Skin Burns: Review of Molecular Mechanisms and Therapeutic Approaches

Ahad Ferdowsi Khosroshahi, PhD; Jafar Soleimani Rad, PhD; Raziyeh Kheirjou, PhD student; Mohammad Reza Ranjkesh, MD; Leila Roshangar, PhD

Disclosures

Wounds. 2019;31(12):308-315. 

In This Article

Approaches to Burn Wound Healing

First Aid

First aid is an essential intervention before receiving medical treatment. Among the current recommendations for the initial treatment of burns is to keep burn wounds cool at about 15°C for 20 minutes. Research has found the use of 2°C to 15°C water is beneficial for wound healing.[44] This first aid technique would increase the rate of reepithelialization, reduce pain, and improve the appearance and thickness of the resultant scar.[45] Nevertheless, using water at 2°C, especially for children or hypothermic patients, is dangerous.

Research[46] also has shown cold water inhibits the release of histamine from damaged tissues and significantly inhibits the activation of kallikrein in human plasma. Kallikrein is one of the kinins (bradykinin and kallidin) that cause vasodilatation and hypotension, and it increases fluid leakage from the vessels and causes local edema. Therefore, kinins inhibition causes a reduction in vasodilatation, vascular permeability, and edema. There is no evidence showing the use of ice in burn wounds is more harmful, but direct contact with ice may increase vascular contractions and damage progression or cause frostbite and protein denaturation in tissue.[44,45]

Traditional and Drug Treatments

Cooling burn wounds with water eliminates heat, preventing further burn development. This is effective if carried out within 20 minutes by immersion in water at 15°C. The current recommendations for first aid treatment of burn injuries should be to use cold running tap water (between 2°C–15°C) on the burn; ice should not be used.[47] Chemical burns should be washed with plenty of water.[48]

Several studies[49,50] have found that the treatment of inflammation is difficult in severe burns. Traditional anti-inflammatory treatments such as nonsteroidal anti-inflammatory drugs or glucocorticoids downregulate prostaglandin synthesis and negatively impact wound healing. However, steroid therapy decreases inflammation, pain, and hospitalization time of burn patients.[51] It also has been reported that non-anti-inflammatory drugs, such as opioids, postpone the early inflammatory phase, accelerate the proliferative phase, and stimulate keratinocyte migration in vitro.[52,53] However, large-scale clinical trials have not yet been conducted to evaluate the efficacy of opioids in wound healing.

Burn Dressings

Since infection prevention is critical, wound coverage should be applied as soon as possible. However, coverage is one of the main challenges in the treatment of severe burns. Wound dressings can be divided into 4 groups: conventional, biological, biosynthetic, or antimicrobial.

Conventional coverage (eg, petroleum gauze or silicone sheets) are used to cover the wounds temporarily; these do not contain antibiotics or medications and tend to stick to the surface of the wound. The frequent conventional dressing changes required also can affect reepithelialization and delay wound healing.

Biological coverages include cadaver allograft skin, xenograft skin, and human amnion and are used to cover burn wounds temporarily to help reepithelization. For immunological reasons, biologics cannot be used as a permanent substitute.

Biosynthetic coverages are composed of epidermal, dermal, or epidermal-dermal combination substitutes that simulate skin function. Several skin substitutes have been used successfully for burn wound treatment such as Karoskin (human cadaver skin with dermal and epidermal cells; Karocell Tissue Engineering AB, Karolinska, Sweden), Glyaderm (glycerol preserved acellular dermal collagen-elastin matrix; Euro Skin Bank, Beverwijk, The Netherlands), and OASIS Wound Matrix (porcine acellular lyophilized small intestinal collagen matrix; Smith+Nephew, Fort Worth, TX).

Antimicrobial dressings are widely used to protect against infections. These products may contain either silver, nanocrystalline silver, cadexomer iodine, or honey as an antimicrobial agent.[54] Antimicrobial dressings, such as silver dressings, can have a preventive effect against infection within the first 48 hours of a burn injury. Generally, a silver dressing should be soaked in sterile water and applied to the wound bed, not in normal saline solution, because chlorine ions can attach to silver ions and reduce the amount of silver delivered to the ulcer. After 48 hours, the silver dressing is removed and the wound is assessed for further treatment. Although silver is poisonous to bacteria, there is evidence that silver prevents keratinocytes and fibroblasts from proliferation and can potentially slow the healing process. It also is recommended to use a moist dressing after the initial antimicrobial dressing.[55] Standard wound management with dressings can significantly rehabilitate the stasis zone and prevent further coagulation. The general purpose of each wound dressing, regardless of burn size and depth, is to prevent infection, promote wound healing, reduce pain, and enhance motion capacity and performance. Burn injury is a dynamic process of changes, especially in the first 48 hours after injury. Therefore, a suitable burn dressing should be firmly used for 48 hours to prevent infection.

Skin Grafting

Skin flap grafting is also part of the gold standard for treatment of full- and deep partial-thickness wounds, because early excision helps to reduce infection and scarring. Puri et al[56] found excision of wound debris within 24 to 48 hours can reduce the amount of fluid loss and infection, decrease the duration of hospitalization and mortality rate, and increase the possibility of transplantation.[56]

Moist Wound Healing

The wound environment is defined as the environment in direct contact with its surface. A dry dressing is defined when there is no obstruction to extracellular fluid and ECM in the wound. The dressing is described as moist when a moisture-containing, controlled hydration dressing is used to cover the wound surface. Finally, it is described as a wet or an occlusive dressing when covered with an impermeable membrane that adheres to the wound border.[57] A dressing that creates and maintains a humid environment seems to provide optimal conditions for wound healing. The moisture under the occlusive dressing not only increases the rate of epithelialization but also improves it by maintenance of moisture similar to an incubator as well as maintenance of wound exudate, which contains cytokines and vital proteins in response to injury. Low oxygen tension in these dressings also promotes the inflammatory phase. However, a dry dressing with gauze does not exhibit these properties; it can impair wound healing and damage tissues when removed. In dry wounds, keratinocytes migrate at a deeper level in order to most effectively proliferate, but in a moist wound environment, keratinocytes can more easily move toward the surface of the wound for closure.[58] A moist wound bed can reduce the risk of infection by creating a hypoxic environment. This hypoxic wound bed amplifies angiogenesis, reduces wound bed pH, and makes the wound uninhabitable by bacteria, ultimately protecting against infection. Moreover, the moist wound environment increases the production of collagen by fibroblasts and helps the ECM synthesis.[58] Wound drainage fluids are a source of soluble factors associated with wound healing. In particular, PDGF, FGF, and EGF; keratinocyte growth factor (KGF [IL-6 and MMP-8]); and VEGF (hepatocyte growth factor [HGF], IL-8, and MMP-1) have been found in the fluid under occlusive dressings.[59] Some wet dressing products (including hydrocolloids, hydrogels, foams, and alginates) are included in Table 2.[58,60]

Cell Therapy in Severe Burn Wound Healing

Regeneration of skin after wound healing depends on several factors, including the availability of primary precursor cells, ECM components, and cytokines for angiogenesis, cell-to-cell and cell-to-matrix interactions. Until now, autologous skin grafts commonly have been used to treat severe burns; however, its efficacy in severe burns is not fully understood because of the limited availability of donated skins. Alternatively, cell therapy uses autologous or allogeneic cell components to repair or regenerate damaged tissue. Cell therapy for burn injury treatment began when Rhienwald and Green[61] isolated and serially cultivated human keratinocytes from a skin biopsy. The following subsections are a small part of the described content to understand the types of cells and their potential role in burn wound healing.[62]

Keratinocyte Stem Cells (KSCs). Based on molecular biomarkers, regenerative capacity, and cell differentiation status, keratinocytes are categorized into KSCs, transient keratinocytes, and differentiated keratinocytes. The KSCs, which comprise about 4% to 8% of the total keratinocyte content in the skin,[63] are seen in the basal membrane of the epidermis and around the skin appendages. These cells asymmetrically are divided to keep undifferentiated stem cell numbers in the basal membrane. In addition, a group of protozoan keratinocyte cells recognized in the peripheral blood is capable of converting to keratinocytes and express cytokeratin, involucrin, and filaggrin proteins.[62,63]

Skin Fibroblasts. Fibroblasts are critical to skin production and improve postburn healing. They produce ECM proteins in the dermis and play a role in the biological functions of skin cells. These cells produce many growth factors and cytokines, including VEGF, PDGF-AA, KGF, basic fibroblast growth factor, HGF, TGF-β1, IL-6, and IL-8. Fibroblasts also can be differentiated into pluripotent stem cells with the capacity to regenerate various tissues.[62,63]

Mesenchymal Stem Cells (MSCs). Mesenchymal stem cells are a specific group of multipotent cells able to self-renew with virtually unlimited differentiation capacity and can be derived from most autologous or allogeneic tissues. These cells can produce growth factors (VEGF, EGF, KGF, IGF, MMP-9, and stem cell factor 1) that are specific to angiogenesis, cell proliferation and differentiation, and establishment of the ECM during wound healing. The MSC also releases cytokines, including TNF-α, interferon lambda, IL-1α, IL-1β, and nitric oxide, to control host immune response.[62,63]

Embryonic and Induced Pluripotent Stem Cells. Human embryonic stem cells (hESCs) are isolated from human embryos, which have an excellent capacity for tissue regeneration. Research has shown hESCs can be differentiated into functional keratinocytes.[64] Although hESCs can be used as a skin substitute in patients with burns, its application is problematic, owing to ethical issues. Takahashi et al[65] obtained pluripotent stem cells (iPSCs), which can be used as an alternative source for hESCs with potential for therapeutic programs. Embryonic stem cells or iPSCs could release growth factors VEGF, FGF-2, TGF-β, GM-CSF, and IL-6 and IL-8 that induce cellular proliferation, differentiation, and migration.[62,63]

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