Inflammation 9
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The document discusses wound healing and fibrosis. It describes that wound healing occurs in three phases: inflammation, proliferation, and maturation. It also discusses primary and secondary wound healing. Primary healing involves wounds with opposed edges that heal with a thin scar, while secondary healing involves wounds with tissue loss that heal with more scarring and contracture. The document also discusses factors that influence wound healing and complications that can arise. It provides details on cutaneous wound healing and fracture healing processes. Finally, it discusses fibrosis, describing that it is excessive collagen deposition in tissue during repair. It notes the role of macrophages and TGF-beta in promoting fibrosis.
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Inflammation 9
- 1. Wound Healing Cutaneous Wound Healing Dr.CSBR.Prasad, M.D. v3-CSBRP-May-2012
- 2. Cutaneous Wound Healing Divided into three phases: 1. Inflammation 2. Proliferation & 3. Maturation v3-CSBRP-May-2012
- 3. 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 v3-CSBRP-May-2012
- 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. Healing by primary union or by FIRST INTENTION • Wounds with opposed edges • Clean / sterile wounds • Example: – Surgical incision v3-CSBRP-May-2012
- 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. 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. Crush injury v3-CSBRP-May-2012
- 10. Crush injury and skin grafting v3-CSBRP-May-2012
- 14. However, the basic mechanisms of healing by primary (first intention) and secondary (second intention) union are similar v3-CSBRP-May-2012
- 15. The most distinct feature that differentiates Primay & Seconday wound healing is… Wound contracture That is seen in healing by second intention v3-CSBRP-May-2012
- 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. Growth Factors and Cytokines Affecting Various Steps in Wound Healing Action Factors Fibroblast migration / PDGF, EGF, FGF, TGF-β, replication 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 v3-CSBRP-May-2012
- 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. 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. 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. 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. Granulation tissue v3-CSBRP-May-2012
- 25. Granulation tissue v3-CSBRP-May-2012
- 26. Omphalocele covered by granulation tissue v3-CSBRP-May-2012
- 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. 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. 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
- 31. Granulation tissue & Scar tissue v3-CSBRP-May-2012
- 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. Factors influencing wound healing Systemic factors Local factors • Nutrition • Infections • Metabolic status • Foreign bodies • Circulatory status • Mechanical factors • Hormones • Size / Location v3-CSBRP-May-2012
- 35. 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 v3-CSBRP-May-2012
- 36. Complications of cutaneous wound healing 1. Deficient scar formation Inadequate formation of granulation tissue or assembly of scar may result in: • Dehiscence • Ulceration v3-CSBRP-May-2012
- 38. Incisional hernia in ED-Syndrome v3-CSBRP-May-2012
- 39. 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 v3-CSBRP-May-2012
- 40. Hypertrophic scar after surgical sutures v3-CSBRP-May-2012
- 41. Hypertrophic scar after burns v3-CSBRP-May-2012
- 43. Scar Keloid v3-CSBRP-May-2012
- 46. 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 v3-CSBRP-May-2012
- 48. Wound Healing Healing of Fracture v3-CSBRP-May-2012
- 49. 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) v3-CSBRP-May-2012
- 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. Hematoma Stage: Hemorrhage, clot formation - within hours v3-CSBRP-May-2012
- 52. 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 v3-CSBRP-May-2012
- 53. Inflammatory Stage: Begins within 48 hours, inflammatory cells appear. Organization and resorption of clot. v3-CSBRP-May-2012
- 54. 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. v3-CSBRP-May-2012
- 55. Hard Callus: One week to several months. When callus has sealed the bone ends. Trabecular bone. v3-CSBRP-May-2012
- 56. Remodelling: Continues for several months. Reorganization of bone; original cortex restored v3-CSBRP-May-2012
- 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. 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. 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
- 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. 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
- 64. 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.
- 65. FIBROSIS - Osteopontin - OPN 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
- 66. FIBROSIS - Scarless healing 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
- 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
- 74. 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.
- 76. Cirrhosis of the Liver