repair of skin wounds by fibrosis
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REPAIR OF SKIN WOUNDS
BY FIBROSIS
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Functions of the skin
Thermoregulation (insulation & evaporation)
Sensory transduction - Detects touch,
pressure, pain and temperature
Protects underlying tissues and organs by acting
as mechanical barrieragainst desiccation,
invasion by microbes, environmental insults
such as UV irradiation, mechanical trauma,chemical or thermal burns
Excretes salts, water and organic wastes
(through the sweat glands)
Synthesis vitamin D3
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Dermis no regeneration
Repair by fibrosis
Pig skin = human skin model Most studies rodents or rabbit
breeding, handling and maintenance
Wound healing studies difficult tocompare differences in model, strain,
sex, age, location and size of wound
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STRUCTURE OF THE SKIN
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Structure of the Adult Mammalian skin
Two main layers epidermis & dermis EPIDERMIS
stratified squamous epithelium
consisting primarily ofkeratinocytes from various
stages of differentiation, from mitotically active basalcells (stratum basale-deepest layer) to the heavily
keratinized superficial cells (stratum corneum) -
sloughed off
Keratinocytes impermeable sheet tight junctions,desmosomes
Stem cells in stratum basale - constantly divide to
self renew and give rise to differentiated
keratinocytes that migrates upwards to replace the
cells of the stratum corneum as they slough off
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THE 5 SUBLAYERS OF EPIDERMIS
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EPIDERMIS
Non epithelial celltypes :
Melanocytes-colour
Langerhans cells -APCs
Merkel cells -mechanoreceptors
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The ECM of the stratum basale contains
hyaluronic acid (HA) for which the basal cells
express the CD44 receptor.
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DERMIS
located beneath the epidermis two layers of fibroblasts which are embedded in
ECM ;
The Papillary layer- next to the basal layer of the
epidermis papillae
DeeperReticular layer
contains most of the skins specialized cells and
structures, including: Blood & Lymph vessels, Hairfollicles, Sweat & Sebaceous glands, Nerve
endings, Collagen & Elastin
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The Papillary Layer
thrown into folds of highly vascularized
loose connective tissue
pervaded by a capillary network -nourishment to the epidermis, and acts as
a heat exchanger
ECM thin collagen and elastic fibers;
mast cells; tissue macrophages; fat cells
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The Reticular Layer
thicker than the papillary layer
characterized by an ECM containing a network
ofcoarse collagen & elastin fibers
larger blood vessels and fewer capillaries
The reticular layer rests on a superficial fascia
or hypodermis (not part of the skin)
Bundles of collagen fibers extending fromreticular layer anchor it onto the hypodermis
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Proteins of the Dermal ECM
three classes Proteoglycans, Fibrous Proteins,Adhesive Proteins
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PROTEOGLYCANS
proteins linked to sulfated
GAGs
Dermatan sulfate, heparan
sulfate & chondroitin sulfate -
prominent in dermal ECM
Significant PGs in dermalECM are the large PG
versican, and the small PG
decorin
Multiple PGs linked to HA Binds water - - resisting
compressive forces and space
for cell migration in injured skin
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FIBROUS PROTEINS
Major Fibrous Proteins in the Dermal ECM
Collagens - give tensile strength
type I (80%) and type III major
Type VI - forms a highly branched network offilaments surrounding the type I collage fibrils
type IV - part of basement membrane of blood
vessels
type VIII - located around hair follicles, andsmall blood vessels
Elastins give resiliency - allowing the skin to be
stretched and then assume its original shape
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The Dermal Adhesive Proteins
Prominent - Fibronectin (Fn), Vitronectin (Vn),
and Tenascin-C (Tn-C)
Fibronectin and Vitronectin serve as a
substrate to which cells can adhere when they
are either migrating or stationary.
Tenascin-C is an antiadhesive protein - with
Fibronectin, helps control the degree of cellularadhesion to the ECM substrate
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Integrins
Proteins of dermal ECM aa recognitionsequences receptor binding
Major cell receptor forECM molecules such
as collagen I, III, and Fibronectin low affinity, heterodimeric linker proteins
consisting of two non covalently associatedtransmembrane glycoprotein subunits and
Functions: adhesion of cells to ECM
migration of cells on ECM
maintenance and modulation of gene expression by
the transmission of signals to the nucleus
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Epidermal Growth Factor Receptor- Tenascin-C
and type I collagen have EGF repeat domains -
bind to EGFR
Other recognition domains protein binding
organization of ECM
Basement membrane synthesized byepidermis connects with papillary layer
Composed of laminin in lamina lucida
Type IV collagen, entactin and perlecan lamina
densa Epidermal cells lamina lucida hemidesmosomes
and integrins
Lamina densa- papillary layer type VII collagen
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The dermal ECM - reservoir for GFs - binding &
releasing them upon injury GFs are signaling molecules that stimulate or
inhibit proliferation, migration and differentiation,
depending upon the cell type
Most GFs - RTK pathways - initiate intracellularphosphorylation cascades by other kinases,
resulting in activation of transcription factors that
up-or down-regulate gene activity
TGF-beta Smad pathway
ECM, GFs, CAM and GF receptors imp for
wound healing
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The Effect of Wound Type & Extent on
Dermal Repair
Injury to the epidermis layer alone - regeneration
without scar formation
wounds that penetrate the dermis - repair by
fibrosis Wounds made by Shallow surgical incisions
(superficial) - simple fibroblast proliferation with
minimal scar formation - little wound space to be
filled in
Deep Incisions, excisional wounds and burns -
wound edges - far apart destruction of
substantial amounts of tissue - repair by the
formation of extensive scar tissue
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Phases of Repair in Excisional Wounds
3 tightly integrated phases - occupy variable timeframes, depending on size of wound:
Hemostasis
Inflammation
Structural Repair
Nine cell types - major roles in the epidermal and
dermal repair process:
Platelets, neutrophils, macrophages, T-cells, mastcells, injured axons of sensory and sympathetic
post-ganglion nerves - hemostasis and inflammation
Epidermal cells, dermal fibroblasts and endothelial
cells - means for structural repair
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Phase I Hemostasis & Clot
Formation
Wound - blood vessels, epidermal and
connective tissue cells & surrounding ECM
First response to wounding HEMOSTASIS -
minutes to stop bleeding and seal off the wound
by 3 mechanisms:
a) Formation of Platelet Clumps
b) Vasoconstrictionc) Formation of Fibrin Clot
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a) Formation ofPlatelet Clumps
The cells in the wall of blood vessel at the site of injury -
release ADP - clumping of platelets to the injury site
Immediately upon an injury, blood flood into thewounded area
Degranulation of clumped platelets upon contact with
exposed collagen in the walls of the injured blood vessels
releasing more ADP (further attracts more platelets),Arachidonic acid, Fibrinogen, Fibronectin,
Thrombospondin, and von Willebrand Factor VIII
AA - converted to thromboxane A2 through COX pathway
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b) Vasoconstriction
Thromboxane A2 and serotonin from injured
nerve axons vasoconstrictors - restrict blood
flow into the wound by constricting the blood
vessels The injured nerves - substance P , a
neuropeptide - mast cells degranulation in the
dermis - releasing histamine increase in the
permeability of vessel walls -allowing furtherleakage of plasma into the wound
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c) Formation of Fibrin Clot
Blood plasma in the wound space contains coagulationfactors - induce clot formation
Hagemann Factor VII, a plasma protein initiates a
cascade of reactions involving about 12 clotting factors (I-
XII) and requireC
a
2+
as an essential cofactor. Tissue factor - produced at the end of cascade and
converts prothrombin to active enzyme thrombin
Thrombin catalyzes the conversion of plasma fibrinogen
to fibrin, the major structural protein of clot
Prothrombin Thrombin
Tissue factor
Fibrinogen Fibrininsoluble clot
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Fibrin molecules -e organized into fibers that
intertwine to form a meshwork - traps RBCs,
WBCs and platelets Meshwork also contains plasma Fibronectin,
Vitronectin as well as Thrombospondin from
degranulated platelets and collagen types I,
III, IV (probably synthesized by monocytes)
Blood Clot Formation (blood cells, platelets, fibrin clot) (SEM x10,980)
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ADP
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Contraction of provisional matrix and
exudation of serum thrombosthenin
Dehydration of clot scab prevents fluidloss
Invasion by cells of immune system
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Phase 2: Inflammation
Within a day after injury, chemotactic factors released during
clot formation
Increase in permeability of surrounding capillaries - attracts
neutrophils, monocytes and T-lymphocytes - crawl out
between endothelial cells into the provisional fibrin matrix
The leukocytes insert themselves into spaces between
endothelial cells via binding of Platelet Endothelial Cell Adhesion
Molecule (PECAM) on the surface of the leukocytes to PECAM
on extrusions of endothelial cell surface.
Neutrophils and monocytes migrate into the clot
simultaneously; neutrophils in greater numbers - use fibronectin
in the clot as an adhesive substrate and express the appropriate
integrin receptor to bind to fibronectin
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After entering the wound and adhering to Fibronectin, the
monocytes differentiate into macrophages
Within the clot, macrophages secrete TGF-, PDGF and other
chemoattractants such as leukotriene B4, monocyte-
chemoattractant proteins 1,2,3 (MCPs), macrophageinflammatory protein 1 and , and the chemotactic protein
CAP37 attract neutrophils and macrophages
Neutrophil influx diminishes within 3-4 days after injury. T-cell
lymphocyte peaks by the end of the first week or later. T cells
particularly the Th1 subset may play a role in regulating
macrophage-induced activities.
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Phase 2: Inflammation
Lasts for 5-7d
Within a day - Chemotactic factors - released
during platelet degranulation and clot formation
including fibrinopeptides (fibrinogen cleavageby thrombin) , fibrin degradation products
produced by the action ofplasmin,
complement fragment C5a, collagen & elastin
fragments
The most important chemoattractants for the
inflammatory phase are TGF- and PDGF
supplied by degranulating platelets.
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TGF- - attracts monocytes
PDGF - attracts neutrophils and monocytes
tPA plasminogen to plasmin
Plasmin activates MMPs and also acts
directly on fibrin
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Important tasks of inflammatory
neutrophils and macrophages
kill bacteria through oxygen-dependent mechanisms that
generate H2O2 and HOCl
Neutrophils also produce bactericidal peptides and
proteins, including the enzyme cathepsin G Neutrophils and macrophages also play a central role in
degrading collagen within the wound - production of
MMPs - MMP-1 and MMP-8
MMP-1 degrades type I and III collagens & MMP-8
degrades type I collagen.
The neutrophils and macrophages clean up the wound
site by phagocytizing dead bacteria, as well as cellular
and molecular debris.
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Neutrophils accelerate keratinocyte
differentiation slowing proilferation andmigration
Continual influx of neutrophils andmacrophages to replace the dead ones
may lead to chronic tissue injury, necrosis andexcessive scarring
Limit to their migration and secretoryactivities and also their removal
Neutrophils apoptosis after few hrs in thewound engulfed by macrophages
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Phase 3 : Structural Repair
Several sub phases:
Re-epithelialization
Formation of Granulation Tissue
Remodelling of Granulation tissue into scar
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Phase 3: Structural Repair
a) Re-epithelializationWithin a few hours after injury - cells in stratum basalelayerof the epidermis at the edge of wound loosen their
attachments to one another and begin migrating as a
sheet through the fibrin clot to cover the wound surface
The migrating cell sheet just expands (does not divide) -
basal cells just interior to the wound edge divide and
feed progeny into the migrating sheet
After the migrating epidermis has expanded to cover the
wound surface, its cells divide vertically to thicken the
epidermis and synthesize a new basement membrane
Excessive damage no regeneration of hair and sweat glands
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b) Development of Granulation Tissue
Within two days after injury, well before the inflammatory
phase is over, fibroblasts begin migrating from the
surrounding dermis into the clot.
Initiated by GFs secreted by macrophages, primarily
PDGF and TGF- - stimulate fibroblast migration and
proliferation
Replacement of fibrin clot by capillary-rich fibroblastic tissue
Simultaneously , new capillaries regenerate into the
nascent fibroblastic tissue, which is now called
granulation tissue because the capillaries give it a
reddish, granular appearance
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Macrophages, fibroblast and capillaries invade the wound
space as a unit biologically interdependent during tissue
repair
The fibroblasts synthesize a new transitional matrix to
replace the fibrin matrix, and the new capillaries carry
oxygen and nutrients to the injury site, to sustain the
metabolism required for these cellular process.
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Source of fibroblasts for structural repair: Resident dermal fibroblast
present in the deep layers of reticular dermis
and hypodermisSynthesize collagen type I
Fibroblast differentiating from circulating
mesenchymal stem cells from bon marrowthat enter the wound from the vasculature.
Synthesize collagen type I and III
Fibroblast Migration and Proliferation
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Heterogeneity in fibroblast population
Sub population of skin fibroblasts show:
1) Variation in morphology.
2) Variation in the amount of collagen
expressed per cell.
3) Variation in their response to cytokines
derived from macrophages
Papillary layer fibroblasts higher metabolic
rate and proliferative activity and cell densityat confluence
Heterogeneity in fibroblasts from healing intra-
oral wounds and fetal dermis
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The movement of fibroblasts into thefibrin matrix of the wound - mediated by
their integrin receptors Fn and HA major components of early
granulation tissue matrix
HA-PG complexes bind water expandEC space fibroblast migration
The fibroblasts express CD 44 receptor -mediates cell attachment to and
locomotion on HA substrate andreceptor for hyaloronan-mediatedmotility (RHAMM) which mediates celllocomotion in response to soluble HA
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Fibronectin
acts as asubstrate for
the migration
of fibroblasts
and vascular
endothelial
cells into the
wound
b bl l f d
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Fibroblasts proliferation, migration and ECM
synthesis in vitro - stimulated by macrophages
through GFs during inflammatory phase TGF
and PDGF
Growth factors:
TGF- (Transforming growth factor) PDGF (Platelet-derived GF) major GF renders
fibroblasts competent to leave G0 and enter G1
Receptor on dermal fibroblasts
FGF-2 (Fibroblast GF)
EGF (Epidermal GF)
IGF-1 (Insulin-like GF)
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Cytokines:
PDGF produced by macrophages
IL-1 (Interlukin) by macrophages
stimulates fibroblasts to produce PDGF
IFN- inhibits fibroblast entry into G1
TGF- & TNF- (Tumor necrosis factor)
stimulate fibroblast proliferation
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As the number offibroblasts invading the woundspace increases and the number of neutrophils
decreases, the fibrin provisional matrix isdegraded into soluble fragments through theconversion ofplasminogen toplasmin by tPA(tissue plasminogen activator) secreted by
endothelial cells of regenerative capillaries, andMMPs (Matrix Metallo Proteinases) secreted byfibroblasts.
When the fibrin degrades, tPA is inhibited and theexpression ofplasminogen activatorinhibitor(PAI) is stimulated, thus reducing theconversion of plasminogen to plasmin.
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ECM Synthesis By Fibroblasts
As fibroblasts invade the wound space, theyreplace the provisional fibrin matrix with an ECM
consisting ofFn, HA, sulfated PGs and type I and III
collagens.
HA predominates over Fibronectin in early
granulation tissue, opening up migration space for
fibroblasts.
Type IIIis the major collagen synthesized at this
time organized in reticular pattern
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Dermal repair then show visible signs of fibrotic
rather than a regenerative pathway.
HA synthesis is replaced by synthesis ofchondroitin
sulfate and dermatan sulfate-PGs.
The fibroblasts synthesize predominantly Type I
collagen and more collagen is synthesized than in
uninjured skin.
Shift in pattern of ECM synthesis PDGF and TGF-
beta
PDGF early stages HA synthesis and later sulfated
GAGs
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TGF-beta early Fn and later Type I
collagen, elastin and sulfated GAGs and;
inhibits collagen degradation by
Downregulation of collagenase gene
Upregulation ofTIMPs
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Angiogenesis in Granulation Tissue
Angiogenesis: The regeneration of new bloodvessels
From pre-existing ones
Crucial regenerative response in all injuredtissues whether the end result is scar tissue
formation or restoration of normal tissue
architecture
adequate supply of oxygen and nutrients
Common elements in fibrotic and
regeneration pathways to promote blood
vessel re eneration
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Low-O2 tension signal for angiogenesis
Initially hypervascularization reddish
app. during remodeling into scar tissue
extra apoptosis
Macrophages said to be involved in
apoptosis of endothelial and their
supporting cells - pericytes
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Reinnervation of granulation tissue
Peripheral sensory and sympatheticpostganglionic nerves - regenerate in healing
wounds
Play a significant role in the formation ofgranulation tissue because of their effects on
inflammation
W
ound 1-2 days degeneration of nervesdistal to injury
Next two weeks hyperinnervation of
granulation tissue
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Subsequent regression
Same pattern of advance and recession as
angiogenesis may be mechanisticallycoupled
Injured sensory and sympatheticpostganglionic nerves appear to help mediatethe inflammation phase (neurogenicinflammation) via antidromic (conduction inreversed direction) stimulation of
neuropeptides such as substance P mastcell activation and degranulation
Intimate microanatomic association of mastcells and nerves in dermis
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Injury to nerves degranulation of mast cells
releases histamine and cytokines
Vasodilation
Increased capillary permeability
Attraction of neutrophils and macrophages
Increased fibroblast activity
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Remodeling ofGranulation Tissue into Scar
Final phase of structural repair - granulationtissue remodeled into a relatively acellularfibrous scar tissue
The scar differs from normal dermis in severalways Fn and HA levels return to normal
Decorin PG is lower than normal skin,
Chondroitin-4-sulfate PG is much higher
Collagen organization uninjured dermis reticular app (basket-weave like)
repaired dermis type I collagen MMPs - cross-linkedby lysyl oxidase into thick bundles parallel to wound
surface
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MMPs produced by epidermis and fibroblasts
Elastin fibers reduced
Scarmaturation vascular and neural
network density normal
Reduction in fibroblast number by apoptosis ~ 6 months in humans
Tensile strength increases with degree of cross-
linking; but not as normal tissue
Feedback loops inhibitory factors to end
the repair process
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Wound contraction in dermal repair
Mammals with loose skin excisional woundclosure aided by contraction of the dermis
Decrease the area to be covered by dermis and
filled in by scar tissue Most importantly in rodents (~90%); lesser in
pigs and humans (50%)
Fetalmammals regeneration in absence ofdermal contraction
Development increase in contraction along
with decreased capacity for regeneration
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f
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Molecular comparison of wounded vs
unwounded skin
Transcriptional profiling
whole skin or fibroblasts
A study by Iyer 8600 gene profiling
Genes Transduction of serum signals Entrance and progression through cell cycle
Wound repair 10 with clotting and hemostasis
8 inflammation 6 re-epithelization
12 angiogenesis
19 remodeling of granulation tissue
200 novel genes with unidentified function
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Fetal skin heals without scarring
Fetal mammalian skin repair w/o scarring
after excisional wound
Less contraction
Rapid re-epithelization and fibroblast
migration
Granulation tissue lays normal ECM
architecture
Late gestation regeneration to adult
response of fibrosis
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Cellular and ECM differences
Collagen and noncollagen protein synthesis higher than normal in fetal and adult ratwounds
Ratio collagen/total protein in wounded adultskin > unwounded adult skin
In fetal skin no significant differencebetween wounded and unwounded skin
No excessive type I collagen in fetal skin andfibril organization in reticular fashion
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Fetal skin normal pattern of collagen
synthesis and architecture
Fetal wound fibroblasts synthesize higher
levels of HA and HA receptor better cell
movement
HA inhibits fetal fibroblast proliferation anddecrease scar formation
Sulfated PG synthesis does not accompany
collagen synthesis in fetal wounds Fetal skin higher type III/type I collagen
ratio
F l d i i l i fl
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Fetal wounds minimal inflammatory
response
Major difference fetal wounds minimal
inflammatory response
Development immune system response to
injury suppresses regeneration in favor of scar
tissue formation
Fewer platelets in fetal wounds
Macrophage no. and persistence lower than
in adult wounds
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Thus, types and proportions of cytokines and
GFs involved in inflammatory response
different in fetal and adult wounds
Lower levels ofPDGF, TGF-1 and 2 and their
receptors in unwounded and wounded fetal
rat skin TGF-beta3 higher in fetal than adult
In adults PDGF induces persistent exp of
IL-6 maintains an environment thatpromotes production and deposition of
fibrotic matrix
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Some studies intrinsic differences in fetaland adult fibroblasts result of differentiation
independent of maturation of immune system
Fetal fibroblasts unique phenotype differsin production of and response to GFs,
synthesis of matrix components, pericellularHA coats and antigenic determinents
Wound environment major determiningfactor
Extent of injury - Tatoos repair by noscarring total area large but smallerindividual injury no inflammatory response