Important Topics
- • Process of Wound Healing
- • Classification of Wound
- • Phases of Wound Healing
- • Growth Factors in Wound Healing
- • Factors Affecting Wound Healing
- • Complications of Wound Healing
- • Treatment of Wound
‘It is a most gratifying sign of the rapid progress of our time that our best textbooks become antiquated so quickly.’
Christian Albert Theodor Billroth (1829 –1894)
Austrian Surgeon
Introduction
- Wound healing is the normal body response to injury (surgical/traumatic) to restore the normal structure and function.
Wound Healing Involves Any of the Two Processes
Classification of Wound
Types of Wound Healing
Three Phases of Wound Healing
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Inflammatory (Reactive) Phase
Day 1
- Immediately after injury, blood vessels are disrupted, resulting in exposure of subendothelial collagen to platelets, leads to platelet aggregation and activation of coagulation pathway.
- The end product of coagulation cascade is fibrin, which plays an important role in clot formation and wound healing. This fibrin acts as scaffold for migration of PMN and monocytes into the wound. It also serves as a reservoir for cytokines.
- Platetet and granulocytes release a number of substances, such as platelet derived growth factor (PDGF), transforming growth factor-β (TGF-β), fibronectin, serotonin and histamine.
Day 1–4
- Leukocytes begin to migrate out from the vessels to the wound. The release of histamine and serotonin causes increased vascular permeability and various chemotactic factors facilitate migration.
- PMNs are the first inflammatory cells to enter the wound. Increased vascular permeability and presence of chemotactic substancs (e.g. IL-1, TNF-α, TGF-β, PDGF) facilitate migration of PMNs. In the first 24–48 hours, neutrophils make about 50% of all cells in the wound.These PMNs phagocytize bacteria, foreign material and devitalized tissue. They also release TNF-α2 (an important cytokine for angiogenesis and collagen synthesis) and collagenases. Over time, neutrophils are removed by apoptosis or macrophage phagocytosis.
- Macrophages start to migrate in the wound after about 48 hours of injury, and present till healing proces is completed. Macrophages also participate in phagocytosis. They synthesize oxygen radical and nitric oxide, release cytokines and growth factors such as TGF-β, VEGF, Insulin-like growth factor (IGF), epithelial growth factor (EGF) and thereby regulate cell proliferation, matrix synthesis, remodelling and angiogenesis.
- T lymphocyles also migrate to the wound usually about 5–7 days after injury. They take part in wound healing by producing stimulatory cytokines (e.g. IL–2) and inhibitory cytokines (e.g. TGF-β, TNF-α).
Proliferative (Reparative) Phase
- It is the second phase of healing.
- This phase involves angiogenesis, fibroplasia and epithelialization, and spans from day 4 to day 12.
- Angiogenesis—Endothelial cell migration, its replication and new capillary tube formation result from complex interaction of extracellular matrix material (e.g. fibronectin, hyaluronic acid) and cytokines (e.g. TGF-β, IL-8, VEGF). The angiogenesis is regulated by TNF-α, TGF-β, VEGF, PDGF those are derived from platelets, macrophages, damaged epithelial cells.Metabolic environment of the wound also influences angiogenesis. Increased lactate, decrease pH and oxygen tension result in reduction of NAD+ (inhibitor or angiogenesis).
- Fibroplasia—The quiscent fibroblasts are chemoattracted to the injury site, where it replicates and proliferates, being stimulated by macrophage and platelet derived cytokines (e.g. TGF-β, EGF, IGF–1). PDGF is the most potent chemotactic and mitogenic factor for fibroblasts.The activated fibroblasts now synthesize collagen and other components of extracellular matrix (ECM). ECM consists of fibroblast-derived collagen monomer, proteoglycans and fibronectin. Two types of collagen are important for wound repair, Type I and Type III. Among them, Type III collagen plays significant role. Collagen synthesis significantly begins about 1 week postinjury. Oxygen, vitamin C, iron are cofactors for cross-linkge of collagen fibers. Fibroblasts also produce matrix metalloproteinases (MMP) which helps to degrade matrix substances resulting in smooth migration of fibroblasts.
- Epithelialization—Epithelialization of wound develops due to migration of epithelial cells from the edges of wound, mediated by EGF, TGF-β, PDGF, IGF-1.Migration of epithelial cells occur at the rate of 1 mm/day and it begins within hours after injury. The attachments between hemidesmosomes of the basal cells and the laminin of the basal lamina are broken down, leading to migration of epithelial cells.Reepithelialization is completed within 48 hours in approximated incised wound.
[If epithelium and superficial dermis is only damaged, then the repair process involves reepithelialization without any fibroplasia (no scar formation at all).]
Maturational (Remodeling) Phase
- Wound contraction:
- This process involves movement of the wound edge toward the center of the wound by the action of myofibroblasts.
- The process starts 4–5 days after injury and continues for 12–15 days.
- Matrix metalloproteinases (MMPs) are important factors for wound contraction.
- Remodeling:
- The process begins about 21 days after injury.
- Collagen synthesis is downregulated, collagen (type III) is broken down by MMPs and replaced by denser collagen (collagen I) that is organized along the lines of stress. An early wound consists of about 30% type III collagen (uninjured connective tissue composed of 80–90% type I collagen and 10–20% type III collagen). Higher concentration of type III collagen in matrix, more weaker the wound.With time, the ratio of type I and III collagen changed to the ratio of intact connective tissue.
- Cellularity of the wound decreases.
- As a result, a mature, avascular, acellular collagen rich scar develops.
- This process reaches a steady state after 12–18 months. By about 6 months, the wound regains 80% of the strength of an unwounded tissue.
[A well-healed wound never achieves the strength of an unwounded tissue. By 3 weeks, the tissue strength reaches 30% of original strength. After 3 months, the strength reaches the maximum, about 80% of its original strength.]
- Healing by secondary intention:
- The pathological process and phases are almost same, the differences are quantitative.
Role of Growth Factors in Healing
- Different growth factors are:
- Platelet-derived growth factor (PDGF)
- Transforming growth factor α and β (TGF-α, TGF-β)
- Fibroblast growth factor (FGF)
- Vascular endothelial growth factor (VEGF)
- Granulocyte-macrophage colony-stimulating factor (GM-CSF)
- Insulin-like growth factor (IGF-1, IGF-2).
- Growth factors act on cells by surface receptor binding.
- Growth factors have different actions on different cells:
- Chemotaxis of PMNs, macrophages, fibroblasts
- Stimulation of angiogenesis
- Stimulation of fibroblasts leads to replication and proliferation
- Stimulation of collagen synthesis
- Regulation of ECM synthesis.
Factors Affecting Wound Healing
Systemic Factors
- Malnutrition—Normal healing process is delayed and impaired, leads to weak scar formation.
- Hypoxic wound environment—Optimal collagen synthesis for wound healing requires oxygen as a cofactor.Factors causing hypoxia in wound (e.g. cardiac failure, arterial insufficiency, excessive tension on tissue) affect proper wound healing.
- Diabetes mellitus—The lack of insulin (insulin restores collagen synthesis and granulation tissue formation) and hyperglycemia (by affecting the migration and phagocytic function of inflammatory cells and proliferation of fibroblasts and endothelial cells) leads to impaired wound healing.Diabetic wound also lacks adequate growth factors.
- Chronic renal and hepatic disease—Decreased collagen synthesis leads to weak scar formation.
- Collagen vascular disease—The disease itself as well as medications are responsible for impaired inflammatory cell migration and collagen deposition.
- Smoking—Impairs wound healing by causing cutaneous vasoconstriction, nicotine impairs collagen synthesis.
- Steroid and antineoplastic drugs—Steroids inhibit the inflammatory phase of wound healing. It impairs collagen synthesis, inhibit epithelialization and wound contraction.Antineoplastic drugs impair proliferation of fibroblasts as well as inhibit the inflammatory phase of wound healing.
- Vitamin and mineral deficiency— Vitamin C deficiency leads to failure in collagen synthesis as well as cross-linking. Vitamin A increases the inflammatory responses after injury increases the migration of macrophages, helps its activation. It also increase collagen synthesis.Vitamin A can restore wound healing that are impaired by diabetes, radiation, cyclophosphamide.Zinc deficiency leads to decreased fibroblast proliferation, delayed epithelialization, decreased collagen synthesis.
Local Factors
- Infection: Presence of infection delays wound healing. Infection alters the effects of cytokines, leads to delayed healing.
- Wound hypoxia: Local damage to the vessels following trauma, edema around the wound, excessive tension due to suturing lead to wound hypoxia.Hypoxia leads to impaired fibroblast proliferation and collagen synthesis.
- Edema: Leads to increased tendency to skin breach and development of infection.
- Ionizing radiation: Leads to abnormal wound healing.
- Chemical agents: Chlorhexidine or povidone-iodine impairs inflammatory cell migration, leads to delayed wound healing.
Complications of Abnormal Wound Healing
- Altered pigmentation: Most of the scars are hypopigmented, hyperpigmentation may also occur.
- Tattooing: Dirt or soot particles may become implanted in untidy wounds and results in tattooing of scar.
- Hypertrophic scar: Raised scar that confines of the original wound.
- Both increased collagen production and collagen breakdown, but the final result is excess collagen in tissue.
- Stretched collagen bundles are aligned in same plane of epidermis, whereas the collagen bundles are randomly arranged and relaxed in normal scar.
- More cellular and vascular than normal scar, also contains aggregates of abundant fibroblasts, vessels and collagen fibers.
- A hypertrophic scar can develop anywhere in the body and frequently regress spontaneously.
- The development of hypertrophic scar can be minimized by choosing appropriate direction of incisions (hypertrophic scar usually occur at areas of tension and flexor surface).
- Custom made pressure garments aids collagen maturation, increases collagenase activity and makes the scar less cellular.
- Keloid: Keloids are proliferative scar that grows beyond the limits of the wound.
- Thicker, more abundant stretched collagen bundles aligned in the same place of the epidermis, as well as acellular.
- Rarely regress spontaneously.
- Genetic predisposition is present.
- More common in darker-pigmented peoples—African and Asian population.
- May develop after surgery, burn, tattoos, ear piercing.
- Certatin body parts have increased tendency of keloid formation—Presternal, deltoid, earlobe, upper back.
- Treatment: Intralesional corticosteroids (e.g. triamcinolone acetate) is the first line of treatment.
- Surgery and postoperative interstitial radiotherapy is the another option.
- Chronic nonhealing wound—e.g. diabetic ulcer, pressure sore.
Wound Closure Techniques
- Suturing— e.g. skin suturing with nonabsorbable, monofilament suture
- Stapling—Allows quick closure
- Steri-strips—
- Least invasive way of skin closure
- Particularly used after suture or staple removal.
- Skin adhesive (octyl-cyanoacrylate)—
- Provide a waterproof, antimicrobial barrier
- No need of removal of suture or staples.
Treatment of Wound
- History taking
- Examination of wound—
- To assess depth
- To identify foreign bodies, dirt
- Presence of nonviable tissue.
- Tetanus prophylaxis
- Local care of the wound—
- Antibiotics—Choice of antibiotic depends on organisms most likely to be found in the wound and patient's immune status.
- Dressing—
- The goal of dressing is to provide an ideal environment for wound healing
- Characteristics of ideal dressing—
- Cost effective
- Permeable to gases and water vapor
- Impermeable to microorganisms
- Comfortable
- Nonirritant
- Minimal pain during change of dressing.
- Different types of dressing—
- Occlusive and semiocclusive dressing
- Hydrophilic and hydrophobic dressing
- Medical dressing
- Alginates
- Absorbent dressing.