibroblasts
4-Deposition of ECM,synthesis of collagen (scar formation)
5-Maturation and reorganization of the fibrous tissue (remodeling)

5. Repair involves
a. The proliferation of various cells e.g.(Vascular endothelial cells,Fibroblastssource
of the fibrous tissue).
b. Close interactions between cells and the extracellular matrix (ECM).
The proliferation of the above cell types is driven by:
1.Growth factors: including Transforming Growth Factor β (TGF-β), Platelet-
derived growth factor(PDGF) and Fibroblast Growth Factor (FGF).2. Hormones3.
Cytokines(IL-1 & TNF).4. Signals from the ECM .

6. EXTRACELLULAR MATRIX (ECM) AND CELL-MATRIX INTERACTIONS
Tissue repair depends not only on growth factor activity but also on interactions between cells
and ECMcomponents.
The ECM is composed of three groups of macromolecules:1-fibrous structural proteins, such as
collagens and elastins that provide tensile strength and recoil; 2-adhesive glycoproteins that
connect the matrix elements to one another and to cells; 3- proteoglycans and hyaluronan that
provide flexibility andLubrication Of ECM:
1-Interstitial matrix, which is present in the spaces between mesenchymal (connective tissue)
cells, andbetween epithelium and supportive vascular and smooth muscle structures; it is
synthesized by themesenchymal cells (e.g., fibroblasts). Its major constituents are fibrillar and
nonfibrillar collagens, as well asfibronectin, elastin, proteoglycans, hyaluronate, and other
elements.
2-Basement membrane, which lies under the epithelium and is synthesized by overlying
epithelium andunderlying mesenchymal cells; it tends to form a platelike. Its major constituents
areamorphous nonfibrillar type IV collagen and laminin.

8. The sequence of events in Wound Healing
1-Formation of Blood Clot: Wounding causes the rapid activation of
coagulation pathways, which results in the formation of a blood clot on the
wound surface. In addition to entrapped red cells, the clot contains fibrin,
fibronectin,and complement components. The clot serves to stop bleedingand
also as a scaffold for migrating cells, which are attracted by growth factors,
cytokines and chemokines released into the area.
2-Formation of Granulation Tissue:Fibroblasts and vascularendothelial cells
proliferate in the first 24 to 72 hours ofthe repair process to form a specialized
type of tissue calledgranulation tissue, which is a hallmark of tissue repair.
Theterm derives from its pink, soft, granular appearance on the surface of
wounds. Its characteristic histologic feature is the presence of new small blood
vessels (angiogenesis) and the proliferationof fibroblasts. These new vessels
are leaky,allowing the passage of plasma proteins and fluid into the
extravascular space.The same growth factors that regulate fibroblast
proliferation also participate instimulating ECM synthesis.By 5 to 7 days,
granulation tissue fills the wound area andneovascularization is maximal.

9. 3-Cell Proliferation and Collagen Deposition: Neutrophils are largely
replaced by macrophages by 48 to 96 hours. Macrophages are key cellular
constituents of tissue repair, clearing extracellular debris, fibrin, and other
foreign material at the site of repair, and promoting angiogenesis and ECM
deposition.
4-Scar Formation: The leukocytic infiltrate, edema, andincreased vascularity
largely disappear during the secondweek. Blanching begins, accomplished by
the increased accumulationof collagen within the wound area and regression of
vascular channels. Ultimately, the original granulation tissue is converted into a
pale, avascular scar, composed of spindle-shaped fibroblasts, dense collagen,
fragments of elastic tissue, and other ECM components.By the end of the first
month, the scar is made up of acellular connective tissue devoid of
inflammatory infiltrate, covered by intact epidermis.

10. FIGURE:A, Granulation tissue showing numerous blood vessels, edema, and a loose ECM containing occasional
inflammatory cells. Collagen is stained blue by the trichrome stain.

11. Connective Tissue Remodeling
The replacement of granulation tissue with a scar involves changes in
the composition of the ECM. The balance between ECM synthesis
and degradation results in remodeling of the connective tissue
framework – an important feature of tissue repair. 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.Degradation of collagen and other ECM proteins is
achieved by matrix metalloproteinases (MMPs) enzymes
.

12. Fibrosis
fibrosisis used more broadly to denote is the excessive deposition of collagen and
other ECM components in a tissue. As already mentioned, the terms scar and
fibrosis are used interchangeably, but fibrosis most often indicates the deposition
of collagen in chronic inflammatory diseases (cirrhosis, chronic
pancreatitis,pulmonary fibrosis). The basic mechanisms that occur in the
development of fibrosis associated with chronic inflammatory diseases are
generally similar to the mechanisms of skin wound healing. However, in contrast
to the short-lived stimulus that triggers the orderly steps of wound healing in the
skin, the injurious stimulus caused by infections, autoimmune reactions, trauma,
and other types of tissue injury persists in chronic diseases, causing organ
dysfunction and often organ failure.

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