Wound Healing

Behrooz A. Torkian MD

Introduction

Basis of repair of tissues Enables surgical treatment May take advantage for our benefit Complications Modification and Enhancement

Phases of Wound Healing

1. Vascular and inflammatory phase 2. Reepithelization 3. Granulation tissue formation 4. Fibroplasia and matrix formation 5. Wound contraction 6. Neovascularization 7. Matrix and collagen remodelling

Vascular

Initial vasoconstriction (5-10 min) then vasodilation (persistent) Exposure of subendothelial von Willebrand / factor VII, and fibrillar collagen platelet plug Hageman factor (XII) initiation of clotting cascade and fibrin clot formation

Clotting Cascade
Intrinsic Pathway
Surface Contact Collagen FXII activator F XII F XI F XIIa
Ca2+

Extrinsic Pathway
Tissue/Cell Defect

F VIIa F XIa
Ca2+

Ca2+

F VII

F IX
F VIII

F IXa

F VIIIa Platelet Factor 3

F III (Tissue Thromboplastin) Factor F Xa

F Va Ca2+ FV

Factor F X

Ca2+

Factor F X

Prothrombin I F XIIIa Crosslinked Fibrin Meshwork F XIII Fibrin polymers

Ca2+

Thrombin

Fibrin monomers

Fibrinogen

Inflammatory

Platelets

Polymorphonuclear leukocytes Macrophages (replace PMNs after 5 days) Fibroblasts (recruited by chemotactic factors released by the above cells)

derived growth factor (PDGF), proteases and vasoactive substances such as serotonin and histamine

Reepithelization

Migration (wound edges, hair follicles, adnexa) Proliferation (48-72 hours) Sutured wounds have a layer of keratinocytes within 24-48 hours

Keratinocytes

Fibronectin

Collagenases and neutral proteases debridement Plasminogen activator clot dissolution Type V collagen Requires moisture for epithelial migration

Cross links to fibrin matrix/scaffold for keratinocyte adhesion and migration Functions as an early component of the extracellular matrix. Binds to collagen and interacts with matrix glycosaminoglycans. Has chemotactic properties for macrophages, fibroblasts and endothelial and epidermal cells. Promotes opsonization and phagocytosis. Forms a component of the fibronexus. Forms scaffolding for collagen deposition

Granulation

Highly vascular network of glycoproteins, collagen and glycosaminoglycans Fibroblasts

collagen Elastin Fibronectin Sulfated and nonsulfated Glycosaminoglycans Proteases

Inflammatory cells

Fibroplasia

Fibroblasts Mainly Type III collagen first Replaced by type I and II collagen Hydroxylation of proline and lysine
Iron, copper, vitamin C Crosslinkage

Contraction

Myofibroblasts Fibronexus (Singer)

Connections between intracellular actin microfilaments and extracellular collagen, fibronectin, and between myofibroblasts Transmits force along entire network Centripetal contraction

Neovascularization

Fibronectin Macrophage derived angiogenic factor Endothelial migration

Wound Remodeling

Increased tensile strength Decreased bulk, and erythema Replacement of fibronectin by collagen Dehydration
Promotes further crosslinkage of collagen Reorientation of collagen to parallel skin collagen.

Local Factors

Infection Technique (wound edge ischemia) Hematoma Foreign body reaction Tissue ischemia Topical medications and dressings

Systemic Factors

Deficiency states
Insulin Protein (nitrogen balance) Vitamins

A slower re-epithelization C Collagen K clot formation Zinc, copper, iron, manganese

Trace minerals and elements

Systemic Factors

Medications
Glucocorticoids Anticoagulants Antineoplastic drugs Cyclosporin A Colchicine Penicillamine Zinc sulfate (high doses) Beta amino proprionitrile

Growth Factors

Epidermal growth factor Macrophage derived growth factor (MDGF) Platelet derived growth factor (PDGF) Thrombin Insulin Lymphokines

PDGF
TGF-alpha TGF-beta EGF FbGF KGF TNF IL-1,2,6,8 IFN-alpha, beta, delta VEGF IGF-I

Chemotaxis, Fb, angiogenesis contraction

Keratinocyte and Fb activation Fibroplasia, angiogenesis, Beta-3 has some antiscarring effects Keratinocytes Fb and keratinocyte , angiogenesis Migration, differentiation, proliferation Macrophage activation Macrophage activation Angiogenesis, vascular permeability Reepithelization and granulation

Thromboxane A2 Vasoconstriction

Plasminogen activator inhibitor -1

Found to be elevated in Keloid scars PAI-1 -/- knockout mice show accelerated wound healing after cutaneous injury PAI-1 seems to regulate fibrinolytic and proteolytic activity during the replacement of fibrin by collagen. PAI-1 is upregulated in cultured fibroblasts in a hypoxic environment

Metalloproteinases & Tissue Inhibitor of Metalloproteinases

Regulatory role in fibroblasia and scarring

Found in high concentrations in fetal wounds MMP/TIMP is higher in scarless fetal wounds TGF-beta decreased the MMP/TIMP ratio by increasing TIMP May promote more rapid epithelization

TGF Beta-1

Higher concentrations and exaggerated response in keloid fibroblasts When added to fetal wounds thicker scars made.

Silicone

Decreases TGF-Beta-2, and contraction of RAFT-fibroblast cultures (Kuhn et. al.) Increased bFGF levels in cultured fibroblasts (HanasonoKoch) Anecdotal evidence

References

Silvia Wagner, PhD et. al. Comparison of inflammatory and systemic sources of growth factors in acute and chronic human wounds, Wound Repair and Regeneration Volume 11 Issue 4 Page 253 - July 2003 doi:10.1046/j.1524475X.2003.11404.x Deodhar AK, Rana RE. Surgical physiology of wound healing: a review. J Postgrad Med [serial online] 1997 43:52-6 http://www.jpgmonline.com/article.asp?issn=00223859;year=1997;volume=43;issue=2;spage=52;epage=6;aulast=Deodhar Ziv PM et. al., Matrix Metalloproteinases and the ontogeny of scarless repair: the other side of the wound healing balance, Plastic and Reconstructive Surgery 110(3):801-11 2002 Bullard KM et. al. Fetal wound healing: Current Biology, World J. Surg 27: 54-61, 2003 Singer AJ, Clark RAF, Cutaneous Wound Healing, NEJM 341(10) 738-46; 2001 Saulis AS, Mogford JH, Mustoe TA.Related Articles, Links Effect of Mederma on hypertrophic scarring in the rabbit ear model. Plast Reconstr Surg. 2002 Jul;110(1):177-83; discussion 184-6. Hanasono MM, Lum J, Carroll LA, Mikulec AA, Koch RJ.Related Articles, Links The effect of silicone gel on basic fibroblast growth factor levels in fibroblast cell culture. Arch Facial Plast Surg. 2004 Mar-Apr;6(2):88-93.