Inflammation 9


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Inflammation 9

  1. 1. Wound HealingCutaneous Wound Healing Dr.CSBR.Prasad, M.D. v3-CSBRP-May-2012
  2. 2. Cutaneous Wound Healing Divided into three phases: 1. Inflammation 2. Proliferation & 3. Maturation v3-CSBRP-May-2012
  3. 3. Cutaneous Wound HealingInflammation: Platelet adhesion and aggregation and the formation of a clot in the surface of the wound, leading to inflammationProliferative phase there is formation of granulation tissue, proliferation and migration of connective tissue cells, and re- epithelialization of the wound surfaceMaturation involves ECM deposition, tissue remodeling, and wound contraction v3-CSBRP-May-2012
  4. 4. 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 v3-CSBRP-May-2012
  5. 5. Healing by primary union or by FIRST INTENTION • Wounds with opposed edges • Clean / sterile wounds • Example: – Surgical incision v3-CSBRP-May-2012
  6. 6. v3-CSBRP-May-2012
  7. 7. 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 v3-CSBRP-May-2012
  8. 8. 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 v3-CSBRP-May-2012
  9. 9. Crush injury v3-CSBRP-May-2012
  10. 10. Crush injury and skin grafting v3-CSBRP-May-2012
  11. 11. v3-CSBRP-May-2012
  12. 12. v3-CSBRP-May-2012
  13. 13. v3-CSBRP-May-2012
  14. 14. However, the basic mechanisms of healing by primary (first intention) and secondary (second intention) union are similar v3-CSBRP-May-2012
  15. 15. The most distinct feature that differentiates Primay & Seconday wound healing is… Wound contractureThat is seen in healing by second intention v3-CSBRP-May-2012
  16. 16. v3-CSBRP-May-2012
  17. 17. 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 v3-CSBRP-May-2012
  18. 18. Growth Factors and Cytokines Affecting Various Steps in Wound HealingAction FactorsFibroblast migration / PDGF, EGF, FGF, TGF-β,replication TNF, IL-1Keratinocyte replication HB-EGF, FGF-7, HGFAngiogenesis VEGF, Angiopoietins, FGFCollagen synthesis TGF-β, PDGFCollagenase secretion PDGF, FGF, TNF; TGF-β inhibitsMonocyte chemotaxis Chemokines, TNF, PDGF, FGF, TGF-β v3-CSBRP-May-2012
  19. 19. 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 v3-CSBRP-May-2012
  20. 20. Neutrophils• Within 24 hours, neutrophils appear at the margins of the incision• They release proteolytic enzymes that clean out debris and invading bacteria v3-CSBRP-May-2012
  21. 21. 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 v3-CSBRP-May-2012
  22. 22. 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 v3-CSBRP-May-2012
  23. 23. Granulation tissue v3-CSBRP-May-2012
  24. 24. v3-CSBRP-May-2012
  25. 25. Granulation tissuev3-CSBRP-May-2012
  26. 26. Omphalocele covered by granulation tissue v3-CSBRP-May-2012
  27. 27. Accumulation of collagen – 2nd week • Reduced number of leucocytes, edema • Regression of vascular channels • Accumulation of collagen • Progressive blanching v3-CSBRP-May-2012
  28. 28. 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 v3-CSBRP-May-2012
  29. 29. 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 v3-CSBRP-May-2012
  30. 30. v3-CSBRP-May-2012
  31. 31. Granulation tissue & Scar tissue v3-CSBRP-May-2012
  32. 32. v3-CSBRP-May-2012
  33. 33. 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 v3-CSBRP-May-2012
  34. 34. Factors influencing wound healingSystemic factors Local factors• Nutrition • Infections• Metabolic status • Foreign bodies• Circulatory status • Mechanical factors• Hormones • Size / Location v3-CSBRP-May-2012
  35. 35. Complications of cutaneous wound healingMay arise from abnormalities in basic components of repair process:1. Deficient scar formation2. Excessive of repair components3. Contractures v3-CSBRP-May-2012
  36. 36. Complications of cutaneous wound healing1. Deficient scar formationInadequate formation of granulation tissue or assembly of scar may result in:• Dehiscence• Ulceration v3-CSBRP-May-2012
  37. 37. v3-CSBRP-May-2012
  38. 38. Incisional hernia in ED-Syndromev3-CSBRP-May-2012
  39. 39. Complications of cutaneous wound healing1. Deficient scar formation2. Excessive of repair components• Hypertrophic scar• Keloid• Proud flesh (exuberant granulation tissue)• Desmoids / aggressive fibromatosis v3-CSBRP-May-2012
  40. 40. Hypertrophic scar after surgical sutures v3-CSBRP-May-2012
  41. 41. Hypertrophic scar after burns v3-CSBRP-May-2012
  42. 42. Scar Keloidv3-CSBRP-May-2012
  43. 43. Scar Keloid v3-CSBRP-May-2012
  44. 44. Keloidv3-CSBRP-May-2012
  45. 45. v3-CSBRP-May-2012
  46. 46. Complications of cutaneous wound healing1. Deficient scar formation2. Excessive of repair components3. Contractures Exaggeration of contracture results in deformities  Eg: After serious burns Contractures prone areas:  Palms  Soles  Anterior thorax v3-CSBRP-May-2012
  47. 47. v3-CSBRP-May-2012
  48. 48. Wound HealingHealing of Fracture v3-CSBRP-May-2012
  49. 49. Fracture• A fracture is a discontinuity of bone usually due to trauma• Its often associated with soft tissue injury (e.g. hemorrhage, necrosis, tearing of muscle, tendon, ligaments, nerves and vessels) v3-CSBRP-May-2012
  50. 50. Healing of Fracture• There are three • 6 stages: processes involved – the hematoma stage in the healing of – inflammatory stage fractures: – formation of – Inflammatory or granulation tissue – reparative and – soft callus – remodelling phases – hard callus, and – remodelling v3-CSBRP-May-2012
  51. 51. Hematoma Stage:Hemorrhage, clot formation - within hours v3-CSBRP-May-2012
  52. 52. This picture shows a sagittal section of a fractured humerous. It is clear this isrecent fracture because there is a large haemtoma and no evidence ofprimary callus fomation v3-CSBRP-May-2012
  53. 53. Inflammatory Stage:Begins within 48 hours, inflammatory cells appear.Organization and resorption of clot. v3-CSBRP-May-2012
  54. 54. Granulation Tissue:From 2 - 12 days. Presence of mesenchymal cells,fibroblasts, new capillariesSoft Callus:One week to several months. Callus grows and bridges thefracture site; cartilage and trabelcular bone laid down. v3-CSBRP-May-2012
  55. 55. Hard Callus:One week to several months. When callus has sealedthe bone ends. Trabecular bone. v3-CSBRP-May-2012
  56. 56. Remodelling:Continues for several months.Reorganization of bone; original cortex restored v3-CSBRP-May-2012
  57. 57. 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 v3-CSBRP-May-2012
  58. 58. 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 v3-CSBRP-May-2012
  59. 59. 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. v3-CSBRP-May-2012
  60. 60. v3-CSBRP-May-2012
  61. 61. FIBROSIS v3-CSBRP-May-2012
  62. 62. 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
  63. 63. FIBROSIS“Classically activated macrophages”Removal of microbes and dead tissuesFactors: IFN-γ and TNF“Alternatively activated macrophages”Little microbicidal activitiesGreater role in tissue remodelling, angiogenesis and scar formationFactors: IL-4 and IL-13
  64. 64. FIBROSIS“Alternatively activated macrophages”produce TGF-β and other growth factors that are involved in the repair processTGF-β is an important fibrogenic agentProduced by most of the cells in granulation tissueCauses fibroblast migration and proliferation,Increased synthesis of collagen and fibronectin, and decreased degradation of ECM due to inhibition of metalloproteinases.
  65. 65. FIBROSIS - Osteopontin - OPNOsteopontin : OPNPlays an important role in fibrosis of theheart, lung, liver, kidneyBlockage of OPN expression decreases theformation of granulation tissue and scarring
  66. 66. FIBROSIS - Scarless healingSecretion of non-fibrogenic forms of TGF-βLack of osteopontinAbsence of a TH2 responseClinically useful antifibrotic agents:Inhibitors of TGF-β bindingAngiogenesis InhibitorsToll-like receptors antagonistsIL-13 blockers
  67. 67. 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
  68. 68. Systemic sclerosis
  69. 69. Ehlers–Danlos syndrome
  70. 70. Chronic glomerulonephritis
  71. 71. Chronic glomerulonephritis
  72. 72. Figures. (A) Left lateral telecardiogram showing thick intense calcification ofthe pericardium consistent with constrictive pericarditis. (B) Increasedrespiratory variation of mitral E velocity on pulsed-wave Dopplerechocardiography of left ventricular inflow.
  73. 73. Cirrhosis of the Liver
  74. 74. ENDv3-CSBRP-May-2012
  75. 75. v3-CSBRP-May-2012