wound healing dr sumer
DESCRIPTION
wound healingTRANSCRIPT
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.