Normal and abnormal wound heaing

wound healing

1. NORMAL AND ABNORMAL WOUND HEAING Dr. UDAY

2. Wound Healing Wound healing is a complex cellular and biochemical cascade that leads to restitution of integrity and function

3. Phases of wound healing Normal wound healing follows a predictable pattern that can be divided into overlapping phases Hemostasis and inflammatory phase Proliferative phase Maturation and remodelling phase

4. Cont.

5. 1.Inflammatory phase It begins immediately following tissue injury Functional priorities are Attainment of hemostasis Removal of dead and devitalized tissues Prevention of colonization and invasive infection by microbial pathogens principally bacteria

6. Inflammatory phase Components of injured tissue including fibrillar collagen and tissue factor act to activate the extrinsic clotting cascade and prevent ongoing hemorrhage. Disrupted blood vessels allow blood elements into the wound ,and platelets clump and form an aggregate to plug the disrupted vessels

7. Inflammatory phase During this process ,platelets degranulate , releasing growth factors such as PDGF and TGF-B The end result of the intrinsic and extrinsic coagulation cascades is the conversion of fibrinogen to fibrin and subsequent polymerization into gel

8. Inflammatory phase This Provisional fibrin matrix acts as the scaffolding for cell migration and inflammatory cells like PMNs, macrophages and lymphocytes are recruited Removal of the provisional fibrin matrix will impair wound healing.

9. Neutrophils The first infiltrating cells to enter the wound site, peaking at 24 to 48 hours Stimulated by Increased vascular permeability local prostaglandin release The presence of chemotactic substances( IL-1,TNF, TGF beta, bacterial product )

10. Neutrophils Primary role : Phagocytosis of bacteria and tissue debris Major source of cytokines early during inflammation, especially TNF-alpha Release proteases such as collagenases, which participate in matrix and ground substance degradation in the early phase of wound healing. No role in collagen deposition or acquisition of mechanical wound strength.

11. MACROPHAGE The second population of inflammatory cells that invades the wound. Derived from circulating monocytes, macrophages achieve significant numbers in the wound by 48 to 96 hours post injury . Present until wound healing is complete

12. Cont.

13. LYMPHOCYTES Less numerous than macrophages T-lymphocyte numbers peak at about 1 week post injury It bridge the transition from the inflammatory to the proliferative phase of healing. The role in wound healing is not fully defined Believed to play an active role in the modulation of the wound environment

14. 2.Proliferative phase Is the second phase of wound healing and roughly spans days 4 through 12 It is during this phase that tissue continuity is re-established. Fibroblasts and endothelial cells are the last cell populations to infiltrate the healing wound. The strongest chemotactic factor for fibroblasts is PDGF

15. Fibroblasts Upon entering the wound environment, recruited fibroblasts first need to proliferate Then become activated by the cytokines and growth factors released from wound macrophages. Primary function is matrix synthesis remodeling Fibroblasts isolated from wounds synthesize more collagen than nonwound fibroblasts

16. Fibroblasts cont. They proliferate less, and they actively carry out matrix contraction . Cytokine-rich wound environment and lactate plays a significant role in this phenotypic alteration and activation

17. Endothelial cells Endothelial cells migrate to the wound. Proliferate extensively during this phase of healing. These cells participate in the formation of new capillaries (angiogenesis) Their migration, replication, and new capillary tubule formation are under the influence of such cytokines and growth factors as TNF-alpha, TGF, and VEGF 19

18. Matrix synthesis Collagen biochemistry Its deposition, maturation, and subsequent remodeling are essential to the functional integrity of the wound. Type I collagen is the major component of extracellular matrix in skin. Type III, which is also normally present in skin, becomes more prominent and important during the repair process.

19. Matrix synthesis cont. Collagen synthesis, as well as post translational modifications, is highly dependent on systemic factors such as adequate oxygen supply, The presence of sufficient nutrients (amino acids and carbohydrates) cofactors (vitamins and trace metals), and The local wound environment (vascular supply and lack of infection)

20. Proteoglycan synthesis Glycosaminoglycans comprise a large portion of the "ground substance" that makes up granulation tissue. The major glycosaminoglycans present in wounds are dermatan and chondroitin sulfate. It is thought that the assembly of collagen subunits into fibrils and fibers is dependent on the lattice provided by the sulfated proteoglycans.

21. Proteoglycan synthesis Cont. As scar collagen is deposited, the proteoglycans are incorporated into the collagen scaffolding. With scar maturation and collagen remodeling, the content of proteoglycans gradually diminishes.

22. 3.Maturation and Remodeling Begins during the fibroplastic phase, and is characterized by a reorganization of previously synthesized collagen. The net wound collagen content is the result of a balance between collagenolysis and collagen synthesis. Collagenolysis is the result of collagenase activity, a class of matrix metalloproteinases(MMP) that require activation

23. Maturation and Remodeling Wound strength and mechanical integrity in the fresh wound are determined by both the quantity and quality of the newly deposited collagen. The deposition of matrix at the wound site follows a characteristic pattern: Fibronectin and collagen type III constitute the early matrix scaffolding, glycosaminoglycan and proteoglycans represent the next significant matrix components, and collagen type I is the final matrix

24. Maturation and Remodeling Fibril formation and fibril cross-linking result in decreased collagen solubility, increased strength, and increased resistance to enzymatic degradation of the collagen matrix Scar remodeling continues for many (6 to 12) months post-injury , gradually resulting in a mature, avascular, and acellular scar. The mechanical strength of the scar never achieves that of the uninjured tissue

25. Epithelialization Is a process restoring external barrier characterized primarily by proliferation and migration of epithelial cells adjacent to the wound. Begins within 1 day of injury and is seen as thickening of the epidermis at the wound edge. Marginal basal cells at the edge of the wound lose their firm attachment to the underlying dermis, enlarge, and begin to migrate across the surface of the provisional matrix

26. Epithelialization cont Re-epithelialization is complete in less than 48 hours in the case of approximated incised wounds. Take substantially longer in the case of larger wounds, in which there is a significant epidermal/dermal defect

27. Epithelialization cont. If only the epithelium and superficial dermis are damaged, then repair consists primarily of re-epithelialization with minimal or no fibroplasia and granulation tissue formation

28. Types of wound healing Wound healing by Primary intention Secondary intention Tertiary intention

29. Healing by primary intention Occurs when the edges are clean and held together with ligatures Little gap to bridge and healing occurs quickly Rapid ingrowth of wound healing cells Restoration of the gap by a small amount of scar tissue

30. Healing by secondary intention Occurs when edges are separated Gap cannot be directly bridged and Extensive epithelial loss Severe contamination Healing occurs slowly Granulation forms from the bottom towards the surface contracture

31. Healing by tertiary intention This process takes place when approximation of wound edges is delayed by 3-5 days There is greater granulation, greater risk of infection and more scar Indications Traumatic wound with tissue devitalization Heavy contamination of wound Surgical debridement of a wound

32. Healing in specific tissue GI TRACT Healing of full-thickness GI wounds begins with a surgical or mechanical re apposition of the bowel ends, which is most often the initial step in the repair process. The submucosa is the layer that imparts the greatest tensile strength and greatest suture- holding capacity, a characteristic that should be kept in mind during surgical repair of the GI tract

33. GI tract Cont. Serosal healing is essential for quickly achieving a watertight seal from the luminal side of the bowel. The importance of the serosa is shown by the significantly higher rates of anastomotic failure observed clinically in segments of bowel that are extraperitoneal and lack serosa (i.e., the esophagus and rectum)

34. GI tract Cont. Injuries to all parts of the GI tract undergo the same sequence of healing as cutaneous wounds. Some differences are Cell type involved in collagen synthesis fibroblast and smooth muscle cell Wound strength rapid recovery to preoperative level Heals with scar in fetal wounds

35. GI tract Cont. Mesothelial (serosal) and mucosal healing can occur without scarring. The early integrity of the anastomosis is dependent on the f ormation of a fibrin seal on the serosal side, which achieves water tightness, and On the suture-holding capacity of the intestinal wall, particularly the submucosal layer

36. GI tract Cont.. There is a significant decrease in marginal strength during the first week due to an early and marked collagenolysis . Collagen breakdown far exceeds collagen synthesis during the first 3 to 5 days . The integrity of the anastomosis represents equilibrium between collagen lysis, which occurs early, and collagen synthesis, which takes a few days to initiate.

37. Bone Most of the phases of healing resemble those observed in dermal healing 1st stage: Hematoma formation consists of an accumulation of blood at the fracture site, which also contains devitalized soft tissue, dead bone, and necrotic marrow. 2nd stage : liquefaction and degradation of nonviable products at the fracture site

38. Bone Cont. 3rd stage : soft callus stage, 3-4 days after injury, soft tissue forms a bridge between the fractured bone segments. 4th stage : hard callus stage, consists of mineralization of the soft callus and conversion to bone. 5th stage : Remodeling , the excessive callus is reabsorbed and the marrow cavity is recanalized .

39. cartilage Cartilage is very avascular and depends on diffusion for transmittal of nutrients across the matrix. Injuries to cartilage may be associated with permanent defects due to the meager and tenuous blood supply. The healing response of cartilage depends on the depth of injury

40. Cartilage Cont. Superficial injury  There is disruption of the proteoglycan matrix and injury to the chondrocytes. There is no inflammatory response, but an increase in synthesis of proteoglycan and collagen dependent entirely on the chondrocyte Therefore, superficial cartilage injuries are slow to heal and often result in persistent structural defects.

41. Cartilage cont. Deep injuries Involve the underlying bone and soft tissue . This leads to the exposure of vascular channels of the surrounding damaged tissue that may help in the formation of granulation tissue. As the granulation tissue is laid down, fibroblasts migrate toward the wound and synthesize fibrous tissue that undergoes chondrification .  Gradually, hyaline cartilage is formed, which restores the structural and functional integrity of the injured site

42. Tendon Tendon and ligament healing progresses in a similar fashion as in other areas of the body (i.e., through hematoma formation, organization, laying down of reparative tissue, and scar formation). Matrix is characterized by accumulation of type I and III collagen along with increased water, DNA, and glycosaminoglycan content. Restoration of the mechanical integrity may never be equal to that of the undamaged tendon.

43. Nerve After all types of injury, the nerve ends progress through a predictable pattern of changes involving three crucial steps: Survival of axonal cell bodies Regeneration of axons that grow across the transected nerve to reach the distal stump, Migration and connection of the regenerating nerve ends to the appropriate nerve ends or organ targets

44. Nerve Cont. Phagocytes remove the degenerating axons and myelin sheath from the distal stump ( wallerian degeneration). Regenerating axonal sprouts extend from the proximal stump and probe the distal stump and the surrounding tissues. Schwann cells ensheath and help in remyelinating the regenerating axons. Functional units are formed when the regenerating axons connect with the appropriate end targets

45. Fetal wound healing The main characteristic of fetal wound healing is the apparent lack of scar formation . In humans, scarring of wounds begins at approximately 24 weeks of gestation. At the beginning of the third trimester, and during this period there is scarless healing; however, there is a loss of the ability to regenerate skin appendages.

46. Fetal wound healing Cont. There are a number of characteristics that may influence the differences between fetal and adult wounds . Wound environment: sterile and stable temperature Inflammatory responses: immature immune system Growth factors: absence of TGF beta Wound matrix: high hyaluronic acid

47. Factors affecting wound healing Systemic factors A ge Nutrition Trauma Metabolic diseases Immunosuppression Connective tissue disorders smoking Local factors Mechanical injury Infection Edema Topical agents Ionizing radiation Necrotic tissue Low oxygen tension Foreign bodies

48. Age The increased incidence of comorbidity may contribute to impaired wound healing Non collagenous protein accumulation at wounded sites is decreased with aging which may impair the mechanical properties of scarring in elderly patients

49. Hypoxia ,Anemia , Hypoperfusion Low oxygen tension has a profoundly deleterious effect on all aspects of wound healing. Optimal collagen synthesis requires oxygen as a cofactor, particularly for the hydroxylation steps . Increasing FiO2 of inspired air for brief periods during and immediately after surgery results in enhanced collagen deposition and in decreased rates of wound infection after elective surgery

50. Steroid and chemotherapeutic drug Steroids inhibit the inflammatory phase of wound healing (angiogenesis, neutrophil and macrophage migration, and fibroblast proliferation) and the release of lysosomal enzymes. Steroids used after the first 3 to 4 days post injury do not affect wound healing as severely as when they are used in the immediate postoperative period.

51. Metabolic disorder Uncontrolled diabetes results in reduced inflammation, angiogenesis, and collagen synthesis The large- and small-vessel disease that is the hallmark of advanced diabetes contributes to local hypoxemia. Defects in granulocyte function, capillary ingrowth, and fibroblast proliferation all have been described in diabetes. Uremia also has been associated with disordered wound healing

52. Vitamins The vitamins most closely involved with wound healing are vitamin C and vitamin A. Vitamin C deficiency leads to a defect in wound healing, particularly via a failure in collagen synthesis and cross-linking. Vitamin A increases the inflammatory response in wound healing, probably by increasing the lability of lysosomal membranes

53. Minerals There are over 150 known enzymes for which zinc is either an integral part or an essential cofactor, and many of these enzymes are critical to wound healing. Zinc deficiency: decreased fibroblast proliferation, decreased collagen synthesis, impaired overall wound strength, and delayed epithelialization

54. Abnormal wound healing Abnormal wound healing includes chronic non heling wound keloid hypertrophic scar

55. Chronic non healing wound

56. Chronic non healing wound

57. Chronic non healing wound

58. Hypertrophic scar Represent an overabundance of fibroplasia in the dermal healing process. Rise above the skin level but stay within the confines of the original wound and often regress over time. Occur after trauma to the skin and may be tender, pruritic, and cause a burning sensation

59. Hypertrophic scar Usually develops within 4 weeks after trauma . Risk increases if epithelialization takes longer than 21 days. Rarely elevated more than 4 mm above the skin level and stay within the boundaries of the wound.

60. Hypertrophic scar Usually occur across areas of tension and flexor surfaces, which tend to be at right angles to joints or skin creases The lesions are initially erythematous and raised, and over time may evolve into pale, flatter scars.

61. Hypertrophic scar Histologically, the collagen bundles are flatter, more random, and the fibers are in a wavy pattern

62. Keloid Can result from surgery, burns, any infectious skin lesion, sometimes spontaneously It tend to occur 3 months to years after the initial insult. Rise above the skin level and extend beyond the border of the original wound and rarely regress spontaneously.

63. Keloid Are 15x more common in darker-pigmented ethnicities Autosomal dominant with incomplete penetration and variable expression. The skin of the earlobe and the deltoid, presternal , and upper back regions have higher incidance of keloid

64. Keloid Histologically the collagen bundles are virtually nonexistent, and the fibers are connected haphazardly in loose sheets with a random orientation to the epithelium. The collagen fibers are larger and thicker and myofibroblasts are generally absent .

65. Keloid Keloid fibroblast synthesize collagen at a rate 20 x greater than that observed in normal dermal fibroblasts, and 3x higher than fibroblasts derived from HTS.

66. Keloid The underlying mechanisms that cause HTSs and keloids are not known . Proposed causes are: The immune system Mechanical tension Prolonged irritation or inflammation

67. Keloid Management principles: surgery intralesional corticosteroid injection, topical application of silicone sheets, the use of radiation or pressure Topical retinoids

68. Emerging trends in wound healing Hyperbaric oxygen therapy VAC dressing Growth factors, including granulocyte colony stimulating factor (G-CSF) and transforming growth factor-β (TGF-β ) Bio debridement by maggots Topical insulin

69. SUMMARY In summary the healing cascade begins with an orderly process of hemostasis and fibrin deposition which leads to an inflammatory cell cascade ,characterized by neutrophils ,macrophages and lymphocytes in the tissue. This is followed by attraction and proliferation of fibroblasts and collagen cross linking and maturation Abnormal wound healing include keloid, hypertrophic scar and chronic wound.

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