Wound Healing

What Are the Mechanisms of Wound Healing?

Wound healing is a natural reaction of our body to tissue injury that involves crosstalk between different cells, cytokines, mediators, and the vascular system to repair the damaged tissue. It involves 4 main phases including homeostasis, inflammatory response, proliferation, and remodeling [1].

1. What Are the Stages of Wound Healing?

Homeostasis Phase

This phase involves blood vessels’ vasoconstriction (tightening) and platelet aggregation to stop blood loss at the injured site.  Platelet aggregation, also known as coagulation, relies on a primary homeostasis stage and a secondary homeostasis stage [2].

In the first stage, platelets aggregate to form a plug that prevents bleeding, and in the second. In the second stage, intrinsic and extrinsic coagulation pathways are activated through a series of clotting factors.

Intrinsic coagulation factors are activated by the wound-exposed endothelial collagen and include factors I (fibrinogen), II (Prothrombin), IX (Christmas factor), X (Stuart-Prower factor), XI (Plasma Thromboplastin), and XII (Hageman factor).

Extrinsic factors, also named stable factors are activated by tissue factors released by damaged endothelial cells and include factors I, II, VII, and X.

Inflammatory Response Phase

After coagulation, the vasoconstriction that characterizes the homeostasis phase is replaced by vasodilation (opening) that promotes the recruitment of inflammatory cells (neutrophils, monocytes, and endothelial cells) to the site of injury and their binding to the scaffolding that was constructed by the platelets’ aggregation.

Once on-site, neutrophils initiate the phagocytosis and killing of pathogens to decontaminate the wound, while also promoting cell proliferation and angiogenesis.

Besides their direct role in the phagocytosis and killing of pathogens, Monocytes which become macrophages, also remove apoptotic cells and support cell proliferation and tissue restoration following injury.

Endothelial cells are the building blocks for vessels, and during wound healing, these cells generate new vessels (angiogenesis) to satisfy the metabolic demands of the highly proliferative healing tissue. 

 Proliferation Phase

In this phase, keratinocytes, fibroblasts, macrophages, and endothelial cells are extensively activated to contribute to the closure, matrix deposition, and angiogenesis at the wound site [3]. 

keratinocytes in the surroundings of the wound migrate across the wound to reform the epidermal layer through a process known as epithelialization [4]. During this process, hair follicle stem cells are also activated to generate hair on the newly healed skin tissue.

While the epithelialization is ongoing, fibroblasts proceed to the breakdown of the fibrin clot and the deposition of a new extracellular matrix (ECM) and collagen to build structures that support the effective wound-healing effort of the other cells [5].

Although macrophages play a role during the inflammatory response phase, their functions during the proliferation phase are also critical in guiding the proper formation of vessels and in supporting fibroblasts in the breakdown of fibrin [6].

Remodeling Phase

This process is associated with the deposition of collagen by fibroblasts to replace the initial fibrin clot. Although collagen deposition contributes to the scarification of the wound, this deposited collagen is different from the one that was initially present in the unwounded tissue and will only confer for up to 80% of pre-wounding strength [7].

Other components that are required for the remodeling phase include myofibroblasts that secrete alpha-smooth muscle actin (α-SMA), necessary for the generation of strong contractile forces and focal adhesions, and elastin that provide skin elasticity to the healed wound.

2. What Slowdown Wound Healing?

Diabetes and Wound Healing

During the inflammatory response phase, vasodilation of the blood vessels is necessary for the recruitment of inflammatory cells (neutrophils, monocytes, and endothelial cells) to the site of injury.

However, due to the high levels of glucose in the blood of diabetics, the arteries are thickened, resulting in vasoconstriction of the blood vessels which slows down wound healing. 

Another pathological process that can slow down wound healing in diabetics is associated with nerve damage that is caused by high levels of glucose which leads to poor blood circulation.

Malnutrition and wound healing

Micronutrients (minerals and vitamins) and macronutrients (Proteins, lipids, and carbohydrates) are required for effective wound healing. For instance, proteins are necessary for the production of enzymes, collagen, and connective tissue during the remodeling phase of wound healing.  

Neutrophils, monocytes, fibroblasts, endothelial cells, and myofibroblasts require glucose to generate energy for their activity during wound healing. Lipids are necessary for the generation of new cellular membranes.

In addition, vitamin A enhances the early inflammatory response phase and promotes epithelial cell differentiation, and vitamin C promotes the migration of neutrophils and is necessary for the production of collagen.

Finally, zinc is required for DNA and protein synthesis, and cell division during the proliferation stage of wound healing [8].

Smoking and Wound Healing

Clinically, it is well accepted that cigarette smoking delays wound healing as the toxic constituents of cigarette smoke such as nicotine, carbon monoxide, and hydrogen cyanide can affect nutritional blood flow to the skin, which impairs healing of the injured tissue.

Carbon monoxide is known to reduce oxygen transport and metabolism’ while hydrogen cyanide is also a known inhibitor of enzymatic systems required for cellular oxidative metabolism and oxygen transport [9]. 

3. How to Improve Wound Healing?

The consumption of the following foods can improve wound healing:

  • – Drinking plenty of water for hydration (if recommended).
  • – Proteins (e.g., in lean meat, beans, lentils, and dairy products).
  • –  Carbohydrates (e.g., in whole-grain bread and cereals, potatoes, and rice)
  • – Vitamins and minerals: vitamin A (e.g., in the liver, milk, eggs, and leafy greens), vitamin C (e.g., in broccoli, strawberries, tomatoes, and kiwi), and Zinc (e.g., in seafood, beans, lentils, and whole-grain bread).

4. Frequently Asked Questions about What Are the Mechanisms of Wound Healing?

What are the stages of wound healing?

Wound healing typically progresses through three main stages: inflammation, proliferation, and remodeling.

What happens during the inflammation stage of wound healing?

During inflammation, the body’s immune response is activated to clear debris and prevent infection. Blood vessels constrict to reduce bleeding, followed by dilation to increase blood flow, bringing white blood cells to the wound site.

What occurs during the proliferation stage of wound healing?

In the proliferation stage, new tissue is formed to repair the wound. This involves the proliferation of fibroblasts, which produce collagen, as well as the formation of new blood vessels (angiogenesis) to supply nutrients to the healing tissue.

What is the role of fibroblasts in wound healing?

Fibroblasts are key cells involved in wound healing. They produce collagen, which provides structural support to the healing tissue, and they also help to contract the wound, reducing its size.

What is angiogenesis and why is it important in wound healing?

Angiogenesis is the formation of new blood vessels. It is crucial in wound healing because it ensures that the healing tissue receives an adequate blood supply, delivering oxygen and nutrients necessary for repair.

How does the remodeling stage contribute to wound healing?

During the remodeling stage, the newly formed tissue undergoes maturation and remodeling. Collagen fibers reorganize to increase tissue strength, and excess scar tissue may be broken down.

This stage can last for months to years, gradually improving the strength and appearance of the healed wound.

What factors can affect the wound healing process?

Various factors, including age, underlying health conditions (such as diabetes or immunodeficiency), nutritional status, medications (such as steroids or chemotherapy), and the presence of infection, can influence the speed and effectiveness of wound healing.

How can I promote optimal wound healing?

To support wound healing, it’s essential to maintain good overall health, including adequate nutrition, hydration, and hygiene.

Following medical advice regarding wound care, avoiding smoking, managing chronic conditions, and protecting the wound from further injury can also facilitate healing.


Wound healing involves the participation of different cells, cytokines, mediators, and the vascular system to repair the damaged tissue. However, to fuel this amazing repair machinery, an appropriate diet that provides proteins, lipids, carbohydrates, vitamins, and minerals is necessary for effective wound healing.


[1] Wallace, H.A., Basehore, B.M. and Zito, P.M., 2017. Wound healing phases.

[2] Chaudhry, R., Usama, S.M. and Babiker, H.M., 2018. Physiology, coagulation pathways.

[3] Wilkinson, H.N. and Hardman, M.J., 2020. Wound healing: Cellular mechanisms and pathological outcomes. Open biology10(9), p.200223.

[4] Santoro, M.M. and Gaudino, G., 2005. Cellular and molecular facets of keratinocyte reepithelization during wound healing. Experimental cell research304(1), pp.274-286.

[5] Driskell, R.R., Lichtenberger, B.M., Hoste, E., Kretzschmar, K., Simons, B.D., Charalambous, M., Ferron, S.R., Herault, Y., Pavlovic, G., Ferguson-Smith, A.C. and Watt, F.M., 2013. Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature504(7479), pp.277-281.

[6] Willenborg, S., Lucas, T., Van Loo, G., Knipper, J.A., Krieg, T., Haase, I., Brachvogel, B., Hammerschmidt, M., Nagy, A., Ferrara, N. and Pasparakis, M., 2012. CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. Blood, The Journal of the American Society of Hematology120(3), pp.613-625.

[7] Young, A. and McNaught, C.E., 2011. The physiology of wound healing. Surgery (Oxford)29(10), pp.475-479.

[8] MacKay, D.J. and Miller, A.L., 2003. Nutritional support for wound healing. Alternative medicine review8(4).

[9] Silverstein, P., 1992. Smoking and wound healing. The American journal of medicine93(1), pp.S22-S24.

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