Wound healing

• The stages of wound healing are haemostasis, inflammatory, proliferative and remodelling
• platelets, macrophages, neutrophils, fibroblasts, monocytes and endothelial cells are all essential for effective wound healing
• Clotting proteins and fibrin, cytokines/chemokines/chemoattractants including insulin like growth factor and platelet derived growth factor, and collagen (scaffolding and framework) are all non-cellular components involved in wound healing
• Haemostasis:

  • Platelets adhere to site of vascular injury
  • Platelet aggregation and activation
  • Haemostatic plug formation
  • Clotting cascade
• Coagulation

  • Vessel rupture: platelet aggregation, vasoconstriction, activation of coagulation cascade
  • Platelet degranulation - release various mediators
  • PDGF
  • IGF-1
  • PAF
  • TGFB-1
  • Fibronectin
  • Serotonin
  • Fibrin clot formation
• Inflammation

  • Damaged cells release cytokines
  • Causes vasodilation
  • Attraction/activation of infiltrating cells (immune cells, part of innate response)
  • Neutrophils
  • Phagocytose bacteria and debris (proteases)
  • Not essential unless wound contaminated
  • Macrophages
  • Debridement/matrix turnover
  • Major source of stimulatory signals
  • Important for wound healing
  • Blood clot and dead macrophage
  • Scab (acts as barrier)
• 1. Bacteria and other pathogens enter wound
  2. Platelets from blood release blood-clotting proteins at wound site
  3. Mast cells secrete factors that mediate vasodilation and vascular constriction. Delivery of blood, plasma and cells to injured area increases
  4. Neutrophils secrete factors that kill and degrade pathogens
  5. Neutrophils and macrophages remove pathogens by phagocytosis
  6. Macrophages secrete cytokines that attract immune cells to the site and activate cells involved in tissue repair
  7. Inflammatory response continues until the foreign material is eliminated and wound is repaired.
• Proliferation/Migration:

  Angiogenesis

  • Oxygen is critical for fibroblasts to produce collagen in order to establish granulation tissue
  • Require formation of new blood vessels
  • Macrophages and kerotinocytes provide angiogenic stimuli (VEGF, fibronectin etc.)
  • Start of endothelial cell buds from existing vessels
  • Sprout towards wound following oxygen gradient
  • Immature vessels differentiate into capillaries, arterioles, venules
• Fibroplasia

  • Fibroblasts
  • Migrate into wound site and replicate (activated by macrophages/mast cells)
  • Dominant cell type at wound edge
  • Synthesise and deposit collagen and proteoglycans
  • Act as scaffolding to hold epidermal cells together
  • Matrix deposition depends on O2 and substrate availability as well as growth factors
• Epithelialisation

  • Epidermal covering (basal keratinocytes) reconstituted from wound margin and hair follicle remnants
  • Keratinocytes migrate across wound
  • Neodermis differentiates and stratifies
  • Favoured by moist environment
  • New epidermal layer weak as dermal layer below not yet regenerated
• Contraction

  • Fibroblasts differentiate to myofibroblasts (similar to smooth muscle cells) that produce contractile proteins, pulling edges of wound together
• Remodelling

  • Formation of new granulation tissue stops
  • Changes collagen composition over time:
  • Type III collagen exchanged for type I (made by myofibroblasts)
  • Collagen fibres oriented in better alignment
  • New blood vessels formed no longer required - removed by apoptosis
  • Fibrous scar formed by collagen cross-linking, increase in fibre size
  • Mature scar has about 80% of the strength of original tissue
• Muscle tissue heals the fastest, in 2-4 weeks.
• Tendon tissue heals in 4-6 weeks
• Bone tissue heals in 6-8 weeks
• Ligament tissue heals in 10-12 weeks
• Cartilage tissue heals in 12 weeks
• Nerve tissue heals at 3-4 mm/day
• Haemostasis (seconds to hours)

  Inflammation (hours to days)

  Proliferation/migration (days to weeks)

  Remodelling (3 weeks - year)
• Local factors that impair wound healing are pressure, drying out/dehydration at wound site, trauma, oedema, infection, necrosis, incontinence and poor oxygen delivery.
• Systemic factors that affect wound healing are malnutrition, obesity, chronic disease (diabetes, anaemia, PVD), vascular insufficiency, immunodeficiency, smoking, stress, poor health, long term steroid use and old age
• Healing by primary intention occurs in wounds with dermal edges that are close together (e.g a scalpel incision).

  The end result of healing by primary intention is (in most cases) a complete return to function, with minimal scarring and loss of skin appendages
• Healing by secondary intention occurs when the sides of the wound are not opposed, therefore healing must occur from the bottom of the wound upwards. Myofibroblasts are vital cells in secondary intention. They are modified smooth muscle cells that contain actin and myosin, and act to contract the wound; decreasing the space between the dermal edges. They also can deposit collagen for scar healing.
• An uncommon complication from wound healing (particularly in people with darker skin), are keloid scars, excessive collagen production, leading to extensive scarring. This can occur in both primary and secondary intention healing.
• Maggots

  Larval stage in metamorphosis of the bluebottle from egg to adult fly. The adult lays its eggs on the carcasses of dead animals and the hatched larvae feed on the decaying flesh. Secreted enzymes break down their food into an edible, liquified form. For these reasons, larvae have been used in a medical capacity, to digest the dead tissue from open wounds
• Sutures/staples/steristrips and glue can be used to close wounds
• • Skin adhesive strips (e.g. Steri-StripsTM) are suitable if no risk factors for infection are present
  • Tissue adhesive glue (e.g. Indermil®) can be used for small lacerations with easily opposable edges (a popular choice in paediatrics)
  • Sutures are typically used for any laceration greater than 5cm, deep dermal wounds, or in locations that are prone to flexion, tension, or wetting
  • Staples can be used for some scalp wounds
• Wound hygiene is the most important therapeutic step in wound healing
• Repair complications include wound dehiscence (deficient healing), keloid (excessive scar formation), adhesions, infection and chronic pain