Omega-3-Rich Fish Skin for Treating Diabetic Foot Ulcers

Abstract and Introduction

Abstract

Introduction: Omega-3–rich fish skin grafts have been shown to accelerate wound healing in full-thickness wounds.

Objective: The goal of this study was to compare the fish skin graft with standard of care (SOC) using collagen alginate dressing in the management of treatment-resistant diabetic foot ulcers (DFUs), defined as superficial ulcers not involving tendon capsule or bone.

Materials and Methods: Patients with DFUs who were first treated with SOC (offloading, appropriate debridement, and moist wound care) for a 2-week screening period were then randomized to either receiving SOC alone or SOC plus fish skin graft applied weekly for up to 12 weeks. The primary endpoint was the percentage of wounds closed at 12 weeks.

Results: Forty-nine patients were included in the final analysis. At 12 weeks, 16 of 24 patients' DFUs (67%) in the fish skin arm were completely closed, compared with 8 of 25 patients' DFUs (32%) in the SOC arm (P value = .0152 [N = 49]; significant at P < .047). At 6 weeks, the percentage area reduction was 41.2% in the SOC arm and 72.8% in the fish skin arm.

Conclusions: The application of fish skin graft to previously nonresponsive DFUs resulted in significantly more fully healed wounds at 12 weeks than SOC alone. The study findings support the use of fish skin graft for chronic DFUs that do not heal with comprehensive SOC treatment.

Introduction

The economic burden of diabetic foot ulcers (DFUs) remains significant in the United States. Historically, annual costs for the treatment of DFUs through Medicare alone have ranged from $6 billion to $19 billion; inclusion of the amount paid by insurance payers could place the total annual costs for DFU management in the United States at twice that level.^[1] In 2010, it was estimated that the mean cost of DFUs per episode of care from a health care public payer perspective was $17 245.^[2] A systematic review of cost-of-illness studies published in 2017 reported that the mean cost of DFUs per episode of care from a health care public payer perspective was $31 024, an amount considerably higher than the previously estimated total.^[3] Of course, the severity of the ulcer and whether it heals affects the cost; another 2017 study from Europe stated that average in-hospital costs were $10 827 USD (range, $702-$82 880) per DFU episode. On avergae, primary healed DFU costs were $4830, single minor amputations were $13 580, multiple minor amputations were $31 835, and major amputations were $73 813 per episode. Costs differed significantly between groups (P < .001).^[4] The most often cited reference on the efficacy of standard of care (SOC) showed approximately 70% of DFUs heal with SOC treatment; at least 30% become chronic wounds.^[5] In addition, SOC treatment is a lengthy process with low efficacy. The percentage of wounds healed with SOC therapy is 24.2% by 12 weeks and 30.9% after 20 weeks.^[5] Over the past 20 years, multiple prospective studies placed SOC closure rates (excluding the use of total contact casting) at 20% to 30%.^[6,7]

A chronic, nonresponsive diabetic foot wound is at high risk for infection, with the potential of leading to lower extremity amputation, even if the wound is not severe.^[8] Therefore, once a DFU forms, timely healing is necessary to stave off infection. A DFU may begin superficially and then spread to the contiguous subcutaneous tissues. Left untreated, the infection will spread to muscles, tendons, bones, and joints, and then progress to septic gangrene, which eventually leads to lower extremity amputation.^[9,10] The difference in cost between infected DFUs with and without amputation is significant, depending on the amputation level.^[4] Patients who have undergone a major amputation have a 65% 4-year mortality rate, while those who have undergone a minor amputation have a 45% 4-year mortality rate.^[11] Older studies indicated that patients who underwent a major amputation had a 68% risk of needing another amputation in the next 5 years.^[12] A 2018 study indicated an incidence of contralateral major amputation of 4.8 per 100 person years.^[13] Therefore, the availability of advanced therapies is crucial to improve healing rates, reduce the risk of amputation, improve patient outcomes, and decrease treatment costs.

Cellular and/or tissue-based products (CTPs) are increasingly used as advanced therapeutics in wound care treatment. One category of these CTPs is extracellular matrices (typically xenografts). These CTPs are made from animal tissues, such as bovine skin, porcine intestinal submucosa, and ovine stomach, and they provide structural support and biological molecules that can modulate wound healing. The microstructure of these products is highly variable, however, owing to differing tissue origins and processing methods. The device used in the present study, fish skin graft (Omega3 Wound; Kerecis), is the intact skin of Atlantic cod, which has been decellularized and sterilized. It closely resembles human skin in composition and structure. The fish skin graft is thicker, however, with a porosity and 3-dimensional microstructure that provide a foundation for efficient ingrowth of dermal and epidermal cells as well as for supporting vascularization. Moreover, the unique biomechanical properties of fish skin promote cell proliferation and differentiation, which are hallmarks for tissue regeneration.^[14]

The fish skin graft is made from the skin of wild-caught Atlantic cod originating from North Atlantic Icelandic fishery. This source yields a dehydrated product that is rich in bioactive compounds, especially omega-3 polyunsaturated fatty acids. While devoid of fish scales, fish skin graft retains 3 basic layers of skin: epidermis, dermis, and hypodermis.^[15] In 2 double-blind, prospective, randomized clinical trials of acute wound healing use of this fish skin graft resulted in significantly faster healing outcomes compared with use of porcine intestinal submucosa and dehydrated chorion amniotic membrane.^[16,17]

Several prospective and retrospective studies involving DFUs treated with fish skin grafts have demonstrated its effect on wound closure. In a study by Dorweiler et al,^[18] weekly application of the fish skin graft to 25 amputated and bone-exposed wounds resulted in closure of 17 wounds (68%) between 9 weeks and 41 weeks. A reduction of analgesics intake was also noted after initiation of fish skin graft treatment. In a study in which 8 patients with diabetes underwent forefoot surgery followed by applications of fish skin graft once a week for 6 weeks, Woodrow et al^[19] reported the wound area was reduced more than 84.9% at 6 weeks with no complications. In 2019, Michael et al^[20] published a retrospective study of 51 patients with 58 full-thickness DFUs that were treated with fish skin graft. The study compared the initial wound surface area at first application of fish skin with the final surface area after a 16-week treatment period. At the 16-week endpoint, a mean reduction in surface area of 87.57% was noted, and 35 of 58 wounds (60.34%) were fully healed. A greater than 90% reduction in surface area was measured in 43 wounds (74.14%), and a greater than 75% reduction was seen in 49 wounds (84.48%). In the 35 wounds in which full healing was achieved, the average number of applications of fish skin was 4.9 and the median time to full healing was 10 weeks.

Although these data are enlightening, this prospective, randomized, controlled trial is intended to further the research on this topic. Therefore, the present authors sought to evaluate the fish skin graft in the care of DFUs. Clearly, randomizing patients with DFUs to gauze and saline as a comparator is not appropriate. Thus, an advanced wound care product was sought. Collagen alginate dressing (Fibracol Plus Collagen Wound Dressing with Alginate; 3M) is an innovative wound dressing technology that has been established in clinical trials^[7,21] as a competitor to biologic wound products. This wound care device is composed of collagen and calcium alginate fibers. It contains 80% more collagen than the original collagen alginate dressing. The unique combination of natural biopolymers created by a patented process incorporates the structural support of collagen and the gel-forming properties of alginates into a sterile, soft, absorbent, conformable topical wound dressing. In the presence of wound fluid, collagen alginate dressing maintains a moist microenvironment at the wound surface that is conducive to the formation of granulation tissue and to epithelialization, thereby enabling rapid healing.^[22,23]

This study was designed to assess the efficacy of the fish skin graft in the treatment of resistant DFUs in comparison with collagen alginate dressings, henceforth referred to as SOC.

Table 1. Inclusion and exclusion criteria
INCLUSION CRITERIA	EXCLUSION CRITERIA
• Aged ≥18 years • Presence of a DFU extending at least through the dermis but not into tendon, muscle, or bone, provided it was below the medial aspect of the malleolus (UT grade 1A/1C) • If 2 or more eligible DFUs were present, the largest ulcer was considered the index ulcer and was the only ulcer evaluated in the study. If other ulcerations were present on the same foot, they were required to be more than 2cm distant from the index ulcer • Index ulcer present for more than 4 weeks prior to SV1 and less than 1 year, as of the date the patient consented to the study • Index ulcer ≥1cm² and ≤25cm² at SV1 and TV1 • Adequate circulation to the affected foot as documented by a dorsal TCOM or SPP ≥40mmHg, or an ABI between 0.7 and 1.3 within 6 months of SV1, using the affected study extremity. As an alternative, arterial Doppler ultrasound could be performed evaluating for biphasic dorsalis pedis and posterior tibial vessels at the level of the ankle; a TBI > 0.6 was also acceptable • The target ulcer had been off-loaded for at least 14 days prior to randomization • Females of childbearing age must have used acceptable methods of contraception (birth control pills, barriers, or abstinence) for and during the study and were willing to undergo pregnancy tests • Patient was required to understand and be willing to participate in the clinical study and be able to adhere to weekly visits	• Index ulcer(s) deemed by the investigator to be caused by a medical condition other than diabetes • Index ulcer suspicious for cancer • Index ulcer on heel • Patients with a history of treatment with immunosuppressants (including systemic corticosteroids >10mg daily dose) >2 weeks, cytotoxic chemotherapy, or application of topical steroids to the ulcer surface within 1 month prior to first SV1; who received such medications during the screening period; or who were anticipated to require such medications during the course of the study • Patients on any investigational drug(s) or therapeutic device(s) within 30 days preceding SV1 • Patients who received a biomedical or topical growth factor for their wound within the previous 30 days • History of radiation at ulcer site (regardless of time since last radiation treatment) • Index ulcer previously treated with or that may need to be treated with any prohibited therapies • Known history of poor adherence to medical treatment • Osteomyelitis or bone infection of the affected foot as verified by X-ray within 30 days prior to randomization. In the event of an ambiguous diagnosis, the principal investigator made the final decision • Pregnancy or breastfeeding • Presence of diabetes with poor metabolic control as documented with an HbA1c >12.0 within 90 days of randomization • End-stage renal disease as evidenced by a serum creatinine ≥3.0mg/dL within 6 months of randomization • Index ulcer reduced in area by 20% or more after 14 days of SOC from SV1 to the TV1/randomization visit • If extensive surgical debridement was necessary during the run-in period (eg, general anaesthesia was required), the patient was not eligible

Table 1. Inclusion and exclusion criteria

INCLUSION CRITERIA

EXCLUSION CRITERIA

• Aged ≥18 years
• Presence of a DFU extending at least through the dermis but not into tendon, muscle, or bone, provided it was below the medial aspect of the malleolus (UT grade 1A/1C)
• If 2 or more eligible DFUs were present, the largest ulcer was considered the index ulcer and was the only ulcer evaluated in the study. If other ulcerations were present on the same foot, they were required to be more than 2cm distant from the index ulcer
• Index ulcer present for more than 4 weeks prior to SV1 and less than 1 year, as of the date the patient consented to the study
• Index ulcer ≥1cm² and ≤25cm² at SV1 and TV1
• Adequate circulation to the affected foot as documented by a dorsal TCOM or SPP ≥40mmHg, or an ABI between 0.7 and 1.3 within 6 months of SV1, using the affected study extremity. As an alternative, arterial Doppler ultrasound could be performed evaluating for biphasic dorsalis pedis and posterior tibial vessels at the level of the ankle; a TBI > 0.6 was also acceptable
• The target ulcer had been off-loaded for at least 14 days prior to randomization
• Females of childbearing age must have used acceptable methods of contraception (birth control pills, barriers, or abstinence) for and during the study and were willing to undergo pregnancy tests
• Patient was required to understand and be willing to participate in the clinical study and be able to adhere to weekly visits

• Index ulcer(s) deemed by the investigator to be caused by a medical condition other than diabetes
• Index ulcer suspicious for cancer
• Index ulcer on heel
• Patients with a history of treatment with immunosuppressants (including systemic corticosteroids >10mg daily dose) >2 weeks, cytotoxic chemotherapy, or application of topical steroids to the ulcer surface within 1 month prior to first SV1; who received such medications during the screening period; or who were anticipated to require such medications during the course of the study
• Patients on any investigational drug(s) or therapeutic device(s) within 30 days preceding SV1
• Patients who received a biomedical or topical growth factor for their wound within the previous 30 days
• History of radiation at ulcer site (regardless of time since last radiation treatment)
• Index ulcer previously treated with or that may need to be treated with any prohibited therapies
• Known history of poor adherence to medical treatment
• Osteomyelitis or bone infection of the affected foot as verified by X-ray within 30 days prior to randomization. In the event of an ambiguous diagnosis, the principal investigator made the final decision
• Pregnancy or breastfeeding
• Presence of diabetes with poor metabolic control as documented with an HbA1c >12.0 within 90 days of randomization
• End-stage renal disease as evidenced by a serum creatinine ≥3.0mg/dL within 6 months of randomization
• Index ulcer reduced in area by 20% or more after 14 days of SOC from SV1 to the TV1/randomization visit
• If extensive surgical debridement was necessary during the run-in period (eg, general anaesthesia was required), the patient was not eligible

VARIABLE	COLLAGEN ALGINATE DRESSING		FISH SKIN GRAFT		P VALUE
VARIABLE	Mean (SD)	Median (IQR)	Mean (SD)	Median (IQR)	P VALUE
Age, y	60.68 (11.87)	61 (52–68)	56.67 (11.18)	58 (48.5–64)	.2842
Height, in	68.13 (4.07)	69 (65.5–71)	69.22 (4.78)	69 (66–72)	.4744
Weight	220.32 (64.46)	215 (175–262)	225.82 (69.49)	202.5 (178–246)	.7169
BMI	34.59 (6.17)	34.05 (30.85–40)	33.08 (8.6)	32.61 (27.82–40)	.5808
HbA1c	7.83 (2)	7.4 (6.2–8)	13.16 (20.42)	7.8 (6.7–8)	.8177
Creatinine	1.33 (0.7)	1.05 (0.86–1)	1.79 (1.88)	1.09 (0.92–1)	.93
TV at baseline	4.59 (4.49)	2.6 (1.83–6)	3.89 (3.28)	2.13 (1–4)	.4356

A Multicenter, Blinded, Randomized Controlled Clinical Trial Evaluating the Effect of Omega-3–Rich Fish Skin in the Treatment of Chronic, Nonresponsive Diabetic Foot Ulcers

Abstract and Introduction

Abstract

Introduction

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

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