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Product
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Regulatory Framing
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Highest level of evidence
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Sample Documentation
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EpiFix
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HCT/P (21 CFR 1271); protective wound covering, supports healing cascade
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Retrospective case series
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The wound has failed to progress despite appropriate standard care for 30 days. Published retrospective study and case series support consideration of dehydrated amnion/chorion membrane in refractory nonhealing wounds. [EpiFix] is planned for application as a human cellular/tissue-based product under 21 CFR Part 1271, to function as a protective wound covering supporting the healing cascade and granulation tissue formation.
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In a 2013 case series (n=4), Sheikh et al. reported that dHACM (EpiFix) supported healing progression in chronic wounds of mixed etiologies (3 postoperative wound dehiscence, 1 traumatic wound) that had failed prior therapies, suggesting a role in refractory nonhealing wounds. [16]
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In 2016, Mrugala et al. reported in a case series of 5 patients with 6 chronic, nonhealing lower-extremity wounds that had failed standard care that treatment with dehydrated human amnion/chorion membrane (dHACM) allograft was associated with substantial wound area reduction and progression to complete healing in most cases, with a median time to closure of approximately 64 days and no reported adverse events. These findings support consideration of dHACM allografts used as wound coverings in the management of complex, nonhealing wounds.
[17]
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In 2018, Garoufalis et al. published a retrospective comparative study (n=117 patients) evaluating dehydrated human amnion/chorion membrane (dHACM, EpiFix) allografts in the treatment of lower-extremity wounds of multiple etiologies, including surgical wounds, pressure ulcer/injuries, arterial ulcers and traumatic wounds. Complete healing occurred in 91.1% of treated patients, with a mean ± standard deviation number of weekly applications per healed wound of 5.1 ± 4.2.
[18]
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Grafix
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HCT/P; homologous use as wound covering
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Retrospective cohort study
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The wound demonstrates inadequate healing despite standard care for 30 days. Published retrospective studies and case series support consideration of placental membranes in chronic and stalled wounds. Grafix is planned for use consistent with its homologous function as a wound covering under 21 CFR Part 1271.
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In a 2015 case series (n=3), Gibbons et al. reported that chronic wounds of multiple etiologies (including a stage 4 pressure injury, a diabetic foot ulcer, and a traumatic wound) that had failed prior advanced therapies progressed to healing following standard of care and adjunct application of cryopreserved placental membrane (Grafix) used as a wound covering. These findings support consideration of placental membrane allografts in complex, nonhealing wounds.
[19]
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In 2017, Johnson et al. published a retrospective comparative outcomes analysis of 79 patients with 101 wounds of multiple etiologies, including chronic, surgical, diabetic, and pressure ulcers/injuries, treated with either viable cryopreserved placental membrane (vCPM; Grafix, n=40) or dehydrated amnion/chorion membrane (dHACM, n=39). The study reported significantly higher wound closure rates following standard of care combined with application of vCPM (63.0%) compared to standard of care and dHACM (18.2%), despite treatment of larger wounds.
[20]
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In a 2019 multicenter retrospective case series (n=78 patients, 98 wounds), Ananian et al. reported that chronic wounds of multiple etiologies (including diabetic, venous, surgical, and other wound types) achieved an overall closure rate of approximately 59% following standard of care and adjunct use of lyopreserved placental membrane containing viable cells (GrafixPL PRIME), with no treatment-related adverse events. Outcomes were comparable to those previously reported for cryopreserved placental membranes. These findings support consideration of placental membrane allografts used as wound coverings, consistent with their homologous function, in the management of complex, nonhealing wounds.
[21]
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TheraSkin
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HCT/P; repair/replacement of human skin
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Retrospective cohort study
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The wound has not demonstrated adequate healing progression despite appropriate care for 30 days. Published retrospective cohort studies support consideration of cryopreserved human skin allografts in chronic wounds. [TheraSkin] is planned for application for the repair of human skin under 21 CFR Part 1271.
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In 2019, Gurtner et al. published a large retrospective propensity-matched cohort study (n = 3,994 lower-extremity wounds) evaluating a cryopreserved human skin allograft (TheraSkin) in conjunction with standard of care (SOC) compared to SOC alone across wounds of multiple etiologies including diabetic, lymphedema, pressure ulcer/injury, radiation, surgical wound, trauma, venous and arterial ulcers. The study demonstrated that TheraSkin + SOC was associated with significantly higher healing rates (68.3% vs 60.3%), greater percent area reduction (78.7% vs 68.9%), fewer
amputations, lower recidivism, and higher treatment completion compared to SOC alone.
[22]
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Kerecis
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510(k); broad wound indications
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Prospective, single-arm (uncontrolled) case series
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The wound has failed to progress despite appropriate standard care for 30 days. Published clinical studies support consideration of fish skin grafts in complex, nonhealing wounds. [Kerecis] is planned for use consistent with its FDA-cleared indications for management of partial- and full-thickness wounds.
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In 2016,
Yang
et al. published a prospective postmarket compassionate clinical evaluation (n = 18 patients) of an acellular fish skin graft (Kerecis) in conjunction with standard of care (SOC) for hard-to-heal lower-extremity chronic ulcers that had failed prior therapies. Patients received SOC and weekly applications of the graft, resulting in a significant reduction in wound surface area (~40%) and wound depth (~48%) after 5 weeks, with progression toward closure observed in treated wounds and no product-related adverse events.
[23]
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In 2021, Tan et al published a case report describing a renal transplant recipient with calciphylaxis-associated chronic skin ulceration, a severe form of ischemic and necrotic soft tissue injury, that had failed prior standard therapies. The patient was treated with intralesional sodium thiosulfate, intravenous sodium thiosulphate and fish skin graft in conjunction with standard of care (SOC), resulting in progressive wound healing and resolution of cutaneous lesions.
[24]
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In 2023, Tickner et al. published an expert consensus statement based on a structured nominal focus group process involving 8 wound care specialists, synthesizing available literature and clinical experience to generate 43 consensus recommendations for the use of intact fish skin grafts (Kerecis) in conjunction with standard of care (SOC) for acute and chronic lower extremity wounds of multiple etiologies, including diabetic foot ulcers, venous leg ulcers, traumatic wounds, and atypical wounds. The recommendations emphasize adherence to SOC - including debridement, offloading, compression therapy, and vascular assessment - prior to initiation of fish skin graft therapy, and support its use as an adjunctive treatment in chronic wounds that fail to demonstrate adequate healing after approximately 4 weeks of SOC.
[25]
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In 2025, Dinter et al. published a retrospective observational real-world study (n = 34 patients, 50 chronic wounds) evaluating an acellular fish skin graft (Kerecis) in conjunction with standard of care (SOC) for chronic, nonhealing wounds of multiple etiologies including lymphedema, pressure ulcers/injuries and burns. Over a 12-week follow-up period, treatment with fish skin graft + SOC was associated with significant reductions in wound surface area (mean reduction ~60.7%), improvement in pain in approximately two-thirds of patients, and complete wound healing in 36.4% of wounds.
[26]
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In 2025, Ivana et al. published a systematic review (n = 158 patients across 6 studies, mostly retrospective) evaluating acellular fish skin grafts in the treatment of chronic wounds of multiple etiologies, including diabetic ulcers, burns, surgical and other complex wounds. Across included studies, fish skin grafts used in conjunction with standard of care (SOC) were associated with accelerated wound healing, with some wounds achieving complete closure as early as 30 days and improved healing rates compared to conventional dressings.
[27]
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Apligraf
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PMA; FDA-approved for DFU/VLU only
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Case series
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The wound has failed to progress despite standard therapy for 30 days. Published case series describe use of bioengineered skin substitutes in complex wounds. Apligraf is FDA-approved for treatment of diabetic foot ulcers and venous leg ulcers; use in this case is being considered based on clinical judgment due to wound complexity and lack of response to standard care.
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In 2006, Shealy et al. published a retrospective case series (n = 16 patients, 18 wounds) evaluating a bioengineered bilayered living cell construct (Apligraf) in conjunction with standard of care (SOC) for complicated surgical and nonsurgical wounds of multiple etiologies, including off-label use on chronic and acute wounds that had failed prior therapies, such as nonhealing surgical, radiation and traumatic wounds. Application of Apligraf + SOC resulted in high rates of healing, with 94% of patients (15/16) achieving complete healing and 89% of wounds (16/18) closing, with healing times ranging from 21 to 550 days.
[28]
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In 2014, Penny et al. published a case study (n = 1 patient with 3 wounds) describing the management of necrobiosis lipoidica–associated chronic lower-extremity ulceration refractory to prior standard therapies over a 6–12 month period. The wounds were treated with a bioengineered bilayered living cell construct (Apligraf) in conjunction with standard of care (SOC). Following initiation of Apligraf + SOC, wounds 1 and 2 achieved closure within 45 days and wound 3 within 68 days, demonstrating substantially improved healing compared to prior treatment courses.
[29]
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