Wounds: Care and Treatment William R. Dougherty, MD FACS Associate Professor of Surgery

Goals Identify elements of wound healing Define differences between acute and chronic wounds Treatment options of acute wounds Treatment options of chronic wounds

Healing and Regeneration Starfish and salamanders heal by regeneration (whole limbs) Mammals heal by a combination of scarring and regeneration.

Surgeons Invocation Give us the ability to operate on the things that cannot be healed To heal the things that can be healed, And the wisdom to know the difference.

Acute Wounds Acute wounds normally heal in a very orderly and efficient manner. Healing is characterized on a four distinct but overlapping faces. Hemostasis, Inflammation, Proliferation, and Remodeling Specific biologic markers characterize and orchestrate the phases healing of the acute wounds.

Cytokines Originally identified cell growth factors, now recognized to have diverse effects. Endocrine, autocrine, paracrine and intracrine. Cell migration, matrix production, enzyme expression and cell differentiation

Cytokines CytokineCell of OriginFunction PDGFPlatelets Macrophages Endothelial cells Cell chemotaxis Mitogenic for fibroblasts Stimulates angiogenesis Stimulates wound contraction TGF-alphaMacrophages T lymphocytes Keratinocytes Mitogenic for keratinocytes and fibroblasts Stimulates keratinocyte migration TGF-betaPlatelets T lymphocytes Macrophages Endothelial cells Keratinocytes Cell chemotaxis stimulates angiogenesis and fibroplasia EGFPlatelets Macrophages Mitogenic for keratinocytes and fibroblasts Stimulates keratinocyte migration Fibroblast growth factorMacrophages Mast cells T lymphocytes Endothelial cells Chemotactic and mitogenic for fibroblasts and keratinocytes Stimulates angiogenesis

Cytokines Fibroblast growth factorFibroblastsStimulates keratinocyte migration, differentiation, and proliferation TNFMacrophages Mast cells T lymphocytes Activates macrophages Mitogenic for fibroblasts Stimulates angiogenesis Interleukin (IL)–1, IL-2, IL-6, and IL- 8 Macrophages Mast cells Keratinocytes Lymphocytes IL-1 - Induces fever and adrenocorticotropic hormone release, enhances TNF-alpha and interferon (INF)–gamma, activates granulocytes and endothelial cells, and stimulates hematopoiesis IL-2 - Activates macrophages, T cells, natural killer cells, and lymphokine-activated killer cells; stimulates differentiation of activated B cells; stimulates proliferation of activated B and T cells; and induces fever IL-6 - Induces fever and enhances release Keratinocyte of acute- phase reactants by the liver IL-8 - Enhances neutrophil adherence, chemotaxis, and granule release INFs (IFN-alpha, -beta, and -delta)Lymphocytes Fibroblasts Activate macrophages Inhibit fibroblast proliferation Thromboxane A2Destroyed wound cells Potent vasoconstrictor

Hemostatic Phase Platelets come into contact with collagen and extracellular matrix. Contact triggers the release of clotting factors as well as essential growth factors and cytokines. PDGF platelet derived growth factor TGFβ transforming growth factor beta

Inflammatory Phase Neutrophils enter the wound site first to remove foreign materials, bacteria and image tissue. Macrophages continue the process of phagocytosis and release more PDGF and TGFβ Rubor, Tumor, Calor and Dolor

Proliferative Phase In response to PDGF and TGFβ fibroblasts migrate in to deposit collagen and extracellular matrix. College is the most abundant protein in the animal kingdom, accounting for 30% of the total protein in the human body. Epithelial migration and new vessel formation are prominent features.

Proliferative Phase Hydroxyproline is key in maintaining tertiary college and structure. Vitamin C deficiency and hypoxia both reduce hydroxyproline Lysyl oxidase (inhibited by steroids) is responsible for cross- linking collagen from

Collagen Type I - Located in all connective tissue except hyaline cartilage and basement membranes Type II - Located in hyaline cartilage Type III - Located in distensible connective tissue (blood vessels) Type IV - Located in basement membranes Type V - Located in all tissues Type VI - Located in all tissues Type VII - Located in the dermal-epidermal junction Type VIII - Located in the Descemet membrane Type IX - Located in hyaline cartilage Type X - Located in hypertrophic cartilage and hyaline cartilage

Remodeling Phase The new collagen matrix is metabolized, cross-link and organized. Native collagen approaches the strength of steel on a weight per weight basis Defects in remodeling main result in low tensile strength or hypertrophic scaring The healed wound reaches 80% of the surrounding normal tissue strength in six to eight weeks

Wound healing phases: Overview Platelets HEMOSTSIS Fibrin Proteoglycans INFLAMMATION Neutrophils Macrophages Lymphocytes PROLIFERATION Time from injury Fibroblasts Collagen Epithelial cells Endothelial cells REMODELING Collagen fibril cross-linking Scar maturation Normal Wound Healing

Factors that influence wound healing Nutrition Bacterial contamination Necrotic tissue / debris Immune / Bone marrow competence Edema Underlying medical conditions Drug therapy Radiation therapy

What’s new: Stem Cells Bone marrow derived stem cells Circulating and fixed Responders to the cell signaling Regenerative components

Acute Wounds: Etiology Trauma Burns Vascular Immune Surgical Pressure Infection

Chronic Wounds Unique biologic markers characterize pathologic healing responses that resulting fibrosis and chronic nonhealing wounds. The efficient and orderly processes lost and the wounds are locked in to the state of chronic inflammation and fibrosis. This is associated with abundant neutrophil infiltration, reactive oxygen species and district in enzymes.

Fibrosis In most conditions of fibrosis are characterized by an increased density of mast cells. Mast cells contain specialized enzymes capable of processing procollagen and it has been suggested that abnormal peptides are produced that can actually stimulate collagen synthesis thus producing fibrosis.

Keloid versus Hypertrophic Scar There is one very significant biological marker that distinguishes keloids from hypertrophic scars and that is the absence of myofibroblasts in keloids and an abundance of these contractile cells in hypertrophic scars.

Common Factors Loss of epithelial integrity Devascularized tissue Contamination Stimulation of cytokine cascade Stimulation of stem cell migration Coagulation, Inflammation, Proliferation and Remodeling

Effects of Pressure Landis (1930) –Average pressure in arteriolar limb 32 mmHg Husain (1953) –Microscopic changes in muscle after 100 mmHg for one hour Dinsdale (1974) –>70 mmHg over 2 hours; irreversible damage –>240mmHg with intermittent relief; no damage

Location of Pressure Sores

The Progression of Disease Hyperemia –Seen within 30 minutes –Disappears after 1 hour Ischemia –Seen after 2 hours –Erythema disappears after 36 hours Necrosis –Seen after 6 hours Ulceration –Within 2 weeks Edberg, Cerny, Stauffer. Phys Ther 53:246, 1973.

Stages

The Simple Solution

Treatment for Acute Wounds Debride Decontaminate Moist wound healing Early Closure

Treatment for Chronic Wounds Debride Anti-inflammation therapy Antibiotic therapy Synthetic substitutes – mod. Cytokines MMPs Recruit stem cells