Pathology Inflammation Lecture 6 and 7

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Tissue Repair: Regeneration & Healing
Repair : Host response to replace dead tissue by Healthy tissue
It occurs by Two processes
1- Regeneration: Replacement of dead cells (tissue ) by proliferation of
parenchymal cells of same type (Return to Normal state )
2- Healing : Replacement by connective (fibrous) tissue resulting in permanent
Scar Formation

Important background facts
cellular proliferation
growth factors
the extracellular matrix



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Tissues of the body are divided into three types according to their regenerative capacity
1- Continuously dividing (labile) tissues
2-Stable (quiescent) tissues
3-Permanent tissues

Tissues of the body are divided into three groups:
1- Continuously dividing (labile) tissues
cells are continuously proliferating
can easily regenerate after injury
contain a pool of stem cells
examples: bone marrow, skin, mucosa GIT, vagina, cervix, bladder
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2.Stable cells: a cell which stop multiplication when growth is complete after birth but
retain ability to multiply when there is a need for that e.g. liver cells ,pancreas ,kidney
fibroblast ,endothelial cell&smooth muscle

3.Permanent cells: Stop multiplication early in neonatal life e.g. neuron ,nerve cardiac
muscle &skeletal muscle


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Very important in tissue repair.
Actions:
stimulate cell division and proliferation
promote cell survival
Huge list! Usually have GF in name:
EGF
TGF
PDGF FGF

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ECM is the network that surrounds cells
Two forms: interstitial matrix and basement membrane
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Does lots of things!
Sequesters water and minerals
Gives cells a scaffold to adhere to
Stores growth factors

Bottom line: ECM regulates proliferation, movement, and differentiation of the
cells living in it.
If you screw up your ECM, you cant regenerate! Youll form a scar instead.

REGENERATION
Occurs all the time in labile tissues
Cells are constantly being lost and replaced
If demand increases, supply increases easily
Occurs in limited form in stable tissues
Remove one kidney: the other one undergoes hypertrophy and
hyperplasia
Remove half of the liver: it will grow back
Only occurs if residual tissue is intact!

SCARRING
If injury is severe, regeneration cant happen
So, fibrosis (a scar) replaces the injured tissue
Four components to this process:
new vessel formation (angiogenesis)
fibroblast proliferation
synthesis of collagen (scar formation)
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remodeling of scar

Healing of skin wounds
1.Healing by primary union (Primary or first intention)
2.Healing by secondary union (Second intention).

Healing by First Intention
Occurs in small clean wounds that close easily
Epithelial regeneration predominates over fibrosis
Healing is fast, with minimal scarring/infection
Examples: Well-approximated surgical incisions

Healing by First Intention: Timeline
By 24 hours
By 3-7 days
Weeks later

By 24 hours
clot forms
neutrophils come in
epithelium begins to regenerate
By 3-7 days
macrophages come in
granulation tissue is formed
new blood vessels
fibroblasts
collagen begins to bridge incision
epithelium increases in thickness
Weeks later
granulation tissue gone
collagen is remodeled
epidermis full, mature (but without dermal appendages)
eventually, scar forms

By the end of first month : scar consists of C.T. without inflammatory cells and covered
by normal Epidermis . Dermal appendage are lost in the line of incision and No rete
ridges.
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Healing by primary union
Injury
Acute inflammation
Removal of the tinny blood clot
Formation of scab at the surface
growth of epithelial cells
granulation tissue is formed between the edges of the wound
mature in to fibrous tissue

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Tissue of Healing
Is formed by day 35
Soft , pink , granular tissue
Consists of proliferating fibroblast , newly formed B.Vs (capillaries ) in loose
ECM and inflammatory cells (macrophage)
progressively G.T. change and mature into dense Fibrous Tissue "(fibrosis) and
scar formation

Wound which heal by secondary union
Infected,
contaminated wound,
large blood clot,
edges are widely separated

Healing by Second Intention
Occurs in larger infected contaminated wounds that have gaps between wound
margins (widely separated edges)
Fibrosis predominates over epithelial regeneration
Healing is slower, with more inflammation and more granulation tissue
formation, and more scarring
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Examples:
Infarction
Large burns ,ulcers &abscess

Secondary union differs from primary union by followings
1- large tissue loss with large defect large blood clot or scab is formed , require more
time to close.
2- Inflammation is more intense.
3- larger amounts of granulation tissue is formed to fill the gap or defect large
Hypertrophic scar .(Keloid)
4- Wound contraction or contracture reduction in size of wound surface by 1/3 to 1/4
from its original size by contraction of myofibroblasts limitation of joint movement .
Contracture deformity in the extremities with limitation of joint movement which
cannot fully extend .
Second intention healing has:
More inflammation
More granulation tissue
Wound contraction


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Skin graft in wound healing
A large wound in which epithelialisation is delayed or impossible can be covered by skin
graft

Wound strength
Sutured wound has 70% of normal skin strength because of the suture
Suture is removed by the end of the first week wound strength is about 10%
of normal skin.
By end of 3
rd
month 70- 80 % of normal skin and persist for life .


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Complications of wound healing
1.Infections & Ulceration
2.Wound dehiscence
3.Implantation Epidermal cyst
4.Keloid formation.
5.Painfull scar.
6.Pigmented scar.
7.Weak scar.
8.Cicatrisation
9.Neoplastic changes
10.Exuberant granulation tissue

Keloid: Raised ugly hypertrophied scar tissue

Factors affecting wound Healing
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1- Infection is the single most important cause of delay in Healing .
2- Poor Blood supply: local venous obstruction, therosclerosis, DM will delay healing
pretibial skin wound heals much slower than face
3- Mechanical Factors : increased local pressure,Torsion, excessive movement
wound to pull apart (wound Dehiscence)
4- Radiation therapy : inhibit cell proliferation ( radiotherapy for malignant tumour
is delayed until the surgical scar has been healed)
5- Foreign body in the wound
6- Adhesion to bony surface
7- Neoplastic changes (Tumour)

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1- Protein calorie malnutrition
2- Vit-c & Zink deficiency inhibit collagen synthesis occurs in severe Burns &
intestinal fistula
3- Diabetes mellitus (DM)
4- Corticosteroid Treatment inhibit fibrosis .
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5- Renal Failure
6- Hematological diseases leukemia
Neutropenia
7- Tumour cachexia.
Mechanisms of wound healing
1-Inflammation
2- Regeneration
3- Formation of new B.Vs (Angiogenesis).
4- Migration and proliferation of fibroblasts.
5- Deposition of ECM and collagen synthesis.
6- Maturation and scar remodeling by collagenase and gelatinase collagen
degradation.

All these complicated process are controlled by variety of mechanism which involve
1-Chemical mediators
2-Growth factors:
e.g. macrophage G.F
Platelet G.F
Epidermal G.F. etc
3-Growth inhibiters: Tumour suppresser gene (Retinoblastoma gene)
4-Extracellular matrix (ECM)

Not all injuries result in permanent damage; some are resolved almost
completely
More often, there is some degree of scarring
Scar is usually good (provides a resilient patch) but occasionally bad (can cause
permanent dysfunction)


With my best wishes