01 Regeneration and Healing
Transcript of 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