Wound Healing

1
Wound Healing

• Behrooz A. Torkian MD

2
Introduction

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

3
Phases of Wound Healing
1. Vascular and inflammatory phase2.
Reepithelization3. Granulation tissue
formation4. Fibroplasia and matrix formation5.
Wound contraction6. Neovascularization7. Matrix
and collagen remodelling
4
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

5
Clotting Cascade
6
Inflammatory

• Platelets
• derived growth factor (PDGF), proteases and
  vasoactive substances such as serotonin and
  histamine
• Polymorphonuclear leukocytes
• Macrophages (replace PMNs after 5 days)
• Fibroblasts (recruited by chemotactic factors
  released by the above cells)

7
Reepithelization

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

8
Keratinocytes

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

9
Granulation

• Highly vascular network of glycoproteins,
  collagen and glycosaminoglycans
• Fibroblasts
• collagen
• Elastin
• Fibronectin
• Sulfated and non-sulfated Glycosaminoglycans
• Proteases
• Inflammatory cells

10
Fibroplasia

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

11
Contraction

• Myofibroblasts
• Fibronexus (Singer)
• Connections between intracellular actin
  microfilaments and extracellular collagen,
  fibronectin, and between myofibroblasts
• Transmits force along entire network
• Centripetal contraction

12
Neovascularization

• Fibronectin
• Macrophage derived angiogenic factor
• Endothelial migration

13
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.

14
(No Transcript)
15
(No Transcript)
16
Local Factors

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

17
Systemic Factors

• Deficiency states
• Insulin
• Protein (nitrogen balance)
• Vitamins
• A slower re-epithelization
• C Collagen
• K clot formation
• Trace minerals and elements
• Zinc, copper, iron, manganese

18
Systemic Factors

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

19
Growth Factors

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

20
(No Transcript)
21
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

22
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

23
TGF Beta-1

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

24
(No Transcript)
25
Silicone

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

26
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 doi10.1046/j.1524-475X.2003.1140
  4.x
• Deodhar AK, Rana RE. Surgical physiology of wound
  healing a review. J Postgrad Med serial online
  1997 4352-6 http//www.jpgmonline.com/article.as
  p?issn0022-3859year1997volume43issue2spage
  52epage6aulastDeodhar
• 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
  Jul110(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-Apr6(2)88-93.