A cellular fish skin is increasingly being used clinically, as a readily safe and effective alternative tissue source for wound repair in chronic nonhealing ulcers of many etiologies.1 Current mammalian acellular dermal matrices (ADM) raise concerns of the potential for autoimmune response, risk of prion diseases, and potential cultural or religious issues that may prohibit the use of porcine or bovine products in many countries.1 The fish-skin material has at least 2 fundamental differences from other biologic materials on the market: 1) no disease transmission risk exists from fish to humans; and 2) the product still contains fats, which are removed during processing of mammalian products. When grafted, the acellular fish skin provides a natural structure to the wound bed that contains natural skin elements and bioactive lipids, which not only acts as a scaffold for revascularization and repopulation of the patients’ cells, but provides anti-inflammatory and antimicrobial properties as well. An in vitro study comparing fish skin to a human amnion/chorion-derived product shows the fish-skin graft is an ideal platform for a 3-dimensional (3D) ingrowth of cells. The fish skin was able to support 3D ingrowth and proliferation of fibroblasts while no cell ingrowth was seen in the amnion/chorion membrane-derived product.2
In its natural state, fish skin is metabolically active and serves as a protective barrier for piscine species from their harsh aquatic environment. Basic features of fish and human skin are evolutionary conserved. The main differences between human and teleost fish skin are the presence of scales instead of hairs and a lack of keratinized layer in the fish skin.3 All scales are removed from the acellular fish-skin graft, while it still consists of 3 basic layers: epidermis, dermis, and hypodermis. In the natural state, the epidermal layer consists of an outer layer rich in microfilaments and collagen; an intermediate layer, with contents such as unicellular mucous secreting glands; and a third anchoring the basal epithelial cells layer
Following injury, mucous cells from the intermediate epithelial layer margins help close wounds by secreting lysosomes, immunoglobulin, C-reactive peptides, and lymphocytes which are transported to the damaged area.3-5 The fish dermis is a highly vascularized collagenous matrix composed of fibroblasts, pigment cells, and scales. Its primary function is to strengthen and protect skin against tensile force. The hypodermis separates the inner face of the dermis from the subjacent muscle cells, which is composed of loosely organized collagen, chromatophores, vasculature, and adipose cells.5 Neutral and acidic glycoconjugates and antimicrobial peptides (AMP) are secreted and expressed from fish skin; examples of AMPs include hepcidin, defense-like peptides, apolipoproteins, and piscidin. This secretion aids in defense against invading pathogens. Antimicrobial peptides found in fish skin have shown to repair wounds and act effectively against pathogenic bacteria, fungi, viruses, or parasites. 4
Acute wounds in healthy individuals heal through a relatively orderly, linear sequence of physiological events that include hemostasis, inflammation, epithelialization, fibroplasia, and maturation.6,7 In chronic wounds, there is an increase in metalloproteinases (MMP) activity and a decrease of their counteractive MMP inhibitors activity. There is also a decreased proliferation and responsiveness to growth factor from fibroblasts, thus leading to impaired migration of keratinocytes and impaired gap junctions, which ultimately hinder the healing process. Chronic, nonhealing ulcers are more likely to occur in patients with underlying disorders, such as peripheral artery disease, diabetes, and venous insufficiency.8-10 There is no single primary factor that contributes to impaired wound healing, but it is well known that chronic wounds usually fail to progress through the stages of wound healing and are arrested in the inflammatory stage. An excessive amount of protein mediators, such as proinflammatory cytokines, play a prominent role in the molecular and cellular processes during the inflammatory stage of skin healing and are known to delay wound healing.11 Research has shown the effects of bioactive lipid mediators—omega-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—reduce inflammatory responses and the transmigration of proinflammatory cytokines across the endothelium.11-13 Omega-3 polyunsaturated fatty acids, EPA, and DHA are found predominately in fish skin, oils, plasma, and cellular tissues.1
The fish-skin graft is a decellularized fish skin harvested from codfish in the North Atlantic. It is a skin substitute containing collagen, fibrin, proteoglycans, and glycosaminoglycans, with the potentially added benefits of bioactive lipid mediators. It furnishes a complex scaffold that provides an optimal environment for a favorable host tissue response, a response characterized by restoration of tissue structure and function, while delivering anti-inflammatory EPA and DHA type omega-3 fatty acids. The primary objective of this study is to assess the percentage of wound closure for hard-to-heal ulcers.