Consensus Recommendations for Optimizing the Use of Intact Fish Skin Graft in the Management of Acute and Chronic Lower Extremity Wounds

LEWs, regardless of their location or classification, pose a severe, rapidly increasing socioeconomic burden worldwide.^1-7 Observational studies from 2000 to 2018 demonstrate a pooled prevalence of 2.21 per 1000 population for chronic wounds and an estimated prevalence of 1.51 per 1000 population for chronic leg ulcers.⁸ A report from the United Kingdom indicates that wounds contribute approximately £5 billion in health care costs annually.⁹ In the United States, for the 15% of Medicare beneficiaries who have wounds (8.2 million beneficiaries), upper range estimated total spending for all wound types was $96.8 billion in 2014, with surgical wounds accounting for the bulk of the cost (upper range estimate, $38.3 billion).¹⁰ 

Chronic wounds reportedly affect approximately 13% of the global population (42.5 million)^11,12; such wounds place an enormous strain on health care systems worldwide. For VLUs alone, 11-year data ending in 2017 in the United Kingdom revealed an annual expense of over £2 billion.¹³ In Australia, the average weekly cost per patient for treating VLUs ranged from A$214.61 to A$294.72.¹⁴ In the United States, it has been reported that over $20 billion is spent annually on wound care.¹¹ In 2014, the annual economic burden of VLUs in the United States was estimated to be $14.9 billion,¹⁵ a skyrocketing increase from 15 years earlier when the reported spend was only $1 billion.^16-18 None of these reported costs include the loss of productivity of affected individuals and their caregivers and family members, or the diminished quality of life of all involved; these costs further increase the already high cost to society of chronic wounds.¹¹ 

In the United States, wounds are classified based on the causative etiology, that is, diabetes, venous insufficiency, traumatic, or atypical.^18-22 Wound presentation can be acute or chronic. Chronic wounds are defined as those that do not progress through the 4 phases of healing in a timely manner and thus deleteriously affect the site of injury, often resulting in further damage^3,23 or even opportunistic infection.²⁴ Chronic wounds are notoriously difficult to treat and often are extremely debilitating, leading to comorbidities such as immobility, depression, anorexia, anemia, and even dementia; hospitalization is often necessary.¹⁹ 

To improve patient quality of life, in addition to preventive care through patient education,²⁵ the management of LEWs involves strict protocols and wound care, which is often quite difficult for the patient.²⁶ Complete closure of chronic cutaneous wounds can be a complex, multifaceted process, with many factors influencing both the quality of and time to healing.^27,28 Best clinical practices focus on debridement, offloading, compression, and infection prevention and control while managing the underlying disease process. The current guidelines for DFUs and VLUs are relatively well-established and include tissue-based therapy.²⁹ Although the materials used are bioengineered³⁰ and synthetically manufactured,³¹ they can derive from natural sources, comprising extracellular matrices from humans or animals.³² One animal-derived material (ie, xenograft) is IFSG (Kerecis MariGen, Kerecis LLC) derived from North Atlantic cod. The proprietary process of manufacturing IFSG relies on the structural and chemical resemblance between cod skin and human skin.^33-35 This process preserves the fish skin’s original form and natural composition.³⁶ Yoon et al³⁷ demonstrated the desired effect of the naturally porous microstructure of IFSG, which promotes efficient ingrowth of dermal and epidermal cells and capillaries. Moreover, the richness in eicosapentaenoic acid and docosahexaenoic acid omega-3 fatty acids of North Atlantic cod skin has shown anti-inflammatory properties,^38-40 which makes IFSG ideal for treating various wounds,⁴¹ especially acute and chronic LEWs.

A published prospective, randomized trial on University of Texas grade 1A/1C DFU provides some direction on how to use the product in that population.⁴² However, at the time of this writing no best practices or clinical guidelines have been published on how to best use IFSG in LEWs. Thus, the authors of the current paper—physicians with extensive clinical experience using IFSG in the management of LEWs—developed consensus recommendations on how best to use the therapy. The primary goal of this article is to help clinicians provide optimal patient care when using IFSG in the management of LEWs based on the authors’ clinical experience as well as their review and knowledge of the current literature and recommendations. Additionally, it is hoped that this consensus will spur future efforts to further define and expand the recommendations for using IFSG in order to identify evidence-based best practices and standardize and disseminate treatment approaches globally. 

These are not intended to be guidelines as the recommendations are not coming from a recognized body, this is a consensus statement based upon the current literature and the extensive experience of recognized experts in this area.⁴³ 

Consensus panel participants

The consensus panel (all coauthors of this article) comprised 8 clinicians who are recognized experts in the field of LEW care and who use IFSG clinically (Table 1). The panel and chair have a median 21.5 years of wound care experience and a median 6.5 years of experience using IFSG. The panelists have a median of 2 published articles or poster presentations on IFSG and a median of 16.75 publications in wound care. The programs represented were equally in academic and nonacademic institutions, with 75% located in an urban setting. The chair is a general and vascular surgeon who is also a professor of surgery. The panel comprised a plastic surgeon, a dermatologist, a family practitioner, 2 podiatrists, and 2 physical therapists. The panel evaluated the results of the literature search and used their personal experience and knowledge to complete the initial online survey and to identify and draft the initial consensus recommendations. These statements became the framework for the discussions that led to the final recommendations.

Evidence to support the consensus recommendations

The pertinent tasks of the chair were to lead a systematic literature search to identify all English-language publications that investigated the use of IFSG for the treatment of LEWs, categorize the resulting main types of LEWs treated, and create questions for NFG discussions if any were left unanswered by the literature. A search of PubMed, ScholarOne, and GoogleScholar databases was conducted prior to the October 2021 meeting. There was no date range, as North Atlantic cod has only been commercially available for less than a decade; the terms searched included: “fish skin,” “piscine graft,” “fish tissue,” “intact fish skin graft,” “Cod skin,” “Omega 3 fatty acid graft.” 

Consensus methodology

A qualitative methodology was used based on the NFG technique.⁴⁴ This method combines a Focus Group exploration and the Nominal Group Technique. Together, these methods allow for in-depth data generation and the development of statements on several topics by ranking (ie, voting), all critical for the quality of the consensus impossible to achieve by a single method. Additionally, NFG is more effective and efficient than other consensus methods, such as the Consensus Development Conference method and Delphi method, which, respectively, require an organization of specific events spanning several days⁴⁵ or disallow panel members for in-person meetings.⁴⁶ 

The authors of the current study performed 2 cycles of the NFG process to develop the consensus statements (Figure 1). Stage 1 included the initiation process, in which the preliminary research and questions were formulated. Stage 2 involved reviews of the literature, evidence, and questions. Stage 3 was subdivided into 2 phases. In stage 3a, the first FG discussion was held to generate the main content, which was then transcribed. Stage 3b involved the first online survey in which statements were voted on and ranked to create the initial consensus statements. The steps in stage 3 were repeated in stage 4 to further discuss (stage 4a), then vote on and rank the statements (stage 4B). Stage 5 consisted of finalizing the consensus document.

Preparations (stages 1 and 2). All panelists participated in a literature search and review on LEWs and IFSG (stage 1); this effort was led by the chair, who has published several literature reviews on IFSG. The results of this effort led to the creation of statements that allowed for the development of consensus around using IFSG to manage chronic LEWs of various etiologies. Before the first in-person meeting of the expert panel (round 1) (ie, FG), information on wound types and the previously mentioned questions were emailed to all panelists on behalf of the chair (stage 2).

Focus groups (stages 3a and 4a). The panel met at the Symposium on Advanced Wound Care Fall 2021 on October 31, 2021, in Las Vegas, Nevada, and the Symposium on Advanced Wound Care Fall 2022 on October 16, 2022, in Las Vegas for the first and second FG meetings, respectively. The first FG in 2021 (stage 3a) involved a discussion of the literature search findings and initial questions, and during the second (FG, in 2022) (stage 4a) the panelists discussed the results of the first online survey voting. Each FG was moderated by the panel chair in a single session of nearly 3 hours with a 10-minute break. Each FG session was audio-recorded. 

Online surveys (stages 3b and 4b). The survey questions were generated from the transcript of the first in-person meeting and circulated by the chair. For both online surveys, panel members were invited to vote on and rank the importance of the consensus statements developed at the preceding FG meeting. The surveys used a 5-point Likert scale, with 5 = strongly agree, 4 = agree, 3 = neither agree nor disagree, 2 = disagree, and 1 = strongly disagree. Each statement was assigned a degree of consensus based on its score (sum of Likert scores × number of voters), which was then assigned 1 of 3 strength levels: full strong consensus (100% agreement [score of 35]), full consensus (80%-99% agreement [score of 28-34]), and no consensus (<80% agreement [score of <28]). Statements with full and full strong consensus (80%-100% agreement) were included in the final report of consensus statements. 

Likert survey scale responses were represented numerically as a distribution ratio (agreed/neither agreed nor disagreed/disagreed) and as a cumulative consensus percentage. In addition, the importance of each statement was categorized, with *** = most important, ** = moderately important, and * = least important. Finally, statements were grouped by wound type, order of importance (most to least), and percentage consensus (highest to lowest).

Consensus statements finalization (stage 5). A final report was created, supported by scientific evidence wherever possible.

Data analysis

The audio data were transcribed by a professional medical writer (Mr Daniel Coaten); after which relevant data were extracted and categorized and then finalized into consensus statements. These statements and categories were then reviewed by the chair prior to being distributed to the NFG.

Generation of initial and revised consensus statements

The chair performed a systematic literature review of all English-language articles to identify the use of IFSG in the treatment of acute and chronic LEWs generally as well as specific types of LEWs. No date range was placed due to the short duration during which IFSG has been available. Wounds identified included DFUs, VLUs, atypical, and traumatic. The following questions and statements of interest emerged:

1. Are there appropriate guidelines or clinical evidence to support the use of IFSG in this LEW group?

2. What is your strategy for utilizing IFSG when treating these types of wounds? (Best practice?)

3. Where does IFSG fit into your treatment paradigm? (Dosing schedule?) 

4. Can there be reasonable expected outcomes in the treatment of these wound types? 

5. What, if any, adjunctive modalities can one use with IFSG? 

The 2 cycles of the NFG process resulted in a total of 43 statements after the second meeting, down from 52 statements at the initial meeting. The final statements include 5 groups of recommendations for the clinical use of IFSG, with general recommendations as well as recommendations for each of the 4 wound types identified (ie, DFU, VLU, atypical, traumatic), incorporating current evidence from the literature and panel experts’ clinical experience (Tables 2-6). Individual statements are classified by wound type and include the associated Likert scale responses and the percentage of consensus achieved after FG rounds 1 and 2. 

General recommendations

The expert recommendations for the optimal use of IFSG regardless of LEW type are shown in Table 2. 

The most significant general recommendation for using IFSG is to determine the etiology of the wound by performing a thorough clinical evaluation and reviewing the results of all related tests. Continuous communication between all involved caregivers is emphasized. The wound must be adequately prepared prior to applying IFSG. The entire wound bed should be debrided as appropriate for the wound type and characteristics; for example, chronic wounds require aggressive subcutaneous debridement. It is critically important that IFSG not be applied in the setting of untreated infections. 

Before using IFSG, the material must be hydrated with enough saline to ensure proper contour and to maximize wound contact, then fixed in place using either adhesive strips or sutures (or, in some cases, staples) combined with a nonstick bolster dressing. The material can be sewn into the base of the wound, as necessary. Although IFSG ultimately engrafts into the wound, occasionally remnants of IFSG remain (ie, white fragments or wound caramelization after debridement). It is crucial to identify these remnants and not disturb or remove them. Periwound hygiene is essential to prevent infection. Notably, IFSG is also effective in full-thickness wounds with exposed structures (eg, bone, tendon). When IFSG is used in combination with NPWT at 75 mm Hg to 125 mm Hg, more rapid than normal engraftment may occur.

Diabetic foot ulcers

The expert panel’s recommendations for the use of IFSG in the management of DFUs are shown in Table 3. The most significant recommendation for the use of IFSG in the management of DFUs is adherence to standard of care practice and appropriate offloading, as well as assessment of adequate wound perfusion. Thus, IFSG is not advised for plantar wounds unless they are appropriately offloaded. 

Adequate debridement is mandatory before the initial application of IFSG. The recommendations highlight the imperative of weekly evaluation visits to assess healing progress and the need for re-debridement prior to reapplication of IFSG, the importance of a bolster dressing, and the need for up to 6 applications to achieve closure (Figure 2). If any IFSG remnants are seen in the wound bed at the time of planned reapplication (Figure 3), they may be left in place and reapplication deferred until the next visit. If wound area reduction of greater than 50% is not achieved after 4 applications of IFSG, it is recommended to stop using IFSG, reassess the wound, and reevaluate the treatment strategy. For wounds with a larger surface area or for exudative wounds, or when also applying NPWT, a fenestrated IFSG is recommended. 

Venous leg ulcers

The panel reached a consensus decision for the use of IFSG in the management of VLUs (Table 4). The most important recommendation is to use multilayer compression for 4 weeks prior to applying IFSG (Figure 4). If the wound area does not reduce in size by 40% to 50% at the end of 4 weeks, IFSG can be introduced. Venous imaging and a thorough arterial assessment are necessary in the diagnosis of VLU. Initial debridement is mandatory in preparing the wound for IFSG application, with consideration for pain management or hybrid debridement techniques, especially in the setting of often painful, chronic forms of VLU. A standard sheet of IFSG with minimal trimming at the edges can be used to approximate the wound edges; nonstick coverage and sterile adhesive strips are used. The frequency and type of further debridement should be based on the patient’s clinical progress. Weekly reapplication of IFSG in conjunction with multilayer compression can aid wound healing. If appropriate edge migration has not occurred after 4 applications of IFSG, it is recommended to stop using the graft, reassess the wound, and reevaluate the treatment strategy. The closure strategy depends on the initial wound size. For wounds with a larger surface area, IFSG can be used as a bridge to epithelialization surgery, primarily autogenous skin grafting, whereas in smaller wounds, it can lead directly to closure. Use of fenestrated IFSG can help avoid fluid buildup under the graft.

Atypical wounds

The panel reached a consensus decision for the use of IFSG in the management of atypical wounds (Table 5). The top recommendation is to implement standard practices prior to applying IFSG (eg, possibly compression therapy, NPWT early and adequate initial debridement at the time of biopsy). For patients without diabetes, hemostasis, or recent trauma, an early biopsy can be valuable, followed by treatment of the underlying wound etiology (eg, rheumatoid arthritis, lupus, hematologic disorders). Depending on the severity of anticipated pain during debridement, higher doses of anesthetics may be required for wound preparation before applying IFSG. Initial surgical debridement is generally preferred for adequate pain control. Atypical wounds often undergo much less frequent debridement compared with other wound types—even with reapplication of IFSG—owing to the severe pain experienced by the patient. Based on the literature that supports pain reduction at skin graft donor sites, some believe (although this is not strongly supported by evidence) that using IFSG may reduce pain in these patients.⁴⁷ However, it was noted by the NFG members that a thorough initial debridement is necessary, which allows for less frequent follow-up debridements. 

Traumatic wounds

The panel reached a consensus decision on the use of IFSG in the management of traumatic wounds (Table 6). Each traumatic injury is unique, and treatment should be tailored accordingly. Thus, the most important consideration is to ensure multidisciplinary supportive care, including maximizing nutrition and stabilizing any underlying medical or orthopedic conditions. Early, adequate, and wide debridement is recommended for wound preparation. However, unlike in the previously described wound types, IFSG should not be applied at the time of initial debridement. Instead, application should be delayed for a few days to allow clinical demarcation. In general, reapplication of IFSG in a stable trauma patient results in more rapid definitive surgical closure (average of 2 applications). In the majority of traumatic wounds, especially larger wounds, the use of fenestrated IFSG in combination with continuous NPWT for 72 to 96 hours is recommended, and early dressing change is advised. 

The final recommendations of the panel summarize the consensus of expert users of IFSG in the United States, based on their experience and on current evidence in the literature. The final recommendations are grouped into 5 categories: general, DFUs, VLUs, atypical wounds, and traumatic wounds.

Diabetic foot ulcers

A recent study showed IFSG to be effective in the management of Wagner grade 1 and 2 DFUs.⁴² In that randomized controlled trial of 102 patients, the use of IFSG was significantly more likely to result in wound closure within 12 weeks compared with the use of collagen alginate therapy. In the IFSG group, the median time to wound closure for those wounds which closed was 7 weeks. To achieve this, it required an average of 6 applications per wound. The percentage wound area reduction was 86.3% with IFSG versus 64.0% for standard of care at 12 weeks (P < .5) (Figure 2). This study also supports many of the panel’s recommendations, such as for comprehensive patient examination, appropriate vascular assessment, adequate early debridement, and serial reapplication in conjunction with offloading. 

Venous leg ulcers

Few prospective trials have been published on the use of IFSG or other CAMPs in the management of VLUs. A very early prospective study showed that 92% of the 25 VLUs treated with IFSG improved in wound area over 4 weeks; 24% closed and 68% improved. Of note, patients treated with IFSG also required fewer antibiotics.⁴⁸ A more recent prospective study evaluated the use of IFSG in the management of so-called hard-to-heal lower extremity chronic ulcers and showed a significant reduction (P < .05) in wound surface area (40%) after 5 weeks of treatment (weekly application of IFSG)⁴⁹ (Figure 4). These ulcers had not reduced in size at all with over 4 weeks of compression. The patients underwent diagnostic venous and arterial imaging, after which all underwent 4 weeks of multilayer compression prior to the initiation of the application of IFSG. An attempt was made to adequately debride the wounds initially, and serial application of IFSG augmented closure and pain relief in very recalcitrant ulcers. The method of using IFSG in these studies was integrated into the panel recommendations.

Atypical wounds

Atypical wounds are those that do not fit into any of the other typical wound categories (ie, venous, arterial, mixed or pressure ulcers, DFUs).^50-52 Atypical wounds are estimated to comprise approximately 20% to 25 % of all chronic wounds.^53-55 Wounds are considered atypical if they display an abnormal presentation, occur in an unusual location, are painful beyond the wound area (in some cases, excruciatingly so), or do not heal within 4 to 12 weeks with suitable treatment.^50,52,56 Owing to the unusual nature of these wounds, correct diagnosis often may be missed or delayed during the differential diagnosis process, which may contribute to prolonged healing times, impaired quality of life,⁵⁷ and ultimately, higher mortality rates.^58-60

Little has been published on the use of IFSG in the management of atypical wounds. However, there is some literature on the use of similar products, and some of those recommendations may be transferrable and applicable to the use of IFSG. For example, one study showed a 42.3% closure rate at a mean time to healing of 220.9 days using bovine collagen-glycosaminoglycan matrix (IDRT) in the management of atypical LEWs.⁶¹ It also cites a 23% closure rate if a tissue product is not used,  and recommends using a STSG in combination with this advanced wound treatment, to date IDRT with STSG may offer the best published results in healing atypical ulcers, such as with an autoimmune etiology. 

The panel members believe that results would be similar with the use of IFSG. Clinician experience and anecdotal patient reports suggest that IFSG performs quite well in the management of atypical wounds. Furthermore, IFSG also appears to possess additional anti-inflammatory and mild local analgesia properties. The exact mechanisms of these properties are not well understood; however, they likely are linked to the naturally present lipids and other preserved extracellular matrix compounds present in IFSG.³⁵ As of this writing, there are no published studies of atypical wounds treated with IFSG and thus, no published clinical data to support the panel’s recommendation. However, the panel believes that the scant literature on the use of all CAMPs in atypical wounds supports the general panel recommendations to diagnose and maximally treat the underlying disease, that biopsy confirmation is helpful, to debride judiciously, to follow up frequently (ie, weekly), and to perform less frequent wound debridement. 

Traumatic wounds

Due to the multiple locations in which trauma wounds are treated, it is difficult to obtain their incidence; looking back to the 1990s, traumatic wounds accounted for approximately 5.4% of all emergency department visits in the United States.^62,63 Whereas the etiology of traumatic wounds may be as varied as the types of wounds themselves, they usually present as one of the following types: incisions, lacerations, abrasions, shearing (degloving), cavitations, fractures, and amputations.⁶⁴ These wounds may be further classified as follows^65-69:

1. Class I: Clean. No signs of infection or inflammation. 

2. Class II: Clean-contaminated. No unusual contamination. These often involve the respiratory, gastrointestinal, or genitourinary tract. Minimal risk of infection.

3. Class III: Contaminated. Open or accidental wounds. Major break in sterile technique. Gross spillage from the gastrointestinal tract. High risk of infection.

4. Class IV: Dirty-infected. Old traumatic wounds. Wounds with necrotic tissue. Wounds with evidence of infection or perforated viscera. Very high risk of infection.

Most traumatic wounds are class III or IV. Thus, in the patient with chronic infection an acute traumatic wound may progress to a chronic wound. 

Because traumatic wounds are acute wounds of a large spectrum that has not been well studied, randomizing treatment of such wounds is a considerable challenge. In general, traumatic wounds can be high or low velocity, can be contaminated or dirty, and can involve large amounts of associated tissue injury. Moreover, traumatic injuries often occur in younger, healthier patients, with devastating consequences. Traumatic wounds can be quite challenging to treat owing to progressive tissue necrosis and potential environmental inoculation into the wounds, which may lead to a robust host response. The goal of using a tissue to facilitate closure is based on the idea that using biologic scaffolds can enhance the speed and functionality of wound closure. Iorio et al⁷⁰ performed a systematic review of the Cochrane and MEDLINE databases to identify reports of application of different matrices in wounds of the upper and lower extremities. 

Acellular fish skin was used in the management of combat-related traumatic injuries during the armed conflict between Armenia and Azerbaijan in 2020.⁷¹ Several patients received IFSG in the 2 medical missions to the combat area. Wounds included large-area full-thickness burn and blast injuries, among others. Most injuries were 3 to 5 days old, and 1 initial debridement had been performed and simple wet-to-dry dressings applied before the first application of IFSG. Some wounds were debrided a second time. In many cases, application of IFSG was followed by NPWT. At 7-day follow-up, readiness for skin grafting was assessed. The surgeons commented that wound granulation occurred several days sooner than they would have predicted using more traditional algorithms of care. No infections were reported in any cases in which IFSG was used. Most importantly, no patients underwent further amputation. Despite the aforementioned experiences and the extensive application of IFSG in trauma centers in the United States, scant literature exists on the use of IFSG in the management of acute trauma. As a result, most data are extrapolated from data on other wound types, such as complex LEWs. One example of this is a small case series of 7 patients with complicated wounds with bone exposure and amputation who were treated with IFSG covered by silicone foam dressings. Complete wound closure was achieved in all patients within 41 weeks.⁷² 

The panel recommendations rely on the literature on IFSG and other CAMPs,⁷³ including the experience reported by Reda et al,⁷¹ recognizing that each wound is unique (ie, challenging to study) and that the most significant consideration is to ensure multidisciplinary supportive care (eg, maximize nutrition, stabilize underlying medical and orthopedic conditions). Although the panel recommends early, adequate, and wide debridement to allow for clinical demarcation, IFSG should not be applied at the first debridement. Using IFSG in a stable trauma patient results in more rapid definitive surgical closure (average of 2 applications). 

This consensus report has some limitations. The consensus is expert based, but it was necessary to include the experiences of individuals rather than of a group, because there are no groups experienced in this type of treatment. The sample size of experts is small; however, it reflects a representative sample from geographically diverse wound programs in the United States that use IFSG. It is impossible to exclude moderator bias in such a setting. These are the first broad-based clinical application recommendations in the field for this graft type. As the use of this product expands worldwide, it is expected that any updates of this consensus will involve experts from other regions of the world. It is hoped that future revisions of the recommendations will address these limitations. 

The strengths of the consensus lie in equalizing power distribution within a group, promoting joined-up thinking in a diverse group, increasing shared understanding, and helping bridge individual expert differences. Bringing together experts in the field promotes broader knowledge in decision-making toward a consensus. By applying a modular structure and anonymous reporting style, the authors of the current study minimized influence bias. In addition, applying the NFG technique minimized individual influence on participants and other social factors. 

The literature search identified one IFSG on the market for LEW treatment with varied, scant evidence on its use. The authors of the current report organized the first forum in the United States to develop recommendations to guide physicians in the optimal use of IFSG.

It is important to reiterate that this document does not represent a clinical practice guideline in that it does not present “systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances,” as defined by the Institute of Medicine (now the National Academy of Medicine) primarily owing to the gaps in the data, especially dose schedule and randomized or dosing (frequency of application) studies.⁷⁴ Nonetheless, it represents a ready-to-use set of recommendations for the use of IFSG in the management of LEWs that both draw from and inform the development of the existing relevant scientific literature. The recommendations are neither static nor definitive. They will require periodic updating as further evidence becomes available.