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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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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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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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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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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Tissue Repair 2011