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Understanding and Promoting Wound Re-epithelialization

For optimal healing, wounded tissue passes through well-defined phases of repair and recovery, including re-epithelialization. This crucial stage of tissue repair can lead to adverse healing outcomes when subjected to unfavorable conditions, interrupted, or poorly managed. 

What is Wound Re-Epithelialization?

Epithelialization refers to the series of cellular and molecular activities that result in the restoration of the damaged epithelium. Re-epithelialization involves the interaction of various chemical signaling molecules (cytokines, growth factors), enzymes, and extracellular matrix components, culminating in the deposition of epithelial materials, such as keratinocytes. 

What Occurs During The Epithelialization Process?

Epithelialization plays a crucial role in wound healing, as it is impossible to achieve wound closure if it fails. This stage of wound repair involves the initiation, proliferation, migration, and differentiation of keratinocytes to injury sites, along with the repair and reordering of compromised dermal structures. Recruited keratinocytes facilitate epithelialization via upregulated mitosis and differentiation at the periphery of wound sites. Along with fibroblast migration beneath the surface, keratinocyte migration at injury sites will cause wound closure in a centripetal fashion. Once wound closure is completed, contact inhibition will stop the fibroblast migration process and trigger the rearrangement of keratinocytes into stratified squamous keratinizing epidermal cells. 

Factors Regulating Wound Healing/Re-Epithelialization

There are several factors, both local and systemic, that contribute to the success or failure of wound re-epithelialization. The most commonly cited variables influencing wound re-epithelialization include:

  • Age
  • Presence of infection
  • Wound type and location
  • Chronic medical conditions
  • Nutrition
  • Tissue perfusion/oxygenation levels
  • Lifestyle choices/patient attitudes to wound care


Like with other biological processes, the normal physiological response to tissue injury starts to deteriorate with age. In old age, the wound healing response tends to slow after injury. Consequently, elderly persons will have a slower inflammatory response to tissue insult and a much longer healing time than a child or young adult. 

Presence of Infection

An underlying viral, bacterial, or fungal infection can have adverse effects on the epithelialization process. The presence of these infectious agents within a wound site will stagnate the healing process by secreting toxins, worsening tissue inflammation, and propagating further tissue death.

Wound Type

The size, severity, and location of a wound will determine the speed with which complete healing can be achieved. Generally, more extensive wounds will require longer healing durations than smaller ones.

Chronic Medical Conditions

Patients diagnosed with chronic medical conditions, such as Type 2 diabetes, hypertension, peripheral arterial disease, and other circulatory abnormalities are more likely to experience a slower rate of wound re-epithelialization than the rest of the population. These diseases can compromise blood flow and nutrient supply to the wound site. 


The calorie and protein demand in a healing wound is higher than the average for an uninjured tissue. Poor nutrition results in a nutrient deficit, protein breakdown, and a slower rate of tissue recovery.

Tissue Perfusion/Oxygenation Levels

Wound tissue perfusion is a critical requirement for optimal wound re-epithelialization. The nature of blood vessels supplying a wound site determines the amount of oxygen and nutrients it receives. An obstructed flow (e.g., arterial insufficiency) will slow or halt wound healing. 

Lifestyle Choices/Patient Attitudes to Wound Care

Common lifestyle choices like smoking, excessive alcohol usage, and poor sleeping patterns can significantly inhibit optimal wound repair. Poor compliance with wound management instructions on dressings, limb elevations, and wound cleanliness will also stunt wound epithelialization and delay the overall healing process. 

Strategies for Optimal Wound Re-Epithelialization

The following efforts can aid various cellular and molecular activities that result in the restoration of the damaged epithelium:

Proper Nutrition

Proper nutrition is a crucial determinant of optimal wound re-epithelialization. Maintaining a balanced diet by eating foods rich in vitamins, polyphenols, and bioflavonoids, such as fruits, vegetables, cereals, and dark chocolates, provides antioxidants that can facilitate wound healing.

Lifestyle Modifications

Quitting smoking and alcohol usage can improve healing outcomes in patients with chronic wounds. Patients with chronic wounds should be counseled to limit their alcohol usage and completely stop smoking. 

Regular Wound Care

Consistent use and replacement of suitable wound dressings as well as implementing appropriate wound care strategies will mitigate the risk of wound contamination by harmful pathogens that could impede the re-epithelialization process.

Chronic Disease Management

The treatment of chronic medical disorders is a critical consideration in wound re-epithelialization. Properly managing diabetes, hypertension and other vascular pathologies will prevent the onset of wound site infections, and allow improved tissue perfusion at wound sites.

Recombinant Growth Factor/ Signalling Protein Therapy

Numerous studies have established the role of growth factors at various stages in the wound healing process. For example, the use of vascular endothelial growth factor A (VEGF-A) in clinical trials has been shown to boost tissue re-epithelialization in persons with diabetic foot wounds. Further, more recent research has shown a matricellular protein CCN1 to speed up wound re-epithelialization by promoting the proliferation and migration of keratinocytes during wound healing. 

Collagen Therapy

Topically applied collagen gels, pastes, and powders are available for use in conjunction with exogenous growth factors. These materials act as a foundation for the use of recombinant growth factors and can be derived from any animal tissue. The most commonly used sources of collagen used in wound re-epithelialization are bovine, porcine, and murine skin, tendons, and tails.

Skin Substitutes

Both cells and tissue harvested from human or animal donors can be used to improve wound re-epithelialization. These treatment materials can be used as a source of cells, enzymes, growth factors, and cytokines that will facilitate rapid wound healing.

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