Wound Healing and Wound Management


Phases of Wound Healing


Phases of Wound Healing
  1. Hemostasis and Inflammation
    • exposure of blood to subendothelial collagen is the initiating factor in wound healing

    1. Hemostasis
      1. Vascular Response
        • biphasic response (1) vasoconstriction → (2) vasodilation
        • vasoconstriction, which serves a hemostatic function, lasts only several minutes
        • vasoconstriction lasts only several minutes, and is followed by vasodilation
        • vasodilation is initially mediated by histamine, which is produced by platelets, mast cells, basophils
        • vasodilation → ↑ vascular permeability, permitting blood-borne factors to enter the wound

      2. Platelet Response
        • forms a hemostatic plug and initiates coagulation
        • produces multiple essential cytokines, which modulate most of the subsequent wound healing events
          • platelet-derived growth factor (PDGF)
          • transforming growth factor-alpha (TGF-α)
          • transforming growth factor-beta (TGF-β)

      3. Coagulation Response
        • intrinsic and extrinsic coagulation cascades serve both hemostatic and inflammatory functions
        • generation of fibrin provides a scaffold for the migration of inflammatory and mesenchymal cells
        • thrombin contributes to the increased vascular permeability seen after injury, facilitates the extravascular migration of inflammatory cells, and may have a role in epithelialization and angiogenesis

    2. Cellular Migration into the Wound
      1. Neutrophils
        • migrate in response to the chemotactic factors released during injury and inflammation (bacterial products, C5a, PGE2, PDGF, IL-1, IL-8, TNF-α)
        • presence in the wound peaks at 24 – 48 hours
        • primary functions are phagocytic and microbicidal
        • produce collagenases, which degrade ground substance and matrix in the early phase of wound healing
        • do not have a role in collagen synthesis, thus are not necessary for wound healing
        • however, there is an increased rate of infection when neutrophils are not present

      2. Macrophages
        • replace the neutrophil as the dominant cell in the wound by the third or fourth day
        • essential for normal wound healing - main cell regulating the proliferative phase
        • main cell regulating the proliferative phases of wound healing
        • play an active role in wound debridement and connective tissue matrix remodeling
        • produce many cytokines that regulate other cellular activities (IL-1, IL-6, TNF-α, TGF-β, VEGF)
        • stimulate angiogenesis and collagen synthesis

      3. T Lymphocytes
        • peak in the wound at one-week post injury
        • essential to wound healing, but exact role is unclear
        • play an active role in the modulation of the wound environment
        • may down-regulate fibroblast collagen synthesis

  2. Proliferation Phase
    1. Fibroblast Migration and Proliferation
      • by the 4th day, the dominant cell in the wound is the fibroblast
      • strongest chemotactic factor for fibroblasts is PDGF
      • fibronectin provides a physical pathway along which the fibroblast can migrate
      • activation of fibroblasts is mediated by cytokines released by wound macrophages

    2. Angiogenesis
      • essential to successful wound healing
      • stimulated by elevated lactate levels, acidic pH, and tissue hypoxia
      • all angiogenesis begins with the endothelial cell
      • new vessels originate as capillaries which sprout from the sides of small vessels in response to local angiogenic factors
      • cytokines (VEGF, TNF-α, TGF-β) stimulate endothelial cell migration and proliferation
      • most of these cytokines are derived from macrophages

    3. Matrix Formation
      • as fibroblasts invade the wound, they manufacture additional new matrices, including glycoproteins, structural proteins, and adhesive proteins

      1. Proteoglycans
        • hyaluronic acid dominates the early wound matrix
        • chondroitan sulfate, dermatan sulfate, heparin sulfate are other common proteoglycans
        • assembly of collagen into fibrils and fibers is dependent upon the structure provided by proteoglycans

      2. Collagens
        • family of fibrous proteins secreted by the fibroblast
        • at least 18 types, but types I and III are most important for wound repair
        • contains the amino acids hydroxylysine and hydroxyproline
        • vitamin C is necessary for collagen production
        • consists of 3 polypeptide chains, each chain twisted into a right-handed helix
        • collagen is secreted into the extracellular space as procollagen
        • procollagen is cleaved to tropocollagen
        • tropocollagen molecules then aggregate into fibrils
        • fibrils are cross-linked in the extracellular matrix and aggregate to form collagen fibers
        • the macrophage is the key cell regulating collagen production by the fibroblast, presumably by secreting growth factors
        • collagen synthesis is highly dependent on systemic factors: adequate oxygen supply, sufficient nutrients, vitamins, trace metals, lack of infection

      3. Elastin
        • secreted into the extracellular matrix as random coils, allowing the network to stretch and recoil

      4. Fibronectin
        • attachment protein
        • aids in cellular attachment
        • modulates the migration of various cell types into the wound
        • chemotactic for fibroblasts

    4. Wound Contraction
      • begins 4 to 5 days after wounding
      • represents the centripetal advancement of the wound edge towards the center of the wound
      • myofibroblast appears to be the responsible cell - it contains actin and myosin filaments and appears when contraction starts and disappears when contraction is complete
      • contraction of a large wound across a joint surface can lead to a contracture
      • skin-grafting is one of the most effective methods of controlling contraction; full-thickness grafts are more effective than partial-thickness grafts

    5. Epithelialization
      • involves 2 major phenomena: migration and mitosis
      • in the first 24 hours after wounding, thickening of the basal layer occurs
      • basal cells then detach from the underlying basement membrane and migrate into the wound
      • cells migrate as a sheet over the collagen-fibronectin wound surface
      • migrating cells originate from the margins of the wound and skin appendages (hair follicles, sebaceous glands)
      • epithelial cell proliferation contributes new cells to the advancing epithelial cell monolayer
      • cells migrate until they reach cells migrating from a different direction (contact inhibition)
      • cellular proliferation continues until a multi-layered epidermis is re-established
      • migration and proliferation is stimulated by epidermal growth factor (EGF)
      • regenerated epithelium has several important differences from normal epithelium:
        • fewer basal cells
        • an abnormal dermal-epidermal junction (no rete pegs)
        • epithelium thicker at the wound edge than in the midportion

  3. Wound Remodeling and Maturation
    • cell and matrix changes in the wound continue long after completion of epithelialization
    • after 21 days, collagen content of the wound becomes stable
    • bursting strength of the wound is only 15% of normal skin at 21 days
    • wound strength increases without further increases in the wound’s collagen content
    • process of scar remodeling increases the wound’s strength by greatly increasing the number of cross-links between collagen fibers
    • by 6 weeks after wounding, the scar reaches 80 - 90 % of its eventual strength
    • bursting strength of scar never reaches that of unwounded skin
    • during terminal wound healing, a continual turnover of collagen molecules occurs as old collagen is broken down and new collagen is synthesized
    • collagen fibers become more linearly organized along stress lines

Factors Affecting Wound Healing

  1. Local Factors
    1. Infection
      • requires > 105 bacteria/gram of tissue
      • foreign bodies, hematomas, necrotic tissue increase the risk of wound infection
      • impaired circulation and radiation further increase the risk
      • systemic diseases such as diabetes, AIDS, uremia, and cancer are associated with increased risk of wound infection
      • best treatment is prevention
      • prevention requires meticulous technique, judicious use of perioperative antibiotics, and good judgement as to which wounds should be closed primarily

    2. Hypoxia
      • delivery of oxygen to healing tissues is critical for all aspects of wound healing
      • adequate tissue oxygenation requires an adequate circulating blood volume, adequate cardiac function, and adequate local vasculature
      • normovolemic anemia is not associated with impaired healing unless the hematocrit drops below 15%
      • smoking impairs oxygenation by acutely stimulating vasoconstriction

    3. Radiation
      • damages the DNA of exposed cells
      • collagen is synthesized to an abnormal degree in irradiated tissue, causing a characteristic fibrosis
      • media of blood vessels thickens and some become occluded, leading to a decreased number of blood vessels in irradiated tissue
      • epidermis becomes thinned
      • irradiated skin is dry because of damage to sebaceous and sweat glands
      • decreased vascularity and increased fibrosis limits the ability of platelets and inflammatory cells to gain access to wounds in irradiated tissue
      • quantity of cytokines released is diminished and causes impairment of virtually all cellular aspects of healing
      • also, irradiated tissue is predisposed to infection
      • vitamin A has been used to reverse the healing impairment caused by radiation therapy

  2. Systemic Factors
    1. Malnutrition
      • inadequate nutrition is devastating to the healing process
      • albumin < 2.0 g/dL represents severe protein malnutrition
      • collagen synthesis stops in the absence of protein intake
      • arginine supplementation increases collagen deposition
      • vitamin C is necessary to produce new, strongly cross-linked collagen
      • vitamin A is essential for normal epithelialization, proteoglycan synthesis, and normal immune function
      • vitamin D is required for bone healing
      • zinc is an essential cofactor in many enzymes critical to wound healing

    2. Cancer
      • cancer patients have impaired healing
      • decreased oral intake may be caused by cachexia or mechanical factors
      • protein catabolism may be accelerated
      • cancer patients may be relatively anergic: macrophages do not migrate or function normally

    3. Old Age
      • older people take longer to heal than younger people
      • increased rates of wound dehiscences and incisional hernias in the elderly
      • in elderly patients, wound disruption occurs with less force than in younger patients
      • increased incidence of underlying diseases predisposes the elderly to impaired healing

    4. Diabetes
      • risk of infection in clean incisions is 5 times higher in diabetics
      • associated with impaired granulocyte chemotaxis and phagocytosis
      • large and small-vessel disease causes local hypoxia
      • pre-op correction of blood sugar levels improves wound outcomes

    5. Steroids
      • inhibit all aspects of the healing process
      • primary problem is a deficiency in inflammatory cell function
      • by diminishing the supply of cytokines, steroids and other immunosuppressive agents profoundly impair macrophage activity and thus subsequent healing capacity
      • topical application of vitamin A stimulates collagen synthesis and epithelialization – this may help overcome the deleterious effects of steroids

    6. Chemotherapy
      • impairs healing primarily through inhibition of cellular proliferation as well as DNA and protein synthesis within the wound
      • if possible, surgery should be delayed for several weeks after the last chemotherapy session

    7. Obesity
      • obese patients have higher incidences of wound complications (30% dehiscence, 17% wound infections, 30% incisional hernias, 19% seromas)
      • obese patients also have a much higher rate of anastomotic leaks
      • this is true even when controlled for comorbid conditions such as diabetes and cardiovascular disease

Wound Complications

  1. Hypertrophic Scars and Keloids
    • result from excessive healing
    • hypertrophic scars rise above the level of the skin, but remain confined to the margins of the original wound
    • keloids extend beyond the confines of the original wound
    • both problems result from excess collagen synthesis by wound fibroblasts
    • increased TGF-β has been implicated
    • hypertrophic scars tend to regress over time; keloids usually do not regress
    • keloids tend to recur after excision alone
    • intralesional injection of triamcinolone, either alone or in conjunction with surgery, is often effective treatment
    • radiation alone is ineffective, but may be combined with surgical excision
    • pressure dressings, topical silastic gel are sometimes used as well

    Hyperplastic Scar and Keloid
  2. Wound Dehiscence
    • dehiscence is a fascial separation due to abdominal wall tension overcoming tissue resilience, suture strength, or knot security
    • evisceration indicates extrusion of visceral contents through the fascial defect and skin
    • local factors contributing to wound disruption include hemorrhage and infection
    • systemic factors include malnutrition, hypoproteinemia, morbid obesity, malignancy, uremia, diabetes, steroids, and increased intra-abdominal pressure (coughing, ascites)

    1. Technical Factors
      • since tension is proportional to incision length, dehiscence is more common when the incision length exceeds 18 cm
      • in the majority of cases, the sutures and knots are intact, but the suture has pulled through the fascia as a result of fascial necrosis
      • fascial necrosis occurs when the sutures are placed too close to the edges or are under too much tension

    2. Clinical Presentation
      • most dehiscences occur at a mean of 8 days post-op
      • profuse serosanguinous drainage from the wound is the classic sign, often preceded by a popping sensation
      • CT or US may be used if the diagnosis is not clear

    3. Management
      • stable patients without evisceration should be returned to the OR for fascial closure
      • unstable patients without evisceration may be treated nonoperatively with a sterile wound dressing and binder
      • if the patient eviscerates, moist sterile towels should be placed over the abdominal contents and the patient returned emergently to the OR
      • fascial retention sutures have historically been used to close dehiscences, but they can cause skin necrosis and pain without significantly reducing the risk of recurrent fascial disruption or incisional hernia

    4. Optimal Fascial Closure Technique
      • STITCH trial
      • simple running closure with a #1 or #2 long-lasting absorbable suture (PDS e.g.)
      • mass closure to incorporate all layers of the abdominal wall (except skin)
      • tissue bites of 5 mm every 5 mm
      • suture length to wound length ratio of 5:1
      • non-strangulating tension on the suture

  3. Peritoneal Adhesions
    • result from peritoneal injury from surgery or intra-abdominal infections
    • injury elicits an inflammatory response that results in fibrin deposition between damaged serosal surfaces
    • fibrinolytic activity often degrades these filmy adhesions
    • if insufficient fibrinolytic activity is present, then permanent fibrous adhesions will form by collagen deposition within 1 week of injury
    • reducing tissue trauma will reduce adhesion formation
    • barrier membrane and gels separate and create barriers between damaged mesothelial surfaces (Seprafilm, Interceed)
    • placement of barrier substances directly over anastomoses is contraindicated because of a higher risk of leak

Wound Management

  1. Irrigation
    • decreases the bacterial load and removes loose material
    • low-pressure irrigation (bulb syringe) is adequate for most cases
    • high-pressure irrigation (pulse lavage) is indicated for highly contaminated wounds

  2. Debridement
    • wounds that have devitalized tissue, contamination, or residual suture material must be debrided down to healthy, bleeding tissue
    • sharp surgical debridement is the primary technique
    • enzymatic debridement with collagenase (Santyl) is a good option for patients who are not surgical candidates
    • biologic debridement (maggot therapy) is occasionally used as a bridge between debridement procedures or for debridement of chronic wounds when surgical debridement cannot be performed

  3. Topical Agents
    1. Silver
      • used to prevent and treat infected wounds
      • very broad spectrum with low toxicity
      • bactericidal
      • active against yeast, fungi, MRSA, VRE
      • silver sulfadiazine (Silvadene) is commonly used on burn wounds
      • needs to be complexed to a delivery system – impregnated dressings, foam, cream

    2. Honey
      • has been used since ancient times for wound management
      • has broad-spectrum antimicrobial activity due to its high osmolarity and high concentration of hydrogen peroxide

    3. Antibacterial Solutions
      • acetic acid, Dakin’s solution, betadine, Iodosorb
      • partially cytotoxic, and so may impair wound healing
      • may be beneficial in selected circumstances (pseudomonas)

    4. Antibacterial Ointments
      • Bacitracin, Neosporin, Polysporin
      • soothing to apply, lubricates wound surface, occlusive
      • useful for small open wounds or burns

    5. Growth Factors
      • goal is to accelerate healing of chronic wounds by flooding the wound with growth factors
      • PDGF (Regranex) is FDA approved for diabetic foot ulcers
      • epidermal growth factor and granulocyte-macrophage colony stimulating factor may be beneficial in chronic venous ulcers

  4. Wound Dressings
    • wound healing is most successful in a warm, moist, clean environment
    • wound dressings need to keep the wound moist, but also absorb excess moisture to prevent maceration of healthy tissue
    • wound dressings should also eliminate dead space and prevent bacterial invasion or proliferation
    • primary choice is between occlusive and absorptive dressings

    1. Occlusive Dressings
      • good choice for most wounds
      • allows for rapid epithelialization, moisture retention, mechanical protection, and a barrier to bacteria
      • hydrocolloids (Duoderm): liquefies to form a moist gel
      • alginates: absorb a great deal of fluid, facilitate autolytic debridement
      • hydrogels: rehydrating agents for dry wounds

    2. Absorptive Dressings
      • used in wounds with a great deal of exudate or high bacterial counts (venous stasis ulcers)
      • prevent maceration of the surrounding skin
      • wide mesh gauze (4 x 4) is commonly used, but it loses effectiveness when it gets saturated
      • new materials are foam based: can absorb large amounts of fluid, and are nonadherent

  5. Negative Pressure Wound Devices
    • can be used in large soft-tissue injuries, contaminated wounds, fistulas
    • remove exudate and infectious materials
    • reduces edema
    • provides a moist wound environment
    • promotes increased capillary blood flow, angiogenesis, and granulation tissue
    • reduces hospital stay and costs
    • efficacy in accelerated wound healing has been documented in clinical trials
    • cons: can be painful, requires a portable pump, fluid loss in large wounds, cost if not covered by insurance

  6. Skin Substitutes
    • burn wounds are the major indications for these products
    • allografts, xenografts, amnion can provide temporary coverage
    • bioengineered skin substitutes are available to provide temporary or permanent coverage
    • provide biologic elements to the wound
    • Alloderm and Integra are acellular and provide dermal matrix elements
    • Apligraf provides dermal and epithelial components
    • main limitation of these products are their expense and need for multiple applications

  7. Hyperbaric Oxygen (HBO)
    • wound ischemia is the most common cause of wound healing failure
    • 100% oxygen is pressurized to 1.5 – 2.5 atmospheres for 60 to 120 minutes over multiple treatments
    • tissue oxygen levels can be 10x higher than usual, and can persist for 2 – 4 hours after treatment ends
    • vascular evaluation and possible revascularization is mandatory prior to starting HBO
    • transcutaneous oxygen pressure measurements (TCOM) are used to assess who is a candidate for HBO
    • TCOM < 35 mm Hg at room air indicates tissue hypoxia
    • TCOM > 200 mm Hg in the chamber suggests patient would benefit from HBO
    • used in carbon monoxide poisoning, radiation injury, compromised skin grafts and flaps, refractory osteomyelitis
    • there is some evidence that HBO therapy reduces the risk of amputation for patients with chronic nonhealing diabetic foot ulcers, provided that the limb has undergone revascularization
    • middle ear barotrauma is the most common complication of HBO
    • pulmonary complications include pneumothorax or tension pneumothorax
    • seizures can result from oxygen toxicity







References

  1. Simmons and Steed, pgs 41 - 55
  2. O’Leary, 4th ed. Pgs 150 - 169
  3. Schwartz, 10th ed., Pgs 241 – 268
  4. Sabiston, 20th ed., Pgs 130 – 160
  5. UpToDate. Basic Principles of Wound Management. David G. Armstrong, DPM, MD, PhD, Andrew J. Meyr, DPM. June 08, 2021, pgs 1 – 42
  6. UpToDate. Complications of Abdominal Surgical Incisions. Mizell, Jason. May 2018, pgs 7 – 10