What is the Role of Fish Skin Graft in Combat Injuries in Austere Conditions?

March - April 2023

What is the Role of Fish Skin Graft in Combat Injuries in Austere Conditions?

Editorial Summary

Military conflict presents a series of challenges for clinicians when treating injured individuals. Blast injuries and burns are common, however access to standardized treatment remains limited in remote and resource scarce environments. Fish skin grafts (FSG) present a unique opportunity to treat both burns and blast injuries incurred in conflict where access to more usual treatments is more logistically challenging. This article will provide an overview of the potential use of FSG in military field hospitals to treat wounds.

Introduction

Blast injuries and burns are prevalent presentations in the context of conflict. Blast injuries result from exposure to a violent release of energy caused by explosions leading to widespread injury and disruption to multiple body systems. Thermal and chemical burns can be component features.1 The use of white phosphorus in combustibles contributes to the severity of chemical burns, which most commonly affect exposed skin on the face and hands. These wounds can result in significant morbidity and mortality. There is also an association with lengthy stays in hospital.2

Managing such injuries during active conflict presents logistical challenges; they can often be highly complex and potentially fatal, requiring urgent action by the clinician to avoid loss of life or life changing injury. Circumstances themselves are challenging with potential ongoing enemy action against both civilians and military personnel.1 Additionally, conditions for storage of equipment for the treatment of injured soldiers is often sub-optimal.

Cadaver skin is the favoured cover for severe burns in the hospital environment; however, this is not practical in austere settings like combat zones and so attempts have been made to address the problem. Cellular derived alternatives are similarly unsuitable due to their storage requirements.3 For example, ultra-low cold storage of allograft is unlikely to be available.4 Therefore, alternative treatments which provide readily accessible and low maintenance options for medical application must be sought.

Fish Skin Grafts

Fish skin has the potential for use in the management of combat related wounds. Acellular matrix derived from the skin of wild-caught Atlantic cod has been developed as a patented graft material, or FSG, by Kerecis™ (Kerecis Omega3, Kerecis, Isafjordur, Iceland). FSG is supplied as a thick sheet with the indications for use given by the manufacturer including partial

Dr Fouad Reda

Plastic Surgeon, Ajapnyak Medical Center

Yerevan, Armenia

Dr Steven Jeffery

Consultant Plastic Surgeon

Birmingham, United Kingdom

Dr Hilmar Kjartansson

Kerecis LLC, Staff Specialist Landspitali University Hospital

Reykjavic, Iceland

“To explore the suitability of FSG for use in field-like hospital environments, it was used to treat injured soldiers in the Nagorno-Karabakh War in 2020.”

properties of fish skin coupled with its compliant structure allowing it to yield to irregular surfaces reduces infection rates by providing good wound coverage and preventing bacterial entry of the wound bed.3

and full-thickness wounds, in addition to trauma wounds.5 FSG is comparatively robust; the relative thickness of the graft material safeguards against environmental irritants which in turn reduces the risk of infection.3,6,7

The biological material collected contains epidermis and dermis layers which remain fully intact.5 Acellular fish skin is advantageous as skin replacement because its basic physical macrostructure is comparable to that of human skin.

The matrix is also composed of mainly type 1 collagen allowing it to bind efficiently with proinflammatory cytokines. The microstructure of acellular fish skin is equally suitable for use on human wounds, with pores in the same size range as human epithelial tissue.8

As the product undergoes only minimal processing, it remains high in natural Omega-3 fatty acids.3 Omega-3 plays an important role in injury resolution. Previous literature has highlighted its bacteriostatic properties and its ability to accelerate wound healing.3,6 FSGs can act as a barrier against bacterial invasion of the wound site. They are also superior to allografts for stimulating cell ingrowth, a fundamental initial step of tissue regeneration.3 Burn injuries and injuries resulting from explosions are associated with significant complications including infection, incomplete healing, and supplementary injury from fragment wounds. The bacteriostatic

The extraction and production process of fish skin is cost effective and eco-friendly. There is no requirement for the use of toxic chemicals, meaning not only does the material retain its structure, but patients treated with FSG are unlikely to suffer hypersensitivity reactions, and the risk of virus transmission is negligible. Its low cost makes it more accessible in areas where high-cost advanced treatments are unobtainable.8

Storage of FSG is relatively low maintenance. It requires only clean, dry storage at room temperature.5 A 3-year shelf life at this temperature also makes the product advantageous for use in field-like hospital conditions. FSG requires just minimal training for use by clinicians with only access to basic sterile medical field equipment and sterile saline needed.4

Efficacy Testing

To explore the suitability of FSG for use in fieldlike hospital environments, it was used to treat injured soldiers in the Nagorno-Karabakh War in 2020. This was an armed conflict between Azerbaijan and Armenia, fought over a region of ethnic and historical significance. Beginning on September 27, 2020, it lasted until a ceasefire on November 10, 2020.4

As the situation in field hospitals worsened, the Armenian government called upon Iceland (Kerecis) for aid in treating injured soldiers, as Armenia and Iceland share historical links.

Physicians Dr. H. Kjartansson from Iceland and Dr S. Jeffery from the United Kingdom travelled to Yerevan near the centre of the

Figure 1: A comparison between fish skin vs. human skin.

conflict, in order to deliver FSG and train field medics on its use in injury management.4 Their primary goal was to use FSG to stabilize and improve the wound bed if needed before skin grafting could be performed. Other aims included improving wound healing time, achieving earlier skin grafting and attaining better cosmetic outcomes.4

The nature of wounds seen in combat has changed as military tactics have progressed. Improvised explosive devices used commonly in modern warfare has increased the number of blast injuries and large surface area burns. This is a shift from penetrating injuries caused by more traditional combat.3 The NagornoKarabakh War was infamous for its use of drones, used for reconnaissance and air-strikes. Long-range weapons were also used. Drone warfare is yet another advancement in modern military strategy.4 The number of casualties from both sides was high, with many injured soldiers suffering burn and flash burn injuries. This was only compounded by reports of the use of white phosphorus as drone ammunition.4

Most burns seen during the conflict were deeppartial or full-thickness burns; however, due to the large numbers of casualties, Armenia’s military hospitals were overwhelmed. This led to an increasing reliance on civilian hospitals. Ultimately, demand for treatment led to extended wait times of more than a week, during which time burns were managed with regular dressings. Although the usual management of burns involves total excision of the burn wound, the increasing demand on hospitals meant patients were treated with partial excision. This can result in further complications including common infections requiring antibiotics, and further surgery.4

Only minimal training is required to use FSG, and it is suitable to cover large surface areas. The material is typically held in place with staples. The use of negative pressure wound therapy (NPWT), or a bolster dressing is also commonplace. Dressings were changed every 3 - 5 days.4

During their time at the hospital, the clinicians consecutively selected several patients requiring treatment. Injuries including largearea full thickness burn and blast injuries were treated using fish skin.4 Most wounds had been managed with initial debridement and simple wet-to-dry dressings before FSG application. Wounds were typically 3 - 5 days old by the time FSG was able to be applied. If further debridement was needed, this was performed, and FSG was applied in combination with NPWT. Follow-up was done 7 days post application of FSG. In some circumstances, more than one FSG was applied.4 Efficacy was ultimately assessed depending on whether the wound was sufficiently prepared for skin grafting.4

Clinical Cases

The following provide examples of three of the injuries treated using FSG during the conflict and the outcomes of each case. They offer evidence of the success of wound treatment with FSG in the field-hospital setting for speeding up the process of wound healing, and in one case serving as a substitute for further skin graft.

Clinical Cases

Case 1 provides an example of the successful use of FSG used in combination with NPWT to treat wounds when access to treatment has been delayed. In this case, the wound was 8 days old by the time FSG was applied. Non-viable tissue was debrided prior to the application of FSG.4

Case 2 is of a 32-year-old male with a right lower open tibial bone fracture. External fixation was used to stabilise the fracture. An open wound (15cm x 21cm) was debrided 3 times to remove non-viable tissue. In total, 3 applications of FSG were used before split-thickness skin grafting (STSG).4 This case presents evidence for the use of FSG on complex wounds and the ability of FSG to temporize and prepare the wound bed for further grafting.

Case 3 presents a 28-year-old male with approximately 75% burns due to an explosion containing white phosphorous. A total of 10 debridements following water jet pressure

cleaning were needed. FSG was then able to be used in place of skin grafting in this case. This demonstrates the successful use of FSG as a substitute to further skin grafting.4

Success of FSG

The use of FSG for treating combat induced burns and blast injuries was highly successful during two trips made by Dr. H. Kjartansson and Dr S. Jeffery. The necessary training of other medics was also minimal. Nominal storage requirement gives FSG an advantage over other skin graft material, in areas which may be remote and storage facilities limited.4 This study documented the first successful deployment of FSG for use in field-hospitals.

Use of FSG was found to induce granulation of the wound bed several days, if not weeks, sooner in all cases; this allowed stepdown in the reconstruction ladder. Earlier skin grafting procedures could be performed and flap surgery was less likely to be required.4

Figure 2: Case 1 demonstrates the use of FSG used to manage a large full-thickness injury resulting from blast injury in a 19-year-old male. The wounds were 8 days old upon presentation. Of note was a large left heel injury where the bone was exposed.4

What is the Role of Fish Skin Graft in Combat Injuries in Austere Conditions?

Training was endorsed by field clinicians at the four other hospitals that the physicians visited in the region.4 This supports other literature which has reported the ease of use of FSG.

Pain levels were not assessed, which must be addressed with further investigation; however, no infections were reported.4

Future Clinical Applications

While the current intention of treatment in military field-like hospitals is to temporize wounds until better treatment can be sought, the use of FSG marks a shift in this strategy. FSG not only temporizes the wound but actively accelerates the healing process, and in some circumstances can be used in place of an alternative graft.3,4,6 This has the potential to make permanent treatment more portable, easily stored, and accessible in field-like military

hospitals and other austere environments. The use of FSG in the cases provided above is, however, an unusual clinical application of the product and there are some limitations to the evidence produced. Given the environment, the study was not controlled and there is no welldocumented assessment of each wound prior to the application of FSG. Sufficient follow-up of each patient is also lacking. NPWT was also used which is the accepted treatment of wounds. It is therefore difficult to ascertain the true efficacy of FSG for each individual case.4

Changes in war tactics, such as the use of drones and targeted air strikes, inevitably produces more burn and complex blast injury victims. The need for a strategy to treat these injuries is woefully unmet by current approaches which are impractical in such austere environments and when local military field hospitals become overwhelmed. FSGs offer an opportunity to

Figure 3: Case 2 shows a large open wound over a lower right tibial fracture. The wound is debrided and temporized with FSG. STSG was then used.4

Figure 4: Case 3 is a male with 75% TBSA burns successfully treated with FSG in place of further skin grafting.4

What is the Role of Fish Skin Graft in Combat Injuries in Austere Conditions?

address this unmet clinical need. FSG is a CEmarked and FDA approved product which is suitable for use in other contexts. Therefore, while its use on this mission is unusual, the use of the product to treat wounds is not experimental.4

Treatment of soldiers in the Nagorno-Karabakh War has demonstrated that FSG has the potential to become the first line treatment of combat wounds. Fish skin can accelerate recovery times, mitigate the need for flap surgery and reduce infection rates, as well as other associated morbidities. Further exploration of FSG which addresses the limitations of this mission is needed; however, the implementation of FSG in austere environments appears to be associated with improved outcomes.4

Key Points

• Acellular matrix from the skin of wildcaught Atlantic cod can be used as graft material or FSG

• FSG has demonstrated antibacterial properties and accelerates wound healing

• FSG requires minimal training and is easily stored and transported

• FSG was exploratively used to treat injured soldiers in the Nagorno-Karabakh War

• The product demonstrated success in accelerating wound healing and reducing the requirement for flap surgery.

References

1. Plurad DS. Blast injury. Mil Med. 2011;176(3):276-82.

2. Davis KG. Acute Management of White Phosphorus Burn. Military Medicine. 2002;167(1):83-4.

3. Magnusson S, Baldursson BT, Kjartansson H, Rolfsson O, Sigurjonsson GF. Regenerative and Antibacterial Properties of Acellular Fish Skin Grafts and Human Amnion/Chorion Membrane: Implications for Tissue Preservation in Combat Casualty Care. Military Medicine. 2017;182(34):383-8.

4. Reda F, Kjartansson H, Jeffery SLA. Use of Fish Skin Graft in Management of Combat Injuries Following Military Drone Assaults in Field-Like Hospital Conditions. Military Medicine. 2023.

5. Kerecis®. Kerecis® Omega3 OR Instructions for Use [Cited 30 Mar 2023]. Available from: https://www.kerecis.com/wp-content/uploads/2021/07/KM-20-0079_v2-IFU-Kerecis-Omega3OR-US.pdf.

6. Magnusson S, Winters C, Baldursson BT, Kjartansson H, Rolfsson O, Sigurjonsson GF. Acceleration of wound healing through utilization of fish skin containing omega-3 fatty acids. Today’s Wound Clinic. 2016;10(5):26–9.

7. Kotronoulas A, López García de Lomana A, Karvelsson ST, Heijink M, Stone R, Giera M, et al. Lipid mediator profiles of burn wound healing: Acellular cod fish skin grafts promote the formation of EPA and DHA derived lipid mediators following seven days of treatment. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2021;175:1-8.

8. Fiakos G, Kuang Z, Lo E. Improved skin regeneration with acellular fish skin grafts. Engineered Regeneration. 2020;1:95-101.

9. Image: Magnusson S, Baldursson BT, Kjartansson H, Rolfsson O, Sigurjonsson GF. Regenerative and Antibacterial Properties of Acellular Fish Skin Grafts and Human Amnion/Chorion Membrane: Implications for Tissue Preservation in Combat Casualty Care. Military Medicine. 2017;182(3-4):383-8.