Wound Healing

Phases of cutaneous wound healing: inflammation,

proliferation, and maturation

(Modified from Broughton G et al: The basic science of wound healing. Plast Reconstr Surg 117:12S–34S, 2006.)

05/27/20 Dep PA FK USU Medan 2015 2

 MECHANISMS OF NORMAL
WOUND HEALING

Normal wound healing processes

divided into 4 overlapping phases:
1.Coagulation (not shown)
2.Inflammatory phase (A)
3.Proliferative phase/granulation
tissue formation (B)
4.Remodeling phase (C)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428147/figure/F1/
 MECHANISMS OF NORMAL WOUND HEALING

• Coagulation and inflammatory phases (A)

– Blood-borne cells-neutrophils, macrophages, platelets  lay critical roles.
– Provide growth factors & provisional matrices  necessary for recruitment of
epidermal & dermal cells into the wound bed
• Proliferative phase (B)
– 3 days after injury, characterized by:
• ↑ keratinocyte and fibroblast proliferation, migration, & ECM synthesis in
response to autocrine, paracrine, and juxtacrine growth factors.
• Angiogenesis/neovascularization
• Granular appearance (granulation tissue)
• 1-2 weeks after injury
– Differentiated fibroblastic cells (myofibroblasts) that present within the granulation
tissue begin to remodel extracellular matrix (C).
– Extracellular matrix remodeling followed by apoptosis of resident cells leads to the
formation of an acellular scar.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428147/figure/F1/
MAJOR TYPES OF CHRONIC WOUNDS

Wound Type Pathology

Venous ulcers Venous insufficiency, thrombosis, varicosis

Arterial ulcers Macroangiopathy, atherosclerosis,

arterial insufficiency

Diabetic ulcers Neuropathy, microangiopathy,

hyperglycemia

Pressure ulcers Immobility, excessive pressure

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428147/table/T1/
 NORMAL VERSUS CHRONIC WOUND
HEALING
• Microenvironment within a normal wound bed (left) is characterized by the
presence of numerous growth factors, a well-organized ECM, and responsive cell
populations.
• Matrix synthesis, exceeds its degradation, and MMP activity is regulated by the
presence of MMP inhibitors (TIMPs).
• Angiogenesis & neovascularization of normal wounds proceed in a timely manner
via well-regulated sprouting of existing blood vessels and recruitment of
endothelial progenitor cells (EPC), respectively.
• Acute wounds characterized by ↓ bacterial burden
• Chronic wounds (right) have ↑ incidence of bacterial biofilms  persistent
inflammation, ↑ proteolysis, and degradation of critical growth factors, receptors,
and/or ECM.
• Cells residing within these wounds are unable to proliferate and/or migrate
effectively perhaps because of the absence of functional receptors or appropriate
promigratory matrix substrates.
• Impaired angiogenesis and neovascularization  hallmarks of chronic wounds,
result in insufficient oxygen and nutrient supply for the cells residing within the
wound bed, which leads to further wound bed mutilation and impaired healing.
NORMAL VERSUS CHRONIC WOUND
HEALING

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428147/figure/F2/
PHYSIOLOGIC IMBALANCE: A KEY
FEATURE OF CHRONIC WOUNDS

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428147/figure/F3/
CHRONIC WOUND CONUNDRUM
Diagrammatic representation of those physiologic functions that are perturbed
or disequilibrated during chronic wound healing.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428147/figure/F4/
 CONTROL OF WOUND HEALING: A
ROLE FOR BACTERIAL COLLAGENASE?
• Bacterial collagenase clinically used for wound debridement
stimulates both endothelial and epithelial responses to injury.
• Degradation of the ECM in close proximity to the cells’ enzyme
allows for efficient cell migration.
• The release of growth factors and liberation of biologically active
matrix fragments that can interact with and activate cellular
receptors ↑ motogenic & mitogenic potential of the cells within
the wound bed, promoting the healing responses.
• Similar to naturally occurring ECM fragments released by bacterial
collagenase in vivo, synthetic matrix-derived peptides identified
and tested in the laboratory can enhance cellular responses to
injury.
• Therefore, the authors propose that the peptides could be used in
combination or as an alternative to the bacterial products, which
foster wound healing in vivo.
 CONTROL OF WOUND HEALING: A
ROLE FOR BACTERIAL COLLAGENASE

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428147/figure/F5/
 Forkhead BoxO-1 (FOXO1) & Re-
Epithelialization
A. Oxidative stress increases in the inflammatory
phase of wound healing.
– FOXO1 down-regulates oxidative stress by activating
antioxidant genes & DNA repair enzymes.
– This facilitates keratinocyte migration & proliferation,
↓ keratinocyte apoptosis  improves wound healing
B. FOXO1 stimulates TGF-β promoter activity
– Resulting in the upregulation of TGF-β expression.
– ↑ TGF-β stimulates expression of integrins & matrix
metalloproteinases (MMPs) to improve wound healing
through ↑ keratinocyte migration & ↓ apoptosis.
Forkhead BoxO-1 (FOXO1) and Re-
Epithelialization

www.mdpi.com/journal/ijms
FOXO1 & Diabetic Wound Healing
• ↓ glucose conditions  FOXO1 promotes wound
healing by ↑ TGF-β levels.
• This leads to ↑ keratinocyte migration & re-
epithelialization.
• However, in high glucose conditions FOXO1 does not
stimulate an increase in TGFβ1. Instead, FOXO1
• increases inflammatory gene expression (increased
CCL20), which interferes with
• keratinocyte migration. Thus, in standard glucose
levels FOXO1 promotes healing but in
• high glucose FOXO1 is detrimental to healing by a
switch in the genes that it regulates