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Tissue Repair: Cellular Growth,Tissue Repair: Cellular Growth,
Fibrosis, and Wound HealingFibrosis, and Wound Healing
Facilitator: Dr. Mgaya
Presenters:
Dr. Harrison Chuwa,
Dr. Simon
Dr. Mbonea
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IntroductionIntroduction
y Replacement of injured or dead cells is
critical to survival.
y Repair of tissues involves two distinct
processes:
Regeneration: replacement of dead cells by
proliferation of cells of the same type
Replacement by connective tissue orfibroplasia.
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CONTROL OF NORMAL CELLCONTROL OF NORMAL CELL
GROWTHGROWTHy The size of a population of cells in adulttissues is determined by the rates of cellproliferation, differentiation, and death by
apoptosis.y Cell proliferation can be stimulated by injury,
mechanical forces acting on tissues, or celldeath.
y The most important factors that regulatecell proliferation are those that recruitquiescent cells into the cell cycle
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Cell Proliferation PotentialCell Proliferation Potential
y Cells are divided into 3 groups based on theirproliferation capacity:
i. Continuous dividing (labile) cells e.g.surface epithelia and cells of the bone marrowand hematopoietic cells
ii. Quiescent (stable) cells- normally with slowturnover but capable of rapid division in responseto stimuli e.g. liver, kidney, fibroblasts, smooth
muscle and endothelial cellsiii. Non-dividing (permanent) cells- can·tundergo division in postnatal life e.g. neurons,skeletal muscle, and cardiac muscle
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Molecular Events in CellMolecular Events in Cell
ProliferationProliferationy Growth factors induce cell proliferation
by affecting the expression of genes
involved in normal growth control
pathways, the proto-oncogenes.
y Alterations in the structure or expression
of these genes can convert them into
oncogenes, which contribute to theuncontrolled growth characteristic of
cancer.
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Molecular Events in CellMolecular Events in Cell
Proliferation cont«Proliferation cont«y There are 3 schemes of intercellular signalingimportant in the regulation of cell proliferation:
i. Autocrine signaling- cells respond to signalingsubstances that they themselves secrete
ii. Paracrine signaling- a cell produces substancesthat affect only a target cell in close proximity
iii. Endocrine signaling- hormones are synthesizedby cells of endocrine organs and act on target
cells distant from their site of synthesis
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Molecular Events in CellMolecular Events in Cell
Proliferation cont«Proliferation cont«y The chain of molecular events induced by
growth factors include the following
components:
Cell Surface Receptors Interaction
Signal Transduction Systems
Transcription Factors and the regulation of
Gene Expression
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Cell Surface Receptors InteractionCell Surface Receptors Interaction
y Cell growth is initiated by binding of a
signaling agent (growth factor) to a
specific receptor frequently located on
the plasma membrane
y The major cell surface receptors involved
in signaling can be grouped into 3 main
categories depending on their activity
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Cell Surface ReceptorsCell Surface Receptors
1. Receptors with Intrinsic Kinase
activity- have intrinsic tyrosine kinase
activity, which is activated by ligand
binding.
2. Receptors without Intrinsic Kinase
activity
3. G protein-linked receptors
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Signal Transduction SystemsSignal Transduction Systems
y Signal transduction is the process by whichextracellular signals are detected and converted intointracellular signals.
y These systems are typically arranged as networks of sequential protein kinases:
a) Mitogen-activated protein (MAP) kinase pathway
b) Phosphoinositide 3-kinase pathway
c) Inositol-lipid pathway
d) Cyclic adenosine monophosphate (cAMP) pathway
e) JAK/STAT pathwayy These systems transfer information to the nucleus
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Transcription Factors and theTranscription Factors and the
Regulation of Gene ExpressionRegulation of Gene Expressiony The signal (information) relayed to the nucleus viathe transduction systems regulates specificchanges that occur in gene expression.
y The regulation is largely achieved at the level of
transcription of genes, a process controlled bytranscription factors.
y Transcription factors are phosphorylated andactivated by specific signaling kinases.
y Among the transcription factors regulating cell
proliferation are a number of proto-oncogenes, inwhich mutation may be associated with tumors,and various types of tumor-suppressor genes (e.g.p53 and Rb)
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Cell Cycle and the Regulation of Cell Cycle and the Regulation of
Cell ProliferationCell Proliferationy The cell growth cycle consists of G1
(presynthetic), S (DNA synthesis), G2(premitotic), and M (mitotic) phases.
y Quiescent cells are in a physiologic statecalled G0
y Two types of molecular controls regulate thepassage of cells through specific phases of the cell cycle
A cascade of protein phosphorylation pathwaysinvolving cyclins and CDKs
A set of checkpoints that monitor completion of molecular events
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Growth InhibitionGrowth Inhibition
y Regulates cell growth by inhibiting cell
growth
y Inhibitors are also largely polypeptide
factors that use receptors, signal
transduction systems, second messengers,
and transcriptional factors.
y E.g. transforming growth factor- (TGF-);Interferon-
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Growth FactorsGrowth Factors
y GFs act by endocrine, paracrine, or
autocrine signaling and in addition to their
growth effects, influence cell movement,
contractility, and differentiation
y The major GFs are as follows:
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Major Growth FactorsMajor Growth Factors
Growth
factors
Symbol Source Functions
Epidermal
growth factor
EGF Platelets, macrophages,
saliva, urine, milk,
plasma
Mitogenic for keratinocytes and
fibroblasts; stimulates keratinocyte
migration and
granulation tissue formation
Transforming
growth factoralpha
TGF- Macrophages, T
lymphocytes,keratinocytes,
and many tissues
Similar to EGF; stimulates replication of
hepatocytes and certain epithelial cells
Hepatocytegrowth
factor/scatter
factor
HGF Mesenchymal cells Enhances proliferation of epithelial andendothelial cells, and of hepatocytes;
increases
cell motility
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Growth
factors
Symbol Source Functions
Vascular
endotheli
al cellgrowth
factor
(isoforms
A, B, C,
D)
VEGF Mesenchymal cells Increases vascular permeability;
mitogenic for endothelial cells
Platelet-
derived
growth
factor
(isoforms
A, B, C, D)
PDGF Platelets, macrophages,
endothelial cells,
keratinocytes, smooth
muscle cells
Chemotactic for PMNs, marcrophages,
fibroblasts, and smooth muscle cells;
activates
PMNs, macrophages, and fibroblasts;
mitogenic for fibroblasts, endothelial cells,
and
smooth muscle cells; stimulates production
of MMPs, fibronectin, and HA; stimulates
angiogenesis and wound contraction;
remodeling; inhibits platelet aggregation;
regulates integrin expression
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Growth
factors
Symbol Source Functions
Fibroblast
growth
factor-1(acidic), -2
(basic) and
family
FGF Macrophages, mast
cells, T lymphocytes,
endothelial cells,fibroblasts, and many
tissues
Macrophages, mast
cells, T lymphocytes,
endothelial cells,
fibroblasts, and manytissues
Chemotactic for fibroblasts;
mitogenic for fibroblasts and
keratinocytes; stimulateskeratinocyte migration,
angiogenesis, fam wound
contraction and matrix
deposition
Transformin
g growth
factor beta
(isoforms 1,2, 3); other
members of
the family
are BMP
and activin
TGF- Platelets, T lymphocytes,
macrophages,
endothelial cells,
keratinocytes, smoothmuscle cells, fibroblasts
Chemotactic for PMNs, macrophages,
lymphocytes, fibroblasts, and smooth
muscle
cells; stimulates TIMP synthesis,keratinocyte migration, angiogenesis,
and fibroplasia;
inhibits production of MMPs and
keratinocyte proliferation; regulates
integrin
expression and other cytokines;induces TGF- production
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row
factors
ym o ource unc ons
Keratinocyte
growth
factor (also
called FGF-7)
K GF Fibroblasts Stimulates keratinocyte migration,
proliferation, and differentiation
Insulin-like
growth factor-
1
IGF-1 Macrophages,
fibroblasts and
other cells
Stimulates synthesis of sulfated proteoglycans,
collagen, keratinocyte migration, and
fibroblast proliferation; endocrine effects
similar to growth hormone
Tumor
necrosis factor
TNF Macrophages,
mast cells, T
lymphocytes
Activates macrophages; regulates other
cytokines; multiple functions
Interleukins IL-1, etc. Macrophages,
mast cells,keratinocytes,
lymphocytes, and
many tissues
Many functions. Some examples: chemotactic
for PMNs (IL-1) and fibroblasts (IL-4),stimulation of MMP-1 synthesis (IL-1),
angiogenesis (IL-8), TIMP synthesis (IL-6);
regulation of other cytokines
Interferons IFN-,
etc.
Lymphocytes and
fibroblasts
Activates macrophages; inhibits fibroblast
proliferation and synthesis of MMPs;
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Extracellular Matrix and Cell MatrixExtracellular Matrix and Cell Matrix
InteractionsInteractionsy ECM markedly influences cell growth and
function.
y The ECM consists of fibrous structural
proteins (e.g. collagen) and adhesive glycoproteins embedded in a gel of proteoglycans and hyaluronan.
y These macromolecules assemble into an
interstitial matrix, present in the spacesbetween cells, or into a basementmembrane, located close to the plasmamembrane of some cells.
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Collagen and Fiber AssemblyCollagen and Fiber Assembly
y Collagens are divided into 14 types: Type I,II, and II are the fibrillar collagens, andtypes IV,V, andVI are amorphous and
present in interstitial tissue and basementmembranes.
y Collagen synthesis involves first synthesisof chains on ribosomes, followed by a
number of enzymatic hdroxylations, whichare necessary to hold the three chainstogether
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Collagen and Fiber Assembly cont«Collagen and Fiber Assembly cont«
y Proteolytic processing of a C-terminalfragment of the procollagen moleculeduring or shortly after secretion from
fibroblasts and smooth muscle cellsresults in the formation of fibrils.
y Extracellular lysyl hydroxylysyl oxidationresults in cross-linkages between chains
of adjacent molecules, which contributeto the tensile strength of collagen(dependent on vitamin C)
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Elastin, Fibrillin, and theElastin, Fibrillin, and the
Microfibrillar Network Microfibrillar Network y Elastin provides tissues with elasticity or
the ability to stretch and recoil.
y Elastic fibers consists of a central core of
elastin , and surrounding peripheral
network consisting of fibrillin.
y NB: inherited defects in fibrillin results in
formation of abnormal elastic fibers inMarfan·s syndrome
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Adhesive Matrix Glycoproteins andAdhesive Matrix Glycoproteins and
IntegrinsIntegrinsy Adhesive matrix glycoproteins and
Integrins link the ECM with specific
integral cell membrane proteins
y They are several types/forms of the
adhesive matrix glycoproteins . They
include:
Fibronectin Laminin
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fibronectinfibronectin
y An adhesion glycoprotein that binds toseveral ECM components ( collagen, heparin,fibrin, proteoglycans) on the one hand and tocell membranes on the other.
y Binding to ECM is mediated by recognitionof a specific amino acid sequence, RGD(arginine, glycine, aspartic acid), present inthe matrix protein.
y
Binding to cells is via integrins or receptorsthat span the cell surface membrane andinteract with the cytoskeleton at points of focal adhesion.
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Fibronectin cont«Fibronectin cont«
y Thus, fibronectin is directly involved in
cell attachment, spreading, and
locomotion and interacts with growth
factors to affect growth anddifferentiation.
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LamininLaminin
y Is a cross-shaped glycoprotein spanning
basement membranes, also binds to cells
through specific receptors and to collagen
type IV and heparin.
y Thus, is involved in cell attachment,
locomotion, and growth.
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IntegrinsIntegrins
y Are the major family of cell surface receptorsthat mediate cellular attachment to the ECM.
y Many integrins are widely expressed, and mostcells have more than one integrins on the cell
surface.y Integrin receptors span the cell membrane and
bind to many components (e.g. fibronectin,laminin, and some collagens) of the ECM byrecognizing the RGD sequence.
y Integrin receptors are important both inorganizing the actin cytoskeleton of cells at pointsof focal adhesion and in transduction of signalsfrom the ECM to the cell interior
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Integrins cont«Integrins cont«
y The mechanical linkage between the
Integrin receptors and the cytoskeletal
signaling system may be a mechanism by
which cells convert mechanical force intobiochemical signals
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Matricellular ProteinsMatricellular Proteins
y Are secreted proteins that do not function asstructural components of the ECM.
y These proteins interact with matrix components,cell surface receptors, or other molecules (e.g.
growth factors, cytokines, or proteases), whichinteract, in turn, with the cell surface.
y The group shares the ability to disrupt cell-matrixinteractions.
y The family of versatile adapter proteins includesSPARC (secreted protein acidic and r ich incysteine, a.k.a osteonectin), thrombospondins , osteopontin and the tenascin family members.
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Proteoglycans and HyaluronanProteoglycans and Hyaluronan
y Proteoglycans are ECM components thatconsists of a core protein linked to one ormore polysaccharides called g lycosamino g lycans.
y Glycosaminoglycans are long repeatingpolymers of modified disaccharides (e.g.heparin sulfate).
y
Proteoglycans can also be integralmembrane proteins, as in the syndecan family,in which the core protein spans the plasmamembrane.
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y Hyaluronan is a huge molecule consisting
of many repeats of a disaccharide.
y It serves as a ligand for core proteins and
cell surface receptors.
y Hyaluronan binds large amounts of water,
which helps give connective tissue turgor
pressure and ability to resist compressionforces.
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SummarySummary
y Cell growth and differentiation involve the
cellular integration of multiple signals.
y Some of these signals are derived from
growth factors and growth inhibitors.
y Others are derived from components in
the ECM and proceed through integrin-
dependent signaling pathways
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REPAIR BY CONNECTIVE TISSUEREPAIR BY CONNECTIVE TISSUE
(FIBROSIS)(FIBROSIS)y Because tissue destruction in wound
healing and chronic inflammation involvesboth parenchymal cells and the stromal
framework, repair cannot beaccomplished solely by regeneration of parenchymal cells.
y Thus, repair involves in large part the
replacement of lost cells and tissues byconnective tissue, which, in time, producesfibrosis and scarring.
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REPAIR BY CONNECTIVE TISSUEREPAIR BY CONNECTIVE TISSUE
(FIBROSIS) cont«(FIBROSIS) cont«y Connective tissue repair is the systematic
processes by which unregenerated damage is
replaced by fibrosis and scarring.
y The initial response to a wound consists of the formation of granulation tissue, which
consists of:
Richly vascular connective tissue
New capillaries
Proliferating fibroblasts
Variable numbers of inflammatory cells
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Processes involved in repair byProcesses involved in repair by
connective tissueconnective tissuey There are four components to this
orderly process
Formation of new blood vessels
(angiogenesis), spanning the wound Migration and proliferation of fibroblasts filling
and bridging the wound (part of fibroplasia)
Deposition of ECM (part of fibroplasia)
Maturation and re-organization of the fibrous
tissue into a scar (a.k.a remodeling )
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Processes involved in repair byProcesses involved in repair by
connective tissue cont«connective tissue cont«1. Angiogenesis
y Is critical for chronic inflammation,
formation of collateral circulation, and
tumor growth.
y Blood vessels are assembled by two
processes:
x Vasculogenesis- a primitive vascular network isassembled during development
x Neovascularization- pre-existing blood vessels
give rise to capillary buds to produce new vessels
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AngiogenesisAngiogenesis
y V asculogenesis- refers to angiogenesis by
mobilization of endothelial precursor cells
(EPCs) from the bone marrow. EPCs are mobilized
from the bone marrow and may migrate to a site of
injury or tumor growth. The homing mechanisms areunknown. At these sites, EPCs differentiate and form
a mature network by linking with existing vessels.
y Neovascularization- i.e. angiogenesis from pre-
existing vessels (capillary growth). Endothelial cellsfrom these vessels become motile and proliferate to
form capillary sprouts
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Steps in AngiogenesisSteps in Angiogenesis
y Multiple steps underlie angiogenesis
Proteolytic degradation of the basementmembrane of the parent vessel
Endothelial cell migration and formation of acapillary sprout
Proliferation and maturation of endothelial cells,which includes remodeling into capillary tubes
Recruitment of periendothelial cells, including
pericytes (for small capillaries) and vascularsmooth muscle cells (for larger vessels) tosupport the endothelial tubes
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Regulation of AngiogenesisRegulation of Angiogenesis
y The formation, maintenance and remodeling
of blood vessels are controlled by the
following:
Growth factors and receptors: many GFs haveangiogenic activity, but VEGF and the
angiopoietins ( Ang ) are particularly important
in establishing and maintaining new blood vessels.
They interact with the corresponding tyrosinekinase receptors (VEGF-R and Tie) uniquely
expressed by endothelial cells. PDGF and its
receptors are in recruiting periendothelial cells
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Regulation of Angiogenesis cont«Regulation of Angiogenesis cont«
ECM proteins, as regulators of angiogenesis: thecell motility and directed migration of endothelialcells that occurs during angiogenesis is regulatedby integrins (e.g. v3), matricellular proteins(e.g. SPARC) and proteases (e.g. plasminogen
activators and matrix metalloproteases) Angiogenesis inhibitors: act to down-regulate
new vessel growth and include certain cytokines(e.g. interf eron-); tissue inhibitors of metalloproteases; certain matricellular proteins
(e.g. thrombospondin); and tumor-derivedfactors, such as angiostatin (a fragment of plasminogen) and endostatin ( a fragment of collagen)
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Processes involved in repair byProcesses involved in repair by
connective tissue cont«connective tissue cont«2. Fibrosis (Fibroplasia)
y Fibrosis occurs within the granulation tissueframework formed at the site of repair andinvolves two processes: Fibroblast migration and proliferation:
increased vascular permeability leads to thedeposition of plasma proteins, such as fibronectinand fibrinogen, which provide a provisionalstroma for ingrowth of fibroblasts. Migration of
fibroblasts and their subsequent proliferation isalso mediated by GFs such as PDGF, EGF, FGFand TGF- and the fibrogenic cytokines IL-1 andTNF-.
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Fibroplasia cont«Fibroplasia cont«
ECM deposition: as repair progresses, thenumber of proliferating endothelial cells andfibroblasts decreases. The fibroblasts becomemore synthetic and deposit increased amount of
collagen and other components of ECM. Collagensynthesis is stimulated by GFs (e.g. PDGF, FGF)and by cytokines (IL-1) secreted by fibroblastsand leukocytes in healing wounds. TGF- isthought to play a role in chronic inflammatory
fibrosis. Eventually the granulation tissue scaffolding is converted into a scar composed of
fibroblasts and collagen.
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Processes involved in repair byProcesses involved in repair by
connective tissue cont«connective tissue cont«3. Tissue remodeling
y The replacement of granulation tissue with ascar involves transitions in the composition
of the ECM.y Some of the GFs that stimulate synthesis of
collagen and other connective tissuemolecules modulate the synthesis and
activation of matrix metalloproteinases(MMPs), enzymes that serve to degradethese ECM components.
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Tissue remodeling cont«Tissue remodeling cont«
y MMPs consist of:- interstitial collagenases: cleave thefibrillar collagen types I,II, and III
- gelatinases (type IV collagenases):
degrade amorphous collagen as well asfibronectin
- stromelysins: act on a variety of ECMcomponents, including proteoglycans, laminin,
fibronectin, and amorphous collagens- membrane-bound MMPs: cell surface-associated proteases
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Tissue remodeling cont«Tissue remodeling cont«
y Secretion of MMPs by fibroblasts and leukocytesis induced by GFs and cytokines and inhibited byTGF-.
y The enzymes are secreted as proenzymes, which
are activated extracellularly.y Activated MMPs can be rapidly inhibited by a
family of specific tissue inhibitors of metalloproteinase (TIMPs).
y The net effect of ECM synthesis versus
degradation results in debridement of injuredsites and remodeling of the connective tissuesframework- important features of both chronicinflammation and wound repair.
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WOUND HEALINGWOUND HEALING
y Is a complex but orderly phenomenoninvolving many of the processes: Induction of acute inflammatory process- by
initial injury
Regeneration of parenchymal cells
Migration and proliferation of both parenchymaland connective tissue cells
Synthesis of ECM proteins
Remodeling of connective tissue and parenchymalcomponents
Collagenization and acquisition of woundstrength
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Healing by First IntentionHealing by First Intention
y Healing of a clean surgical approximated
incision (1st intention) involves an
orchestrated sequence of events, as follows:
0 hours: the incision is filled with clot
3 to 24 hours: neutrophils from the margins
infiltrate the clot. Mitoses begin to appear in
epithelial basal cells; epithelial closure takes place
by 24 to 48 hours Day 3: neutrophils are replaced by macrophages.
Granulation tissue begins to appear
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Healing by First Intention cont«Healing by First Intention cont«
Day 5: the incision space is filled with granulationtissue, neovascularization is maximal, collagenfibrils begin to appear, and epithelial proliferationis now maximal.
Week 2: there is proliferation of fibroblasts andcontinued collagen accumulation to produce ascar. Collagen deposited early in granulationtissue is type III, which is then replaced by adulttype I collagen. Collagen fibers account in largepart for wound strength. Inflammation and newly
formed vessels have largely disappeared. Month 2: scar now consists of connective tissue
devoid of inflammation covered by intactepidermis
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Healing by Second IntentionHealing by Second Intention
y Occurs when there is more extensive lossof tissue, such as infarction, ulceration,abscess formation, and large wounds.
y
Abundant granulation tissue grows infrom the margins to fill the defect, but atthe same time the wound contracts; i.e.the defect is markedly reduced from its
original size.y Myofibroblasts contribute to wound
contraction
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Summary of Wound HealingSummary of Wound Healing
y Wound healing involves orchestrated
events of inflammation; followed by a
stage of fibroplasia characterized by
granulation tissue; followed by ECMdeposition, tissue remodeling, and scarring
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Wound StrengthWound Strength
y Wound strength at the end of first week isapproximately 10% of normal; it is largelydependent on surgical suturing and tissueadhesion.
y The progressive recovery of tensile strengthto 70% to 80% of normal by third month(which may persist for life) is associatedwith: Increased collagen synthesis exceeding collagen
degradation
Cross-linking and increased fiber size of collagenfibers
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Factors Influencing Wound HealingFactors Influencing Wound Healing
y There are several factors which can be
categorized as follows:
a. Systemic factors:x Nutritional status of the host (e.g. protein
nutrition and vitamin C intake)
x Metabolic status (e.g. DM delays healing)
x Circulatory status or inadequacy of blood supply
x Hormones, concurrent glucocorticoid therapy,which hinders the inflammatory-reparative
process
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Factors Influencing Wound HealingFactors Influencing Wound Healing
cont«cont«
b. Local factors:
- infection, which delays healing
- mechanical factors e.g. motion
directly affecting the wound
- Foreign bodies: impede healing
- size, location, and type of the wound
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Pathologic Aspects of WoundPathologic Aspects of Wound
HealingHealingy Complications in wound healing can arise
from abnormalities in any of the basic
repair processes.
y These aberrations can be grouped into 3general categories:
Deficient scar formation
Excessive formation of the repair components Formation of contractures
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Deficient Scar FormationDeficient Scar Formation
y This can lead to 2 types of complications:
Wound dehiscence- dehiscence or rupture of awound is most common after abdominal surgery andis due to increased abdominal pressure. This
mechanical stress on the abdominal wound can begenerated by vomiting, coughing, or ileus.
Ulceration- wounds can ulcerate because of inadequate vascularization during healing. e.g. lowerextremity wounds in individuals with atherosclerotic
peripheral vascular disease typically ulcerateNB: Nonhealing wounds also form in areas devoid of
sensation. These neuropathic ulcers are occasionallyseen in patients with diabetic peripheral neuropathy
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Excessive Formation of RepairExcessive Formation of Repair
ComponentsComponentsy The formation of excessive amounts of g ranulation tissue,
which protrudes above the level of the surrounding skin
and blocks reepithelialization, has been called
exuberant granulation or proud flesh
y The accumulation of excessive amount of colla g en maygive rise to a raised tumorous scar known as a keloid,
or hypertrophic scar .
y Rarely, incisional scars or traumatic injuries may be
followed by exuberant proliferation of fibroblasts and otherconnective tissue elements that may, in fact, recur after
excision. Called desmoids , or aggressive
fibromatoses , these lie in the interface between benign
proliferations and malignant (though low-grade) tumors.
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Formation of ContracturesFormation of Contractures
y Contraction in the size of a wound is animportant part in normal healing process.
y An exaggeration of this process is referred to as acontracture and results in deformities of thewound and the surrounding tissues. e.g. in thehand producing claw deformities and limiting themobility of a joint.
y Contractures are particularly prone to developon the palms, the soles, and the anterior aspect of
the thorax.y Contractures are commonly seen after serious
burns and can compromise the movement of joints.
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