Acellular Fish Skin Graft use for Diabetic Lower Extremity Wound Healing

A Retrospective Study of 58 Ulcerations and a Literature Review

Shannon Michael, DPM; Christopher Winters, DPM; Maliha Khan, DPM


Wounds. 2019;31(10):262-268. 

In This Article

Abstract and Introduction


Objective: This retrospective study evaluates the efficacy of acellular fish skin graft for the treatment of full-thickness diabetic foot ulcers (DFUs). The primary objective is to calculate the total wound surface area (cm2) healed over a 16-week period. The secondary objective is to provide a systematic review on acellular fish skin grafts.

Materials and Methods: There were 51 patients with a total of 58 DFUs treated with an acellular fish skin graft by the principal investigator. The initial wound surface area at first application was compared with the final wound surface area to conclude the percentage of total wound healed over a 16-week treatment period.

Results: At 16 weeks, there was a mean reduction of wound surface area by 87.57% and 35 wounds (60.34%) fully healed. The systematic literature review included 10 fish graft articles, 3 of which specifically evaluated lower extremity ulcers. The reviewed studies supported improved wound healing with fish graft application, with benefits noted in dentistry, neurology, and wound care.

Conclusions: This retrospective study further supports previous evidence that acellular fish skin graft promotes wound healing in DFUs. In particular, a rapid increase in wound healing was observed during the initial 4 weeks following graft application. This study and review of the literature indicated that fish graft encourages wound healing by enabling the wound to transition from a chronic to an acute stage of healing.


In 2017, the Centers for Disease Control and Prevention estimated 30.3 million people in the United States (9.4% of the population) have diabetes.[1] Due to this large patient population, diabetic wounds have become a growing problem. Lev-Tov et al[2] acknowledged that 10% to 25% of these patients develop a diabetes-related foot ulceration. As a result, treatment of diabetic foot ulcers (DFUs) creates a large financial burden of about $38.6 billion in the United States annually.[3] Therefore, extensive research in the treatment of DFUs is necessary to provide the most beneficial and cost-effective care. Diabetic foot ulcers are costly, dangerous, and the leading cause of nontraumatic lower extremity amputations in the United States.[2] The 5-year mortality rate after a nontraumatic lower extremity amputation has been studied extensively with results ranging from 56% to 70%.[4–6]

In order to prevent limb- and life-threatening sequela from diabetes, it is essential that research be conducted to evaluate the effects of wound care products on wound healing. Rapid wound healing is vital to prevent lower extremity amputations. By utilizing the most effective measures to heal wounds, nontraumatic amputation may be avoided in these high-risk patients.

The patient with diabetes is at high risk for amputation due to a delayed wound healing response. In a healthy patient, wound healing progresses in a predictable fashion through 4 stages: hemostasis, inflammation, proliferation, and remodeling. First, the inflammation stage lasts about 2 to 4 days. During this stage, platelets release factors that acquire neutrophils and monocytes, which then draw in lymphocytes and fibroblasts. Next, at days 3 to 7, the proliferation stage progresses with angiogenesis, collagen formation, and epithelialization by fibroblasts. Finally, the remodeling phase lasts up to 1 year; over that time, newly formed capillaries collapse to allow the vascular density and tissue strength of the wounded area to return to normal. Diabetic wounds do not undergo these 3 typical stages and become stuck in the first stage (ie, inflammatory stage), resulting in chronic inflammation and delayed wound healing.[7,8]

Wound care products have been created to encourage a wound to transition from a chronic inflammatory phase into an acute proliferation phase of healing. Numerous xenografts have been developed to assist with the progression of wound healing. In 2013, the US Food and Drug Administration approved Kerecis Omega3 (Kerecis, Isafjordur, Iceland), an acellular fish skin graft, for the treatment of various wounds including diabetic ulcers. Piscine grafts have an advantage over mammalian grafts because they do not risk transmission of disease;[9] therefore, a piscine graft is able to undergo a simpler sterilization process. During mammalian graft sterilization, harsh detergents are used to eliminate any risk of viral transmission, but these detergents also remove fat cells. Since piscine grafts do not undergo the same sterilization process, they are able to retain an omega-3 fat source.[9] Previous research has supported that omega-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), reduce inflammatory responses and advance proinflammatory cytokines that promote wound healing.[10] These factors are found largely in piscine skin.[11] The aforementioned proprietary piscine graft is an acellular intact fish skin that contains omega-3 polyunsaturated fatty acids, which has been shown to assist the wound in leaving the chronic inflammation state.[7]

The acellular fish skin graft is harvested from North Atlantic cod and contains collagen, fibrin, proteoglycans, and glycosaminoglycans; therefore, it acts as a skin substitute.[10] In addition, the omega-3 fatty acids within the acellular fish skin graft promote wound healing by functioning as an anti-inflammatory factor. Utilizing this evidence, the primary purpose of this study is to retrospectively review DFU healing with acellular fish skin graft application. To the best of the authors' knowledge, this is the largest and longest study on DFUs treated with an acellular fish skin graft. The secondary objective is to provide a systematic review on piscine grafts. Ultimately, the present results will be compared with previously published reports on fish graft use for lower extremity wounds.