01 regeneration and healing

8/8/2019 01 Regeneration and Healing

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Department of Anatomic Pathology

Faculty of MedicineBrawijaya University


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Regeneration and HealingDefinition :

RegenerationHealing

Control of Normal Cell Proliferation and Tissue GrowthCell cycle

Tissue Proliferative ActivityGrowth FactorExtracellular Matrix (ECM) and Cell-Matrix InteractionsRepair by Healing, Scar Formation, and Fibrosis

Healing :

Scar FormationCutaneous Wound HealingPrimary UnionSecondary Union

Wound StrengthLocal and Systemic Factors That Influence Wound Healing


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Regeneration1. Definition :

Growth of cells and tissues to replace lost structures

2. Occurs if the ECM framework is not damaged / intact( framework provide for cell migration and maintain thecorrect cell polarity for re-assembly of multilayerstructures )

3. Regenerated cells :- Original cells- Stem cells

Note :Stem cells :- Embryonic stem cells- Adult stem cells

* Hematopoietic stem cells / HSCs* Tissue stem cells

- Asymmetric replication


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Healing

1. Definition :A tissue response

* to a wound (commonly in the skin),

* to inflammatory processes in internal organs,

or* to cell necrosis in organs incapable of

regeneration

2. Occurs if the ECM framework is damaged

3. Healing consists regeneration and scar formation

may restore original structures but involves

collagen deposition and scar formation.


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Control of Normal Cell Proliferation and Tissue

Growth* Repair : Regeneration / growth of cells / tissue

* In adult tissues, the size of cell populations is determined by

the rates of cell proliferation, differentiation, and death by

apoptosis.

* Cell Cycle :


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TISSUE-PROLIFERATIVE ACTIVITY

The cells of the body :

1. Labile (Continuously dividing) tissueCell proliferate throughout life : surface epithelia, oral cavity,vagina, cervix, the secretory ducts of the glands,epithel gastrointestinal tract, uterus, urinary, bone marrow,and hematopoietic tissue. mature cells are derived from stem cells

2. Stable (Quiescent) tissueNormally have a low level of replication (G0 G1 cell cycle) :parenchymal cells of liver, kidneys, pankreas, mesenchymalcells such as fibroblast, smooth muscles, vascularendothelial cells and resting lymphocytes and otherleukocytes.

3. Permanent (Non dividing) tissueContain cell that have left the cell cycle and cannot undergomitotic division in postnatal life : neurons, skeletal andcardiac muscle cell


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Growth FactorEpidermal Growth Factor (EGF) andTransforming Growth Factor- (TGF-)-EGF : * Mitogenic for a variety of epithelial cells,

hepatocytes, and fibroblasts.

* Produced by keratinocytes, macrophages, andother inflammatory cells in wound healing

Hepatocyte Growth Factor (HGF)* Mitogenic effects in hepatocytes, cells of the biliary

epithelium in the liver, and epithelial cells of the lungs,

mammary gland, skin, and others

* Produced by fibroblasts, endothelial cells, and liver non-

parenchymal cells.


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VascularEndothelial Growth Factor (VEGF)

Platelet-Derived Growth Factor (PDGF)* Produced by activated platelets, activated macrophages,

endothelial cells, smooth muscle cells, and many tumor cells.

* Causes migration and proliferation of fibroblasts, smooth

muscle cells, and monocytes

FibroblastGrowth Factor (FGF)* Have a large number of functions :

New blood vessel formation (angiogenesis), wound repair,skeletal muscle development, development of bone marrow

stroma


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ExtracellularMatrix (ECM) and Cell-Matrix

InteractionsThe ECM is secreted locally and assembles into a

network in the spaces surrounding cells.

The ECM serves many functions:

* matrix proteins sequester water that providesturgor to soft tissues

* minerals give rigidity to skeletal tissues.

* reservoir for growth factors controlling cell

proliferation.* provides a substratum for cells to adhere,

migrate and proliferate

*directly modulating cell form and function


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Macromolecules which are constitute the

ECM:(1) fibrous structural proteins, such as the collagens andelastins

(2) adhesive glycoproteins

(3)proteoglycans and hyaluronic acid

1,2 and 3 : assemble into two general organizations:

a. Interstitial matrix

It consists of fibrillar and nonfibrillar collagen, elastin,

fibronectin, proteoglycans, hyaluronate

b. basement membrane (BM)

Produced by epithelial and mesenchymal cells

They consist of a network of amorphous nonfibrillar

collagen (mostly type IV), laminin, heparan sulfate,

proteoglycan, and other glycoproteins.


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Repairby Healing, ScarFormation, and

Fibrosis

Healing : involving a number of processes:yInduction of an inflammatory process in response

to the initial injury, with removal of damaged and

dead tissue

yProliferation and migration of parenchymal and

connective tissue cells

yFormation of new blood vessels (angiogenesis) and

granulation tissue

ySynthesis of ECM proteins and collagen deposition

yTissue remodeling

yWound contraction

y

Acquisition of wound strength


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Scar formation

Growth factors and cytokines released at the site ofinjury induce fibroblast proliferation and migration

into the granulation tissue framework of new blood

vessels and loose ECM that initially forms at the

repair site.

Three processes that participate in the formation of

a scar:

(1) emigration and proliferation of fibroblasts in thesite of injury,

(2) deposition of ECM, and

(3) tissue remodeling.


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Cutaneous wound healingCutaneous wound healing : divided into three phases:

(1) inflammation (early and late);

(2) granulation tissue formation and

reepithelialization;

(3) wound contraction, ECM deposition, and

remodeling

These phases overlap, and their separation is

somewhat arbitrary.


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HEALING BY FIRSTINTENTION (primary union )WOUNDSWITHOPPOSED EDGES

In a clean, uninfected surgical incision

Within 24 hours, neutrophils at the margins of the incision,

moving toward the fibrin clot.

In 24 to 48 hours, epithelial cells move from the wound edgesalong the cut margins of the dermis fuse in the midline

beneath the surface scab producing a continuous but thin

epithelial layer that closes the wound.

By day3, neutrophils replaced by macrophages.

- Granulation tissue invades the incision space.- Collagen fibers present in the margins of the incision,

at first : vertically oriented and do not bridge the incision.

- Epithelial cell proliferation thickens the epidermal layer.


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By day 5, the incisional space is filled with granulation tissue.

Collagen fibrils : more abundant and begin to bridge theincision.

The epidermis normal thickness, surface keratinization.

During the second week : accumulation of collagen,

proliferation of fibroblasts, leukocytic infiltrate, edema,increased vascularity blanching, accumulation of collagen

within the incisional scar, regression of vascular channels.

By the end of the first month, the scar is made up of a cellular

connective tissue , inflammatory infiltrate (-), covered by

intact epidermis, the dermal appendages are permanentlylost. Tensile strength of the wound increases thereafter, but it

may take months for the wounded area to obtain its maximal

strength.


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HEALING BYSECOND INTENTION

(secondary union )WOUNDSWITHSEPARATED EDGES

* In surface wounds that create large defects* Regeneration of parenchymal cells cannot

completely restore the original architecture

abundant granulation tissue


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Figure 3-21 Steps in wound healing by first intention (left) and second intention (right). Note largeamounts of granulation tissue and wound contraction in healing by second intention.


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WOUND STRENGTHAt the end of the first week, wound strength 10%

increases rapidly over the next 4 weeks.

This rate of increase then slows at the third

month after the original incision reaches a plateauat about 70% to 80% of the tensile strength

persist for life.


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LOCALAND SYSTEMIC FACTORSTHAT

INFLUENCEWOUND HEALINGSystemic factors :Nutrition : Protein deficiency, vit C deficiency

inhibit collagen synthesis

Metabolic status : Diabetes mellitus(microangiopathy)

Circulatory status : arteriosclerosis / venous

abnormalities (e.g. varicose veins)

Inadequate blood supplyHormones : glucocorticoids

inhibit collagen synthesis.


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Local factors :Infection : persistent tissue injury and inflammation.

Mechanical factors : early motion of wounds

delay healing, by compressing blood vessels

and separating the edges of the wound.

Foreign bodies : fragments of steel, glass, bone

Location : wounds in richly vascularized areas

e.g.faceheal faster than those in poorly

vascularized ones e.g. foot.

Size : small incisional injuries heal faster and < scarformation than large excisional wounds

Type of wound : wounds caused by blunt trauma

heal slower


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Thank YouFor

Your Attention

01 regeneration and healing

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