Background-According to the CDC, burn injuries account for 1.1 million hospital admissions in the United States, and of those, approximately 4,500 of these people die as a result of their injuries. In addition, up to 10,000 people in the United States die every year of burn-related infections. The use of skin grafts was created in 1869; since then, surgeons have relied on this method. However, as medicine continues to discover and develop more modes of treatment through research, the use of tilapia skin has proven to be much safer and has led to better prognosis. So, in this review, we aimed to review the current literature to assess the strengths and gaps in knowledge about the usage of fish skin in burn patients. Material and methods- Electronic databases Pubmed, Scopus, Web of Science, Clinicaltrials.gov, and Google Scholar were searched using MESH keywords such as “fish skin”, “skin graft”, “Nile tilapia fish skin”, “burns” and “burn wounds” from 2018-2022. A data extraction form including information of author and year, study design, sample size, age, gender, and type of fish skin was done. . All included studies considered bias and ethical criteria and provided valuable information to answer the research question. Results- Of the 166 studies identified during the screening, 12 studies were relevant and were studied in detail during this review after undergoing extensive analysis. Conclusion- The results of trials have proven fastened and satisfactory reepithelialization, better patient compliance in terms of burn-associated pain, no immunological or allergic reaction, reduced infection, shortened hospital stay and treatment costs, all pointing towards the non-inferiority and robustness of fish skin as compared to the previous treatment modalities. Nile Tilapia is an excellent candidate among xenografts in treating burn victims due to all of the above-discussed points, however, more larger-scale trials and studies need to be further conducted and established before its widespread and official use in burn centers. MESH term: Nile tilapia fish skin, fish skin, skin graft, burns, burn wounds 1.1 Introduction Mass trauma and disasters such as explosions and fires can cause a variety of life-threatening injuries, including burns. [1] The use of skin grafts was created in 1869 and since then surgeons around the world have used this method. Since the first use of the skin graft, there have not been many changes to this procedure despite the issues that have arisen due to rejection of the graft. [2] Previously, the treatment of burn injuries involved the use of allogeneic skin grafts from other areas of normal skin in the same patient. However, as medicine continues to develop more information is emerging through research and the use of tilapia skin has been shown to provide much safer and better results for patients. For example, with the use of skin grafts, the patient is subjected to new wounds to graft skin from burns, which increases the risk of surgical complications of allogeneic skin grafting. Furthermore, skin graft rejection in cases where an allogeneic graft is not used also poses a complication. Tilapia skin and acellular fish skin from Atlantic cod fish provide an improved alternative that may not only facilitate but promote faster wound healing, lower risk of infection, and is generally more cost-effective. [3] Thus studies have been done in order to find a more suitable, sustainable, and cost-efficient alternative. This gap in demand can be filled by acellular fish skin grafts. The use of collagen-based biomaterials such as Fish Skin Graft, for cell growth and wound healing, is gaining attention. Collagen has been widely used in pharmaceuticals, cosmetics, and food for its beneficial properties. A protein that has the potential to promote wound healing, Collagen (type I and II), are found in large quantities in fish skin. [4] Since its approval by FDA for wound coverage, Fish skin graft, a novel skin substitute, has seen widespread clinical application. Omega 3-rich acellular fish skin graft is shown to integrate into the wound bed resulting in faster healing with less contraction. [5] In addition, fish skin grafts show promising results in treating diabetic foot ulcers and venous leg ulcers. Hence is worthy of further exploration in treating a variety of other acute and chronic wounds. [3] The purpose of this literature review was to review the current literature to assess the strengths and gaps in knowledge about the use of fish skin in burn patients. 1.2 Methods: Search Method and Strategy: The literature search was performed up to December 2022, using MESH terms: “fish skin”, “skin graft”, “Nile tilapia fish skin”, “burns” and “burn wounds”. We searched on databases like PubMed, Scopus, Web of science, Clinicaltrials.gov and Google Scholar. Eligibility criteria The inclusion criteria for studies consisted of inclusion criteria- articles from the last 5 years including 2018-2022, age >18, original Studies, observational studies, systematic review, and meta-analysis, case series. Exclusion criteria included narrative reviews, editorials, short communications, case studies, articles not in English, articles for which full text is not available. The articles were thoroughly studied In extensive details and made eligible based on relevance to our study. Data Extraction The following data were extracted from eligible studies: author and year, study design, sample size, age, gender, and type of fish skin. 1.3 Results Of the 166 studies identified during the screening, 14 studies were relevant and were studied in detail during this review. However, 2 studies were excluded due to one was a preclinical study and another was a letter to the editor. Finally, 12 studies comprising 4 clinical trials, 2 case reports, 2 case series, 1 cross sectional study, 1 review article, and 1 retrospective and 1 prospective cohort study were included. (Table 1) A phase 3 clinical trial in Brazil compared the use of Nile tilapia fish skin (NTFS) with silver sulfadiazine cream for the treatment of superficial partial thickness burn in a total of 115 subjects. Among them, 57 patients treated with fish skin required fewer days for reepithelialization (p = 0.001) and fewer dressings (p < 0.001) so, patients treated with fish skin needed comparatively short duration of reepithelialization. [6] Similarly, another case report conducted on applying acellular fish skin graft (KerecisTM Omega3 Burn) for treating partial thickness skin burns found reepithelialization time was significantly short compared to traditional methods. [7] A case report in Brazil by Lima-Junior et al. found that on both superficial and deep partial thickness burn, tilapia skin was applied that leads to complete reepithelialization within 12 days and 17 days respectively. [8] Costa B, et al. found time required for complete re epithelialization was 10 days while treating a 3 year old with superficial partial thickness burn. [9] Also, the effectiveness of Nile tilapia skin was reported as a beneficial method for partial thickness burn treatment in low resource countries with no major adverse effects. [10] Similarly, Costa B et al. concluded that this method of treatment could serve as a promising, widely available and low cost option for treatment of pediatric burn. [9] In a randomized control trial conducted by Baosheng et al., the study concluded faster healing rates could be achieved with the use of the collagen hydrogels as wound dressing in refractory wounds. [8] Furthermore, a case series completed by Putri et al., included 4 adults aged of 23-48 years suffering from acute burns affecting 27.5-37% total body surface area, found the limbs treated with tilapia fish skin required less dressing changes when compared to paraffin-impregnated gauze. [11] Additionally, cross linked decullularized tilapia skin was found to have both improved function as well as positive contribution in cell proliferation in a retrospective cohort study by Liu et al. The study emphasized on the efficacy of this graft in treatment of tendon repair. [12] Similarly, a prospective study examining the use of synthetic peptides obtained from tilapia piscidin in wound healing of the skin ((TP2, TP2-5, TP2-6) found favorable effects in cell proliferation when treated with HaCaT keratinocytes. It was also noted the samples displayed pro-angiogenic properties, accelerating wound healing when instilled topically to wounds of mice. [13] In a review conducted by Luze et al., 14 trials were sought out to identify the outcome of acellular fish skin in either burn wounds or split-thickness donor sites. The review discovered an increased rate of wound healing, and decreased pain, dressing changes, as well as costs for treatment. The aceullar fish skin was determined a potential good alternative in the treatment of superficial and partial thickness burns. [9] Similarly, a cross sectional study by Biazar et al., observed with the addition of plasma rich growth factor, adequate healing in full thickness skin wounds by 28th day. The sample also displayed formation of an epidermal layer that closely resembled skin. [14] 1.4 Discussion The treatment of superficial burns has evolved with the advancement of medical science. Different methods have been used to treat partial thickness skin burns. In recent times, the use of Nile tilapia skin (NTFS) for the treatment of superficial burns has drawn a lot of attention due to its tremendously promising results compared to traditionally used methods. Even Nile tilapia skin (NTFS) is being developed as a low-cost xenograft compared to the use of split-skin grafts, carcasses and pig grafts in burn victims, none of which have come to fulfill all the characteristics of an ideal graft and are generally associated with an increased chance of graft rejection. [7] Recent literature reports the usefulness of fish skin in burn victims. Regarding the required number of dressing, fewer dressings were required for superficial partial thickness burn in Nile tilapia skin compared to sulfadiazine cream found in a study by Lima-Junior et al. [6] This finding is also supported by another study where Nile tilapia skin and silver impregnated Sodium Carboxymethylcellulose were compared for superficial partial thickness burn treatment. [15] Similar results were revealed when Nile tilapia skin was used as a xenograft for partial thickness burn wound treatment mainly from thermal sources. [7] Dressing changes are an essential component for successful wound healing. In a comparative case series study, Putri et al., studied the differences between tilapia skin xenograft and paraffin-impregnated gauze, leading to an average reduction of dressing changes of 3.72 and 8.67 for outpatients and inpatients, respectively. [11] Lima-Junior et al. revealed improved associated pain and less amount of analgesic were required for the Nile tilapia fish skin (NTFS) treated group compared to silver sulfadiazine cream treated group in the study. [6] Similar findings revealed while comparing Nile tilapia fish skin (NTFS) and silver impregnated Sodium Carboxymethylcellulose for superficial partial thickness burn treatment and when using NTFS as a xenograft for partial thickness burn mainly from thermal sources. [15, 16] Further supported by a case report on applying acellular fish skin graft (KerecisTM Omega3 Burn) for treating partial thickness skin burns where the required amount of analgesic was also significantly less compared to traditional methods. [10] Better adherence to the wound site was noted when evaluating the effectiveness of Nile tilapia skin as a xenograft for partial thickness burn wound treatment mainly from thermal sources. [16] A case report on a 3-year-old child in Brazil also resulted in appropriate attachment to the wound site. [17] But designing and executing further studies with pragmatic approaches is crucial to learn more about the benefits of using fish skin and its consequences for clinically meaningful advantage. Alam K, et al. showed in his case report that no immunological reactions, no incidence of infection or any kind of reactions were noticed after the application of acellular fish skin graft (KerecisTM Omega3 Burn) for treating split thickness donor sites and partial thickness skin burns compared to previously used cadaveric and pig skin in skin graft [10], these results correlated with Biazar et.al, decellularized tilapia fish skin with plasma-rich growth factor (PRGF) has no allergic reactions and promising biocompatibility. [14] Based on prior studies, the use of Nile tilapia fish skin is cost-effective. The total cost of burn treatment using Nile tilapia fish skin compared to silver sulfadiazine cream was significantly reduced. [6] Hence the use of tilapia skin could serve as a promising, widely available, low-cost option for the treatment of pediatric burns. [17] This could be particularly beneficial in resource-poor third world and war-torn countries, where cheaper and more compatible amputation and burn treatments could take root in health systems as a more viable option for both the patient as well as the health care provider. Supporting the previously exposed ,decellularized tilapia fish skin with plasma-rich growth factor (PRGF) entails a novel cost-effective approach with a reduction in dressing changes, key feature to scale-down medical cost related expenses. [11] In addition, the use of fish skins could be expanded to use in firearms and explosive injuries due to their long storage life at normal room temperature and also the fact that associated fish skin-treated wounds do not require frequent repair and removal. , which is a really ideal property for battlefield wounds. It’s antiviral, anti-inflammatory, antibacterial, and analgesic effect on associated wounds also provides added benefits for subsequent long-term treatment. [3] Nile Tilapia Skin Collagen Hydrogels represent a novel and successful technique to treat burn victims. Baosheng et al., extracted ASC and PSC from tilapia skin, both molecules obtained are type I collagen, which is an essential component of extracellular matrix and a key component in the process of wound healing. The rationale behind these results is built on the assumption of rapid formation and promotion of collagen as well as epidermis layer resulting in a prompt/efficient reepithelization time. [8] Similar results were reported by Biazar et. al, decellularized tilapia fish skin with plasma-rich growth factor (PRGF) that portrays favorable promotion in wound healing and closure in 28 days. [14] Thus, Luze et al., compared standard wound healing treatment, which will generally take two to three weeks, compared with using acellular fish skin graft from Nile tilapia. Tilapia skin grafts yield a significant reduction of 1.43 days and 1.14 days for inpatients and outpatients, respectively. [9] Equally important, the rich presence of collagen in tilapia graft provides an ideal environment under the wet wound healing theory; a moist wound environment gives a scaffold for tissue regeneration and cell migration. [11] Chia-Wen Liu demonstrated the presence of two components derived from tilapia piscidin TP2. The peptides found in Oreochromis niloticus (Nile Tilapia) were TP2-5 and TP2-6 and had pro-angiogenic properties enhancing collagen I, collagen III, and Keratinocyte growth factors. These natural substances can regulate cell migration and activate neovascularization, resulting in wound healing. [13] Furthermore, some tissues in the human body have a low rate of regeneration; tendon tissue is one of these and is considered a challenge. Usually, tendon replacement is done with mammalian-derived scaffolds... Liu et al., yield propitious results for using decellularized tilapia fish skin as an alternative for tendon tissue replacement. Nile tilapia skin has intrinsic properties such as abundant collagen and mechanical strength to promote collagen fibers expression. [12] Even though some disadvantages persist, widespread advantages outweigh the risks. Widespread parameters of benefits including reduced probability of graft rejection, decreased number of required analgesics and dressings and better attachment to the wound site propose significant promising results for future treatment. Additionally, prolonged stability at room temperature along with no adverse or immunological reactions, reduced chance of infection and efficient reepithelization time are in line with the hypothesis. For the resource-poor countries, cost effectiveness of this treatment method could come as a boon for burn treatment. All these amenities exceed the minimal associated risks. Regardless, this review has some limitations. Only published articles were screened, sources from grey literature were not taken into consideration. But we consider that the grey literature would not have influenced the article’s conclusions. In addition, we found a limited number of data, but the majority of the studies were RCTs. 1.5 Conclusion Nile Tilapia is an excellent candidate among xenografts in treating burn victims due to all of the above discussed points, however, larger scale trials and studies need to be further conducted and established before its widespread and official use in burn centers. Appendix Table 1 Study Country Study design Demographic characteristics Type of fish skin Study findings Lima-Junior et al. 2021 [6] Brazil Phase III Randomized Controlled Trial 115 outpatients aged 18 - 70 years with superficial partial-thickness burns affecting 15 % or less of body surface area and no previous treatment. 57 patients were treated with the glycerolized fish skin 58 with silver sulfadiazine cream 1%. Patients treated with fish skin required fewer days for reepithelialization and fewer dressings. They had decreased analgesic needs and visual analogue scale, Burns Specific Pain Anxiety Scale, and Electronic von Frey measurements. Fish skin use reduced the final average treatment-related cost per patient by 42.1 %. Lima-Junior et al. 2020 [15] Brazil Randomized, prospective, open-label, and controlled pilot study 24 participants had ≥18 and ≤70 years of age and superficial partial-thickness burns affecting up to 10% of TBSA Glycerolized Nile tilapia skin (NTS) In the test group, the number of dressings and the patient-reported pain after dressing-related procedures were lower. Analgesic intake, pain-related anxiety, and both patient-reported and objectively measured pain before dressing-related procedures were similar for the treatment groups. No adverse effects. Superiority for burn management when compared with silver-impregnated sodium carboxymethylcellulose dressing. Lima-Junior et al. 2020 [16] Brazil Open-label, monocentric, randomized phase II pilot study 30 children between 2 - 12 years with superficial "partial-thickness" burns admitted less than 72 hours from the thermal injury. In the test group, the tilapia skin was applied. In the control group, a thin layer of silver sulfadiazine cream 1% was applied. Tilapia skin showed good adherence to the wound bed, reducing the number of dressing changes required, the amount of anesthetics used, and providing benefits for the patients and also for healthcare professionals, by reducing the overall workload. The number of days to complete burn wound healing, the total amount of analgesics required throughout the treatment, burn improvement on the day of dressing removal, and pain throughout the treatment were similar to the conventional treatment with silver sulfadiazine. Alam K, et al. 2019 [10] UK Case series 10 patients (6 males), mean age 45 acellular fish skin (KerecisTM Omega3 Burn) There were no adverse reactions noted on the use of the fish skin grafts. No patient had any reaction to the fish skin and there was a zero incidence of infection. The handling of the fish skin was excellent, a robust and pliable xenograft that was easy to apply. The quality of donor site healing was judged to be good in all cases. Both the analgesic effect noted and the relatively short average times until 100% re-epithelialization are promising. Lima-Junior, et al. 2019 [7] Brazil case report 23-year-old male, with no comorbidities Tilapia skin Tilapia skin was applied to the lesions, leading to complete reepithelialization within 12 and 17 days of treatment, respectively. No dressing changes were needed. No side effects. Costa B, et al. 2019 [17] Brazil case report 3-year-old boy, Involvement of 18% of TBSA with superficial partial thickness burns Tilapia skin Good adherence of tilapia skin to the wound bed was detected. Time required for complete re epithelialization was 10 days. No adverse effects. Baosheng et al., 2020 [8] China RCT Tilapia fish skin 2 types of collagen were extracted from the tilapia fish skin, acid-soluble (ASC) and pepsin-soluble (PSC). Due to the favorable characteristics of PSC including its low molecular weight, low antigenicity, and temperature resistance, PSC was used in the development of the hydrogels. The inclusion of PSC yielded increased strength of the samples. No cytotoxicity noted. Luze et al., 2022 [9] Austria Review Acellular fish skin The effects of using acellular fish skin revealed an increased rate of wound healing, along with decreased pain, dressing changes needed, and costs for treatment. The xenografts displayed superior outcomes in both function and aesthetically. May be a good alternative treatment option for superficial and partial thickness burns. Future cohort studies with larger scope warranted. Putri et al., 2022 [11] Indonesia Case series 4 adults between the ages of 23-48 years with acute burns affecting 27.5-37% total body surface area with similar burns affecting entire limbs (both sides of the limbs) Tilapia skin or paraffin-impregnated gauze The subject's limbs treated with tilapia skin displayed a reduction in the number of dressing changes required compared to those treated with paraffin-impregnated gauze. No allergic reactions to either tilapia skin or paraffin gauze. Liu et al., 2022 [12] China Retrospective Cohort Manufactured decellularized Nile tilapia fish skin cross linked with 1-ethyl-3(3-dimethylaminopropyl)-carbodiimide (EDC) and N-hydroxysuccinimide (NHS) The cross linked deceullularized tilapia fish skin displayed enhanced function, in both wet and dry conditions. It proved favorable contribution in cell proliferation in the produced fish skin, including induction of movement and differentiation of tendon-derived stem cells. The study emphasized on the usefulness of this graft for tendon repair. No cytotoxicity noted. Biazar et al., 2022 [14] Iran Cross sectional Acellular fish skin The use of acellular fish skin with plasma rich growth factor (PRGF) in full thickness skin wounds in a rat showed improved and adequate healing by 28th day post-op. The study found some dressings yielded the formation of an epidermal layer that closely resembled skin. Liu et al., 2022 [13] Taiwan Prospective cohort Tilapia fish skin The utilization of TP2-5 and TP2-6 revealed favorable effects in cell proliferation when treated with HaCaT keratinocytes. They also displayed pro-angiogenic properties. When instilled topically in the wounds of mice, the wounds exhibited accelerated healing in comparison to the non-treated wounds. No cytotoxicity noted. TBSA: total body surface area, ASC: Acid-soluble Collagen, PSC: Pepsin-soluble Collagen Reference 1. . 2. Greenwood, J.E., The evolution of acute burn care - retiring the split skin graft. Ann R Coll Surg Engl, 2017. 99(6): p. 432-438. 3. Fiakos, G., Z. Kuang, and E. Lo, Improved skin regeneration with acellular fish skin grafts. Engineered Regeneration, 2020. 1: p. 95-101. 4. Ibrahim, A., et al., Evaluation of fish skin as a biological dressing for metacarpal wounds in donkeys. BMC Veterinary Research, 2020. 16(1): p. 472. 5. Wasiak, J., et al., Dressings for superficial and partial thickness burns. Cochrane Database Syst Rev, 2013. 2013(3): p. Cd002106. 6. Lima Júnior, E.M., et al., Nile Tilapia Fish Skin-Based Wound Dressing Improves Pain and Treatment-Related Costs of Superficial Partial-Thickness Burns: A Phase III Randomized Controlled Trial. Plast Reconstr Surg, 2021. 147(5): p. 1189-1198. 7. Lima-Junior, E.M., et al., Innovative treatment using tilapia skin as a xenograft for partial thickness burns after a gunpowder explosion. J Surg Case Rep, 2019. 2019(6): p. rjz181. 8. Ge, B., et al., Comprehensive Assessment of Nile Tilapia Skin (Oreochromis niloticus) Collagen Hydrogels for Wound Dressings. Mar Drugs, 2020. 18(4). 9. Luze, H., et al., The Use of Acellular Fish Skin Grafts in Burn Wound Management-A Systematic Review. Medicina (Kaunas), 2022. 58(7). 10. Alam, K. and S.L.A. Jeffery, Acellular Fish Skin Grafts for Management of Split Thickness Donor Sites and Partial Thickness Burns: A Case Series. Mil Med, 2019. 184(Suppl 1): p. 16-20. 11. Putri, N.M., et al., Efficacy of tilapia skin xenograft compared to paraffin-impregnated gauze as a full-thickness burn dressing after excisional debridement: A case series. International Journal of Surgery Case Reports, 2022. 95: p. 107240. 12. Liu, Z., et al., Decellularized tilapia fish skin: A novel candidate for tendon tissue engineering. Mater Today Bio, 2022. 17: p. 100488. 13. Liu, C.W., C.Y. Hsieh, and J.Y. Chen, Investigations on the Wound Healing Potential of Tilapia Piscidin (TP)2-5 and TP2-6. Mar Drugs, 2022. 20(3). 14. Biazar, E., et al., Healing effect of acellular fish skin with plasma rich in growth factor on full-thickness skin defects. Int Wound J, 2022. 19(8): p. 2154-2162. 15. Lima Júnior, E.M., et al., A Randomized Comparison Study of Lyophilized Nile Tilapia Skin and Silver-Impregnated Sodium Carboxymethylcellulose for the Treatment of Superficial Partial-Thickness Burns. J Burn Care Res, 2021. 42(1): p. 41-48. 16. Lima Júnior, E.M., et al., Pediatric Burn Treatment Using Tilapia Skin as a Xenograft for Superficial Partial-Thickness Wounds: A Pilot Study. J Burn Care Res, 2020. 41(2): p. 241-247. 17. Costa, B.A., et al., Use of Tilapia Skin as a Xenograft for Pediatric Burn Treatment: A Case Report. J Burn Care Res, 2019. 40(5): p. 714-717.