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Diabetes Watch

Can Fish Skin Grafts Have An Impact For Complex Diabetic Lower Extremity Wounds?

Diabetic lower extremity wounds have a variety of complex underlying etiologies including a combination of neuropathy, peripheral vascular disease, mechanical deformity and trauma. These wounds are often difficult to treat, particularly when healing has stalled. A myriad of advanced wound care products, biologics and skin substitutes are available today to improve the healing process when standard local wound care and offloading methods fail to obtain complete wound closure. 

Acellular matrices function as scaffolds for cellular migration, proliferation and endogenous matrix production to allow for healing and regeneration within wounds.1 These matrices are derived from various sources including natural biological sources, synthetic and composite, which is a combination of biologic and synthetic means. 

In this review, we will focus on the effectiveness of acellular xenografts in healing diabetic foot wounds and surgical dehiscences that may occur after both amputations and elective procedures, and the emergence of a fish skin graft, which has shown promising results thus far.

What Studies Reveal About The Use Of Bovine- And Porcine-Derived Xenografts

PriMatrix® (Integra LifeSciences) is a dermal collagen processed from the fetal bovine dermis. It contains a rich type III collagen, which aids in the wound healing process. This modality provides function and structure similar to autologous extracellular matrix. Clinical indications include DFUs, venous ulcers, pressure ulcers and chronic wounds. Kavros and coworkers demonstrated that PriMatrix was effective in diabetic foot ulcers with 76 percent healed by 12 weeks.2 According to another study by Strauss and Brietstein, 50 percent of DFUs healed with Primatrix despite exposed tendons and bone.3 

Oasis® Ultra Tri-Layer Matrix (Smith and Nephew) is a three-dimensional biomaterial, specifically a porcine small intestinal submucosa matrix (SIS) consisting of acellular collagen-based extracellular matrix. This biomaterial allows for native cells to infiltrate and incorporate into the wound.1,4 This dermal matrix mainly consists of types I, III and IV collagen. This SIS is indicated for and has demonstrated effectiveness for partial and full-thickness wounds, diabetic ulcers, venous ulcers, pressure wounds, and traumatic wounds, including second-degree burns, and surgical wounds.4 Contraindications include third-degree burns, sensitivity to porcine material and cases with excessive exudate, bleeding, acute swelling or infection.4 

In a randomized controlled clinical trial involving 82 patients, the SIS-treated group had a significantly greater proportion of wounds closed by 12 weeks (54 percent) in comparison to a standard wound care control group (32 percent).4

A Closer Look At Key Attributes And Indications For An Emerging Fish Skin Graft

Kerecis® Omega3 Wound graft (Kerecis), a new technology incorporating intact fish skin, is rich in omega-3 polyunsaturated fatty acids. Developed in 2009, the graft consists of skin from Icelandic cod. This graft is the only Food and Drug Administration (FDA)-approved fish skin graft on the market in the United States and aids in wound healing.5 When one applies this modality to wound beds, the graft recruits the body’s own cells and is ultimately turned into living tissue.5 The product itself acts as a bacterial barrier and promotes three-dimensional cellular ingrowth in comparison to human amnion grafts.6 

The indications for the Kerecis Omega3 Wound graft include chronic wounds, diabetic ulcerations, venous and arterial wounds, traumatic wounds and burns. Advantages of Kerecis Omega3 Wound graft include that it is non-allergenic, biocompatible, the lack of a need for a multilayered graft, enhanced cell proliferation, promotion of vascularization and it poses no cultural or religious barriers.7,8

Fish skin also reportedly compares favorably to mammalian skin products without the risk of disease transfer. In one study involving 162 full-thickness, 4 mm wounds on the forearms of 81 people, Baldursson and colleagues compared fish skin acellular dermal matrix to porcine small intestine submucosa extracellular matrix.6 In addition to finding significantly faster healing with the fish skin graft, the study authors also noted no autoimmune reactivity with the fish skin matrix. 

In a double-blind, randomized trial, Kirsner and coworkers compared the fish skin graft and a dehydrated human amnion chorion membrane allograft for the treatment of acute full-thickness wounds.9 In this study involving 170 wounds (85 punch biopsy wounds in each treatment group), the study authors found faster healing with the fish skin graft. In numerous clinical studies, the average number of applications of the Omega3 Wound graft ranged between three to five with complete healing of the wounds occurring within five weeks.7,10-14

Management of complex lower extremity wounds is challenging and multifactorial. Below we share three cases that illustrate our clinical experience with the Kerecis Omega3 Wound graft.

Case Study: Achieving Limb Salvage In A Patient With Gas Gangrene

A 61-year-old male with a past medical history of hypertension, coronary artery disease, cerebrovascular accident and uncontrolled diabetes (hemoglobin A1c of 10 percent) presented with soft tissue emphysema in the first intermetatarsal space of the right foot. 

The index procedure consisted of an incision and drainage with an open transmetatarsal amputation (TMA). Six days postoperatively, the patient underwent primary closure of the TMA. Following this primary closure, a surgical dehiscence developed at the TMA stump at 19 days post-op. Several weeks of conservative care failed to heal the wound. 

We subsequently performed a revisional TMA with application of the Kerecis Omega3 Wound graft. Due to the lack of adequate soft tissue coverage, we utilized a vessel loop-assisted closure to apply indirect tension to the wound edges and initiated negative pressure wound therapy (NPWT). At post-op week seven, the patient returned to the operating room for a repeat wound debridement and a second Kerecis Omega3 Wound graft application. We obtained complete wound closure at 150 days post-op from the initial procedure. The patient currently has no signs of recurrence or adverse events eight months after the initial TMA procedure. 

Case Study: When There Is Acute Sepsis Secondary To A Limb-Threatening Diabetic Foot Infection

A 50-year-old African American male with a past medical history of uncontrolled diabetes (hemoglobin A1c of 11.6 percent) and hypertension presented with acute sepsis secondary to a right diabetic foot infection with associated plantar arch abscess formation and soft tissue emphysema. 

We initially performed an urgent incision and drainage, and a partial fifth ray resection. Due to the soft tissue deficit and underlying osteomyelitis at the resection margin, we proceeded to perform a TMA with Achilles tendon lengthening.   

At 17 days post-op, the patient had dehiscence at the TMA site with significant skin necrosis and exposed bone. While a below-the-knee amputation (BKA) was recommended by orthopedic surgery, the patient chose to proceed with an attempt at limb salvage. 

We performed aggressive surgical debridement of nonviable tissue, applied the Kerecis Omega3 Wound graft and utilized NPWT for the remaining tissue deficit. Complete wound closure occurred 10 months postoperatively. The patient is currently 14 months post-op with no signs of recurrence or adverse events.

Case Study: Addressing Surgical Dehiscence After A First MPJ Arthrodesis and Pan-Metatarsal Head Resection

A 61-year-old male with a past medical history of uncontrolled diabetes (hemoglobin A1c of 14 percent), hypertension and human immunodeficiency virus (HIV) presented with recalcitrant plantar left forefoot ulcerations secondary to underlying osseous deformities. 

We initiated conservative treatment with local wound care and offloading via total contact casting to facilitate closure of the plantar wounds on the left foot. Upon closure of these wounds, we performed a first metatarsophalangeal joint (MPJ) arthrodesis, second through fifth metatarsal head resections and second through fifth digit arthroplasties to address the underlying deformities. 

At two weeks postoperatively, the patient presented with first MPJ incision site dehiscence and exposed hardware with underlying osteomyelitis. The patient returned to the operating room for revisional surgery including irrigation and debridement, removal of infected hardware, debridement of infected bone, application of an external fixator and Kerecis Omega3 Wound graft application. During this hospital admission, the patient also began NPWT. At five weeks post-op, we performed repeat surgical debridement and applied a second Kerecis Omega3 Wound graft. The patient subsequently received a third Kerecis Omega3 Wound graft placement at a local wound care center. 

Granulation tissue formed over the exposed bone with complete wound healing at 12 weeks after the initial arthrodesis, pan-metatarsal head resection and arthroplasty procedures. The scarring at the final follow up was significantly less than expected. The patient is now 12 weeks post-op with no signs of recurrence or adverse events.

In Conclusion

The Kerecis Omega3 Wound graft is a unique fish skin-derived graft that shows promising results in healing complex diabetic wounds as well as postoperative surgical wound dehiscence. In our case series, all three patients used an average of two grafts to complete wound closure. All patients have healed well and no complications have occurred. In our opinion, in comparison to other xenografts on the market, Kerecis Omega3 Wound fish skin graft displays rapid incorporation, the ability to granulate over deep structures including bone and tendon, and provides a robust scaffold when tissue deficit coverage is necessary. This novel fish skin graft shows promising results thus far with no adverse events noted. Further double-blinded, randomized controlled trials are recommended to determine the clinical effectiveness and utility of the Kerecis Omega3 Wound graft for wound healing. 

Dr. Hook is board-certified in foot surgery and reconstructive rearfoot and ankle surgery by the American Board of Podiatric Surgery. He is a Fellow of the American College of Foot and Ankle Surgeons, is in private practice at Midland Orthopedic Associates and is affiliated with the residency program at Mercy Hospital and Medical Center in Chicago. Dr. Hook has disclosed that he is a consultant speaker for Kerecis.

Dr. Cheema is a second-year resident at Mercy Hospital and Medical Center in Chicago.

Diabetes Watch
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By Jonathan L. Hook, DPM, MHA, and Gurleen K. Cheema, DPM
References

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2. Kavros SJ, Dutra T, Gonzalez-Cruz R, et al. The use of PriMatrix, a fetal bovine acellular dermal matrix, in healing chronic diabetic foot ulcers: a prospective multicenter study. Adv Skin Wound Care. 2014;2(8):356-362.

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