1. Biology of Wound Healing

2. Stages of Wound Healing
 Hemostasis
 Inflammation
 Proliferation/Granulation
 Remodeling/Maturation
Wound Healing is a continuous, dynamic process
with distinct & overlapping phases

3. 4 Stages of Wound Healing

4. Stages of Wound Healing

5. Inflammation
 Normal and essential response to injury
 Begins immediately, last 2-7 days
 Goal is to provide hemostasis & clear away bacteria,
foreign material and dead tissues

6. Inflammation
Visible Changes Cells ECM components Key Mediators
Erythema
Heat
Swelling
Pain
Platelets
Mast Cells
Neutrophils
Macrophages
T Lymphocytes
Provisional fibrin
matrix
PDGF
TGF-β
TNF-α
IL-1
IL-6
IL-8
Interleukin-γ

7. Inflammation
 Hemostasis - platelet function
 Vasodilation - meet metabolic demands
 Mast cells - histamine response
 Neutrophils –
 Phagocytic
 Fight bacteria
 Enhance antibiotic function
 Macrophages –
 Phagocytic
 Stimulates fibroblast activity for proliferative phase

8. Proliferation
 Stimulated by inflammatory phase
 Overlaps with inflammatory phase
 Time to completion is partly dependent upon amount
of tissue lost
 Goal is to replace lost dermal tissue with scar tissue

9. Proliferation
Visible Changes Cells ECM
Components
Key Mediators
Eschar sloughing
New epidermis
Granulation
Tissue
Fibroblasts
Endothelial Cells
Keratinocytes
Myofibroblasts
Macrophages
Provisional ECM
Collagen
Elastin
Fibronectin
GAG
Proteoglycans
Integrins
PDGF
FGF
VEGF
TGF-β
IL-10
EGF
IGF

10. Proliferation
 Re-epithelialization
 Angiogenesis
 Collagen deposition
 Growth factor production
 Contraction

11. Proliferation
 Fibroplasia - fibroblast synthesis for granulation tissue
 Endothelial budding - vessels from surrounding tissue
migrate to supply nutrients
 Collagen matrix of collagen, hyaluronic acid and
fibronectin and elastin formation
 Myofibroblasts - wound contraction at margins

12. Remodeling/Maturation
 Remodeling of the Extracellular Matrix (ECM)
 Epithelial cell migration
 Collagen lysis and collagen synthesis balance
 Collagen aligns to applied stress - ROM and positioning
 Scar formation and remodeling
 Lasts 6 months to 2 years
 Tensile strength of wound will not exceed 70-80% of the
original skin

13. Cells Involved in Wound Healing
 Endothelial cells
 Platelets
 Neutrophils
 Monocytes
 Macrophages
 Mast Cells
 Lymphocytes
 Fibroblasts
 Keratinocytes

14. Cells Involved in Wound Healing

15. Endothelial Cells
 Produce Thromboxane A2 and prostaglandin 2-alpha
upon injury
 Potent vasoconstrictors
 Helps to limit hemorrhage/bleeding
 Angiogenesis -physiological process through which
new blood vessels form from pre-existing vessels
 Apoptosis (programmed cell death)
 Scar maturation

16. Platelets
 Major constituent of clot/Fibrin clot formation
 release platelet-derived growth factor (PDGF) and
transforming growth factor beta (TGF-b) from their
alpha granules to attract neutrophils and
macrophages

17. Neutrophils
 Phagocytic
 Fight bacteria
 Enhance antibiotic function
 Scavenge for bacteria and foreign debris

18. Monocytes
 Important phagocytic cell that plays key role in wound
healing
 Differentiates into macrophages

19. Macrophages
 Phagocytic
 Stimulates fibroblast activity for proliferative phase
 Macrophages are the most important mediators of
wound healing
 Macrophages emit growth factors to attract
fibroblasts - chemotaxis
 Essential for the initiation and maintenance of
fibroblast activity

20. Mast Cells
 Histamine response
 Respond to tissue injury by releasing inflammatory
mediators
 Mast cells are known to participate in three phases of
wound healing:
 Inflammatory reaction
 Angiogenesis
 Extracellular-matrix reabsorption.

21. Lymphocytes
 Contribute to the immunologic response to foreign
debris
 Possess the capacity to regulate essential steps wound
healing process
 Exert many of its effects via cytokines
 Capable of modulating fibroblast functions to include:
 Migration
 Replication
 Collagen synthesis

22. Fibroblasts
 Initiate
 Angiogenesis
 Epithelialization
 Collagen formation
 Fibroblasts differentiate into myofibroblasts, causing
tissue contraction during remodeling/maturation
phase
 Lay fibrin strands to act as a framework for cellular
migration

23. Keratinocytes
 Stimulate fibroblasts to synthesize growth factors
 Main cells responsible for the epithelialization phase –
reepithelialization
 Predominant cell type in the epidermis
 Epidermal maturation

24. Growth Factors (aka Cytokines)
• Platelet Derived Growth Factor (PDGF)
• Transforming Growth Factor (TGF-β, TGF-α, & others)
• Epidermal Growth Factor (EGF)
• Hepatocyte Growth Factor (HGF)

25. Growth Factors
Growth factor Abbreviation Main origins Effects
Epidermal Growth
Factor
EGF • Activated
macrophages
• Salivary glands
• Keratinocytes
• Platelets
• Keratinocyte and
fibroblast mitogen
• Keratinocyte migration
• Granulation tissue
formation
Transforming
growth factor-α
TGF-α • Activated
macrophages
• T-lymphocytes
• Keratinocytes
• Platelets
• Hepatocyte and
epithelial cell
proliferation
• Expression of
antimicrobial peptides
• Expression of
chemotactic cytokines

26. Growth Factors
Growth factor Abbreviation Main origins Effects
Hepatocyte Growth
Factor
HGF • Mesenchymal Cells • Epithelial and
endothelial cell
proliferation
• Hepatocyte motility
Vascular
endothelial growth
factor
VEGF • Mesenchymal cells
• Endothelial cells
• Vascular
permeability
• Endothelial cell
proliferation
• Promote
angiogenesis during
tissue hypoxia

27. Growth Factors
Growth factor Abbreviation Main origins Effects
Platelet derived
growth factor
PDGF •Platelets
•Macrophages
•Endothelial
cells
•Smooth muscle
cells
•Keratinocytes
• Granulocyte, macrophage,
fibroblast and smooth
muscle cell chemotaxis
• Granulocyte, macrophage
and fibroblast activation
• Fibroblast, endothelial cell
and smooth muscle cell
proliferation
• Matrix metalloproteinase,
fibronectin and hyaluronan
production
• Angiogenesis
• Wound remodeling
• Integrin expression
regulation

28. Growth Factors
Growth factor Abbreviation Main origins Effects
Transforming
growth factor-β
TGF-β • Platelets
• T-lymphocytes
• Macrophages
• Endothelial cells
• Keratinocytes
• Smooth muscle
cells
• Fibroblasts
• Granulocyte,
macrophage, lymphocyte,
fibroblast and smooth
muscle cell chemotaxis
• TIMP synthesis
• Angiogenesis
• Fibroplasia
• Matrix metalloproteinase
production inhibition
• Keratinocyte
proliferation

29. Factors influencing wound healing
 Oxygenation
 Infection
 Diseases
 Medications
 Stress
 Obesity
 Smoking
 Alcohol consumption
 Age
 Chronic disease
 Immunosuppression
 Sensory impairment
 Presence of foreign
body
 Tissue perfusion
 Malnutrition
 Nutrition
 Chemotherapy
 Radiation Rx
 Trauma
 Infection or microbial
overload

30. Abnormal Wound Healing
Molecular Environment Chronic Wounds Healing Wounds
ECM Damaged Functional
Inflammatory Cytokines High Low
Protease Activity Increased Low
Reactive Oxygen Species Increased Low
Mitogenic Activity Low High
Cell Competence Senescent Mitotically competent

31. Correcting Molecular & Cellular Abnormalities
Clinical Observation Abnormalities Clinical Actions
Infection or Inflammation Increased levels of
cytokines & proteases
Decreased Growth Factor
Activity
Antimicrobials (topical or
systemic)
Anti-inflammatories
Protease inhibitors
Moisture Imbalance Decreased keratinocyte cell
migration
Wound Maceration
Moisture-balancing
dressings, other methods
to remove fluid
Edge Margin non-achieving Nonresponsive wound cells
Altered protease activity
Corrective advanced
therapies