Post on 25-Jan-2017
transcript
Supplement to WOUNDS® February 2015
This supplement was not subject to the WOUNDS® peer review process. The thoughts and opinions expressed in this supplement are those of the authors and not necessarily MiMedx®.
Supported by
2
William W. Li, MD, is President, Medical Director, and
Co-Founder of the Angiogenesis Foundation. He has been
actively engaged in angiogenesis research and clinical devel-
opment for three decades . He has held appointments on the
clinical faculties of Harvard Medical School, Tufts University,
and, Dartmouth Medical School. Dr. Li is a Founding Director of the American College
of Wound Healing and Tissue Repair, an Honorary Fellow of the American College
of Wound Care Specialists, and has served as advisor and consultant to leading
global public and private companies. Dr. Li is involved in national and international
efforts to advance the applications of angiogenesis-based therapeutics across di-
verse medical fields, including oncology/hematology, cardiology, ophthalmology,
vascular surgery, dermatology, and wound care. Dr. Li has been published in many
leading peer-reviewed medical journals. Dr. Li has disclosed that he is a consultant
to MiMedx, Novadaq and Smith & Nephew.
Lisa J. Gould, MD, PhD, FACS, is an Affiliate Professor in the Department of Molec-
ular Pharmacology and Physiology at the University of South Florida. She has served
on the executive board of the Wound Healing Society for more than 10 years and is
an active participant in multiple academic societies. She is also the Director of the
Wound Recovery and Hyperbaric Medicine Center. Dr. Gould
is board certified by the American Board of Plastic Surgery,
achieved a Certificate of Added Qualifications in Hand Sur-
gery, and is a Fellow of the American College of Surgeons.
She has been practicing plastic and reconstructive surgery
with an emphasis on difficult wound problems since 1999, serving as Chief of Plastic
Surgery at the James A. Haley Veterans Hospital (2007-2012), where she provided
wound and surgical care for our nation’s wounded warriors, including treatment of
pressure sores in the 100-bed spinal cord unit. Dr. Gould has disclosed that she is a
consultant to MiMedx.
Vickie R. Driver, DPM, MS, FACFAS, is a Professor of Or-
thopedic Surgery (Clinical) at the Brown University School of
Medicine, the Division Chief of Podiatric Surgery for the New
England VA Healthcare Medical Center in Providence, R.I., and
the Director of Research for Hyperbarics and the Wound Care
Center at Rhode Island Hospital. She is also the President of the Board of Directors for
the Association for the Advancement of Wound Care (AAWC), and has served on the
AAWC Board of Directors for seven years. and a Fellow of the American Board of Foot
and Ankle Surgery. A well-known national and international educator, researcher
and surgeon in the fields of limb preservation and wound healing, Dr. Driver has
published over 100 peer-reviewed journal articles and abstracts, and participated
as an investigator in over 60 clinical research trials. She has directed post-doctoral
fellowship training in both wound healing and limb preservation for 15 years. Dr.
Driver has disclosed that she is a scientific advisor to MiMedx.
Gary Gibbons, MD, is the Medical Director of the South
Shore Hospital Center for Wound Healing in Weymouth, Mas-
sachusetts, and a vascular surgeon by training. Dr. Gibbons
was the first director of the Deaconess/Joslin Diabetic Wound
Center, dedicating his career to diabetic patients with wounds
complicated by peripheral arterial disease who are in need of revascularizarion. Dr.
Gibbons is a Professor of Surgery at the Boston University School of Medicine, and
has been in practice for over 40 years. Dr. Gibbons has disclosed that he is a clinical
consultant to MiMedx, Spiracur, Celleration and Osiris Therapeutics.
Paul Glat, MD, is the Director of the Division of Plastic Sur-
gery, Director of the Burn Unit, and Director of Cleft Palate
and Craniofacial programs at St. Christopher’s Hospital for
Children in Philadelphia. Dr. Glat is consistently in demand as
a guest lecturer at plastic and reconstructive surgery meet-
ings in the United States and abroad. His writings and research have appeared in
several major plastic surgery textbooks and over 90 plastic surgery publications.
Dr. Glat has no potential conflicts of interest to disclose within the context of this
supplement.
PRESENTERS
3
INTRODUCTIONA multidisciplinary expert advisory
panel of five leading physicians was
convened in October, 2014, in Boston,
Massachusetts to determine the appro-
priate use of amniotic tissue products
for the treatment of acute and chron-
ic wounds. Primary objectives of the
expert advisory panel were to discuss
how preserved cytokines and chemo-
kines are helping define the multi-
faceted roles of EpiFix®, a dehydrated
human amnion/chorion membrane
(dHACM) allograft (MiMedx Group Inc.,
Marietta, GA), in the treatment of dia-
betic foot ulcers and venous leg ulcers;
to review the growing body of scien-
tific and clinical evidence associated
with EpiFix®; and to exchange practical
information regarding the use of Epi-
Fix® in addressing challenges in plastic,
cosmetic and reconstructive surgery.
This supplement was created to pro-
vide an overview of the discussions
and emerging data supporting the
clinical use of EpiFix®. Topics of this
supplement include current issues and
advances in treating acute and chronic
wounds in the United States; the evolu-
tion and emergence of amniotic mem-
brane tissues in wound care; different
processing techniques and their effects
on amniotic membrane grafts in facili-
tating healing; the unique structure
of EpiFix®; and functional differences
between EpiFix® and other amniotic
membrane tissue products.
THE PROBLEM OF CHRONIC WOUNDS AND AMNIOTIC MEMBRANE AS A TREATMENT OPTION
Acute and chronic wounds are prev-
alent and burdensome to patients and
the U.S. health care system. It has been
estimated that 1 to 2% of the popula-
tion will experience a chronic wound
during their lifetime. In the U.S. alone,
chronic wounds affect 6.5 million pa-
tients.1 Effective treatments for chron-
ic wounds such as diabetic foot ulcers
(DFUs) and venous leg ulcers (VLUs) are
urgently needed to help reduce time
to healing, associated treatment costs,
and the risk of further complications.
It is estimated that up to 25% of all
people with diabetes will develop a di-
abetic foot ulcer,2 while venous ulcers
account for 70%-90% of ulcers found
on the lower leg.3
Amniotic membrane tissue is a treat-
ment option that has been shown
to facilitate healing of these difficult
wounds. However, to make good clin-
ical decisions regarding the use of am-
niotic membrane tissue, it is important
to understand the nature of the tissue,
the characterization of different tissue
layers as well as the different process-
ing techniques for various amniotic
membrane products and the associat-
ed healing rates.
“The chorion membrane from the amniotic sac is not directly associated with maternal tissue and therefore would not promote an immune response if transplanted.”
— Dr. Gould
4
EpiFix® Dehydrated Human Amnion/Chorion Membrane (dhacm) Therapy
AMNIOTIC TISSUE: ORIGIN OF AMNION AND CHORION
Amniotic membrane, or the amni-
otic sac, is comprised of an inner layer
called the amnion and an outer layer
called the chorion. The amniotic sac is
formed after conception and during the
fetal maturation process.4 The chorionic
plate is intertwined with the placenta
and is often confused with the chorion
membrane, which is part of the amni-
otic sac and does not come in contact
with maternal tissue (Figure 1).
As the embryo continues to grow,
the amnion layer surrounding the fetus
expands and conjoins with the chori-
on within the first trimester of devel-
opment to become the amniotic sac.
Amniotic membranes are composed
principally of three types of material:
structural collagen and extracellular
matrix, biologically active cells and a
large number of important regenera-
tive molecules.
The use of amniotic membrane in
the clinical setting has a history span-
ning over 100 years. At present, amni-
otic products are delivered in multiple
configurations, including single and
multi-layer formats, and they are pro-
cessed with varying techniques. Since
all amniotic tissues are not processed
in the same way, the preserved tissues
cannot be viewed as equal with respect
to their healing properties.
PURION® PROCESSING OF EPIFIX® — THE POWER OF AMNION AND CHORION
When the amniotic sac is being pro-
cessed for use in the clinical setting, the
specific processing technique can affect
the preservation of proteins like growth
factors, cytokines, and chemokines,
thus affecting the stimulus for host cells
to migrate, infiltrate and engraft into
the tissue. EpiFix® features both the am-
nion and chorion layers and, due to the
proprietary PURION® Process utilized,
retains a substantial amount of growth
factors to enhance wound healing.
The PURION® Process for EpiFix® in-
cludes gentle separation of the placen-
Figure 1. During cesarean section procedures and after the baby has been delivered, the placental tissues including the amniotic sac, umbilical cord and the placenta are removed from the mother. Chorion grafts are sourced from the amniotic sac and not the chorionic plate, which contains maternal tissue.
Figure 2. Both the amnion and chorion layers are closely adhered to each other, but between those layers is a spongy layer. The layer can be separated easily during cleaning and processing.
AmnionChorion
Placenta
Umbilical Cord
Amniotic Sac
Chorionic Plate
5
The New Standard in Bioactive Wound Healing
tal tissues, removal of the spongy layer
from between the amnion and chorion
layers (Figure 2), cleansing, reassem-
bling of the amnion and chorion layers,
and gentle tissue dehydration. The PU-
RION® Process removes blood compo-
nents while protecting the intricate ex-
tracellular matrix (ECM) of the amnion
and chorion membrane, leaving intact
cells and the extracellular matrix. When
dehydration is completed, the graft is
cut to multiple sizes, packaged, and
sterilized, yielding an EpiFix® allograft
that can be stored at ambient condi-
tions for up to 5 years.
As mentioned earlier, different pro-
cessing techniques yield varied quan-
tities of preserved growth factors, cy-
tokines, and chemokines. It is known
that some amniotic products use harsh
chemicals and detergents during the
processing phase that may remove the
majority of cellular materials, including
cells, blood, and soluble growth factors.
In comparison, as described above, the
PURION® Processed EpiFix® uses a gen-
tle cleansing wash that removes the
maternal blood while preserving the
growth factors, cytokines, chemokines
and extracellular matrix without dam-
aging the cells. The PURION® Process
retains the native cells and pericellular
matter in the tissue after processing.
EPIFIX® AND SCIENTIFIC RIGORTo further outline the unique ben-
efits of the processing technique uti-
lized for EpiFix®, a series of published
scientific papers in collaboration with
the Georgia Institute of Technology
and the Stanford University Medi-
cal School characterizing PURION®
Processed EpiFix® was discussed by
the panel members. They reviewed
Figure 3b. Relative amount of representative cytokines in single layer amnion products compared with EpiFix®, a PURION® Processed amnion/chorion graft. EpiFix® generally contains substantially greater amounts of growth factors than other tested single-layer amnion prod-ucts. (Adapted from Koob, et al.)5
Figure 3a. Relative amount of representative cytokines in single layer amnion products compared with a MiMedx® PURION® Processed single layer amnion graft for ophthalmic use (AmbioDry2™), which generally contains substantially greater amounts of growth factors than other tested single-layer amnion products. (Adapted from Koob, et al.)5
“The EpiFix® graft has more cytokines and chemokines than amnion alone and as a result of combining both the amnion and chorion layers, it delivers a meaningful clinical difference we can see in the office.”
— Dr. Glat
6
EpiFix® Dehydrated Human Amnion/Chorion Membrane (dhacm) Therapy
proposed mechanisms of action re-
ported in each of the papers. The
panelists also discussed published
scientific papers comparing pro-
cessed amnion-only grafts versus two
MiMedx® grafts, AmbioDry2™, a single
layer amnion opthalmic graft, and Epi-
Fix®, an amnion and chorion layered
graft for the preservation of wound
healing and inflammatory regulators
(Figures 3A and 3B).5-8 An additional
animal study demonstrated that the
PURION® Process was more effective
in preserving wound healing and in-
flammatory regulators than other pro-
cessed tissues tested.9
DIFFERENCES IN TYPES OF SKIN SUBSTITUTES
The effectiveness of cellular ver-
sus bio-preserved cellular materi-
als in treating wounds was debated
between panel members. Amniotic
membrane tissues are ideal for trans-
plantation as they have been found to
be immunologically privileged and do
not require decellularization. This dif-
ferentiates amniotic tissue from a xe-
nograft, which is derived from animal
tissues and needs to be decellularized
to reduce a patient’s immunological
response to the implanted material.
Cellular products can contain living or
non-living cells. Living cell grafts can
contain keratinocytes, fibroblasts and/
or other cells that secrete growth fac-
tors to help induce a patient’s healing
response. The cells act as simple de-
livery systems for introducing growth
factors into the wound. It has been
reported, however, that the cells only
survive up to 72 hours in the wound
environment.10
EPIFIX®: A BIOACTIVE TISSUE MATRIX ALLOGRAFT
EpiFix® is a bioactive tissue matrix
that contains bio-preserved intact,
non-living cells (Figure 4). There are
a multitude of growth factors and cy-
tokines contained within the EpiFix®
allografts even though the cells are
not viable. It has been demonstrat-
ed that EpiFix® induces fibroblasts to
proliferate, migrate, and upregulates
basic fibroblast growth factor (bFGF),
granulocyte stimulating factor (GCSF)
and placental growth factor (PlGF)
biosynthesis.7
Figure 5. There is a long list of growth factor cytokines and chemokines included in dHACM, some of which are known to regulate inflammation and wound healing.6-8
“It is apparent not all amniotic products are identical, and clinicians should understand the differences in regard to membrane layers, processing, preservation of growth factors, and clinical outcomes.”
— Dr. Li
Figure 4. EpiFix® contains intact cells and different amounts of various growth factors.
7
The New Standard in Bioactive Wound Healing
EpiFix® has been shown to contain
more than 50 cytokines and growth
factors (Figure 5), and to promote fi-
broblast and human microvascular
endothelial cell proliferation in vitro.5-8
The cellular signals contained in the
tissue upregulate the production of an-
giogenic factors, and they recruit and
promote engraftment of endogenous
progenitor cells, including hematopoi-
etic cells, likely via stromal cell-derived
factor-1 (SDF-1) and other growth fac-
tors. This indicates that angiogenesis
and postnatal vasculogenesis could
be contributing modes of action for
EpiFix® activity, and that the bioactive
nature causes the surrounding cells to
respond by upregulating biosynthesis
of growth factors to promote healing.9
An important consideration is how
the growth factors interact with each
other. Amnion and chorion contain dif-
ferent amounts and types of the vari-
ous growth factors. The chorion layer is
four to five times thicker and contains
more growth factors as a result (Fig-
ure 6). EpiFix® contains about 20 times
more chemokines and cytokines than
competitive products comprised of
amnion alone (Figure 7).5 In addition,
dermal fibroblasts have demonstrat-
ed an increase in production of bFGF,
GCSF, and PlGF when cultured in the
presence of 5 and 10 mg/mL EpiFix®
extract. These are distinguishing fac-
tors that set EpiFix® apart from amni-
on-only grafts.
A DEEPER LOOK AT ANGIOGENESIS AND WOUND HEALING
When a wound is present, it is vi-
tal to be able to restore the perfusion
provided by the tissue capillaries. Mi-
crocirculation plays a significant role
in angiogenesis because the complex
branching patterns that occur are
specialized depending on the tissue
in which they reside. Endothelial cells
form channels in various ways depend-
Figure 6. Amnion and chorion contain different amounts and types of the various growth factors. This graph depicts the representation of growth factors in amnion and chorion layers of dHACM.5
Figure 7. Growth factor content in EpiFix® vs. selected single layer grafts5
5% Growth Factors
80±6.6%Growth Factors
EpiFix®
Chorion
Amnion
PURION® Processed
Competitor Single Layer Amnion Grafts
Growth Factor Content in EpiFix® vs. Competitive Single Layer Grafts
PURION® processed dHACM contains 20 times more growth factors than competitor single layer amnion products
100
80
60
40
20
0
Perc
enta
ge o
f Gro
wth
Fac
tors
20±6.6%Growth Factors
8
EpiFix® Dehydrated Human Amnion/Chorion Membrane (dhacm) Therapy
ing on the tissue, and if the goal is to
restore capillaries, there must be an un-
derstanding of what control signals are
required to rebuild blood vessels within
the tissue in which they are growing.
With respect to wound angiogen-
esis, there were many early efforts
directed at applying a recombinant
growth factor to injured tissue. In
1998, the wound community had its
first recombinant growth factor with
platelet-derived growth factor (beca-
plermin). While this was a major step
from a biotechnology perspective,
wound care professionals also quick-
ly realized that a single growth factor
has limitations. Since then, there have
been incremental efforts to advance
the science of wound care.
EpiFix® research has contributed to
this area. In a scientific study evaluat-
ing properties that support angiogen-
esis, EpiFix® was shown to stimulate
increased angiogenesis compared to
control over a one-month observation,
when microvessels in the area of an im-
plant were counted.6 While it normally
takes time for blood vessels to gener-
ate, quick initiation of the angiogene-
sis process was observed when EpiFix®
was introduced. Authors of this study
proposed that the quick response may
result from the ability of EpiFix® to stim-
ulate fibroblasts to secrete other import-
ant growth factors that in turn stimulate
other cell types present in a wound to
release their own set of growth factors.6
In a separate study performed at
Stanford University Medical School, Epi-
Fix® was shown to stimulate in vivo mes-
enchymal stem cell (MSC) migration.9
The investigators employed a parabio-
sis model in which one mouse geneti-
cally engineered to have stem cells con-
taining green fluorescent protein (GFP)
was conjoined (shared circulation) with
a wild type or normal mouse (Figure 8).
The GFP mouse acted as a stem cell do-
nor to the wild type mouse when the lat-
ter was implanted with EpiFix®. Results
showed the EpiFix® induced, without
further manipulation, greater recruit-
ment of engrafted GFP cells inside the
implant when compared to the sham
implant, and an acellular bovine der-
mis (PriMatrix®, TEI Biosciences, Boston,
MA) control (Figure 9). The investigation
supported the hypothesis that EpiFix®
could serve as a stem cell magnet that,
when applied to a wound, could attract
endogenous stem cells to engraft into
the area of pathology. EpiFix® contains
growth factors that provoke circulating
progenitor cells to migrate and engraft
at the implant site, resulting in angio-
genesis restoring blood flow to the
damaged tissue (Figure 10).
GROWTH FACTORS IN EPIFIX® INFLUENCE ANGIOGENESIS
After appropriate sharp debridement
and moist wound care, EpiFix® modu-
lates the chronic wound environment,
resulting in normalization of many of
the dysfunctional cellular responses.
During this process, growth factors
and cytokines from EpiFix® amplify
secretion of additional growth factors
from endothelial cells to help acceler-
Figure 8. Parabiosis model to determine the amount of MSC migration and engraftment9
EpiFix®
Sham
Control ADM TEI Primatrix®
EpiFix® implanted in normal mouse
Surgically join skin so mice share blood circulation- ”parabiosis”
BM-MSCs in GFP mouse fluorescent green
GFP + mouse
Normalmouse
“I look to the published scientific and clinical data to determine if I will use a graft, and as we discussed, EpiFix® has the data.”
— Dr. Gould
9
The New Standard in Bioactive Wound Healing
ate wound healing. Additional growth
factor signaling is important and not
limited to just a single growth factor,
but the multitude of growth factors
that are contained in EpiFix® and may
be secreted by responding host cells at
the wound site. These same factors can
be produced by endogenous platelets,
neutrophils, monocytes, macrophages,
and stem cells that are helping the
healing process.
Stem cell participation occurs fairly
early within the wound-healing cas-
cade.11 When stem cells, a stem cell
magnet such as EpiFix®, or growth fac-
tors like SDF-1 are added into this pro-
cess, the biology of wound healing is
presumably being boosted.12 The opti-
mal time to get stem cells into a wound
space is unclear.
When there is a stem cell magnet re-
cruiting endogenous stem cells, these
native stem cells would migrate from
the surrounding tissue or through
the circulation to the local injured tis-
sue as opposed to being injected or
placed topically in a wound as would
be the case with a living cellular ther-
apy. Although inflammation is usually
considered destructive, in this case,
some inflammatory immune cells are
important to provide additional angio-
genic stimulus. The stem cells do not
stay long in the wound, but as soon
as they are incorporated, they release
their own plethora of growth factors,
cytokines, and paracrine factors to be-
Figure 9. Results from a study involving a parabiosis model showed that EpiFix® induced greater recruitment of engrafted GFP cells inside the implant when compared to the sham implant, and an acellular bovine dermis (PriMatrix®, TEI Biosciences, Boston, MA) control. (Adapted from Maan, et al.)9
Figure 10. The investigation supported the hypothesis that EpiFix® could serve as a stem cell magnet that, when applied to a wound, could attract endogenous stem cells to engraft into the area of pathology.9
Day 3 Day 7 Day 14 Day 28
30
25
20
15
10
5
0
GFP
+ C
ells
Intact Skin
Sham Implant
Control ADM
EpiFix®
** Indicates P ≤
0.05 for EpiFix®
compared with
healthy skin and
sham implant.†† Indicates P ≤
0.05 for EpiFix®
compared with
control ADM
(Primatrix®)
**
**
**
††
10
EpiFix® Dehydrated Human Amnion/Chorion Membrane (dhacm) Therapy
gin healing. In order for angiogenesis
and regeneration to occur, adequate
wound bed preparation is imperative
to remove any infection, necrotic tis-
sue, or pressure that may combat en-
graftment of the patient’s stem cells.
As a healing wound returns local
tissue to physiological perfusion, the
need for pro-angiogenic stimulus is
profoundly reduced. The healing tissue
actively down-regulates the production
of growth factors, and inflammation
also subsides. Healed tissues also up-
regulate angiogenesis inhibitory factors
that help prune the microcirculation
to baseline levels required for proper
tissue oxygenation. The expert panel
was intrigued that the cytokine profile
in EpiFix® shows such multiplicity, and
that the release kinetics are also differ-
ent. While more research is needed to
determine how this fits into the physi-
ological model, clearly when wounds
heal normally, they actually rely on this
repertoire of coexisting inhibitors and
stimulators. Maturation at the very end
of angiogenesis to create good stable
blood vessels involves recruitment of
MSCs. In this case, MSCs are the precur-
sors to pericytes and smooth muscle
cells that support the newly formed ves-
sel and stabilize that circulation.
DIABETIC FOOT ULCERS – A GROWING EPIDEMIC
Amidst much new dialogue and
guidelines about treating diabetic
foot ulcers (DFUs), it is apparent that
DFUs are a growing epidemic. In 2005,
80,000 people with diabetes had a
lower extremity amputation, 85% of
which were preceded by an ulcer.13 A
second lower extremity amputation
was required in 30% after 3 years, and
51% after 5 years.14 In addition, it has
been reported that within 3 years of
surgery, there is an approximate 50%
mortality rate in these patients.15 Like-
wise, Armstrong showed that 50% of
patients receiving a diabetes-related
amputation will die within 5 years and
suggested that the impacts of diabe-
tes-related wounds and amputation
are a greater burden on our healthcare
system than cancer. 16
GOOD STANDARD OF CARE TECHNIQUES IMPERATIVE FOR QUALITY HEALING
Preventing amputations in patients
with diabetes should always begin
with good ulcer care, including but
not limited to assessment of the pa-
tient, his or her comorbidities and the
wound, surgical debridement and con-
trol of infection, vascular evaluation
and treatment, off-loading/pressure
relief, and appropriate dressings. While
some diabetic ulcers may be superficial
and can heal with conservative stan-
Ulcers healed SOC (n=12) EpiFix® (n=13) P value
4 Weeks 0 (0%) 10 (77%) <0.001
6 Weeks 1 (8%) 12 (92%) <0.001
Figure 12. Patients treated with EpiFix® showed a 92% healing rate at 6 weeks (P = 0.001) versus 8% healing in patients receiving standard of care. (Adapted from Zelen, et al.)19
Figure 11. This graph represents the mean percentage of reduction of ulcer surface area by week for patients treated with EpiFix® (n=13) or standard of care (n=12). An 80%+ reduction in wound area was seen in EpiFix® patients at week 1 versus 20% in patients receiving standard of care only. (Adapted from Zelen, et al.)19
100
80
60
40
20
0
-20
Percent Surface Area Reduction of Ulcers Over Time
Time Point (Week)
SOC
EpiFix
Ulc
ers
Surf
ace
Are
a Re
duct
ion
(%)
0 1 2 3 4 5 6
n=25
11
The New Standard in Bioactive Wound Healing
dard of care treatment, they are often
notoriously slow to resolve, taking up
to several months to heal. Indeed, one
meta-analysis showed that less than
25% of DFUs heal with conservative
care within 3 months.17 Wound Healing
Society guidelines recommend consid-
eration of advanced wound therapies if
a diabetic ulcer does not reduce in size
by 50% or more after 4 weeks of stan-
dard therapy.18
CLINICAL EVIDENCE SUPPORTS EARLY INTERVENTION WITH EPIFIX® FOR TREATING DFUS
Results of four peer-reviewed clini-
cal studies of EpiFix® for the treatment
of Wagner grade I and II DFUs were
reviewed by the panel. These studies
included a 25-patient randomized,
controlled clinical trial (RCT)19 as well
as a retrospective crossover20 and long-
term follow-up study for this patient
population.21 A prospective 40-patient
randomized comparative study22 of
weekly versus biweekly application of
EpiFix® for the treatment of DFUs was
also reviewed. It is important to note
that a fifth clinical trial was published
after the roundtable convened and has
been included in order to convey the
growing clinical body of evidence for
EpiFix®. This latest RCT is a 60-patient,
multicenter comparative effectiveness
study of EpiFix® vs. Apligraf® (Organo-
genesis, Canton, MA) vs. the standard
of care for the treatment of DFUs.23
The initial RCT compared 4- and
6-week healing rates of 13 patients with
13 wounds treated with EpiFix® versus
12 patients with 12 wounds treated
with moist wound healing (control).19
Wound treatment for both groups in-
cluded surgical debridement, weekly
moist wound healing dressing chang-
es, and offloading. In addition, patients
in the EpiFix® arm of the study received
an EpiFix® graft applied every 2 weeks
under a nonadherent dressing. The re-
sults showed 77% of EpiFix®-treated
wounds healed in 4 weeks and 92%
healed within 6 weeks compared to 0%
and 8% of control wounds, respectively
(P<0.001).19 The EpiFix® group received
an average of 2.5 grafts to closure (Fig-
ures 11 and 12). This low rate of healing
for control is similar to rates reported
with standard of care in other studies of
advanced wound care products rang-
ing from 2-5% at 4 weeks and 4-10%
after 6 weeks.24, 25 Based on published
healing rates of other advanced wound
healing modalities, the initial protocol
for this EpiFix® RCT included enrollment
of 80 patients. However, once the data
showed that 90% of patients treated
with EpiFix® were healed at 6 weeks, it
was recommended by independent ad-
judicators that the trial be concluded.
A follow-up DFU retrospective cross-
over study20 included control patients
from the initial RCT who did not achieve
greater than 50% closure after 6 weeks
and elected to crossover to receive the
EpiFix® treatment. The study patients
served as their own control based on
data collected during the initial 6 weeks
of the RCT. Ninety-one percent of these
patients healed within 10 weeks. 20
A long-term follow-up study of DFUs
healed with EpiFix® in the initial RCT
and crossover studies was also con-
ducted with 18 of the 22 eligible pa-
tients returning for follow-up at 9-12
5.6%
94.4%
Remained Healed
9-12 Month Follow-up Recording Percent of Ulcers
that Remained Healed vs. Ulcers that Reopened (n=18)
Reopened
100
80
60
40
20
0
Figure 13. Long-term follow-up showed 94.4% of patients remained healed at 9-12 months. (Adapt-ed from Zelen, et al.) 21
“As MiMedx® continues to invest in additional clinical studies, one must look at the amount of current and future clinical, scientific and economical data on EpiFix® to help with clinical decision making today.”
— Dr. Driver
12
EpiFix® Dehydrated Human Amnion/Chorion Membrane (dhacm) Therapy
months.21 Follow-up examinations
showed 5.6% (1/18) of patients had a
recurrent DFU and 94.4% remained ful-
ly healed (Figure 13).21
Weekly versus biweekly application
(every other week) of EpiFix® for treat-
ing DFUs has also been investigated in
a prospective, randomized single-cen-
ter clinical trial of 40 patients treat-
ed with EpiFix®.22 The mean time to
complete healing was 4.1 ± 2.9 versus
2.4 ± 1.8 weeks (P = 0.039) in the bi-
weekly versus weekly groups, respec-
tively. Complete healing occurred in
50% versus 90% by 4 weeks in the bi-
weekly and weekly groups, respective-
ly (P = 0.014). The total percent healed
was 92.5% within the 12-week study
period. All but one patient (39/40,
97.5%) had >50% reduction in wound
size within 4 weeks and 37/40 pa-
tients (92.5%) treated with EpiFix® had
complete healing within 12 weeks.21
While a similar number of grafts were
used on each healed wound (biweek-
ly group 2.4 ± 1.5, vs. 2.3 ± 1.8 in the
weekly group, P = 0.841), those wounds
receiving weekly EpiFix® healed 41.5%
faster than those treated with Epi-
Fix® biweekly, despite a greater mean
HbA1c in the patients who received
weekly applications (Figure 14). The re-
sults of these studies validate the initial
RCT data showing that EpiFix® was ef-
fective in healing 90+% of DFUs.
Results of a landmark multicenter
RTC of clinical and economic com-
parative effectiveness of EpiFix® vs.
Apligraf® vs. the standard of care for
the treatment of DFUs were not yet
available at the time of this roundta-
ble panel discussion, but are included
in this supplement.23 The RCT included
60 patients divided into 3 study arms.
Figure 16. Comparison of speed of healing. (Adapted from Zelen, et al.)23
Duration EpiFix® (n=20) Apligraf® (n=20) Standard Care (n=20) EpiFix® Vs. Apligraf® EpiFix® Vs. Standard Care
Median Healing Time 13 Days 49 Days 49 Days P=0.0001 P=0.0001
Figure 15. Comparison of complete healing rates at weeks 4 and 6 (n=60). (Adapted from Zelen, et al.) 23
Complete Healing at 6 Weeks
EpiFix® Apligraf® Control
100%90%80%70%60%50%40%30%20%10%
0%
95%
45%35%
P=0.0006 P=0.0001
Complete Healing at 4 Weeks
EpiFix® Apligraf® Control
100%90%80%70%60%50%40%30%20%10%
0%
85%
35%
P=0.001 P=0.001
30%
Figure 14. Rates of complete healing at 2 week intervals for patients treated with weekly vs. biweekly application of dHACM. (Adapted from Zelen, et al.)21
P=0.009
P=0.014P=0.091
P=0.047 P=0.231
EpiFix® Rates of Healing (n=40)
n=20 n=20n=20 n=20n=20 n=20
13
The New Standard in Bioactive Wound Healing
All patients received weekly sharp de-
bridement and offloading with a re-
movable cast walker. Twenty patients
in the control group received daily col-
lagen-alginate dressing changes with
a moisture-retentive dressing. Twenty
patients in the EpiFix® arm received
weekly applications of EpiFix® and a
moisture-retentive dressing, and 20
patients received weekly applications
of Apligraf®. The endpoints for this
study were the percentage of patients
who achieved complete healing, time
to heal, and cost of treatment. Study
ulcers achieving ≤20% healing with
standard care treatment during the
two-week run-in period remained in
the trial.
The study results are presented in
Figures 15, 16, 17 and 18. These re-
sults show the use of EpiFix® for Wag-
ner grade I and II DFUs healed twice as
many wounds, almost four times faster,
at one-fifth the cost, and had far less
graft wastage (one-sixtieth) compared
to Apligraf®. The results also suggest
that EpiFix® use may well decrease
the direct and indirect costs of DFU
treatment, and prevent longer-term
medical complications such as ampu-
tation. Results from this trial not only
reconfirmed the 90% plus healing rates
Figure 17. Comparison of costs related to graft material used in study. (Adapted from Zelen, et al.) 23
$33,379
$184,315
EpiFix®
Total Cost of Grafts Applied in Study
Apligraf®
$200,000
$175,000
$150,000
$125,000
$100,000
$75,000
$50,000
$25,000
$0
$9,216
$1,669
EpiFix®
Average Patient Graft Cost in Study
Apligraf®
$10,000
$7,500
$5,000
$2,500
$0
Figure 18. Comparison of total grafts purchased, mean number of grafts applied per patient, cm2 of graft material purchased and applied per patient in the study. (Adapted from Zelen, et al.)23
124
43Mean of
2.15 grafts per study
patient
Mean of 6.2 grafts per study
patient
EpiFix®
Total Number of Grafts Purchased in Study
Apligraf®
125
100
75
50
25
0
Num
ber o
f Gra
fts
Purc
hase
d
5,456
154
EpiFix®
Total cm2 of Grafts Purchased
Apligraf®
5,000
4,000
3,000
2,000
1,000
0
cm2
159
68.2
EpiFix®
Total cm2 of Grafts Applied in Study
Apligraf®
160
120
80
40
0
cm2
14
EpiFix® Dehydrated Human Amnion/Chorion Membrane (dhacm) Therapy
of EpiFix® in the treatment of Wag-
ner grade I and II DFUs, the trial also
demonstrated the superiority of EpiFix®
over both Apligraf® and the standard
of care in complete healing, speed to
healing, and cost of treatment.
A LOOK AT VENOUS LEG ULCERS
Venous leg ulcers (VLUs) develop in
an estimated 2.5 million patients per
year in the U.S.,26 costing up to $18 bil-
lion annually.27 Patients with VLUs have
been shown to utilize more medical
resources with two times the cost for
private payers and 50% more for Medi-
care than patients without VLUs.27 The
prevalence of VLUs increases with age
and they are 2 to 3 times more com-
mon in females.28 VLU recurrence rates
range from 54%-78%29 and the many
risk factors include venous insufficien-
cy, obesity, immobility, phlebitis, deep
vein thrombosis, and family history.30
VLUs have a major negative impact on
the quality of life in affected patients
due to pain, physical impairments
(immobility), social impairments, and
psychological effects.31, 32 The average
direct cost of treating a patient with a
VLU is $9,685 per year.33 Many patients
suffer from less tangible costs such as
a decreased capacity to work and time
lost from work.32
When there is impaired venous re-
turn in any part of the system, which
can include deep, superficial, or mixed,
red and white blood cells stick to the
vessel walls and red blood cells (RBCs)
break down. This leaves iron depos-
its in the walls, which leak out into
the tissues. Normally, venous return
brings blood back to the heart, but if
the valves become dysfunctional or
there is an obstruction, the blood flows
back down as far as it can, even into the
feet. This dysfunctional process creates
a chemical response, an inflammato-
ry response with a resultant buildup
of tissue breakdown products within
these tissues. Activated white blood
cells enter the tissues and release their
chemicals, resulting in further tissue
damage, leading to auto-digestion
and increased buildup of degradation
products. This impedes diffusion of ox-
ygen and other nutrients into affected
areas. The result of this impediment
can be death of the tissues surround-
ing the veins, which leads to a venous
ulcer. Venous ulcers typically occur on
the lower leg near the ankle where vein
pressures are highest and are typically
surrounded by skin with a rusty brown
color from extravasated iron deposits.
Figure 19. Superficial and deep venous drainage requires multiple systems through-out the leg, including the superficial system, deep system, and connecting veins, or perforators.
“It is important to remember that the approach to the VLU problem isn’t just about treating wounds, but rather treating patients with wounds who have clinical evidence of venous insufficiency/reflux, and commonly have other comorbidities such as obesity and diabetes contributing to the wound.”
— Dr. Gibbons
15
The New Standard in Bioactive Wound Healing
PRINCIPLES OF STANDARD OF CARE FOR VLUS
Standard therapy for venous dis-
ease incorporates leg compression to
reduce the diameter of the vein, in-
creasing flow velocity, decreasing the
chance of thrombosis and reducing
edema. It activates fibrinolytic activity
in the blood and reduces the filtration
of fluid out of the intravascular space,
improving lymphatic flow and reduc-
ing edema. Graduated compression
reduces reflux and improves venous
outflow for the calf muscle pump to
get blood back to the heart, decreas-
ing venous pressure at rest and with
ambulation (Figure 19).
When there is mixed venous/arterial
disease, the venous disease must be
treated first by revascularizing patients
with peripheral arterial disease, and by
protecting high-risk areas, controlling
edema, and providing good nutrition,
medications, and physical and emo-
tional therapy.34 Also, when addressing
the hostile wound environment, sharp
surgical debridement includes de-
pendently draining pus and removing
devitalized tissue, bone, bacteria pro-
teolytic enzymes and senescent cells.
EPIFIX® FOR THE TREATMENT OF VLUS
EpiFix® has demonstrated effective-
ness in treating VLUs. In a multicenter
RCT, effectiveness of EpiFix® and mul-
tilayer compression versus multilay-
er compression alone was evaluated
in treating VLUs. EpiFix® was applied
once or twice during a 4-week study
period.35 Reduction in wound size
of ≥40% occurred in a significantly
greater numbers of patients receiv-
ing EpiFix® versus those receiving
multilayer compression therapy only
(33/53 [62%] vs 10/31 [32%]; P = 0.005)
(Figure 20). Over the 4-week study pe-
riod, VLUs treated with EpiFix® were
significantly reduced in size compared
to those treated with multilayer com-
pression only (Figure 21). Based on the
surrogate endpoint of ≥40% wound
area reduction within 4 weeks as a
predictor of overall healing,36,37,38 these
data from the first controlled trial of
EpiFix® VLU treatment indicate that
EpiFix® is effective in treating VLUs and
serves as a defining point for further
clinical studies.
Figure 20. Primary study outcome measured the percentage of patients with ≥40% wound reduction over 4 weeks. (Adapted from Serena, et al.)35
Figure 21. Mean percent reduction in size of VLU during the study period. (Adapted from Serena, et al.)35
16
EpiFix® Dehydrated Human Amnion/Chorion Membrane (dhacm) Therapy
EPIFIX® DELIVERS NEW CLINICAL OPTION IN PLASTIC SURGERY
The mechanisms behind the ben-
eficial effects of EpiFix® in treat-
ing chronic extremity wounds may
translate to the treatment of other
types of wounds, including burns,
radiation-induced wounds, surgical
wounds, breast reconstruction, and
pressure ulcers. Other clinical indi-
cations for consideration include
Mohs surgery, laser resurfacing and
hair restoration. The potential advan-
tages of using EpiFix® for burns and
other plastic surgery cases versus
skin grafts include improved mobil-
ity with the applied membrane and
reduction in scarring in the healed
area. EpiFix® helps heal a tissue de-
fect while reducing inflammation. It
reduces scarring and causes no clin-
ical signs of rejection. While there are
no RCT data yet describing the use
of EpiFix® in acute wounds, multi-
ple cases were presented during the
panel meeting of effective EpiFix®
treatment of acute wounds in plastic
surgery. Two acute wound cases are
described below.
CASE REPORTS Case Report 1:
Pediatric Partial-Thickness Burn
A toddler presented with a par-
tial-thickness, typical scald burn on the
face and head (Figure 22). EpiFix® was
applied, and the patient’s pain resolved
quickly after covering the raw nerve
endings in the burn. The patient re-
turned home the day after application
and returned one week later for fol-
low-up (Figure 23). The pain was man-
aged and the burn was healing well at
that point. At 3 to 4 weeks after the ap-
plication, the patient was getting some
pigment back in the skin and showed
no signs of future scarring (Figure 24).
The clinician found the membrane
to be flexible and easy to work with
during the treatment.
Case Report 2:
Non-Healing Wound in a Cancer
Patient
A patient with pancreatic cancer
presented with a non-healing wound
secondary to abdominal resection
(Figure 25). The wound had persisted
for about one year despite multiple
applications of porcine small intesti-
nal submucosa. A new treatment plan
was initiated. The wound was curetted
at the bedside and EpiFix® was applied
(Figure 26). At two weeks post initial
application, the wound was curetted
again and given a second application
(Figure 27). Four weeks following the
first application, the wound was al-
most completely healed (Figure 28).
CONCLUSIONAmniotic membrane is an import-
ant and complex tissue that is natu-
Figure 22. Case Report: A toddler presented with a partial-thickness scald burn on the face.
Figure 23. Case Report: After a dHACM allograft was applied, the patient felt an immediate reduction in pain and at one week, the burn was healing well.
Figure 24. Case Report: At 2-4 weeks, the patient was getting some pigment back in the skin and showed no signs of future scarring.
17
The New Standard in Bioactive Wound Healing
rally derived and contains a variety of
complex cytokines and growth factors
that are required in reproduction as
well as healing. Essentially, amniotic
membrane with amnion and chorion
represent different types of amniotic
sac tissues. The processing method af-
fects the quality of the growth factor
preservation. Unlike other amniotic
membrane tissue, EpiFix® is processed
with the inclusion of chorion layer,
which adds growth factors and cyto-
kines that improve the effectiveness
of the matrix and the overall product,
particularly when compared to amni-
on-only grafts.5-8 A controlled animal
study demonstrated that the PURION®
Process used with EpiFix® is more effec-
tive in preserving wound healing and
inflammatory regulators than another
processed tissue tested.9
There are no living cells in EpiFix®.
This differentiates EpiFix® from other
tissues in that EpiFix® contains nu-
merous bioactive components that
continue to be present and released
over time to promote healing. Mech-
anisms of action of EpiFix® have been
reported in several in vitro and in vivo
scientific studies.5-8 Growth factors
contained within EpiFix® have been
identified in peer-reviewed publica-
tions as have the effects of the growth
factors on various cell types from fi-
broblasts to endothelial cells to stem
cells. Investigators have demonstrated
the capability of EpiFix® to mobilize,
Figure 25. Case Report: A patient with pan-creatic cancer presented with a non-healing wound secondary to abdominal resection.
Figure 26. Case Report: The wound was curet-ted at the bedside and dHACM was applied.
Figure 27. Case Report: At two weeks post-application, it was curetted again and given a second application of dHACM.
Figure 28. Case Report: After two more weeks, the wound was almost completely healed.
BENEFITS OF EPIFIX® AMNIOTIC MEMBRANE TISSUE• EpiFix® is a dehydrated amniotic membrane tissue comprised of both amnion
and chorion membranes.
• EpiFix® helps heal tissue to restore a defect while reducing inflammation.
• EpiFix® reduces scarring and is immunologically privileged.
• There are no living cells in EpiFix®. Unlike other tissues, EpiFix® contains nu-merous bioactive components that are released over time to enhance healing.
• With in vivo studies, with the application of EpiFix®, native stem cells are at-tracted from the surrounding tissue or through the circulation to the base of the local injured tissue as opposed to being injected or placed topically in a wound as would be the case with a living cellular therapy.
• With in vivo and in vitro studies, investigators have demonstrated EpiFix’s® capability to mobilize, recruit and serve as a stem cell magnet to enhance healing.
18
EpiFix® Dehydrated Human Amnion/Chorion Membrane (dhacm) Therapy
recruit and serve as a stem cell magnet
to enhance healing.
Initial EpiFix® RCTs have demon-
strated significantly improved healing
rates over the standard of care in treat-
ing DFUs.19,23 The results significantly
demonstrated a 90% plus healing rate
and with long-term follow-up, 94.4%
remained healed at one year.21 Results
from a most recent landmark multi-
center RCT not only reconfirmed the
90% plus healing rates of EpiFix® in
the treatment of DFUs, the study also
demonstrated the superiority of Epi-
Fix® over both Apligraf® and standard
of care in complete healing, speed
to healing and cost of treatment.23 A
number of randomized, multicenter
trials are being designed or are under-
way to further validate initial research.
In a surrogate study evaluating the
effectiveness of EpiFix® in treating
VLUs, 62% of patients achieved ≥40%
wound closure at 4 weeks.35 These
study results generate useful data that
can guide clinical decision making.
Based on initial scientific data, EpiFix®
appears to accelerate healing of both
DFUs and VLUs, as evidenced by an in-
creased percentage of wounds healed
at all measured time periods, compared
to standard of care treatment.19.23.35 It is
important to note that in order for an-
giogenesis and healing to occur with
EpiFix® application, adequate wound
bed preparation is imperative. EpiFix®
application frequency for DFUs appears
to make a difference in healing rates,
with weekly applications yielding su-
perior outcomes over biweekly applica-
tions.22 Health care providers and payers
will continue to welcome data from ad-
ditional EpiFix® studies involving dia-
betic and venous leg ulcers.
Finally, in addition to the manage-
ment of chronic wounds, the panel
members discussed other important
wound types that may benefit from
treatment with EpiFix®, including burns,
reconstructive surgery, Mohs surgery,
cosmetic or impaired healing situa-
tions such as radiation desquamation,
non-healing wounds in elderly patients,
and all diabetic wounds not healing in a
timely sequence.
References1. Sen CK, Gordillo GM, Roy S, Kirsner R, Lam-
bert L, Hunt TK, Gottrup F, Gurtner GC, Lon-gaker MT. Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair Regen. 2009 Nov-Dec;17(6):763-71. doi: 10.1111/j.1524-475X.2009.00543.x.
2. Singh N, Armstrong DG, Lipsky BA. Prevent-ing foot ulcers in patients with diabetes. JAMA. 2005;293(2):217-228.
3. Fife C, Walker D, Thomson B, Carter M. Limita-tions of daily living activities in patients with venous stasis ulcers undergoing compression bandaging: problems with the concept of self-bandaging. WOUNDS. 2007;19:255-257.
4. Gray H. Anatomy of the Human Body. 20th Edition. Revised and Re-Edited by Warren H. Lewis. Philadelphia: Lea & Febiger, 1918, New York: Bartleby.com, 2000.
5. Koob TJ, Lim JJ, Zabek N, Massee M. Cytokines in single layer amnion allografts compared to multilayer amnion/chorion allografts for wound healing. J Biomed Mater Res B Appl Biomater. 2014 Aug 30. doi: 10.1002/jbm.b.33265. [Epub ahead of print]
6. Koob TJ, Lim JL, Massee M, Zabek N, Rennert
R, Gurtner G, Li W. Angiogenic properties of dehydrated human amnion/chorion al-lografts: therapeutic potential for soft tissue repair and regeneration. Vasc Cell. 2014;6:10.
7. Koob TJ, Lim JJ, Massee M, Zabek N, De-nozière G. Properties of dehydrated human amnion/chorion composite grafts: Impli-cations for wound repair and soft tissue regeneration. Journal of Biomedical Mate-rials Research – Part B: Applied Biomaterials. 2014;102(6):1353-1362.
8. Koob TJ, Rennert R, Zabek N, Masse J, Lim J, Temenoff J, Li W, Gurtner G. Biological prop-erties of dehydrated human amnion/chorion composite graft: implications for chronic wound healing. Int Wound J. 2013;10(5):493-500.
9. Maan ZN, Rennert RC, Koob TJ, Januszyk M, Li WW, Gurtner GC.Cell recruitment by amnion chorion grafts promotes neovascularization. J Surg Res. 2015 Feb;193(2):953-962. doi: 10.1016/j.jss.2014.08.045. Epub 2014 Sep 1.
10. Hocking AM, Gibran NS. Mesenchymal stem cells: paracrine signaling and differentiation during cutaneous wound repair. Exp Cell Res. 2010;316:2213‐19.
11. Li J, Chen J, Kirsner R. Pathophysiology of acute wound healing. Clin Dermatol. 2007 Jan-Feb;25(1):9-18. Review.
12. Nagy JA, Dvorak AM, Dvorak HF. VEGF-A and the induction of pathological angiogenesis. Annu Rev Pathol. 2007;2:251-275.
13. Incidence of diabetic foot ulcer and lower extremity amputation among Medicare ben-eficiaries, 2006 to 2008, www.ahrq.gov.
14. Most R, Sinnock P. The epidemiology of lower extremity amputations in diabetic individu-als. Diabetes Care. 1983;6(1):87-91.
15. Bild D, Selby J, Sinnock P, Bowner W, Braveman P, Showstack J. Lower-extremity amputation in people with diabetes. Epidemiology and prevention. Diabetes Care. 1989;12(1):24-31.
16. Armstrong DG, Wrobel J, Robbins JM. Are diabetes-related wounds and ampu-tations worse than cancer? Int Wound J. 2007;4(4):286-287.
17. Margolis D, Kantor J, Berlin J. Healing of neu-ropathic ulcers: results of a meta-analysis. Di-abetes Care. 1999;22:692-695.
18. Steed DL, Attinger C, Colaizzi T, Crossland M, Franz M, Harkless L, Johnson A, Moosa H, Robson M, Serena T, Sheehan P, Veves A, Wiersma-Bryant L. Guidelines for the treat-ment of diabetic ulcers. Wound Repair Regen. 2006;14(6):680-692.
19. Zelen CM, Serena TE, Denoziere G, Fetterolf
19
The New Standard in Bioactive Wound Healing
DE. A prospective randomised comparative parallel study on amniotic membrane wound graft in the management of diabetic foot ul-cers. Int Wound J. 2013;10(5):502-507.
20. Zelen CM. An evaluation of dehydrated hu-man amniotic membrane allograft in patients with DFUs. J Wound Care. 2013;22(7):347-348.
21. Zelen CM, Serena TE, Fetterolf DE. Dehydrat-ed human amniotic/chorionic membrane al-lografts in patients with chronic diabetic foot ulcers: a long-term follow-up study. Wound Medicine. 2014;4:1-4.
22. Zelen CM, Serena TE, Snyder RJ. A prospec-tive, randomised comparative study of week-ly versus biweekly application of dehydrated human amnion/chorion membrane allograft in the management of diabetic foot ulcers. Int Wound J. 2014 Apr;11(2):122-8. doi: 10.1111/iwj.12242. Epub 2014 Feb 21.
23. Zelen CM, Gould L, Serena TE, Carter MJ, Keller J, Li WW. A prospective, randomised, controlled, multi-centre comparative effec-tiveness study of healing using dehydrated human amnion/chorion membrane allograft, bioengineered skin substitute or standard of care for treatment of chronic lower extremity diabetic ulcers. Int Wound J. 2014 Nov 26. doi: 10.1111/iwj.12395. [Epub ahead of print]
24. Marston WA, Hanft J, Norwood P, Pollak R. Dermagraft Diabetic Foot Ulcer Study Group. The efficacy and safety of Dermagraft in im-proving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care. 2003;26(6):1701-1705.
25. Lavery LA, Fulmer J, Shebetka KA, Regulski M, Vayser D, Fried D, Kashefsky H, Owings TM, Nadarajah J; Grafix Diabetic Foot Ulcer Study Group. The efficacy and safety of Grafix(®) for the treatment of chronic diabetic foot ulcers: results of a multi-centre, controlled, randomised, blinded, clinical trial. Int Wound J. 2014 Oct;11(5):554-60. doi: 10.1111/iwj.12329. Epub 2014 Jul 21.
26. Gillespie DL, Writing Group III of the Pacific Vascular Symposium 6, Kistner B, Glass C, Bailey B, Chopra A, Ennis B, Marston M, Ma-suda E, Moneta G, Nelzen O, Raffetto J, Raju S, Vedantham S, Wright D, Falanga V. Venous ulcer diagnosis, treatment, and prevention of recurrences. J Vasc Surg. 2010;52(5 sup-pl):8S-14S.
27. Rice JB, Desai U, Cummings A, Bimbaum H. Medical, drug and work-loss costs of venous leg ulcers. International Society for Pharma-coeconomics and Outcomes Research (IS-POR) 18th Annual Meeting, May 2013, New Orleans, LA.
28. Fowkes FG, Evans CJ, Lee AJ. Prevalence and risk factors of chronic venous insufficiency. Angiology. 2001;52 Suppl 1:S5-S15.
29. Brem H, Kirsner RS, Falanga V. Protocol for the successful treatment of venous ulcers. Am J Surg. 2004;188(1A suppl):1-8.
30. Valencia IC, Falabella A, Kirsner RS, Eaglstein WH. Chronic venous insufficiency and ve-nous leg ulceration. J Am Acad Dermatol. 2001;44(3):401-421.
31. Herber OR, Schnepp W, Rieger MA. A system-
atic review on the impact of leg ulceration on patients’ quality of life. Health Qual Life Out-comes. 2007;5:44.
32. Phillips T, Stanton B, Provan A, Lew R. A study of the impact of leg ulcers on quality of life: fi-nancial, social, and psychologic implications. J Am Acad Dermatol. 1994;31(1):49-53.
33. Olin JW, Beusterien KM, Childs MB, Seavey C, McHugh L, Griffiths RI. Medical costs of treating venous stasis ulcers: evidence from a retrospective cohort study. Vasc Med. 1999;4(1):1-7.
34. Bryant RA, Nix DP, eds. Acute & Chronic Wounds: Current Management Concepts. 4th ed. St. Louis, MI: Mosby, Inc.; 2011:308-310.
35. Serena TE, Carter MJ, Le LT, Sabo MJ, DiMarco DT, for the EpiFix Study group. A multi-center randomized controlled trial evaluating the use of dehydrated human amnion/chorion membrane allografts and multi-layered com-pression therapy vs. multi-layer compression therapy alone in the treatment of venous leg ulcers. Wound Repair Regen. 2014 Sep 15. doi: 10.1111/wrr.12227. [Epub ahead of print]
36. Phillips TJ, Machado F, Trout R, Porter J, Olin J, Falanga V. Prognostic indicators in venous ulcers. J Am Acad Dermatol. 2000; 43: 627–30.
37. Gelfend JM, Hoffstad O, Margolis DJ. Surrogate endpoints for the treatment of venous leg ul-cers. J Invest Dermatol. 2002; 119:1420–5.
38. Tallman P, Muscare E, Carson P, Eaglstein WH, Falanga V. Initial rate of healing predicts com-plete healing of venous ulcers.Arch Dermatol. 1997; 133: 1231–4.
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Today’s wound healing no longer needs to rely on products containing fragile living cells or the freezers and careful handling they require.
EpiFix® amnion/chorion membrane allografts:
• Attract multiple cell types to aid in wound regeneration1-3
• Demonstrated 90%+ healing rates in three DFU randomized clinical studies and a crossover study; 90%+ remained healed after 9-12 months4-7
• Healed twice as many DFUs 4 times faster at one-fifth the cost of Apligraf® in a prospective, randomized, controlled, multi-center comparative study7
• Achieved ≥40% wound area closure at 4 weeks in 62% of VLU study patients8
EpiFix® sets the new standard for wound closure.
1. Koob TJ, et al. Int Wound J. 2013; doi: 10.1111/iwj.12140.2. Koob TJ, et al. J Biomedical Materials Research. 2014; doi: 10.1002/jbm.b.33141.3. Koob TJ, et al. Vascular Cell 2014. 6:10, doi: 10.1186/2045-824X-6-10.4. Zelen C, et al. Int Wound J. 2013; doi:10.1111/iwj.12097.
Patents and patents pending see: www.mimedx.com/patents EpiFix® and MiMedx® are registered trademarks of MiMedx Group, Inc.©2015 MiMedx Group, Inc. All Rights Reserved.
1775 West Oak Commons Court NE, Marietta, GA 30062 www.mimedx.com EP278.002
5. Zelen C. J Wound Care. 2013, Vol. 22, Iss. 7, 11, pp 347 – 351.6. Zelen C, et al. Int Wound J. 2014; doi: 10.1111/iwj.12242.7. Zelen C, et al. Int Wound J. 2014; doi: 10.1111/iwj.12395.8. Serena TE, et al. Wound Repair Regen. 2014; doi: 10.1111/wrr.12227.
Freezers are for ice cream
Store at ambient conditions • Sizes to fit a variety of wounds • Reduce graft waste & cost to closure
Not for wound healing anymore