- Early, Intermediate, Recovery

Phases of Wound Healing

- Substrate, Inflammatory, Exudative Phase

- Hemostasis & Inflammation

- platelet activation & aggregation release mediators of inflammation

- attracts cellular element & allows exudation of plasma proteins into wound

- neutrophils arrive first, but not necessary for wound healing

Early Phase of Wound Healing

- Wound Contraction (reduces wound size, faster healing, achieved by myofibroblasts)

- Regeneration (replacement of destroyed tissue by same type of tissue (requires survival of stromal framework)

- Repair (scarring) by replacement by fibrous CT

Intermediate Phase of Wound Healing

- achieved by ingrowth of myofibroblasts

- especially important in healing with secondary intention

- leads to faster healing w/ less scar tissue

Wound contraction

- tissues which routinely or continuously divide and regenerate

- Ex: Epithelial surfaces: epidermis, mucous membranes, hematopoietic cells

Labile tissues

- tissues which regenerate if stimulated

- Ex: Glandular organs especially liver, mesenchymal tissues such as fibrous tissue, blood vessels, and bone

Stable (Quiescent) Tissues

- tissues which do NOT regenerate

- Ex: Neurons, lens of the eye and cardiac/skeletal muscle

Permanent (non-dividing) tissues

- epithelium regenerates with BM directing polarity and order but architecture is often this

- Ex: epidermis over scar tissue lacks normal rete ridges, colon mucosa at old ulcers has branched shpaed glands

Abnormal regeneration

- replacement by fibrous CT

- major components of healing by repair/fibrosis

- angiogenesis, fibroplasia/fibrosis

Repair (Scarring)

- formation of new blood vessels

- occurs by budding from pre-existing "parent" blood vessels

- degradation of parent vessel BM,

- migration of endothelial cells toward angiogenic stimulus,

- proliferation of endothelial cells behind leading front of migrating cells,

- maturation of endothelial cells, organizing capillary tubules

Angiogenesis in Wound Healing Repair

- cellular proliferation and migration

- (myo)fibroblasts proliferate and migrate into wound under stimulation by growth factors & cytokines

- fibronectin and laminin are important contributors to directed cell migration

- seen within 2-3 days of injury

- ECM components secreted by fibroblasts

Fibroplasia/Fibrosis of Wound Healing Repair

- fibronectin provide "scaffolding" for cell migration into wound

- hyaluronic acid provide hydration and tissue turgor

Early ECM deposition in Wound Healing Repair

- collagen provides tensile strength to tissue

- significant amount of collagen not seen until about 4 days after injury

- Type III collagen is produced first, later type I

Late ECM deposition in Wound Healing Repair

- hallmark of early wound healing

- starts within 48-72 hrs

- proliferating small vessels and fibroblasts w/ loose delicate CT background

- budding capillaries look like little red bumps. have leaky inter-endothelial junctions (edematous)

Granulation tissue

- scar formation and remodeling

- involves shift in normal balance between collagen production and degradation (net accumulation)

- loose CT --> denser, acellular fibrous tissue

- peak collagen deposition occurs at 2-3 months

- scar becomes flatter, paler, more supple

- 6-18 months for maturation

Maturation Phase of Wound Healing

- occurs in clean uninfected surgical incision

- fills w/ blood containing fibrin and blood cells

- dehydration creates "scab"

- neutrophils appear, basal cells proliferate (day 1)

- macrophages replace neutrophils, granulation invades incision, collagen is laid down vertically, proliferating epithelial cell scover wound surface (by day 3)

- neovascularization is maximal, epithelial surface is regenerated, collagen fibers bridge wound (by day 5)

- sutures are usually removed, but wound has 10% maximal strength (day 7-10)

- type I collagen starts to predominate over type III, vascular channels regress, reduction of edema (2nd wk)

- inflammatory cells/granulation capillaries gone, type III collagen degraded by collagenases, type I collagen has been laid down, cross-linked (1st month)

Primary union or healing by first intention

- large and/or irregular and/or infected wound

- large area requiring repair, leads to large, irregular scar

- wound contraction plays important part

- epithelialization occurs from wound margin (1 mm/day)

- granulation tissue continues to form at wound base

Secondary intention

- directing migration of cells

- influencing differentiation of mesenchymal stem cells

- providing a "scaffold" or "template" for cell growth

- opsonization, cell adhesion/attachment, structural support (turgor/tensile strength)

Extracellular Matrix contributions to Wound Healing

- collagens & elastin

- glycosaminoglycans and proteoglycans

- multiadhesive proteins (fibronectin)

Major components of ECM

- deposited early in wound healing, provide hydration & therefore tissue turgor

- granulation tissue is rish in mucopolysaccharide hyaluronic acid

Glycosaminoglycans & Proteoglycans

- deposited early in wound healing

- first, plasma-derived fibronectin, then mostly tissue-derived (endothelium, moncyte, fibroblast, etc)

- binds to multiple different molecules

Multiadhesive proteins (fibronectin)

- major producers of collagen and collagenases

Fibroblasts

- major contributors to wound wound contraction

- have features of both fibroblasts and smooth muscle

Myofibroblasts

- probably the orchestrating cell of wound healing

- produces cytokines and growth factors

Monocyte/macrophage

- sprout from pre-existing vessels and form capillaries

Endothelial cells

- bind to RGD sequences found on many ECM proteins, influencing cell locomotion, proliferation and differentiation

Integrins

- primary cell-cell interaction during wound healing

Paracrine

- multifunctional growth factor, regulates other cytokines/growth factors involved in repair

- chemotactic for multiple cells (neutrophils, T-cells, monocytes, fibroblasts)

- induces formation of granulation tissue

- promotes fibroblast proliferation and increases collagen production

- inhibits proliferation of many cells

Transforming growth factor-B (TGF-B)

- stimulates proliferation of epithelial cells and fibroblasts

Epidermal growth factor (EGF)

- stored in platelet granules and other cells; released at site of injury

- another major plaery in wound healing

- causes migration and proliferation of fibroblasts, smooth muscle and monocytes

Platelet-derived growth factor (PDGF)

Basic fibroblast growth factor (bFGF) and Vascular endothelial growth factor (VEGF)

Induces angiogenesis

- promotes inflammation, cell migration and fibroblast proliferation

- stimulate production of both collagen and collagenases by fibroblasts

IL-1 and TNF

- if extended volumes of damaged tissue hurt the wound healing process, this must be done

Surgical removal

- must be removed before healing can proceed

- increases risk of bacterial infection

Hematoma

- presence of bacteria sustains inflammation and slows healing

- an important cause of delayed wound healing

Wound infection

- interfere with healing by tending to sustain inflammatory response

Foreign bodies

- slows healings, healing by second intention, may require debridement

Ragged, Irregular wound edges

- cannot mount a good inflammatory response

- slows healing

Leukopenia

- impedes inflammation

- slows healing

- usually cause of non-healing or ulceration

Inadequate blood supply

- protein and vitamin C are both necessary for good healing

- zinc is a cofactor in metallocollagenases necessary for collagen remodeling

Potential Nutrition Issues in Would Healing

- inhibit phospholipases, thus limiting production of inflammatory mediators produced by metabolism of AA

- reduce inflammation

- reduce collagen production which can impede healing

Corticosteroids

- bursting open of a wound

- occurs with infection, inadequate nutrition (vit C deficiency or mechanical stress (vomiting)

Wound dehiscence

- incomplete closure of abdominal fascia allows protrusion of abdominal contents into sac-like extension of scar

- most common with prior wound infection

Incisional hernia

- raised, reddened, may be pruritic, but remains within boundaries of scar

Hypertrophic scar

- progressive scar that tends to recur

- abnormal overgrowth of scar tissue that mushrooms over the edges of the wound

Keloid

- excessive wound contraction with dense fibrosis

- associated with abnormal proliferation of myofibroblasts

Contractures