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Alfred MARCHAL, PhD in organic chemistry, is an internationally recognized antioxidants and aesthetic medicine expert. He has a 35-year academic experience in R&D for pharmaceutical organic synthesis and phytopharmaceuticals. Author of many scientific articles and patents in particular for vitamin C, vitamin K and hyaluronic acid. He runs ALPHASCIENCE Research Department and is board member in pharmaceutical companies.

The four steps of wound healing process

Many factors can interfere, thus causing improper or impaired wound healing. The most significant factors that affect cutaneous wound healing and the potential cellular and/or molecular mechanisms are oxygenation, infection, age and sex hormones, stress, diabetes, obesity, medications, alcoholism, smoking, and nutrition.

 

1st step: Coagulation

The extravasation of blood into the wound is activated to limit loss of blood.
The clot, comprising of fibrin, fibronectin, vitronectin, Von Willebrand factor and thrombospondin, provides the provisional matrix for cellular migration.

 

2ndstep: Inflammation

Primary inflammation 24-48 h

The next phase of healing is inflammation with activation of classical molecular cascade that leads to infiltration in the wound with granulocytes or PMNLs (polymorph nuclear leucocytes. Theses cells are attracted to the wound site within 24 to 48 hours of injury by a number of agents such as C5a, platelets, TGF-beta, formylmethionyl peptide product from bacteria.

 

Secondary inflammation 48-72 h

Monocytes are attracted to the wound by a variety of chemo-attractants, including clotting complements, immunoglobulin G (IgG), collagen and elastin, cytokines such as leukotriene B4, platelets factors IV, PDGF, and TGF-beta.

Macrophages are the most important cells present in the later stage of inflammation process and act as key regulatory cells for repair.

 

3rdstep: Proliferation

Cell proliferation is at first by the migration of fibroblasts, collagen synthesis and angiogenesis. Then there is granulation tissue formation and epithelialization finally.

 

4thstep: Remodelling

Matrix synthesis and the remodelling phase are initiated with the development of granulation tissue and continue over prolonged periods of time.

As the matrix matures, fibronectin and Hyaluronic Acids are broken down. The collagen bundles increases in diameter.

 

Oxidative Stress

Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species (ROS) and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal redox state of cells produce of peroxides and free radicals that damage all components of the cell (proteins, lipids, DNA...).

Oxidative stress from oxidative metabolism causes base damage, as well as strand breaks in DNA. Base damage is mostly indirect and caused by reactive oxygen species (ROS) generated.

For example: O2(superoxide radical), OH (hydroxyl radical) and H2O2(hydrogen peroxide).

 

Further, some reactive oxidative species act as cellular messengers in redox signalling. Thus, oxidative stress can cause disruptions in normal mechanisms of cellular signalling.

 

In humans, oxidative stress is thought to be involved in the development of many diseases and physical effects on the skin.

The ROS play an important role in skin injury and repair.

 

Regulation of wound healing process

The wound-healing process is regulated by a variety of different growth factors, cytokines, and hormones. The innate immune system cells produce proteolytic and pro-inflammatory enzymes cytokines. They also produce and secrete increased amounts of ROS, required to protect the organism from bacteria and other microorganisms. Additionally, several recent studies revealed that they represent the crucial regulators of this process. ROS’s are required for the defense against invading pathogens, and at low concentrations, they are the crucial mediators of intracellular signalling. A previous study showed that low H2O2levels are important for the efficient neoangiogenesis in wounds.

Reactive oxygen species (ROS) are essential during the healing process at multiple stages, ranging from the initial signal that instigates the immune response, to the triggering of intracellular redox-dependent signalling pathways the defence against invading bacteria.

 

In the inflammatory processes the radical species come mainly from neutrophils, eosinophils and macrophages that release O2, converging in the formation of H2O2.

 

Excessive ROS in the wound environment impede new tissue formation. ROS are harmful and can cause severe cellular damage. In human and animal cells in the presence of nitric oxide, calcium, and pathogens, the balance between oxidant and antioxidant systems is affected, promoting the generation and accumulation of ROS in cells, eventually inducing oxidative stress. Oxidative stress can result in DNA damage, mutations, and double-strand aberrations but also induce dysfunction in MAPK/AP-1, NF-κB and JAK/STAT-signalling pathways, apoptosis and autophagy.

 

Intrinsic and extrinsic factors lead to the skin barrier damage, which leads to the disequilibrium in oxidant and antioxidant balance and induces excessive ROS production.

 

The aesthetics acts on the skin will generate ROS with different proportions depending on the size of the wounds (surgery as open wounds or superficial as peeling, lasers and burns).

A large amount of ROS will generate inflammation, pain, discomfort and over pigmentation after TCA peeling and laser.

 

Oxidative stress represents the imbalance between oxidative and antioxidative events.

The non-enzymatic antioxidant system includes vitamins C and E, glutathione (GSH), carotenoids, melatonin, A-lipoic acid, Zn (II)-glycine, and polyphenols, and some of these molecules are exogenous antioxidants.

The skin employs a number of endogenous antioxidant agents to protect the oxidative balance, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), ascorbic acid, and tocopherols. The results presented here indicate that antioxidant treatments may be effective when applied in the therapy of cutaneous diseases where oxidative stress who plays a prominent pathogenic role.

 

The skin regulates the ROS by itself

The antioxidative systems in human skin are interdependent, but they collaborate. The treatment with known antioxidants such as ascorbic acid, tocopherols, and polyphenols increases the resistance of organism to ROS and prevents skin aging and inflammation

 

An overview about oxidation in clinical practice of skin aging[1]

Free radicals are unstable chemical species, highly reactive, being formed by cellular entities of different tissues. Increased production of these species without proper effective action of endogenous and exogenous antioxidant systems generates a condition of oxidative stress.

 

The antioxidants are chemical substances commonly used in clinical practice for topical application and may contribute in the fight against the radical species responsible for many skin damages.

It is an evidence of the benefits brought by the topical application of antioxidants in the skin.

 

Which antioxidants to use?

However, for topical administration of antioxidants to be effective in the prevention and elimination of free radicals it is critical to ensure the stability of the final formulation, since the antioxidant, in most cases, are very unstable and may be oxidized easily, becoming inactive before reaching the site of action. In addition, antioxidants must be properly absorbed through the skin to reach deeper layers of the tissue in the active form.

 

Cell membranes are the main cellular constituents susceptible to oxidation procedure being established, which is known as lipid peroxidation.

Phenolic compounds are formed in the secondary metabolism of plants and have defense functions. It has been observed that they are capable of reacting with free radicals to form stable chemical species. This power of neutralizing the radical structures is due to their chemical structure, which has hydroxyl groups with aromatic rings that confer antioxidant power. We highlight the flavonoids, phenolic acids, simple phenols, coumarins, tannins, and tocopherols.

 

The main indications are for superficial aesthetic procedures. It's very important to use antioxidant before and after peeling, dermabrasion, lasers, Microneedling or Mesotherapy for example.

 

Most compounds must be integrated in modern serum as vectors. We can use polyphenols, Tannic acid, vitamin C, Glutamin, Phytic acid, ginkgo biloba, phytoestrogen, EGCG and curcumine.

 


REFERENCES

[1] Heather L. Orsted. (2019). Basic Principles of Wound Healing.

[2] Xue, J., Yu, C., Sheng, W., Zhu, W., Luo, J., & Zhang, Q. et al. (2017). The Nrf2/GCH1/BH4 Axis Ameliorates Radiation-Induced Skin Injury by Modulating the ROS Cascade.

[3] Kohen, R. (1999). Skin antioxidants: Their role in aging and in oxidative stress — New approaches for their evaluation.

[4] Toshihiro Kurahashi, & Junichi Fujii. (2015). Roles of Antioxidative Enzymes in Wound Healing.

[5] Nicholas Bryan, Helen Ahswin, Neil Smart, & Yves Bayon. REACTIVE OXYGEN SPECIES (ROS) – A FAMILY OF FATE DECIDING MOLECULES PIVOTAL IN CONSTRUCTIVE INFLAMMATION AND WOUND HEALING.

[6] Silas Arandas Monteiro e Silva, Gislaine Ricci Leonardi, & Bozena Michniak-Kohn. (2015). An overview about oxidation in clinical practice of skin aging*.

[7] Xu, H., Zheng, Y., Liu, Q., Liu, L., Luo, F., & Zhou, H. et al. (2017). Reactive Oxygen Species in Skin Repair, Regeneration, Aging, and Inflammation.

[8] Zhu G., Wang Q, Lu S., & Niu Y. (2017). Hydrogen Peroxide: A Potential Wound Therapeutic Target.

[9] Dunnill, C., Patton, T., Brennan, J., Barrett, J., Dryden, M., & Cooke, J. et al. (2015). Reactive oxygen species (ROS) and wound healing: the functional role of ROS and emerging ROS-modulating technologies for augmentation of the healing process.

[9] David E. Eisenbud. Oxygen in Wound Healing Nutrient, Antibiotic, Signaling Molecule, and Therapeutic Agent.

[10] Dai, T., Tanaka, M., Huang, Y., & Hamblin, M. (2017). Chitosan preparations for wounds and burns: antimicrobial and wound-healing effects.

 

 

Alfred MARCHAL, PhD in organic chemistry, is an internationally recognized antioxidants and aesthetic medicine expert. He has a 35-year academic experience in R&D for pharmaceutical organic synthesis and phytopharmaceuticals. Author of many scientific articles and patents in particular for vitamin C, vitamin K and hyaluronic acid. He runs ALPHASCIENCE Research Department and is board member in pharmaceutical companies.

The four steps of wound healing process

Many factors can interfere, thus causing improper or impaired wound healing. The most significant factors that affect cutaneous wound healing and the potential cellular and/or molecular mechanisms are oxygenation, infection, age and sex hormones, stress, diabetes, obesity, medications, alcoholism, smoking, and nutrition.

 

1st step: Coagulation

The extravasation of blood into the wound is activated to limit loss of blood.
The clot, comprising of fibrin, fibronectin, vitronectin, Von Willebrand factor and thrombospondin, provides the provisional matrix for cellular migration.

 

2ndstep: Inflammation

Primary inflammation 24-48 h

The next phase of healing is inflammation with activation of classical molecular cascade that leads to infiltration in the wound with granulocytes or PMNLs (polymorph nuclear leucocytes. Theses cells are attracted to the wound site within 24 to 48 hours of injury by a number of agents such as C5a, platelets, TGF-beta, formylmethionyl peptide product from bacteria.

 

Secondary inflammation 48-72 h

Monocytes are attracted to the wound by a variety of chemo-attractants, including clotting complements, immunoglobulin G (IgG), collagen and elastin, cytokines such as leukotriene B4, platelets factors IV, PDGF, and TGF-beta.

Macrophages are the most important cells present in the later stage of inflammation process and act as key regulatory cells for repair.

 

3rdstep: Proliferation

Cell proliferation is at first by the migration of fibroblasts, collagen synthesis and angiogenesis. Then there is granulation tissue formation and epithelialization finally.

 

4thstep: Remodelling

Matrix synthesis and the remodelling phase are initiated with the development of granulation tissue and continue over prolonged periods of time.

As the matrix matures, fibronectin and Hyaluronic Acids are broken down. The collagen bundles increases in diameter.

 

Oxidative Stress

Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species (ROS) and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal redox state of cells produce of peroxides and free radicals that damage all components of the cell (proteins, lipids, DNA...).

Oxidative stress from oxidative metabolism causes base damage, as well as strand breaks in DNA. Base damage is mostly indirect and caused by reactive oxygen species (ROS) generated.

For example: O2(superoxide radical), OH (hydroxyl radical) and H2O2(hydrogen peroxide).

 

Further, some reactive oxidative species act as cellular messengers in redox signalling. Thus, oxidative stress can cause disruptions in normal mechanisms of cellular signalling.

 

In humans, oxidative stress is thought to be involved in the development of many diseases and physical effects on the skin.

The ROS play an important role in skin injury and repair.

 

Regulation of wound healing process

The wound-healing process is regulated by a variety of different growth factors, cytokines, and hormones. The innate immune system cells produce proteolytic and pro-inflammatory enzymes cytokines. They also produce and secrete increased amounts of ROS, required to protect the organism from bacteria and other microorganisms. Additionally, several recent studies revealed that they represent the crucial regulators of this process. ROS’s are required for the defense against invading pathogens, and at low concentrations, they are the crucial mediators of intracellular signalling. A previous study showed that low H2O2levels are important for the efficient neoangiogenesis in wounds.

Reactive oxygen species (ROS) are essential during the healing process at multiple stages, ranging from the initial signal that instigates the immune response, to the triggering of intracellular redox-dependent signalling pathways the defence against invading bacteria.

 

In the inflammatory processes the radical species come mainly from neutrophils, eosinophils and macrophages that release O2, converging in the formation of H2O2.

 

Excessive ROS in the wound environment impede new tissue formation. ROS are harmful and can cause severe cellular damage. In human and animal cells in the presence of nitric oxide, calcium, and pathogens, the balance between oxidant and antioxidant systems is affected, promoting the generation and accumulation of ROS in cells, eventually inducing oxidative stress. Oxidative stress can result in DNA damage, mutations, and double-strand aberrations but also induce dysfunction in MAPK/AP-1, NF-κB and JAK/STAT-signalling pathways, apoptosis and autophagy.

 

Intrinsic and extrinsic factors lead to the skin barrier damage, which leads to the disequilibrium in oxidant and antioxidant balance and induces excessive ROS production.

 

The aesthetics acts on the skin will generate ROS with different proportions depending on the size of the wounds (surgery as open wounds or superficial as peeling, lasers and burns).

A large amount of ROS will generate inflammation, pain, discomfort and over pigmentation after TCA peeling and laser.

 

Oxidative stress represents the imbalance between oxidative and antioxidative events.

The non-enzymatic antioxidant system includes vitamins C and E, glutathione (GSH), carotenoids, melatonin, A-lipoic acid, Zn (II)-glycine, and polyphenols, and some of these molecules are exogenous antioxidants.

The skin employs a number of endogenous antioxidant agents to protect the oxidative balance, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), ascorbic acid, and tocopherols. The results presented here indicate that antioxidant treatments may be effective when applied in the therapy of cutaneous diseases where oxidative stress who plays a prominent pathogenic role.

 

The skin regulates the ROS by itself

The antioxidative systems in human skin are interdependent, but they collaborate. The treatment with known antioxidants such as ascorbic acid, tocopherols, and polyphenols increases the resistance of organism to ROS and prevents skin aging and inflammation

 

An overview about oxidation in clinical practice of skin aging[1]

Free radicals are unstable chemical species, highly reactive, being formed by cellular entities of different tissues. Increased production of these species without proper effective action of endogenous and exogenous antioxidant systems generates a condition of oxidative stress.

 

The antioxidants are chemical substances commonly used in clinical practice for topical application and may contribute in the fight against the radical species responsible for many skin damages.

It is an evidence of the benefits brought by the topical application of antioxidants in the skin.

 

Which antioxidants to use?

However, for topical administration of antioxidants to be effective in the prevention and elimination of free radicals it is critical to ensure the stability of the final formulation, since the antioxidant, in most cases, are very unstable and may be oxidized easily, becoming inactive before reaching the site of action. In addition, antioxidants must be properly absorbed through the skin to reach deeper layers of the tissue in the active form.

 

Cell membranes are the main cellular constituents susceptible to oxidation procedure being established, which is known as lipid peroxidation.

Phenolic compounds are formed in the secondary metabolism of plants and have defense functions. It has been observed that they are capable of reacting with free radicals to form stable chemical species. This power of neutralizing the radical structures is due to their chemical structure, which has hydroxyl groups with aromatic rings that confer antioxidant power. We highlight the flavonoids, phenolic acids, simple phenols, coumarins, tannins, and tocopherols.

 

The main indications are for superficial aesthetic procedures. It's very important to use antioxidant before and after peeling, dermabrasion, lasers, Microneedling or Mesotherapy for example.

 

Most compounds must be integrated in modern serum as vectors. We can use polyphenols, Tannic acid, vitamin C, Glutamin, Phytic acid, ginkgo biloba, phytoestrogen, EGCG and curcumine.

 


REFERENCES

[1] Heather L. Orsted. (2019). Basic Principles of Wound Healing.

[2] Xue, J., Yu, C., Sheng, W., Zhu, W., Luo, J., & Zhang, Q. et al. (2017). The Nrf2/GCH1/BH4 Axis Ameliorates Radiation-Induced Skin Injury by Modulating the ROS Cascade.

[3] Kohen, R. (1999). Skin antioxidants: Their role in aging and in oxidative stress — New approaches for their evaluation.

[4] Toshihiro Kurahashi, & Junichi Fujii. (2015). Roles of Antioxidative Enzymes in Wound Healing.

[5] Nicholas Bryan, Helen Ahswin, Neil Smart, & Yves Bayon. REACTIVE OXYGEN SPECIES (ROS) – A FAMILY OF FATE DECIDING MOLECULES PIVOTAL IN CONSTRUCTIVE INFLAMMATION AND WOUND HEALING.

[6] Silas Arandas Monteiro e Silva, Gislaine Ricci Leonardi, & Bozena Michniak-Kohn. (2015). An overview about oxidation in clinical practice of skin aging*.

[7] Xu, H., Zheng, Y., Liu, Q., Liu, L., Luo, F., & Zhou, H. et al. (2017). Reactive Oxygen Species in Skin Repair, Regeneration, Aging, and Inflammation.

[8] Zhu G., Wang Q, Lu S., & Niu Y. (2017). Hydrogen Peroxide: A Potential Wound Therapeutic Target.

[9] Dunnill, C., Patton, T., Brennan, J., Barrett, J., Dryden, M., & Cooke, J. et al. (2015). Reactive oxygen species (ROS) and wound healing: the functional role of ROS and emerging ROS-modulating technologies for augmentation of the healing process.

[9] David E. Eisenbud. Oxygen in Wound Healing Nutrient, Antibiotic, Signaling Molecule, and Therapeutic Agent.

[10] Dai, T., Tanaka, M., Huang, Y., & Hamblin, M. (2017). Chitosan preparations for wounds and burns: antimicrobial and wound-healing effects.

 

 

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