wound healing dr sumer

Dr sumer yadav

woundAny violation of live tissue integrity may be

regarded as a woundSkin is the largest organ of the human body.Acute wound- orderly and timely

reparative process - laceration, puncture, abrasion, avulsion, amputation, contusion

Chronic wound – wound not healed in 4 weeks. Venous and arterial ulcers, diabetic ulcers, pressure ulcers.

Three techniques of wound treatmentPrimary intention- all tissue including skin

are closed with suture material.Secondary intention – in which wound is left

open and close naturally.Tertiary intention – in which wound is left

open for number of days and then closed if it found to be clean.

DEFINITION – wound healingResponse of an organism to a physical

disruption of a tissue/organ with an aim to repair or reconstitute the defect and to re-establish homeostasis.

Can be achieved by 2 processes: scar formation & tissue regeneration.

Dynamic balance between these 2 is different in different tissues.

IntroductionDuring healing, a complex cascade of cellular

events occur to achieve resurfacing, reconstitution and restoration of tensile strength of injured tissue.

3 classic but overlapping phases occur: inflammation, proliferation & maturation.

Phases of HealingInflammatory (Reactive) Haemostasis Inflammation

Proliferative (Regenerative/Reparative) Epithelial migration proliferation Maturation

Maturational (Remodeling) Contraction scarring Remodeling

Early Wound Healing Events (Days 1-4)A. Inflammatory or reactive phase

- immediate response to injury

- goals: hemostasis, debridement , sealing of the wound

Events

1.Increase vascular permeability

2.Chemotaxis

3.Secretion of cytokines

4.Growth factor

Inflammatory PhaseBlood vessels are disrupted, resulting in

bleeding. Hemostasis is achieved by formation of platelet plug & activation of extrinsic(initiation) & intrinsic clotting(amplification) pathways.

Formation of a provisional fibrin matrix.Recruitment of inflammatory cells into the

wound by potent chemoattractants.

Inflammatory phaseFibrin and fibronectin form a lattice that

provides scaffold for migration of inflammatory, endothelial, and mesenchymal cells.

Neutrophilic infiltrate appears: removes dead tissue & prevent infection.

Monocytes/macrophages follow neutrophils: orchestrated production of growth factors & phagocytosis.

Inflammatory cells

PMN

- Migration of PMN stops when wound contamination has been controlled

- Don’t survive more than 24 hours

- Increase contamination stimulates PMN resulting to delayed wound healing and destruction of tissues.

- Not essential for wound healing

Inflammatory cells

Macrophages

- Orchestrate release of cytokines/ Process of wound healing/ release of growth factors

- 24 – 48 hours

- Source of TNF /interleukin 1, 6, 8

Macrophage Activities During Wound Healing

Activity Mediators

Phagocytosis Reactive oxygen species Nitric oxide

Débridement Collagenase, elastase

Cell recruitment and activation

Growth factors: PDGF, TGF-, EGF, IGF Cytokines: TNF-, IL-1, IL-6 Fibronectin

Matrix synthesis Growth factors: TGF-, EGF, PDGF Cytokines: TNF-, IL-1, IFN-Enzymes: arginase, collagenase ProstaglandinsNitric oxide

Angiogenesis Growth factors: FGF, VEGFCytokines: TNF- Nitric oxide

Table 8-2 Growth Factors Participating in Wound Healing

Stimulates fibroblasts, keratinocytes, chondrocytes, myoblasts

Mitogenesis: mesoderm and neuroectoderm

Stimulation of angiogenesis (by stimulation of endothelial cell proliferation and migration)

Fibroblasts, endothelial cells, smooth muscle cells, chondrocytes

Fibroblast growth factor (FGF) 

Stimulation of collagen synthesis

Stimulation of angiogenesis  

Mitogenesis: fibroblasts, smooth muscle cells

Chemotaxis: fibroblasts, smooth muscle, monocytes, neutrophils

Platelets, macrophages, monocytes, smooth muscle cells, endothelial cells

Platelet-derived growth factor (PDGF) 

Cellular and Biological Effects

Wound Cell OriginGrowth Factor

Table 8-2 Growth Factors Participating in Wound Healing

Keratinocyte growth factor (KGF) 

Keratinocytes, fibroblasts Significant homology with FGF; stimulates keratinocytes

Epidermal growth factor (EGF) 

Platelets, macrophages, monocytes (also identified in salivary glands, duodenal glands, kidney, and lacrimal glands)

Stimulates proliferation and migration of all epithelial cell types

Transforming growth factor- B     (TGF- B     ) 

Keratinocytes, platelets, macrophages

Homology with EGF; binds to EGF receptor

    Mitogenic and chemotactic for epidermal and endothelial cells

Transforming growth factor- alpha     (TGF-  alpha   ) (3 isoforms:     1,     2,     3)

Platelets, T lymphocytes, macrophages, monocytes, neutrophils

Stimulates angiogenesis TGF-     1stimulates wound

matrix production (fibronectin, collagen glycosaminoglycans); regulation of inflammation 

    TGF-     3 inhibits scar

formation

Late Events in InflammationEntry of lymphocytes.Appearance of mast cell: aberrant scarring?

Inflammatory cells

Lymphocytes

- Peak on 7th day

- Affects fibroblast

- Stimulate cytokines

- Not essential for acute wound healing

B. Proliferative phase

Goal: granulation tissue formation

Events:

1.Angiogenesis

2.Fibroplasia

3.Epithelization

Proliferative PhaseGranulation tissue formation (composed of

fibroblasts, macrophages and emdothelial cells).

Contraction.Re-epithelialization (begins immediately after

injury)Decrease collagen synthesis at 4

weeks after injury

Proliferative phase

Extracellular matrix

- Scaffold for cellular migration

- Composed of fibrin, fibrinogen, fibronectin, vitronectin

Fibronectin and type 3 collagen = early matrix

Type 1 collagen – wound strength later

Proliferative phase

Hydroxylation results in stable triple stranded helix

Vitamin C, TGF B, IgF 1, IgF 2- increase collagen synthesis

Interferon Y , steroids – decreases collagen synthesis

Mesenchymal cell proliferationFibroblasts are the major mesenchymal cells

involved in wound healing, although smooth muscle cells are also involved.

Macrophage products are chemotactic for fibroblasts. PDGF, EGF, TGF, IL-1, lymphocytes are as well.

Replacement of provisional fibrin matrix with type III collagen.

AngiogenesisAngiogenesis reconstructs vasculature in

areas damaged by wounding, stimulated by high lactate levels, acidic pH, decreased O2 tension in tissues.

Recruitment & assembly of bone marrow derived progenitor cells by cytokines is the central theme.

FGF-1 is most potent angiogenic stimulant identified. Heparin important as cofactor, TGF-alpha, beta, prostaglandins also stimulate.

EpithelializationBasal cell layer thickening, elongation,

detachment & migration via interaction with ECM proteins via integrin mediators.

Generation of a provisional BM which includes fibronectin, collagens type 1 and 5.

Epithelial cells proliferation contributes new cells to the monolayer. Contact inhibition when edges come together.

By three keratinocyte functions – migration , proliferation and differentiation.

Remodeling PhaseGoal: scar contraction with collagen

cross-linking, shrinking and loss of edema

Programmed regression of blood vessels & granulation tissue.

Wound contraction.Collagen remodeling.

Maturation phase

Wound contraction – centripetal movement of full thickness of skin

Decreases amount of disorganized scar

Wound contracture, physical restriction, limitation of function- result of wound contraction

Appearance of stimulated fibroblast known as myofibroblast

Fetal Wound HealingYounger the fetus less noticeable is the scarFetal fibroblasts even in adult transplantation heals

with the absence of inflammation Theory: that wound fibroblasts do not become

myofibroblasts until late in gestation. IL6 is high in adult stimulated fibroblasts compared to

fetal stimulated ones with coincides with increased inflammation in adults

Thrombospondin 1 decreases with increase in gestation. It destabilizes matrix contracts in the EC space, facilitates mitogenesis and chemotaxis. Promotes cell associated protease and self supports matrix turnover. Thus inflammation would decrease and there would be less scarring

Collagen19 types identified. Type 1(80-90%) most

common, found in all tissue. The primary collagen in a healed wound.

Type 3(10-20%) seen in early phases of wound healing. Type V smooth muscle, Types 2,11 cartilage, Type 4 in BM.

Wound ContractionBegins approximately 4-5 days after

wounding by action of myofibroblasts.Represents centripetal movement of the

wound edge towards the center of the wound.Maximal contraction occurs for 12-15 days,

although it will continue longer if wound remains open.

Wound ContractionThe wound edges move toward each other at

an average rate of 0.6 to .75 mm/day.Wound contraction depends on laxity of

tissues, so a buttock wound will contract faster than a wound on the scalp or pretibial area.

Wound shape also a factor, square is faster than circular.

Wound ContractionContraction of a wound across a joint can

cause contracture.Can be limited by skin grafts, full better than

split thickness.The earlier the graft the less contraction.Splints temporarily slow contraction.

RemodelingAfter 21 days, net accumulation of collagen

becomes stable. Bursting strength is only 15% of normal at this point. Remodeling dramatically increases this.

3-6 weeks after wounding greatest rate of increase, so at 6 weeks we are at 80% to 90% of eventual strength and at 6months 90% of skin breaking strength.

RemodelingThe number of intra and intermolecular

cross-links between collagen fibers increases dramatically.

A major contributor to the increase in wound breaking strength.

Quantity of Type 3 collagen decreases replaced by Type 1 collagen

Remodeling continues for 12 mos, so scar revision should not be done prematurely.

Local FactorsIscemiaInfection: impairs healing.Smoking: increased platelet adhesiveness,

decreased O2 carrying capacity of blood, abnormal collagen.

Radiation: endarteritis, abnormal fibroblasts.

Systemic FactorsMalnutritionCancerOld AgeDiabetes- impaired neutrophil chemotaxis,

phagocytosis.Steroids and immunosuppression

suppresses macrophage migration, fibroblast proliferation, collagen accumulation, and angiogenesis. Reversed by Vitamin A 25,000 IU per day.

Inadequate RegenerationCNS injuriesBone nonunionCorneal ulcers

Inadequate Scar FormationDiabetic foot ulcers.Sacral pressure sores.Venous stasis ulcers.

Excessive RegenerationNeuromaHyperkeratosis in cutaneous psoriasisAdenomatous polyp formation.

Excessive Scar FormationExcessive healing results in a raised,

thickened scar, with both functional and cosmetic complications.

If it stays within margins of wound it is hypertrophic. Keloids extend beyond the confines of the original injury.

Dark skinned, ages of 2-40. Wound in the presternal or deltoid area, wounds that cross langerhans lines.

Keloids and Hypertrophic ScarsKeloids more familialHypertrophic scars develop soon after injury,

keloids up to a year later.Hypertrophic scars may subside in time,

keloids rarely do.Hypertrophic scars more likely to cause

contracture over joint surface.

Keloids and Hypertrophic ScarsBoth from an overall increase in the quantity

of collagen synthesized.Recent evidence suggests that the fibroblasts

within keloids are different from those within normal dermis in terms of their responsiveness.

No modality of treatment is predictably effective for these lesions.