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Feature Article

Acceleration of Wound Healing Through Utilization of Fish Skin Containing Omega-3 Fatty Acids

Introduction

Normal wound healing progresses through three stages: inflammation, proliferation, and remodeling. Upon injury, hemostasis causes vascular constriction and thrombus formation. Platelets in the wound release factors that recruit neutrophils and monocytes (macrophages), which, in turn, attract lymphocytes and fibroblasts to the site of injury. The inflammation stage lasts 2-4 days from the time of injury. The proliferatory stage overlaps the inflammatory stage, starting at about the third day and lasting for several days. This is characterized by angiogenesis, collagen formation and epithelialization mediated by fibroblasts, and is complete when balance is achieved in collagen formation and its continuous breakdown by matrix metalloproteases. The remodeling stage can extend over one year’s time. At this juncture, collagen remodeling continues, fibroblasts differentiate into myofibroblasts, vascularity decreases, and tissue strength increases.1

When a chronic wound is infected, the human body releases pro-inflammatory lipid mediators and chemotactic agents, such as prostaglandins (PGs) and leukotrienes (LTs) that recruit neutrophils to the inflamed wound. The LTs and PGs then initiate a signaling cascade resulting in the destruction of pathogens while repairing injured tissue. However, in chronic wounds this acute inflammation is sustained, resulting in the chronic inflammation evident in such wounds.2 In the human body, omega-3 polyunsaturated fatty acids are a precursor to signaling molecules — the resolvins, protectins, and maresins collectively known as specialized pro-resolving mediators (SPMs). These SPMs are important for many reasons, including: 1) re-establishing homeostasis and resolution in chronic wounds; 2) their involvement in host defense, pain, and tissue remodeling;3 3) ability to induce anti-inflammatory and pro-resolving signaling pathways; and 4) their link to antimicrobial activity.4

The utilization of Kerecis™ Omega3 fish-skin graft (Figure 1) transplantation technology (especially designed for transplant into damaged tissue such as in chronic wounds) has been proven to enhance the wound care clinician’s ability to heal wounds and potentially improve the lives of some 6.5 million patients living with chronic wounds in the United States5 while potentially reducing healthcare costs. Additionally, studies show fish-skin grafts harbor many bioactive properties due to their natural lipid content and preservation of the native structure.6 The product also recruits human-adipose stem-cell ingrowth,7 acts as a bacterial barrier, and promotes significantly more three-dimensional (3-D) cell ingrowth compared to human amnion allograft.8,9 In a randomized, double-blind clinical trial, the omega-3 wound care application has promoted significantly faster healing compared to a porcine small intestinal submucosa (SIS) product (P=0.041).10 Furthermore, the fish skin reduces the need for use of analgesic medication in recent case studies11,12 and, because there are no known religious and cultural barriers to its use, the fish-skin acellular graft can help potentially underserved communities.13 These advantages further strengthen the product’s and the wound care clinician’s ability to improve the lives of patients and potentially reduce healthcare costs. twc_0516_magnusson_figure1

Healing Properties of Fish Skin

The Kerecis Omega3 is acellular intact fish skin that contains proteins, lipids (including omega-3), and other skin elements in its natural structure that fundamentally differ from other biologic products due to its structural preservation and bioactive lipid content. The omega-3 in the fish-skin graft may also help the wound escape the chronic inflammation state by giving rise to pro-resolving lipid mediators, in the opinion of the authors. The Kerecis Omega3 wound product is used to reconstruct human tissue in wounds. Kerecis Omega3 fish skin is marketed in the U.S., Europe, and Southeast Asia and has been cleared by the U.S. Food and Drug Administration (FDA). Tissue-based wound matrix products from mammals (eg, porcine, ovine, bovine, or equine origin) undergo harsh viral deactivation procedures in which detergents are used to wash all fats from the tissue, leaving behind connective tissue only. No harsh detergents are used in the processing of the fish skin and, therefore, lipids (including omega-3 fatty acids) are largely retained.6 The removal of fats in mammalian-sourced products seems to affect clinical efficacy, and in a recently published randomized controlled study on 162 wounds, twice as many wounds treated with fish skin as compared to SIS healed after 14 days.10

Compared to tissue-based products derived from humans, such as amnion/chorion membrane products, the fish skin structure is porous rather than dense. The porous structure in combination with the natural omega-3 content of the fish skin facilitates 3-D cell ingrowth into the fish skin. Unlike mammalian and human-sourced products, the fish skin possesses no risk of disease transmission10 and offers no known cultural or religious constraints for usage. The product is both halal and kosher compatible and avoids potential conflicts with Sikhism and Hinduism (Vaishnavism).13

Use of Fish Skin

The patented fish-skin graft is increasingly being used to treat wounds of various etiologies (both acute and chronic) within the U.S. After the fish-skin graft is applied to wounds it acts as a substrate for hostile proteases in the wound and, at the same time, releases anti-inflammatory omega-3 fatty acids. The fish-skin graft, which is highly porous with optimum pore size for cell ingrowth (Figure 2), recruits the body’s own cells in its structure. twc_0516_magnusson_figure2

A double-blind clinical trial showed the fish skin healed wounds faster than a porcine SIS matrix product. In this randomized, controlled study, 162 full-thickness, 4-mm wounds on the forearms of 81 subjects were treated either with fish-skin graft or porcine matrix. After 14 days, 13% of the fish skin group had healed compared to 6% of the porcine SIS matrix group. After 21 days, 72.5% of the fish skin group had healed compared to 56% of the porcine matrix. After 25 days, 77.5% of the fish skin and 65% of the porcine SIS matrix group had healed. Overall, the fish skin showed significantly faster healing (P=0.041). The same study also confirmed the fish skin does not provoke autoimmune reactivity. Participants showed no reaction to these additional enzyme-linked immunosorbent assay tests: rheumatoid factor, antinuclear antibody, extractable nuclear antigen, anti-dsDNA, anti-neutrophil cytoplasmic antibody, anti-cyclic citrullinated peptide antibody, and anti-collagen types 1 and 2.10 A recent study conducted in Germany concludes the Omega3 fish skin represents an effective treatment option for complicated wounds of the lower limb among patients living with diabetes to circumvent an otherwise necessary proximalization of amputation level. A reduction of needed analgesics was seen in all patients after fish-skin treatment began.11

A prospective compassionate clinical evaluation conducted in the U.S. concludes the fish-skin graft is effective treatment for chronic lower extremity ulcers that aren’t healing, especially when many other products fail. The same study also noted reduction in pain and drainage after treatment with the fish skin began.12 A recent case study in Sweden that included a patient living with a chronic wound for 25 years healed with the fish skin in two months. Another patient involved in the same study was healed with the fish skin in four months after living with a chronic wound for six years.14 A retrospective clinical study on 68 wounds treated with the Omeag3 fish skin exhibits 87% of the wounds either improved or healed after four weeks of treatment and none of the wounds became worse over the treatment period. None of the participants tested showed allergic response to the fish skin since the major fish allergen parvalbumin is not found within the fish skin but in the flesh of the fish.15

In the real-world setting, this new treatment option is showing dramatic results as well. In one case, a 56-year-old white male in the U.S. suffered from a wound under the first metatarsal head probing to bone with purulence. X-rays confirmed osteomyelitis and the patient had already lost his second toe. He tested positive for methicillin-sensitive Staphylococcus aureus in the wound and in his blood. The patient underwent transmetatarsal amputation in early August 2015 and was discharged within five days. Unfortunately, the wound bled uncontrollably and the patient eventually developed a dehiscence of the incision. A topical collagen dressing was applied to the wound, but the wound did not respond to treatment. The Omega3 treatment began in late September 2015 with application occurring every other week until January 2016 (six applications). By early February the wound was essentially closed (Figure 3). twc_0516_magnusson_figure3

Fish Skin Transplant Vs.Mammalian Matrix

The major differences between fish skin- and mammalian-membrane-based products include structure, bioactive lipid content, and risk of disease transmission. The Atlantic cod (Gadus morhua), which is the source of the Omega3 material, carries no risk of transmitting viral and prion diseases to humans since pathogens of fish have adapted to markedly different environmental conditions.10 Key structural features in Atlantic cod fish skin are similar to human skin16 (Figure 4). The proprietary manufacturing process preserves the native structure and composition (lipids) of the fish-skin graft. The gentle processing of the fish skin ensures the unique bioactive compounds — including bioactive omega-3 — are retained.6 Acellular mammalian-derived products have a much longer shelf life than products containing viable cells, but that advantage comes at a price. Most human infections with zoonoses come from livestock (eg, pigs, cattle, horses, and sheep), which are the sources of most other biological scaffold materials. Because of this risk of human disease transmission, mammalian-derived scaffolds require harsher chemical processing. The FDA requires them to undergo “viral inactivation.” In this process, detergents dissolve all fats from the tissue, leaving behind only the collagenous matrix structure. The harsh treatment removes lipids and other important biological components that are potentially beneficial to wound healing from the tissue.17 twc_0516_magnusson_figure4

More 3-D Cellular Ingrowth Vs. Amnion/Chorion Membrane 

The microstructure of acellular fish skin is thicker and more porous compared to mammalian matrixes and human amnion/chorion membrane tissues. The unique biomechanical properties of the fish skin and its pore size facilitates 3-D cell ingrowth, which is the first step of tissue regeneration. In in vitro tests, the acellular fish-skin grafts showed significantly more (P<0.0001) 3-D ingrowth of cells when compared to human amnion/chorion membrane allograft
(Figure 3).8,9 

The porosity of the fish skin structure and natural omega-3 content are likely to play a key role in its regenerative properties. Another in vitro study done at the U.S. Army Institute of Surgical Research showed fish skin is able to recruit ingrowth of human-adipose-derived mesenchymal stem cells.7

Barrier to Bacterial Invasion

Previous studies have shown omega-3 fatty acids possess antiviral18 and antibacterial19 properties, including the ability to act as a barrier against multidrug-resistant bacteria.20 Test results show the Omega3 fish-skin graft can act as a bacterial barrier for at least 48 hours at optimum bacterial-growth conditions. The omega-3 fatty acids might play a key role in the fish skin’s ability to act as a bacterial barrier.8

Summary

Studies on Kerecis Omega3 show fish-skin grafts harbor many bioactive properties due to natural omega-3 content and preservation of native structure. Kerecis Omega3 recruits human adipose stem cell ingrowth, acts as a bacterial barrier, and promotes more 3-D cell ingrowth compared to human amnion allograft. 

The fish skin also reduces the need for analgesic medication in recent case studies. Furthermore, because there are no known religious and cultural barriers to use, the Omega3 can potentially help underserved communities, improve patients’ lives overall, and reduce costs. 

Skuli Magnusson (sm@kerecis.com) is the corresponding author and a research associate at Kerecis. Christopher Winters is partner with the American Health Network. Baldur Tumi Baldursson is medical director at Kerecis. Hilmar Kjartansson is medical director at Kerecis. Gudmundur Fertram Sigurjonsson is chief executive officer at Kerecis. Ottar Rolfsson is assistant professor at the Center for Systems Biology at the University of Iceland. 

References

1. Guo S, DiPietro L.A Factors Affecting Wound Healing. J Dent Res. 2010;89(3):219–29. 

2. Serhan CN, Petasis NA. Resolvins and protectins in inflammation-resolution. Chem Rev. 2011;111(10):5922–43. 

3. Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014;510(7503):92–101. 

4. Maderna P, Godson C. Lipoxins: resolutionary road. Br J Pharmacol. 2009;158(4):947–59. 

5. Sen CK, Gordillo GM, Roy S, et al. Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair Regen. 2009;17(6):763–71. 

6. Magnusson S, Baldursson BT, Kjartansson H, et al. Decellularized fish skin: characteristics that support tissue repair. Laeknabladid. 2015;101(12):567–73. 

7. Magnusson S, Baldursson B, Konradsdottir F, Rolfsson O, Sigurjonsson G. Acellular fish skin supports stem cell ingrowth: acellular fish skin graft facilitates ingrowth and proliferation of stem cells. Presented at: Military Health System Research Symposium. August 2015; Kissimmee, FL. 

8. Magnusson S, Baldursson BT, Konradsdottir F, Kjartansson H, Rolfsson O, Sigurjonsson GF. Regenerative and antibacterial properties of acellular fish skin grafts and human amnion/chorion membrane: implications for tissue preservation in combat casualty care (unpublished data). 

 9. Magnusson S, Baldursson B, Konradsdottir F, Rolfsson O, Sigurjonsson G. Acellular fish skin reduces wound area and allows for significantly more cell ingrowth than human amnion /chorion membrane allograft. Presented at SAWC Fall. September 2015; Las Vegas, NV.

10. Baldursson BT, Kjartansson H, Konradsdottir F, Gudnason P, Sigurjonsson GF, Lund SH. Healing rate and autoimmune safety of full-thickness wounds treated with fish skin acellular dermal matrix versus porcine small-intestine submucosa: a noninferiority study. Int J Low Extrem Wounds. 2015;14(1)37-43. 

11. Trinh TT, Dünschede F, Vahl CF, Dorweiler B. Marine omega3 wound matrix for the treatment of complicated wounds. Phlebologie. 2016;45(2):93-98.

12. Yang CK, Thais O, Polanco, MD, Lantis II JC. A prospective, postmarket, compassionate clinical evaluation of a novel acellular fish-skin graft which contains omega-3 fatty acids for the closure of hard-to-heal lower extremity chronic ulcers. Wounds. 2016;28(4):112-18.

13. Eriksson A, Burcharth J, Rosenberg J. Animal derived products may conflict with religious patients’ beliefs. BMC Med Ethics. 2013;14:48. 

14. Bentling J. Fantastiska resultat med torskskinn på sår.     SLL Innovation. 2015. Accessed online: http://sllinnovation. se/artikel/fantastiska-resultat-med-torskskinn-pa-sar

15. Magnusson S, Flanagan M, Rolfsson O, Gudmundur F, Sigurjonsson G. Healing profile and fish antibodies of 59 patients treated with acellular fish skin grafts: a retrospective clinical study. Union Vasc Soc Switzerland. 2015.

16. Rakers S, Gebert M, Uppalapati S, et al. 'Fish matters': the relevance of fish skin biology to investigative dermatology. Exp Dermatol. 2010;19(4):313–24. 

17. Hodde J, Hiles M. Virus safety of a porcine-derived medical device: evaluation of a viral inactivation method. Biotechnol Bioeng. 2002;79(2):211–6. 

18. Imai Y. Role of omega-3 PUFA-derived mediators, the protectins, in influenza virus infection. Biochim Biophys Acta. 2015;1851(4):496–502. 

19. Huang CB, Ebersole JL. A novel bioactivity of omega-3 polyunsaturated fatty acids and their ester derivatives. Mol Oral Microbiol. 2010;25(1):75–80. 

20. Mil-Homens D, Bernardes N, Fialho AM. The antibacterial properties of docosahexaenoic omega-3 fatty acid against the cystic fibrosis multiresistant pathogen Burkholderia cenocepacia. FEMS Microbiol Lett. 2012;328(1):61–9.

Feature Article
Skuli Magnusson, BSc; Christopher Winters, DPM; Baldur Tumi Baldursson, PhD, MD; Hilmar Kjartansson, MD; Ottar Rolfsson, PhD; Gudmundur Fertram Sigurjonsson, MSc
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