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Designed for UG Pathology teaching.
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Wound Healing Cutaneous Wound Healing
Dr.CSBR.Prasad, M.D.
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Cutaneous Wound Healing
Divided into three phases:
1. Inflammation
2. Proliferation &
3. Maturation
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Cutaneous Wound Healing
Inflammation: Platelet adhesion and aggregation and the formation of a clot in the surface of the wound, leading to inflammation
Proliferative phase there is formation of granulation tissue, proliferation and migration of connective tissue cells, and re-epithelialization of the wound surface
Maturation involves ECM deposition, tissue remodeling, and wound contraction
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Healing by primary union or by FIRST INTENTION
• Death of a limited number of epithelial and connective tissue cells
• Minimal disruption of epithelial basement membrane continuity
• Formation of a relatively thin scar
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Healing by primary union or by FIRST INTENTION
• Wounds with opposed edges
• Clean / sterile wounds
• Example:
– Surgical incision
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Healing by secondary union or by SECOND INTENTION
• Large defects cause extensive loss of cells and tissue
• More intense inflammatory reactions
• Formation of abundant granulation tissue
• Extensive collagen deposition
• Formation of a big scars
• Contractures
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Healing by secondary union or by SECOND INTENTION
• Wounds with unopposed margins
• Gaps in tissue due to substantial loss
• Infection / foreign bodies
• Examples:
–Crush injury
– Infected wounds
–Burns
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Crush injury v3-CSBRP-May-2012
Crush injury and skin grafting
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However, the basic mechanisms of healing by primary (first intention) and secondary
(second intention) union are similar
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The most distinct feature that differentiates Primay & Seconday
wound healing is…
Wound contracture
That is seen in healing by second intention
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Events in wound healing
• Blood clot formation - immediate
• Neutrophil migration – 24hours
• Proliferation of epithelia at the edge – 24-48hrs
• Deposition of BM – 24-48hrs
• Scab formation – 24 hrs
• Macrophage entry – 3rd day
• Granulation tissue formation – 5th day
• Collagen deposition – 5th day – two weeks
• Wound strengthening – may take months
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Growth Factors and Cytokines Affecting Various Steps in Wound Healing
Action Factors
Fibroblast migration /
replication
PDGF, EGF, FGF, TGF-β,
TNF, IL-1
Keratinocyte replication HB-EGF, FGF-7, HGF
Angiogenesis VEGF, Angiopoietins, FGF
Collagen synthesis TGF-β, PDGF
Collagenase secretion PDGF, FGF, TNF; TGF-β inhibits
Monocyte chemotaxis Chemokines, TNF, PDGF, FGF, TGF-β
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Blood clot
• Wounding causes the rapid activation of coagulation pathways
• Formation of a blood clot on the wound surface
• Clot contains entapped red cells, the clot contains fibrin, fibronectin, and complement components
• The clot serves to stop bleeding and also as a scaffold for migrating cells, which are attracted by growth factors, cytokines and chemokines released into the area
• Dehydration occurs at the external surface of the clot, forming a scab that covers the wound
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Neutrophils
• Within 24 hours, neutrophils appear at the margins of the incision
• They release proteolytic enzymes that clean out debris and invading bacteria
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Formation of Granulation Tissue
The hallmark of tissue repair: Formation of granulation tissue
Granulation tissue consists of: proliferating Fibroblasts and vascular endothelial cells which occurs in the first 24 to 72 hours of the repair process
The term derives from its pink, soft, granular appearance on the surface of wounds
Characteristic histologic feature : Angiogenesis and the proliferation of fibroblasts
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Formation of Granulation Tissue
• These new vessels are leaky, allowing the passage of plasma proteins and fluid into the extravascular space
• Granulation tissue progressively invades the incision space
• By 5 to 7 days, granulation tissue fills the wound area and neovascularization is maximal
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Granulation tissue
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Granulation
tissue
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Omphalocele covered by granulation tissue
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Accumulation of collagen – 2nd week
• Reduced number of leucocytes, edema
• Regression of vascular channels
• Accumulation of collagen
• Progressive blanching
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Progressive accumulation of collagen “SCARRING”
• Cellular connective tissue
• No inflammatory cells
• Complete epithelialization of the surface
• Absence of adnexal structures
• Progressive increase in tensile strength of wound
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Healing by secondary union or by SECOND INTENTION
• Large tissue loss
• More intense inflammatory reaction
• More granulation tissue
• More fibrosis / collagen – substantial scar
• Wound contracture
• Thin epidermis
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Granulation tissue & Scar tissue
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Wound strength
How log it will take for the wound to attain maximal strength?
When sutures may be removed?
• At the end of 1st week – 10% of strength of unwounded skin
• By 3rd month – 70-80% of strength of unwounded skin
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Factors influencing wound healing
Systemic factors
• Nutrition
• Metabolic status
• Circulatory status
• Hormones
Local factors
• Infections
• Foreign bodies
• Mechanical factors
• Size / Location
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Complications of cutaneous wound healing
May arise from abnormalities in basic components of repair process:
1. Deficient scar formation
2. Excessive of repair components
3. Contractures
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Complications of cutaneous wound healing
1. Deficient scar formation
Inadequate formation of granulation tissue or assembly of scar may result in:
• Dehiscence
• Ulceration
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Incisional
hernia in
ED-Syndrome
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Complications of cutaneous wound healing
1. Deficient scar formation
2. Excessive of repair components
• Hypertrophic scar
• Keloid
• Proud flesh (exuberant granulation tissue)
• Desmoids / aggressive fibromatosis
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Hypertrophic scar after surgical sutures v3-CSBRP-May-2012
Hypertrophic scar after burns v3-CSBRP-May-2012
Scar Keloid
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Scar Keloid
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Keloid
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Complications of cutaneous wound healing
1. Deficient scar formation 2. Excessive of repair components 3. Contractures Exaggeration of contracture results in deformities Eg: After serious burns
Contractures prone areas: Palms Soles Anterior thorax
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Wound Healing
Healing of Fracture
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Fracture
• A fracture is a discontinuity of bone usually due to trauma
• It's often associated with soft tissue injury (e.g. hemorrhage, necrosis, tearing of muscle, tendon, ligaments, nerves and vessels)
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Healing of Fracture
• There are three processes involved in the healing of fractures:
– Inflammatory
– reparative and
– remodelling phases
• 6 stages:
– the hematoma stage
– inflammatory stage
– formation of granulation tissue
– soft callus
– 'hard' callus, and
– remodelling
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or
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Hematoma Stage: Hemorrhage, clot formation - within hours
This picture shows a sagittal section of a fractured humerous. It is clear this is
recent fracture because there is a large haemtoma and no evidence of
primary callus fomation
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Inflammatory Stage: Begins within 48 hours, inflammatory cells appear. Organization and resorption of clot.
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Granulation Tissue: From 2 - 12 days. Presence of mesenchymal cells,
fibroblasts, new capillaries
Soft Callus: One week to several months. Callus grows and bridges the
fracture site; cartilage and trabelcular bone laid down.
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Hard Callus: One week to several months. When callus has sealed the bone ends. Trabecular bone.
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Remodelling: Continues for several months.
Reorganization of bone; original cortex restored
Fracture healing rates are:
• Faster in the young than the old
• Slower in the lower limb than the upper limb
• Faster in spongy bone than compact bone
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Systemic Factors Affecting Fracture Healing
• Age: Young patients heal rapidly and have a remarkable ability to remodel and correct angulation deformities. These abilities decrease once skeletal maturity is reached
• Nutrition: A substantial amount of energy is needed for fracture healing to occur. An adequate metabolic stage with sufficient carbohydrates and protein is necessary
• Systemic Diseases: Diseases like osteoporosis, diabetes, and those causing an immunocompromised state will likely delay healing. Illnesses like Marfan’s syndrome and Ehlers-Danlos syndrome cause abnormal musculoskeletal healing
• Hormones: Thyroid hormone, growth hormone, calcitonin, and others play significant roles in bone healing. Corticosteroids impede healing through many mechanisms
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Local Variables Affecting Fracture Healing
• Type of bone: Cancellous (spongy) bone fractures are usually more stable, involve greater surface areas, and have a better blood supply than do cortical (compact) bone fractures. Cancellous bone heals faster than cortical bone.
• Degree of Trauma: The more extensive the injury to bone and surrounding soft tissue, the poorer the outcome. Mild contusions with local bone trauma will heal easily, whereas severely comminuted injuries with extensive soft tissue damage heal poorly.
• Vascular Injury: Inadequate blood supply impairs healing. Especially vulnerable areas are the femoral head, talus, and scaphoid bones.
• Degree of Immobilization: The fracture site must be immobilized for vascular ingrowth and bone healing to occur. Repeated disruptions of repair tissue, especially to areas with marginal blood supply or heavy soft tissue damage, will impair healing.
• Intraarticular Fractures: These fractures communicate with synovial fluid, which contains collagenases that retard bone healing. Joint movement will cause the fracture fragments to more, further impairing union. When intraarticular fractures are comminuted, the fragments tend to float apart owing to loss of soft tissue support.
• Separation of Bone Ends: Normal apposition of fracture fragments is needed for union to occur. Inadequate reduction, excessive traction, or interposition of soft tissue will prevent healing.
• Infection: Infections cause necrosis and edema, take energy away from the healing process, and may increase the mobility of the fracture site.
• Local Pathology: Any disease process that weakens the musculoskeletal tissue, like osteoporosis or osteomalacia, may impair union.
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FIBROSIS
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FIBROSIS
• The term fibrosis is used more broadly to denote the excessive deposition of collagen and other ECM components in a tissue
• The terms scar and fibrosis are used interchangeably
FIBROSIS
“Classically activated macrophages”
Removal of microbes and dead tissues
Factors: IFN-γ and TNF
“Alternatively activated macrophages”
Little microbicidal activities
Greater role in tissue remodelling, angiogenesis and scar formation
Factors: IL-4 and IL-13
FIBROSIS
“Alternatively activated macrophages”
produce TGF-β and other growth factors that are involved in the repair process
TGF-β is an important fibrogenic agent
Produced by most of the cells in granulation tissue
Causes fibroblast migration and proliferation,
Increased synthesis of collagen and fibronectin, and decreased degradation of ECM due to inhibition of metalloproteinases.
Osteopontin : OPN
Plays an important role in fibrosis of the heart, lung, liver, kidney
Blockage of OPN expression decreases the formation of granulation tissue and scarring
FIBROSIS - Osteopontin - OPN
Secretion of non-fibrogenic forms of TGF-β
Lack of osteopontin
Absence of a TH2 response
Clinically useful antifibrotic agents:
Inhibitors of TGF-β binding
Angiogenesis Inhibitors
Toll-like receptors antagonists
IL-13 blockers
FIBROSIS - Scarless healing
Fibrotic disorders
• Liver cirrhosis
• Systemic sclerosis
• Fibrosing diseases of the lung
– Idiopathic pulmonary fibrosis
–Pneumoconioses
–Drug / radiation-induced pulmonay fibrosis
• Chronic pancreatitis
• Glomerulonephritis
• Constrictive pericarditis
Systemic sclerosis
Ehlers–Danlos syndrome
Chronic glomerulonephritis
Chronic glomerulonephritis
Figures. (A) Left lateral telecardiogram showing thick intense calcification of
the pericardium consistent with constrictive pericarditis. (B) Increased
respiratory variation of mitral E velocity on pulsed-wave Doppler
echocardiography of left ventricular inflow.
Cirrhosis of
the Liver
E N D
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