Wound healing

1. Wound healing Danny Silverberg M.D.

3. Phases of healing Early Intermediate Late Terminal

4. Early wound healing events Hemostasis Platelet aggregation Intrinsic and extrinsic coagulation cascade Thrombin, fibrin Vasoconstriction Platelet agregeation Intrinsic and extrinsic coagulation cascade- ( intrinsic- activation of factor 12, ext- exposure to tissue factor which binds to factor 7) both activate thrombin which produces fibrin which acts a matrix for the inflammatory cells Platelet agregeation Intrinsic and extrinsic coagulation cascade- ( intrinsic- activation of factor 12, ext- exposure to tissue factor which binds to factor 7) both activate thrombin which produces fibrin which acts a matrix for the inflammatory cells

5. Early wound healing events Inflammation Vasodilatation Increase in vascular permeability Chemotaxis Cellular response Inflammation- erythema, edema, pain, heat Vasodilatation- histamine, kinins, PGs, LTs, Increase in vascular permiability- aloows migration of PMN, protein Chemotaxis- movement of an organism or cell in response to chemical concentration gradient Cellular inflammatory response- PMN first to be foung in wounded area, engulf foreign material and digest it thropugh hydrolititc enzymes. Monocytes=> macrophages, phagocytoses, stimulate fibroblast proliferation and migration, source of cytokines. Lymphocytes- involved in cellular and humoral immunity. Inflammation- erythema, edema, pain, heat Vasodilatation- histamine, kinins, PGs, LTs, Increase in vascular permiability- aloows migration of PMN, protein Chemotaxis- movement of an organism or cell in response to chemical concentration gradient Cellular inflammatory response- PMN first to be foung in wounded area, engulf foreign material and digest it thropugh hydrolititc enzymes. Monocytes=> macrophages, phagocytoses, stimulate fibroblast proliferation and migration, source of cytokines. Lymphocytes- involved in cellular and humoral immunity.

6. Early wound healing events Homeostasis Neutrophils 48-72h- macrophages 5-7 days- few inflammatory cells. 48-72h- macrophages. stay several days. Essential for normal wound healing 48-72h- macrophages. stay several days. Essential for normal wound healing

8. Intermediate wound healing events Mesenchymal cell chemotaxis and proliferation Angiogenesis Epithelisation 2-4 days after injury Mediated by cytokines Mediated by cytokines- PDGF- PLT derived GF, TGF alfa, beta, EGF (epidermal GF, ) IL1 TNF Mediated by cytokines- PDGF- PLT derived GF, TGF alfa, beta, EGF (epidermal GF, ) IL1 TNF

9. Intermediate wound healing events Mesenchymal cell chemotaxis and proliferation Fibroblasts- migration and proliferation Smooth muscle Angiogenesis- reconstruction of vasculature Stimulate: High lactate, acidic Ph, low O2 tension Endothelial cell migration and proliferation Endothelial cell migration and proliferation Stimulated by cytokines derived from macrophages ( TGF alpha beta, PGs, �) Endothelial cell migration and proliferation Stimulated by cytokines derived from macrophages ( TGF alpha beta, PGs, �)

10. Intermediate wound healing events Epithelisation Partial thickness- Cells derived from wound edges and epithelial appendages. Incisional wound: cellular migration over less then 1 mm. Wound sealed in 24-48h. Cellular detachment Migration Proliferartion differentiation Cells derived from wound edges and epithelial appendages ( hair follicles and sweat and sabaceous glands.) in the central part of the woungs. Cellular detachment- cells detach from the BM in 1st 24h Migration into the wound until they meet cells migrating from opposite dirrection- contact inhibition Proliferation � divuide starting 48-72h ( following migration of PMNs and macrophages differentiation . Cells derived from wound edges and epithelial appendages ( hair follicles and sweat and sabaceous glands.) in the central part of the woungs. Cellular detachment- cells detach from the BM in 1st 24h Migration into the wound until they meet cells migrating from opposite dirrection- contact inhibition Proliferation � divuide starting 48-72h ( following migration of PMNs and macrophages differentiation .

11. Late wound healing events Collagen synthesis 3 helical polypeptide chains Lysine and proline hydroxylation Required for cross-linking collacolla

12. Late wound healing events Collagen synthesis 3-5 days post injury Primarily by fibroblasts Maximum synthesis rate 2-4 weeks Declines after 4 weeks Type 1 collagen most common ( 80-90% of skin collagen) Type 3- seen in early phases of wound healing collacolla

13. Wound contraction Centripetal movement of the wound edges toward the center. ( 0.6-0.7 mm/day) Begins at 4-5 days Maximal contraction 12-15 days Trivial component in closed incisional wounds, significant for closure of open wounds Rate- depends on tissue Circular wounds- slower closure but avoid stenosis Rate- depends on tissue- buttock- loose tissue, contracts more than scalp tissue Rate- depends on tissue- buttock- loose tissue, contracts more than scalp tissue

14. Wound contraction Mechanism- cell mediated processes, not requiring collagen synthesis Myofibroblasts- fibroblasts with myofilaments in cytoplasm Appear in wound day 3-21 Located in periphery- pull wound edges together. Contractures- contraction across joint surface

15. Terminal wound healing events Remodeling- turnover of collagen. Type 3 replaced by type 1 Day 21- net accumulation of wound collagen becomes stable Wound bursting strength- 15% of normal. Week 3-6- greatest rate of increase 6 weeks- 80-90% of eventual strength. 6 months maximum strength ( 90% ). Process continues for 12 months Remodelling- turnover of collagen- old collagen broken down and new collagen is synthesused in a denser, more organised fasion., with increaing intermolecular cross links. Water quantitiy decreases, changes in texture, thickness and color Remodelling- turnover of collagen- old collagen broken down and new collagen is synthesused in a denser, more organised fasion., with increaing intermolecular cross links. Water quantitiy decreases, changes in texture, thickness and color

17. Cytokines and growth factors Primary mediators in wound healing. Endo, para, auto, intracrine function EGF FGF PDGF TGF

18. Growth factors in wound healing

21. Which of the following is primarily responsible for tensile strength in a healing wound 4 days after injury? Collagen Elastin Fibrin Fibronectin Hyaluronic acid Fibrin provides the tensile strength for the first few days after injury until fiobroblasts start producing collagenFibrin provides the tensile strength for the first few days after injury until fiobroblasts start producing collagen

22. Which of the following is primarily responsible for tensile strength in a healing wound 6 weeks after injury? Myofibroblasts Fibrin Fibronectin Collagen Collagen cross linking Collagen cross linking provides increase in tensile strength. Collagen cross linking provides increase in tensile strength.

24. Local factors affecting wound healing Infection foreign body/ necrotic tissue, hematomas local/ systemic factors type of surgery

25. Local factors affecting wound healing Hypoxia and smoking O2 delivery necessary for cellular respiration and hydroxylation of proline and lysine Smoking- vasoconstriction, atherosclerosis, carboxyhemoglobin.

26. Local factors affecting wound healing Radiation Collagen synthesized to abnormal degree- fibrosis Fibrosis of vessels- (media)-occlusion Thinned epidermis, pigmentation Limited access of inflammatory cells and cytokines- impaired healing Damage to fibrocytes and keratinocytes.

27. Systemic factors Malnutrition Limited AA supply for collagen synthesis Consumption of proteins d/t CHD and fat deficiency. Vit C deficiency- diminished hydroxylation of lysine and proline, Vit D- impaired bone healing Zinc- inhibition in cellular proliferation and defficient granulation tissur formation

28. Normal healing is accelerated by which of the following? VitC VitA Zinc Increased local oxygen tension Scarlet red Increased O2 tension stimulates healing , but increases wound strength by only 15-20% at 7 days. ( not clinically significant) Amounts of vitamins highr than physiologic levels don�t acceleatere healing Increased O2 tension stimulates healing , but increases wound strength by only 15-20% at 7 days. ( not clinically significant) Amounts of vitamins highr than physiologic levels don�t acceleatere healing

29. Systemic factors Cancer Cachexia, anorexia Altered host metabolism. Protein catabolism Abnormal inflammatory cell response

30. Systemic factors Old Age Diabetes Impaired healing ( decreased chemotaxis and phagocyte function ) Risk of infection

31. Systemic factors Steroids, immunsuppression Inhibits all aspects of healing process Impaired cellular function, deficiency in inflammatory cell function, cytokine production, fibroblast proliferation All effects ( except contraction ) reversed by Vit A.

32. Hypertrophic scars and kelloids Excessive healing processes- increase in net collagen synthesis raised thickened scar Keloid- Extension beyond wound margin, familial, may develop up to 1 year, rarely subside Hypertrophic scar- Confined to wound margin, light skinned, early after injury, may subside, cause contractures Tx- excision, steroid injection, pressure garments, radiation tx

34. Types of wound closure Primary closure Approximation of acutely disrupted tissue with sutures, staples or tape

35. Types of wound closure Delayed primary closure Approximation of wound margin delayed for several days Prevents wound infection in cases of contamination/foreign bodies/tissue trauma Less bacterial colonization in open wound Normal healing progress occurs

36. Types of wound closure Secondary wound closure Open wound margins approximate by biologic contraction

37. If a patient requires reoperation 1 month after a midline abdominal incision which of the following promotes the most rapid gain in strength of the new incision Separate transverse incision Midline scar is excised with a 1 cm margin Midline incision reopended without scar excision Rate of strength ganed is not effected by incision technique When a nrmally healing wound is disrupted after the 5th day and then reclosed, the return of the wound stregth is more rapid than with primary healing. This is d/t the secondary healing effect- elimination of the lag phase present in primary healing. When a nrmally healing wound is disrupted after the 5th day and then reclosed, the return of the wound stregth is more rapid than with primary healing. This is d/t the secondary healing effect- elimination of the lag phase present in primary healing.