Fish skin acellular dermal matrix: potential in the treatment of chronic wounds

Figures & data

Figure 1 Spectrum of extracellular matrices.

Figure 2 Increased acute wound closure rate seen with AFS over SIS in an acute wound care model.

Notes: Baldursson BT, Kjartansson H, Konrádsdóttir F, et al, 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 (14[1]) pp. 37–43, copyright © 2015 by (SAGE Publications). Reprinted by Permission of SAGE Publications, Inc.¹²
Abbreviations: AFS, acellular fish skin; SIS, small intestine submucosa.

Figure 3 Increased acute wound closure rate seen with AFS over dHACM in an acute wound care model.

Notes: There is a particular difference in wound healing rate seen on days 21 and 25. Reproduced from Lantis II JC, Petursdottir K, Baldursson B, Kirsner RS, Double-Bline WD. Prospective, randomized clinical trial on 170 acute wounds shows significantly faster healing rate with intact fish skin Compared to human amniotic membrane. Presentation at a conference. American Professional Wound Care Association (APWCA) sept 6–8, 2018 in Baltimore, MD, USA.¹³
Abbreviations: AFS, acellular fish skin; dHACM, dehydrated human amnion/chorion membrane.

Figure 4 Efficacy of AFS as a bacterial barrier and the increased efficacy seen with the addition of greater omega-3 fatty acids.

Notes: Magnusson S, Baldursson BT, 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, Mil Med, 2017, 182, S1, 383–388, by permission of Oxford University Press.¹⁴
Abbreviation: AFS, acellular fish skin.

Figure 5 Clinical use of antibiotics before and after the application of AFS in a cohort of chronic wound patients.

Note: Reproduced from Lantis II J, Baldursson B, Magnusson S, Kjartansson SG. Acellular fish skin graft for surgical, trauma, venous and arterial and diabetic wounds: a retrospective clinical study. Paper presented at: 17th Congress of the Asian Society for Vascular Surgery; October 20–23, 2016; Singapore.¹⁵
Abbreviation: AFS, acellular fish skin.

Table 1 Studies evaluating the use of AFS in wound healing

	Study	Title	Study design	Objective	N	Population	Results	Conclusion	Dosage
Fish skin as a treatment for autograft donor sites	Alam and Jeffery^Citation27	The use of omega3 rich fish skin xenograft in the treatment of STSG (splitthickness skin grafting) donor sites	Case study	To test fish skin as a donor-site treatment in patients undergoing skin autografting	10	Patients undergoing split-thickness skin grafting for burn injury	Time to 90% epithelialization was an average of 8.5 days (range 7–13). Time to 100% epithelialization was an average of 11.5 days (range 10–16)	Both the analgesic effect noted and the relatively short average times until 100% reepithelialization are promising and need to be studied further	2–4 applications
Fish skin for complicated wounds	Dorweilier et al^Citation22	Die marine Omega 3 Wundmatrix zur Behandlung komplizierter Wunden	Case series	To report the cumulative experience of three centers for vascular surgery regarding use of fish skin in wound therapy	23	Patients with vascular diseaseand/or diabetes mellitus-associated complicated wounds and partially exposed bony segment wounds	The time to healing varied between 9 and 41 weeks. A reduction of analgesics uptake was noted following fish skin treatment	Fish skin is beneficial to healing with added benefits such as reduced nociception/ analgesic consumption, as well as being a possible treatment option in an outpatient setting	9 applications on average
Improved granulation in wounds with poor circulation	Clasen et al^Citation23	When the fish gives the thrust-granulation tissue in case of poor circulation	Case series	To assess fish skin as a remedy for poor granulation in chronic wounds	3	The three cases were all caused by different pathologies: chronic infection, diabetes mellitus with atherosclerosis, and critical ischemia	Granulation tissue formation was induced in all cases. A complete pain relief was seen in morning VAS after 1 week for patient with chronically painful ulcer	Fish skin grafts successfully kickstarted granulation in all of the wounds	1–5 applications
Fish skin in painful, chronic wound	Cyrek et al^Citation24	Local wound therapy of a chronic resistant venous ulcer with omega 3 wound matrix; an unconventional procedure for the therapy of chronic wounds	Case study	To treat a painful, chronic, and recurrent ulceration which had not responded to several months of traditional wound therapy	1	86-Year-old female with venous insufficiency	Local wound healing with fish skin resulted in a rapid progressive wound healing with complete healing of the ulcerations within 14 weeks	Fish skin achieved a progressive wound reduction, robust granulation, and epithelialization resulting in complete long-term wound healing. A potential beneficial analgesic effect of the fish skin was noted and resulted in reduction of analgesia over time	14 applications
Fish skin for the treatment of complicated wounds: experiences associated with amputations in the lower limb in diabetic patients	Trihn et al^Citation10	Marine omega 3 wound matrix for the treatment of complicated wounds; experiences associated with amputations in the lower limb in diabetic patients	Case series	Last-resort treatment of seven wounds at the level of the thigh (n=2) and the forefoot (n=5) in order to avoid further amputation	5	Patients with diabetes mellitus and complicated wounds in the lower limb with exposed bony segments	In all wounds, a reduction of wound size of 50% could be achieved within the first third of treatment time. Thigh wounds took 26 weeks to achieve wound closure, and forefoot wounds healed at between 13 and 41 weeks. Analgesics intake was reduced for all patients after the fish skin treatment was initiated	Fish skin represents a viable treatment option for complicated wounds in the lower limb of diabetic patients to circumvent any otherwisenecessary proximalization of amputation level	Weekly application for 13–41 weeks
Efficacy of intact fish skin graft compared to dHACM	Manuscript in preparation 2018	Blinded, prospective, randomized, clinical trial on 170 acute wounds shows significantly faster healing rate with intact fish skin compared to dHACM	Double-blinded prospective RCT	Fish skin vs dHACM (MiMedx): comparison of time to heal of wholethickness biopsy wounds	85	Healthy adults	Wounds in the fish skin-treated group healed significantly faster (HR 2.37; 95% Cl: 1.75–3.22; P=0.001) compared to amnion/ chorion allograft-treated wounds	Intact fish skin may be superior to dHACM for debrided chronic wounds given its faster time to healing acute wounds	1.4 applications on average
Effectiveness of fish skin in a high risk patient with hemophilia and other comorbidities	Winters^Citation25	Wound dehiscence on a diabetic patient with hemophilia and high risk of further amputation successfully healed with omega 3 rich fish skin: a case report	Case series	To treat a unique case of dehiscence in a person with diabetes and hemophilia and dehisced chronic wound	1	A 56-year-old male with moderate factor VIII deficiency hemophilia, a history of diabetes, a fused right knee joint, and hepatitis C	Wound healed within 14 weeks after six applications of fish skin	The fish skin was effectively used to treat a chronic wound unresponsive to previous treatments	6 applications
Chronic wounds unresponsive to NPWT	Fagerdahl^Citation26	Wound care with cod skin	Case series	To treat chronic wounds in a realworld environment	16	Patients with chronic wounds which had persisted for 1–49 months (median: 7.3 months) and in whom traditional treatment with NPWT had failed	75% of the wounds healed within the study period	There was efficient and rapid granulation tissue formation seen in many of the wounds and improved esthetic outcomes – reduced scar formation from what would be expected	3 applications on average
Prospective evaluation in chronic hard-to-heal lower-extremity ulcers	Yang et al^Citation11	A prospective, singlecenter, non-blinded, non-comparative, post-market 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	Case series	To test this product in a real-world environment, focusing on hard-to-heal ulcers based on previously defined wound and patient factors	18	Chronic wound patients with at least one “hard-to-heal” criterion	A 40% decrease in wound surface area (P<0.05) and a 48% decrease in wound depths (P<0.05) were observed. Complete closure was seen in three of 18 patients by the end of the study phase	Fish skin is a promising wound-closing adjunctive ECM in this compassionate setting, where many other products may fail	Weekly application for 5 weeks
Testing of safety and efficacy of fish skin for wound care	Baldursson et al^Citation12	Healing rate and autoimmune safety of full-thickness wounds treated with fish skin acellular dermal matrix vs porcine small-intestine submucosa: a noninferiority study	Parallel-group, double-blinded RCT	Fish skin vs porcine SIS ECM (Oasis): comparison of time to heal of wholethickness biopsy wounds	81	Healthy adults	Fish skin showed accelerated wound healing with significantly (P<0.05) more wounds fully healed on days 14, 21, and 25 when compared to pig allograft	Healing time of wounds dressed with fish skin was noninferior to the healing time of wounds dressed with porcine SIS ECM	NA

Abbreviations: AFS, acellular fish skin; dHACM, dehydrated human amnion/chorion membrane; ECM, extracellular matrix; NA, not available; NPWT, negative-pressure wound therapy; RCT, randomized controlled trial; SIS, small intestine submucosa.

Figure 6 Mean wound surface area as noted during the 5-week AFS treatment and 3-week follow-up of venous leg ulcers.¹¹

Notes: *indicates statistic significance. Reproduced with permission from Yang CK, Polanco TO, Lantis 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):112–118. Copyright 2019. Wounds.¹¹
Abbreviation: AFS, acellular fish skin.

Table 2 Likelihood of healing by prognostic factors

Size >2 cm^2	Ulcer grade ≥3	Duration >2 months	Modeled expected likelihood of healing
			0.66
×			0.52
		×	0.53
	×		0.47
×		×	0.33
×	×		0.31
	×	×	0.38
×	×	×	0.22

Notes: The table shows the likelihood that a wound with a given prognostic factor or combination of prognostic factors will heal after 20 weeks. X denotes the presence of one of the prognostic factors.

Figure 7 (A) Post-debrided foot with exposed bone. (B) Completion of transmetatarsal amputation. (C) Placement of AFS. (D) Post-op day 4 with no negative-pressure wound therapy. (E) Three weeks after grafting.

Abbreviation: AFS, acellular fish skin.

Figure 8 Levels of omega-3 and omega-6 fatty acids in various products with y-axis being the percent of fatty acid and x-axis being the type of fatty acid.

Note: Reproduced from Lantis J, Magnusson S, Baldursson B, Kjartansson H, Rolfsson O, Sigurjonsson G. Fish skin omega-3 PUFAs induce cell migration and transcription of ALOX15, a specialized pro-resolving mediator forming lipoxygenase. Paper presented at: SAWC Fall; October 20–22, 2017; Las Vegas, NV.¹⁸

Table 3 Porcine burn model treatment groups

Group number	Burn depth (day 1)	Primary treatment after excision of dead tissue (day 0)	mSTSG application (day 7) (meshing ratio)	Second application of Kerecis (day 7)
1	Full thickness	Kerecis	Yes (1.5:1)	No
2	Full thickness	Kerecis	Yes (3:1)	Yes
3	Full thickness	Cadaver skin	Yes	No
4	Deep partial thickness	PriMatrix	No	No
5	Deep partial thickness	Kerecis	No	Yes

Abbreviation: mSTSG, meshed split thickness skin graft.

Figure 9 Progression of porcine wound closure when treated with AFS with and without skin grafting.

Abbreviations: AFS, acellular fish skin; DPT, deep partial thickness; FBC, fetal bovine collagen.

Baldursson BT, Kjartansson H, Konrádsdóttir F, et al. 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.

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Magnusson S, Baldursson BT, 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. Mil Med. 2017;182(S1):383–388.

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Alam K, Jeffery SLA. Acellular fish skin grafts for management of split thickness donor sites and partial thickness burns: a case series. Military Medicine. 2019;184(1):16–20.

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Clasen TJ, Libich E, Feldmann M. When the fish gives the thrust-granulation tissue in case of poor circulation. Wound Manag. 2017;11(4):183–186.

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Trinh TT, Dünschede F, Vahl C-F, Dorweiler B. Marine omega3 wound matrix for the treatment of complicated wounds. Phlebologie. 2016;45(02):93–98.

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Yang CK, Polanco TO, Lantis 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):112–118.

 Web of Science ®Google Scholar