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Fish‐Skin Grafts Compared to Human Amnion/Chorion Membrane Allografts: A Double‐Blind, Prospective, Randomized, Clinical Trial of Acute Wound Healing


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Chronic, nonhealing wounds consume a great deal of healthcare resources and are a major public health problem, associated with high morbidity and significant economic costs. Skin grafts are commonly used to facilitate wound closure. The grafts can come from the patient's own skin (autograft), a human donor (allograft), or from a different species (xenograft). A fish skin xenograft from cold‐water fish (Atlantic cod, Gadus morhua) is a relatively recent option that shows promising preclinical and clinical results in wound healing. Chronic wounds vary greatly in etiology and nature, requiring large cohorts for effective comparison between therapeutic alternatives. In this study, we attempted to imitate the status of a freshly debrided chronic wound by creating acute full‐thickness wounds, 4 mm in diameter, on healthy volunteers to compare two materials frequently used to treat chronic wounds: fish skin and dHACM. The purpose is to give an indication of the efficacy of the two therapeutic alternatives in the treatment of chronic wounds in a simple, standardized, randomized, controlled, double‐blind study. All volunteers were given two identical punch biopsy wounds, one of which was treated with a fish skin graft and the other with dehydrated human amnion/chorion membrane allograft (dHACM). In the study, 170 wounds were treated (85 wounds per group). The primary endpoint was defined as time to heal (full epithelialization) by blinded assessment at days 14, 18, 21, 25, and 28. The superiority hypothesis was that the fish skin grafts would heal the wounds faster than the dHACM. To evaluate the superiority hypothesis, a mixed Cox proportional hazard model was used. Wounds treated with fish skin healed significantly faster (hazard ratio 2.37; 95% confidence interval: (1.75–3.22; p = 0.0014) compared with wounds treated with dHACM. The results show that acute biopsy wounds treated with fish skin grafts heal faster than wounds treated with dHACM.
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Fish skin grafts compared to human amnion/chorion
membrane allografts: A double-blind, prospective,
randomized clinical trial of acute wound healing
Robert S. Kirsner, MD, PhD
; David J. Margolis, MD, PhD
; Baldur T. Baldursson, MD, PhD
Kristin Petursdottir, MD
; Olafur B. Davidsson, MSc
; Dot Weir, RN, CWON, CWS
John C. Lantis II MD, FACS
1. Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida,
2. Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania,
3. Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania,
4. Department of Dermatology, Landspitali University Hospital of Iceland, Reykjavik, Iceland,
5. Mathematics Division of the Science Institute, University of Iceland, Reykjavik, Iceland,
6. Catholic Health Advanced Wound Healing Centers, Buffalo, New York, and
7. Division of Vascular/Endovascular Surgery, Mount Sinai St. LukesWest Hospitals, Icahn School of Medicine, New York, New York
Reprint requests:
Baldur T. Baldursson, Department of
Dermatology, Landspitali University
Hospital of Iceland, Reykjavik, Iceland.
Manuscript received: December 4, 2018
Accepted in nal form: September 6, 2019
This is an open access article under the
terms of the Creative Commons Attribution
License, which permits use, distribution and
reproduction in any medium, provided the
original work is properly cited.
Chronic, nonhealing wounds consume a great deal of healthcare resources and are a
major public health problem, associated with high morbidity and signicant economic
costs. Skin grafts are commonly used to facilitate wound closure. The grafts can come
from the patients own skin (autograft), a human donor (allograft), or from a different
species (xenograft). A sh skin xenograft from cold-water sh (Atlantic cod, Gadus
morhua) is a relatively recent option that shows promising preclinical and clinical results
in wound healing. Chronic wounds vary greatly in etiology and nature, requiring large
cohorts for effective comparison between therapeutic alternatives. In this study, we
attempted to imitate the status of a freshly debrided chronic wound by creating acute
full-thickness wounds, 4 mm in diameter, on healthy volunteers to compare two mate-
rials frequently used to treat chronic wounds: sh skin and dHACM. The purpose is to
give an indication of the efcacy of the two therapeutic alternatives in the treatment of
chronic wounds in a simple, standardized, randomized, controlled, double-blind study.
All volunteers were given two identicalpunch biopsy wounds, one of which was treated
with a sh skin graft and the other with dehydrated human amnion/chorion membrane
allograft (dHACM). In the study, 170 wounds were treated (85 wounds per group). The
primary endpoint was dened as time to heal (full epithelialization) by blinded assess-
ment at days 14, 18, 21, 25, and 28. The superiority hypothesis was that the sh skin
grafts would heal the wounds faster than the dHACM. To evaluate the superiority
hypothesis, a mixed Cox proportional hazard model was used. Wounds treated with sh
skin healed signicantly faster (hazard ratio 2.37; 95% condence interval: (1.753.22;
p= 0.0014) compared with wounds treated with dHACM. The results show that acute
biopsy wounds treated with sh skin grafts heal faster than wounds treated with
Grafts and materials containing components from processed
human and animal tissues are being used in a range of products
for the purpose of treating acute wounds and hard-to-heal
chronic wounds. Fish skin xenografts are a recent addition. The
grafts (Kerecis
Omega3 Wound, Kerecis, Isafjordur, Iceland)
from North Atlantic Cod (Gadus morhua) are acellular but oth-
erwise structurally intact skin tissue. The grafts are freeze-dried
and possess a shelf life of 3 years. Xenograft materials gener-
ally require extensive processing to reduce the risk of viral or
prion disease transfer.
This processing requires the use of
harsh chemicals that dissolve the soluble components of the
tissue and denature its structure, leaving behind mostly insolu-
ble collagen.
In the case of cod skin, however, no viral inacti-
vation is necessary.
This allows for milder processing, which
retains the structural integrity and the molecular components of
the skin, including the proteoglycans, glycoproteins, soluble
collagen, elastin, laminin, broconectin, lipids, and the Omega-
3 polyunsaturated fatty acids (PUFAs).
Previous work has
dHACM dehydrated Human AMNION/Chorion Membrane
FDA U.S. Food and Drug Administration
PUFA Polyunsaturated Fatty Acid
Wound Rep Reg (2020) 28 7580 © 2019 The Authors. Wound Repair and Regeneration published by Wiley Periodicals, Inc. on behalf of by the Wound
Healing Society. 75
shown these Omega-3 fatty acids to have bacterial barrier and
pain-modulating properties.
Amniotic products have gained wide acceptance in wound
healing, most specically in the treatment ofdiabetic foot ulcers
and venous leg ulcers. Of these products, the most commonly
used in the United States is dehydrated human amnion/chorion
membrane (dHACM; EpiFix
MiMedx Group Inc., Marietta,
GA, USA). dHACM has been shown to be very effective in
treating diabetic foot ulcers.
Amniotic membrane-based
allografts are classied in the United States as donated organ
components and are currently being used in wound and soft-
tissue repair applications. While those membranes do not
undergo viral inactivation, they do undergo vigorous donor
screening. Characterization has found growth factors, cyto-
kines, and protease inhibitors within amnio-chorionic mem-
brane tissues, all of which are suggested to play a role in wound
dHACM is composed of two membranes consisting of
multiple layers, including a single layer of nonviable epithelial
cells, a basement membrane, and an avascular connective tissue
matrix. The membrane undergoes several processing steps,
which include cleaning, immersing the material in a solution
containing antibiotics with or without rinsing, and drying.
Primary objective
Chronic wounds vary greatly in etiology and nature, requiring
large cohorts for effective comparison between therapeutic
alternatives. In this study, we attempted to imitate the status of a
freshly debrided chronic wound by creating acute full-thickness
wounds, 4 mm in diameter, on healthy volunteers to compare
two materials frequently used to treat chronic wounds. The pur-
pose was to give an indication of the efcacy of the two thera-
peutic alternatives in the treatment of chronic wounds in a
simple, standardized, randomized, controlled, double-blind
The primary objective of the study was a head-to-head
comparison of the time to heal for full-thickness wounds on
human volunteers using a 4 mm punch biopsy model.
The superiority hypothesis was that the sh skin grafts
would be faster in time to heal vs. dHACM. The null
hypothesis was therefore that there would have been no sig-
nicant difference between the treatments.
Secondary objectives
The secondary objectives were wound healing at day
28, pain, erythema, infection, and the cost of products used.
Primary endpoints
The primary endpoint was dened as time to heal by blinded
assessment of full epithelialization at days 14, 18, 21, 25,
and 28.
Secondary endpoints
The secondary endpoints were the proportion of wounds
healed at day 28 as assessed by full epithelialization, inci-
dences of pain, erythema, infection, and a cost comparison
derived from the total number of applications of each
Study design and participants
The study was a prospective, double-blinded, randomized,
comparative, clinical trial. The research protocol was approved
by the Icelandic Medicines Agency (, the
Icelandic Data Protection Authority, and the Icelandic National
Bioethics Committee (VSNb2018010033/03.01). All partici-
pants signed an informed consent form consistent with the
World Medical Association (WMA) Declaration of Helsinki
statement of ethical principles for medical research involving
human subjects.
Recruitment took place over a 2-month period, and partici-
pants were recruited using advertisements at the University of
Iceland andthe Iceland University of theArts in Reykjavik, Ice-
land. Healthy volunteers between the ages of 18 and 60 years
were included in the study. Information on demographics, vital
signs, and medical history was recorded. Volunteers were
excluded prior to randomization if theywere using immunosup-
pressive treatment, anticoagulation therapy (i.e., warfarin), or
systemic corticosteroids and if they were suffering from
immune deciency because of disease or iatrogenic, peripheral
vascular disease. Women who were pregnant, breast feeding, or
Figure 1. Representative subject followed up to the healing
of punch wounds. From top to bottom: D0, D7, D14, D25.
Wound on the left side of gure was treated with sh skin
graft, while the right wound was treated with dHACM.
Fish skin compared to dHACM; randomized clinical trial of acute wound healing Kirsner et al.
Wound Rep Reg (2020) 28 7580 © 2019 The Authors. Wound Repair and Regeneration published by Wiley Periodicals, Inc. on behalf of by the Wound
Healing Society.
planning a pregnancy during the course of the clinical trial were
also excluded.
Each patientreceived two full-thickness, 4 mm punch biopsy
wounds created with a standard punch biopsy tool (Figure 1).
Participants acted as their own control, with one forearm wound
randomized to treatment with sh skin and a second wound on
the same forearm treated with dHACM. Two productssh-
skin graft (Kerecis
Omega3 Wound, Kerecis, Isafjordur, Ice-
land) and dHACM (EpiFix
MiMedx Group Inc., Marietta,
GA, USA)were used according to manufacturersinstruc-
tions for use.
Two physicians conducted the study; a trial physician
applied the products, and an evaluating physician, blinded to
the treatment, assessed the wounds and did nothing else. The
blinded physician made the clinical assessment of wound clo-
sure that, following FDA guidelines, needed to be adjudicated
photographically. Three blinded external reviewers then exam-
ined all of the photographs of the wounds independently and
determined the visit at which closure occurred. Thus four
blinded wound-healing professionals evaluated the wounds.
Randomization and blinding
All participants in the study were assigned a unique identica-
tion number, and all received both treatments. Randomization
dictated which wound, laterally or medially located, was treated
with which treatment (sh skin or dHACM). The two products
were randomly applied using an even/odd randomization
scheme. The randomization sequence was accessible to the trial
physician and the statisticians of the trial. The patient and the
evaluating physician were blinded tothe randomization.
Surgery and trial schedule
After local anesthesia (lidocaine hydrochloride10mg/ml and
epinephrine 5 mcg/ml), two full-thickness, 4 mm punch
wounds, 3 cm apart, were made on the proximal anterolateral
aspect of the nondominant forearm. Hemostasis was achieved
with pressure and a 30% ferrous chloride solution. The products
were applied according tothe randomization sequence followed
by a secondary dressing consisting of a waterproof, vapor-trans-
mitting, transparent plastic lm with a centrally placed gauze
pad. Participants were provided with instructions on wound
care and two spare secondary dressings to use if necessary
before follow up. Participants were instructed not to remove the
trial products.
Over the 28-day study period, including the rst study day,
participants had a total of seven visits. On day 3, participants
were contacted by phone by the trial physician to collect infor-
mation on thestatus of their wounds. The participants were seen
on days 7, 14, 18, 21, 25, and 28 for assessment of wound sta-
tus, allowing a visit 1 day later or earlier if necessary.
Wounds were assessed for erythema, infection, and reported
pain or bleeding, and a decision of healed vs. not healed was
made by the evaluating physician. An a priori erythema up to
1 mm on the wound edge was considered normal. Wider ery-
thema was noted as such, and wider erythema with inltration
with or without exudate that exceeded that of other participants
was classied as an infection.
Upon wound inspections, no attempts were made to remove
material from the wounds. Wounds with material still visible in
the wound were deemed not healed. If the material had been
resorbed, or if it was not visible, new material was applied to
the wound. As the studied materials had no claims of absorp-
tion, no attempt was made to evaluate the amount of exudate. In
addition to the healed vs. nonhealed decision of the evaluating
physician, standardized digital photographs were taken and
used for healing assessment (Figure 1). If one of the two
wounds was determined to be healed, then no further evalua-
tions were performed on that participant.
Statistical analysis
The evaluations of four wound-healing professionals produced
a table of outcomes of healed vs. nonhealed wounds for each
time point. To estimate whether the differences in time to heal
between the studied materials in this accumulated data was sig-
nicant, a mixed-effects Cox proportional hazard model was
used. The model incorporates a xed effect for the treatment, a
random individual effect to account for each individual receiv-
ing both wounds, and a random wound effect to account for the
variance introduced by the different reviewers of each wound.
All analysis was performed in R version 3.4.1.
The con-
dence interval for the proportion of wounds healed with each
of the treatments at each time point was estimated with the
Table 1. Demographic data
Demographic data of study population
Female/male ratio 2.1
Age, average 24.1
Age, range 1951
Caucasian 98.8%
African 1.2%
7 1418212528
Average number of healed wounds
Figure 2. Proportion of healed wounds at each time point
with sh skin graft (orange) and dHACM (blue). Wounds
treated with sh skin healed signicantly faster with a hazard
ratio of 2.37 compared to dHACM allograft-treated wounds
(p= 0.0014). Projected healing for 50% of wounds was
22 days for sh skin product and 24 days for amniotic
Kirsner et al. Fish skin compared to dHACM; randomized clinical trial of acute wound healing
Wound Rep Reg (2020) 28 7580 © 2019 The Authors. Wound Repair and Regeneration published by Wiley Periodicals, Inc. on behalf of by the Wound
Healing Society. 77
bootstrap method using 2 million simulations. The model
parameters were estimated using the coxmepackage in R.
For the cost analysis, a two-sided paired t-test was used. A Chi-
square test was used to check for difference in healing in lateral
vs. medial wounds.
Eighty-ve (85) healthy volunteers aged between 19 and
51 years were enrolled with no loss of follow up. Their average
age was 24.1 years, with a standard deviation of 4.6 years. Two
thirds were women. The cohort was primarily of Caucasian ori-
gin, consisting of 84 Caucasians and 1 participant of African
origin (Table 1).
Primary endpoint
From day 14 onward, wounds in the group treated with sh skin
healed to a greater extent on average than those treated with
dHACM (Figure 2). Wounds treated with sh skin healed sig-
nicantly faster with a hazard ratio of 2.37 (95% CI: 1.753.21)
and a p-value of 0.0014 compared to dHACM-treated wounds.
Using a likelihood ratio test, other available covariates, such as
age and gender, were omitted successively from the model as
they did not contribute to a signicantly better model t.
Figure 2 shows a greater proportion of healed wounds treated
with sh skin, where all reviewers were pooled. Similarly, the
healing trajectories of the source materials at each day and per
evaluator show consistent superiority of the sh skin grafts
(Figure 3). The results of the mixed effects Cox proportional
hazard model conrm this difference. The median day of
healing in both treatment arms was 25 days.
Other endpoints
A number of participants reported pruritus (n = 19), and six par-
ticipants developed a minor rash consistent with the application
area of the cover dressing surrounding both wounds and were
treated with another brand of cover dressing. Seven patients
reported mild pain or discomfort around the wound area, most
frequently experienced on the rst 2 days. Two participants still
felt mild pain on day 3, and one reported intermittent pain up to
day 14 without infection or other identiable causes or connec-
tions with other symptoms. Periwound erythema >1 mm was
noted in 10 wounds; four subjects had erythema in both
wounds, and two had erythema only in the wound treated with
sh skin. Thus, differences were not attributable to either treat-
ment type (Table 2). Two subjects (three wounds) experienced
irritation with discharge, one in the dHACM wound and the
other in both wounds. Two subjects exhibited hypergranulation
in one wound, one from each treatment arm. There was no case
of infection that needed treatment with antibiotics; the symp-
toms had subsided at the next dressing change. The sh skin
graft received 1.6 applications per subject on average, while the
dHACM received 1.4 applications per wound.
Of the 47 subjects where one wound healed before the
other, by the indication of one or more evaluators, 20 were
on the lateral side and 27 on the medial side. The difference
between them was not signicant (p= 0.23).
Full-thickness acute wounds treated with sh skin grafts heal
signicantly faster than wounds treated with dehydrated human
amnio-chorionic membrane. There was no difference in the
number of adverse reactions, such as mild erythema or irrita-
tion, between groups.
A previously published clinical trial
of similar design showed that full-thickness acute wounds
treated with sh skin heal signicantly faster than wounds
treated with porcine tissue.
The two studies show that sh skin
grafts enable faster healing of acute wounds than amniotic tis-
sue and porcine tissue.
The wound-healing scores vary between evaluators but
show a consistent difference between treatments (Figure 3).
Several statistical methods exist that are frequently used to
analyze time-to-event curves. One of them is the Cox pro-
portional hazard model, which has been widely used in med-
ical research.
This methodology allows data from
participants with only one wound healed to be used.
While the exact role of sh skin in accelerated healing of
these wounds requires further study, specicpropertiesofthe
sh skin are likely to be important to this result. Unlike the
manufacturing processes for mammalian tissues, the gentle
processing of the cod skin does not include viral deactivation,
preserving the natural structural and the molecular components
of the cod skin. The preservation of the natural three-
dimensional extracellular matrix structure and porosity may be
important for cellular recognition. dHCAM relies on the
7 1418212528
Number of healed wounds
Figure 3. Trajectories of the number of healed wounds to
time by evaluator and wound-healing material. Orange: Intact
sh skin. Blue: dHACM.
Table 2. Incidences of erythema, irritation, and infection at a
given time point (Day) over the course of the trial
dHACM, number of
wounds (day of trial)
Fish skin, number of
wounds (day of trial)
Erythema 2 (7), 2 (14) 4 (7), 2 (14)
Irritation and
1 (7), 1 (14) 1 (7)
Infection 0 0
Fish skin compared to dHACM; randomized clinical trial of acute wound healing Kirsner et al.
Wound Rep Reg (2020) 28 7580 © 2019 The Authors. Wound Repair and Regeneration published by Wiley Periodicals, Inc. on behalf of by the Wound
Healing Society.
presence of fetal-derived growth factors.
While there are
reports of dHCAM healing chronic diabetic foot ulcers in
1 week, this rapid healing effect was not noted in our acute
wound study.
The total fatty acid content of cod skin consists
of >30% Omega-3 PUFAs, while human skin, amnion mem-
brane, and collagen matrix contains 0or < 1% Omega-3 of total
fatty acid content.
Both of these products have similar appli-
cation proles in that they often require ve or more applica-
tions to close a chronic wound.
Therefore, if one has a
signicantly higher or lower cost than the other, this difference
will increase rapidly with a multiple application strategy.
In this model, the differences in the cost of the product also
made the cost of treating wounds with dHACM signicantly
higher than treating with sh skin (p=2.51*10
). dHACM-
treated wounds were, on average, 76% more expensive com-
pared to sh skin-treated wounds in this study. The cost was
calculated using the average sales price of dHACM ($160
USD/square cm based on 2018 Healthcare Common Procedure
Coding System code Q4131) and the average listed sales price
of sh skin ($80 USD/square cm).
This study was designed to minimize the effect of individual
variance between wounds by studying uniform, acute wounds
in healthy patients. When chronic woundsare treated with prod-
ucts such as the sh skin graft and dHACM, they need to be
thoroughly debrided. With debridement, the chronic wounds
approach the physiological state of an acute wound.
fore, results derived from studying acute wounds can have logi-
cal implications for debrided chronic wounds.
When compared head to head to commonly used products, sh
skin has been shown to improve time to closure. However, the
routine need for reapplication for these products in clinical set-
tings and the nature of the chronic wound patient cannot be
reected in this study design. Overall, the product has shown
superiority in this particular model; however, clinical trials on
chronic wounds are required to further validate these results.
The staff members of the Department of Dermatology,
National University Hospital, Reykjavik are thanked for
their help and patience.
Source of funding: We thank the Icelandic Technology
Development Fund for sponsoring this research.
Conicts of Interest: Dr. Petursdottir, Mr. Davidsson, and
Ms. Weir were among the clinical trial investigators and
evaluators for this study sponsored by the Icelandic Tech-
nology Development Fund and do not report any other con-
icts of interest. Dr. Kirsner and Dr. Baldursson are
shareholders of Kerecis Limited, the manufacturer of the
product evaluated in the trial. Dr. Margolis, Dr. Baldursson,
and Dr. Lantis are paid consultants of Kerecis Limited.
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Wound Rep Reg (2020) 28 7580 © 2019 The Authors. Wound Repair and Regeneration published by Wiley Periodicals, Inc. on behalf of by the Wound
Healing Society.
... Kirsner et al. 24 compared fish skin and human amniotic membrane allografts for acute wound healing and reported that the cost of preparation and treatment with human amniotic membrane allografts was 76% more expensive than treatment with fish skin grafts. They stated that unlike mammal tissue production processes, the gentle processing of cod skin did not include viral deactivation, preserving the natural structure and molecular components of the cod skin. ...
... They stated that unlike mammal tissue production processes, the gentle processing of cod skin did not include viral deactivation, preserving the natural structure and molecular components of the cod skin. Furthermore, the total fatty acid content of cod skin contains approximately 30% omega-3 polyunsaturated fatty acid, whereas human skin, amnion membrane, and collagen matrix contain less than 1% omega-3 of total fatty acid content 24,25 . Both these products have similar application profiles in that chronic wounds frequently require five or more applications to be closed. ...
... Both these products have similar application profiles in that chronic wounds frequently require five or more applications to be closed. As a result, if one has a significantly higher or lower cost than the other, the difference will grow quickly with various application strategies 24 . ...
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ABSTRACTBackground: Recently, biological dressings have become popular in treating burn injuries. Fish skinhas non-infectious microbiota, high levels of type 1 and type 3 collagen, and a structural propertysimilar to human skin, making it a promising xenograft for managing burn wounds. In this study, weaimed to evaluate the effectiveness of fish skin as a physiological dressing cover in patients with burninjuries.
... Similar to the above method of fabricating bioengineered biological scaffolds from ex vivo expansion of autologous cells, is the recent investigations into decellularized tissue grafts [175]. Tissue can be isolated from a variety of sources, including human amnion, bovine tissue, and fish [176][177][178]. The process of decellularization removes the unwanted cellular components of the tissue to decrease the risk of rejection and failure of engraftment [179]. ...
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Wound healing is a dynamic series of interconnected events with the ultimate goal of promoting neotissue formation and restoration of anatomical function. Yet, the complexity of wound healing can often result in development of complex, chronic wounds, which currently results in a significant strain and burden to our healthcare system. The advancement of new and effective wound care therapies remains a critical issue, with the current therapeutic modalities often remaining inadequate. Notably, the field of tissue engineering has grown significantly in the last several years, in part, due to the diverse properties and applications of polymeric biomaterials. The interdisciplinary cohesion of the chemical, biological, physical, and material sciences is pertinent to advancing our current understanding of biomaterials and generating new wound care modalities. However, there is still room for closing the gap between the clinical and material science realms in order to more effectively develop novel wound care therapies that aid in the treatment of complex wounds. Thus, in this review, we discuss key material science principles in the context of polymeric biomaterials, provide a clinical breadth to discuss how these properties affect wound dressing design, and the role of polymeric biomaterials in the innovation and design of the next generation of wound dressings.
... Also, various research papers on chronic wounds and on burns have only reported a few clinical case reports on the treatment effect analysis using a pig animal model and donor sites for burn patients. In other word, there is no existing paper comparing the therapeutic effect of fish collagen with pig or bovine collagen [2,7,8]. ...
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Due to its high polyunsaturated fatty acid content, acellular fish skin has emerged as a dermal substitute for the promotion of wound healing as it decreases scar formation while providing pain relief. However, various systematic studies on acellular fish skin, such as its biophysical analysis, in vitro activities, and clinical application, have not been sufficiently investigated. In this study, we conducted a comparative study to evaluate the wound-healing ability of acellular fish skin graft (Kerecis®) with that of the widely used bovine collagen skin graft (ProHeal®). The skin grafts were evaluated not only in terms of their biophysical properties, but also their in vitro cellular activities, using fibroblasts, keratinocytes, and human endothelial cells. The clinical study evaluated wound healing in 52 patients with acute burns who underwent skin grafting on donor sites from January 2019 to December 2020. The study was conducted with two groups; while only Kerecis® was tested in one group, Kerecis® and ProHeal® were compared in the other. In both groups, the application time of the dressing material was one to two days after split-thickness skin grafting to the donor sites. The Kerecis®-treatment group experienced faster healing than the other treatment group. In particular, the average wound healing time using the Kerecis® treatment and the ProHeal® treatment was 10.7 ± 1.5 days and 13.1 ± 1.4 days, respectively. We believe that the faster healing of the Kerecis® treatment, compared to that of the ProHeal® treatment, maybe due to the synergistic effect of the unique biophysical structure and the bioactive components of acellular fish skin.
... Yet another approach in this category involves the use of autograft or allograft and even xenografts from aquamarine sources. It has been noted that the popular approach using fish grafts appears to heal faster when compared to wounds treated with dehydrated Human AMNION/Chorion Membrane (dHACM) and even porcine tissue [33]. ...
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Diabetic wounds are of profound clinical importance. Despite immense efforts directed towards its management, it results in the development of amputations, following a diagnosis of diabetic foot. With a better understanding of the complexities of the microbalance involved in the healing process, researchers have developed advanced methods for the management of wounds as well as diagnostic tools (especially, for wound infections) to be delivered to clinics sooner. In this review, we address the newer developments that hope to drive the transition from bench to bedside in the coming decade.
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Objective To evaluate new medical devices and drugs pertinent to otolaryngology–head and neck surgery that were approved by the Food and Drug Administration (FDA) in 2021. Data Sources Publicly available FDA device and drug approvals from ENT (ear, nose, and throat), anesthesia, neurosurgery, plastic surgery, and general surgery FDA committees. Review Methods FDA device and therapeutic approvals were identified and reviewed by members of the American Academy of Otolaryngology–Head and Neck Surgery’s Medical Devices and Drugs Committee. Two independent reviewers assessed the relevance of devices and drugs to otolaryngologists. Medical devices and drugs were then allocated to their respective subspecialty fields for critical review based on available scientific literature. Conclusions The Medical Devices and Drugs Committee reviewed 1153 devices and 52 novel drugs that received FDA approval in 2021 (67 ENT, 106 anesthesia, 618 general surgery and plastic surgery, 362 neurosurgery). Twenty-three devices and 1 therapeutic agent relevant to otolaryngology were included in the state of the art review. Advances spanned all subspecialties, including over-the-counter hearing aid options in otology, expanding treatment options for rhinitis in rhinology, innovative laser-safe endotracheal tubes in laryngology, novel facial rejuvenation and implant technology in facial plastic surgery, and advances in noninvasive and surgical treatment options for obstructive sleep apnea. Implications for Practice FDA approvals for new technology and pharmaceuticals present new opportunities across subspecialties in otolaryngology. Clinicians’ nuanced understanding of the safety, advantages, and limitations of these innovations ensures ongoing progress in patient care.
Purpose: Inadequate response to wound management is defined as a reduction in the wound area of <40-50% following four weeks of standard of care (SOC) and should be managed with a skin substitute product. We set out to evaluate a novel outcome-based model focusing on the management of hard-to-heal venous leg ulcers (VLUs) and diabetic foot ulcers (DFUs) using SOC treatment or intact fish skin grafts (FSGs) in a regional hospital. Methods: We built an outcome-based model applying surrogate markers and endpoints of wound healing for VLU and DFU to determine the healing trajectory with SOC treatment. We could predict if VLU and DFU would heal by weeks 20 and 24, respectively, after four weeks of evaluating the initial wound area reduction. 51 patients were recruited (26 VLUs and 25 DFUs) and 42 wounds were randomized. 17 wounds deemed unlikely to heal by week 8 received management with FSG as per the Swiss Society for Dermatology and Venereology (SGDV) and the Swiss Association for Woundcare (SAfW) guidelines for the use of skin replacement products, and 26 wounds continued SOC for weeks 5-8. Results/Discussion: 12 wounds managed with FSG beat the modeled SOC healing predictions, with the majority healed >50% sooner and as early as <10% of the time than was predicted. Of these 17, five wounds failed to achieve the required size reduction in Week 4-8 (over 25% improvement in wound area vs. SOC). The FSG were assigned to treatment-resistant VLU and DFUs and were still able to heal these wounds most of the time and even changed the wound's healing trajectory that increased in size in the initial four weeks. Conclusion: This pilot study showed that management with FSG results in faster healing wounds than SOC predicted, while SOC-treated wounds mostly followed model predictions.
Background Large skin defects caused by trauma (e.g., burns) or due to other reasons (e.g., tumor-related skin resections) require sufficient skin replacement. The constant improvement of innovative methods of skin replacement and skin expansion mean that even burn victims with more than 80% body surface burned have a realistic chance of survival. Due to these new developments, not only has survival rate increased, but also quality of life has increased tremendously over the past decades. Methods The aim of this review is to present an overview of current standards and future trends concerning the treatment of skin defects. The main focus is placed on the most important technologies and future trends. Results Autologous skin grafting was developed more than 3500 years ago. Several approaches and techniques have been discovered and established in burn care and plastic surgery since then. Great achievements were made during the 19th and 20th centuries. Many of these old and new techniques are still part of modern burn and plastic surgery. Today, autologous skin grafting is still considered to be the gold standard for many wounds, but new technologies have been developed, ranging from biological to synthetic skin replacement materials. Conclusion Today, old and new technologies are available which allow us new treatment concepts. All this has led to the reconstructive clockwork for reconstructive surgery of the 21st century.
Wound healing is a complex process in tissue regeneration through which the body responds to the dissipated cells as a result of any kind of severe injury. Diabetic and non‐healing wounds are considered an unmet clinical need. Currently, different strategic approaches are widely used in the treatment of acute and chronic wounds which include, but are not limited to, tissue transplantation, cell therapy and wound dressings, and the use of an instrument. A large number of literatures have been published on this topic; however, the most effective clinical treatment remains a challenge. The wound dressing involves the use of a scaffold, usually using biomaterials for the delivery of medication, autologous stem cells, or growth factors from the blood. Antibacterial and anti‐inflammatory drugs are also used to stop the infection as well as accelerate wound healing. With an increase in the ageing population leading to diabetes and associated cutaneous wounds, there is a great need to improve the current treatment strategies. This research critically reviews the current advancement in the therapeutic and clinical approaches for wound healing and tissue regeneration. The results of recent clinical trials suggest that the use of modern dressings and skin substitutes is the easiest, most accessible, and most cost‐effective way to treat chronic wounds with advances in materials science such as graphene as 3D scaffold and biomolecules hold significant promise. The annual market value for successful wound treatment exceeds over $50 billion US dollars, and this will encourage industries as well as academics to investigate the application of emerging smart materials for modern dressings and skin substitutes for wound therapy.
Background: The optimal therapy for deep burn wounds is based on the early debridement of necrotic tissue followed by wound coverage to avoid a systemic inflammatory response and optimize scar-free healing. The outcomes are affected by available resources and underlying patient factors, which represent challenges in burn care and suboptimal outcomes. In this study, we aimed to determine optimal burn-wound management using enzymatic debridement (NexoBrid™, MediWound Germany GmbH, Rüsselsheim, Germany) and intact fish skin (Kerecis® Omega3 Wound, Isafjordur, Iceland). Methods: In this retrospective case series, 12 patients with superficial or deep dermal burn wounds were treated with enzymatic debridement followed by fish skin, Suprathel® (PolyMedics Innovations GmbH, Denkendorf, Germany), or a split-thickness skin graft (STSG). Patients’ outcomes regarding healing and scar quality were collected objectively and subjectively for 12 months after the burn injury. Results: Wounds treated with fish skin demonstrated accelerated wound healing, a significantly higher water-storage capacity, and better pain relief. Furthermore, improved functional and cosmetic outcomes, such as elasticity, skin thickness, and pigmentation, were demonstrated. The pain and itch expressed as POSAS scores (Patient and Observer Scar Assessment Scale) for fish skin decreased compared to those for wounds managed with an STSG or Suprathel. Importantly, fish skin-treated wounds had significantly improved sebum production and skin elasticity than those treated with Suprathel but showed no significant superiority compared to STSG-treated wounds. Conclusions: Enzymatic debridement in combination with intact fish skin grafts resulted in the faster healing of burn wounds and better functional and aesthetic outcomes than split-thickness skin grafts and Suprathel treatment.
Wound healing is a complex process that traverses 4 main phases which overlap and are interdependent. Many patient-related factors can impede healing by disrupting the normal pathways from one phase to the next. Wound-related factors also determine the best techniques or dressings for each patient. Species differences between cats and dogs must be understood for the successful treatment of cats. New techniques such as fish skin graft application, photobiomodulation, and bioelectric dressings hold promise as an addition to our armamentarium against wounds. NPWT, hyperbaric oxygen, regenerative medicine techniques, and low-level laser therapies yield mixed results and large-scale controlled studies are needed.
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Background: Improvised explosive devices and new directed energy weapons are changing warfare injuries from penetrating wounds to large surface area thermal and blast injuries. Acellular fish skin is used for tissue repair and during manufacturing subjected to gentle processing compared to biologic materials derived from mammals. This is due to the absence of viral and prion disease transmission risk, preserving natural structure and composition of the fish skin graft. Objectives: The aim of this study was to assess properties of acellular fish skin relevant for severe battlefield injuries and to compare those properties with those of dehydrated human amnion/chorion membrane. Methods: We evaluated cell ingrowth capabilities of the biological materials with microscopy techniques. Bacterial barrier properties were tested with a 2-chamber model. Results: The microstructure of the acellular fish skin is highly porous, whereas the microstructure of dehydrated human amnion/chorion membrane is mostly nonporous. The fish skin grafts show superior ability to support 3-dimensional ingrowth of cells compared to dehydrated human amnion/chorion membrane (p < 0.0001) and the fish skin is a bacterial barrier for 24 to 48 hours. Conclusion: The unique biomechanical properties of the acellular fish skin graft make it ideal to be used as a conformal cover for severe trauma and burn wounds in the battlefield.
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Introduction: Acellular fish skin of the Atlantic cod (Gadus morhua) is being used to treat chronic wounds. The prevalence of diabetes and the comorbidity of chronic wounds is increasing globally. The aim of the study was to assess the biocompatibility and biological characteristics of acellular fish skin, important for tissue repair. Materials and methods: The structure of the acellular fish skin was examined with microscopy. Biocompatibility of the graft was conducted by a specialized certified laboratory. Protein extracts from the material were analyzed using gel electrophoresis. Cytokine levels were measured with an enzyme linked immunosorbent assay (ELISA). Angiogenic properties were assessed with a chick chorioallantoic membrane (chick CAM) assay. Results: The structure of acellular fish skin is porous and the material is biocompatible. Electrophoresis revealed proteins around the size 115-130 kDa, indicative of collagens. The material did not have significant effect on IL-10, IL-12p40, IL-6 or TNF-α secretion from monocytes or macrophages. Acellular fish skin has significant effect on angiogenesis in the chick CAM assay. Conclusion: The acellular fish skin is not toxic and is not likely to promote inflammatory responses. The graft contains collagen I, promotes angiogenesis and supports cellular ingrowth. Compared to similar products made from mammalian sources, acellular fish skin does not confer a disease risk and contains more bioactive compounds, due to less severe processing. Key words: Fish skin, extracellular matrix, acellular dermal graft, wound healing, tissue repair. Correspondence: Baldur Tumi Baldursson,
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A prospective, randomised, controlled, parallel group, multi-centre clinical trial was conducted at three sites to compare the healing effectiveness of treatment of chronic lower extremity diabetic ulcers with either weekly applications of Apligraf® (Organogenesis, Inc., Canton, MA), EpiFix® (MiMedx Group, Inc., Marietta, GA), or standard wound care with collagen-alginate dressing. The primary study outcome was the percent change in complete wound healing after 4 and 6 weeks of treatment. Secondary outcomes included percent change in wound area per week, velocity of wound closure and a calculation of the amount and cost of Apligraf or EpiFix used. A total of 65 subjects entered the 2-week run-in period and 60 were randomised (20 per group). The proportion of patients in the EpiFix group achieving complete wound closure within 4 and 6 weeks was 85% and 95%, significantly higher (all adjusted P-values ≤ 0·003) than for patients receiving Apligraf (35% and 45%), or standard care (30% and 35%). After 1 week, wounds treated with EpiFix had reduced in area by 83·5% compared with 53·1% for wounds treated with Apligraf. Median time to healing was significantly faster (all adjusted P-values ≤0·001) with EpiFix (13 days) compared to Apligraf (49 days) or standard care (49 days). The mean number of grafts used and the graft cost per patient were lower in the EpiFix group campared to the Apligraf group, at 2·15 grafts at a cost of $1669 versus 6·2 grafts at a cost of $9216, respectively. The results of this study demonstrate the clinical and resource utilisation superiority of EpiFix compared to Apligraf or standard of care, for the treatment of diabetic ulcers of the lower extremities. © 2014 The Authors. International Wound Journal published by Inc and John Wiley & Sons Ltd.
Introduction: A novel piscine acellular fish-skin graft product has 510k clearance on the US market. This product (Omega3, Kerecis, Isafjordur, Iceland) is to be used similarly to extracellular matrices (ECMs) on the market (eg, bovine and porcine) except that it contains fats, including omega-3 polyunsaturated fatty acids that have been associated with anti-inflammatory properties in many studies. While many current ECMs are effective on open wounds, studies have largely excluded application to hard-to-heal ulcers. To test this product in a real-world environment, the authors chose to look specifically at hard-to-heal ulcers based on previously defined wound and patient factors. Methods: The primary objective was to assess the percentage of wound closure area from baseline after 5 weekly fish-skin graft applications in 18 patients with at least 1 "hard-to-heal" criteria. Patients underwent application of the fish skin for 5 sequential weeks, followed by 3 weeks of standard of care. Wound area, skin assessments, and pain were assessed weekly. Results: A 40% decrease in wound surface area (P < 0.05) and a 48% decrease in wound depth was seen with 5 weekly applications of the fish-skin graft and secondary dressing (P < 0.05). Complete closure was seen in 3 of 18 patients by the end of the study phase. Conclusion: This fish-skin product appears to provide promise as an effective wound closing adjunctive ECM. This is true when used in this compassionate setting, where many other products fail. This study lacks a control arm and an aggressive application schedule, but the investigators believe it represents real-world practice.
Introduction: Complicated wounds in the lower extremity can arise as a consequence of insufficient soft-tissue coverage after amputations in diabetic patients. The Kerecis® Omega3 wound matrix is a decellularized skin matrix derived from codfish and represents an alternative treatment option to achieve wound healing. Methods: 5 patients with diabetes mellitus and complicated wounds in the lower limb with exposed bony segments were treated with the Omega3 wound matrix between November 2014 and November 2015. Following initial debridement in the operating room, the wound matrix was applied and covered with a silicone mesh. In the further course, wound treatment was conducted on outpatient setting. Results: In total, 7 wounds were treated with localization at the level of the thigh (n=2) and the forefoot (n=5). For the wounds at the thigh, it took 26 weeks to achieve wound closure, whereas the wounds at the level of the forefoot showed healing times between 13 and 41 weeks. In all patients, a reduction of analgetics intake was noted when the treatment with the Omega3 wound matrix was initiated. Conclusion: The Kerecis® Omega3 wound matrix represents a viable treatment option in complicated wounds in the lower limb of diabetic patients to circumvent an otherwise necessary proximalization of amputation level. Further studies comparing the Omega3 wound matrix with appropriate control groups of standard therapies for soft-tissue conditioning/coverage like negative pressure therapy, biosurgery and other acellular dermal matrices are warranted.
• We prospectively studied 174 patients on whom 226 unsutured parallel incisional (shave) and 3-mm punch skin biopsies were performed. Two wound-care programs, occlusive dressing therapy and conventional therapy, were compared. The biopsy sites were evaluated after 1 or 2 weeks for healing, pain, and infection. We found that healing was unrelated to the indication for biopsy or the patients' age, gender, or race. Occlusive dressing therapy—treated shave biopsy sites were 3.83 times more likely to be healed than those treated with conventional therapy. Regardless of the treatment method, a facial shave biopsy site was 3.6 times more likely to be healed than a biopsy site in other locations. No punch biopsy site had healed after 1 week. At 2 weeks, only 7% and 36% of conventional therapy— and occlusive dressing therapy—treated punch biopsy sites, respectively, had healed. Pain at the biopsy site was six times more common in both shave and punch biopsy sites treated with conventional therapy. The absence of pain with occlusive dressing therapy was significant for both types of biopsy. One punch biopsy site treated with conventional therapy became infected, and one treated with occlusive dressing therapy was suspected of being infected. Forty patients, who had biopsy sites treated with both therapies, preferred occlusive dressing therapy over conventional therapy by a ratio of 3:1 because of ease of wound care and lack of pain. We conclude that occlusive dressing therapy may be the wound management of choice for shave biopsy sites. Since punch biopsy sites do not heal readily, it may be more appropriate to suture them, at least until therapies are developed that more effectively speed their healing. (Arch Dermatol. 1991;127:1679-1683)
Diabetic foot ulcers (DFUs) occur as a result of multifactorial complications and are commonly found in the diabetic community. Underlying disease states such as neuropathy and peripheral vascular disease can slow healing rates, potentially leading to recurrence, amputation, and increased mortality. As with many other disease processes, DFUs have several treatment options, such as debriding agents, alginate seaweed extract, hydrocolloid gels, and amniotic membrane allografts. The presented cases all used a dehydrated human amniotic/chorionic membrane allograft (dHACM; EpiFix) to aid the healing process. Human amniotic epithelial membranes have seen increased usage due to their ability to enhance the healing process and accelerate cellular regeneration. The DFUs healed in all of the five patients treated, and patients saw a full recovery in 2.5-11 weeks. In addition, the healing time decreased in spite of the non-adherence seen in three of the patients. These results suggest another possible use for dHACM; however, further studies are required to confirm these data. This project was self-funded and had no influences outside the fact that Dr Penny is a speaker for MiMedx.
A novel product, the fish skin acellular dermal matrix (ADM) has recently been introduced into the family of biological materials for the treatment of wounds. Hitherto, these products have been produced from the organs of livestock. A noninferiority test was used to compare the effect of fish skin ADM against porcine small-intestine submucosa extracellular matrix in the healing of 162 full-thickness 4-mm wounds on the forearm of 81 volunteers. The fish skin product was noninferior at the primary end point, healing at 28 days. Furthermore, the wounds treated with fish skin acellular matrix healed significantly faster. These results might give the fish skin ADM an advantage because of its environmental neutrality when compared with livestock-derived products. The study results on these acute full-thickness wounds might apply for diabetic foot ulcers and other chronic full-thickness wounds, and the shorter healing time for the fish skin-treated group could influence treatment decisions. To test the autoimmune reactivity of the fish skin, the participants were tested with the following ELISA (enzyme-linked immunosorbent assay) tests: RF, ANA, ENA, anti ds-DNA, ANCA, anti-CCP, and anticollagen I and II. These showed no reactivity. The results demonstrate the claims of safety and efficacy of fish skin ADM for wound care. © The Author(s) 2015.