• Scurvy
• Anemia
• Dermatitis
• Megaloblastic anemia
• Beriberi
• Rickets
• Osteomalacia
• Hemolytic anemia
• Birth defects

I. Types of Vitamins and Their Function in the Body

There are two types of vitamins: water-soluble and fat-soluble vitamins.

1- Water Soluble Vitamins

Most water-soluble vitamins are used immediately by the body and any surplus is eliminated through urine; however, vitamin B12 can be stored in the liver for a prolonged period.

Vitamin B1 (Thiamine)

Vitamin B1 is required for the production of ATP (energy) and for the metabolism of glucose, proteins, and fats by our body cells. It is naturally present in food such as whole grains, legumes, and fish [1].

Vitamin B2 (Riboflavin, Vitamin B₂)

Vitamin B2 is an essential partner for different enzymes that are required for cellular respiration and energy production, including oxidoreductases and flavine adenine dinucleotide (FAD) [2].

Vitamin B2 is naturally present in food including almonds, eggs, meat, milk and dairy products, mushrooms, and green vegetables.

Vitamin B3 (Niacin, Niacinamide)

Vitamin B3 is essential for the synthesis of nicotinamide adenine dinucleotide (NAD), a coenzyme (work together with an enzyme) necessary for the metabolism of cells (e.g., redox reactions), DNA repair, and calcium mobilization within the cells of the body [3].

It is naturally available in food such as eggs, meat, milk, and beans.

Vitamin B5 (Pantothenic Acid)

Vitamin B1 is found in most food and is required for the synthesis of coenzyme A involved in the synthesis and oxidation of fatty acids that are necessary for the production of hormones, energy production from fats, fat storage, and the transfer of information within the cell (signaling) [4].

Vitamin B6 (Pyridoxine, Pyridoxamine)

Vitamin B6 is an essential coenzyme involved in the metabolism of glucose, fat, and proteins [5]. It is mainly found in meat products such as Beef, pork, and fish.

Vitamin B7 (Biotin)

Vitamin B7 is a coenzyme for enzymes that are involved in fatty acids synthesis, gluconeogenesis (glucose metabolism), chromatin stability, and gene expression [6].

It is naturally available in food such as beef liver, salmon, nuts, eggs, avocadoes, pork, and sweet potatoes.

Vitamin B9 (Folic Acid, Folate, Folacin)

Vitamin B9 is required for DNA synthesis and for the activation of vitamin B12 [7]. Many types of food contain vitamin B9; however, due to its instability (e.g., high heat cooking), it is being added to several food sources as a fortifier to prevent a vitamin B9 deficiency.

Vitamin B12 (Cyanocobalamin)

Vitamin B12 is a coenzyme involved in fatty acids and protein metabolisms, DNA synthesis, red blood cells’ maturation, and myelin synthesis (a protein covering neurons) [8].

 It is naturally present in foods such as meat, liver, milk, clams, fortified breakfast cereals, and eggs.

Vitamin C (Ascorbic Acid)

Vitamin C is a well-known antioxidant that also functions as a coenzyme in many enzymatic reactions associated with collagen synthesis, wound healing, and the immune system [9].

 It is naturally available in citrus fruits, guava, kiwifruit, strawberries, brussels sprouts, broccoli, and bell peppers.

2- Fat-Soluble Vitamins

This family of vitamins requires fat and bile acids to be absorbed by the intestine through a process named micellar solubilization.

The Vitamin A Group

Vitamin A is not a single entity but is rather a group of compounds that include retinol, retinal, and carotenoids such as beta-carotene.

These compounds are involved in growth and development, vision, immune response, and genetic regulation [10].

They are naturally found in many foods such as fish and beef liver, cod liver oil, green vegetables (e.g., kale, spinach), carrots, and dairy products (cheese and butter).

The Vitamin D (Calciferol) group

Vitamin D is also a group of compounds that include ergocalciferol (vitamin D₂) and cholecalciferol (vitamin D₃).

They are involved in the intestinal absorption of magnesium, phosphate, and calcium necessary for calcium homeostasis and bone metabolism [11].

They are naturally found in many foods such as beef liver, cod liver oil, eggs, salmon, tuna, mackerel, and sardines.

The Vitamin E group

Vitamin E is another example of a group of vitamin compounds that include the antioxidants tocopherols and tocotrienols that protect the body’s cells from reactive oxygen species [12]. They are naturally available from wheat, seeds, and nuts oils.

Vitamin K (Phylloquinone, Menaquinones)

Vitamin K includes two compounds known as vitamin K₁ (Phylloquinone) and vitamin K₂ (Menaquinones) that are involved in blood coagulation and in the regulation of calcium attachment to the bones [13].

Phylloquinone is naturally found in leafy green vegetables, while menaquinones naturally exist in food such as chicken and beef meat, mollusks, and dairy products (e.g., cheese, yogurt, and milk).

II. Vitamin Deficiency

There are several conditions, diseases, and disorders due to vitamin deficiencies, and here is an overview of the most known ones.

1- Vitamin B1 Deficiency

• Beriberi is a rare genetic disease characterized by effects on the nervous and cardiovascular systems. It may manifest with increased heart rate, swellings of the legs, speech difficulty, mental confusion, and shortness of breath [14].
• Wernicke Encephalopathy is caused by neurological damages that manifest with symptoms of confusion, ataxia (absence of voluntary movements coordination), and ophthalmoparesis (uncontrolled movement of the eye muscles)  [15].

2- Vitamin B2 Deficiency

• Ariboflavinosis is characterized by lesions on the lips and around the corners of the mouth, the nose, and the eyes. In extreme cases, neurological, reproductive, hepatic, and anemic disorders are observed [16].

3- Vitamin B3 Deficiency

• Pellagra is associated with soreness of the mouth, diarrhea, inflamed skin, and dementia [17].

4- Vitamin B5 Deficiency

• Paraesthesia manifests with abnormal and painless sensations in the skin of arms and legs [18].

5- Vitamin B6 Deficiency

• Anemia, that is due to vitamin B6 deficiency, is associated with reduced synthesis of the heme, a necessary component of hemoglobin [19].

6- Vitamin B7 Deficiency

• Dermatitis is associated with dryness and inflammation of the skin leading to rashes and lesions on the face [20].
• Enteritis manifests with symptoms such as fatigue and tiredness, nausea, and vomiting.

7- Vitamin B9 Deficiency

• Birth Defects are associated with abnormal development of the embryo neural tube (brain and spinal cord development) during pregnancy [21].

8- Vitamin B12 Deficiency

• Megaloblastic Anemia is due to the reduction in DNA synthesis associated with the production (proliferation) of red blood cells [22].

9- Vitamin C Deficiency

• Scurvy manifests with symptoms of tiredness and fatigue, sore arms and legs, gum disease, and bleeding from the skin [23].

10 – Vitamin A Deficiency

• Night Blindness is associated with the difficulty of adaptation of the vision from day to night usually due to an anomaly with the retina [24].
• Keratomalacia affects the cornea and conjunctiva of the eye that looks cloudy and opaque resulting in blindness [25].

11- Vitamin D Deficiency

• Rickets (Osteomalacia) is characterized by soft bones in children that lead to bone deformities [26].  

12- Vitamin E Deficiency

Hemolytic Anemia is associated with rupture or breakdown of red blood cells due to the lack of antioxidant protection from vitamin E (antioxidant effect) [27].

13- Vitamin K Deficiency

• Bleeding is due to a defect in the coagulation as vitamin K is required for clot formation to stop bleeding.
• Diathesis is characterized by increased bruising and bleeding.

III. Vitamin Overdose

Vitamin overdose or hypervitaminosis is associated with excessive reserves of vitamins in the body that lead to toxicity, irritability, and overexcitement.

1- Vitamin B3 Overdose

Vitamin B3 overdose can cause flushing with headache, dizziness, and sensations of burning and itching. In certain cases, it can lead to liver damage [28].

2- Vitamin B6 Overdose

The overdose of B6 is associated with neuropathies due to nerve damage such as sensory ataxia (absence of voluntary movements coordination), abnormal and painless sensations in the skin of arms and legs (paraesthesia), and areflexia (absence of muscle reflexes) [29].

3- Vitamin B9 Overdose

An overdose of this vitamin results in nerve damage resulting in neuropathies. It also causes proprioception characterized by difficulty and uncoordinated walking and clumsiness [29].

4- Vitamin A Overdose (Hypervitaminosis A)

Vitamin A overdose has a wide effect on mental health such as depression, dizziness, and mental dullness, and on the liver (toxicity), skin (dry skin), cheilosis (inflammation of the mouth corners), gingivitis, muscle, and joint pains, and fatigue [30].

5- Vitamin D (Hypervitaminosis D) overdose

An overdose of vitamin D manifests with large disorders such as hypercalcemia, hypertension, ectopic calcifications, renal stones, hyperphosphatemia, polyuria and polydipsia, anorexia, depression, nausea, vomiting, and constipation [31].

6- Vitamin E overdose

An overdose of this vitamin results in muscle weakness, fatigue, nausea, and diarrhea. However, higher intake can lead to hemorrhagic stroke and premature death [32].

7- Vitamin K Overdose

An overdose of this vitamin, when consumed orally, is not toxic; however, it can cause toxicity in infants administered with a synthetic precursor (Menadione). Toxicity includes hemolytic anemia, jaundice due to hyperbilirubinemia (increase bilirubin in the blood), and brain damage [33].

Conclusion

Vitamins are essential for the function of the body as they are involved in key metabolic pathways. Although deficiencies in vitamins are low in developed countries, other places in the world are still affected due to malnutrition.

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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.

Conclusion

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.

References

[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 biology, 10(9), p.200223.

[4] Santoro, M.M. and Gaudino, G., 2005. Cellular and molecular facets of keratinocyte reepithelization during wound healing. Experimental cell research, 304(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. Nature, 504(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 Hematology, 120(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 review, 8(4).

[9] Silverstein, P., 1992. Smoking and wound healing. The American journal of medicine, 93(1), pp.S22-S24.

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