Tissue Repair 2011
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Transcript of Tissue Repair 2011
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HEALING
PROCESS
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REPAIR The body ability to replace injured or dead cells
and to repair tissues after inflammation is critical
to survival
The repair of tissue damage can be broadly
seperated into two processes: regeneration andhealing
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Definition.
There are two important distinctions included in repair:
regeneration and healing.
REGENERATION
Refers to growth of cells and tissues to replace loststructures, such as the growth of an amputated limb in
amphibian
In mammals: this term is used in processed applied to
liver (partial hepatectomy) and kidney (unilateralnephrectomy) not really true regeneration
The continuous regeneration applied to epithelial tissue
of skin and GI tract
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Definition.
HEALING, is usually a tissue response to:
1. A wound (commonly in the skin)
2. Inflammatory process in internal organs
3. Cell necrosis in organs incapable of regenerationIn this broad definition may include:
Atherosclerosis: a condition considered to be an
attempt to heal injury of the arterial wall
Healing consists of variable proportions of two distinct
processes: regeneration and laying down of fibrous
tissue (scar formation)
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REPAIRresume
Two distinct processes:Regeneration
Replacement of injured cells by cells of the same type
Fibroplasia / fibrosis
Replacement of injured cells by connective tissue
cell migration
cell proliferation & differentiation
cell-matrix interaction (ECM organization & remodelling)
Repair (proses dasar)
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Mechanism regulatingcell populations
Cell Differentiation
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Cell Differentiation
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Control of Normal Cell Growth
Normal CellInjury
Cell death
Mechanical deformation oftissue
Proliferation
Microenvironment Cellreplication
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Cell Cycle Landmark
1.
2.
3.
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Cell-groups based on the proliferative capacity
Continuously dividing cells (labile cells)
- Surface epithelia of the skin, oral cavity, vagina, cervix
- The lining mucosa of the excretory ducts of glands:
pancreas, salivary glands, billiary tract
- Columnar epithelium of the gastrointestinal tract and uterus
- Transitional epithelium of urinary tract- Cells of the bone marrow and hematopoietic tissue
Quiescent / stable cells (low level replication)
- Parenchymal cells: liver, kidney, pancreas
- Mesenchymal cells: fibroblast, smooth muscle- Vascular endothelial cells
Nondividing / permanent cells
- Neurons, skeletal muscle, heart muscle
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Molecular Events inCell Growth
Cell Signaling (autocrine, paracrine, endocrine)
Cell Surface Receptors
- Receptors with intrinsic tyrosine kinase
activity
- Receptors without intrinsic tyrosine kinaseactivity
- G Protein-Linked Receptors
Signal Transduction System
- MAP-kinase pathway- PI-3 kinase pathway
- IP3
pathway
- cAMP pathway
- JAK/STAT pathway
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General Patterns
of Intracellular
Signaling
C ll f t d i i l
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Cell surface receptors and principalsignal transduction pathways
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Growth Factors and Cytokines AffectingVarious Steps in Wound Healing
Monocyte chemotaxis PDGF, FGF, TGF-
Fibroblast migration PDGF, EGF, FGF, TGF-, TNF, IL-1
Fibroblast proliferation PDGF, EGF, FGF,TNF
Angiogenesis VEGF, Ang, FGF
Collagen synthesis TGF-, PDGF
Collagenase secretion PDGF, EGF, FGF,TNF, TGF- inhibits
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REPAIR
The goal of the repair process is to restore
the tissue to its original state.
The inflammatory reaction contains : The damage
Eliminates the damaging stimulus
Remove injured tissue Initiates the deposition of ECM components
in the area of injury
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Migrasi sel selama repair
1. Lekosit keluar dari vasa darah, menembus membranbasal, masuk ke matrix
2. Endotel lepas dari membran basal, migrasi ke dalammatrix untuk membentuk kapiler baru
3. Perisit lepas masuk ke matrix
4. Fibroblas menjadi bipolar dan migrasi menembus matrixmenuju ke tempat lesi
5. Epitel keratinosit lepas dari kelompoknya, migrasi diantara luka sepanjang matrix dermis
Migrasi sel memicu repair
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Repair by Healing,Scar Formation and Fibrosis
a complex but orderly phenomenon involving a number of processes
Induction of an acute inflammatory process by the
initial injury
Regeneration of parenchymal cells
Migration and proliferation of both parenchymal andconnective tissue cells
Synthesis of ECM proteins
Remodeling of connective tissue and parenchymalcomponents
Collagenization and acquisition of wound strength
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Hal 113
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Granulation tissue & mature scar
Numerous blood vessels, edemaand a loose ECM containing
inflammatory cells.
collagen
Dense collagen and scattered
vascular channels
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ANGIOGENESIS
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Angiogenesiscapillary sprouting
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Tissue
Remodeling:
MMP regulation
O d l Ph f W d H li
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Orderly Phases of Wound Healing
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Regulation of vascular
morphogenesis by receptortyrosine kinases and theirligands
W d H li
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Wound Healing
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Cutaneous wound, 2-4 days (thrombus)
GF controlling migration of cells are illustrated. Extensive redundancy is present,
and no growth factor is rate limiting. Most factors has multiple effects.
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Cutaneous wound, 4-8 days (thrombus)
Blood vessels are proliferating, and the epidermis is penetrating the thrombus,but not at its surface. The upper portion will become an eschar or scab.
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Summary of healing process
1. A fibrin clot forms and fill the wound gap. Fibronectin inthe extravasated plasma is cross-linked to fibrin,collagen, and other ECM component by the action oftransglutaminases provides a provisional mechanicalstabilization of the wound (0-4 hours)
2. Macrophages recruited to the wound area, process cellremnants, and damaged ECM. The binding of fibronectinto cell membranes, collagens, proteoglycans, DNA, andbacteria (opsonization) facilitates phagocytosis by thesemacrophages and contributes to the removal of debris(1-3 days).
3. Fibronectin, cell debris, and bacterial products arechemoattractants for a variety of cells that recruited tothe wound site (2-4)
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4. As a new ECM is deposited at the wound site, the initialfibrin clot is lysed by a combination of extracellularproteolytic enzymes and phagocytosis (2-4 days)
5. Concurrent with fibrin removal, there is deposition of
temporary matrix formed by proteoglycan, glycoprotein,and type III collagens (2-5 days)
6. Final phase of the repair reaction.
Eventualoly temporary matrix is removed by a
combination of extracellular and intracellular digestion,and the definitive matrix, rich in type one collagen, isdeposited (5 days-weeks)
Summary of healing process
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Systemic factors influence healing
Nutrition (deficiency vitamine C)
Metabolic status (DM)
Circulatory status Hormones (glucocorticoid inhibit
collagen synthesis)
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Local factors influence healing
Infection
Mechanical factors Foreign bodies
Size: location, and type of wound
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Pathologic Aspects of Wound Repair
Deficient scar formation
- wound dehiscence
- ulceration
Excessive formation of the repair components
- hypertrophic scar
- exuberant granulation granuloma
- desmoid (aggressive fibromatosis
Formation of contractures deformities of the wound and surrounding tissue
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Healing of skin ulcers
Pressure ulcer of the skin, commonly
found in diabetic patient
Skin ulcer with large gap between
the edges of the lesion
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Healing of skin ulcers
A thin layer of epidermal epithelization
and extensive tissue granulation
formation in the dermis
Continuing reepithelization of the
epidermis and woud contraction
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Healing of skin ulcers
KELOID
Excess collagen deposition in skin forming a raised scarknown as keloid.
INJURY
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INJURY
VASCULAR & CELLULAR RESPONSE
ACUTE INFLAMMATORY EXUDATION
Stimulus promptly destroyed Stimulus not promptly destroyed
No/minimal necrosis of cells Tissue of stable Necrosis of cells
or labile cells
Exudate Exudate Tissue ofresolved organized Framework Framework permanent cells
intact destroyed
Restitution of Scarring Regeneration Scarring Scarring
normal structure Restitution of
Fibrinopurulent normal structure Bacterial Myocardial
Mild heat injury - pericarditis abscess infarction
- peritonitis Lobar pneumonia
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FRACTURE
The most common bone lesion Fracture is defined as a discontinuity of bone
A force powerful enough to fracture a bone may also
injures the adjacent soft tissue results in:
1. Extensive muscle necrosis2. Hemorrhage (shearing of capillary beds and larger
vessels of soft tissue)
3. Tearing of tendineous insertions & ligamentous
attachment
4. Nerve damage, caused by stretching or direct tearing
of the nerve
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FRACTURE
Traumatic and non traumatic fracture
Complete and incomplete fracture (greenstick)
Closed (simple) fracture
Compound fracture
Comminuted fracture
Pathologic fracture
Stress fracture
FRACTURE: h i f h li
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FRACTURE: mechanism of healing process
rupture of blood vessels hematoma (fills the
fracture gap & surrounds the area of bone injury,provides fibrin mesh)
simultaneously
degranulated pletelets and migrating inflammatorycells release PDGF, TGF-, FGF, and ILs
activate the osteoprogenitor cells
in the periosteum, medullary cavity, and surroundingsoft tissue
stimulate the production of osteoclastic andosteoblastic activity
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FRACTURE: mechanism of healing process
B M t i
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Bone Matrix
Active osteoblast synthesizing bone matrix. The surrounding spindlecells represent osteoprogenitor cells.
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Two osteoclasts resorbing bone
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Paracrine molecularmechanisms that
regulate osteoclasts
formation andfunction.
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FRACTURE..
By the end of the first week:
The hematoma is organized
The adjecent tissue is being modulated for futurematrix production
The fractured ends of the bones are being
remodeled
Soft tissue callus / procallus
provides some anchorage between the ends of thefractured bones
(No structural rigidity for weight bearing)
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FRACTURE: mechanism of healing process
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Activated osteoprogenitor cells deposit wovenbone in the subperiosteal trabeculae,perpendicularly to cortical axis and within the
medullary cavity
Activated mesenchymal tissue cells differentiateinto chondroblast fibrocartilage and hyaline
cartilage enveloping the fracture site
Woven bone approaches the newly formedcartilage at the fracture line enchondral
ossification the fracture ends are bridged by
a bony callus
FRACTURE:next step
Fracture Callus
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Fracture Callus
Osteoid tissue Bony callus
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Woven bone deposited
on
the surface of pre-
existing lamellar bone
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FRACTURE
The healing of a fracture is divided into 3phases:
1. The inflammatory phase
2. The reparative phase
3. The remodeling phase
S G
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I. FASA RADANG
1-2 hari sesudah fraktur ruptur vasadarah pada perios, otot, dan jaringanlunak hemoragi hebat
Nekrosis luas pada tulang daerah fraktur
hallmark untuk tulang mati: tidak adaosteosit dan lakuna osteosit kosong
2-5 hari hemoragi bekuan darah
resorbsi, neovaskularisasi dari tepijendalan darah dalam 7 hari jendalandiorganisasi oleh invasi vasa darah danfibrosis
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I. FASA RADANG
Sesudah 7 hari mulai terbentuk wovenbone dimulai dari tepi jendalan, sel
mesenkimal pluropotensial (dari jaringanlunak dan sumsum tulang) osteoblasmembentuk woven bone dan kartilagoosifikasi enkondral kalus (jaringan
granulasi berisi tulang dan kartilago)
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II. FASA REPARATIF
Mulai minggu ke 2 sampai berbulankemudian (tergantung pada derajatgerakan dan fiksasi fraktur) pada
saat ini sel-sel radang tidak ditemukanlagi
Proses reparasi melibatkan diferensiasi
sel-sel pluripotensial menjadi fibroblasdan osteoblas
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II. FASA REPARATIF
Reparasi mula dari tepi ke tengah frakturuntuk menyelesaikan proses:
1. Mengorganisasi dan meresorbsijendalan darah
2. Menyediakan neovaskularisasi untuk
membentuk kalus, yang akan menjem-batani daerah fraktur
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III. FASA REMODELING
Basic multicellular unit (BMU): kerja samaosteroklas dan osteoblas prosespembentkan dan resorpsi homeostasismasa tulang
Tulang tumbuh dan membesarmodeling maturitas penghancurandan pembaharuan remodeling
Pada orang dewasa ada 1jt BMU yangaktif remodeling 10 % skeleton/th
Bone remodeling
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gseqence
Initiated by the appearance of
osteoclasts on a bone surface
previously lined by fusiform cells
After development of aresorption bay, osteoclast are
replaced by osteoblast
Deposit new bone
The bone loss that attend aging
(senile osteoporosis) is due to
incomplete filling of
resorption bays.
RESUME
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RESUME Migration of cells initiate repair
ECM sustains the repair process
ECM components are elaborated and modified in repair
Remodeling is the long-lasting phase of repair
Cell proliferation is evoked by cytokines & matrix
Integrated molecular signals mediate proliferation and differentiation
Three protein family transduce signals to the nucleus Outcomes of injury include repair and regeneration
Wound healing exhibit a defined sequence
The cell cycle leads to mitosis
Cells can be classified by their proliferative potential
Regeneration is mediated by either stem cells or stable cells
Local factors may retard healing
Specific sites exhibit different repair pattern
Wound repair is often suboptimal
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The basic Process of wound healing
Migration of cells initiate repair
ECM sustains the repair process
ECM components are elaborated and modified inrepair
Remodeling is the long-lasting phase of repair
Cell proliferation is evoked by cytokines & matrix
Integrated molecular signals mediate proliferationand differentiation
Three protein family transduce signals to thenucleus
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Repair
Outcomes of injury include repair andregeneration
Wound healing exhibit a defined sequence
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Regeneration
The cell cycle leads to mitosis
Cells can be classified by their proliferativepotential
Regeneration is mediated by either stemcells or stable cells
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Conditions that modify repair
Local factors may retard healing
Specific sites exhibit different repair pattern Wound repair is often suboptimal
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Vascular Endothelial Growth Factor(isoform A,B,C,D)
(VEGF)
Sumber Fungsi
Sel menkimal Meningkatkan permeabilitasvaskular, mitogenik terhadap
sel endotelial
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Platelet Derived Growth Factor (isoform A,B,C,D)
(EGF)
Sumber Fungsi
Platelet,makrofag,endotel,
keratinosit, selotot polos,
Kemotaktik untuk pmn, makrofag,fibroblas, dan otot polos
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Transforming Growth Factor Alpha
(TGF-)
Sumber Fungsi
Makrofag, limfositT, keratinosit,jaringan lain
Meningkatkan proliferasi sel-sel epitelial dan endotelial,hepatosit, dan motilitas sel
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