TISSUE REPAIR: By Connective tissue deposition. Angiogenesis & Tissue remodeling

TISSUE REPAIR BY CONNECTIVE TISSUE DEPOSITION ( SCARRING)

If repair cannot be accomplished by regeneration alone, then Replacement of the injured cells with connective tissue takes places which “patches” the tissue and this is referred to as SCAR.

The various steps involved in the formation of scar is as illustrated below

The predominant cells involved in release of growth factors for the deposition of connective tissue are macrophages. These are alternatively(M2) activated macrophages which are anti inflmmatory and help in tissue repair and fibrosis as illustrated below

ANGIOGENESIS and Formation of granulation tissue

Angiogenesis is Process of new blood vessel development FROM EXISTING VESSELS in contrast to vasculogenesis which is Process of new blood vessel development, de novo in the embryo from the stem cells which are mesodermal in origin.
The steps involved in angiogenesis is as below
1. vasodilataion and increased vascular permeabilitity of the vessels near the site of injury. This is brought about by nitric oxide.
2. Separation of pericytes brought about by nitric oxide.
3. vascular endothelial growth factor released by macrophages/paltelets/leukocytes diffuses through the basement membrane thereby conversion of endothelial cell into a specalised cells with filopodia called as TIP cells.
4&5. the tipcells releases chemicals which neutralises the basement membrane, thereby resulting in the formation of vascular sprout. the cells behind the tip cells are called as stalk cells.
6. there is propogation of tip cell towards the site of injury along with endothelial cell proliferation behind the tip cell resulting in enlogation of the stalk.This is brought about by VEGF-AFibroblast growth factors (FGF-2).
The elongation is also assisted by various matrix metalloproteinases which cleaves the extracellular matrix.
7&8. vacuoles develop in the endothelial cells resultig in fusion and remodelling to form a tubular structurem which are now immature capillary tubes ( without the basement membrane)
9 & 10. fusion of tip cells with adjacent vascular sprout resulting in anastomosis of vessels.
11. once the inflammation is diminished, the endothelial cell proliferation stops andthere is deposition of basement membrane and recruitment of pericytes resulting in the formation of mature capillary tubes.

The steps involved in angiogenisis is illustrated in the image below

simultaneously, connective tissue deposition takes place by Migration & Proliferation of FIBROBLASTS into the site of injury and Deposition of matrix proteins produced by these cells.
SO teh outcome is the formation of GRANULATION TISSUE which appears as Pink soft granular appearance on the surface of healing wounds.

Photograph contributed by Dr Prabhakar

SCAR MATURATION: As healing progress, there will be decrease in formation of new blood vessels and fibroblast roliferation and increase in the deposition of collagen. This results in conversion of highly vascular granulation tissue to large avascular scar.T his is referred to as scar maturation.

SCAR CONTRACTION: some of the fibroblasts aquire smooth muscle function and are called as myofibroblasts which help in contraction of the scar.

TISSUE REMODELING:
The final remodeling of the tissue is by the action of various matrix metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs) as depicted in the illustration below.