Wound Healing (Dong NAVDF) Flashcards by Treasa Clifford

Wound HEALING vs wound REPAIR

Healing = regeneration. Back to OG. Keratinocytes + endothelial cells

Repair = scarring. Compromised function. Fibroblasts

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4 phases of wound healing

1) Hemostasis/coagulation
2) Inflammation (neutrophils, then macs)
3) Repair/granulation phase
4) Remodeling/scar formation

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Order of cells involved in wound healing (plt, mac, fibro, neut)

1) PLATELETS ARE FIRST
2) Neutrophils
3) Macrophages
4) Fibrocytes

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Which are the FIRST cells in wound healing

Platelets

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What allows platelets to bind to each other

Thromboxane

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What mediates linkage of platelets with exposed collagen

von wilibrand factor

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What marks the END of the coagulation phase

Fibrin clot

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Factors of intrinsic coagulation cascade

Factors 11, 9, 8

Not $12, but $11.98

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Factors of common coagulation cascade

Factors 10, 1 (aka fibrinogen)

“Small change = $10, $1”

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Factors of the extrinsic cascade

Factor 7

Uses tissue factor to convert to factor 1, aka fibrinogen

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What mediates conversion of fibrinogen to fibrin

Thrombin

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What do damaged cells release to initiate hemostasis

Histamine
Serotonin
Catecholamines

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What happens to the blood vessels during hemostasis? (Vasoconstriction vs vasodilation)

Initially: Vasoconstriction to stop bleeding

Later: Vasodilation to recruit WBC

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Platelet activation pathway

1) Tissue injury
2) Exposed collagen recruits platelets (VWB F)
2) Coagulation cascade –> fibrinogen to fibrin via thrombin
3) Quiet platelet becomes activated via exposure to collagen, thrombin, ADP, TXA2
4) Active platelet releases DENSE granules (ADP, ATP, Serotonin) and TXA2 to activate more platelets
4) Active platelet releases ALPHA granules (fibrinogen, fibronectin, PDGF, P-selectin) to attract more neutrophils, macrophages
5) Platelets release stores of TGF-B, which induces fibrocyte activity, recruits more neut/mac

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Contents of Dense Granules (Platelets)

1) Serotonin
2) ADP
3) ATP

Induce aggregation of platelets
*Construction and adherence

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Contents of Alpha Granules (Platelets)

1) Fibrinogen
2) Fibronectin
3) PDGF
4) P-selectin

*Fibrin clot factors
*Chemokines for neut/mac/fibroblasts

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More important thing STORED in platelets, functions

TGF B

Activates neut/mac
Stimulates fibroblasts to myofibroblasts

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Cells that stores TGF B

Platelets

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Factors involved in LYSIS of fibrin clot (4)

1) Plasminogen activator (initiates lysis)
2) Antithrombin III
3) Protein C (factor 5, 8)
4) Prostacyclin C (limit platelet aggregation)

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Timeframe for neutrophils to come to wound

Minutes to 72hr

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Adhesion molecules involved in neutrophils ROLLING

Selectins

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Which Selectins on which cell types?

P selectin- platelets
E selectins - endothelial cell
L selectin- leukocytes

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Adhesion molecules involved in neutrophil ADHESION/activation

Integrins (ICAM, VCAM)

hold neutrophils TIGHTLY

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What binds to ICAM on endothelial cells

LFA-1 on neutrophil

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What binds to VCAM on endothelial cells

VLA on neutrophil

Which adhesion molecules allow diapedesis? (3)

1) PECAM1 2) JAM-1 (tight junctions) 3) VE-cadherin (adherens junctions)

When do macrophages enter wound healing site?

24-48hr

Which TYPE of macrophage is involved in wound healing?

What are M1 macrophages

Phagocytize bacteria + neuts, induce inflammation, scavenge debris Stimulated by TNF alpha

TNFalpha will induce which TYPE of macrophage

What are M2 macrophages

Repair, help with wound healing. Suppress immune system Stimualted by TGF Beta

TGF B will induce which TYPE of macrophage

Time frame of REPAIR phase of wound healing

2-10d

4 "steps" of Repair Phase

1) Granulation tissue formation (3-4d) 2) Fibroplasia, wound contraction (triggered by hypoxia. Fibroblasts respond to TGF-B) 3) Angiogenesis 4) Re-epithelialization

What stimulates fibroblasts to turn into myofibroblasts for wound contracture

TGF B PDGF Increases collagen integrin receptor alpha-2 expression

Type of Collagen INITIALLY in wound healing, granulation tissue

Collagen 3, less strong

Type of Collagen in MATURE wound healing, remodeling phase

Collagen 1, stronger

Type of collagen in vessels and hypertrophic scars

Collagen 5

Most abundant type of collagen in basement membrane

Collagen 4

When does wound contraction peak?

2 weeks

What type of collagen is present in scar tissue

Collagen 1

What type of collagen is present in granulation tissue

Collagen 3

Which 2 growth factors stimulation wound contracture

1) PDGF (induce fibroblast to myofibroblast) 2) TGF-B1 (stim fibroblast contraction, myofibroblast differentiation, production of HA and RHAMM)

What is the receptor for HA

RHAMM

What is the function of GAGs in wound healing

Moist environment

What is the fastest and most abundant GAG in wound healing

Where in cells is HA synthesized

Plasma membrane

When does angiogenesis start after wounding

Day 2

What stimulates angiogenesis (4)

1) Macrophage-released cytokines 2) Decreased O2 3) Lactic acid 4) Growth factors (VEGF, bFGF)

What are the 2 growth factors that stimulate angiogenesis

VEGF bFGF (basic fibroblast GF)

Where do keratinocytes for re-epithelialization come from?

*Neighboring keratinocytes *Hair follicle stem cells (bulge) *Sebaceous glands *Claws

If there is a full thickness wound, what to keratinocytes NEED to migrate over?

Granulation tissue

How do keratinocytes re-epithelialize with partial thickness wound?

Leap frog

What are lamellipodia

How keratinocytes migrate; little projections

Process of lamellipodia migration

1) Focal adhesion 2) Extension --> forms lamellipodia 3) Adhesion --> new focal adhesion at tip of lamellipodia 4) Translocation --> Contraction, cell body moves to the new focal adhesion 5) De-adhesion --> lets go of old focal adhesion

Stimulation of lamellipodia formation

Low Ca2+ High Mg2+

What are keratinocytes able to migrate over?

1) COL 1, 3, 5 2) Fibronectin 3) Fibrin 4) Tenascin 5) Vitronectin

Can keratinocytes cross the BMZ directly?

NO. MMP degrades the BMZ, so keratinocytes can reach it once GRANULATION tissue is formed

What is "contact inhibition"

When keratinocytes reach each other, they know to stop migration.

What is the final strength of the scar compared to original, healthy skin

70% strength

What signal helps with remodeling and scar formation

TGF-B

Which species has delayed collagen synthesis

Cats Forms day 19. "pseudo-healing". Indolent pocket wounds.

Where does granulation tissue begin in cats

Periphery of wound

Which species has an early inflammatory response

Dogs

Where does granulation tissue begin in dogs

Center of the wound Day 7.5 More direct cutaneous vessels

Which species has weak/prolonged inflammation phase

Horses

Which species has exuberant granulation tissue

Horse --> proud flesh

Which disease in horses is equivalent to keloids in people

Proud flesh -Increased TGF beta -Mast cell hyperplasia

T or F: Proud flesh can invade healthy skin

Which scar is characterized by NO myofibroblasts

Proud flesh

Which scar is characterized by ABUNDANT myofibroblasts

Hypertrophic scars Noninvasive Widely spaced collagen

Acronym to assess complications in wound healing= TIME. What does this mean?

TIME T= nonviable tissue I = inflammation, infection. Inflammation phase should be done in 3d, so if persistent, check for infection M= moisture E= epithelialization

Which growth factor is overexpressed in proud flesh. Which cell is hyperplastic in proud flesh?

TGF-B1 Mast cell hyperplasia

What is the difference between a wound DRESSING and wound BANDAGE

BANDAGE: Control swelling, immobilization 3 Layers 1) Dressing 2) Absorb deleterious factors 3) Hold layers together DRESSING: Cover + protection *Absorb excess exudate *Stimulate repair (non-antigenic, not too moist, occludes dead space)

In which phase of wound healing is honey a good dressing?

Inflammatory + Repair phase

Functions of honey dressing

-Debridement -Hyperosmotic effects * -Dehydrates microorganisms + Manuka factor (uMF) * -Reduces tissue edema -Stimulates granulation tissue

Functions of granulated sugar

*Hyperosmotic effects Inferior option: No antiinflammatory /wound healing effects Needs to be 1 cm thick Painful

Function of fish skin (tilapia, cod)

-Excellent skin adherence -Induces growth factors (EpidermalGF, FGF) -Antimicrobial activity -OFA 3: bacterial barrier, pain modulating

Function of negative pressure wound therapy

-Debridement -Aids in contraction -Increased perfusion -Decreased edema -Removes detrimental cytokines

Contraindications for negative pressure wound therapy

-Exsanguination -Neoplasia -Necrotic tissue/eschar

Benefits of HBOT (3)

-Hyper-oxygenation -Leukocyte oxidative killing capacity (Mac ROS) -Synergistic with antibiotics/antifungals

Which medications are synergistic with HBOT (4)

1) Fluoroquinolones 2) Aminoglycosides 3) Beta-lactams 4) Amphotericin B

Contraindications for HBOT (3)

-Pneumothorax -Seizures, uncontrolled -Unconscious patient, coma

Effect of serotonin and thromboxane A2 from platelet dense granules

Vasoconstriction Amplify platelet activation/recruitment

Effect of Fibrinogen, vWF, factor V from platelet alpha granules

Stimulate more platelet aggregation --> platelet plug

Where in platelets are PDGF, TGF-B, VEGF made/stored?

Alpha granules

Which phase of wound healing would you expect to see exudate (septic or nonseptic)

Inflammatory phase (neutrophils getting eaten up by macs)

Predominant cell type in repair phase

1) M2 2) Fibroblasts 3) Endothelial cells 4) Keratinocytes **Marked increased in fibro, endo, KC during "proliferation" phase

What do fibroblasts bind to, to make scar?

Fibronectin of provisional ECM

Structural proteins of scar

Collagen, elastin

Adhesive proteins of scar

Fibronectin

Ground substance in scar

Hyaluron (HA), Proteoglycans (PG)

Which cell types of repair phase secrete proteases?

All of them (M2, fibloblasts, KC, endothelial cells)

Members of MMP family (3)

-Collagenases -Gelatinases -Stromelysins

What breaks down old blood vessels?

MMP Heparinase From endothelial cells

Inhibitors of angiogenesis (3)

Angiostatin Endostatin Antithrombin III

Risk factors for poor wound healing (6)

1) Infection 2) Medications 3) Comorbidities (age, endocrine, liver/kidney, neoplasia, immune-med) 4) Nutrition (need Glu, protein, Mg, Vit A) 5) Location 6) Radiation tx

How do wounds heal for rats/mice

Contraction

How do wounds heal for pigs?

Re-epithelialization Since skin is tightly adhered to underlying structures, limited ability for contracture

Where on body is proud flesh most common

Distal limb wounds

Who has more wound contraction: horses or ponies?

Ponies --> less proud flesh than horses

Collagen dressing

-Hydrophilic: maintain moist wound environment -Scaffold for fibroblasts

Platelet-derived products dressing

*Enhance fibroblast proliferation *accelerate epithelial differentiation Indication: decubital ulcers in dogs, horses

Mesenchymal stem cell dressing

*Make many SC lines *Anti-inflammatory, pain modulating *Immunmodulation

Bioelectric dressing

*Mimics physiologic currents at wound edge across wound surface *Use AFTER inflammatory phase *Antimicrobial, prevent biofilm *Moist environment *Increases epithelialization

3 "stages" platelets go through during hemostasis

1) Aggregation 2) Platelet plug 3) Fibrin clot