Wound reepithelialization is key in the goal of wound closure. Reepithelialization is a coordinated multifactorial systemic process that involves formation of new epithelium and skin appendages. The epithelialization process can be stalled by a number of factors, all of which must be resolved before wound healing can move forward. Common stalling factors include:¹

• Excess matrix metalloproteases
• Impaired fibroblast signaling
• ECM instability
• Stalled keratinocyte migration

When the reepithelialization process fails, there may be negative outcomes for the wound and the patient, such as the development of a hypertrophic scar. Mitigating abnormalities within the healing process to promote reepithelialization and enhance wound closure is imperative. Wounds with impaired reepithelialization can be caused by many variables, such as those listed above, and by other factors, such as diabetes, trauma, burns, bacterial infections, tissue hypoxia, local ischemia, exudates, and excessive levels of inflammatory cytokines causing a continuous state of inflammation. A continuous state of inflammation may cause the cell pool to have an increase of cellular senescence and decreased cellular response to growth factors.^2,3

The Reepithelialization Process

Epithelium

New epithelium and skin appendages activate proliferation, migration, and differentiation of keratinocytes and reconstitution of the protection of the underlying dermal structures. This process helps restore the epidermal barrier to prevent infection and excessive moisture loss.⁴ Keratinocytes reepithelialize through enhanced migration and mitosis located at the wound periphery within the epidermis, while fibroblasts migrate beneath the wound site close to the wound.⁵ When the wound area is covered, the contact inhibition stops migration while triggering differentiation of keratinocytes into stratified squamous keratinizing epidermal cells.⁶

Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) play a vital role in anti-inflammation, cell migration, proliferation and differentiation, biological processes, and signaling pathways of activation and or inhibition.⁵ There continues to be a mystery in the mechanism and involvement of mesenchymal stem cells (MSCs).

Advanced Therapies for Reepithelialization

There are a number of advanced therapies that can help to promote reepithelialization by resolving the issues that resulted in the stalling of the wound in the first place.

Collagen Therapies

Collagen advanced wound care products are effective in providing a scaffolding for the application of exogenous growth factors to wounds when applied to live or granulating tissue. There are many forms of collagen such as pads, sheets, pastes, solutions, powders, particles, and gels. Collagen can be derived from any animal tissue; however, the collagen properties differ depending on the animal tissue that is extracted. The most common sources are bovine skin and tendons; porcine skin, intestine, and bladder mucosa; and rat tail.⁷ Full-thickness wounds have been studied with porcine models, validating the effects of the collagen matrix implants on granulation tissue formation, wound contraction, and reepithelialization.⁸

Cellular and/or Tissue-Based Products

Cellular and/or Tissue-Based Products, also known as skin substitutes, consist of various combinations of cellular and acellular components, with the intention to stimulate the host to regenerate lost tissue, replacing the wound with functional skin derived from human and/or animal donors.⁹ Cellular, or otherwise known as bioengineered cellular therapies, provide fibroblasts and keratinocytes to generate a source of growth factors, cytokines, and enzymes promoting tissue regeneration.¹⁰ There is a broad range category of natural and synthetic products used to create extracellular matrix (ECM) for tissue growth. These products contain materials such as collagen or polyglactin. Acellular products provide an extracellular matrix (ECM) into which cells can migrate and boost tissue regeneration.¹¹

Other Considerations to Promote Reepithelialization

Malnutrition consists of deficiencies, excess, or imbalances in a patients’ intake of energy and or nutrients.¹² Protein loss negatively affects the immune system, wound healing, biological and molecular processes. Adequate carbohydrates are necessary for fibroblast migration during the proliferative phase. Arginine, glutamine, iron, zinc, vitamins A, B, C, D, and other micronutrients are necessary for the inflammatory process and synthesis of collagen.¹³ Consider offering high protein, high calorie supplements between meals for chronic wound patients (30-35kcal/kg of body weight, 1.2-1.5g protein/kg of body weight). Arginine and micronutrient supplements can also be considered as indicated.¹⁴

Using one or more methods of debridement helps promote healing, reduces risk of infection, and enhances wound healing outcomes. Biological, enzymatic, autolytic, mechanical, and surgical debridement methods should be included in the patient’s plan of care; clinicians should ensure they are using a patient-centered approach when selecting a debridement method, as not all methods are appropriate for all patients. Debridement methods provide consistency for wound bed preparation and advance healing to reepithelialization.¹⁵

Conclusion

Wound chronicity occurs when the normal transition of the healing cascade has failed, causing the wound to stall in the inflammatory phase. The wound structure and function can be restored utilizing one or more treatment modalities, such as debridement methods and advanced wound care products as indicated. Critical factors such as bacterial balance, nutrition, and an optimal moist environment will promote reepithelialization and wound healing.

Reference

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2. Mulder GD, Vande Berg JS. Cellular senescence and matrix metalloproteinase activity in chronic wounds: relevance to debridement and new technologies. J Am Podiatr Med Assoc. 2002;92(1):34-37.

3. Ribeiro J, Pereira T, Amorim I, et al. Cell therapy with human MSCs isolated from the umbilical cord Wharton jelly associated to a PVA membrane in the treatment of chronic skin wounds. Int J Med Sci. 2014;11(10):979-987.

4. Krishnaswamy VR, Korrapati PS. Role of dermatopontin in re-epithelialization: implications on keratinocyte migration and proliferation. Scientific Reports. 2014;4:7385.

5. Coulombe PA. Wound epithelialization: accelerating the pace of discovery. J Investig Dermatol. 2003;121(2):219-230.

6. Walter MNM, Wright KT, Fuller HR, MacNeil S, Johnson WEB. Mesenchymal stem cell-conditioned medium accelerates skin wound healing: an in vitro study of fibroblast and keratinocyte scratch assays. Exp Cell Res. 2010;316(7):1271-1281.

7. Badylak SF. Transplant Immunol. 2004; 12:367-377.

8. Collagen based biomaterials for wound healing. Biopolymers. NIH Public Access. Author Manuscript. 2014; 101(8): 821-833. Doi: 10.1002/bip.22486

9. Skin substitutes for treating chronic wounds. Agency for Healthcare Research and Quality (AHRQ); 2018. Updated 2019. https://effectivehealthcare.ahrq.gov/products/skin-substitutes/protocol. Accessed February 20, 2020.

10. Savoji H, Godau B, Hassani MS, Akbari M. Skin tissue substitutes and biomaterial risk assessment and testing. Front Bioeng Biotechnol. 2018;6:86.

11. Frykberg RG, Banks J. Challenges in the treatment of chronic wounds. Adv Wound Care (New Rochelle). 2015;4(9):560-82.

12. Malnutrition. World Health Organization. 2018. https://www.who.int/en/news-room/fact-sheets/detail/malnutrition. Accessed February 21, 2020.

13. Barchitta M, Maugeri A, Favara G, San Lio RM, Evola G, et al. Nutrition and Wound Healing: An Overview Focusing on the Beneficial Effects of Curcumin. Int J Mol Sci. 2019; 20(5): 1119. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429075/ Accessed February 21, 2020.

14. Van Anholt, R., L. Sobotka, E. Meijer, et al. Specific nutritional support accelerates pressure ulcer healing and reduces wound care intensity in non-malnourished patients. Nutrition 2010;26(9):867-72.

15. Leaper D. Sharp technique for wound debridement. World Wide Wounds. 2002. http://www.worldwidewounds.com/2002/december/Leaper/Sharp-Debridement.h…. Accessed February 21, 2020.