• Immediate Vasospasm leads to relaxation Platelets aggregate to exposed collagen and a network of fibrin forms - Reduces blood loss - Binds edges of the wound together - Initiate angiogenesis (PDGF, TGFβ)- growth factors are released, which are important for the proliferative phase

Test 2- Wound Healing Flashcards by Magenta Kline

wound

injured tissue

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repair

replacement of injured tissue

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Healing begins…

Healing begins immediately after a wound develops

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Hemostasis

• Immediate

Vasospasm leads to relaxation

Platelets aggregate to exposed

collagen and a network of fibrin forms

Reduces blood loss
Binds edges of the wound

together

Initiate angiogenesis (PDGF,

TGFβ)- growth factors are released, which are important for the proliferative phase

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Phases of wound healing

Hemostasis
Inflammation-“clean up”
Proliferation- 1 week in
Maturation- weeks in ;

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Inflammation

24-96 hours

Cardinal signs of inflammation seen

Some ECM components are chemotactic

Degradation–leukocytes“clean up” cell debris from the injury

Leukocytes secrete chemotactic

and growth factors leads to proliferation

phase

If excessive, can reduce healing

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Degradation

leukocytes“clean

up” cell debris from the injury

Leukocytes secrete chemotactic

and growth factorsproliferation

phase

If excessive, can reduce healing

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Proliferation

3-7 days, lasting up to 3-4 weeks

Regeneration of tissue:

- Endothelium (angiogenesis)

- Epithelium (epithelialization)

- Connective tissue (fibrosis)

Granulation tissue forms

Stem cells in a quiescent stage are

influenced by cytokines / growth factors

—Limited by proliferative potential of cell

types involved

Fibroblasts proliferate to fortify the

woundcollagen deposition

Decreases with age and disease

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Maturation

Begins 3-4 weeks after injury, after proliferation, can last years

Remodeling of granulation tissue, maturation of fibrosis, and wound contraction

Required for return of tensile strength

Re-establishment of cell interactions

Vascular regression

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Wound Healing by Primary Intention

Wounds with opposed edges

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Wound healing by Secondary Infection

Gaping wounds

Septic wounds

Foreign bodies

Wound with delayed healing process

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Primary vs secondary infection

both have the same phases of wound healing

THE DIFFERENCE IS, the extent to which it has to be healed.

Primary can be healed in about 3-5 days.

Before secondary intention can occur, you have to have healthy granulation tissue, so it will take longer.

Scar will be much bigger in secondary intention and the tensile strength of the wound will be decreased.

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Note large amounts of granulation tissue and wound contraction in the healing by

secondary intention

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Degradation

Must remove junk before healing can occur

Things in the center of a wound:

– Dead cells

– Leukocytes

– Cytokines

– Serum/clotting proteins

– ECMsubstances

How leukocytes do it:

– Phagocytosisandlysosomaldegradation

– Degranulationandreleaseofdigestive enzymes

– Matrix metalloproteinases–very important for degrading the ECM

Must remove junk before healing can occur

Things in the center of a wound:

– Dead cells

– Leukocytes

– Cytokines

– Serum/clotting proteins

– ECMsubstances

How leukocytes do it:

– Phagocytosisandlysosomaldegradation

– Degranulationandreleaseofdigestive enzymes

– Matrixmetalloproteinases–very important for degrading the ECM

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Phase of Wound Healing

Degradation

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A tissues ability to return to normal depends on

A tissues ability to return to normal depends on:

Retention of ECM structural framework

Regenerative capacity of cells

Labile/Continuously dividing cells

– Proliferate throughout life, replacing those cells that are destroyed

– Ex: epithelial cells of liver, kidney, lung, pancreas, skin, mucous membranes

Quiescent/Stable cells

– Low level of replication; undergo rapid division in response to stimuli

– Capable of reconstituting the tissue of origin

– Ex: smooth muscle, fibrocytes, vascular endothelial cells, chondrocytes, osteocytes

Permanent cell/Non-dividing cells

– Have left the cell cycle & cannot undergo mitotic division in postnatal life

– Ex: Neurons, cardiac & skeletal muscle

Regeneration of Epithelium (Epithelialization)

Proliferate immediately at denuded surfaces

Must disassemble connections to the basement membrane and junctional complexes with neighboring cells

Must express surface receptors that bind ECM

Intact basement membrane greatly facilitates!

Regulated by contact inhibition

Kidney from a calf with renal tubular necrosis and regeneration due to oak bud toxicosis

Role of the extracellular matrix (ECM) in regeneration and repair.

Liver regeneration with restoration of normal tissue after injury requires an intact cellular matrix.

If the matrix is damaged the injury is repaired by fibrous tissue deposition and scar formation.

Growth factors

Needed for cellular

– Proliferation
– Differentiation

EGF – bind receptors on epithelial cells thenactivates MAPK then induces G0 phase cell cycle

Stem Cells

Stem Cells – important source for epithelial regeneration

Embryonic – pluripotent; isolated from blastocysts

Tissue stem cells- most in WOUND HEALING

– Not pluripotent; restricted lineage- specific differentiation capacity- depends on what tissue it is in

– Bone marrow(bone marrow, umbilical cord) – hematopoietic and mesenchymal cells- greater capacity-

– Skeletal muscle “satellite cells”

Regeneration: Endothelium (Angiogenesis)

Formation of new blood vessels from existing ones
PDGF,FGF,VEGF-Abind GF-R’s on endothelial cells induce vascular formation by…

– Endothelial proliferation
– Recruitment of pericytes
– Deposition of ECM proteins

Regeneration of Connective Tissue

Fibroplasia – migration & proliferation of fibroblasts

Fibrosis – scar formation by connective tissue remodeling

Factors that favor fibrosis:

– Severe and prolonged tissue injury

– Loss of tissue framework (basement membranes)

– Large amounts of exudate/inflammation

– Lack of renewable cell populations

Fibrous connective tissue

– Dense accumulation of fibroblasts and collagen – With time, the collagen becomes more densely packed – Persists for years (life)

Consequences of fibrosis

- Loss of functional parenchymal tissue - Alteration of physical properties of tissue

Granulation Tissue

• Distinctive arrangement of connective tissue fibers, fibroblasts, and blood vessels – **Fibroblasts and connective tissue grow parallel to wound surface** **– Blood vessels arranged perpendicular to fibrosis** Fragile capillaries – bleeds easily Granular surface **Can be excessive, a type of hypertrophic scar termed proud flesh**

Granulation Tissue

When good granulation tissue goes bad... “Proud flesh” (aka exuberant granulation tissue)

Wound contraction

A normal part of the maturation phase of wound healing But can be bad when connective tissue contracts and place tension on surrounding tissues May immobilize or deform the tissue (ex: burns) Mediated by myofibroblasts – Form within wounds in response to TGF-β – Increase with time and severity

Conditions with Impaired Wound Healing

Tension on a tissue Prolonged inflammation – Local infection, foreign material – Abundant necrotic tissue Disorders in collagen synthesis – Protein malnutrition – Hyperadrenocorticism – antagonistic effect of steroids – Inherited defects – osteogenesis imperfecta, Ehlers-Danlos syndrome – Scurvy(vitaminCdeficiency) Poor blood supply – Diabetes mellitus – impaired angiogenesis • Impaired ability of cellular regeneration – Chemotherapy – Old age – Denervatedtissue

What phase of wound healing is this, if there is necrosis and neutrophils?

early inflammation stages

What stage of wound healing is this?

Proliferation. You can see the hypertrophic epithelial cells toward the center of the picture.

Angiogenesis process

1. proteolysis of ECM 2. Migration and chemotaxis 3. proliferation 4. lumen formation, maturation, and inhibition of growth 5. increased permeability through gaps and transcytosis or * *A** , Bone marrow. EPCs are mobilized from the bone marrow and may migrate to a site of injury. The homing mechanisms have not yet been defined. At these sites, EPCs differentiate and form a mature network by linking with existing vessels. * *B,** Preexisting vessels (capillary growth). In angiogenesis from preexisting vessels, endothelial cells from these vessels become motile and proliferate to form capillary sprouts. Regardless of the initiating mechanism, vessel maturation (stabilization) involves the recruitment of pericytes and smooth muscle cells to from the periendothelial layer

What is this?

Fibrous connective tissue

Synthesis of ECM

– Collagen, elastin, fibronectin, laminin – Growth factors induces fibroblasts to synthesize collagen – Collagen = triple helices with lots of cross-linkage providing tensile strength TGF-β Produced by platelets & leukocytes Is important for fibroblast migration & proliferation, and collagen/ECM protein synthesis

Consequences of fibrosis liver- nodular surface

fibriotic liver stained with Thrichrome stain

What is this?

Granulation tissue- VERY GOOD