Wound Healing

Phases of Wound Healing

inflammatory (includes hemostasis), proliferation (or repair), and remodeling (or maturation), some overlap between these processes in vivo

Inflammatory Phase

first phase of wound healing, begins with hemostasis, acute inflammation and late inflammation, ends with debridement

Proliferation Phase

second phase of wound healing, fibroplasia, angiogenesis, and epithelialization, all of these processes promote granulation tissue, predominant cells include fibroblasts, endothelial cells, and epithelial cells

Remodeling Phase

third and last phase of wound healing, reorganization of collagen for strength; type III collagen changed to type I, can occur for up to months-years, ECM reorganization, scar formation

Response to Vascular Damage

rapid but transient vasoconstriction, mediators released from damaged endothelium and platelets (endothelin, thromboxane A2, prostaglandins); platelet activation, exposure to subendothelium collagen and associated ECM, vWF binds Gplb, ADP released from dense granules recruits more platelets

Vasoconstriction Mediators

released from endothelium and platelets, includes endothelin, thromboxane A2, and prostaglandins

Gplb

platelet surface protein that binds vWF during platelet activation

Vasodilation

increased vascular permeability brining more cells to injured site, mediated by PGI2 and PGD2 (prostaglandins), NO, serotonin, and histamine

Blood Clot

hemostatic plug forming barrier to infection and fluid loss, makes substrate for provisional extracellular matrix (wound bed), mediated by platelets organized into the clot and release cytokines and growth factors, coagulation pathways and complement activation, cross-linking of fibrin and fibronectin

Signs of Inflammation

redness, edema, heat, pain, and loss of function, predominantly mediated by neutrophils and macrophages

Early Inflammation

includes neutrophil infiltration and is the predominant cell type for 24-48 hours, phagocytosis and debridement, undergo apoptosis and debris is cleared by macrophages

Late Inflammation

macrophages predominate after 48-73 hours, M1 macrophages are proinflammatory and phagocytose, later M2 macrophages modifies the provisional ECM and are anti-inflammatory and pro-wound healing

Matrix Metalloproteinases (MMPs)

enzymes including collagenase and gelatinase produced by M1 macrophages to allow for easier migration in late inflammation

M1 Macrophages

phagocytosis and pro-inflammatory macrophages in late inflammation, releases cytokines IL-1 and TNF-alpha

M2 Macrophages

later cells in late inflammation that is anti-inflammatory and pro-wound healing, releases FGF, TGF-beta, VEGF, MMPs; leads to repair phase

Lag Phase

aka inflammatory phase, wound strength lags behind by 3-5 days, strength of wound maintained by fibrin clot between edges

Fibroplasia

mesenchymal cells differentiate into fibroblasts for collagen deposition (type III to I), and proteoglycan production and FGF, also differentiate into myofibroblasts for contraction and expressing TGF-beta

Angiogenesis

endothelial sprouting, chemotaxis and mitogenic mediators (largely from macrophages and VEGF), stimulated by low oxygen and increased lactic acid

Granulation Tissue

specialized tissue formed during the proliferation phase of wound healing, functions for wound contraction (myoepithelial cells), fills tissue deficit, protects wound, barrier to infection, and scaffold

Epithelization

mobilization and migration via EGF from macrophages and platelets, proliferation, 4-5 days after injury

Partial Thickness Wound Epithelization

occurs when an abrasion is present, variable portion of dermis unaffected (does not extend to subcutis), can include adnexal re-epithelization using hair follicle epithelium

Adnexal Re-Epithelization

use of hair follicle epithelium instead of peripheral migration from the edge of the wound bed

Full Thickness Wound Epithelization

occurs via wounds contraction and epithelization, adnexal structures do not regenerate and need peripheral migration

Cat Wound Healing

50% less strength in 7 days compared to dogs, lower production of collagen in early healing, less granulation tissue, may have faster contraction than dogs

Endogenous Factors Prolonging Healing

altered microcirculation, uremia, diabetes, liver disease, infection

Exogenous Factors Prolonging Healing

vitamins and minerals (Vit A and C deficiency) and steroids (hyperadrenocorticism), cytotoxic drugs, radiation therapy, and antiseptics

Vitamin A Deficiency

impairs re-epithelization and angiogenesis

Vitamin C Deficiency

leads to impaired collagen cross-linking and impaired neutrophil apoptosis

Extracellular Matrix Reorganization

part of the remodeling phase where cellularity decreases, collagen bundles cross-link, and MMPs and TIMPs (tissue inhibitors of MMPs) help refine structure

Platelet-Derived Growth Factor (PDGF)

important growth factor released from platelets, macrophages, endothelial cells, and keratinocytes

Transforming Growth Factor-alpha (TGF-alpha)

important growth factor released from macrophages, T-lymphocytes, and keratinocytes

Transforming Growth Factor-beta (TGF-beta)

important growth factor released from platelets, T-lymphocytes, macrophages, endothelial cells, keratinocytes, and fibroblasts

Epidermal Growth Factor (EGF)

important growth factor released from platelets and macrophages

Vascular Endothelial Growth Factor (VEGF)

important growth factor released from keratinocytes and macrophages to promote angiogenesis

Fibroblast Growth Factor (FGF)

important growth factor released from macrophages, mast cells, T-lymphocytes, endothelial cells, and fibroblasts